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Questions and Answers
What is the primary action of captopril as an ACE inhibitor?
Captopril primarily abolishes the pressor action of Ang I without blocking Ang II receptors.
How does captopril affect bradykinin levels in the body?
Captopril increases plasma kinin levels by preventing the degradation of bradykinin.
What role do kinins play in the acute action of ACE inhibitors?
Kinins contribute to the acute vasodepressor action of ACE inhibitors but have little role in long-term blood pressure regulation.
What side effects may be caused by elevated levels of kinins and prostaglandins due to ACE inhibitors?
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In what circumstances does the initial response to ACE inhibitors show a marked fall in blood pressure?
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How does captopril affect individuals who are normotensive and sodium-replete?
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What is the significance of captopril being described as a prototype ACE inhibitor?
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What is the impact of captopril on substance P metabolism?
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What role does the Renin-Angiotensin System (RAS) play in essential hypertension?
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How do ACE inhibitors affect the production of Angiotensin I and Angiotensin II?
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What is the primary mechanism through which captopril causes hypotension?
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Describe the impact of captopril on renal blood flow despite substantial blood pressure falls.
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What happens to plasma renin and Angiotensin I levels following the administration of ACE inhibitors?
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What pharmacokinetic properties are associated with orally administered captopril?
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Explain why postural hypotension is not a significant issue with ACE inhibitors.
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What are the general adverse effects associated with ACE inhibitors like captopril?
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Study Notes
ACE Inhibitors
- Captopril is the first orally active ACE inhibitor, introduced in 1977.
- ACE inhibitors are a class of medications that block the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor.
- ACE inhibitors work by blocking the action of angiotensin-converting enzyme (ACE), which is responsible for converting angiotensin I to angiotensin II.
- ACE inhibitors can lower blood pressure, improve heart function, and prevent kidney damage.
- ACE inhibitors are used to treat a variety of conditions, including hypertension, heart failure, and diabetic nephropathy.
- ACE inhibitors have also been shown to reduce the risk of stroke and heart attack.
- The mechanism of action of ACE inhibitors is to block the conversion of angiotensin I to angiotensin II, thereby reducing vasoconstriction and aldosterone secretion.
Captopril's Mechanism of Action
- Captopril is a sulfhydryl containing dipeptide surrogate of proline which abolishes the pressor action of angiotensin I but not that of angiotensin II. It does not block AT1 or AT2 receptors.
- ACE is a relatively nonspecific enzyme; splits off a dipeptidyl segment from several peptides including bradykinin, substance P, a natural stem cell regulating peptide, enkephalins, etc. in addition to angiotensin I.
- Captopril increases plasma kinin levels and potentiates the hypotensive action of exogenously administered bradykinin.
- Pretreatment with B2 kinin receptor antagonist has shown that kinins do contribute to the acute vasodepressor action of ACE inhibitors, but they appear to have little role in the long-term hypotensive effect.
- Elevated kinins (and PGs whose synthesis is enhanced by kinins) may be responsible for cough and angioedema induced by ACE inhibitors in susceptible individuals.
- ACE inhibitors interfere with degradation of substance P.
- Rise in the level of stem cell regulator peptide caused by ACE inhibitors could, in part, be responsible for their cardioprotective effect in CHF.
Captopril's Effect on Blood Pressure
- Captopril lowers blood pressure, but in the short-term, magnitude of response is dependent on the sodium status and the level of renin-angiotensin system (RAS) activity.
- In normotensive sodium replete individuals, the fall in blood pressure attending initial few doses of ACE inhibitors is modest.
- Fall in blood pressure is more marked when sodium has been depleted by dietary restriction or diuretics, because renin level is high.
- In CHF, the renin level is raised and antihypertensive doses of captopril initially cause marked fall in blood pressure. ACE inhibitor therapy in these situations has to be initiated at much lower doses.
- A greater fall in blood pressure also occurs in renovascular, accelerated and malignant hypertension.
- In essential hypertension, it has been found that RAS is overactive in 20%, normal in 60% and hypoactive in the rest. Thus, this system contributes to maintenance of vascular tone in over 80% cases and its inhibition results in lowering of blood pressure.
- Treatment with ACE inhibitors causes feedback increase in renin release resulting in overproduction of angiotensin I.
- Since its conversion to Angiotensin II is blocked, angiotensin I is diverted to produce more Ang (I-7) which has vasodilator property, and could contribute to the BP lowering action of ACE inhibitors.
- In the long-term however, no correlation has been observed between plasma renin activity (PRA) and magnitude of fall in blood pressure due to captopril.
Captopril's Effects on the Cardiovascular System
- Captopril-induced hypotension is a result of decrease in total peripheral resistance.
- The arterioles dilate and compliance of larger arteries is increased.
- Both systolic and diastolic blood pressure fall.
- Cardiac output is not affected.
- Cardiovascular reflexes are not interfered with and there is little dilatation of capacitance vessels. As such, postural hypotension is not a problem.
- Reflex sympathetic stimulation does not occur despite vasodilation, and ACE inhibitors can be safely used in patients with ischemic heart disease.
- The renal blood flow is not compromised even when blood pressure falls substantially. This is due to greater dilatation of renal vessels (angiotensin II markedly constricts them).
- Cerebral and coronary blood flow are also not compromised.
Captopril's Effects on Hormones
- Reflex (postural) changes in plasma aldosterone are abolished and basal levels are somewhat decreased as a consequence of loss of its regulation by angiotensin II.
- However, physiologically sufficient mineralocorticoid is still secreted under the influence of ACTH and plasma potassium.
- Levels of plasma renin and angiotensin I are increased as a compensatory measure, but the physiological significance of this appears to be minor (most actions are exerted through generation of angiotensin II ).
Captopril's Pharmacokinetics
- About 70% of orally administered captopril is absorbed.
- Presence of food in stomach reduces its bioavailability.
- Penetration in brain is poor.
- It is partly metabolized and partly excreted unchanged in urine.
- The plasma half-life is ~2 hours, but actions last for 6-12 hours.
Captopril's Adverse Effects
- The adverse effect profile of all ACE inhibitors is similar.
- Captopril is well tolerated but the most common adverse effects include:
- Hypotension
- Cough
- Angioedema
- Hyperkalemia
- Renal dysfunction
- Fetal toxicity
- Neutropenia
- Hepatic dysfunction
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Description
This quiz delves into ACE inhibitors, focusing on their function, benefits, and specific information about Captopril, the first orally active ACE inhibitor. Learn how these medications work to lower blood pressure and prevent heart and kidney issues. Test your knowledge on their mechanisms and clinical applications.
