antihypertensive drugs Department of pharmacology Liming zhou （周黎明）

1. antihypertensive drugs Department of pharmacology Liming zhou（周黎明） 2010,3

2. Blood pressureBP = CO x TPR

3. Physiology of cardiovascularElectrical activity • Na+ channel inactivate quickly • Ca2+ channels inactivate slowly • Ca2+ responsible for plateau depolarisation

5. Autonomic nervous system • Parasympathetic • Sympathetic • Long term adjustments • Increased sympathetic activity increases renin release by the kidney and causes sodium and water retention. • Trophic effect on blood vessels

6. Origin of Autonomic activity • Inputs from afferents -arterial barorecptors and blood borne hormones (angiotensin II). • Inputs to spinal preganglionic neurons involved in cardivascular regulation originate in the brainstem, pons, hypothalamus. Mostly, rostral ventrolateral medulla. • Barorecptor adaptation.

7. G-protein-coupled receptors • Slow transmission • G-protein-coupled receptors (GPCRs) • contain a conserved structure of seven transmembrane a-helices

8. G-protein-coupled receptors • Bind ligands and are stabilized. • Lack catalytic activity, but agonist binding promotes the dissociation of G-proteins into Gai and Gb subunits. • Effector molecules: adenyl cyclase, phopholipases, and ion channels. • Regulate the production of second messengers.

10. Parasympathetic nervous system • Resting heart rate is controlled by muscarinic Gai-coupled receptors • i = inhibitory action on adenyl cyclase • And Sinoatrial node inhibition by Gai and Gb subunits.

11. Sympathetic nervous system • Modulates activity of smooth muscle, cardiac muscle and glandular cells. • Noraderenaline released at post ganglionic sympathetic nerve endings • Sympathomimetics and sympatholytics

12. Sympathetic nervous system • types of AR have been cloned • 1: three types • 2: three types • : three types

13. Location of ARs • 1: vessels • 2: Bronchial smooth muscle • 2: presynaptic membranes • 1: are the most common in cardiac muscle comprising 75-80% of total b-ARs • There are only a small number of a-ARs • 10:1

14. Sympathetic stimulation • Increases developed contractions (inotropy). • Accelerates relaxation (lusitropy)and [Ca2+] decline. • Increases cAMP, PKA • Phosphorylation of L-type Ca2+ channels, troponin I and myosinbinding protein C.

16. Hypertension • Increase in balance between between sympathetic and parasympathetic control. • Impaired baroreflex • Increased plasma or tissue angiotensin II

17. Hypertension • Hypertension is defined as systolic blood pressure (SBP) of 140 mmHg or greater, diastolic blood pressure (DBP) of 90 mmHg or greater - Arbitrary • 1 in 5 adults have systolic and/or diastolic blood pressure above 140/90

19. Hypertension: Etiology • Primary hypertension (90-95% of cases) • Secondary hypertension (selected causes) • Renal (e.g., RAS) • Pheochromocytoma • Primary aldosteronism • Cushing’s syndrome

20. Coarctation of the aorta • Hyperthyroidism • Hypothyroidism • Hyperparathyroidism • Chronic alcohol use • Drugs

21. Hypertension: Etiology • Studies demonstrate a clear relationship betweenblood pressure and cardiovascular morbidity andmortality.

22. High blood pressure increases the risk of: • Stroke • Angina • Myocardial infarction • Heart failure • Renal dysfunction • Blindness • Death from a cardiovascular cause

23. Genetics of hypertension • Blood pressure levels are correlated among family members, a fact attributable to common genetic background, shared environment, or lifestyle habits.

24. High blood pressure appears to be a complex trait that does not follow the classic Mendelian rules of inheritance attributable to a single gene locus. • Exceptions are a few rare forms of hypertension, such as those related to a single mutation involving a chimeric 11-beta-hydroxylase/aldosterone synthase gene.

25. Major Risk Factors Smoking Dyslipidemia Diabetes mellitus Age older than 60 years Sex (men and postmenopausal women) Family history of cardiovascular disease: women under age 65 or men under age 55 Risk factors and target organs

26. Target Organ Damage/Clinical • Cardiovascular Disease • Heart diseases • Left ventricular hypertrophy • Angina/prior myocardial infarction • Prior coronary revascularization • Heart failure • Stroke or transient ischaemic attack • Nephropathy • Peripheral arterial disease • Retinopathy

28. Lifestyle changes • Lose weight if overweight. • Limit alcohol intake to no more than 30 ml ethanol ( 720 ml beer, 300 ml wine) per day or 15 ml ethanol per day for women. • Increase aerobic physical activity (30 to 45 minutes most days of the week.

29. Reduce sodium intake to no more than 100 mmol per day (2.4 g sodium or 6 g sodium chloride). • Maintain adequate intake of dietary potassium (approximately 90 mmol per day). • Maintain adequate intake of dietary calcium and magnesium for general health. • Stop smoking and reduce intake of dietary saturated fat and cholesterol for overall cardiovascular health.

