22. Opioids Flashcards
What is the difference between an opiate and an opioid?
The term opiate refers to naturally
occurring compounds
that are derivatives of opium,
which have morphine-like properties.
Opium comes from the sap
of the opium poppy,
and examples of opiates
are morphine and codeine.
An opioid is a synthetic substance
that stimulates the opioid receptor,
e.g. fentanyl and alfentanil.
How do opioids exert their effects?
Opioids work by stimulating presynaptic
Gi-protein-coupled opioid receptors.
Binding of the ligand causes the following events:
> Closure of voltage-gated Ca2+ channels
> Decreased cAMP production
> Stimulation of K+ efflux from the cell
> Hyperpolarisation of the cell membrane.
> This leads to decreased
excitability of the cell and therefore decreased
neurotransmitter release and pain transmission.
Classify the opioid receptors.
There are four main types of opioid receptor,
and some of these have subtypes.
The receptors were named for the
process through which they were discovered:
> μ receptor (subtypes μ1, μ2, μ3):
morphine was used to identify it
> κ receptor (subtypes κ1, κ2, κ3):
ketocyclazocine was used to identify it
> δ receptor (subtypes δ1, δ2):
found in the vas deferens of mice
> NOP receptor:
nociceptin orphanin
FQ peptide receptor
(most recently identified).
The accepted nomenclature for these receptors
is now MOP (μ), KOP (κ), DOP (δ) and NOP (N/OFQ), as decided by the International Union of Pharmacology (see Table 22.1).
What is tolerance?
why does it occur
Tolerance refers to a decreasing response
to repeated dosing of a drug.
Over time, a larger dose is
needed to produce the same effect.
There are two theories as
to how this develops:
either because of receptor downregulation
or because with repeated doses of opioid
there is uncoupling of the receptor from its G protein.
Morphine seems to cause uncoupling,
but not down-regulation of its receptors.
Table 22.1 Opioid receptor classification
Receptor type Location Action when stimulated
MOP Brain – especially areas
involved with
sensory and motor perception
and integration. Abundant in
periaqueductal grey.
Spinal cord
μ1
> Analgesia
> Physical dependence
μ2 > Respiratory depression > Reduced peristalsis > Euphoria > Meiosis
DOP
Brain
> Analgesia
> Antidepressant
> Physical dependence
KOP
Brain
Spinal cord
> Spinal analgesia
Sedation
Meiosis
NOP
Brain
Spinal cord
> Anxiety
Depression
Affects learning and memory
Involved in tolerance
> Natural ligand may set body’s pain threshold, and so administration of an agonist may mean less MOP agonism is needed to achieve pain relief.
What is dependence?
What is addiction?
A physically dependent patient will need
to repeatedly administer the drug
to avoid suffering from withdrawal symptoms.
Addiction is characterised by the patient’s behaviour resulting from their dependence.
An addict will: > Crave and seek out the drug > Have no control over their drug use > Use the drug compulsively > Continue to use the drug even if it is causing them harm.
What are the symptoms of opioid withdrawal?
Symptoms include:
> Anxiety and fear
> Adrenergic hyperactivity
> Malaise
> Abdominal cramps
> Sweating
> Yawning
How will you manage postoperative pain control in an opioid-dependent patient?
When treating dependent patients,
their baseline pre-existing opioid
dosage should be continued
and
additional pain relief should be
administered as required.
The patient will be tolerant to
opioids and so may need more
than the ‘average patient’ to
achieve pain relief.
For this reason pethidine should be avoided
as large doses may cause the
proconvulsant metabolite
nor-pethidine to accumulate.
It is sensible to include simple analgesia and regional techniques where possible.
If the patient is on a methadone programme, ascertain their daily requirements and continue this dosage perioperatively.
If the patient is abstinent,
they may be reluctant to use opioids
for pain relief,
but there is no evidence to suggest that the appropriate use of
opioids will precipitate a relapse.
