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ADVERSE DRUG EVENTS

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Title: ADVERSE DRUG EVENTS


1
ADVERSE DRUG EVENTS
  • Géza T. Terézhalmy, D.D.S., M.A. Professor and
    Dean Emeritus School of Dental
    Medicine Case Western Reserve
    University Cleveland, Ohio

2
Adverse Drug Events
  • Clinicians and patients both acknowledge the
    major role played by drugs in modern health care

3
Adverse Drug Events
4
Adverse Drug Events
  • There are no absolutely safe biologically
    active therapeutic agents

5
Adverse Drug Events
  • Therapeutic agents seldom exert their beneficial
    effects without also causing adverse drug events

6
Adverse Drug Events
  • OHCP should be aware of the spectrum of
    drug-induced events and should be actively
    involved both in monitoring for and reporting
    such events

7
Adverse Drug Events
  • Etiology and epidemiology
  • 75 of office visits to general medical
    practitioners and internists are associated with
    the initiation or continuation of pharmacotherapy
  • 3 to 11 of hospital admissions are attributed
    to adverse drug events
  • 0.3 to 44 of hospitalizations are complicated
    by adverse drug events

8
Adverse Drug Events
  • Etiology and epidemiology
  • The FDA has the most rigorous approval
    requirements in the world
  • Clinical trials cannot and are not expected to
    uncover every potential adverse drug event
  • Pre-marketing study populations generally include
    3,000 to 4,000 subjects
  • Only adverse events, which occur more frequently
    than 1 in 1,000 will be observed
  • Detecting an adverse event with a incidence of 1
    in 10,000 would require a study population of
    30,000

9
Adverse Drug Events
  • Etiology and epidemiology
  • Classification of adverse drug events
  • Type A reactions
  • Associated with the administration of therapeutic
    dosages of a drug (exception drug overdose)
  • Usually predictable and avoidable
  • Responsible for most adverse drug events
  • Overdose
  • Cytotoxic reactions
  • Drug-drug interactions
  • Drug-food interactions
  • Drug-disease interactions

10
Adverse Drug Events
  • Etiology and epidemiology
  • Classification of adverse drug events
  • Type B reactions
  • Generally independent of dose
  • Rarely predictable or avoidable
  • While they are uncommon, they are often among
    the most serious and potentially life
    threatening
  • Idiosyncratic reactions
  • Immunologic/allergic reactions
  • Pseudo-allergic reactions
  • Teratogenic effects
  • Oncogenic effects

11
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Cytotoxic effects
  • Formation of unstable or reactive metabolites
    related to some abnormality that interferes with
    normal metabolism and/or excretion of a drug
  • Two mechanisms
  • Oxidative pathway the formation of electrophilic
    compounds, which bind covalently with cellular
    macromolecules
  • Reductive pathway gives rise to intermediate
    compounds with an excess of electrons, which
    interact with O2 to produce free radicals

12
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Two or more drugs administered at the same time
    or in close sequence
  • May act independently
  • May interact to ? or ? the magnitude or duration
    of action of one or more of the drugs
  • May interact to cause an unintended reaction
  • Drug-drug interactions all seem to have either a
    pharmacodynamic or a pharmacokinetic basis

13
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacodynamic mechanisms
  • The intended or expected effect produced by a
    given plasma level of drug A is altered in the
    presence of drug B
  • Pharmacological drug-drug interactions
  • Physiological drug-drug interactions
  • Chemical drug-drug interactions
  • Drug-related receptor alterations

14
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacodynamic mechanisms
  • Pharmacological drug-drug interactions
  • Drug A and drug B compete for the same receptor
    site and as a function of their respective
    concentrations either produce (an agonist) or
    prevent (an antagonist) an effect respectively
  • opioids vs. naloxone
  • acetylcholine vs. atropine
  • epinephrine vs. adrenergic receptor blocking
    agents

15
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacodynamic mechanisms
  • Physiological interactions
  • Drug A and drug B interact with different
    receptor sites and either enhance each others
    action or produce an opposing effect via
    different cellular mechanisms
  • cholinergic agents vs diazepam
  • epinephrine vs. lidocaine
  • epinephrine vs. histamine

16
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacodynamic mechanisms
  • Chemical interactions
  • Drug A interacts with drug B and prevents drug B
    from interacting with its intended receptor
  • protamine sulfate vs. heparin

