Adverse Drug Reactions:

Classification and Mechanisms

Munir Pirmohamed NHS Chair of Pharmacogenetics

Department of Molecular and Clinical Pharmacology

Institute of Translational Medicine

University of Liverpool

Definitions

WHO definition

any undesirable effect of a drug beyond its anticipated therapeutic effects occurring during clinical use.

Edwards and Aronson, Lancet, 2000; 356(9237):1255-9

an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product

Definition

New EU Pharmacovigilance Legislation ( DIRECTIVE 2010/84/EU; 15 Dec 2010)

the definition of the term ‘adverse reaction’ should be amended to ensure that it covers noxious and unintended effects resulting not only from the authorised use of a medicinal product at normal doses, but also from medication errors and uses outside the terms of the marketing authorisation, including the misuse and abuse of the medicinal product.

Many Different Classifications of Adverse Drug Reactions

ABCDE classification

Type A: Predictable, acute, related to mechanism of action

Type B: Idiosyncratic, unpredictable, acute / sub-acute, not related to

known mechanism

Type C: Consequence of cumulative effect of long-term therapy

Type D: Delayed, caused by teratogenic or carcinogenic mechanisms

Type E: End of dose (withdrawal) reactions

Dose Timing Susceptibility

DoTS Classification

BMJ. 2003 Nov 22;327(7425):1222-5

The Burden of Adverse Drug Reactions

Admission

(6.5%)

In patients

(14.7%)

Emergency Room

(2.5%)

Primary Care

(25%)

Dose-Response Curve

• External dose • Internal dose

• Parent drug • Metabolites

Adverse

drug reaction

Primary pharmacology Secondary pharmacology

Augmentation of known actions

Often involves different organ system, but rationalisable

from the known pharmacology

Example

-blocker-induced bradycardia

-blocker-induced bronchospasm

Example

Type Example Toxicity Mechanism

Pharmaceutical Phenytoin Phenytoin toxicity (ataxia,

nystagmus, etc)

Increase in bioavailability as a result of a change in

formulation

Pharmacokinetic (can involve absorption,

distribution, metabolism and

excretion)

Digoxin Digoxin toxicity (nausea,

arrhythmias, etc)

Decreased elimination if renal function is impaired

Pharmacodynamic Indomethacin Left ventricular failure

Water and sodium retention

Genetic Nortriptyline Confusion Reduced hepatic elimination as a result of a deficiency of

CYP2D6

Drug-drug interactions (can involve any of the

above processes)

Lithium-nonsteroidal

anti-inflammatory

drugs

Lithium toxicity Inhibition of excretion of lithium

Pharmacologically Predictable ADRs

Mechanism of Terfenadine Cardiotoxicity

TERFENADINE

CARDIAC

DISEASE

Carboxylic acid metabolite

ANTIHISTAMINE ACTIONS

P450

LIVER

DISEASE

KETOCONAZOLE

ERYTHROMYCIN OVERDOSE

Prolonged Q-T interval

Torsade de Pointes

DEATH

PHARMACOKINETIC PHARMACODYNAMIC

TERFENADINE

PLASMA

CONCENTRATION

EFFECT OF

TERFENADINE

Number of users UK:

600,000

Dose (mg) range per day:

0.5-20

Fold variability in dose:

40

Major bleeding rate per 100-person years:

2.6

Ranking in ADR list:

3

Warfarin

Approved for human use in 1954

Variation in Dose Requirements

Stable dose (mg/day)

Freq

uen

cy

0 2 4 6 8 10 12 14

0

10

2

0

30

4

0

50

INR Incidence Rate

<2 4.11

2.1-3.0 3.78

3.1-4.0 15.78

>4.1 99.26

UK prospective cohort data

Hylek et al, 2007

OH

OH

CH3

R

O

O

CH3

R

O

VKORC1

Carboxylase

epoxidase

Warfarin

O

CH3

O

O

OH

R CYP1A2 CYP3A4

Metabolites

Warfarin

Cotting factors II, VII, IX, X

S CYP2C9

Vitamin K

Variability in Dose Requirements: Clinical Factors

Comorbid diseases

Compliance

Concomitant medications

Nutritional status

Gender

BMI

Age

Determinants of Anticoagulation Control

McLeod and Jonas, 2009

Dabigatran Warnings

Warnings about bleeding risk issued by Japan, Australia, New Zealand, US and EU

Renal Clearance

Important determinant of systemic exposure for (mostly) hydrophilic drugs

Affected by

Age

Disease

Genetic Factors

Drug-drug interactions

Effect of bendrofluazide administration on lithium levels in a 54 year old woman with a recurrent bipolar affective disorder

0.5

1

1.5

2

2.5

5 10 15 20

1.3 mmol/litre

Target range

0.3 mmol/litre

Time (weeks)

