Amiodarone

• Amiodarone (Class I and III Channel Blocker)

  • Overview:

    • A benzofurane derivative, 37% iodine by weight, structurally similar to thyroxine

      • may cause hypothyroidism or hyperthyroidism (frequency: 2%-4%)

        • Insidious development

        • Patients with previous thyroid dysfunction: more likely to develop amiodarone-mediated thyroid effects

        • Hyperthyroidism: most readily evidenced by increased plasma level of triiodothyronine

          • Secondary to iodine release from parent drugs;

          • Often refractory to conventional treatment

            • intolerant of beta-adrenergic receptor blockade (because of underlying cardiac disease)

          • Following failed medical management: surgical thyroidectomy is appropriate

            • bilateral superficial cervical plexus block has been used for anesthetic management of subtotal thyroidectomy in this patient group

        • Hypothyroidism: most readily evidenced by increased plasma level of thyroid-stimulating hormone (TSH)

      • may interfere with certain radiologic procedures (Iodine accumulation)

    • Approved for use only in treatment of serious ventricular arrhythmias (USA)

      • also used for refractory supraventricular arrhythmias

    • Numerous adverse effects.

  • Metabolism & Excretion

    • Long elimination halftime: 29 days

    • Minimal renal excretion

    • Principal metabolite (desmethylamiodarone) -- longer elimination halftime compared to amiodarone

    • Extensive protein binding

    • Amiodarone concentrated in the myocardium (10-50 times plasma concentration)

  • Cardiovascular Properties and Uses:

    • Used in patients with ventricular tachycardia or fibrillation resistant to treatment with other drugs.

    • Effective inhibitor of abnormal automaticity.

    • Oral administration, preoperatively, reduces likelihood of atrial fibrillation following cardiac surgery.

    • Suppresses tachyarrhythmias associate with Wolff-Parkinson-White syndrome

      • secondary to depression of conduction in the AV node and accessory bypass tracts.

    • Similar to beta-blockers (unlike most class I antiarrhythmics), amiodarone decreases mortality after myocardial infarction

    • Antiarrhythmic effectiveness begins within 72 hours following initiation of oral treatment; nearly immediate effect following IV administration

      • Following discontinuation of chronic oral therapy: pharmacological effects may last up to two months (long elimination half-time)

  • Mechanism of Action

    • Blocks sodium and potassium channels and prolongs action potential duration.

    • Prolongs effective refractory period in:

      1. SA node

      2. AV node

      3. ventricle

      4. atrium

      5. His-Purkinje system

      6. accessory bypass tracts (Wolff-Parkinson-White syndrome)

  • Vascular Effects

    • Noncompetitive alpha and beta adrenergic receptor blocker

    • Systemic vasodilation

    • Antianginal properties, secondary to coronary vasodilation

  • Side Effects

    • Pulmonary:

      • Most serious adverse effect seen in long-term therapy is a rapidly progressive pulmonary fibrosis which may be fatal

        • Frequency: 5%-15% treated patients

        • Mortality rate: 5% to 10%

        • Cause: unknown (possibly related to amiodarone-mediated generation of free oxygen radicals in the lung)

        • Two types of amiodarone-pulmonary toxicity clinical presentations:

          1. More common: Slow, insidious, progressive dyspnea, cough, weight loss, pulmonary infiltration (chest x-ray)

          2. Acute onset: dyspnea, cough, arterial hypoxemia.

    • Anesthetic Implications: pulmonary

      • Suggested restriction of inspired oxygen concentration in patients receiving amiodarone and undergoing general anesthesia close level possible while retaining adequate systemic oxygenation

      • Postoperative pulmonary edema has been reported in patients treated with amiodarone chronically-- resembles acute onset form of amiodarone toxicity.

      • In patients with preexisting amiodarone-cause pulmonary damage are at increased risk for adult respiratory distress syndrome following surgery requiring cardiopulmonary bypass.

  • Cardiovascular Effects:

    • Prolongation of QT interval (ECG); increased incidence of ventricular tachyarrhythmias (including torsades de pointes)

    • Bradycardia (atropine-resistant)

    • Catecholamine responsiveness: diminished due to alpha and beta-receptor blocking activity

    • Hypotension; A-V block (following IV administration)

    • Anesthetic Implications: cardiovascular

      • With general anesthesia -- enhanced antiadrenergic action, presentation as:

        • A-V block, sinus arrest, decrease cardiac output, hypotension

        • Sinus arrest more likely in the presence of anesthetics that inhibit SA nodal automaticity (e.g. lidocaine, halothane)

        • Consideration should be given for temporary ventricular pacemaker and sympathomimetic administration (e.g. isoproterenol) for patients taking amiodarone and scheduled undergo surgery.

  • Ocular and other Side Effects:

    • Corneal microdeposits-- common;usually no visual impairment

    • Photosensitivity, rash: 10% frequency

    • Rare: cyanotic discoloration (slate-gray facial pigmentation)

    • Neurological:

      • peripheral neuropathy; sleep disturbance, headache, tremor, some skeletal muscle weakness

  • Drug-drug interaction

    • Potent inhibitor of hepatic metabolism or renal elimination of many drugs.

      • Warfarin, quinidine gluconate , procainamide and digoxin are examples of drugs which may require dosage reduction during amiodarone (Cordarone).

    • Amiodarone displaces digoxin from protein binding sites

      • Digoxin levels may increase as much as 70%

      • Digoxin dose should be decreased as much as 50% when amiodarone is administered concurrently

    Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton & Lange, 1998, pp 216-241; Stoelting, R.K., "Cardiac Antidysrhythmic Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 331-343

Category: Pharmacology Notes