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PHAR > PHAR5 - Applying PD/PK Theory (Opioids) > Flashcards

PHAR5 - Applying PD/PK Theory (Opioids) Flashcards

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1
Q

Name three common opioids.

A

Morphine. Codeine. Heroin.

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2
Q

Discuss the structural differences between morphine and codeine.

A

Morphine contains two hydroxyl groups.

Codeine contains an ether group with a methyl substitute in the place of one hydroxyl group.

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3
Q

Discuss the structural differences between morphine and heroin.

A

Morphine contains two hydroxyl groups.

Heroin contains two acetyl groups.

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4
Q

Discuss the structural differences between codeine and heroin.

A

Codeine contains one hydroxyl group and one ether + methyl group.
Heroin contains two acetyl groups in the place of the two hydroxyl groups.

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5
Q

Rank the lipid solubility of codeine, heroin and morphine.

A

Heroin - most lipid soluble.
Codeine - intermediate lipid solubility.
Morphine - least lipid soluble.

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6
Q

Discuss one similarity between the chemical structures of morphine, codeine and heroin.

A

Phenanthrene ring. Consists of three fused aromatic rings.

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7
Q

Which chemical group of the opioid molecules contributes to their lipid solubility? What is the link between this group and the lipid solubility of the molecule? Explain.

A

Hydroxyl groups.
More hydroxyl groups mean lower lipid solubility. OH group undergoes hydrogen bonding with water meaning it is more water soluble than lipid soluble.

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8
Q

Why is heroin the most lipid soluble opioid?

A

Contains no OH groups so is least water soluble and most lipid soluble.

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9
Q

Why is morphine the least lipid soluble opioid?

A

Contains 2 OH groups (most) so is most water soluble so least lipid soluble.

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10
Q

What are the two chemical structural features of opioids that increase their affinity for the opioid receptor?

A

Position three OH group. Tertiary nitrogen atom with 2 or less carbon atoms in its side chain.

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11
Q

How many drug binding sites does the opioid receptor contain?

A

3 binding sites

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12
Q

How does the tertiary nitrogen atom bind to the opioid receptor?

A

Ionic bonding.

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13
Q

How does the position three OH group bind to the opioid receptor?

A

Hydrogen bonding.

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14
Q

What are the three types of forces that allow the interaction of opioids with opioid receptors?

A

Van deer Waals.
Hydrogen bonding.
Ionic bonding.

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15
Q

Which part of the chemical structure of opioids has a large effect on the efficacy of the opioid?

A

The number of carbons on the tertiary nitrogen atom.

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16
Q

Discuss the link between the number of carbon atoms on the tertiary nitrogen atom of the opioid, and its respective efficacy.

A

If there are 2 or less carbon atoms, the opioid is able to have efficacy for the opioid receptor - effect is produced.
If there is 3 or more carbon atoms, the opioid is unable to have efficacy for the opioid receptor - effect is not produced.

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17
Q

Give one example of an antagonist for the opioid receptor.

A

Naxolone.

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18
Q

Why is naxolone considered an antagonist?

A

Contains 3 carbon atoms on the side chain of the tertiary nitrogen atom. As a result, has zero efficacy. Therefore, it is an antagonist.

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19
Q

Discuss the basic interaction between an opioid and the opioid receptor.

A

Opioid forms attractive forces between all binding sites of the opioid receptor.

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20
Q

Why are codeine and heroin considered to have a lower affinity for the opioid receptor, comparative to morphine?

A

Lack the position three OH group therefore affinity for opioid receptor is reduced.

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21
Q

Discuss the balance between the lipid solubility and affinity of morphine.

A

Morphine has low lipid solubility, so is unable to pass across the membrane, but has high affinity for the opioid receptor, due to the position three OH group.

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22
Q

Discuss the balance between the lipid solubility and affinity of codeine.

A

Codeine has high lipid solubility, so is able to cross the membrane to access the receptor, however has lower affinity for the receptor, due to the lack of the position three OH group.

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23
Q

Discuss the balance between the lipid solubility and affinity of heroin.

