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Parasympathomimetic Drugs

Also known as Cholinergic drugs or Cholinomimetic drugs or Cholinoceptor activating drugs.

Definition

These are the group of drugs which produce effects resembling those produced by the stimulation of parasympathetic autonomic nervous system on the target organs

Neurotransmitter involved is acetylcholine. Most of the peripheral autonomic nervous system fibers cause synthesis and release of acetylcholine. They activate the parasympathomimetic system, thus called cholinergic fibers.

All preganglionic and most of parasympathomimetic postganglionic and some postganglionic sympathetic fibers, adrenal medulla and skeletal somatic muscle fibers constitute the cholinergic fibers.

Parasympathomimetics were discovered form muscarine alkaloid obtained from natural source, which produces effects by affecting organs similar to parasympathetic system, thus receptors were termed muscarinic receptors.

Nicotine was discovered to act on skeletal muscle NMJ and autonomic ganglia, such receptors were termed nicotinic. They were further discovered by Dale.

Synthesis, storage, Release & inactivation

Already discussed.

Mechanism of Action

a. G –protein linked (Muscarinic), through transmembrane 2nd messenger signaling

b. Ligand gated Ion channels (Nicotinic)

Muscarinic receptors act through DAG/IP3 second messenger system.

Cholinergic Receptors

1. Muscarinic

M1 = Nerves, Stomach, Brain

Antagonist:   Pirenzepine

M2 = Heart, Nerves, Smooth Muscle.

Antagonist:    Gallamine

M3 = Glands, Endothelium, Smooth Muscle.

M4 and M5 newly discovered, role not yet known

Muscarinic receptors act through the IP3/DAG cascade. They also cause activation of guanylcyclase activity by increasing cGMP (decrease cAMP in heart and smooth muscles). Calcium is released from sarcoplasmic and endoplasmic reticulum.

M1, M3 and M5 act through IP3/DAG cascade

M2 and M4 act by decreasing the levels of cAMP activating the K+ channels.

2. Nicotinic

a. Present in neuromuscular junction, NM

Agonist:  Phenyl Trimethyl Ammonium

Antagonist:  Tubocurarine

b. Present in autonomic ganglia, adrenal medulla, NN

Agonist:   Dimethyl phenyl piperazinium

Antagonist:  Hexamethonium

Classification

A.   Directly Acting –act by causing release of acetyl choline
B.   Indirectly Acting –inactivate enzymes involved like pseudocholine esterase, thus hydrolysis of acetylcholine does not occur

A. Directly Acting Cholinergic Drugs:

I. Choline Esters

Acetylcholine

Carbachol

Methacholine

Bethanechol

II. Cholinomimetic Alkaloids
a.         Mainly Muscarinic Agonists

Natural Alkaloids:

Muscarine

Pilocarpine

Arecholine

Synthetic Alkaloid:                            

Oxotramorine

Selective M3 agonists

Cevimeline

b.         Mainly Nicotinic Agonists     

Natural Alkaloids:

Nicotine

Lobeline

Synthetic Alkaloids:

Dimethyl phenyl piperazinium (DMPP)

Varenicline

Tertiary alkaloids

Pilocarpine

Nicotine

Lobeline

Quaternary amines

Muscarine

B. Indirectly Acting Cholinergic Drugs (Anticholinesterases)

I- Reversible

a. Carbamates

b. Alcohols

II- Irreversible

 

I- Reversible

a. Carbamates                       
Tertiary amines         

Physostigmine

Quaternary Ammonium compounds

Neostigmine

Pyridostigmine

Distigmine

Ambenonium

Demecarium

b. Alcohols

Edrophonium

c. Miscellaneous

Tacrine

Donepezil

Galantamine

Rivastigmine

II.  Irreversible Anticholinesterases (Organophosphorus Compounds)
1. Therapeutically useful:

Ecothiophate

2. War Gases:

Sarin

Tuban,

Soman

3. Insecticides:-

Parathion

Malathion

DiisopropylFlurophosphate (DFP)

Tetramethyl Pyrophosphate (TMPP)

Octamethyl Pyrophosphotetraamide (OMPA)

Continue Reading

Acetylcholine

Carbachol

Methacholine

Bethanechol

Muscarine and Pilocarpine

Nicotine and Lobeline

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