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EDRA > 2.3 Opioids > Flashcards

2.3 Opioids Flashcards

1
Q

Draw the Steps involved in pain pathway

A

page 50/353 of regional book

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2
Q

Analgesics Sites of action / mechanism / examples

Transduction

A

Transduction:

act at the site of injury
and prevent action of
inflammatory mediators

NSAIDs
Antihistaminics
Membrane-stabilising agents
Opioids
Bradykinin and serotonin antagonists
Local anaesthetics
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3
Q

Analgesics Sites of action / mechanism / examples

Transmission

A

Transmission:

alter nerve conduction

Local anaesthetics

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4
Q

Analgesics Sites of action / mechanism / examples

Modulation:

A

Modulation:

modify spinal and supraspinal modulation

Intrathecal and epidural opioids
α2 Agonists NMDA antagonists:

ketamine,
magnesium,
tramadol

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5
Q

Analgesics Sites of action / mechanism / examples

Perception:

A

Perception:

act centrally to reduce perception

Parenteral opioids
α2 Agonists
General anaesthetics

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6
Q

Analgesics Sites of action x4

A

Transduction

Transmission

Modulation

Perception

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7
Q

Opioid receptors are what type

A

Opioid receptors are a

group of G protein–coupled receptors
with .

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8
Q

what are their ligands

A

opioids as ligands

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9
Q

Name endogenous opioids

A 
The endogenous opioids are 
dynorphins, 
enkephalins,
endorphins 
and nocioceptin.
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10
Q

Are receptors localised to central tissues

A 
Opiate receptors are 
distributed widely in the
brain, 
spinal cord 
and peripheral tissues.
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11
Q

Name the opioid receptors

A

OP1 - Kop

OP2 - Dop

OP3 - Mop

OP4 - Nop

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12
Q

Receptor Endogenous Desirable Undesirable

OP1

A

OP1
(KOP/Ќ)

Dynorphin
β- Endorphin

Analgesia

Dysphoria, psychomimetic effects, dieresis

KOP inhibits descending inhibitory pathways, hence is anti-analgesic

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13
Q

Receptor Endogenous Desirable Undesirable

OP2

A

OP2
(DOP/δ)

Enkephalin
β- Endorphin

Supraspinal and spinal analgesia,

sedation
Constipation,
physical dependence

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14
Q

Receptor Endogenous Desirable Undesirable

OP3

A

OP3
(MOP/μ)

Enkephalin
β- Endorphin

Supraspinal and
spinal analgesia,

sedation
Respiratory depression, 
bradycardia, 
miosis, 
urinary retention, 
pruritis, 
nausea and vomiting, 
constipation,
physical dependence
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15
Q

Where is MOP

A

MOP is present
in para-aqueductal grey (PAG) of brain
and
descending inhibitory control pathway,

and mediates most of the
actions of opioids.

It augments descending inhibition
(reducing pain or
providing analgesia).

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16
Q

Receptor Endogenous Desirable Undesirable

OP4

A

OP4
(NOP)

Nociception

Nil

Anti-analgesia

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17
Q

Is the sigma receptor and Opioid receptor

A

The effects of sigma (σ) receptor are
not antagonised by naloxone,

and hence this receptor is
not classified as an
opioid receptor anymore.

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18
Q

Activation of opioid receptor
by an opioid molecule produces:

3 effects

A
  1. Hyperpolarisation by K+ efflux
  2. Inhibition of Ca+ influx,
    preventing neurotransmitter release
  3. Inhibition of adenylate cyclase
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19
Q

Site and action Effects Example

Presynaptic

A

Site and action

1 Inhibition of adenylate cyclase
(needed for Ca+ influx)

2 Inhibition of Ca+ influx

3 Facilitation of K+ efflux
(hyperpolarisation)

Effects
Failure of excitatory neurotransmitter
release (glutamate) at dorsal horn

Example
KOP and NOP:
prevent Ca+ influx

MOP, DOP: facilitate
K efflux

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20
Q

Site and action Effects Example

Post-synaptic

A

Post-synaptic

Facilitation of K+ efflux
(hyperpolarisation)

Failure of action potential generation

MOP, DOP: facilitate
K+ efflux

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21
Q

Opiate refers

A 
Opiate refers to only the alkaloids 
in opium and the 
natural and 
semisynthetic derivatives 
of opium.
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22
Q

The term opioid

A

The term ‘opioid’ includes all
naturally occurring or synthetic drugs

that have stereospecific actions at
opioid receptors,
the effects of which can
be antagonised by naloxone.

