1

Drugs affecting the central nervous system

16. Drugs stimulating the central nervous system

Drugs stimulating CNS comprise analeptic, psychoactive and nootropic

drugs.

This division is not precise, because many of these drugs demonstrate

multidirectional action.

2

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.

Caffeine and some of its derivatives (eg. phencamine and kofanol) are

examples of analeptics. In Poland only caffeine has been registered.

N

N

N

N

O

O

H3C

CH3

CH3Coffein, COFFEINUM NATRIUM BENZOICUM

3,7-Dihydro-1,3,7-trimethyl-1H-purine-2,6-dion

Caffeine and other methylxanthines are:

phosphodiesterase inhibitors, which results in an increased concentration of

cAMP in cells and increased activity

adenosine receptor antagonists; removes the inhibiting influence of

adenosine on the functions of the CNS and, in effect, the excitation of the CNS

is observed.

3

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 blood

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 metabolism centre, the thermoregulatory

centre (increasing the body temperature).

Caffeine demonstrates inotropic-positive action on the cardiac muscle.

Diuretic effect is also observed.

4

Caffeine is used:

in the failure of cardiac and vessel circulation

as a drug 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, insomnia, attention problems, muscle tremor,

arrhythmia, allergic reactions and gastrointestinal disturbance.

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

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16.2. Psychoactive drugsThe 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:

anxiety, 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 amphetamine

dexamphetamine, metamphetamine, methylphenidat, pemolin have not been

registered in many countries, including Poland.

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• amphetamine

• dexamphetamine

• methamphetamine

• methylphenidate

• pemoline and others

NH2

CH3* Amphetamine

Dexamphetamine (dextrorotatory isomer) demonstrates two

times greater activity than Levamphetamine.

ONH

O

CH3

Methylphenidate

7

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.

Dextroamphetamine 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.

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Methylphenidate has CNS stimulant 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 medications 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, dexmethylphenidate has been

approved in the United States for the treatment of ADHD.

N

O

H

CH3

H3C

Atomoxetine (NE reuptake inhibitor) is a

nonstimulant drug approved for ADHD in

children and adults. It is not recommended for

patients with narrow-angle glaucoma.

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Therapeutic uses (2)

Narcolepsy

Narcolepsy is a relatively rare sleep disorder

that is characterized by uncontrollable bouts of

sleepiness during the day. It is sometimes

accompanied by catalepsy.

In therapy of the narcolepsy the following are

used:

- amphetamine and methylphenidate

- modafinil and its R-enantiomer armodafinil

Modafinil produces fewer psychoactive and euphoric effects as vell

as, alterations in mood, perception, thinking and feelings typical of

other CNS stimulants.

S

O

NH2

O

Modafinil,

PROVIGIL

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Nicotine

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 alcohol as the most abused drug.

Mechanism of action. 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 euphoria 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.

N

N

H

CH3

11

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

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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

bupropion (an antidepressant which reduces the crawing for

cigarettes).

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Varenicline

Varenicline is a partial agonist at 42 neuronal nicotinic

acetylcholine 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 tobacco.

Patients should be monitored for suicidal thoughts, vivid

nightmares and mood changes.

N

N

N

H

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Cocaine

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 dopamine. This depletion triggers

the vicious cycle of crawing for cocaine that temporarilly relieves

severe depression.

H3C

CH3

O

O

N O

O

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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 adrenergic 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.

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Therapeutic uses

Cocaine has a local anesthetic action that represents the only

current rationale for the therapeutic use of cocaine.

For example, cocaine is applied topically as a local anesthetic

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.

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Adverse effects

• Anxiety

• Depression

• Toxic effects: Cocaine can induce seizures as well as fatal

cardiac arrhythmia. Use of IV diazepam 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.

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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.

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Pyrrolidone derivatives

Pyrrolidone derivatives can be considered as -aminobutyric acid derivatives.

Piracetam was the first nootropic drug introduced into therapy.

N

O

O

NH2

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

vessels, which improves brain microcirculation.

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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 narcotic intoxication, in carbon

oxide poisoning.

Piracetam analogues such as oxiracetam, pramiracetam, aniracetam and

linopirdine have been introduced into therapy, whereas the following compounds are

in clinical trials: monocyclic (etiracetam, nefiracetam and dupracetam), bicyclic

(dimiracetam and rolziracetam) and piperazine derivatives (tenilsetam).

