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MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic.

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Presentation on theme: "MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic."— Presentation transcript:

1 MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

2 MCMP 407 Action Potential Na + Ca 2+    ACH Acetylcholinesterase Na + Sympathetic Ganglionic Synapse Preganglionic neuronPostganglionic neuron Nicotinic Receptor

3 MCMP 407 Action Potential Ca 2+ Na + NE Sympathetic Organ Synapse G Effector Organ Postganglionic neuron Adrenergic Receptor

4 MCMP 407 Action Potential Na + Pharmacologic manipulation of the adrenergic system Presynaptic neuron H+H+ Effector organ Ca 2+ Na + Tyrosine Dopamine DA NE (-) Uptake 2 Uptake 1 Na +, Cl - NE    MAO

5 MCMP 407 Synthesis of catecholamines COOH HOCH 2 CHNH 2 COOH HO HO HOCH 2 CH 2 NH 2 TYROSINE DOPA DOPAMINE NOREPINEPHRINE EPINEPHRINE tyrosine hydroxylase aromatic L-amino acid decarboxylase dopamine  -hydroxylase phenylethanolamine- N-methyltransferase

6 MCMP 407 Metabolism of norepinephrine Norepinephrine 3-Methoxy-4-hydroxymandelic acid (Vanilylmandelic acid; VMA) Monoamine Oxidase (MAO) 3,4-Dihydroxyphenyl- glycolaldehyde Aldehyde Reductase Catechol O-Methyl- transferase (COMT) 3,4-Dihydroxyphenyl- ethylene glycol 3-Methoxy-4-hydroxy- phenylethylene glycol 1) Alcohol Dehydrogenase 2) Aldehyde Dehydrogenase

7 MCMP 407 Metabolism of norepinephrine Norepinephrine 3,4-Dihydroxymandelic Acid 3-Methoxy-4-hydroxymandelic acid (Vanilylmandelic acid; VMA) Normetanephrine COMT 1) MAO 2) Aldehyde Dehydrogenase 1) MAO 2) Aldehyde Dehydrogenase

8 MCMP 407 Direct acting adrenergic receptor agonists HO HOCH OH CH 2 NH CH 3 HO HOCH OH CH 2 NH 2 HO HOCH 2 CH 2 NH 2 Dopamine (Intropin) Norepinephrine (Levophed) Epinephrine (Adrenalin)

9 MCMP 407 Receptors and signal transduction in the ANS Adrenergic Receptors  1A 11 22  1B  1D  2A  2B  2C 11 22 33

10 MCMP 407 Direct acting adrenergic receptor agonists:  1 receptors l Phenylephrine (Neosynephrine) l Methoxamine (Vasoxyl) l Oxymetazoline (Visine) Phenylephrine HO CHCH 2 NHCH 3 OH G q Phospho- lipase C (+) PIP 2 IP 3 Diacylglycerol Increase Ca 2+ Activate Protein KinaseC Response

11 MCMP 407 Direct acting adrenergic receptor agonists:  2 receptors l Clonidine (Catapres) l Methyldopa (Aldomet) l Guanabenz (Wytensin) l Guanfacine (Tenex) l Tizanidine (Zanaflex) Clonidine NH 3 COOH G I (-) ATPcAMP ReducecAMP-Dependent ProteinKinaseActivity Response X (+) K + Adenylate Cyclase

12 MCMP 407 Direct acting adrenergic receptor agonists:  receptors Non-selective l Isoproterenol (Isuprel)  1 -selective l Dobutamine (Dobutrex) l Dopamine (Intropin)  2 -selective l Terbutaline (Brethine, Bricanyl) l Metaproterenol (Metaprel, Alupent) l Albuterol (Proventil, Ventolin) l Salmeterol (Serevent) l Ritodrine (Yutopar) Isoproterenol HO HOCHCH 2 NHCH CH 3 CH 3 OH

13 MCMP 407 Direct acting adrenergic receptor agonists:  receptors G S (+) ATPcAMP IncreasecAMP-Dependent ProteinKinaseActivity Response NH 3 COOH Adenylate Cyclase

14 MCMP 407 Molecular actions of norepinephrine I II IIIIV V VI VII Asp 113 Ser 204 Ser 207 Phe 290

15 MCMP 407 Selectivity of adrenergic receptor agonists Phenylephrine Epinephrine Norepinephrine Isoproterenol

16 MCMP 407 Cardiovascular effects of sympathomimetics PULSE RATE (min) BLOOD PRESSURE (mm Hg) 80 PERIPHERAL RESISTANCE TIME (min) NorepinephrineEpinephrine Isoproterenol

17 MCMP 407 Direct acting adrenergic receptor agonists: Norepinephrine and Epinephrine Potent  and  1 receptor agonist l Substrate for MAO and COMT l Parenteral administration l Used as a pressor l Sodium bisulfite used in preparations to prevent oxidation l-Norepinephrine (Levophed)

