Naloxone
Synonym(s):(5α)-4,5-Epoxy-3,14-dihydroxy-17-(2-propen-1-yl)morphinan-6-one
- CAS NO.:465-65-6
- Empirical Formula: C19H21NO4
- Molecular Weight: 327.37
- MDL number: MFCD00242634
- EINECS: 207-365-7
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-03-19 15:37:50
What is Naloxone?
Absorption
An intranasal dose of naloxone is 42-47% bioavailable. An 8 mg dose of nasal naloxone reaches a Cmax of 12.3-12.8 ng/mL, with a Tmax of 0.25 hours, and an AUC of 16.7-19.0 h*ng/mL. A 0.4 mg intramuscular dose reaches a Cmax of 0.876-0.910 ng/mL, with a Tmax of 0.25 hours, and an AUC of 1.94-1.95 h*ng/mL. A 2 mg intravenous dose reaches a Cmax of 26.2 ng/mL with an AUC of 12.8 h*ng/mL.
Toxicity
If a patient has not taken opioids, naloxone does not have a significant effect on patients.
The oral LD50 in mice and rats is >1 g/kg. The intraperitoneal LD50 is 80 mg/kg in mice and 239 mg/kg in rats. The subcutaneous LD50 is 286 mg/kg in mice and 500 mg/kg in rats.
Description
It is worth mentioning that N-allylic substitution in a number of morphine derivatives, as a rule, leads to antagonistic properties. Naloxone is a few times stronger than nalorphine as an antagonist. It blocks opiate receptors. It eliminates central and peripheral action of opioids, including respiratory depression. Naloxone is used upon overdose of narcotic analgesics.
Description
Naloxone—sold primarily under the trade name Narcan—has been widely publicized as a “rescue” drug for people whose lives are in danger from opioid overdoses. But this complex multiring compound has a long history.
Naloxone, a relative of morphine, has been recognized as an opiate antagonist since the early 1960s, when Mozes J. Lewenstein and Jack Fishman patented its synthesis in the United States, and the Japanese company Sankyo (now Daiichi Sankyo) patented it in Britain, among other countries.
In 1971, the US Food and Drug Administration approved it for treating opiate overdoses by intravenous or intramuscular injection. The moribund patient often begins breathing and regains consciousness immediately.
The rapid rise in prescription painkiller and heroin overdoses in the past decade spurred practitioners to seek ways other than injection to administer naloxone. At first, people improvised devices to deliver the drug nasally, but the results were often inadequate because of improper personnel training or inconsistent dosages.
In 2012, Phil Skolnick at the National Institute on Drug Abuse and Roger Crystal, CEO of Opiant Pharmaceuticals (formerly Lightlake Therapeutics) joined forces to?develop an intranasal naloxone applicator?that would be easy to use and would supply a known amount of drug. FDA approved the device in November 2015.
In February of this year, Opiant/Lightlake’s partner Adapt Pharma began to distribute Narcan nasal spray in the 38 states where it has been approved for use without a prescription. In the meantime, the Kaléo pharmaceutical company has begun to distribute Evzio, a new naloxone autoinjector.
Originator
Narcan,Du Pont,US,1971
The Uses of Naloxone
Naloxone is a specific opioid antagonist. Narcotic antagonist.
The Uses of Naloxone
antineoplastic
Indications
Naloxone nasal sprays are indicated for the reversal of an opioid overdose or suspected opioid overdose: it is intended for immediate administration as emergency therapy in settings where opioids may be present. Intramuscular, intravenous, and subcutaneous injections are indicated for complete or partial reversal of opioid depression, diagnosis of known or suspected opioid overdose, and as an adjunct therapy in the treatment of septic shock.
Sublingual tablets and films are formulated with buprenorphine for the treatment of opioid dependence. Naloxone is also formulated with pentazocine as an oral tablet for severe pain.
Intramuscular or subcutaneous naloxone autoinjectors are used for the emergency treatment of people 12 years of age and older where the use of high-potency opioids such as fentanyl analogues as a chemical weapon, is suspected.
Naloxone has been used off-label for the treatment of neuraxial opioid-induced pruritus.
Background
Naloxone is an opioid antagonist medication used to block or reverse the effects of opioid drugs, particularly within the setting of drug overdoses which are rapidly becoming a leading cause of death worldwide. More specifically, naloxone has a high affinity for μ-opioid receptors, where it acts as an inverse agonist, causing the rapid removal of any other drugs bound to these receptors. When taken in large quantities, opioid medications such as morphine, hydromorphone, methadone, heroin, or fentanyl are capable of causing life-threatening symptoms such as respiratory depression, reduced heart rate, slurred speech, drowsiness, and constricted pupils. If untreated, this can progress to vomiting, absent pulse and breathing, loss of consciousness, and even death. Naloxone is indicated for the rapid reversal of these symptoms of central nervous system depression in opioid overdose. It's important to note that naloxone only works on opioid receptors within the body, and is therefore not capable of reversing the effects of non-opioid medications such as stimulants like methamphetamine or cocaine, or benzodiazepines like lorazepam or diazepam.
