Drugs Acting on the Heart PDF

Action of drugs on the cardiovascular system LO 1 Describe the types of drugs used to treat patients with common cardiovascular disorders  Cardiovascular drugs are used to treat: – Arrhythmias – Heart failure – Blood clotting disorders – Ischemic heart diseases – Hypert...

Action of drugs on the cardiovascular system LO 1 Describe the types of drugs used to treat patients with common cardiovascular disorders  Cardiovascular drugs are used to treat: – Arrhythmias – Heart failure – Blood clotting disorders – Ischemic heart diseases – Hypertension  Drugs can alter: – The rate and rhythm of the heart – The force of myocardial contractility – Peripheral resistance – Blood volume – Coronary arteries blood flow Some drugs can act at more than one site. LO 2 Understand how arrhythmias can arise  Disturbances of cardiac rhythm (arrhythmias or dysrhythmias) Abnormality of heart rate or rhythm Tachycardia – Ventricular tachycardia – Supraventricular tachycardia Bradycardia Atrial flutter Atrial fibrillation Ventricular fibrillation Causes of arrhythmias include: Ectopic Pacemaker activity Damaged area of myocardium because depolarised and spontaneously active. Latent pacemaker region activated due to ischaemia Dominate over SA node After-Depolarisations Abnormal depolarisations following the action potential Thought to be caused by high intracellular Ca2+ Longer AP leads to longer QT interval Re-entry loop Conduction delay Normal spread of excitation disrupted due to damaged area Incomplete conduction damage (uni-directional block)  Re-entrant mechanism for generating arrythmias normal spread of excitation Block of conduction through damaged area region impulses cancel out at this point Incomplete conduction damage (unidirectional block) - excitation can take a long route to spread the wrong way through the damaged area, setting up a circus of excitation Re-entry loops It is possible to get several small re- entry loops in the atria, leading to atrial fibrillation LO 3 Describe the classes of anti-arrhythmic drugs and the principles of their therapeutic use Drugs affecting the rate and rhythm of the heart There are 4 basic classes of anti- arrhythmic drugs. I. Drugs that block voltage-sensitive sodium channels II. Antagonists of β- adrenoreceptors III. Drugs that block potassium channels IV. Drugs that block calcium channels Drugs which block voltage-dependant Na+ channels (class I) Typical example is the local anaesthetic lidocaine Only blocks voltage gated Na+ channels in open or inactive state Dissociates rapidly in time for next AP  Lidocaine Is sometimes used following MI if patient shows signs of ventricular tachycardia – given intravenously Damaged areas of myocardium may be depolarised and fire automatically More Na+ channels are open in depolarised tissue – lidocaine blocks these Na+ channels – prevents automatic firing of depolarised ventricular tissue Not used prophylactically following MI  β-adrenoreceptor antagonists (class II) Examples: propranolol, atenolol (Beta blockers) We have selective and non- selective β- blockers Block sympathetic action –act at β1-adrenoreceptors in the heart  β-blockers Used following myocardial infarction – MI causes increased sympathetic activity β-blockers prevent ventricular arrhythmias – arrhythmias may be due to increased sympathetic activity also reduce O2 demand – reduce myocardial ischaemia – beneficial following MI  Drugs that block K+ channels (class III) Class III anti-arrhythmics Prolong the action potential – mainly by blocking K+ channels This lengthens the absolute refractory period Prevents another AP occurring too soon Class III antiarrhythmic absolute absolute refractory refractory period period 0 200 400 600 800 0 200 400 Time (ms)  Drugs that block K+ channels Prolongs the action potential Not generally used because they can be also be pro- arrhythmic One exception – amiodarone Included as a type III anti-arrhythmic, but has other actions in addition to blocking K+ channels Used to treat tachycardia associated with Wolff- Parkinson-White syndrome (re-entry loop due to an extra conduction pathway)  Drugs that block Ca2+ channels (class IV) Example: verapamil Decreases slope of pacemaker action potential at SA node Decreases AV nodal conduction Decreases force of contraction (negative inotropy) – Also cause some coronary and peripheral vasodilation – The dihydropyridine Ca2+ channel blockers are not effective in preventing arrhythmias, but do act on vascular smooth muscle  Adenosine Produced endogenously Acts on A1 receptors at AV node Enhances K+ conductance – hyperpolarises cells of conducting tissue Anti-arrhythmic – Administered intravenously – Doesn’t belong in any of the classes mentioned LO 4 Define the term inotropic drug and the circumstances under which these drugs can be used Inotropic drugs are drugs that affect the force of contraction of the heart. Negatively inotropic drugs are used in circumstances where it is beneficial to reduce the workload of the heart, for example after a myocardial infarction. This reduces the O2 requirement of the heart and limits further damage. -blockers are examples of negative inotropic drugs. Positive Inotropic drugs are used in circumstances where the heart needs to beat more strongly, for example cardiogenic shock or acute but reversible heart failure (eg following cardiac surgery). -adrenoceptor agonist, e.g. dobutamine are examples of positive inotropic drugs. LO 5 Describe how drugs can be used