Organophosphorus compounds

1. ORGANOPHOSPHORUS
COMPOUNDS
DR.VIVEK PAUL BENJAMIN,M.D (GEN.MEDICINE)

2. ORGANOPHOSPHATES (ORGANOPHOSPHORUS
COMPOUNDS)
• Calling these compounds “organophosphates” is not correct, and they
should be referred to as “organophosphorus compounds”.

3. HISTORY
• Organophosphorus (OP) compounds are organic
derivatives of phosphorus that have largely been used as
pesticides and nerve agents.
• Early pioneers in the field include Jean Louis
Lassaigne (early 19th century)
and Philippe de Clermont
• Tetraethylpyrophosphate was synthesized in 1854 as the
first OP cholinesterase inhibitor.
Philippe de Clermont

4. • In 1932, German chemist Willy Lange and his
graduate student, Gerde von Krueger, first
described the cholinergic nervous system
effects of organophosphates, noting a choking
sensation and a dimming of vision after
exposure on themselves, which they
attributed to the esters themselves

5. This discovery later inspired German
chemist Gerhard Schrader at company IG
Farben in the 1930s to experiment with these
compounds as insecticides. Their potential use
as chemical warfare agents soon became
apparent, and the Nazi government put
Schrader in charge of developing
organophosphate (in the broader sense of the
word) nerve gases

6. • Schrader's laboratory discovered the G series of
weapons, which included Sarin, Tabun, and Soman.
The Nazis produced large quantities of these
compounds, though did not use them during
World War II
• Sarin is a colorless, odorless, tasteless, human-
made chemical warfare agent. It was originally
developed in Germany in the 1930's as a pesticide.
Sarin is a nerve agent-it disrupts the functioning of
the nervous system. Nerve agents are the most
toxic and rapidly acting of all known chemical
warfare agents. Sarin is highly toxic in both its
liquid and vapor states.

7. Historic Use
• Iraq used sarin in the 1980-1988 war with Iran. The Japanese religious sect,
Aum Shinriko, released sarin in Matsumoto in 1994 and the Tokyo subway in
1995. In May 2004, the presence of sarin was detected in the debris of a
bomb that exploded in Iraq.

8. • Organophosphorus (OP) compounds are widely used as pesticides, especially in developing
countries.
• Case fatality following deliberate ingestion is high (5–20%).
• Nerve agents, developed for chemical warfare, are derived from OP insecticides and are much
more toxic.
• They are commonly classified as G (originally synthesised in Germany) or V (‘venomous’)
agents.
• The ‘G’ agents, such as tabun, sarin and soman, are volatile, absorbed by inhalation or via the
skin, and dissipate rapidly after use.
• ‘V’ agents, such as VX, are contact poisons unless aerosolised, and contaminate ground for
weeks or months.

9. VARIETY

14. Organophosphates MOA:
1.Organophosphates are powerful inhibitors of
acetylcholinesterase.{acetylycholine = acetic acid
and choline}.
2.Although organophosphates differ structurally
from acetylcholine, they can bind to the
acetylcholinesterase molecule at the active site a
nd phosphorylate.
3.Once the acetylcholinesterase is
phosphorylated, over the next 24 to 48 hours an
alkyl group is eventually lost from the conjugate,
further exacerbating the situation. As this
occurs, the enzyme can no longer spontaneously
hydrolyse and becomes permanently
inactivated.

15. 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).

