NSAIDS + gout Flashcards
acetylsalicylic acid (aspirin)
ASA covalently and irreversibly modifies both COX-1 and COX-2 by
acetylating serine-530 in the active site
Acetylation results in a steric block, preventing arachidonic acid from binding
Note: Acetylation of COX-2 retains the COX activity although the reaction
produces a different product, 15-R-HETE
T1/2: ASA: 20 min
salicylate: 3-5 h
irreversible blocks thrombocyte COX -> inability to transcribe new COX -> inhibiton for 8-10 days (life-time of that platelet)
- Salicylate elimination is 1st order at low and moderate doses;
- When total body salicylate > 600mg (>3.5g/d), elimination is zero order
Acetylsalicylic acid (aspirin, ASA)
irreversible COX inhibitor (COX-1>COX-2)
Effects:
Dose-Dependent Effects:
Low: < 300mg
blocks platelet aggregation
Intermediate: 300-2400mg/day
antipyretic and analgesic effects
High: 2400-4000mg/day
anti-inflammatory effects
Indications
art. thrombotic events (prevention and treatment)
mild/moderate pain, fever
inflammatory conditions (but high doses are required, not optimal)
decreases risk for TIA, unstable agina, coronary artery thrombosis, MI, thrombosis after bypass
long term: reduce risk of colon cancer
Kinetics:
good absorption, at low doses significant first pass metabolism
short half life, converted to salicylic acid (by esterases), which is further metabolized in the liver (at higher doses eliminated by zero-order kinetics - risk of accumulation and metabolic acidosis
Intoxication: Metab acidosis, respiratory depression, hyperpyrexia, coma. Treatment: NaHCO3 i.v. + symptomatic.
Other (non-acetylated) salicylates: salicylate (keratolytic + desinfectant), methyl salicylate (ointment to relieve joint/muscle pains, causes hyperemia), diflunisal (analgesic, weak antipyretic effect), 5-ASA (in IBD). magnesium choline salicylate, sodium salcylate, salicyl salicylate
SE (dose-dependant): uricosuric?, tinnitus, central hyperventilation, fever dehydration, metabolic acidosis, Vasomotor collapse, Come, Hypoprothrombinemia, renal and respiratory failure
hepatotoxicity (can be reversible, dose-dependent, or Reye syndrome in children with viral infection)
hyperuricemia (at the regular, 1-2 g/day dose, in gout not recommended),
hyperventillation,
bleeding (inhibition of platelets)
Aspirin overdose: restlessness, irritability, unorganized excessive speech, dizziness, confusion, abnormally excited mood, hallucination, drowsiness, loss of conciousness, double vision, uncontrolled shaking seizures, burning throat pain, vomiting pain, decreased urination
Contraindications: A) Pregnancy B) Haemophilic patients C) Hypersensitivity reaction to aspirin D) Viral infections mainly in children E) Peptic ulcers
colchicin
inhibits migration of inflammatory cells, has considerable toxicity (vomiting, diarrhea, neurotoxicity, liver/kidney damage).
1st line
oral reabsorption and T1/2=9hours
excreted in bile and urine
relieves the pain and inflammation in 12-24 hours without altering the metabolism or exretion of urates and without other analgesic effect
binds the IC protein tubulin, thereby preventing polymerization into microtubules and leading to the inhibition of leukocyte migration and phagocytosis
also inhibits formation of leukotirene B4 and IL-1ß
indications: gout, also used between attacks as prophylaxis, prevents attacks of acute mediterrainean fever, may also be effective in sarcoid arthritis and in hepatic cirrhosis, treat and prevent pericarditis, pleurisy and coronary artery disease,
SE: mediated by inhibiting tubulin polymerization and cell mitosis, often cause diarrhea, occaisionally: nausea, vomiting and abdominal pain,
hepatic necrosis, acute renal failure and DIC and seizure have been observed
rarely: hair loss, BM suppression, peripheral neuritis, myopathy, (death)
mnost severe effects have been associated with IV admin.
allopurinol
purine structure, it inhibits xanthine oxidase and the hypoxanthine-xanthine-uric acid conversion
It is metabolized by xanthine oxidase to (book: alloxanthine?) oxipurinol, a long-acting active metabolite
used between attacks
80% oral bioavailability- serum T1/2 2 hourrs- once a day admin.
1st line in chronic gout
in the beginning colchecine or NSAIDs should be used to achieve level of allopurinol
SE: at the beginning of treatment can provoke acute attack + rarely causes severe allergic reaction (skin with maculopapular leasions)
Inhibits the metabolism of azathioprine and 6-mercaptopurine, increases their toxicity.
nausea, vomiting, diarrhea, peripheral neuritis, necrotizing vasculitis, BM suppression, aplastic anemia, Hepatic toxicity and interstitial nephritis, exfoliative dermatitis (isolated cases), rarely results in cataracts by binding to the lens
interactions: may increase the effect of cyclophosphamide, inhibits the metabolism of probenecid and oral anticoagulants and may increase hepatic iron deposition , cheotherapeutic purins must be reduced when given with allopurinol (75%)
rasburicase
recombinant urate oxidase (uricase) , catalyzes the conversion of uric acid to allantoin. Slowly infused for a few days during chemotherapy.
