Pharmacology of the Sympathetic Nervous System I
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1 Pharmacology of the Sympathetic Nervous System I Neurons of the ANS Edward JN Ishac, Ph.D. Smith Building, oom 742 eishac@vcu.edu or Department of Pharmacology and Toxicology Medical College of Virginia Campus of Virginia Commonwealth University ichmond, Virginia, USA Sympathetic Nervous System Adrenergic Nerve Terminal Norepinephrine (NE) = Noradrenaline (NA) Epinephrine (EPI) = Adrenaline (AD, AD) Noradrenergic = Adrenergic Isoproterenol = Isoprenaline (ISO) Noradrenergic Neuron Neuronal (Uptake1) vs Extraneuronal (Uptake2) Neuronal Uptake Uptake % Cocaine TCA Extraneuronal Uptake % 1
2 vs vs Location in cell Location in body Effect of inhibition on NE levels Mitochondrial outer membrane symp. nerve, placenta ( A ) platelets ( B ) liver, kidney, brain ( A + B ) increases NE level in symp. neuron, potentiates release by tyramine-like drugs cytosol most tissues, not in sympath. nerve minor/no effect HO HO CH 3 O HO Inhibitors: Tolcapone, Pyrogallol Parkinson s D with l-dopa (rarely used, liver failure) Inhibitors: Depression CH 2 N H O C OH CH 2OH Non-selective Tranylcypromine, Pargyline Inhibitors: Selective Depression -A Clorgiline Parkinson D -B Selegiline O C H Metabolism of Catecholamines Metabolism by either or, inactivates drug Major Metabolites VMA MOPEG eceptor Subtypes α-eceptors 1948 β-eceptors α 1 -eceptors 70 s 90 s α 2 -eceptors 60 s α 1A α 1B α 1C α 1D α 2A α 2B α 2C α 2D β 1 β 2 β 3 90 s PLC Ca ++ IP 3 DAG A/C camp A/C Adrenergic Agents elative Selectivity Second Messengers ECEPTO TISSUE ACTIONS Alpha 1 most vascular smooth muscle contraction EPI > or = NE >> ISO pupillary dilator muscle contraction (dilation) pilomotor smooth muscle erects hair vas deferens contraction liver intestinal smooth muscle relaxation intestinal sphincters contraction Alpha 2 some vascular smooth muscle contraction NE > EPI >> ISO nerve terminals (NE & Ach) inhibit transmitter release platelets aggregation fat cells inhibition of lipolysis eceptor α 1 α 2 β 1 Location Effector tissues: smooth muscle, glands Nerve endings, smooth smooth muscle Cardiac muscle, juxtaglomerular apparatus G Protein Gq Gi 2nd Messenger Ca 2+, IP 3, DAG camp Beta 1 heart force, rate, conduction velocity ISO > EPI = NE coronary blood vessels dilatation kidney renin release Beta 2 bronchial smooth muscle relaxation ISO > or = EPI >> NE uterine smooth muscle relaxation intestinal smooth muscle relaxation vascular smooth muscle relaxation liver NA nerve terminals facilitation of release β 2 β 3 D 1, D 5 D 2 D 3 D 4 Smooth muscle, lung Adipose cells enal, vascular SM, brain Brain, cardiovascular camp Beta 3 fat cells lipolysis ISO = NE > EPI X 2
3 Phospholipase C Adenylate Cyclase G-Protein coupled receptors G-Protein coupled receptors Adrenergic Alpha1-receptors Stimulate All Beta-receptors D1, D5-receptors Cholinergic M1 M3 M5 Inhibit Alpha2-receptors D2, D3, D4-receptors M2, M4-receptors α1-a Hepatocyte norepinephrine / epinephrine β2-a α1-a Vasculature norepinephrine / epinephrine β2-a IP 3 / DAG IP 3 / DAG Ca++ / PKC protein kinase A Ca++ / PKC protein kinase A Ca++-dependent phosphorylase K. phosphorylase kinase Vasoconstriction Vasodilation phosphorylase a phosphorylase a Increase resistance Decrease resistance glucose-1-p Increase BP?????? Decrease BP Catecholamines A. Norepinephrine (limited use, pressor agent, shock) Activates: both alpha, beta 1, beta 3, beta 2 (weakest) Substrate for &, does not cross BBB OH OH Catechol B. Epinephrine (DOC - Allergic reaction) Activates both alpha, beta 