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Antianginal drugs are drugs used for the treatment of ischemic disease (coronary heart disease). Ischemic heart disease (IHD) is characterized by disbalance between myocardium demand and coronary supply. FACTORS DETERMINING MYOCARDUM OXYGEN DEMAND: 1. contractility of myocardium 2. (HR) 3. tension of myocardium wall at the end of (), and its` maximal tension during (). FACTORS DETERMINING MYOCARDIAL BLOOD SUPPLY 1. pressure that ensures movement of blood through coronary vessels, it is the difference between the pressures in coronary sinuses (intramyocardial pressure) and aorta. The higher is the intramyocardial pressure (for example preload increase), the lower is the perfused pressure and the worse is the myocardial blood supply. 2. resistance and diameter of coronary , which depends on the external factors (which bring to passive changes of resistance and diameter of coronary vessels), internal factors (which cause active changes in them) and blood viscosity.

2.1. To the external factors belongs extravascular myocardial compression (the compression of coronary vessels due to the heart contraction during systole), especially intramural coronary vessels. In these vessels, blood supply nearly completely ceases during systole. So, 67-90% of the heart blood supply is realized during diastole, especially at its beginning, when the myocardium is fully relaxed. In this case subendocardial arteries become mainly compressed (picture 1).

2.2. To the internal factors belongs local-self –regulating mechanisms (due to pO2 and/or

pCO2 level changes), nervous (activation of α-adrenorecpetors causes

and stimulation of M-cholino- and β2-adrenoreceptors brings to of coronary arteries) and humoral factors (EDRF, prostacycline etc.). 1

Picture 1: Extravascular myocardial compression of coronary arteries

3. Passability of coronary arteries( the existence of atherosclerotic plugs and/or thrombs). There are the following types of IHD. 1.Sudden coronary death 2. pectoris 2.1. Exertional angina 2.2. Vasospastic angina or Prinzmetal`s angina 3. Myocardial infarction 4. Postinfarction cardiosclerosis 5.Arrhyhtmias 6. During exertional angina the attacks can be precipitated during physical or emotional loading, which can lead to increase in oxygen demand, because coronary vessels have atherosclerotic plug, they can`t be adequately dilated and support adequate blood flow. In vasospastic angina attacks can be precipitated due to of vessels.

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Based on the above mentioned, we can state that the main goal of IHD treatment is a restoration of the balance between oxygen requirement and blood supply of myocardium, which can be achieved by the: 1. improvement of blood supply 2. reduction of myocardium oxygen demand 3. improvement of blood supply and at the same time reduction of the myocardium oxygen demand. The main goals of the angina pectoris treatment are: 1. Elimination of angina attacks 2. Prevention of angina attack development, which supposes the long-term treatment of the patients. Classification of antianginal drugs 1. Drugs reducing heart oxygen demand, simultaneously improving blood supply:  Organic nitrates  L-type Ca2+ -channel blockers  K+-channel activators 2. Drugs predominantly reducing oxygen demand: 2.1. β-adrenoblockers 2.2. Bradycardic drugs

3. Drugs improving myocardial blood supply:  Spasmolytic drugs  Drugs removing coronary spasm by reflex mechanism Drugs, which are included in the complex treatment of IHD, but aren`t considered to be antianginal drugs: 1. cardioprotectors 2. antiaggregants 3. 4. fibrinolytics 5. hypolipidemic drugs – . 3

1. Drugs decreasing the heart oxygen demand and simultaneously improving blood supply

Organic nitrates was for the first time synthesized in 1846 by Ascanio Sobrero. He found out that the sublingual usage of small doses of nitroglycerin causes headache. A year later, Konstantin Hering determined the curing doses of nitroglycerin and obtained nitroglycerin tablets. At the present three groups of organic nitrates are used: 1. Nitroglycerin 2. derivatives-Isomac, Isodinit, Cardicet 3. Isosorbide 5- mononitrate derivatives-Olicard, Monochinkve, Mono Rom retard Practically, it is more convenient to classify them according to the duration of their action 1. nitrates with short duration of action (the duration is up to 1 hour), 2. nitrates of moderate duration of action (1-6 hours), 3. nitrates with long duration action (6-24 hours).

