Pharmacology and Therapeutics-IV

Semester VI

Drug Toxicology-IV
CNS Depressants
25-06-2010
Dr. Ishrat Waheed, MPhil, PhD
HEC Foreign Professor/Head,
Pharmacology & Therapeutics
RIPS
Islamabad
 CNS DEPRESSANTS
I. Sedative/Hypnotics, Anxiolytics
II. Alcohols

• All are very addictive and cause withdrawal symptoms

(mild anxiety, convulsions, seizures).
• All of these drugs create "lethal potentiation" when
combined.

Alcohol<>Anxiolytics<>Hypnotics<> Anesthetics
 Overview
• Sedative-hypnotics are a group of drugs that cause
CNS depression.
• Alcohol, benzodiazepines and barbiturates are the
most commonly used agents in this class.
• Other agents include the nonbarbiturate
nonbenzodiazepine sedative-hypnotics, such as
buspirone, zolpidem, alcohols, glutethimide, chloral
hydrate, meprobamate, methaqualone, methyprylon,
carisoprodol, and gamma-hydroxybutyrate (GHB) and
its analog gamma-butyrolactone (GBL).
• Most severe sedative-hypnotic poisonings are
deliberate (suicidal). These agents are also commonly
abused as recreational drugs.
 Sedative/Hypnotics

I. Barbiturates
II. Benzodiazepines
III. Methaqualone

• Can be procured readily from illicit sources.

 Clinical uses of sedative-hypnotic
drugs
● For the relief of anxiety (sedatives; antianxiety; minor tranquilizers)
● For presurgical amnesia/anesthesia
● Management of insomnia (hypnotics)
● Treatment of epilepsy and seizure states
● For the control of withdrawal from ethanol and sedative-
hypnotics
● As a component of balanced anesthesia (intravenous
administration)
● For muscle relaxation in specific neuromuscular disorders
● As diagnostic aids or for treatment in psychiatry
 Sedative Hypnotics
Barbiturates:
Used clinically as anticonvulsant, anti-anxiety
drugs or preanesthetics.

Street Names
• Phenobarbital purple hearts
• Pentobarbital yellow jackets
• Secobarbital red devils
• Amobarbital blue angels
 Barbiturates

• Ultrashort acting - Methohexital (Brevital) and

thiopental (Pentothal)

• Short and intermediate acting - Amobarbital

(Amytal), pentobarbital (Nembutal), secobarbital
(Seconal), and butalbital (Fioricet, Fiorinal)

• Long acting - Phenobarbital (Luminal)

 Nonbarbiturates
• Benzodiazepines
• Carbamates - Meprobamate (Miltown)
• Chloral Derivatives - Chloral hydrate (Noctec)
• Ethchlorvynol (Placidyl)
• Piperidines - Glutethimide (Doriden) and methyprylon
(Noludar)
• Quinazolinone - Methaqualone (Quaalude)
• Imidazopyridine - Zolpidem (Ambien), zaleplon (Sonata),
eszopiclone (Lunesta) and alpidem
• Antihistamines (over-the-counter sleep aids) -
Diphenhydramine and doxylamine
• GHB- Gamma-hydroxybutyrate
Figure 22-1. Dose-response curves for two hypothetical sedative-hypnotics
 Sedative/Hypnotics
A. Pharmacology
• Well absorbed after oral administration
• Form active metabolites
• Patients experience rebound insomnia or anxiety.
• Gross binges of intoxication that last several
days. Others ingest large quantities on a daily
basis and remain chronically intoxicated.
• They are teratogenic if used during pregnancy
(malformations of the limbs, facial features, CNS,
heart, skeleton).
 Sedative Hypnotics
Mechanism of Action
Enhance GABAergic Transmission
Barbiturates
Prolong the opening of the channel
associated with GABA binding, increasing
conductance.
Benzodiazepines
Facilitates the activity of GABA to open
the channel.
 Sedative Hypnotics
The GABA receptor is a pentameric structure
that forms a Cl- channel.
• The receptor complex includes distinct
binding sites for benzodiazepines,
barbiturates and GABA-like
substances.
• GABA transmission exerts an inhibitory
effect on norepinephrine (NE),
dopamine (DA), serotonin (5-HT), and
acetylcholine (ACh) pathways.
 Sedative/Hypnotics
BARBs • Major site of action
for these drugs is at
BDZs
GABA AGONISTS
GABAergic synapses.
• Inhibitory Synapse.
• GABA-A receptors =>
γ Cl- Channels.
α β • Hyperpolarization.
β α
 Sedative/Hypnotics
a. Concurrent or substitute use
- May be lethal with other depressants.
- Co-abused with alcohol, amphetamines, cocaine.
- Not likely to abuse narcotics, but not vice-versa.

