PHARMACOLOGY Toxicology Dra Dando 12 February 2008 Joyce “,.

POISONING • • Overdose of drugs, medicaments, chemicals and biological substances “acute” poisoning versus “chronic’ poisoning  Acute: 24 -48 hrs of exposure  Chronic: weeks, months, years of exposure Father of toxicology: Paracelsus   Carbon monoxide Quinine o Anti-protozoal

 Opiates (Morphine, Novaine, Heroin, Codeine)

GENERAL PRINCIPLES  Emergency stabilization o First thing to do  Clinical evaluation o Include good Hx taking & thorough PE  Elimination of the poison  Excretion of the absorbed substance  Administration of antidotes o Important for certain specific poisons or drugs  Supportive therapy and observation  Disposition EMERGENCY STABILIZATION  Maintain adequate Airway o Remove obstructions o Conditions wherein suction cannot be done: caustic substances (causes ulceration of GI mucosa) hydrocarbons (causes aspiration)  Ensure adequate Breathing/Ventilation o Nasal cannula, intubation

RECOMMENDED IV FLUIDS  Hypotensive patients  NSS  Adult for maintenance  NSS  D5 Acetated Ringer’s solution  Pediatric for maintenance  D5 0.3% NaCl (hypo)

 Maintain adequate Circulation (put IV lines,

 Treat convulsions (e.g Diazepam) o Diazepam: 1st line of Tx for active
seizures and status epilepticus

 Correct metabolic abnormalities (Electrolytes,
glucose, acid-base) o Base: used for severe metabolic acidosis (Tx: Na, bicarbonate) o Glucose: for hypoglycemia (Dextrose 50-50 concentration) Treat coma (e.g Flumazenil) o Flumazenil: 1) Tx for BZD (diazepam) overdose 2) Tx for coma (but not as first line agent) - coma due to overdose of valium

POISON COMMONLY ASSOCIATED WITH CONVULSIONS  Aminophylline  Amphetamines  Carbon monoxide  Cocaine  Cyanide  Ethylene glycol  Hypoglycemic agents  Isoniazid – triad of coma, metabolic acidosis, intractable seizures  Lead  MAO inhibitors  Mefenamic Acid (usual side effect: GI irritation; overdose: seizures)  Opioids  Organophosphates  Phenothiazines  Salicylates (Aspirin)  Strychnine  Theophylline  Tricyclic antidepressants  Withdrawal of narcotics, diazepam or ethanol  Signs of ethanol withdrawal o Irritable o Agitated o Seizure CAUSES OF CONVULSION IN POISONED PATIENTS  Direct convulsant effect of the poisons  Cerebral hypoxia from respiratory or cardiovascular depressive effect of drugs  Hypoglycemia  Severe muscle spasm due to spinal o peripheral effects on the mechanism controlling muscle tone  Withdrawal reactions in patients with physical dependence on abused drugs  Decreased seizure threshold in an epileptic patient TREATMENT OF CONVULSION

COMMON CAUSE OF HYPOXIA  Alcohol  Cyanide o In silver jewelry cleaners  Organophosphates o In pesticies
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Diazepam o Adult: 5mg IV o Children:0.3mg/kg o Only compatible fluid is blood (direct) Lorazepam (Ativan) o Adult: 2.5-10mg IV o Children: 0.05-1 mg/dose o Withdrawn from the marked d/t its associated side effects o Short acting, long duration Phenytoin o LD: 15-20mg/kg IV o Adult: 50mg/min o Children: 1mg/kg/min o Inducer of CYP450 o Maintenance drug Pyridoxine (B6) o Adult: 5g IV o Children: 80-120mg/kg o For INH poisoning o Tx of convulsions due to unknown etiology Hypothermia Alcohol Barbiturates Carbon monoxide General anesthetics Opioids Phenothiazenes Sedative-hypnotics Tricyclic antidepressants Hyperthermia

• • • •

Time exposure  Needs to be very specific  e.g.: N-acetylcysteine, antidote for paracetamol overdose; effective only in the first 6 hrs after ingestion  e.g. lavage of poison is only good for the 1st 24hours Mode exposure  Rectal  Transplacental  Oral  Etc Intake of other substances Circumstances prior to poisoning Current medications Past medical history Any home remedies taken *Organophosphate/carbamate poisoning: manifests with DUMBEL

