NSAIDs Flashcards
Acetyl Salicylic Acid [Aspirin]
Salicyclic Acid Derivatives
(don’t know chemical groups)
salicylate ester of acetic acid
irreversibly acetylates/inactivates COX in platelets, megakaryocytes
(4-7 days, life of platelet)
anti-inflammatory, antithrombotic effects (inactivates platelets)
Mesalamine (5-amino salicylic acid) [Apriso®]
Salicyclic Acid Derivative
- reversible inhib COX-1 and COX-2
toxicity: GI, CNS, nasophary., hypersn
used for UC
Diflunisal
Salicyclic Acid Derivative
reversible inhib. of COX
analgesic, anti-inflammatory
little antipyretic activity
long 1/2 life (8-12 hrs), inc. pt compliance
less GI SEs, don’t use in pts with anti-ASA sn.
tox: GI (mild), ha, renal, hypersn
Indomethacin [IndocinR]
Acetic Acid Derivative
rev. inhib COX 1 and 2
tox: GI, bleeding, CV, CNS
use: RA (NOT JRA), OA, tocolytic agent
Etodolac
Acetic Acid Derivative
more COX-2 selectivity
tox: GI, less sev.
use: FA, OA, postop analgesic
Diclofenac
Acetic Acid Derivative
rev. inhib COX 1 and 2
tox: GI, CNS
use: RA, OA, anagesia/dysmenorrhea
Tolmetin
Acetic Acid Derivative
rev. inhib COX 1 and 2
tox: GI, CNS, anaphylaxis!
use: RA, JRA*, OA
Ketorolac
Acetic Acid Derivative
rev. inhib COX 1 and 2
tox: GI, CNS
use: mod sev, acute pain, NOT for RA/OA
Ibuprofen [MotrinR, AdvilR]
Propionic Acid Derivative
rev. inhib COX 1 and 2
tox: GI (less than ASA, indometh.), ocular disturbs, hypersn rash, avoid during preg/breast feeding
uses: RA, OA, analgesia, dysmenorrhea, fever
Naproxen [AnaproxR, NaprosynR, AleveR]
Propionic Acid Derivative
rev. inhib COX 1 and 2
tox: GI
Ketoprofen
Propionic Acid Derivative
rev. inhib COX 1 and 2
tox: GI, CNS
use: RHA, OA, analgesia, dysmenorrhea
Oxaprozin [DayproR]
Propionic Acid Derivative
rev. inhib COX 1 and 2
(1x/day)
tox: GI
use: RA, OA
Piroxicam (FeldeneR)
Enolic Acid Derivative: Oxicam
rev. inhib COX 1 and 2
tox: GI
use: RA, OA
Meloxicam (MobicR)
Enolic Acid Derivative: Oxicam
rev. inhib COX 2 > 1
tox: GI
use: OA
Nabumetone
Non acidic compound (Alkanones)
rev. inhib COX 2 > 1
activated by liver
tox: GI, CNS
use: RA, OA
Acetaminophen [TylenolR]
Para aminophenol derivative
weak inhibition COX-1,2,3
antipyretic by acting on hypothalamic heat-regulating center
tox: *hepatotoxicity, *nephrotoxicity, hypersn
uses: antipyretic, analgesic, OA
platelets only have..
