Opioids Flashcards
- Define pain
- Define the following types of pain:
a. NOCICEPTIVE PAIN
b. NEUROPATHIC PAIN
c. Visceral pain
d. Chronic pain
- PAIN is an unpleasant SENSORY and EMOTIONAL experience associated with potential or actual tissue damage As it is subjective it is also defined as what the patient says it is.
2a) NOCICEPTIVE is due to noxious stimulus via nociceptors
b) NEUROPATHIC is due to dysfunction of the nervous system
c) Visceral from organs (e.g. gallbladder)
d) CHRONIC PAIN is pain >12 weeks or when it is thought to not be due to the original insult
- What do nociceptors respond to?
- What chemical mediators do they respond to?
- Describe the transition of pain.
- Chemical, mechanical or thermal damage
- INITIATE: H+, K+ Acetylcholine, Histamine, Serotonin (5-HT)
SENSETIVE: Prostagladin, Leucotrines, Sustance P, Calcitonin gene-related peptide
- Primary afferent fibres –> Small Alpha-beta (2-5 micrometer diameter) conduct SHARP PAIN rapidly (40m/s), as REXED LAMINAE II and V Primary fibres–> Unmyelinated C fibres (<2 micrometers diameter), conduct dull pain slowly (2m/s) Enter DORSAL HORN and synapse at different site. Rexed laminae II
Describe the gate theory of pain
The SUBSTANSIA GELATINOSA (Lamina II) integrates inputs from where 2nd order neurones from ascending spinothalamic tract and spinoreticular pathways on the contralateral side. Descending pathways and larger AB fibres conducting touch stimulate inhibitory interneurones within the SUBSTANSIA GELATINOSA and inhibit C fibre inputs. Pain can be altered by altering neural pathway from the origin to the CNS
Define Opiates and opioids
OPIATES= natural substances with morphine like properties
OPIOIDS= more general term that includes synthetic drugs with an affinity for opioid receptors
They are basic amines
- Describe the make up of opiate/opiod receptors and there actions
- How are opioid receptors classified and why are they so named?
- All receptors are G-proteins that span membranes seven times and are inhibitory
When stimulated they cause voltage sensitive Ca2+ channels to close –> HYPERPOLERISATION by K+ efflux and ADENYLASE CYCLASE inhibition –> decrease cAMP–> inhibitory neurotransmitter release between nerve cells
- Mu (μ)- morphine was the first ligand found to bind to it
Kappa (K)- ketcyclazocine was the first ligand found to bind to this
Delta (𝛿)- first found in the vas deferens
Newer classification system groups them into:
MOP
KOP
DOP
NOP
- Where are MOP or μ receptors found?
- What affects do they cause?
- Found in:
- Cererbral cortex
- Basal ganglia
- Spinal cord (pre-synaptically on primary afferent neurones in dorsal horn
- Peri-aqueductal grey (origing of descending inhibatory control pathway)
- Cause:
- Analgesia
- meiosis (due to actions on Edinger- Westphal nucleus)
- euphoria
- resp depression
- bradycardia
- inhibition of gut motility–> constipation
- Describe the location and effects of DOP or 𝛿 receptors
- Describe the activation and resulting effects of NOP receptors
- Discuss KOP or K receptors activation and their effects
DOP or 𝛿 receptors
- less widespread in CNS
- analgesia, resp depression
NOP
- when stimulated by NOCICEPTIN/ORPHARIN FQ peptide the NOP proceduces effects like μ
- Acts on spinal and supraspinal levels
- Hyperalgesia (low doses)
- Analgesia
- Long lasting analgesia
- anxiety
- depression
- appetite modulation
KOP or K recpetors
- different effects to μ
- less resp depression
- has μ anatagonism therefre limit their use
Describe the types of receptors and there effects
Receptor Effects
MOP/ Mu Analgesia, meiosis, euphoria, resp depression, Bradycardia, decrease gut motility
KOP/ Kappa Analgesia, sedation, meiosis
DOP/ delta Analgesia, resp depression
NOP Anxiety, depression, appetite modulation
- What is morphine?
- Draw its structure
- Describe its presentations and uses, inc doses and methods of injection with minuses of these
- Naturally occuring PHENANTHRENE DERIVATIVE and is a Mu receptor agonist
- Comes as tablets, suspension and suppositories, slow-release capsules and granules
Oral dose 5-20mg four
Parental preparations contains 10-30mg/ml for IV or IM
IM 0.1-0.2mg/kg four hourly
IV titrate to effect
Avoid S/C due to poor lipid solublity therefore
Delayed resp depression following intrathecal/ epidural adminsitation may occur due to poor lipid sol
Describe the effects of morphine
ANALGESIA- particularly effective for visercal pain, less for sharp or superfical pain
RESP DEPRESSSION- decrease sensivitivity of the brain stem to CO2 while its response to hypoxia is less effected. If hypoxic stimulus is removed by suplimental oxygen then resp depression may occur.
