RAPID PHARMACY REVIEW PAGE 2

Sympatholytics

Beta blockers

Use: recommended (with diuretics) as initial therapy, especially for patients with rapid resting heart rate (atrial fibrillation, tachycardia), ischemic heart disease (angina pectoris, MI)

Mechanism: ↓ cAMP à ↓ heart contraction and rate.  Other: ↓ rennin secretion à↓ cardiac output, central ↓ in sympathetic output.  Block autonomic reflex response (e.g tachycardia).

Examples (x-olol): atenolol, , propranolol, timolol, acebutolol, betaxolol, bisoprolol, carteolol, metoprolol, nadolol, penbutolol, pindolol, esmolol, labetalol, carvedilol

Nonselective B1 (heart) - B2 (lung) blockers: propranolol, nadolol, timolol.

Selective B1 (heart) blockers: atenolol, metoprolol, acebutolol (A.M.A.), betaxolol, bisoprolol.  Less likely to mask hypoglycemiaàuse in DM.

Intrinsic sympathomimetics (partial agonists, P.A.): pindolol, acebutolol, carteolol, penbutolol

Labetalol: beta (1/2) and alpha-1 blocker (racemic mixture), for hypertensive crisis due to pheochromocytoma (tumor with ↑ catecholamines).  SE: bronchospam, orthostatic hypotension, urinary retention.

Carvedilol: beta (1/2) + alpha blocker and vasodilator. 

Timolol: mainly for ocular hypertension (B1/B2).

Esmolol: ultrashort duration of action, IV.              

Carteolol: ↓ lipid solubilityà↓ CNS penetration.     

Propranolol: -ve inotrophic/chronotropic à ↓ oxygen demand à angina

Side effects, interactions, and precautions:

·         Withdrawal syndrome if suddenly d/c à↑ anginal attacks, MI, rebound in BP above normal

·         ↑ lipids, hypertriglyceridemia

·         Impotence and ↓ libido à ↓ compliance

·         NSAID’s à may ↓ effect of beta blockers

·         ↑ SE with neurologic disorders if drug enters CNS à ↑ poor memory, depression, fatigue, lethargy

·         ↓ kidney blood flow à ↓ glomerular filtration.

Contraindications:

·         Ca channel blockers

·         CHF à cardiac decompensation due to ↓ contractibility and ↓ electrical conduction

·         DM àmay mask tachycardia (hypoglycemia), ↓ BG

·         COPD, asthma, bronchospams (selectivity is dose dependent)

·         Peripheral vascular disease / Raynaud’s phenomenon à vasoconstriction

Peripherial alpha-1 blockers

Examples (x-osin): prazosin, terazosin, doxazosin

Mechanism: block peripheral postsynaptic alpha-1 adrenergic receptors à vasodilation (arterioles and veins).  

First dose syncope: within 60 min of first dose à postural hypotension, dizziness, headache, palpitation, tachycardia, sweating.  Minimize by starting with low dose at bedtime. 

Other SE: diarrhea, weight gain, edema, dry mouth, sexual dysfunction.

Uses: refractory ↑ BP, CHF,

Central alpha-2 agonists

Mechanism: act on central presynaptic alpha-2 inhibitory receptors to ↓ sympathetic flow to cardiovascular system à ↓ peripheral resistance

Examples: methyldopa, clonidine, guanabenz, guanfacine.

General SE: rebound hypertension (if abruptly d/c), sedation, dry mouth

Methyldopa: SE: hemolytic anemia (+ve Coomb’s test) with prolonged use, SLE, orthostatic hypotension, fluid accumulation, fever/flu-symptoms (due to liver damage).  CI: MAOI (↓ methyldopa activity), hepatic disease.  Safest in pregnancy. 

Clonidine: safer with renal impairment.  ↓ BP, heart rate. SE: depression (CI: alcohol), initial ↑ then ↓ in BP (with IV).  No orthostatic hypotension (cardiovascular reflex blocked).  Available as weekly patch.  Also analgesic (alpha-2 agonist in spinal cord) and used pre-anesthetically to ↓ BP.  Rapid onset, long duration.

Guanabenz/guanfacine: SE: dizziness, ↓ heart rate.  CI: other sedatives, coronary insufficiency, MI, hepatic/renal disease.

Postganglionic adrenergic neuron transmitter blockers

Use: ↑↑ SE à avoid if possible, obsolete.  Possibly for severe refractory hypertension (other drugs ineffective).

Guanethidine / Guanadrel:  very powerful à not first choice for ↑BP.  Mechanism: ↓ release norepinephrine from adrenergic nerve endings (depletes NEp). Does not enter CNS à not sedation.  ↑↑ SE: sodium / water retention, orthostatic hypotension, impotence, diarrhea. CI: cocaine/TCA à ↓ effect

Reserpine:  Low dose with other antihypertensives (e.g. diuretics). Mechanism: depletes catecholamines centrally and peripherally.  SE: drowsiness, dizziness.  CI: depression (cause nightmares, suicide), peptic ulcer. 

Vasodilators

Use: last line of treatment. Do not use alone (cause ↑ heart rate, heart output, plasma rennin).  Directly relax peripheral vascular smooth muscles. Commonly used in hypertensive crisis (IV). 

General SE: tachycardia, headache, dizziness, fluid retention, nasal congestion.

CI: coronary vascular disease à the reflex cardiac stimulation (tachycardia) will ↑ myocardial oxygen demand.

Diazoxide, Minoxidil à potassium channel activators à membrane hyperpolarization à arteriolar vasodilation.  Hydralazine à ↑ NO (EDRF) à arteriolar vasodilation. 

Hydralazine: dilates arteries (renal, cerebral).  Triggers sympathetic compensatory reactions.  SE: reflex (barorecceptor) ↑ heart rate/output (may cause angina), ↑ stroke volume, reversible systemic lupus erythematosus (SLE) à fatigue, fever à regular blood counts.

Minoxidil: dilates arteries.  SE: Hypertrichosis (used to treat male pattern baldness; alopecia), tachycardia reflex (give beta blocker), pulmonary hypertension. 

Diazoxide: dilates arteries. Quick and prolonged action.  For hypertensive crisis.

Nitroprusside: dilates arteries and veins.  44% cyanide.  Mechanism: reacts with oxyhemoglobin (forms methemoglobin), forms nitric oxide which activates guanylyl cyclase.  First choice for hypertensive crisis (IV, short duration).  Use for controlled hypotension during surgical anesthesia (bloodless surgery, good cerebral perfusion).  Also for heart failure (acute/chronic).  Avoid in infants.  Solution in water is susceptible to photolysis.

Calcium channel blockers

Use: initial treatment for patients with angina, bronchospam, Raynaud’s disease.  For ↑BP in elderly / Africans with low renin.

Mechanism: block voltage-gated slow calcium channels à ↓ Ca influx à vascular smooth muscle relaxation (more for arteries) à ↓ BP.  Different agents: systemic / coronary vasodilation, SA/AV nodal depression, ↓ myocardial contractility.

SE: ↓ BP, dizziness, headache, flushing, edema, ↑ beta blocker effect (AV block).  Amlodipine: pruritus

Diltiazem / Verapamil à↓ cardiac contractility, ↓ AV conduction.  Diltiazem: for arrhythmia and angina.  Verapamil: similar action to diltiazem (more ↓ electrical conduction).  Verapamil SE: constipation, bradycardia.  CI: beta blockers à CHF / bradychardia, ↓ electrical conduction to AV node.  Avoid diltiazem and verapamil in patients with AV / SA node problems. 

Dihydropyridines (nifedipine / nicardipine / nitredipine) à vasodilation but no cardiac effects (no effect on SA / AV node) à reflex sympathethetic response à tachycardia. ↓ SE with SR form. 

Second generation dihydropyridine derivatives (related to nifedipine): amlodipine, isradipine, felodipine, nicardipine, nisoldipine. Chemically related to nifedipine.  Selective effect on target tissues.  Less reflex tachycardia.

Nimodipine: ↑ lipid solubilityàenters brainàfor cerebral spasm

Angiotensin Converting Enzyme (ACE) inhibitors

Examples (x-pril): benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, perindopril. 

Use: ↑ BP, diabetes with renal problems (delays diabetic neuropathy and glomerculosclerosis), renal disease, left ventricular dysfunction, good for CHF. 

Mechanism: renin-angiotensin-aldosterone system à long term BP control.  ↓ Renin (aspartyl protease) à ↑ hydrolysis of angiotensiongen to angiotensin I.  ↓ ACE (peptidyl dipeptidase) à conversion of angiotensin I (weak peptide vasoconstrictor) to angiotensin II (potent rapid peptide vasoconstrictor, i.e. pressor)à ↑ release of aldosterone à Na/water retentionà ↑ fluid volume.  ACE blocks the breakdown of bradykinin (à cough).

SE: initial dry cough, angioedema (skin swelling), hyperkalemia (↓ aldosterone à↓ K excretion), syncope, neutropenia, proteinuria, rhinorrhea, renal damage.

CI: effect ↓ by NSAID (e.g. ibuprofen), renal problems, K⁺ sparing diuretics / K⁺ supplements (à ↑↑ hyperkalemia).  Pregnancy X.   ↑ dose gradually.

Enalapril: prodrug, converts to the active metabolite enalaprilat (w/ can be used for hypertensive crisis). 

Lisinopril: long-acting enalapril analog.  .

Longer duration ACE inhibitors (once daily): benazepril, fosinopril, moexipril, trandolapril, perindopril, ramipril, quinapril.

Zankiren: renin inhibitor

Angiotensin II (type I) receptor antagonists

Examples (x-sartan): candesartan cilexetil, eprosartan, irbesartan, losartan, telmisartan, valsartan.

Mechanism: nonpeptide antagonists of angiotensin II receptor (AT1 subtype) in vasculature, heart, kidney, brain à vasodilation, ↓ aldosterone release from adrenal gland à ↑ Na/water excretion à ↓ blood volume.  Less effective than ACE inhibitors.  No effect on bradykinin.

SE: hyperkalemia (monitor renal function), NO cough or angioedema (unlike ACE inhibitors).

CI: K⁺ supplements, K⁺ sparing diuretics, diabetics with nephropathy, CHF.

Hypertensive crisis

Definition: systolic > 200 or diastolic > 140 à ↑↑ quick organ damage. 

Reduction of BP must be gradual (15 mmHg over first hour) to avoid compromising organ perfusion (esp. cerebral)

Drugs: vasodilatos (nitroprusside, hydralazine, diazoxide, nicardipine, nitroglycerin), enalaprilat, adrenergic inhibitors (labetolol, esmolol, phentolamine (alpha blocker)), fenoldopam (dopamine D1 agonist, vasodilator),  trimethaphan (ganglionic blocker)

40. Congestive Heart Failure

Introduction

Definition: condition due the inability of the ventricle to deliver adequate quantities of blood to the metabolizing tissues during normal activity or at rest.  It’s called ‘Congestive’ because of the edema caused by fluid backup due to poor pump function.

Etiology: common in the elderly.  CHF is not an independent diagnosis as it is superimposed on an underlying cause (usually coronary artery disease). 

Low-output failure: metabolic demands are normal but heart is unable to deliver be enough blood output.  This is the most common type.

High-output failure: due to ↑ metabolic demands (hyperthyroidism, anemia).

Treatment goals: remove underlying cause (drugs, anemia, hyperthyroid); relieve symptoms / ↑ pump function (↓ metabolic demand, ↓ fluid volume excess, digitalis, inotropes, cardiac transplant).

Pathophysiology

CHF à compensatory mechanisms to normalize cardiac output (stroke volume x heart rate) à ∆ left ventricle geometry à ventricular dilation, hypertrophy, ↑ cardiac wall thickness (cardiac remodeling).

Compensation

Sympathetic response: ↓ cardiac output à sympathetic activation à ↑ Ep, NEp  à ↑ heart rate, ↑ blood flow to vital organs (brain, heart).

Hormonal stimulation: sympathetic blood flow redistribution à ↓ renal perfusion à ↓ glomerular filtration rate à sodium / water retention, activation of renin-angioensin-aldosterone system à more sodium retention, volume expansion. 

Concentric cardiac hypertrophy: ventricular remodeling.

Frank-Starling mechanism: ↑ blood volume à ↑ cardiac chamber stretch to accommodate excess fluid (distention) à ↑ contractile force to expel fluid to the arteries. 

Decompensation

Over time, compensatory mechanisms become exhausted and ineffective à viscous cycle of compensation à compensation become self-defeating.  Afterload: tension in ventricular muscles during contraction, amount of force needed for the ventricle to overcome pressure in the artery, also called ‘intravascular systolic pressure’. Preload: force exerted on the ventricular muscle at the end of diastole that determines degree of muscle stretch, also called ‘ventricular end diastolic pressure’.  As fluid volume ↑ à ↑ demand on exhausted pump à fluid backup à symptoms of CHF. 

Clinical evaluation

Symptoms are due to blood backing up behind the failing ventricle.  Symptoms are first related to the failing side, then to both sides. 

Left-sided CHF

Blood can’t be pumped from the left ventricle to the peripheral circulation à left ventricle can’t accept blood from left atrium and lung à blood back up in pulmonary alveoli à pulmonary edema.

Symptoms: dyspnea, less effort to trigger exertional dyspnea, wheezing cough, exertional fatigue, nocturia.  Paroxysmal (sudden) nocturnal dyspnea and orthopnea result from volume pooling in the recumbent position à relieved by propping with pillow or sitting upright.

Physical findings: Crackles indicate air movement through fluid-filled passages, tachycardia (early compensatory mechanism).

Diagnostic tests: cardiomegaly (heart enlargement), left ventricular hypertrophy, pulmonary congestion.

Right-sided CHF

Blood can’t be pumped from the right ventricle to the lung à right ventricle can’t accept blood from right atrium and circulation à blood back up in whole body à systemic edema.

Symptoms: tightness and swelling (fingers, skin), nausea, vomiting, abdominal pain on exertion due to liver enlargement.

Physical findings: vein distention due to ↑ venous pressure, tender enlarged liver, bilateral leg edema.

Diagnostic tests: ↑ liver enzymes (ALT) due to liver congestion.

Therapy

Bed rest

Advantages: ↓ metabolic needs, ↓ heart workload, ↓ heart rate and dyspnea, ↑ diuresis à ↓ fluid volume.

Disadvantages: venous stasis à thromboembolism, ↓ risk by using anti-embolism stockings, leg exercises.

Dietary controls

Small frequent meals with ↓ calories à ↓ metabolic demand

↓ sodium (3g/d) to ↓ volume.  Education patient about sodium containing products (antacids, NSAIDs, sodium bicarbonate, baking soda, water softeners).

