ADVERSE DRUG EVENTS

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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

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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 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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Adverse Drug EventsType B Reactions

• Etiology and epidemiology
• Allergic/immune reactions
• Type I (immediate) hypersensitivity

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Adverse Drug EventsType B Reactions

• Etiology and epidemiology
• Allergic/immune reactions
• Type II (cytotoxic) hypersensitivity

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Adverse Drug EventsType B Reactions

• Etiology and epidemiology
• Allergic/immune reactions
• Type III (immune-complex) hypersensitivity

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Adverse Drug EventsType B Reactions

• Etiology and epidemiology
• Allergic/immune reactions
• Type IV (delayed) hypersensitivity

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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

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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

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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

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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 EventsType A Reactions

• Clinical manifestations
• Cytotoxic reactions

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Adverse Drug EventsType A Cytotoxic Reactions
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Adverse Drug EventsType A Cytotoxic Reactions
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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

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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

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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

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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

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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

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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

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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)

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Adverse Drug EventsType A Reactions

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

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Adverse Drug EventsType A Reactions Xerostomia
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Adverse Drug EventsType A Reactions

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

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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

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Adverse Drug EventsType A Reactions Bleeding
Diatheses
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Adverse Drug EventsType 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 EventsType 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 EventsType A Reactions

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

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Adverse Drug EventsType A Reactions Viral
Infections
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Adverse Drug EventsType A Reactions

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

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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

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Adverse Drug EventsType 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 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

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Adverse Drug EventsType B Reactions

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

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Adverse Drug EventsType B Reactions

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

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Adverse Drug EventsType B Reactions

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

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Adverse Drug EventsType B Reactions

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

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Adverse Drug EventsType B Reactions

• Clinical manifestations
• Lichenoid mucositis
• diuretics
• beta1-adrenergic antagonists
• ACE-inhibitors
• COX-1 inhibitors

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Adverse Drug EventsType B Reactions

• Clinical manifestations
• Erythema multiforme
• Stevens-Johnson syndrome
• sulfonamides
• anticonvulsive agents
• COX-1 inhibitors

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Adverse Drug EventsType B Reactions SJS
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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

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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

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Adverse Drug EventsType 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 EventsType B Reactions Teratogenic
Effects
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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

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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

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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

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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

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

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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
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Adverse Drug Events
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Adverse Drug Events