CHOLINERGICS&

ANTICHOLINERGICS

By: Mrs. Kalaivani Sathish.

Assistant Professor,PIMS - PANIPAT

NERVOUS SYSTEM

NEUROTRANSMITTERS• A chemical substance which is released at the end of a

nerve fibre by the arrival of a nerve impulse and, by

diffusing across the synapse or junction, effects the

transfer of the impulse to another nerve fibre, a muscle

fibre, or some other structure.

• In ANS the neurotransmitter released are Acetylcholine,

Nor Adrenaline and Dopamine.

• In Adrenal Medulla they are Adrenaline and Nor

Adrenaline.

CHOLINERGIC RECEPTORS• There are two classes of cholinergic

receptors.• Muscarinic and Nicotinic receptors • Muscarinic Receptors are present in

Heart, Smooth Muscles, Glands, Eyes and CNS.(M1 to M5)

• Nicotinic receptors are present in the neuro muscular junction, Autonomic Ganglia and Adrenal Medulla. (NM, NN)

CHOLINERGIC DRUGS• These are chemicals, that acts at the same sites as

Ach, and there by mimics its action. They are called as Para Sympathomimetics or Cholinimimetics.

• Classification1. Ester of Choline

Acetyl choline Metha choline Carbachol2. Cholinomimetic Alkaloids Pilocarpine Muscarine3. Anti cholinesterase Reversible – Neostigmine, Physostigmine,

Pyridosdigmine

CHOLINERGIC DRUGSIrreversible – Organo Phosporous compounds.

Action of Acetylcholine:1. Muscarinic Actiona. Heart – Ach is similar to that of vagal

stimulation, it reduces the heart rate and force of contraction. Larger doses AV conduction is depressed.

b. Blood Vessels – Ach relax the vascular smooth muscles and dilates the blood vessels. The BP falls down.

c. Smooth Muscles – Increase the tone of all smooth muscles: 1. GIT – Tone and Peristalsis enhanced, 2. Urinary Bladder – Contraction Occurs, Promotes voiding of urine. 3. Bronchial Smooth Muscles – Broncho spasm

CHOLINERGIC DRUGSAction of Acetylcholine:1. Muscarinic Actiond. Secretory Gland – Ach enhance the secretion of all

glands, e.g. Gastric, Nasal, Salivary, Lacrimal etc.e. Eye – Ach brings about constriction of pupil.

(Miosis)

2, Nicotinic Actiona. NMJ - Ach brings about the contraction of

skeletal muscle by stimulating NM receptors present in the NMJ resulting in paralysis.

b. Autonomic Ganglia – Ach stimulates the sympathetic and parasympathetic ganglia and adrenal medulla.

CHOLINERGIC DRUGS

2, Nicotinic Actionc. CNS – Ach is a neurotransmitter in several sites in

the CNS.

Pharmacokinetics1. Ach is destroyed in guts when given orally.2. It is rapidly metabolized by pseudo cholinesterase

in the plasma.3. Used only in 1 % eye drop to produce miosis,

during some eye surgeries.Adverse EffectsDiarrhoea, flushing, Salivation, bradycardia,

sweating, bronchospasm

CHOLINOMIMETIC ALKALOIDS• Pilocarpine is an alkaloid obtained from the

leaves of pilocarpus microphyllus.• Like Ach it stimulates the Cholinergic receptors,

but its muscarinic actions are prominent.• It apply to eye, it causes miosis, spasm of

accommodation and fall in intra occular tension. It also increases sweat and salivary secretions.

• Adverse Effects: When used as eyedrops, burning sensation and painful spasm of accommodation, corneal edema can occur. Long term use can cause retinal detachment.

USES• Pilocarpine is used in glaucoma• Pilocarpine ocusert is available, and it

can deliver pilocarpine for 7 days.• It also used alternatively with

Mydraiatics like homatrophine.to break the adhesion between iris and lens.

• Used to counter the dryness of mouth.

GLAUCOMA• It is an eye disease, it is a chronic progressive

optic neuropthy often associated with increase IOP.

ANTICHOLINESTERASE• Anticholinesterase or cholinesterase

inhibitor are drugs which inhibits the enzyme cholinesterase.

• Mechanism of Action: As the structure of anticholinesterase, resemble that of Ach, they bind to acetyl cholinesterase and inactivate them.

• Acetylcholine» Cholineseterase

• Choline + Acetic Acid

• Ach is not hydrolysed and it accumulates.• The actions of all these drugs are due to the

accumulated Ach.• The structure of Ach E contains an anionic site

and an esteratic site.• Reversible anticholinesterases except

edrophonium bind to both anionic and esteractic site.

