RAPID PHARMACY REVIEW

1. Drug Product Development

Introduction

Active pharmaceutical ingredient (API): component that produces pharmacological activity (drug substance).  May be produced by chemical synthesis, from natural product, enzymatic reaction, recombinant DNA, fermentation, etc.

New chemical entity (NCE): drug substance with unknown clinical, toxicological, physical, chemical properties.  According to the FDA, NCE is an unapproved API.

Drug product: finished dosage form containing API and excipients.

Generic drug products: after patent expiration of brand drug.  Therapeutically equivalent to the brand and has the same drug amount in the same dosage form.  Must be bioequivalent (same rate and extent of absorption) à same clinical results.  May differ from brand in excipients (tablets only unless safety studies are done) or physical appearance.

Abbreviated New Drug Application (ANDA): submitted to the FDA for approval of generic drugs.  Preclinical safety and efficacy studies are not required.  Human bioequivalence is needed (on healthy human volunteers).  Chemistry, manufacturing and controls for generics are similar to the brand. 

Specialty drug products: existing products developed for new delivery system or new therapeutic indication.  Safety and efficacy studies are not required.  Example nitroglycerin transdermal patch after sublignual tablets.

New drug approval

Preclinical (animal safety / pharma) à IND à Phase I (healthy human safety) à Phase II (↓# patients) à Phase III (↑# patients) à NDA à FDA green light for marketing àPhase IV (scale up) à Phase V (continuous improvements).

Preclinical stage: animal pharmacology and toxicology to determine safety and efficacy.  Formulation is not final. 

Phase I: Submit an Investigational New Drug (IND) à clinical studies on healthy volunteers to determine toxicity and tolerance.  For oral drugs à simple hard gelatin capsule. 

Phase II: small number of patients under close supervision.  Dose-response studies to determine optimum dosage for treatment.  Determine the therapeutic index (toxic dose/effective dose).  Develop final drug formulation (bioequivalent to that used in initial clinical studies).  Start chronic toxicity studies for 2 years in 2 species.

Phase III: large-scale multicenter clinical studies with final dosage form (from phase II) to determine safety and efficacy in patients. Watch for new, rare, toxic or side effects.

NDA submission: FDA satisfaction with safety and efficacy for marketing.

Phase IV: scale-up in preparation for marketing. Only minor modifications on the formulation are allowed. 

Phase V: continuous drug product improvements after marketing. 

Product development

New chemical entities

Preformulation:

Physical and chemical characterization of the drug and dosage form during preclinical phase.  Includes general properties (particle size / shape, polymorphism, crystalline structure, density, surface area, hygroscopicity), solubility (dissolution, pH-solubility profile, various solvents), chemical properties (surface energy, pH stability profile, pKa, temperature stability, excipient interactions), stability analytical methods. 

Formulation development: continuing process.

Injections: final formulation is developed in preclinical phase, stability in solution is critical, few excipients allowed, no bioavailability for IV.  

Topicals / local: final formulation developed in phase I, study release in in vitro diffusion cell models, local irritation and systemic absorption are the issues.

Topicals / systemic: drug delivery through skin / mucosa / rectum, final formulation in phase III. 

Oral drugs: final formulation in phase II. 

Final product considerations: size, shape, color, taste, skin feel, viscosity, physical appearance, production equipment / site.

Product line extensions:

Dosage forms with change in physical form or strength but not use or indication.  Usually occurs during Phases III, IV, V.

Regulatory approval: based on stability, analytical / manufacturing controls, bioequivalence studies, clinical trials

Solid products:

Different strength in a tablet or capsule form à only bioequivalence required (simplest case).  Easier if in vitro dissolution / in vivo bioavailability correlation exists.

Modified release: clinical trials required.

If new indication à new NDA and new efficacy studies.

Liquid products:

If an extension of a liquid à same as above for solids

If an extension of a solid à if big difference in extent / rate of absorption à new clinical trials.

Preapproval inspections

Manufacturing facility is inspected prior to NDA / ANDA approval or after a major reported change to NDA / ANDA.

Includes: general cGMP inspection, reviews documentation, verifies traceability of information to documentation, consults the chemistry / manfucaturing / control (CMC) section of NDA / ANDA, make a final recommendation.

Scale-up and post-approval changes (SUPAC)

Guidelines to ¯ # of manufacutring changes that require preapproval by the FDA. 

Examples: minor formulation changes, change site of manufacture, batch size ­ or ¯, change manufacturing process / equipment. 

1. Very minor changes not requiring approval are reported in an annual report. Examples: compliance with guidance, label description, deletion of colorant, expiration date extension, ∆ container / closure type (not size), analytical method

2. Changes being effected supplement: minor changes but require some validation, documentation.  A supplement but no pre-approval is required.  Examples: new specs, label changes on clinical info, different cGMP manufacturing facility but same process.

3. Preapproval supplement: major changes require specific preapproval.  Examples: adding or deleting an ingredient, relaxing specs, deleting a spec or method, method of manufacture, in-process controls.

Therapeutic and Bio-equivalence: must be shown for any change.  Minor change à comparable dissolution profiles.  Major change à in vivo bioequivalence study. 

GMPs

Minimum requirements for manufacturing, processing, packing, or holding drugs. Include criteria for personnel, facilities, processes to ensure final product has the correct identity, strength, quality, purity.

Quality Control (QC): department responsible for establishing process and product specifications. The QC dept test the product and verifies specs are met. This includes acceptance / rejection of incoming raw materials, packaging components, water, drug products, environmental conditions.

Quality Assurance (QA): a department that determines that the systems and facilities are adequate and that written procedures are followed.

2. Pharmaceutical Calculations and Statistics

Fundamentals of measurement and calculation

Inverse proportion: the inverse of the ‘scissors’ method is used in case of dilutions.  Example: 100 ml of 10% solution is diluted to 200 ml, what is the final concentration?  Inverse ‘scissors’ à 200/10 = 100/x à 5%.

Aliquot: used when the sensitivity of the measurement device is not great enough for the required measurement. 

Example: balance sensitivity is 6 mg, accuracy is +/-5% à minimum weighable quantity is: 5/100=6/x = 120 mg. If you need to weigh 10 mg drug à add a diluent to get a final concentration of 120 mg drug in the diluted mixture (120x120 = 1440 mg) à then weigh 120 mg of the diluted mixture.

Systems of measure: Apothecaries’ system of fluid measure, Apothecaries’ system for measuring weight, Avoirdupois system for measuring weight (pound, ounce, grain=65 mg), metric system.

Children doses

First choice: body weight or mass and mg/kg dosing.

Fried’s rule for infants: (age in month / 150) x adult dose

Clark’s rule: (weight in lb / 150) x adult dose

Child’s dosage based on body surface area: (BSA in m2 / 1.73) x adult dose

Percentage, ratio strength, concentrations

Percentage w/v, Percentage v/v, Percentage w/w, Ratio strength

Be careful 3 g drug in 27 g water is 10% solution (3/30) BUT 3 g drug in 30 g water is 9% (3/33).

Molarity: number of moles of solute dissolved in 1 liter of solution

Molality: number of moles of solute dissolved in 1 kg of solution. Advantage over molarity: using weight avoids problems with volume expansion or contraction upon the addition of solutes.

Normality: is the number of equivalent weights of solute per liter of solution. Equivalent weight = atomic weight or molecular weight / valence. Preferred way of expressing concentration of acids, bases and electrolytes. One equivalent is the quantity that supplies or donates one mole of H+ or OH-.  One equivalent of acid reacts with one equivalent of base.

Mole fraction: ratio of number of moles of one component to the total moles of a mixture or solution.

Dilution and concentration

Constant amount of drug à volume is inversely proportional to concentration. 

Quantity1 x concentration1 = quantity2 x concentration2. 

Allegation medial: method for calculating average concentration of a mixture of two or more substances.

Allegation alternate: method for calculating number of parts (relative amounts) of two or more components of known concentration to be mixed when final concentration is known. IMPORTANT. See example is page 16.

Dilution of alcohols: alcohol + water à volume contraction. Use w/w instead of v/v for accuracy.

Percentage strength: of concentrated acids is expressed in w/w.  For diluted acid à w/v.  To determine the volume of concentrated acid for dilution, use specific gravity.

Electrolyte solutions

Divalent: calcium, ferrous, magnesium, sulfate.  Trivalent: aluminum, ferric, citrate.  All others are monovalent.

Milliequivalents (mEq)

Definition: amount in mg equivalent to a solute equal to 0.001 of its gram equivalent weight. 

Unit used to express concentration of electrolytes

Milliosmoles (mOsmol)

Osmotic pressure is directly proportional to the total number of particles in solution. Unit for measuring osmotic concentration: mOsmol.

For non-electrolytes: 1 millimole = 1 mOsmol (1 molecule = 1 particle)

For electrolytes: number of particles depends on degree of dissociation.

Example: completely dissociated KCl à 1 millimole = 2 mOsmol (2 particles, K and Cl for each molecule).

Example: completely dissociated CaCl2 à 1 millimole = 3 mOsmol

↑ solute concentration à ↑ interaction between dissolved particles à ↓ actual osmolar concentration compared to ideal osmolar concentration.

Isotonic solutions

Isosmotic: solution with the same osmotic pressure.

Isotonic: solution with the same osmotic pressure as body fluids.

Hypotonic: solution with ↓ osmotic pressure than body fluid (opposite is hypertonic)

Preparation of isotonic solutions

Colligative properties (e.g. freezing point depression) are representative of the number of particles in solution.

Dissolve 1 g MWt of non-electrolyte in 1 L of water à depression of freezing point by -1.86 C. 

For electrolytes: freezing point depression = -1.86 x number of species produces upon dissociation.

Freezing point depression of body fluids = -0.52 C. 

Take dissociation of weak electrolytes into account.

In weak solutions, every 2 ions produce 1.8 ions, every 3 ions produce 2.6 ions (about 10% loss).

NaCl equivalents

Definition: the amount of NaCl that is equivalent to the amount of particular drug in question. 

Isotonic fluid: 0.9% NaCl. 

Example: NaCl equivalent for KCl to 0.78 à 1 gram KCl = 0.78 g of NaCl.

Calculating amount of NaCl required to adjust isotonicity: calculate the total amount of NaCl required (volume x 0.9%) à calculate the NaCl equivalent of all substances in the solution à calculate and add the difference as NaCl or another material (as NaCl equivalent).

Statistics

Frequency distribution: classify individual observations into categories corresponding to fixed numeric intervals (interval frequencies) à plot number of observations in each category versus category descriptor. 

Normal distribution: bell-shaped (Gaussian) curve. 

Estimates of population mean: the population mean is the best estimate of the true value. Sample mean: arithmetic average.  Accuracy: degree to which measured value agrees with true value.  Error (bias): difference between measured value and true value.  Median: midmost value of a data distribution (average of two midmost values if even number of observations).  Normal distribution à median = mean.  Median is less affected by outliers or skewed distribution.  Mode: most frequently occurring value in a distribution, it is useful for non-normal distributions especially bimodal distributions.

Estimates of variability: infinite # of observations à population variance.  Finite # of observations à sample variance.  Range: useful to describe variability only in very small number of observations.  Standard deviation: square root of variance. Precision (reproducibility): degree to which replicate measurements made exactly the same way agree with each other (expressed as relative standard deviation). 

Standard deviation of the mean (standard error): estimate of variability or error in the mean obtained from N observations.  SE = SD/(sq. root of N). Used to establish confidence intervals.

3. Pharmaceutical Principles and Drug Dosage Forms

I.  Intermolecular forces of attraction

Atoms vary in electronegativity, so, electron sharing between atoms will be unequal.  So, the molecule behaves like a dipole over a covalent bond.

Dipole moment (mu) = distance of charge separation X charge

Nonpolar molecules: perfect symmetry and dipole moment = zero.  Example: carbon tetrachloride. 

When the negative pole of a dipole approach the positive pole of another à molecular attraction called “dipole-dipole interaction”. 

If similar poles approach à molecular repulsion (intermolecular repulsive forces)

Types of intermolecular forces of attraction

Van der Waals forces (liquids)

Induced dipole induced dipole (London dispersion force): when a transient dipole in a nonpolar molecule induces another transient dipole in another molecule.   Force = 0.5-1 Kcal/mole

Dipole-induced dipole (Debye induction force): A transient dipole is induced by a permanent dipole.  Force = 2 Kcal/mole

Permanent dipole (Keesom orientation force): 4 Kcal/mole

Hydrogen bonds

Hydrogen ions are small and have a large electrostatic field, so it approaches highly electronegative atoms (O, F, Cl, N, S) and interact electrostatically to form a hydrogen bond. Force = 5 Kcal/mole. 

Ion-ion, ion-dipole, ion-induced dipole

Force of positive-negative ion interaction in the solid state = 150 Kcal/mole.  Covalent and ionic forces are much stronger than van der Waals forces.

 

States of matter

Gases

Molecules move in straight path at high speed until they randomly collide with another molecule, creating pressure.  Intermolecular forces ~ zero.

Ideal gas law: 

Pressure (P) x Volume (V) = number of moles (n) X Molar Gas Constant (R) X Temperature (T)

Gases in pharmacy:  anesthetics (nitrous oxide, halothane), compressed oxygen, liquefiable aerosol propellants (nitrogen, CO2, hydrocarbons, halohydrocarbons), ethylene oxide for sterilization of heat labile objects. 

Volatile liquids (ether, halothane, methoxyfurane) are used as anesthetics.  Amyl nitrite (volatile liquid) is inhaled as a vasodilator in acute angina.

Sublimation: a solid is heated directly to the gaseous or vapor state (or vice versa, also called deposition) without passing through the liquid state.  Examples: camphor, iodine.

Liquids

Van der Waals intermolecular forces are sufficient to impose some ordering.  Hydrogen bonding ­ cohesion in liquids. 

Surface and interfacial tension

Molecules at the surface of the liquid experience a net inward pull from the interior and they tend to contract.  This makes liquids assume a spherical shape as it is the volume with minimum surface and least free energy.

Surface free energy / surface tension: the work required to ­ the surface area A of the liquid by 1 unit area.  Example: SFE for water = 72 mN/m.

Interfacial tension:  at the surface of two immiscible liquids. 

Viscosity

Viscosity = shear stress / shear rate

Non-Newtonian viscosity: exhibit shear dependent or time dependent (apparent) viscosity. 

Shear dependent viscosity: Shear thickening (dilatancy) as in suspensions of small deflocculated particles with high solid content.  Shear thinning (pseudoplastic): as in polymer solutions.  Plastic (Bingham body): as in flocculated particles in concentrated suspensions that have yield value. 

Time dependent viscosity: yield value of plastic systems may be time dependent.  Thixotropic systems are shear thinning but they do not recover viscosity after shear is removed, i.e., structural recovery is slow compared to structural breakdown.  It occurs in heterogenous systems with three dimensional structural network (gel-sol transformation).  Negative (anti)thixotropy: viscosity ­ with ­ shear up to an equilibrium (sol-gel transformation). 

Solids

High intermolecular forces. 

Crystalline solids: fixed molecular order, distinct melting point, anisotropic (properties are nto the same in all directions).

Amorphous solids: randomly arranged molecules, nondistinct melting point, isotropic (properties are the same in all direction). 

Polymorphs: substance has more than one crystalline form.  Different molecular arrangments / crystalline lattice structure, melting point, solubility, dissolution rate, density, stability.  Polymorphs are common in steroids, theobroma oil, cocoa butter. 

Latent heat of fusion:  heat absorbed when 1 g of solid melts.

III.  Physicochemical behavior

Homogenous systems

Solution: homogenous system in which a solute is molecularly dispersed or dissolved in a solvent. 

Nonelectrolytes: substances that do not form ions in solution, e.g., estradiol, glycerin, urea, sucrose.  Solution doesn’t conduct electricity.

Electrolytes: form ions in solutions.  Solution conducts electricity.  Can be strong (completely ionized in water; HCl, NaCl) or weak (partially ionized; aspirin, atropine). 

Colligative properties:

Depend on the total number of ionic and nonionic solute molecules in solution.  They are dependent on ionization but independent of other chemical properties of the solute. 

Vapor pressure depression: (Raoult’s law): partial vapor pressure is equal to the product of the mole fraction of the component in solution and the vapor pressure of the pure component.

Boiling point elevation and freezing / melting point depression

Osmotic pressure: Osmosis is the process by which solvent molecules pass through semipermeable membrane from dilute solution to concentrated solution.  That is because solvent molecules have lower chemical potential in concentrated solution.  Osmotic pressure is the pressure that must be applied to solution to prevent the flow of pure solvent.  It is defined by the van’t Hoff equation. 

Electrolyte solutions and ionic equilibria

Arrhenius dissociation theory: an acid is a substance that liberates H⁺ (donates protons) in water, a base liberates OH^- (accpets protons).  Lowry Bronsted theory: applies to both aqueous and nonaqueous systems.  In water, a free proton combines with water forming hydronium ion (H₃O⁺).  A strong acid in water can behave as a weak acid in a different solvent. 

Lewis theory: defines acid as a molecule or ion that accepts an electron pair from another atom.  A base donates an electron pair to be shared with another atom. 

pH is the negative logarithm of molar H+ concentration.

As pH ¯, H+ concentration ­ exponentially. 

Ionization: is the complete separation fo the ions in a crystal lattice when the salt is dissolved.  Dissociation: is the separation of ions in solution when the ions are associated by interionic interactions.  For weak electrolytes, dissociation is reversible.  According to the law of mass action, ­ concentration of dissociation products results in ¯ dissociation.  pKa is the dissociation constant of a weak acid.  pKb is used for weak bases. 

Acids and bases that can accept or donate more than one proton will have more than one dissociation constant. 

Henderson-Hasselbalch equation:  describes the relationship between ionized and nonionized species of a weak electrolyte (base is UP).  pH = pKa when [dissociated species] = [nondissociated species], i.e., 50% ionization. 

Solubility of a weak electrolyte varies as a function of pH.  Solubility of a weak acid ­ with ­ pH.  Opposite is true for weak bases. 

Buffer: a mixture of salt with acid or base that resists changes in pH when small quantities of acid or salt are added.  Buffer is a combination of weak acid and its conjugate base (salt) (more common), or a weak base and its conjugate acid (salt). 

Buffer capacity:  is the number of gram equivalents in an acid or base that changes the pH of 1 liter buffer by 1 unit.  Maximum buffer capacity occurs when pH = pKa.   Higher concentration of buffer constituents ­ buffer capacity due to the ­ acid or base reserve. 

Heterogenous (disperse) systems:

Suspension: two phas system that is composed of solid material dispersed in a liquid.  Particle size is > 0.5 mm. 

Emulsion: heterogeneous system that consists of one immiscible liquid dispersed in another as droplets.  Droplets diameter > 0.1 micron.  Emulsions are inherently unstable because the droplet tend to coalesce.  An emulsifying agent is used to prevent coalescence. 

In ideal (not real) dispersion, the dispersed particles are uniform in size and do not interact. 

Stokes’s law defines Sedimentation rate.  The rate ­ with ­ particle size and the difference in density between particles and medium.  The rate ¯ with ­ medium viscosity. 

High particulate (dispersed phase) concentration leads to ­ particle collision and ­ aggregation, coalsecnce, instability. 

Avoidance of particle-particle interactions: if particles have similar electrical charge (e.g. from the surfactant).  Zeta potential (magnitude of the charge) is the difference in electrical potential between the particle charged surface and dispesion medium.  When zeta potential is high (<25 mV), interparticulate repulsive forces > attractive forces, which results in deflocculation and stability.  

Coalescence of droplets in O/W emulsions is ¯ by electrostatic repulsion of similarly charged particles. 

Creaming: is the reversible separation of a layer of emulsified particles.  Mixing or shaking may be sufficient to reconstitute the emulsion. 

Phase inversion:  from o/w to w/o emulsion or vice versa. 

IV Chemical kinetics and drug stability

Degradation rate depends on concentration, temperature, pH, solvents, additives, light, radiation, catalysts (polyvalent cations), surfactants, buffers, complexing agents. 

Order of reaction: the way in which the concentration affects rate. 

Zero order:  rate is independent of concentration, e.g., 5 mg/hr, i.e., straight line concentration vs. time.

First order:  rate depends on the first power of concentration, e.g., 5% / hr.  Concentration ¯ exponentially with time.  Straight line log concentration vs. time.  t1/2 = 0.693/k,  t90% = 0.104/k.  Half life is concentration independent. 

Temperature: ­ T à ­ reaction rate (Arrenius equation). 

Solvent:  may change pKa, surface tension, viscosity, reaction rate, etc.  Additional reaction pathways may be created (e.g. aspirin in ethanol). 

pH: H+ catalysis occurs at ¯ pH, OH- catalysis occurs to ­ pH.  Rate constant at intermediate pH range is usually lower than at ­ or ¯ pH.  pH of optimum stability (point of inflection) is measured. 

Aromatic esters (benzocaine, procaine, tetracaine) ­ t1/2 is presence of caffeine due to complex formation. 

Modes of pharmaceutical degradation:

Hydrolysis: most common.  Occurs for esters, amides, lactams.  H+ and OH- are the most common catalysts.  Esters easily hydrolize and should be avoided in liquids.

Oxidation:  by oxygen in the air or in solvent.  Oxidizable compounds should be packed in an inert atmosphere (nitrogen or CO2).  Oxidation involves free radical mechanism and chain reaction.  Free radicals take electrons from other compounds.  Antioxidants react with free radicals by providing electrons.  Antioxidants include: ascorbic acid, tocopherols, sodium bisulfite, sodium sulfite, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate. 

Photolysis: degradation in sunlight or room light.  Molecules may absorb the proper wavelenght of light (usually <400 nm) and acquire sufficient energy to undergo reaction.  Prevent by using opaque container or amber glass bottle.  Examle: sodium nitroprusside in water. 

Determination of shelf life.  It’s affected by storage temperature.  Preparation is considered fit if it varies from nominal concentration by no more than 65% provided the decomposition products are not more toxic.  Stability testing at 4 C and room temperature (22C).  Rate of decomposition is determined.  Temperature-ccelerated stability is also conducted.  Arrhenius equation can be used.  T90% can also be calculated.

Drug dosage forms:

Oral solutions

May contains polyols (e.g. sorbitol, glycerin) to ↓ crystallization, modify solubility, taste, mouth feel. 

Advantages (over solid forms): more homogenous, easier to swallow, ↑ bioavailability and ↓ onset of action for slow dissolution drugs.  Disadvantage: bulkier, degrade faster, ↑ interactions with constituents

Types of water:

Purified water USP: obtained from distillation, reverse osmosis, ion exchange.  Solids < 10 ppm.  pH = 57.  It can not be used for ophthalmics or parenterals.  

Water for injection USP: purified water that is pyrogen free

Sterile water for injection USP: water for injection that is sterilized and packaged in single dose containers < 1 liter for type I or II glass

Bacteriostatic water for injection USP: sterile water for injection containing bacteriostatic agent(s) in one or multiple dose containers < 30 ml in type I or II glass.  

Sterile water for inhalation USP: purified by distillation or reverse osmosis and rendered sterile. It contains no antimicrobials.

Sterile water for irrigation USP:  water for injection that is sterilized and contains no antimicrobials. 

Oral drug solutions

Syrups: contains ↑ sugar concentration.  Sweet and viscous.  Syrup NF (simple syrup): 85% w/v sugar.  Sugars have low solvent capacity for water soluble drugs because hydrogen bonding between sugar and water is very strong.  Dilute sucrose solutions are excellent media for microbial growth.  As sugar concentration approaches saturation, the solution becomes self-preserved, however temperature fluctuations may cause sugar crystallization.  Syrup USP  is self-preserved with ↓ crystallization potential. 

Elixirs: contain alcohol as a solvent (5-40%).  Elixirs become turbid when diluted by aqueous liquids.  Alcohol ↑ salt taste.  Salts also have limited solubility in alcohol.  Aromatic elixir NF: mixture of two alcohol  concentrations resulting in 22% alcohol. 

Miscellaneous solutions

Aromatic waters:  are saturated aqueous solutions of volatile oils.  Used for flavoring.  Stored in tight, light resistant containers.  Adding large amount of water soluble drug may cause insoluble layer to form (salting out) due to better attraction with the water solvent than the oils. 

Spirits (essences): volatile substances in 50-90% alcohol.  It water is added, oils separate.  Used medicinally or as flavors.  Store in tight containers. 

Tinctures:   stable alcohol solutions of chemicals or soluble constituents or vegetable drugs.  Prepared using extraction using maceration or percolation.  Alcohol content varies widely. 

Fluidextracts:  liquid extracts of vegetable drugs that contain alcohol as a solvent, preservative, or both.   Prepared by percolation.  Ten times as concentrated and potent as tinctures (100% vs. 10%). 

Mouthwashes: use alcohol or glycerin to dissolve volatile ingredients.

Astringents: locally applied solutions that ppt protein.  Astringents ↓ cell permeability without causing injury.  They cause constriction, wrinkling and blanching of skin.  They ↓ secretions and are used as antiperspirants.  Examples: alulminum acetate, aluminum subacetate, calcium hydroxide.

Antibacterial topical solutions:  e.g. benzalkonium chloride, strong iodine, providone-iodine. .

Suspensions

Magmas: suspensions of finely divided material in a small amount of water.

Drugs may be packed dry to avoid instability in aqueous dispersions. 

Advantages:

Sustained effect: requires dissolution or diffusion step.  Stability: drug degradation is slower than in a solution.  Taste: for insoluble drugs used in suspension.  Solubility:  when solvent is not available. Example: only water can be used in ophthalmics, but suspension offer an alternative.

Preparation: first solids are wetted by levigation (addition of nonsolvent levigating agent to solid material to form a paste).  A surfactant can be used.  Then suspending agent is added as aqueous dispersion by geometric dilution. 

Suspending agents:

1. Hydrophilic colloids

↑ viscosity by binding with water.  Support microbial growth and require preservation.  Mostly anionic, except methyl cellulose (neutral) and chitosan (cationic), therefore incompatible with quaternary antimicrobials.  Insoluble in alcohol.

Acacia: used as 35% water dispersion (mucilage).  Neutral pH.

Tragacanth: 6% mucilage (less needed). 

Methyl cellulose: heat and light stable polymer.  Soluble in cold but not hot water.  Prepared using boiling water.

Carboxy methyl cellulose: anionic and water soluble. 

2. Clays

Anionic silicates.  Strongly hydrated and exhibit thixotropy.  Examples: bentonite (5% magma), veegum.

Emulsions

Advantages:

↑ Solubility: e.g. oil soluble drug in aqueous formulation.  ↑ Stability: usually better than in aqueous solution.  ↑ Drug action: as in IM injections.  ↑ Taste: oil soluble drug hidden in aqueous outer phase.  ↑ Appearance: as in oily material for topical application.

Phases of emulsions: most are 2-phases.  Internal phase (dispersed or discontinuous phase) in an external phase (dispersion medium or continuous phase).

Type of emulsion is determined by relative phase volumes and emulsifying agent used (more important).  Maximum volume of internal phase is 74%. 

Emulsifying agents: lower interfacial tension and form a film at the interface. 

Natural emulsifying agents: see hydrophilic colloids under suspending agents (acacia, tragacanth, celluloses).  Also pectin, gelatin and agar.  Agar: ↑ viscosity.  Gelatin: 1%, can be anionic or cationic. 

Preparation methods:

1. Wet gum (English) method: emulsion of fixed oil, water, acacia.  Make mucilage of water and acacia, then add oil gradually.

2. Dry gum (Continental) method: emulsion of fixed oil, water, acacia.  Fixed oil added to acacia and then water is all added at once followed by rapid titration. 

Electrolyte in high concentration can break the emulsion.  Add last.

Alcohol can dehydrate and ppt hyrocolloids.  Use in ↓ concentration.

3. Bottle method: similar to dry method.  Used for volatile oils. 

4. Nascent soap method: by mixing equal portions of oil and alkali solution to form soap, which acts as an emulsifying agent.   Example: olive oil (contains oleic acid, free fatty acid) and lime water à calcium oleate for calamine lotion. 

The drug can be added after emulsion formation if it is soluble in the external phase.  If drug is soluble in internal phase, it should be dissolved first during emulsion formation.

Synthetic emulsifying agents:

1. Anionic: Soaps form w/o except alkali soap. Examples: SLS 

2. Cationic: e.g. benzalkonium chloride.  Incompatible with soap.

3. Nonionic: Spans (sorbitan esters, ↑ HLB) for w/o, Tweens (polysorbates, ↓ HLB) for o/w

Ointments

Used as emollients (make skin more pliable), protective barriers, or vehicles for drugs.

Ointment bases

1. Oleaginous bases:  not washable.  Petrolatum: occlusive, does not rancid, use wax to ↑ viscosity.  Synthetic esters: e.g. glyceryl monostearate, isopropyl myristate, butyl palmitate, PEG, long chain alcohols.  Lanolins: e.g. lanolin oil and hydrogenated lanolin.

2. Absorption bases: anhydrous, water-insoluble, not washable, but can absorb water. Example: anhydrous lanolin (wool fat), hydrophilic petrolatum (petrolatum, bees wax, stearyl alcohol, cholesterol), e.g. Aquaphor. 

3. Emulsion bases: Hydrous wool fat (lanolin): w/o with 25% water, emollient and occlusive.  Cold cream: w/o with almond oil, white wax, sodium borate.  Vanishing cream: o/w with ↑ water and humectants (PEG, glycerin).  Hydrophilic ointment: o/w with SLS. 

4. Water soluble bases: washable and absorb water.  PEG ointment: PEG 400 and 4000 by fusion method.  PG and PG-alcohol: forms clear gel with 2% hydroxypropyl cellulose.

Preparation: metal spatula may interact with iodine or mercuric salts.  Use levigation or fusion method. 

Fusion method: used for solids with ↑ melting point.  Oil phase melted with highest melting point materials first.  Heat water soluble ingredient separately to above the highest melting point.  Mixed the two phases in the appropriate order for o/w or w/o. 

Suppositories

Used for local (hemorrhoids, infection) or systemic effect.

Systemic effect bypasses the first pass metabolism

Used when oral route is not possible, e.g., infants, nausea, vomiting, GI distress, coma, debilitation.

Types of suppositories:

1. Rectal: cylindrical, tapered bullet like.  Adult: 2 g.

2. Vaginal: oval, 5 g, for antiseptics, contraceptives, anti-infective.

3. Urethral: long (6 cm), tapered, local anti-infective.

Suppository bases:

Minimum 30 C narrow, sharp melting point.  Oil soluble drug has ↑ mucous absorption from an oil base, and vice versa. 

Bases that melt: cocoa butter (theobroma oil), witepsol (saturated fatty acid mixture), wecobee (from coconut oil); or Bases that dissolve: PEG.

Preparation: the suppository is molded with the fingers after a plastic mass is formed. 

1. Hand-rolling: Correct the amount of base needed based on the quantity of the drug and density of the base.

2. Compression: Mixture is placed into compression device.  Pressure is applied and mixture is forced into lubricated mold cavities. Used with cocoa butter. 

3. Fusion (molds): most common.  Use mineral oil to lubricate mold.  Pour melt continuously to avoid layering.  Avoid for thermolabile drugs and insoluble powders (settle).

Powders

Advantages: compounding flexibility, chemical stability, rapid ingredients dispersion.   Disadvantages: time consuming preparation, inaccurate dosing, unsuitable for bad taste  / hygroscopic drugs.

Milling: mechanical process of reducing particle size (comminution).  Micrometrics: is the study of particles. 

Advantages of milling: ↑ surface area à ↑ dissolution rate and bioavailability (e.g. griseofulvin), à ↑ drying of wet masses.  ↑ ointment texture / stability / appearance.  ↑ uniform distribution of colorants.  Particles of same size à ↑ mixing, ↓ segregation. 

Disadvantages of milling: may change polymorphic form à ↓ activity.  ↑ heat / adsorption à degradation.  Flow problems and segregation.  ↑ static charge à particle aggregation / ↓ dissolution.  ↑ surface area à ↑ air adsorption / ↓ wettability. 

Comminution techniques: Trituration à reducing particle size or mixing with a mortar and pestle.  Pulverization by intervention à a solvent is added to help pulverization and then evaporated (e.g. alcohol to camphor).  Used with gummy substances that reagglomerate or resist grinding.  Levigation à add a nonsolvent (levigating agent, e.g., mineral oil) to form a past and help pulverization in mortar and pestle or ointment slab and spatula.  Avoid gritty feel of solids. 

Mixing powders:

Spatulation: using spatula to mix small amounts of powder on paper or pill tile.  Not possible for potent drugs or large quantities.  Useful to eutectic mixtures (mixture melting point is lower than each ingredient), such as phenol, camphor, menthol, thymol, aspirin, phenyl salicylate, phenacetin.  Inert diluent can be used to minimize contact (MgO, MgCO3, kaolin, starch). 

Trituration: used both to comminute and mix.  For comminution, use porcelain or ceramic mortar with rough surface.  For mixing, colorants and easy cleaning, use glass mortar. 

Geometric dilution: used for mixing potent drugs with large amount of diluent.  First mix equal amounts of drug and diluent in a mortar by trituration, repeat until diluent is used up. 

Sifting: powders are passed through sifters similar to flour sifters, resulting in a light fluffy product.  Not suitable for potent drugs. 

Tumbling: mix powders in a large container rotated by motor. 

Use and packaging of powders:

As bulk powders or divided powders. For bulk powders, a perforated sifter can is used for external dusting or an aerosol container is used for spraying onto skin. 

Powders dispensed in bulk: antacids and laxatives (e.g. PEG is mixed with a drink).  Douches are mixed with water and applied vaginally.  Dentifrices and dental cleansing powders.  Powders for ear, nose, throat, tooth sockets, vagina.  Non potent substances. 

Divided powders: dispensed usually in folded paper (chartulae).  If drug is not potent, approximate portions by block and divide method (do not weight).

Special problems:  volatile substances (camphor, menthol, essential oils) à use sealed containers.  Liquids à added to divided powders in small amounts.  Hygroscopic substances become moist à divide, add diluent, double wrap.  Eutectic mixtures.

Capsules

Hard gelatin capsules

Storage: contain 15% water, so when ↓ humidity à capsules become brittle, when ↑ humidity à capsules become shapeless. 

Size: empty capsules are numbered (000 à largest / 600 mg, 5 à smallest / 30 mg).  Large capsules are for veterinary use. May add lubricant to ↑ flow or wetting agent to ↑ dissolution. 

Filling: by the punch method.  Powder is placed on paper and the capsule is pressed into powder until filled. 

