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ACE INHIBITORS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) This is a group of angiotensin-converting-enzyme inhibitors used primarily as antihypertensives, but also as treatment for congestive heart failure refractory to traditional therapies.
    B) GERMANY: ACE inhibitors available in Germany include Captopril, Enalapril, Lisinopril, Perindopril and Trandolapril

Specific Substances

    A) CAPTOPRIL (synonym)
    1) SQ 14225
    2) (1(2S)-3-mercapto-2-methyl-propionyl)-L-proline
    3) CAS 6257-86-2
    ENALAPRIL (synonym)
    1) MK-421
    2) N-(1-Ethoxycarbonyl-3-phenylpropyl)-L-anal-
    3) L-proline hydrogen maleate
    LISINOPRIL (synonym)
    1) L-154826
    2) MK-521
    3) N-(N-((S)-1-carbixy-3-phenylpropyl)
    4) -L-lysyl)-L-proline
    5) Molecular Formula: C21-H31-N3-O5
    6) CAS 76547-98-3 (Lisinopril)
    7) CAS 83915-83-7 (Lisinopril dihydrate)
    PERINDOPRIL ERBUMINE
    1) S-9490-3
    2) McN-A-2833-109
    3) Molecular formula C19-H32-N2-O5-C4-H11-N
    4) CAS 82834-16-0
    RAMIPRIL (synonym)
    1) Hoe-498
    2) CAS 87333-19-5
    GENERAL TERMS
    1) ACEI
    2) ANGIOTENSIN CONVERTING ENZYME INHIBITORS

    1.2.1) MOLECULAR FORMULA
    1) CAPTOPRIL: C9-H15-N-O3-S
    2) ENALAPRIL MALEATE: C20-H28-N2-O5-C4H4O4
    3) LISINOPRIL: C21-H31-N3-O5-2H2O
    4) RAMIPRIL: C23-H32-N2-O5
    5) BENAZEPRIL HYDROCHLORIDE: C24H28N2O5.HCl
    6) ENALAPRIL MALEATE: C20H28N2O5.C4H4O4
    7) ENALAPRILAT: C18H24N2O5.2H2O
    8) FOSINOPRIL SODIUM: C30H45NNaO7P
    9) LISINOPRIL: C21H31N3O5.2H2O
    10) MOEXIPRIL HYDROCHLORIDE: C27H34N2O7.HCl
    11) PERINDOPRIL ERBUMINE: C19H32N2O5C4H11N
    12) QUINAPRIL HYDROCHLORIDE: C25H30N2O5.HCl
    13) RAMIPRIL: C23H32N2O5
    14) TRANDOLAPRIL: C24H34N2O5

Available Forms Sources

    A) FORMS
    1) CAPTOPRIL(R) Squibb, available in 12.5, 25, 50 and 100 mg tablets
    2) ENALAPRIL: Vasotec(R) by MSD, available in 5, 10, and 2:0 mg tablets
    3) LISINOPRIL
    a) Zestril(R) by Stuart, available in 5, 10, and 20 mg tablets
    b) Prinivil(R) by MSD, available in 5, 10, 20, and 40 mg tablets
    4) PERINDOPRIL: Aceon(R) Solvay Pharmaceuticals, Inc, available in 2, 4, and 8 mg tablets
    5) RAMIPRIL: Available as 1.25 mg, 2.5 mg, 5 mg, and 10 mg tablets (Prod Info ALTACE(R) oral tablets, 2011).
    6) FOREIGN TRADE NAMES
    a) CAPTOPRIL
    1) Acepril (UK)
    2) Alopresin (Spain)
    3) Capoten (Australia, Canada, Denmark, Italy, Norway, South Africa, Spain, Sweden, UK)
    4) Captolane (France)
    5) Cesplon (Spain)
    6) Cor Tensobon (Germany)
    7) Dilabar (Spain)
    8) Garranil (Spain)
    9) Lopirin (Germany, Switzerland)
    10) Lopril (France)
    11) Tensobon (Germany)
    12) Tensoprel (Spain)
    b) ENALAPRIL
    1) Pres (Germany)
    2) Xanef (Germany)
    c) LISINOPRIL
    1) Acerbon (Germany)
    2) Carace (UK)
    3) Coric (Germany)
    d) PERINDOPRIL
    1) Coversum (Germany)
    e) TRANDOLAPRIL
    1) Gopten (Germany)
    2) Udrik (Germany)

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Treatment of hypertension, congestive heart failure (CHF), diabetic nephropathy, and post myocardial infarction.
    B) EPIDEMIOLOGY: Exposures are common, but toxicity is generally mild.
    C) PHARMACOLOGY: These agents inhibit angiotensin-converting enzymes (ACE), thus preventing conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor and stimulator of aldosterone secretion (aldosterone suppression reduces sodium and water retention). ACE inhibitors also prevent the breakdown of bradykinin (a potent vasodilator). The net result is vasodilatation, decreased peripheral vascular resistance, decreased blood pressure, increased cardiac output, and a relative increase in renal, cerebral, and coronary blood flow.
    D) TOXICOLOGY: The toxic effect of an ACE inhibitor is an extension of its pharmacologic effect. The elevation in bradykinin concentration appears to be the primary cause of both ACE inhibitor-induced angioedema and cough. ACE inhibitors may also inhibit the metabolism of enkephalins and potentiate their opioid effect, which includes lowering blood pressure.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Dry cough, hypotension, hyperkalemia, renal insufficiency in patients with renal artery stenosis, maculopapular rash, angioneurotic edema, neutropenia, and hepatotoxicity.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild hypotension.
    2) SEVERE TOXICITY: Severe hypotension, syncope, hyperkalemia, bradycardia and renal failure.
    0.2.20) REPRODUCTIVE
    A) Fetal and neonatal morbidity and death have occurred from the use of ACE inhibitors during any trimester of pregnancy with reports of spontaneous abortion, oligohydramnios, and newborn renal dysfunction. The occurrence of oligohydramnios is possibly due to decreased fetal renal function. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported; although, causality to drug therapy has not been established. In general, ACE inhibitors demonstrated little or no teratogenicity in animal studies.
    B) BENAZEPRIL, BENAZEPRIL/HYDROCHLOROTHIAZIDE, CAPTOPRIL, and PERINDOPRIL are classified as FDA pregnancy category D.
    C) CAPTOPRIL/HYDROCHLOROTHIAZIDE, ENALAPRIL, ENALAPRILAT, ENALAPRIL/HYDROCHLOROTHIAZIDE, FOSINOPRIL, FOSINOPRIL/HYDROCHLOROTHIAZIDE, LISINOPRIL/HYDROCHLOROTHIAZIDE, MOEXIPRIL, MOEXIPRIL/HYDROCHLOROTHIAZIDE, QUINAPRIL, QUINAPRIL/HYDROCHLOROTHIAZIDE, RAMIPRIL, and TRANDOLAPRIL are classified as FDA pregnancy category C (first trimester) and D (second and third trimesters).
    D) Most ACE INHIBITORS are excreted in human milk in very small amounts. Overall, ACE INHIBITORS demonstrated no impairment to fertility in animal studies.

Laboratory Monitoring

    A) Monitor vital signs frequently. Routine laboratory tests are not usually necessary.
    B) Other labs such as serum electrolytes, renal function, and ECG should be ordered, if clinically indicated.
    C) ACE inhibitor levels are not readily available and not useful in acute management.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Most patients will have no symptoms, but patients with mild orthostatic hypotension can be treated by remaining prone. Those who remain hypotensive can be treated with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Adequate circulatory support with IV fluids and vasopressors (if needed) should be assured if the patient presents with circulatory collapse. Correct severe hyperkalemia using standard treatments such as glucose, insulin, calcium, sodium bicarbonate, sodium polystyrene sulfate and hemodialysis.
    C) DECONTAMINATION
    1) PREHOSPITAL: As severe toxicity is very rare, prehospital decontamination is generally not recommended.
    2) HOSPITAL: Administer activated charcoal if the patient presents early after large ingestion, with appropriate level of consciousness, patent airway, and can drink the charcoal. Gastric lavage is generally not necessary as life threatening toxicity is rare.
    D) AIRWAY MANAGEMENT
    1) Patients who have severe angioedema may require fiber optic or surgical airway procedures.
    E) ANTIDOTE
    1) Angiotensin infusion at doses ranging from 8.5 to 18 mcg/minute has been successful in reversing hypotension in patients who did not respond to volume and pressor infusions, but is not available in the United States.
    F) NALOXONE
    1) Although the role of naloxone in the setting of ACE inhibitor overdose remains unclear, it may be considered especially in cases of severe hypotension where fluid overload is a concern. The dose of naloxone should be administered in titrated doses starting with 0.2 to 2 mg IV repeated every 2 to 3 minutes to improve blood pressure; maximum dose 8 mg. Pediatrics: 0.01 to 0.1 mg/kg, repeated every 2 to 3 minutes as needed.
    G) ENHANCED ELIMINATION
    1) ACE inhibitors are dialyzable, but hemodialysis is not used because supportive care is usually effective.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Pediatric patients can be observed at home if they have ingested less than 2 times the defined daily dose (DDD) of an ACE inhibitor and they remain asymptomatic. The DDD of specific ACE inhibitors are as follows:
    1) Captopril: 50 mg
    2) Enalapril: 10 mg
    3) Fosinopril: 15 mg
    4) Lisinopril: 10 mg
    5) Perindopril: 4 mg
    6) Ramipril: 2.5 mg
    7) Trandolapril: 2 mg
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions, and children who are symptomatic or who have ingested at least 2 times the defined daily dose (DDD) of an ACE inhibitor should be referred to a healthcare facility for observation and evaluation. The DDD of specific ACE inhibitors are as follows:
    1) Captopril: 50 mg
    2) Enalapril: 10 mg
    3) Fosinopril: 15 mg
    4) Lisinopril: 10 mg
    5) Perindopril: 4 mg
    6) Ramipril: 2.5 mg
    7) Trandolapril: 2 mg
    3) ADMISSION CRITERIA: Symptomatic or hypotensive patients should be admitted to a monitored bed.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity, or in whom the diagnosis is not clear.
    I) PITFALLS
    1) Failure to recognize difficult airway in patients with angioedema. If patients develop severe toxicity, evaluate for co-ingested substances.
    J) PHARMACOKINETICS
    1) CAPTOPRIL: Onset 30 minutes, duration 8 to 12 hours, and 70% absorbed. Peak concentrations about 1 hour; 25% protein bound, volume of distribution 0.7 L/kg, 50% hepatic metabolism, renal elimination, and half-life 1.9 hours.
    2) ENALAPRIL: Onset 1 to 4 hours, duration 12 to 24 hours, and 60% absorbed. Peak concentrations 1 hour, 50% protein bound, active hepatic metabolite (enalaprilat) which is renally eliminated. Half-life: enalapril 1.3 hours; enalaprilat 11 hours.
    3) LISINOPRIL: Onset 1 hour, duration 24 hours, and about 25% absorbed. Peak concentration 6 to 8 hours, minimal protein binding, volume of distribution 124 liters, elimination: mostly fecal followed by renal and half-life 12 hours.
    4) PERINDOPRIL: Onset 1.5 hours, duration 24 hours, 20% to 30% absorbed, and 60% protein bound. Volume of distribution 0.33 L/kg, extensive hepatic metabolism, 75% renal and 25% fecal elimination of metabolites. Half-life 1 hour.
    K) TOXICOKINETICS
    1) Captopril: Apparent half-life in one overdose was 34 hours. Lisinopril: Apparent half-life in one overdose was 14.9 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Other antihypertensive agents poisoning; beta-blocker poisoning; calcium channel blocker poisoning; or anaphylaxis.

