LIDOCAINE
For more information about lidocaine, see Chapter 24.
Use
Lidocaineis important in the treatment of ventricular tachy- cardia and fibrillation, often as an adjunct to DC cardioversion.
An effective plasma concentration is rapidly achieved by giv- ing a bolus intravenously followed by a constant rate infusion.
Mechanism of action
Lidocaineis a class Ib agent that blocks Nachannels, redu- cing the rate of increase of the cardiac action potential and increasing the effective refractory period. It selectively blocks open or inactivated channels and dissociates very rapidly.
Adverse effects
These include the following:
1. central nervous system – drowsiness, twitching, paraesthesia, nausea and vomiting; focal followed by generalized seizures;
2. cardiovascular system – bradycardia, cardiac depression (negative inotropic effect) and asystole.
Pharmacokinetics
Oral bioavailability is poor because of presystemic metabolism and lidocaineis given intravenously. It is metabolized in the liver, its clearance being limited by hepatic blood flow. Heart fail- ure reduces lidocaineclearance, predisposing to toxicity unless the dose is reduced. The difference between therapeutic and toxic plasma concentrations is small. Monoethylglycylxylidide (MEGX) and glycylxylidide (GX) are active metabolites with less anti-dysrhythmic action than lidocaine, but with central nervous system toxicity. The mean half-life of lidocaineis approximately two hours in healthy subjects.
Drug interactions
Negative inotropes reduce lidocaine clearance by reducing hepatic blood flow and consequently predispose to accumula- tion and toxicity.
OTHER CLASS I DRUGS
Other class I drugs have been widely used in the past, but are now used much less frequently. Some of these drugs are shown in Table 32.1.
β-ADRENORECEPTOR ANTAGONISTS
For more information, see also Chapters 28, 29 and 31.
Use
Anti-dysrhythmic properties of β-adrenoceptor antagonists are useful in the following clinical situations:
• patients who have survived myocardial infarction (irrespective of any ECG evidence of dysrhythmia);
β-adrenoceptor antagonists prolong life in this situation;
SELECTEDANTI-DYSRHYTHMICDRUGS 223
• inappropriate sinus tachycardia (e.g. in association with panic attacks);
• paroxysmal supraventricular tachycardias that are precipitated by emotion or exercise;
• rapid atrial fibrillation that is inadequately controlled by digoxin;
• tachydysrhythmias of thyrotoxicosis;
• tachydysrhythmias of phaeochromocytoma, after adequateα-receptor blockade.
Atenololis available for intravenous use after myocardial infarction. Esmolol is a cardioselective β-adrenoceptor antag- onist for intravenous use with a short duration of action (its elim- ination half-life is approximately 10 minutes). β-Adrenoceptor antagonists are given more commonly by mouth when used for the above indications.
Contraindications and cautions Contraindications include the following;
• asthma, chronic obstructive pulmonary disease;
• peripheral vascular disease;
• Raynaud’s phenomenon;
• uncompensated heart failure (β-blockers are actually beneficial in stable patients (see Chapter 31), but have to be introduced cautiously).
Drug interactions
• Beta-blockers inhibit drug metabolism indirectly by decreasing hepatic blood flow secondary to decreased cardiac output. This causes accumulation of drugs such as lidocainethat have such a high hepatic extraction ratio that their clearance reflects hepatic blood flow.
• Pharmacodynamic interactions include increased negative inotropic effects with verapamil(if given intravenously this can be fatal), lidocaine,disopyramideor other negative inotropes. Exaggerated and prolonged hypoglycaemia occurs with insulinand oral hypoglycaemic drugs.
AMIODARONE Use
Amiodaroneis highly effective, but its use is limited by the severity of its adverse effects during chronic administration. It is effective in a wide variety of dysrhythmias, including:
• supraventricular dysrhythmias– resistant atrial fibrillation or flutter, re-entrant tachycardias (e.g. WPW syndrome);
• ventricular dysrhythmias– recurrent ventricular tachycardia or fibrillation.
It can be given intravenously, via a central intravenous line, in emergency situations as discussed above, or orally if rapid dysrhythmia control is not required.
