Test 2 Medicinal Chemistry of Nonnarcotic and Narcotic Analgesics

Question 1

classifications of NNA

Answer 1

• Antipyretic Analgesics
• Anti-Inflammatory drugs (+ antipyretic + analgesic)
• Selective COX II inhibitors

Question 2

How was APAP formulated?

Answer 2

it’s an active metabolite of acetanilide and phenacetin which they both had toxic effects but APAP did not

Question 3

How does our body combat against APAP toxicity / what is the antidote?

Answer 3

• our liver conjugates metabolite with glutathione and excretes it
• N-acetylcysteine is an antidote

Question 4

How does alcohol affect APAP toxicity?

Answer 4

• it induces CYP2E/3A4 which will produce more of the hepatotoxic metabolite: NAPQI

Question 5

What are the major ways in which APAP is metabolized?

Answer 5

• sulfation

- glucuronidation

Question 6

Aspirin

Answer 6

• unstable in solution due to hydrolysis

- absorbed in stomach and upper small intestine as intact form

Question 7

Salicylamide

Answer 7

• weak acid: pKa = 8.2

- poorly soluble in water but stable solution can be made at pH 9

Question 8

Salicylate salts

Answer 8

• lower GI side effects and stable in aqueous solutions

- will be converted into salicylic acid

Question 9

Diflunisal

Answer 9

• Dolobid
• pKa = 3.3
• more potent than ASA
• fewer side effects, longer half life
• for RA and OA

Question 10

Why are Aryl- and Heteroarylacetic Acids classified as such?

Answer 10

because they are prodrugs and will metabolize to carboxylic acid

Question 11

unique characteristic about Sulindac

Answer 11

Prodrug: metabolic activation

Question 12

IBP

Answer 12

• there are S and R forms
• they are bioequivalent -> R form is inverted to S form
• we take a racemic mixture

Question 13

oxicams

Answer 13

• Non-carboxylic acid
• Extended half life: 38 hr -> single daily dosing
• Selective COX-2 inhibitor

Question 14

Phenol group

Answer 14

• Mostly unionized at pH 7.4

- Hydrogen bond donor – to His residue of receptor binding site

Question 15

Cationic amine

Answer 15

binding to Asp residue of opioid receptor binding site

Question 16

Natural levorotatory (-) morphine

Answer 16

• Opioid receptors: L (-) form&raquo_space; R (+) form

- But both L and R forms are antitussive: dextrometrophan

Question 17

common metabolism

Answer 17

• N-dealkylation – CYP3A4
• O-dealkylation – CYP2D6
• Hydrolysis
• Phase 2 conjugations -> C6-glucuronated metabolite: more active

Question 18

Morphine sulfate

Answer 18

• Potent and selective µ agonist
• Polar: logDpH7.4 = 0.48
• Poor oral bioavailability due to polar character and high metabolic rate
• Active metabolite: morphine-6-glucuronide > morphine by 50-fold
• not good for patients with renal failure

Question 19

Levorphanol

Answer 19

• increased lipophilicity due to loss of C6OH
• better BBB transport
• longer duration of action
• for chronic pain

Question 20

Buprenorphine

Answer 20

• increased lipophilicity due to cyclopropylmethyl group
• C7 side chain
• Long half life: 37 hrs: once-daily dosing

Question 21

Naloxone

Answer 21

double bond at the end is metabolized (by oxidation) easy and becomes inactive => cannot be given orally

Question 22

Methylnaltrexone

Answer 22

• Quaternary analog
• No BBB penetration, no CNS effects
• Resorting bowel function in patients on chronic opioid therapy

Question 23

Meperidine HCl

Answer 23

• Flexible à can adjust confirmation to fit to the µ receptor
• Analgesic potency: 1/10 of morphine
• metabolite normerperidine: 50% potency, extended half life, may cause neuro side effects not reversed by naloxone

Question 24

Fentanyl citrate

Answer 24

• Very sedative and euphoria-inducing analgesic
• Potent: 50-100 fold that of morphine
• Adverse reaction: resp. depression

Question 25

Sufetanil citrate

Answer 25

• Higher

* More potent: 5-10-fold to fentanyl, 600-800-fold to morphine

Question 26

Remifentanil HCl

Answer 26

• Hydrolysis of the terminal ester à deactivation

* Very short (3-10 min) biologic half-life

Question 27

methadone

Answer 27

• Prolonged duration of action due to the active metabolites with long half life
• Used in addiction recovery program
• for buccal administration, more alkaline salive -> enhanced absorption

Question 28

tramadol

Answer 28

a racemic mixture of cis isomers

Question 29

tapentadol

Answer 29

pure 1R,2R-(-)-isomer