1、Drugs used to treat hypertension2006Hypertension-risk factor for:ischemic heart disease,stroke,renal failure and heart failureCategory Normal High normalHypertension Stage 1 Stage 2 Stage 3 Stage 4SystolicDiastolic13085139210120Classification of BPArterial blood pressure(BP)is determined by cardiac
2、output(MV)and peripheral vascular resistance(PR).BP=CO x PRCardiac output may be increased in children or young adults during the earliest stages of essential hypertensionPeripheral resistance is determined by the caliber and total cross-sectional area of the resistance vessels(small arteries and ar
3、terioles)in the various tissues.-Influence of predisposing factorsHypertensionEssential(primary)-most(90-95%)patients with persistent arterial hypertension-genesis of hypertension unknown-predisposing factors:Secondary-is secondary to some distinct disease:Renal+renovascular desease (artery stenosis
4、)Hormonal defects (Cushings syndrome,phaeochromocytoma)Mechanical defect (coarctation of aorta)Hypertension in pregnancyDrug-induced hypertension (sympatomimetics,glucocorticoids)Neurologic deseasesusceptive(obesity,stress,salt intake,lack of Mg2+,K+,Ca2+,ethanol dose,smoking)non-susceptive(positive
5、 family history,insulin resistance,age,sex,defect of local vasomotoric regualtion)1.Baroreceptors -they are responsible for rapid adjustment in blood pressure2.Kidney -plays a key role in long-term control of blood pressure and in the pathogenesis of hypertension -excretion of salt and water control
6、s intravascular volume,which influences the force of contraction of the heart by the Starling mechanism -secretion of renin(1/3 of patients)increases production of angiotensin II causes direct constriction of resistance vessels and stimulation of aldosterone synthesis in the adrenal cortex increases
7、 renal sodium absorption and intravascular volume -renal disease(vascular,parenchymal or obstructive)is a cause of arterial hypertension3.Non-renal mechanisms neuronal mechanisms sympathetic nervous system(continual background of vasoconstrictor tone),and endocrine and autocrine/paracrine mechanisms
8、 (NO vs,endothelin)Clinically important consequences of hypertension(end organ damage“)include damage both to large and small blood vessels as well as left-ventricular hypertrophy(increased arterial pressure causes an increased risk of arterial rupture and bleeding from a weak spot in the arterial w
9、all)!THERAPY OF HYPERTENSIONA.Non-pharmacological-lifestyle -decrease of salt intake -reduction of body weight -restriction of smoking and drinking excessive amounts of alcohol-regular physical activity and relaxation,lack of stress -increased intake of Mg2+,K+,Ca2+-fruit,vegetablesGuidelines for ma
10、nagement of hypertension:report of the fourth working party of the British Hypertension Society 2004BHS IV.J Hum Hypertens 2004;18:13985.*BNF 51th edition,2006The following thresholds for treatment are recommended:Accelerated(malignant)hypertension(with papilloedema or fundal haemorrhages and exudat
11、es)or acute cardiovascular complications,admit for immediate treatment;Where the initial blood pressure is systolic 220 mmHg or diastolic 120 mmHg,treat immediately;Where the initial blood pressure is systolic 180219 mmHg or diastolic 110119 mmHg,confirm over 12 weeks then treat if these values are
12、sustained;Where the initial blood pressure is systolic 160179 mmHg or diastolic 100109 mmHg,and the patient has cardiovascular complications,target-organ damage(e.g.left ventricular hypertrophy,renal impairment)or diabetes mellitus(type 1 or 2),confirm over 34 weeks then treat if these values are su
13、stained;Where the initial blood pressure is systolic 160179 mmHg or diastolic 100109 mmHg,but the patient has no cardiovascular complications,no target-organ damage,or no diabetes,advise lifestyle changes,reassess weekly initially and treat if these values are sustained on repeat measurements over 4
