Med Chem Lecture 12

Front 1

Antipyretic Analgetics in this drug class include ____ and ___ actions but lack ____ effects

Back 1

analgeticand antipyretic actions but lack anti-inflammatory effects.

Front 2

Antipyretics interfere with those processes by which ______ factors produce fever, but they do not appear to lower ________in afebrile subjects.

Back 2

pyrogenic

body temperature

Front 3

It had been historically accepted that the antipyretics exert their actions within the ______

Back 3

central nervous system (CNS

Front 4

It had been historically accepted that the antipyretics exert their actions within the central nervous system (CNS), primarily at the ___ ___ ____

Back 4

hypothalamic thermoregulatory center

Front 5

What are 3 antipyretic analgetics?

Back 5

Acetanilide

Phenacetin

Acetaminophen

Front 6

The fact that acetaminophen is an effective antipyretic/analgetic but an ineffective anti-inflammatory agent may result from its greater inhibition of ______ _______ via inhibition of the _____ isoform in the ____compared with that in the periphery.

Back 6

prostaglandin biosynthesis via inhibition of the COX-3 isoform in the CNS

Front 7

______was introduced into therapy in 1886 under the name antifebrin as an antipyretic/analgetic agent but was subsequently found to be too toxic, particularly at high doses, to be useful.

Back 7

Acetanilide

Front 8

_____was introduced the following year and remained in use until the 1960s because of reports of nephrotoxicity.

Back 8

Phenacetin

Front 9

______is longer acting than acetaminophen despite the fact that it is metabolized to acetaminophen but is a weaker antipyretic.

Back 9

Phenacetin

Front 10

______remains the only useful agent of this group and is widely used as a nonprescription antipyretic/analgetic under a variety of trade names (Tylenol, Patrol, and Tempera)

Back 10

acetaminophen

Front 11

The analgetic activity of acetaminophen iscomparable to that of aspirin, but acetaminophen lacks useful ____ ____ activity

Back 11

anti-inflammatory

Front 12

Acetaminophen advantages over aspirin as an analgetic, however, are that individuals who are ___ to salicylates generally respond well to acetaminophen.

Back 12

Hypersensitive

Front 13

____ and ___ are both metabolized to acetaminopen

Back 13

Both acetanilide and phenacetin

Front 14

acetanilide and phenacetin both undergo hydrolysis to yield what?

Back 14

aniline derivatives that produce significant side effects

Front 15

acetaminophen is undergoes rapid ____ ___ metabolism in the __ __

Back 15

first-pass metabolism in the GI tract.

Front 16

A minor, but significant, product of both acetaminophen and phenacetin is the _____

Back 16

N-hydroxyamide

Front 17

A minor, but significant, product of both acetaminophen and phenacetin is the N-hydroxyamide produced by a ____ and ____

Back 17

CYP2E1 and CYP3A4

Front 18

A minor, but significant, product of both acetaminophen and phenacetin is the N-hydroxyamide produced by a CYP2E1 and CYP3A4. The N-hydroxyamide is then converted to a reactive toxic metabolite, an ______

Back 18

acetyliminoquinone.

Front 19

acetyliminoquinone iminoquinoneis detoxified by conjugation with hepatic ____

Back 19

glutathione.

Front 20

In cases of ingestion of large doses or overdoses of acetaminophen, however, hepatic stores of glutathione may be depleted by more than ____%

Back 20

70

Front 21

n cases of ingestion of large doses or overdoses of acetaminophen, however, hepatic stores of glutathione may be depleted by more than 70%, allowing the reactive quinone to interact with soft ____ functional groups, primarily ___ groups, on _____ proteins

Back 21

nucleophilic

SH groups

hepatic proteins

Front 22

In cases of ingestion of large doses or overdoses of acetaminophen, however, hepatic stores of glutathione may be depleted by more than 70%, allowing the reactive quinone to interact with soft nucleophilic functional groups, primarily -SH groups, on hepatic proteins, resulting in the formation of covalent adducts that produce ___ ____

Back 22

produce hepatic necrosis.

