藥理學(xué)課件：Adrenoceptor antagonists

1、Adrenoceptor antagonists2 Drugs blocking adrenoceptors vary dramatically according to the drugs selectivity for and receptors. Their major effect is to occupy either or receptors and prevent their activation by catecholamines and related agonists.Adrenoceptor antagonistsAlpha-Blocking DrugsA. Classi

2、fication based on: selective affinity for alpha receptors, 1. non-selective long-acting alpha blockers： Phenoxybenzamine short-acting alpha blockers： Phentolamine, tolazoline 2. Alpha1-selective blockers: prazosin3. Alpha2-selective blockers: YohimbineBASIC PHARMACOLOGY OF THE ALPHA RECEPTOR ANTAGON

3、IST DRUGSPHARMACOLOGIC EFFECTSA. Cardiovascular EffectsB. Other EffectsCardiovascular Effects-1 block receptors, dilate vascular smooth muscle, lower peripheral resistance and BP Epinephrine reversal In the case of agonists with both and 2 effects (eg, epinephrine) , selective receptor antagonism ma

4、y convert a pressor to a depressor response. Epinephrine reversalTop: Effects of phentolamine, an -receptorblocking drug, on blood pressure in an anesthetized dog. Epinephrine reversal is demonstrated by tracings showing the response to epinephrine before (middle) and after (bottom) phentolamine. Al

5、l drugs given intravenously. BP, blood pressure; HR, heart rate.HR：2Epinephrine reversalHR：2HR：1Cardiovascular Effects-2 Cause postural hypotension due to antagonism of SNS stimulation of 1 receptors in vascular smooth muscle. Cause reflex tachycardia tachycardia may be exaggerated because 2-presyna

6、ptic receptors are blocked. e.g. phenoxybenzamine, phentolamine, tolazoline Blockade of receptors in other tissues elicits miosis (small pupils) and nasal stuffiness. 1 receptors are expressed in the base of the bladder and the prostate, and their blockade decreases resistance to the flow of urine.

7、Other EffectsSPECIFIC AGENTS11 Phentolamine-1Competitive antagonist at both 1 and 2 receptors. Blood vessels: Blockade of 1-R on vascular smooth muscle, reduces peripheral resistance, BP decreased Cardiac stimulation: antagonism of presynaptic 2 receptors (leading to enhanced release of NE from symp

8、athetic nerves) and sympathetic activation from baroreflex mechanisms.1221antagonismNA+ vessel contrictionBPNA 13 Minor inhibitory effects at serotonin receptors and agonist effects at muscarinic and H1 and H2 histamine receptors. Adverse effects cardiac stimulation, which may cause severe tachycard

9、ia, arrhythmias, and myocardial ischemia.Phentolamine-2Phenoxybenzamine Attenuation of catecholamine-induced vasoconstriction. Reduces blood pressure when sympathetic tone is high. Cardiac output may be increased because of reflex effects and because of some blockade of presynaptic 2 receptors in ca

10、rdiac sympathetic nervesAdverse effects: orthostatic hypotension and tachycardia. Nasal stuffiness also occurs CLINICAL PHARMACOLOGY OF THE ALPHA RECEPTOR BLOCKING DRUGSlPheochromocytoma lCarcinoid tumor: phenoxybenzamine (5-HT blocking)lAccidental local infiltration of alpha agonist:lShocklOverdose

11、 of sympathomimeticslRaynaud s phenomenonlCHF and acute myocardial infarction Pheochromocytoma A tumor of the adrenal medulla or sympathetic ganglion cells, secreting catecholamines, especially NE and epinephrine. The major clinical use of phenoxybenzamine is in the management of pheochromocytoma. P

12、reoperative period helps to control hypertension and tends to reverse chronic changesPeripheral Vascular Disease Individuals with Raynauds phenomenon and other conditions involving excessive reversible vasospasm in the peripheral circulation do benefit from prazosin or phenoxybenzamineAdverse effect

13、s of Alpha blockersl Orthostatic hypotension (venodilatation)l Reflex tachycardia (nonselective selective)l First dose hypotension (take before going to bed)l Nausea/vomitingl Caution in patients with coronary artery disease (CAD or CHD): anginaBASIC PHARMACOLOGY OF THE BETA RECEPTOR ANTAGONIST DRUG

14、S Beta-Blocking DrugsA. Classification and MechanismslAll are competitive antagonistslPropranolol is prototypelClassification is based onl Beta subtypes selectivityl Partial agonist activityClassification and Mechanisms Receptor selectivityNonselective: propranolol1 -selective: metoprolol, atenolol

15、2 -selective: butoxamine (research only)Combined - and -blocking: labetalolPharmacodynamics of the Beta-Receptor Antagonist DrugsEffects on the Cardiovascular System-1Heart Negative inotropic and chronotropic effects Negative dromotropic effect Slowed atrioventricular conduction with an increased PR

16、 interval is a related result of adrenoceptor blockade in the atrioventricular node. Angina, chronic heart failure, myocardial infarction. Effects on the Cardiovascular System-2Blood vessel： Lower BP in patients with hypertension, do not usually cause hypotension in healthy individuals with normal B

17、P. Acute effects of these drugs may include a rise in peripheral resistance. Chronic drug administration leads to a fall in peripheral resistance in patients with hypertension.Effects on the Respiratory Tract Blockade of the 2 receptors in bronchus increases airway resistance, particularly in asthma

18、.Metabolic and Endocrine Effects Beta-receptor antagonists such as propranolol inhibit SNS stimulation of lipolysis. increased plasma concentrations of very-low-density lipoproteins (VLDL) and decreased concentrations of HDL cholesterol. Both of these changes are potentially unfavorable in terms of

19、risk of cardiovascular disease. Partially inhibited glycogenolysis in the human liver Delay recovery of blood glucose after insuline Effects on the Eye Beta-blocking agents reduce intraocular pressure, especially in glaucoma. The mechanism usually reported is decreased aqueous humor production. Effe

20、cts Not Related to Beta-Blockade-1 Intrinsic sympathomimetic activity (ISA) partial agonistic activity (PAA) Most -blocking drugs are pure antagonists; ie, after being occupied, -R causes no activation. Some are partial agonists; ie, they cause partial activation of the receptor, less than that caus

21、ed 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 of endogenous agonists. Effects Not Related to Beta-Blockade -2 Membrane stabilizing action: in large dose (local anesthetic action) This action is the result of local anesthetic blockade of sodium channels. Clinic