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  2. 2. A CASE SCENARIO... • A 35-year-old man presents with a blood pressure of 150/95 mm Hg. • He has been generally healthy, is sedentary, drinks several cocktails per day, and does not smoke cigarettes. • He has a family history of hypertension, and his father died of a myocardial infarction at age 55. • Physical examination is remarkable only for moderate obesity. • Total cholesterol is 220 • High-density lipoprotein (HDL) cholesterol level is 40 mg/dL. • Fasting glucose is 105 mg/dL. • Chest X-ray is normal. • Electrocardiogram shows left ventricular enlargement. • How would you treat this patient?
  3. 3. 1. List the Classification of Anti-hypertensive drugs according to the site of action 2. Describe the pharmacological basis for use of thiazides and other diuretics in hypertension 3. Describe the MOA, pharmacologic effects, ADR and indications for ACEIs and ARBs 4. List out the use of following drugs to treat hypertension ( CCB, Ganglion blocking drugs, Adrenergic neuron blocking drugs, Beta receptor antagonists, alpha receptor antagonists, vasodilators) 5. List out the Advantages and limitations of combining antihypertensives 6. Describe the Pharmacological agents used in PIH and ISH
  4. 4. DEFINING HYPERTENSION • Hypertension, also known as high or raised blood pressure, is a condition in which the blood vessels have persistently raised pressure. • Hypertension is diagnosed if, when it is measured on two different days, the systolic blood pressure readings on both days is ≥140 mmHg and/or the diastolic blood pressure readings on both days is ≥90 mmHg
  5. 5. A BRIEF HISTORY • 1950s Veratrum and Sodium thiocyanate - toxic and difficult to use Ganglion blockers - effective but varied side effects Reserpine - Very effective but caused Mental depression Hydralazine - Marked side effects when used alone • 1960s Methyldopa, Beta blockers, Thiazides, Loop diuretics, Clonidine 1961 - Guanithidine - improvement on ganglion blockers
  6. 6. Contd.. • 1970s Alpha 1 blocker - prazosin introduced • 1980 - 1990s ACE inhibitors, ARBs, CCB • 1995 Imidazolines, Neutral endopeptidase inhibitors • 2007 Direct renin inhibitors - Aliskiren • Nov 2022 Baxdrostat - AAldosterone synthesis inhibitor for resistant hypertension https://www.sciencedaily.com/releases/2022/11/221107192302.htm Currently in Phase 2 trials
  7. 7. • THIAZIDES - Diuretic of choice for uncomplicated hypertension; have similar efficacy. • Enhance the effect of other antihypertensive agents. • Chlorthalidone has longer t1/2 - 48hrs compared to hydrochlorothiazide (< 24 hours)
  8. 8. ABSORPTION, FATE AND EXCRETION: • well absorbed from the intestine • effect starts within one hour. • distributed throughout the ECF and are relatively concentrated in the kidney. • crosses the placental barrier. • excreted in urine.
  9. 9. Anti-hypertensive action of thiazides is lost when 1. salt intake is high 2. NSAID intake
  10. 10. Actions of thiazides
  11. 11. • No effect on capacitance vessels, sympathetic reflexes are not impaired. • Postural hypotension is rare • Average fall in MAP - 10 mm Hg • Potentiate other Anti-hypertensives except DHP CCB. • Hence prevents tolerance to other agents by not allowing expansion of plasma volume
  12. 12. Thiazides should be used at low doses only because by increasing the dose, antihypertensive effect does not increase but adverse effects tend to increase. Indapamide: • Effective as an antihypertensive at lower doses than those required for the diuretic effect (due to its direct vasodilatory action). • It also produces less metabolic adverse effects (hypokalemia, hyperglycemia, hyperuricemia etc.) and can be used as an antihypertensive in diabetic patients (whereas other thiazides are contra-indicated).
