Anticholinesterases

SUDHAKAR LAKAVATH
PHARMACOLOGY
 Case scenario
• A patient is brought to the casuality with the signs and
symptoms of decreased respiration, rate and depth, miosis,
muscle twitching, fasiculations, increased
secretions,diarrhea,convulsions with loss of consciousness.

1. What could be the drug causing above signs and symptoms?

2. How will you manage the case?

Anticholinesterases
• Drugs that prolong the existence of
acetylcholine after it is released from
cholinergic nerve endings
• Inhibit both acetylcholinesterase and
butyrylcholinesterase.
 Anticholinesterases
REVERSIBLE IRREVERSIBLE
 Carbamates  Organophosphorus
 Physostigmine compounds
 Neostigmine  Parathion
 Pyridostigmine  Malathion
 Edrophonium  Sabun, Sarin, Soman
 Carbamates
 Carbaryl
 Propoxur
 War gas poisoning
(Tabun, Sarin, Soman)
 Insecticides
• Three types of insecticides
– Organophosphorus
• Parathion, Malathion
• Diazinon (Tik-20)
– Carbamates
• Propoxur (Baygon)
• Carbaryl (Sevin)
– Organochlorine compounds
• DDT
• BHC (Gammaxane)
• Endrine
• Chlordane
 Mechanism of acetylcholine hydrolysis by acetylcholinesterase.

Nair V P , Hunter J M Contin Educ Anaesth Crit Care Pain

2004;4:164-168

Continuing Education in Anaesthesia, Critical Care & Pain | Volume 4 Number 5 2004 © The
Board of Management and Trustees of the British Journal of Anaesthesia 2004
 Metabolism of Acetylcholine

Acetylcholine Cholinesterase

mSec

Acetic acid + Acetylated

Choline Cholinesterase
• The acetylated enzyme is hydrolysed rapidly
and free enzyme and acetic acid are formed.
• Approximately 10 000 molecules of
acetylcholine are hydrolysed per second in
each active site.
Effect of Reversible Anticholinesterases

Acetylcholine Cholinesterase

Neostigmine
Hours

Acetic acid + Carbamylated

Choline Cholinesterase
Effect of Organophosphorus compounds
Poisoning

Acetylcholine Cholinesterase

Organophosphorus
compounds

Phosphorylated
Acetic acid + Cholinesterase
Choline
Organophosphorus poisoning
 Organophosphorus Compound

Phosphoric Acid Parathion

 Incidence
• The most common poisoning in India is
Organophosphorus poisoning because of its
easy availability.
• Types of poisoning:
– Ingestion for suicide (common)
– Absorption through the skin during spraying
– War gas poisoning (Tabun, Sarin, Soman)
 Organophosphorus Compounds
• Inhibition of cholinesterase (irreversible)
• Phosphorylation of enzyme
• Muscarinic, Nicotinic and Central effects of
Acetylcholine overactivity
• Delayed neuropathy
 Poisoning
• Intoxication occurs following
– ingestion via the GI tract
(mostly suicidal)
– absorption through the skin
(accidental)
– inhalation through the respiratory tract
(accidental)
 Pathology
• OP depress both true cholinesterase
(acetylcholine esterase) and pseudo
cholinesterase (butylcholine esterase)
• True cholinesterase is present in myoneural
junction and in RBC
• Pseudo cholinesterase is present in plasma
• Serum cholinesterase is easier to measure.
• Serum CHE > 50% of normal: No clinical sign
• Serum CHE < 25% of normal: Clinical signs
 Pharmacokinetics
• Most OP are highly lipid soluble compounds
• Well absorbed from intact skin, oral mucous
membranes, conjunctiva and the GIT and
respiratory tracts.
• Rapidly redistributed to all body tissues;
highest concentrations in liver and kidneys.
• Easily cross BBB and produce potent effects
on the CNS.
 Pharmacokinetics
• Metabolism: principally by oxidation in the liver
with conjugation and esterase hydrolysis
• t½ : minutes - hours.
• The oxidative metabolites of malathion and
parathion are active; subsequently hydrolyzed
into inactive metabolites.
• Elimination of OP compounds and its
metabolites occur mainly via urine, bile and
faeces.
 Treatment of OP Poisoning
• Muscarinic receptors
– Antidote: Atropine
• Nicotinic receptors
– Antidote: Pralidoxime (PAM)
• Central Nervous System
– No antidote
– Atropine acts partially only in high dose
– Only supportive measures
 Onset of Symptoms
• Following exposure to OP compounds, the
toxic features are usually obvious within 30
minutes to 3 hours.
• Delay in some cases depending on the rate
and amount of systemic absorption
 Clinical Features
• Broadly classified as secondary to the
– (a) muscarinic effects
– (b) nicotinic effects and
– (c) central receptor stimulation.
• Early cases: predominantly with parasympathetic
overactivity, and a characteristic garlic smell.
• The end result: a multi-system manifestation
involving the GI, respiratory, cardiovascular and
nervous systems, as well as involvement of skeletal
muscle, other organs and metabolic effects such as
hyperglycemia
 Muscarinic Symptoms
Cardiovascular Gastrointestinal Genitourinary
• Bradycardia • Nausea/ • Urinary
vomiting
• Hypotension continence
• Increased
salivation Eyes
Respiratory • Abdominal • Blurred vision
• Rhinorrhoea cramps • Increased
• Bronchorrhoea • Diarrhoea lacrimation
• Faecal • Miosis
• Bronchospasm incontinence
• Cough Glands
• Excessive salivation
 Nicotinic symptoms
Cardiovascular Musculoskeletal
• Tachycardia • Weakness
• Hypertension • Fasiculations
• Cramps
• Paralysis
 Central Symptoms
• Anxiety • Dysarthria
• Restlessness • Tremors
• Ataxia • Coma
• Convulsions • Absent reflexes
• Insomnia • Respiratory
depression
• Circulatory collapse
 Coma
Convulsion Pinpoint Pupil
Headache Blurred Vision
Excessive tearing
Dizziness
Salivation

