Effects of Adrenergic Drugs Depend on 1 Expression of the receptor type and number in a specific tissue organ i e brochial smooth muscle has 2 receptors only 2 The affinity of the drug for a specif adrenergic receptor i e NE 1 3 Indirect or reflex effects i e NE decrease HR 4 Know receptor expression and affinity for the drug predict effect in most cases Metyrosine Reserpine Synthesis Epi 2R DA Transport NE 2R Storage Clonidine Guanethidine Bretylium Amphetamine Blockers MAO Phenelzine Cocaine Secretion NE Epi Uptake 1 Uptake 2 1R 2R 1R 3 Tyrosine 2 HO4 5 1 6 act COMT H C Dopa OH O HO Tyrosine Hydrolase limiting step HO C C NH2 H act MAO H C OH O C C NH2 H NE 1 2 1 2 Epi 1 2 1 2 DA D1 2 1 HO HO Dopamine Decarboxylase H H C C H HO HO OH C H Epinephrine N CH3 CH CH3 2 Dopamine Dopamine Hydroxylase H CH2 NH2 Phenylethanolamine HO N methyltransferaseHO Isoproterenol OH H C H C Norepinephrine NH2 Norepinephrine HO 3 1 HO 4 HO 5 OH H 2 6 C C NH2 H act H MAO act COMT Large alkyl substitutions of the NH2 increase and decrease activity i e Isoproterenol 2 specific drugs have large substitutions Substitutions of OH C3 and or C4 decrease activity but also decreases metabolization by COMT increasing bioavailability i e Phenylephrine OH on C3 and C5 increase 2 selectivity Substitutions at the carbon block MAO and prolong action i e Ephedrine and Amphetamine Substitutions at the carb decrease CNS but increase agonist action Norepinephrine 1 2R 1R Epinephrine 1 2R 1R Smooth muscle contraction HEART Blood vessels vasoconst Increase contraction Iris radial musc mydriasis HR output conduction Skin pilomotor musc 2R Presynaptic Terminals decrease NE release Postsynaptic Terminals CNS multiple Platelet aggregation Dopamine DAR Smooth musc relaxation RENAL SPLANCHNIC 2R Smooth musc relaxation LUNG UTERUS 3R Lipolysis and Thermogenesis NE 1 2 1 2 Epi 1 2 1 2 DA D1 2 1 Effect 100 50 0 1 Receptor Epi DA 100 1 Receptor NE NE 50 0 Drug Concentration Epi NE 10mg min Start Stop beats min Heart Rate 100 50 mm Hg Blood Pressure 180 120 60 Peripheral Resistance Reflex Bradyc SP EPI 10mg min Start Stop 1 MAP SP MAP DP DP 1 2 Isoprot 10mg min Start Stop 1 Dopamine 10mg min Start Stop 1 SP SP MAP MAP DP DP 2 D1 NE 10mg min Start Stop beats min Heart Rate 100 50 mm Hg Blood Pressure 180 120 60 Peripheral Resistance Reflex Bradyc SP MAP Inhibitory Neuron Vasomotor Center Nucleus Tractus Solitarius Excitatory Neuron Motor Nucleus Vagus ACh NE ACh Autonomic Ganglia DP 1 Baroreceptors response to changes in MAP 1 receptors in vascular ACh HR NE smooth muscle vasoconstriction EPI beats min Heart Rate 10mg min Start Stop Rate Contractility Automaticity Veloc Conduct 100 50 1 Blood Pressure mm Hg SA node Atria 180 120 SP MAP DP 60 HR CO 2 Velocity conduction Effect Refract Period Ventricule Contractility Work O2 consumption Efficiency Low Doses Peripheral Resistance AV node Conduction High Doses 22 11 1 Dopamine Isoproterenol beats min Heart Rate 100 50 Start Stop 1 mm Hg Blood Pressure Start HR CO 1 Stop 1 HR CO Higher Doses 180 SP SP 120 MAP MAP 60 DP DP 2 Skeletal musc Peripheral Resistance 2 Renal Splachnic D1 D1 BLOOD VESSELS Depends on the agonist and vascular bed Skin Mucous memb Vasoconst Vasoconst D1 vasodilat Splanchnic Vasoconst 2 