  13. 13. • Once a day dosing, flat dose-response curve • No fluid retention, No tolerance • No CNS side effects • No postural hypotension • More effective in patients with Isolated systolic hypertension • Reduces risk of osteoporosis in older women and post-menopausal women • Low cost
  14. 14. • 1960s -70s Thiazides were used as monotherapy - dosage was 50mg/day of HCZ / Chlorthalidone Side effects noted were: • Hypokalemia - muscle pain, fatigue, loss of energy, Torsedes de pointes resulting in sudden cardiac death • Erectile dysfunction in males • Carbohydrate intolerance, precipitation of diabetes ( due to inhibition of insulin release because of hypokalemia) • Dyslipidemia - rise in total and LDL cholesterol, lowering of HDL - increases risk of atherogenesis • Hyperuricaemia - Inhibition of urate excretion - precipitates gout
  15. 15. ALLHAT (2002) - The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial - Thiazides are first choice anti-hypertensive. Low dose Thiazides <25mg/day were very effective. Side effects were only because of increasing the dose. Advantages of low dose thiazides: 1. Significant hypokalemia doesn’t occur 2. Continuous ECG monitoring - no incidence of increase in arrhythmias 3. Very minimal effects on blood glucose and lipid profile - so can be used in diabetes 4. Reduces Fatal and non fatal MI risk by 27-44% 5. Reduces stroke risk by 31-49% 6. Reduces left ventricular hypertrophy
  16. 16. • Potent, oral diuretic. • Not recommended for long term Rx • Indicated in severe hypertension with CHF and renal dysfunction. • Indacrinone can be used in patients of gout because it inhibits reabsorption of uric acid in the nephron (other loop diuretics and thiazides cause hyperuricemia).
  17. 17. • Rapidly absorbed (60-100%) from the GI tract. • Food reduces its bioavailability. • The onset of action is quick and the duration short. • Given IV, the diuresis begins within 2 minutes and lasts for 2-3 hours. • Excreted within 4 hours by kidney • Fifty per cent of the dose is excreted unchanged in urine; the rest is conjugated with glucuronide in the kidney. • Hence, in patients with renal insufficiency the plasma t½ is prolonged.
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  20. 20. DOSAGE FORMS:
  21. 21. (1) Aldosterone antagonist: Spironolactone, eplerenone. (2) Direct inhibitors of renal epithelial sodium channels: Triamterene and Amiloride - They have no anti-hypertensive action. These drugs are combined with loop or thiazide diuretics to prevent or correct hypokalemia.
  22. 22. SPIRONOLACTONE: • Acts by competitive antagonism of aldosterone, in the distal part of the nephron • Prevents potassium secretion and thus decreases sodium reabsorption. • Given orally, its full response is observed after 3-5 days. • Short t½ of 1.6 hrs. • Major action is due to an active metabolite, canrenone (t½ 17 hr). • When combined with thiazide or loop diuretics it prevents loss of potassium. • Metabolised to several inactive compounds.
  23. 23. PHARMACOLOGICAL USES OF SPIRONOLACTONE: • By itself it is not an antihypertensive agent. • As an add-on drug, it may be particularly useful in hypertensive patients with significant hypokalemia • Drug of choice in primary hyperaldosteronism. • Add-on drug in congestive heart failure. ADVERSE REACTIONS OF SPIRONOLACTONE • Hyperkalemia • Endocrine effects: decreased libido, gynecomastia, impotence and menstrual irregularity. • Miscellaneous effects: lethargy and drowsiness. • It may increase blood urea nitrogen and serum uric acid levels. • Gastritis Preparation and dosage: Spironolactone is supplied as a microcrystalline preparation, 25 mg tablet. Dose : 100-200 mg per day (maximum 400 mg) in divided doses.
