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References 1. 2. 3. 4. Casarett & Doull’s: Essentials of Toxicology, 2nd Ed., 2010 by Curtis Klaassen and John Watkins III Poisoning and Drug Overdose, 6th Ed., 2012 by Kent R. Olson Goldfrank's Toxicologic Emergencies, 10th Ed. 2014 by Lewis R. Goldfrank Emergency Toxicology, 2nd Ed., 1998 by Peter Viccellio Toxicology (1203562) (2 credit hours) Dr. khawla abu hammour Department of Biopharmaceutics & Clinical Pharmacy University of Jordan E.mail: [email protected] INTRODUCTION: TOXICOLOGY IN PERSPECTIVE DEFINITIONS & TERMINOLOGY • Toxicology: (toxicum) & (logia)….the Study of Poisons • Poisons: are drugs that have almost exclusively harmful effects • • • • However, Paracelsus (1493–1541) famously stated that “THE DOSE MAKES THE POISON” Toxins?? biologic origin, ie, synthesized by plants or animals, in contrast to inorganic poisons (lead and iron) Toxicology: is the branch of pharmacology that deals with the undesirable effects of chemicals on living systems Modern toxicology goes beyond this….study of molecular biology using toxicants TOXICOLOGY DISCIPLINES Environmental toxicology: • study the effects of chemicals that are contaminants of food, water, soil, or the atmosphere Industrial (occupational) toxicology: • Toxic exposure in the work place or during product testing Clinical (medical) toxicology: focus on the diagnosis, management and prevention of poisoning or ADEs due to medications, occupational and environmental toxins, and biological agents TOXICOLOGY DISCIPLINES Veterinary toxicology Forensic toxicology: is the use of toxicology to aid medical and legal investigation of death Nanotoxicology: is the study of the toxicity of nanoparticles (<100 nm diameter). Because of large surface area to volume ratio, nanomaterials have unique properties compared with their larger counterparts What is a Poison?? “All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy” Paracelsus (1493-1541) Water Intoxication? Water poisoning….fatal disturbance in brain functions when the normal balance of electrolytes in the body is pushed outside of safe limits (e.g., hyponatremia) by overhydration Intravenous LD50 of distilled water in mouse is 44ml/kg Intravenous LD50 of isotonic saline in mouse is 68ml/kg What is a Poison?? Poisoning or exposure?? Many people consider that poisoning start the moment exposure occurs In reality, we are exposed to a wide variety of toxic substances each day from food and water that we ingest, and air that we breath We do not display toxic symptoms, we are not actually poisoned What is Response? Change from normal state – could be molecular, cellular, organ, or organism level……the symptoms The degree and spectra of responses depend upon the dose and the organism Immediate vs. Delayed (carcinogenic) Reversible vs. Irreversible (liver vs. brain, teratogenic effect) Local vs. Systemic Graded vs. Quantal……degrees of the same damage vs. all or none Allergic Reactions & Idiosyncratic Reactions….ADRs Dose The amount of chemical entering the body This is usually given as: mg of chemical / kg of body weight = mg/kg The dose is dependent upon: The environmental concentration The exposure pathway The length of exposure The frequency of exposure The properties of the toxicant Exposure: Pathways Routes and Sites of Exposure: Ingestion (GIT), (first pass effect) Inhalation (Lungs): rapid absorption, because of large alveolar surface area Dermal/Topical (Skin), absorption varies with area of application and drug formulation, but usually absorption is slower than other routes Injection Ex. Lidocaine and Verapamil (antiarrhythmic drugs) Intravenous, intramuscular, intraperitoneal Typical response of Routes and Sites of Exposure: i.v > inhalation > i.p > i.m > oral > topical Exposure: Duration Toxicologists usually divide the exposure of experimental animals to chemicals into 4 categories……: Acute < 24hr Usually 1 exposure Sub-acute 1 month Repeated exposure Sub-chronic 1-3 months Repeated exposure Chronic > 3 months Repeated exposure Over time, the amount of chemical in the body can build up, it can redistribute, or it can overcome repair and removal mechanisms Lethal injection by capital punishment….. The other time-related factor that is important in the temporal characterization of repeated exposures is the frequency of exposure The relationship between elimination rate and frequency of exposure Dose Response Relationship The magnitude of drug effect depends on the drug concentration at the receptor site, which is in turn determined by the dose of drug administered and by factors of the drug pharmacokinetic profile There is a graded dose-response relationship in each individual and a quantal dose-response relationship in a population Graded-dose response relationship The response to a drug is a graded effect, meaning that the measured effect is continuous over a range of doses Graded dose response curves are constructed by plotting the magnitude of the response against increasing doses of a drug (or log dose) Dose-Response Relationship As the dose of a toxicant increases, so does the response Steep curve….relative small dose changes cause large response changes Graded-dose response relationship Two important properties of drugs can be determined by the graded dose response curves: Potency Maximal toxicity ‘U’ Shape of the Dose-Response Curve Quantal-dose response relationship The quantal (all or none) dose-effect curve often characterizes the distribution of responses to different doses in a population of individual organisms Median toxic dose(TD50): the dose at which 50% of individuals/population exhibit a particular toxic effect If the toxic effect is death of the animal, a median lethal dose (LD50) may be experimentally defined Median effective dose (ED50) LD50 The dose of chemical required to produce death in 50% of the organism exposed to it LD50 is not an absolute description of the compound toxicity in all individuals…..Variations No. of individuals Quantal-dose response relationship Hyper susceptible Sever Response Resistant Majority Mild Response Toxicity rating chart Rating Oral Lethal Dose Partially non toxic >15 g/kg Slightly toxic 5-15 g/kg Moderately toxic 0.5-5 g/kg Very toxic 50-500 mg/kg Extremely toxic 5-50 mg/kg Super toxic <5 mg/kg of animals Assumptions in Deriving the DoseResponse Relationship 1. 