1, beta 2, beta 3 (weakest) Substrate for &, does not cross BBB C. Dopamine (DOC shock) Precursor of NE and EPI Activates alpha 1, dopamine receptors Substrate for &, does not cross BBB D. Isoproterenol (asthma, cardiac stimulant) Activates all beta receptors Substrate for, does not cross BBB CH2 CH2 NH Phenylethylamine None effective orally Do not cross BBB Actions brief DOC Drug of Choice Non-Catecholamines Beta agonists Selective beta2-agonists: albuterol, ritodrine, metaproterenol, terbutaline Uses: asthma, premature labor Oral: Onset 1-2 hrs, Inhal: Onset 5-10 min, duration 4-6 hrs duration 3-4 hrs (fewer side effects) Adverse effects: cardiovascular ( H, BP) Selective beta1-agonists: dobutamine, prenalternol Uses: Congestive heart failure Increase force, no change in H or oxygen demand 3
4 Non-Catecholamines Alpha agonists Selective alpha1-agonists: methoxamine, phenylephrine, metaraminol (direct & indirect actions, orally active) Uses: hypotension or shock, nasal decongestant Selective alpha2-agonists: clonidine, α-methyldopa (prodrug), guanfacine Uses: hypertension (CNS action) opioid withdrawal (decrease severity) Side effects: impotence, dry mouth, rebound HT Dopamine Agonists Bromocriptine, Pramprexole: - Parkinsons Disease - estless leg syndrome (LS) - SE: drowsiness Fenoldopam: -D 1A -agonist, no action on α1- or β-as - used for acute hypertension - iv short-term infusion (<48 hrs) -SE: ocular pressure, H Indirectly-acting Sympathomimetics (displace transmitter) Amphetamine, methamphetamine, methylpenidate CNS stimulant, performance enhancer, physical & mental abuse alertness, mood, self-confidence, concentration, psychological dependence, tolerance, tachyphylaxis 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 inhibitors) Sudafed phenylephrine vs pseudoephedrine Crystal Meth Drug Abuse Manufacturers, including Sudafed-maker Pfizer Inc., switched to phenylephrine from pseudoephedrine the past year after passage of a law requiring all pseudoephedrine products be sold from behind pharmacy counters. After 1.5 years of drug use 4
5 Indirectly-acting Sympathomimetics (cont.) 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 inhibitors) Neuronal Uptake Inhibition Inhibit neuronal uptake (Uptake1) Can prevent the action of indirectly acting agents (e.g. amphetamine) and can potentiate the effects of NE (ie. not removed from synaptic junction). Neuronal Uptake 1: 70-80% Cocaine Tricyclic antidepressants (Imipramine, amitriptylline) High dose: block alpha- & M-rec. Atomoxetine (used for ADHD) Guanethedine (competes for uptake) Location in cell Location in body Effect of inhibition on NE levels Inhibitors Clinical use of inhibitors Interactions vs Mitochondrial outer membrane symp. nerve, placenta ( A ) platelets ( B ) liver, kidney, brain ( A + B ) Increases NE level in symp. neuron, potentiates release by tyramine-like drugs Pargyline, tranylcypromine (non-selective) Clorgyline ( A -selective) Selegiline ( B -selective) Depression (non-selective or A -selective) Parkinson s disease ( B -selective) inhibitors potentiate effects of tyramine (due mainly to blocking metabolism of tyramine by in liver) cytosol most tissues, not in symp. nerve none/minor effect Tolcapone, Entacapone, Pyrogallol Parkinson s D None, liver failure Parkinson s Disease General population 1:1000, over 60 1:75 Tremor, stiffness, or clumsiness, usually involving one side, difficulty walking, fatigue, depression Progressive destruction of the dopaminergic nigrostriatal pathway Elevated cholinergic activity Treatment options: inhibitors: Dopamine agonists: bromocriptine pramiprexole L-Dopa Anticholinergics: benztropine Decarboxylase inhibitor: carbidopa Amantadine: Inhibit D- uptake, M-rec, NMDAblock, release dopamine Tyramine Interaction with Inhibitors Can cause hypertensive crisis ( BP, H) I and Tyramine Crisis Blood pressure, Heart rate Treatment: α-blocker or labetalol (α-, β-blocker) Aged cheese & red wine are rich in tyramine Normally dietary tyramine is metabolized by With inhibition, octopamine is produced and stored in vesicles with NE Aged cheese, red wine are rich in tyramine 5
