ICP 2024 Toxicology PDF

ICP Toxicology ICP 2024 Learning outcomes By the end of this session, participants will be able to: 1. Briefly outline the presentation of common toxicities due to illicit drug use 2. Outline the key signs & symptoms of NMS, serotonin syndrome, paracetamol OD, lithium toxicity, sodium...

ICP Toxicology ICP 2024 Learning outcomes By the end of this session, participants will be able to: 1. Briefly outline the presentation of common toxicities due to illicit drug use 2. Outline the key signs & symptoms of NMS, serotonin syndrome, paracetamol OD, lithium toxicity, sodium nitrite poisoning, Clonidine toxicity, propranolol toxicity & carbon monoxide poisoning 3. Describe the presentation and management of a tricyclic antidepressant overdose within the scope of an ICP 4. Explain why sodium bicarbonate is used in the management of TCA OD 5. Describe the presentation and pre-hospital management of an organophosphate poisoning within the scope of an ICP 6. Briefly describe the clinical classification of toxins from envenomation 7. Explain the pre-hospital management of envenomation by snake & spider bites 8. Outline the presentation and management of blue-ringed octopus and Cone shell envenomation Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome (NMS) is a rare, but potentially life-threatening condition that develops due to antipsychotic (neuroleptics) medications All the antipsychotics (1st and 2nd gen) (E.g. Droperidol, Haloperidol, olanzapine) can precipitate NMS, but also dopamine antagonist anti-emetics such as metoclopramide Occurs over days to weeks Can occur after a single-dose of medication MoA: Dopaminergic blockade in the basal ganglia and hypothalamus (i.e. regulation of motor control and thermoregulation and ANS) Signs & Symptoms include: Labile blood pressure (autonomic instability) Muscle rigidity Altered mental status Tachycardia Hyperthermia Dilated pupils AKI Diaphoresis Hyporeflexia Rhabdomyolysis Neuroleptic Malignant Syndrome – lead pipe rigidity Serotonin Syndrome Is a group of pathological symptoms that may occur as a result of serotonergic medications Can be mild, moderate or severe; severe cases can be fatal Can result from: ❖ Increase in single medication ❖ Change in one serotonergic medications to another without adequate washout period ❖ Interaction between prescribed and illicit drugs (E.g. SSRI, SNRIs, TCA, MAOi, St John’s Wort, opioids, MDMA, Cocaine, ICE) ❖ Deliberate or accidental overdose Symptom onset is within hours to < 24hrs of toxicity occurring Serotonin syndrome is the triad of CNS, autonomic and neuromuscular dysfunction Serotonin Syndrome shivers Neuromuscular Autonomic CNS / Altered S Shits, shakes and seizures Excitation hyperactivity Mental Status H Hyperreflexia & Clonus Tremor Hyperthermia Delirium I Increased temperature Hyperreflexia Diaphoresis Confusion V Vital Sign instability Clonus (rhythmic Tachycardia Agitation E muscle spasms) Encephalopathy (Altered LOC) R Restlessness & agitation Hypertension Restlessness S Sweating (diaphoresis) Tachypnoea Hunter Serotonin Toxicity Criteria Serotonin Syndrome – Hyperreflexia and Clonus  Lithium Toxicity Used in clinical practice as a mood stabiliser in mental health disorders ✓ E.g bipolar, major depression, self-harming behaviours Complex MoA thought to decrease excitatory and increase GABAinergic neurotransmitters and increases serotonin release and serotonergic receptor sensitivity Toxicity can result in renal damage, coma, seizures or death Causes include: ✓ Intentional OD, change in dosage, 20 to dehydration, renal failure, concomitant NSAID or ACEI use S&S Nausea, vomiting, tremors/myoclonus, confusion, visual disturbance, dizziness, polyuria, polydipsia Treatment Fluid resuscitation to reduce AKI Recognition is the key and transport Symptomatic patients taking lithium and a history of V&D/Gastro or dehydration should be transported for evaluation Lithium Toxicity - myoclonus  Sodium Nitrite Poisoning Sodium Nitrite and Sodium Nitrate are naturally occurring substances found in foods, plants and also medication Overdose is usually self-harm and kits can be bought online Deaths are not common: 17 deaths between 2009 - 2018 in Australia (National Coronial Information System, 2021) SN toxicity converts the iron atom of hemoglobin from ferrous (Fe2+) into the Ferric (Fe3+) state (forming methaemoglobin). This is subsequently incapable of binding to oxygen (or transporting oxygen)  Sodium Nitrite Poisoning Symptoms of methemoglobinemia result from inadequate oxygen transport