Seminar 1: Pharmacology of Osteoarthritis PDF

Seminar 1 Pharmacology of Osteoarthritis 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 What is Osteoarthritis?  Osteoartrithis OSTEOARTHRITIS Osteoarthritis is a progressive and disabling joint disorder caused...

Seminar 1 Pharmacology of Osteoarthritis 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 What is Osteoarthritis?  Osteoartrithis OSTEOARTHRITIS Osteoarthritis is a progressive and disabling joint disorder caused by a chronic and degenerative inflammatory process that significantly reduces the patient's quality of life. This process results in: -pain -bone deformation -loss of joint function Osteoartrithis ¿ Osteoarthritis or Rheumatoid Arthritis ? AUTOIMMUNE ORIGIN (RA) INFLAMMATORY ORIGIN (Cartilage degradation) reduce inflammation Osteoartrithis Epidemiology of OA Symptomatic OA: more common in women than in men, especially after the age of 60 IT IS THE SIXTH LEADING CAUSE OF DISABILITY IN THE WORLD Work restriction significantly higher than that of the healthy control population: -reduction of the working days -Premature abandonment of work due to disease progression (WORLD HEALTH ORGANIZATION)  Osteoartrithis Etiopathogenesis Osteoarthritis has a multifactorial etiopathogenesis: the main cause of the development of OA is an imbalance between the synthesis and degradation of the extracellular matrix of cartilage, which creates a chronic inflammatory process. Fig.1. Response of the arthritic joint to the mechanical effort. This generates the activation of the degradative enzymes of cartilage and the release of proinflammatory mediators that participate in the aetiopathogenesis of OA. Osteoartrithis Etiopathogenesis Articular cartilage is a variety of connective, avascular, aneural, and alymphatic tissue that lines the joint surfaces of diarthrosis. It is made up of cells (chondrocytes and synviocytes) and an extracellular matrix (ECM) that gives it its peculiar mechanical properties Chondrocytes and synoviocytes: Main producers of collagen and hyaluronic acid. During the progression of OA: ✓ Reduction of collagen and HA synthesis ✓ Reduction of synthesis and MW of HA (reduction of lubricating and buffering property of this polymer) ✓ Activation of catabolic activity of chondrocytes Osteoartrithis Risk factors Systemic Age Sex Hormones Increased Local Ethnicity susceptibility Obesity Genetics Injury/Surgery Congenital/developmental conditions Employment Mechanical factors SEVERE MANIFESTING PATHOLOGY Osteoartrithis Kellgren and Lawrence classification  Osteoartrithis Diagnosis Three key factors: patient history, objective examination, and x-ray. Objective Test: Physical and gait evaluation: the patient should be examined in both a standing and supine position; the range of movement (ROM), both active and passive, is evaluated. Radiography: It is the most important way to reach a definitive diagnosis of osteoarthritis of the knee. Representative radiographs of lateral PATHOLOGICAL CONDITIONS: Reduction/loss of joint space and the femoral cartilage changes from three patients (A-B, C-D, and E-F, respectively) at presence of osteophytes baseline and after 12 months Treatment of osteoarthritis Osteoartrithis TREATMENT OF OSTEOARTHRITIS PREVENTIVE TREATMENT PHARMACOLOGICAL TREATMENT SURGICAL TREATMENT OA TREATMENT PREVENTIVE TREATMENT Weight loss Obesity is the main risk factor for OA Physical exercise Activities with less joint impact such as swimming and cycling are preferred. Physiotherapy Exercises aimed at increasing periarticular muscle strength tend to confer more stability to the knee joint and reduce symptoms. OA TREATMENT SURGICAL TREATMENT CONSERVATION REPLACEMENT This option is generally considered when the disease is high in the Kellegren and Symptomatic treatment Unicompartmental Lawrence classification and when