L13 Adverse Drug reaction

Question 1

Adverse Drug reaction and events

Answer 1

Adverse drug reaction and adverse drug event are
terms that refer to harmful or undesirable response
to a drug

Question 2

Adverse drug event

Answer 2

an adverse drug event is harm caused by appropriate
or inappropriate use of a drug

Question 3

Adverse drug reaction

Answer 3

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)

Question 4

Adverse drug event vs reaction

Answer 4

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)

Question 5

Adverse drug reaction (ADR) on health system

Answer 5

a significant burden to the health system and economy
- hospitalisation and/or prolonged hospital stay
- number of incidents continue to increase

Question 6

top leading medications for ADR

Answer 6

Anticoagulants
Opioids and analgesics
Antineoplastic antibiotics

Question 7

Elderly patients are at increased risk of ADRs

Answer 7

• changed pharmacokinetic and pharmacodynamic properties due to ageing
• polypharmacy - drug-drug interactions
• inappropriate prescribing (risk > benefit)

Question 8

Elderly patient change in absorption

Answer 8

little clinical impact despite reduced surface area and slowed gastric emptying

Question 9

Elderly patient change in metabolism

Answer 9

impaired CYP-mediated metabolism (conjugation is less affected)
* consideration for hepatically cleared drugs (P1).
* Because liver function decreases with age.

Question 10

Elderly patient change in distribution

Answer 10

*↑ body fat and ↓ total body water
* ↑ Vd for lipophilic drugs but ↓ Vd for hydrophilic drugs

Question 11

Elderly patient change in excretion

Answer 11

reduced GFR due to reduced renal size and nephron functions
* consideration for renally cleared drugs

Question 12

Elderly patient change in protein binding

Answer 12

decreased plasma albumin level.
↓ drug binding and therefore ↑ free drug level for action

Question 13

Elderly patient change in drug action

Answer 13

More sensitive to medications

Question 14

Pregnant women are at increased risk of ADRs

Answer 14

• changed pharmacokinetic properties
• the main concern is drug teratogenicity - prenatal toxicity
  º placenta is a partial barrier
  º prescribing medicines in pregnancy (TGA categorisation)

Question 15

Pregnant women change in Absorption

Answer 15

increased gastric pH alters ionisation of drugs
* absorption of weak bases ↑ and weak acids ↓; slower GI mobility ↓ absorption

Question 16

Pregnant women change in Distribution

Answer 16

↑ body fat and total body water
* can increase Vd
for lipophilic drugs and hydrophilic drugs

Question 17

Pregnant women change in Metabolism

Answer 17

↑ cardiac output leads to ↑ hepatic metabolism; ↑ activity of drug-metabolising enzymes, e.g., key CYP enzymes and UGT

Question 18

Pregnant women change in excretion

Answer 18

↑ cardiac output leads to ↑ renal clearance

Question 19

Pregnant women change in protein binding

Answer 19

decreased plasma albumin level
* ↓ drug binding and therefore ↑ free drug level for action

Question 20

Pediatric patients at increased risk of ADRs

Answer 20

• 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

Question 21

polypharmacy

Answer 21

• complex or multiple diseases, e.g., autism spectrum
  disorder
• risk of drug-drug interactions

Question 22

pharmacogenetics

Answer 22

• e.g., anticancer treatment

Question 23

Pharmacovigilance

Answer 23

Detection, assessment, understanding and prevention of ADRs.
Certain, likely, possible
Unlikely, unclassified, unclassifiable

Question 24

TGA (Therapeutic Goods Administration), Australia

Answer 24

• Blue card adverse reaction reporting form
• Medicines Safety Update - provides information on drug safety and emerging safety
  issues

Question 25

Adverse drug reactions are traditionally classified as

Answer 25

Type A or Type B

Question 26

Type A name

Answer 26

Augmented (morphine)

Question 27

Type B name

Answer 27

Bizzare (penicillin)

Question 28

Type C name

Answer 28

Chronic (corticosteroids)

Question 29

Type D name

Answer 29

Delayed (teratogens)

