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Pharmacology & Toxicology > PHAR5: Opiods > Flashcards

PHAR5: Opiods Flashcards

Applying PD/PK theory to exemplar drugs - physcoactive drugs; opioids

1
Q

What is the difference between opioid and opiate?

A
  • Opioid refers to all drugs with opiate-like activity

- Opiate refers to a natural based alkaloid derived from the papaver somniferum plant

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2
Q

In terms of opioids’ mechanism of action, what type of drug is it classed as primarily?

A

Depressant

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3
Q

What is the most prevalent natural opiate? Name two others

A

Morphine

Codeine and Heroine (synthetic)

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4
Q

What are the structural similarities and differences between morphine, codeine and heroine?

A
  • They all share a common phenanthrene ring core

- They have different side chains on the left side of the molecule

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5
Q

What are the other names given to codeine and heroine?

A
  • Codeine: Methyl morphine (ether of the group with a methyl substitution)
  • Heroine: Diacetyl morphine (ester of the group with two acetyl substitutions)
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6
Q

Rank Codeine, morphine and heroine in terms of lipid solubility. The most lipid soluble being 1. Explain why.

A
  1. Heroine (0 polar groups)
  2. Codeine (1 polar hydroxyl group)
  3. Morphine (2 polar hydroxyl groups)
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7
Q

Which parts of the morphine-like opioids are important for anchorage to its receptor? (thus determining the affinity of the opioid for the receptor)

A
  • Tertiary nitrogen (forms an ionic bond with receptor)

- Hydroxyl group at position 3 (forms H bond with receptor)

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8
Q

What does the efficacy of morphine-like opioids depend on?

A

Side chains that extend from the tertiary nitrogen: If it possesses two carbons or fewer it will be able to activate the receptor. 3 or more C and the drug cannot activate the receptor

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9
Q

What is the antagonist for morphine?

A

Naloxone

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10
Q

Why do codeine and heroine have a low affinity for the opioid receptor?

A

They do not posses a hydroxyl group at position 3

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11
Q

Explain the conundrum between C/M/H and efficacy.

A

Heroine and Codeine are more lipid soluble than Morphine so can penetrate the brain more effectively and reach the receptor; but once they reach the receptor, codeine and heroine will not bind to the receptor as effectively as morphine.

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12
Q

What are the most common method for administering C/M/H?

A

Heroine - intravenously
Codeine - orally
Morphine - intravenous or oral

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13
Q

Are opioids bases or acids?

A

Weak bases

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14
Q

Morphine has a pKA of 8. Roughly what ratio of ionised to unionised morphine will there be in the stomach (pH=3), blood (pH=7.4) and urine (pH=8).

A
  • Stomach 100,000:1
  • Blood 3.98:1
  • Urine 1:1
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15
Q

If you orally administer morphine, in which body compartment will it be sufficiently unionised to be absorbed?

A

In the later parts of the small intestine.. the terminal ileum has the same pH as blood - a proportion can then be absorbed across the small intestine

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16
Q

Apart from the ioinsed:unionised ratio in the blood stream, will anything else impact bioavailability of morphine?

A

Hepatic first metabolism will metabolise some of the opioid prior to reaching the systemic circulation further reducing the bioavailability of the drug

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17
Q

What metabolites have a strong affinity for the opioid receptor?

A

Morphine-6-glucuronide (metabolite of heroine)

6-acetyl-morphine

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18
Q

What must happen to heroine and codeine in order for them to bind to opioid receptor?

A

They must be a metabolised to have active metabolites

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19
Q

Describe the structure of 6-acetyl-morphine

A

It is an intermediate between morphine and heroine. It has one less hydroxyl group (which are important for affinity) than morphine and one fewer acetyl group (which are important for lipid solubility) than heroine.
- It has a hydroxyl group at position 3

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20
Q

What are the properties of 6-acetyl-morphine?

A
  • It is less lipid soluble than heroine and but it retains a strong affinity for the opioid receptor
  • As it retains one of the acetyl groups, it is more lipid soluble than morphine
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21
Q

List the three steps of pharmacokinetics of heroine

A

1) Intravenous injection of heroine
2) Some of the heroine rapidly accumulates in the brain (high lipid solubility). Here some of it can be metabolised to 6-acetyl-morphine by esterases
3) A larger amount of heroine is metabolised in the liver to 6-acetyl-morphine. Now it is less lipid soluble but ut is still able to accumulate in the brain, where is has a greater ability to bind to the relevant opioid receptor

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22
Q

Which is considered more potent between heroine and morphine and why?

