A- CHOLIN ESTERASEA- CHOLIN ESTERASE

المالح فاضل محمد ثامر المالح حسان فاضل محمد ثامر حسان

Group – B -Group – B -

2- carbachol2- carbachol Potent Potent agonist activity.agonist activity. direct act :Nonselective (Muscarinic / direct act :Nonselective (Muscarinic /

Nicotinic)Nicotinic) ..

USES:USES: 1. Topically for glaucoma;1. Topically for glaucoma; 2. intraocular for miosis in surgery.2. intraocular for miosis in surgery. 3. expel gases3. expel gases 4. stimulate intestinal motility. 4. stimulate intestinal motility. 5.relive urinary retention 5.relive urinary retention Side Effects: Side Effects: Corneal edema; decreased visionCorneal edema; decreased vision..

33 - -bethanecholbethanechol

ActionAction:: Potent muscarinic agonist (directly Potent muscarinic agonist (directly

stimulate Muscarinic receptors)stimulate Muscarinic receptors) Orally effective, also administered by Orally effective, also administered by

subcutaneous injection.subcutaneous injection. Increased hydrolytic stabilityIncreased hydrolytic stability

Therapeutic applicationsTherapeutic applications: : For the relief of post-surgical urinary For the relief of post-surgical urinary

retention and abdominal distention And retention and abdominal distention And stimulate atonic bladderstimulate atonic bladder

((Stimulant of GI tract smooth muscle and urinary Stimulant of GI tract smooth muscle and urinary bladder).bladder).

Adverse effectsAdverse effects: : Low toxicity, no serious side effects. Low toxicity, no serious side effects. Should be used with caution in asthmatic Should be used with caution in asthmatic

patients.patients.

4-Methacholine ----- 4-Methacholine -----

More stable than acetylcholine.More stable than acetylcholine. More selective action (muscarinic > nicotinic).More selective action (muscarinic > nicotinic).

B- Natural alkaloid :B- Natural alkaloid : muscarine , arecolin , muscarine , arecolin , pilocarpine pilocarpine

PilocarpinePilocarpine Natural product. Isolated from the leaves of Natural product. Isolated from the leaves of

Pilocarpus jaborandiPilocarpus jaborandi.. Actions :Actions : decrease in IOP , miosisdecrease in IOP , miosis stimulator of secretions.stimulator of secretions. Available as ophthalmicAvailable as ophthalmic

solution, gel, tablet .solution, gel, tablet .

Systemic effects: Systemic effects: include copious sweating, salivation and include copious sweating, salivation and gastric secretion.gastric secretion.

Uses:Uses: lowering of IOP therefore Used in the treatment of lowering of IOP therefore Used in the treatment of

glaucoma glaucoma treatment of xerostomia (dry mouth). treatment of xerostomia (dry mouth). Adverse effects: Adverse effects: 1-blurred vision 1-blurred vision 2- lacrimation 2- lacrimation 3- sever sweating3- sever sweating

4-bronchospsm4-bronchospsm

GlaucomaGlaucoma

disease characterized by increase of disease characterized by increase of intra ocular pressure, atrophy of optic intra ocular pressure, atrophy of optic disc ,loss in the field of vision.disc ,loss in the field of vision.

Glaucoma : Glaucoma : divided into 2 divided into 2 types types

1-open wide angle Glaucoma (chronic)1-open wide angle Glaucoma (chronic)

2-narrow closed angle Glaucoma (acute)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 Parasymathomimetic drug:drug:

1- direct acting cholinergic 1- direct acting cholinergic

agent (Natural and choline agent (Natural and choline

esterase )esterase )

2- Indirect acting cholinergic 2- Indirect acting cholinergic

agent: agent: Divided into Divided into

reversible & irreversible reversible & irreversible

2- Indirect acting 2- Indirect acting cholinergic cholinergic

agent: agent: Divided into Divided into

reversible & irreversible reversible & irreversible

reversiblereversible Acetylcholinesterase Inhibitors (AChEI) Acetylcholinesterase Inhibitors (AChEI)

(cholinesterase enzyme inhibitors (ChEI)(cholinesterase enzyme inhibitors (ChEI) Inhibition of acetylcholinesterase Inhibition of acetylcholinesterase

(AChE) lead to increases the (AChE) lead to increases the concentration of acetylcholine (ACh) concentration of acetylcholine (ACh) in the synapse. in the synapse.

