Opiates and Opioids

opioid

All compounds that work at opioid receptors

opiate

naturally occurring alkaloids

opioid receptors

• Mu

• Kappa

• Delta

• Opioid-like receptor 1

Pain

unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage

Nociceptive pain

• most common type of pain

• detects of harmful stimuli by nociceptors around the body

• may be mechanical, chemical, or thermal in nature

• usually have a high threshold, but when activated, they send electrical signals of pain to the CNS and the brain to deliver the perception of pain

• described as sharp or throbbing pain

Neuropathic pain

• associated with damage to the neurons in the body, following an infection or injury to the area

• results in messages of pain being sent to the CNS and brain regardless of noxious stimuli

• often described as shooting pain as it travels along the nerves

• some patients report a constant sensation of pain

Pain pathway

1. transduction

2. conduction

3. transmission

4. perception

5. modulation

6. descending modulation

Endorphins

• endogenous morphine

• alpha, beta, gamma endorphins

• endogenous opioid peptides that function as neurotransmitter

• produced during exercise, excitement, pain, consumption of spicy food,love, and orgasm

• resemble opiates in their abilities to produce analgesia and a feeling of well-being

• prevent nerve cells from releasing more pain signals

• blocks sites, reducing intensity of pain

• body produces at least 20 different endorphins

• beta-endorphin appears to be the endorphin that has the strongest affect on the brain

• inhibit GABA which increases dopamine

• enhance immune system

• relieve pain

• reduce stress

• postpone aging process

Enkephalin

• regulates nociception in the body

• binds to delta receptors

• produces some analgesia

• many delta agonists may also cause seizures

Dynorphins

• arise from the precursor protein pro-dynophin

• exert their effects primarily through kappa receptors

Mu receptor

• inhibitory G-protein coupled receptor

• inhibits adenylate cyclase activity lowering cAMP levels

• regulates

  • appetite and eating

  • sensory perception of pain

  • locomotive behavior

  • wound healing

  • acute inflammatory responses

• Endorphins>enkephalins>dynorphins

Delta receptor

• inhibitory 7-transmembrane G protein coupled receptor

• enkaphlins and endogenous ligands

• heavily expressed in basal ganglia

• activation produces analgesia

• enkephalins>endorphins>dynorphins

Kappa receptor

• G protein coupled receptor

• binds dynorphin as the primary ligand

• may provide natural addiction control

• dynorphins»endorphins>enkephalins

Narcotic

applied to any drug that induced sleep

ADME of opioids

• Absorption

  • oral, injection, smoking, transdermal

• Distribution

• Metabolism

  • CYP2D6 for more potent metabolites

  • CYP3A4 minor

• Excretion

  • conjugation with glucuronide

    • mostly urine and bile

Beta-arrestins

• G-protein coupled receptors

• receptor desensitization

Opioid agonsits

• morphine, hydromorphone, oxymorphone

• codeine, hydrocodone, dihydrocodone, oxycodone

• meperidine

• fentanyl, alfentanil, sufentanil

• methadone, tramadol

• diphenoxylate, loperamide

Chemistry of Opioids

• aromatic core

• weak case

• phenantherene core

• 6-membrane nitrogen

• expoxy ring

opioid antagonists

• naloxone

• naltrexone

mixed opioid agonist/antagonists

• pentazocine

• nalbuphine

• butorphanol

• buprenorphine

Morphine

• benchmark of opioid analgesics

• acts directly on the CNS

• high potential for addiction

• Mu receptor

Codeine

• 10-15% is metabolized to morphine

• used orally for analgesia and an antitussive

• pro-drug

hydrocodone

• semi-synthetic opioid

• increased toxicity and increased addition

• metabolized to hydromorphone and dihydrocodeine

• used orally

hydromorphone

• a metabolite of hydrocodone

• increased mg potency relative to morphine

• used by IV and oral administration

oxycodone

• semi-synthetic

• 15% metabolized to oxymorphone

• highly abused

oxymorphone

• metabolite of oxycodone and very potent semi-synthetic opioid

• agonize mu and kappa receptors

Fentanyl

• most potent and fast-acting opioid

• used orally

• binds to mu receptors

Methadone

• agonist at mu and kappa receptors

• synthetic

• used orally

• metabolized by CYP 3A4

• used for opioid treatment

Tramadol

• oral opioid

• mu receptor agonist

• serotonin releasing agent

• NE inhibitor

Diphenoxylate and Loperamide

• antidirraheal

• OIC

Buprenorphine

• different activity on mu and kappa receptors

• long lasting pain relief

• metabolized to norbuprenorphine

Naloxone

• used as an HCl salt

• used to treat overdose by opioids

Naltrexone

• base compouhd of the oral route to treat opioid addiction