Category Archives: Analgesics

Pentazocine: Partial Pleasure

Woohoo!  Partial Agonists!

Not excited yet?  Well, maybe your level of enthusiasm has only been moderately increased.  Coincidentally, that phenomenon is similar to the action of pentazocine (Talwin), a opioid partial agonist in the agonist/antagonist class of opioid analgesics.  First, a brief review of what all of these a-words mean (for more details visit the Pharmacodynamics section under the tab “Basics of Pharmacology”)

1. Agonist: a drug that makes a receptor “go”.  This can happen through several mechanisms, including directly binding to a receptor or preventing the clearance of other agonists.

2. Antagonist: the nemesis of the agonist.  A substance that “turns off” a receptor, blocks it, or prevents agonists from binding.

3. Partial agonist: a drug that acts on a receptor and makes it “go”, but at a more moderate level than an agonist.

Anyway, back to pentazocine, which is IMHO a very cool drug.  It is a opioid partial agonist that binds directly to opiate receptors, causing a more moderate analgesic effect than opioid agonists like morphine.  This action in and of itself is pretty rockin’. But check this out: not only does pentazocine irreversibly bind to the receptors, but it kicks off any bound agonist in its path!  This is why pentazocine is considered an agonist/antagonist. It acts like an antagonist, bullying those agonists away, but still makes the cell do something!  Astounding!

Pentazocine is used as an analgesic for moderate to severe pain.  If it is enough analgesia for a person, it is a great choice; since this drug has a lessened effect on opioid receptors compared to, say, morphine or hydromorphone, it will also have fewer severe side effects (like reduced respirations!).

Now consider this:  If a person has already been taking an opiate (these facts can be hidden…assess!) should you give them pentazocine?  NO WAY!  Remember, pentazocine punts those comfortably-bound agonists off of the receptors and replaces them! Someone who already has some opiates on board, no matter what kind (heroin, cough syrup with codeine, hydrocodone, oxycontin…)can go straight into withdrawal.  Yikes!  Withdrawal from opiates is uncomfortable, painful, and generally accompanied by vomiting, which is just no fun for anyone involved.  Especially the nurse*.

 

*Yes, yes, a very selfish statement considering the nurse is not the one barfing and having intolerable night sweats.  But we do get some credit for remaining calm and soothing while being yacked on. 😉

 

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Celecoxib: Celebrate Celectivity

As you may have guessed, celecoxib (Celebrex) is the answer to the question: “If blocking COX-1 is so much of a problem, why does it have to happen?”  Of course, the real answer is that it is extremely complicated to formulate a drug that is so selective.

Celecoxib was developed as a drug for arthritis.  It is a selective COX-2 inhibitor, so it annihilates inflammation, kills pain, brings down fevers, and causes vasoconstriction (which also helps quell the inflammation), all without touching the homeostatic, protective side of things. So, great, right?

Well, celecoxib does its job well, but a little too well in some respects.  Although it doesn’t mess with protective COX-1, it does cause an awful amount of vasoconstriction.  It’s possible that the fact that non-selective NSAIDs mess with platelet aggregation actually makes this a little less of a problem with them.

Celecoxib carries a big risk for heart attack and stroke, primarily due to vasoconstriction. Since the blood isn’t thinned at all by this drug (a purposefully-avoided side effect!), the constriction of the blood vessels can be very problematic.  Also, the people to whom this drug is marketed (those with arthritis) tend to be older and thus at greater risk for these complications anyway!

Ah, well it was a good try.  Celecoxib is an effective and selective drug, but we have to be very watchful of its dangerous effects.

Acetaminophen: If You Think That’s Hard to Say, Try N-Acetyl-P-Aminophenol

Ah, the drug by many names.  N-acetyl-P-aminophenol is the chemical name of acetaminophen (USA)/paracetamol (Canada, UK).  It’s most common trade name, you may know, is Tylenol.

Acetaminophen, although it does eventually inhibit COX-2 (we think*), is not considered an NSAID. This is because, although it is simply fabulous for reducing fever and producing mild analgesia, it is lousy at anything anti-inflammatory. So we can’t call it a “non-steroidal anti-inflammatory”, get it?   It also doesn’t inhibit platelet production like NSAIDs, so it’s okay to take with blood thinners.  Why, you ask?  Well, as are many things in our world, that is a matter up for debate.  It is possible that the structure of acetaminophen allows for metabolites that have further actions, or for a reduced inhibition of certain COX-2 products.  What we do know for sure is:

1) If you have a fever, acetaminophen is a great way to reduce it

2) If you have some mild to moderate pain, acetaminophen is a great way to kill it

3) Acetaminophen kicks the s*** out of your liver.

