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Ask the Pharmacist Drug-induced oedema, Trimovate® alternatives and tacrilomus Rod Tucker, a pharmacist with a special interest in dermatology, answers more questions submitted by DN readers. If you have a burning question that you’d like to see answered in a future issue, please email it to [email protected] entitling your email: Ask the Pharmacist. Q. Which drugs can contribute to leg oedema and why? A. Water accounts for nearly 60% of total body weight and is contained either within cells (intracellular) or between cells (extracellular).The extracellular compartment consists of the intravascular plasma volume and interstitial fluid, ie the fluid that surrounds cells in a tissue.The interstitial fluid is a source of nutrients and oxygen for cells as well as a means of removal of metabolic waste products and carbon dioxide and this exchange occurs via the capillary network. Nutrients and oxygen are replenished from the arterial blood supply and waste products removed into the venous system.To prevent a buildup of interstitial fluid any excess is drained away through the lymphatic system. The volume of interstitial fluid is maintained by the balance of two opposing forces, which dictate whether fluid moves into the interstitium or back into the plasma: the hydrostatic (or fluid pressure) generated from blood entering the capillary network and the osmotic (or oncotic) pressure of the plasma generated by the presence of proteins.The direction of flow depends on the difference between these two pressures so that: direction of flow = hydrostatic pressure – oncotic pressure. If this difference is positive, fluid moves into the interstitium; if negative, fluid 50 moves from the interstitium back into the capillaries. At the arterial or pre-capillary end, the hydrostatic pressure is greater than the oncotic pressure of the plasma and therefore fluid moves into the interstitium. Conversely, at the venous or post-capillary end, the hydrostatic pressure is less than the oncotic pressure and thus fluid moves back into the capillaries. The term ‘oedema’ refers to an accumulation of fluid in the interstitium and can occur through one of four mechanisms: 1 Reduced outflow due to blockage of the lymphatic system 2 Increased capillary hydrostatic pressure 3 Reduced plasma oncotic pressure 4 Increased capillary wall permeability. Several conditions can lead to oedema. Lymphoedema affects drainage (1), venous congestion caused by congestive heart failure and hypertension increases hydrostatic pressure (2), nephrotic syndrome and cirrhosis decrease the protein content of the plasma (3), and finally allergic reactions or infections increase capillary wall permeability (4). The increased fluid in the interstitium reduces the volume of fluid circulating within the intravascular network and this activates the renin-angiotensin-aldosterone (RAA) system which promotes sodium and water retention to maintain plasma volume, thus exacerbating the problem of fluid overload. Which drugs cause peripheral oedema? Peripheral oedema is characterised by swelling of the ankles and/or lower leg and can be caused by a number of medical conditions (Cho, Atwood, 2002). However, it can be induced by several commonly prescribed medicines, including: Dermatological Nursing, 2014, Vol 13, No 1 50-52 Ask the Pharm C.indd 50 8 Calcium channel blockers (CCBs), eg amlodipine 8 Non-steroidal anti-inflammatory drugs (NSAIDs), eg diclofenac 8 Corticosteroids, eg prednisolone, oral contraceptives. Other classes of drugs that are known to cause oedema and the possible mechanisms involved are listed in Table 1. How do drugs induce peripheral oedema? The mechanism through which CCBs cause peripheral oedema is due to a reduction in arterial blood pressure that is not matched in the venous system. Consequently, there is greater hydrostatic pressure in the pre-capillary network thus forcing more fluid into the interstitium. NSAID drugs cause oedema as a consequence of their mode of action. By inhibiting cyclooxygenase enzymes (COX-1 and COX-2) this leads to an inhibition of a number of prostaglandins, some of which serve to maintain kidney function. Without these prostaglandins, glomerular filtration is reduced and this triggers retention of sodium and water (via the RAA system), which increases blood pressure and subsequently arteriolar hydrostatic pressure leading to oedema. In fact, a second potential problem when using NSAIDs is the risk of hypertension. Corticosteroids cause oedema because of their chemical similarity to aldosterone, which is part of the RAA system.These drugs can therefore stimulate the aldosterone receptor leading to increased fluid retention and oedema. What can be done about drug-induced peripheral oedema? Health professionals should review a patient’s medicine if peripheral oedema develops to rule out a possible drug cause. If a medicine known to cause the problem www.bdng.org.uk 04/03/2014 14:30 ask the pharmacist is being taken, stopping or changing the treatment will usually resolve the problem and this is a more appropriate course of action than use of diuretics. References Cho S, Atwood JE (2002) Peripheral edema. Am J Med 113(7): 580-86 Q. What are the alternatives for Trimovate® cream? A. Pharmacies are currently experiencing supply problems with Trimovate® cream, a combination product that contains clobetasone, oxytetracycline and nystatin. The indications for Trimovate® cream include “the treatment and management of steroid responsive