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Home , Aniracetam, Dimiracetam, Dupracetam, Etiracetam, Meclofenoxate, Nefiracetam

Drugs affecting the central

16. stimulating the

Drugs stimulating CNS comprise analeptic, psychoactive and drugs. This division is not precise, because many of these drugs demonstrate multidirectional action.

1 16.1. Analeptic drugs

The analeptics stimulate mainly the function of the respiratory and vasomotor centre, but some of them also influence the intellectual function of the brain. and some of its derivatives (eg. phencamine and kofanol) are examples of analeptics. In Poland only caffeine has been registered.

CH O 3 Coffein, COFFEINUM NATRIUM BENZOICUM H3C N N

O N N 3,7-Dihydro-1,3,7-trimethyl-1H--2,6-dion

CH3 Caffeine and other methylxanthines are:

 phosphodiesterase inhibitors, which results in an increased concentration of cAMP in cells and increased activity  antagonists; removes the inhibiting influence of adenosine on the functions of the CNS and, in effect, the excitation of the CNS is observed. 2 Caffeine acts on the cerebral cortex, the autonomous nervous system centre and on the striated muscles. In low doses, caffeine acts almost exclusively on the psychic functions of the cerebral cortex, facilitating thinking and removing fatigue and somnolence. However, a person under the influence of caffeine may find it difficult to concentrate. In high doses caffeine a flight of ideas and sleep disturbances. The stimulation of the vasomotor centre by caffeine leads to:  contraction of the intestinal vessels and displacement of the from the abdominal cavity to the muscles, skin and brain  contraction of the brain vessels, because of which caffeine may alleviate headaches caused by dilation of the brain vessels. Caffeine is also found to have stimulating effect on the respiratory centre (only when it is inhibited), the centre, the thermoregulatory centre (increasing the body temperature).

Caffeine demonstrates inotropic-positive action on the cardiac muscle. effect is also observed. 3 Caffeine is used:

 in the failure of cardiac and vessel circulation  as a stimulating the psychic function of the cerebral cortex  as a drug contracting overdilated brain vessels to remedy headache.

Caffeine is contraindicated when the disturbance of the cardiac rhythm occurs.

The adverse effects observed when caffeine is used, especially in high doses, include headache, , problems, muscle tremor, arrhythmia, allergic reactions and gastrointestinal disturbance.

A dose of caffeine exceeding 15-20 times a therapeutic dose is lethal.

4 16.2. Psychoactive drugs The psychoactive drugs influence especially the intellectual and emotional functions of the brain. Their action involves:  increasing intellectual activity, attention focus, perception of stimuli, etc., both in the normal emotional state and in depression  removing the feeling of fatigue and sleepiness  enhancing of psychomotor activity

However, the psychoactive drugs demonstrate many dangerous adverse effects:  , insomnia, psychic overexcitement, flight of ideas, muscle tremor, convulsions, headache, hallucination, tendency to vident reactions include suicidal thoughts  hypertension, which can lead to heart failure resulting in death  xerostomia, vomiting, diarrhea  euforia and drug dependence. Because of the many adverse effects, such psychoactive drugs such as dexamphetamine, metamphetamine, methylphenidat, pemolin have not been 5 registered in many countries, including Poland. CH • amphetamine * 3 Amphetamine • dexamphetamine NH2 • •

• and others H Methylphenidate N O CH3 O

Dexamphetamine (dextrorotatory isomer) demonstrates two times greater activity than Levamphetamine.

6 Therapeutic uses (1)

. ADHD (Attention deficit hyperactivity disorder) Some young children are hyperkinetic and lack the ability to be involved in any one activity for longer than a few minutes. and the amphetamine, derivative methylphenidate are able to improve attention and to alleviate many of the behavioral problems associated with this syndrome, and to reduce the hyperkinesia that such children demonstrate. Lisdexamphetamine is a prodrug that is converted to the active component dextroamphetamine after gastointestinal absorption and metabolism. The drug prolongs the patient’s span of attention allowing better function in a school atmosphere.

7 H3C (NE ) is a O nonstimulant drug approved for ADHD in CH3 N children and adults. It is not recommended for H patients with narrow-angle glaucoma.

Methylphenidate has CNS properties similar to those of amphetamine and may also lead to abuse, although its addictive potential is controversial. It is presently one of the most prescribed in children. It is estimated that methylphenidate is taken daily by 4 to 6 million children in the United States for ADHD. The pharmacologically active isomer, has been approved in the United States for the treatment of ADHD.

