Download Pharmacology Objectives 5

Pharmacology
Lecture 5 Pharmacogenetics
1) Define pharmacogenetics. Pharmacogenetics is the study of how individual genetic
differences influence the variability in responses to drugs.
2) Understand the major mechanisms through which genetic variation can alter
responses to drugs. The most common type of variation change is a change in a
single nucleotide pair termed a single nucleotide polymorphism or SNP. If SNPs
occur in the coding region of a gene they can have qualitative effects on gene
function. Quantitative effects may be due to SNPs on the promoter region or the
mRNA tail thus altering stability. Insertions and deletions are less common than
SNPs but they also contribute to genetic variation. Gene products that affect drug
response include: enzymes (metabolism), receptors, and transporters.
3) Describe an inherited trait that influences drug metabolism in a clinically
significant fashion.
a) Atypical plasma cholinesterase – results from an SNP that reduces its affinity for
choline esters resulting in prolonged response to succinylcholine (1:3000pop).
b) N-Acetyltransferase (NAT) Polymorphism – NAT 1 and 2 act on many drugs
transferring an acetyl group from acetyl Co-A to amines producing an amide thus
enhancing elimination. Polymorphism of NAT2 results in people with slow and
people with rapid acetylation of certain drugs (e.g. isoniazid, hydralazine, and
dapsone).
Slow acetylators of isoniazid may develop a peripheral neuropathy due its
blocking of pyridoxal phosphokinase (required for myelin sheaths) unless given
supplemental pyridoxine (Vitamin B6).
The anticonvulsant phenytoin can be toxic when given with isoniazid in a slow
acetylator.
c) Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency – an X-linked disorder
that reduces the ability of RBCs to respond to oxidative stress. The antimalarial
drug primaquine causes hemolytic anemia in susceptible individuals. In fact, more
than 50 drugs may cause hemolysis in people with G6PD deficiency.
d) Cytochrome P450 polymorphisms – CYP2D6 has polymorphisms resulting in
poor metabolizers (5-10% white pop.) and extensive metabolizers. Poor
metabolizers may experience toxicity to certain drugs such as beta-blockers and
tricyclic antidepressants. They may also poorly metabolize codeine to morphine.
CYP2C19 polymorphisms result in higher cure rates for H pylori in poor
metabolizers of proton pump inhibitors (omeprazole and lansoprazole).
e) Thiopurine methyltransferase (TPMT) deficiency – administration of azathiorine
and mercaptopurine for autoimmune, dermatologic, and hematologic disorders
results in fatal myelosuppression in people with TPMT deficiency (1:300).
f) MDR1 polymorphisms – gene produces a transporter (P-glycoprotein) that may
affect the efficacy and toxicity of lipophilic drugs transported by P-glycoprotein
(antibiotics, vinblastine, and cyclosporin A).
g) Β2-Adrenergic receptor polymorphisms – results in variable responses to inhaled
β2 agonist (bronchodilator) albuterol.
Polymorphism
Phase 1 enzyme
CYP2C19 (PM)
CYP2D6 (PM)
Phase 2 enzymes
Atypical Cholinesterase
NAT2 (slow acetylator)
TPMT
Receptors
Β2AR
Other Drug targets
P-glycoprotein
Drug
Clinical Outcome
Omeprazole
Codeine
Increased ulcer cure rate
Failure to form morphine from codeine –
Inadequate pain control
Succinylcholine
Isoniazid
Azathioprine
Mercaptopurine
Prolonged neuromuscular blockade-apnea
Peripheral neuropathy
Myelosuppression
Albuterol
Altered Responsiveness of airways to the β2
agonist – clinical significance still under study.
Polymorphisms identified but functional
significance is yet to be determined