Sedatives and Hypnotics

John A. Harvey, Ph.D.

Department of Pharmacology and
Physiology
 Sleep Disorders Occur in About 33% of the
Population at Any Given Time

30-35% due to psychiatric illness

15-20% due to primary causes
10-15% due to alcohol and other drugs
10-15% due to limb movement disorders
5-10% due to sleep apnea
5-10% due to medical illness
 EEG Sleep Stages
Awake Highly Frequency Low Amplitude

Stage 1 Relaxed Awake -Alpha Frequency Low

Amplitude

Stage 2 Non REM Sleep - Lower Frequency Higher

Amplitude

Stage 3&4 Slow Wave Sleep Very Low Frequency and

High Amplitude

REM Sleep As in Stage 1 State But Not Awake

Dreaming occurs
 REM Sleep
Occurs 1-Hour or More After Onset of
Sleep
Sensitive to Sedative Hypnotics
State of Dreaming
Rapid Eye Movements (REM)
Ponto-Geniculo-Occipital Spikes
Muscular Relaxation
Drooling
Immediate Onset in Narcolepsy
 REM
Awake

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

Peak Blood Metabolites Elimination

Agent Levels (Hours) Half-Life (Hours)

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

Drug Name Duration Action

Phenobarbital Long (6-12 hrs)

Pentobarbital Medium (4-6 hrs)

Secobarbital Short/Med (3-6 hrs)

 Summary

Benzodiazepines and Zolpidem act at the

benzodiazepine site of the GABAA complex to
increase the frequency of chloride channel
openings and thus increase inhibition.

Barbiturates act at the barbiturate site of the

GABAA complex to increase the duration of
chloride channel openings and thus increase
inhibition as well as blocking the AMPA
receptor thus decreasing glutamate induced
excitation.
 Principles of Drug Abuse

John A. Harvey, Ph.D.

Department of Pharmacology and Physiology
Drexel University College of Medicine
Philadelphia, PA
 (A) (B) (B/A)
% Ever % % Risk of
Drug Used Addiction Addiction

Tobacco 75.6 24.4 31.9

Alcohol 91.5 14.1 15.4
Illicit Drugs 51.0 7.5 14.7
Cannabis 46.3 4.2 9.1
Cocaine 16.2 2.7 16.7
Stimulants 15.3 1.7 11.2
Anxiolytics 12.7 1.2 9.2
Analgesics 9.7 0.7 7.5
Psychedelics 10.6 0.5 4.9
Heroin 1.5 0.4 23.1
Inhalants 6.8 0.3 3.7
 Pharmacological Variables

A. Tolerance

1) Tolerance can be 200 fold: e.g., 1g diazepam daily

or 1.5 g of methamphetamine daily. Tolerance is surmountable.

2) Tolerance is typically lost in 10 to 14 days.

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

1) Pharmacokinetic tolerance. Microsomal enzymes. Produces a

limited amount of tolerance.

2) Pharmacodynamic tolerance cellular changes. Up and Down

regulation of receptors and other consequences of altered gene
expression. Responsible for large amounts of tolerance.

3) Behavioral tolerance learned and conditioned. Conditioned

tolerance is responsible for conditioned withdrawal symptoms.

4) Cross tolerance occurs within a drug class.

5) Inverse tolerance: sensitization can persist for years.

 Physical Dependence

1. Physical dependence: inferred from occurrence of abstinence

syndrome upon abrupt drug withdrawal.

2. Due to occurrence of cellular tolerance resulting from altered gene

expression.

3. Lost in 2 to 3 weeks but other bodily adaptations may take a year

or more to return to normal.

4. Type of withdrawal syndrome depends on drug category. Cross

dependence is the basis for some drug therapies. e.g. methadone.

5. Conditioned drug dependence inferred from withdrawal symptoms

to environmental stimuli in the absence of physical dependence.
It is characterized by intense craving.
 Terminology of Drug Abuse

A. Non-medical or non-accepted recreational use of a drug.

B. Terms used include compulsive drug use, drug addiction

substance dependence.

1) Use of these terms does not imply the existence of tolerance

or physical dependence.

2) Tolerance and physical dependence do not imply addiction.

C. Tolerance and physical dependence are biological phenomenon

resulting from frequent drug use and can occur in an individual
who is not addicted to the drug.
CRAVING

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.

