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MEDICAL PHARMACOLOGY – PCOL 425
FALL 2009 – CHOLINERGIC AGONISM AND ANTAGONISM MODULE
MARCELO G. BONINI
Assistant Professor
College of Medicine
[email protected]
312-996-4741
Overview
- Cholinergic action
The junction, molecular mechanism, sites of action
- Muscarinic Receptor
Structure, types, coupling with G-Proteins
- Cholinomimetic Drugs
Structure, general features, organ effects
- Cholinomimetic Drugs
Therapeutic uses, toxicology
- Muscarinic Antagonism
Drugs, therapeutic uses, toxicity
Neurons and neurotransmitters – general overview
MOVIE
http://www.youtube.com/watch?v=DF04XPBj5uc
Generalized Cholinergic Junction
Acetylcholine binding and receptor structural
changes
Cholinergic action (molecular mechanism)
Intracellular signaling triggered by acetylcholine in the smooth muscle
Main molecular players: M3, Heterotrimeric protein Gq, PLC/IP3, Ca(2+), MLCK
Cholinergic action (molecular mechanism)
Intracellular signaling triggered by acetylcholine in the Heart
Main molecular players: M2, heterotrimeric G Protein Gi, Adenylyl cyclase
Cholinergic action (molecular mechanism)
Intracellular signaling triggered by acetylcholine in the endothelium
eNOS
Nitric oxide synthase
L-Arg
eNOS
L-Citruline
●NO
Major molecular players: M3, heterotrimeric G Protein Gq, Ca(2+)-CaM, eNOS, NO
Cholinergic action (molecular mechanism)
acetylcholine mediated endothelium-dependent vasodilation
Start Here
+ACh
NO probe
- ACh
NO probe
Cholinergic action (molecular mechanism)
(endothelium present)
+
(endothelium absent)
-
Endothelium dependence of Ach-induced vasodilation of
pre-constricted arterial rings
Sites of Cholinergic Activity
-Preganglionic synapses of both sympathetic and parasympathetic ganglia
- Parasympathetic postganglionic neuroeffector junctions
- All somatic motor end plates on skeletal muscles
RECEPTOR
INTRACELLULAR
TRANSDUCER
ELECTRICAL
MECHANICAL
PHYSIOLOGICAL
RESPONSES
M2
Gi
M4
Go
Adenylyl cyclase
cAMP
Hyperpolarization (heart)
Cardiac inhibition
Antagonism of smooth
muscle relaxation
M1
M3
M5
Gq
Phospholipase C
Diacyl-glycerol IP3
Depolarization
Smooth muscle contraction
Glandular secretion
Muscarinic receptor types
experiments that led to their discovery
M1 - Neurotransmission in Cortex and Ganglia
(-/-) mice - abrogation of pilocarpine – induced seizures
M2 - Agonist-mediated bradycardia, tremor, autoinhibition of release in several
brain regions
(-/-) mice - loss of oxytremorine-induced tremors; loss of
agonist-induced bradycardia; diminished hypothermia
M3 - Smooth muscle contraction, gland secreation, pupil dilation, food intake
and possibly weight gain
(-/-) mice - loss of agonist-induced bronchoconstriction,
higher basal pupil dilation, reduction of
agonist-induced salivation
M4 and M5 – Central Nervous System (CNS) roles.
Classes of cholinergic stimulants
Direct-acting
Indirect-acting
Receptor agonists
Cholinesterase inhibitors
Carbamates
Choline esters
ACETYLCHOLINE
BETHANECOL
Alkaloids
PILOCARPINE
PHYSOSTIGMINE
NEOSTIGMINE
PYRIDOSTIGMINE
EDROPHONIUM
Phosphates
ISOFLUROPHATE
Antidote
PRALIDOXIMINE
Chemical Structure of Cholinergic agonists
Quaternary ammonium
Tertiary amine
Pilocarpine – source/history
• Chewing pilocarpus caused salivation
Amazon
Experiments performed in Brazil in 1874, isolated in 1875, methacholine and
carbachol studies in 1911
Absorption, metabolism, distribution
- Absorption: polarity dependent (poor for ACh,
quaternary ammonium), intravenous,
subcutaneous and intramuscular for local effects
(Ach)
- Metabolism: Highly dependent on the
susceptibility to acetylcholinesterase (AChE)
Compound
Acetylcholine chloride
Methacholine chloride
Carbachol chloride
Bethanechol chloride
Susceptibility (AChE)
High (++++)
Low (+)
Negligible
Negligible
Muscarinic
Effect
High (limited by AChE)
Highest (++++)
Medium (++)
Medium (++)
Organ effects – Eye/Cardiovascular
- Eyes: contraction of ciliary muscle and smooth muscle of
the iris sphincter (miosis) – aqueous humor outflow,
drainage of the anterior chamber
- Cardiovascular: Bradycardia (possibly preceded by
tachycardia), vasodilation (all vascular beds including
pulmonary and coronary – M3) and hypotension,
reduction of the contraction strength (atrial and
ventricular cells, IK+ , ICa2+ diastolic depolarization , NOinhibitable ATP?), negative chronotropic effect (inhibition
of adrenergic activation).
Organ effects – GI/urinary bladder
- GI - increases in tone, amplitude of contractions, and peristaltic
activity of the stomach and intestines, enhances secretory
activity of the gastrointestinal tract.
- Urinary bladder - increase ureteral peristalsis, contract the
detrusor muscle of the urinary bladder, increase the maximal
voluntary voiding pressure, and decrease the capacity of the
bladder.
