And Related Agents

Cholinergic Drugs and Related Agents

Mimic the action of acetylcholine or,Blocks the action of acetylcholine (ACh)

*Cholinergc Drugs - stimulates the parasympathetic nervous system (rest and digest).

Acetylcholineis one of many

neurotransmitters in the autonomic nervous system (ANS)

only neurotransmitter used in the motor division of the somatic nervous system

Cholinergic Receptors

Nicotinic receptors- 2 Subtypes

Muscarinic receptors- 5 Subtypes

Nicotinic Receptorscoupled directly to ion channelsfirst neurotransmitter isolated and purified in an active

formIt is a glycoprotein embedded into the polysynaptic

membrane that can be obtained from the electric organs of the marine ray, Torpedo californica and the electric eel, Electrophorus electricus.

When the neurotransmitter ACh binds to the nicotinic receptor, it causes a change in the permeability of the membrane to allow passage of small cations Ca2, Na, and K. This depolarization results in muscular contraction at a neuromuscular junction or, as occurs in autonomic ganglia, continuation of the nerve impulse.

Nicotinic receptor subtypes

N1 N2

At the neuromuscular junction Found in autonomic ganglia

blocked by succinycholine, d-tubocurarine, and decamethonium and stimulated by phenyltrimethylammonium

blocked by hexamethonium and trimethaphan but stimulated by tetramethylammonium and dimethyl 4-phenylpiperazinium

Muscarinic Receptors

play an essential role n regulating the function of organs innervated by the autonomic nervous system to maintain homeostasis.

Its action can result to stimulation/inhibition of the organ system that is affected.

Muscarinic Receptor subtypesM-

receptors subtypes

M1 M2 M3 M4 M5

Other name

neural Cardiac muscarinic receptors

Glandular muscarinic receptors

Location Exocrine glands and autonomic ganglia

Atria and conducting tissue of the heart

Exocrine glands and smooth muscle

CNS Substantia nigra (cns)

Function Affects arousal attention, REM, emotional response, affective disorder

Cardiac inhibition

Lacrimal, salivaryMostly stimulatory effect

Direct regulatory action on K and Ca ion channels

May regulate dopamine release at terminals within the striatum

Second messenger systemPhosphoinositol System

Adenyl Cyclase

Ion Channel

Cholinergic NeurochemistryCholinergic neurons synthesize, stores and releases

ACh . It describes any neuron which mainly uses the neurotransmitter acetylcholine (ACh) to send its messages.

Cholinergic neurons provide the primary source of acetylcholine to the cerebral cortex, and are known for their role in promoting cortical activation during both wakefulness and during rapid eye movement (REM) sleep.

Neurochemistry is the specific study of neurochemicals including neurotransmitters and other molecules (such as psychopharmaceuticals) that influence the function of neurons.

CHOLINERGIC AGONISTcholinergic agents; parasympathomimetic; mimics effect of parasympathetic nervous system

neuroransmittersA substance (or ligand) is cholinergic if it is capable of

producing, altering, or releasing acetylcholine ("indirect-acting") or mimicking its behaviour at one or more of the body's acetylcholine receptor types ("direct-acting").

Cholinergic Stereochemistryis the study of the chemistry involved in the relative

spatial arrangement of cholinergic atoms and molecules.

Has 3 techniques

X-ray crystallographyis a method of

determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and diffracts into many specific directions.

Nuclear magnetic resonance a physical phenomenon in

which nuclei in a magnetic field absorb and re-emit electromagnetic radiation.

This energy is at a specific resonance frequency which depends on the strength of the magnetic field and the magnetic properties of the isotope of the atoms

Molecular Modelling by computation

encompasses all theoretical methods and computational techniques used to model or mimic the behavior of molecules.

STRUCTURE – ACTIVITY RELATONSHIPS

is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical groups responsible for evoking a target biological effect in the organism.

