Chapter 5 Adverse Drug Reactions (ADRs) Flashcards
Pharmacological (intrinsic) Reaction:
Often predictable based on the drug’s mechanism of action
Typically dose related
Comprise the majority of ADRs
Chapter 5 Summary
According to the FDA 660,000 serious adverse drug reactions (ADRs) are reported annually. Resulting in ER visits and hospitalizations.
Reported 120,000 deaths annually.
3-6% of hospital admissions are from ADRs
10-15% of hospitalized patients experience an ADR
Total cost associated with ADRs estimated around $3.5-$136 billion per year
What are some exaggerated physiological response related to the pharmacology of the drug.
Hypotension from beta blocker metoprolol
Diarrhea from fat-blocking drug orlistat
Insomnia from stimulant methylphenidate
pharmacological ADRs are based on secondary pharmacology
Weight gain from atypical antipsychotic olanzapine
Flatulence from fiber supplement psyllium
Myopathy from HMG-CoA reductase inhibitor simvastatin
What is being done to try to reduce ADRs
Preclinical trials are focusing on secondary adverse effects to predict what will occur when a drug is administered.
Idiosyncratic Reaction:
Unpredictable, serious, mortality possible.
Triggered by immune system, receptor mutations, drug interactions, metabolism differences, pharmaceutical variations, or biological system variation unmasking.
Immune system identifies drug molecules as foreign.
What percent of ADRS are predictable and dose-related
85%-90%
Unpredictable and Not Dose-Related
10%-15%
Hapten Hypothesis:
Drugs act as haptens, small molecules provoking immune responses.
When they bind to carrier proteins, usually through covalent bonds, they become antigenic.
Reactive metabolites from individual metabolic processes can also act as haptens, triggering immune reactions.
Hapten Drug Examples
Penicillin
It covalently binds to a protein to produce a type 1 hypersensitivity(anaphylaxis) reaction.
Non-hapten Immune response
Chemically inert drugs are unable to bind to proteins.
A drug or its metabolite must be able to covalently bond to a protein to form a hapten-carrier complex.
This complex triggers immune responses, which can manifest as
Type I, II, III, or IV hypersensitivity reactions.
Non-Hapten immune response Drugs
Lidocaine, sulfamethoxazole, mepivacaine, celecoxib, carbamazepine, lamotrigine, and ciprofloxacin.
Type I Hypersensitivity Reaction
Triggered by reexposure to an antigen.
Can be local or systemic, affecting various body systems.
Involves release of mediators (histamine, leukotrienes, prostaglandins) from mast cells, basophils, and inflammatory cells activated by IgE.
Symptoms can occur immediately or be delayed by several hours.
Type I Hypersensitivity Management
Epinephrine, antihistamines, and corticosteroids.
Type I Reaction drugs
Antibiotics (penicillin, cephalosporins, sulfonamides
Neuromuscular blockers (Succinylcholine, vecuronium, pancuronium, atracurium)
Chemotherapeutic agents (carboplatin, oxaliplatin)
Monoclonal antibodies (cetuximab, rituximab)
Type II hypersensitivity Reaction
Involves antibody-dependent cytotoxicity.
It can affect various organs and tissues.
Antibodies bind to cell surface antigens, leading to cell destruction.
Destruction occurs via complement system activation or by macrophages.
What causes Drug-induced immune thrombocytopenia (DITP)
is primarily caused by medications but can also result from food or herbal products.
Drug-dependent antibodies bind to glycoproteins, leading to an antibody-platelet reaction.
This reaction causes thrombocytopenia, a decrease in platelet count.
Name some medications associated with the risk of Drug-induced immune thrombocytopenia (DITP).
Abciximab, argatroban, beta-lactam antibiotics, carbamazepine, eptifibatide, linezolid, phenytoin, quinine, sulfonamide, rifampin, ranitidine, tirofiban, trimethoprim-sulfamethoxazole, valproic acid, and vancomycin.
How does Drug-induced immune thrombocytopenia (DITP) occur with heparin?
Heparin binds to platelet factor 4 (PF4) proteins, forming an antigenic complex.
IgG antibodies then bind to the platelets, marking them as foreign.
Complement activation leads to platelet destruction and thrombocytopenia.
Hemolytic anemia and neutropenia can occur when drugs bind to RBC antigens, activating complement and causing cell lysis.
