Hypertension intorduction and Pharmacotherapeutics .pptx

Hypertension intorduction and Pharmacotherapeutics

1. Hypertension Dr. Ajith JS Pharm D , Asst. Prof MET-IOP Nashik.

2. Introduction Hypertension is a common disease that is defined simply as persistently elevated arterial blood pressure (BP)” or Defined as a condition where blood pressure is elevated to an extent where clinical benefits obtained from blood pressure lowering.

3. Classification : The Seventh Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) classifies adult blood pressure as below: CLASSIFICATION OF BLOOD PRESSURE SYSTOLIC BLOOD PRESSURE (mmHg) DIASTOLIC BLOOD PRESSURE (mmHg) Normal <120 <80 Pre-hypertension 120-139 80-89 Stage 1 hypertension 140-159 90-99 Stage 2 hypertension ≥160 ≥100

4. Risk Factors Age People with diabetes or renal failure Smoking Hyperlipidaemia Obesity Sedentary lifestyle

5. Complications Myocardial Infarction Stroke Cerebral/brainstem infarction Cerebral haemorrhage Lacunar syndromes Multi-infarct disease Hypertensive encephalopathy/malignant hypertension Dissecting aortic aneurysm Hypertensive nephrosclerosis Peripheral vascular disease

6. Worldwide, HTN ranks #1 in cause of death among 26 health factors (12.8% or 7 million deaths / year)* 46% more than attributed to tobacco. HTN ranks third behind underweight and unsafe sex in factors responsible for burden of disease 10%-25% population are expected to benefit from drug treatment of hypertension. EPIDEMIOLOGY

7. 90-95% of cases of hypertension there is no underlying medical illness to cause high blood pressure (Primary or Essential HTN).* 5-10% of cases are secondary to some other disease process (Secondary HTN) * Starting at a BP of 115/75 mm Hg, risk of cardiovascular disease doubles with every 20/10 mm Hg increase.*

8. Hypertension Prevalence by Age and Gender

9. Obesity (BMI > 30 kg/m 2 ) by age and gender

10. Etiology Essential or Primary hypertension identifying the exact underlying abnormality is not possible Genetic factors may play an important role Secondary hypertension comorbid disease or a drug most of the cases, secondary hypertension is due to renal dysfunction resulting from chronic kidney disease or renovascular disease

11. Disease Drugs Associated with Hypertension in Humans Chronic kidney disease Prescription drugs Cushing’s syndrome Corticosteroids, ACTH Coarctation of the aorta Estrogens Obstructive sleep apnea NSAIDs,COX-2 inhibitors Parathyroid disease Phenylpropanolamine and analogues Pheochromocytoma Cyclosporine and tacrolimus Primary aldosteronism Erythropoietin Renovascular disease Sibutramine Thyroid disease Antidepressants Street Drugs and Other Natural Products Cocaine and cocaine withdrawal phenylpropanolamine analogues Nicotine and withdrawal, anabolic steroids, narcotic withdrawal, methylphenidate, phencyclidine, ketamine, ergotamine and Other ergot-containing herbal products, St. John’s wort Food Substances Sodium, Ethanol, Licorice Chemical Elements and Other Industrial Chemicals Lead, mercury, thallium and other heavy metals, lithium

12. Potential Mechanism of Pathogenesis Increased cardiac output Increased cardiac preload: Increased fluid volume from excess sodium intake or renal sodium retention (from reduced number of nephrons or decreased glomerular filtration) Venous constriction: Excess stimulation of the RAAS Sympathetic nervous system overactivity Increased peripheral Resistance Functional vascular constriction: Excess stimulation of the RAAS Sympathetic nervous system overactivity Genetic alterations of cell membranes Endothelial-derived factors Structural vascular hypertrophy: Excess stimulation of the RAAS Sympathetic nervous system overactivity Genetic alterations of cell membranes Endothelial-derived factors Hyperinsulinemia resulting from obesity or the metabolic syndrome

13. Hypertensive Crises BP >180/120 mmHg Hypertensive Urgency Without end organ damage Oral antihypertensives Decrease BP, in hours to days, to Stage I Hypertensive Emergency With end organ damage IV antihypertensive Decrease BP, in minutes to hours, to DBP <110mmhg

14. Pathophysiology Humoral Mechanism RAAS Natriuretic hormone Insulin Resistance and Hyperinsulinemia Neuronal Regulation Peripheral Autoregulatory Component Vascular Endothelial Mechanism Electrolytes and Other Chemical

