Neurons of the ANS Pharmacology of the Sympathetic Nervous System I Edward JN Ishac, Ph.D. Smith Building, Room 742 eishac@vcu.edu 8-2127 or 8-2126 Department of Pharmacology and Toxicology Medical College of Virginia Campus of Virginia Commonwealth University Richmond, Virginia, USA Noradrenergic Neuron Adrenergic Nerve Terminal Neuronal (Uptake1) vs Extraneuronal (Uptake2) MAO vs COMT MAO COMT Neuronal Uptake Uptake 1 Location Mitochondrial outer membrane cytosol 70-80% in cell Cocaine Location symp. nerve, placenta (MAO A ) most TCA in body platelets (MAO B ) tissues, liver, kidney, brain (MAO A + MAO B ) not in MAO sympath. Extraneuronal nerve Uptake 2 Effect of increases NE level in symp. neuron, minor/no 10-20% inhibition potentiates release by tyramine-like effect COMT on NE drugs levels 1
Metabolism of Catecholamines MAO vs COMT Major Metabolites Metabolism by either MAO or COMT MAO VMA COMT, inactivates drug MOPEG O R R HO CH 3 O MAO H COMT R N R R C H CH 2 HO HO O R CH 2 OH R C OH Inhibitors: Tolcapone, Pyrogallol Inhibitors: Non-selective Parkinson’s D with l-Dopa Depression Tranylcypromine, Pargyline (rarely used, liver failure) Inhibitors: Selective Depression MAO-A Clorgiline Parkinson’ D MAO-B Selegiline Adrenergic Agents – Relative Selectivity Receptor Subtypes RECEPTOR TISSUE ACTIONS Alpha 1 most vascular smooth muscle contraction α -Receptors 1948 β -Receptors EPI > or = NE >> ISO pupillary dilator muscle contraction (dilation) pilomotor smooth muscle erects hair vas deferens contraction liver glycogenolysis intestinal smooth muscle relaxation 70’s intestinal sphincters contraction Alpha 2 some vascular smooth muscle contraction α 1 -Receptors α 2 -Receptors NE > EPI >> ISO nerve terminals (NE & Ach) inhibit transmitter release platelets aggregation 90’s fat cells inhibition of lipolysis ↑ force, rate, conduction velocity Beta 1 heart ISO > EPI = NE coronary blood vessels dilatation 60’s kidney renin release α 1A α 1B α 1C α 1D α 2A α 2B α 2C α 2D β 1 β 2 β 3 90’s Beta 2 bronchial smooth muscle relaxation ISO > or = EPI >> NE uterine smooth muscle relaxation intestinal smooth muscle relaxation PLC A/C A/C vascular smooth muscle relaxation ↑ Ca ++ liver glycogenolysis ↓ cAMP ↑ cAMP NA nerve terminals facilitation of release ↑ IP 3 DAG Beta 3 fat cells lipolysis ISO = NE > EPI Second Messengers Phospholipase C 2 nd Messenger Receptor Location G Protein α 1 Effector tissues: smooth Gq ↑ Ca 2+ , ↑ IP 3 , DAG muscle, glands G-Protein coupled α 2 ↓ cAMP Nerve endings, smooth Gi receptors smooth muscle β 1 ↑ cAMP Cardiac muscle, Gs Adrenergic juxtaglomerular apparatus Alpha1-receptors β 2 ↑ cAMP Smooth muscle, lung Gs β 3 ↑ cAMP Cholinergic Adipose cells Gs M1 ↑ cAMP D 1 , D 5 Renal, vascular SM, brain Gs M3 M5 ↓ cAMP D 2 D 3 D 4 Brain, cardiovascular Gs X 2
Hepatocyte Adenylate Cyclase norepinephrine / epinephrine α 1-AR β 2-AR IP 3 / DAG ↑ cAMP G-Protein coupled receptors Ca++ / PKC protein kinase A Stimulate All Beta-receptors D1, D5-receptors Ca++-dependent phosphorylase kinase phosphorylase K. Inhibit Alpha2-receptors phosphorylase a phosphorylase a D2, D3, D4-receptors M2, M4-receptors glycogenolysis glycogenolysis ↑ glucose-1-P Vasculature OH 3 2 Catecholamines norepinephrine / epinephrine 1 4 OH CH2 CH2 NH 2 α 1-AR β 2-AR 5 6 Catechol Phenylethylamine IP 3 / DAG ↑ cAMP A. Norepinephrine (limited use, pressor agent, shock) • Activates: both alpha, beta 1 , beta 3 , beta 2 (weakest) • Substrate for MAO & COMT, does not cross BBB Ca++ / PKC protein kinase A B. Epinephrine (DOC - Allergic reaction ) None effective • Activates both alpha, beta 1 , beta 2 , beta 3 (weakest) orally Vasoconstriction • Substrate for MAO & COMT, does not cross BBB Vasodilation Do not cross BBB C. Dopamine (DOC – shock) Actions brief • Precursor of NE and EPI • Activates alpha 1 , dopamine receptors Increase resistance Decrease resistance DOC • Substrate for MAO & COMT, does not cross BBB Drug of Choice D. Isoproterenol (asthma, cardiac stimulant) Increase BP • Activates all beta receptors Decrease BP ?????? • Substrate for COMT, does not cross BBB Non-Catecholamines – Beta agonists Non-Catecholamines – Alpha agonists • Selective beta2-agonists: albuterol, ritodrine, metaproterenol, terbutaline • Selective alpha1-agonists: methoxamine, phenylephrine, Uses: asthma, premature labor metaraminol (direct & indirect actions, orally active) Oral: Onset 1-2 hrs, duration 4-6 hrs Uses: hypotension or shock, nasal decongestant Inhal: Onset 5-10 min, duration 3-4 hrs (fewer side effects) • Selective alpha2-agonists: clonidine, α -methyldopa (prodrug), guanfacine • Adverse effects: cardiovascular ( ↑ HR, ↓ BP) Uses: hypertension (CNS action) opioid withdrawal (decrease severity) • Selective beta1-agonists: dobutamine, prenalternol Side effects : impotence, dry mouth, rebound HT Uses: Congestive heart failure Increase force, no change in HR or oxygen demand 3
