Summer Training Guide 4th Stage-2023(2)(1).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-It may take several weeks before the full antihypertensive effects of ACEIs are seen. Therefore, evaluating BP response 2 to 4 weeks after starting or changing the dose of an ACEI is appropriate (5). 5-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 (6). B-For hypertension the first dose should preferably be given at bedtime (2). 6-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) (6). 7-Angioedema is a serious potential complication of ACEi therapy. It occurs in less than 1% of the population. Symptoms include lip and tongue swelling and possibly difficulty breathing. Drug withdrawal necessary. An is Angiotensin II receptor blocker (ARBs) can generally be used in patients with a history of ACE inhibitor-induced angioedema, with careful monitoring (6) (cross-reactivity 2.5%)(7). 8-Monitoring requirements: Renal function and electrolytes should be checked before starting ACE inhibitors (or increasing the dose) and monitored during treatment (2). Patients with an increase in serum creatinine of greater than 30% should have their ACEI therapy temporarily discontinued (5) until further evaluation can be made (4). 9-An ACEi, as well as an ARB or direct renin inhibitor, are contraindicated in pregnancy (6). 10-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). 11  ACE inhibitors Scientific name Trade names Dosage form 1 2 3 4 5 Any extra notes: 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 (6). 5-In select situations, the addition of ARBs (Candesartan and valsartan) to ACE- Is (Combination therapy) for patients with heart failure has demonstrated additional incremental benefits (4). 6-Imortant: unlike ACE inhibitors, they are less likely to cause the persistent dry cough (2) (less than 1%) (7) 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). 7-Like ACE inhibitors, they may cause renal insufficiency, hyperkalemia, and orthostatic hypotension (6). 8-Monitoring requirements: Monitor potassium concentration, particularly in the elderly and in patients with renal impairment (2). 12  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). 3-Discontinue ACE inhibitors 36 hours prior to initiating the ARNI (6) (due to an increased risk for angioedema) (4); no waiting period is needed in patients receiving an ARB (6). 4-Sacubitril/valsartan is contraindicated in patients with a history of angioedema associated with an ACE inhibitor or ARB. It is also contraindicated in pregnancy and should not be used concurrently with ACE inhibitors or other ARBs (6). 5-Monitoring requirements: Monitor renal function and potassium 1–2 weeks after initiating therapy or increasing the dose (7). Scientific name Trade name Dosage form 1 Valsartan/sacubitril Any extra notes: 13 2.4-Renin inhibitor 1-Aliskiren is a renin inhibitor that is licensed for the treatment of hypertension(2). 2-Aliskiren role in the management of hypertension is limited (6). 3-Many of the cautions and adverse effects seen with ACE inhibitors and ARBs apply to aliskiren. It is contraindicated in pregnancy due to known teratogenic effects (6). Scientific name Trade name Dosage form 1 Any extra notes: 2.5-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- Table 2-1: Different properties of β-blockers. Criteria Examples Water solubility Atenolol , Nadolol, Bisoprolol Lipid soluble Oxprenolol, Metoprolol, Propranolol, Carvedilol Intrinsic sympathomimetic Oxprenolol, Pindolol activity(ISA) β1-Selectivity Atenolol , Metoprolol, Bisoprolol, Nebivolol Nonselective Oxprenolol, Nadolol, Pindolol , Propranolol Mixed α and β blocker Carvedilol 4-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). 5-Important: when β-blockers are used for heart failure: 14  Initiate β-blockers in stable patients who have no or minimal evidence of fluid overload (6). Because of their negative inotropic effects, start β-blockers in very low doses with slow upward dose titration to avoid symptomatic worsening (doses should be doubled no more often than every 2 weeks, as tolerated, until the target or maximally tolerated dose is reached) (6). When used in heart failure, carvedilol should be taken with food to reduce the risk of hypotension (3). 6-Esmolol is a relatively cardioselective beta-blocker with a very short duration of action, used intravenously for the short-term treatment of supraventricular arrhythmias (2). 7-Sotalol, a non-cardioselective beta-blocker with additional class III anti- arrhythmic activity, is used for prophylaxis in paroxysmal supraventricular arrhythmias (2). 8-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 (6). 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) (6). 9-Oxprenolol, and pindolol have intrinsic sympathomimetic activity (ISA); they tend to cause less bradycardia than the other beta-blockers and may also cause less coldness of the extremities (2). 