Transdermal delivery of drugs anaesthetic implications
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Transdermal Delivery of Drugs — Anaesthetic Implications
Principles of Transdermal Drug Delivery
Transdermal delivery requires drugs to cross the stratum corneum, the principal barrier. For a drug to be suitable, it must possess:
- Low molecular weight (< 400 Da)
- High lipophilicity (octanol–water partition coefficient up to 10,000)
- High potency (typically < 10 mg/day dose)
- Low skin irritation potential
- High solubility in both water and oil
The main advantages include:
- Avoidance of hepatic first-pass metabolism
- Avoidance of GI degradation and side effects
- Maintained steady-state plasma concentrations (no peaks and troughs)
- Improved compliance and reduced dosing frequency
- Non-invasive, painless administration
— Dermatology 2-Volume Set 5e; Miller's Anesthesia 10e
Pathways of Absorption
- Transcellular / intercellular lipid pathway — the predominant route, through the tortuous extracellular lipid bilayers of the stratum corneum
- Appendageal route — via hair follicles and sweat ducts (enhanced by iontophoresis)
- Electroporation pathway — direct stratum corneum puncture, enabled by physical methods
Factors that increase absorption (clinically important for the anaesthetist):
- Fever / raised skin temperature (e.g. ~33% increase in fentanyl absorption at 40°C)
- Skin inflammation or disrupted barrier
- Prolonged occlusion → stratum corneum hydration
- Application site skin thickness
— Dermatology 2-Volume Set 5e; Miller's Anesthesia 10e
Key Drugs with Anaesthetic Relevance
1. Transdermal Fentanyl (TTS Fentanyl)
| Feature | Detail |
|---|---|
| Available strengths | 12.5, 25, 50, 75, 100 mcg/h (72-hour patches) |
| Onset | Detectable plasma levels in 1–2 h; full effect in 12–24 h |
| Mean peak plasma levels | Proportional: ~0.3 ng/mL (12.5 mcg/h) to 2.5 ng/mL (100 mcg/h) |
| Effect of fever (40°C) | ~33% increase in plasma concentration → risk of acute overdose |
Perioperative considerations:
- Patients on TTS fentanyl for chronic or cancer pain should generally keep the patch in place perioperatively; it forms their baseline opioid requirement
- The 12–24 hour onset/offset means intraoperative supplementation is still required for acute surgical pain
- Removing the patch does not immediately terminate drug delivery due to a dermal depot
- TTS fentanyl has been studied for acute postoperative pain (e.g. after laparoscopic cholecystectomy — a 25 mcg/h patch applied 14 h preoperatively matched IV fentanyl infusion for pain scores), but side effects (severe nausea preoperatively) limit its routine use in this setting
- Fatal overdose is a documented risk — in Australia, deaths rose from 0 to 2.23/million population between 2003–2015 with increasing utilisation
— Miller's Anesthesia 10e, p. 2846–2847
2. Transdermal Buprenorphine (TTS Buprenorphine)
| Feature | Detail |
|---|---|
| Available strengths (USA) | 5, 7.5, 10, 15, 20 mcg/h |
| Bioavailability | ~15% after 7-day application |
| Duration | 7-day patches |
Perioperative considerations:
- Buprenorphine's partial agonist / ceiling effect and high μ-receptor affinity create challenges: it may block the analgesic effect of additional full agonist opioids given intraoperatively/postoperatively
- Patients on TTS buprenorphine for opioid use disorder (OUD) or chronic pain represent a particular challenge — they have both opioid tolerance and receptor occupancy issues
- When the patch was applied prior to surgery and left in situ for the full 7 days, studies showed reduced postoperative pain, lower rescue analgesic consumption, and patient satisfaction in gynaecological and orthopaedic surgery
- Its lipophilicity and low molecular weight make it pharmacologically ideal for transdermal delivery
— Miller's Anesthesia 10e, p. 2847–2848
3. Transdermal Lidocaine / Local Anaesthetics
- Lidocaine patches (e.g. Lidoderm 5%) are used for localised neuropathic pain (e.g. post-herpetic neuralgia)
- Systemic absorption is low (~3% of the dose), making systemic toxicity uncommon at therapeutic use, but relevant in the context of other local anaesthetic administrations (e.g. regional blocks)
- Pre-operative topical EMLA (eutectic mixture of local anaesthetics — lidocaine + prilocaine) is widely used for needle insertion/vascular access; prilocaine can cause methaemoglobinaemia at high doses, particularly in neonates
— Dermatology 2-Volume Set 5e; Miller's Anesthesia 10e
4. Other Transdermal Drugs Relevant to Anaesthesia
| Drug | Indication | Anaesthetic Relevance |
|---|---|---|
| Scopolamine | Motion sickness / PONV prophylaxis | Anticholinergic effects; useful transdermal alternative for PONV prevention |
| Clonidine | Hypertension, chronic pain | α₂-agonist effects; can reduce MAC, produce sedation and haemodynamic effects |
| Glyceryl trinitrate (GTN) | Angina | Vasodilation; relevant to intraoperative haemodynamic management |
| Capsaicin (8% patch) | Neuropathic pain | Intense local burning on application; may require topical anaesthesia |
| Testosterone / estradiol | Hormone replacement | Avoid first-pass metabolism; stable serum levels |
Enhancement Strategies — Anaesthetic Context
Chemical enhancers (e.g. ethanol, propylene glycol, azone) work by disrupting stratum corneum lipid bilayers to increase permeability. They are incorporated into patch formulations.
Physical enhancers used or relevant clinically:
- Iontophoresis — electric current drives ionic drug across skin; used for fentanyl (iontophoretic transdermal system, ITS fentanyl) and local anaesthetics for procedural analgesia
- Ultrasound (phonophoresis) — enhances penetration of topical agents
- Microneedles — create micropores for delivery of larger molecules
- Occlusive dressings — hydrate stratum corneum; significantly increase absorption of topical steroids and other agents applied under them
— Dermatology 2-Volume Set 5e
Key Anaesthetic Implications — Summary
| Scenario | Implication |
|---|---|
| Patient with TTS fentanyl patch in-situ | Continue patch; supplement for surgical stimulus; monitor for additive opioid depression; never apply heating blanket directly over patch |
| Fever intraoperatively | ~33% rise in fentanyl absorption from patch → increased risk of opioid overdose/respiratory depression |
| Patient on TTS buprenorphine for OUD | Partial agonist blocks full-agonist opioids; high-dose full agonists may be needed; consider multimodal/regional analgesia |
| Post-op pain management | TTS fentanyl has slow onset (12–24 h); inadequate for acute pain alone — supplement with IV/neuraxial analgesia |
| PONV prevention | Transdermal scopolamine (applied behind ear night before) is an effective adjunct |
| Local anaesthetic toxicity | Cumulative load from patches + regional blocks must be accounted for |
| Removing a patch | Does NOT immediately stop drug absorption — a dermal reservoir persists |
| Skin site management | Rotate sites; avoid broken skin; avoid covering patch with heating devices |
References:
- Miller's Anesthesia, 2-Volume Set, 10e — "Transdermal Therapeutic System", pp. 2846–2848
- Dermatology 2-Volume Set 5e — Chapter 124, pp. 2641–2643
- Goodman & Gilman's The Pharmacological Basis of Therapeutics — "Transdermal Delivery Systems"
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