TOXICOLOGY LECTURES Introduction 2 1 million cases of

TOXICOLOGY LECTURES

Introduction • 2. 1 million cases of human exposures reported in 2000 • 92% of the exposures occurred at home – 14% occurred in a health care facility – 2% occurred at work • Children > 3 years were involved in 40% of the cases • 52. 7% occurred in children > 6 years • Male predominance is found among poison exposures younger than 13 years • Children > 6 comprised 2. 2% of the fatalities • 59% of fatalities occur in the 20 -49 year age group

Introduction, cont. • 85. 9% of poison exposure were unintentional – suicide intent was present in 7. 5% of the cases – therapeutic errors comprised 7% of exposures • 920 fatalities reported – 94% of adolescent and 79% of adults were intentional • • Automatic capital offense to poison someone Most poisonings occur at home just before meal time Most poisonings enter the body orally - 76. 2% More people die in the US from suicides than from homicides

Substances most frequently involved in Human Exposures • • Analgesics - 10% Cleaning substances - 9. 5% Cosmetics and personal care products - 9. 4% Foreign bodies - 5. 0% Plants - 4. 9% Cough and cold preparations - 4. 5% Bites and envenomations - 4. 2%

Substances most frequently involved in Pediatric poisonings • • Cosmetics and personal care products - 13. 3% Cleaning substances - 10. 5% Analgesics - 7. 2% Foreign bodies - 6. 8% Plants - 6. 6% Topicals - 6. 3% Cough and cold preparations - 5. 3%

Substances most frequently involved in Adult Exposures • • • Analgesics - 13. 3% Sedatives/hypnotics/antipsychotics - 9. 8% Cleaning substances - 9. 5% Antidepressants - 8% Bites/envenomations - 7. 9% Alcohols - 5. 4%

Frequency of Plant exposure by Plant type • • • Capsicum annuum - pepper plant Spathiphyllum spp. - peace lilly Philodendron Ilex spp. - holy Euphorbia spp. - poinsettia Phytolacca sp. - poke week, ink berry

Categories with largest number of deaths • Analgesics – involved in 30% of fatalities – acetaminophen, aspirin and other salicylates = 72% – 84% of the fatalities were intentional • Antidepressants – 69% involved TCA’s • Sedatives/hypnotics/antipsychotics – benzodiazepines account for 36% • Cardiovascular drugs • Alcohols

Deaths associated with street drug exposure • Highest proportion of exposures result in fatalities • Amphetamines and cocaine - account for 61% of street drug deaths (39 in 2000) • Ecstasy - involved in 23 fatalities – all occurred in persons 17 -24 years of age • Heroin - 29% of deaths

Pediatric fatalities • 20 of the 920 cases involved children > 6 yrs – 10 involved substances found around the home – 3 were intentional • 6 deaths in 6 -12 year olds – 4 were suicides – 1 was a murder • 66 deaths in 13 -19 year olds – 38% were suicides – 47% due to substance abuse

Other deaths • Carbon monoxide - 25 deaths • 3 deaths from envenomations – 2 rattlesnake and one scorpion • 5 plant ingestion related deaths – 3 due to Jimson Weed

Definition of terms • Toxicology - the study of poisons • Toxicologist - one who studies poisons • Hazard - likelihood an event will occur based on how the product is packaged, formulated, or its accessibility • Risk - the probability that an event will occur based on patient vulnerability • Toxic substance - poisons • Poison - any chemical substance which can cause harm • Drug overdose - taking a harmful amount of a drug

Definition of terms • Antidotes: from the Greek anti - against and didonai - to give – the remedy for counteracting a poison – 3 types: • chemical - reacts chemically with the poison to form a harmless compound, ie. chelators and heavy metals • mechanical - prevents absorption, ie. activated charcoal • physiologic - counteracts the effects of the poison by producing opposite physiologic effects, ie. atropine and organophosphate poisoning – Universal antidote - 2 parts activated charcoal, 1 part magnesium oxide and 1 part tannic acid

Historical perspective • Poisonings date to antiquity • Deuteronomy 14: 9 -10, Moses said do not eat fish which do not have fins or scales cause it is unclean • Job 6: 4 mentions poisoned arrows • 1500 BC the Ebers papyrus • King of Pontus first to develop antidotes in the first century before Christ

Historical perspective, cont. • Plato reported the death of Socrates by hemlock (Conium maculatum) • 13 th century Peter of Abanos reviewed the literature and divided poisons into those of plant, animal and mineral origin • Paracelsus, 1493 -1541 said that “all substances are poisons, there is none which is not poisonous. Solely the dose determines that which is poisonous or not. ”