2. 3. 4. Confirms that a chemical is responsible for a particular effect Establishes the lowest dose for which an effect occurs – threshold effect (µg’s….g’s) Individuals vary in their response to a certain dose of xenobiotic The magnitude of the response is related to the dose………!!!!! TI = TD50 / ED50 For non-drug chemicals: Margin of Safety LD50 Shift to the left….shift to the right!!! !!!……Molecular Target Concept Agonist Antagonist Toxicodynamics & Kinetics Toxicokinetics: Disposition (ADME) Toxicokinetics is the quantitation of the time course of toxicants in the body during the processes of absorption, distribution, biotransformation, and excretion or clearance of toxicants In other words, toxicokinetics is a reflection of how the body handles toxicants as indicated by the plasma concentration of that xenobiotic at various time points The end result of these toxicokinetic processes is a biologically toxic concentration of the toxicant/s Absorption Ability of a chemical to enter the blood stream (GI tract, skin, lungs) Absorption: RATE & EXTENT The rate is of toxicological importance coz is the main determinant of the peak plasma concentration The extent determine the total body exposure or internal dose The fraction absorbed…..bioavailability(F) Comparing to i.v (1 or 100%) Absorption Route of exposure Inhalation: readily absorb gases into the blood via the alveoli (large alveolar surface, high blood flow) Particle size is the main determinant, ≤ 1μm penetrate the alveolar sacs of the lungs (nanoparticles!!) Enteral administration: particle size, surface area, blood flow rate, pKa, intestinal motility?? Factors influencing Toxicity Oral is related to: • Solid forms? Tendency to clump together • Presence of food: protein and fat delay absorption, carbohydrate beverages increase absorption • Chance to readily metabolize…and “hoped” detoxify!! 1st pass effect Absorption Dermal: fortunately not very permeable Absorption through epidermis by passive diffusion (stratum corneum thickness, condition of skin, blood flow, small size) …..then dermis by diffusion….systemic circulation Parenteral: I.V, I.P, I.M, S.C Physicochemical properties of the toxicant.. Distribution The process in which a chemical agent translocates throughout the body Blood carries the agent to and from its site of action, storage depots, organ of transformation, and organs of elimination Storage in adipose tissue: very lipophilic compounds (DDT) will store in fat Rapid mobilization of the fat (starvation) can rapidly increase blood concentration Liver and kidney: high binding capacity for several chemicals Storage in bone: chemicals analogues to calcium, fluoride, lead, strontium Distribution: storage & binding Rate of distribution dependent upon Blood flow Characteristics of toxicant (affinity for the tissue, and the partition coefficient) Binding plasma proteins: in equilibrium with the free portion, displacement by another agent Distribution may change over time BBB……tight capillary endothelial cells ELIMINATION = EXCRETION + METABOLISM Elimination Toxicants are eliminated from the body by several routes Urinary excretion Exhalation Volatile compound are exhaled by breathing Biliary excretion via fecal excretion Water soluble products are filtered out of the blood by the kidney and excreted into the urine Compounds can be extracted by the liver and excreted into the bile. The bile drains into the small intestine and is eliminated in the feces Milk, Sweat, Saliva Metabolism (biotransformation) Toxicity depends on the concentration of active compound at the target site over time The process by which the administered chemical (parent compound) are modified by the organsim by enzymatic reactions 1st objective – make chemical agents more water soluble and easier to excrete Increase solubility ---- decrease amount at target Increase ionization ---- increase excretion rate ---- decrease toxicity Bioactivation/toxication ---- biotransformation can result in the formation of reactive metabolites Metabolism (biotransformation) Can drastically affect the rate of clearance of compounds Can occur at any point during the compound’s journey from absorption to excretion Key organs in biotrasnformation Liver (principal) Intestine, Lung, kidney Biotransformation pathways o Phase I: make the toxicant more water soluble o Phase II: links with a soluble endogenous agent Factors influencing Toxicity Poisoning do not always follow the “text-book” descriptions commonly listed for them S&S that are often stated as being pathognomonic for a particular toxic episode may or may not be evident with each case of poisoning An experimentally determined acute oral toxicity expression, such as LD50 value, is not an absolute description of the compound’s toxicity in all individuals Imp. principle to be always kept in mind when evaluating a victim’s response to a toxic chemical is that there are numerous factors that may modify the patient’s response to the toxic agent Those factors are the same as those which determine a drug’s pharmacologic action Factors influencing Toxicity 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. COMPOSITION OF THE TOXIC AGENT DOSE & CONCENTRATION ROUTE