10-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). 11-Beta-blockers can precipitate bronchospasm and should therefore usually be avoided in patients with a history of asthma (2). 12-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). 13-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). 15 14-Beta-blockers can mask the signs and symptoms of hypoglycemia (such as tachycardia) (except sweating). However, beta-blockers are not contra-indicated in diabetes, although the cardioselective beta-blockers may be preferred (2, 5). 15-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, 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 (6). 16-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: 2.6-Calcium-channel blockers (CCBs) 1-These agents block calcium channels in the peripheral blood vessels and/or the heart (8). 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 (6). 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 16 with coronary vasospasm (2). 3-Nimodipine is related to nifedipine but the smooth muscle relaxant effect preferentially acts on cerebral arteries. Its use is confined to prevention and treatment of vascular spasm following aneurysmal subarachnoid hemorrhage (2). 4-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). 5-Amlodipine and felodipine have a longer duration of action and can be given once daily (2). 6-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). 7- 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). 8-Amlodipine tablets from various suppliers may contain different salts (e.g. amlodipine besilate, amlodipine maleate, and amlodipine mesilate) but the strength is expressed in terms of amlodipine (base); tablets containing different salts are considered interchangeable (2). 9-Different versions of modified-release preparations may not have the same clinical effect. To avoid confusion between these different formulations of nifedipine and diltiazem, prescribers should specify the brand to be dispensed (2). 10-Tablet membrane of (Tildiem retard ® and Adalat ® LA) may pass through gastro-intestinal tract unchanged, but being porous has no effect on efficacy (2). CCBs Scientific name Trade names Dosage form 1 2 3 4 5 6 17 Any extra notes: 2.7-Diuretics 1-The principal groups of diuretics are as follows (Table 2-2). Table 2-2: 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). (6) 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 (5). 5-Thiazides are believed to lose their effectiveness when creatinine clearance decreases to less than 30 mL/minute. Metolazone is an exception in that its activity may be preserved in these patients (5). Unlike thiazides, loop diuretics maintain their effectiveness in the presence of impaired renal function, although higher doses may be necessary (6). 6-Potassium-sparing diuretics are weak antihypertensives when used alone. Their primary use is in combination with another diuretic to counteract potassium- wasting properties (6). 7-Because they do not alter disease progression or prolong survival, diuretics are not required for HF patients without fluid retention (6). 8-Chlortalidone, a thiazide-related compound, has a longer duration of action than the thiazides and may be given on alternate days to control edema. Metolazone is particularly effective when combined with a loop diuretic (even in renal failure) (2). 9-Xipamide and indapamide are chemically related to chlortalidone. Indapamide is claimed to lower blood pressure with less metabolic disturbance, particularly less aggravation of diabetes mellitus (2). 18 10-Spironolactone is of value in the treatment of edema and ascites caused by cirrhosis of the liver; furosemide can be used as an adjunct. Low doses of spironolactone are beneficial in moderate to severe heart failure (2). 11-Mannitol is an osmotic diuretic that can be used to treat cerebral edema and raised intra-ocular pressure (2). 12-I.V Furosemide doses greater than 50 mg given by intravenous infusion only. Give continuously in sodium chloride 0.9% ; glucose solutions are unsuitable (2). 13-Hypokalemia can occur with both thiazide and loop diuretics. Potassium- sparing diuretics may cause hyperkalemia (6). 14-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). 15-In concentrations of 15% or greater, mannitol may crystallize when exposed to low temperatures. Do not use a mannitol solution containing crystals. If such crystallization occurs, the recommended procedure for resolubilization is to heat the mannitol in a dry heat cabinet to 70 °C for flexible plastic containers with the overwrap intact or to 80 °C for glass containers with vigorous shaking. The use of a water bath is not recommended (9). Diuretics Scientific name Trade names Dosage form 1 2 3 4 5 6 Any extra notes: 19 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 (5). 