15. Humoral Mechanism Natriuretic hormone inhibits sodium and potassium ATPase and interferes with sodium transport across cell membranes block the active transport of sodium out of arteriolar smooth muscle cells . increased intracellular concentration of sodium ultimately would increase vascular tone and BP

16. Insulin Resistance and Hyperinsulinemia (Metabolic syndrome) may lead to hypertension because of renal sodium retention and enhanced sympathetic nervous system activity

17. Other possible mechanisms Insulin has growth hormone–like actions that can induce hypertrophy of vascular smooth muscle cells. Insulin also may elevate BP by increasing intracellular calcium, which leads to increased vascular resistance

18. Neuronal Regulation CNS & ANS are involved in the regulation of arterial BP. α and β presynaptic receptors play a role in negative and positive feedback to the norepinephrine containing vesicles located near the neuronal ending

19. Neuronal Regulation presynaptic α 2 exerts a negative inhibition on norepinephrine release. postsynaptic α 1 –receptors on arterioles and venules results in vasoconstriction

20. Neuronal Regulation presynaptic β-receptors facilitates further release of norepinephrine β1-receptors in the heart results in an increase in heart rate and contractility, β2-receptors in the arterioles and venules causes vasodilation

21. Neuronal Regulation purpose of these neuronal mechanisms is to regulate BP and maintain homeostasis Pathologic disturbances in any of the four major components autonomic nerve fibers, adrenergic receptors, Baroreceptors,or central nervous system could lead to chronically elevated BP.

22. Peripheral Autoregulatory Component Abnormalities in renal or tissue autoregulatory systems could cause hypertension. renal defect in sodium excretion may develop first, cause resetting of tissue autoregulatory processes, resulting in a higher arterial BP. The kidney usually maintains BP through a volume pressure–adaptive mechanism.

23. When BP drops, kidneys increases retention of sodium and water. lead to plasma volume expansion, increases BP . Conversely , when BP rises above normal, renal sodium and water excretion are increased reduce plasma volume and cardiac output, maintain homeostatic BP conditions

24. Local autoregulatory processes maintain tissue oxygenation Local arteriolar vasoconstriction when tissue oxygen demand low to normal and vasodilation during increased metabolic demand Intrinsic defects in renal adaptive mechanisms Plasma volume expansion & increased blood flow during normal BP Activation of local auto regulatory process – vasoconstriction to offset increased blood flow. Increased PVR, if sustained results in thickened arteriolar walls

25. Vascular Endothelial Mechanism Deficiency in the local synthesis of vasodilating substances e.g., prostacyclin and bradykinin Excess vasoconstricting substances e.g., angiotensin II and endothelin I contribute to essential hypertension, atherosclerosis, and other diseases.

26. Vascular Endothelial Mechanism Nitric oxide is produced in the endothelium, relaxes the vascular epithelium, very potent vasodilator. Nitric oxide system is an important regulator of arterial BP. Hypertensive patients may have an intrinsic deficiency in nitric oxide release, resulting in inadequate vasodilation. role of nitric oxide in hypertension is unclear, it may be a pharmacologic target in the future

27. Electrolytes and Other Chemical Sodium Clinical studies have shown consistently that dietary sodium restriction lowers BP in many (but not all) patients with elevated BP. The exact mechanisms by which excess sodium leads to hypertension are not known

28. Calcium A lack of dietary calcium can disturb the balance between intracellular and extracellular calcium, resulting in an increased intracellular calcium concentration. This imbalance can alter vascular smooth muscle function by increasing peripheral vascular resistance. Some studies have shown that dietary calcium supplementation results in a modest BP reduction in hypertensive patients.

29. Potassium Potassium depletion may increase peripheral vascular resistance, clinical significance of small serum potassium concentration changes is unclear Uric acid Hyperuricemia has been associated with an increased risk of cardiovascular events in hypertensive patients remains controversial because of inconsistent data

30. Symptoms: Most patients are asymptomatic. However some patients complains of Headache Confusion and deficit memory Sleepiness Difficulty in breathing Tingling and numbness of hands and feet. Signs: The only sign of hypertension is elevated blood pressure measured using sphygmomanometer.

31. Arterial blood pressure Arterial BP is the measured pressure in the arterial wall in millimeters of mercury Pulse pressure Difference between SBP and DBP Mean Arterial Pressure Arterial BP CO is the major determinant of SBP, where as TPR largely determines DBP

32. Isolated systolic hypertension DBP less than or equal to 90mmHg SBP greater than or equal to 140mmHg Increases the risk of Cardiovascular morbidity an mortality

33. Goals of the treatment Bring down the elevated BP to the normal value To reduce hypertension associated morbidity and mortality which is related to target organ damage e.g. heart failure, stroke, retinopathy, chronic kidney disease.

