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Adverse Drug Reactions (ADRs):- PPT / PDF

Description

Adverse Drug Reactions
What is ADRs?

What is ADR ?
WHO Definition
Any response to a drug which
is noxious & unintended & which occurs at doses in man for prophylaxis, diagnosis or treatment.
• History about ADRs
• Common Causes of ADRs
• Factors affecting Adverse Drug Reactions
• Classification of ADRs
• Type A (Augmented) reactions
• Type B (Bizarre) reactions
• Type C ( Chronic)
• Type D (Delayed) reactions
• Type E (End of use) reactions
• Types of ADRs
• Classification of ADRs :
• Side effects
• Side effects….(Drug discovery)
• Toxic effect:
An adverse effect of a drug produced by an exaggeration of the effect that produce the therapeutic response.
• Predictable toxic effects
• Unpredictable toxic effects
• Idiosyncrasy
• Drug allergy
• Grading system for hypersensitivity reactions
• Intolerance
• Tachyphylaxis:
• Difference between Tachyphylaxis and Tolerance
• Photosensitivity
• Drug dependence
• Mutagenecity and Carcinogenicity
• Iatrogenic(Physician induced)
• Teratogenicity
• Individual variation in response to
• B) Variation in concentration of an
endogenous receptor ligand
• A) Alteration in concentration of
drug that reaches the receptors
• C) Alteration in number or function
of receptor
• D) Changes in components of
response distal to the receptor
• How to recognize ADRs
• Role of Pharmacist in the management of ADRs
• Aims of knowing ADRs
 To improve patient care and safety
 To improve public health and safety
 To contribute to the assessment of benefit, harm, effectiveness and risk of medicine.

  • Subject:- pharmacology 1
  • Course:- B.pharm (pharmacy),
  • Semester:- 4th sem , sem :- 4

ADVERSE DRUG
  REACTIONS
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                What is ADRs?


WHO Definition
Any response to a drug which
is noxious & unintended &
which occurs at doses in man
for prophylaxis, diagnosis or
treatment.



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             History about ADRs
1922 : JAUNDICE associated with the use of SALVARSAN,
an organic arsenical used in the treatment of Syphillis.


In 1937: In USA, 107 people died from taking an ELIXIR OF
SULFANILAMIDE          that    contained     the     SOLVENT
DIETHYLENE GLYCOL.


Establishment of the FOOD AND DRUG ADMINISTRATION
(FDA), which was given the task of enquiring into the safety
of new drugs before allowing them to be marketed.
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•   1958: Thalidomide marketed in West Germany as a non
barbiturate hypnotic & for morning      sickness during
pregnancy.


   In 1959 - 1961, it was reported in that there was an
outbreak of PHOCOMELIA (hypoplastic and aplastic limb
deformities) in the new born babies.




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   The THALIDOMIDE INCIDENT led to a public outcry, to
    the   institution   all   round   the   world   of   DRUG
    REGULATORY AUTHORITIES, to the development of a
    much more sophisticated approach to the preclinical
    testing and clinical evaluation of drugs before marketing,
    and to a greatly increased awareness of adverse effect
    of drugs and methods of detecting them.



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      Common Causes of ADRs
   Failing to take the correct dosages at the correct times.
   Overdosing.
   Allergies to chemical components of the medicine.
   Combining the medicine with alcohol.
   Taking other drugs or preparations that interact with the
    medicine.
   Taking a medicine that was prescribed for someone
    else.
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      Factors affecting Adverse
           Drug Reactions
   Patient-related factors
    Age
    Sex
    Genetic influences
    Concurrent diseases (renal,liver, cardiac)
    Previous adverse drug reactions
    Compliance with dosing regimen
    Total number of medications
    Misc. (diet, smoking, environmental exposure)

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     Factors affecting Adverse
          Drug Reactions
Drug-related factors:

   Dose

   Duration

   Inherent toxicity of the agent

   Pharmacodynamic properties

   Pharmacokinetic properties

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            Classification of ADRs
    Depending on
    Onset of event: Acute (<60 minutes), Sub-acute (1-24 hrs)
and Latent (>2 days)
    Type of reaction: (Wills and brown)
1.       A (Augmented)
2.       B (Bizarre)
3.       C (Chronic)
4.       D (Delayed)
5.       E (End of treatment)
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      Classification of ADRs
   Severity: Minor, Moderate, Severe, Lethal ADRs


   Others: Side effects, Secondary effects, Toxic
effects,   Intolerance,   Idiosyncrasy,   Drug   allergy,
Mutagenicity, Photosensitivity, Drug Dependence,
Drug       Withdrawal     Reactions,      Teratogenicity,
Carcinogenicity, Drug induced disease (Iatrogenic).


