Drugs acting on CNS

CNS Stimulant
(Drugs of Abuse)

Dr. Muhammad Sarfraz

College of Pharmacy Al-Ain University
Al Ain, UAE.
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Stimulants (Drugs of Abuse)

“Stimulants are substances which tends to increase
behavioral activity when administered”.

“Drugs that speed up the CNS; produce wakefulness and

a sense of energy and well being”.

Stimulants are also referred as “uppers” as they up your

energy and alertness.
 Molecular Basis of CNS Stimulation 3

Imbalance between the inhibitory and excitatory

processes as in brain. This hyperexcitability of neurons
results from:
 Potentiation or excitement of excitatory
neurotransmission (e.g Amphetamine)
 Depression or antagonism of inhibitory transmission
 (e.g Strychnine)
 Presynaptic control of neurotransmitter release (e.g
Picrotoxin)
 CNS stimulants
1. Psychomotor stimulants
cause: Excitement, Euphoria, Decrease feeling of fatigue
and Increase motor activity
Ex. Methylxanthines (caffeine, theobromine, theophylline),
nicotine, cocaine, amphetamine, atomoxetine, modafinil,
methylphenidate.

2. Hallucinogens (psychotomimetic)
Affect thought, perception, and mood
Ex. Lysergic acid diethylamide (LSD), Phencyclidine (PCP),
Tetrahydrocannabinol (THC), Rimonabant.
 Amphetamine
• Is a non catecholamine (shows a neurologic and clinical
effects quite similar to those of cocaine).
• Dextro-amphetamine is the major member of this class
of compounds,
• Methamphetamine (Speed) is derivative of
amphetamine that can be smoked and it is preferred
by many abusers.
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• MOA:
Block the reuptake of
norepinephrine and
dopamine into the
presynaptic neuron and
increase the release of
these monoamines into
the extra-neuronal
space.
Actions 7

a) CNS:
Major behavioral effects of amphetamine results from
combination of the dopamine and NE release
properties
• Increased alertness
• Decreased fatigue
• Decreased appetite
• Insomina

b) Sympathetic Nervous system: By indirectly stimulating

the receptors through NE release
 Therapeutic uses of amphetamine 8

Narcolepsy (Day time sleepiness):

 A rare sleep disorder characterized by un-controllable bouts of
sleepiness during the day. It is sometimes accompanied by
catalepsy (loss of muscle control) and even paralysis brought on
by strong emotions such as laughter, however it is sleepiness for
which the patient is treated with drugs such as Amphetamine or
Methamphetamine.
 Recently Modafinil (wakefulness promoting agent) and its R-
enantiomer Amodafinil have become available to treat
narcolepsy. Modafinil produces few psychoactive and euphoric
effects with fewer alterations in perception, mood ,thinking and
feelings typical of other CNS stimulants.
Therapeutic uses of amphetamine 9

Attention-deficit hyperactivity disorder (ADHD):

Some young children are hyperkinetic and lack the ability to be
involved in any activity for longer than a few minutes.
Dextroamphetamine and the amphetamine derivative
methylphenidate can help improve attention spans and alleviate
many of the behavioral problems associated with this
syndrome, in addition to reducing the hyperkinesia that such
children demonstrate.

Atomoxetine is a nonstimulant drug approved for ADHD in

children and adults. It is a norepinephrine-reuptake inhibitor.
Therefore, it is not habit forming and is not a controlled
substance.
Therapeutic uses of amphetamine

