What are the potential side effects of medications?

Medication Side Effects: A Comprehensive Overview

Medication side effects are common, occurring in 2-5% of children and varying widely by drug class, with most being mild and transient, though serious reactions require immediate recognition and management. 1

Understanding Side Effects vs. Adverse Drug Reactions

Adverse drug effects and adverse drug reactions represent distinct concepts that are often conflated:

• Adverse drug effects are potentially harmful physiological or pathological changes detected through laboratory tests (biochemical, hematological, immunological) or clinical investigations, which may or may not produce clinically appreciable symptoms 2
• Adverse drug reactions are appreciably harmful or unpleasant clinical manifestations (symptoms and/or signs) resulting from medication use 2
• No medicine has a single physiological effect—all medications cause unwanted effects in addition to their intended action, even at recommended doses 3

Categories of Adverse Reactions

Predictable Reactions

• Side effects, toxicity, and drug interactions can be anticipated based on pharmacological properties and should be discussed before initiating therapy 4
• The majority of side effects encountered during acute treatment phases (stomachaches, sedation, insomnia) respond to dose reduction or discontinuation and have little lasting significance 5

Unpredictable Reactions

• Intolerance reactions represent exaggerated pharmacological or toxic effects among vulnerable patient subsets 4
• Allergic reactions can be mediated through IgE-mediated mechanisms, serum-sickness-like reactions, direct inflammatory mediator release, or poorly understood immune mechanisms 4
• Idiosyncratic reactions are not predictable from pharmacological actions and often result from pharmacogenetic variations in drug metabolism 4

Common Side Effects by Drug Class

Psychotropic Medications in Children

Stimulants (for ADHD):

• Common side effects include insomnia, anorexia, headaches, social withdrawal, tics, and weight loss 5
• Almost all stimulant-related side effects are rare and short-lived, responding to dose or timing adjustments 5
• Seven side effects occur more frequently than placebo: delayed sleep onset, reduced appetite, weight loss, tics, stomachache, headache, and jitteriness 5
• Severe movement disorders, obsessive-compulsive ruminations, or psychotic symptoms are very rare and disappear when medication is stopped 5

Antipsychotics:

• Young patients, particularly males, are at higher risk for extrapyramidal symptoms including acute dystonia (sudden spastic muscle contractions, potentially life-threatening with laryngospasm) 6
• Parkinsonism (bradykinesia, tremors, rigidity) may be difficult to differentiate from negative psychosis symptoms 6
• Akathisia (severe restlessness) occurs in 44% of patients receiving IV prochlorperazine within one hour 6
• Tardive dyskinesia (involuntary facial and extremity movements) occurs in approximately 5% of young patients per year, more common with typical antipsychotics 6
• Neuroleptic malignant syndrome is potentially lethal, consisting of mental status changes, fever, muscle rigidity, and autonomic dysfunction, with mortality <10-15% currently 6
• Atypical antipsychotics cause significant metabolic effects, with clozapine causing weight gain in 31% of patients 7
• QT interval prolongation can lead to dangerous arrhythmias including torsades de pointes 6
• Cognitive effects include sedation, cognitive blunting, memory deficits (especially with anticholinergic agents), and apathy 6

Anticholinergic Medications (e.g., biperiden):

• CNS impairment including delirium and slowed comprehension, particularly in older adults 8
• Sedation, drowsiness, visual disturbances, urinary retention, constipation, and dry mouth 8
• Increased fall risk in elderly due to sedation and impaired mobility 8

Antidepressants

Tricyclic antidepressants:

• Cardiotoxic, hypotensive, and anticholinergic effects, though desipramine and nortriptyline have lower risk profiles 5
• Tachycardia may occur with desipramine 5

SSRIs:

• Sweating, tremors, nervousness, insomnia or somnolence, dizziness, gastrointestinal disturbances, and sexual dysfunction 5
• Fluoxetine has a very long half-life, meaning side effects may not manifest for weeks 5