34. Goal BP - JNC 8 General >60 yrs – <150/90 mm Hg General < 60 Yrs - <140/90 mm Hg DM - < 140/90 mm Hg CKD - <140/90mm Hg

35. Overview Non-pharmacological Pharmacological Special population

36. MODIFICATION RECOMMENDATION APPROX. SYSTOLIC BLOOD PRESSURE REDUCTION (mm Hg) Weight reduction if overweight Maintaining normal body weight (body mass index 18.5-24.9 Kg/m 2 )     5-20/10Kg weight loss Adopt DASH (Dietary Approaches to Stop Hypertension) eating plan Consuming a diet rich in fruits, vegetables and low fat dairy products with a reduced content of saturated and total fat     8-14   Dietary sodium restriction Restricting daily dietary sodium intake to less than or equal to 2.4G sodium or 6G of sodium chloride     2-8   Physical activity Regular aerobic physical activity like brisk walking at least 30 min/day, most days of week   4-9   Moderate alcohol consumption if alcoholic Limiting alcohol consumption to less than or equal to 30mL ethanol/day for men and 15mL ethanol for women   2-4 Non Pharmacological therapy

37. Pharmacological methods Classification of drugs: Diuretics, beta-blockers, Angiotensin converting enzyme inhibitors (ACEIs), Angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs). Other agents like alpha blockers, central alpha2 agonists, adrenergic inhibitors and vasodilators

38. Selection of Drugs Compelling indications or contraindications Coexisting conditions Risk factors and presence of target organ damage Age Adverse effects Race A vailability of the drug and past experience of the physician

39. Algorithm for treatment of hypertension Initial Drug Therapy Choices No Compelling Indications Compelling Indications Stage 1 Hypertension (SBP 140–159 or DBP 90–99 mm Hg) Stage 2 Hypertension SBP > 160 or DPB >100 mm Hg Thiazide diuretics ,ACE inhibitor, ARB, CCB Two Drug combinations thiazide -type diuretic with an ACE inhibitor, or ARB, or CCB Prehypertension Life style modifications

40. Std Pharmacotherapy Add on Compelling Indication(s) Left Ventricular Function Diuretic with ACE inhibitor then add beta bloker ` Post MI Beta Blocker then ACE I Or ARBs Coronary Artery diseases DM CKD Stroke Beta Blocker then ACE I Or ARBs ACE I or ARBs ACE I or ARBs Diuretic with ACE inhibitor ARBs ARBs Or Aldosteron antagonist Aldosterone antagonost CCB Diuretics Diuretic Beta Blocker CCB

41. Thiazide Diuretics Thiazides Mechanism: inhibit Na/K pumps in the distal tubule Examples: Hydrocholorthiazide 12.5-25 mg daily Chlorthalidone 12.5-50 mg daily Indapamide 1.25–2.5 mg daily Metolazone 2.5–5 mg daily Effective first line agent and provides synergistic benefit As single agent more effective if CrCl >30 ml/min Compelling indications: HF, High CAD risk, Diabetes, Stroke, ISH

42. Loop Diuretics Thiazides Loops Mechanism: Inhibit Na/K/ Cl ATPase in ascending loop of henle (Dose in the morning and afternoon to avoid nocturnal diuresis , higher doses may be needed for patients with severely decreased glomerular filtration rate or left ventricular dysfunction) Examples Bumetanide 0.5–4 mg Furosemide ( Lasix ) 20–80 mg Torsemide 5–10 mg Typically only beneficial in patients with resistant HTN and evidence of fluid; effective if CrCl <30 ml/min

43. Aldosterone Receptor Antagonists Thiazides Loops Aldosterone Ant. Mechanism: inhibit aldosterone’s effect at the receptor, reducing Na and water retention Examples: Spironolactone 25 mg daily Can provide as much as 25 mmHg BP reduction on top of 4 drug regimen in resistant hypertension Monitor SCr and K Compelling indications: HF

44. Nitrates Thiazides Loops Aldosterone Ant. Nitrates Mechanism: Direct venodilation by release of nitric oxide Examples: Isosorbide dinitrate 10 mg TID In renal patients with resistant hypertension addition to 3-4 drug regimen may help get patient to goal Provide 8h nitrate free interval daily Compelling indications: Angina

