central stimulants & anorexics

[Alfa]

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amphetamines


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<TD vAlign=center> The amphetamine class of stimulants are potent indirect-acting sympathomimetics which cause release of the excitatory neurotransmitters dopamine and norepinephrine from storage vesicles in the CNS. Phenethylamine (PEA), a constituent of cheese and chocolate, is the simplest of these structures. It is reported to accrue in higher quantities in the brains of people "in love."
Adding a methyl group to the alpha carbon on PEA yields dextroamphetamine; this methyl group inhibits oxidation by MAO, which degrades both the amphetamines and the neurotransmitters they release. Amphetamine is used medically as an adjunct to antidepressants in refractory cases of depression, and as an anorexic in refractory cases of obesity. Because of its abuse potential it has been classified as a schedule II drug by the DEA; this is the most restrictive category next to schedule I drugs, which have no recognized medical uses (e.g. LSD).
Methylation at the nitrogen of amphetamine yields methamphetamine, a street drug with a longer half-life than the parent drug. Methamphetamine is usually sold as the free base, is known colloquially as "crystal," "meth," "crystal meth," or "rock."
The dopaminergic neurons activated by amphetamine are particularly dense in the reward pathway from the pleasure center and limbic system to the cerebrum. This depletes neuronal stores of neurotransmitters, which sets up a demand for progressively higher doses to achieve the same "high," and accounts for the sometimes profound depression which follows a drug binge (the "crash").
Prolonged use of amphetamines often precipitates psychotic behavior and delusions, often frank paranoia, probably from massive depletion of endogenous amines and associated cognitive dysfunction. Acute toxicity may include seizures or even cardiac arrest. Neurologically, use of methamphetamine has been implicated in irreversible damage to dopaminergic neurons.
Cathinone is an amphetamine analog that occurs in a plant (khat) widely used in the Middle East and Turkey. The presence of a ketone oxygen at the beta carbon may facilitate vesicular uptake and subsequent displacement. Methylcathinone recently appeared as a drug of abuse on the black market. Diethylpropion and ethamivan are similar compounds.
Methylphenidate (Ritalin) is another amphetamine spin-off which has found application against attention deficit hyperactivity disorder (ADHD, ADD). Recent studies imply that Ritalin may also act on serotonergic systems; this may be important in explaining the paradoxical calming effect of stimulants on ADHD patients.
Amphetamine analogs somewhat less potent than amphetamine itself are often employed as diet drugs. Fenfluramine also appears to have serotonin agonist or releasing activity.
Fenfluramine and phentermine were previously dispensed in combination as Fen-Phen, a popular appetite suppressant with several putative health hazards of recent note, including pulmonary hypertension, heart valve dysfunction, and serotonergic damage nerve damage. The drug was withdrawn along with the individual drugs; however, it (they) may be reintroduced, since there is recent evidence that if used in the recommended dosages for short trials, the health risks are not great.
Pemoline (Cylert) departs further from the amphetamine skeleton, but probably works similarly; it is also used in ADD.
Sibutramine (Meridia) is a new weight-loss drug (anorexic) that (through its metabolites) inhibits reuptake of norepinephrine, dopamine, and serotonin, but does not promote monoamine release like the amphetamines.</TD></TR></T></T></TABLE></CENTER>
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ecstasy class designer drugs


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<TD vAlign=center> The synthetic compound MDMA, like its "designer drug" predecessors DOM (STP) and MDA and the more recent 2-CB, comprises a mescaline-like compound with stimulant and hallucinatory properties. Like the amphetamines, MDMA releases excitatory catecholamines, but it also augments serotonin. Often described as an "empathogen" or a "hug drug," it is said that the anxiety of an excessive adrenaline effect is pleasantly offset by the well-being imparted by the calming effect due to serotonin. MDMA has been shown to cause permanent damage to serotonin nerve terminals; this is probably dose-related, as has been seen with other serotonin agonists like dexfenfluramine.</TD></TR></T></T></TABLE></CENTER>
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cocaine


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<TD vAlign=center> Cocaine is a potent central stimulant which blocks the neuronal reuptake of excitatory neurotransmitters dopamine and norepinephrine. These systems are responsible for the communication of satiety, arousal, and pleasure from the limbic system to the frontal lobe. Because of the powerful high, cocaine is one of the most psychologically addictive substances known. In contrast to heroin, no clinically useful antagonist is available to treat cocaine addiction, and some unique approaches are being tried experimentally. These include the use of monoclonal antibodies to produce a cocaine "vaccine" (a host of scavenging antibodies) and site-specific mutations of the genome to enhance production of butyrlcholinesterase, a potent systemic enzyme that inactivates cocaine.
Although it is still used clinically as a topical anesthetic on nasal and ocular tissues, it has a long history of use and abuse in both Western and non-Western cultures. The hydrochloride salt is sold as a street drug for sniffing, while crack, intended for smoking, consists of the (adulterated) free base.
Cocaine toxicity can include tachycardia (fast pulse) as well as arrhythmia; proper contraction of the chambers of the heart is a physically and neurologically complex task which is subject to interruption or interference. Secondary destruction or damage to heart tissue can occur from anoxia during arrhythmic episodes.
The structure of cocaine is not unlike that of atropine (shown for reference), a strong muscarinic antagonist. Like many small alkaloids, cocaine imparts local and topical anesthetic effects. At least one experiment showed that experienced cocaine users could not detect substitution of a lidocaine nasal solution (a local anesthetic, also shown) for one of cocaine. This may say more about the power of the psychological component of drug use to activate, before the fact, the very pathways the user expects to activate with the drug (stimulation, euphoria).
Benzoylecgonine is the major, inactive metabolite of cocaine in the human organism. This is the metabolite targeted by most urine drug screens. Similar compounds are also found in the Coca plant. Fencamfine is another CNS stimulant with a polycyclic structure similar to cocaine.</TD></TR></T></T></TABLE></CENTER>
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caffeine


