ADR

1. Lok RajBhandari

2. All Drugs are
Dangerous
No Drugs are
Dangerous if
used properly
How dangerous a drug
is depends on the skill of
the prescriber
The most
dangerous drugs
have the greatest
potential for
benefit
Some drugs are
dangerous in
acute poisoning
but not when
used
therapeutically
Some drugs
have a low
therapeutic ratio
Some drugs have a
low incidence of
harmful effects
Some adverse
effects can be
predicted if you
know the
pharmacology
(Type A); some
are not (Type B)
Some adverse
effects occur
after a delay or
after stopping
BAD
GOOD

3.  Adverse effect is ‘ any undersirable or
unintended consequences of drug
administration’
 It include all noxious effect
 ADR is any noxious change which is
suspected to be due to a drug, occurs at
therapeutic doses, require treatment or
decrease in dose or indicates caution in the
future use of same drug
 Common cause– multiple drug therapy
elderly
prolong drug therapy

4. Any noxious, unintended, undesired effect
of a drug which occurs at doses used for
prophylaxis, diagnosis, or therapy,
excluding therapeutic failures, intentional
and accidental overdose and drug abuse,
and does not include AEs due to errors in
drug administration.

5. 30% of medical inpatients
develop an ADR
3% of all hospital admissions
are due to ADRs
Risk of an allergic reaction is
approximately 1-3% for most
drugs

6. ADR is divide into
 Predictable ( Type A) reactions
 UnPredictable ( Type B) reactions
Predictable ( Type A) reactions
 Based on pharmacological properties of drug
 Dose dependent
 Related to drug’s actions
 Occur in normal patients
 They are common 80% of adverse effects
 Preventable and reversible
◦ E.g : side effect, toxic effects & consequences of drug
withdrawal.

8. Unpredictable ( Type B) reactions
 It is based on pecularities of the patients
and not on drug’s known action
 Dose-independent
 Not related to drug’s actions
 Related to immune response (allergy)
 Less common
 More serious
 Require withdrawal of drug
 Some reaction can be predicted and prevented if their
genetic basis is known

10. 10
Adapted From: http://www.aafp.org/afp/20031101/1781.html
Nonimmunologic
Predictable
Pharmacologic side effect Dry mouth from antihistamines
Secondary pharmacologic side effect Thrush while taking antibiotics
Drug toxicity Hepatotoxicity from methotrexate
Drug-drug interactions Seizure from theophylline while taking erythromycin
Drug overdose Seizure from excessive lidocaine (Xylocaine)
Unpredictable
Allergic Anaphylactoid reaction after radiocontrast media
Idiosyncratic Hemolytic anemia in a patient with G6PD deficiency after primaquine therapy
Intolerance Tinnitus after a single, small dose of aspirin
G6PD = glucose-6-phosphate dehydrogenase.

11. 11
Adapted From: http://www.vh.org/adult/provider/pharmacyservices/PTNews/2003/may.html

12. Severity of ADR
Minor :No therapy, antidotes or
hospitalization
Moderate : Require change in drug therapy,
specific treatment or prolong hospital stay
Severe : Potentially life threatening, cause
permanent damage or require intensive
care
Lethal : Directly or indirectly contributes to
death

13. 1. Avoid all inappropriate use of drugs in the context of
patient’s clinical condition
2. Use appropriate dose, route and frequency of drug
administration based on patient’s specific variables
3. Never use any drug unless there is good indication.
4. If the patient is pregnant do not use the drug unless the
need is imperative.

14. 5. Elicit and take into consideration previous
history of drug reactions like allergic disease
6. Rule out possibilities of drug interaction when
more than one drug is prescribed
7. Carry out appropriate laboratory monitoring
( prothrombin time with warfarin, serum drug
level with lithium)
8. Prescribe as few drugs as possible and give
clear instructions
9. Where possible use familiar drugs. With new
drugs be particularly alert for ADRs and
unexpected event.

16. ADR may be categorized into:
1. Side effect:
 Unwanted but often unavoidable effect that
occur at therapeutic dose
 Decrease dose --- decrease symptom
 It is based on the same action as the
therapeutic effect:
◦ Example :
◦ Atropine - preanaesthetic medication
( antisecretory action)- dryness of mouth ( SE)
◦ Aspirin - decrease PG-- gsatritis
◦ Acetazolamide - diuretics( increase HCO3
excretion)-- acidosis

17. 2. Secondary effect:
 These are indirect consequences of a primary
action of the drug
Example : suppression of bacterial flora by
tetracycline causes superinfection.
3. Toxic effect:
 Excessive pharmacological action of drug due to
overdosage or prolonged use.
 Overdose may be accidental, homicidal, suicidal
or usual dose of gentamicin in renal failure
 Predictable, dose related
◦ Example : morphine -- respiratory depression
overdosage
◦ Imipramine -- antidepressant --- cardiac arrthymia
◦ Streptomycin -- vestibular damage-- prolong use
◦ Severe hypoglycemia--- overdose Insulin