45. ACEI & ARB’s Thiazides Loops Aldosterone Ant. Nitrates ACEI ARB Veins Mechanism: Inhibit vasoconstriction by inhibiting synthesis or blocking action of angiotensin II; provides balanced vasdilation Examples: Benazepril 10–40 mg Captopril 25–150 mg Enalapril 5-40 mg Fosinopril 10-40 mg Lisinopril 10-40 mg Moexipril 7.5-30 mg Perindopril 4-16 mg Quinapril 10-80 mg Ramipril 2.5-10 mg Trandolapril 1-4 mg Eprosartan 600–800 mg Irbesartan 150–300 mg Losartan 50–100 mg Olmesartan 20–40 mg Telmisartan 20–80 mg Valsartan 80–32 mg Monitor: SCr , K Compelling indications: HF, post-MI, High CAD risk, Diabetes, CKD, Stroke

46. Beta Blockers Beta Blockers Heart Mechanism: Competitively inhibit the binding of catecholamines to beta-adrenergic receptors Examples: Atenolol 25-100 mg PO daily Metoprolol 25 -100 mg PO daily or BID Carvedilol 6.25-25 mg PO BID Monitor: HR, Blood Glucose in DM Not contraindicated in asthma or COPD but use caution Compelling indications: HF, post-MI, High CAD risk, Diabetes

47. β- Blockers Cardioselective Atenolol 25–100 mg od Betaxolol 5–20 mg od Bisoprolol 2.5–10 mg od Metoprolol tartrate 100–400mg BID Metoprolol succinate 50–200 mg od Nonselective Nadolol 40–120 mg Propranolol 160–480 mg bid Timolol 10–40 od Intrinsic sympathomimetic activity Acebutolol 200-800mg bid Carteolol 2.5-10 mg od Penbutolol 10-40 mg od Pindolol 10-60 mg bid

48. Mixed α- and β- blockers Carvedilol 12.5-50 mg bid Carvedilol phosphate 20-80 mg od Labetalol 200-800 mg bid Calcium channel blockers Mechanism: Decrease calcium influx into cells of vascular smooth muscle Dihydropyridines Amlodipine 2.5 -10 mg od Felodipine 5-20 mg od Isradipine 5-10 mg bid Isradipine SR 5-20 mg od Nicardipine SR 60-120 bid Nifedipine long-acting 30-90 od Nisoldipine 10 -40 od

49. Nondihydropyridines Diltiazem SR 180–360 mg bid Verapamil SR 180–480 mg od or bd Verapamil ER 180–420 mg od

50. Alpha 2 Agonists: Central Acting Agents Via Central Mechanism: Clonidine Heart Mechanism: false neurotransmitters reduce sympathetic outflow reducing sympathetic tone Examples: Clonidine 0.1-0.6 mg PO BID-TID; patch Methyldopa, Guanabenz , Guanfacine Monitor: HR Side effects often limiting: Dry mouth, orthostasis , sedation Clonidine patch can be useful in elderly patients with labile blood pressure

51. Vasodilators Dihydropyridine CCBs Hydralazine Minoxidil Arteries Mechanism: Direct vasodilation of arterioles via increased intracellular cAMP Examples: Hydralazine 20-400 mg BID-QID Minoxidil 2.5-40 mg PO daily-BID Monitor: HR (can cause reflex tachycardia), Na/Water retention Hydralazine is an alternative in HF if ACEI contraindicated Consider minoxidil in refractory patients on multi-drug regimens

52. Alpha 1 Blockers Alpha 1 Blockers Arteries Mechanism: Inhibit peripheral post-synaptic alpha1 receptors causing vasodilation Examples: Terazosin 1 – 20 mg daily Doxazosin 1 – 16 mg daily Cause marked orthostatic hypotension, give dose at bedtime Consider only as add on therapy Can be beneficial in patients with BPH

53. First line agents Diuretics ACE/ ARBs CCBs

54. Management of hypertension in special populations Hypertension in older people: All antihypertensive drug classes are effective in older hypertensives . Thiazide -type diuretics recommended by JNC-7. Avoid direct vasodilators and central adrenergic drugs. Drug selection should be an individualized decision. Start low; go slow!

55. older people The goal of treatment in older patients should be the same as in younger patients (to below140/90 mm Hg if at all possible), Goal of SBP below 160 mm Hg may be necessary in those patients with marked systolic hypertension.

