ORGANOPHOSPHATE

POISONING

Dr.U.P.Rathnakar
MD.DIH.PGDHM
www.scribd.com
www.pharmacologyfordummies.blogspot.com
 What is the link?
• Cholinergic drugs [Agonists of Ach Rec.]
Cholinomimitics OR
Directly acting cholinergics OR

Anti-Cholinesterases Indirectly acting

Cholinomimitics

Antagonists Anti-cholinergics Musc.Rec.Antagonists

N.M.Blockers Antagonists at N.M.Junction

Ganglion blockers
 Anticholinesterases
[Indirectly acting cholinergics]

Reversible anticholinesterases
Carbamates Acridine
Tacrine.
• Physostigmine
• Neostigmine
• Pyridostigmine
• Edrophonium
• Ambenonium
• Demecarium
• Rivastigmine,
• Donepezil,
• Galantamine.
 Anticholinesterases
[Indirectly acting cholinergics]

Irreversible anticholinesterases

Organophosphates: Carbamates:
• Echothiophate Carbaryl*
• Parathion* Propoxur*
• Malathion*
• Diazinon*
• Tabun# *Insecticides
# Nerve gases-
• Sarin#
chemical warfare
• Soman#
Carbamylation [Therapeutic]
and
Phosphorylation [Poisoning]

Reaction
Very Slow
Or
irreversible
 REVERSIBLE
ANTICHOLINESTERASES-USES
MIOTIC
• Glaucoma
• Reverse the effect of mydriatics
• Alternated with mydriatics-to
break irido-corneal adhesions
 REVERSIBLE
ANTICHOLINESTERASES-USES
• Postoperative paralytic ileus/urinary retension
[Neostigmine]
• Postoperative decurarization [Neostigmine
preceded by Atropine]
• Cobra bite [Neostigmine+Atropine]
• Belladona [Atropine] poisoning-Physostigmine
• Alzheimer’s disease-Tacrine, rivastgmine,
donepezil, galantamine [cerebroselective]
• Drug over dosage-e.g. TCA

• Myasthenia gravis
 Irreversible anticholinesterases
Organophosphates
• Echothiophate –used in glaucoma
• Parathion
• Malathion Insecticides
• Diazinon
• Tabun
• Sarin Nerve gases
• Soman
 Entry into body

• Transdermal
• Inhaled
• Ingested
 Mechanism Of Action

 Organophosphorous
 compounds bind to acetylcholinesterase
 overabundance of acetylcholine in the synapse
 Compound undergoes a conformational change
(aging) renders the enzyme irreversibly resistant to
reactivation.
 Carbamate
 Compounds unlike organophosphates, are transient
cholinesterase inhibitors.
 OP Poisoning
• Occupational
• Accidental
• Homicidal
• Suicidal
• Chemical warfare
Clinical Features (Acute Toxicity)

Paralysis
 Types of toxicity
• Acute cholinergic syndrome
• Intermediate syndrome
• Delayed Neurotoxicity
• Warfare
 Clinical Features (Acute Toxicity)
• Generally manifests in minutes to hours
• Evidence of cholinergic excess
• Parasympathetic-Sympathetic-Nicotinic
DUMBELLS= Diarrhea ,
SLUDGe =Salivation, Diaphoresis
Lacrimation, Urination
Urination, Miosis 
Defecation, Bradycardia 
Emesis 
Gastric Emptying. Lacrimation
Lethargy
BBB= Bradycardia,
Salivation
Bronchorrhea,
Bronchospasm.
 TREATMENT
A-B–C

• Airway: Bronchoconstriction
• Breathing: Paralysis of resp.muscles
• Circulation: Hypotension Vs Hypertension
 TREATMENT
Acute
• General supportive measures:
• Termination of exposure, copious washing , airway,
respiration , oxygen, DIAZEPAM, tt shock
• Anticholinergics Atropine i.v.
- Sufficent doses i.v. [For muscarinic effects]-till
atropinization-maintained for 1-2 weeks
• Cholinesterase reactivators
• Pralidoxime - Sufficiently early i.v.
[For Nicotinic effects]
 Oximes-MOA
[Cholinesterase reactivators]