A

Heroine is considered more potent, this is due to its metabolite 6-acetyl-morphine

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23
Q

What can codeine be metabolised into?

A
  • Morphine (important part of the opioid-like actions of codeine)
  • Norcodeine
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24
Q

What are the majority of opioids metabolised by in the liver?

A

CYP3A4 and CYP2D6

Cytochrome p450 subtypes

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25
Q

Describe the action of CYP3A4 and CYP2D6

A

CYP3A4: Fast metabolism which deactivates codeine to norcodeine
CYP2D6: Slow metabolism which activates codeine to morphine (codeine is a pro-drug)

26
Q

What percentage of codeine is metabolised to morphine?

A

10%

Which is why it is considered a weak opioid

27
Q

In terms of affinity for the receptor and lipid solubility, how does morphine-6-glucuronide compare with morphine?

A
  • Affinity to opioid receptor is equal (both contain a tertiary nitrogen and hydroxyl group at position 3)
  • Lipid solubility is less than morphine (glucuronides are larger polar groups added to molecules during phase II metabolism to help excrete the molecules from the body)
28
Q

Discuss excretion of opioids

A

As they are weak bases and urine is slightly alkaline, they will be more unionised and therefore more likely to diffuse across the kidney tubules and back into the bloodstream.
+ the more lipid soluble it is the better it will be reabsorbed into blood from KT, therefore the drugs will accumulate in the body due to low excretion
- pharmacokinetic factors that influence the opioid drugs have a huge baring on the therapeutic/toxic effect of these drugs

29
Q

What are the three different subtypes of opioid receptors?

A
  • mu
  • delta
  • kappa
30
Q

What are the endogenous agonists for the opioid receptor?

A

Endorphins (most selective for mu)
Enkephalins (most selective for delta)
Dynorphins (most selective for kappa)

31
Q

Which receptor are most of the opioid effects mediated through?

A

The mu receptor

32
Q

Name the two types of responses to opioids

A
  • general cellular response

- specific response depending on tissue opioids are acting on

33
Q

Explain opioids general cellular effect

A

Depressant: binds to receptor leading to…

1) Inhibits adenylate cyclase > preventing production of cAMP
2) Inhibits Ca2+ entry > decreasing stimulus for exocytosis
3) Increases K+ efflux > increasing hyperpolarisation (reducing cell depolarisation) preventing activation

34
Q

What is the most well known effect of opioid drugs?

A

Analgesia (pain relief)

35
Q

Explain how the brain receives pain signals

A

Peripheral pain goes to a sensory neuron > Relayed along sensory neurones to dorsal horn of spinal cord > sensory neurones synapse with spinothalamic neurones > relayed along spinothalamic neurones to thalamus which determines where to send the pain signal

36
Q

Where does the thalamus send pain signals first?

A

The periaqueductal grey region (PAG)

37
Q

What does the periaqueductal grey region do?

A

It acts as the integrating centre for the initiation of pain tolerance. Receives signals from cortex and thalamus and determines the level of activation of the nucleus raphe magnus.

38
Q

Where else does the thalamus send pain signals? Why?

A

The cortex, e.g. if you’ve experience this pain before - to help determine what level of signal to send to the PAG. E.g. to make the pain more or less severe

39
Q

What is the cortex’s role in pain regulation?

A

It is involved in processing the pain information and then it regulates the pain tolerance signal generated by PAG

40
Q

What is the nucleus raphe magnus (NRM)?

A

The effector arm of the pain tolerance pathway

41
Q

What does nucleus raphe magnus do?

A

Decreases transmission of the peripheral pain signals being received from dorsal horn

42
Q

What is the name of the element of the pain tolerance pathway that is independent of the PAG integrating centre?

A

Nucleus reticularis paragigantocellularis (NRPG)

43
Q

How does the Nucleus reticularis paragigantocellularis (NRPG) work? what is the importance of this?

