Toxicology

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Toxicology: Study of poisonous substances, their actions on the living organisms, their detection by laboratory methods and measures taken to counteract their biologic effects Study of substances introduced into the body Toxicos = poison; Logos = study All drugs of abuse (except barbiturates and cannabinoids) are: o Basic amino group - containing compounds o Mostly contain benzene rings Therapeutic drug monitoring Branch of clinical chemistry that specializes in measurement of medication levels in the blood Main focus = drugs by narrow therapeutic ranges (drugs that can usually be over or underdosed)

Indications: To determine the relationship between plasma drug concentration and pharmacologic effects Knowledge of the drug level influences management Narrow therapeutic window Potential patient compliance problems Drug doses can't be optimized by clinical observation alone Reasons: Non-therapeutic: Dose too low, malabsorption, rapid metabolism Toxic levels: Overdose (dose too high or too frequent), reduced renal function, reduced hepatic metabolism Drug action 1. Replacing / acting substances for missing chemicals 2. Increase or stimulate certain activities 3. Decrease or slows down certain activities 4. Interferes with the functions of foreign cells Factors influencing the relationships between drug dosage and the intensity of its effect: 1. Drug prescribed — compliance; correct drug 2. Dose taken — absorption, distribution, metabolism, excretion 3. Plasma concentration — diffusion or active transport protein binding in blood 4. Concentration at the site of action — tissue responsiveness; effects of other drugs 5. Intensity of effects—over or underdose Factors of body response to drugs: 1. Weight, age, gender 2. Physiological factors: diurnal rhythm of nervous and endocrine system, acid-base balance, hydration and electrolyte imbalance. 3. Others: Pathologic factors, Immunological factors, Environmental factors, Tolerance, Accumulation Areas of toxicology 1. Detection of drug of abuse 2. Monitoring therapeutic drug level 3. Detection of environmental consciousness 4. Detection of toxin in poisons

Classification of drugs; According to origin o Natural or Synthetic According to legal classification (Philippines) o RA 9165: Comprehensive Dangerous Drug Act of 2002 o PD 1619: for volatile substances (rugby, thinners) o RA 6425: Dangerous drugs act of 1972; prohibited and regulated drugs According to international classification o Narcotics: Produces sleep, stupor and relieves pain o Psychotropic substances: Any drug having a particular affinity or effect on the psyche o Designer drugs: Related to but slightly different from controlled substances, designed by clandestine chemist According to effects o Stimulants: Increase alertness and physical disposition (Amphetamines, caffeine, cocaine, methamphetamine, shabu) o Hallucinogens: Drugs that affect sensation, thinking, selfawareness, emotion (Ecstasy, Lysergic acid diethylamide (LSD), Marijuana, mescaline, phencyclidine (PCP), psilocybin) o Narcotics: Drugs that relieve and induce sleep (Codeine, heroin, morphine) o Sedatives/Depressants: Drugs that reduce anxiety and excitement (Alcohol, barbiturates) Drug techniques in serum and urine: 1.

Immunochemical method a) Enzyme mediated for immunologic techniques (EMIT) b) Fluorescent polarization Principle: competitive binding immunoassay o Direct competition: Immobilized drug conjugate competes with drug/metabolites of a limited amount of chemical labeled antibody o Displacement: Displacement of a chemically labeled drug conjugate already bound to an equal amount of test antibody.

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Chromatographic procedures a) Thin layer chromatography (TLC) b) High performance liquid chromatography (HPLC) Cross reactivity (interferences): o Drug and drug metabolites with significant structural similarities to the target analyte may cross-react with target analyte specific antibodies, producing false positive results o Degree to which any substrate other than the target substrate interacts with an antibody

Drug metabolism: Drug administration: oral, intravenous, inhalation Drug detection: depends on the ff: 1. Absorption: structure and composition, diffusion and transport, physiochemical factors in penetration 2. Disposition: distribution, pH partition principle, electrochemical and donnan distribution, biotransformation 3. Elimination

Drug -

A chemical substance that brings about physical, physiological, behavioral and/or psychological change in a person taking it. A chemical substance other food which is intended to affect the structure or function of the body of man or animal All medicine are drugs but not all drugs are medicine

Drug abuse Any non-medical use of drugs that cause physical, psychological, legal, economic, or social damage to the user or to people affected by the user's behavior Abuse usually refers to illegal drugs but may also be applicable to drugs that are available legally, such as prescribed medications and certain over-the-counter medications

Biotransformation: Degradative: Drug molecule is diminished to a smaller structure Synthetic: 1 or more atoms may be added to the molecule Phase I: oxidation, reduction and hydrolysis Phase II: conjugation (esterification, amidation, mixed anhydride formation, hemiacetal formation, etherization). Drugs of abuse: Cocaine, Opium, Tranquilizer, Sedatives, Dopaminergic pathway stimulants, Hallucinogens In the Philippines: What are the drugs tested? 1. Most common: marijuana, cocaine, amphetamine, opiates, PCP 2. Other popular tests: methamphetamines, benzodiazepines, barbiturates, oxycodone, ecstasy.

