Drugs acting on central nervous system

Introduction - Drugs Acting Upon the Central Nervous System:
The central nervous system directs the functions of all tissues of the body. The peripheral nervous system receives thousands of sensory inputs and transmits them to the brain via the spinal cord. The brain processes this incoming information and discards 99% as unimportant. After sensory information has been evaluated, selected areas of the central nervous system initiate nerve impulses to organs or tissue to make an appropriate response.
Chemical influences are capable of producing a myriad of effects on the activity and function of the central nervous system. Since our knowledge of different regions of brain function and the neurotransmitters in the brain is limited, the explanations for the mechanisms of drug action may be vague. The known neurotransmitters are: acetylcholine which is involved with memory and learning; norepinephrine which is involved with mania-depression and emotions; and serotonin which is involved with biological rhythms, sleep, emotion, and pain.
1.Central Nervous System Stimulants:
Stimulants are drugs that exert their action through excitation of the central nervous system. Psychic stimulants include caffeine, cocaine, and various amphetamines. These drugs are used to enhance mental alertness and reduce drowsiness and fatigue. However, increasing the dosage of caffeine above 200 mg (about 2 cups of coffee) does not increase mental performance but may increase nervousness, irritability, tremors, and headache. Heavy coffee drinkers become psychically dependent upon caffeine. If caffeine is withheld, a person may experience mild withdrawal symptoms characterized by irritability, nervousness, and headache.
Caffeine and the chemically related xanthines, theophylline and theobromine, decrease in the order given in their stimulatory action. They may be included in some over-the-counter drugs.
The action of caffeine is to block adenosine receptors as an antagonist. As caffeine has a similar structure to the adenosine group. This means that caffeine will fit adenosine receptors as well as adenosine itself. It inhibits the release of neurotransmitters from presynaptic sites but works in concert with norepinephrine or angiotensin to augment their actions. Antagonism of adenosine receptors by caffeine would appear to promote neurotransmitter release, thus explaining the stimulatory effects of caffeine.
The stimulation caused by amphetamines is caused by excessive release of norepinephrine from storage sites in the peripheral nervous system. It is not known whether the same action occurs in the central nervous system. Two other theories for their action are that they are degraded slower than norepinephrine or that they could act on serotonin receptor sites.
Therapeutic doses of amphetamine elevate mood, reduce feelings of fatigue and hunger, facilitate powers of concentration, and increase the desire and capacity to carry out work. They induce exhilarating feelings of power, strength, energy, self-assertion, focus and enhanced motivation. The need to sleep or eat is diminished.
Levoamphetamine (Benzedrine), dextroamphetamine (Dexedrine), and methamphetamine (Methedrine) are collectively referred to as amphetamines.
Benzedrine is a mixture of both the dextro and levoamphetamine isomers. The dextro isomer is several times more potent than the levo isomer.
The misuse and abuse of amphetamines is a significant problem which may include the house wife taking diet pills, athletes desiring an improved performance, the truck driver driving non-stop coast to-coast, or a student cramming all night for an exam.
 Laevoamphetamine (Benzedrine), dextroamphetamine (Dexedrine),
and methamphetamine (Methedrine) are collectively referred to as amphetamines.
The amphetamines are potent psychomotor stimulants. Their use causes a release of the excitatory neurotransmitters dopamine and noradrenaline (norepinephrine) from storage vesicles in the CNS. Amphetamines may be sniffed, swallowed, snorted or injected. They induce exhilarating feelings of power, strength, energy, self-assertion, focus and enhanced motivation. The need to sleep or eat is diminished. The release of dopamine typically induces a sense of aroused euphoria which may last several hours: unlike cocaine, amphetamine is not readily broken down by the body. Feelings are intensified. The user may feel he can take on the world.
The euphoria doesn't last. There follows an intense mental depression and fatigue. Amphetamine depletes the neuronal stores of dopamine in the mesolimbic pleasure centres of the brain.
More than any other illegal drug, speed is associated with violence and anti-social behavior. Occasional light and infrequent use is probably relatively harmless; but heavy chronic use can lead to stereotypies of behavior, depressive disorders, "meth bugs" akin to cocaine-induced formication, strain on the cardiovascular system, increasing behavioral disintegration, and outright "amphetamine psychosis".
Amphetamine is structurally related to ephedrine, a natural stimulant found in plants of the genus Ephedra. It is also structurally related to adrenaline, the body's "fight or flight" hormone. Amphetamine was first synthesised by Edeleano in Germany in 1887, but it only entered clinical medicine in the late 1920s when its psychostimulant effect was recognised. The US medical and pharmaceutical establishment was worried that supplies of ephedra in faraway China would be exhausted. Amphetamine promised a cheap and synthetic substitute. Like ephedrine, amphetamine dilates the bronchial small sacs of the lungs, a great blessing for sufferers from breathing disorders. So in 1932, Smith, Kline and French introduced the famous Benzedrine Inhaler.
Amphetamine sulphate was aggressively marketed for asthmatics, hay-fever sufferers and anyone with a cold. Amphetamine was soon available in pill form too. "Pep pills" were sold over the counter for all manner of ailments. Doctors prescribed amphetamine for depression, Parkinson's disease, epilepsy, travel-sickness, night-blindness, hyperactive disorders of children, obesity, narcolepsy, impotence, and apathy in old age


