NSAIDs Flashcards
What is the MOA of NSAIDs?
inhibits prostaglandin synthase enzymes COX 2 and COX 1
General adverse effects are renal, cardiovascular etc.
These enzymes contribute to the generation of auto-regulatory and homeostatic paranoids -> inflammation
substrate is Arachidonic Acid
Which COX enzyme is around constitutively and which is mostly responsible for the GI affects? Which is responsible for the therapeutic affects?
COX 1 - constitutive, has housekeeping functions, inhibition is responsible for GI affects
COX 2 - inducible, inflammatory, inhibition is the primary mediator of the therapeutic affects.
what is acetaminophen not considered an NSAID? All NSAIDs do what?
It has weak anti-inflammatory properties.
Inhibit prostanoid biosynthesis
they are anti-pyretic, analgesic and anti-inflammatory
what are the pharmacokinetic class properties of NSAIDs?
Rapid onset, mostly albumin bound and accumulates in sites of inflammation and synovial fluid.
glomerular filtration / tubular secretion of metabolites
half life - 6 to 10 hrs
Which NSAIDs are most selective for Cox2?
Meloxicam
Diclofenac
which NSAIDs are specific/selective to Cox2?
Celecoxib
What are the NSAIDs that are mostly equal affinity (or willing binds) or nonselective for the COX enzymes?
Aspirin Indomethacin Ketorolac Acetaminophen Ibuprofen Naproxen
All have slightly more affinity for Cox1 except Acetaminophen, Ibuprofen and Naproxen, these drugs are more nonselective
which NSAIDs is an irreversible inhibitor of COX1/2?
Aspirin - potentially the reason it makes a good anti-platelet?
what are all the therapuetic uses for NSAIDS?
Analgesia, Antipyretic, Antiinflammatory
Antiplatlet - aspirin
closure of a patent ductus arteriosus
phthalmic inflammation
Niacin tolerability - prevents associated flushing
PG (prostaglandin?) upreg disorders - systemic mastocytosis and Bartter’s syndrome
PGE2 and PGI2 are inihibited by NSAIDs, these are important for which functions? Their inhibition explains what?
Inhibiting gastric secretion by the parietal cells
enhancing mucosal blood flow
promote the secretion of cytoprotective mucus in the intestine
Explains GI related adverse effects like GI ulcers
What are the risk factors for GI adverse effects?
H. Pylori infection
mucosal injury
alcohol consumption
concurrent anticoagulant
concurrent glucocorticoid use
what are the cardiovascular affects of TXA2, PGI2 and PGE2? Why are these affects important?
TXA2 - COX1, induces platelet shape changes, aggregation and local vasoconstriction
PGI2, COX2, inhibits platelet aggregation and causes local vasodilation
PGE2 - COX2, vasodilatory effects on renal arterioles and medullary blood flow, promotes NaCl excretion
This is important because NSAIDs and COX-2 selective increase risk of CV events, especially in high doses
exception - aspirin.
increased risk of edema, hyperkalemia and hypertensive complications
what is the mechanism behind Cox-2 inhibition caused thrombus?
inhibition of PGI2 in endothelial cells allows unopposed platelet aggregation and vasoconstriction mediated by TXA2
what are the renal AE’s associated with tNSAIDs and COX-2 selectives?
worsening renal function, cerebrovascular adverse events and salt/water retention
PG are important in patient with marginally functioning kidneys
what are PGE2 and PGI2 renal functions?
