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PHARMACOGENETICS

TERATOGENESIS
• pharmacogenetics:-study of genetic basis for
variability in drug response.

• It deals with genetic influences on drug action as


well as on drug handling by the body.

• Pharmacogenomics is use of genetic information to


guide the choice of drug and dose on an individual
basis.

• Personalized medicine.
Same symptoms,
Different patients
Same findings,
Same disease? Same drug
Same dose

Differential drug efficacy


Different Effects
At a recommended prescribed dosage—
a drug is efficacious in most.
not efficacious in others.
Lack of efficacy
harmful in a few.
Unexpected side-effects
People react differently to drugs Toxic responders
Non-responders
“One size does not fit all …” Responders

Patients with drug toxicity

Genotyping
Patients with non-response
to drug therapy

Patient population with


same disease phenotype Patients with normal
response to drug therapy
DNA is Information
• DNA • ENGLISH

• 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

I. 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% or more in the population
MOLECULAR MECHANISM OF GENETIC POLYMORPHISM
Genetic Polymorphism-
Means Genetic variation occurring with a frequency of 1% or
more in the population
1. SNP (single nucleotide polymorphism): most frequent type
• Difference in a single base of the genomic sequence.
• SNP can occur- In exons (may alter the structure of proteins
and may lead to functional consequences)
• In introns (may influence splicing)
• In the regulatory regions (may influence expression of the
gene) -Promoter , Intronic , Intergenic etc
• Single Nucleotide Polymorphisms (SNPs)
A key to human variability
• DNA sequence variation at a single nucleotide that may alter the

*
function of the encoded protein

Functional but altered


Functional protein protein
Polymorphisms are common and contribute to common
diseases and influence our response to medications
For example a SNP might change the DNA sequence
AAGCTTAC
to ATGCTTAC
• 2. Insertion/deletion polymorphism: insertion or
deletion of a few nucleotides
• 3. Variable number tandem repeats: variation in the
number of times a sequence of several hundred base
pairs is repeated
• 4. Simple tandem repeats (microsatellites): 2-4
nucleotides repeated a variable number of times
• Genotype: gene structure encoding for the given
characteristics .
• Determination of genotype: PCR, Gel-
electrophoresis.
• Phenotype: the manifestation of the genotype,
which can be observed and can be influenced by
other factors.
• Determination of phenotype:
a)determination of metabolic rate (level of original
drug/metabolite in urine) after administration of a
given dose of the drug,
b) pharmacokinetic parameters are measured (half-
life, clearance, plasma levels)
15

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

Barbiturates Genetic defect in porphyrin Acute intermittent


syns & activity of δ-ALA porphyria.
Synthase
Metoprolol, CYP2D6 abnormality Poor metabolism.
debrisoquine Orthostatic Hypotension
Antidepressant & Toxicity.
antipsychotics CYP2D6 deficiency
Codeine-Morphine Codeine Morphine Fails to produce analgesia.

Halothane + Abnormal ca2+ channel Malignant Hyperthermia.


succinylcholine (Ryanodine R)- Sk.M
Phenytoin Abnormality in hydrolysis Phenytoin toxicity.

Mydriatics Narrow iridocorneal angle Ppt. Angle closure


glaucoma.
Alcohol Relatively low rate of Ethanol sensitivity
metabolism
DRUGS Pharmacogenetic variation Clinical significance

Glucocorticosteroi Unknown (A.R) Glaucoma/ I.O.P


ds

Oxidizing drugs Methaemoglobin reductase Methaemoglobinaemia


deficiency(A.R) (drug induced Haemolysis)

Phenacetin M.F.O in liver microsomes that Phenacetin induced


de- ethylates Phenacetin(A.R) Methaemoglobinaemia

Dicoumarol M.F.O in liver microsomes that Dicoumarol sensitivity


hydroxlates Dicoumarol

Sulfonamides Arg substituted for his at 63rd position Acute hemolytic anemia
of β-chain of Hb (Hb- Zurich)

Sulfisoxazole Hb composed of 4β-chains (A.D) Acute hemolytic anemia


Haemoglobin-M-(H-disease)