Also known as the brand name product Narcan, naloxone is currently available by intramuscular (IM) or subcutaneous (SubQ) injection, nasal spray, or intravenous (IV) infusion. Naloxone IM injections are commonly available in the form of "kits", which is ideal for making overdose treatment accessible and readily available for administration by minimally trained individuals within the community. Kits commonly include the supplies necessary to treat an overdose in a non-medical setting such as alcohol swabs, syringes, a rescue breathing mask, and instructions for use. Frequently also carried by medical and emergency personnel and at events known to be associated with heavy drug use like music festivals, naloxone kits are considered a key component of harm reduction strategies. There are over-the-counter nasal sprays available.
When injected intramuscularly (IM), naloxone acts within three to five minutes. Administration of naloxone is associated with very few side effects. Notably, if injected into a person not currently using opioid medications, there would be no noticeable effects at all. However, for individuals using opioid medications or experiencing an overdose, IM injection of naloxone rapidly reverses opioid effects and can cause the injected individual to immediately experience withdrawal symptoms. Common symptoms of opioid withdrawal include nausea, vomiting, sweating, runny nose, aches, and diarrhea. Although certainly physically uncomfortable, opioid withdrawal symptoms are not life-threatening; administration of naloxone is, therefore, appropriate for any person appearing to have any symptoms of an opioid overdose. Due to its short duration of action, persons injected with naloxone should be monitored for responsiveness and potentially injected a second time or taken to the hospital.
Naloxone is also available within the combination product Suboxone with the opioid medication buprenorphine. Suboxone is used for the maintenance treatment of opioid dependence and addiction. When taken orally, naloxone has no pharmacological effect and does not reduce the effectiveness of the opioid effect of buprenorphine. The primary purpose of including naloxone within Suboxone is to act as a deterrent to injection, as injected naloxone would rapidly reverse the effects of buprenorphine.
Naloxone was granted FDA approval on 13 April 1971.
Definition
ChEBI: A synthetic morphinane alkaloid that is morphinone in which the enone double bond has been reduced to a single bond, the hydrogen at position 14 has been replaced by a hydroxy group, and the methyl group attached to the nitrogen has been replaced by an all l group. A specific opioid antagonist, it is used (commonly as its hydrochloride salt) to reverse the effects of opioids, both following their use of opioids during surgery and in cases of known or suspected opioid overdose.
Manufacturing Process
10 grams of 14-hydroxydihydromorphinone (oxymorphone) was converted
into its diacetate by warming it on the steam bath with 80 cc of acetic
anhydride for about 2 hours. The acetic anhydride was removed on the water
bath under a vacuum of about 30 mm absolute pressure. The melting point of
the residue was 220°C. The residue was taken up in 100 cc of chloroform. An
equal amount by weight of cyanogen bromide was added and the mixture was
refluxed at about 60°C for about 5 hours. After refluxing, the mixture was
washed with 100 cc of a 5% aqueous hydrochloric acid solution, dried over
sodium sulfate and the chloroform removed by evaporation under a vacuum of
about 30 mm. The residue had a melting point of 240°C.
The residue was then heated at about 90°C for 16 hours on a steam bath with
300 cc of 20% aqueous hydrochloric acid solution, and treated with a small
amount, e.g., 1 gram of charcoal. The hydrochloric acid was then removed
under a vacuum of 15 mm, the residue dissolved in 30 cc of water and
precipitated by the addition of 2.4 cc of concentrated aqueous ammonia. The
precipitate was filtered off and dried. It consists of 14-
hydroxydihydronormorphinone. It is soluble in ethanol.
The 14-hydroxydihydronormorphinone was suspended in 200 cc of pure ethyl
alcohol, half its weight of sodium bicarbonate and half its weight of allyl
bromide added and the resulting mixture was refluxed at about 75°C for 48
hours. The solution was cooled, e.g., to 10°C and filtered and the alcohol
removed under a vacuum of 30 mm. The residue was dissolved in chloroform
and filtered. The chloroform was removed under a vacuum of 30 mm and the
residue was crystallized from ethylacetate. The crystallized product, N-allyl-
1,4-hydroxydihydronormorphinone, has a melting point of 184°C, is soluble in
chloroform and insoluble in petroleum ether. The yield amounts to 20% based
on the weight of the reacted 14-hydroxydihydromorphinone.
brand name
Narcan (Bristol-Myers Squibb); Narcan (Endo).
Therapeutic Function
Narcotic antagonist
Biological Functions
Because of its fast onset (minutes), naloxone (Narcan)
administered IV is used most frequently for the reversal
of opioid overdose. However, it fails to block some
side effects of the opioids that are mediated by the δ-
receptor, such as hallucinations. The rapid offset of
naloxone makes it necessary to administer the drug repeatedly
until the opioid agonist has cleared the system
to prevent relapse into overdose. The half-life of naloxone
in plasma is 1 hour. It is rapidly metabolized via glucuronidation in the liver and cleared by the kidney.
