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Integrated Drug Structure, Action, and Therapeutics > Anesthetics and Analgesics - Proteau's Drugs > Flashcards

Anesthetics and Analgesics - Proteau's Drugs Flashcards

1
Q

What structural features are important in cocaine’s function as an anesthetic? What is the main route of metabolism?

A

The benzoate ester. Ester hydrolysis from the two esters.

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2
Q

Why is procaine better than cocaine as an anesthetic? Does it still undergo the same route of metabolism?

A

There are little CNS effects or tissue irritation. Yes, it still undergoes ester hydrolysis on the benzoate ester. It also has a tertiary amine.

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3
Q

What are the allergic reactions of those using procaine due to?

A

The PABA product

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4
Q

What are the three pieces of general anesthetics?

A
  1. Lipophilic portion - aromatic ring
  2. Intermediate chain - ester or amide (ketone or ether less common)
  3. Hydrophilic portion - tertiary amine between 7.5-9.0 pKa
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5
Q

In amino ester local anesthetics, what increases potency of the anesthetic?

A

An EWG in the ortho or para position

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6
Q

What is the potency of tetracaine in comparison to procaine?

A

It is 50x more potent. Due to butyl mainly (EWG)

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7
Q

Which medications give PABA or PABA-like metabolites?

A

Procaine, tetracaine, chloroprocaine, benzocaine

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8
Q

What is the potency of procaine compared to chloroprocaine?

A

Chloroprocaine is 2x more potent. The Cl makes the ester more susceptible to hydrolysis.

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9
Q

What feature of benzocaine makes it only able to be used topically?

A

It lacks a tertiary amine, and so can’t be protonated at physiological pH. Highly lipophilic.

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10
Q

What are the problems with amino esters?

A

They form PABA or PABA-like products, and have fast ester hydrolysis.

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11
Q

Compare amino amide local anesthetics and amino esters:

A

Amino amides are faster, more intense, and longer acting (no ester hydrolysis) anesthetics than amino esters. There is no PABA. Metabolism is CYP 1A2 giving you (inactive) 3-hydroxylation or (active) N-deethylation.

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12
Q

What is bupivacaine used as? What is the main problem with it?

A

Used as a racemate: both enantiomers have local anesthetic action. It has some cardiotoxicity.

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13
Q

What has a longer duration of action, bupivacaine or lidocaine?

A

Bupivacaine.

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14
Q

What is the difference between bupivacaine and ropivacaine?

A

Not too much, except that ropivacaine is not associated with cardiotoxicity, as it is only the S enantiomer (R associated with cardiotoxicity). Also it has an N-propyl group instead of the n-butyl group of bupivacaine.

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15
Q

Which drug is mainly used for dental procedures?

A

Articaine. Rapid ester hydrolysis.

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16
Q

What is articaine formulated as? How is it’s level of cardiotoxicity?

A

A racemate. It has good action at the local site of injection, but has rapid ester hydrolysis to an inactive carboxylate with no affinity for sodium channels.

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17
Q

What is pramoxine in? Dyclonine?

A

Neosporin & pain relief, and Sucrets. These are the ether and ketone amino local anesthetics, respectively.

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18
Q

What are “met” and “leu” enkephalins and what is the difference?

A

They are both enkephalins, which are an endogenous opioid in the body. They are a chain of four similar amino acids (Tyr-Gly-Gly-Phe) and one variable amino acid (Met or Leu). Met has an +HN at the head, while Leu has a 3+HN at the head. The positive charges are important to binding at the opioid receptor.

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19
Q

What are the three types of opioid receptors? Which will we focus on for pain?

A

Mu, delta, kappa. We will focus on Mu for pain.

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20
Q

What is the prototype of opioids?

A

morphine

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21
Q

Morphine SAR: Modifications that decrease activity?

A
  • Remove 3 OH group
  • Replace 3 OH with 3 O-meth
  • Add 3 CH3CO ester
  • Remove N methyl
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22
Q

Morphine SAR: Modifications that increase activity?

A
  • Remove 6 OH
  • Reduce 7,8 double bond
  • Add a 14beta OH group
  • CH3CO ester at 6
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23
Q

Which enantiomer of morphine is active at opioid receptors?

A
  • (-). (+) is inactive
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24
Q

What is the metabolism of morphine? Are the metabolites active?

A

Glucuronidation at 3 and 6. 50% of the metabolism happens at 3 (inactive product) and 15% at 6 (active M6G product). Minor routes are N-demethylation (~5% inactive) and sulfonation at 3 (<5% inactive).

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25
Q

What is the half-life of morphine and it’s active metabolite?

A

2-3 hours for morphine and 6&1/2 hours for M6G.

