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pharmacogenetics dds.ppt
1.
2. 1. Definition – Pharmacogenetics
2. Variation in drug response
3. Pharmacogenetic importance
4. Elementary genetics
5. Single gene PK disorders
6. Therapeutic drugs & clinically available PG tests
7. Conclusion
3. .PHARMACOGENTICS : Pharma & Genetics
Pharma – The greek word i,.e Pharmacon, related to Drugs.
Genetics – related to genes / genome.
The study of the genetics basis for variation in drug response.
PHARMACOGENOMICS : It employs the tools for surveying
the entie genome to assess mutigenic determinants of drug
response.
PERSONALISED MEDICINES : Individualising drug therapy in
light of genomic information.
4. To use genetic information specific to an individual patient to
preselect a drug that will be effective and not cause toxicity.
Better than relying on trials and error supported by physical
clues.
USFDA : Addition of pharmacogenomics labelling
information to the package inserts of over 50 drugs.
5. Inter individual variation in response to drugs – Serious
problem
Results in Lack of efficacy/Unexpected side effects
Variation:
Pharmacokinetic
Pharmacodynamic
Idiosyncratic
6. Too much/not enough drug at site of action.
Metabolism
Transporters
Plasma protein binding
7. Thiopurine drugs ( tioguanine, Mercaptopurine and its prodrug
Azathioprine) and TPMT(Thiopurine-S-methyltransferase)
activity : Bone marrow and liver toxicity.
About 1 in 300 Caucasians and African-Americans are TPMT-
deficient .
5-Fluorouracil (5-FU) and DPYD(dihydropyrimidine
dehydrogenase ) activity: Decreased metabolism
leukocytopenia, stomatitis, diarrhea, nausea and vomiting
8.
9. PD->/<effect of a drug at a given concentration at site of action
Interindividual variation in
•Drug targets
G-proteins
•Immune Molecules
•Receptors
•Ion channel and enzymes
10. Qualitatively abnormal reaction that occurs only in a
few exposed individuals
Results from differences in enzymes or immune
mechanisms.
11.
12.
13. Defination :
A gene is the basic instruction –a sequence of nucleic acids ( DNA
or, in the case of certain viruses RNA ), while an allele is one
variant of that gene. Referreing to having a gene for disease for eg.
Sickle cell disease is caused by a mutant allele of a haemoglobin
gene.
An allele is an alt. form of a gene ( one
member of a pair ) that is located at a
specific position on a specific
chromosomes.
17. Different alternative sequences at a locus within DNA
strand(alleles) that persist in a population through several
generations.
A rise due to mutation.
Increase in frequency over generations-selective advantage
18. SNPs are DNA sequence variations that occur
when a single nucleotide in the genome
sequence is altered.
May entail substitution of one nucleotide to
another(C for T).
Result in ‘frame shift’ in translation
19. Result can be loss of protein synthesis, abnormal
protein synthesis or an abnormal rate of protein
synthesis.
Individuals differ from each other approx. every 300-
1000 nucleotides with an estimated total of 30 million
SNP.
Can occur in coding & non coding regions
Important determinant of disease-e.g. Inherited
Thrombophilia
20. Mutation in
(F5) gene
causes
V Leiden
F5 instruct for
making
protein
coagulation
controled by several
protein including
APC.
Increased risk of
Venous
Thrombosis
In Case of
Hemorrhage
than
thrombosis
23. Suxamethonium or succinylcholine sensitivity
;rate of metabolism
Mendelian Autosomal Recessive trait Short
acting NM blocker
Plasma cholinesterase
24. Genetic abnormality of calcium channels with skeleton
muscle.
Autosomal dominant inherited.
Idiosyncratic ADR due to SXM on Ryanodine receptor
Also due to halogenated inhalational agents ( induced
anaesthesia by blocking CNS neurotransmission
teRapid rise of body
perature,
muscle rigidity,
Rapid heart beat
25. Mechanism: Sudden rise in
release Ca2+ from sarcoplasmic
stores leading to muscle
contraction & hyper metabolic
rate.
Potentially fatal
26. Treatment:
Dantrolene 1 mg/kg i.v repeated up to 10mg/kg.
(prevents release of Ca2+ from sarcoplasmic
reticulum)
Symptomatic Rx of Hyperthermia
Rx of Cardiac arrhythmias
27. • Inherited hepatic disorder, Autosomal
dominant
• Deficiency of HBMS (hydroxymethylbilane
synthase)
• Mutation in gene coding Porphobilinogen
deaminase(PBGD)
28. • mitochondrial DNA mutation
• Mitochondrial 12S ribosone
RNA gene.