OF EXPOSURE METABOLISM OF THE TOXICANT STATE OF HEALTH AGE & MATURITY NUTRITIONAL STATE GENETICS GENDER ENVIRONMENTAL FACTORS Factors influencing Toxicity 1. Composition of the toxic agent: A basic fallacy: responsible toxicant is the pure substance Physiochemical composition of toxicant: solubility, charge, hydrophobicity, powder/dust • Solid vs Liquid • Poisoning is more with liquid and small particles (particle size) Factors influencing Toxicity 1. Composition of the toxic agent: E.g: Cr3+ relatively non-toxic, Cr6+ causes skin and nasal corrosion and lung cancer PH: strong acids or bases vs mild acids and basics Stability: paraldehyde…..acetaldehyde pulmonary edema) (nausea, Factors influencing Toxicity 2. Dose and concentration: Most important factor: e.g. acute ethanol exposure causes CNS depression, chronic exposure liver cirrhosis Diluted solutions absorbed) 3. Route of exposure Vs concentrated solution (easily Factors influencing Toxicity 4. Metabolism of the toxicant 1st pass effect • NOT ALWAYS Ox. • MeOH effects Formaldehyde + Formic acid …serious side 5. State of health: • Hepatic, renal insufficiency • Diarrhea or constipation may decrease or increase the time of contact between chemical and absorptive site • Hypertension may exacerbate response to chemical with sympathomimetic activity Factors influencing Toxicity 6. Age and maturity • Chloramphenicol….grey baby syndrome • Geriatric….generalized decrease in blood supply to tissue…..decrease in toxicity….(not always) • P.O drugs….absorption decrease • Diseases (hepatic, renal, CV)….decrease detoxification, excretion, distribution Factors influencing Toxicity 7. Nutritional state • Empty stomach or food contents (pH, high fat,….) Ca2+ in milk and tetracycline Fatty food increase absorption of griseofulvin Tyramine rich food and MAO inhibitors Hypoalbuminemia: greater amount of free drug Factors influencing Toxicity 9. Gender • Difference in absorption….. • Difference in metabolism rate…. • Differences in quantities of muscle mass and fat tissue….in i.m injection Factors influencing Toxicity 8. Genetics: (Genetic toxicology….normal Gaussian curve) • Species, strain variation, inter-individual variations • Succinylcholine metabolized by pseudocholisterenase into succinylmonocholine + choline then…. Esterase (liver) Succinic acid + choline • G6PD deficiency…..protect RBCs from oxidative damage, may cause hemolytic anemia Principle in management of poisoned patient What to do, and in what order to do it?! “The surest poison is time” Ralph Waldo Emerson (1803-1882) Poisoning in Jordan Period during 2006-2008 at the National Drug and Poison Information Center (NDPIC) (poisoning emergency no. 109) The problem is underestimated and sometimes unreported The most common reason of poisoning was unintentional (49.39%), followed by suicidal attempts (23.94%) The highest incidence was in children less or equal to 5 years (34.9%), then 20-29 years (~23%) Poisoning in Jordan The major cause of poisoning was due to drugs (42%) of all exposures, where acetaminophen products were responsible for most of the cases within this category (13.4%) then benzodiazepines, NSAID and then antihistamines Bites and stings were relatively highly prevalent (23.7% of exposures), which is justified by the geographical nature of Jordan Then household products, hydrocarbons and pesticides How Does the Poisoned Patient Die? Many toxins depress the central nervous system (CNS)…coma A comatose patients frequently lose their airway protective reflexes and their respiratory drive ………may die as a result of airway obstruction by the flaccid tongue, aspiration of gastric contents in the tracheobronchial tree, or respiratory arrest ......most commonly due to overdoses of narcotics and sedative-hypnotic drugs (eg, barbiturates and alcohol) How Does the Poisoned Patient Die? Cardiovascular toxicity……Hypotension may be due to depression of cardiac contractility Hypovolemia resulting from vomiting, diarrhea Peripheral vascular collapse due to blockade of -adrenoceptormediated vascular tone Lethal cardiac arrhythmias…….overdose of ephedrine, amphetamines, cocaine, digitalis, and theophylline Hypothermia or hyperthermia can also produce severe hypotension How Does the Poisoned Patient Die? Seizures may cause pulmonary aspiration, hypoxia, brain damage Cellular hypoxia may occur in spite of adequate ventilation (poisons that interfere with transport or utilization of oxygen cyanide, HS, CO..) Other organ system damage may be delayed in onset….. acetaminophen or certain mushrooms / paraquat Finally some patients may die because the behavioral effects of the ingested drug may result in traumatic injury (alcohol/sedative-hypnotic drugs) A 62-year-old woman with a history of depression is found in her apartment in a lethargic state. An empty bottle of bupropion is on the bedside table. In the emergency department, she is unresponsive to verbal and painful stimuli. She has a brief generalized seizure, followed by a respiratory arrest. The emergency physician performs endotracheal intubation and administers a drug intravenously, followed by another substance via a nasogastric tube. The patient is admitted to the intensive care unit for continued supportive care and recovers the next morning. What drug might be used intravenously to prevent further seizures? What substance is commonly used to adsorb drugs still present in the gastrointestinal tract? Principle in management of poisoned patient While the majority of poisoned patients are awake and have stable vital signs, some may present unconscious or in shock…..so….: 1. Always assess the condition of the patients “ABCD”…clinical evaluation 2. Decide what must be done and in what order 3. Once the patient is stabilized, and only then, try to identify the poison, the quantity involved and how much time has been elapsed since exposure 4. Then, proceed with decontaminating / antidoting the poison ABCD A Airway B Breathing C Circulation D Dextrose Airway……Ensure airway and protect cervical spine Airway Assessment: Consider to breath and speak to assess air entry Signs of obstruction (flaccid tongue, vomitus….) Apnea, dysphonia, cyanosis, airway distress Management Goals: Optimize the airway position……force the flaccid tongue forward and maximize the airway opening Prevent aspiration Permit adequate oxygenation Airway……Ensure airway and protect cervical spine The following techniques are useful:. Caution: Do not perform neck manipulation if you suspect a neck injury. Place the neck and head in the “sniffing” position, with the neck flexed forward and the head extended….