Basic physiologic properties of myocardium: automaticity conduction

1. Basic physiologic properties of myocardium: automaticity conduction excitability (refractoriness) contractility

2. M (1) Aorta SA node VCI Atrial myocardium AV node 1 . SA node bundle Internodal links fibre AV uzel Purk. fibre ventricle His bundle ECG T P U QRS Purkinje fibre 0.4 0.6 0.2 Time (s) According to Katzung's Basic & Clinical Pharmacology. McGraw-Hill Medical; 9 edition (December 15, 2003)

3. According to Katzung's Basic & Clinical Pharmacology. McGraw-Hill Medical; 9 edition (December 15, 2003)

4. Arrhythmias are defined by exclusion - i.e., any rhythm that is not a normal sinus rhythm (NSR) is an arrhythmia. • Abnormal automaticity •  Sick sinus syndrome •  Pacemaker activity that originates anywhere other than in the sinoatrial node = abnormal autom. • Abnormal conduction •  Conduction of an impulse that does not follow the physiological path (defined previously)  e.g. reenters tissue previously excited = reentry •  conduction – heart block

5. Normal Re-entry According to Katzung's Basic & Clinical Pharmacology. McGraw-Hill Medical; 9 edition (December 15, 2003)

6. A few of the clinically important arrhythmias are: atrial flutter, atrial fibrillation (AF), atrioventricular nodal reentry (a common type of [SVT]), premature ventricular beats (PVBs), ventricular tachycardia (VT), ventricular fibrilation (VF).

7. General principles of management anti-arrhythmic are among the most dangerous drugs at the clinician´s disposal most appropriate treatment is almost never a drug bradyarrhythmias – consider pacing tachyarrhythmias – DC cardioversion treat patient not cardiogram – look for underlying process - ions, thyreotoxicosis, drugs, ischemia, aneurysm, valvular or congenital heart disease avoid ´coctails´ of drugs

8. I. Sodium channel blockers II. b-adrenoceptor blockers III. Potassium channel blockers IV. Calcium channel blockers V. Miscellaneous

9. Class I. - sodium channel blocking drugs all of them behave like local anesthetics – reduce the maximum rate of depolarisation during phase 0. Na+ channels – resting, open and refractory states Class IA agents (prototype, quinidine) prolong the action potential and reduce Vmax (++). Class IB drugs shorten the action potential in some cardiac tissues (prototype, lidocaine) and  Vmax (±). Class IC drugs have no effect on action potential duration (prototype, propafenon) but  Vmax. selectivity abnormal pacemakers?  - proarrhythomogenic -  mortality - out

10. According to Katzung's Basic & Clinical Pharmacology. McGraw-Hill Medical; 9 edition (December 15, 2003)

11. Quinidine – class Ia C a r d i a c effects: direct (concentration dependent) A-V depressant negative inotropic concentration independent parasympatolytic increase action potential (AP) duration and the effective QT interval. E x t r a c a r d i a c effects: quinidine possesses alpha adrenoceptor-blocking properties that can cause vasodilation and a reflex increase in sinoatrial nodal rate.

12. Toxicity: antimuscarinic actions - increased sinus rate and increased atrioventricular conduction - (verapamil, a beta-blocker, digitalis). prolongation of QT 1-5%) - "quinidine syncope" -torsade de pointes depress contractility - lower blood pressure cinchonism (headache, tinnitus); gastrointestinal upset; and allergic reactions (eg, thrombocytopenic purpura).

13. Lidocaine - class IB • acute ventricular arrhythmias – AIM – i.v. – 100 mg • rapid dissociation from Na+ channels • CNS stimulation • drowsiness, twitching, nausea, vomiting, convulsions - diazepam; • cardiovascular depression – bradycardia + cardiac depression (neg. inotropic) (usually minor); • allergy • Mexiletine, fenytoin - they have little effects on the ECG.

14. Class II. (beta-blockers) • Beta-adenoreceptor blockade  reduction in cAMP • results in the reduction of both sodium and calcium currents the suppression of abnormal pacemakers. • AV node • Local anesthetic (membrane stabilizing) rare at the concentrations achieved clinically. • Cardiovascular effects(negative ionotropic, dromotropic, chronotropic • and bathmotropic effect •  cardiac output  decrease of blood pressure • b2 receptors  mild increase of peripheral vascular resistance.

15. Properties of several b-receptor-blocking drugs Pharmacokinetics - bioavailability and duration of action vary widely Esmolol is a short-acting beta-blocker that is only used parenteraly. Nadolol is the longest acting beta-blocker. Acebutolol and atenolol are less lipid soluble than the older beta- blockers and probably enter the CNS to lesser extent.

