IVMS-CNS Pharmacology Intro to Drugs of Abuse III-Stimulants
1. CNS Pharmacology-
Introduction to Drugs of Abuse
III/Stimulants
Prepared and Presented by:
Marc Imhotep Cray, M.D.
Professor Pharmacology
Clinical:
E-Medicine Article
Cocaine-Related Psychiatric
Disorders
2. 2
CNS Stimulants
1. Cocaine, Crack (free base or hydrochloride)
2. Amphetamines
3. Methylxanthines:
caffeine, theophyline, theobromide
4. Nicotine
3. 3
A. Pharmacology
Cocaine and amphetamines have very similar effects
on mood, patterns of abuse, the type of dependence
produced, and their toxic effects
Differences are mainly in the pharmacokinetics (t½ of
cocaine is shorter (50-90min) vs longer (5-10hrs) t½ for
amphetamines)
Cocaine-HCl is injected I.V. => “rush” or “flash =>
euphoria
Rate of absorption is limited by local vasoconstriction.
Cocaine free base (“crack”, “rock”) is smoked => delivered
directly to pulmonary circulation, left heart and brain
Cocaine
4. 4
a. Acute effects
Causes an initial but
temporary euphoria, “rush”
Causes craving within 30
minutes of taking the drug
Increase alertness, feeling of
elation and well
being, increased
energy, feelings of
competence, increased
sexuality
The user becomes more
talkative, restless and often
more irritable
Consciousness is clear, but
delusions may occur as well
as visual, tactile
(formication) and auditory
hallucinations
These drugs are
sympathomimetic, thus,
they cause HR, BP,
skeletal muscle tension,
but musculature of the
bronchi and intestines relax
Cocaine
5. 5
Given unlimited access to the drugs, animals will
self-administer these drug until they die
B. Acute toxicity/Overdose
“Runs” – Uninterrupted sequences of stimulant
abuse to maintain a continuous state of
intoxication, to extend pleasurable feeling, and to
postpone the postintoxication “crash” than
ensues as the drug effects subside
Cocaine
7. 7
Acute tolerance may occur in such
people, particularly in those taking the drug
I.V., resulting in the need of increasingly larger
doses
This spiral of tolerance and dose increases
continues until the drug is depleted or the person
collapses from exhaustion
Drug taking and drug seeking take a compulsive
character
Cocaine
8. 8
Stimulant overdose results in excessive activation of
the sympathetic nervous system and cardiac toxicity
tachycardia and hypertension
myocardial infarction
cerebrovascular hemorrhage
Cocaine can cause coronary vasospasms and cardiac
dysrhythmias
CNS symptoms include anxiety feelings of paranoia and impending
doom, and restlessness
Users exhibit unpredictable behavior and may become
violent
Cocaine
9. 9
Treatment of overdose
- Beta blockers => for autonomic hyperactivity
1 blockade (Atenolol, metoprolol, esmolol and non-
selective : labetolol).
This treatment is controversial: Problems with using non-
selective blockers may lead to unopposed effects =>
BP
- Nitroglycerine or other nitrites/nitrates for angina
- Calcium channel blockers (verapamil, diltiazem) for
hypertension
- Ice baths for high fever.
- Acidify urine to hasten excretion
Cocaine
10. 10
After the acute toxic effects are handled:
Antidepressants for depression
Haloperidol for psychosis
Alprazolam for panic attacks
Cocaine
11. 11
E. Mechanism of Action
Inhibition of DA reuptake => increase of DA
concentration in N. accumbens
Everywhere else it also causes:
1. Increase activation of DA receptors
2. Negative feedback inhibition
3. May also produce dopamine release from nerve
endings
4. Inhibition of NE and 5-HT reuptake also occurs
Cocaine
15. 15
Amphetamines
1. dextro, levo-Amphetamine,
2. Methylphenidate (Ritalin®, use to treat
attention deficit and hyperactivity disorders in
children),
3. Phenmetrazine (used to treat obesity),
4. Methamphetamine (“crystal”, “speed”, “ICE”)
5. methylendioxyamphetamine, (MDA).