Soft gelatin capsules

Preparation: from gelatin shells.  Glycerin or polyhydric alcohol (sorbitol) is added to make shells more elastic.  Contain preservatives (sorbic acid, parabens). 

Uniformity and disintegration

Uniformity is demonstrated by weight variation or content uniformity.  Disintegration are usually not requires unless they are enteric coated. 

Contents may be designed for sprinkling on food (e.g. Theo-Dur Sprinkle). 

Tablets

Advantages of solid dosage forms: accurate dose, easy shipping / handling, less shelf space, no preservative, no taste masking problems, more stable / longer expiration.

Advantages of liquid dosage forms: more effective (antacids, adsorbents), easier to swallow.

Advantages of tablets; precise dose, ↓ content variability, ↓ manufacturing cost, easy packaging and shipping, easy to identify, easy to swallow, specific release forms, stable, tamperproof. 

Disadvantages of tablets: difficult compression, difficult formulation / ↓ bioavailability (poor wetting, ↓ dissolution, ↑ dose).

Ideal tablet: free of defects, strong / durable, stable, predictable drug release.

Tablet design and formulation (excipients)

Diluents: fillers to make up the tablet bulk of ↓ dose drugs.  May ↑ cohesion, flow, or direct compression.  Examples: kaolin, lactose, mannitol, sugar, starch, microcrystalline cellulose, calcium phosphate. Do not use calcium salts with tetracycline (↓ absorption).

Binders / adhesives: added dry or liquid to ↑ granulation or direct compression. Examples: cornstarch, glucose, molasses, natural gum (acacia, may be contaminated), celluloses (methylcellulose, CMC, microcrystalline cellulose), gelatins, provide (PVP).  Liquid binders are more effective. 

↑↑ à too hard, ↓ dissolution.  ↓↓ à soft crumbling tablets.

Disintegrants: ↑ disintegration on gastric fluid contact (critical for dissolution and bioavailability).  They draw water to tablet, swell and burst.  Examples: cornstarch, potato starch, sodium starch glycolate, celluloses (sodium CMC), clays (veegum, bentonite), cation exchange resins. 

A portion can be added with the diluent and another with the lubricant after granulation à double disintegration. 

Lubricants / antiadherents / glidants: lubricants à ↓ friction between tablet and die upon ejection (talc, magnesium stearate, calcium stearate).  Anti-adherents à ↓ sticking, adhesion of granules to the punches or die.  Glidants à ↓ particle friction à ↑ powder / granule flow.

Colors / dyes: disguise off-color drugs, product ID. FDC dyes are applied in solution.  Lakes are dyes absorbed on a hydrous oxide (dry powder). 

Flavoring agents: only for chewable or mouth dissolving tablets.  Flavor oils or powders are ↑ stable, water soluble flavor are ↓ stable. Maximum: 0.75%. 

Artificial sweeteners: only for chewable or mouth dissolving tablets.  May come with diluent  (mannitol, lactose).  Other agents; saccharin, aspartame. 

Adsorbents: hold fluid in apparently dry state. Example: magnesium oxide, magnesium carbonate, bentonite. 

Tablet types and classes

For oral ingestion:

May be mask taste, color, odor, control release, enteric coating, incorporate another drug, avoid incompatibility, ↑ appearance.

Compressed: from powders, crystals or granules with or without excipients.  No coating. 

Multiple compressed: layered à compress tablet granules around previously compressed granules, then repeat.  Compression coated / dry coated à made by feeding previously compressed tablet to a machine that compresses an shell around it à separate incompatible drugs, provide repeat action / prolonged action.

Repeat-action: multiple compressed tablet where the outer shell rapidly disintegrates in the stomach.  Example: Repetabs, Extentabs.  The components of the inner layer are insoluble in the stomach but soluble in the intestine. 

Delayed action / enteric coated: delays drug release to prevent stomach destruction, prevent stomach irritation, or better stomach absorption.  Enteric: intact in stomach, release in intestine (e.g. Ecotrin). 

Sugar / chocolate-coated: to protect drug from air / humidity, mask taste / odor.  Process includes seal coating (waterproofing), subcoating, syrup coating (for smoothing, coloring), polishing.  Disadvantage: time consuming, require expertise, bulky coats. 

Film coated: compressed tablets coated with water soluble or insoluble polymer (HPMC, povidone, PEG).  Film is colored, ↑ durable, ↓ chipping, ↓ bulky (3% wt ↑), ↓ time consuming than sugar coating.  May contain film former, plasticizer, surfactant, opacifier, sweetner, color, flavor, glossant, volatile solvent.

Air-suspension coated: fed into vertical cylinder and supported by air column (Wurster process) where the coating solution is applied. 

Chewable: disintegrate rapidly when showed or dissolved.  Contains flavored and colored mannitol.  Used for children, multivitamins, antacids, antibiotics.

Used in oral cavity

Buccal / sublingual: allow absorption through oral mucosa after dissolution.  Avoid gastric destruction or intestinal ↓ absorption.  Examples: sublingual nitroglycerin, buccal progesterone. 

Troches / lozenges / dental cones: dissolves slowly in the mouth and provide local effect. 

Used to prepare solutions:

Effervescent: made by compressing granular effervescent salts (citric acid, tartaric acid, sodium bicarbonate) that release CO2 when contacting water. Example: alkalinizing analgesics (Alka-Seltzer, ↑ dissolution, absorption). 

Other tablets to prepare solution: dispensing tabs, hypodermic tabs, tab triturates.

Processing problems

Capping: separation of the top or bottom crown from main body of tab.  Lamination: separation of tab into two or ↑ layers.  Usually due to air entrapment.

Picking: removal of the surface material by a punch. Sticking: adhesion of material to the die wall.  Due to excess moisture or melting ingredient. 

Mottling: unequal color distribution.  Due to different color drug vs. excipient or drug degradation. 

Tablet evaluation and control

General appearance: size, shape, color, odor, taste, surface, texture, physical flaws, consistency, marking legibility.

Hardness / friability resistance: Hardness affects dissolution / disintegration.  Slow dissolved tabs are harder, vice versa.  Hardness tester measure force required to break tab.  Friabilators measure weight loss when tabs roll and fall (<1%).  Chewable / effervescent tabs are highly friable, require special packaging. 

Weight variation: USP standards apply to tabs containing >50 mg drug where drug is > 50% of total weight. 

Content uniformity: USP standards apply if drug <50 mg.

Disintegration: USP test is conducted in vitro.  Disintegration time: nitroglycerin (2 min), aspirin (5 min), most other drugs (<30 min), buccal tabs (4hr), enteric coated (none in 1 hr is simulated gastric fluid, within 2 hr in simulated intestinal fluid). 

Dissolution: standards in USP.  Increased emphasis on dissolution replaced disintegration for many drugs. 

 

Aerosols

Pressurized dosage forms that deliver drugs topically or systemically with the aid of liquefied or propelled gas (propellant). 

Valve allows pressurized product to be expelled continuously or intermittently when the actuator is pressed.  Dip tube conveys the formulation for the container’s bottom to the valve. 

Metered dose inhalers (MDIs): aerosol systems for systemic or pulmonary delivery.  They contain fine drug mist solution or dispersion.  1 Actuation = 1 dose. 

Propellants: compressed gases (CO2, N2, NO), ↓ pressure with time due to ↑ head space.  Liquefiable gases: saturated hydrocarbons, hydrofluorocarbons, dimethyl ether, chlorofluorocarbons (CFC).  CFC are banned now. 

Advantages: push-button dispensing convenience, stability of closed container (protects from light, moisture, air, microbes), ↓ tampering, wide product range.  Disadvantage: propellants are environmental hazard. 

Controlled release dosage forms

They release drug slowly.  Also known as delayed-release, sustained-action, prolonged-action, sustained-release, prolonged-release, timed-release, slow-release, extended-action, extended-release. 

Advantages: ↑ compliance, ↓ total drug used, ↓ local or systemic SE, ↓ drug accumulation / potentiation / loss of activity with prolonged use, ↑ treatment efficiency, rapid condition control, ↑ bioavailability, ↓ level fluctuation, ↓ cost.

Coated beads or granules:

Examples: Theo-Dur Sprinke, Spansules, Sequels,.

Produce drug level similar to multiple dosing. 

Non-aqueous (e.g. alcohol) drug solution is coated onto small inert beads or granules (starch/sugar).  Beads may be made of drug if dose is ↑.  Some granules take no further coating to give immediate release.  Otherwise, coats of a lipid (e.g. beeswax) or cellulosic (e.g. ethylcellulose) material are applied.  Thickness is varied by varying # of coats to provide SR. 

Microencapsulation

Example: Bayer time-release aspirin.

Solids, liquids or gases are encased in microscopic capsules. 

Coacervation: most common method of encapsulation.  A hydrophilic substance is added to a colloidal drug dispersion and causes layering and formation of microcapsules. 

Film forming substances for coating (natural or synthetic) include shellacs, waxes, gelatin, starches, cellulose acetate phthalate, ethylcellulose.  After the coating dissolves, the drug is immediately available. 

Matrix tablets:

Examples: Gradumet, Lontabs, Dospan, Slow-K

Use hydrophilic polymers (methyl cellulose, HPMC), insoluble plastics (polyethylene, polyvinyl acetate, polymethacrylate), fatty compounds (waxes, glyceryl tristearate). 

The drug is mixed with matrix material then compressed. 

The immediate dose is coated as a top layer. 

Osmotic systems:

Example: Oros system (Alza)

Oral osmotic pump composed of a core tablet and semipermeable coating that has a small hole (0.4 mm) produced by laser beam for drug exit.  The system requires only osmotic pressure to be effective and is independent of pH.   

Drug release rate is controlled by changing surface area, membrane nature, or hole diameter.

Ion-exchange resins:

Example: biphenamine (amphetamine and dextroamphetamine), lonamin (phentermine), Pennkinetic system. 

Ion exchange resins are complexed with drugs by passage of a cationic drug solution through a column that contains the resin.  The drug is complexed to the resin by replacement of hydrogen atoms.  Then the resin-drug complex is washed and tableted. 

Release is dependent on ionic environment in GI and resin properties (↓ pH  à ↑ release).

Complex formation:

Example: hydroxypropyl-beta-cyclodextrin forms a chemical complex slowly dissolves depending on pH. 

Hydrocolloid systems:

Example: Valrelease (SR diazepam) includes hydrodynamically balanced system (HBS).  HBS contains a matrix that is ↓ dense than gastric acid, so it remains buoyant.  Multiple hydrocolloid layers swell when contacting gastric acid and slowly erode releasing the drug. 

4. Biopharmaceutics and Drug Delivery Systems

Drug transport and absorption

Transport across cell membranes

Cell membrane: is a semipermeable structure composed of lipids and proteins.  Proteins, protein bound drugs and macromolecules do not cross cell membranes easily.  Nonpolar lipid soluble and smaller molecular weight drugs diffuse through cell membranes faster. 

Passive diffusion / partitioning: passive diffusion is dominant within the cytoplasm or in interstitial fluid (Fick’s law).  Passive transport across cell membranes involves successive partitioning of solute between aqueous and lipid phase as well as diffusion within phases.  Nonionized drugs are more lipid soluble and partition better across cell membranes.

Carrier-mediated transport: Active transport: drug moves against concentration gradient, requires energy, carrier may be selective for drugs that resemble natural substrates, system may saturate at ­ concentrations, process may be competitive.  Facilitated diffusion: carrier mediated transport that occurs with a concentration gradient and does not require energy. 

Paracellular transport: drug transport across tight junction between cells or channels.  It involves diffusion and convective (bulk) flow of water and dissolved molecules 

Vesicular transport: the process of engulfing particles by a cell.  Only mechanism that does not require water solubility for absorption.  Pinocytosis: engulfment of small solute or fluid volumes. Phagocytosis: engulfment of large particles or macromolecules by macrophages. 

Endo/Exo-cytosis: movement of macromolecules in and out of the cell. 

Transport proteins: (e.g. P-glycoprotein) are embedded in the lipid bilayer of cell membranes.  These are ATP energy dependent pumps.  Work closely with cytochrome P450 3A4 to ¯ intracellullar drug concentration.  Substrates: cyclosporin, nifedipine, digoxin.   

Routes of drug administration

Parenteral: IV Bolus is directly injected to the blood stream, very quick action / SE.  IV infusion:  constant input rate maintains constant plasma concentration.  Intra-arterial: to achieve ­ concentration in specific tissue before systemic drug absorption, mostly diagnostic and chemotherapy. IM:  rate of absorption depends on muscle vascularity, drug lipid solubility / matrix.  SC:  ¯ vasculature à slow absorption.  Intra-articular: into the joint.  Intrathecal: into the spinal cord.  Intradermal: into the dermis. 

Enteral: Buccal / sublingual: allows nonpolar lipid soluble drug absorption, bypassing first pass metabolism.  Peroral: most common, convenient, safe.  Disadvantages: inconsistent / incomplete absorption (gastric emptying, intestinal motility), GI enzyme digestion, acid pH decomposition, GI irritation, first pass metabolism.  Absorption is usually by passive diffusion.  Duodenum is the main absorption site (villi / microvilli à ­ surface area).  Residence time (period of contact) is needed for absorption. Double peak: cimetidine or acetaminophen as immediate release on empty stomach produce two peak plasma level.  Rectal: drug in solution (enama) or suppository is placed in the rectum.  Drugs absorbed in the lower 2/3 bypass the liver first pass metabolism. 

Respiratory: Intranasal: as spray or drops for local (decongestant, steroid) or systemic effect.  Pulmonary: inhaled perorally (nebulizer, MDE) into pulmonary tree.  Particles > 60 um à deposit on trachea.  Particles > 20 um à do not reach bronchioles.  Particles 2-6 um à reach alveolar ducts.  Particles 1-2 um à retained in the alveoli.  Particles < 0.6 um à exhaled, not deposited. 

Transdermal (percutaneous): suitable for small lipid soluble molecules (clonidine, nitroglycerin, fentanyl, scopolamine, testosterone, estradiol). 

Local activity: topical antibiotics, anti-infectives, antifungals, loacal anesthetics.  Minimum systemic absorption.

Biopharmaceutical principles

Physicochemical properties

Drug dissolution: bioavailability rate limiting step for drugs with limited solubility.  Diffusion is described by Noyes Whitney equation (similar to Fick’s law). 

Drug solubility in a saturated solution is a static equilibrium property.  Dissolution rate is a dynamic property with a rate.

Particle size / surface area: inversely related.  ­ surface area à ­ dissolution rate.  For some hydrophobic drugs, ¯¯ particle size à aggregation to ¯ surface free energy.  To prevent aggregate formation, small particles are molecularly dispersed in PEG, PVP (povidone), dextrose.  Examples: Griseofluvin molecular dissolution in water soluble carrier (PEG 400) à ­ bioavailability.

Partition coefficient: ratio of solubility at equilibrium in nonaqueous solvent (n-octanol) to that in aqueous solvent (water).  Hydrophilic drugs (­ water solubility) à dissolution. 

Ionization: ionized form is more polar and more water soluble.  Based on Henerson-Hasselbalch equation.

Salt formation: type of salt affects dissolution, bioavailability, duration of action, stability, irritation, toxicity.  Soluble salt may be ¯ stable than nonionized form (e.g. sodium aspirin vs. aspirin). 

Effervescent forms: contains acid drug and sodium bicarobnate, tartaric acid, citric acid.  Water is added prior to use.  Excess sodium bicarbonate forms an alkaline solution in which the drug dissolves.  CO2 is formed by the decomposition of carbonic acid.  For weak acids, potassium and sodium salts are more soluble than polyvalent cation salts.  For weak bases, common water soluble salts include hydrochloride, sulfate, citrate, gluconate. 

Polymorphism: ability to exist in > 1 crystalline form.  Polymorphs have different physical properties.  Amorphous non-crystalline forms have ­ dissolution. 

Chirality: drug exists as optically active stereoisomers or enantiomers à different PK / PD.  Most chiral drugs are used as racemic mixtures.  Example: ibuprofen has R and S enantiomers, only S is active. 

Hydrates: drug may exist in hydrated, solvated form and anhydrous form.  Anhydrous ampicillin dissolves faster than hydrated ampicillin. 

Complex formation: Chelates are complexes involving a ring-like structure and a metal.  Natural chelates: hemoglobin, cyanocobalamin, insulin).  Tetracycline forms a chelate with polyvalent metal ions à ¯ water solubility à ¯ absorption.  Many drugs adsorb strongly on charcoal or clay (kaolin, bentonite) by forming complexes.  Theophylline + ethylene diamine à ­ water soluble complex (aminophylline).  Many drugs are complexed with cyclodextrins to ­ solubility.  Large drug complexes (drug-protein) do not cross cell membranes easily à free drug must first dissociate for absorption or glomerular filtration. 

Delivery system formulation

Complex formulation à bioavailability issues.  For oral solid dosage forms, dissolution is the rate limiting step. For CR or SR, release from the delivery system is the rate limiting step.

Solutions: are homogeneous mixtures of solutes dispersed molecularly in a dissolving medium.  Aqueous solution is the most bioavailable and consistent form (no dissolution).  Oral solutions are used as reference preparations for solid oral forms.  Elixir (drug dissolved in hydroalcoholic solution) has ­ bioavailability.  Alcohol ­ solubility.  However, drug may ppt when elixir is diluted in the GI with food, but absorption is still rapid because of ­ surface area.  A viscous drug solution (syrup) may ¯ mixing, dilution and GI gastric emptying.

Suspensions: bioavailability from suspension is similar to solutions due to ­ surface area.  Suspending agents: hydrophilic colloids (celluloses, acacia, xantham gum).  ­ viscosity may have issues as syrups above. 

Capsules: Hard gelatin caps are simple (contain powders) and preferred new drugs early clinical trials.  Soft gelatin caps contain nonaqueous solution, suspension or powder.  It may have ­ bioavailability if water miscible vehicle is used (e.g. lanoxicaps), and vice versa.  Aging and storage may affect gelatin shell moisture content and bioavailability.

Compressed tablets:  ­ ratio of excipients : drug à ­ possiblity of excipients affecting bioavailability.  Lubricants are usually hydrophobic, water-insoluble à ¯ drug surface wetting à ¯ dissolution and bioavailability.  Surfactants ­ dissolution and bioavailability. 

Modified release dosage forms: products that alter the rate or timing of drug release.  More stringent quality control is used.  Dose dumping, abrupt drug release, is a problem.  Allows ¯ in dosing frequency.  They provide more flat consistent plasma concentration that avoids toxicity and lack of efficacy.  A loading dose may be used.  Delayed release control the timing of release, e.g. enteric coating. 

Transdermals: have occlusive backing film to prevent TEWL to ­ hydration and permeation.  Concentration gradient is maintained by a drug reservoir. 

Targeted drug delivery: place the drug at or near the receptor (e.g. specific cell such as tumor, organ, tissue).  Systems include macromolecular drug carriers (proteins), liposomes, nanoparticles, monoclonal antibodies. 

Inserts and implants: drug is impregnated into a biodegradable material and released slowly.  Inserted into vaginal, buccal cavity, skin.  Example: l-norgestrol implant is inserted in the upper arm for 5-year contraception. 

6. Basic Pharmacokinetics

Introduction

Rates and orders of reactions

Reaction rate: velocity of the reaction

Reaction order: way in which the drug (reactant) affects the rate

Zero order reaction: drug concentration changes with time at a constant rate. Rate constant = Ko (concentration / time; mg/ml/hr).  Linear correlation of concentration vs. time with slope=Ko and intercept = Co. 

First order reaction: change of concentration with time is the product of the rate constant and concentration of the remaining drug.  Drug concentration decreases by a fixed percent in each time unit.  Linear correlation of log concentration with time.  Rate constant )K) = 1/hour.  Half life t_1/2=0.693/k. 

Models and compartments

Model: mathematical description to express quantitative relations in a biological system.

Compartment: group of tissues with similar blood flow and drug affinity.

Drug distribution

Drugs distribute quickly to tissues with ↑ blood flow

Drug cross capillaries by passive diffusion and hydrostatic pressure.

Drugs easily cross the capillaries of the kidney glomerulus.

Brain capillaries are surrounded by glial cells forming a thick lipid membrane (BBB) à ↓ diffusion of polar and ionic hydrophilic drugs.

Tissue accumulation due to drug/tissue physicochemical or affinity.

Lipid soluble drug à accumulate in adipose (fat) tissue

Tetracycline à accumulate in bone (calcium Complexation).

Plasma protein binding: results in a big complex à can’t cross membranes.  Albumin: major plasma protein for drug binding.  Alpha1-glycoprotein: binds basic drugs (e.g. propranolol) in the plasma. ↑ bound drugs (e.g. phenytoin) can be displaced by other ↑ bound drug à ↑ free unbound drug à in effect / toxicity.

One-compartment model

Intravenous bolus injection

Very rapid drug entry.  Rate of absorption is negligible.

Entire body is one compartment à all tissue equilibrate rapidly.

Drug elimination: first order kinetics. Elimination rate constant = renal excretion rate constant + metabolism (biotransformation) rate constant

Some controlled release oral drugs have zero absorption rate constant.

Apparent volume of distribution (Vd): hypothetical volume of body fluid in which drug is dissolved. Vd is needed to estimate amount of drug in the body (Db) relative to concentration in plasma (Cp). 

Cp = Db / Vd

More drug distribution into tissues à ↓ Cp à ↑ Vd

Single oral dose

Rapid absorption then elimination, both with first order kinetics.

Time to reach max concentration (tmax) depends only on absorption and elimination rate constants but not on Vd or Db. 

AUC: calculated using trapezoidal rule by integrating the plasma drug concentration over time.  AUC depends on Do, Vd, elimination K but not absorption K.

Lag time: at the beginning of systemic drug absorption, e.g. due to delay in gastric emptying.

Intravenous infusion

Absorption: zero order.  Elimination: first order (when infusion stops)

Steady state concentration (Css): target plateau drug concentration where fraction of drug absorbed = fraction of drug eliminated.

Loading dose (D_L): initial IV bolus dose to produce Css as rapidly as possible.  Start IV infusion at the same time.

D_L: amount of drug that, when dissolved in the apparent Vd, produces the desired Dss.  Reaching 07% of Css without D_L takes ~ t1/2.  Time to reach Css depends on the drug elimination half life. 

IV infusion: ideal for drugs with narrow therapeutic window (controls Cp).

Intermittent intravenous infusion

Drug is infused for short periods to prevent accumulation and toxicity.

Used for aminoglycosides (e.g. gentamicin).

Multiple doses

Drug is given intermittently in multiple-dose regimen for continuous or prolonged therapeutic activity to treat chronic disease.

Give new dose before previous dose completely eliminated à Cp accumulation à ↑ to Css.

At steady state: Cp fluctuations between a max and a min (C^∞_min-max). 

Superposition principle: assumes that previous drug doses have no effect on subsequent doses à total Cp = cumulative residual Cp from each previous dose.

Dosing rate = dose size (Do) / dose interval (e.g. X mg/hr).

Same dosing rate à same average Css but may be different (C^∞_min-max).

Some AB à multiple rapid IV bolus injections.

Oral immediate release drug products (multiple doses) à rapid absorption, slow elimination.

Maintenance dose (D_M): after loading dose to maintain Cp at Css.  If D_M dosing interaval = elimination t1/2 à D_L = 2 x D_M

Multi-compartment models

Drug distributes into different tissue groups at different rates.  Tissues with ↑ blood flow equilibrate rapidly with the drug. 

Two-compartment model (IV bolus): First, rapid distribution into highly perfused tissue (central compartment) à rapid decline in Cp (distribution phase).  Both are first-order processes.  Then, slow distribution into peripheral tissues (tissue compartment) à slow decline in Cp after equilibration (elimination phase).  Vd = Vd at steady state + central + tissue compartment volumes.

Two-compartment model (oral): two-compartment ONLY if absorption is rapid but distribution is slow. 

Models with additional compartments: example of a third compartment: deep tissue space.  If frequent interval dosing à third compartment accumulation.

Elimination rate constant: two constants; one for elimination from central compartment, the other for elimination after complete distribution.

Nonlinear pharmacokinetics

Also known as capacity-limited, dose-dependent, or saturation PK.

Result from the saturation of an enzyme of carrier-mediated system.

Do not follow first-order kinetics as the dose ↑.

AUC or drug excreted in urine are not proportional to dose

Elimination t1/2 may ↑ at ↑ doses.

Michaelis-Menten equation: describe velocity of enzyme reactions in nonlinear PK. It described rate of change of Cp after IV bolus. If Cp is ↑ à the equation is a zero-order rate of elimination. If Cp is ↓↓ à first-order.

Note that first-order PK = linear PK

Clearance

Total body clearance (Cl_T)

Cl_T  = drug elimination rate / Cp = K x Vd

Cl_T  and Vd are independent variables.  T1/2 is a dependent variable.

A constant volume of the Vd is cleared from the body per unit time.

First order PK: Cl_T = renal clearance + non-renal (hepatic) clearance

↓ Cl_T  à ↑ t1/2.   ↑ Vd à ↑ t1/2

Renal drug excretion

Major route of elimination for: polar drugs, water-soluble drugs, drugs with ↓ MWt (<500), drugs that are biotransformed slowly.

Glomerular filtration: passive process that filters small molecules.  Drugs that are bound to plasma proteins are too big to be filtered.  Creatinine and inulin undergo only glomerular filtration (not tubular secretion or reabsorption) à used to measure glomercular filtration rate (GFR). 

Tubular reabsorption: passive process that follow Fick’s first law of diffusion to reabsorb lipid-soluble and non-ionized weak electrolytes drugs back to the systemic circulation.  If ionized or water-soluble à excreted in the urine.  Diuretic à ↑ urine flow à ↓ time for reabsorption à ↑ drug excretion.

Active tubular secretion: carrier-mediated active transport system that requires energy.  Two systems: for weak acids and weak bases.  Competitive nature: e.g. probenecid (weak acid) compete for the same system as penicillin à ↓ penicillin excretion. Another example: p-aminohippurate.  Measure using effective renal blood flow (ERBF).

Renal clearance (Cl_R)

It is the volume of drug in the plasma remove by the kidney per unit time.

Cl_R = rate of drug excretion / Cp = ml/minute.

Clearance ratio: relates drug clearance to inulin clearance (GFR).  If = 1 à filtration only.  If < 1 à filtration + reabsorption.  If > 1 à filtration + active tubular secretion. 

Hepatic clearance

Volume of drug-containing plasma cleared by the liver per unit time.

Measurement of hepatic clearance (Cl_H)

Main mechanism for non-renal clearance.  Measured indirectly (difference between total and renal clearance). 

Cl_H  = hepatic blood flow x extraction ratio.

Extraction ratio: drug fraction irreversibly removed by an organ or tissue as the drug-containing plasma perfuses the tissue.

Blood flow, intrinsic clearance, protein binding

All these factors affect hepatic clearance.

Blood flow: to the liver is ~ 1.5 L/min.  After oral GI absorption à to mesenteric vessels à to hepatic portal vein à through the liver à to hepatic vein à to systemic circulation.

Intrinsic clearance: ability of the liver to remove the drug independent of blood flow due to inherent ability of the biotransformation enzymes (oxidases) to metabolize the drug as it enters the liver. This is affected by enzyme inducers (Phenobarbital, tobacco) and inhibitors (cimetidine, lead). 

Protein binding: bound drugs are not easily cleared by the liver or kidney. Only free drug crosses the membrane into the tissue and is available to metabolizing enzymes.

Biliary drug excretion

Active transport (secretion) process. Separate systems for weak acids and weak bases.

Excretes ↑ MWt drugs (>500) or polar drugs (digoxin, reserpine, glucuronide conjugates).

Drugs may be recycled by enterohepatic circulation. GI absorption à mesenteric vessels à hepatic portal veins à liver à secrete to the bile à store in gallbladder à empty into the GI through the bile duct (recirculation).

First pass effect (pre-systemic elimination)

Portion of oral drugs may be eliminated before systemic absorption due to rapid drug biotransformation by liver enzymes. 

Measure absolute bioavailability (F).  If F < 1 à some drug was eliminated before systemic absorption.

Common for drug with high liver extraction ratio. 

If ↑ first-pass effect à ↑ dose (e.g. propranolol, penicillin), different route (e.g. nitroglycerin, insulin), or modified dosage form (e.g. mesalamine).

Non-compartment models

Some PK parameters can be estimated with non-compartment methods using comparison of the AUCs.

Mean residence time (MRT): average time for the drug molecules to reside in the body.  Called Mean Transit Time or Sojourn Time. It depends on the route of administration.  Assumes elimination from the central compartment. MRT = total residence time of all drug molecules in the body / total number of drug molecules.

Mean absorption time (MAT): difference between MRT and MRT_IV and an extravascular route.

Clearance: volume of plasma cleared of the drug per unit time. 

Steady-state volume of distribution (Vss): amount of drug in the body at steady sate and the average steady-state drug concentration.

Clinical pharmacokinetics

The application of PK principles to the rational design of an individualized dosage regimen. 

Objectives: maintenance of an optimum drug concentration at the receptor site to produce effect for the desired period, and minimization of SE.

Toxicokinetics

Application of PK principles to the design, conduct, and interpretation of drug sate evaluation studies.

Used to validate dose-related exposures in animals in preclinical drug development to predict human toxicity. 

Clinical toxicology: study of SE of drugs and poisons.  PK in intoxicated patient (↑↑ dose) may be very different from a patient taking therapeutic doses.

Population pharmacokinetics

Study of sources and correlation of variability in drug concentration in the target patient population.  Includes PK and non-PK parameters such as age, gender, weight, creatinine clearance, concomitant disease.

7. Bioavailability and bioequivalence

Definitions

Bioavailability: measurement of the rate and extent to which the active moiety becomes available at the site of action.  It is also the rate and extent of active drug that is systemically absorbed.

Bioequivalent drug products: a generic drug product is considered bioequivalent to the reference brand drug product if both products are pharmaceutical equivalents and have statistically the same bioavailability for the same dose, in the same chemical form, similar dosage form, by same route of administration, under same experimental conditions.

Generics: requires abbreviated NDA for FDA approval after patent expiration. Must be a therapeutic equivalent but may differ in shape, scoring, packaging, excipients, expiration dates, labeling.

Pharmaceutical equivalents: drug product that contain the same active drug, same salt, ester or chemical form, same dosage form, identical in strength and route of administration.  May differ in release mechanism, shape, scoring, packaging, excipients.

Reference drug product: usually the currently marketed brand name with full NDA and patent protection. 

Therapeutic equivalent drug products: are pharmaceutical equivalents that can be expected to have the same clinical effect and safety profile under same conditions. 

Pharmaceutical alternatives: are drug products that contain the same therapeutic moiety but are different salts, ester or complexes or are different strength or dosage forms (tablet vs cap, instant release vs SR).

Bioavailability and bioequivalence

Acute pharmacologic effect

Examples: change in heart rate, blood pressure, ECG, clotting time, Forced Expiratory Volume (FEV1).  Alternative to plasma concentration when that is not possible or inappropriate.  Measure effect vs. time.  Onset time: time from drug administration till achieving the minimum effective concentration (MEC) at the receptor site as evidenced by pharmacological response.  Intensity: proportional to the # of receptors occupied by the drug up to a maximum pharmacological effect, which may occur before, at or after peak drug absorption.  Duration of action: time for which the drug concentration remains above MEC.  Therapeutic window: concentration between the MEC and minimum toxic concentration (MTC).  As concentration ↑ à other receptor interactions lead to SE.  In vitro test (e.g. dissolution) can be used instead if statistical correlation to in vivo data has been established.  Example: dermato-PK for topical drugs for local effect.

Plasma drug concentration

Most common method for measuring systemic bioavailability. 

Time for peak plasma concentration (Tmax): relates the rate constant for drug absorption and elimination.  Absorption depends on the dosage form and formula, while elimination is only drug dependent. 

Peak plasma concentration (Cmax): Cmax at Tmax relates to the intensity of pharmacological response.  Ideally Cmax should be within the therapeutic window. 

AUC vs time: relates the amount or extent of systemic drug absorption. AUC is calculated using the trapezoidal rule, expressed as mg.hr/ml

Urinary drug excretion

Accurate method if the active moiety is excreted unchanged in ↑ quantities in urine.  Cumulative amount of active drug excreted in urine is related to extent of systemic drug absorption. Rate of drug excretion is related to rate of systemic absorption. Time for complete excretion relates to the total time for complete systemic absorption and excretion.

Relative and absolute bioavailability

Relative bioavailability: systemic availability of the drug from a dosage form as compared to reference standard given by the same route.  It is a ratio of the AUCs (maximum is 1 or 100%).  Very important for generic bioequivalence studies.

Absolute bioavailability (F): fraction of drug that is systemically absorbed.  It’s the ratio of AUC for oral dosage form / AUC for IV.  A parenteral IV drug solution has F = 1. 

Bioequivalence for solid dosage forms

Design of bioequivalence studies

Guidance provided by Division of Bioequivalence, Office of Generic Drugs, FDA.  All studies are done with healthy subjects.

Fasting study: blood samples are taken at zero time, and appropriate intervals to obtain adequate description of concentration vs. time profile.

Food intervention study: required if bioavailability is known to be affected by food.  Give products immediately after a standard high fat content breakfast. 

Multiple dose steady-state study: required for extended release products in addition to single-dose fasting and food intervention study.  Measure three consecutive days of trough concentrations (Cmin) to ascertain steady state.  Last morning dose is given after overnight fast, continue fasting for 2 hours.  Take blood samples.

In vitro bioequivalence waiver: a comparative in vitro dissolution may be used instead for some immediate release oral dosage forms.  No bioequivalence study is required for certain solution products (oral, parenteral, ophthalmic).

 

PK data evaluation

Single dose studies: calculate AUC to last quantifiable concentration, AUC to infinity, Tmax, Cmax, elimination rate constant (K), elimination half life (t1/2).

Multiple dos studies: steady state AUC, AUC to last quantifiable concentration, Tmax, Cmax, Cmin, % fluctuation (Cmax-Cmin / Cmin). 

Statistical data evaluation

Drug considered bioequivalent if difference from reference is < -20% or +25%.  ANOVA is done on log transformed AUC and Cmax data. The 90% confidence interavals of the means of AUC and Cmax should be 80-125% of the reference product. 

Drug production selection

Generic drug substitution

It’s dispensing generic drug in place the prescribed product.  The substituted drug has to be a therapeutic equivalent. 