Antidepressant drugs are used to restore mentally depressed patients to an improved mental status. Depression results from a deficiency of norepinephrine at receptors in the brain. Mechanisms that increase their effective concentration at the receptor sites should alleviate depression. Antidepressant drugs act by one or more of the following stimulation type mechanisms:
a) Increase release of norepinephrine:
Amphetamines and electroconvulsive therapy act by this mechanism. Amphetamines mimic norepinephrine.
b) Prevent inactivation of norepinephrine:
Monoamine oxidase (MAO) inhibitors are thought to act as antidepressant agents in part by preventing the breakdown and inactivation of norepinephrine.
c) Prevent the re uptake of norepinephrine:
the action of norepinephrine at the receptor site is terminated by the re uptake of norepinephrine by the neuron from which it was originally released.
Tricyclic Antidepressants:
The tricyclic antidepressants are the most effective drugs presently available for the treatment of depression. These act by increasing the release of norepinephrine. Amphetamine and cocaine can also act in this manner.
Tricyclic Antidepressants:
Imipramine, amitriptylin, and other closely related drugs are among the drugs currently most widely used for the treatment of major depression.
imipramine (Tofranil)
desipramine (Norpramin)
The activity of the tricyclic drugs depends on the central ring of seven or eight atoms which confers an angled or twisted conformation. The side chain must have at least 2 carbons although 3 appear to be better. The amine group may be either tertiary or secondary.
All tricyclic antidepressants block the re-uptake of norepinephrine at nerve terminals. However, the potency and selectivity for the inhibition of the uptake of norepinephrine, serotonin, and dopamine vary greatly among the agents. The tertiary amine tricyclics seem to inhibit the serotonin uptake pump, whereas the secondary amine ones seem better in switching off the NE pump. For instance, imipramine is a potent and selective blocker of serotonin transport, while desipramine inhibits the uptake of norepinephrine.

Serotonin (5-hydroxytryptamine or 5-HT) is a monoamine neurotransmitter found in cardiovascular tissue, in endothelial cells, in blood cells, and in the central nervous system. The role of serotonin in neurological function is diverse, and there is little doubt that serotonin is an important CNS neurotransmitter.
Although some of the serotonin is metabolized by monoamine oxidase, most of the serotonin released into the post-synaptic space is removed by the neuron through a re uptake mechanism inhibited by the tricyclic antidepressants and the newer, more selective antidepressant re uptake inhibitors such as fluoxetine and sertraline.

