Organophosphate poisoning -introduction mechanism ,clinical features ,investigation, management.

1. ORGANOPHOSPHATE
POISONING

2. INTRODUCTION
Organophosphate compounds are widely used in agricultural sector
as PESTICIDES & as chemical war fare.
Case fatality following deliberate ingestion is high (15–30%).
Easily accessible, hence associated with self poisoning 200,000
/500,00 mortality associated self-poisoning with pesticides in rural
Asia.
50-70 % in hospital based study.
15-30% in India
Suicidal rate with OPC 20.6- 56.3%.
Organophosphates are among the most popular and most widely
used insecticides in India.

3. • Organophosphates are anti-esterase insecticides, and exert their
acute effects by causing overstimulation at cholinergic nerve
terminals. This process occurs in both insects and humans.

4. Normally, acetylcholinesterase
catalyzes the degradation of the
neurotransmitter acetylcholine in
the synapse (yellow panel).
Organophosphate pesticides
phosphorylate acetylcholine,
thereby reducing the ability of the
enzyme to break down the
neurotransmitter (red panel)
Accumulation of (ACH) in
cholinergic synapses
Overstimulation of (Ach)
receptors in postsynaptic
neuron

5. This produces an accumulation of acetylcholine in the central and
peripheral nervous systems, resulting in an acute cholinergic
syndrome via continuous neurotransmission.
The clinical onset of cholinergic over-stimulation can vary from
almost instantaneous to several hours after exposure.

6. Mechanism of toxicity
OP compounds inactivate acetylcholinesterase (AChE), resulting in
the accumulation of acetylcholine (ACh) in cholinergic synapses.
After the process (termed ‘ageing’) has taken place, new enzyme
needs to be synthesised before function can be restored.
The rate of ‘ageing’ is an important determinant of toxicity and is
more rapid with dimethyl (3.7 hrs) than diethyl (31 hrs) compounds
and especially rapid after exposure to nerve agents (soman in
particular), which cause ‘ageing’ within minutes.

7. Irreversibly bind to serine-OH group at active site of
acetylcholinesterase (AChE) & establish covalent bond
(phosphorylation)
AGING: loss of alkyl group + strengthening of
covalent bond
Phosphorylated AChE is very stable
Inhibition of enzyme activity accumulation of ACh in
the synapse and NMJ
Overstimulation of cholinergic receptors

8. Toxicokinetics
• ■ Organophosphates can be absorbed by any route including
Transdermal, Transconjunctival, Inhalational, across the GI and GU
mucosa, and through direct injection.
• ■ Manifestations usually begin within a few minutes to few hours,
but may be delayed upto 12 hours or more in the case of certain
compounds (e.g. fenthion, parathion).

9. Clinical features
• OP poisoning causes an
Acute cholinergic phase,
 Intermediate syndrome,
Organophosphate-induced delayed polyneuropathy (OPIDN).
• The onset, severity and duration of poisoning depend on the route of
exposure and agent involved.

10. Acute cholinergic syndrome
• This usually starts within a few minutes of exposure and nicotinic or
muscarinic features may be present.( within first 24 hrs)

11. • Garlic-like odor
• Vomiting and profuse Diarrhoea are typical following ingestion.
• Bronchoconstriction, Bronchorrhoea and Salivation may cause
severe Respiratory compromise.
• Excess Sweating and Miosis are characteristic and the presence of
muscular fasciculation strongly suggests the diagnosis, although this
feature is often absent, even in serious poisoning.
• Subsequently, Generalized flaccid paralysis may develop and affect
Respiratory and Ocular muscles, resulting in Respiratory failure.
• Ataxia, Coma, Convulsions, Cardiac repolarization abnormalities and
torsades de pointes may occur.

