Mechanisms and classification of adverse drug reactions
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Mechanisms and Classification of Adverse Drug Reactions. Professor Phil Routledge Department of Pharmacology, Therapeutics and Toxicology, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University April 2012.

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Mechanisms and classification of adverse drug reactions

Mechanisms and Classification of Adverse Drug Reactions

Professor Phil Routledge

Department of Pharmacology, Therapeutics and Toxicology, Institute of Molecular and Experimental Medicine, School of Medicine,

Cardiff University

April 2012


Mechanisms and classification of adverse drug reactions

INCIDENCE OF ADVERSE DRUG REACTIONS IN HOSPITALISED PATIENTS

  • 39 prospective studies from US hospitals

  • Incidence of serious ADRs was 6.7% (CI 5.2-8.2)

  • Incidence of fatal ADRs 0.32% (CI 0.23-0.41)

  • Between 4th and 6th leading cause of death

Lazarou J et al. JAMA 1998; 279: 1200-1205


Mechanisms and classification of adverse drug reactions

CAUSES OF DEATH IN THE USA 1994

1. Heart disease

2. Cancer

3. Stroke

4. Pulmonary disease

5.ADVERSE DRUG REACTIONS

6Road traffic accidents

Lazarou J et al. JAMA 1998; 279: 1200-1205


Mechanisms and classification of adverse drug reactions

Deaths in England and Wales from medication errors and adverse effects of medicines (1990 to 2000)

from “A Spoonful of sugar: medicines management in NHS hospitals” Audit Commission 2001


Adr workshop

ADR WORKSHOP

  • HOW WOULD YOU EXPLAIN THE SYMPTOM/SIGN COMPLEX?

  • COULD THEY BE RELATED TO ANY OF THE MEDICINES LISTED?

  • IF SO, ARE THEY LIKELY TO BE TYPE A OR TYPE B ADRs?

  • IF SO, WHAT IS THE LIKELY MECHANISM (Pharmaceutical, pharmacokinetic or pharmacodynamic)

  • ARE THERE ANY POSSIBLE GENETIC FACTORS?

  • WHAT WOULD YOU DO FOR THE PATIENT?


Mechanisms and classification of adverse drug reactions

CARD 1

( For advice on reporting reactions see

IN CONFIDENCE__COMMITTEE ON SAFETY OF MEDICINES

Adverse Reactions to Drugs

section of BNF )

REPORT ON SUSPECTED ADVERSE REACTIONS

Bloggs

Josephine

PATIENT'S DETAILS

OTHER NAMES

SURNAME

59 yrs

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental.

DATE OF BIRTH ( OR AGE )

75 kg

F

WEIGHT ( kg )

SEX :

M

Hospital if relevant

Consultant in charge/GP Principal

Hospital number

SUSPECTED DRUG ( Give brand name of drug and batch number if

ROUTE

DAILY DOSE

known)

Prosthetic

Continuing

DATE STOPPED

DATE STARTED

THERAPEUTIC INDICATION

mitral valve

SUSPECTED REACTIONS

REPORTING DOCTOR

Name

Continuing

Address

DATE REACTION STARTED

DATE REACTION ENDED

OUTCOME ( e.g. fatal, recovered, continuing )

SEND TO CSM, FREEPOST, LONDON SW8 5BR

Telephone

Speciality

OR if you are in one of the following NHS regions:

Signature

Date

TO CSM Mersey, FREEPOST, Liverpool L3 3AB

If you would like information about

OR CSM West Midlands, FREEPOST, Birmingham B15 1BR

other reports associated with the

OR CSM Northern, FREEPOST 1085, Newcastle upon Tyne NE1 1BR

suspected drug, tick here

PTO

OR CSM Wales, FREEPOST, Cardiff CF4 1ZZ

DATE DRUG

THERAPEUTIC

OTHER DRUGS

ROUTE

DATE DRUG

DAILY DOSE

STARTED

TAKEN IN THE LAST

STOPPED

INDICATION

3 MONTHS INCLUDING

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental.

SELF-MEDICATION

Give brand name if

known

none

Write

if no other

drug has been taken

Heart

Continuing

Failure

Additional information including medical history, investigations, known allergies, suspected

drug interactions relevant to the reaction and LMP for drugs taken during pregnancy.

Patient previously well-controlled on 5 mg warfarin

  • HOW WOULD YOU EXPLAIN THE SYMPTOM/SIGN COMPLEX?

  • COULD THEY BE RELATED TO ANY OF THE MEDICINES LISTED?

  • IF SO, ARE THEY LIKELY TO BE TYPE A OR TYPE B ADRs?

  • IF SO, WHAT IS THE LIKELY MECHANISM (Pharmaceutical, pharmacokinetic or pharmacodynamic)

  • ARE THERE ANY POSSIBLE GENETIC FACTORS?

  • WHAT WOULD YOU DO FOR THE PATIENT?

