Adverse drug reactions by organ system

An adverse drug reaction (ADR) is any harmful or unintended response to a medicine occurring at doses normally used in humans. ADRs are a major public health problem, particularly in older populations where polypharmacy and age-related changes in drug handling amplify risk. The causal link between a drug and a clinical event is not always obvious; clinicians use temporal reasoning to classify the relationship. A reaction is probable when the time course fits, it is not explained by other drugs or disease, and withdrawal leads to clinical improvement. It is possible when another cause could also explain the event, and unlikely when the timing is implausible or a clear alternative explanation exists. This classification underpins clinical diagnosis and pharmacovigilance. ^[2]

ADRs can be classified by mechanism: Type A (augmented, dose-dependent, predictable) and Type B (bizarre, idiosyncratic, dose-independent). Most organ-specific reactions discussed here are Type A, but some—like severe skin reactions—are Type B. The risk of an ADR is not uniform across drug classes. For example, in older adults hospitalised with an ADR, hormones (primarily systemic agents) and bacterial vaccines carry a higher than average risk of repeat admission for another ADR, reflecting the known severe side-effect profiles of antineoplastic and hormonal therapies. This observation highlights that some drug categories are intrinsically more dangerous, and that a prior ADR is a risk factor for future ones. ^[2]

To understand drug safety, one must distinguish between adverse drug events (ADEs) and adverse drug reactions (ADRs). An ADE is an untoward medical occurrence during treatment, which does not necessarily have a causal relationship with the pharmaceutical product. ADEs encompass both ADRs and medication errors (MEs).

Medication errors are defined as any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is controlled by the health care professional, patient, or consumer. These errors can occur at any stage, including prescribing, order communication, labelling, packaging, nomenclature, compounding, dispensing, distribution, administration, education, monitoring, and use.

Pharmacovigilance systems rely on spontaneous reporting to detect safety issues. A healthy national pharmacovigilance system is indicated by annual reporting rates of over 200 adverse drug event reports per million inhabitants. However, underreporting remains a significant challenge. It is estimated that only 2% to 4% of non-serious ADEs and 10% of serious ADEs are reported spontaneously by healthcare professionals. ^[7]

Clinical vigilance is particularly important in specific populations, such as older patients, where ADRs represent a major public health problem. When evaluating drug safety, clinicians must be aware that combined treatment regimens can increase risk. For example, the incidence of serious tocolytic-related ADRs is higher in women receiving combined courses of tocolytics.

Drugs injure every organ system, but the patterns and frequencies differ markedly. The table below summarises key examples and their typical presentations.

Cardiovascular. Drug-induced hypotension is common, especially with vasodilators. Nifedipine, a calcium channel blocker used as a tocolytic, causes serious ADRs in 0.9% of women when given as a single course, and most of these reactions are related to its effect on blood pressure. β adrenoceptor agonists (e.g. salbutamol, terbutaline) cause tachycardia, palpitations and hypotension; in tocolytic use, the incidence of serious ADRs with a single β mimetic is 1.7%. Arrhythmias can follow QT-prolonging drugs (e.g. macrolides, antipsychotics), and heart failure may be precipitated by NSAIDs or thiazolidinediones. ^[3]

Endocrine. Corticosteroids cause hyperglycaemia, adrenal suppression and Cushing's syndrome with prolonged use. Amiodarone can induce both hypothyroidism and hyperthyroidism. Antineoplastic hormonal agents (e.g. aromatase inhibitors) cause oestrogen withdrawal effects. The higher risk of repeat ADRs from hormones and primarily systemic agents is well recognised, as severe side effects of these drugs are known.

Reproductive. Tocolytics are a paradigm for reproductive ADRs. The overall incidence of serious tocolytic-related ADRs is low (0.7%), but in women receiving combined courses of tocolytics (16.2% of all patients), the incidence rises to 1.6–2.5%. Since combined treatment is not more effective than single or sequential treatment, it should be discouraged. β mimetics have the highest single-drug incidence (1.7%), while nifedipine is lower (0.9%) and atosiban has no serious ADRs in single use. Indometacin and atosiban are the only tocolytics not associated with serious ADRs in women. In multiple pregnancy, nifedipine causes serious ADRs in 2% of women and combined treatment in 2.4%, though these were not statistically significant. β mimetics or multiple tocolytics are associated with a high incidence of ADRs. ^[3]

Gastrointestinal. NSAIDs cause gastritis, peptic ulcers and bleeding by inhibiting mucosal prostaglandins. Methotrexate causes nausea, stomatitis and hepatotoxicity. Many antibiotics cause Clostridioides difficile colitis. Drug-induced liver injury ranges from asymptomatic transaminitis (statins, isoniazid) to fulminant hepatitis (paracetamol overdose).

