Antiarrhythmic drugs
Antiarrhythmic drugs
Rhythm of heart depends on cardiac factors:
- The state of cardiac pacemaker;
- The state of conduction system;
- Metabolism and blood supply of myocardium;
Extra-cardiac factors:
- Nervous and endocrine regulation of heart.
Etiology of cardiac arrhythmia
- Myocardial ischemia;
- Heart diseases;
- Electrolytic disturbances;
- Changes of acid-basic state;
- Intoxication with chemical substances;
- Disturbances of heart innervation;
- Endocrine and infection diseases.
Pathogenesis of arrhythmia
The disturbances of automatism, conductivity of the conduction system and cardiomyocytes.
Extra-cardiac mechanisms
- The disturbances of automatism are manifested by the changes in impulse generation in physiological pacemaker (SA-node) or by the appearance of ectopic foci of excitation. All the anti-arrhythmic drugs reduce the automatism.
- The disturbances of conductivity are manifested by the blockades of conduction system of the heart. One can notice the conductivity disturbance in AV-node by the extension of P-R interval in ECG while the one in intraventricular – by the extension of QRST. The functional block of conduction can be one-sided. In this case arrhythmias are developed according to the “reentry”-mechanism. This is the way arrhythmias are developed both in atria and in ventricles. All the anti-arrhythmic drugs slow down the conductivity.
- The changes in size of the effective refractory period (the period of inexcitability between the two spreading impulses). During the refractory period impulses are not perceived. The shorter the effective refractory period is, the more frequently extrasystoles appear as well as the conduction of more frequent impulses. The majority of anti-arrhythmic drugs increase the effective refractory period except the drugs from IC subgroup (Flecainide, Propaphenon).
- Decrease of excitability (low threshold of action potential) is typical at the use of many anti-arrhythmic drugs.
- The reduction of myocardial contractility when the patient is treated with anti-arrhythmic drugs leads to the lower cardiac output. It must be taken into consideration in case of heart failure.
- The changes in tone of adrenergic and cholinergic innervations of heart. Neurogenic stimulation of β1-adrenoreceptors in heart fastens the depolarization process, what leads to more rapid rhythm of heart. The conductivity in SA- and AV-node gets improved. Repolarization and duration of action potential get shorter. It facilitates the formation of arrhythmias. High concentration of catecholamines and thyroid hormones (in case of hyperthyroidism) in blood is also one of the causes of arrhythmia. The opposite action is performed by the increased cholinergic innervation. The function of SA-node is most obviously depressed.
Classification of anti-arrhythmic drugs used for tachiarrythmia and extrasystole
Sodium channel blockers (membrane stabilizers; group I)
Subgroup IA (Quinidine and Quinidine-like drugs): Quinidin sulphate, Novocainamid, Disopyramid, Аjmalin;
Subgroup IB: Lidocaine, Дифенин, Pyromecaine, Trimecaine, Mexiletine;
Subgroup IС: Flecainide, Propaphenon, Etmozine, Ethacyzin;
- β-adrenoblockers;
- Potassium channel blockers (they increase the duration of repolarization and action potential): Amiodaron, Оrnid, Sotalol;
- Slow calcium channel blockers: Verapamil, Diltiazem;
- Other drugs: cardiac glycosides (Adenosine phosphate, cholinoblockers (Atropine), potassium and magnesium drugs.
1st class of anti-arrhythnic drugs. Sodium channel blockers. Membrane stabilizers
Ia subgroup:
Quinidine – alkaloid of a fever-tree (cinchona).
Pharmacodynamics. When acting on cardiomyocytes and Purkinje's fibers Quinidine blocks Na+- channels and slows down the depolarization processes. It blocks К+- channels and slows down repolarization. In increases the effective refractory period, decreases the functions of excitability and automatism that is helpful in the treatment of tachiarrhythmia and extrasystole. Quinidine exerts a week depressing effect onto the cells of SA-node. It also inhibits conductivity in AV-node. Due to its cholinoblocking effect it eliminates the inhibiting influence of nervus vagus that is why AV-conductivity get gradually lower. Inhibition of conductivity is helpful in the treatment of arrhythmia of “reentry”-type. It relaxes the myocardial contractility. When taken orally, anti-arrhythmic effect is achieved in 2-3 hours. The duration of action – 6-8 hours.
