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Transcript
أهالً بكم يا سنة خامسة دعونا نتفق مقرر الطب الشرعى و السموم اإلكلينيكية 200درجة إمتحانان دوريان +إمتحان للمعرفة الشاملة %60عملى % 40 +نظرى تشمل درجة العملى على: 3إمتحانات عملية (طب شرعى +سموم +طبشرعى و سموم) تقارير طبية إصابية -أنشطة علمية General Toxicology Introduction Prof. Nahed Moustafa Head of Forensic Med.& Clinical Toxicology Department • A 3 -year-old girl was brought to the emergency department (ED) for evaluation of a seizure. Her mother stated that the child was previously well and had no other medical problems; 3hours ago the child looked tired and she noticed that there were missing tablets from the bottle of medication of her elder son. • On examination: the girl had a generalized tonic-clonic seizure that lasted approximately 1 minute; with vital signs of blood pressure, 90/50 mm Hg; pulse 160 beats/ min; respiratory rate 26 breaths/min. Her pupils were dilated and poorly reactive to light with dry mouth and dry flushed skin. ECG changes showed prolonged (QRS) interval. • The residents in ED decided that there should be rapid elimination of the toxic medication after stabilization of the case. One of them suggested that the girl needed immediate hemodialysis while the other suggested that she needed gastric lavage with multiple doses of activated charcoal. Toxic substance • Is any chemical that is capable of producing detrimental action on a living organism • As a result of damage, there is an alteration of structural components or functional process which may produce injury or death • Any chemical may be poisonous at a given dose and route of administration • Breathing too much pure oxygen, drinking excessive amount of water can cause poisoning or even death Acute toxicity: Subway passengers affected by sarin gas planted in central Tokyo (quoted from Evison et al, 2002). تسمم حاد(:لدغ الثعابين) األعراض الموضعية: • أثار اللدغ • اآلم موضعية • تورم األنسجة المحيطة • اآلم بالغدد الليمفاوية Opium: (acute/ chronic) Chronic Toxicity Chronic toxicity Copyright ©2004 BMJ Publishing Group Ltd. Maziak, W et al. Tob Control 2004;13:327-333 Diversity of Toxicology Occupational Forensic Environmental Veterinary Medical Pharmacokinetics: Important Definitions • Is the mathematical study of the drugs, • Describe dynamic changes in body drug concentrations regarding: -absorption -distribution -metabolism -excretion • Elimination = metabolism & excretion • Toxicokinetics: apply the previous def. in an overdosed pt. Pharmacodynamics • Is the interaction of the drug with biologic receptors & mechanisms of action • It is the basis for therapeutic or toxic effects Knowledge of pharmacokinetics & toxicokinetics • Allow the physician to plan a rational approach to the definitive management of the intoxicated patient after the Vital functions have been stabilized Imp Terms Volume of distribution (Vd) is: • Not a “real” vol • Hypothetical vol of body fluid that would be necessary if the total amount of drug were distributed at the same concentration as plasma • Vd = dose/ C Vd: liters or milliliters per kg dose: drug in milligram or gram C: peak conc (milligram, gram) per liter Blood concentration (C): • May be measured to determine if more specific measures are needed • C = dose / Vd Half- life (t ½): • Time required to reduce the bl. Conc. of the drug to half • T ½= 0.693 / Ke • Ke = elimination rate constant • Ke is the % of the total amount of drug in the body removed per unit of time & is a function of clearance and volume of distribution Vd • The apparent Vd is • When the Vd is large, useful as it relates the the tissue conc is plasma or serum conc large and the plasma of the drug to the total conc small amount of drug in the • When the Vd is small, body most of the drug • Vd is related to body remains in the plasma water Vd Vd is affected by: • Proportion of body fat • Protein binding of the drug - acidic agents bind to albumin - basic agents bind to alpha-1- glycoprotein • Tissue bindings of the drugs • Physiological & pathological conditions Vd in Toxicology: • Calculate the amount of substance in the body to help verify the history of the quantity ingested • Predict the peak bl conc of the drug • Decide whether to apply extracorporeal elimination of the toxic substance Vd - example A 60-kg patient presents with a history of ingestion twenty 100-mg phenytoin capsule 15 minutes ago. Will this patient develop manifestations of toxicity? Answer: Conc. = dose / Vd = 20 x 100 mg 0.75 litre/kg x 60 kg = 2000 mg/ 45 liters = 44.4 mg / liter Phenytoin toxicity is