Genetic variations can affect how individuals respond to common medications. The study examines how inherited traits influence drug metabolism and response for several drugs. For example, variations in CYP2C9 and VKORC1 genes impact warfarin dosing requirements and bleeding risk. CYP2C19 polymorphisms also influence the effectiveness of clopidogrel by affecting its conversion to active metabolites. Testing for genetic polymorphisms may help predict treatment outcomes and risk of side effects from certain medications.

1. GeneticVariations
effect on responses of some
common medications
Ahmad K. Al-Jalehawi
MSc. Clinical Pharmacy
Al-Kafeel university

3. National Institutes of Health. Genetics home reference. http://ghr.nlm.nih.gov/glossary. Accessed May 21,
2015

4. • Unlike other sources of variability, inherited traits remain an individual's
characteristic for a lifetime.
• Pharmacogenetics: is the study of inherited variations in drug response
• A polymorphism is defined as a DNA sequence variant present in >1% of the
general population.
• If a DNA sequence variant is present in <1% of the population,
it is defined as a mutation.

7. The much smaller intrapair variability in plateau plasma concentration of nortriptyline between nine identical
twins than between 12 fraternal twins indicates that genetics plays a major role in nortriptyline pharmacokinetics.
Female (dark color); male (light color).
Alexanderson B, Evans DA, Sjöqvist F. Steady-state plasma levels of nortriptyline in twins: influence of genetic
factors and drug therapy. Br Med J 1969;4:764–768.

12. Plasma metoprolol concentrations after a single oral dose of 200-mg metoprolol tartrate were much higher in poor
(colored line) than in extensive (black line) CYP2D6 metabolizers. Because metoprolol is a drug of high hepatic
clearance, the difference between poor and extensive metabolizers is expressed in the large difference in oral
bioavailability, because of differences in first-pass hepatic loss. (From: Lennard MS, Silas JH, Freestone S, et al.
Oxidative phenotype—a major determinant of metoprolol metabolism and response. Reprinted by permission of

13. Cardiovascular disorders that reflect sources of pharmacogenomics variability.

14. WARFARIN
• The dose requirement and risk of bleeding are influenced by intake of vitamin K, illness, age,
gender, concurrent medication, body surface, and genetics.
• In addition to the possible or demonstrated influence of a large number of genes, warfarin’s
effect is influenced by two major genes: one involved in its biotransformation (CYP2C9) and
the other involved in its mechanism of action (VKORC1)
• Warfarin is administered as a racemic mixture of the R and S stereoisomers.
• (S)-warfarin is two to five times more potent than (R)-warfarin and is mainly metabolized by
CYP2C9.
• (R)-warfarin is mainly metabolized via CYP3A4, with involvement of several other cytochrome
P450 enzymes.

15. • An investigation of the pharmacodynamics and pharmacokinetic properties of
warfarin showed the additive involvement of two genes to determine its dosage.
• One of these genes encodes CYP2C9, which is responsible for approximately 80% of
the metabolic clearance of the pharmacologically potent S-enantiomer of warfarin.
• There are three allele types: CYP2C9*1, *2, and *3, and both CYP2C*2 and *3
• cause a reduction in warfarin clearance.
• A 10-fold difference in warfarin clearance was observed between groups of
individuals having the genotype of the highest metabolizer (CYP2C9*1
homozygote) and lowest metabolizer (CYP2C9*3/*3).

16. • The VKORC1 gene encodes the vitamin K epoxide reductase enzyme.
• Warfarin exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase, which
catalyzes the conversion of vitamin K epoxide to vitamin K
• Polymorphisms in CYP2C9 and VKORC1 account for approximately 40% of the variance in
warfarin dose .
• Variations of the VKORC1 gene that might require an adjustment in the dose of warfarin
occur in up to 89% of Asians and in about one third of Caucasians and African Americans.
• Patients with CYP2C9*2 or CYP2C9*3 alleles may have decreased CYP2C9 activities by
50–90%, thus requiring lower warfarin doses

17. CLOPIDOGREL
• numerous genetic polymorphisms have been linked to reduced platelet
inhibition and lack of clinical efficacy of antiplatelet drugs, particularly
clopidogrel and aspirin
• SNPs in certain genes involved in clopidogrel metabolism, transport,
and signaling could affect the pharmacokinetics and pharmacodynamics
of clopidogrel, which include CYP1A2, CYP2C19, CYP3A4, CYP3A5, P-
glycoprotein (ABCB1), paraoxonase 1 (PON1), and P2Y12.
• Persuasive evidence suggests that genetic variability in CYP2C19 affects
the efficacy of clopidogrel and has a role in preventing cardiovascular
events