Pharmacokinetics. It is absorbed in small intestine, bioavailibility – 70-80%, Т1/2 - 6-7 hours. Biotransformation – in liver; excretion – through kidneys.
Quinidine is prescribed for p/o use in case of permanent or paroxysmal forms of atrial fibrillation, ventricular, supraventricular paroxysmal tachycardia, ventricular and atrial extrasystoles.
Quinidine
Side effects:
- Low heart force;
- Low AP, dizziness, fainting;
- Disturbance of AV-conductivity;
- Ringing in ears, hearing impairment, dizziness, headache, visual impairment, disorientation;
- Nausea, vomiting, diarrhea;
- Thrombocytopenia, hemolytic anemia;
- Allergic reactions;
- In 5% of patients it may cause cardiac arrhythmias.
Contraindications: intracardiac blockades, extended Q-T interval, cardiogenic shock, presence of thrombocytopenic purpura in anamnesis conditioned by the previous use of quinidine.
Dosage forms: 0,1 and 0,2 g tabs. They are taken 30 min before meal or 2 hours after meal.
Procainamide (Novocainamide)
The onset of action is 5-10 min. after being ingested. Administered i/v – immediate action. Duration of action – 3-4 hours, tablets of prolonged action – 5-7 hours.
Dosage forms: tablets – 0,25; 0,375; 0,5 g; retard tablets – 0,25, 0,5, 0,75 and 1,0 g. For the injections – 10 % in 5,0 ml ampoules.
Ib subgroup
Lidocaine (Xycaine)
It is a local anesthetic and arrhythmic drug. It decreases moderately the automatism, excitability and conductivity. It decreases insignificantly the conductivity in AV-node and does not affect SA-node. It is only used for ventricular tachiarrhythmia, especially, for myocardial infarction, for arrhythmias induced by cardiac glycosides.Adverse reactions:- Moderate inhibition of AV-conduction (contraindicated for II-III type AV-block);
- High nervous irritability, dizziness;
- paresthesia;
- tremor.
Administration routs: for the relief of ventricular rhythm disturbances – i/v administration of 0,08-0,12 g of 2% solution, if necessary – continually: 1-4 mg/min. I/m 10% solution – 0,1 – 0,3 g every 3-4hours.Dosage forms: 1% and2% in 5 and 10 ml ampoules; 2% - 2 ml ampoules.
Ic subgroup Propafenone (Propanorm, Rytmonorm)
Pharmacodynamics. It significantly inhibits the excitability and conduction. It increases the effective refractory period of Purkinje’s fibers and the fibers of working myocardium. It dicreases AV-conduction. It exerts a slight β-adrenoblocking action. Effective for supraventricular arrhythmia (paroxysms of atrial fibrillation, paroxysmal supraventricular tachycardia), ventricular extrasystoles and tachiarrhythmias.Pharmacokinetics. Completely absorbed if taken orally, but bioavailibility – 3,4-10%. It is conditioned by the first-pass effect. Т1/2 – 2-10 hours. Binding to plasma proteins – 95%. Metabolism – in liver. Excretion – with bile. Administration routes: p/o – 0,15 g х 3 times a day. I/v – 0,5 mg/kg with the dose increasing up to 1-2 mg/kg, speed of administration – 1 mg/min.Adverse reactions:- Exerts a prominent arrhythmogenic effect in 10 % of patients;
- Relaxes myocardial contraction;
- Dizziness, headaches;
- Constipation, dyspepsia;
- Orthostatic hypotension (in the elderly), bradycardia, cardiac blocks;
- Skin allergic reactions, rarely – bronchospasm, cholestasis, agranulocytosis.
Dosage forms: 0,15 and 0,3 g tabs0,35% solution for injections – 10 and 20 ml.
