Opioid Analgesics

Question 1

What is the difference between opioids and opiates?

Answer 1

• Opiates - substances from poppy - e.g. morphine, codeine
• Opioids - endogenous and synthetic compounds that produce morphine-like effects

Question 2

Name 2 endogenous opioids.

Answer 2

Endorphins and enkephalins

Question 3

Describe the presyaptic and postsynaptic mechanisms of opioid action. Explain how these produce analgesic effects.

Answer 3

Presynaptic:

• Reduced N-type VGCCs > reduced NT release
• Increased K⁺ channels > hyperpolarisation > reduced VGCCs > reduced NT release

Postsynaptic:

• Increased K⁺ channels > hyperpolarisation > decreased neuronal firing

Question 4

How do opioids increase descending inhibition of pain?

Answer 4

• Opioids “switch off” inhibitory interneurons in the periaqueductal grey matter via MOP, DOP and KOP
• This region is the origin of the descending inhibitory pain pathway
• Thus opioids produce disinhibition of the descending inhibitory pathway and so increase descending inhibition of pain

Question 5

Why do opioids cause euphoria?

Answer 5

• Opioids increase dopamine transmission by disinhibition of the dopaminergic neurons of the VTA
• μ receptor-mediated inhibition of GABAergic interneurons in VTA increases dopamine transmission in the mesolimbic and mesocortical pathways
• Mesolimbic pathway projects to the ventral striatum - “reward area” - comprised of nucleus accumbens and olfactory tubercle
• μ receptor-mediated inhibition of GABAergic interneurons occurs both in the VTA and within the destination itself, the ventral striatum

Question 6

Explain why opioids cause respiratory depression.

Answer 6

• Opioid receptors are found in respiratory areas of brain - pre-Botzinger complex, medullary nuclei chemoreceptors
• Opioids cause suppression of respiratory pattern and chemoreceptors less sensitive to PCO₂
• Increases in arterial PCO₂ do not produce the normal expected increase in ventilation rate
• Respiratory failure is the most common cause of death in opioid overdose

Question 7

Describe the basic characteristics of the 3 main opioid receptors.

Answer 7

• μ receptor (MOP) - associated with actions of morphine and analgesia
• δ receptor (DOP)
• κ receptor (KOP)

All opioid receptors are G protein-coupled and are G_i/0 linked

Question 8

Compare and contrast the major characteristics of the most common opioids: codeine, methadone and diamorphine (heroin).

Answer 8

• Codeine: less potency, mild analgesia, combined with NSAIDs
• Methadone: oral delivery, long t_1/2, only one hit, prevents opioid withdrawal symptoms
• Diamorphine: pro-drug, inceased lipid solubility, quicker “hit”
• All weak bases, pKa ~ 8, intestinal absorption
• Significant 1st pass metabolism
• Poor bioavailability - 20-30%
• Thus usually given i.v./i.m.

Question 9

Describe the 2 main metabolites of morphine and their significance.

Answer 9

• Morphine-3-glucuronide - inactive
• Morphine-6-glucuronide - active
• Both excreted by kidneys - careful in patients with kidney failure - may cause opioid build-up

Question 10

Name a partial agonist of opioid receptors that is used to treat heroin addiction.

Answer 10

Buprenorphine

Question 11

What is naxolone?

Answer 11

Opioid antagonist - blocks all opioid receptors, reverses morphine-induced symptoms, used to reverse overdose problems

Question 12

Opioid overdose causes what triad of symptoms?

Answer 12

1. Respiratory depression
2. CNS depression/coma
3. Pin-point pupils (constricted)