• Appetite suppression: Phentermine and diethylpropion

are sympathomimetic amines that are related structurally
to amphetamine.
• These agents are used for their appetite-suppressant
effects in the management of obesity.
Adverse effects
• The amphetamines may cause addiction, leading to
dependence, tolerance, and drug-seeking behaviour. In
addition, they have the following undesirable effects.
• a. CNS effects: Adverse effects of amphetamine usage
include insomnia, irritability, weakness, dizziness, tremor,
and hyperactive reflexes. Amphetamine can also cause
confusion, delirium, panic states, and suicidal tendencies,
especially in mentally ill patients. Chronic amphetamine
use produces a state of “amphetamine psychosis” that
resembles the psychotic episodes associated with
schizophrenia.
Adverse effects
• b. Cardiovascular effects: In addition to its CNS effects,
amphetamine causes palpitations, cardiac arrhythmias,
hypertension, anginal pain, and circulatory collapse.
Headache, chills, and excessive sweating may also occur.
• c. GI system effects: Amphetamine acts on the GI system,
causing anorexia, nausea, vomiting, abdominal cramps,
and diarrhoea.
• d. Contraindications: Patients with hypertension,
cardiovascular disease, hyperthyroidism, glaucoma, or a
history of drug abuse or those taking MAO inhibitors
should not be treated with amphetamine.
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Nicotine
• It is active ingredient in tobacco
• Nicotine remains important because:

It is 2nd only to caffeine as most widely used

It is 2nd only to alcohol as most abused drug
Nicotine
• Actions:
• CNS: Nicotine is highly lipid soluble and
readily crosses the blood–brain barrier.
• Cigarette smoking or administration of 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 also an appetite suppressant
 Nicotine
• Peripheral effects: The peripheral effects of nicotine are complex.
• Stimulation of sympathetic ganglia as well as of the adrenal
medulla increases blood pressure and heart rate.
• Thus, use of tobacco is particularly harmful in hypertensive patients.
• Many patients with peripheral vascular disease experience an
exacerbation of symptoms with smoking.
• In addition, nicotine induced vasoconstriction can decrease coronary
blood flow, adversely affecting a patient with angina.
• Stimulation of parasympathetic ganglia also increases motor
activity of the bowel.
• At higher doses, blood pressure falls and activity ceases in both the
gastrointestinal (GI) tract and bladder musculature as a result of a
nicotine-induced block of parasympathetic ganglia.
 Nicotine
• Adverse effects: The CNS effects of nicotine
include irritability and tremors.
• Nicotine may also cause intestinal cramps,
diarrhoea, and increased heart rate and
blood pressure.
Withdrawal syndrome: As with the other drugs in this class,
nicotine is an addictive substance, and physical dependence
develops rapidly and can be severe.
Withdrawal is characterized by irritability, anxiety,
restlessness, difficulty concentrating, headaches, and
insomnia.
Appetite is affected, and GI upset often occurs
Nicotine
• The transdermal patch and chewing gum containing
nicotine have been shown to reduce nicotine withdrawal
symptoms and to help smokers stop smoking.
• For example, the blood concentration of nicotine
obtained from nicotine chewing gum is typically about
one-half the peak level observed with smoking .
• Other forms of nicotine replacement used for smoking
cessation include the inhaler, nasal spray, and lozenges.
• Bupropion, an antidepressant , can reduce the craving for
cigarettes
Cocaine (Highly Addictive Drug)
• Strong stimulant mostly used as a recreational drug.
• Commonly snorted , inhaled or injected into the veins.
• It is addictive and after short period of use, there is high
risk that dependence will occur.
MOA
• Blockade of the reuptake of
the monoamine(NE, serotonin
and Dopamine) into the
presynaptic terminals from
which these neurotransmitters
are released.
Thus potentiate the CNS
and peripheral effects of
these neurotransmitters.
Pharmacological effects
A- CNS-behavioral effects result from powerful stimulation of cortex
and brain stem.
 Cocaine acutely increases mental awareness and produces a
feeling of wellbeing and euphoria similar to that produced 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 vasomotor
depression.
 Pharmacological effects :
b. Sympathetic NS: peripherally potentiate the action of NE→
fight or flight
c. Hyperthermia:
 impair sweating & cutaneous vasodilation

 ↓Perception of thermal discomfort

d. 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,
Uses

• Its clinical use is as local anesthetic in particular in eye,

ear and throat surgery.
• Cocaine is the only local anesthetic that causes
vasoconstriction
 Methylphenidate 23