2-Most fixed-dose combinations include a thiazide diuretic. Other fixed-dose combination products combine a CCB with either an ACEI or ARB (5). Fixed-dose combination products Scientific name Trade name Dosage form 1 2 3 4 5 2.8-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 2-3) (2, 6): Table 2-3: Types of lipid regulating drugs (2, 6) 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 Alirocumab, Evolocumab, Lomitapide , Mipomerson and Omega-3 fatty acid compounds 2.8.1-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 (6). 21 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 and for the treatment of various dyslipidemia disorders in patients with no evidence of cardiovascular disease (primary prevention) and in patients with documented coronary artery disease (secondary prevention) (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 (5) (Cholesterol synthesis in the liver peaks during the early morning (midnight to 3 a.m.) (3). 5-Relative LDL–lowering efficacy of statins are shown in table 2-4 (7). Table 2-4: Relative LDL–lowering efficacy of statins (7). 6-The most common adverse effects reported include muscle pain and weakness (myalgias), headache, GI symptoms, including dyspepsia, flatus, constipation, and abdominal pain, and skin rashes. These symptoms are usually mild and often dissipate with continued therapy (5). 7-Less common adverse effects include myopathy, elevated hepatic transaminases, and diabetes (5). 8-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). 9-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). 10-Avoid drinking grapefruit juice with statins metabolized by the CYP3A4 system (1)[ lovastatin, simvastatin, atorvastatin (avoid excess quantities :> 1.2 L/day)] (7). 21 2.8.2-Fibrates 1-Fibrates are mainly used for the treatment of hypertriglyceridemia (1). 2-Fenofibrate is the preferred agent when used in combination with statins due to the potential for fewer drug interactions (1). 3-Bezafibrate and fenofibrate are given with or just after food while gemfibrozil is given 30 to 60 minutes before food (2). 2.8.3-Bile acid sequestrants (BAS) 1-Bile acid sequestrants act by binding bile acids, preventing their reabsorption; this promotes hepatic conversion of cholesterol into bile acids; the resultant increased LDL-receptor activity of liver cells increases the clearance of LDL- cholesterol from the plasma (2). 2-May increase TG concentrations (7). 3-Older BAS (colestyramine, colestipol) are not well tolerated due to numerous GI side effects and the unpleasant granular texture of the powder. Therefore, colesevelam is currently the preferred agent (5). 4-Other uses: A-Colesevelam is also approved by the FDA for use in type 2 diabetes to improve glycemic control (5). B-Colestyramine is also used for pruritus associated with partial biliary obstruction and primary biliary cirrhosis. It also used for diarrhea associated with Crohn‘s disease, ileal resection vagotomy, diabetic vagal neuropathy, and radiation (2). 5-They interfere with the absorption of fat-soluble vitamins (supplements of vitamins A, D, K, and folic acid may be required when treatment is prolonged) (2). 6-Colestyramine and colestipol may reduce or delay the absorption of medications when co-administered. This can be minimized by administering other medications 1 hour before or 4 hours after the resin dose (5). 7-Adminstarion: A-Colesevelam tablet is given with or just after food (2). B-Colestipol Granules: The contents of each sachet should be mixed with at least 100 mL of water or other suitable liquid such as fruit juice or skimmed milk. Alternatively it can be mixed with thin soups, cereals, yoghurt, or pulpy fruits ensuring at least 100 mL of liquid is provided (2). C-Colestyramine Powder :The contents of each sachet should be mixed with at least 150 mL of water or other suitable liquid such as fruit juice, skimmed milk, thin soups, and pulpy fruits with a high moisture content (2). 22 2.8.4-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-Ezetimibe should not be prescribed as a first-line agent. It is specifically used in combination with a statin to lower LDL. An additional lowering of approximately 25% in LDL can be seen when ezetimibe is combined with a statin(1). 3-Ezetimibe is taken without regard to meals (1). 2.8.5-Nicotinic acid (niacin )derivatives 1-Nicotinic acid and its derivatives reduce triglycerides and increases HDL cholesterol and may also modestly reduce LDL-cholesterol (3). 2-Niacin is indicated for patients with elevated triglycerides, low HDL cholesterol, and elevated LDL cholesterol (4). 