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23
Q

TABLE 2.11 Classification of opioids by synthesis

Endogenous

Natural

A

Endogenous Semi-synthetic Fully synthetic Opioid-like drugs

Endorphins
Enkephalin
Dynorphine
Nociception

Morphine
Codeine
Thebaine

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24
Q

Semi-synthetic

Fully synthetic

Opioid-like drugs

A

Semi-synthetic

Heroin
Hydromorphone
Hydrocodone
Oxymorphone
Oxycodone
Buprenorphine
Dextrometharphan

Fully synthetic

Pethidine
Fentanyl
Alfentanyl 
Remifentanyl
Sufentanil

Opioid-like drugs

Tramadol

25
Q

Opioids by action @ receptor

MOP

agonist

partial

antagonist

A

MOP (μ)

Agonist
Morphine, pethidine, methadone,
fentanyl, alfentanyl,
remifentanyl sufentanil

Partial agonist
Buprenorphine

Antagonist
Naloxone
Naltrexone
Pentazocine
Nalorphine
26
Q

Opioids by action @ receptor

DOP

agonist

antagonist

A

DOP (δ)

ag
Morphine (μ > δ) Pentazocine
Nalorphine

antag
Naloxone
Naltrexone

27
Q

What is tolerance

context of opioids

A

Tolerance and dependence are induced
by chronic exposure to opioids.

Tolerance means that
higher doses of opioids
are required to
produce the same effect,

reducing the maximum response attainable.

28
Q

what is responsible for tolerance

A

It is mainly due to

receptor desensitisation.

29
Q

Does tolerance develop to adverse effects of opioids

A

Tolerance develops to most of the
adverse effects as well,

like 
dysphoria, 
itching, 
urinary retention and 
respiratory depression,
30
Q

does tolerance occur to adverse effects the same rate

is there any side effects that do not display tolerance

A

but occurs more slowly to the
analgesia and
other physical side effects.

However, tolerance does not develop to constipation or miosis.

31
Q

How is analgesic efficacy determined

A

Analgesic efficacy is determined

by calculating the
‘number needed to treat (NNT)’.

NNT is defined as the

average number of patients
who need to be treated (with analgesic drug)

to prevent one additional bad outcome
(pain).

32
Q

What is it the inverse of

A

It is defined as the inverse of the absolute risk reduction.

NNT =

                            1 \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ (proportion of patients with  at least 50% pain relief with analgesic – proportion of patients with  at least 50% pain relief with placebo)
33
Q

How can analgesics be compared

A

Various analgesics have been compared in the

Oxford league table of analgesic efficacy.

Codeine 60 mg is least efficacious,
while selective COX-2 inhibitors are most efficacious.

34
Q

Opioids and their metabolites
Drug
Morphine

Enzyme system

A

Morphine

UGT2B7

Morphine-6-glucuronide
(10% but active)
Morphine-3-glucuronide
(80% but inactive)

35
Q

Moprhine

Active metabolite

Actions

A

M6G: analgesia
M3G: hyperalgesia

36
Q

Opioids and their metabolites
Drug

Diamorphine

Enzyme system

Active metabolite

Actions

A

Diamorphine

Ester hydrolysis

6-Monoacetylmorphine (MAM)

and

morphine

Morphine is active component

37
Q

Opioids and their metabolites
Drug

Pethidine

Enzyme system

Active metabolite

Actions

A

Pethidine

CYP3A4

Norpethidine

50% analgesic action;
neurotoxicity

38
Q

Opioids and their metabolites
Drug
Codeine

Enzyme system

Active metabolite

Actions

A

Codeine

CYP2D6

Morphine, nor codeine Morphine:

analgesia

39
Q

Opioids and their metabolites
Drug
Tramadol

Enzyme system

Active metabolite

Actions

A

Tramadol

CYP2D6

O-desmethyltramadol (M1 metabolite)

Analgesia

40
Q

Inactive metabolite of fentanyl

What is proparacetamol

A

norfentanyl is an inactive metabolite of fentanyl;

propacetamol is a prodrug of paracetamol.

41
Q

Conversion of Morphine PO into diff routes / drugs

Take 10 pO

IV morphine

IM

S/C

S/C diamorphine

Periop doses +-/

A

Route Ratio (as compared to oral morphine)

Example
Oral morphine 1 : 1 30 mg

Intravenous morphine 1 : 3 10 mg

Intramuscular morphine 1 : 2 15 mg

Subcutaneous morphine 1 : 2 15 mg

Subcutaneous diamorphine 1 : 4
(as diamorphine has two molecules of morphine)
7.5 mg

Perioperative doses ± 20%

42
Q

Epidural dose of Morphine

Intrathecal

Compared to PO dose

A

Epidural dose of morphine is 1 : 10 of oral (up to 5 mg),

while intrathecal is 1 : 100 (100–200 mcg).

