Adverse Drug Reactions and Drug toxicity

Terms

Adverse drug reactions

Side effects
Toxic effects Drug hypersensitivity/Allergy Secondary effects Idiosyncrasy Drug interaction Complications

ADR - WHO definition

ANY REACTION TO A DRUG WHICH IS NOXIOUS AND UNINTENDED AND WHICH OCCURS AT DOSES USED IN MAN FOR PROPHYLAXIS, DIAGNOSIS, OR THERAPY OF DISEASE, OR FOR THE MODIFICATION OF A PHYSIOLOGICAL FUNCTION EXCLUDE - therapeutic failure, accidental, deliberate excessive dosage of maladministration, abuse, non compliance, medication errors

Side Effects

ANY UNINTENDED EFFECTS OF A PHARMACEUTICAL PROPDUCT OCCURING AT DOSES NORMALLY USED IN MAN WHICH IS RELATED TO THE PHARMACOLOGICAL PROPERTIES OF THE DRUG tolerance

Toxicity

Adverse symptom or other effect produced by an excessive or prolonged chemical exposure to a drug

Adverse Drug Events

ADR

An injury resulting from medical intervention related to a drug Allergy/Toxic/Interaction

BMJ 1999;318:127

Adverse event/adverse experience - Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment Side effect - Any unintended effect of a pharmaceutical product occurring at doses normally used in man, which is related to the pharmacological proprieties of the drug

Essential elements of this definition are the pharmacological nature of the effect, that the phenomenon is unintended, and that there is no overt overdose

 ADR

5%

10-20% 0.1% 0.01%

BMJ 1998;316:1295-8

Epidemiology of ADRs
substantial morbidity and mortality estimates of incidence vary with study methods,
population, and ADR definition

4th to 6th leading cause of death among hospitalized

patients*

6.7% incidence of serious ADRs* 0.3% to 7% of all hospital admissions annual dollar costs in the billions 30% to 60% are preventable
*JAMA. 1998;279:1200-1205.

Predisposing factors to ADRs

DRUG FACTORS Dose/Duration/Route/Number of medications - drug interactions/preparation PATIENT FACTORS Race&genetic polymorphism PK variables Age/Sex Disease state Behavioral factors

ADR Classification

Pharmacological - type A, B Causality Karch & Lasagna - definite(certain), probable, possible,
conditional, doubtful(unlikely)

WHO - Certain, Probable or likely, Possible, Unlikely

Statistical - specific, non specific Severity - minor, moderate, severe Frequency - common, occasional, rare, very rare Mechanism - idiosyncrasy, hypersensitivity, intolerance, drug interaction, side effect, toxic rxn

ADR Classification -severity

MILD

No antidote, therapy, or prolongation of hospitalization necessary

MODERATE

Require changes in therapy, not necessary discontinue drug, may prolong hospitalization

SEVERE

Potentially life-threatening, require discontinuation of drug and specific treatment of ADR

LETHAL

ADR Classification -causality

DEFINITE

follow reasonable temporal sequence follow known pattern of response confirmed by improvement on removal and by
reappearance on rechallenge cannot be explained by known dis characteristics

PROBABLE POSSIBLE CONDITIONAL

DOUBTFUL

ADR Classification -causality

CERTAIN

follow reasonable temporal sequence follow known pattern of response confirmed by improvement on removal and by
reappearance on rechallenge cannot be explained by known dis characteristics

PROBABLE or LIKELY POSSIBLE UNLIKELY

Classification - Severity
FDA Serious ADR Result in death Life-threatening Require hospitalization Prolong hospitalization Cause disability Cause congenital anomalies Require intervention to prevent
permanent injury

ADR Pharmacological Classification

Type A (Augmented pharmacological effects) Predictable pharmacological reactions Type B (Bizarre effects) Unpredictable idiosyncratic reactions Type C (Chronic effects) Long-term effects Type D (End of treatment effects) Delayed effects

Lawson DH. Epidemiology. In: Davies DM, editor. Daviess textbook of adverse drug reactions, 1998.

ADR Pharmacological Classification Type A

Extension of pharmacologic effect Predictable pharmacological reactions Dose-dependent High incidence Low mortality More common than type B Readily reversible on reducing the dose Example: Bradycardia & beta-blockers
Hemorrhage & warfarin Drowsiness & benzodiazepine

ADR Pharmacological Classification Type B

Unpredictable idiosyncratic reactions Rare & Bizarre Unrelated to dose Often life-threatening Example:
Hyperthermia & Penicillin induced anaphylaxis Chloramphenicol - aplastic anemia

ADR Pharmacological Classification Type C

associated with long-term use

involves dose accumulation

e.g., phenacetin and interstitial

nephritis or antimalarials and ocular toxicity

ADR Pharmacological Classification Type D

delayed effects (dose

independent) Carcinogenicity (e.g., immunosuppressants) Teratogenicity (e.g., fetal hydantoin syndrome)