Confused Anorexic

Seru

m li

thiu

m c

on

cen

trat

ion

(m

mo

l/lit

re)

Bendrofluazide, 5 mg

Lithium carbonate 1.2 g

Manic

Drug Metabolism and Adverse Drug Reactions

DRUG Cellular

accumulation Response

Cell Damage

Cell Death

Carcinogenicity

Hypersensitivity

Toxic metabolites

Stable metabolites

Excretion

Phase I/II/III Chemical Stress Modification of: Nucleic acid enzyme, transporter, signalling protein, receptor, random autologous protein

bioactivation

bioinactivation

Physiolgical, Pharmacological and Toxicological aspects of metabolism of xenobiotics and endobiotics

Bioactivation

DetoxicationGLUCURONIDE

SULPHATE

GSH

COVALENT BINDING TOXICITY

Overdose

• Recommended dose - 4g. Toxic dose >4g

• Most common form DILI in US & UK

• Centrilobular damage

• Concern over chronic administration

• Limit pack size

• Treatment with N-acetylcysteine

• Cannot design out toxicity

Acetaminophen (paracetamol)

Mechanism of Nrf2-regulated Gene Induction

Proteasomal proteolysis

Antioxidant response element

Cell defence genes

GSH depletion Adduct formation Protein oxidation

Keap1

Nrf2

Nrf2

Nrf2

Glutamate Cysteine Ligase

Glutathione transferases NAD(P)H quinone oxidoreductase

Haem oxygenase Glucuronyl transferase

Catalase

Goldring et al Hepatology 2004; Copple et al Hepatology 2008; Reisman et al, 2009

Immune-Mediated Adverse Drug Reactions

Delayed Hypersensitivity Cutaneous Reactions

Maculopapular exanthem

Hypersensitivity syndrome

Stevens-Johnson

Syndrome

Toxic Epidermal Necrolysis

Seve

rity

Mo

rtal

ity

Rar

ity

Drug Dendritic cell

T cell

MHC II

TCR

Signal 1 – MHC-restricted antigen Signal 2 – Co-stimulation

Curtsinger et al., 1999, 2003

Stimulation of Naïve T-cells

Co-stimulation CD40, CD80 / CD86

Innate response

Il-1 / Il-12

Drug Dendritic cell

T cell

MHC II

TCR

Signal 1 – MHC-restricted antigen Signal 2 – Co-stimulation Signal 3 – Innate response

Stimulation of Naïve T-cells

Co-stimulation CD40, CD80 / CD86

Curtsinger et al., 1999, 2003

Type 1

Tissue damage in skin

CD4

CD8

Type 2

Innate response

Il-1 / Il-12

Drug Dendritic cell

T cell

MHC II

TCR

Signal 1 – MHC-restricted antigen Signal 2 – Co-stimulation Signal 3 – Innate response

Stimulation of Naïve T-cells

Co-stimulation CD40, CD80 / CD86

Curtsinger et al., 1999, 2003

MHC Region on Short Arm of Chromosome 6

3.6Mb on 6p21.3

150 genes, many of involved in autoimmune and inflammatory disorders

>40% involved in immune system and T-lymphocyte signalling

Many genes with unknown functions

Drug Hypersensitivity: From Bedside to Laboratory and Back to Clinic

Clinical phenotype

0

10

20

30

40

50

60

0 0.5 1 2.5 5 10

Patient 1

Stim

ula

tio

n in

dex

Immunological phenotype

Causal chemical

Association with HLA-B*5701

Clinical genotype

N

N

NH

N

NNH2

CHO

Positive patch test

Effect of Introduction of HLA-B*5701 Genotyping on Abacavir Hypersensitivity

Incidence before and after testing for HLA-B*5701

Country Pre testing Post testing Reference

Australia 7% <1% Rauch et al, 2006

France 12% 0% Zucman et al, 2007

UK (London) 7.8% 2% Waters et al, 2007

Other HLA associations Carbamazepine HLA-B*1502 SJS/TEN (Han Chinese) HLA-A*3101 Various phenotypes Allopurinol HLA-B*5801 SCAR

DILI and HLA Allele Association

Drug HLA association Allele frequency in cohort Homozyg Heterozyg

Flucloxacillin B*5701 0.035 1 25

Ximelagatran DRB1*0701 0.145 10 91

Lumiracoxib DRB1 *1501 0.017 0 13

Co-amoxiclav DRB1 *1501 0.156 10 100

Ticlopidine A*3303 0.013 1 8

Diclofenac DRB1*15 0.156 10 100

Kindmark et al., 2008; Daly et al., 2009; Donaldson et al., 2010; Kamali et al., 2009; Hirata et al., 2008; Singer, 2010

Summary

Adverse drug reactions common

Many different mechanisms – most of these are complex and involve different parameters

Interaction between drug, host and environment a factor in mechanism

Interventions to overcome ADRs therefore likely to be complex