高血压英文ppt精品课件drugs used to treat

Drugs used to treat hypertension 2006 Hypertension - risk 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 cardiac 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 arteries and arterioles) in the various tissues. - Influence of predisposing factors Hypertension Essential (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) 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+, ethanol dose, smoking) non-susceptive (positive family history, insulin resistance, age, sex, defect of local vasomotoric regualtion) 1. Baroreceptors - they are responsible for rapid adjustment in blood pressure 2. Kidney 3. - plays a key role in long-term control of blood pressure and in 4. the pathogenesis of hypertension 5. - excretion of salt and water controls intravascular volume, 6. which influences the force of contraction of the heart by the 7. Starling mechanism 8. - 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 renal sodium absorption and intravascular volume 9. - renal disease (vascular, parenchymal or obstructive) is a 10. cause of arterial hypertension Non-renal mechanisms neuronal mechanisms sympathetic nervous system (continual background of vasoconstrictor tone), 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 rupture and bleeding from a weak spot in the arterial wall) ! THERAPY OF HYPERTENSION A.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, 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 (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 or diastolic 110 119 mmHg, confirm over 12 weeks then treat if these values are sustained; Where the initial blood pressure is systolic 160179 mmHg or diastolic 100 109 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 sustained; Where the initial blood pressure is systolic 160179 mmHg or diastolic 100 109 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 412 weeks; *BNF 51th edition, 2006 Where the initial blood pressure is systolic 140159 mmHg or diastolic 90 99 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 systolic 140159 mmHg or diastolic 90 99 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 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 nerves a) a -adrenoreceptor antagonists Mechanism of action: - 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 blockers with ISA - ergot alcaloids a non-selective - phentolamine a1 selective - prazosin, uradipil, b. long-acting a1 antagonists - doxazosin, terazosin non-competitive with long-term action, non-selective - phenoxybenzamin Toxicity: 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, weakness, 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, vomiting, diarrhoea - urinary incontinece - priapism, nasal congestion 2. Drugs influencing sympathetic nerves Phaeochromocytoma Long-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 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 mainly 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 nerves b) b -adrenoreceptor antagonists Mechanism of action: - the fall in cardiac output BP - they reduce renin 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 within vascular tissues is stimulated by b2-agonists. 2. Drugs influencing sympathetic nerves cardio-selective: b1 blockers atenolol, metoprolol b1 blockers with ISA acebutol b1 + a1 blockers labetalol, carvedilol cardio non-selective: b1 + b2 blockers metiprolol, propranolol, nadolol b1 + b2 blockers with ISA pindolol, bopindolol b-adrenoreceptor antagonists Note: 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 lesser vasospasms and negative inotropic effect 2. Drugs influencing sympathetic nerves Adverse effects Cardiovascular adverse effects, which are extension of the beta blockade, include: - bradycardia - antrioventricular blockade - congestive heart failure (unstable) - asthmatic attacks (in patients with airway disease) - 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 nerves c) Centrally acting drugs a2-agonist actions Methyldopa false transmitter Clonidine, Moxonidine direct a2-agonist, imidazol receptor agonists 2. 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 seldom 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 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 sympathetic nerves 3. 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 causing 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) * blockade of calcium channels (reduce intracellular calcium concentration relax aretriolar smooth muscle, reduce peripheral vascular resistance) A) DIRECT ACTING minoxidil, diazoxide, sodium nitroprusside, hydralazine Minoxidil - therapy of severe hypertension resistant to other drugs - prodrug its metabolite (minoxidil 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 - compensatory responses are preserved (may include salt retention and tachycardia) suitable combination with diuretics or b-blockers 3. Vasodilators Diazoxide - given by rapid iv. injection (less than 30 seconds)* in hypertensive emergencies - potassium channel opener - glucose intolerance due to reduced insulin