| Indication |
For the treatment of cancer patients with severe pain that breaks through their regular narcotic therapy. |
| Pharmacodynamics |
Fentanyl is an opioid analgesic. Fentanyl interacts
predominately with the opioid mu-receptor but also binds to kappa and
delta-type opioid receptors. These mu-binding sites are discretely
distributed in the human brain, spinal cord, and other tissues. In
clinical settings, Fentanyl exerts its principal pharmacologic effects
on the central nervous system. Its primary actions of therapeutic value
are analgesia and sedation. Fentanyl may increase the patient's
tolerance for pain and decrease the perception of suffering, although
the presence of the pain itself may still be recognized. In addition to
analgesia, alterations in mood, euphoria and dysphoria, and drowsiness
commonly occur. Fentanyl depresses the respiratory centers, depresses
the cough reflex, and constricts the pupils. |
| Mechanism of action |
Opiate receptors are coupled with G-protein receptors and function
as both positive and negative regulators of synaptic transmission via
G-proteins that activate effector proteins. Binding of the opiate
stimulates the exchange of GTP for GDP on the G-protein complex. As the
effector system is adenylate cyclase and cAMP located at the inner
surface of the plasma membrane, opioids decrease intracellular cAMP by
inhibiting adenylate cyclase. Subsequently, the release of nociceptive
neurotransmitters such as substance P, GABA, dopamine, acetylcholine and
noradrenaline is inhibited. Opioids also inhibit the release of
vasopressin, somatostatin, insulin and glucagon. Fentanyl's analgesic
activity is, most likely, due to its conversion to morphine. Opioids
close N-type voltage-operated calcium channels (OP2-receptor agonist)
and open calcium-dependent inwardly rectifying potassium channels (OP3
and OP1 receptor agonist). This results in hyperpolarization and reduced
neuronal excitability. |
| Absorption |
Bioavailability is 92% following transdermal administration and 50% following buccal administration. |
| Volume of distribution |
- 3 to 8 L/kg [Surgical Patients]
- 0.8 to 8 [Hepatically Impaired Patients]
|
| Protein binding |
80-85% |
| Metabolism |
Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. |
| Route of elimination |
Fentanyl is metabolized primarily via human cytochrome P450 3A4
isoenzyme system and mostly eliminated in urine. Within 72 hours of IV
fentanyl administration, approximately 75% of the dose is excreted in
urine, mostly as metabolites with less than 10% representing unchanged
drug. |
| Half life |
7 (range 3-12) hours |
| Clearance |
- 27 – 75 L/h [Surgical Patients receving IV administration]
- 3 – 80 L/h [Hepatically Impaired Patients receving IV administration]
- 30 – 78 L/h [Renally Impaired Patients receving IV administration]
|
| Toxicity |
Fentanyl has an LD50 of 3.1 milligrams per kilogram in rats, and,
0.03 milligrams per kilogram in monkeys. The LD50 in humans is not
known. |
