pharma fouda 2_p37-41.pdf

Part 5 5: Drug g therap py of go out █ Basiic information Gout iss a form of inflammatoory arthritiss due to deposittion of mo onosodiumm urate cryystals in the joii...

Part 5 5: Drug g therap py of go out █ Basiic information Gout iss a form of inflammatoory arthritiss due to deposittion of mo onosodiumm urate cryystals in the joiint tissue.. It is caaused by chronic hyperuricemia (u uric acid > 7 mg/dll = 0.42 mmol/L L). emistry Bioche  Uric c acid is the end product p o f purine mettabolism byb xanthene e oxidase e enzyme.  Thee majorityy of body’s uric acid is exccreted by the t renal PCT. P Som me drugs (e.g g. diuretics) may y interfer e with exccretion of uric acid at this ssegment lead ding to its retention.  Thee renal excretion e of uric acid is enhhanced by alkalization of urine. Causes s of hyperruricemia  Deccreased uric u acid excretion: e account for 9 90% of ca ases of prim mary gout: – Drugs: e.g. diurettics, aspirin, pyrazina amide, ethambutol. – Kidneyy diseases.  Incrreased uric acid pro oduction: – High protein diet. – During treatmentt of some hhematologic maligna ancies (e.g.. leukemia)) due to tissue breakdown b n (tumor lyysis syndro ome). – Sex-linnked uricac ciduria (Lessch-Nyhann syndrome).  xed causes: alcohol.. Mix Pathog genesis off gouty artthritis  Whe en serum uric acid d increase es, monosodium ura ate crystalls are selectively preccipitated in n, and arouund the joiint tissue causing c irritation and d inflammattion.  PNLLs and ma acrophages come an nd phagoc cytose the "foreign" uric acid crystals cau using swelling and infflammation n of the artticular tissue.  Leu ukocytes eventually e die d with th he release of proteolytic enzym mes and innflamm- atorry mediatoors (e.g. LT TB4, IL1, PGGs, etc) caausing seve ere inflammmation. 136 █ HYP POURICEM MIC DRUG GS ▌Uric cosuric drugs: d Prrobeneciid anism of action: Mecha a it ha as biphasic c action:  In SSmall doses: it inhib bits tubula ar Secretiion of org ganic acidds (e.g. uric acid, pennicillin, rifam mpin) by in nhibiting orrganic acid d transportters in tubuular cells.  In la aRge dose es (≥500 mg m twice/da ay): it inhib bits tubular Reabsorrption of uricu acid by iinhibiting the urate trransporter (URAT1), leading to ↑ excretio on of uric acid. a Therap peutic use es  As a uricosuriic agent in chronic goout.  To p prolong the t½ of some acidic drugs e.g. penicillin and d rifampicin n by inhibittion of theiir renal exc cretion. Advers se effects – Gasstric irritatio on, skin ra ash, and ra arely intersttitial nephrritis and ap plastic ane emia. 137  – If given during the acute attack, it can aggravate the inflammation because rapid lowering of serum uric acid during the acute attack causes mobilization of uric acid crystals from the tissue stores and aggravates the acute inflammation. Precautions during the use of uricosuric drugs – They should not be used during the acute attack but 2-3 weeks after the acute attack has been subsided. – Excess fluids and alkalinization of urine help uric acid excretion and prevent stone formation. – Aspirin may decrease uric acid excretion and antagonize probenecid. ▌Inhibitors of uric acid synthesis: Allopurinol Mechanism of action  Allopurinol is a synthetic purine analogue. It inhibits xanthine oxidase enzyme leading to inhibition of uric acid synthesis.  It has long duration of action because both the parent compound and its metabolite are potent inhibitors of xanthine oxidase. Therapeutic uses  Recurrent attacks of gout (more than 2 attacks per year): the target uric acid level is 5 mg/dl (0.3 mmol/L). Start with 100 mg once daily then gradually increase the dose every 1-2 weeks to reach 300 mg/d.  As an adjuvant therapy during treatment of hematologic malignancies (e.g. leukemia) to prevent hyperuricemia resulting from tissue destruction.  Patients with Lesch-Nyhan syndrome should receive allopurinol for life. Adverse effects – Gastric irritation and hypersensitivity reactions (skin rash). – Precipitation of acute gout at the start of therapy due to mobilization of the deposited uric acid crystals from tissue stores leading to transient hyperuricemia Precautions: – Do not give allopurinol during the acute attack of gout. – Give prophylactic cover with NSAIDs or colchicine to avoid exacerbation of gout at the start of therapy. Drug interactions Mercaptopurine, azathioprine, and theophylline are metabolized by xanthine oxidase, and coadministration with allopurinol will dramatically increase levels of these drugs. 138 ▌Increase uric acid metabolism: Pegloticase  Pegloticase is a recent recombinant form of porcine uricase, the enzyme that converts uric acid into the water-soluble allantoin.  It is given as 8 mg i.v. /2 weeks. It can lower serum uric acid within 24 hours..  It is indicated in severe gout not responding to other agents. █ ANTI-INFLAMMATORY DRUGS Colchicine Mechanism of action  Colchicine is a plant alkaloid. It binds to intracellular microtubular system leading to inhibition of leukocyte motility, phagocytosis, and cell division (mitotic blocker).  It inhibits the release of LTB4 and other mediators by leukocytes. Therapeutic uses  Acute attacks of gout: – It is specific for gouty arthritis. Other arthritic pains are not relieved by Familial Mediterranean colchicine. Fever (FMF) – It has slower onset than NSAIDs and Also known as (recurrent corticosteroids. Reduction of polyserositis) is an inflammation and relief from pain occur autosomal recessive disorder 12–24 hours after oral administration. which typically presents by – Because of its slow onset and high the second decade. It is toxicity, it is not a first-choice drug in characterized by recurrent acute gouty arthritis unless the patient episodes of abdominal pain has contraindication for NSAIDs or (due to peritonitis), pleurisy, corticosteroids. pericarditis, arthritis. Attacks typically last 1-3 days. – The recommended dose is 1.2 mg orally (2 tablets) initially followed by one tablet (0.6 mg)/ 12 hour until the attack resolves.  Familial Mediterranean fever (FMF): by an unclear mechanism. Adverse effects – The most common: diarrhea. Why? Because the GIT epithelium has rapid rate of turnover. High oral doses of colchicine will inhibit this continuous renewal of GIT epithelium (by inhibiting cell 139  division) leading to accumulation of toxins and bacterial products with diarrhea. – The most rare: alopecia and myopathy. – The most serious: aplastic anemia and agranulocytosis (bone marrow depression). NSAIDs Indomethacin and naproxen – Indomethacin and naproxen are FDA approved NSAIDs for acute gouty arthritis although other NSAIDs can also work (but not aspirin). – They provide symptomatic relief in acute attacks faster than colchicine. – Their dose must be reduced if taken with probenecid because probenecid inhibits their renal excretion. Corticosteroids – They are used as anti-inflammatory agents when colchicine and NSAIDs are not sufficient to control the acute attacks or when they are contraindicated. – For more details about the mechanism, see endocrine pharmacology. 140