14、12 weeks;*BNF 51th edition,2006 Where the initial blood pressure is systolic 140159 mmHg or diastolic 9099 mmHg and the patient has cardiovascular complications,target-organ damage or diabetes,confirm within 12 weeks and treat if these values are sustained;Where the initial blood pressure is systoli
15、c 140159 mmHg or diastolic 9099 mmHg and no cardiovascular complications,no target-organ damage,or no diabetes,advise lifestyle changes and reassess monthly;treat persistent mild hypertension if the 10-year cardiovascular disease risk is 20%.An optimal target systolic blood pressure 140 mmHg and dia
16、stolic blood pressure 4 L urine/24 h)Imporatant drug interaction may occurs if loop diuretic is given with Li+(thymoprofylactic drug).Decrease of Na+reabsorption can lead to increase of Li+reabsorption toxicity.2.Drugs influencing sympathetic nervesa)a a-adrenoreceptor antagonistsMechanism of action
17、:-vasodilatation(reduce vascular resistence)and decreased blood pressure by antagonizing of tonic action of noradrenaline on a1 receptors(vascular smooth muscle)competitive with:a.short-term action:a a blockers with ISA-ergot alcaloidsa a non-selective-phentolaminea a1 1 selective-prazosin,uradipil,
18、b.long-acting a a1 1 antagonists-doxazosin,terazosin non-competitive with long-term action,non-selective-phenoxybenzaminToxicity:the most important toxicities of the alpha-blockers are simple extensions of their a-blocking effects type A adverse effects-the main manifestations are:-drowsiness,weakne
19、ss,orthostatic hypotension(first dose bedtime administration)-and for the nonselective agents,reflex tachycardia-in patients with coronary disease,angina may be precipitated by the tachycardia(less frequent in selective alpha1-blockers)-oral administration of any of these drugs can cause nausea,vomi
20、ting,diarrhoea-urinary incontinece -priapism,nasal congestion2.Drugs influencing sympathetic nervesPhaeochromocytomaLong-term management of phaeochromocytoma involves surgery.Alpha-blockers are used in the short-term management of hypertensive episodes in phaeochromocytoma.Once alpha blockade is est
21、ablished,tachycardia can be controlled by the cautious addition of a beta-blocker;a cardioselective beta-blocker is preferred.Phenoxybenzamine,a powerful alpha-blocker,is effective in the management of phaeochromocytoma but it has many side-effects.Phentolamine is a short-acting alpha-blocker used m
22、ainly during surgery of phaeochromocytoma;its use for the diagnosis of phaeochromocytoma has been superseded by measurement of catecholamines in blood and urine.2.Drugs influencing sympathetic nervesb)b b-adrenoreceptor antagonistsMechanism of action:-the fall in cardiac output BP-they reduce renin
23、secretion-CNS-effects?-additional mechanisms involve baroreceptors or other homeostatic adaptations Possible mechanisms include:b-adrenoceptors located on sympathetic nerve terminals can promote noradrenaline release,and this is prevented by b-receptor antagonists local generation of angiotensin II
24、within vascular tissues is stimulated by b2-agonists.2.Drugs influencing sympathetic nervescardio-selective:b b1 1 blockersatenolol,metoprolol b b1 1 blockers with ISAacebutol b b1 1+a+a1 1 blockerslabetalol,carvedilol cardio non-selective:b b1 1+b+b2 2 blockersmetiprolol,propranolol,nadolol b b1 1+
25、b+b2 2 blockers with ISApindolol,bopindololb b-adrenoreceptor antagonistsNote:Partial agonist activity(intrinsic sympathomimetic activity ISA)-may be an advantage in treating patients with asthma because these drugs will cause bronchodilation;they have moderate(lower)effect on lipid metabolism,cause
