Other Antiarrhythmics

Digoxin and other cardiac glycosides5

Crude digitalis is a preparation of the dried leaf of the foxglove plant Digitalis purpurea or lanata. Digitalis contains a number of active glycosides (digoxin, lanatosides) whose actions are qualitatively similar, differing principally in rapidity of onset and duration; the pure individual glycosides are used. The following account refers to all the cardiac glycosides but digoxin is the principal one.

Mode of action. Cardiac glycosides affect the heart both directly and indirectly in complex interactions,

5 In 1775 Dr William Withering was making a routine journey from Birmingham (England), his home, to see patients at the Stafford Infirmary. Whilst the carriage horses were being changed half way, he was asked to see an old dropsical woman. He thought she would die and so some weeks later, when he heard of her recovery, was interested enough to enquire into the cause. Recovery was attributed to a herb tea containing some 20 ingredients, amongst which Withering, already the author of a botanical textbook, found it 'not very difficult... to perceive that the active herb could be no other than the foxglove'. He began to investigate its properties, trying it on the poor of Birmingham, whom he used to see without fee each day. The results were inconclusive and his interest flagged until one day he heard that the principal of an Oxford College had been cured by foxglove after 'some of the first physicians of the age had declared that they could do no more for him'. This put a new complexion on the matter and, pursuing his investigation, Withering found that foxglove extract caused diuresis in some oedematous patients. He defined the type of patient who might benefit from it and, equally important, he standardised his foxglove leaf preparations and was able to lay down accurate dosage schedules. His advice, with little amplification, would serve today (Withering W 1785 An account of the foxglove. Robinson, London).

some of which oppose each other. The direct effect is to inhibit the membrane-bound sodium-potassium adenosine-triphosphatase (Na+, K+-ATPase) enzyme that supplies energy for the system that pumps sodium out of and transports potassium into contracting and conducting cells. By reducing the exchange of extracellular sodium with intracellular calcium, digoxin raises the store of intracellular calcium, which facilitates muscular contraction. The indirect effect is to enhance vagal activity by complex peripheral and central mechanisms. The clinically important consequences are:

• On the contracting cells: increased contractility and excitability

• On SA and AV nodes and conducting tissue: decreased generation and propagation.

Uses. Digoxin is not strictly an flf/f/arrhythmic agent but rather it modulates the response to arrhythmias. Its most useful property, in this respect, is to slow conduction through the AV node. The main uses are in:

• Atrial fibrillation, benefiting chiefly by the vagal effect on the AV node, reducing conduction through it and thus slowing the ventricular rate.

• Atrial flutter, benefiting by the vagus nerve action of shortening the refractory period of the atrial muscle so that flutter is converted to fibrillation (in which state the ventricular rate is more readily controlled). Electrical cardioversion is preferred.

• Cardiac failure, benefiting chiefly by the direct action to increase myocardial contractility. Digoxin is still occasionally used in chronic left ventricular or congestive cardiac failure due to ischaemic, hypertensive or valvular heart disease, especially in the short term. This is no longer a major indication following the introduction of other groups of drugs.

Pharmacokinetics. Digoxin is usually administered by mouth. It is eliminated 85% unchanged by the kidney and the remainder is metabolised by the liver. The t|/2 is 36 h.

Dose and therapeutic plasma concentration: see Table 24.1. Reduced dose of digoxin is necessary in: renal impairment (see above); the elderly (probably from decline in renal clearance with age); electrolyte disturbances (hypokalaemia accentuates the potential for adverse effects of digoxin, as does hypo-magnesaemia); hypothyroid patients (who are intolerant of digoxin).

Adverse effects. Abnormal cardiac rhythms usually take the form of ectopic arrhythmias (ventricular ectopic beats, ventricular tachyarrhythmias, paroxysmal supraventricular tachycardia) and heart block. Gastrointestinal effects include anorexia which usually precedes vomiting and is a warning that dosage is excessive. Diarrhoea may also occur. Visual effects include disturbances of colour vision, e.g. yellow (xanthopsia) but also red or green vision, photophobia and blurring. Gynaecomastia may occur in men and breast enlargement in women with long-term use (cardiac glycosides have structural resemblance to oestrogen). Mental effects include confusion, restlessness, agitation, nightmares and acute psychoses.

Acute digoxin poisoning causes initial nausea and vomiting and hyperkalemia because inhibition of the Na+, K+-ATPase pump prevents intracellular accumulation of potassium. The ECG changes (see Table 24.1) of prolonged use of digoxin may be absent. There may be exaggerated sinus arrhythmia, bradycardia and ectopic rhythms with or without heart block.

