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MCMP 407 Organization of The Nervous Organization of The Nervous System System Central Nervous System Peripheral Nervous System Somatic Nervous System Autonomic Nervous System Sympathetic Parasympatheti c

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

MCMP 407

Organization of The Nervous SystemOrganization of The Nervous System

Central Nervous System Peripheral Nervous System

Somatic Nervous SystemAutonomic Nervous System

Sympathetic Parasympathetic

Page 2: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Action Potential

Na+

Ca 2+

ACH

Acetylcholinesterase

Na+

Sympathetic Ganglionic Synapse

Preganglionic neuron Postganglionic neuron

Nicotinic

Receptor

Page 3: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Action Potential

Ca 2+

Na+

NE

Sympathetic Organ Synapse

G

EffectorOrgan

Postganglionic neuron

Adrenergic

Receptor

Page 4: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Action Potential

Na+

Pharmacologic manipulation of the adrenergic system

Presynaptic neuron

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

DA

NE

(-)

Uptake 2

Uptake 1Na+, Cl-

NE

NENENE

NE

MAO

Page 5: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Synthesis of Synthesis of catecholaminescatecholamines

HO CH2 CH NH2

HO

HO CH

OH

CH2 NH

CH3

HO

HO CH

OH

CH2 NH2

COOH

HO CH2 CH NH2

COOH

HO

HO

HO CH2 CH2 NH2

TYROSINE

DOPA

DOPAMINE

NOREPINEPHRINE

EPINEPHRINE

tyrosine hydroxylase

aromatic L-amino acid decarboxylase

dopamine -hydroxylase

phenylethanolamine-N-methyltransferase

Page 6: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Metabolism of norepinephrineMetabolism of norepinephrine

Norepinephrine

3-Methoxy-4-hydroxymandelic acid

(Vanilylmandelic acid; VMA)

Monoamine Oxidase (MAO)HO

HO

NH2

OH

HO

HO

CHO

OH

HO

HO

CH2OH

OH

H3CO

HO

CH2OH

OH

H3CO

HO

CO2H

OH

3,4-Dihydroxyphenyl-

glycolaldehydeAldehyde

Reductase

Catechol O-Methyl-

transferase (COMT)3,4-Dihydroxyphenyl-

ethylene glycol

3-Methoxy-4-hydroxy-

phenylethylene glycol

1) Alcohol Dehydrogenase

2) Aldehyde Dehydrogenase

Page 7: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Metabolism of norepinephrineMetabolism of norepinephrine

Norepinephrine 3,4-Dihydroxymandelic Acid

3-Methoxy-4-hydroxymandelic acid

(Vanilylmandelic acid; VMA)Normetanephrine

HO

HO

NH2

OH

HO

HO

CO2H

OH

H3CO

HO

CO2H

OH

H3CO

HO

OH

NH2

COMT COMT

1) MAO

2) Aldehyde Dehydrogenase

1) MAO

2) Aldehyde Dehydrogenase

Page 8: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonistsDirect acting adrenergic receptor agonists

HO

HO CH

OH

CH2 NH

CH3

HO

HO CH

OH

CH2 NH2

HO

HO CH2 CH2 NH2Dopamine(Intropin)

Norepinephrine(Levophed)

Epinephrine(Adrenalin)

Page 9: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Receptors and signal transduction in the ANSReceptors and signal transduction in the ANS

Adrenergic Receptors

1A

1 2

1B 1D 2A 2B 2C 1 2 3

Page 10: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: 11 receptors receptors

Phenylephrine (Neosynephrine) Methoxamine (Vasoxyl) Oxymetazoline (Visine)

Phenylephrine

HO

CH CH2 NH CH3

OH

NH3

COOH

Gq

Phospho -lipase C

(+)

PIP2

IP3 Diacylglycerol

Increase Ca2+ Activate ProteinKinase C

Response

Page 11: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: 22 receptors receptors