Other antidepressants:

• Nefazodone requires monitoring for hepatotoxicity 5
• Bupropion should not be used in patients with seizure disorders 5

Antimicrobials

Tuberculosis medications:

• Cycloserine causes CNS effects ranging from headache/restlessness to psychosis and seizures (16% at 500mg twice daily, 3% at 500mg once daily) 5
• Ethionamide and other TB medications have overlapping hepatotoxicity risks 5
• Rifampin and rifabutin cause extensive drug interactions by decreasing levels of numerous concomitant medications 5

Antimalarials:

• Mefloquine causes vomiting (3% during prophylaxis), dizziness, myalgia, nausea, fever, headache, and neuropsychiatric events 9
• Dizziness, vertigo, tinnitus, hearing impairment, and loss of balance may continue for months or years after discontinuation and may be permanent 9
• Severe neuropsychiatric disorders include neuropathies, convulsions, anxiety, depression, hallucinations, and suicidal ideation 9
• Atovaquone-proguanil causes diarrhea, abdominal pain, nausea, vomiting, and headache (≥5% in adults) 10

Dermatologic Medications

Isotretinoin (for severe acne):

• Cardiovascular: chest pain, edema, flushing, palpitation, stroke, syncope, thrombosis 5
• CNS: aggressive behavior, depression, emotional instability, fatigue, headache, psychosis, suicidal ideation/attempts, violent behavior, pseudotumor cerebri, seizure 5
• Dermatologic: alopecia, cheilitis, dry skin, photosensitivity 5
• Metabolic: elevated glucose, cholesterol, triglycerides 5
• GI: bleeding/inflammation of gums, colitis, esophagitis, inflammatory bowel disease, pancreatitis 5
• Hematologic: agranulocytosis, anemia, neutropenia, thrombocytopenia 5
• Hepatic: elevated transaminases, hepatitis 5

Spironolactone (off-label for acne):

• Hyperkalemia, electrolyte disturbances, metabolic acidosis 5
• Potential feminization of male fetus if taken during pregnancy 5
• GI: diarrhea, nausea, vomiting, gastric hemorrhage 5
• Dermatologic: rash, Stevens-Johnson syndrome, toxic epidermal necrolysis 5

Oral contraceptives (for acne):

• Cardiovascular: thromboembolism, MI, stroke, hypertension, pulmonary embolism, retinal vein thrombosis 5
• Hepatic: cholestasis, liver neoplasm 5
• Neurologic: headache, migraine, hemorrhagic cerebral infarction 5
• Psychiatric: depression, irritability, labile affect 5
• Reproductive: breakthrough bleeding, breast tenderness, menstrual disorders, reduced libido 5

Risk Factors and Prevention

Patient-Specific Considerations

• The higher the number of medications, the higher the risk of adverse reactions 3
• Patient- and family-specific risks must be considered (e.g., antipsychotic-induced weight gain in obese children with family history of type 2 diabetes) 5
• Pharmacokinetic and pharmacodynamic parameters differ in children compared to adults and must be considered before prescribing 11
• Dehydration, physical exhaustion, preexisting brain disease, and concomitant psychotropic medications increase risk for neuroleptic malignant syndrome 6

Prescribing Practices

• Practitioners should be familiar with adverse effects of every drug they use and ensure every prescribed drug is strictly necessary 1
• Prescribing clinicians should be vigilant in withholding unnecessary drugs, such as antibiotics for viral infections 11
• Duration of drug therapy should be limited to the minimum time compatible with full recovery 1
• Understanding the mode of action before administering medicines can predict and prevent harmful interactions, exaggerated side effects, and responses at unintended sites 3