Pharmacodynamics. Hemodynamic effects of nitrates are similar to those of the endothelial vasodilator NO. In the arteries and NO is produced during L-arginin , with participation of NO-synthatase. In arteries NO is produced more than in veins, though in veins is much more sensitive towards NO. There are known two varieties of NO synthetase - the structural (constitutive, endothelial) and inducible ones. The structural NO-synthetase is endothelial Ca2+-calmadulin-dependent enzyme, which is present also in thrombocytes, neurons, and is characterized by a low degree of activation. The inducible NO synthetase is produced under the influence of immunogenic and pre- inflammatory factors (γ-interferon, interleukin-1).

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Due to the participation of endothelial glutathione – S - transferase sulfydryl groups, nitrates are transformated into form, after which, reactive, free-radical NO is formed, which, as a lipophylic compound quickly penetrates into the smooth muscles, where activates cytoplasmic guanylate cyclase. As a result, the quantity of cGMP increases. By activation of special protein kinases cGMP brings to dephosphorylation of light chains, preventing formation of actomyosin. So relaxation of smooth muscles occurs. Besides, the increased quantity of cGMP may restrict penetration of Ca2+ into the cell. Besides above mentioned vasodilating effect, NO also stimulates prostacycline and PgE synthesis, which possess vasodilative and antiaggregant properties. Half life of NO is 6-30 sec. Systemic effects of organic nitrates Cardiovascular system Mechanisms of antianginal effect of nitrates are: 1. Decrease in preload. In low therapeutic doses, nitrates mainly dilate veins. Dilation of veins results in their increased capacity, due to which the reverse blood flow to the heart and also preload becomes decreased. Decreased preload results in lowering of the enddiastolic pressure of ventricles that reduces the heart oxygen requirement. Moreover decreased enddiastolic pressure of ventricles brings to the improvement of blood supply in subendocardial part of myocardium. 2. Decrease in afterload. Nitrates in the middle therapeutic doses dilate , resulting in a reduction of general peripheral resistance and afterload. In this case systolic BP is mainly reduced. 3. Dilation of coronary vessels. As it is known, ischemia stimulates dilation of coronary vessels. In the conditions of myocardial ischemia acidosis develops which brings to dilation of coronary vessels by compensatory mechanism, meanwhile the vessels with atherosclerosis cannot be dilated. Nitrates mainly dilate large coronary vessels of epicardium, in a result of which in the vessels with atherosclerotic affection pressure gradient for blood supply of ischemia area becomes increased (improved). Moreover, nitrates also eliminate spasms of coronary vessels, so they are effective also in treatment of vasospastic angina (picture 2).

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4. Nitrates improve collateral blood supply directly as well as indirectly. Nitrates can directly dilate collateral coronary vessels, increasing the quantity of functioning collateral vessels. Besides, by reducing the intraventricular pressure and volume, and decreasing myocardial wall tension, they indirectly decrease the external compression of collateral vessels. 5. Antiaggregant action. Nitrates increasing the quantity of cGMP in thrombocytes, inhibit thrombocyte aggregation preventing a thrombus formation in the coronary lumen. Picture 2. Action of organic nitrates on coronary blood flow

Smooth muscles Organic nitrates relax all smooth muscles-bronchi, esophagus, biliary ducts, gall bladder, Ody’s sphincter, urethra, also uterus. Pharmacokinetics Organic nitrates differ from each other mainly by their pharmacokinetic properties. Nitroglycerin. During oral rout of administration nitroglycerin and its depot preparations with gradually dissolving active substance (Sustak forte, Nitrong forte) have an insignificant antianginal effect. It is explained by the fact that nitroglycerin, being a lipophylic is completely absorbed from intestines, and in the liver with participation of nitrate reductase undergoes to biotransformation, in a result of which 80-90% of the drug becomes neutralized.

