Analgesics Medchem Flashcards
Cocaine
First local anesthetic (initially noticed it could numb tongue)
Benzoate ester is important for anesthetic properties
CNS effects, allergic reactions, tissue irritation | poor stability in aqueous solutions (rapidly ester hydrolyzed)
Procaine
Lacks many of the side effects of Cocaine
Low potency and short duration (ester hydrolysis)
Some have allergic reactions to Procaine (resulting from para-amino benzoic acid hydrolysis product, PABA)
Tetracaine
Butyl group
50X more potent than procaine
Hydrolyzed slower than procaine
Can still generate PABA-like or PABA metabolites
Chloroprocaine
2X more potent than Procaine
Shorter duration than procaine
Cl makes the ester more susceptible to hydrolysis
Yields a PABA-like metabolite
Benzocaine
*PABA backbone*
First used topically as an anesthetic
Lacks N,N-diethyl amine of procaine
Can’t protonate benzocaine at physiological pH
Highly lipophilic (only used topically)
Products: Lanacane, Solarcaine spray
Isogramine (1935, natural product with some anesthetic properties)
Used as template to develop amino amide local anesthetics
Lidocaine
Prototype for other effective amino amide local anesthetics
Produced faster, more intense and longer acting local anesthesia compared with procaine | longer duration of action due to slower rate of hydrolysis (amide vs ester)
Can bes used in patients sensitive to amino ester locals (No PABA metabolites)
Ortho methyl slows hydrolysis | CYP1A2 metabolism by 3-hydroxylation or N-deethylation (active)
Bupivacaine
N-butyl group | piperidine
Used as a racemate | both enantiomers have local anesthetic action
Longer duration of action compared with lidocaine
Has some cardiotoxicity
Ropivacaine
N-propyl in place of n-butyl of bupivacaine
Used as the single S-enantiomer | R-enantiomer is associated with cardiotoxicity
Articaine
Thiophene | Secondary Amine | Ortho ester group (hydrolysis occurs here)
Used as racemate
Used extensively in dental procedures
Good duration at local site of injection but minimal systemic toxicity (due to rapid ester hydrolysis to inactive carboxylate)
Pramoxin
In neosporin + pain relief
Used in some OTCs | typically topical
Dyclonine
Used in some OTCs | typically topical
(in Sucrets)
(-) - Morphine
(-) -enantiomer is active; synthetic
(+) -enantiomer is completely inactive at opioid receptors
Morphine SAR (as mu receptor agonist)
Modifications that decrease activity: remove 3-hydroxy, replace 3-OH with a 3-OMe, CH3CO ester at position 3, remove the N-methyl
Modifications that increase activity: remove position 6 hydroxy, reduce the 7,8-double bond, add a 14B hydroxy group, CH3CO ester at position 6
Extensive first pass metabolism (affects oral vs IV dosing)
Major routes: Glucuronidation at position 3 (50%, inactive), Glucuronidation at position 6 (15%, active and may contribute to analgesia with long term use, T1/2 of metabolite is 6.5 hours)
Minor Routes: N-demethylation (5%, inactive), Sulfonation at position 3 (less than 5%, inactive)
T1/2 = 2-3 hours
3,6-Diacetylmorphine (Heroin)
Morphine prodrug
More lipophilic than morphine (rapid CNS access - once in CNS, esterases preferentially remove 3-acetyl)
6-acetyl morphine is active opioid (more portent than morphine)
Further conversion to morphine occurs
(-)-Codein (3-O-methylmorphine)
Codeine is more lipophilic than morphine | position 3 is blocked | less first pass metabolism
Metabolism: N-demethylation by 3A4 (inactive), O-demethylation by 2D6 (Morphine, contributes to analgesia)
*2D6 poor metabolizers won’t get effective analgesia from Codeine
**2D6 ultrametabolizers have higher overdose risk
***Codeine has anti-tussive properties, not dependent on O-demethylation
Hydromorphone
7,8-dihydro | b-ketone
8x more potent than morphine
Maine route of metabolism is glucuronidation at position 3 (inactive
(-)-Hydrocodone bitartrate (3-0-demethylhydromorphone)
2D6 metabolism to hydromorphone (contributes significantly to analgesia)
Conversion to hydromorphone by 2D6 not necessary for analgesia
(-) - Oxymorphone
10X more potent than morphine
Maine route is glucuronidation at position 3 (inactive)
T1/2 = 3-4 hours
(14B-hydroxyhydromorphone)
(-)-Oxycodone HCl
2D6 metabolism to Oxymorphone (active)
Effective as an analgesic in 2D6 poor metabolizers
T1/2 = 4 hours
(3-0-methyloxymorphone)
(-)-Levorphanol
T1/2 = 12 hours
