PHARMACOLOGY OF ANTIARRHYTHMIC DRUGS.pptx

anti arrythmics

1. PHARMACOLOGY OF ANTIARRHYTHMIC DRUGS Moderator : Dr. Swarna Latha mam (Assistan t professor) Speaker : Dr . P.Raghava ( PGY 1 )

2. ARRYTHMIA Definition : Disturbances in the h eart rate , rhythm , impulse generation or conduction of electrical impulses responsible for membrane depolarization. Pharmacologic treatment of is based on understanding of the electrophysiologic basis of the abnormality and the mechanism of action of the therapeutic drug to be administered.

3. Introduction : Cardiac arrhythmias occur commonly in the perioperative period. Arrhythmias that require treatment are most commonly s upraventricular ( Atrial fibrillation common. ) physiologic mechanisms 1. Reent ry 2. enhanced a utomaticity .

4. Factors Hypoxemia, Electrolyte ( hypokalemiahypomagnesemia Acid base abnormalities , myocardial ischemia , ( Alkalosis is more likely than Acidosis) altered sympathetic nervous system activity , administration of certain drugs

5. MECHANISM OF ACTION : Antiarrhythmic drugs produce pharmacologic effects by blocking passage of ions across Sodium, Potassium and Calcium ion channels present in the heart.

6. CLASSIFICATION (singh and vaughan william’s classification) Class 1 drugs : inhibit fast Sodium channels during depolarization (phase ) of action potential. Class 1A : lengthen both action potential duration and effective refractory period reflecting blockade of both Sodium and Potassium channels. Class 1B : are less powerful Sodium channel blockers. Class 1C : are potent Sodium channel blockers. Class 2 drugs : these are beta adrenergic antagonists,decrease the rate of spontaneous phase 4 depolarization resulting in decreased autonomic nervous system activity. Class 3 drugs : block Potassium ion channels resulting in prolongation of cardiac depolarization,action potential duration and effective refractory period. Class 4 drugs : act by inhibiting inward slow calcium ion currents.

7. Q U I N I D I N E : Cl a s s 1 A d r u g e f f e c t i v e in t r e a tme n t o f a c u t e an d c h r o n ic s up r a ve n t ri c u l a r a rr h y t h m i a s , (that are associated with Wolff Parkinson white syndrome are effectively suppressed by quinidine) Due to its side effect profile and low therapeutic index it is rarely used. O r a l l y in a d o s e o f 20 - 40 m g QID, therapeutic blood level is 1.2 – 4.0 mcg/ml. MOA : It decreases the slope of Phase 4 depolarization Quinidine is a dextroisomer of Quinine , like quinine it has antimalarial and antipyretic effects.

8. Metabolism : It is hydroxylated in liver and excreted in urine. Enzyme induction significantly shortens the duration of action of quinidine . Concurrent administration of Phenytoin may lower blood levels of quinidine by enhancing liver clearance . Side effects : low therapeutic ratio. reflex increase in SNS activity ( this atropine like action opposes its direct depressant actions on SA and AV nodes and is why Digitalis is often given before quinidine therapy.) Allergic reactions Thrombocytopenia Cinchonism ( Tinnitus , decreased hearing acuity , blurring of vision and gastrointestinal upset) Also interferes with normal neuromuscular transmission and may accentuate the effect of neuromuscular blocking drugs

9. PROCAINAMIDE : Can be given IV at rate not exceeding 100 mg every 5 min till rhythm is c o n t r o l l e d . ( m a x i m u m 1 5 m g / k g ), can also be given orally MOA :It is an analogue of Local anesthetic Procaine. Electrophysiologic action similar to quinidine but produces less prolongation of QTc interval on ECG. Metabolism :eliminated by renal excretion and hepatic metabolism. 40-60% excreted unchanged in urine ( N-acetyl procainamide (NAPA) - k+ channel blocking property , which is cardioactive contributes to antiarrhythmic effects of procainamide ) .

10. Side effects : Nausea and Vomiting ( m/c early n on-Cardiac complication ) Hypotension ( due to direct myocardial depression ) Chronic use syndrome that resembles SLE ( Chronic administration can cause a Serositis, Arthritis, Pleurisy or Pericarditis may develop but unlike SLE Vasculitis is not usually present. Allergic rash, Leucopenia, Thrombocytopenia

11. D I S OP Y R A M I D E : Oral absorption is almost complete , Therapeutic concentration is 2-4 mcg/mg. Not available in IV formulation. Metabolism : 50% excreted unchanged by kidneys. ( Dealkylated metabolite with less antiarrhythmic and atropine like activity than parent drug. ) Side effects : Dry mouth,Urinary hesitancy (Anticholinergic activity) Paradoxical Ventricular Tachycardia. Significant myocardial depressant effect can precipitate CCF and hypotension.

