2.3 b Opioid Derivatives and Non Opiod

Question 1

Diamorphine

What is it

How it is metabolised
to what

Answer 1

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.

Question 2

What drug is the effective

How potent is it

diacetylmrphine

Answer 2

Its analgesic action is then mediated by morphine.

Because it has two morphine molecules,
it is twice as potent.

Question 3

Diamorphine

Lipid solubility vs morphine (vs fentanyl)

Answer 3

It has higher lipid solubility than morphine

(but lower than fentanyl/ sufentanil).

Question 4

Diamorphine

Lip solubility affect its administration

1st pass metab

Answer 4

This makes it particularly well suited
for subcutaneous administration.

Orally, it has a high first-pass metabolism.

Question 5

Diamorphine

Intrathecal duration

How does the affect side effect

Answer 5

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.

Question 6

Diamorphine ?drug of abuse

Answer 6

As it causes high euphoria,
it is a drug of abuse
(street name is heroin).

Question 7

Methadone

Lipid solubility

1st pass

PO bioavailability

protein binding

Answer 7

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%)

Question 8

Methadone

How is it metabolised

Duration of action

How is this useful

Answer 8

and it undergoes rapid
N-demethylation to inactive metabolites.

It has a longer duration of action (30 hours),

hence prevents withdrawal reactions.

Question 9

What is its MOA

How is this useful

Answer 9

It is an NMDA antagonist,

and has been found useful
in many opioid resistant
chronic pain states.

Question 10

Codeine

Is it prodrug

Potency of Morphine?

Answer 10

Codeine

It is methylmorphine
(prodrug)

Has one-tenth the potency of morphine.

Question 11

Codeine

PO avail

other route?

Dose

What route is avoided + why (d/t)

Answer 11

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).

Question 12

Codeine

Metabolism

Answer 12

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%).

Question 13

Codeine

Is there any genetic variations

How does this affect

Is there any drug that displays same

Answer 13

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.

Question 14

Positive side effect Codeine

Main adverse

Is there a compound drug twice as potent

Answer 14

It is a potent antitussive, with constipation being its main adverse effect.

Dihydrocodeine is twice as potent.

Question 15

Tramadol

Type of drug
acts on ?strength

Answer 15

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).

Question 16

Tramadol

Other hormone / Neurochemical effects

How does this produce analgesia

Answer 16

It is a
norepinephrine
serotonin reuptake inhibitor

producing analgesia by
enhancing descending
inhibitory pathways

(which need NE and 5-HT for stimulation)

Question 17

Tramadol what is the risk of MOA causes

+ caution with what drugs

Answer 17

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.

Question 18

Tramadol

PO bioavailability

How is it metabolised

via what enzyme

is there any issue with this type of breakdown

Answer 18

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.

Question 19

Tramadol

Do opioids cause shivering

What is the most limiting S/E of Tramadol
what mechanism
how rx

Abuse potential high?

Answer 19

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

Question 20

Pethidine

Type of drug

Lipid solubility
How does this affect where its commonly used

Answer 20

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.

Question 21

Pethidine

Potency V Morphine

What is it broken down to
% activity
How is this metabolite excreted

Answer 21

One-tenth the potency of morphine.

Metabolised to norpethidine

(active metabolite with 50% activity)

which can accumulate in renal failure

Question 22

Fentanyl

Potency v Morphine

Lipid solubility

How does this affect its intrathecal admin + S/E

Answer 22

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.

Question 23

Fentanyl
Why used Paeds

Whats metabolised to
% activity

Answer 23

Useful in paediatrics due to its shorter action than morphine.

Metabolised to inactive norfentanyl.

Question 24

Alfentanil:

Potency V Morphine

Answer 24

Ten times the potency of morphine.

Question 25

Alfentanil:

Compare it to fentanyl

• Lipid solubility
• pKa (fraction unionised drug)
• speed onset

Answer 25

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.

Question 26

Remifentanil:

How administered

Intrathecal use?
Why

Answer 26

Used as an infusion only.

Not used intrathecally
(as commercial preparation has glycine).

Question 27

Remifentanil:

Metabolism

Context sensitive t1/2

does it accumulate?

Answer 27

Metabolised by ester hydrolysis,

having a context-sensitive half-life of
4 minutes.

Hence does not accumulate
despite prolonged infusions.

Question 28

Remifentanil

Problem with use for analgesia intra op

Answer 28

However, analgesia does not
continue post-operatively,

and a morphine bolus is required
at the end of surgery for
postoperative analgesia.

Question 29

Naloxone:

What is it
at which receptor

What type of compound

Answer 29

It is an opioid receptor antagonist

at all three receptors.

It is an N-allyl derivative of oxymorphone.

Question 30

Naloxone:

What is its use?

What is its onset and duration

Issues with reversal
what patient group is very susceptible

Answer 30

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.

Question 31

Paracetamol:

Uses

Where does it affect PG

Answer 31

It is a weak analgesic,
antipyretic
very weak anti-inflammatory.

It inhibits CNS prostaglandin synthesis.

Question 32

Dose Paracetamol

is it more or less effective v morphine when combined with weak opioid

Answer 32

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.

Question 33

What’s propacetamol

Answer 33

Propacetamol is the prodrug form of paracetamol (intravenous
formulation). The intravenous formulation is more effective than the
oral.

Question 34

How is Paracetamol metabolised

To what

How is this broken down

Answer 34

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).

Question 35

What does this lead to in paracetamol OD

How is this Rx

Answer 35

hence paracetamol overdose results
in glutathione depletion
and consequent hepatotoxicity.

This can be treated with

methionine
(promotes glutathione synthesis)

Question 36

NSAIDs:

How do they work

Role of X involved in analgesia

Answer 36

act by reversible
cyclooxygenase (COX) inhibition.

2 isoenzymes

COX-2: inducible.
Expressed at the
site of injury in
response to inflammation.

Question 37

NSAIDs

Role of COX 1

Answer 37

Two isoenzymes are found:

COX-1: 
constitutively expressed in kidneys 
(prostaglandin production
for maintenance of 
renal blood flow) 

and

gastric mucosa
(protection against acidity).

Question 38

NSAIDs

Protein binding

Vd

Answer 38

They have high protein binding
and
low volume of distribution.

Question 39

Adverse effects:

x7

Answer 39

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).

Question 40

Selective COX 2 Inhibitors

Do they reduce side effects?

Do they have an serious S/E

Answer 40

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).

Question 41

Selective COX 2 Inhibitors

5 examples and are they in use?

Answer 41

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.

Question 42

How does one deal with a true opioid allergy and analgesia

Answer 42

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.

Question 43

Morphine derivatives

Answer 43

Morphine derivatives 
Morphine
Hydro/oxycodone
Hydro/oxymorphine
Butarphanol
Nalbuphine
Pentazocine

Question 44

Phenylpiperidines

Answer 44

Phenylpiperidines

Fentanyl
Sufentanil
Remifentanil
Alfentanil
Pethidine

Question 45

Diphenylheptanes

Answer 45

Diphenylheptanes

Methadone
Propoxyphene