-高血压英文PPT精品课件Antihypert.ppt

1、Antihypertensive DrugsHypertension 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 failureDefinitionElev

2、ation 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 casesThe left ventric

3、le 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 hypert

4、ensive 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 prevale

5、nce 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 D

6、iagnosis is generally based on repeated, reproducible measurements of elevated blood pressure and not on patient symptoms. Patient compliance is a major obstacle to therapyStages of HypertensionStageDiastolic Range (mm Hg)Systolic Range (mm Hg)High Normal85-89130-139Stage 190-99140-159Stage 2100-109

7、160-179Stage 3 109179Treatment RationaleLong-term goal of antihypertensive therapy:Reduce mortality due to hypertension-induced disease Stroke Congestive heart failure Coronary artery disease Nephropathy Peripheral artery disease RetinopathyWays of Lowering Blood Pressure Reduce cardiac output (-blo

8、ckers, Ca2+ channel blockers) Reduce plasma volume (diuretics) Reduce peripheral vascular resistance (vasodilators)MAP = CO X TPRIndividualized Care Risk factors considered Monotherapy is instituted Non pharmacological therapy tried first Considerations for choice of initial monotherapy: Renin statu

9、s Coexisting cardiovascular conditions Other conditionsHomeostasis of Blood PressureDeterminants 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 resistanceAP = CO x TPR Eac

10、h of these factors can be manipulated by drug therapy Treatment of hypertension seeks to lower CO and/or TPR.For Short-Term Neural ControlBaroreceptor reflex Sit or stand up quickly, BP fallsneural responses reestablish normal BP or Sudden increase in stroke volume, BP rises, neural responses reesta

11、blish normal BP Figure 15-22Sympathetic nervous controlLong-term Renal Control of BP: DirectPressure DiuresisBlood volume too high, RenalSympathetic vasoconstriction reducedMore fluid enters kidney, more urine formed Lowers BP via lower blood volumeBlood pressure too low, RenalSympathetic vasoconstr

12、iction risesLess fluid enters kidney, less urine formedRaises BP by higher blood volumeFigure 15-9Renal 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-angiotensi

13、n systemSummary 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 urine2. Vasoconstriction / vasodilation MAJOR ANTIHYPERTENSIVE DRUGS1) Diuretics - Thiazides

14、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

15、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 (Hyd

16、rodiuril), chlorthalidone (Hygroton furosemide spironolactone1.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 eff

17、ects 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 d

18、ecrease are probably related to a depletion of body Na+ stores which leads to:a) a decrease of interstitial fluid volumeb) 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 hormonesThi

19、azide diuretics: mechanism of actionCOThen Effect of thiazides on BP: kineticThiazide 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

20、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 blockersThiazide Diuretics: side-effects. Major Side-effects: a) K loss (minimized by using low doses, diet, use of combos with K-sparing diuretic

21、s). b) hyperuricemia (bad for gout) c) hyperglycemia, glucose intolerance (bad for diabetes) d)increase LDL & VLDL (bad for atherosclerosis) Beneficial effect: Ca-sparing (good for osteoporosis)Furosemide and high ceiling diuretics Use in hypertension is limited . On their own they are not very effe

22、ctive at lowering BP Main indications are: a) severe hypertension when several drugs with Na-retaining properties are used (e.g. hydralazine, major sympatholytics). Usually a beta-blocker is also required . b) when GFR is 30-40 ml/min c) in CHF or cirrhosis. Propranolol Nadolol nonselective Pindolol

23、 - nonselective; 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 pheochromocytomasBeta-a

24、drenergic antagonistsBeta-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 s

25、ome vascular beds. c) in the CNS (controversial) Beta-blockers: mechanism of action in hypertensionBeta-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 en

26、ergy (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. Withdr

27、awal: 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 peri

28、pheral 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 card

29、iac depression Non-selective, beta-1 selective and blockers with ISA work equally well. Can be combined with ACEI, dihydropyridines (cautiously), other vasodilators. Renin-angiotensin systemACE inhibitors: mechanism of antihypertensive action ACEIs AII and bradykinin (vasodilator). In the context of

30、 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 contractilityACEIs: mechan

31、ism of actionACEIs: 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 thiaz

32、ide) 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. Ca

33、n 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

34、) 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

35、 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 & AT1 blockers AngII Bradykinin AT1-R AT2-R Vasoco

36、nstriction Vasorelaxation AngII Bradykinin AT1-R AT-2RVasoconstrictionVasorelaxationACEIsAT1 R antagonistsNormal Reduced IncreasedDHPs:mechanism of actionSNA is minimalwith long-lasting DHPsDihydropyridine Ca channel blockers Mechanism of antihypertensive action: arteriolar vasodilation, TPR drop. D

37、HPs are slightly more potent antihypertensives than verapamil or diltiazem Side-effects: a) orthostatic hypotension b) reflex tachycardia may lead to cardiac ischemia and/or arrhythmias (minimized by using slow-onset and long-lasting preps) c) headache, flushing, dizziness d) pedal oedema. Non-selec

38、tive Ca channel blockers: mechanism of actionNon-selective Ca channel blockers: side-effects Side-effects: a) SA node inhibition: probably good as it prevents the baroreflex mediated tachycardia b) increase in AV node refractoriness. Good for SVTs but can produce AV block in patients with cardiac co

39、nduction problems. c) decrease cardiac contractilityCentrally Acting Drugs Clonidine activates alpha2 and imidazoline receptors in thevasomotor center of the medulla which inhibits the sympatheticnervous system. Considered a second-line drug or for special cases(ie methyldopa in pregnant hypertensiv

40、e patients). A reduced heart rate and cardiac output account for reductionin blood pressure.Alpha-2 adrenergic agonists Clonidine, guanabenz, guanfacine, alpha-methyl dopa (the latter is a prodrug converted into alpha-methyl NE). Mechanisms of action: sympatholytics; reduce CO & TPR a) Major site: C

41、NS. Reduce activity of sympathetic nerves by action on vasomotor center b) peripheral site: reduce release of NE from sympathetic terminalsCentrally Acting Drugs Antihypertensive effect results from action in the CNS causing a reduced sympathetic nerve firing rate. Prototype: clonidineMechanism of a

42、ction of clonidinePeripheral effectCentral effectAlpha-2 adrenergic agonists: side-effects1. Sedation2. Depression3. Dry mouth, constipation.4. Rebound hypertension (clonidine but not alphamethyl-dopa)5. Impairment of sexual function6. Na retention (improved by use of diuretics)Alpha-2 adrenergic ag

43、onists: 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 block

44、ers 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 out

45、flow. 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: p

46、ostural 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 diureticVasodilators: Hydralazine & Minoxi

47、dil 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 refl

48、ex 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

49、 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 waterAlpha 1-blockers: mechanism of actionAlpha-1 adrenergic antagonists: therapeutic use1.Can be used for monotherapy of mild h

50、ypertension 2.May improve LDL/HDL ratio3.Effects additive with thiazide diuretics and ACEI.4.Should not be combined with vasodilators (e.g. dihydropyridines): tachycardia.5.Good for patients with benign prostatic hyperplasia.Alpha-1 adrenergic antagonists: difference between agents Prototype: prazos