GI- Nausea and vomiting; chemoreceptors stim via 5 HT3 and dopamine receptors. Cells in vomiting centre are depressed. Decreased bowel motion and contriction of the sphincter of Oddi (leads leading to increase biliary pressure)
CNS- Sedation, dyphoria, euphoria
CVS- decrease HR and BP due to histamine release
HISTAMINE RELEASE- above and bronchospasm, itching, and rash (maybe reversed by naloxone). Itching is more marked in intrathecal/epidural injection, but not assoc with rash. Slower administration helps
MUSCLE RIGIDITY- due to opiod receptor interaction with doperminergic and GABA pathways in substantia nigra and striatum
MEIOSIS- stimulation of the Edinger-Westphal nucleus. Reversed by atropine.
ENDOCRINE- inhibition ACTH, prolactin and GH. Increase ADH leads to impaired H2O excretion and sodium decrease sodium
URINARY- increased bladder and sphincter tone leading to retention
Describe the kinetics of morphine
ABSORPTION:
Oral- morphine is ionized
- weak base (pKa 8)
- absorption is delayed until in more alkaline environment, unionised in SB
- 30% bioavailiblity to do first pass metabolism
DISTRIBUTION:
- PEAK AT 10 MINS IV AND 30 MINS IM
- Duration 3-4 hours
- Conc falls slowly in brain due to poor lipid solubility therefore conc in blood does not correlate with effects
METABOLISM:
- Mainly liver but also kidney
- 70% MORPHINE 3-GLUCURONIDE, MORPHINE 6-GLUCURONIDE = 13x more potent
- also gets N-demethylated
EXCRETION:
- Renally
- Neonates have increase sensitivity due to increase hepatic conjugation capacity
- Elderly peak plasma levels are higher due to decreased volumeof distribution
- Describe diamorphine
- Draw its structure
- Presentation and use
- DIACETYLATED morphine derivative
- it has no affinity for opiod receptors but is a PRODRUG with active metabolitis that cause its effects
- about 2x potent as morphine
- causes the greatest euphoria (hence abuse)
- 10 mg tabs and white powder for injection 5,10,30,100,500mg diamorphine hydrochloride
- Easily disolved
- Severe pain and dyspnoea (assoc pulmonary oedema) at 2.5-10mg IV
- Intrathecally 0.1-0.4mg
- Epidural 1-3mg
- 10 mg tabs and white powder for injection 5,10,30,100,500mg diamorphine hydrochloride
Describe the kinetics of diamorphine
Absorption:
- Highly lipid soluble
- Well absorbed from gut and subcutaneously
- low bio availablity due to extensive 1st pass metabolism
Distribution:
- 40% protein bound
- pKa = 7.6
- 37% unionizied at pH 7.4
Metabolism:
- Rapid metabolism in LIVER, PLASMA and CNS by ESTER HYDROLYSIS
- –> 6 monoacetyl morphine and morphine (leading to analgesic effects
Excretion:
- 1/2 life is 5 mins
- Renal excretion
Draw a table to summarise the opiates and antagonist and their receptor affinity
Codeine
- Describe it and its preparations
- What are its uses?
- What are the kinetics of codeine?
1.
- 3-methylmorphine
- 1/10th the potency of morphine
- oral and IM dose is 30-60mg. IV route can cause decrease BP (probably due to histamine release therefore avoided)
- Acts as a prodrug to morphine
2.
- Antitusssive
- Anti-diaorrhoel
- Hypnotic
- Anxiolytic
- Pain killer
3.
- Methyl group reduces 1st pass metabolism therefore slightly better oral bioavalibility than morphine (50%)
- 5-15% is eliminated unchanged in urine
- Rest via metabolic pathways in the liver
- 6-hydroxyglucuronidation –> codeine-6-glucaronide
- 10-20% is N demythylated–> norcodeine
- upto 15% is O-demethylated–>morphine
- of all metabolities only MORPHINE has significant mew effects
- CYP2D6 is non-inducable and exhibits genetic polymorphism so poor metabolisers experience poor pain relief
- 9% of UK but 30% Hing Kong Chinese
- Fast metabolisers have increased levels of morphine and get side effects hence not for under 12s
Draw a diagram to show the metabolism of codeine
Describe Dihydrocodeine
- Synthetic opioid
- similar to codeine as are its metabolic pathways
- Approx 2x more potent
- Oral bioavailability 20%
- Less dependent on CYP2D6
- Therefore more predictable affects
- Describe fentanyl
- Presentation
- Uses
1.
- Synthetic PHENYLPIPERIDONE
- Rapid onset
- μ-receptor agonist
- Less likely to cause histamine release
- High doses (50-150mcg/kg) decreae or eliminate metabolic stress response to surgery but are assoc with bradycardia and chest wall rigidity
2.
