Test 2 Medicinal Chemistry of Nonnarcotic and Narcotic Analgesics Flashcards
classifications of NNA
- Antipyretic Analgesics
- Anti-Inflammatory drugs (+ antipyretic + analgesic)
- Selective COX II inhibitors
How was APAP formulated?
it’s an active metabolite of acetanilide and phenacetin which they both had toxic effects but APAP did not
How does our body combat against APAP toxicity / what is the antidote?
- our liver conjugates metabolite with glutathione and excretes it
- N-acetylcysteine is an antidote
How does alcohol affect APAP toxicity?
- it induces CYP2E/3A4 which will produce more of the hepatotoxic metabolite: NAPQI
What are the major ways in which APAP is metabolized?
- sulfation
- glucuronidation
Aspirin
- unstable in solution due to hydrolysis
- absorbed in stomach and upper small intestine as intact form
Salicylamide
- weak acid: pKa = 8.2
- poorly soluble in water but stable solution can be made at pH 9
Salicylate salts
- lower GI side effects and stable in aqueous solutions
- will be converted into salicylic acid
Diflunisal
- Dolobid
- pKa = 3.3
- more potent than ASA
- fewer side effects, longer half life
- for RA and OA
Why are Aryl- and Heteroarylacetic Acids classified as such?
because they are prodrugs and will metabolize to carboxylic acid
unique characteristic about Sulindac
Prodrug: metabolic activation
IBP
- there are S and R forms
- they are bioequivalent -> R form is inverted to S form
- we take a racemic mixture
oxicams
- Non-carboxylic acid
- Extended half life: 38 hr -> single daily dosing
- Selective COX-2 inhibitor
Phenol group
- Mostly unionized at pH 7.4
- Hydrogen bond donor – to His residue of receptor binding site
Cationic amine
binding to Asp residue of opioid receptor binding site
Natural levorotatory (-) morphine
- Opioid receptors: L (-) form»_space; R (+) form
- But both L and R forms are antitussive: dextrometrophan
common metabolism
- N-dealkylation – CYP3A4
- O-dealkylation – CYP2D6
- Hydrolysis
- Phase 2 conjugations -> C6-glucuronated metabolite: more active
Morphine sulfate
- 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
Levorphanol
- increased lipophilicity due to loss of C6OH
- better BBB transport
- longer duration of action
- for chronic pain
Buprenorphine
- increased lipophilicity due to cyclopropylmethyl group
- C7 side chain
- Long half life: 37 hrs: once-daily dosing
Naloxone
double bond at the end is metabolized (by oxidation) easy and becomes inactive => cannot be given orally
Methylnaltrexone
- Quaternary analog
- No BBB penetration, no CNS effects
- Resorting bowel function in patients on chronic opioid therapy
Meperidine HCl
- 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
Fentanyl citrate
- Very sedative and euphoria-inducing analgesic
- Potent: 50-100 fold that of morphine
- Adverse reaction: resp. depression
Sufetanil citrate
- Higher
* More potent: 5-10-fold to fentanyl, 600-800-fold to morphine
Remifentanil HCl
- Hydrolysis of the terminal ester à deactivation
* Very short (3-10 min) biologic half-life
methadone
- 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
tramadol
a racemic mixture of cis isomers
tapentadol
pure 1R,2R-(-)-isomer
