Opioids Flashcards
Differentiate opioids from opiates
Opiate - drugs derived from opium (e.g. morphine, codeine, heroin)
Opioid - broad class of opiate analogues that have morphine-like activity
What is the traditional classification of commonly used opioids?
Natural compounds
- Codeine
- Morphine
Semi-synthetic compounds
- Buprenorphine
- Hydrocodone
- Oxycodone
- Naloxone
Synthetic compounds
- Fentanil
- Alfentanil
- Sufentanil
- Remifentanil
- Tramadol
- Meperidine
- Methadone
- Nalbuphine
What is the functional classification of commonly used opioids
Full Agonists
- Codeine
- Morphine
- Hydrocodone
- Oxycodone
- Fentanyl
- Alfentanil
- Sufentanil
- Remifentanil
- Meperidine
- Methadone
Partial agonists
- Tramadol
- Buprenorphine
- Nalbuphine
Centrally acting antagonists
1. Naloxone
Peripherally acting antagonists
1. Methylnaltrexone
How is the oral absorption for most opioids and what is the bioavailability for most opioids. Name the exceptions
Almost all opioids are well absorbed orally
- Tramadol is 100% absorbed orally
Almost all opioids undergo significant hepatic first pass metabolism and have low-ish bioavailability (30% –> 70%)
- remifentanyl 0% bioavailability
- buprenorphine 15% bioavailability
Compare transmucosal absorption of fentanyl and remifentanil
Fentanyl –> slow transmucosal absorption (7 minutes)
Remifentanil –> fast transmucosal absorption
What is the dose of intranasal fentanyl in paediatrics and how long does it take to work?
1 - 2 ug/kg (repeat dose of 0.5 - 0.75 ug/kg after 10 - 20 minutes)
Takes about 7 minutes to work
Describe the pkA and unionized fraction of NB opioids.
Which opioid is the most important exception to the general trend and what are the implications pf this
Opioids are weak bases. Most of them have a pKa close to 8.0 - 9.0
Fentanyl pKa 8.4 9% unionized at pH 7.4
Exception NB
- Alfentanil has a pKa of 6.5
- -> 90% unionized at pH of 7.4 –> Rapid onset
Fentanyl has an octanol:water coefficient of 717
Alfentanil has an octanol:water coefficient of 128
This means that Fentanyl is significantly more lipid soluble than alfentanil.
Why then is the onset of alfentanil faster than fentanyl
Alfentanil has a pKa of 6.5 which means that 90% of it is in its unionized form at physiological pH of 7.4
Fentanyl has a pKa of 8,4 which means that 90% of it is in its ionized form at physiological pH of 7.4
Hence alfentanil is faster
Why does morphine last longer than fentanyl despite its shorter elimination half life?
HIGH OCTANOL:WATER PARTITION CO-EFFICIENT = HIGH LIPID SOLUBILITY
High lipid solubility
–> faster onset (but requires unionized drug so depends also on pKa)
Low lipid solubility
–> Longer duration of action as can’t diffuse out of spinal space/brain.
–> E.g.
Morphine: octanol:water 1.42 + t1/2 = 3 hours
Fentanyl: octanol:water 717 + t 1/2 = 3.5 hours
–> Morphine’s lower lipid solubility means it takes longer to diffuse out of the CNS and therefore has a longer duration of action despite having a shorter t1/2
Where are opioids metabolised, what are the exceptions, which agents have active metabolites
Hepatic metabolism
Renal excretion of metabolites
Morphine
–> Morphine-6-glucuronide (active)
Heroine
–> Morphine (active)
Codeine
–> Morphine (active)
Oxycodone
–> noroxycodone (active)
Tramadol
–> O - desmethyltramadol (active)
NB
Methadone –> inactive metabolite EDDP
Differentiate factors that stimulate nociceptors vs substances that sensitize nociceptors
Stimulating factors:
- Mechanical stimuli
- Thermal stimuli
- Chemical stimuli
- -> H
- -> B
- -> K+
- -> ACh
- -> 5 HT
- -> H+
Sensitising factors:
- Prostaglandins
- Leukotrienes
- Substance P
Name the two nerve fibres that conduct pain and differentiate these fibres properties
A delta
- Diameter: 4 um
- Velocity: 40 m/s
- Synapse: Dorsal horn - Rexed laminae 4 and 5
C fibres
- Diameter: < 2 um
- Velocity: 2 m/s
- Synapse: dorsal horn - Rexed laminae 2 (substantia gelatinosa)
What is the gate theory of pain
A beta touch fibres and descending pathways stimulate inhibitory interneurons that prevent the conduction of nociceptive impulses to the CNS –> i.e. close the gate on C fibres..
