Opioids Analgesics Flashcards
Describe the 3 different forms of analgesia
Local anaesthetics; analgesia close to the source of the pain
Central analgesia; analgesia through central/ spinal sites
GA; loss of consciousness +/- analgesia
How are the majority of opioid analgesics metabolised?
CYP enzymes p450 metabolic enzymes) in phase 1 of metabolism
Which opioid stands out in terms of metabolism?
Morphine; not metabolised by CYP in phase 1
Alternatively; morphine is metabolised in phase 2 via glucuronidation (kidney) via UGT2B7
This property of a lack of interaction with p450 (liver) enzymes makes it a useful drug as it is unlikely to interact with other drug metabolism
Describe the impact of CYP2D6 polymorphisms in opioid metabolism
Prone to polymorphisms e.g. ultra rapid metabolisers (strong analgesia and possible overdose; 1-2%) Extensive metabolisers (88%) Intermediate metabolises (8%) and poor metabolizers (8% - poor analgesia)
Are codeine and hydrocodone pharmacologically active as its inert state?
No; metabolised by CYP2D6 to morphine where there is binding to opioid receptors
Describe the impact of age on the prescribing of opioids
In general, older patients tend to have a reduced clearance
Describe the effect of sex on the prescribing of opioids
Majority have no effects between sexes except;
Oxycodone; concentrations around 25% higher in women than men
Describe the impact of ethnicity on the prescribing of opioids
Chinese patients tend to have a higher clearance of morphine (influence with enzymes involved with glucoronidation)
CYP2D6 allele variants may alter metabolism of codeine and hydrocodone; more common in Asian or African descent
Describe the impact of hepatic impairment on opioid prescribing
Dose adjustment recommended with morphine, codeine, oxycodone, methadone, hydromorphone
Oxycodone CI in hepatic impairment
Hydrocodone and codeine are often administered in combo with paracetamol; monitor LFTs
Describe the impact of renal impairment on opioid prescribing
Dose adjustment recommended for all
Caution with morphine (renally excreted)
Describe the impact of substrates, inhibitors and inducers of p450 on the metabolism of opiates
Substrates such as statins, BZD, SSRIs and psych drugs also require p450 to be metabolised which therefore individuals who are taking these drugs should be treated with some opioids cautiously as the other drugs may be competing for metabolism
Inhibitors such as chemo agents, anti-fungal, antiretroviral drugs - these drugs bind to p450 and inhibit the enzyme action. Enhanced levels of opioids
Inducers such as statins and anticonvulsant agents act to increase the expression of p450; reduced circulating level of opioids
Describe the 3 opioid receptors
MOPr (mu)
DOPr (delta)
KOPr (kappa)
What is alternative splicing?
Multiple different forms of mRNA can be produced from one single gene via splicing of exons and introns splicing
What is the interest with mu opioid receptor alternative splicing?
Alternative exons can be included in the mRNA
This can give rise to different types of mRNA in different cells
This results in the receptors having different functional properties
Variability between mu receptors in different brain regions
Can opioid receptors comibine?
Yes; wealth of evidence to show that mu and delta receptors can combine to form heterooligomers/ dimers
Describe the basic pharmacology of mu receptors
Gene; OPRM1
Selective agonist; DAMGO
G protein; Gi/o
Effectors; decreased adenylyl cyclase, increased potassium, decreased calcium
Numerous alternative splicing variants reported
Polymorphisms; 118 A-G; decreases morphine and alfentanil effects
Describe the basic pharmacology of delta receptors
Gene; OPRD1
Selective agonist; DPDPE
G protein; Gi/o
Effectors; decreased adenylyl cyclase, increased potassium, decreased calcium
Alternative splicing >1 likely
Polymorphisms; several, involved in naltrexone response in alcoholics
Describe the basic pharmacology of kappa receptors
Gene; OPRK1
Selective agonist; U50
G protein; Gi/o
Effectors; decreased adenylyl cyclase, increased potassium, decreased calcium
Alternative splicing >1
Polymorphisms involved in naltrexone response in alcoholics
Describe the basic pharmacology of nocicpetin receptors
Gene; ORL1
Selective agonist; nociceptin
G protein; Gi/o
Effectors; decreased adenylyl cyclase, increased K+, decreased Ca2+
3 alternative splicing variants reported
Polymorphisms involved with opioid addiction
How can muR polymorphisms affect opioid analgesia?
