���ADVERSE DRUG REACTIONS (ADRS)��Dr Bassi PU MBBS,MSc, FMCP�University of Abuja�MbBS Lecture series

Outline

• Definition of adverse drug reactions
• Discuss epidemiology of ADRs
• Causes/Risk factors
• Detection of ADR
• Diagnostic Approaches
• Managements &Therapy

- Often no clear separation...

Definition

• WHO
• response to a drug that is noxious and unintended and that occurs at doses used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic function

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• excludes therapeutic failures, overdose, drug abuse, noncompliance, and medication errors

Side effect

• Unintended effect occurring at normal dose related to the pharmacological properties of a drug

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• Based on same action as therapeutic effect- • e.g. atropine in preanesthetic medication
• On different facet of action-
• Antihistaminics produce sedation
• Therapeutic in one context , S/E in another-
• Codeine for cough produces
• constipation, can be used as a
• therapeutic effect in traveller dirrhoea.

Secondary Effects

• Indirect consequences of a primary drug action.
• Opportunistic infections due to broad spectrum of antibiotic use ,
• due to alteration of normal flora.

Definitions

• Toxicity
• Direct action of the drug , at high dose , damaging the cells – e.g.
• Liver damage from Paracetamol overdose.
• Intolerance
• Low threshold to the normal pharmacodynamic action of the drug.
• Appearance of characteristic toxic effects of a drug in an individual at therapeutic doses
• Idiosyncrasy
• Genetically determined abnormal reactivity to a chemical e.g.
• Barbiturates- excitement & mental confusion in some.

Adapted from Bates et al.

Adverse Drug Events

Medication

Errors

(preventable)

Adverse Drug Event: preventable or unpredicted medication event---with harm to patient

Adverse Drug

Events

(ME & ADR)

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

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• *JAMA. 1998;279:1200-1205.

Classification

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• Onset
• Severity
• Type

Classification

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• Onset of event:
• Acute
• within 60 minutes
• Sub-acute
• 1 to 24 hours
• Latent
• > 2 days

Classification - Severity

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• Severity of reaction: There is no universal scale for describing or measuring the severity of an adverse drug reaction. Assessment is largely subjective. Reactions can be described as

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• Mild
• bothersome but requires no change in therapy
• Moderate
• requires change in therapy, additional treatment, hospitalization
• Severe
• disabling or life-threatening

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• Lethal (deadly)

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Classification - Severity

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Mild adverse drug reactions

• Mild reactions usually described as of minor significance include
• Digestive disturbances (such as nausea, constipation, diarrhea)
• Headaches,Fatigue,Vague muscle aches, Malaise (a general feeling of illness or discomfort)
• Changes in sleep patterns
• However, such reactions can be very distressing to people who experience them.
• As a result, people may be less willing to take their drug as instructed, and the goals of treatment may not be achieved.

Classification - Severity

• Moderate adverse drug reactions
• Moderate reactions include Rashes (especially if they are extensive and persistent), Visual disturbances (especially in people who wear corrective lenses), Muscle tremor, Difficulty with urination (a common effect of many drugs in older men)
• Any perceptible change in mood or mental function
• Certain changes in blood components, such as a temporary, reversible decrease in the white blood cell count or in blood levels of some substances, such as glucose
• Also, reactions that are usually described as mild are considered moderate if the person experiencing them considers them distinctly annoying, distressing, or intolerable.
• Severe adverse drug reactions
• Severe reactions include those that may be life threatening (such as liver failure, abnormal heart rhythms, certain types of allergic reactions), that result in persistent or significant disability or hospitalization, and that cause a birth defect. Severe reactions are relatively rare

Classification - Severity

• People who develop a severe reaction usually must stop using the drug and must be treated. However, doctors must sometimes continue giving high-risk drugs (for example, chemotherapy to people with cancer or immunosuppressant to people undergoing organ transplantation).
• Doctors use every possible means to control a severe adverse drug reaction.

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Lethal adverse drug reactions

• Lethal reactions are those in which a drug reaction directly or indirectly caused death.
• These reactions are typically severe reactions that were not detected in time or did not respond to treatment.
• Lethal reactions can be the reasons that some drugs are withdrawn from the market (such as troglitazone and terfenadine).