2nd class of antiarrhythmic drugs (β - adrenoblockers)
β- adrenoblockers: Propranolol, Metoprolol, Atenolol, Bisoprolol(see lecture №6 «Adrenoblockers»). Pharmacodynamics. By blocking β-adrenoreceptors, β- adrenoblockers eliminate the stimulating influence of sympathetic innervation on heart and because of that there’s a reduction of automatism: of SA-node, AV-node, Purkinje’s fibers. β-adrenoblockers are mainly used for supraventricular tachyarrhythmia and extrasystole. In case of fibrillation and flutter of atra β-adrenoblockers do not eliminate atrial arrhythmia but, by hampering AV-conduction, it normalizes the heart rate of the ventricles. At ventricular extrasystoles β-adrenoblockers are effective in cases of intensified automatism.
3rd class of anti-arrhythmic drugs. Calcium channel blockers. Drugs retarding repolarization
Drugs: Amiodarone, Bretylium, Sotalol, Ibutilide, dofetilide, Nibentan.Pharmacodynamics. They block potassium channels, prolong the action potential, repolarization, reduce conduction, prolong the effective refractory peroid, exert membrane-stabilizing and adrenoblocking actions. That’s why Amiodarone and Sotalol perform antianginal action as well. Amiodarone blocks the transformation of triiodothyronine into thyroxin, relaxes the influence of thyroid hormones on myocardium. Amiodarone (Cordarone) – iodine-containing compound (similar to thyroid hormones).Pharmacokinetics. Taken orally, Amiodarone is slowly absorbed. Bioavailiability – 20-55%. Binding to plasma proteins – 97-99%. Т1/2 - 2,5-10 days – at the beginning of the treatment, up to 30-110 days if used for a long time. Metabolism – in liver with the formation of an active metabolite. Excretion – with bile. At renal failure it doesn’t accumulate. Indications: it is used for the treatment and prevention of supraventricular and ventricular arrhythmia, preexcitation syndrome (WPW-syndrome – Wolff-Parkinson-White syndrome), for the treatment of exertional angina and rest angina. Adverse reactions: - bradycardia, cardiac blocks; at the rapid i/v administration – hypotension; growth of heart failure;
- If used for a longer period of time, in 5-15% cases patients develop interstitial pulmonary fibrosis;
- If taken by pregnant women – embryotoxicity;
- Neurologic disorders: headache, sleep disorder, memory disorder, paresthesia.
Dosage forms: 0,2 g tablets; 5% - 3 ml ampoules. Prescribed – 0,2 х 2-3 times a day. For the relief of acute rhythm disturbances one administers 5 mg/kg in 5% -200,0 ml of glucose i/v slowly up to 2-3 times a day monitoring ECG and AP.
4th class of antiarrhythmic drugs. Calcium channel blockers
One distinguishes receptor-dependent Са2+ - channels in cell membranes. Those channels open when the action potential is distributed along the cell membrane (for the depolarization of the cell membrane). Calcium channel blockers block the potential-dependent Са2+-channels. There are several types of potential-dependent Са2+ - channels: L, T, N, P – types. The drugs block Са2+ - channels of L-type. Such channels are found on the membranes of cells in various tissues. They have the most functional value in heart and arterial vessels. Besides, these drugs exert slight broncholytic, tocolytic, antiaggregant and antisclerotic actions.
Verapamil (Isoptin, Finoptin)
Mostly used as an anti-arrhythmic drug. Pharmacodynamics. Verapamil decreases the automatism of SA-node and slows down the heart rate. It inhibits the conductivity and automatism of AV-node, relaxes the heart force, dilates coronary and peripheral arterial vessels, reduces AP. Pharmacokinetics. If taken orally, it is well absorbed. Сmax – 1,5-3 hours. Т1/2 varies from 2,5 to 7,5 hours – after a single administration. And 4,5-12 hours after the repeated use. Bioavailiability – 20-35% what can be explained by intensive biotransformation of the drug in liver (presystemic metabolism). Excretion – through kidneys and intestines. Indications: Verapamil is used for supraventricular tachyarrhythmias, in particular, associated with the reentry-mechanism in AV-node. At fibrillation and flutter of atria Verapamil, hampering AV-conductivity, normalizes ventricular heart rate. At the ventricular arrhythmia the drug is not effective enough. Verapamil is also used for vasospastic angina (Prinzmetal's angina), arterial hypertension, for the prevention of migraines. Adverse reactions:- Bradycardia, reduction of myocardial contractility, hampered AV-conduction;
- Arterial hypotension, dizziness, hot flushes;
- Constipation;
- Edema of ankles (it is connected with the selective dilation of arterioles and precapillaries in the region of arteriovenous shunts – arteries dilate but not veins; insufficient veinous outflow);
- myalgia, arthralgia, paresthesia;
- hyperprolactinemia, gynecomastia.
