ADVERSE DRUG EVENTS Géza T. Terézhalmy, D.D.S., M.A. Professor and Dean Emeritus School of Dental...

ADVERSE DRUG EVENTS

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

04/21/23 Terezhalmy 2

Adverse Drug EventsAdverse Drug Events

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





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



• Therapeutic agents seldom exert their beneficial effects without also causing 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



• 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



• 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 eventPre-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



• Etiology and epidemiology• Classification of adverse drug events

• Type A reactionsAssociated with the administration of therapeutic dosages

of a drug (exception: drug overdose)Usually predictable and avoidableResponsible for most adverse drug events

Overdose Cytotoxic reactions Drug-drug interactions Drug-food interactions Drug-disease interactions



• Etiology and epidemiology• Classification of adverse drug events

• Type B reactionsGenerally independent of doseRarely predictable or avoidableWhile 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


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




• Etiology and epidemiology• Drug-drug interactions

• Two or more drugs administered at the same time or in close sequence

May act independentlyMay interact to or the magnitude or duration of

action of one or more of the drugsMay interact to cause an unintended reaction

• Drug-drug interactions all seem to have either a pharmacodynamic or a pharmacokinetic basis





• Pharmacodynamic mechanismsThe 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





• Pharmacodynamic mechanismsPharmacological 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





• Pharmacodynamic mechanismsPhysiological 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





• Pharmacodynamic mechanismsChemical interactions

Drug A interacts with drug B and prevents drug B from interacting with its intended receptor

protamine sulfate vs. heparin





• Pharmacodynamic mechanismsDrug-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





• Pharmacokinetic mechanismsFollowing 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





• 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





• 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





• 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





• 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






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






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





• 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





• 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





• 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




• 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





• Interactions affecting absorptionChemical 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





• Interactions affecting metabolismComponents 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




• 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 mechanismsPharmacokinetic mechanisms





• Pharmacodynamic mechanismsNon-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





• Pharmacodynamic mechanismsBeta1-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





• Pharmacodynamic mechanismsBeta1-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





• Pharmacodynamic mechanismsCOX-1 inhibitors block cyclooxygenase-dependent

prostaglandin and thrombaxane A2 synthesis

Exacerbate peptic ulcer disease and gastroesophageal reflux disease in susceptible patients





• Pharmacodynamic mechanismsHypothyroidism

sensitivity to CNS depressants in susceptible patients

Hyperthyroidism

susceptibility to epinephrine-induced hypertension and cardiac arrhythmia





• Pharmacokinetic mechanismsCardiac 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


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




• 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

occursMost reactions occur in young or middle aged adultsDrug allergy is twice a frequent in women than in man





• Type I (immediate) hypersensitivity





• Type II (cytotoxic) hypersensitivity





• Type III (immune-complex) hypersensitivity





• Type IV (delayed) hypersensitivity




• Etiology and epidemiology• Pseudoallergic reactions

• Cannot be explained on an immunologic basis• Occur in patients who had no prior exposure to the

drugCertain 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




• 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




• Etiology and epidemiology• Oncogenic effects

• Primary oncogenic effectsProduced by certain procarcinogenic drugs, which have

been converted into carcinogens by polymorphic oxidative reactions

Reactive metabolites bind covalently to DNA

• Secondary oncogenic effectsTherapeutic 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





• 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




• Clinical manifestations• Cytotoxic reactions


Adverse Drug EventsType A: Cytotoxic Reactions








• Clinical manifestations• Gastrointestinal disturbances

• Nausea and vomitingVomiting 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





• ConstipationDiet, functional abnormalities, colonic disease, rectal

problems, neurological disease, metabolic disorders, drugs

anticholinergic agents, antihistamines, antidepressants, anticonvulsants, antiparkinsonian

drugs, opioid analgesics, antacids





• 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




• 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




• 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




• 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




• 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)




