DoctorRx1986

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I just had a wisdom tooth extraction today. My oral surgeon prescribed Tylenol 3, which consists of Acetaminophen and 30 mg Codeine Phosphate for pain control. I just have several questions about the mechanism of action of this medication. From my understanding as a fall 2008 incoming P1 student, codeine itself is an inactive drug, namely a prodrug, that is metabolized in the body into its active form, morphine, by the CYP450 enzyme system. The molecule binds to mu-opioid receptors in the central nervous system to produce analgesic effects. First of all, why exactly is sedation and analgesia produced simply by binding to a mu-opioid receptor? What is the significance of binding to these receptors? Are these receptors somehow connected with GABA and thereby produce sedation by increasing the quantity of this neurotransmitter just like benzodiazepines do? Exactly why am I experiencing the sedation and drowsiness at this very moment? I love the feeling, but I cannot help myself with my curiosity and fascination that comes from just looking at these little white tablets in my orange bottle.

Why do slight differences in functional groups on the otherwise similar looking molecule have such a dramatic effect in drug potency? For example, I've read that diacetylmorphine, which is heroin, and contains a similar structure to codeine and morphine, is far more potent than codeine. I obviously knew this, but why does the presence of those two acetyl groups, CH3CO, have any difference in potency? What do those acetyl groups do to make heroin more potent?

Sorry about all these questions, but if you guys are truly pharmacy students who love the material, you should be fascinated by all of this and not only view my post, but actually ANSWER IT as well. So, everyone, chime in! :love:
 

BMBiology

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Binding to the mu receptors give you the analgesic and euphoria feeling but it can also cause physical dependence and respiratory depression. You are feeling sedated right now because codeine also binds to kappa receptors which causes sedation and analgesic effect.
 

MountainPharmD

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If I remember correctly codiene is coverted to about 10% morphine.
 

BMBiology

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In terms of potency, codeine is converted to morphine via 2D6 and is about 15% of morphine.
 

PharmDstudent

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[FONT=Verdana,][SIZE=-1]
*CYP2D6
[/SIZE]. [FONT=Verdana,].[FONT=Verdana,][SIZE=-1]The body converts codeine into morphine (~10%) by using the so called P450 cytochrome pathway, especially cytochrome 2d6 (cyp2d6). Unfortunately, cyp2d6 is missing in about 7% of the white population, and its manifestation is quite variable in the rest. Individuals who inherited a cyp2d6 deficiency will get many of the adverse effects associated with codeine but little euphoria. If codeine just doesn't work for you, this may be why.[/SIZE].


[FONT=Verdana,][SIZE=-1]Codeine is absorbed quickly from the GI tract and it's first pass through the liver results in very little loss of the drug. This contrasts with morphine in which over 90% of the drug is metabolized in the first pass through the liver resulting in a considerable loss of potency when administered orally. This is why codeine is a common opiate in the relief of pain, the ease of oral administration.
[/SIZE].​
 

BMBiology

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I will take UCLA pain management guidelines over opioid.com any day! Nice try though.
 
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DoctorRx1986

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PharmD and Bio, I commend both of you for your apparent passion and determination to demonstrate just how accurate or thorough your knowledge is. Excellent example for an incoming P1 student like me! :)
 

PharmDstudent

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Pharmacy Times
Codeine
Codeine is a prodrug with no analgesic activity. About 10% of a dose of codeine is converted in the body by CYP2D6 to morphine, an active metabolite
(http://www.pharmacytimes.com/issues/articles/2005-05_2238.asp)


I'm starting to think that those folks in California like to exaggerate a bit *cough* global warming *cough* *cough*. :D

PharmD and Bio, I commend both of you for your apparent passion and determination to demonstrate just how accurate or thorough your knowledge is. Excellent example for an incoming P1 student like me! :)
Come on... let me pick on him a little. We all need a good challenge.


