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ADs1----------------------------------------------EXAM2 Flashcards

1
Q

Definition of ADRs

Second type: unexpected

A

AD drug experience that is not listed in current labeling-> greater severity, specificity

Must be reported within 3 days

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2
Q

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?
A
  • 64%
  • 10 prescriptions for every person in the US
  • 4 or more
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3
Q

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

A

Kefauver- harris amendment 1962

Required what: efficacy
Established what: GUIDELINES FOR REPORTING
Rationale: thalidomide exposure to pregnant women and fetal anomalies

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4
Q

Reporting of ADRs

Medwatch- serious ADRs

A

Resulting in death, life prolonged hospitalization, disability, congenital anomaly, permanent impairment/damage

Medications
Medical Devices
Special Nutritional Products
Other products regulated by the FDA

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5
Q

Vaccine ADs

A

You cannot report ADs of vaccines on MedWatch

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6
Q

Causality- strength of association

Dechallenge- stop medication->ADR stops->decreases or gets better

A

Rechallenge: start med-> adr reoccurs

Temporal sequence: signs, symp do not start prior to administration

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7
Q

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

A

Usually only for short time

But some drugs cause serious ADRs at very low frequencies and would require more exposure to detect the reaction

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8
Q

Identifying ADRs

A

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

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9
Q

Identifying ADRs

A

Study size as a function of frequency

Higher risk populations-clinical trials

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10
Q

Types of ADRs

A

Predictable
Type A or Augmented -80% of ADRs
3 types of predictable

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11
Q

Types of ADRs- predictable

Direct extension of intended effect
Eg) decrease in glucose w sulfonylurea- glyburide

A

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)

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12
Q

Unpredictable ADRs

Type B or Bizarre

A

Not related to pharmacologic doses

What percentage? 20%

3 types of unpredictable

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13
Q

Unpredictable ADRs

  1. Intolerance
    Eg. Tinnitus w aspirin (ears), Syncope w alpha blockers
A
  1. 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)
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14
Q

Unpredictable ADRs

  1. Allergic/hypersensitivity
A

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

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15
Q

Immunologic classifications of ADRs

A

Anaphylactic/anaphylaxis or Type I
Cytotoxic rxn or type Ii
Immunocomplex or type III
Cell mediated or type IV

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16
Q

Anaphylatic/anaphylaxis

Eg, penicillin

A

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

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17
Q

Type 2- Cytotoxic Reactions

What immune globulins are involved?IgG,IgM

Is complement involved? Yes
Are mediators involved? No

A

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

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18
Q

Immunocomplex

Deposition of antigen and antibody complex to tissue

A

Eg) serum sickness, vasculitis, SLE, glomerulonephritis

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19
Q

Cell- mediated

What is another name for cell-reactions?
Delayed hypersensitivity

A

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

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20
Q

Side effect vs allergy

A

I am allergic to codeine

I am allergic to penicillin and erythromycin

Ask what happens? If diarrhea, it’s not allergic, side effect!

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21
Q

ADR indicator drugs

A 
Naloxone
Atropine
Flumazenil
Epinephrine
Diphenhydramine
Corticosteroids
Vt K
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22
Q

Patient Variables

  • elderly: dec hepatic/renal func; dec albumin=inc unbound or free drug
  • neonates: placental transfer of drugs; lack of info; altered ADME
A

-genetics; screening tests not easily performed

-immunodeficiency states; development of drug specific antibodies
Eg. HIV pt, Bactrim

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23
Q

Drug Variables

  • Route of Administration: IV compared to PO
  • Product Formulation: Sustained
    release, Would there be less variation in serum drug concentration? (Yes)
A
  • Duration of Therapy: NSAIDs-> GI bleeding w high dose and longer exposure
  • Dose: Meperidine (Demerol)->seizures due to metabolite
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24
Q

Cross reactivity and sensitivity

Definition:

