Anesthetics and Analgesics - Proteau's Drugs Flashcards
What structural features are important in cocaine’s function as an anesthetic? What is the main route of metabolism?
The benzoate ester. Ester hydrolysis from the two esters.
Why is procaine better than cocaine as an anesthetic? Does it still undergo the same route of metabolism?
There are little CNS effects or tissue irritation. Yes, it still undergoes ester hydrolysis on the benzoate ester. It also has a tertiary amine.
What are the allergic reactions of those using procaine due to?
The PABA product
What are the three pieces of general anesthetics?
- Lipophilic portion - aromatic ring
- Intermediate chain - ester or amide (ketone or ether less common)
- Hydrophilic portion - tertiary amine between 7.5-9.0 pKa
In amino ester local anesthetics, what increases potency of the anesthetic?
An EWG in the ortho or para position
What is the potency of tetracaine in comparison to procaine?
It is 50x more potent. Due to butyl mainly (EWG)
Which medications give PABA or PABA-like metabolites?
Procaine, tetracaine, chloroprocaine, benzocaine
What is the potency of procaine compared to chloroprocaine?
Chloroprocaine is 2x more potent. The Cl makes the ester more susceptible to hydrolysis.
What feature of benzocaine makes it only able to be used topically?
It lacks a tertiary amine, and so can’t be protonated at physiological pH. Highly lipophilic.
What are the problems with amino esters?
They form PABA or PABA-like products, and have fast ester hydrolysis.
Compare amino amide local anesthetics and amino esters:
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.
What is bupivacaine used as? What is the main problem with it?
Used as a racemate: both enantiomers have local anesthetic action. It has some cardiotoxicity.
What has a longer duration of action, bupivacaine or lidocaine?
Bupivacaine.
What is the difference between bupivacaine and ropivacaine?
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.
Which drug is mainly used for dental procedures?
Articaine. Rapid ester hydrolysis.
What is articaine formulated as? How is it’s level of cardiotoxicity?
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.
What is pramoxine in? Dyclonine?
Neosporin & pain relief, and Sucrets. These are the ether and ketone amino local anesthetics, respectively.
What are “met” and “leu” enkephalins and what is the difference?
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.
What are the three types of opioid receptors? Which will we focus on for pain?
Mu, delta, kappa. We will focus on Mu for pain.
What is the prototype of opioids?
morphine
Morphine SAR: Modifications that decrease activity?
- Remove 3 OH group
- Replace 3 OH with 3 O-meth
- Add 3 CH3CO ester
- Remove N methyl
Morphine SAR: Modifications that increase activity?
- Remove 6 OH
- Reduce 7,8 double bond
- Add a 14beta OH group
- CH3CO ester at 6
Which enantiomer of morphine is active at opioid receptors?
- (-). (+) is inactive
What is the metabolism of morphine? Are the metabolites active?
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).
What is the half-life of morphine and it’s active metabolite?
2-3 hours for morphine and 6&1/2 hours for M6G.
What drug is 3,6-diacetylmorphine?
Heroin. It is a morphine prodrug.
Which is more potent, morphine or heroin? Why?
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.
Is codeine a prodrug?
No, because it has antitussive properties as the actual drug. 2D6 O-demethylation is used to get morphine.
What is the issue with poor and rapid metabolism of CYP 2D6 and codeine?
Poor metabolizers will not get adequate analgesia, while rapid metabolizers will have to worry about potential overdoses.
What does hydrocodone use to metabolize? Is is a prodrug.
2D6 to hydromorphone. It is not a prodrug: both hydrocodone and its metabolite contribute to the analgesic action.
What is the potency of hydromorphone compared to morphine? Metabolism?
It is 8x more potent than morphine. The main route of metabolism is glucuronidation at position 3.
Compare the potency of oxymorphone to morphine. What is the main route of metabolism?
It is 10x more potent than morphine, and the main route of metabolism is glucuronidation.
What is the similarity between oxycodone and hydrocodone?
They both have intrinsic activity and do not rely on 2D6 for sole analgesia.
What and how is oxycodone metabolized to?
Metabolized to oxymorphone by 2D6 (active). T1/2 = 4 hours.
What is (+) dextromethorphan a mirror image of?
(-) 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.
What is the potency of levophanol? Metabolism? Extra properties?
Slightly more potent than morphine. Glucuronidation. NMDA antagonist properties.
Which drug has just two rings?
Meperidine
What is the potency of meperidine? What is the metabolism?
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).
What is methadone formulated as?
A racemate. R (-) isomer is active at mu receptors. Both R (-) and S (+) enantiomers have NMDA antagonist properties.
Compare methadone and morphine potency. What is the half-life of methadone?
Equipotent to morphine. It is long and variable… about 24 hours.
What is the route of metabolism of methadone?
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.
