Antiarrythmic drugs


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Antiarrythmic drugs

  1. 1. Antiarrhythmic Drugs Dr. Hiwa K. Saaed PhD Pharmacology
  2. 2. Antiarrhythmic Drugs • Antiarrhythmic drugs Prevent or treat irregularities of cardiac rhythm • Half of all cardiac deaths are due to cardiac arrhythmias • Arrhythmias are due to a disturbance of the electrical impulses which regulate the heart. • cardiac arrhythmias may require RX, because the heart that are beat…………..CAN REDUCE CARDIAC OUTPUT 1. too slowly (bradycardia) 2. too rapidly (tachycardia), 3. regularly (sinus tachycardia or sinus bradycardia) 4. Or irregularly (atrial fibrillation). • The normal heart rate is between 60-100 beats/ minute
  3. 3. What is an Arrhythmia? The arrhythmias are conceptually simple-dysfunctions cause abnormalities in – impulse formation (abnormal automaticity) – conduction in the myocardium (reentry), – or combination of both. However, in the clinic, arrhythmias present as a complex family of disorders that show a variety of symptoms.
  4. 4. Normal heartbeat and atrial arrhythmia Normal rhythm Atrial arrhythmia AV septum To function efficiently, heart needs to contract sequentially (atria, then ventricles) and in synchronicity: SA node→ atrial muscle → AV node (0.15 sec) → bundle of His → Purkinje fibers → ventricular (0.1 sec) Therefore Arrhythmia is defined as any rhythm that does not start at the SA node Or that is not under the usual autonomic control
  5. 5. The heart cavity from which the arrhythmia originates gives the name to the arrhythmia Supraventricular • Ectopic (Extrasystole or PC) (atrial or AV nodal) • Tachycardia (atrial or AV nodal) • Atrial fibrillation and flutter Ventricular • Ectopic (Extrasystole or PC) • Tachycardia • Ventricular fibrillation and flutter NB: more than 3 Ectopic impulses are called tachycardia otherwise they are called premature contraction
  6. 6. Cardiac arrhythmias Arrhythmias are a frequent problem in clinical practice, occurring in up to: – 25% of patients treated with digitalis – 50% of anesthetized patients – 80% of patients with MI • are often associated with hyperthyroidism and electrolyte disorders Factors that precipitate of arrhythmia – Cardiac ischemia, – Hypoxia, – Acidosis, alkalosis – Electrolyte disturbances – Excessive catecholamine exposure – Exposure to toxic substances – Unknown etiology
  7. 7. Cardiac electrophysiology The heart is self-excitable, initiating its own rhythmic contractions,1% autorhythmic cell” SA & AV node, they don’t contract:, SLOW response, Slow upstroke velocity , a smaller magnitude of AP and a brief plateau, No fast Na+ channel, the AP is caused by Ca+2 99% contractile cells, FAST response
  8. 8. The basic events that occur during the formation of the action potential :
  9. 9. Cardiac Action Potential • Divided into five phases (0,1,2,3,4) – Phase 4 - Diastole depolarization the resting membrane potential is maintained by K+ efflux and slow Na+ & Ca2+ influx • Except for the SA node, the heart rests. • Addition of current into cardiac muscle (stimulation) causes – Phase 0 – rapid depolarization- opening of fast Na+ channels • Drives Na+ into cell (inward current), changing membrane potential • Transient outward current due to movement of Cl- and K+
  10. 10. Cardiac Action Potential (con’t) Phase 1 – initial rapid repolarization – Closure of the fast Na+ channels – it is followed by a brief and incomplete period of repolarization. – K+ efflux: This period is mediated by a temporary movement of K+ from the intracellular to the extracellular space. – Cl- influx. – Phase 0 and 1 together correspond to the R and S waves of the ECG
  11. 11. • Phase 2 - plateau phase – sustained by the balance between Ca+ influx and K + efflux – Unique to the cardiac action potential – Normally blocks any premature stimulator signals (other muscle tissue can accept additional stimulation and increase contractility in a summation effect) – This initiates a slow repolarization, and creates a plateau in the action potential. Cardiac contraction is mediated by phase 2. – Corresponds to ST segment of the ECG. Cardiac Action Potential (con’t)
  12. 12. • Phase 3 – rapid repolarization – The calcium channels close. The process of repolarization is accelerated. – K+ channels remain open, Allows K+ to build up outside the cell, causing the cell to repolarize – K + channels finally close when membrane potential reaches certain level – Corresponds to T wave on the ECG Cardiac Action Potential (con’t)
  13. 13. ECG (EKG) showing wave segments Contraction of atria Contraction of ventricles Repolarization of ventricles The electrical events that occur in the heart are reflected in the ECG waveform.