A

Heroin has high lipid solubility, so is able to cross the membrane to access the receptor, however has lower affinity for the receptor, due to the lack of the position three OH group.

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24
Q

What is the common route of administration for morphine?

A

Intravenous and oral.

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25
What is the common route of administration for codeine?
Oral route.
26
What is the common route of administration for heroin?
Intravenous.
27
Give three less common routes of administration for opioid drugs.
Intra-muscular - injection. Trans-dermal - patch. Sub-lingual - lollipops.
28
Is morphine a weak base or acid?
Weak base.
29
What is the bioavailability of an opioid drug administered via the intravenous route of administration ?
100% as all the drug enters systemic circulation.
30
Despite having a high bioavailability, not all the opioid drug can access tissue. Why?
Ionised to unionised ratio is greater than 1 therefore more ionised drug is present. This is less lipid soluble meaning it cannot cross the lipid membrane to leave the blood and access the tissues.
31
Discuss the bioavailability of opioid drug administered vial the oral route.
Bioavailability varies. Ileum pH means that there is more ionised than unionised drug therefore less is able to enter the bloodstream due to being less lipid soluble in the ionised state.
32
What is first pass metabolism?
Metabolism of a drug that occurs in the liver prior to the drug entering systemic circulation.
33
Why are some opioids considered more potent than others?
Metabolism of some opioids produces active metabolites which can further the effect produced thus making the drug to be considered more potent.
34
Give one metabolite of morphine.
Morphine-6-glucuronide.
35
Give one metabolite of heroin.
6-acetyl- morphine.
36
Give one metabolite of codeine.
Norcodeine.
37
Discuss similarities and differences in affinity and efficacy between morphine and its metabolite morphine-6-glucuronide.
Both contain position three OH group and tertiary nitrogen with less than 3 carbons therefore possess high affinity and efficacy for opioid receptor.
38
Discuss similarities and differences in affinity and efficacy between heroin and its metabolite 6-acetyl-morphine.
Heroin posses no hydroxyl group however the metabolite does. Both posses the tertiary nitrogen atom. Metabolite 6-acetyl-morphine therefore has greater affinity for opioid receptor.
39
Discuss similarities and differences in affinity and efficacy between codeine and its metabolite norcodeine.
Neither posses the OH group in position three therefore both lack affinity for the opioid receptor.
40
Discuss the differences in water and lipid solubility between heroin (two acetyl groups) and its metabolite 6-acetyl-morphine (one OH and one acetyl group).
OH group in metabolite makes it less lipid soluble/more water soluble. But dose increase affinity for opioid receptor.
41
Where does heroin accumulate and why?
Accumulates in the brain due to being highly lipid soluble.
42
Where does the metabolism of heroin occur?
Both brain and liver. Primarily the liver.
43
What enzymes are responsible for heroin metabolism?
Esterase enzymes.
44
Why can 6-acetyl-morphine (metabolite of heroin) accumulate in the brain?
Despite being more water soluble than heroin due to OH group, it still has a large lipid soluble component so can cross the blood brain barrier.
45
Why is heroin considered more potent than morphine?
Active metabolite produced with high lipid solubility meaning it remains in the body.
46
What two chemical structures can codeine be metabolised into?
Norcodeine. Morphine.
47
What chemical process is needed to convert codeine into the metabolite morphine?
Oxygen demethylation.
48
What chemical process is needed to convert codeine into norcodeine?
Nitrogen demethylation.
49
Where does the metabolism of codeine occur?
Liver.
50
What enzymes carry out codeine metabolism?
Cytochrome P450 enzymes. | CYP3A4 and CYP2A6
51
What is the CYP3A4 enzyme responsible for? Discuss the speed of the process.
Metabolism of codeine into norcodeine. Fast metabolism.
52
What is the CYP2A6 enzyme responsible for? Discuss the speed of the process.
Metabolism of codeine into morphine. Slow metabolic process.
53
Is codeine is pro drug?
Yes. Codeine itself is relatively weak opioid however some is metabolised into morphine which is a stronger opioid.
54
What percentage of codeine is metabolised into morphine?
Small amount, approx 10%.
55
