CVS Pharmacology - Pharma.pptx pharmacology

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1. Pharmacology I for Pharmacy students Cardiovascular System Abenezer Aklog ( B.Pharm , MSc.) Cardiovascular system Abenezer Aklog 1

2. CVS pharmacology Antihypertensive Drugs 2 Cardiovascular system Abenezer Aklog

3. Hypertension (HTN) Introduction Hypertension is defined as persistently elevated arterial blood pressure (BP ) Is the most common cardiovascular disease in developed countries (up to 27% of US adult population) – affected > 1 billion people world wide The prevalence of HTN is significantly increasing in developing countries The American Heart Association (AHA) defines hypertension as arterial blood pressure higher than 140/90mmHg (based on three measurements at different times ) 3 Cardiovascular system Abenezer Aklog

4. Hypertension (HTN) Introduction Arterial BP is the pressure in the arterial wall measured in millimeters of mercury (mm Hg) The two typical arterial BP values are systolic BP (SBP) and diastolic BP ( DBP ) SBP is achieved during cardiac contraction and represents the peak value DBP is achieved after contraction when the cardiac chambers are filling , and represents the nadir value The difference between SBP and DBP is called the pulse pressure and is a measure of arterial wall tension 4 Cardiovascular system Abenezer Aklog

5. Hypertension (HTN) Introduction Sustained arterial BP damages blood vessels in multiple organs including kidney , heart, & brain Leads to an increased incidence of renal failure , coronary heart disease , heart failure, stroke , & dementia CV morbidity & mortality ↑ as both SBP & DBP rise , but elderly (>50yrs), the SBP & pulse pressure are better predictors of complications than DBP Effective pharmacologic lowering of BP has been shown to prevent damage to blood vessels & to substantially reduce morbidity & mortality rates 5 Cardiovascular system Abenezer Aklog

6. Hypertension (HTN) Classification based on Etiologic Etiologically, HTN is classified into primary and secondary hypertension Primary (Essential) hypertension – exact cause is unknown ( 90% ) Multiple risk factors are associated with the development of 1 HTN Diabetes, Obesity, lifestyle (decrease physical activity, smoking, Excess alcohol, Diet [high Na intake]), psychological stress, Genetics Secondary hypertension – as a result of other known Causes ( 10% ) Renal parenchymal disease (GN), Renal artery constriction, coarctation of the aorta, pheochromocytoma, Conn’s disease (primary aldosteronism ), Cushing’s disease, Drug 6 Cardiovascular system Abenezer Aklog

7. Hypertension (HTN) Classification based on BP Value (Stages) Prehypertension is not considered a disease category, but identifies patients whose BP is likely to increase into the classification of HTN in the future 7 Cardiovascular system Abenezer Aklog

8. Hypertension (HTN) Classification based on BP Value (Stages) Hypertensive crises : are clinical situations where BP values are very elevated, typically greater than 180/120 mmHg They are categorized as either a hypertensive urgency or emergency Hypertensive urgencies : are high elevations in BP without acute or progressing target-organ injury Hypertensive emergencies : are extreme elevations in BP that are accompanied by acute or progressing target-organ damage 8 Cardiovascular system Abenezer Aklog

9. Hypertension (HTN) Blood Pressure (BP) Regulation BP is mathematically defined as the product of cardiac output and total peripheral resistance according to the following equation: BP = Cardiac output (CO) × Total peripheral resistance (TPR) CO is determined by stroke volume (SV) and heart rate ; SV is related to myocardial contractility and to the size of the vascular compartment TPR is determined by functional and anatomic changes in small arteries and arterioles 9 Cardiovascular system Abenezer Aklog

10. Hypertension (HTN) Blood Pressure (BP) Regulation In both normal & hypertensive individuals , BP is maintained by moment-to-moment regulation of CO & TPR exerted at 4 anatomic sites Arterioles, Post capillary venules , Heart & the kidney Baroreflexes act in combination with humoral mechanisms to coordinate function at these four control sites and to maintain normal BP Local release of vasoactive substances from vascular endothelium may also be involved in the regulation of vascular resistance E.g. Endothelin ( Vasoconstrictor ), and Nitric Oxide ( Vasodilator ) 10 Cardiovascular system Abenezer Aklog

11. Hypertension (HTN) Blood Pressure (BP) Regulation – Neuronal (ANS) Regulation Stimulation of presynaptic α-receptors (α 2 ) exerts a – Ve inhibition on NE release Stimulation of presynaptic β-receptors facilitates NE release Stimulation of postsynaptic α-receptors (α 1 ) on arterioles and venules results in vasoconstriction Stimulation of postsynaptic β 1 -receptors in the heart results in an increase in HR and contractility , Whereas stimulation of postsynaptic β 2 -receptors in the arterioles and venules causes vasodilation 11 Cardiovascular system Abenezer Aklog

12. Hypertension (HTN) Blood Pressure (BP) Regulation – Baroreflex Moment-Moment Regulation Baroreflexes, integral part of the ANS, are responsible for the rapid , moment-to-moment regulation of BP A fall in BP causes pressure-sensitive neurons (baroreceptors in the aortic arch & carotid sinuses ) to send fewer impulses to CV centers in the brainstem This prompts a reflex response of ↑ ed sympathetic & ↓ ed parasympathetic output to the heart & vasculature, resulting in vasoconstriction & ↑ ed CO This will ultimately lead to a compensatory rise in BP 12 Cardiovascular system Abenezer Aklog

13. Hypertension (HTN) Blood Pressure (BP) Regulation – Humoral Regulation (Slow response) Involved in the long term (hours to days) control of BP The most important humoral factor is the enzyme Renin that is produced by the juxtaglomerular cells in the kidney The release of renin is modulated by several factors : - Activate RAAS Intrarenal factors – renal perfusion pressure, Catecholamines (stimulate SNS on the afferent arterioles), angiotensin II Extrarenal factors – ↓ sodium , chloride, and potassium). 13 Cardiovascular system Abenezer Aklog RAAS – Renin-Angiotensin-Aldosterone System

14. Hypertension (HTN) Dysregulation of Blood Pressure (BP) – HTN Pathogenesis Major pathophysiological mechanisms of hypertension include: Activation of the sympathetic nervous system Activation of the RAAS Endothelial dysfunction (Decreased NO & Increased endothelin ) Oxidative stress (Increase Reactive Oxygen Species [ROS]) Left untreated, HTN can lead to heart disease, kidney disease, and stroke 14 Cardiovascular system Abenezer Aklog

15. Hypertension (HTN) HTN Treatment The overall goal of treating hypertension is to reduce hypertension-associated morbidity and mortality Treatment program of lifestyle modifications (Non-pharmacologic) and drug therapy (Pharmacologic) can dec BP and the risk of long-term complications Lifestyle modification alone is considered appropriate therapy for patients with prehypertension However, lifestyle modifications alone are not considered adequate for patients with hypertension and additional CV risk factors 15 Cardiovascular system Abenezer Aklog

16. Hypertension (HTN) HTN Treatment – Non-Pharmacologic Weight loss – body mass index 18.5–24.9 kg/m2 Sodium restriction – 1.5g/day sodium, or 3.8 g/day sodium chloride DASH diet – diet rich in fruits, vegetables, and low-fat dairy products Increased physical activity – at least 30 min/day daily Decreased alcohol intake - ≤2 drinks/day in men and ≤1 drink/day in women Cessation of cigarette smoking 16 Cardiovascular system Abenezer Aklog

17. Antihypertensive Drugs HTN Treatment – Pharmacologic – Antihypertensive drugs All antihypertensive agents act at one or more of the 4 anatomic control sites & can be categorized as: Diuretics Sympathoplegic agents  Drugs that interfere with the RAAS Calcium channel blockers Direct acting vasodilators  17 Cardiovascular system Abenezer Aklog

18. Antihypertensive Drugs Antihypertensive drugs – Diuretics Diuretics, preferably a thiazide , are first-line agents for hypertension 18 Cardiovascular system Abenezer Aklog Diuretics Thiazides & related agents : hydrochlorothiazide, chlorthalidone , indapamide , metolazone Loop diuretics : furosemide, torsemide , ethacrynic acid K + -sparing diuretics : amiloride , triamterene, spironolactone, eplerenone

19. Antihypertensive Drugs Antihypertensive drugs – Diuretics – PD The exact mechanism for reduction of arterial blood pressure by diuretics is not certain. The initial action of thiazide diuretics decreases extracellular volume . However, the hypotensive effect is maintained during long-term therapy due to decreased vascular resistance ; CO returns to pretreatment values , and extracellular volume returns to almost normal due to compensatory responses such as activation of the RAAS . 19 Cardiovascular system Abenezer Aklog

20. Antihypertensive Drugs Antihypertensive drugs – Diuretics – Thiazides and Related agents Are used in combination with sympatholytic agents or vasodilators in severe hypertension to control the retention of Na + caused by these agents The effectiveness of thiazides as diuretics or antihypertensive agents is progressively diminished when the GFR falls below 30 mL/min . One exception is metolazone , which retains efficacy in patients with this degree of renal insufficiency Can be used in patients with chronic kidney disease (CKD) 20 Cardiovascular system Abenezer Aklog

21. Antihypertensive Drugs Antihypertensive drugs – Diuretics – Thiazides and Related agents Induce hypokalemia , hyperuricemia , and, to a lesser extent, hyperglycemia in some patients. All thiazide-like drugs cross the placenta . While they have no direct adverse effects on the fetus, administration of a thiazide during pregnancy increases a risk of transient volume depletion that may result in placental hypoperfusion . Because the thiazides appear in breast milk, they should be avoided by nursing mothers. 21 Cardiovascular system Abenezer Aklog

22. Antihypertensive Drugs Antihypertensive drugs – Diuretics – Loop Diuretics Less effective than thiazides in patients with normal renal function . Most likely related to the short duration of action (Short t 1/2 ) The strong initial diuretic effect is followed by a rebound mediated activation of the RAAS . When a loop diuretic is given twice daily , the acute diuresis can be excessive and lead to more side effects than occur with a slower-acting, milder thiazide diuretic . 22 Cardiovascular system Abenezer Aklog

23. Antihypertensive Drugs Antihypertensive drugs – Diuretics – Loop Diuretics Used in combination with sympatholytic agents and vasodilators for hypertension refractory to thiazide treatment Indicated in – severe HTN , when multiple drugs with sodium-retaining properties are used; in renal insufficiency, and HF or cirrhosis, in which Na + retention is marked Often are preferred over thiazides in patients with CKD when estimated GFR is less than 30 mL/min/1.73 m 2 Loop diuretics cause decreased renal vascular resistance and increased renal blood flow 23 Cardiovascular system Abenezer Aklog

24. Antihypertensive Drugs Antihypertensive drugs – Diuretics – K+-Sparing ( ENaC blockers) Amiloride and Triamterene Can be used with thiazides in adults with low serum K + , but should be avoided with GFR <45 ml/min . Their primary use is in combination with another diuretic to counteract potassium-wasting properties The importance of ENaC for HTN is illustrated by the fact that an inherited form of hypertension, Liddle syndrome, is due to hyperactivity of ENaC . 24 Cardiovascular system Abenezer Aklog

25. Antihypertensive Drugs Antihypertensive drugs – Diuretics – K+-Sparing (MRAs) Spironolactone and Eplerenone The action of MRAs is delayed for about 3 days and is long lasting because MRAs regulate the density of the channel protein in the tubule membrane. Preferred for the treatment of primary aldosteronism and in resistant hypertension Potassium-sparing diuretics may cause hyperkalemia , especially in patients with CKD or diabetes – caution has to be exercised 25 Cardiovascular system Abenezer Aklog

26. Antihypertensive Drugs Antihypertensive drugs – Sympathoplegic Agents Primary mechanism of action Dec. sympathetic activity to heart &/or blood vessels Decease CO and/or TPR Most drugs elicit compensatory renal effects Sodium & water retention  expand blood volume  Inc CO Effective if used concomitantly with diuretics 26 Cardiovascular system Abenezer Aklog

27. Antihypertensive Drugs Antihypertensive drugs – Sympathoplegic Agents Centrally Acting Sympathoplegic Drugs Ganglion-Blocking Agents Adrenergic Neuron–Blocking Agents Adrenoceptor Antagonists Alpha ( α1) Blockers, Non selective α- blockers Beta Blockers Alpha & Beta Blockers 27 Cardiovascular system Abenezer Aklog

28. Antihypertensive Drugs Antihypertensive drugs – Sympathoplegic– Centrally Acting Agents Included in this group are Methyldopa , Clonidine , Guanabenz , Guanfacine Reduce sympathetic outflow from vasomotor centers in the brain stem But allow these centers to retain or even inc their sensitivity to baroreceptor control Methyldopa and clonidine produce slightly different hemodynamic effects Clonidine lowers HR and CO more than does methyldopa Indicating that they may act primarily on different populations of neurons Guanabenz and guanfacine share the central effects of clonidine 28 Cardiovascular system Abenezer Aklog

29. Antihypertensive Drugs Sympathoplegic– Centrally Acting Agents – Methyldopa An analog of L-dopa and a prodrug that is converted to α- methyldopamine and α- methylnorepinephrine The α- methylNE is then taken-up by the neuronal vesicles and will be released during sympathetic stimulation Antihypertensive action appears to be due to stimulation of central α 2 adrenoceptors by these metabolites Used primarily for hypertension during pregnancy Lowers BP chiefly by reducing peripheral vascular resistance 29 Cardiovascular system Abenezer Aklog

