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Autonomic Pharmacology II

Joan M. Lakoski, Ph.D.


August 30, 2005

PHARMACOLOGY OF
AUTONOMIC DRUGS
DEPARTMENT OF PAHRAMCOLOGY
FACULTY OF MEDICINE JENDERAL SOEDIRMAN UNIVERSITY

Lokoski, 2005

Adrenergic and Cholinergic Receptors

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

Adrenergic Receptors:
Receptor Subtypes Activated by EPI/NE
α-adrenergic
α receptors ß-adrenergic receptors
(Epinephrine > Isoproterenol) (Isoproterenol>Epinephrine)

α1-adrenergic receptors ß 1-adrenergic


(Phenylephrine > Clonidine) receptors
(EPI = NE)

ß2-adrenergic
receptors
α2-adrenergic receptors (EPI > NE)
(Clonidine > Phenylephrine)
ß3-adrenergic
receptors
(NE > EPI)

Cholinergic Receptors: Receptors Activated by ACh

Muscarinic Receptors
(Activated by muscarine from Amanita muscaria)

Nicotinic Receptors
M1 (Activated by nicotine from tobacco)
(Nerve Cells)

M2 NM
(Heart &
SM) (Neuromuscular)
M3 (Blocked by
(Heart & NN
SM) Tubocurarine) Autonomic
M4 ganglia,
(SM & Adrenal
Glands) M5 medulla &
(?)
CNS
(Blocked by Trimethaphan)

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

Actions of Autonomic Nerves:


Adrenergic and Cholinergic Responses

Catecholamine Function in Autonomic Nervous System


Sympathetic Somatic
Parasympathetic Sympathetic (Cholinergic) (Motor Nerve)
Preganglionic
Neuron

Transmitter ACh ACh ACh ACh

Receptor nicotinic nicotinic nicotinic nicotinic

Postganglionic
Neuron

Transmitter ACh NE NE,


NE EPI ACh
ACh
Receptor muscarinic adrenergic adrenergic muscarinic nicotinic
(sympathetic
cholinergic) (nmj)

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

PARASYMPATHOMIMETICS
(CHOLINOMIMETICS):
Drugs that facilitate or mimic some
or all of the actions of the
parasympathetic nervous system

Muscarinic
receptor Anticholinesterases
agonists

Cholinergic Agonists

Acetylcholine
Cholinomemetics
Function to increase activity in cholinergic neurons

Two main targets of drug action:


Postsynaptic receptor
Acetylcholinesterase enzyme that breaks down ACh

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

ACh degraded by
cholinesterase
enzymes

Enzymes catalyze
hydrolysis of ACh to
choline and acetic acid

Acetylcholinesterase (AChE)
Pseudocholinesterase
(pseudo-ChE)

Direct Cholinergic Agonists

Esters
Methacholine
Carbachol
Bethanechol

Alkaloids Alkaloids are not


Muscarine metabolized by
Pilocarpine cholinesterases

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

Pilocarpine

-Origin of the Drug


-South American Shrub
- Pilocarpus jaborandi
-Isolated in 1875
-Chemical Structure

- Cholinergic Parasympathomimetic agent

Reaction Mechanism
- Pilocarpine binds to muscarinic receptor
- Activates receptor binds G-protein
- Removal of GDP and addition of GTP to G-protein
- Dissociation of G-protein from muscarinic receptor
- Separation of G-protein into alpha and beta-gamma
subunits
- Alpha subunit interacts with and activates Phospholipase C -
Phosphatidyl inositol biphosphate (PIP) complex
- Phospholipase breaks down PIP into inositol
1,4,5-triphosphate (IP3)and diacylglycerol (both 2o)
- IP3 interacts with ER membrane which releases Ca2+

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

Muscle Action

- Ca2+ binds to calmodulin forming a complex


- This complex binds to caldesmon
- When caldesmon is bound by Ca2+/calmodulin complex
this allows myosin-actin interactions to occur
-The muscle contracts

Marieb Fig 16-7

The End Result


- Contraction of pupil and stimulation of ciliary muscle
- Tension on scleral spur opening trabecular meshwork
- Increased out flow, lowering of pressure

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

Low doses of muscarinic agonists relax arterial smooth


muscle and produce a fall in blood pressure

Directly Acting Parasympathomimetic Drugs on the


Heart

ACh release onto the heart


by the vagus nerve
slows the heart rate
Paradoxical effect: A low dose of a muscarinic agonist can
sometimes increase heart rate

The decrease in blood pressure produced by stimulation of the


endothelial muscarinic receptors triggers activation of
compensatory sympathetic reflex stimulation of the heart

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

Adverse Effects

Potentially severe adverse effects can


result from systemic administration of
cholinomimetic drugs

Cholinesterase Inhibitors
Slow or prevent degradation of
ACh released into synapse
Reversible inhibitors
(water soluble)

Edrophonium

Neostigmine
Physotigmine
Pydridostigmine

Irreversible inhibitors Organophosphates


(lipid soluble/cross BBB)

