Clinical Pharmacology and Therapeutics

350 FUNGAL AND NON-HIV VIRAL INFECTIONS
Case history
A 35-year-old female with schizophrenia and insulin-dependent diabetes mellitus developed a severe oral Candida infection. She was
being treated with pimozide for her psychosis and combined glargine insulin with short-acting insulins at meal times. She was started
on itraconazole, 100 mg daily, and after a few days her oropharyngeal symptoms were improving. About five days into the treatment,
she was brought into a local hospital Accident and Emergency Department with torsades de pointes (polymorphic ventricular tachycardia)
that was difficult to treat initially, but which eventually responded to administration of intravenous magnesium and direct current
(DC) cardioversion. There was no evidence of an acute myocardial ischaemia/infarction on post-reversion or subsequent ECGs. The
patient’s cardiac enzymes were not diagnostic of a myocardial infarction. Her electrolyte and magnesium concentrations measured
immediately on admission were normal.
Question
What is the likely cause of this patient’s life-threatening dysrhythmia and how could this have been avoided?
Answer
In this case, the recent prescription of itraconazole and the serious cardiac event while the patient was on this drug are temporally
linked. It is widely known that all azoles can inhibit CYP3A which happens to be the enzyme responsible for metabolizing
pimozide. Pimozide has recently been found (like cisapride and terfenadine – now both removed from prescription) to cause prolongation
of the QT interval in humans in a concentration-dependent manner. Thus, there is an increased likelihood of a patient
developing ventricular tachycardia (VT) if the concentrations of pimozide are increased, as occurs when its metabolism is inhibited
by a drug (e.g. itraconazole) that inhibits hepatic CYP3A. This is exactly what happened here. Other common drugs whose concentrations
increase (with an attendant increase in their toxicity) if prescribed concurrently with azoles (which should be avoided) are
listed in Table 45.4.
Table 45.4: Important interactions with azole antifungals
Drug or drug class
Ciclosporin (and Tacrolimus-FK 506)
Warfarin
Benzodiazepines – alprazolam, triazolam
diazepam, etc.
HMG CoA reductase inhibitors (statins,
except pravastatin)
Calcium channel blockers
Sildenafil citrate (Viagra)
Toxicity caused by azole-mediated reduced
hepatic metabolism
Nephroxicity and seizures
Haemorrhage
Increased somnolence
Myositis and rhabdomyolysis
Hypotension
Protracted hypotension
In this patient, the problem could have been avoided by either changing to an alternative anti-psychotic with least QTc prolonging
properties (e.g. clozapine, quetiapine) prior to starting the azole or, if pimozide was such a necessary component of therapy,
using a topical polyene, such as amphotericin or nystatin lozenges, to cure her oral Candida. Neither of these polyene antifungal
agents inhibit CYP3A-mediated hepatic drug metabolism.
Key points
Anti-influenza and antiviral hepatitis agents
• Influenza virus is susceptible to neuraminidase
inhibitors, oseltamivir/zanamivir.
• Neuraminidase inhibitors produce viral aggregation at
cell surface and reduce respiratory spread of virus.
• Oseltamivir adverse effects mainly involve gastrointestinal
upsets.
• Interferon-alfa plus ribavirin is effective against chronic
hepatitis B and C.
• Resistant hepatitis B or C: use lamivudine or adefovir
dipiroxil.
FURTHER READING
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Boucher HW, Groll AH, Chiou CC, Walsh TJ. Newer systemic antifungal
agents: pharmacokinetics, safety and efficacy. Drugs 2004; 64:
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Como JA, Dismukes WE. Oral azole drugs as systemic antifungal
therapy. New England Journal of Medicine 1994; 330: 263–72.
De Clercq E. Antiviral drugs in current clinical use. Journal of Clinical
Virology 2004; 30: 115–33.
Francois IE, Aerts AM, Cammue BP, Thevissen K. Currently used
antimycotics: spectrum, mode of action and resistance occurrence.
Current Drug Targets 2005; 6: 895–907.
McCullers JA. Antiviral therapy of influenza. Expert Opinion on
Investigational Drugs 2005; 14: 305–12.