Toxicology PDF

General Toxicology Toxicology: Literally, it means a study of poisons on living organisms. The term is derived from Greek and Latin origins (L. toxicum = poison; G. toxikom = arrow poison; L. logia = science or study). Toxicology deals with: a) Source b) Kinetics c) Action d) Diagnosis [c...

General Toxicology Toxicology: Literally, it means a study of poisons on living organisms. The term is derived from Greek and Latin origins (L. toxicum = poison; G. toxikom = arrow poison; L. logia = science or study). Toxicology deals with: a) Source b) Kinetics c) Action d) Diagnosis [clinical effects, DD and laboratory investigations] e) Prevention and Treatment of poisoning. N.B. All substances known to man are poisons, and only the dose determines the effect. [e.g. Therapeutics are considered poisons if given in large doses]. Classification of poisons: Poisons are classified according to the followings: 1- Nature: solid, liquid and gaseous poisons. 2- Site of action: a) local [Inorganic corrosives] b) Remote [Alkaloids and most Therapeutics] c) Local & Remote [Metals and Organic Corrosives] 3- Target organ:  Central Nervous System (CNS) CNS stimulants e.g. Amphetamines, cocaine, strychnine. CNS depressants e.g. Hypnotics, narcotics, alcohol and anesthetics. Classification of poisons: 3- Target organs  GIT: e.g. Metals and Corrosives.  Kidneys: Mercury, phenol and Cadmium  Liver: Paracetamol, Iron and carbon tetrachloride.  CVS: Digitalis and aconitine  Lungs: Metal fumes  Factors Modifying Toxic effects  Factors related to the poison [Pharmacokinetic factors]: The state of the toxic agent: The dose: Route of administration: The descending order of toxicity of the other routes includes; inhalation > IV > intraperitoneal > subcutaneous > intramuscular > intradermal> oral >topical. Cumulation: i.e. the rate of intake exceeds the rate of elimination e.g. digitalis. Chemical interaction: Addition i.e. he chemicals involved added to the effects of each others (1+1=2) e.g. Aspirin + paracetamel (doubled analgesic effect) Synergism: when one chemical increases or markedly exaggerates the effect of another (1+1= 3) e.g. Alcohol + Barbiturate (severe CNS depression) Antagonism: when one chemical diminishes or completely abolishes the effect of another. e.g. BAL +Lead Metabolism of toxic agent: Unfortunately, some poisons are metabolized to equally active or even more active compounds e.g. methanol gives rise to formaldehyde and formic acid which are more toxic compounds.  Factors Modifying Toxic effects  Factors related to the patient [Host factors]:  G.I.T: pH of stomach : increased gastric acidity enhances acid poison toxicity (e.g. aspirin). While, achlorhydria decreases toxicity of potassium cyanide. Amount of food Type of food  Age  State of health  Toxicogenetics [Idiosyncrasy] Abnormal response to drugs. Hereditary basis e.g. favism & sulphonamide in G 6-P D patients lead to hemolytic anemia hypersensitivity = Allergy Exaggerated response to the drug e.g. Aspirin or penicillin. It is an antigen- antibody reaction.  Tolerance Diagnosis of poisoning  History  Clinical examination  Laboratory investigations Diagnosis of poisoning History Sudden appearance of symptoms in a healthy person. Symptoms appearing in a group of persons taking the same food. History of recent purchase of a poison or the presence of syringe, drug or empty bottle nearby the patient. History of failure, financial or emotional troubles or presence of suicidal note. Diagnosis of poisoning Clinical examination Vital signs [BP, pulse, Resp, Temp]. very dilated or pinpoint pupils ~ Neurological examination + pupil’s state. Chest + Abdomen. Skin + smell of breath. N.B. Toxidromes:. (Toxic Finger prints) are signs & symptoms that are observed after an exposure to a substance which are helpful to establish a diagnosis. Diagnosis of poisoning Laboratory investigations A) In living + dead persons: Qualitative and Quantitative analysis of the poison from: [Blood, urine, vomitus, stool, hair, nail] and organs from dead only B) In living only ECG+EEG. Electrolytes and arterial blood gases (ABG) Liver+ Kidney Functions, etc. Diagnosis of poisoning Postmortem picture Search for:  Stomach: Smell (phenol, opium, organophosphorus and cyanide) Ulcers ( corrosives) Seeds or tablets  Skin: Smell Eschars [colored ulcers] (black in sulphuric acid, yellow in nitric, white turns brown in phenol) Site of injections [In addicts] Diagnosis of poisoning Postmortem picture Search for: Brain: For edema or congestion (CO)  Respiratory system: For signs of asphyxia (barbiturates, opium, CO and HCN)  Postmortem changes: Hypostasis Rigor Mortis (earlier in convulsants e.g. amphetamines and strychnine) Putrefaction ‘( delayed in dehydration as in arsenic poisoning) Coma & the poisoning N.B. Causes of coma: Toxic (CNS depressants, anticholinergics and toxin causing cellular hypoxia e.g. HCN & CO) Pathologic (hepatic failure, renal failure, metabolic e.g. hypoglycemia, hypertensive encephiopathy, etc.) Traumatic (head injuries). Coma & the poisoning Coma scales: I- Rapid evaluation of the level of consciousness AVPU system: it is a rapid mean of documenting the level of consciousness (A=alert, V=verbal response, P= response to pain and U = unresponsive). II- Definitive monitoring of toxic coma: In definitive monitoring of toxic coma some prefer to use Reed’s coma scale, as Glasgow coma scale overestimates the degree of impairment. Coma & the poisoning Reed’s coma scale Scale 0 1 2 3 4 Deep Conscious level Sleep Stupor Coma Coma coma Answer questions Painful stimuli Reflexes No respiratory or circulatory depression Treatment of poisoning I- Supportive therapy II- Gastrointestinal Decontamination III- Elimination of the poison from the blood IV- Antidotes Treatment of poisoning Treat the patient not the poison Treatment of poisoning I- Supportive therapy = [Treat the patient not the poison] = [Support the ABCs]  Airway [keep it patent] by: 1- Head: extended 2- Tongue: prevent from [falling back against the pharynx by using oropharyngeal tube 3- Dentures or foreign bodies: Must be removed 4- Tubes for: Suction of secretions Endo tracheal tube in case of prolonged coma Tracheostomy tube in upper airway obstruction. Treatment of poisoning I- Supportive therapy  Breathing [O2 therapy] by: Simple Face mask Nasal cannula Mechanical ventilation Treatment of poisoning I- Supportive therapy Circulation: - Hypotension mast be treated by IV fluids. Drugs. - Vasopressors [Dopamine] - Inotropics [Digitalis] - Arrhythmia must be treated by : Antiarrhythmic Drugs. [lidocaine. phenytion etc..] Treatment of poisoning I- Supportive therapy  CNS : [Altered Mental status] Coma cocktail should be used as diagnostic or therapeutic agents. 1) Dextrose : All comatosed patients should receive concentrated dextrose unless hypoglycemia is excluded by an immediate bedside test. 50m1 of a 50% solution I.V. 2) Thiamine :100mg I.V. for possible Wernick’ s encephalopathy in alcoholics. 3) Naloxone [Narcan] : 2mg IV. For adult & 0.03mg/kg IV for children [To exclude opiate overdose]. Treatment of poisoning II) Gastrointestinal Decontamination [i.e Removal of the poison from GIT& prevention of absorption] The three general methods of G.I.T decontamination Involve: Gastric emptying by [emesis or gastric lavage). Activated charcoal (AC) [adsorbs the poison & prevents its absorption]. Cathartics & whole bowel irrigation (WBI) [they enhance excretion of poisons from the GIT]. Treatment of poisoning II) Gastrointestinal Decontamination [i.e Removal of the poison from GIT& prevention of absorption] Emesis Definition: Removal of the stomach contents by inducing vomiting. Indication: Recent ingestion of substances [within 3 hours post ingestion]. Methods of emesis: A - Mechanical B- Chemical: Peripherally acting. Centrally acting. Mixed [Peripherally + centrally]  Contraindications of emesis Patient Poison CNS. Problems: a) Coma: fear of asphyxia & aspiration pneumonia. b) Convulsions: as it may induce new attack of convulsion. * Chronic poisoning Serious CVS diseases: [as it will cause electrolyte * Corrosives [Inorganic]:- fear of perforation imbalance and effort on heart] * Volatile hydrocarbons [kerosene] :-fear of * GIT problems: aspiration pneumonia. * Poisons result in rapid onset of CNS depression -Varices [as it will cause bleeding] [phenol]:- - Recent gastric operation. absent gag reflex and fear of aspiration pneumonia. Infants under 6 months ( poor gag and air way protective reflexes) or neurologically impaired patients: (poor air way protective reflexes) Treatment of poisoning II) Gastrointestinal Decontamination [i.e Removal of the poison from GIT& prevention of absorption] Gastric Lavage Definition: Removal of the stomach contents by washing using a tube. Indication: Recent ingestion of substances. [Within 3 hrs post ingestion & emesis failed]. But it may be useful as long as 12 hrs post ingestion in some poisons as: Poisons which stick to stomach [Salicylates make aspirin cake]. Poisons which slow down motility of stomach [Barbiturate]. Poisons which secreted in stomach [Morphine]. Treatment of poisoning II) Gastrointestinal Decontamination [i.e Removal of the poison from GIT& prevention of absorption] Contraindications of gastric lavage [are the same as for emesis] except: Coma & volatile hydrocarbons - Lavage is allowable after inserting a cuffed endotracheal tube to prevent aspiration pneumonia. Convulsions - Lavage can be performed under general anesthesia. Cardiac dysrhythmias must be controlled before gastric lavage is initiated, as insertion of the tube may create vagal response - cardiac arrest Treatment of poisoning II) Gastrointestinal Decontamination [i.e Removal of the poison from GIT& prevention of absorption] Procedure of gastric lavage The tube: Rounded with multiple holes on the sides of its tip 1.5rnetre in length, 1.5cm in diameter It has a mark at a distance of 50cm from its lower end, which is the distance between the front of teeth & epigastrium. Treatment of poisoning II) Gastrointestinal Decontamination [i.e Removal of the poison from GIT& prevention of absorption] To be sure that the tube is in the stomach and not entered the trachea must be assessed by: 1) No cough, dyspnea or cyanosis. 