expected as this value is above the normal therapeutic range of 10-20 mg / liter Imp Terms Bioavailability is: • Relative amount of drug that enters the systemic circulation from an administered dosage form • The rate at which the drug appears in the systemic circulation Absorption Is the process by which the drug enters the body Absorption It depends on: • Route of administration • Dissociation (ability to become non-ionized, favoring absorption) • Dissolution (ability of solid dosage form to become soluble) • Concentration • Blood flow to the site • Area of the absorptive site Protein binding • Drugs are transported in the bloodstream either: - attached to carrier proteins - or unbound in solution (free drugs) • Bound drugs are unable to cross cell membranes & unable to exert biological effects • Free drugs are able to cross lipoprotein membranes & able to exert pharmacologic effects Metabolism • Is the biochemical transformation of a drug • It is the process by which the body transforms a drug & makes it more watersoluble so the drug can be eliminated more rapidly via the kidney into urine • Biotransformation can produce metabolites that are active & toxic. Ex; parathion is metabolized to parathoxon, its toxic metabolite Excretion • Is the final means of drug elimination either as metabolites or unchanged parent drug • Excretion through the lungs is the major route for gaseous substances • Kidneys are the most imp route of excretion of nonvolatile water-soluble drugs • Additional routes include sweat, saliva, milk, bile and feaces Excretion Entero-hepatic circulation: • Drugs & chemicals excreted into the bile enter the intestine and are either reabsorbed into the blood or eliminated in the feces • Some drugs are excreted as water-soluble glcuronide conjugates that are hydrolyzed by intestinal bacteria resulting in reforming of the parent drug or metabolite that is reabsorbed into the blood • This process of excretion into bile & reabsorption into the intestine is known as enterohepatic circulation Excretion: entero-hepatic circulation: • Examples: digitalis, DDT derivatives, INH, nonsteroidal antiinflammatory, phenothiazines, TCAs, salicylates • Repeated doses of activated charcoal have been shown to be effective by preventing reabsorption • Continuous gastric lavage is also effective Ion trapping • Drugs can be weak acids or bases • They become ionized in solution when they lose or gain a hydrogen ion • Ionized (polar) compounds do not easily cross cell membranes & so they become trapped in the compartment in which they are more ionized • Weak acids (aspirin) is better reabsorbed in acidic media and better excreted in alkaline media • Alkalinization with sodium bicarbonate is used to hasten the excretion of salicylates • Weak bases (amphetamine) is better reabsorbed in alkaline media and better excreted in acidic media • Acidification of urine is no longer used General Toxicology (2) Prof. Nahed Moustafa Head of Forensic Med. & Clin. Toxicology Dep. The Emergency Management of Poisoning Poison: is a substance that usually kills, injuries, or impairs an organism The General Approach to Poisoning: • Emergency management • Clinical evaluation • Elimination of poison from (GIT, skin, eyes….) • Elimination of the absorbed part • Antidotes • Supportive therapy • Observation and disposition (1) Emergency Management • Airway: adequate ventilation & perfusion • Rapid intubation if needed • Maintenance of all vital signs (temp,….) • IV line: - Naloxone: 2 mg IV - Thiamine: 100 mg IV - Dextrose: 50%, 50 ml IV • Antidotes: if needed: mentioned later (2) Clinical Evaluation: History & Physical Exam Poisoning should be suspected in any patient with multi-system involvement until proved otherwise (2) Clinical Evaluation: History & Physical Exam • Acute poisoning often presents with: - coma - cardiac arrhythmia - seizures - metabolic acidosis - GIT disturbance - Toxidromes or as isolated events (2) Clinical Evaluation: History & Physical Exam Toxidromes: • Coma + pinpoint pupils + fasciculation + secretions = cholinergic (o.ph., nicotine, carbamate) • Coma + pinpoint pupils + hypothermia + hypotension = opioids • Hallucinations + dilated pupils + fever + dry skin+….