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Organization of The Nervous System

Organization of The Nervous System. Central Nervous System. Peripheral Nervous System. Autonomic Nervous System. Somatic Nervous System. Sympathetic. Parasympathetic. a. b. a. Sympathetic Ganglionic Synapse. Acetylcholinesterase. Ca 2+. Na +. ACH. Action Potential. Nicotinic

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Organization of The Nervous System

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  1. Organization of The Nervous System Central Nervous System Peripheral Nervous System Autonomic Nervous System Somatic Nervous System Sympathetic Parasympathetic

  2. a b a Sympathetic Ganglionic Synapse Acetylcholinesterase Ca2+ Na+ ACH Action Potential Nicotinic Receptor Na+ Preganglionic neuron Postganglionic neuron

  3. Na+ Sympathetic Organ Synapse Ca2+ Effector Organ G NE Action Potential Adrenergic Receptor Postganglionic neuron

  4. Action Potential Pharmacologic manipulation of the adrenergic system Na+ Presynaptic neuron Tyrosine Na+ Dopamine Tyrosine MAO H+ DA NE NE Ca2+ Uptake 1 a2 (-) Na+, Cl- NE NE NE NE Uptake 2 a1 b Effector organ

  5. H O C H C H N H 2 2 H O H O C H C H N H 2 2 O H H O H O C H C H N H 2 O H C H 3 Synthesis of catecholamines T Y R O S I N E C O O H t y r o s i n e h y d r o x y l a s e H O H O C H C H N H D O P A 2 2 C O O H a r o m a t i c L - a m i n o a c i d d e c a r b o x y l a s e H O H O C H D O P A M I N E C H N H 2 2 2 b d o p a m i n e - h y d r o x y l a s e N O R E P I N E P H R I N E p h e n y l e t h a n o l a m i n e - N - m e t h y l t r a n s f e r a s e E P I N E P H R I N E

  6. Metabolism of norepinephrine Monoamine Oxidase (MAO) 3,4-Dihydroxyphenyl- glycolaldehyde Norepinephrine Aldehyde Reductase Catechol O-Methyl- transferase (COMT) 3,4-Dihydroxyphenyl- ethylene glycol 1) Alcohol Dehydrogenase 2) Aldehyde Dehydrogenase 3-Methoxy-4-hydroxymandelic acid (Vanilylmandelic acid; VMA) 3-Methoxy-4-hydroxy- phenylethylene glycol

  7. Metabolism of norepinephrine 1) MAO 2) Aldehyde Dehydrogenase 3,4-Dihydroxymandelic Acid Norepinephrine COMT COMT 1) MAO 2) Aldehyde Dehydrogenase 3-Methoxy-4-hydroxymandelic acid (Vanilylmandelic acid; VMA) Normetanephrine

  8. Direct acting adrenergic receptor agonists H O Dopamine (Intropin) H O C H C H N H 2 2 2 H O Norepinephrine (Levophed) H O C H C H N H 2 2 O H H O Epinephrine (Adrenalin) H O C H C H N H 2 O H C H 3

  9. a1 a2 b a1B a1D a2A a2B a2C b1 b2 Receptors and signal transduction in the ANS Adrenergic Receptors a1A b3

  10. NH 3 COOH Direct acting adrenergic receptor agonists:a1 receptors Phospho - • Phenylephrine (Neosynephrine) • Methoxamine (Vasoxyl) • Oxymetazoline (Visine) lipase C (+) G q PIP 2 H O IP Diacylglycerol 3 C H C H N H C H 2 3 2+ Increase Ca Activate Protein Kinase C O H P h e n y l e p h r i n e Response

  11. Direct acting adrenergic receptor agonists:a2 receptors • Clonidine (Catapres) • Methyldopa (Aldomet) • Guanabenz (Wytensin) • Guanfacine (Tenex) • Tizanidine (Zanaflex) NH 3 Adenylate Cyclase (-) G I X K + (+) ATP cAMP COOH Reduce cAMP -Dependent Protein Kinase Activity C l o n i d i n e Response

