Adverse Drug Reactions Flashcards
1
Q
What is an adverse drug reaction?
A
- Noxious or unintended reaction to a drug
- Administered in standard dose and by proper route for a purpose of prophylaxis, diagnosis or treatment of a specific disease
2
Q
What are drug-related cases underlying ADR and drug hypersensitivity?
A
- Chemical structure
- Toxic metabolites
3
Q
What are patient-related cases underlying ADR and drug hypersensitivity?
A
- Polymorphisms in gene-coding enzymes
- Metabolic deficiency
- Predisposing HLA-allele- HLA-B*5701 and abacavir hypersensitivity
- Aberrant immune activation
4
Q
What is type A?
A
- Augmented
- Dose-related, predictable, known pharmacological actions of drug
- Adjusted dose can reduce ADR
5
Q
Give an example of type A ADR?
A
- Warfarin blocks vitamin K metabolism
- Blood thinning
- Primary action of blood causes excessive bleeding
6
Q
What are the mechanisms of type A reactions?
A
- Exaggerated therapeutic response at target site (e.g. bleeding with warfarin)
- Desired pharmacological effect at another site (e.g. headache with GTN)
- Additional (secondary) pharmacological action (e.g. prolongation if QT interval- many drugs)
7
Q
Describe how a desired pharmacological effect can occur at another site with GTN as an example (type A)
A
- GTN- glyceryl trinitrate- treatment of angina, acute MI and severe HT
- GTN-nitro-vasodilator-prodrug needs to be denitrated to produce NO
- Immediate headaches connected to vasodilation
- Migraines (calcinotic gene related peptide glutamate/ change in ion channel function)
- Drug-drug interaction- GTN used with vasodilators in ED can cause severe hypotension, circulatory collapse and death
8
Q
Describe how secondary pharmacological action can occur using prolonged QT interval as an example (type A)
A
- Occurs at drug combination
- Torsade de pointes
- QT interval represents depolarisation and repolarisation of ventricles
- Prolongation of QT increases person’s risk of developing abnormal heart rhythm- ventricular tachycardia- tornado de pointes
- May lead to death
9
Q
What is the QT interval?
A
- Measure of time between start of the Q wave and end of T wave in heart’s electrical cycle
10
Q
What factors predispose to type A pharmacological ADRs?
A
- Dose
- Pharmaceutical variation in drug formulation
- PK and pharmacodynamic abnormalities
- Drug-drug interactions
- Likelihood of developing adverse interaction also increases with number of drugs prescribed
11
Q
What is Type C?
A
- Chemical
- Could be inefficiency of enzymes or overdose
- Sometimes- chemically reactive metabolites detoxified by cell defence mechanisms- imbalance between bioactivation/ bioinactivation may result after overdoses
- Leads to formation of large amounts of chemically-reactive metabolites- overwhelm cellular detoxification capacity
- Leads to cell damage
12
Q
Give two examples of Type C ADR
A
- Paracetamol –> hepatotoxic quinone imine
- Azathiprine–> myelotoxic 6-mercaptopurine
13
Q
Describe phase 1 of drug metabolism
A
- Native drug- CYP450–> reactive intermediate
- Reactive intermediate –> direct toxicity
14
Q
Describe phase 2 of drug metabolism
A
Removal of detoxication between reactive intermediate and inner metabolite
15
Q
What happens to paracetamol in overdose?
A
- Saturation of phase 2 pathways results in a greater proportion of drug undergoing bioactivation
- Leads to glutathione depletion- allows toxic metabolite to bind to proteins
- Resulting in hepatocellular damage
16
Q
How is paracetemol metabolised?
A
- 10% phase 1: paracetamol–> CYP450 –> quinone-imine
- In healthy person- 90% glutathione pathway
- Removal of glutathione pathway
- Quinone-imine–> hepatotoxicity
17
Q
Describe the metabolism of Isoniazid
A
- If N-acetyl trans
- Isoniazid–> impaired acetylation –> neuropathy
- Isoniazid induced peripheral neuropathy in people deficient in enzyme N-acetyl transferase
18
Q
Describe the metabolism azathiprine
A
- Chemotherapy drug- now rarely used in chemotherapy, but more for immunosuppression in organ transplantation and auto-immune disease
- Active metabolite, 6-mercaptopurine, is myelotoxic and must be further detoxified by thiopurine methyl transferase
- Azathioprine–> 6-mercaptopurine –> myelotoxicity
19
Q
What is type B?
A
- (Bizarre) Not dose-related, unpredictable
- Idiosyncratic
- Immune-based drug hypersensitivity
20
Q
What is type D?