(chin lift to open the airway) Apply the “jaw thrust” maneuver to create forward movement of the tongue without flexing or extending the neck. https://www.youtube.com/watch?v=r3ckgEQEE_o Place the patient in a head-down, left-sided position…..allows the tongue to fall forward and secretions or vomitus to drain out of the mouth….(lateral decupitus position) Oral axis Pharyngeal axis Tracheal axis Airway The airway can also be maintained with artificial oropharyngeal or nasopharyngeal airway devices Placed in the mouth or nose to lift the tongue and push it forward. Airway Endotracheal intubation: attempted only by those with training Complications: vomiting with pulmonary aspiration; local trauma to the oropharynx, nasopharynx, and larynx; inadvertent intubation of the esophagus or a main-stem bronchus; and failure to intubate the patient after respiratory arrest has been induced by a neuromuscular blocker Indications: Unable to protect airway Inadequate spontaneous ventilation Arterial blood gases (pCO2 > 60%) Profound shock GCS (Glasgow Coma Scale) ≤ 8 Orotracheal or nasotracheal intubation Two routes for endotracheal intubation. A: Nasotracheal intubation. B: Orotracheal intubation. 13-15 mild injury, 9-12 moderate injury, 8 or less severe injury Breathing Pulse Oximetry By observation and oximetry (monitor the saturation of pt’s Hb) Ventilatory failure…..most common cause of death in poisoned patients: Hypoxia……brain damage, cardiac arrhythmias, and cardiac arrest Hypercarbia…...acidosis (may contribute to arrhythmias) LOOK for mental status, chest movement, respiratory rate LISTEN for air escaping during exhalation, sound of obstruction FEEL for the flow of air, chest wall for crepitus ASSESS tracheal position, auscultation of all lung fields Circulation Check skin color, temperature, capillary refill Check blood pressure and pulse rate and rhythm Management: stop major external bleeding Begin continuous ECG monitoring Altered mental status A decreased level of consciousness is the most common serious complication of drug overdose or poisoning Coma sometimes represents a postictal phenomenon after a drug- or toxin-induced seizure Coma may also be caused by brain injury associated with infarction or intracranial bleeding Coma frequently is accompanied by respiratory depression, which is a major cause of death May be complicated by hypotension, hypothermia, hyperthermia, and rhabdomyolysis Disability Assess level of consciousness by AVPU method A…..ALERT V…..responds to VERBAL stimuli P…..responds to PAINFUL stimuli U…..UNRESPONSIVE Size and reactivity of pupils Movement of upper and lower extremities The DONT Cocktail Administer supplemental oxygen Dextrose: All patients with depressed consciousness should receive concentrated dextrose unless hypoglycemia is ruled out Adults: 50% dextrose, 50 mL (25 g) IV. Children: 25% dextrose, 2 mL/kg IV Thiamine: is a cofactor in a number of metabolic pathways allowing aerobic metabolism to produce ATP and, Important in normal neuronal conduction The DONT Cocktail Given to prevent or treat Wernicke's syndrome resulting from thiamine deficiency in alcoholic patients (poor diet) and others with suspected vitamin deficiencies (100 mg, in the IV bottle or intramuscularly) Naloxone: All patients with CNS depression and respiratory depression should receive naloxone! If artificially ventilated…..not immediately necessary Caution: may precipitate abrupt opioid withdrawal The DONT Cocktail DOSE: 0.4 mg IV (may also be given intramuscularly) If there is no response within 1–2 minutes, give naloxone, 2 mg IV If there is still no response and opioid overdose is highly suspected give naloxone, 10–20 mg IV Exposure Remove clothes and other items that interferes with a full evaluation 1. History Historical data should include the type of toxin Route of exposure intravenous) (e.g. ingestion, inhalation, Also ask about prior suicide attempts or psychiatric history If the patient is a female in reproductive years, ask about pregnancy and obtain pregnancy test Identify the toxicant SAMPLE S: substance, amount, time, correlate symptom A: allergies, age, gender, wt M: medication (including prescription drugs, OTC medication, vitamins, and herbal preparation) P: past diseases, substance abuse or intentional ingestion L: last meal….influence absorption E: events leading to current condition ODORS Acetone Garlic • Isopropyl alcohol • Ethanol • Arsenic • Organophosphates Bitter almonds Rotten eggs • Cyanide • Sulfide Not absolute… the odor may be subtle and may be obscured by the smell of emesis or by other ambient odors. In addition, the ability to smell an odor may vary Blood Pressure HYPERTENSION Sympathomimetics Amphetamines Cocaine MAOI Nicotine HYPOTENSION Antipsychotic Nitrates Beta blockers Opioids Calcium channel blockers Sedative-hypnotics Ethanol Tricyclic antidepressants (with tachycardia) Pulse TACHYCARDIA Amphetamines Atropine Antihistamines Caffeine Cyanide Nitrates BRADYCARDIA Beta blockers Calcium channel blockers Clonidine Digitalis Mushrooms Organophosphates Sedative hypnotics RESPIRATION HYPERVENTILATION Rapid respirations are typical of toxins that produce metabolic acidosis or cellular asphyxia.. Salicylates Carbon monoxide Ethylene glycol Hydrocarbons HYPOVENTILATION Anesthetics Cyanide Ethanol Sedative hypnotics Opioids TEMPERATURE HYPERTHERMIA (>40°C): Sympathomimetics Amphetamines MAOI Anticholinergic Drugs producing seizures or muscular rigidity TEMPERATURE HYPOTHERMIA (<32°C): CNS depressants (barbiturates, opioids, ethanol) Hypoglycemic agents Drugs that cause vasodilation …..