December 9, 2019
Pharmacology – OPIOIDS (MADE EASY)

Pharmacology – OPIOIDS (MADE EASY)

In this lecture we’re gonna cover the pharmacology
of opioids so let’s get right into it. Opioids, sometimes called narcotics, are a
group of drugs that act on the central nervous system to produce morphine-like effects such
as pain relief and euphoria. Now, in order to gain better understanding
of their mechanism of action first we need to talk about the transmission of pain. So, pain begins at the nociceptors, which
are simply the branching ends of sensory neurons found within the peripheral nervous system. These high threshold primary sensory neurons
respond to damage to the body by transmitting the painful stimulus to the second-order neurons
in the dorsal horn of the spinal cord. From there the signal is carried through the
spinothalamic tract to the thalamus, and then to the somatosensory cortex where pain is
perceived. Now, on a microscopic level, the pain signal
takes the form of a series of action potentials that fire repeatedly depending on the intensity
of pain. To enhance movement across the synaptic cleft,
transmitter chemicals are released from the presynaptic neurons, including glutamate,
substance P, and calcitonin gene-related peptide, CGRP for short. Glutamate is one of the most important neurotransmitters
for pain and can activate both NMDA and AMPA receptors, which permit influx of positively
charged calcium and sodium ions respectively. As you may recall, the flow of positively
charged ions into the neuron, makes the neuron more likely to fire. In this way glutamate excites the second-order
neurons in the dorsal horn, which leads to propagation of a sharp, localized pain signal. Substance P, on the other hand, binds to the
neurokinin-1, NK-1 for short, which leads to intracellular signaling that
involves activation of arachidonic acid pathways, nitric oxide synthesis and activation of NMDA receptors. NMDA receptors are activated when Substance
P attaches to NK-1 receptors and then gets incorporated into the cell, activating Protein
Kinase-C. This action removes the magnesium that under
normal conditions is blocking NMDA receptor. This in turn allows glutamate to attach to
the NMDA receptor and thus permit the inflow of calcium ions, ultimately causing the pain
signal to increase and fire more frequently. Lastly, the released CGRP binds to its receptor
on second order neurons leading to changes in receptor expression and function and thereby
altered neuronal activity. This in turn contributes to the so-called
central sensitization that is characterized by lowered threshold for evoking action potentials. Now fortunately for us, our bodies can cope
with certain amount of pain by releasing so-called endogenous opioids. There are three major families of endogenous
opioids: the enkephalins, dynorphins, and endorphins. Endogenous opioids exert their effects by
binding to opioid receptors, which are abundantly present in the central and peripheral nervous
systems. There are three major types of opioid receptors,
that is; µ (mu), δ (delta) and k (kappa). In general, all three receptors differ in
their cellular distribution, their relative affinity for various opioid ligands and their
contribution to specific opioid effects. All opioid receptors are 7-transmembrane spanning
proteins that couple to inhibitory G-proteins and they are all present in high concentrations
in the dorsal horn of the spinal cord. Activation of these receptors by an agonist,
such as the endogenous μ-opioid peptide endorphin causes closing of the voltage-gated calcium channels
on the presynaptic nerve terminals which in turn decreases the release of neurotransmitters,
such as glutamate, substance P and calcitonin-gene-related-peptide. In addition to that, activation of opioid
receptors leads to opening of potassium channels, allowing efflux of potassium ions which in
turn results in hyperpolarization, rendering neurons less sensitive to excitatory inputs. Now, the majority of currently available opioid
analgesics act primarily at the μ-opioid receptors essentially mimicking the effects
of endogenous opioid peptides. However, while naturally-derived opioids can
only reach a certain potency, the synthetically-produced opioids are refined and processed to be much
more powerful. The examples of synthetic opioid agonists
are; Fentanyl, Hydrocodone, Hydromorphone, Methadone, Meperidine, Oxycodone, and Oxymorphone. As a side note here, its important to note
that Methadone is not only a potent μ-receptor agonist but also a potent antagonist of the
NMDA receptor as well as norepinephrine and serotonin reuptake inhibitor. These properties make Methadone useful for
treatment of both nociceptive and neuropathic pain. Now, in addition to producing analgesia, activation