Mechanism of action
Amiodaroneis a class III agent, prolonging the duration of the action potential but with no effect on its rate of rise.
Adverse effects and contraindications
Adverse effects are many and varied, and are common when the plasma amiodaroneconcentration exceeds 2.5 mg/L.
1. Cardiac effects– the ECG may show prolonged QT, U-waves or deformed T-waves, but these are not in themselves an indication to discontinue treatment.
Amiodaronecan cause ventricular tachycardia of the variety known as torsades de pointes. Care is needed in patients with heart failure and the drug is contraindicated in the presence of sinus bradycardia or AV block.
2. Eye–Amiodaronecauses corneal microdeposits in almost all patients during prolonged use. Patients may report coloured haloes without a change in visual acuity. The deposits are only seen on slit-lamp examination and gradually regress if the drug is stopped.
3. Skin– photosensitivity rashes occur in 10–30% of patients.
Topical application of compounds which reflect both UV- A and visible light can help (e.g. zinc oxide), whereas ordinary sunscreen does not; and patients should be advised to avoid exposure to direct sunlight and to wear a broad-brimmed hat in sunny weather. Patients sometimes develop blue-grey pigmentation of exposed areas. This is a separate phenomenon to phototoxicity.
4. Thyroid–amiodaronecontains 37% iodine by weight and therefore may precipitate hyperthyroidism in susceptible individuals; or conversely it can cause hypothyroidism, due to alterations in thyroid hormone metabolism, with a rise in thyroxine (T4) and reverse tri-iodothyronine (rT3), a normal or low T3and a flat thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH).
Thyroid function (T3, T4and TSH) should be assessed before starting treatment and annually thereafter, or more often if the clinical picture suggests thyroid dysfunction.
5. Pulmonary fibrosis– may develop with prolonged use. This potentially serious problem usually but not always improves on stopping the drug.
6. Hepatitis– transient elevation of hepatic enzymes may occur and occasionally severe hepatitis develops. It is idiosyncratic and non-dose-related.
7. Peripheral neuropathy– occurs in the first month of treatment and reverses on stopping dosing. Proximal muscle weakness, ataxia, tremor, nightmares, insomnia and headache are also reported.
Pharmacokinetics
Amiodarone is variably absorbed (20–80%) when adminis- tered orally. However, both the parent drug and its main metabolite, desethyl amiodarone (the plasma concentration of which exceeds that of the parent drug), are highly lipid sol- uble. This is reflected in a very large volume of distribution (approximately 5000 L). It is highly plasma protein bound (over 90%) and accumulates in all tissues, particularly the heart. It is only slowly eliminated via the liver, with a t1/2of 28–45 days. Consequently, anti-dysrhythmic activity may con- tinue for several months after dosing has been stopped, and a loading dose is needed if a rapid effect is needed.
224 CARDIAC DYSRHYTHMIAS
Drug interactions
Amiodarone potentiates warfarin by inhibiting its metab- olism. It can precipitate digoxin toxicity (the digoxin dose should be reduced by 50% when amiodaroneis added) and can cause severe bradycardia if used with β-adrenoceptor antagonists or verapamil.
SOTALOL Use
Sotalolhas uses similar to amiodarone, but a different spec- trum of adverse effects. The plasma Kconcentration should be monitored during chronic use and corrected if it is low in order to reduce the risk of torsades de pointes (see below).
Mechanism of action
Sotalol is unique among β-adrenoceptor antagonists in possessing substantial class III activity. It is a racemate, the
D-isomer possessing exclusively class III activity. A clinical trial of D-sotalol(the ‘SWORD’ study) indicated that it reduces survival in patients with ventricular ectopic activity. The racem- ate is preferred.
Adverse effects and contraindications
Since it prolongs the cardiac action potential (detected on the ECG as a prolonged QT interval) it can cause ventricular tachycardia of the torsades de pointes variety, like amio- darone. Hypokalaemia predisposes to this effect. The beta- blocking activity of sotalolcontraindicates its use in patients with obstructive airways disease, unstable heart failure, peripheral vascular disease or heart block.
Drug interactions
Diuretics predispose to torsades de pointes by causing elec- trolyte disturbance (hypokalaemia/hypomagnesaemia).