secretion (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 suspected if there is unexplained weight loss, arthritis 3. Vasodilators *BNF 51th edition, 2006 Sodium 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 toxicity) - Releases NO - the stock solution should be diluted and covered with foil to prevent photodeactivation - adverse effects: too rapid reduction of BP, nausea, palpitation, dizziness cyanide metabolite accumulation tachycardia, hyperventilation, arrhythmias, acidosis 3. Vasodilators B) INDIRECT 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 differ in selectivity for calcium channels in vascular smooth muscles and cardiac tissues - orally active suitable for long-term use 3. Vasodilators DIHYDROPYRIDINES (nifedipine, nicardipine) - evoke vasodilatation resulting in sympathetic reflex activation, - relatively selective for vascular smooth muscle (arterial) amlodipine, lacidipine, isradipine, felodipine 2nd generation - longer duration of action once daily - do not reduce myocardial contractility do not produce clinical deterioration in heart failure nimodipine preferentially acts on cerebral arteries prevention of vascular spasm following aneurysmal subarachnoid haemorrhage Indication: all grades of essential hypertension - alone (nifedipine, amlodipine) in patients with mild hypertension for patients in whom thiazide diuretics and b-blockers are contraindicated - combinations angina (with beta-blockers) 3. Vasodilators verapamil, diltiazem - effects on the voltage-dependent channels in cardiac conducting tissue - vasodilatation - it also blocks Ca2+ entry in gastrointestinal smooth muscle and consequently causes constipation 3. Vasodilators Drug Effect on heart rate Adverse effects Nifedipine Headache, flushing, ankle swelling Amlodipine Ankle swelling Nimodipine Flushing, headache Diltiazem Generally mild Verapamil Constipation, marked negative inotropic action Adverse effects of calcium channel-blocking agents Calcium channel blockers do not affect concentrations of plasma cholesterol or triglycerides, or extracellular calcium homeostasis. 3. Vasodilators 4. Angiotensin-converting 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 nephropathy ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACEI) Captopril, enalapril, quinapril, lisinopril, perindopril, ramipril Indications Mechanism 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 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 vascular smooth muscle and some other cells = remodelling 4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc. angiotensin- converting enzyme Angiotensin I (inactive) Angiotensin II (active vasoconstrictor) Bradykinin (active vasodilator) Inactive metabolites ACE inhibitors 4. Angiotensin-converting enzyme 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 tachycardia 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 essential hypertension and post-infarction state Dilatation of arteriol reduction of peripheral vascular resistance, blood pressure and afterload Increase of Na+ and decrease of K+ excretion in kidney 4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc. Pharmacokinetics: - active when administered orally - most of ACEIs are highly polar, eliminated in the urine, without CNS penetration fosinopril - metabolized by the liver captopril, lisinopril - active per se enalapril, quinapril - prodrugs require metabolic conversion to active metabolites enalapril, quinapril and lisinopril - given once daily captopril - administered twice daily However, ACE inhibitors are effective in many patients with low renin as well as those with high renin hypertension and there is only a poor correlation between inhibition of plasma-converting enzyme and chronic antihypertensive effect, possibly because of the importance of converting enzyme in various key tissues rather than in the plasma. 4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc. ACE inhibitors Drug Duration of effect (hours) Short-acting: captopril 6-8 Medially-acting: enalapril 12 quinapril Long-acting: perindopril 24lisinopril spirapril ramipril 4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc. Adverse effects and contraindications of ACEI: -are generally well tolerated. Adverse effects include: First dose hypotension - particularly in those receiving diuretic therapy; the first dose should preferably be given at bedtime. Dry cough - the most frequent (5-30%) symptom; could be reduced by treatment with sulindac (inhibits prostaglandin biosynthesis) Urticaria and angioneurotic edema - kinin concentrations urticarial reactions and angioneurotic edema) Functional renal failure - occurs predictably in patients with hemodynamically bilateral renal artery stenosis, and in patients with renal artery stenosis in the vessel supplying a single functional kidney (though they protect the diabetic kidney) - ! renovascular disease ! Fetal injury - results in oligohydramnios, craniofacial malformations - contraindication in pregnancy 4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc. Hyperkalemia monitor ! - ACEIs cause a