Drug-related actions

↑ ejection fraction can be achieved by:

1. Directly ↑ heart contractility using inotropic agents: dopamine, dobutamine, milrinone, amrinone.

2. ↓ resistance to ejection by relaxing peripheral blood vessels: vasodilators such as hydralazine, nitroprusside, nitrates

3. Affecting cardiac remodeling: ACE inhibitors, beta blockers, vasodilators (nitrates).

Addressing the underlying problem is more important than symptoms.

Digitalis glycosides (Digoxin)

Source: Plant steroidal glycosides.  Digoxin: from Digitalis lanata;  Digitoxin: from Digitalis pupurea;  Ouabain: from Strophanthus gratus.

Chemistry: Sugar (glycone portion) + steroidal nucleus (aglycone/genin portion) bonded with glycoside (ether) linkage.  ↑ hydroxyl groupsà ↑ polarityà  ↓ protein binding / liver biotransformation / renal reabsorptionà ↓ duration of action.  Ouabinà v. short durationà only IV.

Mechanism: Inhibit Na⁺/K⁺ ATPase à ↑ intracellular Na⁺, ↓ intracellular K⁺, ↑ calcium entry à +ve inotropic effect, ↑ CO, ↑ renal blood flow (perfusion) à deactivate RAAS à ↑ diuresis, ↓ edema, prolongs PR interval in EKG.  Also: ↑ vagal tone in SA nodeà -ve chronotropic effect, ↓ CNS sympathetic flow, systemic vasoconstriction.

Use: CHF, left ventricular systolic dysfunction, rapid atrial fibrillations / flutter, paroxysmal atrial tachycardia. (CI in ventricular fibrillation / flutter).

Dosage forms: tablet, capsule, injection, elixir.

Dosing: Rapid digitalization: IV in acute need, steady state in 1 day.  Slow digitalization: orally, steady state in 1 week.  Serum levels: first ↑ sharply and then ↓ sharply as drug enters the heart.  Measure after 5 hr of dosing (steady state). Target: 1 ng/ml.

Potassium: antagonize digitalis effect.  ↓ potassium à ↑ digitalis toxicity.  DI with potassium altering drugs (diuretics, ACE inhibitors).

Magnesium: inversely related to digitalis effect (↓ Mg à ↑ toxicity) (similar to potassium).

Calcium: ↑ digitalis inotropic effect.  ↑ calcium à arrhythmia.

Metabolism: in the kidneys.  Serum creatinine affects elimination.

Toxicity: common due to narrow therapeutic index.  Can be fatal.  ↑ toxicity with quinidine, verapamil, amiodarone.  Early: GI (anorexia, diarrhea, nausea, vomiting), CNS (headache, confusion, delirium, muscle weakness, fatigue, visual disturbance).  Later: ventricular fibrillation / flutter, AV block, atrial tachycardia, premature ventricular contraction. Treatment of toxicity: d/c digitalis and any potassium depleting drug, give potassium IV if hypokalemic, treat arrhythmia with lidocaine IV, cholestyramine to prevent absorption (binds digitalis), purified digoxin-specific Fab fragment antibodies.

Inotropic drugs (IV emergency use)

Dopamine: ↓ dose: ↑ kidney blood flow, ↑ urine output.  Moderate dose: ↑ cardiac output.  ↑ dose: ↑ peripheral resistance, ↑ pulmonary pressure, tachycardia.  Very short t1/2.

Dobutamine: similar chemical/pharmacological alternative to dopamine.

Amrinone / milrinone à bipyridine derivatives.  Mechanism: inhibit phosphodiesterate (PDE) isozyme in heart cells à ↑ cAMP à vasodilation, ↑ cardiac contractility.  SE: thrombocytopenia, hypotension, headache.

Amrinone: nonglycoside, non-sympathomimetic inotrope. Unstable in dextrose à use saline for IV (sodium may also be a problem in CHF). 

Milrinone: renally excreted.

Diuretics

Used for all CHF patients with fluid retention / edema.

Monitor fluid loss and ↓ in edema by following body weight

Thiazides: effective, commonly used.  Disadv: weak, hypokalemia.

Loop: v. effective, orally / IV for acute pulmonary edema. Hypokalemia.

Potassium sparing: weak, balance the hypokalemia.

Aldosterone antagonists: e.g. spironolactone. 

ACE inhibitors

For long term, not acute, management of CHF.  First line agents.

Mechanism: ↓ enzyme for converting angiotensin I to angiotensin II (potent vasoconstrictor) à ↓ total peripheral resistance à ↓ afterload.  ↓ angiotensin II also à ↓ aldosterone release à ↓ sodium / water retension à ↓ venous return and ↓ preload.

Vasodilators

Mechanism: ↓ afterload (artery dilation) / ↓ preload (venous dilation) à ↓ pulmonary congestion, ↑ cardiac output.

Nitroprusside: IV, dilates both veins and arteries.

Prazosin: alpha-1 blocker, dilates both veins and arteries.

Hydralazine: dilates arteries.

Nitrates: dilates veins.  Higher dose for CHF than for angina.

Beta blockers

For long term, not acute, management of CHF.

Only carvedilol (Beta-1-2-Alpha-1 blocker) is approved for CHF.

Actions of norepinephrine: peripheral vasoconstriction, sodium retention by the kidney, cardiac hypertrophy, arrhythmia, hypokalemia, cell death (apoptosis) due to ↑ stress.

Calcium channel blockers

No evidence of benefit in CHF symptoms.  Do not use.  Verapamil is particularly contraindicated because of the significant –ve inotropic effect.  Nifidipines are less dangerous (no heart effect)

41. Thromboembolic Disease

Introduction

Defintion: venous thromboembolic disease (VTED) occurs when elements of the Virchow’s triad (vascular injury, venous stasis, hypercoaglate state (¯ protein C / S, antirhombin III)) are present resulting in deep venous thrombosis (DVT) and pulmonary embolism (PE). Incidence: total is 500K, symptomatic is 250K.

Risk factors: patient specific (age>40, obesity, varicose veins, immobility, pregnancy, ­ dose estrogen, hypercoagulate state, lupus anticoagulant), illness / surgery (pelvic / hip / lower limb trauma or surgery or cancer, MI, heart failure, inflammatory bowel, sepsis, kidney disease, polycythemia).

Prevention: nonpharmacologic (¯ venous stasis with external pneumatic compression or graduate compression stockings), pharmacologic (anticoagulant drugs or heparins).

Oral anticoagulants – warfarin

Indications

Prevention of: VTED (1ry, 2ry), systemic arterial embolism in prosthetic heart valve or atrial fibrillation, acute MI in peripheral arterial disease, stroke and death in acute MI, venous thrombosis, pulmonary embolism, coronary occlusion in acute MI.

Mechanism

Chemistry: Coumarin derivatives (warfarin, dicumarol) are water insoluble weak acids.  Chemically related to vitamin K.  ↑ protein bound.  ↑ liver metabolism. ↓ therapeutic index. Therefore, ↑↑ drug interactions.

Mechanism: antagonists of vitamin K.  ↓ reductase responsible for interconversion of vitamin K and its epoxide à liver production of defective (¯) vitamin K-dependent coagulant proteins or clotting factors (2 (prothrombin), 7, 9, 10). Does not work in vivo.

PK

Warfarin is a racemic mixtuer of equal R/S forms

Rapid absorption à C_max in 90 minutes.

­ inter-individual variability in dose response.

Used mostly orally, but also IV.  Pregnancy X.

Effect and depletion of clotting factors occurs after 3 day.  Meanwhile, use UFH or LMWH if needed (5 day overlap).  Effect also take time to wear off after d/c.  Dose: 2.5-10 mg.  Duration: 3-12 months.

Monitoring

Initial daily monitoring of prothrombin time (PT) and international normalized ratio (INR).  Then ¯ frequency of monitoring gradually to every 4 weeks. PT results are highly dependent of type of reagent.

INR = patient PT / mean lab control PT. Target: 2-3  (­risk à 2.5-3.5). 

ISI: International Sensitivity Index, a measure of thromboplastin responsiveness to ¯ in clotting factors. ¯ ISI à ­ responsive reagent à PT ~ INR

Warfarin is sensitive to metabolic enhancers / inhibitors, vitamin K.

Antibiotics à ↓ GI bacterial flora à ↓ vitramin K à ↑ warfarin toxicity.

SE: hemorrhage / bleeding (treat with vitamin K, i.e. phytonadione IM/SC), skin necrosis (due to ↓ protein C), urticaria, purpura, alopecia.

Unfractionated heparin

Chemistry: large very acidic muco-polysaccharide molecule

Indications: IV/SC with warfarin for proven VTED. Prevents / treats DVT, PE.  Works in vivo to prevent clotting of blood samples.  Avoid IM (à hematoma).

Mechanism: inhibition / inactivation of thrombin (factor IIa, converts fibrinogen to fibrin clot), activated factor Xa (converts prothrombin II to thrombin IIa), by antithrombin (AT) III.

PK: plasma proteins other than AT III compete for heparin binding.  Short t1/2.  Large molecule à can’t cross placenta à safer in pregnancy.

Clearance: combination of saturable and non-saturable first-order kinetic models.  Involve rapid followed by gradual elimination. 

­ inter- and intra- individual variability (due to ∆ plasma proteins and clearance).

Administration: start with a 70 units/kg loading dose for fast response, then continuous dose (1000 unit/hr or weight-based)

SE: hemorrhage, thrombocytopenia (common), urticaria. Antidote: protamine sulfate (ver basic protein).

Monitoring: measure activated partial thromboplastin time (aPTT) (patient aPTT / mean lab control aPTT) à target: 1.5-2.5, but is dependent on the reagent.  Heparin assay may also be used for monitoring.

Low molecular weight heparin

Examples (x-parin): enoxaparin (Lovenox), dalteparin, ardeparin

Chemistry: fragments of standard heparin produced by controlled chemical or enzymatic depolymerization of heparin. Minimum 18 saccharide units. Very acidic à anions at physiologic pH à ↓ absorption from GI.  Given only parenterally as sodium salts. Heparin: mean MWt 15K.  LMWH: mean MWt 5K.

Indications: prevention and treatment of venous thromboembolism (venous thrombosis, VTED, unstable angina pectoris, MI, surgery).

Mechanism: very similar to heparin with more effect on Xa than on IIa.

PK: ¯¯ binding to heparin-binding proteins than heparin à ­ bioavailability at ¯ doses and more predictable effect / uniform absorption.  ¯ binding to endothelial cells à ­ plasma t1/2 and dose-independent renal clearance. ↓ SE than heparin.

aPTTT can NOT be used to monitor effect.  No approbriate assay available.

Danaparoid: low MWt heparinoid.   It’s a glycosaminoglycan from porcine mucosa.  Similar mechanism / uses. CI: bleeding and pork product sensitivity. 

Lepirudin

Chemistry: recombinant DNA (almost identical to hirudin).

Mechanism: ↓ thrombin (factor IIa) thrombogenic activity (antithrombin).

Use: anticoagulant in case of heparin-induced thrombocytopenia.

SE: cerebral bleeding, allergic/ skin reactions.

Antiplatelet agents

Aspirin: Mechanism: ↓ dose à permanent inhibition of COX à ↓ thromboxane A2.  Use: ↓ mortality post-MI, prevent MI reinfarction.

Ticlopidine / clopidrogel: Mechanism: interfere with ADP-induced platelet-fibrinogen binding à ↓ glycoprotein GPIIb/IIIa receptor. Use: ↓ MI, stroke risk.  SE: ↑↑, diarrhea, rash, GI upset, neutropenia.

Fab fragments (Abciximab): Mechanism: monoclonal antibodies against GPIIb/IIIa receptor à ↓ platelet interaction. Use: coronary angioplasty, atheroctomy.  SE: bleeding, thrombocytopenia, antibody formation, arrhythmia.

Eptifibatide / Tirofiban: Mechanism: same as Abciximab.  Use: acute coronary syndrome, coronary angioplasty.  Glycoprotein IIb/IIIa receptor antagonists à ↓ fibrinogen, adhesion ligands.  SE: bleeding, fever, headache.

Dipyridamole:  Mechanism: ↓ RBC adenosine, ↓ phosphodiesterase (à ↑ cAMP), ↓ thromboxane A2.  Use: for thromboembolism prophylaxis after valve replacement.  SE: nausea, GI upset, headache, rash, dizziness. Also relax smooth muscles, ↓ coronary vascular resistance (↑blood flow). 

Anagrelide: Mechanism: ↓ platelet production. Use: ↓ platelet count in thrombocythemia. SE: CHF, MI, heart block, arrhythmia.

Cilostazol: Mechanism: PDE III inhibitors à ↑ cAMP à vasodilation.  SE: CHF.

Thrombolytic agents

General Mechanism: ↑ conversion of plasminogen to plasmin (serine protease), which hydrolyzes fibrin and dissolves clots.

General SE: bleeding (GI / GU / intracranial / catheter site), and allergic reactions (skin rash, bronchospasm, edema, urticaria).

Alteplase / reteplase (t-PA): recombinant DNA-derived tissue plasminogen activators (t-PA) consisting of amino acids. Called ‘Clot Selective’ because it acts on fibrin-bound plasminogen.  SE: acute MI, acute pulmonary embolism.  No allergy issues (human-derived)

Streptokinase: protein derived from cultures of Group C beta-hemolytic streptococci (à hypersensitivity).  ↓ fibrinogen and factors 5 & 8.  Acts on bound & free plasminogen (not selective). Use: acute MI, DVT, arterial thrombosis.

Anistreplase: also called ‘Anisolyated Plasminogen Streptokinase Activator Complex, APSAC’.  Prodrug, activated in vivo by deacylation.  Use: acute MI, coronary arterial thromobi.  SE: arrhythmia, ↓ BP

Urokinase: two-chain serine protease from cultured human kidney cells. Mechanism: enzymatically active (plasminogen à plasmin).  Use: coronary arterial thrombi, pulmonary embolism.

42. Infectious Diseases

43. Seizure Disorders

44. Parkinson’s disease

Disease state and pathology

Slowly progressive degenerative neurologic disease.

Incidence: over 50 years of age (mostly 60’s)= 0.1%.

Pathogenesis: Depigmentation of substantia nigra.  Loss of dopaminergic input to the basal ganglia (extrapyramidal system) which is responsible for initiating, modulating, sequencing motor activity à motor disability.  Parkinson’s is due to imbalance between dopamine (inhibitory neurotransmitter, ¯) and acetylcholine (excitatory neurotransmitter, ­). 

Diagnosis: depends on clinical findings, tests to rule out secondary cause, PET scan to visualize dopamine uptake in substantia nigra and basal ganglia. 

Etiology

Primary (idiopathic): called classic Parkinson’s or paralysis agitans. Most common.  Incurable disease.  Can be due to absorption of highly potent neurotoxins (CO, manganese solvent, MPTP) or exposure to cell toxic hydrogen peroxide and free radicals; both products of dopamine catabolism.

