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1、1 Adrenoceptor Antagonists(P66)Case 1nA patient with pheochromocytoma(嗜铬细胞瘤) had a BP of 250/150 mmHg and was i.v. injected phentolamine rapidly, resulted in BP decreasing to 65/40 mmHg.nWhy this happened, how to deal with the condition?3 receptors and prevent their activation by catecholamines and
2、related agonists.Classification: -R antagonists -R antagonists , antagonists. Their major effect is to occupy either, or 4 Beta-receptor antagonist drugs are firmly established in the treatment of hypertension, ischemic heart disease, arrhythmias, endocrinologic and neurologic disorders, and other c
3、onditions.5 1 - Adrenoceptor Antagonists Classification-receptor antagonists may bereversible or irreversible. Selective or non-selectiveReversible antagonists can dissociate from receptors. Phentolamine, tolazoline, prazosin and labetalol are reversible. Phenoxybenzamine is irreversible. 6 In the c
4、ase of epinephrine with both and 2 effects, receptor antagonism may convert a pressor to a depressor response which is called adrenaline reversal. - antagonist drugs block receptors, dilate vascular smooth muscle, lower peripheral resistance and BP; can prevent the pressor effects of agonists.Epi, 0
5、.5 g/kgEpinephrine Reversal Epi, 5 g/kg (atropinized)Inject Epi, 5 g/kg. Pretreatment: atropine and 5 mg/kg phentolamine Phentolamine (regitin) a potent competitive antagonist at both1 and 2 receptors. 1. Blood vessel: reduces peripheral resistance 2. Heart: can stimulate the heart due to baroreflex
6、 mechanisms resulting in sympathetic stimulation. blocks 2 receptors, enhance release of NE from sympathetic nerves, contributing to cardiac stimulation via receptors. 3. also activate M and histamine (H) receptors, has multiple potential actions, Non-selective antagonists(P67)Clinical usesnPeripher
7、al vascular occlusive diseasesnLocal use to reverse the intense local vasoconstriction caused by NA leaknpheochromocytoma (secrete catecholamines).nShocknInfarction and CHFnOther uses10 Peripheral Vascular Disease The-receptor-blocking drugs have been used in the treatment of peripheral vascular occ
8、lusive disease. Local Vasoconstrictor Phentolamine has been used to reverse the vasoconstriction caused by infiltration of agonists (NE)into subcutis during intravenous administration. The antagonist is administered by local infiltration into the ischemic tissue.11 Adverse effects1.postural hypotens
9、ion and reflex tachycardia. due to antagonism of sympathetic nervous system stimulation of 1 receptors in venous smooth muscle. 2.tachycardia, arrhythmias, myocardial ischemia and nasal congestion as well as headache.12 Tolazoline is similar to phentolamine. It has limited clinical application in th
10、e treatment of pulmonary hypertension in newborn infants with respiratory distress syndrome. 13 Phenoxybenzamine(酚卞明) binds covalently to receptors, causing irreversible blockade of long duration (2 d). reduces BP when sympathetic tone is high and little fall in BP in normal supine(仰卧) individuals.