Prescribability: current basis for FDA approval of therapeutic equivalent generic product.  It’s measurement of average bioequivalence where test and reference population means are statistically the same. 

Switchability: assures that the substituted product produces the same response in the individual patient.  It’s the measurement of the individual bioequivalence including intra-subject variability and subject-by-formulation effects.

Therapeutic substitution

The process of dispensing a therapeutic alternative.  For example: dispensing amoxicillin for ampicillin.  The substituted drug is usually in the same therapeutic class (e.g. calcium channel blockers) and is expected to have a similar clinical profile. 

Formulary issues

A formulary is a list of drugs.  Positive formulary: lists all drugs that may be substituted.  Negative formulary: lists drugs which can’t be substituted.  Restrictive formulary: lists only drugs that may be reimbursed without justification by the prescriber.  States provide guidance for drug product selection through formulary. 

FDA annually publishes Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”). It is also published in the USP/DI Volume III. 

Orange Book Codes:  A Rated: drug products that are considered therapeutically equivalent.  B Rated: drug products that are not considered therapeutically equivalent.  AB Rated: products meeting bioequivalence requirements.

8. Organic Chemistry and Biochemistry

Organic chemistry

Functional groups affect hydrophilicity, lipophilicity, reactivity, shelf life, stability, biotransformation, metabolism.

Alkanes

Also called paraffins, saturated hydrocarbons.

General formula: R-CH2-CH3. Lipid soluble. 

Common reactions: halogenation, combustion.

Chemically inert to air, heat, light, acids, bases.  Stable in vivo.

Alkenes

Also called olefins, unsaturated hydrocarbons.

General formula: R-CH=CH2.  Lipid soluble.

Common reactions: addition of hydrogen or halogen, hydration (to form glycols), oxidation (to form peroxides).

Volatile alkenes and peroxides may explode in presence of O2 and spark

Stable in vivo.  Hydration, peroxidation, reduction may occur.

Aromatic hydrocarbons

Based on benzene.  Exhibit multicenter bonding.  Lipid soluble.

Common reactions: halogenation, alkylation, nitration, sulfonation.

Chemically stable.

In vivo: hydroxylation, diol formation.

Alkyl halides

Halogenated hydrocarbons.  General formula: R-CH2-X. 

Lipid soluble.  ↑ degree of halogenation à ↑ Solubility.

Common reactions: dehyro-halogenation, nucleophilic substitution.

Stable on the shelf.  Not readily metabolized in vivo.

Alcohols

Contains OH group.  May be primary (R-CH2-OH), secondary (R1/R2-CH-OH), or tertiary (R1/R2/R3-C-OH). 

Alcohols are lipid soluble.

Low molecular weight alcohols are water soluble.  ↑ hydrocarbon chain length à ↓ water solubility.

Common reactions: oxidation, esterification.

Oxidation: primary alcohol à aldehyde à acid.  Secondary alcohol à ketone.  Tertiary alcohol à not oxidized.

Stable on shelf.  In vivo: oxidation, sulfation, glucuronidation.

Phenols

Aromatic compounds containing OH groups directly connected to aromatic ring.  Monophenols à one OH.  Catechols à two OH. 

Phenol (carbolic acid): water soluble.  ↑ ring substitution à ↓ water solubility.  Most phenols are lipid soluble. 

Common reactions: with strong bases to form phenoxide ion, esterification with acids, oxidation to form colored quinones.

On the shelf: oxidation with air or ferric ions.

In vivo: sulfation, glucuronidation, aromatic hydroxylation, o-methylation.

Ethers

General formula: R-O-R.

Lipid soluble.  Partially water soluble.  ↑ hydrocarbon chain à ↓ water solubility.

Common reaction: oxidation to form peroxides (may explode).

In vivo: o-dealkylation. Stability ↑ with size of alkyl group.

Aldehydes

General formula: R-CHO (contains a carbonyl group C=O).

Lipid soluble.  Low molecular weight aldehytes are also water soluble.

Common reactions: oxidation (to acids, in vivo and in vitro) and acetal formation.

Ketones

General formula: R-CO-R (contains a carbonyl group C=O).

Lipid soluble.  Low molecular weight ketones are also water soluble.

Nonreactive and very stable on the shelf. 

In vivo: some oxidation or reduction.

Amines

Contain an amino group (-NH2).  Primary (R-NH2), secondary (R1/R2-NH), tertiary (R1/R2/R3-N), quaternary (R1/R2/R3/R4-N+ X-).

Lipid soluble.  Low molecular weight amines à water solubility.  ↑ branching à ↓ water solubility (primary amines and most soluble).  Quaternary amines (ionic) and amine salts are water soluble. 

Common reactions: oxidation (air oxidation on shelf), salt formation with acids.  Aromatic amines are ↓ basic à ↓ reactive with acids.

In vivo:  glucuronidatin, sulfation, methylation.  1ryà oxidative deaminatin.  12y/2ry à acetylation.  2ry/3ry à dealkylation.

Carboxylic acids

General formula: R-COOH (Carboxyl group –COOH). 

Lipid soluble. Low molecular weight acid and Na/K salts à water soluble. 

Common reactions: salt formation with bases, esterification, decarboxylation.

Very stable on shelf.  In vivo: conjugation (with glucuronic acid, glycine, glutamine), beta oxidation.

Esters

General formula (R-COOR). 

Lipid soluble.  Low molecular weight esters are slightly water soluble.

Common reaction: hydrolysis to form carboxylic acid and alcohol (in vivo by esterases / in vitro).

Amides

General formula: R-CONH2 or R-CONR1/R2 (lactam form).

Lipid soluble.  Low molecular weight amides are slightly water soluble.

No common reactions.  Very stable on shelf. 

In vivo: enzymatic hydrolysis by amidases in the liver.

Biochemistry

Amino acid and proteins

Monomeric units of protein (peptide bonds). Formula: NH2-CH-R/-COOH.  Proteins are made of 20 AA, differ in R side chain (alpha (C)).

Protein hydrolysis to AAs by acids, bases, enzymes.

AA ionize (depending on pH) to zwitterions structure (NH3⁺-CH-COO^-/R) à ↓ water solubility, ↑ melting point. 

Levels of protein structure: primary, secondary (alpha/beta), 3ry, 4ry.

Carbohydrates

Polyhydroxy aldehydes or ketones

Monosaccharides: simple single unit sugars, e.g., glucose, fructose.

Oligosaccharides: short chains of monosaccharides joined covalently, e.g. sucrose (has to convert into glucose, fructose before GI absorption), maltose (hydrolyzed by maltase into 2x glucose), lactose (milk sugar, has to convert into galactose, glucose before GI absorption).

Polysaccharides: long chains of monosaccharides, e.g., cellulose, glycogen.

Pyrimidines and purines

Bases à bond with ribose à nucleosides à bond with phosphoric acid à nucleotides à building blocks of nucleic acid.

Exhibit tautomerism (isomerism): can be keto or enol.

Pyrimidines bases: cytosine, uracil, thymine.

Purine bases: adenine, guanine

DNA bases: thymine, cytosine, adenine, guanine

RNA bases: uracil, cytosine, adenine, guanine.

Biopolymers

Enzymes

Linked amino acid chains (proteins) à catalysts for biological reactions.  They reactions’ ↓ activation energy but do not change reaction equilibrium point, are used up or changed in the reaction.  May require cofactors or coenzymes.

Cofactor: inorganic (metal ion) or nonprotein organic molecule.  Prosthetic group: cofactor firmly bound to apoenzyme (protein portion of a complex enzyme). Coenzymes: organic cofactor that is not firmly bound but actively involved in catalysis. Holoenzyme: complete catalytically active enzyme system.

Lyases: removes functional group (deaminase, decarboxylase).

Ligases: bind two molecules (e.g. DNA ligase à 2 nucleotides).

Isomerases: change DàL, cisàtrans, vice versa.

Polysaccharides

Also called glycans.  Long chain polymers of carbohydrates.

Homopolysaccharides: Contains one type of monomeric units. Starch à plant’s reserve food, two glucose polymers (linear water soluble amylose, and branched water insoluble amylopectin), enzymatic hydrolysis à maltose (glucose disaccharide).  Glycogen à branched D-glucose chain, polysaccharide storage in animal cells (liver, muscles).  Cellulose à water soluble, in plant cell wall, linear D-glucose chain, can’t be digested (hydrolyzed) by humans.

Heteropolysaccharides: contains two or more monomeric units.  Heparin à acid mucopolysaccharide with sulfate derivatives, contains glucosamine, in lung tissue, used to prevent clotting.  Hyaluronic acid à in bacterial cell wall, virteous humor, synovial fluid, contains glucosamine.  

Nucleic acids

Linear polymers of nucleotides à pyrimidine and purine bases linked to ribose or deoxyribose sugars (nucleosides) and bound to phosphate groups.

Phosphodiester bonds: join successive DNA / RNA nucleotides.

DNA: compared to RNA it lacks an OH group and contains T rather than U. (DàT, RàU).

DNA: two complementary alpha helical strands coiled to form double helix. Hydrogen bonding between specific base pairs hold the strands together.  Hydrophobic bases are on the inside of the helix.  Hydrophilic deoxyribose phosphate on the outside.

Backbone: alternating phosphate and pentose units with a purine or pyrimidine attached to each.

Strong acids associated with cellular cations and basic proteins (histones, protamines).

rRNA (ribosomal): in ribosomes.

mRNA (messenger): the template for protein synthesis à specifies the polypeptide amino acid sequence.

tRNA (transfer): carries activated amino acids to ribosomes for incorporation to the growing polypeptide chain.

Biochemical metabolism

Factors affecting metabolism: substrate concentration, enzymes, allosteric (regulatory) enzymes, hormones, compartmentation.

Catabolism: degradation reactions that release energy for useful work (e.g. mechanical, osmotic, biosynthetic).

Anabolism: biosynthetic (build-up) reactions that consumer energy to form new biochemical compounds (metabolites).

Amphibolic pathways: may be used for anabolic or catabolic purposes.  Example: Krebs cycle, it breaks down metabolites to release 90% of the organism’s energy, but it also uses metabolites for form compounds such as AA.

Bioenergetics

Substrate level phosphorylation: forms one unit of ATP per unit of metabolite, no oxygen required.

Oxidative phosphorylation: forms 2 or more ATP per unit of metabolite.  Uses oxidoreductase enzymes (e.g. dehydrogenases) using cofactors NAD (nicotinamide A dinucleotide) or FAD (flavin).  Energy released from the reaction is used to form ATP in the mitochondria.

Carbohydrate metabolism

Catabolism: releases energy from carbohydrates.

Glycogenolysis: breakdown of glycogen into glucose phosphate in the liver, skeletal muscles à controlled by glucagon and epinephrine.

Glycolysis: breakdown of sugar phosphates (e.g. glucose, fructose, glycerol) into pyruvate (aerobically) or lactate (anaerobically) to produce energy (ATP)

Anabolism: consumes energy to build complex from simple molecules

Glycogenesis: formation of glycogen in the liver and muscles from glucose in diet à controlled by insulin.

Gluconeogenesis: formation of glucose from noncarbohydrate sources (e.g. lactate, pyruvate). 

Krebs cycle

Location: in the mitochondria.  Absent in RBCs (no mitochondria)

Catabolism: converts pyruvate (glycolysis), acetyl CoA (fatty acid degradation) and amino acids à into CO2 and water with release of energy. Oxygen dependent (aerobic).

Anabolism: forms amino acids (aspartate, glutamate) and heme ring from metabolites.

Electron transport: accept electrons and hydrogen from oxidation of Krebs cycle metabolites and couples the energy released to make ATP.

Lipid metabolism

Catabolism

Triglycerides stores in fat cells (adipocytes) are hydrolyzed by hormone-sensitive lipases into three fatty acids and glycerol

Fatty acids: broken down by beta oxidation to acetyl CoA à to Krebs cycle à breaks down to CO2, water and energy release. 

Ketogenesis: very rapid break down of fatty acids leading to formation of ketone bodies (as in DM).

Glycerol: enters glycolysis à oxidized to pyruvate à to Krebs cycle à CO2 and water.

Steroids: may be converted to bile acids, vitamin D, hormones.

Anabolism

Fatty acids: formed in the cytoplasm.  Unsaturation occurs I the mitochondria or endoplasmic reticulum.  Essential fatty acids: linoleic acid (can not be synthesized, diet is only sources).

Terpenes: derived from acetyl CoA.  Include: cholesterol, steroids, fat soluble vitamins (ADEK), bile acids.

Sphingolipids: forms a ceramide backbone with fatty acids. Joins with other compounds to form cerebrosides, sphingomyelin

Phosphatidyl compounds: i.e. phosphatidyl choline (lecithin), ethanolamine.

Nitrogen metabolism

Catabolism

Amino acids: amino group is removed by transaminase.  Carbon skeleton is broken down to acetyl CoA or citric acid derivatives à oxidized to CO2 and water for energy.  Glycogenic amino acids form glucose as needed by guconeogenesis.

Purines: 90% is salvaged, 10% degrade to uric acid using xanthine oxidase.

Pyrimidines: breaks down to B-alanine, ammonia, CO2

Anabolism

Amino acids: from citric acid cycle intermediates.  Essential AA: TIM (threonine, isoleucine, methionine), HALL (histidine, arginine, lysine, leucine), PVT (phenylalanine, valine, tryptophan) à PVT TIM HALL

Purines / Pyrimidines: from aspartate, carbamoyl phosphate, CO2, other AA.

Nitrogen excretion

Excess nitrogen is toxic à must be eliminated, mainly as urea. 

Urea synthesis: in the liver using the Krebs-Henseleit pathway.  Amino acid à AA transferases (transaminases) + pyridoxine (vitamin B6) as coenzyme à Ammonia à + glutamate à glutamine à + CO2 à carbamoyl phosphate à urea cycle à urea.  

Uric acid synthesis: most purines are salvages.  Remaining purines are excreted as uric acid. 

9.     Microbiology

Taxonomy and nomenclature

Taxonomy

Classification or ordering into groups based on degree of relatedness.

Bacteria are named using the Linnaean or binomial system (genus species = homo sapiens = human)

Morphology

Cultural morphology

Based on size, shape and texture or colonies grown inj axenic (pure) cultures

Each colony originates from a Colony Forming Unit (CFU) consisting of a single cell or group of adherent cells

Microscopic morphology

Based on size, shape and arrangement of bacterial cells

Stains

Bacteria are small and transparent à must be stained to be examined by light microscopy

Simple

Single dye colors the cells (e.g. gentian violet, safranin)

Gram

Gram-positive = purple

Gram-negative = pink

Acid-fast

Stains only cells that have an outer layer of a waxy lipid (acid-fast) not those lacking that layer (non acid-fast)

Spore

Heat is used to facilitate the dye entering the spore

Capsule

Two dyes stain the cell and backgrounds allowing the visualization of the unstained capsular material

Bacterial cell shape and arrangement

Cocci (spherical)

-Chains (streptococci)                            -Pairs / diplococci (streptococcus pneumoniae)

-Clusters (staphylocci)                -Packets

Bacilli Cylindrical rod-shaped (pseudomonads, Escherichia)

Coccobacilli (combination of small rods or flattened cocci)

Spirochetes (helical like a corkscrew)

Fusobacteria (tapered ends and slightly curved)

Filamentous (organisms are branching)

Vibrios (comma shaped)

Pleomorphic (exist in varied forms)

Other parameters

Presence or spores, capsules or slime layers

Mobility or type of flagella

Monotrichous = single flagella at either pole

Amphitrichous = flagellum at both poles

Lophotrichous = flagella at either or both poles

Peritrichous = flagella distributed evenly all around

Structure of the prokaryotic cell

Overview

Small and simple in design

Less complex inside, more complex outside

Lack a true nucleus, nuclear membrane or intracytoplasmic membraneous organelles (e.g., endoplasmic reticulum)

Cytoplasm is immobile (no endo or exocytosis)

Multiply asexually by binary fission (no mitosis)

Protein synthesis mediated by 70s not 80s ribosomes

Genetic materialàsingle supercoiled circular strand of DNA (nucleoid)

External structures

Capsule and slime layer

Flagella

Pili (fimbriae)

Cell wall periplasmic space and cytoplasmic membrane

Internal structures

Microbial physiology

Metabolism and energy production

Genetics

10. Immunology

11. Biotechnology

12. Principles of PD / Med Chemistry

Effects of drugs

Drug action is the results of interaction between drug molecules and cellular components (receptors) à modulate ongoing cellular processes à alteration of function.

Drug receptor: any macromolecular component

Physiological receptors: receptors for endogenous ligands.  Example: adrenergic receptors for catecholamines.

Agonist: drugs that resemble the effects of endogenous molecules.  Example: bethanechol stimulates cholinergic receptors.

Pharmacologic antagonists: drugs that lack intrinsic activity and produce effects by ↓ action of endogenous molecules at receptors.  Competitive: propranolol competes with catecholamines at beta receptors.  Noncompetitive: MAO irreversible inhibitor tranylcypromine. 

Partial antagonist: inhibits endogenous ligand from binding to the receptor but has some intrinsic activity.  Example: nalorphine on opiate receptors.

Physiological antagonism: drug acts independently at different receptor to produce opposing action.  Example: epinephrine and acetylcholine.

Neutralizing antagonism: two drugs bind to each other to form inactive compound.  Example: digoxin-binding antibody sequesters digoxin.

Mechanisms of drug action

Cell surface receptors: can be proteins, glycoproteins or nucleic acids.  Can be located at the cell surface, cytoplasm, or inside the nucleus.  Receptor binding is very specific.  Interactions: van der Waals, ionic, hydrogen, covalent à influence duration and reversibility of drug action.  Interaction depends on chemical structure of drug and receptor. 

Signal transduction by cell-surface receptors: drug receptor binding triggers signal through second messenger or effector in the cycoplasm.  Example: isoproterenol binds beta receptor (coupled to adenylate cyclase via stimulatory G protein) à↑ cAMP.  Second messengers may cause change in protein synthesis.

Signaling mediated by intracellular receptors: drugs bind to soluble DNA-binding protein cytoplasmic receptors à regulate gene transcription.  Examples: thyroid hormone, steroid hormones, vitamin D, retinoids.

Target cell desensitization / hypersensitization: cellular protective mechanisms exist to maintain homeostasis and prevent overstimulation / understimulation of target cells.  Down regulation: occur due to continuous prolonged drug exposure à ↓ receptor #.  Desensitization: is the result of down regulation.  Effect of subsequent drug exposure is ↓.   Example: chronic albuterol use à down regulation of beta receptors à tolerance.  Heterogenous desensitization: nonspecific desensitization by altering components of the signaling pathway.  Hyperactivity/hypersensitivity: due to long term exposure to antagonists followed by abrupt cessation à new receptor synthesis à upregulation. 

Pharmacologic effects not mediated by receptors: Colligative drug effects lack requirement for specific structures.  Examples: volatile general anesthetics are lipophilic à interact with cell membrane lipid bilayer à ↓ excitability.  Cathartics (mg sulfate, sorbitol) à ↑ osmolarity of intestinal fluids.  Antimetabolites: structural analogs of endogenous compounds à incorporated into cellular components, examples: methotrexate, 5-fluorouracil, cytarabine.  Antacids: such as Al hydroxide, Ca carbonate, Mg hydroxide act by ionic interaction to ↓ gastric acidity

Concentration-effect relationship

↑ dose à ↑ concentration at site of action à ↑ effect à up to a ceiling.

Quantal dose-response curve: # of patients exhibiting a defined response by specific drug dose.  Bell shaped. 

Graded dose-response curve: magnitude of drug effect vs. drug dose.  Efficacy is measured by the maximum effect.  Potency compared different molar doses of different drugs needed to produce the same effect. 

Log dose-response curve: drug effect vs. log dose.  Used to compare efficacy and potency of different drugs with same mechanism of action (same slope).  Efficacy; determined by the height of the curve (Emax).  Potency: compared using ED50 (dose producing 50% of Emax).  Competitive antagonist: parallel shift to the right, same Emax is achieve but at ↑ dose.  Noncompetitive antagonist: nonparallel shift to the right, lower Emax (action cannot overcome if more agonist is present). 

Enhancement of drug effect

Addition: two different drugs with same effect à cumulative effect. Example: trimethoprim and sulfamethoxazole inhibit two different steps in folic acid synthesis à ↓↓ bacterial growth. 

Synergism: two different drug with same effect à effect is ↑ than cumulative sum.  Example: penicillin and gentamicin against pseudomonas.

Potentiation: one drug with no effect alone will ↑ effect of another active drug.  Example: carbidopa (inactive dopa analog) ↓ degradation of levodopa. 

Selectivity of drug action

Therapeutic index: TD50/ED50 (median toxic dose / median effective dose).

Margin of safety: minimum toxic dose for 0.1% of population (TD0.1) / minimum effective dose for 99.9% of population (ED99.9).  More practical

Drug sources and major classes

Natural products

Alkaloids (x-ine): plant-derived nitrogen containing compounds.  Alkaline.  Examples: morphine (opium poppy), atropine (belladonna), colchicine (autumn crocus, neutral). 

Peptides / polypeptides: polymers of amino acids.  From humans or animals.  Smaller than proteins.  No oral activity, short half life.  Example: somatostatin, glucagon. 

Steroids: from humans or animal.  Estradiol, testosterone, hydrocortisone.

Hormones: chemicals formed in one organ and carried in the blood to another.  Mostly steroids or proteins.  Made synthetically, by recombinant DNA (insulin) or from animals (thyroid, conjugated estrogens).

Glycosides: sugar moiety bound to non-sugar (aglycone) moiety by glycosidic bond.  From plant (digitoxin) or microbial (streptomycin, doxorubicin).

Vitamins: Water soluble: B1 (thiamine), B2 (riboflavin), B3 (niacin), B6 (pyridoxine), B12 (cyanocobalamin), C (ascorbic acid), folic acid, pantothenic acid, H (biotic).  Lipid soluble: A (retinol), D (ergocalciferol), E (alpha-tocopherol), K (phytonadione). 

Polysaccharides: polymers of sugar from animals or humans (heparin).

Antibiotics: penicillin, tetracycline, doxorubicin.

Synthetic products

Drugs synthesized from organic compounds. May have chemical structure resembling active natural products (hydroxymorphone à morphine, ampicillin à penicillin). 

Peptidomimetics: molecules with no peptide bonds, molecular weight < 700, activity similar to original peptide (e.g. losartan). 

Drug action and physiochemical properties

Drugs must enter and be transported by body fluids.  Drugs must pass membrane barriers, escape ↑ distribution to site of loss, penetrate to active site, be removed from active site, metabolized to a form easily excreted. 

Drug polarity: relative measure of lipid and water solubility.  Measured in Partition Coefficient: ratio of solubility in organic solvent to solubility in aqueous solvent (log value). 

Water solubility: depends on ionic character and hydrogen ion bonding.  Nitrogen and oxygen containing functional groups à ↑ water solubility.  Required for GI dissolution, parenteral solutions, ophthalmic solutions, good urine concentration.

Lipid solubility: ↑ by nonionizable hydrocarbon chains and ring systems.  Required for penetrating GI lipid barrier, penetrating BBB, IM depot injectables.

Ionization constant (Ka): indicates the relative strength of acids and bases.  Expressed in negative log (pKa). 

Strong acids: HCl, H2SO4, HNO3 (nitric), HClO4 (perchloric), HBr, HIO3 (iodic). 

Strong bases: NaOH, KOH, MgOH2, CaOH2, BaOH2, quaternary ammonium hydroxides. 

Weak acids: organic acids containing carboxylic (-COOH), phenolic (Ar-OH), sulfonic (-SO2H), sulfonamide (-SO2NH-R), imide (-CO-NH-CO-), beta carbonyl (-CO-CHR-CO-) groups. 

Weak bases: organic bases containing amino groups (1ry –NH2, 2ry -NHR, 3ry –NR2) and saturated heterocyclic nitrogen.  Aromatic or unsaturated heterocyclic nitrogen are very weak bases à do not form salts. 

Le Chatelier’s priniciple governs ionization (weak acid at ↓ pH à ↓ ionization à cross lipid membranes). 

Rule of nines: |pH-pKa|=1 à 90:10 (1 nine), |pH-pKa|=2 à 99:1 (2 nines). 

Salts: virtually all salts are strong electrolytes.  Inorganic salts: made by combining drugs with inorganic acids or bases (HCl, NaOH).  Salt form has ↑ water solubility à ↑ dissolution. Organic salts: made by combining acidic and basic organic molecules à ↑ lipid solubility à depot injections (e.g. penicillin procaine).   Amphoteric salts: contain acidic and basic functional groups à form internal salts or zwitterions à solubility problems. 

Neutralization reaction: e.g., occur when an acidic solution of an organic salt is mixed with a basic solution.  The nonionized organic acid or base will ppt à IV drug incompatibility. 

Drugs whose cation ends with –onium or –inium and anoic is Cl, Br, I, nitrate, sulfate (e.g. benzalkonium chloride, cetylpyridinium chloride) are quaternary ammonium salts à neural solution in water.

Structure and pharmacologic activity

Drug structure specificity

Structurally non-specific drugs: drug interaction with cell membrane depends more on the drug’s physical properties than on its chemical structure.  Interaction usually depends on cell membrane’s lipid nature and drug’s lipid attraction.  Examples: general anesthetics, some hypnotics, some bactericidal agents.

Structurally specific drugs: pharmacologic activity depends on drug binding to specific endogenous receptors.

Drug receptor binding

Receptor site theories: Lock-key theory: over-simplification that assumes a complete complementary relationship between drug and receptor. Induced fit theory: also assumes a complete complementary relationship between drug and receptor but provides for mutual conformational changes between drug and receptor, it can explain phenomenon of allosteric inhibition. Occupational theory of response: further postulates that intensity of pharmacologic response is proportional to number of occupied receptors.

Receptor site binding: ability of a drug to bind to specific receptor is mostly determined by its chemical structure not physical properties. Chemical reactivity influences its bonding ability and exactness of fit to the receptor.  Drug interaction is similar to fitting a jigsaw puzzle pieces, only drugs of similar shape and chemical structure can bind and producer response.  Usually only a portion of the drug molecule is involved in receptor binding.  Pharmacophore: functional group that is critical for receptor interaction.  Drugs with similar pharmacophores may have similar qualitative but not quantitative activity.  Agonist: good receptor fit à ↑ affinity à ↑ response.  Antagonist: drug with some binding but no pharmacophore à no response but it blocks other drugs from binding.

Stereochemistry

Types of stereoisomers: optical, geometric, conformational.

Optical isomers: contains at least one chiral (asymmetric) carbon (four different substitutes). 

Enantiomers: optical isomers that are mirror image of each other, identical physical and chemical properties, potentially different potency, receptor fit, activity, metabolism, etc.  One enantiomer rotate the plane of polarized light clockwise (dextro, D, +), the other counter clockwise (Leve, L, -).  Example: dextrorphanol à narcotic analgesic and antitussive, levorphanl à only antitussive. Racemic mixture: equal mixgture of D and L enantiomers, optically inactive.

Diastereomers: stereoisomers which are neither mirror image, nor superimposable.  Drug must have a minimum of 2 chiral centers. Different physicochemical properties (solubility, volatility, melting point).

Epimers: special type of diastereomers, compounds are identical in all aspects except stereochemistry around one chiral center. Epimerization is important for drug degradation and inactivation.

Geometric (cis-trans) isomers: occurs due to restricted rotation around a chemical bond (double bond, rigid ring system).  Cis-trans are not mirror images, have different physicochemical and pharmacologic properties, because functional groups can be separated by different distances à not equal fit to receptors.  If functional groups are pharmacophores à different biologic activity.  Example: cis-diethylstilbestrol has 7% estrogenic activity of trans-diethylstilbestrol. 

Conformational isomers (rotamers, conformers): non-superimposable molecule orientations due to atoms rotation around single bonds.  Common for most drugs, allows drugs to bind to multiple receptors.  Example: Ach 2-forms: transàmuscarinic, gauche à nicotinic

Bioisosteres: molecules containing groups that are spatially and electronically equivalent, same physicochemical properties.  Isosteric replacement of functional groups à alter metabolism à ∆ potency, SE, activity, duration of action (e.g. procainamide, an amide, has longer duration of action than procaine, an ester).  Isosteric analogs: may act as antagonists (e.g. alloxanthine is a xanthine oxidase inhibitor, compared to its isostere, xanthine, the enzyme substrate).

Mechanisms of drug action

Interaction with receptors

Agonists: have both affinity and intrinsic activity with the receptor.

Partial agonists: interact with same receptors but with similar affinity but lower intrinsic activity à ↓ response.

Pharmacologic antagonists: bind to the same receptor as the agonist but with no intrinsic activity.  Can be reversible, irreversible, competitive, noncompetitive (like enzyme inhibitors).

Chemical antagonists: two compounds react à inactivation of both.  Example: heparin (acidic polysaccharide) with protamine (basic protein), chelating agents as metal poisoning antidotes (EDTA for calcium / lead, penicillamine for copper, dimercaprol for mercury / gold / arsenic).

Functional / physical antagonists: produce antagonistic physiologic actions by binding at separate receptors.  Example: acetylcholine, NEp. 

Interaction with enzymes

Activation

Due to ↑ enzyme protein synthesis.

Examples: barbiturates, antiepileptics (phenytoin), rifampin, antihistamines, griseofulvin, oral contraceptives.

Mechanism: by allosteric binding or coezymes such as vitamins (esp vitamin B complex), cofactors (Na, , Mg, Ca, Zn, Fe). 

Inhibition

Due to interaction with the apoenzyme, coenzyme or enzyme.

Reversible inhibition: results from non-covalent interaction. Equilibrium exists between bound and free drug.

Irreversible inhibition: results from covalent stable interaction. 

Competitive inhibition: occurs when there is a mutually exclusive binding of the substrate and inhibitor.

Noncompetitive inhibition: occurs when the drug binds to an allosteric site on the enzyme. 

Interaction with DNA/RNA

Inhibition of nucleotide biosynthesis: caused by folate, purine, pyrimidine antimetabolites. Folic acid analogs: e.g. methotrexate, trimetrexate, ↓ dihydrofolate reductase à ↓ purine, thymidylate.  Purine analogs: e.g. 6-mercaptopurine, thioguanine, act as antagonists in the purine bases synthesis.  Pyrimidine analog: e.g. 5-fluorouracil, ↓ thymidine synthase.

Inhibition of RNA/DNA biosynthesis: due to interference with nucleic acid synthesis.  Use mainly as antineoplastic agents (Cancer chapter).

Inhibition of protein synthesis

Tetracyclines: ↓ tRNA binding to ribosomes and block release of completed peptides from ribosomes.

Erythromycin, chloramphenicol: bind to ribosomes, ↓ peptidyl transferase, ↓ formation of peptide bond, ↓ peptide chain formation

Aminoglycosides: binding to ribosomes à formation of abnormal protein, ↓ addition of AAs to peptide chain, misreading of mRNA tempelate à incorporation of incorrect AAs in peptide chain.

Interaction with cell membranes

Digitalis glycosides: ↓ cell membrane Na-K pump à ↓ K influx, ↓ Na outflow.

Quinidine: prolong polarized and depolarized states of membrane potential in myocardial membranes.

Local anesthetics: interfere with membrane permeability to Na-K à block impulse conduction in nerve cell membranes.

Polyene antifungals: e.g. nystatin, amphotericin B, alter membrane permeability.

Antibiotics: e.g. polymyxin B, colistin, alter membrane permeability

Acetylcholine: ↑ membrane permeability to cations.

Proton pump inhibitors: ↓ H+/K+ pump in parietal cell membranes à ↓ efflux of protons to the stomach.

Nonspecific action

Form monomolecular layer over entire areas of cells.  Large dose is given.  Examples: volatile general anesthetic gases (ether, nitrous oxide), some depressants (ethanol, chloral hydrate), antiseptics (phenol, rubbing alcohol).

13. Autonomic and Central Nervous Systems

Receptor summary tables

Inhibitory receptors	Excitatory receptors
Types: M2, Alpha-2, D2, GABA, Opioid (mu, delta, kappa) Action: ↓ cAMP, ↑ K conductance, ↓ Ca conductance, ↑ Cl conductance (GABA)	Types: M1, Nicotinic, Alpha1, Beta-1, D1, Glutamate, H1-2. Action: ↑ cAMP, ↓ K conductance, ↑ Ca (cation) conductance, ↑ IP3/DAG

Mechanism	Adrenergic	Cholinergic
Ganglion blocker	Hexamethonium, mecamylamine
↓ neurotransmitter synthesis	Bretylium, guanethidine	Botulinum toxin
↓ neurotransmitter release	Amphetamine, tyramine
↑ neurotransmitter release	Reserpine
↓ neurotransmitter storage	Cocaine, desipramine	Not a major mechanism
↓ neurotransmitter metabolism	Pargyline (MAOAI), selegiline (MAOBI), tolcapone (COMTI)	Neostigmine, physostigmine

Organ / tissue	Receptor	Action
Heart	B1	↑ conduction velocity, ↑ contraction rate /force
	M	↓ conduction velocity, ↓ contraction rate /force
Arterioles	Alpha-1	Constricts cerebra, cutaneous, visceral arterioles
	Beta-2	Dilates skeletal muscle arterioles
Eye	Alpha-1	Iris contracts à mydriasis
	M	Sphincter / ciliary contraction à miosis
Lung	Beta-2	Relaxes bronchial / tracheal muscles
	M	Contraction, ↑ secretions
Urinary bladder	Alpha-1	Contracts sphincter muscles
	M	Relax sphincters, contracts smooth muscles.
Intestine	Alpha-beta	↓ peristalsis
	Apha-1	Contracts sphincter
	M	↑ motility (perisalsis), relax sphincters, ↑ secretions
Uterus	Alpha-1	Contraction
	Beta-2	Relaxation
Fat (adipose) tissue	Beta-3	Adipolysis, mobilize fatty acids
Glands	M	↑ secretions (eye, sweat, saliva, nasal)

Adrenergic agonists

Direct-acting agonists: Examples: Ep, NEp, terbutaline, dobutamine, naphazoline. Alpha agonist: phenhylephrine.  Beta agonist: isoproterenol

Catecholamine (Ep, NEp) synthesis: Tyrosinse à tyrosine hydroxylase à DOPA à dopa decaroxylase à dopamine à dopamine hydroxylase à NEp à Ep.

Catecholamine deactivation: methylation by catechol O-methyltransferase (COMT) and oxidative deamination by monoamine oxidase (MAO).

Indirect acting agonists (sympathomimetics): Chemically related to catecholamines.  Act by ↑ neurotransmitter release.  Examples: amphetamine, tyramine, ephedrine.