Chest pain ? AMI


Mechanisms and classification of adverse drug reactions

Routledge PA, Harris W, Mathew S and Monypenny IJ. Retromammary haemorrhage and warfarin therapy. Postgrad Med J. 74: 347-8 (1998)


Mechanisms and classification of adverse drug reactions

70% of ADRs.Predictable and therefore often avoidable

CLASSIFICATION OF ADRSType A versus Type B ADRs


Mechanisms and classification of adverse drug reactions

Philippus Aureolus Theophrastus Bombastus von Hohenheim 1538

All substances are poisons;

there is none which is not a

poison. The right dose

differentiates a poison from

a remedy.


Mechanisms and classification of adverse drug reactions

Adverse drug reactions as cause of admission to hospital

  • 18,820 patients admitted oversix months to a Liverpool Hospital and assessed for cause of admission

  • prevalence 6.5%, with ADR directly leading to the admissionin 80% of cases

  • Overall fatality was 0.15%

  • Most reactions were either definitelyor possibly avoidable(Type A ADRs)

  • Drugs most commonly implicated in causingthese admissions included low dose aspirin, diuretics, warfarin,and non-steroidal anti-inflammatory drugs other than aspirin,the most common reaction being gastrointestinal bleeding

Pirmohamed M et al. BMJ 2004;329:15-19


Mechanisms and classification of adverse drug reactions

A more complicated classification


Mechanisms and classification of adverse drug reactions

EIDOS: a mechanistic classification

DoTS: a clinical

pharmacological classification

Drug

Dose-relatedness

Drug

Extrinsic

Distribution

Patient

Adverse reaction

Intrinsic

Outcome

Patient

Adverse reaction

Susceptibility factors

Time-course

Classifying adverse drug reactions: two complementary systems

Ferner & Aronson. Drug Saf 2010;33:13-23

Aronson & Ferner. BMJ 2003;327:1222-5


Mechanisms and classification of adverse drug reactions

Mechanisms of Type A adverse drug reactions

  • Pharmaceutical

    • parent compound

    • excipients

  • Pharmacokinetic

    • metabolism

    • excretion

  • Pharmacodynamic

What the body does to the drug

What the drug does to the body

Routledge PA. "Adverse Drug Reaction and Interactions: Mechanisms, Risk Factors, Detection, Management and Prevention" in Stephen's Detection of New Adverse Drug Reactions Talbot, John / Waller, Patrick (eds.) John Wiley and Sons (2004)


Mechanisms and classification of adverse drug reactions

RISK FACTORS FOR ANTICOAGULANT

ASSOCIATED BLEEDING


Mechanisms and classification of adverse drug reactions

Audit of anticoagulant therapy and acute hospital admissions

  • St Mary’s Hospital London: over 3 months 1480 acute admissions, 112 (7.6%) on anticoagulant therapy

  • 74 had INRs in normal range

  • 29 over-anticoagulated, of which 17 (59%) admitted with bleeding symptoms

  • Reasons for over coagulation were:

    • Poor patient compliance (31%)

    • Influence of other medications (17%)

    • Congestive heart failure (28%)

    • Unknown (24%)

  • Overall 1.5% of all hospital admissions were due to warfarin complications and 16/21 patients with bleeding had INRs > 4.5

Hirri & Green, Clin Lab Haematol 2002; 1: 43-45


Mechanisms and classification of adverse drug reactions

CARD 2

CA

80kg

70

12345

Co-Amoxiclav (Augmentin)

po

750 mg

1/04/95

9/04/95

Diverticulitis

JAUNDICE

16/05/95

17/11/95

Metoclopramide

po 10mg 1/04/95 1/04/95 Nausea

Se. Bilirubin 94 umol/l, Alk Phos 324 iu/l, AST 228 iu/l, Gamma GT 276 iu/l. Ultrasound showed no abnormality.

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental.

  • HOW WOULD YOU EXPLAIN THE SYMPTOM/SIGN COMPLEX?

  • COULD THEY BE RELATED TO ANY OF THE MEDICINES LISTED?

  • IF SO, ARE THEY LIKELY TO BE TYPE A OR TYPE B ADRs?

  • IF SO, WHAT IS THE LIKELY MECHANISM (Pharmaceutical, pharmacokinetic or pharmacodynamic)

  • ARE THERE ANY POSSIBLE GENETIC FACTORS?

  • WHAT WOULD YOU DO FOR THE PATIENT?

Kombucha tea po 2 cups Nov 94 Cont. Arthritis

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental.

24/11/95


Mechanisms and classification of adverse drug reactions

JAUNDICE AND CO-AMOXICLAV

  • Type B ADR, reporting rate 1 in 56,000 scripts in 1991

  • Clavulanate likely causative agent

  • 50 % reports concern patients aged > 60y 70% of reactions occurred after stopping drug (up to 6 weeks’ delay)

    • Current Problems in Pharmacoviilance19:2 (1993)

Smith PM, Wilton A, Routledge PA. European Journal of Gastroenterology & Hepatology 1991;3:95-96.


Mechanisms and classification of adverse drug reactions

DRUG INDUCED LIVER INJURY (DILI)

DRUG ASSOCIATED LIVER INJURY (DALI?)

