Antiarrhythmic agents

Ionic basis of membrane potential and automaticity •Membrane potential •transmembrane potential of cardiac cells determined by •[Na+], [K+], and [Ca++] across cell membrane •permeability of the membrane to each ion •movement of ions across the cell membrane in response to their electrical and concentration gradients •depend on aqueous protein channels •occurring at specific times during the cardiac cycle when the channels are open •produce currents that form the basis of cardiac action potential •Ion channels •ion-specific •fast and slow channels •flux of ions through them are gated •probably flexible peptide chains or energy barriers •each type of channel has its own gate (2 types of gates, m and h) •each type of gate is opened or closed by specific transmembrane voltage, ionic, or metabolic conditions •with each action potential, Na+, Ca++ enter and K+ leaves the cell •Na+/K+ ATPase and other active ion carriers indirectly contribute to the transmembrane potential by maintaining the gradients necessary for diffusion through channels •some ion pumps and exchangers produce net current flow, by exchanging more Na+ for less K+ and are termed electrogenic •Distribution of ions and basis of resting membrane potential
Ion Na+ K+ Ca++ ECF (mmol/l) 145 4 2 ICF (mmol/l) 10 135 10-4 Em +70 -94 +132

NC Hwang 2008

•Calcium L-type channels •opening is voltage-dependent, but requires a more positive membrane potential than cardiac sodium channels •responsible for phase 2 of the action potential of SA and AV nodal cells, atrial, Purkinje and ventricular cells •calcium current entering the cell in phase 2 is intense and prolonged •slow to activate (open) and slow to inactivate (close) •calcium channel activation •pacemaker cells
0 3 4 Slow Ca++ channel K+ channel Outside Inside Ca++ Ca++ Ca++ Ca++ 0 3 4

Phase 0 Fast Na+ channel Slow Ca++ channel K+ channel Outside Inside Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ 2 3 4 2 0 3 4 0 2 3

ICF concentrations are estimated free cytosolic, not total intracellular •Sodium channels •activation (opening) is voltage-dependent •responsible for initial rapid (phase 0) depolarisation of atrial, Purkinje, and ventricular cells •Na+ current entering the cell during phase 0 is intense and brief •activation (opening) and inactivation (closing) is very rapid •SA and AV nodal cells have relatively few sodium channels and therefore lack a rapid phase depolarisation •sodium channel activation
Phase 0 Fast Na+ channel Slow Ca++ channel K+ channel Outside Inside Na+ Na+ Na+ Na+ Na+ 2 3 4 2 0 3 4 0 2 3

•Potassium channels •responsible for “delayed rectifier current” •activated during the repolarisation (phase 3) of action potential •when potassium channel opens, concentration gradient would drive ion out of the cell, but electrical gradient would drive it in (in equilibrium) •potassium channel activation
Phase 0 Fast Na+ channel Slow Ca++ channel K+ channel Outside Inside K+ K+ K+ K+ K+ K+ K+ K+ 2 3 4 2 0 3 4 0 2 3

•Effect of plasma potassium concentration on pacemaker cells •hyperkalaemia results in slowing or stopping the pacemaker •hypokalaemia will facilitate ectopic pacemakers

•Sodium channel blockade •results in •slowing of rate and amplitude of phase 0 depolarisation •reduction in cell excitability and automaticity •reduction in conduction velocity •slow recovery from sodium channel blockade results in lengthening of refractory period

Automaticity •Ionic basis of automaticity

•agents with high affinity for activated channels •affects phase 0 •quinidine, procainamide, disopyramide, lignocaine •agents with high affinity for inactivated channels •affects phase 2 •amiodarone, lignocaine, tocainide, mexiletine •Neural control of automaticity •sympathetic system (catecholamine) increases phase 4 depolarisation •increase rate of decrease of gK during phase 4 •increase gCa •Calcium channel blockade •reduces amplitude and length (time) of phase 2 in atrial, Purkinje and ventricular cells •affects tissue that depend exclusively on calcium current (SA and AV nodes) •verapamil, diltiazem •decreases automaticity •affects phase 4 •disopyramide, amiodarone •decrease AV conduction •PR interval increases •results in negative inotropy and increased effective refractory period

•parasympathetic system (acetylcholine) decreases phase 4 depolarisation leading to increased negativity of Vm •increase gK via a special set of K+ channels leading to membrane hyperpolarisation •decrease gCa •strong vagal stimulation may abolish spontaneous discharge for some time

