CNS - STIMULANTS

Dr. M. Masoom Akhtar

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 CNS - stimulants
are classified according to their action into:
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 (psychotomimetic): Affect thought, perception, and

mood, therefore produce
 profound changes in thought patterns & mood,

 little effect on the brain stem & spinal cord

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

Tetrahydrocannabinol (THC), Rimonabant.

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Psychomotor stimulants
Q. What are Stimulants?
Chemical structure are similar to monoamine
neurotransmitters. All are indirect-acting sympathomimetics:
1. Many CNS stimulants release catecholamines,
Therefore, their effects are abolished by prior treatment
with reserpine or guanethidine
Ex: amphetamine, dextroamphetamine, methamphetamine,
methylphenidate (Ritalin), ephedrine, pseudoephedrine
(a stereoisomer of ephedrine), tyramine.
2. Other CNS stimulants block the reuptake of
catecholamines (NE and DA) and serotonin:
EX. Cocaine, sibutramine (reduct)®, modafinil

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Psychomotor stimulants
3. Antidepressants drugs with stimulant effects:
Atomoxetine– a relatively selective NE reuptake inhibitor (ADHD),
Bupropion – blocks the reuptake of both NE and DA.
4. The methylxanthines are adenosine receptor
antagonists. Drugs within this class are NOT
generally considered “psychomotor” stimulants, but
they have distinct stimulant effects caffeine,
theophylline.

NB: MAO and COMT inhibitors (indirect-acting adrenergic agonists),

but they are not traditionally considered to be stimulants.

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Therapeutic Indications of 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.
 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 for CNS Stimulants:
anorexia, insomnia, asthenia, psychopathic personality, a
history of homicidal or suicidal tendencies.

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1. Psychomotor stimulants

A. methylxanthines
1. Theophylline (found in tea) : long-acting, prescribed for
night-time asthma
2. Theobromine: found in cocoa.
3. Caffeine: (short-acting) the most widely consumed
 found in coffee (200 mg/cup),
 carbonated soft drinks (60 mg/can),
 cocoa and chocolate

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Mechanism of action: include
several mechanism have been proposed
Mechanism of action of methylxanthine
1-It inhibits phosphodiesterase enz. → ↑ cAMP

↑ calcium
m in CNS
NS & heart ↓calcium in Smooth muscles

2- Adenosine (A1, A2 and A3) receptors antagonist almost equally,

which explains many of its cardiac effects
A2 receptors antagonist responsible for CNS stimulation &
smooth muscles relaxation

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Actions
a. CNS:
decrease in fatigue, increased alertness: 100-200 mg caffeine in
1 or 2 cups of coffees
Anxiety & tremors- 1.5 g of caffeine: 12-15 cups of coffee
Spinal cord stimulation: 2-5 g (very high dose)
Tolerance can rapidly develop
Withdrawal symptoms: feeling of fatigue & sedation.
b. CVS: at high dose of caffeine +ve inotropic and chronotropic
effects on the heart, ↑COP
c. Diuretic action: mild ↑ urinary output of Na+, Cl- and K+
d. Gastric mucosa: all methylxanthines stimulate secretion of
HCl
e. Respiratory smooth muscle: bronchodilator, Rx asthma
replaced by β-agonists, corticosteroids.

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Pharmacokinetics
 The methylxanthines are well absorbed orally.
 Caffeine distributes throughout the body, including the
brain. The drugs cross the placenta to the fetus and is
secreted into the mother's milk.
 All are metabolized in the liver, generally by the CYP1A2
pathway, the metabolites are then excreted in the urine.

Adverse effects
 Moderate doses: insomnia, anxiety, agitation
 High doses: emesis, convulsion
 Lethal dose (10 gm of caffeine): cardiac arrhythmia
 Suddenly stop: lethargy, irritability, headache

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B. Nicotine:
 Nicotine is the active ingredient in tobacco.
 Used in smoking cessation therapy,
Nicotine remains important, because it is 2nd only to
caffeine as the most widely used CNS stimulant and 2nd
only to alcohol as the most abused drug.