Clonidine (Catapres) Methyldopa (Aldomet) Guanabenz (Wytensin) Guanfacine (Tenex) Tizanidine (Zanaflex)

Clonidine

NH3

COOH

GI

(-)

ATP cAMP

Reduce cAMP-DependentProtein Kinase Activity

Response

X(+)K+

Adenylate Cyclase

N

NH

HN

Cl

Cl

Page 12: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: receptors receptors

Non-selective Isoproterenol (Isuprel)

1-selective Dobutamine (Dobutrex) Dopamine (Intropin)

2-selective Terbutaline (Brethine, Bricanyl) Metaproterenol (Metaprel, Alupent) Albuterol (Proventil, Ventolin) Salmeterol (Serevent) Ritodrine (Yutopar)

Isoproterenol

HO

HO CH CH2 NH CH

CH3

CH3OH

Page 13: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: receptors receptors

GS

(+)

ATP cAMP

Increase cAMP -DependentProtein Kinase Activity

Response

NH3

COOH

Adenylate Cyclase

Page 14: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

HO

HO

Molecular actions of norepinephrineMolecular actions of norepinephrine

I

II

III IV

V

VIVII

Asp 113

Ser 204

Ser 207

Phe 290

OH

OH

H3N

OH

CO2

Page 15: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Selectivity of adrenergic receptor agonistsSelectivity of adrenergic receptor agonists

-10 -8 -6 -40

50

100

Log [drug]

1

Ad

ren

erg

icre

cep

tor

acti

va

tio

n

-10 -8 -6 -40

50

100

Log [drug]

1

Ad

rene

rgic

rec

epto

r ac

tiva

tion

-10 -8 -6 -40

50

100

Log [drug]

2

Ad

ren

erg

icre

cep

tor

acti

va

tio

n

Phenylephrine

Epinephrine

Norepinephrine

Isoproterenol

Page 16: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Cardiovascular effects of sympathomimeticsCardiovascular effects of sympathomimetics

100

50

PULSERATE(min)

180

120BLOOD

PRESSURE(mm Hg)

80

PERIPHERALRESISTANCE

0 15 0 15 0 15TIME(min)

Norepinephrine Epinephrine Isoproterenol

Page 17: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: Norepinephrine and EpinephrineNorepinephrine and Epinephrine

Potent and 1 receptor agonist Substrate for MAO and COMT Parenteral administration Used as a pressor Sodium bisulfite used in

preparations to prevent oxidation

l-Norepinephrine (Levophed)

HO

HO

NH2

OHH

Page 18: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: Norepinephrine and EpinephrineNorepinephrine and Epinephrine

Potent , 1, and 2 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)

HO

HO

NHCH3

OHH

Page 19: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: 1 receptor agonists1 receptor agonists

Potent 1 receptor agonist Substrate for MAO Administration: Parenteral, oral,

local Uses: Mydriasis without

cycloplegia, glaucoma, pressor, nasal decongestant

Phenylephrine (Neo-Synephrine)

HO NHCH3

OHH

Methoxamine (Vasoxyl)

NH2

OHH

H3CH

OCH3

H3CO Potent 1 receptor agonist Potent vasoconstrictor Parenteral administration Use: Pressor agent

Page 20: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: 1 receptor agonists: 2-aralkylimidazolines1 receptor agonists: 2-aralkylimidazolines

N

NH

XRR = substituted aromatic ring structure

X = methylene or amino

N

NH

XRN

NH

XR

H+

H HN

N

XR

H

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.