Antiarrhythmic therapy •Arrhythmia •an abnormality of the rate, regularity, or site of origin of the cardiac impulse; or a disturbance in conduction resulting in an alteration of the normal sequence of activation of the atria and ventricles •caused by •abnormal pacemaker activity (impulse generation, automaticity) •abnormal impulse propagation (conduction) •Factors precipitating arrhythmias •ischaemia •hypoxia •acid base imbalance •electrolyte abnormalities •excessive catecholamine exposure •autonomic influences •drug toxicity (digoxin or antiarrhythmic agents) •overstretching of the cardiac muscles •scarred myocardium •Antiarrhythmic therapy – strategies •sodium channel blockade •calcium channel blockade •potassium channel blockade •blockade of sympathetic effects on the heart

•agents with high affinity for activated channels •affects phase 0 •verapamil •agents with high affinity for inactivated channels •affects phase 2 •verapamil •Potassium channel blockade •blockade prolongs action potential duration and an increase in effective refractory period

•may be associated with torsade de pointes •Beta adrenoceptor blockade •β blockers indirectly reduce the phase 4 slope and decreases automaticity by blocking the positive chronotropic action of noradrenaline in the heart •amiodarone, β blockers

•Key features of antiarrhythmic agents •very low affinity for rested channels •block electrical activity when there is tachycardia where many channel activations and inactivations occur per unit time (use-dependent) •at therapeutic dosages •suppression of ectopic automaticity and abnormal conduction in depolarised cell •minimal effects on electrical activity in normally polarised parts of the heart •may become proarrhythmic or arrhythmogenic during •tachycardia (development of block), •acidosis (slower recovery from block) or •hyperkalaemia •reduction of reentry arrhythmias •steady state reduction in the number of available unblocked channels •prolongation of recovery time of the channels still able to reach the rested and available state, which increases the effective refractory period •as a result, early extrasystoles are unable to propagate at all, later impulses propagate more slowly and are subjected to bidirectional conduction block •with larger dosages •conduction in normal tissue is depressed, eventually resulting in drug-induced arrhythmias •Reduction in unblocked channels without antiarrhythmic therapy with antiarrhythmic therapy % of channels available

Classification of drugs used in cardiac arrhythmias Singh-Vaughan William Classification •Class I agents •all reduce phase 0 and phase 4 Na+ currents in susceptible cells •subdivided into 3 subgroups, IA, IB, IC based on their effects on repolarisation and potency towards blocking the sodium channel

•Class II agents •beta blockers •decrease in gradient of phase 4 (increase RR interval) •Class III agents •all prolong •APD in susceptible cardiac cells by reducing outward phase 3 K+ current, Ikr •effective refractory period (prolonged QT interval, RR interval) •repolarisation •little effect on rate of depolarisation (no effect on QRS) •amiodarone, bretylium, sotalol, ibutilide, dofetilide




-60 mV

Resting membrane potential •Prolongation in recovery time
without anti-arrhythmic therapy with anti-arrhythmic therapy Recovery time constant (ms) 100,000 10,000 1000 100 10 0



•Class IV agents •AV nodal L-type calcium channel blockers •all reduce inward Ca++ current, ICa, during action potential and during phase 4, decreasing the slope of phase 4 •conduction velocity is slowed and refractoriness is prolonged (increase RR interval) •verapamil, diltiazem, bepridil

| -120 -100 -80 -60 mV Resting membrane potential



•available in oral and intravenous formulations, for the treatment of atrial fibrillation, flutter, ventricular tachycardia, AV nodal reentrant arrhythmias, WolffParkinson-White tachycardia, malaria •actions •use-dependent block of Na+ channels •blocks K+ channels •blocks α adrenergic receptors •blocks muscarinic receptors •antiarrhythmic effects •slows SA node •depresses conduction and excitability (esp. depolarised cells) •depresses pacemaker rate (esp. ectopic pacemakers) •reduction in repolarising outward current, increased effective refractory period, lengthens action potential duration, reflected in the ECG as a lengthening of QT interval •recovery from block is slower and less complete in depolarised than in fully polarised tissue •reduces the maximum reentry frequency and can slow tachycardias, converts one-way conduction block into twoway block, thus abolishing the circuit •effects on blood vessels •possesses α adrenoceptor-blocking properties, can cause vasodilatation, reflex increase in sinoatrial node rate •effects most prominent after intravenous administration •adverse effects •α adrenoceptor-blocking properties •hypotension and reflex tachycardia •antimuscarinic action •works against direct effect on SAN and AVN •torsade de pointe (2-8% of patients) •cinchonism: syndrome characterised by nausea, vomiting, diarrhoea, tinnitus, headache, auditory and visual disturbances, vertigo •hypersensitivity reactions •rashes, fever, angioneurotic oedema, hepatitis, reversible thrombocytopenia •pharmacokinetics •absorption: rapidly absorbed from gastrointestinal tract •distribution: 80% bound to plasma proteins •metabolism: metabolised in liver •t½ about 6 hours, longer in presence of congestive heart failure, liver and renal impairment •excretion: 20% excreted unchanged in the urine •enhanced excretion in acid urine •preparation •as sulphate, gluconate, or polygalacturonate salt •dosing •therapeutic plasma concentration is 3-5 µg/ml •rarely administered parenterally because of risk of hypotension (vasodilatation and decrease myocardial contractility)

