PHAR 5: Applying PD/PK Theory - Opioids Flashcards
1
Q
What is the difference between opioid and opiate?
A
- opioid: covers all drugs with opiate-like activity
- opiates: refer to natural plant based alkaloids derived from the papaver somniferum plant (opium poppy)
2
Q
Classify morphine and heroin
A
- morphine (the major alkaloid within the opium poppy) is an opiate and an opioid
- Heroin, a synthetic derivative, would only be classed as an opioid
3
Q
What is the primary cellular mechanism of action of opioids?
A
- opioids primarily have a depressant effect
4
Q
Observe the learning outcomes of this session
A
5
Q
Observe the chemical structure of morphine
A
6
Q
Describe codeine and heroin
- natural or synthetic?
Observe their chemical structures
A
- Codeine: another natural opiate from the opium poppy
- Heroin: a synthetic opioid
- interesting note; Heroin was originally produced by the Bayer Chemical Company as a non-addictive alternative opioid to morphine!
7
Q
Compare the chemical structures of morphine, codeine and heroin
A
- From a structural point of view, there is very little difference between the three opioids.
- In fact, if we were to superimpose the three structures on top of each other (see below), you can see that they all share a common phenanthrene ring core (highlighted in orange)
- the only differences are the side chains to the left of the molecule.
- You can also name these opioids in the following way;
- Morphine: effectively the alcohol of this group with two hydroxyl groups.
- Methyl morphine: also known as codeine, and is the ether of the group with a methyl substitution.
- Diacetyl morphine: also known as heroin, and is the ester of the group with two acetyl substitutions.
- Clearly these small changes in structure will influence the pharmacokinetic profiles of the three drugs.
8
Q
Can you determine the relative lipid solubility of codeine, heroin and morphine?
A
- Heroin
- 0 polar hydroxyl groups
- most lipid soluble - Codeine:
- 1 polar hydroxyl groups
- more lipid soluble than morphine - Morphine:
- 2 polar hydroxyl groups
- least lipid soluble
9
Q
How does the structure of morphine influence its pharmacodynamics?
A
- In the case of morphine-like opioids, it is the tertiary nitrogen and the hydroxyl group at position 3 (top left) that is important for anchoring the molecule to the receptor
- i.e. determines the affinity of the opioid for the receptor.
10
Q
What determines the efficacy of morphine (or other opiates)?
A
- the efficacy of the drug is determined by the side chain that extends from the tertiary nitrogen.
- If we first consider the tertiary nitrogen and associated side chain.
- The diagram below shows the chemical structures of morphine (agonist) and naloxone (corresponding antagonist).
- The orange box shows the tertiary nitrogen that both drugs possess and which allows both drugs to bind to the receptor – from session 1: both agonists and antagonists possess affinity.
- The blue box shows the side chains associated with the tertiary nitrogen.
- If the side chain possesses 2 carbons or less, then it can activate the receptor i.e. possesses efficacy – this is the case with morphine.
- If the side chain possesses 3 or more carbons, then the bound drug cannot activate the receptor
- i.e. has no efficacy – this is the case with naloxone.
- From session 1: Only agonists possess efficacy, whereas antagonists possess no efficacy.
11
Q
What are the most important binding sites for morphine?
A
- There are a number of binding sites that are important for the binding affinity of morphine for this receptor.
- The two most important are:
1) the tertiary nitrogen binding site (discussed above) utilizing an ionic bond and
2) the position 3 hydroxyl binding site utilizing hydrogen bonding.
12
Q
Describe how these binding sites cause morphine, codeine and heroin to bind differently
A
- The first thing you should recognize is that morphine possesses a hydroxyl group at position 3, whereas codeine and heroin do not.
- Therefore, morphine should bind effectively to the receptor (high affinity) whereas codeine and heroin should not (low affinity).
- In terms of what we have discussed so far, heroin and codeine are more lipid soluble than morphine so should penetrate the brain more effectively and reach the receptor, but once they reach the receptor codeine and heroin will not bind to the receptor as effectively as morphine.
- An interesting conundrum – one we will revisit in the next section!
- Overall, we have shown that small changes in structure influence the ability of the opioids to access the tissues in the first place (lipid solubility) and once they have gained access, their ability to bind to the relevant target (e.g. receptor affinity) and activate that target to produce a response.
13
Q
What are the most common methods for administering opioids?
A
- intra-venous
- oral route
- intra-muscular injection
- transdermal patch
- even an opioid lollipop (sub-lingual)
14
Q
What are the most common forms of administration for the three opioids we are discussing?
A
- intra-venous:
- heroin
- morphine
- oral:
- morphine
- codeine
15
Q
Observe this table of the ratio of ionised to unionised morphine in different body compartments
A
16
Q
Using this table, discuss how much of the morphine is unionised and free to diffuse into tissues
- intravenously
- oral
A
- If we look at the ratio of ionised to unionised morphine in the blood, we can see that the ratio is roughly 4:1
- i.e. about 20% of the drug in the blood is unionised and free to diffuse into tissues.