Pralidoxime[2-PAM]
Obidoxime
Diacetyl-monoxime[DAM]
Oxime –phosphate
diffuses

Oxime +
Phosphorous

Reaction
Very Slow
Or
irreversible

Oximes attach
to anionic site
 Oximes
• Ineffective against carbamates-Anionic site is not
free
• Contra indicated-intrinsic anti-ChE activity
• More effective at nicotinic
• Poor in muscarunic sites
• Not at all in CNS-does not cross BBB
• Not effective after phosphorylated enzyme under
goes aging
• Atropine is the DOC-Oxime is secondary drug
 Chronic OP poisoning
• Fluorine compounds
• Polyneuritis and demyelination of nerves
• Sensory loss → Motor loss → LMN palsy →
Spasticity → Upper motor neurone paralysis
• Mechanism → not inhibition of ChE
• Takes years to recover
 Nerve agents [Nerve gases]

• These chemicals are liquid at room

temperature,
• Phosphorus-containing
• organic chemicals (organophosphates)
• Weapons of mass destruction
Nerve gases[Anticholinesterases]
Gulf war syndrome

• Approximately 250,000 of the 697,000

veterans who served in the 1991 Gulf
War are afflicted with enduring chronic
multi-symptom illness,
• A wide range of acute and chronic
symptoms have included fatigue, loss of
muscle control, headaches, dizziness and
loss of balance, memory problems,
muscle and joint pain, indigestion, skin
problems, immune system problems, and
birth defects.
• Nerve Gas??
• Pyridostigmine??
Nerve gases
• Miosis, profuse salivation,
convulsions, involuntary
urination and defecation and
eventual death by asphyxiation
• Nerve agents can also be
absorbed through the skin
• Or portal of entry into the body
is the respiratory system
• Protection-full body suit in
addition to a respirator.
 Anticholinergics
[Cholinoceptor antagonists]

Dr.U.P.Rathnakar
MD.DIH.PGDHM
www.scribd.com
www.pharmacologyfordummies.blogspot.com
 What is the link?
• Cholinergic drugs Drugs act like ACh Act at sites &
receptors
Where Ach acts
[Agonists of Ach Rec.]
Cholinomimitics OR
Directly acting cholinergics OR
Ganglia-NN
Indirectly acting Sk.muscles-NM
Cholinomimitics Heart,Lungs,
Int.]Musc
Eye, Sweat
Inhibit degradation of Ach glands]M12345
By AChE[Cholinesterase] Anti-Cholinesterases Increase duration of
Action of ACh

Antagonists Anti-cholinergics Musc.Rec.Antagonists

N.M.Blockers Antagonists at N.M.Junction

Ganglion blockers
 ANTICHOLINERGICS

Competitive antagonists of
acetylcholine at cholinergic sites
Site of action of anti-cholinergics

s
ni c blocker
Ga n g l io

NM Blockers

Antimuscarinics
 Anticholinergic drugs
[Classification]

Natural alkaloids Semisynthetic Synthetic compounds

derivatives
•Atropine •Homatropine •Mydriatics
•Scopolamine •Atropine Cycclopentolate& Tropicamide

[Hyoscine] methonitrate •Antisecretory-

•Hyoscine butyl antispasmodics
Quaternary
bromide Propatheline, Glycopyrrolate

•Ipratropium Tertiary
bromide Dicyclomine, Pirenzepine

•Tiotropium •Antiparkinsonian
Trihexyphenydyl, Biperiden,
bromide Benztropine
•Vasicoselective
Oxybutynin, Flavoxate
 SOURCE AND CHEMISTRY