  • Amoxicillin-clavulanate

  • Ebrotidine

  • INH + RIP +PIZ

  • Ibuprofen

  • Flutamide

  • Ticlopidine

  • Diclofenac

  • Isoniazid

  • Medicinal herbs

  • Nimesulide

  • Amoxicillin-clavulanate (41)

  • Lofepramine (31)

  • Carbamazepine (19)

  • Diclofenac (19)

  • Azathioprine (18)

  • Ciprofloxacin (17)

  • Flucloxacillin (16)

  • Chlorpromazine (14)

  • Fusidic acid (13)

  • Amiodarone (12)

Andrade RJ et al. Drug-Induced Liver Injury: An Analysis of 461 Incidences Submitted to the Spanish Registry Over a 10-Year Period . Gastroenterology 2005; 129: 512-521

CVS Krishna, personal communication.


Mechanisms and classification of adverse drug reactions

30% of ADRs.Less predictable and therefore often unavoidable

CLASSIFICATION OF ADRSType A versus Type B ADRs


Mechanisms and classification of adverse drug reactions

Mechanisms of Type B adverse drug reactions

  • Allergic

  • Pseudoallergic

  • Pharmacogenetic susceptibility

Routledge PA. "Adverse Drug Reaction and Interactions: Mechanisms, Risk Factors, Detection, Management and Prevention" in Stephen's Detection of New Adverse Drug Reactions Talbot, John / Waller, Patrick (eds.) John Wiley and Sons (2004)


Mechanisms and classification of adverse drug reactions

http://www-immuno.path.cam.ac.uk/~immuno/part1/lec13/lec13_97.html


Mechanisms and classification of adverse drug reactions

Human leucocyte antigen class II genotype in susceptibility & resistance to co-amoxiclav-induced liver injury

  • In 61 cases of co-amoxiclav-associated DILI, HLA-DRB1*15 was increased in patients (53%) versus both treated (33%: OR=2.29: 95% CI: 1.00-5.26) and population controls (30%: OR=2.59:95% CI: 1.44-4.68: p=0.002)

  • DRB1*07 reduced in patients (9.8%) compared to both treated (35%: OR=0.18: 95% CI: 0.06-0.52: p=0.0011, pc=0.0154) and population controls (29%: OR=0.266: 95% CI: 0.11-0.65: p=0.0019, pc=0.0266).

  • Results confirm the previously reported significant genetic risk for HLA-DRB1*15 and also provide evidence of a protective effect of the HLA-DRB1*07 family of alleles

Donaldson PT et al. J Hepatol. 2010; 53:1049-53. Epub 2010 Aug 1


Mechanisms and classification of adverse drug reactions

CARD 3

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental.

DY

75

45

  • HOW WOULD YOU EXPLAIN THE SYMPTOM/SIGN COMPLEX?

  • COULD THEY BE RELATED TO ANY OF THE MEDICINES LISTED?

  • IF SO, ARE THEY LIKELY TO BE TYPE A OR TYPE B ADRs?

  • IF SO, WHAT IS THE LIKELY MECHANISM (Pharmaceutical, pharmacokinetic or pharmacodynamic)

  • ARE THERE ANY POSSIBLE GENETIC FACTORS?

  • WHAT WOULD YOU DO FOR THE PATIENT?

CLOZAPINE (Clozaril)

ORAL

450mg

12/12/02

1/02/03

SCHIZOPHRENIA

Sinus Tachycardia, Dyspnoea, fever, ST depression on ECG, eosinophilia

23/01/03

3/02/03

Lorazepam (Ativan)

oral

4mg

Nov 2000

continuing

anxiety

Patient consumes 24 units alcohol weekly

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental.

For Teaching Purposes only


Mechanisms and classification of adverse drug reactions

MYOCARDITIS AND CLOZAPINE

  • Reported from 4 countries with incidence between 5 and 100 cases per 100,000 patient-years. Fatality rate 3-30 cases per 100,000 patient-years

  • Type B reaction

  • Tachycardia (present in 25%) during first month may be premonitory sign

  • Nearly always within first 8 weeks of treatment

  • Rechallenge not warranted


Mechanisms and classification of adverse drug reactions

Clozapine-associated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993-2003.

  • 116 case reports of suspected myocarditis amongst clozapine-treated patients (c.1% treated patients).

  • Median age 30 years (SD 11.1 years) compared with 37 years from the Clozapine registry

  • Developed within median 16 days

  • Over nine-tenths prescribed clozapine 100-450 mg/day

  • 60 patients (52%) recovered

  • 12 patients (10%) died

  • Wide diversity of non-specific symptoms in afflicted patients

  • Case-control study would be suitable for investigation of baseline predictors.

Haas SJ et al. Drug Saf. 2007;30(1):47-57.


Mechanisms and classification of adverse drug reactions

left ventricular myocardium shows vacuolization (arrow), disruption of myocardial fibers (arrowheads), and widespread foci of chronic inflammatory cells consisting of lymphocytes, eosinophils, and plasma cells (H&E, orig. ×200).

Ansari A et al. Tex Heart Inst J. 2003; 30(1): 76–79


Mechanisms and classification of adverse drug reactions

Reversible Myocarditis in a Patient Receiving Clozapine

Kirpekar VC, Deshpande SM & Joshi PP

Indian Heart J 2001; 53: 779–781


Mechanisms and classification of adverse drug reactions

Drugs Known to Cause Toxic Myocarditis

Ansari A et al. Tex Heart Inst J. 2003; 30(1): 76–79.