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Antihistamines Amphetamines Isoniazid Phenytoin Salicylates Xanthines Anticholinergics: Atropine Cocaine Phenothiazines Quinidine Sulfonamides

POISONS WITH DELAYED MANIFESTAIONS Ethylene glycol 6 hours o Present in anti12 hours freeze 36 hours Salicylates 48 hours Paracetamol 48 hours Paraquat Methanol 4 weeks o Toxic alcohol Thyroxine *Vodka - among alcohols, has the highest alcohol content - converts ethylene glycol and methanol to less toxic form - amount to be given needs to be computed COMPLETE CLINICAL EVALUATION  Complete physical examination  Evaluate general status  Examine skin  Characterize odor of patient’s breath  Auscultate the lungs  Listen to patient’s heart  Check the abdomen  Do a complete neurologic exam  Skin changes in poisoning  Bullae: barbiturates, CO  Diaphoresis: OP, salicylate, amphetamine  Jaundice: paracetamol  Dry and warm: atropine, anticholinergic  Flushed: anticholinergics, alcohol, cyanide, atrophine odors  Brerath odors  Bitter: almonds, cyanide  Fruity: DKA, isopropanol  Oil of wintergreen: methylsalicylate  Rotten eggs: sulfur dioxide, hydrogen sulfide  Pears: chloral hydrate  Garlic: arsenic, OP  Mothballs: camphor (like the one in vicks) Bradycardia Tachycardia

TREATMENT OF COMA OF UNKNOWN ETIOLOGY • Thiamine (vit B1) 100mg IV o Tx of Wernicke Korsakoff Synd in alcoholic px • Glucose o Adult: 50-100ml D50-50 o Children:2ml/kg d10 o Most pts present with hypoglycemia esp. in alcoholic intoxication o Wernicke-Korsakoff syndrome  d/t sever B1 deficiency  administer B1 first before giving glucose • Naloxone o Adult: 2mg IV every 3-5mins o Children: 10mcg/kg o For opiate overdose (coma) o Expensive o Given to newborns whose mothers underwent CS causing respiratory difficult in their babies COMPLETE CLINICAL EVALUATION • Good history taking (d/t vulnerability of children) INFORMATION TO BE ELICITED DURING HISTORY

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Propranolol Anticholinesterase Clonidine, codeine, Ca-channel blocker Ethanol Digitalis

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Iron CO, cyanide Organophocphate Phenothiazine Ethanol, ethylene glycol Free-base cocaine Anticholinergics Antihistamines Amphetamines Sympathomimetics Salicylates, solvents Theopylline Miosis

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Mydriasis Tachycardia Hypertension Hyperthermia Seizures

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Miosis Bradycardia Hypotension Hyperventilation Coma



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Antihistamines Antidepressants Sympathomimetics Isoniazid Anticholinergics

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Cholinergics, clonidine Opiates, Organophosphate Phenothiazines, pilocarpine, pontine bleed Sedative-hypnotics

• • • • • • • • • • •

Ethylene gycol Theophylline, toluene Alcoholic ketoacidosis Lactic acidosis Aminoglycosides Cyanide, CO Isoniazid, Iron Diabetic ketoacidosis Grand Mal seizures Aspirin (salicylate) Paraldehyde, phenformin

*Triad   

of opiate overdose: Coma Respiratory depression Pinpoint pupils

Clinical Evaluation: Check for Toxidromes  Signs and symptoms taken collectively can characterize a suspected toxicant  These groups of manifestations are observed to occur consistently with particular poisons o Intractable seizures + Coma + Metabolic acidosis = INH Poisoning *Intractable seizures despite administration of diazepam