2) Aspiration brings up gastric contents. 3 ) Absence of bubbling when the end of the tube is immersed in water during expiration, but present only during inspiration. 4) No Breath sounds can be heard from the end of the tube. Treatment of poisoning II) Gastrointestinal Decontamination [i.e Removal of the poison from GIT& prevention of absorption] Activated charcoal - Can be used alone. after emesis and with or after gastric lavage. Source: it is manufactured by pyrolysis of wood or other carbonaceous material which is then oxidized at high temperature using steam, air, Co2 or o2 to enhance pore development. The final product has surface area of 950-2000 m2/g. Action: The charcoal particles have many pores& holes [One molecule of A.C adsorb 10 molecules of poisons] which adsorb (bind) poisons in GIT and hence decrease their absorption. Dose: 50gm — 100gm in adults [orally, mixed with H2o] 15gm — 30gm in children. Treatment of poisoning II) Gastrointestinal Decontamination [i.e Removal of the poison from GIT& prevention of absorption] N.B. Poisons poorly adsorbed by Activated Charcoal: C--Cyanide and Corrosives. H--Heavy metals (Iron, Lead, Arsenic, Lithium and Mercury). A--Alcohols. R--Rapid onset or absorption (Cyanide and Strychnine). C--Chlorine and iodine. O--Others insoluble in water (substances in tablet form). A--Aliphatic and poorly adsorbed hydrocarbons (petroleum distillates). L--Laxatives (sodium, magnesium and potassium) Treatment of poisoning II) Gastrointestinal Decontamination [i.e Removal of the poison from GIT& prevention of absorption] Cathartics [Purgatives] The commonly used cathartics are magnesium sulphate, magnesium citrate and sorbitol (some commercial preparations of A.C. come premix with sorbitol). Types: Osmotic cathartics: MgSO4 30gm in adult 250 mg/kg in children or Sorbitol 1g/kg only once. Oil cathartics: Castor oil. Treatment of poisoning II) Gastrointestinal Decontamination [i.e Removal of the poison from GIT& prevention of absorption] Whole bowel irrigation Definition: Irrigation of the entire GIT non absorbable isotonic electrolyte solution containing Polyethylene Glycol through nasogastric tube until the bowel has been cleansed rapidly of the poison. Indications: Poorly adsorbed drugs by Activated Charcoal [see before] Preparations which are slow release e.g. Salicylates and Calcium channel blockers Packets of illicit drugs (e.g. Cocaine or Heroin). Treatment of poisoning III- Elimination of the poison from the blood (enhanced elimination)  Forced diuresis and alteration of the urine pH (ion trapping):  Extracorporeal methods which include:  Dialysis: Hemo [Artificial kidney] or Peritoneal.  Haemoperfusion.  Plasmapheresis.  Treatment of poisoning III- Elimination of the poison from the blood (enhanced elimination) a) Forced dieresis Definition: Removal of the poison from the blood through increasing the glomerular filtration rate. Types: Osmotic: Mannitol (20%) Fluid: DNS The objective is to maintain a urine output of 300-500ml/hr or 8-14 L/day.  Treatment of poisoning III- Elimination of the poison from the blood (enhanced elimination) b) Alteration of the urine pH (ion trapping) Definition: Changing PH of urine making the poison ionized “ion trapping” [i.e. poison can’t be reabsorbed through the cells of the renal tubule as ionized drugs are poorly absorbable through cell membranes] this will lead to increase Excretion. Principles of ion trapping: Alkalinization of urine in acidic drugs e.g. salicylates and barbiturates. Solution: [NaHCo3] 1-2 mg/ kg/ in 5% dextrose Keep urine pH 7.5-8.0 Acidification of urine in alkaline drugs e.g. Amphetamine, Quindine and PCP. Treatment of poisoning III- Elimination of the poison from the blood (enhanced elimination) Dialysis (hemo- & peritoneal) Indications: like N said 1) Renal failure and the poison is excreted by kidneys - 2) Liver failure and the poison is metabolized by the liver 3) Prolonged coma Contraindications: 1) Non - dialyzable drugs or poisons 2) Presence of coagulopathy. 3) Pregnancy in case of peritoneal dialysis. Treatment of poisoning III- Elimination of the poison from the blood (enhanced elimination) Hemoperfusion Indications: For clearing toxic substances that are poorly eliminated by dialysis [Non dialyzable substances] i.e. High molecular weight. High lipid solubility. High protein binding. Low water solubility. Contraindications: If the toxic agent cannot effectively be absorbable to charcoal. Treatment of poisoning III- Elimination of the poison from the blood (enhanced elimination) Plasma pharesis Mechanism: A volume of blood is removed, and all blood components except the plasma are returned to the circulation. The plasma is replaced with a crystalloid solution. Indications: Toxins which are poorly dialyzed or filtered. Contraindications: Bleeding disorders. Treatment of poisoning IV- Antidotes (I) Local (II) Physiological [systemic] A) Physicomechanical e.g. Chelators B) Chemical * EDTA * BAL * DMSA & DMPS * Penicillamine * Deferoxamine Treatment of poisoning IV- Antidotes Physicomechanical Adsorbents Delmulcents Entanglers Dissolvents Protect the Dissolve the Used to adsorb stomach Catch the poisons. the toxic agents mucosa by solid objects e.g. Ethanol 10% coating it e.g. Activated e.g. cotton used to dissolve e.g. Milk & egg charcoal for pins phenol white Treatment of poisoning IV- Antidotes (chemical) (1) Neutralization (2) precipitation (3) Reduction (4) Oxidation * Weak alkalis used to neutralize acidic corrosives. [obsolete] Mercuric chloride *Weak acids used to [divalent, toxic] *Ca ppt. Oxalic acid neutralize alkaline *MgSo4 ppt Lead Is reduced Oxidation by H2O2 or corrosives. [obsolete] by Na Due to:- KmnO4 1/5000 formaldhy de (1) Exothermic heat used for: *Skimmed milk ppt sulfoxylate reaction increase mercury *Plants destructive effect Mercurous *Cyanide * Tannic acid (strong (2) Co2 formation chloride tea) ppt plants [Monovalent, non when NaHCo3 is used, toxic) gastric perforation occurs. Alcohol Ethyl Alcohol [Ethanol] Alcohol Ethanol is one of the oldest drugs recognized by man and is the primary alcohol present in beers, wines and distilled spirits. Ethanol is a clear, colorless liquid that has a very slight pleasant odor. Source: From fermentation of sugar. Ethyl Alcohol [Ethanol] Alcohol Uses: Beverages: e.g. wines and whisky. Over — the counter products: - Mouth washes. - Aftershave lotions. - Hair sprays. - Cough and cold preparations. Solvent Ethyl Alcohol [Ethanol] Alcohol Pharmacokinetics of ethanol: Absorption: Major (80%) (from small intestine) Minor (20%) (From stomach & large intestine) Distribution: - To all tissues and body fluids, and parallels the water content of each. - Passes the blood brain barrier. - Passes placenta. Metabolism: 90-98% of the absorbed ethanol is removed from the body by enzymatic oxidation primarily in the liver but to a lesser extent in the kidney. Ethyl Alcohol [Ethanol] Alcohol Pharmacokinetics of ethanol: Excretion: 2-10% Ethanol excreted unchanged through. - Urine. - Breath. - Small amounts can be detected in sweat, tears, bile, gastric juice and other secretions. Ethyl Alcohol [Ethanol] Alcohol Conditions of poisoning: Accidental: - Addicts. - Children. -Workers. Homicidal: to facilitate rape & robbery (as barbiturates). Suicidal: rare Ethyl Alcohol [Ethanol] Alcohol Mechanism of action: Lowers your reaction time  CNS: depression is the principal effect of ethanol. Ethanol exerts its action through direct effect on neuronal membrane possibly due to inhibition of Na- K- ATP. The effect of ethanol on the CNS is directly proportional to the blood concentration.  Peripheral: Vasodilatation false sensation of heat (Central thermal auto regulation is inhibited, so temperature is low).  Ethanol metabolism leads to significant decrease in NAD/ NADH ratio in the liver. This results in: - Significant hypoglycemia partly due to inhibition of gluconeogenesis - Reduction in the metabolism of glycerol, resulting in accumulation of fat in the liver. - Accumulation of lactic acid & ketoacids [metabolic acidosis]. Ethyl Alcohol [Ethanol] Alcohol Toxic dose: - Generally, 0.7g/kg of pure ethanol will produce a blood level of 100mg/dL which is considered legally intoxicated. - The level sufficient to cause deep coma or respiratory depression is highly variable, depending on the individual’s degree of tolerance to ethanol. Although levels above 300 mg/dL usually causes coma in novice drinkers, chronic alcoholics may awake with levels of 500-600 mg/dL or higher. Ethyl Alcohol [Ethanol] Alcohol Clinical presentation: Depends on blood Ethanol level 1) Mild toxicity: [stage of excitation] - Blood alcohol level ranges between 0.05 - 0.15%. - There is Inhibition of centers which control judgment & behaviors. - Euphoria. - Talkativeness and behavioral changes. Ethyl Alcohol [Ethanol] Alcohol Clinical presentation: 2) Moderate toxicity: [stage of incoordination] - Blood alcohol level ranges between 0.15 - 0.3%. Motor incoordination: - Drunkard (staggering) gait. - Tremors of hands. - Slurred speech. - Decreased motor skills. Diaphragm: Sudden contraction - Hiccough. Eyes: Diplopia. GIT: vomiting. Skin: flushed (alcohol flush). Ethyl Alcohol [Ethanol] Alcohol Clinical presentation: 3) Severe toxicity: [stage of seizures & coma] - Blood alcohol level is more than 0.5%. - Severe depression of medullary centers. Seizures. Shock: - Temperature ( ) - B.P ( ) - Pulse (rapid & weak). - Resp. (rapid & shallow). Breath: Alcoholic smell. Pupil : McEwen’s sign [constricted pupil that dilate on pinching the skin of face or neck]. Coma with respiratory depression. Cause of death : Central asphyxia. Ethyl Alcohol [Ethanol] Alcohol Investigations:  Rapid tests  Chemical analysis  Blood chemistry Ethyl Alcohol [Ethanol] Alcohol Investigations:  Rapid tests: Finger to nose test. To walk along a straight line. Buttoning and unbuttoning.  Chemical analysis: to detect alcohol in: Breath [Breath analyser] used by police. It is simple colorimetric test that gives relative accurate approximation of the blood alcohol level. Urine. Blood.  