Lecture#4 Psoriasis-pptx.pdf

Psoriasis Pharmacology Dalal Alkhelb, PhD Sultan Almudimeegh, PhD [email protected] [email protected] Office: F17 Office:1B34 Department of Pharmacology &Toxicology  Learning Objectives 1. Understand Pharmacological Tre...

Psoriasis Pharmacology Dalal Alkhelb, PhD Sultan Almudimeegh, PhD [email protected] [email protected] Office: F17 Office:1B34 Department of Pharmacology &Toxicology  Learning Objectives 1. Understand Pharmacological Treatments for Psoriasis: Identify the mechanisms, indications, and effectiveness of topical agents, systemic therapies, and biologics used in psoriasis treatment 2. Recognize Key Adverse Reactions and Drug Interactions: Discuss critical adverse reactions, drug interactions, and contraindications associated with psoriasis treatments 2  Psoriasis It is a systemic inflammatory disease 1 mediated by progressive T-lymphocytes. It results from a complex interplay between multiple genetic factors and environmental influences. Genetic predisposition and precipitating “trigger” factors play a role in the “march of psoriasis.” This march of innate and adaptive immune responses results in clinical manifestations (e.g., keratinocyte proliferation) and is possibly responsible for psoriatic comorbidities. 3  Psoriasis Diagnosis Usually, it is based on the characteristic psoriatic lesion and not on laboratory tests. Types psoriatic lesions Plaque psoriasis (psoriasis vulgaris) - most common. Guttate psoriasis MY Pustular psoriasis Erythrodermic psoriasis Inverse psoriasis Psoriasis Area and Severity Index (PASI) score and Body Surface Area index (BSA) are used to determine the severity of psoriasis: Mild Psoriasis, Moderate Psoriasis, and Severe https://affderm.com/psoriasis-symptoms-causes-treatment/ Psoriasis. 4  Pathogenesis Risk Factors Obesity Injury to the skin Infection Drugs, smoking, alcohol Psychogenic stress 5 Boehncke W. H. (2018). Systemic Inflammation and Cardiovascular Comorbidity in Psoriasis Patients: Causes and Consequences. Frontiers in immunology, 9, 579. https://doi.org/10.3389/fimmu.2018.00579 Pathophysiology of Psoriasis https://link.springer.com/article/10.1007/s10787-023-01178-0 6  Goals of therapy Treatment goals for patients with psoriasis are to: 1. Minimize signs such as plaques and scales 2. Alleviate symptoms such as pruritus 3. Reduce the frequency of flare-ups 4. Maintain a tailored and appropriate treatment plan for associated comorbid conditions (i.e., metabolic syndrome, psoriatic arthritis, or clinical depression) Tailored plans using a combination of pharmacological agents and non-pharmacological options are used to achieve these goals 7  Psoriasis Treatment Factors Influencing Treatment Choice: Severity and extent of the disease Patient preference Comorbidities Access to healthcare Treatment Options: Non-pharmacologic (stress management, sunscreen, and moisturizer) Topical therapies Systemic therapies Pharmacological treatment Biologics Phototherapy https://www.dermcoll.edu.au/atoz/phototherapy/ 8  Pharmacological Treatment Topical: Systemic: First choice for mild to moderate Moderate to severe psoriasis if not controlled by disease. topical agents or symptoms severe enough to Can be combined with other treatment interfere with the quality of life options for extensive or moderate to Traditional immunosuppressants: severe psoriasis. Acitretin 80% of psoriasis patients have mild to moderate disease. Cyclosporine Methotrexate Corticosteroids Janus Kinase (JAK) Inhibitors Vitamin D3 analogues Biologics: Retinoids TNF-α Inhibitors (Adalimumab, Calcineurin Inhibitors certolizumab, etanercept and Infliximab). IL-12/23 Inhibitors: Ustekinumab IL-17 Inhibitors: Ixekizumab , bimekizumab and secukinumab 9  Topical therapy: Corticosteroids (TCS) Mechanism of action Bind to intracellular corticosteroid receptors and regulates the gene transcription of proinflammatory cytokines. Effects: Anti-Inflammatory: Reduces inflammation by decreasing pro- inflammatory cytokines and mediators. Antiproliferative: Inhibits cell proliferation, including lymphocytes. Vasoconstrictive: Decreases vascular permeability and reduces swelling. Immunosuppression: Suppresses the immune response by affecting immune cell function. 