Opioids Flashcards
Morphine structure
The reference opioid. A phenanthrene derivative (naturally occuring opioid)
Morphine preparations
IV - clear colourless solution 10-30mg/mL of morphine sulphate
Intrathecal - clear colourless solution of 0.5mg/mL (500mcg/mL) of preservative free morphine sulphate
PO - 5-200mg tablets and syrup 2-20mg/ml
PR - 15-30mg
Morphine doses
IV = 0.05-0.1mg/kg Q4H PO = 5-20mg Q4H SC/IM = 0.1-0.2mg/kg Q4H Intrathecal = 0.2-1mg Epidural 2-4mg
Morphine absorption
30% oral bioavailability due to extensive hepatic first pass metabolism.
IM/IV peak effects 10-30 mins after administration with duration of action 3-4 hours
Morphine distribution
VD 3.5L/kg. 35% protein bound (low)
weak base (pKa 8) - 23% unionised at physiological pH.
Low lipid solubility. Poor BBB permeability - therefore slow onset and offset
Morphine metabolism
Metabolised primarily by liver. Main process is glucuronidation
- 85% to morphine-3-glucorinide - inactive but may show some Mu activity
- 10% to morphine-6-glucorinide - similar Mu receptor affinity, pharmacological effects and duration of action but significantly more potent analgesic effects (contributes greatly to analgesic effects of morphine).
- 5% N-demethylation
NB morphine can be used in liver failure as compensatory glucoronidation occurs in kidneys
Morphine excretion
Urinary excretion of small amounts of unchanged morphine and the M6G.
10% biliary excretion of unchanged morphine and its metabolites.
Clearance 15ml/min/kg. Elimination t1/2 = 1.5-3.5 hours
NB morphine should be avoided with renal failure as morphine and M6G will accummulate.
Pethidine structure
Synthetic opioid - phenylpiperidine derivative
Pethidine mechanism of action
Main MOA is Mu and Kappa opioid receptor agonist
Other effects:
- anticholinergic effects due to being structurally similar to atropine. Causes increased HR, dry mouth, mydriasis
- alpha-2 agonist - decrease shivering
- LA effect - blocks VG-Na channels when given neuraxially and impairs nerve conduction
Pethidine clinical uses
1) analgesia for moderate to severe pain. 10x less potent and also shorter acting than morphine but quicker onset due to increased lipid solubility
- post-op can be given as PCA (prolonged use associated with norpethidine toxicity) or epidurally
2) treatment of post-op shivering - due to kappa and alpha 2 adrenoreceptor effects
3) anti-spasmodic effect to treat biliary / renal colic due to its anti-cholinergic effects
NB does not have anti-tussive effects
Pethidine preperations and doses
Tablet 50mg (well absorbed orally)
Clear colourless solution of pethidine HCL (10 or 50mg/mL) for IV/IM. Dose 25-100mg.
Epidural use 25mg.
Pethidine distribution
- VD 4L/kg, 60% protein binding
- weak base 8.7 (5% unionised at physiological pH
- High lipid solubility
Pethidine metabolism
Extensive hepatic metabolism(>90%)
- ester hydrolysis to pethidinic acid (inactive)
- N-demethylation to norpethidine (active metabolite with 50% analgesic activity) which is then hydrolysed to norpethidinic acid
NB: norpethidine is toxic. Toxicity causes seizures, hallucinations, confusion etc. Cannot be reversed with naloxone. Toxicity occurs with prolonged use or renal failure.
Pethidine elimination
Urinary excretion. pH dependent, acidification of urine can increase excretion up to 25%.
Clearance 10-20ml/min/kg
Elimination half life 3-5 hours
Pethidine side effects
Tachycardia due to anti-cholinergic effects. Also dry mouth and mydriasis (not miosis)
Interacts with MAOis and SSRIs to cause serotonin syndrome (inhibits serotonin reuptake centrally)
Fentanyl structure and mechanism of action
Synthetic phenylpiperidine derivative with a rapid onset of action.
