Cardiac Drugs Powerpoint Lecture.pptx

Cardiac Drugs 1. Angina Nitrates...

Cardiac Drugs 1. Angina Nitrates Beta-Adrenoceptor Antagonists Calcium Channel Blockers Dr J Haylor, School of Medicine, UCLan UM1010 Semester 1, 2023 This lecture deals with two aspects of drugs and the heart, fristly the acute and the chronic treatment of angina, which may lead to damaged cardiac tissue and myocardial infarction and secondly in the acute and chronic treatment of heart failure. It has been recorded in 2 bitesize sessions, the first of which deals with the nitrates, beta-blockers and calcium  Angina Stable Angina Imbalance in supply/demand oxygen by the heart Referred pain - K+, lactate on afferent fibres 90% Angina pectoris (atheroma), 10% Variant angina (vasospasm) Perfusion of myocardium intermittent Ischaemic areas maximally dilated Angina pectoris - coronary vasodilators no effect Pain in stable angina is produced by an imbalance between the supply and demand of oxygen by the heart. It is due to 2 major causes, the presence of atheromatous plaques in the coronary artery resulting in the angina of effort (angina pectoris) and coronary vasospasm, the variant form sometimes known as Prinzmetals angina. Remember the blood supply to the myocardium is intermittent, being perfused during diastole from the outside to the inner regions of the heart, as shown by the unshaded area in the diagram on the left. The first target for the relief of angina pain might thought to be increasing blood supply by reducing resistance through dilation of coronary arterioles, increasing the perfusion gradient. However, when blood flow is reduced in a coronary artery by the presence of atheromatous plaques, coronary arterioles distal to the block become maximally dilated in an attempt to improve perfusion. Therefore, coronary arteriolar vasodilators will only dilate areas proximal to the plaque, and reduce rather than increase perfusion to the ischaemic area.2So, how do drugs improve the balance between oxygen supply and demand in the relief of angina pain?  Alfred Nobel (1833-1896) History: Anti-Anginal Drugs William Murrell James Black (1853-1912) (1924-2010) GLYCERYL TRINITRATE PROPRANOL OL Two important discoveries lead to the development of anti-anginal drugs. The first nitroglycerin, used by Alfred Nobel to produce dynamite and gelignite, was found by an English physician, William Murrell to treat angina in 1879, nitroglycerin was eventually used to treat angina in Nobel himself. The second was the development of beta blocking drugs by James Black a pharmacologist, using a scientific approach, modifying the structure of adrenaline to produce the first beta blocker, propranolol in 1961. Developed to treat angina and arrhythmia, beta-blockers also improve mortality in patients with chronic heart failure.  Angina Glyceryl Trinitrate Acute attack of stable angina Venodilation - venous capacitance , preload filling pressure , ventricular volume , end-diastolic pressure Nitric Cytosolic Oxide Guanylat cGMP e (NO) Cyclase Peripheral Vasodilator - blood pressure (afterload) Arterial Vasodilator - vasospasm reduced, collateral flow improved Oral spray or sublingual tablet Positive Inotrope - weak Problem - TOLERANCE Acute attacks in stable angina are relieved using glyceryl trinitrate delivered sublingually as either tablets or sublingual spray. The sublingual route avoids extensive liver metabolism. GTN maybe considered as a prodrug, converted by aldehyde dehydrogenase in mitochondria of the blood vessel wall generating nitric oxide, NO is also an endogenous vasodilator. NO stimulates a cytoplasmic guanylate cyclase in smooth muscle to generate cGMP which in turn activates a cGMP kinase to reduce intracellular calcium and to dephosphorylate the muscle protein myosin resulting in vasodilation. Mechanisms involved lowering intracellular calcium include stimulating the removal of calcium from the cell by a calcium ATP-ase and increasing the uptake of calcium into intracellular stores. GTN relieves angina pain by reducing oxygen demand firstly through venodilation (increasing venous capacitance) reducing the preload on the heart and secondly through peripheral arteriolar dilation reducing the afterload on the heart. To a lesser extent, arterial vasodilation improves collateral blood flow and vasospasm increasing oxygen supply. The acute use of nitrates means that in the angina of effort, angina pectoris, they maybe taken prior to exertion. As in asthma however, drugs used to provide acute relief of angina pain can also induce tolerance and have to be used intermittently to allow a recovery time. However, unlike the tolerance to SABA agents in asthma, nitrate  Nitrate Alternatives Isosorbide Mononitrate olerance prevented by removing treatment