  12. Direct acting adrenergic receptor agonists:b receptors Non-selective • Isoproterenol (Isuprel) b1-selective • Dobutamine (Dobutrex) • Dopamine (Intropin) b2-selective • Terbutaline (Brethine, Bricanyl) • Metaproterenol (Metaprel, Alupent) • Albuterol (Proventil, Ventolin) • Salmeterol (Serevent) • Ritodrine (Yutopar) H O C H 3 H O C H C H N H C H 2 C H 3 O H I s o p r o t e r e n o l

  13. Direct acting adrenergic receptor agonists:b receptors NH 3 Adenylate Cyclase (+) G S ATP cAMP COOH Increase cAMP -Dependent Protein Kinase Activity Response

  14. Molecular actions of norepinephrine VI Phe 290 VII Ser 207 I V Ser 204 II III IV Asp 113

  15. Selectivity of adrenergic receptor agonists Phenylephrine Epinephrine Norepinephrine Isoproterenol

  16. Cardiovascular effects of sympathomimetics Isoproterenol Norepinephrine Epinephrine 100 PULSE RATE (min) 50 180 BLOOD PRESSURE (mm Hg) 120 80 PERIPHERAL RESISTANCE 0 15 0 15 0 15 TIME (min)

  17. Direct acting adrenergic receptor agonists:Norepinephrine and Epinephrine • Potent a and b1 receptor agonist • Substrate for MAO and COMT • Parenteral administration • Used as a pressor • Sodium bisulfite used in preparations to prevent oxidation l-Norepinephrine (Levophed)

  18. Direct acting adrenergic receptor agonists:Norepinephrine and Epinephrine • Potent a, b1, and b2 receptor agonist • Substrate for MAO and COMT • Parenteral administration • Sodium bisulfite used in preparations to prevent oxidation • Available as many salts: hydrochloride, nitrate, bitartrate • Uses: Anaphylaxis, glaucoma, in combination with local anesthetics Epinephrine (Adrenalin)

  19. Direct acting adrenergic receptor agonists:a1 receptor agonists • Potent a1 receptor agonist • Substrate for MAO • Administration: Parenteral, oral, local • Uses: Mydriasis without cycloplegia, glaucoma, pressor, nasal decongestant Phenylephrine (Neo-Synephrine) • Potent a1 receptor agonist • Potent vasoconstrictor • Parenteral administration • Use: Pressor agent Methoxamine (Vasoxyl)

  20. Direct acting adrenergic receptor agonists:a1 receptor agonists: 2-aralkylimidazolines R = substituted aromatic ring structure X = methylene or amino The imidazoline cation is resonance stabilized allowing the + charge to be spread over the entire three atom system. Thus, imidazolines are more basic than simple aliphatic amines.

  21. Direct acting adrenergic receptor agonists:a1 receptor agonists: 2-aralkylimidazolines • Partial agonists at a receptors • Administered locally/topically to promote vasoconstriction • Basic nature of imidazoline ring causes compounds to exist in ionized form at physiologic pH • Tachyphylaxis/Desensitization • Uses: Nasal and ophthalmic decongestants R= R= Naphazoline (Privine) Tetrahydrozoline (Visine) R= Oxymetazoline (Afrin, Visine)

  22. Direct acting adrenergic receptor agonists:a2 receptor agonists • (Phenylimino)imidazolidine • Selective a2 receptor agonist • The basicity of the guanidine group (pKa = 13.6) is decreased (to pKa = 8.0) because of the attachment to the dichlorophenyl ring • Clinical effect linked to activation of a2 receptors in the nucleus of the solitary tract (cardiovascular center) • Administration: Oral, parenteral, transdermal • Uses: Hypertension, opiate withdrawal Clonidine (Catapres)