Secondary: small percentage, usually curable.  Drugs: dopamine antagonists / antipsychotics (phenothiazines (chlorpromazine, perphenazine), haloperidol, reserpine).  Toxins: CO, heavy metals (manganese, mercury, MPTP).  Infections: syphilis, encephalitis.  Others: Wilson’s disease, arteriosclerosis. 

Pseudo-Parkinson’s: due ↑ dose of older (traditional) antipsychotic agents, more in the elderly

Signs and symptoms

Tremor: initial complaint.  Most evident at rest (resting tremor) and with ¯ frequency movement.  Pill-rolling tremor: involve thumb and forefinger.  Action tremor: with activity. 

Limb rigidity: ratchet-like movement when limb is moved passively

Akinesia (difficult) / bradykinesia (slow): including masked-face (fixed expression) with ¯ spontaneous emotional responses. 

Postural difficulty: walking with stooped, flexed posture, ¯ arm swing in rhythm with the legs. 

Mental status: depression (50%), dementia (25%), psychosis.

2ry disease effects: cardiovascular (orthostatic hypotension, arrhythmia), GI (constipation, ­ salivation), ­ urinary frequency, impotence, hallucinations.

Unified Parkinson’s Disease Rating Scale (UPDRS): used to monitor disease progress and evaluate drug efficacy.  Includes: mental status, behavior, mood, daily activities (speech, swallowing, walking, etc), clinicians motor evaluation (speech, mobility, tremor, etc). 

Treatment:

Non-drug: Exercise / physical therapy: very beneficial for mobility and mood.  Nutrition: to ¯ risk of poor nutrition, weight loss, ¯ muscle mass.  ­ fiber and fluid intake to prevent constipation.  ­ calcium to preserve bone structure.  ­ antioxidants (e.g. vitamin E) to ¯ oxidative stress.  Psychological rehabilitation: support for patient, family.  May need to treat depression, dementia.  

Drugs: TCA (anticholinergic, dopaminergic, for depression).  Beta blocker (propranolol, ­ lipid solubility), BZD, primidone for action tremor.  Diphenhydramine: antihistamine with anticholinergic effect for mild tremor (CNS SE, avoid in elderly).

Principles of therapy: if drug fails à use another class, except bromocriptine and pergolide (try both in sequence).  Build dose gradually up.  Never d/c drug suddenly. 

Late disease disabilities: Levodopa à motor fluctuation, dyskinesia, ¯ response à control by changing dose and timing.  Non-levodopa: urinary urgency à oxybutynin, constipation à fiber / PEG,  ­ salivation à antihistamines / anticholinergics, ­ sweating à beta blocker / anticholinergic, orthostatic hypotension à desmopressin, pain à amitriptyline, depression / dysphagia à liquid levodopa, daytime sleepiness à selegiline.  

Definitions: Dyskinesias: reversible jerky movements.  On-off effect: oscillations in response and sudden changes in mobility from no symptoms to full symptoms within minutes.  End-dose (wearing-off) effect: may improve by shortening the dosing interval.  Drug holiday: temporary d/c of levodopa to reverse down-regulation of dopamine receptors and regain efficacy. 

Individual drugs

Anticholinergic agents

Examples: benztropine, trihexyphenidyl (both structurally related to atropine), biperidene, procyclidine, orphenadrine. 

Use: mild symptoms, esp. tremors (not bradykinesia / pos. imbalance).

Mechanism: block action of acetylcholine in basal ganglia.

SE: dry mouth, ¯ sweating (à ¯ heat tolerance), urinary retention, constipation (use stool softener), delayed gastric emptying, ­ intraocular tension, GI upset, dizziness, agitation, hallucinations, hypotension.

CI: obstructed GI or GU, glaucoma, cardiac disease. Avoid drugs with anticholinergic activity (antihistamines, antidepressants, phenothiazines), ­ digoxin level.  Avoid combo with haloperidol (­ tardive dyskinesia severeity, schizophrenia, ¯ haloperidol level).

Dopamine precursor (Levodopa/carbidopa)

Most effective.  ¯ effect / ­ SE in 4 years. Dopamine can’t cross BBB (not used). 

Mechanism: Levodopa: converted by dopa decarboxylase to dopamine à ­ dopamine in CNS (crosses BBB).  Carbidopa:  levodopa analog that does not cross BBB à ¯ peripheral decarboxylation of levodopa à ¯ peripheral SE, ­ CNS bioavailability, ¯ dose needed by 75%.

SE: due to peripheral conversion to dopamine (GI upset, arrhythmia, postural hypotension).  Others: hallucinations, psychosis, blood dyscriasis, GI upset, insomnia

CI: glaucoma, may activate malignant melanoma.  Pyridoxine (vit B6) à ↑ peripheral decaroxylation à ↓ effect.  MAOIà hypertension.  TCA / Food ¯ absorption.  Metoclopramide: ­ levodopa level.

General dopamine agonist SE: ↓ BP, syncope, arrhythmia, insomnia, hallucinations, psychosis.

Direct acting dopamine agonists

Ergot alkaloids (ergolines): bromocriptine, pergolide.  Others: pramipexole, ropinirole.  All mimic dopamine effect (direct agonist).

Bromocriptine

SE: first-dose cardiovascular collapse (postrual hypotension, fainting, tachycardia, dysrhythmias, dizziness), hallucinations, pulmonary toxicity, GI upset.  V. long t_1/2.  ­ response variability.

Pergolide

Mechanism: semisynthetic ergosine derivative. 1000x more potent than bromocriptine. ¯ prolactin, ¯ LH, ­ growth hormone.

SE: dysrhythmias, ↓ BP, hallucinations, insomnia, GI upset

CI: 90% protein bound (cautious with other protein bound drugs), antipscychotics à contradictory effects.

Non-ergot dopamine agonists

Examples: pramipexole, ropinirole

Mechanism: bind to dopamine D2/D3 receptors. Also, antioxidant/O₂ free radical scavenger, moderate antidepressant.

Start ¯ dose and ­ gradually to titrate best balance of efficacy / SE.  Also d/c gradually. ¯ levodopa dose if used together.

SE: ¯ compared to non-selective agonists (motor fluctuations, dyskinesia).  Orthostatic hypotension, syncope, bradycardia, hallucinations, GI upset,

CI: liver metabolism. pramipexole: cimetidine ¯ clearance.  Ropinirole: smoking ­ metabolism, ciprofloxacin ¯ metabolism.

Indirect acting dopamine agonists

MAO-I: Selegiline

Mechanism: MAO-B selective inhibitor à ¯ catecholamine (dopamine) breakdown in the brain (MAO-A is in the GI, MAO-B is in the brain).  Used when levodopa wears off.  Only MAO-A metabolizes tyramine (exogenous amine in beer, wine, cheese, smoked meat) à hypertensive crisis if inhibited. 

SE: hypertensive crisis (possibly with tyramine but ↓ risk), ­ levodopa SE, dizziness, hallucinations, insomnia, orthostatic hypotension, syncope, arrhythmia, GI upset/bleeding.

CI: meperidine, other opioids. 

Catechol-O-methyltransferase (COMT) inhibitors

Examples (x-capone): tolcapone

Mechanism: Selective reversible inhibitor of COMT; main enzyme for peripheral and central metabolism of catecholamines including levodopa to O-methyldopa (doubles levodopa t1/2).  It can be combined with selective MAO-B inhibitor (selegiline).

SE: liver toxicity (jaundice, lethargy, fatigue, appetite loss, clay colored feces, monitor ALS/AST), orthostatic hypotension, hallucinations, diarrhea, ­ levodopa SE, rhabdomyolysis.

Amantadine

Mechanism: antiviral agent used to prevent influenza. It ¯ dopamine pre-synaptic reuptake, ­ dopamine synthesis and release.  Some anticholinergic effect (¯ tremor, ridigity, bradykinesia). Fast acting drug (effect within few weeks). Drug tolerance occurs (d/c for a few weeks or use only when needed).

SE: anticholinergic SE, hallucinations, dizziness, seizures, CHF, reversible skin rash (livedo reticularis), blood effect, insomnia, ∆ speech.

CI: ­ effect of anticholinergics, HCTZ/triamterene à ¯ excretion à ­ blood level. 

Surgical treatment

Require needle insertion in the brain à possible hemorrhage.

Deep brain stimulation: implant ­ frequency electrode into target site and connect lead to SC pace maker à functional inhibition of target regions in the brain.

Globus pallidus internus pallidotomy: surgical resection of parts of the globus pallidus.

Retal nigral transplantation: implantation of embryonic dopaminergic cells to replace degenerated neuronal cells.

45. Schizophrenia

Pathophysiology

Genetic studies: 10x ­ in risk with family history.  50% chance in both of monozygotic twins.

Neurophysiologic theories: mainly due to ­ dopamine.  Serotonin and glutamate may play a role.  Dopamine may ¯ in some brain areas.

Psychosocial theories: may be triggers but not causes.  Stress, ¯ interpersonal skills, bad family communications, socioeconomic factors.

Population prevalence: 1%. 

Diagnosis

Using Diagnostic and Statistical Manual (DSM) of Mental Disorders.  Diagnosis by exclusion after ruling out medical and mental causes of psychosis.  Symptoms: delusions, hallucinations, disorganized speech / behavior, negative symptoms (6 months + 1 month active symptoms causing social or occupational dysfunction). 

Types: paranoid (delusions of grandeur or persecution), catatonic (psychomotor disturbances), disorganized (incoherent responses), residual (history but no acute psychosis), undifferentiated.

No known cure.  Objective is to relieve symptoms and restore function.

Treatment: pharmacotherapy, psychotherapy. 

Antipsychotics

Agent selection: based on patient history and drug safety.  Atypical antipsychotics in new diagnosis or first episode (safer drugs).  Antipsychotics are more effective for ¯ positive symptoms.  Maximum effect: 6-8 weeks.  One episode à d/c gradually after 6 months.  Multiple episodes: indefinite treatment. 

Typical antipsychotics

Examples:  phenothiazines (chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, trifluperazine), haloperidol, loxapine, molindone.

Mechanism: block dopamine (D2) activity.  Cause hyperprolactinemia.

Potency: ­ potency à ­ extrapyramidal symptoms.  ¯ potency à sedation, anti-cholinergic, cardiovascular SE.

Efficacy: as good as the typical drugs for the positive but not the negative symptoms.  Generally, more SE than the typical drugs.

Extra-pyramidal SE

Acute dystonias: sudden muscle spasms (neck, jaw, back, eyes).  Common in the first 2 days.  Treatment: IV/IM anticholinergic (diphenhydramine, benztropine).

Akathisia: motor restlessness, inner tension and agitation, urge to move (pacing).  Common in the first weeks or months.  Treatment; anticholinergic, beta blocker, BZD.   

Pseudoparkinsonism: parkinsonism induce by dopmine blockade.  Common in the first weeks or months.  Treatment: anticholinergic or switch to atyptical drug.

Tardive dyskinesia (TD): latent extrapyramidal effect (after months / years).  Abnormal movement (face, tongue, shoulders, hipds, extremities, fingers, toes, etc).  Movements are fixed (dystonic) and rhythmic.  It’s due to prolonged dopamine blockade à dopamine receptor up-regulation à ­ sensitivity to stimulation.  Treatment: may be irreversible, d/c therapy, when ¯ dose symptoms may first worsen due to dopmaine blockade and still up-regulated receptors, ­ dose may initially mask symptoms but will remerge later.  Best approach is prevention (monitor). 

Neuroleptic malignant syndrome (NMS)

Uncommon but sudden onset, serious and may be fatal.  Symptoms: extrapyramidal effects, hyperthermia, tachycardia, ­¯ BP, incontinence.  Management: d/c drug, bromocriptine or dantrolene (muscle relaxant), supportive therapy.

Atypical antipsychotics

Examples: risperidone, olanzapine, clozapine, quetiapine.

Block serotonin more than dopamione-2 receptors.

Less extrapyramidal SE than typicals.  No hyper-prolactinemia.

Treat negative symptoms better than typicals.

Clozapine: only drug with no EPS/TD.  Only effective drug for refractory patients.  However, use as last resort due to agranulocytosis (monitor CBC weekly).  It has ­­ anticholinergic SE. 

Other condiserations

SE by recptor type: histamine H1 à sedation;  serotonin 5-HT à weight gain; dopamine D2 à EPS / hyperprolactinemia; muscarinic à anticholinergic / cognitive / tachycardia; alpha-1 à orthostatic hypotension / reflex tachycardia. 

Rapid tranquilization: for acute psychosis with agitation and aggression.  Use injectable typical drug (IM haloperidol). 

Noncompliant patient: use long acting IM drugs every 3 weeks; either haloperidol decanoate or fluphenazine decanoate.  Convert existing oral dose to its injectable equivalent. 

Switching drugs: cross taper and titrate (¯ old, ­ new). 

Adjunctive therapy: if 3 agent tried unsuccesfully à use clozapine or augmentative therapy (BZD anixiolytics or modd stabilizers such as lithium, valproic acid or carbamazepine).

46. Mood Disorders

Mood range:  depressionàdysthymia (dysphoria)àeuthymiaàeuphoria (hypomania)àmania

Dysphoria (dysthemia): mood depression below normal range but above depression.

Euphoria (hypomania): mood elevations above normal range but below mania extreme.

Euthymia: the range of normal fluctuation in mood

Mood disorders: sustained elevation or depression in mood that impairs ability to function in the society.  Risk of suicide:x10-20. 

Major Depression

Incidence: more in women (2x men).  15-20% chance in woman’s lifetime. 

Etiology: Biogenic amine theory: due to depletion of serotonin and norepinephrine.  Dysregulation theory: cyclic nature of depression is due to impaired balance of neutrotransmitters not absolute ↓ or ↑.  Familial history plays a role. 

Clinical depression: ↓ mood,anhedonia, appetite ↑ ↓ , weight ↑ ↓, sleep ↑ ↓, psychomotor ↑ ↓, fatigue, worthlessness, guild, ↓ thinking / concentration, suicidal

Diagnosis: using Diagnostic and Statistical Manual (DSM) IV criteria.  Patient must have persistent symptoms for 2 weeks. 

Treatment:

Psychotherapy, pharmacotherapy, and electroconvulsive therapy. 

Pharmacotherapy with antiderpssants is 50-60% effective.  It has three phases: acute (6 wk, resolve symptoms), continuation (6-9 months, prevents relapse) and maintenance (3 or > years, prevents recurrence).

Drug selection: all drugs are equally effective with different mechanisms and SE.  Select drug with SE profile that complements the disease process.  For example, depression with psychomotor agitation à sedative antidepressant, depression with psychomotor retardation à activating antidepressant. 