26、 lesser vasospasms and negative inotropic effect2.Drugs influencing sympathetic nervesAdverse effectsCardiovascular adverse effects,which are extension of the betablockade,include:-bradycardia-antrioventricular blockade-congestive heart failure(unstable)-asthmatic attacks(in patients with airway dis
27、ease)-premonitory symptoms of hypoglycemia from insulin overdosage (eg,tachycardia,tremor and anxiety,may be marked)-CNS adverse effects-sedation,fatigue,and sleep alterations.2.Drugs influencing sympathetic nervesc)Centrally acting drugsa a2-agonist actionsMethyldopafalse transmitterClonidine,Moxon
28、idinedirect a2-agonist,imidazol receptor agonists2.Drugs influencing sympathetic nerves-limited use in the treatment of hypertension.-methyldopa hypertension during pregnancy-methyldopa causes symptoms of drowsiness and fatigue that are intolerable to many adult patients in long-term use-they are se
29、ldom used to treat essential hypertension-clonidine is potent but poorly tolerated(rebound hypertension,if it is discontinued abruptly,is an uncommon but severe problem)Adverse effects:-drowsiness,fatigue(esp.methyldopa),depression,nightmares(methyldopa-rarely extrapyramidal features)driving!-nasal
30、congestion,anticholinergic symptoms(constipation,bradycardia)clonidine-dry mouth-hepatitis,drug fever(with methyldopa)-sexual dysfunction,salt and water retention-hypertensive rebound associated with anxiety,sweating,tachycardia and extrasystoles(rarely hypertensive crisis)2.Drugs influencing sympat
31、hetic nerves3.Vasodilators-drugs which dilate blood vessels(and decrease peripheral vascular resistance)by acting on smooth muscle cells through non-autonomic mechanisms:*release of nitric oxide (NO stimulates guanylyl cyclase and increase cGMP in smooth muscles reduction of cytoplasmic Ca2+by causi
32、ng Ca2+sequestration in the endoplasmic reticulum relaxation of both arterioles and venous capacitance vessels,lowering peripheral vascular resistance and reducing cardiac pre-as well as afterload)*opening of potassium channels (leads to hyperpolarization and relaxation of vascular smooth muscle)*bl
33、ockade of calcium channels (reduce intracellular calcium concentration relax aretriolar smooth muscle,reduce peripheral vascular resistance)A)DIRECT ACTINGminoxidil,diazoxide,sodium nitroprusside,hydralazine Minoxidil-therapy of severe hypertension resistant to other drugs-prodrug its metabolite(min
34、oxidil sulfate)is a potassium channel opener(repolarization+relaxation of vascular smooth muscle)-more effect on arterioles than on veins-orally active-Adverse:Na+and water retention coadministration with beta-vlocker and diuretic is mandatory for this drug,oedemas,hypertrichosis,breast tenderness-c
35、ompensatory responses are preserved(may include salt retention and tachycardia)suitable combination with diuretics or b-blockers 3.VasodilatorsDiazoxide-given by rapid iv.injection(less than 30 seconds)*in hypertensive emergencies-potassium channel opener-glucose intolerance due to reduced insulin s
36、ecretion(used in patients with inoperable insulinoma)-adverse:Na+and water retention,hyperglycaemia,hirsutism Hydralazine-rapidly and fairly absorbed after oral administration-arteriolar resistance-useful for hypertensive crisis during pregnancy-AE:Na+and water retention,systemic lupus erythematosus
37、 suspected if there is unexplained weight loss,arthritis3.Vasodilators*BNF 51th edition,2006Sodium nitroprusside-short-acting agent(few minutes)administrated by infusion in hypertensive emergencies(hypertensive encephalopathy,shock,cardiac dysfunction)for max 24 hours(risk of cumulation of cyanide t
38、oxicity)-Releases NO-the stock solution should be diluted and covered with foil to prevent photodeactivation-adverse effects:too rapid reduction of BP,nausea,palpitation,dizzinesscyanide metabolite accumulation tachycardia,hyperventilation,arrhythmias,acidosisCNCNCNCNFeNOCN-+-+3.VasodilatorsB)INDIRE