• It has CNS stimulant properties similar to those of

amphetamine and may also lead to abuse.
• Methylphenidate is more potent dopamine transport
inhibitor than cocaine thus making more dopamine
available.
• It has less potential for abuse than cocaine , because it
enters the brain much more slowly than cocaine and does
not increase dopamine levels as rapidly.
 Methylphenidate
• Pharmacokinetics: Both methylphenidate and dexmethylphenidate are
readily absorbed after oral administration. Methylphenidate is
available in extended-release oral formulations and as a transdermal
patch for once-daily application. The de-esterified product, ritalinic
acid, is excreted in urine.
• 4. Adverse effects: GI adverse effects are the most common and
include abdominal pain and nausea.
• Other reactions include anorexia, insomnia, nervousness, and fever. In
seizure patients, methylphenidate may increase seizure frequency,
especially if the patient is taking antidepressants.
• It is contraindicated in patients with glaucoma. Methylphenidate can
inhibit the metabolism of warfarin, phenytoin, phenobarbital, primidone,
and the tricyclic antidepressants.
Uses 25

1. ADHD :
Methylphenidate and its active isomer
,Dexmethylphenidate have been used for decades in
the treatment of ADHD in children aged 6 to 16.
2. Narcolepsy:
It is also effective in treatment of narcolepsy.
Narcolepsy: (day time sleepiness)

 Amphetamine, methylphenidate.

 Recently, a new drug, modafinil (wakefulness- promoting

agent) and its R-enantiomer derivative, armodafinil, have
become available to treat narcolepsy.

 Modafinil produces fewer psychoactive and euphoric

effects as well as, alterations in mood, perception, thinking,
and feelings typical of other CNS stimulants.
 Methylxanthines

• The methylxanthines include theophylline,

which is found in tea; theobromine , 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.
Methylxanthines
CNS: The caffeine contained in one to two cups of coffee
(100 to 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 to 15 cups of coffee)
produces anxiety and tremors.
The spinal cord is stimulated only by very high doses (2 to
5 g) of caffeine.
Tolerance can rapidly develop to the stimulating properties
of caffeine, and withdrawal consists of feelings of fatigue
and sedation.
 Methylxanthines continuation
• 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.]
• 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
Methylxanthines
• Therapeutic uses:
• Caffeine and its derivatives relax the smooth muscles of
the bronchioles. [Note: Previously the mainstay of asthma
therapy, theophylline has been largely replaced by other
agents, such as β2 agonists and corticosteroids
• Caffeine is also used in combination with the analgesics
acetaminophen and aspirin for the management of
headaches in both prescription and over-the-counter
products.
 Methylxanthine a/e
• 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.
• Death from caffeine is, therefore, highly unlikely.
• Lethargy, irritability, and headache occur in users who
routinely consume more than 600 mg of caffeine per
day (roughly six cups of coffee per day) and then
suddenly stop.
 Hallucinogens 2/12/2024

32

• Hallucinogens (also referred to as psychedelic or Psychomimetic

drugs and Psychotogens) .

• Hallucinogens are a class of drugs that cause hallucinations—

profound distortions in a person’s perceptions of reality
accompanied with bright colorful changes in environment and by a
plasticity of constantly changing shapes and colors.

• They produce profound changes in thought patterns and mood with

little effect on brain stem and spinal cord .

