Drugs Used for Hypertension

1. Drugs Used for Hypertension Philip Marcus, MD MPH

2. Hypertension: Epidemiology • Elevation in Blood Pressure • High Prevalence in US population • Affects up to 24% of adults • Over 50 million people affected in US • Untreated in a large percentage • Only 53% treated • Lack of treatment may result in irreversible damage

3. Primary (Essential) Hypertension: • No identifiable cause • Accounts for 95%+/- of cases • Clusters in families • Chronic and progressive • Populations at risk: • Elderly • Postmenopausal females • African-Americans • Obese • Drug therapy lowers BP • Does not eliminate underlying pathology • Treatment generally lifelong • Smoking and Obesity are cofactors

4. Primary Hypertension: Pathophysiology • Increased sympathetic activity • Increased production of sodium retaining hormones and vasoconstrictors • Long term sodium intake • Inadequate potassium/calcium intake • Increased renin secretion • Deficiency of endogenous vasodilators • Prostaglandin, Prostacyclin • Nitric Oxide • Obesity and Insulin resistance

5. Classification of Hypertension:

6. Secondary Hypertension: • Chronic Renal Disease 4% • Renovascular Disease 2% • Coarctation of Aorta 0.3% • Primary Aldosteronism 0.2% • Cushing’s Syndrome 0.1% • Oral Contraceptive Use 1% • Pheochromocytoma 0.1% • Sleep Apnea • 50% have significant hypertension

7. Consequences of Hypertension: • Untreated hypertension leads to increase in morbidity and mortality • Heart Disease • LV Hypertrophy and Congestive Heart Failure • Coronary Artery Disease • Renal Disease • Increased prevalence despite available treatment • Retinal Disease • Cerebral Vascular Disease • Stroke

8. Benefits of Antihypertensive Treatment • Greater in elderly than in younger patients over short term (5 years) • Older persons at higher immediate and absolute risk of developing cardiovascular events • Prevalence of preexisting cardiovascular disease greater • Systolic hypertension is associated with greater cardiovascular risk than diastolic • Systolic hypertension more prevalent in elderly • Smoking less common in older persons • Smokers respond less well to antihypertensive treatment • Most large trials involving elderly are more recent than those involving younger patients • Use treatment regimens with fewer adverse effects • Benefits of therapy increase over time • Long-term benefits may be greater in younger patients

9. Non-Drug Management of Hypertension: Lifestyle Modification • Weight reduction • Sodium restriction • Alcohol restriction • Smoking cessation • Exercise • Maintenance of dietary potassium(>100 mEq/day) and calcium intake • Dietary Approaches to Stop Hypertension (DASH) • Reductions in BP in persons on diet rich in fruits, vegetables, and low-fat dairy products • Lowered BP in all subgroups • Appel, et al, NEJM 1997; 336:1117

10. Physiologic Control of Blood Pressure • BP = C.O. x SVR • C.O. = H.R. x Stroke Volume • Factors to be considered: • Heart Rate • Blood Volume • Contractility • Arteriolar Constriction

11. HR x SV Arterial Pressure Cardiac Output Peripheral Resistance = X 1. Heart Rate 2. Contractility 3. Blood Volume 4. Venous Return Arteriolar Constriction

12. Mechanisms Regulating Blood Pressure: • Sympathetic Nervous System • Baroreceptors • Medullary vasomotor center • Renin Angiotensin System • Angiotensinogen • a-2 globulin • Activated by Renin • Produced by JG cells • Increased by decreased renal blood flow • Increased with b-1 stimulation • Observed clinically with renal artery stenosis, hypotension

13. Mechanisms Regulating Blood Pressure: • Renin Angiotensin System • Angiotensin I • Product of renin action on angiotensinogen • Converted by Angiotensin-Converting Enzyme • Primarily in vasculature and lung • Angiotensin II • Acts on Angiotensin Receptors (AT1) • Causes vasoconstriction • Causes release of Aldosterone • Converted to Angiotensin III in adrenal • Aldosterone • Results in Na retention and K loss • Expands extracellular fluid volume • Action of Angiotensin II and Aldosterone results in decrease in renin secretion

18. Sites of Antihypertensive Drug Action • Central Nervous System • Vasomotor center • Suppresses sympathetic outflow • Cardiac • Resistance Vessels (arterioles) • Results in: • Reduction in Heart Rate • Decrease in Contractility • Vasodilatation • Typical drugs: • Clonidine, • Methyldopa

19. Sites of Antihypertensive Drug Action • Sympathetic Ganglia • Ganglionic blockade reduces sympathetic stimulation to heart and blood vessels • Cause vasodilatation and reduction in HR • Rarely used anymore • Trimethaphan last remaining agent • Adrenergic Nerve Terminals • Decreases NE release • Results in decreased stimulation of heart and blood vessels • Guanethidine, reserpine

