Dr. Hiwa K. Saaed, BSc, HD, MSc. PhD
Department of Pharmacology & Toxicology
College of Pharmacy/ University of Sulaimani
• Unlike other mental disorders, anxiety can be both:
– a normal emotion
– and a psychiatric illness.
• It is a universal human emotion, and a certain amount is
useful to the individual, acting as a stimulant and
• but when it becomes excessive and disproportionate to
the situation, an anxiety state develops; it becomes a
pathological (disabling) and needs treatment.
It usually involves both:
• Mental features
– worry, fear, difficulty concentration, sleep
• Physical symptoms
– Tachycardia; muscle aches, nausea, shortness of
breath, trembling, pacing
• Generalized anxiety disorder (GAD): apprehensive and
tense for no particular reason.
• Panic disorder: unexpected attacks of anxiety.
• Phobic disorders: fears certain situation “agoraphobia”
• Obsessive compulsive disorder: repetitive, anxiety
driven behavior or obsessive thoughts and doubts
(check things more than once)
• Post-traumatic stress disorder (rape or warefare)
#Secondary due to medical causes or substances
The sedative-hypnotics belong to a
chemically heterogeneous class of drug.
The most important are:
• Benzodiazepines (BZs), Diazepam,
• Non benzodiazepines:
buspirone, zolpidem, and Zaleplon
• Barbiturates: phenobarbital,
• Miscellaneous: carbamates, alcohol
Benzodiazepines Barbiturates Miscellaneous
Intermediate Short Buspirone
acting acting Chloral hydrate
Long Long Zaleplon
acting acting Zolpidem
THE EFFECTS OF CNS
– Sedatives cause mild depression and relaxation
• Anxiolytic—drugs that relieve anxiety
Site of action is on the limbic system which regulates
thought and mental function.
– Hypnotics induce drowsiness and encourage
• Amnesiac effects can cause the loss of
Site of action is on the midbrain and ascending RAS
which maintain wakefulness.
THE EFFECTS OF CNS
• The same drug can cause different
effects based on dose.
– Low dose (sedatives—relieve anxiety and promote
– Higher doses (hypnotics—can cause drowsiness
and promote sleep)
– Even higher doses (anesthetics—can cause
anesthesia and are used for patient management
MECHANISMS OF ACTION
• Most S-H drugs facilitate the actions of
GABA, a major inhibitory transmitter in the
• GABAA receptor activation leads to
increased Cl- ion influx;
• GABAB receptor activation causes increased
efflux of K+.
• Both mechanisms result in membrane
The pentapeptide structure of the GABAA receptor has
binding sites for BZs and for other drugs, including
Barbiturates and ethanol.
DURATION OF ACTION
• Short acting (2-8 hrs)
• Intermediate (10-20 hrs)
temazepam, lorazepam, alprazolam,
oxazepam, nitrazepam, estrazolam
• Long acting (1-3 days):
chlordiazepoxide, diazepam, flurazepam,
MECHANISMS OF ACTION
Affect neurons that have receptors for the
BZs potentiate GABA → increase frequency
of Cl- ion channel opening→ causes
hyperpolarization→ raise firing threshold→
and thus inhibits the formation of action
potentials inhibitory effect on different sites of the
brain especially motor cortex, and limbic system.
GABA—inhibitory transmitter in brain regions
– Limbic system (alter mood)
– RAS (cause drowsiness)
– Motor cortex (relax muscles)
Most of them are well absorbed orally.
Bzs are lipid soluble and widely distributed
Redistribution from CNS to skeletal muscles, adipose tissue.
Cross placental barrier during pregnancy and are excreted
in milk (Fetal & neonatal depression).
Highly bound to plasma protein.
All Bzs are metabolized in the liver
Phase I: ( liver microsomal system)
Phase II: glucouronide conjugation and excreted in the urine.
Many of Phase I metabolites are active: Increase
elimination half life of the parent compound ,
cumulative effect with multiple doses.
EXCEPT No active metabolites are formed for (LEO)
Lorazepam, Estazolam, Oxazepam.
ACTIONS AND THERAPEUTIC DOSES:
BZs have neither antipsychotic activity nor analgesic. They don’t affect
Reduction of anxiety at low dose: alprazolam, lorazepam, oxazepam,
diazepam and chlordiazepoxide.
Alprazolam has anxiolytic-antidepressant effect.
Diazepam is preferred in acute panic-anxiety.
Chlordiazepoxide is preferred in chronic anxiety states.
Sedative and hypnotic actions at higher dose:
not all, three most commonly prescribed BZs are:
– long acting flurazepam,
– intermediate temazepam
– short acting triazolam.
and Two non BZs:
– Zolpidem & Zaleplon.