dermatoses where candidal or bacterial infection is present, suspected or likely to occur…” … “these include infected eczemas, intertrigo, napkin rash, anogenital pruritus and seborrhoeic dermatitis.” (eMC, 2007.) In pursuit of an alternative product, it is worth reviewing the management of these conditions to determine whether Trimovate® can be easily replaced. Infected eczema Flares of atopic eczema require the use of topical steroids and the skin can often become infected with staphylococcus aureus. However, a systematic review found that there was no convincing evidence that addition of antibacterial treatment led to improvements above those from using a topical steroid alone (Birnie et al, 2008). Nevertheless, in clinical practice topical antibacterial-steroid combination treatments are widely used and appear to be effective. If Trimovate® cream is prescribed to treat localised infected eczema, suitable alternatives include Betnovate® C or Fucibet® (PCDS, 2014). Intertrigo This is an inflammatory reaction in body folds and is caused by a combination of factors such as heat, friction and maceration of skin. Infection normally occurs with candida yeasts but coexistent bacterial infection may be present. In a recent systematic review of the treatments for intertrigo in adults, it was difficult to make recommendations about the relative effectiveness of the different interventions. With respect to combination products (ie, steroidantibiotic-antifungal or even antiseptic agents), the reviewers commented that “although the study authors (of included studies) claimed the combinations worked, no firm conclusions about any of the combinations can be made due to weak research designs and the small sample sizes” (Mistiaen, van HalmWalters, 2010). Nevertheless, the absence of evidence from clinical studies does not mean that Trimovate® is ineffective. In practice the cream does work but the lack of comparative studies simply means that we don’t know if it works any better than the alternatives. If Trimovate® cream is prescribed for intertrigo, alternatives will include single agent antifungals, topical steroids or topical immunomodulators (Selden, 2012). Table 1. Drugs that can cause peripheral oedema and possible mode of action. Drug class Mechanism Antipsychotics, eg risperidone, olanzapine Unknown but because these drugs cause vasodilatation, it is possible that this increases hydrostatic pressure in the pre-capillary network. Thiazolidinediones, eg pioglitazone, rosiglitazone Unknown but possibly related to increased blood volume and hence hydrostatic pressure. Vasodilators (antihypertensive drugs), eg minoxidil Vasodilator effect leading to activation of the RAA system leading to sodium/water retention. In addition, arteriolar dilatation increases hydrostatic pressure. www.bdng.org.uk 50-52 Ask the Pharm C.indd 51 Napkin rash Nappy rash is an irritant contact dermatitis confined to the nappy area often colonised with candida albicans, though if not treated further colonisation with bacteria such as staph aureus can occur. If Trimovate® cream is prescribed for napkin rash, use topical imidazoles; if signs of bacterial infection are present, treat with oral flucloxacillin (or erythromycin or clarithromycin if allergic to penicillin) (NICE CKS, 2013). Anogenital pruritus Irritation around the anus or perianal area is a common complaint that causes a great deal of discomfort for patients.There are several potential common causes such as faecal soiling as well as allergic or irritant dermatitis, psoriasis and bacterial or fungal infections. If Trimovate® cream is prescribed for anogenital pruritus, use topical steroids alone, imidazoles if a fungal infection is suspected, mupirocin or fusidic acid topically where bacterial infection is present/suspected and oral antibiotics if it is a long-term problem (Siddiqi et al, 2008). Seborrhoeic dermatitis Seborrheoic dermatitis is an inflammatory condition affecting the scalp, face and body in areas with a high number of sebaceous glands. The Primary Care Dermatology Society actually advises against the use of products such as Daktacort® (miconazole and hydrocortisone) or Trimovate® because this might lead to overuse of topical steroids on the face (PCDS, 2013). If Trimovate® cream is prescribed for seborrhoeic dermatitis, use topical imidazoles, although topical steroids can be used short-term to help settle inflammation (NICE CKS, 2013). Conclusion Suitable alternatives to Trimovate® are available to manage the licensed indications. Whether Trimovate® is more effective than these alternatives needs further research. In the meantime, clinical experience will inform on whether the potential replacements provide a satisfactory resolution of symptoms. Dermatological Nursing, 2014, Vol 13, No 1 51 04/03/2014 14:30 Ask the Pharmacist References Birnie A, Bath-Hextall F, Ravenscroft J, Williams HC (2008) Interventions to reduce Staphylococcus aureus in the management of atopic eczema. Coch Rev 3. Art. no: CD003871. DOI: 10.1002/14651858. CD003871.pub2 eMC (2007) Summary of Product Characteristics Trimovate cream. Available at: www.medicines.org.uk/emc/medicine/13574/ SPC/Trimovate/#INDICATIONS Mistiaen P, van Halm-Walters M (2010) Prevention and treatment of intertrigo in large skin folds of adults: a systematic review. BMC Nurs 9:12 NICE CKS (2013) Nappy rash. Clinical Knowledge Summaries. Available at: cks.nice.org.uk/nappyrash#!scenariorecommendation:2 NICE CKS (2013) Seborrheoic dermatitis. Clinical Knowledge Summaries. Available at: cks.nice.org.uk/seborrhoeicdermatitis#!topicsummary PCDS (2013) Eczema: atopic eczema. Primary Care Dermatology Society. Available at: www.pcds.org.uk/clinical-guidance/atopiceczema#management PCDS (2013) Seborrhoeic dermatitis. Primary Care Dermatology Society. Available at: www.pcds.org.uk/clinical-guidance/ seborrhoeic-eczema#management Selden ST (2012) Intertrigo. Medscape. Available at: emedicine.medscape.com/ article/1087691-overview Siddiqi S, Vijay V, Ward M, Warren S (2008) Pruritus Ani. Ann R Coll Surg Engl 90(6): 457-463 Q. Can children prescribed topical tacrolimus receive live vaccinations? A. Tacrolimus was isolated in 1984 from a Japanese soil bacterium and introduced in 1989 as an oral immunosuppressive agent to prevent rejection of transplant organs. The precise mechanism through which tacrolimus causes immunosuppression is unclear but thought to be due to inhibition of T-lymphocyte activation. Patients who are immunocompromised either because of specific drug treatment or for medical reasons have an increased risk of infection because they are unable to mount a sufficient response to immunisation. These patients should therefore avoid live 52 vaccines as this allows the virus to replicate and in some instances can induce infection. The manufacturer of oral tacrolimus (Adoport®) advises against the use of live attenuated vaccines. found that treatment did not affect seropositive responses to vaccination against tetanus, diphtheria, measles or rubella (Papp et al, 2005). In 2000, a topical formulation of tacrolimus was developed for the treatment of atopic eczema. Due to the risks associated with the oral formulation, concerns have been expressed that the topical preparation might also lead to immunosuppression, especially in children, who receive live vaccines such as the MMR (measles, mumps and rubella) and oral polio. Does this mean that children prescribed topical tacrolimus cannot be given live vaccinations? Although the SPC for Protopic® does not provide any specific guidance on the administration of live vaccines in relation to use of the product, the available evidence would appear to suggest that topical tacrolimus does not affect the immune response to live vaccination. While there are no data available for the use of tacrolimus in conjunction with either MMR or polio, it seems reasonable to assume, given the current evidence, that topical immunomodulators are unlikely to impair the body’s ability to produce sufficient antibodies in response to the use of live vaccines. Nonetheless, the decision whether or not to vaccinate remains a clinical one and should be based on the immune status of the individual patient. According to the SPC for Protopic® the elimination half-life after repeated application is 65 hours in children (eMC, 2013). Consequently, parents who wish to stop using the drug before vaccination should wait at least 3 days to be sure that the drug has cleared from the body. Clinical evidence For tacrolimus to cause immunosuppression, the drug needs to reach a sufficient concentration in the blood stream. In a study exploring repeated application of tacrolimus ointment in children aged between 6 and 12, plasma levels of tacrolimus reached only 3% of those obtained from oral administration in liver transplant patients (Harper et al, 2005).Therefore, plasma levels remain low after topical application which suggests that it would be safe to administer live vaccines to children. Nevertheless, this study did not consider the more important question of whether antibody production was impaired after the use of live vaccines in conjunction with topical tacrolimus.Two specific studies were designed to address this specific question. In the first study, 23 children prescribed topical tacrolimus for 7 weeks were vaccinated with pneumococcal polysaccharide vaccine during treatment. It was observed that all children developed protected antibody responses (Stiehm et al, 2005) suggesting that the effect of the drug is limited to the skin. In the second study, children aged between 2 and 11 years were prescribed tacrolimus ointment 0.03% and vaccinated against meningococcal serogroup C disease and the authors found that 99.1% of children developed sufficient antibody titre (Hofman et al, 2006). Furthermore, in a two-year study in children prescribed pimecrolimus (another topical immunomodulator for eczema) it was Dermatological Nursing, 2014, Vol 13, No 1 50-52 Ask the Pharm C.indd 52 Bottom line References eMC (2013) Protopic® Summary of Product Characteristics. Available at: www.medicines. org.uk/emc/medicine/8884/SPC/Protopic+0.03+ +ointment/#PHARMACOKINETIC_PROPS Harper J, Smith C, Rubins A, et al (2005) A multicenter study of the pharmacokinetics of tacrolimus ointment after first and repeated application to children with atopic dermatitis. J Invest Dermatol 124(4): 695-699 Hofman T, Cranswick N, Kuna P, et al (2006) Tacrolimus ointment does not affect the immediate response to vaccination, the generation of immune memory, or humoral and cell-mediated immunity in children. Arch Dis Child 91(11): 905-910 Papp K (2005) Long-term treatment of atopic dermatitis with pimecrolimus cream 1% in infants does not interfere with the development of protective antibodies after vaccination. J Am Acad Dermatol 52(2): 247-53 Stiehm E, Roberts R, Kaplan M, et al (2005) Pneumococcal seroconversion after vaccination for children with atopic dermatitis treated with tacrolimus ointment. J Am Acad Dermatol 53(2 suppl 2): S206-13 DN www.bdng.org.uk 04/03/2014 14:30