L13 Adverse Drug reaction Flashcards
Adverse Drug reaction and events
Adverse drug reaction and adverse drug event are
terms that refer to harmful or undesirable response
to a drug
Adverse drug event
an adverse drug event is harm caused by appropriate
or inappropriate use of a drug
Adverse drug reaction
adverse drug reactions are a subset of these events, wherein harm is directly caused by a drug under appropriate use (i.e., at normal doses)
Adverse drug event vs reaction
an adverse drug event is harm caused by appropriate or inappropriate use of a drug whereas adverse drug reactions are a subset of these events, wherein harm is directly caused by a drug under appropriate use (i.e., at normal doses)
Adverse drug reaction (ADR) on health system
a significant burden to the health system and economy
- hospitalisation and/or prolonged hospital stay
- number of incidents continue to increase
top leading medications for ADR
Anticoagulants
Opioids and analgesics
Antineoplastic antibiotics
Elderly patients are at increased risk of ADRs
- changed pharmacokinetic and pharmacodynamic properties due to ageing
- polypharmacy - drug-drug interactions
- inappropriate prescribing (risk > benefit)
Elderly patient change in absorption
little clinical impact despite reduced surface area and slowed gastric emptying
Elderly patient change in metabolism
impaired CYP-mediated metabolism (conjugation is less affected)
* consideration for hepatically cleared drugs (P1).
* Because liver function decreases with age.
Elderly patient change in distribution
*↑ body fat and ↓ total body water
* ↑ Vd for lipophilic drugs but ↓ Vd for hydrophilic drugs
Elderly patient change in excretion
reduced GFR due to reduced renal size and nephron functions
* consideration for renally cleared drugs
Elderly patient change in protein binding
decreased plasma albumin level.
↓ drug binding and therefore ↑ free drug level for action
Elderly patient change in drug action
More sensitive to medications
Pregnant women are at increased risk of ADRs
- changed pharmacokinetic properties
- the main concern is drug teratogenicity - prenatal toxicity
º placenta is a partial barrier
º prescribing medicines in pregnancy (TGA categorisation)
Pregnant women change in Absorption
increased gastric pH alters ionisation of drugs
* absorption of weak bases ↑ and weak acids ↓; slower GI mobility ↓ absorption
Pregnant women change in Distribution
↑ body fat and total body water
* can increase Vd
for lipophilic drugs and hydrophilic drugs
Pregnant women change in Metabolism
↑ cardiac output leads to ↑ hepatic metabolism; ↑ activity of drug-metabolising enzymes, e.g., key CYP enzymes and UGT
Pregnant women change in excretion
↑ cardiac output leads to ↑ renal clearance
Pregnant women change in protein binding
decreased plasma albumin level
* ↓ drug binding and therefore ↑ free drug level for action
Pediatric patients at increased risk of ADRs
- ontogeny of drug-metabolising enzymes, receptors, and transporters
- development of drug clearance capacity
- dosing based on adult formula (per kg body weight) may be inappropriate
- drugs are poorly studied in this group - off-label prescription
polypharmacy
- complex or multiple diseases, e.g., autism spectrum
disorder - risk of drug-drug interactions
pharmacogenetics
- e.g., anticancer treatment
Pharmacovigilance
Detection, assessment, understanding and prevention of ADRs.