Contraindications:- II and III type of AV-block;
- Congestive heart failure. It mustn’t be prescribed together with cardiac glycosides, β-adrenoblockers (high concentration in blood, bradycardia, slow AV-conduction).
Dosage forms: 0,04; 0,08 and 0,12 g tablets and dragee; 0,2 and 0,24 g retard-tablets. 0,25% solution for injections in 2 ml ampoules.
It is a local anesthetic and arrhythmic drug. It decreases moderately the automatism, excitability and conductivity. It decreases insignificantly the conductivity in AV-node and does not affect SA-node. It is only used for ventricular tachiarrhythmia, especially, for myocardial infarction, for arrhythmias induced by cardiac glycosides.
Adverse reactions:
- Moderate inhibition of AV-conduction (contraindicated for II-III type AV-block);
- High nervous irritability, dizziness;
- paresthesia;
- tremor.
Administration routs: for the relief of ventricular rhythm disturbances – i/v administration of 0,08-0,12 g of 2% solution, if necessary – continually: 1-4 mg/min. I/m 10% solution – 0,1 – 0,3 g every 3-4hours.
Dosage forms: 1% and2% in 5 and 10 ml ampoules; 2% - 2 ml ampoules.
Ic subgroup Propafenone (Propanorm, Rytmonorm)
Pharmacodynamics. It significantly inhibits the excitability and conduction. It increases the effective refractory period of Purkinje’s fibers and the fibers of working myocardium. It dicreases AV-conduction. It exerts a slight β-adrenoblocking action. Effective for supraventricular arrhythmia (paroxysms of atrial fibrillation, paroxysmal supraventricular tachycardia), ventricular extrasystoles and tachiarrhythmias.
Pharmacokinetics. Completely absorbed if taken orally, but bioavailibility – 3,4-10%. It is conditioned by the first-pass effect. Т1/2 – 2-10 hours. Binding to plasma proteins – 95%. Metabolism – in liver. Excretion – with bile.
Administration routes: p/o – 0,15 g х 3 times a day. I/v – 0,5 mg/kg with the dose increasing up to 1-2 mg/kg, speed of administration – 1 mg/min.
Adverse reactions:
- Exerts a prominent arrhythmogenic effect in 10 % of patients;
- Relaxes myocardial contraction;
- Dizziness, headaches;
- Constipation, dyspepsia;
- Orthostatic hypotension (in the elderly), bradycardia, cardiac blocks;
- Skin allergic reactions, rarely – bronchospasm, cholestasis, agranulocytosis.
Dosage forms: 0,15 and 0,3 g tabs0,35% solution for injections – 10 and 20 ml.
2nd class of antiarrhythmic drugs (β - adrenoblockers)
β- adrenoblockers: Propranolol, Metoprolol, Atenolol, Bisoprolol(see lecture №6 «Adrenoblockers»).
Pharmacodynamics. By blocking β-adrenoreceptors, β- adrenoblockers eliminate the stimulating influence of sympathetic innervation on heart and because of that there’s a reduction of automatism: of SA-node, AV-node, Purkinje’s fibers.
β-adrenoblockers are mainly used for supraventricular tachyarrhythmia and extrasystole. In case of fibrillation and flutter of atra β-adrenoblockers do not eliminate atrial arrhythmia but, by hampering AV-conduction, it normalizes the heart rate of the ventricles. At ventricular extrasystoles β-adrenoblockers are effective in cases of intensified automatism.
3rd class of anti-arrhythmic drugs. Calcium channel blockers. Drugs retarding repolarization
Drugs: Amiodarone, Bretylium, Sotalol, Ibutilide, dofetilide, Nibentan.