(especially if accompanied by cold environment) N.B: commonly bradycardia accompanied by hypotension and EYE FINDINGS Miosis: Cholinergic Clonidine Insecticides Narcotics Phenothiazines EYE FINDINGS Mydriasis: Anticholinergic Sympathomimetic Withdrawal states Nystagmus: Horizontal……phenytoin, alcohol, barbiturates Both vertical & horizontal: strongly suggest phencyclidine poisoning OTHERS Absent bowel sounds: paralytic ileus……anticholinergic intoxication or perforation coz of acid ingestion Hyperactive bowel sounds, abdominal cramping and diarrhea….organophosphates, A muscaria Determine if bladder distention and urinary retention exist…..anticholinergic intoxication Skin appearance: red, white, blue, warm, cool, dry, moist, piloerection (opioid withdrawal) Decontamination Gastric exposure Inhalation exposure Dermal exposure Ocular exposure The decision to perform GI decontamination is based upon the specific poison(s) ingested, the time from ingestion to presentation, presenting symptoms, and the predicted severity of poisoning. GI decontamination is most likely to benefit patients who: ●Present for care soon after ingestion (usually within one to two hours) ●Have ingested a poison and amount suspected to cause toxicity ●Do not have clinical factors that make decontamination dangerous Inhalation exposure Irritant gases exposure!! mainly in industry, but also after mixing cleansing agents at home, or smoke inhalation in structural fires Health care providers should protect themselves from contamination Eg.: “organophosphate, fumes of H2S, cyanide, ammonia, formaldehyde” Inhalation exposure Treatment: Immediate removal from hazardous environment 100% humidified O2 Assisted ventilation Bronchodilators Observe for noncardiogenic pulmonary edema. Early signs and symptoms include “dyspnea, tachypnea, hypoxemia” Monitor arterial blood gases or oximetry, chest x-ray, and pulmonary function Dermal exposure Attendant should wear protective gear “gloves, goggles, shoe cover” Remove contaminated clothes, contact lenses and jewelry and place them in a plastic bag Gently rinse and wash skin with copious amount of water for at least 30min….start with lukewarm water “vasoconstriction” Use soap to remove oily substances Caustic contamination may need prolonged irrigation Some substances may react with water, should be brushed off e.g. chlorosulfonic acid, Ca oxide, titanium tetrachloride For some substances, local application of certain chemical compound as soaks may be useful Hydrofluoric acid…calcium gluconate 2.5% Oxalic acid…calcium gluconate Phenol…mineral oil or other oil White phosphorous…copper sulfate 1% Ocular exposure At least 15-20min irrigation with fully retracted eyelids Don’t neutralize acid or alkali; continue irrigation until pH of the tear is neutral After irrigation examine the eye for corneal damage Ophthalmogist consultation: Ophthalmogist may instill topical cycloplegic agent, e.g. 5% homatropine or 2% scopolamine to prevent spasm of ciliary body Topical antibiotic (sulfisoxazole or gentamicin) Apply a sterile patch Decontamination Gastric Decontamination Inhalation exposure Dermal exposure Ocular exposure Decontamination Gastric decontamination (decrease absorption) Dilution Emesis Gastric lavage Activated charcoal Cathartics Whole bowel irrigation Gastric Decontamination Controversy about the roles of emesis, gastric lavage, activated charcoal, and cathartics to decontaminate the gastrointestinal tract Little medical support for gut-emptying procedures, especially after a delay of 60 minutes or more very little of the ingested dose is removed by emesis or gastric lavage Moreover, simple oral administration of activated charcoal without prior gut emptying seems to be as effective as the traditional sequence of gut emptying followed by charcoal Gastric Decontamination However, in some circumstances, aggressive gut decontamination may potentially be life saving, even after more than 1–2 hours Examples: ingestion of highly toxic drugs (eg, calcium antagonists, colchicine), ingestion of massive amounts of a drug (eg, 150–200 aspirin tablets), and ingestion of sustainedrelease or enteric-coated products Decontamination Gastric decontamination (decrease absorption) Dilution Emesis Gastric lavage Activated charcoal Cathartics Whole bowel irrigation DILUTION Must acidic or alkaline substances be neutralized..??.........NEVER!!!...heat! 55-ml of sulfuric water……temperature acid, mixed solution of with 54ml 79ºC; with 1000ml…still 14ºC “To dilute or no dilute…this is the question!” DILUTION Dilution of the poison: 1. 1-2 cupfuls of water to children 2. 2-3 cupfuls of water to adult 3. A better rule to give a quantity comfortable swallowed Water?? 