ADVERSE DRUG EVENTS

Presentation Transcript

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

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

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

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

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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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Most known drug-food interactions appear to be associated with pharmacokinetic mechanisms

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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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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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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A drug prescribed for the treatment of one disease can adversely affect a different condition that has been generally well controlled

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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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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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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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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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Hypothyroidism

 sensitivity to CNS depressants in susceptible patients

Hyperthyroidism

 susceptibility to epinephrine-induced hypertension and cardiac arrhythmia

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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

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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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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Type I (immediate) hypersensitivity

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Type II (cytotoxic) hypersensitivity

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Type III (immune-complex) hypersensitivity

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Type IV (delayed) hypersensitivity

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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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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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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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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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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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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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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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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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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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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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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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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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Mucositis

Drugs that arrest the growth and maturation of normal cells

antineoplastic agents

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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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Bacterial infections

Drugs that alter the normal flora

antibacterial agents

Drugs that cause immuno-suppression

immuno-suppressants

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Fungal infections

Drugs that alter the normal flora

antibacterial agents

immuno-suppressants

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Viral infections

immuno-suppressants

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Adverse Drug EventsType A Reactions: Viral Infections

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Gingival hyperplasia

phenytoin, calcium-channel blocking agents, cyclosporine

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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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Inadequate nutrition

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

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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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Allergic/ immunologic reactions

Type I (immediate) hypersensitivity reaction

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Type II (cytotoxic) hypersensitivity reaction

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Type III (immune-complex) hypersensitivity reaction

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Type IV (delayed) hypersensitivity reaction

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Lichenoid mucositis

diuretics
beta1-adrenergic antagonists
ACE-inhibitors
COX-1 inhibitors

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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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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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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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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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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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Oncogenic effects

Kaposi sarcoma

5.6 %

vs. 0.03-0.07 %

60 % non-visceral

Skin
Oral ( 2 %)

Visceral

Skin (24 %)
Oral 3 %

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Oncogenic effects

Lympho-proliferative disease
Lymphomas
Leiomyoma
Leiomyosarcoma
Spindle-cell sarcoma

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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 notimpossible

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