WEEK 2 - Drug Toxicity, Drug interactions, & Pharmacogenomics Flashcards
What is drug toxicity?
Toxicity refers to how poisonous / harmful a substance can be.
Drug toxicity is any harmful effect caused by a medicine / drug.
Explain drug induced organ toxicity, including the two types of organs usually effected by drug toxicity, briefly explain why…
There are two tissues particularly vulnerable to the toxic effects of drugs; the liver (hepatotoxicity), and the kidneys (nephrotoxicity).
Liver;
- is the largest organ in the body.
- blood from the intestine passes through the liver via the hepatic portal vein.
- metabolises a large proportion of drugs, and is susceptible to their toxic effects.
Kidneys;
- highly perfused.
- major route of excretion for many drugs and their metabolites.
- filtration and reabsorption can lead to high concentrations of drug / metabolite in the medulla.
List the 3 mechanisms of toxicity, and give a brief example if possible…
1) Predictable pharmacological effects;
- mechanisms are an extension of the pharmacology.
- on target; binding to intended receptor (dose too high)
- off target; binding to unintended receptor.
2) Immune mediated effects:
- drugs can rigger immune receptors; large protein drugs can activate the immune system directly, whereas small drug molecules aren’t usually immunogenicity but can act as haptens (bind to the endogenous protein and the complex triggers an immune response).
- includes; hypersensitivity reactions, infusion reactions, and drug induced autoimmunity.
3) Direct cellular toxicity:
- can lead to carcinogens.
- detrimental regulatory responses to cellular damage.
Explain hypersensitivity, regarding immune mediated toxicity…
Hypersensitivity is a reaction in which our own body’s immune cells overreact to an antigen and cause excessive inflammation and damage to our own body’s cells.
Overreaction to an antigen —> normally harmless environmental antigen (Allergy) OR self antigen (Autoimmunity).
List how many, and what types of drug mediated hypersensitivity reactions there are. If possible briefly explain each one…
There are 4 types of drug mediated hypersensitivity reactions:
Type 1 - immediate Hypersensitivity / Anaphylaxis:
- Most allergic reactions.
- Consists of IgE productions, and mast cell degranulation (histamine, serotonin release, inflammation, bronchoconstriction, vasodilation, and flares in skin).
- Can be local / systemic with varying severity.
- Rapid onset (<1 hour).
Type 2 - Antiody dependent cytotoxic hypersensitivity:
- Consists of drugs binding to cells (including RBS, neutrophils, or platelets).
- Is recognised by IgG or IgM.
- Cell lysis occurs due to; complement fixation, cytotoxic T cells, or phagocytosis by macrophages.
- The symptoms are based on the cell type destroyed.
- Time onset; within 24 hours.
Type 3 - Immune complex mediated:
- Consists of Human Anti-Mouse Antibodies (HAMA).
- Produced by the body in response to administration of monoclonal antibodies.
- Can cause reactions.
- Replacement of mouse immunoglobulin constant regions with human ones is important to reduce immunogenicity.
Type 4 - Cell-Mediated:
- Consists of the activated of TH1, TH17, and cytotoxic T-cells.
- The delayed response; first exposure doesn’t normally induce a response, subsequent exposures lead to T cell activation, and the onset usually > 48 hours (may take weeks).
- Symptoms are usually skin related; contact dermatitis with topic anti-histamines.
Explain what infusion reactions are, what symptoms someone may experience, and their causes…
Infusion reactions occur due to the infusion of drugs especially monoclonal antibodies and cytotoxins. This usually occurs during infusion, or within hours after. The severity varies.
Symptoms include;
- fever / choking chills.
- flushing / itching.
- alterations in heart rate and BP.
- dysphasia / chest discomfort.
- back / abdominal pain.
- nausea / vomiting / diarrhoea.
- skin rashes.
Causes include;
- Hypersensitivity reaction.
- Pseudoallergic (most common).