MORPHINE
Preparation
Doses
Use
MORPHINE
Naturally occurring opiate
- Tablets: 5/10/30/60/200 mg
- Syrup: 2/10/20 mg/mL
- Suppository: 15/30 mg
• Solution: 10/15/30 mg/mL for
IV and neuro-axial use
NB preservative free for
neuro-axial use
DOSE • Oral: 5–40 mg/4 hourly • Rectal: 15–30 mg/4 hourly • IV: 0.05–0.1 mg/kg/4 hourly • IM/SC: 0.1–0.2 mg/kg/4 hourly • Intrathecal 0.1–1 mg • Epidural 1–5 mg
USES • Analgesia • Sedation on ITU • Palliative care • CCF
Morphine MOA
MOA
• Agonist at MOP and KOP
G-protein coupled opioid
receptors
- Binding of the ligand causes the following events:
- Closure of voltage-gated Ca2+ channels
- Decreased cAMP production
- Stimulation of K+ efflux from the cell
• Hyperpolarisation of the cell membrane
and
decreased excitability of cell decreasing
neurotransmitter release and pain transmission
CHEMICAL PROPERTIES
- Naturally occurring phenanthrene derivative
- Weak base, pKa 8.0 ionised in stomach
Morphine
A
D
M
E
METABOLISM
AND EXCRETION
• Hepatic metabolism to:
• morphine-3- glucuronide (inactive)
and
• morphine-6- glucuronide
(active with 13x potency of morphine)
• Excreted in urine
• Neonates have ^^ sensitivity,
because of immature hepatic metabolism
• Dose with care in liver impairment
ABSORPTION/
DISTRIBUTION
• Well absorbed orally (from small bowel as
ionised in stomach)
- Extensive first-pass metabolism
- Oral bioavailability at 15–20%
- 20–40%PPB
- VD 3.4–4.7 L/kg
- Low lipid solubility
- Peak effect 10–30 min, duration 3–4 hours
EFFECTS Morphine
CVS
• No direct effects
• If histamine release occurs, may cause
hypotension
• Mild bradycardia secondary to \/ sympathetic tone
RS
• Dose dependent
respiratory depression
(\/ RR > \/ VT)
- \/ Sensitivity to pCO2
- Antitussive
- Bronchospasm with histamine release
CNS
- Analgesia
- Sedation
- Euphoria
- Hallucinations
- Meiosis: Edinger-Westphal nucleus
- Seizures and muscular rigidity with high dose
GI
• ↓ Motility
• ↓ Gastric acid, pancreatic and bile secretion
• Nausea and vomiting: CTZ stimulation
via 5-HT3 and dopamine receptors
GU
• Inc Tone in uterus, bladder detrusor and sphincter
muscles – can cause retention
SKIN
- Pruritis
- Rash
ENDO • ↓ ACTH • ↓ Gonadotrophic hormones • Inc ADH causing hypernatraemia and water secretion
DIAMORPHINE
- Tablets: 10 mg
- Powder: 5/10/30/100/500 mg vials
DOSE
- 2.5–5 mg IV for pulmonary oedema/MI
- 0.1–0.4 mg intrathecally
- 1–3 mg epidurally
- Can give SC as very lipid-soluble
MOA
• Metabolites act at MOP or KOP receptors
• Diamorphine itself has no affinity
for opioid receptors
CHEMICAL PROPERTIES
• Synthetic diacetylated morphine derivative
• Prodrug
METABOLISM
AND EXCRETION
• Hydrolysed by plasma enzymes
and by RBCs,
(probably by esterases and
pseudocholinesterases)
to 6-O-acetylmorphine,
the active form of the drug
- 6-O-acetylmorphine glucuronidated to morphine
- 50–60% excreted in urine as morphine derivative
ABSORPTION/ DISTRIBUTION • Well absorbed • Extensive first-pass metabolism • Bioavailability low • Protein binding 40% • t½ 3 min
USES • Analgesia • Sedation on ITU • Palliative care • CCF • Drug of abuse as causes euphoria
EFFECTS • As for morphine • Thought to cause less nausea and vomiting and constipation than morphine Di
ALFENTANIL
Synthetic opiod
Dose
MOA
Synthetic opioid
• Clear colourless solution:
500 μg/mL or 5 mg/mL
DOSE
• 5–25 μg/kg
MOA
• Highly selective MOP opioid receptor agonist
CHEMICAL PROPERTIES
• Synthetic phenylpiperidine derivative
• pKa 6.5 so 87% un-ionised at pH 7.4.