12. LIDOCAINE : Used principally for suppressi on of Ventricular arrhythmia ( reentry cardiac arrhythmias such as PVCs & VT) Dose 2mg/kg IV can be given , ( decrease 50% of initial dose in low cardiac output pts) MOA : It decreases the rate of Phase 4 spontaneous depolarization. Metabolism : Metabolised in liver ( metabolites have cardiac antiarrhythmic activity. )

13. . Side effects : Devoid of side effects when plasma concentration remains less than 5 mcg/ml. Toxic plasma concentrations of 5-10 mcg/ml produces peripheral vasodilation and direct myocardial depression resulting in hypotension. Seizures are possible at doses of 5-10 mcg/ml. CNS depression,apnea,cardiac arrest at concentrations > 10 mcg/ml DOC - ventricular arrythmias occuring due to digitalis toxicity Ineffective in case of atrial arrythmias MEXILETINE It is derived f lignocaine and all properties similar to lignocaine

14. PHENYTOIN : IV dosage is 1.5 mg/kg every 5 min until the cardiac arrhythmia is controlled or 10-15 mg/kg until a max of 1000 mg is administered. Phenytoin can precipitate in 5% dextrose in water , it is preferable to give drug via a delivery tubing containing normal saline. Slow IV injection into large peripheral or central vein is recommended to minimize the likelihood of discomfort or thrombosis at the injection site. MOA :Shortens QTc interval more than other antiarrhythmic drugs. Metabolism : Metabolised by liver. Blood levels of phenytoin can be lowered by drugs such as barbiturates . Warfarin may inhibit metabolism and increase phenytoin blood levels.

15. Side effects : Toxicity- Cerebellar disturbances,ataxia,nystagmus,slurred speech,sedation,mental confusion (blood level > 18 mcg/ml) Partially inhibits insulin secretion . Drug induced bonemarrow depression. Nausea,skin rash,Megaloblastic anemia

16. Indications of class Ia agents supraventricular tachycardia ventricular tachycardia symptomatic ventricular premature beats prevention of ventricular fibrillation can be used for convertion of AF to NSR but only along with AV node blocking agent(digoxin, verapamil, beta blockers) beacuse they increase AV nodal conductivity resulting in paroxysmal tachycardia Indications of class Ib agents only used for ventricular arrythmias Indications of class Ic agents They have maximum proarrythmic property indicated for only resistant and life threatening ventricular arrythmias - VT/VF also indicated for refractory SVT

17. BETA Adrenergic antagonists : are effective for the treatment of cardiac arrhythmias related to enhanced activity of sympathetic nervous system. Propranolol , Esmolol , Metaprolol. o r a l d o s e 1 -8 mg e v e r y 6 - 8 h r s . MOA : Block ing effects of adrenaline and noradrenaline at beta (1) receptors of the heart , which causes a decrease in sympathetic activity on the heart They decrease the slope of phase 4 and also decrease the conduction through AV node.

18. Me t a bo li sm : e x t en s iv e ly m e t a b o l i z e d in liv e r ( 4-hydroxypropranolol with weak beta antiadrenergic effect contributes to antiarrhythmic activity) Side effects :Bradycardia , Hypotension, Myocardial depression Bronchospasm. congestive heart failure( accentuate) Use of propranolol in patients with pre existing AV block is not recommended. Mental depression and Fatigue.

19. SVT Esmolol- shortest acting beta blocker (given IV) Atrial flutter/ Atrial fibrillation ( emergency control of ventricular rate )

20. AMIODARONE : Wide spectrum of activity against refactory supraventricular and ventricular tachyarrhthmias. 5mg/kg IV over 2-5 min produces prompt antiarrhythmic effect. Therapeutic blood concentration 1.0-3.5 mcg/ml. After discontinuation of chronic oral therapy pharmacologic effect of amiodarone lasts for prolonged period (upto 60 days ) It contains 37 .5 % iodine by weight and structurally resembles Thyroxine. - can lead to hyperthyroidism It inhibits 5’ de iodinase - peripheral convertion of T4 to T3 doesnt occur , so can cause hypothyroidism.

21. MOA- antiadrenergic effect , antianginal drug by dilating coronary arteries and increasing coronary blood flow. widest antiarrythmic spectrum ( possess properties of all anti arrythmic drugs- Na channel blockade, k channel blockade, ca channel blockade)

22. Side effects of amioadarone In chronically treated patients if daily dosage exceeds >400mg. 1)Pulmonary toxicity:most serious side effect pulmonary alveolitis. 2)Cardiovascular:proarrhythmic effect (Torsades de pointes) 3) ocular 4) Dermatologic, Slate gray pigmentation of the face, photosensitivity 5) Neurologic, Peripheral neuropathy,tremors,sleep disturbances,headache . 6) Hepatic: Fatty liver. 7) Corneal microdeposits and optic neuropathies. .