My last effort:
Approximately 10 percent of the administered codeine is demethylated to morphine, which may account for its analgesic activity.
RxList
(http://209.85.215.104/search?q=cache:LDwmQwmUeB8J:www.rxlist.com/cgi/generic/acetcod_cp.htm+codeine+metabolized&hl=en&ct=clnk&cd=28&gl=us&client=firefox-a)
 
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DoctorRx1986

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I took my first tablet for pain control at 4 pm and the second one at 8 pm. I am to take no more than 6 tablets over 24 hours. I don't feel any particular sedation, now that I think about it. All I feel is a mild respiratory depression. I'm finding it a little more difficult to breathe, but that's about it. No drowsiness or anything else.
 

BMBiology

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I took my first tablet for pain control at 4 pm and the second one at 8 pm. I am to take no more than 6 tablets over 24 hours. I don't feel any particular sedation, now that I think about it. All I feel is a mild respiratory depression. I'm finding it a little more difficult to breathe, but that's about it. No drowsiness or anything else.
sedation is precursor to respiratory depression so be careful. I would stop if you are having a hard time breathing. Did your dentist give you an NSAID for inflammation? Most patients need IBU 800mg tid or 600mg qid for dental procedure.
 

PharmDstudent

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Good read, btw and yes it says codeine is ~15% of morphine. Stop trying so hard. :laugh:
I like a challenge. I've been bored lately, which isn't good for me because boredom makes me sad and depressed.

I've been working, cooking, cleaning, playing on the computer, and planning little vacations. It still isn't enough though. I found a few old books that look interesting, so I might start reading on my own again.

Perhaps I'm due for a street car ride into the French Quarter. Maybe I'll catch an IMAX movie while I'm down there- Dolphins and Whales 3D or Sea Monsters 3D?
 
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DoctorRx1986

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sedation is precursor to respiratory depression so be careful. I would stop if you are having a hard time breathing. Did your dentist give you an NSAID for inflammation? Most patients need IBU 800mg tid or 600mg qid for dental procedure.

No, and I'm surprised this guy didn't do so. I changed dentists recently and this was my first time with this dentist. He is an oral surgeon. The guy was a complete arrogant, ahole, who surely prescribed the pain medication, but not for inflammation. Last time I had my bottom wisdom teeth extracted, the dentist prescribed Ibuprofen 800 mg TID. This guy didn't. When I first told him I had hydrocodone and Ibuprofen with another dentist, he seemed surprised. I was too numb to even realize he didn't prescribed a NSAID.
 

PharmDstudent

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No, and I'm surprised this guy didn't do so. I changed dentists recently and this was my first time with this dentist. He is an oral surgeon. The guy was a complete arrogant, ahole, who surely prescribed the pain medication, but not for inflammation. Last time I had my bottom wisdom teeth extracted, the dentist prescribed Ibuprofen 800 mg TID. This guy didn't. When I first told him I had hydrocodone and Ibuprofen with another dentist, he seemed surprised. I was too numb to even realize he didn't prescribed a NSAID.
Chill or they'll lock it!
 

WVUPharm2007

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You shoulda got Lortab instead.
 

BMBiology

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No, and I'm surprised this guy didn't do so. I changed dentists recently and this was my first time with this dentist. He is an oral surgeon. The guy was a complete arrogant, ahole, who surely prescribed the pain medication, but not for inflammation. Last time I had my bottom wisdom teeth extracted, the dentist prescribed Ibuprofen 800 mg TID. This guy didn't. When I first told him I had hydrocodone and Ibuprofen with another dentist, he seemed surprised. I was too numb to even realize he didn't prescribed a NSAID.
Three Letters: OTC
 

BMBiology

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I like a challenge. I've been bored lately, which isn't good for me because boredom makes me sad and depressed.

I've been working, cooking, cleaning, playing on the computer, and planning little vacations. It still isn't enough though. I found a few old books that look interesting, so I might start reading on my own again.
Are you bipolar by any chance?
 