derfor faster onset than fentanyl
even though < lipid soluble
• Smaller VD than fentanyl so in spite of
lower clearance its t½ is shorter
METABOLISM
AND EXCRETION
• Hepatic metabolism mostly by N-dealkylation
to noralfentanil
• Excreted in urine
ABSORPTION/
DISTRIBUTION
• Protein binding 85–92%
• VD 0.6 L/kg
USES
• Short-acting analgesic (fast onset and offset)
• Obtunding hypertensive
response to airway manipulation
• Sedation
EFFECTS
As for morphine BUT:
• 10–20x as potent
• Vagally mediated bradycardia
FENTANYL
properties
dose
preparation
Use
Synthetic opioid • Clear colourless solution: 50 μg/mL • Patches: 25/50/75/100 μg/hr lasting 72 hours • Lozenges/lollypops: 200 μg–1.6 mg over 15 min • Patient-controlled transdermal system (PCTS): 40 μg over 10 min
DOSE • As adjunct during induction of anaesthesia 1–100 μg/kg • Pain relief, 1 μg/kg, repeat • Spinal 10–30 μg • Epidural 25–100 μg dose titrating to pain
USES • Perioperative analgesia • Obtunds hypertensive response to airway manipulation • Opioid-based anaesthesia • Sedation by infusion • Chronic pain
Fentanyl
A
D
M
E
ABSORPTION/
DISTRIBUTION
- Absorbed orally, from small intestine
- Bioavailability 33%
- Protein binding 80–95%
- VD 0.88–4.41 L/kg
• Short duration of action
due to redistribution
METABOLISM AND EXCRETION
• Hepatic metabolism
• N-dealkylation to norfentanyl (inactive)
then hydroxylation and
amide hydrolysis to hydroxypropionyl derivatives
• Inactive metabolites excreted in urine
Fentanyl
EFFECTS
EFFECTS
As for morphine BUT:
- 50–80x as potent
- Less histamine release
- Decreases stress response to surgery
- Associated with bradycardia
- Chest wall rigidity with high doses
Fentanyl MOA
chem prop
pka
MOA
• Potent agonist at MOP receptor
CHEMICAL PROPERTIES
- Synthetic phenylpiperidine
- Highly lipid soluble (600x morphine)
- Highly ionised in stomach (99.9%)
- pKa 8.4 (9% un-ionised at pH 7.4)
REMIFENTANIL
Synthetic opioid
• White crystalline powder:
1/2/5 mg per vial,
reconstitute with
0.9% saline
• Give as IV infusion
DOSE
• 0.05–2 μg/kg/min
CHEMICAL PROPERTIES
• Because of rapid hydrolysis,
effect of infusion is
gone within 10 min
of discontinuation.
There is no residual analgesia
MOA
• Pure MOP opioid receptor agonist
ABSORPTION/ DISTRIBUTION
- Only given IV
- t½ 2 hours
• Effects last only 10 min from
termination of infusion
• Context insensitive half-life
METABOLISM AND EXCRETION
• Undergoes rapid ester hydrolysis
by non-specific plasma/tissue esterases
to carboxylic acid derivatives.
These are plentiful and
therefore not saturated by infusion
• Excreted in urine
USES
• Analgesia during general anaesthesia
• Hypotensive anaesthesia
• Sedation on ICU and for procedures,
e.g. awake
fibre optic intubation
EFFECTS
As for morphine BUT:
• 50–80x as potent
• Bradycardia (may be profound)
especially following bolus
PETHIDINE
Preparation
Dose
MOA
Metabolism + excretion
Absorption + Distribution
PETHIDINE
Synthetic phenylpiperidine derivative
- Tablets: 50 mg
- Solution: 10/50 mg/mL
DOSE
Adult:
• Oral: 50–150 mg 4 hourly
- IM: 25–150 mg 4 hourly
- IV: 25–100 mg 4 hourly
- Epidural: 25 mg
Child:
- Oral: 0.5–2 mg/kg
- IM: 0.5–2 mg/kg
MOA
• Agonist at MOP and KOP opioid receptors
• NB not reversed by naloxone
METABOLISM AND EXCRETION
• Hepatic metabolism by N-demethylation to norpethidine (50% as potent as parent)
then hydrolysed to pethidinic acid
• Excreted in urine, accumulates in renal failure
ABSORPTION/ DISTRIBUTION
• Oral bioavailability 50%
(subject to first-pass metabolism)
- Protein binding 50–70%
- VD 4 L/kg
- t½ 2.4–7 hours
• Crosses placenta where norpethidine accumulates in fetus. Fetal levels peak 4 hourly after maternal dosing. Fetal t½ 3x that of mother
