Anti hypertensive Drugs

High blood pressure (hypertension) is when your blood pressure is 140/90 mmHg or above most of the time.

1. By: Lontoc,Shelah Mae H. BSMLS III-D 2014 Drugs Used in Hypertension

2. The Heart

3. Introduction Hypertension Systolic Blood Pressure (SBP) Diastolic Blood Pressure (DBP) > 140 mmHg > 90 mmHg

4. Hypertension <20% of cases are due to SECONDARY factors factors that can be clearly defined and corrected Pheochromocytoma Coarctation of the aorta Renal vascular disease Adrenal cortical tumors

5. Types of Hypertension Essential Secondary A disorder of unknown origin affecting the Blood Pressure regulating mechanisms Secondary to other disease processes Environmental Factors Stress Na+ Intake Obesity Smoking ****************************************************

6. Hypertension Most cases are IDIOPATHIC (primary or essential hypertension) Strategies for treatment are based on determination of arterial pressure Reductions of blood volume Sympathetic tone Vascular smooth muscle tone Angiotensin effects

7. Hypertension Unfortunately, the BARORECEPTOR REFLEX and the RENIN RESPONSE in primary hypertension are reset to maintain the higher blood pressure. As a result, they respond to lower blood pressure with compensatory homeostatic responses which may be significant. Compensatory mechanisms can be counteracted with: Beta blockers (for tachycardia) Diuretics or angiotensin antagonists (for salt and water retention)

8. Antihypertensive Drugs

9. Drugs used in Hypertension Diuretics Sympathoplegics — blockers of Vasodilators Angiotensin antagonists Renin inhibitor Alpha or beta receptors Nerve terminals Ganglia CNS sympathetic outflow ACE inhibitors Receptor blockers Older oral vasodilators Calcium blockers Parenteral vasodilators

10. Mechanisms of Action Diuresis Sympathoplegia Vasodilation Antagonism of angiotensin Renin inhibition

11. Diuretics – Mechanisms of Action Drugs that lower blood pressure by: reduction of blood volume d epleting the body of sodium Some have direct vasodilating effects Effective at lowering BP by 10-15 mm Hg Provide adequate treatment for MILD or MODERATE essential hypertension

12. Diuretics – Mechanisms of Action Most important diuretics for treating hypertension are: Thiazides ( e.g hydrochlorothiazide) Loop diuretics (e.g. furosemide)

13. Diuretics - Thiazides Thiazides Adequate in mild hypertension When given, the maximum antihypertensive effect is often achieved with doses lower than those required for the maximum diuretic effect.

14. Diuretics - Thiazides MECHANISM OF ACTION Act mainly on proximal part of convoluted tubule Sodium excretion and urine volume are increased by interference with transfer across cell membranes which results on reduced in blood volume However, changes in cardiac output and extracellular fluid volume are transient and, in the long-term, the major haemodynamic effect is a reduction in peripheral resistance due to subtle alterations in the contractile responses of vascular smooth muscle.

15. Diuretics - Thiazides PHARMACOKINETICS Well-absorbed orally Widely distributed subject to a variable degree of hepatic metabolism The effect on the kidney depends upon excretion into the renal tubule; efficacy falls with increasing renal impairment .

16. ADVERSE EFFECTS OF THIAZIDES-1 Initially, they were used at high doses which caused a high incidence of adverse effects. Lower doses now used cause fewer adverse effects . Among them are: HYPOKALEMIA DEHYDRATION (particularly in the elderly) leading to POSTURAL HYPOTENSION HYPERGLYCEMIA possibly because of impaired insulin release secondary to hypokalemia HYPERURICEMIA because thiazides compete with urate for tubular secretion

17. ADVERSE EFFECTS OF THIAZIDES-2 HYPERLIPIDEMIA ; mechanism unknown but cholesterol increases usually trivial (1% increase) IMPOTENCE HYPONATREMIA due to thirst, sodium lo s loss, inappropriate ADH secretion (can cause confusion in the elderly), usually after prolonged use

18. Less common problems HYPERSENSITIVITY - may manifest as interstitial nephritis, pancreatitis, rashes, blood dyscrasias (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 HYPERCALCEMIA ADVERSE EFFECTS OF THIAZIDES-3

19. Sympathoplegics -Mechanisms of Action Drugs that interfere with sympathetic (SANS) control of cardiovascular function Reduces: Venous tone Heart rate Contractile force of the heart Cardiac output Total peripheral resistance

20. Sympathoplegics -Mechanisms of Action Centrally acting Sympathoplegic Drugs Ganglion-blocking agents Adrenergic Neuron-Blocking Agents Andrenoreceptor Antagonists a. Alpha b. Beta 5. Inhibitors of Angiotensin

21. Sympathoplegics - Centrally acting Sympathoplegic Drugs Mechanism of Action These agents reduce sympathetic outflow from vasopressor centers in the brainstem but allow these centers retain or even increase their sensitivity to baroreceptor control Antihypertensive and toxic actions of these drug are generally less dependent on posture than are the effects of drugs that act directly on peripheral sympathetic neurons

