1. The document discusses several classes of central nervous system stimulants including methylxanthines, nicotine, cocaine, amphetamines, and hallucinogens. 2. Methylxanthines like caffeine and theophylline are phosphodiesterase inhibitors that increase levels of cyclic nucleotides, and they also block adenosine receptors. Nicotine stimulates ganglia at low doses but blocks them at high doses. 3. Cocaine, amphetamines, and MDMA prolong the actions of neurotransmitters like dopamine and serotonin, producing euphoria. Hallucinogens profoundly alter mood and thought patterns while sparing motor function.

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Lecture 7
“ CNS Stimulants“
Pharmacology III (3463)
Prof. Dr. Mohammed Farrag El Yamany

2. CNS Stimulants
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3. CNS Stimulants
 Psychomotor stimulants (cause excitement, euphoria,
decrease feelings of fatigue, and increase motor
activity)
e.g. caffeine, Theophylline, amphetamine
 Hallucinogens (produce profound changes in thought
patterns and mood, with little effect on the brainstem
and spinal cord)
e.g. THC, PCP, LSD
The CNS stimulants have diverse clinical
uses and are important as drugs of
abuse
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4. Methylxanthines
(Theophylline, Theobromine & Caffeine)
Mechanism of action:
 phosphodiesterase inhibitors →↑cAMP, cGMP
 Blocking of adenosine receptors (A1 receptor)
N.B.:
 ↑cAMP and A1 receptor blocking → bronchodilation
 Theophylline is used to treat bronchial asthma
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5. • The methylxanthines are well
absorbed orally & distributes
to all body & brain , can cross
the placenta to the fetus and
are secreted into the breast
milk.
• All methylxanthines are
metabolized in the liver, and
then excreted in the urine
Pharmacokinetics:
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6. Actions
a) CNS (dose-dependent)
 Fatigue, alertness (normal dose)
 Anxiety, insomnia, tremors (high dose)
 Tolerance develops rapidly (withdrawal symptoms: fatigue
& sedation)
N.B. Effect of caffeine on CNS is
dose-dependent
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7. Actions (cont.)
b) CVS
High dose: +ve inotropic,+ve chronotropic
(C.I. Angina and arrythmia)
c) Kidney
Weak diuretic (↑ G.F.R)
d) Gastric mucosa
↑ HCL (C.I. Peptic Ulcer)
e) Bronchi
Bronchodilation (theophylline)
f) Cerebral bl. V
V.C → Caffeine in migraine headache with ergotamine
Caffeine in normal headache with paracetamol and aspirin
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8. 1. Theophylline: bronchial asthma (now
replaced by β2-agonists).
2. Caffeine
 migraine headache with ergotamine
 normal headache with paracetamol
and aspirin
Therapeutic uses:
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9.  insomnia, anxiety, agitation, tachycardia and arrythmia.
 Sudden withdrawal of caffeine → headache, lethargy and
irritability.
Adverse effects of Caffeine
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10. B. Nicotine
Mechanism of action:
 Low doses: ganglionic stimulant (NN stimulant)
 High doses: ganglionic blocker (NN blocker)
N.B. The mechanism of action of
nicotine is dose-dependent
(central & peripheral)
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11. Actions
CNS
 Low doses:
Euphoria, arousal, relaxation
Improves attention & learning.
 High doses:
respiratory paralysis (↓R.C) & severe
hypotension.
 Appetite suppressant
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12. Actions (cont.)
Peripheral effects
 Stimulation of symp. ganglia & adrenal medulla:
↑ BP, HR, VC and ↓ coronary blood flow ( CI: hypertension and angina)
 Stimulation of parasymp. ganglia: ↑ GIT & Bladder motility
 At high doses: block symp. Ganglia………… fall in BP
block parasym. Ganglia………decreased activity of
GIT and Bladder
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13. Therapeutic uses and
adverse effects
 No use except in smoking cessation therapy
Transdermal patch and chewing gum nicotine reduce
withdrawal symptoms & help to stop smoking
Adverse effects
Irritability, tremors, intestinal cramps, diarrhea,
increases HR & BP
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14. Withdrawal symptoms
 Nicotine is addictive →physical dependence
 Withdrawal symptoms: irritability, anxiety, restlessness,
headache and insomnia
 Appetite is affected & GI pain.
Treatment: nicotine replacement therapy (gums,
transdermal patches), Bupropion (decrease craving)
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15. Varenicline
 Varenicline is a partial agonist at neuronal nicotinic
acetylcholine receptors in the CNS.
 Because varenicline is only a partial agonist at these
receptors, it produces less euphoric effects than nicotine
(nicotine is a full agonist). Thus, it is useful as an adjunct in
the management of smoking cessation in patients with
nicotine withdrawal symptoms.
 Patients taking varenicline should be monitored for suicidal
thoughts, vivid nightmares, and mood changes.
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17. C. Cocaine
 Highly addictive drug, Schedule II
Mechanism of action:
 Blockade of reuptake of monoamines (NE, 5HT,
DA) into the presynaptic terminals.
 Prolongation of CNS & peripheral actions of
monoamines; in particular prolongation of DA in
LIMBIC SYSTEM (pleasure system)……euphoria
 CHRONIC USE ….depletion of DA stores
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18. Blockade of reuptake of
monoamines
(NE, 5-HT & DA).
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19. Actions
CNS
 Stimulation of cortex & brainstem… ..behavioral effects
 Feeling of well-being, euphoria.
 Hallucinations, delusions, paranoia & grandiosity.
 Increases motor activity
 High doses: convulsions followed by respiratory and
vasomotor depression.
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20. Actions (cont.)