30. Antihypertensive Drugs Sympathoplegic– Centrally Acting Agents – Methyldopa It enters the brain via an aromatic amino acid transporter Has short plasma t 1/2 (2hrs) but its effect persists for at least 24hrs Because the effect depends on accumulation and storage of the metabolite ( α- methylNE ) in the vesicles of nerve endings, the action persists after the parent drug has disappeared from the circulation ADR – most common is sedation (@ onset of Tx ) , long Tx – Lack of conce . Lactation , can occur both in men and in women 30 Cardiovascular system Abenezer Aklog

31. Antihypertensive Drugs Sympathoplegic– Centrally Acting Agents – Clonidine BP lowering results from reduction of CO due to decreased HR and relaxation of capacitance vessels , and a reduction in peripheral resistance Stimulate α 2A R in the brainstem – decrease sympathetic out flow from CNS At higher doses it stimulate α 2B R in vessels – causing vasoconstriction Responsible for the loss of therapeutic effect that is observed with higher doses Has been used in hypertensive pts for the Dx of pheochromocytoma Effective in reducing early morning hypertension in pts treated with antiHTN 31 Cardiovascular system Abenezer Aklog

32. Antihypertensive Drugs Sympathoplegic– Centrally Acting Agents – Clonidine Lipid-soluble and rapidly enters the brain Has relatively short half-life and its antihypertensive effect is directly related to blood concentration Oral clonidine must be given twice a day (or as a patch ) to maintain smooth BP control Available as a transdermal patch that allows weekly dosing ADR – Sedation & xerostomia are prominent Abrupt cessation may lead to rebound HTN/ HTNive crisis 32 Cardiovascular system Abenezer Aklog

33. Antihypertensive Drugs Sympathoplegic– Ganglion Blocking Agents – Trimethaphan , Mecamylamin Drugs that block activation of postganglionic autonomic neurons by acetylcholine – Historically 1 st line agents Are no longer available clinically because of intolerable toxicities Competitively block nicotinic cholinoceptors on postganglionic neurons in both sympathetic and parasympathetic ganglia ADR – Sympathoplegia – orthostatic hypotension and sexual dysfunction Parasympathoplegia - constipation, urinary retention, blurred vision, dry mouth 33 Cardiovascular system Abenezer Aklog

34. Antihypertensive Drugs Sympathoplegic– Adrenergic Neuron Blocking Agents – Reserpine An alkaloid extracted from the roots of an Indian plant Blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines – Interfere with aminergic vesicular transporters Occurs throughout the body, resulting in depletion of NE, DA, and 5-HT in both central and peripheral neurons Lowers blood pressure by a combination of decreased CO and PVR Has longer half life (24-48hrs) and effects may last for days 34 Cardiovascular system Abenezer Aklog

35. Antihypertensive Drugs Sympathoplegic– Adrenergic Neuron Blocking Agents – Reserpine – ADR Cause significant Na + & fluid retention Should be given with a diuretic At low doses , it produces little postural hypotension May produce extrapyramidal effects resembling Parkinson’s disease High doses characteristically produce sedation , lassitude , nightmares, and severe mental depression – C/I in pts with depression Often produces mild diarrhea and GI cramps and inc . gastric acid secretion 35 Cardiovascular system Abenezer Aklog

36. Antihypertensive Drugs Sympathoplegic– Adrenergic Neuron Blocking Agents – Guanethidine Inhibits the release of NE from sympathetic nerve endings Pharmacologic activity requires transport into neuronal terminals by NET Effect blocked by TCA , Cocaine , Amphetamine Concentrated in vesicles and deplete NE from these stores So acts as pseudo NT – has no intrinsic activity at adrenoceptors It is too polar to enter CNS Because of it’s long t 1/2 (5 days), the onset of sympathoplegia is gradual 36 Cardiovascular system Abenezer Aklog

37. Antihypertensive Drugs Sympathoplegic– Adrenergic Neuron Blocking – Guanethidine – ADRs Often associated with symptomatic postural hypotension and hypotension following exercise(esp. at high doses) May be associated with delayed or retrograde ejaculation in men Commonly causes diarrhea , which results from increased GI motility Can produce hypertensive crisis by releasing catecholamines in patients with pheochromocytoma No significant CNS adverse effects as it cannot cross the BBB 37 Cardiovascular system Abenezer Aklog

38. Antihypertensive Drugs Sympathoplegic– Adrenoceptor Antagonists – β –Blockers 38 Cardiovascular system Abenezer Aklog Group of β‐ blockers Member Drugs Nonselective β‐ blockers Propranolol , Nadolol, Pindolol*, Carteolol *, Penbutolol *, Sotalol, Timolol Selective β 1 ‐ blockers Acebutolol *, Atenolol, Betaxolol , Bisoprolol, Esmolol , Metoprolol Third‐generation β‐ blockers (possess other novel activities) Carvedilol, Labetalol, Nebivolol * Contain intrinsic sympathetic activity

39. Antihypertensive Drugs Sympathoplegic– Adrenoceptor Antagonists – β –Blockers MOA β- adrenoceptor blockade Decrease myocardial contractility, HR & CO Some are capable of decreasing TPR Decrease renin secretion (depressing the RAAS) Most of them have been shown to be effective in lowering blood pressure Advantageous in patient which have other co-morbidities such as HF and MI 39 Cardiovascular system Abenezer Aklog

40. Antihypertensive Drugs Sympathoplegic– Adrenoceptor Antagonists – β –Blockers Although they have similar PD effects, their PK properties differ significantly in ways that may influence their clinical usefulness & side effects On the basis of their PK properties , they can be classified into 2 classes Those eliminated by hepatic metabolism , & Highly lipid soluble, variable BA, enter the CNS Those excreted unchanged by the kidney Low lipid solubility, less variable BA, and do not cross the BBB 40 Cardiovascular system Abenezer Aklog β‐Blocker Lipid solubility Oral BA(%) half‐life (h) Metabolism and elimination Atenolol Low 50 6–7 No metabolism; eliminated in unchanged form in the urine Bisoprolol Moderate 80 9–12 CYP3A4; eliminated in unchanged form (50% of dose) & metabolites in the urine Carvedilol High 25–35 7–10 CYP2D6 and CYP2C9 (major); CYP3A4 (minor); eliminated in the bile/feces Esmolol (iv) Low 9 min Esterases; eliminated in the urine Labetalol Low 25 6–8 Glucuronidation; eliminated in the urine Metoprolol High 50 3–7 CYP2D6 ; eliminated in the urine Nebivolol Low Unknown 12–19 Glucuronidation; CYP2D6; eliminated in the urine and feces Propranolol Very high 25 3–6 CYP2D6; glucuronidation ; eliminated in the urine

41. Antihypertensive Drugs Sympathoplegic– Adrenoceptor Antagonists – β –Blockers – Propranolol Highly lipophilic and almost completely absorbed after oral administration Undergoes extensive and highly variable first-pass metabolism . Readily enters the CNS Has active metabolite 4-OH propranolol , and the effective t 1/2 then becomes longer. Dec BA by concomitant ingestion of food and during long-term admin of the drug. Has broad therapeutic uses : ( HTN , arrhythmias, anxiety, migraine, Esophageal varices, Thyrotoxicosis) 41 Cardiovascular system Abenezer Aklog

42. Antihypertensive Drugs Adrenoceptor Antagonists – β –Blockers – Metoprolol, and Atenolol Are cardioselective and are the most widely used β blockers in the Tx of HTN Advantageous in treating hypertensive patients who also suffer from asthma , diabetes , or peripheral vascular disease . Metoprolol is extensively metabolized by CYP2D6 with high first-pass metabolism – show polymorphic differences in metabolism Has short t 1/2 of 4–6 hrs , but the extended-release preparation can be dosed once daily Atenolol is not extensively metabolized and is excreted primarily in the urine 42 Cardiovascular system Abenezer Aklog

43. Antihypertensive Drugs Adrenoceptor Antagonists – β –Blockers – Metoprolol, and Atenolol Are cardioselective and are the most widely used β blockers in the Tx of HTN Advantageous in treating hypertensive patients who also suffer from asthma , diabetes , or peripheral vascular disease . Metoprolol is extensively metabolized by CYP2D6 with high first-pass metabolism – show polymorphic differences in metabolism Has short t 1/2 of 4–6 hrs , but the extended-release preparation can be dosed once daily Atenolol is not extensively metabolized and is excreted primarily in the urine 43 Cardiovascular system Abenezer Aklog

44. Antihypertensive Drugs β –Blockers – Pindolol, Acebutolol , and Penbutolol Are partial agonists, i.e , β-blockers with some ISA They lower blood pressure but are rarely used in hypertension Depress CO or HR less than other β blockers, perhaps because of significantly greater agonist than antagonist effects at β 2 receptors This may be particularly beneficial for patients with bradyarrhythmias or peripheral vascular disease 44 Cardiovascular system Abenezer Aklog

45. Antihypertensive Drugs β –Blockers – Labetalol, Carvedilol , and Nebivolol These drugs have both β-blocking and vasodilating effects ( α –blocking) . Labetalol lower BP by reduction of peripheral vascular resistance without significant alteration in HR or CO Also Inhibits of neuronal uptake of NE (cocaine-like effect ) Useful for Tx hypertensive emergencies and hypertension of Pheochromocytoma – it is admin. by IV route Used in pregnancy-induced hypertensive crisis (low placental transfer) 45 Cardiovascular system Abenezer Aklog

46. Antihypertensive Drugs β –Blockers – Labetalol, Carvedilol , and Nebivolol The ratio of β to α 1 antagonist potency for carvedilol is ~10:1 (greater than labetalol [3:1]). Dissociates slowly from its receptor, explaining why the duration of action is longer than the short t 1/2 ( 2.2 hrs ) Has antioxidant & anti-inflammatory properties ( for CHF) Highly lipophilic and more than 95% protein bound – metabolized by liver No significant PK change in elderly and renal insufficiency 46 Cardiovascular system Abenezer Aklog

47. Antihypertensive Drugs β –Blockers – Labetalol, Carvedilol , and Nebivolol Nebivolol is long-acting , and highly selective β 1 adren o ceptor antagonist Stimulates NO-mediated vasodilation via induction of endothelial nitric oxide synthase Is devoid of Intrinsic sympathomimetic effects as well as Membrane-stabilizing activity and α 1 receptor blocking properties. Undergoes extensive first-pass metabolism , primarily by CYP2D6 . 47 Cardiovascular system Abenezer Aklog

48. Antihypertensive Drugs β –Blockers – Esmolol Is a β 1 -selective blocker that is rapidly metabolized via hydrolysis by red blood cell esterases It has a short t 1/2 (9–10min) and is administered by constant IV infusion Used for management of intraoperative and postoperative hypertension , Sometimes for hypertensive emergencies , particularly when hypertension is associated with tachycardia or risk of aggravation of HF 48 Cardiovascular system Abenezer Aklog

49. Antihypertensive Drugs Adrenoceptor Antagonists – β –Blockers – Therapeutic Uses Not first line except under comorbid conditions (e.g. CAD, HF) β Blockers (i.e . bisoprolol , carvedilol, metoprolol, or nebivolol ) are highly preferred drugs for HTN patients with conditions such as MI , IHD , HFrEF May be preferred for younger patients with signs of increased sympathetic drive . Vasodilating β blockers (e.g., carvedilol, nebivolol ) may be preferred in patients with peripheral artery disease . Can be combined with diuretics for additive effects 49 Cardiovascular system Abenezer Aklog

50. Antihypertensive Drugs Adrenoceptor Antagonists – β –Blockers – Adverse Effects Cardiac ADR – extensions of pharmacological actions – bradycardia, AV block, decrease contractility (predispose to HF) Smooth Muscle spasm – bronchoconstriction (high with nonselective agents) Low dose β 1 -selective agents or agents with ISA can be used in asthmatic pts CNS ADRs – Insomnia, Night mares, depression, fatigability – commonly seen with lipophilic agents (e.g. Propranolol) Metabolic ADRs – inc. plasma TG level and dec HDL-c, delay recovery from hypoglycemia or mask sxms of hypoglycemia 50 Cardiovascular system Abenezer Aklog

51. Antihypertensive Drugs Adrenoceptor Antagonists – β –Blockers – Adverse Effects Sudden discontinuation → angina pectoris & MI may occur in pts with IHD Dosage should be tapered gradually over 10–14 days prior to discontinuation Fatigue and erectile dysfunction (impotence) Drug Interactions Combined with verapamil or diltiazem , may depress SA & AV nodes Cimetidine may ↑ plasma level of hepatically metabolized β - blockers Rifampicin & phenobarbital (enzyme induction) have the opposite effect 51 Cardiovascular system Abenezer Aklog

52. Antihypertensive Drugs Adrenoceptor Antagonists – α –Blockers Include selective agents ( Prazosin , terazosin , and doxazosin ) and non-selective agents ( phentolamine and phenoxybenzamine ) Selective agent cause less reflex tachycardia when lowering BP than do nonselective α antagonists They allow NE to exert unopposed negative feedback (mediated by presynaptic α 2 receptors ) on its own release Reduce arterial pressure by dilating both resistance and capacitance vessels 52 Cardiovascular system Abenezer Aklog

53. Antihypertensive Drugs Adrenoceptor Antagonists – α –Blockers Initially, α 1 blockers reduce arteriolar resistance and increase venous capacitance This causes a sympathetically mediated reflex increase in HR and plasma renin activity . During long-term therapy, vasodilation persists, but CO, HR, and plasma renin activity return to normal. Renal blood flow is unchanged during therapy with an α 1 blocker. 53 Cardiovascular system Abenezer Aklog