6. methylenedioxymetamphetamine, (MDMA,
ecstasy, XTC)
16. 16
Amphetamines
A. Pharmacology:
Used as nasal decongestants (benzedrine,
replaced by propylhexedrine)
Used as antidepressants and to treat obesity
(anorectic) => can cause dependence
Used to stay awake
17. 17
Present clinical therapeutic use, only in narcolepsy.
Amphetamine and methamphetamine -HCl (speed),
Amphetamine or methamphetamine => I.V.
D-methamphetamine (“ice”) => smoked like cocaine
but has a much longer duration of action
Psychological Dependence
- Similar to Cocaine
- May cause hallucinations MDA, DOM, MDMA
Amphetamines
19. 19
A. Pharmacology
One of the most widely used licit drugs
Drug found exclusively in the tobacco plant (Nicotiana
tabacum, serves as a natural insecticide), which is
harvested, cured, and manufactured into snuff, chewing
tobacco, pipe tobacco, cigars and cigarettes
Nicotine is absorbed best by the lungs and it is
distributed rapidly throughout the body
It has a half-life of about 30 min.
Highly lipophylic: Crosses BBB and placenta
Nicotine
20. 20
a. Acute Effects
Fibrinolytic activity
Free fatty acids
Epinephrine and NE release from adrenal gland
Sympathetic and Parasympathetic activity
ACTH release from pituitary
depolarization of thermo, mechano, and nociceptors
depolarization of carotid body and other ganglia
depolarization of baroreceptors
depolarization of chemoreceptors in area posterma =>
Stimulation of emetic centers
Nicotine
22. 22
B. Acute Intoxication
Respiratory arrest due to blockade of respiratory centers
and neuromuscular junctions controlling breathing
C. Chronic effects
Associated diseases: Heart disease, lung
disease, cancer, babies with small birth weight, asthma in
children, others
D. Detoxification treatment
Smoking therapy => substitution, tapering off: nicotine
gum (Nicorette), nicotine patches, nicotine nasal spray
Nicotine
23. 23
E. Withdrawal
Withdrawal symptoms include nervousness,
anxiety, drowsiness, lightheadedness,
insomnia, dizziness, tremor, sleep
disturbances, decrease inability to
concentrate, irritability and an intense craving
for tobacco
Other physical symptoms include nausea,
headache, constipation and an increase in
appetite and increase body weight
Nicotine
24. 24
F. Mechanism of action
- Primary site of action is nicotinic ACh
receptors (peripheral and CNS) where it
stimulates at low doses and blocks at high doses
- Stimulates release of DA from VTA terminals
onto N. accumbens
- Presynaptic receptors regulate release of neuro-
transmitters:
NE, EPI, DA, ACh, GABA
Nicotine
27. 27
I. Psychedelics and hallucinogens
Indolamines: Lysergic acid diethylamide (LSD), morning
glory seed
(LSM), psilocybin, psilocin, ibogaine, dimethyltryptamine
(DMT).
Phenyethylamines:
mescaline, bufotenin, dimethoxymethyl-amphetamine
(DOM).
II. Cannabis/ Marihuana: delta-9-THC
III. Dissociative anesthetics: Ketamine, Phencyclidine (PCP)
IV. Anticholinergics: Mandrake root, jimson
weed, atropine, scopolamine
Drugs causing
hallucinations, delusions or
delusions
28. 28
A. Pharmacology
These four classes of drugs are usually considered
together because of their prominent feature of
intoxication (hallucinations, delusions, illusions),
But they differ in almost every aspect: chemical
structure, mechanism of action, CNS receptor involved,
picture of intoxication, type and seriousness of their
toxic effects
They occur naturally in plants, mushrooms and in some
frogs
Hallucinogens
29. 29
a. Acute Effects
At low doses:
Euphoria; Changes in affect (mood): anxiety,
tension, labile mood;
Thought and feeling disorders: perceptual
changes (distortion), depersonalization, illusions
visual hallucinations, time and visual distortions,
synesthesias; nausea, pupils are dilated, HR, BP,
temperature, reflexes, tremors
Panic, paranoia
Hallucinogens
30. 30
At high doses:
Dangerous behavior may cause accidents.