nicorandil uch as patch removal) at night 100% bioavailable low dose - nitrate high dose - K/ATP channel agonist Glyceryl trinitrate itself may be delivered continuously, rather than intermittently, using either skin patches or a 2% ointment. Tolerance, using patches can be avoided by day-time treatment and the removal of patches at night. An oral nitrate, isosorbide mononitrate may be taken daily which unlike GTN has a bioavailability close to 100% but has a similar mechanism of action generating NO. Nicorandil has a dual mode of action, it is a nitrate vasodilator which at higher doses also opens ATP-dependent K+ channels to cause hyperpolarisation of vascular smooth muscle, which contributes to the vascular effect. Nicorandil, unlike GTN does not appear to induce tolerance and may activate guanylate cyclase directly.  Propranolol - β-adrenoceptor antagonist propranolol James isoprenaline Black Propranolol is considered to be one of the most important contributions to clinical medicine and pharmacology of the 20th century. Propranolol (β-adrenoceptor antagonist) has been described as the greatest breakthrough in the treatment heart disease since the discovery of digitalis. The major drug group used in maintenance therapy to reduce the number of angina attacks are the beta adrenoceptor antagonists, commonly known as beta-blockers. Beta-blockers were designed to inhibit the action of adrenaline and the sympathetic nervous system on the heart. Modifications to the amine portion of adrenaline first produced the beta- adrenoceptor agonist isoprenaline, modification to the ring structure of which then produced the first beta-adrencopetor antagonist propranolol. Propranolol was described as the greatest breakthrough in the treatment of heart disease since the discovery of digitalis.  -Blockers in Angina  Angina Pectoris B-blockers have 3 major effects Negative inotrope (O2 demand  ) Reduces heart rate (distribution of O2 supply ) Antihypertensive - reduces afterload (O2 demand  ) Beta-blockers reduce the incidence of periods of anginal pain by altering the balance between oxygen supply and demand to the heart in 3 separate ways. Oxygen demand is reduced by inhibiting myocardial contractility (negative inotrope) and by reducing the afterload on the heart by lowering systemic blood pressure. In addition, the distribution of oxygen supply to the inner myocardium is improved by slowing the heart rate (a negative chronotropic effect), increasing time for blood to perfuse from the outside to the inner regions of the heart within each heart beat. The major benefit of beta blockers will be in the relief of angina pain caused by atheroma rather than by coronary vasospasm. 7  Βeta-adrenoceptor Antagonism propranol ol cAMP Ca 2+↓ Heart rate ↓ Conduction ↓ Contraction ↓ Beta-blockers antagonise the effect of the sympathetic nervous system and circulating adrenaline, reducing the activation of cell membrane adenylate cyclase, reducing cAMP and calcium entry into the cell. The reduction in cellular calcium entry slows the heart rate, decreases cardiac conduction and reduces myocardial contractility.  Propranolol : Adverse Effects Bradycardia (1) Bronchoconstriction (2) Peripheral Vasoconstriction ( 2) Hypoglycaemia ( 2) Diarrhoea CNS Non-selective B-blockers have their primary adverse effects through inhibition of beta-2 adrenoceptors producing cold hands and cold feet from peripheral vasoconstriction and potential bronchoconstriction in the lung, so are contraindicated in patients with asthma. In addition, in the asthmatic patient, non-selective beta-blockade would prevent salbutamol, a beta-2 adrenoceptor agonist, from inducing its therapeutic effect.  Selective  -adrenoceptor antagonist β-adrenoceptor subtypes 1st generation 2nd generation β1 - heart (rate, force, propranolol bisoprolol automaticity) - kidney (renin) (non-selective ( 1-selective antagonist) antagonist) β2 - lung (bronchodilation) Major use - skeletal muscle (vasodilation) Bisoprolol > Atenolol = - GI tract (motility↓, sphincter close) Propranolol β3 - bladder (relaxation) (65%) (15%) (15%) Openprescribing.net Sept 2019 The first beta-1 selective B-blocker, atenolol had a 30-fold selectivity for the beta1 receptor. In addition, atenolol is water soluble, doesn’t cross the blood brain barrier and is renally excreted. Both propranolol and atenolol are still in common use today but the major beta1-selective antagonist in use in the UK today is bisoprolol with about a 75-fold selectivity for the beta-1 adrenoceptor. However, the statistics do not define whether the use of the beta blocker is to treat angina, hypertension or heart failure. 