2/22/2011

Topic

Drug intoxication
..
E-mail: sudvan@kku.ac.th

Briefly reviewed of new indication in GI decontamination Common drugs intoxication - Diagnosis - Early management absorption elimination - Specific treatment : antidotes

www.ra.mahidol.ac.th

1367

(insecticides) (herbicides)

(Pesticide)

(Organophosphate)

(rodenticide) (Fungicide)

(insecticides)

(Carbamate) (Organochlorine) (Pyrethoid)

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51 . . CC: PI: PE: An elderly man with coma BP 210/120 mmHg PR 160/min RR 24/min Not pale, no jaundice Pinpoint pupil both sides, salivation & sweating Heart: techycardia, no murmur Lung: secretion sound both lungs Abdomen: active bowel sound Ext: fasciculation at upper extremities and anterior chest wall

Decontamination

Gastric lavage Single dose activated charcoal

Increase elimination

- (Acetylcholinesterase enzyme, AchE) - (actylcholine, Ach) -

Multiple dose activated charcoal Hemodialysis

Ach

Ach

AchE

AchE

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Cholinergic Postganglionic fiber parasympathetic

Preganglionic sympathetic

Somatic motor

Central nervous system

Receptor

Effector cell (muscarinic)

Ganglion (nicotinic)

Striated muscle (nicotinic)

CNS neurons (muscarinic & nicotinic)

Diarrhea Urination Miosis Bradycardia Bronchrorrhea Emesis Lacrimation Salivation

Tachycardia Hypertension Mydriasis Diaphoresis

Fasciculations Weakness Paralysis Muscle cramps

Anxiety Ataxia Dysarthria Confusion Coma Seizures Respiratory Depression Tremors

Investigation

True Cholinesterase (RBC)

Cholinesterase level
Plasma Cholinesterase

1. - (airway) - (breathing) - (circulation) 2. (decontamination) - (gastric decontamination) 1. 3.

2. (decontamination)( ) - (skin decontamination) - (eye decontamination) 3. - atropine - Pralidoxime (2-PAM) 4.

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Atropine
Inhibit muscarinic receptor
Dose 0.5-2.0 mg then double dose q 5 min until atropinization is achieved Monitor - HR >60/min, <150/min

Pralidoxime (2-PAM)

- Pupil > 3 mm - Decrease secretion

Pralidoxime (2-PAM)
Initial dose: 1-2 gm IV drip in NSS 100 ml > 15-30 min then repeat the initial dose in 1 hr Maintenance dose: 1% solution (1 g in 100 ml NSS) IV drip 200-500 mg/hr (titrate to the desired clinical response)

Monitor: Nicotinic receptor sign - Muscle power : extremities, tidal volume Side effect - nausea, vomiting, dizziness, hyperventilation - rapid IV administration HR, laryngospasm, muscle rigidity and neuromuscular blockade

52 . . CC: 1/2 PI :

PE : An elderly man with coma BP 210/120 mmHg PR 160/min RR 24/min - not pale, no jaundice - pin point pupil both sides - salivation - Heart : tachycardia, no murmur - Lung : secretion sound both lungs - Abdomen : soft, not tender liver and spleen impalpable active bowel sound - Ext : fasciculation at upper extremities and anterior chest wall, sweating

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Clinical course
Day 1 - vital sign stable pupil size 3-4 min fasciculation Treatment On: Respirator

Intermediate Syndrome 1- 4 days after acute poisoning Sign: cranial nerve palsy paralysis of proximal limb muscle, neck muscle & respiratory 5- 65% in pt with OP poisoning

Atropine, 2-PAM Day 2 E4VTM6, Motor power gr III-IV, tidal vol 300-350 On respirator, Atropine Day 3 Wean of respirator Day 5 D/C Plasma cholinesterase level = 109.2 mu/ml (<1600)

Fenthion, monocrotophos, dimethoate, methamidophos etc.

DDx: redistribution of organophosphate

Recovery occurs 5- 18 days after symptom onset Cranial nerves, respiratory muscle, proximal limb strength, ability to flex neck EEG: postsynaptic neuromuscular junction dysfunction Treatment: supportive treatment

Organophosphate Induce Delayed Polyneuropathy (OPIDP)

After 2- 4 wks after acute poisoning Not all OP causing acute choliner crisis cause OPIDP Not all cases of OPIDP preceded by acute cholinergic crisis Associated with phosphorylation and aging of neuropathy target esterase (NTE)

Symptoms: - cramping muscle pains in legs - rapidly progressive weakness: lower then upper ext - Minor sensory symptoms Physical examination: - Predominantly motor neuropathy - Weakness of distal limb muscles (leg> arm) - Muscle atrophy - depressed deep tendon reflexes - Occasionally loss of bowel or bladder control

EEG: axonal degeneration and secondary demyelination

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Case 2

45 1
PI: 1 .