10  Topical therapy: Corticosteroids (TCS) Examples Systemic adverse effects More than 4 weeks Super potent : Rare but can happen with super potent Clobetasol propionate 0.05% TCS with extended use: Betamethasone dipropionate 0.05% osteoporosis ointment catabolic effects on supporting Mid-strength tissues (muscle, tendon, bone, skin) Betamethasone dipropionate 0.05% spray hypertension aggravation of diabetes mellitus Desoximetasone 0.05% cream and gel glaucoma or cataracts Least Potent increased risk of infection hypothalamic-pituitary-adrenal (HPA) Hydrocortisone 0.5%, 1%, 2%, 2.5% in different formulation. axis suppression Cutaneous adverse effects: Skin atrophy, acne, contact dermatitis, Topical corticosteroids have been the mainstay of perioral dermatitis or folliculitis, hypertrichosis, and hypopigmentation therapy for most psoriasis patients for over half a century. 11  Topical Corticosteroids Formulation These corticosteroids are available in various formulations, such as creams, ointments, gels, and lotions, to suit different types of psoriasis and patient needs The primary differentiation among corticosteroids lies in their potency differences Potency classification is based on affinities for the glucocorticoid receptor & anti-inflammatory activity, clinical experience, and drug formulation Ointments > Creams > Gels > Foams > Sprays > Lotions (Least potent) 12  Topical therapy: Vitamin D3 Analogs Mechanism of action Precautions and Contraindications Binds to the vitamin D nuclear receptor, Considered the safest long-term topical treatments leading to increased expression of genes Hypercalcemia and hypercalciuria were observed that modulate epidermal differentiation with very high doses or systemic administration and inflammation Note: It shouldn’t be applied after the phototherapy Examples Drug interaction Calcipotriene Concomitant use with acidic topical agents (e.g., Calcitriol salicylic or lactic acid) might inactivate Cutaneous Adverse effects calcipotriene. Calcipotriene might be partially degraded by Perilesional irritation hydrocortisone valerate Mild photosensitivity 13  ‫املستعصية‬ Topical therapy: Retinoids Used in intractable psoriasis Mechanism of action Cutaneous adverse effects: Retinoids affect gene expression by Erythema, burning and stinging sensation activating two families of nuclear Desquamation receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs) Xerosis (dry skin) Retinoids that target RARs predominantly Precautions and Contraindications affect cellular differentiation and Teratogenic and contraindicated during proliferation pregnancy whereas retinoids that target RXRs predominantly induce apoptosis Examples Tretinoin Adapalene Tazarotene 14  Topical therapy: Calcineurin Inhibitors Calcineurin inhibitors are FDA-approved for atopic dermatitis but used off-label for psoriasis Mechanism of action Binds to the intracellular protein FK506-binding protein 12 (FKBP-12) to form a complex that inhibits calcineurin Calcineurin is a phosphatase involved in T-cell activation and the production of cytokines such as interleukin-2 (IL-2) Examples: Tacrolimus Pimecrolimus Side Effects: Local burning and itching Tacrolimus Modulates TGF-β Signaling to Induce Epithelial-Mesenchymal Transition in Human 15 Renal Proximal Tubule Epithelial Cells Systematic Drugs 16  Systematic Traditional immunosuppressants Methotrexate Mechanism of action Precautions and Contraindications Methotrexate is a folate analogue that Abortifacient and teratogenic inhibits the enzyme dihydrofolate Use with caution in patients with compromised liver reductase Drug interaction This inhibition impairs the synthesis of purines and pyrimidines, which are Serum albumin binding interactions: necessary for DNA and RNA synthesis Salicylates Adverse effects Phenytoin Hepatotoxicity Sulfonamides/trimethoprim Ciprofloxacin Bone marrow suppression Thiazide diuretics Pulmonary fibrosis Folic acid supplementation? For decades, methotrexate has been the mainstay of systemic therapy for patients with moderate to severe psoriasis. 