Mechanisms and classification of adverse drug reactions

Difficulties in identifying Iatrogenic Disease

  • The body has only a limited number of response to noxious stimuli so that iatrogenic disease may resemble disease caused by other mechanisms

  • There are rarely specific haematological, biochemical or histological tests to identify iatrogenic disease

  • Evidence may therefore be only circumstantial


Mechanisms and classification of adverse drug reactions

Criteria for identifying Adverse Drug Reactions

  • Timing of event relative to drug administration (and possible withdrawal)

  • Previous evidence in literature implicating drug

  • Absence of alternative explanations for event

  • Effects of rechallenge (when warranted)


Mechanisms and classification of adverse drug reactions

Cutaneous and Ocular Reactions to Practolol

Felix RH wt al. Br Med J. 1974; 4: 321–324.


Mechanisms and classification of adverse drug reactions

PRACTOLOL

  • Company Safety database in 2100 subjects showed seven rashes (0.33%) and no eye complaints(Wiseman et al 1971)

  • However GP trial records indicated eye complaints in 20% and rash in 23% (including half of those with eye complaints)(Skegg and Doll 1977)

  • Record all adverse events in clinical trials, not just suspected adverse drug reactions(Skegg and Doll 1977)

    • Adverse event: “A particular untoward happening experienced by a patient, undesirable either generally or in the context of his/her disease”(Finney 1965)


Mechanisms and classification of adverse drug reactions

THE POPULARITY OF A MEDICINE

This drug cures everyone. It’s the best thing since sliced bread!

This drug got approved by NICE. What a nice drug

This is a promising new drug. Let’s send a story to the Daily Mail

This drug can kill! I wouldn’t give it to a dog!


Mechanisms and classification of adverse drug reactions

CARD 4

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental.

AL

55

49

  • HOW WOULD YOU EXPLAIN THE SYMPTOM/SIGN COMPLEX?

  • COULD THEY BE RELATED TO ANY OF THE MEDICINES LISTED?

  • IF SO, ARE THEY LIKELY TO BE TYPE A OR TYPE B ADRs?

  • IF SO, WHAT IS THE LIKELY MECHANISM (Pharmaceutical, pharmacokinetic or pharmacodynamic)

  • ARE THERE ANY POSSIBLE GENETIC FACTORS?

  • WHAT WOULD YOU DO FOR THE PATIENT?

PREMARIN

ORAL

1.25mg

Jan 2002

Feb 3rd 2003

Menopausal symptoms

Transient weakness Left arm and leg (lasting 12 hours)

Feb 2nd 2003

Feb 3rd 2003

Xiaoke Wan (Traditional Chinese Herbal Medicine)

One tablet

Oct. 2000

Continuing

Oral

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental.

For Teaching Purposes only


Mechanisms and classification of adverse drug reactions

US WOMENS’ HEALTH INITIATIVE

  • Randomised controlled trial for 5 years in 16,000 asymptomatic post-menopausal women (mean 63, range 50-79 y)

  • CHD increased from 30 to 37 cases per 10,000 women

  • Stroke increased from 21-29 cases per 10,000 women

  • Breast cancer increased (30-38), colorectal cancer fell (16 to 10), hip fracture fell (15 to 10) cases per 10,000 women

  • Manson JE et al. New Engl J Med 2003; 349:523-534 (CHD findings)


Mechanisms and classification of adverse drug reactions

US WOMENS’ HEALTH INITIATIVE

  • A 24% overall increase in the risk of CHD (6 more heart attacks annually per 10,000 women using E+P

  • An 81% increased risk of CHD in the first year after starting E+P

  • Women who had higher baseline low-density lipoprotein (LDL) cholesterol levels at the beginning of the study were at particularly high risk of CHD with E+P use

  • New Engl J Med 2003; 349:523-534


Mechanisms and classification of adverse drug reactions

US WOMENS’ HEALTH INITIATIVE


Mechanisms and classification of adverse drug reactions

Aspirin and bleeding into the bowel

Aspirin and bleeding into the brain

Aspirin and Reye’s Syndrome

DETECTION OF ADRs

Sensitivity of methods

Patients exposed to drug prior

to marketing ( mean=2,500 )

Clinical trials ( pre-marketing )

Spontaneous post-marketing reporting schemes

( e.g. Yellow Card reports )

1 in

1 in 100

1 in 1000

1 in 10,000

1 in 100,000

1million

Incidence of ADR


Mechanisms and classification of adverse drug reactions

Baseline Risk and Risk Reduction

  • Relative risk reduction is often more impressive than absolute risk reduction

  • The lower the event rate in the control group, the larger the difference between relative risk reduction and absolute risk reduction

Learning Tools for Evidence-Based Clinical Practice

Risk Reduction:Absolute and Relative Risk Reduction. Alexandra Barratt, Peter C. Wyer, Rose Hatala, Thomas McGinn, Antonio L. Dans, Sheri Keitz, Virginia Moyer, Gordon Guyatt

Robert Hayward (interactive version) for the Evidence-Based Medicine Teaching Tips Working Group


Mechanisms and classification of adverse drug reactions

Xiaoke/ Xiaoke-wan January 2004

In August 2003 the Agency seized a specific range of Xiaoke pills from a traditional Chinese outlet in Essex. The pills were labelled as containing glibenclamide, a prescription only medicine (POM) which can lead to a life threatening drop in blood sugar levels. Glibenclamide is an antihyperglycaemic drug which can be prescribed by qualified doctors to lower blood glucose levels in the management of diabetes. Improper use could result in coma and death. The Agency is looking into the possible illegal supply of the drug.