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26
Q

What drug is 3,6-diacetylmorphine?

A

Heroin. It is a morphine prodrug.

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27
Q

Which is more potent, morphine or heroin? Why?

A

Heroin is a morphine prodrug. It is not active itself, but its metabolite 6-acetyl morphine is more potent than morphine (esterase preferentially remove the 3-acetyl ester). 6-acetyl morphine is further metabolized to morphine.

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28
Q

Is codeine a prodrug?

A

No, because it has antitussive properties as the actual drug. 2D6 O-demethylation is used to get morphine.

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29
Q

What is the issue with poor and rapid metabolism of CYP 2D6 and codeine?

A

Poor metabolizers will not get adequate analgesia, while rapid metabolizers will have to worry about potential overdoses.

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30
Q

What does hydrocodone use to metabolize? Is is a prodrug.

A

2D6 to hydromorphone. It is not a prodrug: both hydrocodone and its metabolite contribute to the analgesic action.

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31
Q

What is the potency of hydromorphone compared to morphine? Metabolism?

A

It is 8x more potent than morphine. The main route of metabolism is glucuronidation at position 3.

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32
Q

Compare the potency of oxymorphone to morphine. What is the main route of metabolism?

A

It is 10x more potent than morphine, and the main route of metabolism is glucuronidation.

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33
Q

What is the similarity between oxycodone and hydrocodone?

A

They both have intrinsic activity and do not rely on 2D6 for sole analgesia.

34
Q

What and how is oxycodone metabolized to?

A

Metabolized to oxymorphone by 2D6 (active). T1/2 = 4 hours.

35
Q

What is (+) dextromethorphan a mirror image of?

A

(-) Levorphanol (which is codeine minus one 5-membered ring). It is an o-methyl derivative of the enantiomer. Does not act opioid receptors, it is an NMDA antagonist.

36
Q

What is the potency of levophanol? Metabolism? Extra properties?

A

Slightly more potent than morphine. Glucuronidation. NMDA antagonist properties.

37
Q

Which drug has just two rings?

A

Meperidine

38
Q

What is the potency of meperidine? What is the metabolism?

A

1/10th the potency of morphine. Ester hydrolysis leads to an inactive metabolite. 3A4, 2B6 makes normeperidine (which is weakly active but contributes to toxicity).

39
Q

What is methadone formulated as?

A

A racemate. R (-) isomer is active at mu receptors. Both R (-) and S (+) enantiomers have NMDA antagonist properties.

40
Q

Compare methadone and morphine potency. What is the half-life of methadone?

A

Equipotent to morphine. It is long and variable… about 24 hours.

41
Q

What is the route of metabolism of methadone?

A

The major route is 3A4/2B6, which reduces from a tertiary amine to a secondary amine. There is an intermolecular attack on the secondary amine to form a new ringed intermediate, which is hydrolyzed non-enzymatically to an inactive pyrrolidine.

42
Q

Since 2D6 is not used in metabolizing methadone, why is there such a range in half-lives?

A

Because there are genetic polymorphisms in 2B6.

43
Q

What is tramadol formulated as?

A

A racemate of R,R and S,S cis isomers.

44
Q

What is the metabolism of tramadol?

A

2D6, which means poor metabolizers have significant changes in half-lives.

45
Q

What type of agonist activity is present in tramadol?

A

Mu receptor agonist activity, and some 5HT and NE reuptake inhibition (not enough to be used as an antidepressant).

  • R,R 5HT reuptake inhibition, R,R o-demethylated metabolite is a weak mu agonist
  • S,S isomer and its o-demethylated metabolite have NE reuptake inhibition
46
Q

What is tapentadol formulated as? What is its main route of metabolism? What is its agonist activity.

A

A single R,R enantiomer. Similar to tramadol except doesn’t have the cyclohexane and lacks o-methyl (no 2D6). Glucuronidation. Weak mu agonist and a NE reuptake inhibitor.

47
Q

Which has the longer half-life, tramadol or tapentadol?

A

Tramadol is 6 hours, tapentadol is 4 hours.

48
Q

What is the potency of fentanyl compared to morphine? Duration of action?

A

100x more potent than morphine. Shorter duration of action due to greater lipophilicity and greater distribution out of CNS.

49
Q

What is the metabolism of fentanyl?

A

3A4 to inactive N-dealkylation product.

50
Q

What is the half-life of fentanyl?

A

5-15 hours?

51
Q

What does the addition of the oxymethyl group in sufentanil do?

A

It adds lipophilicity… It is more potent than fentanyl with a shorter duration of action.

52
Q

What is the metabolism of sufentanil?

A

Same as fentanyl: 3A4 N-dealkylation to an inactive product.

53
Q

What is the structural difference between remifentanil and fentanyl?