  24. 24. 44
  25. 25. EPLERENONE • Blocks the mineralocorticoid receptors in the kidney, heart, blood vessels and brain more selectively than spironolactone. • Metabolised by the liver - t½ of 4 -6 hours. • Adverse reactions: GI intolerance, dizziness, hyperkalemia and hypertriglyceridemia. • Advantage over spironolactone is the lower incidence of endocrine side effects. It is used to treat: (a)Hypertension, in the dose of 50 mg OD, increased to 100 mg OD (maximum dose) within 4 weeks, as required, (b) Post MI CHF, in one half of the above dosage. (c) It is also used in the combined oral contraceptive pill, Yasmin
  26. 26. Absorption: Oral Bioavailability: ~3% Peak Plasma Time: 1-3 hr Onset of action: Optimum effect achieved within 2 weeks Effects are decreased when taken with a high fat meal Metabolism: In liver by CYP3A4 In preclinical studies, P-gp was found to be the major efflux system involved in intestinal absorption and elimination via biliary excretion of aliskiren Excretion: Half-life: 24 hr Excretion: Urine (~25%)
  27. 27. Pharmacokinetics: 53
  29. 29. ACE INHIBITORS: (Prototype drug - captopril)
  30. 30. • All ACEI are prodrugs except captopril and lisinopril • Bioavailability of about 65%. • Absorption is reduced by food and so it is given 1 hour before a meal. • Metabolism: liver (50%) • Metabolites: captopril-cysteine disulfide (inactive) • Renal excretion (95%) Dosage Forms & Strengths of captopril: Tablet - 12.5mg, 25mg, 50mg, 100mg
  32. 32. • Dry cough - possibly due to increase in bradykinin levels • Hyperkalemia, particularly in patients with renal insufficiency and in those taking a potassium sparing diuretic. • Skin rashes, disturbances of the sense of taste, vitiligo • Headache, GI disturbances, muscle cramps and rarely leucopenia. • Proteinuria (>1 g/day) has been described. • Angioedema. • Foetal toxicity in animals and should be avoided in pregnancy.
  33. 33. 63
  34. 34. Status in Hypertension: • Presently the first-line antihypertensives. • ACE inhibitors are useful in the treatment of hypertension of all grades due to all causes. • Addition of a diuretic potentiates their antihypertensive efficacy (90%) CLINICAL TRIALS: 1. AIRE (1993) - Acute Infarction Ramipril Efficacy Study 2. HOPE (2000) - Heart Outcomes Prevention Evaluation 3. ALLHAT (2002) - The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial All the prospective studies confirmed the anti-hypertensive and cardioprotective effects of ACE inhibitors. They are more effective in younger hypertensives (<55 yrs)
  35. 35. INDICATIONS: They are specially indicated as antihypertensives in: a. Hypertension with left ventricular hypertrophy - because hypertrophy is gradually reversed by ACE inhibitors. b. Patients with diabetes mellitus - because ACE-I slow the development of nephropathy. c. Renal diseases with hypertension - ACE inhibitors slow the progression of chronic renal diseases like glomerulosclerosis. d. Patients with co-existing IHD including post-MI patients. e. In severe hypertension, they may be combined with other antihypertensives like β-blockers, CCBs or diuretics
  36. 36. Contraindication for ACEI: (1) Severe bilateral renal artery stenosis as they reduce GFR and may cause renal failure, (2) Aortic stenosis, (3) Coarctation of the aorta; and (4) Pregnancy.
  37. 37. ENALAPRIL: • It is a prodrug and is converted in the body to the active metabolite enalaprilat. • Food does not interfere with its absorption. • It is more potent. • Its action is slower but lasts longer. • It is less liable to cause taste disturbances, leucopenia and glomerulopathy • Enalaprilat is the only drug in this class available intravenously.
  38. 38. • block the AT1 receptors, • Pharmacologic effects are similar to those of ACE inhibitors • ARBs do not increase bradykinin levels. • Used as first-line agents for the treatment of hypertension, especially in patients with a compelling indication of diabetes, heart failure, or chronic kidney disease. • ARBs should not be combined with an ACE inhibitor for the treatment of hypertension due to similar mechanisms and adverse effects. • teratogenic
  39. 39. • Pharmacokinetics are similar to ACEIs • All indications, adverse effects and contra- indications of ACEI also apply to ARB except that incidence of cough and angioedema is less with ARB. • Metabolized by hepatic P450 enzyme CYP2C9.