ACTIONS AND THERAPEUTIC DOSES:
• Anterograde amnesia:
short acting BZs used in premedication for endoscopic,
In anesthesia :
Preanesthetic medication diazepam
Induction of balanced anesthesia (Midazolam)
• Anticonvulsant: Treatment of epilepsy
Diazepam – Lorazepam: Status epilepticus
Clonazepam-Clorazepate: absence , myoclonic seizures.
ACTIONS AND THERAPEUTIC DOSES:
• To control Alcohol withdrawal symptoms:
chlordiazepoxide, chlorazepate, diazepam &
• 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
INDICATIONS AND DRUG
• Tolerance: reduction in drug effect requiring
an increase in dosage to maintain the same
• 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
• 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.
Abrupt discontinuation, particularly if high doses
used for prolong period.
WD symptoms with BZs are less intense than with
ethanol or barbiturates;
ADVERSE EFFECTS OF BZS
• Drowsiness and confusion
• Ataxia at high doses-precludes activities
• Cognitive impairment:
↓long term recall,
↓acquisition of knowledge
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),
• are more selective hypnotics
• are not effective in chronic anxiety, seizure
disorders, or muscle relaxing.
• Possibly less tolerance occur with prolong use
• and lower abuse liability and dependence than
• they show no withdrawal effects, Minimal
ZOLPIDEM AND ZALEPLON
• Rapidly absorbed, rapid onset with short
duration (2-3 hrs)
• Zaleplon is very similar to zolpidem in its
• but ZALEPLON causes fewer residual effect on
pseudomotor and cognitive function compared
with zolpidem or the BZs due to short t1/2 < 1hr
totally different anxiolytic from BZs, no effects on
GABA systems, possible partial agonist at 5-
HT1A receptors some affinity for D2 & 5-HT2A.
• 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
• No additive CNS depression with other drugs.
• Formerly used as sedative hypnotic replaced
by BZs, because barbiturates induce:
2. drug metabolizing enzyme,
3. physical dependence
4. and very severe withdrawal symptom.
5. Flumazenil does not block the effects of
BARBITURATES MECHANISM OF ACTION
• interact with GABA receptors, the binding site is distinct
from that of the BZs.
• 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 (sub anesthetic dose).
• at high doses (anesthetics conc. of pentobarbital-reticular
activating system inhibition), also
– open Cl- ion channels directly
– and block high frequency Na+ channels).
Duration of Action of
• Long acting (1-2 days)
• Short (3-8hrs) Sedative & Hypnotic
Pentobarbital, secobarbital and
• Ultrashort (20 min) I.V induction
ADVERSE EFFECTS OF
• Dose-dependent CNS depression, with nystagmus and
ataxia progressing to respiratory depression, coma, and
• no specific antidote in overdose.
• Additive CNS depression with other drugs.
All barbiturates are weak acids, lipid soluble, absorbed
orally. distribute throughout the body
Thiopentone is highly lipid soluble (high rate of entry into
CNS- quick onset of action).
Redistribute in the body from the brain to skeletal
muscles- adipose tissues.
metabolized in the liver to inactive metabolites
Excreted in the urine.
Alkalinization increases excretion (NaHCO3)
Cross the placenta ( pregnancy).
• 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
-extreme sensitivity to light
-and excretion of dark pigments in the urine.
WHY BENZODIZEPINES HAS REPLACED
They do not produce anesthesia in
high doses & patient can be aroused.
These are not enzyme inducers,
Very low abuse liability.
Lesser distortion of normal
Bzs have no hyperalgesia.
Bzs can be used as day time
Do not effect respiratory or cvs
There is a specific antagonist-
Produce loss of consciousness and
have low margin of safety
High abuse liability.
Marked suppression of REM sleep.
Unacceptable drowsiness is seen.
Causes respiratory and depression
No specific antagonist.
it has low tendency for habituation and thus is useful for
patients wit anxiety who have a history of drug abuse.
• Melatonin: synthesized from 5HT, significant
role in diurnal cycles and sleep-wake behavior.
• Ramelteon: melatonin receptor (MT1 and MT2)
agonist with sleep promoting activities.
– It has been approved for chronic insomnia and
considered free from dependence potential.
• PROPRANOLOL has efficacy in performance anxiety
and social phobias.
• Tricyclicantidepressants (TCA) and SSRI
• Opiod analgesics
SOME OUTDATED HYPNOTICS:
• Chloral hydrate:
– is a trichlorinated derivative of acetaldehyde that is
converted to the active metabolite, trichloroethanol in
– little effect on respiration and BP in therapeutic dose.
– Large doses suppress all type of convulsions with
rapid onset of action.
– It has strong aromatic odor and unpleasant taste.