Since 2D6 is not used in metabolizing methadone, why is there such a range in half-lives?
Because there are genetic polymorphisms in 2B6.
What is tramadol formulated as?
A racemate of R,R and S,S cis isomers.
What is the metabolism of tramadol?
2D6, which means poor metabolizers have significant changes in half-lives.
What type of agonist activity is present in tramadol?
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
What is tapentadol formulated as? What is its main route of metabolism? What is its agonist activity.
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.
Which has the longer half-life, tramadol or tapentadol?
Tramadol is 6 hours, tapentadol is 4 hours.
What is the potency of fentanyl compared to morphine? Duration of action?
100x more potent than morphine. Shorter duration of action due to greater lipophilicity and greater distribution out of CNS.
What is the metabolism of fentanyl?
3A4 to inactive N-dealkylation product.
What is the half-life of fentanyl?
5-15 hours?
What does the addition of the oxymethyl group in sufentanil do?
It adds lipophilicity… It is more potent than fentanyl with a shorter duration of action.
What is the metabolism of sufentanil?
Same as fentanyl: 3A4 N-dealkylation to an inactive product.
What is the structural difference between remifentanil and fentanyl?
Remifentanyl has two ester groups. It is less potent than either fentanyl or sufentanil, but more potent than morphine.
What is the half-life and indication of remifentanyl?
The half-life is about 6 minutes, and it is used IV
What is the metabolism of remifentanyl?
Ester hydrolysis to inactive carboxylates.
What is the function of the phenol in morphine?
It binds to the T (for tyrosine) binding site in a mu receptor.
Why can methadone (and fentanyl, meperidine) have a phenyl and still bind to the mu receptor?
Because they have phenyl rings, which bind to a different area on the mu receptor. The phenyl binds to the P (phenylalanine site).
What activities does naloxone have?
Full antagonist at mu, delta, kappa.
What is the half-life and metabolism of naloxone?
60-90 minutes, rapidly inactivated through glucuronidation (used intranasally or by injection)
What activities does naltrexone have?
Full antagonist at mu, delta, kappa receptors. Also has active metabolite that contributes to antagonist action.
What is the half-life and route of metabolism of naltrexone?
3-4 hours, reduced to 6-beta neltrexol which is an active metabolite (full antagonist at all opioid receptors as well)
What is better orally, naloxone or naltrexone?
Naltrexone.
Which antagonist has a quaternary nitrogen? Where does it work?
Mehtylnaltrexone bromide. It is a peripherally acting mu antagonist.
What is the indication for methylnaltrexone? Half-life and metabolism?
Opioid-induced constipation. 8 hours for half-life, 70% is excreted unchanged.
Which antagonist is a substrate for p-glycoprotein in the BBB? What is its indication?
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.
What is the half-life and metabolism of naloxegol?
6-11 hours, 3A4 action on PEG tail.
Which antagonist has zwitterionic characteristics? What is its metabolism?
Alvimopan, which gives it limited CNS access. Peripherally acting antagonist. Amide hydrolysis gives an active carboxylate metabolite.
What is the half-life of alvimopan and its metabolite?
10-17 hours, and 10-18 hours.
What activity does (-) Butorphanol tartrate have? Metabolism?
Mu antagonist, kappa agonist. Goes through hydroxylation on the cyclobutyl ring for inactive primary, and glucuronidation minor (also inactive)
What is the activity of (-) Nalbuphine? Metabolism?
mu antagonist, kappa agonist. Two products: N-dealkylation yields normal buphine, and oxidation yields 6-keto-nalbuphine. Both are considered inactive.
Which drugs have partial mu agonist activity?
Pentazocine and buprenorphine
What is the formulation of pentazocine? Metabolism?
A racemic mixture. Hydroxylation occurs at the terminal methyl, then further oxidation to inactive carboxylate.
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?
Buprenorphine. Known to increase potency (for agonists). The cyclo-structure gives the antagonist/partial agonist properties.
What is the activity of buprenorphine? Metabolism?
Partial mu and partial kappa agonist. 3A4 to norbuprenorphine.
What is the activity of norbuprenorphine?
It is a potent mu agonist (since the cycle-structure was removed) and possibly contributes to overall action. It does contribute to respiratory depression.
What antidiarrheal agents are there? Are they peripherally or centrally acting? Why?
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.
What does the addition of atropine to diphenoxylate do?
It deters abuse.
What is the metabolism of diphenoxylate?
Hydrolysis forms a carboxylate metabolite, which is a more potent agonist than diphenoxylate.
What is the new drug that supposedly has fewer side effects due to the unique way it binds to the mu receptor?
Oliceridine. Apparently it does’t cause as much respiratory depression or constipation.
What is the kappa opioid agonist that lacks a basic nitrogen?
Salvinorin A. It is linked to a hallucinogenic plant.
