Opioid agonists, mixed agonist-antagonists and partial agonists

Video summary

Opioid full agonists are drugs that bind to and activate opioid receptors in the body. They are used to treat pain and can also produce feelings of euphoria, which has led to their abuse and addiction potential. Examples of opioid agonists include morphine, codeine, and oxycodone.

Mixed agonist-antagonists bind to and activate opioid receptors to a certain extent, but also have the ability to block or inhibit the effects of other opioids. They can also be used to treat pain and may have a lower risk of abuse and addiction compared to full agonists.

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Introduction0:00–0:24

Opioid medications are used mainly to control pain. Some of them are also used to treat diarrhea and cough when treating pain.
The goal should be to use short acting opioids at the lowest effective dose for the shortest duration possible and slowly increase the dose only as needed as a class opioids share one thing in common.

Physiology0:24–2:02

They bind to opioid receptors in the brain. Spinal cord and gastrointestinal tract.
Some are endogenous meaning they are produced naturally by the body like endorphins named for endogenous morphine due to their similar effects in the body.
But others are exogenous meaning they come from outside the body like heroin and morphine, which come from the opium poppy, a flowering plant that oozes a milky white liquid.
To understand how opioids work. Let's zoom in on a region of the spinal cord that has opioid receptors.
Normally in the absence of endorphins, nociceptor fibers carry pain signals from the body to the dorsal or posterior horn of the spinal cord where they release neurotransmitters like glutamate substance P and calcitonin gene related peptide.
These neurotransmitters cause pain signals to be transmitted to the brain via ascending pain pathways. Now, let's say someone goes to play a rigorous game of badminton.
Exercise releases endorphins which activates the three major opioid receptors located on neurons called the Mu Kappa and delta receptors.
As endorphins or other opioids bind to these receptors in the presynaptic terminals of nociceptive fibers. They inhibit the opening of calcium channels, preventing calcium influx and thereby blocking the release of pain causing neurotransmitters like glutamate substance P and calcitonin gene related peptide.
At the same time. Endorphins also bind to post synaptic neurons opening potassium channels.
Here leading to hyperpolarization and decreased excitability of the neuron. These effects together reduce the transmission of pain signals to the brain.

Mechanism of action2:02–2:42

If we move up to the brain's reward pathway made up of midbrain regions like the ventral tegmental area, nucleus accumbens and prefrontal cortex.
We find another important effect of opioids. Here.
Inhibitory neurons normally release gamma Aminobutyric acid or Gaba at the presynaptic terminal, which in turn inhibits post synaptic dopaminergic neurons leading to decreased dopamine release when endorphins or opioids come in and bind to the opioid receptors.

Full agonists2:42–4:31

On these inhibitory gabaergic neurons, they cause a decrease in Gabaa release with less Gabaa around there is less inhibition of dopaminergic neurons and therefore more dopamine more dopamine leads to a calming sensation and feelings of pleasure or euphoria.
Now switching gears from dopamine, some opioids also affect serotonergic pathways in response to certain opioids descending tracts from the brain activate neurons that release serotonin in the spinal cord, reducing ascending pain transmission.
An important connection here is that when serotonergic opioids are combined with medications that also increase serotonin levels.
It could potentially lead to a life threatening condition. Called serotonin syndrome.
Last but not least. Let's take a look at the noradrenergic pathways.
Here, opioids have an inhibitory effect on noradrenergic neurons in the brain, especially in the locus cyrius leading to a decrease in norepinephrine release.
This contributes to the sedative effect of opioids and is one of the reasons why they may lead to respiratory depression.
Ok. So even though all opioids bind to opioid receptors, not all of them have the same effect.
Some opioids like morphine act just like endorphins. And when they bind to the opioid receptors, they trigger a full range of opioid effects like analgesia, euphoria and sedation.
These are called full agonists. Others like traMADol activate opioid receptors but have a weaker effect.
These opioids are called partial agonists. There is a ceiling effect on the analgesia they can provide meaning it won't progress beyond a certain point.

Partial agonists4:31–5:35

Even with additional dosing, they also cause less respiratory depression and euphoria than full agonists. Now, some opioids act preferably on new receptors, others on Kappa or delta receptors.
In fact, they can have an agonist effect on one receptor and an antagonist effect on others. These are called mixed agonist antagonists.
First, let's look at some full agonists. Commonly used medications in this class include morphine, methadone, fentaNYL meperidine, codeine HYDROcodone and oxyCODONE.
Although not a medication, heroin is also a full agonist. Many routes of medication administration can be used for opioids, but some of the most common are orally intravenously or through patches on the skin.
As in the case of fentaNYL, fentaNYL is a highly potent full agonist and is typically only used to control severe pain that couldn't be eased with other opioid medications.

