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Therapeutics II (Spring) > Pharmacology of Opiates > Flashcards

Pharmacology of Opiates Flashcards

1
Q

Two types of opium alkaloids

A

-Phenanthrenes (morphine, codeine, thebaine)
-Benzylisquinolines (noscapine, papaverine)
-opiATEs are only naturally occuring opioids

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2
Q
A
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3
Q

Genes for endogenous opioids

A

-peptides active endogenously
-large precursor proteins cleaved into more opioid subtype selective peptides (precursors)
-degree of redundancy
1. POMC (mu)
2. Preproenkephalin (delta and mu)
3. Prodynoprphin (kappa)
4. Nociceptin/Orphanin FQ (not precursor)

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4
Q
  1. Pro-opiomelanocortin (POMC)
A

-B-endorphin -> mu opioid

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5
Q

Preproenkephalin

A

-Leu-enkephalin -> delta opioid
-Met-enkephalin = mu and delta

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6
Q

Prodynorphin

A

-dynorphin -> kappa opioid

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7
Q

Nocicceptin Orphanin FQ

A

not precursor

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8
Q

Types of opioid receptors

A

-GPCR
-Mu
-Kappa
-Delta
-Nociceptin, orphanin FQ receptor
-sigma (not opioid)

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9
Q

GPCR opioid receptor

A

-Family A-peptide receptors
-Gi/o (inhibit cAMP)
-open GIRK potassium channels
-close calcium channels
-presynaptic (Gi) = dec NT release
-post-synaptic (GBy) = activate GIRK = efflux of K = hyperpolarization = less firing

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10
Q

Opioid receptor signal transduction

A

-presynaptic (Gi) = inhibit Ca channel = dec NT release
-post-synaptic (GBy) = activate GIRK (GBy) = efflux of K = hyperpolarization (less firing)

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11
Q

Mu opioid receptor

A

-think Morphine
-POMC to beta-endorphines (endogenous morphine)
-also met-encephalin precursor?
-use for analgesia, sedation, antitussive
-not as effective for chronic pain
-cancer pain, palliative, PCA
-suppression of cough center in medulla oblongata (codeine)
-help breakthrough pain
-can start dose as soon as pain reemerges

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12
Q

Beta-endorphins

A

-endogenous morphine
-mu receptor
-pro-opiomelanocortin (POMC) precursor
-component of runner’s high

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13
Q

Opioid induced side effect mostly ON-TARGET effects

A

-resp depression (brain stem, pre-botzinger complex in medulla)
-constipation (Gi tract)
-Pruritus (SIDE EFFECT NOT ALLERGY)
-addiction
-urinary retention (ADH release)
-N/V (chemoreceptor trigger zone in medulla)
-Miosis (oculomotor nerve (PAG) not mepiridine (anti-cholinergic effects)?

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14
Q

Kappa opioid receptor

A

-Prodynorphin to Dynorphins (preprodynorphin natural ligand)
-activation is dysphoric, aversive
-potential use for addiction! tx (dec DA release)
-counterbalance mu opioid receptor effects!
-think Ketocyclazocine

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15
Q

Delta opioid receptor

A

-enkephalins (preproenkephalin) ligand
-more dynamic expression (intracellular, externalized upon chronic stimuli)
-role in hypoxia/ischemia/stroke (hibernation)
-dec anxiety, depression
-tx alcoholism
-relieve hyperalgesia, chronic pain
-side effect siezures
-no FDA approved delta opioids
-think deferins

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16
Q

Opioid site of action

A

-ventral tegmental area to nucleus accumbens
-slide 15 idk

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17
Q

Depressant DA release (similar to stimulants)

A
  1. opioid binds mu receptor
  2. Gi signaling inhibits NT release
  3. less GABA to activate GABA-A
  4. less inhibition of DA neuron activity
  5. inc DA release
  6. inc activation of DA receptors

-slide 16

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18
Q

Metabolism of morphine/phenanthrenes

A

-readily absorbed
-first-pass (25% bioavailability!)
-hepatic
-CYP2D6 and 3A4!!
-genetic differences
-t1/2 inc with liver disease
-Glucuronidation ar 3 and 6
-morphine-6-glucuronide (M6G) still potnet

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19
Q

Morphine/phenanthrene excretion

A

-Glomerular filtration
-90% excreted in 24h

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20
Q

Active opioid metabolites

A

-heroin (morphine), codeine (morphine), tramadol (o-desmethyltramadol) = prodrugs
-NOT fentanyl and methadone
-onset/duration influenced by lipophilicity

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21
Q

Lipophilicity

A

-low lipophilicity = slower BBB crossing = prolonged duration (morphine)

-high lipo = rapid onset = short duration (fentanyl)

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22
Q

CYP3A4

A

-makes opioids starting with NOR (think FOUR for NOR)
-norhydrocodone, noroxycodone, noroxymorphone
-oxycodone (semi-synthetic) metabolized by CYP3A4 to noroxycodone in liver

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23
Q

CYP2D6 Ultra-rapid metabolizers (UM)

A

-UM high prevalence
-upto 50% higher plasma concentrations of morphine when given codiene
-higher adverse effects

24
Q

CYP2D6 poor metabolizers (PMs)

A

-more common in whites
-no effect from codeine
-same incidence of adverse events

25
Fentanyl
-very very potent -100x morphine -50x heroin -used for breakthrough pain in palliative care
26
Opioid scheduling
-class II
27
Opioid agonists
-Sufentanil, Remifentanil, alfentanil (anesthesia/sedation, breakdown by plasma esterases due to ester linkage) -fentanyl IV, patch, lollipop -Hydromorphone, oxymorphone (no opioid-active metabolites) IV or oral liquid PCA -morphine IV, po -Hydrocodone -Tramadol -Meperidine
28
Su/Remi/Alfenanil
-opioid agonist -anesthesia/sedation -breakdown by plasma esterases due to ester linkage!
29
Hydromorphone, oxymorphone
-no opioid-active metabolites -IV, oral liquid - PCA
30
Morphine
-covered by medicare (preferred over oxycontin) -MScontin: ER, longer acting, lower "rush," M6G contribution to pain relief, Risk for abuse if IV injected at once
31
Tramadol, Tapentadol
-has SNRI properties! (stimulate 5HT release by blocking 5HT and NE reuptake) -mild opiate analgesic -mild neuropathic pain tx -use when you don't want to use stronger opioid -schedule IV (tramadol)
32
Meperidine
-used to treat rigors (shivering) -has toxic metabolite NORmeperidine (CYP3A4): no analgesic activity, neurotoxic (tremors, twiches, seizures) -renally excreted -AVOID in pt w dec renal function (accumulation)
33
Methadone
-NMDA ANTAGONIST -used for opioid dependence -prolonged QTc side effect -chronic pain
34
why would antagonism at NMDA receptors be useful
35
Opioids for cough/antitussive
-codeine -dextromethorphan
36
dextromethorphan
-enantiomer of levomethorphan (opioid) -LIMITED opioid activity -act as SSRI, NMDA ANTAGONIST at high doses
37
Opioids for anti-diarrheal
-Diphenoxylate w atropine -loperamide (stong Pqp substrate = low BBB penetration) -eluxadoline
38
Eluxadoline
-IBS w diarrhea -Mu/Kappa agonist -Delta ANTAgonist -enteric localization
39
Pentazocine
-K agonist -partial agonist/ANTAgonism at mu -parenterally -side effects: less dysphoria, hallucination, inc BP and HR
40
Nalbuphine
-full agonist at K -mu ANTAgonist -antagonism = withdrawal -parenteral
41
Buprenorphine
-partial mu agonist -weak K agonist -weak delta ANTAgonist -used in opioid replacement therapy
42
opioids that act at mor and kor for moderate pain
-pentazocine -nalbuphine -buprenorphine
43
Preventative and acute management of ileus and constipation
-senna -PEG (Miralax) -dioctyl sodium sulfosuccinate/docusate
44
Senna
-irritates colon -cause fluid secretion -COLONIC contration!
45
PEG
-stool softener -osmostic inc in GI water content
46
Dioctyl sodium sulfosuccinate/docusate
-stool softener -peristalsis >400mg/day
47
Opioid tolerance
-analgesic effects -nausea -urinary retention -resp depression (biggest risk in withdrawal) -euphoria
48
limited/no tolerance
-constipation -itch -miosis
49
Treatment for opioid dependence
-methadone -buprenorphine -naltrexone -narcan
50
Methadone
-full mu agonist -cross tolerance -provide relief from withdrawal -slow acting -accumulates w repeated dose (t1/2=8-50h) -racemic mix - + is NMDA ANTAgonist
51
Buprenorphine
-mu partial agonist -ceiling effects -blocks full agonist effect (antagonist use, use 4h after last heroin use) -some agonism = less withdrawal -subutex: abuse potential -subboxone partially blocks agonist effects when taken IV
52
Naltrexone
-IM -ER -qmonth -decent oral bioavailability as revia qd -4h t1/2 -will cause withdrawal -works better id pt has been drug free for 1 month or more
53
Naloxone vs naltrexone
Naloxone: -IV or nasal, not PO -LIMITED oral bioavailability -rapid onset, short t1/2 (30-90min) Naltrexone: -PO -decent bioavailability -medium t1/2 (4h)
54
Narcan (naloxone)
-IV or nose -limited bioavailability -rapid onset 1-2min -t1/2 30-90min SHORT -give multiple shots to avoid resp depression -REPEAT every 2-5min if not concious -causes strong withdrawal -more doses needed for fentanyl and synthetic opioids
55
Neonatal abstinence syndrome
-tremors, yawning, poor feeding, sweating -24-48h after birth upto 5-10days -heroin, opiates, methadone -cause serous withdrawal in baby -can last upto 4-6 months -seizures can occur to babies of methadone users -opioids can be present in breastmilk
56
Neonatal abstinence tx
NONpharma: -swaddling -hypercaloric feedings -freq feedings -observe sleep, temp, wt, sx -rehydration w IV fluids if severe dehydration PHARMA: -morphine sulfate (oral morphine diluted to 0.4mg/ml) -sublingual buprenorphine -methadone 0.05-0.1mg/kg/dose q6h -morphine and buprenorphine linked w shorter hospital stay than methadone! -clonidine may also be useful
57
slide 40 summary
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Therapeutics II (Spring) (51 decks)

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