Page 21: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: 1 receptor agonists: 2-aralkylimidazolines1 receptor agonists: 2-aralkylimidazolines

N

NH

R

CH2

CH2

H3C

H3C

C(CH3)3

OH

R= R=

R=

Naphazoline (Privine) Tetrahydrozoline

(Visine)

Oxymetazoline (Afrin, Visine)

Partial agonists at 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

Page 22: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: 2 receptor agonists2 receptor agonists

(Phenylimino)imidazolidine Selective 2 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 2 receptors in the nucleus of the solitary tract (cardiovascular center)

Administration: Oral, parenteral, transdermal

Uses: Hypertension, opiate withdrawal

Clonidine (Catapres)

N

NH

HN

Cl

Cl

Page 23: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

2-Adrenergic Agonists Reduce Blood Pressure by 2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the BrainReducing Sympathetic Output from the Brain

Brain

Brain Stem (Cardiovascular Control Center)

Kidney

Heart

Y

Sympathetic ganglion

1 Receptors

2 Receptors

Y

1 ReceptorsY1 Receptors

Page 24: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

2-Adrenergic Agonists Reduce Blood Pressure by 2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the BrainReducing Sympathetic Output from the Brain

Brain

Brain Stem (Cardiovascular Control Center)

Kidney

Heart

Y

Sympathetic ganglion

1 Receptors

2 Receptors

Y

1 Receptors

Y1 Receptors

Decreased sympathetic tone• Decr. HR• Decr. Contractility• Decr. Renin release• Decr. Vasoconstriction

Page 25: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: 2 receptor agonists2 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)

CH

Cl

Cl

N

NH

NH

NH2

Guanfacine (Tenex)

CH2

Cl

Cl

CO

NH

NH2

NH

Page 26: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic Direct acting adrenergic receptor agonists:receptor agonists: 2 receptor agonists2 receptor agonists

Methyldopa (Aldomet) A prodrug metabolized to active

2 receptor agonist, (1R, 2S)--methylnorepinephrine

Act at CNS 2 receptors to decrease sympathetic outflow

Water soluble, ester hydrochloride salt Methyldopate is used for parenteral solutions

Administration: Methyldopa, oral; Methyldopate; parenteral

Uses: Hypertension

HO

HO

NH3Cl

H3CCO2Et

HO

HO

NH2

H3CCO2H

HO

HO

NH2

H3CH

HO

HO

NH2

H3CH

OHH

Methyldopate

Methyldopa

-Methyldopamine

(1R, 2S)--methylnorepinephrine

Esterases

L-Aromatic AminoAcid Decarboxylase

Dopamine-Hydroxylase

Page 27: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Clinical pharmacology of Clinical pharmacology of 2 receptor agonists2 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

Page 28: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: receptor agonists receptor agonists

Non-selective 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)

HO NHCH(CH3)2

OHH

HO

Page 29: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: receptor agonists receptor agonists

Resorcinol derivatives Selective 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)

HOHN

OHH

OH

R

R= CH(CH3)2

R= C(CH3)3Terbutaline (Bricanyl, Brethine)

Page 30: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: receptor agonists receptor agonists

Albuterol (Ventolin, Proventil)

Salmeterol (Serevent)

HN

OHH

CH2OH

R

R= CH2(CH3)5O(CH2)4Ph

R= C(CH3)3

HO

Meta hydroxymethyl derivatives Selective 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

Page 31: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: Long acting Long acting receptor agonists receptor agonists

Selective receptor agonists Bronchodilation Not metabolized by MAO or COMT Onset of action:

Salmeterol 10-20 minFormoterol < 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

H HN

R

CH2OH

Salmeterol (Serevent)R= CH2(CH3)5O(CH2)4Ph

OH

HO

H HN

NH

OH

HO

OHC

CH3OCH3

Formoterol (Foradil)

Page 32: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: receptor agonists receptor agonists

Ritodrine (Yutopar)

Selective receptor agonists

Administration: Oral, parenteral

Uses: Tocolytic

HO

OHHN

CH3OH

Page 33: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Direct acting adrenergic receptor agonists:Direct acting adrenergic receptor agonists: receptor agonists receptor agonists

Dobutamine (Dobutrex)