Both (from COX2) cause arteriolar
vasodilation which maintains local RBF and GFR
Both increase medullary blood flow and decrease tubular Na+ reabsorption
PGE2 is responsible for the regulation of salt and water excretion in collecting ducts
PG also cause release of renin
Analgesic nephropathy - causes and presentation
chronic high-dose analgesic
combinations
Aspirin (or other NSAID) \+ Acetaminophen \+ and caffeine or codeine (Excedrin)
headache, dizziness, tinnitus, rash pruritis, eccymosis, purpura
Rarer - agranulocytosis,
thrombocytopenia, aplastic
anemia
Aspirin intolerance/hypersensitivity
vasomotor rhinitis, generalized urticaria, bronchoconstriction, laryngeal edema, flushing, hypotension, show
Asthma - reaction with aspirin in asthma patient can provoke a life threatening reaction - extends to all NSAIDs
NSAIDs use should be cautioned in what type of patients?
elderly
CV risk - hypertension, heart failure, fluid retention
coagulation disorders
GI ulcer or bleed
severe hepatic or renal impairment
contraindication for NSAID use
Asthma
hypersensitivity rxn
coronary artery bypass graft increase the risk of MI and stroke
NSAIDs and pregnancy
associated with miscarriage in the first trimester and prolonged labor in the 3rd.
IN fetus - oligohydraminios
NSAIDs can be used to closed a patent ductus arteriosus
crosses placenta, in breast milk
How do NSAIDs interact with diuretics?
weakens sodium excretion affects and causes hyperkalemia
How do NSAIDs interact with antihypertensives?
Antagonism of anti-HTN
effects
How do NSAIDs interact with ACE inhibitors or ARBs?
Decreases GFR
causes hyperkalemia and bradycardia.
What drug reactions increase GI mucosal injury? (NSAIDS + _______________)
Alcohol
glucocorticoids
Aspirin
What interactions increase risk of bleeding (NSAIDs)?
Anticoagulants
Antiplatlets
Fibrinolytics
SSRI’s
NSAIDs can displace certain narrow therapeutic drugs from albumin and increase toxicity, what are the drugs?
Methotrexate (MTX toxicities)
Warfarin (bleeding)
Sulfonylureas (hypoglycemia)
How do NSAIDs interact with Lithium? ?
can reduce renal excretion of lithium, increasing concentration to toxic levels
Aspirin
Oral: Rapid absorption
Rectal: Slow, erratic
distributes onto platelets
esterase hydrolysis in GI mucosa
half life of 20 min
Aspirin covalently acetylates allosteric sites on COX-1 and COX-2 preventing PG synthesis
antiflammatory affect works by inhibition of COX2
antiplatlet effects - irreversible inhibition of TXA synthesis while after COX2 gets inihibited more protein is made allowing synthesis of prostaglandins
Salicylic Acid
local use only because widely distributes
saturable Hepatic conjugation with renal excretion
Reversible inhibition of COX-1 and COX-2
ointments and patches, mesalamine for IBS/D
Aspirin: Dose-related adverse effects
Most common - Bleeding disorders, peptic ulcer, erosive gastritis and asthma
high doses - Tinnitus, vertigo, hyperventilation, and respiratory alkalosis
Very high doses -Metabolic acidosis, dehydration, hyperthermia, collapse, coma, and death
Hepatotoxicity: Associated with high dose, chronic use; delayed onset; reversible
Reye’s syndrome
Aspirin use in children and adolescents with viral illness
Severe and often fatal
Characterized by the acute onset of encephalopathy, liver dysfunction, and
fatty infiltration of the liver and other viscera
Aspirin triad sensitivity reaction
- chronic rhinosinusitis
- nasal polyps
- severe bronchial asthma
Salicylism:
Acute or chronic poisoning
with aspirin or other salicylates
Serum salicylate values above 40 mg/dL (2.9 mmol/L) are
associated with toxicity.
