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1、Adrenergic AgonistsSteps of Catecholamie SynthesisTyrosine tyrosine hydroxylase DOPADOPA DOPA decarboxylase dopamineDA DA -decarboxylase NENE is taken up and stored in granulesNE not stored in storage granules are called as mobile pool (MAO can metabolize these)NE releases via exocytosis as Ca2+ ent
2、ers.NE attaches to receptors in the post-synaptic neuronRoutes of NE after releaseNE can be transported back into the pre-synpatic neuron (reuptake 1)NE can activate the presynaptic receptors (-2 for negative feedback)NE can be metabolized by COMT enzyme (reuptake 2)About the adrenergic systemSympat
3、hetic nervous system exerts its effects by acting on: , , and D receptors receptors are subdivided into 1 and 2 receptors are subdivided into 1 and 2 and 3D = Dopamine receptorsRole of SNSImportant regulator of the activities of heart and peripheral vasculature, especially in responses to exercise a
4、nd stress Drugs that mimic the actions of epinephrine are called sympathomimetic drugs or adrenergic drugsHas a wide range of effects and uses5Review of the receptors of the SNS1 Blood vesselsPupil (Iris)Smooth muscle (GI/GU) VasoconstrictionMydriasissphincter contraction Constipation and Urinary re
5、tention2 Presynaptic neurons Reduces release of norepinephrine (as a negative feedback mechanism) bradycardia, hypotension1 HeartContraction Increased heart rate2 Smooth musclesRelaxation Bronchodilation, urinary retention, constipation, uterus relaxation3Fat cellslipolysisDArteriesArteriodilation o
6、f Arteries (Renal, Mesenteric, Coronary) Basic Pharmacology of Sympathomimetics Phenylethylamine is the parent compound from which sympathomimetic drugs are derived. This compound consists of a benzene ring with an ethylamine side chain. Substitutions may be made (1) on the terminal amino group, (2)
7、 on the benzene ring, (3) on the or -carbons. Substitution by -OH group at the 3 and 4 positions yield catecholamines. Basic Pharmacology of Sympathomimetics Phenylethylamine is the parent compound from which sympathomimetic drugs are derived. This compound consists of a benzene ring with an ethylam
8、ine side chain. The modification of phenylethylamine change the affinity of the drugs for receptors, the intrinsic ability and pharmacokinetics. Receptor Types Alpha Beta DopamineORGAN SYSTEM EFFECTS OF SYMPATHOMIMETIC DRUGSCardiovascular System Blood Vessels Vascular smooth muscle tone is regulated
9、 by adrenoceptors 1 increase arterial resistance. 1 increases heart rate.2 causes smooth muscle relaxation with slight decrease in arterial resistance decrease BP11Blood Pressure A relatively pure 1 agonist such as phenylephrine increases peripheral arterial resistanceThis leads to a dose-dependent
10、rise in blood pressure A relatively pure agonist such as isoproterenol decreases peripheral resistance by activating 2 receptors (smooth muscle relaxation)12Effects of an -selective (phenylephrine), -selective (isoproterenol), and nonselective (epinephrine) sympathomimetic, given as an intravenous b
11、olus injection to a dog. Reflexes are blunted but not eliminated in this anesthetized animal. BP, blood pressure; HR, heart rate.a1-Ra, -R1, 2-RNoncardiac Effects of SympathomimeticsEye The radial pupillary dilator muscle of the iris contains 1 receptors. Activation causes mydriasis and stimulants a
12、lso have important effects on intraocular pressure. agonists decreases the outflow of aqueous humor from the eye and antagonists (timolol) decrease the production of aqueous humor. 16Respiratory Tract Bronchial smooth muscle contains 2 receptors that cause bronchodilation The blood vessels of the up
13、per respiratory tract mucosa contain 1 receptors. 1 agonists cause vasoconstriction.17Genitourinary TractThe bladder base, urethral sphincter, and prostate contain 1 receptors that mediate contraction and therefore promote urinary retention. are found in the Uterus causing smooth muscle relaxation.
14、MetabolismActivation of adrenoceptors in fat cells leads to increased lipolysis with enhanced release of free fatty acids and glycerol into the blood.Enhance glycogenolysis in human liver, which leads to increased glucose release into the circulation, mediated mainly by , -R.Organ system effects: CN
15、SCatecholamines do not cross the BBB effectivelyVery high doses-aggressiveness, marked anxiety and convulsions20SPECIFIC SYMPATHOMIMETIC DRUGSEpinephrine, AgonistsA very potent vasoconstrictor and cardiac stimulant. The rise in systolic BP: heart 1 receptors : positive inotropic, chronotropic and dr
16、omotropic effect. vascular 1 receptors : vasoconstrictionactivates 2 receptors in skeletal muscle blood vessels, leading to dilation. 22EpinephrineUses: Cardiac arrestAnaphylaxisAnaphylactic ShockAsthmaAngioedema and serum sicknessIncreases local anesthetic action (by vasoconstriction) 1：250 000Cont
17、raindications:Hyperthyroidism, ArrthymiasAnaphylaxisImmediate (type I) IgE-mediated reactionsCharacterized by bronchospasm, mucous membrane congestion, angioedema, and severe hypotension Treatment: Epinephrine and SteroidsNorepinephrine 1/2, 1-RBlood vessel vascular 1 receptors: vasoconstriction cor
18、onary arteries：vasodilation agonism of presynaptic 2 receptors (leading to reduce releasing of NE from sympathetic nerves)BP: BP increaseHeart agonism of 1-R, BP increaseHR decrease （reflex）Phenylephrine 1-R Selective AgonistsCauses vasoconstriction of vessels. Nasal and ophthalmic preparations.Uses
19、: Nasal Decongestant, MydriasisContraindications: Closed angle Glaucoma. 26DopamineAt low concentrations: stimulates D1 receptors, causes Vasodilation of arteries (renal, coronary, GI)At intermediate doses: stiumates 1 receptors tachycardiaAt high doses: stimuates 1 receptors VasoconstrictionUses: C
20、ardiogenic shock (1 stimulation), CHF (congestive heart failure), Hypotension (1 stimulation)Adverse effects: Tachycardia, arrythmiasIsoproterenol-1, 2-R agonistVery potent -receptor agonist and has little effect on receptors. Leads to an increase Heart rate (1) with a decrease in blood pressure (2)
21、This lead to a marked increase in cardiac output associated with a fall in diastolic and mean arterial pressure29Clinic usesCardiac arrestAsthmaShockAtrioventricular blockBeta 1 agonistsDobutamine: Increases heart rate. Clinic used cardiogenic shock, acute heart failure.Beta 2 agonists for AsthmaSho
22、rt acting (rescue drugs): Albuterol, TerbutalineLong acting (maintenance drugs): SalmetrolInhaled agonists is used in Asthma. Causes smooth muscle relaxation at the bronchus (bronchodilaton)Adverse drug effects: Tachycardia, tremors, palpitationsSummaryKnow about production and metabolism of NEKnow the different receptors of the SNS, the organs they are in, and their net effectsKnow about SNS effect of Eyes, BP, HR, Respiratory system, and GU tractKnow about alpha 1 agonists, alpha 2 agonists, and Beta agonists. Mechanism, Indictions, Side effects