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Classification - Severity

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

Types of adverse drug reactions

Type -A [Augmented] and Type B [Bizarre] effects.

Other classifications also include

• Type C (‘C’ for continuous or chronic),
• Type D (‘D’ for delayed)
• Type E (‘E’ for end of use), and
• Type F (‘F’ for failure) effects.

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Classification of ADRs:Wills and brown

Type A (Augmented)

Type B (Bizarre)

Type C (Chemical)

Type D (Delayed)

Type E (Exit/End of treatment)

Type F (Familial)

Type G (Genotoxicity)

Type H (Hypersensitivity)

Type U (Un classified)

Types of adverse drug reactions

• Type -A [Augmented] refers to predictable dose-dependent responses which are exaggerated pharmacological actions at usual therapeutic doses. This could occur in everyone if enough of the drug is given because they are due to excess of normal, predictable dose-related,
• Xteristics
• Common
• There are in many instances avoidable.
• extension of pharmacologic effect
• often predictable and dose dependent
• Can be experimentally reproduced
• responsible for at least two-thirds of ADRs
• constitute approximately 80% of adverse drug reactions
• Known before licensing

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Type -A [Augmented] cont.

Example

• Lisinopril & postural hypotension,
• Insulin & hypoglycemia,
• tricyclic antidepressants, and Dry mouth
• opioids and respiratory depression
• propranolol and heart block,
• anticholinergics and dry mouth
• bleeding when using the anticoagulant warfarin
• nausea from digoxin.

Management of Type Reactions

• Reduce dose or withhold drug
• Consider effects of concomitant therapy

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Types of adverse drug reactions

Type B [Bizarre] refers to unpredictable, non dose dependent, novel responses to a

drug occurs only in some people Most times there are unavoidable.

Xteristics

• idiosyncratic or immunologic reactions or Drug allergy/hypersensitivity reactions
• rare and
• Often unpredictable
• Litle or no dose relationship
• Occur in predisposed, intolerant patients – may explain by by rare genetic polymorphism.
• High mortality

examples

• e.g., chloramphenicol and aplastic anemia
• fixed dose reaction of sulphonamides.
• Anaphylactic reactions with Penicillin
• Malignant hyperthermia with anaesthesia
• Manangement: Withold and Avoid in future

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Drug allergy

• Drug allergy; also known as hypersensitive reaction due to antigen-antibody interactions
• 1st dose acts as an antigen
• Antibody is produced against the antigen in the body
• Subsequent dose causes antigen-antibody reaction
• e.g. Penicillin induced anaphylaxis (Type 1 hypersensitivity reaction)

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Types of adverse drug Allergy

Types of allergic reactions

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• 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

Types C ADRs

Type C is associated with the long term use of a drug and is related to cumulative use (‘C’ for continuous or chronic). It is chronic and of delayed onset.

It tend to be both serious and (relatively) common and have profound effect on public health

Xteristics

• Uncommon
• Dose related and time related
• Associated with long-term therapy
• Involves dose accumulation
• Often no suggestive time relationship
• And connection often difficult to prove
• Use of drug increases frequency of “spontaneous reporting”

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Types C cont.

Examples

• NSAIDS-induced renal failure (Phenacetin and interstitial nephritis)
• oral contraceptive induced diabetic microangiopathy
• breast tumors or antimalarials and ocular toxicity.
• Hypopituitery- adrenal axis suppression by corticosteroids oteonecrosis of the jaw with biphosphonate

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Management

• Reduce dose or withhold; withdrawal
• may have to be prolonged

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Types of adverse drug reactions

Type D refers to a delayed type of reaction (‘D’ for delayed). May present years after drug was administered.

Xteristics

• - Uncommon
• - Time related
• - usually dose-related and occur sometime after drug use
• - delayed effects (dose independent)

Examples

• - Vaginal cancer in daughters whom mother was treated by diethylstilbestrol
• Carcinogenicity (e.g., immunosuppressants)
• - Teratogenicity (e.g., fetal hydantoin syndrome)
• - bladder cancers following long term cyclophosphomide,
• - gene toxicity of some drugs,
• - Leucopenia – Limoustine
• - carcinoma of the renal pelvis following phenacetin etc.