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Depot drug forms of the nitroglycerine have more bioavailability and duration of action (up to the 6 hours). That is why nitroglycerin preparations are mainly used by sublingual rout with the purpose to stop angina attacks. In this case half - life is 1-3 min and duration of action is 15-20 min. Nowadays there are available another drug forms of nitroglycerin-buccal polymeric films (which are applied on the upper jaw gum), ointments, patches etc. having a longer duration of action and can be used for prevention of angina attacks. Nitroglycerin can be used also by intravenous injections. Isosorbide dinitrate preparations - Isomac, Isodinit, Cardicet have broad clinical implementation. During oral rout of administration they are completely absorbed from gastro- intestinal tract, but bioavailability is 10-20%. Biotransformation takes place in the liver. In a result of biotransformation two substances are produced - isosorbide-5-mononitrate, bioavailability of which is 90% and isosorbide-2-mononitrate which is comparatively less active. Duration of the action of isosorbide dinitrate preparations varies from 3-4 hrs to 4-6hrs. Nowadays there are available slow releasing and long acting drug forms of isosorbide dinitrate - Isomac retard, Cardicet retard etc. Isosobide-5-mononitrate preparations - Olicard, Monochinkve, Mono Rom retard are the most efficient drugs for IHD treatment. As isosorbide-5-mononitrate is not metabolized in the liver and has high-90% bioavailability and long duration of action (24hours).

Side-effects: 1. Headache, caused by the dilation and increased permeability of cerebral vessels, that results in intracranial pressure increase. This side effect can be relieved using drugs, which are increasing the venous tension, such as menthol, validol, cordiamine, caffeine etc. Tolerance is developed to this side-effect. 2. Orthostatic , often appears in persons taking nitrates in a vertical position of the body. 3. Paradoxal response toward nitrates. In this case frequency of angina attacks becomes more which myocardial ischemia makes deeper. 4. Drug dependence.

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5. Withdrawal syndrome. Sharp discontinuation of nitrate treatment can lead to the aggravation of IHD up to the development of acute myocardial infarction. Withdrawal syndrome is less common for long acting nitrates and isosorbide-5-mononitrate derivatives. 6. Tolerance (cross). The tolerance develops in a case of regular treatment with nitrates. First of all tolerance develops toward long acting nitrates. After discontinuation of nitrate usage clinical efficiency of these drugs can be restored in 3-5 days. Cross-tolerance develops towards all derivatives of organic nitrates. More slowly tolerance develops toward isosorbide- 5-mononitrate. In this case tolerance can be developed in two levels-cellular and systemic. During cellular level of tolerance development quantity of restored glutathione in

endothelium becomes reduced, as during the NO formation from NO2, an oxidation of gluthatione sulfhydril groups into disulfide groups takes place. This type of tolerance development is called “real vascular” tolerance. Moreover an activation of phosphodiestherase takes place in a result of which inactivation of cGMP becomes more intensive. During systemic level of tolerance development the following mechanisms are known:  stimulation of sympathetic activity by reflex mechanism, increase in the quantity of vasoconstrictive mediators (, II),  worsening of renal blood supply that results in increase in circulating . To prevent tolerance development it is necessary to make an accurate dosage of nitrates with an interval of 10-12 hours between two doses. Parallely sulfhydril group donators-N- acetylcystein, methionin, some sulfhydril group containing ACE inhibitors, such as , perindopril can be used. Uses 1. Angina pectoris. 2. Chronic heart failure or acute left ventricular insufficiency if there is no arterial hypotension. 3. Acute myocardial infarction of the left , if there is no arterial hypotension. In this case nitroglycerin i./v. injections are mainly performed. 4. Surgical interventions on the heart, for example angioplasty of coronary arteries. 5. Biliary colic. 8

6. Esophagospasm, even a sublingual administration of nitroglycerin may relieve the pain. The indices of the efficiency of nitrate treatment are a slight headache, heart rate increase (in 7-10 beats), decrease of arterial pressure in 10-15%, decrease in the frequency and duration of angina attacks, improvement of tolerance to physical load. ¼-th patients with angina pectoris are resistant to nitrates by nature. Molsidomin (Sidnopharm) Molsidomin is a derivate of sidnonime. Pharmacodynamics. molecule contains functionally active NO group. Hemodynamic effects are similar to nitrates. Pharmacokinetics. It can be used by both oral (duration of action is 12 hrs) rout of administration and intravenous injections. Uses. 1. removement (sublingual rout) and prevention of angina attacks 2. chronic heart failure 3. pulmonary . Sid-effects: Compared to nitrates less often headache, hypotension. Tolerance is not typical.

