Transcript Adrenergic Agonists

MCMP 407
Organization of The Nervous System
Central Nervous System
Autonomic Nervous System
Sympathetic
Peripheral Nervous System
Somatic Nervous System
Parasympathetic
MCMP 407
Sympathetic Ganglionic Synapse
Acetylcholinesterase
Na+
aba
ACH
Action Potential
Na+
Preganglionic neuron
Nicotinic
Receptor
Postganglionic neuron
MCMP 407
Sympathetic Organ Synapse
Effector
Organ
Na+
Action Potential
NE
Adrenergic
Receptor
Postganglionic neuron
MCMP 407
Pharmacologic manipulation of the adrenergic system
Presynaptic neuron
Tyrosine
Na+
Dopamine
Tyrosine
Action Potential
H+
DA
NE
NE
Uptake 1
a2
(-)
NE
NE
NE
NE
Uptake 2
a1
Effector organ
b
MCMP 407
HO
CH2
CH
NH2 TYROSINE
COOH
tyrosine hydroxylase
Synthesis of
catecholamines
HO
HO
CH2
CH
NH2 DOPA
COOH
aromatic L-amino acid decarboxylase
HO
HO
CH2
CH2
NH2 DOPAMINE
dopamine b -hydroxylase
HO
HO
CH
CH2
NH2 NOREPINEPHRINE
OH
phenylethanolamineN-methyltransferase
HO
HO
CH
OH
CH2
NH
CH3
EPINEPHRINE
MCMP 407
Metabolism of norepinephrine
OH
HO
OH
NH2
Monoamine Oxidase (MAO)
HO
HO
CHO
HO
Norepinephrine
Aldehyde
Reductase
3,4-Dihydroxyphenylglycolaldehyde
OH
HO
CH2OH
Catechol O-Methyltransferase (COMT)
HO
3,4-Dihydroxyphenylethylene glycol
OH
H3CO
OH
CH2OH
HO
3-Methoxy-4-hydroxyphenylethylene glycol
H3CO
1) Alcohol Dehydrogenase
CO2H
2) Aldehyde Dehydrogenase
HO
3-Methoxy-4-hydroxymandelic acid
(Vanilylmandelic acid; VMA)
MCMP 407
Metabolism of norepinephrine
OH
HO
1) MAO
NH2
2) Aldehyde Dehydrogenase
HO
OH
HO
CO2H
HO
3,4-Dihydroxymandelic Acid
Norepinephrine
COMT
COMT
OH
H3CO
HO
Normetanephrine
NH2
1) MAO
2) Aldehyde Dehydrogenase H3CO
OH
CO2H
HO
3-Methoxy-4-hydroxymandelic acid
(Vanilylmandelic acid; VMA)
MCMP 407
Direct acting adrenergic receptor agonists
HO
HO
CH2
CH2
NH2
Dopamine
(Intropin)
CH
CH2
NH2
Norepinephrine
(Levophed)
CH2
NH
Epinephrine
(Adrenalin)
HO
HO
OH
HO
HO
CH
OH
CH3
MCMP 407
Receptors and signal transduction in the ANS
Adrenergic Receptors
a1
a1A
a1B
a2
a1D
a2A
a2B
b
a2C
b1
b2
b3
MCMP 407
Direct acting adrenergic receptor agonists:
a1 receptors
NH 3



Phospho lipase C
Phenylephrine (Neosynephrine)
Methoxamine (Vasoxyl)
Oxymetazoline (Visine)
(+)
Gq
PIP 2
HO
COOH
CH
CH2 NH
OH
CH3
IP 3
Diacylglycerol
Increase Ca 2+
Activate Protein
Kinase C
Phenylephrine
Response
MCMP 407
Direct acting adrenergic receptor agonists:
a2 receptors





Clonidine (Catapres)
Methyldopa (Aldomet)
Guanabenz (Wytensin)
Guanfacine (Tenex)
Tizanidine (Zanaflex)
NH3
(-)
Adenylate Cyclase
GI
Cl
H
N
Cl
Clonidine
N
K+
X
(+)
ATP
cAMP
COOH
N
H
Reduce cAMP-Dependent
Protein Kinase Activity
Response
MCMP 407
Direct acting adrenergic receptor agonists:
b receptors
HO
Non-selective
 Isoproterenol (Isuprel)
b1-selective
 Dobutamine (Dobutrex)
 Dopamine (Intropin)
CH3
HO
b2-selective
 Terbutaline (Brethine, Bricanyl)
 Metaproterenol (Metaprel, Alupent)
 Albuterol (Proventil, Ventolin)
 Salmeterol (Serevent)
 Ritodrine (Yutopar)
CH
CH2 NH
OH
Isoproterenol
CH
CH3
MCMP 407
Direct acting adrenergic receptor agonists:
b receptors
NH3
(+)
Adenylate Cyclase
GS
ATP
cAMP
COOH
Increase cAMP-Dependent
Protein Kinase Activity
Response
MCMP 407
Molecular actions of norepinephrine
VII
Phe 290
VI
Ser 207
OH
I
HO
OH
V
OH
HO
Ser 204
II
H3N
CO2
III
Asp 113
IV
MCMP 407
b 1 Adrenergic
receptor activation
100
50
100
50
0
-10
-8
-6
-4
Log [drug]
0
-10
-8
-6
Log [drug]
Phenylephrine
Epinephrine
Norepinephrine
Isoproterenol
-4
b 2 Adrenergic
receptor activation
a 1 Adrenergic
receptor activation
Selectivity of adrenergic receptor agonists
100
50
0
-10
-8
-6
Log [drug]
-4
MCMP 407
Cardiovascular effects of sympathomimetics
Norepinephrine
Isoproterenol
Epinephrine
PULSE 100
RATE
(min)
50
180
BLOOD
PRESSURE 120
(mm Hg)
80
PERIPHERAL
RESISTANCE
0
15
0
15
TIME
(min)
0
15
MCMP 407
Direct acting adrenergic receptor agonists:
Norepinephrine and Epinephrine
H
HO
OH

