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

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Amrinone (Inamrinone) - Cardiovascular Poisons

Inamrinone, a bipyridine derivative is a noncatecholamine cardiotonic agent with positive inotropic effects and vasodila-tory properties.

PHOSPHODIESTERASE INHIBITORS

Inamrinone, dipyridamole, enoximone, milrinone, pimobendan, vesnarinone. The important examples are discussed here.

Amrinone (Inamrinone)

As of April 2000, the name of amrinone was changed to “inamrinone” to reduce the number of accidental injuries and deaths associated with the cardiac drug names inamrinone and amiodarone.

Inamrinone, a bipyridine derivative is a noncatecholamine cardiotonic agent with positive inotropic effects and vasodila-tory properties.

Uses

Treatment of

·              Refractory congestive heart failure.

·              Pulmonary hypertension.

·              Post-operative heart failure.

Toxicokinetics

namrinone is usually administered intravenously. Oral inam-rinone was discontinued due to reports of a higher incidence of gastrointestinal adverse effects when compared to the intra- venous form. Plasma half-life varies from 2.6 to 3.6 hours.

Volume of distribution is 1.2 litres/kg. 10 to 40% of the drug is excreted unchanged. Several metabolites have been identified in the urine, and include N-glycolate (8%), N-acetate (5%), and O-glucuronide and N-glucuronide (less than 5% each).

Elimination half-life is 3.6 hours in normal subjects; 5.8 hours in patients with congestive heart failure.

Mode of Action

The inotropic action of inamrinone is due to selective inhibition of phosphodiesterase III, with subsequent increase in cardiac cyclic AMP concentration.

Inamrinone does not inhibit the cardiac Na+-K+-dependant ATP.

The recommended adult dosage for inamrinone is an initial intravenous loading dose of 0.75 ml/kg over 2 to 3 minutes followed by a continuous infusion of 5 to 10 mcg/kg/min, with the total daily dosage not to exceed 10 ml/kg/day.

Adverse Effects

■■  Headache, nausea, vomiting, diarrhoea, and abdominal pain occur occasionally.

■■  Reduced tear secretion and dysosmia have been reported with inamrinone.

■■  Bright yellow discolouration of nails has been described following therapeutic use.

■■  Thrombocytopenia can occur in upto 34% of patients taking the drug on a long-term basis. Pancytopenia has been reported following short-term, high-dose IV therapy.

■■  Intravenous use is also associated with hypotension, ventricular arrhythmias, hepatotoxicity, metabolic acidosis, and GIT disturbances (vomiting, diarrhoea, abdominal pain).

■■  The commercial preparation of inamrinone contains sodium metabisulfite which can cause allergic reactions in suscep-tible patients (e.g. asthmatics).

Drug Interactions

·              Additive inotropic effects are seen with cardiac glycosides.

·              Severe hypotension may occur when disopyramide isadministered together with inamrinone.

·              Dextrose must not be used when administering inamrinone, since chemical interaction and precipitation can occur.

Toxic (Clinical) Features

The following manifestations have been reported in inamrinone overdose: severe hypotension, ventricular arrhythmias, throm-bocytopenia, hepatotoxicity, metabolic acidosis, oliguria, and cardiac arrest.

Treatment

·      Admit patient to cardiac intensive care unit. Monitor vital signs and cardiac parameters continuously.

·      Treat hypotension with IV fluids and pressor agents as required. 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.

·      For arrhythmias: Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalaemia, hypocalcaemia, and hypomagnesaemia). Lignocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Sotalol is an alternative for stable monomorphic ventricular tachycardia. Amiodarone and sotalol should be used with caution. Unstable rhythms require cardio-version. Atropine may be used when severe bradycardia is present and PVCs are thought to represent an escape complex.

·              Particular attention must be paid to ventilatory support, oxygen administration, electrolyte studies (especially potas-sium levels), complete blood count, and hepatic and renal function tests.


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