![etiology
Ischemia/hypoxemia
Imbalance of the parasympathetic & sympathetic
branches of the ANS
Serum electrolyte imbalance[K+ & Ca ++]
Activation of RAAS
Pharmacologic therapy
Inherited causes (rare)
Arrhythmia associated with acquired heart diseases viz
CHF, viral myocarditis etc
Infarction of the heart muscle](https://image.slidesharecdn.com/antiarryhtmia-140610041746-phpapp01/85/ANTIARRHYTHMIC-AGENTS-IN-VETERINARY-PRACTICE-8-320.jpg)
ANTIARRHYTHMIC AGENTS IN VETERINARY PRACTICE.
- 1. ANTIARRHYTHMIC AGENTS IN VETERINARY PRACTICE PRESENTED BY SINDHU K MVSC SCHOLAR, DEPT OF VPT, COVAS, POOKODE.
- 2. ARRYTHMIA Is an abnormality in the rate , regularity , or site of origin of cardiac impulse or a disruption in impulse conduction such that the normal sequence of atrial & ventricular activation is changed.
- 5. Cardiac Action Potential Divided into five phases (0,1,2,3,4) Phase 4 - resting phase (resting membrane potential) Phase cardiac cells remain in until stimulated Associated with diastole portion of heart cycle Addition of current into cardiac muscle (stimulation) causes Phase 0 – opening of fast Na channels and rapid depolarization Drives Na+ into cell (inward current), changing membrane potential Transient outward current due to movement of Cl- and K+ Phase 1 – initial rapid repolarization Closure of the fast Na+ channels Phase 0 and 1 together correspond to the R and S waves of the ECG
- 6. Cardiac Action Potential (con’t) Phase 2 - plateau phase sustained by the balance between the inward movement of Ca+ and outward movement of K + Has a long duration compared to other nerve and muscle tissue Normally blocks any premature stimulator signals (other muscle tissue can accept additional stimulation and increase contractility in a summation effect) Corresponds to ST segment of the ECG. Phase 3 – repolarization 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
- 7. +30 mV 0 mV -80 mV -90 mV OUTSIDE MEMBRANE INSIDE Na+ 0 4 3 2 1 K+ Ca++K+ At p K+ Na+ K+ Ca++ Na+ K+ Na+ Resting open Inactivated Phase zero depolarization Early repolarization Plateau phase Rapid Repolarization phase Phase 4 depolarization
- 8. etiology Ischemia/hypoxemia Imbalance of the parasympathetic & sympathetic branches of the ANS Serum electrolyte imbalance[K+ & Ca ++] Activation of RAAS Pharmacologic therapy Inherited causes (rare) Arrhythmia associated with acquired heart diseases viz CHF, viral myocarditis etc Infarction of the heart muscle
- 9. A: Contractile cell B: Autorhythmic cell: spontaneous depolarization at phase 4 Transmembrane Potentials of Myocardial Cells
- 10. Alterations of normal automaticity Autonomic neurotransmitters
- 11. . Structural & electrical remodeling, hemodynamic changes & neuroendocrine signals each influence the ion channel function, intracellular calcium response, intercellular communications & matrix composition. Cardiac arrhythmias arise from 2 primary abnormality 1) Impulse initiation{spontaneous automaticity & triggered activity} 2) Impulse propagation{conduction }
- 12. Impulse initiation Establishes heart rate Determined primarily by the rate of diastolic depolarization ie., slope of phase 4 In normal heart : heart rate is autonomically controlled Decreased by Acetylcholine release from parasympathetic nerves & Increased by Norepinephrine release from adrenal cortex
- 13. b) Trigerred automaticity +30 mV 0 mV -80 mV -90 mV Delayed After Depolarisation (DAD) Intracellular cal. Overload (Ischemia reperfusion, adr.stress, digitalis intoxication or heart failure)
- 14. Disturbances in automaticity Automatic cells of the SA node are dominant pacemaker , reaching threshold first with the resultant propagating impulse exciting all other potential pacemaker cells before they spontaneously attain threshold values If automaticity of the SA node is depressed/the spontaneous firing rate in some other tissue (latent pacemaker)is accelerated , region of the heart other than SA node serves as pace maker & initiates ectopic impulses
- 15. 1.The slope of phase 4 can be affected by a no of abnormal conditions. Enhanced automaticity occurs when the rate of spontaneous diastolic depolarization increases sufficiently to allow emergence of pathologically slowed or increased rates { sinus tachycardia } 2.Ectopic foci(pace makers that normally are latent) May emerge & may cause tachycardia if the frequency exceeds that of sinoatrial node.
