Pharmacology

• Etiology


  Specific cause of hypertension established in only 10–15% of patients
• Essential or primary hypertension


  Patients in whom no specific cause of hypertension are said to have
• Secondary hypertension


  Patients with a specific etiology are said to have
• Factors contributing to the development of hypertension

  • Genetic factors
  • Psychological stress
  • Environmental factors
  • Dietary factors
• Heritability of essential hypertension

  Estimated to be about 30%
• Classification of hypertension on the basis of blood pressure (JNC 7; 2003)


  • Optimal
  • Normal
  • High normal
  • Grade 1 hypertension
  • Grade 2 hypertension
  • Grade 3 hypertension
  • Isolated systolic hypertension
• Hydraulic equation


  Arterial blood pressure (BP) is directly proportionate to the product of the blood flow (cardiac output, CO) and the resistance to passage of blood through precapillary arterioles (peripheral vascular resistance, PVR)
• BP = CARDIAC OUTPUT x PERIPHERAL VASCULAR RESISTANCE
• In both normal & hypertensive individuals, BP is maintained by moment-to-moment regulation of cardiac output & peripheral vascular resistance
• Anatomic sites of B.P. control

  • Arterioles (resistance)
  • Venules (capacitance)
  • Heart (pump output)
  • Kidneys (volume)
• Baroreflexes


  Controlled by autonomic nervous system & humoral mechanisms including renin-angiotensin aldosterone system, coordinate the anatomic sites of BP control
• Difference between normal & hypertensive patients

  Baroreceptors are set to higher levels in hypertensive patients
• Currently used anti-hypertensive agents

  • Diuretics
  • Sympatholytics drugs
  • Calcium channel blockers
  • ACE inhibitors
  • Angiotensin II receptor antagonists
  • Direct renin inhibitors
  • Vasodilators
• Diuretics


  • Thiazide & related agents
  • Loop diuretics
  • K+ sparing diuretics
• Sympatholytics drugs


  • β receptor antagonists
  • α receptor antagonists
  • Mixed α-β antagonists
  • Centrally acting
• Blood pressure is maintained by moment-to-moment regulation of cardiac output and peripheral vascular resistance exerted at three anatomic sites: arterioles, postcapillary (capacitance) venules, and heart
• Regulation of blood pressure is mediated by baroreflexes and humoral mechanisms, including the renin-angiotensin-aldosterone system, and local release of vasoactive substances
• Antihypertensive agents


  • Diuretics
  • ACE inhibitors
  • Angiotensin (AT1 receptor) blockers
  • Direct renin inhibitor
  • β Adrenergic blockers
  • Calcium channel blockers
  • β + α Adrenergic blockers
  • α Adrenergic blockers
  • Central sympatholytics
  • Vasodilators
• Thiazide diuretics


  Lower blood pressure initially by increasing sodium and water excretion
• Mechanism of antihypertensive action of thiazide diuretics

  Act on kidneys to increase excretion of Na and H2O, leading to a decrease in blood volume, COP and hence BP. After 4-6 weeks, compensatory mechanisms operate but a small Na deficit in the vessel wall reduces stiffness leading to vasodilation and fall in TPR, sustaining the BP reduction
• Mechanism of antihypertensive action of loop diuretics

  Fall in BP is dependent only on reduction in plasma volume & cardiac output, without a persistent Na deficit and fall in TPR
• K+ sparing diuretics


  Act by blocking sodium and chloride reabsorption in the kidneys, even in patients with poor renal function or who have not responded to thiazide diuretics. They cause decreased renal vascular resistance and increased renal blood flow
• Drawbacks of diuretics as antihypertensives

  • Hypokalaemia
  • Hyperglycemia
  • Hyperlipidemia
  • Hyperuricaemia
  • Sudden cardiac death - torsades de pointes due to hypokalemia
• Current status of diuretics

  Thiazides are mild antihypertensives, causing a fall of about 10 mm Hg in BP. They are used alone only in mild hypertension (stage 1), but low dose thiazide therapy is preferred with a potassium sparing diuretic as first choice in the elderly. They can be used in combination in any grade of hypertension. Indapamide is a modified thiazide with minimal side effects. Loop diuretics are indicated in hypertension only if complicated by chronic renal failure, refractory CHF, resistance to thiazides, or marked fluid retention. K+ sparing diuretics are used only in conjunction with other diuretics
• Diuretics


  Used as antihypertensives
• Thiazides


  • Mild antihypertensives, cause fall of about 10mm Hg in BP
  • Used only in mild HTN (stage 1 HTN)
  • Low dose of thiazide therapy is used preferably with a potassium sparing diuretic as first choice in elderly
  • Prevent tolerance to other antihypertensives
  • Can be used as combination in any grade of HTN
• Indapamide


  Modified thiazide with minimal side effects, has very mild diuretic action and is used mainly as antihypertensive and not as diuretic
• Loop diuretics


  • Cause more fluid & electrolyte imbalance
  • Indicated in HTN only if it is complicated by chronic renal failure, refractory CHF, resistance to thiazides, marked fluid retention
• Potassium sparing diuretics


  • Used only in conjunction with Thiazides to prevent K+ loss & to supplement their antihypertensive action
• Types of diuretics


  • Thiazides
  • Loop diuretics
  • Potassium sparing diuretics
• Antihypertensive drug classes


  • Diuretics
  • ACE inhibitors
  • Renin Inhibitors
  • Angiotensin blockers
• ACE (Angiotensin Converting Enzyme) Inhibitors


  Inhibit the Renin Angiotensin Aldosterone system (RAAS)
• RAAS


  1. Renin is produced by JG cells of kidney in response to fall in BP or blood volume

  2. Renin acts on angiotensinogen to convert it to Angiotensin-I

  3. Angiotensin-I is rapidly converted to Angiotensin-II by ACE

  4. Angiotensin-II causes vasoconstriction and stimulates aldosterone secretion from adrenal cortex

  5. Aldosterone promotes Na+ & water reabsorption by kidneys leading to increased blood volume & BP
• ACE inhibitors


  Inhibit synthesis of Angiotensin II by inhibiting ACE, leading to decrease in total peripheral resistance and blood volume, fall in diastolic and systolic BP
• Desirable properties of ACE inhibitors as antihypertensives

  • No postural hypotension
  • Not much electrolyte imbalance
  • Renal perfusion well maintained
  • Reverses ventricular hypertrophy
  • No hyperuricemia
  • No deleterious effect on plasma lipid profile
  • No rebound hypertension
  • Only minimal worsening of quality of life
• Adverse effects of ACE inhibitors

  • Cough
  • Hyperkalemia
  • First dose hypotension
  • Angioedema
  • Rashes, urticaria
  • Dysgeusia
  • Foetopathic effects
  • Neutropenia
  • Proteinuria
  • Acute renal failure
• Captopril


  • Sulfhydryl containing dipeptide, not a prodrug, has drawbacks mentioned earlier, half life 2 hrs, multiple doses
• Enalapril


  • Prodrug converted to enalaprilate, more potent, longer duration of action, absorption not affected by food, rash and loss of taste less frequent, slower onset of action hence first dose hypotension less marked
• Other uses of ACE inhibitors

  • Congestive Heart Failure
  • Myocardial Infarction
  • Prophylaxis of high CVS risk subjects
  • Diabetic Nephropathy
  • Schleroderma crisis
• ACE inhibitors are recommended as first-line treatment of hypertension in patients with a variety of compelling indications, including high coronary disease risk or history of diabetes, stroke, heart failure, myocardial infarction, or chronic kidney disease