Hydrogen Catalase in RBC (A.R) Acatalasia


Peroxide deficiency
DRUGS Pharmacogenetic Clinical significance
variation
Sparteine Abnormal aminoxidase Sparteine induced diplopia,
(A.R) blurred vision

Tolbutamide M.F.oxidase (A.R) Tolbutamide induced cardiac


-slow metabolisers death

Methyl/ Propyl thiouracil unknown Inability to taste


phenylthiourea
ACE inhibitors Angiotensin converting High Risk of heart disease
enzyme - abnormal
Anti -oestrogen Cyp2D6 Therp. failure- poor
Tamoxifen(pro drug) Metabolisers
Proton pump inhibitors Cyp 2C19 Toxicity-poor metabolisers
(Omeprazole) Therp. Failure- Extensive.M
(high doses required)
Oestrogens lack of Glucuronyl Hyperbilirubinaemia
transferase (Gilberts syndrome)
DRUGS Pharmacogenetic Clinical significance
variation

COMT inhibitors Catechol –O-Methyl Poor/intermediate/extensive


(Entacapone) Transferase (COMT) metabolisers.

Alcoholics Transketolase Wernicke - Korsakov syndrome


deficiency/abnormal

Nicotine, H2 receptor Flavin -Containing fish- odour syndrome due to a


antagonists , Monooxygenases (FMOs)- lack of metabolism
antipsychotics, anti- deficiency
emetics

UGT1A1 substrates UGT-lack of Biliurubin Types I and II Crigler-Najjar


Gemfibrozil, statins glucuronidation syndrome
Some examples of genetic polymorphism in drug metabolism. (phase I)
DEFECT DRUG & THERAPEUTIC USE C.SIGNIFICANCE
Oxidation Bufuralol (β-blocker) Exacerbation of β-blockade,
Nausea.
Oxidation Debrisoquine (Anti.HTN) Orthostatic HTN.

Oxidation Ethanol Facial Flushing , Cardiac


symptoms.
Oxidation Mephentyoin(Anti. Epileptic) Toxicity

Oxidation Sparteine Oxytocic symptoms

Oxidation Tolbutamide (Hypoglycemic) Cardio toxicity

N- Acetylation INH (Anti.TB) Peripheral neuropathy

N- Acetylation Hdyralazine (Anti.HTN) Lupus erythmatosus like


syndrome
Ester hydrolysis Sch (N.M.Blocker) Prolonged apnea
Drugs Genetic Polymorphism Clinical significance
In binding ptns-Phase-1

BZD/Haloperidol Binding affinity Displacement reactions

Copper Deficiency of ceruloplasmin Wilsons disease

Iron excessive iron absorption into small Hemochromatosis


intestine due to lack of binding
ptns/ transporters.
Drugs Genetic Polymorphism Clinical significance
Transporters –Phase-1

Antidepressant drugs 5-HT transporter response

Antiarrhymic drugs Na/K transporters Drug induced long QTc-


Syndrome.

Antitumour drugs MDR1/P-gp Cancer resistance


Ph.K Genetic polymorphism – Drug affected
phase-2
Histamine N-methyl transferase Histamine

UDP-Glucuronyl transferase Androgens, ibuprofen,


morphine

Sulfotransferases (SLUTs) Acetaminophen, dopamine ,


epinephrine

Catechol –O-Methyl Transferase (COMT)- Catecholamine, L-dopa, methyldopa

Thiopurine S-methyl Transferase 6-MP & Azathiopurine

N- Acetyl Transferase(NAT1) Sulfamethoxazole

N- Acetyl Transferase(NAT2) Dapsone, Hydralazine,I NH,


Procainamide.
Examples of Ph.Dynamic
Genetic Polymorphisms Drug Targets
PROTEIN DRUG AFFECTED-examples

5-lipoxygenase Zileuton-anti asthmatic

Angiotensin converting enzyme(ACE) ACE inhibitors- lisinopril

Apolipoprotein E/LDL receptor Statins

β-2 Adrenergic receptors β-blockers

Epidermal growth factor receptor(EGFR)/ Gefitinib


HER1

Sulfonylurea receptors Tolbutamide

Vitamin-K epoxide reductase Complex 1 Warfarin


(VKORC1)
G6PD DEFICIENCY-HAEMOLYSIS
NAD NADH

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

6-MP is not converted to active metabolite, so drug response failure


Thiopurine Metabolism

TPMT
ALA Synthase
• Succinyl CoA+ glycine amino laevulinic acid(ALA)