Side effects5:35–7:18

It's also used as an anesthetic medication due to its rapid onset and short duration of action. Codeine is a weaker full agonist and is often taken orally with other analgesics like acetaminophen to treat moderate pain.
Like after a dental procedure, opioids can also act on the brainstem s cough center to suppress cough, making codeine and HYDROcodone useful antitussive options in adults with severe cough that is refractory to other medications.
Historically, meperidine was used for labor and other pain management but has fallen out of use due to side effects and the availability of safer alternatives.
Unfortunately, opioids have a high risk of causing dependence and the euphoric feelings they produce especially the full agonists can lead to substance use disorder.
Methadone is a full agonist that does not cause the euphoric rush of other opioids and it has a long half life. So it's often given to decrease withdrawal symptoms for people with opioid use disorder.
An added benefit is that it also blocks the euphoric feeling that comes from taking other opioids. So it helps to prevent future misuse.
There are also some opioids that don't have significant analgesic effects. For example, loperamide, a peripherally acting mu opioid agonist is used to reduce the motility of the gastrointestinal tract and treat diarrhea.
It mostly stays in the gut and is actively transported out of the central nervous system at standard doses. Therefore, it has less potential for misuse than other opioids.

Memory palace7:18–10:24

Now, common partial agonists include buprenorphine, butorphanol, pentazocine and traMADol. The first three are also classified as mixed agonist antagonist.
Buprenorphine is a partial agonist at the MU receptor, but an antagonist at the Kappa receptor. While butorphanol is an agonist at the Kappa receptor, but partial agonist or antagonist at the MU receptor, this means that when given alone, it acts as a partial agonist at the MU receptor.
But if a full agonist is present at the same time, Binor will block it from binding, acting as an antagonist. Pentazine is a full agonist at the Kappa receptor and a partial agonist and a weak antagonist at the MU receptor.
All three can be used to manage moderate pain that is not controlled by other medications. However, butorphanol and pentazine are rarely used in practice.
TraMADol is a partial agonist at the Mu receptor and is used for moderate to severe pain often after surgery. Now, when these medications compete for the same receptors as full agonists, they lead to a decrease in the overall effect of the full agonist and can even displace them from the receptors.
On one hand, this can be a good thing. As a partial agonist, buprenorphine can stimulate opioid receptors enough to decrease cravings and help with mild withdrawal symptoms in people with opioid use disorder without triggering euphoric feelings or respiratory depression.
However, because they displace full agonists, these medications can cause significant withdrawal symptoms if given to someone with physical dependency on a full agonist.
Ok, let's move on to side effects in the central nervous system. Stimulation of mu opioid receptors can cause euphoria.
But the stimulation of kappa receptors can lead to the opposite dysphoria where the person feels unhappy and uneasy. Stimulation of opioid receptors in the gi tract causes a decrease in motility and constipation but they increase tone in the biliary tract which can worsen the pain of biliary colic.
Other side effects include pinpoint pupils or pupillary constriction, flushing and nausea. The development of opioid use disorder is a devastating and debilitating potential consequence of opioid treatment, opioids effects on the reward centers of the brain along with the potential to rapidly develop tolerance and dependence, make them highly addictive where a use disorder can develop after even just one week of use.
This is why minimizing duration of use and careful counseling is crucial when prescribing and dispensing opioids. In addition, opioids should be avoided whenever possible during pregnancy because they can also lead to dependence in the baby and are linked to poor pregnancy outcomes for both mothers and babies.

Review10:24–11:13

Now, another dangerous potential outcome of opioid use is overdose. First in an overdose, there's central nervous system depression which can lead to coma.
Since C NS depression is additive with depressants like alcohol and other medications like barbiturates, they should never be used together.
The most common cause of death from opioid use is respiratory depression caused by decreased activity in the medulla. The part of the brain that regulates breathing, this causes increased carbon dioxide retention.
So it accumulates and causes dilation of blood vessels, including those in the brain, cerebral vasodilation increases intracranial pressure, which is why opioids are also contraindicated in patients with head injury.