of the opioid receptors in other parts of the body can bring about many side effects. For example, all opioids produce some degree
of nausea, which is due to direct stimulation of the chemoreceptor trigger zone in the medulla. All opioid receptor agonists also produce
a dose-dependent respiratory depression. Opioids primarily cause respiratory depression
by reducing brain stem respiratory center responsiveness to carbon dioxide. They also depress the respiratory centers
in the pons and medulla, which are involved in regulating respiratory rhythmicity. In addition to that, opioids produce an antitussive
effect by depressing the cough center in the medulla. Opioids are known to be associated with suppression
of the immune system, as opioid receptors are involved with regulation of immunity. Morphine as well as Meperidine may provoke
release of histamine, which plays a major role in producing hypotension. Furthermore, when given by injection Morphine
and Meperidine can cause dilation of cutaneous blood vessels, which results in the flushing
of skin of the face, neck, and upper thorax. Meperidine in particular produces tachycardia
due to its structural similarity to Atropine. Other opioids generally produce a dose-dependent
bradycardia by increasing the centrally mediated vagal stimulation. All opioids can cause itching via central
action on pruritoceptive neural circuits. Opioids also decrease gastric motility and
prolong gastric emptying time, which may cause constipation. Likewise, opioids depress renal function and
produce antidiuretic effects. They also increase sphincter tone and thus
may cause urinary retention. Now, the biggest problem with opioids is that
they have the potential to cause addiction by causing both physical and psychological
dependence. The euphoric effect appears to involve GABA-inhibitory
interneurons of the ventral tegmental area of the brain. Normally, GABA reduces the amount of dopamine
released in the nucleus accumbens, which is a brain structure that is part of our pleasure
and reward system. However, when opioids attach to and activate
the µ receptors in that area, the release of GABA becomes suppressed. This in turn increases dopamine activity and
thereby increases the amount of pleasure felt. Now, on the other hand, prolonged, regular
use of opioids leads to desensitization of receptor signaling and down-regulation of
the receptors and thus a decrease in sensitivity to the effects of opioids. As a result, when regular opioid use is reduced
or suddenly stopped, the lack of receptor activity is manifested as withdrawal symptoms. These symptoms generally are opposite to the
pharmacological effects of the opioid drugs. So, now rather than causing constipation and
slowing respiration, the brain stem triggers diarrhea and elevates blood pressure. Instead of triggering happiness, the nucleus
accumbens and amygdala reinforce feelings of dysphoria and anxiety. All of this negativity feeds into the prefrontal
cortex, further pushing a desire for opioids. Now, before we end I wanted to briefly discuss
couple more agents that interact with opioid receptors but in a different way than the
agents that we discussed so far. The first one is a partial µ receptor agonist
called Buprenorphine. So, while a full opioid agonist binds to the
µ receptor, activates it by changing its shape and thus induces a full receptor response,
a partial agonist binds to the receptor and activates it with a smaller shape change which
leads to only a partial receptor response. In other words, the effects of partial agonists
increase only until they reach a plateau. Like all opioids, Buprenorphine can cause
respiratory depression and euphoria, but its maximal effects are much smaller than those
of full agonists. The benefits of this are lower risk of abuse,
addiction, and side effects. One last thing to keep in mind is that Buprenorphine
is also an antagonist at the δ and κ receptors and because of that it
is referred to as mixed agonist-antagonist. However, the contributions of these actions
to its analgesic profile are currently unclear. Now, let’s move on to our last agent that
is Naloxone. So, Naloxone is an opioid antagonist that
can be used to block or reverse the effects of opioid drugs. Naloxone works by knocking off the opioids
attached to the receptors in the brain, thereby temporarily stopping the opioid effect. This is possible because Naloxone has a stronger
affinity for opioid receptors and thus is able to kick the opioids out and block them
from attaching again. So during an emergency situation when a person’s
breathing has slowed down or stopped due to an opioid overdose, Naloxone can quickly restore
normal breathing and save the life. And with that I wanted to thank you for watching,
I hope you found this video useful and as always stay tuned for more.