Actions of Nicotine:
Low dose: ganglionic depolarization
High dose: ganglionic blockade

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Actions of Nicotine
I. CNS:
1. Low dose: euphoria, arousal, relaxation, improves
attention, learning, problem solving and reaction time.
2. High dose: CNS paralysis, severe hypotension
(medullary paralysis)

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

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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,
 90% of nicotine inhaled in smoke is absorbed.
 Tolerance to toxic effects of nicotine develops rapidly.

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Adverse effects:

 CNS; irritability and tremors

 Intestinal cramps, diarrhea
 ↑HR & BP

Withdrawal syndrome: nicotine is addictive substance,

 physical dependence on nicotine develops rapidly and can
be severe.
 Bupropion: can reduce the craving for cigarettes

 Transdermal patch and chewing gum containing nicotine

 Varenicline

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Varenicline (Chantix in the USA and Champix in Canada):

 partial agonist at Nn receptor in 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.

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 C. 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 or “rush” by prolongation of
dopaminergic effects in the brain’s pleasure system (limbic
system).
 It is this immediate positive reinforcement, followed rapidly by the
negative reinforcement, that makes the drug, particularly in this
form, so addictive.
 Chronic intake of cocaine depletes dopamine. This depletion
triggers the vicious cycle of craving for cocaine that temporarily
relieves severe depression.

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Cocaine

 Cocaine has minimal bioavailability when taken by the

oral route.
 Instead, the cocaine hydrochloride powder is snorted, or
solubilized and injected. The cocaine powder cannot be
effectively smoked, as it is destroyed upon heating.
 However, crack cocaine, an alkaloidal form, can be
smoked.

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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.
 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.

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2. Actions:
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.

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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

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D. Amphetamine
 Is a non catecholamine, (shows neurologic and clinical
effects quite similar to those of cocaine),
 dextroamphetamine is the major member of this class
compounds.
 methamphetamine (speed) is a derivative of
amphetamine that can be smoked and it is preferred by
many abusers.
 Methylenedioxymethamphetamine (also known as
MDMA, or Ecstasy or Molly) is a synthetic derivative of
methamphetamine with both stimulant and
hallucinogenic properties.

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1. Mechanism of action:
Amphetamine, act by
 releasing intracellular stores of
catecholamines.
 also inhibits MAO, high level CAOs are
readily released into synaptic spaces.
2. Actions:
a. CNS: a combination of its dopamine and NE release
enhancing properties.
Amphetamine stimulates the entire cerebrospinal axis, brainstem,
and medulla.This lead to increase alertness, decrease fatigue,
depressed appetite, and insomnia.
b. Sympathetic Nervous System: indirectly stimulating the
receptors through NE release.

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4. Adverse effects:
addiction, dependence, tolerance, and drug seeking
behavior.
a. CNS: insomnia, irritability, weakness, dizziness, tremor,
hyperactive reflex, confusion, delirium, panic states, and
suicidal tendencies, especially in mentally ill patients.
-Chronic amphetamine use produce a state of
“amphetamine psychosis” that resembles the psychotic
episodes associated with schizophrenia.
Overdoses are treated with chlorpromazine or haloperidol,
which relieve the CNS symptoms as well as the HTN
because of their α–blocking effects.
The anorectic effect of amphetamine is due to its action in
the lateral hypothalamic feeding center.
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4. Adverse effects:
b. CVS: palpitations, cardiac arrhythmia, HTN, anginal
pain, and circulatory collapse. Headache, chills, and
excess sweating may also occur.
c. GIT: anorexia, nausea, vomiting, abdominal cramps, and
diarrhea.
Contraindications:
HTN, CV diseases, Hyperthyroidism, Glaucoma, Patients
with a history of drug abuse

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Narcolepsy:

 Amphetamine, methylphenidate.
 Recently, a new drug, modafinil 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.

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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.

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Methylphenidate (Ritalin)®
 It has CNS stimulant properties similar to those of
amphetamine and may also lead to abuse, although its
addictive potential is controversial.
 It is taken daily by 4-6 million children in the USA. The
pharmacologically active isomer, Dexmethylphenidate,
has been approved in the USA for the Rx of ADHD.
 Methylphenidate is a 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.

