Lec:5 Pharmacology dr.

hussam

CNS stimulants
CNS stimulants are drugs which increase the muscular (motor) and
the mental (sensory) activities .Their effects vary from the increase in
the alertness and wakefulness (as with caffeine) to the production of
convulsion (as with strychnine) or death due to over stimulation. CNS
stimulants are the psychoactive drugs that induce temporary
improvement in either mental or physical function or both. CNS
stimulants have few clinical uses and are important as drugs of
abuse.

Factors that limit the therapeutic usefulness include:

1. Dependence: Psychological and physiological.

2. Tolerance to the euphoric and anorectic effects

Behavioral Manifestations of CNS Stimulation :

Mild elevation in alertness, decrease in drowsiness and lessening of

fatigue (Analeptic effect), increased nervousness and anxiety -
convulsions.

There are two types of CNS stimulants:

1. Psychomotor stimulants: cause excitement, euphoria, Decrease

feeling of fatigue & Increase motor activity Ex.,
Methylxanthines (caffeine, theobromine, theophylline),
nicotine, cocaine, amphetamine, atomoxetine, modafinil,
methylphenidate.

2. Hallucinogens or Psychomimetic drugs: Affect thought,

perception, and mood.

Ex. Lysergic acid diethylamide (LSD), Phencyclidine (PCP),

Tetrahydrocannabinol (THC), Rimonabant.

Therapeutic Indications and Contraindications for CNS Stimulants:

Obesity (anorectic agents). Attention Deficit Hyperactivity Disorder

(ADHD); lack the ability to be involved in any one activity for longer
than a few minutes.

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Narcolepsy: It is a relatively rare sleep disorder that is characterized

by uncontrollable bouts of sleepiness during the day. It is sometimes
accompanied by catalepsy, a loss in muscle control, or even paralysis
brought on by strong emotion, such as laughter.

Contraindications: patients with anorexia, insomnia, asthenia,

psychopathic personality, a history of homicidal or suicidal
tendencies.

1. Psychomotor stimulants:

A. Methylxanthines: The methylxanthines include theophylline,

which is found in tea; theobromine, which is found in cocoa; and
caffeine. Caffeine, the most widely consumed stimulant in the world,
is found in highest concentration in certain coffee products (for
example, espresso), but it is also present in tea, cola drinks, energy
drinks, chocolate candy, and cocoa.

Mechanism of action: Several mechanisms have been proposed for

the actions of methylxanthines, including translocation of
extracellular calcium, increase in cyclic adenosine monophosphate
and cyclic guanosine monophosphate caused by inhibition of
phosphodiesterase, and blockade of adenosine receptors.

Actions:

Central nervous system: The caffeine contained in one to two cups

of coffee (100-200 mg) causes a decrease in fatigue and increased
mental alertness as a result of stimulating the cortex and other areas
of the brain. Consumption of 1.5 g of caffeine (12-15 cups of
coffee)produces anxiety and tremors. The spinal cord is stimulated
only by very high doses (2-5 g) of caffeine. Tolerance can rapidly
develop to the stimulating properties of caffeine, and withdrawal
consists of feelings of fatigue and sedation.

Cardiovascular system: A high dose of caffeine has positive

inotropic and chronotropic effects on the heart.[Note: Increased
contractility can be harmful to patients with angina pectoris. In
others, an accelerated heart rate can trigger premature ventricular
contractions.]

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Diuretic action: Caffeine has a mild diuretic action that increases

urinary output of sodium, chloride, and potassium.

Gastric mucosa: Because methylxanthines stimulate secretion of

gastric acid, individuals with peptic ulcers should avoid foods and
beverages containing methylxanthines.

Therapeutic uses: Caffeine and its derivatives relax the smooth

muscles of the bronchioles. Theophylline has been largely replaced by
other agents, such as β2 agonists and corticosteroids, for the
treatment of asthma. Caffeine is also used in combination with the
analgesic’s acetaminophen and aspirin for the management of
headaches in both prescription and over-the-counter products.
Caffeine is often used by the general public to maintain wakefulness
and temporarily reduce fatigue.

Pharmacokinetics: The methylxanthines are well absorbed orally.

Caffeine distributes throughout the body, including the brain. These
drugs cross the placenta to the fetus and are secreted into the breast
milk. All methylxanthines are metabolized in the liver, generally by
the cytochrome P450(CYP)1A2 pathway, and the metabolites are
excreted in the urine.

Adverse effects: Moderate doses of caffeine cause insomnia, anxiety,

and agitation. A high dosage is required for toxicity, which is
manifested by emesis and convulsions. The lethal dose is 10 g of
caffeine (about 100 cups of coffee), which induces cardiac
arrhythmias. Lethargy, irritability, and headache occur in users who
routinely consume more than600 mg of caffeine per day (roughly six
cups of coffee per day) and then suddenly stop.