1. Reduce gastric irritation 2. Add bulk to the stomach needed later for emesis Carbohydrated beverages??....NO!! CO2 distension of the stomach….opening pyloric sphincter Milk??....NO!! Increase absorption of lipophilic toxicant…&....delay emetic action of ipecac General consideration Fluids should not be forced Excessive liquid may distend the stomach…premature evacuation In case of solid form do not dilute Household products….dilution Nothing administered orally to unconscious patient or if gag reflux absent Decontamination Gastric decontamination (decrease absorption) Dilution Emesis Gastric lavage Activated charcoal Cathartics Whole bowel irrigation EMESIS Emesis can be induced with ipecac syrup Chemically induced emesis is no more approved as a 1st line procedure for antidoting poisons….activated charcoal Decrease absorption dangerous….? Precautions!!!! of drug but sometimes EMESIS Do not induce vomiting if the poison is a: Convulsant, or sedative-hypnotic Hydrocarbon Corrosive acid or alkali Do not induce vomiting if the patient: Unconscious or comatose Absence of gag reflex Have severe CVD extremely weakened blood vessels < 6 months in age (poorly developed gag reflex) SYRUP OF IPECAC (1648) Indications: Children that recently ingested known substances that are not well adsorbed by activated charcoal for whom transport time to a healthcare facility is delayed….save time Less traumatic than gastric lavage Remove particles of material too large to pass through the opening of a lavage tube Recommended dose of syrup of Ipecac AGE QUANTITY < 1 yr 5-10 ml <5 yr 15 ml Adult 30 ml After 10–15 minutes, give 2–3 glasses of water SYRUP OF IPECAC Ipecac induce vomiting has 2 phases: Early: within 15-20 min….direct stimulation of GIT Late: after 20 min….direct stimulation of medullary chemoreceptor trigger zone The dose may be repeated once if no response within 15-20 min Repeat the fluid administration Have the patient sit up or move around, because this sometimes stimulates vomiting If the second dose of ipecac does not induce vomiting, use an alternative method of gut decontamination Syrup of Ipecac: side effects Drowsiness occurs in about 20% and diarrhea in 25% of children Persistent vomiting may delay administration of activated charcoal or oral antidotes Protracted forceful vomiting may result in hemorrhagic gastritis Intracerebral bleeding in elderly patients, diaphragmatic rupture, aspiration pneumonia Repeated daily use (bulimic patients) may result in cardiac arrhythmias owing to accumulation of cardiotoxic alkaloids Convulsion, skeletal muscle weakness SYRUP OF IPECAC Collect vomits and inspect for fragments of pills, note appearance, color and odor In emergency and no ipecac syrup: 2-3 tablespoons of liquid detergent (not powdered or concentrated) in a glass of water (direct stimulation of gastric mucosa within 10 min.) No other acceptable alternative…..! Never salt water….fatal hypernatremia Manual digital stimulation, copper sulfate, apomorphine, and other emetics are unsafe and should not be used SYRUP OF IPECAC Contraindications: Loss of airway protection reflexes Caustic or corrosive Toxicant produce abrupt loss of conscious (ethanol, ultrashort BZDs, short acting barbiturate, heterocyclic antidepressant) Seizures (amphetamine, cocaine, ibuprofen >400mg/kg) Petroleum distillate Infant <6 months age Prior significant vomiting or hematoemesis Absence of bowel sound…gastric lavage Special situations (late pregnancy, elderly, HTN) Decontamination Gastric decontamination (decrease absorption) Dilution Emesis Gastric lavage Activated charcoal Cathartics Whole bowel irrigation GASTRIC LAVAGE Process of washing out the stomach with various solutions including lukewarm water, saline, sodium bicarb. Indicated when emesis is contraindicated Preferred method for adult (co-operative) already in medical facility Effective within 30–60 minutes of the ingestion…. Usefulness decrease with time Still useful several hours after ingestion of agents that slow gastric emptying (eg. anticholinergic drugs) Gastric lavage Indications The American Association of Poison Centers (AAPC) and the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) have issued a joint statement that gastric lavage should not be employed routinely, if ever, in the management of poisoned patients The patient is placed on the left lateral decubitus position (pylorus pointed up) to permit pooling of gastric contents with head lower than the rest of the body. The largest catheter is inserted into the stomach GASTRIC LAVAGE Attempt to aspirate as much of the stomach content as possible then… Lavage fluids should be introduced into the stomach (50100ml aliquots for children) and (200- to 300-ml aliquots for adults) Lavage till clear Complication (3%) aspiration pneumonia, esophageal perforation, electrolyte imbalance Advantages: dilute and remove corrosive liquids and prepare the stomach for endoscopy GASTRIC LAVAGE Do not perform in any patient with an impaired level of consciousness unless the airway is protected by a cuffed endotracheal tube….prevent aspiration In patients < 2 years, no cuff is needed because the endotracheal tube fits snugly A specific antidote is then given if available; otherwise, a slurry of activated charcoal is given Do not perform if ingestion of tablets (especially big in size) GASTRIC LAVAGE CONTRAINDICATION: Caustic or corrosive*….perforation Uncontrolled convulsion….aspiration HC & petroleum distillate Comatose….endotracheal intubation Cardiac dysrhythmia….must be first controlled Decontamination Gastric decontamination (decrease absorption) Dilution Emesis Gastric lavage Activated charcoal Cathartics Whole bowel irrigation ACTIVATED CHARCOAL Is a highly adsorbent powdered material produced by the superheating of wood pulp Form of carbon that has been processed in order to make it very porous with a large surface area to adsorb chemicals ……it is highly effective in adsorbing most toxins when given in a ratio of approximately 10 to 1 (charcoal to toxin) Only a few toxins are poorly adsorbed to charcoal and in some cases this requires a higher ratio (eg, for cyanide a ratio of about 100:1 is necessary) ACTIVATED CHARCOAL Indications: whenever an emetic cannot be used, following successful chemical induction of emesis, or when the patient is unconscious In ED, compliance is assumed after emesis, during or after lavage Given even if the offending substance is not well adsorbed to charcoal in case other substances have been co-ingested Give activated charcoal aqueous suspension orally or by gastric tube. Initial dose (1 g/kg) Then 0.5g/kg every 2-6hrs ACTIVATED CHARCOAL Within 30-60 min of ingestion Should not be given within 30-60 min of syrup of ipecac unless the victim has already vomited (adsorbed on charcoal) In the stomach and intestine, poisons diffuse through the numerous pores on the charcoal surface and form tight chemical bonds This charcoal-chemical complex then passes out of the body Risk: pulmonary aspiration due to loss of airway reflex Substances poorly adsorbed by activated charcoal Alkali Iron Lithium Ethylene glycol Mineral acids Fluoride Potassium Heavy metals Cyanide* Rapid onset ACTIVATED CHARCOAL ADDITIONAL USES: Long acting sustained release (9-10hr later ingestion) Enterohepatic circulation Fecal discoloration frequently occurs. Black stools may be utilized as a diagnostic sign of gastrointestinal transit Can be given at home?? Available in pharmacies? Substances with enterohepatic circulation Chloral hydrate NSAIDS Colchicine Phencyclidine Digitalis Salicylates INH TCA ACTIVATED CHARCOAL CONTRAINDICATION: Absence of bowel sounds Sign of intestinal obstruction Lack of airway protection Child less that 1year…cathartic effect May decrease the absorption of the antidote given later Decontamination Gastric decontamination (decrease absorption) Dilution Emesis Gastric lavage Activated charcoal Cathartics Whole bowel irrigation Cathartics Whenever contact time between the poison and absorption site is reduced, the potential for toxicity is likewise less Cathartics Controversy remains over the use of cathartics to hasten elimination of toxins from the gastrointestinal tract Few data exist to support their efficacy…..some toxicologists still use cathartics routinely when giving activated charcoal even To enhance GI transit of the charcoal-toxin complex Administer the cathartic (Mg citrate, Na phosphate, sorbitol) along with activated charcoal or mixed together as a slurry The evacuation action of saline cathartics may require several hours for completion Contraindications Patient has electrolyte disturbance Bowel sound absent Evidences for bowel obstruction Sodium- and magnesium-containing cathartics should not be used in patients with fluid overload or renal insufficiency respectively Evidence of GI bleeding Patient with diarrhea <1yr (electrolyte disturbances) Decontamination Gastric decontamination (decrease absorption) Dilution Emesis Gastric lavage Activated charcoal Cathartics Whole bowel irrigation Whole Bowel Irrigation WBI: aggressive form of GIT decontamination attempt to cleanse the bowel by the enteral administration of large volume of an osmotically balanced nonabsorbable polyethylene glycol electrolyte solution (PEG-ES) which induces a liquid stool Contains the osmotically active sugar (PEG) with sodium sulfate, sodium chloride, sodium bicarb and potassium chloride to maintain electrolyte balance Whole Bowel Irrigation Rarely performed because risk-benefit analysis reserves this intervention for life-threatening indication: Ingestion of sustained-release or enteric coated preparations (valproic acid, verapamil or diltiazem) Agent that do not bind to charcoal (iron, other heavy metals, lithium) No good clinical outcome is expected with antidote administration and the patient presents before established severe toxicity Complications such as: N, V Whole Bowel Irrigation TECHNIQUE: Use nasogastric tube Dose: Adult 2L/hr, < 5yrs 35ml/kg/hr Continue irrigation until rectal effluent is clear (~6hr) Administer metoclopramide to minimize vomiting Stop if abdominal distension or loss of bowel sounds are noted Contraindications Good outcome assured with antidote therapy Uncooperative patient….inability to place a nasogastric tube Uncontrolled vomiting (extensive hematomesis) Ileus and bowel obstruction Perforation or peritonitis Gastrointestinal decontamination METHODS TO ENHANCE ELIMINATION OF TOXIC AGENT Urinary manipulation Extracorporeal methods Peritonial dialysis Hemodialisis Hemoperfusion Enhanced Elimination 3 critical questions must be answered: A. Does the patient need enhanced removal? 1. Severe or critical intoxication with a deteriorating condition despite maximal supportive care (eg, phenobarbital overdose with intractable hypotension) 2. The normal or usual route of elimination is impaired (eg, lithium overdose in a patient with renal failure) 3. The patient has ingested a known lethal dose or has a lethal blood level (eg, theophylline or methanol) 4. The patient has underlying medical problems that could further complicate the situation Enhanced Elimination B. Is the drug or toxin accessible to the removal procedure? The drug ‘poison’ should be located primarily within the bloodstream or in the extracellular fluid…..If extensively distributed to tissues, it is not likely to be easily removed 1. The volume of distribution (Vd) provides info on the accessibility of the drug: Very large Vd……Small Vd 2. Protein binding……highly protein-bound drugs have low free drug concentrations……difficult to remove by dialysis Enhanced Elimination C. Will the method work?.......Does the removal procedure efficiently extract the toxin from the blood? 