Flashcards in Anesthetics and Analgesics - Proteau's Drugs Deck (80)
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?
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
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?
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 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.