Limitations to the classification •drugs of the same class tend to produce similar electrophysiologic effects, their clinical actions may differ substantially •not all drugs from the same class will produce the same overall effects •drugs from one class may have significant effects in another class •metabolites of many of the drugs contribute to or are primarily responsible for their antiarrhythmic actions •procainamide and N-acetylprocainamide •encainide and 3-methoxy-O-desmethylencainide •stereoisomers of several drugs can have different actions •stereoisomer of disopyramide have opposite actions on repolarisation, the predominant effect in a given patient depends on the degree of stereospecificity exhibited in elimination of the drug by that patient •only the l-isomer of sotalol has beta blocking activity •adenosine, digoxin, magnesium, alinidine (a chloride channel blocker) have antiarrhythmic actions, but whose actions do not fit the standard 4 classes Functional classification 1=Na+, 2=β, 3=K+, 4=Ca++ •supraventricular arrhythmias •verapamil(1,4), diltiazem(4), adenosine(4), digitalis •ventricular arrhythmias •lignocaine(1), mexiletine(1), tocainide(1), bretylium(1,2,3,4), magnesium •supraventricular and ventricular •procainamide(1,3), quinidine(1,3), disopyramide(1,3,4), flecainide(1,3), beta-blockers(1,2), amiodarone(1,2,3,4) Class I antiarrhythmic agents Quinidine •member of the cinchona alkaloids •quinidine is the d-stereoisomer of quinine •has all of the actions of this agent, including, antimalarial, antipyretic, and oxytocic effects •but actions on the myocardium are far more potent than quinine

Proacainamide •available in oral and intravenous formulations, for the treatment of life threatening ventricular arrhythmias atrial fibrillation/flutter •drug of 2nd choice after lignocaine for treatment of sustained ventricular arrhythmias associated with acute myocardial infarction •actions •use-dependent block of Na+ channels •blocks K+ channels •blocks α adrenergic receptors •blocks muscarinic receptors •therapeutic effects •decreases conduction •depresses cardiac excitability •slows SA node •increases effective refractory period •effects on the heart, compared with quinidine •less effective in suppressing abnormal ectopic pacemaker activity •more effective in blocking sodium channels in depolarised cells •less prominent antimuscarinic action •direct depressant effects on SA node not as effectively counterbalanced by drug-induced vagolysis as with quinidine •other effects •ganglion-blocking properties resulting in vasodilatation and hypotension, particularly with rapid intravenous administration •at therapeutic concentrations, peripheral vascular effects less prominent than those of quinidine •adverse effects •cardiac •antimuscarinic effect, negative inotropic effect, new arrhythmias, torsade de pointes (in renal impaired patient) •syndrome resembling lupus erythematosus (30%) •arthralgia and arthritis, pleuritis, pericarditis, parenchymal pulmonary disease, serologic abnormalities (raise titres of antinuclear antibody) •nausea, diarrhoea •hepatitis •giddiness, psychosis, depression, hallucination •hypersensitivity reaction (fever, agranulocytosis, Raynaud’s syndrome, myalgia, skin rashes, digital vasculitits) •pharmacokinetics •well absorbed orally with 75% bioavailability •metabolism •major metabolite is N-acetylprocainamide (NAPA), which has class III activity •high plasma concentration of NAPA with fast acetylators •t½ about 3-4 hours