17  Systematic Traditional immunosuppressants Cyclosporine V Mechanism of action Drug interaction ‫هذه االدوية تقلل من تكسر الدواء‬ Systemic calcineurin inhibitor CYP3A4 substrate: Calcineurin inhibitor suppresses T-cell Oral contraceptives, SSRIs (fluoxetine), activation and calcium channel blockers will increase cyclosporine levels Adverse effects Some anticonvulsants will decrease the Nephrotoxicity activity of cyclosporine Hypertension ‫هذه االدوية تزيد من تكسر الدواء‬ Hyperlipidaemia Precautions and Contraindications Intermittent short-course therapy For 12 weeks only to reduce the nephrotoxicity 18  Systematic Traditional immunosuppressants Acitretin Used in intractable psoriasis Precautions and Contraindications Mechanism of action Teratogenic and contraindicated during pregnancy Retinoids affect gene expression by Patients who plan to become pregnant during activating two families of nuclear therapy or within at least 3 years after stopping receptors, retinoic acid receptors (RARs) treatment. and retinoid X receptors (RXRs) Adverse effects Hypertriglyceridemia or hyperlipidemia mucocutaneous adverse effects: Dry skin, chapped lips, nasal irritation, dry eyes, oral mucosa dryness, and thin hair 19  Systematic Traditional immunosuppressants Janus Kinase (JAK) Inhibitors Mechanism of action Precautions and Contraindications Decrease the activity of JAK, which is Caution when using with other a critical signaling component for immunosuppressants inflammatory cytokines and Vaccinations: avoid live vaccines during treatment chemokines Example Ruxolitinib Tofacitinib Adverse effects Infections: Risk of upper respiratory infections, urinary tract infections, and other opportunistic infections Headache, diarrhea, nausea 20  Systematic Biologics Biologics can be very effective in moderate to severe psoriasis however, they might increase the risk of infection. Generally, expensive due to their: Complex Manufacturing Process Research and Development Costs Specialized Storage and Handling Market Exclusivity and Patent Protections 21  Systematic Biologics TNF-α Inhibitors Mechanism of action Precautions and Contraindications Reduce inflammation by targeting and Active infections, immunizations especially with live neutralizing TNF-alpha, a key mediator of vaccines the inflammatory response. Use with caution in autoimmune diseases such as Examples peripheral and central demyelinating disorders Adalimumab, certolizumab, etanercept Concomitant use of an anti-TNF agent with another and Infliximab biological immunosuppressive agent is contraindicated (drug interaction) Adverse effects Anti-TNF agents are generally well- tolerated Increased infection risk, reactivation of latent TB Increased risk of malignancies Can worsen chronic heart failure (CHF) 22  Systematic Biologics IL-23 Inhibitors Mechanism of action Precautions and Contraindications Active infections Reduce inflammation by targeting and immunizations especially live vaccines neutralizing IL-23, a key mediator of the individuals with autoimmune diseases. inflammatory response Drug interaction Examples Biologics Immunosuppressants Guselkumab, tildrakizumab, and Live vaccines risankizumab Adverse effects Infection risk Malignancy (rare) 23  Systematic Biologics IL-12/23 Inhibitors Mechanism of action Precautions and Contraindications Reducing inflammation by targeting and Active infections neutralizing IL-12/23, a key mediator of the inflammatory response. Immunizations especially live vaccines Individuals with autoimmune diseases Examples Ustekinumab Drug interaction Adverse effects Biologics, Immunosuppressants and vaccines Generally well-tolerated Infection risk malignancy (rare) 24  Systematic Biologics IL-17 Inhibitors Mechanism of action Precautions and Contraindications Reducing inflammation by targeting and Patients with active infections neutralizing IL-17, a key mediator of the Immunizations especially live vaccines inflammatory response Individuals with autoimmune diseases Examples Drug interaction Ixekizumab & bimekizumab and Biologics, Immunosuppressants and vaccines secukinumab Adverse effects Generally well-tolerated Infection risk malignancy (rare). 25 Thank you 26