Inhibitors of channels Inhibitors of calcium channels possess their antianginal effect blocking potential-dependent calcium channels of Lm type, localized in the heart, in smooth muscles of arterioles and large arteries. Mechanisms of antianginal effect of inhibitors of calcium channels are: 1. decrease in the heart oxygen demand due to the decreased contraction force and frequency (only phenylalkilamine and benzothiazepine derivatives), reduction in preload (only Nifedipine) and afterload (all groups) 2. improvement of the heart blood supply due to dilation of coronary vessels, removal of their spasm and improvement of the function of collateral vessels 3. cardioprotective effect, due to the decreased activating effect of calcium ions on lyzosomal proteolytic enzymes and ATP-ase 4. antiaggregant and antiatherosclerotic effects. Antiaggregant action appears in high doses. In thrombocytes verapamil and disturb calcium ion kinetics, block

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phosphodiestherase as well as A2 formation, stimulate prostacycline production in vascular endothelium. In trombocytes nifedipine inhibit also phospholypase

A2, disturbing the release. Nifedipine is also an antagonist for thromboxane receptors. Calcium channel-blocking agents, possess also an antiatherosclerotic effect, due to their ability to prevent the cholesterol accumulation in macrophages, inhibit peroxidation and stimulate production of lipoproteins of high density. Antiatherosclerotic action has mainly , Isradipine and Lacidipine. Side-effects. Dihydropyridine derivates, especially Nifedipine with the short duration of action, can bring to the sharp decrease of arterial pressure, which worsens myocardial ischemia especially in patients with expressed atherosclerotic affection of arteries. In this case “stealing syndrome of coronary vessels” can develop (picture 3) in a result of dilation of intact, healthy coronary arteries, while the blood supply of the ischemic areas becomes more impaired. Actually, the vessels affected by atherosclerosis are unable to dilate under the action of calcium channel blockers, as in conditions of ischemia they are already maximally dilated. Moreover, Nifedipine sharply decreasing indirectly stimulates sympathetic nervous system activity, resulting in the development of tachycardia. Tachycardia in its turn increases heart oxygen requirement, which worsens ischemia. Picture 3: Stealing phenomenon of coronary arteries

Ischemia Stealing Normal induced Nitrates arteriols dilation of phenomenon arterioles

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Uses of calcium channel blockers 1. Vasospastic angina. The preference is given to the drugs of prolonged action, as attacks of vasospastic angina usually happen at night or in the morning. 2. Stable exertional angina pectoris. 3. . In this case Dihydropyridine derivatives should be combined with β- adrenoblockers. Nifedipine shouldn’t be used because of stealing phenomenon development. 4. Acute myocardial infarction (except nifedipine). 5. Secondary (nifedipine). 6. Raynaud’s syndrome (nifedipine).

Potassium channel activating drugs New potassium channel-activating drugs, such as , , Cromacalim etc., are widely used nowadays for treatment of IHD. Pharmacodynamics Potassium channel activating drugs activate ATP-dependent potassium channels; as a result, there takes place outflow of potassium ions from the cells, which results in hyperpolarization of cardiac conductive system, contractile myocardium and smooth muscles of vessels. Hyperpolarization brings to the inhibition of potential-dependent calcium channels and decrease in calcium ion penetration into the cells. Mechanisms for antianginal effect of potassium channel activating drugs are:  Dilation of coronary arteries and improvement of coronary blood supply  Dilation of peripheral arteries and veins, decrease of pre- and afterload  Only nicorandil, being a donator of NO groups, can more efficiently dilate veins and arteries (cGMP). Thus nicorandil dilates both big epicardial arteries and deep resistant coronary arteries, also inhibits aggregation. Pharmacokinetics. Nicorandil can be used by sublingual and oral routs of administration. In case of sublingual application, the homodynamic effect appears in 30 minutes. Half - life is 1 hour. Side-effects. Headache, dizziness, arterial hypotension, heartbeat, , dyspepsia. Uses: Angina pectoris, arterial hypertension.

