Pharmacology-II Chapter 8 PDF

Pharmacology-II Course code PMS-616 By Dr. Junaid Athar Khattak Drugs acting on Cardiovascular system (Anti-Hypertensive Drugs) 4th Semester, Chapter 8 Institute of paramedical sciences, Khyber Medical University Peshawar...

Pharmacology-II Course code PMS-616 By Dr. Junaid Athar Khattak Drugs acting on Cardiovascular system (Anti-Hypertensive Drugs) 4th Semester, Chapter 8 Institute of paramedical sciences, Khyber Medical University Peshawar 1  Major diseases Hypertension Coronary heart disease Diseases of Congestive heart failure/Heart cardiovascular failure system Angina Heart Attack Cardiac Arrythmias 2  o Following are the major classes of drugs that will affect cardiovascular system: Drugs for heart failure Antianginal drugs Anti Hyperlipidemic drugs Drugs acting on Blood drugs (Anticoagulants) Cardiovascular Anti‐hypertensive drugs system Diuretics o The above all drugs are included in our syllabus, and we will study each of these drugs in detail 3  Anti-hypertensive drugs What is blood pressure? Blood pressure is the force exerted by blood against the walls blood vessels. Factors that determine the blood pressure: 1- Cardiac output (CO): Cardiac output is the volume of blood the heart pumps per minute 2- Total peripheral resistance (PR). 3- Elasticity of the aorta and large arteries. 4- Blood volume and circulatory capacity. BP = CO X PR 4  What is hypertension? Hypertension is defined as having a blood pressure higher than 140/ 90 mmHg 5 6 Blood Pressure 7  Baroreceptors and sympathetic nervous system Baroreceptors are pressure sensors. Their function is to sense pressure changes. These are mechanoreceptors located in the carotid sinus and in the aortic arch. Their function is to sense pressure changes by responding to change in the tension of the arterial wall. Baroreflex or baroreceptor reflex is a homeostatic mechanisms that helps to maintain blood pressure at nearly normal level. 8 Location and innervation of arterial baroreceptors 9 Carotid Arteries 10 11 The renin-angiotensin system (RAS) plays an integral role in blood pressure 12  Classification of Anti‐hypertensive drugs o Following are the major classes of drugs that lowers elevated blood pressure 1. Beta adrenergic blockers 2. Diuretics 3. Calcium channel blockers 4. Angiotensin converting enzyme inhibitors 5. Angiotensin receptor blockers 6. Direct arterial vasodilators (self study) 7. Drug used in hypertensive emergency 13  1 4 1. BETA BLOCKERS (Class of anti hypertensive drugs)  Introduction to Beta-blockers and β Receptors Beta-blockers are drugs that bind to beta- receptors. These drugs block the binding of norepinephrine and epinephrine to these receptors. Beta-blockers are sympatholytic drugs. β1-receptors are located commonly in the heart and kidneys. β2- receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. β3- adrenergic receptors are in fat cells. 15  Classification of Beta-blockers o Two major groups are as follows 1) Selective β1 Blockers: 2) Nonselective β Blockers (β1 & β2): Members include: A) Without ISA  Atenolol Members include  Propranolol  Esmolol  Timolol  Acebutalol  Sotalol  Metoprolol B) With ISA (Intrinsic sympathetic activity)/  Bisoprolol Partial agonist  Betaxolol  Pindolol C) With additional α Blocking activity  Labetalol  Carvedilol 16  Anti hypertensive mechanism of Beta Blockers Heart: Blockade of beta1-receptors in the Sino-atrial node reduces heart rate (negative chronotropic effect) and blockade of beta1-receptors in the myocardium decrease cardiac contractility (negative inotropic effect). Kidney: Blockade of beta1-receptors inhibit the release of renin from juxta- glomerular cells and thereby reduce the activity of the renin-angiotensin- aldosterone system. 