1、Drugs used to treat hypertension,2006,Hypertensionrisk factor for: ischemic heart disease, stroke, renal failure and heart failure,Category Normal High normal Hypertension Stage 1 Stage 2 Stage 3 Stage 4,Systolic Diastolic 210 120,Classification of BP,Arterial blood pressure (BP) is determined by ca
2、rdiac output (MV) and peripheral vascular resistance (PR).,BP = CO x PR,Cardiac output may be increased in children or young adults during the earliest stages of essential hypertension,Peripheral resistance is determined by the caliber and total cross-sectional area of the resistance vessels (small
3、arteries and arterioles) in the various tissues. - Influence of predisposing factors,Hypertension,Essential (primary) - most (90-95 %) patients with persistent arterial hypertensiongenesis of hypertension unknownpredisposing factors:,Secondaryis secondary to some distinct disease:Renal + renovascula
4、r desease (artery stenosis) Hormonal defects (Cushings syndrome, phaeochromocytoma) Mechanical defect(coarctation of aorta) Hypertension in pregnancy Drug-induced hypertension(sympatomimetics, glucocorticoids) Neurologic desease,susceptive (obesity, stress, salt intake, lack of Mg2+, K+, Ca2+, ethan
5、ol dose, smoking),non-susceptive (positive family history, insulin resistance, age, sex, defect of local vasomotoric regualtion),Baroreceptors - they are responsible for rapid adjustment in blood pressureKidney- plays a key role in long-term control of blood pressure and in the pathogenesis of hyper
6、tension- excretion of salt and water controls intravascular volume,which influences the force of contraction of the heart by theStarling mechanism- secretion of renin (1/3 of patients) increases production of angiotensin II causes direct constriction of resistance vessels and stimulation of aldoster
7、one synthesis in the adrenal cortex increases renal sodium absorption and intravascular volume- renal disease (vascular, parenchymal or obstructive) is acause of arterial hypertension,Non-renal mechanisms neuronal mechanisms sympathetic nervous system (continual background of vasoconstrictor tone),
8、and endocrine and autocrine/paracrine mechanisms(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 rup
9、ture and bleeding from a weak spot in the arterial wall) !,THERAPY OF HYPERTENSION,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- increas
10、ed intake of Mg2+, K+, Ca2+ - fruit, vegetables,Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society 2004BHS IV. J Hum Hypertens 2004; 18: 13985.*,*BNF 51th edition, 2006,The following thresholds for treatment are recommended:Accelerated (
11、malignant) hypertension (with papilloedema or fundal haemorrhages and exudates) 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
12、 or diastolic 110119 mmHg, confirm over 12 weeks then treat if these values are 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
13、diabetes mellitus (type 1 or 2), confirm over 34 weeks then treat if these values are sustained;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, re
14、assess weekly initially and treat if these values are sustained on repeat measurements over 412 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 wi
15、thin 12 weeks and treat if these values are sustained;Where the initial blood pressure is systolic 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
16、10-year cardiovascular disease risk is 20%.An optimal target systolic blood pressure 140 mmHg and diastolic blood pressure 85 mmHg is suggested.In some individuals it may not be possible to reduce blood pressure below the suggested targets despite the use of appropriate therapy.,*BNF 51th edition, 2
17、006,Drug treatment of hypertensionNo consistent or important differences have been found between the major classes of antihypertensive drugs in terms of antihypertensive efficacy, side-effects or changes to quality of life. The choice of antihypertensive drug will depend on the relevant indications
18、or contra-indications for the individual patient:,1. Diuretics 2. Drugs influencing sympathetic nerves 3. Vasodilators 4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 receptor,*BNF 51th edition, 2006,Thiazides particularly indicated for hypertension in the elderly; a contra-indic
19、ation is gout;Beta-blockers indications include myocardial infarction, angina; compelling contra-indications include asthma, heart block;ACE inhibitors indications include heart failure, left ventricular dysfunction and diabetic nephropathy; contra-indications include renovascular disease and pregna
