CARDIAC GLYCOSIDES, ANTIARRHYTHICS AND DRUGS, USED IN ISCHEMIC HEART DISEASE

2005-04-09T08:18:00.000-07:00

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CARDIAC GLYCOSIDES
Cardiac glycosides – compounds containing steroid nucleus, lactone ring, and polysaccharide chains, are found in several plants. Most well known of them are Digitalis purpurea, Digitalis lanata and Strophanthus gratus. Now the most commonly prescribed cardiac glycoside is Digoxin because of its convenient pharmacokinetics, routes of administration and availability of measurement in serum.

Mode of action
All cardiac glycosides are highly selective inhibitors of the active transport of Na and K across cell membranes, by binding to specific site of Na-K-ATPase, the enzymatic equivalent of the cellular Na-“pump”. This inhibition causes activation of Na-Ca-exchanger and increase of intracellular Ca levels, which interact with contractile proteins of myocardial cells and increasing the contractility of cardiac muscle.

Effects
1) Positive inotropic effect – increasing of the heart velocity and contractility.
2) Negative chronotropic effect – decreasing of heart automatisity and increasing maximal diastolic resting membrane potential in sino-atrial and atrio-ventricular nodes, causing in this way decreased heart conduction.
3) Vasoconstriction in rapid IV administration - transient effect, via inhibition of Na-K-ATPase and increasing of Ca entry cause effect on vascular smooth muscles.

Pharmacokinetics and dosing
Digoxin’s half-life is 48 hours, this permits a once-a-day dosing; then the drug is started, during first week loading dose is given (“digitalisation”), then the treatment is continued with maintenance doses.
Digoxin excreted mainly with urine (most part is unchanged). Tissue reservoir of digoxin is skeletal muscles, so dosing should be based on estimated lean body mass. Monitoring is required during administration (target serum concentration is about 1.0 nanogramm/ml).

Drug interactions of digoxin
Cholestiramine, kaolin-pectin, neomycine, sulfasalasine – decreasing absorption of digoxin
Propafenon, quinidine, verapamile, amiodarone – decreasing distributing volume and renal excretion
Thyroxine – increasing distribution volume and renal clearance
Erythromycine, omeprazole, tetracycline – increasing absorption of digoxin
Captopril, diltiazem, nifedipine, cyclosporine – variable decreasing clearance and distribution volume
Beta-blockers, Ca-blockers, flecainide – decrease heart conduction (enhance negative chronotropic effect of digoxin)
Kaliuretic diuretics – decrease serum and tissue K levels, increase digoxin-induced Na-K-ATP-ase inhibition.

Digoxin toxicity
Digoxin toxicity is more likely to appear in chronic use, in hypokalemic state, and in concurrent use of certain drugs (certain diuretics and heart conduction inhibitors). There are many toxic effects in few body systems:
Psychiatric – delirium, confusion, dizziness, malaise.
Visual – disturbed color vision
Gastrointestinal – anorexia, nausea, vomiting, abdominal pain.
Respiratory – enhanced ventilation
Cardiac – proarrhythmic effects (heart blocks and cardiac arrest)
Antidote therapy – (in presence of toxic effects) – antidigoxin immunotherapy (Fab), administrated intravenously; also advised potassium chloride infusion (even if serum potassium levels are normal).

The cardiac cycle. Image from Purves et al., Life: The Science of Biology, 4th Edition,
ANTIARRHYTHMICS
Antiarrhythmic drug therapy forms the mainstay of management for most important arrhythmias.
Aniarrhythmic drugs divided on classes by their electrophysiological effects.

Class I drugs - sodium channel blockers.
All reduce the maximal rate of depolarization of the action potential and thereby slow conduction. They are divided into classes Ia, Ib, and Ic based on the kinetics of their receptor effects. Drugs with short onset and offset belong to class Ib, those with prolonged effects to class Ic, and those with intermediate effects to class Ia. Class I agents include the older antiarrhythmic drugs (eg, quinidine). They are very effective in suppressing ventricular ectopic beats (VEBs), but to a varying degree, they depress left ventricular performance, and all have been associated with arrhythmogenesis (proarrhythmia effects).