Haematologic. Bone marrow suppression is a dose-limiting toxicity of many antineoplastics and some antibiotics (chloramphenicol). Drug-induced immune haemolytic anaemia occurs with penicillins and cephalosporins. Heparin-induced thrombocytopenia is a prothrombotic state requiring immediate cessation. The severe side effects of antineoplastic drugs are well known and contribute to the higher risk of repeat ADRs from primarily systemic agents.

Musculoskeletal. Statins cause myopathy and rarely rhabdomyolysis, especially with interacting drugs (e.g. fibrates, macrolides). Corticosteroids cause osteoporosis and avascular necrosis. Fluoroquinolones can cause tendon rupture, particularly in older adults.

Skin. Maculopapular rashes are common with aminopenicillins and sulfonamides. Severe cutaneous adverse reactions (SCARs) include Stevens-Johnson syndrome and toxic epidermal necrolysis, often triggered by allopurinol, anticonvulsants or sulfonamides. DRESS (drug reaction with eosinophilia and systemic symptoms) involves skin, fever, lymphadenopathy and organ involvement.

Neurologic. Lidocaine toxicity causes perioral numbness, tinnitus and seizures. Isoniazid causes peripheral neuropathy (prevented by pyridoxine). Metoclopramide causes extrapyramidal reactions. Anticholinergics cause confusion and delirium, particularly in older adults.

Renal. Aminoglycosides cause acute tubular necrosis, especially with prolonged courses or concurrent NSAIDs. ACE inhibitors and ARBs can cause acute kidney injury in volume-depleted patients. Diuretics cause electrolyte depletion (hypokalaemia, hyponatraemia). Contrast media cause contrast-induced nephropathy.

Respiratory. β blockers can precipitate bronchospasm in asthmatics. Amiodarone causes pulmonary fibrosis. Methotrexate can cause pneumonitis. Opioids cause respiratory depression, a dose-dependent central effect.

Multiorgan. Anaphylaxis is a rapid, IgE-mediated systemic reaction (e.g. penicillins, latex). TTP (thrombotic thrombocytopenic purpura) occurs with quinine and ticlopidine. Drug-induced lupus (procainamide, hydralazine) affects skin, joints and kidneys. These reactions require immediate recognition and withdrawal of the offending agent.

Adverse drug reactions (ADRs) manifest across multiple organ systems and require careful clinical evaluation from first principles. The identification and diagnosis of an ADR depend significantly on clinical judgment, where senior hospital doctors such as consultants and registrars make the initial diagnosis, and junior doctors record these findings in text on a structured hospital separation abstract. This clinical documentation is subsequently processed by qualified clinical coders who utilize ICD-9, ICD-9-CM, or ICD-10-AM coding manuals to categorize external causes and contributing factors, obtaining additional information from medical notes as needed.

To understand organ system toxicities, investigators frequently examine specific therapeutic classes, such as tocolytic drugs used in obstetrics. Beta adrenoceptor agonists are known to cause adverse effects in women more often than any other tocolytic drug. Conversely, clinical trials demonstrate that the oxytocin receptor antagonist atosiban is associated with fewer adverse effects compared with beta adrenoceptor agonists, showing a relative risk of 0.04 with a 95 percent confidence interval from 0.02 to 0.11, while maintaining comparable effectiveness in delaying birth for 48 hours with a relative risk of 1.1 and a 95 percent confidence interval from 0.9 to 1.2. However, when compared with placebo, atosiban does not reduce the incidence of neonatal respiratory distress syndrome, which is a serious complication of prematurity. ^[3]

When evaluating drug safety profiles in routine clinical practice, patient cohorts display distinct baseline characteristics. For example, a multicentre study of women treated with tocolytic drugs revealed a mean maternal age of 29.8 years with an interquartile range of 26.4 to 33.3 years, and a mean gestational age of 29 weeks with an interquartile range of 27 to 31 weeks. Subgroup analyses using logistic regression evaluate potential contributing factors to these adverse drug reactions, including multiple gestation, medical history, or any obstetric comorbidity. Routine clinical settings capture both low-risk and high-risk cases, though intense monitoring in formal trial settings is required to reliably capture all mild side effects, as prospective multicentre cohort studies may experience under-reporting due to variable blood pressure monitoring intensity across hospitals. ^[3]

Investigating a suspected adverse drug reaction (ADR) requires a structured approach that combines clinical assessment with targeted laboratory and diagnostic testing. The goal is to confirm the causal relationship between the drug and the observed effect, exclude alternative causes, and guide future management.

