Ace Inhibitors

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      • Drugs that inhibit the activity of the Renin–Angiotensin System
        • ACE inhibitors and ARBs are indicated in all patients with left ventricular (LV) dysfunction, whether symptomatic or asymptomatic
        • ACE inhibitors
          • prevent or slow the progression of heart failure in patients with ventricular dysfunction.
          • useful for treating hypertension.
      • Principles of the renin–angiotensin system
        • Factors that increase renin
          • Reduced arterial pressure
          • decreased sodium delivery to the cortex
          • increased sodium at the distal tubule,
          • stimulation of sympathetic activity all.
        • Renin cleaves the protein angiotensinogen and releases the decapeptide angiotensin I.
        • Angiotensin I is converted enzymatically (mostly in the lung) to an octapeptide, angiotensin II (AgII or Ag1-8), by the activity of ACE
        • further metabolism produces the heptapeptide angiotensin III (Ag2-8)
        • Both angiotensin II and angiotensin III stimulate the release of aldosterone.
        • Angiotensin I can also be metabolized by ACE2 to Ag1-7.
        • The actions of Ag1-7 oppose those of AgII.
        • Angiotensin II
          • a vasoconstricting agent
          • causes sodium retention via release of aldosterone
        • angiotensin III is less active as a vasoconstricting agent than angiotensin II.
        • The actions of angiotensin II are mediated by AT1, AT2, and AT4 receptors located in most tis- sues.
          • The pressor actions of angiotensin II are mediated by AT1 receptors.
          • Ag1-7 acts via the MARS receptor.
        • Angiotensin II can be produced locally (e.g., in the myocardium, kidney, adrenals, or in vessel walls by the action of non-ACE pathways) by the action of chymases and cathepsins.
        • Because angiotensin I is produced via pathways other than the ACE pathway, angiotensin II receptor antagonists may be more effective and specific in reducing angiotensin II actions.
      • ACE inhibitors
        • Mechanism.
          • inhibit the production of angiotensin II from angiotensin I
          • counteractelevated peripheral vascular resistance and sodium and water retention resulting from angiotensin II and aldosterone.
          • increase cardiac output and induce systemic arteriolar dilation (reduce afterload).
          • Cause venodilation and induce natriuresis,thereby reducing preload.
        • Therapeutic uses.
          • very useful in long-term therapy of CHF
          • reduce risk of recurrent post-myocardial infarction (MI), and treating hypertension.
          • advantage of producing minimal electrolyte disturbances and fewer adverse effects than many other agents used to treat hypertension.
        • Selected drugs
          • Enalapril
            • a prodrug
            • deesterified in the liver to produce enalaprilat,which inhibits ACE.
            • Therapeutic uses.
              • Enalapril is a first-line drug in the treatment of CHF
              • is used to treat mild-to-severe hypertension.
              • Diuretics enhance its activity.
              • Also used to slow the progression of renal disease, especially in diabetic patients.
            • Adverse effects and contraindications
              • Blood dyscrasias and aplastic anemia are rare but serious adverse effects of enalapril.
              • Renal function may be impaired.
          • Captopril
            • the first ACE inhibitor
            • the only sulfur-containing ACE inhibitor
            • absorbed from the gastrointestinal (GI) tract and is metabolized to disulfide conjugates
            • Drug absorption is decreased by 30% by food.
            • It does not enter the CNS.
            • Captopril produces adverse effects that include rash, taste disturbance, pruritus, weight loss, and anorexia.
          • Lisinopril
            • ACE inhibitor that permits once-a-day dosing.
            • The bioavailability of lisinopril is not affected by food.
        • Adverse effects common to all ACE inhibitors include
          • dry cough and, rarely, angioedema
          • both thought to be due to increased bradykinin levels
          • hypotension,
          • hyperkalemia.
      • Angiotensin II receptor blockers (ARBs)
        • Mechanism of action
          • The actions of angiotensin II are mediated by receptors that are 7-transmembrane proteins that couple to numerous signal transduction pathways.
          • AT1 receptors are responsible for
            • pressor actions
            • increased aldosterone biosynthesis
            • proliferative and fibrotic actions of angiotensin II.
          • In general, AT2 receptors antagonize the action of AT1 receptors.
          • AT4 receptors
            • bind angiotensin IV
            • seem to be involved in memory and learning.
          • In several clinical trials ARBs have proved as effective as ACE inhibitors in reducing mortal- ity from CHF or following an MI.

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        • ARBs : prototype drug—valsartan
          • Mechanism.
            • Valsartan is an imidazole derivative with high affinity for AT1 receptors (about 20,000-fold higher than for AT2 receptors).
            • Oral doses are absorbed rapidly.
            • Peak levels of the drug are obtained in about 3 hours,
            • it has a half-life of about 6 hours.
            • Valsartan is excreted in the feces, probably via biliary excretion.
          • Therapeutic uses.
            • as effective as captopril in patients with left ventricular dysfunction following an MI. as effective as ACE inhibitors in reducing blood pressure
            • is available in combination with hydrochlorothiazide for patients refractory to monotherapy.
          • Adverse effects and contraindications.
            • Dizziness and hyperkalemiacan occur with valsartan
            • Since ARBs do not lead to accumulation of kinins, the incidence of both the nonproductive cough and angioedema associated with ACE inhibitors is reduced.
        • Renin inhibitors- Aliskiren
          • a small molecule inhibitor of renin.
          • It is administered orally
          • eliminated mostly unchanged in the urine
          • as effective as ACE inhibitors or ARBs for reducing blood pressure.
          • Diarrhea, angioedema, and hyperkalemia have been reported.
          • The incidence of cough is reduced compared to ACE inhibitors.

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