Quinidine - class Ia drug that prolongs action potential and refractoriness. Quinidine syncope is a potentially dangerous effect caused by torsade de pointes; the syncope is idiosyncratic and not predictable. If an initial test dose of quinidine sulfate is tolerated, subsequent oral maintenance dosage is usually 200 to 400 mg q 4 to 6 h. Target plasma concentrations lie between 2 and 6 µg/mL. Elimination half-life (t 1/2) is 6 to 7 h. About 30% of patients develop adverse reactions. GI problems (diarrhea, colic, flatulence) are the most common, fever, thrombocytopenia, and liver function abnormalities also occur. Quinidine is a broad-spectrum agent, effective for the suppression of VEBs and VT and for the control of narrow QRS tachycardias, including atrial flutter and fibrillation. It is one of few drugs that may convert atrial fibrillation to sinus rhythm.

Procainamide - class Ia drug, has much less effect than quinidine on refractoriness. It can be given cautiously IV as 100 mg over 1 to 2 min repeated q 5 min to a usual maximum total dose of 600 mg (rarely up to 1 gm), while monitoring BP and ECG. Oral procainamide has a short elimination t 1/2 (<4>12 mo) will develop serologic abnormalities (notably a positive antinuclear factor test), and up to 40% will have symptoms and signs of hypersensitivity (arthralgia, fever, pleural effusions). The main metabolite, N-acetylprocainamide (NAPA), also has antiarrhythmic effects and contributes to procainamide's efficacy and toxicity.

Disopyramide - a class Ia agent, produces little change in refractory period. It has powerful anticholinergic effects that play only a minor role in arrhythmia management but are responsible for urinary retention and glaucoma; less serious effects - dryness of the mouth, problems of accommodation, bowel upset. Disopyramide has negative inotropic effects, particularly when used parenterally, and it should be used cautiously in patients with markedly impaired left ventricular function. Oral dosing is usually 100 or 150 mg q 6 h. Parenteral dosing - an initial IV dose of 1.5 mg/kg, followed by an IV infusion of 0.4 mg/kg/h. Disopyramide has an elimination t 1/2 of 5 to 7 h. Target plasma concentrations lie between 3 and 6 µg/mL.

Lidocaine - class Ib agent with substantial first-pass hepatic metabolism, is used only parenterally. It produces minimal myocardial depression and has little effect on the sinus node, atrium, or A-V node but acts powerfully upon His, Purkinje, and ventricular myocardial tissue. It can suppress the ventricular arrhythmias that complicate MI (VEBs, VT) and can reduce the incidence of primary ventricular fibrillation (VF) when given prophylactically in early acute MI.. The usual regimen is 100 mg IV over 2 min followed by a further 50 mg IV 5 min later if the arrhythmia has not reverted. An infusion of 4 mg/min (2 mg/min in those >65 yr) should then be started. If continued for >12 h, toxic levels may be reached. Concomitant β-blocker therapy increases the risk of toxicity, and the lidocaine dose should be halved. Lidocaine's elimination t 1/2 is 30 to 60 min. Target plasma concentrations are 2 to 5 µg/L. Unwanted effects are neurologic (tremor, convulsions). Drowsiness, delirium, and paresthesias may occur with too rapid administration.

Mexiletine - class Ib drug, is an analog of lidocaine with similar electrophysiologic actions but has little or no first-pass hepatic metabolism. Oral dosing is 200 to 250 mg q 8 h. A slow release preparation may be given as 360 mg q 12 h. IV dosing is complicated by mexiletine's large volume of distribution. An initial IV dose of 2 mg/kg given at a rate of 25 mg/min should be followed by a 250-mg infusion over 1 h, a 250-mg infusion over the next 2 h, and a maintenance infusion thereafter of 0.5 mg/min. Mexiletine's elimination t 1/2 is 6 to 12 h, and target plasma concentrations - 1-2 µg/mL. Mexiletine, like lidocaine, has few cardiovascular unwanted effects, but GI (nausea, vomiting) and CNS (tremor, convulsions) effects may limit its acceptability.