APRM1 A11G gene variant can decrease morphine’s analgesic responses post op
Carriers of G-allele observed to exhibit higher opioid analgesic requirements
Strongest in Asian patients, morphine users and those receiving surgery to a viscus
Where are opioid receptors expressed in the pain pathways?
Throughout;
Expressed in the primary afferent nociceptors, particularly are presynaptic terminal (to inhibit sub P and glutamate release to prevent excitation of DH neurons)
Thalamus
Cortex
Also involved with descending inhibitory control of pain pathway (disinhibit the neurons in PAG to allow for descending inhibitory influences in pain)
What creates the central pore of a voltage activated calcium channel?
Alpha 1
What subunits support and modify the actions of the calcium subunit?
Alpha 2
Delta
Beta - influences inactivation and voltage dependent activation
Gamma
Alpha 1 = pore conducting, contains pore loops which give selectivity to calcium ions
Are there different types of voltage activated calcium channels?
Yes
Not all are inhibited by opioid binding
Describe VA Ca2+ channels Cav 1.1-1.4
CaV 1.1-1.4; all sensitive to dihydropyridine (specific antagonist) = L type calcium channel (channel supports currents that are long lasting and therefore show less inactivation)
Excitation-contraction coupling of cardiac myocytes
Hormone release; regulates transcription, synaptic regulation, nT release from sensory cells
Describe VA Ca2+ channels Cav 3.1-3.3
No specific antagonist
T type channel; transient, inactivate more rapidly then L type
Pacemaker cells; repetitive firing
Describe VA Ca2+ channel Cav 2.3
R type; resistant to inactivation
Selective antagonist; SNX-482
Dendritic calcium transients
Describe VA Ca2+ channel CaV 2.2
N current; nerve terminal
Found on nerve cell terminals and dendrites
Controls nT release; dendritic Ca2+ transients; hormone release
Describe Va Ca2+ channel CaV 2.1
P/Q current; purkinje cells of cerebellum with a specific splice variant
nT release, dendritic calcium transients, hormonal release
Which calcium channels are most relevant to opioids?
CaV 2.1 and 2.2
Located at nerve terminals where they can affect nT release
These can be inhibited by opioid binding
Describe the different types of calcium channels on their influence of neurons
L-type; cell soma, Influences gene expression
T-type; participate in rising phase of action potential as it travels through axon hillock
N and P/Q type; presynaptic where they control calcium entry into synaptic terminal; instrumental on vesicle docking and nT release
What is the impact of mu opioid receptor coupling to calcium channels via whole cell patch clamp recording?
Beta gamma subunit of G protein binds to calcium channel to exert its effects - inactivation
Presence of DAMGO there is an inhibition of part of the voltage activated calcium current (but not completely) - therefore suggests that there are other types of calcium channel types in the cell (not just N, P/Q) such as resistant L or T type calcium channels
Describe tolerance to opioids
Adaptation that occurs in the neurons that respond to neurons leading to reduced sensitivity and reduced analgesia
However, this is not a reduction in efficacy but instead a reduction in potency - higher doses are required to create the same level of analgesia
What other aspect of opioid analgesic side effect can tolerance create?
Opioid induced hyperalgesia
Pain initially goes down on exposure to morphine, after prolonged exposure there is a paradoxical recovery of pain perception, but individuals can become hyperalgesic
This is due to tolerance to endogenous opioid production - lack of potency of exogenous analgesics but also a decline of innate ability to resist pain via endogenous opioid signalling mechanisms
Stimuli that previously doesn’t cause pain becomes painful (allodynia) resulting in a hypersensitivity to pain (hyperalgesia)