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Manageent: Often intractable

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Types of adverse drug reactions

Type E refers to withdrawal or end of use adverse drug reactions (‘E’ for end of use).

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Xteristics

Uncommon and related to discontinuation that is too abrupt

Examples

• Addisonian crisis (adrenal insufficiency) following steroid withdrawal
• opiate withdrawal syndrome
• rebound convulsions on withdrawal of carbamazepine in non-epileptic patients
• myocardial infarction following beta blocker withdrawal
• Withdrawal syndrome with opiates or benzodiazepines (e.g., insomnia, anxiety)

Management: Reintroduce drug and withdraw slowly

Types F adverse drug reactions

Type F refers to unexpected failure of therapy (‘F’ for failure).

Xteristics

• - Oten common
• -often dose-related
• - caused by drug interactions

Examples

• inadequate dosage of an oral contraceptive
• use of concomitant administration with enzyme –inducing drugs.
• Resistance to antimicrobial agents

Management: Increase dosage. Consider effects of concomitant therapy

Comparison between Type A and Type B adverse drug reactions

Common Causes of ADRs

• Antibiotics
• Antineoplastics*
• Anticoagulants
• Cardiovascular drugs*
• Hypoglycemics
• Antihypertensives
• NSAID/Analgesics
• Diagnostic agents
• CNS drugs*
• ARTs?????

*account for 69% of fatal ADRs

Body Systems Commonly Involved

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• Hematologic
• CNS
• Dermatologic/Allergic
• Metabolic
• Cardiovascular
• Gastrointestinal
• Renal/Genitourinary
• Respiratory
• Sensory

Body Systems Commonly Involved

There are varied complex mechanism

involve in adverse drug reactions. From

the patient population characteristics

like age, sex, population size, genetic

constitutions, and tendency to allergy,

disease, personality or habit , to

Predisposing factors – renal function,

liver function, pharmacokinetic and

pharmacodynamics factors etc

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Impact of genetics�

• Genetic constitution of an individual play a vital role in ADRs, as every individual responds differently to drugs as a result of their genetic constitutions.
• This genetic variation can exist as a result of single mutant gene (as in polymorphism or discontinuous variation), or polygenic influences e.g. Drug-induced haemolytic anaemia as a result of G6PD deficiency with drugs like 8-aminoquinolines, antimicrobials and some analgesics.

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ADR Risk Factors

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• 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

�Factors Masking Adverse Drug Reactions�

ADR are most times unrecognized due to a number of factors:

1)They may mimic natural disease eg phenothiazine - induced hepatitis.

2)They may appear as an odd or bizarre reaction from an innocent drug like pseudolymphoma from Phenytoin.

3)The appearance of the reaction may be delayed like in mucocutaneous syndrome due to practolol, adenocarcinoma of the vagina in children whose mothers received high dose oestrogen during pregnancy or valvular heart disease following fenfluramine administration.

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�Factors Masking Adverse Drug Reactions�

• 4)ADR may cause the relapse of a natural disease or evoke a disorder in a naturally susceptible subject e.g. diabetes by thiazides and glaucoma by atropine and
• 5) It may be masked by the nature and complex clinical situation as in antiarrhythmic drugs with a proarrhythmic effect
• 6) Environmental factors causing ADRs includes simple pollution
• - eg with Halothane in the air of operating theatre, causing abortion in female staff;
• - Penicillin in air of hospital or milk cause drug (hypersensitivity) allergy.

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ADR Detection

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• Subjective report
• patient complaint
• Objective report:
• direct observation of event
• abnormal findings
• physical exam
• laboratory test
• diagnostic procedure

ADR Detection in Clinical Trials

• Methods
• Standard laboratory tests
• Diagnostic tests
• Complete history and physical
• Adverse drug event questionnaire
• Extensive checklist of symptoms categorized by body system
• Review-of-systems approach
• Qualitative and quantitative

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ADR Detection in Clinical Trials

• Limitations
• exposure limited to few individuals
• rare and unusual ADRs not detected
• 3000 patients at risk are needed to detect ADR with incidence of 1/1000 with 95% certainty
• exposure is often short-term
• latent ADRs missed
• external validity
• may exclude children, elderly, women of child-bearing age; and patients with severe form of disease, multiple co-morbidities, and those taking multiple medications

Preliminary Assessment

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• Preliminary description of event:
• Who, what, when, where, how?
• Who is involved?
• What is the most likely causative agent?
• Is this an exacerbation of a pre-existing condition?
• Alternative explanations / differential diagnosis
• When did the event take place?
• Where did the event occur?
• How has the event been managed thus far?

