Exam 2: Lecture 2, NSAIDs

Question 1

What is inflammation?

Answer 1

Protective response of the body to tissue injury

Question 2

What can cause tissue injury?

Answer 2

Trauma, chemicals or microbiologic agents

inflammation may cause progressive tissue injury

Question 3

Inflammation is the first step in….

Answer 3

a big number of pathophysiological processes

and

in a variety of immunological disorders

Question 4

NSAID’s are…

Answer 4

Analgesic = mild/moderate pain

Antipyretic (fever reducer) in fever pt, little effect on normal people

Anti-inflammatory = arthritis, osteoarthritis, musculoskeletal disorders

Question 5

NSAId’s used for self treatment for….

Answer 5

Headaches, Dental Pain, and Muscle Pain

Question 6

NSAID common properties

Answer 6

weak organic acids (except nabumetone = keto prodrug)

Well absorbed

Highly metabolized phase I and II

Biliary excretion and reabsorption through the enterohepatic circulation

GI irritation correlate with the amount in enterohepatic circulation

After repeated doses, NSAIDs found in synovial fluid

Question 7

NSAID’s primary mech of action

Answer 7

COX inhibition

act indirectly, don’t block PG receptors, no effect on previously formed PG’s

Question 8

Cox-1

Answer 8

Found in many tissues, important under normal conditions

Question 9

Cox-2

Answer 9

Found in inflammatory tissue, expressed during inflammation

Renal tissue - exception, found in normal tissue

Question 10

Cox-1 vs Cox-2

Answer 10

Channel in Cox 2 wider than in Cox 1

some drugs can get into Cox 2, not Cox 1

Question 11

How do NSAID’s block Cox?

Answer 11

Enter channel, and block it. (Except aspirin)

Bind to arginine via H-bonds

Cause reversible inhibition of Cox

Question 12

How does aspirin work?

Answer 12

Acetylates the enzyme (Cox) at serine and causes irreversible inhibition of Cox

Question 13

Which prostaglandins do NSAID’s suppress?

Answer 13

PGE2
PGD2
PGF2a
PGI

TXA2

Question 14

Aspirin Clinical I

Answer 14

inhibit platelet aggregation

produces anticoagulant effect + prevent thrombosis

reduce inflammation

reduce pain via reduce PGE2 synthesis

Peripherally inhibit PGs in inflamed tissue

Question 15

Aspirin Clinical II

Answer 15

Antipyretic effect mediated though the hypothalamus (CNS)

No effect on temp in healthy individuals, but effect with those that have fever (by reducing PGE2 synthesis)

Question 16

Aspirin Absorption

Answer 16

Oral + stomach absorption = rapid

Upper portion of Small intestine = major site of absorption

Rectal = slow and unpredictable absorption

Question 17

Aspirin Excretion

Answer 17

Alkalization of urine increases salicylates excretion

via increase ionization and decreased reabsorption in the renal tube.

Question 18

Aspirin Effect on Blood I

Answer 18

decrease platelet aggregation

recommended in individual with 1 or more MIs

prevents incidence of first MI and Transient ischemic attacks

Question 19

Aspirin Effect on Blood II

Answer 19

TXA2 synthesis in platelets reduced, recovers only when new platelets formed

takes 7 days to recover from single dose

increase bleeding time, shouldn’t be taken 1 week before surgery

Question 20

Aspirin effect on Cardiovascular system

Answer 20

therapeutic dose = no effect

High dose = effect smooth muscle
Toxic dose = cause central vasomotor paralysis

Question 21

Aspirin effect on Respiratory System

Answer 21

directly effects respiratory center

Toxic doses can depress respiratory center, cause metabolic acidosis

indirectly increases O2 consumption in skeletal muscle
Indirectly increases CO2 production in skeletal muscles