3 Categories of the Alteration on the MoleculeOnium groupEster functionCholine moeity

ProductsOxotremorine[1-(pyrrolidono)-4-

pyrrolidino- 2-butyne]CNS muscarinic

stimulantStudied to be a drug

treatment on Alzheimer’s disease

Arecoline

Alkaloid obtain from seed of betel nut (Areca catechu)

CHOLINERGIC RECEPTOR ANTAGONISTSblocks the neurotransmitter acetylcholine in

the central and the peripheral nervous system. cholinergic blockers, parasympatholytics or anticholinergic

Acetylcholine chloride

Carbachol

Betanechol Chloride, USP

PILOCARPAINE HCL

Cholinesterase inhibitorsbind to cholinesterase resulting in increased

acetylcholine in the synapses, causing increased parasympathetic activity

Acetylcholinesterase - an enzyme that rapidly breaks down the neurotransmitter, acetylcholine, so that it does not over-stimulate post-synaptic nerves, muscles, and exocrine glands

Acetylcholinesterase inhibitor - a chemical that binds to the enzyme, cholinesterase, and prevents it from breaking down the neurotransmitter, acetylcholine.

2 types of cholinesterase:Acetylcholinesterase (AChE) – its inhibition

prolongs the duration of the neurotransmitter in the junction and produces pharmacological effects similar to those observed when ACh is administered.

Butyrylcholinesterase (BuChE) – (pseudocholinesterase), is located in human plasma. Has catalytic property similar to AChE

2 TYPES OF ACETYCHOLINETRANFERASE INHIBITORS

REVERSIBLE INHIBITORS– has therapeutic application

IRREVERSIBLE INHIBITORS – these chemicals are nerve poisons and had been use in warfare, bioterrorism, and as agricultural insecticides. They permit ACh to accumulate at nerve endings and exacerbate ACh-like actions.

Physostigmine, USP

Physostigma venemosum.topical application in the

treatment of glaucomaantidote for atropine

poisoning and other antcholinergic drugs.

Neostigmine Bromide - antidote to

nondepolarizing neuromuscular blocking drugs

treatment of myasthenia gravis.

Demecarium bromide, USP – long acting miotic use

to treat wide angle glaucoma and accommodative esotropia.

Donezepil– indicated for the

treatment of mild-to-moderate Alzheimer’s disease

GalantamineLeucojum aestivum

belonging to the Amaryllidaceae family and from the bulbs of the daffodil, Narcissus pseudonarcissus;

no effect on butyrylcholinesterase; acts at allosteric nicotinic sites, further enhancing its cholinergic activity.

Rivastigmine – the FDA approved its

use in mild-to-moderate Alzheimer’s disease in April 2000.

In July 2007, it was granted approval for use in managing mild-to-moderate dementia associated with Parkinson’s disease.

Irrevrsible InhibitorsIsofluorphate, USP(Floropryl) - Stable in

peanut oil (1 yr).Solutions in peanut oil

can be sterilized by autoclaving;

Should be stored in glass containers, discoloration when decomposed;

treatment of glaucoma

Malathion - Water insoluble

phophodithioate esterused as agricultural

insecticide; generally, cause

poisoning only by ingestion of large doses.

Parathion - (Thipos); Decomposed at pH

above 7.5; causes poisoning by

inhalation or dermal absorption;

Used as an agrcultural insecticide

Hexaethyltetraphosphate (HETP) and Tetraethylpyrophosphate (TEPP) - Developed by the Germans

during WWII; Insecticide against aphids;

Fruit trees or vegetables sprayed retain no harmful residue after a period of a few days or weeks, depending on the weather conditions.;

Workers spraying with these agents should use extreme caution so that vapors are not breathed and none of the vapor or liquid comes in contact with the eyes or skin.

CHOLINERGIC BLOCKING AGENTS

Anticholinergic action by drugs and chemicals apparently depends on their ability to reduce the number of free receptors that can interact with Ach.

Some theories indicate that the amount of drug-receptor complex formed at a given time depends on the affinity of the drug for the receptor and that a drug that acts as an agonist must also possess another property called efficacy or intrinsic activity.