2.3 b Opioid Derivatives and Non Opiod Flashcards
Diamorphine
What is it
How it is metabolised
to what
It is diacetylmorphine
(having two molecules of morphine).
It is a prodrug that is metabolised to 6 Monoacetylmorphine (6-MAM)
and then to morphine through ester hydrolysis.
What drug is the effective
How potent is it
diacetylmrphine
Its analgesic action is then mediated by morphine.
Because it has two morphine molecules,
it is twice as potent.
Diamorphine
Lipid solubility vs morphine (vs fentanyl)
It has higher lipid solubility than morphine
(but lower than fentanyl/ sufentanil).
Diamorphine
Lip solubility affect its administration
1st pass metab
This makes it particularly well suited
for subcutaneous administration.
Orally, it has a high first-pass metabolism.
Diamorphine
Intrathecal duration
How does the affect side effect
Given intrathecally, it has a
shorter duration of action than morphine
(6 vs 12 hours)
because of its higher lipid solubility.
This reduces the likelihood of
delayed respiratory depression
when compared with morphine.
Diamorphine ?drug of abuse
As it causes high euphoria,
it is a drug of abuse
(street name is heroin).
Methadone
Lipid solubility
1st pass
PO bioavailability
protein binding
It is a synthetic opioid agonist
used extensively in opioid deaddiction.
It is highly lipid-soluble,
has a low first-pass metabolism,
high oral bioavailability (80%),
high protein binding (90%)
Methadone
How is it metabolised
Duration of action
How is this useful
and it undergoes rapid
N-demethylation to inactive metabolites.
It has a longer duration of action (30 hours),
hence prevents withdrawal reactions.
What is its MOA
How is this useful
It is an NMDA antagonist,
and has been found useful
in many opioid resistant
chronic pain states.
Codeine
Is it prodrug
Potency of Morphine?
Codeine
It is methylmorphine
(prodrug)
Has one-tenth the potency of morphine.
Codeine
PO avail
other route?
Dose
What route is avoided + why (d/t)
Used orally (bioavailability 50%) or intramuscularly in doses:
30– 60 mg (adult) and
0.5–1.0 mg/kg (paediatric).
The intravenous route is avoided
because of hypotension
(histamine release).
Codeine
Metabolism
Metabolism is by:
1 glucuronidation (20%) to codeine-glucuronide
2 N-demethylation (10%–20%) to norcodeine
3 O-demethylation (5%–15%) to morphine by CYP2D6: responsible for its analgesic action
4 excretion unchanged (15%).
Codeine
Is there any genetic variations
How does this affect
Is there any drug that displays same
CYP2D6 exhibits genetic polymorphism,
hence poor metabolisers have poor analgesia.
Tramadol undergoes similar
O-demethylation to O-desmethyltramadol
(higher affinity than parent compound)
via CYP2D6.
Poor metabolisers show reduced
analgesic activity to tramadol as well.
Positive side effect Codeine
Main adverse
Is there a compound drug twice as potent
It is a potent antitussive, with constipation being its main adverse effect.
Dihydrocodeine is twice as potent.
Tramadol
Type of drug
acts on ?strength
It is a phenylpiperidine analogue of codeine.
It is an opioid-like drug having a
weak agonist effect on
MOP (μ) receptors.
Its effects are reversed by naloxone.
It is a norepinephrine and
serotonin reuptake inhibitor
producing analgesia by
enhancing descending inhibitory pathways
(which need NE and 5-HT for stimulation).
Tramadol
Other hormone / Neurochemical effects
How does this produce analgesia
It is a
norepinephrine
serotonin reuptake inhibitor
producing analgesia by
enhancing descending
inhibitory pathways
(which need NE and 5-HT for stimulation)
Tramadol what is the risk of MOA causes
+ caution with what drugs
For the same reason,
it potentiates 5-HT (serotonin) levels
when administered concurrently
with MAO inhibitors,
producing serotonin syndrome.
It may lower seizure threshold and so should be avoided in epileptics.
Tramadol
PO bioavailability
How is it metabolised
via what enzyme
is there any issue with this type of breakdown
It has high oral bioavailability
(70%)
and undergoes
O-demethylation to O-desmethyltramadol
(higher affinity than parent compound)
via CYP2D6.
Poor metabolisers show reduced analgesic
activity to tramadol.
Tramadol
Do opioids cause shivering
What is the most limiting S/E of Tramadol
what mechanism
how rx
Abuse potential high?
Opioids are used to treat
post-operative shivering
(pethidine and tramadol in particular).
Nausea is the most limiting side effect
(due to 5-HT action on CTZ);
take ondansetron.
It has a low abuse potential and hence it is not a controlled drug
Pethidine
Type of drug
Lipid solubility
How does this affect where its commonly used
Is an anticholinergic drug that was later
found to have analgesic actions.
Higher lipid solubility
hastens the onset,
but also offers higher transfer
to foetus when given during labour.
Pethidine
Potency V Morphine
What is it broken down to
% activity
How is this metabolite excreted
One-tenth the potency of morphine.
Metabolised to norpethidine
(active metabolite with 50% activity)
which can accumulate in renal failure
Fentanyl
Potency v Morphine
Lipid solubility
How does this affect its intrathecal admin + S/E
Hundred times the potency of morphine.
