Opioids Flashcards
Describe how pain is sensed by the brain
Tissue damage causes cells to break down. This releases bradykinin, 5HT and prostaglandins
These stimulate nociceptors for pain within tissues which release substance P and glutamate
Substance P agonises inflammtion
Glutamate stimulates afferent nerves to stimulate action potential in dorsal horn (laminae I and V)
Fibres enter dorsal horn and synapse. Secondary order neurones decussate and asecnd up the spinothalamic track up to the thalamus and then to the cortex
What are the two types of afferent pain fibres
A-delta fibres - sharp pain. Are myelinated and fast conducting to cause quick response
C-fibres - dull pain. Unmyelinated. Are stimulated after sharp pain settled
What are the peripheral and contral modulators of pain
Peripherally have substantia gelatinosa
Centrally have periaqueductal grey
How does the substantia gelatinosa act to modulate pain
Stimulation of A-beta fibres (by told rub it better) causes stimulation of substantia gelatinosa which causes inhibition of pain fibres in the dorsal horn
This inhibits pain signals to the thalamus
How does the periaqueductal grey modulate pain
Pain signals to thalamus are sent to cortex which then inhibit periaqueductal grey
Thalamus and cortex can interpret pain and act on periaqueductal grey matter to stimulate it
This sends inhibitory signals down spinal cord - 5HT and endogenous opioids modulate
This reduces pain signal to thalamus and reduces pain felt
What are the three endogenous opioid receptors
MOP - mu
DOP - delta
KOP - K
Describe MOP opioid receptors
MOP are found in supraspinal and GI tract
Activation causes decreased cAMP causing efflux of K, resulting in hyperpolarisation and decreased substance P release
Endogenous opioids acting on MOP - enkephalins and beta-endorphins
Cause analgesia, depression, euphoria, dependence, respiratory sedation
Describe DOP opioid receptors
DOP have wide distribution
DOP activation causes decreased cAMP which causes influx of Ca and hyperpolarisation resulting in decreased substance P release
Enkephalins act on DOP
Receptor activation causes analgesia, inhibition of dopamine and modulation of Mu
Describe KOP opioid receptors
KOP are found in spinal cord, brain and periphery
Activation causes decreased cAMP causing influx of Ca and efflux of K
This results in hyperpolarisation and decreased substance P release
Dynorphins act on it
Activation causes analgesia, diuresis and dysphoria
Name some opioids
Strong agonist - morphine, fentanyl (heroin, alfetnanil)
Moderate agonist - codeine
Mixed agonist/antagonist - buprenorphine
Antagonist - naloxone (naltrexone)
Other - tramadol
Describe the pharmacokinetics of morphine and how it acts to modulate pain
Given IV, PO, IM, SC, PR - gut absorption erratic and there is significant first pass effect so rarely given PO
Enters all tissues but morphine struggles to cross blood-brain barrier
Metabolised in the liver and excreted via the kidneys
Acts on MOP receptors and causes complete activation of MOP receptors
Causes analgesia and euphoria
What are the metabolites of morphine and what effects do they have
Morphine is metabolised to produce M6G and M3G
M6G has analgesic effect
M3G has neuroexcitatory effect and irritates the brain as it crosses the BBB
Name some side effects of morphine
Respiratory depression - reduces responsiveness of the medullary centre to CO2
Emesis
GI tract - decreased motility and increased sphincter tone -> constipation, nausea and vomiting
Cardiovascular
Miosis
Histamine release - can cause asthama attack
Describe the pharmacokinetics of fentanyl and how it acts in the body
Given IV, epidural intrathecal, nasal
High bioavailability
Highly lipophilic and highly protein bound but has short t1/2
High level of CNS crossing
Metabolised in the liver and excreted via kidneys
Higher potency than morphine - higher affinity for MOP and higher intrinsic activity
Cause analgesia and anaesthetic
Name some side effects of fentanyl
Respiratory depression
Constipation
Vomiting
Describe the pharmacokinetics of codeine and name some side effects
Given PO or SC
Metabolised via CYP2D6 to morphine - variable expression of CYP2D6 means codeine effects vary in patients
Eliminated via liver and kidneys
Has lower potency than morphine as has lower affinity and lower intrinsic efficacy
Used for mild-moderate pain analgesic
Causes constipation and respiratory depression
Contraindicated in children <12
Describe the pharmacokinetics of buprenorphine and how it affects the body
Given transdermal, buccal, sublingual
Given for chronic pain, palliative care, moderate to severe pain, opioid addiction
Very lipophilic -> wide body distribution and has long t1/2
Metabolised via CYP3A4 and then excreted via the biliary system (also via kidneys but less so)
Has very high affinity for MOP and will displace other opioids from MOP receptors and will bind tightly for a long time to cause sustained, long effect
Name some side effects of buprenorphine
Respiratory depression
Low BP
Nausea
Dizziness
Describe the pharmacokinetics of naloxone and how it affects the body
Naloxone is given IV, IM, intranasal, PO
Has low PO bioavailability due to first pass metabolism
Rapid onset of action and is lipophilic -> readily distributes
Has very high affinity for MOP receptors (greatest apart from buprenorphine)
Metabolised via liver and excreted renally
Short action duration and short t1/2 - given as slow infusion for opioid overdose as otherwise its effects will wear off quickly and patient will suffer overdose again
How does a patient develop opioid tolerance
If synthetic opioid given, both synthetic and endogenous opioids bind to receptors on a cell to both cause effects - will result in a higher number of receptors being filled than normal
This causes the cell to upregulate their receptor production due to high number of receptor binding
As cell has made more receptors, there is not enough opioid to bind to receptors to cause a response if synthetic opioid dose is not changed
In order to cause a response, will need an increased synthetic opioid dose
What is given to treat opioid tolerance and withdrawal
Give methadone
Methadone has agonist activity - removes side effects and improves withdrawal side effects but does not cause a high
Slowly dose is titrated down to down-regulate opioid receptor number
What are the effects of an overdose
Dependence
Vomiting
Constipation
Hypotension and bradycardia
Decreased sex drive
Histamine release
Miosis
Drowsiness
Repiratory depression - apnoea
Which patients should you give special consideration to before prescribing opioids
Manual labourers
Drivers
Elderly
Bedbound
Asthmatics
Biliary tract obstruction
Respiratory disease
Renally impaired
Pregnant
Name some contraindications of opioids
Hepatic failure
Acute respiratory distress
Comatome
Head injuries and raised ICP - M3G crosses BBB and causes inflammatory and irritability to make head injuries worse