• Atropine -Atropa belladonna Or Datura

stramonium-tertiary amine
• Scopolamine  (hyoscine) -Hyoscyamus niger,
• Tertiary derivatives- used -effects on the eye or the
CNS[mydriatrics or antiparkinsonians]
• Quaternary amines -more peripheral effects with
reduced CNS effects[Antispasmodics]
• Antihistaminic -antipsychotic -antidepressant - have
similar structures
• Hence antimuscarinic side effects.
 Pharmacokinetics

ABSORPTION
• Natural alkaloids and most tertiary
antimuscarinic drugs are well absorbed from the
gut and conjunctival membranes.
• Even absorbed across the skin (transdermal
route-scopolamine).
• Only 10–30% of a dose of a quaternary drug is
absorbed after oral administration,
 Pharmacokinetics

• DISTRIBUTION
• Atropine and tertiary agents are widely distributed in the body.

• Significant levels –in CNS within 30 minutes to 1 hour, and this

can limit the dose tolerated when the drug is taken for its
peripheral effects.

• Scopolamine is rapidly and fully distributed into the CNS where it

has greater effects than most other antimuscarinic drugs.

• Quaternary derivatives are poorly taken up by the brain and

therefore are relatively free—at low doses—of CNS effects.
 Pharmacokinetics
• METABOLISM AND EXCRETION
• Atropine-Rapid phase is 2 hours and that of the slow phase
is approximately 13 hours.
• About 50% of the dose is excreted unchanged in the urine.
• The drug's effect on
parasympathetic function declines
rapidly in all organs except the eye.
Effects on the iris and ciliary
muscle persist for 72 hours.
 Pharmacodynamics
• Atropine causes reversible (surmountable) blockade of
cholinomimetic actions at muscarinic receptors;
• Muscarinic antagonists not just neutral compounds that
occupy the receptor and prevent agonist binding.
• Muscarinic receptors are constitutively active,
• Drugs that block the actions of acetylcholine are inverse
agonists
• Shift the equilibrium to the inactive state of the receptor.
• Muscarinic blocking drugs that are inverse agonists
include atropine, pirenzepine, trihexyphenidyl,
 Tissue selectivity
• Most sensitive to atropine are the salivary, bronchial,
and sweat glands.
• Secretion of acid by the gastric parietal cells is the least
sensitive.
• Atropine is highly selective for muscarinic receptors.
• Its potency at nicotinic receptors is much lower,
• Atropine does not distinguish among the M1, M2, and M3
subgroups of muscarinic receptors.
• Quaternary- Poor absorption, do not cross BBB, more
nicotinic and ganglionic actions, longer acting
• Differences between Atropine and Scopolamine????
 Systemic Effects
CNS
• Medullary-Excitation
• Vestibular-depression
• Basal ganglion-↓Cholinergic
activity
• High doses-Disorientation,
hallucination, coma
Eye
• Passive mydriasis
• Cycloplegia
• Reduce lacrimal secretion
• Belladona!!!
• The name belladonna derives from the alleged
use of this preparation by Italian women to
dilate their pupils
• Modern-day fashion models are known to use
this same device for visual appeal
Active and Passive
Mydriasis
• WHEN A ADRENERGIC
STIMULANT IS GIVEN- THE
DILATOR PUPILLAE MUSCLE
CONTRACTS LEADING TO
• MYDRIASIS.
• ACTIVE MYDRIASIS.
• [No cycloplegia]
• [Light reflex ++]

• ANTICHOLINERGICS-UN-
OPPOSED ACTION OF THE
DILATOR PUPILLAE
- MYDRIASIS.
- PASSIVE MYDRIASIS
• [Cycloplegia++]
• [No light rehlex]
 Active Passive
Mydriasis Passive mydriasis
Drug Adrenergic Anticholinergic