Therapy initiation: start with half of the lowest dose to minimize SE à ↑ to target range in 1-2 weeks, then titrate based on response. GRADUAL.

Lag time exists between therapy initiation and clinical response due to changes in postsynaptic receptor sensitivity.  Resolution of anxiety and insomnia in 1-2 week.  Full effect in 4-6 weeks. 

Serotonin syndrome: tremor, seizure, hyperreflexia, hypomania, agitation, fever, diarrhea, confusion.  May occur when two serotonin enhancing drugs are used concomitantly or close to each other (e.g. MAOI, SSRI). 

Serotonin withdrawal syndrome: lethargy, myalgia, chills, dizziness, flu-like symptoms

Tricyclic Amines (TCA)

Examples: amitriptyline, nortriptyline, protriptyline, imipramine, trimipramine, desipramine, doexpin

Serum concentrations are established for some drugs.

Mechanism: blocks serotonin and norepinephrine reuptake.  Also bind to cholinergic, histaminergic, alpha-adrenergic receptors (SE). 

SE: anticholinergic (blurred vision, dry mouth, constipation, urinary retention), alpha blockade (orthostatic hypotension), antihistamine (sedation, take at bedtime), ↓ seizure threshold, ECG changes, lethal if overdoes. 

Not first choice for depression.  Other uses: neuropathic pain, insomnia.  

Monoamine oxidase inhibitors (MAOI)

Examples: phenelzine, tranylcypromine, isocarboxazid. 

Mechanism: ↓ monoamine oxidase à block break down of biogenic amines à ↑ serotonin and norepinephrine in the brain

Not first choice for depression.  Only for depression with agitation, hypersomnia, anxiety. 

↑ SE: orthostatic hypotension, weight gain, edema, sexual dysfunction.  Isocarboxazid à liver damage. 

May result in accumulation of sympathomimetic amines à hypertensive crisis à CI with decongestants, foods with tyramines (aged cheese, wine). 

MAO: 2 wk washout period before start or when D/C. 

Bupropion (Wellbuterin)

Mechanism: ↓ reuptake of epinephrine, serotonin, dopamine. 

SE: stimulation similar to SSRI à give in the morning, ↑ seizure esp with eating disorders. 

Selective Serotonin Reuptake Inhibitors (SSRI)

Examples: fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylsertraline, fluvoxamine (for OCD). 

Mechanism: selectively block serotonin reuptake à ↑ level

↓ SE: stimulation and insomnia (give in the morning), GI, sexual dysfunction, (weight gain?). 

Abrupt D/C à serotonin withdrawal syndrome (except fluoxetine) à D/C gradually. 

Metabolized by cytochrome P-450 à drug interactions. 

Fluoxetine: norfluoxetine has long t1/2 à5 wk washout period after D/C. 

Venlafaxine (Effexor)

Mechanism: ↓ reuptake of epinephrine, serotonin, dopamine (similar to bupropion).  CI: MAOI.  Dose gradually. 

SE: nausea, GI (take with food), sustained hypertension (monitor BP).  

Trazadone

Low dose is commonly used for insomnia with stimulating antidepressants.

Mechanism: ↑ serotonin.  ↑ SE: sedation, hypotension, GI

Nefazodone

Structure is similar to trazadone.  Mechanism: ↑ serotonin. 

SE (↓ than trazadone): sedation, hypotension, GI, dry mouth. 

Interaction: ↑ protein binding à interact with warfarin, phenytoin.  Cytochrome P-450 inhibitor à ↑ drugs metabolized by P-450. 

Mirtazapine

Mechanism: ↓ presynaptic  alpha-2 receptors à ↑ norepinephrine and 5-HT central concentration. Specific affinity to 5-HT1 receptors à ↓ SE compared to SSI (no insomnia, agitation, sexual dysfunction).  Blocks H1 à sedation, and 5-HT2c à ↑ appetite. 

SE: sedation (take at bedtime), weight gain, dry mouth.

Bipolar disorder

Incidence: 1% of the population.  More common in female teens or early 20’s.

Etiology: Family history in 90% (genetics).  Due to imbalance and fluctuation in neurotransmitter levels. 

↑ norepinephrine à manic episode, ↓ norepinephrine à depression. 

↓ GABA (gamma-aminobutyric acid, inhibitory neurotransmitter) à mania, due to unopposed excitatory neurotransmitters (norepinephrine, dopamine).

↓ calcium in CSF à mania.  ↑ calcium in CSF à depression. 

G protein: involved in signal transduction and activation of other neurotransmitters.   Hyperactive G protein à mood instability. 

Glutamate binding to G proteins linked to NMDA is involved. 

Psychosocial and physical stressors trigger early episodes.

Diagnosis:  using DSM-IV and history of mania and depression. 

Mania: elevated, expansive or irritable mood for 1 week.  Grandiose ideations, expansive self-esteem, ↓ sleep, racing thoughts, distraction, psychomotor agitation, dangerous activities.

Mixed episode (mood incongruent): mania and depression symptoms. 

Bipolar I: manic or mixed episode.

Bipolar II: depressive and hypomanic episode. 

Cyclothymia: depressive and manic symptoms for 2 years.

Rapid cycling: four depressive, manic, hypmanic or mixed episodes in 12 months

Clinical course: untreated episodes last days to months.  Interval between episodes: 1-2 years.  Episode sequence is unpredictable.  Early onset à bad prognosis.

Treatment

Acute, maintenance and continuation phases (like depression). 

Antipsychotics, antidepressants, and mood stabilizers may be used. 

Antipsychotics: short term therapy during acute mania to ↓ psychosis and agitation. 

Antidepressants: use for depression with suicidal tendency.  Use cautiously to avoid triggering mania. 

Lithium

First line therapy (except for mixed episodes or rapid cycling). 

Monovalent cation like Na and K.  Citrate salt à liquid,  carbonate salt à tablet. 

Food may delay absorption.  Take with food to avoid rapid rise in serum concentration and SE. 

Highly distributed but takes 3 days à delayed response. 

Eliminated through the kidneys with no metabolism.

Mechanism: unknown.  ↓ norepinephrine / serotonin, ↑ membrane stabilization, ↑ cAMP / cGMP (2^nd messengers).

Dose: narrow therapeutic index. Can be used to acute mania (↑ and ↓ dose gradually, quick action for mania but slow for deperssion) or preventative maintenance (mania, depression).  Require Cp monitoring. If high dose à psychosis, psychomotor agitation à give BZD or antipsychotics.

SE: ↑↑↑.  Monitor Cp.  Categorized into early, long term, and toxicity. Polydipsia, polyuria, nocturia, dry mouth, weight gain, ↓ libido, tremors, CNS.

Toxicity: use emesis, gastric lavage, hemo- or peritoneal dialysis but not charcoal.

CI: renal failure, pregnancy 1^st trimester.

Interactions: drugs that ↑ serotonin à serotonin syndrome.  With BZD, antipsychotics à ↑ neurotoxicity.

Valproic Acid (VA)

Indications: anticonvulsant that works as a mood stabilizer. Can be used in acute episodes or as a mood stabilizer.

Forms: elixir à sodium valproate, capsules à VPA, enteric coated tabs à divalproex, injections à sodium valproate sodium

SE: ↑↑.  Monitor Cp.  Blood (agranulocytosis, thrombocytopenia), weight gain, liver / pancreas damage, GI upset (↓ in divalproex).

CI: sensitive to enzyme inhibitors and inducers.

CBZ

Indications: anticonvulsant that works as a mood stabilizer. Use in bipolar if lithium fails.

Mechanism: modulate NEp and cAMP (G protein-linked 2^nd messenger system).

SE: CNS: drowsiness, dizziness, blurred vision, diplobia, nystagmus, confusion, headache.  Dose related: blood dyscrasias, ↑ dose gradually to avoid SE, GI upset (take with food). Non dose related: skin SE.  Metabolic enzyme inducer (drug interactions, monitor Cp). Complete monitoring (blood count, live function, BUN, electrolytes, TSH).

New Mood stabilizers (anticonvulsants) (gabapentin, lamotrigine)

Indications: both mood elevation during epilepsy. Not approved, though, for mood stabilization (no systematic data).

Lamotrigine: structure is similar to phenytoin and CBZ.  Mechanism: block sodium-mediated release of glutamate and aspartate, may also block GABA and Ach release. SE: dizziness, blurred vision / diplobia, GI upset, rash / photosensitivity.

Gabapentin: structure is similar to GABA (but no effect on GABA). Mechanism: unknown. ↑ dose gradually.  Short t1/2 à frequent administration. SE: somnolence, dizziness, nystagmus, fatigue.

Other topics

Use of dual mood stabilizers

Combination of lithium and CBZ or VPA.  Watch for leukocytosis / leukopenia. Do not combine CBZ and VPA (↑↑ blood dyscrasias).  May also combine one of the three (older drugs) with one of the two newer drugs (above).

Mood stabilizers in pregnancy

Older drugs (lithium, VPA, CBZ) may cause birth defects. If necessary, use lithium only in 2^nd and 3^rd trimester.  If necessary, give folic acid with VPA to ↓ risk.

47. Asthma and COPD

Asthma

Definition

Reversible chronic airway inflammation.  It involves obstruction, ↑ airway responsiveness, episodic asthma symptoms.  Pathologic changes are not permanent.

Classification: mild intermittent, and persistent (mild, moderate, severe) 

Incidence: 15 million Americans (one third children).  50% of children outgrow asthma by mid-teens, may return to asthma later in life. 

Etiology

Allergens (pollen, dust mite, animal dander, mold, food), occupational exposures (chemicals, flour, wood, textile dust), viral respiratory infections, exercise, emotions (anxiety, laughter, stress, crying), irritant exposure (odors, chemicals, irritants), environmental exposure (weather change, cold air, smoke, sulfer dioxide), drugs (hypersensitivity, aspirin, NSAID, cholinergics (bethanechol), anti-adrenergics (B blockers)).

Allergic rhinitis is twice as common in asthmatics.

Pathology / pathophysiology

Postmortem examination: smooth muscle hypertrophy, airway plugs (inflammatory cells, debris, proteins, mucus), vessel vasodilatation, inflammatory cellular infiltrate, collagen deposition.

Major contributing processes

Inflammatory cells: such as mast cells, eosinophils, activated T cells, macrophages, epithelial cells à secrete mediators.

Airway obstruction: due to bronchoconstriction, airway wall edema, mucus plug formation, airway remodeling, smooth muscle hypertrophy, hyperplasia.  Obstruction à ↓ ventilation à ventilation / perfusion (V/Q) imbalance à hypoxemia and ↓ partial pressure of arterial oxygen (PaO₂). 

Hyper-responsiveness: ↑ response to stimuli due to ↑ inflammatory mediators and infiltration by inflammatory cells.

Airway inflammation: contributes to hyper-responsiveness, obstruction, respiratory symptoms, ↓ muco-ciliary function, ↑ airway permeability to allergens / irritants.

Autonomic neutral control: ↑ cholinergic sensitivity à↑ parasympathetic tone, reflex bronchoconstriction.  

Airway remodeling: due to persistent inflammation in poorly controlled asthma à collagen deposition and fibrosis à permanent airway abnormalities. 

Sequencing of events in asthma

Triggering: exposure to trigger (allergen, aspirin, virus, etc) à antigen binds to IgE à attach to activated mast cells.  Early response: begins in < 30 min and resolves in < 2hr, blocked by beta agonist or cromolyns.  Late response: begins 6 hr after trigger, persistent airway obstruction, inflammation, hyper-responsiveness, occurs in 50% of cases, may last several days, blocked by corticosteroids or cromolyns.

Signaling: inflammatory cells (mast cells, lymphocytes, eosinophils, macrophages, epithelial cells) release chemical signals (cytokines, chemokines, eicosanoids, leukotrienes) à attract more inflammatory cells. 

Migration: influx of inflammatory cells (eosinophils, lymphocytes, monocytes, granulocytes); ↑ adhesion molecules à attract cells to the airways. 

Cell activation: required before cells can release inflammatory mediators.  Eosinophils activation à ↑ inflammatory mediators à smooth muscle constriction, initiate chemotaxis.  Leukotrienes à bronchoconstriction, ↑ mucus, ↑ vascular permeability, ↑ responsiveness.  Other mediators recruit more inflammatory cells to the airways in the late asthmatic response.

Tissue stimulation and damage: due to release of inflammatory mediators from activated cells.  Epithelial damage à ↑ airway responsiveness à may cause remodeling. 

Clinical evaluation

Physical findings

Acute exacerbations: occur suddenly or gradually, usually at night or early morning.  Shortness of breath, tachypnea, tachycardia, wheezing at end of exhalation, chest tightness, cough. 

Chronic poorly controlled severe asthma: chronic hyper-inflation, barrel chest. 

Signs of respiratory distress: cyanosis (↓ PaO2 / ↑ PaCO2), use of accessory muscles, inability to speak in sentences, ↓ mental status, PEFR < 50% of normal. 

Potentially fatal asthma: history of sudden severe exacerbations, poor self-perception of asthma, history of intubation or ICU admission, visits to ER or hospitalization for asthma, frequent beta agonist use (>2 canisters / month).

Diagnostic tests

Pulmonary function tests: determine degree of obstruction, may be normal between exacerbations.  Forced expiratory volume in 1 second (FEV₁): ↓ during exacerbation.  Air trapping and lung hyperventilation à ↑ residual volume (RV), ↑ total lung capacity (TLC).  Peak expiratory flow rate (PEFR): correlates with FEV1, used to monitor therapy, triggers, need for emergency care.  Measure PEFR in early morning before medications, and may be again midday.  Diurnal variation > 20% in PEFR indicate ↑ responsiveness, and poor control.

Blood analysis: ↑ WBC count during acute exacerbation, eosinophilia, leukocytosis (due to WBC demargination due to corticosteroids). 

Sputum analysis: may reveal eosinophils, clumps of epithelial cells, bacterial if infected, mucous in small airways.

Pulse oximetry: noninvasive measure of degree of hypoxemia during acute exacerbation.  It measures oxygen saturation in arterial blood (SaO2) and pulse. 

Arterial blood gas: help gauge the severity of exacerbations.  Early stages à hyper-ventilation à ↓ PaCO2 à fatigue of respiratory muscles.  Respiratory acidosis: poor prognostic sign à respiratory fatigue à ↓ respiratory rate à ↑ PaCO₂.

ECG: may show sinus tachycardia, especially in the elderly.

Chest radiograph: may show pneumonia, hyperinflation.

Allergy skin and radioallergosorbent test:  identify possible allergic triggers.