• Not able to take normal decision making because drug interfere

with normal rational thought
 Classification of Hallucinogens 33

Affect; Thought, perception and mood, e.g

1. Lysergic acid diethylamide (LSD)
2. Tetrahydrocannabinol (THC)
 Lysergic Acid Diethylamide (LSD)
• It is also known as acid, blotter, doses, hits, microdots,
sugar cubes, trips, tabs, or window panes—is one of the
most potent mood- and perception- altering
hallucinogenic drugs.
• It is an exceptionally potent psychotomimetic drug.
• It is not considered an addictive drug since it does not
produce compulsive drug-seeking behavior.
• Users refer to their experience as a “trip” and to acute
adverse reactions as a “bad trip”.
• These experiences are long and typically begin to clear
after about 12 hours.
Actions of LSD
• Massive increase in neural activity in some brain
regions
• - Activates sympathetic nervous system (causes
pupillary dilation, increased blood pressure,
piloerection, and increased body temperature)
• - Parasympathetic nervous system (increase in
salivation and nausea)
MOA
• Multiple sites in the CNS are affected by lysergic acid
diethylamide (LSD.
• The drug shows serotonin (5-HT) agonist activity at
presynaptic 5-HT1 receptors in the midbrain, and it
also stimulates 5-HT2 receptors.
Uses
Treatment of alcoholism
Pain and cluster headache relief
End of life anxiety for spiritual purpose and to
enhance creativity
 Tetrahydrocannabinol (THC)
• The main psychoactive alkaloid contained in marijuana is
THC which is available as Dronabinol .
• THC produce euphoria
followed by drowsiness and relaxation.
Actions
• THC has a variety of pharmacologic effects that resemble
those of amphetamines, LSD, alcohol, sedatives, atropine, and
morphine.

• The early stage is one of being "high" and is characterized by

euphoria, uncontrollable laughter, alteration of time sense,
depersonalization, and sharpened vision.

• Later, the user becomes relaxed and experiences introspective

and dream-like states if not actual sleep.
USES
1. Pain Relief
• One of the most common uses of medical marijuana is for pain
relief. And as it turns out, THC is responsible for its pain-
relieving effects.
• Likewise, cannabis has been shown to be especially effective
against neuropathic pain, or nerve-related pain.
2. PTSD
• Post-traumatic stress disorder (PTSD) is another common reason
to use medical marijuana. The high from THC is also associated
with temporary impairments of memory.
USES
• Impaired memory is often therapeutic for those who struggle to
forget painful memories, such as patients who suffer from PTSD.
Recent studies confirm that oral doses of THC can help relieve
a variety of PTSD-related symptoms including flashbacks,
agitation and nightmares.
3. Nausea and Vomiting
• THC has been available in pill form for treating nausea and
vomiting in cancer patients since the 1980s.
• Marinol, a pill containing synthetic THC, was the first THC-
based medication to be approved by the FDA for this purpose.
Since then, other THC pills have been developed and
prescribed to patients undergoing chemotherapy, including a
pill called Cesamet.
 USES
4. Appetite Stimulant
• THC is known to work as a powerful appetite stimulant in both healthy and
sick individuals. Similarly, Marinol and Cesamet are regularly prescribed to
boost appetite in patients with cancer and HIV-associated wasting syndrome.
• A number of studies conducted with Marinol suggest that THC can also
stimulate weight gain in patients with anorexia.
5. Asthma
• Treating asthma may not seem like an obvious use for medical marijuana. But
as it turns out, THC’s ability to improve breathing in asthmatics is supported
by research dating back to the 1970s.
6. Galucoma
In 1971, during a systematic investigation of its effects in healthy cannabis users,
it was observed that cannabis reduces intraocular pressure.
 Pharmacokinetics Action Uses Adverse effect
 CNS stimulation
 well absorbed  Diuresis
Methylxanthines :
 caffeine distributes  Cardiac  Caffeine + ergot alkaloid
 Theophylline throughout the body muscle (Ergotamine): treat migraine
tea and to the fetus and
stimulation headache
 Theobromine mother’s milk  Theophylline: prophylaxis for
 Relaxation of
cocoa  metabolized by liver chronic asthma (bronchodilator)
smooth muscle,
 Caffein by CYP1A2pathway especially
 excreted in urine bronchial muscle
e
 Stimulate HCL secretion
coffee
(peptic ulcers patients
should avoid them)