Benzodiazepine overdose
Hypnotic drugs Anxiolytic drugs Anticonvulsants Muscle relaxant

PH:

PE: BP 120/80 mmHg, PR 70/min RR 16/min Drowsiness, pupil 3 mm RTL not pale conjunctiva, no icteric sclera lung: equal breath sound, no adventitious sound heart: no murmur

Clinical Presentation Mechanism of action -Potentiate activity of GABA - GABA is major inhibitory neuron in CNS -Depend on dose amount of ingestion, tolerance - Symptoms & signs - CNS depression: drowsy, stuporous, ataxia without focal neurologic abnormality - aroused by painful or verbal stimulation

- Coma, hypotension, respiratory depression uncommon, other drug ingested

Treatment 1. Basic life support 2. Early management 1. Prevent absorption- gastric lavage, activated charcoal 2. Enhance elimination 3. Antidote: flumazenil

Flumazenil
-Competitive antagonist of benzodiazepines receptor - Displace benzodiazepines from binding site - Reverse sedative, anxiolytic, anticonvultant, ataxic, anesthetic and muscle relaxant effect. Not become a routine antidote

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Contraindication to the use of flumazenil -Prior seizure history or current treatment of seizure - History of ingestion of substance capable of provoking seizure or cardiac dysrhythmia - Long-term use of benzodiazepine - EKG evidence of TCA overdose - Abnormal vital sign

-First pass metabolism - Intravenous form - Dose 0.6-1 mg IV slowly at rate of 0.1mg/min - Resedation: 0.25-1 mg/h IV drip

Case 3 CC. 2 amitriptyline 1 10 3-5

PH. 4 amitriptyline 50 mg

EKG on administration Vital sign: BP 100/60 mmHg, PR 120 /min, RR 20/min, BT 36 oC PE : Stupor, Pupils 3 mm SRTL BE, not pale, no jaundice Heart : Peripheral pulse are equal in all ext. tachycardia, no murmur Lung : normal BS, no adventitious sound Abdomen : soft, no guarding, no hepatosplenomegaly Ext : no cyanosis, no edema

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Cyclic Antidepressants Toxicity

Toxicologic Properties Myocardium Inh voltage-gated sodium channels ( quinidine like effect) conduction velocity threshold for excitability Potassium channel blocking action potential duration

EKG on administration

Cyclic Antidepressants
Inh Na+ channel Wide QRS
Drug 1st generation Amitriptyline anticholinergic Prolong QRS cpx hypotension seizure

Inh Cl + channel

Seizure
Clomipramine Desipramine Nortriptyline

++++ ++++ ++ +++ +++

++++ ++++ ++++ ++++ ++++

++++ ++++ +++ +++ ++++

++++ ++++ ++++ ++++ ++++

Anticholinergic Alpha blocked BP drop

Imipramine

Drug 2nd generation fluoxetine Sertraline Fluvoxamine Paroxetine

anticholinergic

Prolong QRS cpx

hypotension

seizure

Diagnosis

0 0 0 0

0 + 0 0

0 0 0 0

0 0 0 0

1. History and Physical examination 2. Lab: EKG, electrolyte, glucose Blood level : > 1000 ng/ml cardiac dysrhythmias, seizure,coma

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When will admimistrate TCA overdose patients? Admit any patient with a QRS > 100msec. Admit any patient with a seizure. Patients who have been decontaminated, who never seize or develop abnormal EKG's (other than sinus tachycardia) can be safely discharged after 6 hours of observation if otherwise stable. Patients with significant symptoms or any EKG changes, or persistent mild symptoms should be admitted and monitored until CNS returns to baseline and normal EKG for 24 hours.