20、ncy; when thiazides and beta-blockers are contra-indicated, not tolerated, or fail to control blood pressureAngiotensin-II receptor antagonists are alternatives for those who cannot tolerate ACE inhibitors because of persistent dry cough, but they have the same contra-indications as ACE inhibitors;C
21、alcium-channel blockers. a) Dihydropyridine calcium-channel blockers are valuable in isolated systolic hypertension in the elderly when a low-dose thiazide is contra-indicated or not tolerated. b) Rate-limiting calcium-channel blockers (e.g. diltiazem, verapamil) may be valuable in angina; contra-in
22、dications include heart failure and heart block;Alpha-blockers a possible indication is prostatism; a contra-indication is urinary incontinence.,*BNF 51th edition, 2006,A single antihypertensive drug is often not adequate and other antihypertensive drugs are usually added in a step-wise manner until
23、 control is achieved. Unless it is necessary to lower the blood pressure urgently, an interval of at least 4 weeks should be allowed to determine response.Where two antihypertensive drugs are needed 1. an ACE inhibitor or an angiotensin-II receptor antagonist or a beta-blocker may be combined with 2
24、. either a thiazide or a calcium-channel blocker.If control is inadequate with 2 drugs, a thiazide and a calcium-channel blocker may be added. In patients at high risk of diabetes it is best to avoid a combination of a beta-blocker and a thiazide. In patients with primary hyperaldosteronism, spirono
25、lactone is effective.Response to drug treatment for hypertension may be affected by the patients age and ethnic background. A beta-blocker or an ACE inhibitor may be the most appropriate initial drug in younger Caucasians; Afro-Caribbean patients respond less well to these drugs and a thiazide or a
26、calcium-channel blocker may be chosen for initial treatment.,*BNF 51th edition, 2006,1. DIURETICS,drugs of first choice for treating patients with mild hypertensionoften combined with another drug in treatment of more severe hypertension,THIAZIDES hydrochlorothiazide, clopamid, chlorthalidoneindapam
27、id, metipamid,- preferable (to loop diuretics) for the treatment of uncomplicated hypertension - given by mouth as a single morning dose - begin to act within 1-2 hours and work for 12-24 hours - treatment should be started using a low dose,Thiazides,Lumen urine,Distal convoluted tubule,Interstitium
28、 - blood,Mechanism of action: = lower blood pressure by reduction of blood volume and by direct vascular effect inhibition of sodium chloride transport in the early segment of the distal convoluted tubule natriuresis, decrease in preload and cardiacoutput - renal effectslow decrease of total periphe
29、ral resistance (raised initially) during chronic treatment, suggesting an action on resistance vessels - extrarenal effectscompensatory responses to pressor agents including angiotensin II and noradrenaline are reduced during chronic treatment with thiazidesused with loop diuretic - synergistic effe
30、ct occurs,Adverse effects: - Idiosyncratic reactions (rashes - may be photosensitiv, purpura) - Increased plasma renin (which limits the magnitude of their effect on BP) - Metabolic and electrolyte changesHyponatremiaHypokalemia (combine with potassium-sparing diuretics)HypomagnesemiaHyperuricemia (
31、most diuretics reduce urate clearance)Hyperglycemia Hypercalcemia(thiazides reduce urinary calcium ion clearance precipitate clinically significant hypercalcemia in hypertensive patients withhyperparathyroidism)Hypercholesterolemia (a small in plasma cholesterol concentration),LOOP DIURETICS furosem
32、id,- useful in hypertensive patients with moderate or severe renalimpairment, or in patients with hypertensive heart failure. - relatively short-acting (diuresis occurs over the 4 hours following adose) used in hypertension if response to thiazides is inadequateMechanism of action: - they inhibit th
33、e co-transport of Na+, K+ and Cl- - of Ca2+ and Mg2+ excretion - they have useful pulmonary vasodilating effects (unknown mechanism),Lumen urine,Thick ascendinglimb,Furosemide,Interstitium - blood,Toxicity: - hypokalemic metabolic alkalosis (increased excretion of K+) - ototoxicity (dose dependent,
