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Therapeutics > Exam 1 NSAIDS > Flashcards

Exam 1 NSAIDS Flashcards

1
Q

Which NSAID has the longest history?

A

aspirin

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2
Q

What is inflammation?

A
  1. occurs upon infections or noxious stimuli
  2. eliminates harmful agents and necrotic cells
  3. initiates the healing process
  4. may injure normal tissues → too strong response, prolonged response, inappropriate response
  5. signs → heat, redness, swelling, pain, loss of function
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3
Q

What are the chemical mediators of inflammation?

A
  1. vasoactive amines → histamine and serotonin
  2. eicosanoids → prostaglandins, leukotrienes, and lipoxins
  3. platelet activating factor (PAF)
  4. cytokines → TNF, interleukin (IL), chemokines → acute inflammation and chronic inflammation is interferon gamma
  5. complement components → C3a and C5a
  6. coagulation and kinin systems → bradykinin, thrombin, fibrinopeptides
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4
Q

What are eicosanoids?

A
  1. short lived mediators (seconds to minutes)
  2. autocrine and paracrine signaling
  3. bind to GPCRs in target cells → generation of cAMP is dilation and release of calcium is constriction
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5
Q

What does PGE2 do?

A

dilate blood vessels and bronchi and has oxytocic dilation of uterus

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6
Q

What does PGF2alpha do?

A

constricts blood vessels and bronchi and oxytocic constriction of uterus

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7
Q

What does PGI2 do?

A

dilates blood vessels and inhibits platelet aggregation

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7
Q

What does PGI2 do?

A

dilates blood vessels and inhibits platelet aggregation

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8
Q

What does TXA2 do?

A

constricts blood vessels and aggregates platelets

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9
Q

What is arachidonic acid?

A
  1. 20 carbon polyunsaturated fatty acids that are essential → get it from food
  2. most abundant and important precursor of eicosanoids
  3. released from membrane phospholipids by phospholipase A2
  4. corticosteroids suppress the production of phospholipase A2 → will shut down the production of eicosanoids
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10
Q

What are the 4 different pathways of the oxygenation of arachidonic acid?

A
  1. PGH synthase COX pathway → prostaglandins, thromboxanes
  2. lipoxygenase pathway → leukotrienes
  3. epoxygenase (cytochrome P450) pathway
  4. isoprostane pathway (free radical reaction)
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11
Q

What is PGH synthase?

A
  1. PGH synthase has both cyclooxygenase and hydroperoxidase activities
  2. COX reaction → radical mediated
  3. hydroperoxidase reaction → conversion of hydroperoxyl group (OOH) to hydroxyl group (OH)
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12
Q

What are the isoforms of PGH synthase?

A
  1. PGH synthase 1 → COX 1 which is constitutively expressed in various tissues and have housekeeping functions like gastric cytoprotection
  2. PGH synthase 2 → COX 2 which is expressed upon stimulus in inflammatory and immune cells and stimulated by growth factors, tumor promoters and cytokines
  3. inhibited by NSAIDS
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13
Q

What is the precursor to make the different prostaglandins?

A

PGH2

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14
Q

What is the difference between prostaglandins and thromboxanes?

A

prostaglandins → in vascular endothelia, PGI2 is vasodilator and inhibits platelet aggregation → if too much bleeding may occur
thromboxanes → in platelets, TXA2 is vasoconstrictor and induces platelet aggregation → if too much can increase heart attack or stroke

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15
Q

What is alprostadil?

A
  1. PGE1
  2. relaxes smooth muscles and expand blood vessels
  3. used for erectile dysfunction by injection or as a suppository
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16
Q

What is misoprostol?

A
  1. PGE1 derivative
  2. cytoprotective to prevent peptic ulcer
  3. terminates early pregnancy in combination with mifepristone (RU-486)
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17
Q

What is latanoprost?

A
  1. topically active PGF2a derivative (prodrug)
  2. contricts blood vessels
  3. used in ophthalmology to treat high pressure inside the eye (glaucoma)
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18
Q

What is prostacyclin (epoprostenol)?