A
- Delayed
- E.g. carcinogenesis or teratogenesis (thalidomide)
Rare
21
Q
What type E?
A
- End of dose
- Effects following cessation of drug, e.g. first after benzodiazepines
Rare
22
Q
Describe ADR-Type B
A
- Toxic epidermal necrolysis
- Can affect single and multiple organ systems, but skin is most commonly involved
23
Q
How can a drug activate the immune system?
A
- Native drug binds protein and creates haptens
- Recognised by the immune system
24
Q
Describe drugs as an antigen
A
- Interaction between MHC molecule with T-cell
- Impossible for penicillin to be presented
- β-lactams are haptens
- Needs to form covalent complex with proteins- haptenize
25
Describe the structure of β-lactams and give examples
- Penicillins, cephalosporins, carbapenems, monobactams, β-lactamase inhibitors
- Haptens- penicilloyl moiety spontaneously forms complexes with serum proteins
- -Carbamazepine metabolite forms complexes with proteins
- Sensitised-haptenated protein becomes an allergen
26
Describe the types of hypersensitivty
- Type 1- IgE dependent
- Type 4- T-cell dependent
- Haptenated protein recognised by IgE molecule
- Penicillin- muscle relaxant
27
What happens in the early phase of hypersensitivity?
- Histamine, prostaglandins
- Itching and swelling
- Haptenated protein can cross-link FCER on Mast cell
28
Describe early phase hypersensitive reaction
- Seconds-min after haptenated protein exposed
- Mediated by histamine
- Histamine- vasodilation- redness
- Skin lesion- wheal-and-flare
- Persistent reaction- oedema and urticaria
- Certain mast cell products can influence structural cell biology
29
What cells might make cell derived products influence?
- Vascular endothelial cells
- Epithelial cells
- Fibroblasts
- Smooth muscle cells
- Nerve cells- itching
30
Describe the late phase of hypersensitivity reaction
- Mast cells with FCER cross-linked by an allergen recruit neutrophils, eosinophils and Th2 T cells
31
Describe type 1 hypersensitive reactions
- Urticaria (angioedema), asthma, anaphylaxis
- β-lactams- penicillins and cephalosporins
- Drugs in anaesthetics
- - Muscle relaxants (70% of peri-operative anaphylaxis)
- - Suxamethonium, vecuronium
32
Describe type 4 hypersensitivity reactions
- 1-3 day delay in sensitised or 7-14 days after continuous exposure
- Skin-main
- 2-3% on in patients
- Mediated by T-lymphocytes
- Multiple symptoms, rare for each single drug
- DTH reactions in skin observed after systemic administration- 7-10 days after initial- associated with fever
33
How are CD4 T helper cells and CD8 cytotoxic T cells primed?
- Depends on innate immune system activating capacity of substances co-exposed with antigen
- Co-signals for cell differentiation and status of cells/cytokines in microenvironment CD4 naive T cell- differentiates to
- Th1, 2, 9, 17 or 22 type memory and effector cells
34
What is the ability of T cell subsets to promote inflam responses based on?
- Based on respective cytokine profiles,
- response to chemokine
- interaction with other cells, subsets can promote different types of inflammatory responses
35
How can a drug be presented to a T cell?
- Happen-Like drugs (penicillins) can covalently bind to soluble/ cell-attached proteins
- Pro-haptens (sulphometoxazole) require metabolism to become haptens
- Haptens can bind to MHC complex and change repertoire of peptides presented by MHC
36
What is the pharmacological interaction concept?
- Drug can bind directly to T cell receptor
37
How do CD4 T cell and CD8 T cells present differently in delayed type hypersensitivity?
- CD4- Maculopapular or eczematous drug eruptions- MHC-1 restricted drug presentation
- CD8- more severe skin symptoms (e.g. bullous skin disease)
38
What are eczematous delayed hypersensitivity reactions caused by?
- Th1
- Tc1
(contact allergic DHR)
39
What are drug induced exanthems delayed hypersensitive reactions caused by?
- Th2
| - Tc2
40
What are drug reactions with eosinophilia and systemic systems (DRESS) caused by?
- Th2
| - Tc2
41
What delayed hypersensitive reactions does CD8+ T cell cause?
- Eythema multiforme
- Stevens-Jonson syndroms (SJS)
- Toxic epidermal Necrolysis (TEN)
42
What causes Acute generalised exanthematous pustulosis (AGEP)?
- IL8-T cells
| - Neutrophils
43
What do Type 4a correspond to and involve?
- Corresponds to Th1 reactions with high IFN/TNF secretion
| - Involves monocyte/ macrophage activation
