Clinical Toxicology Lecture 4.5 - September 2020 PDF

PHAR 4107 CLINICAL TOXICOLOGY BY: NALINI KALLOO F A C U LT Y O F M E D I C A L S C I E N C E S THE UNIVERSITY OF THE WEST INDIES SEPTEMBER 2020 IMPORTANT NOTICE TO STUDENTS You are hereby prohibited from reproducing, re-publishing, re-broadcasting, re-posting, re-transmitting...

PHAR 4107 CLINICAL TOXICOLOGY BY: NALINI KALLOO F A C U LT Y O F M E D I C A L S C I E N C E S THE UNIVERSITY OF THE WEST INDIES SEPTEMBER 2020 IMPORTANT NOTICE TO STUDENTS You are hereby prohibited from reproducing, re-publishing, re-broadcasting, re-posting, re-transmitting or transferring in whole or in part any Course Outlines, Course Materials or Lectures which have been provided to you as part of your course of study at The University of the West Indies (The UWI), without the prior permission of The UWI its authorised agents or copyright holders. September 2020  LEARNING OUTCOMES At the end of this lecture you should be able to: 1. Describe the clinical features of poisoning, discuss critically the importance of making a diagnosis and demonstrate how the laboratory may support the management of the poisoned patient. 2. Describe the potential stages in the development of toxicity. 3. Describe the mechanism of toxic action, clinical features and management of these features associated with poisoning from CNS depressants September 2020 VETERINARY TOXICOLOGY The spectrum of undesired effects of toxicants are similar between animals and humans. In addition to likelihood of exposure, host factors such as species/ breed of animal, age, weight and general health status of animal also plays a role on whether a toxicosis will develop or not. Animals presenting with signs that are suspected to be related to poisonings need to be fully evaluated in order to rule out the possibility of an unrelated illness. Published data on demographics of poisonings of animals in Trinidad and Tobago are not yet available (ongoing). Provision of an accurate history to veterinarian is important. In animal poisonings, the cause of the animal’s condition may not be known, particularly in cases where exposure was not witnessed. Having a systemic approach to these patients is paramount to identifying major health issues present. Patient stabilization is essential to keep the patient alive while the underlying problem is diagnosed and treated. September 2020 MANAGEMENT OF EXPOSURES- SMALL ANIMALS Oral decontamination can be done through inducing emesis with 3% hydrogen peroxide ( between 1 to 3 teaspoons, given the weight of animal). Given after soft meal such as bread or canned meal. Adverse effects can occur and this must be adequately supervised by veterinarian. Other oral decontamination procedures include; diluents, activated charcoal, cathartics, gastric lavage and enemas Inhalation, dermal and ocular decontamination procedures as explained before. September 2020  DIAGNOSIS OF POISONING Need to have information: proper patient history, laboratory analyses along with the clinical signs. Acute poisonings Due to a sudden exposure. Example?? Objective is to make sure that the clinical effects are due to a poison and not part of a disease process. The diagnosis must then fit the symptoms exhibited by patient and the circumstances surrounding the incident. Allows forecasting of features that may develop and also identifies the need for specific treatment. September 2020  Identification of the poison is not always possible. Remember- all things are poison; specific treatments and antidotes are a tiny minority. Hence, the reason for symptomatic support approach. Clinical features of an acute poisoning: – Neurological features – Impairment of consciousness – Muscle tone and limb reflexes – Abnormalities of pupils and eye movements – Abnormal movements – Skin blisters September 2020 Chronic Poisoning Exposure over time. Example?? In which setting is chronic poisoning more common? September 2020 CLUES FROM LABORATORY ANALYSES ↑ K+ or ↓K+ : Agents that inhibit or stimulate the membrane sodium/potassium pump. ↑/↓ GLU Liver function tests Renal function tests Anion or osmolal gaps: can offer clue to cause of metabolic acidosis and the serum osmilaity. ↓ [HCO3]- or ↑ [HCO3]- : Agents that induce acidosis/alkalosis. September 2020 SERUM ANION GAP AG = [Na+]– ([Cl- ] + [HCO3-] All in (meq/L) units Normal AG ≤ 12 meq/L ↑ AG indicates metabolic acidosis September 2020 September 2020 OSMOL GAP OG= measured serum osmolality − calculated serum osmolarity Units in (mosm) Calc. Osm = 2 [Na+ ]+ [𝐺𝐿𝑈] [𝐵𝑈𝑁] 18 + 2.8 {Units: GLU&BUN: mg/dL ; Na: meq/L} Normal osmol gap < 10 mosm September 2020 Also: Acetone and propylene glycol September 2020 In some instances, you may be able to smell certain charcteristic odours coming from the mouth or body of the victim. Eg.Alcohol on the breath of a person intoxicated. September 2020 COMPLICATIONS THAT MAY OCCUR WITH POISONINGS Hypothermia Hyperthermia Convulsions Urinary retention Rhabdomyolysis (breakdown of muscles) September 2020  MECHANISMS OF TOXIC ACTION The principle of the “soil and the seed” can be applied to an understanding of the mechanisms of toxicity. While the xenobiotic (the seed) is crucial, toxicity is also markedly dependent on the characteristics of the organism (the soil). September 2020  These characteristics may be genetic or acquired (unwanted side effects or drug interactions). Upon exposure to the toxicant, there may be direct reaction with the target molecule or the toxicant may cause alteration of the biological environment that the toxicant was introduced to. September 2020  Potential stages in the development of toxicity September 2020  THE NERVOUS SYSTEM Neurotoxicity refers to the ability of an agent to adversely affect the structural or functional integrity of the nervous system. These toxicants may cause neuronopathies, axonopathies and myelinopathies or they may impact the process of neurotransmission. September 2020  Toxicants that cause 1.neuronopathies: doxorubicin, methyl mercury, trimethyltin; 2.axonopathies: organophosporus compounds and other industrial compounds; 3.myelineopathies: Lead, tellurium For the purposes of this lecture we are looking at substances that alter neurotransmissions. September 2020 neuron showing (1) cell body and dendrites, (2) myelinating cells (3) Axon (4) synapse. Some forms of toxicity are due to interruption of the process of neurotransmission, either through blocking excitation or by excessive stimulation, rather than actual cell death. September 2020 CNS DEPRESSANTS ✓Alcohols ✓Prescription drugs ✓Illegal drugs September 2020  WHAT ARE CNS DEPRESSANTS? Commonly described as “downers” Used to temporarily diminish the function of the CNS. They inhibit stimulation! Include alcohols and also a wide variety of drugs used as sedatives, hypnotics (sleeping pills), anti-anxiety tranquilizers, anaesthetics, and anti-convulsants. September 2020  GENERAL CHARACTERISTICS OF CNS DEPRESSANTS They all enhance actions of GABA in some way or another. ✓Increasing GABA at the neuronal synapse inhibits the generation of the action potential of the neuron, thereby making it less likely to excite nearby neurons. They inhibit the cognitive function of the brain At low doses, they appear to have a stimulatory effect. September 2020 RECAP: GABA ( γ-AMINOBUTYRIC ACID) Main roles of GABA: - Reduce physical tension - Decrease heart rate - Reduce Anxiety - Reduce compulsivity - Reduce Insomnia - Elevates pain threshold - Reduces blood pressure September 2020  GABA- RECEPTOR IONOPHORE COMPLEX September 2020  ALCOHOLS (R-OH) ETHANOL, METHANOL & ETHYLENE G LY C O L ALCOHOLS Alcohols are used in various cleaners, polishes, and methylated spirits. They are also present in ethanolic beverages, mouthwashes, perfumes and aftershaves. Medically: alcohol is used to sterilize surfaces, is often a preservative or solvent in liquid and cream medications. Alcohol is widely used as a solvent in industrial and scientific processes. September 2020 KINETICS OF ETHANOL Rapid absorption: 20% absorption occurs in the stomach, 80% in the intestine. Factors affecting absorption: oConsumption of food oConcentration of alcohol oCarbonation of beverages oMixed drinks vs.