Blood chemistry: There is ketoacidosis. Ethyl Alcohol [Ethanol] Alcohol Treatment:  Supportive measures [ABCs] see general toxicology. Top priority should include care of respiration (insure patent airway, oxygen therapy and assisted ventilation if necessary).  GIT Decontamination Gastric lavage by NaHCo3 , leave strong coffee in the stomach at the end of lavage. Activated charcoal not bind Ethanol so not used Elimination of the absorbed poison Forced alkaline diuresis [see general toxicology] Haemodialysis is very effective (Ethanol has small Vd & low molecular weight). It is indicated in: Severe intoxication, Acid-base and /or electrolyte disturbance. Ethyl Alcohol [Ethanol] Alcohol Treatment:  Antidotes: No specific antidote, but Vit B6 may accelerate ethanol metabolism through stimulation of alcohol dehydrogenase enzyme.  Symptomatic: Metabolic acidosis: NaHCo3 Hypoglycemia: 10-50% dextrose solution IV. Hypothermia: Warming the patient. Shock : fluid expansion and dobutamine. Methyl Alcohol [Methanol] “Wood alcohol” Alcohol Methanol is the alcohol with the simplest structure, but the one most likely to cause serious human toxicity. Source: From distillation of wood. Uses: It is used to adulterate ethyl alcohol [cheap, tax free] Solvent, fuel, paint remover, household cleaners. Methyl Alcohol [Methanol] “Wood alcohol” Alcohol Pharmacokinetics of methanol: Absorption: Rapidly and completely absorbed from the GIT. Inhalation and cutaneous absorption are also reported. Distribution: - As Ethanol. - Distributed mainly to optic nerve. Metabolism: (90% in liver) Excretion: - Mainly through liver, other routes include kidneys and lungs. NB: Metabolism (1/7- 1/5 that of ethanol) & Excretion of Methanol is slower than Ethanol [Cunmulation] Methyl Alcohol [Methanol] “Wood alcohol” Alcohol Conditions of poisoning: Mainly: Accidental: - Drinking adulterated Ethanol. - Children. - Workers. Methyl Alcohol [Methanol] “Wood alcohol” Alcohol Mechanism of action: CNS depressant (more than Ethanol) G.I.T irritation Metabolic acidosis due to accumulation of formic acid (six times more toxic than methanol) and lactic acid which is generated by lowering of hepatic NAD/NADH ratios). Ocular toxicity (formic acid inhibits cytochrome oxidase in the optic nerve resulting in cellular ischemia and obligatory anaerobic metabolism). Methyl Alcohol [Methanol] “Wood alcohol” Alcohol Clinical presentations: Visual : Visual blurring, ocular pain, papilledema, optic atrophy and irreversible blindness (25% of the cases). Metabolic Acidosis : Moderate to severe, is secondary to the toxic metabolites of methanol. It is responsible for the tachypnea (air hunger), confusion. headache and weakness. Severe metabolic acidosis may produce life threatening hyperkalemia. Gastrointestinal: Vomiting, abdominal cramps and dehydration. Methyl Alcohol [Methanol] “Wood alcohol” Alcohol Clinical presentations: CNS: - Disorientation, Stupor and Coma: It is caused by acidosis and accumulation of formic acid in the CSF. - Convulsions (serious). - Encephalopathy. - Respiratory Depression follows air hunger (acidotic breathing). It is correlated with severity of acidosis and coma. Shock Due to depression of VMC, severe vomiting and myocardial depression secondary to acidosis and hyperkalemia. Methyl Alcohol [Methanol] “Wood alcohol” Alcohol Investigations: Serum methanol level. Fundus Examination and Visual Evoked Potential: Initial and serial examinations are essential to assess optic nerve affection. Arterial blood gases and serum electrolytes to monitor acidosis and hyperkalemia. Cause of death : Central asphyxia Methyl Alcohol [Methanol] “Wood alcohol” Alcohol Treatment:  Supportive measures [ABCs] Oxygen, Airway, Breathing, Circulation support.  GIT Decontamination Gastric lavage by NaHCO3. Activated charcoal not bind Methanol so not used.  Elimination of the absorbed poison:- Forced alkaline diuresis Haemodialysis is indicated in: History of ingesting 30ml [0.4mg/Kg] Methanol blood level > 20 mg / dL Visual symptoms. Severe metabolic acidosis. Methyl Alcohol [Methanol] “Wood alcohol” Alcohol Treatment:  Antidotes: Ethanol: - It compete with methanol for alcohol dehydrogenase enzyme (higher affinity to ethanol), to inhibit its metabolism to its toxic metabolites -Dose: l gm/kg/30min of 10% solution, followed by 0.5 gm/kg/4 hours to maintain blood ethanol at l00-l50mg/dL 4-methyl pyrazole (4-MP): - Strong inhibitor of alcohol dehydrogenase enzyme, blocking methanol metabolism to its toxic metabolites, and allowing methanol to be excreted as parent compound. - Advantages: It doesn’t cause CNS depression like ethanol. - Dose: 15mg/kg. Methyl Alcohol [Methanol] “Wood alcohol” Alcohol Treatment: Folinic acid (leucovorin) and folic acid: - For conversion of formic acid to Co2 & H20. -Dose: 50mg/4hrs IV.  Symptomatic: Metabolic acidosis: NaHCo3 Hypoglycaemia: 10-50% dextrose solution IV. Hypothermia: Warming the pateint. Shock : fluid expansion and dobutamine. Convulsions: Diazepam. Thank y u Paraphenylene Diamine (PPD) Hair dye poisoning Paraphenylene diamine (PPD) has been used internationally as a key ingredient in different hair dye formulations to produce a variety of shades depending on its concentration  In Sudan PPD is used by women to color their hair and as a dye when added to henna (Lawasonia alba) to color the palms and soles  The toxicity of PPD occurs through skin absorption  It is well known that PPD is an allergen  Its major systemic problem occurs when ingested accidentally, or during self harm or homicidal acts Toxic dose is 3-5mg.  Systemic poisoning Acute poisoning with PPD causes a characteristic: – Severe oedema of the face and neck often requiring tracheostomy, – Swollen dry hard tongue – Chocolate brown color of the urine PPD intoxication is a multisystem poison and can cause rhabdomyolysis and acute renal failure (ARF) Flaccid paralysis, severe gastrointestinal manifestations, cardiotoxicity and arrhythmias were also reported This form of severe intoxication is fatal if not treated aggressively  There is no specific antidote available  Clinical Presentation Clinical symptoms Percentage Oedema 94% Acute respiratory insufficiency 56% - Trachial intubations 72% - Tracheostomy 21% Signs of rhabdomyolysis 88% GIT symptoms (Abdominal pain) 53% Oliguric acute renal failure 32% PPD intoxication is a major health problem in Sudan, Morocco and Indian  Acute PPD poisoning is the most frequent cause of suicidal attempts requiring hospitalization in Morocco  In adult practice 70 – 90% of PPD poisoning is due to suicidal attempts  The mortality rate range between 10.6 -38.7%  Statistics from the ENT teaching hospital in Khartoum from 1995 to 2005 showed PPD intoxication in 3159 patient with an average of 287.1 per year  The common age group affected was 15 - 24 years 52%  There was a predominance of females 80.7%, and the majority of cases 87% were due to suicidal attempts The mortality rate of PPD intoxication can be decreased by early recognition, prompt referral and aggressive supportive treatment.  Investigation -Blood for PPD -Urine for PPD -RFT -LFT -ECG  management - ABC - Angioneurotic edema ………> tracheostomy - Respiratory failure …………> Ventilator - Fluids - Gastric lavage - Renal dialysis Amphetamines What is amphetamines What are amphetamines? Amphetamines are psycho-stimulant drugs, which means they speed up the messages travelling between the brain and the body. Some types of amphetamines are prescribed by doctors to treat conditions such as Loading… (ADHD) and narcolepsy (where a person has an uncontrollable urge to sleep). Amphetamines have also been used to treat Parkinson’s disease. Other types of amphetamines, such as speed, are produced and sold illegally. Amphetamines have been also been taken as performance enhancement drugs. The most potent form is crystal methamphetamine (ice).  What is ICE then? Crystal methamphetamine (‘ice’, ice drug) is a colorless , odorless stimulant drug, which means it speeds up the messages travelling between the brain and the body. It’s stronger, more addictive and therefore has more harmful side effects than the powder form of methamphetamine known as speed. Ice usually comes as small chunky clear crystals that look like ice or fragments of glass. It can also come as white or brownish crystal-like powder with a strong smell and bitter taste. Other names Crystal meth, shabu, crystal, glass, shard. Poor man’s Cocaine WHAT ARE SOME LOCAL NAMES?  It can be -Smoked, -Injected, -Snorted, -Swallowed. Ice is generally smoked (feel the effect almost immediately) or Loading… injected (15 to 30 seconds to feel the effects). It is sometimes swallowed (15 to 20 minutes to feel the effects) or snorted (3 to 5 minutes to feel the effects). And its commonly abused because of long lasting euphoric effect it produces, however higher purity level may produce longer laster and more intense physcological effect. Why is it illegal? Crystal methamphetamines is a schedule II substance under the Controlled Substances Act Schedule II which include cocaine and PCP have a high potential for abuse Abuse of these drugs may lead to severe psychological or physical dependance What does ice do to the body? Indirect Agonist for: -Dopamine -Noradrenaline -5-HT (serotonin) Mechanism: -Blocks monoamine reuptake -Inhibits MAO metabolism -Inhibits vesicular storage -Reverse reuptake Effect of ice on systems Long -Term Effects Anxiety, confusion and sleep problems Hallucinations and delusions Methamphetamine psychosis Psychotic behaviour Chronic depression Severe weight loss Brain damage Clinical presentation Loading… Mood symptoms Anxiety and restlessness Panic Aggression Racing thoughts Severe depression following a methamphetamine binge Euphoria Violent mood swings Delusions of power Behavioural symptoms Risky sexual behaviour Wanting to quit or cut down on methamphetamine use without being able to Violence Avoiding hobbies and activities that were once considered pleasurable Borrowing or stealing money Preoccupation with “chasing the next high” Pulling away from friends and family Engaging in unsafe activities Physical symptoms Marked weight loss Cardiac arrhythmias Malnutrition Respiratory problems Acne or picking scars Loss of elasticity of the skin “Meth Mouth” Brain damage Seizures Psychological symptoms Marked confusion Memory loss Disorganized lifestyle Paranoia Psychosis Hallucinations Total break from reality  While injecting drugs, there is an increased risk of: -tetanus -infection -vein damage. If sharing needles there is an increased risk of: -Hepatitis B & C -HIV and AIDS. Snorting ice can damage the nasal passage and cause nose bleeds. Overdose Its taking a large amount or have one strong batch this will cause chest pain breathing problems fits or uncontrolled jerking extreme agitation, confusion, clumsiness sudden, severe headache unconsciousness stroke, heart attack or immediate death.  