17
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacodynamic mechanisms
  • Drug-related receptor alterations
  • Drug A, when administered chronically, may either
    ? or ? the number of its own receptors or alter
    the adaptability of its receptors to
    physiological events
  • alpha1-adrenergic receptor agonists down-regulate
    their own receptors
  • beta1-adrenergic receptor antagonists up-regulate
    their own receptors

18
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacokinetic mechanisms
  • Following concomitant administration, drug A may
    ? or ? the plasma level of drug B
  • Interactions affecting absorption
  • Interactions affecting distribution
  • Interactions affecting metabolism
  • Interactions affecting renal excretion
  • Interactions affecting biliary excretion

19
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacokinetic mechanisms
  • Interactions affecting absorption
  • Drug A, by causing vasoconstriction, interferes
    with the systemic absorption of drug B
  • epinephrine ? the systemic absorption of
    lidocaine
  • Drug A, by forming a complex with drug B,
    interferes with the systemic absorption of drug B
  • calcium ? the systemic absorption of tetracycline

20
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacokinetic mechanisms
  • Interactions affecting absorption
  • Drug A, by delaying gastric emptying, delays the
    systemic absorption of drug B, which is absorbed
    primarily in the small intestine
  • opioids delay the absorption of acetaminophen
  • Drug A, by elevating gastric pH, prevents the
    absorption of drug B (weak acids)
  • antacids ? absorption of acetylsalicylic acid

21
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacokinetic mechanisms
  • Interactions affecting distribution
  • Drug A ( a weak acid), by competing for plasma
    protein binding with drug B, ? the plasma level
    of drug B
  • acetylsalicylic acid ? the plasma level of many
    drugs

22
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacokinetic mechanisms
  • Interactions affecting metabolism
  • Drug A, by ? or ? hepatic microsomal enzyme
    activity responsible for the metabolism of drug
    B, ? or ? plasma level of drug B respectively
  • H2-receptor antagonists ? the plasma level
    of many drugs
  • macrolides, azole antifungal agents, ethanol
    (chronic use) ? plasma level of many drugs

23
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacokinetic mechanisms
  • Interactions affecting metabolism
  • Drug A, by ? hepatic non-microsomal enzyme
    activity responsible for the metabolism of drug
    B, ? the plasma level of drug B
  • MAO-inhibitors ? the plasma level of
    benzodiazepines

24
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacokinetic mechanisms
  • Interactions affecting metabolism
  • Drug A, by inhibiting the enzyme acetaldehyde
    dehydrogenize, interferes with the further
    metabolism of intermediate metabolites (oxidation
    products) of drug B
  • disulfuram and metronidazole interfere with the
    metabolism of ethanol

25
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacokinetic mechanisms
  • Interactions affecting renal excretion
  • Drug A, which competes with drug B for the same
    excretory transport mechanisms in the proximal
    tubules, ? the plasma level of drug B
  • acetylsalicylic acid and probenecid ? the plasma
    level of penicillin and other weak acids

26
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacokinetic mechanisms
  • Interactions affecting renal excretion
  • Drug A, by alkalizing the urine, ? the plasma
    level of drug B
  • sodium bicarbonate ? the plasma
    level of weak acids
  • Drug A, by acidifying the urine, ? the plasma
    level of drug B
  • ammonium chloride ? the plasma
    level of weak bases

27
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-drug interactions
  • Pharmacokinetic mechanisms
  • Interactions affecting biliary excretion
  • Drug A, by increasing bile flow and the synthesis
    of proteins, which function in biliary
    conjugation mechanisms, ? the plasma level of
    drug B
  • Phenobarbital ? the plasma level of many drugs
  • Drug A binds drug B, which undergoes extensive
    hepatic recirculation, ? the plasma level of drug
    B
  • activated charcoal and cholestyramine ? the
    plasma level of many drugs

28
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-food interactions
  • Most known drug-food interactions appear to be
    associated with pharmacokinetic mechanisms
  • Interactions affecting absorption
  • Nutrients may act as a mechanical barrier that
    prevents drug access to mucosal surfaces and
    ? the rate of absorption of some drugs
  • Nutrients with high fatty acid content may
    actually ? the rate of absorption of drugs with
    high lipid solubility