Range Of Toxicity

    A) TOXICITY: ADULTS: Patients have ingested the following with only mild hypotension reported: 7.5 g captopril, 300 mg enalapril, and 420 mg lisinopril. Moderate hypotension (median BP 75/36) was observed in 10 adults after ingesting a median ramipril dose of 210 mg (range: 100 to 280); 4 had coingested other cardiovascular agents and 2 coingested alcohol; all cases recovered. Fatalities have occurred after ingestions of 1125 mg captopril and 180 mg perindopril. CHILDREN: In one study, children remained asymptomatic after ingestions of up to 100 mg captopril or 30 mg enalapril.
    B) THERAPEUTIC DOSE: Varies with agent. CAPTOPRIL: ADULT: 37.5 to 150 mg/day in 3 divided doses. PEDIATRIC: 0.5 to 4 mg/kg/day divided. ENALAPRIL: ADULT: 2.5 to 20 mg/day. PEDIATRIC: Initial: 0.08 mg/kg/day (up to 5 mg). Adjust to blood pressure response LISINOPRIL: ADULT: 5 to 40 mg/day orally. PEDIATRIC: 0.07 mg/kg/day; maximum 5 mg. PERINDOPRIL: ADULT: 4 to 16 mg in 1 or 2 divided doses; maximum 16 mg/day. RAMIPRIL: ADULT: 2.5 to 20 mg once daily; maximum: 20 mg daily.

Clinical Effects

Summary Of Exposure

    A) USES: Treatment of hypertension, congestive heart failure (CHF), diabetic nephropathy, and post myocardial infarction.
    B) EPIDEMIOLOGY: Exposures are common, but toxicity is generally mild.
    C) PHARMACOLOGY: These agents inhibit angiotensin-converting enzymes (ACE), thus preventing conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor and stimulator of aldosterone secretion (aldosterone suppression reduces sodium and water retention). ACE inhibitors also prevent the breakdown of bradykinin (a potent vasodilator). The net result is vasodilatation, decreased peripheral vascular resistance, decreased blood pressure, increased cardiac output, and a relative increase in renal, cerebral, and coronary blood flow.
    D) TOXICOLOGY: The toxic effect of an ACE inhibitor is an extension of its pharmacologic effect. The elevation in bradykinin concentration appears to be the primary cause of both ACE inhibitor-induced angioedema and cough. ACE inhibitors may also inhibit the metabolism of enkephalins and potentiate their opioid effect, which includes lowering blood pressure.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Dry cough, hypotension, hyperkalemia, renal insufficiency in patients with renal artery stenosis, maculopapular rash, angioneurotic edema, neutropenia, and hepatotoxicity.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild hypotension.
    2) SEVERE TOXICITY: Severe hypotension, syncope, hyperkalemia, bradycardia and renal failure.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Profound hypotension has been reported with captopril and enalapril therapeutically (Coulshed et al, 1985; Cleland et al, 1985), and rarely after overdose. Generally, hypotension after overdose of up to 300 mg of enalapril and 5 g of captopril has been mild (Turhan et al, 1985; Waeber et al, 1984a).
    2) RETROSPECTIVE STUDY: Data from 33 overdose cases involving an ACE inhibitor were reviewed. Enalapril was ingested by 11 patients, ramipril by 10 patients, lisinopril by 9 patients, perindopril in 2 patients, and captopril in one patient. Co-ingestants were also noted. Trough blood pressure occurred in approximately 4 to 8 hours from the time of ingestion regardless of the ACE inhibitor ingested. The median decrease for systolic blood pressure was 50 mm Hg, for diastolic blood pressure was 35 mm Hg, and 39 mm Hg for mean blood pressure. Ramipril was noted to cause a slightly more significant fall in blood pressure compared with the other ACE inhibitors. Only one patient required aggressive treatment with pressors. The majority of patients recovered with administration of intravenous fluids (Christie et al, 2006; Lucas et al, 2006).
    3) CASE REPORT: Ingestion of 750 mg of captopril and 10 mg of alprazolam resulted in profound hypotension, which recurred at approximately 18 and 24 hours post-ingestion in a 33-year-old woman (Augenstein et al, 1988).
    4) CASE REPORT: Profound hypotension developed in a 45-year-old man with idiopathic dilated cardiomyopathy (ejection fraction 23%) who was inadvertently given 25 mg lisinopril instead of 2.5 mg. Therapy with intravenous dobutamine (20 mcg/kg/min), dopamine (20 mcg/kg/min), and norepinephrine (14.5 mcg/kg/min) was ineffective in correcting hypotension. Blood pressure improved with an infusion of angiotensin amide at 9 mcg/minute (Trilli & Johnson, 1994).
    5) CASE REPORT: Hypotension developed in a tetraplegic man 3 days after beginning lisinopril 5 mg/day (Schmitt et al, 1994). It was postulated that patients with spinal cord injury might be prone to ACE inhibitor-induced hypotension because of increased reliance on the renin-angiotensin-aldosterone axis to maintain blood pressure in the face of decreased sympathetic tone.
    6) CASE REPORT: Severe hypotension developed in a 75-year-old woman with poor nutritional status and chronic rheumatoid arthritis who received 10 mg of enalapril for transient hypertension that developed after a left lower lobe lung resection for squamous cell carcinoma. Hypotension was felt to be a result of volume depletion combined with ACE inhibitor-induced arterial and venous dilation, and was resistant to treatment with volume and pressors. The patient developed colonic ischemia, underwent a colectomy and died 7 days later of septic complications (Schweizer et al, 2000).
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Severe bradycardia developed in 3 patients administered 5 to 10 mg of enalapril therapeutically (Cleland et al, 1985).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Bronchospasm has been reported with the therapeutic use of captopril (Semple & Herd, 1986; Popa, 1987).
    B) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough associated with ACE inhibitor therapy is well-documented. Although the exact mechanism is unknown, increased sensitivity of the cough reflex may be due to accumulation or persistence of inflammatory mediators such as bradykinins, substance P, or prostaglandins within the airway. Cough occurs with a variable incidence ranging up to 39%.
    b) Women are affected 3:1 compared with men. Drug discontinuation and substitution of an alternative antihypertensive agent is the only reliable effective approach to treatment if the condition is found not to be self-limiting or tolerable (Israili & Hall, 1992; Fuller & Choudry, 1987; Just, 1989).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) LOSS OF TASTE
    1) WITH THERAPEUTIC USE
    a) Taste loss (ageusia) has been reported with therapeutic treatment (Isles et al, 1983).
    B) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) Pancreatitis has only been reported with chronic therapeutic use of lisinopril and enalapril (Maringhini et al, 1997; Gershon & Olshaker, 1998).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Hepatotoxicity has been associated with captopril therapy (Vandenburg et al, 1981; Deira et al, 1997).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) KIDNEY DISEASE
    1) Nephrotic syndrome might be expected in overdose, but has never yet been reported. It has been seen when ACE inhibitors have been used in higher dose therapy in patients with impaired renal function (Isles et al, 1983). Reversible renal failure during therapy has also been reported (Colavita et al, 1983).
    B) ALBUMINURIA
    1) Proteinuria has been reported (1% to 22%) with therapeutic treatment, but it is unknown if it would occur in overdose (Isles et al, 1983).
    C) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 51-year-old man presented to the emergency department with lethargy and incoherent speech after ingesting 27 10-mg lisinopril tablets (3.18 mg/kg) over the course of 3 or fewer days. Initial vital sign measurements indicated that he was not hypotensive. Laboratory data, obtained at admission, revealed hyperkalemia (serum potassium 8.51 mEq/L) and acute renal insufficiency (serum creatinine 17.68 mg/dL [historically, 0.97 mg/dL]). Following administration of IV calcium gluconate, IV sodium bicarbonate, sodium polystyrene sulfonate, insulin/dextrose, and daily hemodialysis for 3 days, the patient's condition improved, with improvement of kidney function and resolution of his hyperkalemia (Belay & Nusair, 2013).
    2) Acute renal insufficiency developed in a patient with dilated cardiomyopathy (ejection fraction 23%) who developed profound hypotension after inadvertent administration of 25 mg lisinopril. Renal function returned nearly to baseline after 8 days (Trilli & Johnson, 1994).
    3) Renal failure may develop after therapeutic use in patients in whom renal perfusion is dependent on angiotensin II. This includes patients with renal artery stenosis, volume depletion and severe congestive heart failure (CHF) (Shohaib & Raweily, 2000; Mignat & Unger, 1995).
    4) CASE REPORT: A 28-year-old man developed coma, hypotension, bradycardia and rhabdomyolysis complicated by acute renal failure after ingesting 4 tablets containing verapamil 180 milligrams and trandolapril 2 mg each (Gokel et al, 2000).
    5) CASE REPORT: A 24-year-old man presented with acute renal failure, consisting of bilateral flank pain and decreased urine output, two days after intentionally ingesting 150 to 200 mg of quinapril. Renal ultrasonography showed bilateral diffuse increased echotexture, and serum BUN and creatinine levels peaked at 74 mg/dL and 8.3 mg/dL, respectively. The patient recovered without hemodialysis (Suchard & Bearie, 2001).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia is a side effect (0.3%) of chronic captopril therapy (Colavita et al, 1983). A portion of those patients who develop neutropenia progress to agranulocytosis (Prod Info captopril oral tablets, 2003).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 7-year-old girl with focal segmental glomerulosclerosis and nephrotic syndrome developed anemia (hemoglobin fall from 12.7 g/dL to 6.2 g/dL) 3 months after beginning enalapril therapy. Hemoglobin increased again after enalapril was discontinued (Sackey, 1998).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Various types of dermatitis have been reported with therapeutic use of ACE inhibitors. Types of rashes have included pemphigus, exfoliative dermatitis, and lichenoid eruptions (Richardson, 1985; Roten et al, 1995). Based upon limited data, the incidence of rash with captopril appears to be 4 times that of enalapril. The overall incidence of rash ranges from 6.1% to 10.9%, and is dose-dependent (Richardson, 1985).
    B) CUTANEOUS ERUPTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A lupus erythematosus-like eruption was reported in a 53-year-old taking captopril 50 mg twice daily. The eruption subsided 48 hours after discontinuation and reoccurred when a further dose was given. The eruptions were associated with sun-exposed areas (Patri et al, 1985).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 28-year-old man developed coma, hypotension, bradycardia and rhabdomyolysis complicated by acute renal failure after ingesting 4 tablets containing verapamil 180 mg and trandolapril 2 mg each (Gokel et al, 2000).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANGIOEDEMA
    1) WITH THERAPEUTIC USE
    a) Angioedema has been well described in patients taking therapeutic doses of ACE inhibitors, and may develop after months or years of uneventful therapy with these agents. It most often involves swelling of the neck, face, and tongue and may cause difficulty speaking and swallowing. In severe cases, dyspnea, chest pain, and airway compromise may develop (O'Donnell, 1998).
    b) INCIDENCE: estimated at 0.1% to 0.7% of patients taking these agents (Sabroe & Black, 1997), and may be more prevalent in patients of African origin (Gibbs et al, 1999).

