Pharmacotherapy of hypertension

1. Pharmacotherapy of hypertension

2. Hypertension according to WHO and Joint National Committee, hypertension is defined as SBP>140 and DBP>90

3. Blood pressure It’s the lateral pressure exerted by the flowing column of blood On the vessel walls. Normal value : 120/80 mmHg HYPERTENSION IS NOT A DISEASE, BUT ITS AN IMPORTANT RISK FACTOR FOR MANY UNDERLYING DISEASES

4. Types of hypertension • Essential hypertension ( primary ) -patients with arterial hypertension & no definable cause • Secondary hypertension -Individuals in whom a specific structural organ or a genetic defect is responsible for hypertension

5. Essential hypertension Factors causing are 1.Genetic factors 2.Foetal factors 3.Environmental factors (Risk factors) -Smoking -Alcohol consumption -Na+ intake -Stress Obesity leads to Insulin resistance -Hyper insulinemia causes vaso constriction -Modified ion transport mechanisms

6. Secondary hypertension Causes:- 80% of the cases are renal -Diabetic nephropathy -Chronic glomerulonephritis -Renovascular disease Endocrine causes -cushings syndrome -Pheochromocytoma -Acromegaly -Cohn’s syndrome

7. CVS -Coarctation of aorta Drug effects -oral contraceptive pills -Steroids -vasopressins -MAO- inhibitor

8. CLINICAL ASPECTS OF HYPERTENSION APPROACH TO THE PATIENT When hypertension is suspected , BP should be Measured at least twice during two separate Examinations after initial screening

9. CATOGORY SBP DBP

10. Signs & symptoms • Most patients have no signs & symptoms . • When symptoms are present they fall into three categories 1 . symptoms related to elevated BP 2 . symptoms related to hypertensive vascular disease 3 . symptoms related to underlying disease, in the case of secondary hypertension

11. 1. Symptoms related to elevated BP • Headache – localised to occipital region • Dizziness • Easy fatigability • Palpitations

12. 2 . symptoms related to vascular disease • Epistaxis • Blurring of vision • Episodes of dizziness • Angina pectoris • Dyspnoea – due to cardiac failure

13. 3 . symptoms related to underlying disease • Polyuria, polydypsia, muscle weeknes - in patients with primary aldosteronism • Weight gain – in patients with Cushings syndrome • Episodic headache, palpitations, postural dizziness – in patients with pheochromocytoma

14. Physical examination • General appearance • Fundoscopic findings • Examination of heart • Abdominal examination • Compare BP and pulse in two upper extremeties and in supine and standing positions

15. Management I- non pharmacological therapy If SBP < 140 mmhg DBP < 90 mm hg It includes • wt reduction , BMI <25 kg /m2 • Low fat & saturated fat diet • Low sodium diet < 6 gms daily • Limited alcohol consumption • Dynamic exercise • Increased fruit & vegetable consumption • Decreased smoking II- drug therapy

16. Lifestyle Modifications • Reduce weight to normal BMI (<25kg/m2): 5-20 mmHg/10kg loss • DASH eating plan: 8-14 mmHg • Dietary sodium reduction: 2-8 mmHg • Increase physical activity: 4-9 mmHg • Reduce alcohol consumption: 2- 4 mmHg

17. DASH Diet Dietary Approaches to Stop Hypertension • Fruits, • vegetables, low fat dairy • foods, and reduced • sodium intake • Includes whole grains, • poultry, fish, nuts • Reduced amounts of red • meat, sugar, total and • saturated fat, and • cholesterol

18. Anti hypertensive drugs

19. Diuretics • Thiazides • Hydrochlorothiazide, chlorthalidone • Indapamide • High ceiling diuretics • Furosemide • K+ sparing diuretics • Spironolactone, amiloride • ACE inhibitors • Captopril , enalapril, ramipril , lisinopril, perindopril , fosinopril • Angiotensin receptor blockers ( at 1 blockers ) • losartan , valsartan , irbesartan , telmisartan

20. 4. Calcium channel blockers • Verapamil , diltiazem , nifedipine , amlodipine , felodipine , nitrendipine 5. Α+β adrenergic blockers • Labetelol , carvedilol 6. Α adrenergic blockers • Prazosin , terazosin , doxazosin , phentolamine , phenoxybenzamine 7. Central sympatholytics • Clonidine , methyl dopa 8. Vasodilators • Arteriolar • Hydralazine , minoxidil , diazoxide • Arteriolar plus venous • Sodium nitroprusside

22. DIURETICS

23. Classification 1. Thiazide diuretics - Hydrochlorthiazide -Chlorthalidone -Indapamide 2. High ceiling diuretics -Furosemide 3. K+ sparing -spironolactone -Amiloride

25. Diuretics (water pills) • Diuretics are the drugs that have the ability to increase urinary excretion of salt and water by acting over different parts of nephron. • Alcohol, caffeine, digoxin, theophylline water intake increase urine output. But these are not classical diuretics, they are called physiological diuretics. • Getting rid of excess salt and fluid helps lower blood pressure and can make it easier for your heart to pump. • Diuretics may be used to treat a number of heart-related conditions, including high blood pressure, heart failure, kidney and liver problems, and glaucoma.

