D12 - Drug toxicity Flashcards
Toxicity
- an unwanted drug effect that occurs at supratherapeutic doses
ADR - adverse drug reaction
- an unwanted drug effect that occurs at normal therapeutic doses - Problem that arises in a patient who is taking the recommended dose
Pharmacovigilance
- The process of identifying, monitoring and effectively reducing adverse drug reactions
- Risk awareness
ADRs - extent of the problem
- Top ten causes of death - Liability for health car providers, and account for many lawsuits
MRP = Medication related problems
MRP
Medication related problems
- The elderly
- Due to cognitive decline, struggle to keep abreast of medications
○ Very vulnerable to prescribing errors, administration errors, nonadherence, DDIs and ADRs during ‘transitions of care’ - being moved between doctors, hospitals and care facilities etc.
○ More likely to receive multiple drugs
○ ADR risks increase with polypharmacy
○ Physiological changes accompany old age
§ Drug plasma levels may be higher due to liver/kidney changesPharmacokinetic changes occurring in the elderly1. Absorption - reduced oral absorption - surface area of small intestine is reduced (minor effect) 2. Volume of distribution - total body fat increases and total body water declines - Vdist may increase for lipophilic drugs and decrease for hydrophilic drugs 3. Protein binding - reduction in protein binding - decrease production of albumin and decreased circulating concentrations - increased free drugs concentrations 4. Hepatic metabolism - the liver slows down with decreased drug metabolism by CP450 - CL of hepatic clearance may be decreased significantly 5. Renal clearance - reduction in glomerular filtration rate, decrease in clearance an increase half life of renally-cleared drugs
Pharmacokinetic changes occurring in the elderly
- Absorption - reduced oral absorption - surface area of small intestine is reduced (minor effect)
2. Volume of distribution - total body fat increases and total body water declines - Vdist may increase for lipophilic drugs and decrease for hydrophilic drugs
3. Protein binding - reduction in protein binding - decrease production of albumin and decreased circulating concentrations - increased free drugs concentrations
4. Hepatic metabolism - the liver slows down with decreased drug metabolism by CP450 - CL of hepatic clearance may be decreased significantly
5. Renal clearance - reduction in glomerular filtration rate, decrease in clearance an increase half life of renally-cleared drugs
- Children
- Physiological differences between children and adults
- Different hepatic metabolism and renal excretion
- Diverse population
○ PK differences between newborns, toddlers, pre-schoolers, teenagers - Most medicines are studied poorly in juvenile patients
- Efficacy and side effect profiles may be very different
○ Dosing based on adult mg per kg formula may be inappropriate - Clinical trails done in adults not children
- Pregnant women
- Many physiological differences
○ Increase in maternal body fat and total body water
○ Decrease in plasma protein levels, especially albumin
○ Increase in maternal blood volume and cardiac out put
§ Effects Vdist for drugs - esp. hydrophilic drugs
○ Increase in blood flow to the kidneys and uteroplacental unit- Delayed gastric emptying and gastrointestinal motility
○ Gastric reflux
○ Pressure building up due to growing of uterus - Altered activity of hepatic drug metabolising enzymes
○ Increase in P450
○ Certain drugs may be cleared more rapidly by the liver - Teratogenicity of drugs a major concern
○ Changes in development of the fetus
○ Structural changes / CNS development - In Australia - 7 category system recommending what drugs should be used in pregnant women and what medication exists
- Delayed gastric emptying and gastrointestinal motility
Classifying adverse drug reactions
- Type A
○ On target
○ Augmented ADRs are predictable on pharmacological grounds
○ Stronger than expected
○ Exaggerated manifestation on normal effects of the drug- Type B
○ Off target/bizarre
○ Serious, life threatening can cause death
○ Less common
○ Unrelated to the known pharmacological properties of the drug - unpredictable
○ Often more due to the patient