Treatment We may use physical restraints in overdoses (or acute intoxication) or chemical restraints (sedation)to prevent harm to themselves or others. Physical restraints may be bandages or cuffs restricting a person’s movement. People who overdose may turn hostile because of methamphetamine-induced paranoia. Then aim to treat the life-threatening signs and symptoms present: -a compromised airway -seizures -tachycardia -hyperthermia Gastric Lavage with alkaloid antidotes (warm water with KMno4- if taken orally) and/or activated charcoal. We may administer a crystalloid intravenously to eliminate the drug through the urine. It will prevent sudden kidney failure. Crystalloids are mineral salts and other small, water-soluble molecules. Cases that present with significant end organ failure Intravenous phentolamine, nitroprusside or nitroglycerin. General supportive care e.g. antibiotics for infections. Diazepam and chlorpromazine for sedation are effective in treating ice induced chorea and seizure management There are also drugs like imipramine and fluxetine adjuvent agents to treat the symptoms. Coming down It can take several days to come down from using ice. The following effects may be experienced during this time: difficulty sleeping and exhaustion headaches, dizziness and blurred vision paranoia, hallucinations and confusion irritability and feeling ‘down’  Using a depressant drug such as alcohol, benzodiazepines, or cannabis to help with the come-down effects may result in a cycle of dependence on both types of drugs. Autopsy Picture/Findings Recent needle puncture marks, irregular linear scars and skin infections ( the cubital fossa, anterior aspects of the arm, medial side of the ankles, the inguinal are and the neck) Crank Bugs, what one is said to feel crawling on or under the skin during a drug-induced hallucination. Users itch and scratch which causes the open sores. Extreme weight loss, bony prominences and rib cage prominent ‘Meth mouth’ Canker Bugs Meth mouth  Methamphetamine in blood concentrations/samples, and in urine Pathologic changes in the heart that lead to cardiac arrhythmias myocardial fibrosis and /or coronary artery fibrosis. Systemic infections such as Hepatitis B /C Some even have severe burns Addiction: The “Binge & Crash” Drug Thedrug boosts the release of a neurotransmitter called dopamine, leading to an increase of this chemical in the brain. Crystal meth causes an intense elevated or euphoric mood. Experiencing these unnatural levels of dopamine causes a strong desire to continue using the drug. It becomes addictive because your body experiences intense cravings to maintain the extremely euphoric state, which often results in constant redosing and binge- like behaviour to achieve that goal. Heavy Metals Mercury Hg Hydrargyrum Toxicity Dr. Isam Elhassan Specialist of Forensic Medicine & Clinical Toxicology  Mercury Sources: Cavities 1- Elemental (metalic): forfilling Hg vapour, dental amalgam, thermometers & sphygmomanometer Toxicity after inhalation only If swallowed it is poorly absorbed 2- Inorganic salts: Calomel (mercurous chloride) insoluble purgative. Chronic mercury Poisoning in children exposed to mercurous chloride in teething lotions and diaper powders if absorbed it will result in pink teeth (Acrodynia) Which manifested by: Mercury Acrodynia: Insomnia, hypertension, peeling of skin, alopecia, pink and painful hands. Acute renal failure within 24hrs Mercuric chloride (HgCl2) >> disinfectant Mercurial fulminate >> percussion cap 3- Organic mercurial salts >> diuretics and fungicidal. Methyl mercury and ethyl mercury are well known as environmental contaminants that have been incorporated and concentrated in the aquatic food chain Mercury and shime react cos when Hg I get depressed Mechanism of action: Mercury reacts with sulfhydryl (-SH) group resulting in depression of the cellular enzymatic mechanisms Elemental mercury vapor and organic mercurial compounds are particularly toxic to the CNS, while inorganic mercuric salts are corrosive and nephrotoxic Mercury Acute mercury toxicity Clinical presentation: 1- GIT:  Metallic taste  Burning sensation from mouth to stomach  Nausea & blood tinged vomiting  Tenesmus [mercurial dysentery] >> diarrhea with mucus & blood  Dehydration & collapse Mercury Acute mercury toxicity Clinical presentation: 2- Renal:  Acute toxic glomerulonephritis >> oliguria with albumin and blood cast >> anuria & RF 3- Corrosive bronchitis >> pulmonary edema & nervous manifestations (tremors, & increased excitability) in exposure to mercury vapor Mercury Acute mercury toxicity Causes of death: 24 hours >> dehydration 10 days >> RF Mercury Acute mercury toxicity Treatment: 1. Remove from further exposure 2- Gastric lavage: using one of the local antidotes  Egg white & skimmed milk >> ppt of Hg albuminate  Sodium formaldehyde sulfoxylate >> reducing agent (HgCl2 >> HgCl insoluble) Mercury Chronic mercury toxicity “Mercurialism” Clinical presentation:  GIT Oral >> Salivation (an early sign) Gray line on the gum Gingivitis (swollen, painful, bleeding gingiva) loose teeth Gangrene (cancrum oris) Mercury Chronic mercury toxicity “Mercurialism” Clinical presentation:  GIT Intestinal >> Mercurial dysentery (diarrhea, mucus & blood)  Renal >> Albuminuria, hematuria granular and hyaline casts >> Oliguria & renal failure Mercury Chronic mercury toxicity “Mercurialism” Clinical presentation:  CNS: >> kinetic tremors (cerebellar affection)  Psychic: >> Hg erethism: shyness, loss of confidence, vague fears, depression (neurosis)  Skin >> Dermatitis  Eye: Mercurialentis (discoloration of capsule of eye lens) Mercury Chronic mercury toxicity “Mercurialism” Treatment: I. Prophylactic treatment:  periodic medical examinations of exposed workers  proper exhaust ventilation, dust filters, protective clothing, masks, gloves and boots  Intake of proper amounts of Ca, Zn & Fe Mercury Chronic mercury toxicity “Mercurialism” Treatment: II. Curative treatment: 1. Stop further exposure 2. Physiological antidotes (Chelation therapy): o D-penicillamine o BAL & its oral analogues DMSA & DMPS 3. Symptomatic  Mouth hygiene  Tranquilizers  Atropine >> salivation  Na hyposulphite for dermatitis Thank you Organophosphate and Carbomate Insecticides pesticides  Pesticides are group of chemicals used for killing of undesirable pests (both plants & animals).  Classified as  insecticides  rodenticides  fungicides  herbicides Organophosphorus compounds Are used as liquid or powder. They are absorbed by ingestion, Inhalation or through the skin  Organophosphates and carbomates are used extensively throughout the world.  are involved in about 3 million cases of human poisoning and cause about 40.000 death.  Ach synthesis : choline acetyl transferase Choline + Acetyl CO A Ach (cytoplasm of nerve ending) Acetyl choline esterase Acetyl choline choline + acetate AchE cluster in post synaptic membrane of cholinergic synapse plasma AchE called false AchE capable to hydrolyzing Ach but has different properties Ach receptors  2main types: Muscarinic receptors on smooth muscles & gland, they block by atropine Nicotinic receptors (in sympathetic ganglia small amount of Ach stimulate post ganglion neurons, large amount block transmission of impulses from pre to post neurons) which subdivided to those found in neuromuscular junction & in autonomic ganglia Both receptor are found in large number in the brain. Pathophysiology : compounds Organophosphate  OPCs & carbamate bound to active site of AchE & inhibit it so increase Ach in synapse & neuromuscular junction causing muscarinic & nicotinic s/s. ~ and signs symptoms High Ach in post ganglionic muscarinic synapse causes parasympathetic activity of smooth muscles (GIT, lung, heart, bladder & secretary gland) & increase activity of post ganglionic sympathetic receptors for sweat glands…(SLUDGE/BBB). S-salivation B- Bronchorrhea L-lacrimation Bronchospasm B- U-vrination B- Bradycardia D-diarrhea distress G-Gastrointestinal E-Emesis  High Ach at nicotinic motor endplate cause persistent depolarization of skeletal muscles with fasciculations, progressive weakness & hypotonicity. OPs cross BBB causing seizures, respiratory depression & CNS depression. Acute poisoning occurs in: Self-ingestion or injection. Accidental poisoning -due to contamination of food stuff. Swallow of liquid preparations kept at home by children. Dermal contamination due to user ignorance to wear protective clothing. Action:-  Organophosphates and carbomates act by inhibiting cholinesterases  accumulation of acetylcholine at central and peripheral cholinergic nerve endings, including neuromuscular junctions.  Carbomates produce relatively short lived inhibition of cholinesterase, since the carbomate enzyme complex tends to dissociate spontaneously.  Factors Which Determine the Speed of Onset and Severity of Poisoning:- The rate of phosphorylation of the enzyme The rate of spontaneous hydrolysis of the phosphorylated enzyme and release of active enzyme (reactivation).  The rate of ageing of the phosphorylated enzyme complex by the process of dealkylation of the organophosphate component. Once this happens, reactivation is impossible.  Difference between OPs & carbamate is that carbamate hydrolyzed from AchE site within 24 hrs, OPs undergo aging which occur when phosphorlated AchE loses an alkyl side chain & becoming irreversibly inactivated.  Manifestations of Poisoning:- local.  Blistering and redness of the skin  Eye splashes lead to miosis and blurring of vision. L Pupil get small (constrictl Systemic.  