Captopril

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Captopril

Drug Class: ACE Inhibitor (Angiotensin-Converting Enzyme Inhibitor) Prototype: First orally active ACE inhibitor; prototype of the sulfhydryl-containing class Brand name (former): Capoten

Historical Background

Captopril's development arose from research into snake venom. In the 1960s, Ferreira and colleagues found that venom from the Brazilian pit viper (Bothrops jararaca) contains bradykinin-potentiating peptides that inhibit kinase II, the same enzyme as ACE. Ondetti, Cushman, and colleagues reasoned that inhibition of ACE could be achieved by succinyl amino acids corresponding to the dipeptide cleaved by ACE, leading to the synthesis of captopril - the first orally effective ACE inhibitor. - Goodman & Gilman's Pharmacological Basis of Therapeutics

Mechanism of Action

Captopril blocks ACE, which normally catalyzes two reactions:

Conversion of angiotensin I (AngI) to angiotensin II (AngII) - a potent vasoconstrictor
Degradation of bradykinin - a vasodilator peptide

By inhibiting ACE, captopril produces:

Decreased AngII → reduced vasoconstriction and reduced aldosterone secretion → natriuresis and decreased BP
Increased bradykinin → stimulates nitric oxide and prostacyclin production → vasodilation of arterioles and veins
Increased renin release (loss of negative feedback) and increased formation of vasodilator peptides Ang(1-7) and Ang(1-9)
Increased Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline), a stem cell regulator contributing to cardioprotective effects

The net result is:

Reduced peripheral vascular resistance (afterload)
Reduced cardiac preload and afterload
Efferent arteriolar vasodilation in the kidney, reducing intraglomerular pressure
Regression of left ventricular hypertrophy over time
Lippincott Illustrated Reviews: Pharmacology; Goodman & Gilman's

Chemical Classification

ACE inhibitors are divided into three groups based on structure:

Sulfhydryl-containing - captopril (prototype of this group)
Dicarboxyl-containing - enalapril, lisinopril, ramipril, perindopril, benazepril, quinapril, moexipril, trandolapril
Phosphorus-containing - fosinopril

Captopril is unique in this classification as it contains a sulfhydryl (-SH) group which may confer additional properties but is also responsible for some unique side effects (rash, taste disturbance, rarely neutropenia).

Pharmacokinetics

Parameter	Detail
Administration	Oral
Formulations	Tabs: 12.5, 25, 50, 100 mg; Oral suspension: 1 mg/mL
Prodrug?	No - captopril is an active drug (unlike most other ACE inhibitors which are prodrugs)
Bioavailability	Well absorbed orally; should be taken on an empty stomach (1 hour before or 2 hours after meals) - food reduces absorption
Onset	Within 15-30 minutes of administration
Peak effect	1-2 hours
Elimination	Predominantly renal - 40-50% excreted as captopril, remainder as captopril disulfide dimers and captopril-cysteine disulfide
Dose frequency	2-3 times daily (shorter duration of action vs. other ACE inhibitors)
CYP	Substrate of CYP 450 2D6

Because captopril and lisinopril are not prodrugs, they may be preferred in patients with severe hepatic impairment (other ACE inhibitors require hepatic conversion to active metabolites).

Goodman & Gilman's; Lippincott; Harriet Lane Handbook

Dosing

Adults (Hypertension):

Initial: 12.5-25 mg BID-TID
Titrate weekly by 25 mg/dose as needed
Usual range: 25-100 mg/24 hr
Maximum: 450 mg/24 hr

Heart Failure (Adult):

Initiate at 6.25 mg three times daily

Pediatric (Hypertension):

Neonate: 0.01-0.05 mg/kg/dose PO Q8-12 hr
Infant: Initially 0.05-0.3 mg/kg/dose PO BID-TID; max 6 mg/kg/24 hr
Child: Initially 0.3-0.5 mg/kg/dose PO BID-TID; max 6 mg/kg/24 hr (up to 450 mg/24 hr)
Adolescent: same as adult

Lower initial doses should be used in patients with sodium/water depletion due to diuretic therapy (heightened hypotension risk). Adjust dose in renal failure.

