| What are main cholinergic agonist drugs? | Mimic action of Ach (cholinergic drugs, cholinomimetics, parasmpathomimetics)
They are two classes
Direct acting (muscarinic [choline esters, alkaloids], nicotinic)
Indirect acting (organophosphates [very long acting], carbamates [intermediate long acting], and endophonium [short acting]) |
| What are direct acting cholinergic agonists? | 2 groups, choline esters (Ach and synthetic esters of choline, such as Carbachol and Bethanchol), and Naturally occurring alkaloids (pilocarpine)
All have longer durations of actions than Ach, little specificity in their actions limiting their clinical usefullness. |
| How is Ach as direct acting cholinergic agonist? | Quaternary amonium, cannot penetrate membranes, not very important since cholinesterase rapid inactivation.
Decreases HR and CO (negative chronotropy), Decreases BP (activates M3 receptors of endothelia cause vasodilation), Increases saliva and intestinal secretion and motility, bronchiolar increased secretions, expulsion of urine increasing tone of detursor muscle, stimulate ciliary muscle contration for near vision, contraction of sphincter for miosis. |
| How is Bethanechol as direct acting cholinergic agonist? | structure like Ach, acetate replaced by carbamate, choline methylated.
Not hydrolyzed by acetylcholinesterase, inactivated by hydrolysis by other esterases.
Lack nicotinic action! due to methylation, but has strong muscarinic activity.
Major actions on bladder and GI, duration of action 1 hour.
Actions: increase intestinal motility and secretions, stimulates detursor muscle of bladder whereas sphincter is relaxed, causing expulsion of urine.
Therapeutic uses: uro treatment in case of atonic bladder (postpartum/ post op/ non obstructive urinary retention).
treat megacolon (abnormal colon dilation).
Adverse effects (generalized cholinergic effects sweating, salivation, decreased BP, nausea, abdo pain, diarrhea, bronchospasm |
| How is Carbochol (carbamylcholine) as direct acting cholinergic agonist? | Ester of carbamic acid and poor substrate for acetylcholinesterase, positive charged quaternary amonium, biotransformed by other esterases, much slower rate, muscarinic effect and causes release of Epi by nicotinic action.
admin intraocular solution/injection, high potency, no selectivity, long duration of action so rarely used therapeutically except in the eye.
Used as miotic for treating glaucoma/ ophthalmic surgery |
| How is Pilocarpine as direct acting cholinergic agonist? | Alkaloid tertiary amine, stable to hydrolysis by acetylcholinesterase, uncharged penetrate CNS at therapeutic doses, exhibits muscarinic effects primarily in ophthalmology.
Oral doses for treatment of Xerostomia (stimulate salivary and lacrimal secretions) resulting from radiation tx for cancer of head and neck.
Opthalmic solution treats open angel glaucoma lowers intraocular pressure within few minutes following ocular instillation
Causes contraction of iris sphincter results in miosis and contraction of ciliary muscles cause near focus vision.
Causes marked diaphoresis (2-3 liters of sweat may be secreted)
Enter brain and cause CNS disturbances |
| How are anti-cholinesterases as indirect acting cholinergic agonists? | Inhibitors of acetylcholinesterase prolong lifetime of acetylcholine resulting in accumulation of acetylcholine in synaptic space.
Provoke a response in cholinoreceptors in body including ANS muscarinic and nicotinic receptors, neuromuscular junctions and in the brain
They are intermediate/ short-acting drugs with reversible effects
Include Physostigmine, Neostigmine, Edrophonium, Tacrine, Pyridostigmine, Donepezil, Rivastigmine, Galantamine |
| How is physostigmine as anti acetylcholinesterase? | Nitrogenous carbamic acid ester in plants (Calabar) tertiary amine.
Substrate for acetylcholinesterase forms stable enzyme substrate intermediate reversibly inhibiting the enzyme, results in potentiation of cholinergic activity throughout the body.
Actions (intermediate acting, stimulates cholinergic sites at CNS)
Therapeutic uses: increases GI and bladder motility, produces miosis and spasm of accomodation lowering intraocular pressure, treats overdoses such as atropine, phenothiazines (antipsychotic), and tricyclic antidepressants.
Adverse reactions: CNS convulsions in high doses, bradycardia and fall of CO, paralysis of skeletal muscle by increasing Ach at nicotinic receptors in neuromuscular synapse causing flaccid paralysis |
| How is neostigmine as anti-acetylcholinesterase? | Quaternary amine enters CNS poorly long acting.
Synthetic compound carbamic acid ester, enhances gastric contraction and increases secretion of gastric acid, stimulates motor activity of small intestine and colon.
Treats detursor atony of urinary bladder in case of urinary retention.
Antidote of tubocurarine (Ach antagonist) and other competitive neuromuscular blocking agents.
Symptomatic treatment of Myasthenia gravis |
| How is Edrophonium as anti-cholinesterase? | Quaternary amine used as clinical test for Myasthenia gravis, it will markedly increase muscle strength in MG patients, often causes some cramping but lasts only few minutes (prototype of short acting agents) |
| How is Pyridostigmine as anti-cholinesterase? | Sometimes used to treat MG |
| How are Tacrine, Rivastigmine and Galantamine as anti-cholinesterases? | In patients with loss of cholinergic neurons like Alzheimers, anticholinesterases are used to remedy the loss of cognitive function, Tacrine first one available but replaced due to hepatotoxicity.
The others cannot stop progression of the disease but delay it.
GI distress is primary adverse effect (Vomiting and nausea) |
| What are irreversible anticholinesterases? | Synthetic organophosphate compounds have capacity to bind covalently to acetylcholinesterase, results in long-lasting increase in acetylcholine at all sites where it is released.
Related compounds like parathion are employed as insecticids, many of theme are toxic and used as military nerve agents |
| How is Echothiophate (Phospholine Iodide) as irreversible anticholinesterase? | Organophosphate covalently binds via phosphate group to serine-OH group at active site of acetylcholinesterase.
Permenantly inactivates acetylcholinesterase, and its activity requires synthesis of new molecules, following the covalent modification, the enzyme slowly releases one of its ethyl groups, which is called aging, make it possible for chemical reactivators such as Pralidoxime (PAM) to break this bond.
Actions (generalized cholinergic stimulation, paralysis of motor function causing breathing difficulty, convulsions)
Atropine in high dosage can reverse many of muscarinic and central effects of it.
Used as ophthalmic solution to treat chronic open angel glaucoma.
Effect lasts up to one week, not first-lline glaucoma treatment, may be topical use |
| How is reactivation of acetylcholinesterases by Pralidoxime (PAM) after action of echothiophate? | PAM reactivates acetylcholinesterase but is unable to penetrate into CNS, charged group allows it to reach anionic site of enzyme, displaces phosphate group of organophosphate and regenerate the enzyme, given before aging of alkylated enzymes occur, can reverse the effects of echothiophate except in CNS |
| What are clinical manifestations of nerve agent exposure (weapon) Tabun-Sarin- Soman? | . |
| What are some irreversible acetylcholinesterase inhibitors? | . |