The speed of onset depends on the route and magnitude of exposure.  The features of organophosphate and carbomate poisoning are a mixture of peripheral muscarinic effects of excess acetylcholine on  the gastrointestinal tract  bronchi  Heart  bladder  sweat, salivary and lacrimal glands nicotinic actions at neuromuscular junctions and sympathetic ganglia and CNS effects.  Mild Poisoning: * CNS stimulant effect (nicotinic effects) as  Anxiety  restlessness  insomnia  nightmares  tiredness  dizziness  headache *(muscarinic effects):  Nausea  vomiting  abdominal colic  diarrhea urine to stool or pass urgent need  tenesmus -  Increased secretions: sweating excessive salivation lacrimation, urination and diarrhea (SLUD Synd-)  Miosis (pinpoint pupil)  Bronchospasm & bronchorrhea  Moderate Poisoning: *Shows nicotinic effects as:  Twitches, muscle fasciculation's, tremors, paralysis Involving respiratory muscles  Fatigue, generalized weakness sufficient to make walking impossible and speech difficult.  Severe Poisoning: *Impaired consciousness *flaccid paralysis of limb muscles (affecting proximal groups more than distal ones) *Pulmonary edema *cyanosis *convulsions and atrial fibrillation. *Depressed respiration, asphyxia  Diagnosis:- -In absence of history of exposure diagnosis is difficult. -Gastrointestinal symptoms with fever and polymorph leucocytosis may lead to wrong diagnosis of gastroenteritis. -Reduction in activity of cholinesterase confirms the diagnosis. -In severe poisoning activity is reduced to less than 10% of normal activity.  Management:- Removal of clothing and washing of contaminating skin with soap and water. Gastric lavage. Blood sample to measure cholinesterase activity Removal of respiratory secretions and correction of hypoxia. Replacement of fluid loss due to vomiting, diarrhea and pulmonary oedema. So as with all poisons supportive treatment treat the symptoms and you give prevent absorption  antipoison ~ Atropine is the drug of choice. Given in a dose of 2 mg intravenously every 10-30 minutes / adult till relief is obtained or signs of atropinization are obvious. (Children 0.02- 0.05 mg/Kg). Diazepam (5-10 mg I/V) to reduce anxiety and restlessness. ~ nicotinic receptor Symptoms Mortality rate up to 25% in severe poisoning. oximes Oxime compounds are used as antidotes for nerve agents. A  nerve agent inactivates acetylcholinesterase molecules by phosphorylation of the molecule. Oxime compounds can reactivate acetylcholinesterate by attaching to the phosphorus atom and forming an oxime-phosphonate which then splits away from the acetylcholinesterase molecule. The most effective oxime nerve-agent antidotes are pralidoxime (also known as 2-PAM),  Late complications and acute intoxication include: Cranial nerves and brain stem lesions developed 1-4 days. Peripheral neuropathy due to axonal degeneration starts 2-3 weeks after exposure. Insomnia, inability to concentrate and depression. Paraquat (Bipyridyl Compound) Paraquat is the trade name for N,N′-dimethyl- 4,4′-bipyridinium dichloride, one of the most widely used herbicides in the world. A large majority (93%) of fatalities from paraquat poisoning are cases of intentional self- administration, i.e., suicides. Fatal dose 4 mg/kg Paraquat Pure paraquat, when ingested, is highly toxic to mammals, including humans; potentially leading to acute respiratory distress syndrome (ARDS), and there are no specific antidotes. However, fuller's earth or activated charcoal is an effective treatment, if taken in time. Death may occur up to 30 days after ingestion C.P. of Paraquat poisoning Stage (1) 1 – 5 days Local corrosive action blood up coughing - hemoptysis ~ - ulceration of mucous membranes - nausea, diarrhea - oliguria ↓ reduced urine output  C.P. of Paraquat poisoning Stage (2) 2 – 8 days Signs of liver, kidney, cardiac damage - jaundice - fever - tachycardia - myocarditis - respiratory distress, cyanosis - elevated BUN, serum bilirubin L blood wren nitrogen C.P. of Paraquat poisoning Stage (3) 3 – 14 days Pulmonary fibrosis - cough, dyspnea, tachpnea - edema, pleaural effusion - atelectasis- a long condition does not where part fully expand of the collapses or - low arterial O tension 2 - increased alveolar O tension 2 gradient - respiratory failure  Paraquat Herbicides Diquat 2,4dichlorophenoxyacetic acid Color : Blue-green emetic agent  GSH GSSG.. O2 O2 O H Paraquat Lung Lipid peroxidation Type I and II pneumocyte cell death & alveolitis Lung fibrosis paraquat 1. Basic life support ๒. Prevent absorption ๒.๑ Gastric lavage O2 ๒.๒ Fuller’s earth ๒.๓ MOM ๓๐ ml q ๖ hrs ๒.๔ Skin decontamination 3. Increase elimination 3.1 Hemodialysis/ Hemoperfusion 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 - Chlorphenairamine 4 mg 1 tab po qid 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 Thank You  Digitalis The cardiac glycosides, of which digitalis is the most commonly known, have intensive history in pharmacotherapy.  Source: Cardiac glycosides are the active principles in many plants: - Digitalis purpurea. (Purple foxglove). - Digitalis Lanata. (White foxglove). – - Mediterranean sea onion (sea squil1). - Oleander.  Digitalis  Active principle: Digoxin, Digitoxin, Digitalin and Digitonin. - Digoxin is the most commonly prescribed digitalis preparations. - Digoxin uses include congestive heart failure and atrial arrhythmias. It is available as 0.125 and 0.25 mg tablets. Digitalis  Condition of poisoning:  Accidental: Therapeutic overdose. Children.  Suicidal.  Digitalis  Mechanism of action: I- Therapeutic dose: a- Elongate diastolic period, so improve filling of heart i.e. – ve chronotropic(↓HR.). b- Enforce systolic power - improve contraction. i.e. + ve Inotropic ( ↑ CO). c- Increase renal blood flow. II- Toxic dose: a- Cardiac poison. b- GIT affection. c- Visual Manifestations. d- CNS Manifestations.  Digitalis  Pathophysiology: 1- Stimulates vagus [Bradycardia] 2- Inhibits Na+ - K+ ATPase lead to:  Increase intracellular sodium.  Increase intracellular calcium.  Increase extracellular potassium “hyperkalemia” (in acute toxicity only while in chronic toxicity, the serum K level is usually normal or low owing to concurrent diuretic therapy).  Digitalis  Clinical presentation: A- Cardiac: Arrhythmias- [The most frequent manifestations] Tachyarrhythmias Brady arrhythmias Atrial: 1- Tachycardia 2- Flutter 1- Sinus bradycardia 3- Fibrillation. 2- A- V block Ventricular: 3- Sinus arrest. 1- Extra systoles. 2- Tachycardia. 3- Fibrillation.  Digitalis  Clinical presentation: B- GIT: [The earliest manifestation]. Anorexia, nausea, vomiting, colic and diarrhea. C- Visual: Green yellow vision [rods & Cones affection]. D- CN.S: Headache, delirium, disorientation & drowsiness. Digitalis  Cause of death: Arrhythmias and cardiac arrest.  Digitalis  Investigations: a- E.CG and continuous cardiac monitor, look for bradycardia, heart block, atrial and ventricular arrhythmias. b- Electrolytes levels: Hyperkalemia in acute toxicity and it is a primary predictor of need for antidotal therapy. Hypokalemia in chronic toxicity and it exacerbates toxicity as well. Hypercalcemia and hypomagnesemia exacerbate toxicity as well. c- Kidney function tests (renal impairment alters elimination of glycosides). d- Digoxin level Therapeutic blood level is 2ng/ml. Concentrations exceeding l5ng/ml carry serious prognosis.  Digitalis  Treatment: I- Prevention from further exposure. II- Supportive measures. III- GIT decontamination. IV- Physiological antidote.  Digitalis  Treatment: II- Supportive measures: ABC with special emphasis on supporting respiratory and cardiac functions. Treat the arrhythmias. A- Treat electrolytes disturbance: i. ↑K (Acute toxicity — insulin in 5%glucose to avoid hypoglycemia). ii. ↓K (chronic toxicity): -__KC1. iii. ↑Ca __Non Ca EDTA. B- Anti arrhythmic drugs: 1- Phenytion(250mg slow IV followed by l00mg/8hr.) 2- Lidocaine(1mg/kg loading dose followed by maintenance infusion) treat :- Atrial arrhythmias. Ventricular arrhythmias. 3- Atropine (0.5-1mg IV) treat:- Heart block. Bradycardia.  Digitalis  Treatment: III. G. I T decontamination: Emesis 1- Gastric lavage especially if vomiting is ineffective. 2- Local antidote:  Charcoal. (Multiple doses).  Cholestyramine [interrupt the enterohepatic circulation].  Digitalis  Treatment: IV- Physiological antidote: Digibind [Fab] (Digoxin- specific antibody fragments) Dose: based on total body load of digoxin. Many equations have been postulated to calculate the dose. Indication 1- Serum digoxin level above 10ng/ml in adults and >5 ng/ml in children or ingestion of > 10 mg in adults and > 4mg in children. 2- Severe cardiac arrhythmias. 3- Severe hyperkalemia (>5-5.5 mEq/L). 4- Heart block even 1st degree. Action: Reverses tissue binding (binds to digoxin and to a lesser extent, digitoxin and other cardiac glycosides and the inactive complex that is formed is rapidly excreted in urine).  Digitalis  Treatment: IV- Physiological antidote: Digoxin: amount the digoxin ~ in sarum a concentration Body Load (mg) = (SDC ng/ml)(5.6)(wt in kg) 1000 Each vial of antidote contains 40 mg, this will bind 0.6 mg digoxin So could be patient comes in after overdosing on digoxin they have a serum digoxin question a a of vials of antidote (or my of antidote) would concentration 250 ng/ml and they weigh 110 kg how many this patient need. 250)X5 6)xo. => 154 (body load) = 256 67. 