Treatment of overdose. Overdose with digoxin is now uncommon. For severe digoxin poisoning infusion of the digoxin-specific binding (Fab) fragment (Digibind) of the antibody to digoxin, neutralises digoxin in the plasma and is an effective treatment. Because it lacks the Fc segment, this fragment is nonimmunogenic and it is sufficiently small to be eliminated as the digoxin-antibody complex in the urine. It may interfere with the subsequent radioimmunoassay of digoxin in plasma. Phenytoin i.v. may be effective for ventricular arrhythmias, and atropine for bradycardia. Electrical pacing may be needed, but direct current shock may cause ventricular fibrillation.

Interactions. Depletion of body potassium from therapy with diuretics or with adrenal steroids may lead to cardiac arrhythmias (as may be anticipated from its action on Na+, K+-ATPase, above). Verapamil, nifedipine, quinidine and amiodarone raise steady-state plasma digoxin concentrations (see above) and the digoxin dose should be lowered when any of these is added. The likelihood of AV block due to digoxin is increased by verapamil and by |3-adrenoceptor blockers.

Adenosine

Adenosine is an endogenous purine nucleotide which slows atrioventricular conduction and dilates coronary and peripheral arteries. It is rapidly metabolised by circulating adenosine deaminase and also enters cells; hence its residence in plasma is brief (t1/ several seconds) and it must be given rapidly i.v. Administered as a bolus injection, adenosine is useful for distinguishing the origin of (ECG) 'broad QRS complex' tachycardias, i.e. whether ventricular, or supraventricular with aberrant conduction. If the latter is the case AV block with adenosine allows the P waves to be seen and the diagnosis to be made; adenosine thus has the same effect as carotid massage (see below). Evidence also indicates that adenosine is effective for terminating paroxysmal supraventricular (re-entrant) tachycardias, including episodes in patients with Wolff-Parkinson-White syndrome. The initial dose in adults is 3 mg over 2 seconds with continuous ECG monitoring, with doubling increments every 1-2 minutes. The average total dose is 125 micrograms/kg. Adenosine is an alternative to verapamil for supraventricular tachycardia and is possibly safer (because adenosine is short-acting and not negatively inotropic), as verapamil is dangerous if used mistakenly in a ventricular tachycardia. Adverse effects from adenosine are not serious because of the brevity of its action but may cause very distressing dyspnoea, facial flushing, chest pain and transient arrhythmias, e.g. bradycardia. Adenosine should not be given to asthmatics or to patients with second or third degree AV block or sick sinus syndrome (unless a pacemaker is in place).

Cardiac effects of the autonomic nervous system

Some drugs used for arrhythmias exert their actions through the autonomic nervous system by mimicking or antagonising the effects of the sympathetic or parasympathetic nerves that supply the heart. The neurotransmitters in these two branches of the autonomic system, noradrenaline and acetylcholine, are functionally antagonistic by having opposing actions on cyclic AMP production within the car-diomyocyte. Their receptors are coupled to the two trimeric GTP-binding proteins, Gs and Gi, which stimulate and inhibit adenylyl cyclase, respectively.

The sympathetic division (adrenergic component of the autonomic nervous system), when stimulated, has the following effects on the heart (receptor effects):

• Tachycardia due to increased rate of discharge of the SA node

• Increased automaticity in the AV node and His-Purkinje system

• Increase in conductivity in the His-Purkinje system

• Increased force of contraction

• Shortening of the refractory period.

Isoprenaline (isoprotenerol), a ^-adrenoceptor agonist, can be used to accelerate the heart when there is extreme bradycardia due to heart block, prior to the insertion of an implanted pacemaker; this is now rarely needed. Adverse effects are those expected of p-adrenoceptor agonists and include tremor, flushing, sweating, palpitation, headache and diarrhoea.

The vagus nerve (cholinergic, parasympathetic), when stimulated, has the following effects on the heart:

• Bradycardia due to depression of the SAnode

• Slowing of conduction through and increased refractoriness of the AV node

• Shortening of the refractory period of atrial muscle cells

• Decreased myocardial excitability.

These effects are used in the therapy of arrhythmias.

There is also reduced force of contraction of atrial and ventricular muscle cells.

The vagus nerve may be stimulated reflexly by various physical manoeuvres. Vagal stimulation may slow or terminate supraventricular arrhythmias and should if possible be carried out under ECG control.

Carotid sinus massage activates stretch receptors: external pressure is applied gently to one side at a time but never to both sides at once. Some individuals are very sensitive to the procedure and develop severe bradycardia and hypotension.

Other methods include the Valsalva manoeuvre (deep inspiration followed by expiration against a closed glottis, which both stimulates stretch receptors in the lung and reduces venous return to the heart); the Muller procedure (deep expiration followed by inspiration against a closed glottis); production of nausea and retching by inviting patients to put their own fingers down their throat.

The effects of vagus nerve activity are blocked by atropine (antimuscarinic action), an action that is used to accelerate the heart during episodes of sinus bradycardia as may occur after myocardial infarction. The dose is 0.6 mg i.v. and repeated as necessary to a maximum of 3 mg per day. Adverse effects are those of muscarinic blockade, namely dry mouth, blurred vision, urinary retention, confusion and hallucination.

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