29
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-food interactions
  • Interactions affecting absorption
  • Chemical interactions between a drug and food
    component can result in the formation of inactive
    complexes and ? the absorption of the drug
  • calcium ? the absorption of tetracyclines
  • ferrous or ferric salts ? the absorption of
    tetracyclines and fluoroquinolones
  • zinc ? the absorption of fluoroquinolones

30
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-food interactions
  • Interactions affecting metabolism
  • Components of some nutrients can inhibit CYP450
    isoenzymes and ? the metabolism of some drugs
  • grapefruit juice ? the metabolism of warfarin,
    benzodiazepines, and calcium-channel blocking
    agents

31
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-disease interactions
  • A drug prescribed for the treatment of one
    disease can adversely affect a different
    condition that has been generally well controlled
  • Pharmacodynamic mechanisms
  • Pharmacokinetic mechanisms

32
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-disease interactions
  • Pharmacodynamic mechanisms
  • Non-selective beta1-adrenergic receptor
    antagonists, prescribed for the treatment of
    chronic stable angina, hypertension, or cardiac
    arrhythmia can increase airway resistance by
    interacting with beta2-adrenergic receptors
  • induce asthma in susceptible patients

33
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-disease interactions
  • Pharmacodynamic mechanisms
  • Beta1-adrenergic receptor antagonists and
    calcium-channel blocking agents prescribed for
    the treatment of chronic stable angina,
    hypertension, or cardiac arrhythmia interacting
    with their own receptors
  • precipitate cardiac complications secondary to
    negative inotropism (decreased contractility),
    decreased nodal conductance, and peripheral
    vasodilatation (cardiac steal syndrome) in
    susceptible patients

34
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-disease interactions
  • Pharmacodynamic mechanisms
  • Beta1-adrenergic receptor antagonists can
    adversely affect carbohydrate metabolism and
    inhibit epinephrine-mediated hyperglycemic
    response to insulin
  • Increase the risk of hypoglycemia and mask some
    of its clinical manifestations in diabetic
    patients

35
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-disease interactions
  • Pharmacodynamic mechanisms
  • COX-1 inhibitors block cyclooxygenase-dependent
    prostaglandin and thrombaxane A2 synthesis
  • Exacerbate peptic ulcer disease and
    gastroesophageal reflux disease in susceptible
    patients

36
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-disease interactions
  • Pharmacodynamic mechanisms
  • Hypothyroidism
  • ? sensitivity to CNS depressants in susceptible
    patients
  • Hyperthyroidism
  • ? susceptibility to epinephrine-induced
    hypertension and cardiac arrhythmia

37
Adverse Drug EventsType A Reactions
  • Etiology and epidemiology
  • Drug-disease interactions
  • Pharmacokinetic mechanisms
  • Cardiac dysfunction
  • ? metabolism and excretion of drugs
  • Hepatic dysfunction
  • ? metabolism and biliary and renal
    excretion of drugs
  • Renal dysfunction
  • ? hepatic metabolism and renal excretion of drugs

38
Adverse Drug EventsType B Reactions
  • Etiology and epidemiology
  • Idiosyncratic reactions
  • Drug metabolism is largely dominated by oxidation
    reactions catalyzed by the cytochrome P450 enzyme
    system
  • Genetic polymorphism is the primary factor
    responsible for inter-individual variability in
    response to drugs
  • Therapeutic consequences
  • intrinsic characteristics of the drug
  • importance of the deficient metabolic pathway
  • existence of alternative pathways

39
Adverse Drug EventsType B Reactions
  • Etiology and epidemiology
  • Allergic/immune reactions
  • In susceptible patients alkylation and/or
    oxidation of cellular macromolecules by drug
    metabolites can lead to the production of
    immunogens
  • Not related to the dose administered
  • Specificity to a given agent
  • Transferability by antibodies or lymphocytes
  • Recurrence when re-exposure to the offending drug
    occurs
  • Most reactions occur in young or middle aged
    adults
  • Drug allergy is twice a frequent in women than in
    man

40
Adverse Drug EventsType B Reactions
  • Etiology and epidemiology
  • Allergic/immune reactions
  • Type I (immediate) hypersensitivity

