2. Pharmacology-4 PHL 425 Fifth Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212Email: aeashour@ksu.edu.sa

3. Management of Psoriasis, Topical preparations, contd. 5.Coal Tar. It is a complex mixture of substances produced during carbonization and distillation of coal  The exact MOA of tar in psoriasis is not well characterized, but it includes antiproliferative, antipruritic and antibacterial effects  In the chronic stages of psoriasis, tar preparations are quite useful and offer an alternative to the use of topical corticosteroids  Goeckerman regimen: Tar is usually used in combination with UVB phototherapy (the application of 1% crude coal tar in a hydrophilic ointment before daily irradiation with UVB) This is the oldest and used to be the most frequently used treatment for patients with moderate-to-severe disease. It is effective within 2 to 3 weeks. This treatment leads to remission of psoriasis in at least 80% of patients The difficulties with this treatment are the time required for exposure to coal tar and UVB, patients' dislike of the smelly, irritant coal-tar preparations and the expense of the treatment. In rare cases, skin cancer has been induced by this treatment This treatment is no longer popular because of its poorly tolerated side effects, and it is not more effective than calcipotriene

4. Management of Psoriasis, Systemic Treatments II.Systemic Treatments: Although the majority of patients with limited chronic plaque psoriasis may be treated successfully with one or more topical agents, approximately 20% require more aggressive treatment Systemic treatment should be limited to patients with physically, socially or economically disabling psoriasis that has not responded to topical treatment The short-term side effects of PUVA are nausea, burning and pruritus. The long-term problems are an increased risk of photodamage to the skin and of cancer related to the cumulative exposure to UVA radiation The therapeutic index of this treatment is high if the cumulative exposure to UVA radiation is less than that likely to cause cancer or severe photodamage. To minimize the cumulative dose of radiation, PUVA can be combined with the oral retinoid etretinate (see later) Oral and topical retinoids are synergistic with oral PUVA, while reducing their dose and the number of phototherapy treatments can be reduced, with the added benefit of a potential reduction in skin carcinogenesis 1.PUVA: See before (2 nd Lecture) PUVA is a highly effective treatment with a significant duration of remission. In over 85% of patients, skin lesions disappear after 20 to 30 treatments. Therapy is usually given 2-3 times per week. Maintenance therapy involves as little as once every 2-4 weeks, with eventual discontinuation of treatment Most patients accept PUVA therapy because of the high likelihood of response and the absence of need for topical medication between treatments

5. Management of Psoriasis, Systemic Treatments Retinoids are considered excellent for use in combination with other treatments and when used with UVB or PUVA, their dose and the number of phototherapy treatments can be reduced, with the added benefit of a potential reduction in skin carcinogenesis Systemic retinoid toxicity is similar to hypervitaminosis A; hence, mucocutaneous side- effects (e.g., skin dryness, conjunctivitis, and hair loss) are common. Other side-effects include hyperlipidaemia, osteoporosis and ligamentous calcifications Systemic retinoids should be considered with extreme caution in women of childbearing potential because of teratogenicity 2.Oral retinoids: They are vitamin A derivatives, and they have been used in the treatment of psoriasis for the past two decades These synthetic hormones bind to nuclear retinoid receptors, thereby altering gene transcription and returning keratinocyte proliferation and differentiation to normal The original third generation retinoid used for psoriasis, etretinate, was superseded by its natural metabolite, acitretin, which was shown to have similar efficacy with a better pharmacokinetic profile Oral retinoids are especially effective in the treatment of erythrodermic and pustular variants of psoriasis Since they are not immunosuppressive, retinoids might have a role in the treatment of psoriasis in children, patients with HIV infection and those who are prone to cancer

6.  The uptake of MTX into the cell is mediated by the reduced folate carrier (green) (1) and by an endocytotic pathway activated by a folate receptor (blue) (2)  Once inside the cell, MTX is polyglutamylated by the enzyme folylpolyglutamate synthase (3)  Both MTX and its polyglutamates (Glu) are potent inhibitors of DHFR, an enzyme that converts dihydrofolate (FH2) to FH4 (4)  The depletion of FH4, leads to an impairment of both purine and thymidine synthesis, an inhibition of DNA replication and cell death in rapidly dividing tissues, including the hyperproliferative psoriatic epidermis. MTX also stimulate apoptosis and death of activated T lymphocytes (immunosuppressive effect) Management of Psoriasis, Systemic Treatments, contd. 3.Methotrexate (MTX): It is an antimetabolite. It is a folic acid analog and the main folate antagonist Folic acid Methotrexate

7. Management of Psoriasis, Systemic Treatments, MTX Despite the advent of new therapies, MTX continues to play a central role as an affordable, gold standard treatment for recalcitrant psoriasis and psoriatic arthritis MTX is widely used for the treatment of rheumatoid arthritis and autoimmune diseases, and it is one of the most widely used antimetabolites in cancer chemotherapy Because of its teratogenicity, MTX is absolutely contraindicated during pregnancy Bone marrow suppression is the most common cause of death attributable to this treatment; hence, appropriate screening every 1–3 months is essential. A number of drugs, including sulphonamides and their derivatives, may potentiate the risk of bone marrow suppression Dose: The cell cycle in psoriatic keratinocytes is rapid. Oral administration of MTX in 3 doses (usually 2.5 to 5 mg each) at 12-hour intervals, with the three doses given once weekly, can inhibit the replication of these cells with minimal side effects When stability or adequate clearance is achieved, the lowest effective dose of MTX should be sought by tapering the dose slowly by about 2·5 mg per month The patient's hematologic status and renal and liver function should be normal if methotrexate is to be given Adequate renal function is necessary because 85% of the drug is excreted through the kidneys, and patients with poor renal function have sustained increases in plasma drug concentrations, leading to acute side effects, including leukopenia and acute GI erosions The chief long-term side effect of MTX therapy is cirrhosis; patients with a history of liver disease or excessive alcohol intake and those with abnormal liver function should not receive the drug