Management of specific poisons: Organophosphates and carbamate Alcohol

1. Management of specific poisons:Organophosphates and carbamateAlcohol Dr. Manisha Desai University College of Medical Sciences & GTB Hospital, Delhi

2. History • 1854 -Synthesis of OP compound (TEPP)- by Phillipe de Clermont. Not used actively then. • 1930- Gerhard Schrader,German synthesised parathion.His priority shifted to nerve gas agents; used during World War 2 • Early 1900 Carbamates were developed in Africa from calabar bean. Physostigmine, used to treat glaucoma • 50 years later, neostigmine, was synthesized and used for the treatment of myasthenia gravis • In 1960s and 1970s, carbamates were synthesized for pesticidal use.

3. CMs are preferred for pesticide use over OPs because the former are safer reversible inhibitors of AChE unlike OP. • In 1984, an estimated 4 lakhpeople were exposed to a toxic methyl isocyanate gas (used in the production of CM pesticides) that leaked from the Union Carbide plant in Bhopal, India. • Annual incidence of acute insecticide poisoning - 3 million (approx.) worldwide.

4. CHOLINERGIC POISONING Cholinergic (anticholinesterase) agents are used in • clinical medicine (neostigmine, physostigmine) • as insecticide • as weapon of mass destruction(tabun,sarin,soman) Most anticholinersterase poisoning occurs during the • agricultural use (accidental dermal contamination) • home use of aerosol insecticide • accidental and suicidal ingestion

5. ORGANOPHOSPHORUS POISONING

6. STRUCTURE • OP insecticides are anticholinesterase agents; esters, amides or thiol derivatives of phosphoric acid. • The R1 and R2 moieties are alkyl or aryl group and linked by oxygen and sulphur atom to phosphorus R1 O or S P R2 RL P=O - phosphate, oxon P=S - Phosphorothioate R1, R2 – alkyl or aryl grp ( two methyl or two ethyl grp) RL – leaving group; least stable, displaced on phosphorylation of AChE. Specific to individual OP

7. Phosphorothioates,P=S Phosphates,P=O (Diazinon, Parathion) (Dichlorvos) -Require biological activation; - Biologically active; early delayed symptom onset symptom onset -Stored extensively in fat, prolonged intoxication, clinical relapse after apparent recovery.

8. Dimethyl OP (dichlorvas, malathion, dimethoate) Diethyl OP (chlorpyrifos,diazinon,parathion) Dimethyl phosphorylated AChE – - faster rate of spontaneous re activation - may recover without oxime therapy

9. How does AChE act? • The entire process takes about 150 microseconds • True AChE – nervous tissue, surface of RBCs. • ButyrylChE/PseudoChE- serum, liver.

10. What do OP do? Alkyl phosphorylation of Serine-OH group at the esteric site of enzyme.

12. Forms an irreversible covalent phosphate linkage • Extent of inhibition of AChE depends on the rate constant for the • reaction and the time that the enzyme is exposed to the drug

13. Further fate of the enzyme • REACTIVATION – spontaneous hydrolysis of the enzyme- OP complex may take many hrs. -accelerated by oximes. -with Carbamate poisoning, enzyme activity resumes in 24hrs • AGEING - strengthening the phosphorus-enzyme bond by breakage of one of the oxygen –phosphorus bond of the inhibitor - Once ageing has occurred ,the complex is difficult to split even with oximes - Enzyme resynthesis is the only mean to restore function

14. Pharmacokinetics Effectively absorbed by all routes • Dermal / conjunctival • Inhalational – during spraying • Gastrointestinal Ingestion

15. …..Pharmacokinetics (contd.) • Phase 1 reactions : ↓ - Oxidativedesulfuration, dearylation ↓ Reactive oxon metabolite (P=S → P=O (oxons)) Ex: Parathion → Paraoxon (1000 fold increase in potency) All Ops must be in oxon formation (P=O) to inhibit AChE - Hydrolysis by paraoxanases, esterases • Phase 2 reactions: Conjugation – metabolites are water soluble and readily excreted