3-Adverse events frequently limit niacin use (6). A-Niacin use is limited by cutaneous reactions such as flushing and pruritus of the face and body. The use of aspirin (4) (325 mg (6)) or a nonsteroidal anti-inflammatory drug (NSAID) 30 minutes prior to taking niacin can help alleviate these reactions because they are mediated by an increase in prostaglandin (4). B-In addition, taking niacin with food and avoiding hot liquids or alcohol at the time niacin is taken is helpful in minimizing flushing and pruritus (4). C-Lastly, slow titration of the niacin dose to minimize and/or prevent flushing (4). D-Rise in serum transaminase values are seen with all niacin formulations, but the worst cases have been reported with slow-release niacin (slow-release products should not be recommended due to increased hepatotoxicity risk) (1). E-Immediate-release products have the least hepatotoxicity; however, they must be dosed three times daily and can cause significant flushing (1). F-Most experts prefer Niaspan (extended-release niacin) because it causes less flushing than immediate-release niacin, is dosed once daily, and is associated with less liver toxicity than sustained-release (1). 4-Acipimox capsule is given with or just after food (2). 2.8.6-Others 1-Fish oil supplementation (omega-3 polyunsaturated fatty acids) lowers TG by 26%–45% (10). 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). 23 2-PCSK9 Inhibitors: Alirocumab and evolocumab reduce LDL-C by as much as 60% when added to statin therapy. The drugs are administered by subcutaneous injection either biweekly or once monthly. The most common adverse effect is injection site reactions, which can be minimized by allowing the injection to come to room temperature before use and icing the site before injecting. PCSK9 inhibitor use has been limited because of high cost (6). 3-Lomitapide and Mipomersen are indicated as an adjunct to diet and lipid- lowering treatments to reduce cholesterol in patients with homozygous familial hypercholesterolemia. Their labeling contain black box warnings for severe hepatotoxicity (6). 4-Volanesorsen lowers serum triglycerides. It is indicated for familial chylomicronaemia syndrome (2). 5-Bempedoic acid inhibits cholesterol synthesis in the liver, thereby lowering LDL-cholesterol. It is indicated for primary hypercholesterolemia or mixed dyslipidemia in patients who have not responded adequately to other appropriate measures (2). Lipid-regulating drugs Scientific name Trade names Dosage form 1 2 3 4 5 6 Any extra notes: 2.9-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 24 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 (5). 4-Patient education about sublingual glyceryl trinitrate (Table 2-5) Table 2-5: 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 (10). 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 (5). 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 (6). 3-The tablets should be dispensed in the original, unopened manufacturer‘s container and stored in the original brown bottle (5). 4-The bottle should be stored in a cool, dry place, but not refrigerated. The bottle should be closed tightly after each opening (5). 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 (5). 5-Transdermal GTN patches, isosorbide dinitrate (ISDN) and isosorbide mononitrate (ISMN) are most commonly prescribed for long-term prevention (prophylaxis) of angina episodes (6). 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) (5). 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 ) (5). 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 (5). 25 10-Concomitant administration with phosphodiesterase type 5 inhibitors (within 24 hours for sildenafil and vardenafil, 48 hours for tadalafil) is contraindicated due to the risk of life-threatening hypotension (5). 11-Rectal ointment should be discarded 8 weeks after first opening (2). 12-With intravenous GTN: use glass or polyethylene apparatus is preferable; loss of potency will occur if PVC is used (2). 13-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). 14-Patients using transdermal nitroglycerin may experience skin erythema and inflammation. Initiating therapy with smaller doses and rotating the application site can mitigate some of the adverse effects of transdermal NTG (6). Nitrates Scientific name Trade names Dosage form 1 2 3 Any extra notes: 2.10-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). 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). 26 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-Clopidogrel, in combination with low-dose aspirin (dual antiplatelet therapy) are used in patients with non-ST elevation acute coronary syndromes, in patients with ST elevation acute coronary syndromes, and following percutaneous coronary intervention. The duration of antiplatelet therapy vary according to these indications. Aspirin therapy should continue indefinitely (2). Clopidogrel is also licensed, in combination with low-dose aspirin, in patients with atrial fibrillation (and at least one risk factor for a vascular event), and for whom warfarin is unsuitable (2). 