Chemistry of opioids and opioid antagonists 4

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21 Terms

1
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Meperidine

MOR agonist

flexible structure

overlaps with structure of morphine

10-20x as potent as morphine

<p>MOR agonist</p><p>flexible structure</p><p>overlaps with structure of morphine</p><p>10-20x as potent as morphine</p>
2
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Meperidine metabolism: CYP3A4

N-demethylation

Normeperidine

½ as potent as meperidine

can cause seizures (increased serotonin)

<p>N-demethylation</p><p>Normeperidine</p><p>½ as potent as meperidine</p><p>can cause seizures (increased serotonin)</p>
3
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Meperidine metabolism: hydrolysis

makes meperidinic acid

<p>makes meperidinic acid</p>
4
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Alvimopan

PAMORA

undergoes amide hydrolysis by intestinal flora to an active metabolite

zwitterion - not well absorbed

oral admin

indicated for the acceleration of time to upper and lower GI recovery following large or small bowel resection surgery with primary anastimosis

<p>PAMORA</p><p>undergoes amide hydrolysis by intestinal flora to an active metabolite</p><p>zwitterion - not well absorbed</p><p>oral admin</p><p>indicated for the acceleration of time to upper and lower GI recovery following large or small bowel resection surgery with primary anastimosis</p>
5
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Lubiprostone

PGE derivative

not a PAMORA
Tx OIC

<p>PGE derivative</p><p>not a PAMORA<br>Tx OIC</p>
6
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Diphenoxylate

prodrug

formulated with atropine (Lomotil)

rapid hydrolysis in vivo (to difenoxin)

Tx diarrhea, MOR agonist

<p>prodrug</p><p>formulated with atropine (Lomotil)</p><p>rapid hydrolysis in vivo (to difenoxin)</p><p>Tx diarrhea, MOR agonist</p>
7
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Difenoxin

Tx diarrhea, MOR agonist

formulated with atropine (Motofen)

active

zwitterion

<p>Tx diarrhea, MOR agonist</p><p>formulated with atropine (Motofen)</p><p>active</p><p>zwitterion</p>
8
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Loperamide

MOR agonist (oral)

Tx diarrhea

No CNS effects (slow dissolution, 1st pass metabolism, pgp substrate)

1st pass: N-demethylation by CYP3A4 and CYP2C8

<p>MOR agonist (oral)</p><p>Tx diarrhea </p><p>No CNS effects (slow dissolution, 1st pass metabolism, pgp substrate)</p><p>1st pass: N-demethylation by CYP3A4 and CYP2C8</p>
9
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Abuse of loperamide

40-100culx higher dose

take with cimetidine (inhibits CYP3A4)

enzymes and pgp are saturatable

can lead to ventricular arrhythmias - can be fatal

10
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Eluxadoline

oral admin, poor oral bioavailability

- poor GI absorption

- zwitterion

1st pass extraction via OATP1B1 (pulls drug into bile)

MOR agonist, KOR agonist, DOR antagonist (may mitigate OIC)

Tx IBS with diarrhea

<p>oral admin, poor oral bioavailability</p><p>- poor GI absorption</p><p>- zwitterion</p><p>1st pass extraction via OATP1B1 (pulls drug into bile)</p><p>MOR agonist, KOR agonist, DOR antagonist (may mitigate OIC)</p><p>Tx IBS with diarrhea</p>
11
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Methadone

ring opened phenylpiperidine derivative

L-isomer = active

analgesic

DOA = 4-8h

elimination t ½ = 8-59h

more potent than morphine

<p>ring opened phenylpiperidine derivative</p><p>L-isomer = active</p><p>analgesic</p><p>DOA = 4-8h</p><p>elimination t ½ = 8-59h</p><p>more potent than morphine</p>
12
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Methadone metabolism: major pathway

N-demethylation to Normethadone

then intramolecular ring formation occurs

inactive metabolite = end product

<p>N-demethylation to Normethadone</p><p>then intramolecular ring formation occurs</p><p>inactive metabolite = end product</p>
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methadone metabolism: minor pathway

reduction to methadol

N-demethylation to normethadol

N-demethylation to dinormethadol

these metabolites are active

less active than methadone, but can be very long acting

<p>reduction to methadol</p><p>N-demethylation to normethadol</p><p>N-demethylation to dinormethadol</p><p>these metabolites are active</p><p>less active than methadone, but can be very long acting</p>
14
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Tramadol

dual-action opioid

MOR agonist

reuptake activity

synergistic analgesic effect

<p>dual-action opioid</p><p>MOR agonist</p><p>reuptake activity</p><p>synergistic analgesic effect</p>
15
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tapentadol

MOR agonist

NE reuptake inhibitor

Decreased incidence of nausea/vomiting

orally active

<p>MOR agonist</p><p>NE reuptake inhibitor</p><p>Decreased incidence of nausea/vomiting</p><p>orally active</p>
16
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Fentanyl

80x as potent as morphine

onset = minutes

DOA = 30-60 minutes

<p>80x as potent as morphine</p><p>onset = minutes</p><p>DOA = 30-60 minutes</p>
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Sufentanil

600-800x as potent as morphine

onset = minutes

DOA = 40 minutes

<p>600-800x as potent as morphine</p><p>onset = minutes</p><p>DOA = 40 minutes</p>
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Alfentanil

25x as potent as morphine

onset = immediate

pka = 6.5

<p>25x as potent as morphine</p><p>onset = immediate</p><p>pka = 6.5</p>
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Remifentanil

80x as potent as morphine

onset = 1-5 minutes

recovery = 3-5 minutes

elimination independent of hepatic metabolism or renal excretion - by esterases in plasma

soft drug

<p>80x as potent as morphine</p><p>onset = 1-5 minutes</p><p>recovery = 3-5 minutes</p><p>elimination independent of hepatic metabolism or renal excretion - by esterases in plasma</p><p>soft drug</p>
20
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Oliceridine

Biased agonist

favors G-protein path over beta-arrestin path

less SE

<p>Biased agonist</p><p>favors G-protein path over beta-arrestin path</p><p>less SE</p>
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Difelikefalin

KORA

Tx chronic kidney disease associated pruritis

- dysfunction of opioid receptors, increased MOR, decreased KOR

under investigation for acute postoperative pain

<p>KORA </p><p>Tx chronic kidney disease associated pruritis</p><p>- dysfunction of opioid receptors, increased MOR, decreased KOR</p><p>under investigation for acute postoperative pain</p>