EPIDEMOLOGY OF ADR
CAUSES OF ADR
ADR RICK FACTORS
CLASSIFICATION OF ADRS
MANIFESTATIONS OF ADR
PREVENTION OF ADR
SOURCES OF ADR DATA
What is ADR?
Any response to a drug which is noxious and unintended, which occurs at doses
normally used in man for prophylaxis, diagnosis or therapy of disease, or for the modification of physiological functions.
Adverse Drug Event & Adverse Drug Reaction ???ADE
When a patient develops any unwanted symptoms during drug therapy it is called an adverse drug event.
ADR If the ADE is believed to be caused by the drug therapy , then the reaction is called an adverse drug reaction.
Epidemiology of ADRs
4th to 6th leading cause of death among hospitalized patients
6.7% incidence of serious ADRs
1% to 4% of all acute hospital admissions 5% to 20% of inpatients suffer an ADR at some point in their admission.Upto 3% of deaths in hospital in-patients are due to ADR.30% to 60% are however preventable Common Causes of ADRs Anti cancer drugs* Cardiovascular drugs* CNS drugs*Antibiotics
*account for 69% of fatal ADRs
ADR Risk Factors
Age (children and elderly)
Multiple co-morbid conditions
Inappropriate medication prescribing, use, or monitoring
Prior history of ADRs
Extent (dose) and duration of exposure
Depending on the severity
Depending on the onset of event
Depending on the cause
DEPENDING ON THE SEVERITY
MILD: No antidote, therapy or prolongation of hospitalization is required
MODERATE: Requires a change in drug therapy, specific
treatment, or an increase in hospitalization by at least one day
SEVERE: Potentially life-threatening, causes permanent damage or requires intensive medical care
LETHAL: Directly or indirectly contributes to the death of the patient
FDA CRITERIA FOR SERIOUS ADR !
is a five color rating scale to communicate overall drug risk
Red (high risk)
Orange (elevated risk)
Yellow (guarded risk)
Blue (general risk)
Green (low risk)
Definite: Reaction resolved when the drug was discontinuedand recurred when the patient was rechallenged with the drug.
Probable: Reaction resolved when the drug was discontinued and when the reaction cannot not be explained by an existing clinical condition. Possible: Suspected drug was continued or numerous drugs were discontinued simultaneously.Doubtful: There is no reasonable temporal relationship
between the reaction and the drug
Examples of causality algorithms Kramer Naranjo and JonesCLASSIFICATION BASED ON ONSET OF EVENTACUTE
WITHIN 60 MINUTES
1 TO 24 HRS
DEPENDING ON THE CAUSE
Type A: Augmented pharmacologic effects – dose dependent and predictable
Type B: (Bizarre)dose independent and unpredictable
Type C: Chronic effects
Type D: Delayed effects
Type E: End-of-treatment effects
Type F: Failure of therapy
Type A reactions
Exaggeration of a drugs normal pharmacological actions when given at the usual therapeutic dose. They are normally dose dependent.
cushingoid reactions to corticosteroids
hypoglycaemia with insulin.
Type A reactions also include reactions that are not directly related to the desired pharmacological action of the drug The effect is due to action of the drug at another site.
e.g. dry mouth associated with tricyclic antidepressants.
Unwanted but often unavoidable pharmacodynamic effects that occur at therapeutic doses of the drug.
Side effect may be based on the same action as the therapeutic effect. E.g. sedation with antihistamines, atropine causing dryness of mouth.
Side effect may also be based on a different facet of action – e.g Estrogen causes nausea which is unrelated to their anti-ovulatory action.
They are indirect consequences of the main pharmacodynamic action of drug. e.g. development of super infection after suppression of bacterial flora by antibiotics. Weakening of host defenses after the use of corticosteroids. Toxicity
Exaggerated Form Of Side Effects Which Occur Due To Overdoses Or After Prolonged Use Of The Drug.
PHARMACODYNAMIC-bleeding due to high doses of heparin PHARMACOKINETIC– Use of gentamicin in renal insufficiency can cause nephrotoxicity.
