Disease State Management

Transcription

1 Why Study the Autonomic ervous System? Pathophysiology Medicinal Chemistry Therapeutics AS Pharmacology Disease State Management

2 rganization of The ervous System Central ervous System Peripheral ervous System Autonomic ervous System Somatic ervous System Sympathetic Parasympathetic

3 Summary of sympathetic neurons and synapses Preganglionic neurons Short Synapse with postganglionic neurons near spinal cord Release acetylcholine (AC) to activate nicotinic receptors on postganglionic neurons Postganglionic neurons Long Synapse on the target organ Release norepinephrine to activate adrenergic receptors on target organs

4 ow do we define neuron types in the AS? Parasympathetic C 3 C C 3 C3 Sympathetic C 2 C 2 Acetylcholine C 3 C C 2 2 orepinephrine (oradrenaline) 3 C C 2 C 3 C3 Muscarine C 3 C 3 C C 2 C 3 icotine Epinephrine (Adrenaline)

5 Sympathetic Ganglionic Synapse Ca 2+ Acetylcholinesterase a + Action Potential AC a b a icotinic a + Receptor Preganglionic neuron Postganglionic neuron

6 Sympathetic rgan Synapse a + Ca 2+ G Effector rgan Action Potential E Adrenergic Receptor Postganglionic neuron

7 C 2 C 2 C TYRSIE Synthesis of catecholamines tyrosine hydroxylase C 2 C 2 DPA C aromatic L-amino acid decarboxylase C 2 C 2 2 DPAMIE dopamine b-hydroxylase C C 2 2 REPIEPRIE phenylethanolamine- -methyltransferase C C 2 EPIEPRIE C 3

8 Pharmacologic manipulation of the adrenergic system Presynaptic neuron a + Dopamine a + Tyrosine Tyrosine Action Potential + DA MA Ca 2+ a 2 E (-) E E Uptake 1 a +, Cl - Uptake 2 E E E a 1 Effector organ b

9 Metabolism of norepinephrine 2 Monoamine xidase (MA) C orepinephrine Aldehyde Reductase 3,4-Dihydroxyphenylglycolaldehyde Catechol -Methyltransferase (CMT) C 2 3,4-Dihydroxyphenylethylene glycol 3 C C 2 3-Methoxy-4-hydroxyphenylethylene glycol 1) Alcohol Dehydrogenase 2) Aldehyde Dehydrogenase 3 C C 2 3-Methoxy-4-hydroxymandelic acid (Vanilylmandelic acid; VMA)

10 Metabolism of norepinephrine 2 1) MA 2) Aldehyde Dehydrogenase C 2 orepinephrine 3,4-Dihydroxymandelic Acid CMT CMT 3 C 2 1) MA 2) Aldehyde Dehydrogenase 3 C C 2 ormetanephrine 3-Methoxy-4-hydroxymandelic acid (Vanilylmandelic acid; VMA)

11 DIRECT ACTIG ADREERGIC RECEPTR AGISTS: A 1 RECEPTRS 3 PEYLEPRIE (ESYEPRIE) METXAMIE (VASXYL) XYMETAZLIE (VISIE) Phospholipase C (+) G q PIP 2 C IP 3 Diacylglycerol C C 2 C 3 Increase Ca 2+ Activate Protein Kinase C Phenylephrine Response

12 DIRECT ACTIG ADREERGIC RECEPTR AGISTS: A 2 RECEPTRS CLIDIE (CATAPRES) METYLDPA (ALDMET) 3 GUAABEZ (WYTESI) GUAFACIE (TEEX) TIZAIDIE (ZAAFLEX) Cl Cl Clonidine K + (+) C G I (-) ATP Adenylate Cyclase X camp Reduce camp-dependent Protein Kinase Activity Response

13 Direct acting adrenergic receptor agonists: b receptors 3 G S (+) Adenylate Cyclase C ATP camp Increase camp-dependent Protein Kinase Activity Response

14 2 P 2 P P ATP camp Adenylyl cyclase P Phospho diesterase 2 3 P AMP

15 MLECULAR ACTIS F REPIEPRIE I II VII 3 Phe 290 VI The pict ure can' t be disp laye d. Ser 207 VTh e pic tur e can 't be dis pla yed. Ser 204 C 2 III The picture can't be display ed. Asp 113 IV

16 3 / 2 / 1 2 R 1 R 3 4 / 5 / 6 / R2 R1 SUBSTITUTI R2 SUBSTITUTI R3 SUBSTITUTI

17 R1 SUBSTITUTI Isoproterenol Colterol

18 R2 SUBSTITUTI SMALL ALKYL GRUPS, METYL R ETYL, MAY BE PRESET TE CARB- 2. SUC SUBSTITUTI SLWS METABLISM BY (MA) BUT AS LITTLE VERALL EFFECT DURATI F ACTI I CATECLAMIES RESISTACE T MA ACTIVITY IS MRE IMPRTAT I CATECL IDIRECT ACTIG PEYLETYLAMIES.

19 R 3 C ethylnorepinephrine: R= isoetharine : R=C(C 3 ) 2

20 R3 SUBSTITUTI Albuterol Metaproterenol C 3 Ritodrine C 3 C C 3 C 3 Phenylephrine Metaraminol C 3 Methoxamine

21 DPAMIE REPIEPRIE EPIEPRIE DIPIVEFRIE ( 3 C) 3 C C C 3 ( 3 C) 3 C C Dipivefrin Esterases Epinephrine + 2(C 3 ) 3 CC 2

22 aphazoline: R = C 2 Tetrahydrozoline R = R 3 C xymetazoline: R = C 2 C(C 3 ) 3 3 C 3 C Xylometazoline R = C 2 C(C 3 ) 3 3 C

23 3 C 2 C 2 Methyldopa L-Aromatic Amino Acid Decarboxylase 3 C 2 alpha-methyl dopamine Dopamine Beta-hydroxylase 2 3 C alpha-methyl norepinephrine " METABLIC CVERSI F METYLDPA T ALPA- METYL REPIEPRIE"

24 Pirbuterol Terbutaline Salmeterol

25 Bitolterol C(C 3 ) C 2 Colterol p-toluic acid C 3

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27 2 2 3 C Amphetamine p-tyramine S S C 3 C 3 L-(+)-Pseudoephedrine