26. Classification of diuretics according to efficacy/potency • High efficacy/high ceiling diuretics • Prevents 15-25% reabsorption of salt & water, e.g; Loop diuretics • Moderate efficacy diuretics • Prevents 5-10% reabsorption of salt & water, e.g; Thiazide diuretics • Low efficacy diuretics • Prevents 5% (maximum) reabsorption of salt & water, e.g; K+ sparing diuretics, Osmotic diuretics, Carbonic anhydrase inhibitors.

27. . Thiazide diuretics • Thiazides are the most widely used of the diuretic drugs. They are called “celling diuretics” because increasing the dose above normal does not promote a further diuretic response. • Mechanism of action of thiazide: In the distal convoluted tubule thiazides cause secretion of waterDecrease blood volume Decrease BP. • In prolonged use may cause vasodilation  Decrease peripheral resistance  Decrease BP

29. Thiazides - Pharmacokinetics • All thiazides are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid by that system. As a result, thiazide use may decrease uric acid secretion and elevate serum uric acid level. • Not effective at low glomerular filtration rates. • - Although hydrochlorothiazide is the most widely used diuretic for hypertension, chlorthalidone may be more effective because of its much longer half-life.

30. Clinical Indications of thiazide • Hpertension: Theyreduce blood pressure and associated risk of CVA/strokeand MI in hypertension - They should be considered first-line therapy in hypertension(effective, safe and cheap) • Heart failure • Nephrolithiasisdue to idiopathic hypercalciuria - Condition characterized by recurrent stone formation in the kidneys due to excess calcium excretion - Thiazide diuretics used to prevent calcium loss and protect the kidneys • Nephrogenicdiabetes insipidus. • Thiazides allow increased solute excretion in the urine, breaking the Polydipsia-Polyuria cycle.

31. ADVERSE EFFECTS OF THIAZIDES • HYPOKALEMIA • HYPONATREMIA • DEHYDRATION (particularly in the elderly) leading to POSTURAL HYPOTENSION • HYPERCALCEMIA • HYPERGLYCEMIA possibly because of impaired insulin release secondary to hypokalemia. • HYPERURICEMIA • HYPERLIPIDEMIA • HYPERSENSITIVITY - may manifest as interstitial nephritis, pancreatitis, rashes, blood dyscriasis (all very rare) • METABOLIC ALKALOSIS due to increased sodium load at the distal convoluted tubule which stimulates the sodium/hydrogen exchanger to reabsorb sodium and excrete hydrogen • IMPOTENCE

32. Dosage of thiazide Contraindications: Excessive use of any diuretic is dangerous in patients with hepatic cirrhosis, borderline renal failure, or heart failure

33. . Loop diuretics • furosemide and ethacrynic acid. bumetanide and torsemide are sulfonamide loop diuretics. They are called high celling diuretics • The loop diuretics acts promptly, even among patients who have poor renal function or have not responded to thiazides or other diuretics. • Mechanism of action: • Loop diuretics inhibit Sodium-Potassium-Chloride Transporter 2 (NKCC2), in the thick ascending limb of Henle’s loop. • By inhibiting this transporter, the loop diuretics (TAL) reduce the reabsorption of NaCl • It also diminish the lumen-positive potential that comes from K+ recycling. This positive potential normally drives divalent cation reabsorption in theTAL and by reducing this potential, loop diuretics cause an increase in Mg2+ and Ca2+ excretion.

35. LOOP DIURETICS - PHARMACOKINETICS • Rapid GI absorption. Also given i.m. and i.v. • Extensively protein bound in plasma • Short half-lives in general CLINICAL USES OF LOOP DIURETICS • Edema due to congestive heart failure , nephrotic syndrome or cirrhosis • Acute pulmonary edema *Acute hypercalcemia • Hyperkalemia, acute renal failure, and anion overdose. ADVERSE EFFECTS OF LOOP DIURETICS • Hypokalemia, hyponatremia & hypocalcemia(in contrast to thiazides) • Dehydrationand postural hypotension • metabolic alkalosis • hypercholesterolemia, hyperuricemia, hyperglycemia, • Hypersensitivity • OTOTOXICITY (especially if given by rapid IV bolus)