ADR type

Nature of abnorm Incidence Predictable? Morbidity

A
quantitative high yes high

B
qualitative low no low

Mortality
Prevention

usually low
adjust dose

usually high
avoid drug

Treatment

reduce dose

discontinue

ADR type

ISONIAZID SULFONAMIDE TETRACYCLINE

A
Peripheral neuropathy Diarrhea Uremia Tooth deformity

B
Hepatotoxicity Agranulocytosis Photosensitivity

INSULIN anemia

Hypoglycemia

Hemolytic

 type A ADR

Pharmaceutical causes

Drug quantity Drug release

Pharmacokinetic causes

Drug absorption Drug distribution Drug elimination

Pharmacodynamic causes

Drug receptor Homeostatic mechanism Disease

 type B ADR

Pharmaceutical causes

Degradation product Excipients

Pharmacokinetic causes Pharmacodynamic causes

Genetics Immunologic Neoplastic/teratological

ADR Risk Factors

Age (children and elderly) Multiple medications Multiple co-morbid conditions Inappropriate medication prescribing, use, or monitoring End-organ dysfunction Altered physiology Prior history of ADRs Extent (dose) and duration of exposure Genetic predisposition

Immunological mechanism of allergic reactions

Type I Immediate-type (or anaphylactic), mediated by IgE or possibly the IgG Autoallergy (autoimmunity), autosensitization being mediated by lymphocytes or antibodies Arthus-type, mediated by IgG, IgM, and complement Delayed-type hypersensitivity

Type II

Type III

Type IV

ASSEM E-SK. Drug allergy and tests for its detection. In: Davies DM, editor. Daviess textbook of adverse drug reactions, 1998.

Allergic reactions

Types of allergic reactions

Type I - immediate, anaphylactic (IgE) e.g., anaphylaxis with penicillins Type II - cytotoxic antibody (IgG, IgM) e.g., methyldopa and hemolytic anemia Type III - serum sickness (IgG, IgM) antigen-antibody complex e.g., procainamide-induced lupus Type IV - delayed hypersensitivity (T cell) e.g., contact dermatitis

ADR Information
Incidence and prevalence Mechanism and pathogenesis Clinical presentation and diagnosis Time course Dose relationship Reversibility Cross-reactivity/Cross-allergenicity Treatment and prognosis

ADR Information Resources

Tertiary
Reference books
Medical and pharmacotherapy textbooks Package inserts, PDR, AHFS, USPDI Specialized ADR resources Meylers Side Effects of Drugs Textbook of Adverse Drug Reactions Drug interactions resources Micromedex databases (e.g., TOMES, POISINDEX, DRUGDEX)

Review articles

ADR Information Resources

Secondary
MEDLARS databases (e.g., Medline, Toxline,

Cancerline, Toxnet) Excerpta Medica (Embase) International Pharmaceutical Abstracts Sedbase Current Contents Biological Abstracts (Biosis) Science Citation Index Clin-Alert and Reactions

ADR Information Resources

Primary
Spontaneous reports or unpublished data
FDA Manufacturer

Anecdotal and descriptive reports

Case reports, case series

Observational studies
Case-control, cross-sectional, cohort

Experimental and other studies

Clinical trials Meta-analyses

Causality Assessment
Prior reports of reaction Temporal relationship De-challenge Re-challenge Dose-response relationship Alternative etiologies Objective confirmation Past history of reaction to same or similar medication

Causality Assessment
Examples of causality algorithms
Kramer Naranjo and Jones
Highly probable Probable Possible Doubtful

Causality outcomes

To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score.

Naranjo ADR Probability Scale

Naranjo CA. Clin Pharmacol Ther 1981;30:239-45

1. Are there previous conclusive reports on this reaction? 2. Did the adverse event appear after the suspected drug was administered? 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 4. Did the adverse reactions appear when the drug was readministered? 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? 6. Did the reaction reappear when a placebo was given? 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence?

Yes +1 +2 +1

No 0 -1 0

Do Not Know 0 0 0

Score ____ ____ ____

+2 -1

-1 +2

0 0

____ ____

-1 +1

+1 0

0 0

____ ____

+1

____

+1

____

+1

0 Total Score

____ ____

Total Score 9 5-8 1-4 0

ADR Probability Classification Highly Probable Probable Possible Doubtful

Management Options

Discontinue the offending agent if:

it can be safely stopped the event is life-threatening or intolerable there is a reasonable alternative continuing the medication will further exacerbate the patients

Continue the medication (modified as needed) if:

it is medically necessary there is no reasonable alternative the problem is mild and will resolve with time

condition

Management Options
Discontinue non-essential medications Administer appropriate treatment
e.g., atropine, benztropine, dextrose, antihistamines,

Provide supportive or palliative care

analgesics or antipruritics

epinephrine, naloxone, phenytoin, phytonadione, protamine, sodium polystyrene sulfonate, digibind, flumazenil, corticosteroids, glucagon

e.g., hydration, glucocorticoids, warm / cold compresses,

Consider rechallenge or desensitization

Follow-up and Re-evaluation

Patients progress Course of event Delayed reactions Response to treatment Specific monitoring parameters