SE: allergy, fever. gout flare during initial treatment, may develope AB against rasburicase, anaphylaxis, nephrolithiasis, athralgia, muscle spasm, headache anemia, nausea, less frequent: Upper respiratory tract infection, peripheral edema, UTI, diarrhea
must be avoided in patients with G6PD DEFICIENCY DUE TO HEMOLYTIC ANEMIA
metamizole
Metamizole (noraminophenazone)
strong analgesic and antipyretic action after absorption
only mildly reduces inflammation
relative safe GI profile.
relaxes smooth muscles and can effectively alleviate visceral pains
it has limited use in most countries, due to its potential hematologic side effect (agranulocytosis, ~ 1:1.000.000, genetic predisposition?
naproxen
long half life (14 h), used as analgesic (dysmenorrhea) and antiinflammatory agent
not a short half live
free fraction is higher in women than in male
but half life is similar in both sexes
available as a slow release formulation, oral suspension,topical solution and opthalmic solution
SE: rare cases of allergic pneumonitis, leukocytoclastic vasculitis, pseudoporphyria, GI bleeding 2x of ibuprofen
primarily used to alleviate inflammation and pain, usually inhibit COX-1 stronger than COX-2
do not accumulate in the body (except in synovial fluid).
ibuprofen
safer than ASA (can be given to children),
reduces pain and fever, at higher doses also inflammation
first choice drug to close patent ductus arteriosus in preterm babys, (don´t take it when pregnancy?)
low dosis primarily for analgesia
short half life
cream, gel and IV or oral
ibuprofen effects urine output less than indomethacine+ less fluid retention
primarily used to alleviate inflammation and pain, usually inhibit COX-1 stronger than COX-2
do not accumulate in the body (except in synovial fluid).
relative contraindication:
- nasal polyps
- angioedema
- bronchiospastic reactivity to aspirin
SE: aseptic meningitis (SLE patients) and fluid retention
ibuprofen antagonizes the irreversible platelet inhibitoion by aspirin if administered together. may also decrease the total anti-inflammatory effect
agranulocytosis and aplastic anemia (rare)
(dex)ketoprofen
inhibits LOX as well, it has short half life
concomitant administration of probenecid elevates ketoprofen levels and prolongs its half life
primarily used to alleviate inflammation and pain, usually inhibit COX-1 stronger than COX-2
do not accumulate in the body (except in synovial fluid).
major adverse effects: on GI and CNS
phenylbutazone
strong anti-inflammatory effect
considerable side effects, given only in severe inflammatory conditions, systemically for max 1 week (except Bechterew’s disease)
can also be used topically (may cause allergy).
indomethacin
- COX-1>COX-2, inhibits also the migration of inflammatory cells and proliferation of lymphocytes
- also inhibits phospholipase A and C, reduce neutrophil migration and decreases B- and T-cell proliferation
- strong antiinflammatory action, but due to its significant adverse effects (headache, ulcer, cytopenia, edema) it has limited use (severe inflammatory conditions, if other NSAIDs failed or cannot be used)
- Effectively reduces fever in Hodgkin’s diseases
accelerates closure of DUCTUS arteriosus
ophthalmic preparation of conjunctivitis
indication: gingival inflammation (oral rinse preparation)
epidural injection for pain relief
SE: pancreatitis, headache (15-25%), dizziness, confusion, depression, renal papillary necrosis
Short acting strong antiinflammatory compounds
diclofenac
-COX-1 ≈ COX-2
- used as antinflammatory agent and analgesic
- it accumulates in synovial fluid, can be given to children
- SE: elevation of serum aminotransferases, may increase the risk of thrombosis, CV effects
less GI ulcers than others (may be combined with misoprostol decreases ulcer risk but causes diarrhea)
elevated amino-transferases occurs more commonly with this drug
impairs renal blood flow and GFR
opthalmic preparation available
topical gel for solar keratosis
also: oral mouthwash, I.M., suppository
Short acting strong antiinflammatory compounds
meloxicam
meloxicam inhibits somewhat stronger COX-2. (less selective than celecoxib)
Long duration of action (20-70 h T1/2), mainly antiinflammatory drugs
selective COX-2 inhibitors do not affect platelet function while GI safety improves , increase incedence of edema, hypertension , MI
also inhibits synthesis of thromboxane A2
celecoxib
are used mainly as antiinflammatory drugs, celecoxib may cause allergic reaction (sulfonamide structure)
(more) selective COX-2 (20x more than cox-1) inhibition
higher risk of cardiovascular events but fewer ulcer
because it is a sulphonamide it may cause rashes
interacts occasionally witgh warfarin because it is metabilzed by CYP2C9
selective COX-2 inhibitors do not affect platelet function while GI safety improves , increase incedence of edema, hypertension , MI
not effecting the housekkeping COX-1 found in GI, kidney and platelets
black box warning CV risk
Probenecid, sulfinpyrazone
not on the list
they inhibit the reabsorption of uric acid in the proximal tubuli.
Second choice drugs, if allopurinol is poorly tolerated (allergy).
SE: urate stones, at the beginning of treatment they can provoke acute attack, probenecid potentiates the effect of penicillins and increases their toxicity
acute treatment of gout
NSAIDs (except: salicylates, tolmetine)
corticosteroids
Colchicine
