MCMP 407

Organization of The Nervous System

Central Nervous System Peripheral Nervous System

Autonomic Nervous System

Somatic Nervous System

Sympathetic

Parasympathetic

MCMP 407
Sympathetic Ganglionic Synapse
Acetylcholinesterase

Na+

Action Potential

EFE

ACH

Nicotinic Receptor

Na+
Preganglionic neuron

Postganglionic neuron

MCMP 407
Sympathetic Organ Synapse

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Na+

Effector Organ

Action Potential

NE
Adrenergic Receptor

Postganglionic neuron

MCMP 407
Pharmacologic manipulation of the adrenergic system
Presynaptic neuron Na+
Dopamine Tyrosine Action Potential
H+

Tyrosine

DA NE

NE

E

Uptake 1 (-)
NE NE NE NE

Uptake 2 E F

Effector organ

MCMP 407
Synthesis of catecholamines

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HO

CH2

CH COOH

NH2 TYROSINE

tyrosine hydroxylase HO HO CH2 CH COOH aromatic L-amino acid decarboxylase NH2 DOPA

HO HO CH2

CH2

NH2 DOPAMINE

dopamine F -hydroxylase HO HO CH OH phenylethanolamineN-methyltransferase CH2 NH2 NOREPINEPHRINE

HO HO CH OH

CH2

NH CH3

EPINEPHRINE

MCMP 407
Metabolism of norepinephrine
OH HO NH2 OH

Monoamine Oxidase (MAO)

HO

CHO

HO

Norepinephrine

HO

Aldehyde Reductase
OH HO CH2OH

3,4-Dihydroxyphenylglycolaldehyde

Catechol O-Methyltransferase (COMT)

OH H3CO CH2OH

HO

3,4-Dihydroxyphenylethylene glycol
OH H3CO

1) Alcohol Dehydrogenase

CO2H

HO

3-Methoxy-4-hydroxyphenylethylene glycol

2) Aldehyde Dehydrogenase HO 3-Methoxy-4-hydroxymandelic acid (Vanilylmandelic acid; VMA)

MCMP 407
Metabolism of norepinephrine
OH HO NH2 OH HO CO2H

1) MAO 2) Aldehyde Dehydrogenase

HO

HO

Norepinephrine

3,4-Dihydroxymandelic Acid

COMT

COMT

OH H3CO NH2

1) MAO 2) Aldehyde Dehydrogenase H3CO

HO

OH CO2H

HO

Normetanephrine

3-Methoxy-4-hydroxymandelic acid (Vanilylmandelic acid; VMA)

MCMP 407
Direct acting adrenergic receptor agonists
HO HO CH2 CH2 NH2

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Dopamine (Intropin)

HO HO CH OH CH2 NH2

Norepinephrine (Levophed)

HO HO CH OH CH2 NH CH3

Epinephrine (Adrenalin)

MCMP 407
Receptors and signal transduction in the ANS
Adrenergic Receptors

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E1

E2

E1A

E1B

E1D

E2A

E2B

E2C

F1

F2

F3

MCMP 407
Direct acting adrenergic receptor agonists: E1 receptors NH 3
  

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

Phospho lipase C

(+)

Gq
PIP 2

HO
COOH IP 3 Increase Ca 2+ Diacylglycerol Activate Protein Kinase C

CH OH

CH2 NH

CH3

Phenylephrine
Response

MCMP 407
Direct acting adrenergic receptor agonists: E2 receptors
    

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

NH3

(-)

Adenylate Cyclase

Cl H N Cl Clonidine N N H

GI

K+

(+) ATP COOH

X
cAMP Reduce cAMP-Dependent Protein Kinase Activity

Response

MCMP 407
Direct acting adrenergic receptor agonists: F receptors
Non-selective  Isoproterenol (Isuprel) F1-selective  Dobutamine (Dobutrex)  Dopamine (Intropin)
HO HO CH3 CH OH CH2 NH CH CH3

Isoproterenol

F2-selective  Terbutaline (Brethine, Bricanyl)  Metaproterenol (Metaprel, Alupent)  Albuterol (Proventil, Ventolin)  Salmeterol (Serevent)  Ritodrine (Yutopar)

MCMP 407
Direct acting adrenergic receptor agonists: F receptors
NH3

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(+)

Adenylate Cyclase

GS

ATP COOH

cAMP

Increase cAMP-Dependent Protein Kinase Activity Response

MCMP 407
Molecular actions of norepinephrine

VII I

Phe 290

VI
OH HO Ser 207

OH

OH
HO

V
Ser 204

II

H3N CO2

III

Asp 113

IV

MCMP 407
Selectivity of adrenergic receptor agonists
F 1 Adrenergic receptor activation 100

E 1 Adrenergic receptor activation

100

50

50

0 -10 -8 -6 -4 Log [drug]