vasodilat Skeletal musc Vasoconst 2 vasodilat Venose Tone HEART Most effects are 1 Electical Increase in Rate Automaticity Veloc Conduct Decrease in Effect Refract Period Mechanical Increase contractility CO work and O2 consumption Respiratory Tract 2 in bronchia and 1 in vessels 2 dilation Bronchial Smooth musc Vasoconst Vessels EYE contraction Radial pupillary dilator decreases increases Intraocular Pressure METABOLIC 3 increases lipolysis Fat cells glycogenolysis Liver 2 increases K uptake Cells Insulin Renin Glucagon 2 decrease 2 increase secretion GASTROINTESTINAL and relaxation Smooth muscle GENITOURINARY 2 relaxation Uterus Bladder base urethral sphincter contraction urine continence prostate Ductus deferens seminal ves contraction ejaculation prostate Mechanism of Action 1 Directly Acting Sympathomimetics Their effects are not abolished by chronic denervation of post ganglionic neurons reserpine or cocaine 2 Indirectly Acting Sympathomimetics Their effect is abolished by reserpine denervation of post ganglionic neurons and cocaine 3 Mixed action Some effects are present after reserpine or cocaine HO HO 1 Selective HO OH CH CH2 NH2 CH For Comparison Norepinephrine 1 1 CH2 N OH 1 1 long acting HO H3CO OH CH CH CH3 H CH3 Phenylephrine Neosynephrine 1 only direct acting Systemic Vasoconstrictors hypotension CH CH NH2 HO Ophtalmic Mydriatics CH3 Nasal Decongestants Methylnorepinephrine Appetite Suppressant HO OH NH2 Metaraminol 1 1 direct and indirect acting long action NH CH2 C N CH2 Tetrahydrozoline Visine 1 only OH CH H3CO CH CH3 NH2 Methoxamine 1 only direct acting 2 Selective HO Cl COOH CH2 CH NH2 HO NH CH3 MethylDOPA Antihypertensive CNS act It is metabolized to methylNE and displaces NE from storage Activates presynap 2 Cl NH CH N N Cl Clonidine Catapres 2 agonist 1 antagonist Antihypertensive Postural hypotension Activates 2 in CNS decreases NE release BP HR Sedation and sexual dysfunction Cl NH C NH2 Guanabenz 2 in CNS decreases BP Cl N H N NH CH2 Cl C O NH C NH2 Guanfacine 2 in CNS decreases BP Selectivity HO HO OH OH CH CH2 N For Comparison Epinephrine CH2 CH2 NH2 CH3 Amphetamine HO CH2 CH2 NH2 CH3 Hydroxyamphetamine H CH3 H N CH CH2 CH3 CH3 Ephedrine Crosses BBB CNS stimulant Broncodilator Potency l periphery d CNS Increase SP DP reflex decrease HR arrithmias Releases biogenic amines from storage sites Anoretic used in obesity Attention deficit hyperactivity disorder Toxicity restlessness hyperactive reflexes insomnia convulsions and coma Treatment Na Nitopruside or blockerphentolamine hypert sedation urine acidification Selective HO HO HO OH CH CH2 N H CH3 Epinephrine Used in anaphylactic shock cardiac arrest HO OH CH CH2 N CH CH3 2 Isoproterenol only Used in bradycardia or heart shock HO HO H CH2 CH2 NH CH H2C H2C CH3 Dobutamine only isomer 1 agonist 1 antagonist receptor agonist Inotropic chronotropic TPR unchanged Indications Cardiac Heart Failure MI OH 2 Selective use to compare OH HO CH2 N CH HO Isoproterenol 1 2 only HO OH CH CH2 N HO H CH CH3 2 H CH CH3 3 HO Terbutaline Brethine CH HO Broncodilators Uterine relaxant No COMT subst CH2 HO HO CH CH CH3 NH CH2 H2C Ritodrine 2 1 OH CH2 N H CH CH3 2 Metaproterenol Alupent 2 1 HO 2 1 HO OH OH CH CH2 N H CH CH3 2
View Full Document
Unlocking...