Opioids

Question 1

1. What are the three major groups of endogenous opioid peptides and what are they pre-cursors?
2. Where are the Leucine and Methionine Enkephalins dristibuted through CNS?
3. Beta-endorphins come from where and are associated with what?

Answer 1

1. Enkephalins (pre: proenkephalin), Endorphins (pre: proopiomelanocortin), Dynorphins (pre: prodynorphin)
2. Widely distributed, especially in interneurons, including those associated with pain pathways
3. Beta-endorphins occur in the hypothalamus and n. solitarius and pituitary. It is co-released with ACTH in response to stress.

Question 2

1. What is the endogenous ligand for the MU receptor?
2. What is the endogenous ligand for the KAPPA receptor?
3. What is the endogenous ligand for the DELTA receptor?

Answer 2

1. MU: Enkephalins, B-endorphins
2. KAPPA: Dynorphins
3. DELTA: Enkephalins, B-endorphins

Question 3

1. What are the drug ligands for the MU receptor?
2. What is the drug ligand for the KAPPA receptor?
3. What is the drug ligand for the DELTA receptor?

Answer 3

1. MU: Morphine, Fentanyl, Methadone, Meperidine, Buprenorphine
2. KAPPA: Nalbuphine
3. DELTA: NONE

Question 4

What is the mechanism of action for morphine?

Answer 4

Morphine binds MU receptor → G-protein reduction in cAMP → blocks calcium entry and opens K⁺ channels → decreased Ca concentration decreases neurotransmitter release

Question 5

1. What receptors in what area of the brain might be involved in Opioid dependance?
2. What may be responsible for the dysphoric actions of nalbuphine?

Answer 5

1. MU and DELTA receptors in the limbic areas
2. KAPPA receptors in the limbic structures

Question 6

1. What is referred to by “narcotic”?
2. What is referred to by “opiate”?

Answer 6

1. Any drug that produces a stuporous, sleep-like state & may or may not be analgesic.
2. Drugs derived from opium or have a morphine-like pharmacological profile

Question 7

1. What is the relative oral absorption for morphine compared to IV?
2. What affects the onset of action of opioids?

Answer 7

1. Approximately 1/3
2. Degree of lipophilicity (Heroin highly lipophilic)

Question 8

1. What is the difference between Morphine and Codeine?
2. Why is Codeine less efficacious than Morphine?
3. How is Heroin associated with Morphine?

Answer 8

1. Codeine is a methylated pro-drug for Morphine.
2. Not all of the Codeine is converted to Morphine but may still bind in the Codeine form
3. It is diacetylmorphine and is converted to monoacetyl-morphine

Question 9

How do opioids create cough suppression? Which drugs are commonly used for this?

Answer 9

They suppress brainstem cough centers (may not be mediated by opioid receptors)
Codeine and Dextromethorphan

Question 10

How are opioids used for an antidiarrheal effect? What unwanted side effect is associated with this?

Answer 10

Peripheral MU receptors on GI nerves. Same effect can cause constipation.

Question 11

Why do opiates cause nausea?

Answer 11

Stimulation of CTZ (chemoreceptor trigger zone) in area postrema. More significant effect when standing.

Question 12

What are the endocrine effects of Opiates?

Answer 12

1. Decreased LH release - MU mediated
2. Increased ADH secretion - MU mediated
3. Decreased ADH secretion - KAPPA mediated

Question 13

Why do opiates cause miosis (pupillary constriction)?

Answer 13

They stimulate the Edinger-Westphal nucleus of the oculomotor nerve.
There is no tolerance to this effect.

Question 14

1. What is the oral to parenteral potency ratio of Morphine?
2. What is the duration of analgesia for Morphine?

Answer 14

1. 3-4 to 1 potency for oral to parenteral
2. Duration of analgesia is 4-5 hours.

Question 15

1. What is the relative potency of Methadone?
2. What is the relative duration of action?
3. What is it primarily used for?

Answer 15

1. Methadone is equipotent with morphine.
2. It has a longer duration of action than morphine.
3. It is used in the treatment of opioid abuse and chronic pain

Question 16

1. What is the relative potency of Fentanyl?
2. What is the relative duration of action?
3. How is it primarily available?

Answer 16

1. Fentanyl is 100X as potent as morphine.
2. It is short-acting - 1 to 1.5 hours
3. It is available in injectable form and transdermal patch

(Considered “medical heroin”)

Question 17

1. What is the relative duration of Meperidine?
2. Why isn’t it used as much anymore?

Answer 17

1. It has a shorter duration of analgesia than Morphine
2. It forms a toxic metabolite that can accumulate with frequent use. It has significant interactions with MAO-I’s.

Question 18

1. What is the indication for Codeine?
2. How much Codeine is required to reach a Morphine like efficacy?

Answer 18

1. Mild to moderate pain
2. Morphine life efficacy NOT achievable at any dose of Codeine

Question 19

1. What are two oral preparations of opioids that are commonly used for moderate to severe pain?
2. Which one is more commonly combined with an NSAID or acetaminophen?

Answer 19

1. Oxycodone and Hydrocodone
2. Hydrocodone

Question 20

What is the relative potency of Hydromorphone compared to morphine?

Answer 20

2-3X as potent

Question 21

1. What is the mechanism of action of Nalbuphine?
2. What is its relative efficacy and potency?
3. What is the advantage to Nalbuphine over Morphine?
4. What is the drawback to Nalbuphine?
5. What is its limitation in administration?

Answer 21

1. MU-antagonist and KAPPA-agonist
2. Similar to Morphine.
3. Little euphoria and low abuse potential
4. Can precipitate withdrawal in opiate dependent patients.
5. Only available by injection.

Question 22

1. What drug is a partial MU-agonist but 20-50x more potent than morphine?
2. What are the components of Suboxone?

Answer 22

1. Buprenorphine
2. Buprenorphine and Naloxone

Question 23

1. What is the mechanism for Naloxone?
2. What is the duration of action?

Answer 23

1. High affinity MU-antagonist. Lower affinity for KAPPA and DELTA.
2. 1-2 hours

Question 24

What drug is a long acting (24+ hrs.) opioid antagonist? What is it used for?

Answer 24

Naltrexone. It is used in treatment of alcoholism and opiate addiction.

Question 25

1. What is the mechanism/function for **Dextromethorphan**? 2. What is the mechanism for **Tramadol**?

Answer 25

1. Not a MU agonist like its isomer levorphanol but is a cough suppressant with some NMDA antagonism. 2. Weak MU-agonist and blocks NE and 5-HT uptake.

Question 26

1. What opioid side effect do patients generate rapid tolerance to? 2. What side effects do patients generate little or no tolerance to? 3. What side effects do patients gradually generate tolerance to?

Answer 26

1. Nausea and vomiting 2. Miosis and Constipation 3. Analgesia, Euphoria, Respiratory depression, endocrine dysfunction.

Question 27

1. What withdrawal symptoms develop after 6-12 hrs? 2. What symptoms develop after 12-24 hrs?

Answer 27

1. Restlessness, lacrimation, rhinorrhea, sweating, yawning 2. Above plus irritability, tremor, dilated pupils, anorexia, piloerection

Question 28

What makes alcohol withdrawal life threatening but opiate withdrawal not life threatening?

Answer 28

There is no risk of convulsions/seizures or encephalopathy with opiate withdrawal like there is with alcohol withdrawal.