Selective Serotonin Re uptake Inhibitors:
In recent years, selective serotonin re uptake inhibitors have been introduced for the treatment of depression. Prozac is the most famous drug in this class. Clomiprimine, fluoxetine (Prozac), sertraline and paroxetine selectively block the re uptake of serotonin, thereby increasing the levels of serotonin in the central nervous system. Note the similarities and differences between the tricyclic antidepressants and the selective serotonin re uptake inhibitors. Clomipramine has been useful in the treatment of obsessive-compulsive disorders.

monoamine Oxidase (MAO) Inhibitors:
Monoamine oxidase (MAO) causes the oxidative deamination of norephinephrine, serotonin, and other amines. This oxidation is the method of reducing the concentration of the neurotransmitter after it has sent the signal at the receptor site. A drug which inhibits this enzyme has the effect of increasing the concentration of the norepinephrine which in turn causes a stimulation effect.
Most MAO inhibitors are hydrazine derivatives. Hydrazine is highly reactive and may form a strong covalent bond with MAO with consequent inhibition for up to 5 days.
These drugs are less effective and produce more side effects than the tricyclic antidepressants. For example, they lower blood pressure and were at one time used to treat hypertension. Their use in psychiatry has also become very limited as the tricyclic antidepressants have come to dominate the treatment of depression and allied conditions. Thus, MAOIs are used most often when tricyclic antidepressants give unsatisfactory results.
MAO Inhibitors:
Phenelzine is the hydrazine analog of phenylethylamine, a substrate of MAO. This and several other MAOIs, such as isocarboxazide, are structurally related to amphetamine and were synthesized in an attempt to enhance central stimulant properties.
phenelzine (Nardil)
isocarboxazid (Marplan)

3.Hallucinogenic Drugs
Hallucinogenic agents, also called psychomimetic agents, are capable of producing hallucinations, sensory illusions and bizarre thoughts. The primary effect of these compounds is to consistently alter thought and sensory perceptions. Some of these drugs are used in medicine to produce model psychoses as aids in psychotherapy. Another purpose is to investigate the relationship of mind, brain, and biochemistry with the purpose of elucidating mental diseases such as schizophrenia.
A large body of evidence links the action of hallucinogenic agents to effects at serotonin receptor sites in the central nervous system. Whether the receptor site is stimulated or blocked is not exactly known. The serotonin receptor site may consist of three polar or ionic areas to complement the structure of serotonin as shown in the graphic on the left.
Mescalin and Psilocybin:
The drugs shown in the graphic can be isolated from natural sources: lysergic acid amide from morning glory seeds, psilocybin from the "magic mushroom", Psilocybe mexicana.
The hallucinogenic molecules fit into the same receptors as the neuro-transmitter, and over-stimulate them, leading to false signals being created.
Mescaline is isolated from a peyote cactus. The natives of Central America first made use of these drugs in religious ceremonies, believing the vivid, colorful hallucinations had religious significance. The Aztecs even had professional mystics and prophets who achieved their inspiration by eating the mescaline-containing peyote cactus (Lophophora williamsii). Indeed, the cactus was so important to the Aztecs that they named it teo-nancacyl, or "God's Flesh". This plant was said to have been distributed to the guests at the coronation of Montezuma to make the ceremony seem even more spectacular.
LSD is one of the most powerful hallucinogenic drugs known. LSD stimulates centers of the sympathetic nervous system in the midbrain, which leads to pupillary dilation, increase in body temperature, and rise in the blood-sugar level. LSD also has a serotonin-blocking effect.
The hallucinogenic effects of lysergic acid diethylamide (LSD) are also the result of the complex interactions of the drug with both the serotoninergic and dopaminergic systems.
During the first hour after ingestion, the user may experience visual changes with extreme changes in mood. The user may also suffer impaired depth and time perception, with distorted perception of the size and shape of objects, movements, color, sound, touch and the user's own body image.
Serotonin (5-hydroxytryptamine or 5-HT) is a monoamine neurotransmitter found in cardiovascular tissue, in endothelial cells, in blood cells, and in the central nervous system. The role of serotonin in neurological function is diverse, and there is little doubt that serotonin is an important CNS neurotransmitter.
Although some of the serotonin is metabolized by monoamine oxidase, most of the serotonin released into the post-synaptic space is removed by the neuron through a re uptake mechanism inhibited by the tricyclic antidepressants and the newer, more selective antidepressant re uptake inhibitors such as fluoxetine and sertraline.
Selective Serotonin Re uptake Inhibitors:
In recent years, selective serotonin re uptake inhibitors have been introduced for the treatment of depression. Prozac is the most famous drug in this class. Clomiprimine, fluoxetine (Prozac), sertraline and paroxetine selectively block the re uptake of serotonin, thereby increasing the levels of serotonin in the central nervous system. Note the similarities and differences between the tricyclic antidepressants and the selective serotonin re uptake inhibitors. Clomipramine has been useful in the treatment of obsessive-compulsive disorders.