Post-junctional alpha-1: Location:  iris, arteries, veins, hair follicle muscles, heart, GI sphincters. Agonist effect: vasoconstriction, smooth muscle contraction.  Examples: phenylephrine.

Pre-junctional alpha-2: Effect:  ↓ neurotransmitter release, lipolysis, platelet aggregation.  Examples: clonidine, methylnorepinephrine.

Beta-1: Location: heart. Effect: ↑ force / rate of contraction. Examples: dobutamine.  

Beta-2: Location: bronchial / vascular smooth muscles.  Effect: smooth muscle dilatation / relaxation. Examples: albuterol, terbutaline.

Beta-3: Location: fat cells. Effect: lipolysis (for obesity).

Epinephrine: medullary hormone, stimulate all receptors (alpha1-2, beta1-2). Use: treat bronchospasm, hypersensitivity / anaphylactic reactions, ↑ duration effect of local anesthetics (SC), restore cardiac activity in cardiac arrest, glaucoma (topically, vasoconstriction à ↓ aqueous humor production).

Norepinephrine: adrenergic neurotransmitter, stimulate alpha1-2, beta-1 (weak beta-2).

Phenylephrine: alpha-1 agonist.  Use: pressor in hypotensive emergency, ↑ duration effect of local anesthetics, nasal decongestion

Alpha-1 agonists for nasal decongestion: phenylephrine, oxymetazoline, xylometazoline, phenylpropanolamine

Alpha-2 agonists (clonidine, methyldopa, guanfacine, guanabenz): for ↑ BP.  Clonidine is used to ↓ intraocular pressure during surgery.

Isoproterenol: beta1-2 agonist, bronchodilator, cardiac stimulant in cardiac shock / arrest.

Dobutamine: beta-1 agonist, improve heart function in CHF emergency.

Beta-2 agonists (albuterol, terbutaline, metaproterenol): systemic or local bronchodilators for asthma.

General SE: arrhythmias, pulmonary hypertension, edema, cerebral hemorrhage, rebound nasal congestion, anxiety.

Adrenergic antagonists

Alpha blockers: include ergotamine, prazosin (alpha-1), phenoxybenzamine (nonselecive, irreversible), tolazoline.

Beta blockers: similar structure to beta agonists.  Examples: metoprolol (beta-1), propranolol (nonselective).

Prazosin (x-azosin): vasodilation à for hypertension and BPH symptoms.  SE: first dose syncope, de BP, dizziness, drowsiness, palpitation, fluid retention, priapism (continuous penis erection).

Phenoxybenzamine / phentolamine: nonselective alpha blockers, treat vasospasm, acute hypertensive emergency (e.g. pheochromocytoma, MAOI, sympathomimetics). SE: ↓ BP, tachycardia, ↓ ejaculation, miosis, nasal congesion.  Tolazoline: for neonatal pulmonary hypertension.

Labetolol: alpha-1 and beta1-2 blocker, for hypertension.

Propranolol: nonselective beta blocker, for prophylaxis of angina pectoris, ventricular arrhythmias, migraine, for hypertension, ↓ heart rate in anxiety and hyperthyroidism.  SE: bradycardia, CHF, bronchoconstriction, ↑ triglycerides, ↓ HDL, depression.  Sudden d/c is cadiotoxic. 

B1 blockers (acetbutolol, metoprolol, atenolol): for hypetension, arrhythmia, angina.

For glaucoma: eye drops of timolol (B1-2 blocker) and betaxolol (B1 blocker).

Cholinegic agonists

Nicotinic receptors: Location: at postganglionic neuroeffector sites.

Muscarinic receptors: Location: at all autonomic ganglia and at the neuromuscular junction of somatic nervous system.

Acetylcholine: endogenous neurotransmitter, very short half life (v. rapid hydrolysis by AChE), ester of acetic acid and choline, very potent.

Direct acting agonists: structurally similar to acetylcholine but more resistant to AChE à longer duration. Examples: methacholine, bethanecol. Use: non-obstructive urinary retention (bethanechol), glaucoma (pilocarpine, miosis).

Indirect acting agonists: most are AChE inhibitors.  Reversible inhibitors: most are carbamates (carbamic acid esters), e.g. physostigmine, neostigmine, pyridostigmine. Irreversible inhibitors: organophosphate esters, insecticides, nerve gas, e.g. isoflurophate, echothiophate. Use: glaucoma (miosis), myasthenia gravis, hypercholinergic crisis (neuromuscular junction depolarization blockade), anticholinergic toxicity.

General SE: bronchospasm, abdominal cramps, ↓ BP, syncope, ↓ heart rate, salivation, sweating, lacrimation, miosis, flushing, tremors, diarrhea.

Cholinegic antagonists

Quaternary nitrogen: doesn’t pass BBB, e.g. ipratropium, glycopyrrolate, propantheline.

Tertiary nitrogen: pass BBB, e.g. benztropine, dicyclomine, pirenzepine, tropicamide.

Uses: ↓ gland / bronchial secretion before anesthesia (atropine, glycopyrrolate), induce sedation / ↓ motion sickness (scopolamine), ↓ vagal stimulation of the heart (atropine), produce mydriasis / cycloplegia (homatropine), ↓ GI spasms (propantheline), asthma (ipratropium), Parkinson’s / extrapyramidal disorders (benztropine, trihexyphenidyl), cholinergic toxicity (atropine).

Ganglionic blockers: e.g. mecamylamine, trimethaphan, for hypertensive crisis.

SE: mydriasis, ↑ intraocular pressure, blurred vision, dry mouth, constipation, urinary retention, fever, nervousness, drowsiness, dizziness, tachycardia.

Neuromuscular blockers

Nondepolarizing (competitive) drugs

Examples (x-curine, x-curonium, x-curium): curare alkaloids (tubocurarine, metocurine, contain a tertiary amine), and synthetic analogs (atracurium, doxacurium, mivacurium, pancuronium, vecuronium, pipercuronium). 

Mechanism: compete with ACh for nicotinic receptors at the NMJ à ↓ end-palate potential à depolarization potential not reached. Action is overcome by ↑ dose cholinesterase inhibitor.

Uses:

SE: respiratory paralysis, histamine release, bronchospasm, tachycardia

Depolarizing (noncompetitive) drugs

Examples: succinyl choline (pseudo-cholinesterase metabolism à short action), galantamine. Contain quaternary nitrogen.

Mechanism: desensitize nicotinic receptors at NMJ.  React with nicotinic receptors à long (2 min) depolarization of excitable membrane à ↓ receptor sensitivity à unresponsive.  Similar effect to excess ACh.

Uses:

SE: respiratory paralysis, painful muscle fasciculation, Muscarinic response (bradycardia, ↑ secretion, cardiac arrest).

General anesthetics

Effect: depress CNS and induce reversible state of analgesia, amnesia, unconsciousness, ↓ sensory / autonomic reflexes, skeletal muscle relaxation, loss of all sensation.

Ideal drug: rapid smooth induction and rapid recovery.

General SE: respiratory / CNS / CV depression.  Halothane à ↑ sensitivity to catecholamines.

Volatile (inhalation) anesthetics:

Examples: simple lipophilic molecules, nitrous oxide (N2O, inorganic), halothane (halogenated HC), ethers (x-flurane, methoxyflurane, isoflurane, desflurane, sevoflurane).

Mechanism: absorbed and excreted through the lungs.  May be supplemented with analgesics (↓ anesthetic dose), skeletal muscle relaxants, antimuscarinics (↓ bronichial secretions during surgery).

Halothane à ↑ heart sensitivity to catecholamines, arrhythmia.

Nonvolatile (IV) anesthetics

Water soluble: Ultra-short acting barbiturates (thiopental), ketamine, BZD (diazepam, midazolam), morphine, fentanyl, droperidol. 

Imidazole: propylene glycol solution.  Propofol: emulsion.

Use: induce drowsiness and relaxation before inhalational general anesthesia.

Local anesthetics

Most are structurally similar to cocaine.

Ester drugs: rapid hydrolysis by plasma esterases à short action. Examples: cocaine, procaine, chloroprocaine, benzocaine, tetracaine.

Amide drugs: longer acting, liver metabolism. Examples: lidocaine, dibucaine, mepivacaine, bupivacaine, etidoacione, prilocaine. (VELD)

Mechanism: block Na channels in nerve membrane à reversible block of nerve impulse conduction, reversible loss of sensation, no loss of consciousness. At tissue pH à lipophilic, uncharged, 2ry or 3ry amine form à diffuse through connective tissue and cell membrane à enter nerve cells à convert to ionized charged ammonium cation active form à block generation of action potential à remain trapped in cell (ionized à can’t cross cell membrane).

Epinephrine: mix with local anesthetic à vasoconstriction à ↓ blood flow à ↓ systemic absorption à longer local effect, no systemic toxicity.

Use: regional nerve block for pain relief, anesthesia for minor operations, topical anesthesia (dyclonine and pramoxine as throat lozenges and hemorrhoids cream), anesthesia for lower limb / pelvic / obstetric surgery when injected in the epidural.

SE: systemic absorption à seizures, CNS / respiratory / myocardial depression.

Antipsychotics

Typical (classical) drugs: phenothiazines, thioxanthines (x-othixene, thiothixene, chlorprothixene), butyrophenones (haloperidol).

Atypical (newer) drugs: clozapine, risperidone, pimozide, loxapine, molindone, quetapione, sertindole, remoxipride.  Advantages: more effective for negative symptoms, ↓ extrapyramidal SE.

Phenothiazines (x-omazine, x-perazine): chlorpromazine, triflupromazine, prochlorperazine, trifluoperazine, fluphenazine, thioridazine.  Fluphenazine esters (decanoate, enanthate) à very lipophilic à very long acting.

Mechanism: block dopamine receptors in the brain (extrapyramidal SE).  Other possible effects: H1, alpha1, muscarinic.  Atypical drugs: also serotonin antagonism.

SE: Central: drowsiness, extrapyramidal (akathesia, dystonia, akinesia, tardive dyskinesia), poikilothermy, ↑ appetite, weight gain, ↑ release of hormones.  Peripheral: postural hypotension, reflex tachycardia, impaired ejaculation, dry mouth, blurred vision, liver toxicity.

Antidepresseants / antimanics

MAO-I: phenelzine, isocarboxazid (↓ potent), tanylcypromine (↑ potent). Mechanism: block oxidative deamination of brain biogenic amines (NEp, serotonin). Effect takes 3 weeks. Use: depression, phobic anxiety, narcolepsy, ↑ SE à ↓ use. SE: CNS (stimulation, tremor, agitation, mania, insomnia), ↓ BP, anticholinergic SE (constipation, dry mouth, urinary retention).  DI: tyramine foods, sympathomimetic drugs (hypertensive crises),

TCA: secondary or tertiary amines, x-ipramine, x-triptyline, x-pin (doxepin, amoxapine, dibenzoxazepine). Mechanism: ↓ CNS re-reuptake of biogenic amines (Nep, serotonin).  Also block beta, serotonin receptors, ↓ reuptake.  Use: depression, enuresis (bedwetting), obsessive-compulsion, anxiety.  SE: CNS (drowsiness, confusion), ↓ BP, tachycardia, anticholinergic SE, bone marrow depression, mania.

Atypical antidepressants: bupropion, trazadone, mefazadone, SSRI, venlafaxine. Mechanism: ↓ CNS re-reuptake of biogenic amines. SE: similar to TCA + blurred vision, tinnitus, sex dysfunction.

Antimanics (mood stabilizers): lithium carbonate, valproic acid, carbamazepine. Mechanism: lithium ∆ transmembrane Na exchange, ∆ neurotransmitter release, ↓ inositol metabolism. Use: manic depression / bipolar disease. SE: lithium causes ↑ urination, fine hand tremor (↓ with time).

Anxiolytics / sedative-hypnotics

Examples: BZD (diazepam, alprozlam, flurazepam, halazepam, oxazepam, prazepam, lorazepam, chlordiazepoxide, clorazepate), buspirone, zolpidem.

Old drugs: barbiturates, hydroxyzine à no longer used due to ↑ risk of tolerance, dependence, withdrawal reactions, and ↑ SE (↑ CNS depression).

Diazepam: not basic enough to form water soluble salt with acid à dissolve in propylene glycol for IV, may ppt if mixed with water.

Barbiturates: derivatives of barbituric acid. Long / branched / unsaturated side chain à ↑ lipid solubility à ↑ metabolism, ↓ onset, ↓ duration of action, ↑ potency. Phenobarbital (barbiturates) à strong enzyme inducer. Weak acids, in overdose à alkalinize the urine à ↑ excretion.

BZD: Mechanism: GABA-ergic, ↑ chloride channel opening à ↑ chloride conduction à ↑ membrane hyperpolarization. Also CNS depression (hypnotic, anesthetic, anticonvulsant, muscle relaxant, ↑ alcohol depression). Use: anxiety, insomnia, pre-anesthesia, during acute alcohol withdrawal. SE: CNS depression, ataxia, confusion, abuse / dependence.

Buspirone (x-pirone): Mechanism: bind to central dopamine, serotonin receptors. No CNS depression (hypnosis, anti-convulsion, alcohol interaction, no abuse, no rebound anxiety). Use: anxiolytic (effect takes a week). SE: headache, dizziness.

Zolpidem (Ambien): Mechanism: strong sedation but ↓ anxiolytic effect (for insomnia). Use: insomnia.  No abuse, rebound insomnia, or respiratory depression.

Barbiturate: Mechanism: similar to BZD. Use: Ultra-short acting barbiturates (thiopental): induce anesthesia.  Long acting barbiturates (phenobarb): antiepileptics. SE: hypnosis, drowsiness, nystagmus, bradycardia, ↓ BP, anemia, liver toxicity, respiratory depression.  DI: enzyme induction

Chloral hydrate: aldehyde prodrug. Use: induce sleep, pre-anesthesia.  SE: toxic active cumulative metabolite, CNS depression, ↑ alcohol effect, leukopenia. DI: enzyme induction

Antiepileptics

Older agents: long-acting barbiturates (phenobarb, mephobarb, metharbital, primidone), phenytoin (hydantoin), succinimides (ethosuximide, phensuximide), valproic acid, trimethadione, dimethadione.

Newer agents: carbamazepine, BZD (diazepam, clonazepam, clorazepate), gabapentin (GABA analog), lamotrigine, felbamate.

Pharmacology: ↓ or prevent excessive discharge and ↓ spread of excitation from CNS seizure center.

Phenytoin: ↑ Na efflux

Barbiturates, BZD, valproic acid: ↑ GABA-ergic inhibitory neuronal function.

Tonic-clonic (grand mal) à carbamazepine, pheytoin, phenobarb.

Uses:

Status epilepticus à diazepam, phenytoin, phenobarb

Absence (petit mal) à clonazepam, phenobarb, valpric acid

Myoclonic à clonazepam

Partial à gabapentin, lamotrigine, flebamate

Pscyhomotor à carbamazepine, phenytoin, phenobarb

General SE: CNS (drowsiness, confusion, diplobia, nystagmus), blood toxicity, allergy, Stevens-Johnson, birth defects (no safe drugs here).

Phenytoin: gingival hyperplasia, arrhythmias.

IV barbiturates / BZD SE: CV collapse, respiratory depression

14. Autacoids

Autacoids are local autopharmacological agents or local hormones.  May also function as neurotransmitters (e.g. histamine, serotonin).  Also include leukotrienes (discussed later).

Histamine

Chemistry: bioamine derived from dietary histidine.  H1-antagonists: diphenhydramine, dimenhydrinate, doxylamine, clemastine, meclizine, cyclizine, hydroxyzine, cyproheptadine, promethazine, chlorpheniramine, brompheniramine, tripelennamine, pyrilamine.   New H1 antagonists (loratadine, desloratadine, fexofenadine, cetirizine, astemazole, acrivastine) are less sedating due to their inability to cross BBB.  H2-antagonists: ranitidine, cimetidine, famotidine, nizatidine. 

Pharmacology: H1-receptors: allergic and anaphylactic responses (bronchoconstriction, vasodilation, spasmodic GI smooth muscle contraction, ↑ capillary permeability, itching, pain).  H2-receptors: ↑ secretion of gastric acid, pepsin, intrinsic factor. 

Indications: exogenous histamine may be used for diagnosing gastric acid function (not very safe).  H1-blockers: ↓ allergy symptoms (seasonal rhinitis, conjunctivitis), common cold (rhinovirus) infection, urticaria. Agents with ↑ anticholinergic effect (meclizine, cyclizine, dimenhydrinate, diphenhydramine): motion sickness and vertigo nausea and vomiting.  Promethazine: antiemetic.  Hydoxyzine: mild anxiolytic.  H2-blockers: gastric hypersecrtion (ulcers, Zollinger-Ellison, GERD). 

SE: H1-blockers: CNS (sedation, depression, fatigue, except in new agents), GI upset, anticholinergic (dry mouth, constipation).  Non-sedating H1-blockers: arrhythmia, especially with hepatic enzyme inhibitors, grapefruit.  H2-blockers: CNS (dizziness, confusion), liver / kidney damage, liver enzyme inhibition (cimetidine), androgenic effects (cimetidine). 

Serotonin

Chemistry: serotonin is 5-HT (5-hydroxytryptamine).  Bioamine synthesized from tryptophan.  Serotonin agonists (triptans): idole derivatives of serotonin.  Also cisapride, benzamide, ergot alkaloids (ergonovine, dihydroergotamine, bromocriptine, methylsergide, partial agonists / antagonists).  Serotonin antagonists: ondasetron, granisetron. 

Pharmacology: Serotonin: vasoconstriction, platelet aggregation, nausea / vomiting, anxiety, depression, appetite, ↑ acetylcholine release. Serotonin agonists: Cisapride: releases Ach (treat GERD, off market).  Serotonin antagonists: prevents nausea / vomiting.

Indications: Agonists: drugs use the serotonin system to affect the CNS and modulate behavior (dexfenfluramine as anorexiant, buspirone as anxiolytic, SSRI for depression).  Triptans and ergots are used for migraines.  Ergots are used to postpartum hemorrhage (vasoconstriction uterine contraction).  Bromocriptine is used to prevent post partum breast enlargement.  Antagonists: prevents nausea and vomiting due to cancer chemotherapy.

SE: Agonists: dizziness, tight chest, coronary vasoconstriction (CI in angina, ↑BP). Cisapride: arrhythmia, diarrhea. Ergots: cold / ischemic extremities, GI upset. Antagonists: headache, dizziness, constipation.

Prostaglandins

Chemistry: derivatives of prostanoic acid (ringed structure).  Membrance phospholipids à phospholipase A2 à arachidonic acid à COX enzyme à PG.  COX I: protects gastric mucosa (PG), homeostasis (thromboxane synthesis).  COX II: expressed only in response to inflammation or injury.  PG classification subscripts relates to the number and position of double bonds in the aliphatic chains. 

Pharmacology: Endogenous: release in response to insults (chemical, bacterial, mechanical).  Cause pain and edema.  Physiologic responses: PGI: vasodilation, ↓ platelet aggregation, ↑ gastric release of bicarbonate and mucus (protect epithelium).  PGE: ↓ platelet aggregation, ↓ gastric acid secretion, broncho-relaxation.  PGD/PGF: bronchoconstriction. 

Indications: PGE1 analogs: misoprostol to prevent NSAID induced GI ulcers, alprostadil for impotence due to erectile dysfunction.  PGE2 analogs: dinoprostone is abortifacient, for cervical ripening in pregnancy. PGF2alpha analogs: latanoprost topically to ↓ intraocular pressure in glaucoma, carboprost is abortifacient (not available in US). PGI analog: epoprostenol treats pulmonary hypertension.

SE for PGE: CNS (irritability, fever, seizures, headache), cardiovascular (hypotention, arrhythmia, flushing), respiratory depression, hematologic (anemia, thrombocytopenia), diarrhea, abortion. 

16. Endocrinology

Pituitary hormones

Posterior pituitary hormones

Oxytocin: octapeptide. Action: stimulate uterine contraction, induce labor.  Use: promote delivery, control postpartum bleeding. SE: uterine spasm / rupture, fetal effects (bradycardia, jaundice), water intoxication / coma.

Vasopressin: octapeptide. Action: vasopressor and anti-diuretic. hormone (ADH) activity.  It ↑ reabsorption of water at distal renal tubules.  Use: neurogenic diabetes insipidus, postoperative abdominal distention. SE: GI cramps, vomiting, tremor, sweating, bronchoconstriction.

Anterior pituitary hormones

Protein molecules: available therapeutically, include: corticotropin, thyrotropin, thyrotropin-releasing hormone, growth hormone

Corticotropin: also known as Adrenocorticotropic hormone (ACTH).  Single chain 39-AA polypeptide. Action: stimulate adrenal cortex to secrete adrenocorticosteroids. Use: diagnosis of adrenal insufficiency.

Growth Hormone: also known as Somatotropin, 191-AA chain. Action: stimulate protein, carbohydrate and lipid metabolism to ↑ cell, tissue, organ growth. Use: for children with growth failure due to ↓ endogenous growth hormone secretion. SE: antibody formation.

Thyrotropin: also known as Thyroid Stimulating Hormone (TSH). It’s a glycoprotein.

Thyrotropin-Releasing Hormone: tripeptide.

Pituitary gonadotropins: not available therapeutically, include: Follicle-Stimulating Hormone (FSH), Luetinizing Hormone (LH), Prolactin (Luteotropic Hormone, LH), menotropin (human Menopausal gonadotropin, hMG).

Menotropin: produce ovarian follicular growth and induce ovulation by FSH and LH-like actions. Use: induce ovulation and pregnancy in anovulatory infertile women, ↑ spermatogenesis in men. SE: gynecomastia in men, hypersensitivity, thromboembolism, ovary enlargement.

Gonadal hormones

Estrogen

Estrogen receptors: in the nucleus in the vagina, uterus, mammary glands, anterior pituitary, hypothalamus à alter mRNA. 

Uses: oral contraceptives (with progestins), menopause symptoms, acne, osteoporosis, prostate cancer.

SE: edema / fluid retention, weight gain, ↑ triglycerides, hypertension, thromboembolism, MI, stroke, GI upset, endometrial cancer.

Estradiol: principal estrogenic hormone, in equilibrium with estrone.  Estradiol esters are used as IM injections in oil for depot action (valerate, cypionate).  The esters hydrolyze slowly in muscle tissue before absorption (prodrugs). 

Synthetic estrogens: resist first pass metabolism à ↑ oral efficacy.  Examples: ethinyl estradiol, 3-methyl ether mestranol (contraceptives), quinestrol (ERT).

Non-steroidal synthetic estrogens: e.g. diethylstilbestrol.

Estrogen antagonists: e.g. clomiphene, tamoxifen citrate, toremifene citrate.  Uses: clomiphene à induce ovulation, tamoxifen à breast cancer.

Aromatase inhibitors: anastrozole, letrozole (non-steroidal) à ↓ conversion of androgens to estrogens. Use: advanced breast cancer.

Selective estrogen receptor modulators (SERM): raloxifene à ↓ bone resorption, ↓ bone turnover. Estrogen effect on bone and lipids but estrogen antagonist effect on uterus and breast. Use: prevention of osteoporosis.

Progestins

Progesterone: C-21 natural steroidal progestin.

Synthetic progestins: 17alpha-hydroxyprogesterones, 17alpha-ethinylandrogens. ↑ lipid solubility, ↓ first pass metabolism, ↑ oral effect

Mechanism: similar to estrogens (intracellular receptors à ∆ mRNA).

Uses: oral contraceptives (alone or with estrogens), uterine bleeding, dysmenorrhea, endometriosis.

SE: irregular period, breakthrough bleading, amenorrhea, weight gain, edema.

17alpha-hydroxyprogesterones: e.g. medroxyprogesterone acetate, megestrol acetate

17alpha-ethinylandrogens: e.g. norethindrone, norgestrel, androgens with progesterone activity.  Used as oral contraceptives.

Androgens / anabolic steroids

Testosterone: C-19 steroid natural androgen / anabolic agent.

Androgens: testosterone 17-enanthate (ester with long IM action), fluoxymesterone (oral).

Anabolics: oxandrolone, dromostanolone.

Mechanism: testosterone à 5alpha-reductase (in cytoplasm) à dihydrotestosterone à bind to androgen receptor in nucleus à ∆ mRNA

Uses: androgen replacement, breast cancer, endometriosis, female hypopituitarism (with estrogens), treating –ve nitrogen balance, anemia.

SE: fluid retention, ↑ LDL, ↓ HDL, female masculinity, ↓ female fertility.

Anti-androgens: flutamide, bicalutamide, nilutamide (all non-steroids) à competitive androgen inhibition by receptor binding. Use: prostate cancer (with luteinizing hormone releasing hormone).

5alpha-reducatse inhibitors: finasteride à ↓ conversion of testosterone to dihydrotestosterone.  Use: BPH, androgenic alopecia.

Adrenocorticosteroids

Synthesis: in the adrenal cortex.

All steroids have fused reduced 17-carbon-atom ring.

Most natural steroids have some mineralo- and gluco- effect.

All require cytoplasmic receptors to transfer to the nuclei of target tissue cells.

Uses: replacement therapy (adrenal insufficiency), last resort for severe disabling arthritis, severe allergic reactions, ulcerative colitis, kidney disease, cerebral edema, topical anti-inflammatory.

SE: peptic ulcer, GI bleeding, ↑ intraocular / intracranial pressure, headache, muscle weakness, skin atrophy, edema, weight gain, excitation, irritability, hypertension, hyperglycemia, osteoporosis, flushing, hirsutism, cushingoid moon face / buffalo hump, ↓ immunity, ↑ infections.

Mineralocorticoids: ↑ Na retention, ↑ K excretion.

Glucocorticoids: anti-inflammatory, protein-catabolic, immunosuppressant.

Cortisone / hydrocortisone: natural glucocorticoids. Synthetic and semi-synthetic glucocorticoids try to ↓ mineralocorticoid activity.  Examples: prednisone, prednisolone, triamcinolone, betamethasone, dexamethasone.

Aldosterone: natural mineralocoritoid.  Synthetics: fludrocortisone acetate, desoxycoriticosterone acetate.

Antianemic agents

Iron

Iron preparations: ferrous salts are better absorbed from GI than ferric salts.  Examples: ferrous sulfate, ferrous gluconate, ferrous fumarate. Iron dextran (IV) = colloidal complex of ferric hydroxide and low molecular weight dextrans.

Iron (ferrous salts): easy GI absorption à stored in bone marrow, liver, spleen as ferritin and hemosiderin à incorporate into hemoglobin à iron reversibly binds molecular oxygen. 

Iron (ferrous salts): iron deficiency anemia (hypochromic, microcytic RBCs à poor oxygen transport).

Cyanbocobalamin (Vit B12): nucleotide-like macro-molecule.  Includes cyanide and cobalt.

Iron (ferrous salts): GI distress, constipation, diarrhea, heartburn

Vitamin B12 (cyanocobalamin)

Vit B12: easy GI absorption in the presence of intrinsic (Castle’s) factor (glycoprotein produced by gastric parietal cells).  Deficiency causes megaloblastic anemia and demyelination of nerve cells à irreversible CNS damage.  Important for cell growth.

Vit B12: megaloblastic anemia due to vit B12 deficiency (hyperchromic, macrocytic, immature RBCs).

Vit B12: no common SE

Folic acid

Folic acid: structure includes PABA, glutamic acid.

Folic acid: easy GI absorption, stored intracellularly.  Precursor for several coenzymes (derivatives of tetrahydrofolic acid).  Deficiency causes megaloblastic anemia but not neurologic damage.

Folic acid: megaloblastic anemia due to folic acid deficiency.

Folic acid: rare allergy if taken parenterally.

Thyroid hormones / inhibitors (52)

Synthesis of thyroid hormones

Concentration of iodide in thyroid gland à iodination of tyrosine residues on thyrogobulin (glycoprotein) à proteolysis of thyroglobulin into T4 (thyroxine, levothyroxine), and T3 (triiodothyronine, liothyronine). 

T4 is less potent but has longer duration than T3.

T4 converts to T3 by peripheral deiodination.

Control: involves hypothalamic-pituitary-thyroid feedback.  TRH is secreted by hypothalamus à ↑ release of TSH (thyrotropin) by the anterior pituitary à ↑ production of T4/T3 in thyroid.

Thyroid preparations

Action: mimic the activity of endogenous thyroid hormones à regulate growth and development, calorigenic and metabolic activity, positive inotropic / chronotropic effects (sensitize beta receptors).

Use: hypothyroidism (e.g. Myxedema), Myxedema coma, cretinism, simple goiter, endemic goiter.

SE: rare, palpitations, nervousness, insomnia, weight loss.

Sodium salts of T4/T3.  T4 can be given alone (converts to T3).

Liotrix: 4:1 mixture of levothyroxine sodium to liothyronine sodium, no advantages over levothyroxine only.

Thyroid USP: from dried defatted thyroid gland of domestic animals. Standardized based on iodine content.

Thyroglobulin: purified extract of frozen porcine or bovine thyroid gland, contains T4 and T3.

Thyrotropin (TSH): purified and lyophilized hormone from bovine anterior pituitary. Use: detection and treatment of thyroid cancer. SE: anaphylaxis, urticaria, gland swelling, tachycardia, arrhythmia, GI upset.

Thyroid inhibitors

Use: treat hyperthyroidism (e.g. Grave’s disease, toxic adenoma).

Ionic inhibitors: such as thiocyanate (SCN-) and perchlorate (ClO4-), inorganic monovalent anions à ↓ concentration of iodide by the thyroid. Use: rarely use as drugs, but metabolism of foods (e.g. cabbage) and drugs (e.g. nitroprusside) can produce excess SCN-. 

↑ concentration iodides: such as Lugol’s solution, iodides ↓ their own transport, ↓ synthesis of mediators, ↓ hormone release. Use: before thyroid surgery to make gland firmed and ↓ its size. SE: Iodism (↑ salivation, skin rashes, eyelid swelling, sore gum/teeth/larynx/pharynx).

Radioactive iodine (¹³¹I) sodium: trapped by thyroid gland à incorporated into tyrosine / thyroid hormone.  Radioactive beta particles à local destruction of thyroid cells. SE: delayed hypothyroidism.

Thiourylenes: ↓ thyroid synthesis. Examples: propylthiouracil, methimazole.  Use: with ¹³¹I to control mild hyperthyroidism. SE: urticaria, dermatitis, blood toxicity, joint pain / stiffness.

17. Drug Metabolism and Interactions

Drug metabolism

Definition: drug metabolism (or biotransformation) is the biochemical changes drugs an foreign chemicals (xenobiotics) undergo in the body leading to formation of metabolites.

Inactive metabolites: examples: hydrolysis of procaine to p-aminobenzoic acid, oxidation of 6-mercaptopurine to 6-mercapturic acid.

Metabolites with similar activity: examples: codeine is demethylated to morphine (↑ activity), acetohexamide is reduced to l-hydroxyhexamide (↑ activity), imipramine demethylated to desipramine (same activity).

Metabolites with altered activity: retinoic acid (vitamin A) is isomerized to anti-cancer agent isoretinoic acid, antidepressant iproniazid is dealkylated to anti-TB isoniazid.

Bioactivated metabolites (prodrugs): enalapril hydrolyzed to enalaprilat, suldinac is reduce to the active sulfide, levodopa is decarboxylated to dopamine.

Biotransformation pathways

Phase I reactions

Polar functional groups are introduced to the molecule, or unmasked by oxidation, reduction, hydrolysis.

Oxidation:

Most common reaction. Mostly in the liver.  Catalyzed by cytochrome P450.

Cytochrome P450: oxidases, bound to smooth endoplasmic reticulum, require NADH, exist in multiple isoforms (CYP11Ax, CYP17By, etc) à large # of substrates. Involved in metabolism or bile acids, steroids, xenobiotics / drugs. 

Oxidized drug à ↑ polarity / water solubility à ↓ tubular reabsorption à ↑ urine excretion. 

Reduction

Same goal as oxidation (↑ polarity by reductases). 

GI bacterial flora à azo and nitro reduction reactions.

Enzymatic hydrolysis

Addition of water across a bond à ↑ polar metabolites.

Esterase: present in the plasma and tissues, nonspecific, hydrolyzes esters to alcohol and acid, responsible for activation of many prodrugs.  Example: procaine.

Amidase: hydrolyze amides into amines and acid (deamidation) in the liver.  Example: procainamide.

Phase II reactions

Functional groups of the original drug or a phase I metabolite are masked by a conjugation reaction à ↑↑ polar metabolites à ↑ excretion, no crossing of cell membranes (pharmacologically inactive, no toxicity).

Conjugation reactions: combine parent drug (or metabolite) with certain natural endogenous constituents (glucuronic acid, glutamine, glycine, sulfate, glutathione).  Requires high energy molecule and an enzyme.

High energy molecule: consist of coenzyme bound to endogenous substrate, parent drug, or metabolite.

Enzyme: called transferases, found in the liver and catalyze the reaction.

Glucuronidation: most common conjugation pathway due to large supply of glucuronic acid (high energy form reacts using glucuronyl transferase).  Common with OH group (form ethers) and COOh group (form esters).  Reaction adds 3-OH groups and 1-COOH group à ↑↑ hydrophilicity.  Glucuronides with ↑ MWt à bile excretion à to intestines à intestinal beta-glucuronidase hydrolyze the conjugate à reabsorption.

Sulfate conjugation: using sulfo-transferase.

Amino acid conjugation: reaction of glycine or glutamine with aliphatic or aromatic acids to form amides using N-acyltransferase.

Glutathione conjugation: very critical for preventing toxicity from harmful electrophilic agents (halides, epoxides).  Glutathione (tripeptide) + electrophile + glutathione S-transferase à mercapturic acid. 

Methylation: of oxygen- nitrogen- or sulfer-containing drugs à less polar but inactive metabolites.  Example: COMT methylates catecholamines such as epinephrine.

Acetylation: à less polar metabolites with N-acetyl-transferase. Metabolites (e.g. of sulfonamides) may accumulate in the kidney à crystalluria / tissue damage.

Factors influencing metabolism

Species differences

Qualitative differences: occur mainly in Phase II reactions.  Determines the actual metabolic pathway.  It can result from a genetic deficiency of a particular enzyme or difference in a particular endogenous substrate.

Quantitative differences: occur mainly in phase I reactions. Due to difference in the enzyme level, presence of species specific isozymes, amount of endogenous inhibitor or inducer, extent of competing reactions.