18. 4. Intolerance :
 It is the appearance of characteristic toxic
effect of a drug in an individual at
therapeutic doses
 It is converse of tolerance and indicates a
low threshold of the individual to the action
of the drug
◦ Example : single dose of triflupromazine induces
muscular dystonias in some individual
◦ Few doses of carbamazipine may cause ataxia in
some patients
◦ Chloroquine -- vomitting and abdominal pain in
occasional pts

19. Tolerance :
 It result from regular drug use and can be defined
as a state in which a particular dose elicit a
smaller response than it formely did.
 As tolerance increases, higher and higher doses
are needed to elicit desired effects.
Cross- tolerance:
 It is state in which tolerance to one drug confers
tolerance to another drug.
 Cross tolerance generally develop among drugs
within a particular class but not between drugs in
different classes.
 Examples :
◦ Tolerance to one opoid ( heroin) confers cross
tolerance to other opoids( meperidine) but not to CNS
depressant, psychostimulant, nicotine.

20. 5. Idiosyncrasy:
 It is genetically determined abnormal reactivity to
chemical
 Certain uncharacteristic drug effect due to
peculiarities of an individual are included among
idiosyncratic reaction
◦ Example ;barbiturates causes excitement and mental
confusion in some individual
6.Drug allergy:
◦ It is immunologically mediated reaction producing
sterotype symptoms which are unrelated to the
pharmacodynamic profile of the drug and are largely
independent of dosage. This is called
mild itching --- rashes ---- anaphylactic

22. 22
Used with permission from Michelle Ehrlich, MD and eMedicine.com, Inc., 2005

23. 23
Used with permission from Carl Allen, DDS and eMedicine.com, Inc., 2005

24. Treatment of drug allergy:
◦ Antihistamine beneficial in Type I
◦ Inject adrenaline 0.5mg i.m
◦ I.V glucocorticoid use in Type II, III, IV

25. Drug that frequently cause allergic reactions are :
 Penicillin
 Tetracycline
 Cephalosporin
 Salicylates
 Anti tuberculosis
 Carbamazepine

26. 7. Photosensitivity :
It is cutaneous reactions resulting from drug
induced sensitization of the skin to UV
radiation
Two types :
1. Phototoxic:
1. Drug or its metabolites accumulates in the skin,
absorb light and undergoes a photochemical &
photobiological reaction resulting into local tissue
damage i.e sunburn, erthema, edema, blistering
followed by hyperpigmentation
2. Example : tetracycline, floroquinolones
2. Photoallergic :
1. Drug or metabolites induces a cell-mediated
immune response which on exposure to light
produce eczematous contact dermatitis ( wheal,
flare) exposure to sun.
2. Examples : sulfonamides, griseofulvin, chloroquine

27. 8. Drug dependence:
Drugs capable of altering mood and feeling are
liable to repetitive use to derive euphoria,
withdrawal from reality, social adjustment etc
Use of drug for personal satisfaction often in the
face of known risks to health
1. Psychological dependence:
1. It is said to have developed when the individual
believes that the optimal state of well being is
achieved only through the action of drug
2. Example : opoids, cocaine, BZD
1. Physical dependence:
1. It is altered physiological state produced by repeated
administration of a drug which necessitates the
continued presence of the drug to maintain the
physiological equilibrium.
2. Discontinuation - withdrawal syndrome
3. Example : Opoids, barbiturates, amphetamine etc

28. Drug abuse :
◦ Refers to use of drug by self medication in a
manner and amount that deviates from approved
medical and social pattern in a given culture at a
given time.
◦ It refer to use of an illicit drugs
Drug addiction:
◦ It is the pattern of compulsive drug use
characterized by overwhelming involvement.
◦ Even after withdrawal some get relapse
◦ Example :amphetamine, cocaine, canabis
produce addiction but no physical dependence
◦ Nalorphine  physical dependence abut no
seeking behaviour

29. Drug habituation :
It denotes less intensive involvement with the drug
so that its withdrawal produces only mild
discomfort.
Consumption of tea, coffee, tobacco, social drinking
are regards as habituation, physical dependence
is absent.