• Most common predisposing
mutation
• 30-60% ototoxicity in
china(Aminoglycosides-cheap)
29. Bind to Bacterial ribosomes
For a single dose in
susceptible individuals.
Screening for this
variant appropriate in
children
Increased affinity to
ribosomes in hair cells
in ear for several
months
Aminoglycosides
30. • Rate of Metabolism differs with
race
• Oriental races- accumulation
of acetaldehyde.
• Due to slower rate of oxidation
of acetaldehyde as a result of
genetic polymorphism
Especially in
Japanese
31. Around 80% of Asians have a variant gene ADH1B
Almost all Chinese and Koreans- ADH1C
Coding alcohol dehydrogenase -toxic acetaldehyde at
a much higher efficiency
50% of Asians, the increased acetaldehyde
accumulation, the mitochondrial ALDH2 allele,
less functional acetaldehyde dehydrogenase enzyme,
32.
33. Understanding human genome
Simpler methods identify
genetic information
Genetic information specific to
. individual
Preselect
effective drug
No
toxicity
No trial
& error
34. Anticipated to be one of the first applications of
human genome sequencing.
Development slowed by various scientific ,
commercial, political and educational barriers.
Cost effectiveness
Evidence in support of atest is less convincing
than the ideal of an RCT of PG informed
prescribing strategy versus current best practice
35. 1.Variants of different HLA strongly linked to
susceptibility to severe idiosyncratic
reactions
2.Genes controlling aspects of drug
metabolism
3.Genes encoding drug targets
36.
37. Abacavir-Reverse transcriptase inhibitor
Highly effective - HIV Infection
Severe Rashes
Susceptibility linked to HLA variant
HLAB*5701
38. Carbamazepine
Severe life threatening rashes
Stevens Johnson Syndrome
Toxic epidermal Necrolysis
Almost only in Asians
FDA recommends Chinese patients to be screened for
this allele
Similar problem with Phenytoin for same allele
39.
40. prodrug Azathioprine
Treat Leukemia's(ALL),Inflammatory
Bowel disease & Immunosuppression
Cause Bone marrow & Liver toxicity
Detoxified by Thiopurine S
methyltransferase(TPMT) present in
blood cells & by Xanthine oxidase
Thioguanine,Mercaptopurine & its
Low TPMT
activity
High
TPMT
Reduced
efficacy
Lower
conc
TGN
Bone marrow
Toxicity
High Conc of
active TGN in
blood
41. Phenotyping (by a blood test for TPMT activity)
Genotyping TPMT Alleles
TPMT*3A,TPMT*3C,TPMT*2 is recommended.
Careful monitoring of WBC count & drug
interaction with allopurinol(due its effect on
Xanthine Oxidase)
42. Effective antipsychotic drug
Agranulocytosis 1% of patients
Studies-small
Specificity and sensitivity yet to be
established
43. Extensively used to treat solid Tumours.
Unpredictable mucocutaneous toxicity.
Detoxified by dihydropyrimidine
dehydrogenase(DPYD)-clinically identifiable
multiple genetic variants
FDA recommends no to be given to those with
DPYD deficiency
44. TAMOXIFEN variation
Suggested link between CYP2D6
genotype& efficacy.
Genotyping tests available.
Tetrabenzaine used to
Huntington's disease may also be
influenced by cyp2d6
Estrogen
antagonist
ENDOXIFEN
CYP2D6
Polymorphic
45. Topoisomerase I inhibitor.
Marked activity against colorectal & lung
cancers(minority)
Toxicity(Diarrhoea & BM suppression very severe
Active metabolite SN-38
Gilberts
UDP glucuronyltransferase
Reduced activity Hyberbilirubinemia
syndrome
46.
47. • Herceptin is mAB that antagonizes
epidermal growth factor(EGF) by binding to
one of its receptors(human epidermal
growth factor receptor 2-HER2)
HER2 in tumour
• Somatic mutation
tissue
48. o DASATINIB –dual BCR/ABL & Src tyrosine
kinase inhibitor
o Used in hematological
malignancies(Philadelphia chromosome)
o CML ALL
o Mutation (T3151) in BCR/ABL confers
resistance to inhibitory effect of dasatinib.
51. WARFARIN
Dosing individualized by measuring
INR(International normalized ratio)
Thrombotic effects(lack of efficacy)
Adverse effects(bleeding) common
PG testing proposed based on polymorphism in its
key target, vitamin K epoxide reductase(VKOR)
&CYP2C9 GENOTYPE involved in its metabolism
52. Ph proves that concept of susceptibility to ADR can
be genetically determined
Offers possibility of a more armacogenetics
Precise ‘Personalised ‘ Medicine for several drugs
& disorders.
Field of intense research, rapid progress.
Challenge remains about its feasibility in
Clinical setup