○ Often major immunological components
- Type B
Type A
○ 85-90 % pf ADRs
○ Predictable - prescriber can quickly recognise
○ Can occur in any patient
○ Influenced by administered dose - more likely in a patient given a high dose
○ Can often be avoided by switching to an alternative drug, changing dosing regimen
○ Usually identified during premarketing trials
Eg. Insulin Hypoglycaemia ○ Pancreatic hormone facilitating uptake of glucose into cells ○ Diabetic patients are insulin resistant § Need insulin boosting drugs or insulin injections ○ To much can cause hypoglycaemia, an excessively low blood sugar level § Protracted severe hypoglycaemia is life threatening ○ Excessive reduction in sugar levels ○ Too much insulin can kill a patient
Eg. Insulin Hypoglycaemia
○ Pancreatic hormone facilitating uptake of glucose into cells
○ Diabetic patients are insulin resistant
§ Need insulin boosting drugs or insulin injections
○ To much can cause hypoglycaemia, an excessively low blood sugar level
§ Protracted severe hypoglycaemia is life threatening
○ Excessive reduction in sugar levels
○ Too much insulin can kill a patient
Type B
○ Usually occur at a site remote to that of the primary drug action eg. skin
○ More problematic, less common
○ Hypersensitivity reactions - only in vulnerable patients
§ Often said to be unpredictable
○ Often discovered after a new medicine is marketed and used in many people
○ Can be idiosyncratic - involve patients with inherited genetic traits
§ Eg. Drug metabolism variants or inability to compensate for drug induced effects
○ They can be allergies that involves an immunological component
Drug allergies
○ Most significant
○ Key consideration is the time taken for onset of adverse reaction after the last drug dose
○ 2 types
○ Immediate reactions
§ Occurs less than an hour after the dose taken
§ Mainly IgE mediated
§ Bronchospasm, anaphylactic shock, rhinitis, conjunctivitis, angioedema, anaphylaxis, urticaria
○ Non-immediate reaction
§ Variable cutaneous symptoms occurring greater than an hour and up to several days after the last drug dose
□ Urticaria, maculopapular eruptions, fixed drug eruptions, vasculitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)
§ T cell mediated
Immediate reactions
○ Involve IgE production by antigen-specific B lymphocytes
○ IgE antibodies bind to high-affinity Fc receptors on the surface of mast cells and basophils
○ Only present days/weeks/months after prior expose to the drug
§ Period of prior use - sensitization is initiated
§ Months after treatment is finished, re-exposure triggers symptoms
§ Immediate because re-administration result in immediate manifestation of drug reactions
○ Involve immunoglobulin E production by antigen specific B lymphocytes
○ Bond to mast cells and basophils
○ IgE is cross linked causing activation of the mast cell and release od histamine and other mediators
○ Symptoms appear within 1 hour - itching, skin reddening, urticaria
Non-immediate - T cell mediated
○ Mainly skin - cutaneous toxicity
○ Any organ can be involved
○ Time taken between the elicitation and the dose of the drug is more than one hour - can take days
○ Period of sensitization
○ Conditions show up during first course of treatment - does not need reuse of the drug
○ Antigen is internalised after processing by. Dendritic cells - presented to naïve t cells - adaptive immune response
○ T cells migrate to the skin
○ When re-exposed to the antigen - release of damaging cytokines and cytotoxins including perforins and granzymes
○ T cell mediated conditions are severe and con result in death
Toxicity
- Above the recommended range above the therapeutic range
- Can manifest in target organs often the liver -
○ Liver -hepatotoxicity
○ nephrotoxicity - kidneys
○ pneumotoxicity - lungs
○ Cardiotoxicity - heart
○ Neurotoxicity - CNS and PNS - Localised in tissues often
- Cancer - older cancer drugs
○ Cytotoxic agents designed to cause DNA damage but can cause secondary tumour because of damage in other tissues - Unborn infant
○ Thalidomide poising - shortening of upper and lower limbs
○ Growth retardation - low birth weight
○ CNS impairment
- Can manifest in target organs often the liver -