Discuss the difference in lipid solubility between morphine and its metabolite morphine-6-glucuronide.
Metabolite is far less lipid soluble due to glucuronide group added during phase 2 metabolism. (More OH groups possessed so more water soluble).
56
Discuss excretion of opioids in alkaline urine conditions.
Alkaline conditions mean weak base opioids are more unionised. Unionised means greater lipid solubility and less water solubility. Unable to be excreted in urine.
57
Discuss excretion of opioids in acidic urine conditions.
Acidic conditions means more ionised weak base opioids. This means greater water solubility and reduced lipid solubility. Able to be excreted.
58
Based on the normal physiological pH of urine, do opioids tend to babe excreted or accumulated readily?
Urine is usually alkaline. Opioids are weak bases so tend to accumulate in the body than be excreted in urine.
59
What are the three types of opioid receptors and their respective endogenous agonist?
Mu receptor - endorphins. Delta receptor - enkephalins. Kappa receptor - dynorphins.
60
Do the endogenous agonists for opioid receptors interact with one type of receptor only?
Are able to interact with all types of opioid receptors however possess higher selectivity for one specific receptor type.
61
Which receptor subtype do opioid drugs generally interact with?
Mu receptors.
62
Give three mechanisms by which opioids have depressant effects.
1. Inhibition of adenylate cyclase - less cAMP produced - less cellular activity. 2. Inhibition of Ca2+ influx preventing exocytosis of some neurotransmitters. 3. Stimulation of K+ efflux - longer state of hyperpolarisation - prevents action potential from being propagated.
63
What effect do opioid drugs have on adenylate cyclase enzymes?
Inhibition their action. Reduced cAMP production so decreased cellular activity.
64
What effect do opioid drugs have on Ca2+ ion channels?
Inhibit the influx of Ca2+ into the neurone through the ion channel. Prevents calcium mediated exocytosis from occurring. Can prevent release of specific neurotransmitter which decreases cellular activity.
65
What effect do opioid drugs have on K+ ion channels?
Stimulate K+ efflux through ion channel. Hyperpolarisation prolonged. Depolarisation and propagation of action potential is slowed. Cellular activity decreased.
66
What is a common therapeutic effect of opioids?
Analgesics.
67
Define the pain perception pathway.
Signals sent from the peripheral nerves to the thalamus via the spinothalamic neurons.
68
Define the pain tolerance pathway.
Signals sent from the thalamus to various structures within brain and spinal cord to reduced pain feelings.
69
Why are spinothalamic neurons so called?
Send signals from the spine to the thalamus.
70
Discuss a general overview of how pain is felt.
Pain signals sent from the periphery to the dorsal horn via activated sensory neurons. These synapse at the dorsal horn onto spinothalamic neurons which send pain signals to the thalamus.
71
Discuss the role of the periaqueductal grey reign (PAG) in the pain pathway.
Receives pain signals from the thalamus, cortex and hypothalamus. Considered the integrating centre for pain tolerance. Relays signals to the nucleus raphe Magnus.
72
Discuss the role of the cortex in the pain pathway.
Receives pain signals from the thalamus. Sends pain signals to the periaqueductal grey region. Involved in memory therefore pain signals are relative to pain signals from memory - e.g. if burn had been previously felt, the current burn would either be more or less severe than the previous one.
73
Discuss the role of the nucleus raphe Magnus in the pain pathway.
Receives signals from the nucleus reticularis paragigantocellularis and periaqueductal grey region. Sends inhibitory signals to the dorsal horn to reduce pain signal transmission. Neurons from here project to the substantia gelatinosa of the dorsal horn.
74
Discuss the role of the nucleus reticularis paragigantocellularis in the pain pathway.
A region that is independent of the thalamus. Receives pain signals directly from the spinothalamic neurons. This activation results in the activation of the nucleus raphe magnus which has neurons that project to the substantia gelatinosa of the dorsAl horn to inhibit pain signals transmission.
75
What is the advantage of the nucleus reticularis paragigantocellularis?
Ensures that pain signals are quickly diminished.
76
What is the role of the hypothalamus in the pain pathway?
Monitors general health of the body. Increased health means pain signals are likely to be less. This is due to more signals being sent o the periaqueductal grey region to reduce pain transmission.