- If you administer opioids via the intravenous route, then that is 20% of the 100% injected (remember intravenous drugs are 100% bioavailable).
- If you administer via the oral route, then it is a lot more complicated.
- The drug will only be sufficiently unionised in the later parts of the small intestine (as you can see from the diagram, the terminal ileum is the same pH as the blood).
- A proportion will then be absorbed across the small intestine.
17
Q
Apart from the pH of different body parts, what else impacts bioavailability for morphine administered orally?
A
- Hepatic first metabolism (in the liver) will also metabolise some of the opioids prior to reaching the systemic circulation further reducing the bioavailability of the drug.
- Metabolism of opioids is very complex and greatly influences the effectiveness of the drugs.
- For most of the opioids, there are a number of different metabolites that can be produced – some of these metabolites will possess activity – known as active metabolites.
- Some of these metabolites will be inert and exert no activity at all.
18
Q
Consider the diagram below which contains the three opioids we have discussed so far and a common metabolite for each of these drugs.
Using the knowledge you gained from the previous section, tick the box alongside each structure if you think that the drug will bind strongly to the opioid receptor i.e. possesses high affinity (if you don’t succeed first time, try again and resubmit).
A
- What you learnt in the previous section is that the two major structural elements that must be present for effective receptor binding is a ‘tertiary nitrogen’ and a ‘hydroxyl group at position 3’.
- The only three structures that contain this are – morphine, morphine-6-glucuronide and 6 acetyl-morphine.
- We also mentioned above that heroin and codeine despite being more lipid soluble than morphine and therefore more able to penetrate the brain effectively and reach the receptor, would not bind to the receptor as effectively as morphine.
- Therefore, metabolism of heroin and codeine must take place in order for these drugs to bind effectively to the receptor – they must produce ‘active’ metabolites.
19
Q
Describe one of the major metabolites of heroin
A
- one of the major metabolites is 6 acetyl-morphine. 6 acetyl-morphine is effectively an intermediate of morphine and heroin
- i.e. it possesses one less hydroxyl group than morphine and one less acetyl group than heroin
20
Q
Describe the chemical structure of 6-acetyl-morphine
A
- 6-acetyl-morphine possesses the hydroxyl group at position three.
- As a result, it will be less lipid soluble than heroin, due to the loss of the extra acetyl group, but it will retain strong affinity for the opioid receptor – this is something heroin does not possess.
- In addition, the fact that it retains one of the acetyl groups means that 6-acetyl-morphine will be more lipid soluble than morphine and penetrate the brain more rapidly, and therefore access the relevant brain areas more easily.
23
Q
How is codeine metabolised to have opioid-like effects?
A
- neither codeine, nor the metabolite norcodeine, should have much affinity for the opioid receptor
- but codeine can be metabolized to both norcodeine AND morphine
- Therefore, it is the conversion of codeine to morphine that appears to be important for the opioid-like actions of codeine.
26
Q
Indicate the relative affinity and lipid solubility of the metabolite morphine-6-glucuronide compared with the parent molecule, morphine.
A
- in terms of affinity for the opioid receptor, morphine-6-glucuronide is roughly equal to morphine
- both drugs contain a tertiary nitrogen and a hydroxyl group at position three
- in terms of lipid solubility, morphine-6-glucuronide is less soluble than morphine
- glucuronide molecules are large polar groups that are added to molecules during phase II metabolism to help excrete the molecule from the body
31
Q
What is the response when opioids bind to their target opioid receptor?
A
- there is a general cellular response to opioids and then there is a specific response depending on the tissue where the opioids are acting.
- In terms of the general cellular response, opioids have a depressant effect on cells.
32
Q
Describe the potential mechanisms for the depressant effect caused by opioids
A
- Inhibit adenylate cyclase
- thus preventing the production of cAMP
- this would lead to a generalised decrease in cellular activity - Inhibit calcium entry into the cell
- this can have a very specific depressant effect in terms of decreasing the stimulus for exocytosis - Enhance potassium efflux from the cell
- this also has a very specific depressant effect in terms of increasing hyperpolarisation
- this reducing cell depolarisation (and consequent activation)
34
Q
UNFINISHED Describe how pain signals are received by the brain and how the brain then regulates that signal
A
- you should watch the video in detail and make notes but here are the main screenshots
- any peripheral pain signal is going to activate a sensory neuron.
- that peripheral signal is then relayed along sensory neurones and the sensory neurones relay that pain signal into the dorsal horn of the spinal cord.
- Within the dorsal horn, these sensory neurons then synapse with spinothalamic neurones.
- Now, these are the neurones that are going to relay this information from spinal cord up into the brain.