This results in This results in prolonging the action prolonging the action of ACh, producing both muscarinic of ACh, producing both muscarinic and nicotinic responses.and nicotinic responses.

Anticholinestrases Anticholinestrases (reversible)(reversible)

Acetylcholinestrase is an enzyme that Acetylcholinestrase is an enzyme that cleaves cleaves Ach to Ach to acetate and choline.acetate and choline.

Drugs that Drugs that inhibit this enzyme inhibit this enzyme provide provide cholinergic action.cholinergic action.

AGENTS AFFECTING AGENTS AFFECTING CHOLINERGIC TRANSMISSIONCHOLINERGIC TRANSMISSION

HemicholiniumHemicholiniumLatrotoxinLatrotoxinVesamicolVesamicolBotulinus toxinBotulinus toxinCalciumCalciumPhysostigminePhysostigmineAtropineAtropined-Tubocurarined-Tubocurarine

11 - -physostigminephysostigmine

Natural product, isolated from the seeds of Natural product, isolated from the seeds of Physostigma venenosumPhysostigma venenosum

Physostigmine : Sensitive to heat, light, Physostigmine : Sensitive to heat, light, moisture etc.moisture etc.

Diffuses into the CNSDiffuses into the CNS

physostigminephysostigmine

Actions:Actions: Stimulate Muscarinic & Nicotinic sits .Stimulate Muscarinic & Nicotinic sits . Stimulate Stimulate NicotinicNicotinic receptors of receptors of

neuromuscular junctions.neuromuscular junctions. Duration of action about 2-3 hr. Duration of action about 2-3 hr. Stimulate CNSStimulate CNS

physostigminephysostigmineTherapeutics uses:Therapeutics uses: Topically in eye.Topically in eye. Anti dote Anti dote for for atropine (atropine (treat over dose of treat over dose of

anticholinergic drugs.anticholinergic drugs. Treatment of myasthenia gravies.Treatment of myasthenia gravies. increase intestinal & bladder motility increase intestinal & bladder motility Terminate the effect of Terminate the effect of tubocurarine.tubocurarine. Topical application in the treatment of Topical application in the treatment of

glaucomaglaucoma

physostigminephysostigmine

Adverse effects:Adverse effects:

-convulsions-convulsions

-Bradycardia-Bradycardia

-paralysis of skeletal muscles-paralysis of skeletal muscles

22 - -neostigmineneostigmine Chemically more stable than physostigmineChemically more stable than physostigmine Longer duration of action (2-4 hr)Longer duration of action (2-4 hr) Neostigmine administered orally or ivNeostigmine administered orally or iv

*adverse effects: *adverse effects:

generalized cholinergic stimulation.generalized cholinergic stimulation.

**Therapeutics uses:Therapeutics uses:

1- 1- stimulate bladder & GIT.stimulate bladder & GIT.

2- antidote of tubocurarine.2- antidote of tubocurarine.

3- treat of myasthenia gravis.3- treat of myasthenia gravis.

4- 4- The most frequent use of neostigmine is The most frequent use of neostigmine is to prevent atony of the intestinal, skeletal,to prevent atony of the intestinal, skeletal,

and bladder musculature.and bladder musculature. 5- Also used as urinary stimulant.5- Also used as urinary stimulant.