77
What is the role of the locus coerulus in the pain pathway?
Receives signals from the thalamus. Sends signals directly to the dorsal horn to inhibit the firing of spinaothalamic neurons meaning pain is diminished.
78
Discuss the link between the locus coerulus and the fight or flight response.
The locus coerulus is involved in the sympathetic nervous systems fight or flight response. Pain signals are diminished meaning that individuals will not feel pain during the stressful situation. Following this, pain will however be felt.
79
Discuss location of the substantia gelatinosa and neurons within it.
Located in the dorsal horn. Sensory neurons end here and spinothalamic neurons start here. Descending neurons of the nucleus raphe magnus end here also.
80
Discuss the role of the substantia gelatinosa.
Modulates pain signals. Receives signals from the nucleus raphe magnus and locus coerulus. Decreases pain felt.
81
What is the effect of opioids on the firing rate of the peripheral sensory neurone? Explain.
Decreases. Less peripheral sensory neurone activation means less pain felt and signals are not transmitted to the thalamus via the spinothalamic neurons.
82
What is the effect of opioids on the firing rate of the periaqueductal grey region? Explain.
Increases. The PAG is involved in decrease pain signal transmission because it is part of the pain tolerance pathway. Increasing its firing rate means that the nucleus raphe magnus is increased which can further decrease the dorsal horn activity.
83
What is the effect of opioids on the firing rate of the nucleus reticularis paragigantocellularis? Explain.
Increases. Able to diminish pain signals by signalling to the nucleus raphe magnus.
84
What is the effect of opioids on the firing rate of the thalamus? Explain.
Decreases. Less pain is felt if the thalamus decreases as this is where the spinothalamic neurons project to.
85
What is the effect of opioids on the firing rate of the spinothalamic neurons? Explain.
Pain signal is not sent rom the peripheral sensory neurons to the thalamus so less pain is felt.
86
What other effects are opioid drugs able to produce?
Euphoric high, anti-tussive effect and nausea.
87
Where do dopaminergic neurons in the brain project from and project to?
From the ventral tegmental area to the nucleus accumbens.
88
Discuss the way in which opioid cause an euphoric high.
Opioids interact with mu receptor on GABA neuron. Prevents firing of GABA neurone meaning it is unable to suppress firing of dopaminergic neuron. Dopamingeric neuron continues to fire so high is felt.
89
Discuss disinhibition.
Deactivation of an inhibitory neurone.
90
Discuss the link between GABA neurons and dopaminergic neurons.
GABA neurons we constitutively firing. This results in the suppression of the dopaminergic neuron. Prevents the euphoric high being felt all the time.
91
Discuss how opioid drugs contribute to the anti-tussive effect.
Opioid drugs have a depressant effect on afferent neurons which send cough stimulus signals to the brain from the airways. As a result, less coughing occurs.
92
Discuss how opioid drugs are able to induce nausea.
Opioid drugs have a disinhibition effect on GABA neurons. This results in increased activation of chemoreceptor trigger zone neurons. Results in feelings of nausea.
93
What is a toxic effect of opioid drugs?
Respiratory depression
94
What structure is the respiratory control centre?
The medulla.
95
How does the medulla control respiration?
Maintains respiratory rhythm by altering rate and depth of breathing.
96
Which structure sends information to the medulla regarding respiratory control?
Central chemoreceptors.
97
Discuss how chemoreceptors identify high carbon dioxide levels.
Carbon dioxide forms H+ ions via equilibrium reaction with water. This change is detected by chemoreceptors.
98
Where do the opioid drugs have their depressant effects when producing the respiratory depression toxic effect?
Central chemoreceptors. | Respiratory control centre.
99
Is morphine a full or partial agonist? Why?
Full agonist. Produces a maximal response which can result in toxic respiratory depression effects.
100
Discuss the use of partial agonists for opioid addicts.
Partial agonists are able to produce sub maximal analgesic effects however do not have the risk of respiratory depression associated with them, therefore are safer for use by opioid addicts.
101
Is heroin a full or partial agonist?
Full agonist.

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