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Stage 1
Stage 2
Stage 3
and 4
0 1 2 3 4 5 6 7 8
Time (hours)
GABA (-aminobutyric acid) is the major
inhibitory neurotransmitter in the mammalian CNS.
Allosteric modulation of GABAA function by
actions at the benzodiazepine binding site
Benzodiazepines and drugs that act at the benzodiazepine modulatory
site on the GABAA receptor-chloride channel molecular complex
Zolpidem 1 No 2-3
(Ambien)
Triazolam 1 No 2-3
(Halcion)
Alprazolam 1-2 No 12-15
(Xanax)
Temazepam 2-3 Active 10-40
(Restoril)
Diazepam 1-2 Active 20-80
(Valium)
Flurazepam 1-2 Active 40-100
(Dalmane)
Some barbiturates used for sedation
A. Tolerance
3) Tolerance does not develop to a drug, but to the effects of the drug.
4) Tolerance to drug effect and to drug lethality can differ and affect
the therapeutic index. True of CNS depressants.
Acute INJECTION
ACUTE Injection
SUBJECTS
of Subjects 100
ED50 = 35
80 LD50 = 75
60
PercentOF
40
PERCENT
20
0
0 20 40 60 80 100
BARBITURATE
Barbiturate DOSE
Arbitrary Dose
After Chronic
CHRONIC Injection
INJECTION
SUBJECTS
of Subjects 100
ED50 = 55
80 LD50 = 75
60
PercentOF
40
PERCENT
20
0
0 20 40 60 80 100
BARBITURATE
Barbiturate DOSE
Arbitrary Dose
Types of Tolerance
NOT
ADDICT DRUG WITHDRAWAL PATIENT
ADDICTED
Drugs are Abused Because of Their Rewarding Effects
1. Reward is mediated by activation of the DA mesolimbic system.
Psychedelics such as LSD and LSD-Like drugs all act as partial agonists at the
5-HT2A receptors located throughout brain (Cortex, hippocampus, caudate,
brain stem, cerebellum, spinal cord and motor nuclei).
Control MDMA
B. Dissociative anesthetics: PCP (Phencyclidine) and PCP-Like Drugs
Glutamate Glycine
3. Both antagonists and agonists have been synthesized that are specific
for the two receptor subtypes.
1. Ethanol
2. Benzodiazepines
3. Barbiturates
ETHANOL
1 Drink = shot of liquor, glass of beer, glass of wine
Drinks Blood Acute Clinical Effects
Per Hour Alcohol
(mg/dL)
1 or 2 50 Sedation, euphoria, relaxed, increased
reaction time
3 to 6 100-150 Initial depression of CNS, motor
incoordination (ataxia), slurred speech,
impaired visual acuity, emotional lability
>6 200 Emesis, stupor, frank drunkenness
5. Since ethanol crosses the placental barrier it also produces fetal toxicity
the fetal alcohol syndrome, a major cause of mental retardation.
Aldehyde dehydrogenase
Blocked by Disulfiram
3. Both licit and illicit use over extended periods produces physical
dependence. Withdrawal symptoms can be difficult to differentiate from
re-emergence of the anxiety symptoms for which the drug may have been
prescribed.
B. Benzodiazepines (cont)
5. Withdrawal symptoms from low doses are usually mild, but symptoms of
withdrawal from high doses include grand mal seizures and delirium.
Anticonvulsant medication can be used (e.g., carbamazepine and
phenobarbital).
C. Barbiturates
LSD and LSD-like hallucinogens (LSD, DMT, MDMA, ETC): Agonists at the
5-HT2A receptor.