Angiotensin II Receptor Antagonists - Sympatholytic Drug Cardiovascular Poison

Angiotensin II Receptor Antagonists

·              These drugs are similar to ACE inhibitors in that they inhibit the effects of angiotensin II, but instead of blocking the forma-tion of angiotensin II, they act as antagonists at its receptors. Angiotensin II receptor antagonists selectively bind and, therefore, block the AT(1) receptor subtype. This class of drug blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II on smooth muscle and the adrenal gland. The benefit of this different mode of action is that the bradykinin system is unaffected, and hence cough and angioneurotic oedema do not occur.

·              Examples include losartan, tasosartan, and valsartan.

Adverse Effects

■■Dizziness, insomnia, headache, muscle cramps, and leg pain occurred during clinical studies. Hyperkalaemia (greater than 20% increase in serum potassium) occurred during clinical trials with valsartan.

■■  These drugs can potentially cause oliguria and azotaemia in patients whose renal function may depend on function of the renin-angiotensin-aldosterone system (e.g. severe CHF or renal artery stenosis).

■■  Reversible hepatotoxicity has been reported.

■■  Angioedema has also been reported.

■■  Angiotensin II receptor antagonists should be discon-tinued as soon as possible when pregnancy is detected. Severe foetal deformity has been reported in humans and animal models. Foetal death has been reported in one case following exposure to losartan during weeks 20 to 31 of pregnancy. Oligohydramnios was present along with a pattern of foetal abnormalities associated with angiotensin II antagonists.

Clinical (Toxic) Features

·              Hypotension, tachy-/bradycardia, hyperkalaemia. Bradycardia could occur from parasympathetic (vagal) stimulation.

Treatment

·      Symptomatic and supportive measures.

·      Monitor renal and liver function tests in symptomatic patients or following significant overdose.

·      Monitor blood pressure and heart rate frequently following a significant ingestion. Consider cardiac monitoring.

·      If hypotensive, give 500 to 2000 ml crystalloid initially (20 ml/kg in children) and titrate to desired effect (stabi-lisation of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension. Vasopressors should be used in refractory cases unresponsive to repeated doses of noradrenaline and after vigorous intravenous crystalloid rehydration.

·              Based on the high degree of protein binding of most of these agents, haemodialysis would not be effective.

Forensic Issues (Antihypertensives)

·              Most cases of antihypertensive drug overdose are accidental (for e.g. in children), or suicidal. Paediatric poisoning arises out of parental negligence rendering these and other dangerous pharmaceutical preparations easily accessible to toddlers. Tragically, deaths have occurred in some cases.

·              Among the various antihypertensives, the beta blockershave frequently been implicated in serious poisoning, with propranolol being the commonest agent implicated. Reserpine increases suicidal tendency among patients.

·              Extended (or sustained) release antihypertensives are generally associated with prolonged and more profound effects in overdose.

·              Calcium channel blockers are increasingly being reported in serious overdoses, while the safest drugs appear to be ACE inhibitors.

·              An abuse potential for clonidine has been identified in treatment-seeking opiate abusers, particularly those with concurrent cocaine use. Chewing of clonidine patches has been reported as a mechanism of abuse in drug-seeking individuals. Two patterns of clonidine use included: illicit use to decrease opiate withdrawal as well as for its sedating effect, and, illicit use for its psychoactive effects, including the interaction with methadone, in addition to decreasing opiate withdrawal. Physical withdrawal symptoms were reported in 57% of 30 patients abusing clonidine when the drug was stopped.

·     Hypoxic-ischaemic encephalopathy with permanent mental regression has been reported in a 3-year-old boy following clonidine poisoning in a case of Munchausen by proxy. Prior to this event, the boy had several lethargic episodes during hospitalisations when the mother was present. Hypothermia, respiratory depression and arterial hypotension also occurred during some of these episodes.