Arthroscopy Total knee arthroplasty preventive and pharmacological Joint Surface Repair Procedures treatments are ineffective. Cartilage Autologous chondrocyte transplant (ACT) Autologous osteochondral transplantation (OCT) Bone microfracture, perforation, and aberration arthroplasty Joint Alignment Procedure Osteotomy: proximal tibial or distal femoral OA TREATMENT PHARMACOLOGICAL TREATMENT There are currently no specific pharmacological therapies that can prevent the progression of joint damage caused by OA, only palliative therapy of symptoms. SYMPTOMATIC TREATMENT CHONDROPROTECTIVE TREATMENT ✓ Analgesic Drugs: paracetamol, tramadol ✓ Symptomatic slow acting drugs for ✓ Anti-inflammatory drugs: NSAIDs, COXIB osteoarthritis (SYSADOA) ✓ Intra-articular injection of corticosteroids injection in the knee NEW THERAPIES ✓ Platelet-rich plasma (PRP) ✓ Resinferatoxin (?) PHARMACOLOGICAL TREATMENT SYMPTOMATIC TREATMENT Analgesic treatment 1) Paracetamol not anti inflammatory only analgesis It represents the first-line drug for the treatment of minor osteoarthritis Mechanism of action: Unknown/inhibits COX-3 at the CNS level analgesic effect Oral administration, efficacy at dose D=650 mg, hepatic metabolism ADRs: risk of overdose (15 g) Hepatocellular over 50g necrosis due to toxic metabolite formation(N-acetylbenzoquinone imine), normally neutralized by endogenous glutathione. Very safe at the recommended dose, useful in gastric problems or taking oral anticoagulants PHARMACOLOGICAL TREATMENT SYMPTOMATIC TREATMENT Analgesic treatment 2) Tramadol opoid Opioid used for the treatment of moderate and severe OA Mechanism of action: Racemic combination, centrally acting μ-agonist and SNRI (serotonin/norepinephrine reuptake inhibitor) doble effect ▪ Oral absorption ▪ Active metabolite that prolongates its half-life ▪ ADRs: nausea, vomiting, sedation, dry mouth, hypotension, GI discomfort ▪ Less risk of developing tolerance and dependence than other opioids It exists in tablets together with paracetamol to enhance the analgesic less dep effect PHARMACOLOGICAL TREATMENT SYMPTOMATIC TREATMENT Treatment with anti-inflammatories non steoridal 1) NSAIDs Mainly diclofenac, aceclofenac, piroxicam and meloxicam Mechanism of action: COX inhibition and blockade of the synthesis of prostaglandins >>> anti- inflammatory effect ADRs: gastro-lesive effects, interaction with oral anticoagulants ▪ Piroxicam and Meloxicam long half-life: one daily ▪ *To prevent ulceration and gastric bleeding, take with a proton pump inhibitor (omeprazole) 2) Celecoxib Mechanism of action: Selective inhibition of COX-2 ADRs: increased cardiovascular risk (inhibition of PGI synthesis and increase in TXA2). PHARMACOLOGICAL TREATMENT SYMPTOMATIC TREATMENT Treatment with anti-inflammatories 3) Intra-articular corticosteroid injections triamcinolone, metilprednisolone y betametasone Drugs with anti-inflammatory and immunosuppressive properties. Administered directly to the affected joint (fluoroscopy or ultrasound to ensure precise placement) Objective: inhibiting the activity of inflammatory mediators and cytokines, modulating the immune response (rheumatoid arthritis) Direct administration into the joint to minimize systemic effects associated with oral corticosteroid administration Some people experience relief for weeks or even months. ADRs: increased possibility of infection, immunosuppression, osteoporosis PHARMACOLOGICAL TREATMENT CHONDROPROTECTIVE TREATMENT Symptomatic, slow-acting drugs SYSADOA Symptomatic Slow Acting Drugs for OsteoArthritis New drugs for the treatment of OA Safe and low cost-effectiveness Slow onset of effect Overall efficacy similar to that of NSAIDs and prolonged effect even for a few months after treatment withdrawal(carry over effect) These are products that are normally part of the extracellular matrix of cartilage