The New Zealand Health Ministry has also identified the presence of glibenclamide in a traditional Chinese medicine called Xiaoke-wan.


Mechanisms and classification of adverse drug reactions

CARD 5

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental

XX

60kg

70 years

  • HOW WOULD YOU EXPLAIN THE SYMPTOM/SIGN COMPLEX?

  • COULD THEY BE RELATED TO ANY OF THE MEDICINES LISTED?

  • IF SO, ARE THEY LIKELY TO BE TYPE A OR TYPE B ADRs?

  • IF SO, WHAT IS THE LIKELY MECHANISM (Pharmaceutical, pharmacokinetic or pharmacodynamic)

  • ARE THERE ANY POSSIBLE GENETIC FACTORS?

  • WHAT WOULD YOU DO FOR THE PATIENT?

Infliximab (Remicade)

Rheumatoid arthritis

IV infusion

3mg/kg x 7 doses

Sept 2001

April 2002

Weight loss, fever of unknown origin

April 2002

Continuing

Prednisolone

5mg

May 1999

Continuing

Rheumatoid arthritis

Fever of 38.5, often at night, dry cough. Weight loss 4Kg. Tuberculin skin test negative in April 2000

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental.

April 2002


Mechanisms and classification of adverse drug reactions

Increase COX2, PGE2, NO, Adhesion molecules, IL6, chemokines, collagenases and procoagulant activity

ETANERCEPT INFLIXIMAB ADALIMUMAB

ANAKINRA

IL-1

TNF-

Increases TNF-, osteoclast activation and angiogenic factors

Increases IL-1 and cell death


Mechanisms and classification of adverse drug reactions

Tuberculosis Associated with Blocking Agents Against Tumor Necrosis Factor-Alpha (California, 2002 - 2003)

Morbidity and Mortality Weekly Report (MMWR) 2004; 53: 683-686

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5330a4.htm


Mechanisms and classification of adverse drug reactions

Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report

  • Interoggated BIOBADASER, launched in February 2000 by Spanish Society of Rheumatology

  • Estimated incidence of TB associated with infliximab in RA patients was 1,893 per 100,000 in the year 2000 and 1,113 per 100,000 in the year 2001

  • After official guidelines were established for TB prevention in patients treated with biologics, only 1 new TB case registered

Gomez-Reino et al.Arthritis Rheum. 2003;48:2122-7.


Infliximab and tuberculosis

INFLIXIMAB AND TUBERCULOSIS

  • Patients should be evaluated for tuberculosis before treatment.

  • Active tuberculosis should be treated with standard treatment for at least 2 months before starting infliximab

  • Patients who have previously received adequate treatment for tuberculosis can start infliximab but should be monitored every 3 months for possible recurrence

  • In patients without active tuberculosis but who were previously not treated adequately, chemoprophylaxis should ideally be completed before starting infliximab

  • Patients should be advised to seek medical attention if symptoms suggestive of tuberculosis (e.g. persistent cough, weight loss, and fever) develop

http://www.bnf.org/bnf/


Mechanisms and classification of adverse drug reactions

CARD 6

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental

T de P

80 y

  • HOW WOULD YOU EXPLAIN THE SYMPTOM/SIGN COMPLEX?

  • COULD THEY BE RELATED TO ANY OF THE MEDICINES LISTED?

  • IF SO, ARE THEY LIKELY TO BE TYPE A OR TYPE B ADRs?

  • IF SO, WHAT IS THE LIKELY MECHANISM (Pharmaceutical, pharmacokinetic or pharmacodynamic)

  • ARE THERE ANY POSSIBLE GENETIC FACTORS?

  • WHAT WOULD YOU DO FOR THE PATIENT?

Thioridazine (Melleril)

Oral

100 mg/day

July 2001

Cont.

Agitation

Palpitations and syncope

13/12/2001

Amoxycillin (Amoxil)

Oral

500 mg/day

7/12/01

15/12/01

URTI

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental.

Rhythm strip from patient (attached)


Mechanisms and classification of adverse drug reactions

ANTIPSYCHOTICS AND SUDDEN DEATH

TORSADES DE POINTES

  • Sudden unexpected death occurs almost twice as often in populations treated with antipsychotics as in normal populations

  • There are still only 10-15 such events in 10,000 person-years of observation


Mechanisms and classification of adverse drug reactions

TORSADES DE POINTES

Torsades de Points

Torsardes de Points

Torsardes de Pointes

Torsades des Pointes

Torsades des Points

Torsardes des Pontes

Torsade de Pointes

Torsades de Point

Torsaad de Ponts

Torsades des Point


Mechanisms and classification of adverse drug reactions

QTc (corrected for heart rate) = 0.35-0.43 seconds

QT INTERVAL


Mechanisms and classification of adverse drug reactions

TORSADES DE POINTES

  • Over forty marketed drugs and an equivalent number of drugs under development have been found to block potassium channels, prolong the QT interval and induce, in some individuals, torsades de pointes

