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Chapter: Modern Medical Toxicology: Cardiovascular Poisons: Diurets, Antihypertensives and Antiarrhythmics

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Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors) - Sympatholytic Drug Cardiovascular Poison

Angiotensin converting enzyme (ACE) inhibitors are highly popular drugs in the treatment of hypertension.

Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors)

Angiotensin converting enzyme (ACE) inhibitors are highly popular drugs in the treatment of hypertension. Examples include benazepril, captopril, cilazepril, delapril, enalapril, fosinopril, lisinopril, moexipril, pentopril, perindopril, quinapril, ramipril, spirapril, trandolapril.

Mode of Action

These agents are specific inhibitors of peptidyldipeptide carboxyhydrolase, the enzyme which converts angiotensin I to angiotensin II; thus preventing vasoconstriction. They may also inhibit bradykinin degradation resulting in a decrease in blood pressure. ACE inhibitors act by inhibiting the conver-sion of angiotensin I to angiotensin II in the lung and vascular endothelium. This results in vasodilation, decreased peripheral vascular resistance, decreased blood pressure, increased cardiac output, and a slight increase in renal, cerebral, and coronary blood flow.

Toxicokinetics

These drugs are generally well absorbed orally and have highly variable half-lives, volumes of distribution, and protein binding.

Adverse Effects

■■  Skin rash, dysgeusia, chronic cough, bronchospasm, neutropenia, hyperkalaemia, hypotension, proteinuria, renal insufficiency, pancreatitis, hepatotoxicity, leukopenia, and occasionally angioneurotic oedema. Hyperkalaemia has been a reported side effect of captopril, enalapril, lisinopril, or perindopril therapy, and may be exacerbated when used in combination with potassium-sparing diuretics and is more common in patients with chronic renal failure.

■■Pancreatitis has only been reported with chronic thera-peutic use of lisinopril and enalapril. Hepatotoxicity has been associated with captopril therapy. Renal failure may develop after therapeutic use in patients in whom renal perfusion is dependant on angiotensin II. This includes patients with renal artery stenosis, volume depletion, and severe CHF.

■■  ACE inhibitors must not be used in pregnancy since they are teratogenic and can cause a number of foetal anoma-lies including defects in skull ossification, pulmonary hypoplasia, neonatal hypertension, and renal failure. Hypotension, neonatal anaemia, hyperkalemia, neonatal skull hypoplasia, anuria, and renal failure have occurred in foetuses and neonates. Oligohydramnios has also occurred, possibly due to decreased foetal renal function, and has been associated with limb contractures, craniofacial deformities, hypoplastic lung development.

■■  Angioneurotic oedema occurs in about 0.1% of patients receiving ACE inhibitors and commonly involves perior-bital, perioral, and oropharyngeal tissues. It may develop after months or years of uneventful therapy with these agents. In severe cases dyspnoea, chest pain, and airway compromise may develop. Elevation of bradykinin levels induced by ACE inhibitors is said to be the main cause. Treatment involves maintenance of airway (with naso-pharyngeal airway, intubation, or surgical intervention, depending on the case), and standard antiallergic drug therapy (adrenaline, diphenhydramine, and corticoster-oids). However, there is no evidence to suggest that ACE inhibitor-induced angioneurotic oedema is an allergic phenomenon.

■■  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. This troublesome side effect occurs with a variable incidence ranging up to 39%. Cough induced by chronic ACE inhibitor therapy responds well to sodium cromoglycate. Women are affected 3:1 compared to men. Drug discontinuation and substitution of an alternative antihypertensive agent may have to be resorted to if the condition is severe and does not respond to any treatment measures.

■■Various types of dermatitis have been reported with chronic use of ACE inhibitors. With therapeutic use, the overall incidence of rashes ranges from 6.1 to 10.9% and is dose-dependant.

Drug Interactions

·              Concomitant use of captopril and allopurinol has rarely been associated with a serum sickness or Stevens-Johnson syndrome.

·              Hypoglycaemia has been reported with simultaneous use of ACE inhibitors and insulin or oral hypoglycaemic agents. The combination of cyclosporin and ACE inhibitors may cause acute renal failure, although this is rare.

·              The combination of ACE inhibitors and potassium sparing diuretics may cause hyperkalaemia.

·              The combination of NSAIDs and ACE inhibitors may cause renal insufficiency.

·              Several cases of life-threatening anaphylactoid reactions have been reported in patients receiving ACE inhibitors and haemodialysis with a polyacrylonitrile membrane dialyzer (AN69).

Clinical (Toxic) Features

·              In many cases of overdose, patients remain asymptomatic.

·              Hypotension, hyperkalaemia, and renal failure: while hypotension is generally not very severe, occasional cases have been reported of profound hypotension.

·              Fatalities are rare, but have been reported.

Treatment

·              Monitor BUN and serum creatinine if there is evidence disease. Monitor vital signs, particularly blood pressure. Administration of activated charcoal in the usual manner.

·              Correction of hypotension with IV colloids and/or crystal- loids. If this fails, dopamine or adrenaline or noradrenaline may be used with caution. Infuse 10 to 20 ml/kg of isotonic fluid and place in Trendelenburg position. If hypotension persists, administer dopamine or noradrenaline. Consider central venous pressure monitoring to guide further fluid therapy.

·              Angiotensin infusion at doses ranging from 8.5 to 18 mcg/ patients who did not respond to volume and pressor infu-sions.

·              Naloxone is said to be effective in reversing hypotension induced by ACE inhibitor overdose.

·              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.

·              Haemodialysis may be beneficial.

 

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