ELIMINATION OF THE POISON • External Decontamination – bathing of pt with alkaline soap e.g perla, ivory, dove • Emptying the stomach o Emesis – only in adults *pediatrics have risk for aspiration o Gastric lavage – H20, NSS, Na Bicarbonate, activated charcoal • Limiting GI absorption o Activated charcoal o Demulcents (watusi) / neutralizing agents (raw egg white: to prevent absorption) SUBSTANCES NOT ABSORBED BY ACTIVATED CHARCOAL  Alcohol – rapid absorption  Cyanide  Iron o Lavage with NaHCO3  Lithium - dialysis  Petroleum distillates (hydrocarbons)  Caustic agents SUBSTANCES WITH RECIRCULATION • Aspirin • Cyclosporine • Digoxin • Meprobamate • Paracetamol • Phenothiazine • Phenytoin • Salicylate • TCAD • Anticoagulants • Carbamazepine • Dapsone • Gluthetimide • Methamphetamine EXTRAHEPATIC

Anticholinergic / Antidepressant Toxidrome  Hyperthermia: “hot as a hare”  Dry mucosa: “dry as a bone”  Flushed skin: “red as a beet”  Dilated pupils: “blind as a bat”  Confusion / delirium: “mad as a hatter” Cholinergic Toxidrome (S&Sx of organophosphate and carbamate poisoning)  Diarrhea, diaphoresis  Urination

    

Miosis, muscle fasciculations Bradycardia, bronchoconstriction Emesis Lacrimation Salivation Opiates / Narcotics


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• • • • •

Phencyclidine Phenobarbital Piroxicam Theophylline Organochlorines

*Formalin ingestion:  No antidote  Give H2 blockers  Surgery (cut the part with ulceration) ENHANCEMENT OF ELIMINATION OF ABSORBED SUBSTANCES • Forced diuresis o Mannitol 20% - osmotic diuretic o Furosemide – loop diuretic • Alkalinization therapy o Sodium bicarbonate – for weak acids: INH poisoning • Acidification therapy (for weak bases: Methamphetamine/shabu) o Ascorbic acid o Ammonium chloride • Dialysis and hemoperfusion • Multiple dose activated charcoal INDICATIONS FOR DIALYSIS • Amanita phalloides (mushroom) – very dangerous and lethal causing renal failure • Antifreeze (glycol type) o Tx: ethanol e.g. vodka via NGT; prevents conversion to more toxic from • Heavy metals in soluble compounds o Tx with EDTA or chelators • Heavy metals after chelation • Methanol ANTIDOTES FOR PATIENTS UNKNOWN ETIOLOGY • Naloxone • Glucose • Thiamine WITH COMA OF

(Fe3+) state, resulting in the inability to transport oxygen and carbon dioxide) o Sodium Thiosulfate: binds with cyanide-methemoglobin complex to detoxify o Used in PGH, a raw material that is compounded and prepared whenever it is needed Reduction in conversion to more toxic compounds  Ethanol o For tx of methanol and ethylene glycol poisoning Competitive inhibition at receptor site  Atropine (physiologic antidote) – for organophosphate/carbamate poisoning; inhibits the enzyme acetylcholinesterase)  Pralidoxime (pharmacologic antidote) Bypassing the effects of the poison  Oxygen for CN poisoning  Pyridoxine for INH poisoning Antibody interacting with poison  Digoxin antibody fragments (Digibind) – not available locally *Locally: nadia-nadia  Snake antivernin (available in RITM) species of Philippine cobra cause paralysis Tx: activated charcoal

ANTIDOTE FOR PATIENTS WITH SEIZURE OF UNKNOWN ETIOLOGY • Pyridoxine (Vitamin B6) USE OF ANTIDOTES Mechanisms:  Inert Complex Formation  Chelating agents (DMSA, NAPA) o Tx of heavy metal poisoning  DMSA: suximer?  NAPA: N-acetyl-penicillamic acid – mercury, arsenic, lead  Accelerated detoxification  Cyanide antidote kit – available in US only  Sodium nitrite and sodium thiosulfate o Sodium nitrite: Induce methemoglobinemia (a condition in which the iron within hemoglobin is oxidized from the ferrous (Fe2+) state to the ferric

