Download MBBS (Bachelor of Medicine, Bachelor of Surgery) Dermatology PPT 29 Systemic Drug Therapy In Dermatology II Lecture Notes
Systemic Drug Therapy in
Dermatology - II
Clinical vignette
? A 45 year old male presents with well-defined erythematous papules
and plaques, which are surmounted with large, silvery loose scales.
There is also associated joint pain
? Provisional diagnosis
? Psoriasis with psoriatic arthritis
? The treating physician plans an immunosuppressive (e.g.
methotrexate) and with other routine investigations (e.g. CBCs, ESR,
BUN, creatinine etc.), orders serum virological markers (for HBV, HCV,
HIV)
? In a tropical country like India, which other infection/ inv. is also
routinely indicated before treatment
? Tuberculosis
? CXR
Methotrexate (MTX)
? An antimetabolite Used as a chemotherapeutic agent since the early
1950s
? Immunosuppressive and antiinflammatory effects
? Used therapeutically in a variety of rheumatological, gastrointestinal,
neurological and dermatological inflammatory disorders
Uses
? Severe psoriasis with/without arthritis
? Offlabel (often as a steroidsparing agent) in immunobul ous disorders (pemphigus,
bul ous pemphigoid, cicatricial pemphigoid and epidermolysis bul osa acquisita),
? Connective tissue diseases (dermatomyositis, lupus erythematosus and scleroderma),
? Vasculitides
? Neutrophilic dermatoses (pyoderma gangrenosum and Sweet syndrome)
? Other inflammatory (such as atopic eczema, sarcoidosis, cutaneous Crohn disease and
chronic idiopathic urticaria) and proliferative (mycosis fungoides, S?zary syndrome,
pityriasis lichenoides and pityriasis rubra pilaris) disorders
Efficacy in psoriasis
? In treatment of psoriasis and psoriatic arthritis - MTX is considered
the "gold standard"
? Based on several studies - Approximately 45% of patients see a 75%
improvement in their Psoriasis Area and Severity Index (PASI) score
? Takes - 4 to 8 weeks to see a response to changes in MTX dosage
Doses
? In dermatological usage, MTX is usually taken orally in weekly (rather
than daily) doses,
? Also - Intramuscular, intravenous, subcutaneous
? Usual weekly dose ? 7.5-20 mg
Mechanisms of action
? A structural analogue of folic acid
? MTX blocks the metabolism of folic acid through competitive
inhibition of dihydrofolate reductase (DHFR)
? DHFR catalyses the conversion of DHF to tetrahydrofolate (THF), a
singlecarbon transfer source essential to the generation of purine &
pyrimidine nucleotides Therefore for nucleic acid and protein
synthesis
Risks, Precautions, Common ADRs
Pretreatment screening
Ongoing monitoring
Liver biopsy
? The gold standard to assess MTX-induced liver fibrosis - Percutaneous
needle biopsy
? Patients without risk factors for liver injury - Current
recommendations suggest consideration of liver biopsy after 3.5 to 4
g total cumulative dosage.
? For patients with risk factors - For MTX-induced liver injury, a delayed
baseline liver biopsy should be considered (after 2-6 months of use,
when it is apparent the medication is efficacious, well tolerated, and
likely to be continued) and again at a cumulative dose of 1.0 to 1.5 g
Folate Supplementation
? Daily supplementation with 1 to 5 mg of folate - Reduced adverse
effects and toxicities without compromising the efficacy of MTX
? Nausea, vomiting, diarrhea, alopecia, stomatitis and oral ulceration,
elevated transaminases, and mild myelosuppression ? May be
prevented
? Pneumonitis & moderate to severe myelosuppression - Not mitigated
by folate supplementation
Overdose
? MTX overdose ? Must be treated promptly (within 24-36 hours after
overdose) with folinic acid (leucovorin)
? Folinic acid is metabolized in vivo to tetrahydrofolate in the absence
of dihydrofolate reductase - Provides an alternative supply of DNA
and RNA precursors
? An oral dose of 10 mg/m2, or 15 to 25 mg every 6 hours for 6 to 10
doses should be given on first suspicion of MTX overdose without
delay for a serum assay
? If serum assay is available, oral or parenteral doses may be continued
every 6 hours until the serum concentration of MTX falls to less than
10-8 M
Drug Interactions
Azathioprine
? A potent immunosuppressive, antiinflammatory and antiproliferative
drug
? To prevent graft rejection and to treat haematological malignancies
and a variety of rheumatological, gastrointestinal, neurological and
dermatological inflammatory disorders
Uses
? Pemphigus and pemphigoid
? Often used as an adjunct to other immunosuppressive agents such as
prednisolone and may exert a steroidsparing effect
? Systemic lupus erythematosus and dermatomyositis
? Atopic eczema
? Chronic actinic dermatitis
? Also for use in - Lichen planus, contact dermatitis, polymorphic light
eruption, leukocytoclastic vasculitis, pyoderma gangrenosum, Beh?et
disease and chronic cutaneous lupus erythematosus
MoA
? Azathioprine is a prodrug that is metabolized to 6-mercaptopurine (6-
MP) and acts as an immunosuppressant/ anti-inflammatory
? Has better availability when given by mouth than 6-MP
? 6-MP is further anabolized via hypoxanthineguanine phosphoribosyl
transferase (HGPRT) ultimately to a purine analog, 6-thioguanine
(6-TG) which inhibits RNA and DNA synthesis and repair
immunosuppression
CIs & Common ADRS
Doses
? Usual dose: 1-2.5 mg/kg
? Azathioprine can be initiated as monotherapy
? Initially combined with prednisone is often used in steroid-responsive
bullous disorders
Cyclophosphamide
? Cyclophosphamide is an alkylating agent and acts primarily by