5-membered ring with oxygen has been eliminated
Slightly more potent than morphine
Glucuronidation at position 3 (also has NMDA receptor antagonist properties)
(+)-Dextromethorphan
0-methyl derivative of enantiomer of levorphanol
Cough suppressant action NOT acting at opioid receptors
NMDA receptor antagonist
NOT AN OPIOID
Meperidine Hydrochloride
“4-phenylpiperidines”
Phenyl group | Piperidine group | two rings out of 5; achiral
T1/2 = 3-4 hours
1/10th the potency of morphine
Metabolism: Ester hydrolysis (inactive), N-demethylation (3A4, 2B6) to Normeperidine (T1/2=20-30 hours, very week mu agonist, contributes to toxicity)
(+/-)-Methadone HCl (Synthetic)
Used as racemate | R(-) is active at mu receptors | both R(-) and S(+) have NMDA receptor antagonist properties
Aproximately equipotent to morphine
T1/2 = 24 hours average (wide range)
Methadone -> Normethadone (3A4/2B6) –> Intermediate (intramolecular attack of secondary amine on ketone carbonyl, non enzymatic) –> Inactive pyrrolidine (by rapid non-enzymatic loss of water)
Tramadol
Two rings | Two stereogenic centers
Used as racemate of the R,R and S,S (cis) isomers
Combination of mu receptor agonism and 5HT and NE reuptake inhibition
R,R-5HT reuptake inhibition
R,R-O-Demethylated metabolite (T1/2 = 7 hours), weak mu agonist
S,S isomer and is O-demethylated matbolite is weak NE reuptake inhibitor
Trapentadol
T1/2 = 4 hours
Similar structure to tramadol, but without the cyclohexane and lacks o-methyl (no 2D6 metabolism)
Single R,R-enantiomer (weak mu agonist and NE reuptake inhibitor)
Glucuronidation is key metabolism
Fentanyl Citrate (synthetic)
3 rings, no stereocenters (achiral) | 4-anilido group rather than 4-phenyl of meperidine | Additional phenyl ring
Approximately 100 times more potent than morphine
Shorter duration compared with morphine (greater lipophilicity and then redistribution of fentanyl out of CNS)
3A4 N-dealkylation (inactive)
Sufentanil Citrate
Thiophene group
T1/2 = 2.5 hours
More potent than fentanyl and shorter duration
3A4 N-dealkylation (inactive)
Remifentanil
Two ester groups (rapid hydrolysis to inactive carboxylate)
More potent than morphine
Very short acting opioid
T1/2 = 6 minutes (used IV)
Naloxone
Allyl group (oxymorphone structure)
Full antagonist at mu, delta and kappa receptors
T1/2 = 60-90 minutes
Rapidly inactivated after oral administration (glucuronidation) | used by injection or intranasal
Naltrexone
N-cyclopropylmethyl group
Orally available
Reduction (major) to 6B-naltrexol (active antagonist that conributes to overall action)
Can also be glucuronidated to inactivation
T1/2 = 3-4 hours
Methylnaltrexone bromide
Quaternary nitrogen
Peripherally acting mu antagonist to treat OIC
T1/2 = 8 hours
Much less metabolism (70% excreted unchanged)
Naloxegol
T1/2 = 6-11 hours
Polyethyleneglycol (PEG) - pegylated derivative of alpha-naloxol
Peripheral mu antaonist for OIC
Substrate for PGP in BBB; PEG tail reduces diffusion across BBB
Metabolism by 3A4 on PEG tail
Avimopan
T1/2 = 10-17 hours
Modified 4-phenylpiperidine (related to meperidine)
High affinity for mu receptors
Peripherally acting antagonist
Zwitterionic character limits CNS access
Amide hydrolysis to carboxylate metabolite (t1/2 = 10-18 hours) also acts as peripheral antagonist
(-)-Butorphanol tartrate
Mu antagonist | kappa agonist
Levorphanol-like | cyclobutylmethyl
T1/2 = 4.5-5.5 hours
Major metabolism: Hydroxylation on cyclobutyl ring (inactive)
(-)-Nalbuphine
Mu antagonist | kappa agonist
T1/2 = 5 hous
Nornalbuphine (N-dealkylation) | 6 keto-nalbuphine
(-)-Pentazocine HCl
Mu partial agonist, Kappa agonist
Used as racemic mixture
Hydroxylation at the terminal methyl, then furthe oxidation to inactive carboxylate
Also available as penazocine with naloxone to prevent oral abuse
Buprenorphine
T1/2 = 37 hours
Partial mu agonist, partial kappa agonist
Very potent
N-dealkylation (3A4) to Norbuprenorphine (potent mu agonist, may contribute to respiratory depression)
Cyclopropyl methyl group like naltrexone (antagonist)
Diphenoxylate HCl (with Atropine = Lomotil)
Mainly peripherally acting opioid agonist
Hydrolysis to carboxylate metabolite (difenoxin, more potent as agonist than diphenoxylate, Zwitterionic character that contributes to CNS access)
Loperamide HCl
Peripheral action
Substrate for PGP in BBB
Can be abused in mass doses
