MCMP 407
Organization of The Nervous SystemOrganization of The Nervous System
Central Nervous System Peripheral Nervous System
Somatic Nervous SystemAutonomic Nervous System
Sympathetic Parasympathetic
MCMP 407
Action Potential
Na+
Ca 2+
ACH
Acetylcholinesterase
Na+
Sympathetic Ganglionic Synapse
Preganglionic neuron Postganglionic neuron
Nicotinic
Receptor
MCMP 407
Action Potential
Ca 2+
Na+
NE
Sympathetic Organ Synapse
G
EffectorOrgan
Postganglionic neuron
Adrenergic
Receptor
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
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
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
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
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)
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
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
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
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
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)
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
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)
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
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
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
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
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
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
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
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
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
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
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
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
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