  40. 40. Special features of losartan: – Produce active metabolite - 5-Carboxylic acid (E-3174) (active metabolite; 40 times as potent as losartan in angiotensin II-blocking activity) – Has anti-platelet action due to competitive antagonism of TXA2. – Mild uricosuric effect Telmisartan has additional PPAR-δ agonistic activity. This activity can help in patients with dysglycemia. Telmisartan is longest acting whereas eprosartan is shortest acting ARB.
  41. 41. 1. LIFE (2002) - LCZ696 In Advanced Heart FailurE 2. VALUE (2004) - Valsartan Antihypertensive Long-term Use Evaluation Outcomes in hypertensive patients with valsartan or amlodipine. 3. SCOPE (2004) - Study on COgnition and Prognosis in Elderly Stroke prevention with candesartan in elderly with ISH. 4. JLIGHT (2004) - Japanese Losartan therapy Intended for Global renal protection in HyperTensive patients. All these trials attested the favourable effects of ARBs on morbidity and mortality in hypertensive patients.
  42. 42. CCB belong to 3 chemically distinct classes: 1. Phenylalkylamines e.g., Verapamil • Least selective • Has significant effects on both cardiac and vascular smooth muscle cells. 2. Dihydropyridines (DHP) e.g., Nifedipine, Amlodipine, etc. Greater affinity for vascular calcium channels than the calcium channels in the heart. They are beneficial in treating hypertension. They show little interaction with other cardiovascular drugs, such as digoxin or warfarin. 3. Benzothiazepines e.g., Diltiazem. Affects both cardiac and vascular smooth muscle cells.
  43. 43. 82
  44. 44. 83
  45. 45. • Most of these agents have short half-lives (3 to 8 hours) following an oral dose. • Sustained-release preparations are available and permit once-daily dosing. • Amlodipine has a very long half-life and does not require a sustained-release formulation • As these drugs are metabolised by liver, dose adjustment in patients with renal disease is less critical. • They are potent vasodilators. • Calcium channel blockers do not dilate veins.
  46. 46. • Nifedipine - hypertensive emergencies. • Nifedipine and other short half-life dihydropyridines are not recommended for long term treatment of hypertension. • CCB are useful in impaired renal function or asthma, and in acute hypertension during pregnancy. • As a monotherapy particularly in moderately hypertensive patients with diabetes mellitus. • Diltiazem and amlodipine are as effective as diuretics, beta-blockers or their combination, in the long term treatment of essential hypertension.
  47. 47. VERAPAMIL - 1st degree AV block, constipation. Verapamil and diltiazem - avoided in patients with heart failure or with atrioventricular block due to their negative inotropic and dromotropic effects. DIHYDROPYRIDINES - Dizziness, headache, feeling of fatigue caused by a decrease in blood pressure, Peripheral edema, gingival hyperplasia. CCB have no significant CNS effects. Edema of feet may be observed.
  48. 48. 90
  49. 49. DOSAGE FORMS:
  50. 50. CLEVIDIPINE Clevidipine is a dihydropyridine L-type calcium channel blocker, highly selective for vascular smooth muscle. It reduces mean arterial blood pressure by decreasing systemic vascular resistance. Used in patients with acute hypertension who cannot take drugs orally. Pharmacokinetics: • Onset: 2-4 minutes • Protein Bound: 99.5% • Metabolized in blood and extravascular tissues • Half-Life: Initial 1 minute; terminal 15 minutes • Excretion: Urine (63-74%); feces (7-22%) Dosage forms: Intra venous emulsion - 1–2 mg/hour IV infusion. 95
  51. 51. 1. HINT, TRENT, SPRINT I & II - Increased mortality / re-infarction in patients treated with standard nifedipine or other short acting DHPs. Possibly because of repeated surges of adrenergic discharge and marked swings of BP due to short action of rapidly acting DHP. 2. These were not seen in long acting DHP and Verapamil / diltiazem - DAVIT I & II
  52. 52. contd.. 3. Syst-EUR - Systolic hypertension in Europe shows that Nitrendipine reduces cardiovascular morbidity and mortality in elderly hypertensives 4. ACCOMPLISH (2008) and ASCOT-BPLA (2005) - Superior efficacy of amlodipine both as monotherapy and when combined with an ACEI for reducing CVS events in high risk HTN patients 5. ALLHAT and Syst-EUR - Stroke prevention by CCB • CCBs are next to ACEI in slowing diabetic nephropathy • Most useful anti-hypertensives in cyclosporine induced Hypertension in renal transplant recipients.