6-Both prasugrel and ticagrelor are more potent than clopidogrel. Prasugrel has the fewest significant drug–drug interactions of the oral P2Y12 inhibitors (4). 7-Abciximab, eptifibatide, or tirofiban may be administered for some patients undergoing percutaneous coronary intervention (PCI) (2). 8-Aspirin is also used as an analgesic and antipyretic (2). 9-Pregnant women are at high risk of developing preeclampsia if they have chronic kidney disease, diabetes mellitus, autoimmune disease, chronic hypertension, or if they have had hypertension during a previous pregnancy; these women are advised to take aspirin once daily [unlicensed indication] from week 12 of pregnancy until the baby is born (2). 10-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). 11-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). 12-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). 13-Aspirin tablet commonly formulated as enteric coated tablet to decrease GIT irritation. Antiplatelet drugs Scientific name Trade names Dosage form 1 2 3 27 4 5 Any extra notes: 2.11-Anticoagulants 1-Anticoagulants are used in the treatment and prophylaxis of thromboembolic disorders (3). 2-Different types of anticoagulants are available (Table 2-6) (2). Table 2-6: Types of anticoagulants (2). Parenteral anticoagulants Oral anticoagulants 1 Unfractionated Heparin (UFH) 1 Warfarin 2 Low molecular weight heparins Direct Oral Anticoagulants (LMWHs) (dalteparin, enoxaparin and (DOACs) Dabigatran, tinzaparin) Rivaroxaban, apixaban , 3 Parenteral direct thrombin inhibitor 2 betrixaban, and edoxaban (lepirudin, bivalirudin, argatroban, and desirudin) 4 Fondaparinux 2.11.1-Unfractionated heparin (UFH) 1-UFH can be administered via the intravenous (IV) or subcutaneous (SC) route (4). 2-For the treatment of Venous thromboembolism (VTE), UFH is generally given as a continuous IV infusion (4). 3-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). 4-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 (6). C-Heparin-induced thrombocytopenia (HIT) is a very serious adverse effect associated with UFH use (4) that requires immediate intervention (discontinue 28  heparin and initiate alternative anticoagulation with a parenteral direct thrombin inhibitor) (6). 2.11.2-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 (6). 2-LMWHs can be easily administered in the outpatient setting, thus enabling the treatment of VTE at home (4). 3-Because LMWH anticoagulant response is predictable when given SC, routine laboratory monitoring is unnecessary (6). 4-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 (6). 5-Thrombocytopenia can occur with LMWHs, but the incidence of HIT is three times lower than with UFH (6). 2.11.3-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). 2-Warfarin also inhibits the anticoagulant proteins C and S. Reductions in the concentration of natural anticoagulants before the clotting factors are depleted can lead to a paradoxical hypercoagulable state during the first few days of warfarin therapy. It is for this reason that patients with acute thrombosis should receive a fast-acting anticoagulant (heparin, LMWH, or fondaparinux) while transitioning to warfarin therapy (4). 3-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). 4-In patients with acute VTE, a rapid-acting anticoagulant (UFH, LMWH, or fondaparinux) should be overlapped with warfarin for a minimum of 5 days and until the INR is greater than 2 and stable (4). 5-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). 6-Warfarin is prone to numerous clinically significant drug–drug and drug–food interactions. Patients on warfarin should be questioned at every encounter to 29 assess for any potential interactions with foods, drugs, herbal products, and nutritional supplements (4). 7-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). 2.11.4-Direct oral anticoagulants: 1-These currently include two categories, direct thrombin (factor IIa) inhibitor (DTI) (dabigatran) and direct Xa inhibitors (rivaroxaban, apixaban, and edoxaban) (11). 2-As compared to warfarin, these oral anticoagulants have a more rapid onset, shorter half-life, wider therapeutic window, and more predictable pharmacokinetics (11). 3-These features allow for sole oral therapy without the need for an overlapping parenteral agent (with the exception of edoxaban for VTE), no need for titration or dose adjustments in patients with normal renal function, and no need for routine monitoring (11). 4-When used for the treatment or prophylaxis of recurrent VTE, edoxaban and dabigatran must be given only after at least 5 days of subcutaneous (SC) anticoagulation with UFH, LMWH, or fondaparinux (2, 6). 