23. Indications refractory VT/ VF AF to maintain NSR As prophylaxis in all arrythmias except torsedes de pointes

24. SOTALOL non selective beta blocker lipid insoluble actions of both class 2 and class 3 agents used for Atrial and ventricular arrythmias, A-V re-entrant arrythmias.

25. IBUTILIDE structural analog of sotalol no beta blocking property used for AFib,Aflutter (IV use only ) only drug approved by FDA - for acute conversion of AFib /Aflutter to NSR

26. VERAPAMIL AND DILTIAZEM : Usual dosage 5-10 mg/kg IV.(verapamil) Usual dosage 20 mg IV diltiazem) MOA :these are calcium channel blockers , decrease rate of spontaneous phase 4 depolarization. (L type voltage gated calcium channels ) Metabolism :70 % eliminated by kidneys , 15 % present in bile. Metabolite Norverapamil contributes to the parent drug antiarrhythmic effect .

27. Side effects of verapamil 1)AV block ( more likely in patients with preexisting defects in conduction of cardiac impulses.) 2)Direct myocardial depression and decreased cardiac output ( are likely to be exaggerated in patients with poor left ventricular function.) Uses : Verapamil -DOC for treatment of SVT and prophylaxis of PSVT

28. DIGITALIS : MOA: increses vagal activity , c a n sl o w c o ndu c t i o n o f c a r di a c i m puls e s th r o u g h AV node Conversely enhances conduction of cardiac impulses through accessory bypass tracts and can dangerously increase the ventricular response rate in patients with Wolff-Parkinson-White syndrome. O ral dose : 0.5-1.0 mg in divided doses over 12-24 hrs. Digitalis toxicity is a risk and may manifest as virtually any cardiac arrhythmia ( most commonly atrial tachycardia with block)

29. ADENOSINE : Usual dose 6mg IV followed if necessary by a repeat injection of 6-12 mg IV 3 min later. Effective alternative to calcium channel blockers for acute treatment of PSVT, including conduction through accessory pathways in Wolff Parkinson White syndrome. MOA :stimulates cardiac adenosine receptors to increase potassium ion currents , and hyperpolarize cardiac cell membranes and AV node

30. Side effects : 1) facial flushing,headache,dyspnea,chest discomfort,nausea . Rapid IV administration transient AV block, bronchospasm . Several theories have been proposed to account for adenosine receptors on bronchial smootrh muscle,mast cell degranulation and stimulation of prostaglandin formation.

31. Principles in the clinical use of antiarrhthmic drugs 1. identifying & removing the precipitating factor. 2. establish the goals of treatment 3. mininimising the risks

32. 1)Identify and remove precipitating factors ( Hypoxia,electrolyte disturbances , especially Hypokalemia),myocardial ischemia and certain drugs. 2)Establish the goals of treatment choosing among therapeutic approaches 3 options are available in patients with atrial fibrillation: 1)reduce the ventricular response using AV nodal blocking agents such as Digitalis,verapamil,diltiazem,or beta blockers. 2)restore and maintain normal rhythm using drugs such as amiodarone. 3)decide not to implement antiarrhythmic therapy especially if patient is asymptomatic.

33. 3)Minimize risks : a) Antiarrhythmic drugs can cause arrhythmias ( possibility of provoking new arrhthmias ) with potentially For example treating a ventricular tachycardia with verapamil not only may be ineffective but also can cause catastrophic cardiovascular collapse. b) Monitoring of plasma concentration c) Patient specific contraindications For example patients with history of congestive heart failure are particularly prone to develop heart failure during disopyramide therapy.

34. PRO ARRYTHMIC EFFECTS 1)TORSADES DE POINTES : Triggered by early afterdepolarization in a setting of delayed repolarization and increased duration of refractoriness manifesting as prolongation of the QTc interval on ECG. CLASS 1A and CLASS 3 drugs provide the setting for Torsades de pointes. 2)INCESSANT VENTRICULAR TACHYCARDIA : May be precipitated by drugs that slow conduction of cardiac impulses sufficiently to create a continuous ventricular tachycardia circuit. Seen with high doses of CLASS 1C drugs and in patients with a prior history of sustained VT and poor left ventricular function.

35. WIDE COMPLEX VENTRICULAR RHYTHM : Is defined as a cardiac rhythm with rate >100bpm and QRS width >120 milliseconds. Is usually associated with CLASS 1C drugs in the setting of structural heart disease . Excessive plasma concentrations of the drug or an abrupt change in the dose may result in this arrhythmia.

36. References Stoeltings Pharmacology and Physiology 5th edition Stoeltings Anesthesia and co existing diseases 8th edition K.D Tripathi Medical Pharmaclogy 8th edition

37. THANK YOU.