Complications

Status asthmaticus: severe asthma exacerbation that fails to respond to therapy à life threatening.  Symptoms: ↓ consciousness, cyanosis, ↑ PaCO₂, PEFR < 100 L/min or FEV1 < 1 liter.  Treatment: oxygen, inhaled beta agonist, anticholinergic, IV steroids.  If respiratory acidosis à tracheal intubation, mechanical ventilation. 

Pneumothorax: acute exacerbation with air accumulation in the pleural space.  Symptoms: chest pain, dyspnea, cough, anxiety, lung collapse.  Treatment: oxygen, pleural air aspiration, analgesics. 

Atelectasis: airway obstruction à ↓ gas exchange during respiration à collapsed lung.  Symptoms: worsening dyspnea and anxiety, hyperventilation, ↓ breath sounds, cyanosis.  Treatment: postural drainage, chest percussion, coughing / breathing exercise, bronchodilators, bronchoscopy to remove secretions. 

Therapy principles

Acute exacerbations

At home: depends on EFV or PEFR.  If < 50% of personal best à aggressive treatment.  Limit inhaled albuterol to 3 treatments of 3 buffs by MDI at 20 min intervals or one nebulizer treatment.  If response is poor à use oral corticosteroid, go to ER if needed.

In the hospital: inhaled albuterol, mechanical oxygen ventilation (up to 90% saturation), anticholinergic, oral or IV corticosteroids, intubation. 

Persistent asthma

Step-down approach: aggressive.  Start treatment one step above assessed severity for rapid control, review every 3 months.  Then, do gradual step-wise reduction in treatment.

Step-up approach: start treatment at the same step as assessed severity, and adjust upward as needed.  Always, control environment to avoid triggers.  If daily or ↑ use of inhaled albuterol à consider long-term therapy (e.g. anti-inflammatory). A rescue course of systemic corticosteroids may be used.

Exercise-induced bronchospasm (EIB)

Warm-up period helps prevent EIB.  Prevent EIB by using short acting beta agonist (albuterol) 15 min before exercise, long acting beta agonist (salmeterol) 45 min before exercise, or cromolyn sodium 1 hr before exercise.  Keep albuterol handy.

Chronic asthma (NIH guidelines)

Severe persistent: ↑ dose inhaled steroid + ↓ dose oral steroid + long acting bronchodilator (inhaled or oral salmeterol, SR theophylline). 

Moderate persistent:  inhaled steroid + long acting bronchodilator for nigh time symptoms (inhaled or oral salmeterol, SR theophylline) (drop oral steroid).

Mild persistent: only one of the following: ↓ dose inhaled steroid, inhaled cromolyn, SR theophylline, leukotriene modifier.

Mild intermittent: no daily medications.  Albuterol for attacks.

Therapeutic agents

Beta agonists

Short acting: albuterol (R- and S- isomers), levalbuterol (only active R-enantiomer), metaproterenol, pirbuterol, for acute exacerbation and EIB prophylaxis. 

Long acting: salmeterol, formoterol for asthma maintenance, EIB prophylaxis, nocturnal symptoms, ↑↑ albuterol use, COPD.

Mechanism: stimulate beta 2 receptors à ↑ adenyl cyclase à ↑ cAMP à bronchodilation, ↑ mucociliary clearance, ↓ inflammatory cell mediator release. 

SE: tremors (due to B2 activation in skeletal muscles), gluconeogenesis (↑ glucose), activation of Na K ATPase, cardiac stimulation (due to partial B1 stimulation: palpitation, tachycardia), nervousness, headache. 

Administration: inhalation ↓ systemic SE (preferred over oral).  Always use salmeterol with inhaled steroid, except for EIB prophylaxis.  May combine long and short acting.

Tachyphylaxis: occurs due to regular use.  It’s due to down-regulation due to moving of beta receptors from cell surface to inside the cell.  Effect may be reversed with steroids. 

Paradoxical bronchoconstriction: due to cold-Freon effect or use of adjuvants.

↑ bronchial hyperactivity: due to irritants such as methacholine and histamine.  May be due to albuterol’s S-isomer.

Drug interactions: hypertensive crisis with MAO inhibitors, TCA and methyldopa.  Beta blockers (e.g. propranolol) à bronchospasm. Combined with sympathomimetics à ↑ heart effect, vasoconstriction (prevent by alpha blockers, phenolamine).  

Corticosteroids

Mechanism:  Bind to glucocorticoid receptors in the cell cytoplasm à alter gene transcription à ↓ inflammatory response, ↓ airway hyper-responsiveness, ↓ mucus.

Use: in case of allergic component. Added only when anticholinergic / beta agonist combo is ineffective.

Systemic steroids: used for rapid response during acute exacerbations (few hours). 

IV steroids: hydrocortisone and methylprednisone.  Alternative to oral steroids to prevent respiratory arrest in hospitals.  Switch to oral steroids after stabilization.

Oral steroids: prednisone, prednisolone.  Used in emergencies if possible when there is no risk of respiratory arrest.  Used in burst doses for a week.  Dose tapering may be required. 

Inhaled steroids: fluticasone, flunisolide, triamcinolone, beclomethasone, budesonide. Used for chronic treatment, not for acute exacerbations.  Less SE and less efficacy.  ↑ steroid penetration into bronchial tree by giving bronchodilator several minutes prior.

Systemic steroids SE: hyperglycemia, ↑ BP, CHF, peptic ulcer, immunosuppression, chronic infections, osteoporosis, glaucoma, depression, psychosis, cataract, skin changes.  If long term, minimize SE by giving morning dose or alternate day dosing. 

Inhaled steroids SE: fungal infection, voice hoarseness, dry mouth. May ↓ children growth velocity, but uncontrolled asthma also retards growth.  Systemic SE with large doses.  Gargle and wash mouth after use to ↓ fungal infections, systemic absorption.

Interactions:  enzyme inducers (rifampin, barbiturates, hydantoins) à ↑ steroid metabolism.  Oral contraceptives, estrogens, enzyme inhibitors à ↓ steroid clearance. ↑↑ hypokalemia with thiazide and loop diuretics, amphoterecin à ↑ digitalis toxicity.  Cyclosporine à ↑ steroid concentration.  

Leukotriene modifiers

Leukotrienes: derivatives of fatty acids formed by lipoxygenase. No ring structure. Covalently linked to 2-3 amino acids.  Slow reacting substances of anaphylaxis.à ↑ eosinophil and neutrophil migration, ↑ leukocyte adhesion, ↑ neutrophil and monocyte aggregation, ↑ capillary permeability, ↑ smooth muscle contraction, ↑ mucous secretion, bronchoconstriction, . 

Effect: anti-inflammatory and bronchodilation à ↓ steroid dose. 

Leukotriene receptor antagonists (x-lukast)

Examples: zafirlukast, montelukast

Mechanism: prevent interaction of leukotrienes with receptors by ↓ cysteinyl leukotriene-1 à block effect of histamine in asthma and allergy reactions. 

Take zafirlukast on empty stomach (max absorption).

SE: ↓↓, can be used in children.  GI upset, dizziness.

Churg-Strauss syndrome: eosinophilic vasculitis angiitus when steroids are d/c or ↓. 

DI: enzyme inhibitor, ↑ effect of warfarin / theophylline.

Lipoxygenase inhibitor (Zileuton)

Mechanism: blocks 5-lipoxygenase à ↓ leukotrienes synthesis from arachidonic acid. 

SE: liver dysfunction and ↑ ALT (monitor, esp in alcoholics).  Others (mild): headache, GI upset, myalgia.  

DI: ↑ effect of warfarin, theophylline, propranolol.

Mast cell stabilizers (Cromolyn, nedocromil Na)

Effects: Nonsteroidal anti-inflammatory. Less effective than steroids.  Used only for asthma maintenance, EIB prevention. 

Mechanism: ↓ mast cell degranulation, ↓ inflammatory cells.

SE: ↓↓, used in children.  Wheezing, coughing, nasal congestion, throat irritation / dryness.

Methyl xanthines (theophylline)

Use: alternative to B-agonists and steroids in acute attacks and to long acting B-agonist in persistent asthma.  Combine with inhaled steroids à control night or early morning symptoms. 

Effects: ↓ mucus, ↑ mucociliary transport, ↑ respiration, anti-inflammatory, ↑ renal diuresis. 

Mechanism: ↓ phosphodiesterase à ↑ cAMP, antagonize adenosine receptors.  Less bronchodilation than B-agonists. 

Oral (SR): ↑ compliance.  ↓ fat tissue distribution, calculate dose based on lean body weight.  Gradually titrate dose upward.

IV: rare.  Start with loading dose, then maintenance infusion. 

Theophylline anhydrous à oral solids, theophylline monohydrate à oral solutions.  Aminophylline à IV. 

SE:  palpitations, restlessness, nervousness, insomnia, seizures, GI upset, diarrhea, dizziness.  Do not use in pregnancy. 

Therapeutic drug monitoring: monitor SE, serum level, other drugs use. Clearance is age and condition specific. 

Interactions: multiple drug and other interactions.  ↑ clearance (↓ level) with smoking, ↑ protein.  ↓ clearance (↑ level) with age (↑↑ or ↓↓) , fats and carbohydrates, CHF. 

CI: peptic ulcer or uncontrolled seizure. 

Anticholinergics

Postganglionic muscarinic block à bronchodilation.

Use: more effective in COPD than in asthma. 

Ipratropium sodium: quaternary ammonium compound. Used with or as an alternative to beta agonist in acute attacks.  Slow onset and long duration compared to beta agonists à give regularly.  SE: ↑ intraocular pressure if touches the eye, ↓ anticholinergic. 

Atropine aerosols, glycopyrrolate (quaternary ammonium compound): rarely used due to ↑ SE and ↓ efficacy.  Used in nebulizers

Other drugs

Antihistamines: if patient has allergic rhinitis.  Prevent release of histamine mediated response that influence asthma.

Antibiotics: used to treat infections (change in volume, color, viscosity of sputum).  Sputum cultures are useless because COPD are chronically seeded.  Chronic antibiotic preventative used can be considered in case of frequent exacerbations.  M. pneumoniae or Legionella pneumophilia à macrolide .  C. pneumoniae à oral doxycycline.  Pneumonia in the hospital à 2^nd or 3^rd generation cephalosporin or beta-lactam with b-lactamase inhibitor. 

Magnesium sulfate (IV): cause little bronchodilation, ↑ respiratory muscle strength in hypomagnesemic patients. 

Immunotherapy: may ↑ lung function, ↓ symptoms.

Non-pharmacologic

Humidified O₂: ↓ flow rate helps reverse hypoxemia (use if PaO₂ < 55 mmHg), esp. at night/during exercise. Goal: SaO2 > 90%. 

Heliox: helium / oxygen mixture that is less dense than air à ↑ ventilation during acute attack. 

IV fluids: and electrolytes are given if volume is depleted.

Environmental control: avoid allergens and triggers.  Use allergen-resistant mattresses / pillow encasements, ↑ filtration vacuum cleaners, avoid ferry pets, carpets and draperies.

Vaccines: used to prevent infections that may trigger asthma (e.g. influenza and polyvalent pneumococcals).   

Drug delivery options

MDIs:  accurate with good technique and a spacer.  A facemask may be needed for children.  Wait 1 min between buffs. 

Spacers and holding chambers: ↓ drug deposition in the upper airway, ↓ oral absorption, ↓ local / systemic SE.  Spacers are important for ↑ dose steroids or if hand-lung coordination is poor. 

Nebulizers: require ↓ patient coordination.  Disadvantages: cost, time consuming, ↑ size, inconsistent drug delivery.  Used in ↑ dose beta agonists, anticholinergics, cromolyn in children.

Dry powder inhalers: more common, avoid the use of Freon propellants, easier to use.  First load the dose, and then inhale rapidly.  No spacers.  Keep away from moisture. 

COPD

Chronic bronchitis

Definition: excessive mucus production by the tracheo-bronchial tree à edema and bronchial inflammation à airway obstruction.

Pathophysiology: respiratory tissue inflammation à vasodilation, congestion, mucosal edema à ↑ mucus.  Neutrophils infiltration.  Cilia impairment.  Cartilage atrophy.  Airways become blocked by thick, tenacious mucus secretions à sputum rich productive cough.  Normally sterile airways become colonized by Strept pneumoniae, H influenza, Mycoplasma.  Recurrent viral / bacterial infections à ↓ body defenses, ↑ mucus accumulation, ↓ ciliary activity.  Airway degeneration à ↓ gas exchange à exertional dyspnea.  Hypoximia, ↑ PaCO2 (hypercapnia). 

Physical findings: chronic productive cough after age 45 (first in winter, worse in the morning).  Progressive exertional dyspnea, obesity, wheezing, prolonged expiration, right ventricular failure, cyanosis (called “blue bloater”)

Diagnostic tests: hypoxemia à ↑ erythropoiesis à polycythemia (↑ RBCs).  ↑ WBC due to infections.  Sputum: thick, colored (if infected), ↑ neutrophils, microorganisms. Arterial blood gas: ↓ PaO2 (hypoxemia), ↑ PaCO2 (hypercapnia).  ↓ FEV1.  Right ventricular hypertrophy and cor pulmonale in ECG. 

Emphysema

Definition: permanent alveolar enlargement and destruction of the alveolar walls, ↓ alveolar surface area.

Pathophysiology: Inflammation, ↑ mucus secretion à alveoli air trapping. à tissue damage à ↓ space into which normal lung tissue expands..  Alveoli merge à ↑ space for air trapping.  Alveolar wall destruction à small airways collapse.  Hypercapnia and respiratory acidosis are uncommon because of compensatory ↑ in respiratory rate.

Physical findings: cough is chronic but less productive than in chronic bronchitis, starts at age 55.  Exertional dyspnea is progressive, constant, more severe than in bronchitis. Other findings: weight loss, tachypnea, prolonged expiration, ↓ breath sounds.  Patient usually maintain good oxygenation through tachypnea à “pink buffer”.

Diagnostic tests: small chance of ↓ AAT in blood or infections in sputum. ↓ PaO2 and ↑ PaCO2 in arterial blood gas, ↓ FEV1. 

Etiology

Smoking: causes pulmonary hyperactivity and persistent airway obstruction.  Alpha-1 antitrypsin (AAT) is a serine protease inhibitor à ↓ neutrophil elastase.  ↑ risk of COPD when smoking is combined with genetic ATT deficiency. 

Others: exposure to irritants (sulfur dioxide, polluted air, noxious gases, dusts), family history, social, economic factors. 

Complications

Pulmonary hypertension: lung congestion à ↓ pulmonary vascular bed space à pulmonary hypertension à cor pulmonale (right ventricular hypertrophy) à right heart failure.

Acute respiratory failure: advanced emphysema à brain respiratory center damage à ↓ cerebral oxygenation à ↑ PaCO2 à hypoxia, respiratory acidosis à respiratory failure.