Signs & Symptoms: ✓ Relative hypovolaemic shock due to vasodilation ✓ Cyanosis ✓ Altered LOC ✓ Seizures ✓ Methemoglobinemia expected with serious exposures SpO2 often ~ 85% but this is inaccurate Blood is chocolate-brown in colour (20 to the ferric iron state) Treatment is supportive with high-flow O2, fluids and (in- hospital) methylene blue Methylene blue facilitates the use of NADPH to reduce methaemoglobin back into normal haemoglobin Clonidine Toxicity MoA: Centrally acting Alpha 2 receptor agonist Used to treat: hypertension, ADHD, Autism, migraines, sleep disorders, Tourette’s Syndrome Clonidine toxicity is now one of the most common reasons for PICU admission in Australia (Nickson, 2024) and calls to the PICNSW (Chiew, 2024) Toxicity occurs at 10microg/kg (For a 6yo 25kg = 2 tablets) Onset within 30min-4hrs; duration of effects 24-72hrs S&S: Somnolence Miosis (pupil constriction) Bradycardia Hypotension Hypoventilation Treatment: ABC supportive care Bradycardia usually responds well to atropine Hypotension with fluids Naloxone likely ineffective with our doses  MDMA Toxicity 3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic drug possessing stimulant, empathogen and mild hallucinogenic properties Also known as Ecstasy, XTC, E, Molly, eccy, pingers… MDMA increases serotonin and noradrenaline in the neural synapse (via reuptake inhibition, pre-synaptic vesicle changes and reversal of SERT) credit MDMA Toxicity Drugs sold as MDMA may not contain any MDMA. They can be a mix of amphetamines, para- methoxyamphetamine (PMA), PMMA, ketamine, NBOMe, or other substances This is potentially harmful as PMA and PMMA have more toxic effects (and are less euphoric) than MDMA. It also takes longer to feel these effects, so people may take another pill in the mistaken belief that the first has not worked, sometimes resulting in overdose (ADF, 2021) From 1 July 2023, MDMA (and psilocybin) can be prescribed in Australia (TGA, 2023) MDMA Toxicity Causes a serotonergic toxidrome with effects including: ✓ Jaw clenching, teeth grinding, serotonin syndrome, autonomic hyperstimulation and cardiac events ✓ Hyponatraemia ✓ Rhabdomyolysis and acute kidney injury with possible hyperkalaemia ✓ Hyperpyrexia (40.9-43° C) is rare but may also occur ✓ Cerebral oedema, confusion, seizures, death Cerebral oedema - aetiology is multifactorial: o water intoxication o excessive sweating o Hypervolaemia due to Syndrome of Inappropriate Diuretic Hormone (SIADH) Treatment: symptomatic management, fluids, rapid cooling, HyperK management (GHB) GAMMA HYDROXYBUTYRATE Naturally occurring neurotransmitter, GHB is both a precursor and metabolite of GABA (Steuer, 2022) GHB binds to GHB and GABA (A & B) receptors as an agonist Readily crosses BBB GHB was developed in the 1960s as an anaesthetic agent, but its use in anaesthesia remained limited due to inadequate analgesia, emergence delirium and proconvulsive effect (Benzer, 2022) Street names: G, GBH, Grievous Bodily Harm, Fantasy, Liquid Ecstasy Tablets may also be made with GBL (Gamma butyrolactone - a precursor of GHB) rather than GHB It is rapidly metabolised to GHB and in effect have identical clinical features GBL is thought to be about twice as potent as GHB, with quicker onset and decay in action Odourless, colourless liquid, slightly salty in taste (GHB) GAMMA HYDROXYBUTYRATE Taken for its anxiolytic, hypnotic, euphoric and disinhibition effects The effects usually occur within 15-20 minutes and last up to 3-4 hours Overdose presentation: ✓ Amnesia ✓ GCS – often 3 (may fluctuate with stimuli) ✓ Respiratory depression & periods of apnoea ✓ Bruxism ✓ Bradycardia ✓ Hypotension May induce: N&V, delusions, depression, vertigo, hallucinations, myoclonus and seizures Treatment: supportive ABCs, airway management; consider Sexual Assault Paracetamol OD Untreated paracetamol poisoning may cause varying degrees of liver injury over the 2 to 4 days following ingestion: ❖ ≥ 10g or ≥ 200 mg/kg (Adult & Paed) (RCH, 2021; Chiew et al, 2020) ❖ >12g may be fatal MoA: Liver metabolism is overwhelmed. An alternative metabolic pathway is used which produces a toxic metabolite that causes hepatic and renal necrosis Symptom Onset: o < 24hrs asymptomatic, nausea & vomiting, diaphoresis, malaise o 18 – 72hrs: (R) upper quadrant pain, tachycardia o 72 – 96hrs: Abdominal pain, tender hepatic edge, GI haemorrhage, jaundice, N & V, fatality Paracetamol OD - Treatment Supportive Care - ABC Treat co-ingestion – e.g. naloxone Consider mental health aspects of intentional OD In-hospital Rx: N-acetylcystine (Parvolex®) is a safe and effective antidote It acts as a precursor for glutathione, promoting normal conjugation of any remaining paracetamol, and also supplies thiols that function as antioxidants It is very effective when given during the first 8 hours after a paracetamol overdose. The effectiveness is reduced as the time interval increases, but it can still help when given up to 24 hours after the overdose#  Tricyclic Antidepressant Overdose Tricyclic antidepressant use: Depression, chronic pain, migraine, peripheral neuropathies, nocturnal enuresis (Esp. children) MoA: Noradrenaline and serotonin reuptake inhibitors Common Tricyclic anti-depressants (TCAs) include: amitriptyline, clomipramine, dothiepin, doxepin, imipramine and nortriptyline Overdose symptoms and toxicity can occur: > 10mg/kg in adults > 5mg/kg in children Severe toxicity results from ingestion of more than 20mg/kg; overdose can result in fatality Tricyclics mediate their cardiotoxic effects via: Blockade of myocardial fast sodium channels (QRS prolongation, tall R wave in aVR), Inhibition of potassium channels (QTc prolongation) and direct myocardial depression Other toxic effects are produced by anti-muscarinic, histamine (H1) and α1-adrenergic receptor antagonism (tachycardia, ↓LOC, hypotension)  Tricyclic Antidepressant Overdose Anticholinergic effects Agitation, delirium, dilated pupils, warm dry skin, tachycardia Neurotoxicity Sedation, coma, seizures Cardiotoxicity Tachycardia, wide QRS, ventricular dysrhythmias, hypotension Coma, seizures and cardiovascular toxicity manifest rapidly and are frequently fatal without aggressive intervention Two main concerns: Seizures (QRS > 100ms predictive of seizures) Ventricular dysrhythmias & hypotension  Tricyclic Antidepressant overdose – ECG Changes Often seen on ECG: Dominant R wave in aVR Source: https://litfl.com/tricyclic-overdose-sodium-channel-blocker-toxicity/ TCA Toxicity ECG Sodium Bicarbonate in TCA Overdose Sodium bicarbonate is the mainstay pharmacological therapy available to paramedics to manage serious tricyclic antidepressant overdose Avoidance of acidaemia is also important >> target low normal ETCO2 Indications include wide QRS with seizure, dysrhythmias, hypotension or coma An important reversible cause to consider in cardiac arrest Why Sodium Bicarbonate in TCA OD? 1. Plasma alkalinisation increases TCA plasma protein binding and thus decreases active drug ❖ Protein binding sequesters the drug and decreases the unbound fraction and thus toxicity 2. Plasma alkalinisation corrects acidosis ❖ Additional HCO3- raises plasma pH 3. Intracellular alkalosis decreases TCA-receptor binding ❖ Alkalinisation favours the non-ionized state which does not bind to Na+ channels 4. Increased sodium load over-riding sodium channel blockade ❖ Increases the transmembrane Na+ gradient 5. Additional sodium promotes intravascular volume loading ❖ Water follows sodium Propranolol Overdose Propranolol is a beta blocker but is also a sodium channel blocker Sodium bicarbonate may be useful so call CAL A mainstay of treatment includes mechanical circulatory support (eCPR)  Propranolol (Mechanism of Toxicity) Beta adrenergic receptor blockade (β1 and β2) Competitive antagonism of beta receptors leads to decreased intracellular cAMP with reduced chronotropy and inotropy β2 antagonism may lead to bronchospasm Sodium channel blockade Sodium channel blockade in the myocardium leads to prolonged cardiac action potential with QRS widening and ventricular dysrhythmias Neurotoxic effects due to sodium channel block include seizures and coma Ingestion of > 1 g of propranolol in 24 hours can potentially be lethal and lead to profound bradycardia, bradyarrhythmias, hypotension, bronchospasm (Shahrokhi & Gupta. 2023) Organophosphate Poisoning The OP pesticide group consists of around 30 identifiably distinct chemicals that are synthesised and added to approximately 700 products OP pesticides are used on fruit, vegetable, grain, pasture seed, ornamental, cotton, and viticultural crops, on livestock and domestic animals, as well as for building pest control Examples: Malathion, Parathion, Fenthion Systemic absorption occurs via: Mucus membranes Skin Lungs GI exposure (e.g. eyes) Organophosphate Poisoning - MoA Once absorbed, the molecule binds to acetylcholinesterase, making the enzyme inactive This leads to an overabundance of acetylcholine within synapses and neuromuscular junctions Overstimulation of nicotinic receptors found at neuromuscular junctions causing fasciculations and myoclonic