in the treatment of heart failure  Heart Failure What is heart failure? – Failure of the heart to provide sufficient output to meet the body’s requirements or demand Features – Reduced force of contraction – Reduced cardiac output – Reduced tissue perfusion – Oedema  Drugs used in the treatment of heart failure Positive inotropic , increase cardiac output – cardiac glycosides – β-adrenergic agonists Dobutamine Dopamine Isoprenaline Drugs which reduce work load of the heart – reduce afterload and preload  Drugs which increase the force of contraction of the heart Cardiac glycosides – Have been used to treat heart failure for over 200 years – improves symptoms but not long term outcome Digoxin is the prototype – Extracted from leaves of the foxglove digitalis purpurea or digitalis lanata – Blocks Na+/K+ ATPase  Action of cardiac glycosides Ca2+ is extruded via the Na+-Ca2+ exchanger Na+ - Ca2+ Na+ – driven by Na+ exchanger [Na+] moving down K+ concentration gradient Na+ Na+ - K+ cardiac glycosides ATPase block Na+/K+ Ca2+ ATPase rise in [Na+]in  Action of cardiac glycosides Rise in intracellular Na+ leads to decrease in activity of Na+-Ca2+ exchanger Na+ - Ca2+ Na+ exchanger [Na+] Causes increase in K+ [Ca2+]in Na+ – more Ca2+ stored in Na+ - K+ SR [Ca2+] ATPase Ca2+ Increased force of contraction  Action of cardiac glycosides Block Na+/K+ ATPase Increase in Na+ concentration inside the cells leads to an inhibition of the Na+/ Ca2+ exchanger Increase Ca2+ concentration inside cardiac myocytes – Positive inotropic effect – Increased force of contraction Action of cardiac glycosides on heart rate cardiac glycosides also cause increased vagal activity – action via central nervous system – slows AV conduction – slows the heart rate  Drugs which increase myocardial contractility β – adrenoreceptor agonists e.g. dobutamine – acts on β1 receptors Uses: – Cardiogenic shock – Acute but reversible heart failure (e.g. following cardiac surgery)  Drugs which reduce the workload of the heart: ACE-inhibitors Drugs which inhibit the action of angiotensin converting enzyme are important in the treatment of heart failure Prevent the conversion of angiotensin I to angiotensin II Angiotensin II acts on the kidneys to increase Na+ and water re-absorption Angiotensin II is also a vasoconstrictor  ACE-inhibitors Decrease vasomotor tone (blood pressure) Reduce afterload of the heart Decrease fluid retention (blood volume) Reduce preload of the heart Reduce work load of the heart  Drugs which reduce the work load of the heart Diuretics ( ↓ pre-load ) β–adrenoceptor antagonists (β- blockers) LO 6 Describe how drugs can be used in the treatment of Angina  Angina (Myocardial ischaemia) Occurs when O2 supply to the heart does not meet its need Ischemia of heart tissue – chest pain Usually pain with exertion Due to narrowing of the coronary arteries  Treating Angina Reduce the work load of the heart – β-adrenoreceptor blockers – Ca2+ channel antagonists – organic nitrates Improve the blood supply to the heart – organic nitrates – Ca2+ channel antagonists  Action of Organic Nitrates Reaction of organic nitrates with thiols (-SH groups) in vascular smooth muscle causes NO2- to be released NO2- is reduced to NO (Nitric Oxide) Examples of Organic NO is a powerful Nitrates vasodilator glyceryl trinitrate isosorbide dinitrate Nitric Oxide causes vasodilation vascular smooth muscle cell guanylate + cyclase NO GTP cGMP PKG [Ca2+]in NO activates guanylate cyclase increases cGMP lowers intracellular [Ca2+] causes relaxation of vascular smooth muscle How does this help alleviate symptoms? PRIMARY ACTION action on venous system venodilation lowers preload – Reduces work load of the heart – Heart fills less therefore force of contraction reduced (Starling’s Law) – This lowers O2 demand SECONDARY ACTION Action on coronary arteries improves O2 delivery to the ischaemic myocardium – acts on collateral arteries rather than arterioles  Action of organic nitrates on collateral arteries no drug atheromatous effect of nitrate plaque collateral collateral dilated normal fully arteriolar dilated tone arterioles blood flow to ischaemic area increased blood flow to ischaemic area LO 7 Understand the risk of thrombus formation with certain cardiovascular conditions and understand how to treat this  Anti-thrombotic drugs Certain heart conditions carry an increased risk of thrombus formation –Atrial fibrillation –Acute myocardial infarction –Mechanical prosthetic heart valves  Anti-thrombotic drugs Anticoagulants – Heparin (given intravenously) inhibits thrombin used acutely for short term action – Fractionated heparin (subcutaneous injection) – Warfarin (given orally) antagonises action of vitamin K can be used long term Anti-platelet drugs – Aspirin , dipyridamol and globidogrel following acute MI or high risk of MI LO 8 Describe how drugs can be used in the treatment of Hypertension  Hypertension Associated with increases in blood volume. – Na+ and water retention by the kidneys Possible treatments – diuretics – ACE-inhibitors – β-blockers – Ca2+ channel blockers which act at vascular smooth muscle – α1-adrenoceptor antagonists  Hypertension Diuretics – decrease Na+ and water retention by kidney decrease blood volume ACE-inhibitors – decrease Na+ and water retention by kidney – decrease total peripheral resistance - vasodilation β-blockers – decrease cardiac output Ca2+ channel blockers selective for vascular smooth muscle – vasodilation α1 – adrenoceptor antagonist – vasodilation