34、reversible) - decrease of Mg2+ plasma concentration (hypomagnesemia) - hyperuricemia (competition with uric acid about tubular secretion) - sulfonamide allergy - risk of dehydration ( 4 L urine/ 24 h)Imporatant drug interaction may occurs if loop diuretic is given with Li+ (thymoprofylactic drug). D
35、ecrease of Na+ reabsorption can lead to increase of Li+ reabsorption toxicity.,2. Drugs influencing sympathetic nerves,a) a -adrenoreceptor antagonists,Mechanism of action: - vasodilatation (reduce vascular resistence) and decreased blood pressure by antagonizing of tonic action of noradrenaline on
36、a1 receptors (vascular smooth muscle),competitive with: a. short-term action:a blockers with ISA - ergot alcaloidsa non-selective - phentolaminea1 selective - prazosin, uradipil,b. long-acting a1 antagonists - doxazosin, terazosin,non-competitive with long-term action, non-selective - phenoxybenzami
37、n,Toxicity:the most important toxicities of the alpha-blockers are simpleextensions of their a-blocking effects type A adverse effects- the main manifestations are:- drowsiness, weakness, orthostatic hypotension (first dose bedtime administration) - and for the nonselective agents, reflex tachycardi
38、a - 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, vomiting, diarrhoea - urinary incontinece - priapism, nasal congestion,2. Drugs influencing sympathetic nerve
39、s,PhaeochromocytomaLong-term management of phaeochromocytoma involves surgery. Alpha-blockers are used in the short-term management of hypertensive episodes in phaeochromocytoma. Once alpha blockade is established, tachycardia can be controlled by the cautious addition of a beta-blocker; a cardiosel
40、ective 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 mainly during surgery of phaeochromocytoma; its use for the diagnosis of phaeochromocytoma
41、has been superseded by measurement of catecholamines in blood and urine.,2. Drugs influencing sympathetic nerves,b) b -adrenoreceptor antagonists,Mechanism of action:the fall in cardiac output BP - they reduce renin secretionCNS-effects ?additional mechanisms involve baroreceptors or other homeostat
42、ic adaptations Possible mechanisms include: b-adrenoceptors located on sympathetic nerve terminals can promote noradrenaline release, and this is prevented by b-receptor antagonistslocal generation of angiotensin II within vascular tissues is stimulatedby b2-agonists.,2. Drugs influencing sympatheti
43、c nerves,cardio-selective: b1 blockers atenolol, metoprololb1 blockers with ISA acebutolb1 + a1 blockers labetalol, carvedilolcardio non-selective:b1 + b2 blockers metiprolol, propranolol, nadololb1 + b2 blockers with ISA pindolol, bopindolol,b-adrenoreceptor antagonists,Note: Partial agonist activi
44、ty (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 lesser vasospasms and negative inotropic effect,2. Drugs influencing sympathetic nerves,Adve
45、rse effectsCardiovascular adverse effects, which are extension of the beta blockade, include:bradycardiaantrioventricular blockadecongestive heart failure (unstable)asthmatic attacks (in patients with airway disease)premonitory symptoms of hypoglycemia from insulin overdosage (eg, tachycardia, tremo
46、r and anxiety, may be marked)CNS adverse effects - sedation, fatigue, and sleep alterations.,2. Drugs influencing sympathetic nerves,c) Centrally acting drugs,a2-agonist actions,Methyldopafalse transmitter Clonidine, Moxonidinedirect a2-agonist, imidazol receptor agonists,2. Drugs influencing sympat
47、hetic nerves,- limited use in the treatment of hypertension. - methyldopa hypertension during pregnancy - methyldopa causes symptoms of drowsiness and fatigue that areintolerable to many adult patients in long-term use - they are seldom used to treat essential hypertension - clonidine is potent but
48、poorly tolerated (rebound hypertension, if it isdiscontinued abruptly, is an uncommon but severe problem),Adverse effects:- drowsiness, fatigue (esp. methyldopa), depression, nightmares (methyldopa - rarely extrapyramidal features) driving! - nasal congestion, anticholinergic symptoms (constipation,
49、 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 sympathetic nerves,3. Vasodilators,dr
50、ugs 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 causing Ca2+sequestration in t
51、he 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)* blockade of calcium channels(reduce intracellular calcium concentration relax aretriolar smoothmuscle, reduce peripheral vascular resistance),