NH2


HO
l-Norepinephrine (Levophed)


Potent a and b1 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 a, b1, and b2 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:
a1 receptor agonists
H
OH
HO

NHCH3


Phenylephrine (Neo-Synephrine)
H

Potent a1 receptor agonist
Substrate for MAO
Administration: Parenteral,
oral, local
Uses: Mydriasis without
cycloplegia, glaucoma,
pressor, nasal decongestant
OH
H3CO
H3 C
NH2

H

OCH3
Methoxamine (Vasoxyl)


Potent a1 receptor agonist
Potent vasoconstrictor
Parenteral administration
Use: Pressor agent
MCMP 407
Direct acting adrenergic receptor agonists:
a1 receptor agonists: 2-aralkylimidazolines
N
R
R = substituted aromatic ring structure
X
X = methylene or amino
N
H
H+
H
N
N
R
R
X
N
H
H
N
R
X
N
H
X
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:
a1 receptor agonists: 2-aralkylimidazolines
N
R
N
H
R=
CH2
Naphazoline (Privine)
H3 C
R=
CH2
H3 C
 Partial agonists at a receptors
 Administered locally/topically
to promote vasoconstriction
R=
 Basic nature of imidazoline
ring causes compounds to
exist in ionized form at
physiologic pH
Tetrahydrozoline
(Visine)
 Tachyphylaxis/Desensitization
 Uses: Nasal and ophthalmic
decongestants
C(CH3)3
OH
Oxymetazoline (Afrin, Visine)
MCMP 407
Direct acting adrenergic receptor agonists:
a2 receptor agonists
Cl
H
N
Cl
N
N
H
Clonidine (Catapres)
 (Phenylimino)imidazolidine
 Selective a2 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 a2 receptors in the nucleus of
the solitary tract (cardiovascular
center)
 Administration: Oral, parenteral,
transdermal
 Uses: Hypertension, opiate
withdrawal
MCMP 407
a2-Adrenergic Agonists Reduce Blood Pressure by
Reducing Sympathetic Output from the Brain
Brain
Brain Stem (Cardiovascular Control
Center)
a Receptors
Sympathetic
ganglion
2
b1 Receptors
Heart
b1 Receptors
Kidney
a1 Receptors
MCMP 407
a2-Adrenergic Agonists Reduce Blood Pressure by
Reducing Sympathetic Output from the Brain
Brain
Brain Stem (Cardiovascular Control
Center)
a Receptors
Sympathetic
ganglion
2
Decreased sympathetic tone
• Decr. HR
• Decr. Contractility
• Decr. Renin release
• Decr. Vasoconstriction
b1 Receptors
Heart
b1 Receptors
Kidney
a1 Receptors
MCMP 407
Direct acting adrenergic receptor agonists:
a2 receptor agonists
NH2
Cl
NH
CH
N
NH
Cl
Guanabenz (Wytensin)
NH2
Cl
NH
CH2 C
NH
O
Cl
Guanfacine (Tenex)
 “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
MCMP 407
Direct acting adrenergic
receptor agonists:
a2 receptor agonists
HO
NH3
H3C
Cl
CO2Et
Methyldopate
HO
Esterases
 Methyldopa (Aldomet)
HO
 A prodrug metabolized to active
a2 receptor agonist, (1R, 2S)-a- HO
methylnorepinephrine
 Act at CNS a2 receptors to
HO
decrease sympathetic outflow
 Water soluble, ester hydrochloride
HO
salt Methyldopate is used for
parenteral solutions
 Administration: Methyldopa, oral;
Methyldopate; parenteral
HO
 Uses: Hypertension
HO
NH2
H3C
CO2H Methyldopa
L-Aromatic Amino
Acid Decarboxylase
NH2
H3C
H
a-Methyldopamine
Dopamine
b-Hydroxylase
H
OH
NH2
H
H3C
(1R, 2S)-a-methylnorepinephrine
MCMP 407
Clinical pharmacology of a2 receptor agonists
Other Uses:
Apraclonidine (Iopidine): Glaucoma
Tizanidine (Zanaflex): Muscle spasticity
Adverse effects of a2-adrenergic receptor agonists:
Sedation, Na+ and water retention, dry mouth, withdrawal syndrome
MCMP 407
Direct acting adrenergic receptor agonists:
b receptor agonists
H
HO
Non-selective b 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