4.Barbiturate Drugs
Central Nervous System Depressants - Sedative - Hypnotic Agents
Hypnotic and sedative drugs are non-selective, general depressants of the central nervous system. If the dose is relatively low, a sedative action results in a reduction in restlessness and emotional tension. A larger dose of the same drug produces a hypnotic sleep inducing effect. As the dosage is increased further, the result is anesthesia or death if the dosage is sufficiently high.
The barbiturates once enjoyed a long period of extensive use as sedative-hypnotic drugs; however, except for a few specialized uses, they have been largely replaced by the much safer benzodiazepines.
Barbiturates are CNS depressants and are similar, in many ways, to the depressant effects of alcohol. To date, there are about 2,500 derivatives of barbituric acid of which only 15 are used medically. The first barbiturate was synthesized from barbituric acid in 1864. The original use of barbiturates was to replace drugs such as opiates, bromides, and alcohol to induce sleep.
The hyponotic and sedative effects produced by barbiturates are usually ascribed to their interference of nerve transmission to the cortex. Various theories for the action of barbiturates include: changes in ion movements across the cell membrane; interactions with cholinergic and non cholinergic receptor sites; impairment of biochemical reactions which provide energy; and depression of selected areas of the brain.
The structures of the barbiturates can be related to the duration of effective action. Although over 2000 derivatives of barbituric acid have been synthesized only about a dozen are currently used. All of the barbiturates are related to the structure of barbituric acid shown below.
The duration of effect depends mainly on the alkyl groups attached to carbon # 5 which confer lipid solubility to the drug. The duration of effective action decreases as the total number of carbons at C # 5 increases. To be more specific, a long effect is achieved by a short chain and/or phenyl group. A short duration effect occurs when there are the most carbons and branches in the alkyl chains.
The term benzodiazepine refers to the portion of the structure composed of a benzene ring (A) fused to a seven-membered diazepine ring (B). However, since all of the important benzodiazepines contain a aryl substituent ring C) and a 1, 4-diazepine ring, the term has come to mean the aryl-1,4-benzodiazepines. There are several useful benzodiazepines available: chlordiazepoxide (Librium) and diazapam (Valium).
The actions of benzodiazepines are a result of increased activation of receptors by gamma-aminobutyric acid (GABA). Benzodiazepine receptors are located on the alpha subunit of the GABA receptor located almost exclusively on postsynaptic nerve endings in the CNS (especially cerebral cortex). Benzodiazepines enhance the GABA transmitter in the opening of postsynaptic chloride channels which leads to hyperpolarization of cell membranes. That is, they "bend" the receptor slightly so that GABA molecules attach to and activate their receptors more effectively and more often.

5.Narcotic Analgesic Drugs
Narcotic agents are potent analgesics which are effective for the relief of severe pain. Analgesics are selective central nervous system depressants used to relieve pain. The term analgesic means "without pain". Even in therapeutic doses, narcotic analgesics can cause respiratory depression, nausea, and drowsiness. Long term administration produces tolerance, psychic, and physical dependence called addiction.
Narcotic agents may be classified into four categories:
1) Morphine and codeine - natural alkaloids of opium.
2) Synthetic derivatives of morphine such as heroin.
3) Synthetic agents which resemble the morphine structure.
4) Narcotic antagonists which are used as antidotes for overdoses of narcotic analgesics.
The main pharmacological action of analgesics is on the cerebrum and medulla of the central nervous system. Another effect is on the smooth muscle and glandular secretions of the respiratory and gastro-intestinal tract. The precise mechanism of action is unknown although the narcotics appear to interact with specific receptor sites to interfere with pain impulses.
Receptor Site:
A schematic for an analgesic receptor site may look as shown in the graphic on the left with morphine. Three areas are needed: a flat areas to accommodate a flat nonpolar aromatic ring, a cavity to accept another series of rings perpendicular, and an anionic site for polar interaction of the amine group.
Natural Peptide Analgesics - Enkephalins:
Recently investigators have discovered two compounds in the brain called enkephalins which resemble morphine in structure. Each one is a peptide composed of 5 amino acids and differ only in the last amino acid. The peptide sequences are: tyr-gly-gly-phe-leu and tyr-gly-gly-phe-met. Molecular models show that the structures of the enkephalins has some similarities with morphine. The main feature in common appears to be the aromatic ring with the -OH group attached (tyr). Methadone and other similar analgesics have 2 aromatic rings which would be similar to the enkephalins (tyr and phe).
Analgesics may relieve pain by preventing the release of acetylcholine. Enkephalin molecules are released from a nerve cell and bind to analgesic receptor sites on the nerve cell sending the impulse. The binding of enkephalin or morphine-like drugs changes the shape of the nerve sending the impulse in such a fashion as to prevent the cell from releasing acetylcholine. As a result, the pain impulse cannot be transmitted and the brain does not preceive pain.