jerks. Eventually flaccid paralysis Nicotinic receptors also are found in the adrenal glands, which may cause hypertension, sweating, tachycardia Organophosphate poisoning also produces symptoms based on its action at muscarinic receptors Organophosphate insecticides do not OFF-GAS and minimal risk of nosocomial organophosphate poisoning. The smell relates to a hydrocarbon solvent, not the pesticide Organophosphates Common mnemonics that capture the muscarinic effects of organophosphate poisonings are: DUMBELS or SLUDGE D = Defecation/diaphoresis S= Salivation U = Urination L= Lacrimation M = Miosis U = Urination B = Bronchospasm/bronchorrhea D = Defecation E = Emesis G = GI distress L = Lacrimation E = Emesis S = Salivation ECG will frequently be a sinus bradycardia due to muscarinic agonist activity When death occurs, the most common reason is respiratory failure stemming from bronchoconstriction, bronchorrhea, central respiratory depression or weakness/paralysis of the respiratory muscles (Robb, 2022) OP Prehospital Treatment PPE – Protect yourself Early notification to ED Decontaminate as early as possible Remove clothes and accessories Supportive care – ABCs IV/IO access IV fluids (hypovolaemia M25) Atropine - Muscarinic receptor antagonist OP Prehospital Treatment Carbon monoxide Carbon monoxide (CO) is an odourless, colourless, tasteless gas 220 greater affinity for Hb than O2 Sources: petrol-powered pumps, outdoor heaters, generators used indoors, gas stoves (inc caravans), outdoor cookers - particularly those with charcoal beads New vehicles are unlikely to result in CO poisoning but can still occur (CO2 toxicity is the major issue in post 1986 vehicles) Patients often asymptomatic until too late and unconscious Headache followed by hypoxic signs (e.g. confusion, delirium, ↓ LOC) May be accidental or intentional exposure Rx 100% O2  Snake Bites Around 100 venomous snakes are found in Australia Venomous Elapids include: Browns, Blacks, Tigers, Taipans, death adders & sea snakes Other venous snakes include cobras, vipers, rattlesnake (not in Aust. but found in captivity, zoos and private collections) Majority of snake bites are ‘dry bites’ or cause no harm, but every bite should be treated as potentially lethal # Toxins are systemically absorbed and distributed via lymphatic system Snake Bites Anti-venoms available across Australia Most are made from horse serum and have potential to be immunogenic Antivenom hypersensitivity (25%) or anaphylaxis can occur (10%) (Isbister et al, 2008) Anaphylactoid reactions may be more likely to occur in those who are atopic or who have previously received equine serum Treat anaphylaxis as per usual CPG (i.e. adrenaline, CSL) Clinical Toxin categories: Haemotoxic, Neurotoxic and Cytotoxic Snakebite - Haemotoxins Toxin activates proteins that induce clotting, are vasoactive and some have true anti-coagulant effects In small prey this leads to clotting and stroke In humans, due to the larger blood volume and clotting factors, formation of microthrombi overwhelm clotting factors leading to consumption coagulopathy (bleeding) Snake bites that are haemotoxic include: Browns (severe coagulopathy), Tigers and Taipans Snakebite - Neurotoxins Toxin interferes with nerve signalling Most often as a competitive antagonist ; sometimes as an excitatory agonist or pre-synaptic Ca2+ channel blocker causing vesicle depletion Commonly affect the neuromuscular junction leading to flaccid paralysis (including respiratory muscles and results in failure) If excitatory leads to fasciculations and spastic paralysis (coral snake, mambas) Other nervous system signs & symptoms include parathesia, dysarthria, altered LOC Examples: tiger, black snakes, taipans (profound paralysis), death adders Snakebite – Cytotoxins Myotoxic effects skeletal muscle breakdown – leading to rhabdomyolysis and myoglobinuria and AKI Cardiotoxic effects – heart muscle damage General toxicity to cells: Local tissue damage Oedema Blistering Necrosis Examples: mulgas, black snakes, sea snakes, cobras and vipers, rattlesnake Funnel Web Spider The clinical features arise from excessive activity of the autonomic and peripheral nervous system Neurotoxins induce the spontaneous and repetitive firing of action potentials in autonomic and motor neurons, leading to catecholamine surge Massive and simultaneous firing of both SNS and PSNS This occurs due to the prevention of sodium channels from inactivating, causing excessive propagation of the action potential Median time to onset of envenoming is ~28 minutes and usually