Front 23

Salicylic acid itself was first obtained in 1838 from _____

Back 23

salicin

Front 24

salicylic acid itself was first obtained in 1838 from salicin, a glycoside present in most what?

Back 24

willow and poplar bark

Front 25

Interestingly, Hippocrates prescribed chewing willow bark for pain relief in the fifth century AD. What was this bark?

Back 25

Salicin

Front 26

In 1860, Kolbe synthesized salicylic acid from ___ ___and __ ___that inexpensively produced large quantities

Back 26

sodium phenoxide and carbon dioxide,

Front 27

. Aspirin is ___ to ____ times more potent against COX-1 than against COX-2.

Back 27

10 to 100

Front 28

Aspirin’s actions on COX-1 prevent both ___ and ___ of arachidonic acid

Back 28

endoperoxide and 15-peroxidation

Front 29

Aspirin’s actions on COX-1 prevent both endoperoxide and 15-peroxidation of arachidonic acid, but its action on COX-2 does not prevent formation of _____ arachidonic acid

Back 29

15-OOH

Front 30

The arylalkanoic acids share, to various extents, the property of inhibition of ____ ___

Back 30

prostaglandin biosynthesis

Front 31

The arylalkanoic acids share, to various extents, the property of inhibition of prostaglandin biosynthesis by inhibiting ___ and ___

Back 31

COX-1 and COX-2 with varying degrees of selectivity.

Front 32

Arlyalkanoic Acids
are classified into two classes ___ and ___ acids

Back 32

“arylacetic” and “arylpropionic” acids.

Front 33

All nonselective COX inhibitors possess an ____ functional group

Back 33

acidic

Front 34

All nonselective COX inhibitors possess an acidic functional group, in this case a carboxylic acid functional group. The aryl and heteroaryl rings in these examples are attached to the α-position of acetic acid. The potency of these compounds is usually directly proportional to the ____ of the carboxyl group

Back 34

acidity (pka)

Front 35

The conformation of_________ plays a crucial role in its anti-inflammatory activity.

Back 35

indomethacin

Front 36

The conformation of indomethacinplays a crucial role in its anti-inflammatory activity. Which conformation is preffered

Back 36

low energy conformation

Front 37

The conformation of indomethacin plays a crucial role in its anti-inflammatory activity. In the (preffered) low energy conformation, the ______group is oriented on the same (“cis”) and is also non____ to the indole ring

Back 37

p-chlorobenzoyl

noncoplanar

Front 38

The conformation of indomethacinplays a crucial role in its anti-inflammatory activity. In the (preffered) low energy conformation, the p-chlorobenzoyl group is oriented on the same (“cis”) side as the indoleheteroaryl ring and is also noncoplanar (perpendicular) to the indole ring. When a methyl group is substituted at the α-position of the acetic acid (H = Me), the compound is _______as the (S) isomer only.

Back 38

equipotent

Front 39

The activity of sulindac is dependent on the stereochemistry of the ___ ___ __

Back 39

benzylidene double bond.

Front 40

The conformation of sulindac is"__"when the aryl ring is on the same (cis) side as the ring bearing a fluorine atom.

Back 40

Z

Front 41

The -isomer is a much more potent anti-inflammatory agent than the -isomer,

Back 41

Z than E

Front 42

The (Z)-isomer is a much more potent anti-inflammatory agent than the (E)-isomer, suggesting that (Z)-sulindac and indomethacin assume similar conformations at the active site of the arachidonic acid ___ enzyme

Back 42

COX

Front 43

Sulindac is a ____ that is converted to the active form,___

Back 43

prodrug

the sulfide

Front 44

Sulindac is a prodrug that is converted to the active form (the sulfide), which inhibits the COX system approximately ___ more than ____

Back 44

8x

aspirin

Front 45

Sulindac is a prodrug that is converted to the active form (the sulfide), which inhibits the COX system approximately 8X more than aspirin. The active form is a ____ form of the drug, where as most of the metabolism of sulindac is ___

