Biochemistry of (tap water) iontophoresis?

Question

I'm curious to know what science has to say about the biochemical processes of tap water iontophoresis. I was trying to find some insights from the mechanism of action to answer things like:

• Why does it block sweat glands?
• How does it affect other types of glands/cells in the (epi-) dermis, i.e., what are the side effects?
• What are the processes that trigger reddening of the skin and tingling/pain in the first place? For instance, is this the result of direct stimulation of e.g. TRPV1 or rather the result of destroyed cells triggering an immune response.

Searching for a good resource of the science behind iontophoresis on Google/PubMed seems to be difficult because information is commonly targeted for iontophoresis end-users and publications often focus on the drug administration aspect.

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Side-note: personal iontophoresis fun fact

I was using iontophoresis on my hands with room-temperature water on one hand, and fridge-temperature water on the other hand. After 4 weeks of daily application, I noticed a significant difference between the two hands: In my case, cold-water iontophoresis seems to be much more efficient in blocking sweat glands. I couldn't find this effect in literature, but I'm wondering if it could be explained from the underlying biochemical processes.

Answer 1

Tap‐water iontophoresis (TWI) using direct current (DC) is considered by some to be the most effective therapy in palmoplantar hyperhidrosis, although it is debated that botulinum toxin injections may be better (Wade, et al. 2018).

How does TWI block sweat glands, and what are the side effects?

The mechanism of action is unknown. It is hypothesised that an interrupted stimulus‐secretion‐coupling leads to a functional disturbance of sweat secretion (Reinauer, et al. 1993), which is most likely a transient functional disturbance of the secretory mechanism of eccrine glands (Hölzle, 2018).

Side‐effects of this method are discomfort, with burning and tingling, and skin irritation, including erythema and vesicles. Incorrect use may induce iontophoretic burns at sites of minor skin injury. Elaborate safety measures are required to prevent electric shock (Reinauer, et al. 1993).

References

Hölzle E. (2018) Iontophoresis. In: John S., Johansen J., Rustemeyer T., Elsner P., Maibach H. (eds) Kanerva’s Occupational Dermatology, 1-14. doi: 10.1007/978-3-319-40221-5_95-2

Reinauer, S., Neusser, A., Schauf, G., & Hölzle, E. (1993). Iontophoresis with alternating current and direct current offset (AC/DC iontophoresis): a new approach for the treatment of hyperhidrosis. British Journal of Dermatology, 129(2), 166-169. doi: 10.1111/j.1365-2133.1993.tb03521.x

Wade, R., Llewellyn, A., Jones‐Diette, J., Wright, K., Rice, S., Layton, A. M., ... & Woolacott, N. (2018). Management of hyperhidrosis in secondary care. British Journal of Dermatology, 179(3), e138-e138. doi: 10.1111/bjd.17044

Answer 2

After some more research it looks like the answers to these questions are indeed still unknown. A recent 2018 article on Proposed mechanism of action of tap water iontophoresis for treatment of hyperhidrosis summarizes:

Tap water iontophoresis is commonly used to treat hyperhidrosis, yet the mechanism of action for this treatment remains unknown.

[...]

Several hypothesized mechanisms of action have been proposed for this treatment, including the reversible disruption of ion channels (Collin & Whatling, 2000), dermal injury resulting in abnormal keratinization and plugging of the sweat duct (Gordon & Maibach, 1969; Shelley & Horvath, 1950), blockage of neuroglandular transmission (Holze & Ruzicka, 1986), or inhibition of the secretory mechanism at the cellular level. However, studies to date have failed to reveal changes in the eccrine sweat glands or blockages of sweat ducts following iontophoresis (Hill, Baker, & Jansen, 1981; Holze & Ruzicka, 1986), and thus fail to support these hypothesized mechanisms.

The proposed mechanism of action in this article is:

I propose that iontophoresis works via the production of a colloid formed between the products of dark (mucin) and clear (aqueous solution) cells, and the jamming of nanomineral particles inside the lumen and/or the duct of the sweat gland, creating a blockage that temporarily prevents further sweat production or secretion.

Older references on the mechanism of action:

• Reinauer S, Schauf G, Hubert M, Hölzle E (1992): Mechanism of action of tap water iontophoresis: Functional disturbance of the secretory epithelium
• Hill AC, Baker GF, Jansen GT (1981): Mechanism of action of iontophoresis in the treatment of palmar hyperhidrosis.

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In terms of side effects e.g. effects on skin barrier function, there is some related work on saline iontophoresis:

• Singh J, Gross M, Sage B, Davis HT, Maibach HI (2000): Effect of saline iontophoresis on skin barrier function and cutaneous irritation in four ethnic groups.