54. Antihypertensive Drugs Adrenoceptor Antagonists – α –Blockers BP is reduced more in the upright than in the supine position Retention of salt and water occurs when these drugs are administered without a diuretic The drugs are more effective when used in combination with other agents, such as a β blocker and a diuretic, than when used alone Owing to their beneficial effects in men with prostatic hyperplasia and bladder obstruction symptoms, these drugs are used primarily in men with concurrent hypertension and benign prostatic hyperplasia (BPH) . 54 Cardiovascular system Abenezer Aklog

55. Antihypertensive Drugs Adrenoceptor Antagonists – α –Blockers Prazosin has half life of 3-4 hours Terazosin is extensively metabolized but undergoes very little first-pass metabolism and has a t 1/2 of 12hrs – can often be given once daily Doxazosin has an intermediate BA and a t 1/2 of 22hrs – usually given once daily Long term treatment can cause postural hypotension 55 Cardiovascular system Abenezer Aklog

56. Antihypertensive Drugs Adrenoceptor Antagonists – α –Blockers – Therapeutic Uses and ADRs Are not recommended as monotherapy for HTN pts ( risk of developing HF) Used primarily in conjunction with diuretics , β blockers , and others. ADRs – first-dose phenomenon , in which symptomatic orthostatic hypotension occurs within 30–90 min (or longer) of the initial dose of the drug or after a dosage increase. Pts should take the 1 st dose & subsequent 1 st ↑ ed doses , at bedtime Dizziness, palpitations, headache, and lassitude 56 Cardiovascular system Abenezer Aklog

57. Antihypertensive Drugs Adrenoceptor Antagonists – α –Blockers – Nonselectives The nonselective agents , phentolamine and phenoxybenzamine , are useful in diagnosis and treatment of pheochromocytoma and in other clinical situations associated with exaggerated release of catecholamines E.g., Phentolamine may be combined with propranolol to treat the clonidine withdrawal syndrome Produce more reflex tachycardia than selective agents 57 Cardiovascular system Abenezer Aklog

58. Antihypertensive Drugs Agents acting on the Renin-Angiotensin-Aldosterone system (RAAS) Renin release from the kidney cortex is stimulated by reduced renal arterial pressure , sympathetic neural stimulation , and reduced sodium delivery Renin acts upon angiotensinogen to split off the inactive precursor decapeptide angiotensin I Angiotensin I is then converted, primarily by endothelial ACE , to the arterial vasoconstrictor octapeptide angiotensin II Angiotensin II has vasoconstrictor and sodium retaining activity 58 Cardiovascular system Abenezer Aklog

59. Antihypertensive Drugs Agents acting on the Renin-Angiotensin-Aldosterone system (RAAS) High plasma renin activity occurs in states such as Renal arterial stenosis , some types of intrinsic renal disease , and malignant hypertension, as well as in essential hypertension after treatment with sodium restriction, diuretics, or vasodilators However, even in low-renin hypertensive states , these drugs can lower BP Renin angiotensin aldosterone system ( RAAS ) may be responsible for trophic changes such as cardiac hypertrophy 59 Cardiovascular system Abenezer Aklog

60. Antihypertensive Drugs Agents acting on the Renin-Angiotensin-Aldosterone system (RAAS) Three classes of drugs act specifically on the RAAS Angiotensin converting enzyme (ACE) inhibitors The competitive inhibitors of angiotensin at its receptors Aliskiren , an orally active renin antagonist A fourth group of drugs include the aldosterone receptor antagonists ( eg , spironolactone, eplerenone ) which are diuretics In addition, β blockers can reduce renin secretion 60 Cardiovascular system Abenezer Aklog

61. Antihypertensive Drugs Agents acting on the RAAS – ACE Inhibitors – “- Pril ” Include captopril , enalapril , benazepril , fosinopril , l isinopril , moexipril , perindopril, quinapril, ramipril , and trandolapril Inhibit the converting enzyme peptidyl dipeptidase that hydrolyzes angiotensin I to angiotensin II Under the name plasma kininase , it inactivates bradykinin , a potent vasodilator , which works at least in part by stimulating release of nitric oxide and prostacyclin . 61 Cardiovascular system Abenezer Aklog

62. Antihypertensive Drugs Agents acting on the RAAS – ACE Inhibitors Their hypotensive activity results both from an inhibitory action on the RAAS and a stimulating action on the kallikrein-kinin system Angiotensin II inhibitors ↓ BP principally by decreasing PVR Cardiac output and heart rate are not significantly changed These agents do not result in reflex sympathetic activation due to downward resetting of the baroreceptors or to enhanced parasympathetic activity They can be used safely in persons with ischemic heart disease 62 Cardiovascular system Abenezer Aklog

63. Antihypertensive Drugs Agents acting on the RAAS – ACE Inhibitors Enalapril is an oral prodrug that is converted by hydrolysis enalaprilat Enalaprilat itself is available only for IV use , primarily for hypertensive emergencies Lisinopril , not a prodrug, is a lysine derivative of enalaprilat Captopril is a short acting agent (administered 2–3 times daily) Benazepril , fosinopril , moexipril , perindopril, quinapril, ramipril , and trandolapril are other long-acting members of the class All are prodrugs , like enalapril , and are converted to the active agents by hydrolysis, primarily in the liver All of the ACEI except fosinopril and moexipril are eliminated primarily by the kidneys 63 Cardiovascular system Abenezer Aklog

64. Antihypertensive Drugs Agents acting on the RAAS – ACE Inhibitors They have a particularly useful role in treating patients with chronic kidney disease because they diminish proteinuria and stabilize renal function (even in the absence of lowering of blood pressure) This effect is particularly valuable in diabetes , and these drugs are now recommended in diabetes even in the absence of HTN These benefits probably result from improved intrarenal hemodynamics , with ↓ glomerular efferent arteriolar resistance and a resulting ↓ of intraglomerular capillary pressure 64 Cardiovascular system Abenezer Aklog

65. Antihypertensive Drugs Agents acting on the RAAS – ACE Inhibitors - Toxicity Severe hypotension can occur after initial doses of any ACE inhibitor in patients who are hypovolemic as a result of diuretics , salt restriction , or gastrointestinal fluid loss Hyperkalemia , dry cough sometimes accompanied by wheezing, and angioedema Hyperkalemia is more likely to occur in pts with renal insufficiency or diabetes Acute renal failure (particularly in patients with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney) 65 Cardiovascular system Abenezer Aklog

66. Antihypertensive Drugs Agents acting on the RAAS – ACE Inhibitors - Toxicity ACE inhibitors are contraindicated during the second and third trimesters of pregnancy because of the risk of fetal hypotension , anuria , and renal failure , sometimes associated with fetal malformations or death First trimester exposure to ACE inhibitors increases teratogenic risk Captopril , particularly when given in high doses to patients with renal insufficiency, may cause neutropenia or proteinuria 66 Cardiovascular system Abenezer Aklog

67. Antihypertensive Drugs Agents acting on the RAAS – ACE Inhibitors - Toxicity Minor ADR – Altered sense of taste , allergic skin rashes , and drug fever , which may occur in up to 10% of patients. Important drug interactions include those with potassium supplements or potassium-sparing diuretics , which can result in hyperkalemia Nonsteroidal anti-inflammatory drugs may impair the hypotensive effects of ACE inhibitors Block bradykinin mediated vasodilation , which is at least in part, prostaglandin mediated . 67 Cardiovascular system Abenezer Aklog

68. Antihypertensive Drugs Agents acting on the RAAS – Ang Receptor Blockers (ARBs) –”- Sartan ” Include Losartan , valsartan , candesartan , eprosartan , irbesartan , telmisartan , azilsartan , and olmesartan They have no effect on bradykinin metabolism and are therefore more selective blockers of angiotensin effects than ACE inhibitors They also have the potential for more complete inhibition of angiotensin action compared with ACE inhibitors There are enzymes other than ACE that are capable of generating Ang II 68 Cardiovascular system Abenezer Aklog

69. Antihypertensive Drugs Agents acting on the RAAS – Ang Receptor Blockers (ARBs) –”- Sartan ” They provide benefits similar to those of ACEI in pts with HF and CKD Losartan’s has a t 1/2 of 1-2 hours whereas its metabolite has t 1/2 of 3-4 hours The adverse effects are similar to those described for ACEI, including the hazard of use during pregnancy Cough and angioedema can occur but are less common with ARBs than with ACEIs 69 Cardiovascular system Abenezer Aklog

70. Antihypertensive Drugs Agents acting on the RAAS – Direct Renin Inhibitor - Aliskerin Very potent competitive inhibitor of renin Reduces angiotensin I, II & aldosterone production Alternative antihypertensive drug May cause hyperkalemia in pts with CKD & DM or in those receiving a K-sparing diuretic , aldosterone antagonist , ACEIs , or ARBs Do not use in pregnancy ACE, ARBs and direct renin inhibitors should not be used in combination 70 Cardiovascular system Abenezer Aklog

71. Antihypertensive Drugs Calcium Channel Blockers (CCBs) Voltage-gated Ca 2+ channels (L-type or slow channels) mediate the entry of extracellular Ca 2+ into Smooth muscle and cardiac myocytes SA and AV nodal cells in response to electrical depolarization. CCBs “block” the entry of calcium through the calcium channel in both smooth muscle and myocardium, so that less calcium is available to the contractile apparatus . 71 Cardiovascular system Abenezer Aklog

72. Antihypertensive Drugs Calcium Channel Blockers (CCBs) All Ca 2+ channel antagonists relax arterial smooth muscle and thereby decrease arterial resistance , blood pressure , and cardiac afterload . Ca 2+ channel blockers do not affect cardiac preload significantly when given at normal doses in patients . By inhibiting Ca 2+ influx , CCBs reduce the peak size of the systolic Ca 2+ transient and thereby produce a negative inotropic effect . 72 Cardiovascular system Abenezer Aklog

73. Antihypertensive Drugs Calcium Channel Blockers (CCBs) – 2 Types of CCBs Dihydropyridine CCBs – ”- dipine ” Amlodipine, nifedipine , felodipine , isradipine , nicardipine , and nisoldipine Clevidipine is a newer member (IV) - used in acute hypertension occurring during surgery Non- dihydropyridine CCBs Verapamil , and diltiazem 73 Cardiovascular system Abenezer Aklog

74. Antihypertensive Drugs Calcium Channel Blockers (CCBs) – Dihydropyridines Dilate blood vessels at several fold lower concentrations than those required for decreasing myocardial force . The decrease in arterial BP elicits reflex sympathetic activation , causing an increase in heart rate and contractility . Amlodipine (commonly used) Has slow absorption and a prolonged effect ( Cp with modest peaks and troughs) Allows the body to adapt and is associated with less reflex tachycardia . Felodipine , nitrendipine , and isradipine have similar profiles for chronic treatment 74 Cardiovascular system Abenezer Aklog

75. Antihypertensive Drugs Calcium Channel Blockers (CCBs) – Non- Dihydropyridines Have more direct negative inotropic and chronotropic effects Cause little effect on venous return and preload Verapamil has the greatest depressant effect on the heart and may decrease heart rate and cardiac output Diltiazem has intermediate actions that is between dihydropyridines and verapamil 75 Cardiovascular system Abenezer Aklog Drug Vasodilation ↓ cardiac contractility ↓automaticity (SA node) ↓conduction (AV Node) Verapamil 4 4 5 5 Diltiazem 3 2 5 4 DHPs 5 1 1

76. Antihypertensive Drugs Calcium Channel Blockers (CCBs) – Antihypertensive Uses Preferred drugs as both as monotherapy and in combination with others Effective for Elderly subjects and in African Americans Elderly with isolated systolic hypertension Immediate-release nifedipine and other short-acting dihydropyridines have no place in the chronic management of hypertension . Verapamil and diltiazem also have short t 1/2 , more cardiac side effects, and a high DDI (verapamil) and are therefore not first-line antiHTN . 76 Cardiovascular system Abenezer Aklog

77. Antihypertensive Drugs Calcium Channel Blockers (CCBs) – Adverse Effects Immediate release capsules of nifedipine often cause headache , flushing , and dizziness and can actually worsen myocardial ischemia . Peripheral edema (ankle edema) Cause or aggravate gastroesophageal reflux Constipation : verapamil (25% pts) Non- dihydropyridine CCBs are associated with bradycardia and heart block and should be avoided in HFrEF . 77 Cardiovascular system Abenezer Aklog

78. Antihypertensive Drugs Calcium Channel Blockers (CCBs) – DDI BA increased by strong inhibitors of CYP3A4, such as macrolide and imidazole antibiotics, antiretroviral agents, and grapefruit juice BA is reduced by inducers of CYP3A4, such as rifampin, carbamazepine, and hypericum (St. John’s wort). Verapamil, use declined due to Strong CYP3A4 inhibitor (interaction with simvastatin & atorvastatin) Inhibitor of Pgp (also called MDR1 and ABCB ) ( increase plasma levels of digoxin , cyclosporine , and loperamide ) 78 Cardiovascular system Abenezer Aklog

79. Antihypertensive Drugs Direct Acting Vasodilators 79 Cardiovascular system Abenezer Aklog

80. Antihypertensive Drugs Direct Acting Vasodilators – Hydralazine Directly relaxes arteriolar SM with little effect on venous SM Proposed mechanisms include Inhibition of IP3‐induced calcium release from sarcoplasmic reticulum Release of Nitric Oxide from endothelial cells Activation of an arachidonic acid, COX, and prostacyclin pathway . The vasodilation induces powerful stimulation of sympathetic system (Inc. HR and contractility , Inc. plasma renin activity, and fluid retention) 80 Cardiovascular system Abenezer Aklog