The first step in any investigation is a thorough medication history, including over-the-counter drugs, herbal remedies, and recently discontinued agents. Temporal correlation between drug initiation and symptom onset is essential. When multiple drugs are potentially responsible, the clinician must identify the drug clinically considered to be primarily responsible, as this is the standard approach in pharmacovigilance.

Laboratory investigations serve several purposes. They can confirm the biological plausibility of the reaction, assess organ damage severity, and monitor for complications. Common investigations include:

• Full blood count – for cytopenias, eosinophilia, or evidence of infection
• Liver function tests – for hepatocellular or cholestatic injury patterns
• Renal function tests – serum creatinine, urea, and electrolytes
• Coagulation profile – particularly for drugs affecting haemostasis
• Urinalysis – for nephrotoxicity or hypersensitivity reactions
• ECG – for QT prolongation or arrhythmias with certain drugs

For specific drug classes, more targeted investigations are warranted. Therapeutic drug monitoring is valuable for drugs with narrow therapeutic windows, helping distinguish toxicity from therapeutic failure. However, it is important to note that nearly all (99.6%) prescribed doses in a hospital setting fall within manufacturer-recommended ranges, meaning that toxicity often occurs at standard doses due to individual patient factors such as age, renal impairment, or drug interactions. ^[2]

When assessing severity, clinicians should apply standard criteria. A serious adverse event is one that results in death, is life-threatening, requires hospital admission or prolongs an existing stay, results in persistent or significant disability, or is a congenital anomaly. This classification guides the urgency of investigation and the need for immediate drug withdrawal. ^[3]

In older adults, the threshold for investigation should be lower. ADRs cause 3-6% of all hospital admissions in Western countries, and the risk of recurrence is substantial. Older adults who experienced an ADR in the period 1995-9 had a 2.4-fold greater risk of recurrence than those in 1980-4. This highlights the importance of thorough investigation at the first presentation to identify modifiable risk factors. ^[2]

Finally, when an ADR is confirmed, the investigation should include a review of all concomitant medications. In 3.9% of instances where multiple drugs were implicated, only the primary drug is analysed, but clinically, all potential culprits should be considered for withdrawal or dose adjustment. ^[2]

When evaluating medical interventions from first principles, understanding the intended pathways of pharmacological agents and their associated adverse reactions is essential. In the context of metabolic and endocrine conditions, therapeutic decision-making relies on categorising agents by their primary physiological targets. For instance, lifestyle therapy involving a calorie-restricted diet and exercise with the objective of weight loss is established as a first-line treatment in the presence of overweight or obesity. Similarly, hormonal contraceptives are suggested as the first-line treatment in adolescents with suspected polycystic ovary syndrome if the therapeutic goal is to treat acne, hirsutism, anovulatory symptoms, or to prevent pregnancy. ^[1]

Conversely, other agents occupy secondary or specific niche pathways. Metformin is suggested as a possible treatment if the goal is to treat impaired glucose tolerance or metabolic syndrome, but it is explicitly suggested against for use as a first-line treatment of cutaneous manifestations, for the prevention of pregnancy complications, or for the treatment of obesity. In broader preventive contexts, although the preferred treatment for the prevention of type 2 diabetes mellitus is diet and lifestyle modification, metformin may provide an option for treatment in those who fail lifestyle management despite incurring expense and potential side effects. Furthermore, drugs that modulate estrogen action to achieve pregnancy are recognised as first-line treatment when compared directly with insulin sensitizers. ^[1]

In acute or specialized infectious settings, such as Middle East respiratory syndrome, supportive treatment remains the mainstay of management as no specific drug treatment natively exists. Various antiviral compounds and modulators have been investigated. For example, interferon-alpha2b combined with ribavirin can lessen lung injury and reduce lung titres when administered to rhesus macaques within 8 hours of virus inoculation, showing an improvement in survival at 14 days but not at 28 days in severely ill patients. In vitro analyses show that compounds including chloroquine, chlorpromazine, loperamide, and lopinavir inhibit virus replication with an effective concentration fifty of 3 to 8 micromoles per litre. Additionally, exploratory post-hoc meta-analyses of studies regarding severe influenza and related conditions demonstrated a significant reduction of mortality following antibody treatment compared with placebo or no treatment, yielding a pooled odds ratio of 0.25 with a 95% confidence interval spanning from 0.14 to 0.45. ^{[3] [5]}