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2. 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

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3. Adverse reactions:

 GIT effects are the most common; abdominal pain and

nausea.
 Other reactions include anorexia, insomnia, nervousness,
and fever.
 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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E. Synthetic Cathinones “bath salts,”
 Cathinone is the psychoactive component in an evergreen
shrub called Khat. Work in a manner very similar to
cocaine and amphetamines.
 Bath salts are generally snorted or ingested, but they may
also be injected.
Ex., Methcathinone, butylone, methylene dioxypyrovalerone, and
naphyrone
These products are packaged and labeled in such a way as
to circumvent detection, prosecution, and enforcement.

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CNS Stimulant Coc:wioe
Nc:urotransm,ncrs involved NE.DA.5HT
Mtcharusm(s) of acoon Blocks DA. NE and SHT Blockade: of ~ptakc of NE and
rcuptak in OlS; local DA. rdeasc: amines from anothc:tic
;action from mobile pool, \11.'Cak MAO
Na• dwmd blockade inhibitors
I. Increase NE: sympathomimc:tic drc:ct With increased
heart rate and contractiliry. blood pressure changes. m)-
drwi.s. and central cx.citaoon, hypaactivity
2. Increase DA: psychotic episodes, p;ar.anot:t. twluon.auons.
possible dyskmesw, and ~ c.listu.tba.nce
). Increase SHT: bduVlOral changes. a~ dy$kin~
W. a.nd dec:tt:.ucd sppente
Toxicity I. Excess NE: card.ix anhythmw. gcncn1a.ed &sehcmia with
possible Ml and strokes; acute rcn.al a.nd hcp;ltic &.Jurcs
2. Eroess DA: major ps)"Chosis. cocaine ddinum
3. Excess5HT: possible serotonin ~me
4. All of the ~-e: convulsion. hyperpytcxia.and dc:ath
Cr.avi.ng. severe depression. a.nhedonia, anxiety; maiugc with
an tidc:pl"CSS3Jl ts

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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.

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A. Lysergic acid diethylamide

 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 also
stimulates 5-HT2 receptors.
 Activation of the sympathetic nervous system occurs,
which causes pupillary dilation, increased BP,
piloerection, and increased body temperature.

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A. LSD Adverse effects:

 include hyperreflexia, nausea, and muscular weakness.

 High doses may produce long-lasting psychotic changes
in susceptible individuals.
 Haloperidol and other neuroleptics can block the
hallucinatory action of LSD and quickly abort the
syndrome.

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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.
 The effects of marijuana on γ-aminobutyric acid (GABA)
in the hippocampus diminish the capacity for short-term
memory in users
 decreases muscle strength
 and impairs highly skilled motor activity, such as that
required to drive a car.
 Its wide range of effects includes: appetite stimulation,
xerostomia, visual hallucinations, delusions, and
enhancement of sensory activity
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Mechanism of action:

 THC receptors, designated CB1 receptors, have been

found on inhibitory presynaptic nerve terminals. CB1 is
coupled to a G protein.
 Interestingly, endocannabinoids have been identified in
the CNS.
 These compounds, which bind to the CB1 receptors, are
membrane-derived and are synthesized on demand,
and they may act as local neuromodulators.

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Mechanism of action:

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Pharmacokinetics:

 The effects of THC appear immediately after the drug

is smoked, but maximum effects take about 20
minutes. By 3 hours, the effects largely disappear.
 Dronabinol is administered orally and has a peak effect
in 2 to 4 hours. Its psychoactive effects can last up to 6
hours, but its appetite-stimulant effects may persist for
24 hours.
 It is highly lipid soluble and has a large volume of
distribution.
 THC itself is extensively metabolized by the mixed-
function oxidases.
 Elimination: is largely through the biliary route.

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Therapeutic uses of Dronabinol
1. 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.
 At high doses, a toxic psychosis develops.
Tolerance and mild physical dependence
occur with continued, frequent use of the
drug.
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Rimonabant:
Rimonabant: The CB1-receptor antagonist,
1. Obesity (decrease appetite and body weight in humans).