Indirectly-acting Sympathomimetics (displace transmitter) Tachyphylaxis • Amphetamine, methamphetamine, methylpenidate CNS stimulant, performance enhancer, physical & mental abuse ↑ alertness, mood, self-confidence, concentration, psychological dependence, tolerance, tachyphylaxis • Uses: ADHD, appetite suppression (?), narcolepsy • Toxicity: cardiovascular, restlessness, tremor, insomnia • Ephedrine (mixed) - direct action (alpha- and beta-receptors) - indirect action to release norepinephrine • Uses: nasal decongestant • Tyramine (not a drug, interaction with MAO inhibitors) Crystal Meth Drug Abuse Sudafed phenylephrine vs pseudoephedrine Manufacturers, including Sudafed-maker Pfizer Inc., switched to phenylephrine from pseudoephedrine the past year after passage of a law requiring all After 1.5 years pseudoephedrine products of drug use be sold from behind pharmacy counters. Indirectly-acting Sympathomimetics (cont.) Neuronal Uptake Inhibition • Amphetamine, methamphetamine, methylpenidate Inhibit neuronal uptake (Uptake1) CNS stimulant, performance enhancer, physical & mental abuse Can prevent the action of indirectly ↑ alertness, mood, self-confidence, concentration, acting agents (e.g. amphetamine) and psychological dependence, tolerance, tachyphylaxis can potentiate the effects of NE (ie. not removed from synaptic junction). • Uses: ADHD, appetite suppression (?), narcolepsy Neuronal Uptake 1: 70-80% • Toxicity: cardiovascular, restlessness, tremor, insomnia Cocaine • Ephedrine (mixed) Tricyclic antidepressants direct action (alpha- and beta-receptors) (Imipramine, amitriptylline) indirect action to release norepinephrine High dose: block alpha- & M-rec. • Uses: nasal decongestant Atomoxetine (used for ADHD) • Tyramine (not a drug, interaction with MAO inhibitors) Guanethedine (competes for uptake) 4
MAO vs COMT Parkinson’s Disease MAO COMT • General population 1:1000, over 60 1:75 • Tremor, stiffness, or clumsiness, usually involving one side, difficulty Location in Mitochondrial outer membrane cytosol walking, fatigue, depression cell • Progressive destruction of the dopaminergic nigrostriatal pathway Location in symp. nerve, placenta (MAO A ) most tissues, • Elevated cholinergic activity body platelets (MAO B ) not in symp. • Treatment: liver, kidney, brain (MAO A + MAO B ) nerve • MAO inhibitors: Effect of Increases NE level in symp. neuron, none/minor • Dopamine agonists: inhibition on potentiates release by tyramine-like drugs effect bromocriptine NE levels • L-Dopa Inhibitors Pargyline, tranylcypromine (non-selective) Tolcapone, • Anticholinergics: Clorgyline (MAO A -selective) Pyrogallol benztropine Selegiline (MAO B -selective) • Decarboxylase inhibitor: Clinical use Depression (non-selective or MAO A -selective) Parkinson’s D carbidopa of inhibitors Parkinson’s disease (MAO B -selective) • Amantadine: Inhibit D- Interactions MAO inhibitors potentiate effects of tyramine None, liver uptake, M-rec, NMDA- (due mainly to blocking metabolism of failure block, release dopamine tyramine by MAO in liver) Tyramine Interaction with MAO Inhibitors MAOI and Tyramine Crisis Can cause hypertensive crisis ( ↑ BP, ↑ HR) ↑ Blood pressure, ↑ Heart rate Treatment: α -blocker or labetalol ( α -, β -blocker) Normally dietary tyramine is Aged cheese metabolized by MAO & red wine are rich in tyramine With MAO inhibition, octopamine is produced and stored in vesicles with NE Aged cheese, red wine are rich in tyramine Therapeutic uses: Sympathomimetics 1 Tyramine Interaction with MAO Inhibitors Can cause hypertensive crisis ( ↑ BP, ↑ HR) • Asthma (major use) - bronchodilation with ↓ airway resistance - beta2-selective agents eg. albuterol Aged cheese & red wine are rich in tyramine • Allergic Reactions - acute hypersensitivity reactions (food, bee sting, drug allergy) - epinephrine (DOC) • Nasal Decongestant (common use) - vasoconstriction (ephedrine, phenylephrine) • Hypotension (acute) - intoxication with antihypertensive agents, spinal anesthesia, hemorrhage - phenylephrine, methoxamine, metaraminol 5
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