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ANTIHYPERTENSIVE (23.02.2020) 4classes (1).ppt

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ANTIHYPERTENSIVE DRUGS Dr. Sushma Deo MD; Asst. Professor Dept. Of Pharmacology
Hypertension
• Hypertension • Hypertension is the most common cardiovascular condition. • A persistent and sustained high blood pressure has damaging effects on the heart, brain, kidneys and eyes.
Hypertension is generally classified into two types 1. Primary or essential hypertension : In more than 95% of cases, there is no specific underlying cause.These patients are said to have essential hypertension. 2. Secondary hypertension : It is seen in about 5% of cases. It can be due to a specific disease or drug.
BP • Arterial blood pressure (BP) is determined by cardiac output (CO) and peripheral vascular resistance (PR). • BP=COXPR
Systolic blood pressure (SBP) : it is the maximum pressure recorded during ventricular systole. Diastolic blood pressure (DBP) : It is the minimum pressure recorded during ventricular diastole. Pulse pressure (PP) : SBP-DBP. Mean arterial pressure : DBP+1/3PP.
Classification of blood pressure according to JNC VII CATEGORY BLOOD PRESSURE (mmHg) systolic diastolic Normal <120 <80 Prehypertension 120-139 80-89 Hypertension Stage I (mild) 140-159 90-99 Stage II (moderate) 160- 179 100-109 Stage III (severe) > 180 >110
ANTIHYPERTENSIVE DRUGS Classification 1. ACE Inhibitors: Captopril, enalapril, lisinopril, perindopril, ramipril, benazepril. 2. Angiotension - II- receptor antagonists : Losartan, candesartan, irbesartan, valsartan. 3. Calcium channel blockers : nifedipine SR, amlodipine, nicardipine, nimodipine, felodipine, verapamil, diltiazem. 4. Diuretics a. Thiazides and related agents : Hydrochlorothiazide, chlorthalidone b. Loop diuretics : Furosemide, bumetanide, torsemide. c. Potassium sparing diuretics : Amiloride, triamterene, spironolactone.
5.Sympatholytic drugs a. Centrally acting agents : Clonidine, methyldopa. b. Ganglion blockers : Trimethaphan. c. Neuronal blockers : Reserpine d. Alfa -Adrenergic blockers : (i) Non-selective : Phenoxybenzamine,Phentolamine. (ii) Selective : Prazosin, terazosin e. Beta -Adrenergic blockers : Propranolol, atenolol, metoprolol 6. Vasodilators a. Arteriolar : Hydralazine, Minoxidil, diazoxide b. Arterial and venodilator : Sodium nitroprusside
BRAIN (VMC) HEART BLOOD VESSEL KIDNEY Beta blockers Calcium channel blockers Centrally acting sympatholytics Ganglion blockers Alfa blockers Vasodilators Calcium channel blockers Angiotensin receptor blocker (AT1) Diuretics Beta blockers Renin ACE angiotensinogen Angiotensin I Angiotensin II ACE inhibitors SITE OF ACTION OF THE MAJOR GROUPS OF DRUGS
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS Angiotensin-converting enzyme inhibitors (ACE inhibitors) are frequently used as the first line antihypertensive drugs. They : • inhibit the generation of angiotensin II, which is a potent vasoconstrictor. • inhibit the degradation of bradykinin, which is a potent vasodilator. • stimulate the synthesis of vasodilating PGs through bradykinin. •reduce sympathetic nervous system activity.
• ACE inhibitors are preferred antihypertensive agents in the younger age group. • They are used in all forms of hypertension, especially in patients with diabetes and CHF. • They are preferred in patients with diabetes because they delay or prevent the progression of renal complications.
Mechanism of action (ANGIOTENSIN- CONVERTING ENZYME INHIBITORS ) •ACE inhibitors also reduce aldosterone production hence reduce sodium and water retention. •All these actions contribute to their antihypertensive effect. •They dilate both arteries as well as veins, hence they reduce afterload and prelolad.