- Colourless solution for injection 50mcg/ml
- Transdermal patch releasing25-100mcg/hr for 72hours
- Lozenges 200mcg-16mg over 15 mins
3.
- Pain assoc with minor surgery 1-2mcg/kg IV- lastng about 30mins
- higher doses required to obtund largyngeal reflexes
- High doses 50-100mcg/kg for opiod based anaesthesia, DoA is upto 6 hours here
- Hypnotic is still required
- Spinal (10-25mcg) and epidural (25-100mcg) Resp depression observed with epidural in continous boluses
- High lipid sol ensures no delayed resp depression to and rapid diffusion to spinal cord
What are the kinetics of fentanyl
A:
- pKa 8.4: 9% unionised at pH7.4
- Rapid onset due to high lipid sol (about 600x >morphine)
- Transdermal patches take 12 hours to reach equilibrium
- Dose <3mcg/kg IV= short duration soley due to distribution
- This is prolonged with prolonged administration due to tissue saturation
D:
- Similar clearance to morphine
- 1/2 life is longer than morphine due to high lipid sol and distribution
- Fentanyl may be trapped in acidic area of stomach; 99% ionisied, unionised in more alk SB and absorbed
- Unlikely to increase plasma conc due to rapid 1st pass
M:
- N-demethylated –> Norfentanyl. This and fentanyl are further hydrolised
E:
- These inactive metabolites are excreted in urine
Alfentanyl
- Describe it
- Presentations and uses
- Synthetic PHENYLPIPERIDINE with μ-receptor
- Colourless solution 500mcg or 5mg/ml
Boluses 5-25mcg.kg for short term analgesia
Infusions for sedation but has a prolonged duration of action
Alfentanyl
Kinetics
A:
- pKa 6.5
- 84% unionisied at pH 7.4 therefore able to cross lipid memb
- despite lower sol than Fentanyl it is FASTER (inequipotent doses)
D:
- Smaller vol of dist, clearance, and shorter 1/2 life than fentanyl
M:
- N-demethylated –> noralfentanyl
- Midazolam is metabolised by same hepatic CYP3A3/4 therefore co-administration increases 1/2 life
- Erythromycin may prolong activity by inhib hepatic CYP450
E:
- Conjugated and excreted in urine
Remifentanyl
- Describe
- Presentation
- Uses
- What effects does it have?
- Pure μ-recep agonist, PHENYLPIPERIDINE derivative of fentanyl
- Crystaline white powder in vials 1,2,5 mg Remifentanyl hydrochloride
- Also contain GLYCINE
-
- Not licenced for neuroaxial
- Diluted with 5%Dex, 0.9% or 0.45% Saline. Stable for 24 hours
- Bolus 1mcg/kg over not less than 30s, followed by infusion 0.05-2mcg/kg/min
- additional induction agents and post-op analgesia still required
4.
- Shares morphine effects inc resp depression and chest wall rigidity
- Due to ultra low durstin of action N&V are less common
- Increased HR and BP (maybe reversed by glycopyrolate)
- Analgesia is reversed by naloxone
Remifentanyl
Kinetics
- Rapidly broken down by PLASMA and TISSUE ESTERASES
- 1/2 Life 3-10mins
- DoA determined by metabolism NOT distribution
- As esterases is abundent the duration of administration does not significantly affect DoA (context sensative 1.2 time)
- Unaffected by cholinesterase deficency or anticholinsesterase drugs
- Excretion in urine as carboxylic acid metabolite (1/460th as potent)
- 1.2 life of metabolite is 2 hours in healthy people
- not prolonged in hepatic or renal impairment
Draw a table compairing:
- Morphine
- Pethidine
- Fentanyl
- Alfentanyl
- Pemifentanyl
Compare 1/2 life, clearance, vol of dist, plasma binding, pKa, percentage unionizsed a pH 7.4, protein binding and relative solubility (from octanol:water cofficient)
Oxycodone
- Presentation
- MoA
- Uses
- Kinetics
- Multiple preparation inc TARGINACT
- Oxycodone with naloxone
- 5mg/2.5mg, 10/5mg, 20/10mg, 40/20mg as prolonged release - Both absorbed in gut
> naloxone undergoes significant 1st pass metabolism so no systemic effects. Has local (pre-hepatic) effects on gut and increase constipation
> oxycodone has bioavailability of 85% and exerts systemic effects
- Severe pain with resistant constipation, or patients where constipation would be bad e.g. haemorrhoidectomy and pelvic floor repair
- Mu, Kappa and Delta. 1/2 life 3-5 hours. Metabolised to oxymorphone (very potent), noroxycodone (weakly potent)
More predictable metab than morphine
Pethidine
- Describe it
- Preparations
- Uses
- PHENYLPIPERIDINE-originally designed as an anticholinergic
- Tablets and solution for injection 10-50mg/ml
- IM+IV dose 0.5-1mg/kg 2-3hourly
- Tirtrate to effect
3.
