Analgesics Flashcards
What are the different types of pain?
- Cutaneous: caused by injury to the skin or superficial tissues
- Somatic: originates from ligaments, tendons, bones, blood vessels, and nerves
- Visceral: originates from body’s viscera or organs
- Phantom limb: sensation of pain from a limb that has been lost
- Neuropathic: results of injury or disease to nerve tissue
Conscious experience of sensory information and feeling of unpleasantness as a result of stimulation of?
nociceptors
nociceptors detect?
Thermal, Mechanical, and Chemical stimuli
morphine, oxymorphone, methadone, levorphanol, fentanyl, and oxycodone
These are all known as?
Stong Agonists
Full opioid agonists dont have a ceiling for their effectiveness but they are limited by?
- AEs
- Tolerance, Respiratory depression, constipation
Opioid peptide SAR
- All endogenous opiod peptides have Leu or Met enkephalin as their first five AAs
- Tyrosine at the first position is essential for activity
- After the phenolic group and amine in tyrosine, the next essential feature is the phenyl group of Phe4.
- Enkephalins like have different conformations
- Replacement of L-amino acids with D-amino acids can make peptides resistant to peptidases
- Converting terminal carboxy group into alcohol or amide protects peptide from carboxy peptidases prolonged action
- Introduction of unnatural amino acids or bulky groups to enkephalins affects conformation
- Restriction of conformational mobility has led to receptor selective peptides
Classical morphine SAR
What is absolutely essential for maximal activity?
OH at the 3 position
Heroin
Potency in relation to morphine?
2.5 x more potent
Hydromorphine
Potency in relating to morphine?
6 times more potent
Oxymorphone
Potency in relating to morphine?
6-10 times more potent
Codeine
Potency in relating to morphine?
Explain
1/12 x morphine
Dihydrocodeine
Potency in relating to morphine?
Only in combination with?
- 1/12 times as potent
- Antihistamines, caffeine, and ASA or Acetaminophen
Metabolism of Codeine and Morphine
This takes place in?
All opiate derivatives
Metabolism of Heroin
What can it do why is it so addictive?
Known as a?
What is the active form?
Crosses the BBB reason for addictiveness
Prodrug from morphine
6-Acetylmorphine
What are the characteristic of the Kappa receptor?
Mu?
Kappa
- Analgesia, sedation, dysphoria, miosis, regulation of nociception
MU
- Euphoria, Analgesia, Increased GI time, Emetic effects, thermo regulation
Meperidine
Potency in relating to morphine?
1/5 of morphine
No hydroxyl group
Short acting due to ester
a-prodine and b-prodine
which one is more potent?
Not available in the US because?
MPP+ metabolism MPTP shit
B is more potent
In general _____ are more potent than morphine
Fentanyl derivatives
Remifentanil
Potency in relating to morphine?
What about it?
700-800 x more potent
Extremely short acting due to its 1 amide and 2 esters
Sufentanil
Potency in relating to morphine?
What portion of this molecule increases its lipophilicity?
600-800 x more potent
Sulfur containing ring
Methadone
Potency in relating to morphine?
What else?
Less dosing intervals and euphoria isnt as stong
Tramadol
Potency in relating to morphine?
Mixed action compounds
1/10 morphine
Combination of reuptake blockade and opioid agonism
Tapentadol
Potency in relating to morphine?
More potent than tramadol but less than morphine
Metabolism of Methadone
What are the key features?
Nalmefene
MOA
Duration of action between Butorphanol and nalbuphine
Butorphanol is longer acting because it doesnt have the second point of conjugation
slide 66
Buprenorphine
MOA
Mu partial agonists
ends up antagonizing itself somehow
Pentazocine
MOA
Kappa and S
Weak Mu antagonist
Ziconotide
MOA
What is it?
Proven to be?
With less?
Downside?
- N-type valtage sensitive Ca2+ channel antagonist
- Proven to be just at potent as morphine with less respiratory depresson and no constipation makes sense doesnt act on any of that shit.
- Administered Intrathecally
Methotimeprazine
MOA
WHy isnt it a Neuroleptic?
Not a neuroleptic b/c it has a EDG not a EWG
Nonopioid used for chronic pain
Dextromethorphan
Type?
Why isnt it an opioid?
Antitussive
steriochemistry is wrong
Loperamide
Looks like 2 things
Why can this be OTC?
- Looks like anticholinergic and haloperidol
- Antidiarrheal cant cross the BBB so its OTC
What are the 3 ways you can isolate something to the periphery?
What are examples of these ways?
- PEG group- Naloxegol
- All time positive charge - Methylnaltrexone
- Zwitter ion - Alvimopan
Nalfurafine
Used for?
Pruritis
Itching with mu agonists
potent kappa agonists blocks the itch
Alvimopan
Peripherally acting mu antagonist
zwitter ion
In general when looking for a short acting analgesic you would chose?
Remifentanil, Sufentanil
Remi is the shortes
Krokodil?
Cheap drug of abuse prepared from Codeine
Salvinorin A
Pure?
Kappa Agonist
