Cholinergic Agonists Direct-Acting Cholinomimetics Direct-Acting Cholinergic Agonists (N & M) Cholinergic agonists (parasympathomimetics) mimic the effects of ACh on cholinoceptors. These agents broadly classified into:
Endogenous choline esters, Ach Synthetic esters of choline, carbachol and bethanechol. Naturally occurring alkaloids, nicotine, pilocarpine All of the direct-acting cholinergic drugs have longer durations of action than acetylcholine As a group, the direct-acting agonists show little specificity in their actions, which limits their clinical usefulness
Acetylcholine (Ach) Quaternary ammonium compound -------Site of action -------Both muscarinic and nicotinic activity Therapeutic uses ---- HR & CO (vagal stimulation). Effect of IV Ach on: I.
Heart: ------------ due to ----------------- II. Blood Pressure Injection of Ach vasodilation and lowering BP ( indirect mechanism of action) activates M3 receptors on endothelial cells lining SM of BVs production of nitric oxide from arginine
NO diffuses to vascular SM stimulates PK G production hyperpolarization (SM relaxation through PDE-3 inhibition) III. Other
Actions of ACh GIT: increases salivary secretion and stimulates intestinal secretions and motility. Bronchiolar secretions are also enhanced.
Genitourinary tract: the tone of the detrusor urinae muscle is increased, causing expulsion of urine. Eye, stimulating ciliary muscle contraction for near vision Constriction of the pupillae sphincter muscle, causing miosis Acetylcholine (1% solution) is instilled into the anterior chamber of the eye to produce miosis during ophthalmic surgery.
The Eye Adverse Effects of Cholinomimetics Bethanechol Structurally related to Ach (in which the acetate is replaced by carbamate and the
choline is methylated). Not hydrolyzed by AChE (addition of carbonic acid), / inactivated by other esterases. lacks N actions / have strong M activity Major actions / SMs of the bladder & GIT. Duration of action of about 1 hour.
Bethanechol (cont.) Actions: Direct effect on MRs, intestinal motility & tone??? Detrusor Ms of the bladder ??? whereas the trigone & sphincter ??? Therapeutic applications: Stimulate the atonic bladder, particularly in postpartum or postoperative,
nonobstructive urinary retention. Neurogenic atony ( poor muscular condition ) Megacolon (Hypertrophy & dilation of colon with prolonged constipation). Adverse effects: generalized cholinergic stimulation (?????) Carbachol (carbamylcholine) Potent M & N agonist
Ester of carbamic acid / poor substrate of AChE Actions: On both the CVS & GIT (???) Release of Epi / adrenal medulla Miosis and a spasm of accommodation ??? Therapeutic uses: Rarely used therapeutically ??? except as a miotic / glaucoma
Adverse effects: at ophthalmic doses ??? Glaucoma A disease that damages optic nerve. Occurs when extra fluid increases the pressure on the front chamber
of the eye. A leading cause of blindness for people over 60 years old Blindness can often be prevented with early treatment. Types of glaucoma
Primary open-angle glaucoma Most common, occurs gradually, where the eye does not drain fluid Eye pressure builds and starts to damage the optic nerve. Painless and causes no vision changes at first.
Angle-closure glaucoma (also called closed-angle glaucoma or narrowangle glaucoma, acute) The iris is very close to the drainage angle in the eye. The iris can end up blocking the drainage angle, eye pressure rises very quickly.