Physiologic / disease state

Due to pathologic factors that alter liver function.

Congestive heart failure: ↓ outputà ↓ hepatic blood flow à ↓ metabolism

∆ albumin production à fraction of bound drug. 

Genetic variations

Acetylation rate: depends on the amount of N-acetyl-transferase, which depends on genetic factors.  Fast acetylators à ↑ hepatotoxicity from isoniazid. Slow acetylators à ↑ other isoniazid SE.

PM Phenotype: ↓ metabolism of B-blockers, antiarrhythmics, opioids,  antidepressants.

Drug dosage

↑ dose à may saturated metabolic enzymes.  As the saturation approaches 100% à change from first to zero-order metabolism.

When metabolic pathway is saturated > possible alternative pathways.  Example: therapeutic APAP doses à glucuronic / sulfate conjugation, toxic doses à conjugation is saturated à N-hydroxylation à liver toxicity

Nutritional status

Conjugation agent levels (sulfate, glutathione) is dependent on nutrition

↓ protein diet à ↓ glycine, ↓ oxidative drug metabolism capacity.

Diet ↓ in essential fatty acids (linoleic acid) à ↓ synthesis of certain enzymes à ↓ metabolism of hexobarbital.

Diet ↓ in minerals (Ca, Mg, Zn) à ↓ metabolism.  ↓ Fe à ↑ metabolism.

Diet ↓ in vitamins (A, B, C, E): ↓ C à ↓ oxidation.  ↓ E à ↓ dealkylation, hydroxylation.

Age

Metabolic enzyme systems are not fully developed at birth à ↓ doses in infants / children to avoid SE, especially for glucuronide conjugation.

Older children à liver develops faster than ↑ in body weight à ↓ efficacy.

Elderly à ↓ metabolizing enzymes à ↓ elimination à ↑ Cp à ↑ SE

Gender

Due to ∆ androgen, estrogen, adrenocorticoid activity à ∆ CYP450 isozymes.  Example: oxidative metabolism is faster in men.

Administration route

Oral: first-pass effect à ↑ oral dose

IV: by pass first-pass effect à ↓↓ dose compared to oral dose.

Sublingual / rectal: also bypass first-pass effect.  Variable absorption from rectal administration.

Chemical structure

Presence of certain functional groups influences drug’s metabolic pathway (route, extent, degree of metabolism).

Circadian rhythm

Nocturnal Cp of theophylline, diazepam are ↓ than diurnal Cp.

Extra-hepatic metabolism

Plasma: contains esterases (hydrolyze esters).  Simple esters (procaine, succinyl choline) are rapidly hydrolyzed in the blood. Esterases can also activate prodrugs.

Intestinal mucosa: microsomal oxidation, conjugation (glucuronide, sulfate) à first pass effect of lipid soluble drugs during absorption.

Intestinal bacterial flora: secrete metabolizing enzymes. Ulcerative colitis à ↑ flora. Diarrhea, antibiotics à ↓ flora.   Flora secrete beta glucuronidase à hydrolyze polar glururonide conjugates of bile à reabsorption of free nonpolar bile acids à eneterohepatic circulation.  Flora convert vitamin K to active form, and cyclamate (sweetener) to cyclohexylamine (carcinogen).   Flora produce azoreductase à converts sulfasalazine to 5-aminosalicylic acid (anti-inflammatory) and sulfapyridine (antibacterial).

Stomach acidity: degradation of penicillin G, carbenicillin, erythromycin, tetracycline, peptides / proteins (insulin).

Nasal mucosa: ↑ CYP450 activity and metabolism on nasal decongestants, anesthetics, nicotine, cocaine.

Lung: first pass metabolism of IV, IM, transdermal, SC drugs but to ↓ degree than the liver.  Also, second pass metabolism for drugs leaving the liver.

Placenta: if drug is lipid soluble enough to get to circulation à pass through the placenta too.  Placenta is not a physical or metabolic barrier to xenobiotics.  Very little metabolism occurs.  Smoking induce certain enzymes in pregnant women à ↑ carcinogens from polycyclic HC.

Fetus: depends on fetal age, ↓↓ glucuronic acid conjugation.  Chloramphenical à ↓ glucuronidation à gray baby syndrome.  ↓ bilirubin glucuronide à neonatal hyperbilirubinemia.

Strategies to manage metabolism

Pharmaceutical

Sublingual tablets: deliver drugs directly to systemic circulation, bypassing hepatic first pass metabolism.  Example: nitroglycerin. 

Transdermal products: continuous drug supply for long period of time.  Example: nitroglycerin. 

IM depots: continuous drug supply for long period of time.  Example: highly lipid soluble esters of esradiol (benzoate) and testosterone (enanthate) à slow absorption and activation by hydrolysis. 

Enteric coated tablets: protect acid sensitive drugs.  Examples: omeprazole, erythromycin, methenamine. 

Nasal administration: for lung delivery of peptides (e.g. calcitonin salmon) which has no oral bioavailability.  Lung contains protease inhibitors à peptide stability.

Pharmacologic

Levodopa (L-dopa): amino acid precursor of dopamine (for Parkinson’s).  Unlike dopamine, it can penetrate BBB and reach CNS to be decarboxylated to dopamine. Carbidopa: DOPA decarboxylase inhibitor that does not cross BBB à ↓ peripheral activation and SE. 

Beta-lactam AB: use clavulanic acid (a beta-lactamase inhibitor).

Ifosfamide: alkylating agent à in vivo metabolic activation à nitrogen mustard. Acrolein is a byproduct of metabolic activation à react with nucleophiles on renal proteins à hemorrhagic cystitis.  Combine ifosfamide. with mesna (neutralizes acrolein in the kidney).

Chemical

Testosterone: not orally active due to rapid oxidation of 17-OH group.  Methyl-testosterone: 17alpha-methyl group à ↓ potent but no rapid first pass metabolic deactivation à used orally.  Same for estradiol analogs.

Tolbutamide: oxidation of para-methyl group à rapid deactivation.  Chlorpropamide: non-metabolizable para-chloro group à long t1/2.

Isoproterenol: potent beta agonist for asthma.  Rapid metabolism by COMT (catechol) à poor oral activity.  Metaproterenol: not metabolized by COMT à orally active, long t1/2.

Octreotide: synthetic octa-peptide à ↓ severe diarrhea in tumors, SC.  It mimics action of somatostatin (14-AA peptide, short t1/2, only IV infusion) but resistant to hydrolysis, proteolysis. 

Prodrugs

Require in vivo biotransformation (phase I) to produce activity

The following are potential advantages for prodrugs:

↑ water solubility

Useful for ophthalmic and parenteral formulations

Example: sodium succinate esters, sodium phosphate esters to make water-soluble steroid prodrugs

↑ lipid solubility

↑ duration of action: estradiol lipid-soluble esters (benzoate, valerate, cypionate) à prolonged activity (IM of esters in oil). 

↑ oral absorption: by converting carboxylic acid groups to esters à converted back to active acids by plasma esterases.  Example: lipophilic orally absorbed enalapril à very potent orally inactive enalaprilat.

↑ topical absorption: of steroids by masking hydroxyl groups as esters or acetonides à ↓ polar à ↑ dermal permeability.  Examples: triamcinolone acetonide, betamethosone valerate, diflorasone diacetete.

↑ palatability: sulfisoxazole acetyl (ester, ↓ water solubility, ok taste for children) à sulfisoxazole (bitter)

↓ GI irritation

NSAIDs à ulceration by direct irritant effect of acidic molecules and ↓ of gastro-protective PG.  Sulindac, nabumetone à prodrugs with ↓ GI effect

Site specificity

Methyldopa: structurally similar to L-dopa à transported to CNS à metabolized to active alpha-methyldopamine à central alpha-2 agonist

Omeprazole: activated at acidic pH < 1 à inhibition of H+/K+ATPase.

Formaldehyde: effective urinary tract antiseptic.  Orally à ↑ toxicity.  Methenamine à non-toxic prodrug à hydrolyzes to formaldehyde and ammonium ions in acidic urine (pH<5.5).  Use enteric coating to prevent activation in the stomach.

Olsalazine: polar dimer of 5-aminosalisalyic acid à poor oral absorption.  In large intestine à colonic bacteria cleave azo bond à free active. 

Diethylstilbestrol: synthetic estrogen for prostate cancer à feminizing SE.  Diethylstilbestrol diphosphate (ester prodrug) à activated by acid phosphatase in prostate tumor cells à ↑ local action, ↓ systemic SE. 

↑ shelf-life

Cefamandole: 2^nd generation cephalosporin, unstable in solid dosage forms.  Cefamandole nafate: stable formic acid ester à hydrolyzed by plasma esterases. 

Cyclophosphamide: stable prodrug à in vivo oxidation + nonenzymatic decomposition à active phosphoramide mustard. 

Drug interactions

Types of interactions: drug-drug, drug-food, drug-chemical, drug-laboratory.

Precipitant: drug, food or chemical causing the interaction.

Object: drug affected by the interaction.

Epinephrine, erythromycin à decompose in IV alkaline pH à do not mix with aminophylline (alkaline).

PK interactions

Due to ∆ in absorption, distribution (protein / tissue binding), elimination (excretion / metabolism).

Absorption

Epinephrine (vasoconstrictor) à ↓ percutaneous absorption of lidocaine (local anesthetic).

CHF à ↓ GI blood flow à ↓ drug absorption

MAO inhibitors + foods w/ tyramineà ↓ metabolismà hypertensive crisis

 Antibiotics (erythromycin) à ↓ intestinal flora à ↓ digoxin microbial deactivation à ↑ bioavailability.

Antacids / H2 antagonists à ↑ GI pH à ↓ ketoconazole dissolution

∆ intestinal motility (anticholinergics à ↓,  laxatives à ↑) à ∆ absorption

Cholestyramine / kaolin à digoxin adsorption à ↓ bioavailability

Complexation by divalent cations à ↓ tetracycline bioavailability

Distribution

Due to ∆ in plasma protein binding / displacement or tissue / cellular interactions.  Valproic acid displaces phenytoin and ↓ its liver metabolism à ↑↑ phenytoin.  Quinidine displaces digoxin and ↓ digoxin clearance à ↑↑ digoxin.

Elimination / clearance

Due to ∆ in kidney or liver clearance (enzyme induction / inhibition, enzyme substrate competition, ∆ blood flow) .

Grapefruit juice is a powerful inhibitor of CYP3A4. 

Enzyme inducers: tobacco (polycyclic aromatic HC), barbiturates, rifampin, carbamazepine, phenytoin, omeprazole, troglitazone.

Enzyme inhibitors: cimetidine, ketoconazole, ciprofloxacin, erythromycin, ritonavir / nelfinavir, clopidrogel.

Food-drug interactions

∆ drug absorption.  Example: Complexation of tetracycline + calcium

Delayed/ ↓ absorption: NSAIDs, APAP, antibiotics, ethanol.

↑ absorption: griseoflulvin, metoprolol, phenytoin, propoxyphene

Chemical-drug interactions

Smoking (enzyme induction) à ↑ clearance of theophylline, BZD, TCA

Alcohol: acute use à ↓ metabolism,  chronic use à ↑ metabolism. 

PD interactions

Antagonistic, additive or synergistic effect.

Similar action à excessive or toxic response.  Example: alcohol + antihistamine à both CNS depressants, promethazine + antihistamine à both anticholinergic.

Thiazide diuretic à deplete potassium à ↑ sensitivity to digoxin, deplete sodium à ↑ lithium toxicity, anticoagulant + aspirin à ↑ risk of bleeding. 

Significance and management of interactions

Potential drug interactions

Multiple-drug therapy: including Rx and OTC.  ↑ # à ↑ potential.

Multiple prescribers: different prescribers are not aware of history

Patient compliance: example: tetracycline not on empty stomach.

Patient risk factors: elderly at ↑ risk (∆ body composition, GI transit, drug absorption, distribution, ↓ protein binding, ↓ drug clearance).  Patients with diseases (DB, AIDS, etc) and atopic (hyper-responsive) patients are at ↑ risk.

Clinical significance

Not all interactions are dangerous.  Interacting drugs can be prescribed under supervision with monitoring.  Example: cimetidine with antacids à do not take both at the same time

Some interactions are good à ↑ efficacy, ↓ SE.  Examples: trimethoprim + sulfamethoxazole (↑ efficacy in UTI), amoxicillin + clavulanate potassium (beta lactamase inhibitor à ↑ spectrum), hydrochlorothiazide + enalapril (balance potassium), penicillin + probenicid (↓ tubular secretion, ↑ t1/2), saquinavir + food (↑ absorption).

Likelihood: established, probable, suspected, possible, unlikely

Consider dose side and duration, interaction onset / severity.

Management of drug interactions

Review patient profile: drug history and risk factors

Avoid complex therapeutic regimens

Determine probability of a significant interaction

Suggest alternatives: APAP not aspirin for headache with warfarin

Monitor SE.  Monitor prothrombin time if warfarin is given with sulfonamides (may be prolonged).

Re-evaluate profile when changing therapy.  Example: if d/c a thiazide diuretic à d/c potassium supplement also. 

20. Drug information resources

Drug information resources

Primary (journals)

Benefits: most current source, learn from case studies, new developments, ↑ communications with professionals / consumers, CE credits, prepare for board certification exams.

Limitations: information is not always 100% accurate.

Secondary (abstracts / indexes)

Benefits: enable quick and selective screening of primary literature for specific information. May have enough info to answer the question.

Limitations: only finite number of journal reviewed, lag time between article publication and citation in the index, usually good only to locate the original article (no full answers), contain only interpretations / description of the study which may be misleading (not whole story).

Tertiary (textbooks)

Benefits: easy and convenient access to large number of topics, include background information on drugs / diseases, validity and accuracy of information can be verified by using references.

Limitations: may take years to publish à information may be outdated, chapter author may not have done a thorough literature search, author may have misrepresented the original article.

Considerations: author, publisher, edition, year of publication, scope, presence of bibliography.

Internet

Benefits: expanded searching capabilities, most useful for company specific information, issues currently in the news, alterative medicine, government information.

Limitations: may not be peer reviewed or edited, not always reliable (evaluate source).

Strategies for evaluating information requests

Talk with the inquirer

Determine reason for inquiry: news-related question, medical condition

Clarify drug ID / availability: correct name spelling, generic vs. brand, manufacturer, country, Rx vs. OTC, under investigation drug, dosage form, purpose for use.

Identify / assess product / resource availability

US drugs: American Drug Index, Drug Facts and Comparisons, Drug Topics Red Book, PDR, Martindale the Extra Pharmacopoeia, American Hospital Formulary Service

Foreign drugs: Martindale the Extra Pharmacopoeia, Index Nominum, US Adopted Names, USP Dictionary of Drug Names.

Investigational drugs: Martindale the Extra Pharmacopoeia, Drug Facts and Comparisons, Unlisted Drugs, NDA Pipeline.

Orphan drugs: for rare disease affected < 200,000 people à cost of development is unlikely to be offset by sales à FDA offers assistance and financial incentives to encourage development. Drug Facts and Comparisons, National Information Center for Orphan Drugs and Rare Diseases (NICODARD).

Unknown drugs: are drugs on hand but are not identified à identify by physical characteristics or chemical analysis.  Sources: PDR, Facts and Comparisons, Drug Topics Red Book, Ident-A-Drug Handbook, Lexi-Comp, manufacturer, lab.

Unapproved (off-label) uses: Drug Facts and Comparisons, Martindale the Extra Pharmacopoeia, Index Medicus, Drugdex, USP DI, AHFS

Drug interactions: Drug Interactions Facts, Evaluations of Drug Interactions, Hansten’s Drug Interactions Analysis and Management.

Drug stability / compatibility: Trissel’s Handbook of Injectable Drugs, Trissel’s Stability of Compounded Formulations, King’s Guide to Parenteral Admixtures.

Manufacturer: good source for any missing information.

	US Drugs	Foreign Drugs	Orphan Drugs	Unknown Drugs	Investigational Drugs	Unapproved Drugs	Inter-actions
Facts and Comparisons	X		X	X	X	X	X
Martindale extra pharmacopiea	X	X			X	X
PDR	X			X
Index Nominum		X				X
Red book	X			X
American Drug Index	X
Hospital Formulary	X
US Adopted Names		X
USP Dictionary		X
Unlisted Drugs					X
USP DI						X
Index Medicus						X

Search strategies

Is it a clinical or research-related question? Define as specifically as possible.

Identify appropriate index search terms (keywords, descriptors).

Determine quantity and quality of needed information.

Ascertain as much as possible about the drug and the inquirer.

What is the drug indication? Is the drug approved or not? Patient information (age, sex, weight, medical conditions, other drugs, signs of SE, allergies, etc).

Guidelines for responding to information requests

Do NOT guess

Intended use of information (abuse, misuse).

Organize information and response first.

Tailor to the inquirer’s background (e.g. public vs. professional).

Evaluating a clinical study

Study objective: was the objective clearly stated? One or more objectives?

Study subjects: profile of study population.  Healthy subjects or patients?  Degree of disease severity if patients? Volunteers? Number / ID of subjects (sex, age, race, etc)? Co-morbidities? Inclusion / exclusion criteria? Stratification can be used in case of ↑ inter-patient variability.

Administration of drug treatment: dose, frequency, time of day, route, drug source, dosage form, timing vs. factors affecting absorption (e.g. food), duration.

Study setting: environment, dates, type of professionals making observations, inpatient vs. outpatient, length of study.

Study methods / design: are methods and design clearly described?

Retrospective vs. prospective: Retrospective à examination of past events to find links between variables, relies on patient memory and accurate records, used for rare disease, may lead to a decision to conduct prospective study. Prospective à looks forward in time, can be observational or experimental (clinical trials).

Treatment allocation: Parallel à different patient groups are studied concurrently, identical treatment for all groups except for one variable. Crossover à good control of inter- / intra-patient variability, each group undergoes each treatment, with the sequence reversed for one group vs. the other, includes a washout period.

Control measures: own control (crossover design), concurrent controls, stratification, matched subgroups, run-in period.

Controls: blind assessment / blind patients (double blind vs. open label (non-blind)), randomization, matching dummies (placebos), comparison (to placebo or standard drug).

Analysis: appropriate statistical methods should be used

22. Clinical Toxicology

Overview

Definitions

Clinical toxicology: studies the effects of substances on patients caused by accidental poisoning or intentional overdose of medications, abuse drugs, household products or other chemicals.

Intoxication: toxicity associated with any chemical substance

Poisoning: clinical toxicity secondary to accidental exposure

Overdose: intentional exposure to cause self-injury or death

Information resources

Computerized databases: Poisindex: CD database updated quarterly and used by poison control centers. TOMES: Toxicologic, Occupational Medicine and Environmental Series à info on industrial chemicals.

Printed publications: textbooks and manuals are useful but suffer a lag time of information published in primary literature.

Internet: Center for Disease Control and Prevention, FDA, and National Library of Medicine websites.

Poison control centers: accredited by the AAPCC.  Provides info for the public and health care providers. Most reliable and up to date sources of information.

General management

Supportive care

Evaluate and support vital functions as a first step until patient is stabilized. Airway, Breathing, Circulation (ABC).

Patients with depressed mental status

Hypoglycemia: to rule out or treat à 50 ml of 50% dextrose IV

Glucose can ppt Wernicke-Korsakoff syndrome in thiamine-deficient patients à give IV thiamine push.

Opiate: give naloxone IV push.

History of exposure

Identity: of ingested substance, route of exposure, quantity ingested, time since ingestion, symptoms of overdose, associated illness / injury.

Neurologic examination: seizures, altered consciousness, confusion, ataxia, slurred speech, tremor, headache, syncope.

Cardiopulmonary examination: syncope, palpitations, cough, chest pain, shortness of breath, upper airway burning / irritation.

GI examination: abdominal pain, nausea, vomiting, diarrhea, difficulty swallowing.

Past medical history: Rx/OTC drugs, herbal medicines, alcohol / drug abuse, psychiatric history, allergies, occupational / hobby exposures, travel, domestic violence / neglect.

Routine lab assessment: Complete blood count (CBC), serum electrolytes, BUN, serum creatinine, BG, urinalysis, ECG

Toxicology lab tests

Advantages: confirm or determine substance identity, predict severity of toxic effects, may help guide therapy

Disadvantages: diagnosis is not always specific, not available for all poisons, supportive care is the first priority.

Generally, only qualitative determination is need.  However, quantitative determination is required for some substances (e.g metals, lithium, methanol, APAP, salicylate, theophylline, ethylene glycol)

Skin decontamination

Required when skin absorption may cause systemic toxicity or when contamination substance may produce toxic effects (e.g. acid burns).

Remove clothes, irrigate area with plenty of water.  DO NOT neutralized (exothermic reaction).

Gastric decontamination

Emesis

Contraindications: children < 6 months, CNS depression, seizures, strong acids / alkali, sharp object, compromised airway, coma, convulsions, HC or petroleum distillates, patients already vomiting, substance that are very fast acting.

Syrup of ipecac: consider only if within 60 (even 30) minutes since ingestion, otherwise, no benefit.  Onset of emesis: within 30 minutes, 3 vomiting episodes in 1 hour. SE: diarrhea, drowsiness, lethargy

Gastric lavage

Use: if patient is not alert or has ↓ gag reflex, if ↑↑ quantity was ingestion short while ago or if not responding to ipecac

Procedure: aspire gastric contents à instill 250 ml tap water or saline à aspire à repeat until content is clear for 2 liters.

Activated charcoal

Adsorbs the majority of substances.  Always give ASAP.

Exceptions: iron, lead, mercury, cyanide, lithium, ethanol, methanol, organic solvents, strong acids / alkali.

Form: colloidal dispersion with water or sorbitol.

Avoid multiple doses of cathartics à may cause electrolyte imbalance, dehydration.

SE: charcoal aspiration à avoid if vomiting, bowel obstruction with multiple doses.

Whole bowel irrigation

Effective when charcoal is not available / effective.

Use osmotic cathartic solution (e.g. PEG (Golytely, Colyte).  Continue until rectal effluent is clear.

Forced diuresis / urine pH manipulation

Use: for substance with kidney elimination, ↓ Vd, ↓ protein binding

Alkaline diuresis: ↑ ionization of weak acids (aspirin, long-acting barbiturates (phenobarbital)) à ↓ kidney reabsorption à ↑ elimination. Use IV sodium bicarbonate à urine pH at 8.0, maintain adequate urine output. SE: metabolic alkalosis, hypernatremia, hyperosmolarity, fluid overload.

Acid diuresis: ↑ ionization of weak alkali (amphetamines, phencyclidine, quinidine) à ↓ kidney reabsorption à ↑ elimination.  Use ascorbic acid (vitamin C) or ammonium chloride à urine pH at 5.0.

Dialysis

Last resort for decontamination. Hemodialysis or peritoneal dialysis.

Hemodialysis: used for water soluble substances with ↓ Vd, ↓ MWt, ↓ protein binding. Use for life threatening ingestions of ethylene glycol, methanol. Can correct fluid and electrolyte abnormalities.

Hemoperfusion

Anticoagulated blood is passed through (perfused) a column containing activated charcoal or resin particles. Quicker than hemodialysis. Can NOT correct electrolyte / fluid abnormalities. Less effective for methanol / ethanol. SE: thrombocytopenia, leukopenia, hypoglycemia, hypocalcemia.

Management of specific ingestions

Acetaminophen

Toxicokinetics: mostly metabolized in the liver (Cytochrome P450)à toxic metabolite à liver toxicity, especially in alcoholics / elderly.

Symptoms: phase I (1 day): nausea, vomiting, phase II (2 days): no symptoms, phase III (3 days): abdominal pain, coma, death.

Treatment: ipecac or gastric lavage (within 2 hr), N-acetylcystein (specific antidote, oral / IV). Metoclopramide: ↓ emesis during / ↑ absorption of N-acetylcysteine therapy.

Alcohols

Ethylene glycol

Forms: antifreeze, windshield deicing. Colorless, sweet taste.

Toxicokinetics: live metabolism by alcohol dehydrogenase à glycoaldehydge à by aldehyde dehydrogenase à glycolic acid à glyoxylic acid à oxalic acid (most toxic).

Symptoms: phase I (12 hr): ↓ tendon reflex, ataxia, nystagmus, metabolic acidosis, hypocalcemia, phase II (1 day): tachypnea, cyanosis, tachycardia, pulmonary edema, phase III (2 days): flank pain, oligouric renal failure.

Treatment: gastric lavage (within 30 min), IV ethanol, fomepizole (alcohol dehyrogenase inhibitor), pyridoxine / thiamine (convert glyoxylic acid to non-oxalate metabolites), sodium bicarbonate (correct acidosis), hemodialysis.

Methanol

Forms: gas-line antifreeze, windshield washe.

Toxicokinetics: alcohol dehyrogenase à formaldehyde à formic acid.

Symptoms: phase I: euphoria, muscle weakness, phase II: vomiting, diarrhea, dizziness, headache, dyspnea, blurred vision, photophobia, blindness, cardiac / respiratory depression, metabolic acidosis, hyperglycemia, coma, seizures, death.

Treatment: gastric lavage (NOT charcoal), IV ethanol, fomepizole (alcohol dehydrogenase inhibitor), folic acid (↑ metabolism of format), sodium bicarbonate (correct acidosis), hemodialysis.

Antidepressants

Tricyclic antidpressants

Toxicokinetics: t1/2 = 24 hr, liver metabolism, enterohepatic circulation, ↑↑ plasma protein binding.

Symptoms: atropine-like SE (mydriasis, urinary retention, fever), tachycardia, ↓ BP, pulmonary edema, agitation, confusion, hallucinations, seizures.

Lab data: ECG

Treatment: GI decontamination (activated charcoal), alkalinzation (sodium bicarbonate to ↑ arterial blood pH), phenytoin / BZD (to control seizures, fosphenytoin cause less hypotension than phenytoin), physostigmine (for anticholinergic symptoms, may cause asystole (no heart beat)).

Selective serotonin reuptake inhibitors (SSRI)

Toxicokinetics: t1/2 = 24 hr, liver metabolism

Symptoms: agitation, drowsiness, confusion, seizures

Lab data: ECG

Treatment: gastric lavage, supportive treatment

Anticoagulants

Heparin

Dosage forms: IV, SC

Toxicokinetics: t1/2 = 1 hr, liver metabolism

Symptoms: bleeding, bruising

Lab data: PTT, bleeding time, platelet count

Treatment: Protamine IV (combines with and neutralized heparin), 1 mg protamine neutralized 100 heparin units.

Warfarin

Dosage forms: oral, parenteral

Toxicokinetics: absorbed orally, t1/2 = 36 hr, 99% protein bound, 5-day activity duration.

Symptoms: bleeding, bruising, hematuria, conjunctiva hemorrhage, GI / intracranial bleeding.

Lab data: PT, INR, bleeding time.

Treatment: Phytonadione (vitamin K), blood products with clotting factors.

BZD

Toxicokinetics: liver metabolism

Symptoms: drowsiness, confusion, ataxia

Treatment: supportive (gastric emptying, activated charcoal, cathartic), Flumazenil (IV, short t1/2, careful observation for re-sedation in case of long acting BZD).

Beta blockers

Symptoms: hypotension, bradycardia, atrioventricular block, bronchospasm, hypoglycemia.

Treatment: gastric lavage, activated charcoal, Glucagon, Epinephrine (.

Calcium channel blockers

Symptoms: hypotension, bradycardia, atrioventricular block.  Nifedipine does not affect the heart. Verapamil à pulmonary edema, seizures.

Treatment: GI decontamination (gastric lavage, activated charcoal, whole bowel irrigation). Clacium chlrodie (IV) for hypotension, bradycardia, heart block. Glucagon.

Cocaine

Forms: alkaloid from Erythroxylon coca

Toxicokinetics: good absorption from oral, inhalation, intranasal, IV route. Metabolized in the liver, excreted in the urine.

Symptoms: CNS / sympathetic stimulation (↑BP, tachycardia, seizures, tachypnea). Death due to respiratory failure, cardiac arrest, MI.

Treatment: Symptomatic.  BZD for seizures. Labetolol for hypertension. Neuroleptics for psychosis.

Corrosives

Symptoms: strong acids and alkali cause skin burns.

Treatment: decontamination.  Irrigate exposed skin with water. AVOID neutralization (exothermic reactions à more burns and tissue damage).

Cyanide

Forms: industrial chemicals, nail polish removers.

Toxicokinetics: quick absorbed orally or by inhalation.

Symptoms: headache, dyspnea, ataxia, coma, seizures, death

Treatment: amyl or sodium nitrite à converts hemoglobin to methemoglobin à binds to cyanide ion (cyano-methemoglobin) à sodium thiosulfate to regenerate hemoglobin. Oxygen for dyspnea.  Sodium bicarbonate for acidosis.

Digoxin

Symptoms: confusion, anorexia, GI upset, dysrhythmia.

Lab data: digoxin Cp, serum potassium, ECG.

Treatment: ipecac or activated charcoal, correct blood potassium, heart support, Digoxin specific fab antibodies.

Electrolytes

Magnesium

Forms: cathartics (mg citrate) à ↑ mg with charcoal.

Toxicokinetics: Mg is found intracellularly à kidney elimination

Symptoms: Mild à weakness, ↓ tendon reflexes. Severe à respiratory paralysis, heart block, ECG abnormalities.

Treatment: 10% calcium chloride to temporarily antagonize cardiac effects of Mg.  Use hemodialysis in severe cases.

Potassium

Toxicokinetics: main intracellular cation. ∆ acid-base balance à ∆ potassium.  ↑ pH à ↓ potassium.

Symptoms: cardiac irritability, peripheral weakness, bradycardia, dysrhythmia, ECG abnormalities.

Treatment: Calcium: antagonize cardiac effects of potassium, sodium bicarbonate: ↑ serum pH à move potassium from extracellular to intracellular space, Glucose + insulin: move potassium from extracellular to intracellular space, cation exchange resins (sodium polystyrene sulfonate): bind potassium in exchange for sodium, hemodialysis: last resort for life-threatening hyperkalemia.

Iron

Elemental iron: 33% in fumarate, 20% in sulfate, 12% in gluconate.

Symptoms: phase I (nausea, vomiting, diarrhea, GI bleeding), phase II (improvement within 24 hr), phase III (metabolic acidosis, renal / hepatic failure, pulmonary edema, death).

Lab data: serum iron, hemoglobin, hematocrit, radiopaque pills in radiography.

Treatment: Deferoxime chelates iron (red urine).  Ipecac emesis if within minutes of small quantity ingestion.  Whole bowel irrigation for ↑ quantities. Also, supportive treatment.

Isoniazid

Symptoms: nausea, vomiting, slow speech, ataxia, seizures, coma

Lab data: lactic acidosis, hypoglycemia, hyperkalemia, leukocytosis

Treatment: AVOID emesis (due to ↑ risk of seizures), ↑ quantity à activated charcoal gastric lavage.  Pyridoxine reverses isoniazid induced seizures (infusion in D5W). Sodium bicarbonate for acidosis.

Lead

Forms: paint or gasoline fume inhalation.

Toxicokinetics: slow distribution (t1/2; 2 months).

Symptoms: nausea, vomiting, GI pain, peripheral neuropathy, convulsions, coma.

Lab data: anemia, ↑ lead level in blood.

Treatment: Calcium EDTA (IM/IV), dimercaprol (IM).

Lithium

Toxicokinetics: absorbed orally, not plasma protein bound, small Vd, kidney eliminatin.

Symptoms: Mild à polyuria, blurred vision, tremor, weakness.  Severe à seizures, coma, delirium, fever.

Lab data: determine the degree of toxicity form lithium Cp.

Treatment: sodium polystyrene sulfonate, ipecac (within minutes), whole bowel irrigation (if ↑ quantity), hemodialysis (if acute exposure + severe symptoms). 

Opiates

Toxicokinetics: methadone / heroin à ↑ t1/2

Symptoms: respiratory depression, miosis, ↓ consiousness, hypotension, bradycardia.  opiates are downers.

Treatment: Naloxone (short t1/2, repeated dosing), Nalmefene (longer t1/2).

Organophosphates

Forms: pesticides, chemical warfare agents

Toxicokinetics: absorbed through lungs, skin, GI, conjunctiva

Symptoms: DUMBELSS: diarrhea, urination, miosis, bronchoconstriction, excitation, lacrimation, salivation, sweating.

Lab data: RBC acetylcholinesterase activity.

Treatment: atropine, pralidoxime (both IV).

Salicylates

Toxicokinetics: longer t1/2 at toxic doses

Symptoms: Mild à nausea, vomiting, tinnitus, malaise.  Severe à metabolic acidosis, convulsions, coma.  Other SE: BI bleeding, ↑ PT.

Treatment: ipecac emesis (if within minutes), ↓ doses à  repeated activated charcoal + a cathartic dose, moderate doses à whole bowel irrigation, ↑ doses à hemodialysis. Alkaline diuresis: with sodium bicarbonate to ↑ excretion.  Fluid / electrolyte replacement.  Vitamin K to correct ↓ coagulation.

Theophylline

Toxicokinetics: liver metabolism à highly variable (depends on age, other drugs, disease).

Symptoms: nausea, vomiting, seizures, dysrhythmias. Acute toxicity à hyperglycemia, hypokalemia.  SE are due to ↑ cAMP.

Treatment: supportive (maintain airways, treat seizures, beta blocker (esmolol) treats tachycardia, disrhythmia), ipecac (if within minutes), repeated activated charcoal, whole bowel irrigation (if ↑ quantitiy), charcoal hemoperfusion or hemodialysis.

Dosage forms:

Toxicokinetics:

Symptoms:

Lab data:

Treatment:

23. Federal Pharmacy Law

Federal Controlled Substances Act

Schedules of controlled substances

Drugs that have potential for abuse leading to physical or psychological dependence. Lists are published annually.  US attorney general has the authority to modify lists.

Schedules II-V have accpeted medical uses but schedule I does not. Schedule II has the highest potential for abuse / severe dependence and Schedule V has the least.

Schedule I: drugs can not be kept in the pharmacy or dispensed except for authorized research or investigative reasons. Drugs with ­ abuse potential but no accepted medical use or esablished safety record.  Examples: heroin, marijuana, LSD, ecstacy,

Schedule II: Highly restricted.  Examples: morphine, oxycodone, methyphenidate, amphetamine, methamphetamine, cocaine, opium, fentanyl, short acting barbiturates.

Schedule III: Less potential for abuse / dependence than CI or CII.  Examples: anabolic steroids (testosterone, androgens), hydrocodone / codeine with APAP / aspirin, intermediate acting barbiturates (talbutal).