  53. 53. PHARMACOKINETICS: • It is well absorbed after oral and parenteral administration. • Maximal blood levels are reached within 3 to 4 hours after oral administration. • The drug is acetylated in the liver. Fast acetylators → drug levels → less drug effect Slow acetylators→ drug levels → ADR: SLE • Elimination of the drug is almost complete within 24 hours. • Less than 5% of an oral dose is excreted unchanged in urine. Hence, it can be used even in the presence of renal damage.
  54. 54. PHARMACOLOGICAL ACTIONS: • Direct relaxation of the arteriolar wall. • The effect is slow in onset but prolonged. Even on its IV administration, the BP falls only after 15-20 minutes. • The fall in BP → decrease in the total peripheral resistance ↓ compensatory tachycardia (↑ CO and SV) • The splanchnic, coronary, cerebral and renal blood flow may increase. • It causes increase in plasma renin activity and fluid retention. • It can be given in hypertension during pregnancy (2nd and 3rd trimesters).
  55. 55. ADVERSE REACTIONS: • Gastrointestinal irritation producing nausea, vomiting, gastric hypersecretion, anorexia and diarrhoea. • Cardiac effects: These include palpitation, tachycardia and anginal attacks. • Others like headache, nasal congestion, flushing, tremors and dizziness. • It causes secondary salt and water retention. • Intolerance: The manifestations are fever, skin rash and polyneuritis. • GI haemorrhage and pancytopenia are serious manifestations. • Acute rheumatoid arthritis or SLE like syndrome may develop with large doses (over 600 mg/day) given for prolonged periods.
  56. 56. Preparations and dosage: • Hydralazine hydrochloride tablets 10, 25, and 50 mg. Maximum dose 100 mg daily. • Dihydralazine sulphate 25 mg tablet. • Injection 20 mg for IM/IV use.
  57. 57. 2. SODIUM NITROPRUSSIDE: This drug, known since 1850, has been used as a colour indicator for acetone and aldehydes. It was regarded as a poison because of its cyanide group. Given by IV infusion, it is metabolised to active compound NO which causes relaxation of arterioles and veins. • This results in the reduction in peripheral resistance and venous tone, lowering the after load and the preload. • The myocardial oxygen consumption is reduced with improvement in myocardial function in low output states. • Heart rate and the regional blood flow are little affected. • It increases plasma renin activity. • It is rapidly metabolised to thiocyanate. • The action is of rapid onset but of very short duration
  58. 58. THERAPEUTIC USES: • Hypertensive emergencies. • It is infused IV slowly in the dose of 0.5-5 mcg/kg/min. • In the treatment of severe hypertension, if the BP is not adequately controlled after 10 minutes of infusion at the maximal rate, the drug should be stopped immediately for fear of toxicity. • Nitroprusside must not be stopped abruptly during treatment of heart failure because of the danger of rebound hypertension.
  59. 59. ADVERSE EFFECTS: • Hepatic dysfunction • Thiocyanate toxicity - Prolonged administration of sodium nitroprusside either in high doses or in the presence of renal insufficiency. This results in fatigue, anorexia, nausea, vomiting, sweating, disorientation, psychotic behavior and muscle twitching. Larger doses may cause ataxia, rigidity, convulsions and metabolic acidosis. • Nitrates have a synergistic effect with vasodilator drugs and can lead to sudden fall in BP and collapse.
  60. 60. PREVENTION OF TOXICITY: • Administration of sodium thiosulphate along with nitroprusside prevents the accumulation of cyanide. • Alternatively, hydroxocobalamin may be given which combines with cyanide to form cyanocobalamin which is a nontoxic compound. • Methaemoglobinaemia is also known following infusion of nitroprusside. It should be avoided in pregnancy.
