ADs1----------------------------------------------EXAM2 Flashcards
Definition of ADRs
Second type: unexpected
AD drug experience that is not listed in current labeling-> greater severity, specificity
Must be reported within 3 days
Why are there so many ADRs?
- what % of all pts visits to physicians result in prescriptions
- how many prescriptions for every person in the us?
- the rate of ADrs increases exponentially a patient is on how many medications?
- 64%
- 10 prescriptions for every person in the US
- 4 or more
ADRs and Legislation
Pure Food and Drug Act 1906 Required what:mislabeling or adulteration
Food, Drug, and Cosmetic Act 1938 Required what: safety and purity but no efficacy
Kefauver- harris amendment 1962
Required what: efficacy
Established what: GUIDELINES FOR REPORTING
Rationale: thalidomide exposure to pregnant women and fetal anomalies
Reporting of ADRs
Medwatch- serious ADRs
Resulting in death, life prolonged hospitalization, disability, congenital anomaly, permanent impairment/damage
Medications
Medical Devices
Special Nutritional Products
Other products regulated by the FDA
Vaccine ADs
You cannot report ADs of vaccines on MedWatch
Causality- strength of association
Dechallenge- stop medication->ADR stops->decreases or gets better
Rechallenge: start med-> adr reoccurs
Temporal sequence: signs, symp do not start prior to administration
How well is a drug’s safety defined prior to its approval and marketing?
Most new drugs are approved w an average of how many pts exposures? 1500
Usually only for short time
But some drugs cause serious ADRs at very low frequencies and would require more exposure to detect the reaction
Identifying ADRs
Literature citations: clin-alert, reactions weekly
FDA programs: dear dr letter, medwatch
- just single report to medwatch ultimately led to the removal of terfenadine from market
Identifying ADRs
Study size as a function of frequency
Higher risk populations-clinical trials
Types of ADRs
Predictable
Type A or Augmented -80% of ADRs
3 types of predictable
Types of ADRs- predictable
Direct extension of intended effect
Eg) decrease in glucose w sulfonylurea- glyburide
Unwanted but inseparable pharmacological effect: Eg) dry mouth w anticho, sedation w antihistamines (diphenhydramide)
Secondary or indirect/not related to primary action: Eg) candidiasis w inhaled corticosteroids-(trimacinolone)
Unpredictable ADRs
Type B or Bizarre
Not related to pharmacologic doses
What percentage? 20%
3 types of unpredictable
Unpredictable ADRs
- Intolerance
Eg. Tinnitus w aspirin (ears), Syncope w alpha blockers
- Idiosyncratic
- pseudoallergic: not associate w pharmacologic effect and not an allergic rxn
(eg, NSAID causing aspectic meningitis)
-genetic predisposition (pharmacogenetics)
(Eg, glucose 6 pho dehydrogenase deficiency-slow and fast acetylators)
-opposite effect
(Eg, seizures w antihistamines)
Unpredictable ADRs
- Allergic/hypersensitivity
This doesn’t require a previous exposure
Immediate(0-1h): anaphylaxis, decreased edema
Accelerated(1-72h): urticaria, edema, wheezing
Late(>72h): morbilliform rash
What happens to the reaction time every time the pt is exposed? Decreased
Immunologic classifications of ADRs
Anaphylactic/anaphylaxis or Type I
Cytotoxic rxn or type Ii
Immunocomplex or type III
Cell mediated or type IV
Anaphylatic/anaphylaxis
Eg, penicillin
Immune globuliin- Ig E
What type of rxn- immediate
Mediators- mast cells(major), basophils, leukotriens, histamine, serotonin, bradykinin
Actions-
vasodilation(enhanced permeability)-urticaria
Smooth m contraction-bronchospasm
Decreased blood pressure- shock
Type 2- Cytotoxic Reactions
What immune globulins are involved?IgG,IgM
Is complement involved? Yes
Are mediators involved? No
Damage directed toward cell membrane
– Platelets, white blood cells, red blood cells
– Usually hematologic in nature
Antigen: drug or metabolite and protein and antibody
Antigen + Antibody complex – This complex cause what? Cellular destruction
Immunocomplex
Deposition of antigen and antibody complex to tissue
Eg) serum sickness, vasculitis, SLE, glomerulonephritis
Cell- mediated
What is another name for cell-reactions?
Delayed hypersensitivity
Mechanism of action: T cell recognizes and
antigen and then releases lymphocytes/ cytokines and causes inflammation
mediated
– Example: contact dermatitis
– Example:PPD(mantoux) test for tuberculosis
What is term for a person unable to produce an immune response? Anergy
Side effect vs allergy
I am allergic to codeine
I am allergic to penicillin and erythromycin
Ask what happens? If diarrhea, it’s not allergic, side effect!
ADR indicator drugs
Naloxone Atropine Flumazenil Epinephrine Diphenhydramine Corticosteroids Vt K
Patient Variables
- elderly: dec hepatic/renal func; dec albumin=inc unbound or free drug
- neonates: placental transfer of drugs; lack of info; altered ADME
-genetics; screening tests not easily performed
-immunodeficiency states; development of drug specific antibodies
Eg. HIV pt, Bactrim
Drug Variables
- Route of Administration: IV compared to PO
- Product Formulation: Sustained
release, Would there be less variation in serum drug concentration? (Yes)
- Duration of Therapy: NSAIDs-> GI bleeding w high dose and longer exposure
- Dose: Meperidine (Demerol)->seizures due to metabolite
Cross reactivity and sensitivity
Definition:
- the occurrence of similar reactions when a person is challenged w another drug
- same therapeutic category or similar in structure
Aspirin and non steroidal anti inflammatory agents (NSAIDs)
-there are two types
- type A: bronchospasm, shock Is it hypersensitivity rxn? No Likelihood of cross reactivity -indomethacin>Ibuprofen> acetaminophen -non-acetylated salicylates (eg,choline magnesium trisalicylate (Trilisate) -type B: urticaria, angioedema Is it hypersensitivity rxn? Yes Non-acetylated salicylates
Penicillin and Cephalosporins
What is the percent cross-reactivity between penicillin and cephalosporins? 5-10 %
- rank of generation of cephalosporins
- Imipenem:3%
- Aztreonam: 0%
Majority of rxns occur within how many h? 72h
Aminopenicillins (ampicillin, amoxicillin)
- maculopapular rashes (65%)-> delayed 3-14 days
- urticaria (30-35%)
- higher increase of rash in pt w: viral infections, leukemias, hyperuricemia
Definition of ADRs
First type: serious
AD drug that is Life threatening, permanent disabling causes hospitalization
Must be reported within 15 days
Narcotic analgesics
- Direct histamine release
- Idiosyncratic
-Injection site
- pruritis, rash, urticaria
- systemic (rare)
- dec BP, inc HR,mbronchospasm, laryngeal edema