Hypertension

1. Hypertension Dr. Ajith JS Pharm D , Asst. ProfMET-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.

4. 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 Classification:The Seventh Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) classifies adult blood pressure as below:

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

6. 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

7. EPIDEMIOLOGY • 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.

8. 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.*

9. Hypertension Prevalence by Age and Gender

10. Obesity (BMI > 30 kg/m2) by age and gender

11. 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

13. Potential Mechanism of Pathogenesis

14. 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

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

17. 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

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

19. 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

20. 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

21. Neuronal Regulation • presynaptic α2 exerts a negative inhibition on norepinephrine release. • postsynaptic α1–receptors on arterioles and venules results in vasoconstriction

22. 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

23. 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.

24. PeripheralAutoregulatory 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.

25. 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

26. 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

27. 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.

28. 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

29. 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

30. 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.

31. 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

32. 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.

33. 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

34. 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

35. 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.

36. 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

37. Overview • Non-pharmacological • Pharmacological • Special population

38. APPROX. SYSTOLIC BLOOD PRESSURE REDUCTION (mm Hg) MODIFICATION RECOMMENDATION Maintaining normal body weight (body mass index 18.5-24.9 Kg/m2) Weight reduction if overweight 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 Regular aerobic physical activity like brisk walking at least 30 min/day, most days of week Physical activity 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

39. 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

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

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

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

43. Thiazide Diuretics • 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

44. Loop Diuretics • Mechanism: Inhibit Na/K/ClATPase 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

45. Aldosterone Receptor Antagonists • 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

46. Nitrates • Mechanism: Direct venodilation by release of nitric oxide • Examples: • Isosorbidedinitrate 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

47. ACEI & ARB’s • 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 Veins

48. Beta Blockers • 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 Heart

49. 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 sympathomimeticactivity • Acebutolol 200-800mg bid • Carteolol 2.5-10 mg od • Penbutolol 10-40 mg od • Pindolol 10-60 mg bid

50. 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