1. Antihypertensives or How not to blow your cork

2. Background  Cardiovascular pharmacology must always deal with two problems 1. Treating the disease state (e.g. reducing elevated blood pressure) 2. Accounting for the body’s homeostatic response to the treatment  Individual variation in response, and probable drug interactions, will dictate the correct regimen of drugs to be administered  Goal is to develop regimen using fewest drugs at lowest effective doses  Reduces number and severity of side effects  Increases patient compliance

3. Hypertension  Defined as elevation of arterial blood pressure above a normal value (120/80 mmHg).  Highest risk factor associated with cardiovascular disease  risk doubles with each 20 mm Hg increase in systolic bp over 140 mm Hg  Most cases of hypertension (90%) are due to unknown etiology  called essential hypertension  Normal increase in bp with age (most cases diagnosed in middle age) Note: for this class BP = AP

4. Hypertension is asymptomatic but may increase risk of other pathologies:  Atherosclerosis  Coronary artery disease  Congestive heart failure  Diabetes  Insulin resistance  Stroke  Renal disease  Retinal disease (easiest condition to diagnose)

5. Recall: Regulation of blood pressure due to combination of  Renin-angiotensin-aldosterone system  Sympathetic nervous system  Vasopressin (ADH) system  Fluid retention/excretion by the kidney Note: the most effective antihypertensive drug regimens will impair the function of one or more of the above systems

6. Compensatory mechanisms counteracting decreased blood pressure

7. Classes of Antihypertensive Drugs 1.β blockers 2.Peripherally acting sympatholytics 3.Centrally acting sympatholytics 4.(Diuretics) 5.Angiotensin inhibitors 6.Calcium channel blockers 7.Direct vasodilators

8. Figure 12-2 Summary of sites and mechanisms of action antihypertensives

9. Stages of Hypertension Heart failure Angina Post-myocardial infarction Extensive coronary artery disease Diabetes Chronic kidney failure Recurrent stroke prevention

10. Mechanisms of Action: Diuretics  Will talk about specifics later but generally reduce blood volume by decreasing electrolyte, and thus water, reabsorption in the kidney (increase urine excretion)  Causes reduced plasma volume which decreases CO, which lowers BP

11. Diuretics  amiloride  Thiazides*  burnetanide  chlorthalidone  eplerenone  furosemide (also used in race horses, altitude sickness)  indapamide  metolazone  spironolactone  triamterene

12. Mechanisms of Action: Angiotensin Inhibitors  Angiotensin converting enzyme (ACE) inhibitor  blocks conversion of angiotensin I to angiotensin II  Angiotensin receptor blockers  Reversibly bind to the Ang. I subtype of Ang. II receptors in blood vessels  reduce physiological effect of Ang. II Note: both above have similar antihypertensive effect

13. Angiotensin Inhibitors  ACEs  captopril  enalapril  lisinopril  benazepril  ramipril  Angiotensin receptor blockers  losartan  valsartan  candesartan  telmisartan

14. Mechanisms of Action: Drugs affecting the SNS – Adrenergic β, α receptor antagonists  Many types of β blockers  All competitively antagonize the effects of epinephrine and norepinephrine on β 1 –adrenergic receptors in the heart, and renin-secreting cells of the kidney  α receptor antagonists work only by blocking α 1 receptors on vascular smooth muscle

15. Mechanisms of Action: Drugs affecting the SNS – Sympatholytics CNS active  Work by reducing the firing rate of sympathetic nerves  Mediated by activation of α 2 -adrenergic receptors in the CNS but exact site is unclear  Enter brain after absorption into bloodstream Peripherally acting  Interfere with norepinephrine release from sympathetic nerve terminals  May inhibit formation of catecholamines

16. Adrenergic receptor antagonists ββββ-blockers ppppropanolol aaaatenolol ssssotalol ppppindolol llllabetalol CCCCarvedilol αααα1 receptor antagonists  c c c clonidine αααα-methyldopa gggguanfacine gggguanabenz RRRReserpine – 1st widely used antihypertensive

17. Mechanisms of Action: Ca 2+ Channel Blockers  All excitable tissue contains voltage-dependent Ca 2+ channels  Inhibit inward movement of Ca 2+ through specific (L-type) voltage-dependent Ca 2+ channels  This type of channel prevalent in cardiac and vascular smooth muscle  When Ca 2+ channels are inactivated, Ca 2+ is pumped out of cell, actin dissociates from myosin and muscle relaxes, opening vascular lumen and decreasing resistance, which decreases BP  Major effect is on coronary and peripheral arterioles

18. Ca 2+ channel blockers  Verapamil (1 st one used to treat hypertension)  nifedipine  diltiazem

19. Mechanisms of Action: Direct vasodilators  Most powerful antihypertensive drugs  May cause strong compensatory reactions to bring BP back up  Fluid retention  Increase in  renin-release  heart rate  contractility  Usually used only in severe hypertension or for patients not responding to other antihypertensives

20. Direct vasodilators  Hydralazine  Minoxidil  Pinacidil  Diazoxide

21. Clinical considerations: diuretics  Usually well tolerated, relatively cheap, and work as well as other methods  They are especially effective in African- Americans  At initial treatment urinary excretion increase significantly but after several days returns close to normal, and BP remains depressed

22. Clinical considerations: angiotensin inhibitors  Most effective in patients with elevated plasma renin levels (but this condition is rare)  Still effective in hypertensive patients with normal or even low levels of renin  Useful for treating hypertension associated with other cardiovascular risk factors, like heart failure, stroke, myocardial infarctions, diabetes, and kidney disease

23. Clinical considerations: SNS drugs  The long-term decrease in CO is usually most responsible for lowering BP  For some patients CO returns to normal as TPR decreases  decreased BP continues  β–blockers also inhibit renin release which contributes significantly to decreased BP, especially if renin levels are elevated  Effect on two different systems causes β–blockers to often be used in combination with other antihypertensives (direct vasodilators, α 1 adrenergic receptor blockers) because get three types of effects with only two drugs  β–blockers may also counteract reflex compensatory responses (that increase CO) caused by these other drugs

24. Clinical considerations: SNS drugs (con’t)  Peripheral α 1 adrenergic receptor blockers (prazosin, doxazosin) reduce TPR  may cause fluid retention  may then need to give diuretics to counteract

25. Clinical considerations: Ca 2+ channel blockers  All excitable tissue contains receptors for Ca 2+ channel blockers but not all tissue affected equally  Dependence of tissue on exogenous Ca 2+ dictates sensitivity to blockers  High in cardiac tissue (especially AV node), lower in skeletal muscle  Some may be contraindicated due to other disease states or if using specific drugs  Example - do not use verapamil in cases of heart failure associated with increased TPR  will slow down an already poorly pumping heart  Example - do not use certain β-blockers in combination with Ca 2+ channel blockers in heart failure

26. Drugs for hypertensive emergencies  May have to reduce BP quickly but temporarily  Unexpected side effects of other drugs  Side effects of illegal drugs  Accidental poisoning  Above may cause severe tachycardia  can reduce BP (and HR) by i.v. infusion of nitroprusside  Full effect in seconds  Recovery from effect within a few minutes  Or repeated low-dose i.v. injections of diazoxide  Full effect in 1 to 5 minutes  Recovery within a day

27. Treatment of Hypertension and see Table 12-1