cardiovascular system.pdf

Chapter Two: Cardiovascular System 2.1-Angiotensin-converting enzyme inhibitors (ACE inhibitors) 1-They inhibit ACE, thereby inhibiting the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor (1). 2- Members of the drug class include: (captopril, enalapril, fosinopr...

Chapter Two: Cardiovascular System 2.1-Angiotensin-converting enzyme inhibitors (ACE inhibitors) 1-They inhibit ACE, thereby inhibiting the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor (1). 2- Members of the drug class include: (captopril, enalapril, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, and trandolapril) (2). 3-The main uses of ACE inhibitors are in the management of heart failure, hypertension, and myocardial infarction (3). In addition, they are used for the prevention and treatment of diabetic nephropathy (1) (early evidence of nephropathy is the presence of albumin in the urine) (4). 4-Pronounced hypotension may occur at the start of therapy with ACE inhibitors (first dose hypotension) (3). Therefore: A-Therapy should be started with low doses followed by gradual titration as tolerated to target doses (5). B-For hypertension the first dose should preferably be given at bedtime (2). 5-Other adverse effects include persistent dry cough (3)[see Angiotensin II receptor blocker (ARBs) below]. (Occurs in up to 20% of patients and is thought to be due to inhibition of bradykinin breakdown) (5). 6-An ACEi, as well as an ARB or direct renin inhibitor, are contraindicated in pregnancy (5). 7-Counseling points for the drug class Notify a healthcare professional if a cough develops (1). For hypertension the first dose should preferably be given at bedtime (2). ACE inhibitors Scientific name Trade names Dosage form 1 2 3 4 5 Any extra notes: 11 2.2-Angiotensin II receptor blockers(ARBs). 1-They block the binding of angiotensin II to the AT1 receptor, thereby inhibiting the effects of angiotensin II, a potent vasoconstrictor (1). 2-Members of the drug class include: (azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan) (sartans) (2). 3-They are used for hypertension, heart failure, diabetic nephropathy, and myocardial infarction (1). 4-As with ACE inhibitors, initiate therapy with low doses and then titrate to target doses (5). 5-Imortant: unlike ACE inhibitors, they are less likely to cause the persistent dry cough (2) (less than 1%) (6) which can complicate ACE inhibitor therapy. They are therefore a useful alternative for patients who have to discontinue an ACE inhibitor because of persistent cough (2). Angiotensin II receptor blockers Scientific name Trade names Dosage form 1 2 3 4 5 Any extra notes: 2.3-Angiotensin receptor–neprilysin inhibitor (ARNI) 1-Sacubitril (a neprilysin inhibitor) inhibits the breakdown of natriuretic peptides resulting in varied effects including increased diuresis, natriuresis, and vasodilation (2). 2-The combination of (ARNI) is indicated for chronic heart failure with reduced ejection fraction (Systolic HF) (2). Scientific name Trade name Dosage form 1 Valsartan/sacubitril Any extra notes: 12 2.4-Beta-adrenoceptor blocking drugs (beta-blockers) 1-Beta blockers block response to beta-adrenergic stimulation at the receptor level, which results in decreases in heart rate, myocardial contractility, blood pressure, and myocardial oxygen demand (1). 2-Members of the drug class include (atenolol, bisoprolol, carvedilol, metoprolol, nadolol, oxprenolol, pindolol, and propranolol) (2). 3-Usage for the drug class: Cardiovascular uses: Angina, arrhythmias, heart failure (bisoprolol, carvedilol, metoprolol(1) and nebivolol(2)), hypertension, and myocardial infarction (1). Noncardiovascular uses: Essential tremors, prophylaxis of migraine and of variceal bleeding associated with portal hypertension, management of alcohol withdrawal, anxiety disorders, and treatment of thyrotoxicosis symptoms. Some beta blockers are used as eye drops in the management of glaucoma and ocular hypertension (1, 3). 4-Important: A-β-blockers are effective for reducing blood pressure but other antihypertensives are usually more effective for reducing the incidence of stroke, myocardial infarction, and cardiovascular mortality, especially in the elderly (2). Therefore, for patients with hypertension but without compelling indications, a β-blocker should not be used as the initial first-line agent (5). B-A β-blocker is only an appropriate first-line agent in hypertension when used to treat specific compelling indications (e.g., ischemic heart disease, heart failure) (5). 