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2. Drugs mainly decreasing oxygen requirement of the heart β-adrenoblockers

β-adrenoblockers play a significant role in the treatment of IHD, as they efficiently decrease the frequency of anginal attacks, increase the load tolerance of patients and decrease the patients’ requirement in nitrates. Mechanisms for antianginal effect of β-adrenoblockers: 1. Decrease in frequency of heart contraction, due to which heart oxygen requirement decreases at rest as well as at physical activities. 2. Prolongation of diastole period thus blood supply duration of the heart becomes more. 3. Decrease in contraction force. 4. Inhibition of renin production, decrease of arterial pressure (decreased afterload). 5. Inhibition of lipolysis in adipose , which results in inhibition of free fatty acid oxidation in myocardium; this process requires more oxygen. In the ischemic areas of myocardium β-adrenoblockers improve blood supply, as it is known in ischemic areas the coronary vessels are in a paralytically dilated state (because + of increased levels of CO2 and H ions). In intact areas of myocardium, the spasm of coronary vessels (non-selective β-adrenoblockers) contributes to redistribution of coronary blood flow through the dilated vessels to the ischemic area (Picture 3). Side-effects 1. β-adrenoblockers increasing cardiac end diastolic volume and prolonging the duration of contraction, can increase the oxygen requirement, thus aggravate the course of angina pectoris. That is why for treatment of IHD combined prescription of β- adrenoblockers with other antianginal drugs (for example nitrates) is preferable.

2. Non-selective β-adrenoblockers, blocking β2-adrenoreceptors of coronary vessels, may

aggravate the course of vasospastic, as well as of unstable angina, as blockage of β2- adrenoreceptors does not counteract to the α-adrenoreceptor mediated contraction of coronary vessels any more.

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Uses of β-adrenoblockers. 1. Stable exertion angina pectoris 2. Unstable angina (combined treatment with other antianginal drugs) 3. Acute myocardial infarction, if symptoms of heart failure are absent (combined treatment) 4. Postinfarctional cardiosclerosis. Application of β-adrenoblockers in case of vasospastic angina is contraindicated.

Bradycardic agents Alinidin, Falipamil and the modern drug-Coraxan (Ivabradin) are drugs of this group. Coraxan (Ivabradin) Pharmacodynamics: It has been demonstrated that the bradycardic property of Ivabradine is determined by the inhibition of the Na+/K+ mixed flow in the sinus node (so called inhibition of If flow; mentioned flow providing channels are called wonder channels, become activated during hyperpolarization stage of potential of action). Ivabradin, penetrates through the opened channels and blocks channels from inside, which is expressed by slowing down of spontaneous diastolic depolarization, inhibition of the sinus node automatism and development of bradycardia. As a result, diastole is prolonged, due to which time for heart (especially its subendocardial sections) blood supply becomes prolonged. Bradycardia itself causes decrease in the heart oxygen requirement. Ivabradin does not have a direct action on the coronary vessels, cardiac contractiliy and conductive system. It does not block β- adrenoreceptors and calcium channels. It is prescribed twice daily. Uses are IHD, chronic cardiac failure. One of the side effects is temporary vision disturbances. Withdrawal syndrome isn’t typical.

3. Drugs improving heart oxygen supply To his group belong drugs directly dilating coronary vessels and drugs removing spasm of coronary vessels by reflex mechanism Vasodilators of coronary arteries (Curantil) belongs to this group. Its effect is based on the inhibition of reuptake (myocardium, erythrocyte) and adenosine desaminase enzyme. As a result, the content of adenosine increases, which possesses strong vasodilating activity 13

(mainly resistant vessels become dilated). Besides, dipyridamole also inhibits thrombocyte aggregation. It is necessary to note that Dipyridamole can also bring to the coronary artery stealing phenomenon development (picture 3). Vasodilators removing coronary vasospasm by reflex mechanism Validol: belongs to this group. It is a 25-30% menthol solution of isovaleric acid menthyle ether. Its antianginal efficiency is low. It is mainly used at early stages of angina for removal of light attacks. In this case few drops of Validol is applied on the piece of sugar and use sublingually, or there can be used its sublingual tablets or capsules. By irritating receptors of mouth mucous membrane, validol eliminates coronary vessel spasm by reflex mechanism; as a result the coronary blood circulation becomes improved. If in 2-3 minutes the pain is not removed, the drug should be changed to Nitroglycerin sublingual tablets.

