Pharmacogenetic;

pharmacogenomic

Dr. DATTEN BANGUN MSc,SpFK

Dept.Farmakologi & Therapeutik

Fak.Kedokteran UHN
Medan,
Rx +  = 
Rx +  = 
Rx +  = 
????
 Differences in genetic
constitution

Rx +  = 
Rx +  = 
Rx +  = 
 Interindividual Variability in Drug
Response

Disease Drug Class Rate of Poor Response

Asthma Beta-agonists 40-75%
Hypertension Various 30%
Solid Cancers Various 70%
Depression SSRIs, tricyclics 20-40%
Diabetes Sulfonylureas, others 50%
Arthritis NSAIDs, COX-2 inhibitors 30-60%
Schizophrenia Various 25-75%
 Factors Contributing to Interindividual
Variability in Drug Disposition and
Action
• Age
• Race/ethnicity
• Weight
• Gender PERSONALIZED
• Concomitant Diseases MEDICINE
• Concomitant Drugs
• Social factors
• GENETICS
 Human Genome Project

• Determine the sequence of the 3 billion

nucleotides that make up human DNA
• Characterize variability in the genome
• Identify all the genes in human DNA

• The Era of Genomic Medicine:

– Improve prediction of drug efficacy or toxicity
– Improve the diagnosis of disease
– Earlier detection of genetic predisposition to
disease
 Pharmacogenetics and
pharmacogenomics
 Pharmacogenetics: the effect of
genetic variation on drug response,
including:
– disposition
– safety and tolerability, and
– Efficacy

 Pharmacogenomics: the application

of genome science (genomics) to study of
human variability in drug response.
 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%
 Monogenic vs. Gaussian
Variations
Monogenic
All-or-none function in affected gene Function of affection gene shows
Mendelian inheritance
Examples:
Sickle cell, CYP2D6,
Cystic fibrosis, Rb
Gaussian or polygenic
a range that is defined by ED50
Multiple gene variation involved
Accounts for majority of variation
in drug responses
Disease Susceptibility
Alzheimer’s disease
ApoE4, ApoE2 (19q13), 12q
 Normal Distribution
Contoh:
-Berat badan
-Tinggi badan

Frequency
Banyak faktor
mempengaruhi

Activity
 Polymorphic Distribution

From Pratt WB,Taylor P. Fig 7-5b

 GENETIC
POLYMORPHISMS

Pharmacokinetic Pharmacodynamic
•Transporters •Receptors
•Plasma protein binding •Ion channels
•Metabolism •Enzymes
•Immune molecules
 Genetics or Genomics?

• Pharmacogenetics
– Study of how genetic differences in a SINGLE
gene influence variability in drug response
(i.e., efficacy and toxicity)
• Pharmacogenomics
– Study of how genetic (genome) differences in
MULTIPLE genes influence variability in drug
response (i.e., efficacy and toxicity)
 Potential of Pharmacogenomics
All patients with same diagnosis

1 Non-responders
and toxic
responders

Treat with alternative

2 drug or dose

Responders and patients

not predisposed to toxicity
Treat with
conventional
drug or dose
 Single Nucleotide Polymorphisms
(SNP)
• Pronounced “snip”
• Single base pair difference in the DNA
sequence
– Over 2 million SNPs in the human genome
• Other polymorphisms:
– Insertion/deletion polymorphisms
– Gene duplications
– Gene deletions
 Genomic organization:
chromosomes
• Every human cell with the exception of gametes
contains 23 pairs of chromosomes,plus 1 pair
• sex-chromosome
 Genomic organization:
chromosomes structure
 Chromosomes carry
all of the genetic
material coding for
all the proteins in
every cell
 Chromosomes
consist of DNA
tightly wound
around special
protein structures
called histones.
 Structure of genes
• A segment of DNA containing all of the
information needed to encode for one protein is
called gene. The order and sequence of the
base pairs in a gene determine which protein is
made.
 Transcription of genes
 The transcription of DNA
into messenger RNA is often
assembled from
discontinuous sequences in
the genome called exons,
which are separated by
sequences called introns.
 This process is referred to
as splicing. A genomic
sequence can yield more
than one splicing product.
 Transcription can be
controlled through regulatory
sequences known as the
promoter sequences
 Putting it all together:
translation into protein
• Translation into protein sequences is
accomplished at ribosome
 Mutations in the genome
• One in every 1200 bases
may be different in any
two humans. This
variation, which is called
a polymorphism, is
largley responsible for
differences between how
humans respond to
drugs. Several types of
mutations are associated
with these variations:
 Mutations in the genome
• Mutations can also affect gene expression when
they occur in regulatory or promoter sequences
or in the exon/intron boundary.
 What are SNPs

A Single Nucleotide Polymorphism, or SNP

(pronounced "snip") is a small genetic change, or
variation, that can occur within a person's DNA sequence.
A single base change found in 1% of an ethnically diverse
population is defined as a SNP.
.