1000 my Cannabis Sativa Cannabis is a psychoactive (psychedelic, psychotomimetics, hallocinogen) drug that has been used since ancient times for both medicinal and recreational effects. It is the most widely used illicit drug in the world. Source: - Cannabis sativa. - Cannabis indica. Cannabis Sativa  It is found in forms of: Hashish: dried resin from the flower tops. Hashish oil: dark viscous liquid or concentrate of cannabinoids obtained by solvent extraction of the crude plant material or of the resin. Bango: from dried leaves. Marijuana: Mixure of [Crushed leaves, flower, and stem] Sinsemilla: (‘without seeds’) mixture of flowering tops and leaves of cultivated, unfertilized female plants. THC 8 – 11% Cannabis Sativa  Active principle: The primary psychoactive one is delta -9- T.H.C [delta -9-Tetra hydro cannabinol], canabinol, canabidiol Cannabis Sativa  Route of administration: Smoked: in cigarettes or shisha. Ingested: alone or with coffee or tea. Inhaled: burnt in closed place (glass, cup,..) Tablets :( marinol-dronabinol’THC’) for therapeutic use as stomachic or antiemetic in cancer patients. Other therapeutic uses of cannabinoids: Asthma and glaucoma, as an antidepressant, anticonvulsant and anti-spasmodic Cannabis Sativa  Pharmacokinetics: * Absorption:- Inhalation or ingestion * Distribution: High lipid solubility. Rapidly. distributed to brain and adipose tissues. * Metabolism: by liver. * Excretion: urine and stool. Cannabis Sativa  Condition of poisoning: Accidental:- Overdose by the user. Cannabis Sativa  Mechanism of action: The exact mechanism of THC’s pharmacology remains only partially understood. Receptors for THC have been found in the basal ganglia, cerebral cortex, cerebellum and hippocampus. THC stimulates sympathetic receptors and inhibits parasympathetic receptors. THC possesses CNS stimulation & depression depending upon:  Mood of the user.  Concentration of THC.  Route of administration.  Cannabis Sativa  Clinical presentation: A) Mental: Euphoria: Floating in air, sense of well being and talkativeness. Sexual or erotic dreams. Increase special senses: Auditory [used by musicians] touch and olfactory. Dysphoria. It replaces euphoria due to depression effect. Disorientation of time:- Minutes seems hours i.e. false prolongation of time. [Sexual act is falsely lengthened]. Disorientation of space: Near objects appear far distant [car accidents]. Cannabis Sativa  Clinical presentation: B) Physical: Eyes: Dilated pupil + conjunctival congestion. CVS: Tachycardia + orthostatic hypotension. Resp: Depression of R.C. GIT: Increase appetite to sugars + dry mouth. Bladder: urinary frequency. Cannabis Sativa  Cause of death:  Central asphyxia  Car accidents. Cannabis Sativa  Investigation: * Routine investigations * Blood & urine sample: THC. Cannabis Sativa  Treatment:- of acute toxicity. 1- Supportive measures: ABCs esp- Care of respiration. 2- GIT decontamination: Gastric lavage. Charcoal. 3- Physiological antidote:- No specific antidote. 4- Symptomatic measures: Reassurance. Mild sedation (diazepam) if needed. Psychiatric follow up.  LSD Lysergic Acid Diethylamide (LSD) is an Ergot Alkaloid  psychoactive (psychedelic, psychotomimetics, hallocinogen)  Extremely potent (25 – 50 g orally produce marked behavioral effect  Odorless  Colorless  Tasteless  Liquid or Solid  Taken orally  Tachyphylaxis (rapid production of tolerance)  Rapid recovery from tolerance  Cross tolerance with mescaline & psilocybin  LSD  Source: Natural: Plant: Calviceps purpurae Synthetic: LSD  LSD  Mechanism of Action: Poorly understood, But: The primary action is on the CNS esp. changes in mood and behavior LSD affects both pyr- & extrapyramidal systems LSD affects sym- & parasympathetic systems LSD has sensory effects  LSD  C.P.:  Euphoria; hilarious laughter  Dysphoria; sadness & crying  Visual; more intense color of objects, flat surfaces assume depth, fixed objects undulate and flow  Abnormal Auditory, Tactile, Olfactory & Gustatory sense  LSD  C.P.:  Sympathetic; Mydriasis, hyperthermia, piloerection, hyperglycemia, tachycardia & hairs on skin contracting (goosebumbs) hypertension  Alteration in time perception  Disruption of ego function & fear of self- destruction  Body parts feel unnatural or foreign  LSD  C.P.:  Acute panic reaction  Flashbacks  Prolonged psychosis  Schizophrenia like symptoms  LSD  Cause of Death: Suicide commonly  LSD  Management:  Quiet environment & lighted room at bed time  Reassurance  Sedation, Diazepam  Cloropromazine 50 – 100 mg I.M. (one dose) Drug Dependence Definitions: Drug of abuse: It is the use of a drug by any route (oral, smoking, snuffing, or injection) to produce mood change alteration of the level of consciousness Substance of abuse: Is any substance with pharmacologic effects used for non-medical reasons i.e. in order to produce a state of well being and to avoid discomfort This substance is usually condemned by the society Drug habituation: Is characterized by a desire to take the drug but without compulsion; some degree of psychological Dependence; detrimental effects on the p.t rather than society Drug addiction or drug dependence: It is the compulsive repeated use of a drug or substance resulting in physical, and psychological dependence Drug Dependence Mechanism of drug dependence: The most accepted theory is that: addiction may be a cellular phenomenon whether through cellular adaptation or receptors adaptation; where the cells become accustomed to the presence of the Drug, interruption of continuous administration of the drug or decrease its concentration will result in disturbed function Drug Dependence Characters of dependence: 1- Compulsive desire to take the drug 2- Tolerance 3- Physical dependence 4- Psychic dependence 5- Withdrawal symptoms 6- Detrimental effects on the individual, family and society Drug Dependence Methods of abuse of addicting drugs: 1- Nasal insufflation e.g. heroin 2- Inhalation e.g. cocaine 3- Smoking e.g. hashish 4- I.V e.g. morphine 5- Dissolving tabs then I.V injection Drug Dependence Types of addicts:  Therapeutic addicts  Professional addicts  Street addicts  Congenital addicts Thank you Atropine, Hyosine &Hyoscyamine Source: All parts of the following plants  Datura Fastiosa & Stramonium (Thorn apple)  Atropa Belladona (Black berry)  Hyoscyamus Muticus Active principles:  Atropine & Hyoscyamine (isomers)  Hyosine Atropine, Hyosine &Hyoscyamine Medical uses: Atropine  Ophthalmology – Mydriatic  Chest – Bronchodilator (Asthma)  GIT – Antispasmodic  Urology – Urinary incontinence  Toxicology – Antagonist in:  ( morphine, digitalis and organophosphorus) Hyosine  Used as Truth Serum  In mania as it CNS without initial , thus it combats excitement and induces twilight sleep Atropine, Hyosine &Hyoscyamine Conditions of Poisoning: Accidental:  Children  Therapeutic overdose  Addicts Homicidal: to facilitate rape & robbery Suicidal: overdose of anticholinergic medication Atropine, Hyosine &Hyoscyamine Mechanism of action:  Atropine & Hyoscyamine are ANTICHOLINERGIC - Central: block Ach. release (CNS then ) - Peripheral: block muscarinic action of Ach.  Hyosine - Central: CNS - Peripheral: weak Atropine, Hyosine &Hyoscyamine C.P.:  Peripheral: (Atropinism)  Dysphagia, Horse voice  Constipation & urine retention (GIT & urinary motility)  Dilated fixed pupil  Flushed skin (Atropine flush) due to D of B.V.  Tachycardia + Tachypnea  Atropine fever (inhibit sweating & alterate T.R.C.)  Central: (stimulation)  Restlessness, agitation, disorientation, euphoria, talk & visual hallucination  Occupational delerium  Staggering gait (depression)  Drowsiness, sleep, stupor, coma & cyanosis Atropine, Hyosine &Hyoscyamine Cause of Death: Respiratory depression Investigations: Routine: CBC, ABG & Electrolyte ECG: sinus tachycardia Chemical analysis (Tropin & Tropic acid) D.D.: Alcohol Atropine, Hyosine &Hyoscyamine Treatment:  Supportive measures [ABCs]  GIT decontamination  Local antidote: - A.C. - H2O2 - Na HCO3  Physiological antidote: - Pilocarpine - Physiostigmine  Symptomatic Opium: Heroin Opiates: naturally occuring opium Opioids: Alkaloid compounds have opium or morphine like activity Plant: Papaversomniferum Alkaloid Opium contains, more than 20 alkaloids such as morphine papaverine, thebaine and codeine Opium is ingested or smoked & has a smell [meconic acid]. While morphine is injected only & has no smell Opium: Heroin Classification of opioids: 1. Natural opium derivatives: (codeine and morphine). 2. Semisynthetic agents: (diacetylmorphine “heroin” which is more potent than morphine, stadol, hydrocodone) 3. Synthetic agents:  Meperidine and related (lomotil, Imodium, fentanyl, mepridine” pethidine”)  Methadone and related (methadone, propoxyphene)  Other (pentazocine) Opium: Heroin Uses of Morphine: a) Pain killer [e.g. Burns, Metals, acute myocardial infarction. & corrosive poisoning] b) Treatment of opiate addicts [Gradual withdrawal]. Opium: Heroin Mechanism of action: The opioids exert their effects by interacting with specific opioid receptors in the CNS. The three main opioid receptor types are; mu, kappa and delta. All three mediate analgesia effects. A fourth receptor sigma is no longer considered to be an opioid receptor because it cannot be antagonized by naloxone Opium: Heroin Clinical presentation: 1) Euphoria or dysphoria [distress and fear] - Sleep, stupor —, coma 2) Non cardiogenic pulmonary edema {dyspnea & cyanosis] 3) Constipation and diminished bowel sounds. 4) Respiratory depression with cyanosis &characteristic smell in the breath [if opium]. Opium: Heroin Clinical presentation: 5) Hypothermia. 6) Circulatory collapse. 7) Miosis [pin point pupil] & fixed pupil. 8) Skin boils, cellulitis and needle tracks are observed in IV drug addicts. Opium: Heroin Cause of death: - Respiratory depression [central asphyxia] - Pulmonary edema. - Arrhythmias. - Irreversible brain damage secondary to prolonged hypoxia Thank you Opium: Heroin Investigations:  Routine CBC,ABG, serum electrolytes.  Chemical analysis [Morphine + meconic acid].  Chest X-ray to diagnose pulmonary edema.  ECG to detect hypoxic effect and arrhythmias. Opium: Heroin Treatment: I) Supportive measures [ABCs] - Mainly treat respiratory depression. - Treat coma, seizures, hypotension and non cardiogenic pulmonary edema if they occur. II) GIT Decontamination: by Gastric lavage: a) Using cuffed endotracheal tube even if alert (CNS depression) b) Even if the toxicity is by Morphine which is injected (morphine reexcreted in the stomach) Opium: Heroin Treatment: III) Local antidotes: Using one of alkaloidal antidotes or activated charcoal. IV) Physiological Antidote: A) Antagonists: Atropine 1 ml I.V (≠Vagal stimulation and ↑HR). B) Competitors:  Agonist antagonist  Pure agonist Opium: Heroin Competitors:  Agonist antagonist: [In absence of opiates, they act as agonists on receptors, but in presence of opiates, they act as antagonist]. a) Levallorphane 1mg b) Nalorphine 10mg.  