Sweating
 Tightness of chest
Tachycardia
Elevated BP

Vomiting
Rashes
Reddening Cramps
of skin
Diarrhoea

Tremor

Muscle
Twitching
Muscle
Weakness

Blisters
 Prognosis

• Most fatalities occur within 24 hours

• Fatalities: 5 – 10%

• Recovery usually occurs within 10 days

 Grading of Severity
• Mild:
– Consciousness
– Mild increase in secretions
– Fasciculation
 Severe
• Impaired consciousness
• Copious secretion
• Multiple fasciculation
 Life Threatening
• Stupor
• Abnormal chest X-ray
• PaO2 < 60 mm of Hg
 Cause of Death
(Respiratory Failure)

MUSCARINIC: CENTRAL:
• Hypersecretion, • Paralysis of
patient drowning respiratory centre
in his own in medulla.
secretion
NICOTINIC
• Paralysis of
intercostal muscles
and diaphragm
 Treatment Plan
General Management
• Removal of poison (decontamination)
• Oxygenation
• Maintenance of Circulation
Specific Treatment
• Competitive receptor antagonist of ACh:
Atropine (drug of choice)
• Reactivator of phosphorylated cholinesterase
enzyme - Pralidoxime , an oxime (adjuvant drug)
 Treatment
(Decontamination)
• Skin decontamination is very important step
that should never be neglected or hurried.
• The patient should be removed from the site
of exposure and their clothes removed.
• The patient's body should then be thoroughly
washed with soap and water to prevent
further absorption from the skin.
 Treatment
(Decontamination)
• Gastric emptying should then be considered if the
patient presents within 1 hour of ingestion.
• Gastric lavage is the only means of emptying the
stomach in unconscious patients in which case the
airway needs to be protected.
• The patient should receive activated charcoal 0.5-1
gm/ kg every four hours to promote adsorption in
the gastrointestinal tract.
• Lavage is preferred to enforced emesis as this may
precipitate seizures.
 Treatment
• Establish patent airway
– Start high flow oxygen
– Intubation and ventilation if necessary
• Monitor and maintain circulation
– IV line and glucose saline drip
– If BP is low, vasopressor agent dopamine to be started.
• Catheterization to be done before high doses of
atropine that causes spasm of internal sphincter
and cause retention of urine.
 Specific Antidote
• Atropine (antimuscarinic agent) is the
competitive receptor antagonist at
muscarinic receptor and antagonize the
central effect at high dose
• Availability
– Ampoule 1ml = 0.6 mg
– Ampoule 1 ml = 1 mg
• Before atropine is started,
– correct cyanosis by oxygen
– Catheterise the patient
 Atropine
• 5 ampoules = 3 mg (0.6 × 5 = 3 mg) is given IV
bolus
• Repeat the same dose at the interval of 10
minutes till patient is atropinised.
• Atropine infusion started at the rate of 20 ml
per hour and increase or decrease the rate
basing on symptoms
• No fixed dose of atropine, it depends on how
much OP has been absorbed.
 Signs of atropinization
• Mydriasis (dilated and fixed pupils),
• Decreased secretion (most reliable),
• No bronchial secretion,
• Dryness of tongue.
• Skin: cold and clammy  dry and hot,
• Delirium, restlessness Atropine crossed BBB
• Confusion and convulsion
• Fever, tachycardia
 Atropine withdrawal
• Central signs, fever and tachycardia  lowering
of dose or omission of few doses of atropine
• Atropine must not be withdrawn abruptly, it must
be tapered and stopped slowly over a few days.
• After the sign of initial recovery, patient may
again worsen because of release of poison from
body fat stores or because of development of
intermediate syndrome.
 Alternate to Atropine
• Glycopyrolate, a quarternary ammonium
compound
• Gives better control of secretion
• Less tachycardia
• No CNS symptoms as it does not cross BBB.
 Pralidoxime
• 1 gm 4 – 6 hourly IV, diluted with 20 ml of
glucose.
• Maximum: 12 gm / first 24 hours
• Lower dose according to symptoms for 1 – 2
weeks.
• Available: 1 gm / vial
• Status: Secondary to atropine
• Most effective in the first 24 hours
 Effect of cholinesterase activators