 Highly lipid soluble  Not used therapeutically

Psychomotor stimulants

cross BBBeasily Nicotine receptors in CNS  But secondary to caffeine as

 Cross placenta and where actions occur, such CNSstimulant
reach mother milk as:  Secondary to alcohol the most
Nicotine abused drug (pharmacological
 Metabolized in  arousal and relaxation
and behavioral therapy for
lung, liver and (low doses)
abusers)
urinary  respiratory paralysis  Combined with tars and COin
excretion (high doses) cigarette smoke
 Tolerance to the toxic
effect develops rapidly
 increases mental Short-Term:
awareness. Euphoria
 euphoria. Tachycardia
Respirationrate
 Hallucinations.
Long-Term:
 Stimulates the  potentiates and Agitation
Sympathetic nervous prolongs the CNSand
cocaine Notused Hypertension
system: tachycardia, peripheral actions of Dyspnea
hypertension, these catecholamines
pupillary dilation. nasalcollape
 Cocaine is the only Then:
local anesthetic that seizure
causes Arrhythmias
vasoconstriction . 1
Respiratory failure .
4
4 Pharmacokinetics Action Uses Adverse effect
 indirect
 elevation of the level of
catecholamine
transmitters in synaptic
spaces.

o Absorbed from GIT

100% 1. Attention deficit syndrome.
 releasing intracellular  hypertension
Often administered Uses the derivative
o stores of
 insomnia
Psychomotor stimulants

methylphenidate
by IVor smoking. catecholamines.
 also blocks 2. Narcolepsy.  Anorexia
o Metabolized by the
monoamine oxidase a disorder marked by an  tremors
liver.
(MAO). uncontrollable desire for sleep.  risk of exacerbating
o excreted in the urine.
3. Appetite schizophrenia
Amphetamine o The euphoria lasts 4
CNSEFFECTs: control  risk of dependence.
o methamphetamine to 6 hours "its 4 to 8
times longer than o stimulates the entire (suppresant)  Cerebral
cerebrospinal axis,
cocaine". haemorrhae
cortex, brain stem, and
o Cause: long-term
medulla.
1. addiction Overdoses of amphetamine are
o stimulates the entire psychological effects
- treated with chlorpromazine.
cerebrospinal axis,  psychotic symptoms
dependenc  anxiety depression
cortex, brain stem, and its α-blocking effects on M2,H1,
e  cognitive impairment.
medulla. D1, D2, α1 receptors .
2. tolerance
o This increased
3. drug-
alertness, decreased
seeking
fatigue, depressed
behavior.
appetite, and
o
insomnia.
 Pharmacokinetics Action Uses Adverse effect
4
 Hyper-reflexia.
5  Nausea.
 muscular weakness.

Sometimes high
 Serotonin (5-HT) agonist
 True dependence is activity at presynaptic doses causes:
rare. receptors in the midbrain, produce long-lasting
Lysergic acid
diethylamide
Haloperidol and other binding to both 5-HT1 and 5- psychotic changes in
neuroleptics can block the HT2 receptors. sus- ceptible individuals.
(LSD)
hallucinatory action of LSD  Activation of the sympathetic
nervous system Haloperidol and other
neuroleptics can block the
Psychomimetic Stimulants

hallucinatory action of LSD

and quickly abort the
syndrome.
smoking THC effect:  Dronabinol -
 Euphoria CB • An increased heart rate,
 Uncontrolled laughing (cannabinoid) • Decreased
 Feeling of relaxation receptor
Tetrahydrocannabino: agonist: blood
 Altered time sense THCreceptors found • AIDS patient pressure, and
From leaves of the  Dream like state. endogenously on presynaptic a
nerve terminals that interact who are losing
plant- Cannabis  impairs short- • Reddening of the
synaptically with pyramidal weight.
sativa term memory. conjunctiva.
 mental activity . neurons. • cancer
patients • At high doses, a
 Hashish  decreases
severe toxic psychosis
 Marijuana- muscle
emesis develops.
strength.
• Tolerance and mild
 impairs highly skilled
 Rimonabant - CB physical dependence
motor activity "driving a (cannabinoid) occur with continued
car". receptor frequent use of the
antagonists drug.
• Obesity treatment
by decrease
appetite and body
weight.
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Questions !