20. Sites of Antihypertensive Drug Action • Cardiac b-1 Receptors • Results in decrease in HR and contractility • Vascular a-1 Receptors • Results in vasodilatation • Prazosin, Terazosin, Labetalol • SA node and myocardium • Calcium channel blockers • Verapamil and Diltiazem • Renal tubules • Diuretic agents • Furosemide, Hydrochlorothiazide

21. Diuretics Used in the Treatment of Hypertension

22. Sites of Antihypertensive Drug Action • b-1 Receptors on juxtaglomerular cells • Reduces renin release • Vascular Smooth Muscle • Direct vasodilators • Hydralazine • Angiotensin-Converting Enzyme Inhibitors • Decreases formation on Angiotensin II • Captopril, Enalapril • Angiotensin II Receptor Blockers • Results in blockade of AT1 receptors • Losartan, Candesartan • Similar in action to ACE inhibitors • D1 (dopamine) Receptor Agonists

23. Hypertensive Crisis: • Severe Increase in BP • Diastolic BP > 120 • Rate of rise more important than absolute BP in determining need for EMERGENCYtreatment • Usually occurs in noncompliant or under-medicated patients • In absence of evidence of acute or ongoing target organ damage, no need for acute, aggressive BP reduction

24. Hypertensive Crisis: What constitutes the Hypertensive Emergency? • Encephalopathy • Myocardial Infarction or Unstable Angina • Congestive Heart Failure • Subarachnoid hemorrhage, stroke or intracerebral hemorrhage • Dissecting Aortic Aneurysm • Cocaine overdose • Acute renal insufficiency • Post-operative hypertension

25. Centrally Acting Antiadrenergic Agents: • Act in CNS to reduce firing of sympathetic neurons • Effects are the result of decreased stimulation of a & b receptors in periphery • Stimulate central inhibitory a-2 receptors • Acts on post-synaptic receptors • Exerts inhibitory influence on regions of brain that regulate sympathetic nervous activity • Primary site of action in medulla

26. Centrally Acting Antiadrenergic Agents: • Clonidine (Catapres ®) • 2-imidazoline derivative • Results in decrease in BP, HR and CO • Decreases renal vascular resistance • Renal blood flow unchanged • Lipid soluble • Enters CNS • Side effects common • Dry mouth, dizziness, drowsiness • Gynecomastia, rebound hypertension • Oral and Transdermal route • Also used in drug, alcohol and nicotine withdrawal

27. Centrally Acting Antiadrenergic Agents: • Clonidine HCl • Recently introduced in epidural form • Useful in this formulation for neuropathic pain • Primarily used in patients with neoplastic disease • Produces analgesia at presynaptic and postjunctional a-2 adrenergic receptors in the spinal cord • Prevents pain signal transmission to the brain • Pain relief additive to morphine • Duraclon ™

28. Centrally Acting Antiadrenergic Agents: • Methyldopa (Aldomet ®) • Analog of L-dopa • Action similar to clonidine • Requires uptake into CNS neurons • Converted to methyl-norepinephrine • Results in decrease in BP with little cardiac effects • Large 1st pass effect • Low bioavailability • Oral and IV administration • Side Effects • Positive Coomb’s test, Hemolytic Anemia • Hepatotoxicity • Sedation, Lactation

30. Adrenergic Neuron Blocking Agents: • Act in presynaptic location to reduce NE release from sympathetic neurons • Rarely used in therapy because of side effects • Previously major agents used in treatment • Reserpine and Guanethidine

31. Rauwolfia serpentina

32. Reserpine • Rauwolfia alkaloid • Causes depletion of NE from postganglionic sympathetic neurons • Decreases stimulation of all adrenergic receptors • Effects resemble a + b blockade • Blocks uptake of dopamine into vesicles which prevents NE synthesis • Interferes with ATP and Mg++ dependent uptake • Displaces NE from vesicles causing degradation of NE by MAO • Acts peripherally and in CNS

33. Reserpine • Physiologic Effects • Bradycardia • Decreased Cardiac Output • Vasodilatation • End result is reduction in Blood Pressure • Side Effects • Sedation and Depression • Nasal stuffiness • Orthostatic hypotension • Extrapyramidal effects • GI hypersecretion • Diarrhea, cramps, Increased gastric Acid

34. Guanethidine • Acts presynaptically to inhibit the release of NE from sympathetic neurons • Must first be taken up into terminals of sympathetic nerves • Uptake via active transport for NE • After uptake, will prevent further NE release • Can promote NE release initially • Polar compound • Highly basic Nitrogen • Does NOT enter CNS • Oral route, t1/2 = 5 days

35. Guanethidine • Physiologic Effects • Bradycardia • Decreased Cardiac Output • Vasodilatation • Side Effects • Resemble those of pharmacologic sympathectomy • Orthostatic Hypotension • Diarrhea • Defective ejaculation • Effects decreased by compounds that interfere with uptake • Tricyclic Antidepressants • Cocaine • Phenothiazine drugs