10  Variant Angina Angina Coronary artery Calcium Channel vasospasm – Ca2+ entry Blockers Angina Pectoris Coronary artery atheroma Negative inotrope Antihypertensive – reduces afterload (O2 demand  ) A third group of drugs effective in the treatment of angina are the calcium channel blockers. The variant form of angina which can occur during sleep, forms about 10% of cases in the UK, with a mixture of etiologies also being possible. Variant angina is caused by spasm of the coronary artery induced by calcium influx. Calcium channel blockers (particularly diltiazem) 11 may also provide some benefit in angina pectoris decreasing oxygen demand by inhibiting myocardial contractility and reducing the afterload on the heart by lowering systemic blood pressure.  Calcium Channel Blockers Dihydropyridines Most effective in coronary vasospasm (CCB) L-form calcium channel, inhibits all channel states, works from outside cell CC Use when B-blockers ineffective B Also potential B-Blocker combination (care in the presence of heart failure) amlodipine or nifedipine (sustained release) once daily treatment diltiazem Possibly most effective CCB in angina pectoris modest decrease in heart rate and blood pressure. Verapamil do not use in angina, causes heart block, negative inotrope, * problem with beta blockers and heart failure The most effective CCB in the treatment of variant angina are the dihydropyridines (DHP), including amlodipine with a long duration of action and nifedipine (sustained release form) allowing once daily dosing. Amlodipine inhibits the L form of the calcium channel working from the outside of the cell inhibiting all channel states. Dihydropyridines can be used together with beta-blockers but, with care, since both are negative inotropes. Diltiazem, of all calcium channel blockers, may have the best profile to relieve angina pectoris. The other major calcium channel blocker, verapamil should not be used in angina since it is a stronger negative inotrope and can induce heart block.  Major Drugs for the treatment of Angina Glyceryl trinitrate Isosorbide mononitrate Bisoprolol, atenolol Amlodipine Major drugs used in the treatment of anginal pain include the acute use of glyceryl trinitrate and the chronic use of isosorbide mononitrate, the beta1 selective, beta blockers bisoprolol and atenolol for angina pectoris. The calcium channel blocker amlodipine may be useful in the treatment of coronary artery vasospasm.  Cardiac Drugs 2. Heart Failure Sympathomimetic amines Digoxin Beta-Adrenoceptor Dr J Haylor, School of Medicine, UCLan UM1010 Semester 1 2023 Antagonists The second bitesize session on cardiac drugs deals with the sympathomimetic amines, digoxin and beta-blockers used in the acute and the chronic treatment of heart failure. It includes positive inotropic agents which increase the force of contraction of heart muscle.  Heart Failure ventricular Terminology performance inotrope force of contraction of cardiac muscle chronotrope heart rate (can be positive or Ventricular Fibre negative) Length Two major terms used in the discussion of the effect of drugs on the heart are chronotrope, which is a change in heart rate, and inotrope, which is a change in the force of contraction of cardiac muscle. Drugs may have positive or negative chronotropic and/or inotropic effects. The diagram on the right shows Starlings law of the heart with the relationship between ventricular performance and ventricular fibre length. Line (a) shows the normal increase in ventricular performance produced by increasing ventricular fibre length, increasing the cardiac output required for normal activity, such as walking upstairs or running for a bus. In severe heart failure, this line is depressed to line (c) where the increase in performance is insufficient to perfuse the tissues resulting in pulmonary and systemic congestion.  Inotropic Agents : Sepsis Septic shock is a consequence of a systemic infection characterised by hypotension, unresponsive to fluid resuscitation. 60% patients have cardiac depression with impaired left ventricular function. Acute forms of heart failure can occur, for example, during surgery or intensive care The example being shown here is septic shock. Septic shock is produced by a systemic infection, which is unresponsive to fluid resuscitation, where 60% of patients have decreased cardiac output, reducing the perfusion of the tissues and damaging peripheral organs. Here two acute effects are required firstly to increase cardiac output and secondly to increase systemic blood pressure.  