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

  1. Analgesia
  2. Premed
  3. Palliative analgesia

Fentanyl

  1. Labour analgesia
  2. Cardiac analgesia
  3. Epidural analgesia
  4. 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

PARENTERAL: clear, colourless, 50mcg/mL ampoule TOPICAL PATCH: 25, 50, 75, 100mcg/hr Q72hrs
  • 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