  61. 61. AVAILABLE FORMS • Sodium nitroprusside is supplied as 50 mg powder to be dissolved in 500 ml of 5% dextrose in water, just prior to administration. • When it is exposed to light, it is converted to cyanide; hence a brown or black paper bag over the IV fluid container is necessary. • Translucent plastic tubing may need taping. • Only freshly prepared solution should be used.
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  63. 63. DOSAGE AND AVAILABLE FORMS: Minoxidil is used with a diuretic as a reserve drug in patients with severe hypertension who do not respond to other drugs. Minoxidil is started with a low dose of 5 mg daily and is gradually increased to 40–50 mg. BALDNESS: Activates the gene that controls the protein of hair shaft by this it stimulates the maturation and growth of cells of the hair shaft. Hence it is used topically (2% solution) for the correction of alopecia.
  64. 64. DIAZOXIDE: Related to thiazide diuretics and is a potent arteriolar dilator. MOA - similar to minoxidil ADR: Hyperglycaemia, salt and water retention, palpitation and myocardial ischaemia. THERAPEUTIC USE: It is used intravenously in hypertensive emergencies where monitoring of infusion is not possible. Diazoxide has a long duration of action (24 hours) and is suitable in such situations.
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  66. 66. Fenoldopam: It is a D1 dopamine receptor agonist, brings about dilation of peripheral arteries and also loss of sodium. It has a short t½ of 10 minutes and is given as an IV infusion. USES: Useful in hypertensive emergencies and postoperative hypertension, particularly when there is impaired renal function. Started with a low dose of 0.1 μg/kg/min, it is gradually increased every 20 minutes till adequate response is attained. (maximum dose 1.6 μg/kg/min). Adverse effects: include flushing, headache, palpitation and hypotension. It should be avoided in patients with glaucoma since it can raise the intraocular pressure. Fenoldopam has efficacy similar to sodium nitroprusside but is devoid of thiocyanate-related complications.
  67. 67. Peripheral vascular alpha- receptors are of two types • Postsynaptic α1 receptors which are stimulatory in nature; their activation causes vasoconstriction and • Presynaptic α2 receptors (auto-receptors), which are inhibitory in nature; their activation inhibits NA release.
  68. 68. NON SELECTIVE ALPHA BLOCKERS PHENOXYBENZAMINE Cyclizes spontaneously to highly reactive ethyleniminium intermediate. Competitive block: Blockade is slow onset & longer duration (3-4 days). Also inhibits reuptake of NE. Shifts blood from pulmonary to systemic circuit. Shift fluid from extravascular to vascular compartment - relaxation of postcapillary vessels. PHARMACOKINETICS - Preferred ROA- i.v. Lipid soluble -penetrates brain. Mainly excreted through urine in 24 hrs. Accumulates in adipose tissue on chronic administration. Dose - 20-60 mg/d oral; 1mg/kg/1hr slow i.v infusion. Uses - Pheochromocytoma, occasionally 2° shock, PVD PHENTOLAMINE More potent α-blocker Duration of action is shorter (min). Equally blocks α1 & α2 receptors- NA release ↑sed. Uses - Δsis & intraop.management of pheochromocytoma. HTN due to clonidine withdrawl, cheese reaction. Dermal necrosis due to extravasated i.v NA/DA. Given S.C as local infiltration.
  69. 69. ALPHA 1 BLOCKER Prazosin • Highly selective α1-blocker , α1: α2 selectivity 1000:1 • Fall in BP with only mild tachycardia. • Dilates arterioles more than veins • Postural hypotension occurs as 1st dose effect, minimized by starting with low doses at bed time. • Also inhibits PDE- ↑se cAMP in smooth muscle. PK • Effective orally, BA- 60%. • Highly bound to plasma proteins (α1 acid glycoprotein). • Metabolized in liver, excreted in bile. • t1/2 – 2-3hrs, effect lasts for 6-8hrs. Uses • Primarily as antihypertensive. • LVF not controlled by diuretics & digitalis. • Raynaud’s disease • BPH • Scorpion sting
  70. 70. FIRST DOSE EFFECT • Occurs in 1% patients • Due to profound postural hypotension • Lose consciousness 30-60 min after receiving 1st dose • Minimized by given first dose of the drug at bedtime or in very low initial doses (less than 1mg) • Adviced patients not to drive or do any hazardous activities after taking the dose for 12-24hrs.