A
  • the occurrence of similar reactions when a person is challenged w another drug
  • same therapeutic category or similar in structure
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25
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 ```
26
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
27
Definition of ADRs First type: serious
AD drug that is Life threatening, permanent disabling causes hospitalization Must be reported within 15 days
28
Narcotic analgesics - Direct histamine release - Idiosyncratic -Injection site - pruritis, rash, urticaria
- systemic (rare) | - dec BP, inc HR,mbronchospasm, laryngeal edema
29
Selecting an alternative Narcotic
Allergy-> structure natural, synthetic, semi-synthetic 6-hydroxyl group
30
Local Anesthetics - caine groups - Types of reactions:
-psychomotor: vasovagal rxn, sympathetic -toxic: w what type of administration? IV What type of ADRs? Seizures -allergic: Is this rxn IgE mediated? Yes Is this rxn due to structure of drug? Not likely Is this rxn due to preservatives? Yes, most likely - methylparabens, sulfites
31
Local anesthetics - amides: - esters:
- amides: bupivicaine, dibucaine, etidocaine, lidocaine, mepivaciane, prilocaine - esters: procaine, tetracaine
32
Sulfonamides - SO2NH2
- Antimicrobials - Diuretics - diuretic w no sulfonamide: - ethacrynic acid - ADR associated w ethacrynic acid is ototoxicity - sulfasalazine-> crohn's ds - sulfapyride + aspirin -> GI tract
33
Drug induced Diseases Type III reactions
Type III reactions – Serum Sickness - flu-like syndrome: fever, rash, arthralgia, lymphadenopathy - onset 1-2 wks - key drugs: beta lactams, sulfonamudes, phenytoin, fluoxetine
34
Drug induced Diseases Type III reactions
-vasculitis: inflammation and necrosis of the walls of the small blood vessels -onset: 1-3 wks -
35
Drug induced Diseases Type III reactions - drug induced lupus - Slow or Fast acetylators? Slow – Immune complex with multiple organ system involvement
- Compared to spontaneous lupus - renal complications? No - CNS involvement? No - milder ds? Yes - drug induced lupus reversible? Yes - what happens to complement levels? Inc - what happens to immunoglobulin levels? Inc - antihistone - anti ss DNA - key drugs 1. Procainamide-related to dose > 2000 mg/day 2. Hydralazine
36
Drug induced Diseases Type III reactions Hematologic Disorders
– What percent of all ADRs are blood dyscrasias? 5% – What percent of all fatalities are due to blood dyscrasias? 40%
37
Drug induced Diseases Type III reactions Hematologic Disorders
- thrombocytopenia Heparin, allopurinol, morphine, chlorothiazide, penicillin, diazepam, hydroxychloroquine, phenytoin, digoxin, isoniazid, quinidine
38
Drug induced Diseases Type III reactions Hematologic Disorders - neutropenia/agranulocytosis
Carbamazepine, ibuproten, hydralazine, vancomycin
39
Drug induced Diseases Type III reactions Hematologic Disorders - hemolytic anemia
Sulfonamides, cephlosporins, chlopromazine, hydralazine, quinidine, rifampin,
40
Drug induced Diseases Type III reactions Hematologic Disorders - aplastic anemia (most serious)
Acetazolamide, carbamazepine, chloramphenicol, chloroquine
41
Erythema multiforme Minor (80%)
20-40 yrs Prodrome? No Red/ round macule or papule is known as? Target lesion An example of a primary precipitating factor is? Herpes simplex infection
42
Erythema multiforme Major(40%) = steven johnsons ds
Any age Prodrome? Yes Large bullae and areas of denudation at least how manynnucosal sites? Two - mucosal site examples? Mouth and conjunctiva An example of a primary precipitating factor is? Drugs and herpes simplex infection
43
Toxic Epidermal Necrolysis (TEN)
Age - any Relationship to Stevens-Johnson Syndrome: 1/10 Burning/painful eruptions Percent of body involvement? 30% Sheet-like loss of epidermis – What is the diagnostic sign? Nikolsky sign
44
Associated drugs w SJS and TEN EDNEDNEDNEDN
Sulfonamides Abtibiotics Phenytoin NSAIDs
45
drug and drug interactions Goal and Objectives
Understand the principles of drug-drug drug and drug-food interactions. – Define d-d interactions - Discuss the mechanisms associated with drug drug interactions. interactions. – Describe patients at higher risk for drug interactions. – Describe high risk drugs associated with interactions. - know drug-drug interaction resources. – Discuss potential drug- food interactions – Discuss ethanol/tobacco-drug interactions
46
What percentage of ADRs are drug - drug interactions?
3-5 %
47
Drug interactions: Several mechanisms Drug interactions can occur before or after administration
