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

Ca 2+ Acetylcholinesterase

Na+

ACH

Action Potential
Nicotinic
Receptor
Na +

Preganglionic neuron Postganglionic neuron

 MCMP 407

Sympathetic Organ Synapse

Ca 2+
Effector
Na+ Organ

NE
Action Potential

Adrenergic
Receptor

Postganglionic neuron
 MCMP 407
Pharmacologic manipulation of the adrenergic system
Na+
Presynaptic neuron
Tyrosine
Na+
Dopamine
Tyrosine

Action Potential
H+ O
DA MA

NE NE
Ca2+
Uptake 1
(-) Na+, Cl-
NE
NE NE NE
Uptake 2

Effector organ
 MCMP 407 HO CH2 CH NH2 TYROSINE
COOH

tyrosine hydroxylase
Synthesis of HO

catecholamines HO CH2 CH NH2 DOPA

COOH

aromatic L-amino acid decarboxylase

HO

HO CH2 CH2 NH2 DOPAMINE

dopamine -hydroxylase
HO

HO CH CH2 NH2 NOREPINEPHRINE

OH

phenylethanolamine-
HO N-methyltransferase

HO CH CH2 NH EPINEPHRINE
OH CH3
 MCMP 407
Metabolism of norepinephrine
OH OH
HO NH2 HO
Monoamine Oxidase (MAO) CHO

HO HO
Norepinephrine 3,4-Dihydroxyphenyl-
Aldehyde
glycolaldehyde
Reductase

OH
HO
CH2OH

Catechol O-Methyl- 3,4-Dihydroxyphenyl-

HO
transferase (COMT) ethylene glycol

OH OH
H3CO H3CO
CH2OH CO2H
1) Alcohol Dehydrogenase
HO 2) Aldehyde Dehydrogenase HO
3-Methoxy-4-hydroxy- 3-Methoxy-4-hydroxymandelic acid
phenylethylene glycol (Vanilylmandelic acid; VMA)
 MCMP 407
Metabolism of norepinephrine
OH OH
1) MAO
HO NH2 HO
2) Aldehyde Dehydrogenase CO2H

HO HO
Norepinephrine 3,4-Dihydroxymandelic Acid

COMT COMT

OH OH
1) MAO
H3CO NH2 2) Aldehyde Dehydrogenase H3CO CO2H

HO HO
3-Methoxy-4-hydroxymandelic acid
Normetanephrine
(Vanilylmandelic acid; VMA)
 MCMP 407

Direct acting adrenergic receptor agonists

HO

HO CH2 CH2 NH2 Dopamine

(Intropin)

HO

HO CH CH2 NH2 Norepinephrine

OH
(Levophed)

HO

HO CH CH2 NH Epinephrine
(Adrenalin)
OH CH3
 MCMP 407

Receptors and signal transduction in the ANS

Adrenergic Receptors

1 2

1A 1B 1D 2A 2B 2C 1 2 3
 MCMP 407
Direct acting adrenergic receptor agonists:
1 receptors NH 3

Phospho -
lipase C
Phenylephrine (Neosynephrine)
Methoxamine (Vasoxyl)
Oxymetazoline (Visine)
(+)
Gq

PIP 2

HO
COOH IP 3 Diacylglycerol

CH CH2 NH CH3 2+
Increase Ca Activate Protein
Kinase C
OH

Phenylephrine
Response
 MCMP 407
Direct acting adrenergic receptor agonists:
2 receptors
Clonidine (Catapres) NH3
Methyldopa (Aldomet)
Guanabenz (Wytensin)
Guanfacine (Tenex)
Tizanidine (Zanaflex)

(-) Adenylate Cyclase

GI
Cl
N K+ (+) X
H
N ATP cAMP
COOH
N
H Reduce cAMP-Dependent
Cl Protein Kinase Activity
Clonidine
Response
 MCMP 407
Direct acting adrenergic receptor agonists:
receptors

Non-selective HO
Isoproterenol (Isuprel) CH3
HO CH CH2 NH CH
1-selective CH3
OH
Dobutamine (Dobutrex)
Dopamine (Intropin) Isoproterenol
2-selective
Terbutaline (Brethine, Bricanyl)
Metaproterenol (Metaprel, Alupent)
Albuterol (Proventil, Ventolin)
Salmeterol (Serevent)
Ritodrine (Yutopar)
MCMP 407
Direct acting adrenergic receptor agonists:
receptors
NH3