2. Reward involves DA release in the nucleus accumbens leading to reward/euphoria.

3. This is a biologically determined event shared by all animals.

Human and Rhesus Monkey Show the Same Pattern of Opioid Abuse
Pattern of Alcohol Abuse is the
Same in Human and Rhesus
Monkey

(Arrows indicate withdrawal

symptoms)
Pattern of cocaine abuse
is the same in humans and
monkeys
 Drugs of Abuse

Most potent effects on the brain

Provide clues to endogenous

ligands and their receptors
 Psychomotor Stimulant Actions and Dopamine Pathways
Clues to Schizophrenia
1. Neostriatal pathway to caudate/putamen produces motor stimulation, at higher
doses leading to stereotyped behavior and convulsions

2. Mesolimbic pathway to nucleus accumbens produces elevation of mood, euphoria

and reward

3. Mesocortical pathway to limbic cortex produces enhanced attention, alertness and

associative processing. At higher doses produce .paranoid psychotic reactions.
 Cocaine

Pharmacology. Blocks DA uptake in CNS and NE uptake in PNS.

Duration of action short (half life 10-30 min) and this leads to binging.
Tolerance to euphoric effects but also sensitization. Evidence for
changes in the DAT upon chronic use.
Toxic effects due to cardiovascular effects, cerebral ischemic effects
and seizures.
Fetal effects can be direct including CNS lesions or indirect due to
premature birth. Growing evidence of cocaine syndrome in offspring
due to abnormal development of CNS.
Clinical issues. Withdrawal leads to dysphoria, depression, fatigue and
craving. No drugs available for reliable treatment. Best treatment is a
12 step program.
 Amphetamine and its Substituted Analogs

Pharmacology. Releases DA in CNS and NE in PNS.

Same CNS, PNS and withdrawal effects as seen with cocaine. High
doses produce paranoid psychotic reactions and auditory
hallucinations.
High doses Tolerance to euphoric effects but also sensitization.
CNS toxicity to dopamine neurons at high doses are seen in
experimental animals due to increased levels of DA.
Extreme tolerance is observed with users able to consume as much as
1.6 grams of methamphetamine per day.
Methamphetamine, phenmetrazine, methylphenidate and
diethylproprion produce similar effects.
Use as diet pills (amphetamine, phenylpropanolamine) is not
associated with significant abuse potential. Used for ADHD.
Psychodelic Drugs & Serotonin: Further Clues to Schizophrenia
 Hallucinogens, Psychotomimetics and Psychedelics
Produce perceptual distortions (Hallucinogenic) and/or thought
disturbances (Psychotomimetic) and/or feelings of enhanced
insight and self knowledge often of a spiritual nature (Psychedelic).

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).

1. Hallucinogens: Indoleamines: LSD, DMT, Psilocybin (Psylocin).

2. Hallucinogens: Phenethylamines: Mescaline, DOM. Produce

greater sympathomimetic effects.

3. Psychedelics: MDA and MDMA. May be neurotoxic to serotonin nerve

terminals throughout the brain. Act presynaptically at serotonin
ktransporter.
Axons in Frontal Cortex Stained With Serotonin Antibody

Control MDMA
B. Dissociative anesthetics: PCP (Phencyclidine) and PCP-Like Drugs

1. PCP, ketamine, dizocilpine.

2. Act as noncompetitive blockers of the NMDA associated

calcium channel.

3. All three drugs produce neurotoxicity in cortex and hippocampus.

4. Effects include emotional withdrawal, concrete thinking, and

bizarre responses to projective tests, catatonic posturing,
hallucinations and hostile or assaultive behaviors.

5. Withdrawal symptoms include an agitated psychotic state that can

be treated with diazepam and haloperidol.

6. Thought to provide a model for psychotic behavior

 Ca++ Na+

Glutamate Glycine

Dizocilpine (MK-801), ketamine and

phencyclidine (PCP) block noncompetitvely
the open state NMDA channel
C. Marijuana

1. Major active ingredient is 9-Tetrahydrocannabinol (9-THC).

2. Two major classes of G-protein coupled receptors whose activation

leads to an inhibition of cAMP.

a) CB1 Receptor: Occurs only in brain including cerebral cortex,

hippocampus, caudate nucleus, hypothalamus, mesencephalon,
and cerebellum.

b) CB2 Receptor: Occurs only in periphery including testes, spleen,

leukocytes, lymphocytes.

c) Endogenous ligand is anandamide (Arachidonylethanolamide) an

N-amide derivative of arachidonic acid.
C. Marijuana (Cont)

3. Both antagonists and agonists have been synthesized that are specific
for the two receptor subtypes.

4. Activation of the CB1 receptor is correlated with analgesia, hypothermia,

catalepsy, decreased locomotor activity and memory disturbances.

5. Withdrawal symptoms include restlessness, irritability, mild agitation,

insomnia, nausea-cramping and sleep disturbances.