  72. 72. BETA BLOCKERS • They are the first-line antihypertensive drugs in mild to moderate hypertension with cardiac problems. • β-blockers are effective and well-tolerated and are of special value in patients who also have arrhythmias or angina. • They should not be used alone. • Suitable for combination with other antihypertensives, particularly with drugs that cause tachycardia as their side effect (e.g. vasodilators). • Beta blockers are avoided in patients with peripheral arterial disease.
  73. 73. Atenolol is the preferred β-blocker because of the advantages like once a day dosing, absence of CNS side effects and β1 selectivity. β-blockers should always be tapered while withdrawing. Metoprolol may be given as a sustained release preparation for twice daily use. It is particularly preferred in patients with concurrent hypertension and heart failure. Esmolol is a short-acting β1-blocker with a half life of about 10 min. It is given intravenously as a loading dose of 0.5–1 μg/kg followed by an infusion (50–300 μg/kg/min). Esmolol is suited for use in intraoperative and postoperative hypertension and in hypertensive emergencies.
  74. 74. ALPHA + BETA BLOCKERS Labetalol and carvedilol block α1- and β- receptors. They are used IV in the treatment of hypertension in pheochromocytoma and in hypertensive emergencies.
  75. 75. TO SUMMARIZE
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  78. 78. CLONIDINE MECHANISM OF ACTION: It is a selective α2-agonist. Stimulation of α2 autoreceptors in the CNS (in the vasomotor centre and hypothalamus) decreases central sympathetic outflow, blocks the release of noradrenaline from the nerve terminals leading to a fall in BP and bradycardia
  79. 79. Pharmacological actions: Given IV it produces a transient hypertensive response followed by a prolonged fall in both systolic and diastolic BP accompanied by bradycardia. Initial hypertensive effect is not seen after its oral administration. PHARMACOKINETICS: Bioavailability: Immediate release (75-85%) Protein bound: 20-40% Duration: 6-10 hr. Metabolism in Liver. Elimination Half-life: 12-16 hr. Excretion: Urine
  80. 80. Other Uses 1. In opioid withdrawal: Most withdrawal symptoms in opioid addicts are of sympathetic overactivity and can be benefited by treatment with clonidine. 2. Diabetic neuropathy: Clonidine controls diarrhoea by improving absorption of NaCl and water in the gut by stimulation of α2 receptors in the intestines. 3. With anaesthetics: Clonidine given preoperatively reduces the dose of the general anaesthetic needed due to its analgesic effects.
  81. 81. Preparations: Clonidine hydrochloride 0.1 mg tablets. A transdermal preparation is also available; its effect lasts for 7 days. Guanfacine and Guanabenz are related to clonidine and have actions similar to clonidine. Their duration of action, however, is prolonged. New drugs like moxonidine and rilmenidine are congeners of clonidine with longer half lives. These drugs are selective for imidazoline receptors that modulate the central α2 receptor activity.
  82. 82. AVAILABLE DOSAGE FORMS: Abrupt discontinuation of clonidine therapy can lead to rebound hypertension - Rx with phentolamine
  83. 83. ALPHA METHYL DOPA • An analog of dopa, is a prodrug. • It is metabolised in the body to alpha methyl norepinephrine which is an α2- agonist and acts like clonidine. • It reduces central sympathetic outflow leading to a fall in BP. • Renin levels also fall but renal blood flow is well maintained. • Onset of action is about 4–6 hr • Duration of action 12–24 hr. • Left ventricular hypertrophy is reversed in about 12 weeks of treatment.
