Cholinergic Pharmacology (2)

7/30/2019 Cholinergic Pharmacology (2)

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PHARMACOLOGY OF

CHOLINERGIC AGONISM ANDANTAGONISM


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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


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http://www.youtube.com/watch?v=DF04XPBj5uc

A cholinergic neuroeffector junction


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Generalizedcholinergicneuroeffectorjunction


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Acetylcholine binding and receptor structuralchanges


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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


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Intracellular signaling triggered by acetylcholine in the Heart

Main molecular players: M2, heterotrimeric G Protein Gi, Adenylyl cyclase


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Intracellular signaling triggered by acetylcholine in the endothelium

eNOS

NO

L-Arg

L-Citruline

Major molecular players: M3, heterotrimeric G Protein Gq, Ca(2+)-CaM, eNOS, NO


eNOS

Nitric oxide synthase


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Cholinergic action (molecular mechanism)Acetylcholine mediated endothelium-dependent vasodilation

Start Here

+ACh

NO probe

- ACh

NO probe


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(endothelium present) (endothelium absent)

-

+

Endothelium dependence of ACh-induced vasodilation ofpre-constricted arterial rings


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Sites of Cholinergic Activity

-Preganglionic synapses of both sympathetic and parasympathetic ganglia

- Parasympathetic postganglionic neuroeffector junctions

- All somatic motor end plates on skeletal muscles

M2 M4 M5M3M1

Gi Go

Adenylyl cyclasecAMP

Hyperpolarization (heart)Cardiac inhibitionAntagonism of smooth

muscle relaxation

RECEPTOR

INTRACELLULARTRANSDUCER

ELECTRICALMECHANICALPHYSIOLOGICAL

RESPONSES

Gq

Phospholipase C

Diacyl-glycerol IP3

DepolarizationSmooth muscle contraction

Glandular secretion


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Muscarinic receptor typesexperiments 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 ofagonist-induced bradycardia; diminished hypothermia

M3 - Smooth muscle contraction, gland secretion, 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.


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Classes of cholinergic stimulants

Direct-acting

Receptor agonists

Choline estersACETYLCHOLINEBETHANECOL AlkaloidsPILOCARPINE

ARECHOLINE

Cholinesterase inhibitors

CarbamatesPHYSOSTIGMINE

NEOSTIGMINE

PYRIDOSTIGMINE

EDROPHONIUM

PhosphatesISOFLUROPHATE

Antidote

PRALIDOXIMINE

Indirect-acting


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Chemical Structure of Cholinergic agonists

Tertiary amine

Quaternary ammonium


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Pilocarpine source/history

Chewing pilocarpus caused salivation

Amazon

Experiments performed in Brazil in 1874, isolated in 1875, methacholine and

carbachol studies in 1911


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Absorption, metabolism, distribution

- Absorption: polarity dependent (poor for ACh,quaternary ammonium), intravenous,

subcutaneous and intramuscular for local effects

(Ach)

- Metabolism: Highly dependent on thesusceptibility to acetylcholinesterase (AChE)

Compound Susceptibility (AChE) MuscarinicEffect

Acetylcholine chloride High (++++) High (limited by AChE)Methacholine chloride Low (+) Highest (++++)Carbachol chloride Negligible Medium (++)

Bethanechol chloride Negligible Medium (++)


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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 , NO-inhibitable ATP?), negative chronotropic effect (inhibition

of adrenergic activation).


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- GI - increases in tone, amplitude of contractions, andperistaltic activity of the stomach and intestines,

enhances secretory activity of the gastrointestinal tract.

- Urinary bladder - increase ureteral peristalsis, contractthe detrusor muscle of the urinary bladder, increase themaximal voluntary voiding pressure, and decrease the

capacity of the bladder.

- Other effectsIncreased secretion from all glands thatreceive parasymphatetic enervation (salivary, lacrimal,tracheobronchial, digestive and exocrine sweat glands)

- IMPORTANT - BROCHOCONSTRICTION

Organ effects GI/urinarybladder


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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 bladderwhen 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 themouth).

- Sjogren syndrome (immunologic disorder with destruction of the exocrine glands)

leading to mucosal dryness


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Administration/Precaution/Toxicity

Bethanechol should be administered only by the oral or

subcutaneous route for systemic effects; they also areused locally in the eye.

Antidote - atropine.

Epinephrine may be used to overcome severecardiovascular or bronchoconstrictor responses.

Major contra-indications to the use of the choline esters

asthma, hyperthyroidism, coronary insufficiency, andacid-peptic disease.

Bronchoconstrictor action could precipitate an asthmaticattack


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Administration/Precaution/Toxicity

Hyperthyroid patients may develop atrial fibrillation.

Hypotension induced by these agents can severelyreduce coronary blood flow, especially if it is alreadycompromised.

The gastric acid secretion produced by the choline esterscan aggravate the symptoms of acid-peptic disease.

POSSIBLE SIDE EFFECTSsweating (very common), abdominal cramps, a sensationof tightness in the urinary bladder, difficulty in visualaccommodation for far vision, headache, and salivation.