- Cytokinesis release syndrome (CRS).
Explain what drought induced autoimmunity is, and give an example…
Autoimmunity occurs when the body launches an immune response against its own cells.
Occurs when antibodies are produced against proteins in the cell nucleus, resulting in multi-organ inflammation. the joints, muscles, heart, lungs, and skin are typically affected.
The toxic effects of drugs on cells can lead to;
- regulatory repair responses which cause further tissue damage.
- loss of functional cells / tissues.
- in the case of carcinogens, DNA damage, and mutagenesis - potentially causing cancer.
A popular example of drug induced autoimmunity is Lupus.
Briefly explain teratogenesis…
When drugs are given to a mother during pregnancy, there is a potential for them to adversely affect the foetus.
Can cause large structural malformations during foetal development.
A popular example is the Thalidomide disaster of the 1960’s.
It is now a critical component of toxicology studies as part of new drugs developments.
Briefly explain how to quantify toxicity on a graph…
ED50; the dose of drug that’s effective in 50% of the population.
TD50: dose of drug that causes a toxic response in 50% of the population.
LD50; dose of drug that is lethal in 50% of the population.
Explain the Therapeutic Window in terms of toxicity…
- A range of doses that elicits a therapeutic response, without unacceptable adverse effects.
- Quantified by Therapeutic Index.
TD50 = dose of drug that causes a toxic response in 50% of the population.
ED50 = dose of drug that is effective in 50% of the population.
- Drugs with small therapeutic index may require plasma concentration monitoring.
Explain what an adverse reaction in terms of medicines is…
A response to a medicine which is noxious and unintended, which occurs at doses normally used in humans.
Explain what side effects are, their 2 classifications of side effects, their onset, duration, frequency, severity, and factors affecting …
Side effects are any unintended effect of a pharmaceutical product occurring at doses normally used by a patient which is related to the pharmacological properties of the drug. Can be useful or harmful.
Classification:
- Type A; is predictable and based on drug pharmacology. Often mild, common, dose-dependent, and has a low mortality rate.
- Type B; is unpredictable, and based on genetic differences or other factors. Often severe, uncommon, no clear relationship with dose, and has a high mortality rate.
Onset:
- Immediate.
- Delayed.
- related to stopping the drug.
Duration:
- Acute or Chronic.
Frequency:
- Common; incidence of 1% or more.
- Infrequent; incidence between 0.1% and 1%.
- Rare; incidence less than 0.1%.
Severity:
- A serious adverse reaction is any medial occurrence in relation to a medicine; results in death or is otherwise life threatening, persistent / significant disability, and is associated with a congenital abnormality / birth defect.
- A non serious adverse effects is when it doesn’t fit into the above criteria.
Factors Affecting:
- Dose.
- Polypharmacy (increased risk of interactions).
- Comorbidities.
- Age / Gender.
- Genetic factors.
- History of ADRs.
When do drug interactions occur? Give some examples…
Drug interactions occur when a patient’s response to a drug is modified by:
- Food.
- Nutritional supplements.
- Formulation excipients.
- Environmental factors.
- other drugs or disease.
Briefly explain what drug-drug interactions are…
They are interactions between drugs.
May be beneficial or harmful.
harmful drug-drug interactions are important as they cause 10-20% of the adverse drug reactions that require hospitalisation, and can be avoided.
What are the 4 classifications of drug interactions? If possible give a brief description of each…
1) Pharmacodynamics:
when interacting drugs wither have additive effects (overall effect is increased), or opposing effects (overall effect is decreased or even ‘cancelled out’).
2) Pharmacokinetic:
When one drug changes the systemic concentration of another drug, altering ‘how much’ and for ‘how long’ its present at the site of action.
3) Pharmaceutical drug-drug interactions:
The formulation of one drug is altered by another before it’s administered.
4) Behavioural:
One drug alters the patients behaviour to modify compliance with another drug.