Tocainide -class Ib, is congener of lidocaine, with little or no first-pass hepatic metabolism. Oral dosing is 400 mg q 8 h. Elimination t 1/2 is 11 to 15 h, and target plasma concentrations lie between 4 and 10 µg/mL. IV dosing is 750 mg infused over 30 min. Continued IV dosing is possible (1200 mg over 24 h), but early recourse to oral therapy is advised. Tocainide's kinetics, indications for use, and unwanted effects are similar to those of mexiletine, but significant unwanted effects, including agranulocytosis, are more likely.

Phenytoin - class Ib. It was used extensively for arrhythmia management, particularly suppressing the ventricular arrhythmias of digitalis toxicity. It has a long elimination t ½ (22 h). With the advent of newer agents and the decline of digoxin toxicity (which may better be treated by digoxin immune fab [Digibind®]), it has little continuing antiarrhythmic role.

Class Ic drugs - are among the most powerful antiarrhythmics but have been associated with a significant risk of proarrhythmia and depression of cardiac contractility. At present, the Ic drugs are used in these latter patients only when the arrhythmia has proved unresponsive to other therapy.

Flecainide - class Ic. By a profound effect on the sodium channel, conduction is markedly slowed but refractoriness is little affected. The proarrhythmia risk of the Ic agents is high. Both flecainide and encainide were associated with an increased mortality (arrhythmogenic). Flecainide is given orally 100 mg q 8 or 12 h. Elimination t 1/2 is 12 to 27 h, and target plasma concentrations are 0.2 to 1µg/mL. It usually is well tolerated, but blurred vision and paresthesia are occasionally reported.

Encainide - class Ic, has similar efficacy and toxicity to flecainide. Unlike flecainide, encainide has at least 3 active metabolites, which are variably formed depending on genetically inherited degradation pathways. Oral maintenance is 75 to 150 mg/day in divided doses. Its long biologic t ½ relies on the active metabolites, so that plasma concentrations of the parent compound (elimination t ½ is about 3 h) are of limited clinical value.

Propafenone - class Ic, has effects similar to those of flecainide and similarly proarrhythmic. Despite low and variable bioavailability, saturable first-pass metabolism, and variable protein binding, dosing is simple (450 to 900 mg/day in divided doses). Initial doses should be small (<= 150 mg tid), and increases should not exceed 50% of the previous dose. It has an elimination t 1/2 of 6 to 7 h. Target plasma concentrations lie between 5 and 8 µg/mL.

Class II drugs – β - blocking agents
The antiarrhythmic effects of the β-blocking agents (class II) are efective to VF. In general, β- blockers are well tolerated but may depress left ventricular function, particularly in antiarrhythmic doses. They are contraindicated in bronchospastic airways disease and should be used cautiously in other types of lung disease. GI disturbances, insomnia, and nightmares may occur.

Class III drugs – potassium channels blockers
Interfere with the potassium channel to alter the plateau phase of the action potential and increase refractoriness. Rarely, they can be pro-arrhythmic.

Amiodarone - a powerful class III antiarrhythmic. Amiodarone has a long elimination t 1/2 (>50 days), with substantial delay in onset of action. Initial oral loading doses of 600 to 1200 mg/day for 7 to 10 days. Oral maintenance doses should be the minimum consistent with arrhythmia control, ideally <= 200 mg/day. Cardiovascular toxicity is rare. Amiodarone is too toxic for long-term use, except for serious arrhythmias. Pulmonary fibrosis may be fatal and may occur in up to 5% of patients treated for >5 yr. Other problems - photosensitive dermatitis; hepatic abnormalities; peripheral neuropathy; corneal microdeposits; hypothyroidism and hyperthyroidism. Torsade de pointes is rarely produced by amiodarone. Unless there is no alternative, amiodarone should not be given to children.

Racemic (DL) sotalol - has both class II and III antiarrhythmic properties. Sotalol is given orally as 80 to 160 mg q 12 h. It depresses left ventricular performance and has been associated with arrhythmogenesis.