A

Remifentanyl has two ester groups. It is less potent than either fentanyl or sufentanil, but more potent than morphine.

54
Q

What is the half-life and indication of remifentanyl?

A

The half-life is about 6 minutes, and it is used IV

55
Q

What is the metabolism of remifentanyl?

A

Ester hydrolysis to inactive carboxylates.

56
Q

What is the function of the phenol in morphine?

A

It binds to the T (for tyrosine) binding site in a mu receptor.

57
Q

Why can methadone (and fentanyl, meperidine) have a phenyl and still bind to the mu receptor?

A

Because they have phenyl rings, which bind to a different area on the mu receptor. The phenyl binds to the P (phenylalanine site).

58
Q

What activities does naloxone have?

A

Full antagonist at mu, delta, kappa.

59
Q

What is the half-life and metabolism of naloxone?

A

60-90 minutes, rapidly inactivated through glucuronidation (used intranasally or by injection)

60
Q

What activities does naltrexone have?

A

Full antagonist at mu, delta, kappa receptors. Also has active metabolite that contributes to antagonist action.

61
Q

What is the half-life and route of metabolism of naltrexone?

A

3-4 hours, reduced to 6-beta neltrexol which is an active metabolite (full antagonist at all opioid receptors as well)

62
Q

What is better orally, naloxone or naltrexone?

A

Naltrexone.

63
Q

Which antagonist has a quaternary nitrogen? Where does it work?

A

Mehtylnaltrexone bromide. It is a peripherally acting mu antagonist.

64
Q

What is the indication for methylnaltrexone? Half-life and metabolism?

A

Opioid-induced constipation. 8 hours for half-life, 70% is excreted unchanged.

65
Q

Which antagonist is a substrate for p-glycoprotein in the BBB? What is its indication?

A

Naloxegol. It’s pegylated tail reduces diffusion across the BBB, and it gets kicked back out of the CNS. Only acts peripherally, so its indication is opioid-induced constipation.

66
Q

What is the half-life and metabolism of naloxegol?

A

6-11 hours, 3A4 action on PEG tail.

67
Q

Which antagonist has zwitterionic characteristics? What is its metabolism?

A

Alvimopan, which gives it limited CNS access. Peripherally acting antagonist. Amide hydrolysis gives an active carboxylate metabolite.

68
Q

What is the half-life of alvimopan and its metabolite?

A

10-17 hours, and 10-18 hours.

69
Q

What activity does (-) Butorphanol tartrate have? Metabolism?

A

Mu antagonist, kappa agonist. Goes through hydroxylation on the cyclobutyl ring for inactive primary, and glucuronidation minor (also inactive)

70
Q

What is the activity of (-) Nalbuphine? Metabolism?

A

mu antagonist, kappa agonist. Two products: N-dealkylation yields normal buphine, and oxidation yields 6-keto-nalbuphine. Both are considered inactive.

71
Q

Which drugs have partial mu agonist activity?

A

Pentazocine and buprenorphine

72
Q

What is the formulation of pentazocine? Metabolism?

A

A racemic mixture. Hydroxylation occurs at the terminal methyl, then further oxidation to inactive carboxylate.

73
Q

Which structure has the major turkey-foot structure? What is its purpose? What structure contributes to the partial agonist/antagonist activity at the mu receptor?

A

Buprenorphine. Known to increase potency (for agonists). The cyclo-structure gives the antagonist/partial agonist properties.

74
Q

What is the activity of buprenorphine? Metabolism?

A

Partial mu and partial kappa agonist. 3A4 to norbuprenorphine.

75
Q

What is the activity of norbuprenorphine?

A

It is a potent mu agonist (since the cycle-structure was removed) and possibly contributes to overall action. It does contribute to respiratory depression.

76
Q

What antidiarrheal agents are there? Are they peripherally or centrally acting? Why?

A

Diphenoxylate and loperamide. Diphenoxylate is zwitterionic which limits CNS access, while loperamide is a good substrate for P-glycoprotein in the BBB and therefore gets kicked back out into the periphery.

77
Q

What does the addition of atropine to diphenoxylate do?

A

It deters abuse.

78
Q

What is the metabolism of diphenoxylate?

A

Hydrolysis forms a carboxylate metabolite, which is a more potent agonist than diphenoxylate.

79
Q

What is the new drug that supposedly has fewer side effects due to the unique way it binds to the mu receptor?

A

Oliceridine. Apparently it does’t cause as much respiratory depression or constipation.

80
Q

What is the kappa opioid agonist that lacks a basic nitrogen?

A

Salvinorin A. It is linked to a hallucinogenic plant.

Integrated Drug Structure, Action, and Therapeutics (20 decks)

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