17 Cont’d… Cardiac Effects of beta blockers Decrease contractility (negative inotropy) Decrease heart rate (negative chronotropy) Decrease conduction velocity (negative dromotrope) 18 Sympathetic stimulation of β1 and β2 Gaining of electrons 19  Adverse effects of Beta Blockers Bradycardia Hypotension Atrioventricular (AV) nodal conduction block. Beta-blockers are therefore contraindicated in patients with sinus bradycardia and partial AV block 20  Important about beta blockers Bronchoconstriction can occur when non-selective beta-blockers are given to asthmatic patients. Therefore, non-selective beta-blockers are contraindicated in patients with asthma or chronic obstructive pulmonary disease. Bronchoconstriction occurs because sympathetic nerves innervating the bronchioles normally activate β2-adrenoceptors that promote bronchodilation. Beta-blockers can also mask the tachycardia that serves as a warning sign for insulin-induced hypoglycemia in diabetic patients; therefore, beta-blockers should be used cautiously in diabetics. 21  Renin-Angiotensin-Aldosterone System Renin is a proteolytic enzyme that is released into the circulation by the kidneys. Its release is stimulated by:  Sympathetic nerve activation (acting through β1-adrenoceptors)  Renal artery hypotension (caused by systemic hypotension or renal artery stenosis)  Decreased sodium delivery to the distal tubules of the kidney. The renin-angiotensin-aldosterone system (RAAS) regulate blood volume and systemic vascular resistance, which together influence cardiac output and arterial pressure. There are three important components to this system: 1) renin, 2) angiotensin, and 3) aldosterone. Renin, which is released primarily by the kidneys, stimulates the formation of angiotensin in blood and tissues, which in turn stimulates the release of aldosterone from the adrenal cortex. 22  Angiotensin-II Functions Constricts resistance vessels increasing systemic vascular resistance and arterial pressure Stimulates reabsorption. Increase the release aldosterone, which in turn acts on the kidneys to increase sodium and fluid retention Stimulates the release of vasopressin (antidiuretic hormone, ADH) from the posterior pituitary, which increases fluid retention by the kidneys Stimulates thirst centers within the brain Enhancing sympathetic adrenergic function Stimulates cardiac hypertrophy and vascular hypertrophy. 23  2 4 2. Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors) (Class of anti hypertensive drugs known as RAAS Inhibitors)  Angiotensin converting enzyme (ACE) inhibitors Classification o Members include: Pril family  Benazepril  Captopril  Enalapril  Fosinopril  Lisinopril  Moexipril  Quinapril  Ramipril 25  Mechanism of action / Actions of ACE inhibitors o These drugs will inhibit the conversion of Angiotensin I into angiotensin II by blocking Angiotensin concerting enzyme.  ACE inhibitors have the following actions: Dilate arteries and veins by blocking angiotensin II formation Down regulate sympathetic activity Promote renal excretion of sodium and water (natriuretic and diuretic effects) by blocking the effects of angiotensin II in the kidney and by blocking angiotensin II stimulation of aldosterone secretion. This reduces blood volume, venous pressure and arterial pressure. Inhibit cardiac remodeling associated with chronic hypertension, heart failure, and myocardial infarction. NOTE: In cardiology, ventricular remodeling (or cardiac remodeling) refers to changes in the size, shape, structure, and function of the heart 26  Clinical uses of ACE inhibitors Hypertension Heart Failure Myocardial infaction Diabetic and Nondiabetic Nephropathy 27  Contraindications (Renal Stenosis) Patients with bilateral renal artery stenosis may experience renal failure if ACE inhibitors are administered. The reason is that the elevated circulating and intrarenal angiotensin II in this condition constricts the efferent arteriole more than the afferent arteriole within the kidney, which helps to maintain glomerular capillary pressure and filtration. Removing this constriction by blocking circulating and intrarenal angiotensin II formation can cause an abrupt fall in glomerular filtration rate. 28  Renal artery stenosis Renal artery stenosis is a narrowing of arteries that carry blood to one or both kidneys. 