Bretylium - also possesses class II and class III actions. It may cause marked hypotension and is indicated only for the management of potentially lethal refractory ventricular tachyarrhythmias (intractable VT, recurrent VF). The initial IV dose is 5 mg/kg, followed by 1 to 2 mg/min as a constant infusion; its ventricular effects may be delayed 10 to 20 min. The initial IM dose is 5 to 10 mg/kg, which may be repeated to a total dosage of 30 mg/kg; the maintenance dosage is 5 mg/kg IM q 6 to 8 h. Bretylium usually is effective within 30 min after IM injection. Target plasma concentrations are 1 to 1.5 µg/mL.

Class IV drugs - calcium entry blockers
Calcium antagonists. Nifedipine, like other dihydropyridines, is almost devoid of conduction electrophysiologic effects, but verapamil and diltiazem influence A-V nodal electrophysiology and may alter that of calcium-dependent ischemic cells.

Verapamil - acts principally on the A-V node, slowing conduction. Used IV, it has a special place in the acute management of tachycardias, involve the A-V node. Reportedly, termination rates approach 100% with doses of 5 to 15 mg IV over 10 min. Oral verapamil 40 to 120 mg tid is widely prescribed for arrhythmia prophylaxis, but the substantial first-pass hepatic metabolism may limit its clinical utility.

Diltiazem - has a similar electrophysiologic profile to verapamil. It has a long t ½, but it has no first-pass hepatic metabolism, making it better suited for chronic arrhythmia prophylaxis.

Miscellaneous
Adenosine - a purine nucleoside, which acts through extracellular adenosine receptors to slow or block A-V nodal conduction. It is rapidly metabolized after administration. The dose is 6 mg initially followed by up to 12 mg by rapid IV injection. It can terminate arrhythmias that involve the A-V node. Adenosine may be safer than verapamil for this purpose through its extremely short duration of action, but unwanted effects (dyspnea, chest discomfort, flushing) occur in 30 to 60% of patients. Adenosine may cause bronchospasm and should not be used in asthmatic patients.

NITRATES
Nitroglycerin is a potent smooth-muscle relaxer and vasodilator. Its major sites of action are in the peripheral vascular tree, especially in the venous or capacitance system and on the coronary blood vessels. Even severely atherosclerotic vessels may dilate in areas without atheroma. It also lowers systolic BP, thus reducing myocardial wall tension, a major determinant of myocardial O2 need. Overall, the drug brings myocardial O2 supply and demand into more favorable balance.

Amyl nitrite, an extremely potent vasodilator, may be effective when severe angina is unresponsive to nitroglycerin and complicated by hypertension. An ampul containing 0.18 or 0.3 mL is crushed and its vapor briefly inhaled; the patient should be lying down and in a well-ventilated room. Because of the drug's potency, only 2 or 3 inhalations are required.

Long-acting nitrates are available in oral and cutaneous preparations.

1. Isosorbide dinitrate, orally, is effective within 1 to 2 h, with persistent action for 4 to 6 h. Initial dosage of 10 to 20 mg qid or q 6 h may be increased, depending on response, to 40 mg qid. Sustained release preparations are also available.
2. Pentaerythritol tetranitrate is an oral preparation, effective for about 6 h. The initial dosage of 10 to 20 mg qid or q 6 h may be increased, depending upon response, to 40 mg qid.
3. Cutaneous patches are available in various sizes, each containing a different amount of nitroglycerin; all are designed to provide prolonged therapeutic effect by slow release of drug.
4. Nitroglycerin ointment: The drug is well absorbed from the skin, especially in a moist environment. Dispensed as a 2% preparation (15 mg/2.5 cm [1 in.]), it is applied over the upper torso or arms at 6- to 8-h intervals.

Nitrate tolerance: When plasma concentrations are held constant, tolerance to nitrates develops within 24 h. Severity varies among individuals. Tolerance appears due to sulfhydryl depletion in smooth muscles with resultant reduced activation of cyclic GMP.

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CARDIAC GLYCOSIDES AND ANTIARRHYTHIC DRUGS

CARDIAC GLYCOSIDES, ANTIARRHYTHICS AND DRUGS, USED IN ISCHEMIC HEART DISEASE