ANTIHYPERTENSIVE AGENTS

Philip J. Kadowitz, Ph.D.

Learning Objectives
1. Describe the impact and mechanisms involved in essential hypertension. Explain actions of major classes of antihypertensive drugs.

2.

3.

Describe the use of drugs in the treatment of essential hypertension and of a hypertensive emergency or crisis.

Drugs:

hydralazine, diazoxide, sodium nitroprusside, minoxidil, enalapril, lisinopril, losartan

Drugs Used in the Treatment of Hypertension

1. Diuretics a. Thiazide diuretics important for antihypertensive therapy do not exert their effect simply by lowering plasma volume plasma volume returns to pre-treatment levels, but antihypertensive effect persists alter arteriolar tone b. Potassium-sparing diuretics spironolactone, eplerenone, amiloride, triamterene. c. Loop diuretics (e.g., furosemide) used for edema reduction; decrease plasma volume thereby lowering pressure. Use with low GFR.

2.

Centrally-acting antihypertensive agents: alpha-2 agonists Clonidine (Catapress) acts direclty on alpha-2 receptors in vasomotor center

Methyldopa (Aldomet - metabolized in CNS to -methyl norepinephrine, which acts on 2-receptors in vasomotor center
3. Adrenergic receptor-blocking agents a. -blockers propranolol, metoprolol, atenolol, etc., act on the heart to decrease heart rate and stroke volume; also more slowly to reduce TPR -blockers Prazosin (Minipress) blocks 1 receptors, thereby permitting norepinephrine to act on 2 receptors and inhibit release Non-selective -blockers rarely used, due to reflex tachycardia (phentolamine)

b.

4.

Adrenergic terminal-blocking drugs

Reserpine depletes adarenergic terminals Guanethidine reserpine-like and bretylium-like effects of guanethidine deplete adrenergic terminals of norepinephrine and inhibit transmitter release, thereby reducing sympathetic tone to vessels and heart MAO inhibitors (e.g., tranylcypromine, phenelzine, pargyline ) not used

5.

Direct vasodilators
a. Arteriolar Hydralazine always used with -blocker due to reflex tachycardia and with a diuretic Diazoxide chemically related to thiazide diuretics used in hypertensive crisis Minoxidil used in hypertensive patients refractory to other agents; grows hair

b.

Arteriolar and venous Nitroprusside (Nipride) - used only i.v. in hypertensive crisis; can titrate blood pressure to desired level with infusion (rapid onset, rapid termination of action)

6.

Calcium entry blockers L-type calcium channel blockers

7.

Renin-angiotensin inhibitors
a. ACE inhibitors peptidyl dipeptidase (converting enzyme) inhibitors inhibit formation of angiotensin II (active) from angiotensin I (inactive) inhibit breakdown of bradykinin effective orally cause coughing in up to 25% of patients

Captopril short-acting not a prodrug Enalapril prodrug; long-acting b. Angiotensin receptor antagonists ARBS effective orally, do not alter bradykinin levels Losartan Candesartan Valsartan

Major Drugs

Diuretics Beta-blockers Calcium entry blockers ACE inhibitors

ARBS

New approach to treatment of hypertension

Allhat trial JNC 7 and 8

Figure 11-1. Anatomic sites of blood pressure control.

Figure 11-2. Baroreceptor reflex arc.

Figure 11-3. Sites of action of the major classes of antihypertensive drugs.

Figure 11-4. Guanethidine actions and drug interactions involving the adrenergic neuron. (G, guanethidine; NE, norepinephrine; TCA, tricyclic antidepressants.)

Figure 11-6. Sites of action of ACE inhibitors and angiotensin II receptor blockers. 1 Site of ACE blockade. 2 Site of receptor blockade.

Figure 314. Summary of the three major effects of angiotensin II and the mechanisms that mediate them.