• Clinical manifestations• Xerostomia

• Diuretics• Drugs with

anticholinergic activity antihistamines,

psychotropic drugs, CNS stimulants,

antineoplastic agents


Adverse Drug EventsType A Reactions: Xerostomia

Adverse Drug EventsType A Reactions: Xerostomia




• Clinical manifestations• Mucositis

• Drugs that arrest the growth and maturation of normal cells

antineoplastic agents




• Clinical manifestations• Bleeding diatheses

• Drugs that interfere with platelet function and the coagulation phase of hemostasis

COX-1 inhibitors

clopedigrol, warfarin,

heparin


Adverse Drug EventsType A Reactions: Bleeding Diatheses

Adverse Drug EventsType A Reactions: Bleeding Diatheses




• Clinical manifestations• Bacterial infections

• Drugs that alter the normal flora

antibacterial agents

• Drugs that cause immuno-suppression

immuno-suppressants




• Clinical manifestations• Fungal infections

• Drugs that alter the normal flora

antibacterial agents


immuno-suppressants




• Clinical manifestations• Viral infections


immuno-suppressants


Adverse Drug EventsType A Reactions: Viral Infections

Adverse Drug EventsType A Reactions: Viral Infections




• Clinical manifestations• Gingival

hyperplasia phenytoin,

calcium-channel

blocking agents,

cyclosporine




• 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




• Clinical manifestations• Inadequate nutrition

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

drugs that are hepatotoxic




• 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 doseHyper-reactive patient

The drug produces its usual effect at an unexpectedly low dose




• Clinical manifestations• Allergic/

immunologic reactions

• Type I (immediate) hypersensitivity reaction






• Type II (cytotoxic) hypersensitivity reaction






• Type III (immune-complex) hypersensitivity reaction






• Type IV (delayed) hypersensitivity reaction




• Clinical manifestations• Lichenoid

mucositis diuretics

beta1-adrenergic

antagonists ACE-inhibitors

COX-1 inhibitors




• Clinical manifestations• Erythema

multiforme• Stevens-Johnson

syndrome sulfonamides

anticonvulsive agents

COX-1 inhibitors


Adverse Drug EventsType B Reactions: SJSAdverse Drug Events

Type B Reactions: SJS




• Clinical manifestations• Teratogenic effect

• Drugs given during pregnancy can affect the fetus by producing lethal, toxic, or teratogenic effect

Constricting placental vesselsImpairing gas and nutrient exchange between

fetus and motherProducing hypertonia resulting in anoxic injuryIndirectly, changing the biochemical dynamics

of the mother





• Fetal age, drug potency, and dosage< 20 days after fertilization

An all-or-nothing effect2nd to 3rd trimesters

Unlikely to be teratogenic Alter growth and function of normally formed fetal

organs and tissues





• 3rd to 8th weekNo measurable

effectSpontaneous

abortionSublethal

True teratogenic effect


Adverse Drug EventsType B Reactions: Teratogenic Effects

Adverse Drug EventsType B Reactions: Teratogenic Effects




• 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 yearsLatency 5.3 years





• Kaposi sarcoma 5.6 %

vs. 0.03-0.07 % 60 % non-visceral

Skin Oral ( 2 %)

Visceral Skin (24 %) Oral 3 %





• Lympho-proliferative disease

• Lymphomas

• Leiomyoma

• Leiomyosarcoma

• Spindle-cell sarcoma



• 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



• 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



• 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



• 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



• Reporting adverse drug events• FDA Form 3500

• http://www.fda.gov/medwatch/report/hcp.htmComplete the voluntary form 3500 onlineDownload 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



• Conclusion• ADEs evolve through the same physiological

and pathological pathways as normal disease• Prerequisites to consider ADEs in the differential

diagnosisAn 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 discontinuedClinical experienceFamiliarity with relevant literature about ADEs



• 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



• Conclusion• Timely reporting

of ADEs • Saves lives • Reduces morbidity• Decrease the cost

of health care







Date post:	15-Jan-2016
Category:	Documents
Upload:	ronald-peters
View:	215 times
Download:	0 times

ADVERSE DRUG EVENTS Géza T. Terézhalmy, D.D.S., M.A. Professor and Dean Emeritus School of Dental...

Documents