For the amphetamines:
Visual hallucinations => convulsions, coma
Subjective reason for taking these drugs:
Allows insight into oneself and new ways of
looking at the world
Cross-tolerance between LSD and mescaline
Usually polydrug users
Hallucinogens
31. 31
B. Acute toxicity/Overdose
Depends on the individual drug
1. Tissue toxicity: Some are neurotoxic
2. Psychic toxicity: Acute transient
psychosis, Flash backs
3. Behavioral toxicity: Distorted
behavior, aggressive, violent
Hallucinogens
32. 32
C. Withdrawal
These drugs do not cause physical
dependence, but they have tremendous
abuse potential (psychological dependence)
- Use is more frequently occasional
Hallucinogens
33. 33
D. Mechanism of Action
LSM (from morning glory seeds), LSD
(synthetic), mescaline (from the peyote
cactus) and psilocybin (from mushrooms)
have chemical resemblances to 5-HT, NE
and DA
Scopolamine is a cholinergic antagonist
They all cause hyperarousal of the
CNS
Hallucinogens
34. 34
Systems Affected:
5-HT: Presynaptic agonists. decrease 5-HT
transmission. “Cocktail party effect" all
sensory information goes in. temporal lobe.
Postsynaptic agonists to 5-HT1A and 5-HT1C
receptors.
NE: Postsynaptic agonists. increase NE
activity in temporal lobe. Produce a lot of
“bad trips”. Anxiety and hyperactivity.
Ach: Produce delirium. Anticholinergic
effects. Not addictive.
Hallucinogens
36. 36
A. Pharmacology
From the Indian hemp plant, or Cannabis sativa
Medicinal powers => Egyptians
Probably originated in Central Asia
Delta-9-tetrahydrocannabinol (THC) is the active
ingredient
Marihuana, marijuana, bhang, ganja, hashish or
charas, sinsemilla, red oil, weed, bush
Marijuana (Cannabis)
37. 37
High lipid solubility but does not dissolve well in
water so if taken orally they are absorbed through
the digestive system rather slowly
Smoking causes 50% of cannabinoids to enter the
lungs
Holding the smoke in the lungs maximizes
absorption
Marijuana (Cannabis)
38. 38
B. Mechanism of Action
In 1990 THC receptor was cloned and in 1992
endogenous cannabimimetic was discovered
They named it anandamide (ànanda, in Sanskrit = bliss)
Anandamide is the ethanolamine of arachidonic acid
Cannabinoids as well as anandamide inhibit Adenylate
Cyclase (which produces cAMP) both in brain and
periphery, via G protein-coupled cannabinoid receptors
They also inhibit the N-type calcium channel current, which
may affect regulation of neurotransmitter release
Marijuana (Cannabis)
39. 39
Cannabinoids have effects not related to receptor
function, including activation of PLA2 and intracellular
calcium mobilization
THC causes the release of serotonin, causes an
elevation of ACh and inhibits the synthesis of
prostaglandins
They have also been known to influence levels of
NE, DA and GABA
THC concentrates in the limbic system, particularly in
hippocampus and amygdala and sensory centers for
hearing
Marijuana (Cannabis)
40. 40
A new peripheral cannabinoid receptor, with only 44%
homology to the brain receptor, has been found in
spleen, lymph nodes and leukocytes
Thus, they appear confined to the immune system
Cannabinol, a compound also found in marihuana but
with less psychotropic effects seems to have preference
for this receptor
Dronabinol. Medicinal grade cannabinol. Approved as an
antiemetic
Marijuana (Cannabis)