39、CT ACTING-CALCIUM CHANNEL-BLOCKING AGENTS 1.dihydropyridine(nifedipine,nicardipine,amlodipine)2.diltiazem,verapamil-they block voltage-dependent L-type“calcium channels relaxation of smooth muscle vasodilation reduce peripheral vascular resistance reduction of BP-negatively inotropic drugs-they diff
40、er in selectivity for calcium channels in vascular smooth muscles and cardiac tissues -orally active suitable for long-term use3.VasodilatorsDIHYDROPYRIDINES(nifedipine,nicardipine)-evoke vasodilatation resulting in sympathetic reflex activation,-relatively selective for vascular smooth muscle(arter
41、ial)amlodipine,lacidipine,isradipine,felodipine 2nd generation -longer duration of action once daily-do not reduce myocardial contractility do not produce clinical deterioration in heart failurenimodipine preferentially acts on cerebral arteries prevention of vascular spasm following aneurysmal suba
42、rachnoid haemorrhageIndication:all grades of essential hypertension-alone(nifedipine,amlodipine)in patients with mild hypertension for patients in whom thiazide diuretics and b-blockers are contraindicated-combinationsangina(with beta-blockers)3.Vasodilatorsverapamil,diltiazem-effects on the voltage
43、-dependent channels in cardiac conducting tissue -vasodilatation-it also blocks Ca2+entry in gastrointestinal smooth muscle and consequently causes constipation3.VasodilatorsDrugEffect onheart rateAdverse effectsNifedipine Headache,flushing,ankle swellingAmlodipine Ankle swellingNimodipineFlushing,h
44、eadacheDiltiazemGenerally mildVerapamil Constipation,marked negative inotropic actionAdverse effects of calcium channel-blocking agents Calcium channel blockers do not affect concentrations of plasma cholesterol or triglycerides,or extracellular calcium homeostasis.3.Vasodilators4.Angiotensin-conver
45、ting enzyme inhibitors(ACEI),blockers of AT1 rc.-hypertension where thiazide diuretics and beta-blockers are contraindicated-useful in hypertensive patients with heart failure(beneficial effect)-can limit the size of myocardial infarction-diabetic nephropathyANGIOTENSIN-CONVERTING ENZYME INHIBITORS(
46、ACEI)Captopril,enalapril,quinapril,lisinopril,perindopril,ramiprilIndicationsMechanism of action-ACEI regulates balance between bradykinin(vasodilatation,natriuresis)and angiotensin II(vasoconstriction,Na+-retention)-AT1 receptors-widely distributed in the body(lung-huge surface area of endothelial
47、cells,heart,kidney,striated muscle and brain)and present on the luminal surface of vascular endothelial cells Angiotensin II-vasoconstriction-noradrenaline release from sympathetic nerve terminals-aldosterone secretion from the zona glomerulosa of the adrenal cortex-ADH-is a growth factor for vascul
48、ar smooth muscle and some other cells=remodelling4.Angiotensin-converting enzyme inhibitors(ACEI),blockers of AT1 rc.angiotensin-converting enzymeAngiotensin I(inactive)Angiotensin II(active vasoconstrictor)Bradykinin(active vasodilator)Inactive metabolitesACE inhibitors4.Angiotensin-converting enzy
49、me inhibitors(ACEI),blockers of AT1 rc.Mechanism of action:Converting enzyme inhibitors lower blood pressure by reducing angiotensin II,and also by increasing vasodilator peptides such as bradykinin.Decrease noradrenaline release reduction of sympathetic activity(use is not associated with reflex ta
50、chycardia despite causing arterioral and venous dilatation)Inhibition of aldosterone secretion from the zona glomerulosa contributes to the antihypertensive effects of ACEI Influence on the arteriolar and left ventricular remodelling that are believed to be important in the pathogenesis of human ess
