Clarifying The Unique Differences In Oral Antifungals
A lot has been said about the two older antifungals, griseofulvin and ketoconazole. There have been safety concerns about long-term use of these drugs and this concern has spilled over to the newer drugs. It has always been felt that when you use the older antifungals, you compromise safety, patient compliance and cost-effectiveness as well.
The reason for this is when you treated toe onychomycosis with these drugs, you had to treat for 12 months or more. In order to get to the nail with the older antifungals, it only could get there by incorporation via the nail matrix. Therefore, it took 12 to 18 months to reach the distal nail unit before medications like griseofulvin and ketoconazole could be effective.
There was also a risk of liver toxicity with these drugs because you were treating the patients for a longer period of time. Therefore, liver function tests (LFTs) were required. Additionally, there were potentially serious drug interactions with both ketoconazole and griseofulvin, and the hepatotoxicity with ketoconazole was a major concern.2-4
Finally and very importantly, the cure rates were extremely low with the older antifungals. When there was a cure, the recurrences would occur very quickly.
A Closer Look At The Mechanism Of The Newer Antifungals
Unlike the older antifungals, the newer antifungals get to the nail unit both by incorporation from the nail matrix and the nail bed. These medications are in the nail unit within one, two or three weeks. Therefore, shorter-term therapy is a significant part of their success.
While the two newer classes of oral antifungals address most of these safety and efficacy concerns, there are distinct differences between them in terms of mechanism of action, hepatic metabolism, drug-drug interactions and safety profiles.
Terbinafine is in the allylamine class of oral antifungal drugs. It is important to keep in mind that the allylamine is different from the azoles and the hydroxypyridones. Itraconazole, ketoconazole and fluconazole are all azoles.
Which classes of oral antifungals are fungicidal against dermatophytes?
Azoles are fungistatic. In the case of terbinafine, the minimal inhibitory concentration (MIC) is equivalent to the minimal fungicidal concentration (MFC). That is not the case with the triazoles.
In regard to the pathway of the antifungals, the basic underlying premise is that ergosterol is necessary for the synthesis of the fungal cell membrane (see above chart on the left). The allylamines work by inactivating squalene epoxidase. This results in an accumulation of squalene, which is highly toxic for the fungal cell membrane. This occurs very early in the cycle and at least partially explains why the allylamines are fungicidal. The azoles work against lanosterol alpha-methylase. The azoles facilitate more of an accumulation of lanosterol, which is not nearly as toxic as squalene is against the fungal cell membrane. Indeed, terbinafine is the most effective anti-dermatophyte that we have.2,3,5,6
A Key Point About Hepatic Metabolism
Which classes of oral antifungals are metabolized through the cytochrome P450 system in the liver? Both the azoles and the allylamines have to go through the liver system. The azoles must use the 3A4 system. They do not have the option of being able to go through the other isoenzymes and over 50 percent of the most common drugs used by patients today compete with the 3A4 system. This sets up a potential situation for significant drug to drug interactions.
On the other hand, the allylamines have an option. They can bypass the 3A4 system and use other isoenzymes (see below diagram on the right). Thus, if there is another drug utilizing this system, this competitive inhibition does not take place and there is less likelihood of drug-to-drug interactions.7,8
In other words, it is the active inhibition of the 3A4 site with itraconazole that causes the potential drug interactions. Itraconazole and the azole class are active inhibitors of the 3A4 site whereas terbinafine, an allylamine, is not an active inhibitor of the 3A4 site.
Raising Awareness About Potential Drug Interactions
Keep in mind that all drugs have drug interactions. The key questions are:
• How many drug interactions does the medication have?
• How serious are the potential interactions?
• What is the clinical significance of these interactions?
• What is the probability of these interactions occurring?
Be aware that the potential for drug-drug interactions is not the same for all oral antifungals.
Fifty percent or more of prescription drugs are metabolized by the 3A4 system. They include most statins, many calcium-channel blockers, some sedative/hypnotic agents and oral hypoglycemic agents. These have the capacity for significant and potentially serious drug-drug interactions with triazoles metabolized by the 3A4 system through the liver.8-10
Terbinafine only inhibits cytochrome P450’s 2D6 isoenzyme, but there are drug interactions with terbinafine as well. They include the tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI), beta blockers and type B monoamine oxidase inhibitors. Clinically, these drug interactions have not proven to be a major problem. Nevertheless, one should be aware of these possibilities.3,7,11
Fluconazole is an azole with fungistatic activity but it is not approved by the FDA for the treatment of onychomycosis. It does have this indication in several other countries and can be used under certain circumstances.12
The potency of fluconazole as a cytochrome P3A4 inhibitor is much lower than itraconazole so there is less of a concern, but it is a potent inhibitor of cytochrome P2C9. Therefore, co-administration of fluconazole with phenytoin, warfarin, sulfamethoxazole or losartan may result in clinically significant drug interactions.12,13
In one prospective study done by Hall and co-workers, they looked at terbinafine use in approximately 26,000 patients worldwide. Only 10.5 percent experienced adverse events and of those, 44 percent were either possibly or probably not related to the drug. The number of significant reactions is minimal and the majority are mild, transient, reversible and mostly involve the GI tract and skin.3
Itraconazole has a good safety profile. There is a favorable adverse effect profile in the clinical trials. These were mild to moderate and reversible and included headache, rhinitis, GI symptoms and allergic or skin reactions.10
However, there is a FDA black box warning for itraconazole. It should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure or a history of congestive heart failure. It is important to obtain a careful medical history on all patients to be treated with oral antifungals. In terms of drug interactions, co-administration of the following with itraconazole is contraindicated: Cisapride, pimozide, quinidine, dofetilide and levomethadyl.10
Addressing Pre-Treatment Screening
According to the package insert for terbinafine, pretreatment serum transaminase tests (ALT and AST) are advised for all patients to determine whether preexisting liver disease is present. The FDA has said is it not necessary to do monitoring beyond the screening. If one is more comfortable doing additional monitoring, I think there is nothing wrong with that. One may also want to get an exit LFT to demonstrate normal liver function after treatment has ended.10,11,14
Rare cases of liver toxicity occur with the current oral antifungals. To put this in perspective, liver toxicity with modern antimycotic medications are comparable to some common drugs. For example, there are twice as many reports of cases of liver toxicity from the OTC ibuprofen.15 Over 30 million patients have been treated successfully with the new antifungals worldwide without adverse effects.
Why You Should Confirm The Diagnosis Of Onychomycosis
Before prescribing antifungals, confirm the diagnosis of onychomycosis. If a problem arises and you have not proven the diagnosis, you may have difficulty in justifying therapy.
Proving a diagnosis is very simple. You can do a KOH wet mount, a fungal culture or a PAS stain of the nail plate. This is becoming the standard of care in many areas. These tests are quick and simple, and the results are accurate with PAS well over 90 percent in terms of accuracy whereas culture and KOH are probably closer to around 60 percent, even in experienced hands.
Finally, you may get a patient who has an abnormal nail and you are unsure whether it is a fungus or something else. In these situations, you can do a nail biopsy. This is important in some situations, particularly when you are looking at the feet. I have now seen several patients who had onychomycosis and an underlying squamous cell carcinoma. That is not unusual because onychomycosis is so common in the feet.
In Conclusion
Lingering concerns with older oral antifungals have limited the current prescribing of antifungals. However, the two new classes of drugs have proven to be safer and much more effective in eradicating fungal nail infections. Differences between these classes impact the efficacy and safety profiles. Clearly, terbinafine does have a lower potential for drug-to-drug interactions than the triazoles.