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        Type A (Augmented) reactions
   Reactions which can be predicted from the known
pharmacology of the drug
   Dose dependent
   Can be alleviated by a dose reduction
   common
   Skilled management reduces their incidence.
E.g.
•   Anticoagulants  Bleeding
•   Beta blockers  Bradycardia
•   Nitrates  Headache
•   Prazosin  Postural hypotension         www.remixeducation.in
          Type B (Bizarre) reactions
   A type B reaction is one that is not due to an extension of
    the active pharmacologic properties of the drug; the B
    indicates bizarre. They are called pharmacologically
    unexpected,   unpredictable,   or   idiosyncratic   adverse
    reactions.


   There are two subclasses:
   Immunologic An allergic or hypersensitivity reaction
    occurs as a result of an immunologic mechanism.

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             Type B (Bizarre)
                   reactions
    Idiosyncratic The term idiosyncratic is often used in a
    broad sense to designate qualitatively abnormal adverse
    reactions that occur in a given individual and whose
    mechanism is not yet understood.
    Characteristics of Bizarre Reactions:
   reaction disappears on discontinuation of the drug
   recognizable as an immunological reaction
   undetectable during conventional testing
   little or no relation to the usual pharmacological effects of
    the drug                                   www.remixeducation.in
             Type C ( Chronic)


   Reactions due to long time exposure.

   e.g. Analgesic neuropathy

      Dyskinesia with levodopa




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       Type D (Delayed) reactions

•   Occur due to prolonged exposure.
•   Can be due to accumulation.


E.g.
Carcinogenesis, or short term exposure at a critical time
    e.g.teratogenesis.




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        Type E (End of use) reactions


•   Occur on withdrawal especially when drug is stopped
    abruptly.


E.g.
•   Phenytoin withdrawal  Seizures
•   Steroid withdrawal  Adrenocortical insufficiency.
•   opioid causing the withdrawal syndrome.



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                  Types of ADRs
Type Type of       characteristics     example
     effect
A    Augmented     Dose dependent      Hypoglycaemia-
                   predicted from the  insulin
                   known
                   pharmacology of the
                   drug
B    Bizarre       Unpredictable       Anaphylaxis to
                   Dose independent    penicillin
                   Rare,fatal
C    Chronic       Prolong treatment   Analgesic neuropathy
D    Delayed       After years of      Antipsycotic –turdive
                   treatment           dyskinesia
E    End of use    Withdrawal effect   GC withdrawal
                                       adrenocortical
               Classification of ADRs :
   Depending on Severity

   Minor ADRs: No therapy, antidote or prolongation of
    hospitalization is required.

   Moderate ADRs: Requires change in drug therapy, specific
    treatment or prolongs hospital stay by atleast 1 day.

   Severe      ADRs:    Potentially   life   threatening,   causes
    permanent damage or requires intensive medical treatment.

   Lethal: Directly or indirectly contributes to death of the
    patient.                                    www.remixeducation.in
                    Side effects
   Unwanted but often unavoidable, occur at therapeutic
doses
   Predicted from the pharmacological profile of a drug
   Known to occur in a given percentage of drug recipients
   E.g.
    Atropine dryness of mouth
    Promethazine (anti-allergic) sedation
    Codeine(anti-tussive)constipation Used in Traveller’s
diarrhea
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Side effects….(Drug discovery)
   Occasionally, “adverse” effects may be exploited to
develop an entirely new indication for a drug.
   E.g:
   Unwanted hair growth during Minoxidil treatment of
severely hypertensive patients  development of the
drug for hair growth.
   Sulfonamides used as antibacterials were found to
produce hypoglycemia and acidosis as side effects 
development of Hypoglycemic Sulfonylureas…
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                 Toxic effect:
An adverse effect of a drug produced by an
exaggeration of the effect that produce the therapeutic
response.