41
Adverse Drug EventsType B Reactions
  • Etiology and epidemiology
  • Allergic/immune reactions
  • Type II (cytotoxic) hypersensitivity

42
Adverse Drug EventsType B Reactions
  • Etiology and epidemiology
  • Allergic/immune reactions
  • Type III (immune-complex) hypersensitivity

43
Adverse Drug EventsType B Reactions
  • Etiology and epidemiology
  • Allergic/immune reactions
  • Type IV (delayed) hypersensitivity

44
Adverse Drug EventsType B Reactions
  • Etiology and epidemiology
  • Pseudoallergic reactions
  • Cannot be explained on an immunologic basis
  • Occur in patients who had no prior exposure to
    the drug
  • Certain medications directly activate mast cells
    through non-IgE-receptor pathways and initiate
    the release of bioactive substances
  • Other medications block the degradation of
    bioactive substances
  • Still other medications, by inhibiting the action
    of cyclooxygenase activity, ? synthesis of
    lipoxygenase-dependent leukotrienes

45
Adverse Drug EventsType B Reactions
  • Etiology and epidemiology
  • Teratogenic/developmental effects
  • Teratogens are substances capable of causing
    physical or functional defects in the fetus in
    the absence of toxic effects in the mother
  • Teratogenic effects depend on the accumulation of
    a drug or its metabolite in the fetus at
    critical time periods
  • 3rd to 12th week of gestation

46
Adverse Drug EventsType B Reactions
  • Etiology and epidemiology
  • Oncogenic effects
  • Primary oncogenic effects
  • Produced by certain procarcinogenic drugs, which
    have been converted into carcinogens by
    polymorphic oxidative reactions
  • Reactive metabolites bind covalently to DNA
  • Secondary oncogenic effects
  • Therapeutic immunosuppression in the presence of
    infection with oncogenic viruses
  • HBV, HCV, CMV, HSV, HPV, and EMV
  • Pattern of cancer is different than in the
    general population

47
Adverse Drug Events
48
Adverse Drug Events
  • Clinical manifestations
  • Type A reactions
  • Primary (direct effects) or secondary (indirect
    effects)
  • Dose dependent
  • Exaggerations of direct effects
  • Multiple concurrent side effects
  • Type B reactions
  • Primary (direct effects) or secondary (indirect
    effects)
  • Generally independent of the dose

49
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Cytotoxic reactions

50
Adverse Drug EventsType A Cytotoxic Reactions
51
Adverse Drug EventsType A Cytotoxic Reactions
52
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Gastrointestinal disturbances
  • Nausea and vomiting
  • Vomiting center
  • Chemoreceptor trigger zone
  • Pharynx
  • Gastrointestinal tract
  • Cerebral cortex (emotion, olfaction, visual
    stimuli)
  • Stimulation of the vestibular apparatus
  • opioid-, dopaminergic (D2)-, histaminic (H1)-,
    muscarinic-, and serotonengic (5-HT3)-receptor
    agonists

53
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Gastrointestinal disturbances
  • Constipation
  • Diet, functional abnormalities, colonic disease,
    rectal problems, neurological disease, metabolic
    disorders, drugs
  • anticholinergic agents, antihistamines,
    antidepressants, anticonvulsants,
    antiparkinsonian drugs, opioid analgesics,
    antacids

54
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Gastrointestinal disturbances
  • Diarrhea
  • Chronic
  • Functional abnormalities, colonic disease,
    neurological disease, and metabolic disorders
  • Acute
  • Osmotic changes when poorly absorbable solutes
    are present in the intestine
  • Inhibition of ion transport or stimulation of ion
    secretion
  • Toxins, infection (viral, bacterial), drugs
  • cholinergic agents, antibacterial agents

55
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Urinary incontinence
  • Increased urinary flow
  • diuretics, cholinergic agents
  • Overflow secondary to urinary retention
  • anticholinergic agents, adrenergic agonists
  • Increased ADH release
  • Painful stimuli, fear, anger, drugs
  • opioid analgesics
  • Decrease ADH release
  • alcohol

56
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Mood alterations
  • Depression
  • beta1-adrenergic blocking agents, cardiac
    glycosides, benzodiazepines, phenothiazines,
    corticosteroids,
  • Delirium (acute confusional states)
  • drugs with anticholinergic properties, cardiac
    glycosides, opioid analgesics, benzodiazepines,
    other CNS depressants