SUPPORTIVE THERAPY • Essential for poisoning patients, especially for critically ill • Problems in the critically ill poisoned patients o Depressed sensorium o Impaired ventilation o Impaired cough reflexes o Prone to aspiration o Immobility o Fluid, electrolyte and other ,metabolic problems • Intravenous fluids: replacement and maintenance • Frequent blood and urine pH determination: acidification and alkalinization therapy • Prevention of aspiration • Prevention of decubitus • Ulcer • Treatment of electrolytes, metabolic and temperature problems • Monitoring of vital signs • Monitoring of input and output GOOD SUPPORTIVE AND NURSING CARE IS IMPORTANT DISPOSITION • Observation at the emergency room: atleast 24hrs may be warranted • Frequent reevaluation • Psychiatric evaluation: suicidal patients and substance abusing patients • Childhood poisoning: evaluate for possible child abuse or neglect • Family counseling and education

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• •

Physical or sexual abuse among women Domestic violence 

TOP TEN POISONS (All Ages) IN-PATIENT STATISTICS National Poison Control and Information Service UPPGH YEAR 2006 (N=847) NUMBER PERCENTAGE 1. Ethanol – alcohol 95 11.2 withdrawal pts 2. Kerosene (Gaas) 87 10.3 3. Sodium Hypochlorite 62 7.3 (Zonrox) 4. Mercury (thermometer) 45 5.3 5. Jewelry Cleaner (Cyanide) 35 4.1 6. Hydrochloric acid (Muriatic) 27 3.2 7. Methamphetamine (Shabu) 19 2.2 8. Paracetamol 16 1.9 9. Mixed Pesticides (Baygon) 15 1.8 10. Jathropa seeds (cause 15 1.8 hemorrhagic gastritis)

 Acetic acid  Benzalkonium chloride Pathology: Coagulation necrosis Others  Phenol (e.g. Lysol)

Cyanide salts: Silver jewelry cleaner - mixed with Na Hydroxide

PHARMACEUTICAL AGENTS Paracetamol  Toxic dose: 150-200mg/kg  Toxic metabolite: NAPQI (N-acetyl-pbenzoquinone imine)  GI, liver and renal damage (4 stages)  Antidote: N-Acetylcysteine

 Preparation:





*Na Hydroxide: Liquid sosa 
TOP TEN POISONS (All Ages) TELEPHONE REFERRALS National Poison Control and Information Service UPPGH YEAR 2006 (N=2,682) NUMBER PERCENTAGE 1. Kerosene 192 7.2 2. Sodium Hypochlorite 131 4.9 3. Mixed Pesticides (Baygon) 118 4.4 4. Elemental Mercury 90 3.4 5. Paracetamol 64 2.4 6. Silica gel (shoes) – 62 2.3 nontoxic, causes mild GI manifestation 7. Jewelry Cleaner 57 2.1 8. Ferrous Sulfate 53 2.0 9. Hydrochloric acid 48 1.7 10. Isoniazid 42 1.6

Oral – in sachet Inhalation Average 50-kh man who ingests 15-20 tablets (500 mg) causes toxic injury

 Iron
   Toxic Dose: 20mg/kg GI, CVS, CNS manifestations (4 stages) EGD Antidote: Deferroxamine Causes severe bleeding and hypotension e.g. Flintstones, Gummy bears – contains iron which can cause toxicity

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 Kerosene (Gaas)


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Chemical pneumonitis Presents with cough  cyanosis  seizures Aspiration pneumonia Treatment: Pen G or other beta-lactams (for pneumonia) No antidote Easily absorbed

Isoniazid (INH)  Toxic Dose: 80-100mg/kg  Triad of INH toxicity: seizures, metabolic acidosis  Antidote: Pyridoxine (Vitamin B6)


Solvents  Aliphatic hydrocarbons  Aromatic hydrocarbons  Benzene (ADR: Leukemia)  Toluene (ADR: Kidney failure due chronic exposure)


Aspirin  Acetylsalicylic acid: 100mg/kg (children), 200mg/kg(adults)  Methylsalicylate: 50-500mg/kg or 4ml (1.4mg/ml)  Vomiting, tinnitus (first thing to manifest), metabolic acidosis, seizures, coma, renal failure  Activated charcoal / hemodialysis (causes coma, seizure)

CAUSTIC AGENTS Alkali (ph > 7) Strong alkali: ph >10  No antidote (only supportive): H2 blockers, PPI  Sodium hypochlorite  Sodium hydroxide (e.g liquid sosa)  “LIhiya” (pang-green ng suman)  Main Tx: surgical Pathology: liquefaction necrosis (esophagus and intestine) Strong acid: ph <4 Hydrochloric acid

