Opioid Agonists – Opioid Analgesics

00:01 Now let's go back to the list of opioid analgesics. We have weak, moderate and strong agonists, we also have mixed agonist and antagonists. Let's start with the weak agonists.

00:16 Now, this particular agent is discontinued. It is a weak drug, it used to be used for diarrhoea.

00:23 I only put it there because it's on the one end of the spectrum. Let's move on to the moderate agonists.

00:29 Codeine and oxycodone. These are the most prescribed opioids out there. They are metabolized by cytochrome 2D6 to morphine, which is the active component or active drug. It's actually not quite exactly morphine, but close enough for this lecture.

00:44 There is significant genetic variability in how the cytochrome P450 enzymes metabolize drugs.

00:50 And if you go back to your pharmacokinetic lecture, you'll see that there's many genes that can encode for the metabolism of this, and so different people will have different ways of metabolizing this drug.

01:01 Ingestion of alcohol causes major increases in serum levels. So when you prescribe patients codeine, we want to get them abstained from alcohol.

01:14 In terms of this medication at low doses, codeine is used to suppress cough.

01:21 So, we often put codeine in cough syrups, and in patients who have severe chronic cough, we will actually use codeine tablets on their own. We do not use it for treating diarrhoea, but one of the side effects can be constipation.

01:35 Once again, it is the most commonly prescribed analgesic, and most commonly is combined with acetaminophen to give extra pain control.

01:46 This brings us to the strong agonists. There are several in this category, I've listed four of them.

01:53 There's morphine, meperidine, methadone and fentanyl. Let's go into detail about each of these.

01:59 Let's start off with the metabolism of these drugs.

02:03 Morphine undergoes extensive first-pass metabolism in the liver, which reduces its bioavailability when taken orally.

02:10 As a result, a significant portion of the dose is metabolized before it can exert systemic effects, leading to a lower concentration of active drug reaching the bloodstream.

02:21 Meperidine has hepatic conjugation and renal excretion. Methadone has high fat solubility.

02:28 This is an important consideration because we tend to use this for detoxification programs, so given once, it will stay in the body for a long time.

02:37 Now, fentanyl is a very potent opioid. It is 80 times more powerful than morphine, and 40 times more powerful than heroin.

02:48 In terms of the metabolites, morphine has a metabolite that is as active as morphine.

02:54 Meperidine may cause seizure. So it's important to know this when you're choosing this medication.

03:00 Methadone, the metabolism is going to be highly variable. So, when we're using this in detoxification programs, we have to be very careful that we're not giving too much or too little.

03:13 Fentanyl is predominantly converted by CYP3A4 to norfentanyl, an inactive metabolite, and excreted in the urine.

03:21 In terms of respiratory functions, morphine does cause mild respiratory depression and low blood pressure.

03:28 It can cause nausea and vomiting in some patients as well. With meperidine, your side effect profile is pretty much the same as morphine, but you can actually induce serotonin syndrome and hyperpyrexia.

03:43 Methadone has more respiratory depression, but it is better at analgesia.

03:48 And finally, fentanyl has more respiratory depression, but it has fewer histamine side effects.

03:55 In terms of other side effects, constipation is a real problem with morphine.

04:00 That's because of activity at the mu receptor in the gut.

04:03 Meperidine, on the other hand, may be used in post-anesthetic shivering. Methadone, once again, is a mu receptor agent, and it's also a NMDA receptor agent. And finally, fentanyl is a strong mu agonist and it is used in operative conditions.

04:21 Morphine of course is highly addictive. Meperidine of course is very addictive as well.

04:25 Fentanyl is very addictive. And methadone is singular in that, it is often used in detoxification regimens.

04:35 Have a look at this graph or this table, and make sure that you understand the differences between these opioid analgesics.

04:44 Let's talk about meperidine and serotonin syndrome and hyperpyrexia syndrome.

04:50 I put this slide up so that you can understand the differences between the two.

04:55 Remember that serotonin syndrome can occur with meperidine when used in combination with SSRIs.

05:02 So, patients who are on selective serotonin reuptake inhibitors and meperidine can develop the serotonin syndrome.

05:08 With respect to the hyperpyrexia syndrome, that's when it's being used in combination with monoamine oxidase inhibitors.

05:16 So, very similar symptoms complexes, but very different causes.

05:22 Remember that serotonin syndrome is potentially fatal. And remember that hyperpyrexia may result in seizures or a coma.

05:31 So, meperidine should be used with caution in these patients.