ANSWERS TO CASE 9: DRUGS ACTIVE ON THE RENIN-ANGIOTENSIN SYSTEM

ANSWERS TO CASE - 09 :

DRUGS ACTIVE ON THE RENIN-ANGIOTENSIN SYSTEM

Summary: A 72-year-old man with hypertension and congestive heart failure presents with an ACE inhibitor-induced cough, and is switched to losartan.

  • Mechanism of action of enalapril: Inhibits the conversion of angiotensin I to angiotensin II, this also inhibits the angiotensin II-stimulated release of aldosterone. Angiotensin-converting enzyme (ACE) inhibitors also impair the inactivation of bradykinin.
  • Mechanism of converting enalapril to enalaprilat: Deesterification in the liver.
  • Mechanism of ACE inhibitor-induced cough: Secondary to the increased bradykinin levels, which is caused by reduction in the inactivation of bradykinin.
  • Mechanism of action of angiotensin receptor blockers (ARBs): Antagonists of angiotensin-1 (AT-1) receptors which mediate the pressor effects of angiotensin II.

CLINICAL CORRELATION

ACE inhibitors have gained wide-scale use in medicine for their effectiveness in hypertension, congestive heart failure, coronary artery disease, and renal protection in diabetics. They inhibit the conversion of angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor and stimulates the release of aldosterone, which promotes sodium retention. Angiotensin II also increases catecholamine release by the adrenal medulla and at sympathetic nerves. Inhibition of the production of angiotensin II reduces vascular resistance and sodium and water retention. Another effect of ACE inhibitors is to reduce the inactivation of bradykinin. Active bradykinin is a vasodilator, pro- viding an additive effect in lowering blood pressure. However, raising bradykinin levels contributes to one of the ACE inhibitors’ most bothersome side effects, chronic dry cough. ACE inhibitors in general are well tolerated, but along with cough, can cause hyperkalemia and should be used with caution with potassium-sparing diuretics or in persons with impaired renal function. ARBs are antagonists of the angiotensin I receptor, which mediates the direct vasoconstrictor effect of angiotensin II. This also blocks the release of aldosterone. ARBs do not affect the bradykinin system and therefore do not cause a cough. They are also well tolerated but, like ACE inhibitors, can cause hyperkalemia. Aliskiren (Tekturna), a renin inhibitor has recently been introduced in the United States. It appears to be as efficacious as ACE inhibitors or ARBs, but clinical experience is limited.

APPROACH TO PHARMACOLOGY OF THE RENIN-ANGIOTENSIN SYSTEM

Definitions

Hypertension: From the Seventh Report, Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, normal blood pressure is 120/80 mm Hg. Progressive disease may be staged as prehypertensive (120–139/80–89), Stage 1 (140–159/90–99), and Stage 2 (> 160/> 100).

Bradykinin: A member of a class of peptides, the kinins, that have a variety of effects on the cardiovascular system, including vasodilatation and inflammation.

ARB: Angiotensin receptor blocker, more precisely angiotensin AT-1 receptor blockers.

DISCUSSION

Class

The renin-angiotensin-aldosterone system provides a humoral system for controlling blood pressure and electrolyte levels. The “sensors” in this sys- tem monitor Na+, K+, vascular volume, and blood pressure. A reduction in blood pressure, detected by intrarenal stretch receptors, or a fall in the delivery of Na+ to the distal portions of the nephron results in release of renin from the juxtaglomerular apparatus (JGA). Renin secretion can also be increased through the baroreceptor reflex mediated by increased central nervous system (CNS) outflow and b1-adrenergic receptors on the JGA. Renin is an aspartyl protease that cleaves angiotensinogen, a 56-kD polypeptide produced in the liver, to the decapeptide angiotensin I.

Angiotensin I is biologically inactive and is rapidly converted to the octapeptide angiotensin II by the action of ACE, a dipeptidyl peptidase. Angiotensin II is further metabolized within the brain and in the plasma by aminopeptidase A, which removes the N-terminal aspartic acid to produce angiotensin III, which may itself be further metabolized by aminopeptidase N, which removes the N-terminal arginine yielding angiotensin IV. The latter two metabolites may play a critical role in regulating blood pressure in the brain. Distinct from this classic intravascular pathway for the formation of angiotensins, evidence has accumulated indicating that angiotensins can also be produced within various tissues by a local conversion to angiotensins II, III, and IV.

Angiotensin II has multiple actions that act in concert to increase blood pressure and alter electrolyte levels. Angiotensin II is a potent vasoconstric- tor, 10–40 times more potent than epinephrine, an effect mediated by receptor-coupled Ca2+ channels in vascular smooth muscle cells, as described below. Angiotensin II enhances the release of catecholamines from both the adrenal medulla and at peripheral nerve endings. Within the adrenal cortex, angiotensin II increases the biosynthesis of aldosterone, which leads to an increase in Na+ and water reabsorption in the kidneys and volume expansion. Angiotensin II has several actions within the CNS including altering vagal tone to increase blood pressure, increasing thirst, and increasing the release of antidiuretic hormone.