B. Nicotine:

Nicotine is the active ingredient in tobacco. It used therapeutically

only in smoking cessation therapy, Nicotine 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.

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Actions of Nicotine:

Low dose: ganglionic depolarization

High dose: ganglionic blockade

Actions:

I. CNS: Nicotine is highly lipid soluble and readily crosses the

Blood–brain barrier.

1. Low dose: euphoria, arousal, relaxation, improves attention,

learning, problem solving and reaction time.

2. High dose: central respiratory paralysis.

Nicotine also an appetite suppressant.

II. Peripheral effects:

◼ Stimulation of sympathetic ganglia and adrenal medulla→↑ BP

and HR (harmful in HTN patients)

◼ Stimulation of parasympathetic ganglia→↑ motor activity of the

bowel

◼ At higher doses, BP falls & activating ceases in both GIT and

bladder

Pharmacokinetics:

Highly lipid soluble absorbed everywhere (oral mucosa, lung, GIT,

skin).Crosses the placental membrane, secreted with milk. Most
cigarettes contain 6-8 mg of nicotine, by inhaling tobacco smoke;
the average smoker takes in 1 to 2 mg of nicotine per cigarette.
The acute lethal dose is 60 mg, it absorbed through skin (toxic).

Adverse effects: CNS; irritability and tremors

◼ Intestinal cramps, diarrhea, lung cancer.

◼ ↑HR & BP

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Withdrawal syndrome: nicotine is addictive substance, Withdrawal is

characterized by irritability, anxiety, restlessness, difficulty
concentrating, headaches, and insomnia. Appetite is affected, and GI
upset often occurs.

◼ Physical dependence on nicotine develops rapidly and can be

severe.

◼ Bupropion: antidepressant can reduce the craving for

cigarettes

◼ Transdermal patch and chewing gum containing nicotine

◼ cigarette smoking increases the rate of metabolism for a

number of drugs.

C. Varenicline: is a partial agonist at neuronal nicotinic

acetylcholine receptors in the CNS. It produces less euphoric
effects than those produced by nicotine itself (nicotine is full
agonist at these receptors). Thus, it is useful as an adjunct in the
management of smoking cessation in patients with nicotine
withdrawal symptom. Patients taking varenicline should be
monitored for suicidal thoughts, vivid nightmares, and mood
changes.

D. Cocaine (highly addictive drug):

1. Mechanism of action: blockade of reuptake of the monoamines

(NE, serotonin and dopamine) thus, potentiates and prolongs the CNS
and peripheral actions of these monoamines. Initially produces the
intense euphoria by prolongation of dopaminergic effects in the
brain’s pleasure system (limbic system). Chronic intake of cocaine
depletes dopamine. This depletion triggers the vicious cycle of
craving for cocaine that temporarily relieves severe depression.

2. Actions:

a. CNS-behavioral effects result from powerful stimulation of cortex

and brain stem. Cocaine acutely increase mental awareness and
produces a feeling of wellbeing and euphoria similar to that
produced by amphetamine.

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b. Hyperthermia: impair sweating & cutaneous vasodilation,

↓Perception of thermal discomfort.

c. local anesthetic action: blockade of voltage-activated Na+ channel.

◼ Cocaine is the only LA that causes vasoconstriction, chronic

inhalation of cocaine powder → necrosis and perforation of the
nasal septum

◼ Cocaine is often self-administered by chewing, intranasal

snorting, smoking, or intravenous (IV) injection.

Adverse effects: Anxiety reaction that includes: hypertension,

tachycardia, sweating, and paranoia. Because of the irritability,
many users take cocaine with alcohol. A product of cocaine
metabolites and ethanol is cocaethylene, which is also
psychoactive and cause cardiotoxicity.

◼ Depression: Like all stimulant drugs, cocaine stimulation of the

CNS is followed by a period of mental depression.

◼ Addicts withdrawing from cocaine exhibit physical and

emotional depression as well as agitation. The latter symptom
can be treated with benzodiazepines or phenothiazines.

Toxic effects:

◼ Seizures RX I.V diazepam

◼ Fatal cardiac arrhythmias. propranolol

E. Amphetamine:

◼ Amphetamine is a sympathetic amine that shows neurologic

and clinical effects quite similar to those of cocaine .
Methamphetamine (also known as “speed”) is a derivative of
amphetamine available for prescription use. It can also be
smoked and is preferred by many abusers.

◼ Amphetamine, however, achieves this effect by releasing

intracellular stores of catecholamines.

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◼ Because amphetamine also inhibits monoamine oxidase (MAO)

and is a weak reuptake transport inhibitor, high levels of
catecholamines are readily released into synaptic spaces .The
major behavioral effects of amphetamine result from a
combination of its dopamine and norepinephrine release-
enhancing properties
◼ Amphetamine stimulates the entire cerebrospinal axis, cortex,
brainstem, and medulla. This leads to increased alertness,
decreased fatigue, depressed appetite, and insomnia.

