Pharmacokinetics The extent of absorption of<unk>  into the systemic circulation after nasal insufflation is similar to that after oral ingestion. The rate of absorption after nasal insufflation is somewhat limited by<unk> -induced vasoconstriction of capillaries in the nasal mucosa. The onset of absorption after oral ingestion is delayed because<unk>  is a weak base with a pKa of 8.6, and is thus in an ionized form that is poorly absorbed from the acidic stomach and easily absorbed from the alkaline duodenum. The rate and extent of absorption from inhalation of<unk>  is similar or greater than with intravenous injection, as inhalation provides access directly to the pulmonary capillary bed. The delay in absorption after oral ingestion may account for the popular belief that<unk>  bioavailability from the stomach is lower than after insufflation. Compared to ingestion, the faster absorption of insufflated<unk>  results in quicker attainment of maximum drug effects. Snorting<unk>  produces maximum physiological effects within 40 minutes and maximum psychotropic effects within 20 minutes. Physiological and psychotropic effects from nasally insufflated<unk>  are sustained for approximately 40–60 minutes after the peak effects are attained.<unk>  has a short elimination half life of 0.7-1.5 hours and is extensively metabolized by plasma esterases but also by liver cholinesterases, with only about 1% excreted unchanged in the urine. The metabolism is dominated by hydrolytic ester cleavage, so the eliminated metabolites consist mostly of benzoylecgonine (BE), the major metabolite, and other significant metabolites in lesser amounts such as ecgonine methyl ester (EME) and ecgonine. Further minor metabolites of<unk>  include norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE), and m-hydroxybenzoylecgonine. If consumed with alcohol,<unk>  combines with alcohol in the liver to form<unk> aethylene. Studies have suggested<unk> aethylene is both more euphoric, and has a higher cardiovascular toxicity than<unk>  by itself. Depending on liver and kidney function,<unk>  metabolites are detectable in urine. Benzoylecgonine can be detected in urine within four hours after<unk>  intake and remains detectable in concentrations greater than 150 ng/mL typically for up to eight days after<unk>  is used. Detection of<unk>  metabolites in hair is possible in regular users until the sections of hair grown during use are cut or fall out. Pharmacodynamics The pharmacodynamics of<unk>  involve the complex relationships of neurotransmitters (inhibiting monoamine uptake in rats with ratios of about: serotonin:dopamine = 2:3, serotonin:norepinephrine = 2:5). The most extensively studied effect of<unk>  on the central nervous system is the blockade of the dopamine transporter protein. Dopamine neurotransmitter released during neural signaling is normally recycled via the transporter; i.e., the transporter binds the transmitter and pumps it out of the synaptic cleft back into the presynaptic neuron, where it is taken up into storage vesicles.<unk>  binds tightly at the dopamine transporter forming a complex that blocks the transporter's function. The dopamine transporter can no longer perform its reuptake function, and thus dopamine accumulates in the synaptic cleft. The increased concentration of dopamine in the synapse activates post-synaptic dopamine receptors, which makes the drug rewarding and promotes the compulsive use of<unk> .<unk>  affects certain serotonin (5-HT) receptors; in particular, it has been shown to antagonize the 5-HT3 receptor, which is a ligand-gated ion channel. An overabundance of 5-HT3 receptors is reported in<unk> -conditioned rats, though 5-HT3's role is unclear. The 5-HT2 receptor (particularly the subtypes 5-HT2A, 5-HT2B and 5-HT2C) are involved in the locomotor-activating effects of<unk> .<unk>  has been demonstrated to bind as to directly stabilize the DAT transporter on the open outward-facing conformation. Further,<unk>  binds in such a way as to inhibit a hydrogen bond innate to DAT.<unk> 's binding properties are such that it attaches so this hydrogen bond will not form and is blocked from formation due to the tightly locked orientation of the<unk>  molecule. Research studies have suggested that the affinity for the transporter is not what is involved in the habituation of the substance so much as the conformation and binding properties to where and how on the transporter the molecule binds. Sigma receptors are affected by<unk> , as<unk>  functions as a sigma ligand agonist. Further specific receptors it has been demonstrated to function on are NMDA and the D1 dopamine receptor.<unk>  also blocks sodium channels, thereby interfering with the propagation of action potentials; thus, like lignocaine and novocaine, it acts as a local anesthetic. It also functions on the binding sites to the dopamine and serotonin sodium dependent transport area as targets as separate mechanisms from its reuptake of those transporters; unique to its local anesthetic value which makes it in a class of functionality different from both its own derived phenyltropanes analogues which have that removed. In addition to this,<unk>  has some target binding to the site of the Kappa-opioid receptor.<unk>  also causes vasoconstriction, thus reducing bleeding during minor surgical procedures. Recent research points to an important role of circadian mechanisms and clock genes in behavioral actions of<unk> .<unk>  is known to suppress hunger and appetite by increasing co-localization of sigma σ1R receptors and ghrelin GHS-R1a receptors at the neuronal cell surface, thereby increasing ghrelin-mediated signaling of satiety and possibly via other effects on appetitive hormones. Chronic users may lose their appetite and can experience severe malnutrition and significant weight loss.<unk>  effects, further, are shown to be potentiated for the user when used in conjunction with new surroundings and stimuli, and otherwise novel environs.
Cocaine
Benzocaine
Cannabis 
Cannabis
Nicotine
Heroin
Phencyclidine
Methamphetamine