Mind map11:13–17:17

Since they are already more susceptible to increased intracranial pressure. Lastly, opioid overdose can lead to cardiac problems like bradycardia, other arrhythmias and cardiac arrest.
Finally, if an individual who chronically uses opioids suddenly stops treatment, they could experience withdrawal symptoms like dysphoric mood, myalgias, sweating, pupillary dilation, rhinorrhea, nausea, vomiting and diarrhea, insomnia, excessive yawning and the feeling of skin crawling.
The good news is that over time, an individual can safely taper off their use of opioid treatments altogether, especially with the support of a knowledgeable healthcare provider.
Severe withdrawal symptoms can be managed with methadone and buprenorphine. Buprenorphine is usually combined with the opioid antagonist, naloxone to reduce potential for misuse.
Now, we want to make a simple and fun mnemonic that can help you efficiently memorize and retain all these pharmacology.
Facts. Let's start with a small garden of poppy plants.
The left side is full of fully grown poppies representing full agonists. While the right half contains half grown plants representing partial agonists.
So on the left side of the scene, we'll put a mighty morphine punching ranger fighting a giant roadrunner going me, me and an ox with a fur coat.
They will need analgesics after their fight, which is good since they represent morphine, mepiridine and oxycodone. Now they're disrupting a programmer, writing code for codeine.
His computer is cooled by a water cooler which represents HYDROcodone. This programmer is clearing his throat loudly at the obnoxious brawlers to help you remember, both these medications can also be used to treat coughing.
Next, let's have a mastodon representing methadone hanging up anti-drug posters since they can treat opioid use disorder.
Finally, there's a wizard from a fantasy novel representing fentaNYL. He's sleeping soundly which will help you remember it's sometimes used as an anesthetic.
OK. Moving on to the other side for the partial agonist and mixed agonist antagonist.
We have a burping orphan representing buprenorphine hanging up anti-drug posters. He's got a ball and chain with a large lock on his leg to represent naloxone which is often given with buprenorphine to treat opioid use disorder.
His brother is wearing a butterfly costume for Butorphanol. They are standing inside a pentagram representing pentazine.
Buprenorphine is standing at one point of the star with a mucinol since it's a partial agonist here at the opposite point with a Kappa symbol is butorphanol since he's an agonist for that receptor, they're standing near a tram track representing traMADol and if the tram hits them, they're both gonna need analgesics.
All right, let's go over some side effects. We'll put these towards the bottom of the garden.
Let's do the life-threatening side effects. First, there's an ice cream vendor in the park.
He's got three ice cubes that contain a brain, a heart and a pair of lungs to represent C NS cardiovascular and respiratory depression.
The one with the lungs is crushing an unfrozen brain which represents increased intracranial pressure. Remember that opioids are usually avoided after head trauma like when it gets crushed by a large block of ice.
Next, let's go over some less severe side effects. First, we have the park's famous statue of a man sitting on the toilet called the constipated man.
He's got a pin sticking out of his eye for pinpoint pupils and his cheeks are red, representing flushing. This is very upsetting for a couple in the garden, representing dysphoria.
The woman is pregnant to help you remember that opioids should be avoided if possible during pregnancy. And the husband is vomiting on a giant gallstone by the statue which serves as a reminder that opioids cause nausea and they are also avoided in people with biliary colic.
Finally, at the foot of the statue are some empty beer bottles to help you remember that opioids should not be used with alcohol or other medications that cause sedation.
All right. As a quick recap opioids, stop presynaptic neurons in the spinal cord from releasing pain producing neurotransmitters such as glutamate substance P and calcitonin gene related peptide.
In addition to decreasing excitability of the postsynaptic neuron together reducing the perception of pain. They also have side effects on dopaminergic, serotonergic and noradrenergic pathways.
Three important classifications of opioids are full agonists, partial agonists and mixed agonist antagonists. Full agonists include morphine, methadone, fentaNYL, mepiridine, codeine HYDROcodone and oxyCODONE.
They are more effective for pain relief but have more severe side effects. Partial agonists include buprenorphine, butorphanol pentazine and traMADol.
The first three are also classified as mixed agonist antagonist, opioids can cause side effects like nausea, vomiting, dysphoria, pinpoint pupils, constipation, biliary colic and in the worst cases, coma, respiratory depression and cardiac arrhythmias and arrest.
But wait, there's more, here's a mind map with all of the pneumonics. Go ahead and pause the video so you can test yourself to see what you remember.
Stay tuned for the answers after the credits.