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Preliminary Assessment

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• Determination of urgency:
• What is the patient’s current clinical status?
• How severe is the reaction?

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• Appropriate triage:
• Acute (ER, ICU, Poison Control)

• The diagnosis of ADR is part of the broader diagnosis in a patient.

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• If a patient is taking medicine, the differential diagnosis should include the possibility of an ADR

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Diagnosis of ADR

• Find out is the patient taking a medicinal product, including
• Over the counter (OTC) formulations
• Products that may not be thought of as medicines eg herbal or traditional remedies
• Recreational drugs or
• Drug of abuse &
• Long –term treatments that the patient may forget (such as contraceptives)

- Detail medical Hx

Step 1

• age, race, ethnicity, gender, height, Weight

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• Social history
• tobacco, alcohol, substance abuse, physical activity, environmental or occupational hazards or exposures
• Pertinent family history

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• Nutritional status
• special diets, malnutrition, weight loss

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Demographics

Detailed Description of Event PQRSTA Acronym

P

Q

R

S

T

• History of present illness
• Signs / Symptoms: PQRSTA
• Provoking or palliative factors
• Quality (character or intensity)
• Response to treatment, Radiation, Reports in literature
• Severity / extent, Site (location)
• Temporal relationship (onset, duration, frequency)
• Associated signs and symptoms

Detailed Description of Event

• Find out whether the effect could be due to a medicine.
• If the patient is taking several medicine, the problem is to distinguish which
• If any, its causative
• This is complex, because some patients complaints might be due to other disease or to one or more drugs
• Concurrent conditions or special circumstances
• e.g., dehydration, autoimmune condition, HIV infection, pregnancy, dialysis, breast feeding

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Step 2

Timing

• The time relation between the use of the drug and the occurrence of the reaction should be assessed. Are there plausible linked?
• Does the Rxn occur or get wost as the dose of the drug reaches steady state or when the steady-state dose increased (for dose related drug)
• If a drug interaction is suspected, does the timing of introduction or withdrawal of the interacting drug fit?

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Detail medication Hx

step3

• If there are features of an allergic Rxn, has the patient previously been exposed?

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• If the reaction is congenital abnormality, did drug exposure occur at the appropriate gestational time?

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• If effect is a tumour,was the time lag sufficiently long for the tumour to have grown?

-the answer to this, depend on the tumour kinetics.

step3

• Pattern of Recognition
• The pattern of ADR effect may fit the known pharmacology or allergy pattern of one suspected medicines or chemically related or pharmacologically related compounds
• Some patterns are pathognomonic or nearly so; e.g. in patient taking Digoxin, a combination of heart block & an ectopic arrhythmia will almost certainly be due to the drug
• Information should not be use to rule out an association – ADR may not follow pharmacology

Eg corticosteroids use to suppress immune response, may cause allergic reaction.

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Step 4

-The goal of diagnostic testing is to evaluate biochemical and immunologic markers that confirm activation of a particular immunopathologic pathway to explain the suspected adverse drug effect

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-investigation can be used to aid diagnosis

Eg plasma concentration measurement, biopsies & allergy tests

Patch test and lymphocytes proliferation assay

Investigations

-Lab. test is guided by suspected mechanism useful mainly in type B (Hypersensitivity reaction)

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1.Skin testing

2.Radioallergosorbent (RAST)

3.Serum trptase

4.Direct coombs` test

5. C-reactive protein immune complement studies

6. Antinuclear antibody, antihitone

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Investigations

• Investigation to establish baselne for organ function eg liver, kidney, or thyroid function.
• This will provide means of monitoring what happens after changes in therapy.
• They may also rule out alternative diagnosis eg baseline function for thyroids for patients on Amipdarone

-Rechallenge with the drug should be considered, particulrly if the patient is likely to benefit directly from the knowledge gained.

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Investigations

Which error when this is an ADR?

Thank you

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