ANGIOTENSINOGEN ANGIOTENSIN- I ANGIOTENSIN- II BRADYKININ Increased PG production vasodilation inactive Angiotensin - converting enzyme ACE inhibitors -- -- + Renin kidney Blood vessel vasoconstriction Aldosterone release Heart Cardiac Hypertrophy & remodelling + + + PVR BP Na+ & H20 retention AT1&2 receptors
Pharmacokinetics •ACE inhibitors are usually given orally. •In emergency, enalapril can be given intravenously. •Food reduces the absorption of captopril hence it should be given 1 hour before meals. •They poorly cross the BBB; metabolized in the liver and excreted in urine
Adverse effects Cough (dry Cough) is due to increased bradykinin levels. Appearance of intractable cough is an indication to stop the drug. Angioedema, Proteinuria,Taste alteration Teratogenic effect (growth retardation and neonatal death) - hence contraindicated in pregnancy. Severe hypotension may occur 1-2 hours after taking the first dose. Hence, ACE inhibitors should be started with a small dose and then gradually increased.
Proteinuria, Rashes, Itching, Loss of appetite, Nausea, vomiting and diarrhoea Hyperkalaemia may be seen in patients with renal insufficiency and when combined with K+ sparing diuretics.
Therapeutic uses of ACE inhibitors 1.Hypertension : •Use of ACE inhibitors reduces the incidence of heart disease in hypertensive patients. •ACE inhibitors are useful in all grades of hypertension. •They prevent or retard myocardial hypertrophy and remodeling. 2. CCF : ACE inhibitors should be prescribed to all patients with impaired left ventricular function. 3. MI: •ACE inhibitors should be started within 24 hours in patients with MI. •They have shown both short-term and long-term improvement in survival.
4. Diabetic nephropathy : •ACE inhibitors and angiotensin-II-receptor blockers (ARBs) are preferred drugs in diabetic nephropathy as they control both systemic hypertension and intraglomerular pressure. •Therefore, ACE inhibitors are the preferred antihypertensive in diabetics.
5. Scleroderma renal crisis : • ACE inhibitors produce dramatic improvement in patients with renal crisis and accelerated by hypertension.
ANGIOTENSIN II-RECEPTOR BLOCKERS OR ANGIOTENSION-RECEPTOR ANTAGONISTS •The two types of angiotensin II-receptors are AT1 and AT2. •Most of the effects of angiotensin II are mediated by AT1-receptors. •They are: vasoconstriction, aldosterone secretion and the release of noradrenaline from sympathetic nerve endings.
• The role of AT2-receptors is not known. ARBs competitively inhibit the binding of angiotension II to AT1-receptor subtype. • ARB’s produce effects similar to those of ACE inhibitors. • The efficacy and tolerability are also similar to ACE inhibitors.
• Losartan is less potent than ACE inhibitors, whereas the ARBs, candesartan,valsartan are equipotent to ACE inhibitors. • ARBs do not affect bardykinin production.
SIDE EFFECTS •ARB’s are better tolerated as compared to ACE inhibitors. •They cause headache,hypotension,weakness, rashes,nausea,vomiting and teratogenic effects. •They may cause hyperkalaemia in patients with renal failure or in patients on K+ sparing diuretics. •They are less likely to produce cough or angioedema. •ARBs are used in hypertension,congestive cardiac failure (CCF) and diabetic nephropathy.
• The efficacy and tolerability of ARBs are similar to those of ACE inhibitors. • ARBs are mainly indicated in patients who develop cough with ACE inhibitors. • ARBs also reduce the progression of nephropathy in patients with diabetes.
CALCIUM CHANNEL BLOCKERS (CCBs) •Verapamil, diltiazem and the dihydrophyridines (nifedipine, amlodipine, felodipine, nicardipine, etc) are useful in hypertension. •DHPs are preferred among calcium channel blockers because of their more selective action on blood vessels. mechanism of action CCBs block voltage- sensitive L-type Ca2+ channels by binding to specific site on the alfa1 subunit Prevents entry of Ca2+ into cell No excitation- contraction coupling in the heart and vascular smooth muscles Voltage- sensitive Ca2+ channels are of 5 subtypes. They are L,N,T,P,R subtypes. L-type is predominantly present in cardiac and smooth muscle cells
• The antihypertensive effect of DHPs is mainly due to the reduction of total peripheral resistance. • It causes headache, flushing, palpitation, reflex tachycardia and even may precipitate angina or arrhythmia. • The use of sustained release preparations reduce the incidence of side effects.
• B-Blockers can be used with nifedipine to counteract the reflex tachycardia. • Veapamil and diltiazem do not cause reflex tachyardia because of their greater cardiac depressant effect. • CCBs are particularly useful in elderly patients and also in patients with angina, asthma, peripheral vascular disease, migraine, hyperlipidaemia, diabetes and renal dysfunction.