Muscles Contraction of Paralysis of constrictor

dilator
Cycloplegia Absent Present

Light reflex Present Absent

Conjuctival Constricted No effect

vessels
IOT Decreased or no Increased
change
 Systemic Effects
CVS
• Tachycardia-M2 blockade
• Transient initial bradycardia-
[Not central action]
• Most blood vessels receive no
direct innervation from the
parasympathetic system.
• All vessels contain endothelial
muscarinic receptors that
mediate vasodilation
• These receptors are blocked
by antimuscarinic drugs.
[Efect of injected esters]
• At toxic doses, and in some
individuals at normal doses,
antimuscarinic agents cause
cutaneous vasodilation,
especially in the upper portion
of the body. The mechanism is
unknown.
• Cholinergic system not
involved in vascular tone
• Tachycardia Vs Direct
vasodilation=Net effect
 Systemic Effects
RS GIT
• Can not completely abolish
• Bronchodilation and activity[Enteric nervous
system]
decreased secretions • Salivary secretion
• COPD and effectively blocked
preanesthesia • Gastric-only basal secretion
• Not intestinal and
pancreatic
secretions[Hormonal
control]
 Systemic Effects
GUT Sweat glands
• Relaxes smooth • Atropine suppresses
muscle of the ureters thermoregulatory
sweating
and bladder wall and
• Body temperature is
slows voiding
elevated-therapeutic
• Can precipitate doses in children
urinary retention in
men who have
prostatic hyperplasia
Atropine toxicity
• Hot as a hare,
• Blind as a bat,
• Dry as a bone,
• Red as a beet,
• Mad as a hatter.
 Anticholinergics –Clinical
applications
• Mydriatic & Cycloplegic
• Respiratory disorders-COPD
• CVS disorders
• GIT disorders
• Disorders of urinary system
• Parkinsonism
• Motion sickness
• Preanesthetic
 Mydriasis-Anticholinergics

Drug Onset Duration Remarks

Atropine 30-40 Mts 1 week Useful in children
High ciliary tone
Homatropine 45-60 Mts 1-3 days Unsatisfactory in
children
Cyclopentolate 30-60 Mts 1 day Behavioral
abnormalities in
children[Absorption]

Tropicamide 20-40 Mts 3-6 H Unreliable cycloplegic

 Mydriasis
• To test errors of refraction
• For fundoscopy
• Iritis, iridocyclitis, keratitis
• Rest to iris, anodyne, reduces spasm
• To prevent/break adhesions[Synechiae]
 Respiratory disorders
[Ipratropium & Tiotropium]
• COPD & Bronchitis
• Less effective in B.Asthma
• Orally-dries secretions,
• Mucociliary clearance is affected
• Inhalational route
• Combined with adrenergic agonists
 Cardiovascular disorders

• Increased vagal tone- Bradycardia-

MI, Digitalis toxicity

• Chaga’s disease-Antibodies to M2 rec.

 GIT & Genito-urinary disorders
[Antispasmodic]
• Peptic ulcer-not common[Propantheline,
oxyphenonium]
• Traveller’s diarrhoea
• Intestinal colic, dysmenorrhoea
[Dicyclomine]
• Urinary incontinence
[Oxybutynin, Darifenacin , solifenacin,
Tolterodine and fesoterodine ]
• Valethamate-Cx dialation
 Preanesthetic
• Prior admin.with irritant GA[Ether]
• To reduce secretions & prevent
laryngospasm [????]
Atropine
• With Halothane[Sensitizes the heart]
• To prevent arrhythmias
• To reduce vasovagal reflexes
• Atropine & Glycopyrrolate
 CNS action
Motion sickness
• Hyoscine-oral & Transdermal
• Prophylactically
• Not effective in other vomiting

Parkinsonism
• Trihexyphenydyl, procyclidine,Biperiden
• In mild cases
 Toxicity and DI
Management of Toxicity
• Gastric lavage [if ingested] with KMNO4
• Cold sponging
• Dark room
• Physostigmine i.v.
• Diazepam
DI
Delays gastric emptying-delays absorption
Antihistaminics, TCA-additive effects