the pharmacogenomics require the pharmacology and genomic together to improve the drug responses and the new age drug potential according to individual need
3. INTRODUCTION
• The study of the genome affecting the drug response is called Pharmacogenomics i.e., how the
genetic makeup of an individual effects his/her response to drugs
• The genome has genetic variations either acquired or inherited along with its correlation with gene
expression or SNP which effects the drug response on human body
• Pharmaco + Genomics. Where pharmaco means drugs and genomics means the study of genome
• Like for the drug discovery, the genetic loci responsible for the disease is identified, similarly the
variations are identified
4. • History
• Pythagoras firstly established the correlation between the faba beans consumption and its
effect on body as haemolytic anemia and oxidative stress
• In 1950s, the prolonged paralysis and fatal reaction was common in the patients whose
genetic variants do not have cholinesterase for succinylcholine injection for anesthesia
• The first study approved by the US govt. was on Cytochrome P450, two genes CYP2D6 and
CYP2C19
5. AIM
• To decrease the Adverse Drug reactions (ADR) in the patients and even the normal reactions
• To decrease the polypharmology, i.e., multiple drugs consumption for treatment of one
disease
• Personalised and precise drugs given to the patients
• Eliminate the clinical trial and error method
• To maximise the effects of drugs on patients
6. TERMINOLOGY
• Pharmacokinetics
The ADME (Absorption, Distribution, Metabolism and Excretion) of drug when consumed i.e., the
things that body do to the drugs
• Pharmacodynamics
The biological and physiological effects of the drugs on the body i.e., the things that drugs do to the
body
• Pharmacogenetics
• The relation of single gene and its response to the drugs
7. DRUG-RECEPTOR INTERACTION
• Two types of interaction with drugs:
Agonist
• It will either enhance or have same effect on the
receptor by mimicking the ligand molecule
• Example: the albuterol in asthma when inhaled
binds to the beta receptors to activate adynyl
cyclase for relaxation of bronchi
Antagonist
• It will inhibit the receptor partially or fully
• Example: the beta blockers are used for the
catecholamines during irreversible heart failure
8. PHARMACOKINETIC
INTERACTION
• The main identification of the how much the drug or dosage of drug is required for the proper
response
• The absorption of drug plays an important role as injected drug will show 100% bioavailability while
the injested will go through gastrointestinal to liver which leaves only few percentage of drug for
effect depending on enzyme action or bioavailability
• The excretion of the drug depends kidney filter and absorption, eg, the ABC transporter, P-gp is
responsible to flux out excess of small molecules but if it is upregulated then the efflux increases and
drugs removed even before it could reach target
9. • Between absorption and excretion, there comes the steps which is genes producing enzymes
for metabolising drugs, so any variations in this will effect the response
• There are 3 main genes involved and studied
Cytochrome P450
• The CYP genes are 57 total in number and basis of similarities
in amino acids are categorised in families and subfamilies’
• CYPxyz, where x is family, y is subfamily and z is gene number,
eg, CYP2D6
• 25% affects if polymorphism occurs
VKORC1
• Vitamin K epoxide reductase complex 1
• Warfarin drug (anti coagulant) interacts with VKORC1 and
CYP2C9 and it inhibits the VKORC1 by competitive binding to
receptor
TPMT
• Thriopine S-methyl transferase
• Thriopine drugs used in leukemia of side effect of bone
marrow toxicity inactivated by it
• Any variance in this genes will be fatal for the patient
10. CYP MAIN GENES
CYP genes Drug interacted Fraction of drug
metabolism
Variation percentage
CYP2D6 Codeine 25-30% More than 100 gene
CYP2C9 Warfarin 5% 57 gene variation
CYP2C19 Propanolol 10% 28 gene variation
CYPA34 Cyclosporin 40-45% -
CYPA35 Cyclosporin <1% -
11. PHARMACODYNAMIC INTERACTION
• On Target
• The warfarin drug mimic vitamin K to bind to the VKORC1 competitively as Vitamin K
binds and inhibits it, but it by variation the individual lacks vitamin K, then the anti
coagulant effect is downregulated
• Hydrocortisone diffuses inside the cell membrane and binds to the target, glucocortisoid
which is intially inactivated by heat shock protein but when it binds the heat shock protein
dissociates
12. • Off target
• The adverse drug reactions may occur either directly by inhibiting the pathways or by
indirect
• Indirect ways of reactions , example, the beta receptor blockers given for the treatment of
heart failure could also block other beta receptors present in smooth muscles
14. • Associative method
• Here, the Single nucleotide polymorphism is determines on the microarray of the population
and so if the SNPs are large enough of a genome to be determined under the Genome Wide
Assosciation Studies(GWAS), then it is studied on the large scale by the genetic marker or
the phenotypical expression
• The chi square test is performed for the associative studies while the wadal test is for the
dosage studies
• Expression studies
• Here, the expressions of the genes are considered either by analysing the patients which have
the disease of interest and identifying the potential drugs or analysing the patients already
under treatment for the molecular response
15. APPLICATIONS
• Drug discovery
Disease Gene Target
Lead
optimization
Animal model
and phase 1
Phase 2 Phase 3
Adverse drug reaction
prediction
Associative/Expression method
Screening
16. • Predictive prescribing
• The patients genotypes are classified according to its predictive pehnotype
1. Ultra rapid – increase metabolic activity
2. Extensive – less metabolic activity
3. Intermediate- decrease metabolic activity
4. Poor- little or no metabolic activity
• The patients are prescribed medicines according to the phenotypes predicted and implemented in
clinical practice
17. • Dosage Prediction
• The warfarin drug used as anticoagulant and act on the VKORC1 but if any variant occur in
VKORC1 then the warfarin dosage has to be 20 fold times than other patients due to this one
genetic variation
• Adverse Drug Reaction(ADR)
• Statins, a variant in individuals has been observed that a SNP in statisn cause intolerance
towards it, thus giving rise to ADR, which could be avoided by the pharmacogenomics
19. Case study
• Codeine which Is used as the pain relief, converts into morphine
• But, the alleles present in individuals could hamper the response of this drug
where 1*1* allele involved in extensive metabolism of drug and 1*4* allele involves in
intermediate response, thus affecting the response and so the drugs could be prescribed
according to the alleles and variations present in an individual was precise and personalised
treatment.
