Opioids

Question 1

What is an opiate?

Answer 1

An alkaloid derived from the poppy, Papaver somniferum

Opioid is anything with opiate activity.

Question 2

Give examples of opiates?

Answer 2

Morphine

Codeine

Question 3

Describe the structure-activity of morphine

Answer 3

The tertiary nitrogen on morphine is an analgesia. It permits receptor anchoring. A single methyl group makes it effective.

Changes to the methyl group on the nitrogen will decreases analgesia as well as creating antagonists.

If you extend the side chain to 3+ carbons you generate antagonist.

The two hydroxyl groups on position 3 and 6 are also important for receptor binding. Less important than the tertiary nitrogen group. These hydroxyl group mean that it is not very lipid soluble.

See slide for diagram

Question 4

Describe the structure of heroin in terms of morphine.

Answer 4

heroin is diacetyl morphine

Acetyl groups make heroine more lipid soluble than morphine.

Essentially it is a prodrug. It will have no effect on the opioid receptor.

Question 5

Describe the structure of codeine in terms of morphine.

Answer 5

codiene is methyl morphine. On position 3

Essentially it is a prodrug. It will have no effect on the opioid receptor.

Question 6

What structural elements are necessary for opiate activity?

Answer 6

Quaternary carbon centre
Basic nitrogen (tertiary)
Spacer
Aromatic ring

Compounds such as methadone and fentanyl have these structures even though they don’t look like morphine. They have a open structure.

Question 7

What is the normal route of admission of opioids

Answer 7

• Oral and IV
• Weak bases - pKa above 8 (the more acidic the environment the less well absorbed they are) Good absorption is when the pKa and pH (of the environment: Stomach = 1.5-3.5pH) is roughly the same.

In the small intestine, they will be unionised and more readily absorbed. However, first pass metabolism will decrease the bioavailability.
Blood pH = 7.4. Therefore most opioids will be largely ionised in the blood. Usually <20% unionised. This unionised opioid is the component that can access tissues.

Question 8

What is the link between the potency and lipid solubility?

Answer 8

The more lipid soluble an opioid the more potent it is.
This is because it can diffuse easier into the brain and have its effects. More lipid soluble = can diffuse into the brain faster.

The exception is codeine - less potent due to metabolism

Lipid Solubility: Methadone/Fentanyl&raquo_space; Heroin > Morphine
General rule of thumb – More lipid soluble, more potent.

See slide 14

Question 9

What is the active metabolites of morphine?

Answer 9

M3-G and M6-G
Morphine-3-glucuronide
Morphine-6-glucoronide - u-opioid receptor agonist with potent analgesic activity.

Question 10

What are the active metabolites of heroin and codeine?

Answer 10

Morphine. You’re cleaving off these 2x acetyl and hydroxyl groups. These drugs get into the brain as heroin and codeine before it is converted into morphine.

Question 11

What is the methadone used for?

Answer 11

Used as a heroin substitute to weed people off addiction. The faster a drug is cleared the more addictive. It’s clearance is very slow.

Question 12

What is fentanyl used for?

Answer 12

It is used as an analgesic.

Question 13

Describe the pharmacokinetics of codeine

Answer 13

Codeine is far less potent because the metabolism of codeine to morphine is very slow. The fast metabolism of codeine results in an inactive metabolite norcodeine. Because most of the codeine is fast metabolised only 10% of the codeine is metabolised to produce morphine

Question 14

List some endogenous opioid peptides?

Answer 14

Endorphins
Enkephalins
Dynorphins/neoendorphins

Question 15

What receptors do the different endogenous opioids bind to?

Answer 15

Endorphins –> Mu or delta opioid receptors–> Mu –> pain/sensorimotor (inhibit pain transmission and modify the central perception of pain)

Enkephalins –> Delta –> Motor/cognitive function

Dynorphins/neoendorphins –> kappa –> Neuroendocrine

Question 16

What are the effects of opiate receptors?

Answer 16

Depressant:

• cause hyperpolarisation (increases K+)
• reduce Ca2+ inward current
• decrease adenylate cyclase = decrease of cellular activity.

Question 17

What are the therapeutic effects of opioids?

Answer 17

Analgesia

Euphoria

Depression of cough centre (anti-tussive)

Question 18

What are the negative side effects of opioids?