- 16. Less negative RMP More negative TP Ectopic pacemaker activity
- 17. a) Enhanced automaticity Automatic behavior in sites ordinarily lacking pacemaker activity CAUSES: Ischaemia/digitalis/catecholamines/acidosis/ hypokalemia/stretching of cardiac cells Nonpacemaker nodal tissues: membrane potential comes to -60mv Increased slope of phase 4 depolarisation Become ECTOPIC PACEMAKERS.(AV nodal rhythm, idioventricular rhythm, ectopic beats)
- 18. 2 types of triggered arrhythmias occurs 1}Delayed after – depolarization : occurs after a normal action potential & is followed by an overload of intracellular calcium Eg : arrhythmias associated with myocardial failure , myocardial ischemia , adrenergic stress , digoxin toxicity 2}Early after – depolarization : upstrokes occur during phase 3 repolarization & follow abnormally long action potentials. Eg : results from abnormal inward sodium or calcium channel currents or exchange pumps & associated with very slow heart rates or low extracellular K+
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- 20. Drugs MOA Drugs decreases the rate/slope of phase 4 spontaneous depolarization ,suppressing the ectopic focus such that SA node is allowed to resume its dominance , thus decreases automaticity. Na+/Ca+ channel blockers ; more positive – lengthening the time needed to attain threshold potential by increasing the excitation threshold Hyperpolarisation ; more negative – by increasing the diastolic membrane potential Shortening of the AP duration will inhibit EAD`s(magnesium also inhibit EADs but MOA unknown)
- 22. Disturbances in impulse conduction Associated with a phenomenon of REENTRY or CIRCUS movement. REENTRANT arrhythmias : anatomic functional Anatomic arrhythmias involves 2/more pathways that travel to the same region of the heart but differ in electrophysiology. Functional reentrant arrhythmias are exemplified by pathologies viz ISCHEMIA that markedly slows conduction.
- 23. The concept of REENTRY(Schmidt & Erlanger 1929) Based on very slow conduction velocity An area of heart demonstrating unidirectional block of impulse conduction Abnormally brief refractory period This theory holds that a cardiac impulse can travel circuitously around an anatomic loop of fibers in which slowed conduction velocity & brief refractoriness permit the impulse to arrive at cells that are no longer refractory , there by permitting perpetual reexcitation
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- 25. Reentrant Arrhythmias Anatomic or functional reentrant circuit Unidirectional block on one path; Slow conduction on the other path .