Pharmacodynamics. They block potassium channels, prolong the action potential, repolarization, reduce conduction, prolong the effective refractory peroid, exert membrane-stabilizing and adrenoblocking actions. That’s why Amiodarone and Sotalol perform antianginal action as well. Amiodarone blocks the transformation of triiodothyronine into thyroxin, relaxes the influence of thyroid hormones on myocardium.
Amiodarone (Cordarone) – iodine-containing compound (similar to thyroid hormones).
Pharmacokinetics. Taken orally, Amiodarone is slowly absorbed. Bioavailiability – 20-55%. Binding to plasma proteins – 97-99%. Т1/2 - 2,5-10 days – at the beginning of the treatment, up to 30-110 days if used for a long time. Metabolism – in liver with the formation of an active metabolite. Excretion – with bile. At renal failure it doesn’t accumulate.
Indications: it is used for the treatment and prevention of supraventricular and ventricular arrhythmia, preexcitation syndrome (WPW-syndrome – Wolff-Parkinson-White syndrome), for the treatment of exertional angina and rest angina.
Adverse reactions:
- bradycardia, cardiac blocks; at the rapid i/v administration – hypotension; growth of heart failure;
- If used for a longer period of time, in 5-15% cases patients develop interstitial pulmonary fibrosis;
- If taken by pregnant women – embryotoxicity;
- Neurologic disorders: headache, sleep disorder, memory disorder, paresthesia.
Dosage forms: 0,2 g tablets; 5% - 3 ml ampoules. Prescribed – 0,2 х 2-3 times a day. For the relief of acute rhythm disturbances one administers 5 mg/kg in 5% -200,0 ml of glucose i/v slowly up to 2-3 times a day monitoring ECG and AP.
4th class of antiarrhythmic drugs. Calcium channel blockers
One distinguishes receptor-dependent Са2+ - channels in cell membranes. Those channels open when the action potential is distributed along the cell membrane (for the depolarization of the cell membrane). Calcium channel blockers block the potential-dependent Са2+-channels. There are several types of potential-dependent Са2+ - channels: L, T, N, P – types.
The drugs block Са2+ - channels of L-type. Such channels are found on the membranes of cells in various tissues. They have the most functional value in heart and arterial vessels. Besides, these drugs exert slight broncholytic, tocolytic, antiaggregant and antisclerotic actions.
Verapamil (Isoptin, Finoptin)
Mostly used as an anti-arrhythmic drug.
Pharmacodynamics. Verapamil decreases the automatism of SA-node and slows down the heart rate. It inhibits the conductivity and automatism of AV-node, relaxes the heart force, dilates coronary and peripheral arterial vessels, reduces AP.
Pharmacokinetics. If taken orally, it is well absorbed. Сmax – 1,5-3 hours. Т1/2 varies from 2,5 to 7,5 hours – after a single administration. And 4,5-12 hours after the repeated use. Bioavailiability – 20-35% what can be explained by intensive biotransformation of the drug in liver (presystemic metabolism). Excretion – through kidneys and intestines.
Indications: Verapamil is used for supraventricular tachyarrhythmias, in particular, associated with the reentry-mechanism in AV-node. At fibrillation and flutter of atria Verapamil, hampering AV-conductivity, normalizes ventricular heart rate. At the ventricular arrhythmia the drug is not effective enough. Verapamil is also used for vasospastic angina (Prinzmetal's angina), arterial hypertension, for the prevention of migraines.
Adverse reactions:
- Bradycardia, reduction of myocardial contractility, hampered AV-conduction;
- Arterial hypotension, dizziness, hot flushes;
- Constipation;
- Edema of ankles (it is connected with the selective dilation of arterioles and precapillaries in the region of arteriovenous shunts – arteries dilate but not veins; insufficient veinous outflow);
- myalgia, arthralgia, paresthesia;
- hyperprolactinemia, gynecomastia.
Contraindications:
- II and III type of AV-block;
- Congestive heart failure. It mustn’t be prescribed together with cardiac glycosides, β-adrenoblockers (high concentration in blood, bradycardia, slow AV-conduction).
Dosage forms: 0,04; 0,08 and 0,12 g tablets and dragee; 0,2 and 0,24 g retard-tablets. 0,25% solution for injections in 2 ml ampoules.