Dopamine derivative Available as a racemic mixture (+)-enantiomer: potent 1

receptor agonist (-)-enantiomer: potent 1

receptor agonist, potency for receptors reduced 10X

Net effect is positive inotropic effect on heart with little chronotropic effect

HO

HNHO

CH3

OH

Metabolized by COMT and conjugation, not sensitive to MAO

Short half-life (~2 min) Administered: Parenteral Use: Acute heart failure,

shock

Page 34: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Action Potential

Na+

Indirect-acting sympathomimetics

Presynaptic neuron

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

DA

NE

Uptake 1Na+, Cl-

NE

NENENE

NE

MAO

2

1

3

Page 35: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407 Indirect-acting sympathomimetics:Indirect-acting sympathomimetics:

Amphetamine, pseudoephedrine, ephedrine, phenylpropanolamine, Amphetamine, pseudoephedrine, ephedrine, phenylpropanolamine, tyraminetyramine

Promote release of NE via reverse action of plasma membrane transporter

Clinical uses: Amphetamines: ADHD,

narcolepsy, anorexiant Others: Nasal decongestants

CH2 CH NH2

CH3

Amphetamine

Extracellular

Intracellular

AMPH

NE

NET

Page 36: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

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

NHCH3

OHH

H3CH

NHCH3

HHO

H3CH

D-(-)-Ephedrine

L-(+)-Pseudoephedrine

S

SS

R

Alkaloid 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

Page 37: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

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

D-(-)-Ephedrine

erythro

L-(+)-Pseudoephedrine

threo

H OH

H NHCH3

CH3

HO H

H NHCH3

CH3

Page 38: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Action Potential

Na+

Indirect-acting sympathomimetics: Transporter blockersCocaine Antidepressants

H+

Effector organ

Ca2+

NE

Uptake 1Na+, Cl-

NE

NENENE

NE

2

NENE

Desipramine

Venlafaxine

Page 39: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Action Potential

Na+

Indirect-acting sympathomimetics:

Cocaine Antidepressants

H+

Effector organ

Ca2+

NE

NE

NENENE

2

NENE

Desipramine

Venlafaxine

Cocaine

NENE

NE

NENE

Page 40: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Metabolism of norepinephrineMetabolism of norepinephrine

Norepinephrine

3-Methoxy-4-hydroxymandelic acid

(Vanilylmandelic acid; VMA)

Monoamine Oxidase (MAO)HO

HO

NH2

OH

HO

HO

CHO

OH

HO

HO

CH2OH

OH

H3CO

HO

CH2OH

OH

H3CO

HO

CO2H

OH

3,4-Dihydroxyphenyl-

glycolaldehydeAldehyde

Reductase

Catechol O-Methyl-

transferase (COMT)3,4-Dihydroxyphenyl-

ethylene glycol

3-Methoxy-4-hydroxy-

phenylethylene glycol

1) Alcohol Dehydrogenase

2) Aldehyde Dehydrogenase

Page 41: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Action Potential

Na+

Indirect-acting sympathomimetics: MAO Inhibitors

H+

Effector organ

Ca2+

NE

Na+, Cl-

NE

NENENE

NE

MAO

2

3

Phenelzine

Selegiline

Page 42: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Action Potential

Na+

Indirect-acting sympathomimetics: MAO Inhibitors

H+

Effector organ

Ca2+

NE

Na+, Cl-

NE

NENENE

NE

MAO

2

3

Phenelzine

Selegiline

NE

NE

NE

NE

NENE

NE

NENE

NENE

NE

Page 43: MCMP 407 Organization of The Nervous System Central Nervous SystemPeripheral Nervous System Somatic Nervous SystemAutonomic Nervous System SympatheticParasympathetic

MCMP 407

Indirect-acting sympathomimetics: MAO Inhibitors

H+

Effector organ

NE

NE

NENE

NE

NE

MAO3

Phenelzine

Selegiline

NE

NE

NE

NE

NENE

NE

NENE

NENE

NE

Co-admininstration with otherindirect-acting drugs can lead to hypertensive crisis

Amphetamine,

TyramineNE

NENE

NENE

NE NE