Antihypertensive Drugs

1. Antihypertensive Drugs

2. Hypertension • Hypertension is not a disease • It is an arbitrarily defined disorder to which both environmental and genetic factors contribute • Major risk factor for: • cerebrovascular disease • myocardial infarction • heart failure • peripheral vascular disease • renal failure

3. Definition • Elevation of arterial blood pressure above 140/90 mm Hg. Can be caused by: • an underlying disease process:In 5-10% a cause can be found • (secondary hypertension) • Renal artery stenosis • Hyperaldosteronism • pheochromocytoma • idiopathic process (primary or essential hypertension) In 95% of cases

4. The left ventricle is markedly thickened in this patient with severe hypertension that was untreated for many years. The myocardial fibers have undergone hypertrophy.

5. This left ventricle is very thickened (slightly over 2 cm in thickness), but the rest of the heart is not greatly enlarged. This is typical for hypertensive heart disease. The hypertension creates a greater pressure load on the heart to induce the hypertrophy.

6. Major Risk Factors That Increase Mortality in Hypertension • Smoking • Dyslipidemias • Diabetes Mellitus • Age >60 • Gender: men, postmenopausal women • Family history

7. Prevalence • The hypertension prevalence in the big cities, small to medium cities and class 1 to class 4 rural areas in China was 20.4%, 18.8%, 21.0%, 19.0%, 20.2% and 12.6% respectively • Pakistan (NHSP):the prevalence of hypertension is 17.9% • 24% of the USA adult population representing 43,186,000 persons had hypertension.

8. Diagnosis • Diagnosis is generally based on repeated, reproducible measurements of elevated blood pressure and not on patient symptoms. Patient compliance is a major obstacle to therapy

9. Stage Diastolic Range (mm Hg) Systolic Range (mm Hg) High Normal 85-89 130-139 Stage 1 90-99 140-159 Stage 2 100-109 160-179 Stage 3 > 109 >179 Stages of Hypertension

10. Treatment Rationale Long-term goal of antihypertensive therapy: Reduce mortality due to hypertension-induced disease • Stroke • Congestive heart failure • Coronary artery disease • Nephropathy • Peripheral artery disease • Retinopathy

11. Ways of Lowering Blood Pressure • Reduce cardiac output (ß-blockers, Ca2+ channel blockers) • Reduce plasma volume (diuretics) • Reduce peripheral vascular resistance (vasodilators) MAP = CO X TPR

12. "Individualized Care" • Risk factors considered • Monotherapy is instituted • Non pharmacological therapy tried first • Considerations for choice of initial monotherapy: • Renin status • Coexisting cardiovascular conditions • Other conditions

13. Homeostasis of Blood Pressure

14. Determinants of arterial pressure Blood pressure is controlled by an integrated system • Prime contributors to blood pressure are: • Cardiac output • Stroke volume • Heart rate • Peripheral vascular resistance AP = CO x TPR • Each of these factors can be manipulated by drug therapy Treatment of hypertension seeks to lower CO and/or TPR.

15. For Short-Term Neural Control Baroreceptor reflex Sit or stand up quickly, BP fallsneural responses reestablish normal BP or Sudden increase in stroke volume, BP rises, neural responses reestablish normal BP

17. Figure 15-22

18. Sympathetic nervous control

19. Long-term Renal Control of BP: Direct Pressure Diuresis Blood volume too high, RenalSympathetic vasoconstriction reducedMore fluid enters kidney, more urine formed Lowers BP via lower blood volume Blood pressure too low, Renal Sympathetic vasoconstriction risesLess fluid enters kidney, less urine formedRaises BP by higher blood volume

20. Figure 15-9

21. Renal Control of BP: Indirect If BP too low, increase BP by increasing __________ Kidney cells secrete _______Converts angiotensinogen to angiotensin I_______________________in lung converts angiotensin I to angiotensin II….