– Formulation incompatibility Example: Phenytoin (Dilantin®) is added to solutions of dextrose = a precipitate forms and the phenytoin falls to the bottom of the IV bag as an insoluble salt = therefore, it is no longer available to control seizures. Example: Amphotericin precipitates in saline Example: Aminoglycosides (gentamicin) is physically/chemically incompatible with most
48
Drug interactions: Several mechanisms | Pharmacokinetic interactions
– GI Tract (preventing absorption) Altered gastrointestinal absorption – Altered pH (non- ionized versus ionized) non-ionized= inc absorption - Antacids effect the pH – Separate administration of antacids – Omeprazole (Prilosec) - Less effective with administration of H2 blocker because of decreased pH (enteric coating) – Ketoconazole (Nizoral) and delaviridine (Rescriptor) - Require and acidic environment to be in the non- charged form that is preferentially absorbed
49
Drug interactions: Several mechanisms Pharmacokinetic interactions
– GI Tract (preventing absorption) Altered intestinal bacterial flora – Onset of action and reversal delayed Separating administration times – If a patient is taking digoxin and erythromycin, the amount of digoxin absorbed is increased The erythromycin kills the bacteria that metabolize digoxin in the gut
50
Drug interactions: Several mechanisms Pharmacokinetic interactions
– GI Tract (preventing absorption) Complexation or Chelation – Formation of poorly absorbed complexes – Separate administration time – Tetracycline binds with calcium and iron Decreased absorption of the tetracycline – Bile acid resins bind to thyroid medications Decreased absorption of the thyroid replacement therapy
51
Drug interactions: Several mechanisms Pharmacokinetic interactions – GI Tract (preventing absorption)
-Drug-induced mucosal damage – Unknown mechanism -Antineoplastic agents can cause damage to the gut – Therefore, decreasing absorption of select medications such as digoxin.
52
Dug inter Several mecha Pharmacokinetic interactions -gi tract (preventing absorption)
- altered motility - inc motility Absorption, prokinetic agents, metoclopramide (Reglan) - dec motility Absorption
53
Dug inter Several mecha Pharmacokinetic interactions - plasma
- some drugs can bump other drugs off proteins in the plasma and result in an increased amount of free drug - plasma proteins: albumin, alpha acid glycoprotein - free concentration: available for metabolism and clinical activity - affinity: increased affinity drugs displaces decreased affinity drugs
54
Kidney
- renal excretion - active tubular secretion - proximal portion of renal tubule - saturation ( competition for transport proteins) - use of Probenecid to increase the amt of penicillin in the body - passive tubular secretion - narrow therapeutic index drugs - Thiazide diuretics - dec renal clearance of lithium
55
Liver (metabolism, inducers, inhibitors)
- the majority of drugs are metabolized to what kind of metabolism.? - metabolites can be toxic - acetaminophen= hepatic injury - meperidine = seizures - some are converted to metabolites that retain the same activity as the parent drug - eg, fexofenadine (Allegra): active metabolite of terfenadine that has equal potency - some drugs must be converted to metabolites to become active - eg, enalapri(Vasotec),: must be hydrolyzed to enalaprilat to become active
56
Drug Metabolism Drug metabolism is classified in two phases – Phase I and Phase II
Phase I – Oxidation or reduction reactions Cytochrome P450 oxidative enzymes or reductases – Is this process rate limiting? – Six cytochrome P450 isoforms have been characterized. There is tremendous variability between individuals in terms if expression if cytochrome P450 isoenzymes. For example, CYP2D6 is not present at all in some livers. – Polymorphism
57
Drug Metabolism
Poor metabolizers - if not a prodrug, inc efficacy (inc plasma concent) but inc risk of ADRs - if progrug, then dec efficacy ( dec plasma concen of active drug) but dec risk of ADRs from active drug Extensive metabolizers - normal metabolizers Rapid or ultra rapid metabolizers - if not a prodrug, dec efficacy ( dec plasma concent) - if prodrug, then inc efficacy ( inc plasma concent of active drug), but inc risk of ADRs from active drug
58
Drug metabolism Phase I - polymorphism - CYP1A2
- CYP1A2 Theophylline, imipramine, propranol (inderal) and clozapine metabolized via CYP1A2 CYP1A2 is induced by tobacco smoking CYP1A2 inhibitors Quinolones Fluvoxamine (Luvox) Cimetidine (Tagamet)
59
Drug metabolism Phase I - polymorphism - CYP3A4