16. …..Pharmacokinetics (contd.) Toxicity depends upon • Activation step requirement (P=S or P=O) • Fat solubility • Magnitude of exposure(dose) • Route (onset inhalation > ingestion > dermal) • Suicidal attempt (large amount ingestion likely) • Presence of solvent like xylene/emulsifier (enhances absorption)

17. Exposure

18. CASE REPORT • A 28yr old female presented to ER in an unconscious state with frothing around mouth, and involuntary limb movements.Her clothes had particles of vomitus. A quick history from relatives revealed that patient was found unconscious and unresponsive at home with a half emptybottle beside

20. Examination : vitals – PR-66/min, regular BP-104/60 mm Hg RR- 20/min SpO2 – 94% room air CVS- S1, S2 normal RS – B/L crepitations + CNS – GCS E1V1M5 Pupils bilaterally constricted Fasciculations in limbs B/L plantars - mute

21. PATHOPHYSIOLOGY The acute toxicity of anticholinesterase agents ↓ Irreversible inhibition of enzyme acetylcholinesterase ↓ Accumulation of acetylcholine at • CNS and • PNS - muscarinic sites in PNS, - nicotinic sites at sympathetic, parasympathetic ganglia and - nicotinic sites at NMJ

22. INITIAL CHOLINERGIC PHASE - SIGNS & SYMPTOMS DUMBELS Diarrhea, Diaphoresis Urination Miosis Bronchorrhea Bronchospasm Bradycardia Emesis Lacrimation Salivation

23. Miosis, a typical muscarinic sign is not always present as mydriasis may occur due to concomitant overriding nicotinic stimulation and use of atropine • Other findings- • Hyperamylasemia with or without clinical pancreatitis • ECG abnormalities- AV block, ST segment elevation and arrhythmias

24. DIAGNOSIS • History and high degree of suspicion (awareness of diversity of presentation is the first step) • Examination – typical clinical features • Lab investigations • Cholinesterase assays • Nonspecific test like - Leukocyte count -Blood sugar levels - urinary nitrophenols

25. RBC AChE • Present on surface of RBCs.

26. Butyryl/Pseudo choline esterase • Present in liver and serum

27. …..Cholinestersae assays (cont) • To summarize, as a marker erythrocyte cholinesterase is invariably more specific than plasma cholinesterase. However, some OP, depress plasma cholinesterase to greater extent. • Drawback of AChE assays: Interactions continue to occur between OP, AChE and oximes if the blood sample is left at room temp even for a few mins. Recommended- freshly drawn blood diluted with cold saline (at 4 deg C) and place in freezer at -20 deg C within 5 mins.

28. TREATMENT OF OP POISONING • First aid: -remove patient from the scene of exposure -remove contaminated clothing - skin, eyes washed thoroughly - assess breathing, circulation - place patient in left lateral position with head lower than feet to reduce risk of aspiration • Airway management – supplemental O2 to keep PaO2 > 75 mm Hg - Tracheal intubation and mechanical ventilation (suxamethonium is discourged - prolonged block) - Regular suctioning

29. -gastric decontamination - controversial, - these agents are emetogenic - OP are dissolved in hydrocarbon solvent that result in significant pneumonitis when aspirated - Nasogastric aspiration if patient presents within 1hr of ingestion. - Oral activated charcoal – usually recommended as some OP binds activated charcoal

30. 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.