SNS
PREIPHERALLY: potentiate the action of NE
adrenergic stimulation (tachycardia, ↑ BP, periph. vc, and mydriasis)
Hyperthermia
(a) Increased muscular activity
(b)VC, resulting in decreased heat loss by sweating
(c) A direct central effect on the heat regulating center in the hypothalamus
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21. Therapeutic uses
 Was Used as (Local Anesthesia): it blocks Na-
channels)
 N.B. it is the only LA cause vasoconstriction
 Administration by chewing, intranasal snorting, smoking or I.V.
 Peak after intranasal: 15-20 min.
 More rapid, more dependence: IV or crack smoking (free base)
 Excretion in urine (easily detected)
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22. Adverse effects
 Anxiety, ↑ HR, ↑ BP, paranoia (acute effect after ingestion)
 Fatal arrythmia and risk of MI
 Hyperthermia
 Dependence
 Withdrawal symptoms include physical and emotional
depression
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23. D. Amphetamines
A sympathetic amine, shows neurologic and clinical effects as cocaine.
 Dextroamphetamine (major member),
 Methamphetamine,
 3,4-Methylenedioxymethamphetamine (MDMA or
Ecstasy)
 Methylphenidate similar to amphetamine and also
Schedule II drug
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24. Mechanism of action
 Releases intracellular stores of
CA.
 Inhibits MAO Then high amounts
of CA in the synaptic spaces.
 Weak reuptake transport
inhibitor
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25. Actions
CNS
 Euphoria, ↑ alertness, ↓ fatigue, depressed appetite and
insomnia…..therapeutic uses in hyperactive children, appetite
control and narcolepsy
 At high doses: psychosis, convulsions (ttt /Diazepam).
SNS
 Indirect stimulation of the adrenergic system
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26. Therapeutic uses
A. Attention Deficit Hyperactivity Disorder
(ADHD):
 Hyperkinetic children who lack the ability to be involved in one activity
for more than few minutes
 Methylphenidate, Dextroamphetamine
 New drug: Atomoxetine; selective NE reuptake inhibitor
Unlike methyphenidate which blocks dopamine reuptake than NE,
Atomoxetine is more selective for inhibition of NE reuptake
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27. Therapeutic uses (cont.)
B. Narcolepsy:
 Uncontrollable bouts of sleepiness during the day , sometimes with
catalepsy (loss of muscle control)
 Amphetamine may be used
 Modafinil (first line therapy, unknown mechanism)
produces alertness with few psychoactive and euphoric effects.
 Modafinil has potential for abuse and physical dependence.
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28.  Completely absorbed from the GI tract, metabolized by the liver, and
excreted in the urine.
 Amphetamine has a basic PKa:
Acidification of urine by ammonium chloride or ascorbic acid increases the
ionized species of the drug and so reduces its tubular reabsorption and
increasing its urinary excretion. (Used in intoxication of amphetamines)
 Amphetamine abusers administer the drugs by IV injection and/or by
smoking.
 The euphoria caused by amphetamine lasts 4 - 6 hours, or 4- 8 fold longer
than the effects of cocaine.
Pharmacokinetics of amphetamines:
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29. Adverse effects
CNS
 Cause addiction, dependence, tolerance, and drug seeking behavior.
 Insomnia, irritability, weakness, dizziness, tremors.
 May cause: confusion, delirium , panic states and suicidal tendencies.
 Chronic use:”amphetamine psychosis”(schizophrenia like)
 CNS symptoms: TTT by chlorpromazine, haloperidol
 Anorectic effect: due to the action on the lateral hypothalamic feeding
center
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30. Adverse effects (cont.)
CVS:
Palpitations, cardiac arrhythmias, hypertension, anginal pain
GI system effects:
Anorexia, nausea, vomiting, abdominal cramps & diarrhea.
Contraindications:
Pts with: hypertension, CVS disease, MAO inhibitors.
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31. Hallucinogenics
Tetrahydrocannabinol (THC)
It is the main psychoactive alkaloid contained in marijuana
Mechanism: the action is mediated through THC-receptors (CB1 receptors), which are G-protein
coupled (presynaptic receptors)
N.B.: endogenous cannabinoids act as neuromodulators in CNS → ↑ CB1 receptors →↓
neurotransmitters release
Actions
 Eyphoria followed by relaxation and drowsiness
 It impairs short term memory and mental activity
 It decreases muscle strength, impairs highly skilled motor activity as car driving
 It causes visual hallucination, disturbance in sense of distances, it causes delusions
 It ↑ appetite
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32. Tetrahydrocannabinol (THC) cont.
Side effects
 ↑ HR, ↓ BP, reddening of eye
 At high doses → psychosis
 Tolerance, mild physical dependence occur with continuous frequent use
Uses
 Dronabinol → antiemetic (with cancer chemotherapy)
→ for patients with AIDs who are losing weight (↑ appetite)
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33. Lysergic Acid Diethylamide (LSD)
Mechanism
 It ↑ presynaptic 5HT receptors in midbrain, it blocks 5HT1, 5HT2 receptors in brain
 It activates SNS →↑ BP, mydriasis, ↑ body temperature
Actions
 Visual, clor, auditory hallucinations
N.B.:
 D2-blockers (Haloperidol) → block hallucinogenic effects of LSD
 Tolerance and physical dependence develop
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34. Phencyclidine
Mechanism
 ↓ UI of NE, 5HT, Dopamine
 Block ion channel regulated by NMDA glutamate receptors
Actions
 It causes dissociative analgesia (no pain, without loss of consciousness)
 At higher doses → anaesethia, coma but eyes may remain open
 It has anticholinergic activity (but produce hypersalivation)
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