Sedative-Hypnotic Drugs

Dr. Hiwa K. Saaed, HD, MSc. PhD

Department of Pharmacology & Toxicology
College of Pharmacy/ University of Sulaimani
 Sedatives
Drugs that have an inhibitory effect on the
CNS to the degree that they reduce:
– Nervousness
– Excitability
– Irritability
– without causing sleep
 Hypnotics

• Calm or soothe the CNS to the point that

they cause sleep
 Sedative-Hypnotic Drugs
• is a drug that produces calming or quieting
effect and reduces excitement with a little
effect on motor or mental functions. It may
induce drowsiness.
• most of the drugs used for anxiety states
cause dose-dependent depression of the
CNS that extends to sleep-inducing effects
(hypnosis) and possible anesthesia.
 Sedative-Hypnotic drugs
The sedative-hypnotics belong to a
chemically heterogeneous class of drug.
The most important are:
• Benzodiazepines (BZs), 1963
• Barbiturates, (1963)
• New drugs: buspirone, zolpidem, and
Zaleplon
• Miscellaneous: carbamates, alcohol)
Sedative-Hypnotic Drugs
 Sedative-Hypnotic Drugs/
Overdose
In overdose, depression of respiratory and
vasomotor canters in the medulla occurs with
most drugs in this class,

although the dose-response relationship is

flatter for the benzodiazepines than for older
drugs such as alcohol and barbiturates.
• Tolerance: reduction in drug effect
requiring an increase in dosage to
maintain the same response.
• Physiological dependence: removal of
the drug evokes unpleasant symptoms,
usually the opposite of the drugs effects
• Psychological dependence: the drug
taker feels compelled to use the drug &
suffers anxiety when separated from
drug.
 Pharmacokinetics
Absorption and distribution:
• Most of S-H drugs are lipid soluble and are
absorbed well from GIT.
• With good distribution to the brain
 Pharmacokinetics
• Thiopental (highest lipid solubility) enter
the CNS rapidly, used in anesthesia
induction.
• The CNS effects of thiopental are
terminated by rapid redistribution of the
drug to other highly perfused tissues,
including skeletal muscle.
 Metabolism and excretion
• Many BDZs are converted initially to active
metabolites with long t1/2.
• After several days of therapy with some
drugs (diazepam, flurazepam), accumulation
of active metabolites can lead to excessive
sedation.
• Lorazepam and oxazepam undergo
extrahepatic conjugation and do not form
active metabolite.
 Metabolism
• The barbiturates (except phenobarbital) are
extensively metabolized.
• Chloral hydrate is oxidized to trichloroethanol
an active metabolite.
• Zaleplon > Zolpidem are rapidly metabolized,
short t1/2.
 Mechanisms of action

• Most S-H drugs facilitate the actions of

GABA, a major inhibitory transmitter in
the CNS,
• GABAA receptor activation leads to
increased Cl- ion influx;
• GABAB receptor activation causes
increased efflux of K+. Both
mechanisms result in membrane
hyperpolarization.
GABAA Receptor Complex

BZD binding
GABA
 The pentapeptide structure of the GABAA
receptor has binding sites for BZs and for
other drugs, including Barbiturates and
.ethanol
 BZs Mechanism of action

• BZs potentiate GABA

increase frequency of Cl- ion channel
opening,→causes hyperpolarization → raise
firing threshold →and thus inhibits the
formation of action potentials.

• This action is blocked by flumazenil, a BZ

receptor antagonist.
 Barbiturates Mechanism of action
• Barbiturates interact with GABA receptors,
the binding site is distinct from that of the
BZs.

• Barbiturates potentiate GABA action on Cl-

entry into the neuron by increase the
duration of Cl- ion channel opening.
• In addition, barbiturates can block
excitatory glutamate receptor.

• at high doses (anesthetics conc. Of

pentobarbital), also open Cl- ion channels
directly and block high frequency Na+
channels).

• Flumazenil does not block the effects of

barbiturates.
 Benzodiazepines:
• Are the most commonly used
anxiolytic drugs.

• They have largely replaced

barbiturates & meprobamet, because
the BZs are safer and more effective
 Bzs Classification
• Short acting (2-8 hrs) midazolam
triazolam
• Intermediate (10-20 hrs)
temazepam, lorazepam, alprazolam,
oxazepam, nitrazepam, estrazolam
• Long acting (1-3 days):
chlordiazepoxide, diazepam,
flurazepam, clonazepam,
chlorazepate
 Actions and therapeutic doses:
BZs have neither antipsychotic activity nor analgesic. They
don’t affect ANS
Therapeutic Uses
• Sedation
• Sleep induction
• Skeletal muscle relaxation
• Anxiety relief
• Treatment of alcohol withdrawal
• Agitation
• Depression
• Epilepsy
• Balanced anesthesia
 Reduction of anxiety at low dose;
• alprazolam is the DOC
• diazepam) are preferred in patients require
Rx for prolonged period of time.
 Sedative and hypnotic actions at higher dose;

