Analgesics Medchem Flashcards Preview

Pharmacy School 2016-17 > Analgesics Medchem > Flashcards

Flashcards in Analgesics Medchem Deck (41):
1

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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)

2

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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)

3

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Tetracaine

Butyl group

50X more potent than procaine

Hydrolyzed slower than procaine

Can still generate PABA-like or PABA metabolites

4

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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

5

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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

6

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Isogramine (1935, natural product with some anesthetic properties)

 

Used as template to develop amino amide local anesthetics

7

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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)

8

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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

9

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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

10

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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)

11

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Pramoxin

In neosporin + pain relief

Used in some OTCs | typically topical

12

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Dyclonine
(in Sucrets)

Used in some OTCs | typically topical

13

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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

15

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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

16

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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

17

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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

18

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(-) - Oxymorphone
 (14B-hydroxyhydromorphone)

10X more potent than morphine

Maine route is glucuronidation at position 3 (inactive)

T1/2 = 3-4 hours

19

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(-)-Oxycodone HCl
 (3-0-methyloxymorphone)

2D6 metabolism to Oxymorphone (active)

Effective as an analgesic in 2D6 poor metabolizers

T1/2 = 4 hours

20

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(-)-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)

21

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(+)-Dextromethorphan

0-methyl derivative of enantiomer of levorphanol

Cough suppressant action NOT acting at opioid receptors

NMDA receptor antagonist

NOT AN OPIOID

22

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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)

 

23

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(+/-)-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)

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Methadone -> Normethadone (3A4/2B6) --> Intermediate (intramolecular attack of secondary amine on ketone carbonyl, non enzymatic) --> Inactive pyrrolidine (by rapid non-enzymatic loss of water)

25

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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

26

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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

27

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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)

28

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Sufentanil Citrate

Thiophene group

T1/2 = 2.5 hours

More potent than fentanyl and shorter duration

3A4 N-dealkylation (inactive)

29

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Remifentanil

Two ester groups (rapid hydrolysis to inactive carboxylate) 

More potent than morphine

Very short acting opioid

T1/2 = 6 minutes (used IV)

 

30

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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

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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

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Methylnaltrexone bromide

Quaternary nitrogen

Peripherally acting mu antagonist to treat OIC

T1/2 = 8 hours

Much less metabolism (70% excreted unchanged)

33

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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

34

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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

35

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(-)-Butorphanol tartrate

Mu antagonist | kappa agonist

Levorphanol-like | cyclobutylmethyl

T1/2 = 4.5-5.5 hours

Major metabolism: Hydroxylation on cyclobutyl ring (inactive)

36

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(-)-Nalbuphine

Mu antagonist | kappa agonist

T1/2 = 5 hous

Nornalbuphine (N-dealkylation) | 6 keto-nalbuphine

37

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(-)-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

38

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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)

39

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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)

40

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Loperamide HCl

Peripheral action

Substrate for PGP in BBB

Can be abused in mass doses

41

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