Download MBBS Dermatology PPT 29 Systemic Drug Therapy In Dermatology II Lecture Notes

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

THANK YOU

This post was last modified on 07 April 2022