What is the order of likelihood of these medications causing fatigue: vitamin D, promethazine, primidone, phenazopyridine, pantoprazole, zofran (ondansetron), nebivolol, losartan, Hydrochlorothiazide (HCTZ), furosemide, doxazosin, clonidine, clonazepam, aspirin, amlodipine?

Medications Ranked by Likelihood of Causing Fatigue

Based on the available evidence, these medications should be ranked from highest to lowest likelihood of causing fatigue as follows: clonazepam, primidone, promethazine, clonidine, nebivolol, doxazosin, furosemide, amlodipine, HCTZ, losartan, zofran, phenazopyridine, pantoprazole, aspirin, and vitamin D.

Highest Risk for Fatigue

Benzodiazepines (Clonazepam)

• Clonazepam causes CNS depression through augmentation of GABA, the primary inhibitory neurotransmitter, making it the highest risk medication on this list 1
• Benzodiazepines are specifically noted for causing sedation and drowsiness as dose-related effects 2
• Used for insomnia treatment precisely because of sedating properties, with warnings about residual daytime drowsiness 2

Anticonvulsants (Primidone)

• Primidone carries significant fatigue risk with sleepiness listed as a severe side effect, especially when first starting treatment 3
• Anticonvulsants acting on the GABAergic system have the highest incidence of fatigue among antiepileptic drugs 4
• The FDA label specifically warns about sleepiness that can be severe and problems with walking and moving 3

Antihistamines (Promethazine)

• First-generation antihistamines like promethazine cause significant CNS depression through anticholinergic effects and decreased excitatory activity 1
• These agents commonly cause sedation and drowsiness as primary side effects 1

Moderate-High Risk for Fatigue

Central Alpha-Agonists (Clonidine)

• Clonidine causes drowsiness in approximately 33% of patients and sedation in 10%, making it a significant contributor to fatigue 5
• Dry mouth occurs in 40% and dizziness in 16% of patients, with fatigue and weakness also reported 5
• In adolescent CFS studies, clonidine had a negative effect on physical activity despite reducing sympathetic outflow 6

Beta-Blockers (Nebivolol)

• Beta-blockers cause fatigue, confusion, and limit maximum heart rate and exercise capacity 2
• These effects result from decreased cardiac output and CNS depression 2
• Nebivolol is among the commonly prescribed beta-blockers with these side effects 2

Moderate Risk for Fatigue

Alpha-Blockers (Doxazosin)

• Doxazosin can cause orthostatic hypotension leading to dizziness and secondary fatigue 2
• Alpha-blockers may precipitate or exacerbate fatigue through blood pressure effects 2

Loop Diuretics (Furosemide)

• Furosemide can cause electrolyte imbalances and volume depletion leading to weakness and fatigue 2
• Commonly prescribed for heart failure where fatigue is already prevalent 2

Calcium Channel Blockers (Amlodipine)

• Amlodipine causes fatigue in 4.5% of patients compared to 2.8% with placebo 7
• Additional side effects include dizziness (3.4%), somnolence (1.4%), and peripheral edema which can contribute to exercise intolerance 7
• Hypotension from peripheral arterial dilation may contribute to fatigue symptoms 2

Low-Moderate Risk for Fatigue

Thiazide Diuretics (HCTZ)

• HCTZ can cause electrolyte disturbances and volume depletion contributing to fatigue, though less pronounced than loop diuretics 2
• Among the most commonly prescribed antihypertensives with generally good tolerability 2

ARBs (Losartan)

• Losartan has minimal direct CNS effects and relatively low fatigue incidence compared to other antihypertensives 2
• Well-tolerated with fewer side effects than beta-blockers or calcium channel blockers 2

Minimal Risk for Fatigue

Antiemetics (Zofran/Ondansetron)

• Zofran primarily causes headache and constipation rather than fatigue or sedation 2
• Does not have significant CNS depressant effects 2

Urinary Analgesics (Phenazopyridine)

• Phenazopyridine has minimal systemic effects and no significant CNS penetration causing fatigue
• Primary side effects are related to urine discoloration rather than systemic symptoms

Proton Pump Inhibitors (Pantoprazole)

• Pantoprazole has minimal CNS effects and fatigue is not a commonly reported side effect
• Well-tolerated with primarily gastrointestinal side effects

Antiplatelet Agents (Aspirin)

• Aspirin does not cause direct CNS depression or fatigue 2
• Side effects are primarily gastrointestinal rather than neurological 2

Vitamin Supplementation (Vitamin D)

• Vitamin D supplementation does not cause fatigue; deficiency may actually contribute to fatigue
• No evidence of fatigue as a side effect of appropriate supplementation

Important Clinical Considerations

Polypharmacy significantly increases fatigue risk - patients taking multiple medications from this list will experience additive or synergistic effects on fatigue 8

Dose-dependent effects - many of these medications show dose-related fatigue, particularly clonidine, benzodiazepines, and anticonvulsants 5, 2, 4

Individual variation - age, renal function, hepatic function, and concurrent medications significantly modify fatigue risk 2, 7

Timing matters - medications causing CNS depression should be dosed at bedtime when possible to minimize daytime fatigue 2