Similarly, other drugs that prolong the QT interval should be avoided. These include class Ia anti-dysrhythmic drugs (quinidine, disopyramide), which slow cardiac repolariza- tion as well as depolarization, and several important psy- chotropic drugs, including tricyclic antidepressants and phenothiazines. Histamine H1-antagonists (terfenadine, astemizole) should be avoided for the same reason.
VERAPAMIL Use
Verapamilis used as an anti-dysrhythmic:
• prophylactically to reduce the risk of recurrent SVT, by mouth;
• to reduce the ventricular rate in patients with atrial fibrillation who are not adequately controlled by digoxin alone (but beware interaction causing digoxintoxicity, see below);
• to terminate SVT in patients who are not
haemodynamically compromised. In this setting it is given intravenously over five minutes. Adenosineis generally preferred, but verapamilmay be useful in patients in whom adenosine is contraindicated (e.g. asthmatics).
Mechanism of action
VerapamilblocksL-type voltage-dependent Ca2channels. It is a class IV drug and has greater effects on cardiac conducting tissue than other Ca2antagonists. In common with other cal- cium antagonists, it relaxes the smooth muscle of peripheral arterioles and veins, and of coronary arteries. It is a negative inotrope, as cytoplasmic Ca2is crucial for cardiac contrac- tion. As an anti-dysrhythmic drug, its major effect is to slow intracardiac conduction, particularly through the AV node.
This reduces the ventricular response in atrial fibrillation and flutter, and abolishes most re-entry nodal tachycardias. Mild resting bradycardia is common, together with prolongation of the PR interval.
Adverse effects and contraindications
1. Cardiovascular effects:Verapamilis contraindicated in cardiac failure because of the negative inotropic effect. It is also contraindicated in sick sinus syndrome or intracardiac conduction block. It can cause hypotension, AV block or other bradydysrhythmias. It is contraindicated in WPW syndrome complicated by supraventricular tachycardia, atrial flutter or atrial fibrillation, as it can increase the rate of conduction through the accessory pathway. Verapamil is ineffective in ventricular dysrhythmias and its negative inotropic effect makes its inadvertent use in such
dysrhythmias extremely hazardous.
2. Gastrointestinal tract: About one-third of patients experience constipation, although this can usually be prevented or managed successfully with advice about increased dietary intake of fibre and use of laxatives, if necessary.
3. Other adverse effects: Headache, dizziness and facial flushing are related to vasodilatation (compare with similar or worse symptoms caused by other calcium- channel blockers). Drug rashes, pain in the gums and a metallic taste in the mouth are uncommon.
Drug interactions
The important pharmacodynamic interaction of verapamil with β-adrenoceptor antagonists, which occurs especially when one or other member of the pair is administered intra- venously, contraindicates their combined use by this route.
Verapamil reduces digoxin excretion and the dose of digoxin should therefore be halved when these drugs are combined. For the same reason, verapamilis contraindicated in patients with digoxintoxicity, especially as these drugs also have a potentially fatal additive effect on the AV node.
ADENOSINE Use
Adenosineis used to terminate SVT. In addition to its use in regular narrow complex tachycardia, it is useful diagnos- tically in patients with regular broad complex tachycardia which is suspected of being SVT with aberrant conduction. If adenosineterminates the tachycardia, this implies that the AV node is indeed involved. However, if this diagnosis is wrong SELECTEDANTI-DYSRHYTHMICDRUGS 225
(as is not infrequently the case) and the patient actually has VT, little or no harm results, in contrast to the use of verapamil in VT.
Mechanism of action
Adenosineacts on specific adenosine receptors. A1-receptors block AV nodal conduction. Adenosinealso constricts bronchial smooth muscle by an A1 effect, especially in asthmatics. It relaxes vascular smooth muscle, stimulates nociceptive afferent neurones in the heart and inhibits platelet aggregation via A2-receptors.
Adverse effects and contraindications
Chest pain, flushing, shortness of breath, dizziness and nau- sea are common but short-lived. Chest pain can be alarming if the patient is not warned of its benign nature before the drug is administered. Adenosine is contraindicated in patients with asthma or heart block (unless already paced) and should be used with care in patients with WPW syndrome in whom the ventricular rate during atrial fibrillation may be acceler- ated as a result of blocking the normal AV nodal pathway and hence favouring conduction through the abnormal pathway.