Highly lipid-soluble,
hence dissipates to systemic circulation quickly
when given intrathecally.
This reduces rostral spread potential,
reducing the consequent respiratory depression.
Fentanyl
Why used Paeds
Whats metabolised to
% activity
Useful in paediatrics due to its shorter action than morphine.
Metabolised to inactive norfentanyl.
Alfentanil:
Potency V Morphine
Ten times the potency of morphine.
Alfentanil:
Compare it to fentanyl
- Lipid solubility
- pKa (fraction unionised drug)
- speed onset
Lower lipid solubility than fentanyl,
Lower pKa
6.5 vs 8.4 at pH 7.4
This results in higher fraction of unionised drug
89% vs 9% with fentanyl
resulting in faster onset.
Remifentanil:
How administered
Intrathecal use?
Why
Used as an infusion only.
Not used intrathecally
(as commercial preparation has glycine).
Remifentanil:
Metabolism
Context sensitive t1/2
does it accumulate?
Metabolised by ester hydrolysis,
having a context-sensitive half-life of
4 minutes.
Hence does not accumulate
despite prolonged infusions.
Remifentanil
Problem with use for analgesia intra op
However, analgesia does not
continue post-operatively,
and a morphine bolus is required
at the end of surgery for
postoperative analgesia.
Naloxone:
What is it
at which receptor
What type of compound
It is an opioid receptor antagonist
at all three receptors.
It is an N-allyl derivative of oxymorphone.
Naloxone:
What is its use?
What is its onset and duration
Issues with reversal
what patient group is very susceptible
It is used for opioid overdose
rather than dependence
(naltrexone is used for
opioid and alcohol dependence).
It is short-acting hence
is best given as a bolus
followed by an infusion.
Opioid reversal can
produce withdrawal symptoms,
including seizures and pulmonary edema,
especially in a neonate.
Paracetamol:
Uses
Where does it affect PG
It is a weak analgesic,
antipyretic
very weak anti-inflammatory.
It inhibits CNS prostaglandin synthesis.
Dose Paracetamol
is it more or less effective v morphine when combined with weak opioid
Oral/intravenous dose is 20 mg/kg (adult) and 15 mg/kg (paediatric)
.
Combined with a weaker opioid (tramadol or codeine), its efficacy
may exceed morphine because of synergism.
What’s propacetamol
Propacetamol is the prodrug form of paracetamol (intravenous
formulation). The intravenous formulation is more effective than the
oral.
How is Paracetamol metabolised
To what
How is this broken down
Metabolised in
liver
to N-acetyl-p-benzoquinone imine
(NAPQI),
which is very toxic.
It is rapidly detoxified by glutathione,
+
N-acetylcysteine
(precursor of glutathione).
What does this lead to in paracetamol OD
How is this Rx
hence paracetamol overdose results
in glutathione depletion
and consequent hepatotoxicity.
This can be treated with
methionine
(promotes glutathione synthesis)
NSAIDs:
How do they work
Role of X involved in analgesia
act by reversible
cyclooxygenase (COX) inhibition.
2 isoenzymes
COX-2: inducible.
Expressed at the
site of injury in
response to inflammation.
NSAIDs
Role of COX 1
Two isoenzymes are found:
COX-1: constitutively expressed in kidneys (prostaglandin production for maintenance of renal blood flow)
and
gastric mucosa
(protection against acidity).
NSAIDs
Protein binding
Vd
They have high protein binding
and
low volume of distribution.
Adverse effects:
x7
1 gastric ulceration
(via inhibition of protective prostaglandins)
2 renal damage –
via vasoconstriction due to
inhibition of prostaglandin synthesis
3 asthma exacerbation –
in susceptible individuals (15%) due to
unopposed leukotriene synthesis
4 perioperative bleeding –
inhibit platelet aggregation
5 affect bone healing (equivocal evidence)
6 hepatotoxicity –
transient elevation of transaminases (15%).
7 Drug interactions:
displacement reaction with warfarin
(leading to its toxicity).
Selective COX 2 Inhibitors
Do they reduce side effects?
Do they have an serious S/E
1
Same risk of gastrointestinal ulcers.
2
Same risk of renal side effects.
3
Since they may inhibit vascular
prostacyclin synthesis,
they may promote platelet aggregation,
leading to a higher incidence of myocardial infarction and stroke (compared with non-selective COX inhibitors).
Selective COX 2 Inhibitors
5 examples and are they in use?
Rofecoxib:
withdrawn because of
higher incidence of myocardial
infarction.
Celecoxib:
contraindicated in sulphonamide allergy.
Valdecoxib:
withdrawn due to serious dermatological effects.
Parecoxib:
parenteral preparation.
Lumaricoxib:
liver toxicity.
How does one deal with a true opioid allergy and analgesia
In the event of a true allergy
(severe hypotension, skin rash,
respiratory difficulty and mucosal oedema),
it is advisable to either
1 avoid opioids (use non-opioids) or
2
use opioids of a different
chemical class with
close monitoring.
Morphine derivatives
Morphine derivatives Morphine Hydro/oxycodone Hydro/oxymorphine Butarphanol Nalbuphine Pentazocine
Phenylpiperidines
Phenylpiperidines
Fentanyl Sufentanil Remifentanil Alfentanil Pethidine
Diphenylheptanes
Diphenylheptanes
Methadone
Propoxyphene