81. Antihypertensive Drugs Direct Acting Vasodilators – Hydralazine Well absorbed but undergoes rapid first pass metabolism by liver ( 25% BA ) It is metabolized in part by N-Acetylation – shows polymorphism Fast Vs Slow Acetylators – variable plasma concentration of the drug Not a first line drug for chronic mgt but is approved for treating hypertensive crises accompanying acute glomerular nephritis or eclampsia Elicits the baroreceptor reflex, necessitating coadministration with a diuretic to counteract Na and H 2 O retention and a β-blocker to prevent tachycardia 81 Cardiovascular system Abenezer Aklog

82. Antihypertensive Drugs Direct Acting Vasodilators – Hydralazine – Adverse Effects Headache , nausea, flushing, hypotension, palpitations, tachycardia, dizziness, and angina pectoris. Use cautiously in patients with CAD & elderly Lupus syndrome (autoimmune condition) at high doses Characterized by: arthralgia , myalgia , skin rashes , & fever Because of preferential dilation of arterioles over veins, postural hypotension is not a common problem 82 Cardiovascular system Abenezer Aklog

83. Antihypertensive Drugs Direct Acting Vasodilators – Minoxidil Increase K+ efflux , which hyperpolarizes cells and reduces the activity of L-type calcium channels , and it may stimulate the production of nitric oxide . Vasodilates predominantly arteriolar vessels . Is a more potent vasodilator than hydralazine, and compensatory increases in HR, CO, renin release, and Na + retention are more dramatic It must be used in combination with a β-blocker and a loop diuretic 83 Cardiovascular system Abenezer Aklog

84. Antihypertensive Drugs Direct Acting Vasodilators – Minoxidil Is readily absorbed from the gut. About 90% metabolized by glucorinadation and e xcreted in the urine The elimination half‐life is approximately 4h. Useful for long-term therapy of refractory hypertension , and replace hydralazine when the latter is ineffective ADRS - fluid and salt retention , cardiovascular abnormalities (e.g., pericarditis, pericardial effusion ,), hypertrichosis (growing of body hair) 84 Cardiovascular system Abenezer Aklog

85. Antihypertensive Drugs Direct Acting Vasodilators – Diazoxide Causes K+ efflux to induce arteriolar dilation Was used in the treatment of hypertensive emergencies but fell out of favor at least in part due to the risk of marked falls in blood pressure when large bolus doses of the drug were used. Is administered with furosemide to prevent fluid overload. Also is administered orally to treat patients with various forms of hypoglycemia . 85 Cardiovascular system Abenezer Aklog

86. Antihypertensive Drugs Direct Acting Vasodilators – Diazoxide – Adverse Effects Excessive hypotension – which results in stroke and myocardial infarction The reflex sympathetic response can provoke angina, electrocardiographic evidence of ischemia, and cardiac failure in patients with IHD, Diazoxide should be avoided in this situation It inhibits insulin release from the pancreas and is used to treat hypoglycemia secondary to insulinoma 86 Cardiovascular system Abenezer Aklog

87. Antihypertensive Drugs Direct Acting Vasodilators – Sodium Nitroprusside It is a powerful parenterally administered vasodilator that is used in treating hypertensive emergencies as well as severe heart failure It dilates both arterial and venous vessels , resulting in reduced peripheral vascular resistance and venous return The action occurs as a result of activation of guanylyl cyclase , either via release of nitric oxide or by direct stimulation of the enzyme The result is increased intracellular cGMP , which relaxes vascular SM 87 Cardiovascular system Abenezer Aklog

88. Antihypertensive Drugs Direct Acting Vasodilators – Sodium Nitroprusside In the absence of HF, blood pressure decreases, owing to decreased PVR, whereas CO does not change or decreases slightly In patients with HF and low CO, output often increases owing to afterload reduction PK It is rapidly metabolized by uptake into red blood cells with liberation of cyanide 88 Cardiovascular system Abenezer Aklog

89. Antihypertensive Drugs Direct Acting Vasodilators – Sodium Nitroprusside - PK Cyanide in turn is metabolized by the mitochondrial enzyme rhodanase , in the presence of a sulfur donor, to the less toxic thiocyanate Thiocyanate is distributed in extracellular fluid and slowly eliminated by the kidney It rapidly lowers blood pressure , and its effects disappear within 1–10 minutes after discontinuation It is given by intravenous infusion 89 Cardiovascular system Abenezer Aklog

90. Antihypertensive Drugs Direct Acting Vasodilators – Sodium Nitroprusside – Adverse Effects Hypotension Most serious toxicity is related to accumulation of cyanide; metabolic acidosis, arrhythmias, excessive hypotension, and death Sodium thiosulfate (sulfur donor) or hydroxocobalamin is used to treat cyanide toxicity Thiocyanate toxicity - Weakness, disorientation, psychosis, muscle spasms, and convulsions, Rarely hypothyroidism Methemoglobinemia 90 Cardiovascular system Abenezer Aklog

91. Antihypertensive Drugs Direct Acting Vasodilators – Fenoldopam Peripheral arteriolar dilator used for hypertensive emergencies and postoperative hypertension It acts primarily as an agonist of dopamine D1 receptors , resulting in dilation of peripheral arteries and natriuresis It is rapidly metabolized, primarily by conjugation. Its half-life is 10 minutes and is administered by continuous intravenous infusion ADR - Reflex tachycardia, headache, and flushing, Inc IOP 91 Cardiovascular system Abenezer Aklog

92. Antianginal Drugs Pharmacology of Drugs for Ischemic Heart disease 92 Cardiovascular system Abenezer Aklog

93. Ischemic Heart Disease (IHD) IHD is an umbrella term that encompasses a spectrum of cardiac disorders caused by myocardial ischemia . Myocardial ischemia is a state of decreased perfusion during which the oxygen supply to the myocardium is insufficient to meet its metabolic demands . IHD can be defined as lack of oxygen and decreased or no blood flow to the myocardium resulting from coronary artery narrowing or obstruction . Occurs when there is imbalance between myocardial oxygen supply and demand The most common cause of IHD is atherosclerotic disease of the epicardial coronary artery 93 Cardiovascular system Abenezer Aklog

94. Ischemic Heart Disease (IHD) Pathophysiology – Atherosclerosis Is the fundamental pathophysiological basis of IHD Results in the buildup of plaque in the coronary arteries which subsequently leads to stable angina and ACS . Stable angina is caused by narrowing of the coronary artery and limitation of the blood supply to part of myocardium On the other hand, the sudden rupture of a plaque and the subsequent thrombosis are responsible for ACS . 94 Cardiovascular system Abenezer Aklog

95. Ischemic Heart Disease (IHD) Pathophysiology – Determinants of Oxygen Demand and Supply IHD is mainly due to an imbalance in oxygen supply and demand to myocardial cells Determinant of Oxygen supply Coronary blood flow which is directly related to: Perfusion pressure (aortic diastolic pressure) & Duration of diastole B/c coronary flow drops to negligible values during systole, the duration of diastole becomes a limiting factor for myocardial perfusion during tachycardia 95 Cardiovascular system Abenezer Aklog

96. Ischemic Heart Disease (IHD) Pathophysiology – Determinants of Oxygen Demand and Supply Determinants of Oxygen Demand Heart rate Myocardial contractility Peripheral vascular resistance (afterload) Intra myocardial wall tension during systole Most important determinant because during systole , coronary perfusion is largely impaired resulting in ischemia 96 Cardiovascular system Abenezer Aklog

97. Ischemic Heart Disease (IHD) Symptoms of IHD – Angina Pectoris Is the primary symptom of IHD which characterized by paroxysmal & usually recurrent attacks of substernal or precordial chest discomfort Variously described as constricting , squeezing , choking , or heaviness The pain is precipitated when the oxygen supply to the heart is insufficient to meet oxygen demand Caused by transient ( 15sec – 15min ) myocardial ischemia that falls short of inducing myocyte necrosis 97 Cardiovascular system Abenezer Aklog

98. Ischemic Heart Disease (IHD) Types of Angina Pectoris – Three major Types – 1 Stable/Exertional Angina Underlying Pathology is an atherosclerotic plaque in large coronary arteries Fixed obstruction (plaque) blocks ≈70% of artery (enough during rest) Episodes precipitated by exercise , cold , stress , emotion , heavy meal ↑ work of myocardium (an increase in oxygen demand ) If blockage is >90%, pain will occur at rest Ischemia mostly occur at the inner most layer of myocardium because when the heart is contracting the inner layer is most compressed by the outer layer. 98 Cardiovascular system Abenezer Aklog

99. Ischemic Heart Disease (IHD) Types of Angina Pectoris – Three major Types – 2 Vasospastic Angina Also known as Variant angina or Prinzmetal’s angina Is a rare form of angina & common in females Most important cause is a transient vasospasm of coronary vessels Pain occurs during rest and is not related to exertion , exercise … Ischemia occurs through out all layers of myocardium (sub mural ischemia) Variant angina is relieved by nitroglycerin 99 Cardiovascular system Abenezer Aklog

100. Ischemic Heart Disease (IHD) Types of Angina Pectoris – Three major Types – 3 Unstable Angina Unstable plaque/atheroma (rupture , fissure, ulceration) inititaes platelet aggregation & adhesion with fibrin deposition → Thrombosis The thrombus is dynamic (↑ in size & mass) which can cause severe ischemia ( if > 20 min – may lead to Myocardial Infarction [ MI ]) Can be precipitated by progressively less effort, and even at rest . Does not respond well with nitrates or taking rest Nitrates are given 3 times within 15min and if pain is not relieved , then it is UA 100 Cardiovascular system Abenezer Aklog

101. Ischemic Heart Disease (IHD) Angina Pectoris – Treatment strategies Drug therapy of angina has two goals: Prevention of myocardial infarction (MI) and death Cholesterol lowering drugs and antiplatelet Prevention of myocardial ischemia and anginal pain Antianginal drugs Stable Angina – use drugs that decrease oxygen demand Effect on HR, Contractility, preload, and afterload Variant Angina – use drugs that increase oxygen supply Effect on coronary blood flow Unstable angina – use drugs that increase oxygen supply and decrease demand as well as antiplatelet and fibrinolytic agents 101 Cardiovascular system Abenezer Aklog

102. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment There are three main families of antianginal agents: Organic nitrates (e.g., nitroglycerin), Beta blockers (e.g., metoprolol), and Calcium channel blockers (e.g., verapamil) They ↓ Myocardial O 2 requirement by ↓ ing the determinants of O 2 demand (HR, ventricular volume, BP, & contractility) In some pts, the nitrates & the CCBs may cause a redistribution of coronary flow & ↑ O 2 delivery to ischemic tissue In variant angina , these 2 drug groups also ↑ myocardial O 2 delivery by reversing coronary artery spasm 102 Cardiovascular system Abenezer Aklog

103. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment Drugs may relax vascular smooth muscle in several ways: Increasing intracellular cGMP Organic Nitrates Decreasing Intracellular Ca 2 + Beta blockers and calcium channel blockers Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane Newer agents – Nicorandil , Ranolazine , Ivabradine 103 Cardiovascular system Abenezer Aklog

104. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Organic Nitrates These agents are simple nitric & nitrous acid esters of polyalcohols Nitroglycerin (Glyceryl trinitrate , GTN), Isosorbide dinitrate (ISDN), Isosorbide mononitrate (ISMN) All therapeutically active agents in the nitrate group appear to have identical MOA & similar toxicities , although susceptibility to tolerance may vary Therefore, PK factors govern the choice of agent & mode of therapy 104 Cardiovascular system Abenezer Aklog

105. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Organic Nitrates - MOA Established mechanisms of GTN bioactivation and action include Non-enzymatic reaction with L-cysteine  formation of nitrite and NO by ALDH2  activation of soluble guanylyl cyclase  generation of cGMP . The bio-activation of other nitrovasodilators such as ISDN and ISMN is ALDH2 independent , May suggest the involvement of other enzymes, such as CYPs , xanthine oxidoreductase , and cytosolic ALDH isoforms 105 Cardiovascular system Abenezer Aklog

106. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Organic Nitrates – Effect on VSM Nitrates cause vasodilating effects on both peripheral veins and arteries but with more prominent effects on the veins Veins responding at the lowest conce , and arteries at slightly higher conce Arterioles & precapillary sphincters are dilated least The major antianginal effect is mediated by preload reduction rather than coronary artery dilation Direct coronary vasodilation may be the major effect of GTN in situations where vasospasm compromises myocardial blood flow 106 Cardiovascular system Abenezer Aklog

107. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Organic Nitrates – Other Effects Cardiac Effects – Tachycardia and ↑ cardiac contractility can be evoked by baroreceptors and hormonal mechanisms responding to ↓ BP Retention of salt and water may also be significant, especially with intermediate- and long-acting nitrates Other Smooth Muscles – relaxation of Bronchial , GI , and GUT Action on platelet – Inhibit aggregation of platelet 107 Cardiovascular system Abenezer Aklog

108. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Organic Nitrates – PK (ADME) The liver contains a high-capacity organic nitrate reductase that removes nitrate groups and ultimately inactivates the drug Oral BA of the traditional agents ( GTN and ISDN ) is low (< 40%) For this reason, the sublingual route is used ( bypass 1 st pass effect ) The total duration of effect is brief (15–30 minutes) Other routes of administration available for GTN include transdermal and buccal absorption from slow-release preparations 108 Cardiovascular system Abenezer Aklog

109. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Organic Nitrates – PK (ADME) The liver contains a high-capacity organic nitrate reductase that removes nitrate groups and ultimately inactivates the drug Oral BA of the traditional agents ( GTN and ISDN ) is low (< 40%) For this reason, the sublingual route is used ( bypass 1 st pass effect ) The total duration of effect is brief (15–30 minutes) Other routes of administration available for GTN include transdermal and buccal absorption from slow-release preparations 109 Cardiovascular system Abenezer Aklog Drugs Preparation Onset of action Duration of action GTN Sublingual tablet or spray 1-3 min 25min Oral, sustained release 35 min 4-8hr Trans-dermal 30 min 10-12 hr ISDN Sublingual 5 min 1 hr Oral, slow release 30 min 8 hr ISMN Oral, extended release 30 min >12-24 hr

110. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Organic Nitrates – PK (ADME) The liver contains a high-capacity organic nitrate reductase that removes nitrate groups and ultimately inactivates the drug Oral BA of the traditional agents ( GTN and ISDN ) is low (< 40%) For this reason, the sublingual route is used ( bypass 1 st pass effect ) The total duration of effect is brief (15–30 minutes) Other routes of administration available for GTN include transdermal and buccal absorption from slow-release preparations 110 Cardiovascular system Abenezer Aklog Drugs Oral BA(%) Elimination half‐life Metabolism and excretion GTN  40 1–3 min Hepatic denitration to dinitrates and mononitrates ; renal excretion ISDN 25 45min ; 5h for the active metabolite,5‐mononitrate Hepatic denitration followed by glucuronidation ; renal excretion ISMN ~ 100 5h No significant first‐pass effects; hepatic denitration and renal excretion

111. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Organic Nitrates – Therapeutic Uses Stable Angina Pectoris Short-acting nitrates for immediate therapy (active angina) Sublingual GTN is the most commonly used for acute relief Sublingual ISDN , but not ISMN, is an alternative to GTN Longer-acting nitrates for the prophylaxis of angina Sustained-release oral preparations (ISDN, ISMN & GTN) Chronic treatment with nitrates is not associated with a prognostic benefit and may induce tolerance and endothelial dysfunction. Considered 2 nd c hoice compared to β blockers 111 Cardiovascular system Abenezer Aklog

112. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Organic Nitrates – Therapeutic Uses Variant ( Prinzmetal ) Angina Long-acting nitrates alone are occasionally efficacious in abolishing episodes of variant angina. Additional therapy with Ca 2+ channel blockers usually is required. Ca 2+ channel blockers, but not nitrates, have been shown to influence mortality and the incidence of MI favorably in variant angina. They should generally be included in therapy. 112 Cardiovascular system Abenezer Aklog

113. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Organic Nitrates – Therapeutic Uses Unstable Angina Pectoris ( ACS) Resistance to nitrates classifies angina symptoms as “ unstable ” and is a characteristic feature of ACS , Typically caused by transient or permanent thrombotic occlusion of coronary vessels . Nitrates do not modify this process specifically and are second-line drugs . One major drawback of long-term nitrate therapy is the development of Tolerance 113 Cardiovascular system Abenezer Aklog

114. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Organic Nitrates – Tolerance Refers to a decrease in the apparent effectiveness with continuous or repeated administration of nitrates Mechanisms of nitrate tolerance Impaired nitroglycerin bioconversion to 1,2‐glyceryl dinitrate with decreased formation of nitric oxide ( depletion of sulfhydryl group ) Reduced bioactivity of nitric oxide ( decreased cellular guanylyl cyclase ) Activation of the RAAS and sympathetic nervous system in response to nitrate‐induced vasodilation 114 Cardiovascular system Abenezer Aklog

115. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Organic Nitrates – Tolerance Strategies to minimize tolerance Nitrate free interval (Need 6-8 hr nitrate free time) to restart activity Exertional angina is prominent during day time : nitrate free interval during night Prinzimetal’s angina is precipitated at morning (circadian catecholamine surges, adrenergic supply from adrenaline is more): nitrate free evening Use of alternative agents (BBs or CCBs) Partially prevented or reversed with a sulfhydryl-regenerating . 115 Cardiovascular system Abenezer Aklog

116. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Organic Nitrates – Adverse Effects The major acute toxicities of organic nitrates are direct extension of therapeutic vasodilation Flushing and Throbbing Headache – Tx with acetaminophen or aspirin Orthostatic Hypotension – dizziness, light-headedness, syncope Reflex tachycardia and palpitation – negates Tx so pretreatment with B-blocker Contraindications Hypotension (hypovolemia), use with PDE5 Inhibitors (sildenafil), increased ICP 116 Cardiovascular system Abenezer Aklog

117. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Calcium Channel Blockers (CCBs) Ca 2+ is essential for cardiac nodal cell activity and muscular contraction Ca 2+ influx is increased in ischemia because of the membrane depolarization that hypoxia produces. Ca 2+ entry promotes the activity of several ATP-consuming enzymes , thereby depleting energy stores and worsening the ischemia . The CCBs protect the tissue by inhibiting the entrance of Ca 2+ into cardiac and smooth muscle cells of the coronary and systemic arterial beds 117 Cardiovascular system Abenezer Aklog

118. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Calcium Channel Blockers (CCBs) Mechanism of antianginal effects Reduces myocardial O 2 demand by ↓ myocardial contractile force – Verapamil and Diltiazem ↓ HR – Verapamil and diltiazem Arteriodilation →↓ afterload – Nifedipine , Amlodipine, Verapamil , Diltiazem Increase myocardial O 2 supply Coronary artery dilation – Nifedipine , Amlodipine, Verapamil, Diltiazem 118 Cardiovascular system Abenezer Aklog

119. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Calcium Channel Blockers (CCBs) Dihydropyridines : ( amlodipine, nifedipine ) Antianginal effect mainly by peripheral arterial vasodilation and afterload reduction and not by coronary artery dilation (exception in variant angina). Their efficacy in vasospastic angina is due to relaxation of the coronary arteries . In the vascular system, arterioles appear to be more sensitive than veins Short-acting dihydropyridines should be avoided in CAD because of evidence of increased mortality after an MI Higher risk of reflex tachycardia 119 Cardiovascular system Abenezer Aklog

120. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Calcium Channel Blockers (CCBs) Non- Dihydropyridines ( Verapamil, Diltiazem ) Verapamil has more direct negative inotropic and chronotropic effects Cause a reduction in myocardial O 2 demand Contraindicated in patients with preexisting depressed cardiac function or AV conduction abnormalities Diltiazem has its effect between dihydropyridines & verapamil. Can relieve coronary artery spasm and is particularly useful in patients with variant angina. 120 Cardiovascular system Abenezer Aklog

121. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – CCBs – Therapeutic Uses Variant Angina Ca 2+ channel blockers are effective in about 90% of patients with variant angina. These agents are considered 1 st line and may be combined with nitro-vasodilators. Exertional Angina CCBs are used as 2 nd -line therapy when β-blockers are genuinely C/I Verapamil is a more effective antianginal agent than diltiazem or DHPs & is considered a 1 st choice – must not be combined with β-blockers 121 Cardiovascular system Abenezer Aklog

122. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – CCBs – Therapeutic Uses Unstable Angina (Acute Coronary Syndrome) Verapamil and diltiazem are recommended only for patients who Continue to show signs of ischemia, Do not tolerate β blockers, Have no clinically significant left ventricular dysfunction, and Show no signs of disturbed AV conduction. Dihydropyridines should not be used without concurrent therapy with β blockers. 122 Cardiovascular system Abenezer Aklog

123. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – CCBs – Adverse Effects Serious cardiac depression, including bradycardia , atrioventricular block , cardiac arrest , and heart failure – are rare Relatively short-acting CCBs such as prompt-release nifedipine have the potential to enhance the risk of adverse cardiac events Slow-release and long-acting dihydropyridine CCBs are usually well tolerated Minor toxicities include flushing , dizziness , nausea , constipation , and peripheral edema 123 Cardiovascular system Abenezer Aklog

124. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – β- blockers (BBs) Are the only drug class that is effective in reducing the severity and frequency of attacks of stable angina and in improving survival i n pts who have had MI Therefore are recommended as 1 st line Tx of Pts with stable CAD and UA/ACS . BBs are not useful for vasospastic angina and, if used in isolation, may worsen that condition. Standard compounds for the treatment of angina are β 1 -selective and without ISA (e.g., Atenolol, B isoprolol , or Metoprolol). 124 Cardiovascular system Abenezer Aklog

125. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – β- blockers (BBs) Although they are not vasodilators (with the exception of labetolol , carvedilol and nebivolol ), BBs are extremely useful in the management of effort angina The beneficial effects of BBs are related to their hemodynamic effects — Decreased HR , BP , and contractility — which decrease myocardial oxygen requirements at rest and during exercise Lower HR is also associated with an increase in diastolic perfusion time that may increase coronary perfusion . 125 Cardiovascular system Abenezer Aklog

126. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – β- blockers (BBs) – Untoward Effects Increase in end-diastolic volume (EDV) and an increase in ejection time , both of which tend to increase myocardial oxygen requirement These deleterious effects of BBs can be balanced by the concomitant use of nitrates Combination of BBs with Nitrates – prevent EDV (caused by BB) & reflex tachycardia (caused by nitrates ) Abrupt discontinuation may cause rebound angina and even leads to MI Dose should be gradually tapered off over 2 to 3 weeks 126 Cardiovascular system Abenezer Aklog

127. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – β- blockers (BBs) – Untoward Effects Potential complications include fatigue, impaired exercise tolerance, insomnia, unpleasant dreams, worsening of claudication, and erectile dysfunction Contraindications to the use of β blockers Asthma and other bronchospastic conditions, severe bradycardia, atrioventricular blockade, bradycardia-tachycardia syndrome, and severe unstable left ventricular failure 127 Cardiovascular system Abenezer Aklog

128. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Miscellaneous Agents – Nicorandil Has nitrate-like (cGMP-dependent) properties and acts as an agonist at ATP sensitive potassium ( K ATP ) channels. Dilates both arterial and venous vascular beds Hemodynamic profile between nitrates and dihydropyridines ; decrease afterload more than nitrates Second choice in the prevention of exertional angina Adverse effects : hypotension, headache, buccal and GI ulcers Do not combine with PDE5 inhibitor 128 Cardiovascular system Abenezer Aklog

129. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Miscellaneous Agents – Ranolazine Inhibits late Na + and other cardiac ion currents with weak β blocking and metabolic effects Second choice in the prevention of exertional angina Metabolized mainly via CYP3A4 and less by CYP2D6 with t 1/2 of 7hrs Can prolong the QT interval and should be avoided with other drugs that cause QT prolongation . Excretion : 75 % in the urine and 25% in the feces. 129 Cardiovascular system Abenezer Aklog

130. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Miscellaneous Agents – Ivabradine Selectively decrease HR by inhibiting Hyperpolarization activated cyclic nucleotide gated ( HCN ) currents in SA node . Second choice in the prevention of exertional angina; approved in patients not tolerating β blockers or having HR > 75 under β blockers . Adverse effects : bradycardia, QT prolongation, atrial fibrillation, phosphenes . Contraindication : combination with diltiazem or verapamil 130 Cardiovascular system Abenezer Aklog

131. Ischemic Heart Disease (IHD) Angina Pectoris – Drug Treatment – Miscellaneous Agents – Trimetazidine Its effect is thought to be due to inhibition of long-chain 3-ketoacyl coenzyme A thiolase , the final enzyme in the FFA β-oxidation pathway. Induce metabolic shift from fatty acid to glycolytic metabolism in the heart Provides less ATP but requires less O 2 and may therefore be beneficial in ischemia . Second choice in the prevention of exertional angina May increase the incidence of Parkinson disease. 131 Cardiovascular system Abenezer Aklog

132. Heart Failure (HF) Pharmacology of Drugs For Heart Failure 132 Cardiovascular system Abenezer Aklog

133. Heart Failure (HF) Important terminologies Stroke volume – the fraction of blood the heart pumps out with each beat Determined by preload , force of contraction & afterload Afterload – the pressure that the heart must overcome to pump blood into the arterial system Dependent on the systemic vascular resistance With increased afterload , the heart muscles must work harder to overcome the constricted vascular bed leading to chamber enlargement 133 Cardiovascular system Abenezer Aklog

134. Heart Failure (HF) Important terminologies Preload – the amount of tension ( stretch) applied to a muscle before contraction Determined by: Venous return to heart and Accompanying stretch of the muscle fibers Increasing preload – Increase stroke volume in normal heart Increasing preload in impaired heart – decreased SV. Blood is trapped (congestion) which leads to chamber enlargement 134 Cardiovascular system Abenezer Aklog

135. Heart Failure (HF) Important terminologies Heart failure – The inability of the heart to pump adequate amounts of blood that meets the metabolic requirements of the body It doesn’t mean that the heart stopped working Characterized by: Impaired ventricular performance (right or left or both) Exercise intolerance Shortened life expectancy 135 Cardiovascular system Abenezer Aklog

136. Heart Failure (HF) Important terminologies Ventricular performance is a function of Preload – It is increased in HF because of increased blood volume and venous tone Reduced by Salt restriction , diuretic s and venodilator ( e.g , nitroglycerin ) Afterload – increase in HF and Corrected by agents that reduces arteriolar tone Contractility – Decrease in HF and corrected by Inotropic agents Heart rate – increases in HF and corrected by bradycardic agents 136 Cardiovascular system Abenezer Aklog