= anticholinergics (atropine, antihistaminics….) (2) Clinical Evaluation: History & Physical Exam History: • What? • When? • How much? - Sudden appearance of symptoms in a healthy person - History of drug, poison intake - Symptoms in a group of persons after sharing food (2) Clinical Evaluation: History & Physical Exam Clues on Ph. Exam: • Needle tracks (IV drug abuser) • Bullous lesions (CO, barbiturates) • Odour (kerosene, alcohol) • Perforated nasal septum (cocaine) • Pul. Edema (heroine) • Salivation & lacrimation (O. Phs) (2) Clinical Evaluation: History & Physical Exam Metabolic acidosis: • Assessment: ABGs, serum Na, K, Cl, BUN, creatinine, glucose, urine pH, anion gap • Shown in: methanol, ethanol, cyanide, iron, salicylates, INH Cardiac arrhythmia: • T.C.A.D • Cocaine • Digitalis • CO • Phenothiazine • Beta blockers (2) Clinical Evaluation: History & Physical Exam Seizures: • Anticholinergic • Cocaine • O.Phs • CO • T.C.A.D • Theophyline • TTT: diazepam 10 mg IV, phenytoin or barbiturates Laboratory evaluation: • Acid base balance • CBC • Serum electrolytes • Bl. Conc. Of the drug • Remember “ treat the patient not the lab” (3) Elimination of the Poison GIT decontamination: • Preventing the absorption of toxin is the main line of ttt after ingestion of a toxin has occurred • GIT decontamination = * gastric emptying (emesis, gastric lavage) * adsorbent * catharsis (3) Elimination of the Poison Emesis: The following are not used now: • Apomorphine (CNS dep. , injection) • Cu sulphate (very toxic) • Warm water + salt (hypernatremia) (3) Elimination of the Poison Emesis: Ipecac: • Dried roots of Cephaelis Ipecaunha Plant • Formed of: * emetine: local and central effects – long half life – cumulative toxicity * cephaline: twice potent than emetine in producing vomiting – direct action (3) Elimination of the Poison Ipecac: • Forms: * fluid extract (14 times conc than syrup, very toxic) * syrup (form of choice) • Contraindications: * non toxic subs * non toxic amount * vomiting * corrosives * coma * seizures * loss of protective airway reflexes * pregnancy (3) Elimination of the Poison age Ipecac dosage 0-6 months no ipecac 6-12 months 10 ml, not repeated 1-12 years 15 ml, repeated in 20 min 13 years….. 30 ml, repeated in 20 min (3) Elimination of the Poison Adsorbent: activated charcoal: • Carbonaceous materials (eg; wood, coal, starch) exposed to steam (600900 C) which produces great surface area. Surface binding area = 900- 1500 m2/g • Super-activated charcoal: 3 folds surface area of A. C • Dose: 1 g/ kg (3) Elimination of the Poison Contra-indications of AC: - Substances not well adsorbed by AC: • Alcohols (ethanol, methanol) • Hydrocarbons (kerosene) • Corrosives • Metals & inorganic minerals - Intestinal obstruction, perforation or ileus (3) Elimination of the Poison Indications of multiple dose activated charcoal (MDAC): • Drugs having enterohepatic circulation: digoxin, TCA • Drugs still present in the gut as: * slow release preparations: theophylline * produce concretions: salicylates * slow GI motility: anti cholinergic (3) Elimination of the Poison Catharsis: • Enhance the passage of materials through GIT thus decrease the time of contact between the poison & absorptive surface • Should be avoided in fat soluble poisons as O.Phs or CCl4 (3) Elimination of the Poison Catharsis: types: • Osmotic: Mg sulfate: 15-30 g in glass of water • Irritants: castor oil: 60-100 ml Complications: • Dehydration: imp in extreme of ages • Electrolyte imbalance Contraindications: • GIT hemorrhage • Recent bowel surgery • Intestinal obstruction • Renal failure: Mg load (3) Elimination of the Poison Dermal exposure: • Many poisons can be absorbed through skin: OPhs, hydrocarbons • Remove all clothing • Wash skin with soap& water for 30 min • Do not use forceful flushing of shower as it may scratch the skin & increase absorption (3) Elimination of the Poison Eye exposure: • Wash conjunctiva with running water or saline up to 20 minutes • Solid corrosives should be removed first by forceps • Consult ophthalmologist (3) Elimination of the Poison Elimination of inhaled poison: (CO) • Remove the patient to fresh air, the rescuer should use wet mask • Care of respiration after cleaning the mouth, O2 inhalation… Antidotes Chemical Physical Physiological Antagonism Competitors Chelators Antidotes Physical: • Dilution: water in corrosives • Dissolvent: castor oil in phenol • Adsorbent: activated charcoal Antidotes Chemical: • Neutralization: not used • Precipitation: *tannin for plant alkaloids *albumin for Hg *starch for iodine *Ca hydroxide for oxalic acid • Oxidation: *pure oxygen for CO *M blue& amyl nitrite for cyanide • Reduction: *Na thiosulfate for cyanide Antidotes Physiological: • Antagonism: *atropine (physostigmine) *digitalis (digibind- digoxin immun fab) *O Ph (atropine- oximes) • Competitors: *morphine (naloxone) *methanol (ethyl alcohol) • Chelators: *BAL, EDTA, DMSA, D.pencillamine