Block A - Medicine - Clinical Pharmacology II

Question 1

Determinants of adverse drug interactions

Answer 1

Patient factors:

• Age: deterioration of organ function and enzyme production
• Sex: enzyme expression differences
• Genetic abnormalities: SNPs/ mutations in CYP enzymes, poor metabolizers
• Organ dysfunction

Prescriber factors:
- Wrong prescription, DD interactions

Drug factors:

• Narrow therapeutic window
• Large DD interactions

Question 2

Define Types of DD interactions

Answer 2

Type A (90% of all adverse drug reactions): PREDICTABLE 
- Consequences of the drug primary pharmacological effect

Type B idiosyncratic adverse effects: UNPREDICTABLE
- Multifactorial effects and mechanisms

Type C:
- Continuous reaction due to long term use (e.g steroid effect lasting)

Type D:
- Delayed reactions (e.g. increase risk of cancer after immunosuppression)

Type E:
- End of use reactions/ withdrawal effects (e.g. alcohol withdrawal)

Question 3

Mechanisms of type B DD interactions

Answer 3

Multifactorial:
Genetic/ immunological basis

Drug-drug interactions

Association with viral infections (e.g. penicillin in EBV)

Drug induced autoimmunity (development of abnormal antibody)

Anaphylactoid reaction: pseudo-allergic reactions or Non-immunologic activation of mast cells and basophils

Question 4

Describe possible genetic and immunological abnormalities for type B DD reaction

Answer 4

Genetic:
- Receptor abnormality (= most important cause, e.g. HLA polymorphism)
- Genetic testing greatly reduces chance of idiosyncratic reactions:
Allopurinol HLA-B5801
Carbamazepine HLA-B1502
Abacavir HLA-B*5701

Immunological: Type 1-4 allergic reactions

Question 5

Example of drugs commonly involved in idiosyncratic drug reactions

Answer 5

 Opiates
 Vancomycin
 Ciprofloxacin

Question 6

Examples of type A and type B Adverse drug reactions

Answer 6

Question 7

Examples of type A and type B Adverse drug reactions

Answer 7

Question 8

Types of allergic reactions

Answer 8

 Type I: IgE-mediated reactions

 Type II: IgG/M- mediated reactions

 Type III: immune-mediated reactions

 Type IV: delayed hypersensitivity reactions
Subtype: IVa IVb IVc IVd

Question 9

Compare the main immunological mechanism between 4 types of Type IV allergic reaction

Answer 9

All involves Direct T-cell stimulation and cell-mediated immune reaction

IVa: Macrophage activation via IFNγ, TNFα (TH1 cells)

IVb: Eosinophils activation via IL-5, IL-4/ IL-13 (TH2 cells)

IVc: Cytotoxic T cells directly release Perforin/ granzyme

IVd: Neutrophils activated by CXCL8, GM-CSF (T cells)

Question 10

Examples of different subtypes of Type IV immune reaction

Answer 10

IVa
 Tuberculin reaction
 Contact dermatitis (with IVc)

IVb
 Chronic asthma
 Chronic allergic rhinitis
 Maculopapular exanthema with eosinophilia

IVc
 Contact dermatitis (with IVa)
 Maculopapular and bullous exanthema
 Hepatitis

IVd
 AGEP (acute generalized exanthematous pustulosis)
 Behcet disease

Question 11

Describe purine production and metabolism

Answer 11

Purine production:

• 80% from endogenous pathway: Purines (A, G) are produced from ribose 5- phosphate for DNA and RNA synthesis
• 20% from diet: meat and vegetables (same amount in red and white meat, little in dairy products_

Metabolism:
Excess purines are metabolized to:
o Hypoxanthine, which is converted by xanthine oxidase to xanthine and uric acid
o Xanthine directly
o Uric acid can be converted to allantoin by uricase

Question 12

Diet recommendations for gout

Answer 12

Purines in food:
o Present in organic things (including vegetables)
o Depends on the organ, e.g. liver is high in purine
o Red meat and white meat has little difference in purine content
o Should not be high in pork blood (only source of uric acid = white blood cell)
o Low level in dairy products and milk

Dietary restriction reduces the risk of gouty attack but does not reduce serum uric acid level

Question 13

Indications of urate-lowering drugs

Answer 13

 >1 attack within a year
 Gouty tophi
 Renal impairment
 Uric acid stones (kidney)
 Long-term use of diuretics
 Very high uric acid level (increased risk of renal failure, heart failure)

