FENTANYL

Chemical Properties

Pale Brown Solid

Originator

Fentanyl,Janssen,W. Germany,1963

Uses

Used as an analgesic. Controlled Substance

Uses

Fentanyl is available in a variety of preparations for parenteral, transdermal and transmucosal (including buccal) administration. Because of high firstpass metabolism (~70%) it is not given orally. It is approximately 80–100 times more potent than morphine in the acute seing, although it is approximately 30–40 times as potent when given chronically (e.g. slowrelease transdermal patches). With transdermal administration, the patch and underlying dermis act as a reservoir, and plasma concentration does not reach steady state until approximately 15h after initial application. Plasma concentration also declines slowly after removal (t1/2 ~15–20 h).
Fentanyl is very lipophilic, with a relatively short duration of action. There are several new buccal/transmucosal preparations developed for rapid-onset breakthrough pain. These aim to have a very rapid onset in approximately 10min, although this may not be the case in clinical practice. Fentanyl has a large VD with rapid peripheral tissue uptake, limiting initial hepatic metabolism. This may result in significant variability in plasma concentrations and secondary plasma peaks. It binds to αl-acid glycoprotein and albumin; 40% of the protein-bound fraction is taken up by erythrocytes. The lungs may be important in exerting a first-pass effect on fentanyl (up to 75% of the dose), thus buffering the plasma from high peak drug concentrations.

Definition

ChEBI: The carboxamide resulting from the formal condensation of the aryl amino group of N-phenyl-1-(2-phenylethyl)piperidin-4-amine with propanoic acid.

Manufacturing Process

To the stirred solution of 5 parts of N-(4-piperidyl)propionanilide, 6.85 parts sodium carbonate, 0.05 part potassium iodide in 120 parts hexone is added portionwise a solution of 3.8 parts β-phenylethyl chloride in 24 parts 4- methyl-2-pentanone. The mixture is stirred and refluxed for 27 hours. The reaction mixture is filtered while hot, and the filtrate is evaporated. The oily residue is dissolved in 160 parts diisopropyl ether and the solution is filtered several times until clear, then concentrated to a volume of about 70 parts. The residue is then cooled for about 2 hours at temperatures near 0°C to yield N- [1-(β-phenylethyl)-4-piperidyl]propionanilide, melting at about 83° to 84°C as described in US Patent 3,141,823.
The starting material is prepared by reacting 1-benzyl-4-piperidone with aniline, reducing the condensation product with lithium aluminum hydride, reacting the product thus obtained with propionic anhydride, then hydrogen.

brand name

Duragesic (ALZA).

Therapeutic Function

Narcotic analgesic

General Description

When the 4-phenyl substituent of meperidine was replaced with a 4-aniline with a nitrogen connection, the potency increased. This led to the development of the 4-anilidopiperidine series of compounds. Fentanyl (Sublimaze) was the first compound marketed and was found to be almost 500 times more potent than meperidine. The high lipophilicity of fentanyl gave it a quick onset, and the quick metabolism led to a short duration of action. The combination of potency, quick onset, and quick recovery led to the use of fentanyl as an adjunct anesthetic.

Hazard

Toxic.

Clinical Use

Fentanyl (Sublimaze) and its related phenylpiperidine derivatives are extremely potent drugs.They are used as adjuncts to anesthesia, and fentanyl may be given transdermally as an analgesic and as an oral lozenge for the induction of anesthesia, especially in children who may become anxious if given IV anesthesia.
Fentanyl is 80 to 100 times as potent as morphine. Sufentanil (Sufenta) is 500- to 1,000-fold more potent than morphine, while alfentanil (Alfenta) is approximately 20 times more potent than morphine. Their onset of action is usually less than 20 minutes after administration. Dosage is determined by the lean body mass of the patient, since the drugs are lipophilic and tend to get trapped in body fat, which acts as a reservoir, prolonging their half-life. In addition, redistribution of the drugs from the brain to fat stores leads to a rapid offset of action. Droperidol, a neuroleptic agent, is generally administered in combination with fentanyl for IV anesthesia.
Fentanyl transdermal patches are available for analgesia in chronic pain and for postsurgical patients. The use of the patch is contraindicated, however, for patients immediately after surgery because of the profound respiratory depression associated with its use. The patches must be removed and replaced every 3 days. The onset of action of transdermal fentanyl is slower than that of oral morphine. Thus, patients may require the use of oral analgesics until therapeutic levels of fentanyl are achieved. Fentanyl lozenges have been used to induce anesthesia in children and to reduce pain associated with diagnostic tests or cancer in adult patients. However, all of the adverse side effects associated with morphine are produced with far greater intensity, but shorter duration, by fentanyl in the patch, the lozenge, or IV administration. Given the abuse liability of fentanyl, controversy exists as to the ethics of marketing a lollipop lozenge form.
Sufentanil is much more potent than fentanyl and is indicated specifically for long neurosurgical procedures. In such patients, sufentanil maintains anesthesia over a long period when myocardial and cerebral oxygen balance are critical.

Side effects

In addition to all of the adverse effects and contraindications previously described for morphine, the following contraindications apply specifically to these drugs. They are contraindicated in pregnant women because of their potential teratogenic effects. They also can cause respiratory depression in the mother, which reduces oxygenation of fetal blood, and in the newborn; the incidence of sudden infant death syndrome (SIDS) in the newborn is also increased.
Cardiac patients need to be monitored closely when receiving these drugs because of their bradycardiac effects (which can lead to ectopic arrhythmias), and hypotensive effects resulting from prolonged vasodilation. In addition, the drugs stiffen the chest wall musculature, an effect reversed by naloxone.

Safety Profile

Poison by intraperitoneal routes. Human systemic effects by intravenous route: somnolence, respiratory depression. When heated to decomposition it emits toxic fumes of NOx.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: metabolism increased by rifampicin.
Antidepressants: possible CNS excitation or depression (hypertension or hypotension) in patients also receiving MAOIs (including moclobemide) - avoid concomitant use; possibly increased sedative effects with tricyclics.
Antifungals: concentration increased by triazoles.
Antihistamines: increased sedative effects with sedating antihistamines.
Antipsychotics: enhanced hypotensive and sedative effects.
Antivirals: concentration increased by ritonavir; increased risk of ventricular arrhythmias with saquinavir - avoid.
Cytotoxics: use crizotinib with caution.
Dopaminergics: avoid with selegiline.
Sodium oxybate: enhanced effect of sodium oxybate - avoid concomitant use

Metabolism

Fentanyl is metabolised in the liver by N-dealkylation and hydroxylation via the cytochrome P450 isoenzyme CYP3A4. Metabolites and some unchanged drug are excreted mainly in the urine. The short duration of action is probably due to rapid redistribution into the tissues rather than metabolism and excretion. The relatively longer elimination half-life reflects slower release from tissue depots.The main metabolites of fentanyl, which are excreted in the urine, have been identified as 4-N-(N-propionylanilino) piperidine and 4-N-(Nhydroxypropionylanilino) piperidine; 1-(2-phenethyl)- 4-N-(N-hydroxypropionylanilino) piperidine is a minor metabolite. Fentanyl has no active or toxic metabolites.