Although many SNPs do not produce physical

changes in people, scientists believe that other SNPs may
predispose a person to disease and even influence their
response to a drug regimen.
 SNP Profiles and Response to
Drug Therapy
Breast Cancer Patients

Individual SNP Profiles Are Sorted

Responds to Standard Drug Treatment Does Not Respond to Standard Drug Treatment

SNP profile A SNP profile B

SNP profile E SNP profile C

SNP profile D
Genetic variations that can modify
responses to drugs.

1. Variation in target proteins/target

pathways.
2. Variation in enzymes
3. Variation in genes unrelated to no. 1
& 2  result in indiosyncratic
(typically unpredictable).
Ad.1. Variation in target proteins
Ad.2. Variation in enzymes in metabolism
Ad.2 Contoh :
- INH
- Succinylcholine
- Acatalasia
- Atropinesterase
INH=Isoniazid; 0bat tbc , dimetaboliser
dg proses asetilasi,ensimnya acetylator
Apa pengaruh genetik pada ensim acetylator?

• = 90 % Japanese Rapid acetylator

• = 50 % Western --------”---------
• = Inuit (Arctic ) ----- rapid
• --------- makin ke equator makin sedikit
yang rapid (fast ) acetylator.

Rapid acetylator=== hepatotoxic

Slow acetylator === neuritis--Indonesia
 Polymorphic Distribution

From Pratt WB,Taylor P. Fig 7-5b

Succinylcholine;
= dimetaboliser dg bantuan ensim pseudo-
choline-esterase

Pada beberapa keluarga:

- terdapat kekurangan ensim pseudocholine
esterase ini,shg bisa terjadi paralisa
pernafasan bila diberi succinylcholine-----
HATI-HATI !!!
Family studies indicate variability in
plasma cholinesterase activity
consistent with 2 allelic, autosomal,
codominant genes
 peroxidase ( katalase)
Acatalasia:
= peroxid (H2O2)======== H2O + On
(timbul buih/bubble)

Bila tak ada katalase----- akatalasia

Ad.2 Sex – linked
1.G6PD deficiency  affected older red
cells.
~ Primaquine
~ Acetanilid
 haemolytic
~ Phenacetin
~ Sulfonamide

- Affected X – chromosome
~ Male xy, female xx
 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
Ad.2 Ex. Female Male
I. F1 x x xy
F2 x x x y xx xy

II. Warfarin resistance

Receptor sensitivity berkurang
INCIDENCE OF G6PD DEFICIENCY IN
DIFFERENT ETHNIC POPULATIONS
Ethnic Group Incidence(%)
Ashkenazic Jews 0.4
Sephardic Jews
Kurds 53
Iraq 24
Persia 15
Cochin 10
Yemen 5
North Africa <4

Iranians 8
Greeks 0.7-3
Asiatics
Chinese 2
Filipinos 13
Indians-Parsees 16
Javanese 13
Micronesians <1
Some heritable conditions causing
decreased drug responses:
= Resistance to coumarin anticoagulant
= Resistance to heparin
= Resistance to vitamin D
= Bacterial resistance to drugs:
-genetically determined
-of great clinical importance
Pharmacogenetics in
Clinical Practice:
Why, What and How?
Patient Response to Medicine Varies
“One size does not fit all …”

“I have hypertension which is not being

controlled. My doctor prescribes a drug
for hypertension, we wait 3-4 months to
find it’s not working and then try another
one. In 18 months, I’ve tried 6 new medications
and I’m fast losing confidence in this hit or miss
approach and in my physician”.
Medicines are not Safe or Effective in all Patients

Pharmacogenetics:
To deliver:
‘ the right medicine,in the right dose,
to the right patient’
 Pharmacogenetics:
Practice of medicine

“If it were not for the great variability among

individuals,Medicine might as well be
a science and not an art.”

Sir William Osler, 1892

 Summary
• Pharmacogenetics has and will continue to provide novel
insight into drug development and prescribing.
• Effective implementation in clinical practice may prove
challenging.
• Each application should be explored on a case by case
basis.
• Partnership with healthcare providers and recipients are
vital.

Pharmacogenetic Goal:
Help healthcare providers select more accurately the medicines
most likely to help, and least likely to cause serious side effects
for patients.
Thank you for the attention