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<TD vAlign=center> Caffeine is one of a group of alkaloids called methylxanthines which inhibit the degradation of the second messenger cAMP by the enzyme phosphodiesterase. The cAMP system couples the reception of a neurotransmitter at the far side of synapses to the sequential depolarization pulse down the next nerve. Caffeine also antagonizes presynaptic adenosine receptors, facilitating catecholamine release. Caffeine has been shown to decrease thyroid function; this is probably only one of many homeostatic effects by which the body responds to overactive cAMP systems.
Caffeine occurs naturally in the coffee bean, tea leaves, guarana, and other plants. It is probably the most-used of all psychoactive drugs. Medically, caffeine is used as a stimulant, and to potentiate analgesics such as NSAIDs or mild narcotics. It acts as a vasodilator in the CNS, reducing blood pressure and headache symptoms. It also imparts diuretic and blood-thinning qualities and may reduce formation of kidney stones by increasing urination. Recent research has also suggested that caffeine may release free fatty acids (from stored fat) into the blood, decreasing the need to burn glycogen. It may thus enhance athletic performance.
Cafaminol and caffeic acid also occur in the coffee plant. Fenethylline is another methylxanthine stimulant. Variations on the methylxanthine structure have produced a range of drugs with varying properties, often including vasodilation. Smooth muscle relaxation in the penis allows Viagra to facilitate erection.</TD></TR></T></T></TABLE></CENTER>
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nicotine


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<TD vAlign=center> Nicotine releases dopamine in the mesocorticolimbic pathway and additionally serves as a direct agonist at a subset of cholinergic receptors, accounting for some of its peripheral effects. Downregulation of dopamine receptors (reduction in number and density of receptors) following prolonged use probably accounts for much of the dependence syndrome of this highly addictive drug. The peripheral effects include tachycardia (higher pulse), and vasoconstriction, which raises blood pressure. Like other stimulants it decreases appetite and increases metabolism, and shows some performance enhancement in users.
Nicotine is excreted in the kidney as nornicotine, also present in tobacco, and also psychoactive. Variant structures like anabasine, anatabine, and cotinine can be isolated from tobacco. Cotinine has been used as an antidepressant. Synthetic nicotine derivatives like nikethamide (a cardiotonic) and nicorandil (a cardiac vasodilator) are active at peripheral cholinergic neurons (nicotinic subtype).
Tobacco smoke contains a number of psychoactive compounds besides nicotine. Gaseous toxins like carbon monoxide, small amounts of volatile species like acetone and acetaldehyde, as well as traces of other powerful alkaloids have been isolated. [Parenthetically, the same compounds can be found, in smaller amounts, in human breath, for example.] The addictive profile of nicotine is significantly strengthened by trace acetaldehyde. Acetaldehyde is the major toxic metabolite of ethyl alcohol, and has been posited to react with dopamine in the brain to form a narcotic agonist, TIQ.
Tobacco smoke also contains traces of Harman, a potent GABA-benzodiazepine antagonist of the beta-carboline class. The zwitterion trigonelline is present in coffee and is formed in the body as a metabolite of nicotine. It is interesting to see how the chemistries of various plants and animals overlap, whether by accident or by the necessity to accomplish similar chemical ends.</TD></TR></T></T></TABLE></CENTER>
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arcane CNS stimulants


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<TD vAlign=center> Pentylenetetrazole is an epileptigenic (seizure-producing) agent used experimentally to induce seizures distinct from those invoked by electroshock. It has also been used in opiate overdose. Calcium N-carbamoyl aspartate probably acts as an aspartate and glutamate mimetic.
Strychnine, from the plant "strychnos nux-vomica," is a glycine antagonist. Glycine performs inhibitory functions, especially in the spinal cord. Strychnine has historically been used as a rat poison. It causes convulsive stimulation by blocking the inhibitory function of glycine. Diaboline is a structurally-related compound.
Gelsemine is another structurally complex CNS-stimulant plant alkaloid manufactured. It is evident how useful botanical chemical synthesis processes can be, considering the effort one would have to expend to synthesize these compounds in the laboratory.
The picrotoxin group of stimulants antagonizeGABA, the most prevalent inhibitory CNS neurotransmitter. As with strychnine, this shows how a drug that inhibits the action of an inhibitory system can serve as a (toxic) stimulant.</TD></TR></T></T></TABLE></CENTER>
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other anorexics: Xenical


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<TD> Xenical is a recent weight-loss drug that works by binding to lipolytic enzymes and inhibiting fat absorption. This mechanism is in start contrast to the stimulant approach to combating obesity.</TD></TR></T></T></TABLE></CENTER>Edited by: Alfa