16. TOXIDROME
From time of ingestion, when would you expect clinical features of OP
poisoning to manifest?
•Great variability in toxicity and treatment response depending on OP agent
•Generally, oral/respiratory exposures result in clinical manifestations within
3 hours
•Dermal routes can take up to 12 hours

17. CLINICAL FEATURES
What are the types of paralysis that OPpoisoning cancause?
 Type I – acute cholinergic crisis
 Type II – intermediate syndrome
 Type III – organophosphate induced delayed
polyneuropathy (OPIDP)

18. TYPE 1 (ACUTE CHOLINERGIC CRISIS)
Defecation, diaphoresis
Gastric Emesis
/
B
B
ronchorrhea
ronchospasm
Bradycardia*
• Seen in initial stages and due to persistent depolarisation
SLUDGE/BBB DUMBELS
Salivation Defecation, diaphoresis
Lacrimation Urination
Urination Miosis*
Bronchorrhea/Bronchospasm/Bradycardia*
Emesis
Lacrimation
Salivation
* Sometimes mydriasis and tachycardia observed as sympathetic
ganglia also contain nicotinic receptors
CNS
Nicotinic effects – fasciculations, muscle weakness, paralysis
effects – central respiratory depression, lethargy, seizures, coma

19. CNS Effects—Restlessness, headache, tremor, drowsiness, delirium, slurred speech, ataxia, and
convulsions. Coma supervenes in the later stages.

21. TYPE 1 (ACUTE CHOLINERGIC CRISIS)
• Cardiac
• Cardiac arrhythmias – heart block, QTc prolongation
• Myocardial ischemia – elevated troponin and changes on ECG
• Respiratory
• Respiratory failure – combination of CNSresp. centre depression,
neuromuscular weakness, excessive respiratory secretions and
bronchoconstriction

22. TYPE 2 (INTERMEDIATE SYNDROME)
• 24-48 hours after poisoning, often when
acute cholinergic syndrome signs
decreased/gone
(take care!)
• 10-40% of patients
• Exact pathology not clear
• No clear association between particular
OPpesticide and development of
syndrome
• Persists for 14-20 days
• Resolution within 2-3 weeks (with
adequate supportive care eg. ventilatory
support)
• Recovery usually without sequelae
• What are the characteristic
clinical findings in intermediate
syndrome?
• Weakness of muscles of
respiration (diaphragm,
intercostal muscles, accessory
muscles including neck muscles)
• Weakness of proximal limb
muscles
• Others – cranial nerve
abnormalities, decreased deep
tendon reflexes

23. TYPE 3 (ORGANOPHOSPHATE
INDUCED DELAYED
POLYNEUROPATHY–OPIDP)• 2-3 weeks after poisoning
• Distal degeneration of axons of both peripheral andCNS (The mechanism appears to involve
phosphorylation of esterases in peripheral nervous tissue and results in a “dying back” pattern of axonal degeneration)
• Clinical features
• Transient painful ‘stock & glove’ paraesthesias followed by a symmetrical motor polyneuropathy
characterised by flaccid weakness of lower extremities which ascends to involve upper extremities
• High-stepping gait associated with bilateral foot drop
• Predominantly distal but can involve proximal in severe neurotoxicity
• Risk of development independent of severity of acute cholinergic toxicity
• Recovery 6-12 months – spastic ataxia may be permanent outcome of OPIDP

24. DELAYED
ORGANOPHOSPHATE
ENCEPHALOPATHY (DOPE)• “CNS intermediate”
• New syndrome recognised and described in 2008
• Clinical features
• Normal sensorium then progression to coma days after poisoning (delayed coma)
• Miosed non-reacting pupils
• Extra-pyramidal signs – dystonia, resting tremor, cog-wheel rigidity, choreo-athetosis
• Investigations
• EEG– bi hemispheric slow waves (features consistent with encephalopathy)
• CTbrain and CSFanalysisnormal
• Persistently low pseudo-cholinesterase levels and increasing atropine requirements during
coma
• Prognosis excellent with adequate supportive care

25. 2. Chronic Poisoning:
a. Polyneuropathy: paraesthesias, muscle cramps,
weakness, gait disorders.
b. CNS Effects : drowsiness, confusion, irritability,
anxiety.
c. Sheep Farmer’s Disease : psychiatric
manifestations encountered in sheep farmers
involved in long-term sheep-dip operations.
d. “chronic organophosphate-
induced neuropsychiatric disorder; (COPND)

27. 1. Depression of cholinesterase activity: Serum cholinesterase level (reference range- 5000 –
9000 units).
2. P-Nitrophenol Test: P-nitrophenol is a metabolite of some organophosphates
(e.g. parathion, ethion), and is excreted in the urine. Steam distill 10 ml of urine
and collect the distillate. Add sodium hydroxide (2 pellets) and heat on a water
bath for 10 minutes. Production of yellow colour indicates the presence of p-
nitrophenol. The test can also be done on vomitus or stomach contents.