Pilocarpine Alkaloid / 3 amine /stable to hydrolysis by AChE Less potent than Ach / high penetration to CNS M agonist used in ophthalmology. Miosis and contraction of the ciliary muscle, spasm of accommodation Stimulator of sweat, tears, and saliva Beneficial in promoting salivation in patients with xerostomia resulting
from irradiation of the head and neck Sjgren syndrome (immune system attacks the glands that make tears and saliva (spit). The damage keeps these glands from working right and causes dry eyes and dry mouth) Pilocarpine (cont.) Drug of choice for emergency lowering IOP of both open-angle
and angle-closure glaucoma Within a few minutes, lasts 4 to 8 hours, and can be repeated Topical carbonic anhydrase inhibitors, such as dorzolamide and -adrenergic blockers such as timolol, are effective in treating glaucoma but are not used for emergency lowering of intraocular pressure The miotic action of pilocarpine is also useful in reversing
mydriasis due to atropine Pilocarpine (cont.) Adverse effects: blurred vision, night blindness Poisoning with this agent is characterized by exaggeration of various
parasympathetic effects, including profuse sweating (diaphoresis) and salivation. Parenteral atropine, at doses that can cross the bloodbrain barrier, is administered to counteract the toxicity of pilocarpine. Indirect Cholinergic Agonists Anticholinesterases (Reversible)
Edrophonium Short acting 4 amine (10-20 min) due to renal excretion Used in the diagnosis of myasthenia gravis. IV injection of edrophonium leads to a rapid increase in muscle strength Care must be taken / cholinergic crisis. (atropine is the antidote)
Used to reverse nondepolarizing NMJ Physostigmine Natural 3 amine, 30 min 2 hrs (intermediate) intestinal and bladder motility / atony of either organ Topically on the eye, miosis and spasm of accommodation, as well as IOP used to treat glaucoma / pilocarpine is more effective.
Used for overdoses of drugs with anticholinergic actions, such as atropine, phenothiazines, and tricyclic antidepressants. Adverse effects: CNS / convulsions when high doses are used Bradycardia and a fall in CO may also occur. Paralysis of skeletal muscle.
Pyridostigmine and ambenomium: cholinesterase inhibitors that are used in the chronic management of myasthenia gravis. Adverse effects similar to those of neostigmine Tacrine, donepezil, rivastigmine, and galantamine: patients with Alzheimer's disease have a deficiency of cholinergic neurons in the CNS
led to the development of anticholinesterases as possible remedies for the loss of cognitive function Tacrine was the first to become available, but it has been replaced by the others because of its hepatotoxicity. Donepezil, Rivastigmine, & Galantamine / delay the progression disease, none can stop its progression Gastrointestinal distress is their primary adverse effect
Irreversible Anti-Cholinesterase Agents (Indirect Acting Cholinergic Agonists) Synthetic organophosphate cpds Bind covalently Used for military & agriculture Echothiophate
Organophosphate covalently binds via its phosphate group at the active site of AChE / permanently inactivated Restoration of AChE activity ??? Aging / impossible for chemical reactivators Actions: generalized cholinergic stimulation, paralysis of motor function (causing breathing difficulties), and convulsions
Miosis, decrease IOP Atropine in high dosages can reverse many of the peripheral and some of the central muscarinic effects of echothiophate. Therapeutic uses: treatment of open-angle glaucoma/rarely used
Irreversible AChE inhibitors (mostly organophosphate compounds) are used as agricultural insecticides /led to numerous cases of accidental poisoning with these agents frequently used for suicidal and homicidal purposes Organophosphate nerve gases, e.g. Sarin used as agents of warfare and chemical terrorism Toxicity with these agents is manifested as nicotinic and muscarinic
signs and symptoms (cholinergic crisis Reactivation of acetylcholinesterase Pralidoxime (2-PAM) can reactivate inhibited AChE Unable to penetrate into the CNS and therefore is not useful in treating the CNS effects of organophosphates If given before aging / reverse both M & N peripheral effects of
organophosphates, but not the CNS effects With the newer nerve agents that produce aging of the enzyme complex within seconds Pralidoxime is a weak AChE inhibitor and, at higher doses, may cause side effects similar to other AChE inhibitors Other treatments
Atropine ??? Diazepam is also administered to reduce the persistent convulsion caused by these agents General supportive measures, such as maintenance of patient airway, oxygen supply, and artificial respiration
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