43
Q

Morphine Important facts

What type of pain is morphine very effective against

vs

what type less effective

A

Salient features of morphine are as follows.

Particularly effective for visceral pain,

while less effective for sharp pain.

44
Q

How does morphine cause N+V

where what receptors

A

Nausea and vomiting:

stimulation of CTZ

(5-HT3 and dopamine receptors).

45
Q

Morphine

What side effects of rapid release

by what effect

How is this reversed

A

Can cause histamine release if

administered rapidly or in large doses,

resulting in bronchospasm and hypotension;

take naloxone.

46
Q

Morphine

When do patients experience more severe pruritis

how is it mediated

How is it treated

What other meds can be used to Rx

Is there anything noveau used

A

Pruritus when given intrathecally or epidurally.

It is not histamine mediated
treated with naloxone.

Ondansetron, propofol and
antihistaminics have been used.

Recent peripherally acting antagonists
such as methylnaltrexone 
have been used to 
reverse peripheral side
effects without reversing 
centrally mediated analgesia.
47
Q

Morphine

What effect can it have on the eye

How is this mediated

How is it reversed

A

Meiosis

through stimulation of
Edinger–Westphal nucleus;

reversed by atropine.

48
Q

Morphine

How can it affect fluid balance

A

Can induce antidieresis by

increasing antidiuretic hormone secretion,

resulting in water retention and hyponatremia.

49
Q

Morphine

What affect can it have on ventilation

How is this mediated

A

Chest wall rigidity

mediated by interaction with

dopaminergic and GABAergic

pathways in substantia nigra and striatum.

Difficulty in ventilation can result following administration of opioids at induction:
take with muscle relaxants

50
Q

PK

PO

How is morphine prepared
How does this affect its absorption

How does this affect onset

Whats PO bioavail
why

A

Morphine is a weak base,
hence it is absorbed from the small bowel.

This delays absorption and results in slow onset of oral dose.

Oral bioavailability is 30% because of
high first-pass metabolism in liver.

51
Q

Morphine

IV
IM
Bioavail
Speed onset

How is absorption S/C route

Why

A

Intravenous and intramuscular
bioavailability are higher
and onset is faster
(10 and 30 minutes, respectively).

Because of low lipid solubility,
its absorption from the subcutaneous
route is slow and so is usually avoided.

52
Q

Neuraxial morphine issues

why

A

Neuraxial morphine is

associated with rostral spread

and
delayed respiratory depression.

53
Q

How is morphine metabolised

To what

What are their relative proportions

A

It is metabolised by

UGT2B7 to

active
morphine-6-glucuronide
(M6G)
(10%–30%)

and

an

inactive morphine-3-glucuronide
(M3G)
(70%– 90%).

54
Q

What is the active metabolite of morphine

What is its potency vs Morphine

How is its PK differ

What is an issue with the inactive metabolite

A

M6G is
two to four times as potent as morphine,

is more hydrophilic,
stays in the brain for a
longer period and
undergoes enterohepatic circulation.

M3G may be associated
with morphine induced
hyperalgesia

55
Q

Morphine disposition in susceptible populations
Age < 3 months

Patient group

Characteristic

Effect and implication

A

Age < 3 months

Reduced conjugation
and renal excretion ability

Prolonged duration,
so be cautious;

prefer shorter acting
opioids (fentanyl > morphine)

56
Q

Morphine disposition in susceptible populations

Patient group

Elderly

Characteristic

Effect and implication

A

Elderly

Reduced Lean mass
and hepatic blood flow

Increased sensitivity

Reduce doses

57
Q

Morphine disposition in susceptible populations

Patient group

Characteristic

Effect and implication

High body
mass index

A

High body mass index

Lean body weight < total body weight

Higher chances of obstructive sleep apnoea

Calculate doses according to lean body weight

Careful use of sedatives and opioids in view of
obstructive sleep apnoea

58
Q

Morphine disposition in susceptible populations

Liver failure

Patient group

Characteristic

Effect and implication

A

Liver failure

Reduced metabolism and
increased elimination half-life

Increased sensitivity (along with
encephalopathy)

Cautious use in small titrated doses

59
Q

Morphine disposition in susceptible populations

Patient group

Renal failure

Characteristic

Effect and implication

A

Renal failure

Accumulation of M6G metabolite
(renally excreted)

Uraemic encephalopathy may increase sensitivity

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