Historical perspective, cont. • Middle ages poisoning was considered a hazard of living much like dying in an auto crash is today • Orfila, 1787 -1853, attending physician for Louis 18 th of France, wrote the first book on General Toxicology and is considered the father of modern toxicology

Diversity of Toxicology • Occupational Toxicology - OSHA - The Occupational Safety and Health Act of 1970 grew out of the need to protect workers in the work place • Environmental Toxicology - EPA - study of chemicals that contaminate food, water, soil and the atm. • Forensic Toxicology - medicolegal aspects of poisons • Clinical Toxicology - deals with the pathophysiologic aspects clinical presentation of intoxication

Most Poisonings are Preventable

Child proofing your home • • Do not keep meds in purse or pockets Always put meds away after use Never take or administer meds in the dark Store all poisons in locked containers Store all meds out of children’s reach Never refer to meds as candy Never allow kids to take meds without supervision

Child proofing your home, cont. • • Do not keep poisonous plants in the house Never leave meds on tables, nightstands, etc. Do not store poisons under sinks Always rinse out med bottle before disposal Keep meds and poisons in original containers Use child proof caps on all meds Never borrow or loan meds

Child proofing your home, cont. • Never administer more than the prescribed amount of a med • Never keep outdated meds • Always give or take the whole prescription • Never allow kids to play in garage unattended • Never allow kids to play around running cars • Use “Mr. Yuk” stickers

Child proofing your home, cont. • Educate your children about poisons • Formulate a plan of action in case a poisoning occurs • Stock and keep activated charcoal and syrup of Ipecac in your home • Keep poison control number by phone: – 1 -800 -POISON 1

Symptoms of poisoning in a child • Children may not be able to tell you they have ingested a poison • Err on the side of being conservative if in doubt • Call poison control if you even suspect anything

Symptoms of poisoning in a child • • blistering of the mouth or lips bad odor from mouth burning of the mouth breathing problems dizziness confusion or unconsciousness vomiting or diarrhea convulsions

Household Poison Safety • • • Kitchen Bathroom Garage Common sense approach to medicines How to handle pesticides Know your plants

Emergency Actions for non specific poisons • Call poison control if you suspect poisoning has occurred • If a patient is symptomatic call 911 or transport immediately • Maintain airway • Check and monitor vital signs • Supportive care

The Food and Drug Administration • Report problems with foods, drugs, cosmetics, medical devices, etc. • Did the product cause injury? • Was it improperly labeled? • Was it unsanitary? • Before you report a problem ask was the product used for other than its intended purpose, were instructions followed carefully, was the product out dated? • FDA; 5600 Fishers Lane (HFC-160); Rockville, MD 20857; phone (301) 443 -1240

Principles of Toxin Elimination and preventing absorption

General approach • Call poison control center – 1 -800 -222 -1222 • Remember the ABC’s • Decontaminate the gut, clothing, skin and environment • Monitor vital signs • If patient is symptomatic call 911 • If patient is unconscious - maintain airway

General approach, cont. • If patient is convulsing: – do not stick fingers in mouth – get them to the middle of the floor – remove constrictive clothing, etc. – keep stimuli to a minimum – call 911

General approach, cont. • Try to determine how much they have swallowed – child 1 swallow = 1 tsp. – adult 1 swallow = 1 tbsp. • 50% of histories are incorrect • Try to ID the poison • send original container with patient if possible

Gut decontamination • Once toxic agent is ingested it must be absorbed (unless a local GIT irritant - iron or corrosives) • Prevent absorption – gastric evacuation – administration of an adsorbent – catharsis

Gut decontamination, cont. • Gastric emptying – must be done soon after ingestion – emesis – emetics • • • copper sulfate mustard water zinc sulfate tartar emetics apomorphine soapy water

Emetics, cont. • Syrup of Ipecac – first discovered in Latin America in 1648 – used first in the treatment of dysentery up until about 1900 – prepared from the dried roots of Cephaelis ipecacuanha plant – contains two alkaloids - emetine and cephaline • Use has declined since 1983

Syrup of Ipecac, cont. • Emetine - potent emetic - works systemically and locally. Long half life, has a cumulative toxic effect on the heart. • Cephaline - twice as potent as emetine and is a direct gastrointestinal irritant • Syrup of Ipecac is very effect emetic • Efficacy is not affected by concomitant administration of activated charcoal

Syrup of Ipecac, cont. • Give only to alert awake patients with an intact gag reflex over 6 months of age • Never repeat dose more than once 20 minutes after first administration • Vomiting usually occurs within 20 minutes of administration and continues for 30 to 120 minutes