b. Tolerance
- Pharmacodynamic tolerance exists to most CNS
depressants.
- Tolerance of modest degree to the sedative effects but
not to the respiratory depressant effects.
- Cross-tolerance with alcohol, anesthetics and volatile
intoxicants.
 Sedative/Hypnotics
c. Acute effects
• Euphoria, impaired judgement, loss of self-control
and anterograde amnesic effects.

• Physiological consequences resemble those of

alcohol intoxication. Slowed and slurred speech.
Drowsiness
coma. Fatal with Barbiturates or
mixtures of CNS depressants. Death unlikely with
pure benzodiazepines.
 Sedative/Hypnotics
• Rapid acting barbiturates such as
secobarbital or pentobarbital are more
widely abused than depressants with a
slower onset such as phenobarbital or the
benzodiazepines.
• Drugs with half-lives of 8 to 24 hrs produce
a rapid evolving, severe withdrawal
syndrome.
• Drugs with half-lives of 48 to 96 hrs
produce a slow evolving, less severe but
longer withdrawal.
 Sedative Hypnotics
II.) Benzodiazepines:
Used as anxiolytics and hypnotics.
• Flurazepam => sleeping pills.
• Flunitrazepam => “date rape drug”.
• Diazepam (Valium) => tranquilizer.
• Chlordiazepoxide (Librium) => tranquilizer.
• Clonazepam => anticonvulsant.

• They all cause sedation and muscle relaxation.

• Induce sleep (hypnosis).
• Abuse may cause "BDZ-induced aggression".
Benzodiazapines
 Sedative Hypnotics
III.) Methaqualone (Quaalude) => "Downer",
works as Valium, seriously abused, very
addictive.
- Synthesized as part of an Indian program
looking for antimalarial drugs.
- In 1965 it was approved for prescription
use and placed in Schedule V.
- In 1984 methaqualone was transferred to
Schedule I of the CSA.
 Sedative Hypnotics
B. Acute toxicity/Overdose
Acute Intoxication
Pupils are normal; BP and respiration are
depressed; nystagmus on lateral gaze;
tendon reflexes depressed; ataxia; slurred
speech; confusion; coma; shock => Risk of
Death, particularly with BARBs.

Treatment of overdose
Treatment of overdose w/BDZs: flumazenil
(BDZ receptor blocker).
No treatment for Barbiturates.
 Sedative/Hypnotics
C. Withdrawal:
• Minor: tremors; insomnia (REM rebound); high
fever; clonic blink. Anxiety and dysphoria. Sleep
disturbances.
• 12-16hrs: minor symptoms plus abdominal cramps;
nausea and vomiting, o. hypotension; ⇑ deep
tendon reflexes, hyperreflexia.
• 24hrs: pronounced weakness, course tremors (“the
shakes”), hyperactive reflexes, early illusions and
hallucinations. Hyperpyrexia.
• 48-72hrs: convulsive seizures (“rum fits”); vivid
auditory and visual hallucinations (“the horrors”),
formication, agitation, disorientation, delirium,
paranoid delusions.
 Sedative/ Hypnotics
Hyperthermia, dehydration, electrolyte
imbalance, exhaustion, cardiovascular
collapse => Threat to life.
• Time of onset and symptoms experienced vary with CNS
depressant use, similar to alcohol withdrawal.
• Additive effect of sedative/hypnotics.

Treatment of withdrawal:
• Drug tapered off slowly to prevent onset of withdrawal (reversible only
early in course).
• Stabilization
diazepam, chlordiazepoxide, phenobarbital (cross-
dependence).
• Vomiting, nausea, tremor and twitching
Propranolol or clonidine.
 Drug Overdose & Prehospital Care
• Deaths from poisoning with benzodiazepines alone
are rare, but may be lethal in combination with other
CNS depressants
• Establish ABCs, obtain IV access, provide oxygen,
and perform aggressive supportive care with airway
protection as necessary.
• Ipecac syrup is not recommended for home use
because of the fear of emesis after onset of
respiratory depression.
• Ensure adequate airway and ventilation. Consider
and reassess the need for endotracheal intubation
 ER Management
General
• The most important aspects in managing an overdose situation are,
as usual, the ABCs — airway, breathing, and circulation.