It is highly selective for Mu receptor
Fentanyl preparations
Clear colourless solution 50mcg/mL of fentanyl citrate for IV/IM or epidural use
Topical patch 25-100mcg/hr
Fentanyl clinical uses
1) Analgesia - IV 1-2mcg/kg. 75-125x more potent than morphine
- transdermal patch = 25-100mcg/hr. Slow rate of onset (18hrs) but steady state at that point. Lasts for 72 hours
2) Minimise haemodynamic reaction to surgical stimulation or laryngoscopy
3) Obtund metabolic stress response to surgery (50-150mcg/kg)
4) Augment effects of a neuraxial block (10-25mcg intra-thecal) (25-100mcg epidural)
5) Pre-medication to decrease anxiety, sedation and facilitate induction of GA (esp in kids) - issues with PONV and resp depression
Fentanyl absorption and distribution
Poor bioavailability due to extensive hepatic first pass metabolism. Transdermal works well due to high lipid solubility
Vd 4l/kg, large protein binding
Very high lipid solubility so rapid onset of action as it crosses the BBB easily. Significant first pass pulmonary uptake (75%) and uptake in to inactive tissues (adipose and skeletal muscle) due to lipid solubility
Fentanyl metabolism and excretion
Hepatic metabolism by CYP3A4 to inactive metabolites.
10% of fentanyl excreted unchanged in the urine as well as inactive metabolites.
T1/2 = 3-6hrs (longer than morphine due to increased Vd and same Cl)
CSHT largely prolonged with prolonged infusions or repeated doses due to high uptake by inactive tissues then slow redistribution upon cessation of infusion
Sufentanil structure and mechanism of action
Synthetic phenylpiperidine derivative - thienyl analogue of fentanyl
Highly selective at Mu receptor
Sufentanil preparation and uses
Clear, colourless solution 50mcg/mL of sufentanil citrate for IV or epidural use
Uses:
1) intra-operative analgesia 0.1-0/4mcg/kg or epidural 10-100mcg. (5-10x more potent than fentanyl)
2) minimise haemodynamic response to noxious surgical stimuli
Sufentanil absorption and distribution
Given IV or epidural only. Rapid onset of action 1-6 min, lasting 0.5-8hrs
Vd small - 1.5L (characteristic of sufentanil) due to high protein binding >90% (mainly to alpha 1 glycoprotein).
Very high lipid solubility. Significant first pass pulmonary uptake and uptake in adipose tissue
Sufentanil metabolism
Rapid hepatic metabolism
- N-dealkylation to inactive metabolite nor-sufentanil
- O-demethylation to desmethyl sufentanil (active with 10% activity)
NB very high hepatic extraction ratio therefore hepatic clearance depends on hepatic blood flow
Sufentanil excretion
Metabolites and very small amount of unchanged drug are excreted in the urine
Both also excreted in the bile
NB use cautiously in those with hepatic or renal failure
Alfentanil structure and MOA
Synthetic opioid - phenylpiperidine derivative (analogue of fentanyl).
Highly selective for Mu opioid receptor
Alfentanil preparation and uses
Clear colourless solution 500mcg/mL for IV use
Uses:
1) short term intra-operative analgesia for intense, brief stimulation / pain
2) reliably minimises and blunts haemodynamic responses to intubation if given 90 seconds before with dose of 15mcg/kg
3) Can be used to maintain sedation in ICU - longer CSHT than sufentanil, shorter than fentanyl or morphine
Alfentanil absorption and distribution
Only given IV. Rapid onset of action 1.5 min. Lasts 5-10 min.
Very small Vd 0.6L/kg. Large protein binding >90% mainly to alpha 1 glycoprotein.
Only moderate first pass pulmonary uptake (10%)
Effect site equilibration 1.4min. Despite low ish lipid solubibility it has a low pka of 6.5 meaning at physiological pH 90% of the drug is in the unionised form meaning it can cross to the BBB readily
Alfentanil metabolism
Hepatic metabolism via CYP3A4-mediated N-dealkylation at amide to produce N-phenyl-proprionamide and piperidine to produce noalfentanil. Both inactive.
NB genetic variation in CYP3A4 drug interactions have effects on duration of action
Alfentanil excretion
Metabolites and tiny portion of unchanged drug are excreted in the urine.