18. •CYP2C19 genetic variations comprise one-third of all patients
with a loss-of function allele, resulting in reduced conversion
of clopidogrel to its active metabolite, leading to more
cardiovascular events.
• Genetic variation is commonly seen in Asians. It is estimated
that 50% of Asians have one loss-of-function allele in
CYP2C19, resulting in impaired bioactive conversion of
clopidogrel to its active metabolite

19. • For poor CYP2C19 metabolizers, one of the options is to increase the dose of clopidogrel to
a 600 mg loading dose followed by 150 mg once daily. Platelet response is improved in
poor metabolizers,
• prasugrel is a prodrug that is converted to an active metabolite. However, it is converted
mainly by CYP3A4 and CYP2B6 instead of CYP2C19.
• the FDA approved new labeling of clopidogrel in March 2010. This includes a boxed
warning alerting physicians to the genetic findings and suggests alternative antiplatelet
therapy in CYP2C19*2 homozygotes
• prasugrel and ticagrelor, which are not markedly affected by the CYP2C19 genotype.

21. DV is a 65-year-old man who recently had an acute myocardial infarction (MI). To prevent
subsequent ischemic events, DV’s physician recommends antiplatelet therapy and prescribes
clopidogrel. His current medications included amlodipine 10 mg daily, hydrochlorothiazide 25
mg daily, aspirin 81 mg daily, pravastatin 40 mg daily, metformin ER 850 mg daily, and
clopidogrel 75 mg daily.
Four months later, DV suffered another acute MI, and his physician suspects that the patient has
not been taking his medications as directed, or alternatively, that clopidogrel therapy may have
been unsuccessful
• CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel.
At least one loss-of-function allele is carried by 24% of the white non-Hispanic population, 18% of Mexicans, 33% of
African Americans, and 50% of Asians
• A current FDA-boxed warning states that poor CYP2C19 metabolizers may not benefit from clopidogrel and
recommends that prescribers consider alternative treatment for patients in this category
• Although a higher dose regimen (600 mg loading dose followed by 150 mg once daily) in poor metabolizers
increases antiplatelet response, an appropriate dose regimen for this patient population has not been established in a
clinical outcome trial.
• Switching to prasugrel (Effient) is also another alternative to this problem.

22. STATINS
• Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors competitively
inhibit the enzyme HMG-CoA reductase
• the most important clinical benefits of statin pharmacogenetic knowledge
would be based on identifying a set of genotypes that aid in predicting the
outcomes of statin treatment
in terms of reduced risk for cardiovascular events, together with reduced risk
for
serious ADRs.
• myopathy is the most common side effect of statins, with symptoms ranging
from mild myalgias without creatine kinase (CK) elevation to life-threatening
rhabdomyolysis with markedly elevated CK levels, muscle damage, and acute
renal injury.

23. • there is a heritable component to the risk for statin-induced myopathy. The
strongest data in this regard exist for the solute carrier organic anion
transporter family, member 1B1 (SLCO1B1) gene.
• This gene encodes the organic anion transporting polypeptide (OATP) 1B1,
which transports most statins .

24. •Codeineand morphine exert their analgesic effects through interaction at the µ-opioid
receptor.
• The affinity of codeine for this receptor is approximately 200-fold weaker than that of
morphine. As a result, codeine’s analgesic properties primarily come from its bioactivation in
the liver to morphine via the CYP2D6 enzyme.
• CYP2D6 enzyme activity is highly variable because of single nucleotide polymorphisms and
other alterations of the CYP2D6 gene.
• In approximately 90% of patients, codeine metabolism by CYP2D6 results in expected amounts
of morphine formation.
• However, approximately 1% to 2% of patients are ultrarapid metabolizers, in whom the
expected increased formation of morphine leads to a higher toxicity risk.

25. • Conversely, the approximately 5% to 10% of patients who are classified as poor
metabolizers are at risk of insufficient pain relief with normal codeine dosages.
• Clinicians should consider CYP2D6 testing in patients who have no response to
codeine or tramadol (possible poor metabolizers) or who have unexpected
adverse effects (possible ultrarapid metabolizers)

29. References
• Malcolm Rowland and Thomas N. Tozer. ,Clinical pharmacokinetics and pharmacodynamics ,
concept and applications, 4th edition
• KU-LANG CHANG ,et al . Pharmacogenetics: Using Genetic Information to Guide Drug Therapy
American Family Physician ,2015, 92(7) ,p588. . www.aafp.org/afp
• Xiaodong Feng,Hong-Guang Xie , Applying Pharmacogenomics in Therapeutics , 2016