NSAIDs

Question 1

What is the MOA of NSAIDs?

Answer 1

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

Question 2

Which COX enzyme is around constitutively and which is mostly responsible for the GI affects? Which is responsible for the therapeutic affects?

Answer 2

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.

Question 3

what is acetaminophen not considered an NSAID? All NSAIDs do what?

Answer 3

It has weak anti-inflammatory properties.

Inhibit prostanoid biosynthesis

they are anti-pyretic, analgesic and anti-inflammatory

Question 4

what are the pharmacokinetic class properties of NSAIDs?

Answer 4

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

Question 5

Which NSAIDs are most selective for Cox2?

Answer 5

Meloxicam

Diclofenac

Question 6

which NSAIDs are specific/selective to Cox2?

Answer 6

Celecoxib

Question 7

What are the NSAIDs that are mostly equal affinity (or willing binds) or nonselective for the COX enzymes?

Answer 7

Aspirin 
Indomethacin
Ketorolac
Acetaminophen 
Ibuprofen
Naproxen 

All have slightly more affinity for Cox1 except Acetaminophen, Ibuprofen and Naproxen, these drugs are more nonselective

Question 8

which NSAIDs is an irreversible inhibitor of COX1/2?

Answer 8

Aspirin - potentially the reason it makes a good anti-platelet?

Question 9

what are all the therapuetic uses for NSAIDS?

Answer 9

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

Question 10

PGE2 and PGI2 are inihibited by NSAIDs, these are important for which functions? Their inhibition explains what?

Answer 10

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

Question 11

What are the risk factors for GI adverse effects?

Answer 11

H. Pylori infection

mucosal injury

alcohol consumption

concurrent anticoagulant

concurrent glucocorticoid use

Question 12

what are the cardiovascular affects of TXA2, PGI2 and PGE2? Why are these affects important?

Answer 12

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

Question 13

what is the mechanism behind Cox-2 inhibition caused thrombus?

Answer 13

inhibition of PGI2 in endothelial cells allows unopposed platelet aggregation and vasoconstriction mediated by TXA2

Question 14

what are the renal AE’s associated with tNSAIDs and COX-2 selectives?

Answer 14

worsening renal function, cerebrovascular adverse events and salt/water retention

PG are important in patient with marginally functioning kidneys

Question 15

what are PGE2 and PGI2 renal functions?

Answer 15

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

Question 16

Analgesic nephropathy - causes and presentation

Answer 16

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

Question 17

Aspirin intolerance/hypersensitivity

Answer 17

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

Question 18

NSAIDs use should be cautioned in what type of patients?

Answer 18

elderly

CV risk - hypertension, heart failure, fluid retention

coagulation disorders

GI ulcer or bleed
severe hepatic or renal impairment

Question 19

contraindication for NSAID use

Answer 19

Asthma

hypersensitivity rxn

coronary artery bypass graft increase the risk of MI and stroke

Question 20

NSAIDs and pregnancy

Answer 20

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

Question 21

How do NSAIDs interact with diuretics?

Answer 21

weakens sodium excretion affects and causes hyperkalemia

Question 22

How do NSAIDs interact with antihypertensives?

Answer 22

Antagonism of anti-HTN

effects

Question 23

How do NSAIDs interact with ACE inhibitors or ARBs?

Answer 23

Decreases GFR

causes hyperkalemia and bradycardia.

Question 24

What drug reactions increase GI mucosal injury? (NSAIDS + _______________)

Answer 24

Alcohol

glucocorticoids

Aspirin

Question 25

What interactions increase risk of bleeding (NSAIDs)?

Answer 25

Anticoagulants Antiplatlets Fibrinolytics SSRI's

Question 26

NSAIDs can displace certain narrow therapeutic drugs from albumin and increase toxicity, what are the drugs?

Answer 26

Methotrexate (MTX toxicities) Warfarin (bleeding) Sulfonylureas (hypoglycemia)

Question 27

How do NSAIDs interact with Lithium? ?

Answer 27

can reduce renal excretion of lithium, increasing concentration to toxic levels

Question 28

Aspirin

Answer 28

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

Question 29

Salicylic Acid

Answer 29

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

Question 30

Aspirin: Dose-related adverse effects

Answer 30

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

Question 31

Reye’s syndrome

Answer 31

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

Question 32

Aspirin triad sensitivity reaction

Answer 32

1. chronic rhinosinusitis 2. nasal polyps 3. severe bronchial asthma

Question 33

Salicylism:

Answer 33

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

Question 34

chronic salicylate toxicity

Answer 34

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

Question 35

Treatment of Salicylate Poisoning

Answer 35

Rapid assessment Stabilize airway, breathing, and circulation Supplemental oxygen activated charcoal for GI tract metabolic acidosis - alkalinization with sodium bicarbonate

Question 36

Contraindications, Aspirin & Salicylate Use

Answer 36

GI disease, Coagulation disorders, CHF, hypovolemia, severe hepatic impairment, renal impairment, drug interactions, aspirin sensitivity, hypersensitivity, viral illness is children under 16 and elderly

Question 37

Acetaminophen

Answer 37

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

Question 38

Antidote for Acetaminophen Toxicity

Answer 38

N-Acetylcysteine I.V. or oral -- Restores hepatic glutathione and Enhances the nontoxic sulfate conjugation of acetaminophen

Question 39

Acetaminophen adverse effects and drug interactions

Answer 39

Hypersensitivity reactions and Analgesic nephropathy CYP inducers may decrease effectiveness, decreases absorption of cholestryramine

Question 40

Acetaminophen - Pregnancy, Lactation and kids

Answer 40

safe for occational use when pregnant enters breast milk approved for use in kids and infants

Question 41

Ibuprofen

Answer 41

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

Question 42

Naproxen

Answer 42

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

Question 43

Indomethacin

Answer 43

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

Question 44

Ketorolac

Answer 44

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

Question 45

Diclofenac

Answer 45

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

Question 46

Meloxicam

Answer 46

Enolic Acid Derivatives - Preferentially inhibits COX-2 with high Potency Relief of osteoarthritis and rheumatoid arthritis pain GI and cardiovascular risk CYP2C9-mediated

Question 47

Celecoxib

Answer 47

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