36. Typical dosages of loop diuretics Contraindications: Furosemide, bumetanide, and torsemide may exhibit allergic cross-reactivity in patients who are sensitive to other sulfonamides, but this appears to be very rare

37. . POTASSIUM-SPARING DIURETICS • They act in the collecting tubule to inhibit Na+ reabsorption and K+ excretion. • The major use of potassium-sparing agents is in the treatment of hypertension, most often in combination with a thiazide. • Types: - Aldosterone antagonist: (spironolactone, eplerenone) - Na+ channel inhibitor: (amiloride, triamterene). • Spironolactone is a weak diuretic because most of the filtered Na+is reabsorbed before reaching the CT. • *Aldosteronenormally stimulates the Na+/K+- exchange sites of the collecting tubule

39. CLINICAL USES OF POTASSIUM- SPARING DIURETICS • Hyperaldosteronism • - Primary hypersecretion (Conn’s syndrome) • - Secondary hyperaldosteronism (evoked by heart failure, hepatic cirrhosis, nephrotic syndrome). • In combination with K+ loosing diuretics (loop & thiazide) to prevent K+ excretion. • Eplerenone can slow the progression of albuminuria in diabetic patients. • Eplerenone has been found to reduce myocardial perfusion defects after myocardial infarction. ADVERSE EFFECTS OF POTASSIUM-SPARING DIURETICS • Hyperkalemia • Hyperchloremic Metabolic Acidosis • Gynecomastia • Acute Renal Failure • Kidney Stones

40. Potassium-sparing diuretics and combination preparations Contraindications: Potassium-sparing agents can cause severe, even fatal, hyperkalemia in susceptible patients. Patients with chronic renal insufficiency are especially vulnerable and should rarely be treated with these diuretics.

41. V. Carbonic Anhydrase Inhibitors • . Acetazolamide • Mechanism of action: • H+ + HCO3- H2CO3Carbonic anhydrase_> H2O + CO2 • Accumulation of H+ in the lumen which impairs the transport action of Na+/H+ exchanger • The decreased ability to exchange Na+ for H+ in the presence of acetazolamide results in a mild diuresis. • Additionally, HCO3 is retained in the lumen, with marked elevation in urinary pH. The loss of HCO3- causes a hyperchloremic metabolic acidosis and decreased diuretic efficacy following several days of therapy ( set-off).

43. CLINICAL USES OF CARBONIC ANHYDRASE INHIBITORS • Glaucoma (most common indication) - The reduction of aqueous humor formation by carbonic anhydrase inhibitors decreases the intraocular pressure. • Urinary Alkalinization • Metabolic Alkalosis • Acute Mountain Sickness: Acetazolamide, a mild diuretic, works by stimulating the kidneys to secrete more bicarbonate in the urine, thereby acidifying the blood. This change in pH stimulates the respiratory center to increase the depth and frequency of respiration, thus speeding the natural acclimatization process. An ADVERSE EFFECTS OF CARBONIC ANHYDRASE INHIBITORS • Hyperchloremic Metabolic Acidosis • Renal Stones • Renal Potassium Wasting CONTRAINDICATION: - Hyperammonemia - Hepatic encephalopathy in patients with cirrhosis.

44. Carbonic anhydrase inhibitors used orally in the treatment of glaucoma Changes in urinary electrolyte patterns and body pH in response to diuretic drugs

45. V. Osmotic Diuretics(AQUARETICS) • Hydrophilic chemical substances that are filtered through the glomerulus, such as mannitol and urea • . • Diuresis is due to their ability to carry water with them into the tubular fluid. • M/A: • The presence of a non-reabsorbable solute such as mannitol prevents the normal absorption of water. As a result, urine volume increases. • Osmotic diuretics used to maintain urine flow & save the patient from dialysis e.g treatment for patients with increased intracranial & intraocular pressure or acute renal failure due to shock, drug toxicities, and trauma. • ADVERSE EFFECTS OF OSMOTIC DIURETICS • - Extracellular Volume Expansion, Dehydration, Hyperkalemia, Hypernatremia, and Hyponatremia (When used in patients with severe renal impairment)

48. Central sympatholytics • Clonidine • Moderately potent antihypertensive • High affinity and intrinsic activity for α2a subtype .

49. Mechanism α2A RECEPTORS CLONIDINE IMIDIZOLINE RECEPTORS

50. METHYL DOPA • Alpha methyl analouge of dopa • Precursors of dopamine & noradrenaline • Alphamethyl noradrenaline (na) in the brain acts on central alpha 2 receptors to decrease efferent sympathetic activity • Methyl dopa inhibits enzyme dopa decarboxylase and decreases production of na • Inhibition of postural reflexes is mild