1. Dr. Badar Uddin Umar

2. Drugs have:
Beneficial effects
Harmful effects
Facts
Drugs save life & improve health
Drugs also threaten life

3. “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?”

4. 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

5. 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

6.  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.

7. ADRs are a common clinical problem.
Causes adverse consequences to
patients…
From mere inconvenience to death and
Have very high incidence in clinical
practice

8. 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%)

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
1
Blower et al. Emergency admissions for upper gastrointestinal
disease and their relation to NSAID use. Aliment Pharmacol Ther
1997; 11: 283-291

10. 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

11. ADRs are usually classified depending on
− Onset
− Severity
− Type

12. Acute
 Within 60 minutes
Sub-acute
 1 to 24 hours
Latent
 > 2 days
ADR: Onset of event:

13. 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:

14. Severe
Are 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

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

16. 2 main types:
 Type A (Augmented)
 Type B (Bizarre)
3 other sub-types:
Type C, D & E

17. Type A (known pharmacological adverse drug
reactions)
 Type A reactions represent an Augmentation of
the pharmacological actions of a drug
 Predictable & dose-dependent

18. 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.

19. Type A adverse reactions:
Are of 2 types:
A) Extension of primary effect
B) Secondary effect

20.  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)

21. 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)

22. 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.

23. 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

24. Type B ADRs may be:
1) Idiosyncrasy
2) Drug Allergy or Hypersensitivity

25. 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

26. Idiosyncrasy due to enzyme abnormality
Hemolysis with primaquine
if glucose 6-phosphate dehydrogenase (G6PD)
enzyme deficiency in any person
⇓
If primaquine given
⇓
Hemolysis leading to hemolytic anemia

27. 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

28. 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)

29. 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

30. 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

31. Type D
Delayed effect
ADRs are found long term after use of drug
Teratogenesis
Carcinogenesis
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

32. 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

33. Other teratogenic drugs:
Cytotoxic (anticancer) drugs
Vitamin A (retinoid)
Antithyroid drugs
Steroid preparations
OAHs
oral anticoagulants etc.
In general,all drugs should be avoided in 1st
trimester of pregnancy to avoid teratogenic risk

34. 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

35. 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

36. 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

37. 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

38. ADEs: Most Commonly Involved Drugs:
Antibiotics
Antineoplastics
Cardiovascular drugs
Hypoglycemics
NSAID/Analgesics
CNS drugs

39. Most Common ADEs:
Gastrointestinal tract events 22.1%
Electrolyte/renal 16.7%
Hemorrhagic 12.7%
Metabolic/endocrine 9.5%
Dermatologic (skin) /allergic 7.9%

40. Common Symptoms From ADEs:
Confusion
Nausea
Decreased balance
Change in bowel pattern
Sedation
Orthostatic hypotension

41. 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

42. 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

43. 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

44. Causes of ADRs
ADRs may be due to:
Drug cause
Patient cause
Prescriber’s error---
Type C D & E
Polypharmacy

45. Factors predisposing to ADRs
A) Dose factor:
Due to administration more than therapeutic dose
excessive insulin
⇓
hypoglycaemia

46. B) Pharmaceutical factor:
Due to wrong pharmaceutical preparation
Slow release NSAID
⇓
Release in high concentration due to faulty
preparation
⇓
GIT bleeding

47. C) Pharmacokinetic factor:
Due to decrease kinetic activities
Sulfonylurea
⇓
Decreased elimination in renal insufficiency
⇓
Hypoglycaemia

48. 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

49. Other factors:
age
gender
multiple disease
allergy

50. Prevention of ADRs
Whenever a drug is given a risk is taken
Risks may be avoidable or unavoidable
30-50% ADRs are preventable
Drug interaction
Inappropriate medication
Unnecessary medication

51. Reduction of ADRs can be achieved by:
Better knowledge of diseases
Better knowledge of drugs
Site-specific delivery
Informed, careful and responsible prescribing

52. 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.

53. Discontinue the offending agent if:
it can be safely stopped
the event is life-threatening or intolerable
there is a reasonable alternative
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

54. Discontinue non-essential medications
Administer appropriate treatment
e.g., atropine, antihistamines, epinephrine,
corticosteroids, glucagon etc
Provide supportive or palliative care
e.g., hydration, glucocorticoids, warm / cold
compresses, analgesics etc
Consider desensitization

55. 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.

56. Thank you very much