A
  1. PGI2
  2. powerful vasodilator and inhibitor of platelet aggregation
  3. used to treat pulmonary arterial hypertension by IV injection or inhalation
  4. should not be used with anticoagulants which can induce bleeding disorder
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19
Q

What are the activities of NSAIDS?

A
  1. anti-inflammatory
  2. analgesic
  3. antipyretic
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20
Q

What are the uses of NSAIDS?

A
  1. treatment of moderate pain, fever, and inflammation from acute inflammation
  2. treatment of early stage RA and OA
  3. cancer prevention by preventing unnecessary inflammation
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21
Q

What is the mechanism of action for NSAIDS?

A
  1. inhibition of PGHS or COX which catalyzes the formation of prostaglandins
  2. many NSAIDS inhibit both COX 1 and COX 2
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22
Q

What are the classes of NSAIDS?

A
  1. salicylates → aspirin
  2. arylacetic acids → indomethacin
  3. arylpropionic acids → ibuprofen
  4. non-carboxylate NSAIDS → meloxicam
  5. COX 2 selective NSAIDs → celecoxib
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23
Q

What are side effects of NSAIDs?

A
  1. GI
  2. blood coagulation
  3. renal
  4. hypersensitivity
  5. Reye’s syndrome
  6. CNS
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24
Q

What are the GI side effects of NSAIDs?

A
  1. mild → dyspepsia, nausea, vomiting
  2. severe → blood loss, ulcer, GI hemorrhage
  3. mechanism → acidity of NSAID is the primary insult and the secondary insult is the inhibition of synthesis of cytoprotective prostaglandins in gastric mucosa + inhibits platelet aggregation (more bleeding)
  4. administration with food may decrease side effects
  5. aspirin = indomethacin > naproxen > sulindac (in terms of side effects)
25
Q

If taking an NSAID for prolonged period, doctor will prescribe what kind of NSAID?

A

one that has less side effects like sulindac

26
Q

What are the blood coagulation side effects associated with NSAIDS?

A
  1. aspirin prolongs bleeding time by irreversible inhibition of COX1 and reduced formation of thromboxane
  2. aspirin use before surgery or tooth extraction is contraindicated
  3. can be used to some patients with cardiovascular disease to prevent blood coagulation (low dose with no anti-inflammatory effects) to reduce heart attack and stroke
27
Q

What are the renal side effects of NSAIDs?

A
  1. little effect in normal patients

2. renal failure in patients with cardiovascular, hepatic, and renal diseases

28
Q

What is the hypersensitivity related to NSAIDs?

A
  1. characterized by skin rashes, hives, angioedema, and asthma like syndrome
  2. occurs in 0.3% of the population (10% in asthmatics) → patients have increased leukotriene level and if take NSAID, will block prostaglandin synthesis and production of leukotrienes will increase to cause the skin rash, hives, etc
29
Q

What does 5-lipoxygenase do?

A

produce leukotrienes

30
Q

Why are platelets most affected by aspirin?

A

platelets have no nucleus so they can’t regenerate COX enzymes

31
Q

What is Reye’s syndrome?

A
  1. specific to salicylates
  2. is a rare acute life threatening condition characterized by vomiting, delirium, and coma (20-30% mortality)
  3. brain damage is common in survivors
  4. occurs in children who have had the flu or chicken pox that took aspirin to reduce their fever
  5. aspirin should not be given to anyone under 12 who has a fever
32
Q

What are the CNS effects of NSAIDs?

A

tinnitus, dizziness, headache

33
Q

How do you prevent the GI side effects?

A
  1. misoprostol (synthetic PGE analog) → used prophylactically to prevent NSAID induced gastric ulcers in patients at high risk
  2. proton pump inhibitors (esomeprazole) → greatly reduce acid secretion in stomach and protect against ulceration in the absence of COX 1 activity
  3. combo products for less side effects like naproxen/esomeprazole, naproxen/misoprostol, and diclofenac/misoprostol
34
Q

What drug interactions do NSAIDs have?

