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antihypertensive drugs Department of pharmacology Liming zhou（周黎明） 2007,3 Blood pressure BP = CO x TPR Physiology of cardiovascular Electrical activity Na+ channel inactivate quickly Ca2+ channels inactivate slowly Ca2+ responsible for plateau depolarisation 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 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. G-protein-coupled receptors Slow transmission G-protein-coupled receptors (GPCRs) – contain a conserved structure of seven transmembrane a-helices 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. 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. Sympathetic nervous system Modulates activity of smooth muscle, cardiac muscle and glandular cells. Noraderenaline released at post ganglionic sympathetic nerve endings Sympathomimetics and sympatholytics Sympathetic nervous system types of AR have been cloned a1: three types a2: three types b: three types Location of ARs a1: vessels b2: Bronchial smooth muscle a2: presynaptic membranes b1: are the most common in cardiac muscle comprising 75-80% of total b-ARs There are only a small number of aARs 10:1 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. Hypertension Increase in balance between between sympathetic and parasympathetic control. Impaired baroreflex Increased plasma or tissue angiotensin II 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 Category Systolic (mm Hg) Optimal <120 Normal <130 High130-139 normal Hypertension Stage 1 140-159 Stage 2 160-179 Stage 3 >180 and and or Diastolic (mm Hg) <80 <85 85-89 or or or 90-99 100-109 >110 Hypertension: Etiology Primary hypertension (90-95% of cases) Secondary hypertension (selected causes) – Renal (e.g., RAS) – Pheochromocytoma – Primary aldosteronism – Cushing’s syndrome –Coarctation of the aorta –Hyperthyroidism –Hypothyroidism –Hyperparathyroidism –Chronic alcohol use –Drugs Hypertension: Etiology Studies demonstrate a clear relationship between blood pressure and cardiovascular morbidity and mortality. High blood pressure increases the risk of: –Stroke –Angina –Myocardial infarction –Heart failure –Renal dysfunction –Blindness –Death from a cardiovascular cause Genetics of hypertension Blood pressure levels are correlated among family members, a fact attributable to common genetic background, shared environment, or lifestyle habits. 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 11beta-hydroxylase/aldosterone synthase gene. Risk factors and target organs 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 Target Organ Damage/Clinical Cardiovascular Heart Disease diseases –Left ventricular hypertrophy –Angina/prior myocardial infarction –Prior coronary revascularization –Heart failure Stroke or transient ischaemic attack Nephropathy Peripheral arterial disease Retinopathy 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. 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. 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 Pharmacology b-adrenergic receptor blockers Diuretics Angiotensin-converting enzyme inhibitors Angiotnsin-II receptor blockers Calcium antagonists Other adrenergic inhibitors Direct vasodilators 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). 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. 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. 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) –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) Cardiac output may be reduced by drugs that either inhibit myocardial contractility or decrease ventricular filling pressure. 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. 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. 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. 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. 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). ACE INHIBITORS Pharmacokinetics: Absorbed well in the GI tract; distributed to most body tissues; metabolized in the liver; excreted by the kidneys. ACE INHIBITORS Pharmacodynamics: Act by interfering with the reninangiotensin-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. 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. 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.
