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

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

Dose
Timing
Susceptibility

DoTS
Classification

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

Augmentation of known
actions

Example
-blocker-induced
bradycardia

Secondary pharmacology

Often involves different organ

system, but rationalisable
from the known pharmacology
Example
-blocker-induced
bronchospasm

Pharmacologically Predictable ADRs

Type
Pharmaceutical

Example
Phenytoin

Pharmacokinetic (can
involve absorption,
distribution,
metabolism and
excretion)
Pharmacodynamic

Digoxin

Indomethacin

Genetic

Nortriptyline

Drug-drug interactions
(can involve any of the
above processes)

Lithiumnonsteroidal
antiinflammatory
drugs

Toxicity
Phenytoin toxicity
(ataxia,
nystagmus, etc)
Digoxin toxicity
(nausea,
arrhythmias, etc)

Mechanism
Increase in bioavailability as a
result of a change in
formulation
Decreased elimination if renal
function is impaired

Left ventricular
failure
Confusion

Water and sodium retention

Lithium toxicity

Reduced hepatic elimination as

a result of a deficiency of
CYP2D6
Inhibition of excretion of
lithium

Mechanism of Terfenadine Cardiotoxicity

TERFENADINE

PHARMACODYNAMIC

CARDIAC
DISEASE

P450

Carboxylic acid
metabolite

PHARMACOKINETIC

LIVER KETOCONAZOLE
OVERDOSE
DISEASE ERYTHROMYCIN

EFFECT OF
TERFENADINE

TERFENADINE
PLASMA
CONCENTRATION

Prolonged
Q-T interval

Torsade de Pointes
DEATH

ANTIHISTAMINE
ACTIONS

Warfarin

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:

Approved for human use in 1954

Variation in Dose Requirements

10

20

30

INR
Incidence Rate
<2
4.11
2.1-3.0
3.78

3.1-4.0
>4.1

Frequency

40

50

UK prospective cohort data

10

Stable dose (mg/day)

12

15.78
99.26

14

Hylek et al, 2007

Cotting factors
II, VII, IX, X
O

Carboxylase
CH3
O

OH

epoxidase
OH

O
CH 3

Warfarin

CH 3
O

R
OH

R
O

VKORC1

R
CYP1A2
CYP3A4

S
CYP2C9
Vitamin K

Warfarin

Metabolites

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
Lithium carbonate 1.2 g
Bendrofluazide, 5 mg
Serum lithium concentration (mmol/litre)

2.5
Confused Anorexic

1.5
1.3 mmol/litre
1

Target range
0.5
Manic
5

10
15
Time (weeks)

0.3 mmol/litre
20

Drug Metabolism and Adverse Drug

Reactions

Physiolgical, Pharmacological and Toxicological

aspects of metabolism of xenobiotics and endobiotics
Cellular
accumulation

DRUG

Phase I/II/III

Stable
metabolites

bioactivation

Toxic
metabolites
bioinactivation

Excretion

Chemical
Stress
Modification of:
Nucleic acid
enzyme,
transporter,
signalling protein,
receptor,
random autologous
protein

Response

Cell Damage

Cell Death

Carcinogenicity

Hypersensitivity

Acetaminophen (paracetamol)

Recommended dose - 4g. Toxic dose >4g

Detoxication

Most common form DILI in US & UK

Centrilobular damage
Concern over chronic administration
Limit pack size

Treatment with N-acetylcysteine

Bioactivation

Overdose
GSH

Cannot design out toxicity

COVALENT BINDING TOXICITY

GLUCURONIDE
SULPHATE

Mechanism of Nrf2-regulated Gene Induction

Nrf2

Nrf2

GSH depletion
Adduct formation
Protein oxidation

Nrf2
Keap1

Antioxidant
response element

Cell defence genes

Glutamate Cysteine Ligase

Glutathione transferases
NAD(P)H quinone oxidoreductase
Haem oxygenase
Glucuronyl transferase
Catalase

Proteasomal
proteolysis

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

Immune-Mediated Adverse Drug

Reactions

Delayed Hypersensitivity Cutaneous Reactions

Toxic
Epidermal
Necrolysis

Rarity

StevensJohnson
Syndrome

Mortality

Hypersensitivity
syndrome

Severity

Maculopapular
exanthem

Stimulation of Nave T-cells

TCR
MHC II

Dendritic
cell

T cell

Drug
Co-stimulation
CD40, CD80 / CD86

Signal 1 MHC-restricted antigen

Signal 2 Co-stimulation
Curtsinger et al., 1999, 2003

Stimulation of Nave T-cells

Innate response
Il-1 / Il-12
TCR
MHC II

Dendritic
cell

T cell

Drug
Co-stimulation
CD40, CD80 / CD86

Signal 1 MHC-restricted antigen

Signal 2 Co-stimulation
Signal 3 Innate response
Curtsinger et al., 1999, 2003

Stimulation of Nave T-cells

Innate response
Il-1 / Il-12
TCR
MHC II

Dendritic
cell

CD4

T cell

Drug

CD8

Co-stimulation
CD40, CD80 / CD86
Type 1

Signal 1 MHC-restricted antigen

Signal 2 Co-stimulation
Signal 3 Innate response

Type 2

Tissue damage
in skin

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 genotype

Association with
HLA-B*5701

Causal chemical

Clinical phenotype

H
N

Stimulation index

Patient 1
60
50
40
30
20
10
0

N
H2N

CHO

0 0.5 1

2.5 5

10

Immunological phenotype

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

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
HLA-A*3101
Allopurinol
HLA-B*5801

Reference

SJS/TEN (Han Chinese)

Various phenotypes
SCAR

DILI and HLA Allele Association

Drug

HLA association

Allele frequency in cohort Homozyg Heterozyg

Flucloxacillin

B*5701

0.035

25

Ximelagatran

DRB1*0701

0.145

10

91

Lumiracoxib

DRB1 *1501

0.017

13

Co-amoxiclav

DRB1 *1501

0.156

10

100

Ticlopidine

A*3303

0.013

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