Myasthenia gravisMyasthenia gravis

Autoimmune diseaseAutoimmune disease

Ab against Ab against Ach receptors Ach receptors at neuromuscular junctionat neuromuscular junction

Weakness of skeletal musclesWeakness of skeletal muscles

Edrophonium used for diagnosisEdrophonium used for diagnosis

Neostigmine , pyridostigmine used for treatment Neostigmine , pyridostigmine used for treatment

33--pyridostigminepyridostigmine

** treatment of myasthenia gravis** treatment of myasthenia gravis

**duration of action 3-6hr.**duration of action 3-6hr. PyridostigminePyridostigmine is the most widely is the most widely

used for the treatment of myasthenia used for the treatment of myasthenia gravisgravis

44--EdrophoniumEdrophonium Administered parenterallyAdministered parenterally Rapid onset Rapid onset short duration of action short duration of action 10-20 min( short 10-20 min( short

acting )acting ) Also exhibits direct cholinomimetic effect on Also exhibits direct cholinomimetic effect on

skeletal muscleskeletal muscle Used in the Diagnosis of myasthenia gravis.Used in the Diagnosis of myasthenia gravis. Over dose cause cholinergic crisisOver dose cause cholinergic crisis Atropine is the antidoteAtropine is the antidote

Irreversible cholinestrase Irreversible cholinestrase inhibitorsinhibitors

1- organophosphorus ;; 1- organophosphorus ;;

((malathion & parathionmalathion & parathion)) :used in :used in insecticideinsecticide

2- Tabun & Sarin : nerve gas (chemical 2- Tabun & Sarin : nerve gas (chemical war agent )war agent )

Irreversible InhibitorsIrreversible Inhibitors Compounds containing Compounds containing phosphoryl or phosphoryl or

phosphonic groupphosphonic group that can react with ChE that can react with ChE to form ChE-phosphate complexes stable to to form ChE-phosphate complexes stable to hydrolytic cleavage.hydrolytic cleavage.

Mainly used as agricultural insecticides and Mainly used as agricultural insecticides and nerve gas agents.nerve gas agents.

Mechanism of action Mechanism of action

Combined of o.p.c with choline Combined of o.p.c with choline esterase enzyme irreversible & esterase enzyme irreversible & formation anew compound formation anew compound

O.p.c + chE -------------- o.pO.p.c + chE -------------- o.p——chEchE O.p.c highly lipid solubleO.p.c highly lipid soluble

Adverse effects of Adverse effects of organophosphate compoundsorganophosphate compounds::

Miosis , RhinorrheaMiosis , Rhinorrhea Frontal headache , BronchoconstrictionFrontal headache , Bronchoconstriction Laryngospasm , SalivationLaryngospasm , Salivation GIT disturbances , BradycardiaGIT disturbances , Bradycardia Sweating , LacrimationSweating , Lacrimation Involuntary micturition , Muscle weaknessInvoluntary micturition , Muscle weakness Ataxia, confusion ,Ataxia, confusion , DeathDeath

treatmenttreatment

1- stop exposure1- stop exposure 2-wash skin2-wash skin 3-oxygen supply .3-oxygen supply . 4 replace fluid .4 replace fluid . 5-atropine 5-atropine 6- 2-PAM(Pralidoxime) 6- 2-PAM(Pralidoxime)

Reactivation of acetylecholinestraseReactivation of acetylecholinestrase PralidoximePralidoxime synthetic compound that can synthetic compound that can reactivatereactivate the the

acetylcholinestrase if its given before acetylcholinestrase if its given before agingaging of enzyme ((aging mean: loss of an alkyl gp of enzyme ((aging mean: loss of an alkyl gp from the structure of enzyme)).from the structure of enzyme)).

Pralidoxime Pralidoxime :Effective antidote for :Effective antidote for poisoning by poisoning by parathion and related parathion and related pesticidespesticides

• • Most effective by intramuscular, Most effective by intramuscular, intravenous, or subcutaneous administration intravenous, or subcutaneous administration

• • Treatment is effective if initiated within few Treatment is effective if initiated within few hourshours