Pethidine
Chemical properties
Uses
Effects
CHEMICAL PROPERTIES
• Nil
USES
• Analgesia especially in labour
- Antispasmodic in renal and biliary colic
- Treatment of post-operative shivering
EFFECTS
CVS
• Orthostatic hypotension
• Tachycardia secondary to anticholinergic effects
RS
• Respiratory depression
• ↓ VT > ↓ RR
• ↓ Response to pCO2 and pO2
CNS
• 1⁄10th potency of morphine
- More euphoria
- Less nausea and vomiting
- Miosis and corneal anaesthesia
GI
• Gastric stasis
• Less constipating than morphine
GU
• ↓ Ureteric tone
• /\ Amplitude of contractions of pregnancy
OTHER
- /\ ADH
- ↓ Steroid synthesis
- Severe hypertension with MAOIs
• Norpethide is proconvulsant
therefore caution in high doses
CODEINE
Prep
Dose
MOA
Chem properties
Uses
- Tablets: 15/30/60 mg
- Syrup: 5 mg/mL
- Solution for injection: 60 mg/mL
• Preparations
+
paracetamol/ibuprofen/aspirin
DOSE
• 30–60 mg 6 hourly (adults)
• 1 mg/kg 6 hourly
(children over 12 years old)
MOA
• Codeine has low affinity for opioid receptors
• 10% metabolised to morphine –
acts via MOP and KOP opioid receptors
• Antitussive effects via specific codeine receptors
CHEMICAL PROPERTIES
• Naturally occurring phenanthene alkaloid
– a methylated morphine derivative
USES • Analgesia • Antitussive • Treatment of diarrhoea/high output stomas
MISCELLANEOUS
• Withdrawn from use in children under 12 years
old,
children with sleep apnoea under 18 years
old and
breast feeding mothers because of unpredictable metabolism and
potentially fatal risk of respiratory depression.
TRAMADOL
Type
Dose
Chem Properties
MOA
Synthetic opioid
• Tablets:
50/100 mg,
standard and modified release
• Solution: 100 mg/2 mL
DOSE
• 50–100 mg 6 hourly
CHEMICAL PROPERTIES
- A synthetic opioid cyclohexanol
- Racemic mixture
MOA
• Weak agonist at all opiate receptors,
increased affinity for MOP
• Inhibits reuptake of
noradrenaline
and 5-HT
• Stimulates presynaptic release of 5-HT, so
modulates pain via
descending inhibitory pathways
NALOXONE
Type
DOse
MOA
Uses
Opioid antagonist
• Clear solution for IV use
• 0.2 or 0.4 mg/mL
DOSE
• 0.1–2 mg, titrate to effect.
Onset time 2 min,
duration 20 min
(i.e. shorter than duration of action of morphine,
so may require infusion)
MOA
• Competitive antagonist at opioid receptors
• Highest affinity for MOP
USES
• Reversal of opioid overdose
• Treatment of clonidine overdose
Codeine
A
D
M
E
METABOLISM
AND EXCRETION
• Hepatic metabolism in three ways:
- 10–20% glucuronidation to
codeine-6-glucuronide - 10–20% N-demethylation to
norcodeine - 5–15% O-demethylation to MORPHINE
• NB genetic variability with P450
enzyme CYPZD6 means resulting
dose of morphine is variable.
9% UK population and
30% of Chinese are
slow metabolisers so codeine
will not provide effective analgesia
ABSORPTION/
DISTRIBUTION
• Well absorbed
- Oral bioavailability 60–70%
- 7%PPB
- VD 5.4 L/kg
Tramadol
Metabolism and excretion
METABOLISM
AND EXCRETION
• Hepatic metabolism
- 1 active metabolite – O-desmethyltramadol
- Excreted in urine (90%) and faeces (10%)
ABSORPTION/
DISTRIBUTION
• Oral bioavailability 70–90%
- VD 4 L/kg
- t½ 5–6 hours
USES
• Analgesia
EFFECTS
As for morphine BUT:
• 1/10th potency of morphine • Less respiratory depression • Less constipation • Lowers seizure threshold, so relatively contraindicated in epileptics parents
Nalaxone
Effects
A
D
M
E
EFFECTS CVS • Hypertension • Ventricular arrhythmias RS • Pulmonary hypertension OTHER • Antalgesia
METABOLISM AND EXCRETION
• Hepatic metabolism by glucuronidation
• Excreted in urine
ABSORPTION/ DISTRIBUTION
- Oral bioavailability 90%
- Protein binding 46%
- VD 2 L/kg