- 26. Drugs MOA Reentry can be controlled by drug that either creates bidirectional block or bidirectional conduction through the region of cells causing the unidirectional block Blocking specific ion channels {suppress initiation & automaticity}/ by targeting autonomic functions thus altering initiation or conduction or AP duration {thus refractory period} Drugs that facilitates adenosine / acetylcholine – thus increasing the maximum diastolic or resting potential Drugs used to antagonize adrenergic receptors – thus decreasing the slope of phase 4
- 27. . TACHYARRHYTHMIAS BRADYARRHYTHMIAS Atrial tachycardia , Sinus tachycardia Sinus arrest Junctional tachycardia , supraventricular tachycardia Sick sinus Atrial flutter , atrial fibrillation AV - block Ventricular fibrillation Cardiac arrest Paroxysmal tachycardia
- 28. Arrhythmia Conditions Extrasystole: abnormal automaticity/after depolarization Paroxysmal Supraventricular Tachycardia: 150 - 200/minute (1:1), reentry phenomenon (AV node) Atrial Flutter: 200-350/minute (2:1), reentrant circuit in right atrium Atrial Fibrillation: 350-550/min, electrophysiological inhomogenicity of atrial muscles (bag of worms) Ventricular tachycardia: 4 or more consecutive extrasystole of ventricles Ventricular Fibrillation: rapid irregular contractions – fatal (MI, electrocution) Torsades de pointes: polymorphic ventricular tachycardia, rapid asynchronous complexes, rise and fall in baseline of ECG Atrio-ventricular Block (A-V Block): vagal influence or ischaemia - 1st, 2nd and 3rd degree
- 29. Diagnostic Approaches to Arrhythmias History and physical examination ECG Ambulatory ECG recording: Holter recording Exercise ECG: treadmill test Trans-esophageal electrophysiological study Invasive electrophysiological study (EPS)
- 30. Management of Arrhythmias Antiarrhythmic drugs Cardiac pacemakers DC cardioversion/defibrillation Implantable cardioverter/defibrillater (ICD) Radiofrequency catheter ablation Surgical operation
- 31. Classification of antiarrhythmic drugs Grouped into 4 main classes according to SINGH VAUGHAN WILLIAMS classification introduced in 1970. CLASS I : sodium channel blockers CLASS II : beta adrenoceptor antagonists CLASS III : potassium channel blockers CLASSIV : calcium channel blockers
- 32. +30 mV 0 mV -80 mV -90 mV OUTSIDE MEMBRANE INSIDE Na+ 0 4 3 2 1 K+ Ca++K+ At p K+ Na+ K+ Ca++ Na+ Na+Ca++K+ RATE SLOPE Effective Refractory Period RMP THRESHOLD POTENTIAL Possible MOA of antiarrythmic agents
- 33. Vaughan Williams classification of antiarrhythmic drugs Class I: block sodium channels Ia (quinidine, procainamide, disopyramide) AP Ib (lignocaine) AP Ic (flecainide) AP Class II: β-adrenoceptor antagonists (propranolol, sotalol) Class III: prolong action potential and prolong refractory period (suppress re-entrant rhythms) (amiodarone, sotalol) Class IV: Calcium channel antagonists. Impair impulse propagation in nodal and damaged areas (verapamil, diltiazem) . Phase 4 Phase 0 Phase 1 Phase 2 Phase 3 0 mV -80mV II I III IV `
- 34. Class I : Na channel blockers Class I A drugs : quinidine, procainamide, disopyramide Class I B drugs : lidocaine, mexiletine, tocainide, phenytoin, aprindine Class I C drugs : flecainide, propafenone, moricizine, encainide, indecainide
- 35. Class I: Na+ Channel Blockers IA: Ʈrecovery moderate (1- 10sec) Prolong APD IB: Ʈrecovery fast (<1sec) Shorten APD in some heart tissues IC: Ʈrecovery slow(>10sec) Minimal effect on APD
- 36. Class IA
- 37. QUINIDINE Prototype class IA Quinidine is an alkaloid obtained from cinchona bark & is dextro-isomer of antimalarial drug quinine MOA 1) Blocks myocardial Na+ channels in frequency of use dependent manner 2) Intermediate association with open/inactivated Na channels & intermediate rate of dissociation from resting channels. 3) Prolongs AP due to K+ channel block 4) @ high conc, quinidine also inhibits L type Ca++ channels
