drugs

2. ANTICHOLINESTERASE DRUGS
• Anticholinesterase drugs act by inhibiting enzyme
acetylcholinesterase, thus increasing availability
and prolonging action of Ach
• Anticholinesterase drugs (neostigmine,
pyridostigmine) are most often administered to
facilitate the speed of recovery from the skeletal
muscle effects produced by nondepolarizing
(competitive) neuromuscular-blocking drugs
• Acetylcholinesterase is the primary target of these
drugs, but butyrylcholinesterase is also inhibited

3. Acetylcholinesterase is an extremely active enzyme. In the initial step,
acetylcholine binds to the enzyme's active site and is hydrolyzed, yielding free
choline and the acetylated enzyme. In the second step, the covalent
acetylenzyme bond is split, with the addition of water (hydration). The entire
process takes place in approximately 150 microseconds.
Inhibit the enzyme acetylcholinesterase responsible for the rapid hydrolysis of
the neurotransmitter acetylcholine to choline and acetic acid.
Greater availability at preganglionic sympathetic and parasympathetic nerve
endings and the neuromuscular junction.
Increased availability acetylcholine at the NMJ is reflected by an increase in
the size of the miniature end-plate potentials

4. Mecanism Of Indirect Acting Cholinergic Drugs
• Ach after release is rapidly metabolized by
cholinesterase enzyme
• Indirect cholinergic (anti cholinesterase) bind to
this enzyme
• Binding is either
Reversible (carbamayes e.g.Neostigmine)
Irreversible (organophosphorous compounds e.g.
ecothiophate)
• Prevent destruction of Ach & inc its action

5. Hoe does AchE Act
• The entire process takes about 150 microseconds
• True AChE – nervous tissue, surface of RBCs.
• ButyrylChE/PseudoChE- serum, liver.

6. • Reversible anticholinesterase are also capable of combining with the anionic and esteric sites of
cholinesterase enzyme like ach,but does not form fixed cholinesterase and anticholinesterase
complex like irreversible anticholinesterase.
• This produces temporary inhibition of cholinesterase enz and prevent breakdown of ach thus
increase its conc in synaptic cleft.
• Edrophonium forms reversible complex only with anionic site thus has shorter duration of action.
• Irreversible anticholinesterase combine with esteric site phosphorylating it whose hydrolysis is
extremely slow thus producing an almost irreversible permanent inhibition.
• Ectotiophate forms complexes with both anionic and esteric site so more potent.
• Thus OP compounds permanently inhibit cholinesterase enzyme gradually raising ach level, causing
prolonged depolarization of motor end plate, skeletal muscle paralysis,resp arrest,cardiac arrest
,death

7. Receptors & Location
CHOLINERGIC
RECEPTORS
NICOTINIC
Adrenal
medulla
,Ganglia
(Nn)
NMJ
MUSCARINIC
M1-gastric
ganglia
M2-heart
and CNS
M3-eye,
bladder
bronchus
glands

9. Reversible Cholinesterase Inhibitors
DRUG ROUTE DURATION INDICATIONS
A. Short Acting -
• Edrophonium iv 1–2 hr Diagnosis of myasthenia gravis
(tensilon test)
B. Intermediate Acting -
 Physostigmine Topical 6–12 hr Glaucoma
 Pyridostigmine Oral, i.v, i.m 4 hr Myasthenia gravis,
Reversal of neuromuscular blockade
 Neostigmine Oral, iv 4–6 hr Myasthenia gravis
Reversal of neuromuscular blockade
 Ambenonium Oral 4 hr Myasthenia gravis
C. Newer and Longer acting -
 Demecarium Topical 3–5 days Glaucoma
 Tacrine Alzheimer’s Disease
 Donepezil Alzheimer’s Disease
 Rivastigmine Alzheimer’s Disease
 Gallantamine Alzheimer’s Disease

10. Irreversible Choliesterase Drugs
DRUG ROUTE DURATION INDICATIONS
Echothiophate Topical 3–14 days Glaucoma
Isofluorophate Topical 3–7 days Glaucoma research
Malathion Topical
Parathion Topical
Sarin nerve gas Gas
Tabun nerve gas Gas War Gases
Soman nerve gas Gas

11. Pharmacologic Effects
Cardiovascular Effects
• Bradycardia
• Decrease systemic vascular resistance.
• Cardiac effects attenuated by the administration of atropine
Gastrointestinal and Genitourinary Tract
• Enhance gastric fluid secretion by parietal cells
• Increase the motility of the entire gastrointestinal tract, particularly the large
intestine
• Cause nausea and gastrointestinal disturbances
Glands
• Augment the secretion of bronchial, lacrimal, sweat & salivary glands
• Produce bronchoconstriction increase airway resistance
Eye
• Topical application cause constriction of the sphincter of the iris (miosis) and
ciliary muscle.

