Opioids

Question 1

Types of Opioids?

Answer 1

1. Exogenous

2. Endogenous

Question 2

Exogenous opioids?

Answer 2

1. Synthesis: Natural, semisynthetic & synthetic

2. Receptor binding: Agonist, partial agonist, antaginists and biased agonists.

Question 3

Action of opioids?

Answer 3

On receptors / Peptides

1. Mu opioid receptors (M1,M2 & M3)
2. Kappa opoioid receptor
3. Delta opioid receptor
4. Ophanin FQ/Nociceprion receptor (Not sensitive not naloxone)

Question 4

Mu opioid receptors?

Answer 4

1. M1 - Involved in opioid analgesia
2. M2 - Opioid induced respiratory depression
3. M3 - Opioid induced immune suppression

Question 5

Classes of endogenous opioid receptors?

Answer 5

1. Enkephalins
2. Endorphines
3. Dynorphins

Question 6

Affinity of endogenous opioids?

Answer 6

1. B-endorphins - MOR
2. Met & Leu - enkephalins - KOR
3. Dynorphins - DOR

Question 7

Regulatory functions of endogenous opioids?

Answer 7

1. Nociception, stress, emotion and hedonic responses

2. Thermoregulation, breathing, neuroendocrine function, GI motility and immune responses.

Question 8

Naturally occuring exogenous opioids ?

Answer 8

1. Morphine
2. Codeine
3. Papaverine
4. Thebaine

Question 9

Semi-synthetic exogenous opioids ?

Answer 9

1. Heroin
2. Dihydromorphine, morphinone
3. Thebaine derivatves (bruprenorphine)

Question 10

Synthetic exogenous opioids ?

Answer 10

1. Morphinan derivatives (Levophanol, bulorphanol)
2. Diphenylpropylamine derivatives ( Methadone)
3. Benzomorphan derivatives (Pentazocine)
4. Phenylpiperidine derivatives (Meperidine, fentanyl, sufentanil, alfentanil, remifentanil)

Question 11

Classification according to opioid EC(50) - Plasma concentration at which they exert their effect ?

Answer 11

1. Strong opioids: Alfentanil, fentanyl, sufntanil and remifentanil
2. Intermediate: Morphine, Methadone, Oxycodone, hydromorphine and buprenorphine
3. Weak opioids: Codeine, hydrocodeine, dextropropoxyphene and tramadol

Question 12

Opioid agonists ? ( Full agonists)

Answer 12

Morphine, codeine, meperidine, fentanyl, sufentanil, remifentanil, methadone, tramadol

Question 13

Opioid agonist/antagonist & Partial agonists?

Answer 13

Pentazocine, nalbuphine, butorphanol, buprenorphine

Question 14

Opioid antagonists ? -

No effect alone but reverses the effects of all agonists.

Answer 14

Nalorphine, naloxne, naltrexone, naltrindole, nalmefene

Question 15

Opioid “Biased” agonists?

Answer 15

Oliceridine

Question 16

Inverse agonists ?

Answer 16

Reduces basal receptor activity, drawing an inverse sigmoid. E.g; Naloxone, Naltrexone

Question 17

Mechanism of action of opioids?

Answer 17

1. Peripheral mecahnism - Local release of endogenous opioid like substances that act on opioid receptors located on the primary sensory neuron
2. Direct inhibition of ascending transmission of nociceptive information from spinal cord dorsal horn.
3. Activating pain control pathways descending fromt he midbrain via the rostral ventromedial medulla (RVM) to the spinal cord dorsal horn

Question 18

Sequence after agonist binding to opioid receptor?

Left - G-protein signalling pathway:

Answer 18

1. Dissociation of G-protein into alpha, beta & gamma subunits
2. Inactivation of calcium channels
3. Activation of potassium channels - Reducing excitability of the cell membrane
4. Inhibition of adenyl cyclase
5. Stimulation of mitogen associated protein kinases (MAPKs)
6. Analgesia

Question 19

Right - B-arrestin signalling pathway:

Associated with side effects

Answer 19

1. G-protein receptor kinases phosphorylate active G-protein coupled receptors enabling the recruitment of of B-arrestins
2. Activation of MAPKs

Question 20

New opioid - Oliceridine ?

Answer 20

1. IV MOR biased selective G-protein agonist
2. Selectvely activates G-protein and B-arrestin signalling pathway
3. Preference of G-protein over B-arrestin relative to morphine and fentanyl - Fewer side effects
4. Hepatic metabolism with no metabolites
5. No dose adjustment in patients with renal impairment.
6. Potency equal to morphine

Question 21

New opioid - Tapentadol?

Answer 21

1. Activates the Mu opioid receptor at the spinal and supraspinal sites also norepinephrine reuptake inhibitors (NRI).
2. Affinity for MOR is 50 folds higher than that of morphine
3. Lower side effects

Question 22

Pharmacokinetics of Opioids ?

Answer 22

1. Weak bases

2. Dissociate to ionized and base fraction

Question 23

Ionized fraction of injected opioid?

Answer 23

1. Less lipid soluble
2. Attached to plasma protein and not available to diffuse to the action site.
3. Ionized form is the effective form of molecule. The receptor recognizes the ionized form.

Question 24

Base fraction (free) of injected opioids?

Answer 24

1. More lipid soluble and diffuses to action site.

Question 25

Lipophilic opioids ? Fentanyl / Sufentanil ( High volume of distribution)

Answer 25

1. Low protein binding
2. High volume of distribution
3. Redistribution accounts for loss of analgesic effect in drugs with high vD

Question 26

Low volume of distribution ? Remifentanil / Alfentanil

Answer 26

1. Low volume of distribution
2. High clearance ( Remifentanil)
3. High protein binding (Alfentanil)
4. Clearance is responsible for the drop in plasma concentration (short duration of action).

Question 27

Opioid metabolism?

Answer 27

1. Morphine > Morphine-6-Glucuronide & Morphine-3-Glucuronide (Active)
2. CYP-3A4 & CYP-2D6 are involved in metabolism of; Heroin, Codeine, Fentanyl
3. Genetic variability - Increased & decreased activity of CYP-2D6
4. Remifentanil metabolized within erythrocyte and tissue non-specific esterases.
5. Excreted by kidney or billiary tract into the gut. CKD can lead to accumulation and adverse effects (seizures & CNS depression)

Question 28

Context sensitive half-life ?

Answer 28

Read about this from textbook

Question 29

Biased agonists?

Answer 29

Read about mechanism of action