COX-1 (not COX-2)
Celecoxib (CelebrexR)
COX-2 INHIBITOR
Acetyl Salicylic Acid [Aspirin] GI absorption mechs
more non-ionized ASA in stomach (where it’s acidic)–>can be absorbed by gastric mucosa cell
in mucosa cell: it’s ionized–>stuck there
ionized in sm. int. BUT larger surf. area so absorbed
Acetyl Salicylic Acid [Aspirin] pharmkin
widely distributed through tissues, binds plasma proteins
can diffuse through placenta and BBB–>CNS effects
Acetyl Salicylic Acid [Aspirin] metab/elim
urinary pH changes from 5 to 8 in kidneys (alkalinization with sodium bicarbonate)
*ASA in ionized state, does not diffuse back, excreted), the renal clearance of free ionized salicylate increases from 2-3% of the amount excreted to about 80%
(The opposite happens in acidic urine)
Acetyl Salicylic Acid [Aspirin] GI SEs
dyspepsia, heartburn, epigastric distress, nausea
less frequently vomiting, anorexia, abdominal pain
inc. with high doses/pre-existing ulcer
occult bleeding, gastric mucosal damage, iron def. anemia (case)
reactivate latent gastric and duodenal ulcers
*most freq. with ASA than other salicylates
case: iron def. anemia enteric-coated reg. strength ASA 1 mg warfarin INR 1.15 tablet in ulcer of gastric antrum tx w. endolcac and ASA -DON't DO: synergy
tx w. lasoprazole (PPI)
Misoprostol (Cytotec®)
prostaglandin E1 analogue
can protect stomach by lowering gastric acid production, anti ulcer with ASA tx
ASA otic effects
tinnitus and hearing loss- *reversible
200-300 μg/mL for anti-inflammatory effects, appearance of tinnitus
indicates adequate plasma concentrations have been reached
ASA hepatic effects
reversible, particularly with previous hepatic impairment and high dose salicylates
-must monitor
ASA renal effects
renal medullary ischemia as a result of inhibition of renal prostaglandin synthesis
ASA CV effects
noncardiogenic pulmonary edema, HTN
CI: CHF pts (esp. w. Na)
ASA hematologic effects
(high doses) decrease hematocrit and plasma
iron concentrations
reduce RBC life span
inc. risk of bleeding
CI in patients with bleeding disorders
*discontinue ASA 5-7 days before sx
ASA hypersensitivity rxns
ASA triad?
Type 1
Urticaria and /or angioedema:
aspirin sensitivity asthma nasal polyps (small doses: 20-30mg) *in asthma pts*
foods with salicylate–>hypersn
ASA ped cautions (also teenagers)
symptoms ??
varicella infections (chicken pox) or influenza-like illnesses is reportedly associated with an increased risk of developing Reye’s syndrome
sudden vomiting, violent headaches and belligerence that may progress to delirium and coma
what to use in peds for an anti-pyretic instead of ASA?
ACETAMINOPHEN
ASA Pregnancy, fertility, lactation
safe use has not been established
can diffuse thru placenta and BBB
could be teratogenic, congenital abnormality associations, use only when potential benefits>possible risks to fetus
caution to nursing mothers
maternal and fetal hemorrhagic complication
ASA intoxication
Chronic salicylate intoxication is also known as salicylism
> than 100 mg/kg daily for 2 days or longer
Acute salicylate OD results from ingestion of a single toxic dose
lethal:
10-30g adults
4g kiddos
ASA intox manifests
Tinnitus and hearing loss
Hyperventilation and CNS effects (kiddos)
metabolic acidosis and respiratory alkalosis
CNS stimulation (salicylate jag), then CNS depression–>resp. failure or CV collapse–>coma/death
principal: acid-base and electrolyte disturbances, dehydration, hyperpyrexia, and either hyperglycemia or hypoglycemia
ASA OD tx
immediately!
symptomatic and supportive
enhance salicylate elimination: lavage
prevent further absorption: activated charcoal (2hr)
correct fluid, e-lyt, A/B disturbances
alkalinize urine to
pH 7.5 or greater enhances salicylate excretion (will be neg. charged): IV sodium bicarbonate:
ASA drug interactions
Protein-bound drugs: compete for binding site
don’t use with anticoagulants/thrombolytic agents–>inc. risk bleeding
corticosteroids inc. clearance of ASA
NSAIDs DON’T used in conjunction with other NSAIDs: synergy (GI effects)
ASA dosage for RA, OA, etc
2.4-3.6 g daily
gram-level! at risk for toxicity
NSAIDs adverse effects: CV
HTN: dose-dependent, from inhibition of COX-2 in the kidney
(use w. caution in HTN, dec. cardiac function pts)
fluid retetion and peripherial edema
NSAIDs adverse effects: CNS
diffuse thru BBB and placenta
dizziness, ha (indomethacin, fenoprofen, ketorolac)
psych
somnolence/drowiness
NSAIDs adverse effects: dermatologic
rashes
NSAIDs adverse effects: elderly