- 38. PK of quinidine Nearly completely absorbed from GIT after oral administration Under goes hepatic first pass effect Following I/V administration rapidly passed from blood & distributes into tissues, except brain. Highly protein bound (~90%) Metabolized in liver by hydroxylation Serum ½ life: 6 hours dogs & swine 2 hours cats 2.5 hours cattle 8 hours horses 1 hour goats
- 39. Adverse effects Dogs & cats : anorexia, nausea, vomiting, diarrhea. Horses : swelling of nasal mucosa, urticarial wheals & laminitis Sinus tachycardia, increased ventricular rates in patients atrial fibrillation, hypotension, syncope, pro arrhythmic effects OVER DOSAGE : depressed automaticity & conduction/ tachyarrhytmias QUINIDINE TOXICITY : 25% increase in duration of QRS complex, atrioventricular block, acceleration of ventricular tachyarrythmia Dogs : therapeutic range @ 2.5 – 5 micro g/ml toxic range @ > 10 micro g/ml
- 40. TREATMENT OF QUINIDINE TOXICITY 1)I/V administration of sodium lactate 1/6 M or sodium bicarbonate may reduce cardiotoxic effects by increasing quinidine protein binding 2)Supportive & symptomatic measures Forced diuresis using fluids & diuretics along with reduction of urinary pH may enhance the renal excretion of quinidine
- 41. Contraindications & interactions CI in complete AV block, intraventricular conduction defect, aberrant ectopic impulses, myasthenia gravis, hepatic impairment & drug sensitivity. DRUG INTERACTIONS Increases digoxin, amiodarone, verapamil serum concentration. Enhances negative inotropic & hypotensive effects of beta adrenoceptor antagonists & calcium agonists Alkalinisation of urine decreases excretion Acidification of urine increases quinidine excretion
- 42. CLINICAL INDICATIONS EQUINES : treatment for supraventricular arrhythmias Dose @ 20mg/kg, PO, every 2 hours (maximal dose 60g daily) by stomach tube until arrhythmia is abolished. SMALL ANIMALS : supraventricular arrhythmias associated with anomalous conduction in WOLFF-PARKINSON WHITE SYNDROME. Acute atrial fibrillation Dogs @ 6-20 mg/kg, PO, 3 to 4 times daily Cats @ 4-8 mg/kg, IM, TID.
- 43. Procainamide Similar MOA like quinidine ; affects cardiac automaticity, excitability, responsiveness & conduction. Vagolytic effects are minimal & doesn’t cause a-adrenergic blockade/paradoxical acceleration. Contra-indicated in patients with 2nd / 3rd degree block & with torsades de pointes Indicated for treatment of ventricular arrhythmia than atrial Dogs @ 8-30 mg/kg, PO, TID @ 2-8mg/kg, slow IV over 5 min, then 10-40 microgram/kg/min IV infusion
- 44. Disopyramide Is structurally dissimilar from other antiarrhythmic agents Quinidine like class IA drug that has prominent cardiac depressant & anticholinergic actions, but no a-adrenoceptor blocking property. Not routinely used in veterinary medicine bcoz of its relatively rapid elimination & short half life(<2 hours) disopyramide is considered to be 2nd / 3rd line agent for veterinary use. Dogs @ 6-15 mg/kg, PO, 3 to 4 times a day
- 45. Class IB drugs Lignocaine, phenytoin, mexiletine, tocainide, Phenytoin.
- 46. Lidocaine / Lignocaine Local anesthetic & prototypic class IB Used predominantly for emergency treatment of ventricular arrhythmias & effective only when administered IV MOA : lidocaine directly interacts with the open/inactivated Na+ channels & is relatively selective for partially depolarized cells & those with longer AP duration. Markedly suppresses automaticity in purkinje fibres, improves conduction in depolarized/stretched fibres by increasing RMP to near normal values, as a result of improved conduction, normal transmission is restored in areas of unidirectional blocks.
- 47. Indications Following a therapeutic IV bolus, the onset of action is seen with in 2 min & lasts for 10-20 min. Lidocaine is one of the best antiarrhythmic drugs & first choice for life saving tachyarrhythmias & for most ventricular arrhythmias, principally ventricular tachycardia & ventricular premature complexes Dogs @ 1-2mg/kg, IV bolus, followed by 30-50 microg/kg/min, IV infusion Large animals @ 0.25-0.5 mg/kg, IV.
