| FENTANYL Basic information |
| FENTANYL Chemical Properties |
Melting point | 83-84°C | Boiling point | 466℃ | density | 1.087 | refractive index | 1.6500 (estimate) | Fp | 186℃ | storage temp. | Controlled Substance, -20°C Freezer | solubility | Practically insoluble in water, freely soluble in ethanol (96 per cent) and in methanol | pka | 8.4(at 25℃) | form | A crystalline solid | color | Crystals | Water Solubility | 0.2g/L(25 ºC) | Stability: | Hygroscopic | EPA Substance Registry System | Propanamide, N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]- (437-38-7) |
| FENTANYL Usage And Synthesis |
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. |
| FENTANYL Preparation Products And Raw materials |
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