30. Pharmacology • Drugs used to treat hypertension must lower blood pressure • Some act through the autonomic nervous system • Others by regulating fluid balance or endocrine mechanisms

31. Pharmacology • b-adrenergic receptor blockers • Diuretics • Angiotensin-converting enzyme inhibitors • Angiotnsin-II receptor blockers • Calcium antagonists • Other adrenergic inhibitors • Direct vasodilators

32. SYMPATHOLYTICS • Reduce blood pressure by inhibiting or blocking the sympathetic nervous system. • Classified by site or mechanism of action: central-acting sympathetic nervous system inhibitors (methyldopa – Aldomet), alpha blockers (prazosin – Minipress), mixed alpha and beta blockers (labetalol – Normodyne), and norepinephrine depletors (reserpine – Serpalan).

33. SYMPATHOLYTICS • Pharmacokinetics: • Absorbed well from the GI tract; distributed widely; metabolized in the liver; excreted in the urine. • Pharmacodynamics: • Inhibit stimulation of the sympathetic nervous system causing dilation of the peripheral blood vessels, decreasing cardiac output, and decreasing the BP.

34. SYMPATHOLYTICS • Pharmacotherapeutics: • Beta blockers and diuretics are the initial drugs prescribed to treat hypertension. If the elevated blood pressure is not controlled, then an alpha blocker or alpha-beta blocker may be used. • Drug interactions: involve clonidine (Catapres). • Adverse reactions: hypotension.

37. Diuretics - • Used to adjust volume in hypertension, acute and chronic heart disease, acute and chronic renal failure. • Four main classes: • Carbonic anhydrase inhibitors (proximal tubule and collecting duct)

38. Thiazides and thiazide-like agents (Distal convoluted tubule) • Loop diuretics (Thick ascending limb - interferes with the formation of the hypertonic medullary intersitium) • Potassium sparing diuretics (Late Distal tubule and collecting duct)

39. Cardiac output may be reduced by drugs that either inhibit myocardial contractility or decrease ventricular filling pressure.

40. ANTIHYPERTENSIVES • Act to reduce blood pressure. • Treatment for hypertension begins with beta-blockers (previously mentioned) and diuretics (to follow). • If not effective then the hypertension is treated with sympatholytic drugs, vasodilators, angiotensin-converting enzyme (ACE) inhibitors, or a combination of drugs.

41. VASODIALATORS • Two types: direct vasodilators and calcium channel blockers; both decrease systolic and diastolic blood pressure. • Direct vasodilators act on arteries, veins, or both and include: diazoxide (Hyperstat), Prototype: hydralazine hydrochloride (Apresoline), minoxidil (Rogaine), and nitroprusside sodium (Nitropress). • Calcium channel blockers produce arteriolar relaxation by preventing the entry of calcium into the cells.

42. VASODIALATORS • Pharmacokinetics: • Absorbed rapidly; distributed well; metabolized in the liver; excreted by the kidneys. • Pharmacodynamics: • Direct vasodilators relax peripheral vascular smooth muscles, causing vasodilation, lowering the BP.

43. VASODIALATORS • Pharmacotherapeutics: • Are rarely used alone to treat hypertension. • Drug interactions: may produce additive effects when taken with nitrates. • Adverse reactions: compensatory vasoconstriction and tachycardia.

44. ACE INHIBITORS • Reduce blood pressure by interrupting the renin-angiotensin-aldosterone system. • Include: benazepril hydrochloride (Lotensin), Prototype: captopril (Capoten), enalapril (Vasotec), fosinopril sodium (Monopril), lisinopril (Prinivil), quinapril hydrochloride (Accupril), and ramipril (Altace).

45. ACE INHIBITORS • Pharmacokinetics: • Absorbed well in the GI tract; distributed to most body tissues; metabolized in the liver; excreted by the kidneys.

46. ACE INHIBITORS • Pharmacodynamics: • Act by interfering with the renin-angiotensin-aldosterone system by preventing the conversion of angiotensin I to angiotensin II causing arteriole dilation reducing peripheral vascular resistance. • Also by reducing aldosterone secretion, the excretion of sodium and water is promoted reducing the amount of pumped blood.

47. ACE INHIBITORS • Pharmacotherapeutics: • Used when beta blockers or diuretics are ineffective. • Also used to manage heart failure. • Drug interactions: enhance the hypotensive effects of diuretics and other antihypertensive drugs. • Adverse reactions: headache and fatigue.

48. ANTILIPEMICS • Used to lower abnormally high blood levels of lipids such as cholesterol, triglycerides, and phospholipids. • Include: bile-sequestering drugs (bile acid sequestrants), fibric acid derivatives (fibrates), and cholesterol synthesis inhibitors (HMG-CoA reductase inhibitors – hydroxymethylglutaryl-coenzyme A reductase) or STATINS.