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Drugs used in Heart Failure, Angina, and Arrhythmia. But, first, some muscle review!. Regulation of cardiac myocyte Ca 2+ flux. Regulation of cardiac contractility by β -adrenergic receptors. Cellular Mechanisms of Contractile Pathophysiology. Drugs used in Heart Failure.
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Regulation of cardiac myocyte Ca2+ flux Regulation of cardiac contractility by β-adrenergic receptors
Cellular Mechanisms of Contractile Pathophysiology
Drugs used in Heart Failure • Heart failure: insufficient cardiac output to adequately perfuse the tissues, despite normal filling of the heart. • Congestive heart failure: combined right and left heart failure to produce pulmonary congestion and peripheral edema. • Causes: hypertension, valvular disease, cardiomyopathy, and most commonly, coronay artery disease.
Drugs used in Heart Failure (cont’d) • Low cardiac output incrsns activity stimulates the rate and force of the heart beat and maintains bp by incr vascular resistance. • In the failing heart, this afterload further decr cardiac output. • The resultant decr renal blood flow renin secretion and incr plasma and angiotensin and aldosterone levels • Na+ and H2O retention incr the blood vol and bpincrP(edema).
Drugs used in Heart Failure (cont’d) • These compensatory Δs at first help maintain cardiac output, but in the long run,… • Lead to Δs (e.g., abnormal ventricular dilation) that incr morbidity and mortality. • Only drugs that inhibit these neurohormones involved in these compensatory Δsincr patient survival with CHF (i.e., ACE inhibitors, β-blockers).
Drugs used in Heart Failure (cont’d) • Treatment of mild HF usually starts with an angiotensin converting enzyme (ACE) inhibitor. - decr load on the heart. - decr symptoms. - slow disease progression. - prolong life. - For more severe cases, add a diuretic (e.g., bendroflumethiazide, furosemide). - For severe cases, in which a ACE inhibitor and diuretic fail, then an inotropic drug (e.g., Digoxin), which incr the force of cardiac muscle contraction by incr the rise of [Ca2+]cyto that accompanies each AP (inhibit the Na+/K+-ATPase). [See below] - β-blockers may be added. - Additional diuretics (next time) may be added.
ACE Inhibitors • The most appropriate vasodilators used in HF, because they decr both arterial and venous resistance. • Preventing the incr in (vasoconstrictor) angiotensin II that is often present in HF. • Result: Incr cardiac output and because of the decr in renovascular resistance, there is an incr in RBF… • This, plus the decr in aldosterone, incr Na+ and H2O excretion decr blood vol and venous return to the heart. • Also decr direct growth action that angiotensin has on the heart. • [Angiotensin antagonists (e.g., losartan)may not have the same benefits as ACE inhibitors].
β-Receptor Antagonists (β Blockers) • Acutely, β-blockers can decrease myocardial contractility and worsen HF. • Long-term, however, administration has been shown to improve the survival of stable patients with HF (blocking the damaging effects of overactive sympathetic activity). • Start with a low dose and gradually incr over wks-to-mos. • Carvedilol, bisoprolol, and metaprolol, given with an ACE inhibitor and diuretic for ~1 yr has been shown to reduce mortality from 11-17% to 7-12%.
Inotropic Drugs • Digoxin – a cardiac glycoside extracted from foxglove leaves (Digitalis sp) is the most important inotrope. • Increase the contractile force. • Particularly indicated in patients with atrial fibrillation. • Inhibits the Na+/K+-ATPase, which is responsible for Na+/K+ exchange across the muscle cell membrane incr [Na+]inincr [Ca2+]inincr force of myocardial contraction. • Digoxin and K+ ions compete for a “receptor” (Na+/K+-ATPase) on the ext membrane. • So, the effects of digoxin may be dengerouslyincr by hypokalemia, produced, for example, by diuretics.
Inotropic Drugs (cont’d) • Direct Effects: - AP and refractory period are shortened because.. - The incr [Ca2+]in stimulates K+ channels. - Toxic concentrations cause depol and oscillatory depolarizing after pot appear after normal Aps (caused by incr [Ca2+]in. - If these delayed afterpot reach T0, Aps are generated, causing ‘ectopic’ beats. -With incr toxicity, the ectobic beat itself elicits further beats, causing a self-sustaining arrhythmia (vent tach), which may vent fibrillation.