OH
NHCH(CH3)2
HO
Isoproterenol (Isuprel)
MCMP 407
Direct acting adrenergic receptor agonists:
b receptor agonists
H
HO
OH H
N
R





Metaproterenol (Alupent, Metaprel) 
OH
R=
CH(CH3)2
Terbutaline (Bricanyl, Brethine)
C(CH3)3
R=


Resorcinol derivatives
Selective b2 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:
b receptor agonists
H
OH H
N
R
HO
CH2OH
Albuterol (Ventolin, Proventil)
C(CH3)3
R=
Salmeterol (Serevent)
R=
CH2(CH3)5O(CH2)4Ph








Meta hydroxymethyl derivatives
Selective b2 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 b receptor agonists
OH H
N
H
R
HO
CH2OH




Salmeterol (Serevent)
R= CH2(CH3)5O(CH2)4Ph
H
OH H
N
CH3
HO
OHC


NH
Formoterol (Foradil)
OCH3

Selective b2 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:
b receptor agonists
OH
H
N
HO
CH3
Ritodrine (Yutopar)
OH
 Selective b2 receptor
agonists
 Administration: Oral,
parenteral
 Uses: Tocolytic
MCMP 407
Direct acting adrenergic receptor agonists:
b receptor agonists
H
N
HO
HO
OH
CH3
Dobutamine (Dobutrex)
 Dopamine derivative
 Available as a racemic mixture
 (+)-enantiomer: potent b1
receptor agonist
 (-)-enantiomer: potent a1
receptor agonist, potency for b
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
Tyrosine
Na+
Dopamine
Tyrosine
Action Potential
H+
3
DA
NE
NE
Uptake 1
1
NE
NE
a1
2
NE
Effector organ
NE
b
MCMP 407
Indirect-acting sympathomimetics:
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
NH2
NE
CH3
Amphetamine
Intracellular
MCMP 407
Indirect-acting sympathomimetics:
D-(-)-Ephedrine vs. L-(+)-Pseudoephedrine
H
OH
R
S
H3C
NHCH3
H
D-(-)-Ephedrine
HO
H
S
S
H3C
NHCH3
H
L-(+)-Pseudoephedrine
 Alkaloid obtained from the
stems of Ephedra. Also found
in mahuang.
 D-(-)-Ephedrine has desired
(R)-configuration at b-OH and
(S)-configuration at the a
carbon for direct agonist
activity at adrenergic
receptors
 L-(+)-Pseudoephedrine is the
(S,S)-diastereoisomer; (S)configuration of b-OH reduces
agonist activity-major
mechanism is via reversal of
the transporter
MCMP 407
Indirect-acting sympathomimetics:
D-(-)-Ephedrine vs. L-(+)-Pseudoephedrine
CH3
CH3
H
NHCH3
H
OH
D-(-)-Ephedrine
erythro
H
HO
NHCH3
H
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
a1
2
NE
Effector organ
NE
b
MCMP 407
Indirect-acting sympathomimetics:
Cocaine
Antidepressants
Desipramine
Na+
Venlafaxine
Action Potential
H+
NE
NE
NE
Cocaine
NE
NE
NE
a1
NE
NE
NE
Effector organ
2
NE
NE
NE
b
MCMP 407
Metabolism of norepinephrine
OH
HO
OH
NH2
Monoamine Oxidase (MAO)
HO
HO
CHO
HO
Norepinephrine
Aldehyde
Reductase
3,4-Dihydroxyphenylglycolaldehyde
OH
HO
CH2OH
Catechol O-Methyltransferase (COMT)
HO
3,4-Dihydroxyphenylethylene glycol
OH
H3CO
OH
CH2OH
HO
3-Methoxy-4-hydroxyphenylethylene glycol
H3CO
1) Alcohol Dehydrogenase
CO2H
2) Aldehyde Dehydrogenase
HO
3-Methoxy-4-hydroxymandelic acid
(Vanilylmandelic acid; VMA)
MCMP 407
Indirect-acting sympathomimetics: MAO Inhibitors
Phenelzine
Selegiline
Na+
Action Potential
3
H+
NE
NE
NE
NE
a1
2
NE
Effector organ
NE
b
MCMP 407
Indirect-acting sympathomimetics: MAO Inhibitors
Phenelzine
Selegiline
Na+
NE
NE
NE
Action Potential
3
H+
NE
NE
NE
NE
NE
NE
NE
NE
NE
a1
NE
NE
NE
NE
Effector organ
2
NE
NE
b
MCMP 407
Indirect-acting sympathomimetics: MAO Inhibitors
Co-admininstration with other
indirect-acting drugs can lead
to hypertensive crisis
Phenelzine
Selegiline
NE
NE
NE
3
H+
NE
NE
NE
NE
NE
NE
NE
NE
NE
NE
NE
a1
NE
NE
NE
NE
NE
NE
NE
Effector organ
NE
NE
b
NE
NE