5-Compared to warfarin, the target-specific anticoagulants have a lower risk of intracranial hemorrhage (11). 6-Idarucizumab is a monoclonal antibody fragment used to reverse dabigatran anticoagulation (7). 7-Andexanet alfa is a recombinant form of human factor Xa protein which binds specifically to apixaban or rivaroxaban, thereby reversing their anticoagulant effects (2). 2.11.5-Parenteral direct thrombin inhibitors 1-Several injectable DTIs are available including lepirudin, bivalirudin, argatroban, and desirudin (4). 2-Parenteral DTIs are considered the drugs of choice for the treatment of VTE in patients with a diagnosis or history of HIT (4). 2.11.6-Parenteral Xa inhibitor (Fondaparinux) 1-Fondaparinux is a safe and effective alternative to LMWH for treatment of VTE (6). It is also is approved for prevention of VTE following orthopedic or abdominal surgery (2). 2-Patients receiving fondaparinux do not require routine coagulation testing (6). 31  Anticoagulants Scientific name Trade names Dosage form 1 2 3 4 5 6 7 Any extra notes: 2.12-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 2-7) (12). Table 2-7: classification of Anti-arrhythmic drugs according to principal site of action 2-Atropine is used for bradycardia and AV nodal blockade. In patients with hemodynamically unstable or unresponsive to atropine, epinephrine or dopamine may be administered (4). 31 3-Adenosine is the drug of choice for pharmacologic termination of paroxysmal supraventricular tachycardia (PSVT) (4). 4-Hemodynamically stable torsades de pointes should be treated with I.V magnesium (4). 5-Hemodynamically unstable PSVT, ventricular tachycardia, atrial fibrillation, torsades de pointes, or ventricular fibrillation (already hemodynamically unstable) should be terminated immediately using direct current cardioversion (DCC) (4). 6-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). 7-Although amiodarone is the most commonly used antiarrhythmic, it should be reserved for patients with life-threatening arrhythmias due to its substantial toxicity (1). 8-Adverse Reactions: A-Most Common: Bradycardia, corneal microdeposits, hypotension (more common with IV), hypothyroidism, nausea, vomiting (especially with higher doses), phlebitis (IV form), photosensitivity, prolonged QTc interval (1). B-Rare/Severe/Important: Blue/gray skin discoloration, hyperthyroidism, liver toxicity, pulmonary toxicity (1). C-Monitoring requirements (2): Thyroid function tests should be performed before treatment and then every 6 months. Liver function tests required before treatment and then every 6 months. Serum potassium concentration should be measured before treatment. Chest x-ray required before treatment. With intravenous use ECG monitoring 9-Because of the possibility of phototoxic reactions, patients taking amiodarone should be advised to shield the skin from light during treatment and for several months after discontinuing amiodarone; a wide-spectrum sunscreen to protect against both long-wave ultraviolet and visible light should be used (2). 10-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). 11-Digoxin does not improve survival in patients with HF but does provide symptomatic benefits only (6) (digoxin is added for patients who remain symptomatic despite an optimal HF regimen consisting of an ACE inhibitor or ARB, β-blocker, and diuretic). In patients with concomitant atrial fibrillation, digoxin may occasionally be added to slow ventricular rate (4). 32 12-Loading dose of digoxin (Rapid digitalization) is usually given for atrial fibrillation or flutter (2) (Roughly half of the total loading dose administered as the first dose, with the remaining portion divided and administered every 6–8 hours initially) (1). 13-Sotalol is used for ventricular and supra- ventricular arrhythmias (2). Anti-arrhythmic drugs Scientific name Trade names Dosage form 1 2 3 4 Any extra notes: 2.13-Miscellaneous cardiovascular drugs 2.13.1-Fibrinolytic drugs 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 should be given within 6–12 hours of MI symptom onset, reteplase within 12 hours of symptom onset, but ideally all should be given within 1 hour; use after 12 hours requires specialist advice. Tenecteplase should be given as early as possible and usually within 6 hours of symptom onset (2). 3-Alteplase can be used for other thromboembolic disorders such as deep-vein thrombosis and pulmonary embolism (2). 4-Alteplase is also used for acute ischaemic stroke (2). 5-Serious bleeding calls for discontinuation of the thrombolytic and may require administration of coagulation factors and antifibrinolytic drugs (2). 2.13.2-Antifibrinolytic drugs 1-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). 