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

Adverse drug reactions (ADRs) represent a major public health problem 6.7%of hospitalized patients develop severe 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 estimated to be more than 76billion$

4% of drugs marketed in UK over a 20 year period were withdrawn because of safety issues Many factors contribute to the occurrence of ADRs. those are -Environmental factors - Genetic factors Significant proportions of ADRs may occur because of genetic predisposition(genetic factors.

Certain enzymes metabolise 5 to 25% of all prescribed drugs respectively but in ADRs they metabolize 38 to 75% of drugs

PYTHAGORAS in 510bc,southern Italy reported that ingestion of fava beans can lead to red cell hemolysis in some individuals but not all The same was observed with Primaquine administration in 1956 because of G6PD deficiency. Another classical example reported in 1950 was the occurrence of prolonged apnoea after treatment with Suxamethonium in pts with deficiency of butyrylcholinesterase.

The first ADRs with a P450 polymorphism was the occurrence of hypotension with Debrisoquine led to discovery of CYP2D6. Genes other than those coding for proteins involved in drug disposition may also predispose to ADRs. HLA has been a focus of interest for many years, eg: Hydralazine induced lupus in patients who are HLA-DR4 positive. Individuals who are slow acetylators and HLADR4 positive have a higher risk than those with one risk factor only.

A noxious change which is suspected to be due to a drug, occurs at doses normally used in man, requires treatment or decrease in dose of indicates caution in the future use of the same drug.

Results in death Life threatening Hospital admissions Disability&Incapacity Congenital anomaly or birth defect

 Type

A:Augmented

Type

B:Bizarre reaction

ADRs can occur as an result of variability of either the pharmacokinetic or pharmacodynamic properties of the drug.

Genetic factors

P. kinetic
ADRs Environment al factors

P. dynamic

Gene symbol BCHE,CHE1

title Butyrylcholine esterase

drug SCH

ADR Prolonged apnoea

CYP2C9
CYP1A2 CYP2D6

Cytp450 2c9
Cyt450 1a2 Cytp4502d6

Warfarin
Phenacetin Codeine

Bleeding
hypersensitivity Increased respiratory psychomotor and pupillary effects

GSTM1&GSTT1
GSTM1 GSTM1&GSTT1

Glutathione s transferase
glutathione s transferase Glutathione s transferase

Tacrine
Cisplatin Troglitazone

transaminitis
ototoxicity hepatotoxicity

Gene symbol

Name

Drug Erythromycin Cisapride Clarithromycin

ADR

HERG

Voltage gated K+ channels Ryanodine receptor Mu Opioid receptor G6P dehydrogenase

LQTS Torsa de pointes

RYR1

Halothane

Malignant hyperthermia Addiction

OPRM1

Morphine

G6PD

Primaquine Hemolytic Sulfonamides anemia

Eg: 1.association of CYP2C9 polymorphism with Warfarin dose requirement and the risk of bleeding. 2.slow acetylation has been associated with number of adverse effects. Sulfasalazine vomiting. Isoniazidneuropathy.

 Eg:

phenacetin, an analgesic withdrawn from UK because of its potential to cause -Nephrotoxicity -Carcinogenicity -Methhemoglobinemia.

This is liable to be important when the drug itself is inactive but has an active metabolite responsible for its pharmacological and toxicological activities.

codeine

CYP2D6

morphine

Idiosyncratic drug toxicity is thought to be caused not by the parent drug but by its toxic metabolite by a process termed BIOACTIVATION. Such toxic metabolites can be readily detoxified in the majority of individuals by a process called BIOINACTIVATION.

Eg: sulfamethoxazole

cyp2c9

hydroxylamine

Bioinactivation of toxic metabolites can be non enzymatic and enzymatic(glutathione s transferase). Eg: Cisplatinototoxicity Tacrinetransaminitis Troglitazone hepatotoxicity

Transport proteins that actively mediate the influx and efflux of drugs across cell membranes have an important role in regulating the absorption distribution and excretion of many medicines. Polymorphisms have been described in many of the genes encoding for these proteins.

Efflux pump may mediate toxicity via the following possible pathways-

Reduced activity of efflux pump

Reduced renal and biliary excretion

Increased oral bioavailability

Reduced activity at the level of cell membrane

Increased intracellular levels

Increased toxicity of drugs

ADRs associated with polymorphism in MDR1 gene. Eg: -Tacrolimus- Neurotoxicity

-Cyclosporine- Cyclosporine toxicity

Ex:1 Use of Abacavir Produces hypersensitivity reaction , HLA associated are B-5701,DR-7,DQ-3. 2. CBZ produces Steven-johnson syndrome and toxic epidermal necrolysis, associated with haplotype TNF2-DR3-DQ2. 3.Clozapine induced agranulocytosis associated with HLA haplotypes DRB1-0402,0302 and DQA1-0301.

Ex: 1.Clozapine induced weight gain associated with genes encoding 5-HT2C,3. 2. Clozapine induced tardive dyskinesia associated with genes encoding dopaminergic receptors. 3.Halothane induced malignant hyperthermia is due to mutation in ryanodine receptor gene.

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 and prothrombin genes are known to be risk factors for venous thromboembolism.

Methotrexate induced toxicity: Genetic variability in methyl enetetrahydrofolate reductase(MTHFR) has been found to be associated with higher riskof developing adverse reactions with MTX.

ACE inhibitor induced cough: Polymorphism in ACE and bradykinin B2 receptor genes.

Aithal, G.P., Day, C.P., Kesteven, P.J., and Daly, A.K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. 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. Pharmacogenetic prediction of clozapine response [letter]. Lancet, 2000, 355:1615-1616. Ana Alfirevic, B.kevin park,Pharmacogenetics of ADRs,Clinical practice and Pharmacogenetics. Goodman &Gilmans,Pharmacological basis of therapeutics,11th edition.