A
  1. many NSAIDs are highly bound to serum albumin (90-99%)
  2. NSAIDs may compete for serum albumin binding sites with other drugs that are highly bound to these sites
  3. example: combo with oral anticoagulants → increases plasma concentration of free anticoagulant, the ability of salicylate to produce GI bleeding and inhibit the clotting mechanism aggravates the problem, want to decrease dose of anticoagulant
35
Q

What is the SAR in NSAIDs?

A
  1. commonly contains an acidic group (like COOH)
  2. acidic group is located one carbon atom adjacent to aromatic or heteroaromatic ring
  3. substitution of methyl group on the carbon atom separating the acidic group from the aromatic ring increases activity
  4. second area of lipophilicty that is noncoplanar with the aromatic or heteraromatic ring enhances activity (has to be kinked)
36
Q

What is salicylic acid?

A
  1. a salicylate that was first obtained in 1838 in willow and poplar bark
  2. used in 1875 as antipyretic/antirheumatic agent
  3. slightly acidic and absorbed as an ionic form in the small intestine and from the stomach as acid form
  4. inhibits COX1 and COX2 reversibly
  5. may suppress COX2 induction
37
Q

What is aspirin?

A
  1. salicylate that was used as a drug in 1899
  2. the only NSAID that irreversible inhibits COX by acetylating a serine residue in the active site
  3. absorbed largely as intact form but hydrolyzed rapidly to salicylate by plasma esterase
  4. 2 fold more potent than salicylic acid as analgesic/antipyretic
  5. blocks platelet aggregating factor TXA2 effectively and increases the risk of bleeding but also reduces the risk of MI
  6. not stable in solutions (because of ester)
38
Q

What is salsalate?

A
  1. dimer of salicylic acid → salicylate
  2. hydrolyzed to two salicylates in the small intestine and absorbed
  3. does not cause GI bleeding → does not suppress PGE in stomach
  4. prodrug
39
Q

What is diflunisal?

A
  1. salicylate → more potent analgesic than aspirin but produces fewer side effects
  2. less antipyretic activity than aspirin (doesn’t work well in brain)
  3. 3-4 fold longer half life than aspirin
40
Q

What is indomethacin?

A
  1. one of the most potent NSAIDS in use
  2. high incidence of side effects
  3. not suitable for long term use
  4. not stable in solution due to the hydrolysis of the amide bond
  5. arylacetic acid
41
Q

What is sulindac?

A
  1. prodrug → the sulfoxide group is reduced to the active sulfide intermediate in the circulatory system
  2. less GI side effects
  3. suitable for long term use to treat chronic inflammation
  4. arylacetic acid
42
Q

What is etodolac?

A
  1. arylacetic acid
  2. pyranocarboxylic acid
  3. as potent as indomethacin
  4. somewhat selective for COX2
  5. less GI bleeding
  6. suitable for long term use to manage osteoarthritis
43
Q

What is diclofenac?

A
  1. arylacetic acid
  2. the most widely used NSAID in the world → side effects are mild
  3. as potent as indomethacin
  4. somewhat selective for COX2
  5. inhibits both COX and lipoxygenase pathways → can be used for people with hypersensitivity because of the lipoxygenase
44
Q

What is ibuprofen?

A
  1. arylpropionic acid
  2. popular OTC analgesic
  3. more potent than aspirin but less than indomethacin
  4. moderate degrees of gastric irritation
  5. alpha methyl group enhances it activity and reduces many of its side effects
  6. is a bioequivalent racemic mixture → S enantiomer possesses greater activity in vitro but R enantiomer is converted to S enantiomer enzymatically in vivo
45
Q

What is naproxen?

A
  1. arylpropionic acid
  2. S enantiomer
  3. more potent than ibuprofen
  4. moderate degrees of gastric irritation
  5. used to treat rheumatoid arthritis and osteoarthritis
  6. can use long term
46
Q

What is ketorolac?

A
  1. arylpropionic acid
  2. cyclized heteroarylpropionic acid derivative
  3. for short term management of moderate to severe pain
  4. analgesic activity similar to centrally acting analgesics → like opioids in painkilling
  5. widely accepted alternative to narcotic analgesics
  6. not for long term use due to side effects
47
Q

What is nabumetone?

