DIRECT ACTING INDIRECT ACTING (REVERSIBLE)

Choline Esters Edrophonium - Quaternary amine (actions limited to periphery)

- Prototype

- Short- acting AChE inhibitor

- Prevents hrdrolysis of Ach

- Rapidly absorbed; IV inj- rapid inc in muscle strength

- Short DOA: 10-20 mins

- Diagnosis of MG; assess CHOLINESTERASE INHIBITOR THERAPY (differentiate Cholinergic and Myasthenia Crises)

- Reverse effect of NONDEPOLARIZING NEUROMUSCULAR BLOCKERS (TUBOCURARINE)

- Excess: CHOLINERGIC CRISIS (Antidote: Atropine)

Ach - Quaternary ammonium

- Multiple actions, rapid inactivation by cholinesterases

- Muscarinic and nicotinic activity

Carbachol (carbamylcholine)

- Quaternary amine

- Carbamoyl ester/ ester of carbamic acid

- Lacks methyl group- effect on both CV and GI systems

- Release of EPI fr. Adrenal Medulla

- High potency, receptor non selectivity, long DOA rarely except in EYE as MIOTIC AGENT to treat GLAUCOMA

Physostigmine - Carbamic acid ester (FR. PLANTS)

- Tertiary amine (can enter & stimulate cholinergic sites in the CNS)

- Stimulates Muscarinic/ Nicotinic Sites of ANS; Nicotinic Receptors of NMJ

- Reversibly inactivates AChE

- Intermediate acting agent

- DOA: 2-4hrs

- Atony

- Tx of Glaucoma: Pilocarpine more effective

Betanechol

- OA: 10-20MINS

- DOA: 4-8 HRS

- AE: none/litte ;doses OPHTHA/ lack of systemic penetration

- Unsubstituted carbamoyl ester, related to Ach in which acetate is replaced by carbamate and choline is methylated

- Lacks nicotinic actions

- Strong muscarinic activity

- Atonic bladder

- megacolon

- Treatment of OD with ANTICHOLINERGICS- ATROPINE, PHENOTHIAZINES, TRICYCLIC ANTIDEPRESSANTS

- AE: convulsions, bradycardia (fall in cardiac output); paralysis of skeletal muscle due to (-)of AChE in NMJ – rarely seen in therapeutic doses

Neostigmine - Carbamic acid ester

- Quaternary nitrogen, more polar, absorbed poorly in GI Tract than PHYSOSTIGMINE

- Intermediate DOA: 30mins to 2-Hrs

- ANTIDOTE to TUBOCURARINE

- Used symptomatically to treat MG

- AE: generalized cholinergic stimulation

- Doesn’t cause CNS S/E, not used to overcome toxicity of ANTIMUSCARINIC AGENTS such as ATROPINE

- Contraindicated when urinary or intestinal obstruction is present (peritonitis, IBD)

Naturally- occurring alkaloid Pyridostigmine Ambenonium

- Cholinesterase inhibitors for chronic management of MG

- Intermediate DOA: 3-6hrs, 4-8 hours respectively (longer than Neostigmine 30mins-2hrs)

- AE: same as with NEOSTIGMINE

Pilocarine - Tertiary amine, stable to hydrolysis of AChE

- Uncharged, penetrate CNS

- Muscarinic- used primarily in OPHTHA

- Most potent secretagogue- limited use, lack of selectivity

- Salivation in xerostomia fr. Irradiation of head & neck

- Sjogren’s Syndrome (Pilo tabs with Civemeline)

- Reverse mydriasis due to atropine

- Narrow-angle/ wide-angle Glaucoma (DRUG of CHOICE—emergency lowering of intraocular pressure)

- OA: few mins

- DOA: 4-8 Hrs,can be repeated

CARBONIC ANHYDRASE INHIBITOR

- (ACETAZOLAMIDE) BETA- ADRENERGIC BLOCKER

- (TIMOLOL)

- - TREAT CHRONIC GLAUCOMA/ NOT USED DURING EMERGENCY

Tacrine Donepezil Rivastigmine Galantamine

- First to become available, replaced because of hepatotoxicity

- Patients with ALZHEIMER’S (lack cholinergic neuron in the CNS)- remedy for loss of cognition

- AE: GI stress

INDIRECT ACTING (IRREVERSIBLE) ACHe REACTIVATORS

Pralidoxime - Can reactivate inhibited AChE but unable to penetrate the CNS

- Displaces phosphate group in organophosphate and regenerates the enzyme

- -can reverse effect of ECHOTHIOPHATE except for those in the CNS

- With the newer nerve agents, which produce aging of the enzyme complex

within seconds, pralidoxime is less effective. Pralidoxime is a weak AChE inhibitor and, at higher doses, may cause side effects similar to other AChE inhibitors (see Figures 4.6 and 4.9). In addition, it cannot overcome

- toxicity of reversible AChE inhibitors (for example, physostigmine).

Echothiophate - organophosphate

- longer DOA than PILOCARPINE

- enzyme permanently inactivated and requires the synthesis of new enzyme molecules

- loss of alkyl group( aging) makes it possible for chemical reactivators such as PRALIDOXIME to break bond

- Longer duration of action than PILOCARPINE

- Generalized cholinergic

Atropine Diazepam

- Atropine is administered to prevent muscarinic side effects of these agentsSuch effects include increased bronchial secretion and saliva, bronchoconstriction, and bradycardia.

- also administered to reduce the persistent convulsion caused by these agents. General supportive measures, such as maintenance of patent airway, oxygen supply, and artificial respiration, may be necessary as well

Bethanechol • Used in treatment of urinary retention • Binds preferentially at muscarinic receptors Carbachol • Produces miosis during ocular surgery • Used topically to reduce intraocular pressure in open-angle or narrow-angle glaucoma, particularly in patients who

have become tolerant to pilocarpine

stimulation, paralysis of motor function (causing breathing difficulties)

- Convulsion, intense miosis- treatment use

- ATROPINE REVERSE MANY MUSCARINIC AND SOME CENTRAL EFFECTS OF ECHOTHIOPHATE

- OPHTHALMIC SOLN/ TOPICAL- CHRONIC TX OF OPEN-ANGLE GLAUCOMA

- NOT A FIRST LINE TX IN GLAUCOMA, RISK OF CAUSING CATARACTS

-

Pilocarpine • Reduces intraocular pressure in openangle and narrow-angle glaucoma • Binds preferentially at muscarinic receptors • Uncharged, tertiary amine that can penetrate the CNS Physostigmine • Increases intestinal and bladder motility • Reduces intraocular pressure in glaucoma • Reverses CNS and cardiac e_ects of tricyclic antidepressants

• Reverses CNS e_ects of atropine • Uncharged, tertiary amine that can penetrate the CNS Edrophonium • For diagnosis of myasthenia gravis • As antidote for tubocurarine • Has short duration of action (10 to 20 min) • Used as _rst-line treatments for Azheimer disease, though confers modest bene_t • Have not been shown to reduce healthcare costs or delay institutionalization

• Can be used with memantine (N-methyl-D-aspartate antagonist) with moderate to severe disease

Rivastigmine, galantamine, donepezil Neostigmine • Prevents postoperative abdominal distention and urinary retention • Used in treatment of myasthenia gravis

• Used as an antidote for tubocurarine • Has long duration of action (2 to 4 hrs) Echothiophate • Used in treatment of open-angle glaucoma • Has long duration of action (1 week) Acetylcholine • Has no therapeutic uses