Photosensitising medications some guff Photosensitising medications Arlene McGuire Specialist Clinical Pharmacist Dermatology and Allergy Guys and St Thomas’ NHS Foundation Trust.

Learning Objectives What is drug induced photosensitivity? Phototoxic Vs photoallergic reactions Common Photosensitising drugs Practice points – drug pharmacology/ elimination time/ half life Brief Overview Psoralens

Photosensitivity An increase in skin reactivity to light. This can be to ordinary light or a particular band of light (UVA, UVB or visible spectrum) Can be due to a number of factors: Disease states (e.g. Lupus) Drugs skin type

Drug Induced Photosensitivity Cutaneous reactions due to combined effect chemical & Light Chemicals absorb light similar to their natural wavelength Photosensitising drugs are usually activated with wavelengths of UVA or visible light (UVB less of a problem) Vibration energy transmitted to neighbouring molecules as heat energy. Results in prickling, burning, erythema, sunburn

Drug Induced Photosensitivity Excessive photoactivation of the chemical in the skin can result in Phototoxic or Photoallergic reactions Phototoxic reactions (Direct damage to tissue - Energy Transmitted causes) e.g. Oxygen atoms activated causing cell damage OR chemical binds to DNA & Proteins Photoallergic (Immune mediated response) Ultraviolet exposure changes the structure of the drug Seen by the body's immune system as an invader (antigen). Immune system initiates an allergic response - cause inflammation of the skin in the light-exposed areas

Phototoxic Vs Photoallergic reactions Phototoxicity Photoallergy Incidence High Low Agent Exposure Dose related single exposure Small amount More than one Onset Minutes to hrs 24hrs to 72hrs Distribution Sun exposed skin only All areas Clinical characteristics Sunburn, erythema, Swelling, blistering Eczematous, pruritic lesions Immunological mediated No Type IV immune reaction

Phototoxic Vs Photoallergic reactions Photoallergy - oral sulfonamide Phototoxicity - Phenothiazine

Phototoxic Vs Photoallergic reactions Photoallergic reactions occur less commonly than phototoxic reactions Mostly caused by photosensitising topical agents e.g. para-aminobenzoic acid (PABA) found in some sunscreens, topical salicylate, chlorhexidine. Although some oral photosensitising medications can cause photoallergic reactions, most cause phototoxic reactions. A handful of medications can cause both phototoxic and photoallergic reactions.

Drugs Causing Phototoxicity Drug Class Examples Antibiotics Tetracyclines, Quinolones, Sulphonamides NSAIDS Ibuprofen, Naproxen, Celecoxib, Ketoprofen Retinoids Isotretinoin, Acitretin Statins Atorvastatin, Simvastatin (All) Neuroleptics/ Antihistamines Chlorpromazine, promethazine, thioridazine, thioxanthines Antifungals Terbinafine, Itraconazole, Voriconazole, Griseofluvin Others 5-Fluorouracil, Paclitaxel, Amiodarone, Diltiazem, Enalapril, Quinidine, PABA, Hydroxychloroquine, coal tar, dapsone, oral contraceptives

Drugs Causing Photoallergy Drug Class Examples Hypoglycaemics Sulphonylureas (Gliclazide) NSAIDS Celecoxib, Ketoprofen Retinoids Isotretinoin, Acitretin Statins Atorvastatin, Simvastatin (All) Neuroleptics Chlorpromazine, fluphenazine Antifungals Itraconazole, Griseofluvin Fragrances & Sunscreens Musk ambrette, 6-Methylcoumarin, Para-aminobenzoic acid, Benzophenones

Practice Points Not much published advice! Some research has shown little increased risk of adverse effects when additional photosensitising medications taken during PUVA However in practice has been observed. More risk of adverse events with PUVA than UVB Accurate medication history – include PRN meds Can drug be stopped avoided?

Practice Points YES: Generally most of drug eliminated 5 x ½ life of the drug and add 2-3 days (NOTE renal/hepatic function may alter this) Contact medicines information service Contact specialist pharmacist Consider Patch test area If on more than one choose one with longest half life Cant work out half life for topical treatments- can they be avoided on that day? NO: May have to avoid PUVA or use test areas.