‘Straight’ shots Distribution: vd is equal to that of total body water, rapidly distributes throughout intra and extra cellular fluid. September 2020  Metabolism occurs in the liver: Enzymes needed: o ADH: alcohol dehydrogenase o Catalase- utilizes H2O2 supplied by the actions of NADPH oxidase and xanthine oxidase. o CYP2e1 Genetic polymorphism exists for both Alcohol and aldehyde dehydrogenase. Eliminated via breath, sweat, urine and human Breast milk September 2020 MECHANISM OF TOXIC ACTION- ETHANOL Affects the functions of the GABA ionophore receptor complex. Liver damage (cirrhosis) associated with chronic alcohol abuse is thought to be due to an accumulation of acetaldehyde. Alcohol crosses the placental barrier causing foetal alcohol spectrum disorder (fasd). September 2020  FASD Small size for gestational age or small stature in relation to peers Facial abnormalities such as small eye openings Poor coordination Hyperactive behaviour Learning disabilities Developmental disabilities (e.G., Speech and language delays) Mental retardation or low IQ Problems with daily living Poor reasoning and judgment skills Sleep and sucking disturbances in infancy September 2020 SIGNS AND SYMPTOMS OF POISONING Initial effects: dose-related CNS depression, nausea and vomiting may be observed soon after ingestion. Drowsiness, confusion, decreased level of consciousness and respiratory depression are commonly observed. Hypoglycemia (especially in young children), hypothermia, acid-base disturbances and electrolyte imbalances. Pulmonary aspiration of vomitus and pneumonitis is a major concern. Respiratory depression may occur and death generally results from respiratory complications / failure. Ethanol intoxications are often complicated by co-ingestants September 2020  Mild Ethanol Toxicity Moderate Ethanol Toxicity Severe Ethanol Toxicity Euphoria Ataxia Muscular in- Mild in-coordination Impaired coordination Altered judgement judgement/reflexes Reduced gag reflex Decreased attention Visual impairment Pulmonary aspiration span Decreased Coma sensory/motor skill Respiratory depression Memory impairment Respiratory failure Slurred speech Peripheral vascular collapse September 2020 MANAGEMENT OF ETHANOL TOXICITY Ensure a protected airway is achieved. Ensure emergency stabilisation is received (GCS, airway, respiratory status, blood pressure, blood glucose) GI decontamination: risks outweigh the benefit. Ocular decontamination as necessary. Enhanced elimination by hemodialysis; to clear serum ethanol in life threatening ingestions Supportive care: liver and renal function, observe for seizures, respiratory depression, anion and osmol gap values to keep an eye out for ketoacidosis, serum glucose and electrolytes. September 2020 METHANOL Found in antifreeze and windscreen washing solutions, model airplane fuel, solid camping cooking fuel. Used as a solvent and to denature alcohol. Ingestion of as little as 10ml of pure methanol has caused permanent blindness and about 30 ml can be potentially fatal. Toxicokinetics is similar to that of ethanol with different active metabolites after hepatic metabolism. September 2020 MECHANISM OF TOXICITY- METHANOL Methanol itself has low toxicity but its metabolites are toxic Formic acid is responsible for Acidosis that is observed with methanol toxicity Inhibition of cytochrome oxidase Principle cause for ocular toxicity September 2020 FEATURES OF METHANOL TOXICITY Causes mild and transient inebriation, nausea, vomiting, abdominal pain and CNS depression. Metabolic acidosis Nystagmus, “snowfield vision” or complete blindness Slurred speech, ataxia and altered mental status. ↑ Anion and osmol gap with minimal lactate elevation, ↑ Glu, ↓Mg, K, PO4 Rhabdomyolysis, coagulapathies September 2020  Mild Methanol Moderate Methanol Severe Methanol Toxicity Toxicity Toxicity Nausea Visual disturbances Bradycardia Vomiting Confusion Anuria Headache Hyperventilation Permanent Drowsiness Metabolic acidosis blindness Prolonged seizures Persistent acidosis Coma Death September 2020 MANAGEMENT OF TOXICITY Initial management includes protection of the airways and administration of IV fluids. Late presenters may exhibit severe acidosis or seizures requiring sodium bicarbonate and a benzodiazepine respectively. Gastric decontamination may be performed via nasogastric aspiration; other forms of decontamination are not recommended. Haemodialysis