Schedule IV: Examples: BZD (diazepam, chlordiazepoxide, alprazolam, long acting barbiturates (phenobarbital), propoxyphene, pentazocine, pemoline

Schedule V: May be available w/o Rx but sales are documented. Examples: small amounts of opium or codeine.

Registration requirements

All handlers of controlled drugs have to register with the DEA.

DEA issues an Order To Show Cause to allow the registrant to appeal.

Entities that must register: wholesalers (annual renewals), dispensers (pharmacies, practitioners) (renew every 3 years). Pharmacists / pharmacy employees do not have to register. 

Registration for separate activities: certain activies require separate registartion.  Examples: manufacturing, distributing, dispensing, conducting research, narcotic treatment programs, chemical analysis, importing / exporting, maintenance, disposal, detoxification, packaging.

Registration for separate locations: separate registration for each pharmacy, pharmacy chain, clinic, hospital.  Wholesalers do not have to register if distributing to a registered location.

Registration procedure: submit application to DEA by individual, partners, corporate officer, or person with power of attorney.

Registration action by the DEA: certificate of registration is granted by DEA if appropriate, otherwise it may be denied. 

Modification of registration: e.g. for change of name, address, extension of authorized activities, etc.

Transfer of registration: not allowed except in case of pharmacy ownership transfer.

Suspension / revocation of registration: May be due to imminent danger to public health or safety.  If revoced / suspended ® deliver certificate or registration, any DEA 222 order forms, all controlled substances or place them under seal.

Exemptions from registration: Military officials: can prescribe, administer or dispense but not purchase.  Law-enforcement officials: federal and state.  Civil defense officials: and disaster relief organizations during prolaimed emergencies or disasters.  Agents and employees of registrants: such as pharmacists or delivery personnel.

Termination of registration: death, cease of legal existence (company), d/c business or pratice. DEA must be notified and drugs disposed of.

Required inventories

All registered entities have to conduct biennial inventory.

Initial inventory: must be taken on the day of start or end of business or change of ownership. If no controlled substances in possession ® must be documented.

Biennial inventory: any date within 2 years of the previous inventory.

Inventory procedures: conducted at either the open or close of business. Separate inventory record required for CII ® keep drugs separate.

Inventory content: inventory must contain: date of inventory, dosage form, strength, number of units or volume in each container.  Exact count is required for open bottle of only CII (estimate is OK for other Cs, unless containers contains > 1000 tablets).

Inventory record maintenance: keep inventory separate at the registered location for 2 years. Keep CII inventory separate. Must be readily retrievable. Submission to DEA is not required.

Perpetual inventories: not required.

New or changes in schedules: inventory required for that drug only.

Obtaining controlled substances

CII: DEA Order Form 222 is required. Forms are issued by DEA, serially numbered with the certificate of registration inforamtion. Triplicate copies each. List info for drugs and supplier (one supplier per form). Form is invalid for purchasing 60 days of signature.  Only used by previously authorized and deisgnated individuals. Send copy 1 and 2 to supplier, retain copy 3.  Maintain for 2 years. A purchaser / supplier may cancel part or all of the order by notifying the other party in writing.

CIII-V: no form is required but records need to be maintained (2 years).

Storage of controlled substances

One of two ways: in a securely locked well constructed cabinet OR dispersed throughout the stock of other drugs to prevent theft. Report theft or significant loss immediately to DEA using Form 106.

Disposal of controlled substances

DEA Form 41 must be submitted and pre-authorized.  Always keep records.  Options for disposal: transfer to a registered person or entity (use Form 222 for CII), delivery to or destroy in the presence of DEA agent or office.  Regular disposal of controlled substances: DEA may authorize disposal without pior approval. Always keep records.

Disposal (dispensing) pursuant to a valid Rx

Authorized prescribers

Only by a practioner who is licensed by the state (not federally). Usually: physicians, dentists, vets, podiatrists (DEA starts with A or B).  Other professionals may be licensed but with restrictions (DEA starts with M).

Authentication of DEA number (7 digits): (1 + 3 + 5) + 2x(2 + 4+ 6) ® double digit ® the right digit has to match digit 7.

Purpose for prescribing

Must be in good faith only for legitimate medical reasons during the normal course of pratice (medical history and physical exam performed). A vet can not prescribe for humans. It does not have to be within specialty if physician is a specialist. Can not prescibe controlled drugs for the sole purpose of detoxification of maintenance of addiction (only if within a treatment program).

Prescribing

CII must be written unless it is an emergency ® oral drugs only, no alternative, written Rx is not possible, only necessary quantity, prescriber must be known to the pharmacist ® written Rx must be provided within 7 days of oral Rx (mail or in person), otherwise notify DEA.  CIII-V can be oral or fax. 

Faxed Rx: ok for CIII-V.  For CII ® ok to prepare the Rx but no released to the patient without written Rx ® exceptions include injectable home health, hospice, and LTC Rx (no written Rx required) .

Dispensing a Rx

Time validity: 6 months for CIII-IV and no time limit for CII and CV (although questionable after 6 months).  No limitation on quantity either.  Apply good faith principles.

All information on the Rx must be complete (including S/N).

Label: must have pharmacy name / address, S/N, date of original filling, patient name, prescriber name, drug info, directions, Cautionary Auxilliary Sticker.

Separate record files: CII, CIII-V, other Rx all separate, OR Combine all C with CIII-V or combine CIII-V with non control as long as C is stamped in red on CIII-V.

Refills: no refills for CII.  For CIII-IV ® up to 5 refills in 6 months. No limit for C-V (use good faith).

Maintain either physical or computerized records (certain characteristics).

Partial dispensing: allowed for CIII-IV within 6 months. For CII: allowed only if not enough stock(within 72 hr), or terminally ill patient / LTC (within 60 days).

Transfer of refills (CIII-V): allowed only once.  Write ‘Void’ or ‘Transfer’ on Rx.

Dispensing without a prescription

Only if not a prescription drug. Only pharmacist can dispense only limited quantities (wihtin 48 hr period) with records kept (2 years), in good faith.  Purchaser must be 18 years and present an ID (if not familiar).

Security considerations

Seals / seals: seals required for all packages and containers. Labels must clearly designate the schedule (II-V).

Felony convictions: no registrant may employ felons conviced with a narcotic offense.

DEA inspections

Inspected are conducted only in a reasonable manner and during business hours, only after registrant notification or court warrant. Specifics of the inspection scope must be provided.

Violation under the act

Penalties depend on type of schedule, nature of violation, and knowledge and intent of the violator, first or recurrent offense. Pharmacist must be proven to be negligent not only an inadvertent mistake.  May include civil penalty or imprisonment.

Federal Food, Drug and Cosmetic Act

Passed following the sale of sulfanilamide elixir with deadly diethylene glycol (car antifreeze) in 1937.  Act requires the use of NDA to prove to the FDA that the drug is safe and effective.

Drug: articles intended for use in diagnosis, cure, mitigation, treatment or prevention of disease in man or animals. Also, articles other than food intended to affect the structure or function of the body. Also, articles in the USP.

Legend (Rx) drugs

Includes the following types of drugs: Habit-forming drugs: such as narcotics or hypnotics.  Safety: drugs that are not safe except under supervision of a licensed practioner.

IND: files on a NCE.  Allows the conduct of research to prove safety and efficacy (exemption from the Act). Include phases 1-3.

Phase 1: use on healthy humans to determien metabolism, pharmacology, mechanism, SE.

Phase 2: well-controlled closely monitored studies on small #  of patients to evaluate efficacy for a certain indication and also SE and risks.

Phase 3: expanded clinical trials on patients to confirm safety and efficacy and risk/benefit relationship

NDA: acceptable proof of safety and efficacy to the FDA ® approved for use in certain indications.

Treatment INDs (treatment protocols): allows a practioner to use an investigational drug as treatmetn in serious and life-threatening disease when no alternatives are available.

OTC medications

FDA determined drug is safe for self-administration. Usually, drugs are not habit forming, ¯ toxicity / SE.  Must have adequate clear directions and must comply with FDA monograph (to avoid misbranding).  A legend (Rx) drug may be converted by the FDA to OTC.

Generic / Proprietary drugs

Generic name is the chemical name, common name or official name in the compendium.

ANDA: submitted for drugs that have already been proven safe and effective. The brand / generic must have the same active, dosage form, strength, route, indications, conditions of use.  Only bioavailability and bioequivalence have to be shown.  Approved bioequivalent drugs are listed in the orange book.

Established names for drugs

Established name: Commissioner of the FDA has the authority to designate names.  Name has to be simple and useful.  The FDA recongizes the US Adopted Names Council (USAN) in deriving names for NCE. Otherwise, use the name in the official compendium title. Otherwise, common or usual name is used.

Drug recall

Voluntary manufacturer recall: may be completely voluntary or after several attempts by the FDA to receive court ordered recalls.

Drug recall classification: assigned by the FDA. Class I: potential for serious SE and death.  Class II: potential for temporary or reversible SE or when serious SE are unlikely.  Class III: not likely to cause serious SE

Recall procedure: strategy should consider the depth of the recall, need for public warning.  First layer of notification (to wholesalers) is done by the company. Public notification is made by the FDA in the weekly FDA Enforcement Report.

Misbranding and adulteration

Adulteration: change or variation from official formulary or manufacturer’s standards. Drug contains filthy, putrid, decomposed substance.  Drug was prepared, packed, held under unsanitary conditions where it might have been contaminated. Container has poisonous substance. Drug contains unsafe color. Drug strength, quality or purity is different from claimed compendium standard. Drug contains another substance that ¯ its quality or strength.  OTC that is not properly packaged (tamper-proof) or labeled. Ophthalmic product that is not sterile. cGMP: a drug is adultrated if not manufactured in conformity with cGMP. 

Misbranding: a drug is sold or dispensed with a violative label. False or misleading label.  Imitation or name used of another drug. Insulin or antibiotic that is not batch certified. Drug dispensed in non-child proof container. Label without proper info (drug info, precautions, pharmacy info, Rx#, date, names of patient / prescriber, directions, etc), oral contraceptive / estrogen / progesterone / IUD without patient insert, package, Rx drug without Rx, ophthalmic preparation that is not sterile.

Violations under the Act: exemption in certain cases of good faith (violative product receive by the pharmacy in good faith), receipt of drug with a signed written guaranty from the wholesaler.

Seizures: of adultrated / misbranded product after a court hearing or without a hearing if there is propable cause of danger to public health.

Investigations and inspections: done by the US Secretary of Health and Human Services. Investigations must be authorized, within reasonable limits, time, manner and scope.

Package inserts

Manufacturer’s insert: full disclosure is required by the manufacturer. Enclosed with every commercial container. Contains essential informative and accurate scientific information for safe and effective drug use. It can’t be promotional in tone, false or misleading.

Patient package insert: due to certain SE with certain products, patient inserts must be dispensed, including refills.  That includes the following: Oral contraceptives, IUDs, Estrogen products, Porgestational products, Isoproterenol inhalation products, Miscellaneous (e.g. Isotretinoin ® serious fetal harm if pregnant).  For isoproterenol, label with “Do not exceed prescribed dose.  Contact physician if difficult persists”.

Prescription drug samples

Currently, sample distribution is very restricted. All sale, purchase, trade of samples are banned. Sample records are maintained by the manufacturer for 3 years. Pharmacies can not accept samples. Importation after exporting is illegal.

Medical devices

Safety and effectiveness are required.

Class I: reasonable assurance of safety and quality

Class II: no reasonable assurance of safety and quality, but has sufficient info to establish controls to ensure safety and quality

Class III: no reasonable assurance of safety and quality (generally, they can not be marketed).

Medical device tracking: required if failure may lead to serious SE. Tracking allows recalls.

Manufacturer’s reports: manufacturer, hospitals, pharmacies, etc are required to report to the FDA potential link to death or adverse SE.

Misbranding and adulteration: same as drugs

Poison Prevention Packaging Act

The Act (1970) require child-resistant containers for all drugs (difficult for children under age of 5 to open easily within short period of time). Enforced by the Consumer Product Safety Comission.

Requests for non-child resistant container: request can be made by the prescriber in a specific prescription, but a blanket request can’t be made. Patient can request that for one or all Rx (does not have to be in writing).

Reuse of child-resistant containers: generally prohibited.  Allowed for glass containers when a new child resistant cap is used.

Manufacturer’s packaging: no child-resistant container if the product will be repackaged by the pharmacist, but is required if product will be dispensed directly to the patient.

Exemptions for easy access: OTC non-child-resistant packaged can be sold as long as child-resistant alternative is offered.  Label “For Households Withouth Children” or “Package Not Child Resistant”. 

Hospitals and institutions: the Act applies to houshold substances (“any substance produced or distributed for sale for consumption or use by individuals in the household”). Act does not apply if drug is given by hosptial personnel and not directly dispensed to the patient.

Miscellaneous special packaging: such as furniture polish containing petroleum distillates, drain pipe cleaners, turpentine, pain solvents, lighter fluid.

Exceptions

Sublingual nitroglycerin and sublingual / chewable isosorbide dinitrate at low doses.

Erythromycin ethylsuccinate granules for oral suspension (¯ doses).

Oral contracpetives / conjugated estrogen / norethindrone acetate in memory-aid (mnemonic) packages (¯ dose).

Medroxyprogesterone acetate tablets.

Anhydrous cholestyramine powder.

Colestipol powder (¯ dose)

Potassium supplements (effervescent tablets, liquid, powder) (¯ dose).

Sodium fluoride (tablet / liquid, ¯ dose).

Betamethasone tablets in dispenser packages (¯ dose).

Prednisone or methylprednisolone tablets (¯ dose)

Pancrelipase tablet, capsule, powder (¯ dose)

Mebendazole tablets (¯ dose)

Anti-Tampering Act

Act passed in 1984 due to death from OTC capsules containing cyanide. Applies to consumer products (food, drug, device, cosmetic, other articles).

OTC tamper-resistant packaging: required from some products (contact lens, ophthalmic solutions).  Contain a visible indicator of breach or tampering. Product / tamper-resistant technology design must be distinct to avoid easy duplication by commonly available processes.

OTC tamper-resistant labeling: clearly alert consumers to specific tamper-resistant feature on the package.

Medical devices and cosmetics: required for certain products

Violations: include tampering, false communication or conspiracy for either.

Mailing Prescription Medications

All drugs, including narcotics, can be mailed by the physician or pharmacist. Place drugs in a plain outer container or securely wrap in plain paper.  Make no outside markings that indicate nature of content. Exception: do not mail flammable liquids or alcoholic beverages.

Omnibus Budget Reconciliation Act (OBRA)

The US Constitution states that the federal government has no authority to regulate the practice of pharmacy (done by the states).  Federal government can indirectly affect practice by attaching conditions of participation and reimbursement for federally funded programs.

Medicaid: Rx are paid jointly by federal and state governments. Federal reimbursement require the pharmacist to get a patient and medication history, conduct DUR, offer counseling to the patient.

Manufacturer’s best price: for manufacturer’s to participate in Medicaid, they must offer “best price” (lowest price for the purchaser).

Narcotic Treatment Programs

Methadone can be used as part of a total narcotic addition treatment program. Regulations were established by the FDA and DEA.  It is used for maintenance or detoxification. Facility has to be approved by the FDA, DEA and state authority.

Detoxification treatment: dispensing a narcotic drug in ¯ doses to ¯ withdrawal physiologic or psychologic symptoms.  Maximum period: 6 months.

Maintenance treatment: dispensing a narcotic drug at stable dosage levels to treat heroin or morphine-like dependence.

Requirments for patient admittance: has been physiologically dependent on a narcotic for one year and still is.  Patient participation must be voluntary.  Patient has to sign “Conset to Methadone Treatment” after being infomred properly.

Take home methadone: only to patients, judged by the physician, are responsible in handling narcotic drugs. Patient must come to the clinic for observation at least 6 days a week, then gradually ¯ observations to once a week. Dispense methadone as any CII drug.

24. Reviewing and dispensing prescriptions

Definitions

Prescriptions: orders for medications, non-drug products, and services.  Practitioners may prescribe medications only in their field of practice.

Information in the Rx: patient name and address, date, name and dosage form of the product, product strength, quantity (directly or indirectly), directions to the pharmacist (preparation, labeling), directions for the patient (quantity, schedule, duration, avoid “as directed”), refill information (“as needed” means one year), prescriber information (signature, DEA if controlled).

Medical orders: orders for medications intended for use by patients in an institutional setting.

Information in medication order: patient information, date and time, name and dosage form, product strength, route of administration, signature, directions to the pharmacist, instructions for administration.

Understanding the Rx

Understanding the order: all info must be understood and consistent, including disease condition, reason for treatment, type of units used.

Evaluating appropriateness: follow up if incomplete info was provided. Evaluate allergies, route of administration, drug-drug / food / disease interactions, safety for intended use, proper quantity and dosage, incompatibilities, legitimate prescriber.

Discovering inappropriate Rx: Drug Utilization Review: review medication profiles to ensure appropriateness.  Therapeutic intervention: calling the prescriber to discuss concerns regarding the Rx.  Following the intervention, the Rx may be dispensed as written, with changes or not at all.

Processing the Rx

Involves use of technicians and automation, save pharmacist’s time for patient counseling and education.  Record Rx number, original date of filling, product and quantity dispensed, pharmacist’s initials. 

Product selection: involves generic substitution, formulary / therapeutic substitution policies.

Product preparation steps: obtain proper medication amount, reconstitute if necessary, extemporaneous compounding, assembly of delivery unit, selection of proper package or container.

Labeling: contains name and address of pharmacy, patient’s name, original date of filling, Rx number, directions for use, product name and manufacturer, product strength, quantity dispensed, prescriber name, expiration date, pharmacist initials.  Unit-dose packages: contain one dose or unit of medication, label identifies drug name, strength, lot#, expiration date. Auxiliary labels: to ensure proper medication use, storage, federal transfer of narcotics, etc.

Record-keeping: include patient profile system that includes demographic information (allergies, DOB, disease, weight, occupation, OTC use) and record of all medications.

Dispensing medication and counseling

Counseling patients: evaluate patient’s understanding, supply additional information, proper use, storage, appearance, name, route of administration, duration of use, reason for the Rx, SE (frequency, severity, actions to manage and minimize), OTC or food interactions. 

Counseling health professionals: especially in institutional setting where the professional administers the drug.  Other information: cost, drug-drug or nutrition interactions, physical incompatibilities, interference with lab tests,

Patient monitoring

Pharmaceutical care plan: to ↑ frequency and benefits of desired outcomes.  Includes: assessment (review medical conditions and symptoms), plan (decision on appropriate therapy), monitoring (review outcome goals and endpoints).

Drug-related problems: unnecessary therapy, wrong drug, wrong dose, SE, poor compliance, need for additional therapy.

25. Sterile Products and Parenterals

Introduction

Sterile products: parenterals, irrigating solutions, ophthalmics

Aseptic technique: preparation procedures to maintain sterility

Pyrogens: metabolic byproducts of live and dead microorganisms that cause fever upon injection.

Tonicity: related to osmotic pressure.  Hypotonic solution: ↓ osmotic pressure than blood or 0.9% NaCl.  Cause cells to expand à hemolysis, pain.  Isotonic: exert same osmotic pressure as blood or 0.9% NaCl.  Hypertonic: must be administered through a large vein to avoid phlebitis and ensure rapid dilution.

Clean rooms: areas constructed and maintained to ↓ probability of environmental contamination of sterile products.  They have the following:

High-efficiency particulate air (HEPA) filters: used to clean the air entering the room.  Remove all particulates < 0.3 mm with efficiency ~ 100%.  HEPA filtered rooms are Federal Class 10,000, i.e., they contain <10,000 particles 0.5 mm or larger per cubic foot of air.

Positive-air pressure flow: used to prevent contaminated air from entering a clean room.

Counters: in the clean room are made of easily cleaned nonporous material, e.g., stainless steel.

Wall / floors: free from cracks / crevices, rounded corners, made of nonporous material, easily disinfected.

Air flow: air moved with uniform velocity (90 fpm) along parallel lines.

Laminar flow hoods: clean air work benches in clean rooms designed as aseptic environment for making sterile products (Class 100).  Horizontal: air flow moves across the surface of the work area (disadvantage: no protection for the operator).  Vertical: advantages: air flows down on the work space, which protects the operator, portion of the air is circulated a second time. 

Inspection / certification: for clean rooms and laminar flow hoods is done annually or when moved.  The dioctyl phthalate (DOP) smoke test ensures that no particle > 0.3 mm passes through HEPA filter. Anemometer is used to measure air flow velocity and a particle counter is used to count particles.

Sterilization methods and equipment

Thermal: using either moist or dry heat.  Moist heat (autoclave): most reliable and widely used.  Microorganisms are destroyed by cellular protein coagulation.  Minimum 121 C for 15 minutes. Dry heat: minimum 160 C for 120 minutes.  More potential damage to product due to ↑ temperature.

Chemical (gas): used for surfaces and porous materials (e.g. surgical dressings).  Ethylene oxide is used with gas and moisture.  Residual gas must be dissipated before product use. 

Radioactive: for industrial sterilization of products in sealed packages that can not be heated (e.g. surgical equipment, ophthalmic ointments).  Use either electromagnetic or particulate radiation.  May accelerate drug decomposition.

Mechanical (filtration): removes but does not destroy and clarifies solutions by eliminating particulates.  Depth filter: consists of fritted glass or unglazed porcelain.  Membrane (screen) filter: with thickness of 1-200 mm.  A mesh of millions of microcapillary pores filter the solution by physical sieving.  Pores make up 75% of surface à ↑ flow rate than depth filters.  Particulate filters (0.5-5 mm): remove particles or glass, rubber, plastic, etc. Used to ↓ risk of phlebitis by removing undissolved particles of reconstituted powders, cannot be used for blood, emulsions, suspensions, colloids. Microbial filters (<0.22 mm): ensures microbe removal (cold sterilization).  Either filter can be used as part of the tubing in drug administration (in-line filter).  

Packaging

Ampules: made entirely of glass. Single use.  Disadvantages: glass fragments may contaminate the product during opening à must be filtered, not multiple use. Not commonly used now.

Vials: glass or plastic closed with a rubber stopper and sealed with aluminum crimp. Advantages: can be multiple use (if bacteriostatic agent is added), easier to remove product, no glass fragment risk, no need for filtration.  Disadvantages: coring of rubber stopping can get into product, multiple use can cause microbial contamination.  Drugs that are unstable in solution are packaged in solid form and must be reconstituted with a diluent (sterile water or NaCl) before use.  Lyophilization (freeze drying) can be used to ↑ dissolution rate and permit rapid reconstitution.  Double chamber system: one chamber with sterile water for injection is separated from unreconstituted drug chamber by rubber closure à no need to enter vial twice à ↓ contamination risk.

Add-vantage system: drug is in a vial attacked to an IV bag for reconstitution. Add-vantage vial is screwed into the top of Add-vantage IV bag and rubber diaphragm is dislodged to allow the mixing.

Prefilled syringed: for immediate drug administration in an emergency (epinephrine, atropine). Prefilled cartridges: ready to use parenteral packages with ↑ accuracy and sterility.  Used for narcotics.

Infusion solutions: Small Volume Parenterals (SVP): volume < 100ml. Large VP (LVP): volume > 100ml. 

Packaging materials: Glass: clarity for easy inspection, ↓ interaction with content.  Plastic polymers: durability, easy storage / disposal, ↓ weight, ↑ safety, e.g., PVC and polyolefin. 

Routes of administration

Subcutaneous: usually in the arm or thigh.  Example: insulin.

Intramuscular: e.g. mid-deltoid, gluteus medicus, < 5ml.  Used for prolonged or delayed absorption (e.g. methylprednisolone).

Intravenous: most important and common, immediate therapeutic response, no recall of inadvertent overdose, e.g., antibiotics, cardiac drugs.

Intradermal: only very limited volume, e.g., skin tests and vaccines.

Intra-arterial: deliver ↑ drug concentration into target side with little dilution by circulation, e.g., diagnostic radiopaque materials and antineoplastics.

Hypodermoclysis: injection of large volumes of solution into SC tissue to provide continuous abundant drug supply, e.g., antibiotics for children.

Intraspinal: e.g. local anesthetics during surgery (lidocaine, bupivacaine).

Intra-articular: injection into joint space, e.g., corticosteroids (hydrocortisone, methylprednisone) for arthritis. 

Intrathecal: injection into the spinal fluid, e.g., antibiotics, cancer chemotherapy.

Parenteral preparations

IV admixtures: one or more sterile drug product added to an IV fluid.

IV fluids

Used in preparation of parenteral products (vehicles for IV admixtures).

Dextrose (d-glucose): 5% dextrose in water (D5W).  Used for reconstitution, as hydrating solution.  Higher concentration dextrose (e.g. D10W) provide source of carbohydrates in parenteral nutrition.  pH of D5W is 3.5-6.5 à instability of acid-labile drugs.  Concentration > 15% à give through central vein.  Use cautiously in DM. 

Sodium chloride: usually as 0.9% solution à isotonic (normal saline).  NaCl 0.45% is half-normal saline.  Used for admixtures, fluid and electrolyte replacement.  Bacteriostatic NaCl for injection (0.9%): for multiple reconstitutions (bacteriostatic à benzyl alcohol, propylparaben, methylparaben).  

Water: for reconstitution and dilution of NaCl, dextrose. Use Sterile or Bacteriostatic Water for Injection.

Ringer’s solution: used post-surgically for fluid and electrolyte replacement. Lactated Ringer’s (Hartmann’s solution): contains sodium lactate, NaCl, KCl, CaCl2, may be combined with D5W.  Ringer’s injection: does not contain sodium lactate, may be combined with D5W. 

IV electrolytes

Cations:

Sodium: main extracellular cation, important for interstitial osmotic pressure, tissue hydration, acid-base balance, nerve-impulse transmission, muscle contraction.  Examples: Na chloride, acetate, phosphate.

Potassium: main intracellular cation, important for muscle (esp cardiac) contraction, neuromuscular excitability, protein synthesis, carbohydrate metabolism.  Examples: potassium chloride, phosphate, acetate.

Calcium: important for nerve impulse transmission, muscle contraction, cardiac function, bone formation, cell membrane permeability.  Examples: calcium chloride, gluconate, gluceptate.

Magnesium: important for enzyme activities, muscle excitability, neuromuscular transmission.  Example: magnesium sulfate. 

Anions:

Chloride: main extracellular anion.  With sodium, it controls interstitial osmotic pressure, blood pH.  Examples: sodium, potassium, calcium chloride.

Phosphate: main intracellular anion.  Important for enzyme activities, controlling calcium levels, buffer to prevent changes in acid-base balance.  Examples: sodium, potassium phosphate.

Acetate: bicarbonate precursor à used as alkali to preserve plasma pH.  Examples: sodium, potassium acetate. 

Parenteral antibiotics

Route: direct IV, short term IV infusion, IM, intrathecal. 

Use: serious infections requiring ↑ concentration, GI is inaccessible.

Parenteral antineoplastics

May be toxic and hazardous during prep, administration.

Safe handling: use vertical laminar flow hood, syringes and IV tubing with Luer-Lok fittings, closed-front cuffed surgical gowns, double layered gloves, negative pressure technique, final dosage adjustment with care, special care priming IV sets, prime before adding the drug, special disposal, wash hands, monitor health of personnel.

Patient problems: Infusion phlebitis:  vein inflammation, pain, swelling, heat sensation, site redness, avoid by drug dilution and filtration. Extravasation: infiltration of the drug into SC tissues surround the vein.  Response: local hydrocortisone or anti-inflammatory, antidote with cold compress, warm compress to ↑ blood flow and wash vesicant away from damage tissue. 

Parenteral biotechnology products

Examples: monoclonal antibodies, vaccines, colony-stimulating factors.

Uses: cancer chemotherapy, HIV, hepatitis B, infections, transplant rejection, rheumatoid arthritis, inflammatory bowel, respiratory diseases.

Characteristics: protein and peptide biotechnology drugs: short t1/2, special storage (freezing, refrigeration), avoid vigorous shaking not to destroy protein molecules.

Route: direct IV, IV infusion, IM, SC.  Require reconstitution.

Irrigating solutions

Manufactured by the same standards for IV products but not intended for injection.  Labeling differenced specified in USP, i.e., different acceptable particulate matter levels, volume, container design.

Topical administration: packaged in pour bottles into desired.  For irrigating wounds, moistening dressings, cleaning surgical instruments.

Infusion: e.g., perfuse tissues to maintain integrity of surgical field, remove blood, clear field of view as in urologic surgeries.  Add Neosporin G.U. irrigant, an antibiotic, to ↓ risk of infection.

Dialysis (dialysates): e.g., in renal failure, poisoning, electrolyte disturbances. They remove waste matter, serum electrolytes, toxic products.  Peritoneal dialysis: hypertonic dialysate (dextrose, electrolytes) is infused in the peritoneal cavity via surgically implanted catheter à remove toxins by osmosis and diffusion à finally drain.  Antibiotics, heparin may be added. Hemodialysis: patient’s blood is transfused through a dialyzing membrane that removes toxins.

Needles and syringes

Hypodermic needles

Stainless steel or aluminum. 

Gauge: the outside diameter of the shaft.  Large number (27)à small diameter (13).  SC: 24-25.  IM: 19-22.  Compounding: 18-20. 

Bevels: slanting edges cut into needle tips to facilitate insertion.  Regular bevel: most common, for SC, IM.  Short bevel: used onlyfor shallow penetration (IV).  Intradermal bevel: most beveled. 

Lenghts: from ¼ to 6 inches, depending on desired penetration.  IV: 1¼ - 2½ inch. Compounding parenterals: 1½.  Intradermal / SC: ¼. Intra-cardiac: 3½. 

Syringes

Glass or plastic barrel and tight-fitting plunger, small opening to accommodate needle. 

Luer syringe: oldest, universal attachment for all needle sizes.

Syringe volumes: 0.3 – 60 ml.  Insulin syringes have unit graduations (100 units/ml) rather than volume graduations.

Calibrations: may be metric or English, vary depending on size.

Syringe tips: Luer-Lok: threaded to ensure needle fit tightly, for antineoplastic drugs.  Luer-Slip: unthreaded so needle does not lock into place, may be dislodged.  Eccentric: set off center to allow needle to remain to injection site and minimize venous irritation.  Catheter: used for wound irrigation and enteral feedings and not for injections. 

Intravenous drug delivery

Injections sites

Peripheral vein injection: preferred for non-irritating drugs, isotonic solutions, short term IV therapy.  Use dorsal forearm for venipuncture.

Central vein injection: preferred for hypertonic solutions, long-term IV therapy.  Use thoracic cavity vein, e.g., subcalvian.

Intermittent infusion

Continuous drip infusion: slow infusion to maintain therapeutic level ro provide fluid and electrolyte replacement.  Rate: ml/hr or drops/min.  Use for drugs with narrow therapeutic index, e.g., heparin, aminophylline.

Intermittent infusion: infusion at specific intervals (4hr), for antibiotics. Direct bolus injection: rapidly deliver small volume of undiluted drug.  Use for immediate effect as in emergency.   Additive set infusion: using volume control device, for intermittent delivery of small amounts.  Piggyback method: used when drug cannot be mixed with primary solution, a supplemental secondary solution is infused through the primary system, avoids a second puncture or further dilution.  Admixtures: also called manufacturer’s piggyback, a vehicle is added to the drug, example: Add-Vantage system. 

Intermittent infusion injection devices: also called scalp-vein, heparin-lock, butterfly infusion set.  Permit intermittent delivery without multiple punctures or prolonged venous access.  Use dilute heparin or normal saline to prevent clotting in the cannula.

Pumps and controllers

Pumps

Piston-cylinder mechanism: a syringe like apparatus

Linear peristaltic mechanism: external pressure to expel fluid out of the pumping chamber.

Volumetric pump: for intermittent infusion (e.g. antibiotics), continuous infusion, parenteral nutrition, etc.

Syringe pump: used for intermittent or continuous infusion of drug in concentrated form (e.g. antibiotics, opiates).

Mobile infusion pump: small infusion devices for ambulatory and home patients.  For chemotherapy and opiates.

Implantable pump: surgically planted under skin to provide continuous drug release, usually an opiate.  The pump reservoir is refilled by injecting drug into pump diaphragm.

Patient-controlled analgesia (PCA) pump: used for intermittent or on demand delivery of narcotics.

Benefits: ↑ cost, ↑ training, ↑ accurate flow rate, detect infiltration, occlusion and air, save nurse time.

Controllers

Use no pumping pressure.  Use gravity and control infusion rate by electronic counting of drops.  Compared to pumps: ↓ complex, ↓ expensive, reasonable accuracy, used for uncomplicated infusion but not arterial or small vein infusion.

IV incompatibilities

Types of incompatibilities

Physical: mixing causes visible change in appearance.  Example: evolution of CO2 when sodium bicarbonate and HCl are mixed.  It can be a visible color change or pptn (e.g. phosphate and calcium). 

Chemical: chemical degradation causing toxicity or loss of activity.  Complexation: such as calcium and tetracycline à inactive tetracycline complex.  Oxidation: when a drug loses electrons à color change, inactivity.  Reduction: when a drug gains electrons.  Photolysis: chemical decomposition by light à hydrolysis or oxidation à color change.

Therapeutic: e.g. bacteriostatic (tetracycline) then bactericidal (penicillin G) à ↓ activity of penicillin G.

Factors affecting compatibility

pH: ∆ in pH à ↑ incompatibility.  Acid + base = salt à may ppt.

Temperature: ↑ temp à ↑ degradation.  Use fridge or freezer.

Degree of dilution: ↑ dilution à ↓ ion interaction à ↓ incompatibility.

Length of time in solution: ↑ time à ↑ chance of incompatibility

Order or mixing: do not add incompatible drugs in sequence (e.g. calcium, phosphate), mix well. 

Preventing incompatibilities

Administer solutions quickly after mixing, mix each drug well after addition, ↓ number of mixed drugs, consult references.

Hazards of parenteral drug therapy

Physical

Phlebitis: usually a minor problem, minimize by proper IV insertion technique, dilution of irritating drugs, ↓ infusion rate.

Extravasation: caused by vesicant drugs

Irritation: ↓ by varying injection site and applying moisturizer

Pain: common with peripheral infusion of concentration drugs, ↓ by diluting the drug or switching to central vein.

Air embolism: can be fatal

Infection: critical in central IV lines, can be local or systemic (septicemia). 