137. Heart Failure (HF) Heart Failure A common clinical syndrome representing the end‐stage of a number of different cardiac diseases – HTN, IHD, Valvuar heart disease. Can result from any disorder that reduces myocardial contractility ( systolic dysfunction ) and/or ventricular filling ( diastolic dysfunction ). Systolic failure – results in reduced ejection fraction ( HFrEF ) Diastolic failure – chxed by Stiffening and loss of adequate relaxation but Ejection fraction may be normal (preserved, HFpEF ) 137 Cardiovascular system Abenezer Aklog

138. Heart Failure (HF) Heart Failure The decrease in the CO results in activation of compensatory responses to maintain an adequate CO - Sympathetic nervous system activation – Tachycardia and incr. contractility RAAS activation - An increase in preload results in an increase in stroke volume Via RAAS and SNS activation Vasoconstriction and Ventricular hypertrophy and remodeling – fibrosis and loss of myocytes The compensatory mechanisms will ultimately lead to a decreased cardiac performance 138 Cardiovascular system Abenezer Aklog

139. Heart Failure (HF) Heart Failure – Treatment Strategies Pharmacotherapy aimed at: ↓ Preload Diuretics, ACEIs, ARBs & Venodilators ↓ Afterload ACEIs, ARBs, & Arteriodilators ↑ Contractility Digoxin, β1 – agonists, PDE3 Inhibitors ↓ Remodeling of cardiac muscle ACEIs, ARBs, Aldosterone receptor antagonists 139 Cardiovascular system Abenezer Aklog

140. Heart Failure (HF) Heart Failure – Drug classification – Based on Goal of therapy To achieve improvement in symptoms Diuretics, ACEIs/ARBs, Digitalis To achieve improvement in survival ACEIs/ARBs, Aldosterone receptor antagonists, β- blockers ( eg . Carvedilol, Metoprolol, Bisoprolol , Nebivolol ), Oral nitrates plus hydralazine The management of HF should be aimed at improving both quality of life & survival 140 Cardiovascular system Abenezer Aklog

141. Heart Failure (HF) Heart Failure – Drug classification – Based on Mechanism of Action Drugs without positive (+) inotropic effects – Neurohormonal Modulation Diuretics, ACEIs, ARBs, Vasodilators, β- blockers Drugs with positive (+) inotropic effect Cardiac glycosides : - Digoxin PDE3 Inhibitors : Inamrinone , Milrinone β- adrenoceptor stimulants : dobutamine , dopamine 141 Cardiovascular system Abenezer Aklog

142. Heart Failure (HF) Heart Failure – Drugs without positive (+) inotropic effects - ACEIs Lower the circulating level of Ang II and thereby reduce its deleterious effects – Vasoconstriction, cardiac remodeling and aldosterone release Not only act as vasodilators [ decreasing afterload ] but also reduce aldosterone levels and thereby act as an indirect diuretics [ dec. preload] Have direct antiremodeling effects on the heart, and produce sympatholytic effects Thus moderating the reflex tachycardia that accompanies vasodilation and the lowering of blood pressure 142 Cardiovascular system Abenezer Aklog

143. Heart Failure (HF) Heart Failure – Drugs without positive (+) inotropic effects - ACEIs Because patients with HF often have low renal perfusion pressures , aggressive treatment with ACEIs may induce acute renal failure . Should be initiated at very low doses Dose slowly increased over weeks toward target levels BP, blood creatinine, and K + levels should be monitored. The potentially dangerous acute effects become beneficial with long-term use of ACEIs because the (small) chronic lowering of glomerular pressures protects the glomerulus from fibrotic degeneration . 143 Cardiovascular system Abenezer Aklog

144. Heart Failure (HF) Heart Failure – Drugs without positive (+) inotropic effects – ARBs Are used in patients with systolic HF who are ACEI intolerant Second choice in all stages of heart failure An ACEI intolerance primarily related to persistent dry cough is the most common indication The unopposed activity of AT2 receptor pathways in the presence of AT1 blockade by an ARB seems to confer no therapeutic advantage to ARBs over ACEIs. 144 Cardiovascular system Abenezer Aklog

145. Heart Failure (HF) Heart Failure – Drugs without positive (+) inotropic effects – BBs Competitively reduce β receptor–mediated actions of catecholamines and thus, depending on the activation level of the SNS. Reduce HR and force of contraction , slow relaxation , slow AV conduction , suppress arrhythmias , lower renin levels Protect the heart from the adverse long-term consequences of adrenergic overstimulation, E.g., Increased energy consumption , fibrosis , arrhythmias , and cell death . 145 Cardiovascular system Abenezer Aklog

146. Heart Failure (HF) Heart Failure – Drugs without positive (+) inotropic effects – BBs Have been shown to be effective in reducing the risk of death in patients with chronic (stable) systolic HF . Bisoprolol , Metoprolol, Carvedilol, and Nebivilol All patients with symptomatic heart failure and all patients with left ventricular dysfunction after MI should be treated with a β blocker They should not be administered in new-onset or acutely decompensated heart failure . 146 Cardiovascular system Abenezer Aklog

147. Heart Failure (HF) Heart Failure – Drugs without positive (+) inotropic effects – Diuretics Reduce venous pressure & ventricular preload by reducing blood volume Reduce salt & water retention & edema & its symptoms The reduction of cardiac size, which leads to improved pump efficiency, is of major importance in systolic failure Should be introduced at a low dose and the dose increased according to the clinical response 147 Cardiovascular system Abenezer Aklog

148. Heart Failure (HF) Heart Failure – Drugs without positive (+) inotropic effects – Diuretics Thiazide and Loop Diuretics Decreased kidney perfusion and activation of the RAAS in HF leads to fluid overload and increase in ventricular filling pressure – increase Preload Such fluid overload may result in edema to develop in the lungs and periphery When fluid retention is mild , thiazide & thiazide like diuretics may be used More severe HF should be treated with one of the loop diuretics Have a rapid onset & a relatively short duration of action 148 Cardiovascular system Abenezer Aklog

149. Heart Failure (HF) Heart Failure – Drugs without positive (+) inotropic effects – Diuretics Thiazide and Loop Diuretics With diuretic therapy, Na + loss may cause secondary K + loss Hypokalemia can exacerbate underlying cardiac arrhythmias & contribute to digitalis toxicity Hypokalemia can usually be avoided by reducing Na +  intake , thus ↓ ing Na +  delivery to the K + - secreting collecting tubule Pts who are noncompliant with a low Na +  diet must take: Oral KCl supplements , or addition of a K + -sparing diuretics , or an ACEI 149 Cardiovascular system Abenezer Aklog

150. Heart Failure (HF) Heart Failure – Drugs without positive (+) inotropic effects – Diuretics Mineralocorticoid (Aldosterone) Receptor Antagonists (MRAs) Have a documented life-prolonging effect in patients with HF Likely via blocking aldosterone‐mediated inflammation and CV remodeling , both spironolactone and Eplerenone exert beneficial effects in systolic HF . These agents should be added for all patients with HFrEF w ho are already on ACEI or BB Lower doses have to be used in heart failure 150 Cardiovascular system Abenezer Aklog

151. Heart Failure (HF) Heart Failure – Drugs without positive (+) inotropic effects – Vasodilators The failing heart is highly sensitive to increased arterial resistance (i.e., increased afterload, decreases CO ) Therefore, vasodilators are effective in acute HF b/c they provide reduction in Preload (through venodilation ), or afterload (through arteriolar dilation), or both Venodilators : Organic nitrates Arteriolar dilators : Hydralazine Combined arteriolar & venodilators : Nitroprusside , Nesiritide 151 Cardiovascular system Abenezer Aklog

152. Heart Failure (HF) Heart Failure – Drugs without positive (+) inotropic effects – Vasodilators The choice of the agent should be based on the patients Signs & symptoms Hemodynamic measurements In pts with High filling pressure in whom the principal symptom is dyspnea → ??? In pts in whom fatigue due to low ventricular out put is the principal symptom → ??? In most pts with severe chronic failure that responds poorly to other therapy, the problem usually involves both elevated filling pressures & reduced CO → ??? 152 Cardiovascular system Abenezer Aklog

153. Heart Failure (HF) Heart Failure – Vasodilators – Hydralazine and Nitrates (ISDN) Hydralazine is a direct-acting smooth muscle relaxant with strong antioxidative properties Given simultaneously with nitrate , effectively prevents the development of oxidative stress and nitrate tolerance - reducing ROS-mediated inactivation of NO Combination has beneficial effects on left ventricular function and survival in patients with severe heart failure The combination of hydralazine & nitrates is an alternative regimen i n pts with severe renal impairment , in whom ACEIs & ARBs are C/I 153 Cardiovascular system Abenezer Aklog

154. Heart Failure (HF) Heart Failure – Vasodilators – Nesiritide Manufactured using recombinant techniques Identical to the endogenous B-type natriuretic peptide (BNP) secreted by the ventricular myocardium in response to volume overload/stretch Mimics the vasodilatory & natriuretic actions of the endogenous peptide Resulting in venous & arterial dilation ; - Increases CO; Natriuresis & diuresis & ↓ ed cardiac filling pressures, SNS activity, & RAAS activity Approved for use in acute decompensated HF 154 Cardiovascular system Abenezer Aklog

155. Heart Failure (HF) Heart Failure – Drugs with positive (+) inotropic effects Agents that increase intracellular Ca 2+ level by different mechanisms By interfering with the Na + /K + ATPase Pump Cardiac Glycosides – Digitalis By increasing the generation of cAMP Dobutamine and Dopamine By decreasing degradation of cAMP PDE3 Inhibitors - Milrinone and Inamrinone 155 Cardiovascular system Abenezer Aklog

156. Heart Failure (HF) Heart Failure – Drugs with positive (+) inotropic effects – Digoxin Affect the heart by two different mechanisms Direct Mechanism – competitive inhibition of Na + /K + -ATPase, thereby Inhibits Na + efflux – increasing intracellular Na + concentration Decreases Ca 2+ efflux through Na + /Ca 2+ Exchanger – Increases intracellular Ca 2 + Overall effect is increased contractile force of the heart – Positive Inotropic effect In HF, sympathetic tone is ↑ ed as a compensatory mechanism to decreased CO Digoxin increases contractility & hence SV & CO , therefore reducing the need for sympathetic compensation; thus digoxin reduces the sympathetic tone in HF 156 Cardiovascular system Abenezer Aklog

157. Heart Failure (HF) Heart Failure – Drugs with positive (+) inotropic effects – Digoxin Affect the heart by two different mechanisms Indirect Mechanism – increased parasympathetic nervous system activity Digoxin sensitizes arterial baroreceptors in the carotid sinus & activates the vagal nuclei (in the brainstem ) HR decreases owing to increased PsNS tone of the SA node AV node activity also is reduced , thereby decreasing impulse conduction This is useful in treating patients with atrial fibrillation 157 Cardiovascular system Abenezer Aklog

158. Heart Failure (HF) Heart Failure – Drugs with positive (+) inotropic effects – Digoxin – PK Well absorbed (65–80% BA)from oral route Intestinal microflora may metabolize digoxin, markedly reducing BA Broad spectrum antibiotics may destroy the flora and increase BA & toxicity Has large Vd including the CNS (low plasma but high tissue binding) Mainly (~80%) excreted unchanged by the kidney with t 1/2 of 36hrs Dose adjustment is required in pts with renal failure Target plasma conce is – 0 .5–0.8ng/ml ( narrow therapeutic index ) 158 Cardiovascular system Abenezer Aklog

159. Heart Failure (HF) Heart Failure – Drugs with positive (+) inotropic effects – Digoxin – Uses Digoxin does not improve survival in pts with HF but does provide symptomatic benefits – started only when diuretics and ACEIs fail Digoxin is indicated in pts with HF & Atrial fibrillation Continued symptoms of HF despite optimal doses of diuretics & ACEIs Methods of dosing (digitalization) Slow loading dose : 0.125-0.25 mg/day Rapid method : 0.5-0.75 mg for 3 doses, followed by 0.125-0.25 mg/day 159 Cardiovascular system Abenezer Aklog

160. Heart Failure (HF) Heart Failure – Drugs with positive (+) inotropic effects – Digoxin – ADRs The toxicity of digitalis may be precipitated by several factors such as electrolyte imbalance due to diseases or drugs Electrolyte Imbalance - toxicity is high with hypo K + , & Mg 2+ and hyper Ca 2+ K + & digoxin interact by inhibiting each other's binding to Na + /K + ATPase Ca 2+ facilitates the toxic actions of digoxin by accelerating the overloading of intracellular Ca 2+ stores whereas Mg 2+ antagonizes this effect Diseases that increase intracellular calcium level lead to toxicity Ischemia, Hyperthyroidism, Myocarditis 160 Cardiovascular system Abenezer Aklog

161. Heart Failure (HF) Heart Failure – Drugs with positive (+) inotropic effects – Digoxin – ADRs Toxicities can be divided as cardiac & extra-cardiac manifestations Cardiac Manifestations – causes nearly every rhythm disturbance SA (sinus bradycardia) & AV inhibition (nodal bradycardia) AV block – PR interval prolongation Atrial & ventricular tachycardia through its direct effect on intracellular cations Shorten QT interval due to Ca 2+ loading in the ventricle 161 Cardiovascular system Abenezer Aklog

162. Heart Failure (HF) Heart Failure – Drugs with positive (+) inotropic effects – Digoxin – ADRs Toxicities divided into cardiac & extra-cardiac manifestations Extra-Cardiac Manifestations GIT – anorexia, nausea, vomiting, diarrhea Stimulation of the CTZ in the CNS and Direct irritant effect , CNS – mainly vagal & CTZ stimulation Disorientation, hallucination, visual disturbances (blurred or yellow vision ), restlessness etc Others – Gynecomastia (peripheral estrogenic effect ) and Hyperkalemia 162 Cardiovascular system Abenezer Aklog