6 Tyramine Interaction with Inhibitors Can cause hypertensive crisis ( BP, H) Aged cheese & red wine are rich in tyramine Therapeutic uses: Sympathomimetics 1 Asthma (major use) - bronchodilation with airway resistance - beta2-selective agents eg. albuterol Allergic eactions - 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 Asthma Epinephrine Anaphylaxis Albuterol Terbutaline, Metaproterenol β 2 -selective agonists - bronchodilation Inhalation vs oral - less side effects itodrine - premature labor bronchoconstriction secretions blood pressure Epinephrine - bronchodilation - vasoconstriction Therapeutic uses: Sympathomimetics 1 Asthma (major use) - bronchodilation with airway resistance - beta2-selective agents eg. albuterol Allergic eactions - 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 Therapeutic uses: Sympathomimetics 2 Hypertension - Chronic: centrally acting α2-receptor agonists (clonidine, α-methyl-dopa) - Acute: fenoldopam (D 1A -agonist) Shock (need to treat cause) - dopamine (DOC), epinephrine, NE - blood loss, cardiac failure, septic shock - tissue perfusion, need to maintain BP, cerebral flow Congestive Heart Failure - dobutamine (acute) Cardiac Heart Block & Cardiac Arrest - epinephrine or isoproterenol 6
7 Therapeutic uses: Sympathomimetics 3 Parkinson s Disease - Inhibitors: B : selegiline, : tolcapone - D-agonists: pramiprexole Precursor: L-Dopa Ophthalmic - dilate the pupil (phenylephrine) - glaucoma (epinephrine) also beta-blocking agents used (common) Uterine Contractions - suppress premature labor - ritodrine, terbutaline (not FDA approved) Hyperactivity Disorder (ADHD) - amphetamines, methylphenidate (ritalin) - NE uptake inhibition: atomoxetine Others: [obesity], nacrolepsy: - amphetamines Parkinson s Disease General population 1:1000, over 60 1:75 Tremor, stiffness, or clumsiness, usually involving one side, difficulty walking, fatigue, depression Progressive destruction of the dopaminergic nigrostriatal pathway Elevated cholinergic activity Treatment: inhibitors: Dopamine agonists: bromocriptine, pramiprexole L-Dopa Anticholinergics: benztropine Decarboxylase inhibitor: carbidopa Amantadine: Inhibit D- uptake, M-rec, NMDAblock, release dopamine Therapeutic uses: Sympathomimetics 3 Parkinson s Disease - Inhibitors: B : selegiline, : tolcapone - D-agonists: pramiprexole Precursor: L-Dopa Ophthalmic - dilate the pupil (phenylephrine) - glaucoma (epinephrine) also beta-blocking agents used (common) Uterine Contractions - suppress premature labor - ritodrine, terbutaline (not FDA approved) Hyperactivity Disorder (ADHD) - amphetamines, methylphenidate (ritalin) - NE uptake inhibition: atomoxetine Others: [obesity], nacrolepsy: - amphetamines Toxic effects of Sympathomimetics Extensions of their receptor-mediated effects Cardiovascular (main) - cardiac stimulation (β-a, arrhythmias) - hypertension (α-a, hemorrhage) CNS Especially those that cross BBB (ie. amphetamine) - restlessness - dizziness - insomnia Alpha2-receptor agonists - dry mouth, sedation, impotence 7
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