  • Its incidence can be as high as 2-3% with some drugs

    • The University of Arizona Center for Education and Research on Therapeutics

    • http://www.qtdrugs.org/index.html


Mechanisms and classification of adverse drug reactions

TORSADES DE POINTES AND ANTIPSYCHOTIC AGENTS

  • WITH RISK

  • Chlorpromazine

  • Droperidol

  • Haloperidol

  • Mesoridazine

  • Pimozide

  • Thioridazine

  • POSSIBLY

  • Clozapine

  • Quetiapine

  • Risperidone

  • (Sertindole)

  • Ziprasidone

UNLIKELY

??

http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm#


Mechanisms and classification of adverse drug reactions

SOME DRUGS ASSOCIATED WITH TORSADES DE POINTES

  • Amiodarone

  • Chlorpromazine

  • Cisapride (withdrawn)

  • Clarithromycin

  • Disopyramide

  • Domperidone

  • Droperidol (restricted)

  • Erythromycin

  • Halofantrine

  • Haloperidol

  • Methadone

  • Pentamidine

  • Pimozide

  • Procainamide

  • Quinidine

  • Sertindole (withdrawn)

  • Sotalol

  • Terfenadine (restricted)

  • Thioridazine (withdrawn)


Mechanisms and classification of adverse drug reactions

Arrhythmias and non-sedating antihistamines

No of reports/ Mill DDDs sold

WHO database 1986-96


Mechanisms and classification of adverse drug reactions

Full and Associate Member Countries of the WHO Collaborating Centre for Drug Monitoring (UPPSALA MONITORING CENTRE)


Mechanisms and classification of adverse drug reactions

CYTOCHROME P 450 ENZYMES

  • GENE FAMILY

  • Less than 40 % amino acid sequence identity

  • 1,2,3

  • SUB-FAMILY

  • 40-55 % amino acid sequence identity

  • A, B, C, D, E

  • ISOFORM

  • > 55 % amino acid sequence identity

  • 1, 2, 3, 4, 5, 6


Mechanisms and classification of adverse drug reactions

FEXOFENADINE

CYP3A4

Small intestine

TERFENADINE


Mechanisms and classification of adverse drug reactions

RISK FACTORS FOR DRUG-INDUCED QT PROLONGATION/TORSADES DE POINTES

  • Dose/concentration of offending agent(s)

  • Underlying bradycardia

  • Hypokalaemia/hypomagnesemia

  • Female gender (2 to 4 fold)

  • Recent conversion from AF to sinus rhythm

  • ?Left ventricular hypertrophy

  • Congenital long QT syndromes


Mechanisms and classification of adverse drug reactions

CYP2D6*5

CYP 2D6 POLYMORPHISM

P450 2D6 gene

Wild-type mRNA

Variant RNAs

CYP2D6*1

Ultrarapid

Extensive

Poor

-metaboliser


Mechanisms and classification of adverse drug reactions

CYP 2D6 POLYMORPHISMFrequency of poor metaboliser phenotype

African American 2 %

5-10 %

1%


Mechanisms and classification of adverse drug reactions

CYP 2D6 POLYMORPHISMFrequency of ultra-rapid metaboliser phenotype

Scandinavian 1.5 %

Spanish 7 %

Ethiopian 20 %


Mechanisms and classification of adverse drug reactions

TORSADES DE POINTES

  • First affected family reported in 1957

  • Clinical syndromes include the Romano-Ward and Jervell Lange-Neilsen syndromes

  • Brugada syndrome important cause of sudden death in South-East Asia and is caused by mutation in a sodium channel


Mechanisms and classification of adverse drug reactions

LONG QT SYNDROME

  • Affects 1 in 5000 to 1 in 10,000

  • Genetic channelopathy

  • Presents with syncope or sudden cardiac death (SCD), often at early age

  • QTc> 440ms in males, 450ms in females

  • Three major syndromes, LQT1, LQT2 and LQT3

  • Linkages between chromosomes 3, 7 and 11 in three of the 6 genotypes


Mechanisms and classification of adverse drug reactions

CARD 7

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental.

XX

55 Kg

35 y

Saquinavir (Fortovase)

Oral

1200 mg

Jan 2002

Cont.

HIV-AIDS

Fatigue, nausea, abdominal pain, polydipsia and diarrhoea

21/07/02

Ritonavir (Norvir)

Oral

1200 mg

01/07/02

Cont.

HIV-AIDS

Smoking cannabis daily to improve appetite. Washes tablets down with a carton of fruit juice morning and evening. Uses occasional sildenafil (Viagra) tablet prior to sexual intercourse.

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental.