Harriet Lane Handbook 23rd ed.; Goodman & Gilman's

Therapeutic Uses (Indications)

Captopril and ACE inhibitors broadly are first-line agents in:

Hypertension - especially with compelling indications (CAD, diabetes, stroke, CKD, MI, heart failure)
Heart failure with systolic dysfunction - reduces preload and afterload; improves mortality; first-line agent
Post-myocardial infarction - standard of care; improves ventricular remodeling, prevents LV dysfunction progression
Diabetic nephropathy - slows progression, reduces albuminuria via efferent arteriolar dilation and intraglomerular pressure reduction
Chronic kidney disease - renoprotective
Left ventricular hypertrophy - regression with chronic treatment
Captopril challenge test / Captopril-enhanced renography - used in the diagnostic workup for renovascular hypertension (80-95% sensitivity; tests functional significance of renal artery stenosis)

Lippincott Illustrated Reviews: Pharmacology; Goodman & Gilman's; Brenner & Rector's The Kidney

Adverse Effects

Effect	Notes
Dry cough	Most common (~10% of patients); due to bradykinin and substance P accumulation in pulmonary tree; more common in women; resolves after discontinuation
Angioedema	Rare but potentially life-threatening; swelling of lips, oral mucosa, throat; bradykinin-mediated; risk increased with sirolimus, everolimus, temsirolimus, or sacubitril
Hyperkalemia	Decreased aldosterone → reduced K+ excretion; caution with K+ supplements, K+-sparing diuretics, ARBs
Hypotension	First-dose hypotension especially in volume-depleted patients or high-renin states
Acute kidney injury	Especially in bilateral renal artery stenosis or single functioning kidney (efferent dilation can drop GFR); monitor creatinine - up to 30% rise acceptable
Rash	More common with captopril due to the sulfhydryl group
Dysgeusia (taste disturbance)	Loss or alteration of taste perception; associated with long-term use of captopril specifically
Neutropenia / agranulocytosis	Rare; more common in patients with collagen vascular disease or renal impairment
Proteinuria	Rare
Teratogenicity	Category D/X in 2nd and 3rd trimester - causes fetal renal tubular dysgenesis, hypocalvaria, oligohydramnios; must be discontinued as soon as pregnancy detected

Contraindications

Pregnancy (teratogenic, especially 2nd-3rd trimester)
Bilateral renal artery stenosis (or unilateral in a single functioning kidney)
Prior ACE inhibitor-induced angioedema
Concurrent use with ARBs or aliskiren (increased risk of hypotension, hyperkalemia, renal failure)
High-flux dialysis membranes (anaphylactoid reactions)

Use with caution in: collagen vascular disease, renal impairment, concomitant K+-sparing diuretics or NSAIDs, volume-depleted patients.

Key Drug Interactions

ARBs / Aliskiren - avoid combination; hypotension, hyperkalemia, AKI
K+-sparing diuretics / K+ supplements - hyperkalemia risk
NSAIDs - blunt antihypertensive effect, worsen renal function
Sirolimus / Everolimus / Temsirolimus / Sacubitril - increased angioedema risk
CYP2D6 inhibitors - can affect captopril metabolism

Why Captopril is Unique Among ACE Inhibitors

Feature	Captopril	Others
Prodrug?	No (active drug)	Most are prodrugs (enalapril → enalaprilat)
Chemical group	Sulfhydryl	Dicarboxyl (enalapril, lisinopril) or phosphoryl (fosinopril)
Dosing frequency	2-3x daily	Many are once-daily
Unique side effects	Rash, dysgeusia	Less common
Hepatic impairment	Preferred (no hepatic activation needed)	Most require liver conversion
IV formulation	Not available	Enalaprilat (IV form of enalapril) available

Summary: Captopril is the prototype ACE inhibitor, orally active, short-acting, and sulfhydryl-containing. It blocks conversion of AngI to AngII and inhibits bradykinin breakdown, producing vasodilation, natriuresis, and renal protection. It is indicated for hypertension, heart failure, post-MI, and diabetic nephropathy. Key adverse effects are dry cough and angioedema (bradykinin-mediated), hyperkalemia, first-dose hypotension, and teratogenicity. It must be taken on an empty stomach and dosed 2-3 times daily due to its shorter duration of action compared to newer ACE inhibitors.

Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics; Lippincott Illustrated Reviews: Pharmacology; Katzung's Basic and Clinical Pharmacology 16th ed.; Harriet Lane Handbook 23rd ed.; Brenner & Rector's The Kidney

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