A.U .C N S

Dr. Maha talal

Parasympathomimetic drug:
1- direct acting cholinergic agent 2- Indirect acting cholinergic agent: divided into reversible & irreversible

Parasymathomimetic drug

direct
Cholin esterase
Naturally occurrence alkaloid

A. Directly Acting Cholinergic Drugs : I. Choline Esters Acetylcholine Carbachol Methacholine Bethanechol

A- cholin esterase1-Acetylcholine

Effect of ACH : 1.on the intestine : Increase S.M contraction 2.on the urinary tract : Increase in muscle tone and contraction 3. on blood vessels : vasodilatation

4.on the secretary gland :increase secretion 5. on the S.M of trachea :contract , increase bronchial secretion, bronchoconstriction , 6.on the skeletal Muscle : increase Muscle tone 7. On the heart : bradycardia 8. On the eye : miosis , decrease in I.O.P 9 .On the adrenal gland

Prototypical muscarinic (and nicotinic) agonist, Nonselective action. but a poor therapeutic agent. Chemical/enzymatic instability; Low bioavailability (poorly absorbed); Quick onset and short duration of action. Use: In ocular surgery, causes complete miosis in seconds.


2- carbachol
Potent agonist activity. direct act :Nonselective (Muscarinic / Nicotinic) Also acts indirectly by promoting ACh release and anticholinesterase (weak) activity.

USES: 1. Topically for glaucoma(main use) 2. intraocular for miosis in surgery. 3. expel gases 4. stimulate intestinal motility. 5.relive urinary retention Side Effects: Corneal edema; decreased vision.

3- bethanechol

Action: Potent muscarinic agonist (directly stimulate Muscarinic receptors) Orally effective, also administered by subcutaneous injection.

Therapeutic applications:

1. post-surgical urinary retention. stimulate atonic bladder In urologic treatment, bethanechol is used to stimulate the atonic bladder, particularly retention. 2.Postoperative non-obstructive GITdisorder to prevent constipation.

Adverse effects:

Bethanechol causes the effects of generalized cholinergic stimulation These include 1.sweating, salivation, flushing. 2.Decreased blood pressure 3.nausea, abdominal pain,diarrhea. 4.bronchospasm


4-Methacholine ----- More stable than acetylcholine. Has methyl group in its structure More selective action (muscarinic > nicotinic). Has both muscarinic and nicotinic actions (very mild nicotinic actions )

METHACHOLINE

Therapeutic uses: given as inhalation for diagnostic of asthma. Muscarinic actions are prominent on CVS Cause brady cardia and hypotention.


B- Natural alkaloid
muscarine arecolin pilocarpine

Pilocarpine

Natural product. Isolated from the leaves of Pilocarpus jaborandi. less potent than ACH but is uncharged and can penetrate the CNS at therapeutic doses. Pilocarpine exhibits muscarinic activity and is used primarily in ophthalmology

Pilocarpine

Actions : on eye:decrease in IOP , miosis it experiences a spasm of accommodation. The vision becomes fixed at some particular distance . Systemic effects: include copious sweating, salivation and gastric secretion


USES 1. is the drug of choice for emergency lowering of intraocular pressure of both open-angle and angle-closure glaucoma. This action occurs within a few minutes, lasts 4 to 8 hours, and can be repeated.Available as ophthalmic solution, gel, tablet 2. treatment of xerostomia (dry mouth).

3.The miotic action of pilocarpine is also useful in reversing mydriasis due to atropine

Adverse effects:

1-blurred vision 2- lacrimation 3- sever sweating 4-bronchospasm 5-CNS effect(cross BBB) Cevimeline and pilocarpine used in treatment of sjogrens syndrome(lack of tear and dry mouth)to increase salivation.


Glaucoma
disease characterized by increase of intra ocular pressure, atrophy of optic disc ,loss in the field of vision. Glaucoma : divided into 2 types 1-open wide angle Glaucoma (chronic) 2-narrow closed angle Glaucoma (acute)


Figure 14-5Forms of primary adult glaucoma. (A) In open-angle (chronic) glaucoma, the anterior chamber angle remains open, but drainage of aqueous humor through the canal of Schlemm is impaired; (B) in closed-angle (acute) glaucoma, the angle of the iris and anterior chamber narrows, obstructing the outflow of aqueous humor.