Clearance 6ml/kg/min. Despite slow clearance has small Vd so t1/2 only 1.5 hours
Remifentanil structure and mechanism of action
Synthetic opioid - phenypiperidine derivative (fentanyl analogue with ester bonds)
Pure Mu receptor agonist
Remifentanil preparations
White crystalline powder of remifentanil HCL (1,2,5mg) with glycine buffer. Diluted to 40mcg/mL in normal saline
Remifentanil uses and doses
1) Induction and maintanence of GA with propofol or volatile (IV 0.25-mcg/kg bolus followed by infusion at 0.05-2mcg/kg/min)
2) Intra-operative anaglesia (same dose as above) BUT need additional post-op analgesia
3) Minimises haemodynamic and catecholamine response to surgical stimuli or intubation
4) PCA for labour
5) Sedation for procedures (0.05-0.1mcg/kg/min)
Remifentanil absorption and distribution
Given IV only. Rapid onset of action
Small VD 0.3L/kg, 70% protein bound.
Weak base (pKA 7.1) 70% unionised at physiological pH.
Decreased lipid solubility
Remifentanil metabolism
Rapid metabolism by non-specific plasma esterases via hydrolysis of the ester linkages. Produces remifentanil acid compound (minor activity (1/4600th)
Not metabolised by plasma cholinesterase. Metabolism also independent of renal or liver function
Remifentanil excretion
Remifentanil acid metabolite is excreted in the urine.
High clearance (40mL/kg/min) due to rapid metabolism
Elimination half 3-10min
CSHT fixed at 4 min regardless of length of infusion due to small Vd and rapid clearance.
Methadone structure and mechanism of action
Synthetic opioid. Racemic mixture L and D enantiomers
L-methadone - Potent opioid receptor agonist (M > K and D)
D-methadone - NMDA receptor antagonist only
Methadone clinical uses
1) Analgesia for chronic pain - effective due to good absorption, rapid onset and prolonged duration of action
- neuropathic pain due to NMDA antagonism
- post-op pain due to prolonged duration of action
2) withdrawal symptoms
Methadone pharmacokinetics
well absorbed. 75% OBA due to low first pass metabolism.
High protein binding
Hepatic metabolism to inactive metabolites
Metabolites and unchanged drug excreted in urine
Codeine structure and mechanism of action
Naturally occuring phenanthrene alkaloid
- methlymorphine (has a methly substitution for the hydroxyl group on the 3-carbon on morphine).
Codeine itself has a poor affinity for opioid receptor but high affinity for codeine receptor where it is anti-tussive.
10% of codeine is O-demethylated by the liver (CYP2D^) to morphine metabolite which is a potent Mu agonist
Codeine uses and dose
Analgesia for mild-moderate pain only (10x less potent than morphine)
Anti-tussive.
Oral tablet 15-60mg. Often combined with non-opioid analgesic.
Codeine pharmacokinetics
High oral bioavailability due to methyl group on 3-C of morphine meaning lower hepatic first pass metabolism. I
Vd 5.5L./kg. Low protein binding.
Majority of codeine metabolised in liver via glucuronidation to codeine-6-glucuronide (20%), N-demthylation to norcodeine (20%), O-demethylation to morphine by CYP2D6 (10%)
Metabolites and unchanged drug excreted in urine
Codeine issues and side effects
CYP2D6 polymorphism - 10% caucasians (30% HK chinese) have genetic deficiency of CYP2D6 metabolism of codeine thus do not produce the 10% of morphine and get no analgesic effect.
Causes marked constipation.
Histamine release especially with IV administration
Oxycodone structure and mechanism of action
Semi-synthetic opioid.
Mu and Kappa agonist
Used to treat pain - potency twice that of morphine
Oxycodone pharmacokinetics
Well absorbed from GIT with OBA 60-90%
Vd 2.6L/Kg, 45% protein bound. Weak base, mainly ionised at physiological pH with poor lipid solubility
Hepatic metabolism by CYP450 to several metabolites (some active)
Unchanged drug and metabolites excreted in urine. Clearance 10mL/min/kg
Tramadol structure and mechanism of action
Synthetic opioid - cyclohexanol derivative. Racemic mixture of two enantiomers (+ and -)
Each enantiomer has specific actions
- + enantiomer is an agonist at all opioid receptors (moderate mu affinity, weak kappa and delta) and inhibits serotonin reuptake plus facilitates presynaptic release
- inhibits noradrenaline reuptake
NB racemic mixture is superior to enantiopure preperation as both isomers act synergistically towards its analgesic effect with minimal side effects (Ie decreased resp depression, abuse, sedation, constipation etc)
Tramadol preparations and uses
racemic mixture tablets 50-400mg. IV 50mg/mL.
