Miscellaneous

Drugs used in the treatment of gout: Some drugs are used to treat gout flares while other drugs are used to prevent frequent attacks. NSAIDS, steroids and colchicine are used to treat flare ups of gout. NSAIDS like ibuprofen or indomethacin,may have to be used in high doses to treat gout flares. Colchicine is preferably administered within 12-24 hours of a flare onset. Oral prednisone or intra-articular steroids are used to decrease inflammation during a flare. IL1 receptor antagonists anakinra and antibody to IL1, canakinumab, are new drugs that can be used in acute flares when other drugs are not effective.

Uric acid lowering drugs are used to prevent flares and long term complications. When initiating such drugs, there may be a temporary rise in the frequency of flares. Following drugs are used:

Allopurinol: It decreases uric acid levels by inhibiting the enzyme xanthine oxidase. Adverse effects include nausea, diarrhea, elevated liver enzymes, myelosuppression, acute interstitial nephritis, hypersensitivity, SJS, TEN, rashes, gynecomastia and peripheral neuropathy. Allopurinol should not be used with azathioprine and 6-mercaptopurine as their metabolism is dependent on xanthine oxidase.

Febuxostat: It is a non-purine xanthine oxidase inhibitor. It has a better safety profile than allopurinol and can be prescribed in renal failure as well. Adverse effects include skin rashes, hepatotoxicity and nephrotoxicity. It should be used cautiously in patients with cardiovascular diseases.

Uricosuric drugs: They lower uric acid levels by increasing the secretion of uric acid in the urine. Initially, they may precipitate uric acid stones. They include probenecid, sulfinpyrazone, benzbromarone and lesinurad (inhibits URAT1 and OAT4 or organic anion transporters).

Rasburicase: It is a recombinant urate oxidase enzyme that converts uric acid to allantoin, which can be easily excreted in the urine. Rasburicase is primarily used to treat tumor lysis syndrome as it decreases uric acid levels acutely. It can be used to manage tophaceous gout. Adverse effects include anaphylaxis, methemoglobinemia and infusion site reactions. It is contraindicated in G6PD deficiency as hydrogen peroxide is a product of rasburicase.

Lifestyle modification includes weight loss in obese patients, avoiding alcoholic beverages, meat, high protein diet and sugary drinks. Thiazides and loop diuretics increase uric acid levels and should be stopped or substituted if possible.

NSAIDS or non-steroidal anti-inflammatory drugs: Prostaglandins are formed from arachidonic acid by the action of cyclooxygenase or COX-1 and COX-2 enzymes. The COX-1 enzyme is variably expressed in nearly all tissues, and is responsible for regulating normal cellular processes. COX-2 is mainly expressed in inflammatory states. NSAIDS block the COX enzymes, hence reducing the formation of inflammatory prostaglandins (as well as prostanoids and thromboxanes). COX-1 produces prostaglandins and thromboxane A2 which maintains mucosal barrier in GI tract, renal homeostasis, platelet aggregation and other physiological functions. COX-2 produces prostaglandins that are related to inflammation, pain and fever. Aspirin exerts its effects by non-competitive and irreversible inhibition of COX 1 and 2 enzymes, blocking the conversion of arachidonic acid into PGH2. In platelets TXA2 production is entirely COX-1 dependent and COX-1 binding of aspirin permanently prevents the production of TXA2 and subsequently inhibits platelet aggregation for the duration of the platelets’ life cycle of about 7-10 days.

NSAIDS like ibuprofen, diclofenac, ketorolac, indomethacin and naproxen are non-selective, reversible inhibitors of COX 1 and 2. Celecoxib, rofecoxib and valdecoxib are selective COX 2 inhibitors. Paracetamol inhibits the PGH2 synthase enzyme. It has antipyretic and analgesic effects by central mechanism, but is not anti-inflammatory.

Adverse effects include dyspepsia, peptic ulcers, GI bleeding and perforation, sodium retention, edema, renal failure, renal papillary necrosis, stroke, AMI, hypertension and chronic kidney disease. Diclofenac and COX 2 selective blockers like celecoxib are associated with increased risk of cardiovascular events and stroke (due to indirect increase in COX 1 mediated thromboxane synthesis). NSAID induced gastroduodenal ulcers can be prevented by the use of GI protective agents, such as Misoprostol, H2-receptor antagonists or proton pump inhibitors. Use of COX 2 inhibitors causes less GI ulceration compared to non-selective NSAIDS. Children treated with aspirin during a viral infection may develop Reye’s syndrome with fulminant hepatic necrosis and failure. Aspirin overdose causes respiratory alkalosis initially, followed by metabolic acidosis from mitochondrial toxicity. Toxicity of paracetamol is mainly related to the liver.

Drugs used in the prevention and/or treatment of osteoporosis: They can be divided into two broad groups - antiresorptive and anabolic.

Antiresorptive medications slow down the breakdown or resorption of bone by osteoclasts. This helps to prevent bone loss and lower the risk of fracture. They include the drugs below:

1. Bisphosphonates (alendronate, risedronate, ibandronate and zoledronic acid): They bind to bone and suppress bone resorption, and interrupt osteoclast activity directly through several mechanisms including inhibition of acid production, lysosomal enzymes, and the mevalonate pathway and indirectly through their effects on osteoblasts and macrophages. They also inhibit osteoclast recruitment and induce osteoclast apoptosis. They can be used in the prevention and treatment of osteoporosis including glucocorticoid induced type. Zoledronic acid can be given intravenously and can be given annually. Ibandronate can also be given intravenously. Adverse effects include esophagitis (alendronate), atrial fibrillation, atypical femur fractures, osteonecrosis of the jaw and renal failure.
2. Estrogen therapy or combined HRT with estrogen and progesterone for prevention of osteoporosis
3. Calcitonin: Used by nasal spray or injection for the treatment of osteoporosis.
4. Raloxifene and newer SERM **bazedoxifene **(no endometrial hyperplasia) for prevention (both drugs)and treatment (raloxifene only) of osteoporosis
5. Denosumab: It is a human monoclonal antibody that binds to the receptor activator of nuclear factor kappa B ligand (RANKL). RANKL is secreted by osteoblast precursors and binds to its receptor, RANK, located on osteoclasts. The binding of RANKL to RANK promotes osteoclast proliferation, differentiation, activation and survival. Denosumab inhibits RANKL and osteoclastogenesis and markedly reduces bone resorption. It is administered as a subcutaneous injection every 6 monthly. Adverse effects denosumab hypocalcemia, nausea, musculoskeletal pain, skin infections, dermatologic reactions, cystitis and rarely osteonecrosis of the jaw.

Anabolic medications help to form new bone, increase bone density and can also reduce the risk of fractures. Teriparatide is the only drug in this class.

Teriparatide: It is an injectable recombinant human PTH. Like PTH, it acts directly on osteoblasts and cells of the osteoblast lineage. It promotes differentiation of pre-osteoblasts to osteoblasts and inhibits osteoblast apoptosis, as well as triggers the production of several growth factors in bone, like insulin-like growth factor I (IGF-I). Adverse effects include nausea and headache. It may increase the risk of osteosarcoma.