Study of drug in the community level to assess adverse drug effects

1. FACILITATOR: OSMAR RODRÍGUEZ CORONA. MSc. IN PHARMACEUTICAL SERVICES
PHARMACOLOGIST. ASSISTANT PROFESOR . AGREGATE INVESTIGATOR.
TOPIC II- Pharmacovigilance 2nd
part.
Adverse Drug Reaction (ADR). Classification,
evaluation and report.

2. ADVERSE DRUG REACTIONS
(ADRs) US ADVERSE DRUG EVENT
DO THEY MEAN THE SAME THING ?

3. ADVERSE DRUG EVENT
Is any insult that appears as a result
of the use of drug.

4. Any response to a drug which is noxious and unintended, and which occurs at
doses normally used in man, for: prophylaxis, diagnosis, or therapy of disease,
or for the modification of physiological functions.
ADVERSE DRUGS REACTIONS (ADRs)
EXCLUDING……….
Therapeutic failures
Intentional and accidental overdose
Drug abuse
Errors in drug administration
Taken of: International Drug Monitoring Programme, September, 1991.
http://www.who-umc.org/umc.html

5. RELATIVE OVERDOSE:
Administered drugs to habitual dose, but due, to
characteristic special pharmacokinetics, their systemic
circulating concentrations are higher.
Eg: Patient with renal failure, they have bigger incidence
of deafness, when they are treated with antimicrobials
aminoglycosides. Eg: Streptomycin. There is necessary
and dose adjustment or change the therapy.

6. SECONDARY EFFECT:
Undesirable effect, that It is not due to the main pharmacological
action mechanism, but, It is consequence of the looked for effect.
Ex: bacteriostatic action of the Tetracycline, Ciprofloxacin, or
Chloramphenicol, can alter the intestinal bacterial flora, the square
of Disbacteriosis it would be the secondary action

7. All Drugs are Dangerous No Drugs are Dangerous
if used properly
How dangerous a drug is, depends on the skill
of the prescriber
Some drugs have a low
therapeutic ratio
Some drugs have a low
incidence of horrendous effects
Some adverse effects can be
predicted if you know the
pharmacology (Type A); some
are not predicted (Type B)
Some adverse effects
occur after a delay or after
stopping
BAD
GOOD
ASPECTS TO KEEP IN MIND

8. CLASIFICATION OF ADRs ACORDING TO THEIR
INTENSIVITY OR SEVERITY
MILD : They don't put in risk the patient's life and they are passable
MODERATE: They put in risk the patient's life and the patient needs to
be treated or to suspend the treatment
SERIOUS: They put in risk the patient's life and he/she needs to be
hospitalized, and usually they leaves sequels.
LETAL OR MORTAL: They cause the death

9. CLASIFICATION OF ADRs ACORDING TO
OUTCOME
RECOVERY WITHOUT SEQUELE
RECOVERY WITH SEQUELE
NO RECOVERY
 DEATH

10. CLASSIFICATION OF THE ADRs, ACCORDING TO MECHANISM OF
PRODUCTION
1. COLATERAL EFFECT
2. PARADOXICAL EFFECT
3. TOXIC EFFECT
4. HYPERSENSITIVITY
5. IDIOSYNCRASY
6. EFFECT TERATOGENICO
7. PHENOMENON OF IT BOUNCES
8. TOLERANCE
9. TAQUIFILAXIA
10. DEPENDENCE
11. RESISTANCE OR DRUG IMMUNITY.
12. INTOLERANCE OR HIPERSUCEPTIBILITY
13. HERXHEIMER REACTION
14. VIRAL DRUG-INFECTION INTERACTION
INDEPENDIENT STUDY: Bibliography: Pharmacology General textbook

11. 1 - HYPERSENSITIVITY OR ALLERGIC REACTION:
It is the appearance of an unusual answer after the administration of a medication after the
patient has contacted normal concentrations of this in a more previous occasions
(contact sensitizing and trigger).
It has an immunologic base (Reaction antigen - antibody)
Example: (Fever, angioneurotic edems, Rash, shock anaphylactic). (Penicillins,
Sulphonamides, Aspirin , etc.)
Study Independent:
Types of hypersensitivity reactions :1- Anaphylactic or immediate, 2- cytotoxic, 3- by
immune complex formation and 4- Dilayed ) and examples. General pharmacology
textbook

12. 2 - IDIOSYNCRASY.
Atypical answer to a drug, used in appropriate dose, very tolerated for most of
those that receive it. It happens when the medication is administered for the
first time.
It is genetically certain and very related with enzymatic deficiencies.
Example: Hemolytic crisis for oxidant drugs, in patient with deficit of G-6-P -
Dehydrogenase . EX: Primaquine, ASA, Chloramphenicol, etc.