- The first part of the brain that this information is going to be relayed to is the thalamus, hence the name spinothalamic neurone - a neurone relaying information from spine all the way up to the thalamus.
- So the thalamus basically acts as a gatekeeper for pain signal transmissions.
- So it receives all of the pain signals and then basically determines where to send that information.
- The first point it’s going to send it to is the periaqueductal gray region.
- Once it reaches the thalamus, we then move over into the pain tolerance pathways.
- So once the information gets to the brain the brain now needs to determine what to do with that pain signal and in most cases what the brain wants to do is diminish those feelings of pain so that the pain stimulus doesn’t persist unnecessarily.
- the periaqueductal gray (PAG) region and it basically acts as the integrating centre for the initiation of pain tolerance
- So the thalamus will directly activate this PAG region upon receiving the pain signal from the periphery.
- However, the thalamus also relays that information to other parts of the brain, for example the cortex.
- The cortex is basically involved in processing that information and then it regulates the pain tolerance signal generated by the PAG
- So that signal is then also relayed into this integrating PAG centre.
- So the PAG integrating centre then determines the level of activation of the nucleus raphe magnus.
- Unfinished: more to be written
35
Q
The table below shows 4 different sites where opioids act to induce analgesia.
For each of the sites included please indicate whether you would want to increase or decrease the firing rate of the neurons in this area.
A
37
Q
Describe how dopaminergic neurons make up the reward pathway
Focus on the bottom half of this diagram
A
- people talk about the fact that exercise makes them feel good about themselves and that is proven that exercise can actually stimulate this pathway to cause dopamine release.
- As you can see dopamine release from these neurones you know it’s the dopamine that actually stimulates the feelings of reward, often referred to as euphoria.
- What we have is a dopaminergic neuron that originates in one part of the brain, the VTA that is the ventral tegmental area.
- You can see the cell body for these neurones within the ventral tegmental area and then that projects down to the nucleus accumbens and it’s the sort of postsynaptic neurons that you’ll find within the nucleus accumbens that are activated by dopamine to cause the feelings of reward.
- I’ve mentioned that any sort of natural reward will activate this pathway and the very many drugs of abuse also act through this pathway, via many different mechanisms
38
Q
How do opioids produce a euphoric ‘high’?
A
- gaba neurones are incredibly important inhibitory neurones that are found throughout the brain and they’re often found in parts of the brain where generally speaking that region is suppressed
- So think about that in terms of the reward pathway, you’re not walking around permanently feeling euphoric and that’s because in most instances the gaba neurones are switched on and they are suppressing this particular pathway.
- Now, what the opioids like heroin are going to do is they are actually going to act on these gaba interneurones.
- So you can see the opioid receptor, in this case, the mu-opioid receptor present on the cell body of the gaba interneuron.
- What heroin, morphine and other opioids are going to do is they are going to activate that receptor and they are going to have a depressant effect on this gaba interneuron.
- What you now have is effectively a double negative.
- So you’ve got the opioids having a negative effect on an inhibitory interneurone, so they’re going to switch off this gaba negative effect.
- The end result of that is now your dopaminergic neurone that is mediating feelings of reward is going to fire at a much higher rate you’ve lost the gaba suppression, the gaba inhibition.
- These neurons are now going to start firing at a much higher rate, you’re going to get much more dopamine release, you’re going to get much higher feelings of reward - far greater euphoria.
- So that is basically how heroin, morphine and other opioids cause euphoria.
- It’s a process called disinhibition, switching off and inhibitory neurone.
42
Q
Describe how opioids can induce respiratory depression
A
- the respiratory control centre is responsible for generating and maintaining the rhythm of respiration i.e. inhalation/exhalation to and from the lungs.
- The respiratory control centre alters the rate and depth of breathing based on information received from the central chemoreceptors
- e.g. altered levels of carbon dioxide (sensed after conversion to hydrogen ions by the enzyme carbonic anhydrase).
- Opioids have a depressant effect on the central chemoreceptors (so less information is relayed to the respiratory control centre) and also on the respiratory control centre (which reduces the stimulus to the lungs to inhale/exhale).
43
Q
Consider the log dose response curve for morphine shown below.
The two dotted lines on the dose response curve represent powerful analgesia AND respiratory depression.
Choose which of the dotted lines represent analgesia and which dotted line represents respiratory depression.
A
- we discussed the need for the therapeutic effect to be induced at a lower dose than side effects.
- Analgesia MUST be induced at a lower dose than the potentially fatal respiratory depression as shown above.
- One final point that relates back to session 1 and can be important in treating opioid addiction.
- A partial opioid agonist CANNOT induce a maximal response and in this case cannot cause respiratory depression.
- Therefore, an opioid addict could be given a partial agonist which is less dangerous than a full agonist like morphine or heroin.