Patch Testing MED – Minimum erythema dose for UVB MPD – Minimum phototoxic dose for PUVA Phototoxic test - the MED with the drug is compared with MED without drug. Photopatch testing for photoallergy a smaller dose than the MED is used because the drug may have phototoxic properties

What is Half Life of a drug? Pharmacokinetics: ADME principles Help us estimate how a drug processed and eliminated by the body. Elimination ½ Life = the time required for the concentration of the drug to reach half of its original value. Caution can be complex to interpret - Other factors to consider e.g. accumulation in tissues & active metabolites.

What is Half Life of a drug? Generally... Number ½ lives Elapsed % Drug Remaining 1 50 2 25 3 12.5 4 6.25 5 3.12

Worked Example Patient ES 56 Year old Male Has been on Doxycycline 100mg OD for a week finishing today, Infective exacerbation COPD. Known photosensitising drug. What would you do?

Worked Example Contact local pharmacist/ medicines information centre for wash out period. Half life Doxycycline is 15-24 hours* Patient has normal renal/hepatic function 24 x 5 = 120 hours So may want to wait at least a week before PUVA dose.

Psoralen – A Useful Photosensitising Drug! Natural chemicals found in Figs, celery, Parsley, citrus fruits Use dates back to 1400 BC! In 1974 Term PUVA introduced: Methoxypsoralen used in to increase skin reactivity to UVA (320 -400nm)

Psoralen Mechanism of Action Bonds form between psoralen and DNA in presence of UVA – inhibiting its synthesis. Inhibits Epidermal Growth factor – Down regulation of hyper proliferation of Keratinocytes Forms highly active oxygen molecules – cell destructive Reduce inflammatory markers involved in pathogenesis of psoriasis

Psoralen Dosages 8- Methoxypsoralen 10mg tablets: dose 25mg/m2 : 2hours before Tx 5- Methoxypsoralen 20mg tablets : dose 50mg/m2 : 3 hours before Tx 8- Methoxypsoralen is also available as Gel 0.005% : Bath lotion 1.2% Peak Effect 1.5 to 4.2 hours Duration 3 to 8 hours * (wear protective clothing, sunscreen etc) * Longer in renal impairment

Psoralen Side Effects Hypersensitivity reactions – very rare. Main side effects GI intolerance, nausea. Can Split dose in half and take 30 minutes apart to try and minimize. Can take with a high fat meal – note this will slow absorption time. Dizziness also reported – caution driving if effected and potentiated by alcohol or other medications causing dizziness. Hypersensitivity reactions – very rare.

Psoralen Drug Interactions 8-MOP is a potent inhibitor of the hepatic enzyme Cytochrome P450 Interacts with drugs metabolized by this enzyme e.g. theophylline (low therapeutic index drug) and inducers such as phenytoin Psoralen has additive effect with other photosensitizers 91% protein bound Displaces other drugs that are protein bound e.g. potentially warfarin

Warfarin & Psoralens Psoralens can potentially increase warfarin level in blood Theoretically may increase INR Patients should be advised to inform their anticoagulation clinic will need increased frequency of monitoring.

References The British Association of Dermatologist – Clinical guidelines in Phototherapy Warwick L Morrison, Sangeets Marwaha, Lisa Beck PUVA – induced phototoxicity:Incidence and causes J Am Acad Dermatol 1997;36:183-5 British Photodermatology Group guidelines for PUVA British journal of dermatology 1994 130, 246 – 255 Melvin Lee; Robert E Kalb .Systemic therapy for psoriasis Dermatol Nurs. 2008;20(2):105-111 Warwick L Morison, Phototherapy and Photochemotherapy for Skin Disease, Third Edition (Basic and Clinical Dermatology) Stem RS, Kleinerman RA, Parrish JA, et al. Phototoxic reactions to photoactive drugs in patients treated with PUVA Arch Dermatol 1980;116:1269-71.