K4ii / 17B13 / 16B12: Discuss the advantages and disadvantages of an IV infusion of fentanyl in comparison to morphine
17B13: Exam Report
Compare and contrast the pharmacology of intravenous fentanyl and morphine.
68% of candidates passed this question.
Good candidates produced a well-structured answer and highlighted the differences between the two drugs. It was important to include the dose, potency, time course of effect of both agents, and differences in pharmacokinetic and pharmacodynamic effects. Candidates should have specific knowledge of these important drugs. Many candidates failed to focus the question on intravenous fentanyl and intravenous morphine as asked. No marks were given for information about other routes of administration.
16B12: Exam Report
Compare and contrast the pharmacokinetics and adverse effects of morphine and fentanyl.
20% of candidates passed this question.
This question is best answered in a tabular form, comparing absorption, distribution, metabolism, excretion and the adverse effects.
Common omissions were lack of details on distribution, and not relating lipid solubility to effect. A description of the relative adverse effects was expected, e.g., more histamine release, less bradycardia, rather than listing similar adverse effects, e.g. respiratory depression.
Comparisons of pharmaceutics and pharmacodynamics did not attract any additional marks.
K4ii / 17B13 / 16B12: Compare and contrast Fentanyl and Morphine
Drug
Morphine
Fentanyl
Chemical
Morphine
Exogenous opioid agonist of PHENANTHRENE CLASS
Intermediate onset, long acting
Naturally occurring → 1° alkaloid of poppy
The prototype opioid agonist to which all other opioids are compared
Fentanyl
Synthetic opioid of PHENYLPIPERIDINE CLASS
Rapid acting, intermediate duration
Use
Morphine
- Analgesia
- Premed
- Palliative analgesia
Fentanyl
- Labour analgesia
- Cardiac analgesia
- Epidural analgesia
- Chronic pain – patch
Presentation
Morphine
ORAL: morphine sulphate capsules 5 – 100mg
PARENTERAL: clear, colourless solution, 10mg/mL
Physical properties
- pKa 7.9 → 76% ionised at pH 7.4
Partition coefficient 1.4 → poor lipid solubility
Fentanyl
- Partition coefficient 860 → HIGH LIPID SOLUBILITY (due to piperidine ring)
- High lipid solubility
→ Rapid onset
→ Shorter DoA
→ More potent
Dose/Route
Morphine
ORAL
- Poor OBA 30% → due to high 1st pass metabolism; used for slow release preparation → MS CONTIN (i.e. morphine sulphate controlled release)
- When converting parenteral → oral = x 3
PARENTERAL
- Subcut (palliative), IM, IV
- 1mg/kg
- PCA 1 – 2mg q5mins
EPIDURAL
- 2 – 4mg gives 24hr of analgesia
- Poor lipid solubility ∴ may take 60 mins before enters CSF for onset
INTRATHECAL
- 100 – 300mcg
- Rapid onset s/c deposited in CSF, but prolonged action 24hr & risk respiratory depression
Fentanyl
X 100 more potent than morphine
- IV analgesia = 1mcg/kg
- Blunt response to laryngoscopy = 20mcg/kg
- Surgical anaesthesia (sole agent) = 100mcg/kg
- Epidural = 50 – 100mcg
- Intrathecal = 5 – 20mcg
- Transdermal = 25, 50, 75, 100mcg/hr Q72hrs
Onset
Morphine
15 – 30mins (IV)
40 – 90 mins (IM)
Delayed because poor lipid solubility → long time to cross BBB
Fentanyl
Rapid onset → due to lipid solubility
Effect site equilibrium 4-6 mins
Short DoA 2° lipid solubility → redistributes quickly to skeletal m. & fat
CSHT
Morphine
N/A
Fentanyl
Very long
Ie 180mins at 300min infusion time
→ as duration of infusion exceeds 2hrs, it saturates the ‘inactive sites’
→ so when an infusion is terminated, the plasma [ ] cannot ↓by redistributing to these sites
