SESSION-3-DRUG-TOXICITY-AND-POISONING.pdf

DRUG TOXICITY AND POISONING Dr Dan Estandarte › Toxicology – study of the adverse effects of chemicals on living organisms › The higher the therapeutic index, the safer the drug › Adverse drug reactions (ADRs) are broadly divided into – Predictable - related to pharmacologic actions of the d...

DRUG TOXICITY AND POISONING Dr Dan Estandarte › Toxicology – study of the adverse effects of chemicals on living organisms › The higher the therapeutic index, the safer the drug › Adverse drug reactions (ADRs) are broadly divided into – Predictable - related to pharmacologic actions of the drug in otherwise normal individuals and › Dose-dependent reactions › Drug interactions – Unpredictable - related to an individual’s immunological response and, on occasion, to genetic differences in susceptible patients › Allergic reactions › Idiosyncratic reactions – Idiosyncratic Reactions = adverse effects that cannot be explained by the known mechanisms of action of the offending agent, do not occur at any dose in most patients, and develop mostly unpredictably in susceptible individuals only. › ADRs account for 3% to 6% of all hospital admissions and occur in 10% to 15% of hospitalized patients. TYPES OF THERAPEUTIC DRUG TOXICITY › Dose Dependent Reactions › Allergic Reactions › Idiosyncratic Reactions › Drug-Drug Interactions Dose Dependent Reactions › Incidence and seriousness of the toxicity is proportionately related to the – Concentration of the drug in the body – Duration of the exposure › Classified as – Pharmacological › Dose dependent fashion – Pathological › Presence of pathological finding due to overdose – Genotoxic › Injury to DNA, and may lead to mutagenic or carcinogenic toxicities Allergic Reactions › Results from previous sensitization; mediated by the immune system › Drug allergy is relatively uncommon, accounting for less than 10% of all ADRs › Many children are misdiagnosed as being “allergic” to various medications, particularly antibiotics and end up carrying this label into adulthood › Antigens induce the synthesis of antibodies, usually after a latent period of at least 1-2 weeks › RISK FACTORS FOR DRUG ALLERGY – Drug Factors › Nature of the drug – difficult to predict the sensitizing capacity of a drug prior to widespread clinical use on the basis of its chemical structure – Penicillins, aspirin, and sulfonamides account for over 80 percent of allergic drug reactions – probable that metabolic products of the drugs or minor contaminants are much more reactive, and are responsible for clinical sensitization › Degree of exposure (dose, duration, frequency) – some evidence that sensitization is more likely with higher drug doses and prolonged administration › Route of administration – topical application of a drug is associated with a high incidence of sensitization – intravenous route has been associated with catastrophic anaphylactic reactions › Cross-sensitization – once sensitization to a drug has occurred, the possibility exists of reactivity either to drugs with a close structural chemical relationship or to immunochemically similar metabolite – e.g., cross-reactivity seen among Penicillins and Cephalosporins – Host Factors › Age – some allergic reactions to drugs are probably less frequent in children and elderly patients, possibly owing to immaturity or involution of the immune response › Genetic factors – patients with uncontrolled asthma may be more prone to having severe reactions › Concurrent medical illness – drug reactions should occur less frequently among individuals whose immunologic responsiveness is impaired e.g. HIV › Previous drug reaction – some evidence that patients who have demonstrated drug hypersensitivity in the past may have an increased tendency to develop sensitivity to new drugs, and one should be more cautious in medicating such patients › Multiple allergy syndrome – Multiple drug allergy syndrome (MDAS) is a clinical diagnosis made in patients with adverse reactions to two or more structurally unrelated drugs with an underlying immune- mediated mechanism causing the reaction. › Four General Categories of Drug Allergy Based On The Mechanism Of Immunological Involvement – Type 1: Anaphylactic Reactions – Type II: Cytolytic Reactions – Type III: Arthus Reactions – Type IV: Delayed Hypersensitivity Reactions Type 1: Anaphylactic Reactions › Mediated by IgE antibodies – The fragment constant (Fc; function) portions of IgE bind to receptors on mast cells and basophils – The fragment antigen binding (Fab; variable; specificity) portions of IgE bind to antigen >> › Causes release of various mediators (e.g., histamine, leukotrienes, and prostaglandins) >> vasodilation and an inflammatory response › The main targets of this type of reaction are the – Gastrointestinal (GI) tract (vomiting, diarrhea) – skin (urticaria, pruritus, and atopic dermatitis) – Respiratory system (rhinitis and asthma) – Vasculature (anaphylactic shock) › Responses tend to occur quickly after challenge with an antigen to which the individual has been sensitized and are termed immediate hypersensitivity reactions – Timing of reactions - minutes to hours after drug exposure Type II: Cytolytic Reactions › Specific IgG or IgM antibodies directed at drug-hapten coated cells, e.g. , RBCs, WBCs, platelets – Hapten = a small molecule that, when combined with a larger carrier such as a protein, can elicit the production of antibodies that bind specifically to it (in the free or combined state) › Tagged cells are targeted for destruction by – Complement activation and lysis – Phagocytosis by natural killer cells (NK) and macrophages › Clinical manifestations include hemolytic anemia, neutropenia, thrombocytopenia › Timing of reaction = variable; may take hours to a day Type III: Arthus Reactions › Mediated predominantly by IgG › Tissue deposition of drug-antibody complexes with complement activation and inflammation › Complexes are deposited in the vascular endothelium, where a destructive inflammatory response called serum sickness occurs › Clinical symptoms of serum sickness include fever, rash, arthralgias, lymphadenopathy, urticaria, glomerulonephritis, vasculitis – Several drugs, including commonly used antibiotics, can induce serum sickness-like reactions › 1 to 3 weeks after drug exposure Type IV: Delayed Hypersensitivity Reactions › Mediated by sensitized T-lymphocytes and macrophages › When sensitized cells come in contact with antigen, an inflammatory reaction is generated by the production of cytokines and the subsequent influx of neutrophils and macrophages › Allergic contact dermatitis, maculopapular drug rash › 2 to 7 days after cutaneous drug exposure Idiosyncratic Reactions › Idiosyncrasy is an abnormal reactivity to a chemical that is peculiar to a given individual › Idiosyncratic reactions can result from – Genetic polymorphisms that cause individual differences in drug pharmacokinetics, – Pharmacodynamic factors such as drug-receptor interactions, or – Variability in expression of enzyme activity › Idiosyncratic drug reaction (IDR) has been used in various ways and has no clear definition, but the term is used in this review to designate an adverse reaction that does not occur in most patients treated with a drug and does not involve the therapeutic effect of the drug. Drug-Drug Interactions › Drug interactions may lead to – altered rates of absorption, – altered protein binding, – different rates of biotransformation, or – different rates of excretion of one or both interacting compounds › Pharmacodynamics of a drug can be altered by – competition at receptors, and – nonreceptor pharmacodynamic interactions can occur when two drugs have similar actions through different cellular mechanisms › A drug interaction is said to be additive when the combined effect of two drugs equals the sum of the effect of each agent given alone. › A synergistic effect is one in which the combined effect exceeds the sum of the effects of each drug given alone. › Potentiation describes the creation of a toxic effect from one drug due to the presence of another drug. › Antagonism is the interference of one drug with the action of another PREVENTION OF POISONING Reduction of Medication Errors › “5 Rights” of safe medication administration: – Right drug, – right patient, – right dose, – right route, – right time PRINCIPLES OF TREATMENT OF POISONING › Goals of Treatment – The first goal is to maintain vital physiological functions from impairment – The second goal is to keep the concentration of poison in tissues as low as possible by preventing absorption and enhancing elimination – The third goal is to combat the toxicological effects of the poison at the effector sites › Approach – Initial Stabilization of the Poisoned Patient – Identification of Clinical Patterns of Toxicity › Groups of physical signs and symptoms associated with specific poisoning syndromes are known as toxidromes – Decontamination of the Poisoned Patient › Poisoning exposures may be by inhalation, by dermal or mucosal absorption, by injection, or by ingestion › First step in preventing absorption of poison is to stop any ongoing exposure – If necessary, eyes and skin should be washed copiously – Gastrointestinal decontamination is the process of preventing or reducing absorption of a substance after it has been ingested – Primary strategies for GI decontamination are › Gastric emptying › Adsorption of poison › Whole bowel irrigation › Catharsis Gastric Emptying may be attempted by induced vomiting or gastric lavage › Induced Vomiting – Syrup of Ipecac › Emetic effects due to – local irritant effect on the enteric tract – central effect on the chemoreceptor trigger zone in the area postrema of the medulla › Given orally at a dose of 15 mL for children up to 12 years, and 30 mL for older children and adults › Administration is typically followed by a