Name some medications associated with hemolytic anemia.
Cephalosporins (cefotetan, ceftriaxone), penicillin and penicillin derivatives, NSAIDs, quinidine, quinine, and trimethoprim-sulfamethoxazole.
How does neutropenia or agranulocytosis occur?
Antibodies bind to antigens on neutrophil surfaces.
Neutropenia reaction happens within minutes to hours after administration.
Type III Hypersensitivity Reaction
Also known as complex hypersensitivity.
Formed by aggregates of antigens and IgG/IgM antibodies, leading to insoluble immune complexes.
Deposited in tissues like joints and kidneys, causing inflammation.
Onset typically takes a week or more.
May present as serum sickness, drug fever, or vasculitis.
Common drugs that cause neutropenia/agranulocytosis
Clozapine, antithyroid meds ( methimazole carbimazole), sulfasalazine, clomipramine, trimethoprim-sulfamethoxazole, ACE inhibitors, and H2 receptor antagonists.
Type II Hypersensitivity Treatment
Treatment involves anti-inflammatory and immunosuppressive agents.
What is the Arthus reaction?
Follows tetanus/diphtheria toxoid (Td) vaccination.
Causes local vasculitis, with severe pain, swelling, possible necrosis.
More likely with high Tetanus antibody levels during revaccination.
Results from immune complex deposition and complement activation.
Recommended Td vaccine no more than every 10 years for those with Arthus reaction.
Meds that cause Type III hypersensitivity reactions.
Streptokinase, monoclonal antibodies (rituximab, infliximab, alemtuzumab, omalizumab, natalizumab), rabies vaccine, antivenom, and other antitoxins
What characterizes Type IV hypersensitivity reactions?
Cell-mediated or delayed-type hypersensitivity.
No antibody-mediated reaction; instead, T cell activation and proliferation.
Results from autoimmune, infectious diseases, or contact dermatitis.
Onset within 2-3 days, but can take days or weeks.
Reactions can occur within 24 hours upon rechallenge.
Treatment for Type III Hypersensitivity Reaction
Treated with antihistamines, NSAIDs, corticosteroids.
Symptoms of Type IV Hypersensitivity Reaction
Manifests as contact dermatitis, morbilliform, maculopapular eruptions, Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug-induced hypersensitivity syndrome (DIHS).
What is Drug-induced Hypersensitivity Syndrome (DIHS), also known as DRESS?
Severe reaction causing rash, fever (38*-40°C), eosinophilia, and organ failure.
Known as Drug Rash, Eosinophilia, and Systemic Symptoms.
Name some drugs associated with DRESS syndrome
Abacavir, allopurinol, carbamazepine, dapsone, minocycline, nevirapine, phenobarbital.
DRESS Treatments
Treatments include corticosteroids and other immunosuppressive agents.
ADRs have also been categorized as
Types A-F
Type A
Pharmacological reactions, dose-dependent, predictable (85%-90%).
Type B
Idiosyncratic, not dose-dependent, unpredictable (10%-15%).
Type D
Delayed reactions.
Type C
Result from chronic medication use.
Type E
Result from drug-drug interactions.
Type F
Result from treatment failures.
Time-Related Reactions:
Rapid Reactions, First-dose reactions, early reactions, intermediate reactions, late reactions, delayed reactions
Classification of Immunological Reactions:
Immediate reactions: Symptoms within 1 hour of exposure.
Delayed reactions: Symptoms more than 1 hour after exposure.
Rapid reactions
During or immediately after administration.
First-dose reactions
After the initial dose.
Early reactions
Early in treatment, resolve will continued use.
Intermediate reactions
After repeated exposure.
Late reactions
After prolonged exposure or upon dose reduction/discontinuation.
Delayed reactions
Occur at variable points in time, even after drug discontinuation.
Rapid Reaction Examples
Vancomycin: Maculopapular rash.
Phenytoin: Purple glove syndrome.
Chemotherapy: Hand-foot syndrome.
First-Dose Reaction examples
Doxazosin: Orthostatic hypotension.
Orthoclone OKT3: Cytokine-release syndrome.
Early Reaction Examples
Metformin: Gastrointestinal upset.
Immune hypersensitivities: Immediate or delayed reactions, requiring immediate medical attention.
Intermediate Reaction Examples
Furosemide: Hyperuricemia.