Allergic reaction: due to hypersensitivity to IV solution, additive

Central catheter misplacement: may cause air embolism or pneumothorax, verify proper placement radiologically

Hypothermia: due to shock or cardiac arrest, may be due to cold IV solution, injection solution at room temp only.

Neurotoxicity: serious problem in intrathecal / intraspinal injection of drugs containing preservatives (avoid preservatives)

Mechanical

Pump/controller failure: may cause fluid overload, incorrect dose, or runaway infusion.

IV tubing: can become kinked, split, cracked, produce particles

Glass containers: may break à injury

Rubber vial closures: may interact with drug solution

Particulate matter

Therapeutic

Drug instability: may lead to therapeutic ineffectiveness

Incompatibility: may cause toxicity or ↓ effectiveness

Labeling errors: may cause using incorrect drug or dosage

Drug overdose: may be caused by runaway IV infusion, pump / controller failure, nursing / pharmacy errors.

Preservative toxicity: can be serious, esp in children.  Example: benzyl alcohol in premature infants à gasping syndrome (fatal acidotic toxic state). 

Quality Control / Quality Assurance

Quality control: day-to-day assessment of all operations including analytical testing of raw materials and finished product.

Quality assurance: oversight function, involves the auditing of QC procedures and systems.

Sterility testing: USP standard calls for 10-test samples from large batches, minimum of 2 samples from small batches. Test conducting using membrane sterilization method à membrane is cultured for microbial growth.

Pyrogen testing: qualitative fever response in rabbits or in vitro limulus lysate testing.

Clarity testing: to check for particulate matter. Swirl and look it against light source and dark background.

QA programs: include training, monitoring the manufacturing process, QC check, documentation.

Process validation: a mechanism for ensuring processes consistently result in sterile products of acceptable quality. Includes written procedures, evaluation of aseptic technique by process simulation.

Process stimulation testing: duplicate sterile product production except that a growth media is used instead of drug product.  Incubate final product: no growth à successful aseptic technique.

Documentation: of training procedures, QC results, laminar flow hood certification, production records, etc.

35. Drug use in special patient populations

Pediatrics

PK consideration

PK parameters change as children mature from birth to adolescence.

Gastrointestinal absorption:

Gastric pH: neonates are achlohydric (pH >4) but pH ↑ quickly in the first few weeks of life à ↑ absorption of basic drugs and ↓ absorption of acidic drugs, ↑ absorption of drugs destroyed by acidic pH (penicillins).  

Gastric emptying: long and highly variable in neonates and preemies, normal by age 6 months (t1/2 65 min).  Drugs absorbed in the intestine: ↓ emptying rate à ↓ absorption, ↓ peak concentration.  Formula has ↑ caloric density à 2x as fast gastric emptying in breast fed infants.

Underlying disease state: may ∆ gastric emptying rate, total surface area, absorption of lipids

Bile acid production: ↓ in preemies (1/2) than adults à ↓ fat and drug absorption (e.g. Vitamin D). 

Pancreatic enzyme function: affects absorption of lipid soluble drugs.  Neonates have ↓ lipases à ↓ absorption of chloramphenicol oral suspension.

Percutaneous absorption

Skin hydration à ↑ in neonates and preemies.  SC thickness à normal in newborns, ↓ in preemies.  TEWL à ↑ in neonates. 

Intramuscular absorption

Affected by absorption surface area, blood flow, injection site, muscle activity.  Preemies à ↓ muscle mass, ↓ muscle contractility à erratic IM absorption.  IM absorption is normal in infants and children but is discouraged due to pain.

Distribution

Protein binding: acidic drugs bind to albumin.  Basic drugs bind to alpha1-acid glycoprotein.  Both proteins are ↓ in neonates à ↑ free drug.  Normal levels at 1 year old of age.

Size of body compartments: Extracellular fluid volume is 40% in neonates, 20% at age one.  Polar compounds (e.g. aminoglycosides) distribute into extracullar fluids à loading dose is requires in neonates to rapidly achieve therapeutic concentrations.  Body fat is ↓↓ in preemies, higher in newborns and reaches a peak at one year. A ↓ body fat à ↓ Vd for lipophilic drugs (diazepam).

Endogenous substances: neonates may have ↑ free fatty acid and unconjugated bilirubin à bind to plasma proteins and ↓ degree of drug protein binding (↑ unbound drug).

Bilirubin competes with certain drugs for albumin binding sites. If displaced à potential drug induced kernicterus.

Metabolism

Mostly occur in the liver.  Some occur in the intestine, lung, skin.  Liver metabolism is affected by enzyme inducers (Phenobarbital, phenytoin, carbamazepine, rafampin) and enzyme inhibitors (cimetidine, erythromycin).

Phase I reactions: non-synthetic reactions (oxidation, reduction, hydrolysis, hydroxylation) that usually result in inactive or ↓ activity metabolites.  Most important enzymes are cytochrome P-450 monoxygenase system (50% of adult level at birth). 

Phase II reactions: synthetic conjugation reactions (with glycine, glucuronide, sulfate) that result in polar water soluble inactive compounds for renal and bile elimination.  Enzymes systems are ↓ at birth and ↑ with age.  Glucuronide conjugation à chloramphenical, sulfate conjugation à acetaminophen, sulfonamides à acetylation,

Elimination

Kidney is the major route of elimination for water soluble drugs and metabolites.  Processes involved: glomerular filtration, tubular secretion, tubular reabsorption.  Filtration and secretion ↑ eilimination, reabsorption ↓ elimination.  All processes are ↓ in neonates.  Renal blood flow (important for glomerular filtration) is ↓ in neonates.  Only unbound drugs undergo glomerular filtration.

Problems in drug monitoring

Therapeutic monitoring depends on correlation between serum concentration and therapeutic effect.  The relationships are established for adults and may not work for infants. 

Side effects: Most common with antibiotics (vancomycin, penicillins, cephalosporins), anticonvulsants, narcotics, antiemetics, contrast agents.  Examples: red-man syndrome with vancoymcin, syndrome of inappropriate antidiuretic hormone (SIADH) with carbamazepine. 

Dosing consideration: Body surface area = square root of (height x weight / 3600).  Dose intervals: may be longer for neonates and shorter for older children.

Pregnancy

Fetal development

Withdraw all unnecessary medications 3-6 months before plans for conception.

Blastogenesis: first 2-3 weeks after fertilization.  Germ formation occurs.  Embryonic cells are undifferentiated. 

Organogenesis: 2-8 weeks.  Most critical period of development as organs start to develop.  Drug exposure may cause major congenital malformations. 

Fetal period: 9 weeks to birth. At 9 weeks, the embryo is called a fetus.  Maturation and growth occurs.  Low risk of major congenital malformations. 

Placental transfer of drugs

Functions of placenta: nutrition, respiration, metabolism, excretion, endocrine activity to maintain fetal and maternal well being.  In order for a drug to cause teratogenic or pharmacological effect, it has to pass from the maternal circulation to the fetal circulation through the placenta. 

Placenta is not a protective barrier: most substances pass the placenta by passive diffusion due to concentration gradient.  Placenta acts similar to any other lipid membrane.

Factors affecting drug transfer: Molecular weight: ↓ (< 500 dalton) à cross easily, large (heparin) à does not cross.  pH: weakly acidic and weakly basic drugs cross easily.  Lipid solubility: ↑ à cross easily.  Most oral drugs are designed for optimal lipid membrane transfer.  Drug absorption: during pregnancy à ↓ gastric tone and motility à delayed gastric emptying à ↓ absorption.  Drug distribution: during pregnancy à ↑ Vd with gestational age, ↑ fat content, ↑ total body fluid.  Plasma protein binding: only free unbound drugs cross placenta.  Albumin and alpha1-acid glycroprotein are ↓ during pregnancy à ↓ free drugs.  Placenta membrane becomes thinner with gestational age.  Blood flow ∆ with meals, exercise, drugs and may ∆ placental crossing.

Embyotoxic drugs: may terminate or shortens pregnancy, especially in early pregnancy.  Examples: ACE inhibitors, hormones, antidepressants. 

Teratogenic drugs: risk of teratogenesis is highest during the 1^st trimester à physical malformations, mental abnormalities.  Teratogenic effect depend on the time during gestation when the drug is taken, and organs developing at this point.  FDA Classification: Category A (safety documented in humans), Category B (safety documented in animals, or safe in humans but damaging in animals), Category C (human safety unknown, may be damaging in animals), Category D (damaging in humans, only use in life-threatening situations), Category X (highly damaging in humans and may be animals, absolute contraindication).  Examples: vitamin A derivatives (isotretinoin), ACE inhibitors, warfarin (use heparin instead), estrogens, androgens, thyroids (methimazole, carbimazole, propylthiouracil), cortisone, ethanol (Fetal Alcohol Syndrome, FAS), antibiotics (tetracycline (teeth), metronidazole, quinolone), anticonvulsants (phenytoin, valproic acid, sodium valproate, trimethadione), lithium (Ebstein’s anomaly), antineoplastics (methotrexate, cyclophosphamide, chlorambucil, busulfan), finasteride (avoid handling of tablets and semen of male users).

Fetotoxic drugs: more likely during fetal period (9 weeks to birth).  CNS depression (barbiturates, tranquilizers, antidepressants, narcotics), Neonatal bleeding (NSAIDs, anticoagulants, use Tylenol instead), Drug withdrawal (habitual maternal use of barbiturates, narcotics, benzodiazepines, alcohol), Reduced birth weight (cigarette smokers, alcoholics, drug abusers), constriction of ductus arteriosus (NSAIDs in 3^rd trimester may cause pulmonary hypertension).

Drug excretion in breast milk

Transfer from plasma to breast milk: affected by factors influencing human membrane transfer.  This is, like other membranes, a semipermeable lipid barrier.  Unionized drugs may pass by passive diffusion. Low molecular weight molecules pass through small pores.  Larger molecules must dissolve first in the lipid membrane.

Drug’s physicochemical properties: human milk is more acidic than plasma.  Acidic drugs are unionized à diffuse into milk and back.  Basic drugs become ionized in milk à trapped in milk.  Plasma protein bound drugs can’t pass into milk.  ↑ lipid solubility à ↑ passage to milk. 

Drugs affecting hormonal influence: primary hormone is prolactin.  Bromocriptine à ↓ prolactin à suppress lactation if desired.  Other drugs to ↓ prolactin: L-dopa, ergot alkaloids.  Drugs to ↑ prolactin: metoclopramide, sulpiride. 

Minimizing infant’s drug exposure: choose drugs with no active metabolites, short t1/2, no milk accumulation.  Adjust route of administration, dosing schedule to ↓ infant’s exposure.

Drugs that enter breast milk: narcotics, barbiturates, BZD, alcohol, antidepressants, antipsychotics, metoclopramide, anticholinergics (dicyclomine).

Geriatrics

People >65 years use 33-50% of all prescriptions.  75% of elderly are Rx users.

20% of elderly experience SE.  Incidence of SE is 2-3x higher in elderly.

SE may be overlooked in elderly because they are similar to disease symptoms.

Causes of ↑ SE in elderly: polypharmacy, multiple diseases, more severe diseases, ↓ drug elimination, ↑ sensitivity to drug effects.

One third of elderly use => 6 drugs.

Polypharmacy à ↑ drug interactions, ↑ drug-disease interactions.

↑ noncompliance in elderly especially with females, ↓ socioeconomic status, living alone, polypharmacy, multiple disease, complicated regimens.

Disease à ↑ noncompliance.  Example: macular degeneration, cataract, hearing loss, arthritis, Alzheimer.

Clinical trials during drug development may not test drugs on the elderly (↑ SE).

↑ osteoporosis à ↑ fractures due to falls because of drugs causing dizziness, drowsiness, syncope, hypotension, blurred vision.

Avoid long acting BZD, use lorazepam, oxazepam (no active metabolites, phase I metabolism).

Pharmacokinetics

↓ liver metabolism (phase I) à ↑ drug accumulation

Absorption: can be affected by delayed gastric emptying, ↑ gastric pH, ↓ GI motility.  Usually, the rate but not the extent of absorption is affected.

Distribution: ↑ body fat / lean muscle mass ratio à ↑ Vd of fat soluble drugs (diazepam, propranolol).  ↓ total body water à ↓ Vd of water soluble drugs (acetaminophen). ↓ serum albumin à ↓ protein binding à ↑ free drug (warfarin, phenytoin).

Kidney excretion: very important.  ↓ glomerular filtration, ↓ tubular secretion rate.  50% ↓ in renal function by age 70 in normal patients. Serum creatinine is not a good measure of renal function as creatinine also ↓ with age. ↓ dose of renally eliminated drugs to avoid SE and toxicity.  Examples: digoxin, procainamide, H2 antagonists, lithium, aminoglycosides.

Liver metabolism: ↓ phase I (but not phase II) metabolism and ↓ blood flow à ↑ t1/2, ↑ SE of BZD, some analgesics.  

Pharmacodynamics

Altered response to certain drugs.  ↓ response to beta blockers, ↑ response to analgesics, BZD, warfarin.  Generally, start low and titrate slow.

↑ sensitivity to anticholinergic SE à avoid if possible.

 

36. Clinical laboratory tests

General principles

Monitor therapeutic / SE: e.g. serum uric acid after allopurinol, or liver function after isoniazid.

Estimate proper dose: serum creatinine or creatinine clearance before giving renally excreted drug

Decide on alternative / additional therapy: WBC count after AB

Drug-caused test misinterpretation: false positive urine glucose test after cephalosporin.

Normal test values: usually mean +/- 2 SD.

Standardization: using international system of units (SI).  Basic SI unit is the mole (more physiologically meaningful as reaction occurs at molecular level).

Lab error: due to specimens (spoiled, incomplete, wrong sampling time), bad reagents, inaccurate procedure, technical errors.

Basic battery of tests: with routine physical and hospital admission include ECG, chest x-ray, electrolytes, urinalysis, hemogram.

Types of test: quantitative (normal range), qualitative (-ve / +ve), semi-quantitiatve (1+, 2+, e.g. urine glucose).

Hematological tests

RBCs

RBC count: number of RBCs per cubic mm of blood, an estimate of the blood Hb content. Normal: 4.5 million/mm3 (higher in men).

Hematocrit or packed cell volume (PCV): measures percentage (fraction) by volume of packed RBCs in whole blood after centrifugation.  Hct is usually 3x the Hb value. Normal: 45% (higher in men).  Low Hct à anemia, over hydration, blood loss.  High Hct à polycythemia, dehydration.

Hemoglobin test: measures grams of Hb in 100 ml (1dl) of whole blood, an estimate of the oxygen carrying capacity of RBCs. It depends on the number of RBCs and amount of Hb in each RBC. Normal: 15 g/dl (higher in men).  Low Hb à anemia.

RBC (Wintrobe) indices: info on the size, Hb concent, Hb weight of RBCs.  Used to categorize anemias.  Poikilocytosis: ∆ in RBC shape as in sickle-cell anemia.  Anisocytosis: ∆ in RBC size as in folic acid and iron deficiency anemia.

Mean corpuscular volume (MCV): ratio of Hct to RBC count. Measures average RBC size (anisocytosis).  Normal: 90.  Low MCV à microcytic anemia (iron deficiency).  High MCV à macrocytic anemia (folic acid or vitamin B12 deficiency).

Mean cell Hb (MCH): measures amount of Hb in average RBC.  Normal: 30. 

Mean cell Hb concentration (MCHC): measures average Hb concentration in average RBC.  Normal: 35.  Low MCHC à hypochroma (pale RBCs) as in iron deficiency.

RBC distribution width (RDW): normal RBCs are equal in size à bell-shape normal histogram distribution à high RDW in anemia (iron, folic acid, vitamin B12 deficiency).  RDW is never below normal.

Reticulocyte count: measures immature RBCs (reticulocytes), which contain nuclear material (reticulum), Normal: 1% of all RBCs.  It measures bone marrow production of mature RBCs.  High reticulocyte count à hemolytic anemia, acute blood loss, response to treatment of factor deficiency anemia.  Low reticulocyte count à drug-induced aplastic anemia.

Erythrocyte sedimentation rate (ESR): measures rate of RBC sedimentation of whole uncoagulated blood.  It reflects plasma composition.  Normal: 10 mm/hr (higher in females).  High ESR à acute or chronic infection, tissue necrosis, infarction, malignancy.  Use to follow disease course, differentiate diagnosis (angina à normal ESR, MI à ↑ ESR).

WBCS

WBC count: number of WBCs in whole blood. Normal: 7000 / mm3.  High WBC count (leukocytosis) à due to infection (esp. bacterial), leukemia, tissue necrosis. Low WBC count (leukocytopenia) à due to bone marrow depression due to cancer, lymphoma or antineoplastic drugs.

WBC differential: evaluates the distribution and morphology of WBC cell types including granulocytes (neutrophils, basophils, eosinophils), and non-granulocytes (lymphocytes, monocytes).

Neutrophils: may be mature or immature.  Chemotaxis: congregation of neutrophils at site of tissue damage of foreign body invasion à first line defense à phagocytosis and degradation of invaders.  Neutrophilic leukocytosis (↑#, ↑ fraction of immature cells) à systemic bacterial infection (e.g. pneumonia), viral infection, fungi, stress (physical, emotional, blood loss), inflammatory disease (rheumatism), drug hypersensitivity, tissue necrosis, leukemia, certain drugs (Ep, lithium).   Neutropenia (↓#, < 1000/mm3) à overwhelming infection as bone marrow is unable to keep up with demand, viral infections, chemotherapy drug reactions.  

Basophils: called mast cells in the tissues.  Basophilia (↑#) à leukemia.

Eosinophils: associated with immune reactions. Eosinophilia (↑#) à acute allergic reaction (asthma, hay fever, allergy), parasitic infections. 

Lymphocytes: critical for immunologic activity, produce antibodies. Types: T and B.  Lymphocytosis (↑#) à viral infection.  Lymphocytopenia (↓#) à severe debilitating disease, immunodeficiency, AIDS.  Atypical lymphocytes à in infectious mononucleosis.

Monocytes: phagocytic cells.  Monocytosis (↑#) à TB, bacterial endocarditis, during recovery of acute infections.

Platelets (thrombocytes)

Smallest in size.  Involved in clotting. Normal: 225,000 / mm3. 

Thrombocytopenia: ↓ platelets due to disease or drugs.  Moderate: < 100,000.  Severe: < 50,000.

Serum enzyme tests

Creatinine kinase (CK)

Location: heart, skeletal muscle, brain tissue

Use: aid diagnosis of acute MI (necrosis) or skeletal muscle damage.

Isoenzymes of CK: CK-MM in skeletal muscle (major), CK-MB in heart, CK-BB in brain à used to identify source of damage.

↑ CK-MB à heart necrosis

Interference: exercise, fall, IM injection.

Lactate dehydrogenase (LDH)

LDH converts lactate to pyruvate and vice versa.  Found in all cells.

Isoenzymes: 1 and 2 (heart), 3 (lungs), 4 and 5 (liver, skeletal muscles).

Use: aid diagnosis of MI, liver / lung disease.

Alkaline pohsphatase (ALP)

Location: produced mainly in the liver and bones

Use: serum ALP is sensitive (↑) to biliary obstruction as in bile duct stone.  Serum ALP ↑ due to ↑ osteoblastic activity (e.g. Paget’s disease, hyperparathyroidism, osteomalacia).

Asparatate aminotransferase (AST)

Formerly known as serum glutamic-oxaloacetic transaminase (SGOT)

Location: mainly in the heart and liver.

Use: ↑ AST in acute hepatitis, cirrhosis, fatty liver, passive liver congestion (as in CHF).

Alanine aminotransferase (ALT)

Formerly known as serum glutamic-pyruvic transaminase (SGPT)

Location: mainly in the liver

Use: more specific but less sensitive than AST for liver damage.  ALT ↑ only in severe liver damage.

Cardiac troponins

Use: identify MI injury, prognosis of unstable angina.  More specific than CK-MB.  Troponin T à in cardiac and skeletal muscles.  Tropnonin I à only in cardiac muscle.

Normal: Troponin T à < 0.1 ng/ml, Toponin I à < 1.5 ng/ml.

Liver function tests

Liver enzymes

Certain enzymes (LDH, ALP, AST, ALT) ↑ with liver dysfunction.

They indicate only liver damage but not ability to function

Serum bilirubin

Bilirubin is a breakdown product of hemoglobin, main bile pigment.

Indirect bilirubin (unconjugated): bilirubin released from Hb breakdown, bound to albumin, water insoluble, not filtered by glomerulus. 

Direct bilirubin (conjugated): Unconjugated bilirubin travel to the liver à separate from albumin à conjugate à actively secret to the bile à filtered by the glomerulus.

Normal values: Total bilirubin à 0.5 mg/dl.  Direct bilirubin à 0.1 mg/dl.

↑ bilirubin à tissue deposition à jaundice.  Causes: hemolysis, biliary obstruction, liver cell necrosis.

Hemolysis: ↑ total but not direct bilirubin.  Normal urine.

Biliary obstruction: may be intra-hepatic (e.g. due to chlorpromazine), or extra-hepatic (biliary stone) à ↑ total and direct bilirubin. Bilirubin present in urine à dark color.

Liver cell necrosis: due to viral hepatitis à ↑ total and direct bilirubin. Bilirubin present in urine à dark color.

Serum proteins

Normal total serum protein level: 7 g/dL.  Transport agents.

Albumin: made in the liver (liver disease à ↓albumin )

Globulin: ↓ albumin à compensatory ↑ in globulin.

Urinalysis

Appearance

Normal urine: clear, pale yellow to deep gold color.

Red urine: presence of blood or phenolphthalein (laxative)

Brownish-yellow urine: presence of conjugated bilirubin.

pH

Normal urine: slightly acidic (pH = 6)

Alkaline pH: due to acetazolamide use (bicaronaturia), or due to leaving urine sample at room temperature.

Specific gravity

Normal urine: 1.015

↑ specific gravity: DM, glucose in urine, nephrosis (protein in urin)

↓ specific gravity: due to diabetes insipidus (↓ urine concentration).

Protein

Normal: 65 mg/24 hr.

Glomerular membrane prevents most blood protein from entering urine

Albuminurea: abnormal glomerular permeability.

Proteinuria: due to kidney disease, bladder infection, fever

Glucose

Normal renal threshold for glucose: blood glucose of 180 mg/dl.

Glycosuria: due to DM.

Ketones

Usually absent in urine.  Excreted when body has used available glucose stores and began to metabolize fat due to uncontrolled DM, or due to ↓↓ carbohydrate diet à Ketonuria.

Ketone bodies: betahydroxybutyric acid (major), acetoacetic acid, acetone.

Microscopy

Hematuria: presence of RBCs may indicate trauma, tumor, systemic bleeding.  Squamous cells indicated vaginal contamination due to menstruation in women.

Casts: protein conglomerations may be due to renal disease.

Crystals: pH-dependent, uric acid crystals in acidic urine, phosphate crystals in alkaline urine.

Bacteria: usually absent in urine (sterile), if present may be due to UTI or urethral contamination.

Renal function tests

Renal function ↓ with age.  Use results to adjust drug dosage if needed.

↓ renal function à ↓ urea / creatinine excretion à ↑ their blood levels.

Azotemia/uremia: ↑ retention of nitrogenous waste (BUN / creatinine) in blood.

Renal azotemia: due to renal disease, e.g. glomerculonephritis.

Prerenal azotemia: due to dehydration, ↑ protein intake, hemorrhagic shock.

Postrenal azotemia: tumors or stones in the uterers, urethra, prostate.

Clearance: volume of plasma from which a measured amount of substance is eliminated (cleared) into urine per unit time.  Use to measure glomerular function

BUN (blood urea nitrogen)

Urea: end product of protein metabolism, produced in the liver.

Urea is filtered at the glomerulus, then 40% is reabsorbed at the tubules à urea clearance is 60% of true GFR

Normal BUN: 13 mg/dl.

↓ BUN: due to liver disease

↑ BUN: due to renal disease, ↑ renal blood flow, ↑ protein intake.

Serum creatinine

Creatinine: metabolic breakdown product of muscle creatine phosphate

Normal level: 1 mg/dl, but varies based on the muscle mass

Creatinine excretion: by glomerular filtration and tubular secretion.

↑ serum creatinine à renal insufficiency.

50% ↓ in GFR à doubling of serum creatinine.

Creatinine clearance

Rate at which creatinine is removed from blood by the kidney.

Normal value: 100 ml/min (100 ml of blood cleared of creatinine / min).

Creatinine clearance parallels GFR, more sensitive than BUN.

Creatinine clearance = (urine creatinine concentration x urine rate) / serum creatinine.

Cockroft and Gault equation: used to estimate Clcr based on body weight, age, gender, and serum Cr when urine information is N/A.

Electrolytes

Sodium

Major extracellular cation. Cellular osmosis and water balance: controlled by sodium, potassium, chloride and water. 

Normal level: 140 mEq/L.  Concentration is a ratio of Na to water.

∆ Na à ∆ water balance not electrolyte balance.

Na control: by antidiuretic hormone (ADH) and aldosterone. 

Hypothalamus à release ADH from pituitary gland à ↑ renal reabsorption of sodium.

↓ blood Na,↑ blood K, angiontesin II à aldosterone (mineralocorticoid) release from adrenal cortex à ↑ Na reabsorption in exchange for K urine secretion.

Hyponatremia: due to ↑ Na loss (kidney disease), ↓ Na intake, overhydration (non-saline fluid replacement, ↑ water intake), ↓ mineralocorticoid (↓ Na reabsorption), SIADH.

Hypernatremia: due to ↓ Na excretion, ↑ Na intake (hypertonic IV), dehydration  (loss of free water as in diabetes insipidus), ↑ mineralocorticoid, ↑ Na drug (Na bicarbonate, ticarcillin).

Potassium

Most common intracellular cation.  Normal level: 140 mEq/L intracellular, 4.5 mEq/L in blood (10% extracellular à can not use that measure).

Role: electrical conduction in heart and skeletal muscles, water balance, acid-base balance.

K regulation: by kidneys, aldosterone, blood pH, insulin, K intake.

↑ blood pH à ↓ blood potassium / ↓ blood sodium

Hypokalemia: most K is lost through kidneys, due to vomiting, diarrhea, laxative abuse, diuretics (mannitol, thiazides, loop), ↑ mineralocorticoids, glucosuria, ↓ K intake, metabolic alkalosis / insulin / glucose (all move K intacellularly). Signs: fatigue, dizziness, ECG, pain, confusion

Hyperkalemia: due to ↓ kidney elimination, ↑ K intake, cellular breakdown (tissue damage, hemolysis, burns, infections), metabolic acidosis, potassium sparing diuretics, ACE inhibitors.

Chloride

Major extracellular anion à critical for acid-base balance.

Not important clinically.  Only confirms Na levels.  Normal: 100 mEq/L

Cl retention usually happens with Na and water retention.

Anion gap = sodium – (chloride + bicarbonate)

Hypochloremia: due to fasting, diarrhea, vomiting, diuretics.

Hyperchloremia: usually due to metabolic acidosis, or dehydration, ↑ Cl intake, renal failure.

Bicarbonate / CO2

HCO3-/CO2 is the most important buffering system to maintain pH (acid base balance). Normal level: 25 mEq/L.

Bicarbonate binds to hydrogen to form carbonic acid which can convert to CO2 and water.

Hypobicarbonatemia: due to metabolic acidosis, renal failure, hyperventilation, diarrhea, carbonic anhydrase inhibitors, drug toxicity (salicylate, methanol, ethylene glycol).

Hyperbicarbonatemia: due to metabolic alkalosis, hypoventilation, ↑ bicarbonate intake, diuretics.

Minerals

Calcium

Role: bone integrity, nerve impulse transmission, muscle contraction, pancreatic insulin release, gastric hydrogen ion release, blood coagulation.

Normal level: 10 mg/dl.  Ca reservoir in bones (44% calcium) maintains plasma level. 40% of calcium is bound to plasma proteins (albumin)

Only free unbound ionic calcium is important physiologically à depends on amount of serum protein (albumin)

Hypocalcemia: due to ↓ parathyroid hormone or ↓ vitamin D.  Can be caused by loop diuretics.

Hypercalcemia: due to malignancy or metastasis, hyperparathyroidism, Paget’s disease, thiazide diuretics, ↑ Ca intake, ↑ vitamin D.

Phosphate

PO4 is a major intracellular anion à source of phosphate for ATP and phospholipids synthesis.  Normal level: 4 mg/dl.

Ca and PO4 are affected by same factors à consider together

Hypophosphatemia: due to ↓ vitamin D, hyperparathyroidism, malnutrition / anabolism, aluminum antacids, Ca acetate, alcoholism

Hyperphosphatemia: renal insufficiency, ↑ vitamin D, ↑↓ parathyroid

Magnesium

Second most abundant intracellular and extracellular cation.

Role: activates enzymes for carbohydrate / fat / electrolyte metabolism, protein synthesis, nerve conduction, muscle contraction.

Normal level: 2 mEq/L.

Hypomagnesemia: more common, due to ↓ GI absorption, ↑ GI fluid loss, ↑ renal loss.  Signs: weakness, tremor, ↑ reflexes, arrhythmia.

Hypermagnesemia: due to ↑ Mg intake with renal insufficiency, Addison’s disease.  Signs: bradycardia, flushing, sweating, ↓ Ca.

Summary table

Indicator	Normal	High	Low
RBC Count	4.5 million/mm3	↑ in men, ↑ erythropoiesis as in hypoxemia
Hematocrit (packed cell volume)	45% (~3xHb)	↑ in men, polycythemia, dehydration	anemia, blood loss, over-hydration
Hemoglobin	15 g/dl	↑ in men	anemia
Poikilocytosis	∆ RBC shape	sickle-cell anemia
Anisocytosis	∆ RBC size	folic acid, iron deficiency anemia
Mean corpuscular volume	90: average RBC size, (Hct / RBC count)	folic acid or vitamin B12 deficiency anemia	iron deficiency anemia
Mean cell Hb concentration	35: average Hb / RBC		hypochroma (pale RBCs), ↓ iron anemia
RBC distribution width	Normal distribution	anemia (iron, folic acid, vitamin B12 deficiency)
Reticulocyte count	1% immature RBCs (reticulocytes)	hemolytic anemia, acute blood loss	drug-induced aplastic anemia
Erythrocyte sedimentation rate	10 mm/hr	↑ in females, acute or chronic infection, rheumatoid arthritis, tissue necrosis, MI, malignancy
WBC Count	7000 / mm3	Leukocytosis à infection (esp. bacterial), leukemia, tissue necrosis	Leukocytopenia à bone marrow depression due to cancer, lymphoma, antineoplastic drugs
Neutrophils		Neutrophilic leukocytosis à bacteria (pneumonia), viral, fungi, stress, rheumatism, drug hypersensitivity, tissue necrosis, leukemia	Neutropenia (<1000/mm3) à overwhelming infection, chemothrepay
Lymphocytes		Lymphocytosis à viral infection	Lymphocytopenia à severe debilitating disease, ↓ immunity, AIDS
Basophils		Basophilia à leukemia
Monocytes		Monocytosis à TB, bacterial endocarditis
Eosinophils		Eosinophilia à acute allergy, parasite infection
Platelet Count	225,000 / mm3		Thrombocytopenia (disease or drugs)
Creatinine kinase (CK)		acute MI (necrosis), skeletal muscle damage
Cardiac troponins	Troponin-T<0.1 Toponin I < 1.5 ng/ml.	MI injury, prognosis of unstable angina
Lactate dehydrogenase (LDH)		MI, liver / lung disease
Alkaline pohsphatase (ALP)		biliary obstruction (bile duct stone), Paget’s disease, osteomalacia, hyperparathyroidism
Asparatate aminotransferase (AST) (also celld SGOT)		Acute hepatitis, cirrhosis, fatty liver, liver congestion (as in CHF).
Alanine aminotransferase (ALT) (also called SGPT)		severe liver damage, less sensitive / more specific than AST
Liver enzymes	LDH/ALP/AST/ ALT (above)	liver dysfunction / damage
Total serum bilirubin (Indirect / unconjugated + direct conjugated)	0.5 mg/dl	Jaundice (hemolysis, biliary obstruction, liver cell necrosis)	(↑ bilirubin may also show in urine à dark urine)
Direct serum bilirubin (conjugated)	0.1 mg/dl	biliary obstruction, liver cell necrosis	(not bound to albumin, secreted to bile, filtered)
Serum proteins	7 g/dL		Liver disease, nephritic syndrome, cystic fibrosis)
Urine color	Clear yellow to deep gold	Red à blood or phenolphthalein	Brownish-yellow à conjugated bilirubin
pH	Slightly acidic (6)	Alkaline: acetazolamide, bicaronaturia	Acidic: vitamin C, ammonium chloride
Specific gravity	1.015	DM, glucose or protein (nephrosis) in urine	diabetes insipidus (↓ urine concentration).
Protein	65 mg/24 hr.	∆glomerular permeability, infection, disease
Glucose	180 mg/dl	Glycosuria: due to DM
Ketones	None	Ketonuria: uncontrolled DM
RBCs	None	trauma, tumor, systemic bleeding
Squamous cells	None	vaginal contamination due to menstruation
Casts	None	protein conglomerations due to renal disease
Crystals	None	Acidicà uric acid crystals Alkaline à phosphate
Bacteria	None	UTI, urethral contamination
Blood urea nitrogen	13 mg/dl. (60% of GRF)	renal disease, ↑ renal bl. flow, ↑protein intake	liver disease (protein is broken to urea in liver)
Serum creatinine	1 mg/dl	renal insufficiency
Creatinine clearance	100 ml/min		renal insufficiency
Sodium	140 mEq/L	↑ Na intake, hypertonic IV, dehydration, diabetes insipidus, ↑ Na drug (Na bicarb), ↑ mineralocorticoid).	kidney disease, ↓ dietary intake, ↑ water intake,  overhydration, ↓ mineralocorticoid, SIADH
Potassium	140 mEq/L (only 10% extracellular)	↑ intake, cellular breakdown (hemolysis, burns, infections), metabolic acidosis, K sparing diuretics, ACE-I	↓ K intake, vomiting, diarrhea, laxative abuse, diuretics, glucosuria, metabolic alkalosis, insulin / glucose, ↑ mineralocorticoids
Chloride	100 mEq/L	metabolic acidosis, ↑intake, dehydration, renal failure	fasting, diarrhea, vomiting, diuretics
Bicarbonate	25 mEq/L	metabolic alkalosis, hypoventilation, ↑ bicarbonate intake, diuretics.	metabolic acidosis, renal failure, hyperventilation, diarrhea, carbonic anhydrase inhibitors, salicylate, methanol
Calcium	10 mg/dl	↑ parathyroid, ↑ vitamin D, thiazides, Paget’s disease, ↑ intake, malignancy, metastasis,	↓ parathyroid, ↓ vitamin D, loop diuretics
Phosphate	4 mg/dl	↑ vitamin D, ↓ parathyroid, renal insufficiency	↓ vitamin D, ↑ parathyroid, malnutrition / anabolism, aluminum antacids, Ca acetate, alcoholism
Magnesium	2 mEq/L	↑ intake, renal insufficiency, Addison’s disease.	↓ GI absorption, ↑ GI fluid loss, ↑ renal loss

38. Cardiac Arrhythmias

Introduction

Definition: deviations from the normal heartbeat pattern ® ¯ cardiac output, ¯ BP, ¯ vital organ perfusion. Causes include the following.