13. 3 - COLLATERAL EFFECT (DIFFERENT FROM
SECONDARY ACTION)
It depends on the mechanism of action of the
medication, It almost always appears when it is
administered and the intensity is dependent of the dose,
in general they are not dangerous for the patient's life.
Example: Nitroglycerine: Intense migraine for effect
vasodilator on the arteries meninges.

14. 4 - TOXIC EFFECT OR ON RELATIVE DOSE.
It can appear in all the fellows if the dose is sufficiently high, for direct toxic
effect of the drug or its metabolites. It depends on the dosage, time of exhibition,
of certain pathological states and of the sick person's susceptibility, and the
possibility exists of committing the patient's life.
Example: Ototoxicity and nephrotoxicity for aminoglycosides (Amikacin,
kanamycin, Streptomycin).

15. 5 - Paradoxical effect.
It is an opposed effect to the prospective or habitual that
clinically is same or resemblance to the pathological square for
which the own medication was used.
Example: Bronchodilator in aerosol (Salbutamol), can cause
bronchospasm.

16. 6 - TERATOGENIC EFFECT.
They are the malformations or anomalies of anatomical or functional character
caused in the fetus by the administration of medications to the mother during the
gestation.
Independent study:
 Categories of drug risk during the pregnancy according to the FDA.
(A,B,C,D,E and X)
General pharmacology tesbook

17. 7 – PHENOMENON BOUNCE OR WITHDRAWAL SYNDROME.
It happens for the abrupt suppression of the medication, and it shows a quick
investment and notable of the effect therapeutic initial.
Example: Cimetidine appears multiple peptic ulcers and bleeding., B- blockers
(Hypertension), Steroids (allergic crisis)
8 - TOLERANCE.
Gradual decrease of the answer to a drug when one administers during a lingering time.
Example: Diazepam

18. 9 - TAQUIFILAXIA.
It is the quick decrease of the answer to a drug, when it is administers repeatedly. It is a
short term tolerance.
Example: Ephedrine like bronchodilator.
10-DRUG DEPENDENCE: The patient can not stop the consumption of drug
Independent work. Dependence the nicotine, alcohol, cannabis (marijuana) cocaine and
others drugs.
11- RESISTANCE.
Total loss, of the primary therapeutic answer, the very high doses are even tolerated
without toxicity manifestations. It can be congenital or acquired.
Example: The Cytostatic, Morphine

19. 12-INTOLERANCE.
Very exaggerated undesirable answer that happens with very small dose of the drug. It has genetic origin.
Example: Intolerance to the iodine.
13 - REACTION OF HERXHEIMER.
When using antimicrobial that cause the death of great quantity of microorganism, these microorganism can
liberate toxins that cause toxic effects.
Example: Treatment of the Typhoid fever with Chloramphenicol.
14 - REACTION CAUSED BY THE INTERACTION VIRAL DRUG-INFECTION.
Example: Syndrome of Reye (Encephalopathy with serious Hepatotoxicity). Children with infections for virus
chicken pox zoster or influenza type B, tried with acetylsalicylic acid.

20. A B C
D E F
CLASSIFICATION OF THE ADVERSE DRUG REACTIONS ACCORDING TO
PHARMACOEPIDEMIOLOGICAL CRITERIA OF RAWLINS AND THOMPSON
On this classification are grouped the previous
classifications
INDEPENDIENT STUDY:
GENERAL PHARMACOLOGY TEXTBOOK. CLASSIFICATION OF THE ADVERSE DRUG
REACTIONS ACCORDING TO PHARMACOEPIDEMIOLOGICAL CRITERIA