23/07/02


Mechanisms and classification of adverse drug reactions

DRUG INTERACTIONS

  • Specific subgroup of adverse reactions

  • Account for around 15% of all ADRs

  • Mechanisms similar to ADRs

    • Pharmacokinetic and pharmacodynamic

  • Predictable (so often avoidable)


Mechanisms and classification of adverse drug reactions

SAQUINAVIR (INVIRASE / FORTOVASE)

  • CYP3A4, responsible for 90% of the hepatic metabolism

  • Substrate for p-Glycoprotein (P-gp) in-vitro

  • in healthy volunteers, concomitant administration of RITONAVIR (400mg bd.) and SAQUINAVIR (Fortovase) 800mg bd. resulted in a > 2000 % increase in steady-state saquinavir AUC

  • RITONAVIR pharmacokinetics unaffected by the co-administration of SAQUINAVIR (Fortovase)


Mechanisms and classification of adverse drug reactions

P450 ENZYMES IN HUMAN LIVER MICROSOMES

CYP1A2

CYP2A6

CYP3A (4)

CYP2B6

CYP2C (9&19)

CYP2E1

CYP2D6

As % of immunochemically determined enzyme concentrations

Shimada et al 1994


Mechanisms and classification of adverse drug reactions

SOME INHIBITORS OF DRUG METABOLISM

  • Allopurinol

  • Amiodarone

  • Antifungal agents

  • Some HIV drugs

  • Cimetidine

  • Macrolides

  • Metronidazole

  • Some Quinolones

  • Some SSRIs

  • Sulphonamides


Mechanisms and classification of adverse drug reactions

SOME IMPORTANT DRUG TRANSPORTERS

Di-Peptide Transporter (PEPT) ; Organic Anion Transporter (OAT)

Organic Cation Transporter (OCT) ; P-Glycoprotein (P-GP)

OCT

PEPT

Drug

H+

Drug

H+

OAT

P-glycoprotein

Drug

H+

ADP + H+

ATP

Drug

  • Antihistamines

  • Skeletal muscle relaxants

  • Antiarrhythmics

  • -lactam antibiotics

  • Bestatin (anti-cancer)

  • NSAIDS

  • Statins

  • ACE inhibitors

  • Opioids

  • Some Antihistamines

  • Digoxin

  • Verapamil

  • Some Anti-cancer drugs

  • Quinidine

  • Cyclosporin

  • HIV-1 protease inhibitors


Mechanisms and classification of adverse drug reactions

P-GLYCOPROTEIN AND DRUG DISPOSITION

  • reduces GI ABSORPTION

Gut

Intravascular space

Interstitial space

  • reduces DISTRIBUTION

  • increases EXCRETION


Mechanisms and classification of adverse drug reactions

CARD 8

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental.

AC

60

90

Warfarin

Oral

O.5 mg

July 2003

Cont.

DVT

Skin rash and fall in INR to 1.2

14/10/03

L-thyroxine

Oral

O.2 mg

2001

Cont.

Hypothyroidism

I have recently been taking herbal medicine and fruit juice extract from herbalist for depression

This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental.

Mrs Jane thompson (patient) 6 Edwards Drive, Ynysybwl, South Wales

16/10/03


Mechanisms and classification of adverse drug reactions

SOME ENZYME INDUCERS IN MAN

  • Barbiturates and primidone

  • Carbamazepine and oxcarbazepine

  • Phenytoin

  • Rifampicin and rifabutin

  • Alcohol (CYP2E1)

  • Cigarette smoking (CYP 1A2)

  • Efavirenz

  • St John’s Wort


Mechanisms and classification of adverse drug reactions

St JOHN’S WORT

  • Hypericum perforatum

  • Induces CYP3A4, 1A2, 2C9 and P-Glycoprotein

  • May reduce effects of HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, cyclosporin, oral contraceptives (3A4), anticonvulsants, warfarin (2C9), theophylline (1A2) & digoxin (P-Glycoprotein)


Mechanisms and classification of adverse drug reactions

P450 ENZYMES IN HUMAN LIVER MICROSOMES

CYP1A2

CYP2A6

CYP3A (4)

CYP2B6

CYP2C (9&19)

CYP2E1

CYP2D6

As % of immunochemically determined enzyme concentrations

Shimada et al 1994


Mechanisms and classification of adverse drug reactions

VKCOR Variants


Mechanisms and classification of adverse drug reactions

SOME PHARMACODYNAMIC INTERACTIONS


Mechanisms and classification of adverse drug reactions

ORAL ANTICOAGULANTS and NSAIDs

  • The adjusted incidence of hospitalisation for haemorrhagic peptic ulcer disease in patients aged 65 or more receivingoralanticoagulants was 10.2 per 1000 person years (relative risk compared with non users = 3.3)

  • Relative risk of hospitalisation onNSAIDs= 2.0

  • Relative risk onoral anticoagulantsand NSAIDs was 12.7

  • (Shorr RI et al., Arch Intern Med 1993; 153: 1665-70)

3.3 + 2.0 = 12.7


Mechanisms and classification of adverse drug reactions

HIGH VERSUS LOW THERAPEUTIC RATIO

Low therapeutic ratio drug

Effect as % of maximum

High Therapeutic ratio drug

Toxicity

Efficacy

Log Dose

Therapeutic ratio


Mechanisms and classification of adverse drug reactions

SOME DRUGS WITH A LOW THERAPEUTIC RATIO

  • Antiarrhythmic drugs

  • Anticancer agents

  • Anticoagulants

  • Some antihypertensives

  • Some antidiabetic drugs

  • Disease modifying antirheumatic drugs (DMARDs)