      Predictable               Unpredictable
     Dose dependent                 Allergy
    Rebound response             Idiosyncrasy
   Detected during drug     Not detected during drug
      development                development

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            Predictable toxic effects
   Dose dependent adverse effect may be –


   Direct damaging effect to tissue: Paracetamol overdose
    leads to hepatotoxicity, Aminoglycoside (Gentamicin) causes
    nephrotoxicity.


   Rebound response: abrupt withdrawl after chronic use.
    Glucocorticoid    withdrawal    leads    to     acute     adrenal
    insufficiency.morphine – due to R supersensitivity.
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   Excess pharmacological effect:
Result of excessive pharmacological action of the drug due
to over dosage or prolonged use.
    Excess    insulin-hypoglycemia    even   death    from
hypoglycemic shock
    Antihypertensive - hypotension
    Anticoagulant- severe bleeding.




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        Unpredictable toxic effects


   Dose independent:
   Less than therapeutic dose may lead to toxic effect




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                        Idiosyncrasy

   unusual response to a drug due to genetic abnormality.
   Drug interacts with some unique feature of the individual,
    not    found   in   majority   subjects,   and   produces    the
    uncharacteristic reaction.
   E.g.
   Isoniazid: N-Acetylation affects the metabolism of isoniazid
   Slow N-Acetylation: Isoniazid is more likely to cause
    peripheral neuritis.
   Fast N-Acetylation:cause hepatotoxicity in this group.
                                                www.remixeducation.in
   Succinylcholine can produce apnea in people with
abnormal serum cholinesterase. Their cholinesterase is
incapable of degrading the succinylcholine, thus it builds up
and depolarization blockade results.
   Primaquine, Sulfonamides induce acute hemolytic
anemia      in    patients     with    Glucose-6-Phosphate
Dehydrogenase deficiency.
--They have an inability to regenerate NADPH in RBC.G-6-p
deficiency is most prevalent in blacks. It is rare in Asians.



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                   Drug allergy
 Acquired,    altered reaction of the body to drug.
 Immunologically     mediated reaction.
 occur    even with much smaller doses
 Also   called Drug hypersensitivity
 Not    genetic,not occurred in all
 Occurs    on reexposure
 E.g.    penicillin→1st time →stimulate antibody →Ag-
  Ab reaction →allergy
 Chief     organ: Skin, respiratory tract,GIT,Blood &
  blood vessels                            www.remixeducation.in
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           Grading system for
      hypersensitivity reactions
Grade
        including
         Broad clinical features
                                anaphylaxis
                                  Defining symptoms and signs



1          Cutaneous and             Generalized erythema, periorbital
          subcutaneous only          edema, urticaria, or angioedema
 Mild
2         Cardiovascular,            Dyspnea, stridor, wheeze, nausea,
          respiratory, or            vomiting, dizziness, diaphoresis, chest
Modera    gastrointestinal           or throat tightness, or abdominal
te        involvement                pain
3         Hypoxia, hypotension, or    = 92 % at any stage, hypotension
          neurologic compromise      (systolic BP < 90 mmHg in adults),
Severe                               confusion, collapse, loss of
                                     consciousness, or incontinence
                                     Cyanosis or SpO2

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                       Intolerance
   Appearance of characteristic toxic effects of a drug in an
    individual at therapeutic doses
   Converse of tolerance
   Indicates a low threshold of the individual
   E.g.
   Triflupromazine (single dose)  Muscular dystonias in
    some individuals
   Carbamazepine (few doses) Ataxia in some individuals
   Chloroquine (single tablet)  Vomiting and abdominal
    pain in some individuals

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                       Tolerance
     ↓ pharmacological effect on repeated administration of
     the drug.
    Pharmacokinetic      Tolerance:      ↑    the    enzymes
     responsible for metabolizing the drug.
    e.g.Phenobarbitone induces metabolism of its own by
     increasing its own metabolic enzyme.
    Pharmacodynamic Tolerance: Cellular tolerance, due
     to down-regulation of receptors.




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                      Tachyphylaxis:

   When     responsiveness       diminishes      rapidly     after
    administration of a drug, the response is said to be
    subject to tachyphylaxis.



