高血压英文ppt精品课件antihypertensive

Antihypertensive Drugs 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 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 The left ventricle is markedly thickened in this patient with severe hypertension that was untreated for many years. The myocardial fibers have undergone hypertrophy. 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. Major Risk Factors That Increase Mortality in Hypertension Smoking Dyslipidemias Diabetes Mellitus Age 60 Gender: men, postmenopausal women Family history 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. 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 Stages of Hypertension 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 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 Ways of Lowering Blood Pressure Reduce cardiac output (- blockers, Ca2+ channel blockers) Reduce plasma volume (diuretics) Reduce peripheral vascular resistance (vasodilators) MAP = CO X TPR “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 Homeostasis of Blood Pressure 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. For Short-Term Neural Control Baroreceptor reflex Sit or stand up quickly, BP falls neural responses reestablish normal BP or Sudden increase in stroke volume, BP rises, neural responses reestablish normal BP Figure 15-22 Sympathetic nervous control Long-term Renal Control of BP: Direct Pressure Diuresis Blood volume too high, Renal Sympathetic vasoconstriction reduced More fluid enters kidney, more urine formed Lowers BP via lower blood volume Blood pressure too low, Renal Sympathetic vasoconstriction rises Less fluid enters kidney, less urine formed Raises BP by higher blood volume Figure 15-9 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. Renin-angiotensin system 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 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. Diuretics First -line drug Low dose diuretic therapy is safe and effective in preventing HTN complications hydrochlorothiazide (Hydrodiuril), chlorthalidone (Hygroton furosemide spironolactone 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. 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 Thiazide diuretics: mechanism of action CO Then Effect of thiazides on BP: kinetic 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 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 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 Beta-adrenergic antagonists 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) Beta-blockers: mechanism of action in hypertension 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) 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 Raynauds 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) 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. Renin-angiotensin system 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 ACEIs: mechanism of action 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. 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. Not for pregnant women. Other major uses of ACEIs: diabetic nephropathy, CHF and post MI treatment. 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) 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. Difference between ACEIs reduce CO & TPR a) Major site: CNS. Reduce activity of sympathetic nerves by action on vasomotor center b) peripheral site: reduce release of NE from sympathetic terminals Centrally Acting Drugs Antihypertensive effect results from action in the CNS causing a reduced sympathetic nerve firing rate. Prototype: clonidine Mechanism of action of clonidine Peripheral effect Central effect Alpha-2 adrenergic agonists: side-effects 1. Sedation 2. Depression 3. Dry mouth, constipation. 4. Rebound hypertension (clonidine but not alphamethyl-dopa) Impairment of sexual function Na retention (improved by use of diuretics) Alpha-2 adrenergic agonists: therapeutic status Second-line drugs in hypertension, not used for monotherapy. Use of slow-release patch (clonidine) improves side-effects) Methyl-dopa is safe in pregnancy. Note: alpha-2 adrenergic agonists are used to treat glaucoma, pain, spasticity and opiate withdrawal. Ganglionic blockers Historical interest only. These drugs produce intolerable side-effects (orthostasis, Na retention, GI and sexual dysfunction) trimethaphan was withdrawn in 1996 mecamylamine still available but never used. Reserpine Depletes NE from storage vesicles Major action is in CNS. Reduces sympathetic outflow. Reasonably effective, especially with thiazide. Side-effects: depression, sedation, GI hyperactivity. Cheap, its only virtue. Little used at present. Guanethidine Peripheral sympatholytic drug. Rides the NE transporter, dislodges NE from vesicles and prevents exocytosis. Lots of side-effects: postural hypotension cerebral ischemia, GI hyperactivity, sexual dysfunction Potentially very serious drug interactions (tricyclics, indirectly acting sympathomimetics e.g. cold medicines) Use in hypertension restricted to severe cases. Must be combined with diuretic Vasodilators: Hydralazine & Minoxidil Oral vasodilators used are used for long-term outpatient treatment of severe hypertension in the context of a polydrug therapy. Work by reducing afterload (TPR). Cause marked Na retention and rapidly increase BV (pseudotolerance) i.e. must be used in conjunction with diuretics. Cause marked reflex tachycardia and increased contractility (beta -mediated) ergo must be used with beta- blockers. Minoxidil causes hypertrichosis(growth of body hair). Alpha-1 adrenergic antagonists Mechanism of action: a) antagonize effect of sympathetic tone in arteries and veins (reduce TPR and preload) b) reduce baroreflex via central action (thus produce very little reflex tachycardia). Side-effects: few a) first-dose hypotension (Pb with older patients) b) retention of salt and water Alpha 1-blockers: mechanism of action Alpha-1 adrenergic antagonists: therapeutic use 1. Can be used for monotherapy of mild hypertension 2. May improve LDL/HDL ratio 3. Effects additive with thiazide diuretics and ACEI. 4. Should not be co