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PED3005 Pharmacogenetics > Adverse Drug Reactions > Flashcards

Adverse Drug Reactions Flashcards

1
Q

What are the types of adverse drug reactions?

A

Intrinsic/ type A
idiosyncratic/ type B

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2
Q

Describe what an intrinsic adverse drug reaction is

A

Predictable on the basis of drug concentrations

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3
Q

Describe an idiosyncratic adverse drug reaction

A

Not predictable based on drug pharmacology
Not usually related to the dose
Rare but often serious

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4
Q

What is key to detecting idiosyncratic adverse drug reactions

A

Post marketing surveillance as they’re not normally detected before drug is licensed
Old

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5
Q

What idiosyncratic ADRs are associated with Abacavir, carbamazepine, allopurinol

A

Hypersensitivity/ skin rash

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6
Q

What idiosyncratic ADRs are associated with flucloxacillin

A

Hepatoxicity

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7
Q

What idiosyncratic ADRs are associated with statins

A

Myopathy

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8
Q

What idiosyncratic ADR is associated with a variety of compounds

A

Cardiotoxicity

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9
Q

What results in the maturation of T- cells

A

Presentation of the MHC

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10
Q

What happens after the T-cell matures

A

Become either cytotoxic or helper cells
Cytotoxic more harmful as they can kill host cell

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11
Q

The type of T-cell that matures depends on what

A

The HLA class protein which is presenting the antigen

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12
Q

What are the HLA class I genes expressed on most cells

A

A, B and C genes

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13
Q

What are the HLA class II genes expressed on most cells

A

DR, DQ and DP genes

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14
Q

What genotype has proven to show hypersensitivity to Abacavir

A

One or two HLA B*57:01
Not all patients w this genotype will show a detectable reaction

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15
Q

What happens when T cells from HLA-B*57:01-positive donors are stimulated with abacavir

A

Proliferate and differentiate giving CD8-positive cytotoxic T cells

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16
Q

How does activated abacavir or its metabolite cause an inappropriate T cell response

A

Binds directly to B*57:01 gene product and this leads to inappropriate recognition of self peptides

17
Q

What 2 drugs can induced Stevens-Johnson syndrome (SJS)

A

Carbamazepine and allopurinol

18
Q

What allele is associated with SJS induced by CBZ

A

HLA B*15:02
Usually present in certain East Asian populations e.g chinese

Europeans and Japanese: A*31:01

19
Q

What allele is associated with SJS induced by allopurinol

A

Chinese: HLA B*58:01
Minor effects in Eastern Europeans

20
Q

What is flucloxacillin

A

Beta-lactamase resistant penicillin with isoxazlyl ring

21
Q

Which gene is associated with flucloaxacillin DILI

A

HLA-B*57:01
But doesn’t bind the same way abacavir does
Therefore sensitivity and specify is genotyping lower as predictor

22
Q

What is the mechanism of DILI due to HLA and related gene associations

A

Inappropriate T-cell response
Specific HLA protein interacts w drug complex to peptide inappropriately
Presents this to T-cells causing a reaction
= local cellular damage

23
Q

Describe statin-induce myopathy

A

Ranges from mild myalgia to life threatening rhabdomyolysis

24
Q

What gene has shown an important role in myopathy relating to simvastatin

A

SLCO1B1 variant
= decreased hepatic uptake

25
Q

What is the role of SLCO1B1

A

Encodes main inward hepatic statin transporter

26
Q

What is the effect of the *5 variant of SLCO1B1

A

Risk allele
Higher plasma level of drug in those with decreased activity
May equal increased uptake into muscle tissue = muscle toxicity

27
Q

How can some drugs prolong cardiac repolarisation

A

Usually due to blockage of an outward ion channel with K channels

28
Q

Which individuals have an increased of sudden death due to drug-induced ventricular fibrillation

A

Slight genetic abnormality in K+ channels
More serious abnormalities associated with adult sudden death

29
Q

What do studies on drug induced long-QT show

A

Polymorphisms are contributing but are not a complete explanation for cardio-toxicity
Only represent about 10% of cases

30
Q

Which gene affects the length of QT interval

A

NOS1AP
Nitric oxide signalling may affect cardiac repolarisation

31
Q

in which patients is NOS1AP most common in

A

Those showing QT prolongation in response to several drugs

PED3005 Pharmacogenetics (10 decks)

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