Captopril

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captopril ACE inhibitor clinical pharmacology

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Captopril

Overview

Captopril is the first orally active ACE (angiotensin-converting enzyme) inhibitor. It was developed in the 1970s by Ondetti, Cushman, and colleagues after studying the inhibitory action of teprotide - a nonapeptide from the venom of the Brazilian pit viper (Bothrops jararaca). It belongs to the sulfhydryl-containing class of ACE inhibitors and remains the prototype of the entire drug class.

Goodman & Gilman's The Pharmacological Basis of Therapeutics, p. 615
Lippincott Illustrated Reviews: Pharmacology, p. 302

Mechanism of Action

RAAS cascade showing where ACE inhibitors, renin inhibitors, ARBs, and aldosterone antagonists block the pathway to lower blood pressure

Captopril blocks ACE, which is a zinc-containing dipeptidyl carboxypeptidase (also known as kinase II). This has several consequences:

Blocks AngI → AngII conversion - reduces circulating angiotensin II, decreasing vasoconstriction, aldosterone secretion, and sympathetic activation
Inhibits bradykinin breakdown - ACE is the same enzyme that degrades bradykinin; its inhibition raises bradykinin levels, enhancing production of nitric oxide and prostacyclin (both vasodilators)
Increases Ac-SDKP - a stem cell regulator with cardioprotective effects
Increases renin and AngI - through disruption of negative feedback; excess AngI is shunted to vasodilator peptides such as Ang(1-7)

Net effect: vasodilation of both arterioles and veins, reduced preload and afterload, decreased Na+/water retention.

Goodman & Gilman's, p. 616
Lippincott Pharmacology, p. 302

Pharmacokinetics

Parameter	Detail
Class	Sulfhydryl-containing ACEI (not a prodrug - active as administered)
Bioavailability	~75%, but reduced by 25-30% with food - should be taken on an empty stomach
Ki	1.7 nM (highly potent)
Peak plasma level	~1 hour after oral dose
Protein binding	~30%
Half-life	~2 hours (but prolonged in renal failure)
Elimination	Renal: 40-50% as unchanged captopril; remainder as captopril disulfide dimers and captopril-cysteine disulfide
Dose	6.25 to 150 mg, 2-3 times daily
Prodrug?	No - captopril and lisinopril are the only ACEIs that do NOT require hepatic conversion; preferred in hepatic impairment

Goodman & Gilman's, p. 618
Lippincott Pharmacology, p. 303

Therapeutic Uses

Indication	Notes
Hypertension	First-line; reduces peripheral vascular resistance
Heart failure (HFrEF)	Reduces preload and afterload; first-line along with beta blockers
Post-MI	Improves ventricular remodeling; reduces mortality
Diabetic nephropathy	Slows progression, reduces albuminuria; efferent arteriolar dilation lowers intraglomerular pressure
Chronic kidney disease	First-line in hypertensive CKD patients
Left ventricular hypertrophy	Causes regression with chronic use
Cystinuria	Captopril's sulfhydryl group forms a captopril-cysteine disulfide, increasing cystine solubility ~200-fold
Primary aldosteronism diagnosis	Captopril suppression test: 25-50 mg orally; PAC measured afterward
Renovascular hypertension screening	Captopril-enhanced renography (80-95% sensitivity)

Lippincott Pharmacology, p. 302-303
Brenner & Rector's The Kidney
Campbell Walsh Wein Urology

Adverse Effects

Adverse Effect	Mechanism / Notes
Dry cough	Up to 10% of patients; from bradykinin and substance P accumulation in the pulmonary tree; more common in women; resolves within days of stopping
Angioedema	Rare but life-threatening; swelling of lips, oral mucosa, throat; bradykinin-mediated; more common in ACE inhibitors than ARBs
Hyperkalemia	Reduced aldosterone → reduced K+ excretion; avoid K+ supplements and K+-sparing diuretics
Hypotension	Especially "first-dose hypotension" - worse if volume-depleted or on diuretics
Altered taste (dysgeusia)	More specific to captopril than other ACEIs - attributed to the sulfhydryl group
Skin rash	Also relatively specific to captopril (sulfhydryl group)
Rise in serum creatinine	Up to 30% rise above baseline is acceptable; monitor renal function
Leukopenia	Rare
Teratogenicity	Fetal malformations (renal dysgenesis, skull ossification defects) - contraindicated in pregnancy

Lippincott Pharmacology, p. 303-304
Washington Manual of Medical Therapeutics

Captopril-specific adverse effects (more than other ACEIs): taste disturbances and skin rash due to the sulfhydryl moiety. It is also less commonly used today because it requires 2-3 times daily dosing and causes more side effects than later-generation ACEIs. - Barash Clinical Anesthesia, p. 3255

Contraindications

Pregnancy (all trimesters - teratogenic and fetotoxic)
Bilateral renal artery stenosis (can cause acute renal failure by removing efferent tone)
History of angioedema with any ACEI
Concurrent use with aliskiren in diabetic patients
Concurrent use with ARBs (increased adverse effects without added benefit for hypertension)

Drug Interactions

Potassium supplements / K+-sparing diuretics (spironolactone, amiloride) - risk of hyperkalemia
NSAIDs - blunt antihypertensive effect; worsen renal function
Diuretics - potentiate hypotension (especially first-dose)
Lithium - ACEIs reduce lithium excretion, raising lithium toxicity risk

Key Distinguishing Features vs. Other ACEIs

Feature	Captopril	Others (e.g., enalapril, ramipril)
Active drug (not prodrug)	Yes	Most are prodrugs
Dosing frequency	2-3x daily	Once daily (most)
IV form available	No	Enalaprilat only
Hepatic conversion needed	No	Yes (most)
Sulfhydryl group	Yes	No (dicarboxyl or phosphorus)
Taste/rash more common	Yes	Less so

Summary Mnemonic - "CAPTOPRIL"

C - Cough (dry, bradykinin-mediated)
A - Angioedema
P - Potassium rises (hyperkalemia)
T - Teratogen (contraindicated in pregnancy)
O - Output (cardiac) improved in HF
P - Proteinuria reduced (diabetic nephropathy)
R - Renal artery stenosis: use with caution
I - Inhibits ACE (AngI → AngII blocked)
L - Lowers BP (vasodilation, ↓ aldosterone)

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