Renal Effects of Aspirin - Clinical Pharmacology PDF

Renal e effects: – Anaalgesic neephropathyy: it is cchronic re enal Aspirin in a dose of 75- failu ure due to chronic abuse o of analgessics,...

Renal e effects: – Anaalgesic neephropathyy: it is cchronic re enal Aspirin in a dose of 75- failu ure due to chronic abuse o of analgessics, 150mg is not thought to which produc ce chronicc renal ischhemia duee to have a signnificant effe ect on deccrease syntthesis of reenal PGE2 and PGI2. plasma uraate levels - the – Saltt and wateer retentionn: due to d decrease RBF R British Socciety for Rheu- R matology recommen nd it andd increase aldosteron ne should be continued if re- – Antaagonize diuretic d efffect of d diuretics and quired for cardiovas scular antiihypertensive effects s of β-blocckers: due e to prophylaxiss. deccrease syntthesis of PGE P 2. – Uricc acid excrretion: smaall-to-mode erate doses of asppirin can ↓ uric u acid ex xcretion andd thus con ntraindicate ed in patiennts with gouut. Metabo olic effectts: – High doses cause c oupling of oxidative phosphorrylation → tachycard unco dia and hyp perpyrexia. Uterus s: – Prolongation of pregnancy and d delay of labo or due to inhibition of o PGs nec cessary for uterrine contra action during labor. T The use of NSAAIDs after 20 weeks of pregna ancy is not recoommended d. Therap peutic use es of salicy ylates  As analgesicc and anttipyretic: in mild-to-- mooderate paiin e.g. hea adache, art rthritis, etc. It should notn be used rou utinely as s antipyretic be ecause fevver may bee a norma al pro otective meechanism.  As anti-inflam mmatory and a anti-rrheumatic c: in rheumatic c fever, rheumatoid r d arthritis, osteoarthritis, etc.  As antithrom mbotic: see box. 125   As keratolytic and counter-irritant: – Salicylic acid has keratolytic action and is used for treatment of warts. – Methylsalicylic acid is used as a counter-irritant for local rheumatic pain. Adverse effects of salicylates GIT: – Epigastric pain, nausea and vomiting. – Acute and chronic gastric ulcers (why?). Hepatic: – Mild reversible hepatic injury in adults. – Severe hepatic injury in children: “Reye’s syndrome”. Kidney: – Analgesic nephropathy (why?). – Salt and water retention. – ↓ the diuretic effect of loop diuretics and antihypertensive effects of β-blockers (why?). – Precipitation of acute gout in hyperurecemic patients. Blood: – Increase bleeding tendency: (why?). – Displacement of other drugs from plasma proteins. Uterus: – Prolongation of pregnancy and delay of labor (why?). Hypersensitivity – Bronchospasm (aspirin asthma) in patients with history of reactions: asthma or allergic rhinitis due to accumulation of LTs. Precautions and contraindications  GIT disorders: peptic ulcer, gastritis, hemorrhagic pancreatitis, etc.  Hemorrhagic disorders: hemophilia, thrombocytopenia, etc.  Chronic renal diseases: aspirin may aggravate renal failure  Chronic liver diseases: (those patients have bleeding tendency).  Uncontrolled hypertension: risk of fatal bleeding.  Gout: small-to moderate doses may inhibit uric acid excretion.  Before surgery: aspirin must be stopped at least 7 days before surgery.  Children 100 mg/dl). █ OTHER NSAIDS Diclofenac – One of the most widely used NSAIDs. – Generally, it is less gastric irritant than other NSAIDs but more nephrotoxic. A dose of 150 mg/day can impair renal blood flow and GFR. – It is often combined with PGE analogue misoprostol to decrease gastric ulceration. – Topical gel is available for local rheumatic pain and osteoarthritis of the knee and hands. Sulindac and ketorolac – Both have minimal effect on platelet aggregation. – Sulindac is a prodrug and has long t½. – Ketorolac is a potent analgesic but it can cause severe GIT bleeding. Ibuprofen, fenoprofen, ketoprofen – They have no reported interactions with oral anticoagulants – Ibuprofen is a good alternative to aspirin in children with flu fevers. – Fenoprofen has been reported to induce nephrotoxic syndrome – Long-term use of ibuprofen is associated with an increased incidence of hypertension in women. 127  Indom methacin – It iss a very po otent COX inhibitor b but relaatively moore toxic than oth her NSA AIDs. – It iss approved d to speed the closu ure of patent ductus d arrteriosus in prem mature infants (othherwise it is not used in children); c itt inhibits tthe prod duction of PGs wh hich preve ent clossure of the e ductus. Piroxic cam – It haas long t½ ½ (~ 45 hours). – Likee aspirin and indomethaccin, bleeeding and d ulceratio on are mo ore likely with piro oxicam thaan with oth her NSA AIDs. ▌Sele ective CO OX-2 inhibitors: Celeco oxib, etoric coxib, me eloxicam Selectivve COX-2 inhibitors s are newe er forms of NSAIDss that dire ectly targe et COX-2 enzyme e respon nsible fo or mation and inflamm d pain. Celecoxib iis approxximately 30 0 times more m potennt at inhhibiting COX-2 tha an COX-1 1. Meloxiccam is slightly s se elective foor COX-2 than COX X-1 enzyme e. Seleectivity forr COX-2 re educes th he risk of peptic ulc ceration bu ut does no ot seem tto affect other o adveerse-effectts of NSA AIDs (espec cially the risk r of renaal failure).. Selectivve COX-2 2 inhibitorrs may also incrrease the e risk o of cardiov vascular accidents a s (myocard d- ial infa arction, thrrombosis and a strokee) due to relative in ncrease in TXA2 and platelet ag ggregation n (TXA2 is fformed by COX-1 where PGI2 is formed by b COX-2 ). Rofeco oxib (Vioxxx®) and valdecoxib b were withdraawn from the t market in 2004 an nd 2005 re espectively y because of these potential p adverse e effects. 128  Non-selective COX inhibitors Selective COX-2 inhibitors Mechanism: They inhibit COX-1 (non- They inhibit COX-2 inducible) and COX-2 (inducible) enzyme only (inducible) enzymes Pharmacological Both classes have equal analgesic and antipyretic effects effects: Gastric side effects: Frequent Less frequent Renal side effects: Frequent Frequent Thrombotic Decreased Increased complications: (due to decreased platelet (due to increased platelet aggregation) aggregation) Hypersensitivity Frequent Less frequent reactions: 129