33 2-Tranexamic acid may also be used in hereditary angioedema, epistaxis, and in thrombolytic overdose (2). Scientific name Trade names Dosage form 1 2 2.13.3-Vasodilator antihypertensives (hydralazine, minoxidil, sodium nitroprusside) 1-Vasodilators have a potent hypotensive effect (2). 2-Hydralazine (i.v infusion) is used for hypertensive emergencies (including during pregnancy) (2). 3-Hydralazine is given by mouth as an adjunct to other antihypertensives for the treatment of resistant hypertension but is rarely used; when used alone it causes tachycardia and fluid retention (2). 4-Hydralazine in combination with long acting nitrate is also used for heart failure (2). 5-Sodium nitroprusside is given by i.v infusion to control severe hypertensive emergencies when parenteral treatment is necessary (2). 6-Minoxidil should be reserved for the treatment of severe hypertension resistant to other drugs (2). Scientific name Trade names Dosage form 1 2 2.13.4-Centrally acting antihypertensive drugs 1-Methyldopa is a centrally acting antihypertensive; it may be used for the management of hypertension in pregnancy (2). 2-Clonidine has the disadvantage that sudden withdrawal of treatment may cause severe rebound hypertension. (Note: Clonidine is also used for prevention of recurrent migraine, prevention of vascular headache, and for menopausal symptoms, particularly flushing and vasomotor conditions) (2). Scientific name Trade names Dosage form 1 2 34 2.13.5-Sympathomimetics (inotropic sympathomimetics, vasoconstrictor sympathomimetics) 1-The profound hypotension of shock must be treated promptly to prevent tissue hypoxia and organ failure. Volume replacement is essential to correct the hypovolemia associated with hemorrhage and sepsis but may be detrimental in cardiogenic shock (2). 2-Depending on hemodynamic status, cardiac output may be improved by the use of sympathomimetic inotropes such as adrenaline/epinephrine, dobutamine or dopamine (2). 3-In septic shock, when fluid replacement and inotropic support fail to maintain blood pressure, the vasoconstrictor noradrenaline/norepinephrine may be considered (2). 4-Midodrine is a sympathomimetic agent, which acts on peripheral α-adrenergic receptors to increase arterial resistance, resulting in an increase in blood pressure. It is indicated for severe orthostatic hypotension due to autonomic dysfunction when corrective factors have been ruled out and other forms of treatment are inadequate (2). 5-Metaraminol is a vasoconstrictor sympathomimetic indicated for acute hypotension (2). 2.13.6-Coagulation proteins 1-Human prothrombin complex, Factor IX fraction, Factor VIIa, Factor VIII fraction are used to treat hemorrhage especially that associated with congenital deficiencies of these factor proteins (2). 2.13.7-Peripheral vasodilators (e.g. cilostazol, pentoxifylline) 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) (5). Scientific name Trade names Dosage form 1 2 2.13.8-Others antianginal agents 1-Ranolazine is indicated as adjunctive therapy in the treatment of stable angina in patients inadequately controlled or intolerant of first line antianginal therapies(2). Because it does not substantially affect heart rate (HR) and BP, it is recommended 35 as add-on therapy to traditional antianginal agents for patients who achieve goal HR and BP and still have exertional angina symptoms (6). 2-Nicorandil a potassium-channel opener. It is indicated for Prophylaxis and treatment of stable angina (second-line) (2). 3-Ivabradine lowers the heart rate by its action on the sinus node. It is licensed for the treatment of angina in patients who are in normal sinus rhythm and for mild to severe chronic heart failure (2). 2.13.9-Drugs for pulmonary arterial hypertension 1-Ambrisentan, bosentan, iloprost , macitentan, sildenafil, and tadalafil are licensed for the treatment of pulmonary arterial hypertension (2). 2-Bosentan is also licensed to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease (2). 3-Riociguat is licensed for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (2). Scientific name Trade names Dosage form 1 Any extra notes: 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-Zeind, Caroline S and Carvalho, Michael G. Applied Therapeutics: The clinical use of drugs, 11th ed., 2018. 6-Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 11th Edition. 2021. 7-ACCP Updates in Therapeutics® 2021: The Pharmacotherapy Preparatory Review and Recertification Course. 8-Roger Walker. Clinical Pharmacy and Therapeutics. Sixth edition 2019. 9-Lawrence A. Trissel. Handbook on injectable drugs. 15th ed. 2009. 10-David J Quan, Richard A Helms. Textbook of Therapeutics: Drug and Disease Management. 8th edition. 2006. 11-Pavan Bhat, et al. Washington Manual of Medical Therapeutics, The, 35th Edition. Copyright 2016. 12-Helen Williams.V Arrhythmia : part 1. The pharmaceutical journal (VOL 271) (2003):368-370. 36