Ketoconazole and atorvastatin
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Ketoconazole + Atorvastatin: Drug Interaction
Mechanism
Atorvastatin is primarily metabolized by CYP3A4. Ketoconazole is a potent inhibitor of CYP3A4 (and to a lesser extent CYP2C9 and other CYPs). When co-administered, ketoconazole inhibits the hepatic metabolism of atorvastatin, causing its plasma levels to rise significantly.
- Katzung's Basic and Clinical Pharmacology (16th ed.) states: "The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that inhibit or compete for the 3A4 cytochrome. These include... ketoconazole and its congeners..."
Clinical Consequence
Elevated plasma atorvastatin concentrations increase the risk of statin toxicity, principally:
- Myopathy / Rhabdomyolysis - The most serious risk. Elevated statin levels cause skeletal muscle damage, which can progress to rhabdomyolysis with myoglobinuria and renal injury. Minor CK elevations are common; severe elevations signal impending rhabdomyolysis.
- Hepatotoxicity - Raised statin levels increase the risk of transaminase elevation and hepatic injury. Both ketoconazole (itself hepatotoxic) and atorvastatin carry hepatotoxic potential.
The drug interaction table in Katzung explicitly lists: "HMG-CoA reductase inhibitors: [P] Decreased metabolism of lovastatin, simvastatin, and, to a lesser extent, atorvastatin" - note that atorvastatin is somewhat less susceptible than lovastatin/simvastatin because it has alternate metabolic pathways, but the interaction is still clinically significant.
Which Statins Are Most vs. Least Affected?
| Statin | CYP pathway | Risk with ketoconazole |
|---|---|---|
| Lovastatin, Simvastatin | CYP3A4 (primary) | Highest - contraindicated |
| Atorvastatin | CYP3A4 (primary) | High - avoid or reduce dose |
| Fluvastatin, Rosuvastatin | CYP2C9 (primary) | Also inhibited by ketoconazole (CYP2C9 inhibitor) |
| Pravastatin | Non-CYP (sulfation) | Lowest risk - preferred alternative |
The Textbook of Family Medicine (9th ed.) explicitly states: "The coadministration of drugs or compounds that inhibit cytochrome P450 3A4 (azole-type antifungals [ketoconazole, itraconazole]...) with atorvastatin, simvastatin, and lovastatin is contraindicated."
Katzung further recommends: "Pravastatin and rosuvastatin appear to be the statins of choice for use with... the ketoconazole group of antifungal agents."
Additional Interaction: P-glycoprotein
Ketoconazole is also a P-glycoprotein inhibitor. Atorvastatin is a P-gp substrate, so ketoconazole can additionally reduce atorvastatin's efflux, further increasing its bioavailability and plasma exposure. (Goodman & Gilman's notes this mechanism in the context of drugs like ketoconazole and atorvastatin increasing aliskiren levels via the same P-gp inhibition pathway.)
Clinical Management
- Avoid concurrent use of ketoconazole with atorvastatin (or simvastatin/lovastatin) where possible - considered contraindicated by many guidelines.
- If an azole antifungal is necessary alongside statin therapy, switch to pravastatin (non-CYP metabolized) or use a topical/less systemically absorbed azole.
- If the combination cannot be avoided: use the lowest effective dose of atorvastatin, monitor for muscle pain, weakness, and liver enzymes closely, and check CK if symptoms arise.
- Instruct patients to report muscle pain, tenderness, or dark urine (myoglobinuria) immediately.
Sources:
- Katzung's Basic and Clinical Pharmacology, 16th ed. - Toxicity section (statins), p. 992; Azole drug interactions table
- Textbook of Family Medicine, 9th ed. - Statins section
- Goodman & Gilman's The Pharmacological Basis of Therapeutics - Drug-Drug Interactions
Single breath count
Single breath count (SBC) is a simple bedside test of respiratory function where the patient takes a deep breath and counts aloud as fast as possible until they run out of air. Normal is ≥25. Values below 25 suggest significant respiratory impairment, and below 10 indicates severe compromise.
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Single Breath Count (SBC)
What It Is
Single breath count (SBC) is a simple bedside test of respiratory/pulmonary function. The patient takes a maximal inhalation, then counts aloud (as fast and as far as possible) on that single breath until they can no longer speak.
How to Perform
- Ask the patient to take the deepest breath possible.
- Ask them to count aloud ("1, 2, 3...") as quickly as possible.
- Note the highest number reached before they run out of air.
No equipment needed - it can be done at the bedside in seconds.
Interpretation
| Count | Interpretation |
|---|---|
| ≥ 25 | Normal respiratory function |
| 20 - 24 | Borderline / mild impairment |
| < 20 | Suggests significant respiratory impairment (correlates with reduced vital capacity) |
| < 10 | Severe compromise |
The Harriet Lane Handbook (23rd ed.) states: "Ask the patient to count as high as possible in a single breath; the result correlates with vital capacity and <20 suggests impairment."
Physiological Basis
SBC correlates with Forced Vital Capacity (FVC) - the largest volume of gas a person can expire after maximal inspiration. A reduced SBC reflects reduced FVC, which occurs in:
- Restrictive lung disease
- Neuromuscular weakness (inspiratory and expiratory muscle weakness)
- Severe obstructive disease
As Barash's Clinical Anesthesia (9th ed.) notes: "Single breath count - how many numbers an individual can count after maximal inhalation - correlates with FVC and is a simple bedside maneuver to test pulmonary function."
Clinical Uses
-
Myasthenia Gravis - Widely used to monitor respiratory muscle strength at the bedside. A falling SBC signals worsening respiratory compromise and potential need for intubation. It correlates well with neck flexor muscle strength and spirometry in MG patients.
-
Neuromuscular disease generally - Any condition affecting respiratory muscles (Guillain-Barre syndrome, ALS, muscular dystrophy) can be monitored with serial SBC.
-
Pre-operative assessment - Provides a rapid screen of pulmonary reserve before anesthesia.
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ICU / Emergency - Rapid serial monitoring of patients with evolving respiratory failure (e.g., myasthenic crisis, ascending GBS) to guide timing of intubation.
Advantages
- No equipment required
- Takes less than 30 seconds
- Cooperative patients of any age can perform it
- Correlates well with formal spirometry (FVC)
- Useful for serial monitoring (trend is as important as a single value)
Limitations
- Effort-dependent (requires patient cooperation)
- Affected by speech/language ability
- Does not differentiate the type of pulmonary defect (obstructive vs. restrictive)
- Not a substitute for formal spirometry when precision is needed
Sources: Barash's Clinical Anesthesia, 9th ed.; The Harriet Lane Handbook, 23rd ed. (Johns Hopkins Hospital)
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