5-Atenolol, and nadolol are the most water soluble; they are less likely to enter the brain, and may therefore cause less sleep disturbance and nightmares. They are excreted by the kidneys and dosage reduction is often necessary in renal impairment (2). 6-Beta-blockers can precipitate bronchospasm and should therefore usually be avoided in patients with a history of asthma (2). 7-Atenolol, bisoprolol, metoprolol, and nebivolol, have less effect on the β2 (bronchial) receptors and are, therefore, relatively cardioselective. They have a lesser effect on airways resistance but are not free of this side-effect (2). 8-Beta-blockers are also associated with fatigue, coldness of the extremities (may be less common with those with ISA), and sleep disturbances with nightmares (may be less common with the water-soluble beta-blockers) (2). 9-Abrupt cessation of β-blocker therapy may produce unstable angina, MI, or even death in patients with coronary disease. In patients without heart disease, abrupt discontinuation of β-blockers may be associated with tachycardia, sweating, 13 and generalized malaise in addition to increased BP. For these reasons, the dose should always be tapered gradually over 1 to 2 weeks before discontinuation (5). 10-Counseling points for the drug class: Do not abruptly stop taking medication. Beta blockers should be gradually tapered when stopping (1). Beta-blockers Scientific name Trade name Dosage form 1 2 3 4 5 6 Any extra notes: 2.5-Calcium-channel blockers (CCBs) 1-These agents block calcium channels in the peripheral blood vessels and/or the heart (7). A-Dihydropyridine CCBs (examples: amlodipine, felodipine, nifedipine, isradipine, nicardipine, nimodipine, nisoldipine) (1) : They have a greater selectivity for vascular smooth muscle than for heart and therefore their main effect is vasodilatation (3). B-Non-Dihydropyridine CCBs (examples diltiazem and verapamil): They have a greater selectivity for heart than for vascular smooth muscle (3). Verapamil decreases heart rate. Diltiazem decreases heart rate to a lesser extent than verapamil (5). 2-The main use of CCBs is in the management of angina pectoris and hypertension (both types of CCBs) ; some are also used in cardiac arrhythmias (non-dihydropyridine CCBs) (3). All are valuable in forms of angina associated with coronary vasospasm (2). 3-Verapamil is used also as prophylaxis of cluster headache (2) and migraine prophylaxis (1). Nifedipine is also indicated for Raynaud’s syndrome, postponement of premature labour, hiccup in palliative care, and chronic anal fissure (by rectum using ointment). Diltiazem is also indicated for chronic anal fissure (by rectum using ointment) (2). 14 4-Amlodipine and felodipine have a longer duration of action and can be given once daily (2). 5-Side-effects associated with vasodilatation such as flushing and headache (which become less obtrusive after a few days), and ankle swelling (which may respond only partially to diuretics) are common (2). Constipation is the most common side- effect of verapamil (2). 6- Calcium channel blockers, with the exception of amlodipine, should be avoided in heart failure as they can further depress cardiac function and exacerbate symptoms (2). CCBs Scientific name Trade names Dosage form 1 2 3 4 5 6 Any extra notes: 2.6-Diuretics 1-The principal groups of diuretics are as follows (Table 2-12). Table 2-1: Types of diuretics Diuretic type examples Thiazide and related diuretics Hydrochlorothiazide, Chlortalidone Loop Diuretics Furosemide, Bumetanide and Torasemide Potassium (K+)-sparing diuretics Amiloride and triamterene Aldosterone antagonist Spironolactone Carbonic anhydrase inhibitors Acetazolamide (mainly for glaucoma) Osmotic diuretics Mannitol (used in cerebral edema) 2-Diuretics promote the excretion of water and electrolytes by the kidneys. They are used in the treatment of heart failure, hypertension and other diseases when salt and water retention has resulted in edema (3). 15  (5) 3-Thiazides are the preferred type of diuretic for hypertension. Loop diuretics are the most widely used diuretics in heart failure (4). 