Neurons: functional subunits of the nervous system; have nerve fibers 2 types of nerve fibers: 1. Axons - impulse is sent away from the cell body 2. Dendrites - impulse is delivered to the cell body Major tranquilizers: Example is Haloperidol (Haldol) Used to treat psychotic states such as schizophrenia Block attachment of dopamine to dendritic receptors in the synapse blocking stimulatory effects of dopamine Specimens that can be used in toxicology: Urine, Blood, Hair (used for Arsenic poisoning), Meconium (1st bowel movement of the fetus; nicotine and cocaine), Saliva, Sweat (for detecting tetrahydrocannabinol, amphetamine, PCP) Drugs of abuse 1. Depressants / Downers— tranquilizers, sedative 2. Stimulation— cocaine, amphetamine 3. Hallucinogens— LSD, PCP 4. Analgesics and antidepressants—acetaminophen, salicylates, tricyclic antidepressants Cocaine -

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Street name: Coke, Crack, Gold dust, Star dust, White girls, Speed balls From coca plant; used also in coca-cola Derivative of the alkaloid ecgonine Has dopaminergic effects induces increased calcium influx in dopaminergic neurons: o This activates the phospholipases as second messengers o Release of dopamine in the synapse Cytotoxic effect: formation of nitric oxide free radical produced in the metabolism in the liver Limbic system: cAMP for dopamine release Half-life: 1 – 2 hours Usually cleared within 2 days Used as: Additive in certain foods, Local anesthesia (usually during nasopharyngeal surgery) Route of administration: Nasal (snorting) Potent form: Crack cocaine (free base or purest form) o Passes rapidly across nasal membrane where most or all of it enters the bloodstream rapidly Fatalities have 2 types: 1. Direct toxicity of the drug 2. Crime related to the illicit acquisition Large doses cause: Euphoric state ("high"), Hallucination, Violent behavior, Delusion (strong belief of something despite of evidence), Illusion (false idea or belief) When consumed together with alcohol: COCAETHYLENE (ethanol + cocaine) o Ethanol becomes esterified with cocaine and blocks reuptake of dopamine more effectively than cocaine o Effect: Pronounced vasoconstriction of coronary arteries, Induces increased myocardial oxygen demand Prolonged use of cocaine results in cardiotoxicity o Progressive atherosclerosis and Constriction of coronary arteries that can induce myocardial ischemia Passes readily across the placenta and also into the lactating mammary gland o Mental retardation, Delayed development, Strong drug dependence of newborns, Malformations in utero Cocaine induces platelet aggregation and stimulates productionof plasminogen activator inhibitor Tests: 1. GC-MS (Gas-Chromatography Mass spectroscopy): up to 48 hrs after admin. 2. TLC (Thin layer chromatography): up to several hours Immunoassay: up to 24 - 36 hours Treatment: 1. Hyperexcitable states with cardiac symptoms (palpitations) = benzodiazepines 2. Antidepressants, including fluoroxetine (Prozac)

Opioids -

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Opium -

Provides a quick, intense feeling of pleasure followed by a sense of well-being and calm Screening tests: Immunoassay method Confirmatory test: GC-MS Types of Opiates: 1. Naturally-occurring: from Papaver samniferum (opium poppy) = Opium, Morphine, and Codeine 2. Semi-synthetic = Heroin, Hydromorphone, and Oxycodone 3. Synthetic = Moperidine (Demerol), Fentanyl (Sublimaze), Propoxyphene (Darvon), Methadone (Dolophine) Treatment: Naloxone (Narcan): a specific opiod antagonist that reverses CNS depression

Street name: Blanco, Brown sugar, Kabayo, Kengkoy, Gamot, Matsakao, Pulbos, Sapsap, Tinik Uses: relief of intense pain, cough suppression, treatment of diarrhea, anesthesia Symptoms of abuse: shallow respiration, pinpoint pupils, hypothermia Route of administration: Intravenous Half life: 3 minutes (IV route); effect lasts for 3 hours