Documentation and Reporting

Medical record
Description Management Outcome

Reporting responsibility
JCAHO-mandated reporting programs Food and Drug Administration
post-marketing surveillance particular interest in serious reactions involving new

chemical entities Pharmaceutical manufacturers Publishing in the medical literature

Components of an ADR Report

Product name and manufacturer Patient demographics Description of adverse event and outcome Date of onset Drug start and stop dates/times Dose, frequency, and method Relevant lab test results or other objective evidence De-challenge and re-challenge information Confounding variables

MEDWATCH 3500A Reporting Form

https://www.accessdata. fda.gov/scripts/medwatc h

Drug Toxicity

Therapeutic effects Side effects

Toxic effects
Side effect = action that occurs at therapeutic dose Toxic effect = action that occurs when dosage or blood concentration is above therapeutic level

Therapeutic Index
ratio of drug concentration required to produce
therapeutic effect to concentration producing toxic response

TI = TD50/TE50 TI = LD50/ED50
closer to 1 greater chance of toxicity

Standard margin of safety

[LD1/ED99 -1]*100

Therapeutic index = LD50/ED50

A % response

TI = TI =
Log dose

TI =
10 20 40 100 200

Therapeutic index = LD50/ED50

A % response

TI =5 TI =
Log dose

TI =
10 20 40 100 200

Therapeutic index = LD50/ED50

A % response

TI =5 TI =7
Log dose

TI =
10 20 40 100 200

Therapeutic index = LD50/ED50

A % response

TI =5 TI =7
Log dose

TI =5
10 20 40 100 200

Types of drug toxicity

Predictable, related to the principal pharmacol actions, e.g. bleeding with anticoagulants Predictable, unrelated to the principal pharmacol actions, e.g. liver damage with acetaminophen Unpredictable, unrelated to the principal pharmacol actions, e.g. Allergy Idiosyncrasy

Factors contributing to drug toxicity

USERS age

neonate - chloramphenicol Glucuronyl transferase

chloram -glucuronide urine GRAY BABY SYNDROME

Elderly -

digoxin
(low TI) toxic excrete

Factors contributing to drug toxicity

USERS concomitant diseases

PU Asthma Renal failure

ASPIRIN MORPHINE STREPTOMYCIN

Factors contributing to drug toxicity

USERS Genetic determinants

Drug accumulation N-acetyl Isoniazid transferase

acetylisoniazid
hydrolase

(peripheral neuritis)

acetylhydrazine (liver toxic) SLOW ACETYLATOR FAST ACETYLATOR prolongation of effect hypersensitivity

Factors contributing to drug toxicity

USERS Genetic determinants

Prolongation of drug effect

succinylcholine Hypersensitivity primaquine hemolytic anemia penicillin anaphylactic shock

Factors contributing to drug toxicity

DRUGS Outdated drug

Drug overdose

Tetracycline -> proximal tubule Fanconi syndrome Digoxin -> cardiac arrhythmia Isoproterenol -> tachycardia, HTN Warfarin -> bleeding

Drug interaction

Drug toxicity

Anaphylaxis Anemia Arrhythmia Bone marrow suppression Deafness Kidney damage Liver damage Peptic ulcer Mutagenesis and carcinogenicity Teratogenesis

Hepatotoxicity

Acetaminophen - saturation of conjugation

N-acetyl-p-benzoquinone imine reactive metabolite

Isoniazid - genetic different Halothane - immunological mechanism

OSO3 ST

OH

O GLUCURONIDE

UDPGT

NH COCH3

NH COCH3 CYP

NH COCH3

N COCH3
GSH

OH GS

PROTEIN BINDING

NHCOCH3

CELL DEATH

Nephrotoxicity

NSAIDs/ACEIs

Patients with underlying disease - depend on local vasodilator PG synthesis

NSAID ADRs
1. Owing to pharmacol actions:
Acute ischemic renal failure Sodium, water retention

2. Allergic-type interstitial nephritis

Renal failure/Proteinuria

3. Analgesic nephropathy
Papillary necrosis, Chronic renal failure

Nephrotoxicity

Amphotericin B Aminoglycosides

Mutagenesis/carcinogenesis

Genotoxic carcinogen Epigenetic carcinogen

Teratogen

Thalidomide Retinoids Antiepileptics

Anaphylaxis

Antigen-antibody reaction on mast cells -> histamine, leukotriene, PAF release vasodilation, hypotension, shock 0.01% with penicillin, fatality 9% Epinephrine 1:1,000 IV, IM 0.3-0.6 CC

Hematologic

Hemolytic anemia

quinine, primaquine, sulfonamides, aspirin -G6PD methyldopa, mefenamic acid -

Aplastic anemia
chloramphenicol, phenylbutazone

Bone marrow suppression

chloramphenicol, phenylbutazone, indomethacin, colchicine, chlorambusil

Arrhythmias

Digitalis glycosides Isoproterenol, epinephrine

Antiarrthythmic drugs

Ototoxicity

Aminoglycosides Loop diuretics