This document discusses pharmacogenetics, which is the study of genetically controlled variations in drug response. Key points covered include: - Pharmacogenetics deals with genetic contributions to variations in individual drug response. This can include variations in drug metabolism, transport, targets, and immune response. - Genetic polymorphisms, such as those that effect drug metabolizing enzymes and transporters, can result in differences in drug efficacy and risk of side effects between individuals. - Examples of genetic variations that effect drug response include those involving CYP2D6 metabolism of antidepressants and codeine, TPMT metabolism of thiopurines, and G6PD metabolism of primaquine. - Understanding genetic contributions to

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

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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.

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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%

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Normal Distribution
Frequency
Activity

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Polymorphic Distribution

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

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From: Evans WE, Relling MV. Pharmacogenomics: Translating functional genomics
into rational therapeutics. Science 286:487-491, 1999.
Genetic polymorphisms in drug
metabolizing enzymes

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Atypical Plasma Cholinesterase
•a rapid acting, rapid recovery muscle relaxant - 1951
•usual paralysis lasted 2 to 6 min in patients
•occasional pt exhibited paralysis lasting hrs
•cause identified as an “atypical” plasma cholinesterase
Hydrolysis by pseudocholinesterase
choline succinylmonocholine
O C CH2CH2
O
(H3C)3NH2CH2C C
O
O CH2CH2N(CH3)3
+ +
SUCCINYLCHOLINE

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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.

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• 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.

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

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

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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 .

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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 it
concentration
Of active, inactive or toxic metabolites

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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

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CYP2D6 ACTIVITY
N C NH
NH2
N C NH
NH2
CYP2D6
OH
DEBRISOQUINE
4-HYDROXYDEBRISOQUINE
H
N CH3
OCH3
H
N CH3
OH
DEXTROMETHORPHAN DEXTRORPHAN
CYP2D6

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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

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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

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THIOPURINE METHYLTRANSFERASE (TPMT)
N
N N
H
N
SH
N
N N
H
N
SCH3
TPMT
SAM SAH
6-mercaptopurine 6-methylmercaptopurine

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TPMT POLYMORPHISM

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

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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’

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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

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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 https://www.pharmacogenomics.org