12. Central Nervous System
• AchE inhibitors are Lipid soluble
(Physostigmine & Ops) cross BBB
• Low doses; CNS activation
• High; Coma & Respiratory arrest
Neuromuscular Junctions
• Increase force of contraction (low dose)
• Muscle fasciculation & depolarizing blockade
(high dose) weakness & paralysis

13. Clinical Use
1. Antagonist-Assisted Reversal of Neuromuscular Blockade
 Administered when spontaneous recovery from N-M blockade is occurring.
 Reversal requires only the nicotinic cholinergic effects
 Muscarinic effects attenuated/prevented by atropine or glycopyrrolate
 Co-administration of glycopyrrolate with neostigmine more stable heart rate
 Dose : neostigmine 25- 50 µg/kg IV, glycopyrrolate 0.2 mg/mg of neostigmine
 Combination of atropine and neostigmine initial tachycardia followed by late bradycardia
 Reversal delayed/prevented by -
volatile anaesthetics, Certain antibiotics, hypothermia, respiratory acidosis with a PaCO2 >50
mmHg, hypokalemia and metabolic acidosis

14. 2. Postoperative Analgesia
 Intrathecal (50 to 100 µg) or epidural(1 to 4 µg/kg) injection of neostigmine
 Analgesia in the postoperative period and in chronic pain
 Analgesia by inhibiting the breakdown of spinally released acetylcholine
 Disadvantages of intrathecal neostigmine -
 High incidence of nausea and vomiting
 Pruritus
 Prolongation of the sensory and motor block produced by spinal
Anaesthesia
3. Treatment of Central Nervous System Effects of Certain Drugs
 Central Anticholinergic Syndrome -
Physostigmine antagonizes the restlessness and confusion caused by
atropine or scopolamine
 Opioids -
Physostigmine abolishes the somnolent effects of opioids and may
reverse the depression of the ventilatory response to carbon dioxide
4. Diagnosis and Management of Cardiac Dysrhythmias
 Edrophonium for diagnosis and management of PSVT including those due to
WPW syndrome

15. 5. Treatment of Glaucoma
 Decrease IOP in narrow-angle and wide-angle glaucoma.
 Echothiophate only therapeutic drug of organophosphate group,
used as topical drops for the treatment of glaucoma
6. Alzheimer's Disease
 Tacrine, donepezil, rivastigmine, galantamine are recommended
 Used in mild to moderate Alzheimer's disease
 Tacrine is hepatotoxic
7. Postoperative Shivering
 Physostigmine (40 µg/kg IV) decreases the incidence of
postoperative shivering
 Physostigmine enhances the secretion of neurotransmitters
involved in the control of body temperature, especially at the
hypothalamic thermoregulatory centres

16. 5. Treatment of Myasthenia Gravis
 Increase the availability of endogenous
acetylcholine
 Increase the response of skeletal muscles to
repetitive impulses

17. Carbamate Inhibitors; Physostigmine
• Natural alkaloid
• Tertiary amine derivative
• High lipid solubility
• Rapidly absorbed from git
• More marked muscarinic effect
• Good CNS & corneal penetration

18. Carbamate Inhibitors; Neostigmine
• Neostigmine synthetically prepared
• Quaternary amine
• Less lipid soluble
• Pyridostigmine resembles neostigmine but
has longer DOA
• Some are used as insecticides, Carbaryl
Propoxur

20. Organophosphorus Poisoning
• A. Muscarinic Actions
• 1. Eye:
• a. Circular muscle of iris (M3) contract, ↓ pupil size (miosis)
• b. Ciliary body (M3) contract, eye fixed for near vision
(spasm of accommodation)
• c. Miosis causes opening of angle of anterior chamber,
increases drainage of aqueous humourIOP
• d. Increased lacrimal secretion

21. Pharmacological actions (Cont.)
2. GI:
• Smooth muscle (M3): Wall contract, ↑ peristalsis
• Sphinters, relax hyperacidity peptic ulcer
• Exocrine glands (M3): ↑ secretions
• Mysenteric plexus (M1): ↑ peristalsis & ↑ secretions
3. Genito-urinary (M3): urine incontinence
• U. Bladder wall contract
• Sphincter relax
• Uterus (pregnant) contract (Abortion)