Prevention of absorption
• Gastric lavage may be performed if the patient presents obtunded
within 1 hour of ingestion or rapidly deteriorates while in the
emergency department. The airway should be secured in such
instances prior to gastric intubation and lavage.
• Multi-dose activated charcoal (20-50 g q4h) is recommended for
overdoses with barbiturates, glutethimide, and meprobamate.
• It is not recommended in instances in which GHB or GBL are known
to be the only intoxicants.
•
 Elimination enhancement
• Alkaline diuresis enhances elimination of phenobarbital and
other long-acting barbiturates. It is recommended for all
symptomatic patients with long-acting barbiturate toxicity.
• Consider hemodialysis or hemoperfusion in glutethimide,
methyprylon, phenobarbital, meprobamate, and chloral hydrate
poisoning.
• The use of activated charcoal has become debated, and its
liberal use is discouraged. In general, measures to prevent
absorption (eg, emesis, gastric lavage) or increase excretion
(eg, diuresis, catharsis) of the drug have not been shown
consistently to reduce mortality associated with drug toxicity.
Considerable morbidity is associated with charcoal aspiration.
Its use should be limited to substances that would be well
absorbed and have a high likelihood of toxic dose ingestion.
 Flumazenil (Romazicon)
• Competitively and reversibly binds benzodiazepine receptors
(GABA). Administer slowly; large doses cause agitation and
withdrawal.

• Usually effective after 0.4-1 mg. Although up to 3-5 mg in

massive ingestions have been required.

• In cases of resedation, IV drip at 0.01-0.05 mg/kg/h may be

used.
• Only consider a flumazenil drip if the patient is not habituated to
sedative-hypnotic agents.

Dosage
Adult
• 0.2 mg IV qmin; not to exceed 3-5 mg
Pediatric
• 0.01 IV mg/kg; not to exceed 0.05 mg/kg
 Alcohols
•

Alcohol

Sedative/hypnotics
 Aliphatic Alcohols

Ethanol
• Acute effects: CNS depression, diuresis,
peripheral vasodilation, hypoglycemia
• Chronic effects: fatty liver, alcoholic hepatitis,
cirrhosis
• Developmental effects: low birth weight, poor
muscle coordination mental deficiency
• Metabolism: by alcoholic dehydrogenase (ADH)
to acetaldehyde to acetate to acetyl CoA
Physiological Effects
 Ethyl Alcohol
• Intake of ethanol begins during adolescence.
Ninety percent of high school seniors have tried
alcohol during their life times and 30% report
daily use. Chronic abuse occurs much later.

A. Pharmacology
• Alcohol is readily dissolved in water and lipids
and thus, distributes very evenly throughout the
body. It crosses the blood-brain-barrier as well
as the placenta without difficulty.
 Metabolism of Ethanol

At low conc. EtOH can give rise

to AcetylCoA via ADH.

At high conc. EtOH can

activate P450 oxidases that
form inflammatory Os.

Antidote: Caffeine or other

CNS
stimulants
 Ethanol
E. Mechanism of Action
1. Affects several ion channels:
a. NMDA receptor => allosteric inhibitor.
Physical dependence/withdrawal.
Reinforcement. Behavioral desinhibition.
b. GABAA receptor => allosteric facilitator.
Tolerance.
c. 5-HT3 receptor => sedative, antianxiety
effects.
d. L-type calcium channel => allosteric
modulator.
 Ethanol
2. CNS Control
a. Alcohol effects in the cerebellum =>
disturb equilibrium and posture.
b. Alcohol effects in hippocampus =>
disturb memory formation and retrieval.
c. Alcohol in brainstem and medulla =>
disturb respiratory centers.
 Ethanol
B. Acute Intoxication/Overdose
Loss of inhibition, anxiolysis, sedation,
decreased motor coordination.
Slowed
and slurred speech, ataxia, nystagmus,
drowsiness
coma, confusion; reflexes are
low, respiratory depression or apnea, low
blood pressure
death.
 Respiratory
Depression
BARBS
BDZs
Coma/
Anesthesia
RESPONSE