8 Therapeutic uses (2)

O O . Narcolepsy S NH2 Narcolepsy is a relatively rare sleep disorder that is characterized by uncontrollable bouts of sleepiness during the day. It is sometimes , accompanied by catalepsy. PROVIGIL

In therapy of the narcolepsy the following are used: - amphetamine and methylphenidate - modafinil and its R-enantiomer

Modafinil produces fewer psychoactive and euphoric effects as vell as, alterations in mood, perception, thinking and feelings typical of other CNS . 9 H N N CH3 Although nicotine is not currently used therapeutically (except in smoking cessation therapy), it remains important, because it is second only to caffeine as the most widely used CNS stimulant and second only to as the most abused drug. . In low doses, nicotine causes ganglionic stimulation by depolarization. At high doses, nicotine causes ganglionic blockade. Nicotine receptors exist at a number of sites in the CNS, which participate in the stimulant attributes of the drug. Action. Low doses of nicotine produces some degree of and arousal as well as relaxation. It improves attention, learning, problem solving, and reaction time. High doses of nicotine result in central respiratory paralysis and severe hypotension caused by medullary paralysis. Nicotine is an appetite suppressant. 10 Adverse effects

. CNS - irritability and tremors . the gastrointestinal system – intestinal cramps, diarrhea . the cardiovascular system – increased heart rate and blood pressure . cigarette smoking increases the rate of metabolism for a number of drugs

11 Withdrawal syndrome Nicotine is an addictive substance, and physical dependence on nicotine develops rapidly and can be severe. Withdrawal is characterized by irritability, anxiety, restlessness, difficulty concentrating, headaches, and insomnia. Appetite is affected, and gastrointestinal pain often occurs. Smoking cessation programs that combine pharmacologic and behavioral therapy are the most successful in helping individuals to stop smoking. To help smokers stop smoking the following are used: . the transdermal patch and chewing gum containing nicotine . (an which reduces the crawing for cigarettes). 12 N HN N

Varenicline is a partial at 42 neuronal nicotinic receptors in the CNS. Because it is only a partial agonist at these receptors, it produces less euphoric effects than those produced by nicotine itself (nicotine is a full agonist at these receptors). Thus, it is useful as an adjunct in the management of smoking cessation in patient with nicotine withdrawal symptoms. Additionaly, varenicline tends to attenuate the rewarding effects of nicotine if a person relapses and uses . Patients should be monitored for suicidal thoughts, vivid nightmares and mood changes.

13 O CH3 O H3C N O O Cocaine is highly addictive drug that is currently abused daily by more than 3 million in the United States. Mechanism of action The primary mechanism of action underlying the central and peripheral effects of cocaine is blockade of reuptake of the monoamines (NE, 5-HT, DA) into presynaptic terminals from which these neurotransmitters are released. In particular, the prolongation of dopaminergic effects in the brain’s pleasure system (limbic system) produces the intense euphoria that cocaine initially causes. Chronic intake of cocaine depletes . This depletion triggers the vicious cycle of crawing for cocaine that temporarilly relieves severe depression. 14 Action . CNS: Cocaine acutely increases mental awareness and produces a feeling of wellbeing and eupforia similar to that caused by amphetamine. Like amphetamine, cocaine can produce hallucinations and delusions of paranoia or grandiosity. Cocaine increases motor activity, and at high doses, it causes tremors and convulsions, followed by respiratory and vasomotors depression. . Sympathic nervous system: Peripherally, cocaine potentiates the action of NE, and it produces the „fight or flight” syndrome characteristic of stimulation. This is associated with tachycardia, hypertension, pupillary dilation, and peripheral vasoconstruction. . Hyperthermia: Cocaine is unique among illicit drugs in that death can result not only as a function of dose but also from the drug’s propensity to cause hyperthermia. Even a small dose of intranasal cocaine impairs sweating and cutaneous vasodilatation. 15 Therapeutic uses Cocaine has a local action that represents the only current rationale for the therapeutic use of cocaine. For example, cocaine is applied topically as a during eye, ear, nose, and throat surgery. The local anesthetic action of cocaine is due to a block of voltage- activated sodium channels. An interaction with potassium channels may contribute to the ability of cocaine to cause cardiac arrhythmia.

16 Adverse effects

• Anxiety • Depression • Toxic effects: Cocaine can induce as well as fatal cardiac arrhythmia. Use of IV and propranolol may be required to control cocaine-induced seizures and cardiac arrhythmia, respectively. The incidence of myocardial infarction in cocaine users is unrelated to dose, to duration of use, or to route of administration.

17 16.3. Nootropic drugs (psychoenergizing drugs)

Two groups the nootropic drugs are distinguished:

 nootropic drugs proper, which normalise neuronal metabolism by decreasing the demand for oxygen or preventing the decoupling of oxidative phosphorylation in the mitochondria  drugs improving the blood flow, which results in a better supply of oxygen to the brain tissue.

