Pharmacology of Autonomic Nervous System Cholinergic Agonists

Dr. P Sabetha

Cholinergic (parasympathetic) Responses in the body (Rest & digest stimuli)

Name the Neurotransmitter (NT) receptors in ANS cholinergic system. Name the receptors Ach acts at. Acetylcholine (Ach) is NT in postganglionic parasympathetic nerves and both sympathetic / parasympathetic ganglia.[ANS] However, Ach is also a NT at sites other than ANS. Hence, any cholinergic agonist used as drug will act at all these sites. Hence, it is worthwhile to know all the cholinergic receptors in the body to understand the toxicology or therapeutic uses of cholinergic agonist drugs  Autonomic postganglionic parasympathetic – M (Muscarinic receptor)  Autonomic sympathetic & parasympathetic ganglia - NN ( Nicotinic neuronal)  Skeletal muscle- NM( Nicotinic muscle)  Brain- M (Muscarinic receptor) How the action of NT Ach action is terminated? Acetylcholinesterase (AchE) enzyme present in the synaptic cleft metabolizes NT Ach and terminates its action. NT Ach has short duration of action because of this metabolism. There is one more enzyme Pseudocholinesterase in the liver GIT,blood. The physiological function of this enzyme is not known as there is no circulating Ach in blood. Explain the interaction between Ach & AchE Ach + AchE ↓ Acetylated AchE+ Choline ↓ Hydrolysis Acetate + AchE (reactivated) Acetylated enzyme is immediately hydrolyzed so that the enzyme is regenerated to metabolize another Ach molecule.

Can Ach be used as drug? No, because Ach if given either by oral or injection, immediately metabolized by above mentioned pseudo cholinesterase enzyme. Can the NT Ach action be prolonged? If so, how? Yes. Drugs that structurally resemble Ach can bind to AchE and inhibit the enzyme, so that NT Ach is not metabolized immediately, hence, the duration of NTAch can be prolonged. This will enhance the endogenous cholinergic activity in the body.

Mention chemicals that can inhibit AchE (Anticholinesterase compounds). There are 2 groups of chemicals. 1. Reversible inhibitors (Carbamates). Used in treatment of diseases 2. Irreversible inhibitors (Organophosphates). Mainly are used as insecticides / war gases. Used for suicidal / homicidal purpose. Hence for us toxicological importance. Explain how AchE reversible inhibitors act? These drugs bind to AchE to form carbamylated AchE & Choline. Carbamylated AchE, unlike acetylated AchE is not immediately hydrolyzed so the AchE is not regenerated to metabolize Ach NT. So NT Ach can act for long time at synaptic cleft in brain (M), skeletal muscle (NM) and at autonomic sites (M). However, Carbamylated AchE is hydrolyzed slowly the time for which varies with drugs. Hence, the AchE is still available at synaptic cleft to metabolize NT Ach but life of NTAch is prolonged.

Note: All effects of AchE (reversible / Irreversible) inhibitors on the body are mediated through accumulated NTAch at synaptic cleft. Carbamate + AchE → Carbamylated AchE+ Choline (hours)Slow ↓ Hydrolysis Carbamate + AchE (reactivated)

Explain the therapeutic uses of AchE Reversible inhibitors? Neostigmine (N) & Pyridostigmine (P): Both these drugs do not cross BBB so no action on brain. 1. Myasthenia gravis: Is an auto-immune disease where antibodies are formed against NM receptors. This results in reduction in number of NM receptors and also structural damage to NM junction leading to muscle weakness and easy fatigability. N/ P use accumulates NT Ach that can act on NM receptors over large muscle area improving the muscle contractility and power. However, overdose of N/ P can worsen muscle weakness because of persistent depolarization of skeletal muscle endplate. This must be kept in mind. Corticosteroids are also used to inhibit antibody formation against NM receptor