Inotropic Agents Sympathomimetic Amines H Pharmacological Effects beta1-adrenoceptor agonist - heart rate↑, force of contraction↑ noradrenaline alpha1-adrenoceptor agonist (norepinephrine) vasoconstriction The major pharmacological approach is to stimulate the beta-1 adrenoceptor in the heart by giving an intravenous infusion of a sympathomimetic amine, producing positive chronotropic and inotropic effects. In addition to stimulating the heart, noradrenaline and adrenaline are also alpha-1 adrenoceptor agonists which contract peripheral blood vessels helping to maintain blood pressure. However, in the case of septic shock, noradrenaline is probably the preferred agent, since adrenaline can also stimulate beta-2 adrenoceptors to produce vasodilatation in skeletal muscle, the downside of which potentially, is a build up of lactic acid inducing lactic acidosis.  dobutam Inotropic Agents ine Dobutamine isoprenaline (non-selective) β1 adrenoceptor agonist - inotrope dobutamine (+ve isomer) (β1-selective) IV infusion – onset (1-2 min), steady state 10-12 min Weak - β2 adrenoceptor agonist (vasodilator) acute heart failure - surgical shock, sepsis Dobutamine is a more selective beta-1 adrenoceptor agonist, developed from isoprenaline (the non-selective beta adrenoceptor agonist initially developed for the treatment of asthma). * Racemic mixture -ve (α1 adrenoceptor Dobutamine contains a large substituent on the amine portion of the molecule giving it beta-1 adrenoceptor selectivity. Activation of the beta-1 adrenoceptor in the heart stimulates cell membrane adenylate cyclase, via a G-protein link, to elevate cAMP, enhancing calcium entry and intracellular calcium release from the sarcoplasmic recticulum stimulating the force of agonist) muscle contraction and the heart rate. Dobutamine has a rapid onset of action and is given by intravenous infusion either by addition to an IV bag or via a syringe pump. Like many drug products, dobutamine is administrated as a racemic mixture but only the positive isomer has inotropic activity.  Inotropic Agents Milrinone Phosphodiesterase Inhibitor PDE type 3, cAMP↑ Inotrope Peripheral vasodilator (inodilator) x milrinone Compared to dobutamine Less tachycardia More pulmonary vasodilation More systemic vasodilation Sympathomimetic amines stimulate the heart through activating adenylate cyclase to elevate cardiac cAMP. Another method of elevating the cyclic nucleotide cAMP is to prevent its breakdown, by inhibiting the enzyme phosphodiesterase with milrinone. Perhaps the most well known phosphodiesterase inhibitor is sildenafil (Viagra) which is selective for PDE (type 5). The heart contains mainly, PDE type 3 which is inhibited by milrinone. Sometimes milrinone is called a inodilator, being a better vasodilator than dobutamine in both the systemic and pulmonary circulations.  Chronic Heart Failure Cardiac Glycosides - Digoxin Foxglove aglycone sugar residues William Withering Cardiac Digoxi (1741-1799) Glycosides n Digitalis The first drug preparation used in the treatment of chronic heart failure, known at the time as the dropsy, was an extract of the Foxglove (digitalis purpurea), a plant with purple bell- shaped flowers growing in English hedgerows. The first account was published by William Withering, a Midlands botanist/physician, though its toxic effects also soon became apparent. The active ingredients of the foxglove were described as cardiac glycosides. The structure of the modern day cardiac glycoside, digoxin is shown on the right hand side. It has two component parts, the aglycone which has a steroid-like structure and is attached to 3 plant-based sugars. Digoxin is water soluble and excreted from the body via the kidney requiring a reduction in dose in both the young and the elderly.  extracellular 3Na+ Chronic Heart failure 3Na+ Inotropic action x Cardiac Glycoside (DIGOXIN) of Digoxin ATP-ase antiporter Digoxin is 2K+ a positive inotrope [Na↑] 2Ca2+ without being a positive intracellular INOTROPIC EFFECT chronotrope Digoxin is a positive inotrope without being a positive chronotrope. Initially considered to be a diuretic, studies using isolated heart muscle in the 1970’s with bioluminescent dyes showed the ability of digoxin to increase intracellular free calcium, but the target site of drug action is the sodium pump. The sodium pump is a Na/K ATP-ase, used to re-establish the membrane potential in excitable tissue, including ventricular heart muscle. It is electrogenic and pumps 3Na+ out of the cell for 2K+ ions going into the cell. Digoxin inhibits the Na/K ATP-ase increasing the concentration of sodium inside the cell (the so-called sodium transient). The sodium ion is then swopped for a Ca2+ ion via a Na/Ca antiporter, increasing intracellular free calcium but without any direct effect on calcium transport to produce its inotropic effect.  