Located in liver and Not polymorphic Majority od drugs that cause cardiac arrhythmias by prolonging the QT interval are metabolized via the CYP3A4 CYP3A4 inhibitors- Ketoconazole(hismanal), Itraconazole(Sporanox), Fluconazole(Diflucan), Cimetidine(Tagamet), Clarithromycin(Biaxin), Erythromycin, grapefruit juice CYP3A4 inducers- Carbamazepine(Tegretol), Rifamfin, Rifabutin, Ritonavir, St. John's wort
60
Drug Metabolism Drug metabolism is classified in two phases – Phase I Polymorphism – CYP2C9
Many NSAIDs including COX- metabolized via CYP2C9. Warfarin (S- Warfarin): Metabolized by CYP2C9 and almost all interpatient variability in warfarin levels and anticoagulant effects can be explained in the basis of CYP2C9 activity. CYP2C9 Inhibitor: Fluconazole (Diflucan)
61
Drug Metabolism Drug metabolism is classified in two phases – Phase I Polymorphism – CYP2C19
Many anticonvulsants, diazepam, omeprazole, and several of the tricyclic antidepressants metabolized via CYP2C19 CYP2C19 Inhibitors: Omeprazole (Prilosec® Isoniazid, Ketoconazole
62
Drug metabolism is classified in two phases – Phase I CYP2D6
Many cardiovascular and neurologic drugs metabolized via CYP2D6 – Codeine is a pro – Ultra rapid metabolizers of CYP2D6 may have inadequate responses to standard doses of B blockers, narcotic analgesics or antidepressants. May require higher doses for clinical effectiveness. – CYP2D6 Inhibitors Fluoxetine (Prozac® Paroxetine (Paxil® Haloperidol (Haldol® Quinidine
63
Drug metabolism is classified in two phases – Phase II
Conjugation” of a water soluble entity onto the drug for facilitated excretion in the urine or bile – Sugar, peptide (glutathione), sulfur groups These groups are plentiful in well nourished cells therefore, rarely, rate-limiting
64
Drug metabolism Drug metabolism is classified in two phases Summary
- if 2 drugs are metabolized by the same cytochrome P450 isoenzyme, it is very possible that competitive inhibition could lead to higher than usual levels of either or both of the drugs - if a drug is me metabolized by a specific cytochrome P450 isoenzym and is taken w an inhibitor or inducer of that isoenzyme, an interaction is likely to occur
65
Drug interaction: several mechanism Pharmacodynamic interaction
- occur at the level of drug action Synergistic, 1+1=3 Propranolol, verapamil, Alcohol and benzodiazepine (Iorazepam, diazepam) - antagonistic Warfarin, vt K - altered transport system and effects at receptor Limit access of certain medications into cells Phenothiazines inhibit the neuronal uptake of guanethidine that results in a decreased antihypertensice effect
66
High risk patients
Increased risk due to severity of the ds being treated - Epilepsy, diabetes, asthma Increased risk due to drug interaction potential of therapy Elderly - polypharmacy Polypharmacy - pt on multiple med
67
Considerations When Evaluating a Drug drug interaction
Available literature How is the patient doing? How long has the patient been on the medications? What is the dose of the medications? Laboratory/Monitoring Parameters Does the patient have any concurrent disease states? What is the half-life of medication? What is the metabolism of the medications? life of the medications? Is the drug metabolized via the cytochrome P450 enzyme system Which CYP450 enzyme (e.g., 3A4, 2D6) ADME (absorption, distribution, metabolism, excretion
68
Drug food interactions Foods high in tyramine
- pt taking monoamine oxidase inhibitors (MAOIs: used for the treatment of depressing) must avoid foods high in tyramine because of the risk of a hypertensive crisis - MAOIs prevent gastrointestinal and hhepatic metabolism of tyramine and other pressor amines leading to an increase in blood pressure - foods= green, leafy vegetables, liver (pt education materials) - pt dont necessarily need to change their diet, but the diet must remain constant in the content if foods rich in vt K - effects in INR
69
Drug food interactions Foods high in pyridoxine
-Foods rich in pyridoxine Increase the metabolism of levodopa (Parkinson's Disease) Foods = avocados, beans, bacon, liver, tuna - Nutritional deficiencies Decreased albumin = increase in amount of "free" or unbound drug Diuretics = decrease in amount of potassium (need to supplement accordingly) - Grapefruit juice Grapefruit juice contains a bioflavinoid that inhibits CYP3A4 (in the liver and the gut) and blocks the metabolism of many drugs.
70
Ethanol/Tobacco Interactions
-Ethanol Long term use= inc clearance Short term use= dec clearance -tobacco Enhanced drug metabolism - over the counter and herbal medications Same principles apply
71
ADRs First type
Serious 15 days

Pharm (19 decks)

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