drink of water › Reliably produces emesis in 15-30 minutes › Contraindications for syrup of ipecac administration include – existing or impending CNS depression, – ingestion of a corrosive or hydrocarbon drug (due to the emergence of chemical pneumonia), or – presence of a medical condition that might be exacerbated by vomiting › Gastric Lavage – Procedure involves passing an orogastric tube (24-French for small children, up to 40-French for adults) into the stomach with the patient in the left-lateral decubitus position with head lower than feet – After withdrawing stomach contents, 10 to 15 mL/kg (up to 250 mL) of saline lavage fluid is administered and withdrawn. – This process continues until the lavage fluid returns clear. – Complications of the procedure include mechanical trauma to the stomach or esophagus, pulmonary aspiration of stomach contents, and vagus nerve stimulation Adsorption of a poison refers to the binding of a poison to the surface of another substance › Activated Charcoal – Surface of activated charcoal contains carbon moieties, such as carbonyl and hydroxyl groups, that are capable of binding poisons – Should only be considered if a patient has ingested a potentially toxic amount of poison up to 1 hour before charcoal administration – As a rough estimate, 10 g of activated charcoal is expected to bind ∼1 g of drug – Alcohols, corrosives, hydrocarbons, and metals are not believed to be well adsorbed by charcoal – Complications of activated charcoal therapy include vomiting, constipation, pulmonary aspiration, and death Catharsis › Whole Bowel Irrigation – Involves the enteral administration of large amounts of a high molecular weight, isoosmotic polyethylene glycol electrolyte solution with the goal of passing poison by the rectum before it can be absorbed – Contraindicated in the presence of bowel obstruction or perforation, and may be complicated by abdominal distention or pulmonary aspiration › Cathartics – Two most common categories of simple cathartics are the › Magnesium salts, such as magnesium citrate and magnesium sulfate › Nondigestible carbohydrates, such as sorbitol – Sorbitol is sometimes administered with single dose activated charcoal in an effort to add sweetness and reduce predilection toward constipation › Enhancing the Elimination of Poisons – Once absorbed, the deleterious toxicodynamic effects of some drugs may be reduced by methods that hasten their elimination from the body – Urinary Excretion of some drugs may be enhanced by the process of ion-trapping in alkaline urine › To achieve alkalinization of the urine, 100-150 mEq of sodium bicarbonate in 1L of D5W is infused intravenously at twice the maintenance fluid requirements and then titrated to effect › Urine alkalinization is contraindicated in the presence of renal failure, or when the fluid administration may worsen pulmonary edema or congestive heart failure – Gastrointestinal Excretion of some drugs may be enhanced through use of multiple doses of activated charcoal › Charcoal may interrupt enterohepatic circulation of hepatically metabolized drug excreted in the bile, and › Charcoal may create a diffusion gradient across the GI mucosa and promote movement of drug from the bloodstream onto the charcoal in the intestinal lumen › Activated charcoal may be administered in multiple doses, 12.5 g/h every 1, 2, or 4 hours (smaller doses may be used for children). › Some drugs may be removed from the body by Extracorporeal Techniques such as peritoneal dialysis, hemodialysis, or hemoperfusion (method of filtering the blood extracorporeally) › Antidotal Therapies –Types › Chemical Antidote - chemical inactivation of an absorbed poison › Pharmacologic antidote - competition at a receptor › Physiological antidote may use a different cellular mechanism to overcome the effects of a poison Different Mechanisms of Antidotal Action › Inert Complex Formation – Some antidotes interact with the poison to form an inert complex, which is then excreted form the body – E.g. chelating agents for heavy metals › Accelerated Detoxification – Some antidotes accelerate the detoxification of a poison. – E.g. › thiosulphate accelerates the conversion of cyanide to nontoxic thiocyanate › acetylcysteine acts as a glutathione substitute that combines with hepatotoxic paracetamol metabolites and detoxifies them › Reduced Toxic Conversion – E.g., ethanol, which inhibits the metabolism of methanol to toxic metabolites by competing for the same enzyme (alcohol dehydrogenase) › Receptor Site Competition – Some antidotes displace the poison from specific receptor sites, thereby antagonizing the effects completely – E.g., naloxone, which antagonizes the effects of opiates at stereospecific opioid receptor sites › Receptor Site Blockade – E.g., atropine, which blocks the effects of anti-ChE agents, such as organophosphorus compounds at muscrinic sites › Toxic Effect Bypass – E.g., 100% oxygen in cyanide poisoning END