11、It inhibits reuptake of NE by blocking 2 on presynaptic terminals and increase cardiac output. It also blocks histamine (H1), ACh, and serotonin receptors ,receptors. Clinical uses: Peripheral vascular occlusive diseases; Shock treatment; pheochromocytoma, benign prostatic hyperplasia(良性前列腺增生症)14 Ad
12、verse effects The most important are postural hypotension, tachycardia and nasal stuffiness.Since phenoxybenzamine enters the CNS, it may cause less specific effects, including fatigue, sedation, and nausea. 15 selective -receptor antagonistsAlpha1 selective drugsPrazosin（哌唑嗪） is highly selective fo
13、r 1 receptors, leads to vasodilation. It is effective in the management of hypertension. It has relatively low affinity for 2 receptors (1/ 1000). This may explain the relative absence of tachycardia. Terazosin（特拉唑啉） is another reversible 1-selective antagonist that is effective in hypertension, has
14、 high bioavailability but is extensively metabolized in the liver. Its half-life is 9-12 h.Tamsulosin（坦洛新） high bioavailability, half-life is 9-15 h.Alpha2 selective drugs: yohimbin（育亨宾）16 HypertensionPrazosin family of 1-selective antagonists are efficacious in the treatment of hypertension. The ad
15、verse effect is postural hypotension(体位性低血压), which may be severe after the first dose. Nonselective antagonists are not used in primary hypertension.17 2 -Receptor AntagonistsBeta-blocking drugs occupy receptors and reduce receptor occupy by catecholamines and other agonists. Most -blocking drugs a
16、re pure antagonists; Some are partial agonists; ie, they cause partial activation of the receptor, less than that caused by the full agonist.Partial agonists inhibit the activation of receptors in the presence of high catecholamine concentrations but moderately activate the receptors in the absence
17、of endogenous agonists. Case 2n26 yrs male, got insomnia, palpitation and become thin but with good appetite for half a year. PE: slight exophthalmos (突眼)，BP 150/80 mmHg, pulse &HR 124/min, hand tremor, II degree thyroid enlargement. Lab test found increased level of plasma T3 & T4, decreased TSH le
18、vel.nTreated with propranolol 10 mg, tid19 Classification of the -receptor blocking drugs Some of these antagonists have a higher affinity for 1 than for2 receptorsThe selectivity is dose-related, it tends to diminish at higher concentrations. Other major differences among antagonists relate to thei
19、r pharmacokinetics.Pharmacokinetics of antagonists nOral administrationnVariation in bioavailabilitynPropranolol blood concentration variated between 425 times for the same dose21 Pharmacodynamics of the AntagonistsHowever, some actions may be due to partial agonist activity at receptors (intrinsic
20、sympathomimetic activity, ISA) and local anesthetic action, which differ among the -blockers.Most of the effects of these drugs are due to occupancy and blockade of receptors. Effects on the Cardiovascular System Beta-adrenoceptor-blocking drugs are of major clinical importance in the treatment of h
21、ypertension. .Conventional doses do not cause hypotension in healthy individuals with normal BP. The mechanisms include effects on the heart and blood vessels, the rennin-angiotensin system, and the CNS HeartThe negative inotropic and chronotropic effects.Slowed atrioventricular conduction with an i
22、ncreased PR interval is a related result of adrenoceptor blockade in the atrioventricular node. Vascular System The-antagonists blockade 2-receptors, contracting vessel, antagonize the release of rennin, dilating vessel. In any event, while the acute effects of these drugs may include a rise in peri
23、pheral resistance. Chronic drug administration leads to a fall in peripheral resistance in patients with hypertension.Effects on the Respiratory Tract nBeta 1 antagonists have advantage over nonselective antagonists when blockade of 1 in the heart is desired and 2 blockade is undesirable . nThey sho
24、uld be avoided in patients with asthma.Blockade of the 2 receptors in bronchus increases airwayresistance, particularly in asthma.Metabolic and Endocrine Effects nBeta-receptor antagonists such as propranolol inhibit lipolysis. nThe chronic use of -adrenoceptor antagonists has been associated with i
25、ncreased plasma VLDL and decreased concentrations of HDL cholesterol. Effects on the Eye Several -blocking agents reduce intraocular pressure, especially in glaucomatous eyes. The mechanism is decreasing aqueous humor productionEffects not Related to Beta-BlockadenLocal anesthetic action, also known
26、 as “membrane-stabilizing” action, is a prominent effect of several -blockers. nThis action is the result of local anesthetic blockade of sodium channels. nHowever, this effect is not important, since the concentration in plasma usually achieved by these routes is too low for the anesthesia.Cardiac
27、ArrhythmiasBeta antagonists are effective in both supraventricular and ventricular arrhythmias. By increasing the atrioventricular nodal refractory period, antagonists slow ventricular rates in atrial flutter and fibrillation.They can also reduce ventricular ectopic beats, particularly precipitated
28、by catecholamines. Clinical uses Ischemic Heart DiseasenBeta-adrenoceptor blockers reduce the frequency of anginal episodes and improve exercise tolerance in patients with angina. These actions relate to the blockade of cardiac receptors, resulting in decreased cardiac work and reduction in oxygen d
29、emand. Slowing of the heart rate may contribute to clinical benefits.nHypertensionnThe -adrenoceptor-blocking ndrugs are effective and well ntolerated in hypertension.nWhile many hypertensive patients will respond to a -blocker used alone, the drugs is often used with either a diuretic or a vasodila
30、tor. Other Cardiovascular Disorders nBeta-receptor antagonists can increase stroke volume in some patients with obstructive cardiomyopathy. nThis is due to the slowing of ventricular ejection and decreased outflow resistance. nBeta-antagonists are useful in dissecting aortic aneurysm to decrease the
31、 rate of development of systolic pressure. GlaucomanTimolol and related antagonists are suitable for local use in the eye because they lack local anesthetic properties.nBetaxolol, carteolol, levobunolol, and metipranolol are newer -receptor antagonists for the glaucoma.-blocking drugs can reduce pro
32、duction of aqueous humor and decrease intraocular pressure in glaucoma. HyperthyroidismnThese beneficial effects relate to blockade of adrenoceptors and to the inhibition of peripheral conversion of thyroxine to triiodothyronine. nPropranolol has been used extensively in patients with thyroid storm.