Morphine Street name: M, Dreamer, Ms. Emma, Cube juice, hard stuff, Morph, emsel, pulbos Can relieve pain and induce sleep Derivative of opium, metabolite of heroin Uses: Powerful analgesic, Treatment of acute congestive heart failure Toxicity manifestations: Coma, Pinpoint pupils, Depressed respiration Codeine -

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Street name: School boy Major metabolites: N-acetyl morphine and Morphine Used as: a mild analgesic and as an anti-tussive Route of administration: Intravenous Highly addictive = Addiction recognized by: needle tracks Analog: dextromethorphan (D-3-Methoxy-N-Methylmorphine) o Generally not addictive o Recommended dose: 15 — 30 mg; 3-4 times a day o Light intoxication = 100 — 200 mg o Heavy intoxication = around 1500 mg o Block NMDA receptors (like PCP): 1. Neuronal plasticity and memory 2. Central pain pathways in the brain Effects: Obtundation (lessening of sensation due to anesthesia), Coma, Respiratory arrest, Cardiac arrhythmias, Hypotension (secondary to histamine release) Withdrawal from the drug is exceedingly difficult: Hypothermia, Palpitations, Cold sweats, Nightmares Treatment: Aside from naloxone, in chronic cases especially heroin addiction is treated with Methadone (partial agonist of heroin)

Amphetamines Street name: Eye opener, Lid poppers, Pep pills, Uppers, Hearts Effects: Psychic stimulation, Excitability (euphoric states,increased mental activity, increased mental activity), Increased blood pressure (increased heart rate), Palpitations, Bronchodilation, Anxiety, Prolongs the effects of epinephrine and norepinephrine, Talkativeness, Pallor, Tremulousness (voice is unsteady) Patients may not sleep or eat Orgasm / ejaculation is difficult to achieve (Sexual marathon) Suspiciousness paranoia producing unpredictable violent behavior If fatigue occurs, user may sleep for 24 hours to 48 hours, then eats ravenously Treatment: for Narcolepsy or Narcoleptic and attention deficit disorder

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Anorexic effect:

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Amphetamines: trade name Dexedrine Close resemblance to the adrenergic amines such as epinephrine and nor epinephrine (Sympathomimetic Effects) Acute toxicity: Cardiovascular (flushing or pallor, tachypnea, palpitation, tremor, labile pulse and blood pressure, Arrhythmia, heart block, circulatory collapse, angina), Mental delirium, Acute psychotic syndromes, Acute intoxications Chronic usage: emotional ability, somnolence, loss of appetite, occupational deterioration, mental impairment, social withdrawal o Trauma and ulcer of the tongue and lip: continuous chewing and teeth-grinding movements o Paranoid schizophrenia o Rare: aplastic anemia and fatal pancytopenia

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Methamphetamine (Shabu) Street name: Speed, ice, chalk, crystal, glass, Poor man's cocaine, S, shabs, Siopao, sha. Route of administration: ingestion, inhalation (chasing the dragon), sniffing, injection, smoke , suppository (LEAST common) Effects: o General: anxiety, irritability, irrational behavior o Long term: psychosis similar to schizophrenia, difficulty in concentrating, loss of interest in sex o Physical: chest pain, irregular heartbeat, hypertension, convulsion, death

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Methylenedioxymethamphetamine (MDMA) / 3-4 MDMA: Street name: E, ecstacy, adam, XTC, lover's speed, essence, herbals "designer" hallucinogenic stimulant drug Half-life: 8 – 9 hours Route of administration: Inhalation, Ingestion, Smoking Synthetic drug, structurally related and derived from amphetamine Effects: feeling of euphoria, heightens sexuality, expands consciousness without loss of control, fatal malignant hypothermia, seizures, tachycardia, DIC.