29  Renal artery stenosis and ACE inhibitors Patients with renal artery stenosis, the kidneys release large amounts of renin. High angiotensin II serve to maintain glomerular filtration by two mechanisms: elevation of blood pressure and constriction of efferent glomerular arterioles. When ACE is inhibited, causing angiotensin II levels to fall, the mechanisms that had been supporting glomerular filtration fail, causing urine production to drop 30  Drug-Drug Interactions Diuretics. Diuretics may intensify first-dose hypotension. To prevent this interaction, diuretics should be withdrawn 1 week prior to initiating ACE inhibitor treatment ACE inhibitors increase the risk of hyperkalemia caused by potassium supplements and potassium-sparing diuretics 31 32  3 3 2. Angiotensin receptor blockers (ARBs) (Class of anti hypertensive drugs known as RAAS Inhibitors)  Angiotensin Receptor Blockers (ARBs) Classification o Members include:  Losartan (Prototype)  Valsartan  Telmisartan  Olmesartan  Candesartan  Irbesartan 34  Mechanism of action of Angiotensin receptor blockers o ARBs antagonize the action of angiotensin II in a highly selective manner at the angiotensin II AT1-receptor. o Angiotensin II receptors are subclassified into AT1 and AT2 receptors. o The AT1-receptor mediates all the classical effects of angiotensin II e.g. vasoconstriction, aldosterone release, sympathetic activation and other potentially harmful effects on the cardiovascular system. o The functional role of the AT2-receptor is less well understood but broadly this receptor mediates effects opposite to the AT1- receptor. 35 36 Mechanism of action of Angiotensin receptor blockers (Diagrammatic) 37 Clinical uses of Angiotensin receptor blockers 38 ARBs 39 Adverse affects of Angiotensin receptor blockers 40 Dr y Co ug h 41 Combine slide for ACEIs and ARBs (RAAS inhibitors) 42  4 3 4. Calcium Channel Blockers (CCBs) (Class of anti hypertensive drugs)  Calcium channel blockers (CCBs) Classification o Members include:  Amlodipine (Norvasc) ™  Nimodipine (Nimotop) ™  Nifedipine (Adalat CC) ™ Extended-Release Tablets  Nicardipine  Nisoldipine  Felodipine  Isradipine  Verapamil  Diltiazem 44  Mechanism of action of Calcium channel blockers o Calcium channel blockers decrease the amount of calcium entering cardiac and smooth muscle cells by blocking voltage-gated calcium channels. o This causes blood vessels to relax and widen (vasodilation), improves oxygen supply to the heart 45 Of Calcium channel blockers 46  Calcium-channel blockers effect on heart Calcium-channel blockers bind to L-type calcium channels located on the vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue (sinoatrial and atrioventricular nodes). These channels are responsible for regulating the influx of calcium into muscle cells, which in turn stimulates smooth muscle contraction and cardiac myocyte contraction. In cardiac nodal tissue, L-type calcium channels play an important role in pacemaker currents. Therefore, by blocking calcium entry into the cell, there is, vasodilation, Decreased myocardial force generation (negative inotropy), decreased heart rate (negative chronotropy), Decreased conduction velocity within the heart (negative dromotropy), 47 Clinical uses of Calcium Channel Blockers (CCBs) o Hypertension (Beneficial in patients having comorbidities of Asthma, Diabetes, Angina, and / or peripheral vascular diseases) o Angina Petrous (Due to decrease in Myocardial oxygen consumption and dilatation of coronary artery) o Supraventricular techy arrythmias (Because of its depressant action on SA and AV nodes) o Migraine 48 Major Adverse effects of Calcium Channel Blockers (CCBs) Hypotension Edema (Peripheral/ Ankle) Headache Reflex tachycardia Flushing Fatigue Dizziness Constipation (Verapamil) Flushing AV Block 49 Of Calcium channel blockers 50  5 1 4. DIURETICS (Class of anti hypertensive drugs)  Introduction to Diuretics o A diuretic is any substance that promotes diuresis (increased production of urine). o Diuretics enhance the removal of