Reproductive

    3.20.1) SUMMARY
    A) Fetal and neonatal morbidity and death have occurred from the use of ACE inhibitors during any trimester of pregnancy with reports of spontaneous abortion, oligohydramnios, and newborn renal dysfunction. The occurrence of oligohydramnios is possibly due to decreased fetal renal function. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported; although, causality to drug therapy has not been established. In general, ACE inhibitors demonstrated little or no teratogenicity in animal studies.
    B) BENAZEPRIL, BENAZEPRIL/HYDROCHLOROTHIAZIDE, CAPTOPRIL, and PERINDOPRIL are classified as FDA pregnancy category D.
    C) CAPTOPRIL/HYDROCHLOROTHIAZIDE, ENALAPRIL, ENALAPRILAT, ENALAPRIL/HYDROCHLOROTHIAZIDE, FOSINOPRIL, FOSINOPRIL/HYDROCHLOROTHIAZIDE, LISINOPRIL/HYDROCHLOROTHIAZIDE, MOEXIPRIL, MOEXIPRIL/HYDROCHLOROTHIAZIDE, QUINAPRIL, QUINAPRIL/HYDROCHLOROTHIAZIDE, RAMIPRIL, and TRANDOLAPRIL are classified as FDA pregnancy category C (first trimester) and D (second and third trimesters).
    D) Most ACE INHIBITORS are excreted in human milk in very small amounts. Overall, ACE INHIBITORS demonstrated no impairment to fertility in animal studies.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) In a study of infants exposed to ACE inhibitors during the first trimester alone, the risk of major congenital malformations was increased by a factor of more than 2 (risk ratio 2.71; 95% CI 1.72 to 4.27), compared with those with no fetal exposure to antihypertensives. Eighteen of 209 infants exposed during the first trimester alone were born with malformations; multiple malformations were observed in 7 infants. Malformations included atrial septal defects, ventricular septal defects, patient ductus arteriosus, pulmonic stenosis, spina bifida, microcephaly, renal dysplasia, hypospadias, intestinal atresia, choanal atresia, Hirschsprung's disease, diaphragmatic hernia, and coloboma (Cooper et al, 2006).
    B) LISINOPRIL
    1) A 33-week gestational age boy was delivered by Cesarean section to a hypertensive mother who had been maintained on lisinopril 10 mg daily. At birth, the infant required respiratory support (Apgar scores 4 and 7), was anuric in acute renal failure, and had a markedly hypoplastic skull, consistent with in utero ACE inhibitor exposure. Peritoneal dialysis was successfully initiated on day 10 of life. Initial serum lisinopril levels were 7 nanograms/mL (estimated as 20% of steady state maternal values). Baseline (day 12) ACE activity was suppressed to 7.9 nanomoles/mL/minute. Dialysate concentrations were 3.3 nanograms/mL on day 16, falling rapidly to 0.6 ng/mL by day 21. Serum lisinopril levels were 0.7 nanograms/mL by day 38. First urine output was seen on day 12 (0.23 mL/kg/hour), eventually increasing to between 1.3 and 2.6 mL/kg/hour by day 45. However, renal transplant was required at age 22 months (Bhatt-Mehta & Deluga, 1993).
    C) LACK OF EFFECT
    1) RAMIPRIL: Gliclazide and ramipril use during the first 16 weeks of gestation did not lead to maternal or fetal complications in a pregnant female patient with type 2 diabetes and hypertension. A 42-year-old woman was admitted to an endocrinology unit during week 16 of gestation. One month prior to her last menstrual period, her fasting blood glucose level was 88 mg/dL and hemoglobin A1C level was 5.1%. History included treatment with gliclazide 30 mg/day and ramipril 10 mg/day for 2 years prior to admission. Gliclazide and ramipril were stopped and intensive insulin therapy (4 units of regular insulin 3 times per day and 6 units of NPH insulin once a day) was started during week 17 in an outpatient clinic. Insulin requirements decreased to NPH insulin twice daily after 2 weeks of therapy. Capillary blood fasting glucose, 1-hour postprandial glucose, 2-hour postprandial glucose, fructosamine, and hemoglobin A1C were all within normal limits during a follow-up examination. Methyldopa 500 mg 4 times per day was started to control the patient’s high blood pressure. The patient gave birth to a 3200-g female infant by caesarean section in week 36, and no abnormalities were observed. The infant’s blood glucose, C-peptide, and insulin levels were all within normal limits; abdominal ultrasonography and echocardiography were normal. The child continued to be considered healthy after normal results of physical examination, blood glucose, C-peptide, and insulin levels, and abdominal ultrasonography and echocardiography were observed at 1.5 years of age (Kolagasi et al, 2009).
    2) CAPTOPRIL: A retrospective review of 10 pregnant women treated with low-dose captopril 12.5 to 25 mg/day described improvement in maternal hemodynamics and lack of fetal and neonatal complications. The pregnancies were complicated by severe vasoconstricted hypertension not responsive to aggressive vasodilator therapy and renal insufficiency. Oligohydramnios was not observed in these patients, and none of the infants was born with hypotension, anuria, or pulmonary hypoplasia. Eight of the 9 mothers with thriving infants and none described renal complications in their infants at 6 to 12 months after being released from the hospital (Easterling et al, 2000).
    3) LISINOPRIL: In utero exposure to lisinopril during the first 18 weeks of gestation and again between week 22 and delivery at week 26 plus 6 days was not associated with congenital malformation. The postnatal course, however, was complicated by both necrotizing enterocolitis and persistent oliguria/anuria requiring hospitalization for 102 days. Lisinopril had been taken for chronic hypertension but was spontaneously discontinued by the 39-year-old, gravida 11, mother 2 weeks before presenting, resulting in an initial blood pressure of 200/120 mmHg and 1 g/liter proteinuria. Attempts at blood pressure control with labetalol, methyldopa, and nifedipine were unsuccessful over the next week. Lisinopril was restarted after rejecting options to terminate the pregnancy, and blood pressure stabilized over the next 2 weeks. Between gestation week 18 and 24, amniotic fluid index declined from normal, to 8 and at week 22, to zero. Continuing maternal and fetal deterioration resulted in caesarean-section delivery of a 680 g girl. Abdominal distention from day 1 was confirmed as necrotizing enterocolitis on day 5 requiring jejunostomy until day 52. Urine output remained less than 0.3 mL/kg/hour for the first 6 days, with serum creatinine peaks of 463 mmol/L, declining to 65 mmol/L on day 15. Dialysis was not required (Tomlinson et al, 2000).
    D) ANIMAL STUDIES
    1) CAPTOPRIL: In animal studies, craniofacial malformations were observed at captopril doses about 0.8 to 70 times the maximum recommended human dose on a mg/kg basis in pregnant rabbits (Prod Info CAPOTEN(R) oral tablets, 2011; Prod Info CAPOZIDE(R) oral tablets, 2008).
    2) FOSINOPRIL: In animal studies, orofacial malformations (n=3) and situs inversus (n=1) were observed at fosinopril doses about 80 to 250 times the maximum recommended human dose on a mg/m(2) basis in pregnant rats (Prod Info MONOPRIL(R)-HCT 10/12.5, MONOPRIL(R)-HCT 20/12.5 oral tablets, 2008; Prod Info MONOPRIL(R) tablets, 2003).
    3) LACK OF EFFECT
    a) BENAZEPRIL: In animal studies, teratogenicity was not evident at benazepril doses approximately 60 times, 9 times, and 0.8 times the maximum recommended human dose (MRHD) on a mg/m(2) basis in pregnant rats, mice, and rabbits, respectively (Prod Info LOTENSIN(R) oral tablets, 2006).
    b) BENAZEPRIL/HYDROCHLOROTHIAZIDE: In animal studies, teratogenicity was not evident at benazepril/hydrochlorothiazide doses representing approximately 167 times the maximum recommended human dose on a mg/m(2) basis in pregnant rats and at doses of up to 160 mg/kg/day in pregnant mice (Prod Info LOTENSIN(R) oral tablets, 2006).
    c) CAPTOPRIL: In animal studies, no teratogenic effects were reported following captopril doses up to 150 times and 625 times the maximum recommended human dose in hamsters and rats, respectively (Prod Info CAPOTEN(R) oral tablets, 2011; Prod Info CAPOZIDE(R) oral tablets, 2008).
    d) ENALAPRIL and ENALAPRILAT: In animal studies, teratogenicity was not evident at enalapril doses 57 times and 12 times the maximum recommended human dose in pregnant rats and rabbits, respectively(Prod Info VASOTEC(R) oral tablets, 2007).
    e) ENALAPRIL/HYDROCHLOROTHIAZIDE: In animal studies, teratogenicity was not evident at enalapril and hydrochlorothiazide doses that represented 4.3 times and 0.8 times the maximum recommended human dose, respectively, in pregnant mice or at doses that represented 26 and 1.6 times the MRHD, respectively, in pregnant rats (Prod Info VASERETIC(R) oral tablets, 2007).
    f) FOSINOPRIL: In animal studies, teratogenicity was not evident at fosinopril doses up to 25 times the maximum recommended human dose in rabbits (Prod Info MONOPRIL(R)-HCT 10/12.5, MONOPRIL(R)-HCT 20/12.5 oral tablets, 2008; Prod Info MONOPRIL(R) tablets, 2003).
    g) LISINOPRIL: In animal studies, teratogenicity was not evident at lisinopril doses 55 times, 33 times, and 0.15 times the maximum recommended human dose, respectively, in pregnant mice, rats, and rabbits, respectively (Prod Info PRINIVIL(R) oral tablets, 2006).
    h) MOEXIPRIL: In animal studies, teratogenicity was not evident at moexipril doses that represented approximately 90.9 times and 0.7 times the maximum recommended human dose in pregnant rats and rabbits, respectively (Prod Info UNIVASC(R) oral tablets, 2003).
    i) PERINDOPRIL: In animal studies, teratogenicity was not evident at perindopril doses approximately 6 times, 670 times, 50 times, and 17 times the maximum recommended human dose on a mg/m(2) basis in pregnant mice, rats, rabbits, and monkeys, respectively (Prod Info ACEON(R) oral tablets, 2008).
    j) QUINAPRIL: In animal studies, teratogenicity was not evident at quinapril doses 180 times and 1 time the maximum recommended human dose in pregnant rats and rabbits, respectively (Prod Info ACCUPRIL(R) oral tablets, 2003).
    k) QUINAPRIL/HYDROCHLOROTHIAZIDE: In animal studies, teratogenicity was not evident at quinapril/hydrochlorothiazide doses up to 188/94 times and 0.6/0.3 times, respectively the maximum recommended human dose in pregnant rats and rabbits, respectively (Prod Info ACCURETIC(TM) oral tablets, 2003).
    l) RAMIPRIL: In animal studies, teratogenicity was not evident at ramipril doses approximately 400 times (pregnant rats and monkeys) and 2 times (rabbits) the maximum recommended human dose on a body surface area basis (Prod Info ALTACE(R) oral tablets, 2011).
    m) TRANDOLAPRIL: In animal studies, teratogenicity was not evident at trandolapril doses approximately 10 and 3 times in rabbits, 1250 and 2564 times in rats, and 312 and 108 times in cynomolgus monkeys the maximum recommended human dose on a mg/m(2) basis (Prod Info MAVIK(R) oral tablets, 2003).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The following ACE inhibitors have been classified as FDA category C (first trimester) and FDA category D (second and third trimesters):
    1) CAPTOPRIL/HYDROCHLOROTHIAZIDE (Prod Info CAPOZIDE(R) oral tablets, 2008)
    2) ENALAPRIL and ENALAPRILAT (Prod Info VASOTEC(R) oral tablets, 2007)
    3) ENALAPRIL/HYDROCHLOROTHIAZIDE (Prod Info VASERETIC(R) oral tablets, 2007)
    4) FOSINOPRIL (Prod Info MONOPRIL(R) tablets, 2003)
    5) FOSINOPRIL/HYDROCHLOROTHIAZIDE (Prod Info MONOPRIL(R)-HCT 10/12.5, MONOPRIL(R)-HCT 20/12.5 oral tablets, 2008)
    6) LISINOPRIL/HYDROCHLOROTHIAZIDE (Prod Info PRINZIDE(R) oral tablets, 2008)
    7) MOEXIPRIL (Prod Info UNIVASC(R) oral tablets, 2003)
    8) MOEXIPRIL/HYDROCHLOROTHIAZIDE (Prod Info UNIRETIC(R) oral tablets, 2003)
    9) QUINAPRIL (Prod Info ACCUPRIL(R) oral tablets, 2003)
    10) QUINAPRIL/HYDROCHLOROTHIAZIDE (Prod Info ACCURETIC(TM) oral tablets, 2003)
    11) RAMIPRIL (Prod Info ALTACE(R) oral tablets, 2011)
    12) TRANDOLAPRIL (Prod Info MAVIK(R) oral tablets, 2003)
    2) The following ACE INHIBITORS have been classified as FDA category D:
    1) BENAZEPRIL (Prod Info LOTENSIN(R) oral tablets, 2006).
    2) BENAZEPRIL/HYDROCHLOROTHIAZIDE (Prod Info LOTENSIN HCT(R) oral tablets, 2007)
    3) CAPTOPRIL (Prod Info CAPOTEN(R) oral tablets, 2011).
    4) PERINDOPRIL (Prod Info ACEON(R) oral tablets, 2008).
    B) FETAL INJURY
    1) ACE INHIBITORS may cause fetal or neonatal injury or death when used during any of the 3 trimesters of pregnancy (Barr, 1994; Brent & Beckman, 1991; Mehta & Modi, 1989).
    2) ACE INHIBITORS: Hypotension, neonatal anemia, hyperkalemia, neonatal skull hypoplasia, anuria, and renal failure have occurred in fetuses and neonates. Oligohydramnios has also occurred, possibly due to decreased fetal renal function, and has been associated with limb contractures, craniofacial deformities, and hypoplastic lung development (Prod Info CAPOTEN(R) oral tablets, 2011; Prod Info CAPOZIDE(R) oral tablets, 2008; Steffensen et al, 1998; Cunniff et al, 1990; Scott & Purohit, 1989; DiBianco, 1986).
    3) The relationship between maternal ACE INHIBITOR use and intrauterine growth retardation, prematurity, and patent ductus arteriosus is unclear (Buttar, 1997).