This theoretically increases the risk of ventricular fibrillation;
however, this risk is probably small and should not discour- age the use of adenosine in patients with broad complex tachycardias of uncertain origin.
Pharmacokinetics
Adenosineis rapidly cleared from the circulation by uptake into red blood cells and by enzymes on the luminal surface of endothelial cells. It is deaminated to inosine. The circulatory effects of a bolus therapeutic dose of adenosine last for 20–30 seconds, although effects on the airways in asthmatics persist for longer.
Drug interactions
Dipyridamoleblocks cellular adenosineuptake and potenti- ates its action. Theophyllineblocksadenosinereceptors and inhibits its action.
DIGOXIN
For more information on digoxin, see also Chapter 31.
Use
The main use of digoxinis to control the ventricular rate (and hence improve cardiac output) in patients with atrial fibrilla- tion.Digoxinis usually given orally, but if this is impossible, or if a rapid effect is needed, it can be given intravenously. Since thet1/2is approximately one to two days in patients with nor- mal renal function, repeated administration of a maintenance dose results in a plateau concentration within about three to six days. This is acceptable in many settings, but if clinical circum- stances are more urgent, a therapeutic plasma concentration can be achieved more rapidly by administering a loading dose.
The dose is adjusted according to the response, sometimes sup- plemented by plasma concentration measurement.
Mechanism of action
1. Digoxininhibits membrane Na/Kadenosine
triphosphatase (NaK ATPase), which is responsible for the active extrusion of Nafrom myocardial, as well as other cells. This results in accumulation of intracellular Na, which indirectly increases the intracellular Ca2 content via Na/Ca2exchange and intracellular Ca2storage. The rise in availability of intracellular Ca2 accounts for the positive inotropic effect of digoxin.
2. Slowing of the ventricular rate results from several mechanisms, particularly increased vagal activity:
• delayed conduction through the atrioventricular node and bundle of His;
• increased cardiac output due to the positive inotropic effect of digoxinreduces reflex sympathetic tone;
• small doses of digitalis sensitize the sinoatrial node to vagal impulses. The cellular mechanism of this effect is not known.
ATROPINE Use
Atropine is administered intravenously to patients with haemodynamic compromise due to inappropriate sinus bradycardia. (It is also used for several other non-cardiologi- cal indications, including anaesthetic premedication, topical application to the eye to produce mydriasis and for patients who have been poisoned with organophosphorous anti- cholinesterase drugs; see Chapter 54).
Mechanism of action
Acetylcholine released by the vagus nerve acts on muscarinic receptors in atrial and cardiac conducting tissues. This increases K permeability, thereby shortening the cardiac action potential and slowing the rate of increase of pacemaker potentials and cardiac rate. Atropineis a selective antagonist of acetylcholine at muscarinic receptors, and it thereby coun- ters these actions of acetylcholine, accelerating the heart rate in patients with sinus bradycardia by inhibiting excessive vagal tone.
Adverse effects and contraindications
Parasympathetic blockade by atropineproduces widespread effects, including reduced salivation, lachrymation and sweat- ing, decreased secretions in the gut and respiratory tract, tachycardia, urinary retention in men, constipation, pupillary dilatation and ciliary paralysis. It is contraindicated in patients with narrow-angle glaucoma. Atropine can cause central nervous system effects, including hallucinations.
Pharmacokinetics
Althoughatropineis completely absorbed after oral adminis- tration, it is administered intravenously to obtain a rapid 226 CARDIAC DYSRHYTHMIAS
effect when treating sinus bradycardia, in the event of haemo- dynamic compromise, for example following myocardial infarction.
ADRENALINE Use
Although not usually classed as an ‘anti-dysrhythmic’ drug (it is, of course, powerfully pro-dysrhythmogenic in healthy individuals),adrenaline(also called epinephrine) is used in the emergency treatment of patients with cardiac arrest (whether due to asystole or ventricular fibrillation). For these indications it is administered intravenously (or sometimes directly into the heart or down an endotracheal tube, as dis- cussed in the above section on cardiac arrest). It has important uses other than in cardiac arrest, being essential for the treat- ment of anaphylactic shock (see Chapter 50) and useful in combination with local anaesthetics to reduce the rate of removal from the injection site (see Chapter 24).
