adverse drug reactions
TRANSCRIPT
Drugs have:Beneficial effectsHarmful effects
Facts Drugs save life & improve healthDrugs also threaten life
“Cur’d yesterday of my disease
I died last night of my physician”
- Mathew Prior: 17th Century
From, the remedy worse than the disease
So, the important question is ALWAYS:
“Do the potential benefits of the medication outweigh the potential risks for the individual?”
Definition
‘An adverse drug reaction is any undesirable effect of a drug beyond its anticipated therapeutic effects occurring during clinical use.’
The term (ADR) usually excludes-
nontherapeutic overdosage (e.g. toxicities due to accidental exposure or attempted suicide) and
lack of efficacy of drug
WHO definition:• “Any 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.”
• It excludes therapeutic failures, overdose, drug abuse, noncompliance, and medication errors
Injury resulting from the medical use of a drug. Includes Medication Error & ADR Medication error: An injury resulting from an
error in preparing, procuring, prescribing, dispensing, administering, or monitoring.
Adverse drug reaction (ADR): An injury resulting from the medical use of a drug where no error is involved.
ADRs are a common clinical problem.
Causes adverse consequences to patients…
From mere inconvenience to death and
Have very high incidence in clinical practice
For marketed drugs in USA
Occur in 5% of all hospital admissions
10-20% of hospital inpatients
About 25% in general practice
Significant cause of death (0.5-0.9%)
In the UK Non Steroidal Anti-Inflammatory Drug (NSAID) use alone accounts for1 • 65,000 emergency admissions/year• 12,000 ulcer bleeding episodes/year• 2,000 deaths/year
1Blower et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: 283-291
Consequences of ADRs:
Adversely affects patients’ quality of life
Complicate drug therapy
Decrease compliance and delay cure
Increase cost of patient care
Cause patients to lose confidence in their doctors
May mimic disease, resulting in unnecessary investigations and delay in treatment
Mild
Do not require an antidote, therapy, or prolongation of hospitalization
Commonly known as side-effects
Moderate
Require a change in, but not necessarily cessation of the drug and may prolong hospitalization or require special treatment
ADR: Severity of event:
SevereAre potentially life threatening, requiring
discontinuation of the drug and specific treatment of the adverse reaction
Lethal Directly or indirectly contributes to the patient's
death
• Result in death• Life-threatening• Require hospitalization• Prolong hospitalization• Cause disability• Cause congenital anomalies• Require intervention to prevent permanent
injury
FDA: Serious ADR
Type A (known pharmacological adverse drug reactions)
Type A reactions represent an Augmentation of the pharmacological actions of a drug
Predictable & dose-dependent
Readily reversible on reducing the dose or withdrawing the drug.
Commonest type of ADRs (accounting for over 80% of all ADRs)
Not usually life threatening.
Effects due to extension of the primary pharmacological actions of the drug
Augmentation of the drug's therapeutic actions
Example: Bradycardia with Propranolol(due to effect on desirable beta1 blocking effect)
Effects due to the secondary pharmacology of the drug
The action different from the drug's therapeutic actions
The action still rationalisable from the known pharmacology of the drug
Example: Bronchospasm with propranolol (due to effect on undesirable beta2 blocking effect)
Thus, for propranolol:Bradycardia is primary pharmacological adverse
effects
Bronchospasm is a secondary pharmacological adverse effect.
More emphasis is now placed on the secondary pharmacology of new drugs during preclinical evaluation to anticipate problems that might arise once the drug is given to humans.
Type B adverse reactions: (unknown pharmacological adverse drug reactions)
These are Bizarre
Not predictable i.e., cannot be predicted from the known pharmacology of the drug.
Not dose dependent
Can’t be readily reversed
Less common but often serious
Life threatening
Idiosyncrasy: (Pharmacogenetics)
Inherent qualitative abnormal response to a drug
Due to genetic abnormality, mainly due to deficiency of enzymes in the body
Also may be due to abnormal receptor activity
Incidence:
Happens to very small population
Rare but serious
Idiosyncrasy due to enzyme abnormalityHemolysis with primaquine
if glucose 6-phosphate dehydrogenase (G6PD) enzyme deficiency in any person
⇓If primaquine given
⇓Hemolysis leading to hemolytic anemia
Idiosyncrasy due to receptor abnormality
Malignant hyperthermia with general anesthetics (Halothane)
Sudden huge rise in IC calcium concentration
Increase in muscle contraction
Increase in metabolic activities
Rise of body temperature
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)
Types of allergic reactionsType 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
Type C or Continuous type:
Happens due to long term chronic use of a drug
Involves dose accumulation
e.g. Analgesic nephropathy with Paracetamol / NSAIDs
Type DDelayed effectADRs are found long term after use of drug
TeratogenesisCarcinogenesis
Teratogenesis: birth defect that is evident after birth but the drug taken during 1st trimester of pregnancy
Carcinigenesis: carcinoma detected long after use of a drug
Teratogenesis
Teratogenesis is the abnormal congenital malformation of fetus due to use of some drugs in 1st trimester of pregnancy
(4-10 weeks: period of organogenesis)
Teratogenic drugs:
1st detected teratogenic drug is ‘thalidomide’
It causes ‘phocomelia’--flipper-like limb defect (like penguin)
Thalidomide disaster in early ‘60s
Other teratogenic drugs:
Cytotoxic (anticancer) drugs Vitamin A (retinoid)Antithyroid drugsSteroid preparationsOAHs oral anticoagulants etc.