• Edrophonium binds only to anionic sites and the binding is quickly reversible, hence it is very short acting.Organo Phosphates (OP) binds only to the esteratic sites. But the enzyme is Phosphorylated and the binding is stable.

ANTICHOLINESTERASE CLASSIFICATION

• Reversible – Physostigmine, Neostigmine and Rivastigmine

• Irreversible – a. Organophosphate. E.g. Malathion, sumithion

b. Carbamates – e.g. Carbaryl, aldicarb.

PHYSOSTIGMINE

1. It is an alkaloid, obtained from the plant physostigma venenosum. It is a tertiary ammonium compound, hence it has better peneteration into tissues and also crosses BBB.

2. Avaliable in IV Injection. 3. 0.1 to 1 % eye drops in combination with

pilocarpine nitrate.4. Uses – Glaucoma, atropine poisonning.

NEOSTIGMINEIt is a synthetic quartenary ammonium compound,

poorly absorbed from the gut. Does not cross the BBB.

It is used in myasthenia gravis, post operative paralytic ileus and atony of the urinary bladder.

RIVASTIGMINEIt is a longer acting carbamate that some what

selectively binds to the AchE in the brain.Highly lipid soluble, it absorbs rapidly and reaches the

brain.Uses – Treatment of mild to moderate Alzheimer’s

disease.Dose – 1.5 mg BD. Maximum dose level is 6 mg BD.

USES OF REVERSIBLE ANTICHOLINESTERASE

1. As a myotic – Physostigmine causes miosis, spasm of accommodation and a se IOP. It is used in

a.Glaucomab.Alternatively with a mydriatic to break

adhesions between the iris and the lens.c. To reverse the effect of Mydriatics.

USES OF REVERSIBLE ANTICHOLINESTERASE (Cont…)

2. Myasthenia Gravis – is a chronic auto immune disease, characterized by progressive weakness with rapid and easy fatigability of skeletal muscles.

Treatment – Neostigmine or pyridostigmine or a combination of this may be given.

Neostigmine directly stimulates the NR and there by increase Ach release during each nerve impulse.

USES OF REVERSIBLE ANTICHOLINESTERASE (Cont…)

3. Poisoning due to Anticholinergic drugsPhysostigmine is used in atrophine poisoning, because it

crosses BBB. It reverse all symptoms of atrophine poisoning including CNS effect.

4. Curare Poisoning – Skeletal muscles paralysis caused by curare, can be antagonised by anti ChEs. Edrophonium has fast action, it is less effective than neostigmine.

5. Post Operative Paralytic Ileus and Urinary retention – Neostigmine may be useful.

6. Cobra Bite – Cobra venom is a neuro toxic, causes skeletal muscle paralysis, specific treatment is anti venom, IV Edrophonium prevents respirator paralysis.

USES OF REVERSIBLE ANTICHOLINESTERASE (Cont…)

7. Alzheimer’s Disease – To overcome the deficient cholinergic neurotransmission, Rivastigmine and Donepezil are tried in alzheimer’s disease.

IRREVERSIBLE ANTICHOLINESTERASE

Organo Phosphorous Compounds are powerful inhibitory of AchE.

Effects are similar to cholinergic stimulation as Ach accumulates in the tissues.

OP are highly lipid soluble and hence absorbed from all routes including intact skin. This makes OP Poisoning possible.

Uses - Glaucoma

ORGANO PHOSPHOROUS POISONING

• As OP are used as agriculture and domestic insecticides, poisoning by them is quiet common.

• Poisoning may be occupational as spraying insecticides, accidental or suicidal.

• Symptoms – Muscarinic, Nicotinic and Central effects (Vomiting, abdominal cramps, diarrhoea, miosis, sweating, increased salivary, broncial and gastric secretions and bronchospasm) hypotension, muscular twitching, weakness, convulsions, coma. Death is due to respiratory paralysis.

ORGANO PHOSPHOROUS POISONING

• TREATMENT – If poisoning is through skin, remove clothing and wash the skin with soap and water.

• If consumed by oral route, gastric lavage is given.• Maintain BP and maintain patent airway.• Drug of choice is atrophine IV. 2mg every 10 minute till

pupil dilates.• Maximum dose is 50 – 100 mg.• Carefull monitoring of symptoms due to delayed

absorptions of OP compounds.

ORGANO PHOSPHOROUS POISONING

• TREATMENT (Cont…)• ChE reactivators – Pralidoxime, Obidoxime, Diacetyl

Monoxime are given.• This oxime compounds combines with ChE

organophosphate complex release the binding and set free AchE enzymes.

• They reactivate the cholinesterase enzymes, thus reducing the poisoning effects.