Infection: chronic bronchitis à trapping of excessive air, mucus, bacteria and ↓ coughing and deep breathing à infection. 

Polycythemia: ↑ in RBCs à hypercoagulate state, embolism, stroke. 

Therapy

Anticholinergics: First line treatment for COPD.

Beta blockers, corticosteroids, theophylline, O₂, etc (see above)

Mucolytics: such as acetylcysteine à ↑ sputum clearance, ↓ mucus plugs.  May cause bronchospasm.

Expectorants: such as guaifenesin.  Avoid potassium iodide. 

Chest physiotherapy: loosens secretions, re-expand lungs, ↑ efficacy of respiratory muscle.  More important in outpatient.

Physical rehabilitation: ↑ exercise tolerance and ↑ diaphragm and abdominal muscle tone.

Smoking cessation: and avoidance of irritants.  Use drugs with behavior intervention for maximum success.

Surgery: lung volume reduction therapy

48. Rheumatoid Arthritis

Introduction

Definition: chronic, systemic, autoimmune, inflammation of the synovial joint. 

More common in women (2-3:1).  2% of the population. 

Classification:

Four of the following criteria have to be met

1.  Morning stiffness for 1 hour before improvement

2.  Three joints have fluid or soft tissue swelling

3.  One joint in the hand joints must be swollen. 

4.  Symmetric arthritis: involvement on both sides of the body.

5.  Subcutaneous (rheumatoid) nodules

6.  ↑ serum rheumatoid factor

7.  Radiological erosion or decalcification of bones

May also include extra-articular organ manifestations (GI, infections, etc)

Etiology

Human leukocyte antigen (HLA-DR4) + environmental factor à inappropriate immune response à chronic inflammation

Tumor necrosis factor (TNF) ↑ in RA and Crohn’s disease. 

Infections may ppt RA in predisposed patients, e.g., polyarthritis with lyme disease

Pathogenesis

Vasodilation, edema, sensation of heat, loss of function, ↑ production of thick boggy synovial fluid, effusion accumulation.

Pannus: exuberant synovial thickening due to inward overgrowth of enlarged synovium across the surface of articular cartilage à cartilage degradation, bone loss, x-rayed marginal erosions, bone rubbing, pain.

Clinical course

Variable and unpredictable, polycyclic course (intermittent remissions) or progressive course (relentless rapidly advancing destructive deforming inflammation à permanent join deformities à progressive functional decline, ↓ range of motion, work disability, loss of 4-10 years of life expectancy. 

Early symptoms: aching, joint pain, fatigue, then hand and feet synovitis (swelling, warmth, tenderness). 

Morning stiffness: maximal pain and stiffness on awakening (30 min)

Diagnosis and clinical evaluation

Mainly clinical joint evaluation with lab and x-ray results. 

Rheumatoid nodules: firm, round, rubbery masses in the SC of joints prone to pressure (e.g. elbows).

X-ray: soft tissue swelling, osteoporosis, erosions. 

Laboratory findings: ↑ Rheumatoid factors (antibodies) especially IgG and IgM, ↑ erythrocyte sedimentation rate due to inflammation, microcytic anemia, antinuclear antibody test. 

Monitoring parameters: morning stiffness duration, number of affected joints, severity of pain, range of motion, deformity and circumference of joints, time to walk 50 feet, depression, weight loss, sedimentation rate. 

Therapy

Mechanical therapy

A balanced daily program of rest and exercise (↑ muscle strength and joint motion).  Use lightweight splints during night (or even day) to align joints.  Avoid complete immobilization.  Consider joint replacement. 

Symptomatic pharmacological therapy

Aspirin

First line agent, first as analgesic and then ↑ dose for inflammation.  Dose: 4-5 g daily. 

SE: bleeding and ↓ platelet function (7 days after d/c), tinnitus in ↑ doses, GI (↓ by enteric coating or taking with food)

Nonacetylated salicylates

Examples: salsalate, choline salicylate à safer for aspirin sensitive patients.  ↓ anti-inflammatory effect, ↓ respiratory SE, ↓ effect on platelets.

Other NSAID

Examples: naproxen, ibuprofen, sulindac, piroxicam.  May be better tolerated than aspirin.  Try for 2 weeks before change. 

Chemistry: x-en à propionic acids, others à acetic acids. 

Avoid in asthmatics à may trigger bronchospasm. 

↑ bleeding time /↓ platelet function (effect reverse quickly if d/c)

GI upset, ulceration, hemorrhage (↓ platelets).  ↓ GI ulcers by using misoprostol (Cytotec, ↑ SE: diarrhea) or H₂-antagonists.  Ibuprofen, naproxen à ↓ GI SE à available OTC.  Piroxicam à ↑ GI SE, CI in elderly. 

↓ renal blood flow à renal failure (esp with diuretics or CHF). 

Temporary CNS effects (headache, drowsiness, confusion, anxiety, etc) esp. with indomethacin.  Avoid in the elderly. 

Meclofenamate: diarrhea

COX-2 inhibitors

Rofecoxib, celecoxib, valdecoxib.  Anti-inflammatory, analgesic, antipyretic with ↓↓ GI SE. 

Second line agents

Known as Slow Acting Anti-rheumatic Drugs (SAARD) or Disease Modifying Anti-Rheumatic Drugs (DMARD).  They modulate immune response to ↓ progression of erosion.  All slow are acting (min 3 months for effect), except methotrexate.  Used w/ NSAID.  All have ↑↑ SE. 

Methotrexate (Rheumatrex)

First line for severe RA.  Immunosuppressive folic acid antagonist and antineoplastic. Give a weekly dose, oral or IM. 

Aspirin ↓ methotrexate secretion à ↑ toxicity

SE: GI, bone marrow suppression, hepatitis, ↑ infection.

Give folic acid supplements.  CI in creatinine < 40.  Pregnancy X.

Azathioprine (Imuran)

Purine analogue immunosuppressive antimetabolite.  Converts to 6-mercaptopurine ®  ↓ purine synthesis ® cytotoxicity to dividing cells ® ¯ lymphocyte proliferation. 

SE: GI, hepatitis, bone marrow depression.  Also for leukemia.

Antidote: Leucovorin Ca² (tetrahydrofolic acid derivative)

Gold compounds

IM: gold sodium thiomalate, aurothioglucose. SE: proteinuria.

Oral: auranofin.  SE: metallic taste, diarrhea, GI, stomatitis

General SE: blood toxicity, rash.

Gradual build up of dose.  Try for a min of 6 months

Penicillamine (Depen)

↓ immune response.  Taken on empty stomach to ↑ absorption. Dosing: do low-go slow.  ↑ SE:  rash, fever, proteinuria, hematologic, autoimmune diseases.

Other drugs

Hydroxychloroquine (Plaquenil): antimalarial for mild RA.  ↓ SE: Retinal toxicity (retinopathy) due to drug deposition in the cones à monitor for vision acuity.  GI upset.

Sulfasalazine (Azulfidine): very effective in slowing progress of joint damage. SE: GI, rash, rare blood dyscrasias, hepatitis

Cyclophosphamide (Cytoxan): Toxic antineoplastic prodrug.  SE: ↑↑, hemorrhagic cystitis (treat with mesna), bone marrow depression, sterility, alopecia. 

Etanercept / Infliximab: TNF-alpha inhibitor à ↓ TNF (cytokine) binding to inflammatory cell surface.  Biological Response Modifier.  Given SC.  SE: respiratory infections, autoantibody formation. NO effect of kidney function.

Leflunomide: immuno-modulator. Mechanism: ↓ dihydroorotate dehydrogenase (critical for pyrimidine synthesis).  SE: rash, diarrhea, alopecia, rash, anemia. Pregnancy X.

Mycophenolate mofetil: immuno-suppressant.  SE: diarrhea, GI, hematologic.  Used to prevent cardiact and renal allograft rejection. 

Other drugs: chlorambucil, cyclosporine, minocycline. 

Corticosteroids

Prednisone.  Last resort.  They do not alter the course of RA.  Used for acute flare ups, before action of slow acting drugs kicks in, systemic RA symptoms, or in case of intolerance to other drugs.  Can be used as intra-articular injection if symptoms are localized.  SE: GI bleeding, slow wound healing, hyperglycemia, hypertension, osteoporosis. 

Topical therapy

Capsaicin: for symptomatic treatment.  It’s the pungent ingredient of hot pepper.  Mechanism: depletes and prevents accumulation of substance P, a chemical mediator in pain transmission from the periphery to CNS (sensory nerve fibers).  It produces a sensation of warmth. Use: joint pain, arthritis tenderness, neuralgia, psoriasis.  SE: erythema (reflex vasodilation), histamine release.

Counter-irritants: methyl salicylate, menthol, allyl isothiocyanate, produce a mild inflammatory reaction.  Effect may be actually due to the massage during application not the drug itself. 

Combination second line therapy

Step-down bridge approach: combo of antimalarial, oral gold, parenteral gold and methotrexate.  Remove medications and taper dosage after 3 months to the antimalarial alone. 

Saw-tooth strategy: use second line agent early and serially substitutes with other agents before previous agents lose efficacy. 

Graduated-step paradigm: combo therapy only for patients at active disease.  Escalate treatment as needed.  

49. Hyperuricemia and Gout

Introduction

Hyperuricemia: ↑ serum uric acid > 7 mg/dl. 

Gout: recurrent acute attacks of urate crystal-induced arthritis.  It may include tophi-deposits of monosodium urate.

Incidence: 1% of the population, almost all men.  ↑ risk with alcoholism, obesity. 

Uric acid synthesis: purine à xanthine oxidaze à urice acid (adenine and guanine are purine bases).  One gram in the body.  No biological function.  66% daily turnover. 

Uric acid elimination: 66% through the kidneys, 33% through the GI.

At urine pH (acidic, 4-5) à poorly soluble free uric acid.  At physiologic pH (7.4) à uric acid as monosodium urate salt. 

Asymptomatic hyperuricemia: ↑ serum uric acid but no symptoms of arthritis.  May be harmless. Drug treatment may be unnecessary.  May develop gout later.  Maintain good urine output to prevent stone formation, ↓ purine foods, monitor. 

Etiology

Primary: due to defect in purine metabolism or uric acid excretion.  It is due to uric acid ↑ production or ↓ renal clearance or both.  Under-excretors (90%): excrete < 600 mg/day on a purine restricted diet. 

Secondary: renal failure (↓ excretion), hematologic diseases (↑ nucleic acid breakdown to uric acid). 

Drug induced gout:

Ethanol à ↑ production and ↓ secretion.

Aspirin and salicylates à ↓ uric acid tubular secretion (↓ excretion). 

Diuretics (except spironolactone)àvolume depletion / ↓ tubular secretion.

Cyclosporine, pyrazinamide, levodopa à ↓ urate renal clearance.

Ethambutol, nicotinic acid à compete for urate secretion à ↓ excretion

Cytotoxic drugs à ↑ nucleic acid turnover.

Pathophysiology

Gouty arthritis develop when monosodium urate crystals deposit in the join synovium à inflammatory response à gout attack à join swelling, redness, warmth, tenderness à tophi (urate deposits) à joint deformity, disability, renal impairment.

Renal complications: Acute tubular obstruction: due to uric acid pptn in the ureters and collecting tubes.  Urolithiasis: uric acid stones due to low urine pH.  Chronic urate nephropathy: urate deposits in the renal interstitium. 

Acute gouty arthritis

Painful arthritic attacks of sudden onset.  Triggers: trauma, cold exposure.  Initial attack is abrupt and usually occur at night or early morning à very hot swollen, tender joints. Podagra: attack in the metatorso-phalangeal joint.  Attacks last 1-2 weeks (longer as the disease progresses).  May include fever, chills, malaise. 

Diagnosis: Urate needle-shaped crystals in synovial fluid (-ve birefringence).  Serum ↑ urate, ↑ erythrocyte sedimentation rate, ↑ leukocytes.  Dramatic therapeutic response to colchicine.  Acute attack pattern with remission periods. 

Therapy

Immobilize affected joints.  Start anti-inflammatory drugs immediately.  Start urate-lowering drugs after attack is over.

Colchicine: drug of choice for ↓ pain and inflammation and ending the attack.  Mechanism: antimitotic, ↓ chemotaxis of leukocyte to inflamed area, ↓ phagocytosis and ↓ urate deposition. Orally or IV (never IM or SC due to irritation).  ↑ SE: diarrhea, GI, bone marrow depression, irritation if given IM. 

NSAIDs: if first choice is colchicine is not tolerated or not started immediately.  Examples: indomethacin, naproxen, sulindac.  SE: GI, CNS headache and drowsiness / dizziness.  Take with food.  Aspirin ↓ dose à ↓ uric acid secretion, ↑ dose à ↑ uric acid secretion. 

Corticosteroids: Methylprednisolone acetate given intra-articular with diagnostic / therapeutic aspiration.  Prednisone (oral), Triamcinolone acetonide (IM) or methylprednisolone (IV).

Intercritical gout

Symptom free period between attacks. 

Non-drug urate lowering: ↓ high-purine diet (meats, legumes), ↓ obesity, ↓ alcohol. Limited effect. 

Prophylaxis: ↓ dose colchicine or NSAID. 

Urate lowering therapy (<6 mg/dl): lifelong treatment. 

Allopurinol (isopurine): ↓ production. Mechanism: ↓ xanthine oxidese (↓ xanthine à hypoxanthine à uric acid).  Long acting active metabolite: oxypurinol.  Preferred over uricosurics in case of renal impairment (↓ dose).  SE: reversible rash (↑ incidence with ampicillin), exfoliative dermatitis à treat with prednisone, Stevens-Johnson syndrome.  May ↑ gout attacks if given during the attack due to mobilization of stored urate (give colchicine).  May dissolves tophi.

Uricosurics à ↑ excretion.  Examples: sulfinpyrazone, probenecid (benzoic acid derivative).  Mechanism: ↓ uric acid reabsorption at the proximal convoluted tubules. Do not initiate during acute attacks or give with colchicine.  During the first 6-12 months à may ↑ attacks.  Maintain ↑ fluid intake, urine output and alkaline urine to ↓ risk of renal urate pptn.  Build up dose gradually.  Action is antagonized by salicylates. SE: GI, blood dyscriasis (sulfinpyrazone).  CI: urinary tract stones. 

Chronic tophaceous gout: ↑↑ urate pool.  Large SC tophic. Allopurinol / probenecid combo. 

50. Peptic Ulcer Disease

Introduction

Definitions

Peptic ulcer disease (PUD): circumscribed lesions of upper GI mucosa.

Gastro-esophageal reflux disease (GERD): retrograde movement of gastric contents from stomach into esophagus.  When reflux leads to inflammation and/or ulcerations, it’s called reflux (erosive) esophagitis. 