WVUPharm2007

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Remember that time I threatened to go to the house of and then cut the balls off of some douchebag poster on the dentistry forum for making fun of my wife's mouth pain after oral surgery? That was hilarious.
 

njac

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I took my first tablet for pain control at 4 pm and the second one at 8 pm. I am to take no more than 6 tablets over 24 hours. I don't feel any particular sedation, now that I think about it. All I feel is a mild respiratory depression. I'm finding it a little more difficult to breathe, but that's about it. No drowsiness or anything else.
respiratory suppression occurs at concentration far above those for analgesia.

I think there's some placebo effect here. As a healthy young person you shouldn't get even a semblance of respiratory suppression from 30 mg of codeine q4h.

to reiterate what I've said in other threads: simmer down.
 

RxWildcat

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I doubt that dose would cause dyspnea.
 

PharmDstudent

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Are you bipolar by any chance?
No. I just really hate being bored. I've always been like that. They keep us busy during school, so when summertime comes, I have all the time in the world but nothing to do. It's a Type A's worst nightmare --> a test in patience. :scared:

Most likely, I'll burn some time by studying for the GRE. I might study for the MCAT too, but four more years of school plus residency on top of two more years in pharmacy school before I can graduate is a daunting thought to say the least.
The study books are expensive too.
 

PharmDstudent

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Remember that time I threatened to go to the house of and then cut the balls off of some douchebag poster on the dentistry forum for making fun of my wife's mouth pain after oral surgery? That was hilarious.
Yeah. That was a good thread.
 

Alby

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Opioids interact stereospecifically with protein receptors on the membranes of certain cells in the CNS, on nerve terminals in the periphery and on cells of the gastrointestinal tract and other anatomic regions. The major effects of the opioids are mediated by three major receptor families. These are designated by the Greek letters μ (mu), κ (kappa) and δ (delta), each exhibiting a different specificity for the drug(s) it binds. The analgesic properties of the opioids are primarily mediated by the μ receptors; however, the κ receptors in the dorsal horn also contribute. All three opioid receptors are members of the G protein-coupled receptor family, and inhibit adenylyl cyclase. They are also associated with ion channels, increasing postsynaptic K+ efflux (hyperpolarization) or reducing presynaptic Ca2+ influx, thus impeding neuronal firing and transmitter release.
 

RxWildcat

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why the copy/paste physiology?
 

BlueCrayon

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:laugh:

I'm eating dinner, so my Google skills are handicapped at the moment. Four cheese Lean Pockets are good! :love:
I have nothing intelligent to add to this thread except to say that I think I'm addicted to lean pockets!! :laugh: They might need to ween me off of them with, say, burritos or something. They're like a dollar at target so I take one to work for lunch every day.
 

Alby

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I just had a wisdom tooth extraction today. My oral surgeon prescribed Tylenol 3, which consists of Acetaminophen and 30 mg Codeine Phosphate for pain control. I just have several questions about the mechanism of action of this medication. From my understanding as a fall 2008 incoming P1 student, codeine itself is an inactive drug, namely a prodrug, that is metabolized in the body into its active form, morphine, by the CYP450 enzyme system. The molecule binds to mu-opioid receptors in the central nervous system to produce analgesic effects. First of all, why exactly is sedation and analgesia produced simply by binding to a mu-opioid receptor? What is the significance of binding to these receptors? Are these receptors somehow connected with GABA and thereby produce sedation by increasing the quantity of this neurotransmitter just like benzodiazepines do? Exactly why am I experiencing the sedation and drowsiness at this very moment? I love the feeling, but I cannot help myself with my curiosity and fascination that comes from just looking at these little white tablets in my orange bottle.

Why do slight differences in functional groups on the otherwise similar looking molecule have such a dramatic effect in drug potency? For example, I've read that diacetylmorphine, which is heroin, and contains a similar structure to codeine and morphine, is far more potent than codeine. I obviously knew this, but why does the presence of those two acetyl groups, CH3CO, have any difference in potency? What do those acetyl groups do to make heroin more potent?

Sorry about all these questions, but if you guys are truly pharmacy students who love the material, you should be fascinated by all of this and not only view my post, but actually ANSWER IT as well. So, everyone, chime in! :love:
Because the question was asked.
 
