Cholinoceptor-Activating & Cholinesterase - Inhibiting Drugs

Cholinoceptor-Activating
&
Cholinesterase – Inhibiting Drugs
1
Learning Objectives
 Cholinergic transmission
 Cholinergic drugs (directly acting/indirectly acting )
 Spectrum of action
 Mode of action
 Basic pharmacology (directly and indirectly acting drugs)
 Clinical pharmacology
 Overview
 Case study
2
Hemicholiniums
Vesamicol
Botulinum
Toxin
3
Major autonomic receptor types
Receptor Name Typical Location Result of Ligand Binding
Muscarnic M1 CNS neurons, Sympathetic IP3 & DAG Inc. Intracellular Ca2+
post ganglionic.
Myocardium, Smooth k Adenylyl

Muscarnic M2 muscle, presynaptic site, cyclase
CNS neurons.
Muscarnic M3 Exocrine gland, vessels Like M1 receptor-ligand binding
CNS neurons; vagal nerve Like M2 receptor-ligand binding

Muscarnic M4
ending
Muscarnic M5 VE, cerebral vessels, CNS Like M1 receptor-ligand binding
Post ganglionic neuron, Depolari

Nicotinic NN zation
Pre synaptic Ch terminals.
SM Neuromuscular end Similarly to Nicotinic NN

Nicotinic NM
plate
4
Introduction
5
Spectrum of Action of Cholinomimetic Drugs
Muscarine mimicked the effect of parasympathetic nerve

discharge- Parasympathomimetic.
Effect of acetyl choline & other cholinomimetic drugs at

autonomic neuroeffector junction are called
Parasympathomimetic effects
Muscarinic –high concentration
Nicotinic – Low concentration ; No autonomic effector cell
5
Spectrum of Action of Cholinomimetic Drugs
G protein –linked or Ion channel
families
Muscarinic
Seven Transmembrane domains
Regulates Intracellular Second
messenger/ modulates Ion channels
via G-protein
Muscarinic receptor form dimers or oligomers via function in receptor movement
between ER and Plasma membrane and signaling
Nicotinic receptors part of transmembrane polypeptide whose subunits from cation
selective ion channels
7
Subtypes and characteristic of Cholinoreceptor
7
location and Function of M1/2/3
9
10
Mode of action of Cholinomimetic Drugs
Some Quaternary cholinesterase inhibitors also have a direct mode of action.

Eg Neostigmine-Activates neuromuscular nicotinic Cholinoreceptor directly. Add.
To blocking cholinesterase
Dia: Neostigmine 1.5-2.0 mg IM Preceded by 0.6 mg atropine (DOC; Cobra Bite)
11
Pharmacokinetics
Choline esters poorly absorbed poorly distributed in to the

CNS
All hydrolyzed in the GIT (Less active by Oral Route)
Methacholine is more resistant to hydrolysis
Beta methyl groups are reduced the potency of at Nicotinic

receptors
12
Pharmacokinetics
Tertiary natural cholinomimetic alkaloids well absorbed from

most sites
Nicotine, a lipid soluble –absorbed across the skin
Muscarine less completely absorbed from the GIT than TA
Tertiary amines are toxic when ingested – certain mushrooms
Amines are excreted – kidney
Acidification of the urine accelerates clearance of the TA
13
Pharmacodynamics
• Activation of Parasympathetic nervous system

• On effector cells (Direct action)
• On Nerve terminals (Indirect actions)
• Indirect actions
• Alters indirectly organ function by modulating the effect of
para/sympathetic nervous system.
• Perhaps NANC system
14
15
Pharmacodynamics
• All these effect mediated by the
• DAG- Opening of smooth muscle
binding of G protein directly to
calcium
the channel
• IP3 release calcium from ER and SR
• Muscarinic agonist also increase
• M3/4 inhibits adenylyl cyclase
the cGMP Concentration
activity (Heart and Intestine)
• Activation of muscarinic receptor
also increase Potassium Efflux
• Stimulation of adenylyl cyclase
across cardiac cell membrane
increase the Cyclic AMP Level –
• Dec in ganglionic and smooth
reduced the physiological
muscle cell
response
16
Organ system effects; EYE
1. On conjunctival sac cause
Contraction of Smooth
muscle of iris
Meiosis
2. Contraction;
Ciliary muscle meiosis
Accommodation
Result
Iris pulled away from the
angle of AC and TM
Accommodation
Ciliary muscle opened
17
Organ system effects; CVS
IV infusion of Ach
(20-25mcg/min) causes VD
Increase the HR
Longer dose-Bradycardia & dec.