4-The loop diuretics are more potent than thiazides, and retain their effectiveness in renal insufficiency. Thus, in most patients with HF, loop diuretics are preferred (8). 5-Potassium-sparing diuretics are weak antihypertensives when used alone. Their primary use is in combination with another diuretic to counteract potassium- wasting properties (5). 6-Mannitol is an osmotic diuretic that can be used to treat cerebral edema and raised intra-ocular pressure (2). 7-Hypokalemia can occur with both thiazide and loop diuretics. Potassium- sparing diuretics may cause hyperkalemia (5). 8-Spironolactone is given after food (2). It has an anti-androgenic properties, therefore: A-It may cause side effects like gynecomastia (breast enlargement), and impotence in men (3). B- It has been used for its anti-androgenic properties in some cases of acne and for women with hirsutism (hair on the face) (3). Diuretics Scientific name Trade names Dosage form 1 2 3 4 5 6 Any extra notes: 16 Note : Fixed-dose combination products 1-Several fixed-dose combination products are available , their use can reduce the number of tablets or capsules taken by patients. This has been demonstrated to improve adherence compared with using two separate single-drug products. Improved adherence may increase the likelihood of achieving goal BP values (8). 2-Most fixed-dose combinations include a thiazide diuretic. Other fixed-dose combination products combine a CCB with either an ACEI or ARB (8). Fixed-dose combination products Scientific name Trade name Dosage form 1 2 3 4 5 2.7-Lipid-regulating drugs 1-Lipid regulating drugs are used to modify blood lipid concentrations in the management of dyslipidemias and for the reduction of cardiovascular risk (3). 2-The principal groups of lipid regulating drugs are (Table 2-2) (2, 5): Table 2-2: Types of lipid regulating drugs (2, 5) Class Examples 1 Statins Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, and Simvastatin 2 Fibrates Bezafibrate, Ciprofibrate, Fenofibrate, and Gemfibrozil 3 Nicotinic acid Acipimox, and Nicotinic acid. derivatives 4 Bile acid sequestrants Colesevelam, Colestipol, and Colestyramine., 5 Absorption inhibitors Ezetimibe 6 Others Omega-3 fatty acid compounds 2.7.1-Statins 1-Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, interrupting conversion of HMG-CoA to mevalonate, the rate-limiting step in cholesterol biosynthesis (5). 17 2-Statins are more effective than other lipid-regulating drugs at lowering LDL-cholesterol concentration but they are less effective than the fibrates in reducing triglyceride concentration (2). 3-Statins are used adjunct to diet and exercise for various dyslipidemias (1). 4-Rosuvastatin and atorvastatin have the longest half-lives. The long half-life also allows for administration at any time of day rather than at bedtime for maximum effect, which is recommended for simvastatin, lovastatin, pravastatin, and fluvastatin (8) (Cholesterol synthesis in the liver peaks during the early morning (midnight to 3 a.m.) (3). 5-Muscle toxicity can occur with all statins, however the likelihood increases with higher doses. Therefore, advise patients to report promptly unexplained muscle pain, tenderness, or weakness (2). 6-Liver enzymes should be measured before treatment, and repeated within 3 months and at 12 months of starting treatment, unless indicated at other times by signs or symptoms suggestive of hepatotoxicity (2). 7-Avoid drinking grapefruit juice with statins metabolized by the CYP3A4 system (1)[ lovastatin, simvastatin, atorvastatin (avoid excess quantities :> 1.2 L/day)] (6). 2.7.2-Fibrates 1-Fibrates are mainly used for the treatment of hypertriglyceridemia (1). 2-Bezafibrate and fenofibrate are given with or just after food while gemfibrozil is given 30 to 60 minutes before food (2). 2.7.3-Cholesterol absorption inhibitor (Ezetimibe) 1-Ezetimibe inhibits the intestinal absorption of cholesterol. If used alone, it has a modest effect on lowering LDL-cholesterol, with little effect on other lipoproteins (2). 2-It is specifically used in combination with a statin to lower LDL. Ezetimibe is taken without regard to meals (1). 