Naloxone given orally has a large first-pass effect, which
reduces its potency significantly. Often an overshoot
will follow the administration of naloxone for overdose.
The heart rate and blood pressure of the patient may
rise significantly. The overshoot is thought to be due to
precipitation of acute withdrawal signs by naloxone.
Given alone to nonaddicts, naloxone produces no pharmacological
effects.
Naloxone is approved for use in neonates to reverse
respiratory depression induced by maternal opioid use.
In addition, naloxone has been used to improve circulation
in patients in shock, an effect related to blockade of
endogenous opioids. Other experimental and less well
documented uses for naloxone include reversal of coma
in alcohol overdose, appetite suppression, and alleviation
of dementia from schizophrenia. Side effects of
naloxone are minor.
General Description
Naloxone (Narcan) is a pure antagonist at allopioid receptor subtypes. Structurally, it resembles oxymorphoneexcept that the methyl group on the nitrogen isreplaced by an allyl group. This minor structural change retains high binding affinity to the receptor, but no intrinsicactivity. It is used to reverse the respiratory depressant effectsof opioid overdoses.
Naloxone is administered intravenously with an onset ofaction within 2 minutes. Because it is competing with theopioid for the receptor sites, the dose and frequency of administrationwill depend on the amount and type of narcoticbeing antagonized. Overdoses of long-acting opioids(methadone) may require multiple IV doses of naloxone orcontinuous infusions. Neonates born to opioid-exposedmothers may be given IV naloxone at birth to reverse the effectsof opiates.
Very few metabolism studies on naloxone have beenconducted, although the major metabolite found in the urineis naloxone-3-glucuronide.
Pharmacokinetics
Naloxone is an opioid receptor antagonist indicated in the reversal of opioid overdoses. Naloxone has a shorter duration of action than opioids and multiple doses may be required. The therapeutic window of naloxone is wide, as it has no effect if a patient has not taken opioids. Patients treated with naloxone may experience opioid withdrawal and a person administering naloxone should be aware that reversal of opioid overdoses may not resolve all the symptoms a patient is experiencing if other drugs are involved.
Clinical Use
Naloxone has no analgesic activity. The compound
is the standard antidote to treat opioid adverse
reactions, opioid overdoses, or to stop an intended
use of an opioid compound. Typical indications
are inhibition of opioid-induced respiratory
depression, termination of opioid anesthesia
or protection of neonates following opioid
treatment during labor. Naloxone has a short
duration of action and repetitive administration
may be necessary to antagonize longer acting
agonists. To avoid parenteral misuse of nonscheduled
oral opioid formulations (tilidine,
pentazcocine), a small amount of naloxone is
added which is orally inactivated, but is fully
active after parenteral administration.
Naloxone is orally inactive and is only used
parenterally in single or repetitive doses of 0.4–
2 mg up to a total dose of 10 mg, as an intravenous
bolus injection or by infusion. The compound
is more potent against pure opioid agonists
than against mixed agonist – antagonists.
Caution should be used in opioid-dependent persons
or in persons under high-dose opioid treatment,
as naloxone may precipitate an acute withdrawal
reaction. Naloxone is relatively free of
side effects. Nausea, vomiting, and convulsions
have occasionally been reported.
Synthesis
Naloxone, (-)-17-(allyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one (3.1.92), is synthesized by the alkylation of 14-hydroxydihydronormorphinane (3.1.82) by allylbromide [55¨C58].
Metabolism
Naloxone primarily undergoes glucuronidation to form naloxone-3-glucuronide. Naloxone is also N-dealkylated to noroxymorphone or undergoes 6-keto reduction to naloxol.
Properties of Naloxone
Melting point: | 184° (Lewenstein), 177-178° (Sankyo Co.) |
Boiling point: | 465.27°C (rough estimate) |
alpha | D20 -194.5° (c = 0.93 in CHCl3) |
Density | 1.2223 (rough estimate) |
refractive index | 1.5000 (estimate) |
Flash point: | 9℃ |
storage temp. | 2-8°C |
solubility | Chloroform (Slightly, Heated, Sonicated), DMSO (Slightly), Methanol (Slightly), |
form | Solid |
pka | pKa 7.94/7.82(H2O,t =20/37,I<0.01) (Uncertain) |
color | White to Off-White |
EPA Substance Registry System | Morphinan-6-one, 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)-, (5.alpha.)- (465-65-6) |
Safety information for Naloxone
Signal word | Warning |
Pictogram(s) |
Exclamation Mark Irritant GHS07 |
GHS Hazard Statements |
H302:Acute toxicity,oral |
Precautionary Statement Codes |
P264:Wash hands thoroughly after handling. P264:Wash skin thouroughly after handling. P270:Do not eat, drink or smoke when using this product. P301+P312:IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. P501:Dispose of contents/container to..… |
Computed Descriptors for Naloxone
InChIKey | UZHSEJADLWPNLE-GRGSLBFTSA-N |
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