anticholinestrases by dr. pramod

Anticholinestrases

Acetylcholine as a Neurotransmitter

Neuromuscular Junction

Acetylcholine Metabolism

Acetylcholine Metabolism

Mechanisms of action of indirect cholinergic agonists.

Anticholinestrases

• Anticholinesterases (anti-ChEs) are agents which inhibit ChE, protect ACh from hydrolysis—produce cholinergic effects.

Classification of Anticholinestrases

Organophosphate Insecticides

Hydrolysis of Acetylcholine

Carbamates: Mechanism of Action

• The carbamic acid esters neostigmine and physostigmine are hydrolyzed by AChE, so a labile covalent bond is formed between the drug and the enzyme.

• However, the rate at which this reaction occurs is many orders of magnitude slower than for ACh.

• The resulting enzyme–inhibitor complex has a half- life of approximately 15–30 minutes, corresponding to an effective inhibition lasting 3–8 hours.

Carbamates: Mechanism of action

Organophosphate: Mechanism of action

• Organophosphate compounds are hydrolyzed by AChE, but the resulting phosphorylated enzyme complex is extremely stable and dissociates with a half-life of hundreds of hours.

Organophosphates: Mechanism of action

Pharmacological actions• The actions of anti-ChEs are due to amplification of

endogenous ACh.

• Lipid-soluble agents (physostigmine and organophosphates) have more marked muscarinic and CNS effects; stimulate ganglia but action on skeletal muscles is less prominent.

• Lipid-insoluble agents (neostigmine and other quaternary ammonium compounds) produce more marked effect on the skeletal muscles (direct action on muscle endplate cholinoceptors as well), stimulate ganglia, but muscarinic effects are less prominent. They do not penetrate CNS and have no central effects.

Uses of Anticholinestrases

• As Miotic• In glaucoma: Miotics increase the tone of ciliary

muscle (attached to scleral spur) and sphincter pupillae

• improve alignment of the trabeculae

• outflow facility is increased.

• intraocular tension falls in open angle glaucoma.

Uses of Anticholinestrases

• As Miotic• To prevent formation of adhesions between iris and

lens or iris and cornea, and even to break those which have formed due to iritis

• —a miotic is alternated with a mydriatic.

Uses of Anticholinestrases• Myasthenia gravis

• Development of antibodies directed to the nicotinic receptors (NR) at the muscle endplate.

Uses of Anticholinestrases

• Postoperative paralytic ileus/urinary retention

Uses of Anticholinestrases

• Postoperative decurarization

• Neostigmine-Reverses muscle paralysis induced by competitive neuromuscular blockers.

Uses of Anticholinestrases

• Cobra bite• Cobra venom has a curare like neurotoxin.

Uses of Anticholinestrases

• Belladonna poisoning(Anticholinergic Poisoining)

• Physostigmine 0.5–2 mg i.v. repeated as required is the specific antidote for poisoning with belladonna or other anticholinergics.

• It penetrates blood-brain barrier and antagonizes both central and peripheral actions.

Uses of Anticholinestrases

• Alzheimer’s disease

• AD is a neurodegenerative disorder, primarily affecting cholinergic neurones in the brain.

• The relatively cerebroselective anti-ChEs, rivastigmine, donepezil and galantamine are now commonly used.

Anticholinestrase poisoining

• Anticholinesterases are easily available and extensively used as agricultural and household insecticides; accidental as well as suicidal and homicidal poisoning is common.

Anticholinestrase poisoining• Symptoms• Irritation of eye, lacrimation, salivation, sweating, copious tracheo-bronchial

secretions, miosis, blurring of vision, bronchospasm, breathlessness, colic, involuntary defecation and urination.

• Fall in BP, bradycardia or tachycardia, cardiac arrhythmias, vascular collapse.

• Muscular fasciculations, weakness, respiratory paralysis (central as well as peripheral).

• Irritability, disorientation, unsteadiness, tremor, ataxia, convulsions, coma and death.

• Death is generally due to respiratory failure.

Anticholinestrase poisoining

• Treatment• 1. Termination of further exposure to the poison—fresh

air, wash the skin and mucous membranes with soap and water, gastric lavage according to need.