2.7.4-Others Fish oil supplementation (omega-3 polyunsaturated fatty acids) lowers TG by 26%–45% (9). Used as adjunctive therapy to treat hypertriglyceridemia and as adjunct in secondary prevention in those who have had a myocardial infarction in the preceding 3 months (2). Lipid-regulating drugs Scientific name Trade names Dosage form 1 2 18 3 4 5 6 Any extra notes: 2.8-Nitrates 1-Nitrates are peripheral and coronary vasodilators used in the management of angina pectoris, heart failure, myocardial infarction (3), for anal fissure (by rectum using ointment), and prophylaxis of phlebitis and extravasation (‗5‘ patch only) (2). 2-Sublingual Glyceryl trinitrate (GTN)(Nitroglycerin: NTG) is effective for providing rapid symptomatic relief of angina. The aerosol spray provides an alternative method of rapid relief of symptoms for those who find difficulty in dissolving sublingual preparations (2). 3-If using the GTN spray, patient should apply the spray on or under the tongue and not swallow or inhale it (8). 4-Patient education about sublingual glyceryl trinitrate (Table 2-3) Table 2-3: Patient education about sublingual glyceryl trinitrate 1-In the event of an acute attack, patients should be instructed to sit or lie down, place the dose (spray or tablet) under the tongue, and not swallow the tablet. Relief of pain should occur within 5 minutes (9). If the pain persists or is unimproved 5 minutes after the first dose of GTN, the patient should call an ambulance transport as they may be experiencing an MI. If patient needs more than one tablet, he can take a maximum of three tablets in 15 minutes (8). 2-SL NTG can also be used to prevent acute episodes of angina. When patients want to participate in activities which they know lead to angina, they can take a dose of SL NTG 2 to 5 minutes in advance. This prophylactic dose provides up to 30 minutes of protection and allows patients to participate in activities that they might otherwise be unable (5). 3-The tablets should be dispensed in the original, unopened manufacturer‘s container and stored in the original brown bottle (8). 4-The bottle should be stored in a cool, dry place, but not refrigerated. The bottle should be closed tightly after each opening (8). 5-GTN tablets should be supplied in glass containers of not more than 100 tablets closed with a foil-lined cap, and containing no cotton wool wadding; they should be discarded after 8 weeks in use (2). 6-Expiration dating should be monitored closely, and tablets should be replaced immediately if they are exposed to excessive light, heat, moisture, or air (8). 19 5-Transdermal GTN patches, isosorbide dinitrate (ISDN) and isosorbide mononitrate (ISMN) are most commonly prescribed for long-term prevention (prophylaxis) of angina episodes (5). 6-ISMN is the primary metabolite of ISDN. To minimize the potential development of nitrate tolerance, ISMN should be used in a twice-daily (the first dose is taken on awakening and the second dose about 7 hours later) (8). 7-Modified release formulations of ISMN should only be given once daily (dose to be taken in the morning), and used in this way do not produce tolerance (2). 8-Despite the availability of ISMN, oral ISDN is still commonly used. ISDN needs to be dosed three times a day (7 AM, noon, and 5 PM ) (8). In the case of modified release tablets of ISDN, the second of the two daily doses should be given after about 8 hours rather than after 12 hours (2). 9-Common side effects of nitrate therapy include hypotension, dizziness, and headache (5). Headache usually resolves after about two weeks of continued therapy (4) and may be treated with acetaminophen (8). 10-Rectal ointment should be discarded 8 weeks after first opening (2). 11-Transdermal patch: Apply once daily to skin site that is free of hair and not subject to excessive movement. Avoid areas with cuts or irritations. Do not apply to distal parts of the extremities. Use caution when discarding to keep out of the reach of children or pets. Remove at night for a 12-hour ―nitrate-free interval.‖ May contain metal; remove prior to MRI (1). Nitrates Scientific name Trade names Dosage form 1 2 3 Any extra notes: 2.9-Antiplatelet drugs 1-Antiplatelet drugs reduce platelet aggregation and are used to prevent further thromboembolic events in patients who have suffered myocardial infarction, ischemic stroke or transient ischemic attacks, or unstable angina, and for primary prevention of a thromboembolic event in patients at risk (3). 21 2-Antiplatelet drugs include aspirin, P2Y12 inhibitor antiplatelet [cangrelor (I.V), clopidogrel, prasugrel, ticagrelor), dipyridamole, and Glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide and tirofiban) (2). 