PESTICIDES Organophosphates  Malathione  Chlorpyrifos  SSx: DUMBELS Carbamates  SSx: DUMBELS Pyrethroids  DEET (diethyltolbutamide) present in insect repellants (e.g. lotions)

 Acids (ph < 7)

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causes seizures esp in children >2 y/o Permethrin - anti-pediculosis and scabies: cause seizure

 Organic:

contaminated waters from industrial waste products, air, soil (methylmercury)

Rodenticides  Zinc Phosphides  Coumatetralyl  bleeding (Tx: vitamin K) Herbicides  Chemical pneumonitis

Small-scale mining practices = residue after panning operation where most of the water are removed = no personal protective device is provided = route of entry is skin Mercury in Thermometer “There is approximately 1 gram of mercury in a typical fever thermometer. This is enough mercury to contaminate a lake with a surface area of about 20 acres, to the degree that fish would be unsafe to eat” *Mercury is not actually absorbed if GI is intact but can cross BBB after 24-48 hrs *Tx: cathartics  Organic Chemicals: Methylmercury

MIIXED PESTICIDES (e.g. Baygon)  Carbamates  Propoxur  Pyrethroid  Cyfluthrin  Transfluthrin  S/Sx: DUMBELS  Treatment: Atropine, Activated Charcoal

Effects of Pesticides: - Endocrine disruption (cause problems in reproduction and immune system) Neurodevelopmental effects (e.g autism, cerebral palsy, mental retardation) Immune system (can cause cancer) NON-PHARMACEUTICALS  Silica gel – gastric irritant  Chinese herbal meds (e.g. Ma-Huang – has pseudoephedrine and ephedrine: precursor of methamphetamine)  Button batteries in <7 y/o, the diameter of intestine is >1.5 cm can obstruct trachea, pyloric sphincter endoscopy is done to get it manually  Watusi  Yellow phosphorus – most dangerous (protoplasmic: cause severe hypotension and hypoxia)  Trinitrotoluene (present in dynamite and bombs)  Potassium nitrate  Potassium chlorate  Moth balls  Naphthalene – causes hemolytic anemia in G6PD deficiency pts  Camphor – most toxic

*Mercury vapor – amalgam fillings are chief sources of exposure to mercury vapor Minamata Disease (d/t high levels of methyl mercury in big fishes, e.g. tuna) In 1932, Nippon Chisso Hiyu started to operate an acetaldehyde acetic venyl chloride manufacturing plant using mercury as a catalyst. The plant had been directly discharging its industrial waste into Minamata Bay for 36 years with no adequate facilities. In 1958, Chisso redirected the outlet drainage canal from Minamata Bay into the tributary of the Minamata River which resulted in the contamination of a wider area of Yatshushiro Sea. Increase in number of vaccines recommended for routine use in infants

Para-dichlorobenzene Albatross)



- least toxic, causes slight gastric irritation HEAVY METALS  Mercury (a.k.a Asoge)  Sources:  Elemental: “quicksilver” metal, cinnabar ore, dental amalgam, apparatus, thermometers  Inorganic: antiseptics, vaccines (merthiolate)

Potential increased exposure of infants to mercury from thimerosal in vaccines Ethyl Mercury

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= in children receiving thimerosal in vaccines, the half-life of ethyl mercury in blood was 7-10 days or 1/7 to 1/5 as long as that of methyl mercury = a WHO advisory committee recently concluded that it is safe to continue using thimerosal in vaccine Mercury (Pink Disease) Acrodynia Acrodynia is a rare idiopathic chronic toxic reaction to elemental or inorganic mercury exposure, which occurs mainly in young children. It is characterized by pain in the extremities and oink discoloration with desquamation of the skin Uncommon Syndrome “Pink Disease”  Pain in the extremities  Pinkish discoloration and desquamation  Hypertension  Sweating  Insomnia, irritability, apathy  Considered as idiosyncratic reaction Adverse Effects of Mercury  Elemental acute necrotizing bronchitis pneumonitis, insomnia, forgetfulness, loss of appetite, tremor, erethism, renal toxicity  Inorganic corrosive effects: GI ulceration, perforation, hemorrhage, acrodynia, renal toxicity  Organic - CNS: paresthesia, ataxia, muscle spasticity Infants: psychomotor retardation, blindness, deafness, seizure, cerebral palsy Behavioral and learning delays: deficits in language, attention and memory 