74 thoughts on “Pharmacology – OPIOIDS (MADE EASY)

  1. Sir,
    Since you have done this for free,
    You will get blessings not only from people from this generation,but from the generations to come, this work amazing, acutally am quite amazed to know that selfless people like you are still there, and
    with that I want to thankyou from the bottom of my heart. God bless.

  2. I wanna thank you from the core of my heart Sir, Keep on making these videos YOU ARE AWESOME. and you are helping a lot of Students increase their knowledge and pass their tests. Thank you.

  3. This is the best, most complete and concise explanation I have experienced on this subject. Thank you so much. You have greatly enhanced my learning.

  4. Sir you deserve millions Of milions subscribers becuz you're providing good knownlege…… Free of cost…. Thank you for your great contribution…… About pharmacology…. Sir please also provides other subjects that includes in Pharmacy…….welldone sir…… 😘😘😘😘😎😎😎👏👏👏👍👍👍 ……#LOVEFROMINDIA 🇮🇳🇮🇳🇮🇳🇮🇳

  5. You have no idea how much this has helped me. I have an exam coming up and I have very little time to study as I am working most of the time. A whole chapter simplified into a 10 Mnt long video. Thank you so very much. If I manage to pass , you tube would have a whole lot to do with it.

  6. Thats one thing doing a lecture on a board for free but thats literally on another level doing animations and explaining things so well and for free.
    I wanna thank you for the time you invest in making those videos and they sure rock and improve my knowledge in pharmacology.
    Thanks! 🙏

  7. Kindly sir give lecture on bacteria classification and diseases caused by them…waiting for ur lecture…God bless you.

  8. I guess I was lucky? My doctor stopped prescribing due to being threatened for to long. After 14 years of being on Norco everyday he took me off using the proper method with Suboxone. I only needed it for 5 days.(IF YOUR DOCTOR HAS YOU ON SUBOXONE FOR A LONG PERIOD OF TIME, THEY ARE DOING IT FOR MONEY) It has been about a year and I've never craved the medication. But now my life is lost. On the Norco I started a business. I have been so proud because I started it with 20.00 and it grew fast. I could drive again and even work out. I was eating and sleeping. Now I have no idea who I am. Every doctor tried to put me on anti depressants. But I am not depressed. I think for what happened to me sadness and anger are normal emotions. I fear diabetes. It runs in my family. I am almost always sedentary now and gaining weight, Very different than when I was a body builder and trainer. I gave up driving. I sleep very little and eat very poorly. I can't eat in pain. Now I'm dealing with PTSD from doctors. I had one doctor scream at me. He didn't even bring my file into the room. He didn't even know my name. He called me desperate and an addict and said he was cutting my meds to less than half per day. It was horrible. The staff let me leave to drive home- even though I was having a panic attack and an SVT. My only thought was "I'm losing my business, my livlihood". The next doctor demanded an MRI of my back. I explained that I did not want an epidermal (they are not FDA approved). My back isn't even my worst pain issue. He yelled at me on the phone and hung up. Then a female doctor put me on several anti depressants at one time. I ended up in the ER with serotonin syndrome, and now I have serious white coat issues. I'm am slowly losing my business. I'm trying and don't want to give up. I understand why people are committing suicide. It's not like retiring. You aren't prepared. In a week your life just changes. It's gone. I always tell ppl' that are not in pain…have someone tap on your forehead for a month straight. While you try to eat, sleep, talk on the phone or make big decisions. See how well you concentrate after a month. It's not just the sensation of pain, but it brings madness to your life. I spend much time watching t.v..trying to just focus on the t.v to try to drown out the pain. I can't even read well now. My concentration is poor at best. I am so terrified of doctors that I broke my nose several months ago and fixed it myself. Last month I dislocated my shoulder and again fixed it myself. I respected the medication I was on. I was so thankful. After years of all kinds of therapies, medications that did not work and I was even scammed into trying things like body magnets, copper bracelets, infrared therapy, acupuncture several times and more. I'm not ready to just be a meat suit sitting on the sofa, with a brain that wants to do so much in life. I have another grandchild coming, number 5. And all I can think is 'another grandchild I can't play with or babysit. "They" never made a follow through for us. Once this started there was all kinds of things to help addicts. But we are left chronic pain criminals. Sadly this issue is having a snowball effect. People don't trust doctors anymore. I even know a group of women that are doing home births with no medical help. This is infecting everything. It has not slowed down drug abuse and suicides have increased. I can't believe my countries medical system is doing this to us.

  9. How come buprenorphine doesn't work stronger after a certain dose?
    Is it because all the receptors are then filled and the effect is not too strong cause it stimulates the nerves only partially? That's what I thought out, but I can't really imagine that's how it works.

  10. Didn't skip the ads since it's my only way of saying thank you. Not all heroes wear capes, some make videos like these.

  11. Opioids are the greatest gift mankind has from the natural world… My life is livable with my prescribed opioid.

  12. U r a pharmacology God for a strong reason. I can't thank enough. You are really a kind hearted person. Sharing is caring. As I am a medico what I can wish for u .God bless him with a long healthy and happy life. Loads of love 💖💖💖. U will shine a lot

  13. WOW … you sir have got to be (so far & that i can recall) the only person who has ever got this FULLY CORRECT. I like how you noted that the effect opioids have on breathing really boils down to the sensor that detects how much co2 is present (& in doing so, essentially blocks-to an extent- the alert that warns a person when their co2 levels get too high..& so they would feel that urge to BREATHEEE, to avoid death)…one would be surprised just how few people actual are aware of this, they think opioids just make your lungs not want to move or something.

    Also like how you mentioned the action Methadone has as an SNRI (tho i wouldve also liked to see you do the same for Bupe for it also has an interesting profile of agonism/antagonism). One last thing i was quite pleasantly surprised to hear you mention was the reason as to why Naloxone acts on the receptor as it does.. this is due to its HIGHER AFFINITY in contrast to other opioids!…again, this is unknown to most & it boggles their mind when you try explaining that to them especially when theyre not actually even aware that Naloxone (& naltrexone) are ALSO themselves OPIOIDS. Their mind is usually blown at that point & you then realize they just simply don't have the full in depth understanding as you may have.

    Idk, sometimes i feel like i'm the one going crazy in such a seemingly ignorant-uneducated world, but alas i am humbled once i remind myself just how truly ignorant we all are myself included. Lol, so its all good!

    Thank you much for this, refreshing!!

  14. That's click bait if I ever saw it…I never in my life click on a video so fast in anticipation of an intense euphoria after a quick trip to walmart for some house hold chemicals. Next time you put up a video called"opioids made easy"….it better be a pethadine or fentanyl synthesis

Leave a Reply

Your email address will not be published. Required fields are marked *