Angiotensin II also has effects on the heart and the vasculature that do not directly affect blood pressure. Angiotensin II induces cardiac hypertrophy, is proproliferative, and enhances matrix remodeling and the deposition of matrix proteins, which leads to increased myocardial stiffness. Within vessel walls, angiotensin II is proinflammatory and can stimulate the release of several chemokines.

Three angiotensin receptors mediate these actions. The AT-1 and angiotensin-2 (AT-2) receptors have been described in various tissues. Both are seven-transmembrane receptors that appear to couple to various signaling pathways. AT-1 receptors bind angiotensin II, angiotensin III, and angiotensin IV. This receptor mediates most of the cardiovascular and central responses to angiotensin II, including vasoconstriction of vascular smooth muscle and aldosterone biosynthesis in the adrenal medulla. AT-1 receptors also mediate the cardiac hypertrophic and proproliferative responses to angiotensin II. AT-2 receptors also bind angiotensin II and play a role in the development of the cardiovascular system. In general, activation of AT-2 receptors is physiologically antagonistic to the action of AT-1 receptors. Activation of AT-2 receptors is hypotensive and antiproliferative and is coupled to distinctly different signaling pathways compared to AT-1 receptors. Angiotensin-4 (AT-4) receptors appear to be identical to transmembrane aminopeptidase insulin-regulated aminopeptidase (IRAP) and have a single transmembrane AT-4 receptors are expressed in the numerous tissues and bind angiotensin IV. Activation of these receptors has been reported to regulate cerebral blood flow, and to stimulate endothelial cell expression of plasminogen activator inhibitor, and has effects on both memory and learning.

Inhibition of the renin-angiotension system (RAS) is accomplished pharmacologically in three ways: inhibition of the production of angiotensin II, blockade of AT-1 receptors, or inhibition of renin activity. ACE inhibitors, or peptidyl dipeptidase (PDP) inhibitors, include enalapril, lisinopril, fosinopril, captopril, and seven others. These drugs differ in their chemistry and pharmacokinetic properties, but all are orally active, have the same range of activities, and are equally effective clinically. ACE is the enzyme responsible for both activation of angiotensin I (metabolism to angiotensin II) and inactivation of bradykinin. The decreased metabolism of bradykinin is partly responsible for the hypotensive action of ACE inhibitors, and is also responsible for enhancing the irritability of airways that leads to the dry cough associated with ACE inhibitors.

ARBs block the action of angiotensin II by acting as antagonists at AT-1 receptors. These nonpeptide antagonists include losartan, valsartan, candesartan, and others. ARBs bind with high affinity to AT-1 receptors without interfering with AT-2 or AT-4 receptors.

The ACE inhibitors and ARBs are equally effective in reducing blood pressure. More clinical experience exists with the ACE inhibitors and it has been well established that this class of drugs reduces the risk of second events in patients who have had an MI and in reducing renal damage in patients with diabetic nephropathy. Hypotension and hyperkalemia are adverse effects seen with both classes of RAS inhibitors. Cough and angioedema, caused by increased bradykinin levels, are more frequently seen with the ACE inhibitors.

A newly approved agent, aliskiren, has been approved for use in the treatment of hypertension. Aliskiren is a small molecule inhibitor of renin. In clinical trials of more than 2000 patients, aliskiren was effective in 24-hour blood pressure control. The effect was maintained for at least a year. Aliskiren was about as effective as ACE inhibitors or ARBs but may cause a greater rebound in renin production when discontinued than the other agents.

Structure

Although the various ACE inhibitors have different chemical structures, they are mostly based on extensive modifications of L-proline. The ARBs are also quite distinct chemically: Valsartan is an L-valine derivative, and losartan is an imidazole derivative. Aliskiren was designed based on the crystal structure of renin and is a nonpeptide, small molecule, transition-state mimetic that binds to the active site of the enzyme.

Mechanism of Action

ACE inhibitors are all competitive inhibitors of angiotensin-converting enzyme. ARBs are competitive antagonists of the angiotensin II type 1 receptor (AT-1)

Administration

All ACE inhibitors are available for oral administration. Enalaprilat, the active metabolite of enalapril, is available for intravenous infusion. Aliskiren is an oral agent.

Pharmacokinetics

Most of the current ACE inhibitors are prodrugs and require conversion to the active metabolite in the liver. For example, enalapril is converted to enalapri- lat, fosinopril is converted into fosinoprilat. Captopril and lisinopril are active drugs that do not require metabolism. The onset of action of ACE inhibitors is 0.5–2 hours, and the duration of action is typically 24 hours (captopril is 6 hours). Most are eliminated in the urine.

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