Ceftriaxone: Hemolytic anemia.
Penicillin G: Interstitial nephritis.
Neomycin: Contact dermatitis.
Late Reaction Examples
Corticosteroids: Osteoporosis.
Opioids: Hypogonadism.
Withdrawal symptoms: Various symptoms upon abrupt discontinuation.
Delayed Reaction Examples
Antipsychotics: Tardive dyskinesia.
Polyalkylimide implant injections: Delayed swelling, nodules, fever, arthritis, xerostomia.
What are important management considerations for adverse drug reactions (ADRs)?
Proper medication administration techniques.
Patient education and monitoring.
Consider dose adjustment or discontinuation for severe reactions.
Thoughtful drug tapering to avoid rebound effects or withdrawal symptoms.
Vigilant monitoring for predisposing factors or increased susceptibility.
What are the clinical implications of adverse drug reactions (ADRs)?
Early detection and management through awareness of potential reactions.
Individualized treatment plans to minimize adverse effects.
Collaboration between healthcare providers and patients for optimal outcomes.
Continuous monitoring for long-term effects, even after drug cessation.
What are dose-related adverse drug reactions (ADRs)?
Adverse reactions from excessive dose or failure to adjust doses for age and organ function.
Examples of ADRs
Hypoglycemia from excessive insulin, lithium toxicity in acute renal failure without dose adjustment.
How are adverse drug reactions (ADRs) classified by severity?
Serious ADRs defined by the FDA result in death, hospitalization, disability, congenital abnormalities, or interventions to prevent these outcomes.
Further categorized as mild, moderate, and severe based on clinical effect and outcome.
What are common causes of adverse drug reactions (ADRs)?
Approximately one-third result from medication errors.
Up to one-third result from allergic reactions.
What drug classes have a high incidence of adverse drug reactions (ADRs)?
Insulins (acting on insulin receptors)
Opioid-containing analgesics (acting
on opioid receptors)
Anticoagulants (affecting coagulation enzymes)
Antibiotics (targeting bacterial enzymes)
Antihistamines (antagonizing histamine receptors)
What factors increase the risk of adverse drug reactions (ADRs)?
Genetic variations, including HLA alleles.
Age, sex, polypharmacy, and concomitant medical conditions.
How do HLA alleles contribute to the risk of adverse drug reactions (ADRs)?
HLA alleles like HLA-B*5701 increase the risk of severe T-cell–mediated hypersensitivity reactions to specific medications like abacavir.
Han Chinese individuals carrying HLA-B1502 or HLA-B5801 alleles are at higher risk of hypersensitivity reactions to carbamazepine and allopurinol, respectively.
What age groups are at higher risk of adverse drug reactions (ADRs) and why?
Children and older adults are at higher risk due to dosage considerations and physiological changes.
How does gender influence the risk of adverse drug reactions (ADRs)?
Women may experience more ADRs due to body composition and hormonal fluctuations.
How do drug interactions impact the risk of adverse drug reactions (ADRs)?
Drug interactions, including enzyme induction/inhibition, can alter metabolism and increase ADR risk, such as carbamazepine inducing liver enzymes or amlodipine inhibiting CYP3A4.
How do medical conditions affect the risk of adverse drug reactions (ADRs)?
Liver or renal disease can affect drug metabolism and clearance, altering drug concentrations.
Heart failure decreases liver and kidney perfusion, reducing drug metabolism.
Thyroid dysfunction alters drug metabolism, impacting metabolic activity.
How are adverse drug reactions (ADRs) detected and assessed?
Identification through screening for drug interactions, considering timing, patient factors, and rechallenge.
Naranjo ADR Probability Scale evaluates ADR probability based on various factors.
FDA programs like FAERS and MedWatch allow reporting and monitoring of ADRs for regulatory action.
How are adverse drug reactions (ADRs) and warnings managed?
Discontinue offending drugs if possible, use alternative treatments.
Adjust dosages based on pharmacological effects.
Rechallenge cautiously for causality determination.
Report ADRs to FDA programs for surveillance and regulatory action.
How does the FDA manage risk associated with medications?
FDA mandates Risk Evaluation and Mitigation Strategy (REMS) for manufacturers.
REMS includes various actions like Elements to Assure Safe Use (ETASU), prescriber letters, patient information, and
registration/training requirements for prescribers and pharmacies.