Cardioprotective drugs The most widely used preparation of this group is Trimetazidine (Preductal), which improves energy balance of cardiomyocytes, without having any considerable effect on the . In ischemia conditions, preductal prevents a development of ATP deficiency in cardiomyocytes, as it inhibits 3-ketoacyl CoA thyolase enzyme, due to which beta- oxidation of fatty acids is inhibited. All this results in an activation of oxidation, that requires less oxygen expense; thus, the process of energy formation goes on with considerably less oxygen expense, as for the energy obtained by oxidation more oxygen is necessary. Preductal eliminates intracellular acidosis and shows an antioxidant activity as stimulates glutathione peroxidase which inhibits lipids peroxidation. Pharmacokinetics. Preductal MR is prescribed twice daily during a meal. Indications for use are all manifestations of IHD. Ranolazine /Ranexa/ belongs to the newest cardioprotective agents, which besides inhibition of 3-ketoacyl CoA thiolase enzyme, inhibits also the late sodium ion flow, in a result of which inflow of calcium ions to the cell is decreased. Cardionate: Inhibits gamma-buthyrobetaine-hydroxylase enzyme in heart and synthesis of carnitine leading to increase in vasodilator-gamma-buthyrobetaine level. Cardionate inhibits also the transportation of fatty acids into the cell, preventing the accumulation of non-

14 saturated activated fatty acids in the cell. As a result the metabolism and ATP transport in the heart is regulated, glycolysis is activated. Phosphocreatine /Neoton/: Is considered to be intracellular substance, phosphocreatine derivative, which promotes mechanical energy for contraction. Neotone has anti-ischemic, antiarrhythmic, antioxidant effects. Moreover has also antiaggregant effect, because inhibits platelet adhesion. Available drugs Isosorbide dinitrate (generic Isordil) 5,0, 20, 30, 40mg tablets; Sublingual: 2.5, 5mg sublingual tablets. (Ismo, others) Oral: 10, 20mg tablets; extended-release 30, 60, 120mg tablets Nitroglycerin 0.3, 0.4, 0.6mg tablets Amlodiine 2.5, 5, 10mg tablets Diltiazem (Cardizem, generic) 30, 60, 90, 120mg tablets Nifedipine 10, 20 mg capsules Verapamil 40, 80, 120 mg tablets Preductal MR 35mg tablets Ranexa 500, 1000mg tablets Tests 1. Organic nitrates a) predominantly decrease oxygen demand and don`t have an action on the heart blood supply b) predominantly increase blood supply and don`t decrease oxygen demand c) decrease heart oxygen demand and increase oxygen supply d) directly increase heart contraction force 2. All are the molecular mechanisms of nitrate action, EXCEPT: a) NO -release b) activation of cytosolic guanylatecyclase 15 c) cGMP increase d) activation of myosine light chain kinase 3. Openers of K+-channels relax smooth muscles due to: a) opening of K+- channels and increasing of K+ outflow, hyperpolarization, decrease in Ca2+ inflow b) closing of K+- channels and decreasing of K+ outflow, hyperpolarization, decrease in Ca2+ inflow c) inhibition of cytosolic guanylatecyclase d) inhibition of cytosolic adenylatecyclase 4. Indications of nitroglycerin are: 1.all types of angina 2.silent ischemia of the heart 3.chronic heart failure, which isn’t combined with expressed hypotension 4.acute infarction of the left ventricle a) 1, 2, 3 b) 1, 3, 4 c) 1, 2, 4 d) the all

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