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Chapter: Modern Medical Toxicology: Cardiovascular Poisons: Cardiac Drugs and Lipid Lowering Agents

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Dopamine - Beta Adrenergic Receptor and Dopaminergic Receptor Agonists

Treatment of haemodynamic imbalances in shock syndrome due to: ■■ Congestive heart failure ■■ Myocardial infarction ■■ Endotoxic septicaemia ■■ Open heart surgery ■■ Renal failure ■■ Trauma.

BETA ADRENERGIC RECEPTOR AND DOPAMINERGIC RECEPTOR AGONIST

Out of the several examples of these two groups, only two drugs used in heart failure (dopamine and dobutamine) will be discussed here.

Dopamine

Uses

Treatment of haemodynamic imbalances in shock syndrome due to:

■■  Congestive heart failure

■■  Myocardial infarction

■■  Endotoxic septicaemia

■■  Open heart surgery

■■  Renal failure

■■   Trauma.

Toxicokinetics

Dopamine hydrochloride is an endogenous catecholamine, and is a direct precursor of noradrenaline. It accounts for about one-half of all catecholamines in the brain, and is present in greater quantities than noradrenaline or 5-hydroxytryptamine. Dopaminergic neurons and receptors are highly organised and concentrated in several areas, especially in the basal ganglia and limbic system.

Dopamine is administered only by the intravenous route since it is inactivated when given orally. Volume of distri-bution is approximately 0.89 L/kg, and steady- state plasma concentrations are achieved in 5 to 10 minutes. Elimination half-life of infused dopamine is about 9 minutes, while that of a bolus IV dose is about 2 minutes. Dopamine is extensively metabolised in the liver, and less than 10% of a dose is excreted unchanged in the urine. It is metabolised in liver, kidney, and plasma by monoamine oxidase and catechol- O-methyltrans-ferase to inactive metabolites. About 20% is cleared by the lungs, especially when plasma dopamine levels are high.

Mode of Action

The usual dose is given as an initial intravenous infusion rate of 2 to 5 mcg/kg/min, then titrated up to a maximum of 50 mcg/ kg/min is recommended for maintaining blood pressure control.

·              At low dosages (0.5–2 mcg/kg/min), D1and D2receptorsare activated. D1 receptor activation leads to renal, mesen-teric, cerebral, and coronary vascular dilation. D2 receptor activation causes the blood pressure to remain stable or decrease, while renal plasma flow, glomerular filtration rate, and sodium excretion increase.

·              At higher dosages (2–5 mcg/kg/min), beta adrenoceptors are activated leading to increased cardiac contractility, heart rate, and atrioventricular conduction. Beta1 receptor activation leads to increased cardiac output and systolic blood pressure.

·     At much higher dosages (> 5 mcg/kg/min), alpha1 and alpha2 receptors are activated leading to vasoconstriction. Systolic and diastolic blood pressures increase.

Adverse Effects

·     Tachy-/bradycardia, ectopic beats, palpitations, anginal pain, dyspnoea, hypo-/hypertension, vasoconstriction, mydriasis, vomiting.

·     The following are commonly seen: hypertension (some-times followed by hypotension), myocardial ischaemia or infarction, supraventricular tachyarrhythmias, brady-cardia, or ventricular arrhythmias, pulmonary oedema with rales, rhonchi, dyspnoea, and frothy or bloody sputum.

·     Systemic symptoms have occurred following ocular expo-sure to undiluted parenteral dopamine solution; ocular exposures should be treated as parenteral exposures.

·     Dopamine is contraindicated in phaeochromocytoma, uncorrected tachyarrhythmias, and ventricular fibrillation.

Drug Interactions

·              Halogenated anaesthetics and cyclopropane can precipitate severe arrhythmias.

·              MAOIs potentiate dopamine’s effects.

·              Ergot derivatives and tricyclics increase vasoconstriction.

·              Cardiac effects are antagonised by beta blockers.

Toxic (Clinical) Features

·              Patients with pre-existing vascular disease may be subject to excess ischaemic effects which usually begin after 24 hours of dopamine use and may progress to gangrene of an extremity. Doses of over 10 mcg/kg/min are always risky. Hypertension is invariably induced when large doses of dopamine are admin-istered. Deaths have occurred.

Treatment

·      Admit patient in coronary care unit with cardiac moni-toring and electrocardiographic surveillance.

·      If ischaemia occurs in an extremity, infiltrate the area imme-diately with 10 to 15 ml of a saline solution containing 5 to 10 mg of phentolamine mesylate. Alternatively, 50 mg of phentolamine diluted to 1 mg/ml with 0.9% sodium chloride can be administered in multiple subcutaneous injections of 0.5 mg each to cover the entire area of extravasation. The possible risk of phentolamine-induced hypotension can be minimised by giving these doses over 1 to 2 hours.

·      Intravenous chlorpromazine, 10 mg as a loading dose, and 0.6 mg/min drip has been used for digital ischaemia induced by dopamine.

·      Correct hypovolaemia with adequate fluid replacement.

·              For mild/moderate asymptomatic hypertension, pharma-cologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients. For hyper-tensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20 to 25% within one hour), nitroprusside is preferred.

 

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