Pharmacogenetics

Question 1

Thiopurine Methyltransferase (TPMT)

Answer 1

Metabolizes mercaptopurines. 1 in 300 are homozygous for inactive TMPT

Question 2

What drugs should not be given to TPMT deficient patients and what happens?

Answer 2

Azathioprine and mercaptopurine. Develop toxic concentrations of thiopurines, inducing myelosuppression (mil myelosuppression will occur in heterozygotes)

Question 3

What is the backup mechanism for clearing mercaptopurines and what is the implication of this for TMPT deficient heterozygotes or homozygotes?

Answer 3

Xanthine oxidase. If on allopurinol (for gout) and given azathioprine or mercaptopurine they can exhibit severe myelosuppression

Question 4

What causes acute intermittent porphyria (AIP)?

Answer 4

An error in hydroxymethylbilane (HMB) synthase leads to accumulation of porphobilinogen and ALA

Question 5

How do drugs that trigger exacerbations of Acute Intermittent Porphyria (AIP) do so?

Answer 5

Induce CYP enzymes, increasing demand for heme

Question 6

Signs and symptoms of an AIP exacerbation

Answer 6

Acute neuropathic, non-inflammatory abdominal pain, sympathetic distress, sensory and motor loss, neuropsychiatric symtpoms (restlessness, insomnia, depression, hallucinations, paranoia)

Question 7

Gilberts disease and its cause

Answer 7

Constitutive unconjugated benign hyperbilirubinemia, caused by a deficiency of UDP-Glucoronosyltransferase (UGT) 1A1

Question 8

What patients may have a bad reaction to Irinotecan (chemotherapy) and why?

Answer 8

Patients with UGT1A1 deficiencies. This enzyme glucorinates the drug, and failure of this increases drug half-life and decreases clearance (diarrhea and leukopenia)