Antihypertensive Drugs by Dr. Haseeba Talat (14.03.2020).pdf
- 1. INTRODUCTION Class :3rd Year MBBS Lecture : Antihypertensive drugs Module : Cardiovascular system By : DR. HASEEBA TALAT Designation : Senior Demonstrator Department : Pharmacology, KEMU Time and Day : Saturday 14th March at 8.00 a.m
- 2. DR. HASEEBA TALAT PharmacologyDepartment
- 3. Definition of Hypertension Hypertension is sustained elevation of BP • Systolic pressure ≤ 140mm Hg • Diastolic pressure ≤ 90 mm Hg
- 4. Classification of Hypertension CLASSIFICATION 1.Primary Hypertension Specific cause unknown, 90% of the cases, Also known as essential or idiopathic hypertension 2. Secondary Hypertension Cause is known . 10% of the cases
- 5. Identifiable Causes of SecondaryHypertension Sleep apnea Drug-induced or related causes Chronic kidney disease Primary aldosteronism Renovascular diseases Chronic steroid therapy and Cushing’s syndrome Pheochromocytoma Coarctation of aorta Thyroid or parathyroid disease
- 6. Hypertension Complications Themost common complications of chronic hypertension are target organ diseases occurring in the Brain Heart Kidneys Eyes
- 7. Target Organ Damage Heart Left ventricular hypertrophy Coronary artery disease Myocardial infarcts Heart failure Brain Stroke or transient ischemic attacks Chronic kidney disease, kidney failure Retinopathy
- 8. Normal Blood PressureRegulation Physiologically, CO and PVR is maintained by (1)arterioles (2)postcapillary venules (3)Heart (4)Kidneys Baroreflex and RAAS regulates the above 4 sites In hypertensives – Baroreflex and renal blood-volume control system – set at higher level All antihypertensives act via interfering with normal mechanisms
- 9. Blood Pressure Regulation BP regulation operates in a negative feedback system Baroreceptors and chemoreceptors in the carotid arteries and aortic arch and RAAS in renal vasculature detect changes in arterial blood pressure.
- 10. Baroreceptor reflex arc Postural baroreflex:
- 11. What is Renin– Angiotensin Aldosterone System? (Physiological Background)
- 12. The Renal response Kidneys are responsible for long term blood pressure control by controlling blood volume. Decrease pressure in renal arterioles and sympathetic activity → ↑renin production → ↑angiotensin II production → increased absorption of salt and water. Angiotensin II: Causes direct constriction of renal arterioles Stimulation of aldosterone synthesis – sodium absorption and increase in intravascular blood volume
- 14. Angiotensin-II What arethe chronic ill effects of raised AG-2 1) Hypertension – long standing will cause ventricular hypertrophy 2) Myocardial infarction 3) Renal damage 4) Volume overload and increased T.P.R Cardiac hypertrophy Coronary vascular damage
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- 17. Nonpharmacologic Management of Hypertension Weight reduction Exercise Salt restriction in diet Stress reduction If systolic BP cannot be maintained <140 systolic, proceed to pharmacological treatment.
- 18. How a drugcan lower blood pressure Lower the systematic vesicular resistance Lower Cardiac output. Reduce blood volume Act centrally (CNS)
- 21. Nephron, a functionalunit of kidney Normally used in severe hypertension, in renal insufficiency and in cardiac failure or cirrhosis. Normally used in mild or moderate hypertension with normal renal and cardiac function. Useful to avoid excessive potassium depletion. 1. Diuretics
- 28. ACE inhibitors Captopril,lisinopril., enalapril, ramipril and fosinopril etc.
