Opioids (musculoskeletal pain)

Question 1

What are natural opiates? Give an example.

Answer 1

These are alkaloids found in opium

e.g. morphine.

Question 2

What are semi-synthetic opioids? Give an example.

Answer 2

They are derivatives of natural opiates

e.g. heroin, oxycodone, diamorphine.

Question 3

What are synthetic opioids? Give an example.

Answer 3

These are synthetic compounds

e.g. methadone, tramadol.

Question 4

What are opiate peptides? Give an example.

Answer 4

These are endogenous peptides (naturally occurring within body)
e.g. endorphins, enkephalins.

Question 5

What is the difference between opioids and opiates?

Answer 5

Opiates occur naturally

Question 6

What are all the effects of opium/morphine?

Answer 6

Major effects: analgesia, nausea/vomiting, dependence
Reduced GI motility
Respiratory depression
Cough suppressant 
Pupil constriction
Formication (feeling insects crawling over you)
Sedation/anaesthesia
Euphoria/dysphoria

Question 7

How does taking opioids decrease GI motility?

Answer 7

Opioid receptors are found in the GI tract - individuals who overuse opioids suffer from severe constipation.

Question 8

Describe the structural morphology of morphine (4 points).

Answer 8

1. Contains 5 rings.
2. Basic due to the tertiary amino group (alkaloid) - will be inactive if removed.
3. Contains a phenolic group at position 3 - will be inactive if removed.
4. Contains a benzene aromatic ring.

Question 9

List the 5 functional regions of morphine.

Answer 9

phenol
ether
alcohol
tertiary amine
aromatic benzene ring

Question 10

What is the effect of removing the OH/alcohol group at position 3?

Answer 10

This group influences the lipophilicity of the drug - removing it will make molecule more lipophilic so can cross the blood brain barrier and cause CNS effects.

Question 11

What is the main route of metabolism for morphine?

Answer 11

Via glucuronidation.

Question 12

What is the enzyme involved in the metabolism of morphine?

Answer 12

UGT

= UDP-glucronosyl transferase.

Question 13

How are conjugates excreted after metabolism of morphine?

Answer 13

Mostly excreted in urine - glucuronic acid conjugate

Question 14

Describe morphine-3-glucuronide.

Answer 14

Made by altering the phenol group on position 3 by adding glucuronic acid group - this makes it inactive.
It is an inactive toxic metabolite - 60% of this will be made.

Question 15

Describe morphinr-6-glucuronide.

Answer 15

Made by altering the alcohol group on position 6 by adding glucuronic acid - makes it more lipophilic - increases transport of drug across BBB = increases relative potency of drug by 50 fold.
This is the active metabolite and only 6-10% of this is made.

Question 16

What is morphine-3,6-diglucuronide?

Answer 16

This is the resultant metabolite of morphine after morphine-3-glucuronide and morphine-6-glucuronide are continued to metabolise by UGT enzyme. It is an inactive metabolite.

Question 17

Codeine is a prodrug of morphine. What is a prodrug?

Answer 17

Means that drug is modified after administration to exert its effects.

Question 18

Describe how codeine converts to morphine.

Answer 18

Codeine is produced by methylation of the phenolic OH at position 3. This reduces the activity of morphine.
Metabolism causes demethylation of the phenol group resulting in the potent morphine.

Question 19

Describe conversion of heroin to morphine.

Answer 19

Heroin is produced when the phenol and alcohol group become acetylated (diacetylation) - results in diacetylmorphine = heroin.
Heroin is more active than morphine as acetyl group is more lipophilic hence crosses the BBB. Once it has crossed the BBB, both acetyl groups are removed by esterase enzymes within the brain. Removal results in morphine and can start to exert effects.

Question 20

Heroin is a prodrug of morphine. What are the metabolites and how are they formed?

Answer 20

Metabolites are 3-monoacetylmorphine (3-MAM), 6-monoacetylmorphine (6-MAM) and morphine.
Formed by the action of carboxylesterases.

Question 21

Are the metabolites of heroin active?

Answer 21

Heroin and 3-MAM are inactive at the mu receptors.

Morphine and 6-MAM are active at the mu receptors.

Question 22

What are two mu receptor/opioid receptor antagonists?

Answer 22

Naloxone and Naltrexone

- can be used reverse effects of morphine.

Question 23

What is naloxone?

Answer 23

• used to overcome respiratory depression post surgery
• rapid onset post iv administration
• is a complete antagonist of morphine (no analgesia or respiratory)
• used to treat morphine or diacetylmorphine overdose

Question 24

What is naltrexone?

Answer 24

• not commonly used
• used as an antidote in morphine overdose
• used to assist rehabilitation of opioid-dependent patients

Question 25

What is nalorphine?

Answer 25

• strong antagonist of morphine

- no major analgesic properties but has weak analgesic effects without unwanted side effects

Question 26

Name the 3 opioid receptors.

Answer 26

mu, kappa, delta

- all are GPCRs = G-Protein Coupled Receptors

Question 27

What is the endogenous agonist for delta receptor?

Answer 27

Enkephalins

Question 28

What happens when opioid agonists bind to GPCRs?

Answer 28

They cause a decrease in adenylyl cyclase activity which causes a reduction in cyclic AMP thereby inhibiting the likelihood of neurotransmission. Pain feeling will be absent.
- link this to how beta gamma subunit prevent influx of calcium hence no HT released into synaptic cleft so no neuronal transmission.

Question 29

Describe how the opioid receptors are distributed with respect to analgesia.

Answer 29

Widely distributed in the brain - found in periaqueductal gray, nucleus raphe magnus, thalamus and brainstem.
Found in the spinal cord in the substantia gelatinosa.
Found in the periphery - nociceptors, Ad/C fibres, gut myenteric plexus