  23. a2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain Brain Brain Stem (Cardiovascular Control Center) a2 Receptors Sympathetic ganglion b1 Receptors Y Heart Y b1 Receptors Kidney a1 Receptors Y

  24. a2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain Brain Brain Stem (Cardiovascular Control Center) a2 Receptors Sympathetic ganglion b1 Receptors • Decreased sympathetic tone • Decr. HR • Decr. Contractility • Decr. Renin release • Decr. Vasoconstriction Y Heart Y b1 Receptors Kidney a1 Receptors Y

  25. Direct acting adrenergic receptor agonists:a2 receptor agonists • “Open-ring” imidazolidines • Two atom bridge to the guanidine group decreases the pKa so that the drug is mostly non-ionized at physiological pH • Guanabenz has the shortest t-1/2 at ~ 6 hours. Half-life of clonidine and guanfacine is 12-16 hours • Administration: oral • Uses: Hypertension Guanabenz (Wytensin) Guanfacine (Tenex)

  26. Direct acting adrenergic receptor agonists:a2 receptor agonists Methyldopate Esterases • Methyldopa (Aldomet) • A prodrug metabolized to active a2 receptor agonist, (1R, 2S)-a-methylnorepinephrine • Act at CNS a2 receptors to decrease sympathetic outflow • Water soluble, ester hydrochloride salt Methyldopate is used for parenteral solutions • Administration: Methyldopa, oral; Methyldopate; parenteral • Uses: Hypertension Methyldopa L-Aromatic Amino Acid Decarboxylase a-Methyldopamine Dopamine b-Hydroxylase (1R, 2S)-a-methylnorepinephrine

  27. Clinical pharmacology of a2 receptor agonists Other Uses: Apraclonidine (Iopidine): Glaucoma Tizanidine (Zanaflex): Muscle spasticity Adverse effects of a2-adrenergic receptor agonists: Sedation, Na+ and water retention, dry mouth, withdrawal syndrome

  28. Direct acting adrenergic receptor agonists:b receptor agonists • Non-selective b receptor agonist • Bronchodilation • Increased cardiac output • Metabolized by conjugation reactions (Phase II) and by COMT • Not sensitive to MAO • Administration: Oral, parenteral, local (inhaled) • Uses: Asthma, Chronic Obstructive Pulmonary Disease (COPD), Cardiostimulant Isoproterenol (Isuprel)

  29. Direct acting adrenergic receptor agonists:b receptor agonists • Resorcinol derivatives • Selective b2 receptor agonists • Bronchodilation • Cardiac effects observed only at high doses • Not metabolized by MAO or COMT • Longer duration of action than isoproterenol • Administration: Oral, parenteral, local (inhaled) • Uses: Asthma, COPD; Terbutaline used as tocolytic (prevent premature labor) Metaproterenol (Alupent, Metaprel) Terbutaline (Bricanyl, Brethine)

  30. Direct acting adrenergic receptor agonists:b receptor agonists • Meta hydroxymethyl derivatives • Selective b2 receptor agonists • Bronchodilation • Cardiac effects observed only at high doses • Not metabolized by MAO or COMT • Longer duration of action than isoproterenol • Administration: Oral, local (inhaled); Salmeterol only inhaled • Uses: Asthma, COPD Albuterol (Ventolin, Proventil) Salmeterol (Serevent)

  31. Direct acting adrenergic receptor agonists:Long acting b receptor agonists • Selective b2 receptor agonists • Bronchodilation • Not metabolized by MAO or COMT • Onset of action: • Salmeterol 10-20 min • Formoterol < 5 min • Longer duration of action • Administration: inhaled (metered-dose inhaler and powder) • Uses: Long-term Asthma, COPD • Not recommended for acute treatment of asthma symptoms

  32. Direct acting adrenergic receptor agonists:b receptor agonists • Selective b2 receptor agonists • Administration: Oral, parenteral • Uses: Tocolytic Ritodrine (Yutopar)