•elimination •renal elimination •dose reduction in renal failure •dosing •toxicity arises if plasma concentration >8 µg/ml or NAPA concentration > 20 µg/ml •contraindications and precautions •congestive heart failure •AV conduction effects •digoxin toxicity •myasthenia gravis (can aggravate this condition) Disopyramide •available in oral and intravenous formulations, for the treatment of supraventricular and ventricular arrhythmias •actions •use-dependent block of Na+ channels •blocks K+ channels •blocks Ca++ channels •blocks muscarinic receptors •therapeutic effects •depresses cardiac excitability •slows SA node •decreases conduction •increases effective refractory period •adverse effects •cardiac •toxic concentrations can precipitate arrhythmias (torsades de pointes) •marked reduction in myocardial contractility •may produce heart failure •potential for atrioventricular block •atropine-like activity •urinary retention, dry mouth, blurred vision, constipation, worsening of glaucoma •gastrointestinal symptoms •pharmcokinetics •bioavailability after oral administration about 50% •distribution: extensively protein bound •saturable binding sites, increasing drug dosage increases free drug concentration non-linearly •measurement of plasma concentration may be misleading •metabolism: t½ about 6-8 hours •metabolite N-monodesalkyl disopyramide •excretion by kidney •contraindications and precautions •congestive heart failure •AV conduction defects •myasthenia gravis •enlarged pituitary gland •glaucoma •dosing •available in oral and intravenous formulations •dose reduction with renal impairment •due to risk of precipitating congestive heart failure, loading dose not recommended

Lignocaine •only available in intravenous formulation, effective for the treatment of ventricular arrhythmias (sustained ventricular tachycardia, ventricular fibrillation) and WolffParkinson-White tachycardia •actions •use-dependent block of Na+ channels, high affinity for active and inactive channels •antiarrhythmic effects •depression of rapidly depolarising tissue, effect is minimal on normal heart tissue •very effective agent for suppressing arrhythmias associated with depolarisation (ischaemia, digoxin toxicity) •relatively ineffective against arrhythmias occurring in normally polarised tissues (atrial flutter and fibrillation) •shortens action potential duration, diastole may be prolonged, extending the time for recovery •effective refractory period is also shortened but not to the same degree as the APD, ERP:APD ratio is increased •in striking contrast to quinidine or procainamide, lignocaine causes little or no change in the ECG •the Q-T interval may shorten, but the QRS does not widen •pharmacokinetics •absorption: well absorbed after oral administration •extensive first-pass hepatic metabolism, only 3% of orally administered lignocaine appear in plasma, thus must be given intravenously •kinetics after intravenous administration follow a two compartment model •distribution: rapid and the apparent Vdss ~ 1 L/kg •distribution half-life t½α ~ 8 mins •Vd decreased in patients with congestive heart failure or hypovolaemia •Vd increased in patients with liver disease •affected by the plasma concentration of α1- acid glycoprotein •after myocardial infarction, the acute phase reactant protein increases, making less free lignocaine available •metabolism: elimination half-life t½β ~ 100 mins •t½β determines time to steady state •clearance decreased with congestive heart failure and in liver disease, t½β increased 3 times or more •drugs that decrease liver blood flow (propranolol, cimetidine) reduce lignocaine clearance •with infusions > 24 hours, clearance falls and plasma concentrations rise •elimination •N-dealkylation to monoethylglycine-xylide (MEGX), which in turn is either N-dealkylated to glycine-xylide (GX), or hydrolysed to 2,6xylidine •2,6-xylidine in further metabolised to 4-hydroxy2,6-xylidine, which appears in the urine •MEGX has anti-arrhythmic activity •MEGX t½β = 2 hours GX t½β = 10 hours

•adverse effects •cardiac effects •ventricular arrhythmias in <10% of patients •in patients with acute myocardial infarction, lignocaine precipitates sinoatrial node standstill or worsens impaired conduction •hypotension following depression of myocardial contractility •complete atrioventricular block within the HisPurkinje system may occur in patients with BBB •neurologic •paresthesia, tremor, nausea, lightheadedness, hearing disturbances, slurred speech, convulsions in elderly or vulnerable patient or with rapid intravenous bolus - dose-related, short-lived •contraindications and precautions •congestive heart failure •therapeutic plasma concentration •2-6 µg/ml, achieved by bolus dose of 150-200mg over 15 minutes followed by maintenance of 2-4 mg/min •drugs interactions •negative inotropic action may be potentiated by •disturbances of acid-base, or electrolyte balance •hypoxia •other myocardial depressant drugs •pre-existing myocardial disease •Lignocaine analogues