Yes, sad but true.  Acetaminophen is metabolized in the liver.  That, in and of itself, is not really the problem.  The problem is that when the CYP450 pathway breaks it down, one of the end products is highly hepatotoxic (hurts the liver).  It’s bad.  But the double insult is that only a small percentage of acetaminophen actually goes through the CYP450 pathway!  Most of it is glucorinidated in the liver, which yields nice, non-toxic byproducts.

This risk of toxicity is SUPER important to remember.  It is dangerous for:

1) People who have been on it a long time (like someone who takes it regularly OTC)

2) People who overdose on it (duh)

3) People who drink a lot (or who take it regularly after a night of drinking…try an NSAID with a greasy breakfast)

4) People with liver disease, liver weakness, or are at risk for either

5) People that are taking other hepatotoxic drugs (there are quite a few)

Fun fact (depending on how you look at it, I suppose):  If someone overdoses on acetaminophen, and you catch them fairly early, there is a drug called acetylcysteine (MucoMyst) that can stop some of the liver damage from occurring.  Acetylcysteine is generally used as a mucolytic** for various mucous-producing ailments, but also happens to have a structure that binds to toxic metabolites in the liver.  What luck!  Emphasis on catching it early, though.  Those poor little hepatocytes have a lot of work to do, and will not last long when damaged!

*There are just so many mysteries.  If you are interested in spending an afternoon figuring this out, might I recommend going to http://www.scirus.com and searching for “acetaminophen pharmacodynamics”.  Make sure the search is limited to published research from the last few years.  Wikipedia also has an interesting article with several fun references at the end.  If you learn some promising stuff, don’t forget to share it with me!!

**Mucolytics break up mucous!  This is particularly important in diseases such as Cystic Fibrosis, in which patients suffer from ridiculously thick and difficult-to-expectorate lung secretions. It just so happens that their effects on toxic liver byproducts are therapeutic.

Non-Selective COX Inhibitors: Any COX Will Do!

I know, I’m getting a little carried away with the punny titles, and they aren’t even that good.  What can I say?

The Non-Selective NSAID’s are generally the ones you see every day:  ibuprofen (Advil, Motrin, Nuprin) and aspirinNaproxen sodium is another one of these, but for now let’s chalk it off as more like ibuprofen.
These two drugs (ibuprofen and aspirin) are very similar in site and mode of action, but because of their formulations, individual properties, and potencies, they have a slightly different effect on the body.  Since now you know what COX-1 and COX-2 are responsible for, I’ll just give you a quick run-down of the ups and downs of the non-selective NSAIDs.

Ibuprofen:

Therapeutic effects (from COX-2 inhibition):  Anti-inflammatory, analgesic, mild anti-pyretic, vasoconstrictor

Adverse effects (from COX-1 inhibition):  Mucosal damage, nephrotoxicity, bleeding (especially in the GI tract).  COX-2 inhibition can also cause problems with vasoconstriction, like a rise in blood pressure!

Aspirin:

Therapeutic effects (from COX-1 AND COX-2 inhibition)Anti-inflammatory (C-2), analgesic (C-2), mild anti-pyretic (C-2), vasoconstrictor (C-2), Anti-platelet (C-1).  You may have noticed that in this case, the anti-platelet effects of aspirin can be considered therapeutic.  It has a stronger blood-thinning capacity at normal dose than ibuprophen, which makes it important in stroke/clot/MI prophylaxis!

Adverse effects (from COX-1 inhibition):  Bleeding, bleeding, bleeding.  Especially from the GI tract.  Aspirin is WAY better at stopping thrombus formation than ibuprofen, so it’s a really bad idea to give it to anyone with a tender stomach or bleeding problem.  Just like ibuprophen, it can cause damage to the mucosa and renal system, too!

When we are giving medications, we always have to be aware of existing and potential problems.  As you can see, NSAIDs, especially aspirin, have the potential of causing some serious complications.  On top of all of this, they are OVER THE COUNTER!   Many, many people pop aspirin because it is “good for you” and “no big deal”.  Same thing with ibuprofen.