36. a-1 Adrenergic Blockers: • Useful in hypertension and pheochromocytoma • Selective inhibitors of a-1 receptor • Contrast with phenoxybenzamine and phentolamine • Cause blockade of a-1 & a-2 receptors • Used also for urinary obstruction in BPH • Alternative to surgery • Results in decrease in tone in smooth muscle of bladder neck and prostate • Improves urine flow

37. a-1 Adrenergic Blockers: • Physiologic Effects: • Decrease peripheral vascular resistance • Relax arterial and venous smooth muscle • Results in decrease in Blood Pressure • Minimal changes in Cardiac Output, renal blood flow and GFR • Used orally

38. a-1 Adrenergic Blockers: • Side Effects • Orthostatic Hypotension • Results from blockade of venous a receptors causing pooling when upright • Reflex tachycardia, generally not long-term • Nasal Congestion • Impotence • Interference with ejaculation • Sodium retention and edema • Frequently used with a diuretic • First-dose effect • Exaggerated hypotensive effect • Results in syncope • Adjust first dose to 1/3 to ¼ usual dose at bedtime

39. a-1 Adrenergic Blockers: • Prazosin (Minipress ®) • Initial agent • Short half-life • Terazosin (Hytrin ®) • Longer acting • Half-life = 12 hours • Doxazosin (Cardura ®) • Longest half-life, 20 hours Tamsulosin: Flomax®

40. Vasodilators: • Direct Vasodilators • Hydralazine • Minoxidil • Angiotensin-Converting Enzyme Inhibitors • Angiotensin II Receptor Blockers

41. Vasodilators: • Traditionally not used as primary drugs for hypertension • Produce relaxation of vascular smooth muscle, predominantly arteriolar • Decreases SVR • Decreases Blood Pressure • Result in reflex tachycardia and increased contractility • May precipitate angina • Increase myocardial oxygen consumption • Also result in increase in plasma renin concentration • Sodium and water retention

43. Hydralazine (Apresoline ®) • Hydrazine derivative • Direct arteriolar smooth muscle dilator • Rapidly and almost totally absorbed from GI tract • Significant 1st-pass effect • Peak levels in ½ to 2 hours • Correlates with peak hypotensive effects • t-1/2 2-4 hours, duration of action 6-8 hours • Acetylation • Slow vs. Fast acetylators • 87% protein-bound

44. Hydralazine (Apresoline ®) • Side Effects: • Headache • Nausea, vomiting • Tachycardia, dizziness • Fluid retention • Lupus syndrome • Occurs in up to 10% of patients • Generally with >400 mg/day • Generally reversible upon discontinuation

45. Minoxidil: • Selective arteriolar dilator • ? Effect on opening of K channels • Antagonizes action of intracellular cAMP on K channels • Opens K channels causing relaxation of muscle • No effect on capacitance vessels (veins) • Rapidly and completely absorbed • Extensive metabolism • Eliminated in urine • Hypertrichosis • Occurs in 80% receiving drug > 4 weeks • Used topically to stimulate hair growth (Rogaine®) • Reserved for use in severe hypertension

46. Sodium Nitroprusside (Nipride ®): • Causes arterial and venous smooth muscle relaxation • Decreases preload and afterload • Action more pronounced in upright patient • Increased venous pooling occurs • Renal blood flow and GFR maintained • Increased plasma renin activity • No tachycardia occurs • Mechanism similar to nitrates • Results in increase in cGMP

47. Sodium Nitroprusside

48. Sodium Nitroprusside (Nipride ®): • Used exclusively via intravenous infusion • Onset of action with 1 to 2 minutes • t1/2 of minutes • Used for hypertensive emergencies and severe CHF • Used also for aortic dissection

49. Sodium Nitroprusside (Nipride ®): • Fe++ reacts with –SH compounds in RBC • CN- produced • Reduced to SCN- in liver (rhodanase) • Sodium thiosulfate (S donor) facilitates metabolism of CN- • Hydroxy-cobalamin also combines with CN-(cyanocobalamin) • SCN- excreted in urine • Half-life 3 to 4 days • May accumulate after prolonged use • Causes toxic psychosis • Predisposing factors include renal disease and hyponatremia • Monitor levels >3 days [0.1 mg/ml] • Acute toxicity • Excess vasodilatation and hypotension

50. Diazoxide • Thiazide compound • No diuretic effect • Selective arteriolar dilator • Results in decrease in SVR and BP • Compensatory increase in HR and contractility • Increase Na and water retention • Pharmacokinetics • Administer via bolus IV injection • Extensively bound to albumin • Effects in minutes, half-life = 24 hours • Adverse Effects • Hyperglycemia • Suppresses insulin release • Hyperuricemia • Decreases renal uric acid excretion