Dyspepsia: persistent / recurrent, pain / discomfort in upper abdomen. 

Manifestations

Duodenal ulcers: develop in the first cm of duodenum (bulb).

Gastric ulcers: common in the antrum or antral-fundal junction.

Stress ulcers: from serious trauma or illness, major burn, sepsis.

Zollinger-Ellison syndrome: severe peptic intractable ulcer with extreme gastric hyperacidity and gastrionoma (non-beta islet cell tumor).  Diagnosed by ↑ fasting plasma gastrin concentration.

Stomal (marginal) ulcers: after ulcer surgery or subsequent ulcer recurrence after symptom free period. 

Drug-associated ulcers: chronic ulcerative drug users (e.g. NSAID’s)

Reflex esophagitis: recurrent symptoms (heartburn), altered epithelial morphology.  Heartburn may radiate to the neck.  Other symptoms: belching, chest pain, asthma, cough, hoarseness, laryngitis.

Epidemiology: Duodenal ulcers: 7% incidence.  Gastric ulcers: 0.05%.  May have both gastric and duodenal ulcers.  Onset: 30-50 years. 45% of the population experience heartburn once a month.  15% take indigestion drug twice a week.  Prevalence of dyspepsia: 25% (3% of doctor consultations). Hospitalization / mortality for peptic ulcer are ↓. 

Description: Duodenal ulcers < 1 cm diameter. Gastric ulcer: slightly larger.  Edges are sharply demarcated.  Surrounding mucosa is inflamed and edematous.  Scar may form after healing.  Gastric ulcers may be malignant (10%).

Etiology

Helicobacter pylori (campylobacter pylori):  gram negative spiral bacteria with multiple flagella living in the gastric mucosa.  Produces urease à hydrolyzes urea into ammonia à neutralizes gastric HCl à bacteria survives.  H pylori prevalence ↑ with age.  15% of positive persons develop ulcer. H pylori is present in 90% of gastric and duodenal ulcer and cancer cases.  Eradication may help ulcers and dyspepsia.   

Genetics: ulcer prevalence with first degree relative is 3x the normal rate.  May be due to H pylori presence. Blood type O have ↑ incidence.

NSAIDs: chronic use à ↓ COX-I à ↓ PG synthesis (cytoprotective to mucosa).  Also, allow H⁺ back diffusion into mucosa à injure mucosa

Smoking: ↑ incidence of ulcer, ↓ ulcer healing and ↑ incidence of relapse.  Nicotine ↓ biliary and pancreatic bicarbonate secretion, ↑ stomach emptying into the duodenum. 

Alcohol: known mucosal irritant, especially at concentrations > 20%. 

Coffee: peptides in regular and decaf coffee à ↑ gastrin release à ↑ gastric juice flow.  A direct coffee-ulcer link is not proven.

Associated disorders: ↑ incidence with hyper-parathyroidism, emphysema, rheumatoid arthritis, alcohol cirrhosis.

Advanced age: pylorus degradation à ↑ bile reflux into the stomach à ↑ ulcers.

Corticosteroids: NO link between corticosteroids and ulcers.

Psychological factors: minor factor, contrary to the opposite belief.

Pathophysiology

Ulcers occur due to imbalance between factors protecting gastric mucosa and factors causing mucosal corrosion. 

Protective factors: thick mucosal mucus is a barrier between luminal acid and epithelial cells.  This barrier ↓ inward movement of hydrogen ions and allow neutralization by bicarbonate ions in fluids secreted by the stomach and duodenum.  Alkaline and neutral pancreatic biliary juices buffer acid entering duodenum from the stomach. 

Corrosive factors: gastric mucosa is unable to resist corrosion by irritants such as HCl and pepsin.  Mucosal barrier may not be intact. 

Physiologic factors: Duodenal ulcer: ↑ gastric emptying rate, ↑ post-prandial acid secretion, ↑ serum pepsinogen I, ↑ pepsin secretion, ↑ # of acid producing parietal cells.  Gastric ulcer: ↓ gastric emptying rate, ↓ mucosal resistance, ↑ serum gastrin, ↓ mucosal PG.

GERD: reflux occur via transient lower esophageal sphincter relaxation (TLESR).  People with GERD à ↑ TLESR frequency.

Dyspepsia: caused by PUD, GERD, gastric cancer, biliary tract disease.   

Clinical presentation

Only 50% of patients experience classic ulcer symptoms.  Pain: heartburn, aching, burning, cramping.  May be due to chemical stimulation or spasm.  Duodenal ulcer pain: more localized and often peaks between 12-2 AM.  Gastric ulcer pain: less localized.

Food: may ↓ duodenal ulcer pain but ↑ gastric ulcer and GERD pain.  So, duodenal ulcer patients may gain weight and gastric ulcer patients may lose weight. Pain occurs 1.5-3 hr after meals in duodenal but only 1 hr after meals in gastric ulcer. 

Disease course: usually chronic with remissions and exacerbations.  Relapse may be more common in spring and autumn.  Test for and eradicate H pylori and use maintenance drugs to ↓ recurrence. 

Clinical evaluation

Blood test à hypochromic anemia.  Stool test à occult blood in chronic ulcers.  Gastric secretion tests à hyper-HCl secretion in duodenal ulcers, normal or subnormal HCl secretion in gastric ulcer.  Upper GI barium x-ray: reveals ulcer crater.  Upper GI endoscopy: most conclusive test.  Biopsy: may be necessary to detect malignancy.  H pylori status: using non-invasive (serology or breath test, false negative breath test with PPI, antibiotics or bismuth compounds) or invasive (histological bacterial visualization or urease activity test) tests. 

Complications

Hemorrhage

Clinical picture: fresh blood vomit, bloody / tarry stool, coma, hypovolemic shock (heart rate > 110, systolic BP < 100).

Management: ensure airway, breathing, circulation.  IV crystalloids or colloids (e.g. hetastarch), monitor / correct electrolytes, gastric lavage, vasoconstrictors, antacids, H2 antagonists, PPI, vasopressin (GI muscle and blood vessel contraction). 

Perforation

Sudden acute upper abdominal pain, rebound tenderness, and finally, peritonitis and shock.  Symptoms may ↓ with time (dangerously misleading).  Emergency surgery is needed.

Obstruction

Occurs due to inflammatory edema, spasm or scarring.

Clinical picture: postprandial vomiting / bloating, appetite / weight loss, abdominal distension. 

Management: continuous gastric suction, monitor fluids and electrolyte status, perform saline load test to measure degree of obstruction.  Liquids feeding and daily aspirations may be needed.

Post-surgical complications

Dumping syndrome: rapid gastric emptying in 10% of patients after partial gastrectomy. 

Clinical picture: weakness, dizziness, anxiety, tachycardia, flushing, sweating, abdominal cramps, nausea, vomiting, diarrhea.  Occur between 15 and 120 minutes after the meal. 

Management:  eat six small meals, ↑ protein and fat and ↓ carb.  Ingest fluids 1 hr before or after a meal but not with it.  Give anticholinergics to delay gastric emptying.

Other complications: reflux gastritis, stomal ulceration, diarrhea, malabsorption, early satiety, iron deficiency anemia.

Refractory ulcers

Dyspeptic symptoms after 8 wk therapy.  Perform gastroscopy and biopsy to exclude: Crohn’s disease, TB, lymphoma, carcinoma.

Treatment: only PPI offer maximum acid ↓.  Eradicate H pylori.  D/C NSAID.  Perform surgery if all fails. 

Maintenance regimens

70% of ulcers recur in a year (90% in 2 years) after healing and therapy d/c.  Use long-term maintenance therapy in: concomitant disease, 4 relapses / year, many risk factors (old, male, NSAID, alcohol, smoking, family history, history of complications).   H pyloric eradication ↓ need for continuous therapy. 

Therapy

Antacids

As effective as H₂ antagonists.  Examples: magnesium, aluminum and calcium salts. Antacids are not widely used for PUD.  Continue therapy for only 7 weeks.  Typically given 2 hours after meals at bedtime.  Effect lasts for 3-4 hours. 

Mechanism: Neutralize gastric acid à ↑ gastric pH à ↓ pepsin activity and ↑ mucosal barrier à heat and treat ulcer pain.

Non-systemic antacids: such as magnesium or aluminum are preferred over systemic antacids (e.g. sodium bicarbonate) to avoid alkalosis. 

Liquid antacid: ↑ buffering capacity than tablets but not as convenient. 

Antacid mixtures: such as aluminum hydroxide and magnesium hydroxide ↓ each drug dose and ↑ effect.  Side effects are negated (aluminum à constipation, magnesium à diarrhea). 

Calcium carbonate: not preferred (à acid rebound, delayed pain relief and ulcer healing, constipation, hypercalcemia).  It may produce milk-alkali syndrome esp with milk (hypercalcemia, alkalosis, kidney damage).

Acid neutralizing capacity (ANC): number of mEq of a 1 N solution of HCl that can be brought to a pH of 3.5 (99% neutralization) in 15 minutes.  For duodenal ulcers, 50 mEq/hr or 125 mEq/day of antacid is needed for neutralization.

Precautions:

Use calcium and magnesium carefully in renal disease (e.g. elderly).

Sodium bicarbonate is CI in hypertension, CHF, renal disease, edema.

Use aluminum carefully in patients with dehydration, GI obstruction.

Calcium carbonate + alkali (sodium carbonate) + milk = milk-alkali

Long term aluminum hydroxide use à hypo-phosphatemia, osteomalacia.  Aluminum hydroxide is used to treat hyperphosphatemia.

Interactions:

Generally, take other drugs 30-60 min before antacids.

Avoid antacids (polyvalent cations) with tetracycline (↓ absorption), cipro.

May destroy enteric coating leading to premature release in the stomach.

Interfere with absorption of: ranitidine, cimetidine, iron, digoxin, phenothiazines, anticholinergics.

↓ effect of sucralfate.

H₂ receptor antagonists

Preferred in mild-moderate GERD due to lack of effect on GI motility. 

Mechanism: competitively ↓ action of histamine at parietal cell H2 receptors à ↓ volume and H+ concentration of gastric acid. 

General SE: nausea, dizziness, renal damage (adjust). Absorption is ↓ with antacids (give 1 hr before antacids).  All available oral or IV.

Cimetidine: first drug, ↓ gastric acid by 50%.  SE: liver damage, hematologic (thrombocytopenia, agranulocytosis, aplastic anemia), weak androgenic (gynecomastia), confusion. Cytochrome P-450 inhibitor à ↓ metabolism of phenytoin, theophylline, Phenobarbital, lidocaine, warfarin, imipramine, diazepam, propranolol, procainamide. 

Ranitidine: more potent drug, ↓ gastric acid by 70%.  Used with bismuth citrate and clarithromycin to eradicate H pylori.

Famotidine: most potent, ↓ gastric acid by 94% for 10 hr.

Nizatidine: newest drug, similar to ranitidine. Oral. 

DI: ↓ absorption of drugs requiring acidic pH (e.g. ketoconazole).

Sucralfate

Non-absorbable disaccharide containing sucrose and aluminum. 

Mechanism: adheres to the base of ulcer crater forming a mucosal protectant barrier against acids and bile salts (esp. in duodenal ulcers). Acidic pH is required for polymerization.  

SE: constipation.  Give 1 hr before meals and at bedtime for 6 weeks. 

Interactions: antacids ↓ sucralfate mucosal binding, give 45 min apart.  Surcralfate ↓ absorption of digoxin, iron, phenytoin, cimetidine, tetracyclines, ciprofloxacin.

GI anticholinergics

Examples: atropine, propantheline. No proven value in ulcer healing

Mechanism: ↓ basal and stimulated gastric acid and pepsin secretion. Most effective at night in large doses with antacids à delay gastric emptying.  Or, take 30 min before food (↓ acid by 40%)

SE: dry mouth, blurred vision, urinary retention, constipation, tachycardia

CI: gastric ulcer (they prolong gastric emptying), narrow angle glaucoma.

Prostaglandins (misoprostol)

Mechanism: PG E1 analgoue à ↑ mucus à protect gastric mucosa against NSAID damage, ↑ bicarbonate, ↓ acid.  NSAID à ↓ prostaglandins à ↓ bicarbonate and mucus secretion à damage. 

Use: QID prevention of NSAID induced gastric ulcer in ↑ risk patients.

SE: diarrhea, GI pain (take with food).

CI: abortifacient, pregnancy category X. 

Proton pump inhibitors

Examples (x-prazole): omeprazole, lansoprazole, esmoprazole, rabeprazole, pantoprazole. Omperazole sulfenamide is the active form.

Mechanism: forms a stable disulfide bond with sulfhydryl group near potassium binding site on luminal side of gastric proton pump H⁺ K⁺ ATPase à pump shuts down. 

Very rapid ulcer healing and symptom control compared to other drugs (e.g. H₂ blockers). 90% acid reduction for 24 hr with no achlorhydria. 

Omeprazole is better than ranitidine or misoprostol for preventing or healing NSAID ulcers.  Omperazole can be used in infants. 

SE: headache, diarrhea, GI pain / upset, flatulence.  Take before food.   

Interactions: ↓ absorption of drugs requiring acid pH (ketoconazole, ampicillin, iron).   Omeprazle may ↓ or ↑ cytochrome P-450 metabolism. 

Bismuth compounds

Examples: bismuth subsalicylate (Pepto-Bismol), ranitidine bismuth citrate (RBC), colloidal bismuth subcitrate (not FDA approved).

Mechanism: bismuth prevents adhesion of H pylori to gastric mucosa, ↓ H pylori growth, ↓ release of proteolytic enzymes.

Use: most effective in combination with PPI or antibiotics. 

SE: CNS/neutrotoxicity, dark stool / tongue, headache, diarrhea, rash, salicylism in ↑ doses (tinnitus, hyperpyrexia, confusion, tachycardia).

Antibiotics for H pylori: metronidazole, tetracycline, clarithromycin, amoxicillin, bismuth subsalicylate, omperazole / lansoprazole. Optimum regimen: bismuth subsalicylate QID + metronidazole QID + tetracycline QID + omperazole QD = 2 wk à 90% eradication.

Prokinetic agents

Example: metoclopramide, erythromycin, cisapride (d/c due to ↑ incidence of arrhythmia / torsades).

Mechanism: ↑ ACh release à ↑ gastric emptying (no effect on acid secretion).

SE: diarrhea, GI upset, headache.

Interactions: antifungals (ketoconazole, itraconazole, fluconazole, miconazole) à ↓↓ cisapride metabolism à severe arrhythmia.  Rapid gastric emptying can affect absorption of narrow therapeutic drugs.

CI: arrhythmia, CHF, ischemic heart, renal failure, respiratory failure.

Diet / social modification

Milk may ↑ gastric acid (used to be recommended, no more).  Milk leaves the stomach quickly à no extended buffering.