30. 9. Drug withdrawaL reaction:
 Apart from drug produce dependence
sudden interruption of therapy with other
drugs result adverse conequences.
 Example :
◦ Severe HTN, restlessness - discontinue of
clonidine
◦ Worsening of angina pectoris, MI - stoppage of
beta-blocker
◦ Frequency of seizure increase - stops of
antiepileptic drugs

31. 10. Teratogenicity :
‘Drug induced birth defect’
It refers to capacity of a drugs to cause foetal
abnormalities when administered to the pregnant
women
In 1958-1961 Thalidomide disaster - babies born with
phocomelia ( seal like limbs)
Drugs can affect the faetus at three stages:
1. Fertilization & implantation: 17days, unnoticed failure of
pregnancy
2. Organogenesis: 18-55days, most vulnerable period for
deformities to produce
3. Growth & development: 56days onwards,
developmental & functional abnormalities
Examples : aspirin,phenytoin (D) ,
atropine , morphine ( C),
estrogen, ergometrine( X)
It is wise to avoid all drugs in pregnancy

32. 10. Carcinogenicity & mutagenicity effect
 It refers to ability of certain medication to
cause cancer & genetic defect respectively
 Several anticancer drugs causes cancer
itself
 Neoplastic disease- develops after10-20
years
 Few drugs cause cancer e.g
radioisotopes, estrogen, tobacco
◦ Usually oxidation of drug results in the production
of reactive intermediates which affect genes and
may cause structural changes in the
chromosomes

33. 11. Drug induced diseases:
 These are also called iatragenic ( physician
induced) and are functional disturbances
(disease) caused by drugs which may
persist even after the offending drugs has
been withdrawn and largely eliminated.
◦ Examples : peptic ulcer salicylates &
corticosteroid
◦ Hepatits - isoniazid
◦ Parkinsonism - phenothiazone

37. 37
 Simultaneous use of several different drugs
◦ Drug-drug interactions
 Very young, or very old in age
 Pregnancy
 Breast Feeding
 Hereditary Factors
 Disease states which may effect drug absorption,
metabolism, and/or elimination
Reference: http://www.merck.com/mmhe/sec02/ch015/ch015e.html

38. 38
 Coumadin-NSAID interactions (increased inhibition of
platelet aggregation)
 Antacid and tetracycline
References: Psaty BM, et al, JAMA, 2004 Dec 1; 292 (21), 2622-31
Van Dijk KN, et al, Thromb Haemost, 2004 Jan; 91(1), 95-101
Levin, GM, et al, Psychopharmacol Bull, 2001 Spring, 35 (2) 62-71

39. 39
 Children are often at risk because their capacity to
metabolize drugs is usually not fully developed
◦ Newborns cannot metabolize or eliminate
chloramphenicol, an antibiotic
◦ Children younger than 18 may be at risk of developing
Reye’s syndrome if given acetylsalicylic acid (aspirin)
while infected with chickenpox or influenza
References: http://www.merck.com/mmhe/sec02/ch015/ch015e.html
Shechter T, et al, Pharmacoepidemiol Drug Saf. 2004 Nov 1

40. 40
 ADRs, including drug interactions, are a common
cause of admission to hospitals in the elderly
 Reasons for ADRs in the elderly:
– Concomitant use of several medications
– Disease states leading to drug ADME changes
– Decreased drug ADME activity due to age
 These conditions are exacerbated by malnutrition
and dehydration, common in the elderly
Reference: Routledge P.A., O’Mahoney, M.S., Brit. Journ of Clinical
Pharmacology, 2003, 57 (2), 121-126

41. 41
Use of sulfonamides (antibiotic) can lead
to jaundice and brain damage in the fetus
Warfarin use for anticoagulation can lead
to birth defects, and increased risk of
bleeding problems in newborns and
mothers
Lithium, for manic disorder, can lead to
defects of the heart, lethargy, reduced
muscle tone, and underactivity of the
thyroid gland
Reference: http://www.merck.com/mmhe/sec22/ch259/ch259a.html#tb259_1

42. 42
Similar concerns, as for other children with
underdeveloped capability to metabolize or
excrete
Many drugs can be passed from mother to
infant via breast milk
– Amantadine (antiviral)
– Cyclophosphamide (antineoplastic)
– Cocaine (Schedule 2 FDA drug)
– Carisoprodol (skeletal muscle relaxant)
Reference: http://www.perinatology.com/exposures/druglist.htm

43. 43
 Higher risk of hemolysis in some populations,
such as African, Middle Eastern, and South
East Asian races
– Quinolones
– Antimalarials
Reference: http://www.cppe.man.ac.uk/openlearning/e_adr/section2.asp
Odani A, et al., Clin Pharmacol Ther, 1997 Sep;62(3):287-92

44. 44
Metabolism (Phase I or II) may be
impaired with hepatic disease
– Cirrhosis
– Hepatic Carcinoma
Renal Insufficiency
– Acute or Chronic Renal Failure
– Decreased glomerular filtration rate (GFR)
Drug levels may become toxic if too
high, so dosing modifications may be
indicatedReference: http://www.emedicine.com/med/topic374.htm

45. Thank you