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DoctorRx1986

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respiratory suppression occurs at concentration far above those for analgesia.

I think there's some placebo effect here. As a healthy young person you shouldn't get even a semblance of respiratory suppression from 30 mg of codeine q4h.

to reiterate what I've said in other threads: simmer down.

Is it possible for me to have a deficiency of the CYP2D6 enzyme to properly metabolize/convert the drug into one of its active forms, morphine? I ask this because the pharmacist at Walgreens specifically told me the medication would induce drowsiness, but I haven't felt any at all. I figure perhaps my system is just not very responsive to the drug. In terms of the minor respiratory depression, I also believe this might result from lack of that enzyme, as the drug and its metabolites probably remain accumulated/concentrated in my blood beyond the typical half-life and thereby continue to accumulate every 4 hours to a concentration that is normally beyond analgesia. I started to cut down the once every four hours instruction for this reason...it seems my body doesn't metabolize it well. But then, i'm not a P1 yet...so, correct me if i'm wrong.
 

PharmDstudent

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Is it possible for me to have a deficiency of the CYP2D6 enzyme to properly metabolize/convert the drug into one of its active forms, morphine? I ask this because the pharmacist at Walgreens specifically told me the medication would induce drowsiness, but I haven't felt any at all. I figure perhaps my system is just not very responsive to the drug. In terms of the minor respiratory depression, I also believe this might result from lack of that enzyme, as the drug and its metabolites probably remain accumulated/concentrated in my blood beyond the typical half-life and thereby continue to accumulate every 4 hours to a concentration that is normally beyond analgesia. I started to cut down the once every four hours instruction for this reason...it seems my body doesn't metabolize it well. But then, i'm not a P1 yet...so, correct me if i'm wrong.
The enzyme converts codeine to morphine. If you aren't "making" morphine due to insufficient enzyme production, then you would have less respiratory depression than someone who is converting a higher fraction of the drug into morphine.
less activation of morphine --> less respiratory depression


This is from the Pharmacy Times link that I posted last night:
"Codeine
Codeine is a prodrug with no analgesic activity. About 10% of a dose of codeine is converted in the body by CYP2D6 to morphine, an active metabolite. The morphine is glucuronidated to both active and inactive metabolites that are eliminated by the kidneys. The rest of the codeine is metabolized by glucuronidation and CYP3A4 to inactive metabolites. Thus, CYP2D6 is necessary for much of the analgesic action of codeine.
Most Caucasians rapidly convert codeine to morphine via CYP2D6. Approximately 7% to 10% of Caucasians, however, have a genetic variant that produces limited CYP2D6 activity and slow metabolism of CYP2D6 substrates. In these patients, conversion of codeine to morphine is reduced, as is the analgesic efficacy. Administration of codeine to these patients will not provide the expected degree of analgesia.
Side effects of codeine also are reduced when intrinsic CYP2D6 activity is reduced. Similarly, drugs that reduce CYP2D6 activity will inhibit the analgesic activity of codeine.2,3 The Table lists some common inhibitors of CYP2D6. Whereas not all CYP2D6 inhibitors have been studied with codeine, all would be expected to interact to some extent."
 
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DoctorRx1986

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You haven't talked about your constipation yet, or is that just cause no one told you it'll happen? :smuggrin:

lol, thank god i haven't experienced that :laugh:. As a matter of fact, I don't even suffer from the minor respiratory depression I was afflicted with yesterday.
 

RxWildcat

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Priapism321

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This thread gives me a headache. 44 replies? Tell this kid to look it up the best they can and save all of the sub-standard references and banter.
 

PharmDstudent

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This thread gives me a headache. 44 replies? Tell this kid to look it up the best they can and save all of the sub-standard references and banter.
:rolleyes: I forgot. Priapism321 is his own expert.
 

PharmDstudent

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Come on Priapism321... where's the snide comment or the overly thought out comeback post??? :(
 

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I actually agree with priapism on this one... :eek:

50 posts on T#3... :eek:

:eek: