Fundamentals of Toxicology Lecture Slides PDF

My Surrey Attendance Code: xx-xx-xx Fundamentals of Toxicology Dr Martin Hawes Senior Lecturer Veterinary Pharmac...

My Surrey Attendance Code: xx-xx-xx Fundamentals of Toxicology Dr Martin Hawes Senior Lecturer Veterinary Pharmacology and Therapeutics “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.” Paracelsus (1493-1541) Wednesday, 16 October 2024 1  Learning Outcomes 1. Define lethal dose, adverse event and serious adverse reaction 2. Differentiate acute from chronic toxicity 3. Describe the various situations where toxicity may occur (e.g. during medicines development, as adverse events, poisoning) 4. Explain why toxicity might occur during the 'normal' use of medicines 5. Describe how to deal with a suspected adverse event and make an official report Wednesday, 16 October 2024 2  1. Define lethal dose, adverse event and serious adverse reaction Wednesday, 16 October 2024 3  Pre-read – Key points Lethal doses are … lethal. LD50 is the dose that will kill 50% of a test population. Adverse Drug Reaction / Adverse Drug Event = any harmful or undesirable response to a drug. Regulators have specific definitions for ‘Adverse Event’ and ‘Serious Adverse Event’ for safety assessment and pharmacovigilance purposes… … A serious adverse event is any adverse event which results in death, is life-threatening, results in persistent or significant disability/incapacity, or a congenital anomaly or birth defect. Acute toxicity results from a single dose, or from multiple doses in a short period of time (14d) Chronic toxicity develops as a result of long-term exposure. Toxic effects are cumulative. Wednesday, 16 October 2024 4  3. Describe the various situations where toxicity may occur Wednesday, 16 October 2024 5  A true story …… It’s Sunday morning and your neighbour rings you – She is worried about 2 of her cat’s 8 kittens - both are very ‘flat’. They have been like this for an hour. They are not responsive. She is worried the smallest kitten is going to die. What would you ask your neighbour? What would you do? Wednesday, 16 October 2024 6  Happy ending – all kittens were OK 2 weeks later….. and look at her now Wednesday, 16 October 2024 7  Novel drug development Discovery phase in vitro toxicology studies e.g. AMES Pre-clinical development Acute toxicology studies, 1-4 weeks duration, high dose Reprotoxicology studies Clinical development Chronic toxicology studies, 3-6 months, low-intermediate dose Carcinogenicity studies, 2 years duration, low dose Wednesday, 16 October 2024 8  Sources of toxins Remember what Paracelsus said? Everything is toxic at the right dose….. Plants Animals Fungi Inorganic material Drugs and medicines Pesticides Household chemicals Industrial chemicals Wednesday, 16 October 2024 9  News last week …. Wednesday, 16 October 2024 10  Common sources of poison Xylitol Sycamore (equine) Medicines hypoglycaemia atypical myopathy renal and/or liver failure Grapes and raisins Rat poison Adder bites renal failure haemorrhage shock/ collapse Chocolate Mycotoxins Antifreeze CNS / renal failure / arrhythmias convulsions / coma ataxia / tremors / PU/PD Wednesday, 16 October 2024 11  The dog’s eaten my chocolate – is he going to be OK? 200g bar Theobromine Dogs at risk (kg) ~ 1g All ~ 400mg ~ ≤ 20kg but err on side of caution ~ 2mg None Wednesday, 16 October 2024 12  Veterinary Poisons Information Service https://www.vpisglobal.com/ Wednesday, 16 October 2024 13  Emetics Used primarily to induce vomiting following poisoning Only useful if instigated within ~ 2-3 hours of ingestion Do not induce vomiting if poison is corrosive, severe CNS depression, seizuring, reduced gag reflex, bradycardia apomorphine , ropinirole - dopamine (D2) agonist (stimulates CRTZ dogs) xylazine - α2-adrenergic agonist (stimulates emetic centre cats) Hydrogen peroxide 3% solution oral alternative (stimulates CN IX at pharynx) apomorphine ropinirole xylazine Wednesday, 16 October 2024 14  Decontamination with lavage / activated charcoal Activated charcoal – adsorbant Most effective if used within 1 hour of ingestion – only toxins in the liquid phase in direct contact adsorbed Activated charcoal