Informed Consent and Patient Education

Essential Discussion Points

• Patients and parents should understand that some children respond well to medication, while others do not respond at all 5
• Common and expectable risks, as well as patient-specific risks, must be discussed 5
• Rare but clinically important adverse events (e.g., suicidal ideation during depression treatment) require discussion 5
• Unexpected, unique, and potentially life-threatening events may occur that may or may not be related to medication 5
• Controversies regarding medication use (e.g., suicidality with antidepressants, cardiac risks of stimulants) should be specifically addressed 5

Ongoing Communication

• Much information discussed during consent may not be retained; periodic review of treatment goals, risks, and benefits is required 5
• Reassuring patients and parents that medications will be discontinued if not useful or causing unacceptable side effects may increase comfort with starting treatment 5
• Emphasizing benefits while minimizing risks to enhance agreement is not consistent with good clinical care and may harm the prescriber-patient relationship if significant adverse effects occur 5

Monitoring and Management

Clinical Monitoring

• Clinical monitoring of both efficacy and side effects should occur, with frequency varying by treatment stage 6
• Regular assessment for tardive dyskinesia should occur at least every 3-6 months using standardized measures like the Abnormal Involuntary Movement Scale 6
• Patients receiving prochlorperazine should be monitored with close clinical observation, cardiorespiratory monitoring, pulse oximetry, and/or electrocardiogram when tolerated 6
• Weighing patients at each visit provides objective measurement of appetite loss 5
• Metabolic monitoring should occur at least every 3-6 months to identify changes early 7

Laboratory Monitoring

• Serum potassium, sodium, and renal function monitoring required for spironolactone 5
• Breast and pelvic examinations, Papanicolaou smear, urine pregnancy test, and blood pressure monitoring for oral contraceptives 5
• Cycloserine serum concentration measurements aiming for peak of 20-35 mg/mL help determine optimal dosing 5
• Nortriptyline has therapeutic blood level "window" of 50-150 ng/mL 5

Management of Adverse Reactions

• Early recognition and prompt withholding of the offending drug is essential 1
• Urgent resuscitation is necessary for anaphylactic collapse, but most adverse reactions require only symptomatic treatment 1
• Careful dose lowering or timing changes may alleviate side effects 5
• When insomnia or appetite loss occurs but the medication is highly beneficial, adjunctive tactics are available to ameliorate side effects 5
• Parents of children who have suffered adverse reactions must be aware of this and know the name of the responsible drug 1

Special Populations

Pregnancy and Breastfeeding

• Drug exposure and potential harms should be considered for fetuses and breastfeeding infants 11
• Cycloserine crosses the placenta with limited safety data; use only when no suitable alternatives exist 5
• Rifamate may be used in pregnant women, but Rifater should not be used due to pyrazinamide content 5
• Isotretinoin is absolutely contraindicated in pregnancy 5
• Spironolactone is pregnancy category C but compatible with breastfeeding 5

Pediatric Considerations

• Adverse reactions occur in only 2-5% of children for whom drugs are prescribed 1
• Most adverse reactions in children are mild and transient 1
• Children are increasingly at risk of drug harm/overdose through accidental or intentional ingestion 11
• Parents and caregivers should receive training in proper use, storage, and administration of all drugs 11
• Youth may experience higher rates of certain adverse effects (e.g., agranulocytosis and seizures with clozapine) compared to adults 7

Renal Impairment

• Cycloserine should not be used in patients with creatinine clearance <50 mL/minute unless receiving hemodialysis 5
• Atovaquone-proguanil is contraindicated for prophylaxis in severe renal impairment (creatinine clearance <30 mL/min) 10

Hepatic Disease

• In patients with underlying hepatic disease, single-drug formulations are advisable until safety can be determined 5
• Nefazodone requires monitoring for hepatotoxicity 5
• Elevated liver tests and cases of hepatitis and hepatic failure requiring transplantation have been reported with atovaquone-proguanil prophylaxis 10

Reporting Obligations

Practitioners who encounter unreported adverse reactions have an obligation to notify the appropriate drug monitoring authority 1