28. RESUSCITATION
• Airway – Early Intubation to secure
airway and prevent aspiration
• Breathing – Ensure adequate
ventilation
• Circulation – Obtain large bore IV
access. Start IV fluids if victim is in
hypotension
• Decontamination – Remove any
remnants of the toxin in contact with
the patient.

29. GOALS OF TREATMENT
Reduce absorption of toxin
Enhance elimination
Neutralize toxin

30. REDUCE ABSORPTION
• Removal from skin, eyes and hair
• Emesis induction
• Gastric Lavage
• Activated charcoal and cathartics
• Whole bowel irrigation
• Endoscopic or surgical removal of ingested chemical

31. ATROPINIZATION
Adequacy of atropinization
Mandatory targets:
• SBP > 90 mmHg
• Hr > 110/min
• Clear lung fields
Other targets:
• Pupils mid position
• Bowel sounds just present

32. TARGETS ON SUBSEQUENT DAYS
• Day 2: HR> 100/min
• Day 3: HR> 90/min
• Subsequent days:At least 80/min

33. ATROPINIZATION DOSE
• Blocks the muscarinic manifestations of organophosphates. However, since atropine affects only the
postsynaptic muscarinic receptors, it has no effect on muscle weakness or paralysis
Two approaches:
1.Bolus Dose Adminstration: 2-5 mg Atropine every 10-15 min
• followed by maintainance using reduced doses
2.Incremental dose administration with rapid
escalation:
• 1.8–3 mg Atropine by iv infusion repeat every 5 min interval doubling the dose each
• time 10 - 20%of atropine required for atropininzation every hour by ivinfusion

34. ATROPINE 2 – 3 MG BY IV
BOLUS
Double the dose every 5 min
until atropinization occurs
10-20% of atropine required for atropinisation ashourly
infusion

35. BOLUS DOSE VS INCREMENTAL DOSE
• Incremental dose clearly better in relation to the outcomesof
death and intermediate syndrome.
• Superior to Bolus Dose Regime
• Recommended as standard of care
Studies by Abedin and Blain PG

36. ROLE OF PRALIDOXIME
• Mode of action: It is usually given along with atropine.
Pralidoxime competes for the phosphate moiety of the
organophosphorus compound and releases it from the
acetylcholinesterase enzyme, thereby liberating the latter
and reactivating it.
• Pralidoxime, Obidoxime, Trimedoxime
• WHO recommendation - (30 mg/kg pralidoxime chloride
bolus followed by 8 mg/kg/hour infusion)

37. ACTIVATED CHARCOAL
• No high quality RCTs to support the benefit of
activated charcoal use in acute organophosphate
poisoning.
• Also there is no evidence of harm.

38. GASTRIC LAVAGE
 Decreases absorption by 42% at 20 min
16% at 60 min
 Preferably in awake patients
 Choice of fluid is tap water: 5-10ml/kg
 No evidence that a larger tube is better
 No human studies showing benefit in OPP

39. ALKALINIZATION IN OPP
Using Sodium Bicarbonate
5 mEq/kg in 60 minutes followed by 5–6 mEq/kg/day was
shown to be useful.
Alkalinization products are shown to be less toxic.

40. MAGNESIUM SULPHATE
• Intravenous MgSO4 (4 g) given in the first day after admission have
been shown to decrease hospitalization period and improve outcomes
in patients with OPpoisoning.
• Magnesium sulfate blocks calcium channels and thus reduces
acetylcholine release.
• Also reduces CNSoverstimulation resulting from N-methyl D-aspartate
receptor (NMDAR) activation.

