Pharmacogenetics of Adverse Drug Reactions

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Introduction

Historical overview Definition of ADR

Classification of ADR

Pharmacokinetic variations

Pharmacodynamic variations

Genetic variability in drug metabolizing enzymes

Genetic variability in drug transporters

Immunogenetic & Receptor polymorphism Miscellaneous drug targets

Conclusion

References


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Adverse drug reactions (ADRs) representa major public health problem

6.7%of hospitalized patients developsevere ADRs

In children the overall incidence of ADRs

is as high as 9.5% The overall cost of drug related morbidity

and mortality in US has been estimatedto be more than 76billion$


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4% of drugs marketed in UK over a 20year period were withdrawn because ofsafety issues

Many factors contribute to the

occurrence of ADRs. those are-Environmental factors

- Genetic factors

Significant proportions of ADRs mayoccur because of geneticpredisposition(genetic factors.


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Certain enzymes metabolise 5 to 25% ofall prescribed drugs respectively but inADRs they metabolize 38 to 75% of drugs


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PYTHAGORAS in 510bc,southern Italyreported that ingestion of fava beans canlead to red cell hemolysis in some

individuals but not all The same was observed with Primaquine

administration in 1956 because of G6PDdeficiency.

Another classical example reported in 1950was the occurrence of prolonged apnoeaafter treatment with Suxamethonium in ptswith deficiency of butyrylcholinesterase.


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The first ADRs with a P450 polymorphism wasthe occurrence of hypotension withDebrisoquine led to discovery of CYP2D6.

Genes other than those coding forproteins involved in drug disposition mayalso predispose to ADRs.

HLA has been a focus of interest for manyyears, eg: Hydralazine induced lupus inpatients who are HLA-DR4 positive.

Individuals who are slow acetylators andHLADR4 positive have a higher risk thanthose with one risk factor only.


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A noxious change which is suspected to

be due to a drug, occurs at dosesnormally used in man, requires treatmentor decrease in dose of indicates cautionin the future use of the same drug.


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Results in death

Life threatening

Hospital admissions

Disability&Incapacity

Congenital anomaly or birth defect


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Type A:Augmented

Type B:Bizarre reaction


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ADRs can occur as an result of variability

of either the pharmacokinetic orpharmacodynamic properties of thedrug.


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Geneticfactors

P.kinetic

P.dynamic

ADRs

Environmental factors


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Gene symbol title drug ADR

BCHE,CHE1 Butyrylcholineesterase

SCH Prolongedapnoea

CYP2C9 Cytp450 2c9 Warfarin Bleeding

CYP1A2 Cyt450 1a2 Phenacetin hypersensitivity

CYP2D6 Cytp4502d6 Codeine Increasedrespiratorypsychomotorand pupillaryeffects

GSTM1&GSTT1 Glutathione stransferase Tacrine transaminitis

GSTM1 glutathione stransferase

Cisplatin ototoxicity

GSTM1&GSTT1 Glutathione s

transferase

Troglitazone hepatotoxicity


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Gene symbol Name Drug ADR

HERG Voltage gatedK+

channels

ErythromycinCisapride

ClarithromycinLQTS

Torsa de pointes

RYR1 Ryanodinereceptor

Halothane Malignanthyperthermia

OPRM1 Mu Opioidreceptor

Morphine Addiction

G6PDG6P

dehydrogenase Primaquine

Sulfonamides

Hemolytic

anemia


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Eg:

1.association of CYP2C9 polymorphism

with Warfarin dose requirement and therisk of bleeding.

2.slow acetylation has been associated

with number of adverse effects. Sulfasalazinevomiting.

Isoniazidneuropathy.


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Eg: phenacetin, an analgesicwithdrawn from UK because of its

potential to cause-Nephrotoxicity

-Carcinogenicity

-Methhemoglobinemia.


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This is liable to be important when the drugitself is inactive but has an active metabolite

responsible for its pharmacological andtoxicological activities.

codeine CYP2D6 morphine


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Idiosyncratic drug toxicity is thought to becaused not by the parent drug but by its

toxic metabolite by a process termedBIOACTIVATION.

Such toxic metabolites can be readilydetoxified in the majority of individuals by aprocess called BIOINACTIVATION.

Eg: sulfamethoxazole cyp2c9 hydroxylamine


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Bioinactivation of toxic metabolites can benon enzymatic and enzymatic(glutathiones transferase).

Eg:

Cisplatinototoxicity

Tacrinetransaminitis

Troglitazonehepatotoxicity


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Transport proteins that actively mediatethe influx and efflux of drugs across cell

membranes have an important role inregulating the absorption distributionand excretion of many medicines.

Polymorphisms have been described in

many of the genes encoding for theseproteins.


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Efflux pump may mediate toxicity via thefollowing possible pathways-

Reduced activity of efflux pump

Reduced renal and biliary excretion

Increased oral bioavailability


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Reduced activity at the level of cell membrane

Increased intracellular levels

Increased toxicity of drugs


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ADRs associated with polymorphism inMDR1 gene.

Eg:-Tacrolimus- Neurotoxicity

-Cyclosporine- Cyclosporine toxicity


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Ex:1 Use ofAbacavirProduces hypersensitivityreaction , HLA associated are B-5701,DR-7,DQ-3.

2.CBZ produces Steven-johnson syndrome

and toxic epidermal necrolysis, associated withhaplotype TNF2-DR3-DQ2.

3.Clozapine induced agranulocytosisassociated with HLA haplotypes DRB1-0402,0302and DQA1-0301.


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Ex: 1.Clozapine induced weight gain associatedwith genes encoding 5-HT2C,3.

2.Clozapine induced tardive dyskinesia

associated with genes encoding dopaminergicreceptors.

3.Halothane induced malignanthyperthermia is due to mutation in ryanodinereceptor gene.


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Drug induced long QT interval (LQT):

Mutations in genes coding for cardiac

K+

and Na+

channels may cause LQTS. Oral contraceptive induced venous

thrombo embolism :

Mutations in coagulation factor V andprothrombin genes are known to be riskfactors for venous thromboembolism.


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Methotrexate induced toxicity:

Genetic variability in methylenetetrahydrofolate reductase(MTHFR)has been found to be associated withhigher riskof developing adversereactions with MTX.


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ACE inhibitor induced cough:

Polymorphism in ACE and bradykinin B2receptor genes.


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Aithal, G.P., Day, C.P., Kesteven, P.J., and Daly, A.K.Association of polymorphisms in the cytochrome P450 CYP2C9with warfarin dose requirement and risk of bleedingcomplications. Lancet,1999,353:717-719.

Alving, A.S., Carson, P.E., Flanagan, C.L., and Ickes, C.E.Enzymatic deficiency in primaquine-sensitive erythrocytes.Science,1956,124:484-485.

Arranz, M.J., Munro, J., Birkett, J., et al. Pharmacogeneticprediction of clozapine response [letter].Lancet,2000,355:1615-1616.

Ana Alfirevic, B.kevin park,Pharmacogenetics of ADRs,Clinicalpractice and Pharmacogenetics.

Goodman &Gilmans,Pharmacological basis oftherapeutics,11th edition.


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Pharmacogenetics of Adverse Drug Reactions

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