Lysergic Acid Diethylamide (LSD) Street name: Lucy in the sky of diamonds, wedding bells, acid, white sugar, lightning, cubes, brain eaters. Route of administration:injection or oral administration Effects: Visual hallucination (undulating vision), perceptual distortion, synesthesia (overflow of sensory input so that colors are "heard" and music becomes "palpable", papillary dilatation, uterine contraction, panic reactions such as "bad trip" Usual dosage: 1-2mcg/kg Experience: begins = 1 hr after; peaks = 2-3 hrs; lasts = 8-12 his Metabolized in the liver, excretion through bile Treatment: frequent reassurance, quiet and calm environment, diazepam, Isolation (best treatment) Deaths are usually due to SUICIDES or ACCIDENTS Phencyclidine (PCP) Street name: angel dust or angel hair, crystal super grass, killer joints, ozone, wack, rocket fuel Effects: depression to euphoric state, violent behavior, auditory and visual hallucination, vomiting, hyperventilation, tachycardia, seizure, coma and death Slightly remain unchanged when eliminated in the urine Treatment: patient kept in isolation, in a dark, quiet room.  Treatment with haloperidol (Haldol) results in sedation Barbiturates: Street names: Lily, bala, downers, yellow jackets, blue heavens Major metabolite: Secobarbital Sedative hypnotic, Potentiate heroin Screening test: Immunoassay or TLC Confirmatory test: GC-MS Symptoms of abuse: slurred speech, slowing of mental functions, constricted pupils CNS depression

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Barbiturates are depressants (sedatives or hypnotics) Fat-soluble; pass easily across the BBB Includes the following: o Phenobarbital—long lasting barbiturate used as an anticonvulsant as it reduces the excitability of rapidly firing neurons. o Pentobarbital—short acting Toxic manifestations: depression, cyanosis, hypothermia, hypotension, Cheyne-Stokes respiration

Marijuana Street name: pot, mary Jane, Mr, weed, grass, puff, nangga Psychoactive ingredient: ∆ - tetrahydrocannabinol From dried leaves and flowers of Indian Hemp (Cannabis sativa) Route of administration: Usually smoked but may be ingested orally in brownies and on other foods Death cases may be due to suicides Detectable in urine for several days to a week after single exposure, but in a heavy long term user, it may remain detectable for 21 — 30 days after last dose. Abstinence of 1 time user: can be detected up to 5 th day Heavy users: 21 – 30 days (chronic) Users experience feeling of paranoia, sense of relaxation, mild euphoria and relief of anxiety. High doses may cause: anxiety, fear and paranoia, delusions, depression, disorientation, hallucinations, confusion Psilocybin  Component of magic mushroom  Halucinogen

Toxic agents: Acute toxicity: single short term exposure to the substance Chronic toxicity: repeated exposure Alcohol -

CNS depressant Causes disorientation, euphoria, confusion and may progress to unconsciousness, paralysis and even death Symptoms of alcohol intoxication begin when the concentration is > 0.05% w/w (> 50 mg/dL blood alcohol)

Ethanol (grain alcohol) Most commonly abused drugs Major metabolic pathway: Readily absorbed in the Gil and diffuses easily in tissues The abuse causes acidosis through accumulation of ketones and lactate and also through direct generation of hydrogen ions as alcohol is oxidized Chronic consumption: 50 g of ethanol per day for about 10 years Accumulation of lipids in hepatocytes, Alcoholic hepatitis, Cirrhosis, Adds osmolality to the blood, Inhibit ADH

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Symptoms of intoxication: Blurred vision, Incoordination Slurred speech, Coma, "hangover symptoms" —effects of acetaldehyde Antidote for chronic intoxication: diazepam (for alcoholic mania) Specimen precaution: specimen must be capped all the time to avoid evaporation of alcohol; alcohol-free skin cleanser must be used instead of isopropanol (Benzalkonium chloride) Specimen: serum Conversion of ethanol to acetaldehyde and acetyl coenzyme A by hepatic alcohol dehydrogenase Methods for testing: enzymatic (alcohol dehydrogenase reagent) [PREFFERED], Gas-liquid chrom, and electrochemical oxidation Common lab results: Elevated GGT, AST, AST/ALT ratio (de Ritis ratio), HDL and MCV Fatal dose: 300 400 mL of pure alcohol consumed in < 1 hour Peak: within 1 hr after intake toxic blood level: > 400 mg/dL; > 500 mg/dL (for hemodialysis)