13. Cholinergic features in poisoning
Muscarinic Nicotinic
Respiratory
Bronchorrhoea,
bronchoconstriction
Reduced ventilation
Circulation Bradycardia, hypotension, Tachycardia, hypertension
Higher mental function Anxiety, delirium, psychosis
Muscle - Fasciculation, paralysis
Temperature Fever -
Eyes Diplopia, miosis, lacrimation Mydriasis
Abdomen Vomiting, profuse diarrhoea -
Mouth Salivation -
Skin Sweating -
Complications Coma, seizures, respiratory depression

15. Intermediate syndrome
• About 20% of patients with OP poisoning develop weakness that
spreads rapidly from the ocular muscles to those of the head and
neck, proximal limbs and the muscles of respiration, resulting in
ventilatory failure.
• Onset : 24-96 hrs after poisoning, after the cholinergic phase settles.
Mechanism: Excess Ach at NMJ causes down regulation of nicotinic
receptors and muscles affected.

16. Intermediate syndrome:
Features: Characterized by proximal neck muscles leading to
respiratory distress and failure without muscarinic signs, without
intervention, cyanosis ,coma and death occurs rapidly.
Duration: Lasts for few days to about 3 weeks.
There is no specific treatment and supportive care is needed,
including maintenance of airway and ventilation.

17. OP-Induced Delayed Polyneuropathy (OPIDN)
 Onset: Occurs 2-4 weeks after exposure & associated with demyelination
of axons.
 Mechanism: Due to degeneration of long myelinated nerve fibers. Pure
motor or sensor-motor.
Not caused by cholinesterase inhibition but rather by neuropathy target
esterase (NTE) inhibition.
 Features: Characterized by cramps in the legs , numbness and paresthesia
in the distal upper and lower limbs , shuffling gait , foot and wrist drop.
Other features: wasting, DTR reduced/absent, pyramidal tract signs absent.

18.  Involves distal muscles with relative sparing of neck muscles, cranial
nerves, & proximal muscles.
• Delayed mixed sensorimotor peripheral neuropathies.
• C/o: Symmetric, peripheral neuropathies. Motor > sensory
• Ataxia, gait disturbances.
• • Fate – self-resolution / persistent deficits.
• Recovery is incomplete.

19. • Diagnosis of organophosphate poisoning
Clinical diagnosis : severity of organophosphorus poisoning
(Dreisbach`s)
Grade Symptoms
Mild Nausea.
Moderate
Lacrimation, salivation , miosis ,
fasciculation.
Severe
Incontinence, apneic spells ,ARDS ,
Areflexia seizures, coma.

20. Laboratory:
Red cell cholinesterase.
Plasma cholinesterase (Pseudo, Butyryl(Bu)).
ECG : The most common Ecg abnormality was prolonged QTc and
sinus tachycardia.
ABG : Hypoxemia.

21. Patients at risk
• • Poisoning due to OPs with
delayed metabolism.
• • Severe poisoning.
• • Elevated muscle enzymes.
• • Delayed or inadequate
oxime therapy.

22. Management of OP Poisoning
Hospitalization/ ICU
• 1. Initial stabilization.
• 2. Reduction of exposure.
• 3. Administration of specific
antidote.
• 4. Supportive treatment.
Initial Stabilization of the
patient.
• Clear airway and
• Adequate ventilation because
the patient with acute
organophosphate poisoning
(ACC) commonly presents with
respiratory distress.
• Oxygen- Circulation- iv access-
intubation.
AIM: A systolic BP 80mmhg and urine output >30ml/hr.

23. • Decontamination
• • Dermal spills—wash pesticide spills from the patient with soap and
water and remove and discard contaminated clothes, shoes and any
other material made from leather.
• • Gastric lavage —consider for presentations within 1 or 2 hours,
when the airway is protected. A single aspiration of the gastric
contents may be as useful as lavage.
• • Activated charcoal —50 g may be given orally or nasogastrically to
patients who are cooperative or intubated, particularly if they are
admitted within one or two hours or have severe toxicity.