• 2. Maintain patent airway, positive pressure respiration if it is failing.

• 3. Supportive measures—maintain BP, hydration, control of convulsions with judicious use of diazepam.

Anticholinestrase poisoining• 4. Specific antidotes—• (a) Atropine: highly effective in counteracting the muscarinic

symptoms, but higher doses are required to antagonize the central effects.

• It does not reverse peripheral muscular paralysis which is a nicotinic action.

• All cases of anti-ChE (carbamate or organophosphate) poisoning must be promptly given atropine 2 mg i.v. repeated every 10 min till dryness of mouth or other signs of atropinization appear.

Anticholinestrase poisoining

• 4. Specific antidotes—• (b) Cholinesterase reactivators• Oximes are used to restore neuromuscular transmission

only in case of organophosphate anti-ChE poisoning.

• The phosphorylated ChE reacts very slowly or not at all with water. However, if more reactive OH groups in the form of oximes (generic formula R–CH = N–OH) are provided, reactivation occurs more than a million times faster.

Anticholinestrase poisoining• Pralidoxime (2-PAM) has a positively charged quaternary

nitrogen: attaches to the anionic site of the enzyme which remains unoccupied in the presence of organophosphate inhibitors.

• Its oxime end reacts with the phosphorus atom attached to the esteratic site: the oxime-phosphonate so formed diffuses away leaving the reactivated ChE.

• Pralidoxime is injected i.v. slowly in a dose of 1–2 g (children 20–40 mg/kg).

Thank You

Question 1

• Which of the following drugs or classes of drugs will be useful in treating the symptoms of myasthenia gravis?

• A. Nicotinic antagonists.• B. Muscarinic agonists.• C. Muscarinic antagonists.• D. Anticholinesterase agents.

Question 1

• Correct answer = D. • The function of nicotinic receptors in skeletal muscles is

diminished in myasthenia gravis due to the development of antibodies to nicotinic receptors in the patient’s body (autoimmune disease).

• Any drug that can increase the levels of ACh in the neuromuscular junction can improve symptoms in myasthenia gravis.

• Thus, cholinesterase inhibitors help to improve the symptoms of myas- thenia gravis. Muscarinic drugs have no role in myasthenia gravis, and nicotinic antagonists will worsen the symptoms

Question 2• An elderly female who lives in a farm house was brought to

the emergency room in serious condition after ingesting a liquid from an unlabeled bottle found near her bed, apparently in a suicide attempt. She presented with diarrhea, frequent urination, convulsions, breathing difficulties, constricted pupils (miosis), and excessive salivation. Which of the following is correct regarding this patient?

• A. She most likely consumed an organophosphate pesticide.• B. The symptoms are consistent with sympathetic activation.• C. Her symptoms can be treated using an anticholinesterase

agent.• D. Her symptoms can be treated using a cholinergic agonist.

Question 2• Correct answer = A. The symptoms are consistent with that of

cholinergic crisis. Since the elderly female lives on a farm and since the symptoms are consistent with that of cholinergic crisis (usually caused by cholinesterase inhibitors), it may be assumed that she has consumed an organophosphate pesticide (irreversible cholinesterase inhibitor).

• Assuming that the symptoms are caused by organophosphate poisoning, administering an anticholinesterase agent or a cholinergic agonist will worsen the condition. The symptoms are not consistent with that of sympathetic activation, as sympathetic activation will cause symptoms opposite to that of cholinergic crisis seen in this patient.

Question 3

• Neostigmine is preferred over physostigmine for treating myasthenia gravis because:

• A. It is better absorbed orally• B. It has longer duration of action• C. It has additional direct agonistic action on• nicotinic receptors at the muscle end plate• D. It penetrates blood-brain barrier

Question 3

• Answer : c

Question 4

• The antidote for organophosphate poisoining is:

• A) Atropine( anticholinergic)• B) Neostigmine• C) None of the above

Question 4

• Correct answer: A

Question 5

• Anticholinestrases are useful in following conditions except:

• A) Postoperative Decurarization• B) Myaesthenia Gravis• C) Belladona Poisoining• D) Alzheimers Disease• E) As Mydriatics

Question 5

• Answer: E