22. Renin-angiotensin system

23. Summary of Long Term Renal Control of BP Regulates BP by Changing: 1. Directly – by allowing more or less fluid to enter kidney tubules Indirectly – Reabsorbing more fluid that was already destined to be urine 2. Vasoconstriction / vasodilation

24. MAJOR ANTIHYPERTENSIVE DRUGS 1) Diuretics - Thiazides and congeners. - Loop diuretics. - Potassium-sparing diuretics. 2) Sympatholytic drugs - Centrally acting antiadrenergic agents. - Adrenergic neuron blocking agents. - Alpha adrenergic blockers. - Beta adrenergic blockers. - Alpha-beta adrenergic blockers. 3) Vasodilators - Nitric oxide releasers. - Potassium channel openers. - Calcium channel blockers. 4) Angiotensin inhibitors and antagonists. - Angiotensin Converting Enzyme (ACE) inhibitors. - Angiotensin receptor antagonists.

26. Diuretics • First -line drug • Low dose diuretic therapy is safe and effective in preventing HTN complications • hydrochlorothiazide (Hydrodiuril), chlorthalidone (Hygroton • furosemide • spironolactone

28. 1.Thiazide diuretics • Thiazides are the most effective diuretics to reduce blood pressure in patients with normal renal function. The antihypertensives doses are lower that those required for diuretic effect. • MOA:The initial hypotensive effects of diuretics is associated with a reduction in blood volume and cardiac output. Peripheral vascular resistance is unaffected.

29. After 6-8 weeks of continuous therapy intravascular volume and cardiac output return towards normal while peripheral vascular resistance decreases. - Mechanisms of this decrease are probably related to a depletion of body Na+ stores which leads to: a) a decrease of interstitial fluid volume b) a fall in smooth muscle Na+ concentration that in turn decreases intracellular Ca++ concentration c) a change in response of cell surface receptors to vasoconstrictor hormones

30. Thiazide diuretics: mechanism of action Then CO

31. Effect of thiazides on BP: kinetic

32. Thiazide diuretics: clinical use • Used for monotherapy of mild hypertension and for polydrug therapy of more severe cases. • Therapeutic expectation with monotherapy: 20/10 mmHg drop in 60% of patients. • Use low doses (ceiling effect) to minimize side-effects (K loss). • Low-dose thiazide/low dose beta-blocker combo • Can be used in conjunction with sympatholytics, ACEI, Ca-channel blockers

33. Thiazide Diuretics: side-effects. • Major Side-effects: a) K loss(minimized by using low doses, diet, use of combos with K-sparing diuretics). b) hyperuricemia(bad for gout) c) hyperglycemia, glucose intolerance (bad for diabetes) d)increase LDL & VLDL (bad for atherosclerosis) • Beneficial effect: Ca-sparing (good for osteoporosis)

34. Furosemide and high ceiling diuretics • Use in hypertension is limited . On their own they are not very effective at lowering BP • Main indications are: • a) severe hypertension when several drugs with Na-retaining properties are used (e.g. hydralazine, major sympatholytics). Usually a beta-blocker is also required . b) when GFR is < 30-40 ml/min • c) in CHF or cirrhosis.

35. Beta-adrenergic antagonists • Propranolol • Nadolol"nonselective" • Pindolol - "nonselective";partial agonist (some intrinsic sympathomimetic activity); less bradycardia than other beta-blockers • Metoprolol - beta1 "selective" • Labetolol- ""beta / alpha";higher instance of side effects (orthostatic hypotension; sexual dysfunction); • useful in hypertension of pheochromocytomas

36. Beta-adrenergic antagonists • Mechanism of action: beta-1 blockade a) in heart (they reduce cardiac contractility and CO). b) in kidney (they reduce renin release by sympathetic nerves). Drop in AII produces: - Na loss by kidney (leading to BV reduction) - vascular relaxation in some vascular beds. c) in the CNS (controversial)