    4) CASE REPORT: At 18 weeks gestation, a pregnant woman with chronic hypertension who had self-discontinued LISINOPRIL became acutely hypertensive. Lisinopril was restarted after rejecting options to terminate the pregnancy, and blood pressure stabilized over the next 2 weeks. The infant, delivered at 26 weeks, had initial renal failure followed by acute necrotizing enterocolitis. Renal failure improved at the same time as the necrotizing enterocolitis. On day 102, the infant was discharged with no further complications (Tomlinson et al, 2000).
    5) CASE REPORT: A 33-week gestational age infant was delivered to a hypertensive mother who had been maintained on LISINOPRIL. At birth, the infant required respiratory support, was anuric in acute renal failure, and had a markedly hypoplastic skull, consistent with in utero ACE inhibitor exposure. Peritoneal dialysis was successfully initiated. Baseline ACE activity levels were suppressed and dialysate decreased rapidly. First urine output was seen on day 12 and eventually increased. However, renal transplant was required at age 22 months (Bhatt-Mehta & Deluga, 1993).
    6) CAPTOPRIL/HYDROCHLOROTHIAZIDE: Fetal and neonatal injury and death have been reported in several dozen cases following the use of ACE inhibitors during the second and third trimesters of pregnancy. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and other adverse events with in utero exposure to thiazide diuretics, such as hydrochlorothiazide (Prod Info CAPOZIDE(R) oral tablets, 2008)
    C) ANIMAL STUDIES
    1) ENALAPRIL/HYDROCHLOROTHIAZIDE: Fetal weights were decreased at enalapril/hydrochlorothiazide doses of 4.3 times/0.8 times and 26 times/1.6 times the maximum recommended human dose (MRHD) in pregnant mice and rats, respectively. Fetotoxicity was not evident at enalapril/hydrochlorothiazide doses up to 4.3 times/0.8 times and up to 26 times/1.6 times the MRHD in pregnant mice and rats, respectively (Prod Info VASERETIC(R) oral tablets, 2007).
    2) LISINOPRIL/HYDROCHLOROTHIAZIDE: In animal studies, maternal and fetal toxicity were not evident at lisinopril/hydrochlorothiazide doses that represented 5 times/0.9 times the maximum recommended human dose (MRHD) in pregnant mice. However, lisinopril/hydrochlorothiazide doses that represented approximately 10 times/1.8 times the MRHD in pregnant rats demonstrated decreased maternal and fetal weight gain associated with a delay in fetal ossification down to a daily dose of 3 and 10 mg/kg, respectively. Fetotoxicity was not evident in saline-supplemented rats at the MRHD of lisinopril/hydrochlorothiazide (Prod Info PRINZIDE(R) oral tablets, 2008).
    3) MOEXIPRIL: In animal studies, embryotoxicity and fetotoxicity were not evident at moexipril doses that represented approximately 90.9 times and 0.7 times the MRHD in pregnant rats and rabbits, respectively (Prod Info UNIVASC(R) oral tablets, 2003).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Overall, ACE inhibitors were shown to be excreted in human milk in very small amounts. When administered as a single dose, RAMIPRIL was undetectable in human breast milk. QUINAPRIL was detectable in human breast milk only within the first 4 hours following a single oral dose. It is not known whether LISINOPRIL, MOEXIPRIL, PERINDOPRIL, or TRANDOLAPRIL are excreted in human milk; however, radioactivity was observed in lactating rats following the administration of radioactive LISINOPRIL, PERINDOPRIL, and TRANDOLAPRIL.
    2) BENAZEPRIL: Benazepril and benazeprilat are excreted in human milk. A nursing infant would receive less than 0.1% of the mg/kg maternal dose (Prod Info LOTENSIN(R) oral tablets, 2006).
    3) BENAZEPRIL/HYDROCHLOROTHIAZIDE: Benazepril, benazeprilat, and hydrochlorothiazide are excreted in human milk. A nursing infant would receive less than 0.1% of the mg/kg maternal dose of benazepril (Prod Info LOTENSIN HCT(R) oral tablets, 2007).
    4) CAPTOPRIL: Captopril is excreted in human milk. Concentrations of captopril in human breast milk are approximately 1% of maternal blood levels (Prod Info CAPOTEN(R) oral tablets, 2011; Devlin & Fleiss, 1980).
    5) CAPTOPRIL/HYDROCHLOROTHIAZIDE: Both captopril and hydrochlorothiazide are excreted in human milk (Prod Info CAPOZIDE(R) oral tablets, 2008).
    6) ENALAPRIL and ENALAPRILAT: Enalapril and enalaprilat are excreted in human milk. The milk:serum ratio of enalapril and enalaprilat (the active metabolite) in 5 lactating mothers was minimal. The maximum milk concentrations of enalapril and enalaprilat were 5.9 nanograms/mL and 2.3 nanograms/mL, respectively. Assuming infant ingestion of 150 mL milk/kg/day (the population average), absolute infant exposure would be 885 nanograms/kg/day for enalapril and 345 nanograms/kg/day for enalaprilat, or only 0.27% of the weight-adjusted maternal dose of enalapril. Data are from a single dose study; milk concentrations may be higher at steady state (Redman et al, 1990).
    7) ENALAPRIL/HYDROCHLOROTHIAZIDE: Enalapril, enalaprilat, and hydrochlorothiazide are excreted in human milk (Prod Info VASERETIC(R) oral tablets, 2007).
    8) FOSINOPRIL: Fosinopril is excreted in human milk. Detectable levels of fosinoprilat were observed in human breast milk following maternal ingestion of fosinopril 20 mg daily for three days (Prod Info MONOPRIL(R) tablets, 2003).
    9) LISINOPRIL: lt is not known whether lisinopril is excreted in human milk (Prod Info PRINIVIL(R) oral tablets, 2006).
    10) LISINOPRIL/HYDROCHLOROTHIAZIDE: It is not known whether lisinopril is excreted in human milk, but thiazides are known to appear in human milk (Prod Info PRINZIDE(R) oral tablets, 2008).
    11) MOEXIPRIL: It is not known whether moexipril is excreted in human milk (Prod Info UNIVASC(R) oral tablets, 2003).
    12) MOEXIPRIL/HYDROCHLOROTHIAZIDE: It is not known whether moexipril is excreted into human milk, but thiazides are known to appear in human milk (Prod Info UNIRETIC(R) oral tablets, 2003).
    13) PERINDOPRIL: lt is not known whether perindopril is excreted in human milk (Prod Info ACEON(R) oral tablets, 2008).
    14) QUINAPRIL: Quinapril was detectable in human breast milk only within the first 4 hours following a single 20-mg oral dose; quinaprilat was not detected in milk at any time up to 24 hours after dosing. Quinapril exposure to a breastfeeding infant was estimated to be not more than 1.6% of the maternal dose. Six healthy women who had been breastfeeding from 16 weeks to 9 months volunteered for this study. Following the single dose, plasma concentrations were systematically drawn for 24 hours, and breast milk was expressed and analyzed in 4-hour increments. The milk/plasma AUC was 0.12 for quinapril, and less than 0.03 for quinaprilat, assuming quinaprilat concentrations equal to the lower limit of detection (5 nanograms/L) (Begg et al, 2001).
    15) RAMIPRIL: Ramipril is excreted in human milk. Following maternal ingestion of a single ramipril 10 mg dose, there were undetectable levels of ramipril and its metabolites in the breast milk. However, multiple doses may produce low milk concentrations that cannot be predicted from single doses (Prod Info ALTACE(R) oral tablets, 2011).
    16) TRANDOLAPRIL: lt is not known whether trandolapril or its metabolites are excreted in human milk (Prod Info MAVIK(R) oral tablets, 2003).
    B) ANIMAL STUDIES
    1) LISINOPRIL: In animal studies, milk of lactating rats contained radioactivity following administration of radioactive lisinopril (Prod Info PRINIVIL(R) oral tablets, 2006).
    2) PERINDOPRIL: In animal studies, milk of lactating rats contained radioactivity following administration of radioactive perindopril (Prod Info ACEON(R) oral tablets, 2005).
    3) TRANDOLAPRIL: In animal studies, milk of lactating rats contained radioactivity following administration of radioactive trandolapril (Prod Info MAVIK(R) oral tablets, 2003).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Overall, ACE inhibitors demonstrated no adverse reproductive effects when studied in animals. However, at the time of this review, no data were available to assess the potential effects on human fertility from exposure to ACE inhibitor agents.
    2) BENAZEPRIL: Reproductive adverse effects were not evident at benazepril doses that represented 6 to 60 times the maximum recommended human dose (MRHD) based on body surface area in male and female rats (Prod Info LOTENSIN(R) oral tablets, 2006).
    3) CAPTOPRIL: In rat studies, no impairment of fertility was observed (Prod Info CAPOTEN(R) oral tablets, 2011).
    4) CAPTOPRIL/HYDROCHLOROTHIAZIDE: In rat studies with captopril, no fertility impairments were observed. Mice and rat fertility was not affected when given hydrochlorothiazide doses up to 100 and 4 mg/kg, respectively, before conception and throughout gestation (Prod Info CAPOZIDE(R) oral tablets, 2008).
    5) ENALAPRIL and ENALAPRILAT: Reproductive adverse effects were not evident at enalapril doses that represented 26 times the maximum recommended human dose based on body surface area in male and female rats (Prod Info VASOTEC(R) oral tablets, 2007).
    6) ENALAPRIL/HYDROCHLOROTHIAZIDE: Reproductive adverse effects were not evident at hydrochlorothiazide doses that represented 9 times and 0.7 times the maximum recommended human dose based on body surface area in either sex of mice and rats, respectively (Prod Info VASERETIC(R) oral tablets, 2007).
    7) FOSINOPRIL: Reproductive adverse effects were not evident at fosinopril doses up to 6 times the maximum recommended human dose (MRHD) based on body surface area in male and female rats. However, rats treated with a toxic daily dose of 24 times the MRHD based on body surface area demonstrated a slight increase in pairing time (Prod Info MONOPRIL(R) tablets, 2003).
    8) LISINOPRIL: No adverse effects on reproductive performance were reported in male and female rats administered lisinopril doses that were 188 times and 30 times the maximum human dose based on mg/kg and mg/m2, respectively (Prod Info Zestril(R) oral tablets, 2015).
    9) LISINOPRIL/HYDROCHLOROTHIAZIDE: Reproductive adverse effects were not evident at lisinopril doses up to 33 times the maximum recommended human dose (MRHD) or at hydrochlorothiazide doses that represented 9 times and 0.7 times the MRHD based on body surface area in either sex of mice and rats, respectively (Prod Info PRINZIDE(R) oral tablets, 2008).
    10) MOEXIPRIL: Reproductive effects were not evident at moexipril doses that represented approximately 90.9 times and 0.7 times the maximum recommended human dose (MRHD) in pregnant rats and rabbits, respectively (Prod Info UNIVASC(R) oral tablets, 2003).
    11) MOEXIPRIL/HYDROCHLOROTHIAZIDE: Reproductive effects were not evident at moexipril doses that represented approximately 90.9 times and 0.7 times the maximum recommended human dose (MRHD) in pregnant rats and rabbits, respectively, or at hydrochlorothiazide doses that represented 9 times and 0.7 times the MRHD in either sex of mice and rats (Prod Info UNIRETIC(R) oral tablets, 2003).
    12) PERINDOPRIL: Reproductive adverse effects were not evident at perindopril doses up to 30 times or up to 6 times the maximum recommended human dose based on body surface area in male rats and female rats, respectively, during period of spermatogenesis in males or oogenesis and gestation in females (Prod Info ACEON(R) oral tablets, 2008).
    13) QUINAPRIL: Fertility or reproductive adverse effects were not evident in rats at quinapril doses up to 100 mg/kg/day (60 and 10 times the maximum recommended human dose based on body surface area in rats, respectively) (Prod Info ACCUPRIL(R) oral tablets, 2003).
    14) RAMIPRIL: Reproductive adverse effects were not evident in rats treated with ramipril doses up to 500 mg/kg/day (Prod Info ALTACE(R) oral tablets, 2011).
    15) TRANDOLAPRIL: Reproductive adverse effects were not evident in rats at trandolapril doses up to 1250 times or up to 260 times the maximum recommended human dose based on body surface area (Prod Info MAVIK(R) oral tablets, 2003).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs frequently. Routine laboratory tests are not usually necessary.
    B) Other labs such as serum electrolytes, renal function, and ECG should be ordered, if clinically indicated.
    C) ACE inhibitor levels are not readily available and not useful in acute management.
    4.1.2) SERUM/BLOOD
    A) A BLOOD/SERUM CHEMISTRY
    1) SUMMARY: Routine laboratory tests are not usually necessary. Other labs such as serum electrolytes and renal function should be ordered, if clinically indicated.
    2) Monitor BUN and serum creatinine in both overdoses and therapeutic use (Colavita et al, 1983), particularly if significant hypotension is present or the patient has preexisting renal disease, congestive heart failure (CHF) or hypovolemia. Sodium and potassium levels should be monitored as well.
    3) ACE levels have been monitored in patients who have overdosed on these agents and have not correlated well with toxic effects.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain an ECG as clinically indicated.
    2) MONITORING
    a) Monitor vital signs, including pulse and blood pressure, for at least 24 to 36 hours post-ingestion after significant captopril overdose (Augenstein et al, 1988). Cardiac monitoring may be indicated.