1. The clearance (CL) is the rate at which a given volume of fluid can be "cleared" of the substance CL = extraction ratio x blood flow rate Extraction ratio across the dialysis machine or hemoperfusion column and the blood flow rate through the following system 2. Total clearance…..If the contribution of dialysis is small compared with the total clearance rate, the procedure will contribute little to the overall elimination rate Urinary manipulation: These methods require that the renal route be a significant contributor to total clearance Forced diuresis Increase GFR, used in conjugation with ion trapping to prevent reabsorption Administration of enough fluids to establish a renal flow of 3-5ml/kg/hr Dangerous due to fluid overdose: CHF RF Electrolyte disturbances SIADH Pulmonary edema Cerebral edema Ion trapping Alteration of urine pH prevent renal reabsorption of poison that undergo glomerular filtration and active tubular secretion Many substance are reabsorbed in the nonionized form Urine alkalization (pH= 7.5-8) NaHCO3 ± acetazolamide Urine acidification (PH= 4.5-6) Ascorbic acid, NH4Cl, HCl Alkalinization NaHCO3 1-2 mEq/kg mix with 5% dextrose/0.5 N saline 15ml/kg Infuse i.v over 3-4hrs Check urine PH every hour, maintain at pH7.5-8 Has limited role in Tx of weak acids…the acidic toxin is much less likely to cross the cell membrane leaving the serum to enter the cell Reserved for phenobarbital, salicylate Acidification Ammonium (preferred agent): Monitoring is mandatory of electrolyte status, acid-base status and complication HCl (alternative agent): 75mg/kg/24hr given either i.v. as 2% solution or P.O. in 4-6 divided doses 0.1M HCl solution 0.2 mEq/kg/h i.v. Ascorbic acid (controversial) 2g i.v., 6g p.o. Ion trapping Acidification of the urine is not recommended by many poison centers, may cause metabolic acidosis…. May cause rhabdomyolysis & myoglobinurea Acidification Phencyclidine Amphetamine Quinidine Strychnine Phosphorous Cocaine Urine PH alteration Alkalinization Salicylates Phenobarbital Arsenic INH Lithium Meprobamate Naphthalene Indications: Renal elimination is the 1º route of excretion Significant renal tubular reabsorption of toxin Small Vd Low protein binding Contraindications Renal dysfunction…fluid overload Cardiac insufficiency…pulmonary edema Uncorrected fluid deficit Electrolyte abnormality NH4Cl..hepatic insufficiency Urinary manipulation Extracorporeal methods Peritonial dialysis Hemodialisis Hemoperfusion Extracorporeal methods Peritoneal dialysis, hemodialysis, hemoperfusion, hemofiltration, and plasmapheresis are not ED procedure Shouldn’t replace specific antidote Dialysis • • • Is a process for removing waste and excess water from the blood, and is used primarily to provide an artificial replacement for lost kidney function in people with renal failure Diffusion of solutes across a semi-permeable membrane….substances tend to move from an area of high concentration to an area of low concentration Smaller solutes and fluid pass through the membrane, but the membrane blocks the passage of larger substances (for example, red blood cells, large proteins) Dialysis • Considered for patients intoxicated with: Dialyzable toxin (table) Who are not responding or is deteriorating in spite of good medical care Vd < 1L/kg (phenobarbital, salicylate, theophylline) Protein binding <50% Water soluble Low Mol. Wt. < 500 Da Long elimination T1/2 Drugs and Toxins for Which Dialysis Is effective Amphetamines MAO inhibitors Antibiotics Antihistamines Boric acid Tricyclic antidepressants Calcium Lirium Chloral hydrate Digitalis Fluorides ethanol Iodides Hallucinogens Isoniazid Heroin/opiates Paraldehyde Carbon monoxide Phenobarbital Phenothiazines Potassium Eucalyptus oil Quinidine Iron Salicylates Lead Strychnine Lithium Thiocyanate Belladonna compounds HEMOdialysis Blood is taken from a large vein (usually a femoral vein) and is pumped through the hemodialysis system Drugs and toxins flow passively across the semipermeable membrane down a concentration gradient into a dialysate (electrolyte and buffer) solution Removal of drug is dependent on flow rate—insufficient flow (ie, due to clotting) will reduce clearance proportionately Should be considered immediately if: The patient is stable and has a MeOH or ethylene glycol conc. >50mg/dl Neurological manifestations or Lithium conc.> 4mEq/L Complication: hemorrhage hypocalcemia, and infection (heparin), hypotension, hypoglycemia, BAGELS: • Bromide • Alcohols • Glycols • Electrolytes • Lithium/longacting barbiturates • Salicylate Hemoperfusion Significantly more effective than hemodialysis Same procedure as hemodialysis including anticoagulant, but the blood is pumped directly through a column containing adsorbent material (charcoal or resin) Even if the toxin is lipid soluble, protein bound, or high Mol. Wt. Factors: adsorbability of resin or charcoal, (short acting barbiturates, theophylline, phenytoin), low Vd, plasma conc. of the toxin Similar complications….thrombocytopenia (hemorrhage), hypotension, hypoglycemia, infection and PERITONEAL dialysis Elimination of toxic metabolites from the blood, using the peritoneum as semipermeable membrane for dialysis Dialysate fluid (1-2 L) introduced into the cavity through transcutaneous catheter after local anesthesia, allow to equilibrate for 1-2hrs and then cleaned off Water soluble toxins, poorly protein bound, low MW, low Vd Easiest performed method…(at home), does not require anticoagulation Lowest risk for causing complications Least effective (10-15% as effect as hemodialysis) • CL of toxin depends on dialysate flow rate, Mol. Wt. of the toxin & surface area of the peritoneum PERITONEAL dialysis Effectiveness may be increased by certain drugs…dipyridamole…increases vascular permeability and may increase peritoneal clearance NO if Severe or threatening absorption of toxin for which peritoneal dialysis will need to much time The presence of hypotension, vasoconstriction Not dialyzable toxin Complication: intestine perforation, electrolyte imbalance, infections