Analgesics Medchem Flashcards by John White

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)

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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)

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Tetracaine

Butyl group

50X more potent than procaine

Hydrolyzed slower than procaine

Can still generate PABA-like or PABA metabolites

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Chloroprocaine

2X more potent than Procaine

Shorter duration than procaine

Cl makes the ester more susceptible to hydrolysis

Yields a PABA-like metabolite

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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

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Isogramine (1935, natural product with some anesthetic properties)

Used as template to develop amino amide local anesthetics

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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)

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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

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Ropivacaine

N-propyl in place of n-butyl of bupivacaine

Used as the single S-enantiomer | R-enantiomer is associated with cardiotoxicity

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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)

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Pramoxin

In neosporin + pain relief

Used in some OTCs | typically topical

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Dyclonine

Used in some OTCs | typically topical

(in Sucrets)

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(-) - 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

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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

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(-)-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

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Hydromorphone

7,8-dihydro | b-ketone

8x more potent than morphine

Maine route of metabolism is glucuronidation at position 3 (inactive

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(-)-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