-10 -8 -6 -4 F 2 Adrenergic receptor activation

0 Log [drug]

100

50

Phenylephrine Epinephrine Norepinephrine Isoproterenol

0 -10 -8 -6 -4 Log [drug]

MCMP 407
Cardiovascular effects of sympathomimetics
Norepinephrine PULSE 100 RATE (min) 50 180 BLOOD PRESSURE 120 (mm Hg) 80 Epinephrine

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Isoproterenol

PERIPHERAL RESISTANCE

15

0 TIME (min)

15

15

MCMP 407
Direct acting adrenergic receptor agonists:
Norepinephrine and Epinephrine

H HO

OH NH2

 

HO
l-Norepinephrine (Levophed)

 

Potent E and F1 receptor agonist Substrate for MAO and COMT Parenteral administration Used as a pressor Sodium bisulfite used in preparations to prevent oxidation

MCMP 407
Direct acting adrenergic receptor agonists:
Norepinephrine and Epinephrine


H HO

OH NHCH3

  

HO
Epinephrine (Adrenalin)


Potent E, F1, and F2 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

MCMP 407
Direct acting adrenergic receptor agonists:
E1 receptor agonists

H HO

OH NHCH3

  

Phenylephrine (Neo-Synephrine)

Potent E1 receptor agonist Substrate for MAO Administration: Parenteral, oral, local Uses: Mydriasis without cycloplegia, glaucoma, pressor, nasal decongestant

H H3CO

OH NH2 H 3C OCH3 H
   

Methoxamine (Vasoxyl)

Potent E1 receptor agonist Potent vasoconstrictor Parenteral administration Use: Pressor agent

MCMP 407
Direct acting adrenergic receptor agonists:
E1 receptor agonists: 2-aralkylimidazolines 2-

N R X N H
H+ N R X N H R

R = substituted aromatic ring structure X = methylene or amino

H N X N H R X

H N N 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.

MCMP 407
Direct acting adrenergic receptor agonists:
E1 receptor agonists: 2-aralkylimidazolines 2N R N H R= CH2

Naphazoline (Privine)
H3C R= CH2 H3C

 Partial agonists at E receptors  Administered locally/topically to promote vasoconstriction R=  Basic nature of imidazoline ring causes compounds to exist in ionized form at physiologic pH Tetrahydrozoline  Tachyphylaxis/Desensitization (Visine)  Uses: Nasal and ophthalmic decongestants C(CH3)3
OH

Oxymetazoline (Afrin, Visine)

MCMP 407
Direct acting adrenergic receptor agonists:
E2 receptor agonists  (Phenylimino)imidazolidine  Selective E2 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 E2 receptors in the nucleus of the solitary tract (cardiovascular center)  Administration: Oral, parenteral, transdermal  Uses: Hypertension, opiate withdrawal

Cl H N Cl N N H

Clonidine (Catapres)

MCMP 407
E2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain
Brain Brain Stem (Cardiovascular Control Center) E Receptors
2

Sympathetic ganglion

F1 Receptors Heart F1 Receptors Kidney

E1 Receptors

MCMP 407
E2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain
Brain Brain Stem (Cardiovascular Control Center) E Receptors
2

Sympathetic ganglion

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

F1 Receptors Heart F1 Receptors Kidney

E1 Receptors

MCMP 407
Direct acting adrenergic receptor agonists:
E2 receptor agonists
Cl NH CH Cl N NH NH2

Guanabenz (Wytensin)
NH2 NH CH2 C O Cl NH

Cl

 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

Guanfacine (Tenex)

MCMP 407
Direct acting adrenergic receptor agonists:
E2 receptor agonists

HO H3C HO

NH3 CO2Et

Cl

Methyldopate

Esterases
NH2 H3C CO2H Methyldopa

 Methyldopa (Aldomet) HO  A prodrug metabolized to active E2 receptor agonist, (1R, 2S)-E- HO methylnorepinephrine  Act at CNS E2 receptors to HO decrease sympathetic outflow  Water soluble, ester hydrochloride salt Methyldopate is used for HO parenteral solutions  Administration: Methyldopa, oral; Methyldopate; parenteral HO  Uses: Hypertension
HO

L-Aromatic Amino Acid Decarboxylase

NH2 H3C H

Dopamine F-Hydroxylase
H OH NH2

E-Methyldopamine

H H3C (1R, 2S)-E-methylnorepinephrine

MCMP 407
Clinical pharmacology of E2 receptor agonists Other Uses:
Apraclonidine (Iopidine): Glaucoma Tizanidine (Zanaflex): Muscle spasticity

Adverse effects of E2-adrenergic receptor agonists: Sedation, Na+ and water retention, dry mouth, withdrawal syndrome

MCMP 407
Direct acting adrenergic receptor agonists:
F receptor agonists    OH NHCH(CH3)2 Non-selective F 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

H HO

HO

Isoproterenol (Isuprel)

MCMP 407
Direct acting adrenergic receptor agonists:
F receptor agonists
H HO OH H N

