Term
| Where are endogenous opioids synthesized from? |
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Definition
| All endogenous opioids start as pro-peptides. All have a gly-gly-phe group. Cleaved at Gly-Phe and packaged into vesicles on ER. |
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Term
| Review: How does opioids receptor signalling take place? |
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Definition
| Mu receptor is a Gi receptor, blocks adenylyl cyclase --> no cAMP, no pKA --> efflux of K and hyperpolarization |
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Term
| What is the mechanism of addiction/tolerance/withdrawal? |
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Definition
| Nigrostrial and mesolimbocortical pathways mediate dopamine. VTA --> nucleus accumbens --> prefrontal cortex. Release of dopamine into NUCLEUS ACCUMBENS = reward |
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Term
| How do dynorphins and endorphins affect the nucleus accumbens and VTA? |
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Definition
- Dynorphins - kappa ligands, slow firing of the neuron
- GABA neuron synthesizes GABA --> GABAa (ionotropic) --> also slows firing of the neuron
- Endorphins act on mu on GABA, GABA hyperpolarizes and cannot slow VTA --> more dopamine |
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Term
| What does chronic activation of mu do to other receptors? |
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Definition
Tolerance - decreases cAMP, upregulation of adenylyl cyclase, downregulation of Gi and Mu
Withdrawal - cAMP is higher in the ABSENCE of drug. |
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Term
| How does a prototype opioid (morphine) look and what is its potency? |
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Definition
5 fused rings, one coming up out of the structure. Amine has a single carbon - tertiary amine.
(-) is analgesic
1:6 potency IV vs. PO
-3OH. a -3OCH3 decreases analgesia. |
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Term
| How is morphine metabolized? |
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Definition
In the liver - contraindicated in liver failure
- 3-conjugation - primary metabolite in oral, loss of 50% by first pass. INACTIVE --> none with IV admin.
- 6-glucuronidation - active to a lower degree than morphine. Transferase switches between this and conjugate.
- Normorphine - less active, through demethylation and CYP |
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Term
| What SAR would turn morphine into an antagonist? |
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Definition
3-5 carbons off the amide group
Requirements for antagonism: 5 rings, oxymorphone backbone, -14OH, 3-5 C-substituted N
- Naloxone - 3 carbons
- Naltrexone - cyclic
- Methylnaltrexone - quaternary amine
- Pentazocine - kappa agonist, given w/ naloxone to prevent abuse. only 2 rings.
- Buprenorphine - mixed analgesic, more potent than morphine, but less efficacy
- Butorphanol - Kappa agonist, mu antagonist. More potent but less efficacy than morphine. Not orally active. |
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Term
| What is the SAR for codeine? How is it metabolized? |
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Definition
Same as morphine, except -3OCH3
1:1 IV to PO, but releases histamine IV, never given IV!
- Demethylated by 2D6 to morphine. If someone lacks 2D6 - no analgesia
- Do not give 2d6 inhibitors - celebrex, plavix, fluconazole, SSRIs - codeine won't work. |
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Term
| What is diacetylmorphine? |
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Definition
Heroine!
Acetyl groups at 3- and 6-
Very lipophilic. Hydrolyzes to be 10x more potent. |
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Term
| What are the SARs of hydromorphone and hydrocodone? |
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Definition
- Reduction of 7-8 double bond decreases activity
- -6-ketone increases activity = hydromorphone --> 10x morphine
- Hydrocodone - 3-OCH3 derivative of hydromorphone. More active than codeine |
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Term
| What are the SARs of oxymorphone and oxycodone? |
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Definition
As well as removing the 7-8 double bond and adding a -6-ketone, addition of -14-OH. = oxymorphone.
- oxycodone --> -3-OCH3. Codeine derivative of oxymorphone, resistant to 1st pass metabolism |
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Term
| What are the interactions of a mu agonist in the mu binding site? |
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Definition
- amine - anionic binding site
- phenyl ring - pi stacking with lipophilic surface
-5th ring goes into cavity |
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Term
| What is the SAR of meperidine and how is it used? |
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Definition
Rapid onset and short duration - surgery
Has 1 phenyl ring and 1 amine ring. 1/10 potency of morphine
Demethylates to normeperidine which can build up to toxicity --> strong MAO interactions |
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Term
What is special about the SAR of tramadol?
How is tapentadol related? |
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Definition
+ enantiomer is a weak mu agonist
- enantiomer inhibitits SERT and NET
Is not blocked by naloxone
- Tapentadol - structurally similar, only 1 ring instead of 2. Only blocks NET |
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Term
| How is methadone a useful agent? |
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Definition
| Similar in potency to morphine, (-) is active. Longer duration of potency and orally active. Used to treat symptoms of withdrawal |
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Term
| What are the SARs of the -fentanils? |
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Definition
- Fentanyl - 80X the potency of morphine. 2 amines, short duration. pH 8.5 (base - ionized at 7.5)
- Sufentanil - 4-methoxy and a thiophenyl group, 600x morphine. Used for anesthesia due to short duration.
- Alfentanil - decreased potency and pKa. Half life 90 min.
- Remifentanil - Super rapid metabolism
Alf < Remi < Fentanyl < Sufen |
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Term
| What is the neurovascular hypothesis of migraines? |
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Definition
| Neuropeptides such as neurokinin A, Sub P, and CGRP released from trigeminal nerve --> inflammation and vasodilation. CGRP - Dilation. 5-HT - constriction |
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Term
| What is the serotonin theory of migraines? |
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Definition
High levels = constriction
low levels = dilation --> inflammation
Plasma and platelet 5-HT conc. differ in migraines. Excretion through urinary tract |
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Term
| How does blocking pKA affect a blood vessel? |
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Definition
if pKA is blocked, calcium increases due to calcium channels not being phosphorylated and PLC not inhibited
Calcium increase = constriction --> 5-HT1b |
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Term
| Why does sumatriptan have less of a constricting effect in other vasculature? |
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Definition
Affects only one type of serotonin receptor. Resembles the structure of serotonin.
- Differences: dimethylamino and 5-methylsufonamide
- Required: Indole ring, 2-3 carbon spacer between amide and indole. Tertiary amines more potent. |
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Term
| What interactions does a triptan have with the bio-amine receptor? |
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Definition
| Hydrogen bonding at I, ionic bond at the aspartate of 3 |
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Term
| What differences do triptans have? |
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Definition
Sumatriptan - more SQ bioavailability - MAO-A inhibitor. Can incorporate sulfur into hemoglobin
- Zomig - lasts longer
- Maxalt - Fastest onset, extensive MAO, cannot give to propanolol
- Axert - more oral bioavail. Longer acting, MAO and 2D6/3A4
- Frova - Highest 1B affinity, long half life and not MAO metabolized
- Amerge - not MAO metabolized |
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