- 48. Mexiletine hcl Is structural analogue of lidocaine & reported to produce enhanced antiarrhythmic effects when combined with either quinidine or procainamide therapy Indicated especially frequent ventricular premature beats, ventricular tachycardia & those induced by digitalis toxicity Mexiletine is contraindicated for cats Dogs @ 4-8 mg/kg, PO, TID @ 3-5 mg/kg, IV, followed by 5-10 microg/kg/min, iv infusion
- 49. 1) TOCAINIDE : amide type local anesthetic Indicated in dogs for long term control of ventricular arrhythmias @ 15-20 mg/kg, PO, TID. 2) PHENYTOIN : an antiepileptic drug with class IB antiarrhythmic effects. Indicated for ventricular arrhythmia in dogs @ 10mg/kg, IV, TID, usually in increments of 2-4mg/kg. 3) APRINDINE : effective in controlling pre-mature ventricular beats & ventricular tachycardia Dogs @ 0.1mg/kg IV infusion for 5 min, repeated at 10 min intervals till arrhythmia is controlled, followed by 3mg/kg PO TID
- 50. Class I C drugs Encainide, Flecainide, Propafenone Have minimal effect on repolarization Are most potent sodium channel blockers • Risk of cardiac arrest , sudden death so not used commonly • May be used in severe ventricular arrhythmias
- 51. Ia Ib Ic Moderate Na channel blockade Mild Na channel blockade Marked Na channel blockade Slow rate of rise of Phase 0 Limited effect on Phase 0 Markedly reduces rate of rise of phase 0 Prolong refractoriness by blocking several types of K channels Little effect on refractoriness as there is minimal effect on K channels Prolong refractoriness by blocking delayed rectifier K channels Lengthen APD & repolarization Shorten APD & repolarization No effect on APD & repolarization Prolong PR, QRS QT unaltered or slightly shortened Markedly prolong PR & QRS
- 52. Class II : beta – adrenoceptor antagonists Depress phase 4 depolarization of pacemaker cells, Slow sinus as well as AV nodal conduction : ↓ HR, ↑ PR ↑ ERP, prolong AP Duration by ↓ AV conduction Reduce myocardial oxygen demand Well tolerated, Safer Propranolol, atenolol, esmolol, sotalol, timolol, carazol, bisoprolol.
- 53. MOA Increasing the magnitude of Ca++ current & slowing its inactivation Increases the magnitude of repolarizing K+ & Ca++ current Increases the pace maker current & under pathophysiological conditions increases both DAD & EAD mediated currents Positive inotropic effect In heart activity is mainly through inhibition of beta1 adrenergic receptors, inhibits effect of sympathetic NS by reducing heart rate, decreases intracellular Ca++overload & inhibiting after depolarization mediated automaticity.
- 54. β Adrenergic Stimulation β Blockers ↑ magnitude of Ca2+ current & slows its inactivation ↓ Intracellular Ca2+ overload ↑ Pacemaker current→↑ heart rate ↓Pacemaker current→↓ heart rate ↑ DAD & EAD mediated arrhythmias Inhibits after- depolarization mediated automaticity Epinephrine induces hypokalemia (β2 action) Propranolol blocks this action
- 55. Class III drugs ↑APD & ↑RP by blocking the K+ channels
- 56. Class III : K+ channel blockers Amiodarone, dronedarone, bretylium, bunaftine, ibutilide, nifekalant Amiodarone is Iodone containing agent structurally related to thyroid hormone thyroxine indicated in horses to treat atrial fibrillation @ 5mg/kg/hr, IV, for 1 hour followed by 0.8 mg/kg/hr for 23 hour
- 57. Bretylium Complex electrophysiological effects : partly result of blockade of norepinephrine release release fron adrenergic nerve terminals in heart but major direct action is prolongation of action potential duration & effective refractory period due to K+ channel blockade. Indicated in life threatening ventricular arrhythmias in dogs @ 5-20 mg/kg, IV In pigs used for protection against tachyarrhythmias induced by general anesthesia @ 0.02mg/kg/min, IV infusion.