   

 Metaproterenol (Alupent, Metaprel) 

OH R= CH(CH3)2


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

Resorcinol derivatives Selective F 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)

MCMP 407
Direct acting adrenergic receptor agonists:
F receptor agonists
H OH H N

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HO CH2OH

Albuterol (Ventolin, Proventil) C(CH3)3 R= Salmeterol (Serevent) R= CH2(CH3)5O(CH2)4Ph

Meta hydroxymethyl derivatives Selective F 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

MCMP 407
Direct acting adrenergic receptor agonists:
Long acting F receptor agonists
H OH H N

HO CH2OH Salmeterol (Serevent) R= CH2(CH3)5O(CH2)4Ph H OH H N CH3 NH Formoterol (Foradil)

   

 
OCH3

HO OHC

Selective F 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 (metereddose inhaler and powder) Uses: Long-term Asthma, COPD Not recommended for acute treatment of asthma symptoms

MCMP 407
Direct acting adrenergic receptor agonists:
F receptor agonists

OH H N CH3

HO

OH

Ritodrine (Yutopar)

 Selective F receptor agonists  Administration: Oral, parenteral  Uses: Tocolytic

MCMP 407
Direct acting adrenergic receptor agonists:
F receptor agonists
HO H N CH3 OH

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HO

Dobutamine (Dobutrex)

 Dopamine derivative  Available as a racemic mixture  (+)-enantiomer: potent F1 receptor agonist  (-)-enantiomer: potent E1 receptor agonist, potency for F 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

MCMP 407
Indirect-acting sympathomimetics
Presynaptic neuron Na+
Dopamine Tyrosine Action Potential
H+

Tyrosine

DA NE

3
Uptake 1

NE

1
NE NE NE NE

E

Effector organ

MCMP 407
IndirectIndirect-acting sympathomimetics:

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Amphetamine, pseudoephedrine, ephedrine, phenylpropanolamine, tyramine Promote release of NE via Extracellular reverse action of plasma membrane transporter AMPH Clinical uses:  Amphetamines: ADHD, narcolepsy, anorexiant  Others: Nasal decongestants

NET

CH2 CH CH3

NH2

NE
Intracellular

Amphetamine

MCMP 407
IndirectIndirect-acting sympathomimetics: D-(-)-Ephedrine vs. L-(+)-Pseudoephedrine
H
R

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OH
S

NHCH3 H

H3 C

D-(-)-Ephedrine

HO
S

H
S

NHCH3 H

H3 C

L-(+)-Pseudoephedrine

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

MCMP 407
IndirectIndirect-acting sympathomimetics: D-(-)-Ephedrine vs. L-(+)-Pseudoephedrine
CH3 H H NHCH3 OH H HO CH3 NHCH3 H

D-(-)-Ephedrine erythro

L-(+)-Pseudoephedrine threo

MCMP 407
Indirect-acting sympathomimetics: Transporter blockers
Cocaine Antidepressants
Desipramine Venlafaxine

Na+

Action Potential
H+

NE NE

NE

NE

Uptake 1
NE NE NE NE

E

Effector organ

MCMP 407
Indirect-acting sympathomimetics: Cocaine Antidepressants
Desipramine Venlafaxine

Na+

Action Potential
H+

NE NE

NE Cocaine

NE NE NE NE NE NE NE NE NE

E

Effector organ

MCMP 407
Metabolism of norepinephrine
OH HO NH2 OH

Monoamine Oxidase (MAO)

HO

CHO

HO

Norepinephrine

HO

Aldehyde Reductase
OH HO CH2OH

3,4-Dihydroxyphenylglycolaldehyde

Catechol O-Methyltransferase (COMT)

OH H3CO CH2OH

HO

3,4-Dihydroxyphenylethylene glycol
OH H3CO

1) Alcohol Dehydrogenase

CO2H

HO

3-Methoxy-4-hydroxyphenylethylene glycol

2) Aldehyde Dehydrogenase HO 3-Methoxy-4-hydroxymandelic acid (Vanilylmandelic acid; VMA)

MCMP 407
Indirect-acting sympathomimetics: MAO Inhibitors
Phenelzine Selegiline Na+

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Action Potential
H+

3
NE

NE

NE NE NE NE

E

Effector organ

MCMP 407
Indirect-acting sympathomimetics: MAO Inhibitors
Phenelzine Selegiline
NE NE Action Potential
H+

Na+

NE NE NE NE NE

3
NE

NE NE NE

NE

NE

NE

NE NE

NE

2
NE

E

Effector organ

MCMP 407
Indirect-acting sympathomimetics: MAO Inhibitors
Co-admininstration with other indirect-acting drugs can lead to hypertensive crisis

Phenelzine Selegiline
NE NE NE
H+

3
NE

NE NE

NE NE

NE NE NE

NE NE NE

NE NE

NE

NE

NE

NE NE

NE

NE

NE

NE

E

Effector organ