may be done if presentation is late with a marked metabolic acidosis September 2020  Effective antidotes exist in the form of either ethanol or fomepizole, which are life saving when indicated. Any patient with an elevated osmol or anion gap acidosis requires aggressive treatment, which should include the administration of an antidote. Folinic acid should be administered in conjunction with ethanol or fomepizole to help increase the formation of non-toxic metabolites. It is recommended that patients receiving ethanol therapy be monitored in an intensive care setting and any decline in respiratory drive countered with hyperventilation. September 2020 ETHYLENE GLYCOL Most commonly used as antifreeze in radiator fluids, may be drunk accidently or intentionally. Has a sweet taste A lethal dose is about 100ml by ingestion. September 2020 KINETICS Absorbed rapidly by gut, rapid distribution Metabolism: oxidised by alcohol dehydrogenase to glycoaldehyde, aldehyde dehydrogenase converts glycoaldehyde to glycolic acid. Glycolic acid to glyoxylic acid is slow. Calcium ions chelate oxalic acid to form insoluble calcium oxalate crystals which can be seen in the urine. September 2020 September 2020  The etiology and pathophysiology of the CNS, metabolic, cardiopulmonary, and renal toxicity are primarily due to the formation and accumulation of toxic intermediary metabolites, especially glycolic acid (produces profound acidemia, oxalosis, and renal interstitial edema) and to a lesser but histologically important extent, oxalate production and excretion. September 2020  FEATURES OF ETHYLENE GLYCOL POISONING Stage 1 (30 mins to 12h after ingestion) GI and Neurological involvement Apparent intoxication, as with alcohol Nausea, vomiting Metabolic acidosis CNS depression Those who develop severe CNS manifestations, including seizures and coma, can recover full neurologic function. Cranial nerve palsies may occur in nerves II, V, VII, VIII, IX and XII, typically resolving over weeks to months. September 2020  Stage 2 (12-24h ) Cardiorespiratory and metabolic disturbance Tachycardia Metabolic acidosis Myocarditis Mild hypertension Pulmonary odema Congestive cardiac failure Stage 3 (24-72h) Renal involvement Flank pain, renal angle tenderness, ↓Ca, Acute tubular necrosis Calcium oxalate monohydrate crystalluria September 2020  Mild Ethylene Glycol Moderate Ethylene Severe Ethylene Glycol Toxicity Glycol Toxicity Toxicity Nausea Mild metabolic acidosis Pulmonary edema Vomiting Tachycardia Congestive cardiac Inebriation Hypertension failure Drowsiness Hematuria Anuria Proteinuria Hyperventilation Severe metabolic acidosis Seizures Multiple organ failure Coma Death September 2020 September 2020 MANAGEMENT Supportive measures to combat cardiorespiratory depression should be employed and metabolic acidosis, hypocalcemia and renal failure should be treated conventionally. If the patient presents soon after ingestion the first priority is to inhibit metabolism using IV fomepizole or ethanol (see regimen in methanol section) Hemodialysis removes ethylene glycol, glycoaldehyde and glycolic acid but not oxalates. September 2020 BENEFITS OF FOMEPIZOLE VS. ETHANOL No risk of increased sedation No increased tendency towards hypoglycaemia Fewer side effects (headache, nausea, dizziness) No problems with tolerance Fomepizole is very expensive; ~ $2000 US per mL September 2020  CNS DEPRESSANTS: PRESCRIPTION DRUGS BENZODIAZEPINES & BARBITURATES Benzodiazepines: – Used as a sedative, anxiolytic and in seizure management. – Use and abuse can trigger dependency and tolerance of drug. – Widely abused in certain populations such as psychiatric and substance abuse patients. September 2020 KINETICS OF BENZODIAZEPINES : Well absorbed from GI tract Widely distributed throughout the body, they are highly protein bound and highly lipophilic. Most are metabolised by the liver via glucuronide conjugation. Excreted via urine and also in breast milk NB: Some benzos have pharmacologically active metabolites with half lives exceeding those of the parent compounds. September 2020 MECHANISM OF TOXIC ACTION Benzodiazepines induce a conformational change in the GABA receptor to enhance binding to