Acetylcholine Pralidoxime
Cholinesterase

Organophosphorus
compounds

Phosphorylated
Cholinesterase Phosphonated
Acetic acid + pralidoxime
Choline complex
 Effect of ageing
Acetylcholine Cholinesterase
Pralidoxime
Organophosphorus
compounds

Phosphorylated
Cholinesterase
Acetic acid +
Choline 24 hr

Ageing of
Phosphorylated
Cholinesterase
 Mechanism of Action of Oximes
Free Anionic Site
Pralidoxime

A
Ageing occurs
Oxime-
Anionic Esteratic within 24 hours phosphonate
Site by removal of complex
Site alkyl group

3
Phosphorylated Enzyme 1

4
Hydrolysis 2
B
C
Anionic Esteratic
Anionic Esteratic Site
Site Site
Site

Free Enzyme
 Duration of Treatment
• Atropinization to be maintained for 7 -10 days
till the new CHE is generated in sufficient
quantity.
• During atropinization patient should not be
fed through mouth as atropine may cause
paralytic ileus.
• IV Fluid containing dextrose should be given
 Anticholinesterases - uses
• Residual muscle weakness is common after the
use of long-acting neuromuscular blocking
agents.
• Myasthenia gravis
• Alzheimers disease
• Paralytic ileus
• Glaucoma
• Reversal of intoxication caused by central
anticholinergic drugs
 Myasthenia gravis
• Auto immune disorder
• Antibodies against NM receptor on muscle
end plate
• Symptoms - Muscle weakness, easy fatigue
• Muscles involved –
– Eyelid, external ocular, facial and pharyngeal
muscles
– Limb and respiratory muscles
 Myasthenia gravis
• Treatment
– Neostigmine
– Corticosteroids, immunosupressants
– Plasmapherisis
– Thymectomy
 Myasthenia gravis
Myasthenic crisis
• Acute weakness of respiratory muscles
• Managed by tracheal intubation and ventilator
support
• Treatment by
– Iv methyl prednisolone pulse therapy
– Neostigmine withheld and gradually reintroduced
– plasmapheresis
 Diagnostic tests
• Edrophonium test
• To differentiate cholinergic crisis and
myasthenic crisis
 Alzheimer’s disease
• Donepezil (Aricept)—said to delay progression of the
disease by up to 55 weeks. Does not cause liver
toxicity.
• Galantamine (Reminyl)—newest kid on the block
• Rivastigmine (Exelon) long acting. Twice a day dosing.
• Tacrine (Cognex)—hepatotoxic. Elevated liver
enzymes usu. Within 18 wks. > in women.
Thank You