22. Sympathoplegics - Centrally acting Sympathoplegic Drugs METHYLDOPA Useful in treatment of mild to moderately severe hypertension Lowers blood pressure chiefly by reducing peripheral vascular resistance with a variable reduction in heart rate and cardiac output

23. Sympathoplegics - Centrally acting Sympathoplegic Drugs METHYLDOPA – Pharmacokinetics Enters the brain via an aromatic amino acid transporter Usual oral dose produces its maximal antihypertensive effect in 4-6 hours, effect can persist for up to 24 hours Because effect depends on accumulation and storage of a metabolite (alpha- methylnorepinephrine ) in the vesicles of nerve endings, the action persists after the parent drug has disappeared from the circulation

24. Sympathoplegics - Centrally acting Sympathoplegic Drugs METHYLDOPA – Adverse Effect/Toxicity Overt sedation = most frequent undesirable effect Persistent mental lassitude and impaired mental concentration (long-term therapy) Nightmares,mental depression,vertigo and extra pyramidal signs (occur relatively infrequent) Lactation (increased prolactin secretion) both in men and women

25. Sympathoplegics - Centrally acting Sympathoplegic Drugs METHYLDOPA – Adverse Effect/Toxicity Sudden discontinuance causes REBOUND HYPERTENSION (may be severe) Occasionally causes HEMATOLOGIC IMMUNOTOXICITY and in some patients HEMOLYTIC ANEMIA May cause SEDATION Toxicity is mediated by inhibition of dopaminergic mechanisms in the hypothalamus

26. Sympathoplegics - Ganglion-Blocking Agents Mechanism of Action Competitively block nicotinic cholinoreceptors on postganglionic neurons in both sympathetic and parasympathetic ganglia May directly block the nicotinic acetylcholine channel in the same fashion as neuromascular nicotinic blockers

27. Sympathoplegics - Ganglion-Blocking Agents Hexamethium Extremely powerful blood pressure-lowering drug Major compensatory response: SALT RETENTION Toxicities reflect PARASYMPATHETIC BLOCKADE Blurred vision Constipation Urinary hesitancy Sexual dysfunction SYMPATHETIC BLOCKADE Sexual dysfunction Orthostatic hypotension

28. Sympathoplegics - Adrenergic Neuron-Blocking Agents Mechanism of Action These drugs lower blood pressure by preventing normal physiologic release of norepinephrine from postganglionic sympathetic neurons

29. Sympathoplegics - Adrenergic Neuron-Blocking Agents Guanethidine – Mechanism and Sites of Action Inhibits the release of norepinephrine from sympathetic nerve endings Transported across the sympathetic nerve membrane by the same mechanism that transports norepinephrine itself (NET, uptake 1) and uptake is essential for drug’s action Once it has entered the nerve, it replaces norepinephrine = gradual depletion of norepinephrine stores in nerve endings

30. Sympathoplegics - Adrenergic Neuron-Blocking Agents Guanethidine – Mechanism and Sites of Action Hypotensive action early in the course of therapy is associated with reduced cardiac output due to BRADYCARDIA and RELAXATION of CAPACITANCE VESSELS

31. Sympathoplegics - Adrenergic Neuron-Blocking Agents Guanethidine – Pharmacokinetics Long half-life (5 days) Onset of symptoms is gradual (max effect in 1-2 weeks) Sympathoplegia persists for a comparable period after cessation of therapy Dose should not be ordinarily increase at intervals shorter than 2 weeks

32. Sympathoplegics - Adrenergic Neuron-Blocking Agents Guanethidine – Adverse effects Postural hypotension Hypotension following exercise Decreased blood flow to the heart and brain or OVERT SHOCK Delayed or retrograde ejaculation Diarrhea (increased GI motility due to parasympathetic predominance on controlling the activity of intestinal smooth muscle)

33. Sympathoplegics - Adrenoreceptor Antagonists (BETA) Propanolol 1 st Beta blocker to be effective in hypertension and ischemic heart dsx Used heavily in the treatment of hypertension

34. Sympathoplegics - Adrenoreceptor Antagonists Propanolol – Mechanism and Sites of Action Decreases BP as a result of a decrease cardiac output Inhibits stimulation of renin production by catecholamines It is likely that its effect is due in part to depression of the renin-angiotensin-aldosterone system

35. Sympathoplegics - Adrenoreceptor Antagonists Propanolol – Pharmacokinetics and Dosage Resting bradycardia and a reduction in the heart rate during exercise are indicators of propanolol’s beta-blocking effect Can be administered 1 or 2x a day Slow release preparations are available

36. Sympathoplegics - Adrenoreceptor Antagonists Propanolol – Adverse Effects When discontinued after prolonged use, some patients experience withdrawal symptoms manifested by: Nervousness Tachycardia Increased intensity of angina Increase BP Myocardial infarction has been reported in few patients