- 29. Captopril Sulfhydryl containingdipeptide and abolishes pressor action of Angiotensin-I and not Angiotensin-II and does not block AT receptors Pharmacokinetics: Available only orally, 70% - 75% is absorbed Partly absorbed and partly excreted unchanged in urine Food interferes with its absorption Half life: 2 Hrs, but action stays for 6-12 Hrs
- 31. Pharmacological actions In hypertensive: Lowers P.V.R and thereby mean systolic and diastolic BP. RAS is overactive in 80% of hypertensive cases – inhibition causes lowering of BP. Renal blood flow is maintained – greater dilatation of vessels and decrease in intraglomerular pressure
- 32. ACE inhibitors -Enalapril It’s a prodrug – converted to enalaprilate Advantages over captopril: Longer half life – OD (5-20 mg OD) Absorption not affected by food Rash and loss of taste are less frequent Longer onset of action Less side effects
- 33. ACE inhibitors –Ramipril It’s a popular ACEI now It is also a prodrug with long half life Tissue specific – Protective of heart and kidney Uses: Diabetes with hypertension, CHF, AMI and cardio protective in angina pectoris
- 34. ACE inhibitors –Lisinopril It’s a lysine derivative, Not a prodrug Slow oral absorption – less chance of 1st dose phenomenon Absorption not affected by food and not metabolized – excrete unchanged in urine Long duration of action – single daily dose
- 35. ACE inhibitors –USES 1) Hypertension. 1st line antihypertensive agents 2) Congestive Heart Failure 3) Myocardial Infarction 4) Prophylaxis of high CVS risk subjects 5) Diabetic Nephropathy
- 36. ACE Inhibitors –Adverse effects Cough – persistent brassy cough in 20% cases – inhibition of bradykinin breakdown in lungs Hyperkalemia in renal failure patients with K+ sparing diuretics, NSAID and beta blockers (routine check of K+ level) Hypotension – sharp fall may occur – 1st dose
- 37. Cont… Acute renalfailure: In patients with CHF and bilateral renal artery stenosis Angioedema: swelling of lips, mouth, nose,rashes, urticaria. Dysgeusia: loss or alteration of taste Foetopathic: hypoplasia of organs, growth retardation. (C/I in pregnancy) Neutropenia, Proteinuria
- 40. Angiotensin Receptor Blockers(ARBs) - Angiotensin Receptors: Specific angiotensin receptors are abbreviated as – AT1 and AT2 They are present on the surface of the target cells Most of the physiological actions of angiotensin are mediated via AT1 receptor Losartan is the specific AT1 blocker
- 43. Angiotensin Receptor Blockers(ARBs) - Losartan • Blocks all the actions of AT-I i-e vasoconstriction, sympathetic stimulation, aldosterone release and renal actions of salt and water reabsorption • No inhibition of ACE
- 44. Losartan Cough israre – no interference with bradykinin and other ACE substrates Complete inhibition of AT1 Result in indirect activation of AT2 – vasodilatation (additional benefit) No significant effect in plasma lipid profile, insulin sensitivity and carbohydrate tolerance Mild uricosuric effect However, losartan decreases BP in hypertensive which is for longer period (24 Hrs)
- 45. Losartan Pharmacokinetic: Absorptionnot affected by food but unlike ACEIs its bioavailability is low High first pass metabolis Highly bound to plasma protein Adverse effects: Fetopathic like ACEIs – not to be administered in pregnancy Rare 1st dose effect hypotension Low dysgeusia and dry cough Lower incidence of angioedema
- 54. Beta-adrenergic blockers Advantagesof cardio-selective over non-selective: In asthma In diabetes mellitus In peripheral vascular disease Current status: 1st line of antihypertensive along with diuretics and ACEIs Preferred in young non-obese hypertensive Angina pectoris and post angina patients Post MI patients – useful in preventing mortality In old persons, carvedilol – vasodilatory action can be given
- 56. Αlpha-adrenergic blockers Nonselective ᾳ blockers (phenoxybenzamine, phentolamine), only used in phaechromocytoma. Specific ᾳ-1 blockers (prazosin, terazosin, doxazosin) are used in hypertension PRAZOSIN is the prototype of the alpha-blockers Reduction in T.P.R ↓ Mean B.P reduction ↓ Venous tone reduction ↓ Reduction in CO
- 57. Αlpha-adrenergic blockers. Adverseeffects: Prazosin causes postural hypotension Fluid retention in monotherapy Headache, dry mouth, weakness, dry mouth, blurred vision, rash, drowsiness Current status: Several advantages – improvement of carbohydrate metabolism, lowers LDL and increases HDL Used in addition to other conventional drugs e.g diuretics or beta blockers
- 59. Calcium Channel Blockers- Classification
- 60. a) Calcium Channelblockers Phenylalkylamines: Verapamil Benzothiazepines: Diltiazem Dihydropyridines: Nifedipine,Nicardapine,Isradapine, Fenoldopine,Amlodipine
- 61. Calcium Channel Blockers– Mechanism of action Voltage sensitive Calcium channels are of 3 types: L-Type, T-Type and N-Type Normally, L-Type of channels admit Ca+ and cause depolarization → excitation-contraction coupling through phosphorylation of myosin light chain →contraction of vascular smooth muscle → elevation of BP CCBs block L-Type channel leading to: Smooth Muscle relaxation Negative chronotropic and ionotropic effects in heart DHPs have highest smooth muscle relaxation and vasodilator action followed by verapamil and diltiazem
- 63. MOA of actionof CCBs
- 65. CCBs Dihydropyridines havemore pronounced action on vascular smooth muscles Verapamil has more cardiodepressant action. Diltiazem has intermediate effects.
