Pharmacodynamics<unk> 's primary mechanism of action is as an alt=Two skeletal formulas: left –<unk> , right – adenosine. In the absence of<unk>  and when a person is awake and alert, little adenosine is present in (CNS) neurons. With a continued wakeful state, over time adenosine accumulates in the neuronal synapse, in turn binding to and activating adenosine receptors found on certain CNS neurons; when activated, these receptors produce a cellular response that ultimately increases drowsiness. When<unk>  is consumed, it antagonizes adenosine receptors; in other words,<unk>  prevents adenosine from activating the receptor by blocking the location on the receptor where adenosine binds to it. As a result,<unk>  temporarily prevents or relieves drowsiness, and thus maintains or restores alertness. Receptor and ion channel targets<unk>  is an antagonist of adenosine A2A receptors, and knockout mouse studies have specifically implicated antagonism of the A2A receptor as responsible for the wakefulness-promoting effects of<unk> . Antagonism of A2A receptors in the ventrolateral preoptic area (VLPO) reduces inhibitory GABA neurotransmission to the tuberomammillary nucleus, a histaminergic projection nucleus that activation-dependently promotes arousal. This disinhibition of the tuberomammillary nucleus is the downstream mechanism by which<unk>  produces wakefulness-promoting effects.<unk>  is an antagonist of all four adenosine receptor subtypes (A1, A2A, A2B, and A3), although with varying potencies. The affinity (KD) values of<unk>  for the human adenosine receptors are 12 μM at A1, 2.4 μM at A2A, 13 μM at A2B, and 80 μM at A3. Antagonism of adenosine receptors by<unk>  also stimulates the medullary vagal, vasomotor, and respiratory centers, which increases respiratory rate, reduces heart rate, and constricts blood vessels. Adenosine receptor antagonism also promotes neurotransmitter release (e.g., monoamines and acetylcholine), which endows<unk>  with its stimulant effects; adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system. Heart palpitations are<unk> used by blockade of the A1 receptor. Because<unk>  is both water- and lipid-soluble, it readily crosses the blood–brain barrier that separates the bloodstream from the interior of the brain. Once in the brain, the principal mode of action is as a nonselective antagonist of adenosine receptors (in other words, an agent that reduces the effects of adenosine). The<unk>  molecule is structurally similar to adenosine, and is<unk> pable of binding to adenosine receptors on the surface of cells without activating them, thereby acting as a competitive antagonist. In addition to its activity at adenosine receptors,<unk>  is an inositol trisphosphate receptor 1 antagonist and a voltage-independent activator of the ryanodine receptors (RYR1, RYR2, and RYR3). It is also a competitive antagonist of the ionotropic glycine receptor. Effects on striatal dopamine While<unk>  does not directly bind to any dopamine receptors, it influences the binding activity of dopamine at its receptors in the striatum by binding to adenosine receptors that have formed GPCR heteromers with dopamine receptors, specifically the A1–D1 receptor heterodimer (this is a receptor complex with 1 adenosine A1 receptor and 1 dopamine D1 receptor) and the A2A–D2 receptor heterotetramer (this is a receptor complex with 2 adenosine A2A receptors and 2 dopamine D2 receptors). The A2A–D2 receptor heterotetramer has been identified as a primary pharmacological target of<unk> , primarily because it mediates some of its psychostimulant effects and its pharmacodynamic interactions with dopaminergic psychostimulants.<unk>  also<unk> uses the release of dopamine in the dorsal striatum and nucleus accumbens core (a substructure within the ventral striatum), but not the nucleus accumbens shell, by antagonizing A1 receptors in the axon terminal of dopamine neurons and A1–A2A heterodimers (a receptor complex composed of 1 adenosine A1 receptor and 1 adenosine A2A receptor) in the axon terminal of glutamate neurons. During chronic<unk>  use,<unk> -induced dopamine release within the nucleus accumbens core is markedly reduced due to drug tolerance. Enzyme targets<unk> , like other xanthines, also acts as a phosphodiesterase inhibitor. As a competitive nonselective phosphodiesterase inhibitor,<unk>  raises intracellular<unk> MP, activates protein kinase A, inhibits TNF-alpha and leukotriene synthesis, and reduces inflammation and innate immunity.<unk>  also affects the cholinergic system where it is a moderate inhibitor of the enzyme acetylcholinesterase. Pharmacokinetics<unk>  is metabolized in the liver via a single demethylation, resulting in three primary metabolites, paraxanthine (84%), theobromine (12%), and theophylline (4%), depending on which methyl group is removed.|alt=A diagram featuring 4 skeletal chemical formulas. Top<unk>  relates to similar compounds paraxanthine, theobromine and theophylline. Urinary metabolites of<unk>  in humans at 48 hours post-dose.<unk>  from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and distributed throughout all bodily tissues. Peak blood concentration is reached within 1–2 hours. It is eliminated by first-order kinetics.<unk> <unk> n also be absorbed rectally, evidenced by suppositories of ergotamine tartrate and<unk>  (for the relief of migraine) and of chlorobutanol and<unk>  (for the treatment of hyperemesis). However, rectal absorption is less efficient than oral: the maximum concentration (Cmax) and total amount absorbed (AUC) are both about 30% (i.e., 1/3.5) of the oral amounts.<unk> 's biological half-life – the time required for the body to eliminate one-half of a dose – varies widely among individuals according to factors such as pregnancy, other drugs, liver enzyme function level (needed for<unk>  metabolism) and age. In healthy adults,<unk> 's half-life is between 3 and 7 hours. The half-life is decreased by 30-50% in adult male smokers, approximately doubled in women taking oral contraceptives, and prolonged in the last trimester of pregnancy. In newborns the half-life<unk> n be 80 hours or more, dropping very rapidly with age, possibly to less than the adult value by age 6 months. The antidepressant fluvoxamine (Luvox) reduces the clearance of<unk>  by more than 90%, and increases its elimination half-life more than tenfold; from 4.9 hours to 56 hours.<unk>  is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethylxanthines, each of which has its own effects on the body: * Paraxanthine (84%): Increases lipolysis, leading to elevated glycerol and free fatty acid levels in blood plasma. * Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in the cocoa bean (chocolate). * Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from<unk>  metabolism. 1,3,7-Trimethyluric acid is a minor<unk>  metabolite. Each of these metabolites is further metabolized and then excreted in the urine.<unk> <unk> n accumulate in individuals with severe liver disease, increasing its half-life. A 2011 review found that increased<unk>  intake was associated with a variation in two genes that increase the rate of<unk> <unk> tabolism. Subjects who had this mutation on both chromosomes consumed 40 mg more<unk>  per day than others. This is presumably due to the need for a higher intake to achieve a comparable desired effect, not that the gene led to a disposition for greater incentive of habituation.
Caffeine
Methacholine
Betahistine
Nicotine
Phenylpropanolamine
Molsidomine
Piperoxan
Codeine