Tocainide and mexiletine •class IB antiarrhythmic oral analogs of lignocaine for the treatment of ventricular arrhythmias •modified to reduce first-pass metabolism to make chronic oral therapy effective •effects •electrophysiologic effects and antiarrhythmic actions similar to lignocaine •use-dependent block of Na+ channels, high affinity for active and inactive channels •pharmacokinetics •resistant to first-pass metabolism, can be used by oral route •Vd: tocainide: 3L/kg; mexiletine: 5.0 to 6.6 L/kg •metabolism •both do not have active metabolites; mean t½β: tocainide (14h); mexilitine (6-12h), slightly prolonged in cardiac failure

•adverse effects •dose related but seen frequently at therapeutic dosages •neurologic •drowsiness, disorientation, slurred speech, tremor, blurred vision, lethargy •nausea •haematological effects •rash, fever, bone marrow suppression, agranulocytosis (0.5%), thrombocytopenia •pneumonitis and pulmonary fibrosis Flecainide •class IC antiarrhythmic agent available in oral and intravenous formulations, for the treatment of supraventricular and premature ventricular arrhythmias •potent blocker of Na+ and K+ channels •therapeutic effects •slows heart rate, but effect is not always seen •slows cardiac conduction, greatest effect is on HisPurkinje system and ventricular myocardium •adverse effects •severe exacerbation of arrhythmias •neurologic effects •dizziness, tremors, agitation, headache, visual disturbances •gastrointestinal upset •pharmacokinetics •absorption: well absorbed orally •metabolism & elimination •hepatic metabolism and eliminated by kidney meta-O-dealkylated flecainide, meta-Odealkylated flecainide lactam •t½ about 20 hours •contraindications and precautions •proarrhythmias, mortality among patients treated with flecainide was > 2 fold compared with those treated with placebo (Cardiac Arrhythmia Suppression Trial, CAST) •2nd or 3rd degree heart block •left hemiblock •chronic atrial arrhythmias Class II antiarrhythmic agents - Beta adrenoceptor blocking agents •block beta-adrenoceptor and sodium channel •affect phase 4, decrease automaticity •efficacy for suppression of ventricular ectopic depolarisation is lower than that of sodium channel blockers •prolongation of refractory period and action potential duration •decrease conduction in AV node •esmolol, used primarily as antiarrhythmic agent for intraoperative and other acute arrhythmias

Propranolol •class II antiarrhythmic agent available in oral and intravenous formulations, useful in controlling ventricular response in the presence of atrial arrhythmias •actions •non-selectively blocks β1 and β2 adrenergic receptors •therapeutic effects •negative inotropic and chronotropic effects •antihypertensive •decrease renin production •adverse effects •increased end-diastolic volume •vasospasm •increased airway resistance •CNS disturbances: sleepiness, general depression •blood lipid effects: increase plasma triglycerides and decrease HDL-cholesterol Class III antiarrhythmic agents •agents that prolong effective refractory period and action potential duration •prolong action potential duration •blocking potassium channel •enhancing inward sodium and calcium currents •(undesirable property of) reverse use-dependence •least marked at fast rates, most marked at slow rates •risk of torsade-de-pointes •amiodarone is exception, prolonging action potential at all times Amiodarone •has properties of classes I, II, III, IV •antiarrhythmic agent available in oral and intravenous formulations, for the treatment of supraventricular and ventricular arrhythmias •analogue of thyroid hormone •200 mg tablet containing 75 mg of organic iodine •actions •use-dependent block of Na+ channels, high affinity for inactive channels •blocks K+ channels •weakly blocks Ca++ channels •noncompetitive block of α and β adrenergic receptors •therapeutic effects •prolongs action potential •prolongs refractory period •decreases automaticity •depresses conduction and excitability •reduces heart rate •adverse effects •bradycardia in patients with sinus or atrioventricular nodal disease •heart failure in susceptible patients •pulmonary fibrosis, can be fatal •hepatocellular necrosis •yellowish-brown microcrystal deposits in the cornea •rarely reduction of visual acuity