Describe the sequence of events once opioid receptors are stimulated
Seven serpentine transmembrane inhibitory Heterotrimeric G-protein linked receptors
- -> Inhibition of adenylase cyclase
- -> Reduced cAMP
- -> closure V gated Ca channels (increase + ECF)
- -> K+ efflux (Increase +)
Overall –> increased positive charge outside versus inside –> hyperpolarization of cell membrane –> reduced likelihood of AP generation as resting membrane potential is further away from threshold potential in nociceptive neurons.
Classify the effects of stimulation of different opioid receptors
MOP - Analgaesia
- Respiratory depression
- Hypotension
- Constipation
- Miosis
KOP - Sedation
- Confusion
- Miosis
DOP - Analgaesia
- Respiratory depression
- Constipation
- Mood
NOP - Pro-nociceptive
- Depression
- Appetite modulation
Define context sensitive half time and how it differs from half life
Context-sensitive half time is the time required for the plasma concentration of an infused drug to fall to half the concentration when the infusion is stopped.
It is not a number but rather a function of the duration of drug delivery, which is the context.
What are the advantages and disadvantages of the use of an intravenous infusion of fentanyl in comparison to morphine
FENTANYL
1. EXPENSIVE
2. LONG Context Sensitive Half Time
(due to extensive tissue compartment distribution)
3. CRITICALLY ILL - no accum. active matabolites
4. CRITICALLY ILL - Free fraction increase (PB 80 - 90%)
5. OPIOID WITHDRAWAL more likely (due to high lipid solubility and rapid removal from CNS) –> ICU delirium
6. Beneficial in septic shock - No histamine release
MORPHINE
1. CHEAPER (but increase duration of effect ? longer ICU)
2. Duration INDEPENDENT Context Sensitive Half Time
(due to less extensive tissue compartment distribution)
3. CRITICALLY ILL - accum. of active metabolites
4. CRITICALLY ILL - Free fraction less affected (PB 30 - 25%)
5. OPIOID WITHDRAWAL less likely
6. Beneficial CCF –> Histamine VD
What is the intrathecal dose of fentanyl and morphine and how do these differ in onset and duration when intrathecally administered.
Explain the difference in onset and duration
Fentanyl 10 - 20 ug
- Onset: 5 - 10 minutes
- Duration: 1 - 2 hours
Morphine 0.1 - 0.2mg
- Onset: 45 minutes
- Duration: 18 - 24 hours
The mechanism of the above difference relates to significant difference in lipid solubility between the agents
Fentanyl - VERY high lipid solubility
- Rapid onset
- Rapid offset
- Rapid uptake into capillaries = faster clearance CSF
Morphine - Lower lipid solubility
- Slower onset
- Slower offset
- Slower uptake into capillaries = slower clearance CSF
Which opioids cannot be administered into the intrathecal space and why
- Remifentanil (contains glycine buffer)
- Morphine IV preparation with preservatives
All substances into intrathecal space must be preservative free
How can epidural/intrathecal administration of opioids affect their metabolism and clearance
Haemodynamic effects could reduce renal and hepatic blood flow reducing clearance
How do the pharmacodynamics of intrathecal versus epidural opioids differ
Intrathecal
–> Affects spinal mew opioid receptors + redistributed to the brain stem
Epidural
–> Absorbed systemically to have an effect similar to IV administration
List the side effects of intrathecal/Epidural opioid administration
- Unexpectedly prolonged action
- Hypotension
- Respiratory depression (with higher spinal levels)
- Urinary retention
- Pruritis
Summarise the cellular events subsequent to activation of opioid receptors
Pre-synaptic Seven Serpentine Transmembrane G-protein coupled receptors: mew, kappa, delta, NOP
Activation is INHIBITORY
- Gi –> inhibits AC –> Reduced cAMP
- -> Increased potassium efflux and hyperpolarization
- -> Reduced calcium conductance and reduced neurotransmitter release
Reduced neurotransmission C fibres
Describe the mechanism of opioid induced analgaesia in the spinal cord and brain
SPINAL mew receptor effect
- Presynaptic on primary afferent nociceptive neurons
MIDBRAIN mew-receptor effect
(PERIAQUEDUCTAL GREY MATTER)
- Mew agonism here removes GABA-ergic inhibitory tone on descending inhibitory pain pathways
- This increases descending inhibition on the dorsal horn 2nd order neurons
Describe the mechanism of opioid induced respiratory depression
BRAINSTEM MEW-RECEPTOR EFFECT:
- Decrease rate of firing in the respiratory pacemaker centre (pre-Botzinger complex)
MEDULLARY MEW-RECEPTOR EFFECT:
- Decrease sensitivity of medullary chemoreceptors to hypercapnoea and hypoxia
