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TERATOGENESIS
• pharmacogenetics:-study of genetic basis for
variability in drug response.
• Personalized medicine.
Same symptoms,
Different patients
Same findings,
Same disease? Same drug
Same dose
Genotyping
Patients with non-response
to drug therapy
• A, T, G, C • A b c d e f g….x y z.
• Codon • Word
• Gene • Sentence
• Chromosome • Chapter
• Genome • Book
Composition of the Human Genome
• Mutation/Polymorphism 1 bp
• Unit of genetic code 3 bp
• Coding sequence (exons) 3,000 bp
• Gene (exons and introns) 50,000 bp
• Chromosome 150,000,000 bp
• Human genome 3,000,000,000
bp
Terms in pharmacogenetics-
• Allele-one of two or more alternative forms of a gene
at the same site in a chromosome that determines
alternative characteristics in inheritance.
• Autosome-1 of 22 pairs of chromosomes.
• Autosomal dominant- a trait that is expressed only
in heterozygous state.
• Autosomal recessive- a trait that is expressed only in
homozygous state.
• Homozygous-having identical alleles at the genetic
locus determining character.
• Heterozygous-having different alleles at the genetic
locus determining character.
9
*
function of the encoded protein
GENETIC
POLYMORPHISMS
Pharmacokinetic Pharmacodynamic
•Receptors
•Transporters
•Plasma protein binding •Ion channels
•Enzymes
•Metabolism(Phase1 & 2)
•Immune molecules
• Normal Distribution
Frequency
Activity
Genetically distinct distribution curves for drug response by
individuals in a population.
No. of subjects
UNIMODAL
-normal TRIMODAL-
0 50 100 poor/intermediate/extensive
metabolisers
Units of measurement of
response
50 100 50 100
0
0
BIMODAL-
fast/slow metabolisers
Types of Cytochromes –phase I metabolizing enzymes
Phase II metabolizing
enzymes
Drugs Pharmacogenetic Clinical significance
variation
Succinyl choline Atypical Succinyl choline apnoea
pseudocholinesterase (A.R)
Primaquine,dapsone,qunine, G-6-PD deficiency Haemolysis.
sulfonamides,nalidixic X-linked inheritance.
acid,nitrofurantoin,
menadione
Warfarin Low activity of CYP2C9 bleeding/W. resistance.
6-MP & azathioprine TPMT deficiency Risk of bone marrow
toxicity.
Irinotecan -anticancer UGT1A1*28allele of Neutropenia & diarrhoea
Glucuronyl transferase poor metabolism
5-Flurouracil Dihydropyrimidine 5-Flurouracil toxicity.
dehydrogenase deficiency
(DPD)
Cancer chemotherapeutic Over expression of P-gp Tumour Resistance.
agents
Isoniazid Polymorphism of N-acetyl Neuropathy
transferase2-
Procainamide & Hdyralazine Slow acetylators S.Lupus
Drugs Pharmacogenetic Clinical significance
variation
Sulfonamides Arg substituted for his at 63rd position Acute hemolytic anemia
of β-chain of Hb (Hb- Zurich)
Methaemoglobin
Haemoglobin reductase
Methaemoglobin
NADP NADPH
HMP Shunt pathway
G6PD
Glucose-6- 6-Phosphogluconate
Phosphate
NADP NADPH
Glutathione
Reduced glutathione reductase
Oxidized
glutathione
Required for RBC membrane stability
Haemolysis
Haemolysis can also result from eating of broad
beans(Vicia faba) which contain oxidant alkaloid.
TPMT Catalyzed Methylation of 6-MP
TPMT
AdoMet AdoHcy
6-Mercaptopurine 6-Methylmercaptopurine
TPMT
ALA Synthase
• Succinyl CoA+ glycine amino laevulinic acid(ALA)
ALA dehydrase
SS- -w
n
waa
ri
fa
rin rrffa
arri
ar
rf a
CYP1A1 a inn
-w
R-w
R
CYP1A2 CYP2C9
CYP3A4 Vitamin K
Reductase
(VKORC1)
“…pharmacogenetics
promises to target
treatment to a patient’s
genetic profile…”
Herceptin: Prescribing Information
Personalized
medicine
• Age
• Race/ethnicity
• Weight PERSONALIZ
• Gender ED
• Concomitant Diseases MEDICINE
• Concomitant Drugs
• Social factors
• GENETICS
Teratogenesis
• Teratogenesis -development of fetal abnormalities in
response to drug effect that taken during early stages of
pregnancy.
• Teratogen - is a substance that can induce fetal
abnormalities.
• Drugs can affect the foetus at 3 stages-
fertilization & implantation-
-conception to 17 days- pregnancy failure.
Organogenesis-
-18-55days of gestation
-most valuable period & deformities are produced.
growth & development-
-56 days onwards.
-development & functional abnormalities can occur.
e.g.- NSAIDS-premature closure of ductus arteriosus.
-ACE inhibitors- hypoplasia of organs.
DRUGS abnormality
Alcohol Fetal Alcohol syndrome
Androgens Virilization, multiple congenital defects
Antineoplastic agents multiple congenital defects
Amidarone Goitre
Carbimazole Aplasia cutis
Diethylstilbestrol Vaginal adenosis & adrenocarcinoma
Fibrinolytic drugs Placental separation
Misoprostol, ergotamine Increases uterine tone
Phenytoin multiple congenital defects
Tetracycline's Yellow discoloration, inhibition of bone
growth
Na. valproate Neural tube defects
Warfarin multiple congenital defects
NSAIDs, sulfonamides Kernicterus
Aminogylcosides Effects 8th cranial nerve
BZD’s Floppy infant syndrome-muscular
hypotonia
Chloramphenicol Gray baby syndrome
Thalidomide phocomelia
Thank you #@$