Mortality (any cause) Ventricular The DIG Performance Trial digoxin placebo digoxin 0.25mg/day digoxi + loop diuretics n + ACE inhibitors Ventricular Fibre Length Digoxin improves heart failure by stimulating the cardiac function curve shown on the left. Although the mainstay of the treatment of heart failure for over 150 years, what is the status of digoxin in the treatment of heart failure today? Firstly, digoxin is no longer used in the first line treatment of heart failure. Its modern use is in patients already being treated with both diuretics and drugs which inhibit the renin-angiotensin system such as the ACE inhibitors. The DIG trial was carried out some 20 years ago to establish whether digoxin treatment influenced mortality of patients with chronic heart failure when being treated with diuretics and ACE inhibitors. The answer was it didn’t, although the need for hospitalisation was reduced. This doesn’t mean to say that digoxin isn’t useful in treating heart failure, it is very useful in improving cardiac output and fatigue, enhancing the quality of life and although the use of digoxin has declined over the years, it is still an important drug used in the symptomatic relief of heart failure. The drug treatment of heart failure will be  Chronic Heart Failure Βeta-Blockers bisoprolol β-blockers reduce heart rate and myocardial contractility and for many years Ca 2+↓ were contraindicated in the treatment of heart Heart rate ↓ Conduction ↓ Contraction ↓ failure Beta blockers are negative inotropes, which reduce the force of contraction of cardiac muscle and for over some 30 years were contra-indicated in patients with chronic heart failure. However, studies from Sweden in the late 1970’s suggested that chronic stimulation of sympathetic innervation to the heart might be responsible for remodelling cardiac tissue to produce the condition of chronic heart failure. Beta-adrenoceptor antagonists, commonly known as beta-blockers reduce sympathetic stimulation to the heart.  Beta-Adrenoceptor Antagonist US Carvedilol Study Group (3rd Generation) Patients already receiving loop diuretic, ACE inhibitor & digitalis Probability carvedilol of event survival non-selective β-adrenoceptor antagonist α1- adrenoceptor antagonist carvedil ol racemic mixture placeb S-enantiomer (α1/β) o R-enantiomer (α1 only) Vasodilation but no reflex tachycardia US trials with the beta-blocker carvedilol in the 1990’s highlighted the improved survival in patients with severe heart failure when carvedilol was added to treatment, with a combination of other drugs including loop diuretics, ACE inhibitors and digitalis. Carvedilol was a new, so called 3rd generation beta-blocker, defined as having an additional pharmacological property to beta blockade. In the case of carvedilol, it is antagonism of the alpha-1 adrenoceptor. Carvedilol is a non-selective beta blocker, but only one of its isomers blocks the beta-adrenoceptor while both block the a1-adrenoceptor. The result is additional vasodilation but, in the absence of a reflex increase in heart rate. However, this result also left a question. Is the benefit of carvedilol a general property of beta blockade or a unique property of carvedilol.  Beta Blockers in Chronic Heart Failure Benefit of improved survival first appeared Benefits of B-Blockers in the late 1970’s but it wasn’t until the Now days inhibition of the sympathetic NS with positive clinical trials with Carvedilol in the β-Blockers is one of two mainstay treatments to slow the progression of CHF mid 1990’s that their potential benefit was put into clinical practise. Reduced O2 demand, Reduced mortality and morbidity Left Ventricular End Diastolic Volume Inhibit renin release improves, Anti-arrhythmic Decrease ventricular mass, Reverse remodelling * Titrate dose at start – potential negative inotrope Prevents myocardial cell hypertrophy. Today beta-blockers are one of the main drug groups used to improve mortality in patients with heart failure. Reducing sympathetic stimulation of the heart by blocking the beta-1 adrenoceptor improves left ventricular end diastolic volume (LVEDV), decreasing ventricular mass, reverse remodelling the fibrosis and preventing cellular hypertrophy. The reduction in oxygen demand, is supported by inhibiting renin release together with targeting arrhythmia. However, when initiating treatment, beta-blockers have to be carefully titrated upto their therapeutic dose levels, to avoid their negative inotropic effect.  Important Drugs used in the treatment of Heart Failure noradrenaline digoxin bisoprolol, carvedilol Lecture Outcomes 1. Describe the drugs used to treat angina and MI 2. Understand the importance of inotropic agents in the treatment of heart failure The lecture outcomes covered by these two bitesize recordings includes a description of drugs used to treat angina and the importance of inotropic agents in the treatment of heart failure. The drug treatment of myocardial ischaemia and chronic heart failure will be developed further in year 2.