24. • Antidotes in the
treatment of OP
poisoning.
• • Atropine- Reverses the
muscarinic features.
• • Oxime- Reactivate
cholinesterase and
reverses the nicotinic
features.

25. Suggested symptom based treatment recommendations for organophosphorus
poisoning
Sign or symptom Recommended therapy
Excessive salivation ,lacrimation,
nausea and vomiting, diarrhea
Atropine, Glycopyrrolate
Bronchorrhoea, Bronchospasm Atropine, Ipratropium, Glycopyrrolate
Hypotension Fluids, Atropine, Vasopressors, Inotropes
Bradycardia Atropine, Glycopyrrolate
Eye pain Mydriatics, Cycloplegics
Muscle weakness Oximes
Respiratory failure Intubation and Ventilation, Oximes
Seizures Benzodiazepines

26. Atropine
• • Initial dose: 1.8-3 mg IV every 5-10min until atropinisation.
• • Continuous infusion (8mg atropine in 100ml NS) at rate of 0.02-
0.08mg/kg/hr (0.25-1.0 ml/kg/hr) with additional 1-5mg bolus.
• • May require about 40-1500mg/day.
• • For at least 5-7days.
• • Watch out for OVER ATROPINIZATION.
Early use of sufficient doses of atropine is potentially life-
saving in patients with severe toxicity.

27. Target end points for atropine therapy
• • Clear chest on auscultation with no wheeze.
• • Heart rate> 80/min.
• • Pupils no longer pin point
(does not imply that pupils must be dilated).
• • Dry axilla.
• • Systolic BP > 80 mm Hg.
• Dilated pupils is not a reliable sign of initial atropinisation or end
point for atropine therapy.

28. Pralidoxime (2-PAM)
• An oxime that reactivates phosphorylated cholinesterase.
• Effects: skeletal-neuromuscular junctions (counteracts weakness,
fasciculation and respiratory depression).
• Administration within 48 hours of poison ingestion.
PAM must be given by infusion. Go slow ,both for bolus and
maintenance. A fast infusion can cause vomiting ,hypertension,
cardiac arrhythmias or cardiac arrest.

29. Bolus dose: 30mg/kg (1-2gm) in 100ML of NS over 30min (at a rate
not exceeding 200mg/min), repeat in 1 hour if muscle weakness
persist, then at 8- 12 hours interval if cholinergic signs recur.
Maintenance dose :continuous infusion og 8-12mg/kg per hour.
• Severe case: IV infusion 500mg/hr (max 12gm in 24hours).
• Started after maximal atropinisation.
In severe poisoning requiring atropine, an oxime such as
pralidoxime chloride or obidoxime is generally recommended

30. BENZODIAZEPINES:
Agitation and seizure : Diazepam 10mg slow IV push ,repeated as
necessary .
Upto 30 to 40 mg diazepam per 24 hrs can be given.
Ventilator:
Ventilatory support should be started before the patients develops
resoiratory failure.

31. Other therapies
Magnesium sulfate –blocks ligand-gated calciumchannels ,resulting
in reduced acetylcholine release from presynaptic terminals, thus
improving function at neuromuscular junction, and reduced CNS over
stimulation mediated via NMDA receptors activation.
Sodium bicarbonate in place of oximes.
Alpha2- adrenergic receptors agonist clonidine also reduces
acetylcholine synthesis and release from presynaptic terminal.
Hemodialysis and Hemofiltration.

32. Treatment of IMS
• • Mainly supportive treatment.
• • Complete recovery in 4-18 days if adequate Ventilator support is
Provided.
• • Oximes – Preventive.