often in children - can be fatal due to respiratory failure
signs/symptoms - nausea, vomiting, sweating. tinnitus. vertigo, hyperventilation, tachycardia, hyperactivity, agitation, delirium, hallucination, convulsions, lethargy, stupor
mixed respiratory alkaloids and metabolic acidosis
hyperthermia - sign of severe toxicity
chronic salicylate toxicity
avoid high dose use in patient with renal or hepatic impairment
mortality correlates with CNS salicylates
altered mental status - indication for hemodialysis
nausea, vomiting, tinnitus, hyperventilation, mental confusion, tachycardia and fever
Treatment of Salicylate Poisoning
Rapid assessment
Stabilize airway, breathing, and circulation
Supplemental oxygen
activated charcoal for GI tract
metabolic acidosis - alkalinization with sodium bicarbonate
Contraindications, Aspirin & Salicylate Use
GI disease, Coagulation disorders, CHF, hypovolemia, severe hepatic impairment, renal impairment, drug interactions, aspirin sensitivity, hypersensitivity, viral illness is children under 16 and elderly
Acetaminophen
Oral; rectal; intravenous
Glucuronidation (most), CYP2E1 -> NAPQI and Glutathione detoxification, renal excretion
NAPQI is toxic - hepatic necrosis / fulminant liver failure
lasts 4 to 6 hrs for analgesia, antipyretic longer than 6
Potent inhibitor of COX
Good analgesic and antipyretic effects
Weak anti-inflammatory effects
Antidote for Acetaminophen Toxicity
N-Acetylcysteine
I.V. or oral – Restores hepatic glutathione and Enhances the nontoxic sulfate conjugation of acetaminophen
Acetaminophen adverse effects and drug interactions
Hypersensitivity reactions and Analgesic nephropathy
CYP inducers may decrease effectiveness, decreases absorption of cholestryramine
Acetaminophen - Pregnancy, Lactation and kids
safe for occational use when pregnant
enters breast milk
approved for use in kids and infants
Ibuprofen
IV and oral, rapid absorption and high protein binding
hepatic metabolism and renal excretion
half life is 2 hours, up to 50 in infants
antipyretic for 6 to 8 hours
Approved use in children
Interference with aspirin’s antiplatelet effects
Naproxen
Oral, rapid absorption and high protein binding
hepatic metabolism and renal excretion
12 to 17 hours, analgesic in less than hour, antipyretic lasts for 12
Approved use in children - juvenile arthritis as young as 2
Indomethacin
oral - 100%, rectal, IV with high protein binding and widely distributed
Hepatic; significant enterohepatic circulation with Renal, biliary excretion
half life - adutls 2.5, elderly 3.5 and neonates 12 to 20
Onset ~30 minutes; Duration 4-6 hours
Potent COX inhibition - nonselective
anti-inflammatory, closure of patent ductus arteriosus
Adverse Effects - Headache, dizziness, depression, Nausea, vomiting, heartburn; post-op bleeding
Ketorolac
IV, IM, oral, 100% intralnasal and ophthalmic
high protein binding, hepatic metabolism, renal excretion
5 hr half life with 30 min onset
Nonselective COX-1 and COX-2 inhibitor
Potent analgesia
Adverse effects - peptic ulcers. GI bleeding, perforation of stomach or intestines - may occur without warning
Diclofenac
IV, oral with lower bioavialablity, rectal, transdermal. topical - high protein binding and wide distribution
hepatic metabolism, Urine / feces glucuronide and sulfate conjugates
half life 2 hours, patch 12 hours. quick onset depending on formulation
3 to 4 times daily dosing
COX-2 potency similar to
celecoxib with less affinity for COX1
adverse effects - hepatotoxicity, photosensitivity, serious skin reactions and anaphylaxis
Meloxicam
Enolic Acid Derivatives - Preferentially inhibits
COX-2 with high Potency
Relief of osteoarthritis
and rheumatoid arthritis
pain
GI and
cardiovascular risk
CYP2C9-mediated
Celecoxib
COX-2 Selective NSAID - oral with high plasm protein binding, CYP2C9 metabolism and excreted in feces and urine. Long half life 11 hrs
used for pain, dysmenorrhea, anti-inflammation: • Osteoarthritis • Rheumatoid arthritis • Ankylosing spondylitis • Juvenile arthritis (≥ 2 years old)
just as effiecient as other NSAIDs but reduces GI toxicity
Does not precipitate bronchospasm
in aspirin-sensitive individuals
increased risk for thrombus - TXA2 increased, risk for ischemic DVC
renal toxicity - risk factors are volume depletion, heart failure, cerrosis, diabetic neropathy and hypercalcemia