21. (Augmented/predictable) reactions
 - They are originates for exaggeration of the drug effect
 - They are predictable, or at least, expected.
 - Their intensity depends on the administered dose.
 - Their treatment requires dose adjustment.
 - It can be due to the pharmaceutical form of the medication, drug interaction, or other pathologys
asociate.
- They depend the mechanism of action of the medication
TYPE A:

22. Examples of Type A
• Collateral effects: (e.g sedation with antihistamines)
• Secondary effects: (e.g. development of diarrhea With antibiotic therapy
due to altered gastrointestinal bacterial flora) Ciprofloxacin in high dose
• Drug interaction: (e.g. Theophylline toxicity in the presence of
Erythromycin therapy. By Methabolical Inhibition )

23. Factors predisposing to pharmacological adverse drug reactions
Factor Example Toxicity Mechanism
Pharmaceutical Osmosin Gastrointestinal Release of high
(slow release bleeding concentrations of
indomethacin) active drug locally
in GI
Pharmacokinetic* Digoxin Digoxin toxicity Decreased elimination
(nausea, arrhythmias) if renal function is
impaired
Pharmacodynamic Indomethacin Left ventricular Water and sodium
failure retention
Drug-drug TerfenadineTM Prolonged QT Inhibition of
interaction* Erythromycin interval and metabolism of
torsades de terfenadine by
pointes erythromycin
*Can affect absorption, distribution, metabolism, or excretion.

24. Ways to minimize both pharmacokinetically- and
pharmacodynamically-derived ADRs include
Understanding the pharmacology of the drug being prescribed
Monitoring drugs with a narrow therapeutic window
Avoiding polypharmacy whenever possible

25. Type B (bizarre/unpredictable) reactions
• Cannot be predicted from the pharmacology of the drug
• Type B reactions include idiosyncratic reactions, Hypersensitivity
immunologic or allergic reactions (e.g.anaphylaxis by Penicillins),
• While uncommon, are often among the most serious and potentially life-
threatening of all ADRs, and are a major cause of important drug-induced
disease.
• Not dose dependent, host dependent factors important in genetical
pre-disposition

26. Type B (bizarre/unpredictable) reactions
Reactions Example
Intolerance tinnitus with use of Aspirin)
Hypersensitivity Immunological reaction (e.g.
Anaphylaxis with penicillin
administration.
Pseudoallergic (Non-Immunological) reaction ( radio
contrast dye reaction).
Idiosyncratic reaction (e.g. development of haemolytic
anemia with the use of anti-malarial
drugs in the presence of glucose-6
phosphate dehydrogenase deficiency).

27. Differs among the ADRs type A
and type B

28. Variable A B
Dose Dependent Dose Independent
Nature or adnormality quantitative qualitative
Predictable yes No
Liver or renal
dysfunction
Increase the Toxicity,
depending of the revoval way
No affected
Prevention Dose Adjustment To avoid the use
Treatment lower Dosis Discontinue the
administration
Mortality Usually low Usually high

29. Type “C” (chronic) reactions
These reactions are associated with long-term drug therapy
e.g. Benzodiazepine – tolerance and dependence
Paracetamol- hepatotoxicity.
Aspirin - nephropathy .
They are well known and can be anticipated.
Type “D” (Delayed) reactions
These reactions refer to carcinogenic and teratogenic effects. These reactions are
delayed in onset and are very rare since extensive mutagenicity and carcinogenicity
studies are done before drug is licensed.
E.g. Secondary tumours after treatment with chemotherapy,
Teratogenic effects of phenytoin taken during pregnancy,

30. Type E ( End of treatment) reactions
Bounce phenomenon or withdrawal effect
• The illness for which the medication was indicated
becomes worse
• Occur on withdrawal especially when drug is stopped
abruptly
E.g.
 withdrawal seizures on stopping Phenytoin,
 Adrenocortical insufficiency on withdrawal of steroids
Prednisone

31. As type F is concidered (Failure of Therapy ~ Fail unexpected of the therapy; also
Foreing or strange )
• They often happen for interactions and they are dependent dose.
Example: Fail of the effect of the oral contraceptives, when they are used
with drug enzymatic inductor (Ampicillin).
Although it is a proposed category in a recent way, other authors use it to refer to the
unwanted effects caused at the beginning by other components of the medication,
including exicipients, contaminants or impuritis, (assuming the F to foreign or
stranger).
Type F ADRs

32. PREDISPOSING FACTORS FOR ADRS
THE MAIN CLINICAL FACTORS WHICH INCREASE THE CHANCE THAT PATIENTS
WILL EXPERIENCE AN ADVERSE REACTION ARE LISTED BELOW:
•Age
- The elderly and neonates are at greatest risk
•Gender
- Women are generally at greater risk
•Race
- Ethnic origin may affect drug metabolism
•Impaired excretory mechanisms
- Reduced hepatic and/or renal function
•Specific diseases
- e.g. Asthma and beta-blockers
•Polypharmacy
- Drug interactions (see below)
•Any previous history of an adverse drug reaction.