•deposits in the skin, result in photodermatitis in 25% of patients, in <5% of patients, grayish-blue skin discolouration develops, must avoid exposure to the sun •neurologic effects: peripheral neuropathy, paresthesias, tremors, ataxia, headaches, ataxia, dizziness, depression, nightmares, hallucinations •hypothyroidism and hyperthyroidism:occurs in 5% of patients •hypotension and bradycardia after intravenous infusion •thrombophlebitis •increased serum concentrations of LDL-cholesterol •increased serum concentrations of many drugs •pharmacokinetics •incomplete and erratic oral absorption •bioavailability ~ 22-86% •distribution: Vdss ~ 6.3 l/kg •drug accumulates in adipose and highly perfused tissues •metabolism: t½β ~ 14-59 days •principal metabolite is desethylamiodarone, •activity unknown, t½β ~ 60-90 days •dosing •oral dose: 0.8-1.2 g daily for 2 weeks, followed by maintenance dose of 200-400 mg •intravenous: initially 5 mg/kg over 30-60 minutes, followed by 15 mg/kg (maximum 1.2g over 24 h Bretylium •class III antiarrhythmic agent available in intravenous formulation, for treatment of ventricular fibrillation when lignocaine and cardioversion have failed •lengthens ventricular but not atrial action potential duration and effective refractory period •increases ventricular fibrillation threshold and delays the onset of fibrillation after ischaemia •initial release of noradrenaline •positive inotropic effects when first administered, and may precipitate ventricular arrhythmias at onset of therapy •adverse effects •sympathoplegic actions: postural hypotension •nausea, vomiting Sotalol •class III antiarrhythmic agent available in oral and intravenous formulations, for treatment of supraventricular and ventricular arrhythmias •actions •unselectively blocks beta receptors •blocks potassium channels in cardiac muscle •therapeutic effects •negative inotropic and chronotropic effects •prolongs action potential duration and refractory period •adverse effects •associated with beta blockade: increased end-diastolic volume, vasospasm, bronchospasm •associated with dose-dependent prolongation of repolarisation: torsade de pointes, particularly in the presence of hypokalaemia or bradycardia

•contraindications •reduced ventricular function •peripheral vascular insufficiency •bradycardia or AV node conduction problems •asthma •insulin dependent diabetes •precautions •excreted unchanged by the kidney •dose reduction in renal failure Class IV antiarrhythmic agents - Calcium channel blocking agents Verapamil •class IV antiarrhythmic agent available in oral and intravenous formulations for the treatment of supraventricular arrhythmias •a derivative of papaverine and was first used as a coronary vasodilator •blocks both activated and inactivated L-type calcium channels, which are abundant in cardiac and smooth muscle, and are both use and voltage dependent •slows impulse formation in SA node by 10-15% •prolongs AV nodal conduction •prolongs effective refractory period •decrease rate of phase 4 depolarisation in HisPurkinje fibres •therapeutic effects •coronary artery vasodilatation •peripheral vasodilatation •negative inotropic and chronotropic effects •negative dromotropic effect, slowing conduction through AV node •suppress both early and delayed afterdepolarisations (arising from digoxin toxicity) •adverse effects •hypotension •dependent oedema •myocardial depression, heart failure •gastrointestinal disturbances •pharmacokinetics •absorption: bioavailability after oral absorption is about 20-35% due to extensive first pass metabolism •as extent of metabolism decreases with chronic administration and bioavailability improves •onset of action: effects seen within 1-2 hours, reaching a maximum in 5 hrs after oral administration •peak effect after IV administration seen within 10-15 mins •distribution: 90% bound to plasma protein •metabolism: extensively metabolised by liver, dose reduction in patients with liver impairment •t½β of 5-6 hours, increases after prolonged administration •active metabolite norverapamil possesses approximately 20% of the anti-arrhythmic activity of verapamil, t½β 8-13 hrs •excretion: 70% eliminated by kidney, 15% by gastrointestinal tract

•dosing: for supraventricular tachycardia, in patients without heart failure or sinoatrial or atrioventricular nodal disease: •initial bolus of 5 mg over 2-5 minutes, followed a few minutes later by a second 5 mg dose, thereafter 5-10 mg can be administered every 4-6 hours or a constant infusion •oral doses are higher due to first pass effect •contraindication •congestive heart failure •SA or AV nodal conduction disturbances •ventricular tachycardia •Wolf-Parkinson-White syndrome induced atrial fibrillation •hypotension •digoxin toxicity •drug interactions •beta-blockers - can result in AV block •quinidine - reduce clearance of both drugs, potentially can affect SA and AV nodal activities •digoxin toxicity - can increase digoxin concentrations and aggravate digoxin toxicity •afterdepolarisation •early afterdepolarisations •secondary depolarisations occurring before repolarisation is complete •occur relatively close to the plateau of phase 2 •promoted by •decrease outward current of K+ •increase inward current of Na+/Ca++ •delayed afterdepolarisations •secondary depolarisations occurring early in diastole, after full repolarisation •predisposing factors •digoxin •catecholamines •hypercalcaemia •hypokalcaemia •hyponatraemia Miscellaneous antiarrhythmic agents Digoxin

