Opioids Flashcards
Types of Opioids?
- Exogenous
2. Endogenous
Exogenous opioids?
- Synthesis: Natural, semisynthetic & synthetic
2. Receptor binding: Agonist, partial agonist, antaginists and biased agonists.
Action of opioids?
On receptors / Peptides
- Mu opioid receptors (M1,M2 & M3)
- Kappa opoioid receptor
- Delta opioid receptor
- Ophanin FQ/Nociceprion receptor (Not sensitive not naloxone)
Mu opioid receptors?
- M1 - Involved in opioid analgesia
- M2 - Opioid induced respiratory depression
- M3 - Opioid induced immune suppression
Classes of endogenous opioid receptors?
- Enkephalins
- Endorphines
- Dynorphins
Affinity of endogenous opioids?
- B-endorphins - MOR
- Met & Leu - enkephalins - KOR
- Dynorphins - DOR
Regulatory functions of endogenous opioids?
- Nociception, stress, emotion and hedonic responses
2. Thermoregulation, breathing, neuroendocrine function, GI motility and immune responses.
Naturally occuring exogenous opioids ?
- Morphine
- Codeine
- Papaverine
- Thebaine
Semi-synthetic exogenous opioids ?
- Heroin
- Dihydromorphine, morphinone
- Thebaine derivatves (bruprenorphine)
Synthetic exogenous opioids ?
- Morphinan derivatives (Levophanol, bulorphanol)
- Diphenylpropylamine derivatives ( Methadone)
- Benzomorphan derivatives (Pentazocine)
- Phenylpiperidine derivatives (Meperidine, fentanyl, sufentanil, alfentanil, remifentanil)
Classification according to opioid EC(50) - Plasma concentration at which they exert their effect ?
- Strong opioids: Alfentanil, fentanyl, sufntanil and remifentanil
- Intermediate: Morphine, Methadone, Oxycodone, hydromorphine and buprenorphine
- Weak opioids: Codeine, hydrocodeine, dextropropoxyphene and tramadol
Opioid agonists ? ( Full agonists)
Morphine, codeine, meperidine, fentanyl, sufentanil, remifentanil, methadone, tramadol
Opioid agonist/antagonist & Partial agonists?
Pentazocine, nalbuphine, butorphanol, buprenorphine
Opioid antagonists ? -
No effect alone but reverses the effects of all agonists.
Nalorphine, naloxne, naltrexone, naltrindole, nalmefene
Opioid “Biased” agonists?
Oliceridine
Inverse agonists ?
Reduces basal receptor activity, drawing an inverse sigmoid. E.g; Naloxone, Naltrexone
Mechanism of action of opioids?
- Peripheral mecahnism - Local release of endogenous opioid like substances that act on opioid receptors located on the primary sensory neuron
- Direct inhibition of ascending transmission of nociceptive information from spinal cord dorsal horn.
- Activating pain control pathways descending fromt he midbrain via the rostral ventromedial medulla (RVM) to the spinal cord dorsal horn
Sequence after agonist binding to opioid receptor?
Left - G-protein signalling pathway:
- Dissociation of G-protein into alpha, beta & gamma subunits
- Inactivation of calcium channels
- Activation of potassium channels - Reducing excitability of the cell membrane
- Inhibition of adenyl cyclase
- Stimulation of mitogen associated protein kinases (MAPKs)
- Analgesia
Right - B-arrestin signalling pathway:
Associated with side effects
- G-protein receptor kinases phosphorylate active G-protein coupled receptors enabling the recruitment of of B-arrestins
- Activation of MAPKs
New opioid - Oliceridine ?
- IV MOR biased selective G-protein agonist
- Selectvely activates G-protein and B-arrestin signalling pathway
- Preference of G-protein over B-arrestin relative to morphine and fentanyl - Fewer side effects
- Hepatic metabolism with no metabolites
- No dose adjustment in patients with renal impairment.
- Potency equal to morphine
New opioid - Tapentadol?
- Activates the Mu opioid receptor at the spinal and supraspinal sites also norepinephrine reuptake inhibitors (NRI).
- Affinity for MOR is 50 folds higher than that of morphine
- Lower side effects
Pharmacokinetics of Opioids ?
- Weak bases
2. Dissociate to ionized and base fraction
Ionized fraction of injected opioid?
- Less lipid soluble
- Attached to plasma protein and not available to diffuse to the action site.
- Ionized form is the effective form of molecule. The receptor recognizes the ionized form.
Base fraction (free) of injected opioids?
- More lipid soluble and diffuses to action site.
Lipophilic opioids ? Fentanyl / Sufentanil ( High volume of distribution)
- Low protein binding
- High volume of distribution
- Redistribution accounts for loss of analgesic effect in drugs with high vD
Low volume of distribution ? Remifentanil / Alfentanil
- Low volume of distribution
- High clearance ( Remifentanil)
- High protein binding (Alfentanil)
- Clearance is responsible for the drop in plasma concentration (short duration of action).
Opioid metabolism?
- Morphine > Morphine-6-Glucuronide & Morphine-3-Glucuronide (Active)
- CYP-3A4 & CYP-2D6 are involved in metabolism of; Heroin, Codeine, Fentanyl
- Genetic variability - Increased & decreased activity of CYP-2D6
- Remifentanil metabolized within erythrocyte and tissue non-specific esterases.
- Excreted by kidney or billiary tract into the gut. CKD can lead to accumulation and adverse effects (seizures & CNS depression)
Context sensitive half-life ?
Read about this from textbook
Biased agonists?
Read about mechanism of action