1) analgesia 1-2mg/kg IV Q6H
- used to treat mod-severe pain and those with chronic pain
2) post-op shivering 1mg/kg
Tramadol pharmacokinetics
Well absorbed. OBA 70%.
Vd 4L/kg, low protein binding
Hepatic CYP450 metabolism (Via CYP2D6) via demethylation to several metabolites. O-desmethyltramadol is a major metabolite and the only one with activity. Metabolites then glucuronidated for renal excretion
Unchanged drug and metabolites excreted in urine. Clearance 7-10ml/kg/min.
Elimination t1/2 5-6hrs
Tramadol effects
SImilar to morphine but 5-10x less potent. Less resp depression, sedation, constipation.
No clinically significant CVS effects. No tolerance.
NB analgesic effect only partly reversed by naloxone (30%).
Tramadol issues and drug interactions
TCAs and SSRIs also inhibit serotonin reuptake. Can precipitate serotonin syndrome.
5-HT3 antagonists (eg ondansetron) can interfere with serotonin mediated analgesic effects
- should not be used in patients with epilepsy (lowers seizure threshold)
- emetogenic (increases PONV)
- Increases volatile (MAC) requirement. Higher risk of awareness
- elimination prolonged with hepatic / renal impairment
- Genetic polymorphism of CYP 2D6. 10% of population with not form active metabolite
Tapentadol structure and mechanism of action
Centrally acting opioid analgesic.
Dual mechanism of action:
1) Mu receptor agonist (18x less potent than morphine)
2) Noadrenaline reuptake inhibitor
Tapentadol pharmacokinetics
OBA 32%. Low protein binding of 20%
97% metabolised via conjugation to glucuronides. All metabolites are inactive
Unchanged drug and metabolites excreted in the urine
Naloxone structure and preparation
substituted oxymorphine derivative - N-alkyl group substituted for N-methyl group on oxymorphone
Clear, colourless solution for IV use 400mcg/mL
Naloxone mechanism of action
Reversible (competitive) antagonist at all opioid receptors - highest affinity for Mu
Binds to opioid receptor with high affinity, thus displacing opioid agonist. However it has no intrinsic activity so produces no response.
Naloxone clinical uses
1) Treat opioid induced respiratory depression (1-4mcg/kg/iv)
2) Treat opioid induced pruritis and N + V (especially with neuraxial opioid)
3) Diagnose and treat suspected OD
4) Treatment of shock (very high doses >1mg/kg)
Naloxone doses
1-4mcg/kg IV. Onset within 2 minutes secondary to its very high lipid solubility meaning it crosses the BBB rapidly.
May need supplementary IV boluses or infusion at 5mcg/kg/hr when used to treat overdoses of longer acting opioids because it has a short duration of action
Naloxone pharmacokinetics
Well absorbed from GIT but significant hepatic first pass metabolism so OBA only 2%
Vd 2L/kg. Highly lipid soluble (crosses BBB easily). Weak base, 40% protein bound.
Hepatic metabolism by conjugation with glucuronic acid to naloxone-3-glucuronate.
Unchanged drug and metabolites excreted in urine. Clearance 25mL/kg/min
Naloxone issues and side effects
1) Reversal of respiratory depression comes with associated reversal of analgesia - possible to reverse some resp depression but maintain analgesia
2) CVS stimulation secondary to SNS activation upon withdrawal of analgesia - tachy, hypertension, arrhythmias, APO
3) Withdrawal symptoms in opioid dependent patients
4) N + V if given in high doses fast
5) Increased MAC requirements - can angtagonise volatile agents
Naltrexone basics
Reversible competitive antagonist at all opioid receptors. Effective orally. Useful in treating alcoholism
Nalmefene basics
6-methylene analogue of naltrexone. Similar mechanism to naloxone but longer duration of action