ALA dehydrase

Cytochromes Haem porphyrins Porphobilinogen


Barbiturates-Cytp450.
inducer

Enzymatic defects in Porphyria porphyrins


Acute intermittent porphyria
• Barbiturates induces cyt.p450 enzymes.
• This cyt.p450 is heme containing enzyme.
• As a result cyt.p450 & heme demand.
• synthesis or activity of ALA Synthase-produces more porphyrins than
required- accumulates in blood & causes Acute intermittent porphyria-
Warfarin-risk of bleeding & Resistance
Warfarin

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)

Oxidized Vitamin K Reduced Vitamin K


CO2 O2
Calumenin

Hypofunctional γ-glutamyl Functional


F. II, VII, IX, X carboxylase F. II, VII, IX, X
Protein C, S, Z Proteins C, S, Z
• Pharmacogenetics related to diseases-
1) Down syndrome- children with trisomy 21 excessive
sensitivity to Antimuscarinic drugs.
2) Gout(A.D/polygenic inheritance)-aggravated by following
a)ethanol- metabolized by oxidation
- NAD NADH
pyruvate lactate impairs renal excretion of
uric acid ppt gout in susceptibles.
b)Diuretics- impairs renal excretion of uric acid
-ppt gout in susceptibles.
c)Allopurinol - Xanthine oxidase inhibitor.
- HGPRT activity-Xanthine stones forms.
- HGPRT lacks in Lesch-Nyhan syndrome.
3) Gilberts disease- Hyperbilirubinaemia.
• Pharmacogenetics related to drug resistance-
1) Vit-D resistance rickets-
a) Familial hypophosphatemic rickets-
-sex linked inheritance.
-abnormality is impaired renal phosphate reabsorption.
-response to Vit-D is poor & requires large doses.
b) Vit-D dependency-
Type1-pk.abnormality
- 1α- hydroxylation of Vit-D in kidney.
-responds to high doses of Vit-D & low doses of
calcitriol.
Type2-p.dynamic.abnormality.
-impaired tissue sensitivity to Vit-D & receptor
binding
c) Fanconi syndrome-
-rickets in Fanconi syndrome is due to failure in
T.reabsorption of Phosphate.
-rickets don’t respond to even high doses of Vit-D but
responds to α-calicidol or calcitriol.
3) Coumarin resistance-
-Vit-K epoxide reductase is resistance to inhibition by
Coumarin/warfarin.
4) Sch resistance-
-3 or 4 fold increase in plasma pseudocholinesterase.
5) Insulin Resistance-due to different types of mutation
in gene for the insulin receptor.
Newsweek
June 25, 2001

“…pharmacogenetics
promises to target
treatment to a patient’s
genetic profile…”
Herceptin: Prescribing Information

• HERCEPTIN (Trastuzumab) as a single agent is


indicated for the treatment of patients with
metastatic breast cancer whose tumors
overexpress the HER2 protein and who have
received one or more chemotherapy regimens
for their metastatic disease.

• HERCEPTIN should be used in patients whose


tumors have been evaluated with an assay
validated to predict HER2 protein
overexpression
Roche AmpliChip: FDA-Approved
Genotype assignment is now
increasingly dependent on
DNA-based test performed
with devices such as CHIP

Ampli Chip CYP450 array-used to determine variant genotypes for cytochrome


P450genes that can influence drug metabolism.
"Here's my
sequence..."

Personalized
medicine

The New Yorker


Factors Contributing to Interindividual Variability in Drug
Disposition and Action

• 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

Oral anticoagulants Microcephaly/fetal/ reteroplacental


haemorrhage

Oral sulfonylurea's Fetal/neonatal hypoglycemia.

Pethidine Neonatal resp. depression.

Thiazide diuretics Thrombocytopenia.

Thalidomide phocomelia
Thank you #@$