Oxiracetam, etiracetam, aniracetam, tenilsetam and pramiracetam demonstrate

greater activity than piracetam.

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N

O

O

NH2

HO

Oxiracetam

NEUPAN, NEUROMET

H

N

N

N

O

O

H3C

CH3

CH3

CH3

Pramiracetam

PRAMISTAR

OCH3

O

ON

Aniracetam, DRAGANON,

RESET, SARPUL

N

N

N

O

Linopirdine, AVIVA

H

H S

N

N O

Tenilsetam, TENIMAL

H3C

CH3N

O

OHN

Nefiracetam

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N

N

O

O N

N

O

OHH

N

N

O

O

H2H3C

Dupracetam

Etiracetam

H

N

NO

O

Dimiracetam

N

O O

Rolziracetam

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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.

CH3

H3CO

NH

Deanol = Dimethyloaminoethanol

Deanol phosphate = Dihydrophosphate 2-(dimethyloamino)ethanol

OON

H3C

N

O

CH3

CH3

H

Deanol acetamidobenzoate, BIMANOL

Deanol 4-acetamidobenzoate

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.

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CH3 O

OO

NH3C

Cl

Meclofenoxate, CENTROPHENOXIN

2-(Dimethylamino)ethyl (4-chlorophenoxy)-

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.

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O

O

N

OO

NHO

OH

H3C CH3

CH3

Pirisudanol, NADEX, STIVAN

2-(Dimethylamino)ethyl [(5-hydroxy-4-hydroxy-

methyl)-6-methyl-3-pyridinyl]methyl succinate

Pirisudanol (dimethylaminoethanol and vitamin 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.

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Citicoline and gliatilin are choline esters. Citicoline is metabolized to choline and

5'-cAMP. It is used in disturbances of brain perfusion.

OH

OPOH3C

CH3H3C

+N

-

O

OOH

Choline alfoscerate, GLIATILIN

O

OHHO

O

N

N

NH2

OO P OPO

OH

O

O -

NH3C

CH3H3C

+

Citicoline

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.

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Lecithin (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 vitamins

pharmaceuticals containing certain lecithin components, for example GLIATILIN

(containing choline alforescate), BROS (phosphatydylserine), FOSFORINA

(L-serine dihydrophosphate).

PO3H2

COOH

H2NO

Dexfosfoserine, FOSFORINA, LSOP

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.

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Other nootropic and stimulating drugs

CH3

OH

HO

N

SS

OH

N

H3C

HO

Pyritinol, ENERBOL

Pyritinol (vitamin B6 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).

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O

N

N

O

O

O

Cl

Fipexide, FIPEXIUM

1-(1,3-Benzodioxol-5-ylmethyl)-4-

[(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.

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Drugs improving the brain perfusion

Vinca minor alkaloids (Vincamine, DEVINCAN) and their derivatives (Vinpocetine,

CAVINTON, CERACTIN)

Dihydrolizergic acid derivatives (HYDERGIN) and their synthetic derivatives

(Nicergoline, SERMION, ADAVIN)

Nonselective antagonists of the calcium channel: Flunarizine (SIBELIUM),

Cinnarizine (STUGERON)

Xantine derivatives: Pentoxyfilline (TRENTAL)

Nicotinic acid derivatives: Nicametat (PROVASAN), Nicotinamide (VITAMINUM PP)

Other: Bencyklan (HALIDOR), Naftidrofuryl (DUSODRIL), Suloctidil (SULOCTON).

These drugs are used in the disturbances of the peripheral blood flow and they are

presented in other chapter.

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1. Which of the following formulas are correct for:

- caffeine

- amphetamine

- atomoxetine

- nicotine

a. b. c. d.

N

N

N

N

O

O

H3C

CH3

CH3

NH2

CH3*

N

O

H

CH3

H3C

N

N

H

CH3

32

2. Which of the following formulas are correct for:

- piracetam

- deanol

- phenytoin

- ethosuximide

a. b. c. d.

N

O

O

NH2

CH3

H3CO

NH

R

HO

ON

N

R' H3C

NH

OO

CH3

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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

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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.

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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