Certain, likely, possible
Unlikely, unclassified, unclassifiable
TGA (Therapeutic Goods Administration), Australia
- Blue card adverse reaction reporting form
- Medicines Safety Update - provides information on drug safety and emerging safety
issues
Adverse drug reactions are traditionally classified as
Type A or Type B
Type A name
Augmented (morphine)
Type B name
Bizzare (penicillin)
Type C name
Chronic (corticosteroids)
Type D name
Delayed (teratogens)
Type E name
End of use (benzodiazepines or opioids)
Type F name
Failure (antibiotic resistance)
Type A description
often inherently linked to the pharmacological effects of a drug and show a dose-response
relationship and, thus, can be predicted. e.g., respiratory depression with opioids (guess med)
Type B description
idiosyncratic and have no link with the pharmacological mechanism of action and are thus
unpredictable, e.g., anaphylaxis to (P)
Type C description
dose- (cumulative dose) and time-related, e.g., adrenal suppression with prolonged use of
corticosteroids
Type D description
time-related; occurs after the use of a drug, e.g., carcinogenesis (smoke), teratogenesis
(teratogens)*
Type E description
unwanted effect following the withdrawal of a drug, e.g., withdrawal syndrome with opioids or
benzodiazepines
Type F description
unexpected failure of a drug to produce therapeutic effects, e.g., (a.r)
Opioid use in Australia
- opioid use has been increasing since 1990
- ↑ the use of strong opioids and long-acting formulations
Type A adverse drug reactions with opioids
* the m-opioid receptor (MOR) mediates both therapeutic and adverse effects
- G protein-dependent signalling pathways - analgesic effects (therapuetic)
- G protein-independent signalling pathways (undesirable)
*- respiratory depression (most dangerous) / miosis (pupillary constriction) / euphoria / sedation
/ reduced airway reflexes / nausea and vomiting / constipation
opioids - the m-opioid receptor (MOR)
mediates both therapeutic and adverse effects and coupled with G(a)i
Type B adverse drug reactions
- linked to genetic predisposition (i.e., polymorphism) affecting PK/PD
- drug hypersensitivity reaction
TB:
linked to genetic predisposition (i.e., polymorphism) affecting PK/PD
- PK, e.g., thiopurines and thiopurine methyltransferase (TPMT) activity
- PD, e.g., salbutamol and b2 adrenoceptor
TB: drug hypersensitivity reaction
- prior exposure
- immediate or delayed
- not completely unpredictable
º ↑ risk due to immunogenetic predisposition, e.g., HLA (human leukocyte antigen) alleles
Type 1 and 4 in type B adverse reactions
Type I:
IgE-mediated immediate (< 1hr after last dose)
Type IV:
T cell-mediated (delayed)
Type I IgE-mediated hypersensitivity
a drug of low molecular weight (hapten, e.g., penicillins) and a carrier protein forms a hapten-protein complex
acts as a neo-antigen to the sensitisation phase and effector phase
- symptoms appear (~ an hour) in the skin, e.g., itch, urticaria
- anaphylaxis is the most severe form
[Type I IgE]Sensitisation phase initial exposure
initial exposure → antigen-specific IgE production → IgE binds
to Fc receptor on the surface of mast cells and basophils
[Type I IgE]Effector phase drug re-exposure
drug re-exposure forms antigen → binds to Fc receptor-bound
IgE → stimulates release of preformed mediators
Antigen Binding: This complex binds to the IgE antibodies that are already attached to the Fc receptors on mast cells and basophils.
Types IV T cell-mediated hypersensitivity
Sensitisation phase and effector phase
[Types IV] Sensitisation phase initial exposure
→ processed by dendritic cells through
phagocytosis → dendritic cells migrate to lymph nodes and
present antigen to naïve T cells
[Types IV] Effector phase
drug re-exposure
and subsequent antigen presentation →
sensitised T cells in target tissues activate macrophages to
mediate inflammatory action → tissue damage
After the Type IV sensitisation and effector phase skin is most targeted…
severe cutaneous adverse reaction (SCAR)
severe cutaneous adverse reaction (SCAR)
- severe forms include SJS (Stevens-Johnson Syndrome)
and TEN (toxic epidermal necrolysis) - immunogenetic predisposition, e.g., abacavir and HLAB*5701 (Caucasians)
T cell-mediated drug hypersensitivity - theories
- Hapten
- p-i concept (long name)
- altered peptide repertoire model
- altered TCR repertoire model
hapten theory
drugs of low molecular weight covalently bind to a carrier protein (e.g., lysine residue) to form an antigen
* phagocytosis of the hapten-protein complex by APCs
(antigen presenting cells)
* presentation of antigen with HLA mmolecules by APCs
to T cells → effector response
penicillins form a hapten-protein complex
* Type I hypersensitivity
* Type IV hypersensitivity
p-i concept (pharmacological interaction with immune receptor)
drugs or metabolites interact directly with either HLA or TCR (T cell receptor) → T cell response
- APC processing is not required
- e.g., carbamazepine and HLA-B*15:02
altered peptide repertoire model
self → non-self recognition
* drug binds to the HLA region that accommodates
self-peptide → novel self-peptides now bind → the
altered HLA-self-peptide complex is recognised as
foreign by T cells
- e.g., abacavir and HLA-B*5701
altered TCR repertoire model
drug binds to TCR, and changes HLA recognition