Methods

    A) IMMUNOASSAY
    1) The traditional method was to subject serum and heparinized samples to tri-n-butyl-phosphine reduction followed by N-ethylmaleimide derivation. There is now a new radioimmunoassay available (Tu et al, 1984).
    B) OTHER
    1) Of note, captopril may cause a false-positive test for urine acetone (Prod Info captopril tablets, 2003).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) SUMMARY: Symptomatic or hypotensive patients should be admitted to a monitored bed.
    B) Symptomatic or hypotensive patients should be monitored for at least 24 hours after ingestion, or until symptoms have completely resolved (Lucas et al, 2006).
    6.3.1.2) HOME CRITERIA/ORAL
    A) Children aged 1 to 5 years who accidentally ingested no more than an adult daily therapeutic dose (up to 100 milligrams of captopril or 30 milligrams of enalapril) were safely managed at home, with telephone follow-up for 4 to 6 hours, in 16 cases (Spiller et al, 1989).
    B) In another study of 85 children under the age 6 years who ingested an ACE inhibitor alone, those with ingestions of less than 4 milligrams/kilogram of captopril or less than 1 milligram/kilogram enalapril or lisinopril were observed at home without gastrointestinal decontamination with telephone follow-up for 6 hours. None of the 49 children in this group developed symptoms (Hogue-Murray et al, 1995).
    1) Those with ingestions of 4 to 8 milligrams/kilogram of captopril or 1 to 2 milligram/kilogram enalapril or lisinopril were observed in a health care facility without gastrointestinal decontamination. None of the 27 children in this group developed adverse effects.
    2) Those with ingestions of more than 8 milligrams/kilogram of captopril or more than 2 milligram/kilogram enalapril or lisinopril were observed in a health care facility and received gastrointestinal decontamination. Of the 9 children in this group, one developed effects.
    C) Based on the results of a retrospective poison center review involving unintentional pediatric ingestions of ACE inhibitors, patients can be observed at home if they have ingested less than 2 times the defined daily dose (DDD) of an ACE inhibitor and they remain asymptomatic. The DDD of specific ACE inhibitors are as follows (Balit et al, 2007):
    1) Captopril: 50 mg
    2) Enalapril: 10 mg
    3) Fosinopril: 15 mg
    4) Lisinopril: 10 mg
    5) Perindopril: 4 mg
    6) Ramipril: 2.5 mg
    7) Trandolapril: 2 mg
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) SUMMARY: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity, or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) PEDIATRIC PATIENTS: Based on the results of a retrospective poison center review involving unintentional pediatric ingestions of ACE inhibitors, patients should be referred to a healthcare facility if they are symptomatic, or if they have ingested at least 2 times the defined daily dose (DDD) of an ACE inhibitor. The DDD of specific ACE inhibitors are as follows (Balit et al, 2007):
    1) Captopril: 50 mg
    2) Enalapril: 10 mg
    3) Fosinopril: 15 mg
    4) Lisinopril: 10 mg
    5) Perindopril: 4 mg
    6) Ramipril: 2.5 mg
    7) Trandolapril: 2 mg
    B) ADULT PATIENTS: According to a retrospective study involving adult lisinopril ingestions reported to Texas Poison Control Centers from 1998 to 2005 (Forrester, 2007), the patient should be referred to a health care facility if:
    1) the overdose ingestion is intentional
    2) the patient is symptomatic at the time of the first call
    3) the patient has significant underlying cardiovascular disease, or if the patient is also taking a beta-blocker or other cardiodepressant agent
    4) the maximum amount of lisinopril ingested is either greater than 80 mg or at least 3 tablets (if dose is unknown), or
    5) unable to estimate the maximum amount ingested
    C) Observe patients with careful blood pressure monitoring for a minimum of 6 hours after overdose (Lucas et al, 2006).
    D) Symptomatic or hypotensive patients should be observed for at least 24 hours after ingestion or until symptoms have completely resolved (Lucas et al, 2006).
    E) Patient who have been asymptomatic for 6 hours from the time of ingestion can be considered for discharge (Lucas et al, 2006).

