1. BY :
PHARMACOGENETICS
V L Srividya,
II Pharm.D(PB),
N.E.T. PC,Raichur

2. PHARMACOGENETICS
The study of genetically controlled variations in drug response.
Pharmacogenetics is the special area of biochemical genetics that deals with variation in drug response and
the contribution of genetics to such variation.
It is a subset of Pharmacogenomics and is the study of variations in DNA sequence as related to drug response.

3. Key Concepts and Terms Monogenic: due to allelic variation at a single
gene
Polygenic: due to variations at two or more
genes
Polymorphic: frequently occurring monogenic
variants occurring at a frequency
>1%

4. Normal Distribution
Frequency
Activity

5. Polymorphic Distribution

6. GENETIC POLYMORPHISMS
Pharmacokinetic
Pharmacodynamic
Transporters
Plasma protein binding
Metabolism
Receptors
Ion channels
Enzymes
Immune molecules

7. Genetic polymorphisms in drug metabolizing enzymes
From: Evans WE, Relling MV. Pharmacogenomics: Translating functional genomics into rational therapeutics. Science 286: , 1999.

9. Atypical Plasma Cholinesterase
succinylmonocholine
choline
Hydrolysis by pseudocholinesterase
a rapid acting, rapid recovery muscle relaxant
usual paralysis lasted 2 to 6 min in patients
occasional pt exhibited paralysis lasting hrs
cause identified as an “atypical” plasma cholinesterase

10. Soon after the introduction of muscle relaxant in 1951, an occasional atypical patient was encountered, suffering prolonged muscle paralysis and consequently apnea.These atypical patients showed low activity of plasma cholinesterase.
MALIGNANT HYPERTHERMIA
It is an uncommon complication of general anesthesia. Many inhalants and muscle relaxing agents have been incriminated as precipitating the event.
The clinical features of malignant hyperthermia are muscular rigidity, tachycardia, cyanosis and respiratory acidosis.

11. The disorder is usually inherited as mendelian
autosomal dominant, but about 20% of cases
are sporadic and in a few instances
recessive inheritance.
It is possible that the gene locus is on chromosome
19. But, only a minority of malignant hyperthemia
alleles are localized on chromosome 19.
Another malignant hyperthermia locus has
been proposed on chromosome 17 →
malignant hyperthermia is a heterogeneous condition.

12. Glucose-6-phosphate dehydrogenase activity
Effects >100 million worldwide
CYP
MPO
PGH Synthase
R-NH2
R-NOH
ERYTHROCYTE O2
NADP+ or
GSSG(?)
NAD+
HgbFe+2
HMP Shunt
G-6-PD
Dependent
R-NOH
MetHgb
Reductase
NADPH
or GSH(?)
R-NO
HgbFe+3
NADH
GSH
Reactive
Oxygen
Splenic
Sequestration
Semi-mercaptal
SOD
Catalase
GSH Peroxidase
sulfinamide
Detoxification
Hemolytic
Anemia
R-NH2

13. Drugs and Chemicals Unequivocally Demonstrated to Precipitate Hemolytic Anemia in Subjects with G6PD Deficiency
Acetanilide Nitrofurantoin Primaquine
Methylene Blue Sulfacetamide Nalidixic Acid
Naphthalene Sulfanilamide Sulfapyridine
Sulfamethoxazole

14. ATP – binding (ABC) superfamily
Termed as (MFS)- Major Facilitator Superfamily
Belongs to membrane associated transporter and include diverse group of proteins present in wide variety of organism & Cell types
Currently about 250 ABC transporters (Traffic ATPases) have been identified
50 are identified in humans
Further genome map will reveal more .

15. 3 genetic mechanism influence pharmacotherapy
Pharmacogenetic Trait Clinically Relevant :
3 genetic mechanism influence pharmacotherapy
1 - Genetic Polymorphism of genes  which results in
Altered metabolism of drugs (metabolism of tricyclic antidepressants)
Increased or decreased metabolism of a drug may change its concentration
Of active, inactive or toxic metabolites

16. Hemolysis in glucose -6 –phosphate dehydrogenase deficiency
2 – Genetic variants  may produce unexpected drug effect (toxicity or it may be lethal to patient)
Hemolysis in glucose -6 –phosphate dehydrogenase deficiency
3 – Genetic variation in drug targets
May alter the clinical response & frequency of side effects
Variants of β –adrenergic receptor alter response to β – agonists in asthma patients

17. CYP2D6 ACTIVITY

18. Discovery and Incidence of the PM Phenotype:
Mahgoup et al and Tucker et al. (1977)
explained
Hydroxylation of antihypertensive drug debrisoquine is
polymorphic in nature
Eichlbaum et al showed the oxidation of sparteine is polymorhpic
Metabolic Ratio (MR) of the two drug were
closely correlated &metabolized by the enzyme
CYP2D6
The existence of two or more forms of individuals
within the same animal species (independent
of sex differences).
M EM – Extensive Metabolizers
PM – Poor Metabolizersers

19. DRUGS WHOSE METABOLISM CO-SEGREGATES WITH DEBRISOQUINE
alprenolol amitriptyline bufuralol clomipramine
codeine desipramine encainide ethylmorphine
flecainide fluoxetine guanoxan imipramine
metoprolol nortriptyline paroxetine phenformin
propafenone propranolol

20. THIOPURINE METHYLTRANSFERASE (TPMT)

21. TPMT POLYMORPHISM

22. Future Role of SNPs and Pharmacogenetics
SNP - Single Nucleotide Polymorphisms
……. G G T A A C T G ……
……. G G C A A C T G …...
AS of February 2001, 1.42 million SNPs had been identified in the human genome.

23. Identification of large no. of SNPs is needed
“Genetic fingerprint” – acts as  probable individual
Drug response
Coding region of a gene Coding SNP’s (cSNP’s)  ~30,000 -1,00,000/genome
Cause amino acid changes & changes in protein function or can be neutral
SNP’s inside genes or in regulatory regions (perigenic or pSNP’s)
Cause differences in protein expression
Used “drug response profile’

24. Genetic Polymorphisms of Clinical Relevance Drug Metabolism
Pharmacogenetics of Cancer Chemotherapy
Fatal bone marrow cancer (TPMT) – Thiopurine methyltransferase  mercaptopurine, thioguanine & Azathioprine (to treat  Acute lymphoblastic leukemia (ALL)
Drug Transport
Drug Targets

25. THANK YOU THANK YOU TEXT BOOKS-REFERENCES:
·      1. Werner Kalow, Rachel F Tyndale, Urs A Meyer, Pharmacogenomics, Marcel Dekker Inc., 2001
·      2. J. Licinio, Ma-LiWong, Pharmacogenomics: The Search for Individualized Therapies, Wiley-VCH, 2002
3.Adam Hedgecoe-The politics of personalized medicine – Pharmacogenetics in the Clinic,Cambridge University Press,2004.
4. Mark A. Rothstein Pharmacogenomics- Social,ethical and Clinical dimensions –Wily Liss 2003 5
THANK YOU