Mechanism of action
Adrenaline is a potent and non-selective agonist at both α- and β-adrenoceptors. It causes an increased rate of depolar- ization of cardiac pacemaker potential, thereby increasing heart rate, in addition to increasing the force of contraction of the heart and intense α1-mediated peripheral vasoconstriction (thereby producing a very marked pressor response), which is partly offset by β2-mediated arterial vasodilation.
Adverse effects
Adrenalineis powerfully pro-dysrhythmogenic and increases the work of the heart (and hence its oxygen requirement). Its peripheral vasoconstrictor effect can reduce tissue perfusion.
For these reasons, it is only used systemically in emergency situations.
Pharmacokinetics
Adrenalineis rapidly eliminated from the circulation by a high-affinity/low-capacity uptake process into sympathetic nerve terminals (‘uptake 1’) and by a lower-affinity/higher- capacity process into a variety of tissues (‘uptake 2’). It is subsequently metabolized by monoamine oxidase and catechol-O-methyl transferase, and is excreted in the urine as inactive metabolites, including vanillyl mandelic acid (VMA).
Drug interactions
Tricyclic antidepressants block uptake 1 and so may potenti- ate the action of adrenaline. Adrenoceptor antagonists, both α andβ, block its actions at these receptors.
CALCIUM CHLORIDE Use
Calcium chlorideis uniquely valuable when given (slowly) intravenously for treating the broad complex (‘sine-wave’)
ventricular tachycardia that is a preterminal event in patients with severe hyperkalaemia (often secondary to renal failure; see Chapter 36). Its use may ‘buy time’ during which other meas- ures to lower the plasma potassium concentration (e.g. glucose with insulin, ion-binding resins, dialysis) can take effect or be mobilized. In addition, calcium chloride is used in patients with hypocalcaemia, but these usually present with tetany rather than with cardiac dysrhythmia. It may be useful for treat- ing patients who have received an overdose of Ca2-antago- nists such as verapamilordiltiazem.
Mechanism of action
Ca2 is a divalent cation. Divalent cations are involved in maintaining the stability of the membrane potential in excitable tissues, including the heart. The outer aspects of cell membranes contain fixed negative charges that influence the electric field in the membrane, and hence the state of acti- vation of voltage-dependent ion channels (Naand Ca2) in the membrane. Divalent cations bind to the outer membrane, neutralizing the negative charges and in effect hyperpolariz- ing the membrane. Conversely, if the extracellular concentra- tion of Ca2 falls, Ca2 dissociates from the membrane, rendering it more unstable.
Adverse effects and contraindications
Calcium phosphate can precipitate in the kidneys of patients with hyperphosphataemia, worsening renal function. However, this consideration is irrelevant when one is faced with a hyper- kalaemic patient with broad complex tachycardia.
Drug interactions
• Calcium carbonate precipitates if calcium chloride solution is mixed with sodium bicarbonate. Therefore, these should not be given through the same line, or consecutively without an intervening saline flush.
• Calcium increases digoxintoxicity and calcium chloride must not be administered if this is suspected.
MAGNESIUM Use
Magnesium sulphateby intravenous infusion is used in broad complex tachycardia in the peri-arrest situation, in conjuction with other treatment (DC shock, lidocaineand correction of hypokalaemia). Intravenous magnesium sulphate is some- times effective in treating dysrhythmias caused by digoxinand in drug-induced torsades de pointes. It is invaluable in eclamp- sia in prevention of further convulsions (see Chapter 28).
Magnesium chloride may be particularly useful in settings where magnesium deficiency is common. These include prior chronic diuretic treatment, hypocalcaemia, hypokalaemia, alco- holism, diarrhoea, vomiting, drainage from a fistula, pancreati- tis, hyperaldosteronism or prolonged infusion of intravenous fluid without magnesium supplementation. There is no simple test currently available to detect total body magnesium
SELECTEDANTI-DYSRHYTHMICDRUGS 227