Next time you have a killer hangover, by the way, do yourself a favor and eat something before you assault your mucosa.

NSAIDs: COX Blockers!

Non-steroidal anti-inflammatory drugs are some of the most effective non-opioid pain relievers that we have.  There are lots of kinds of NSAIDs, but luckily, most of them are probably familiar to you!

NSAIDs inhibit part of the arachidonic acid (AA) pathway that leads to the formation of enzymes known as cyclooxogenase (COX) 1 and 2. COX 1 and 2 are an integral part of the synthesis of prostaglandin E (PGE2), a major player in the inflammatory response.

This pathway is a wonderful example of how pictures help us with physiology.

https://i1.wp.com/www.arthritis.co.za/images/nsc.gif

image:  http://www.arthritis.co.za/images/nsc.gif

As you can see from the diagram, COX-1 and COX-2 have some very different effects!  What you see on the right is a representation of COX-2 as part of the inflammatory cascade.  It creates prostaglandin E2 and I2 when cued by cytokines.  Blocking COX-2 means blocking the inflammatory response!  On the left of the diagram is COX-1, which also produces prostaglandin E2, but is not induced by inflammatory signals.  COX-1 produces several other types of prostaglandins, and other substances like thromboxanes, to maintain homeostasis in the body.  This homeostasis is especially important in the GI and renal systems, as all of these substances balance out to protect the mucosa and prevent the blood from being too thin or thick.

Why is this so important?  Well, there are several drugs you probably already know and love (especially for tension headaches and hangovers) that are NSAIDs.  Chances are, the ones you take the most are the least selective!

 

 

Naloxone: The Antidote (aka The Cruel Awakening)

This drug is the OPPOSITE OF FUN.  For real.  You do NOT want naloxone (Narcan) unless you absolutely, positively need it.  Naloxone is an opioid receptor antagonist.  Think about it.  Owwwwww.

The most important thing to know about naloxone is that it is the best way to rescue someone that has either overdosed on or had a bad reaction to morphine/heroin/any opioid.  The reason it is NOT a fun drug is that it actually kicks morphine (and other opioid agonists) off the mu receptors, essentially reversing the peaceful, pain-free, near-death experience and throwing it into the complete opposite.

It’s certainly a nice thing to have around, and an absolute necessity when you are giving an opioid analgesic, but please, use it with care!

Morphine: Haven’t Got Time for the Pain

Morphine is the prototype for opioid analgesics.  This baby is a pure mu receptor agonist, so it has some amazing pain-killing properties!

Pharmacokinetics:

Morphine can be absorbed tons of ways.  It can be given IV, SubQ, IM, PO, intrathecally, and rectally.  You can also snort it but I wouldn’t recommend suggesting that to a patient. It is distributed via the blood stream to the mu receptors in your spinal cord, brain, and small intestine.  That last part is important to remember! The liver metabolizes it and the kidneys excrete it.

Morphine is an example of a drug that does not have a ceiling.  Some drugs have a point of concentration when they actually stop working.  Adverse effects can sometimes still worsen (great, huh?) but with no more nice analgesia.  Morphine can just keep building and building, and it will relieve more and more pain.  This doesn’t mean that people can’t overdose, of course, but it does mean that although it may require more morphine to relieve the pain, more can be given and with good effect.

You may remember that opioid analgesics produce euphoria and reduce pain. They are also CNS depressants, which means we have to be VERY careful to watch patients after they are given morphine.  Why, you ask?  I’m glad you did!

Because CNS depression…

1.  Reduces the respiratory rate.  You want it between 12-20 breaths per minute, but morphine can drop that really quickly.  It also reduces air hunger (your gasping reaction when you are out of breath) so it’s difficult to see unless you are counting breaths.

2. Reduces level of consciousness.  If you patient immediately falls into a deep sleep and their respiratory rate drops, this is a problem.

The other big problem with morphine is that it makes you VERY CONSTIPATED.  You know why?  Because mu receptors are all over your gut!  Morphine slows the digestive tract and can pretty much bring it to a halt.

So when you have a patient that needs morphine, remember you always have to check their respiratory rate and level of consciousness BEFORE you give it to them (to make sure they aren’t already having issues) and AFTER (to make sure they don’t get any issues).