(+) Adenylate Cyclase

GS

ATP cAMP
COOH

Increase cAMP-Dependent
Protein Kinase Activity

Response
MCMP 407
Molecular actions of norepinephrine

Phe 290 VI
VII
OH Ser 207
I HO
OH OH V
HO
Ser 204
II H3 N

CO2

III Asp 113 IV

 MCMP 407
Selectivity of adrenergic receptor agonists
100

receptor activation
1 Adrenergic
100 50
receptor activation
1 Adrenergic

50 0
-10 -8 -6 -4
Log [drug]
0 100

receptor activation
-10 -8 -6 -4
Log [drug] 2 Adrenergic

50
Phenylephrine
Epinephrine
Norepinephrine 0
Isoproterenol -10 -8 -6 -4
Log [drug]
 MCMP 407
Cardiovascular effects of sympathomimetics

Norepinephrine Epinephrine Isoproterenol

100
PULSE
RATE
(min) 50
180
BLOOD
PRESSURE 120
(mm Hg)
80

PERIPHERAL
RESISTANCE

0 15 0 15 0 15
TIME
(min)
 MCMP 407
Direct acting adrenergic receptor agonists:
Norepinephrine and Epinephrine

H OH Potent and 1 receptor agonist

HO NH2 Substrate for MAO and COMT
Parenteral administration
Used as a pressor
Sodium bisulfite used in
HO preparations to prevent oxidation

l-Norepinephrine (Levophed)
 MCMP 407
Direct acting adrenergic receptor agonists:
Norepinephrine and Epinephrine

Potent , 1, and 2 receptor agonist

Substrate for MAO and COMT
Parenteral administration
H OH Sodium bisulfite used in preparations to
prevent oxidation
HO NHCH3 Available as many salts: hydrochloride,
nitrate, bitartrate
Uses: Anaphylaxis, glaucoma, in combination
with local anesthetics
HO
Epinephrine (Adrenalin)
 MCMP 407
Direct acting adrenergic receptor agonists:
1 receptor agonists

H OH Potent 1 receptor agonist

HO NHCH3 Substrate for MAO
Administration: Parenteral, oral,
local
Uses: Mydriasis without
Phenylephrine (Neo-Synephrine) cycloplegia, glaucoma, pressor,
nasal decongestant

H OH
H3CO NH2 Potent 1 receptor agonist
H Potent vasoconstrictor
H 3C
Parenteral administration
OCH3
Use: Pressor agent
Methoxamine (Vasoxyl)
 MCMP 407
Direct acting adrenergic receptor agonists:
1 receptor agonists: 2-aralkylimidazolines

N R = substituted aromatic ring structure

R X
X = methylene or amino
N
H

H+
H H
N N N
R X R X R X
N N N
H H 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:
1 receptor agonists: 2-aralkylimidazolines
N
R
N Partial agonists at receptors
H
Administered locally/topically
R= CH2 R= to promote vasoconstriction
Basic nature of imidazoline
ring causes compounds to
exist in ionized form at
Naphazoline (Privine) Tetrahydrozoline physiologic pH
(Visine) Tachyphylaxis/Desensitization
H3 C
Uses: Nasal and ophthalmic
R= CH2 C(CH3)3 decongestants

H3 C OH
Oxymetazoline (Afrin, Visine)
MCMP 407
Direct acting adrenergic receptor agonists:
2 receptor agonists
(Phenylimino)imidazolidine
Selective 2 receptor agonist
The basicity of the guanidine
Cl
group (pKa = 13.6) is decreased
N (to pKa = 8.0) because of the
H
N attachment to the dichlorophenyl
N ring
H Clinical effect linked to activation
Cl
of 2 receptors in the nucleus of
Clonidine (Catapres)
the solitary tract (cardiovascular
center)
Administration: Oral, parenteral,
transdermal
Uses: Hypertension, opiate
withdrawal
 MCMP 407
2-Adrenergic Agonists Reduce Blood Pressure by
Reducing Sympathetic Output from the Brain

Brain

Brain Stem (Cardiovascular Control

Center) Receptors
2 Sympathetic
ganglion

1 Receptors

Y
Heart Y
1 Receptors

Kidney

1 Receptors
Y
 MCMP 407
2-Adrenergic Agonists Reduce Blood Pressure by
Reducing Sympathetic Output from the Brain

Brain

Brain Stem (Cardiovascular Control

Center) Receptors
2 Sympathetic
ganglion

1 Receptors
Decreased sympathetic tone

Y
Decr. HR Heart Y
Decr. Contractility 1 Receptors
Decr. Renin release
Kidney
Decr. Vasoconstriction

1 Receptors
Y
MCMP 407
Direct acting adrenergic receptor agonists:
2 receptor agonists

Cl NH2
NH Open-ring imidazolidines
CH N Two atom bridge to the guanidine
NH
group decreases the pKa so that
the drug is mostly non-ionized at
Cl
Guanabenz (Wytensin) physiological pH
Guanabenz has the shortest t-1/2
at ~ 6 hours. Half-life of clonidine
Cl NH2 and guanfacine is 12-16 hours
NH Administration: oral
CH2 C NH Uses: Hypertension
O
Cl
Guanfacine (Tenex)
 MCMP 407 HO NH3
Cl
Direct acting adrenergic H3 C
CO2Et
receptor agonists: HO
Methyldopate
2 receptor agonists Esterases

Methyldopa (Aldomet) HO NH2

A prodrug metabolized to active CO2H Methyldopa
H3C
2 receptor agonist, (1R, 2S)-- HO
methylnorepinephrine L-Aromatic Amino
Acid Decarboxylase
Act at CNS 2 receptors to
decrease sympathetic outflow HO NH2

Water soluble, ester hydrochloride H

H3C
salt Methyldopate is used for HO -Methyldopamine
Dopamine
parenteral solutions -Hydroxylase
Administration: Methyldopa, oral; OH
H
Methyldopate; parenteral HO NH2
Uses: Hypertension H
H3C
HO (1R, 2S)--methylnorepinephrine
 MCMP 407
Clinical pharmacology of 2 receptor agonists

Other Uses:
Apraclonidine (Iopidine): Glaucoma
Tizanidine (Zanaflex): Muscle spasticity

Adverse effects of 2-adrenergic receptor agonists:

Sedation, Na+ and water retention, dry mouth, withdrawal syndrome
 MCMP 407
Direct acting adrenergic receptor agonists:
receptor agonists
Non-selective receptor agonist
Bronchodilation
Increased cardiac output
H OH
HO NHCH(CH3)2 Metabolized by conjugation
reactions (Phase II) and by COMT
Not sensitive to MAO
HO Administration: Oral, parenteral,
Isoproterenol (Isuprel) local (inhaled)
Uses: Asthma, Chronic
Obstructive Pulmonary Disease
(COPD), Cardiostimulant
 MCMP 407
Direct acting adrenergic receptor agonists:
receptor agonists
Resorcinol derivatives
H OH H
HO N Selective receptor agonists
R Bronchodilation
Cardiac effects observed only at
high doses
OH Not metabolized by MAO or COMT
Metaproterenol (Alupent, Metaprel) Longer duration of action than
R= CH(CH3)2 isoproterenol
Administration: Oral, parenteral,
Terbutaline (Bricanyl, Brethine) local (inhaled)
R= C(CH3)3 Uses: Asthma, COPD; Terbutaline
used as tocolytic (prevent
premature labor)
 MCMP 407
Direct acting adrenergic receptor agonists:
receptor agonists

H OH H
Meta hydroxymethyl derivatives
N Selective receptor agonists
R Bronchodilation
Cardiac effects observed only at
HO
high doses
CH2OH Not metabolized by MAO or COMT
Longer duration of action than
Albuterol (Ventolin, Proventil) isoproterenol
R= C(CH3)3
Administration: Oral, local
(inhaled); Salmeterol only inhaled
Salmeterol (Serevent)
Uses: Asthma, COPD
R= CH2(CH3)5O(CH2)4Ph
 MCMP 407
Direct acting adrenergic receptor agonists:
Long acting receptor agonists

H OH H Selective receptor agonists

N Bronchodilation
R
Not metabolized by MAO or COMT
HO
Onset of action:
CH2OH
Salmeterol 10-20 min
Salmeterol (Serevent)
R= CH2(CH3)5O(CH2)4Ph Formoterol < 5 min
Longer duration of action
H OH H
N Administration: inhaled (metered-
dose inhaler and powder)
CH3
HO OCH3 Uses: Long-term Asthma, COPD
NH Not recommended for acute
OHC
Formoterol (Foradil) treatment of asthma symptoms
 MCMP 407
Direct acting adrenergic receptor agonists:
receptor agonists

OH
H Selective receptor
N
agonists
CH3
Administration: Oral,
HO OH parenteral
Ritodrine (Yutopar) Uses: Tocolytic
 MCMP 407
Direct acting adrenergic receptor agonists:
receptor agonists OH
H
HO N

CH3
HO
Dobutamine (Dobutrex)
Dopamine derivative Metabolized by COMT and
Available as a racemic mixture conjugation, not sensitive to
(+)-enantiomer: potent 1 MAO
receptor agonist Short half-life (~2 min)
(-)-enantiomer: potent 1 Administered: Parenteral
receptor agonist, potency for Use: Acute heart failure,
receptors reduced 10X shock
Net effect is positive inotropic
effect on heart with little
chronotropic effect
 MCMP 407
Indirect-acting sympathomimetics
Na+
Presynaptic neuron
Tyrosine
Na+
Dopamine
Tyrosine

Action Potential
H+
DA 3 MA
O

NE NE
Ca2+
Uptake 1
1 Na+, Cl-
NE
NE NE
2
NE

Effector organ
 MCMP 407
Indirect-acting sympathomimetics:
Amphetamine, pseudoephedrine, ephedrine, phenylpropanolamine,
tyramine
Promote release of NE via
Extracellular
reverse action of plasma
membrane transporter
Clinical uses: AMPH
Amphetamines: ADHD,
narcolepsy, anorexiant
Others: Nasal decongestants
NET

CH2 CH NH2
CH3 NE

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

H OH Alkaloid obtained from the

NHCH3 stems of Ephedra. Also found
S
R in mahuang.
H D-(-)-Ephedrine has desired
H3 C
(R)-configuration at -OH and
D-(-)-Ephedrine
(S)-configuration at the
carbon for direct agonist
activity at adrenergic
HO H receptors
S NHCH3 L-(+)-Pseudoephedrine is the
S
(S,S)-diastereoisomer; (S)-
H configuration of -OH reduces
H3 C
agonist activity-major
L-(+)-Pseudoephedrine mechanism is via reversal of
the transporter
 MCMP 407
Indirect-acting sympathomimetics:
D-(-)-Ephedrine vs. L-(+)-Pseudoephedrine

CH3 CH3
H NHCH3 H NHCH3
H OH HO H

D-(-)-Ephedrine L-(+)-Pseudoephedrine
erythro threo
 MCMP 407
Indirect-acting sympathomimetics: Transporter blockers
Cocaine
Antidepressants
Desipramine
Na+
Venlafaxine

Action Potential
H+
NE
NE
NE NE
Ca2+
Uptake 1
Na+, Cl-
NE
NE NE
2
NE

Effector organ
 MCMP 407
Indirect-acting sympathomimetics:
Cocaine
Antidepressants
Desipramine Na+
Venlafaxine

Action Potential
H+
NE
NE
NE
Ca2+
Cocaine
NE
NE
NE NE NE
2
NE NE NE
NE

Effector organ
 MCMP 407
Metabolism of norepinephrine
OH OH
HO NH2 HO
Monoamine Oxidase (MAO) CHO

HO HO
Norepinephrine 3,4-Dihydroxyphenyl-
Aldehyde
glycolaldehyde
Reductase

OH
HO
CH2OH

Catechol O-Methyl- 3,4-Dihydroxyphenyl-

HO
transferase (COMT) ethylene glycol

OH OH
H3CO H3CO
CH2OH CO2H
1) Alcohol Dehydrogenase
HO 2) Aldehyde Dehydrogenase HO
3-Methoxy-4-hydroxy- 3-Methoxy-4-hydroxymandelic acid
phenylethylene glycol (Vanilylmandelic acid; VMA)
 MCMP 407
Indirect-acting sympathomimetics: MAO Inhibitors
Phenelzine
Selegiline
Na+

Action Potential
H+ 3 MA
O

NE NE
Ca2+
Na+, Cl-
NE
NE NE
2
NE

Effector organ
 MCMP 407
Indirect-acting sympathomimetics: MAO Inhibitors

Phenelzine
Na +
Selegiline

NE
NE
Action Potential NE
H +
3 MA
O
NE NE
NE
NE NE
NE NE
Ca2+
NE
Na+, Cl-
NE
NE NE NE
NE
NE
2
NE

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

NE
NE
NE
H +
3 MA
O
NE NE
NE
NE NE
NE NE
NE

NE
NE NE Amphetamine,
NE NE NE NE NE
NE NE NE NE Tyramine
NE
NE

Effector organ