Drug Treatment of HypertensionMarcelo G. BoniniDepartment of PharmacologyCollege of MedicineTel. 312-3555948 / Room 3035 COMRBMedical PharmacologyLectures 41 & 42Definition: Systolic BP ≥ 140 mm Hg or 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 mmHgNormalPre-hypertensionStage 1 hypertension Stage 2 hypertensionCategorySystolicDiastolic< 120120-139140-159 ≥ 160andororor< 8080-8990-99≥ 100Classification and management of BP for adultsBased on 7th Report 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 blockerPresent v s optimal systolic BP distributionData from WHO, 2003Increased longevity, physical inactivity, obesity and unhealthy diet contribute to the right-shift of the curve.Hypertension is a leading global risk factor for mortalityThe Lancet, 360:1347 (2002)Hypertension affects 65 millions in the U.S. (NIH estimation)PeripheralresistanceBaroreceptorreflex 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 ResistanceFactors affecting drug treatment of hypertension:• Accuracy of diagnosis; severity of hypertension• Etiology: Primary (essential hypertension) vs. secondary (10-15% patients) • Identifiable causes of hypertension: Pheochromocytoma, renal artery constriction, Cushing’s syndrome (hypercorticism) and Cushing’s disease (over-production of ACTH), primary aldosteronism, thyroid or parathyroid disease, coarctation of the aorta• 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)Development of AHDs - Chronology1930 Veratrum alkaloids (affect sensitivity of baroreceptors; not currentlyin use due to toxicity)1940 Thiocyanates (sodium nitroprusside); ganglion blocking agents(trimethaphan)1950 Catecholamine depletors (reserpine); vasodilators (hydralazine); PNSsympathetic inhibitors (guanethidine); MAO inhibitors (pargyline); diuretics(hydrochlorothiazides)1960 CNS α2 agonists (clonidine); beta blockers (propranolol); methyldopa1970 Alpha1 blockers (prazocin); alpha/beta blockers (labetalol); ACE inhibitors(captopril)1980 Calcium channel blockers (nimodipine)1990 Angiotensin-II receptor antagonists (losartan)2000 Endothelin receptor antagonists (bosentan)Pharmacological mechanism-based classificationDiuretics: Thiazide - HydrochlorothiazideLoop - furosemide, torsemide, ethacrynic acidPotassium-sparing - amiloride, spironolactone, triamtereneSympathoplegic agents:Adrenergic synthesis / release blockers - reserpine, guanethidineCentral α-adrenergic agonists – α-methyl-dopa, 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 - losartanI. 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 3rd world 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 also 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.I. DIURETICSHydrochlorothiazideLoop 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. FurosemideDevuyst, O. (2008) Nat. Genet., 40, 495-496K-sparing diuretics include triamterene, amiloride (both are Na+channel inhibitors), and spironolactone (aldosterone antagonist).Used for treating hypertension in patients who also take digitalis. This class of drugs enhance the natriuretic effects of other diuretics (e.g., thiazides) and counteract the K+ depleting effect of these diuretics.AldosteroneSpironolactoneAdverse 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.II. SYMPATHOPLEGIC AGENTSCentrally acting (on vasomotor center):α-methyldopa, clonidine, guanabenz, guanfacineacting as α2 agonistsBlocking synthesis and/or release of