Adverse drug reactions due to genetic variations

2. AYESHA YOUNAS
PHRM 02151010
M.Phil. Pharmaceutics
Department of Pharmacy

3. ADVERSE DRUG REACTIONS ATTRIBUTED
TO GENETIC DIFFERENCES

4. What is an Adverse drug Reaction?
According to WHO
It is a response to a medicine which is noxious
and unintended, and which occurs at doses
normally used in man for the prophylaxis,
diagnosis, or therapy of disease

5. Why do Patients vary in their
response to Drugs?

7. History:
• As early as the 1950s,Motulsky
“Inheritance might explain variation in individuals response
and adverse effects from drugs”
• In 80s Victor Mckusick
Established Online Mendelian Inheritance in Man (OMIM) in early 80s and
categorized majority of Mendelian Disorders from which became very clear
that there are many different disease alleles for many disorders and adverse
effect.

9. • More recently, a review of the
pharmacogenetic literature showed that a sizable
portion of ADRs (~30%) involved in drug therapy
implicated genetic polymorphism of drug
metabolism by CYP2D6.

10. How genes affect…?
• 1-The way our body processes drugs
(Pharmacokinetics)
• 2-The interaction of drugs with receptors
(Pharmacodynamics)

12. Single Nucleotide Polymorphisms
Single nucleotide polymorphism, also known as simple nucleotide
polymorphism, is a DNA sequence variation occurring commonly within a
population (e.g. 1%) in which a single nucleotide — A, T, C or G — in the
genome differs between members of a biological species or paired
chromosomes.

13. SNPs may / may not alter protein structure

15. DME: Drug-metabolizing enzyme DTP: Drug-transporter protein

16. Prolonged muscle relaxation in some subjects after receiving a cholinergic
drug was explained by an inherited deficiency of a plasma
cholinesterase.
1-Cholinergic drug
Few Examples of ADRs due to genetic
Variation

17. 2- Antimalarial drug
Hemolysis caused by antimalarial drugs is recognized as being
caused by inherited variants of glucose 6-phosphate dehydrogenase

18. 2- Antituberculosis drug
Slow metabolism of isoniazid in some patients (acetylation of
isoniazid) has been found to be the cause of peripheral neuropathy
caused by this drug.

19. • Adverse drug reactions of debrisoquine
(antihypertesive drug) have led to the discovery of the
genetic polymorphism of the drug-metabolizing
enzyme, debrisoquine hydroxylase CYP2D6
• The same isozyme deficiency causes more nausea,
diplopia, and blurred vision after dosing of the
antiarrhythmic drug sparteine in deficient patients.

20. Clinically Important Genetic Polymorphisms of
Drug Metabolism that Influence Drug Response
Enzyme/Receptor Frequency of Polymorphism Drug Drug Effect/Side Effect
CYP2C9 14-28% Warfarin Hemorrhage
CYP2D6 .2-1 % Tolbutamide Hypoglycemia
CYP2C19 8-23% (Asians) Omeprazole
Higher cure rates when given with
clarithromycin
Dihydropyrimidine
dehydrogenase
0.1% Fluorouracil Myelotoxicity, Neurotoxicity
N-acetyltransferase 40-70% Sulphonamides Hypersensitivity
HKCNE2 Clarithromycin Drug induced arrhythmia

22. Warfarin: A dosage story
• Most widely used
anticoagulant in the world
– A “blood thinner”
• Prescribed doses vary widely
(1-40mg / daily)
• Therapeutic index is very low
– High risk of bleeding early
in treatment
• Two genes involved in
metabolism: CYP2C9 and
VKORC1

24. Homozygous wild-type CYP2C9 and VKORC1
Carrier of CYP2C9 mutant allele
Carrier of VKORC1 mutant allele

26. Personalized Medicine
• There is an emerging goal among ‘translational scientists’ to make
medical practice more personalized
• Pharmacogenetics is an important step towards that goal in which we
study the inherited genetic differences in drug metabolic
pathways which can affect individual responses to drugs, both in
terms of therapeutic effect as well as adverse effects.
• The effects of this movement are
seen in many aspects of society