endogenous GABA. This results in an increased frequency of chloride channel opening, this results in hyperpolarisation at the neuronal membrane. September 2020 CLINICAL EFFECTS Mild Benzodiazepine Moderate Severe Benzodiazepine Toxicity Benzodiazepine Toxicity Toxicity Mild CNS Moderate CNS Severe CNS depression depression depression Somnolence Ataxia Respiratory Lethargy Hypotension depression Slurred speech Hypothermia Pulmonary aspiration Bradycardia September 2020 “PARADOXICAL” REACTIONS Agitation Restlessness Excess sedation Crying Hallucinations Aggression Combativeness September 2020 MANAGEMENT OF TOXICOSIS Emergency stabilisation of patient: abcs Close observation and supportive care remains the mainstay of treatment. Decontamination is not recommended unless co ingestion of other drugs is indicated. Enhanced elimination offers no proven benefit. Major concern with od of benzos: respiratory depression which may lead to pulmonary aspiration. September 2020 ANTIDOTAL THERAPY: FLUMAZENIL (ROMAZICON®) Fortunately there is an effective antagonist for benzodiazepine poisonings: flumazenil Short half life, must be re administered Contraindications: oIf full airway protection is achieved, then use of flumazenil is less likely to be needed. oMay induce seizures with chronic users oAnticholinergic signs may occur with usage September 2020 “BENZO WITHDRAWAL SYNDROME” Withdrawal occurs some 1 to 3 days after cessation of drug intake and peaks at 5 to 7 days; the majority of symptoms resolving within a month. Symptoms of benzodiazepine withdrawal include: – Delirium, confusion, psychosis – Fear – Anxiety, irritability – Palpitations – Tremor – Sweating – Fatigue September 2020 CNS DEPRESSANTS: BARBITURATES Derived from barbituric acid, therapeutic use as an anticonvulsant and sedative. Also has a high abuse potential. They are classified according to their duration of action: 1. Short acting: pentobarbital, secobarbital 2. Intermediate acting: amobarbital, aprobarbital, butalbital 3. Long acting: phenobarbital, mephobarbital September 2020 KINETICS Well absorbed orally Highly lipid soluble; barbs are rapidly distributed throughout the body. Metabolised by liver Excreted via urine MOTA Bind to GABA mediated chloride channels, increasing the duration of opening of the channels resulting in synaptic inhibition. September 2020  Mild Barbiturate Toxicity Moderate Barbiturate Toxicity Severe Barbiturate Toxicity Lethargy CNS depression Coma Labile affect Depressed or absent Respiratory depression Mental confusion deep tendon reflexes Hypoxia Slurred speech Slowed respirations Cyanosis Drowsiness Hypotension Ataxia Hypothermia Nystagmus Acidosis Headache Pulmonary edema Dysrhythmias Absent deep tendon reflexes Absent brainstem reflexes Babinski sign present Cardiorespiratory September 2020 failure and arrest MANAGEMENT OF TOXICOSIS Emergency stabilisation and ensure adequate cardiopulmonary respiration. Decontamination: the use of single dose activated charcoal may be of benefit in the case of overdose due to ingestion. Enhanced elimination via urinary alkalinisation may increase longer acting barbs excretion. Haemodialysis may be considered in the case of failure to respond to supportive management. September 2020 Supportive care includes the monitoring of: Level of consciousness Respiratory rate Oxygen saturations Heart rate Blood pressure ECG (12 lead) Body temperature Creatine kinase (if comatose) Liver and kidney function tests Severe barbiturate poisoning may result in persons appearing to be brain dead. September 2020 DERMATOLOGIC EFFECTS Cutaneous bullae that may appear following overdose, seen not only on regions where the body has pressure points, but also on non dependant areas of the body. September 2020  ILLICIT DRUGS M A R I J UA N A , G H B , ‘ R O O F I E S ’ MARIJUANA The dried leaves, seeds and stems of the Cannibis sativa plant. September 2020  Persons may be exposed to marijuana via; Inhalation of smoke and ingestion. The predominant psychoactive chemical in marijuana is Δ-9- Tetrahydrocannabinol (Δ-9-THC). The half life of marijuana is between 20-60 hrs for infrequent users. A complete MOTA has not yet been elucidated, but Δ-9-THC is