57
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Cardiac dysfunction
  • Orthostatic hypotension
  • antihypertensive agents (reduce BP), psychotropic
    drugs (impair autonomic reflexes)
  • Arrhythmia
  • cardiac glycosides, macrolides, calcium-channel
    blocking agents, azoles (antifungal agents),
    protease inhibitors

58
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Equilibrium problems
  • Increased risk of falls (patients with decreased
    vision, impaired mobility and cognition, postural
    hypotension, peripheral neuropathy)
  • drugs that impair autonomic reflexes
    (benzodiazepines, alcohol)

59
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Xerostomia
  • Diuretics
  • Drugs with anticholinergic activity
  • antihistamines, psychotropic drugs, CNS
    stimulants, antineoplastic agents

60
Adverse Drug EventsType A Reactions Xerostomia
61
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Mucositis
  • Drugs that arrest the growth and maturation of
    normal cells
  • antineoplastic agents

62
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Bleeding diatheses
  • Drugs that interfere with platelet function and
    the coagulation phase of hemostasis
  • COX-1 inhibitors clopedigrol, warfarin, heparin

63
Adverse Drug EventsType A Reactions Bleeding
Diatheses
64
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Bacterial infections
  • Drugs that alter the normal flora
  • antibacterial agents
  • Drugs that cause immuno-suppression
  • immuno-suppressants

65
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Fungal infections
  • Drugs that alter the normal flora
  • antibacterial agents
  • Drugs that cause immuno-suppression
  • immuno-suppressants

66
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Viral infections
  • Drugs that cause immuno-suppression
  • immuno-suppressants

67
Adverse Drug EventsType A Reactions Viral
Infections
68
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Gingival hyperplasia
  • phenytoin, calcium-channel blocking agents,
    cyclosporine

69
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Neurological complications
  • Oral pain
  • drugs that cause mucositis and/or
    immuno-suppression
  • certain antineoplastic agents (vincristine)
  • Tardive dyskinesia
  • neuroleptic agents, which alter striatal
    dopaminergic receptor activity
  • Taste alterations
  • drugs that affect trace metal homeostasis

70
Adverse Drug EventsType A Reactions
  • Clinical manifestations
  • Inadequate nutrition
  • drugs that produce nausea, vomiting, diarrhea
  • drugs that produce mucositis, xerostomia,
  • drugs that are hepatotoxic

71
Adverse Drug EventsType B Reactions
  • Clinical manifestations
  • Idiosyncratic reactions
  • An unusual reaction of any intensity observed in
    a small number of patients
  • Hypo-reactive patient
  • The drug produces its usual effect at an
    unexpectedly high dose
  • Hyper-reactive patient
  • The drug produces its usual effect at an
    unexpectedly low dose

72
Adverse Drug EventsType B Reactions
  • Clinical manifestations
  • Allergic/ immunologic reactions
  • Type I (immediate) hypersensitivity reaction

73
Adverse Drug EventsType B Reactions
  • Clinical manifestations
  • Allergic/ immunologic reactions
  • Type II (cytotoxic) hypersensitivity reaction

74
Adverse Drug EventsType B Reactions
  • Clinical manifestations
  • Allergic/ immunologic reactions
  • Type III (immune-complex) hypersensitivity
    reaction

75
Adverse Drug EventsType B Reactions
  • Clinical manifestations
  • Allergic/ immunologic reactions
  • Type IV (delayed) hypersensitivity reaction

76
Adverse Drug EventsType B Reactions
  • Clinical manifestations
  • Lichenoid mucositis
  • diuretics
  • beta1-adrenergic antagonists
  • ACE-inhibitors
  • COX-1 inhibitors

77
Adverse Drug EventsType B Reactions
  • Clinical manifestations
  • Erythema multiforme
  • Stevens-Johnson syndrome
  • sulfonamides
  • anticonvulsive agents
  • COX-1 inhibitors

78
Adverse Drug EventsType B Reactions SJS
79
Adverse Drug EventsType B Reactions
  • Clinical manifestations
  • Teratogenic effect
  • Drugs given during pregnancy can affect the fetus
    by producing lethal, toxic, or teratogenic effect
  • Constricting placental vessels
  • Impairing gas and nutrient exchange between fetus
    and mother
  • Producing hypertonia resulting in anoxic injury
  • Indirectly, changing the biochemical dynamics of
    the mother