Question 14

Drugs hypersensitivity syndromes a/w allopurinol

Prevention of severe drug hypersensitivity

Answer 14

Associated syndromes:
 Drug rash with eosinophilia and systemic symptoms (DRESS)
 Stevens-Johnson syndrome (SJS)
 Toxic epidermal necrolysis (TEN; mortality rate ~50%)

Prevention = Genetic testing to identify HLA-B*5801 allele:

• Family predisposition to allopurinol allergy
• Carried by 1 in 10 Han Chinese

If positive for HLA-B5801:
 Do not prescribe allopurinol
 Give febuxostat instead

Question 15

Classes of NSAIDs

Answer 15

Question 16

Define immediate and delayed allergic reactions

Answer 16

Immediate: reactions within 1h (possible delay due to oral administration: gastric emptying, absorption)

Delayed: Usually after 6h, but typically after days of treatment

Question 17

Define immediate and delayed allergic reactions

Answer 17

Immediate: reactions within 1h (possible delay due to oral administration: gastric emptying, absorption)
- Only Type I HS

Delayed: Usually after 6h, but typically after days of treatment
- Type II, III and IV HS

Question 18

Manifestations of delayed drug allergy

Answer 18

Diverse clinical manifestations:
o Rash
o Lymphadenopathy
o Blood dyscrasias
o Renal dysfunction
o Lupus-like illness
o Vasculitis

Question 19

Mechanism of Type I HS to drugs

Manifestations

Answer 19

Mechanism: I: IgE-mediated HS

• Ag induces crosslinking of drug-specific IgE bound to mast cells and basophils
• degranulation (release vasoactive mediators)

Manifestations: 
Systemic/ localized anaphylaxis (risk when re-exposed):
 Food allergies
 Hives (urticarial rash – not delayed-onset exanthem)
 Angioedema
 Hay fever
 Asthma
 Eczema

Question 20

Commonly implicated drugs with type I HS

Answer 20

 β-lactam antibiotics
 Quinolones
 Neuromuscular blocking agent 
 Platinum- containing chemotherapeutic drugs
 Biologic therapies
 IV:  carbamazepine, allopurinol

Question 21

Test for drug-induced lupus

Answer 21

Anti-histone Ab (present in >95% patients taking procainamide, hydralazine, chlorpromazine, quinidine)

Anti-dsDNA Ab (typically absent if due to procainamide, hydralazine, isoniazid)

ANCA (a/w necrotizing vasculitis)

anti-ENA (extractable nuclear antigen): anti-Sm*, anti-Ro/SSA, anti-La/SSB, anti-RNP

Question 22

Mechanism and manifestation of type II HS to drugs

Answer 22

II: IgG-mediated cytotoxic HS
Ab directed against cell surface antigens mediates cell destruction via:
 ADCC (IgG), including macrophage clearance; or
 Variable complement activation (IgG, IgM)

Manifestations: 
 Blood transfusion reactions
 Autoimmune hemolytic anemia
 Thrombocytopenia
 Neutropenia
 Erythroblastosis fetalis

Question 23

Commonly implicated drugs with type II HS

Answer 23

Question 24

Mechanism and manifestation of Type III HS to drugs

Answer 24

III: immune complex-mediated HS

Mechanism:
Ab against soluble antigen from drugs
Ag- Ab immune complexes deposited in various tissues induce:
 Complement activation;
 Ensuing inflammatory response mediated by massive infiltration of neutrophils (attracted by C5a, opsonized by C3b)

Manifestations: 
 Localized Arthus reaction
 Generalized reactions, e.g.
 Serum sickness (joint pain etc.)
 Glomerulonephritis
 Necrotizing vasculitis
 Drug fever
 Rheumatoid arthritis
 Systemic lupus erythematosus

Question 25

Commonly implicated drugs with type III HS

Answer 25

Question 26

Mechanism and manifestations of Type IV HS to drugs

Answer 26

IV: cell-mediated HS

Mechanism:
Sensitized TH1 cells release variable cytokines that activate macrophages/ eosinophils/ Tc cells/ PMN
Mediate direct cellular damage

Manifestations: (Typically delayed by >48-72h)
 Contact dermatitis
 Stevens-Johnson syndrome/ toxic epidermal necrolysis
 Tubercular lesions
 Graft rejection
 Drug-induced hypersensitivity reactions