-高血压英文课件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 failureDefinitionEleva

2、tion 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 ventricle is mar

3、kedly 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

4、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 c

5、ities,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

6、 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 2100-109160-179Stage 3 109179Treatment

7、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(-blockers,Ca2+channel blockers)Reduc

8、e 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 status Coexisting cardiovascular conditions Ot

9、her 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 Each of these factors can be manipulated by dru

10、g 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 reestablish normal BP Figure 15-22Sympathetic nervous

11、 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 vasoconstriction risesLess fluid enters kidney,less urine for

12、medRaises 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-angiotensin systemSummary of Long Term Renal Control of BP Regul

13、ates 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 and congeners.-Loop diuretics.-Potassium-sparing diuretics.2)

14、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 a

15、ntagonists.-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 spironolactone1.Thiazide diuretics

16、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.

17、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 decrea

18、se 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 hormonesThiazide diuretics:mechanism of actionCOThen Effect of thiazides on BP:kineticThiazide diuretics

19、: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

20、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 diuretics).b)hyperuricemia(bad for gout)c)hyperglycemia,glucose intolerance(bad for diabetes)d)increase LDL&VLDL(bad for

21、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 effective at lowering BP Main indications are:a)severe hypertension when several drugs with Na-retaining properties are used(e.g.hydr

22、alazine,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-nonselective;partial agonist(some intrinsic sympathomimetic activity);less bradycardia than other beta-blockers Metoprolol-beta1 selective

23、Labetolol-beta/alpha;higher instance of side effects(orthostatic hypotension;sexual dysfunction);useful in hypertension of pheochromocytomasBeta-adrenergic antagonistsBeta-adrenergic antagonists Mechanism of action:beta-1 blockade a)in heart(they reduce cardiac contractility and CO).b)in kidney(they

24、 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 hypertensionBeta-adrenergic antagonists:side-effects/1 Bronchoconstriction(minimized

25、 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

26、-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+bet

27、a 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 bined with low dos

28、e 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 systemACE inhibitors:mechanism of ant

29、ihypertensive 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

30、NE (which lowers TPR and CO)d)cardiac contractilityACEIs:mechanism 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 pre

31、sence 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

32、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

33、 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 Prototy

34、pe: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&AT1 blockers AngII Bradykinin AT1-R AT2-

35、R Vasoconstriction 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 d

36、rop.DHPs 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-selective

37、 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 conduction pr

38、oblems.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 hypertensive patients).A

39、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:CNS.Reduce activity of symp

40、athetic 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 action of clonidinePeripheral ef

41、fectCentral 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 agonists:therapeutic status Second-line dru

42、gs 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 in

43、tolerable 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-e

44、ffects: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 dysfunct

45、ion 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&Minoxidil Oral vasodilators used are used for long-term outpatient treatment of severe

46、 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-bl

47、ockers.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)f

48、irst-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 hypertension 2.May improve LDL/HDL ratio3.Effects additive with thiazide diuretics and ACEI.4.Should not b

49、e combined with vasodilators(e.g.dihydropyridines):tachycardia.5.Good for patients with benign prostatic hyperplasia.Alpha-1 adrenergic antagonists:difference between agents Prototype:prazosin Newer agents(terazosin,doxazosin)have longer T1/2.Newer agents can be given once a day.Treatment of mild hy

50、pertension Nonpharmacological(salt restriction,exercise,weight loss)Pharmacological:alternatives for initial treatment include:a)monotherapy with thiazide,ACEI,beta-blocker or alpha-1 blocker or calcium-channel blocker.Drug is selected on the basis of efficacy,concurrent pathologies and individual s