肾上腺素受体激动药.ppt

第十章 肾上腺素受体激动药,Adrenoceptor Agonists,definition,Drugs that mimic the actions of epinephrine or norepinephrine Sympathomimetic drugs,Chemistry,Parent compound: phenylethylamine Change the affinity for or receptors Change pharmacokinetics properties,第一节 构效关系及分类,Chemistry and pharmacokinetics,Substitutions On the benzene ring: increase bioavailability and prolongs the duration of action; increase the distribution of molecule to CNS On the alpha or beta carbons: block oxidation by MAO On the terminal amino group: increase receptors activity isomer,Classification,Depend on the affinity for different groups of receptor , -adrenoceptor agonists -adrenoceptor agonists -adrenoceptor agonists,、-R agonist,Adrenaline Dopamine ephedrine,Adrenaline,At low concentration , effects predominate; at high concentration , effects predominate. 2-R are more sensitive to Adr than the -R.,Pharmacological Effects,Blood vessel effects: constrict (skin vessels, renal vessels) 2 effects: dilate( vessels in skeletal muscle vessels) Coronary blood flow pulmonary blood flow Blood redistribution,Pharmacological Effects,Heart direct effect on 1-R ; increase in heart rate , and increase cardiac output; coronary artery dilate a propensity toward arrhythmias,Pharmacological Effects,blood pressure At low concentration: systolic pressure increase At high concentration: both systolic and diastolic pressure increase,Pharmacological Effects,Smooth muscle: Bronchus:Bronchiolar smooth muscle relaxes(2 effects);blood vessel constrict;Block the release of histamine(2 effects) gastrointestinal tract bladder Eye: ocular pressure reduction skeletal muscle,Pharmacological Effects,Metabolic effects increase in glucoses and lactate production via glycogenolysis inhibition of insulin secretion (-R) increase in free fatty acid and oxygen consumption .,Pharmacological Effects,CNS At therapeutic doses In toxic doses, excitement, agitation, convulsion,pharmacokinetics,Adr- absorption is poor with oral administration Adr- absorption is slow with hyodermic administration can be given iv or im,Therapeutic Uses,cardiac arrest anaphylactic shock Asthma and acute hypersensitivity reaction prolong the duration of local anesthesia Glaucoma,Adverse Effects,Palpitation, headache BP , arrhythmia Hypertension, diabetes mellitus, hyperthyroidism,Drug interactions,General anesthetics Psychotropic drugs blockers,Ephedrine,absorbed when taken orally CNS effects may occur: such as insomnia, nervousness, nausea and agitation resistant to COMT and MAO, so that its action is prolonged Little effect on metabolism Acute tolerance,pharmacological Effects,Cardiac output , HR Blood vessel Blood pressure Relax smooth muscle skeletal muscle CNS: excitement Tachyphylaxis,Clinical Uses,Bronchial asthma Nasal decongestant Hypotension without crisis Adverse reactions: CNS,Dopamine,activate 、1 and dopa-receptor Be metabolized by MAO and COMT quickly No effect on CNS,Dopamine,Blood vessels At low or intermediate concentration: act on D1 receptor, dilate At high concentration : act on -receptor, constrict Heart: positive inotropic effect on the myocardium, increase cardiac output,Pharmacological Effects,Kidney At low or intermediate concentration: reduce arterial resistance in the mesentery and kidney At high concentration: cause vasoconstriction with consequent reduction in renal function,Clinical uses,Shock Acute renal failure Adverse reaction: arrhythmia, reduction in renal function Drug interactions,-adrenoceptor agonists,Norepinephrine(NA/NE) Metaraminol 1 -adrenoceptor agonists: phenylephrine and methoxamine 1 -adrenoceptor agonists: oxymetazoline,apraclonidine,NA/NE,Potent effect of receptor Relative little effect on 1 receptor Little effect on 2 receptor,Pharmacological Effects,Blood vessels: constrict (skin vessels, renal vessels); coronary artery dilate; negative feedback (2 effects) Heart: pacemaker activity, conduction velocity, and intrinsic contractility increase. HR decrease by a reflex response; cardiac output,Pharmacological Effects,Blood pressure: both systolic and diastolic pressure increase Others: blood sugar at high concentration,pharmacokinetics,i.v. drip. Be uptake and metabolized quickly excretion: VMA,normetanephrine,Therapeutic Uses,Neurogenic shock Hypotension Hemorrhage of upper digestive tract,Adverse reaction,Avascular necrosis Acute renal failure Contraindication: hypertension, atherosclerosis, cardiopathy,Metaraminol,excite -R replace the NA in vesicles，increase NA release from vesicles directly More stable to MAO, prolong the action,Pharmacological Effects,similar to NA in its action, but less potent increase systolic and diastolic blood pressure its major therapeutic use is in the treatment of hypotensive state,Phenylephrine, Methoxamine,1-R agonists similar to those of NA, but less potent and has a longer duration of action vasoconstriction, increase arterial pressure, and reflex bradycardia,Clinical Uses,hypotension state; supraventricular paraxosmal pupil mydriasis (Phenylephrine),2-R agonists,Oxymetazoline, apraclondine Clonidine, methyldopa,-R agonist,1 and 2-R agonist Isoprenaline: lower selectivity to both 1 and 2-R, little effect on -R,pharmacological Effects,heart: positive inotropic effect ,increase the heart rate and conduction, cardiac output increase blood vessels : reduction of peripheral vascular resistance in skeletal muscle, renal and mesenteric vascular beds;,pharmacological Effects,blood pressure: diastolic blood pressure falls , systolic blood pressure increase Relax both bronchial and gastrointestinal smooth muscle Metabolic effects,pharmacokinetics,Resistance to MAO less be uptaken aeroso