Pathways

Buprenorphine, trade name subutex, suboxone, zubsolv and bunavail, is a partial agonist of mu-opioid receptors and a kappa-opioid receptor antagonist and is prescribed for opioid addiction to prevent cravings and symptoms of withdrawal. The binding of these receptors causes hyperpolarization and decreased neuronal excitability. Buprenorphine has a longer duration of action due to its slow dissociation from the receptor. This long rate of action causes a long clinical effect and decreases physical dependence. Buprenorphine can also prevent opioid use by inhibiting exogenous opioid effects. This elimination of the rush from the opioid can block the reinforcing behaviour of the drug and may treat opioid addiction. Buprenorphine is available on its own or in combination with naloxone.

Buprenorphine is a partial opioid agonist used for management of severe pain that is not responsive to alternative treatments. Also used for maintenance treatment of opioid addiction. It is a weak partial mu-opioid receptor agonist and a weak kappa-opioid receptor antagonist used for the treatment of severe pain. It is also commonly used as an alternative to methadone for the treatment of severe opioid addiction. Buprenorphine acts as a partial mu-opioid receptor agonist with a high affinity for the receptor, but lower intrinsic activity compared to other full mu-opioid agonists such as heroin, oxycodone, or methadone. This means that buprenorphine preferentially binds the opioid receptor and displaces lower affinity opioids without activating the receptor to a comparable degree. This effect can be beneficial, however, as dose-related side effects such as respiratory depression, sedation, and intoxication also plateau at around 32mg, resulting in a lower risk of overdose compared to methadone and other full agonist opioids. It also means that opioid-dependent patients do not experience sedation or euphoria at the same rate that they might experience with more potent opioids, improving quality of life for patients with severe pain and reducing the reinforcing effects of opioids which can lead to drug-seeking behaviours. Treatment of opioid addiction with buprenorphine, methadone, or slow-release oral morphine (SROM) is termed Opioid Agonist Treatment (OAT) or Opioid Substitution Therapy (OST). The intention of substitution of illicit opioids with the long-acting opioids used in OAT is to prevent withdrawal symptomns for 24-36 hours following dosing to ultimately reduce cravings and drug-seeking behaviours. Use of OAT is also intended to improved social stabilization including a reduction in crime rates, marginalization, incarceration, and use of illicit substances such as heroin or fentanyl. Buprenorphine binds to mu opioid receptors, stimulating 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 GABA is inhibited. Opioids close N-type voltage-operated calcium channels and open calcium-dependent inwardly rectifying potassium channels. This results in hyperpolarization and reduced neuronal excitability.

Bupropion, known as the brand name Wellbutrin, is a norepinephrine/dopamine reuptake inhibitor (NDRI) used most commonly as a treatment for major depressive disorder (MDD), and seasonal affective disorder (SAD). It can also be used as a treatment for smoking cessation. Unlike most other drugs used to treat MDD, bupropion has been found to have no interaction with serotonin transporters. Bupropion works with other drugs to help with other neurological disorders such as seizures, and ADHD with bipolar comorbidity. Bupropion works by weakly inhibiting dopamine and norepinephrine transporters in presynaptic neurons. Dopamine is synthesized from tyrosine which is catalyzed by Tyrosine 3-monooxygenase into L-dopa which is catalyzed by Aromatic-L-amino-acid decarboxylase into dopamine. This mainly occurs in the substantia nigra, ventral tegmental area, and hypothalamus which are all parts of the limbic system where bupropion has the most effect in regulating MDD. Dopamine is released into the synapse where it is much more difficult for it to re-enter the presynaptic neuron due to bupropion inhibiting the sodium-dependent dopamine receptor. This causes dopamine to accumulate in higher concentrations in the synapse. The high concentration of dopamine activates dopamine receptors prolongs the duration of action on dopamine receptors. The D1 dopamine receptor is the receptor found to receptor most associated with MDD. There is also evidence that the D1-D2 heteromer is implicated in MDD, but that has not been studied enough to understand its effects. The D1 dopamine receptor activates Gs coupled protein which with GTP activates adenylate cyclase. Adenylate cyclase catalyzes ATP into cAMP which activates PKA which causes neuronal excitability. This helps regulate mood and behaviour in the brain as well as activating the reward system. Norepinephrine's effects on MDD is less studied and less understood than dopamine. Norepinephrine is synthesized in the locus ceruleus from dopamine which is catalyzed by Dopamine beta-hydroxylase into norepinephrine. Norepinephrine is released into the synapse where it accumulates because bupropion is weakly inhibiting the sodium-dependent noradrenaline receptor which prevents norepinephrine from re-entering the presynaptic neuron. This higher concentration of norepinephrine prolongs the duration of action on adrenergic receptors. Depressed patients have drastically low levels of norepinephrine, but a defeciency in the adrenergic receptors themselves seems to be implicated in MDD as well. Norepinephrine activates Alpha-1A adrenergic receptors in the brain, which are desensitized in the brains of depressed patients and implicated in the limbic system for regulating behaviour and mood. Activation of Alpha-1A receptors activates the Gq signalling cascade which has a variety of excitatory effects on neurons in the brain, especially in the limbic system. The exact effects of norepinephrine in the brain, especially in the brain of patients with MDD is still being researched, and therefore is still not entirely understood. Depression does seem to cause problems with the activation of the receptors which means more norepinephrine is required to see the same effects as in people without MDD. Bupropion does this at least for alpha-1A adregnergic receptors in the limbic system. Alpha-2 adrenergic receptors have been found to have a higher density in the brain of depressed patients, and seem to cause symptoms of depression. Beta adrenergic receptors have also been observed to be highly activated in patients with depression.

Bupropion is an anti-depressant and smoking cessation drug taken orally. It is digested in the stomach and intestine where bupropion is transported out of the the intestine through the epithelial cells through an unknown transport. In the blood it travels to the liver where it is transported into the live through an unknown transport protein. Bupropion is not transported by any major hepatic transporters. On the endoplasmic reticulum in the liver, bupropion is metabolized into Hydroxybupropion by the enzyme Cytochrome P450 2B6, threohydrobupropion by the enzyme 11β-HSD1, and erythrohydrobupropion by a carbonyl reductase enzyme. Hydroxybupropion, threohydrobupropion, and erythrohydrobupropion are all active metabolites of bupropion. Threohydrobupropion and erythrohydrobupropion are very similar metabolites with only a different bond in their structure of the compounds. Hydroxybupropion has been shown to have the same affinity for norepinephrine reuptake transporters, but only 50% of the anti-depressant effects of bupropion. Bupropion is also metabolized into the inactive metabolites (2R)-1-(3-chlorophenyl)-2-[(1-hydroxy-2-methylpropan-2-yl)amino]propan-1-one by the enzymes Cytochrome P450 2B6 or Cytochrome P450 3A4; (2R)-2-(tert-butylamino)-1-(3-chlorophenyl)-3-hydroxypropan-1-one by the enzymes Cytochrome P450 2C19, Cytochrome P450 2B6, or Cytochrome P450 2E1; and (2R)-2-(tert-butylamino)-1-(3-chloro-5-hydroxyphenyl)propan-1-one by the enzymes Cytochrome P450 2B6 or Cytochrome P450 2E1. All of these metabolites are transported out of the liver into the blood vessels or bile by unknown transport proteins. The elimination of the metabolites happens mainly in the kidneys where 87% of the dose is renally excreted. 10% of the dose is excreted fecally through bile to the intestines. 0.5% of the dose is excreted as unchanged bupropion.

Metabolites of Buspirone are predicted with biotransformer.