Pathways

Cocaine is a local anaesthetic used for diagnostic procedures or surgery on or through the nasal cavity. It is administered as a spray in the nose where it enters the blood vessels of the nose and travels through the body. When taken illicitly it is snorted through the nose and enters through the same blood vessels. Cocaine is metabolized in hepatic liver cells. Cocaine diffuses through the liver membrane. On the endoplasmic reticulum membrane it is metabolized by cytochrome P450 3A4 into norcocaine. It is also predicted by biotransformer to metabolize by cytochrome P450 1A2 into benzoylecgonine. Both of these metabolites are inactive and the main metabolite when cocaine is taken on its own. When cocaine is taken with alcohol however, it metabolizes into the active metabolite cocaethylene by the hepatic enzyme carboxylesterase in the endoplasmic reticulum lumen. Norcocaine, benzoylecogonine, and cocaethylene all diffuse through the hepatic cell membrane into the blood where they travel to the kidney and are excreted renally. However, cocaethylene is an active metabolite that is much more toxic than cocaine and has a higher affinity for dopamine re-uptake receptors, and therefore will activate similar pathways to cocaine. It takes much longer for it to be excreted renally than cocaine. Cocaethylene is often fatal.

Cocaine is a local anesthesia and vasoconstrictor that is clinically used during diagnostic proceedures or during surgery in or through the nasal cavity. It comes in drugs called Goprelto and Numbrino which comes as a nasal spray. In these clinical drugs it takes the form of cocaine hydrochloride. The illicit drug has the same effects. It primarily acts on sensory neurons in the nasal cavity, but also inhibits dopamine, serotonin, and norepinephrine re-uptake channels. Cocaine inhibits the sodium-dependent noradrenaline channel which causes norepinephrine to accumulate in the synapse. The high concentration of norepinephrine readily activates both alpha adrenergic receptors in the smooth muscles of blood vessels. This, through the Gq signalling cascade, leads to vasoconstriction of blood vessels especially in the nose. This also causes higher heart rate and higher blood pressure, due to vasoconstriction, in the rest of the body as seen in the norepinephrine subpathway.

Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Codeine's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.

Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Codeine's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.

Codeine is an opioid agonist used for analgesia (pain-relief) and sedation similar to other opioid derivatives like morphine, methadone, fentanyl, hydrocodone and oxycodone. Codeine, like morphine is derived from the poppy plant, Papaver somniferum. Codeine is usually administered orally but can also be given subcutaneously or intramuscularly. When taken orally, it is absorbed through the GI tract into the bloodstream where it travels to the liver to be converted to morphine via P450 enzymes. The morphine that is produced from the conversion goes back into the blood where it will travel to the brain and cross the barrier to gain access to receptors on neurons. Opioids like codeine and morphine are agonists of all opioid receptors (mu, delta, and kappa), but codeine/morphine is more selective for the mu opioid receptor. Morphine will bind to mu opioid type receptors on pre-synaptic neurons. Morphine can also bind to post-synaptic neurons as well adding on to it's overall effects. On pre-synaptic mu opioid receptors, it will cause activation of them triggering inhibition of voltage gated N-type calcium channels adenylyl cyclase. Less calcium influx into the cell reduces neurotransmitter release into the synaptic cleft reducing neuronal transmission. Inhibiting adenylyl cyclase stops the conversion of ATP into cyclic AMP (cAMP) which has affects of analgesia. The mu opioid receptor activates the potassium inward rectifier channel (GIRK) moving more potassium out of the neuron hyperpolarizing the membrane potential. This makes action potentials much harder to achieve as the membrane potential is more negative. Through these effects, codeine reduces neuronal transmission of pain signals into the spinal chord and therefore less pain is perceived. Codeine has many sites of action where it can act on mu opioid receptors. It can act at the periphery to reduce neurogenic inflammation, the cingulate cortex altering the psychological response to pain, A delta and C pain fibres in the dorsal horn of the spinal chord and in the periaqueductal gray/rostral ventral medulla in the descending pain pathway that projects to the substantia gelatinosa. The inhibition of A delta and C pain fibres in the dorsal horn of the spinal chord is very important as it slows the signalling of pain into the spinal chord. Codeine can be used for treating coughing and mild to severe pain. Codeine due to euphoric, tranquil, sedative effects and addictive nature is/can be abused by patients or users who take the drug if not guided by a medical professional. Overdoses of codeine can lead to respiratory depression and eventual death.