33、Excessive catecholamine action is an important aspect of hyperthyroidism. The antagonists have salutary effects in this condition. Neurologic DiseasesnPropranolol reduce the frequency and intensity of migraine headache(偏头疼). nOther -receptor antagonists with preventive efficacy include metoprolol an
34、d probably also atenolol, timolol, and nadolol. nThe mechanism is not known.History of -Adrenoceptor AntagonistsnPropranolol is the standard antagonist. It is a safe and effective drug for many indications布莱克布莱克(1924) 英国药理学家英国药理学家1964年研制出治疗冠心病的代年研制出治疗冠心病的代表药表药心得安心得安。1988年获年获Nobel Prize 。 Sir James W
35、. BlackThe Nobel Prize in Physiology or Medicine 1988 Adverse reaction (p70)1.heart: Beta-receptor blockade depresses myocardial contractility and excitability. Caution must be exercised in using -receptor antagonists in compensated heart failure. Patients with ischemic heart disease may be at incre
36、ased risk if -blockade is suddenly interrupted, which might involve up-regulation of the -receptors.2.Beta 2-receptor blockade by nonselective agents commonly causes worsening of preexisting asthma and airway obstruction in normal individuals.3: others: Beta-blockers may interact with the calcium an
37、tagonist; hypotension, bradycardia, heart failure, conduction abnormalities have all been described. These adverse effects may even arise in susceptible patients taking a topical (ophthalmic) -blocker and oral verapamil. Commonly Used Drugsn1. Non-selective beta-blockersnPropranololnNadololnTimolol:
38、 glucoma nPindolol: ISAn2. Selective beta-blockersn atenololnmetoprolol3 ,Adrenoceptor AntagonistsnDrugs:nLabetalol: nArotinololnCarvedilolnClinical usesnHypertensionnCHFExercisen1. Which of the following is the most likely to occur with parenteral administration of a 1-agonist drug?a) Hypotensionb)
39、 Hypertensionc) Tissue necrosisd) Vasodilatione) Lipolysis2. Prior to an operation to remove a pheochromocytoma (neuroendocrine tumor of the medulla of the adrenal glands), which of the following should be given to the patient?a) -agonistb) -blockerc) -agonistd) -blockern3.Blocking 2 presynaptic rec
40、eptors will do which of the following?a) Stimulate NE releaseb) Inhibit NE releasec) Stimulate DA released) Inhibit DA release n4.Which of the following is NOT an indication for -blocker therapy?a) Hypotensionb) Angina pectorisc) Arrhythmiasd) Myocardial infarctione) Glaucoman5.Angina pectoris, tach
41、ycardia, and arrhythmias are possible adverse effects of which of the following agonists?a) 2-agonistb) 1-agonistc) 3-agonistd) 2-agoniste) 1-agonistn6. Major adverse affects of the 1 blockade include reflex tachycardia and which of the following?a) Orthostatic tachycardiab) Orthostatic bradycardiac
42、) Orthostatic hypertensiond) Orthostatic hypotensionn 7.Which of the following is NOT an adverse affect of the 1 blockade?a) Bradycardiab) Decreased cardiac outputc) AV node blockd) Increased arrhythmiase) Heart failuren8.Which of the following groups of patients is most at risk for adverse effect seen in 2-blockers?a) Asthmaticsb) Congestive heart failure patientsc) Trauma patientsd) Diabetics