DIURETICS: •Chlorothiazide, hydrochlorothiazide and chlorthalidone are the commonly used thiazides. •Drugs causing net loss of Na+ and water in urine
Thiazide diuretics •These are used in uncomplicated mild to moderate hypertension and have a long duration of action. •Potassium sparing diuretics are usually given with thiazides to counteract the K+ loss.
Mechanism of action of Thiazides Thiazides Inhibit Na- Cl- symport in the early part of the DCT CO Promote Na+, H2O excretion BP Na+ concentration in the Vascular smooth muscles PVR BP On chronic therapy
Adverse effects Hypokalaemia, hyperglycaemia, hyperuricaemia, hyperlipidaemia, hypercalcaemia, impotence and decreased libido. Advantages 1. Have long duration of action 2. Thiazide diuretics are cheaper. 3. They are well tolerated even in elderly patients. 4. They decrease the incidence of fracture in elderly patients by reducing urinary Ca2+ excretion. Loop diuretics These have shorter duration of action, therefore, are not used in hypertension except in the present of renal or cardiac failure.
SYMPATHOLYTICS Centrally acting sympatholytics Clonidine is a centrally acting antihypertensive drug. Mechanism of action of Clonidine Clonidine is effective orally, highly lipid soluble and rapidly crosses the blood brain barrier (BBB). It has a short duration of action, required twice a day administration. Transdermal patch of Clonidine controls BP for a week. BRAIN STEM Alfa 2A Clonidine stimulates alfa 2A receptors in the VMC Sympathetic outflow from VMC Heart Blood vessel HR, CO PVR BP
Adverse effects •Dryness of mouth and eyes, sedation, depression, bradycardia, impotence, nausea, dizziness, parotid gland swelling and pain are the adverse effects of clonidine. •Sudden stoppage of Clonidine after prolonged use may causes withdrawal syndrome headache, nervousness, tachycardia, sweating, tremors, palpitation and rebound hypertension.
Uses Clonidine is used : 1.In hypertension. 2.To treat withdrawal symptoms in Opioids and alcohol addicts. 3.As pre-anaesthetic agent. 4.To reduce postmenopausal hot flushes 5.Glaucoma 6.Prophylaxis of migraine
alfa-Methyldopa It is a centrally acting sympatholytic drug. MOA of alfa- methyldopa Alfa- Methyldopa Alfa- methyldopamine Stimulates Alfa2- VMC sympathetic outflow HR, PVR BP
Adverse effects •These include nasal stuffiness, headache, sedation, mental depression, dryness of mouth, bradycardia, impotence, extra pyramidal symptoms •Clonidine and methyldopa are usually employed as the second or third line agents because of high incidence of side effects. •Methyldopa is one of the preferred antihypertensive drugs during pregnancy.
Adrenergic neuronal blocker Reserpine •It has both central and peripheral actions. •Reserpine enters adrenergic neuron, binds to the storage vesicle and inhibits the vesicular catecholamine (DA and NA) uptake and storage. Tyrosine DOPA DA DA NA Storage vesicle Reserpine -- -- Effector cell NA ………….