2. induce psychiatric disturbances, such as anxiety and

depression, during clinical trials.

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Phencyclidine:

 Phencyclidine (also known as PCP, or “angel dust”)

 inhibits the reuptake of dopamine, 5-HT, and
norepinephrine.
 The major action of phencyclidine is to block the ion
channel regulated by the NMDA subtype of glutamate
receptor. This action prevents the passage of critical
ions (particularly Ca2+) through the channel.
 Phencyclidine also has anticholinergic activity but,
surprisingly, produces hypersalivation.

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Phencyclidine:

 Phencyclidine, an analog of ketamine, causes

dissociative anesthesia (insensitivity to pain, without
loss of consciousness) and analgesia.
 At increased dosages, anesthesia, stupor, or coma
result, but strangely, the eyes may remain open.
Increased sensitivity to external stimuli exists, and the
CNS actions may persist for a week.

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Hallucinoge Marijuan Hallucinoge
ns a ns
Neurotransmitters Many Slff
involved
Mechanis o actio Lnteracti of Interaction with
m f n on CB1 THC
with and CB2 several subtypes of
cannabinoid SHT receptors
receptors in CNS and
Effect periphery Sedation, Hallucinogen,
s euphoria, t HR, sympathomimetic,
conjunctiva, causes dysesthesias
Toxicit delusions. Poorly
y hallucinations described,
Associated flashbacks
Withdraw with likely
Poorly
al smoking, characterized
possible
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llashbacks
III. Ethanol (EtOH)
 Alcohol is the most commonly abused substance in
modern society.
 Alcoholism decreases life expectancy by 10 to 15 years.
 Ethanol exerts its desired and toxic effects through:
 enhancing the effects of the GABA,

 inducing the release of endogenous opioids,

 and altering levels of serotonin and dopamine.

 Ethanol is a selective CNS depressant at low doses,

resulting in decreased inhibitions and the characteristic
drunken behavior.
 At high doses, it is a general CNS depressant, which can
result in coma and respiratory depression.

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Ethanol
Ethanol is absorbed from the stomach and duodenum, and
food slows and decreases absorption.
Peak ethanol levels are generally achieved in 20 minutes to
1 hour of ingestion.
Ethanol is metabolized by alcohol dehydrogenase to
acetaldehyde and then by aldehyde dehydrogenase to
acetate in the liver.
It is metabolized by zero-order elimination at approximately
15 to 40 mg/dL/h.
There is a constant blood-to-breath ratio of 2100:1.
Medical management of acute ethanol toxicity includes
symptomatic supportive care and the administration of
thiamine and folic acid to prevent/treat Wernicke
encephalopathy and macrocytic anemia.

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Ethanol
Chronic ethanol abuse can cause profound hepatic,
cardiovascular, pulmonary, hematologic, endocrine,
metabolic, and CNS damage.
Sudden cessation of ethanol ingestion in a heavy drinker
can precipitate withdrawal manifested by tachycardia,
sweating, tremor, anxiety, agitation, hallucinations, and
convulsions.
Alcohol withdrawal is a life-threatening situation that should
be medically managed with symptomatic/supportive care,
benzodiazepines, and long-term addiction treatment.

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Drugs used in the treatment of alcohol dependenc
dependence:

A. Disulfiram blocks the oxidation of acetaldehyde to

acetic acid by inhibiting aldehyde dehydrogenase. This
results in the accumulation of acetaldehyde in the blood,
causing flushing, tachycardia, hyperventilation, and
nausea.
B. Naltrexone Naltrexone is a long-acting opioid
antagonist that should be used in conjunction with
supportive psychotherapy. Naltrexone is better tolerated
than disulfiram.
C. Acamprosate should also be used in conjunction with
supportive psychotherapy.

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IV. Prescription Drug Abuse

o Some commonly abused prescription drugs include

opioids, benzodiazepines, and barbiturates, with opioids
outpacing the other prescription drugs by a large margin.
o Visits to the emergency department related to misuse of
pharmaceuticals now exceed those related to illicit drug
use, and prescription pain relievers also now account for
more deaths than heroin and cocaine combined.

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