  84. 84. USES: Methyldopa is used in mild to moderate hypertension along with a diuretic. It is safe in hypertension during pregnancy and is the preferred antihypertensive in such patients. Started with 250 mg twice daily, the dose may be increased to a maximum of 750 mg BD. ADVERSE EFFECTS: Sedation, dryness of mouth and nose, nightmares, depression, vertigo, extrapyramidal signs, raised prolactin levels, headache, postural hypotension, impotence, hemolytic anemia On prolonged use, salt and water retention may blunt the antihypertensive effect (called pseudotolerance) and needs a diuretic to be added.
  85. 85. • These drugs inhibit the NN type of nicotinic receptors that are present on the autonomic ganglia (both sympathetic and parasympathetic). • The therapeutic effect (decrease in blood pressure) is due to the decrease in neurotransmission through sympathetic ganglia whereas decreased transmission through parasympathetic ganglia is responsible for the adverse effects like urinary retention and dry mouth. • Hexamethonium and trimethaphan are the drugs in this group and are used as antidotes for nicotine poisoning.
  86. 86. • Trimethaphan is given intravenously to produce controlled hypotension during certain surgical procedures due to its rapid and short action (15 minutes) • Trimethapan is used along with nitroprusside as a slow i.v. infusion for hypertensive emergencies in aortic dissection.
  87. 87. Guanethidine: depletes the stores of noradrenaline in the adrenergic neurons and also blocks its release. Because of the adverse effects like postural hypotension, diarrhoea and sexual dysfunction, guanethidine is not used.
  88. 88. Reserpine It is an alkaloid obtained from Rauwolfia serpentina (Sarpagandhi) that grows in India. MECHANISM OF ACTION: • In the adrenergic neurons, it binds to the vesicles that store monoamines like noradrenaline, dopamine and 5-HT and destroys these vesicles. • Reserpine thus depletes the stores of these monoamines and reduces BP. • Depletion of monoamines particularly dopamine is thought to be responsible for the antipsychotic effects of reserpine
  89. 89. USES: Hypertension Initial - 0.5 mg daily for 1 or 2 weeks Maintenance - 0.1-0.25 mg PO OD Use higher dosages cautiously occurrence of mental depression or other adverse reactions may increase Psychiatric Disorders 0.5 mg daily, but may range from 0.1 to 1 mg; titrate dose according to patient response Tardive Dyskinesia 0.25 mg q6hr; may increase by 0.1-0.25 mg to a total of 5 mg daily
  90. 90. ADVERSE EFFECTS: drowsiness, depression, nightmares, parkinsonism, postural hypotension, oedema, weight gain, gynaecomastia and sexual dysfunction AVAILABLE FORMS AND DOSAGES: tablet - 0.1mg, 0.25mg It is not currently in clinical practice
  91. 91. 181
  92. 92. 182
  93. 93. 183 Major determinant - Aorta
  94. 94. 187
  95. 95. 189
  96. 96. 190
  97. 97. 191
  98. 98. 192
  99. 99. WHO guidelines 2021
  100. 100. CASE SCENARIO ANSWER The patient has Joint National Committee stage 1 hypertension. The strong family history suggests that this patient has essential hypertension. Need to do ECHO, LFT, RFT, Sr. electrolytes Non-Pharmacological management - behavioral, including dietary changes and aerobic exercise. 198
  101. 101. CONTD.. Thiazide diuretics in low doses are inexpensive, have relatively few side effects, and are effective in many patients with mild hypertension. Other first-line agents include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers. A single agent should be prescribed and the patient reassessed in a month. If a second agent is needed, one of the two agents should be a thiazide diuretic. Once blood pressure is controlled, patients should be followed periodically to reinforce the need for compliance with both lifestyle changes and medications. 199
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  104. 104. REFERENCES: 1. Goodman and Gilman’s Pharmacological basis of therapeutics 13th edition 2. Katzung Clinical Pharmacology 15th edition 3. KD Tripathi Essentials of Medical Pharmacology 8th edition 4. RS Satoskar Pharmacology and Pharmacotherapeutics 26th edition Web references - Google, slideshare, Osmosis videos, Pubmed 202