Drug toxicology

• What is pharmacology?


  -The study of the effect of drugs on the function of living systems
• What is toxicology?


  -The study of the effect of poisons on the function of living systems

  -"The dose makes the poison"
• What are the 6 chemical agents that can cause toxicity?

  -Drugs

  -Insecticides/herbicides

  -Plant toxins (digoxin)

  -Animal toxins

  -Chemical weapons( sarin: novichok)

  -Radioactive elements (polonium 210)
• What is an Adverse drug reaction?

  -Noxious or unintended responses occurring at therapeutic doses ~ 5% of all acute hospital admissions
• Describe a Type A adverse reaction of a drug:

  -Augmemnted

  -Related to known pharmacology, but undesirable

  -Common, dose-related and predictable
• Examples Type A ADRs

  -Haemorrhage with anticoagulants

  -Respiratory depression with opioids

  -Sedation with anxiolytic and older antihistamine drugs
• Describe a Type B adverse reaction of a drug:

  -Bizarre

  -Unrelated to known pharmacology

  -Rare, unpredictable & often idiosyncratic
• Example type B ADRs

  -Anaphylaxis with penicillin

  -Allergic liver damage by halothane

  -Bone marrow suppression by chloramphenicol

  -Individual allergy/genetic basis
• What is toxikinetics?


  -The effects of the body on the poison
• Absorption toxikinetics:


  -Ingestion: mercury and dioxin in fish

  pesticides in produce

  salmonella (diary), botulinum (meat) toxins

  -Inhalation: asbestos, nerve gases
• Metabolism toxikinetics:


  -Phase I by cytochrome P450 (oxidation, reduction, hydrolysis)

  -Phase II conjugation to allow excretion in urine and bile
• Excretion toxikinetics:


  -Toxins not excreted stored in:

  -bone (eg. lead)

  -fat (eg. DDE a metabolite of the pesticide DDT dichlorodiphenyl trichloroethane)

  -The toxin may be released slowly into the body
• What is detoxification?


  -Compound rendered less toxic
• What is toxification?


  -Relatively inert compound converted into toxin
• What is an allergic response?

  -Common form of ADR, usually with a different time course to pharmacological effects

  -4 clinical syndromes
• Name & describe the 4 clinical syndromes of allergic reactions:

  -Type I hypersensitivity reaction is IgE-mediated mast cell degranulation

  
  

  -Type II antibody mediated cytotoxic hypersensitivity-

  involves haematological reactions i.e. those pertaining to the blood cells

  and blood-forming organs

  
  

  -Type III immune complex-mediated hypersensitivity

  
  

  -Type IV delayed-type hypersensitivity
• What does a Type I hypersensitivity reaction trigger?

  -Anaphylactic shock

  -Low MW antigen enters (penicillin, peanut oil, bee venom)

  -Binds to hapten and forms immunogenic conjugate

  -Binds to mast cell

  -IgE recognition triggers histamine release

  -Causes bronchoconstriction, vasodilation & inflammation

  -Treat with adrenaline
• What does a Type II hypersensitivity reaction cause ?

  -Depletion of RBCs, neutrophils or platelets

  -Toxic antigen binds to RBC

  -IgG binds to RBC and triggers complement mediated lysis

  -If T cell binds triggers T cells mediated cell lysis

  -Drugs in this category include sulphonamides, certain NSDAIS, quinine & heparin
• What are the 4 superfamilies of receptors?

  -Ligand-gated ion channels ionotropic receptors

  voltage-gated ion channels

  -GPCRs - G protein coupled receptors (metabotropic receptors)

  -Enzyme-linked receptors (tyrosine kinase activity)

  -Nuclear receptors (regulate gene transcription)
• Examples of animal toxin that blocks ion-conduction:

  -a-bungarotoxin on nicotinic acetylcholine receptor (nAChR
• What do dendrotoxins do?

  -Block voltage gates potassium channels

  -Found in black and green mamba
• Which toxins act on voltage gated calcium channels?

  -w-conotoxin from coneshell

  -w-agatoxin - from funnel web spider

  -SNX-482 from tarantula
• What does tetrodotoxin do?

  -Acts on sodium channels to block action potentials
• What are the cellular effects of enzyme mediated toxicology?

  -Increased secretion

  (eyes watering, nose running)

  -Convulsions

  -Bradycardia,

  hypotension

  -Bronchoconstriction

  respiratory

  depression
• Examples of Irreversible anticholinesterase:

  -parathion

  -Sarin

  -Novichok
• What are oximes?


  -Strong nucleophiles that reactivate AChesterase
• What is the bodies first line of defence against biological nerve gas?

  -Atropine- mAChR blocker- central respiratory depression

  -Pralidoxime- reactivation of acetylcholinesterase
• Biochemical pathways of toxicology:

  -Cyanide inhibits mitochondrial cytochrome c oxidase to prevent cellular respiration

  -Carbon monoxide displaces oxygen from haemoglobin causing hypoxia
• Which two organs are susceptible to toxin damage?

  -Liver

  -Kidney
• Hepatotoxicity causes:


  -Hepatic necrosis from

  paracetamol poisoning

  -Paracetamol binds to protein thiol groups
• Chronic liver damage:


  -Cirrhosis

  -long-term ethanol abuse causes cellular toxicity, inflammation and malnutrition as ethanol becomes a food source
• What does halothane do?

  -Covalently binds to liver proteins to trigger autoimmune reaction in hepatitis
• Clinical relevance of paracetamol:

  -Prominent cause of hepatic poisoning

  -48 % of all poison admissions and 200+ deaths/year

  -Overdose is due to enzyme saturation & glutathione depletion

  -Treat with glutathione precursors like Acetylcysteine & Methionine
• Nephrotoxicity:


  -Organ-Directed Toxicity

  -Can cause changes in GFR, allergic and chronic nephritis
• Allergic and chronic nephritis:

  -Allergic due to reaction to NSAIDs like fenoprofen and antibiotics like metacillin

  -Chronic due to long term use of NSAIDs and paracetamol
• What are Proto-oncogenes?


  -Class of genes involved in carcinogenesis

  -Promote cell cycle progression

  -EXAMPLE: constitutive activity of growth factor tyrosine-kinase receptors can cause neoplastic transformation
• What are tumour-suppressor genes?

  -Class of genes involved in carcinogenesis

  -Inhibit cell cycle progression

  -EXMAPLE: mutations in tumour suppression gene product p53 (prevalent in smokers)
• What is teratogenicity?


  -The creation of birth defects during foetal development

  -Teratogens are the substances that induce birth defects e.g.., Thalidomide

  (S)-enantiomer
• Case study: Contergan


  -Contains thalidomide

  -Marketed as a non-lethal hypnotic and sedative

  -Recommended as and ant-emetic to treat morning sickness in pregnant women

  -Teratogenic effects in 100% of foetuses exposed 3-6 week gestation

  -~8-12,000 infants were born with deformities caused by thalidomide, and only about 5,000 of these survived beyond childhood

  -Case dismissed
• Thalidomide uses today:


  -Treat leprosy and multiple myeloma due to inhibitory activity on tumour necrosis factor (TNF)-a production