163. Heart Failure (HF) Heart Failure – Drugs with positive (+) inotropic effects – Digoxin – ADRs Management of Digoxin toxicity Lidocaine and K + infusion (40–60 mmol /d) For tachycardic ventricular arrhythmias and hypokalemia Atropine (0.5–1 mg) IV For extreme sinus bradycardia, sinoatrial block, or AV block grade II or III Antidigoxin Fab fragments ( Digibind , Digifab ) Highly effective in binding digoxin and digitoxin and greatly enhance their renal excretion 163 Cardiovascular system Abenezer Aklog

164. Heart Failure (HF) Heart Failure – Drugs with positive (+) inotropic effects – Digoxin – DDIs Digoxin is a substrate of P- gp , and inhibitors of p- gp may lead to toxicity Clarithromycin , verapamil, quinidine, and amiodarone inhibit P- gp Caution with other drugs that slow AV conduction , β- blockers, verapamil, and diltiazem. Diuretics , amphotericin B, and corticosteroids – precipitate hypokalemia and will potentiate digitalis-induced arrhythmias. 164 Cardiovascular system Abenezer Aklog

165. Heart Failure (HF) Heart Failure – Drugs with positive (+) inotropic effects – Bipyridines Bipyridines are PDE 3 Inhibitors – Include Inamrinone and milrinone Inhibition of PDE-3 results in an increase in IC cAMP , which leads to positive inotropy & vasodilation – “ Inodilators ” ↑ Contractility by ↑Ca flux in the cardiac myocytes during the AP May also alter the IC movements of Ca by influencing the SR Have an important arterio & veno -dilating effects ADRs – hypotension, arrhythmias, thrombocytopenia , and liver toxicity Toxicity is higher with Inamrinone 165 Cardiovascular system Abenezer Aklog

166. Heart Failure (HF) Heart Failure – Drugs with positive (+) inotropic effects – Dobutamine Racemic mixture with β 1, β 2 , and variable α 1 agonist effect It may benefit some pts with chronic HF ( acute decompensated HF ) It is a positive inotropic agent Increases IC cAMP levels , which leads to an increase in CO & a decrease in ventricular filling pressure It may cause tachycardia & may ↑myocardial O 2 consumption As a result , it has potential to produce angina or arrhythmias in pts with CAD 166 Cardiovascular system Abenezer Aklog

167. Heart Failure (HF) Heart Failure – Drugs with positive (+) inotropic effects – Dopamine Has a conce . Dependent effect on the CVS [ D 1 - ≤2 μ g/kg / min; β - 2–5 μ g/kg/min; α - 5–15 μ g/kg/min]; HF&shock Its pharmacologic actions may be preferable to dobutamine or milrinone in pts with Marked systemic hypotension or Cardiogenic shock in the face of elevated ventricular filling pressures 167 Cardiovascular system Abenezer Aklog

168. Arrhythmias Pharmacology of Drugs For arrhythmias 168 Cardiovascular system Abenezer Aklog

169. Arrhythmias Cardiac Electrophysiology The heart functions via both electrical and mechanical activity Electrical Activity – Impulse (Action Potential) generation and conduction Mechanical – atrial and ventricular contraction Mechanical activity of the heart occurs as a result of the electrical activity of the heart Electrical depolarization of the atria results in atrial contraction , and ventricular depolarization is followed by ventricular contraction Malfunction of the heart’s electrical conduction system may result in dysfunctional atrial and/or ventricular contraction – decrease ventricular pumping 169 Cardiovascular system Abenezer Aklog

170. Arrhythmias Cardiac Electrophysiology – Cardiac Conduction Pathways Origin of electrical activity is in the SA node which generates 60-100 impulses/min Serves as pacemaker b/c it discharges faster than other cells After the SA node discharges, impulses spread rapidly through the atria along the internodal pathways – then the atria contracts in unison Impulses originating in the atria must travel through the AV node to reach the ventricles – here impulse conduction is slowed Impulses leave the AV node to reach the His-Purkinje system which then depolarizes the ventricles and produce ventricular contraction 170 Cardiovascular system Abenezer Aklog

171. Arrhythmias Cardiac Electrophysiology – Cardiac Action Potentials Cardiac APs are generated by the movement of ions into and out of cells Ion transport is regulated by voltage gated channels ( NaC , KC, CaC ) Na Channels – Voltage gated fast Na current ( I Na ) exist in 3 conformations Resting state , activated/open state & inactivated/refractory state The channels has 2 gates m ( activation) & h ( inactivation) Both of w/c are sensitive to voltage changes 171 Cardiovascular system Abenezer Aklog

172. Arrhythmias Cardiac Electrophysiology – Cardiac Action Potentials In the heart, two kinds of action potentials occur; fast and slow APs They differ in Mechanism by which they are generated Fast APs – Use Na + currents Slow APs – Use Ca 2+ currents Kinds of cells in which they occur Fast APs – Occur in atria and ventricle muscles and His- P urkinje system Slow APs – Occur in SA and AV node 172 Cardiovascular system Abenezer Aklog

173. Arrhythmias Cardiac Electrophysiology – Cardiac Action Potentials – Fast APs In the heart, two kinds of action potentials occur; fast and slow APs They differ in Mechanism by which they are generated Fast APs – Use Na + currents Slow APs – Use Ca 2+ currents Kinds of cells in which they occur Fast APs – Occur in atria, ventricle and His- purkinje fibers Slow APs – Occur in SA and AV node 173 Cardiovascular system Abenezer Aklog

174. Arrhythmias Cardiac Electrophysiology – Cardiac Action Potentials – Slow APs In the heart, two kinds of action potentials occur; fast and slow APs They differ in Mechanism by which they are generated Fast APs – Use Na + currents Slow APs – Use Ca 2+ currents Kinds of cells in which they occur Fast APs – Occur in atria, ventricle and His- purkinje fibers Slow APs – Occur in SA and AV node 174 Cardiovascular system Abenezer Aklog

175. Arrhythmias Cardiac Electrophysiology – Cardiac Action Potentials – Slow Aps - SAN Nodal tissue, especially that of the SA node , is heavily innervated by both PsNS and SNS fibers activating M 2 and β 1 R, respectively. Phase 4 slope is acc. by ↑ cAMP resulting from β 1 R activation and slowed by ↓ cAMP resulting from M 2 R activation ↑ cAMP – ↑ upstroke velocity in pacemakers by ↑ Ca 2+ current and shorten AP duration by ↑ K + current and also ↑ HR by ↑ I f ↓ cAMP – activate K + current thereby slowing depolarization and thus ↓ HR 175 Cardiovascular system Abenezer Aklog

176. Arrhythmias Cardiac Electrophysiology – Cardiac Action Potentials – Summary In the heart, two kinds of action potentials occur; fast and slow APs They differ in Mechanism by which they are generated Fast APs – Use Na + currents Slow APs – Use Ca 2+ currents Kinds of cells in which they occur Fast APs – Occur in atria, ventricle and His- purkinje fibers Slow APs – Occur in SA and AV node 176 Cardiovascular system Abenezer Aklog

177. Arrhythmias Cardiac Electrophysiology – Cardiac APs– Refractory Periods After an electrical impulse is initiated and conducted , there is a period of time during which cells and fibers cannot be depolarized again This period of time is referred to as the Effective refractory period ( ERP ) and corresponds to phase 1, 2, and half of phase 3 of the AP There is a period of time following the E RP during which a premature electrical stimulus can be conducted , and is often conducted abnormally This period of time is called the relative refractory period ( RRP ) and corresponds to the final half of phase 3 177 Cardiovascular system Abenezer Aklog

178. Arrhythmias Abnormal Cardiac Electrophysiology – Arrhythmias Are abnormalities in the rate and/or rhythm of the heartbeat Caused by alteration of the electrical impulses that regulate cardiac rhythm They are broadly classified as Tachyarrhythmia – abnormality associated with increased HR Supraventricular and Ventricular tachyarrhythmia Bradyarrhythmia – abnormality associated with slowed HR SA nodal dysfunction and AV block 178 Cardiovascular system Abenezer Aklog

179. Arrhythmias Arrhythmias – Mechanisms In general, cardiac arrhythmias are caused by Abnormal impulse formation ; Altered Automaticity Triggered Activity Abnormal impulse conduction ; or Reentry V s Conduction block Both 179 Cardiovascular system Abenezer Aklog

180. Arrhythmias Arrhythmias – Abnormal impulse formation – Altered Automaticity May occur in cells that normally display spontaneous diastolic depolarization — the SA and AV nodes and the His-Purkinje system Latent pacemaker fibers begin to spontaneously & abnormally initiate an impulse – resulting in enhanced automaticity – accelerated generation of AP - ↑ HR Occurs as a consequence of a variety of pathophysiologic states: ↑ ed endogenous or exogenous catecholamines Electrolyte disturbances e.g. hypokalemia Hypoxia or ischemia Mechanical effects e.g. stretch & Drugs [e.g . digitalis] 180 Cardiovascular system Abenezer Aklog

181. Arrhythmias Arrhythmias – Abnormal impulse formation – Triggered Activity Under some pathophysiologic conditions, a normal cardiac AP may be interrupted or followed by an abnormal depolarization Occur only after an initial normal , or “ triggering ,” AP and so are termed triggered rhythms Or after depolarizations After depolarizations ( ADs ) may interrupt During Phase 3 Repolarization – Early After Depolarization (EAD) After complete Phase 3 Repolarization – Delayed After Depolarization (DAD) 181 Cardiovascular system Abenezer Aklog

182. Arrhythmias Arrhythmias – Abnormal impulse formation – Triggered Activity – EAD A fundamental condition that underlies the development of EADs is AP and QT prolongation ( prolonged repolarization ) – due to dysfunction of K + Ch If repolarization time is prolonged , then Na + channels are recovered from inactive to resting state  leading to EAD EADs are usually exacerbated at slow HR and are thought to contribute to the development of long QT-related arrhythmias – “torsade de pointes” Causes – HypoK + , HypoMg 2+ , Bradycardia, drugs (class IA, III) 182 Cardiovascular system Abenezer Aklog

183. Arrhythmias Arrhythmias – Abnormal impulse formation – Triggered Activity – DAD Occurs following completion of phase 3 of the AP Occurs mainly when cells are loaded with extra cations ( Ca 2+ , Na + ) Excess cations allow the cell to reach threshold potential which generate full AP A normal AP may be followed by a DAD – Under conditions of Myocardial ischemia , adrenergic stress, digitalis intoxication , and HF They are exacerbated by fast HR 183 Cardiovascular system Abenezer Aklog

184. Arrhythmias Arrhythmias – Abnormal impulse conduction – AV Block When AV is blocked by drugs (Adenosine, BBs , CCBs, Digitalis) When AV is totally blocked , new pacemaker from purkinje : ventricular rate is slowed than normal ( QRS complex widening ) 1 st degree heart block – impulse transmission via AV node is delayed 2 nd degree heart block – some impulses failed to be transmitted via the AV node 3 rd degree heart block – complete inhibition of impulse transmission via AV node 184 Cardiovascular system Abenezer Aklog

185. Arrhythmias Arrhythmias – Abnormal impulse conduction – “Re-Entry” It is defined as circulation of an activation wave around an inexcitable obstacle – “ Circus Movement ” In order for reentry to occur, three conditions must be present. There must be At least two pathways down which an electrical impulse may travel (which is the case in the majority of cardiac fibers); A “ unidirectional block ” in one of the conduction pathways (this “unidirectional block” is sometimes a result of prolonged refractoriness in this pathway); and Slowing of the velocity of impulse conduction down the other conduction pathway 185 Cardiovascular system Abenezer Aklog

186. Fast Conduction Path Slow Recovery Slow Conduction Path Fast Recovery Premature Beat Impulse Cardiac Conduction Tissue An arrhythmia is triggered by a premature beat The beat cannot gain entry into the fast conducting pathway because of its long refractory period and therefore travels down the slow conducting pathway only Repolarizing Tissue (long refractory period) The “Re-Entry” 186

187. The wave of excitation from the premature beat arrives at the distal end of the fast conducting pathway, which has now recovered and therefore travels retrogradely (backwards) up the fast pathway Fast Conduction Path Slow Recovery Slow Conduction Path Fast Recovery Cardiac Conduction Tissue The “Re-Entry” 187

188. On arriving at the top of the fast pathway it finds the slow pathway has recovered and therefore the wave of excitation ‘re-enters’ the pathway and continues in a ‘circular’ movement. This creates the re-entry circuit Fast Conduction Path Slow Recovery Slow Conduction Path Fast Recovery Cardiac Conduction Tissue The “Re-Entry” 188

189. Arrhythmias Arrhythmias – Treatment Strategies Drugs for altered/enhanced spontaneous automaticity Decrease phase 4 slope ( NaCB , CCB, BB) Increase threshold potential ( NaCB [ nonpacemaker ] or CCB [ pacemaker cells]) Increase maximum diastolic potential (↓RMP ) & decrease slope ( vagus & adenosine) Increase action potential duration(KCB): prolonged repolarization & total number of AP decreased. 189 Cardiovascular system Abenezer Aklog

190. Arrhythmias Arrhythmias – Treatment Strategies Drugs for triggered automaticity Early after depolarization (EAD) Reduce duration of action potential by ↑ HR (hence, repolarization is completed before Na + channels are activated) Isoproterenol , MgSO 4 & pacing of heart Delayed after depolarization (DAD) – reduce IC Ca 2+ loading CCBs - ↓Ca 2+ over load NaCB - ↑ TP 190 Cardiovascular system Abenezer Aklog