  14. 14. Normal ECG • The P wave: atrial depolarization. • The PR interval: the amount of time the electrical impulse takes to travel from the SA node through the AV node (0.12 to 0.2 seconds). • The QRS represents the amount of time it takes the ventricles to depolarize. In normal conduction, ventricular depolarization occurs rapidly; this rapid conduction is reflected in a narrow QRS interval (< 0.1 sec). • The T wave represents ventricular repolarization. • The QT interval : time that it takes the ventricles to depolarize and repolarize; start of the QRS complex to the end of repolarization (or the end of the T wave). • The normal QT interval is <.44 sec.
  15. 15. Abnormal ECG Waveform • During the early part of the QT interval, the ventricles are completely refractory and unable to respond to another electrical impulse. • During the latter part of the interval, the ventricles are only partially refractory and may respond to some impulses but not to others. Abnormal ECG Waveform • When changes occur in the normal cardiac cycle, the normal ECG waveform is altered to reflect them. For example, • prolonged QT interval: prolonged ventricular repolarization. • prolonged PR interval: A slowing of conduction from the SA node through the AV node. • QRS that is wider than usual or bizarre in shape: Abnormal conduction of the electrical impulse through the ventricles.
  16. 16. 1. Disorders of impulse formation (Abnormal automaticity): • The SA node shows the fastest rate of Phase 4 depolarization, • However, if cardiac sites other than the SA node show enhanced automaticity, they may generate competing stimuli, and arrhythmias may arise. • Cardiac myopathy: Abnormal automaticity may also occur if the myocardial cells are damaged (for example, by hypoxia or potassium imbalance).
  17. 17. 2. Disorders of impulse conduction May result in abnormality in rate: – Bradycardia (if have AV block) – Tachycardia (if reentrant circuit occurs) Reentrant circuit
  18. 18. State-dependent use • Therapeutically useful channel-blocking drugs bind readily to – activated channels (ie, during phase 0) – or inactivated channels (ie, during phase 2) • but bind poorly or not at all to rested channels. • Therefore, these drugs block electrical activity when there is a fast tachycardia rized tissue. Cardiac Na+ channels
  19. 19. BASIC PHARMACOLOGY OF THE ANTIARRHYTHMIC AGENTS • Biggest problem – antiarrhythmics can cause arrhythmia! – Example: Treatment of a non-life threatening tachycardia may cause fatal ventricular arrhythmia – Must be vigilant in determining dosing, blood levels, and in follow-up when prescribing antiarrhythmics • Arrhythmias are caused by abnormal pacemaker activity or impulse propagation. Thus, the aim of therapy is to: 1. reduce ectopic pacemaker activity 2. and modify conduction or refractoriness in reentry circuits to disable circus movement.
  20. 20. Therapeutic overview Vaughan Williams classification 1. Na+ channel blockade Class I 2. β-adrenergic receptor blockade Class II 3. Prolong repolarization Class III 4. Ca2+ channel blockade Class IV Miscellaneous • Adenosine • Digitalis glycosides • K+ • Mg2+
  21. 21. Classification of antiarrhythmic drugs Drugs Mechanism of action comment IA Na+ Channel blocker Moderately Slows phase 0 depolarization in ventricle APD and ERP IB Na+ Channel blocker Shortens phase 3 repolarization in ventricle APD and ERP IC Na+ Channel blocker Markedly Slows phase 0 depolarization in ventricle no effect on APD and ERP II Β adrenergic blocker Inhibits phase 4 depolarization in SA and AV nodes III K+ Channel blocker Prolongs Phase 3 repolarization in ventricle APD and ERP IV Ca+2 Channel blocker Inhibits action potential in SA and AV nodes
  22. 22. Class I – blocker’s of fast Na+ channels • Subclass IA – Cause moderate Phase 0 depression – Prolong repolarization – Increased duration of action potential – Includes • Quinidine – 1st antiarrhythmic used, treat both atrial and ventricular arrhythmias, increases refractory period • Procainamide - increases refractory period but side effects • Disopyramide – extended duration of action, used only for treating ventricular arrhythmias
  23. 23. Class I – blocker’s of fast Na+ channels
  24. 24. Quinidine- indications and MOA • Indication: both VA and SVA • Blocks activated Na+ channel: ↓slope of phase 0 and 4 • Inhibit K+ current:↑phase 3 • Both above effects ↑ Action potential ↑ QT interval • α-blocking  vasodilation reflex tachycardia • Antimuscarinic effect Pharmacokinetics and Drug Interactions • ~80% bound to plasma protein, metabolized by liver; interacts with enzyme inducer and inhibitors 1. ↑digoxin plasma level displace it from tissue and ↓renal excretion. 2. ↑ plasma level of oral anticoagulant & barbiturates.