3-Aspirin is given following coronary bypass surgery. It is also used in atrial fibrillation, for intermittent claudication, for stable angina and acute coronary syndromes, for use following placement of coronary stents and for use in stroke (2). 4-Clopidogrel monotherapy may be an alternative when aspirin is contra- indicated, for example in those with aspirin hypersensitivity, or when aspirin is not tolerated despite the addition of a proton pump inhibitor (2). 5-Aspirin is also used as an analgesic and antipyretic (2). 6-Owing to an association with Reye’s syndrome, aspirin-containing preparations should not be given to children under 16 years, unless specifically indicated, e.g. for Kawasaki disease (2). 7-Contra-indications of aspirin include: Active peptic ulceration, bleeding disorders, children under 16 years (risk of Reye‘s syndrome), haemophilia. previous peptic ulceration (analgesic dose) and cardiac failure (analgesic dose) (2). 8-Aspirin is contraindicated in history of hypersensitivity to aspirin or any other NSAID—which includes those in whom attacks of asthma, angioedema, urticaria, or rhinitis have been precipitated by aspirin or any other NSAID (2). 9-Aspirin tablet commonly formulated as enteric coated tablet to decrease GIT irritation. Antiplatelet drugs Scientific name Trade names Dosage form 1 2 3 4 5 Any extra notes: 2.10-Anticoagulants 1-Anticoagulants are used in the treatment and prophylaxis of thromboembolic disorders (3). 21 2-Different types of anticoagulants are available (Table 2-4) (2). Table 2-4: Types of anticoagulants (2). Parenteral anticoagulants Oral anticoagulants 1 Unfractionated Heparin (UFH) 1 Warfarin Low molecular weight heparins Direct Oral Anticoagulants (LMWHs) (dalteparin, enoxaparin and (DOACs) Dabigatran, 2 tinzaparin) 2 Rivaroxaban, apixaban , betrixaban, and edoxaban 2.10.1-Unfractionated heparin (UFH) 1-UFH can be administered via the intravenous (IV) or subcutaneous (SC) route (4). 2-The activated partial thromboplastin time (aPTT) is the most widely used test in clinical practice to monitor UFH. Traditionally, therapeutic aPTT range is defined as 1.5 to 2.5 times the control aPTT value (4). 3-Side effects associated with UFH include bleeding, thrombocytopenia, and with prolonged use, alopecia, hyperkalemia, and osteoporosis (4). A-Bleeding is the most common adverse effect associated with antithrombotic drugs including UFH therapy. Patients receiving UFH therapy should be closely monitored for signs and symptoms of bleeding, including epistaxis, hemoptysis, hematuria, hematemesis, and melena (4). B-If major bleeding occurs, discontinue UFH immediately and give IV protamine sulfate (5). 2.10.2-Low-molecular-weight heparins 1-Advantages of LMWHs over UFH include: (A) predictable anticoagulation dose response, (B) improved SC bioavailability, (C) dose-independent clearance, (D) longer biologic half-life, E) lower incidence of thrombocytopenia, and (F) reduced need for routine laboratory monitoring (5). 2-As with other anticoagulants, bleeding is the most common adverse effect of LMWH therapy, but major bleeding may be less common than with UFH. If major bleeding occurs, administer protamine sulfate IV, although it cannot neutralize the anticoagulant effect completely (5). 3-Thrombocytopenia can occur with LMWHs, but the incidence of HIT is three times lower than with UFH (5). 2.10.3-Warfarin 1-Warfarin inhibits the production of vitamin K–dependent clotting factors. Warfarin has no effect on circulating coagulation factors that have been previously formed, and its therapeutic antithrombotic activity is delayed for 5 to 7 days (4). 22 2-Monitor warfarin therapy by the international normalized ratio (INR); the recommended target INR for treatment and prevention of VTE is 2.5, with an acceptable range of 2 to 3(4). 3-Similar to other anticoagulants, warfarin’s primary side effect is bleeding. Bleeding in the gastrointestinal tract is most common. Intracranial hemorrhage (ICH) is one of the most serious complications because it often causes severe disability and death (4). 4-Warfarin is prone to numerous clinically significant drug–drug and drug–food interactions. Patients on warfarin should be questioned at every encounter to assess for any potential interactions with foods, drugs, herbal products, and nutritional supplements (4). 