Question 30

Type E name

Answer 30

End of use (benzodiazepines or opioids)

Question 31

Type F name

Answer 31

Failure (antibiotic resistance)

Question 32

Type A description

Answer 32

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)

Question 33

Type B description

Answer 33

idiosyncratic and have no link with the pharmacological mechanism of action and are thus
unpredictable, e.g., anaphylaxis to (P)

Question 34

Type C description

Answer 34

dose- (cumulative dose) and time-related, e.g., adrenal suppression with prolonged use of
corticosteroids

Question 35

Type D description

Answer 35

time-related; occurs after the use of a drug, e.g., carcinogenesis (smoke), teratogenesis
(teratogens)*

Question 36

Type E description

Answer 36

unwanted effect following the withdrawal of a drug, e.g., withdrawal syndrome with opioids or
benzodiazepines

Question 37

Type F description

Answer 37

unexpected failure of a drug to produce therapeutic effects, e.g., (a.r)

Question 38

Opioid use in Australia

Answer 38

• opioid use has been increasing since 1990
• ↑ the use of strong opioids and long-acting formulations

Question 39

Type A adverse drug reactions with opioids
* the m-opioid receptor (MOR) mediates both therapeutic and adverse effects

Answer 39

• 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

Question 40

opioids - the m-opioid receptor (MOR)

Answer 40

mediates both therapeutic and adverse effects and coupled with G(a)i

Question 41

Type B adverse drug reactions

Answer 41

• linked to genetic predisposition (i.e., polymorphism) affecting PK/PD
• drug hypersensitivity reaction

Question 42

TB:
linked to genetic predisposition (i.e., polymorphism) affecting PK/PD

Answer 42

• PK, e.g., thiopurines and thiopurine methyltransferase (TPMT) activity
• PD, e.g., salbutamol and b2 adrenoceptor

Question 43

TB: drug hypersensitivity reaction

Answer 43

• prior exposure
• immediate or delayed
• not completely unpredictable
  º ↑ risk due to immunogenetic predisposition, e.g., HLA (human leukocyte antigen) alleles

Question 44

Type 1 and 4 in type B adverse reactions

Answer 44

Type I:
IgE-mediated immediate (< 1hr after last dose)

Type IV:
T cell-mediated (delayed)

Question 45

Type I IgE-mediated hypersensitivity

Answer 45

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

Question 46

[Type I IgE]Sensitisation phase initial exposure

Answer 46

initial exposure → antigen-specific IgE production → IgE binds
to Fc receptor on the surface of mast cells and basophils

Question 47

[Type I IgE]Effector phase drug re-exposure

Answer 47

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.

Question 48

Types IV T cell-mediated hypersensitivity

Answer 48

Sensitisation phase and effector phase

Question 49

[Types IV] Sensitisation phase initial exposure

Answer 49

→ processed by dendritic cells through
phagocytosis → dendritic cells migrate to lymph nodes and
present antigen to naïve T cells

Question 50

[Types IV] Effector phase
drug re-exposure

Answer 50

and subsequent antigen presentation →
sensitised T cells in target tissues activate macrophages to
mediate inflammatory action → tissue damage

Question 51

After the Type IV sensitisation and effector phase skin is most targeted…

Answer 51

severe cutaneous adverse reaction (SCAR)

Question 52

severe cutaneous adverse reaction (SCAR)

Answer 52

• severe forms include SJS (Stevens-Johnson Syndrome)
  and TEN (toxic epidermal necrolysis)
• immunogenetic predisposition, e.g., abacavir and HLAB*5701 (Caucasians)

Question 53

T cell-mediated drug hypersensitivity - theories

Answer 53

• Hapten
• p-i concept (long name)
• altered peptide repertoire model
• altered TCR repertoire model

Question 54

hapten theory

Answer 54

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

Question 55

p-i concept (pharmacological interaction with immune receptor)

Answer 55

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

Question 56

altered peptide repertoire model

Answer 56

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

Question 57

altered TCR repertoire model

Answer 57

drug binds to TCR, and changes HLA recognition