  25. 25. Quinidine- adverse effects Cardiac Adverse effects: • torsade depoints (↑QT interval) twisting of peak in ECG • Proarrhythmogenic effects, AV block or asystole (toxic dose) Extracardiac Adverse effects: • GIT; DNV • Cinchonism: headache, dizziness, confusion, tinnitus, deafness, blurring of vision • Quinidine syncope because of VA (↑QT); • light headedness and fainting
  26. 26. Procainamide • Both VA, SVA (less sensistive) & PVCs • Orally, IV & IM • Electrophysiological effects are similar to Quinidine. • Less antimuscarinic • but more ganglionic blocking effects. Procainamide- adverse effects • Lupus erythromatous-like syndrome; rash, small joints arthralgia & arthritis • Pleuritis & pericarditis • Hypotension because of ? • Toxic dose: • Asystole, Torsade de points, Hallucination & psychosis
  27. 27. Disopyramide • Both VA & SVA (Treatment and Prophylaxis) • Orally & I.V • Very similar to Quinine EXCEPT more Negative inotropic and antimuscarinic effects • Less side effects & allergy than Quinidine Adverse effects • Cardiac toxicity similar to quinidine • Torsade de points • HF because of negative inotropic effects • Antimuscarinic effects: dry mouth, urinary retention, constipation, Contraindications: glaucoma, BPH,
  28. 28. • Weak Phase 0 depression • Shortened depolarization • Decreased action potential duration – Lidocaine (also acts as local anesthetic) – blocks Na+ channels mostly in ventricular cells, also good for digitalis- associated arrhythmias – Mexiletine - oral lidocaine derivative, similar activity – Phenytoin – anticonvulsant that also works as antiarrhythmic similar to lidocaine Subclass IB: Lidocaine, mexiletine, tocainide, phenytoin
  29. 29. Subclass IB: Lidocaine, mexiletine, tocainide, phenytoin
  30. 30. Class IB-Lidocaine • t1/2 1-1.5 hr given by I.V loading dose followed by I.V infusion • Block both activated & inactivated Na+ channel • ↓The slope of phase 0 & 4 • No ECG changes in PR & QRS Main uses: • VA following MI and local anesthesia NB: Reduce the dose in liver disease and heart failure Adverse Effects: CNS: drowsiness, numbness, parathesia, slurred speeches, difficulty of swallowing, convulsions, nystagmus, tremor, Diplopia Heart: AV block, ↓contractility
  31. 31. Class IB: Tocainide & Mexilitine Are congeners of lidocaine, and they can be administered orally, resist to 1st pass effects Mexilitine has also shown significant efficacy in relieving chronic pain, especially due to diastolic hypertrophy & nerve injury Mexiletine is used for chronic treatment of ventricular arrhythmias associated with previous MI. Tocainide is used for treatment of ventricular tachyarrhythmias. cause pulmonary fibrosis & liver toxic, much less used Cardiac: Bradycardia, Av block, hypotension, ventricular tachycardia Extracardiac: anorexia, nausea, tremor, Pulmonary fibrosis & bone marrow aplasia
  32. 32. Phenytoin • An anticonvulsant that bind to inactivated Na+ channel and prolong the inactivated state • Long t1/2, zero order kinetic difficult to use Drug of choice for Treatment: • Ventricular arrhythmia • digoxin-induced atrial and ventricular Arrhythmia Adverse effects: gingival hyperplasia, ataxia
  33. 33. • Strong Phase 0 depression • No effect of depolarization • No effect on action potential duration • Flecainide (initially developed as a local anesthetic) – Potent blocker of Na+ shorten AP – Potent blocker of K+ prolong AP – Net result no change – Slows conduction in all parts of heart, – Also inhibits abnormal automaticity Proarrhytmogenic : reserved for life threatening SVA & VA in pts without myocardial structural abnormalities Subclass IC: flecainide, propafenone, moricizine
  34. 34. Subclass IC: flecainide, propafenone, moricizine
  35. 35. Class IC- Flecainide, Propafenone & moricizine • Propafenone – Has some structural similarities to propranolol – Weak β – blocker – Also some Ca2+ channel blockade – Also slows conduction – VA & SVA: its spectrum of action similar to that flecainide – AE: metallic taste & constipation • Moricizine – Derivative of phenothiazine – Mechanism of action similar to flecainide-VA – Proarrhythmogenic
  36. 36. Class 1 A, B & C Class I ↓Conduction ERP Automaticity Contraction Site ECG change IA Moderate ↑ Depressed by all More marked for abnormal foci depressed VA &SVA ↑QT IB Minimal ↓ No Only VA ─ IC v. marked ─ depressed VA &SVA ↑QT