crosslinking DNA - A classic cell cycle-nonspecific cytotoxic drug
? In oncology - Used as an antineoplastic agent
? In dermatology - Used as an immunosuppressive and steroid-sparing
agent particularly for autoimmune blistering disorders and systemic
vasculitis
Indications
? In dermatology, used in only the most serious diseases
? In particular - Pemphigus vulgaris - In combination with steroids -
Evidence supports its steroid-sparing benefits
? Cyclophosphamide - Also used for the treatment of mucous
membrane pemphigoid
? Other diseases that may respond - Pyoderma gangrenosum,
necrobiotic xanthogranuloma, cutaneous amyloidosis, lichen
myxedematosus, giant cell reticulohistiocytoma, primary cutaneous
diffuse large B-cell lymphoma and mycosis fungoides
Doses
? Oral doses - Typically 1 to 3 mg/kg/d either divided or as a single
morning dose
ADRs
Mycophenolate mofetil
? Mycophenolate mofetil (MMF) potent immunosuppressant
? Prodrug of mycophenolic acid (MPA) Used primarily to prevent
solidorgan graft rejection
Dermatological uses
? MMF has a predictably beneficial effect in the treatment of
immunobullous disorders (in particular pemphigus and pemphigoid)
? A less consistent effect in psoriasis, atopic eczema, connective tissue
disorders and vasculitides
Dose
? Twicedaily dosing
? Starting dose for dermatological indications 250 mg BD first week
? Until a maximum of 1.5 g twice daily is reached
? Dosage should be tailored to individual tolerance
? The clinical response is slow
Ciclosporin
? Ciclosporin is a highly effective and rapidly acting potent inhibitor of
Tcell function
? Central importance in the management of severe inflammatory skin
disease, particularly psoriasis
Indications
? Cicloporin psoriasis (plaque type) and atopic eczema
? Common offlabel uses include chronic urticaria, pyoderma
gangrenosum, hand eczema and palmoplantar pustulosis
ADRs
? MC - Hypertension, nephrotoxicity, hyperlipidaemia, myalgia and headache
? Others include gingival hyperplasia, fatigue, gastrointestinal disturbances,
? tremor and paraesthesiae in the hands and feet
? A variety of metabolic abnormalities (hyperbilirubinaemia, hypercalcaemia,
? hypomagnesaemia, hyperuricaemia)
? Most are dose related and respond rapidly to dose reduction/ treatment
cessation
? Longer term use carries significant, predictable risk, particularly of
nephrotoxicity, and is general y not recommended
Doses
? Start - In the lower dose range (2.5 mg/kg/day), escalating to higher
doses (up to 5 mg/kg/day) after a month of therapy in the event of a
poor response
? If disease is acute, severe and/or unstable -5 mg/kg/day
? The lowest possible therapeutic dose should be used
? Ciclosporin remains an extremely useful, predictably effective and
generally welltolerated drug for shortterm use
? Longterm use is complicated by nephrotoxicity
? Potent immunosuppression.
Thalidomide
? Hypnosedative, immunomodulatory, and neural/vascular tissue
effects
? Initially removed from the market because of severe teratogenic
effects (phocomelia) in 1961
Indications
? Thalidomide - Later found to be effective in treating erythema
nodosum leprosum
? Off-label use treating dermatoses including AIDS-related Kaposi
sarcoma, pyoderma gangrenosum, bullous pemphigoid, prurigo
nodularis, uremic pruritus
Dose and regimens
? The dose range for dermatological conditions is 50?300 mg/day,
taken as a single dose at bedtime to reduce the impact of sedation
Systemic retinoids
? The synthetic retinoids are a class of organic molecules derived from
and with similar biological activity to the naturally occurring vitamin A
group of retinoids, which includes retinol, retinal and retinoic acid
Indications
? Isotretinoin is licensed for the treatment of severe acne resistant to
adequate courses of standard therapy, although offlabel it has been
used in rosacea, hidradenitis suppurativa and dissecting cellulitis of
the scalp
? Alitretinoin has a product license to treat severe chronic hand eczema
? Also been approved by FDA for the topical treatment of the
cutaneous lesions of Kaposi sarcoma
? Acitretin severe psoriasis, resistant to standard therapies,
palmoplantar pustulosis, inherited ichthyoses and Darier disease
? Bexarotene is indicated for the treatment of the cutaneous
manifestations of advanced cutaneous Tcell lymphoma
? Retinoids have also been used offlicense to treat pityriasis rubra
pilaris, lupus erythematosus and lichen planus
Doses
ADRs
Pretreatment screening
? Women of childbearing potential - explicit counsel ing on the teratogenicity
of retinoids
? Either adopt birth control measures or abstain from coitus
? Pregnancy should be excluded prior to commencing retinoid therapy
? Pregnancy should be avoided for the duration of therapy and for an
appropriate time thereafter (1 month for isotretinoin, alitretinoin and
bexarotene, and 2 years for acitretin)
? The recommendations regarding isotretinoin, which can be adapted of the
other retinoids, suggest that women deemed at risk of conceiving should
be recruited into the isotretinoin pregnancy prevention plan (iPLEDGE in
the USA
Monitoring
? Reasonable followup Monthly clinical evaluation
? Blood tests (liver function tests and fasting lipid profile, with
occasional renal function tests and full blood count) for 3?6 months,
then 3monthly reviews with blood tests
? Thyroid function should be monitored in patients receiving
alitretinoin and bexarotene
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This post was last modified on 07 April 2022