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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

6. 6
Cocaine/Amphetamines
DRUG TAKING CRAVING
The Blues
FATIGUE
DEPRESSION
HYPERPHAGIA
CRASH
sleep
DRUG TAKING
CRAVING
DRUG TAKING
DRUG TAKING
CRAVING
“The Run”

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

12. 12
Dopamine reuptake inhibitors

13. 13
GLUCOSE METABOLISM
normalRed: high activity
Blue: low activity
Cocaine

14. 14

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

18. 18
Psychoactive: Club
Drugs & Inhalants
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

21. 21
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

25. 25

26. 26
Drugs causing
hallucinations, delusions or
delusions
1. Psychedelics and hallucinogens
2. Marihuana (Cannabis)
3. Dissociative anesthetics (PCP)
4. Anticholinergics

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

35. 35
Marijuana (Cannabis)

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)

41. 41

42. 42
eMedicine Articles on Addiction
 Alcohol-Related Psychosis
 Alcoholism
 Amphetamine-Related
Psychiatric Disorders
 Caffeine-Related Psychiatric
Disorders
 Cannabis Compound Abuse
 Cocaine-Related Psychiatric
Disorders
 Hallucinogens
 Inhalant-Related Psychiatric
Disorders
 Injecting Drug Use
 Nicotine Addiction
 Opioid Abuse
 Phencyclidine (PCP)-Related
Psychiatric Disorders
 Sedative, Hypnotic,
Anxiolytic Use Disorders
 Stimulants
 Substance-Induced Mood
Disorders: Depression and
Mania