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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 hasvirtually 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.


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Toxicity/Mycetism

Exageration of all symptoms of muscarinic agonism

Significance: Higher consumption of wild mushrooms

(culinary)

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

A. muscaria


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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


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Muscarinic antagonism

Attropa belladona

Muscarinic receptor

antagonists reduce the

effects of ACh bycompetitively inhibiting its

binding to muscarinic

cholinergic receptors


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History/sources Atropa belladona -used in the renaissance

Deadly nightshade - used in the middle ages to produce polongedpoisoning

Jimson plant leaves burned in India to treat Asthma (1800) purification

of atropine (1831)


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Muscarinic Antagonists

ATROPINE

SCOPOLAMINE


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Muscarinic AntagonistsATROPINE

SCOPOLAMINE Atropa belladona

- Atropine and Scopolamine are belladona alkaloids(competitive inhibitors)

-Drugs differ in their CNS effects, scopolamine permeates theblood-brain barrier

-At therapeutic doses atropine has negligible effect upon the CNS,scopolamine even at low doses has prominent CNS effects.


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Mechanism of drug action

- Competitively block muscarinic receptors

- Salivary, bronchial, and sweat glands are

most sensitive to atropine

- Smooth muscle and heart are intermediatein responsiveness

- In the eye, causes pupil dilation and difficulty for far

vision accomodation

- Relaxation of the GI, slows peristalsis


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Effect of muscarinic inhibitor in the eyePupil dilation vs accomodation


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Effect of muscarinic inhibition in theheart and salivary glands

- Increases the heart rate after a transient bradychardia at the low dose- Diminishes gland excretory function


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Graphic summary of atropine effects


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Organ effect drug reviewAntidotes

ORGAN DRUG APPLICATIONCNS Benztropine Treat Parkinsons 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


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Sources of Anticholinergic PoisoningGroup Examples

Antihistamines

(H1-receptor antagonists)

Diphenhydramine, Chlorpheniramine

Dimenhydrinate

Antiparkinsonian drugs Benztropine, Trihexyphenidyl

Antipsychotics Chlorpromazine, Thioridazine, Loxapine

Antispasmodics Dicyclomine, Propantheline

Belladonna alkaloids and related drugs Atropine, Scopolamine

Belladonna alkaloid-containing plants Deadly nightshade, Angels trumpet

JimsonweedCyclic antidepressants Amitriptyline, Doxepin, Fluoxetine

Cycloplegics and mydriatics Cyclopentolate, Tropicamide

Muscle relaxants Orphenadrine, Cyclobenzaprine


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Toxicity of muscarinic antagonists

DRY AS BONE, RED AS A BEET, MAD AS HATTER.

Dry is a consequence of decreased sweating, salivationand lacrimation

Red is a result of reflex peripheral (cutaneous)vasodilation to dissipate heat (hyperthermia)

Mad is a result of the CNS effects of muscarinicinhibition which can lead to sedation, amnesia(hypersensitivity), or hallucination


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Effects of Atropine in Relation toDose

0.5 mg Slight cardiac slowing;

some dryness of mouth;

inhibition of sweating

1 mg Definite dryness of mouth;

thirst;

acceleration of heart, sometimes preceded by slowing;

mild dilation of pupils

2 mg Rapid heart rate;

palpitation;

marked dryness of mouth

dilated pupils

Some blurring of near vision


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5 mg All the above symptoms marked

difficulty in speaking and swallowing

restlessness and fatigue; headache

Dry, hot skin difficulty in micturition

reduced intestinal peristalsis

10 mg and more

Above symptoms more marked Rapid and weak

Iris practically obliterated; vision very blurred; skin flushed, hot, dry,

and scarlet; ataxia,

Restlessness, and excitement; hallucinations and delirium; coma

Effects of Atropine in Relation toDose


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Ganglia and autonomicnerves

Pirenzepine

The extent to which the slow EPSPs can alter

impulse transmission through the different

sympathetic and parasympathetic ganglia isdifficult to assess

Effects of pirenzepine on responses of end

organs suggest a physiological modulatory

function for the ganglionic M1 receptor


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Pirenzepine

Inhibits gastric acid secretion at doses that have

little effect on salivation or heart rate.

Since the muscarinic receptors on the parietal

cells do not appear to have a high affinity forpirenzepine,

M1 receptor responsible for alterations in gastric

acid secretion may be localized in intramural

ganglia.


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Pirenzepine

Blockade of ganglionic muscarinic

receptors (rather than those at the

neuroeffector junction) apparently

underlies the capacity of pirenzepine toinhibit relaxation of the lower esophageal

sphincter

Likewise, blockade of parasympatheticganglia may contribute to the response to

muscarinic antagonists in lung and heart


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Preview

- Indirect cholinergic agonism (Inhibition of AChE)

- Nicotine-acetylcholine agonism / antagonism

- Therapeutic use and toxicology

Cholinergic Pharmacology (2)

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