adverse drug events by I66V751d

VIEWS: 11 PAGES: 96

									        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
    Adverse Drug Events


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

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    Adverse Drug Events




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    Adverse Drug Events



                   • There are no
                     “absolutely” safe
                     biologically active
                     therapeutic agents



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    Adverse Drug Events


• Therapeutic agents
  seldom exert their
  beneficial effects
  without also
  causing adverse
  drug events

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    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
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            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

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            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

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            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
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            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
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            Adverse Drug Events
             Type 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

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            Adverse Drug Events
             Type 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

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            Adverse Drug Events
             Type 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


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            Adverse Drug Events
             Type 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
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            Adverse Drug Events
             Type 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 other’s action or
                     produce an opposing effect via different cellular
                     mechanisms


                                           cholinergic agents vs diazepam
                                                epinephrine vs. lidocaine
                                                epinephrine vs. histamine
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            Adverse Drug Events
             Type 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
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            Adverse Drug Events
             Type 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
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    Adverse Drug Events
     Type 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

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    Adverse Drug Events
     Type 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

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    Adverse Drug Events
     Type 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

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    Adverse Drug Events
     Type 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

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    Adverse Drug Events
     Type 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
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    Adverse Drug Events
     Type 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
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    Adverse Drug Events
     Type 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
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    Adverse Drug Events
     Type 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

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    Adverse Drug Events
     Type 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
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    Adverse Drug Events
     Type 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
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    Adverse Drug Events
     Type 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

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    Adverse Drug Events
     Type 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

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    Adverse Drug Events
     Type 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

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    Adverse Drug Events
     Type 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




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    Adverse Drug Events
     Type 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

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    Adverse Drug Events
     Type 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

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    Adverse Drug Events
     Type 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

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    Adverse Drug Events
     Type 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

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    Adverse Drug Events
     Type 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

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    Adverse Drug Events
     Type 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
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    Adverse Drug Events
     Type 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

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    Adverse Drug Events
     Type 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

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




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




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




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




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    Adverse Drug Events
     Type 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
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    Adverse Drug Events
     Type 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



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    Adverse Drug Events
     Type 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
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    Adverse Drug Events




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                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

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                Adverse Drug Events
                 Type A Reactions

• Clinical manifestations
  • Cytotoxic reactions




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    Adverse Drug Events
 Type A: Cytotoxic Reactions




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    Adverse Drug Events
 Type A: Cytotoxic Reactions




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            Adverse Drug Events
             Type 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

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            Adverse Drug Events
             Type 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

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            Adverse Drug Events
             Type 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
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            Adverse Drug Events
             Type 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

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            Adverse Drug Events
             Type 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



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            Adverse Drug Events
             Type 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



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            Adverse Drug Events
             Type 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)

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            Adverse Drug Events
             Type A Reactions

• Clinical
  manifestations
    • Xerostomia
            • Diuretics
            • Drugs with
              anticholinergic activity
                        antihistamines,
                           psychotropic
                             drugs, CNS
                              stimulants,
                          antineoplastic
                                  agents


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    Adverse Drug Events
Type A Reactions: Xerostomia




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            Adverse Drug Events
             Type A Reactions

• Clinical
  manifestations
    • Mucositis
            • Drugs that arrest the
              growth and
              maturation of
              normal cells
                      antineoplastic
                              agents


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            Adverse Drug Events
             Type A Reactions

• Clinical manifestations
    • Bleeding diatheses
            • Drugs that interfere
              with platelet function
              and the coagulation
              phase of hemostasis
                               COX-1
                               inhibitors
                            clopedigrol,
                                warfarin,
                                 heparin


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        Adverse Drug Events
Type A Reactions: Bleeding Diatheses




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            Adverse Drug Events
             Type A Reactions

• Clinical
  manifestations
    • Bacterial infections
            • Drugs that alter the
              normal flora
                       antibacterial
                              agents
            • Drugs that cause
              immuno-
              suppression
                          immuno-
                        suppressants
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            Adverse Drug Events
             Type A Reactions