18 MCMP 407 Direct acting adrenergic receptor agonists: Norepinephrine and Epinephrine  Potent ,  1, and  2 receptor agonist u Substrate for MAO and COMT u Parenteral administration u Sodium bisulfite used in preparations to prevent oxidation u Available as many salts: hydrochloride, nitrate, bitartrate u Uses: Anaphylaxis, glaucoma, in combination with local anesthetics Epinephrine (Adrenalin)

19 MCMP 407 Direct acting adrenergic receptor agonists:  1 receptor agonists  Potent  1 receptor agonist v Substrate for MAO v Administration: Parenteral, oral, local v Uses: Mydriasis without cycloplegia, glaucoma, pressor, nasal decongestant Phenylephrine (Neo-Synephrine) Methoxamine (Vasoxyl)  Potent  1 receptor agonist v Potent vasoconstrictor v Parenteral administration v Use: Pressor agent

20 MCMP 407 Direct acting adrenergic receptor agonists:  1 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 MCMP 407 Direct acting adrenergic receptor agonists:  1 receptor agonists: 2-aralkylimidazolines R= Naphazoline (Privine)Tetrahydrozoline (Visine) Oxymetazoline (Afrin, Visine)  Partial agonists at  receptors vAdministered locally/topically to promote vasoconstriction vBasic nature of imidazoline ring causes compounds to exist in ionized form at physiologic pH vTachyphylaxis/Desensitization vUses: Nasal and ophthalmic decongestants

22 MCMP 407 Direct acting adrenergic receptor agonists:  2 receptor agonists v(Phenylimino)imidazolidine  Selective  2 receptor agonist vThe 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  2 receptors in the nucleus of the solitary tract (cardiovascular center) vAdministration: Oral, parenteral, transdermal vUses: Hypertension, opiate withdrawal Clonidine (Catapres)

23 MCMP 407  2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain Brain Brain Stem (Cardiovascular Control Center) Kidney Heart Y Sympathetic ganglion  1 Receptors  2 Receptors Y  1 Receptors Y  1 Receptors

24 MCMP 407  2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain Brain Brain Stem (Cardiovascular Control Center) Kidney Heart Y Sympathetic ganglion  1 Receptors  2 Receptors Y  1 Receptors Y  1 Receptors Decreased sympathetic tone Decr. HR Decr. Contractility Decr. Renin release Decr. Vasoconstriction

25 MCMP 407 Direct acting adrenergic receptor agonists:  2 receptor agonists v“Open-ring” imidazolidines vTwo atom bridge to the guanidine group decreases the pKa so that the drug is mostly non-ionized at physiological pH vGuanabenz has the shortest t-1/2 at ~ 6 hours. Half-life of clonidine and guanfacine is hours vAdministration: oral vUses: Hypertension Guanabenz (Wytensin) Guanfacine (Tenex)

26 MCMP 407 Direct acting adrenergic receptor agonists:  2 receptor agonists vMethyldopa (Aldomet)  A prodrug metabolized to active  2 receptor agonist, (1R, 2S)-  - methylnorepinephrine  Act at CNS  2 receptors to decrease sympathetic outflow vWater soluble, ester hydrochloride salt Methyldopate is used for parenteral solutions vAdministration: Methyldopa, oral; Methyldopate; parenteral vUses: Hypertension Methyldopate Methyldopa  -Methyldopamine (1R, 2S)-  -methylnorepinephrine Esterases L-Aromatic Amino Acid Decarboxylase Dopamine  -Hydroxylase

27 MCMP 407 Clinical pharmacology of  2 receptor agonists Adverse effects of  2 -adrenergic receptor agonists: Sedation, Na + and water retention, dry mouth, withdrawal syndrome Other Uses: Apraclonidine (Iopidine): Glaucoma Tizanidine (Zanaflex): Muscle spasticity

28 MCMP 407 Direct acting adrenergic receptor agonists:  receptor agonists  Non-selective  receptor agonist vBronchodilation vIncreased cardiac output vMetabolized by conjugation reactions (Phase II) and by COMT vNot sensitive to MAO vAdministration: Oral, parenteral, local (inhaled) vUses: Asthma, Chronic Obstructive Pulmonary Disease (COPD), Cardiostimulant Isoproterenol (Isuprel)

29 MCMP 407 Direct acting adrenergic receptor agonists:  receptor agonists vResorcinol derivatives  Selective  receptor agonists vBronchodilation vCardiac effects observed only at high doses vNot metabolized by MAO or COMT vLonger duration of action than isoproterenol vAdministration: Oral, parenteral, local (inhaled) vUses: Asthma, COPD; Terbutaline used as tocolytic (prevent premature labor) Metaproterenol (Alupent, Metaprel) Terbutaline (Bricanyl, Brethine)