In general, all drugs should be avoided in 1st trimester of pregnancy to avoid teratogenic risk
Type E
Ending of drug use
ADRs are manifested after withdrawal of a drug which was used for a long period
When glucocorticoid is abruptly withdrawn/discontinued after prolonged use
Adrenocortical insufficiency
Suddenly body suffers from glucocorticoid crisis
Who might get an ADR?
Anyone who takes a medicine Differential diagnosis should include the
possibility of an ADR if the patient is taking any form of medication
Who is most at risk from ADRs?
Patients who;
are young, or old or female
are taking multiple therapies
50% of patients on 5 drugs or more
have more than one medical problem
have a history of allergy or a previous reaction to drugs
What should raise suspicion of an ADR?
A symptom that….
appears soon after a new drug is started
appears after a dosage increase
disappears when the drug is stopped
reappears when a drug is restarted
ADEs: Most Commonly Involved Drugs:
Antibiotics
Antineoplastics
Cardiovascular drugs
Hypoglycemics
NSAID/Analgesics
CNS drugs
Most Common ADEs:
Gastrointestinal tract events 22.1%
Electrolyte/renal 16.7%
Hemorrhagic 12.7%
Metabolic/endocrine 9.5%
Dermatologic (skin) /allergic 7.9%
Common Symptoms From ADEs:
Confusion
Nausea
Decreased balance
Change in bowel pattern
Sedation
Orthostatic hypotension
What conditions are often drug related?
Anaphylaxis
antibiotics, iron dextran injection
Stevens Johnson Syndrome
associated with carbamazepine, antibiotics
Blood dyscrasias
neutropenia with methotrexate and gold salts
thrombocytopenia with heparin
What questions should be asked if suspect an ADR?
Does the patient have a history of other drug-induced problems?
ask the patient
Does the patient take more than one drug ?
could an interaction be causing the ADR?
long term medication is unlikely to cause new problems
What else ...? When did the reaction or symptoms begin?
timings are useful
Have any of the clinical measurements or lab results recently become abnormal?
Does the patient have any medical problems?that could be causing the symptoms?some diseases predispose patients to ADRs
Causes of ADRs
ADRs may be due to:Drug causePatient causePrescriber’s error---
Type C D & E
Polypharmacy
Factors predisposing to ADRsA) Dose factor:Due to administration more than therapeutic dose
excessive insulin⇓
hypoglycaemia
B) Pharmaceutical factor:Due to wrong pharmaceutical preparation
Slow release NSAID⇓
Release in high concentration due to faulty preparation
⇓GIT bleeding
C) Pharmacokinetic factor:Due to decrease kinetic activities
Sulfonylurea⇓
Decreased elimination in renal insufficiency⇓
Hypoglycaemia
D) Pharmacodynamic factor:Due to drug’s mechanism of action
NSAID⇓
LVF due to salt & water retention
E) Polypharmacy: Drug-drug interaction factor:Erythromycin + terfenadine= Arrhythmia
Prevention of ADRs
Whenever a drug is given a risk is taken
Risks may be avoidable or unavoidable
30-50% ADRs are preventableDrug interaction
Inappropriate medication
Unnecessary medication
Reduction of ADRs can be achieved by:
Better knowledge of diseases
Better knowledge of drugs
Site-specific delivery
Informed, careful and responsible prescribing
Management of ADRs:
Mild ADRs can often be recognized before they
become serious.
If an ADR occurs, the type and precipitating factors
must be determined immediately if possible.
Discontinue the offending agent if:it can be safely stoppedthe event is life-threatening or intolerablethere is a reasonable alternative
Continue the medication (modified as needed) if:it is medically necessarythere is no reasonable alternativethe problem is mild and will resolve with time
Discontinue non-essential medications
Administer appropriate treatmente.g., atropine, antihistamines, epinephrine,
corticosteroids, glucagon etc
Provide supportive or palliative caree.g., hydration, glucocorticoids, warm / cold
compresses, analgesics etc
Consider desensitization
Generally,
For dose-related ADRs:
Modify the dose or reduce precipitating factors
For ADRs unrelated to dose:
The drug usually should be withdrawn and re-exposure should be avoided.