Monitoring

    A) Monitor vital signs frequently. Routine laboratory tests are not usually necessary.
    B) Other labs such as serum electrolytes, renal function, and ECG should be ordered, if clinically indicated.
    C) ACE inhibitor levels are not readily available and not useful in acute management.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Most patients will have no symptoms, but patients with mild orthostatic hypotension can be treated by remaining prone. Those who remain hypotensive can be treated with IV fluids. For severe toxicity, adequate circulatory support with IV fluids and vasopressors (if needed) should be assured if the patient presents with circulatory collapse. Correct severe hyperkalemia using standard treatments such as glucose, insulin, calcium, sodium bicarbonate, sodium polystyrene sulfate and hemodialysis.
    B) AIRWAY MANAGEMENT
    1) Early endotracheal intubation should be considered in patients with ACE inhibitor induced angioedema. Orotracheal intubation may be technically difficult in patients with severe tongue swelling; be prepared to obtain a surgical airway.
    C) MONITORING OF PATIENT
    1) Monitor vital signs frequently, including pulse and blood pressure, for at least 24 to 36 hours post-ingestion after a significant ACEI overdose (Augenstein et al, 1988; Lucas et al, 2006). Cardiac monitoring may be indicated.
    2) Routine laboratory tests are not usually necessary. ACE inhibitor levels are not readily available and not useful in acute management. Other labs such as serum electrolytes, renal function, and ECG should be ordered if clinically indicated.
    D) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) Hypotension may respond to naloxone.
    3) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    4) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    5) ANGIOTENSIN AMIDE
    a) Angiotensin infusion at doses ranging from 8.5 to 18 mcg/minute has been successful in reversing hypotension in patients who did not respond to volume and pressor infusions.
    1) CASE REPORT: A case report described a 45-year-old man with idiopathic dilated cardiomyopathy (ejection fraction 23%) who was inadvertently given 25 mg lisinopril instead of 2.5 mg. Therapy with intravenous dobutamine (20 mcg/kg/min), dopamine (20 mcg/kg/min), and norepinephrine (14.5 mcg/kg/min) was ineffective in correcting hypotension (Trilli & Johnson, 1994).
    a) An infusion of angiotensin amide was started at 8.5 mcg/minute and titrated up to 9 mcg/minute, and norepinephrine and dopamine were weaned and stopped. The blood pressure rose immediately and stabilized over the next several hours. Angiotensin amide was next weaned and stopped. The patient recovered uneventfully from this hypotensive episode over an 8-day period.
    2) CASE REPORT: A 44-year-old man developed hypotension and junctional bradycardia after ingesting enalapril (30 x 10 mg), verapamil (30 x 240 mg sustained release), and temazepam (10 x 10 mg). Intravenous fluids, calcium, ephedrine, atropine, dopamine (3 mcg/kg/min) and epinephrine (0.02 mcg/kg/min) did not improve his pulse or blood pressure and oliguria developed. Blood pressure improved and sinus rhythm and urine output improved after infusion of angiotensin titrated to 18 micrograms/hour (Jackson et al, 1993).
    6) NALOXONE
    a) SUMMARY: Administration of naloxone has been reported to antagonize the hypotensive effect of captopril in animals and humans. There is a single case report stating naloxone was ineffective in a hypotensive, 22-year-old man, with a history of intravenous drug abuse. Additional clinical evidence is needed to evaluate the efficacy of naloxone for treatment of hypotension secondary to ACE inhibitor overdose.
    b) In adult volunteers, pretreatment with naloxone prevented captopril-induced decreases in systolic blood pressure (Ajayi et al, 1985). Additional evidence supporting naloxone's ability to antagonize the hypotensive effects of captopril exist in both animal models (Geh et al, 1986; Montastruc et al, 1984) and humans (Millar et al, 1983).
    c) A 31-year-old woman developed hypotension (systolic blood pressure, 70 mmHg) associated with a witnessed ingestion of 500 milligrams of captopril, which promptly reversed following administration of 1.6 milligrams of intravenous naloxone. The patient became hypotensive again at 10 minutes following naloxone administration, which responded to 2 milligrams of intravenous naloxone (Varon & Duncan, 1991).
    1) Initial episode of hypotension was unresponsive to rapid intravenous administration of 1000 milliliters of normal saline. Massive volume resuscitation was relatively contraindicated in this patient because of the presence of renal insufficiency.
    2) No opioids, narcotics, or other drugs were detected by toxicologic assay (gas chromatography, thin-layer chromatography) of serum obtained at admission.
    d) Administration of an intravenous bolus dose of 10 milligrams of naloxone and infusion of 0.04 milligrams of naloxone per minute for one hour did not alter the level of consciousness or hypotension associated with an ingestion of 750 milligrams of captopril in a 22-year-old man, with a past history of intravenous drug abuse (Barr et al, 1991). Clinical evidence for alcohol ingestion, opioid overdose, or recent intravenous injection were lacking. The authors did not report the results of any quantitative or qualitative serum or urine toxicologic analyses.

Enhanced Elimination

    A) SUMMARY
    1) ACE inhibitors are dialyzable, but hemodialysis is not used because supportive care is usually effective.
    B) HEMODIALYSIS
    1) Hemodialysis is expected to effectively remove captopril, but has not been necessary in overdoses to date (Prod Info captopril tablets, 2003a; Hirakata et al, 1981). In one study of chronic hemodialysis patients, a 4-hour run of hemodialysis removed 35 percent of a dose of captopril (Duchin et al, 1984).
    2) Hemodialysis clearance of perindopril and its active metabolite perindoprilat is 52 mL/min and 67 mL/min, respectively (Prod Info Aceon(R) Package Insert, 1999).
    3) CASE REPORT/LISINOPRIL: A 51-year-old man presented to the emergency department with lethargy and incoherent speech after ingesting 27 10-mg lisinopril tablets (3.18 mg/kg) over the course of 3 or fewer days. Initial vital sign measurements indicated that he was not hypotensive. Laboratory data, obtained at admission, revealed hyperkalemia (serum potassium 8.51 mEq/L) and acute renal insufficiency (serum creatinine 17.68 mg/dL [historically, 0.97 mg/dL]). Following administration of IV calcium gluconate, IV sodium bicarbonate, sodium polystyrene sulfonate, insulin/dextrose, and daily hemodialysis for 3 days, the patient's condition improved, with improvement of kidney function and resolution of his hyperkalemia (Belay & Nusair, 2013).

Abstracts

Case Reports

    A) SPECIFIC AGENT
    1) ENALAPRIL: A 46-year-old woman with severe essential hypertension and a history of right-sided cerebrovascular accident (CVA) ingested enalapril 300 mg and oxazepam 225 mg. Four hours post-ingestion, the patient was stuporous but not in respiratory distress. A hypotensive episode was observed which was easily controlled with intravenous fluids (normal saline and plasma). Occasional premature ventricular contractions were recorded; however, pulse rate demonstrated no tendency to increase. Serum enalaprilat concentration was 1450 mcg/L at 10 hours post-ingestion. Corresponding enalapril serum levels were 50 mcg/L. Blood pressure remained normal and the patient was discharged after 3 weeks of uneventful observation. These data suggest that enalapril does not produce significant cardiovascular toxicity following overdose (Waeber et al, 1984a).
    2) ENALAPRIL: An overdose with enalapril (440 mg plus 42 mg warfarin) produced severe hypotension (50/30 mmHg) and stupor in a 56-year-old woman who had been receiving therapeutic enalapril for congestive heart failure. Normal saline and plasma infusions were required to maintain blood pressure. During the first 2 days following overdose, 6.8 liters of crystalloid were administered to maintain blood pressure. Renal function deteriorated with acidosis, hyperkalemia, hyperphosphatemia, hyponatremia, and hypochloremia occurring. The patient eventually recovered, but died secondary to intractable heart failure at 40 days. Enalapril serum concentration at 40 hours post-ingestion was 2850 nanograms/mL, more than 200 times the concentration required to block the activity of angiotensin-converting enzyme. Intravenous infusion of normal saline is suggested as the treatment of choice for enalapril overdose to maintain blood pressure (Lau, 1986).
    3) CAPTOPRIL: A 33-year-old woman who ingested 750 mg of captopril and 10 mg of alprazolam presented with lethargy and profound hypotension (systolic blood pressure, 80 mmHg) about 5 hours post-ingestion, which responded to IV fluids and dopamine. Hypotension recurred at about 18 and 24 hours post-ingestion and responded to fluid challenges or increased rate of dopamine infusion. Plasma captopril levels were 5952 nanograms/mL six hours post-ingestion. The apparent elimination half-life was 34 hours (Augenstein et al, 1988).
    4) CAPTOPRIL: A case report described a 36-year-old woman who overdosed on 5 g of captopril. The only sign or symptom noted was mild orthostatic hypotension 2 days post-ingestion. Another patient who ingested 1500 mg remained asymptomatic (Turhan et al, 1985).
    5) LISINOPRIL: A 57-year-old man ingested approximately 420 mg of lisinopril and 225 mg of amitriptyline following an argument with his wife. He presented 1.5 hours post-ingestion, drowsy and confused, but responding to commands. Blood pressure was 95/60 mmHg, with a heart rate of 100 beats/minute. ECG demonstrated atrial ectopic beats and a QRS interval of 110 milliseconds. Gastric lavage produced no tablet fragments. Activated charcoal (50 g in sorbitol) was administered down the tube. Intravenous saline was started. His mental status and blood pressure improved within 3 hours after ingestion. He subsequently recovered fully and was discharged on the evening of the second hospital day (Dawson et al, 1990).

Range Of Toxicity

Summary

    A) TOXICITY: ADULTS: Patients have ingested the following with only mild hypotension reported: 7.5 g captopril, 300 mg enalapril, and 420 mg lisinopril. Moderate hypotension (median BP 75/36) was observed in 10 adults after ingesting a median ramipril dose of 210 mg (range: 100 to 280); 4 had coingested other cardiovascular agents and 2 coingested alcohol; all cases recovered. Fatalities have occurred after ingestions of 1125 mg captopril and 180 mg perindopril. CHILDREN: In one study, children remained asymptomatic after ingestions of up to 100 mg captopril or 30 mg enalapril.
    B) THERAPEUTIC DOSE: Varies with agent. CAPTOPRIL: ADULT: 37.5 to 150 mg/day in 3 divided doses. PEDIATRIC: 0.5 to 4 mg/kg/day divided. ENALAPRIL: ADULT: 2.5 to 20 mg/day. PEDIATRIC: Initial: 0.08 mg/kg/day (up to 5 mg). Adjust to blood pressure response LISINOPRIL: ADULT: 5 to 40 mg/day orally. PEDIATRIC: 0.07 mg/kg/day; maximum 5 mg. PERINDOPRIL: ADULT: 4 to 16 mg in 1 or 2 divided doses; maximum 16 mg/day. RAMIPRIL: ADULT: 2.5 to 20 mg once daily; maximum: 20 mg daily.

