Toxicology I & II Flashcards
Define pharmacology and toxicology
- Pharmacology: the study of the effect of drugs on the function of living systems
- Toxicology: the study of the effect of poison on the function of living systems
Describe the two types of adverse drug reactions
Describe molecular mechanism of toxicology: allergy responses
- Common type of ADR
- Four basic clinical syndromes: Type I, II, III, IV
- Type I: hypersensitivity reaction - IgE mediated mast cell degranulation
- Type II: antibody mediated cytototoxic hypersensitivity - involve 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
Describe type I allergy, what triggers it
Describe type II allergy condition
Describe the second mechanism of toxicololgy: receptor, ion channel and enzyme mediated toxicity
Drugs can target and interefere with these
- 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)
- Enzymes
- Carriers
First line of defence against biological nerve gases
- Atropine- mAChR blocker- central respiratory depression
- Pralidoxime- reactivation of acetylcholinesterase
Describe the third molecular mechanism of toxicology: biochemical pathways
(i) Cyanide inhibits mitochondrial cytochrome c oxidase to prevent cellular respiration
(ii) Carbon monoxide: displaces oxygen from haemoglobin causing hypoxia
Describe the fourth molecular mechanism of toxicology: organ-directed toxicity (liver)
Organs particularly susceptible to toxin damage are liver and kidney
(i) hepatic necrosis - paracetamol poisoning
(ii) hepatic inflammation (hepatitis) - halothane can covalently bind to liver proteins to trigger an autoimmune reaction
(iii) chronic liver damage (cirrhosis) - long-term ethanol abuse causes cellular toxicity and inflammation and malnutrition as ethanol becomes a food source
Describe the fourth molecular mechanism of toxicology: Organ-directed toxicity (kidneys)
Nephroxity - damage to kidneys
- Certain drugs can directly targets part of the kidney such as renal tubes and glomeruli
(i) changes in glomerular filration rate (GFR) - Largely due to drugs that alter blood flow ,NSAIDs (eg. aspirin) reduce prostaglandins which in turn reduces blood flow/GFR, ACE inhibitors (eg. ramipril) increase blood flow/GFR
(ii) allergic nephritis - allergic reaction to NSAIDs (eg. fenoprofen) and antibiotics (eg. metacillin)
(iii) chronic nephritis - long-term NSAID and paracetamol use
Describe the fifth molecular mechanism of toxicology: Mutagenesis and carcinogens
- Mutagens cause changes to cell DNA that are passed on when cell divides, if this produces a neoplastic cell the agent is termed a carcinogen.
2 major classes of gene are involved in carcinogenesis: - Proto-oncogenes: promote cell cycle progression
eg. constitutive activity of growth factor tyrosine-kinase receptors can cause neoplastic transformation - Tumour-suppressor genes: inhibit cell cycle progression
eg. mutations in tumour suppression gene product p53 (prevalent in smokers)
Describe the sixth molecular mechanism of toxicology: tetratogenicity
- Teratogenesis: the creation of birth defects during fetal development
- Teratogens: substances that induce birth defects
- E.g. thalidomide due to enantiomer
High doses of any drug causes toxicity
Name examples of drugs falling under each category
Induction of allergic reactions
Receptors, ion channels and enzyme-mediated toxicity
Biochemical pathways
Organ-directed toxicity
Mutagenesis and carcinogenesis
Teratogenesis
Describe the stages of drug development
Around two years for each stage
Preclinical drug development testing: how does the mutagenicity test work e.g. Ames test
- In Vitro test
- strains of Salmonella typhimurium bacteria cannot synthesis histidine
- mutant grown on histidine-containing media
- drug and a liver microsomal enzyme preparation (to test for reactive metabolites) added
- histidine becomes depleted and only back-mutants can grow
- mutation rate measured
Name and describe some other preclinical drug testings
What is LD50
- Lethal dose = LD50
- The dose of drug which kills 50% of treated animals within a specified time
What does NOAEL and LOAEL mean in terms of preliminary toxic testing
- NOAEL - no observed adverse effects level
- Its the highest conc that doesn’t produce a toxic response
- LOAEL lowest observed adverse effect level
- Lowest conc that produces a toxic response
How do we calculate HED
- HED is derived from NOAEL
- Takes into account ADME
- Converting from animals to humans
What is the therapeutic index
The ratio of the dose of the drug that produces an unwanted
(toxic) effect to that producing a wanted (therapeutic) effect
= LD50 / ED50
Green is therapeutic red ix toxic
How to calculate therapeutix index
Why do the plasma levels for theophylline need to be monitored?