•structure •cyclo-pentano-perhydro-phenanthrene nucleus •has a lipophilic (steroid nucleus) and hydrophilic (lactone ring, hydroxyl, and sugar) group, sugar molecules at C3 •lack an easily ionisable group, hence their solubility is not pH-dependent •mechanism of action •binds to Na+/K+ ATPase, the membrane bound transporter, aka sodium pump •results in a gradual increase in the intracellular Na+ and a gradual but small decrease in intracellular K+ •leads to increased automaticity and development of ectopic rhythm, and decrease in maximal diastolic membrane potential •the less negative the membrane potential at the onset of action potential, the less steep will be the slope of phase 0, leading to reduction in conduction velocity

•Na+/K+ ATPase •several different forms of the enzymes, which consist of α and β subunits •binding sites for Na+, K+, ATP and digoxin are on α subunit •3α and 2β, explains different affinities for cardiac glycosides in different tissues •low concentrations of digoxin stimulate the enzyme •large concentrations inhibit enzyme, explaining positive inotropic effect •electrical effects on Purkinje fibres •action potential duration is decreased due to •shortening of phase 2 caused by increased intracellular calcium, followed by increased potassium conductance •increase in the slope of phase 4 depolarisation •reduction of the resting membrane potential (made less negative), further shortens action potential duration •shortening of action potential contributes to the shortening of atrial and ventricular refractory periods

•ventricular arrhythmias with digoxin •digoxin can initiate extra impulses by 2 means •enhancement of normal phase 4 depolarisation, especially at low serum concentrations of K+ •appearance of delayed afterdepolarisations •development of delayed afterdepolarisation

•atrial muscle •decreased action potential duration and effective refractory period •increased conduction velocity •AV node •slow conduction through the node, possibly to the point of complete block, and greatly prolong the effective refractory period •acetylcholine causes hyperpolarisation in some fibres •the reduction in the action potential amplitude and dV/dt in phase 0 •the delayed recovery of excitability •sympathetic effects •sympathetic outflow sensitises the myocardium and exaggerates all the toxic effects of the drug •changes in sympathetic activity are complex •high doses decrease the sensitivity of the SA and AV nodes to catecholamines •digoxin may inhibit neuronal re-uptake of noradrenaline •noradrenaline plays an important role in digoxin induced arrhythmias •β blockers attenuate, or prevent some induced disturbances of ventricular rhythm •adverse effects •cardiac effects •atrioventricular block •abnormal automaticity •ventricular arrhythmias, bigeminy •gastrointestinal tract •due to direct effect or stimulation of CTZ •anorexia, nausea, vomiting, diarrhoea •central nervous system •vagal and chemoreceptor zone stimulation •disorientation, hallucination, visual disturbances, aberrations of colour perception, agitation, convulsion •hormonal •gynaecomastia •due to either a peripheral oestrogen action of the steroid drugs or hypothalamic stimulation •renal system: diuresis •inhibition of ATPase-dependent transport processes affecting production of aqueous humor and cerebrospinal fluid; and sodium reabsorption in the kidney •interactions •potassium and digitalis •inhibit each other’s binding to Na+/K+ ATPase •hyperkalaemia reduces the enzyme-inhibiting actions of cardiac glycosides, and inhibits abnormal cardiac automaticity •hypokalaemia facilitates the action of glycosides •moderate increase in extracellular K+ reduces the effects of digitalis, especially the toxic effects •calcium and digitalis •hypercalcaemia increases the risk of digitalisinduced arrhythmia