  33. Direct acting adrenergic receptor agonists:b receptor agonists Dobutamine (Dobutrex) • Dopamine derivative • Available as a racemic mixture • (+)-enantiomer: potent b1 receptor agonist • (-)-enantiomer: potent a1 receptor agonist, potency for b receptors reduced 10X • Net effect is positive inotropic effect on heart with little chronotropic effect • Metabolized by COMT and conjugation, not sensitive to MAO • Short half-life (~2 min) • Administered: Parenteral • Use: Acute heart failure, shock

  34. Action Potential Indirect-acting sympathomimetics Na+ Presynaptic neuron Tyrosine Na+ Dopamine Tyrosine 3 MAO H+ DA NE NE Ca2+ Uptake 1 1 Na+, Cl- NE 2 NE NE NE a1 b Effector organ

  35. Indirect-acting sympathomimetics:Amphetamine, pseudoephedrine, ephedrine, phenylpropanolamine, tyramine Promote release of NE via reverse action of plasma membrane transporter Clinical uses: • Amphetamines: ADHD, narcolepsy, anorexiant • Others: Nasal decongestants Extracellular AMPH NET C H C H N H 2 2 NE C H 3 A m p h e t a m i n e Intracellular

  36. Indirect-acting sympathomimetics: D-(-)-Ephedrine vs. L-(+)-Pseudoephedrine • Alkaloid obtained from the stems of Ephedra. Also found in mahuang. • D-(-)-Ephedrine has desired (R)-configuration at b-OH and (S)-configuration at the a carbon for direct agonist activity at adrenergic receptors S R D-(-)-Ephedrine • L-(+)-Pseudoephedrine is the (S,S)-diastereoisomer; (S)-configuration of b-OH reduces agonist activity-major mechanism is via reversal of the transporter S S L-(+)-Pseudoephedrine

  37. Indirect-acting sympathomimetics: D-(-)-Ephedrine vs. L-(+)-Pseudoephedrine D-(-)-Ephedrine erythro L-(+)-Pseudoephedrine threo

  38. Action Potential Indirect-acting sympathomimetics: Transporter blockers Cocaine Antidepressants Desipramine Venlafaxine Na+ H+ NE NE NE NE Ca2+ Uptake 1 Na+, Cl- NE 2 NE NE NE a1 b Effector organ

  39. Action Potential Indirect-acting sympathomimetics: Cocaine Antidepressants Na+ Desipramine Venlafaxine H+ NE NE NE Ca2+ Cocaine NE NE 2 NE NE NE NE NE NE NE a1 b Effector organ

  40. Metabolism of norepinephrine Monoamine Oxidase (MAO) 3,4-Dihydroxyphenyl- glycolaldehyde Norepinephrine Aldehyde Reductase Catechol O-Methyl- transferase (COMT) 3,4-Dihydroxyphenyl- ethylene glycol 1) Alcohol Dehydrogenase 2) Aldehyde Dehydrogenase 3-Methoxy-4-hydroxymandelic acid (Vanilylmandelic acid; VMA) 3-Methoxy-4-hydroxy- phenylethylene glycol

  41. Action Potential Indirect-acting sympathomimetics: MAO Inhibitors Phenelzine Selegiline Na+ 3 MAO H+ NE NE Ca2+ Na+, Cl- NE 2 NE NE NE a1 b Effector organ

  42. Action Potential Indirect-acting sympathomimetics: MAO Inhibitors Phenelzine Selegiline Na+ NE NE NE 3 MAO H+ NE NE NE NE NE NE NE Ca2+ NE Na+, Cl- NE 2 NE NE NE NE NE NE a1 b Effector organ

  43. Indirect-acting sympathomimetics: MAO Inhibitors Co-admininstration with other indirect-acting drugs can lead to hypertensive crisis Phenelzine Selegiline NE NE NE 3 MAO H+ NE NE NE NE NE NE NE NE NE NE Amphetamine, Tyramine NE NE NE NE NE NE NE NE NE NE NE NE a1 b Effector organ

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