A
  1. non-carboxylate
  2. nonacidic prodrug
  3. metabolized rapidly to 6-methoxynaphthalene-acetic acid (6-MNA) which is an effective inhibitor of COX
  4. minimum gastric side effects
  5. potent anti-inflammatory but weak analgesic activity → can’t get to hypothalamus
  6. good like naproxen
48
Q

What is meoxicam?

A
  1. non-carboxylate and belongs to the oxicam class which resembles the peroxy radical intermediate in COX
  2. enolic acid
  3. long acting, single daily use
  4. as potent as indomethacin
  5. somewhat selective for COX2
49
Q

What are the more potent NSAIDs?

A

sulindac < diclofenac < indomethacin < meloxicam (doses are smaller as it goes from left to right)

50
Q

What are the consequences of COX1 inhibition?

A
  1. stomach irritation and ulceration → decreased production of cytoprotective prostaglandins and bleeding from inhibition of thromboxane formation
  2. blockade of platelet aggregation
  3. inhibition of uterine motility
  4. inhibition of prostaglandin mediated renal function
  5. hypersensitivity reactions
51
Q

Why do we want to inhibit COX2 more?

A

gives anti-inflammatory effects with lower incidence of gastric ulceration compared to COX1

52
Q

COX inhibitor graph

A

right side → COX 1 selective

left side → COX 2 selective

53
Q

What are selective COX2 inhibitors?

A
  1. valine in the NSAID binding site of COX2 is substituted for isoleucine in that of COX1 (isoleucine is larger)
  2. selective COX2 inhibitors exploit the larger NSAID binding site in COX2 with larger and relatively rigid substituents (since COX 1 has isoleucine and COX has valine)
  3. FDA classifies only Celecoxib, rofecoxib (good for long term use), and valdecoxib as selective COX2 inhibitors
54
Q

What are the side effects of selective COX2 inhibitors?

A
  1. results in elevated blood pressure and accelerated atherogenesis (heart attack)
  2. constitutive expression of COX2 in endothelium is critical for production of PGI2
  3. selective COX2 inhibitors do not affect production of TXA2 by COX1 → heightened thrombotic response on the rupture of atherosclerotic plaque
  4. selective COX2 inhibitors increase cardiovascular hazard
  5. celecoxib is the only one still on the market
55
Q

What is celecoxib?

A
  1. brand name is Celebrex
  2. first NSAID to be marketed as a selective COX2 inhibitor
  3. used for osteoarthritis and rheumatoid arthritis
  4. good efficacy against pain, inflammation, and fever
  5. as potent as naproxen
  6. less risk of GI side effects
  7. no antiplatelet activity → doesn’t inhibit COX1
  8. can still cause increased risk of heart attack
56
Q

What are the activities of acetaminophen?

A
  1. analgesic and antipyretic effects similar to aspirin → but NOT an NSAID
  2. much weaker as an anti-inflammatory agent
57
Q

What is the mechanism of action of acetaminophen?

A
  1. does not inhibit arachidonic acid binding to PGHS
  2. scavenges peroxynitrite required for PGH synthase activity → peroxynitrite is a major oxidant for PGH synthase activity in the CNS where high concentrations are present in inflammation so acetaminophen scavenging is overwhelmed
  3. reduce radicals and suppress activity of prostaglandins in the CNS
58
Q

How does acetaminophen have fewer adverse effects compared to aspirin?

A
  1. lower incidence of GI disturbance
  2. tolerated in patients with blood coagulation disorders
  3. not associated with Reye’s syndrome → children can take it
  4. may cause a rash but low incidence of hypersensitivity
  5. does not cross react with aspirin
59
Q

How is acetaminophen toxic?

A
  1. cytochrome P450 mediated N-hydroxylation to form N-acetylimidoquinone (ketone instead of OH) which reacts with glutathione → toxic doses overload glutathione and cell damage occurs in the liver
  2. painful if die from overdose because it takes days to week
60
Q

Can you take NSAID and acetaminophen at the same time?

A

YES! but no 2 NSAIDs together!

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