   Tachyphylaxis to    the     Action   of   Topically     Applied
    Corticosteroids




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            Difference between
        Tachyphylaxis and Tolerance
   Tachyphylaxis is the result of frequent doses over a short
    period of time and tolerance is the result of chronic
    administration over a long period. It can be predicted from
    the word origin. ‘Tachy-‘ means very fast as is used for
    tachycardia, ‘-phylaxis’ means defense, and the word is
    composed of these, tachyphlaxis, which means rapid
    decrease in the response to a drug after repeated doses
    (over a short period). A typical example of tachyphyalaxis
    is epinephrine’s action on vessels (blood pressure).
    Repetitive stimulus over a short time causes the depletion
    of a vasoconstricting substance, which results in the
    attenuation of response. Tolerance can occur with
    morphine or an alcoholic beverage.         www.remixeducation.in
                Photosensitivity
   Cutaneous reaction resulting from drug induced
    sensitization of the skin to UV radiation. The reactions
    are of two types.


   Phototoxic: Drug or its metabolite accumulates in the
    skin, absorbs light and undergoes a photochemical
    reaction resulting in local tissue damage (sunburn-like,
    i.e., erythema, edema, blistering, hyper pigmentation)
    E.g. Tetracyclines (esp. Demeclocycline), and Tar
    products, Nalidixic acid, Fluoroquinolones, Sulfones etc



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              Photosensitivity

   Photoallergic: Drug or its metabolite induces a
    cell mediated immune response which on exposure
    to light (longer wave length) produces a papular or
    eczematous contact dermatitis like picture.
    E.g. Sulfonamides, Sulfonylureas, Griseofulvin,
    Chloroquine, Chlorpromazine




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              Drug dependence
 Drugs capable of altering mood and feelings are liable to
  repetitive use to derive euphoria, withdrawal from reality,
  social adjustment, etc.
 Psychological dependence: Individual believes that
  optimal state of well being is achieved only through the
  actions of the drug.
 E.g. Opioids, Cocaine.
 Physical     dependence: Altered physiological state
  produced by repeated administration of a drug which
  necessitates the continued presence of the drug to
  maintain physiological equilibrium. Discontinuation of the
  drug results in a characteristic withdrawal (abstinence)
  syndrome.
 E.g. Opioids, Barbiturates, Alcohol, Benzodiazepines

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                  Drug dependence
   Drug abuse: Use of a drug by self medication in a manner
    and amount, that deviates from the approved medical and
    social patterns in a given culture at a given time.
    Drug abuse refers to any use of an illicit drug.


   Drug addiction: Compulsive drug use characterized by
    overwhelming involvement with the use of a drug.


   Drug habituation: Less intensive involvement with the drug,
    withdrawal produces only mild discomfort.
   Habituation and addiction imply different degrees of
    psychological dependence.
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Mutagenecity and Carcinogenicity

   Capacity of a drug to cause genetic defects and cancer
    respectively.
   Chemical carcinogenesis generally takes several (10-40)
    years to develop.
   Unpredictable
e.g.
       Estrogen- Endometrial carcinoma.
       OCP- Ca cervix, breast Ca
       Iron S/C or I/M – blackening of area – increase
        incidence of sarcoma (cause is unknown).
       Anticancer drug.
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Iatrogenic(Physician
      induced)




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                  Teratogenicity
   Capacity of a drug to cause foetal abnormalities when
    administered to the pregnant mother.
   Drugs can affect the foetus at 3 stages:
       •   Fertilization and implantation (Conception to 17
           days): failure of pregnancy which often goes
           unnoticed.
       •   Organogenesis (18 days to 55 days): most
           vulnerable period, deformities are produced.
       •   Growth      and development     (>56     days):
           developmental and functional abnormalities can
           occur. E.g:
   Thalidomide Phocomelia, multiple defects
   Anticancer drugs  Cleft palate, hydrocephalus,
    multiple defects.                www.remixeducation.in
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          Drugs known to be
                 teratogenic
 Anticancer drugs – Methotrexate – multiple deformity.

   Steroid – cleft palate and other.

   Oral anticoagulants – bony abnormality (Hypoplastic
    nasal structures), optic atrophy, mental retardation.

   Oral hypoglycemic agents - multiple deformity.

   Androgenic hormone – virilization, hermaphrodite, lid
    retraction.