6. Therapeutic use has been suggested for treatment of anorexia in aids

patients, as an antiemetic during chemotherapy, analgesic in chronic
pain, in movement disorders and glaucoma.

1) Dronabinol (Marinol), an agonist, has been developed as an

antinausea and antiemetic drug.

2. Levonantradol has been developed for possible use as an

analgesic and antispasmodic.
Central Nervous System Depressants

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

300-400 Initial vasomotor and respiratory

depression, coma

> 500 Respiratory depression, death

A. Ethanol

1. Pharmacology. Reduces excitation by inhibition of receptor and enhances

inhibition by actions at modulatory site on GABA-A supramolecular
complex, and at 5-HT3 receptors located on GABA neurons.

2. Tolerance results in a decrease in the therapeutic index since tolerance

to the depression of respiratory neurons occurs more slowly than to
sedation. Cross-tolerance to other sedative-hypnotic drugs such as
benzodiazepines and barbiturates.

3. Cellular tolerance involves up-regulation of the NMDA receptor and

down regulation of GABA receptor and thus withdrawal can be
accompanied by grand mal convulsions.
A. Ethanol (cont)

4. Toxicity includes liver disease, cardiovascular disease, endocrine

and gastrointestinal effects, malnutrition and CNS conditions such as
severe depression (often leading to suicide) and alcoholic Korsakoffs
syndrome consisting of a loss of short-term memory and an inability to
acquire new skills.

5. Since ethanol crosses the placental barrier it also produces fetal toxicity
the fetal alcohol syndrome, a major cause of mental retardation.

6. Withdrawal symptoms can be treated with short acting benzodiazepines

(e.g., oxazepam).

7. Treatment for addiction is best accomplished by behavioral approaches,

e.g., a 12 step program. Pharmacological treatments with disulfiram,
naltrexone, lithium and SSRIs have not been successful.
 Alcohol dehydrogenase or MEOS

(1) Ethanol Acetaldehyde

Aldehyde dehydrogenase
Blocked by Disulfiram

(2) Acetaldehyde Acetate

Large Increases in Acetaldehyde Produces Facial Flushing,

Nausea, Vomiting, Diziness and Headache
B) Benzodiazepines

1. Actions are at the modulatory site on the GABA-A complex.

2. Tolerance and physical dependence are slow in developing (several months),

and occur to the sedative effects with little evidence of tolerance to the
anti-anxiety effects or to the effects on memory.

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)

4. Intentional abuse is rare. It may occur for production of a high but

also may involve use to heighten the effects of other drugs (e.g.,
methadone) or to reduce unwanted side effects (e.g., cocaine).

5. Addiction can lead to enormous escalation of dose, e.g., while 5-20 mg

of diazepam per day is typical for anti-anxiety, abusers may take over
1000 mg/day and not appear grossly sedated.

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

1. Pharmacology: Block excitatory (glutamate) and enhance inhibitory

(GABA) neurons.

2. Tolerance results in a decreased therapeutic index.

3. Physical dependence involves an upregulation of MDA receptors and

down regulation of GABA receptors.

4. Withdrawal symptoms resemble those seen with benzodiazepines

including seizures. Treatment as for benzodiazepines.
D. OPIOIDS

1. Pharmacology. Analgesia and euphoria are mediated by

actions at the -opioid receptor.

2. Tolerance can lead to 100 fold increases in dose. Tolerance occurs

to respiratory depressant, sedative and emetic effects.

3. Duration of action about 4 hours so dosing occurs 2-4 times/day.

4. Treatment of addiction based on cross tolerance (e.g., methadone

or clonidine).
Summary of Abused Drugs and Their Receptor Targets

Alcohol and barbiturates: Depress excitatory (glutamate) actions at the NMDA

receptor and enhance inhibitory (GABA) actions at the GABA-A complex.

Benzodiazepines: Enhance inhibitory (GABA) actions at the benzodiazepine

modulatory site of the GABA-A complex.

Opioids: Act at the -opioid receptor.

Cocaine: Blocks the DA transporter in CNS.

AMPHETAMINES: Presynaptic release of DA in CNS.

CAFFEINE: Antagonists at the adenosine receptor.

NICOTINE: Agonists at the nicotinic receptor in brain.

LSD and LSD-like hallucinogens (LSD, DMT, MDMA, ETC): Agonists at the
5-HT2A receptor.

Phencyclidine (PCP): Noncompetitive NMDA calcium channel blocker.

Marijuana: Agonist at cannabinoid CB1 and CB2 Receptors.