5-Vitamin K is the antidote of warfarin (1). In cases of life-threatening bleeding, fresh-frozen plasma or clotting factor concentrates should also be administered, in addition to IV vitamin K (4). 2.10.4-Direct oral anticoagulants: 1-These currently include two categories, direct thrombin (factor IIa) inhibitor (DTI) (dabigatran) and direct Xa inhibitors (rivaroxaban, apixaban, and edoxaban) (10). 2-As compared to warfarin, these oral anticoagulants have a more rapid onset, shorter half-life, wider therapeutic window, and more predictable pharmacokinetics (10). Anticoagulants Scientific name Trade names Dosage form 1 2 3 4 5 6 7 Any extra notes: 23 2.11-Anti-arrhythmic drugs 1-Anti-arrhythmic drugs can be classified clinically into those that act on supraventricular arrhythmias (e.g. verapamil), those that act on both supraventricular and ventricular arrhythmias (e.g. amiodarone), and those that act on ventricular arrhythmias (e.g. lidocaine) (2) (Table 2-5) (11). Table 2-5: classification of Anti-arrhythmic drugs according to principal site of action 2-Amiodarone is the most commonly used antiarrhythmic agent. It is used for rate and rhythm control of atrial fibrillation and to treat and prevent ventricular arrhythmias (1). 3-Although amiodarone is the most commonly used antiarrhythmic, it should be reserved for patients with life-threatening arrhythmias due to its substantial toxicity (1). 4-Digoxin is a cardiac glycoside that increases the force of myocardial contraction (so used for HF) and reduces conductivity within the atrioventricular (AV) node (so used for atrial fibrillation or flutter) (2). Anti-arrhythmic drugs Scientific name Trade names Dosage form 1 2 3 4 Any extra notes: 24 2.12-Miscellaneous cardiovascular drugs 2.12.1-Fibrinolytic drugs (alteplase, reteplase, tenecteplase) 1-Thrombolytic drugs are indicated for any patient with acute ST-segment elevation myocardial infarction (STEMI) for whom the benefit is likely to outweigh the risk of treatment (2). 2-Alteplase can be used for other thromboembolic disorders such as deep-vein thrombosis and pulmonary embolism (2). Alteplase is also used for acute ischaemic stroke (2). 3-Serious bleeding calls for discontinuation of the thrombolytic and may require administration of coagulation factors and antifibrinolytic drugs (2). 2.12.2-Antifibrinolytic drugs Fibrin dissolution can be impaired by the administration of tranexamic acid, which inhibits fibrinolysis. It can be used to prevent bleeding or to treat bleeding associated with excessive fibrinolysis (e.g. in surgery, dental extraction, and obstetric disorders) and in the management of menorrhagia (2). Scientific name Trade names Dosage form 1 2 2.12.3-Centrally acting antihypertensive drugs Methyldopa is a centrally acting antihypertensive; it may be used for the management of hypertension in pregnancy (2). Scientific name Trade names Dosage form 1 2 2.12.4-Peripheral vasodilators (e.g. cilostazol, pentoxifylline) 1-Peripheral vascular disease can be either occlusive (e.g. intermittent claudication) in which occlusion of the peripheral arteries is caused by atherosclerosis, or vasospastic (e.g. Raynaud’s syndrome) (2). 2-Cilostazol is licensed for use in intermittent claudication to improve walking (2). 3-Pentoxifylline is another agent approved by the FDA for the treatment intermittent claudication (limited role) (8). Scientific name Trade names Dosage form 1 2 25 References 1-Michael AM, Jason. Frequently prescribed medications. Third edition 2019. 2-BNF-81 (2021) 3-Martindale: The Complete Drug Reference, 38th Edition. Pharmaceutical Press 2014. 4- Marie A. Chisholm-Burns.Pharmacotherapy Principles & Practice. 5th edition. 2019. 5-Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 11th Edition. 2021. 6-ACCP Updates in Therapeutics® 2021: The Pharmacotherapy Preparatory Review and Recertification Course. 7-Roger Walker. Clinical Pharmacy and Therapeutics. Sixth edition 2019 8-Zeind, Caroline S and Carvalho, Michael G. Applied Therapeutics: The clinical use of drugs, 11th ed., 2018. 9-David J Quan, Richard A Helms. Textbook of Therapeutics: Drug and Disease Management. 8th edition. 2006. 10-Pavan Bhat, et al. Washington Manual of Medical Therapeutics, The, 35th Edition. Copyright 2016. 11-Helen Williams.V Arrhythmia : part 1. The pharmaceutical journal (VOL 271) (2003):368-370. 26