Opioid analgesics

Question 1

Morphine

Answer 1

Mu agonist.

Question 2

Hydrocodone

Answer 2

Mu agonist.

Question 3

Oxycodone

Answer 3

Mu agonist.

Question 4

Codeine

Answer 4

Mu agonist.

Question 5

Tramadol

Answer 5

Mu agonist.

Tramadol – mu agonist but also blocks monoamine uptake (an antidepressant action)

Question 6

Fentanyl (many facts)

Answer 6

Mu agonist.

Fentanyl and relatives: extremely potent piperidines (Schedule II).
100 times more potent than morphine used in peri-operative and post-operative pain management (IV administration)
very short duration of action (1 hr vs. 4-6 hr for morphine)
used as adjuncts to surgical anesthesia (fast, short-acting; no histamine release)
requires mechanical ventilation at high doses to due to severe respiratory depression.

High abuse by physicians.

Question 7

Buprenorphine

Answer 7

Mu partial agonist.

can precipitate mild withdrawal, can cause analgesia and can partially antagonize the effects of morphine. Long acting-used in maintenance therapy. Available in a patch.

Question 8

Naloxone

Answer 8

Mu antagonist.

competitive antagonist
short duration of action, may require re-administration in treatment of overdoses with long acting agonists
no oral availability

Question 9

Naproxen

Answer 9

Nonselective cox1/cox2 inhibitor (NSAID - like)

Question 10

Celecoxib

Answer 10

Cox-2 selective inhibitor.

Question 11

Ketamine

Answer 11

NMDA receptor agonist.

Question 12

Anticonvulsants

Answer 12

Gabapentin,

Question 13

Antidepressents

Answer 13

SSRIs, SNRIs, tricyclics

Question 14

Describe enkephalins.

Answer 14

Enkephalins are peptides. Released locally, not stable sysyemwide. They are so unstable you can’t store and make then directly. SO they are made as a precursor and cleaved to the actual agonist. Tyr and Phe are phenyl ring structures. The gly can make kinks…so it’s not suprising that these compounds can bind the same receptor.

Question 15

Describe endorphins.

Answer 15

Bigger than the enkephalins, also produces from a precursor peptide (POMC). Somewhat more stable and can act at a longer distance than enkephalin.

B-endorphin: 31 amino acids, most active “endorphin”

Question 16

What are the characteristics of the Mu receptor?

Answer 16

Mu are the most important for analgesia. They are also the target of the most important side effect (respiratory depression). Mu—morphine

Question 17

What are the characteristics of the delta receptor?

Answer 17

Delta receptors are also involved in analgesia. There are not selected drugs that target only delta. There is interest b/c delta isn’t a cause of resp dep.

Question 18

What are the characteristics of the kappa receptor?

Answer 18

Kappa- spinal cord, there are selective drugs (pentazocin).

Question 19

In general, opioids decrease neuronal firing. How (3)?

Answer 19

Presynapse – inhibit neurotransmitter release, whatever that terminal may be. Mechanism is by inhibition of VGCC. These are prominent in the presynaptic membrane. The Bgamma subunit is the way the channel is inhibited.

They also can lead to activation of potassium channels. IN this case, they are opened by bgamma binding to them, which hyperpolarizes them, decreasing their excitability. This can happen PRE of POST synaptically, but is prominent in postsynapse.

Through the alpha subinut (Gi) you can decrease cAMP levels. In general, PKA tends to phosphorylate targets that are pro-excitatory. So by lowering cAMP you decrease excit.

Question 20

Opioids have two distinct mechanisms of inhibiting transmission in the pain pathways. Describe them.

What is the third way that opioids work?

Answer 20

Ist mech: OP receptors present on both sides of the ascending pain synapse (junction of nociceptive receptor and 2nd neuron ascending in the spinothalamic tract)

2nd Mech: activation of descending pain pathway: much of the transmission involves 5HT and NE.

Opioids are generally inhibitory, so how do they activate the PAG? They turn on the circuit by “disinhibition”. They act on GABAnergic inhibitory neurons in the PAG.

[OP directly affect pain transmission. But they have other effects. In general, they induce tranquility, euphoria, so the sensation of the pain is percieved as less negative. This involved the limbic, locus coeruleus, and ventral tegmentum (important for reward/drug abuse)]

Question 21

Opioid drugs eliminate which pain, sharp (first) or dull (second)?

Do they treat neuropathic pain?

Do they treat fever?

Answer 21

Dull, second pain.

Most effective for nociceptive pain, but are less effective in treating neuropathic pain. Still used for this purpose, but not that great.

Not antipyretic, won’t control fever. However, many are prescribed with NSAID

Question 22

Which receptors are involved with the euophoric response vs. the dysphoric response?

Answer 22

Euphoria is more likely with a rapid administration of a lipid soluble drug. Involves the mu receptors, and activation of the brain reward pathways.

Dysphoric reactions involve the kappa (not the mu) receptors.

Question 23

How do opioids create respiratory depression?

Answer 23

Due to a decrease in sensitivity to CO2 in brain stem respiratory centers. increase in blood CO2 levels leads to cerebral vasodilation

Opioids contraindicated in head injury due to cerebral vasodilation sfx. Also must consider if ppl have compromised respiratory function.

Question 24

What is the DM ingredient in many OTC medications? How does it act?

Answer 24

Dextromethorphan = DM ingredient in many OTC medications. Mediated by inhibitory effects in cough center of medulla.

• non-analgesic opiates (dextromethorphan, noscapine) are preferred because of their lower abuse potential. However, dextromethorphan has been abused due to its additional activity as a dissociative agent (block of NMDA receptors like PCP and ketamine) Dissociating agent – induce hallucinations

Question 25

Pupillary constriction is due to excitation of the ______ (specific) and this response (does/does not) disappear with drug tolerance.

Answer 25

Edinger Westphal nucleus

Does not

Question 26

What liver enzyme metabolizes codeine to morphine?

Answer 26

Codeine – CYP2D6.

Question 27

What are the symptoms of opiate withdrawal? Can they kill you?

Answer 27

Symptoms of withdrawal are opposite those caused by acute opioids, and are described as “flu-like”:
Dilated pupils, insomnia, restlessness, yawning, rhinorrhea, sweating, diarrhea, nausea, cramps, chills