→ so for plasma F to ↓ it must be eliminated by hepatic metabolism
MoA
Morphine
µOP agonist (x100 less affinity for κOP)
- µOP located throughout CNS
- µOP concentrated in periaqueductal grey matter near 4th ventricle & substantia gelatinosa of dorsal horn of SC
Gi GPCR
- Closure of voltage sensitive Ca2+ channel on presynaptic membrane → ↓intrac Ca2+
- Post synaptic stimulation of K efflux → hyperpolarisation
- Inhibition of AC → ↓cAMP
OVERALL
- ↓cell membrane excitability
- ↓transmission nociceptive signals
µ1 → supraspinal analgesia
µ2 → spinal analgesia
Fentanyl
MOP +++
kOP +
δ OP –
Gi GPCR
- Closure of voltage sensitive Ca2+ channel on presynaptic membrane → ↓intrac Ca2+
- Post synaptic stimulation of K efflux → hyperpolarisation
- Inhibition of AC → ↓cAMP
OVERALL
- ↓cell membrane excitability
- ↓transmission nociceptive signals
PD
Morphine
CNS
- Analgesia
- Sedation
- Miosis
RESP
- Ventilatory depression
- ↓CO2 responsiveness
- ↓RR & MV
- Blunts airway reflexes
CVS
- ↓SVR 2° histamine & ↓symp tone
- ↓HR due to stimulation of vagal nuclei in medulla
- May directly depress AV node conduction
GI
- N&V
- Biliary colic
- Constipation
- Delayed gastric emptying
IMMUNO
- Histamine release
- Reactivation of herpes with neuraxial administration
Fentanyl
CNS – Analgesia
CVS – ↓HR more common cf. M
RESP – respiratory depression → most marked of all opioids. POTENT ANTITUSSIVE & chest wall rigidity
GI – less N&V
IMMUNO – less histamine release
PK
Morphine
A
Poor OBA 30%
High 1st pass metabolism
D
Large 3.2L/kg
(v H2O soluble)
PPB 35%
Crosses placenta + immature neonatal BBB = neonatal depression
At peak plasma [ ] only <0.1% dose has entered CNS
Peak [ ] in biophase occurs 15 – 30 mins following IV admin
Poor CNS penetration because:
- 76% ionised at pH7.4
- Poor lipid soluble of UNIONISED %
- PPB
Rapid conjugation with glucuronic acid
M
Hepatic biotransformation
MAJOR ROUTE OF ELIMINATION
High HER 0.7
∴ high 1st pass metabolism → only 30% oral dose reaches circulation
INTRAHEPATIC GLUCURONIDATION
- Main metabolism pathway
- Conjugated with glucuronic acid
- M3G (>80%)
- M6G (<10%)
- M6G still active & more potent at µOP
EXTRAHEPATIC GLUCURONIDATION
- Esp in kidneys
DEALKYL (methyl) ATION
- Demethylated to normorphine
- <5% of dose
- Small amount CODEINE made this way
CLEARANCE
- 15mL/kg/min
- M plasma clearance exceeds Hepatic Plasma Flow
- ∴ HBF = rate limiting step for M elimination & extrahepatic metabolism must be occurring
E
<5% dose excreted unchanged
t ½ B = 180 mins; short elimination ½ life consistent with DoA 3 – 4hrs
Fentanyl
A
Transdermal patch peak plasma 18hrs (∴ not for acute analgesia)
D
4L/kg
Larger cf. M
↑lipid solubility = rapid & extensive tissue penetration
PPB 80%
Tissue affinities
- Lungs → large, inactive storage site; 75% dose = pulmonary uptake
Fat & skeletal m. → redistribution sites
M
Liver
N-Demethylation
- To norfentanyl
- Less potent cf. F
High HER
∴ depends on HBF
Half times
- Elim t ½
→ short DoA
→ Prolonged elim t 1/2, longer cf. M
→ Due to larger VD
→ F taken up to ‘inactive sites’ (lungs, fat, skeletal m) is redistributed back into plasma
E
Norfentanyl excreted by kidneys
10% unchanged
(Given in renal failure as metabolites are not pharmacologically active)
Adverse Effects
Morphine
Muscle rigidity
Ouch! Muscle spasm, colic, constipation
Resp depression
Pruritus
Histamine release & ↓BP
IDC for urinary retention
N & V
Euphoria/sedation/confusion
Illicit → tolerance/depression
Viral reactivation (neuraxial)
Fentanyl
Chest wall rigidity
Respiratory depression
Dependence
- Author: Krisoula Zahariou