41. • A male student, aged 20 years, was admitted in neuro ICU with an episode of seizure and altered sensorium. He had no
premorbid illness. He had travelled to Mumbai four days before admission. Relatives denied consumption of any poison and
medications. At the time of hospitalization, he was restless and was in postictal state. Vital signs revealed pulse rate of
62/minute, blood pressure of 120/80 mmHg, respiratory rate of 14 per minute, afebrile, and had plenty of oral secretions.
Neurological examination revealed GCS of 6/15 with reduced movements of all four limbs. Pupils were pin point bilaterally
with absent Doll’s eye movement. Plantar reflex was extensor bilaterally. Deep tendon reflexes were sluggish. There were no
fasciculation and no smell of OP compound. He had cellulitis of left arm.

42. • Examination of chest showed bilateral crepitations. Examination of other systems was normal.
Investigations at admission showed normal renal functions, liver functions, and normal serum levels of
sodium, potassium, calcium, and magnesium. Blood picture showed leukocytosis. Chest X-ray showed
bilateral haziness suggesting acute respiratory distress syndrome. Ultrasonography of left arm showed
pus collection in the intramuscular plane. Debridement was done and 250 ml of pus was drained. At this
point of time, differential diagnosis of metabolic encephalopathy, toxic encephalopathy due to sepsis,
possible brain stem diseases, and OP poisoning/drug over dosage were considered. Computed
tomography and magnetic resonance imaging scan of the brain, lumbar puncture and CSF analysis were
done and they were normal. His EKG, cardiac enzymes, and echocardiography were normal and blood,
urine, and pus cultures were sterile. Screening for benzodiazepine, antiepileptic drugs were negative.
Serum cholinesterase level was 1234 units (reference range- 5000 – 9000 units).

43. • On day 2, he developed respiratory distress with carbon dioxide retention, ABG revealed PaCO2 of 54
mmHg, and he required ventilator support. At this point of time, we had reasonably excluded metabolic
and structural causes for his problem; hence, possibility of OP poisoning was considered on the basis of
respiratory failure, pulmonary secretions, supported by low plasma cholinesterase level. Ryle’s tube
aspiration was done at the time of hospitalization and gastric aspirate was minimal. Empirically, he was
treated with atropine and pralidoxime along with broad spectrum antibiotics. Atropine was given 5 mg
bolus, followed by infusion at the rate of 2 mg/h, and the dose was titrated as per his clinical response
and signs of atropinisation. Response to atropine treatment was good and over five days gradual
improvement in sensorium was noticed. Pralidoxime was given at a dose of 1 gm infusion, three times
per day for initial two days.

44. • He was treated with phenytoin sodium for seizures. Initial antibiotics were piperacillin-tazobactam and
metronidazole but during the course of illness, there were worsening of chest shadows and antibiotics
were changed to meropenem and linezolid. Cultures of endotracheal tube secretions were sterile. His
chest X-ray and oxygenation improved. In the initial three to four days, fluctuation in the sensorium was
noticed but continued to have neuroparalysis, neck muscle weakness, and his respiratory efforts were
poor. His restlessness was controlled with diazepam. He continued to require ventilator support for
breathing.

45. • We kept talking to relatives regarding possible consumption of OP poison, but they had no clue about
any such event. Plasma cholinesterase level was repeated and value had gone down to 934 units. His
restlessness was better, became more alert and neuroparalysis started recovering slowly. The entire
problem got sorted out on sixth day, when he communicated to us in writing that he had injected
metacid (methyl parathion) to his left arm while travelling in train. He required ventilator support for 12
days and recovered completely. He revealed that he had injected poison with suicidal intention and all
the legal protocols were done as per the hospital rules. Following recovery, he was evaluated by
psychiatrists and revealed that injection of poison was an impulsive act due to poor social and financial
support from family.