Managing therapies that act across systemic pathways also requires rigorous evaluation of adverse events, particularly in vulnerable populations such as women undergoing treatment for preterm labour. Observational cohorts evaluate maternal complications by recording characteristics such as gestational age, parity, cervical dilation, blood loss, and comorbidities including cardiopulmonary disease, pre-eclampsia, hypertension, diabetes, placenta abnormalities, or polyhydramnios. Causality assessment of any adverse event requiring cessation of treatment utilises World Health Organization categories: certain, probable, possible, unlikely, conditional, and non-assessable. Important criteria for this causality assessment include the association in time between administration and the event, pharmacological features, medical plausibility, and the exclusion of other potential causes, with rechallenge leading to a classification of certain if the event recurs. ^[3]

Adverse drug reactions (ADRs) do not affect all patients equally. Age, comorbidity, genetic background, and even geography shape both the risk of a first ADR and the likelihood of recurrence. Understanding these differences is essential for safe prescribing in vulnerable groups.

Older adults

Older patients carry a disproportionate burden of ADRs. In a population-based study using linked administrative data from all public and private hospitals in Western Australia (population 2.09 million in 2007), the study population comprised all residents aged ≥60 with a hospital admission related to an ADR. This age threshold reflects the clinical reality that polypharmacy, reduced renal and hepatic clearance, and multiple comorbidities converge in later life. The Charlson comorbidity index, calculated by adding scores assigned to each specific diagnosis using the Dartmouth-Manitoba algorithms for ICD coded administrative data, was used to measure the burden of coexisting disease at the time of the first ADR. Higher comorbidity scores predict not only more frequent ADRs but also worse outcomes once an ADR occurs. ^[2]

Risk of recurrent ADRs

Some drug classes carry a greater than average risk of repeat ADRs. In the same Western Australian cohort, three drug categories were associated with elevated adjusted hazard ratios for repeat ADRs: hormones (1.51, 95% CI 1.34 to 1.69), primarily systemic agents including antineoplastics, immunosuppressives, and antineoplastic antibiotics (2.12, 95% CI 1.89 to 2.38), and bacterial vaccines (4.06, 95% CI 2.00 to 8.26). The bacterial vaccine category had low counts for both first-time and repeat ADRs, so its very high hazard ratio should be interpreted cautiously. For clinicians, this means that a patient who has suffered an ADR to an antineoplastic or immunosuppressive agent is more than twice as likely to experience another ADR on re-exposure or with subsequent therapy—an important consideration when planning treatment cycles. ^[2]

Pregnancy and reproductive health

Pregnancy represents a special population where the risk-benefit calculus of drug therapy shifts dramatically. The thiazolidinedione troglitazone was removed from the U.S. market by the Food and Drug Administration due to hepatic toxicity, and rosiglitazone use was restricted due to excess cardiovascular events. A recent FDA advisory linked pioglitazone to bladder cancer. For infertility treatment in PCOS, the risk-benefit ratio may be less favourable because animal studies suggest thiazolidinediones may be associated with fetal loss (FDA Pregnancy Category C). This illustrates a core principle: a drug's adverse effect profile in one population (non-pregnant adults) may not capture risks that emerge in another (the fetus). ^[1]

Global and occupational perspectives

Seroprevalence data illustrate how occupational contact alters risk: although seroprevalence in the general populations is 0.15%, 2.3% of camel shepherds and 3.6% of slaughterhouse workers were MERS-CoV-antibody positive. This pattern demonstrates that population-level averages can mask dramatically different risk profiles in subgroups defined by occupation or geography—a principle that applies e ^[5]

Key clinical messages

• Always calculate comorbidity burden before prescribing; a high Charlson score flags elevated ADR risk.
• Exercise particular vigilance with hormones, antineoplastics, and immunosuppressives—these carry above-average risk of repeat ADRs.
• In women of reproductive age, check pregnancy category and consider fetal risk before prescribing.
• Remember that population seroprevalence or ADR rates may not apply to individual patients with unique occupational or genetic exposures.

Adverse drug reactions (ADRs) are noxious, unintended responses to medicines occurring at doses normally used in clinical practice. Systematically evaluating ADRs by organ system enables rapid bedside pattern recognition, preventing diagnostic delays and unnecessary investigative cascades.

