Opiods Flashcards
How do opioids block nociceptive signalling?
- They block the release of fast (Glu) and slow (SP, CGRP) transmitters from being released from the presynaptic terminal
What are the types of Opiod receptor?
- 4 types of G-protein coupled receptors
- Mostly expressed on neurones
- Analgesic effects:
- µ receptors in periphery, spinal cord and brain
- δ receptors in periphery
- k receptors in the spinal cord
- Nociception
What are opiod peptides?
- Opiod peptides derive from the clevage of larger protein precursors
- Enkephalins
- Endorphins
- Dynorphins
- Endomorphins
What are Enkephalins?
- Widely distributed in the CNS amd immune cells
- µ & δ receptor agonist
What are Endorphins?
- Widely distibuted in brain
- µ receptor agonists
What are Dynorphins?
- Widely distributed in CNS
- Highest selectivity for receptors
What are Endomorphins?
- µ receptor agonists
- More potent than other endogenous opiods
What is the G-protein activation mechanism?
- Upon binding of an agonist, there is an exchange of GDP for GTP in a-subunit of G-protein
- The subunits of the activated G-protein then dissociate
- The a-i-subunit inhibits the enzyme adenylyl cyclase-Causes dec in cAMP levels
- The b-gamma subunit causes an efflux of K+ through K+ channles (GIRK channels) causing hyperpolarisation (post-synapse)
- The b-gamma subunit also inhibits voltage-gated Ca2+ channels (VGCC channels), causes inhibition of NT release (pre-synapse)
- Leads to inhibition of Neurotransmission
Give some examples of Agonist opiod receptor ligands.
- Alfentanil
- Codeine
- Fentanyl
- Methadone
- Morphine
- Tramadol
- (peripherally acting)
- Loperamide
(Differences in: OR selectivity, relative intrinsic efficacy, Ligand binding kinetics)
Give some examples of Antagonist opiod receptor ligands.
- Nalmefine
- Naloxone
- Naltrexone
Peripherally acting:
* Mathylnatrexone
* Naldemedine
* Naloxegol
What are the opiod CNS pharmacodynamics overall effects?
- Analgesia
- Euphoria
- Respiratory depression
- Cough suppression
- Nausea and vomiting
- Pupillary constriction
- Inhib of GI tone and motility
- Histamine release from mast cells
Explain the analgesic effects of Opiod CNS pharmacodynamics.
- Anti-nociception AND reduce affective component of pain
- Effective in most acute severe pain and chronic pain
Explain the euphoria effects of Opiod CNS pharmacodynamics.
- Feeling of well being and reduced anxiety
- Mainly MOP mediated, possibly offset by KOP-mediated dysphoria
Explain the respiratory depression effects of Opiod CNS pharmacodynamics.
- Dec in respiratory rates through MOP expressed in brainstem
- All analgesic doses reduce respiration (can be fatal), but no CVS depression
Explain the Cough suppression effects of Opiod CNS pharmacodynamics.
- Poor correlation with respiratory depressive actions
- Codeine effective at sub-analgesic doses
Explain the Nausea and vomiting effects of Opiod CNS pharmacodynamics.
- Debilitating but usually transient
Explain the inhibition of GI tone and motility effects of Opiod CNS pharmacodynamics.
- Constipation
- Slow drug absorption
Explain the histamine release from mast cells effects of Opiod CNS pharmacodynamics.
- Opiod receptor-independent
- Causes opiod-induced itch and urticaria
What are desireable effects of opiod agonists?
- Analgesia
- Anti-diarrhoea
- Anti-tussive
What are the non-medicinal effects of opiod agonists?
- Euphoria (rush)
- Prolonged sences of contentment
What are the adverse effects of opiod agonists?
- Respiratory depression
- Nausea and vomiting
- Dizziness & confusion
- Pupiloconstriction
- Constipation
- Addiction
- Tolerance
- Pruritis
What is tolerance?
- The need to increase the dose to maintain a given effect
- Develops rapidly and compromises therapy with inc risks of side effects
What is dependance?
- Consists of physical dependance:
1. The development of a physiological withdrawal syndrome - A strong psychological dependance
2. A desire to take the drug irrespective of adverse consequences
What is the mechanism for GCPR regulation?
- Receptor phosphorylation and uncoupling from G protein
- The phosphorylated receptor recruits arrestin
- Arrestins facilitate receptor internalisation
- Upon removal of stimulus the receptor can recycle to PM
- However, prolonged stimulation can trigger receptor degredation