30 MCMP 407 Direct acting adrenergic receptor agonists:  receptor agonists Albuterol (Ventolin, Proventil) Salmeterol (Serevent) vMeta hydroxymethyl derivatives  Selective  receptor agonists vBronchodilation vCardiac effects observed only at high doses vNot metabolized by MAO or COMT vLonger duration of action than isoproterenol vAdministration: Oral, local (inhaled); Salmeterol only inhaled vUses: Asthma, COPD

31 MCMP 407 Direct acting adrenergic receptor agonists: Long acting  receptor agonists  Selective  receptor agonists vBronchodilation vNot metabolized by MAO or COMT vOnset of action: ØSalmeterol min ØFormoterol < 5 min vLonger duration of action vAdministration: inhaled (metered- dose inhaler and powder) vUses: Long-term Asthma, COPD vNot recommended for acute treatment of asthma symptoms

32 MCMP 407 Direct acting adrenergic receptor agonists:  receptor agonists Ritodrine (Yutopar)  Selective  receptor agonists vAdministration: Oral, parenteral vUses: Tocolytic

33 MCMP 407 Direct acting adrenergic receptor agonists:  receptor agonists Dobutamine (Dobutrex) vDopamine derivative vAvailable as a racemic mixture  (+)-enantiomer: potent  1 receptor agonist  (-)-enantiomer: potent  1 receptor agonist, potency for  receptors reduced 10X vNet effect is positive inotropic effect on heart with little chronotropic effect vMetabolized by COMT and conjugation, not sensitive to MAO vShort half-life (~2 min) vAdministered: Parenteral vUse: Acute heart failure, shock

34 MCMP 407 Action Potential Na + Indirect-acting sympathomimetics Presynaptic neuron H+H+ Effector organ Ca 2+ Na + Tyrosine Dopamine DA NE Uptake 1 Na +, Cl - NE   MAO 2 1 3

35 MCMP 407 Indirect-acting sympathomimetics: Amphetamine, pseudoephedrine, ephedrine, phenylpropanolamine, tyramine Promote release of NE via reverse action of plasma membrane transporter Clinical uses: l Amphetamines: ADHD, narcolepsy, anorexiant l Others: Nasal decongestants CH 2 CHNH 2 CH 3 Amphetamine Extracellular Intracellular AMPH NE NET

36 MCMP 407 Indirect-acting sympathomimetics: D-(-)-Ephedrine vs. L-(+)-Pseudoephedrine D-(-)-Ephedrine L-(+)-Pseudoephedrine S S S R lAlkaloid obtained from the stems of Ephedra. Also found in mahuang. D-(-)-Ephedrine has desired (R)-configuration at  -OH and (S)-configuration at the  carbon for direct agonist activity at adrenergic receptors L-(+)-Pseudoephedrine is the (S,S)-diastereoisomer; (S)- configuration of  -OH reduces agonist activity-major mechanism is via reversal of the transporter

37 MCMP 407 Indirect-acting sympathomimetics: D-(-)-Ephedrine vs. L-(+)-Pseudoephedrine D-(-)-Ephedrine erythro L-(+)-Pseudoephedrine threo

38 MCMP 407 Action Potential Na + Indirect-acting sympathomimetics: Transporter blockers Cocaine Antidepressants H+H+ Effector organ Ca 2+ NE Uptake 1 Na +, Cl - NE   2 Desipramine Venlafaxine

39 MCMP 407 Action Potential Na + Indirect-acting sympathomimetics: Cocaine Antidepressants H+H+ Effector organ Ca 2+ NE   2 Desipramine Venlafaxine Cocaine NE

40 MCMP 407 Metabolism of norepinephrine Norepinephrine 3-Methoxy-4-hydroxymandelic acid (Vanilylmandelic acid; VMA) Monoamine Oxidase (MAO) 3,4-Dihydroxyphenyl- glycolaldehyde Aldehyde Reductase Catechol O-Methyl- transferase (COMT) 3,4-Dihydroxyphenyl- ethylene glycol 3-Methoxy-4-hydroxy- phenylethylene glycol 1) Alcohol Dehydrogenase 2) Aldehyde Dehydrogenase

41 MCMP 407 Action Potential Na + Indirect-acting sympathomimetics: MAO Inhibitors H+H+ Effector organ Ca 2+ NE Na +, Cl - NE   MAO 2 3 Phenelzine Selegiline

42 MCMP 407 Action Potential Na + Indirect-acting sympathomimetics: MAO Inhibitors H+H+ Effector organ Ca 2+ NE Na +, Cl - NE   MAO 2 3 Phenelzine Selegiline NE

43 MCMP 407 Indirect-acting sympathomimetics: MAO Inhibitors H+H+ Effector organ NE   MAO 3 Phenelzine Selegiline NE Co-admininstration with other indirect-acting drugs can lead to hypertensive crisis Amphetamine, Tyramine NE


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