Therapeutic Dose

    7.2.1) ADULT
    A) CAPTOPRIL
    1) HYPERTENSION: The recommended initial dose is 25 mg orally 2 or 3 times per day. One to two weeks after beginning initial therapy, the dose may be increased to 50 mg two or three times daily if therapeutic goal has not been reached (Prod Info captopril oral tablets, 2003).
    2) HEART FAILURE: The usual recommended dose is 25 to 50 mg orally 3 times daily. The maximum daily dose is 450 mg (Prod Info captopril oral tablets, 2003).
    3) MYOCARDIAL INFARCTION: Following a single oral dose of 6.25 mg, the initial dosage regimen is 12.5 mg orally 3 times daily. The dose can be increased to 25 mg 3 times daily over the next several days. A target dose of 50 mg 3 times daily may be achieved as tolerated over the next several weeks (Prod Info captopril oral tablets, 2003).
    B) ENALAPRIL
    1) HYPERTENSION: The recommended initial dose is 5 mg orally once daily, if the patient is not taking a diuretic. The usual dosage regimen is 10 to 40 mg/day as a single dose or in 2 divided doses (Prod Info EPANED(TM) oral solution, 2013; Prod Info VASOTEC(R) oral tablets, 2008).
    2) HEART FAILURE: The recommended initial oral dose is 2.5 mg. The recommended dosage regimen is 2.5 to 20 mg twice daily. During clinical trials, the maximum daily dose was 40 mg administered in divided doses (Prod Info VASOTEC(R) oral tablets, 2008).
    3) ASYMPTOMATIC LEFT VENTRICULAR DYSFUNCTION: During clinical efficacy trials, the recommended dose was 2.5 mg twice daily titrated, as tolerated, up to a targeted daily dose of 20 mg in divided doses (Prod Info VASOTEC(R) oral tablets, 2008).
    C) LISINOPRIL
    1) HYPERTENSION: The recommended initial dose is 10 mg orally once daily. The usual dosage regimen is 20 to 40 mg/day as a single daily dose. Doses up to 80 mg have been used, but do not appear to provide any greater response (Prod Info Zestril(R) oral tablets, 2014; Prod Info PRINIVIL(R) oral tablets, 2008).
    2) HEART FAILURE: The recommended initial dose is 5 mg orally once daily along with a diuretic and usually digitalis (Prod Info Zestril(R) oral tablets, 2014; Prod Info PRINIVIL(R) oral tablets, 2008). The usual dosage regimen is 5 to 20 mg/day as a single daily dose (Prod Info PRINIVIL(R) oral tablets, 2008). MAX: 40 mg once daily (Prod Info Zestril(R) oral tablets, 2014)
    3) ACUTE MYOCARDIAL INFARCTION: The recommended initial dose, given within 24 hours after the onset of symptoms of an acute myocardial infarction, is 5 mg followed by 5 mg after 24 hours, 10 mg after 48 hours, then 10 mg once daily for 6 weeks (Prod Info Zestril(R) oral tablets, 2014; Prod Info PRINIVIL(R) oral tablets, 2008).
    D) PERINDOPRIL
    1) HYPERTENSION: The recommended initial dose is 4 mg orally once daily. The usual dosage regimen is 4 to 8 mg orally once daily or in 2 divided doses. Maximum dose: 16 mg/day (Prod Info ACEON(R) oral tablets, 2008).
    2) STABLE CORONARY ARTERY DISEASE: The recommended initial dose is 4 mg orally once daily for 2 weeks, then increased as tolerated to a maintenance dose of 8 mg once daily (Prod Info ACEON(R) oral tablets, 2008).
    E) PERINDOPRIL ARGININE/AMLODIPINE
    1) INITIAL DOSE: Perindopril arginine 3.5 mg/amlodipine 2.5 mg orally once daily. Dose may be increased as needed every 7 to 14 days. MAX DOSE: Perindopril arginine 14 mg/amlodipine 10 mg once daily (Prod Info PRESTALIA(R) oral tablets, 2015)
    F) RAMIPRIL
    1) HYPERTENSION: Initial dose: 2.5 to 20 mg orally once daily. Adjust dosage according to blood pressure response after 2 to 4 weeks of therapy. Maintenance dose: 2.5 to 20 mg daily as a single dose or in two divided doses (Prod Info ALTACE(R) oral capsules, 2010).
    2) REDUCE RISK OF MYOCARDIAL INFARCTION: 2.5 mg orally once daily for 1 week, 5 mg once daily for 3 weeks, and increased as tolerated to a maintenance dose of 10 mg once daily to reduce the risk of myocardial infarction, stroke or death from cardiovascular events (Prod Info ALTACE(R) oral capsules, 2010).
    3) HEART FAILURE: Initial dose: 2.5 mg orally twice daily; decrease to 1.25 mg twice daily if patient becomes hypotensive. Increase dose as tolerated toward a target dose of 5 mg twice daily, with dosage increases about 3 weeks apart (Prod Info ALTACE(R) oral capsules, 2010).
    7.2.2) PEDIATRIC
    A) CAPTOPRIL
    1) GENERAL: The safety and effectiveness have not been established in pediatric patients; however, there is limited experience of use in children in the literature (Prod Info captopril oral tablets, 2003).
    2) INFANTS LESS THAN 12 MONTHS OLD: 0.1 to 0.5 mg/kg/day orally in 2 or 3 divided doses (divided every 8 to 12 hours). Adjust dose and interval based on response up to a maximum dose of 6 mg/kg/day (Robinson et al, 2005; Kovacevic et al, 2003; Lewis & Chabot, 1993; Shaw et al, 1988; Sinaiko et al, 1986; Mirkin & Newman, 1985).
    3) CHILDREN: Initial: 0.25 to 1.5 mg/kg/day orally in 2 or 3 divided doses (divided every 8 to 12 hours). Adjust dose and interval based on response up to a maximum dose of 6 mg/kg/day (Robinson et al, 2005; Montane et al, 2003; Alehan & Ozkutlu, 1998; Sozuer et al, 1994; Lewis & Chabot, 1993; Morsi et al, 1992; Sinaiko et al, 1986; Bouissou et al, 1986; Callis et al, 1986; Mirkin & Newman, 1985).
    B) ENALAPRIL
    1) Enalapril is NOT recommended for use in neonates or children with a glomerular filtration rate of less than 30 mL/min/1.73 m(2) because of a lack of data (Prod Info EPANED(TM) oral solution, 2013; Prod Info VASOTEC(R) oral tablets, 2008).
    2) HYPERTENSIVE PATIENTS: Initial: Begin at 0.08 mg/kg/day given once daily. Adjust dose according to blood pressure response (Prod Info EPANED(TM) oral solution, 2013; Prod Info VASOTEC(R) oral tablets, 2008).
    a) Maximum: Up to 5 mg/day (Prod Info EPANED(TM) oral solution, 2013; Prod Info VASOTEC(R) oral tablets, 2008).
    3) Doses above 0.58 mg/kg (or in excess of 40 mg) have not been studied in children (Prod Info EPANED(TM) oral solution, 2013; Prod Info VASOTEC(R) oral tablets, 2008).
    4) INFANTS: 0.04 to 0.08 mg/kg/day orally once daily. Adjust dose and interval based on response up to a maximum dose of 0.5 mg/kg/day (Prod Info VASOTEC(R) oral tablets, 2008; Robinson et al, 2005).
    5) CHILDREN: 0.08 mg/kg/day orally once daily. Adjust dose and interval based on response up to a maximum dose of 0.6 mg/kg/day or 40 mg/day (Prod Info VASOTEC(R) oral tablets, 2008; Robinson et al, 2005; Wells et al, 2002; Wasilewska & Zoch-Zwierz, 2004; Montane et al, 2003; Delucchi et al, 2000; Lama et al, 2000; Proesmans et al, 1996; Leversha et al, 1994; Eronen et al, 1991). Starting doses of 0.2 mg/kg/day and increasing gradually to higher doses, 0.5 to 0.6 mg/kg/day, have been used in children with steroid-resistant nephrotic syndrome; treatment goal, 40% to 50% decrease in proteinuria (Bagga et al, 2004; Delucchi et al, 2000).
    C) ENALAPRILAT
    1) 5 to 10 mcg/kg IV every 8 to 24 hours depending on response; maximum 1.25 mg/dose (Flynn & Tullus, 2009; Fivush et al, 1997; Rheuban et al, 1990). Titrate subsequent doses and interval based on amount and duration of response. In one study, doses up to 40 mcg/kg (maximum 1.25 mg/dose) every 6 hours were used in children with postoperative hypertension after surgical repair of coarctation of the aorta (Rouine-Rapp et al, 2003).
    D) LISINOPRIL
    1) Lisinopril is NOT recommended for use in children less than 6 years or in pediatric patients with a glomerular filtration rate of less than 30 mL/min/1.73 m(2) because of a lack of data (Prod Info Zestril(R) oral tablets, 2014; Prod Info PRINIVIL(R) oral tablets, 2008).
    2) CHILDREN GREATER THAN 6 YEARS OLD: The recommended starting dose is 0.07 mg/kg orally once daily, up to 5 mg. Adjust dose according to blood pressure response (Prod Info Zestril(R) oral tablets, 2014; Prod Info PRINIVIL(R) oral tablets, 2008). MAX: 0.61 mg/kg (up to 40 mg) once daily (Prod Info Zestril(R) oral tablets, 2014)
    3) Doses above 0.61 mg/kg (or in excess of 40 mg) have not been studied in children (Prod Info Zestril(R) oral tablets, 2014; Prod Info PRINIVIL(R) oral tablets, 2008).
    E) PERINDOPRIL ARGININE/AMLODIPINE
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info PRESTALIA(R) oral tablets, 2015).
    F) PERINDOPRIL ERBUMINE
    1) The safety and effectiveness of perindopril erbumine have not been established in pediatric patients (Prod Info ACEON(R) oral tablets, 2008).
    G) RAMIPRIL
    1) The safety and effectiveness of ramipril have not been established in pediatric patients (Prod Info ALTACE(R) oral capsules, 2010).

Minimum Lethal Exposure

    A) CAPTOPRIL: A 75-year-old man died after intentionally ingesting approximately ninety (90) 12.5 mg captopril tablets (Park et al, 1990).
    B) PERINDOPRIL: One patient developed hypothermia, circulatory arrest, and died after ingesting up to 180 mg perindopril (Prod Info ACEON(R) oral tablets, 2005).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) ADULT
    a) CAPTOPRIL: Patients have ingested up to 7.5 g of captopril with only mild hypotension (Turhan et al, 1985; Lechleitner et al, 1990).
    b) CAPTOPRIL: Severe hypotension was reported in an adult after ingesting 750 mg of captopril and 10 mg of alprazolam (Augenstein et al, 1988).
    c) ENALAPRIL: Patients have ingested up to 300 mg of enalapril with only mild hypotension (Waeber et al, 1984).
    d) LISINOPRIL: A 57-year-old man ingested an estimated 420 mg of lisinopril and 225 mg of amitriptyline developed hypotension (blood pressure 95/60 mmHg), which responded to intravenous saline (Dawson et al, 1990).
    e) LISINOPRIL: A 51-year-old man presented to the emergency department with lethargy and incoherent speech after ingesting 27 10-mg lisinopril tablets (3.18 mg/kg) over the course of 3 or fewer days. Initial vital sign measurements indicated that he was not hypotensive. Laboratory data, obtained at admission, revealed hyperkalemia (serum potassium 8.51 mEq/L) and acute renal insufficiency (serum creatinine 17.68 mg/dL [historically, 0.97 mg/dL]). Following administration of IV calcium gluconate, IV sodium bicarbonate, sodium polystyrene sulfonate, insulin/dextrose, and daily hemodialysis for 3 days, the patient's condition improved, with improvement of kidney function and resolution of his hyperkalemia (Belay & Nusair, 2013).
    f) RAMIPRIL: Moderate hypotension (median BP 75/36) was observed in 10 adults after ingesting a median ramipril dose of 210 mg (range: 100 to 280); 4 had coingested other cardiovascular agents and 2 coingested alcohol; all cases recovered (Christie et al, 2006).
    2) PEDIATRIC
    a) CAPTOPRIL: Children aged 1 to 5 years remained asymptomatic by subjective observation after ingesting up to 100 mg with no treatment, and up to 300 mg with gastric emptying by syrup of ipecac (Spiller et al, 1989); however, vital signs were not obtained in 50% of the cases.
    b) ENALAPRIL: Children aged 1 to 5 years remained asymptomatic after ingesting up to 30 mg (Spiller et al, 1989).
    c) PERINDOPRIL: A retrospective poison center review identified one episode of transient hypotension (65/40 mmHg), which resolved without treatment, in a 2.5-year-old, who ingested 28 mg perindopril (seven times the daily dose). No other episodes were evident during 7 hours of observation (Balit et al, 2007).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORTS
    a) CAPTOPRIL: Severe hypotension was reported in an adult with a plasma captopril level of 5952 nanograms/milliliter on the first day of ingestion (Augenstein et al, 1988).
    b) CAPTOPRIL: Mild hypotension was reported in a 43-year-old patient with mild heart failure. The plasma concentration of captopril reached 20 micrograms/milliliter at 7 hours post-ingestion. This patient received intensive supportive care beginning at 3 hours post-ingestion (Lechleitner et al, 1990).
    c) CAPTOPRIL: The postmortem plasma captopril concentration was 60.4 milligrams/liter in a 75-year-old male who ingested approximately 90 tablets of captopril, each tablet containing 12.5 milligrams (Park et al, 1990).
    d) LISINOPRIL: (THERAPEUTIC): The usual therapeutic range is 20 to 70 nanograms/milliliter (Jackson et al, 1988).
    1) OVERDOSE: Lisinopril plasma concentrations measured by radioimmunoassay drawn at 7.5, 11.5, 19.25, and 72 hours after ingestion were over 500, 472, 214, and 24 nanograms/milliliter in a 57-year-old male who ingested an estimated 420 milligrams of lisinopril and 225 milligrams of amitriptyline (Dawson et al, 1990).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) CAPTOPRIL
    1) LD50- (ORAL)MOUSE:
    a) 2500 mg/kg (RTECS, 2001)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) >2400 mg/kg (RTECS, 2001)
    3) LD50- (ORAL)RAT:
    a) 4245 mg/kg (RTECS, 2001)
    4) LD50- (SUBCUTANEOUS)RAT:
    a) >600 mg/kg (RTECS, 2001)
    B) ENALAPRIL
    1) LD50- (ORAL)MOUSE:
    a) 3507 mg/kg (RTECS, 2001)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 1160 mg/kg (RTECS, 2001)
    3) LD50- (ORAL)RAT:
    a) 2973 mg/kg (RTECS, 2001)
    4) LD50- (SUBCUTANEOUS)RAT:
    a) 1418 mg/kg (RTECS, 2001)
    C) LISINOPRIL
    1) LD50- (ORAL)MOUSE:
    a) greater than 20 g/kg (Prod Info Zestril(R), 1987)
    2) LD50- (ORAL)RAT:
    a) greater than 20 g/kg (Prod Info Zestril(R), 1987)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) These agents are specific inhibitors of peptidyldipeptide carboxyhydrolase, the enzyme which converts angiotensin I to angiotensin II; thus preventing vasoconstriction (Ferguson & Vlasses, 1981). They may also inhibit bradykinin degradation resulting in a decrease in blood pressure.