The nootropic drugs are mainly pyrrolidone and aminoethanol derivatives.

18 Pyrrolidone derivatives

Pyrrolidone derivatives can be considered as -aminobutyric acid derivatives. was the first nootropic drug introduced into therapy. O

NH2 N O Piracetam, NOOTROPIL

2-Oxo-1-pyrrolidinacetamide Piracetam:

 increases the resistance of nervous cells to hypoxia and intensifies the synthesis and use of high-energy compounds, which results in the improvement learning ability, memory and attention  affects the rheological properties of the blood by:

 decreasing thrombocyte aggregation and increasing the elasticity of red blood cells

 decreasing vascular resistance and increasing the elasticity of capillary 19 vessels, which improves brain microcirculation. Piracetam is rapidly and totally absorbed after oral administration. Its maximal concentration in the blood is reached after 45 minutes and in the cerebrospinal fluid after 2-8 h. The time-life of piracetam in the blood is 4-5 h, in plasma and the cerebrospinal fluid 6-8 h. This time elongates in kidney insufficiency. It is eliminated in urin as unchanged drug during 30 h.

Piracetam is used:

 in disturbances of memory and attention in older individuals  in CNS-related apoplexy, and vertigo  in children with behavior and reading problems  in chronic or acute alcoholism, in chronic or acute intoxication, in carbon oxide poisoning.

Piracetam analogues such as , , and have been introduced into therapy, whereas the following compounds are in clinical trials: monocyclic (, and ), bicyclic ( and ) and derivatives (tenilsetam). Oxiracetam, etiracetam, aniracetam, tenilsetam and pramiracetam demonstrate greater activity than piracetam. 20 O H C CH O 3 3 O CH3 NH2 N CH N 3 O N O H N O CH3 N O

HO Oxiracetam Pramiracetam Aniracetam, DRAGANON, NEUPAN, NEUROMET PRAMISTAR RESET, SARPUL

H3C N H O O N O N N H CH N N O 3 H S N

Linopirdine, AVIVA Tenilsetam, TENIMAL Nefiracetam

21 O O N N Dupracetam H H N O N O

O

H3C NH2 Etiracetam N O

H N O Dimiracetam N O

N Rolziracetam O O

22 Aminoethanol derivatives

The aminoethanol esters are considered to be acetylcholine precursors. They increase the oxidative phosphorylation and penetration of glucose into neurons. Indications to use them are the same as those of piracetam.

Deanol = Dimethyloaminoethanol CH3 N O H Deanol phosphate = Dihydrophosphate 2-(dimethyloamino)ethanol H3C

CH 3 O Deanol acetamidobenzoate, BIMANOL N H3C O O Deanol 4-acetamidobenzoate N CH3 H Deanol is used in the form of dihydrophosphate and 4-acetaminobenzoate (BIMANOL). Deanol increases interneuronal conductivity, improves the patient’s mood, increases his psychomotor drive and acts antidepressively. Deanol is used in chronic emotional disturbances, depressive neurosis, in certain forms of schizophrenia and in sclerotic encephalopathy. In children it is used in the treatment of attention disturbances, learning difficulties and in chronic fatigue and noctural miction. 23 CH 3 O , CENTROPHENOXIN N O H3C O 2-(Dimethylamino)ethyl (4-chlorophenoxy)- Cl acetate

Meclofenoxate:

 counteracts hypoxia, which is caused by both insufficient oxygen supply and problems with the use of oxygen  improves the use of glucose by the brain, which facilitates the maintenance of energetic balance when an insufficient supply of oxygen and aging of brain cells are observed  dilates the brain vessels, especially in the substantia nigra.

Meclofenoxate is used in the disturbances of behavior and memory caused by brain aging, after injuries, brain trauma and in anesthesia to decrease the unwanted symptoms after analgesia.

24 H C N CH 3 O 3 , NADEX, STIVAN O N HO O CH3 2-(Dimethylamino)ethyl [(5-hydroxy-4-hydroxy- O OH methyl)-6-methyl-3-pyridinyl]methyl succinate

Pirisudanol (dimethylaminoethanol and B6 succinate):

 stimulates the reticular system  improves the hemodynamic and metabolic functions of neurons  increases the use of glucose  sensitizes the brain circulation to carbon dioxide.

Pirisudanol is used in the treatment of memory and attention problems, in retarded psychic development in children.

25 and gliatilin are esters. Citicoline is metabolized to choline and 5'-cAMP. It is used in disturbances of brain perfusion.

