#3 Musculoskeletal Flashcards
Non-steroidal anti-inflammatory drugs
= COX inhibitor Blocking COX2 = good, COX 1 bad = housekeeping
• They work by interfering with the production of autacoids ( which are molecules formed by one set of cells that alter the functioning of other cells) – many induce pain and the mediators include the eicosanoids derived from arachidonic acid main types = Prostaglandins (PG), Thromboxane A2 (TxA2) & Leukotrienes(LT)
• Cox inhibitors as they prevent the enzyme cyclooxygenase breaking down arachidonic acid into Endoperoxides which is broken down by enzymes such as prostaglandin isomerase, prostacyclin synthase, and thromboxane synthase into PG TxA2 and LT which are collectively called Prostanoids
• Diclofenac Celecoxib + Meloxicam have increased selectivity for COX-2 inhibition compared to 1 – vice versa.
• Diclofenac (T)(SUP)(DMI)(INJ)(II), Ibuprofen (T)(OS)(SYR)(GRAN), Aspirin (T)(ODT)(SUP) Paracetamol (T)(C)(ST)(OS)(SUP)(INJ), Naproxen (T)
• Indications = Pain and inflammation in rheumatic disease and other musculoskeletal disorders, acute gout
Corticosteroids
Immunosuppressant
• Prednisolone has predominantly glucocorticoid activity. Corticosteroids are used where anti-inflammatory +/ immunosuppressive treatments are required.
• Glucocorticoids are gene activating drugs, are lipid soluble so can diffuse into cell and bind to glucocorticoid receptors in cytoplasm which enters the cell nucleus to regulate gene expression = affect production of mRNA. Glucocorticoids can induce the production of annexin-1 (ipcortin-1) which inhibits phospholipase a2 = powerful anti-inflammatory response affecting eicosanoid + interleukin-2 production & reduce leukocytes
• Prednisolone (T)(INJ) and hydrocortisone
• Indications = Moderate to severe arthritis; ankylosing spondylitis() RA
Cytokine modulators
- Drugs that supress the rheumatic disease process: DMARDs suppress/modify immune response – slow progression of RA but increase risk of infection interfere with normal immunological response
Sodium Aurothiomalate=
Gold compound which has anti-rheumatic effects (INJ)
• Mechanism unclear, but could include inhibiting prostaglandin synthesis, and inhibition of IL-1-2 and TNF-α production. Reducing T-lymphocyte, phagocyte activity and neutrophil migration
• Indications = Active progressive rheumatoid arthritis, effective in palindromic rheumatism
Methotrexate =
= Inhibition of enzymes involved in purine metabolism (T) (Parenteral INJ)
• An analogue of folic acid – It inhibits dihydrofolate reductase to prevent the conversion of dihydrofolic acid to tetrahydrofolic acid for nucleic acid synthesis.
• It decreases production of IL-1 and TNF- cytokines, but increase the production of IL-10, which is inhibitory, and adenosine production may also be increased, which then acts as an anti-inflammatory paracrine.
• Can only be given ONCE A WEEK as it accumulated intracellularly and has potentially severe/fatal side effects
• NSAIDs reduce renal clearance of methotrexate = monitoring but can be given together. V CANT
• Serious interaction with TRIMETHOPRIM which also acts on dihydrofolate reductase –together actively supress bone marrow agranulocytosis (def in wbc secreting granules in blood) + neutropenia (few rbc in blood)
• Indications = Moderate to severe active rheumatoid arthritis, cancer chemotherapy
Azathioprine
Reduces activity of immune system (T) (INJ)
• A prodrug that is converted into 6-metacaptapuring which inhibits proliferation of B and T lymphocytes by a cytotoxic action on dividing cells
• Inhibits both cell mediated and antibody mediated immune reactions = increased risk on infections/fever
• May supress bone marrow – presenting a sore throat = seek urgent medical attention.
• Indications = Moderate to severe rheumatoid arthritis , stop transplant sorgan rejection
Leflunomide
Pyrimidine synthesis inhibitor (T)
• Inhibits dihydroorate dehydrogenase which is involved in pyramidine production
• Also inhibits B and T-lymphocyte proliferation
• Is associated with Steven-Johnson syndrome?
• Indications = Moderate to severe rheumatoid arthritis, active psoriatic arthritis
Sulfasalazine
= Inhibitor of NF-κB (T)
• Once administered released sulfapyridine which reduces lymphocyte proliferation by interfering with folate metabolism and reducing cytokine production.
• Indications = Active rheumatoid arthritis
Antimalarials
:
Chloroquine & Hydroxychloroquine
Chloroquine = Inhibits lymphocyte proliferation (T) (SYR) Hydroxychloroquine= Reduces inflammation (T)
• Stored in tissue = long half-life – takes months to reach steady state in blood = slow onset of clinical action – generally reserved only for mild RA – as not as effective as other DMARDS
• Not fully understood. May inhibit lysosomes, neutrophils, IL-1 and TNF-production, phospholipase A2
• Indications = Active rheumatoid arthritis & juvenile idiopathic arthritis systemic/discoid lupus erythematosus
Penicillamine
= Immunosuppressant (T)
• May reduce T-lymphocyte activity and inhibit rheumatoid factor from binding to immunoglobulin = preventing the formation of immune complexes in RA.
• Its enantiomer L-penicillamine is toxic as it inhibits the action of pyridoxine.
• Indications = Active progressive rheumatoid arthritis, effective in palindromic rheumatism ANTIMALARIALS
Cytokine modulators
biological DMARDs
• Cytokines are non-antibody proteins that act as intercellular mediators. Differ from other intercellular mediators and endocrine hormones as they are produced by a number of tissues or cell types rather than specialized glands.
• They act locally as paracrine or autocrine molecules rather than endocrine hormones
• Used in combination with methotrexate = improve chances by 50%
• IL (Interleukin) = any of a class of glycoproteins produced by leucocytes for regulating immune responses.
• TNF-Tumour Necrosis Factor) – involved in systemic inflammation
Adalimumab
(mono-clonal antibody) = Binds to TNF
• Is a full human monoclonal antibody against TNF. They attach to circulating TNF and stop it binding to its receptors
• Indications = Moderate to severe active rheumatoid arthritis when response to DMARDS has been inadequate, or the condition is severe
Infliximab
(monoclonal antibody) (mono-clonal antibody)= Binds to TNF
• Is a chimeric monoclonal antibody (contains both murine and human components) against TNF
• Like Adalimumab it attached to circulating TNF and stop it binding to its receptors
• Indications = Treatment of moderate active rheumatoid arthritis in combination with methotrexate when the response to other DMARDS is inadequate, or the condition is severe
Etanercept
(mono-clonal antibody)= TNF inhibitor
• Contains soluble TNF receptors bound tohuman IgG1
• Works by mopping up excess TNF to dampen down the immune response
• Indications = Treatment of moderate or severe arthritis alone or in combination with methotrexate when the response to other DMARDS is inadequate, or the condition is severe