Back 45

reduced

oxidative

Front 46

Nabumetone lacks ___ functional group

Back 46

acidic

Front 47

Nabumetone is rapidly metabolized after absorption to form the major active metabolite _-_____-_-__ __

Back 47

6-methoxynaphthalene-2-acetic acid (6MNA),

Front 48

Nabumetone is rapidly metabolised after absorption to form the major active metabolite 6-methoxynaphthalene-2-acetic acid (6MNA), which is an effective inhibitor of ___

Back 48

COX

Front 49

Since nabumetone is not acidic, primary insult to the stomach is ___

Back 49

reduced

Front 50

Nabumetone is also an ineffective inhibitor of ____ ____in ____ ___ and thus produce minimal ___ insult

Back 50

is also an ineffective inhibitor of prostaglandin cyclooxygenase in gastric mucosa,

secondary

Front 51

6MNA has a chemical structure very similar to that of ____

Back 51

naproxen

Front 52

Aryl and Heteroarylpropionic Acids
are _-substituted ____ acids

Back 52

2-substituted propionicacids

Front 53

Aryl and Heteroarylpropionic Acids have 2-substituted propionicacids have an additional methyl group that in most cases increases _____ activity and reduces __ ___

Back 53

anti-inflammatory activity and reduces side effects.

Front 54

ketorolac, which has its methyl group _____ onto the ___ ring.

Back 54

ketorolac, which has its methyl group cyclized onto the pyrrole ring.

Front 55

The fenamic acids are ___-_____ anthranilic acids

Back 55

nitrogen substituted

Front 56

N-Arylanthranilic Acids (Fenamic Acids)

Substitution on the anthranilic acid portion of these drugs usually ___ activity

Back 56

reduce

Front 57

N-Arylanthranilic Acids (Fenamic Acids)

Substitution on the anthranilic acid portion of these drugs usually reduced activity, whereas substitution on the _____ ring gave mixed results

Back 57

N-aryl

Front 58

Meclofenamic acid posesses _____greater anti-inflammatory activity than mefenamic acid

Back 58

25x

Front 59

The oxicams are ____or ____- substituted ___ that contain an acidic _______.

Back 59

The oxicams are N-aryl- or N-heteroaryl-substituted amides that contain an acidic enolichydrogen.

Front 60

At oxicams physiologic pH, the ____form of _____ predominates

Back 60

physiologic pH, the anionic form of Piroxicam predominates

Front 61

At physiologic pH, the anionic form of Piroxicam predominates. The enolic hydrogen is as acidic as a ______ __

Back 61

carboxylic acid

Front 62

At physiologic pH, the anionic form of Piroxicam predominates. The enolic hydrogen is as acidic as a carboxylic acid (pKa = 4-6). This is due to stabilization of the ___ anion by ____ bonding

Back 62

enolate anion by hydrogen bonding.

Front 63

The _____ in the ____ ring (a pyridine) adds stabilization to the _____ form and demonstrates why the N-heteroaryl amides have ___ pKas and thus almost ____ times higher anti-inflammatory activity.

Back 63

The nitrogen in the heterocyclic ring (a pyridine) adds stabilization to the resonance form and demonstrates why the N-heteroaryl amides have lower pKas and thus almost 7X higher anti-inflammatory activity.

Front 64

Selective COX-2 Inhibitors
Because many of the beneficial (GI protective) aspects of the cyclooxygenase enzyme are associated with the ___ isoform

Back 64

cox-1

Front 65

Because many of the beneficial (GI protective) aspects of the cyclooxygenase enzyme are associated with the COX-1 isoform, many drugs were developed to have higher levels of ____ selectivity over ____

Back 65

COX-2 selectivity over COX-1

Front 66

Selective COX-2 Inhibitors drugs have less ___ toxicity,

Back 66

GI

Front 67

While these Selective COX-2 Inhibitors have less GI toxicity, there have been numerous reports of serious ___and ____ side effects when these drugs are used.

Back 67

hepatic and cardiovascular

Front 68

_______is the only currently marketed selective COX-2 inhibitor.

Back 68

Celecoxib (celebrex)