- 58. Calcium channel blockers (Class IV) • Inhibit the inward movement of calcium ↓ contractility, automaticity , and AV conduction. • Verapamil & diltiazem
- 59. Class IV : Ca++ channel blockers 1) Diphenylalkylamine derivatives : verapamil, gallopamil 2) Benzothiazepine derivatives : diltiazem, clentiazem 3) Dihydropyridine derivatives : nifedipine, amlodipine
- 60. Diphenylalkylamine derivatives VERAPAMIL depresses CA mediated depolarization suppresses automaticity in SA node, AV node & purkinji fibres resulting in suppression of both ectopic & triggered mechanism Decreases intracellular free calcium concentration & reduces the force of cardiac contraction causing vasodilation. Reflex sympathetic stimulation due to direct vasodilatory effect partly counteracts the cardiac slowing action of verapamil. It is contraindicated in sick sinus syndrome, cardiogenic shock, severe CHF, cardiac glycoside toxicity
- 61. indications Supraventricular tachyarrhythmias, sustained & paroxysmal tachycardia, excessive ventricular hypertrophy, atrial flutter & fibrillation. Humans – treatment of hypertension, angina pectoris, cardiac arrhythmia & cluster headaches, also effective medication for prevention of migrane. Dogs @ 1-5mg/kg/, PO, TID @ 0.05-0.2 mg/kg slow IV over period of 2-5 min followed by IV infusion 2-10 microgram/kg/min.
- 62. Benzothiazepine derivatives DILTIAZEM : Ca++ channel blocking activity in both myocardial & smooth muscle cells. It prevents transmembrane influx of extracellular Ca++ ions in myocardial cells & vascular smooth muscles producing vasodilation, negative chronotropic, negative inotropic & negative dromotropic effects Indicated for treatment of atrial fibrillation, supraventricular tachycardias, hypertropic cardiomyopathy, systemic hypertension Dogs @ 0.5-1.25mg/kg, PO, TID @ 0.25mg/kg, IV, over 2 min. dose may be repeated if required
- 63. Dihydropyridine derivatives Nifedipine, amlodipine, nicardipine, nitrendipine, felodipine These drugs have high affinity for vascular Ca++ channels & have more potent vasodilator effect. Nifedipine is prototype drug mainly used as antianginal & antihypertensive drug in human medicine. Has little significance in veterinary practice. Amlodipine indicated in cats for systemic hypertension @ 0.625-1.25 mg (total dose), PO, SID
- 64. Miscellaneous agents Cardiac glycosides – complex effect by virtue of prolongation of the effective refractory period of AV node. Digoxin controls the ventricular response-rate & force in atrial fibrillation, atrial flutter & supraventricular tachycardia. Digitalis glycosides in high doses are ANTIARRHYTHMIC
- 65. Adenosine ADENOSINE : modulates physiological process through 4 adenosine receptors subtypes A1,A2a,A2b,A3 all belonging to super family G proteins Has extremely short duration of action in humans say 15 sec Activity is mediated by stimulation of specific time dependent outward K+ current, which appears to be identical to one stimulated by Ach. Contraindicated in 2nd & 3rd degree block, sick sinus syndrome, hypotension & asthma. Use in veterinary medications is limited.
- 66. references HS SANDHU Essentials of veterinary pharmacology and toxicology, 2nd edition. H RICHARD ADAMS Veterinary pharmacology and therapeutics, 8th edition. GOOGLE IMAGES ONLINE SEARCH RELATED TOPICS
- 67. THANK YOU
Editor's Notes
- #8: RMP IS -90 MV Cardiac bounded by a lipoprotein membrane which has receptor channels crossing it WHEN AN ATRIAL OR VENTRICULAR CELL RECIEVES An action potential it starts depolarising in response to it..and sodium starts entering it Intracellular negativity starts diminishing When such depolarisation reaches a threshold potential, the sodium channels open abruptly Na enters cell in large quantities CELL MEMBRANE ACTION POTENTIAL CHANGES FROM -90 TO ALMOST +30MV Phase 0: rapid depolarisation…fast selective inflow of na ions During latter part, ca ions also enter the cell via na channels Frther in phase 1 and 2 ca ions enter thru slow ca channels THE CONFORMATION OF THE SODIUM CHANNELS HENCE CHANGES TO INACTIVE STATE The ca which enters the cell in dis manner causes release of ca from sarcoplasmic reticulumraising the conc of ca within the cells This intracellular free ca interacts with actin myocin system and causes contraction of heart Afetr this, phase 1: short rapid repolarisation due to beginning of outflow of potassium