AV node conduction velocity
Hypotension
SA node, Purkinje cells & AV

muscle cells
Hyperpolarization Diastolic depolarization

18
Organ system effects; Genitourinary tract
Stimulate the detrusor muscle

Stim..
and relax the trigone and Detrusor
Sphincter muscle Muscle
Relaxation Relaxation
Promoting voiding
19
Indirectly acting Cholinomimetics
Absorption
Quaternary carbamates from the conjunctiva, skin, gut and
lungs is predictably poor
Insoluble in lipids
Oral administration is required larger dose
Physostigmine well absorbed
metabolized by non specific esterase
20
Organ systemic effect; CNS
In low conc. Lipid soluble drugs causes diffuses activation of

electroencephalogram and a subjective altering response
High Conc. Convulsion, coma, Respiratory distress
21
Organ systemic effect; Eye, GIT and UT
Similar to the effect of Directly acting Cholinergics
22
Organ systemic effect; CVS
VAGAL NERVE ACTIVATION
Dec. Contractility
CO falls
Inc. Vascular resistance
23
24
25
In mid-afternoon, a coworker brings 43 years-old JM to the
emergency department because he is unable to continue picking
vegetables . He is unable to continue picking vegetables. His gait
is unsteady and he walks with support from his colleagues. JM
has difficulty speaking and swallowing, his vision is blurred, and
his eyes are filled with tears. His coworker notes that JM was
working in a field that has been sprayed early in the morning with
a material that had the odor of sulfur. Within 3 hours after
starting his work, JM complained of tightness in his chest that
made breathing difficult, and he called for help before becoming
disoriented.
How would you proceed to evaluate and treat JM? What should
be done for his coworkers?
22
The patient's presentation is characteristic of poisoning by OP
cholinesterase inhibitors. Ask the coworkers if he can identify
the agent used. Decontaminate the patient by removal of
clothing and washing affected areas. Ensure open airway and
ventilate oxygen. For muscarinic excess. Administer atropine
0.5-5 mg) Iv until signs of muscarinic excess ( dyspnea,
lacrimation, confusion). Subside. To treat nicotinic excess,
infuse 2-PAM (Initially 1-2% solution in 15-30 min) followed by
infusion of 1% solution (200-500mg/h) until muscle
fasciculation cease. If needed, decontaminate the coworker and
isolate all contaminated clothing
23

Cholinoceptor-Activating & Cholinesterase - Inhibiting Drugs

Uploaded by

Copyright:

Available Formats

Cholinoceptor-Activating & Cholinesterase - Inhibiting Drugs

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Cholinoceptor-Activating & Cholinesterase - Inhibiting Drugs

Uploaded by

Copyright:

Available Formats

Cholinoceptor-Activating

Myocardium, Smooth k Adenylyl

Muscarnic M3 Exocrine gland, vessels Like M1 receptor-ligand binding

CNS neurons; vagal nerve Like M2 receptor-ligand binding

Post ganglionic neuron, Depolari

SM Neuromuscular end Similarly to Nicotinic NN

Muscarine mimicked the effect of parasympathetic nerve

Effect of acetyl choline & other cholinomimetic drugs at

Some Quaternary cholinesterase inhibitors also have a direct mode of action.

Choline esters poorly absorbed poorly distributed in to the

All hydrolyzed in the GIT (Less active by Oral Route)

Methacholine is more resistant to hydrolysis

Beta methyl groups are reduced the potency of at Nicotinic

Tertiary natural cholinomimetic alkaloids well absorbed from

Nicotine, a lipid soluble –absorbed across the skin

Muscarine less completely absorbed from the GIT than TA

Tertiary amines are toxic when ingested – certain mushrooms

Amines are excreted – kidney

Acidification of the urine accelerates clearance of the TA

• Activation of Parasympathetic nervous system

Longer dose-Bradycardia & dec.

SA node, Purkinje cells & AV

Hyperpolarization Diastolic depolarization

Stimulate the detrusor muscle

Oral administration is required larger dose

Physostigmine well absorbed

metabolized by non specific esterase

In low conc. Lipid soluble drugs causes diffuses activation of

High Conc. Convulsion, coma, Respiratory distress

Similar to the effect of Directly acting Cholinergics

VAGAL NERVE ACTIVATION

Inc. Vascular resistance

You might also like