16. Esmolol •  very short-acting  intravenous administration  in acute surgical arrhythmias. • Carvedilol, metoprolol, atenolol • prophylactic drugs IHD (ischemic heart disease), • hypertrophic cardiomyopathy, • inappropriate sinus tachycardia (eg. panic attack) • paroxysmal supraventricular tachycardias precipitated by emotion or exercise • tachyarrhythmias of thyreotoxicosis • tachyarrhythmias of phaeochromocytoma, after adequate alfa- receptor blockade

17. Adverse effects and toxicity • bradycardia, antrioventricular blockade • congestive heart failure • asthmatic attacks (in patients with airway disease) • premonitory symptoms of hypoglycemia from insulin overdosage • (eg, tachycardia, tremor and anxiety, may be marked) • CNS adverse effects - sedation, fatigue, and sleep alterations. • Atenolol, nadolol less lipid soluble b-blockers less marked • CNS action.

18. According to Katzung's Basic & Clinical Pharmacology. McGraw-Hill Medical; 9 edition (December 15, 2003)

19. Class III. (potassium channel blockers) • Sotalol • beta-blocker and K+ blocker • i.v./p.o.– extremely polar – renal elimination • Adverse effects - torsade de pointes (! hypokalaemia + ECG monitoring) + • beta-blockade  bradycardia, asthma etc. • Bretylium • - sympathoplegic action and a potassium channel-blocking effect. • - only indication - refractory postmyocardial infarction arrhythmias, eg. recurrent ventricular fibrillation. • - rarely used - new arrhythmias or marked hypotension.

20. Amiodarone • - most efficacious antiarrhythmic drug – oral x i.v. • - resistant atrial and ventricular tachyarrhythmias • Mechanism of action • - it blocks sodium, calcium, and potassium channels and beta-adrenoceptors • - reduction of the slope od diastolic depolarization (beta and Ca2+) • AP prolongation - increase in effective refractory period (K+) – reverse use-dependent • Pharmacokinetics • huge Vd (>5000 l), protein binding > 99.5 %, elimination – hepatic metabolism – bile, t1/2 = 20-60 days

21. Amiodarone toxicity - common above 2.5 mgL - TDM - thyroid dysfunction (hyper- or hypothyroidism) – 30 % - cardiac effect - prolongation of QT interval – torsade de pointes - eye - cornea - microcrystalline deposits - linear opacity – coloured halo - slit-lamp - skin – photosensitivity rash 10-30 % - blue-grey pigmentation - pulmonary fibrosis - hepatopaty - periferal neuropaty, GIT disturbance.

22. According to Katzung's Basic & Clinical Pharmacology. McGraw-Hill Medical; 9 edition (December 15, 2003)

23. Class IV. (calcium channel blockers) • Verapamil • - state-dependent selective depression of L-type voltage-dependent Ca2+ channels – SA a AV node   conduction velocity +  effective refractory period -  PR interval • relaxation of smooth muscle (arterioles, coronary arteries) • negative inotropic • Indication • SVT - atrioventricular nodal reentry – i.v. + monitoring ECG – where adenosin is contraindicated (eg. astmatics) • profylactically for SVT – oral • Pharmacokinetics • F = 10-20 %, metabolism, protein binding > 80 %, t1/2 = 3-7 h, • SR formulations

24. Adverse effects and contraindications Cardiovascular effects – negative inotropic effect + blockade of conduction – hypotension, AV block or other bradyarrhythmias – COI – WPW, SSS, intracardiac block, ventricular arrhythmias Gastrointestinal tract – constipation 30-35 % - dietary fibre Vasodilatation – headache, dizziness and facial flushing, ankle swelling Rush

25. Class V. Miscellaneous antiarrhythmic drugs • Adenosine: • extremely effective in abolishing AV nodal arrhythmias – i.v. bolus – SVT • extremely short duration of action – t1/2 = 3-10 s – uptake to ery + mtb. on the surface of endotelium • Pharmacodynamic • A1-receptor block AV nodal conduction • bronchoconstriction • A2-receptors vasodilatation •  pain sensation • inhibition of platelet aggregation • AE: chest pain, flushing, shortness of breath, dizziness and nausea

26. Digitalis Potassium ion Magnesium ion Bradyarrhythmias Atropine Adrenaline Isoprenaline

27. According to Katzung's Basic & Clinical Pharmacology. McGraw-Hill Medical; 9 edition (December 15, 2003)