37. Sympathoplegics - Adrenoreceptor Antagonists (ALPHA) Prazosin – Mechanism of Action Selectively blocks alpha receptors in arterioles and venules Produce less reflex tachycardia when lowering BP than nonselective alpha-antagonists Alpha blockers reduce arterial pressure by dilating both resistance and capacitance vessels BP reduced more in upright than in supine position Salt and water retention occurs if administered without diuretics More effective in combination with other agents such as beta-blocker and a diuretic

38. Sympathoplegics - Adrenoreceptor Antagonists (ALPHA) Prazosin – Pharmacokinetics & Dosage Half-life (3-4 hours) Initial dose 3mg/d Maintenance dose range 10-30 mg/d

39. Sympathoplegics - Adrenoreceptor Antagonists (ALPHA) Prazosin – Adverse Effects Dizziness Palpitations Headache Lassitude ORTHOSTATIC HYPOTENSION

40. Vasodilators Drugs that dilate blood vessels by acting directly on smooth muscle cells through nonautonomic mechanisms Compensatory responses: SALT RETENTION and TACHYCARDIA Four major mechanisms 1. release of nitric oxide 2. opening of Potassium channels (leads to hyperpolarization) 3. blockade of calcium channels 4. activation of D 1 dopamine receptors

41. Vasodilators Mechanism of Smooth Muscle Relaxation Examples Release of nitric oxide from drug or endothelium Nitroprusside Hyperpolarization of vascular smooth muscle through opening of potassium channels Diazoxide Reduction of calcium influx via L-type channels Verapamil Activation of dopamine D 1 receptors Fenoldopam

42. Vasodilators Hydralazine Dilate arterioles but not veins Orally active suitable for chronic therapy Acts through the release of nitric oxide from endothelial cells Rarely used at high dosage because of its toxicity (limited efficacy) Uses: 1) Moderate hypertension when 1 st line fails – with beta-blockers and diuretics 2) Hypertension in Pregnancy

43. Vasodilators Hydralazine – Pharmacokinetics&Dosage Well-absorbed and rapidly metabolized by the liver during first-pass metabolism so bioavailability is low ( ave. 25%) variable among individuals Half-life ranges from 1.5 to 3 hours Vascular effect persist longer than do blood concentrations possible due to avid binding to vascular tissue Usual dosage ranges 40 mg/d to 200 mg/d Higher doses = greater vasodilation Dosing two to three times daily provides smooth control of blood pressure

44. Vasodilators Hydralazine –Adverse Effects Headache Nausea Anorexia Palpitations Sweating Flushing

45. Vasodilators Hydralazine –Adverse Effects In Px with ischemic heart dsx , reflex tachycardia and sympathetic stimulation may provoke ANGINA or ISCHEMIC ARRYTHMIAS With dosages of 400 mg/d or more, there’s 10-20% incidence of a syndrome characterized by arthralgia, myalgia, skin rashes and fever that resembles Lupus erythematosus (drug-induces LE) Peripheral neuropathy and drug fever are uncommon

46. Inhibitors of Angiotensin Mechanism of Action Reduce aldosterone levels ANGIOTENSIN II – major stimulant of aldosterone release) Cause Potassium retention Potassium accumulation may be marked if px has Renal impairment High-potassium diet Takes potassium-sparing diuretics

47. Captopril – Mechanism of Action Angiotensin-converting enzyme (ACE) inhibitor Inhibits ACE, kininase II, peptidyl dipeptidase Cause a reduction in blood levels of Angiotensin II and aldosterone Increase in endogenous vasodilators of the kinin family ( bradykinin ) Inhibitors of Angiotensin

48. Captopril – Pharmacokinetics Available only orally, 70% - 75% is absorbed Partly absorbed and partly excreted unchanged in urine Food interferes with its absorption Half life: 2 Hrs , but action stays for 6-12 Hrs Inhibitors of Angiotensin

49. Captopril – Adverse Effects Cough – persistent brassy cough in 30% cases – inhibition of bradykinin and substance P breakdown in lungs Hyperkalemia in renal failure patients with K+ sparing diuretics, NSAID and beta blockers (routine check of K+ level) Hypotension – sharp fall may occur – 1 st dose Acute renal failure: CHF and bilateral renal artery stenosis Angioedema: swelling of lips, mouth, nose etc. Inhibitors of Angiotensin

50. Captopril – Adverse Effects Rashes, urticaria etc Dysgeusia : loss or alteration of taste Foetopathic : hypoplasia of organs, growth retardation etc Neutripenia Contraindications : Pregnancy, bilateral renal artery stenosis, hypersensitivity and hyperkalaemia Inhibitors of Angiotensin

51. Hypertension Initial treatment Decreased blood pressure Increased Sympathetic outflow Increased renin release Tachycardia Salt and water retention Compensatory responses Increased blood pressure Beta Blockers, reserpine Diuretics, ACE inhibitors Compensatory responses ( red boxes ) to decreased blood pressure when treating hypertension. The initial treatment that causes the compensatory responses might be a vasodilator. Arrows with minus signs indicate drugs used ( white boxes ) to minimize the compensatory responses.

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