ACE I Toxicity

Angiotensin Converting Enzyme Inhibitor (ACE inhibitor)
Toxicity
In addition to their antihypertensive properties, angiotensin-converting
enzyme (ACE) inhibitors have been widely accepted for their capacity to slow
progressive renal, cardiac, and/or vascular disease. Outcome studies with a
variety of ACE inhibitors have resulted in usage indications in conditions,
such as congestive heart failure, post-myocardial infarction, and diabetic
nephropathy. Most recently, a treatment indication has been granted to the
ACE inhibitor ramipril for reducing cardiovascular events in the high-risk
cardiac patient without evident left ventricular dysfunction.
Classification:
ACE Inhibitors can be divided into three groups based on their molecular
structure:
 Sulfhydryl-containing agents:
o Captopril, the first ACE inhibitor
 Dicarboxylate-containing agents:
o Enalapril
o Ramipril
o Quinapril
o Perindopril
o Lisinopril
o Benazepril
 Phosphonate-containing agents:
o Fosinopril
Pharmacokinetics
All of the ACE inhibitors are orally bioavailable as a drug or prodrug.
All but captopril and lisinopril undergo hepatic conversion to active
metabolites, so these agents may be preferred in patients with severe hepatic
1
impairment. Fosinopril is the only ACE inhibitor that is not eliminated
primarily by the kidneys and does not require dose adjustment in patients with
renal impairment. Enalapril is the only drug in this class available
intravenously. These drugs are generally well absorbed orally and have highly
variable half-lives, volumes of distribution, and protein binding.
Mechanism of action:
ACE inhibitors reduce the activity of the renin-angiotensin-
aldosterone system (RAAS) as the primary etiologic (causal) event in the
development of hypertension,
2
Clinical use of ACE Inhibitor:
ACE inhibitors slow the progression of diabetic nephropathy and
decrease albuminuria and, thus, have a compelling indication for use in
patients with diabetic nephropathy. Beneficial effects on renal function may
result from decreasing intraglomerular pressures, due to efferent arteriolar
vasodilation. ACE inhibitors are a standard in the care of a patient following
a myocardial infarction and first-line agents in the treatment of patients with
systolic dysfunction. Chronic treatment with ACE inhibitors achieves
sustained blood pressure reduction, regression of left ventricular hypertrophy,
and prevention of ventricular remodeling after a myocardial infarction. ACE
inhibitors are first-line drugs for treating heart failure, hypertensive patients
with chronic kidney disease, and patients at increased risk of coronary artery
disease. All of the ACE inhibitors are equally effective in the treatment of
hypertension at equivalent doses.
Therapeutic and Maximal dose of ACE inhibitor:
Drug Dose Start dosing Usual dose Maximal dose
Benazepril 10 mg 10 10-20 80 mg
Captopril 50 mg 12.5-25 mg 25-50 mg 450 mg
Enapril 5 mg 5 mg 10-40 mg 40 mg
Fosinopril 10 mg 10 mg 10-40 mg 80 mg
Moexipril 7.5 mg 7.5 mg 7.5-30 mg 30 mg
Perindopril 4 mg 4 mg 4-8 mg 16 mg
Quinapril 10 mg 10 mg 20-80 mg 80 mg
Ramipril 2.5 mg 2.5 mg 2.5-20 mg 20 mg
Trandolpril 2 mg 1 mg 2-4 mg 8 mg
3
Adverse and Toxic effect of ACE inhibitor:
 Hypotension, headache, dizziness, fatigue, nausea
and renal impairment. ACE inhibitors might increase inflammation-
related pain, perhaps mediated by the buildup of bradykinin that
accompanies ACE inhibition.
 Dry cough – this is the most frequent symptom (5–30% of cases) during
chronic dosing. The cause is unknown, but it may be due to kinin
accumulation stimulating cough.
 Functional renal failure – this occurs predictably in patients with
hemodynamically significant bilateral renal artery stenosis, and in
patients with renal artery stenosis in the vessel supplying a single
functional kidney, acute reduction in renal function in this setting is that
glomerular filtration dependent on angiotensin-II-mediated efferent
arteriolar vasoconstriction, and when angiotensin II synthesis is
inhibited, glomerular capillary pressure falls and glomerular filtration
ceases. This should be borne in mind particularly in ageing patients
with atheromatous disease.
 Hyperkalaemia is potentially hazardous in patients with renal
impairment and great caution must be exercised in this setting. This is
even more important when such patients are also prescribed potassium
supplements and/or potassium-sparing diuretics.
 Fetal injury – ACEI cause renal agenesis/failure in the fetus, resulting
in oligohydramnios. ACEI are therefore contraindicated in pregnancy.
 Sulphhydryl group-related effects – high-dose captopril causes heavy
proteinuria, neutropenia, rash and taste disturbance, attributable to its
sulfhydryl group.
4
 ACE inhibitors cause angioedema most commonly present with
swelling of the lips, tongue, or face, although another presentation is
episodic abdominal pain due to intestinal angioedema.
Range of toxicity:
Adults: Patients have ingested the following with only mild hypotension
reported: 7.5 g captopril, 300 mg enalapril, and 420 mg lisinopril. Fatalities
have occurred after ingestions of 1125 mg captopril and 180 mg perindopril.
Children: Less than 6 years old remained asymptomatic after ingestion of up
to 8 mg/kg captopril or up to 2 mg/kg enalapril or lisinopril without
gastrointestinal decontamination. In one study, children remained
asymptomatic after ingestions of up to 100 mg captopril or 30 mg enalapril.
Diagnosis of Toxicity:
Depend on the following:
1) Case history
2) Clinical signs
3) Blood pressure
4) BUN (6–20 mg/dL)
5) serum creatinine
6) ECG
7) Electorlytes (Na, K and Cl)
Treatment:
1. Stabilization: Initially, evaluate and correct immediate life-threatening
complications (eg, airway, breathing, and circulation). The most
common symptom of ACE-inhibitor overdose is hypotension.
2. Emesis: Ipecac which can be administered within 30 to 90 minutes of
ingestion.
5
Dose of ipecac syrup:
 Adult: Dose: 15 to 30 milliliters
 Adolescent: Dose: 15 to 30 milliliters
 Child 1 to 12 years: Dose: 15 milliliters
 Child 6 to 12 months: Dose: 5 to 10 milliliters. Position: child
in left lateral decubitus position to reduce risk of aspiration.
3. Activated charcoal: Consider prehospital administration of activated

charcoal as an aqueous slurry in patients with apotentially toxic
ingestion who are awake and able to protect their airway. Activated
charcoal is most effective when administered within one hour of
ingestion.
4. Hypotensive episode: Infuse 10 to 20 milliliters/kilogram of isotonic
fluid and keep the patient supine. If hypotension persists, administer
dopamine or norepinephrine.
5. Angiotensin Amide: 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.
6. NALOXONE: Administration of naloxone has been reported to
antagonize the hypotensive effect of captopril.
7. Hemodialysis
NOTE:
Asymptomatic patients should be observed for at least four hours
post ingestion with frequent monitoring of vital signs. Symptomatic or
hypotensive patients should be admitted for at least 24 hours post
ingestion or until symptoms have completely resolved.

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Angiotensin Converting Enzyme Inhibitor (ACE inhibitor)

3. Activated charcoal: Consider prehospital administration of activated

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