1. not all, three most commonly prescribed

BZs are:
• long acting flurazepam,
• intermediate temazepam
• short acting triazolam.
2. And Two non BZs: Zolpidem & Zaleplon.
• Anterograde amnesia; short acting BZs
used in premedication for endoscopic,
bronchoscopic, angioplasty

• Anticonvulsant; clonazepam is useful in

chronic Rx of epilepsy,

• Alcohol withdrawal symptoms:

chlordiazepoxide, chlorazepate, diazepam
& oxazepam are useful in the Rx of
alcohol withdrawal.
• Muscle relaxant at higher doses;
diazepam is useful in the Rx of skeletal
muscle spasm

• Other actions: in higher doses BZs

decrease BP and increase HR. diazepam
decreases nocturnal gastric acid secretion
 Tolerance
• Chronic use leads to tolerance (cross with
other S-H drugs), possibly via
downregulation of BZ receptors.

• The antianxiety effects of the BZ are less

subject to tolerance than sedative and
hypnotic effects.
 Dependence & Withdrawal symptoms
Abrupt discontinuation, particularly if high doses
used for prolong period.
WD symptoms with BZs are less intense than with
ethanol or barbiturates;
• Confusion,
• anxiety,
• agitation,
• restlessness,
• insomnia
• and tension
• Because of long t1/2 of some BZs,
withdrawal symptoms may occur slowly
and last a number of days after
discontinuation of therapy.
 Adverse effects of BZs:

• Drowsiness and confusion

• Ataxia at high doses-precludes
activities like driving
• Cognitive impairment:
↓long term recall,
↓ acquisition of knowledge
 BZs antagonist
Flumazenil: I.V only, reverses the effect of
the BZs (competitive antagonist), onset is
rapid, and duration is short.
 Miscellaneous; non benzodiazepines
-Zolpidem and Zaleplon
• They act on BZ1 (a subtype of BZ receptor
family),
• they are more selective hypnotics
• they are not effective in chronic anxiety,
for seizure disorders, or for muscle
relaxing.
• Possibly less tolerance occur with prolong
use and lower abuse liability and
dependence than BZs.
• they show no withdrawal effects, Minimal
rebound insomnia
• Rapidly absorbed, rapid onset with short
duration (2-3 hrs)
• Zaleplon is very similar to zolpidem in its
hypnotic action
• but it causes fewer residual effect on
pseudomotor and cognitive function
compared with zolpidem or the BZs due to
short t1/2 < 1hr
 Buspirone:
totally different anxiolytic from BZs, no
effects on GABA systems, possible partial
agonist at 5-HT1A receptors some affinity
for D2 & 5-HT2A.

Indication:
• Indicated for generalized anxiety disorders
but takes 1 to 2 weeks to exert anxiolytic
effects.
• Buspirone lucks anticonvulsant and Muscle
relaxant property of BZs and cause minimal
sedation.
• No additive CNS depression with other
drugs.
• Adverse effects:
hypothermia,
increase prolactin,
headache,
dizziness,
nervousness
 Barbiturates:

• Formerly used as sedative hypnotic

replaced by BZs, because barbiturates
induce tolerance, drug metabolizing
enzyme, physical dependence and very
severe withdrawal symptom.
 Classification
• Long acting (1-2 days)
Phenobarbital; anticonvulsant

• Short (3-8hrs) Pentobarbital,

secobarbital and amobarbital Use:
sedative & Hypnotic

• Ultrashort (20 min) Thiopental

Use: I.V induction of anesthesia
 Adverse effects of Barbiturates:
• Dose-dependent CNS depression, with
nystagmus and ataxia progressing to
respiratory depression, coma, and possible
mortality.
• no specific antidote in overdose.
• Additive CNS depression with other drugs.
 Metabolites:
• Hepatic metabolism (some to active metabolite).
• Induction of Cytochrome P450 is characteristic
and may lead to drug interactions.
• Because of increase heme synthesis, they are
contraindicated in porphyrias

Porphyrias: a hereditary disorder of hemoglobin

metabolism causing mental disturbance,
extreme sensitivity to light and excretion of dark
pigments in the urine.
 Non barbiturate sedative:

• Chloral hydrate: is a trichlorinated

derivative of acetaldehyde that is
converted to the active metabolite,
trichloroethanol in the body.
 Miscellaneous

• antihistamines: hydroxyzine, diphenhydramine

and doxylamine
• Hydroxyzine: antihistamine with antiemetic
activity, it has low tendency for habituation and thus
is useful for patients wit anxiety who have a history
of drug abuse.
• Propranolol has efficacy in performance anxiety
and social phobias.
• TCA and SSRI
• Opiod analgesics
• Ethanol
 CNS Depressants:
Nursing Implications
• Give 15 to 30 minutes before bedtime for
maximum effectiveness in inducing sleep.
• Most benzodiazepines (except
flurazepam) cause REM rebound and a
tired feeling the next day; use with caution
in the elderly.
• Patients should be instructed to avoid
alcohol and other CNS depressants.
 CNS Depressants:
Nursing Implications
• Monitor for therapeutic effects
– Increased ability to sleep at night
– Fewer awakenings
– Shorter sleep induction time
– Few side effects, such as hangover effects
– Improved sense of well-being because of
improved sleep