•associated with overloading of intracellular stores and oscillations in the free intracellular Ca++ concentration •on reaching threshold, an action potential (premature ventricular depolarisation) can be elicited which is coupled to the preceding normal one •bigeminy results if afterpotentials in the Purkinje conducting system regularly reaches threshold •with further toxicity, each afterpotential-evoked action potential will itself elicit a suprathreshold afterpotential, and a self-sustaining arrhythmia (ventricular tachycardia) will be established •if allowed to progress, ventricular fibrillation may develop •effect on nodal tissue •at clinical concentrations, digoxin has little direct effect on the SA node, mostly reflex changes •toxic concentrations can depolarise the SA node and depress impulse formation •most of the clinical effects are mediated through reflex autonomic changes •high concentrations depress the AV node, decreased conduction velocity and increased effective refractory period, ultimately complete AV block •effect on atrial and ventricular muscle •the reduction in the action potential duration is not marked but decrease in the QT interval of ECG •an increase slope in phase 2 and a decrease slope in phase 3 •S-T and T wave ECG changes •indirect actions of digoxin •the indirect effects of digoxin predominate over and tend to oppose the direct effects at therapeutic concentrations •at lower dose range, parasympathetic effects predominate, •at toxic concentrations, sympathetic outflow is increased by digoxin •parasympathetic effects •SA node •decreased sinus rate seen in the failing heart •glycoside induced increase in efferent vagal tone •reciprocal decrease in sympathetic tone •an increase in the resting membrane potential (more negative) •a decrease in latent automaticity (phase 4)

•magnesium and digitalis •magnesium effects opposite of calcium •hypomagnesaemia is a risk factor for arrhythmias •pharmacokinetics •absorption: 85% of oral dose is absorbed •10% of individuals harbour enteric bacteria that inactivate digoxin in the gut, greatly reducing bioavailability and require higher than average maintenance dosage •treatment with antibiotic will suddenly increase bioavailability, resulting in toxicity •product formulation can modify bioavailability of digoxin, betamethyldigoxin, a semisynthetic derivative of digoxin is completely absorbed from the gut and is metabolised to digoxin in the body •distribution: 95% protein bound and well distributed to tissues •high tissue concentrations for digoxin (10-50 times higher than plasma concentrations) in heart, kidney, and liver •metabolism: not extensively metabolised in humans, t½β 40 hours (>1.5 days) •occasionally some individuals metabolize digoxin rapidly to inactive metabolite, dihydrodigoxin •decreased in hyperthyroidism •increased in uraemia, congestive heart failure, elderly and hypothyroidism •excretion: 66% excreted unchanged in kidneys •as renal clearance parallels creatinine clearance, excretion is slowed in patients with renal disease •dosing •rapid control, intravenous loading 0.75 to 1 mg/kg •half the dose can be given over 20 minutes, the rest over 10-20 minutes •maintenance dose at intervals of 4-8 hours •too rapid, will induce nausea and risk of arrhythmias Adenosine •a nucleoside, is an important autocoid and endogenous vasodilator in man •acts on adenosine receptors, P1-purine receptors, short duration of action •P1-receptor •subdivided depending upon whether they inhibit (A1) or activate (A2) adenylate cyclase •G-protein coupled receptor •blocked by methylxanthines •these are distinct from P2-purine receptors, which are activated by ATP and are not blocked by the methylxanthines •mechanisms of action •marked hyperpolarisation through enhanced potassium conductance through one type of K+ channel in atrial tissue that is directly linked to A1-receptors •this involves direct interaction of a G-protein with the channel, cAMP synthesis is unaffected •inhibition of cAMP-induced calcium influx

•effects •direct negative inotropic effect •inhibition of atrioventricular nodal conduction •increasing atrioventricular refractory period •vasodilatation •induced hypotension •cerebral and coronary blood flow increases pulmonary vascular resistance decreases but not to the same extent as systemic vascular resistance •decrease GFR in the kidney, by causing contraction of mesangial cells •indications •paroxysmal supraventricular tachycardia, •rarely for ventricular tachycardia •dosing •6 mg IV rapid bolus, followed if necessary by a dose of 12 mg •drug interactions •inhibited by theophylline •potentiated by adenosine uptake inhibitors such as dipyridamole •adverse effects •flushing, headache, hypotension, nausea •bronchospasm •induction of short-lived high-grade atrioventricular block •transient atrial fibrillation •paresthesia •contraindications and precautions •2nd or 3rd degree heart block •sick sinus syndrome Magnesium •used for patients with digoxin induced arrhythmias who are hypomagnesaemic, and with torsade de pointes •mechanism of action •influence Na+/K+ ATPase, sodium channels, certain potassium channels and calcium channels •dosing •1 g over 20 minutes, repeated once if required Potassium •effects of increasing serum potassium •resting potential depolarising action •membrane potential stabilising action, caused by increased potassium permeability •effects of hyperkalaemia •depression of ectopic pacemakers (severe hyperkalaemia suppresses the SA node) and can cause re-entry arrhythmias •slowing of conduction •effects of hypokalaemia •risk of early and delayed afterdepolarisation, ectopic pacemaker activity, especially in digoxin toxicity •indication •maintaining normokalaemia

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