Gastric lavage Wednesday, 16 October 2024 15  4. Explain why toxicity might occur during the 'normal' use of medicines Wednesday, 16 October 2024 16  4. Toxicity during the 'normal' use of medicines Type A – Augmented Toxic effects predictable and related to the principle pharmacological action (e.g. bleeding with anticoagulants) Dose-dependent and more common than Type B Type B – Bizarre Toxic effects unrelated to the principle pharmacological action (e.g. hypersensitivity reaction) Type C – Chronic Cumulative toxicity after prolonged use Type D – Delayed Teratogenic or carcinogenic effects Type E – End of use Toxic effects appear when the drug is stopped Rawlins & Thompson (1985) classification Wednesday, 16 October 2024 17  Hypersensitivity reactions Wednesday, 16 October 2024 18  5. Describe how to deal with a suspected adverse event and make an official report Wednesday, 16 October 2024 19  Pharmacovigilance Pharmacovigilance is the science and activities associated with the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem Safety data is generated during drug development, but is limited We have a responsibility to report unexpected adverse events to improve the safety database An unexpected adverse event is an adverse event of which the nature, severity or outcome is not consistent with approved labeling or approved documents describing expected adverse events for a VMP (EMA definition) Wednesday, 16 October 2024 20  VMD Veterinary Pharmacovigilance Annual Review Accessible at https://www.gov.uk/government/publications/veterinary-medicines-pharmacovigilance-annual-review-2016 Wednesday, 16 October 2024 21 Wednesday, 16 October 2024 22  5. Reporting a suspected adverse event Information required to make an SAR report: An identified reporter e.g. veterinarian, pharmacist, owner, member of public Details of the affected animal or human age, sex, species The product concerned name and marketing authorisation holder Details of the SAR e.g. concurrent diseases, other medications, start and end of date of treatment, other relevant history or investigations Wednesday, 16 October 2024 23 Wednesday, 16 October 2024 24 Wednesday, 16 October 2024 25  Key Points LO - Define lethal dose, adverse event and serious adverse reaction LD50 is the dose that will kill 50% of the test population An adverse event is any observation in animals, whether or not considered to be product related, that is unfavorable and unintended and that occurs after any use of VMP (off-label and on-label uses) A serious adverse event is any adverse event which results in death, is life-threatening, results in persistent or significant disability/incapacity, or a congenital anomaly or birth defect Wednesday, 16 October 2024 26  Key Points LO - Differentiate acute from chronic toxicity Acute toxicity results either from a single dose, or from multiple doses in a short period of time (usually within 14 days of the administration of the substance) Chronic toxicity develops as a result of long term exposure. Toxic effects are cumulative. LO - Describe the various situations where toxicity may occur (e.g. during medicines development, as adverse events, poisoning) Toxicity can occur in many situations, including normal use of medicines, accidental ingestions of substances, environmental exposure, novel drug development Wednesday, 16 October 2024 27  Key Points LO - Explain why toxicity might occur during the 'normal' use of medicines Toxicity can occur during the normal use of medicines. Reactions can be classified as: Type A – Augmented Type B – Bizarre Including Type I-IV hypersensitivity reactions Type C – Chronic Type D – Delayed Type E – End of use Wednesday, 16 October 2024 28  Key Points LO - Describe how to deal with a suspected adverse event and make an official report Vets have a responsibility to report unexpected adverse reactions to improve knowledge about the safety of medicines Suspected adverse events are reported to the VMD (UK) The information required to make a report includes an identified reporter, details of the affected animal or human, the product concerned and details of the suspected adverse reaction Wednesday, 16 October 2024 29