Certain drugs in high doses may cause poisoning Eg:hepatic failure with high dose Paracetamol DRUG INTERACTION
(e.g. Theophylline toxicity in the presence of erythromycin therapy)
PHARMACODYNAMIC EFFECTS(TYPE B REACTIONS)
Not expected from the known pharmacological actions of the drug. Not normally dose dependent.
Examples:Anaphylaxis with penicillin
Skin rashes with antibiotics
Agranulocytosis with carbimazole.
Type 1Examples type 1
Type II(within 72 hrs )
(within 72 hrs )
antibody reacts with antigen or hapten
activation of killer T cells or macrophages cytotoxicityExamples type 2Autoimmune haemolytic anaemia
Haemolytic disease of newborn
Type III(72 hrs-1-2 wks) deposition of soluble circulating antigen-antibody ICs in vessels or tissue.
Immune complex (IC) reactions polymorphonuclear cell migration and release of lysosomal proteolytic enzymes and permeability factors in tissues acute inflammation. Examples Type 3
Autoimmune (e.g. SLE, glomerulonephritis, rheumatoid arthritis)
Low-grade persistent infections (e.g. viral hepatitis)
Disease caused by environmental antigens (e.g. farmer’s lung)
Cell mediated caused by sensitized T lymphocytes after contact with a specific antigen.
Genetically determined drug responses
Pharmacogenetic variations among some individuals shows quantitative differences in drug response.egs:
phase 1 drug metabolism
phase 2 drug metabolism
PHARMACOGENETIC VARIATIONS IN PHASE 1 DRUG METABOLISM
Eg- Succinylcholine toxicity
PHASE 2 DRUG METABOLISM
Acetylator status The acetylator status of an individual significantly affects the nature of adverse effects with drugs which are mainly metabolised by n-acetylation.
These are harmful and sometimes fatal reactions that occur in a small minority of individuals,for which the cause is not yet known.
Eg:occurence of aplastic anemia with chloramphenicol
Thiazide diuretics induced erectile impotence
Associated with long-term use.
Involves dose accumulation
e.g., phenacetin and interstitial nephritis or Chloroquine and ocular toxicity
Delayed effects (dose independent)
Carcinogenicity (e.g., immunosuppressants)
Teratogenicity (e.g., fetal hydantoin syndrome)
Withdrawal symptoms that became apparent after the early withdrawal of a drug.
Example- Pulmonary edema after stopping diuretics - Opiate withdrawal syndrome.
Type F Failure of treatment.MANIFESTATIONS OF ADR
Liver damage is produced by several mechanisms of cell injury, paracetamol exemplifies many of these.
Reversible cholestatic jaundice-chlorpromazine
CARDIAC-ARRHYTHMIAS,CARDIAC ARREST-DIGOXIN,QUININE,AMINOPHYLLINE VALVULAR FIBROSIS-
Principal pharmacological action
Inhibition of prostaglandin biosynthesis
Inhibition of angiotensin 2 mediated efferent arteriolar vasoconstriction
Eg: ACE inhibitors
UNRELATED TO PRINCIPAL PHARMACOLOGICAL ACTION
(ALLERGIC TYPE INTERSTITIAL NEPHRITIS)
CHRONIC RENAL FAILURE
ABNORMALITIES OF TASTE AND SMELL
Ear drops(chloramphenicol,acetic acid 2%)
Vigabatrine,tamoxifen-visual field constriction
EXAMPLES OF IMPLICATED DRUGS
PENICILLINS,NSAIDS,SULFONAMIDES, CAPTOPRIL,ENALAPRIL CORTICOSTERIODS,ANDROGENIC & ANABOLIC STERIODS,PHENYTION,DANAZOL NSAIDS,SULFONAMIDES,GOLD SALTSTOPICAL ANTIMICROBIALS-PENICILLIN,CHLORAMPHENICOL,NEOMYCIN, TOPICAL ANTIHISTAMINES,CREAM & LOTION PRESERVATIVESSKIN REACTION PURPURA STEVENS JHONSON SYNDROME SLE LIKE REACTIONEXAMPLES OF IMPLICATED DRUGS
ANTICOAGULANTS, CORTICOSTERIODS SULFONAMIDES,BARBITURTE, PHENYTION HYDRALIZINE SKIN REACTION PHOTOSENSITIVITY ALOPECIA HIRSUTISMEXAMPLES OF IMPLICATED DRUGS
TETRACYCLINES CYTOTOXIC DRUGS,OCP,ANDROGEN ANDROGENS,ANABOLIC STERIODSElectrolyte disturbances
NSAIDS-SODIUM RETENTION & EDEMAENDOCRINE DISTURBANCES
OCP-suppress lactation in nursing mothers
Glucocorticoids-decrease synthesis of acth & endogenous cortisol
INFERTILITY AND SEXUAL IMPOTENCE
BEHAVIORAL AND CNS
Amphetamines-disorientation,confusion,inability to concentrate
MUTAGENESIS AND CARCINOGENICITY
Involves modification of DNA
Mutation of proto oncogenes or tumour suppressor genes leads to carcinogenesis
Carcinogens can be-
It is the capacity of a drug to cause fetal abnormalities when administered to the pregnant mother.
