Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

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ReversibleTertiary amines

PhysostigmineQuaternary Ammonium compounds

NeostigminePyridostigmineDistigmineAmbenoniumDemecariumTacrine

Miscelloneous DonepezilGalantamineRivastigmine

Irreversible Anticholinesterases(Organophosphorus Compounds)

Ecothiophate2) War Gases:

SarinTuban,Soman

3) Insecticides:-ParathionMalathionDiisopropyl Flurophosphate (DFP)Tetramethyl Pyrophosphate (TMPP)Octamethyl Pyrophosphotetra amide (OMPA)

ACETYLCHOLINESTERASE

1)Present in cholinergic sites,RBCs, gray matter2)Very fast hydrolysis of ACh3)Can hydrolyse methacholine,4) canot hydrolysebenzocholine, butyryl choline

5)More sensitive tophysostigmine

6)Termination of Ach action

BUTYRYLCHOLINESTERASE

1)Present in white matter,plasma, liver, intestine(White PIL)2)Slow hydrolysis3)Not hydrolysed4)benzocholine, butyryl cholinehydrolysed

6)More sensitive toorganophosphates

Hydrolysis of ingested esters

PhysostigmineNatural alkaloidTertiary amine derivativeGood oral absorptionCNS actions are presentPenetrates corneaDirect action on cholinoceptorsAbsentProminent effect on autonomiceffectorsUses- miotic(glaucoma)Dose -0.1-1% eye dropsSystemic eff-4-6hrs

NeostigmineSynthetic derivativeQuaternary ammonium compLess oral absorptionAbsentPoor penetrationAction oncholinoceptor ispresentProminent effect on skeletalMusclesUses –myasthenia gravis0.5-2.5mg sc3-4hrs

A disease characterized by raised intraocularpressure(IOP) and progressive optic neuropathy with lossof retinal neurons and their axons (nerve fiber layer)resulting in blindness if left untreated.Aqueous humourpass b/w lens and irisgo outthrough pupilPrimary –respond to drugs

a)Narrow angle/angle closure/acute congestive-medical emergency-drug and partial iridectomyb) simple/open angle/chronic/-loss of trabacular

mesh work patency is lostSecondary- partly respondsCongenital-less responsive

1) Beta-Blockers [levobunolol, timolol, carteolol,betaxolol]

Mechanism: Act on ciliary body to production ofaqueous humor

Administration: Topical drops to avoid systemic effectsUse twice a day (except Timolol)

Side Effects: Cardiovascular (bradycardia, asystole,syncope), bronchoconstriction (avoid with b1-selective betaxolol), depression

2) Alpha-2 Adrenergic Agonists [apraclonidine,brimonidine]Mechanism: production of aqueous humorMay become less effective over timeAdministration: Topical drops

Side Effects: Lethargy, fatigue, dry mouth[apraclonidine is a derivative of clonidine(antihypertensive) which cannot cross BBB tocause systemic hypotension]

Brimonidine -never used in infantsIn younger children can cause slowed breathingand heartbeatIn older children Stinging / irritation

3)Carbonic Anhydrase Inhibitors [acetazolamide,dorzolamide]

Mechanism: Blocks Carbonic Anhlydrase-II enzymeblocks production of bicarbonate ions (transportedto posterior chamber, carrying osmotic water flow) production of aqueous humor

Better tolerated in children than adultsUsually used in addition to drops

Administration: OralSide Effects: Metabolic disturbances (electrolytebalance, acid-base balance) malaise, kidney stones,possible (rare) aplastic anemia

1)Parasympathomimetics [pilocarpine, carbachol,echothiophate]

Mechanism: contractile force of ciliary body muscle, outflow via TM

Administration: Topical drops or gel, (slow-releaseplastic insert)

Side Effects: Headache, induced miopia. Few systemicSE for direct-acting agonists vs. AchE inhibitors(diarrhea, cramps, prolonged paralysis in setting ofsuccinylcholine).