Management 1. Basic life support 2. GI decontamination Gastric lavage Single dose activated charcoal 3. Enhance Elimination multiple dose activated Charcoal Acidified urine: not recommend Hemodialysis: not be useful because of high Vd and protein binding

4. Specific treatment Wide complex dysrhythmias -TCA effect on voltage gate sodium channels - Sodium bicarbonate : increase conc. of extracellular sodium and improving gradient across the sodium channel. - Reduce the binding of TCA to sodium channel NaHCO3: bolus 1-2 mEq/kg then 100-150 mEq in 5% D/W 1000 ml IV drip titate over 4-6 hr to keep blood pH 7.5-7.55

EKG on administration

After NaHCO3 & Xylocard

Before Discharge

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Hypotension - adrenergic blocking NSS or Ringer late solution 10-30 ml/kg Loss of vascular tone: direct-acting adrenergic agonist such as norepinephrine Loss of inotropy : direct acting 1- adrenergic agonist such as dobutamine Awareness in using dopamine : stimulate 2 adrenergic receptor : indirect stimulation of dopamine release of norepinephrine

Seizure Benzodiazepines: diazepam, lorazepam, midazolam Neuromuscular blockade, general anesthesia Phenytoin is not recommend : prodysrhythmic effect

Symptomatic and supportive treatments

THANK YOU

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Case 1
15 . . CC : 12 . PTA PI : 12 hr PTA 1 2 -1 PH : - & -

PE : A Thai woman, good consciousness V/S BT 37.5oC, RR 20 /min, BP 111/66 mmHg, PR 109/min HEENT: Pupil 3 mm RTL, BE not pale, no jaundice, pharynx & tonsil erythema Heart : normal S1S2, no murmur Lung : clear Abdomen : Soft, not tender active bowel sound Ext : no edema, no petechiae

Toxicodynamic Mechanism
01/11 BUN Cr Cholesterol Total protein Alb Glob TB DB ALT AST Alk phos 20.7 1.4 139 8.8 5.3 3.5 0.6 0.1 25 31 86 3/11 64.6 8.2 115 7.0 3.6 3.4 1.0 0.2 17 33 61

Pentose phosphate pathway

NADPH

NADP+

PQ2+
PQ reductase

PQ+ .

O2 .

O2

. 2O2 + 2H O2 + Fe3+ . O2 + H2O2 + Fe2+ H2O2 + Fe2+ .

H2O2 O2 + Fe2+

Route of Absorption
Skin Eyes Upper airway

. OH + OH + Fe3+ . OH + OH + Fe3+

Lipid peroxidation , protein and DNA degradation

Ingestion
Cell death

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Clinical Presentation (Ingestion) 1. Initial phase

- Herbicides causticity Buccopharyngeal, esophageal, epigastric and gastric pain Vomiting (emetic additives in commercial preparation) Abdominal colic and diarrhea

2. Second phase (2- 4 days)

Renal failure: pure tubulopathy with proximal predominance tubular necrosis fully recovery without sequelae Liver failure: centrilobular hepatocellular necrosis

3. Third phase (5 days to several weeks)

- Type I and II alveolar epithelium - Proliferation and extensive fibrosis - Clinical presentation and radiographic change appear several days after ingestion - Pulmonary change depends on amount of paraquat ingested
Oropharyngeal ulceration and corrosion

Paraquat Lung

Ocular injury
Br J Ophthalmol 2002;86:350

Day 1
Crit Care Med 2002;30:2584

Day 28

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alkaline sodium dithionate 2 Paraquat

O2

3
GSH GSSH

O2

OH Lipid peroxidation

Lung cumulation

Type I and II pneumocyte cell death

Paraquat

Alveolitis

Fibrosis

paraquat
1. Basic life support
( O2 Supplement until PaO2< 50 mmHg or respiratory distress)

paraquat
3. Increase elimination 3.1 Hemodialysis/ Hemoperfusion - HD renal CL (not reduce mortality) - HPF not available or ARF - HPF within 4 hrs after ingestion and continued for 6- 8 hrs - No indication of repeated HPF

2. Prevent absorption
2.1 Gastric lavage 2.2 Fullers earth/ activated charcoal/ bentonite 2.3 MOM 30 ml

paraquat
4. Modification of tissue toxicities 4.1 Modulate inflammatory responses - Cyclophosphamide 5mg/kg/day IV divided to every 8 hr - Dexamethazone 10 mg IV q 8 hr

4.2 Prevent oxidation - Vit C (500mg/amp) 6 g/day IV - Vit E (400 i.u./ tab) 2 tabs qid - N-acetylcysteine (300mg/amp) 50mg/kg every 8 hr

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