2. For Reversal of Postoperative skeletal muscle paralysis: Neostigmine NM receptor (reversible) antagonists are used to produce skeletal muscle paralysis during surgery. After surgery, skeletal muscle paralysis needs to be overcome. Increase the concentration of Ach (agonist) by using N this overcomes NM receptor antagonism. 3. Alzheimer’s disease: Rivastigmine; Donepezil. This condition is a progressive dementia due to degeneration of the cholinergic neurons in brain. Rivastigmine & Donepezil are reversible AchE inhibitors that can penetrate BBB well because of which better desired effect on brain and less peripheral Ach mediated adverse effects. 4. Post operative Gastrointestinal / bladder atony. During surgery, manual handling of visceral organs can result in paralysis of bladder or intestines. Excess cholinergic activity by N/ P can improve the contractions thereby functions of bladder & intestines. Bethanechol (a direct M receptor agonist that is not metabolized by AchE) can be used for the same purpose. 5. Glaucoma: Demecarium, (also Ecothiophate an OP compound or/ Pilocarpine a M receptor agonist) used as eye drops. ( discussed by Ophthalmologist later years) Mention the cautions/ contraindications for the use of Anti cholinesterases? Bronchial asthma; Peptic ulcer; AV blcok Classify Irreversible anti cholinesterase compounds / organophosphates (OP)  Used in therapy (Glaucoma) – Ecothiophate  Insecticides - Parathion; Malathion, Diazinon  War gases - Tabun; Sarin; Soman All organophosphates [except for Ecothiophate] are of toxicological importance ie; doctors encounter patients consuming organophosphates with suicidal / homicidal purpose

Explain the basis behind toxicology of OP poisoning OP compounds react with AchE to form phosphorylated AchE which will never undergo hydrolysis (irreversible inhibition of AchE) so the AchE is never ever reactivated. Ach accumulates at cholinergic nerve endings until sufficient new AchE molecules are synthesized to metabolize Ach which is a matter of few days (around 10days). Until then accumulated NTAch keep acting at M receptors and brings about exaggerated parasympathetic responses (refer class slide handouts for normal physiological parasympathetic responses). However, at NM junction (skeletal muscle), Ach accumulated does not bring about exaggerated skeletal muscle contraction. On the other hand, Initial depolarization followed by persistent depolarization of skeletal muscle end plate leads to inactivation of Na channels; the end plate potential fails to propagate as action potential, leading to inability of the muscle to contract. This results in flaccid paralysis of skeletal muscle. Intercostal muscle and diaphragm paralysis leads to respiratory failure and death. What happens to phosphorylated AchE in above case? Phosphorylated AchE does undergo degradation but without regenerating AchE. So AchE is never regenerated. Sufficient concentration of new AchE molecules need to be synthesized for metabolism of accumulated NTAch. What is the basis of treatment of OP poisoning? Supportive Measures: Maintain BP, hydration, control of convulsions (Benzodiazepine) Specific measures: Prevent / counter the actions of accumulated Ach until sufficient concentrations of new AchE synthesized ( may be around 10 days) At parasympathetic sites (M): NTAch accumulated at M receptors brings about exaggerated responses – So block all the M receptors by using Atropine (IV injection) until sufficient amount of new AchE synthesized to metabolize accumulated Ach. At skeletal muscle (NM): Unlike above, don’t block NM receptors which will worsen respiratory paralysis. Instead assist respiration to patient until sufficient amount of new AchE synthesized to metabolize accumulated Ach. However, there is a drug Pralidoxime / Obidoxime which can reactivate the AchE selectively at NM receptors. This drug is effective only if used within 24 hrs of poisoning. This drug use may minimize the need for artificial respiration. Phosphate + AchE → Phosphorylated AchE+ Choline (IV) Pralidoxime ↓ (effective if used within 24 hrs ) (Reactivated)AchE + Oxime phosphonate  We are treating the patient till metabolism of NT Ach is assumed back.  Atropine is a must whereas Oxime is optional in treatment of OP poisoning.

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