Methanol (Wood alcohol) Common solvent and contaminant of homemade liquors Converted first to formaldehyde, then finally to formic acid in the liver by alcohol dehydrogenase Symptoms of intoxication: Frank blindness (ocular toxicity) and metabolic acidosis Preferred method: GC -MS Screening test: computation of osmolal gap Fatal dose: 60 - 250 mL Toxic blood level: > 50 mg/dL Isopropanol (Rubbing alcohol) Rapidly absorbed by the GIT Metabolized by the hepatic alcohol dehydrogenase to acetone Symptoms of intoxication: CNS depression and hypertension Preferred method: gas chromatography Antidote: activated charcoal Fatal dose: 250 mL Ethvlene glycol (1,2-ethanediol) Common constituent of hydraulic fluid and antifreeze Crystal of urine: calcium oxalate Converted to oxalic add and glycolic acid by hepatic alcohol dehydrogenase Symptoms of intoxication: Metabolic acidosis, Depressed reflexes, Anuria, Necrosis, Mode of treatment: inhibit the action of alcohol dehydrogenase Indication of toxicity: deposition of calcium oxalate crystals in the renal tubules Major metabolite: glycolic acid (acute toxicity and death) Preferred method: HPLC Fatal dose: 100 grams Carbon monoxide (CO) Colorless, odorless, tasteless gas Produced by incomplete combustion of carbon containing substances like gasoline engines, organic materials in fire and cigarette smoke Binds with heme Higher affinity to hemoglobin transport than oxygen Color of Blood: Cherry Red (acute) Stimulates production of nitrous oxide -> hypotension and neurologic changes Major toxic effect: Tissue hypoxemia or hypoxia Toxic level: 20% of carbon monoxide Indication for acute toxicity: Cherry Red (also on skin) Sample for testing: EDTA whole blood Definitive method for testing: cooximetry (carboxyhemoglobin) Cyanide (Metals) Common suicidal agent, Can be solid, gas, or in solution Super toxic substance (fast acting) Death may occur less than an hour Components of insecticides and rodenticides

Arsenic   -

Pyrolysis product — burning of plastics Toxicity if through binding to iron (ferric and ferrous) -> hypoxia Inhibition of electron transport and cell death Indication of toxicity: Odor of bitter almonds (breath) Toxic levels: > 2ug/mL (ingested in large quantities and absorbed in ionized form) Common suicide agent Ant poisons, rodenticides, paints and metal alloys Inhibits sulfhydryl enzymes; crosses the placenta Hair and nail ("MEES LINES") for long—term exposure Blood and urine for short — term exposure Indication of toxicity : Odor of garlic (breath and metallic taste) Acute fatal dosage: 120 mg (arsenic trioxide),30 ppm (arsenic gas) Antidote: British anti-lewisite(BAL) arsenic rescue of affected cells Test: Reinsch test, AAS

Cadmium Used in electroplating and galvanizing Pigment in paints and plastics Poisoning can be a result from ingestion of acidic foods stored or prepared in metal containers made up of cadmium Toxicity: destruction of epithelial cells in the lungs and accumulation in renal tubules ltai-itai disease: severe osteomalacia and osteoporosis from long term consumption of cadmium contaminated rice Half-life: 10-30 years Specimen: urine or whole blood Lab method: AAS Lead -

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Mercury -

Blocks delta aminolevulinic acid (ALA) synthetase, pyrimidine-5'nucleotidase, and Na-K---dependent ATPase Source: paints, gasoline Mode of acquisition: ingestion or inhalation Effects: anemia, birth defects, ADHD, low ICI Susceptible areas: CNS and PNS Toxicity: urinary ALA, free RBC protoporphyrin and basophilic stippling in RBCs Toxic dose: > 0.5 mg/day; fatal: > 70 ug/dL Chelation therapy: EDTA and dimercaptosuccinic acid (DMA) Toxic effects: Lead palsy Vit D and heme synthesis interference Diminished integrity of RBC membrane Combines with matrix of the bones (Half-life: 32 years) "wrist drop or foot drop" manifestation (peripheral neuropathy) Labs: o Whole blood: quantitative tests o Urine: recent exposure o Morning urine for delta ALA: diagnosis of lead poisoning o Serum or plasma should not be used Lab tests: o Screening: Zinc protoporphyrin test (fluorometric test), ALAD (D -ALA dehydratase test) — sensitive method o In vivo x-ray fluorescence of bones — lead burden o AAS and Inductively coupled plasma emission spectrophotometry (ICP- MS)

Binds with sulfhydryl proteins (change in structure and functions) Enzyme inhibitor Forms: elemental or metallic, mercurous, mercuric and alkyl Acquisition: inhalation, skin absorption, and ingestion Toxic effects: General: organ dysfunction, Elemental: pink disease (acrodyna) and erethism, Alkyl: congenital Minimata disease Samples: whole blood and 24-hr urine Route of excretion: bile Method: reinsch test; simple test to detect large amounts of mercury in urine (also for antimony, bismuth and selenium);

Pesticides Includes the organophosphates and carbamates Act by inhibiting the action of acetylcholinesterases, so acetylcholine accumulates at the neuromuscular junction

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