Alfa- Adrenergic blockers Non-selective drugs are not preferred for essential hypertension.They are used in special conditions like : 1. Pheochromocytoma. 2. Clonidine withdrawal. 3. Cheese reaction. Alfa- Blockers Non- selective blockers Alfa-1 and alfa-2 Selective alfa-1 blocker Block both Alfa-1 and alfa-2 receptors in The blood vessels Vasodilation and fall in BP (due to alfa-1 blockade) Increase noradrenalin release (due to presynaptic alfa-2 blockade) Heart rate Block selectively alfa-1 vascular receptors by Competitive mechanism Arterial and venodilatation Alfa-2 receptors are not blocked, hence there is no increase in the level of NA Therefore, reflex tachycardia is minimal
Αlpha-adrenergic blockers.  Adverse effects:  Prazosin causes postural hypotension – start 0.5 mg at bed time with increasing dose and upto 10 mg daily  Fluid retention in monotherapy  Headache, dry mouth, weakness, dry mouth, blurred vision, rash, drowsiness and failure of ejaculation in males  Current status:  Several advantages – improvement of carbohydrate metabolism – diabetics, lowers LDL and increases HDL, symptomatic improvement in BHP  But not used as first line agent, used in addition with other conventional drugs which are failing – diuretic or beta blocker  Doses: Available as 0.5 mg, 1 mg, 2.5 mg, 5 mg etc. dose:1-4 mg thrice daily (Minipress/Prazopress)
Beta-adrenergic blockers  Non selective: Propranolol (others: nadolol, timolol, pindolol, labetolol)  Cardioselective: Metoprolol (others: atenolol, esmolol, betaxolol)
Beta-adrenergic blockers  Advantages:  No postural hypotension  No salt and water retention  Low incidence of side effects  Low cost  Once a day regime  Preferred in young non-obese patients, prevention of sudden cardiac death in post infarction patients and progression of CHF  Drawbacks (side effects):  Fatigue, lethargy– decreased work capacity  Loss of libido – impotence  Cognitive defects – forgetfulness  Therefore cardio-selective drugs are preferred now
Beta- blockers block Kidney Beta-1 Heart Beta-1 Brain beta HR FOC CO BP RENIN RELEASE BP SYMPATHETIC OUTFLOW BP
Vasodilators: Arteriolar: minoxidil, diazoxide, hyralazine. minoxidil, diazoxide activate K+ channels (K+ channel openers) K+ efflux Hyperpolarization of vascular Smooth muscle vasodilatation BP
Minoxidil •It is a powerful arteriolar dilatator. •It is effective orally. •It causes reflex tachycardia, Na+ and water retention with edema. •Hence, minoxidil is used with a Beta-blocker and a loop diuretic. •Topical minoxidil is used to promote hair growth in male-type of baldness. (Minoxidil topical solutions and sprays are available).
Diazoxide •It is used in the treatment of hypertensive emergencies. •It is administered intravenously and has a long duration of action (6-24 hours). •It also relaxes uterine smooth muscle. •Adverse effects are reflex tachycardia, hyperglycaemia, sodium and water retention.
Hydralizine •It is a directly acting arteriolar dilator. •It is administered orally. •The side effects are reflex tachycardia, palpitation, sodium and water retention, which can be countered by combining hydralizine with a diuretic and a Beta- blocker.
Sodium nitroprusside •It is a powerful arteriolar and venodilator. • It has a rapid onset and short duration of action hence administered by i.v. infusion. •Sodium nitroprusside is a drug of choice for hypertensive crisis but can also be used to improve cardiac output in CCF
• Nitroprusside can cause severe hypotension, hence close monitoring of BP is required. • Prolonged administration may cause anorexia, nausea and vomiting, fatigue, disorientation, toxic psychosis due to accumulation of cyanide, which in turn may lead to severe lactic acidosis.
MOA: (sodium nitroprusside) Sodium nitroprusside Generates nitric oxide (NO) Relaxes vascular Smooth muscles vasodilatation HEART VENODILATOR ARTERIOLAR DILATOR POOLING OF BLOOD IN VEINS VENOUS RETURN PRELOAD CO MYOCARDIAL WORK PVR AFTERLOAD BP O2 DEMAND
TREATMENT OF HYPERTENSION 1. Non-pharmacological approaches helpful to control hypertension are weight reduction, sodium restriction, alcohol restriction, aerobic exercise, mental relaxation, cessation of smoking and consumption of potassium rich diet. DRUGS TO BE AVOIDED IN SPECIFIC CONDITIONS •ASTHMA •PERIPHERAL VASCULAR DISEASE --------- •DIABETES •HYPERLIPIDAEMIA----- THIAZIDES, BATA- BLOCKERS •GOUT------------------------ THIAZIDES •SEXUALLY ACTIVE MALES------ ALFA-1 BLOCKERS, DIURETICS NON-SELECTIVE BETA- BLOCKERS
MALIGNANT HYPERTENSION •It is characterized by a very high blood pressure (diastolic>130 mm of Hg) with progressive end organ damage such as retinopathy, renal dysfunction and / or hypertensive encephalopathy. •It is a medical emergency. •The preferred drug to treat the condition is sodium nitroprusside (i.v. infusion).
Imp TU Questions 1.Classify antihypertensive drugs. Mention indications and adverse effects of Enalapril. 2.Enumerate the uses and contraindications of beta blockers. 3.Differences between ACE inhibitors and angiotensin antagoinsts.
4.Describe vasodilators in the therapy of hypertension. 5.Briefly describe the management of action of ACE inhibitors . List their therapeutic uses.
ANTIHYPERTENSIVE (23.02.2020) 4classes (1).ppt