22. 4. CVS:
• Heart (M2):
• SA node, bradycardia
• AV node, Slow conduction
• Atria, ↑ automaticity
5. Resp (M3):
• Bronchial smooth muscle → contract
• Exocrine glands, ↑ secretions
6. Sweat glands:
• Thermoregulatory (M3), ↑ sweating

24. Various mnemonics have been used to describe the
muscarinic signs of OP poisoning:
SLUDGE
• Salivation
• Lacrimation
• Urine incontinence
• Diarrhoea,
• Gastrointestinal
• Cramps
• Emesis
DUMBELS
• Diarrhoea
• Urination
• Miosis
• Bronchospasm
• Emesis
• Lacrimation
• Salivation

25. Pharmacological Actions
B. Nicotinic Actions
Results from accumulation of Ach at the motor end plate &
autonomic ganglia, leading to persistent depolarization of
skeletal muscle – smooth muscles weakness, fasciculation theb
generalized muscle paralysis
C. CNS Effects
restless, tremors, confusion, convulsion, coma
Depression of respiratory & CVS
DEATH due to;- Muscarinic;pulmonary oedema
Nicotinic; respiratory muscles paralysis
CNS;

26. Management (Diagnosis and Treatment)
1. Definitive diagnosis: established by demonstrating
decreased cholinesterase activity:
• a. Serum and RBC cholinesterase should be measured
(pseudo and true)
• b. Reduction of cholinesterase activity by 50% seen
with acute symptoms of toxicity
• c. Symptoms depend on rate and level of depletion,
with rate being more critical

27. 2- Stabilization
• a. ABCs endotracheal intubation and frequent
suctioning often required
• b. continuous cardiac monitoring
• c. benzodiazepines for seizures
• d. decontamination: lavage and activated
charcoal
– 1. remove all clothing, decontaminate skin
– 2. avoid direct skin contact with ED personnel

28. Assessment of severity of OP poisoning
ICU admission if grade ≥ 2
Brent, Wallace, Burkhart, et al. Organophosphorus and carbamate insecticides, Methanol
poisoning. Critical care Toxicology. Diagnosis and management of the critically poisoned
patient. Philadelphia, Elsevier Mosby, 2005 : pp 937-947

29. 3- Antiodotal therapy
• Atropine:
• 1. Non-competitively antagonizes both muscarinic and CNS effects
of organophosphate poisoning alleviating bronchial secretions,
salivation, sweating, cramps, vomiting, and bradycardia
• 2. Therapeutic dose in symptomatic patients: 2-4 mg in adults
(0.05mg/kg in kids) q 15 min. until pt. atropinized
• 3. Administration does not require confirmation by
acetylcholinesterase levels
• 4. Drying of secretions is endpoint of full atropinization

30. 2-PAM (Pralidoxime)
• 1. 2-PAM is specific antidote that effectively reverses phosphorylation of the
cholinesterase enzyme when given within 24h post exposure
• 2. treats muscle weakness, fasciculation, and altered LOC
• 3. indication for use: severe organophosphate poisoning with respiratory
depression and muscle weakness
• 4. dosage: 1-2 gm in adults, 20-50mg/kg in kids
• -a.may repeat bolus every 8 hours or institute continuous infusion
• Obidoxim: Passes BBB, regenerates Ch.E of CNS
• Why oximes are contraindicated in carbamate poisoning ?
• The site on which oximes bind and reactivate the enzyme (anionic site) is occupied
by carbamates whereas it is free in the organophosphate poisoning.

31. • By the loss of one of the
alkyl group the
phosporylated enzyme
may become resistant
to hydrolysis thus
causing irreversibility.
• Reactivation time of
carbamylated enzyme is
less(30mins) whereas
phospory. E is more
than regeneration time.

32. • Vital Signs
• ECG
• Close Observation of any change
• Psychiatric Evaluation

33. 5. Prognosis and Disposition
• Disposition
• a. ICU during antidote administration
• b. monitor 48 hours after the last dose of atropine
Prognosis
• a. Full recovery in 1-2 weeks with optimum therapy
• b. outpatient follow-up for signs of intermediate
syndrome
• c. high fatality rate with in 24 hours in undertreated
patients with signs of severe toxicity