Adverse drug reaction
From IDWiki
Background
- Any noxious and unintended response to a drug or natural health product that occurs at a normal dose
- A serious adverse drug reaction is one that requires inpatient hospitalization (or prolongation of existing hospitalization), causes congenital malformation, results in persistent or significant disability or incapacity, is life threatening, or results in death
- Also known as a serious adverse event
- A serious unexpected adverse drug reaction is one that is not identified in the brochure or label of the drug or natural health product
- Also known as a suspected unexpected serious adverse reaction
Risk Factors
- Extremes of ages (elderly and young)
- Polypharmacy
- Pregnancy
- Breastfeeding
- Genetic factors
- e.g. specific genes predispose to AG ototoxicity
- Comorbidities, including renal and hepatic dysfunction
- Antimicrobials are one of the largest causes of adverse drug reactions
Immune-mediated Hypersensitivity Reactions
- See also Hypersensitivity reaction
| Type | Description | Examples |
|---|---|---|
| I | immediate IgE-mediated reaction | anaphylaxis |
| II | antibody-mediated cytotoxic reaction | hemolytic anemia from penicillin |
| III | immune complex-mediated reaction | serum sickness from cephalosporins |
| IV | delayed cell-mediated reaction | DRESS |
| IVa | delayed Th1-mediated reaction | |
| IVb | delayed Th2-mediated reaction | |
| IVc | delayed CD8 T-cell-mediated reaction | |
| IVd | delayed T-cell-mediated neutrophilic reaction |
Non-immune-mediated Hypersensitivity Reactions
| Type | Description | Examples |
|---|---|---|
| Type A | Understood pharmacologic effects | serotonin syndrome from linezolid, thrush after antibiotics, drug toxicities, drug-drug interactions |
| Type B | Idiosyncratic | |
| Type C | Chronic effects | |
| Type D | Delayed effects, including carcinogenic or teratogenic |
Major Examples
Fluoroquinolones
- CNS: dizziness, HA, sleep disturbance, hallucinations, seizures, depression, peripheral neuropathy (3%)
- Seizures, especially with concomitant NSAIDs or theophylline due to GABA binding and NMDA activation
- Cipro worst culprit
- Seizures, especially with concomitant NSAIDs or theophylline due to GABA binding and NMDA activation
- QT prolongation
- Tendon rupture
- 90% was Achilles tendon; 50% bilateral
- Cipro caused 90% of cases
- Risk persists for up to a year
- Most cases resolve after discontinuation
- Risk factors: elderly, concomitant steroids, renal failure, diabetes, history of MSK disorders, male sex
- Steroids cause chondrocyte apoptosis
Beta Lactams
- Seizures
- Inhibits GABA release
- More common with renal failure, elderly, high doses
- 1 to 10 days after starting the abx
- Resolves 2 to 7 days after stopping
Metronidazole
- Peripheral neuropathy
- Usually reversible but takes time
- Starts after 4 weeks or 42 grams
- Free radicals causing nerve damage, and metronidazole causes degeneration
- Resolves in 2 to 24 weeks
Nitrofurantoin
- Pulmonary fibrosis
- May be acute or chronic (9 days vs months or years)
- No fevers, eosinophilia, or pleural effusions
- Risk factosr include CKD, high prolonged doses, older age, female sex
- Mechanism is toxic metabolites induce injury of lung microsomes with oxidative stress
- Acute: Type I or III hypersensitivity, resolves with discontinuation
- Chronic: cell-mediated or toxic response, fibrosis is irreversible
Drug Fevers
- Most commonly beta lactams and Septra
- Caused by byproducts of hepatically created metabolites?
- Can be high fevers; relative bradycardia, patient appears well, no rigors, maybe liver enzymes up, normal eosinophils, often left shift of elevated WBC
- Usually takes 5 to 10 days
- Normalizes withing 72 hours of discontinuation
QT Prolongation
- Risk factors include electrolyte abnormalities, age, female sex, structural heart disease, bradycardia, hypothyroidism, CNS process, obesity, genetics, alcohol and cocaine use
- Potassium wasting diuretics
- Antiarrhythmics
- Drug-drug interactions
- Higher dose
- Route of drug (IV > PO)
- EMA paper QT prolongation
- Concern if the drug causes 30-60 ms increase
- Clear concern if QTc >500 ms or increases by >60 ms
- Check repeat ECG at 3 to 5 days
Diarrhea
- Antibiotics are 25% of drug-induced diarrhea
- Appears within days, resolves after discontinuing
- Mechanism includes diruption of normal gut flora, which can also cause impaired fermentation
- Highest risk includes macrolides (promotility), fluroquinolones, amoxicillin/clavulatate
Acute Tubular Necrosis
- Aminoglycosides
- Vancomycin
- Inter
Interstitial Nephritis
- Typically beta lactams
- Oliguria, malaise, anorexisa, nausea/vomiting
- Rash, fever, eosinophils, arthralgias
- T-cell mediated hypersensitivity
- Reversible over weeks
- Should probably avoid the whole class of antibiotics
Rash
- Amipicillin is the msot common penicillin, more commoly in women, especially with viral infections
- Maculopapular rash
- Most common
- Not immediate (>1 hour after dose)
- Mechanism is T-cell mediated
Neutropenia/Thrombocytopenia
- From beta lactams
- Can either be from induced antibody formation against wthe bloodline with immune complex formation; can also have a direct marrow effect
- Anemia is rare, but can get autoimmune hemolytic anemia
- At least 10 days of penicillin before you see bone marrow suppression
- Start to recover after 3 to 4 days of discontinuation if it was marrow suppression
- Longer if immune-mediated reaction
- Linezolid, vancomycin,
Aplastic anemia
- From Septra
Daptomycin
- Asymptomatic CK rise:
- 8/8 patients in one case series were able to resume with normalized CK by withholding a dose and resuming 24 h later