31. TREATMENT OF OP POISONING • Atropine • Oximes ANTIDOTES • Diazepam

32. Atropine in OP poisoning • Atropine is competitive antagonist of Ach at muscarinic receptor • Has no effect on muscle weakness and paralysis • No effect on AChE reactivation ROLE • Control of pulmonary secretion and bronchorrhoea • Control seizures and CNS manifestation of poisoning

33. …..Atropine (cont) • DOSE – - Adult - 1-3mg iv (0.05mg/kg) bolus * 3 mins. – -Children – 0.015-0.05mg/kg iv bolus ↓ repeated or doubled every 5-10 mins until HR>80 per min/clear chest/symptoms improve ↓ atropine infusion started (10-20% of total initial dose every hour )

34. Atropine nebulisation – in bronchorrhea. Dose - 1 amp diluted with 2 ml NS. 1% atropine nasal drops have recently been developed esp for war conditions (when nerve gases are used) because i.v. cannulation might be difficult in mass casualties and i.minj takes time to act Ref : Internet

35. - Inadequate atropine - cholinergic features will reappear. - Excess atropine- agitation, hyperthermia,ileus , urinary retention develops (Atropine toxicity) ↓ stop infusion ; restart infusion after 30-60 mins (70-80% initial rate) • Duration of maintenance atropine- usually 24-48 hrs (longer in severe cases), gradually withdrawn over 3-5 days

36. 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

37. Glycopyrrolate • Equally effective with fewer side effects • Does not cross CNS • ROLE Adjunct, when secretions are copious In atropine toxicity • Dose – 7.5 mg in 200 ml NS titrated infusion or 0.2 mg im stat repeated 6 hrly

38. Diazepam • ROLE : - Reduces anxiety and restlessness - Reduces muscle fasciculation - Arrests seizures - Reduces morbidity and mortality - Beneficial role even in absence of seizure • Dose- Adult- 5-10 mg iv * 3 mins, repeated every 10-15 mins (max 30mg in adults) Children - 0.2-0.3mg/kg iv * 3 mins

39. OXIMES IN OP POISONING

40. Mechanism of action

41. …..oximes (cont) • Monopyridinium oxime- pralidoxime Bispyridinium oxime- obidoxime, trimedoxime • Rote of administration- intravenous, oral and intramuscular • Appropriate plasma level of 20-40mg/L for pralidoxime; 4mg/L for obidoxime

42. …..oximes (cont) • DOSE WHO guideline recommends- Pralidoxime in 30mg/kg iv × 10-20 min → 8mg/kg/hr infusion Obidoxime – 250mg iv → 0.4mg/kg/hr infusion • Duration of Oxime infusion - continued till atropine is needed or until irreversible clinical improvement is achieved

43. …..oximes (cont) Possible explanation for the ineffectiveness of oximes are • Slow reactivation • Insufficient dose • Formation of phosphoryloxime during the reactivation process may paradoxically inhibit acetylcholinesterase

44. Adverse effects of oximes • Transient increase in neuromuscular block • Nausea, vomiting following the bolus dose • Pralidoxime - pressor response and ECG changes • Obidoxime – transient liver damage

45. Supportive Treatment • Vasopressor therapy • Diuretic – pulmonary edema • Antibiotics • Temperature regulation

46. Criteria for ICU discharge in OP poisoning • Normal RBC or plasma cholinesterase activity • No recurrence of symptoms or signs of cholinergic excess 24 hrs after discontinuation of oxime therapy

47. Medical management of OP poisoning demands close observation, timely institution of antidote in adequate doses and duration and good supportive care

48. INTERMEDIATE SYNDROME • Characterized by absent muscarinic symptoms with continued nicotinic symptoms and persistent AChE inhibition • C/f onset = 24 – 72 hrs after acute cholinergic crisis • Pathophysiology – inadequate oxime dosing -Most likely due to lesions in post synaptic striated muscle regions - Myonecrosis due to oxidative cellular damage Later studies – down regulation or desensitization of nicotinic ACh receptors at post junctional membrane

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

50. ……IMS (cont) Clinical features – NICOTINIC SYMPTOMS • Paralysis of proximal limb muscles, neck flexors, cranial nerves, respiratory muscles, decreased DTR • Rapid onset of difficulty in breathing • Sensory impairment is not a feature