56. Hypertension in children and adolescent: Diuretics, beta-blockers, ACE inhibitors and long acting CCBs are preferred. Drugs to be avoided: ACE inhibitors and ARBs are contraindicated in sexually active girls as these agents are teratogenic.

57. Hypertension in pregnancy : Preeclampsia – HTN at 20 gestation wks with proteinuria Preeclampsia + convulsions – delivery definitive treatment IV antihypertensives prior to induction of labour (hydralazine/labetolol) Drug of choice – Methyl dopa (stable uteroplacental blood flow and fetal hemodynamics) B blockers and CCB’s effective alternatives ACE inhibitors – absolute contraindication

58. Hypertension in women Oral contraceptive use – increased susceptibility to HTN Also seen in HRT but not preclude use in hypertension Regular BP monitoring in women on OC, HRT ACEI & ARB contraindicated in intended pregnancy Postmenopausal women with osteoporosis – thiazide diuretics

59. Preeclampsia No benefit with aspirin or calcium--Ra Methyldopa still drug of choice Atenolol , metoprolol and labetalol are safe and effective in late pregnancy Calcium antagonists are good—with Magnesium can potentiate hypotension Hydralazine is parenteral drug of choice

60. Hypertension with pulmonary disease (asthma or Chronic Obstructive Pulmonary Disease): Drugs to be avoided: Non-selective beta blockers should be avoided in hypertensive patients with either asthma or Chronic Obstructive Pulmonary Disease.

61. Hypertension with Dyslipidaemia: Alpha blockers decreases low density lipoprotein (LDL) cholesterol and increases high density lipoprotein (HDL) cholesterol levels. ACE inhibitors and CCBs have no effects on serum cholesterol. Thiazide diuretics and beta blockers with intrinsic sympathomimetic activity have adverse effects on serum lipids.

62. Hypertensive Urgency Hypertensive urgencies are ideally managed by adjusting maintenance therapy by adding a new antihypertensive and/or increasing the dose of a present medication. Very rapid reductions in BP to goal values should be discouraged. Hypertensive urgency requires BP reductions with oral Antihypertensive agents to stage 1 values over a period of several hours to several days. Acute administration of a short-acting oral antihypertensive ( captopril , clonidine or labetalol ) followed by careful observation for several hours to assure a gradual reduction in BP is an option for hypertensive urgency. Captopril : 5 – 50 mg at 1 to 2 hr interval Clonidine : 0.2 mg initialy followed by 0.2 mg hourly until the DBP fall below 110 mm Hg. Total 0.7 mg Labetalol :200 – 400 mg followed by additional dose every 2 to 3 hours

63. Hypertensive Emergency Require immediate BP reduction to limit new or progressing target-organ damage Hypertensive emergencies require parenteral therapy, at least initially. The goal in hypertensive emergencies is not to lower BP to less than 140/90 mm Hg; rather, a reduction in mean arterial pressure of up to 25% within minutes to hours is the initial target.

64. If then stable, BP can be reduced to 160/ 100–110 mm Hg within the next 2 to 6 hours. If patients tolerate this reduction, additional gradual reductions toward goal BP values can be attempted after 24 to 48 hours . The exception to this guideline is for patients with an acute ischemic stroke where maintaining an elevated BP is needed for a much longer period of time

65. Parenteral Antihypertensive Agents for Hypertensive Emergency

66. Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trail Randomized, double blind, multi-center, study Conducted between 1994-2002, average follow-up 4.9 years N=33,357 Evaluate weather CCB, ACEI or Doxazosin would decrease fatal coronary heart disease, or non-fatal MI when compared to a diuretic

67. Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trail Conclusion ACEI and Dihydropyridine CCB’s are no better than thiazide type diuretics at reducing cardiovascular risk Antihypertensive therapy based on thiazide type diuretics yields better BP control Thiazide type diuretics are significantly less expensive Thiazide type diuretics are an effective economical first choice antihypertensive

68. Low Dose Combinations Meta-analysis of 354 randomized trials of antihypertensives: BB, ACEI, ARB, & CCB Dose of each agent expressed as a multiple of a standard dose n=56,000 patients Placebo adjusted reductions in SBP and DBP Prevalence in adverse effects based on dose

69. Low Dose Combinations All five drug categories produced similar BP reductions Blood pressure reduction achieved with half standard dose was only 20% lower than standard dose

70. Low Dose Combinations Adverse effects in all drug categories, except ACEI, were dose related Prevalence of adverse effects in combination was less than additive Conclusion: Utilization of low dose combination therapy can effectively reduce blood pressure while limiting the incidence of side effects

71. Thank you