Summary

Tizanidine and ketoconazole have a significant drug interaction that can lead to dangerous increases in tizanidine blood levels. This interaction occurs because ketoconazole inhibits the enzyme responsible for tizanidine metabolism, potentially causing severe hypotension and sedation.

Introduction

Tizanidine is a centrally-acting alpha-2 adrenergic agonist muscle relaxant primarily used to treat muscle spasticity associated with conditions like multiple sclerosis and spinal cord injuries. Ketoconazole is a potent antifungal medication belonging to the azole class, commonly prescribed for systemic fungal infections. Both medications are metabolized through specific liver enzyme pathways, which creates the potential for clinically significant drug interactions when used together.

Mechanism of Interaction

The interaction between tizanidine and ketoconazole occurs through cytochrome P450 enzyme inhibition. Tizanidine is primarily metabolized by the CYP1A2 enzyme system in the liver. Ketoconazole is a potent inhibitor of multiple cytochrome P450 enzymes, including CYP1A2. When ketoconazole inhibits CYP1A2, it significantly reduces the metabolism and clearance of tizanidine from the body. This results in dramatically increased tizanidine plasma concentrations, potentially reaching levels 7-10 times higher than normal, leading to enhanced pharmacological effects and increased risk of adverse reactions.

Risks and Symptoms

The primary risks of this drug interaction include severe hypotension (dangerously low blood pressure), excessive sedation, dizziness, and potential cardiovascular collapse. Patients may experience profound drowsiness, confusion, and impaired motor coordination. The hypotensive effects can be particularly dangerous in elderly patients or those with existing cardiovascular conditions. Additional risks include increased fall risk due to sedation and orthostatic hypotension, potential respiratory depression in severe cases, and prolonged recovery time from tizanidine's effects. This interaction is considered contraindicated due to the severity and unpredictability of the enhanced effects.

Management and Precautions

The concurrent use of tizanidine and ketoconazole is generally contraindicated and should be avoided. If antifungal treatment is necessary in patients taking tizanidine, alternative antifungal agents with less CYP1A2 inhibition potential should be considered, such as fluconazole (though caution is still warranted) or topical antifungals when appropriate. If the combination cannot be avoided in exceptional circumstances, tizanidine should be discontinued or the dose significantly reduced under close medical supervision. Patients should be monitored for signs of hypotension, excessive sedation, and other adverse effects. Blood pressure monitoring, assessment of mental status, and evaluation of motor function are essential. Healthcare providers should review all medications for potential interactions before prescribing either drug.

Tizanidine interactions with food and lifestyle

Tizanidine should not be taken with alcohol as it can significantly increase sedation and drowsiness, potentially leading to dangerous levels of central nervous system depression. Food can affect tizanidine absorption - taking tizanidine with food increases absorption and peak concentrations, while taking it on an empty stomach results in lower but more consistent absorption. Patients should be consistent in how they take tizanidine (always with food or always without food) to maintain stable drug levels. Smoking may reduce tizanidine effectiveness due to enzyme induction.

Ketoconazole interactions with food and lifestyle

Ketoconazole requires an acidic environment for optimal absorption. Take ketoconazole with food or an acidic beverage to enhance absorption. Avoid taking ketoconazole with antacids, H2 blockers, or proton pump inhibitors as these medications reduce stomach acid and significantly decrease ketoconazole absorption. If antacids must be used, take them at least 2 hours after ketoconazole. Alcohol should be avoided during ketoconazole treatment as both ketoconazole and alcohol can cause liver toxicity, and concurrent use may increase the risk of hepatotoxicity. Grapefruit juice may increase ketoconazole blood levels and should be avoided to prevent increased risk of side effects.