Morphine and Codeine:
Morphine exerts a narcotic action manifested by analgesia, drowsiness, changes in mood, and mental clouding. The major medical action of morphine sought in the CNS is analgesia.
Opiates suppress the "cough center" which is also located in the brainstem, the medulla. Such an action is thought to underlie the use of opiate narcotics as cough suppressants. Codeine appears to be particularly effective in this action and is widely used for this purpose.
narcotic analgesics cause an addictive physical dependence. If the drug is discontinued, withdrawal symptoms are experienced. Although the reasons for addiction and withdrawal symptoms are not completely known, recent experiments have provided some information. A nucleotide known as cyclicadenosine monophosphate (cAMP) is synthesized with the aid of the enzyme adenylate cyclase. Enkephalin and morphine-like drugs inhibit this enzyme and thus decrease the amount of cAMP in the cells. In order to compensate for the decreased cAMP, the cells synthesize more enzyme in an attempt to produce more cAMP. Since more enzyme has been produced, more morphine is required as an inhibitor to keep the cAMP at a low level. This cycle repeats itself causing an increase in the tolerance level and increasing the amounts of morphine required. If morphine is suddenly withheld, withdrawal symptoms are probably caused by a high concentration of cAMP since the synthesizing enzyme, adenylate cyclase, is no longer being inhibited.
Morphine and codeine are contained in opium from the poppy (Papaver Somniterum) plant found in Turkey, Mexico, Southeast Asia, China, and India. This plant is 3-4 feet tall with 5-8 egg shaped capsules on top. Ten days after the poppy blooms in June, incisions are made in the capsules permitting a milky fluid to ooze out. The following day the gummy mass (now brown) is carefully scraped off and pressed into cakes of raw opium to dry.
Opium contains over 20 compounds but only morphine (10%) and codeine (0.5%) are of any importance. Morphine is extracted from the opium and isolated in a relatively pure form. Since codeine is in such low concentration, it is synthesized from morphine by an ether-type methylation of an alcohol group. Codeine has only a fraction of the potency compared to morphine. It is used with aspirin and as a cough suppressant.