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

• Clinical
  manifestations
    • Viral infections
            • Drugs that cause
              immuno-
              suppression


                         immuno-
                       suppressants


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      Adverse Drug Events
Type A Reactions: Viral Infections




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            Adverse Drug Events
             Type A Reactions

• Clinical
  manifestations
    • Gingival
      hyperplasia
                  phenytoin,
                     calcium-
                      channel
                     blocking
                       agents,
                 cyclosporine

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            Adverse Drug Events
             Type 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
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            Adverse Drug Events
             Type A Reactions

• Clinical manifestations
    • Inadequate nutrition




                    drugs that produce nausea, vomiting, diarrhea
                        drugs that produce mucositis, xerostomia,
                                        drugs that are hepatotoxic


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            Adverse Drug Events
             Type 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



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            Adverse Drug Events
             Type B Reactions


• Clinical
  manifestations
    • Allergic/
      immunologic
      reactions
            • Type I (immediate)
              hypersensitivity
              reaction

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            Adverse Drug Events
             Type B Reactions


• Clinical
  manifestations
    • Allergic/
      immunologic
      reactions
            • Type II (cytotoxic)
              hypersensitivity
              reaction

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            Adverse Drug Events
             Type B Reactions

• Clinical
  manifestations
    • Allergic/
      immunologic
      reactions
            • Type III (immune-
              complex)
              hypersensitivity
              reaction

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            Adverse Drug Events
             Type B Reactions


• Clinical
  manifestations
    • Allergic/
      immunologic
      reactions
            • Type IV (delayed)
              hypersensitivity
              reaction

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            Adverse Drug Events
             Type B Reactions

• Clinical
  manifestations
    • Lichenoid
      mucositis
                     diuretics
                        beta1-
                    adrenergic
                   antagonists
                ACE-inhibitors
                      COX-1
                     inhibitors
8/31/2012                     Terezhalmy   76
            Adverse Drug Events
             Type B Reactions

• Clinical
  manifestations
    • Erythema
      multiforme
            • Stevens-Johnson
              syndrome
                     sulfonamides
                    anticonvulsive
                             agents
                           COX-1
                          inhibitors
8/31/2012                         Terezhalmy   77
             Adverse Drug Events
            Type B Reactions: SJS




8/31/2012              Terezhalmy   78
            Adverse Drug Events
             Type 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
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            Adverse Drug Events
             Type B Reactions


• Clinical manifestations
    • Teratogenic effect
            • Fetal age, drug potency, and dosage
                < 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


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            Adverse Drug Events
             Type B Reactions

• Clinical
  manifestations
    • Teratogenic effect
            • 3rd to 8th week
                No measurable
                 effect
                Spontaneous
                 abortion
                Sublethal
                    True
                      teratogenic
                      effect

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        Adverse Drug Events
Type B Reactions: Teratogenic Effects




    8/31/2012      Terezhalmy       82
            Adverse Drug Events
             Type 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

8/31/2012                            Terezhalmy   83
            Adverse Drug Events
             Type 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 %


8/31/2012                              Terezhalmy   84
            Adverse Drug Events
             Type B Reactions

• Clinical
  manifestations
    • Oncogenic effects
            • Lympho-
              proliferative disease
            • Lymphomas
            • Leiomyoma
            • Leiomyosarcoma
            • Spindle-cell
              sarcoma
8/31/2012                         Terezhalmy   85
            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

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            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

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            Adverse Drug Events



• Diagnosing adverse drug events
    • Step 4
            • Stop drug therapy and monitor the patient’s status
    • Step 5
            • If appropriate, restart drug therapy and monitor for
              recurrence of adverse drug event



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            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
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            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


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            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
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            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
8/31/2012                 Terezhalmy   92
            Adverse Drug Events



• Conclusion
    • Timely reporting
      of ADEs
            • Saves lives
            • Reduces morbidity
            • Decrease the cost
              of health care


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            Adverse Drug Events




8/31/2012             Terezhalmy   94
            Adverse Drug Events




8/31/2012             Terezhalmy   95
            Adverse Drug Events




8/31/2012             Terezhalmy   96

								
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