Concepts for the talk. Poisoning by Topical Medications The Toxicology of Transdermal Drug Delivery. Early patches. The transdermal patch

Transcription

1 Concepts for the talk Poisoning by Topical Medications The Toxicology of Transdermal Drug Delivery Lewis Nelson, M.D. New York University School of Medicine New York City Poison Control Center Understand the toxicokinetics of transdermal medications Describe the potential clinical problems with the use of transdermal patches The transdermal patch Early patches Simple route of administration Less obvious than most other routes Better compliance Pharmacokinetically favorable (?) First patch Scopolamine Motion sickness Second Nitroglycerin Fentanyl (1990) Global Patch Sales, 2007 Benefits of Patches Pharmacokinetics Steady plasma concentrations Particularly for drugs with short half lives Reduced side effects Less swings in concentration Improved compliance Daily or even weekly dosing Avoidance of first pass metabolism For poorly bioavailable compounds

2 Ethinyl estradiol from patch Ortho Evra Prescribing information Ethinyl estradiol pill vs patch Why are there not more patches? Few drugs have the right molecular requirements to be put into a transdermal patch. Potency Largest daily dose patch is 21 mg Molecular weight < 500 Da Lipophilicity Not too much, not too little Ortho Evra Prescribing information Epidermis Delivery Pathway Dermis Subcutis [P] [E] Nerve Capillary Lymphatics Stratum corneum (horny layer) Keratinized epidermal cells (lipophilic) Hygroscopic but impermeable to water Stratum corneum Transitional cell layer Granular layer Spinous layer Basal layer Basement membrane Based on: Concentration gradient Diffusivity Fick s s law

3 Delivery Pathway Concentration gradient Intercellular Largely lipid Intracellular Largely water Intercellular route Transcellular route Ability of drug to partition into stratum corneum Ability of drug to partition out of stratum corneum into underlying tissue The octanol-water partition coefficient. Fentanyl: 717 Morphine: 0.7 Nicotine: 15 Permeation enhancers increase permeability of stratum corneum Physicochemical properties Very lipophilic compounds cross stratum corneum readily Cannot readily enter aqueous phases Reservoir effect Human properties accounting for PK variability Skin hydration Dermal metabolism of chemical Altered blood flow Temperature Site of application Thickness of stratum corneum Human properties Site of application Human properties Variable pharmacokinetics Sobue S et. al. J Clin Pharmacol Dec;45(12):

4 Human properties Variable pharmacokinetics Human properties Law of unintended consequences Ortho Evra Prescribing information Patch technology Reservoir patch Reservoir Matrix (drug in adhesive) Fentanyl patch Dose ( g/h) Size (cm 2 ) Fentanyl content (mg) Patch leak potential/recalls Matrix patch Fentanyl patch Mylan Technologies Dose ( g/h) Size (cm 2 ) Fentanyl content (mg)

5 Fentanyl Patches: Box Warning (unintended consequences) Use with persistent chronic pain, already receiving opioids Increased risk of hypoventilation, therefore, contraindicated in patients with: No opioid tolerance, acute pain, post-op op pain, mild pain, intermittent pain How do people get in trouble with patches??? Mucosal application Heat Multiple patches Injection Disposal Mucosal absorption No stratum corneum Oral mucosal absorption TABLE 2. Signs of Toxicity After Exposure to Transdermal Nicotine Patches in 36 Children Oral Exposures* (N 18) Dermal Exposures (N 18) No symptoms 13 (72%) No symptoms 9 (50%) Burning tongue 2 Nausea/ vomiting 7 Gag/ vomit 2 Dizzy/ lethargic 3 Fussiness 1 Skin irritation 2 Fatigue 1 Pallor 1 Diarrhea 1 Tachycardia 1 Fussiness 1 * One child in the oral exposures group had both vomiting and fussiness. Four children in the dermal exposures group had two or more symptoms. Coon TP, et al. Ann Emerg Med 2005;46:473. Woolf A, et al. Pediatrics 1997;99;E4 Controlled Heat Prosser J, et al. J Med Toxicol 2010;6(4): Ashburn MA, et al. J Pain 2003;4:

6 Uncontrolled heat Fentanyl patch abuse potential Anesth Analg 2001;93:647 8 Prosser J, et al. J Med Toxicol 2010;6(4): Abuse What is left in a patch? Fentanyl patch tea bag Barrueto F. Vet Human Toxicol 2004;46: Smoking fentanyl patch Marquardt KA, Tharratt RS. J Toxicol Clin Toxicol 1994;32:75-8. Taking patches from dead people Flannagan LM, et al. J Forensic Sci 1996;41:320 Yerasi AB, et al. Am J Health-Syst Pharm 1997; 54:85-6 Nine patches from hospice patients 3 days of continuous use mg remaining in the 2.5-mg patches mg remaining in the 10.0-mg patches % 84.4% of the original contents. Marquardt MA. Ann Pharmacother 1995;29: Management of Patch Poisoning Offset kinetics Fentanyl patch After removal there is continued systemic absorption from residual fentanyl in the skin Serum concentrations fall 50%, on average, in 17 hours

7 New and Upcoming Technology New and Upcoming Technology Iontophoresis: : a few milliamperes of current Pilocarpine in cystic fibrosis test Lidocaine anesthesia Electroporation: short, high-voltage electrical pulses Believed to form transient aqueous pores in the stratum corneum Water soluble drugs and peptides? Ultrasound or sonophoresis EMLA cream Microneedles: : Transdermal patches with microscopic projections µm m in length make microscopic punctures that painlessly deliver drug Cutaneous vaccines for tetanus and influenza. Summary Patches have many pharmacotherapeutic benefits. There are also many risks Unpredictable pharmacology Difficult to titrate Unfamiliar dosage format The future of these, like long acting medications, is bright..and concerning. Questions?