CH H C 3 O 3 O Choline alfoscerate, GLIATILIN N + P H3C O OH - O OH NH2 N Citicoline CH O 3 O - OH N H3C N H3C + O P O P O O O O HO OH Citicoline:

 stimulates the synthesis of phospholipids  contracts brain edema  may increases the resistance of the brain to hypoxia and decreases neurological disturbances caused by ischemia  decreases the concentration of free fatty acids

 restores dopaminergic transmission. 26 (phospholipid) contains mainly phosphatydylethanolamine, phosphatydylserine and phosphatydylinozytol and additionally other substances such as triacylglicerols, free fatty acids and carbohydrates.

In therapy the following are used:

 pharmaceuticals containing lecithin such as BUERLECITHIN, LECITAN (containing soybean lecithin and soybean oil ) and pharmaceuticals containing lecithin, glucose and  pharmaceuticals containing certain lecithin components, for example GLIATILIN (containing choline alforescate), BROS (phosphatydylserine), FOSFORINA (L- dihydrophosphate).

COOH O Dexfosfoserine, FOSFORINA, LSOP H2N PO3H2 L-serine dihydroposphate

Because the components of lecithin are the components of the cell membrane, it is thought that lecithin or its components can be used in the degeneration of CNS. Additionally, lecithin products are used in convalescence, in physical and nervous exhaustion, in hyperlipidemia and in the treatment of the respiratory failure caused by the deficiency of surfactant in premature babies. 27 Other nootropic and stimulating drugs

H3C N OH

S OH , ENERBOL HO S

HO N CH3

Pyritinol ( bisulfide derivative) acts beneficially in memory disturbances (action is observed after long-lasting administration) and it also demonstrates anti- inflammatory action.

Pyritinol is used in the states of nervous exhaustion, after the injury, stroke inflammation of the brain, in the metabolic disorders, brain circulation problems, in migraine, trigeminal neuralgia, mental and psychic retardation in children and in rheumatoid arthritis (anti-inflammatory action).

28 O O , FIPEXIUM O O N N 1-(1,3-Benzodioxol-5-ylmethyl)-4- Cl [(4-chlorophenoxy)acetyl]piperazine

Fipexide stimulates the CNS but does not demonstrate amfetamine action. It is believed that fipexide decreases the number of serotonin receptors during long- lasting administration. Fipexide is used in functional psycho-physical exhaustion.

29 Drugs improving the brain perfusion

 Vinca minor alkaloids (, DEVINCAN) and their derivatives (, CAVINTON, CERACTIN)  Dihydrolizergic acid derivatives (HYDERGIN) and their synthetic derivatives (, SERMION, ADAVIN)  Nonselective antagonists of the calcium channel: Flunarizine (SIBELIUM), (STUGERON)  Xantine derivatives: Pentoxyfilline (TRENTAL)  Nicotinic acid derivatives: Nicametat (PROVASAN), (VITAMINUM PP)  Other: Bencyklan (HALIDOR), (DUSODRIL), (SULOCTON).

These drugs are used in the disturbances of the peripheral blood flow and they are presented in other chapter.

30 1. Which of the following formulas are correct for:

- caffeine - amphetamine - atomoxetine - nicotine

H3C O CH3 H C H 3 N * CH3 O N N CH3 N N O N CH NH2 H N 3 CH3

a. b. c. d.

31 2. Which of the following formulas are correct for:

- piracetam - deanol - -

H O N H CH3 O O N O NH2 N CH3 H C O H N O R' 3 N H3C O R

a. b. c. d.

32 3. Choose the incorrect answer. a) Fipexide stimulates the CNS but does not demonstrate amfetamine action. b) Pyritinol is vitamin B6 bisulfide derivative c) Citicoline stimulates the synthesis of phospholipids d) Meclofenoxate improves the use of glucose by the brain, e) Piracetam increasing thrombocyte aggregation and increasing the elasticity of red blood cells

33 4. Choose the incorrect answers. a) Caffeine is selective phosphodiesterase inhibitors. b) Caffeine demonstrates inotropic-positive action on the cardiac muscle. c) Caffeine is contraindicated when the disturbance of the cardiac rhythm occurs. d) Levamphetamine demonstrates greater activity than Dexamphetamine. e) In therapy of the narcolepsy the following are used: amphetamine, methylphenidate, modafinil and armodafinil.

34 5. Choose the incorrect answer. Caffeine is used: a) as a drug contracting overdilated brain vessels to remedy headache b) as a drug stimulating the psychic function of the cerebral cortex c) in the failure of cardiac and vessel circulation d) as diuretic e) in diagnosis as a drug incrasing the release of HCl

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