Question 22

Aspirin effect on GI system

Answer 22

decrease PGE2/PGE2a = decrease mucus protection

Dose related gastric ulceration, bleeding, erosive gastritis

worsening of peptic ulcer, gastric bleeding leading to iron-deficiency

Epigrastic distress, nausea and vomiting by irritating mucosa lining

Stimulate CTZ in CNS
Should be taken with food + significant act water

Question 23

Aspirin effects on Urinary System

Answer 23

determine effect on urinary system

Decreased PGI2 production = decrease kidney blood flow = increase Na/H20 retention = edema and hyperkalimia

may increase circulating plasma volume by 20%

Question 24

Aspirin decrease inflammation by…

Answer 24

decreasing PGs, PGI2, and TXA2

Question 25

Aspirin decrease platelet aggregation by…

Answer 25

Decrease TXA2

Question 26

Aspirin increase ulcer formation by…

Answer 26

Decrease PGE2, PGE2a = Decrease Mucous

Question 27

Aspirin increasing edema by…

Answer 27

decrease PGI2 = decrease blood flow = decrease filtration = increase NA/H20 = increase edema

Question 28

effects of Large and toxic Aspirin doses

Answer 28

uncouple oxidative phosphorylation

deplete glycogen in liver/skeletal muscle = hyperglycemia/glycosuria

reduce lipogenesis by blocking incorporating of acetates into FA

cause sig nitrogen loss through aminoaciduria

Question 29

Low Doses aspirin?

Answer 29

<300mg/day = antipyretic and analgesic effects

Question 30

Moderate doses Aspirin?

Answer 30

300-2400 mg/day = antipyretic and analgesic effects

Question 31

High doses Aspirin?

Answer 31

2400 - 4000mg/day = anti-inflammatory effects

Question 32

Major adverse effects moderate dose aspirin?

Answer 32

Epigastic pain
nausea
vomiting
skin rashes
asthma
vertigo
tinnitus
hyperventilation = Respiratory alkalosis

Question 33

Major adverse effects high dose aspirin?

Answer 33

Metabolic acidosis
dehydration
hyperthermia
collapse
Coma
Death

Question 34

Aspirin serious Warning

Answer 34

Children with viral infection at greater risk of developing Reyes Syndrome if given aspirin

20-40% mortality, dialysis used to remove salicylates

Children should be given acetaminophen instead of aspirin

Question 35

New NSAIDs

Answer 35

treatment of arthritis and osteoarthritis

cause GI disturbances similar to aspirin but lower incidence

removed through kidney, sig risk of renal damage in patient with preexisting renal disease

Ibuprofen and Naproxen better tolerated than Indomethacin

Question 36

Ibuprofen

Answer 36

Reversibly inhibit thromboxane synthesis by blocking COX-1

Short duration (2hr)

should not be used during pregnancy or nursing

more effective analgesic than aspirin, same anti-inflammatory

used in arthritis, dysmenorrhea, muscle inflammation, peptic ulcer, and renal damage. used to accelerate closure of patent ductus arteriousus

Question 37

Naproxen

Answer 37

bind to plasma proteins, does not cross placenta

half life = 14hr, 2 doses per day

isolated case of renal dysfunction/thrombocytopenia/agranulocytosis

Question 38

Indomethacin

Answer 38

potent

Reversibly inhibit thromboxane synthesis by blocking COX-1

used to accelerate closure of patent ductus arteriousus

more effective anti-inflame than aspirin or other NSAIDs

Inhibits PLA,PLC
reduces neutrophil migration, T-Cell and B-Cell proliferation

Serious toxicity = limiting factor

Question 39

Percentage of Adverse effects indomethacin?

Answer 39

50% of patients

20% of patients adverse effects = intolerable

Question 40

Acetaminophen

Answer 40

inhibits prostaglandin synthesis in CNS

Weak cyclooxyrgenase inhibitor in peripheral tissue

** No anti-inflammatory effect **

No anti-platelet effect

No effect on Cardiovascular, respiratory, GI, acid-base regualtion

** OD = hepatic necrosis **

Question 41

Acetaminophen Clinical

Answer 41

one of most important drugs in treatment of mild/moderate pain

used in patient that don’t req anti-inflam effects

substitute for aspirin in patients with increased rick of Reye’s syndrome, gastric complains

low toxicity - used in all headache products

Question 42

Acetaminophen Adverse effects

Answer 42

in small doses = no sig side effect

Dangerous in OD = serious hepatic necrosis
Antidote = N-acetylcystein I.V (bind to toxic metabolites) if given within 10 hrs or methionine given orally

Renal tubular necrosis and hypoglycemic coma can also occur