Heroin is synthesized from morphine by a relatively simple esterification reaction of two alcohol (phenol) groups with acetic anhydride (equivalent to acetic acid). Heroin is much more potent than morphine but without the respiratory depression effect. A possible reason may be that heroin passes the blood-brain barrier much more rapidly than morphine. Once in the brain, the heroin is hydrolyzed to morphine which is responsible for its activity.
Synthetic narcotic analgesics may include the following:
Meperidine is the most common subsitute for morphine. It exerts several pharmacological effects: analgesic, local anesthetic, and mild antihistamine. This multiple activity may be explained by its structural resemblance to morphine, atropine, and histamine.
Methadone is more active and more toxic than morphine. It can be used for the relief of may types of pain. In addition it is used as a narcotic substitute in addiction treatment because it prevents morphine abstinence syndrome.
Methadone was synthesized by German chemists during Wold War II when the United States and our allies cut off their opium supply. And it is difficult to fight a war without analgesics so the Germans went to work and synthesized a number of medications in use today, including demerol and darvon which is structurally simular to methadone. And before we go further lets clear up another myth. Methadone, or dolophine was not named after Adolf Hitler. The "dol" in dolophine comes from the latin root "dolor." The female name Dolores is derived from it and the term dol is used in pain research to measure pain e.g., one dol is 1 unit of pain.
Even methadone, which looks strikingly different from other opioid agonists, has steric forces which produce a configuration that closely resembles that of other opiates. See the graphic on the left and the top graphic on this page. In other words, steric forces bend the molecule of methadone into the correct configuration to fit into the opiate receptor.
When you take methadone it first must be metabolized in the liver to a product that your body can use. Excess methadone is also stored in the liver and blood stream and this is how methadone works its 'time release trick' and last for 24 hours or more. Once in the blood stream metabolized methadone is slowly passed to the brain when it is needed to fill opiate receptors. Methadone is the effective treatment for heroin addiction. It works to smooth the ups and down of heroin craving and allows the person to function nomrally.
"Buprenorphine, an analgesic originally used IV for pre/post surgical analgesia and related, was approved not many years ago for opiate addiction treatment (brand names Subutex and, with naxolone added to help reduce IV abuse, Suboxone.  It is provided as a sublingual tablet, available a many, but not all, pharmacies.  As a practical matter, a big advantage over methadone is that it can be prescribed within a physician’s office setting, not a “methadone clinic.” The prescribing physician has to be certified to prescribe it, is issued a separate (2nd) DEA number, and is limited in the number of patients that may be seen for this treatment.  Another advantage is that it does not have the abuse potential of methadone; it merely fills the opiate receptors to eliminate physical cravings.  Onset of withdrawal from buprenorphine is slow, and the symptoms of withdrawal are generally milder, when compared with withdrawal from true opiates.  It has been used in prison settings to effectuate a fairly painless withdrawal process in as little as 5 days, although in a typical setting the patient will be weaned off buprenorphine over a period of 4-8 weeks, and occasionally will continue on a maintenance dose."

Narcotic Antagonists:
Narcotic Antagonists prevent or abolish excessive respiratory depression caused by the administration of morphine or related compounds. They act by competing for the same analgesic receptor sites. They are structurally related to morphine with the exception of the group attached to nitrogen.
Nalorphine precipitates withdrawal symptoms and produces behavioral disturbances in addition to the antogonism action. Naloxane is a pure antagonist with no morphine like effects. It blocks the euphoric effect of heroin when given before heroin.
Naltrexone became clinically available in 1985 as a new narcotic antagonist. Its actions resemble those of naloxone, but naltrexone is well is well absorbed orally and is long acting, necessitating only a dose of 50 to 100 mg. Therefore, it is useful in narcotic treatment programs where it is desired to maintain an individual on chronic therapy with a narcotic antagonist. In individuals taking naltrexone, subsequent injection of an opiate will produce little or no effect. Naltrexone appears to be particularly effective for the treatment of narcotic dependence in addicts who have more to gain by being drug-free rather than drug dependant.

6.Local Anesthetics
Unlike other drugs which act in the region of the synapse, local anesthetics are agents that reversibly block the generation and conduction of nerve impulses along a nerve fiber. They depress impulses from sensory nerves of the skin, surfaces of mucosa, and muscles to the central nervous system. These agents are widely used in surgery, dentistry, and ophthalmology to block transmission of impulses in peripheral nerve endings.
Most local anesthetics can be represented by the following general formula. In both the official chemical name and the proprietary name, a local anesthetic drug can be recognized by the "-caine" ending.
the ester linkage can also be an amide linkage. The most recent research indicates that the local anesthetic binds to a phospholipid in the nerve membrane and inhibits the ability of the phospholipid to bind Ca+2 ions.
Practically all of the free-base forms of the drugs are liquids. For this reason most of these drugs are used as salts (chloride, sulfate, etc.) which are water soluble, odorless, and crystalline solids. As esters these drugs are easily hydrolyzed with consequent loss of activity. The amide form of the drug is more stable and resistant to hydrolysis.
 eg- Benzocaine and Lidocaine:


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