Naloxone Hydrochloride

This is a curated page. Report corrections to Microbewiki.

Pharmacology of Naloxone Hydrochloride

Figure 1:Standard Naloxone administration set with a pre-filled syringe with 2mg of naloxone in 2ml of saline. [http://www.wbal.com/article/113090

Naloxone hydrochloride, known by the brand name Narcan, is an opiate antagonist medication used primarily to reverse or lessen the effects of an opiate overdose. It was first synthesized in 1982 by Jack Fishman of Rockefeller University. Later that year, Harold Blumberg of New York Medical College, found that the newly synthesized drug was a “potent, rapid-acting, and relatively pure narcotic antagonist. ”. When delivered into the blood stream it travels to the brain. Naloxone’s hydrophilic properties allows it to easily cross the blood brain barriers where it can make its way to the opiate receptors of the brain and, due to its high affinity for the opiate receptors it outcompetes opiates and binds to the receptors. The three opioid receptors are the mu, kappa and delta receptors. They all have analgesic (pain relieving) properties when activated however the mu receptor also causes respiratory depression. This is important for naloxone because it has the highest affinity for the mu receptor. In a person with any levels of opiates, whether naturally or artificially there, naloxone will prevent those opiates from binding and affecting the opiate receptors. This in turn stops any symptoms of an opiate overdose, and thus the reason for its use in overdoses. Naturally occurring opiates come in the form of endorphins in your body. They are vitally important to short term survival in critical situations. Endorphins will bind to the opioid receptors and create a temporary effect by blocking pain. They are released following injury and can give a person time to remove them selves from a dangerous situation. The effect of endorphins is short lived and they eventually detach from the receptor and pain ensues. This is why you often don’t feel pain immediately after getting injury. When there is no presence of opiates in the brain naloxone will continue to bind to the opiate receptors, however it won’t have any symptomatic effects either positively or negatively. This is due to the fact that it is a pure opioid receptor antagonist. This means that it has no agonist effect, which in this case would be an analgesic effect seen by opiates. Earlier opioid receptor antagonists, like nalorphine, had antagonistic effect on one of the receptors but had an agonist effect on another making it inefficient at treating overdoses. Again for this reason naloxone is an ideal medication for opiate overdoses, because even if it is not an opiate overdose there is no adverse effects of giving the medication. This unique pharmacological effect had lead to the universal adaptation of the use of naloxone in any person with suspected opiate overdose.

Opiate Receptors and Signs of an Overdose

Figure 2: Opiate 7-Transmembrane G-Protein Coupled Receptor which when activated inhibits neurotransmitter release. [http://ceaccp.oxfordjournals.org/content/5/1/22.full

The opiate receptors are 7-Transmembrane G-Protein Coupled Receptors (GPCR), outlined in Figure 2. When the ligand (opiate) binds to the receptor on the transmembrane protein it causes an exchange of GDP for GTP on the alpha subunit of the protein, which causes both the alpha and beta subunit to disassociate from the receptor protein. This disassociation has three effects. The first is the closing of voltage sensitive Ca2+ channels. The second is the pumping out of K+. This hyperpolarizes the neuron. The third step is the inhibition of anenalyte cyclase, which prevents the conversion of ATP to cyclic adenosine monophosphate (cAMP). cAMP is an important secondary cell signaling molecule. All of this contributes to a reduction in function of the cells by not allowing the release of neurotransmitters, which are vital to cell signaling and transmission of a signal. When the GTP is hydrolyzed into GDP the alpha and beta subunits reassemble and rebind to the receptor protein and the ligand disassociates and the signal given by the opiate G-Protein Coupled Receptor is terminated. The inhibition of neurotransmitters in neurons is what gives opiates its analgesic or pain relieving effects. When an excess of opiates are taken there is an effect on breathing due to the lack of the ability of neurons to detect changes in CO2 levels due to dampening of signals passed on by carbon dioxide chemoreceptors. What kills persons from an opiate overdose is respiratory depression leading to respiratory arrest and then cardiac arrest. The signs of current opiate overdose are known as the “opiate overdose triad”. Those three symptoms are pinpoint pupils, unconsciousness, and respiratory depression. Left untreated this will lead to death..

Section 2

Include some current research, with at least one figure showing data.

Section 3

Include some current research, with at least one figure showing data.

References

[1] Hodgkin, J. and Partridge, F.A. "Caenorhabditis elegans meets microsporidia: the nematode killers from Paris." 2008. PLoS Biology 6:2634-2637.

Authored for BIOL 291.00 Health Service and Biomedical Analysis, taught by Joan Slonczewski, 2016, Kenyon College.