Pharmacology of Opioids Flashcards
What are opioids?
Any substance (natural or synthetic) that mediate an analgesic effect through opioid receptors that can be blocked by naloxone
Natural (Endogenous) –>
Morphine, codeine (Papaver somniferum)
Semi-synthetic (Derivatives of morphine)
Diamorphine, dihydrocodeine, buprenorphine, naloxone
Examples of synthetic opioids:
Synthetic
- Phenylpiperidine series
Pethidine, fentanyl, alfentanyl, remifentanyl
- Diphenylpropylamine series
Methodone, dextropropoxyphene - Benzomorphan series
Pentazocine - Thebaine derivatives
Buprenorphine
Clinical effects of Opioids:
- Setting nociceptive threshold
- Controlling nociceptive processing
- Role in cognition
- Modulation of autonomic function
- Modulation of endocrine function
- Modulation of endocrine function
Endogenous Opioids:
Enkephalins
- Met-enkephalin
- Leu-enkaphalin
Endorphins
- a-neoendorphin
- b-neoendorphin
- g-neoendorphin
Dynorphins
- Dynorphin A
- Dynorphin B
Endomorphins
- Endomorphin 1
- Endomorphin 2
All are derived from precursor proteins by proteolytic cleavage of proopiomelanocortin (POMC)
What are opioid receptors?
Defined by structural similarity and sensitivity to naloxone
IUPHAR nomenclature:
MOP: m1; m2; m3
DOP: d1; d2.
KOP: k1a; k1b; k2a; k2b; k3
(NOP – nociceptin : non-opioid member of opioid family)
Dop = delta (delta 1 and 2)
Kop = kappa
NOP = a lot of drug development is aimed towards this in
Ligand and receptor relationship:
MOP
B-endorphins
Endomorphin 1
Endomorphin 2
KOP
Dynorphin A
Dynorphin B
DOP
Met-enkephalin
Leu-enkephalin
NOP
nociceptin
Opioid receptor mechanism:
G protein coupled receptors (Gi/Go)
- Presynaptic
Postsynaptic
Depends on where they’re located
Inhibits adenylate cyclase
Decreases cAMP
Decreases neurotransmitter release
Activation of voltage-gated inward rectifying K+ channels
Hyperpolarises cells
Decreases responsiveness to depolarising stimuli
Reduces neurotransmitter release
Inhibition of voltage-gated (N-type) Ca2+ channels
Reduces neurotransmitter release
Opioid receptor location:
- Vagal Centres
- Chemoreceptors of Area Postrema
- Oculomotor Centre
- Antinociceptive system
(Brain & Spinal Cord) - Smooth muscle
- stomach
- bowel
- bladder
- Pain sensation
- Mood alertness
- Respiratory Centre
Definitions: Pain
- Is a natural defensive awareness and response to a noxious stimulus
- It is the higher centre processing of signals which allows the body to minimise exposure to and damage from the noxious stimuli
- Psychological factors will influence the extent to which an individual will feel suffering and distress with pain
Definitions: Nociception
The sensory processing associated with firing of small diameter nociceptive afferents
Activated by different stimuli
- Chemical
- Mechanical – crushing trauma
- Thermal - cold or hot
- -> C-fibres – unmyelinated; dull, diffuse burning pain
- -> Ad fibres – myelinated; sharp localised pain
Stimulation of nociceptors:
Cancer cells, inflammatory cells, tissue injury, osteolysis --> Noxious factors: - Bradykinins - Prostaglandins - Nerve growth factor - Serotonin - ATP - H+ --> Nociceptors = inflammation - Sensory neuron to dorsal root ganglion to spinal cords to brain = PAIN
Ascending Pain Pathway:
Nociceptor is stimulated
- Action potential travels along axon to cell body in dorsal ganglion (first order afferent)
- Action potential potentiated along to dorsal horn
- Signal transferred to next nerve: crosses over to other side of spinal cord (second order afferent) I
- Action potential travels to thalamus
- Signal transferred to next nerve (third order afferent) which terminates in somatosensory cortex – this maps out to different parts in the body to find exact location.
Descending Pathway:
- Somatosensory cortex connects with brain regions which co-ordinate the response
- The amygdala, anterior cingulate cortex, insular cortex and hypothalamus send projections to the periaqueductal grey (integrates response)
- PAG sends signal to rostroventral medulla
- RVM sends signal to dorsal horn, where nerve interacts with the ascending pathway
What are pathways:
- Not just connection of nerves.
- The signals are communicated between nerves using neurotransmitters
- “Pain” transmitters – cause us to perceive and feel paimn
- -> Glutamate; substance P; CGRP (Calcitonin gene-related peptide); nitric oxide. All tend to be released as part of the ascending pathway.
“Analgesic” transmitters – descending pathway – dampen down
- Endogenous opioids; 5HT; noradrenaline; endocannibinoids
- glycine; GABA
Role of the opioid receptors in pain:
- MOP involved in motor and sensory processing
- MOP also involved in integration and perception of pain
- Located presynaptically on primary afferent neurones in the dorsal horn
- Inhibit glutamate release and therefore transmission of nociceptive stimuli
- MOP also in high concentrations in PAG
- Prevent GABA neurones inhibiting descending control pathway.
- -> GABA tonically inhibits 5HT and NA nerves that project from RVM to dorsal horn
- -> Removing this tonic control allows 5HT and NA nerves to fire and release these transmitters onto ascending pathway
- -> 5HT and NA inhibitory receptors then prevent the transmission of signal along the ascending pathway
- DOP receptors are located presynaptically on primary afferent neurones in the dorsal horn and secondary afferent neurones in the brain
- Inhibit neurotransmitter release and therefore transmission of nociceptive stimuli
- KOP receptors are highly expressed in the brainstem
Opioid analgesics full agonists:
- MOP receptors (weak KOP receptors)
- Morphine, diamorphine, fentanyl, pethidine, dihydrocodeine, codeine, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, oxycodone, oxymorphone