Answer 18

Depression of respiration (medulla)

Stimulation of chemoreceptor trigger zone (nausea/vomiting)

Pupillary Constriction

G.I. Effects

Question 19

How do opioids cause analgesia?

Answer 19

Decrease pain perception

Increase pain tolerance

Opioids target the dorsal horn, periphery, PAG and NRPG. They enhance pain tolerance.

Dorsal horn - suppress the relay of pain
Activate the pain tolerance pathway

Question 20

Describe the pain pathway. Draw a diagram.

Answer 20

Peripheral pain: sensory neurones detect tissue damage –> relay signal to dorsal horn –> spinothalamic neurones go to the thalamus –> goes to the cortex

Thalamus also signals to the PAG. This controls pain tolerance. The cortex can then increase/decrease the pain tolerance by influencing the PAG.

The PAG then activates the NRM (Nucleus Raphe Magnus) which will send descending fibres down the spinal cord to the dorsal horn and interfere with the pain transmission. The NRM will suppress the pain feeling. The NRM is in the RVM (Rostral Ventral Medulla)

The NRPG (nucleus reticularis paragigantocellularis) is an immediate negative feed back mechanism to suppress the pain. It works independent of the thalamus.

The hypothalamus is constantly relaying to the PAG about your constant state of health. It can interfere with the signal so the pain will remain - to prevent further damage to you if you are not fit and healthy

LC (Locus coeruleus) - sympathetic nervous system works independently and directly inhibits the dorsal horn = suppressing pain.

Within the dorsal horn itself there is a direct inhibition and also the substantia gelatinosa. Descending nerves from the NRM inhibit the the spinothalamic nerves. The SG is like a mini brain in the spinal cord - inhibits spinothalamic pain relay.

See slide for diagram

Question 21

How does opioids cause euphoria?

Answer 21

Same mechanism as cannabis

opiods bind to mu-receptor . switching off GABA. So it doesn’t inhibit the dopamine receptor anymore.

Question 22

How do opioids act as anti-tussives?

Answer 22

1) Stimulation of mechano - or chemoreceptors. (throat, respiratory passages or stretch receptors in lung)

Ach/NK C-fibres (nociceptive) relay to vagus. Opiods inhibit these fibres meaning there is no impulse to medulla.

2) Afferent impulses to cough centre (medulla)

5HT1A receptors suppress serotonin. Serotonin is anticough. Opioids block these receptors so the levels of serotonin increases.

3) Efferent impulses via PSN and motor nerves to diaphragm, intercostal muscles and lung
4) Increases contraction of muscles –> cough

Question 23

How do opioids causes respiratory depression?

Answer 23

Central chemoreceptors detect levels of PaCO2 which signals to Medullary control centre.

Prebotzinger complex provides constant tonic stimulus for breathing in the medulla. It is active during inspiration and is inhibited by opioids

These both provide a key stimulus to breath. Opioids target both of these areas.

See diagram

Question 24

How do opioids cause nausea and vomiting?

Answer 24

See diagram

Opioids activate mu receptors in the chemoreceptor triggering zone - medullary vomiting centre.

Question 25

How do opioids cause miosis?

Answer 25

Opioids switch on the parasympathetic nerves by binding to the opioid receptors in the edinger-westphal nucleus.

Question 26

What are the effects of the opioids in the enteric nervous system?

Answer 26

Causes constipation –> opioid receptors everywhere in the gut. opioids suppress gut function = constipation.

Question 27

How do opiods cause urticaria

Answer 27

Opiods with a hydroxyl group on position 6 activates mast cells leading to histamine release. Allergic response type.

Question 28

How do you become tolerant to opioids?

Answer 28

Chronic use causes upregulation of arrestin. This protein causes receptor internalisation. So there are less opioid receptors on the cell so you become tolerant

Question 29

Describe opioid dependence?

Answer 29

Withdrawal associated with:

• Psychological craving
• Physical withdrawal (resembling flu)

Upregulation of cAMP –> causes the cells to be more active. There is upregulation to try and maintain the homeostasis of the cell as the opioids are suppressors.

Question 30

What is seen in opioid overdose?

Answer 30

Coma

Respiratory depression

Pin-point pupils

Hypotension

Treatment: Naloxone (opioid antagonist) i.v. This has 3 carbon atoms coming of the tertiary nitrogen.