Syrup of Ipecac, cont. • Dosing guidelines 0 -6 months 6 -12 months 12 mon. - 12 years > 12 years no ipecac 10 ml, do not repeat dose 15 ml, can be repeated once 30 ml, can be repeated once Remember 15 ml = 1 tbsp. = 3 tsp. = 1/2 ounce

Syrup of Ipecac, cont. • Contraindications - do not give – if corrosive agents have been ingested – if low viscosity hydrocarbons are ingested – if patient is having a seizure – if patient is comatose – if patient has ingested an agent which can cause a seizure or coma – if patient does not have intact airway reflexes

Gut decontamination, cont. • Gastric lavage - “pumping the stomach” – done in a hospital setting • Administration of an adsorbent – any agent capable of binding to the toxic agent in the GIT and preventing the agents absorption – once the agent is bound, the toxin-adsorbent complex is excreted in the feces

Adsorbents, cont. • Activated Charcoal – first used by Hippocrates to bond toxic agents – part of the universal antidote • burnt toast and tea – “activated” - by micropulverizing and exposing it to steam and acid (compare activated with a surface binding area of 1000 m 2/gm verses “unactivated” carbonaceous material at 3 m 2/gm) • Use has increased since 1983

Activated Charcoal, cont. • One 50 gram dose has the binding surface area of 10 football fields • Available in tablets, capsules, powder and suspension (most useful) • Substances not well adsorbed: – alcohols – hydrocarbons – heavy metals and inorganic minerals – corrosives

Activated Charcoal, cont. • Dosing – try to achieve a 10: 1 charcoal to toxin ratio, give 10 times as much charcoal as the toxin ingested – 1 gm/kg BW also works well – children must usually have a nasogastric tube instilled because they usually will not drink the gritty black slurry • Administered to about 7% of patients – aspiration of AC partially responsible for 8 deaths, given to patients who ingested CNS depressants

Gut decontamination, cont. • Cathartics - purgatives, laxatives – drugs which promote evacuation of the bowel – facilitate the expulsion of the toxin • Commonly used cathartics – sorbitol – mannitol – magnesium sulfate – magnesium citrate 1 -2 g/kg BW 200 mg/kg (C); 10 -20 g (A) 225 mg/kg (C); 17. 5 g (A)

Cathartics, cont. • Mechanism of action – osmotic agents – stimulate GIT motility • Scientific efficacy is uncertain • Contraindications: do not use in patients – with absent bowel sounds – with cardiovascular or renal disease or electrolyte imbalance

Drugs used to treat Depression

Tricyclic antidepressants • Most common cause of death due to prescription drug overdose; • Reasons: – wide spread availability to suicide prone patients (patients with depression) – severity of CV and CNS effects – limited efficacy of aval. treatments for OD • Mechanism of action – inhibit re-uptake of catecholamines and serotonin neurotransmitters

TCA’s, cont. • Examples – Amitriptyline - Elavil – Nortriptyline (Pamelor, Aventyl) – Imipramine - Tofranil – Desipramine (Norpramin)

TCA’s, cont. • Clinical presentation – Life threatening OD is usually associated with ingestion of > 1 gram – Cardiovascular - sinus tachycardia, prolonged QRS interval, ventricular arrhythmias, hypotension – CNS - seizures, coma – hyperthermia – ileus – Urinary retention

TCA’s, cont. • Treatment – give activated charcoal (may require repeated doses due to pharmacologic bezoar formation) – give sorbitol (a cathartic) – do not induce vomiting - because of possibility of rapid onset of seizures and risk of aspiration

Lithium carbonate • Used in the treatment of depressive and bipolar disorders, therefore it is used in a population at relatively high risk for overdose • Narrow therapeutic index and intoxication is a relatively frequent complication of therapy • Gradual onset of intoxication is far more common that acute toxicity • Acute overdose carries a 25% mortality

Lithium carbonate • Once used as a salt substitute and was an ingredient of 7 -Up • 10, 000 toxic exposures occur each year with 2000 being considered moderate to severe toxicities • There has been a gradual increase in toxicities over the past 10 years • 10% of exposures are in children > 19 years of age

Lithium, cont. • Mechanism of action: – CNS is major organ system affected – competes for sodium, potassium, magnesium and calcium and displaces them from intracellular sites – numerous biochemical mechanisms that affect receptor sensitivity and bring about changes in neurotransmission

Lithium, cont. • Clinical presentation: – CNS - fine hand tremors, hyperirritability, spastic movements memory impairment, anxiety, delirium – GI tract - severe gastroenteritis – CVS - arrhythmias, hypotension, circulatory failure – should not be taken during pregnancy as it is teratogenic causing cardiac anomalies in the fetus (esp. of the tricuspid valve)

Lithium, cont. • Treatment – induce vomiting – activated charcoal – transport to a medical facility