2)Nonspecific Adrenergic Agonists [epinephrine,dipivefrin]

Mechanism: uveoscleral outflow of aqueoushumor

Administration: Topical dropsSide Effects: Can precipitate acute attack in patients

with narrow iris-corneal angle, headaches,cardiovascular arrhythmia, tachycardia

The defect in neuromuscular transmission in MyastheniaGravis is due to:The muscle end-plate membrane is distorted

Acetylcholine receptors are lost from the tips of the folds,and antibodies attach to the postsynaptic membraneAch is released normally but absence of receptors preventsthe transmitter binding to the muscle membrane

Immuno-precipitation assayEdrophonium (Tensilon test)-2mg IVPatients with MG have low numbers of AChR at theNMJAch released from the motor nerve terminal ismetabolized by Acetylcholine esteraseEdrophonium is a short acting Acetylcholine EsteraseInhibitor that improves muscle weaknessmyastheniaCondition worsens cholinergic crisispersistantdepolarisation of motar end plate

1.Reversible anti-AchENeostigmine-15-30 mg, per day orally

0.5-0.25mg im/scPyridostigmine-60mg-tid orallyAmbenonium-2.5-5mg orally

2.Glucocorticoids –prednisolone-10mg OD3.Immunosuppressants

Azathioprine 2.5mg/kg per dayCyclosprine-2-5mg/kg per day

4.Thymectomy –myasthenia with thymoma5.Plasmapheresis –for non responders to thymectomy and

treatment with steroids

Organophosphates = Organic Compounds + PhosphateGroupNo Clinical Uses For These Compounds.Agricultural Insecticides And FungicidesHousehold Garden SpraysFly And Insect SpraysPoisoning -Cutaneous

Ingestion (Accidental Or Suicidal)InhalationInjection

op inactivate acetyl cholinesterase (Ach E).establishment of a covalent bond with ache.once Ach E - inactivated, ach accumulatesthroughout the nervous system →overstimulation of muscarinic and nicotinicreceptors.

Muscarinic Effects By organ systems include the following:

Cardiovascular - Bradycardia, Hypotension

Respiratory - Rhinorrhea, Bronchorrhea, Bronchospasm, Cough,

Severe Respiratory Distress

Gastrointestinal - Hypersalivation, Nausea And Vomiting,

Abdominal Pain, Diarrhea

Genitourinary - Incontinence

Ocular - Blurred Vision, Miosis

Glands - Increased Lacrimation, Diaphoresis

Once an organophosphate binds to AChE, the enzymecan undergo one of the following:

• Endogenous hydrolysis of the phosphorylated enzymeby esterases or paraoxonases

• Reactivation by a strong nucleophile such aspralidoxime (2-PAM)

• Irreversible binding and permanent enzymeinactivation (aging)

The onset and severity of symptoms depend on thespecific compound, amount, route of exposure, andrate of metabolic degradation

Mild ( ≥ 40% ache)No specific treatmentClearing the airway,Adequate ventilation-consider oxygenationRemove soiled clothesWash contaminated skin to prevent further absorption.

2. Patients With Systemic Features –Gastric lavage within an hour followed by activatedCharcoal administered via nasogastric tube

Wash the patient – to prevent cutaneous absorptionWash soiled clothes

IV Atropine 2mgs every 15 minutes till signs ofatropinization are seen

Add an oxime E.G. Pralidoxime

Consider ICU Care If In Coma Or Unconscious

Organophosphorus poisoning-treatment

PAM-pralidoxime-Current Recommendation IsAdministration Within 48 H Of OP Poisoning.,Administer Atropine Concomitantly-↓ RespiratorySecretions.

1-2 G (20-40 Mg/Kg) IV In 100 ml NS/D5W Over 15-30Min ; Repeat In 1 H If Muscle Weakness Is Not Relieved;Then Repeat Q3-8h If Signs Of Poisoning Recur.Alternatively, Continuous Drip; Start With Bolus Of 25-50 Mg/Kg And Then 10-20Mg/Kg/h

Organophosphorus poisoning-treatment

Potentiate Effects Of GABA And Facilitate InhibitoryGABA Neurotransmission

For Treatment Of Seizures. Depresses All Levels Of CNS(Eg, Limbic And Reticular Formation) By IncreasingActivity Of GABA.

5-15 Mg IV Q5-10 Min, Repeat As Needed; ConsiderHigher Doses If Needed

Routinely Used In OP Poisoning For Treatment OfAgitated Delirium And Seizures

Diazepam Reduces Respiratory Failure (Rats) AndCognitive Deficit (Primates)