ulcers
spontaneous bleeding
NSAIDs adverse effects: GI
gastric/duodenal ulcers
inhib. PG production (gastric cells have COX1)
*can occur anytime, with or without warning symptoms in patients receiving NSAID therapy chronically
factors assoc. with inc. risk GI ulcer
smoking, etOH
bleeding
NSAIDs adverse effects: hematologic
autoimmune hemolytic anemia (Type II drug allergy)-IgG, IgM with Tolmetin, *reversible
-remove offending drug, tx with corticosteroids
platelet (COX1) aggregation less and dec. duration than with ASA
*reversible
NSAIDs may prolong bleeding time-affect coagulation cascade
NSAIDs hypersn. rxns
rare in ASA (3 hrs after)
manifests as asthma, anaphylaxix, acute resp. distress, rapid fall in BP- shock-like, angioedema, dyspnea, angiitis
NSAIDs adverse effects: lactation
DON’T use NSAIDS in nursing mothers because the potential effects on the infant’s cardiovascular system
NSAIDs adverse effects: renal
COX 2 constitutively expressed
NSAIDs inhibit COX-2–>inhibit renal PG synthesis:
progressive renal impairment
Acute renal insufficiency
Interstitial nephritis
hyper Na+, K+
Papillary necrosis (chronic renal injury)
NSAIDs adverse effects: pregnancy
- inhibit prostaglandin E2 synthesis may induce the closure of the fetal ductus arteriosus
- can prolong labor (avoid, esp during 3rd trimester)
use: FDA-labelled NSAIDS for closure of patent ductus arteriosus in
premature infants, are either indomethacin (ha) or ibuprofen
NSAIDs drug interaxns
All NSAIDs bind to plasma proteins
Celecoxib, last COX-2 standing
inhibition of prostaglandin synthesis, via inhibition of cyclooxygenase-2 (COX-2)
Metabolism is via cytochrome P450 2C9 (drug interactions)
Elim by hepatic metabolism
celecoxib CIs
not for pts who have allergic-type reactions to sulfonamides
OR experience asthma, urticaria or allergic-type reactions after taking aspirin or other NSAIDs
celecoxib adverse effects
GI: less since not COX 1 inhib, but still some GI CNS resp skin psych
endothelial cells have
COX-1 and COX-2–>PGI2
vasodilaiton and declumping
platelets have
COX-1–>TXA2
vasoconstriction and aggregation (via TXA2)
*not inhib. by selective COX-2 inhibitors, had to remove from market exc. celecoxib (milder)
acetaminophen affects
paracetamol
affect on fever by action on hypothalamic
heat-reg center
weakly inhibits COX1, 2, 3? (spliced)
acetaminophen pharmkin
metabolized by the hepatic microsomal
enzymes to acetaminophen sulfate and acetaminophen glucuronide (typ. excreted)
- small amount metab by cytP450 to N-acetyl-p-benzoquinoneimine, which is highly reactive to cellular proteins and thus becomes toxic to both liver and kidney (norm. detox by glutathione)
- toxicity in large amounts*
acetamin SEs
hepatotoxicity*** (reversible) potentially fatal hepatic centrilobular necrosis
nephrotoxicity
acetominophen OD
antidote?
gastric lavage
oral N-acetylcystein (Mucomyst)- restores glutathione levels-neutralizes toxic metabolites
use w.in 8 hrs post-ingestion
ASA used for
mild-mod pain, fever, inflamm. disease
also: prevention of arterial and venous thrombosis
NSAIDs
mostly used as anti-inflammatory agents
both analgesic and antipyretic properties
reversible inhibition of COX 1 and 2
absorbed rapidly and completely, pKa 3.5-6.3 (acidic)
protein bound, variable half life
NSAIDs for RA
all except Ketorolac, Meloxicam, Mefenamic acid
NSAIDs for OA
all except Ketorolac and Mefenamic acid
JRA tx
Tolmetin and naproxen
Ibuprofen hypersensitivity
severe rxns w. fever, rash, abd pain, ha, N/V, liver damage and meningitis in pts w. SLE or other collagen diseases
may not start immediately
celecoxib uses
OA, RA, acute pain, dysmenorrhea, familial adenomatous polyposis
why other selective COX 2 drugs were taken off the market
CV problems from uninhibited COX-1–>platelets–>prod. TXA2–>vasoconstriction and aggregation
COX-1 inhibitor:
ibuprofen–>inhib COX1–>prevents TXA2 release–>inhibits platelet aggregation and vasoconstriction
endothelium cells (COX-2) NOT inhibited by ibuprofen–>still releases PGI2–>unopposed vasodilation and declumping
COX-2 inhibitors: celecoxib
affects endothelial cells (COX-2)–>NO release PGI2–>inhibits vasodilation and decamping
BUT platelets (COX-1) still release TXA2-->*vasoconstriction and aggregation UNOPPOSED*-->CV problems
all COX-2s removed except celecoxib: milder effects
don’t take more than ?? g acetaminophen/day
alcoholics?
acetominophen uses
analgesic
antipyretic
weaker anti-inflammatory than ASA
mild-mod pain
OA
