CHAPTER 2-7: ANGIOTENSIN BLOCKERS AND ACE INHIBITORS

INTRODUCTION

The angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor (AR) blockers are widely used for the treatment of patients with hypertension or heart failure and patients who have had a myocardial infarction. Currently, at least 10 ACE inhibitors and 7 AR blockers are marketed in the United States.

MECHANISM OF TOXICITY

1. ACE inhibitors reduce vasoconstriction and aldosterone activity by blocking the enzyme that converts angiotensin I to angiotensin II. AR blockers directly inhibit the action of angiotensin II.

2. All the ACE inhibitors except captopril and lisinopril are prodrugs that must be metabolized to their active moieties (eg, enalapril is converted to enalaprilat) following oral administration.

3. Angioedema and cough associated with ACE inhibitors are thought to be mediated by bradykinin, which normally is broken down by angiotensin-converting enzyme. However, it has also been rarely reported with AR blockers, which do not alter bradykinin elimination.

4. Rare cases of acute liver injury (hepatocellular and/or cholestatic) have been associated with both ACE inhibitors and AR blockers, by unclear mechanisms.

5. Pharmacokinetics (see also Table II–66). The volume of distribution (Vd) of ACE inhibitors is fairly small (eg, 0.7 L/kg for captopril). The parent drugs are rapidly converted to their active metabolites, with half-lives of 0.75–1.5 hours. The active metabolites have elimination half-lives of 5.9–35 hours. The AR blockers have half-lives of 5–24 hours; losartan has an active metabolite.

TOXIC DOSE

Only mild toxicity has resulted from most reported overdoses of up to 7.5 g of captopril, 440 mg of enalapril (serum level 2.8 mg/L at 15 hours), and 420 mg of lisinopril. A 75-year-old man was found dead after ingesting approximately 1,125 mg of captopril. A 45-year-old woman recovered without sequelae after intentional ingestion of 160 mg of candesartan cilexetil along with several other drugs. A 2.5-year-old girl ingested 2 mg/kg of perindopril and experienced an asymptomatic transient drop in blood pressure to 65/45 mm Hg approximately 4 hours later. A 14-month-old boy ingested 15 mg/kg of irbesartan and reportedly became unsteady on his feet within 1 hour of ingestion and had mild hypotension, but he was acting normally 3 hours later and was discharged home.

CLINICAL PRESENTATION

1. Hypotension, usually responsive to fluid therapy, has been reported with acute overdose. Bradycardia may also occur.

2. Hyperkalemia has been reported with therapeutic use, especially in patients with renal insufficiency and those taking nonsteroidal anti-inflammatory drugs.

3. Bradykinin-mediated effects in patients taking therapeutic doses of ACE inhibitors include dry cough (generally mild but often persistent and annoying) and acute angioedema, usually involving the tongue, lips, and face, which may lead to life-threatening airway obstruction.

DIAGNOSIS

Is based on a history of exposure.

1. Specific levels. Blood levels are not readily available and do not correlate with clinical effects.

2. Other useful laboratory studies include electrolytes, ...