  37. 37. Class II – β–adrenergic blockers • Based on two major actions 1) blockade of myocardial β–adrenergic receptors↓cAMP  ↓ both Na+ & Ca+ current 2) Direct membrane-stabilizing effects related to Na+ channel blockade ↓both automaticity & HR and suppression of abnormal pacemaker activity – The AV node is particularly sensitive to β-blockers – The PR interval is usually prolonged by β-blockers
  38. 38. Class II- β–adrenergic blockers Propranolol – Slows SA node and ectopic pacemaking – Can block arrhythmias induced by exercise or apprehension – Other β–adrenergic blockers have similar therapeutic effect – Metoprolol ,Nadolol, Atenolol, Acebutolol, Pindolol, Sotalol, Timolol; prophylactic in MI – Esmolol (very short acting; I.V exclusively for acute surgical arrhythmia) • Toxicities: pts with arrhythmias are more prone to decrease in COP induced by these drugs than are pts with normal heart
  39. 39. Class III – K+ channel blockers Developed because some patients negatively sensitive to Na+ channel blockers (they died!) Cause delay in repolarization and prolonged refractory period Includes: Sotalol, Ibutilide are prototype Amiodarone – markedly prolongs action potential by delaying K+ efflux but many other effects characteristic of other classes Ibutilide – slows inward movement of Na+ in addition to delaying K + influx. Bretylium – is an older drug that combines general sympathoplegic actions & a K+ channel blocking effects in ischemic tissues, first developed to treat hypertension but found to also suppress VF associated with MI Dofetilide - is a newer K+ channel blocker prolongs action potential by delaying K+ efflux with no other effects
  40. 40. Class III – K+ channel blockers
  41. 41. Class III – K+ channel blockers Class III (sotalol, Ibutilide, amiodarone, dofetilide) & class I (quinidine & NAPC) prolong the AP duration ↑ERP prevent tachycardia ↑QT interval Bretylim also produces AP prolongation but causes little ECG change • Bretylium is used for refractory VF & V tachycardia during times of cardiac arrest • AE: postural hypotension, arrhythmogenic Sotalol: effective in both SVA & VA 80-320mg/ daily/oral • AE; tdp, sinus brady cardia, asthma • Ibutilide and Dofetilide are recommended for A. flutter and A. fibrilation • AE: tdp
  42. 42. Class III-Amiodarone • Structurally related to thyroid hormone • Effective in most types of arrhythmias & is most efficacious of all antiarrhythmic, because of toxicities, mainly used in arrhythmias that are resistant to other drugs. • Blocks Na+, Ca+2 & K+ channels and α-& β-receptors • Marked prolongs the QT interval & QRS duration, it increases Atrial, AV and Ventricular refractory period Clinicali use: Long term but last choose. • In patients with AF there is no time for admin of digoxin because of long t1/2 • As alternative for DC shock when not available • The best to control WPW syndrome
  43. 43. Amiodarone-adverse effects • Toxicity because of accumulation • Hepatic, cardiac, pulmonary fibrosis 20% • Thyroid hypo- or hyperthyroidism • Skin photosensitivity-blue discoloration • Nerves peripheral neuritis • Corneal deposits • Kidney not involved • ↑Digoxin level • NB. Rarely cause new arrhythmia b Ca+2, Na+, K+ and α-& β- blockade
  44. 44. Class IV – L-Ca2+ channel blockers Verapamil & diltiazem • slow rate of AV-conduction in patients with atrial fibrillation • ↑ERP  ↑PR interval • Includes – Verapamil – blocks Na+ channels in addition to Ca2+; also slows SA node in tachycardia Suppression of SA node; bradycardia Slowing of AV node: abolish AV reentry – Diltiazem Class IV: Drug of choice for SVA: A flutter and fibrillation b?
  45. 45. Class IV – L-Ca2+ channel blockers Verapamil & diltiazem
  46. 46. Miscellaneous Adenosine I.V bolus (6-12 mg) V. effective, short t1/2 15 secs • Markedly slows or completely blocks conduction in AV node* Probably by hyperpolarizing this tissue through ↑K+ (Ach- sensitive K + channel in SA & AV node) and ↓Ca+2 currents • DOC for SVT due to* replaced verapamil for this use • AE: flushing, hypotension, dyspnea, chest pain Digitalis: rapid atrial or AV nodal arrhythmias atrial flutter and atrial fibrillation. • K+ depress ectopic pacemaker including those caused by digitalis • Mg+2 effective in some cases of tdp and digitalis induced arrhythmia
  47. 47. Effects on Conduction, Refractory Period and ECG Class ECG PR ECG QRS ECG QT Conduction velocity Refractory Period IA +/0 + ++ ↓, ↑ (low dose) ↑ IB 0 0 0/- No/little ↓ ↓ IC + ++ + Much ↓ No/little ↓ II ++ 0 0 ↓ in SAN/AVN ↑ in SAN/AVN III 0 0 ++ No effect ↑↑ IV ++ 0 0 ↓ in SAN/AVN ↑ in SAN/AVN