Opioid Analgesics I & II

Question 1

Describe the structure of morphine and what accounts for the variation in potency/efficacy/solubility etc

Answer 1

it’s a five ring structure; variation is due to chemical radicals and modifications at positions 3,6, and 17

Question 2

What is considered to be an endogenous opioid peptide?

Answer 2

endorphins! they inhibit responses to painful stimuli; their precursor has commonality w/ACTH, MSH, b-LPH; modulate GI, endocrine and autonomic function and have rewarding (addictive) properties (runner’s high!)

Question 3

How do opioids act on opioid receptors?

Answer 3

They are agonists to the receptors that: inhibit release of substance P, inhibit ascending transmission from the dorsal horn, activate pain control circuits descending from midbrain

Question 4

What type of receptors are opioid receptors and what is the signaling process?

Answer 4

GPCR: G proteins bind–>activates GTP–> effector protein activated–>inhibits adenyl cyclase –>activates K currents and suppresses voltage gated Ca currents

Question 5

What are the different opioid receptor subtypes?

Answer 5

Mu: MOST IMPORTANT, most prescribed
Delta: analgesia but doesn’t cross BBB
Kappa
Nociception opioid receptor

Question 6

What are the general effects/side effects of opioids?

Answer 6

analgesia, mood alteration/reward, neuroendocrine, miosis, convulsions, depressed respiration, antitussive (cough), nausea/emesis, GI effects, GU (urinary retention), skin (vasodilation/urticaria)

Question 7

How are opioids absorbed? metabolized? excreted?

Answer 7

Absorbed: GI (sublingual, oral, rectal)

Metabolized: significant first pass metabolism in liver; then conjugation w/glucuronic acid in liver

Excreted: by kidney

Question 8

What is the Cmax for oral, SC/IM, IV admin of opioids? When is steady state achieved?

Answer 8

Oral: 1h; SC/IM: 30 min; IV: 6m

steady state for all routes of administration = 1 day except for immediate release (3-5hrs)

Question 9

What are the major metabolites of morphine?

Answer 9

morphine-6-glucuronide: active metabolite with higher potency

morphine-3-glucoronide: little receptor affinity (so most analgesia comes from m-6 metabolite)

Question 10

Why is codeine considered a weak analgesic?

Answer 10

it has low receptor affinity, and the analgesia that does result is only from the 10% of the drug that gets demethylated to morphine

Question 11

What happens to people that cannot convert codeine to morphine?

Answer 11

they have issues with CYP2D6 thus they cannot convert the drug and have side effects without analgesia

Question 12

What is the most commonly used opioid for antitussive effects (cough suppression)

Answer 12

Codeine

Question 13

What type of drug is Tramadol and what is it’s MOA?

Answer 13

synthetic codeine analog and weak Mu agonist; its demethylated form is more potent

MOA: analgesia from inhibition of NE and serotonin reuptake

Question 14

What type of pain does Tramadol treat?

Answer 14

good for mild to moderate pain, less effective for severe pain (but also less constipating)

Question 15

What’s everything you should know about Fentanyl?

Answer 15

1) very potent with very long 1/2 life
2) much more lipid soluble than morphine
3) delayed effect and toxicity/overdose common
4) transdermal patch useful for longterm Rx (ensure adherence to skin)
5) may not be as effective if patient is very thin
6) wait a week between dose changes

Question 16

What is everything you should know about Methadone?

Answer 16

1) extended duration of action (don’t change dose more than 1x/wk)
2) it’s 90% bound to plasma proteins thus has gradual accumulation in tissues
3) used to treat chronic pain and heroin addicts
4) overdoses common

Question 17

What type of drug is Oxycodone? what derivative of this drug has widespread abuse and overdose associated with it?

Answer 17

1) very effective potent oral analgesic

2) oxycontin–>it’s long acting extended release

Question 18

Why is Meperidine no longer used?

Answer 18

metabolite toxicity (normeperidine)

Question 19

Which two drugs are analogs to Meperidine that treat diarrhea and what is their MOA?

Answer 19

Diphenoxylate and Loperamide

MOA: slows peristalsis via opioid receptors in intestine, and possibly decreases GI secretion

Question 20

What is the opioid antagonist used to treat opioid toxicity and how is it administered?

Answer 20

Naloxone – continuous infusion (parenteral) because oral admin is almost completely metabolized by the liver; note that it can also induce withdrawal symptoms…

Question 21

What opioid antagonist is approved for treatment of alcoholism?

Answer 21

Naltrexone

Question 22

What is the caution with acetaminophen usage?

Answer 22

Note that many opioids come in combo w/acetaminophen and patients may already be taking acetaminophen. Physicians forget to ask –>inadvertently take too much

Question 23

When would you use breakthrough dosing

Answer 23

if patient is going to physical therapy/being active and needs an IMMEDIATE (not extended) release opioid for short term relief; can give 5-15% of normal total 24hr dose and only after Cmax is reached

Question 24

Why are mixed agonist-antagonists not recommended?

Answer 24

the antagonists compete w/the agonists to cause withdrawal; analgesic ceiling effect; and high risk of psychomimetic adverse effects

Question 25

What is the mechanism of tolerance in opioid drugs?

Answer 25

due to modification of opioid receptors which may involve phosphorylation or receptor internalization

Question 26

What is meant by abstinence syndrome?

Answer 26

When someone who is physically dependent has abrupt withdrawal from the drug and experiences agitation, abdominal pain, nausea/vomiting, diarrhea, *yawning, piloerection)

Question 27

What is meant by equianalgesic dosing?

Answer 27

converting to alternative routes of delivery or between different opioids to maintain state of analgesia (leaving hospital, insurance change, etc)

Question 28

What are the common side effects of taking opioids? What are the uncommon side effects?

Answer 28

Common: constipation, dry mouth, N/V, sedation, sweats

Uncommon: bad dreams/hallucinations, dysphoria/delirium, myoclonus/seizures, pruritus/urticaria, respiratory depression, urinary retention

Question 29

What can be used to treat the following side effects: sedation? respiratory depression? urticaria/pruritus?

Answer 29

1) psychostimulant like methylphenidate
2) naloxone
3) nonsedating antihistamines (fexofenadine, loratidine)

Question 30

What two side effects of opioids to people usually continue to have (ie, don’t develop tolerance to)?

Answer 30

Pupillary constriction and constipation

Question 31

What works and doesn’t work for treating constipation associated with opioid use?

Answer 31

diet and bulk forming agents (ie metamucil) don’t work; tx with stimulant laxative, stool softener, pro kinetic agent, osmotic laxative

Question 32

Who are at the highest risk for opioid overdose

Answer 32

Patients that see multiple doctors (typically involved in drug diversion)