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
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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
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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
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