  • Tricyclic antidepressants (TCAs)

  • NSAIDs

  • Neuroleptic drugs

  • Opioid analgesics


Mechanisms and classification of adverse drug reactions

Pharmacogenomic Biomarkers as Predictors of Adverse Drug Reactions

Ingelman-Sundberg M. N Engl J Med 2008;358:637-639


Mechanisms and classification of adverse drug reactions

ABACAVIR AND HYPERSENSITIVITY

http://en.wikipedia.org/wiki/File:Abacavir_(Ziagen)_300mg.jpg

http://www.hivandhepatitis.com/0_images_2008/abacavir_hypersens.gif


Mechanisms and classification of adverse drug reactions

Screening for Hypersensitivity to Abacavir.

Mallal S et al. (PREDICT-1) N Engl J Med 2008;358:568-579


Mechanisms and classification of adverse drug reactions

Cost-effectiveness of HLA-B* 5701 genetic screening to guide initial antiretroviral therapy for HIV

Roses AD. Nature Reviews Drug Discovery 2008; 7, 807-817

Cost-effectiveness Ratio for HLA-B*5701 Testing versus No Testing by Population Prevalence of HLA-B*5701

Test cost $68.00

Schackman BR et al. AIDS. 2008 Oct 1;22(15):2025-33.


Mechanisms and classification of adverse drug reactions

Stevens Johnson Syndrome http://missinglink.ucsf.edu/lm/DermatologyGlossary/img/Dermatology%20Glossary/Glossary%20Clinical%20Images/Stevens_Johnson-28.jpg

Toxic Epidermal Necrolysishttp://www.adr.org.uk/images/ten.jpg

CARBAMAZEPINE HYPERSENSITIVITY

FDA Advice

Patients with ancestry from areas in which HLA-B*1502 is present should be screened for the HLA-B*1502 allele before starting treatment with carbamazepine. If they test positive, carbamazepine should not be started unless the expected benefit clearly outweighs the increased risk of serious skin reactions

Population Frequency HLA-B*1502

Philippines Ivatan 22.0

Taiwan Puyuma 18.0

China Guangxi Maonan 14.8

China Yunnan Lisu 12.3

Taiwan Tao 12.0

Singapore Chinese Han 11.6

China Guangzhou 11.0

Hong Kong Chinese10.2


Mechanisms and classification of adverse drug reactions

Phenytoin hypersensitivity

Drug SafetyUpdate

January 2010

  • HLA-B*1502 may be associated with increased risk of developing SJS in individuals of Thai or Han Chinese ethnic origin when treated with phenytoin

  • If these patients aknown to be HLA-B*1502-positive, phenytoin should be avoided when alternative therapy can be given

  • Use of phenytoin should only be considered if the benefits thought to outweigh the risks

  • In Caucasian and Japanese population, frequency of HLA-B*1502 extremely low, and thus not possible at present to conclude on risk association


Mechanisms and classification of adverse drug reactions

Carbamazepine-associated skin reactions: Distribution of the HLA-A*3101 Allele across the spectrum of clinical phenotypes

McCormack M et al. N Engl J Med 2011;364:1134-1143


Mechanisms and classification of adverse drug reactions

FUTURE DEVELOPMENTS

  • Increased availability of pharmacogenetic testing

  • Personal pharmacogenetic profiling

  • Pharmacogenetically-based prescribing guidelines

  • Development of new drugs based on specific genotypes (“drug stratification”)

Wolf et al. BMJ 2000; 320: 987-90


Mechanisms and classification of adverse drug reactions

Genes by Calvin Klein

NHS

CYP 2C9: EXTENSIVE

CYP 2C19: POOR

CYP 2D6: EXTENSIVE

NAT2: SLOW

TPMT: EXTENSIVE

HLA-B*5701,DR7,DQ3

1234 1234 1234 1234

PHILIP A ROUTLEDGE

EXPIRES END 10/09


Mechanisms and classification of adverse drug reactions

gadolinium MRI contrast agents and nephrogenic systemic fibrosis

http://www.med.nyu.edu/dermatology/sem_conf/101706-4.html


Mechanisms and classification of adverse drug reactions

FINAL CONCLUSION

Surveillance must continue during the drug-development process and throughout the life-span of the drug as a therapeutic agent

Rawlins MD. Pharmacovigilance lost, regained or postponed? J Royal Coll. Physicians Lond. 1995; 29: 41-9


Mechanisms and classification of adverse drug reactions

THANK YOU

Any Questions?

[email protected]


Further reading

FURTHER READING

  • Ardern-Jones MR & Friedmann PS. Skin manifestations of drug allergy. Br J Clin Pharmacol. 2011; 71: 672-83.

  • Drug Interactions: Cytochrome P450 inhibitors: (Reference source to P450 isoform substrates and inhibitors)http://medicine.iupui.edu/flockhart/table.htm

  • Pirmohamed M. Pharmacogenetics of idiosyncratic adverse drug reactions. Handb Exp Pharmacol. 2010;(196):477-91

  • Thong BY & Tan TC. Epidemiology and risk factors for drug allergy. Br J Clin Pharmacol. 2011; 71: 684-700


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