ANTIHYPERTENSIVE AGENTS

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ANTIHYPERTENSIVE AGENTS

• Philip J. Kadowitz, Ph.D.

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Learning Objectives

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

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Drugs Used in the Treatment of Hypertension

• 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.

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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
• b. ? -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)

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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

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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

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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

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Major Drugs

• ? Diuretics
• ? Beta-blockers
• ? Calcium entry blockers
• ? ACE inhibitors
• ? ARBS

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New approach to treatment of hypertension

• ? Allhat trial
• ? JNC 7 and 8

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Figure 11-1. Anatomic sites of blood pressure
control.
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Figure 11-2. Baroreceptor reflex arc.
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Figure 11-3. Sites of action of the major
classes of antihypertensive drugs.
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Figure 11-4. Guanethidine actions and drug
interactions involving the adrenergic neuron. (G,
guanethidine NE, norepinephrine TCA, tricyclic
antidepressants.)
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Figure 11-6. Sites of action of ACE inhibitors
and angiotensin II receptor blockers. 1 Site of
ACE blockade. 2 Site of receptor blockade.
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Figure 314. Summary of the three major effects
of angiotensin II and the mechanisms that mediate
them.