80
Adverse Drug EventsType B Reactions
  • Clinical manifestations
  • Teratogenic effect
  • Fetal age, drug potency, and dosage
  • lt 20 days after fertilization
  • An all-or-nothing effect
  • 2nd to 3rd trimesters
  • Unlikely to be teratogenic
  • Alter growth and function of normally formed
    fetal organs and tissues

81
Adverse Drug EventsType B Reactions
  • Clinical manifestations
  • Teratogenic effect
  • 3rd to 8th week
  • No measurable effect
  • Spontaneous abortion
  • Sublethal
  • True teratogenic effect

82
Adverse Drug EventsType B Reactions Teratogenic
Effects
83
Adverse Drug EventsType B Reactions
  • Clinical manifestations
  • Oncogenic effects
  • SCC of the skin
  • SCC of the lips
  • 7 to 8.1
  • vs. 0.3
  • Average age 42 years
  • vs. 60 years
  • Latency 5.3 years

84
Adverse Drug EventsType B Reactions
  • Clinical manifestations
  • Oncogenic effects
  • Kaposi sarcoma
  • 5.6
  • vs. 0.03-0.07
  • 60 non-visceral
  • Skin
  • Oral ( 2 )
  • Visceral
  • Skin (24 )
  • Oral 3

85
Adverse Drug EventsType B Reactions
  • Clinical manifestations
  • Oncogenic effects
  • Lympho-proliferative disease
  • Lymphomas
  • Leiomyoma
  • Leiomyosarcoma
  • Spindle-cell sarcoma

86
Adverse Drug Events
  • Preventing adverse drug events
  • Rational approach to the pharmacological
    management of oral/odontogenic disease
  • Accurate diagnosis
  • Critical assessment of the need for
    pharmacotherapy
  • Benefits versus risks of drug therapy
  • Individualization of drug therapy
  • Patient education
  • Continuous reassessment of drug therapy

87
Adverse Drug Events
  • Diagnosing adverse drug events
  • Step 1
  • Identify the drug(s) taken by the patient
  • Step 2
  • Verify that the onset of signs and symptoms was
    after the initiation of pharmacological
    intervention
  • Step 3
  • Determine the time interval between the
    initiation of drug therapy and the onset of the
    adverse drug event

88
Adverse Drug Events
  • Diagnosing adverse drug events
  • Step 4
  • Stop drug therapy and monitor the patients
    status
  • Step 5
  • If appropriate, restart drug therapy and monitor
    for recurrence of adverse drug event

89
Adverse Drug Events
  • Reporting adverse drug events
  • An event is serious and should be reported when
    the patient outcome is
  • Death
  • Life-threatening
  • Hospitalization
  • Disability
  • Congenital anomaly
  • Requires intervention to prevent permanent
    impairment or damage

90
Adverse Drug Events
  • Reporting adverse drug events
  • FDA Form 3500
  • http//www.fda.gov/medwatch/report/hcp.htm
  • Complete the voluntary form 3500 online
  • Download a copy of the form
  • Fax it to 1-800-FDA-0178
    OR
  • Mail it back using the postage-paid addressed
    form
  • Call 1-800-FDA-1088 to report by telephone

91
Adverse Drug Events
  • Conclusion
  • ADEs evolve through the same physiological and
    pathological pathways as normal disease
  • Prerequisites to consider ADEs in the
    differential diagnosis
  • An awareness that an ever increasing number of
    patients are taking more and more medications
    (polypharmacy)
  • Recognition that many drugs will remain in the
    body for weeks after therapy is discontinued
  • Clinical experience
  • Familiarity with relevant literature about ADEs

92
Adverse Drug Events
  • Conclusion
  • Recognize that some ADEs occur rarely and
    detection based on clinical experience or reports
    in the medical literature at time is difficult if
    not impossible

93
Adverse Drug Events
  • Conclusion
  • Timely reporting of ADEs
  • Saves lives
  • Reduces morbidity
  • Decrease the cost of health care

94
Adverse Drug Events
95
Adverse Drug Events
96
Adverse Drug Events
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