Pure Antagonist: a) Naloxone b) Nalmefene c) Naltrxone  Cocaine The Coca plant had been used by the natives of the South America 1200 years ago. Cocaine is one of the most popular drugs of abuse. Source: Cocaine is a bitter white crystalline alkaloid, which is found in the leaves of Erythroxylon coca plant (0.5-1% cocaine).  Cocaine Uses:  Local anaesthetic (Marcaine)  Antiarrhythmic (Xylocaine)  Drug abuse  Sports doping  Anorexigenic Cocaine Conditions of poisoning:- Accidental: * Over dose in addicts * Medical over dose (anesthetic)  Cocaine Routes of administration: mlowe o ~ impure Sniffing the powder which is usually adulterated by other less expensive substances as theophylline, quinine, talc powder, Smoking as free base (crack). Inhalation I.V. (usually with heroin).  Cocaine Mechanism of action: system mimics effects of sympathetic nervous ~ Sympathomimetic and a strong C.N.S stimulant Interferes with the reuptake epinephrine & norepinephrine. Blocks the reuptake of dopamine. Interferes with serotonin activity. Local anesthetic: Blocks the fast inward Na-channel.  Cocaine Causes of death: Hyperthermia Central asphyxia and/or circulatory collapse. (body oxygen supply is reduced or cut off due to failure in CNS  Cocaine Clinical presentations: CNS manifestations: - Euphoria, agitation, insomnia and talkativeness. - Headache, mental confusion and hallucination. - Exaggerated reflexes, convulsions and even status epilepticus. than 5 mins Lseizures that last longer - Hyperthermia, which is the major cause of death in stimulation - Increased respiratory depth and rate. - Loss of reflexes, irregular respiration, cyanosis, coma and death.  Cocaine Clinical presentations: CVS manifestations:  Elevated blood pressure (may precipitate hemorrhagic stroke).  Arrhythmias (sinus tachycardia, ventricular tachycardia or fibrillation).  Coronary artery spasm or thrombosis which may result in myocardial L causes prinzmetal anging infarction.  Circulatory collapse.  Cocaine Clinical presentations: Other manifestations:  Renal failure may result from shock and decreased renal perfusion or rhabdomyolysis and myoglobinurea.  Perforation of nasal septum after chronic sniffing of adulterated drug.  Accidental subcutaneous injection of cocaine may cause localized Necrotic ulcers “coke burns” Rhabdo-stricted musle myo-muscle lysis-breakdown  Cocaine Investigations: blood gas Arterial - Routine investigations ( CBC, ABG, kidney function tests, serum electrolytes) - Serum enzymes (CPK, AST, ALT,..etc.) - Detection of benzoylecgonine ( principle metabolite of cocaine) in urine by thin layer chromatography, high performance liquid chromatography (HPLC) or gas chromatography (GC) is used for diagnosis of cocaine overdose (can detected up to 2-3 days).  Cocaine Treatment: * Supportive (ABCs) - CNS stimulation--chlorpromazine. - Convulsions --- diazepam. - Hypertension-- alpha blocker e.g. Sodium nitroprusside - Hyperthermia--- chlorpromazine + salicylate  Cocaine Treatment: * GIT decontamination: - Emesis and gastric lavage are performed only in the absence of seizures. * Enhanced elimination: - Forced acid diuresis increases urine execration of the drug, but carry the risk of metabolic acidosis  Cocaine Treatment: * Symptomatic: - Cool quite environment---to minimize stimuli - Lithium---for cocaine psychosis - Propranolol---for hypertension and tachycardia. Cocaine dependence “Cocainism” Cocaine Street name: Crack - It is prepared from cocaine hydrochloride in the form of colorless, crystalline substance that makes popping or cracking sound when heated (hence the name crack). It can be mixed into cigarette and smoked or heated on water bath and inhaled. - Cocaine is euphoriant, decreasing physical and mental fatigue and increasing the sex activity. Tolerance and physical dependence to cocaine develop rapidly. Cocaine dependence “Cocainism” Clinical Picture: 1. Mental change: lack of concentration, dementia. 2. Physical effects:  Anorexia, progressive weight loss (wasting).  Pallor of the face due to vasoconstriction (VC).  Dilated reactive pupils, tremors, insomnia, and hypertension  Lost sense of smell.  Perforated nasal septum Cocaine dependence “Cocainism” Clinical Picture: 3. Moral changes: patient becomes aggressive and dangerous. 4. Psychological changes: Hallucinations → the chronic effects on the sensory nerve endings give rise to Magnan’s symptoms which is feeling of sand under the skin or to cocaine bugs, with sensation as if insects creep under the skin with severe itching. with meth overdose like with crank bugs Cocaine dependence “Cocainism” Clinical Picture: Withdrawal symptoms: Physical dependence occurs to cocaine but withdrawal symptoms are not serious as that with opiates. It includes irritability, neurological pain in arms and legs and tendency to violence. Cocaine dependence “Cocainism” Treatment:  Abrupt withdrawal in an institute.  Psychological care, tranquilizers.  Symptomatic treatment.  Hypertension & arrhythmias → beta blockers. Thank you  Sedative Hypnotics Benzodiazepines (BZ) Dr. Isam Elhassan Specialist of Forensic Medicine & Clinical Toxicology Benzodiazepines (BZ) Benzodiazepines are the most commonly prescribed psychotropic drug. effective and toxic close so less likely to have a wide margin between cause fatal overdose They are generally felt to have high therapeutic indices, which allowed them to replace barbiturates and other more toxic agents as first-line anxiolytics and hypnotics. Lanti anxiety L sleep aid medication Chronic use of BZ may lead to tolerance and dependence. Benzodiazepines (BZ) Common benzodiazepines Diazepam [valium] Lorazepam [ativan] Flunitrazepam [Rohipnol] Bromazepam [Calmipam] Clonazepam [Rivotrill] Midazolam [Dormicum]  Benzodiazepines (BZ) Classification according to duration of action Ultrashort (< 6h) Short (12 – 18h) Medium (24h) Long (24 – 48h) Triazolam Lorazepam Alprazolam Diazepam Midazolam Oxazepam Nitrazepam Clonazepam Temazepam Chlorzepate Chlordiazepoxide flurazepam  Benzodiazepines (BZ) pharmacokinetics Absorption active from  Oral: - well absorbed - chlorazepate (prodrug) gastric Nordazepam inactive HCL (active & rapidly absorbed) form of drug  IV: - Midazolam as IV anathesia - Diazepam as IV anasthesia & anticonvulsant  IM: - Slow absorption - lorazepam may be used in status epilepticus when IV is difficult Benzodiazepines (BZ) pharmacokinetics Distribution All over the body – passes BBB & placental barrier Redistributed & gradually accumulate in body fat Highly bound to plasma protein Benzodiazepines (BZ) pharmacokinetics Metabolism most of them – oxidation producing active metabolites followed by conjugation with glucuronic acid Some of them – conjugate directly with glucuronic acid producing inactive metabolites (as Nitrazepam/Clonazepam) Benzodiazepines (BZ) pharmacokinetics excretion In urine after conjugation with glucuronic acid Benzodiazepines (BZ) Mechanism of action BZ exert their effects through high affinity binding to BZ receptors that located at the alpha subunit of the GABAA receptors. The net effect of BZ on GABAA receptors is to increase the frequency of opening at the GABAA chloride channel  Benzodiazepines (BZ) toxicity C.P: CNS depression is the main presentation of BZ overdose ( less than Barbiturate) black of muscle coordination deepcoma activity Drowsiness, stupor, ataxia and low grade coma - Profound coma significant hypotension, respiratory depression or hypothermia is extremely uncommon in isolated BZ overdoses Death from isolated BZ overdose is rare NB: BZ overdose is generally safer than Barbiturate Benzodiazepines (BZ) toxicity Investigations  Routine investigations:  CBC  Electrolytes  ABG  RFT  Specific investigation:  Serum BZ concentrations using GCMS or immunoassays. Benzodiazepines (BZ) toxicity Treatment I. Supportive [ABCs] see general toxicology II. GIT Decontamination III. Elimination of the poison from blood Benzodiazepines (BZ) toxicity Treatment I. Supportive [ABCs] Care of coma and vital functions Endotracheal intubations, airway and assisted ventilation if necessary Shock control (IV fluids and dobutamine) Warming with blanket. Coma cocktail (naloxone, thiamine and glucose) ? Antibiotics for pneumonias Benzodiazepines (BZ) toxicity Treatment II. GIT Decontamination a. Emesis : if the patient is alert and gag reflex is present b. Gastric Lavage with cuffed endotracheal tube [up to 12 hrs post ingestion due to decreased GIT motility] c. Activated charcoal. d. Multiple — dose activated charcoal [MDAC]: in (long — acting). e. Cathartics (e.g. sorbitol)  Benzodiazepines (BZ) toxicity Treatment III. Elimination of the poison from blood Forced alkaline diuersis: [see general toxicology] for long acting barbiturates [excreted by kidneys] N.B other barbiturates have limited renal excretion [metabolized mainly by liver]. Hemodialysis and hemoperfusion: Have been successfully utilized in barbiturate overdoses with refractory hypotension and dense coma. Hemodialysis and hemoperfusion should be reserved for extreme cases where prolonged coma is anticipated.  Benzodiazepines (BZ) toxicity Treatment IV- Antidotes Specific antidote: * Flumazenil [Anexatel] Action : Flumazentil is a competitive BZ receptor antagonist , thus antagonizes the action of benzodiazepines advantage: Effective within minutes in treating isolated BZ overdose. d- Disadvantage: - Not used in combined toxicity [BZ+ drugs causing seizures] Thank you Analgesic, antipyretic and anti-inflammatory drugs Salicylate poisoning is potentially life-threatening ingestion. Most households have enough aspirin in the medicine cabinet to produce life-threatening ingestion. Available preparations: 1. Aspirin (acetyl salicylic acid). 2. Various cold preparations. 3. Topical preparations such as Methyl salicylate “oil of wintergreen” (counter irritant) and salicylic acid (topical keratolytic).  