-Labour
>high lipid sol enables small amount to cross the placenta. Following metab to NORPETHIDINE it accumulates in foetus
- Levels peak at 4 hourly after IM dose
- Due to foetal clearance the 1/2 life of PETHIDINE and NORPETHADINE are prolonged by a factor of 3
Pethindine
Describe its effects
Shares common opioid effects with some differences:
- Anticholinergic:
> produces less meiosis and a degree of mydriasis
>dry mouth
>increase HR
- GUT: less biliary tract spasm
- Interactions:
. MAOI; due to central serotoninergic hyperactivity due to pethadines inhib of serotonin re-uptake and MAOI- induced decrease in amin breakdown
———> COMA, labile circulation, convulsions and hyperpyrexia
Pethidine
Kinetics
A:
- More lipid sol than morphine therefore faster onset
- oral bioav 50%
M:
- Met by liver ester hydrolysis—> pethidinic acid and N-demylation—> NORPETHIDINE
- NORPETHIDINE has 1/2 the analgesic activity of pethidine
- Long 1/2 life (14-21hours) than pethidine
- Accum in RF
- Assoc with hallucinations and seizures in accumulation
- NOT reversed by naloxone
Duration is 120-150mins
E:
Norpethidine and pethidinic acid excreted in urine with small amounts unchanged pethidine
Methadone
- Describe its uses and actions and effects
- Kinetics
1.
- Used for opiate weaning in addiction
- Less sedating than morphine
- NMDA anatgonist
- May be benefitical in certain neuropathic pain
2.
A: 90% protein bound
M: Liver metabolism into multiple inactive metab
low 1st pass therefore oral bioavail = 75%
D: 1/2 18-36hrs (long)
E: 40% excreted unchanged in urine
-enchanced in acidic conditions
Tramadol
- Describe
- Preparations
- MoA
- Effects
1.
- Cyclohexanol Derivative
- Racemic mixture
- each enantiomer produces spec actions
- 1/5th-1/10th power of morphine
2.
- Tablets, capsules ans sachets 50-400mg MR
- IM, IV 100mg in 2ml
3.
- Agonist at all opioid recep particularly mu receptors
- Not a CD
- Also inhib re-uptake of noradrenaline and 5 HT
- Stimulates 5 HT release –> provides alternative pathways for analgesia involiving inhib pathway in the Spinal cord
4.
- In equi-analgesic dose it produces less resp depression and constipation
- Reversed by naloxone
Tramadol
- Interaction
- Kinetics
1.
- Potential to interact with drugs that inhib central 5-HT or Noradrenaline re-uptake
- e.g. TCA and SSRI–> seizures
- Should not be used in patients with epilepsy
2.
A:
- Well absorbed in gut; bioavailability 70%, increase to 90% after repeat dose
M: CYP2D6, 3A4 and 2B6 and subsequent glucauronidation —> number of metabolites (ic O-desmethyltramadol) only this is analgesic
D: Vol of dis = 4L/kg
E: Urine, 1/2 life 5-6 hours
Tapentadol
- Describe
- Use
- Dose
- Kinetics
- Dual action with mu and noradrenaline re-uptake inhib (NARI)
Avoid in MAOIs within 14 days
- Acute pain but may also be useful due to its duel mechanism
- intial dose 50mg 4-6 hourly
- Bioavailability of 30%
- 20% protein bound
Conjugated in liver
Excreted by kidneys
1/2 life 4 hours
Pentazocine
Describe
Little resp depression
Causes nausea, vomiting, hallucinations and dysphoria
Rarely used
Buprenorphine
- Describe
- Kinetics
- Structural similar to but more potent than morphine
SL ir Transdermal
- Duration 10 hours due to receptor binding
Due to its receptor binding it produces analgesia at low conc (mew recp) but with increased doses the NOP effects take over to produce anti-analgesic effects
Metab: by CYP3A4 and then conjugated
E: 70% excreted in bile rest in urine
Nausea and vomiting are severe and prolonged
Nalburphine
Describe
- Equipotent to morphine
- Ceiling effect with resp depression and analgesia
- Reversed by naloxone
Naloxone
- Describe
- Effects
- Dose and duration of action
1.Pure opioid anatagonist
Reverses mu, kappa and delta recp
- affinity is highest for mu- receptors
2. Causes (occassionally)
inccreased BP
Pulm oedema
Cardiac arrhythmias
Anatalgesia
- 1-4mcg/kg IV
30-40min
- shorter than morphine and high dose fentanyl so supplemenry doses/ infusion may be needed