Inotropic Drugs (cont’d) • Indirect Effects: • Digoxinincrvagal activity and faciliatesmuscarinic transmission to the heart. This… • Slow HR • Slows atrioventricular conductance. iii. Prolongs the refractory period of the atrioventrivular node. Effects on Other Organs: Digoxin may cause anorexia, nausea, vomiting or diarrhea by affecting the smooth muscle of the gut.
Inotropic Drugs (cont’d) • Toxicity: -Digoxin toxicity is quite common because arrhythmias can occur at concentrations that are only 2-3 x that of the optimal therapeutic dose. - Treatment may entail K supplements, antiarrhythmic drugs (lidocaine or phenytoin) or even digoxin-specific Ab fragments (Fab).
Sympathomimetic Agents • Activate cardiac β-receptors AC cAMPphosphorylation of L-type Ca2+ channels (opens) incr [Ca2+]influx and the force of myocardial contraction. • Dobutamine used in acute severe HF. • Dopamine incr renal perfusion by stimulates dopamine receptors in the renal vasculature.
Drugs Used in Angina – Pathogenesis of Acute Coronary Syndrome
Drugs Used in Angina • Angina pectoris – ischemia of the heart muscle as a result of coronary artery occlusion or blockage. • Drugs use to decr the work load of the heart and hence, O2 demand. • Nitrates are the 1st-line drugs peripheral vasodilation, especially in the veins by acting on vascular smooth muscle that involves the formation of NO and [cGMP]cyto.
Nitrates (cont’d) • The cGMP pooling of blood in the veins decr venous return and the ventricular vol is decr. • Decr in the distension of the heart wall decr O2 demand and the pain is quickly relieved.
Nitrates • Short-acting nitrates: Glycerol trinitrate (sl, tablet, or spray) acts for ~ 30 min. -More useful in preventing attacks than in stopping them once they have begun. -Patches (transdermal) have longer duration of action (~ 24 hr). • Long-acting nitrates are more stable and effective for several hr. • Isosorbidedinitrate widely used, but metabolized rapidly by liver. • Isosorbidemononitrate (active metabolite) of dinitrate avoids the variable absorption and unpredictable 1st pass metabolism of the dinitrate.
Nitrates (cont’d) • Adverse effects: Aterial dilation headaches, hypotension and fainting, and in severe cases, reflex tachycardia. - Can be counteracted with β-blockers. - Prolonged high doses can methemaglobinemia. Mechamism of action: Starts with formation of nitrite ions (see figure).
Nitrates (cont’d) • Tolerance to nitrates occurs regularly, but is poorly understood. • But, perhaps depletion of sulphydral group donors may be involved, because tolerance to nitrates in vitro can sometimes be reversed by N-acetylcysteine. -Peroxynitrite formed from NO inhibits cGMP formation from GTP.
β-Adrenoceptor Antagonists • Used as an angina prophylaxis. • Better to use cardio-selective (e.g., atenolol, metoprolol) β-blockers, rather than nonspecific ones (propranolol). • All β-blockers must be avoided in asthmatics as they may pptbronchospasms.
Calcium Antagonists • Widely used for angina and with fewer side-effects than with the β-Blockers. • Ca antagonists block L-type VG Ca channels in arterial smooth muscle relaxation and vasodilation. • Ca channels in the myocardium and conducting tissues of the heart are also affected by Ca antagonists, which… • Produce negative inotropic effects by decr Ca2+ influx during the plateau phase of the AP.
Calcium Antagonists (cont’d) • Dihydropyridines (e.g., nifidipine, amlopidine) have relatively little effect on the heart because they have much higher affinity for channels in the inactive state. • Such channels are found more in vascular smooth muscle because it is more depolarized than cardiac muscle (50 vs. 80 mV). • At clinical used doses, vasodilation reflex increase in sympathetic tone that mild tach and counteracts the mild inotropic effect. • Alopidine < nifidipine, verapamil < diltiazem depress the SA node mild resting bradycardia. • Verapamil binds preferentially to open channels and is less affected by the RMP. • Conduction at the AV node is slowed and slows the ventricular rate of atrial arrhythmias.
