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Pharmacology > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

What is the MOA of NSAIDs?

A

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

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2
Q

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

A

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.

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3
Q

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

A

It has weak anti-inflammatory properties.

Inhibit prostanoid biosynthesis

they are anti-pyretic, analgesic and anti-inflammatory

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4
Q

what are the pharmacokinetic class properties of NSAIDs?

A

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

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5
Q

Which NSAIDs are most selective for Cox2?

A

Meloxicam

Diclofenac

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6
Q

which NSAIDs are specific/selective to Cox2?

A

Celecoxib

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7
Q

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

A 
Aspirin 
Indomethacin
Ketorolac
Acetaminophen 
Ibuprofen
Naproxen

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

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8
Q

which NSAIDs is an irreversible inhibitor of COX1/2?

A

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

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9
Q

what are all the therapuetic uses for NSAIDS?

A

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

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10
Q

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

A

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

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11
Q

What are the risk factors for GI adverse effects?

A

H. Pylori infection

mucosal injury

alcohol consumption

concurrent anticoagulant

concurrent glucocorticoid use

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12
Q

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

A

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

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13
Q

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

A

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

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14
Q

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

A

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

PG are important in patient with marginally functioning kidneys

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15
Q

what are PGE2 and PGI2 renal functions?

A

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

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16
Q

Analgesic nephropathy - causes and presentation

A

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

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17
Q

Aspirin intolerance/hypersensitivity

A

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

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18
Q

NSAIDs use should be cautioned in what type of patients?

A

elderly

CV risk - hypertension, heart failure, fluid retention

coagulation disorders

GI ulcer or bleed
severe hepatic or renal impairment

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19
Q

contraindication for NSAID use

A

Asthma

hypersensitivity rxn

coronary artery bypass graft increase the risk of MI and stroke

20
Q

NSAIDs and pregnancy

A

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

21
Q

How do NSAIDs interact with diuretics?

A

weakens sodium excretion affects and causes hyperkalemia

22
Q

How do NSAIDs interact with antihypertensives?

A

Antagonism of anti-HTN

effects

23
Q

How do NSAIDs interact with ACE inhibitors or ARBs?

A

Decreases GFR

causes hyperkalemia and bradycardia.

24
Q

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

A

Alcohol

glucocorticoids

Aspirin

25
Q

What interactions increase risk of bleeding (NSAIDs)?

A

Anticoagulants

Antiplatlets

Fibrinolytics

SSRI’s

26
Q

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

A

Methotrexate (MTX toxicities)

Warfarin (bleeding)

Sulfonylureas (hypoglycemia)

27
Q

How do NSAIDs interact with Lithium? ?

A

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

28
Q

Aspirin

A

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

29
Q

Salicylic Acid

A

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

30
Q

Aspirin: Dose-related adverse effects

A

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

31
Q

Reye’s syndrome

A

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

32
Q

Aspirin triad sensitivity reaction

A
  1. chronic rhinosinusitis
  2. nasal polyps
  3. severe bronchial asthma
33
Q

Salicylism:

A

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

34
Q

chronic salicylate toxicity

A

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

35
Q

Treatment of Salicylate Poisoning

A

Rapid assessment
Stabilize airway, breathing, and circulation
Supplemental oxygen

activated charcoal for GI tract

metabolic acidosis - alkalinization with sodium bicarbonate

36
Q

Contraindications, Aspirin & Salicylate Use

A

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

37
Q

Acetaminophen

A

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

38
Q

Antidote for Acetaminophen Toxicity

A

N-Acetylcysteine

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

39
Q

Acetaminophen adverse effects and drug interactions

A

Hypersensitivity reactions and Analgesic nephropathy

CYP inducers may decrease effectiveness, decreases absorption of cholestryramine

40
Q

Acetaminophen - Pregnancy, Lactation and kids

A

safe for occational use when pregnant

enters breast milk

approved for use in kids and infants

41
Q

Ibuprofen

A

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

42
Q

Naproxen

A

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

43
Q

Indomethacin

A

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

44
Q

Ketorolac

A

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

45
Q

Diclofenac

A

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

46
Q

Meloxicam

A

Enolic Acid Derivatives - Preferentially inhibits
COX-2 with high Potency

Relief of osteoarthritis
and rheumatoid arthritis
pain

GI and
cardiovascular risk

CYP2C9-mediated

47
Q

Celecoxib

A

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

Pharmacology (23 decks)

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