sodium and water from body through kidneys. o Diuretics mainly promote the excretion of the Na+, Cl- or HCO3- and water. o Net result of Diuretics: Increase the urine flow Change urine pH Change the ionic composition of the urine and blood 52  Introduction to Diuretics oNatural Diuretics Ginger.... Parsley.... Caffeine 53 Introduction to Diuretics (Cont) 54  Classification of Diuretics Diuretics have the following classes 1) Thiazide Diuretics: 2) Loop Diuretics: Members include: Members include  Chlorothiazide  Furosemide  Torsemide  Hydrochlorothiazide  Bumetanide  Chlorthalidone  Ethacrynic acid  Metolazone 3) Potassium Sparing Diuretics:  Indapamide Members include  Spironolactone  Eplerenone  Amiloride  Triamterene 55  Classification of Diuretics (Cont) 4) Carbonic Anhydrase Inhibitors: Members include:  Acetazolamide 5) Osmotic Diuretics: Members include:  Mannitol  Urea 56  Thiazide Diuretics 1) Thiazide Diuretics: Members include:  Chlorothiazide  Hydrochlorothiazide  Chlorthalidone  Metolazone  Indapamide 57  Mechanism of action of Thiazide Diuretics These drugs Inhibit sodium-chloride transporter in the distal tubule. This transporter normally reabsorbs about 5% of filtered sodium. 58  Clinical uses of Thiazide Diuretics o These can be used clinically for: Hypertension Heart Failure… drug of choice in mild to moderate HF, if the thiazide fails, loop diuretics may be useful Hypercalciuria Diabetes insipidus 59  Adverse effects of Thiazide Diuretics o Most of the adverse effects involve problems in fluid and electrolyte balance Hypokalemia Hyponatremia Hyperuricemia Hypercalcemia Hyperglycemia Volume depletion… This can cause orthostatic hypotension or light headedness Hyperlipidemia Hypersensitivity 60 Contraindications of Thiazide Diuretics 61  Loop Diuretics These are the most efficacious diuretics currently available These diuretics selectively inhibit Nacl reabsorption in the thick ascending limb of Henle (TAL) TAL has the largest Nacl absorptive capacity (25-30% of filtered Nacl) Available both in oral as well as parenteral preparations These are rapidly absorbed Duration of action is relatively brief, 2-4 hours. Secreted into the urine Furosemide is the most commonly used of these drugs Bumetanide is much more potent than Furosemide, and its use is increasing 62  Classification of Loop Diuretics Members include  Furosemide  Torsemide  Bumetanide  Ethacrynic acid 63 64  Pharmacokinetics of Loop Diuretics These are rapidly absorbed drugs Both oral and parenteral preparations are available for Loop diuretics Their duration of action is relatively brief, 2-4 hours They are secreted into the urine 65  Pharmacodynamics of Loop Diuretics o Loop diuretics inhibit the Na+ / K+ / 2Cl- Co-transporter in the luminal in the ascending limb of the Loop of Henle. o Reabsorption of these ions is decreased 66  Clinical uses of Loop Diuretics o Acute Pulmonary edema.. Drug of choice o May be used for other edematous conditions o Herat failure o Hypercalcemia… useful in treating hypercalcemia along with hydration, because they stimulate tubular Ca++ excretion o Hyperkalemia o Anion overdose 67  Adverse effects of Loop Diuretics o Ototoxicity… sever when used with antibiotics (Aminoglycosides) o Hypokalemia o Hypomagnesemia o Hypotension o Acute hypovolemia o Hyperuricemia o o 68 Introduction to Potassium Sparing Diuretics 69 Pharmacokinetics of Potassium Sparing Diuretics 70  Potassium Sparing Diuretics 3) Potassium Sparing Diuretics classification: Members include  Spironolactone Aldosterone antagonists  Eplerenone  Amiloride Direct Na channel inhibitors  Triamterene 71 Pharmacodynamics of Potassium Sparing Diuretics 72 Pharmacodynamics of Potassium Sparing Diuretics (Cont…) 73 Clinical uses of Potassium Sparing Diuretics 74 Adverse effects of Potassium Sparing Diuretics 75 Contra indications of Potassium Sparing Diuretics 76  Self study (Lippincott's Book) 4) Carbonic Anhydrase Inhibitors: Members include:  Acetazolamide 5) Osmotic Diuretics: Members include:  Mannitol  Urea 77 78