Small frequent meals may ↑ ulcer pain by causing acid rebound (used to be recommended, no more)

Strict dietary limitations are now considered unnecessary.

Avoid certain foods: caffeinated drinks, alcohol, smoking, NSAIDs.

Surgery

Used in complicated, incapacitating ulcer unresponsive to therapy.

Vagotomy: severs a branch of the vagus nerve à ↓ HCl secretion.

Antrectomy: removes the antrum à ↓ some acid secreting mucosa.

Others: gastrectomy, funoplication.

51. Diabetes

Introduction

Definition

1. Dysfunction in metabolism of fat, carbohydrate, protein, insulin

2. Dysfunction of blood vessels and nerves function and structure

2-10% of US population (half undiagnosed)

Classification

General common symptoms: polydipsia, polyuria, dry skin, polyphagia, fatigue, frequent skin / vaginal infections, visual disturbances. 

1. Type 1 (Insulin-Dependent, Juvenile-Onset, Ketosis-Prone)

Insulin production/secretion is destroyed.  Usually in children and adults <30.  Prone to ketoacidosis (accumulation of ketone bodies).  Dependent on exogenous insulin replacement.  10% of all diabetes.

Etiology:  a. Genetics: ↑ w/ family history.  Linked to Human Leukocyte Antigen (HLA) system.  b. Environment: virus (e.g. rubella), toxic chemical triggers genetics / autoimmunity.  c. Autoimmunity: anti-insulin and anti-beta-cell antibodies usually present

Clinical presentation: abrupt onset, acute presentation.  Unintentional weight loss w/ or w/o ketoacidosis.

2. Type 2 (Non-Insulin-Dependent, Adult-Onset)

Endogenous insulin is normal, ↑ or ↓.  May or may not need exogenous insulin.  90% of all diabetes (esp. in the elderly).  Adults >30.  80% are also obese.  Not prone to ketosis except during stress (infection, surgery, trauma). 

Etiology:  a. Genetics: 90% concordance between monozygotic twins.  15% chance in offspring of diabetics.  b. ↓ beta cell: à ↓ insulin.   c. Insulin site defect à insulin-resistant tissue (insensitivity)

Clinical presentation: develops gradually. Evidence of damage to retina, kidneys, peripheral vasculature.

3. Gestational (pregnancy)

Glucose intolerance detected during (late) pregnancy (3% of pregnants).  Test tolerance 6 wk post-partum.  Usually returns to normal. 

4. Other types (Secondary Diabetes)

Due to disease of pancreas, genetics, endocrinopathies (Cushing’s), drugs (thiazides, loops, corticostroids,  à hyperglycemia)

5. Diabetes insipidus: Cause: pituitary disease with ↓ production of antidiuretic hormone (ADH) à kidney can’t conserve water, lithium (↓ sodium reabsorption).  Symptoms: polyuria (20 L / d), severe thirst, polydipsia, watch for dehydration.  Treatment: anti-diuretic hormone (vasopressin) analogs à desmopressin (oral), lypressin (nasal), maintain fluids / electrolytes.  (Desmopressin is also used in Hemophilia A and von Willebrand’s disease).

Pathophysiology

Normal glucose regulation

Insulin:

Structure: endocrine hormone secreted by beta-cells of pancreas.  It is a 51-amino acid chain with two polypeptide chains and two inter-chain disulfide bonds.  It is derived from proinsulin (86 amino acids).  Proinsulin can be used to determine the purity fo insulin products.

Mechanism: glucose à ATP closes potassium channels à membrane depolarization à calcium influx à fusion of insulin granules à insulin release. Insulin and glucose à activate N/K ATPase force potassium into the cells à hypokalemia.

• Glucose effects: ↑ glucose transport across cell membranes, ↑ glucose storage as glycogen in muscles / liver (glycogenesis), ↓ glucose formation from glycogen in muscles / liver (glycogenolysis), ↓ glucose formation from amino acids (gluconeogenesis)
• ↓ breakdown of fatty acids to ketone bodies (lipolysis) (insulin prevents ketoacidosis à absent in type II DM), ↑ adipose (fat) tissue formation from triglycerides and fatty acids. 
• ↑ incorporation of amino acids into proteins

Counter-regulatory hormones: glucagon (from pancreas alpha-cells), epinephrine, norepinephrine, growth hormone, cortisol.

• Glycogen: carbohydrate consisting of branched chains of glucose units.  Principal form of carbohydrate storage, mainly in the liver and muscles.  Breaks down easily to glucose when needed.  

Abnormal glucose regulation

General

Insulin insufficiency, resistance à hyperglycemia.  Liver: ↑ glycogenolysis, ↑ neoglucogenesis, ↓ glycogenesis.  Muscle (peripheral tissue): ↓ glucose uptake à cells use protein as energy source à protein breakdown à ↑ carbohydrates / glucose à ↑ hyperglycemia. 

Renal glucose threshold: 180 mg/dl.  ↑ BG concentration à exceeds kidney’s glucose reabsorptive capacity à glucose excreted into urine (glucosuria) à osmotic diuresis à dehydration, electrolyte abnormalities à coma, death. 

Diabetic Ketoacidosis (DK) (Type 1)

No insulin to break glucose à triglycerides breakdown (lipolysis) à free fatty acids and glycerol.  ↑ glycerol à ↑ liver glucose production à ↑ hyperglycemia.  Free fatty acids à acidosis à breakdown in the liver à ketone bodies à kidney excretion à ketonuria à exceeds kidney excretion limit à ketonemia à coma, death.  A ketone body: acetoacetate à converted in the liver to acetone à excreted through the lungs à acetone fruity breath.  ↑ anion gap (Na⁺ – (Cl^- + HCO^-3))

Ketone bodies urine detection: add sodium nitroprusside and ammonia à purple color.  May also occur in severe vomiting or starvation.

Initially, the body compensates for acidosis by ∆ breathing patterns (Kussmaul: rapid deep breathing) and by blood buffering systems (bicarbonates, proteins).

If Type 2 DM à Hyperglycemic hyperosmolar nonketotic syndrome (HHNK), presence of even ↓ insulin prevents fat breakdown, ketonemia, ketoacidosis (Ketosis-resistant).

Laboratory findings

Diagnostic criteria: 1. Random BG > 200 mg/dl with classic DM symptoms (polydipsia, polyuria, polyphagia, weight loss).  2. Fasting BG > 125 mg/dl.  3. 2-hour BG > 200 mg/dl during an oral glucose tolerance test (OGTT) using 75 g anhydrous glucose in water. 

DM predisposition: Impaired fasting glucose (IFG): fasting BG 110-125 mg/dl.   Impaired glucose tolerance (IGT): 2-hr OGTT BG 140-200 mg/dl. 

Gestational diabetes: testing is done at 26 weeks in all women (unless ↓ risk: normal weight, no family history, and <25 year).  Glucose tolerance: 50 g, after 1 hr à if > 140 à glucose tolerance: 100 g, 3 hr. 

Goals of management: euglycemia with no symptoms, prevent acute complications, prevent vascular and neuropathic disease, prevent / treat risk factors (↑ BP, ↑ blood lipids), normal life expectancy and quality of life. 

Patient education and self care

↓ Modifiable risk factors: smoking, ↑ BP, ↑ blood lipids, BMI > 27. 

Identify BG patterns: effect of diet, exercise, medications on BG.

Foot care: ↑ lower-extremity complications due to neuropathy, peripheral vascular disease, trauma, infections.  Inspect shoes and feet skin color and integrity daily.  Clean feet daily and dry well.  Do not use hand to sense water temperature if neuropathic (sensation loss).  Trim nails.  Moisturize dry skin but NOT between the toes.  Wear well fitting shoes and cotton socks.  Avoid walking barefooted.  Do not self-treat skin foot conditions. 

Skin care: dry skin is common due to diuresis and dehydration or anhidrosis (autonomic ↓ in perspiration,) à use aqueous non-alcoholic moisturizers.  ↑ skin infections due to ↑ BG and ↓ circulation.  Always use sunscreen (sun burn à ↑ BG).  Avoid skin trauma.  Keep skin clean and regularly inspect for abrasions, swelling, pain. 

Dental care: DM accelerates periodontal disease.  Should effectively brush and floss, and have an annual exam.

Eye care: DM is the leading cause of visual impairment and blindness.  Should have annual dilated eye exam. 

Assessment of glycemic control

Self monitoring of blood glucose (SMBG): allows assessment of response to factors affecting BG (diet, drugs, stress, etc).  Gives immediate feedback to adjust diet, exercise, insulin, etc. 

Urine glucose testing: only retrospective information (not recommended). 

Urine ketone monitoring: more important during illness, infection, trauma (even for type 2), type 1 patients with BG consistently >250 mg/dl, pregnant diabetics, patients on a diet to lose weight. 

Hemoglobin A_1c test (glycol-hemoglobin, glycosylated hemoglobin): long term BG monitoring, reflects average BG over 7-16 weeks.  Stable for 120 days (RBC lifespan).  Perform 1-2x / year.  Hemoglobin A_1c < 7% is targeted (normal = 6% (130 mg/dl), if >8% à additional intervention).  BG ~ A_1c x 20-30.  Glycosylated fructosamine test: measures BG control over 3 weeks. Useful for short-term follow-ups (e.g. pregnancy). 

Acute changes in glycemic control

Hyperglycemia

Mild to moderate hyperglycemia

BG 200-250 mg/dl. Rapid onset (hr). No metabolic abnormalities.

Acute: due to illness, emotional distress, or ↑ dietary calories.

Rebound (Somogyi effect): rebound hyperglycemia following severe/prolonged hypoglycemia, e.g. overnight insulin reaction).

May be ↑ BG pattern in early morning due to counter-regulatory hormones.

Moderate to servere hyperglycemia

BG > 250 mg//dl.  Few days duration with acidosis or ketosis (Diabetic Ketoacidosis, DKA). 

Common in children with undiagnosed Type 1 DM.

Precipitating factors: stress, infection, ↑ alcohol consumption, improper insulin therapy, dietary noncompliance.

Physical findings: Kussmaul’s respirations, acetone breath odor, dehydration, dry skin, ↓ consciousness (confusion, coma), abdominal pain.  Can be deadly.

Therapy: insulin IV infusion (Regular), fluid / electrolyte replacement. 

Severe hyperglycemia

BG > 500 mg/dl.  ↑ serum osmolarity.  Duration: days/weeks.

Mostly in Type 2 DM.  Higher mortality rate than DKA.

Precipitating factors: conditions that ↑ insulin requirement and predispose to dehydration (burns, GI bleeding, CNS injury, MI), use of glucogenic drugs (steroids, glucagon, thiazide diuretics), high glucose products (peritoneal dialysis, enteral nutrition). 

Physical findings: ↑↑ dehydration, ↑ serum osmolarity (> 280 mOs), no ketosis / acidosis (hyperglycemic hyperosmolar nonketotic syndrome, HHNK), polyuria, polydipsia, hypotension, tachycardia, palpitations, rapid respiration, nausea, vomiting, abdominal discomfort, ↓ CNS function (confusion, coma, seizures, myoclonic jerking).

Therapy: insulin, fluid / electrolyte replacement.

Hypoglycemia

Mild hypoglycemia symptoms: adrenergic (tachycardia, palpitations, shakiness), cholinergic (sweating), mild CNS glucopenia (↓ concentration, dizziness, hunger). 

Moderate hypoglycemia: ↑ CNS effect à confusion, motor impairment, no unconsciousness.

Severe hypoglycemia: coma, seizure, motor impairment.

Pseudo- hypoglycemia: hypoglycemic symptoms perceived (mostly adrenergic) but BG is normal.

Hypoglycemia unawareness: no or little symptoms but BG is low.  Sweating or neurologic impairment is noticed. 

Precipitating factors: excess insulin or oral hypoglycermic, delayed or ↓ food, ↑ exercise, alcohol, drug interaction ↓ BG, ↓ progesterone in menstruation, new insulin bottle with full potency, gastroparesis (delayed stomach emptying), change in insulin injection site (↑ absorption if SC near exercising muscle).

Treatment of hypoglycemia: if conscious à 10-15 g fast acting simple oral carbohydrate (milk, juice, regular soda), 3 g glucose tablet or hard candy, honey, glucose gel.  Repeat in 10-15 min if BG is not back to normal.  If unconscious à IV glucose (10-15% dextrose) or glucagons injection (1 mg IM, SC, or IV). 

Long-term complications

Macrovascular

Atherosclerosis: coronary, cerebrovascular, peripheral

Peripheral vascular disease: pain, chronic “cold feet”, insufficient circulation to heal distal lesions à gangrene

Hypertension: with diabetes à ↑↑ cardiovascular disease, stroke, transient ischemic events.   Causes acceleration of retinopathy, nephropathy, atherosclerosis.  Hyperinsulinemia / insulin resistance à diabetic hypertension.  

Coronary artery disease: autonomic neuropathy à Silent myocardial infarction (atypical, no chest pain).

Management:  daily ↓ dose aspirin, ACE inhibitor (for ↑ BP), cardio selective beta blocker (for cardiac disease).

Eye (retionopathy)

Consequence of microvascular changes, leading cause of new blindness.  Treatment: laser photocoagulation.

Nonproliferative (background) retinophathy: retinal microaneurysms, blot hemorrhages, retinal edema, hard exudates, macula edema

Preproliferative retinopathy: ↑ abnormality of tiny vessels, retinal ischemia, white patches of oxygen-starved retina (soft or cotton-wool spots).

Proliferative retinopathy: lack of oxygen à weak vessel grow or proliferate (neovascularization) from retinal surface to vitreous cavity.  Fragile vessels may bleed into vitreous cavity à hemorrhage à obscured vision à scar tissue and new vessels grow à vitreous pull on the retina à retinal detachment. 

Nephropathy

Most common cause of End Stage Renal Disease (ESRD)

↑ microalbuminuria, positive dipstick (clinical) albuminuria, proteinuria / ↑ BP, ↓ glomerular filtration, ↑ creatinine.

ACE inhibitors helpful, ↓ protein intake, treat UTI.  For ESRD à fluid / electrolyte restriction, dialysis. 

Neuropathy

Peripheral neuropathy: esp. in sensiomotor nervous system.  Symptoms first in distal lower extremities then upper extremities (Stocking-glove distribution).  Signs: impaired perception of pain / temperature à numbness / tingling, impaired balance, ↓ proprioception (perception of body parts movement), motor nerve damage à muscle weakness / atrophy.

Autonomic neuropathy: genitourinary à neurogenic bladder, sexual dysfunction.  GI à gastroparesis, nocturnal diarrhea, fecal incontinence, chronic constipation.  Cardiovascular à orthostatic hypotension, cardiac denervation.