191. Arrhythmias Arrhythmias – Treatment Strategies Drugs for abnormal impulse conduction Second-or third-degree AV nodal blockade requires treatment, because bradycardia usually results in symptoms Atropine or Epinephrine For reentrant tachy arrhythmia due to ischemia or fibrosis Increase effective refractory period by NaCB or KCB (fast response tissue) & CCB ( slow response tissue) 191 Cardiovascular system Abenezer Aklog

192. Arrhythmias Antiarrhythmic drugs – Classification Antiarrhythmic drugs are classified in to four classes based on their MOA on cardiac electrophysiology – “ Vaughan William's classification ” Class I Agents – block sodium channels ( NaCBs ) Based on potency to block NaC and effect on repolarization Class IA – Quinidine, Procainamide, Disopyramide Class IB – Lidocaine , Mexiletine , Phenytoin, Tocainide Class IC – Flecainide, Propafenone 192 Cardiovascular system Abenezer Aklog

193. Arrhythmias Antiarrhythmic drugs – Classification - Vaughan William's classification Class II Agents – Antisympathetic agents ( β -blockers ) Propranolol, Acebutolol , Esmolol , Metoprolol Class III Agents : K + channel blockers (KCBs) Am iod arone, Dronedarone , Ibutilide , Dofetilide , Sotalol , Bretylium Class IV Agents : Selective Slow ( L-type ) Ca 2+ channel blockers (CCBs) Verapamil and Diltiazem Miscellaneous Agents : Actions do not fit to any of the above classes Digoxin and Adenosine 193 Cardiovascular system Abenezer Aklog

194. Arrhythmias Antiarrhythmic drugs – Class I Agents Show a greater degree of blockade in tissues that are frequently depolarizing/ firing rapidly – this property is called “ Use or State dependence effect ” Preferentially bind to NaC when they are at active (open ) and/or inactive states Dissociation occurs when the channels are at rest Use has declined due to their proarrhythmic effects , particularly in patients with reduced LVF and CAD . 194 Cardiovascular system Abenezer Aklog Subclass NaC blockage Binding and dissociation from sodium channels Affinity for sodium channels IA Moderate Intermediate in terms of the rapidity of binding and dissociation High affinity for open state IB Weak Have the most rapid binding and dissociation from the receptor High affinity for both open and inactivated states IC Strong Have the slowest binding and dissociation from the receptor High affinity for Open state

195. Arrhythmias Antiarrhythmic drugs – Class IA – Quinidine Lower dose – has anticholinergic effect and blocks vagal input to the heart Increases HR and AV conduction  Ventricular tachycardia Also blocks α -adrenergic receptors  Vasodilation Therapeutic doses - Depress pacemaker rate ( automaticity ) and slow conduction and excitability , and prolong QT interval (delays repolarization) Uses – prevent reentrant arrhythmias and arrhythmias due to increased automaticity – AFL, AFib , PSVT, and VFib 195 Cardiovascular system Abenezer Aklog

196. Arrhythmias Antiarrhythmic drugs – Class IA – Quinidine – PK (ADME) and ADRs Well absorbed (70% BA), high plasma protein binding 80% metabolized by CYP3A4 , 20% excreted unchanged Inhibits CYP2D6 and P- gp transporter ADRs – Cinchonism (tinnitus , flushing, blurred vision, dizziness), Hypotension Widen QRS complex and Marked QT prolongation  Torsade de pointes ( Tdp ) D DI – inc absorption and displace digoxin from plasma protein binding 196 Cardiovascular system Abenezer Aklog

197. Arrhythmias Antiarrhythmic drugs – Class IA – Procainamide Exerts similar electrophysiological effects with quinidine but lacks vagolytic and α adrenergic blocking activity Metabolized via N- actyltransferase (genotype variation) to N-acetyl Procainamide (NAPA) →active metabolite NAPA has little Na + blocking activity , while retaining K + blocking activity Parent drug slows conduction whereas active metabolite prolongs QT interval Use – for supraventricular as well as ventricular tachycardia 197 Cardiovascular system Abenezer Aklog

198. Arrhythmias Antiarrhythmic drugs – Class IA – Procainamide - ADRs Systemic Lupus erythematosus (SLE) like syndrome – autoimmune antibodies to NAPA accumulate with long term therapy esp in slow acetylators Blood Dyscriasis – thrombocytopenia, neutropenia, agranulocytosis Cardiac toxicity – QT prolongation and Torsade de pointes Ganglionic blockade may lead to hypotension 198 Cardiovascular system Abenezer Aklog

199. Arrhythmias Antiarrhythmic drugs – Class IA – Disopyramide Has greater anti cholinergic activity with no alpha effect A drug that slows AV conduction should be administered with disopyramide Produces a negative inotropic effect  precipitate heart failure ADRs – Anticholinergic ( dry eyes/mouth, urinary retention, constipation) Prolong QT intervals ( Torsade de pointes ) Depression of contractility can precipitate or worsen heart failure; 199 Cardiovascular system Abenezer Aklog

200. Arrhythmias Antiarrhythmic drugs – Class IB Have greater affinity for both open and inactivated states of Na channels Inhibit the inward Na current , thus reducing the rate of rise of the AP ( phase ). Dissociate from the Na channel more rapidly than other Class I drugs Shorten APD and slightly prolong ERP thereby blocking propagation of premature impulses  Inhibiting reentry Particularly effective in blocking rapidly firing tissues, such as ischemic tissue Where there is a higher likelihood of NaC being in the open or inactivated state 200 Cardiovascular system Abenezer Aklog

201. Arrhythmias Antiarrhythmic drugs – Class IB – Lidocaine Highly selective for damaged tissues (Ischemic tissues) Agent of choice for termination of VT & digoxin toxicity (DAD) Not useful in atrial arrhythmias, possibly because Atrial APs are so short that the NaC is in the inactivated state only briefly compared with diastolic (recovery) times , which are relatively long . PK – not given orally b/c of first pass metabolism and thus given by IV Dose adjustment in hepatic disease and heart failure 201 Cardiovascular system Abenezer Aklog

202. Arrhythmias Antiarrhythmic drugs – Class IB – Lidocaine - ADRs CNS toxicity – Seizures at large IV dose and altered consciousness Least cardiotoxic – doesn’t affect PR, QRS complex, and QT interval Antiarrhythmic drugs – Class IB – Mexiletin An analogue of lidocaine that has been modified to reduce first-pass hepatic metabolism and permit chronic oral therapy . Similar electrophysiological actions with lidocaine. Approved for ventricular arrhythmia (associated with previous MI) 202 Cardiovascular system Abenezer Aklog

203. Arrhythmias Antiarrhythmic drugs – Class IC – Flecainide, Propafenone Potent blocker of fast Na channels esp in His-Purkinje fibers Detach very slowly from their binding to the channels during diastole Markedly slows Phase 0 depolarization ( slowed conduction ) in atrial and ventricular muscle fibers  widen QRS complex on ECG Minimal effect on APD & ERP of ventricular myocardial cells Flecainide - Risk of severe proarrhythmia in patients with structural heart disease Propafenone – has β adrenergic receptor antagonist effect 203 Cardiovascular system Abenezer Aklog

204. Arrhythmias Antiarrhythmic drugs – Class II Agents – β -Blockers Prevents β-receptor activation, which would normally ↑ cAMP ↓ SA automaticity & AV nodal activity (Prolong PR), and ↑AV refractoriness ↓ slope of phase 4 of AP in pacemakers Uses : for a variety of arrhythmias, including AF Tachyarrhythmias caused by sympathetic excess Prophylaxis post-MI and in SVT Ventricular arrhythmias following MI Esmolol (IV) is used in acute SVTs 204 Cardiovascular system Abenezer Aklog

205. Arrhythmias Antiarrhythmic drugs – Class III Agents – KCBs – Amiodarone A structural analogue of thyroid hormone with Class III antiarrhythmic effects It also mimics effects of classes I, II, & IV Cardiac effects include Delays repolarization , and thereby prolongs the APD and ERP Reduced automaticity in the SA node , Reduced contractility , and reduced conduction velocity in the AV node , ventricles , and His-Purkinje system 205 Cardiovascular system Abenezer Aklog

206. Arrhythmias Antiarrhythmic drugs – Class III Agents – KCBs – Amiodarone – PK Has poor oral BA (~30 %) presumably due to poor absorption Highly lipophilic and binds extensively to tissues (thus has large Vd ) Metabolized by CYP3A4 to desethyl -amiodarone (an active metabolite) Has long t 1/2 >80 days ; which increases the risk of toxicity The antiarrhythmic effects may last for weeks or months after the drug is discontinued . 206 Cardiovascular system Abenezer Aklog

207. Arrhythmias Antiarrhythmic drugs – Class III Agents – KCBs – Amiodarone – Uses Has broad spectrum of activity Because of toxicity, it is approved only for life-threatening ventricular dysrhythmias that have been refractory to safer agents Recurrent ventricular fibrillation and Recurrent hemodynamically unstable ventricular tachycardia But also is most effective drug for atrial fibrillation Convert atrial fibrillation to normal sinus rhythm and maintain normal sinus rhythm 207 Cardiovascular system Abenezer Aklog

208. Arrhythmias Antiarrhythmic drugs – Class III Agents – KCBs – Amiodarone – ADR Pulmonary Toxicity – Lung damage—hypersensitivity pneumonitis , interstitial/alveolar pneumonitis, pulmonary fibrosis ( monitor pulmonary fun ) Cardiac toxicity – - ve ino , dromo , and chronotropic effect, and risk of heart block Thyroid Toxicity – may cause hypothyroidism or hyperthyroidism (assess baseline and monitor thyroid function (TSH , T3, T4) Liver Toxicity – can injure the liver (baseline and monitor AST, ALT, ALP) Other ADRs – GI (A/N/V), photosensitivity, blue-gray skin discoloration, optic neuropathy, Corneal microdeposite , CNS (ataxia, dizziness, tremor) Not recommended during pregnancy and breast feeding 208 Cardiovascular system Abenezer Aklog

209. Arrhythmias Antiarrhythmic drugs – Class III Agents – KCBs – Dronedarone Analogue of amiodarone with low toxicity profile but also with lower efficacy Possess similar mechanisms of actions of amiodarone Does not contain the iodine moiety (lacks thyroid effects) Indicated for oral therapy of atrial flutter and paroxysmal or persistent atrial fibrillation ADRs – common are diarrhea, weakness, nausea, and photosensitivity Hepatotoxicity and increase risk of mortality in pts with severe HF 209 Cardiovascular system Abenezer Aklog

210. Arrhythmias Antiarrhythmic drugs – Class III Agents – KCBs – Sotalol Has β AR blocking activity besides its class III antiarrhythmic effect No significant role on conduction velocity in fast response tissues ( No Na + effect ) PK – well absorbed and excreted unchanged in urine ( t 1/2 – 12hrs ) Adjust dose in pts with renal insufficiency Uses – approved in patients with VT, PSVT, and AF. ADRs – cause EAD & torsade de pointes (major toxicity with sotalol overdose) especially when the serum K + concentration is low 210 Cardiovascular system Abenezer Aklog PSVT – Paroxysmal supraventricular tachycardia

211. Arrhythmias Antiarrhythmic drugs – Class IV Agents – CCBs – Verapamil & Diltiazem Block both activated and inactivated L-type Ca 2+ channels Decrease phase 0 & phase 4; ↓ SA & AV nodal activity and ↑ refractoriness More effective against atrial than against v entricular arrhythmias Useful in treating reentrant SVT and in reducing the ventricular rate in atrial flutter and fibrillation . Usually not indicated for VT – hypotension and VF can occur Only rarely converts AF to sinus rhythm 211 Cardiovascular system Abenezer Aklog

212. Arrhythmias Antiarrhythmic drugs – Miscellaneous Agents – Adenosine Activates adenosine receptors → G i -coupled -↓ cAMP → ↑ I KAch & ↓ I Ca Shorten APD but prolong hyperpolarization & refractoriness in SA and AV node PK – Very Short t 1/2 (<10 sec ): rapid uptake by erythrocytes and endothelial cells (then deactivated by adenosine deaminase ) – admin rapidly by IV route Uses – DOC for paroxysmal SVT & AV nodal arrythimias ADRs – minimal ( short t 1/2 ) but flushing , hypotension, chest pain, & dyspnea DDIs – theophylline (antagonist at A R), Dipyridamole (inhibit its uptake) 212 Cardiovascular system Abenezer Aklog

213. Arrhythmias Antiarrhythmic drugs – Miscellaneous Agents – Digoxin Exert prominent vagotonic actions at AV node Used to control ventricular response rate in AF and flutter. At toxic concentrations, digoxin causes ectopic ventricular beats that may result in VT and fibrillation (DAD related). Serum trough conce of 1.0 to 2.0 ng/mL are desirable for AF or flutter , Whereas lower conce of 0.5 to 0.8 ng/mL are targeted for systolic heart failure . 213 Cardiovascular system Abenezer Aklog

214. Arrhythmias Antiarrhythmic drugs – Miscellaneous Agents – Magnesium Sulfate Mg 2 + is necessary for the transport of Na + , Ca 2+ , and K + across cell membranes. It slows the rate of SA node impulse formation and prolongs conduction time along the myocardial tissue . Only IV but not oral MgSO 4 is known to have antiarrhythmic effect Is the drug of choice for treating the potentially fatal polymorphic ventricular arrhythmia, torsade de pointes, and digoxin-induced arrhythmias . 214 Cardiovascular system Abenezer Aklog