   Tetracycline – inhibit bony growth.

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                                                     Cont’d
   Trimethoprim – cleft palate.

   Phenytoin, carbamazepine, valproate -Malformation of
    fingers,cleft palate,neural tube defect(spina bifida)

   Diethylstilbestrol - Oral contraceptive is no longer used
    because it causes reproductive cancers in daughters born
    to mothers taking the drug.

   Androgen- virulization of female fetus

   Aminoglycosides, Chloroquine – Deafness.


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Individual variation in response to
                         drug
 Variation due to age, sex, body weight, surface area,
    nutrition, alcoholic, cigarette smoking, pregnancy, genetic
    factor, environment, and pathological condition.


   4 general mechanism:

   A) Alteration in concentration of
    drug that reaches the receptors –
   rate of absorption of a drug
   distributing it through body compartments
   clearing the drug from the blood.

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   B) Variation in concentration of an
    endogenous receptor ligand –
   variability in responses to pharmacological antagonist.
   propranolol will markedly slow the HR of a patient whose
    endogenous catecholamine are elevated (as in
    pheochromocytoma), but will not affect the resting HR of
    a well trained marathon runner.

   C) Alteration in number or function
    of receptor –
   ↑ or ↓ in number or alteration in efficiency of coupling of
    receptor to distal effector mechanism – change in
    responsiveness.
                                            www.remixeducation.in
    e.g.Thyroid hormone increase number of β receptor in
     heart and increase sensitivity of cardiac muscle to
     catecholamine – tachycardia of thyrotoxicosis.


    D) Changes in components of
     response distal to the receptor –
     Response depend on the functional integrity of
     biochemical process in the responding cell and
     physiological regulation by interacting organ system.




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        How to recognize ADRs
   Ensure, medicine received & actually taken by the
    patient at the dose advised.
   Verify the onset of suspected ADR is after taking the
    drug.
   Determine the time interval between drug taken – onset
    of event.
   Evaluate the suspected ADR after discontinuing the
    drug / reduced dose, monitor status.
   Analyse the alternate cause (other than the drug).
   Use relevant literature & experienced physician opinion.
   Report the ADR
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                       Cont’d…


   Medicines are supposed to save lives Dying from a disease
    is sometimes unavoidable; dying from a medicine is
    unacceptable. Lepakhin V. Geneva 2005.




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Cont’d…
   Among the Leading cause of death-




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        Aims of knowing ADRs

   To improve patient care and safety

   To improve public health and safety

   To contribute to the assessment of benefit, harm,
    effectiveness and risk of medicine.




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      Role of Pharmacist in the
       management of ADRs
   Pharmacists should exert leadership in the
    development, maintenance, and ongoing evaluation of
    ADR programs. They should obtain formal
    endorsement or approval of such programs through
    appropriate committees (e.g., a pharmacy and
    therapeutics committee and the executive committee of
    the medical staff) and the organization’s administration.
    In settings where applicable, input into the design of
    the program should be obtained from the medical staff,
    nursing staff, quality improvement staff, medical
    records department, and risk managers.
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       Role of Pharmacist in the
        management of ADRs
    The pharmacist should facilitate
1.   Analysis of each reported ADR.
2.   Identification of drugs and patients at high risk for
     being involved in ADRs.
3.   The development of policies and procedures for the
     ADR-monitoring and reporting program.
4.   A description of the responsibilities and interactions
     of pharmacists, physicians, nurses, risk managers,
     and other health professionals in the ADR program.
5.   Use of the ADR program for educational purposes.
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   Role of Pharmacist in the
    management of ADRs
6. Development, maintenance, and evaluation of ADR
   records within the organization.
7. The organizational dissemination and use             of
   information obtained through the ADR program.
8. Reporting of serious ADRs to the FDA or the
   manufacturer (or both).
9. Publication and presentation of important ADRs to the
   medical community.


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     Role of Pharmacist in the
      management of ADRs
   Direct patient care roles for pharmacists should
    include patient counseling on ADRs, identification
    and documentation in the patient’s medical record of
    high-risk patients, monitoring to ensure that serum
    drug concentrations remain within acceptable
    therapeutic ranges, and adjusting doses in
    appropriate patients (e.g., patients with impaired
    renal or hepatic function).



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Thank you
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