Toxicologic Mechanism

    A) CARDIOVASCULAR: These agents may have different effects depending on the cardiovascular status of the patient. Preexisting heart or vascular disease, elevated renin levels, sodium depletion, or hypovolemia can affect the response to an exposure of ACE inhibitors in therapeutic or toxic doses. One study suggested that the cardiovascular effects in normotensive, normonatremic patients were most likely due to hormonal effects and not angiotensin-converting enzyme inhibition (Kiowski et al, 1992).
    B) NEPHROTOXICITY: This agent is thought to have a direct toxic effect (Colavita et al, 1983).
    C) These agents can be removed by hemodialysis (Prod Info VASOTEC(R) oral tablets, 2008; Prod Info PRINIVIL(R) oral tablets, 2008), but it is usually unnecessary.

Physicochemical

Physical Characteristics

    A) CAPTOPRIL is a white to off-white crystalline powder with a slightly sulfurous odor. It is soluble in water (approximately 160 mg/mL), methanol, and ethanol, and sparingly soluble in chloroform and ethyl acetate (Prod Info captopril oral tablets, 2003).
    B) ENALAPRIL MALEATE is a white to off-white crystalline powder, which is freely soluble in methanol, soluble in ethanol, and sparingly soluble in water (Prod Info VASOTEC(R) oral tablets, 2008).
    C) LISINOPRIL is a white to off-white, crystalline powder that is soluble in water, sparingly soluble in methanol, and practically insoluble in ethanol (Prod Info ZESTORETIC(R) oral tablets, 2009).
    D) RAMIPRIL is a white, crystalline, substance that is soluble in polar organic solvents and buffered aqueous solutions (Prod Info ALTACE(R) oral tablets, 2011).
    E) BENAZEPRIL HYDROCHLORIDE is a white to off-white, crystalline powder which is soluble (greater than 100 mg/mL) in methanol, in ethanol, and in water (Prod Info Lotensin(R) oral tablets, 2012).
    F) CAPTOPRIL is a white to off-white, crystalline powder, which may have a slight sulfurous odor. It is sparingly soluble in chloroform and ethyl acetate; and soluble in methanol, ethanol, and water (approximately 160 mg/mL) (Prod Info CAPOTEN(R) oral tablets, 2011).
    G) ENALAPRIL MALEATE is a white to off-white, crystalline powder, which is freely soluble in methanol, soluble in ethanol, and sparingly soluble in water (Prod Info VASOTEC(R) oral tablets, 2008).
    H) ENALAPRILAT is a white to off-white, crystalline powder, which sparingly soluble in methanol and slightly soluble in water (Prod Info enalaprilat injection solution for intravenous injection, 2010).
    I) FOSINOPRIL SODIUM is a white to off-white, crystalline powder, which is slightly soluble in hexane; soluble in methanol, ethanol, and water (100 mg/mL) (Prod Info MONOPRIL(R) oral tablets, 2008).
    J) LISINOPRIL is a white to off-white, crystalline powder, which is practically insoluble in ethanol, sparingly soluble in methanol, and soluble in water (Prod Info PRINIVIL(R) oral tablets, 2011).
    K) MOEXIPRIL HYDROCHLORIDE is a fine, white to off-white powder which is soluble (approximately 10% weight-to-volume) in distilled water at room temperature (Prod Info univasc(R) oral tablets, 2012).
    L) PERINDOPRIL ERBUMINE is a white, crystalline powder, which is freely soluble in chloroform, alcohol, and water (60% weight-to-weight) (Prod Info ACEON(R) oral tablets, 2011).
    M) QUINAPRIL HYDROCHLORIDE is a white to off-white, amorphous powder, which is freely soluble in aqueous solvents (Prod Info Accupril(R) oral tablets, 2011).
    N) RAMIPRIL is a white, crystalline substance which is soluble in buffered aqueous solutions and polar organic solvents and has a melting point between 105 and 112 degrees C (Prod Info ALTACE(R) oral tablets, 2011a).
    O) TRANDOLAPRIL is a white or almost white powder which is soluble in chloroform, methanol, and dichloromethane (greater than 100 mg/mL) (Prod Info MAVIK(R) oral tablets, 2012).

Molecular Weight

    A) CAPTOPRIL: 217.29 (Prod Info captopril oral tablets, 2003)
    B) ENALAPRIL MALEATE: 492.53 (Prod Info VASOTEC(R) oral tablets, 2008)
    C) LISINOPRIL: 441.53 (Prod Info ZESTORETIC(R) oral tablets, 2009)
    D) RAMIPRIL: 416.5 (Prod Info ALTACE(R) oral tablets, 2011)
    E) BENAZEPRIL HYDROCHLORIDE: 460.96 (Prod Info Lotensin(R) oral tablets, 2012)
    F) CAPTOPRIL: 217.29 (Prod Info CAPOTEN(R) oral tablets, 2011)
    G) ENALAPRIL MALEATE: 492.53 (Prod Info VASOTEC(R) oral tablets, 2008)
    H) ENALAPRILAT: 384.43 (Prod Info enalaprilat injection solution for intravenous injection, 2010)
    I) FOSINOPRIL SODIUM: 585.65 (Prod Info MONOPRIL(R) oral tablets, 2008)
    J) LISINOPRIL: 441.52 (Prod Info PRINIVIL(R) oral tablets, 2011)
    K) MOEXIPRIL HYDROCHLORIDE: 535.04 (Prod Info univasc(R) oral tablets, 2012)
    L) PERINDOPRIL: 368.47 (Prod Info ACEON(R) oral tablets, 2011)
    M) PERINDOPRIL ERBUMINE: 441.61 (Prod Info ACEON(R) oral tablets, 2011)
    N) QUINAPRIL HYDROCHLORIDE: 474.98 (Prod Info Accupril(R) oral tablets, 2011)
    O) RAMIPRIL: 416.5 (Prod Info ALTACE(R) oral tablets, 2011a)
    P) TRANDOLAPRIL: 430.54 (Prod Info MAVIK(R) oral tablets, 2012)

References

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    86) Product Information: ACCUPRIL(R) oral tablets, quinapril hcl oral tablets. Pfizer Pharmaceuticals, New York, NY, 2003.
    87) Product Information: ACCURETIC(TM) oral tablets, quinapril hcl, hydrochlorothiazide oral tablets. Pfizer,Inc, New York, NY, 2003.
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    97) Product Information: CAPOTEN(R) oral tablets, captopril oral tablets. Par Pharmaceutical Companies, Inc. (per FDA), Spring Valley, NY, 2011.
    98) Product Information: CAPOZIDE(R) oral tablets, captopril and hydrochlorothiazide oral tablets. Par Pharmaceutical Companies, Inc., Spring Valley, NY, 2008.
    99) Product Information: EPANED(TM) oral solution, enalapril oral solution. Silvergate Pharmaceuticals (per manufacturer), Greenwood Village, CO, 2013.
    100) Product Information: LOTENSIN HCT(R) oral tablets, benazepril hcl, hctz oral tablets. Novartis Pharmaceuticals Corporation, Suffern, NY, 2007.
    101) Product Information: LOTENSIN(R) oral tablets, benazepril hcl oral tablets. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2006.
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    106) Product Information: MONOPRIL(R) tablets, fosinopril sodium tablets. Bristol-Myers Squibb Company, Princeton, NJ, 2003.
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    108) Product Information: PRESTALIA(R) oral tablets, perindopril arginine amlodipine oral tablets. SYMPLMED LLC (per FDA), Cincinnati, OH, 2015.
    109) Product Information: PRINIVIL(R) oral tablets, lisinopril oral tablets. Merck & Co,Inc, Whitehouse Station, NJ, 2006.
    110) Product Information: PRINIVIL(R) oral tablets, lisinopril oral tablets. Merck & Co.,Inc, Whitehouse Station, NY, 2008.
    111) Product Information: PRINIVIL(R) oral tablets, lisinopril oral tablets. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2011.
    112) Product Information: PRINZIDE(R) oral tablets, lisinopril-hydrochlorothiazide oral tablets. Merck & Co,Inc, Whitehouse Station, NJ, 2008.
    113) Product Information: UNIRETIC(R) oral tablets, moexipril hcl, hydrochlorothiazide oral tablets. Schwarz Pharma, Milwaukee, WI, 2003.
    114) Product Information: UNIVASC(R) oral tablets, moexipril hcl oral tablets. Schwarz Pharma, Milwaukee, WI, 2003.
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    117) Product Information: VASOTEC(R) oral tablets, enalapril maleate oral tablets. Biovail Pharmaceuticals,Inc, Bridgewater, NJ, 2007.
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    122) Product Information: captopril tablets, captopril tablets. Sandoz, Broomfield, CO, 2003.
    123) Product Information: captopril tablets, captopril tablets. Sandoz, Broomfield, CO, 2003a.
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