Therapeutic uses: Factors that limit the therapeutic usefulness of

amphetamine include psychological and physiologic dependence.

1. Attention deficit hyperactivity disorder: Children with

attention deficit hyperactivity disorder (ADHD)are
hyperkinetic and lack the ability to be involved in any activity
for longer than a few minutes. Dextroamphetamine,
lisdexamfetamine, methamphetamine, and the mixed
amphetamine salts are stimulant drugs that help improve
attention span and alleviate many of the behavioral problems
associated with this syndrome, in addition to reducing
hyperkinesia. Stimulants are considered first-line agents in the
treatment of ADHD.
2. Narcolepsy: Narcolepsy is a relatively rare sleep disorder that
is characterized by uncontrollable bouts of sleepiness during
the day. The sleepiness can be treated with drugs, such as the
mixed amphetamine salts, methylphenidate, modafinil, or
armodafinil.
3. Appetite suppression: Phentermine and diethylpropion are
sympathomimetic amines that are related structurally to
amphetamine. These agents are used for appetite suppressant
effects in the management of obesity.
Pharmacokinetics: Amphetamine is completely absorbed
from the GI tract, metabolized by the liver, and excreted in the
urine. Amphetamine abusers often administer the drug by IV
injection and/or by smoking.

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3. Adverse effects:

The amphetamines may cause addiction, dependence, tolerance, and

drug seeking behavior. Insomnia, irritability, weakness, dizziness,
tremor, hyperactive reflex, confusion, delirium, panic states, and
suicidal tendencies, especially in mentally ill patients. amphetamine
may cause palpitations, cardiac arrhythmias, hypertension, anginal
pain, and circulatory collapse. The cardiovascular adverse effects
have contributed to sudden cardiac death in persons with underlying
cardiac abnormalities or risks that may have not been recognized
prior to stimulant use. Amphetamine acts on the GI system, causing
anorexia, nausea, vomiting ,abdominal cramps, and diarrhea.

Overdoses are treated with chlorpromazine or haloperidol, which

relieve the CNS symptoms as well as the HTN because of their α–
blocking effects.

Contraindications: HTN, CV diseases, Hyperthyroidism, Glaucoma,

Patients with a history of drug abuse or those taking MAO inhibitors
should not be treated with amphetamine.

Atomoxetine: approved for ADHD in children and adults. It is a NE

reuptake inhibitor (should not be taken by individual on MAOI).It is
not habit forming and is not a controlled substance.

Methylphenidate (Ritalin) ®: It has CNS stimulant properties similar

to those of amphetamine and may also lead to abuse, although its
addictive potential is controversial.

Therapeutic uses: Methylphenidate has been used for several

decades in the treatment of ADHD in children aged 6 to 16. It is also
effective in the treatment of narcolepsy. Unlike methylphenidate,
dexmethylphenidate is not indicated in the treatment of narcolepsy.

Adverse reactions: GIT effects are the most common; abdominal pain
and nausea.

In seizure patients, methylphenidate seems to increase the seizure

frequency, especially if the patient is taking antidepressants.
Methylphenidate is contraindicated in patients with glaucoma.

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◼ Recently, a new drug, modafinil and its R-enantiomer

derivative, armodafinil, have become first line treatment for
narcolepsy.

II. Hallucinogens (psychotomimetic): A few drugs have the ability to

induce altered perceptual states reminiscent of dreams, are
accompanied by bright, colourful changes in the environment and by
a plasticity of constantly changing shapes and colour.

The individual under the influence of these drugs is incapable of

normal decision making, because the drug interferes with rational
thought.

A. Lysergic acid diethylamide: The drug shows serotonin (5-HT)

agonist activity at presynaptic 5-HT1 receptors in the midbrain, and
also stimulates 5-HT2 receptors. Activation of the sympathetic
nervous system occurs, which causes pupillary dilation, increased BP,
piloerection, and increased body temperature.

Adverse effects: include hyperreflexia, nausea, and muscular

weakness

Haloperidol and other neuroleptics can block the hallucinatory action

of LSD and quickly abort the syndrome.

B. Tetrahydrocannabinol (THC): The main psychoactive alkaloid

contained in marijuana is tetrahydrocannabinol (THC), which is
available as dronabinol. THC can produce euphoria, followed by
drowsiness and relaxation. THC receptors, designated CB1 receptors,
have been found on inhibitory presynaptic nerve terminals. CB1 is
coupled to a G protein.

1. Therapeutic uses of Dronabinol: as an appetite stimulant for

patients with acquired immunodeficiency syndrome who are
losing weight.

2. It is also sometimes given for the severe emesis caused by

some cancer chemotherapeutic agents.

Adverse effects: include increased heart rate, decreased blood

pressure, and reddening of the conjunctiva.

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