- 66. Calcium Channel Blockers Advantages: Unlike diuretics no adverse metabolic effects but mild adverse effects like – dizziness, fatigue No sedation or CNS effect Can be given in asthma, angina and PVDs No renal and male sexual function impairment No adverse fetal effects and can be given in pregnancy
- 68. Vasodilators Relax smoothmuscle in blood vessels resulting in dilatation and decreased peripheral vascular resistance Reduce afterload so helpful in heart failure
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- 70. VASODILATORS Oral Vasodilators(Hydralazine and minoxidil) used for long term out patient therapy of hypertension Parenteral Vasodilators (fenoldopam, nitroprusside, Diazoxide) are used in hypertensive emergencies
- 71. Mechanism of action POTASSIUM CHANNEL OPENERS Minoxidil Diazoxide DIRECT VASODIALATORS Hydralazine Na nitroprusside
- 72. b) Potassium channelopeners Mechanism: open K-channels of vascular smooth muscle cells K-efflux hyperpolarization vasodilatation lower PVR lower BP Adverse effects: reflex tachycardia, Na and fluid retention, (Diazoxide: hyperuricemia, hyperglycemia –used in hypoglycemia)
- 73. Vasodilators - Minoxidil Powerful vasodilator, mainly 2 major uses – antihypertensive and alopecia Prodrug and converted to an active metabolite which acts by hyperpolarization of smooth muscles and thereby relaxation of Smooth muscles. Rarely indicated in hypertension especially in life threatening ones Orally not used any more MOA of hair growth: Enhanced microcirculation around hair follicles and also by direct stimulation of follicles S.E : hypertrichosis
- 74. Direct Vasodilator -Hydralazine Directly acting vasodilator MOA: hydralazine molecules combine with receptors in the endothelium of arterioles – NO release – relaxation of vascular smooth muscle – fall in BP Subsequently, fall in BP – stimulation of adrenergic system leading to Cardiac stimulation producing palpitation and rise in CO even in IHD and patients – anginal attack Tachycardia Increased Renin secretion – Na+ retention These effects are countered by administration of beta blockers and diuretics
- 75. Sodium Nitroprusside Rapidlyacting vasodilator Dialates arterioles and veins thus reducing T.P.R and CO (decrease in venous return) Improves ventricular function in heart failure by reducing preload MOA: RBCs convert nitroprusside to NO, a potent vasodialator. Uses: Hypertensive Emergencies. Given as IV infusion.
- 78. Vasodilators Limited effect whenused alone. Vasodilating action that lowers BP also stimulates SNS. This, in turn, triggers reflexive compensatory mechanisms that raise BP
- 83. Centrally acting Drugs Alpha-Methyldopa: a prodrug Precursor of Dopamine and NA MOA: Converted to alpha methyl noradrenaline which acts on alpha-2 receptors in brain and causes inhibition of adrenergic discharge in medulla – fall in PVR and fall in BP Not used therapeutically now except in Hypertension during pregnancy Clonidine: Imidazoline derivative, partial agonist of central alpha- 2 receptor Not frequently used now because of tolerance and withdrawal hypertension
- 87. Hypertensive emergency Severe,abrupt elevation of BP The rate of increase in BP is more important than the absolute value. Most common in patients with the history of HTN who have failed to comply with the medications or who have been under medicated
- 88. Clinical Manisfestations Cerebrovascularaccident or head injury with high BP Left ventricular failure with pulmonary edema due to hypertension Hypertensive encephalopathy Angina or MI with raised BP Acute renal failure with high BP Eclampsia Pheochromocytoma, cheese reaction and clonidine withdrawal
- 91. Treatment Drug Dosage: Sodium Nitroprusside (20-300 mcg/min) GTN (5-20 mcg/min) Esmolol (0.5 mg/kg bolus) and 50-200mcg/kg/min Phentolamine – (5-10 mg IV)