Conditions of poisoning: * Accidental: - In children occurs due to accidental ingestion by the child himself or accidental intoxication during treatment because fever pyrexia due to aspirin overdose may be mistaken for fever of infection with further administration of aspirin. - The elderly patient may suffer chronic toxicity following a gradual alteration in the patient’s metabolic elimination processes. * Suicidal: by young adolescents, it leads to morbidity rather than mortality due to large fatal dose. so its usuallay failed a suicide attempt just leads to illness  Mechanism of action: 1- Therapeutic action: reduces inflammation ~ pain Therapeutic salicylate levels result in anti-inflammatory, releit reduce fever analgesic and antipyretic effects primarily through inhibition of prostaglandin biosynthesis. 2- Toxic action and clinical presentations: a. GIT irritation manifested by: Burning pain in mouth and throat. Nausea and vomiting Gastric erosion and ulceration leading to GIT bleeding especially hematemesis. Lvomitting blood b. Hematology: bleeding tendencies due to: inhibition of prothrombin synthesis (↑prothrombin time). Inhibition of platelet function (↑bleeding time). ~ type I hypersensitivity c. Hypersensitivity reaction (Allergy): hives Urticaria and skin rash. Precipitation of bronchial asthma. Angioneurotic edema. Ledemn in deep levels of the skin Ns d. CNS: Salicylates cause central stimulation: Restlessness, excitability, delirium, and convulsions (due to increased Co2). Coma occurs in severe cases with inhibition of vasomotor and respiratory centers. e. Kidney : renal compromise occurs due to: Direct effect of aspirin →renal tubular necrosis → uremia. Indirect effect due to decreased renal perfusion due to dehydration. f. Hyperthermia: due to Uncoupling of oxidative phosphorylation with subsequent increase in cellular metabolic rate. Dehydration secondary to fluid loss by sweating and vomiting. g. Salicylism: high pitched tinnitus, vertigo, deafness may occur with therapeutic and toxic doses. This effect is due to 8th cranial nerve involvement. LVestibulocochlear It is reversible. h. Liver: mild liver necrosis may occur. i. Metabolic disorders: Initially there is short period of hyperglycemia (due to glycolysis) followed by hypoglycemia either late in acute toxicity or in chronic toxicity (due to depletion of glycogen stores). j. Fluid and electrolyte disturbances: 1. Dehydration due to increased metabolic rate and hyperthermia (sweating). Vomiting and hyperventilation are other contributing factors. 2. Hypokalemia due to K loss in urine.  the CNS the centre the brain in the early stages of salicylate poisoning and respiratory in are stimulated by the toxin this leads to increase in the depth and rate of breathing (hyperventilation ( ina ions (Ho and hydrogen ions more CO2 is exhaled by the lungs broken down into bicarbonate frm carbonic acid (H) which is withHo to the blood and combines normaarei acid produced > less - It in blood - > less acidic /more Alkaline blood less carbonic so more expelled CO2 - k- Acid-base imbalance: * It is one of the most common manifestations of salicylate poisoning. * Respiratory alkalosis is the predominant early acid-base disturbance and it is due to CNS and respiratory center stimulation → increased depth and rate of respiration’ increased CO2 expired by the lungs less plasma CO2 → less carbonic acid is formed →↑ HCO3/H2CO3 ratio and pH of the blood (respiratory alkalosis).  Fatal dose: 390 mg/kg BW. (Adult aspirin tablet contains 320 mg of acetyl salicylic acid. Therefore, 60-70 tablets are needed for fatal outcome) Fatal serum level: >100 mg %. Causes of death 1. Early (12-24hrs): central respiratory failure and cardiac arrhythmias (acidosis). 2. Delayed (few days): renal failure and hemorrhage.  Investigations: 1. Blood salicylate level: to assess severity of poisoning (not before hours). 2. Coagulation profile: prothrombin time and concentration and bleeding time. 3. Arterial pH, CO2, HCO3, and potassium (K) to assess acid base disturbance 4. Kidney an4. liver function tests. 5. X-Ray: aspirin concretions may be visualized in the stomach.  Treatment: 1- Supportive measures: ABCs (see general toxicology) Establish adequate airway, cardiovascular and respiratory support. 2- GIT decontamination: - Emesis by syrup of ipecac. - Gastric lavage using sodium bicarbonate. - Activated charcoal and MDAC to prevent on going absorption of salicylate. - Whole bowel irrigation is more effective in elimination. - Saline cathartics. 3- Excretion of the poison from the blood: - Forced alkaline diuresis: effective in metabolic acidosis and moderate toxicity. - Hemodialysis is indicated in severe cases and / or renal dysfunction. 4- Symptomatic: a. Metabolic acidosis → IV. Na HCO3. b. GIT irritation demulcents. c. Dehydration → IV fluids. d. seizures → diazeparn. e. bleeding tendencies →Vit. K or blood transfusion. f. Hyperthermia → cold foments and ice enema. g. Hypoglycemia → add glucose to IV fluids.  Acetaminophen (paracetamol) Acetaminophen (paracetamol) (APAP), N-acetyl-p- aminophenol, one of the coal tar analgesics, is a major active metabolite of phenacetin and acetanilide. It follows aspirin as a major cause of poisoning. Conditions of poisoning - Accidental: most common especially in children. - Suicidal (rare)  Mechanism of action: 1. Therapeutic action: It has the same analgesic and antipyretic actions as aspirin due to its potent inhibitory effect on synthesis of central prostaglandin (PG): On the contrary, the anti- inflammatory action is very weak due to its weak inhibitory action on synthesis of peripheral PG. 1. Toxic action: - The liver: The main hazard of APAP is liver damage. Mechanism: In therapeutic dose, acetaminophen is rapidly absorbed from the stomach and upper GIT to be metabolized in the liver through: * Major pathway: 90% of APAP is conjugated with glucuronide and sulfate → non toxic conjugate. * Minor pathway: 4% of APAP is metabolized via cytochrome P 450 mixed function oxidase system → toxic metabolite that is subsequently reduced by sulfhydryl (- SH) group of glutathione → non toxic compound. In overdose: APAP saturates conjugation pathways and produces an increase in toxic metabolite that overwhelms the glutathione detoxification mechanism (depletion of glutathione stores).The toxic metabolite then will bind to —SH group of hepatic cellular protein → centri-lobular necrosis. - The kidneys: Tubular necrosis. Clinical presentations: The clinical course passes into four phases that may overlap. Phase 1:30 min- 24 hrs. (GIT symptoms) - Malaise and diaphoresis. - Nausea and vomiting. - Drowsiness (no loss of consciousness). Phase II: 24-72 hrs. (Apparent recovery & blood chemistry changes) - Pain and tenderness in the right hypochondrium. - Altered liver function tests: Elevation in serum enzymes (AST, ALT, LDH) and bilirubin. Prolongation of prothrombin time may occur. Phase III: 72-96 hrs. (Fulminant liver failure) - Liver failure (jaundice, coagulation defects and encephalopathy and altered conscious level). - The condition is potentially reversible. Phase IV: 7-10 days (Prognosis) - Recovery: resolution of hepatic dysfunction and complete hepatic recovery occurs within 3-6 months. - Death: in severe cases due to multi-organ failure. Fatal dose: 15 g (a tablet contain 325-500 mg) Investigations: 1- Serum level of acetaminophen to assess degree of toxicity. 2- Liver function tests and prothrombin time. 3- Kidney function tests.  Treatment: 1- Supportive measures: ABCs (see general toxicology) 2- GIT decontamination: - Emesis by syrup of ipecac. - Gastric lavage - Activated charcoal and MDAC to prevent ongoing absorption of APAP and are given after antidote therapy to prevent adsorption of NAC. - Saline cathartics. Are preferred to enhance elimination from GIT. 3- Excretion of the poison from the blood: hemodialysis for renal failure. 4- Specific antidotes: i. N- acetyl Cysteine (NAC): - Mechanism: * It is metabolized by the hepatocyte to a glutathione precursor (cysteine) that provides protective levels of glutathione to detoxify the hepatotoxic metabolite by providing — SH group (minor pathway). * Enhance sulfation conjugation by providing sulfur (major pathway). - Forms and dose: Oral (mucomyst). Intravenous (parvolex) not approved in USA as it may cause anaphylactic reaction.  Should be initiated as early as possible because it is the only method to prevent hepatic necrosis. Initial loading dose (140 mg/kg), followed by maintenance doses (70 mg/kg/4hours for 3days). ii. No other antidotes proven to be effective as NAC. The suggested antidotes include, cimetidine (cytochrome antagonist) and methionine. 5- Symptomatic: Liver support: dextrose, sorbitol, etc. Corrosive Poisons :Inorganic Acids Example: – concentrated sulphuric – Nitric – hydrochloric acid. Action: is local corrosion only. Oral fatal dose is 4 ml. Poisoning is: – accidental by skin contamination, ingestion or inhalation of fumes – homicidal throwing of concentrated acid on the face. Corrosive burns  Clinical signs : – Local corrosion on skin – If taken orally it will cause the follwing: Severe burning pain from mouth to stomach. Severe colic and bloody vomitus with pieces of gastric mucosa, vomitus is strongly acidic, – dark due to acid haemation – black charring in sulphuric acid – yellow in nitric. Dehydration with thirst  wine low Oligouria and constipation. Shock with weak rapid pulse and hypotension. Evidence of corrosion on lips and mouth. Oedemaof the glottis and stridor and cyanosis. Death in few hours from shock and dehydration or few days from perforation and peritonitis. If the patient survives, oesophogeal stricture may occur with dysphaga. – Inhalation of Acid Fumes presents with: Burning pain in chest. Severe cough and dysnoea. Oedema of glottis and stridor. Pulmonary oedema. Cyanosis and death from asphyxia. Broncho pneumonia may occur.  Treatment: – Emetic and gastric lavage are contraindicated for fear of gastric perforation, also carbonates and bicarbonates due to evolution of CO2 causing gastric distension and rupture. – Give water orally to dilute the acid. – Antidote neutralization by weak alkalies as magnesium oxide or lime water (Ca hydroxide) or soap solution. the best is milk to avoid heat production, egg albumin, olive oil, or butter. – Morphine 8-15 mg I/V to relieve pain, shock and pulmonary oedema – I/V fluids for dehydration. – Tracheostomy for oedema of glottis and treat pulmonary oedema. – Antibiotics + corticosteroids are recommended by some