37. Beta-blockers: mechanism of action in hypertension

38. Beta-adrenergic antagonists: side-effects/1 • Bronchoconstriction (minimized by using beta-1 selective drug; bad for asthmatics) • Increase in LDL/HDL ratio (bad for atherosclerosis) • Depression, loss of energy (CNS effect) • Increase AV node refractoriness (good for SVTs but could be bad if abnormal SA or AV nodes) • Decreased cardiac contractility (good for angina, good or bad for CHF)

39. Beta-adrenergic antagonists: side-effects/2 • Block prodromal signs of hypoglycemia in insulin-dependant diabetics. • Withdrawal: Rebound hypertension and cardiac ischemia • Cold extremities. May precipitate or worsen Raynaud’s disease (vasospasm of extremities due to beta-blockade of AV shunts). Labetatol (alpha + beta blocker) or blocker with ISA may be prefered in this case. • Adverse effect in patients with occlusive peripheral vascular disease (Production or aggravation of intermittent claudication. IC is due to low calf blood flow)

40. Beta-blockers: clinical use in hypertension • Can be used alone for monotherapy . • combined with low dose thiazide • Should not be combined with verapamil or diltiazem to avoid excessive cardiac depression • Non-selective, beta-1 selective and blockers with ISA work equally well. • Can be combined with ACEI, dihydropyridines (cautiously), other vasodilators.

41. Renin-angiotensin system

42. ACE inhibitors: mechanism of antihypertensive action • ACEIs  AII and  bradykinin (vasodilator). • In the context of hypertension ACEIs work: by  preload and  afterload via: a)  arteriolar dilation ( TPR). b) Na reabsorption by kidney (hemodynamic effect on kidney and drop in aldosterone secretion). This reduces blood volume and preload c)  release of NE (which lowers TPR and CO) d)  cardiac contractility

43. ACEIs: mechanism of action

44. ACEIs: side-effects/drug interactions • SAFE, effective and well-tolerated. Few side-effects but some potentially serious. • Common side-effects are due to bradykinin accumulation : cough, skin rashes, angioedema • Hyperkalemia (bad in presence of K-sparing diuretic, good in presence of thiazide) • First dose orthostatic hypotension (can be severe in hypovolemic patient e.g. using diuretics) • Risk of severe foetal pbs. • Acute Renal failure in patient with high grade renal artery stenosis.

45. Use of ACEIs in hypertension • Excellent first line agent for monotherapy in absence of renal ischemia. • Can be combined with beta-blockers or thiazides diuretics (NOT with K-sparing diuretics) or alpha-1 blockers for enhanced effectiveness. • Notfor pregnant women. • Other major uses of ACEIs: diabetic nephropathy, CHF and post MI treatment.

46. ACEIs differences between agents • Little difference except: • T1/2. a) short (2 hrs) e.g. captopril b) long (~ 10-12 hrs) e.g. enalapril, linosipril, fosinopril, several others. • Excretion: a) renal (most drugs). Doses should be reduced in patients with renal insufficiency. b) some liver metabolism (fosinopril)

47. Angiotensin receptor antagonists • Prototype: Losartan. • Block AT1 not AT2 receptors, no effect on bradykinin. • Less efficacious than ACEIs (??) • Effect potentiated by thiazide. • Produces neither cough nor angiodema (bradykinin effects) but other side-effects are the same as those of ACEIs.

48. Difference between ACEIs & AT1 blockers AT1 R antagonists ACEIs AngII Bradykinin AT1-RAT-2R VasoconstrictionVasorelaxation AngII Bradykinin AT1-R AT2-R VasoconstrictionVasorelaxation Normal Reduced Increased

49. DHPs:mechanism of action SNA  is minimal with long- lasting DHPs

50. Dihydropyridine Ca channel blockers • Mechanism of antihypertensive action: arteriolar vasodilation, TPR drop. • DHPs are slightly more potent antihypertensives than verapamil or diltiazem • Side-effects: • a) orthostatic hypotension • b) reflex tachycardia may lead to cardiac ischemia and/or arrhythmias • (minimized by using slow-onset and long-lasting preps) • c) headache, flushing, dizziness d) pedal oedema.