33. METHODS OF PHARMACOVIGILANCE
METHODS SOURCES OF OBTAINING ADRMS DETECTEDS
Statistical analysis Records of mortality
and morbility
Acute and sub-acute
reactions
Intensive
Monitoring inpatient
 Clinical record of
patient
 Interviews
Acute and sub-acute
reactions
Voluntary
Notification
 Yellow card or
expontaneus report
Unknown ADR
ADR of low-intensity
Pharmacoepidemiol
ogycal studies
Ex. Case control studies, Cohorte studies,
studies of drug utilización, clinical estudies,
Case study, studies of series of cases. traverse
 Research results
 Publications
 Early detection of ADR
 New drugs ADR

34. SPONTANEOUS REPORT OF ADRs SUSPICION.
Model through which the suspicion is notified that relationship
exists between the administration of a medication and the
appearance of the ADR
The same one picks up the referred basic data of the patient, to
the drug and the possible ADR
The information is sent to the Pharmacovigilance centers where
it is controlled, it analyzes and they are defined stocks in this
respect.

37. STANDARDIZED METHODS TO DETERMINE IMPUTABILITY OF THE ADRs
1- Karch F.E., Lassagna 1977
2- Dangouman J. et al. 1978
3- Blanc S.P. et al. 1979
4- Kramer M.S. et al. 1979
5- Venulet J.A. et al. 1980
6-Emanueli A. et al. 1980
7- Naranjo C.A. et al. 1981
8- Jones J. 1982
9- Lagier G. et al. 1983
10-Stephens H. 1984
These methods allow to know if the adverse event is an ADR or not

38. CLASIFICATION OF ADRs ACORDING IMPUTABILITY
PROVED OR ULTIMATELY
PROBABLE
POSSIBLE
QUESTIONABLE OR CONDITIONAL

39. ASPECTS THAT DEFINE THE ADR IMPUTABILITY
PROVED PROBABLE POSIBLE QUESTONABLE
1 - it shows a reasonable
temporary relationship after the
administration of the medication,
or it has been determined the
plasmatic levels of the drug in
liquids or fabrics.
YES YES YES YES
2 - well-known answer pattern
shows with the suspicious
medication.
YES YES YES OR NO NO
3 - you confirms by means of
improvement when suspending
the treatment, and
 it reappears when Its
administers again.
YES
YES
YES
YOU DON’T
NOW
NO
NO
NO
NO
4 - It cannot explain to himself
for the characteristics of the
YES YES YNO NO

40. PHARMACOVIGILANCE
What ADRs should be reported?
 Unknown ( are not reported in the bibliography)
 Unexpected
 All that appear with new drugs
 Serious (also when it is known)
 Fatal or life-threatening
 Malformations
 Unexpected beneficial effects
 Unexpected ineffectiveness

41. SOME ADRs OF SPECIAL
MONITORING BY
PHARMACOVIGILANCE

42. 'Thalidomide Babies'
Phocomelia flipper-like limbs
TERATOGENIC EFFECT

43. Angioedema
 Penicillin
 Sulfonamide

44. Erythema multiforme:
 Sulfonamide,
 Barbiturate
 NSAIDs
 Phenyltoin
 Allopurinol

45. Fixed-drug eruptions:
 Tetracyclin
 Sulfonamide

46. Toxic Epidermal Necrolysis (TEN):
 Penicillin
 Sulfonamide
 Barbiturate
 Hydantoin
 Nsaids
 Phenyltoin
 Allopurinol

47. STEVEN JOHNSON SYNDROME:
 Penicillin
 Sulfonamide
 Barbiturate
 Hydantoin
 Nsaids
 Phenyltoin
 Allopurinol