prevent the entry of certain naturally occurring substances and drugs into the cells of the vital organs.
protect against xenobiotics
direct observation of event
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?
Preliminary AssessmentDetermination of urgency:
What is the patient’s current clinical status?
How severe is the reaction?
Acute (ER, ICU, Poison Control)
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 patient’s condition
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
Discontinue non-essential medications
Administer appropriate treatment
e.g., atropine, epinephrine, corticosteroids, glucagon
Provide supportive or palliative care
e.g., hydration, warm / cold compresses, analgesics etc..
Consider rechallenge or desensitization
Follow-up and Re-evaluation
Course of event
Response to treatment
Specific monitoring parameters
PREVENTION OF ADRs
Use only necessary drugs and only when indicated.
Correct dosage and correct route.
Do not use a drug about which complete profile is not known.
Advice patient to report back immediately, in case of any untoward reaction.
Clean record of all drugs prescribed with the diagnosis.
Keep emergency medicines handy in case of anaphylactic reactions
Follow the instructions given by the drug manufacturer regarding route of administration and storage.
The main sources of ADR data:
(a) Spontaneous reporting by doctors, pharmacists nurses etc.
(b) ADR monitoring schemes in hospitals
(c) Clinical trials (all phases including postmarketing surveillance)
(d) Vital statistics (mortality, morbidity registers, birth registers for congenital defects)
(e) Special studies (case control studies, cohort studies)
Who has defined it as “the science and activities relating to the detection,assessment,understanding,and prevention of adverse effects or any other possible drug related problems.”
Early detection of unknown ADR & interactions.
Detection of increases in frequency of ADR (known).
Risk factors & possible MOA underlying ADR
4) estimate benefit/risk analysis.
5) disseminate information needed to improve drug prescribing & regulation.
Records medication related errors.
Analyses those errors.
Promotes patient safety
Prevent “preventable errors”
HIERARCHIAL STRUCTURE OF PHARMACOVIGILANCE CENTRES IN INDIA
NATIONAL PHARMACOVIGILANCE PROGRAMME
WHAT TO REPORT?
ALL REACTIONS TO ANY DRUG WHICH ARE SUSPECTED.
WHO CAN REPORT?
ANY HEALTH CARE PROFESSIONAL
WHERE TO REPORT?
WHAT HAPPENS WHEN YOU REPORT?
SENT TO CDSCO DCGI
CALL BACK THE DRUG/CHANGE THE LABEL
ANY OTHER REGULATORY INTERVENTIONS
Components of an ADR Report
Product name and manufacturer
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
Pharmacological basics of therapeutics – Goodman and Gillman , 12th edition
Pharmacology and pharmacotherapeutics; RS Sathoskar , 21st edition
Principles of medical pharm ; Harold Kalant 6th edition
Oxford book of medicine 5th edition , Vol I
Rang & Dale
Katzung text book of pharmacology