Parasymathomimetic drug:

1- direct acting cholinergic agent (Natural and choline esterase ) 2- Indirect acting cholinergic agent: Divided into reversible & irreversible

2- Indirect acting cholinergic agent: Divided into reversible & irreversible

Anticholinestrases (reversible)
Acetylcholinestrase is an enzyme that cleaves Ach to acetate and choline. Drugs that inhibit this enzyme provide cholinergic action.

AGENTS AFFECTING CHOLINERGIC TRANSMISSION

Hemicholinium Latrotoxin Vesamicol Botulinus toxin Calcium Physostigmine Atropine d-Tubocurarine

reversible

Acetylcholinesterase Inhibitors (AChEI) (cholinesterase enzyme inhibitors (ChEI) Inhibition of acetylcholinesterase (AChE) lead to increases the concentration of acetylcholine (ACh) in the synapse. This results in prolonging the action of ACh, producing both muscarinic and nicotinic responses.


1- physostigmine
Actions: Stimulate Muscarinic & Nicotinic sits . Stimulate Nicotinic receptors of neuromuscular junctions. Duration of action about 2-4 hr. Stimulate CNS


Natural product, isolated from the seeds of Physostigma venenosum The drug increases intestinal and bladder motility. Antidote for atropine poisoning(central and peripheral) Topical application in the treatment of glaucoma(non specific)

physostigmine

increase intestinal & bladder motility. \ used in the treatment of overdoses of drugs with anticholinergic actions, such as atropine(central and peripheral).

physostigmine

Adverse effects: -convulsions -Bradycardia -paralysis of skeletal muscles

Myasthenia gravis

Autoimmune disease Ab against Ach receptors at neuromuscular junction Weakness of skeletal muscles Edrophonium used for diagnosis Neostigmine , pyridostigmine used for treatment

2- neostigmine

Chemically more stable than physostigmine Longer duration of action (2-4 hr) Neostigmine administered orally or iv . Its effect on skeletal muscle is greater than that of physostigmine, Not cross CNS.

*Therapeutics uses: 1- stimulate bladder & GIT. 2- antidote of tubocurarine(competitive neuromuscular-blocking agents). . 3-manage symptoms of myasthenia gravis.

Adverse effects

generalized cholinergic stimulation, such as salivation, flushing, decreased blood pressure. nausea, abdominal pain, diarrhea, and bronchospasm

3-pyridostigmine

** treatment of myasthenia gravis **duration of action 3-6hr. Pyridostigmine is the most widely used for the chronic treatment of myasthenia gravis.

4-Edrophonium

Administered parenterally Rapid onset I.V. short duration of action 10-20 min( short acting ) Also exhibits direct cholinomimetic effect on skeletal muscle Used in the Diagnosis of myasthenia gravis. Over dose cause cholinergic crisis Atropine is the antidote

Indirect Acting Agents used to treat Alzheimer’s disease Anticholinesterase with specific CNS. Donepezil (Aricept)—said to delay progression of the disease by up to 55 weeks. Does not cause liver toxicity.Rivastigmine long acting. Twice a day dosing. Tacrine (Cognex)—hepatoxic. Elevated liver enzymes usu.

Irreversible cholinestrase inhibitors

1- organophosphorus ;; (malathion & parathion) :used in insecticide 2- Tabun & Sarin : nerve gas (chemical war agent )


Irreversible Inhibitors Compounds containing phosphoryl or phosphonic group that can react with ChE to form ChE-phosphate complexes stable to hydrolytic cleavage. Mainly used as agricultural insecticides and nerve gas agents.



Mechanism of action
Combined of o.p.c with choline esterase enzyme irreversible & formation anew compound O.p.c + chE -------------- o.p—chEO.p.c highly lipid soluble

Adverse effects of organophosphate compounds:

Miosis , Rhinorrhea Frontal headache , Bronchoconstriction Emesis,Diarrhea, Involuntary micturition Bradycardia Lacrimation ,Salivation. Muscle weakness confusion ,paralysis of respiratory muscle.(DUMBBLES) Death

treatment

1- stop exposure 2-wash skin 3-oxygen supply . 4 replace fluid . 5-atropine 6-Diazepam is also administered to reduce the persistent convulsion caused by these agents. 7- 2-PAM(Pralidoxime)

Reactivation of acetylecholinestrase

Pralidoxime synthetic compound that can reactivate the acetylcholinestrase if its given before aging of enzyme ((aging mean: loss of an alkyl gp from the structure of enzyme)).Pralidoxime :Effective antidote for poisoning by parathion • Most effective by intramuscular, intravenous, or subcutaneous administration • Treatment is effective if initiated within few hours