and entry of cloride ions into the cells, MEMBRANE CHARGE CHANGES FROM +30 TO ALMOST 0 MV IN VERY SHORT TIME Phase 2 : prolonged plateau phase.. Balance bw ca enterin the cell and k leavin the cell..VOLTAGE SENSITIVE SLOW l type CA CHANNELS OPEN …SLOW INWARD CA CURRENT BALANCED BY SLOW OUTWARD K CURRENT..DEPOLARISATION = REPOLARISATION Phase 3 : rapid repolarisation.. CA CHANNELS CLOSE…K CHANNELS OPEN..Contimued extrusion of k…RESUMES INITIAL NEGATIVITY FROM PHASE 0 TO 3 THERE HAS BEEN A GAIN OF NA AND A LOSS OF K ..THIS IS NOW REVERTED AND BALANCED BY NA K ATPASE Phase 4: resting phase..ELECTRICALLY STABLE… Ionic reconstitution of cell is reachieved by na k exchange pump RMP MAINTAINED BY OUTWARD K LEAK CURRENTS AND NA CA EXCHANGERS The cycle is then repeated Inactivation gates of sodium channels in resting membranes close over the potential range of -75 to -55mv Cardiac sodium channel protein shows 3 different conformations Depolarisation to threshold voltage results in opening of the activation gates of sodium channel thus causing markerdly increased sodium permeability Brief intense sodium current , conductance of fast sodium channel suddenly increases in response to depolarising stimulUs Very large influx of na accounts for phase 0 depolarisation Clusure of inactivation gates result Remain inactivated till mid phase 3 to permit a new propagated response to external stimulus…refractory period.. Cardiac calcium channels are L type Phase 1 and 2 : turning off nodium current, waxing and waning of calcium curent, slow development of repolarising potassium current, calcium enters ..potassium leaves.. Phase 3: complete inactivation of sodium and calcium currents and full opening of potassium 2 types of main potassium currents involved in phase 3 : ikr and iks Certain potassium channels are open at rest also…”inward rectifier” channels In addition there are 2 energy requiring exchange pumps in cardiac myocyte cell membrane…na k exchange pump…and and na-ca exchange pump Normally na ions concentrated extracellularly and vice versa for k cions Thus have a tendency odf diffusion along concentration gradient This diffusion is opposed by na k pump This pump operates contimuously and does not switch on and off during action potential of cardiac cells
- #14: Late Afterdepolarizations Secondary deflection after attaining RMP Increased intracellular Ca2+ overload Adrenergic stress, digitalis intoxication, ischemia-reperfusion AFTRE attaining Resting membrane potential, a secondary deflection occurs.. If this reaches threshold potential..it initiates a single premature AP GENERALLY OCCURS FROM CALCIUM OVERLOAD..digitalis toxicity..ischaemia reperfusion
- #17: Ectopic pacemaker activity is encouraged by Faster phase 4 depolarization due to ishemia Less negative resting membrane potential More negative threshold potential due to ishemia
- #29: Atrial fibrillation - Atria remains dilated and quiver like bag of worms Torsades de pointes – polymorphic ventricular tachycardia
- #33: Surprisingly few mechanisms of antiarythmic action In general these drugs have these action..they act by altering.. Rate of phase 0 depolarisation Slope of phase 0 depolarisation..blocks reentrant impulses…quinidine, procainamide, disopyramide, lignocaine and verapamil posess this action Increasing the effective refractory period..thus duration of action potential..and blocking reentrant impulses…quinidine, procainamide, propanolol and potassium posess this action Making the resting membrane potential even more negative and decreasing the slope of phase 4..thus supressing automaticity…this action is shown by all antiarrythmic drugs….it supresses the enhanced automaticity of ectopic foci ..examples are lignocaine and phenytoin Making the threshold potential less negative i.e. shifting it towards 0…again supresses enhanced automaticity of ectopic focii..quinidine..procainamide, propanolol and potassium posess this action In general, altering the na and ca channels, alter the threshold potential and altering the potassium channels will alter the length of refractory period and thus duration of action potential
- #56: Class III drugs block outward K+ channels during phase III of action potential These drugs prolong the duration of action potential without without affecting phase 0 of action potential or resting membrane potential they instead prolong ERP