Parathion Atropine
Clinically useful in treatment
carbamates with Soman
Sarin of organophosphate
a quartinary poisoning
amine group

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

Acetylcholinesterase inhibitors
O
O P F
Organophosphates
O
Irreversible
Covalent
Isofluorophate; DFP
(Floropryl) modification to
AChE
I- Longer acting
O
H 3C
H3C N CH2 CH2 S P OC2H5 Used in the
CH3 OC2H5 treatment of
Echothiophate glaucoma
(Phospholine Iodide)

Acetylcholinesterase
O
inhibitors
H 3C P F
Organophosphates
O
Nerve gases
Irreversible
Sarin
Covalent
modification to
AChE
CH3CH3 O
H 3C C CH O P F
CH3 CH3
Soman

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

Acetylcholinesterase inhibitors
O
S
C2H5 O C Organophosphates
O CH S P OCH3
C2H5 O C CH2 OCH3 Insecticides
Malathion Irreversible
Covalent
CH3
modification to
N S
AChE
H3C O P OC2H5 Rapidly inactivated
CH N
OC2H5 in mammals
H3C Diazinon

Antidote for AChE “poisoning”


Pralidoxime
Chloride
(Protopam; 2-
2-
pyridine aldoxime
N methyl chloride; 2-
2-
HO N PAM)
Cl- CH3 Antidote for
pesticide or nerve
gas poisoning
Most effective if
given within a few
hours of exposure

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

Clinical pharmacology of acetylcholinesterase


inhibitors

Type of Route of
Drug inhibition administration Clinical Use

Edrophonium Rev IM or IV Diagnostic for Myasthenia Gravis


Neostigmine Rev IM, IV, or oral Myasthenia Gravis, post-operative ileus and
bladder distention, surgical adjunct
Physostigmine Rev IM, IV, or local Glaucoma, Alzheimer’s disease, antidote to
anticholinergic overdose
Tacrine Rev Oral Alzheimer’s disease
Donepezil Rev Oral Alzheimer’s disease
Isofluorophate Irrev Local Glaucoma
Echothiophate Irrev Local Glaucoma

Contraindications to the use of


parasympathomimetic drugs
 Asthma
 COPD
 Peptic ulcer
 Obstruction of the urinary or GI tract

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

Cholinergic agent side effects and


toxicity
SLUD Also:
Salivation Increased
Lacrimation sweating
Urination Decreased heart
Defecation rate
Pupils constricted
Treatment: CNS activation
 Cholinergic receptor antagonist (Atropine)
 If irreversible AChE inhibitor, 2-PAM (Pralidoxime)

PARASYMPATHOLYTICS
(ANTICHOLINERGICS):
Drugs that reduce or inhibit some or
all of the actions of the
parasympathetic nervous system

Muscarinic
receptor Ganglionic
antagonists blocking drugs

Prototype: Atropine Hexamethonium


Other: Scopolamine Trimethapan
Mecamylamine

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

SYMPATHOMIMETICS:
Drugs that facilitate or mimic some or all
of the actions of the sympathetic
nervous system

Direct Indirect
Acting Acting

α-adrenergic agonists Drugs that facilitate NE release

β-adrenergic agonists Drugs that block NE uptake

Adrenergic Agonists
Direct-Acting:
E and NE activate both α and β receptors
NE has a relatively low affinity for β receptors

Phenylephrine (α1 agonist)


Clonidine (α2 agonist)

Dobutamine (β1 agonist)


Isoproterenol (β1 = β2 agonist)
Terbutaline (β2 agonist)

Dopamine

Indirect--Acting:
Indirect
Ephedrine
Phenylpropanolamine
Amphetamine

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

SYMPATHOLYTICS:
Drugs that reduce or inhibit some or all
of the actions of the sympathetic
nervous system

Ganglionic Centrally acting Drugs that


blocking sympatholytics inhibit NE
drugs synthesis
Adrenergic
neuronal α-adrenergic
blocking drugs antagonists

NE depleting β-adrenergic
drugs antagonists

Adrenergic Antagonists
• α-Blockers • β-Blockers
– Prazosin (α1) Non-cardioselective
• Propranolol
– Phentolamine • Pindolol
– Yohimbine (α2) • Timolol
Cardioselective
(β1 for heart)
Labetalol acebutolol
Both α- and β- atenolol
blocking activity metoprolol

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

Summary of Adrenergic and Cholinergic Responses

Summary of Adrenergic and Cholinergic Responses

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

Summary of Adrenergic and Cholinergic Responses

Summary of Adrenergic and Cholinergic Responses

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

Interactions of Drugs with


the Autonomic Nervous System

Predicting Responses of
Drugs that Interact with the
Autonomic Nervous System

Baroreceptor Reflex

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Autonomic Pharmacology II
Joan M. Lakoski, Ph.D.
August 30, 2005

REFERENCIES

Craig and Stitzel, Modern Pharmacology,


6th Edition (2004), Chapters 9 – 14.

Goodman & Gilman, The Pharmacological Basis


of Therapeutics, 10th Edition (2001),
Chapters 6 – 10.

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