34. • Exam Important
• Muscarinic signs of OPC poisoning can be remembered as SLUDGE-
DUMBEELLS: Salivation, Lacrimation, Urination, Defecation, Gastric upset,
Emesis, etc..
• Delayed onset polyneuropathy after organophosphorous poisoning is seen
after 2-4 weeks.
• Fatality rate of organophosphorous poisoning in India is 15-30%.
• In organophosphorous compound poisoning, organophosphorous
compound is a Phosphorylated enzyme irreversibly inhibit cholinesterase.
• Most specific test for organophosphorous poisoning is Plasma
cholinestrase level.
• Organophosphate inhibits Esteratic site of AchEs.
• Antidote for organophosphorous poisoning is Atropine

36. CHRONIC POISONING:
• It usually occurs as an occupational hazard in agriculturists, especially
those who are engaged in pesticide spraying of crops.
• Route of exposure is usually inhalation or contamination of skin.

37. CHRONIC POISONING…
• The following features—
Polyneuropathy: paraesthesias, muscle cramps, weakness, gait
disorders.
CNS Effects : drowsiness, confusion, irritability, anxiety.
Sheep Farmer’s Disease : psychiatric manifestations encountered in
sheep farmers involved in long-term sheep-dip operations.
Organophosphate poisoning has been associated with a variety of
subacute or delayed onset chronic neurological, neurobehavioural, or
psychiatric syndromes.

39. CARBAMATE POISONING
Medicinal forms include Physostigmine , Pyridostigmine and
Neostigmine .
Cholinesterase inhibitors that are STRUCTURALLY RELATED TO
ORGANOPHOSPHATES.
 Transiently and reversibly inhibit cholinesterase (<6hrs).
Regeneration of enzyme occurs within minutes to hours, therefore
aging dose not occur.

40. CARBAMATE POISONING…
Symptoms of intoxication are similar to organophosphates , but are
of shorter duration.
Carbamates do not effectively penetrate into CNS , so LESS CENTRAL
TOXICITY and no seizures.
Atropine therapy usually not needed for longer than 6-12 hours.
Avoid PRALIDOXIME (2-PAM): Since irreversible binding dose not
occur, it is not occur, it is not needed, and potentially can worsen
some carbamate poisonings.

43. ORGANOCHLORINE:
Acute organochlorine poisoning
Prodromal symptoms: tremor, ataxia , myoclonus , dizziness,
confusion, paresthesia of mouth , nausea, vomiting.
Typical presentation : STATUS EPILEPTICUS , followed by respiratory
failure ,cardiac arrhythmias , rhabdomyolysis and acute renal failure.
Treatment :-
Control seizure- the same ways as status epilepticus. -
Benzodiazepines, Phenobarbital, Phenytoin.
Prevent complications

44. Sub acute organochlorine poisoning
Hyperexcitability stage : Tachycardia , Tremor, Hyper reflexia.
Treatment: Symptomatic treatment - Anxiolytic.
Enhance elimination – cholestyramine.

45. Chronic organochlorine poisoning:
Organochlorine insecticides interfere with endocrine and
reproductive systems.
Individuals who work with the insecticides show low sperm count
and motility , infertility and abortion.
The insecticides can be carcinogenic to animals.

47. • Signs of organophosphorous poisoning are all EXCEPT:
A Bradycardia
B Salivation
C Miosis
D Bronchodilatation

48. • Delayed onset polyneuropathy after organophosphorous poisoning
is seen after a period of
A 1-2 weeks
B 2-4 weeks
C 4-6 weeks
D 6-8 weeks

49. Most specific test for organophosphorous poisoning is:
A RBC cholinesterase level
B Plasma cholinestrase level
C RBC uroporphyrin level
D Measurment of serum level of organophosphorous

50. • Asthma like symptoms is seen in … poisoning?
• What is the case fatality rate of organophosphorous poisoning in
India?
• A 20 yrs aged patient, presents in coma with pin point pupils and
fasciculations but no fever. Most probable diagnosis ?
• Antidote for organophosphorous poisoning is?

51. • Best indicator for beneficial effect of atropine in a patient with
organophosphorous poisoning ?