Drug-induced skin reactions range from mild exanthems to life-threatening severe cutaneous adverse reactions (SCARs). Hyperandrogenic manifestations, such as acne, can also be triggered or exacerbated by drug therapies (e.g., corticosteroids, androgens, or lithium). In women with polycystic ovary syndrome (PCOS), background dermatological disease must be distinguished from newly acquired drug effects; acne prevalence itself ranges from 14% to 25% in this group. ^[1]

When tracking dermatological changes, androgenic alopecia is an important marker of hyperandrogenism that can be formally assessed:

• Graded using subjective scoring systems such as the Ludwig score. ^[1]
• Associated with underlying metabolic syndrome and insulin resistance.
• Presents later and less frequently than other hyperandrogenic signs but carries marked psychological morbidity.

Metabolic ADRs often stem from agents designed to target carbohydrate and lipid pathways. Biguanides such as metformin alter cellular respiration by inhibiting mitochondrial complex I, which reduces hepatic gluconeogenesis and augments peripheral insulin sensitivity:

• Metformin tolerability is improved by initiating treatment at 500 mg of slow release daily.
• The dose is titrated over weeks to months up to a target dose of 2 g daily.
• Lactic acidosis is a rare but critical adverse effect, predominantly occurring in patients with pre-existing renal impairment or other significant systemic illnesses. ^[6]
• Although widely used off-label for metabolic and ovulatory dysfunction in conditions affecting up to 18% of reproductive-age women based on Rotterdam criteria, neither metformin nor oral contraceptive pills (OCPs) are formally approved by most regulatory authorities specifically for PCOS. ^[6]

A major diagnostic pitfall is failing to establish whether an apparent drug toxicity represents an independent medical condition or physiological maturation.

Physiological adolescent development frequently mimics endocrine or metabolic adverse reactions. For instance, irregular menstrual bleeding following the initiation of psychotropic or hormonal medications in teenagers is frequently misattributed to the drug:

• Anovulatory cycles account for 85% of menstrual cycles in the first post-menarcheal year. ^[1]
• Anovulatory cycles drop to 59% in the third year after menarche. ^[1]
• Normal anovulatory frequency declines to 25% by the sixth year post-menarche. ^[1]
• Up to two-thirds of adolescents with PCOS display menstrual symptoms, with one-third presenting with primary amenorrhea or dysfunctional uterine bleeding. ^[1]
• Evaluation for underlying pathology like PCOS is warranted when oligomenorrhea or amenorrhea persists 2 years beyond menarche. ^[1]

In intensive care, determining cessation of function in drug toxicity or brain death requires strict criteria to avoid tragic diagnostic errors:

• For determination of death by circulatory criteria (DCC), continuously monitoring via a well-functioning indwelling arterial catheter is required to avoid false-positive and false-negative errors. ^[4]
• A pulse pressure of zero corresponds to mechanical asystole. ^[4]
• Setting a pulse pressure threshold greater than 5 mm Hg introduces a dangerous risk of declaring death in an individual with persistent brain activity. ^[4]
• When continuous invasive arterial lines are deployed, persisting electrocardiographic activity does not preclude death, meaning electrical asystole is not mandatory. ^[4]
• Non-invasive methods such as auscultation or palpation must never be relied upon alone to determine lack of circulation. ^[4]

Organ-specific adverse drug reaction monitoring forms the cornerstone of pharmacovigilance across acute care, reproductive endocrinology, and critical care units.

In outpatient practice, clomiphene is generally used as initial medical therapy. ^[6]

In neurointensive care, managing drug overdoses, neurovascular catastrophes, and organ preservation mandates adherence to precise criteria. Determining death requires careful separation between biological cessation, clinical determination, and legal certification:

• For DCC, the legal time of death must be documented as the exact time when the mandated observation period is complete. ^[4]
• Invasive arterial lines provide continuous verification of the absence of mechanical ejection without relying on palpation.
• In select cases where invasive arterial lines are unavailable and electrocardiography is utilised, an isoelectric ECG tracing is necessary to indicate cessation of circulation. ^[4]

In ambulatory clinics, dermatological surveillance identifies hyperandrogenic adverse effects versus endogenous disease:

• Acne prevalence in hyperandrogenic cohorts ranges from 14% to 25%.
• Community-based prevalence studies show that PCOS affects approximately 18% (17.8 ± 2.8%) of women under Rotterdam criteria. ^[6]
• A remarkable 70% of affected women remain undiagnosed in the community. ^[6]
• Identifying medication-related exacerbations requires screening for underlying polycystic changes, insulin resistance, and hyperandrogenaemia before modifying therapy.