believed to affect the GABA neurotransmitter system. September 2020  KINETICS OF MARIJUANA Well absorbed orally (~10-20% Bioavailability) very well absorbed via inhalation ( ~2-35% Bioavailability) Highly bound to plasma proteins, accumulation in fatty tissues Metabolised by lung and liver to active and inactive metabolites. Eliminated in urine and by greater extent via faeces. September 2020 SYMPTOMS OF TOXICOSIS Vomiting, diarrhoea, increased appetite, abdominal pain, dry mouth. Euphoric feeling, sedation, altered sensory perception, ↓motor co ordination, ↓ muscle strength, tremor, dizziness, psychosis ( anxiety, hallucinations, delusions, panic attacks, paranoid behaviour) Palpitations, hypotension. Monitor for ECG changes. ↓ Respiratory rate, cyanosis Eyes may be glassy with eventual mydriasis, nystagmus, hyperemia. Other symptoms: hypothermia, pale skin Chronic Effects:“Amotivational syndrome”, pulmonary diseases, obesity September 2020  Mild THC Toxicity Moderate THC Severe THC Toxicity Toxicity Mild euphoria Short term memory Decreased motor Increased sensory impairment coordination awareness Mild confusion Decreased muscle Somnolence Impaired judgement strength Relaxation Depersonalization Tremor Reddening of eyes Mood alterations Sedation and conjunctiva Depression Slurred speech Minor distortions of Ataxia time perception Respiratory Dry mouth and depression throat Tachycardia September 2020 MANAGEMENT OF TOXICOSIS Management is mainly supportive. There is no antidote for massive intoxications. Symptoms usually resolve without intervention. ✓Very rarely massive intoxications occur in ‘body packers’ who ingest packets of hashish for trans shipment - with rupturing of packets. Decontamination is not recommended as risk outweigh benefit. Enhanced elimination offers no added benefit. September 2020 MANAGEMENT OF MARIJUANA TOXICOSIS In providing supportive therapy, you should monitor the patient’s: Level of consciousness Respiratory rate, ABGs, pulse oximetry Heart rate/rhythm ECG Blood pressure Fluid balance Electrolytes Acid- base disturbance Also observe for vomiting and seizure activity September 2020 ‘GHB’ : γ- HYDROXYBUTYRATE Initially indicated as an anaesthetic but recalled due to ineffectiveness Used as xyrem® (sodium oxybate) for the treatment of narcolepsy. Colourless, odourless liquid with a salty taste free of suspended matter or white crystalline powder GHB is abused as a ‘club drug’ for its euphoric properties. Also used for drug-facilitated sexual assault as it is fast acting and has amnesic properties. September 2020 MECHANISM OF TOXIC ACTION It is an endogenous chemical normally found in the basal ganglia. Synthesised from gamma butyrolactone (GBL), metabolised to gaba (and other metabolites). Gamma hydroxybutyrate (GHB) acts as: - An inhibitory neurotransmitter regulating dopaminergic neurons - A central nervous system depressant with euphoria-inducing capabilities. September 2020 KINETICS Rapidly absorbed: quick onset of action and duration of about 8 hrs. Rapidly distributed: can cross BBB and placenta, not widely protein bound. Metabolism: hepatic metabolism, undergoes first pass metabolism, one of the metabolites is succinate, which is used in the kreb’s cycle. Excretion: in urine and CO2 (via kreb’s cycle) September 2020  Mild Gamma- Moderate Gamma- Severe Gamma- Hydroxybutyrate Hydroxybutyrate Hydroxybutyrate Toxicity Toxicity Toxicity Euphoria Bradycardia Respiratory Drowsiness Hypotension depression Dizziness Myoclonic jerking Profound coma Confusion Hypothermia Rhabdomyolysis Disorientation (mild) Seizure Vomiting Agitation Respiratory Ataxia arrest Miosis September 2020 MANAGEMENT Treatment following this intoxication is mainly supportive care. There are no antidotes for this compound. GI decontamination and enhanced elimination strategies provide no benefit to the treatment. September 2020 ROHYPNOL (FLUNITRAZEPAM) Therapeutic benzodiazepine derivative - hypnosedative. A white or yellowish crystalline powder, slightly soluble in ethanol. Street slang: ‘roofies’ This is a benzodiazepine derived drug, therefore the MOTA would be basically the same as a benzo. Same for kinetics and management of toxicosis. September 2020