ORAL ADMINISTRATION Diacerein INTRA-ARTICULAR ADMINISTRATION Chondroitin sulphate (CS) Hyaluronic acid viscosupplementations at low and high Glucosamine sulphate (GS) MW SYSADOA 1) Chondroitin sulfate The CS is part of the group of glycosaminoglycans (GAGs), which are important structural constituents of the ECM. Mechanisms of Action:Anti-inflammatory activity at the cellular level (inhibition of factors such as TNF-α, IL-1β, COX-2, PGE2, y NFκB) Stimulation of proteoglycan synthesis and endogenous HA. Reduction of catabolic activity of chondrocytes by inhibiting various proteolytic enzymes. Exogenous sulfated GAGs have been shown to have positive effects on chondrocyte Reduction of apoptosis, nitric oxideradicaland free radicals. metabolism, influencing cartilage restoration Protective effect of the cellular components of cartilage orof cartilage. preventing further degradation of the matrix during disease progression. Positive effect on bone imbalance in osteoarthritis subchondral bone. SYSADOA 2)Glucosamine Sulphate Glucosamine is a naturally occurring amino-monosaccharide and is the substrate for the biosynthesis of cartilage proteoglycans. Slow onset of action (2-3 weeks) Carry over effect: its effectiveness is maintained for up to 2 months after treatment discontinuation Unknown mechanism of action: Considered useful for rebuilding cartilage and relieving arthritis symptoms, anti-inflammatory potential. The combination of CS + glucosamine Increases the analgesic and anti-inflammatory effect in patients with OA SYSADOA 3) Diacerein Chemical synthesis molecule Prodrug: active metabolite RHEIN Slow onset of action (4-6 weeks) Carry over effect: its effectiveness is maintained for up to 2 months after treatment discontinuation Mechanism of action:directly inhibits IL-1β and intervenes in the inflammatory cascade initiated by this cytokine. Decreases the expression of ECM-degrading enzymes (MMPs) The main problem with this drug used in prolonged treatments is the appearance of gastrointestinal adverse effects (diarrhea) that do not favor its continued administration. SYSADOA Hyaluronic acid in viscosupplementation It belongs is a GAG, main component of synovial fluid, extracellular matrix of skin and cartilage. Produced by chondrocytes and synviocytes Lubricant and shock absorber properties In OA, the HA of the synovial fluid is depolymerized decrease in MW and viscoelasticity, increases the susceptibility of cartilage to injury. HA HIGH MW (> 10^6 DA) Antiangiogenic function Anti-inflammatory effect Promotes tissue damage repair HA remains in the synovial space 1-6 Lubricant months depending on its MW and hyaluronidase activity NEW THERAPIES Platelet-rich plasma(PRP) PRP represent a revolution in the world plasma -> activate platenets -> fromation de GF of sports medicine and traumatology Plasma of an autologous nature High effectiveness, easy handling and low cost It owes its effect to platelets that produce precious growth factors (GF) 3 injections every 1-2 weeks High safety: as it is autologous, PRP is well tolerated, with a low incidence of infections and mild local inflammation. Although PRP infiltration is well-tolerated and safe in the short term, its long-term safety is not yet fully established. NEW THERAPIES Resiniferatoxin(RTX) New experimental non-opioid drug for the treatment of OA-associated pain It has reached Phase III and will benefit from an expedited process for FDA approval Capsaicin analogue, natural origin Activates the vanilloid receptor 1 (TRPV1) in a subpopulation of primary afferent sensory neurons involved in nociception High security profile no dependant or tolerance Resiniferatoxin if approved could be a vital non-opioid therapeutic option for the treatment of OA, offering long- lasting analgesia and improving the functionality of the affected joint QUESTIONS?