Ataxia
ETOH
Sedation

Anticonvulsant

Anxiolytic

DOSE
 Ethanol

Fetal Alcohol Syndrome

• Children exposed to alcohol in utero may exhibit a wide range of
developmental disabilities and cognitive and behavioral deficits that
reflect damage to the developing neurons.
• These effects may include: mental retardation, attention deficit
disorders, perceptual problems, memory and learning disabilities, and
psychomotor dysfunction.
• Fetal Alcohol Syndrome (FAS), which is characterized by central
nervous system impairments, growth retardation and characteristic facial
dysmorphology is the most severe, manifestation of alcohol
neuratogenesis.
 Alcohol Withdrawal
C. Withdrawal Syndrome
• When an alcoholic stops drinking, withdrawal symptoms
begin within six to 48 hours and peak about 24 to 35 hours
after the last drink. During this period the inhibition of brain
activity caused by alcohol is abruptly reversed. Stress
hormones are over-produced and the central nervous system
becomes over-excited. Depending on severity, withdrawal
symptoms may include the following:
– Fever.
– Rapid heart beat.
– Changes in blood pressure either higher or lower.
– Extremely aggressive behavior.
– Hallucinations and other mental disturbances.
– Seizures occur in about 10% of adults during withdrawal, and in about
60% of these patients, the seizures are multiple. The time between the
first and last seizure is usually six hours or less.
– About 5% of alcoholic patients experience delirium tremens, which
usually develops two to four days after the last drink.
 Delirium Tremens
C. Withdrawal Syndrome (con’t)
In severe cases, it can develop into:
“Delirium Tremens”:
Insomnia, tremulousness, REM rebound, reflexes
are high, weakness, anorexia, orthostatic
hypotension, sweating, agitation
Delirium, vivid auditory and visual hallucinations;
convulsions and seizures (probably caused by
increase NMDA receptor number and
hyperexcitability), may generate “status
epilepticus”.
Disorientation, paranoid delusions, hyperthermia
dehydration, cardiovascular collapse.
Risk of death
 Ethanol
Treatment of Withdrawal
Benzodiazepines.
• To inhibit nerve-cell excitability in the brain.
• Relieve withdrawal symptoms.
• Help prevent progression to delirium tremens.
• Reduce the risk for seizures.
• Benzodiazepines may be administered intravenously or
orally, depending on the severity of symptoms. These drugs
vary in how long they are effective.

diazepam (Valium) alprazolam (Xanax)

lorazepam (Ativan) midazolam (Versed)
oxazepam (Serax)
benzodiazepines are usually not prescribed for more than two
weeks or administered for more than three nights per week
 Ethanol DETOX
D. Treatment of Dependence
• Detox Center/Clinic
• Disulfiram (antabuse) *
• CCC (citrate calcium carbamate)*

*Both of these drugs are acetaldehyde dehydrogenase blockers.

• Drinking alcohol with these drugs produces increased
concentration of acetaldehyde and this makes the person sick.
• Sometimes tranquilizers and antidepressants are given to
relieve the anxiety.
• DETOX is best in a hospital setting.
• AAA to prevent relapse.
 Methanol
Methanol: plasma conc.> 20mg/dl
• Acute effects: CNS depression, acidosis,
blindness, death
• Metabolism by ADH to formic acid.
– One of the most critical (non-reversible) effects of
methanol consumption is blindness caused by the
formic acid metabolite.
• Treatment: IV 10% Ethanol therapy (3-67 hrs),
Hemodialysis (9-90 hrs)
 Glycols
Ethylene glycol
– Used in antifreeze in automobiles.
– Low volatility.
– Metabolism to oxalic acid.
– Kidney and neurotoxicity due to deposition
of Ca oxalate crystals.
– Metabolic acidosis results from metabolism
by alcohol dehydrogenase (ADH) to glycolic
acid.
 Ethylene Glycol Ethers
• Used in lacquers, printing inks, brake fluids,
gasoline additives
• Well absorbed through skin
• Reproductive effects: Testicular atropy - infertility
• Fetal toxicity and cardiovascular malformations
• Toxicity of ethylene glycol ethers >>> propylene
glycol ethers

• Treatment: Ethanol therapy, Hemodialysis