1Drug Treatment of HypertensionRichard D. YeDepartment of PharmacologyCollege of MedicineTel. 312-996-5087 / Room 4143 COMRBE-mail: [email protected]: Systolic BP ≥ 140 mm Hgor Diastolic BP ≥ 90 mm Hg• Diagnosis is based on multiple (≥ 3) measurements, on different days• For patients having diabetes or chronic kidney disease (high-risk group), diagnosis of hypertension is made with BP ≥ 130/80 mmHg2NormalPre-hypertensionStage 1 hypertension Stage 2 hypertensionCategorySystolicDiastolic< 120120-139140-159≥ 160andororor< 8080-8990-99≥ 100Classification and management of BP for adultsBased on 7thReport of the Joint National Committee on Detection, Evaluation, and Treatment of High BP (JNC 7)LifestylemodificationEncourageYesYesYesInitial drugtherapyNot neededNo, or treatCompelling indicationsDiuretic, ACEI, ARB, β-blocker, CCB,Combination; + compelling indicationsTwo-drug combo (diuretic and ACEI,or ARB or β-blocker or CCB;Also treat compelling indicationsDiuretic here means thiazide-type; ACEI, ACE inhibitor; ARB, angiotensin receptor blocker; β-blocker, β-adrenergic receptor blocker; CCB, calcium channel blocker Hypertension is a leading global risk factor for mortalityThe Lancet, 360:1347 (2002)Hypertension affects 65 millions in the U.S. (NIH estimation)3PeripheralresistanceBaroreceptorreflex arcSodium/volumeVenulescapacitanceStrokevolumeHeart ratecontractilityNa+/Ca2+exchangeRenin-angiotensin-aldosteroneCardiacoutputArterialBloodPressureCNS / sympathetic nervesBP = CO × PVRAortic archcarotid sinusesβ1-ARα1-ARBaroreceptorsBP = CO × PVRMAP = CO × TPRandMAP = Mean Arterial Pressure = (SBP – DBP) / 3 + DBPCO = Cardiac OutputTPR = Total Peripheral Resistance4Factors affecting drug treatment of hypertension:• Accuracy of diagnosis; severity of hypertension• Etiology: Primary (essential hypertension) vs. secondary (10-15% patients)e.g., pheochromocytoma, renal artery constriction, Cushing’s syndrome• Pre-existing risk factors and medical conditions (smoking, hyperlipidemia, diabetes, congestive heart failure, asthma, current medications…)• Individualization (age, gender, ethnicity); patient compliance• Single drug (monotherapy) vs. multiple drug (polypharmacy)Mechanism-based classification of AHDsDiuretics: Thiazide - HydrochlorothiazideLoop - furosemide, torsemide, ethacrynic acidPotassium-sparing - amiloride, spironolactone, triamtereneSympathoplegic agents:Adrenergic synthesis / release blockers - reserpine, granethidineCentral α-adrenergic agonists – α-methodopa, clonidineα−blockers - prazosin, tetrazosin, doxazosinβ−blockers - propranolol, nadolol, timolol, metoprolol, acebutolol, penbutolol, pindololGanglion blocker - TrimethaphanDirect vasodilators: hydralazine, minoxidil, sodium nitroprusside, diazoxideCalcium channel blockers: nifedipine, amlodipine, felodipine, diltiazem, verapamil AT-II antagonists & ACE inhibitors:ACE inhbitors – captopril, enalapril, enalaprilat, lisinopril, benazeprilAT-II receptor antagonists - losartan5I. DIURETICSFirst-line drug for hypertension. Relatively safe and effective.Suitable for older adults. Can be given orally. Use alone or with otherantihypertensive agents. Low cost and mostly available in 3rdworld countries. Mechanism of action: Diuretics lower BP by depleting body sodium stores. Full effectstake 2 steps: (1) initial reduction of total blood volume and hencecardiac output; peripheral vascular resistance may increase; (2)when CO returns to normal (takes 6-8 weeks), PVR declines.Therapeutic use:Thiazide diuretics, such as hydrochlorothiazide, act on distalconvoluted tubule and inhibit Na+-Cl-symport. Can counteractthe Na+and H2O retention effect of direct vasodilators such ashydralazine and therefore are beneficial for combined use.Particularly useful for elderly patients, but not effective when kidneyfunction is inadequate.Thiazides reduce blood K+and Mg2+levels, and induce hypokalemia.It retains Ca2+and decreases urine Ca2+ content. It is necessary to monitor serum K+level in patients with cardiac arrhythmias and when digitalis is in use.6Loop diuretics, including furosemide, torsemide, and ethacrynic acid, are more powerful than thiazides. They are often used for treatment of severe hypertension when direct vasodilators are administered and Na+and H2O retention becomes a problem. Can be used in patients not responding to thiazides. Increase urine Ca2+content. K-sparing diuretics include triamterene, amiloride (both are Na+channel inhibitors), and spironolactone (aldosterone antagonist).Used for treating hypertension in patients given digitalis. Alsoenhance the natriuretic effects of other diuretics (e.g., thiazides) andcounteract the K+depleting effect of these diuretics.Adverse effects and toxicity: (1) Depletion of K+(except K+-sparing diuretics), leading to hypo-kalemia.(2) Increase uric acid concentration and precipitate gout.(3) Increase serum lipid concentrations. Diuretics are not used fortreating hypertension in patients with hyperlipidemia or diabetes.(4) Gynecomastia with spironolactone.7II. SYMPATHOPLEGIC AGENTSCentrally acting (on vasomotor center):α-methyldopa, clonidine, guanabenz, guanfacineacting as α2 agonistsBlocking synthesis and/or release of NE:reserpine, guanethidine, granadrelBlocking β-adrenoceptors:propranolol, metoprolol, labetalol, etc.Blocking sympathetic ganglia:trimethaphanBlocking α1-adrenoceptors in vessels:prazosin, doxazosin, tetrazosinBlocking renin release:propranolol and other β-blockersCentrally-acting adrenergic drugs:A 2-imidazoline derivative that reduces sympatheticand increases parasympathetic tone, leading to BPlowering and bradycardia.Mechanism of action: Clonidine binds α2-AR with higher affinity than α1-AR.The α2-agonistic activity contributes to its BP lowering effect due to negativefeedback at the presynaptic neurons. When given i.v., clonidine induces abrief rise of BP, which is followed by proloned hypotension. In addition, clonidine is thought to bind imidazoline receptors (IR) that have notbeen fully characterized at molecular level. Similar drugs: guanabenz and guanfacineClonidine8Therapeutic use: Clonidine reduces CO due to decreased heart rate andrelaxation of capacitance vessels. Used for treatment of mild to moderatehypertension, often together with diuretics. Because it decreases renalvascular resistance, it maintains renal blood flow and glomerular filtrationand therefore can be used in patients with renal