FENTANYL

Absorption

Fentanyl sublingual tablets are 54% bioavailable, transmucosal lozenges are 50% bioavailable, buccal tablets are 65% bioavailable, sublingual spray is 76% bioavailable, and nasal spray is 20% more bioavailable than transmucosal (or approximately 64% bioavailable).
Fentanyl transmucosal lozenges reach a Cmax of 0.4±0.1ng/mL for a 200μg dose and 2.5±0.6ng/mL for a 1600μg dose with a Tmax of 20-40 minutes. The AUC was 172±96ng*min/mL for a 200μg dose and 1508±1360ng*min/mL for a 1600μg dose.
Fentanyl sublingual spray reached a Cmax of 0.20±0.06ng/mL for a 100μg dose and 1.61±0.60ng/mL for an 800μg dose with a Tmax of 0.69-1.25 hours, decreasing as the dose increased. The AUC was 1.25±0.67ng*h/mL for a 100μg dose and 10.38±3.70ng*h/mL for a 800μg dose.
Fentanyl transdermal systems reached a Cmax of 0.24±0.20ng/mL with a Tmax of 3.6±1.3h for a 25μg/h dose. The AUC was 0.42±0.35ng/mL*h.
Fentanyl nasal spray reaches a Cmax of 815±301pg/mL with a Tmax of less than 1 hour for a 200μg/100μL dose. The AUC was 3772pg*h/mL.

Toxicity

Fentanyl has an intravenous LD50 of 2.91mg/kg in rats, an oral LD50 of 18mg/kg in rats and 368mg/kg in mice. The LD50 in humans is not known.
Symptoms of overdose include respiratory depression, somnolence, stupor, coma, skeletal muscle flaccidity, cold and clammy skin, pupillary constriction, pulmonary edema, bradycardia, hypotension, airway obstruction, atypical snoring, and death. In case of overdose, patients should receive naloxone or nalmefene to reverse the action of the opioids as well as supportive measures to maintain the airway or advanced life support in the case of cardiac arrest.

Description

Fentanyl is a potent, and now notorious, opioid painkiller. As much as 100 times more potent than morphine, it acts quickly, but it remains in the body for only a short time, which is why it is usually administered in a patch.
Fentanyl is an agonist of μ-opioid receptors, which control pain but also can cause euphoria and lead to addiction. It is the most widely used synthetic opioid and is on the World Health Organization’s List of Essential Medicines.
In 1959, Belgian physician Paul Janssen and co-workers at his pharmaceutical company, Janssen Pharmaceutica, synthesized fentanyl as one in a series of opioid painkillers. In the 1990s, the company introduced the fentanyl patch.
Fentanyl is a key player in the current opioid abuse epidemic in the United States. It is so potent that people who deal with overdose victims and drug dealers must wear personal protective equipment to avoid exposure to the drug. To assist these responders, manufacturers of analytical equipment have developed detection devices that?rapidly detect fentanyl and other narcotics without opening containers of the drugs.

Chemical properties

Pale Brown Solid

Originator

Fentanyl,Janssen,W. Germany,1963

The Uses of FENTANYL

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.

The Uses of FENTANYL

Used as an analgesic. Controlled Substance

Indications

Fentanyl intravenous or intramuscular injections are indicated for short term analgesia during induction, maintenance, and recovery from general or regional anesthesia. These injections are also used with a neuroleptic for premedication, induction, and as an adjunct to maintenance of anesthesia. Finally, fentanyl intravenous or intramuscular injections are used with oxygen for anesthesia in high risk patients.
Fentanyl sublingual tablets, transmucosal lozenges, buccal tablets, sublingual sprays, transdermal systems, and nasal sprays are indicated for the management of breakthrough pain in opioid tolerant cancer patients who require around the clock pain management.

Background

Fentanyl, a potent opioid agonist, was developed in the 1950s to fill a need for strong and rapid analgesia. Because of these characteristics, fentanyl is commonly used to treat chronic cancer pain or in anesthesia. Fentanyl is related to other opioids like morphine and oxycodone.
Fentanyl's high potency has also made it a common adulterant in illicit drugs, especially heroin. In 2017, 47600 overdose deaths in the United States involved some opioid (over 2/3 of all overdose deaths). Opioid overdoses kill an average of 11 Canadians daily.
Fentanyl was FDA approved in 1968.

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.

Pharmacokinetics

Fentanyl produces strong analgesia through its activation of opioid receptors. It has a duration of action of several hours and a wider therapeutic index as patients develop tolerance to opioids. Fentanyl is associated with a risk of addiction and abuse and should not be mixed with alcohol or benzodiazepines.

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 metabolized to a number of inactive metabolites. Fentanyl is 99% N-dealkylated to norfentanyl by cytochrome P450. It can also be amide hydrolyzed to despropionylfentanyl, or alkyl hydroxylated to hydroxyfentanyl which is N-dealkylated to hydroxynorfentanyl.

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.