- Other effects – Increased secretion from all glands that
receive parasymphatetic enervation (salivary, lacrimal,
tracheobronchial, digestive and exocrine sweat glands)
- IMPORTANT - BROCHOCONSTRICTION
Therapeutic uses (BETHANECHOL)
•
Bethanechol chloride (carbamylmethylcholine chloride; URECHOLINE)
•
Stimulant of the smooth muscle of the GI tract and the urinary bladder.
•
Postoperative abdominal distension and gastric retention or gastroparesis.
Urinary retention and inadequate emptying of the bladder when organic
obstruction is absent:
- postoperative
- postpartum urinary retention
- certain cases of chronic hypotonic or neurogenic bladder.
-alternative to pilocarpine to promote salivation Xerostomia (dryness of the
mouth).
-Sjogren syndrome (immunologic disorder with destruction of the
exocrine glands) leading to mucosal dryness
Administration/Precaution/Toxicity
•
Bethanechol should be administered only by the oral or subcutaneous route for
systemic effects; they also are used locally in the eye.
•Antidote - atropine.
•Epinephrine may be used to overcome severe cardiovascular or
bronchoconstrictor responses.
•Among the major contra-indications to the use of the choline esters are
asthma, hyperthyroidism, coronary insufficiency, and acid-peptic disease.
•
Bronchoconstrictor action could precipitate an asthmatic attack
•
Hyperthyroid patients may develop atrial fibrillation.
•
Hypotension induced by these agents can severely reduce coronary blood
flow, especially if it is already compromised.
•
The gastric acid secretion produced by the choline esters can aggravate the
symptoms of acid-peptic disease.
POSSIBLE SIDE EFFECTS : sweating (very common), abdominal cramps, a
sensation of tightness in the urinary bladder, difficulty in visual
accommodation for far vision, headache, and salivation.
Therapeutic use/toxicity
(carbachol/methacholine)
• Carbachol usually is not employed for these purposes
because of its relatively larger component of nicotinic
action at autonomic ganglia.
The unpredictability of the intensity of response has
virtually eliminated the use of methacholine or other
cholinergic agonists as vasodilators and cardiac
vagomimetic agents.
• Methacholine chloride (acetyl-b-methylcholine chloride;
PROVOCHOLINE) may be administered for diagnosis
of bronchial hyperreactivity and asthmatic conditions.
Toxicity/Mycetism
• Exageration of all symptoms of muscarinic agonism
• Significance: Higher consumption of wild mushrooms
(culinary)
A. muscaria
30-60 minutes, salivation, lacrimation, excessive sweating, nausea, vomiting
diarrhea, bronchospasm, headache, visual disturbances, abdominal colic,
bradychardia, hypotension, shock
ALL SYMPTOMS REVERTED BY ATROPINE1 - 2 mg intramuscular
Mycetism/non muscarinic
• Amanita phalloides – deadly nightcap
• Inhibits mRNA synthesis – 24 h symptom free period followed by liver and
kidney malfunction, death within 4-7 days
A. phalloides
A. muscaria
Muscarinic antagonism
Attropa belladona
History/sources
• Atropa belladona - used in the renaissance
• Deadly nightshade - used in the middle ages to produce polonged
poisoning
Jimson plant leaves burned in India to treat Asthma (1800) purification
of atropine (1831)
Muscarinic Antagonists
ATROPINE
SCOPOLAMINE
Muscarinic Antagonists
ATROPINE
SCOPOLAMINE
Attropa belladona
- Atropine and Scopolamine are belladona alkaloids
(competitive inhibitors)
-Drugs differ in their CNS effects, scopolamine permeates the
blood-brain barrier
-At therapeutic doses atropine has negligible effect upon the CNS,
scopolamine even at low doses has prominent CNS effects.
Mechanism of drug action
- Competitively block muscarinic receptors
- Salivary, bronchial, and sweat glands are
most sensitive to atropine
- Smooth muscle and heart are intermediate
in responsiveness
- In the eye, causes pupil dilation and difficulty for far
vision accomodation
- Relaxation of the GI, slows peristalsis
Effect of muscarinic inhibitor in the eye
Pupil dilation vs accomodation
Effect of muscarinic inhibition in the
heart and salivary glands
- Increases the heart rate after a transient bradychardia at the low dose
- Diminishes gland excretory function
Graphic summary of atropine effects
Organ effect – drug review
Antidotes
• ORGAN
DRUG
APPLICATION
Benztropine
Treat Parkinson’s disease
Scopolamine
Prevent/Reduce motion sickness
Eye
Atropine
Pupil dilation
Bronchi
Ipatropium
Bronchodilate in Asthma, COPD
GI
Methscopolamine
Reduce motility/cramps
GU
Oxybutinin
Treat transient cystitis
Postoperative bladder spasms
CNS
Toxicity of muscarinic antagonists
• “DRY AS BONE, RED AS A BEET, MAD AS HATTER.”
• Dry is a consequence of decreased sweating, salivation
and lacrimation
• Red is a result of reflex peripheral (cutaneous)
vasodilation to dissipate heat (hyperthermia)
• Mad is a result of the CNS effects of muscarinic
inhibition which can lead to sedation, amnesia
(hypersensitivity), or hallucination
Preview
- Indirect cholinergic agonism (Inhibition of AChE)
- Nicotine-acetylcholine agonism / antagonism
- Therapeutic use and toxicology