Calcium Antagonists (cont’d) • The negative inotropic effects of verapamil and diltiazem are partially offset by the reflex incr in adrenergic tone and the decr in afterload. • Tobacco smoking: Smoking is prothromic and atherogenic – it decr coronary blood flow and the nicotine-induced rise in HR and bpincr O2 demand of the heart. • Also, carboxyHbdecr O2-carrying capacity of Hb. • Some patients markedly improve on giving up smoking.
Drugs used in Arrhythmia • Rhythm of the heart determined by pacemaker cells in the SAN. • Supraventrocular arrhythmias arise in the atrial myocardium (AVN), whereas ventricular arrhythmias arise in the ventricles. • Ectopic focus: firing at a higher rate than the normal SAN cells. • Re-entry mechanism: Delayed APs (some pathology) re-invade near-by muscle fibers, which, no longer being refractory, again depolarize, establishing a loop of depolarizaiton (circus movement).
Drugs used in Arrhythmia (cont’d) Three Classes: • Supraventricular arrhythmias • Ventricular arrythmias • Drugs used in both.
The Action Potential in Skeletal and Cardiac Muscle Figure 20.15
Drugs used in Arrhythmia (cont’d) Drugs used in Supraventricular arrhythmias • Adenosine stimulates A1-adenosine receptors and opens Ach-sensitive K+ channels. - This hyperpolarizes the cell membrabe in the AVN and slows conduction in the AVN (by inhibiting Ca2+ channels). • Digoxin stimulates vagal activity Ach release which slows conduction and prolongs the RP in the AVN and Bundle of His. • By delaying atrioventricular conductance, digoxinincr the degree of block and slows and strengthens the ventricular beat. • Verapamil blocks L-type Ca channels, especially on the AVN, where conduction is entirely dependent on Ca2+ spikes. - Also inhibits Ca2+ influx during the plateau phase of the AP and therefore, has negative inotropic action.
Drugs used in Arrhythmia (cont’d) Drugs used in ventricular arrythmias • Class 1B agents block VD Na+ channels. • Lidocaine (iv) used after myocardial infarction. - blocks inactivated Na+ channels. - works in ischemic (anoxia causes depol and antithrombogenic activity), but not healthy, tissue.
Drugs used in Arrhythmia (cont’d) Drugs used in supraventricular and ventricular arrythmias • Class IA agents block open VD Na+ channels. • Slow Phase 0 and lengthen the RP • Produce a freq (use)-dependent block. • During diastole, when the Na+ channels are closed, Class IA agents dissocrel slowly; so, if the freq is high, drug is still bound to the channel, which, therefore, cannot contribute to the AP.
Drugs used in Arrhythmia (cont’d) Drugs used in supraventricular and ventricular arrythmias • Disopyramide (po) and quinidine to prevent recurrent ventricular arrythmias. - has negative inotropic effects. - may cause hypotension and may aggravate cardiac failure. - Other side-effects: nausea, vomiting, marked anticholinergic effect.
Drugs used in Arrhythmia (cont’d) Drugs used in supraventricular and ventricular arrythmias • Class IC agents dissociate very slowly from Na+ channels and strongly depress myocardial conduction. - Flecainide – used mainly in prophylaxis of paroxysmal atrial fibrillation. - has negative inotropic effects.
Drugs used in Arrhythmia (cont’d) Drugs used in supraventricular and ventricular arrythmias • Class III agents slow the repolarization (Phase 3) and prolong the AP and RP in all cardiac tissues. • Amiodarone blocks several channels (e.g., K+ and inactivated Na+ channels) and β-adrenoceptors. - Often effective when other drugs have failed, but should be used sparingly, as it causes serious side-effects (e.g., photosensitivity, thyroid disorders, neuropathy, and pulmonary alveolitis). Sotalol has both Class III and Class II (β-blocking) actions, but lacks the side-effects of amiodarone, but has the side-effects of β-blockers.