Nails and Sweat: Onychomycosis and Hyperhidrosis

The nail is a fortress, and that is the whole problem

Onychomycosis is a fungal infection living inside dead keratin — the hardest place in the body to deliver a drug. Onychomycosis — usually caused by dermatophytes such as Trichophyton rubrum — is infection of the nail plate. The plate is not living tissue you can perfuse with a bloodstream; it is a dense, compacted sheet of keratin, essentially armour. A cream or ointment sits on the surface and barely diffuses into it, so the fungus, buried under and within the plate, is untouched. This is a pure drug-delivery problem, and it echoes the keratin and skin-barrier principles from the Foundations chapter: the same stratum-corneum physics that keeps water in and irritants out also keeps antifungals from reaching the infection. Because the drug cannot easily go in from the top, definitive treatment usually has to come from within — carried through the blood into the nail bed and matrix as the nail is being made.

First, prove it is actually fungal. Before committing a patient to months of an oral drug, confirm the diagnosis — because not every ugly, thickened nail is fungal. Psoriasis, chronic trauma, lichen planus and eczema all produce dystrophic nails that look identical to the naked eye, and none of them will improve on an antifungal. So the rule is: sample the nail first. Direct microscopy of nail clippings with potassium hydroxide (KOH) dissolves the keratin and reveals fungal hyphae; culture or PCR identifies the organism. Treating a non-fungal dystrophy with terbinafine exposes the patient to drug risk for zero benefit — a classic avoidable error.

Oral therapy: terbinafine first, itraconazole second

First-line is oral terbinafine, an allylimine antifungal. Its mechanism is worth knowing because it differs from the azoles: terbinafine inhibits squalene epoxidase, an early enzyme in fungal ergosterol synthesis. Blocking it does two things — it starves the fungus of ergosterol (the fungal equivalent of cholesterol in the cell membrane) and it causes toxic squalene to accumulate inside the cell. That second effect makes terbinafine fungicidal — it kills the dermatophyte outright rather than merely holding it in check — which is why it clears nail infection more reliably than older options. It is taken daily for roughly six weeks for fingernails and twelve weeks for the slower-growing toenails, and it concentrates avidly in keratin, persisting in the nail long after the course ends. These antifungal mechanisms are developed in full in the Antifungals chapter of the Antimicrobials section.

Terbinafine is generally well tolerated, but two cautions define its monitoring. First, hepatotoxicity: terbinafine can rarely cause liver injury, so baseline liver function tests are checked and it is avoided in active liver disease. Second, a quirk students love in exams — it can cause a disturbance or loss of taste (dysgeusia), occasionally lasting weeks. It is also a moderate inhibitor of CYP2D6, worth remembering in patients on drugs metabolised by that enzyme. The alternative is oral itraconazole, a triazole that works by the more familiar azole mechanism — inhibiting lanosterol 14-alpha-demethylase (a CYP-dependent enzyme) to block ergosterol synthesis. Itraconazole is often given as pulse dosing: one week on, three weeks off, repeated over several cycles, which limits total drug exposure. Its defining hazard is drug interactions: itraconazole is a potent inhibitor of CYP3A4, so it raises levels of a long list of co-prescribed drugs (statins, certain benzodiazepines, some anticoagulants and many others), and it carries a negative inotropic warning in heart failure. Those CYP interactions are exactly the theme running through the Antimicrobials section.

Topicals exist, but know their narrow lane. Topical antifungal nail lacquers — amorolfine, ciclopirox and the newer efinaconazole — are reserved for mild, distal disease that spares the matrix (the growing root), or for patients who cannot take an oral drug. They are painted on for many months, and their cure rates trail well behind oral therapy precisely because of the penetration problem. Efinaconazole was engineered with lower keratin affinity and better spreading to penetrate the plate more effectively, which improved topical results, but oral terbinafine remains the benchmark for anything more than early, limited involvement. Whichever route is chosen, the timeline is dictated not by how fast the drug acts but by how fast the nail grows: the diseased plate must be replaced from the root outward, so a toenail can take nine to twelve months to look normal even when the fungus is dead within weeks.

Hyperhidrosis and the sweat gland's secret

Excessive sweating is not a gland problem — it is a wiring problem. Primary hyperhidrosis is sweating far beyond what thermoregulation requires — typically focal, at the palms, soles and axillae — driven by an over-active sympathetic signal to otherwise normal eccrine sweat glands. To treat it rationally you have to know one fact that surprises almost everyone the first time: eccrine sweat glands are innervated by the sympathetic nervous system, but their postganglionic fibres release acetylcholine, not noradrenaline. Everywhere else in the sympathetic outflow the postganglionic transmitter is noradrenaline acting on adrenergic receptors; the sweat gland is the textbook exception, using acetylcholine acting on muscarinic (M3) receptors. This is drawn out in detail in the Autonomic Nervous System chapter, and it is the single most useful thing to hold in mind, because it explains why every effective pharmacological therapy either plugs the duct or blocks that cholinergic signal.

The stepwise ladder: from a salt to a scalpel

Start mechanical and topical; escalate only as needed. First-line is topical aluminium chloride (aluminium chloride hexahydrate). It is not a nerve drug at all — it works mechanically, forming plugs of aluminium-protein complex that physically obstruct the sweat duct opening at the skin surface. It is cheap and effective for mild axillary disease; its main drawback is skin irritation, worst when applied to damp skin. The next topical step is glycopyrronium (glycopyrrolate), an anticholinergic applied to the skin — as a cloth wipe for the underarms or a cream for the face — that blocks the muscarinic receptors on the sweat gland locally, sweating stopped at the receptor rather than the duct. Delivering the antimuscarinic topically is the whole point: you get the local effect while sparing the patient most of the systemic dryness that oral anticholinergics cause.

For palms and soles, and for stubborn cases, the physical and injected options take over. Iontophoresis passes a weak electrical current through water in which the hands or feet are immersed; over repeated sessions it reduces palmar and plantar sweating, probably by temporarily disrupting the duct, and it is a mainstay for those sites. When topicals and iontophoresis fail, botulinum toxin type A injections are transformative. Botulinum toxin cleaves the SNARE proteins that vesicles need to fuse and release their contents, so the cholinergic nerve terminal can no longer release acetylcholine onto the gland — the signal is silenced at the neuroglandular junction. A grid of tiny intradermal injections across an axilla or palm stops sweating for months until the nerve terminals regenerate, at which point the injections are repeated. It is the same mechanism you meet with botulinum toxin elsewhere in the Autonomic Nervous System chapter — block acetylcholine release — applied here to a gland instead of a muscle.

Oral drugs and surgery sit at the far end for widespread or refractory disease. When sweating is generalised rather than confined to one or two sites, an oral anticholinergic such as oxybutynin can be used — the same muscarinic blockade, now delivered systemically. The catch is that muscarinic receptors are everywhere, so a systemic antimuscarinic brings the whole predictable anticholinergic syndrome: dry mouth, blurred vision, constipation, urinary retention and, in older patients, confusion. Those class-wide side effects — the mnemonic of "dry as a bone, blind as a bat, mad as a hatter" — are taught in the Autonomic Nervous System chapter and apply verbatim here; they are why oral therapy is a compromise reserved for diffuse disease. The last resort is surgical: endoscopic thoracic sympathectomy, in which the sympathetic chain feeding the hands is cut. It reliably dries the palms but is genuinely last-line, because it commonly causes compensatory sweating — the body reroutes and sweats heavily elsewhere — which can be worse than the original complaint.