CYANIDE inhibits cytochrome oxidase CNS Effects: shock, profound lactic acidosis Toxic blood level: >0.5 mcg/ml

Cyanogen-containing plants  Linamarin in cassava cake – associated Sxs: DUMBELS Cyanide salts  Metal polishing (jewelry cleaners) Cyanide Antidote Kit  Amyl nitrite, sodium thiosulfate



RED TIDE POISONING Diarrheic shellfish poisoning  Okadaic acid (OA) and its derivatives Amnesic or poisoning  Domoic acid encephalopathic shellfish

Paralytic shellfish poisoning  Saxitoxin and gonyautoxin (GTX) Neurotoxic shellfish poisoning (NSP)  Brevetoxin

 Lead (a.k.a tingga)
 Pregnant women and their developing fetuses are at high-risk because lead readily crosses the placenta For every 10mcg/dl increase in BLL, children’s IQ dropped by 4-7 points A higher proportion of learning disabilities was found among school-aged children with biological parents who ere lead poisoned as children 50 years previously Source: paints, lipstick, gasoline, hair dyes

Department of Health Criteria for Detecting PSP  Ataxia +  Additional 2 Motor Distrubances + Dysphagia Inability to stand Vomiting Dyspnea Paralysis  Additional 2 Sensory Disturbances Dizziness Headache Lightheadedness Paresthesias Dysthesia Hot flashes Numbness

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Arsenic Poisoning  Keratotic lesions  cancerous  Patients from Bangladesh dig a well

PLANT TOXINS Jathropa Seeds  Contents: toxalbumins = ricin (toxic content causing hemorrhagic gastritis), curcin, tannic acid  Effects: abdominal pain, nausea, vomiting, hepatic injury, muscle twitching, weakness, salvation, sweating, dehydration, hemorrhagic gastritis  Tx: activated charcoal

Specific Treatment

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With known or suspected toxin

(-) Respiratory Distress Observe for 24 hrs Asymptomatic Respi Failure Discharge hrs x 24h Ventilatory support
Respi Distress edrophonium Test dose of

(+) Respi Distress 

Give raw egg whites in cases of corrosive ingestion 8-12 egg whites (adult) 4-6 egg whites (children) Give 1-5% baking soda solution in cases of shellfish and iron poisoning 1 teaspoon + 100mL water

(-) Respi Failure


NaHCO3 q 5 hr Observe x 24 hrs

NaHCO3 q 5

PREVENTIVE MEASURES • Wash vegetables / fruits thoroughly • Support integrated pest management • Avoid use of mercury thermometers • Flush cold water tap before use • Dispose chemical containers properly • Promote healthy lifestyle: “Say no to drugs” • Do regular inventory of drugs and chemicals in the house • Proper storage or labels National Poison Management and Control Center UPCM – Philippine General Hospital Hotline Numbers: 5241078 or 5218450 loc. 2311

With Response

Public Health Issues  Reporting to DOH  Shellfish / Fish Advisory  Monitoring of other possible patients  Monitoring of levels of toxins in the area (BFAR) SUBSTANCE ABUSE Sedatives  Diazepam (Valium)  Lorazepam (Ativan)  Flunitrazepam (Rohypnol)  Sleeping Pills (Stinox, Unisom) *Ecstasy - side effect: bruxism - causes seizure, severe dehydration - more toxic than shabu Smoking and Alcohol FIRST AID MANAGEMENT OF POISONING CASES GOAL OF TREATMENT: to limit absorption of poison remove from toxic environment decontamination Maneuvers REMEMBER THE DONT’S:  Do not induce vomiting in the following situations: drowsy and comatose patients poor gag reflex ingestion of corrosive and hydrocarbon if the ingestion has occurred for more than one hour late pregnancy (last 3 months of pregnancy) presence of heart disease  Do not give milk or vinegar :milk is not a universal antidote

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