Abnormal impulse formation: D heart rate (∆ autmaticity, brady- tachy-cardia), rhythm, site of impulse origin

Abnormal impulse conduction: abnormal sequence of atrial / ventricular activation, conduction block / delay, re-entry (impulse re-routed through areas where it has already traveled ® double-depolarization ® extra impulse).

Supraventricular arrhythmia: ­ atuomaticity (from SA node) or re-enntry conduction.

Ventricular arrhythmia: due abnormal (ectopic) pacemaker triggering ventricular contraction before SA node fires.  Common in MI.

Causes: heart disease (coronary artery / valvular / rheumatic / ischemic disease, infections), MI, drug toxicity (digitalis), ­ sympathetic tone, ¯ parasympathetic tone, vagal stimulation (stool straining), ­ oxygen demand (stress, exercise, fever), metabolic disturbances, hypertension, hyperkalemia, hypocalcemia, COPD, thryoid ¯­.

Electrophysiology

Conduction system

Two electrical sequences: 1. Impulse formation: occurs first as a result of automatic electrical impulse.  2. Impulse transmission: occurs second to signaling the heart to contract.

SA node à AV node à Bundle of His à Purkinje fibers

Conduction system structures (see figure): tissues that can generate or conduct electrical impulses.  Sinoatrial (SA) node: main heart pacemaker, in the wall of the right atrium, spontaneously start action potential triggering atrium contraction.  Atrioventricular (AV) node: in the lower interatrial septum, delays impulse briefly to allow complete atrium contraction and ventricle filling before ventricle contraction.  Bundle of His: muscle fibers from the AV junction, impulses travel along bundle branches.  Purkinje fibers: network that ends in the ventricular surface ® ventricle contraction.

Latent pacemakers: AV node, bundle of His and Purkinje fibers contain cells that can generate impulses but at slower firing rate (called Overdrive Suppression in case of SA node damage or depression).  

Myocardial action potential

Depolarization and repolarization: caused due to Na / K exchange ® D in electrical potential across cell membrane. Has to occur before cardiac contraction.

Phase 0 (rapid depolarization): rapid sodium influx to cell, cell membrane electrical charge changes from –ve to +ve.

Phase 1 (early rapid repolarization): Na channels close, potassium leaves the cell ® return to resting potential.

Phase 2 (plateau, absolute refractory period): more potassium out, also calcium enters the cell, cell cannot respond to any stimulus

Phase 3 (final rapid ventricular repolarization): more potassium ions out ® complete repolarization ® membrane electrical charge back to –ve.  Called relative refractory period: phase 3, responds only to strong stimuli.

Phase 4 (slow depolarization): back to resting state with potassium in and sodium and calcium out.

Fast channels (sodium): in heart muscle cells ® rapid depolarization.

Slow channels (calcium): electrical cells of SA node and AV junction ® slow depolarization.

Electrocardiography (ECG) (PQRST)

P wave: atrium depolarization (activation).

PR inverval: impulse spreads from atria to Purkinje fibers.  Delay by AV node to allow ventricle filling. ↑ by digitalis.

QRS complex: ventricular depolarization.  ↑ by mexiletine, quinidine, class IC

ST segment: beginning of ventricular repolarization, phase 2 (absolute refractory period), ↓ in angina

T wave: ventricular repolarization (phase 3), inverted in angina

QT: ventricular depolarization and repolarization. ↑ by quinidine, procainamide, sotalol,

Clinical evaluation

Physical findings

Chest pain, ¯ brain perfusion ® anxiety / confusion, dyspnea, cyanosis, abnormal pulse rate / rhythm, palpitations, ¯ BP, syncope, weakness, convulsions, ¯ urine output.

Diagnostic test results

ECG: a 12-lead ECG provides definitive diagnosis.

Electrophysiologic testing: intracardiac procedure that determines the location of ectopic center and the need for packemaker / surgery. Probes are hooked through veins and arteries ® each heart segment is stimulated until arrhythmia occurs.

His bundle study: locates origin of heart block / re-entry pattern

Laboratory findings: test for hyperkalemia or hypocalcemia.

Drugs

Class	Action	Drugs
IA	Sodium channel blockers, ¯ conduction Also prolong repolaziation (K blocker)	quinidine, procainamide, disopyramide
IB	Sodium channel blockers, ¯ condcution	lidocaine, phenytoin, tocainide, mexiletine
IC	Sodium channel blockers, ¯¯ condcution	flecainide, propafenone, moricizine
II	Beta blockers	propranolol, acebutolol, esmolol
III	Potassium channel blocker ® prolong action potential.	Bretylium, sotalol, amiodarone
IV	Calcium (slow) channel blockers	verapamil, diltiazem
Other		adeonsine, magnesium, atropine, digoxin

Class I (sodium / fast channel blockers)

Mechanism: slow sodium flow into cells during phase 0 (rapid depolarization) ® slow impulse conduction through AV node. IA prolong repolarization (refractory period).  IB shorten repolarization.

Class IA

CI: cardiogenic shock, AV block (w/o pacemaker).

If ­­ AV conduction: slow conduction using verapamil / digoxin.

If toxic arrhythmia occurs: give catecholamines, glucagon, or sodium lactate.

Quinidine

Cinchona alkaloids: quinidine is an optical isomer of quinine. Quinine oral sulfate or gluconate salt (not preferred IM/IV).

Mechanism: Na⁺ and also K⁺ channel blocker.

SE: GI upset, diarrhea (use Al hydroxide), Narrow therapeutic index (target 3 ug/ml).  Toxicity: ¯ conduction ® SA block.  Cinchonism: tinnitus, hearing loss, blurred vision, photophobia, diplobia, psychosis.

CI: AV block, prolonged QT interval (may cause torsades, quinidine syncope and sudden death). ¯ dose in liver dysfunction and elderly.

DI: cause digitalis toxicity, severe ¯ BP with vasodilators, alkalinizers cause ­ toxicity.

Procainamide

IV/IM (acute) and as SR orally (long term therapy).

N-acetylprocainamide: active metabolite.

SE: SLE (arthlagia, myalgia, fatigue), anticholinergic, ¯ GI upset than quinidine. Narrow therapeutic index (target 7 ug/ml). Toxicity: ventricular arrhythmia, ¯ conduction ® SA block.   

CI: procaine hypersensitivity, myasthenia gravis, prolonged QT interval, torsades, AV block, SLE.  ¯ dose in CHF (due to ¯ Vd), in kidney or liver damage.

Disopyramide

SE: ventricular dysfucntion, anticholinergic (dry mouth, constipation, etc). Targel level: 3 ug/ml. Used orally

CI: AV block, cardiogenic shock, CHF, myasthenia gravis.

Class IB

Lidocaine

IV/IM.  For arrhythmia due to MI and heart surgery

SE: hemodynamic compromise, CNS (dizziness, resltessness, tremors, convulsions), tinnitus, blurred vision. Target: 4 ug/ml.  Toxic metabolites (glycinexylidide).

DI: ­ toxicity with phenytoin and beta blockers.

Phenytoin

Orally or IV.  To treat digitalis-induced arrhythmia (mostly), acute MI, heart surgery. 

SE: SLE, gingival hyperplasia, nystagmus, CNS (drowsiness, ataxia, vertigo), cardiac SE. Target: 14 ug/ml.  Chronic use can cause toxicity. Multiple drug intractions ® ­ toxicity.

Hypersensitivity reactions: blood, skin, Stevens-Johnson, and liver.

Tocainide

Similar structure to lidocaine except taken orally (avoid in lidocaine hypersensitivity).

SE: CNS (dizziness, restlessness, tremors, confusion), GI upset, diarrhea, blurred vision, blood. Target: 6 ug/ml.

Mexiletine

Similar structure to lidocaine but ¯ first-pass metabolism ® taken orally.

SE: dizziness, ataxia, ¯ BP, ­ QRS complex, blood, liver. Toxicity: tremor. Target: 1 ug/ml.

Class IC

Prolong QRS complex, slow of phase 0 (rapid depolarization) and slow conduction, no effect on repolarization. May ­ mortality due to pro-arrhythmic effect ® use is questionable. Orally.

Flecainide: Use only in refractory life-threatening ventricular arrhythmia.  SE: -ve inotropic effect (CI in CHF), CNS (dizziness, headache, tremor), GI upset, blurred vision. Target: 1 ug/ml.

Propafenone: SE: dizziness, headache, GI upset, bitter taste. Target: 0.5 ug/ml.

Moricizine: SE: dizziness, headache, GI upset.

IC: CV (arrhythmia esp in MI), eye toxicity (blurring, diplobia)

Class II (beta blockers)

Approved drugs for arrhythmia: propranolol, esmolol, acebutolol

Mechanism: ↓ heart stimulation, ↓ AV impulse conduction, ↑ refractory period à ↓ heart rate, ↓ heart oxygen demand.

Propranolol: IV or oral for tachy-arrhythmia due to catecholamine stimulation, digitalis-induced ventricular arrhythmias. SE: ↓ BP, cardiac arrest (↓ AV conduction), fatigue, bronchospasm.  Sudden d/c à acute MI, arrhythmia, angina à ↓ dose gradually.  CI: AV block, cardiogenic shock, CHF, asthma, DB (masks hypoglycemia).

Esmolol: very short t1/2 (minutes), give IV. SE: ↓ BP, dizziness, headache, fatigue, GI upset, bronchospasm. CI: CHF.

Class III (potassium channel blockers)

Mechanism: potassium channel blockers, prolong refractory period and action potential / repolarization. No effect on conduction or contractility.

Amiodarone: oral or IV, prophylactically to control refractory ventricular arrhythmia.  Oral effect may take days / weeks, very long t1/2 (2 months). Mechanism: sodium, beta, potassium and calcium blocker properties.  SE: pulmonary toxicity, eye damage, photosensitivity, liver toxicity, thyroid toxicity (hypo / hyper), CNS toxicity, ↓ BP, ↓ heart rate.  DI: ↑ level / effect of many drugs (calcium channel blockers, beta blockers, IA antiarrhythmics, digitalis, warfarin).

Bretylium: quaternary ammonium, short term IV or IM only for life-threatening ventricular arrhythmias.  SE: ↓ BP.  CI: digitalis-induced arrhythmia

Sotalol: orally, also a beta blocker. SE: beta blocker (↓ BP, prolonged repolarization (QT), bronchospasm, bradycardia).

Class IV (calcium / slow channel blockers)

Use: supraventricular arrhythmias. Verpamil and diltiazem but not nifedipine are used for arrhythmias (IV and oral).

Mechanism: ↓ calcium influx in phase 2 (action potential plateau, sustained depolarization), ↑ effective refractory period, depress phase 4 depolarization, ↓ SA and AV conduction (dominant calcium channels)

SE: verapamil may cause constipation.

CI: AV block, ¯¯ BP, beta blockers, CHF / digitals use, MI

DI: affected by and affect other drugs that are liver metabolized.

Class IV: verapamil, diltiazem, block slow inward.

Unclassified antiarrhythmics

Adenosine

Mechanism: naturally occurring nucleoside in all body cells. Acts on G-protein coupled adenosine receptors à ↑ AV node refractoriness à ¯ AV conduction, ¯ re-entry through AV node.

Given IV (very short t1/2, 10 seconds).

SE: short-lived flushing, ¯ BP, sweating, palpitations, short breath, chest pressure (bronchospasm, X theophylline).

DI: antagonize methylxanthines (caffeine, theophylline) effect.

Other uses: ­ exercise tolerance during exercise testing.

Atropine

Use: IV for sympathetic sinus bradycardia.

Mechanism: blocks vagal effects on SA node ® ­ AV conduction ® ­ heart rate.

Initial doses may cause reflex bradycardia.

Also Digoxin: vagotonic response of impulse generation à ↑ AV node refractoriness.

37. Coronary Artery Disease

Definition

Ischemic heart disease: insufficient supply of oxygen to the heart (oxygen demand > supply). 

Risk factors: hyperlipidemia (cholesterol > 200 mg/dl, LDL > 130 mg/dl, HDL < 35 mg/dl), hypertension, smoking, diabetes, obesity, family history, sedentary life style, chronic stress type A personality, ↑ age, male gender, oral contraceptives, gout. 

Factors that ↑ O2 demand: exercise, smoking, cold temp.

Etiology

1. ↓ blood flow: atherosclerosis with or without coronary thrombosis is the most common cause.  Coronary arteries are progressively narrowed by smooth muscle cell proliferation and accumulation of lipid deposits (plaque).   Coronary artery spasm is a sustained contraction that can occur spontaneously or induced by irritation (catheter, hemorrhage), cold exposure, ergot drugs.  The spasm can cause Prinzmetal angina or MI.  Traumatic injury such as impact of steering wheel on the chest.  Embolic events can also occur abruptly. 

2. ↓ blood oxygenation: blood oxygen carrying capacity ↓ in anemia. 

3. ↑ oxygen demand: can occur with exertion or emotional stress (sympathetic stimulation).  Systole: two phases (contraction and ejection).  Contractile (inotropic) state affects oxygen requirement.  ↑ ejection time à ↑ oxygen demand. 

Angina Pectoris

Episodic reversible oxygen insufficiency.  May be caused oxygen imbalance (tachycardia, anemia, hyperthyroidism, hypotension, arterial hypoxemia). . 

Patient complaints: squeezing pressure, sharp pain, burning, aching, bursting, indigestion-like discomfort, radiating pain to the arms / legs / neck / shoulders / back. 

Physical examination: usually not revealing, especially between attacks.  Note history, risk factors, description of attacks, precipitation patterns, intensity, duration, relieving factors. 

Treat risk factors: Hypertension should be controlled.  Obesity should be ↓ through diet and exercise.  Smoking should be stopped, but watch for anxiety.  Quitting results in 50% ↓ in morality.  Transdermal nicotine patches helps quitting over 10 weeks using decreasing doses of nicotine.  Nicotine gum and bupropion can also be used.  Also, clonidine.

Types

Stable (classic / exertion) angina: most common form, usually due to a fixed obstruction in a coronary artery. Triggered by exertion, emotional stress or heavy meal and relieved by rest or nitroglycerin.  The pain builds a peak radiating to the jaw, neck, shoulder, arms and then subsides. 

Prinzmetal’s angina (vasospastic or variant angina): due to coronary artery spasm (↓ blood flow).  Initially occurs at rest, pain may disrupt sleep.  Calcium channel blockers are preferred over beta blockers.  Nitroglycerin may not help. 

Unstable angina: due to significant coronary artery vasospasm and platelet aggregation.  Characteristics: may occur at rest, ↓ response to nitroglycerin, pattern change / ↑ severity.  Progressive unstable angina may signal imminent MI.  Immediate hospitalization required.

Nocturnal angina (angina decubitus): occurs in the recumbent position and is not related to rest or exertion.  Occurs due to ↑ ventricular volume (↑ demand).  Relieved by diuretics (↓ left ventricular volume).  Nitrates may improve nocturnal dyspnea. 

Diagnostic tests

ECG: normal in 60% of patients.  May show ↑ Q-wave, T-wave inversion, ↓ ST segment. 

Stress / exercise ECG: helps diagnose patients with normal ECG.  ↓ ST-segment. 

Stress perfusion imaging: with ²⁰¹thallium or ^99mtechnetium sestamibi.  Expensive. 

Pharmacologic stress test: when coronary artery disease is suspected but patient can’t exercise.  Use IV dipyridamole, adenosine (↓ AV conduction), dobumatime to induce cardiac ischemia in ECG. 

Coronary arteriography / cardiac catheterization: very specific, sensitive, invasive, expensive, risky (2% mortality rate). 

Antihyperlipidemics

Bile acid sequestrants: Cholestyramine chloride is a basic anion-exchange resin. Colestipol HCl is a copolymer.  Mechanism: insoluble, nonabsorbable, hydrophilic, anion-exchange resins bind bile acids in the intestine à ↑ bile acid synthesis from cholesterol à cholesterol depletion.  SE: bad taste (before meals), GI upset, constipation, bloating, dyspepsia, ↓ other drugs’ absorption (e.g. digoxin, may use in toxicity), fat soluble vitamine (ADEK) deficiency. 

Statins: lovastatin, atrovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin.  Preferred in the evening.  Mechanism: ↓ HMG-CoA reductase (converts HMG-CoA to mevalonate; precursor for cholesterol) à ↓ cholesterol synthesis.  SE: liver toxicity, monitor creatine kinase (CK) in case of skeletal muscle complaints (myopathy, rhabdomyolysis), headache, rash.  CI: fibrates / cyclosporins à ↑ risk of liver damage.

Fibric acid derivatives: gemfibrozil, clofibrate, fenofibrate (micronized prodrug).  Mechanism: ↓ synthesis / ↑ catabolism of triglycerides / cholesterol.  SE: GI upset, ↑ liver function (monitor combined use for statins).

Niacin (nicotinic acid): SE: flushing / itching (tolerance in 2 weeks, may be ↓ with aspirin), ↑ liver function, GI upset. 

Other drugs: probucol, eicosapentaenoic acid (EPA), docashexanoic acid (DHA).  Probucol SE: arrhythmia, syncope. 

Nitrates

Chemistry: Nitrites (amyl nitrite) à organic esters of nitrous acid, Amyl nitrite: very volatile, flammable liquid, by inhalation for CN poisoning.  Nitrates (nitroglycerin, isosorbide) à organic esters of nitric acid.  Nitroglycerin: very volatile, flammable, special storage, dispense in original glass container, protect from body heat, special IV plastic tubes to avoid absorption and loss of effect, extensive first pass effect (use transdermal or sublingual).

Dosage form: Nitroglycerin: sublingual / buccal tabs, topical ointment, transdermal, IV.  Isosorbide mono / dinitrate: tablets.

Mechanism: fast acting, form free radical nitric oxide (NO, endothelium-derived relaxing factor, EDRF) à activates guanylyl cyclase à ↑ cGMP à dephosphorylation of myosin light chain à muscle relaxation, venous dilation (↓ vascular resistance) à peripheral blood pooling à ↓ venous return à ↓ preload (left ventricular volume) à↓ respiratory symptoms (shortness of breath,  nocturnal dyspnea).  Also ↓ arterial pressure à ↓ afterload à ↓ oxygen demand. Also some ↓ in afterload. 

Use: use sublinigual (up to 3 tabs in 15 minutes), transmucosal (buccal tabs / spary) or IV nitroglycerin for acute attacks of angina pectoris.  Sublingual tabs / oral tablets / transdermals can be used prophylactically before known stress (eating, sex).  IV nitroglycerin is used for emergency unstable angina. 

SE: may ↓ BP à reflex tachycardia / postural hypotension, headache (transient, temporary, prevented by Tylenol 15-30 beforehand), dizziness, methemoglobinemia

Nitrate tolerance: loss of efficacy, avoid by requiring 12hr nitrate free periods.  Otherwise, higher doses may be required. 

Beta blockers

Mechanism: ↓ sympathetic heart stimulation (B1) à ↓ heart rate and contractility (-ve inotropic / chronotropic) à ↓ oxygen demand at rest / exertion, ↓ arterial blood pressure. 

Use: with nitrates to ↓ frequency and severity of exertional angina. May narrow coronary artery à combine with calcium blocker, avoid in Prinzmetal’s angina.  Use propranolol.

SE: bronchoconstriction, mask hypoglycemia (tachycardia), cardiac compensation (fatigue, shortness of breath, edema, dyspnea).  Withdrawal syndrome and angina / MI if suddenly d/c. 

Calcium channel blockers

Mechanism: prevent / reverse coronary spasm by ↓ calcium influx into smooth / cardiac muscle à ↑ blood flow / oxygen supply.  Also ↓ dilate arterioles and ↓ heart contractility à ↓ total peripheral resistance à ↓ oxygen demand / afterload. 

Use: 2^nd choice to nitrates and beta blockers in stable angina (may combine).  Critical in Prinzmetal’s angina / angina at rest. 

Diltiazem / verapamil / bepridil: watch for heart block / cardiac compensation due to –ve inotropic effect.  Careful with other –ve inotropic drugs (beta blockers, anti-arrhythmics).  Verapamil constipation à straining and ↑ oxygen demand. 

Nifedipine: peripheral vasodilation, limited –ve inotropic effect.  SE: hypotension, tachycardia (combine with beta blocker), dizziness, edema. 

Other drugs:

Maximal therapy: nitrate, CCB, beta blocker combination.

Morphine: in unstable angina when nitroglycerin fails. 

Aspirin: use indefinitely in stable and unstable angina. 

Heparin/enoxaparin/dalteparin: with aspirin in unstable angina.

Myocardial infarction

Severe prolonged deprivation of oxygen to part of the heart à irreversible necrosis.  Usually due to occlusive thrombus near a ruptured atherosclerotic plaque.  May lead to ventricular fibrillation (most disorganized arrhythmia) à cardiac arrest and death (sudden death syndrome).  Mortality rate: 30%. 

Signs and symptoms:

Persistent severe chest pain or pressure (crushing, squeezing, elephant heavy).  Pains beings in the chest and may radiate to the left arm, neck, leg, etc.  Onset of pain is not associated with exertion.  Unlike in angina, pain persists > 30 minutes and is not relieved by nitroglycerin.  MI may be silent (no pain).  Other symptoms: anxiety, impending doom, sweating, GI upset. 

Complications

Lethal (ventricular) arrhythmia: arrhythmias resistant to lidocaine may respond to procainamide and bretylium. 

CHF: left ventricular failure à pulmonary congestion à diuretics.  Digoxin ↑ contractility, compensate for heart damage. 

Cardiogenic shock: due to ↓ cardiac output.  Occurs when area of infarction > 40% and compensatory mechanisms are ineffective. Vasopressors (alpha stimulants to ↑ BP) and inotropes may be used.  Use vasodilators (nitropursside) to ↓ preload and afterload.  Intra-aortic balloon pump may be used. 

Diagnostic tests

Because MI is life threatening emergency, diagnosis is presumed and treatment is initiated based on complaints and immediate 12-lead ECG. 

Serial 12-lead ECG: abnormalities may be absent in the first few hours.  ST elevation.  Ventricular premature beats and ventricular arrhythmia are the most common arrhythmia. 

Cardiac enzymes: creatine kinase (MB-CK) is elevated within hours, peaks at 24 h and back to normal at 72 h.  Cardiac troponin I and T (cTnI, cTnT) patterns are similar to MB-CK but more sensitive.  Lactase dehydrogenase (LDH) use is not longer common.  Cardiac imaging include ^99mtc pyrophosphate scintigraphy, myocardial perfusion, radionucleotide ventriculography, coronary angiography. 

Treatment:

Nitrates: may ↓ chest pain à ↓ anxiety and ↓ catecholamine release (↓ coronary spasm à less ↑ in oxygen demand).  

Morphine: causes venous pooling and ↓ preload, cardiac workload, oxygen consumption (IV).  Drug of choice to ↓ MI pain and anxiety. SE: orthostatic hypotension, respiratory depression, constipation (use docusate).  Vagomimetic effect à bradyarrhythmia (if excessive à reverse using atropine).

Oxygen: Three liters/min via nasal cannula for chest pain, hypoxia and ischemia

Warfarin: for treatment of acute MI to ↓ mortality, prevent recurrence, ↓ complications (stroke).  Target INR: 2.5-3.5. 

Antiplatelet agents: abciximab, eptifibatide, tirofiban à ↓ platelet glycoprotein receptors. 

Beta blockers: propranolol, metoprolol, atenolol.  Given in early acute MI to ↓ oxygen demand, cardiac workload, ischemia, infarction à ↓ post MI mortality.

ACE inhibitors: after MI to ↑ exercise capacity, ↓ mortality in case of CHF, ↓ ventricular remodeling. 

Antihyperlipidemics: ↓ cholesterol à ↓ MI mortality.

Calcium channel blockers: avoid in acute MI or in left ventricular malfunction.  ↓ incidence of reinfarction. 

Dipyridamole: relax smooth muscles, ↓ coronary vascular resistance (↑blood flow).  Also, anti-platelet action. Used for angina pectoris prophylaxis. SE: ↓ BP, headache, dizziness.

Others: intra-aortic balloon, coronary angiography, PTCA.

Thrombolytic agents

Atherosclerotic plaques are made of lipids and fibrous proteins. Lesion rupture triggers release of serotonins, thromboxane A2 and adenosine diphosphate alteplase à platelet aggregation à clot.  The resulting fibrin traps RBCs, platelets, plasma proteins to form thrombus.  Clot dissolution is caused by conversion of plasminogen to plasmin mediated by plasmingoen activators.  Use as early as possible (<12 h after pain starts). 

Absolute CI: internal / eye hemorrhage, intracranial / intraspinal injury, pregnancy, aneurysm, ↑↑hypertension.

Recombinant tissue plasminogen activator (t-PA): front-loaded regimen (IV bolus then infusion). 

Streptokinase (SK): SE: systemic antibody formation à ↑ chances of refractory response and allergy if repeated within 6 months (avoid if unknown).  Monitor for bleeding, reperfusion arrhythmia (within 30 min), hypotension, anaphylaxis. 

Other thrombolytic agents: reteplase, tenecteplase, anisoylated plasminogen streptokinase activator complex (APSAC).

Post thrombolysis adjunctive therapy: antiplatelet and anticoagulant therapy after reperfusion to prevent reoccolusion, ischemia and reinfarcation.

Aspirin: during thrombolyic therapy à ↓ post-infarct mortality.  Also: clopidrogel, ticlopidine, dipyridamole.

Heparin: with thrombolytics to prevent reocclusion after reperfusion, ↓ mortality in MI. Give bolus then infusion.  Goal: maintain APTT (activated partial thromboplastin time) at 1.5 – 20 times control.  Avoid combining with streptokinase (↑ bleeding).  Give SC, but not IM.  Alternatives: ↓ MWt heparins (enoxaparin, dalteparin).

39. Hypertension

Pathophysiology

Arterial pressure = cardiac output X Peripheral Resistance

Cardiac output = heart rate X stroke volume

Conditions that increase stroke volume: fever, aortic regurgitation, thyrotoxicosis

Starling's Law: ↑ ventricular stretch à ↑ myocardial contractility

↑ blood volume returning à ↑ ventricular dilation

Initiators of baroreceptor reflexes: stretch receptors located in the wall of large chest and neck arteries

Causes of hypertension: Cushing's disease, oral contraceptives, acromegaly, polycystic kidney disease

Hypertension of unknown etiology: essential hypertension, toxemia of pregnancy, acute intermittent porphyria

Essential hypertension: unknown cause (90% of cases).  Chronic vasoconstriction (↑ tone).

Endocrine hypertension: pheochromocytoma (tumor causing ↑ in catecholamine release)

Renal hypertension: chronic pyelonephritis.

Neurogenic hypertension: familial dysautonomia

Other causes: aortic coarctation

Factors causing systolic hypertension with wide pulse pressure: ↑ stroke volume. ↓ aortic compliance

Anesthetized patients receiving antihypertensives à ↑↑ responses to body position changes and acute blood loss, altered responses to sympathomimetic drugs

Perioperatively: antihypertensive drug treatment should be maintained

Rapid increases in BPà vagal center excitation à negative iontropic effect (↓ contractility), negative chronotropic effect (↓ heart rate).

Africans: use Ca channel blockers and diuretic (CaD) (ACE inhibitors/beta blockersàless effective)

Generally, avoid prescribing two drugs from the same therapeutic class.

Effectiveness of antihypertensive drugs is highly unpredictable, requires dose/drug adjustments.

Withdrawal antihypertensives gradually to reduce SE (e.g. MI with b-blocker)

Elderly: esp. vulnerable to CNS SE, orthostatic hypotension.  Lower doses may be needed. 

Diuretics

Use: recommended (with beta blockers) as initial therapy for BP.  Diuretics are also used for CHF, edema, fluid retention.

Precaution: take during the day to avoid interruption of sleep due to frequent urination.  May raise lithium level (CI)

Thiazide diuretics

Examples: Chlorthiazide, hydrochlorthiazide, cyclothiazide, polythiazide, trichlormethiazide, methyclothiazide, hydroflumethiazide, benzthizide, bendroflumethiazide, chlorthalidone, metolazone, indapamide.  Structure: most are related to sulfonamides.

Mechanism: Act on Na⁺/Cl^- co-transporter at the distal convoluted tubule.  Other actions: directly dilate arterioles, ↓ total fluid (extravascular) volume, ↓ cardiac output.

Effects:

1. ↑ urinary excretion of Na⁺ / water due to ↓ Na / Cl reabsorption

2. ↑ urinary excretion of K⁺ and bicarbonate à hypokalemiaà ↑ potassium dietary intake, use supplements / potassium sparing diuretics

3. ↑ blood glucose (hyperglycermia, care with diabetics), ↑ uric acid retention (hyperuricemia, care with gout), ↑ serum lipids (hyperlipidemia), ↑ calcium levels (hypercalcemia)

4. ↑ effect on other antihypertensives by ↓ re-expansion of extracellular / plasma volumes.

SE: electrolyte imbalance (↓K, ↓Mg, ↑Caàdehydration, postural hypotension, dizziness, headache, fatigue, hypovolemic shock, arrhythmia, palpitation), metabolic alkalosis, ↓ K à muscle cramps, light sensitivity / rash (use sunscreen), ↑ uric acid / gout, ↑ lipoproteins, ↑ BG, sulfonamide hypersensitivity.

Interactions: NSAIDs (e.g. ibuprofen) à ↓ renal perfusion à ↓ effect of thiazides.  Sulfasenstivity. Hyperlipidemia à ↑ risk of coronary artery disease.  Digitoxin (↑ toxicity due to hypokalemia)

↓ urinary Ca excretion à use for kidney stones (calcium nephrolithiasis). 

Metolazone: most effective thiazide diuretic.

Chronic useà↑ water reabsoprtionà↓ polyuria and polydipsia in diabetes insipidus (instead of ADH) (??)

Loop (high-ceiling) diuretics

Examples: furosemide, torsemide, bumetanide (all are sulfonamide derivatives), ethacrynic acid.  Most intense, shortest duration action.

Use: patients intolerant / irresponsive to thiazides, or with renal impairment (↓↓ golmerular filtration rate).  Very strong diureticsànot routinely used for hypertension.  Used in edema in CHF / liver cirrhosis / kidney disease / lungs, hypercalcemia

Mechanism: Blocks Na⁺/K⁺/2Cl^- co-transporter in the thick ascending limb of Loop of Henle (luminal side)à­ excretion of water, Na⁺, K⁺, Ca²⁺, Mg²⁺, Cl^- à metabolic alkalosis.  ↑ BG, ↑ blood lipids, ↑ uric acid. 

SE: dehydration, ↓ BP, hypovolemia, ↓ K, ↓ Ca, metabolic alkalosis, ↑ uric acid, ↑ BG, ↑ lipids,  tinnitus, transient hearing loss (CI aminoglycosides), sulfonamide hypersensitivity, blurred vision, blood toxicity, distal tubular hypertrophy (with chronic use).

Interactions: like thiazedsàNSAIDs (e.g. ibuprofen) à ↓ effect, aminoglycosides à ototoxicity, digoxin à ↑ toxicity (↓ K).

Potassium sparing diuretics

Examples: spironolactone, amiloride, triametrene.

Use: when if ↑ K⁺ loss and not corrected by supplements.  May combine with thiazides / loops to balance potassium.  Least potent diuretics. 

Uses: prevent hypokalemia from thiazide / loop diuretics, edema from CHF, liver cirrhosis, hyperaldosteronism (Spironolactone).

Triamterene, amiloride mechanism: block Na⁺ channels at collecting duct à ↓ Na⁺ exchange with K⁺ and H à ↓ K⁺ and H⁺ excretion à alkaline urine.

Triamterene SE:  hyperkalemia, headache, dizziness, ↑ uric acid, ↓ dihyrofolate reductase à methemoglobinemia in case of alcoholic cirrhosis. CI: history of kidney stones

Spironolactone: synthetic steroidal competitive inhibitor of aldosterone at mineralocorticoid receptors at the collecting duct à ↓ sodium-potassium exchange à ↓ potassium excretion à alkaline urine à use in hyperaldosteronism.  SE: gynecomastia, hirsutism, menstrual disruption, lethargy, hyperkalemia. 

Interactions: ACE inhibitors and potassium supplements à ↑ risk of hyperkalemia.  Renal impairment.

Osmotic diuretics

Examples: mannitol, glycerin, urea

Mechanism: highly polar, water soluble inert chemicals, freely filtered at the glomerulus but poorly reabsorbed from renal tubules à ↑ osmolarity of glomerular filtrate à ↓ tubular reabsorption of water à ↑ diuresis à  ↑ water, Na⁺, Cl^-, bicarbonate excretion à alkaline urine.

Use: prevent oliguria, anuria, ↓ cerebral edema, ↓ intracranial pressure, ↓ intraocular pressure (glaucoma).

SE: headache, blurred vision.  Not absorbed well by the gut (causes osmotic diarrhea)à only given IV.

Carbonic anhydrase inhibitors

Examples: acetazolamide, related to sulfonamides

Mechanism: ↓ carbonic anhydrase at the proximal tubules à ↓ sodium bicarbonate / Na reabsorption à ↑ water, Na⁺, K⁺, bicarbonate excretion à alkaline urine.  ↓ affect due to Na reabsorption in distal sites

Use: glaucoma (aqueous humor has ↑ bicarbonate), acute mountain sickness, alkaline urine and ↑ excretion of acidic drugs (aspirin, urate), edema.

SE: hyperchloremic metabolic acidosis (due to bicarbonate loss), sulfonamide hypersensitivity, CNS depression, drowsiness, fatigue, constipation, blood SE (bone marrow depression, thrombocytopenia, hemolytic anemia, leukopenia, agranulocytosis)

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