A

The region is directly activated by the ascending spinothalamic neurones. The NRPG can then directly activate the nucleus raphe magnus (NRM).
It means that you are getting an element of pain tolerance before the brain even really does much processing of that information

44
Q

What does the hypothalamus do with regards to pain tolerance?

A

Monitors the current state of health of the organism and this is information that is constantly being relayed to the PAG thus having a modifying effect on pain tolerance.
e.g. If you’re in good health, pain tolerance pathway is enhanced (more suppression)

45
Q

What is another important part of effector arm of the sympathetic nervous system and what does it do?
Give an example of when this is necessary?

A

The Locus Coeruleus. It can directly inhibit the pain’s transmission to the spinothalamic neurones.

  • In a fight or flight situation when you can’t be concerned about the pain from your tiger bite (too much of a distraction)
  • Or if youre exercising the sympathetic nervous system is activated so you don’t feel the injury as much.
46
Q

Name the mini brain in the dorsal horn

A

Substantia gelatinosa

47
Q

How does the substantia gelatinosa work?

A

Pain stimuli from the periphery have to travel through the substantia gelatinosa: at which point the pain can be modulated. This happens by descending neurones from the NRM that project onto the substantia gelatinosa allowing the substantia gelatinosa to interfere with the pain transmission from sensory neurones to the spinothalamic neurones (diminishing the feelings of pain).

48
Q

To have an analgesic effect, do you want to decrease or increase the firing rate of the following areas?

1) peripheral sensory neurone
2) periaqueductal grey region
3) nucleus reticularis paragigantocellularis
4) thalamus
5) spinothalamic neurones

A

1) peripheral sensory neurone = decrease
2) periaqueductal grey region = increase
3) nucleus reticularis paragigantocellularis = increase
4) thalamus = decrease
5) spinothalamic neurones = decrease

49
Q

In order to induce euphoria …

A

.. A drug must activate dopaminergic neurones within the reward pathway

50
Q

Where do dopaminergic neurones originate from?

A

The Ventral Tegmental Area (VTA) (cell bodies are here)

51
Q

Where do dopaminergic neurones project down to?

A

The nucleus accumbens (It is here where postsynaptic neurones are activated by dopamine to cause feelings of reward)

52
Q

How do opioids induce a euphoric high if they are depressant drugs?

A

They activate the mu receptor on a GABA neurone and have a depressant effect on it. Therefore we have a double negative as an inhibitor is being inhibited. Now that GABA suppression has been lost, the dopaminergic receptor will fire at a much higher rate - a process called disinhibition.

53
Q

Name the two other classical effects of opioids?

A
  • anti-tussive effect

- nausea inducing effect

54
Q

Explain the anti-tussive effect

A

Opioids have a depressant effect, decreasing the activation of afferent nerves that relay a cough stimulus from the airways to the brain.

55
Q

Explain the nausea inducing effect

A

Opioids increase the activation of neurones projecting from the chemoreceptor trigger zone (CTZ) which stimulates feelings of nausea. Opioids have a depressant effect on GABAergic neurones, disinhibiting CTZ neurones

56
Q

An opioid overdose can lead to?

A

Respiratory depression which can eventually lead to suffocation

57
Q

What is the respiratory control centre responsible for?

A

Generating and maintaining the rhythm of respiration (inhalation and exhalation from the lungs). Altering the depth and rate of breathing based on information received from the central chemoreceptors e.g. altered levels of CO2

58
Q

How are altered levels of CO2 monitored by the body?

A

Sensed after the conversion to hydrogen ions by the enzyme carbonic anhydrase

59
Q

How can opioids induce respiratory depression?

A

Opioids have a depressant effect on the chemoreceptors (so less information is relayed to the respiratory control centre) as well as a depressant effect on the respiratory control centre itself (which reduces the stimulus to the lungs to inhale/exhale)

60
Q

When looking at a log dose curve, for morphine and its effect of analgesia and respiratory depression, which line would be beneath the other?

A

Analgesic effect is below respiratory depression: analgesia is induced at a lower dose

61
Q

What is one way to treat an opioid addict?

A

Give them a partial agonist because it cannot induce a maximal response and cause respiratory depression, which is less dangerous than a full agonist like morphine or heroine

Pharmacology & Toxicology (8 decks)

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