‫بسم هللا الرحمن الرحيم‬

Sudan University for Science & Technology

Faculty of Pharmacy
Fourth year- sem 7
Pharmacology 3
Lecture 2: 18.12.2023
Drugs Acting on the Central Nervous System
Sedative & Hypnotics and anxiolytic drugs
Mohammed Taj Eldin Abdalla
B. Pharm., M. Pharm., Clinical Pharmacology
Email: Mohammedtaj654@gmail.com
2023
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❖ Lectures Outlines
❖At the end of this lecture students should be able to:
1. Describe general concepts about Sedatives & Hypnotics and anxiolytic
drugs.
2. Mention the Classification of Sedatives & Hypnotics and anxiolytic
drugs.
3. Explain Safety and efficacy measures, MOA, pharmacological effects,
Pharmacokinetics, and ADRs of Benzodiazepines.
4. Describe MOA, Pharmacokinetics, and ADRs of Barbiturates.
5. Describe MOA, Pharmacokinetics, and ADRs of Newer Sedatives &
Hypnotics, and anxiolytic drugs.
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Anxiety Insomnia

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 Sedative & Hypnotics and anxiolytics
drugs
❖Assignment of a drug to the sedative-hypnotic class indicates that its major
therapeutic use is to cause Sedation (with concomitant relief of anxiety) or to
encourage sleep.
❖Anxiety: an uncomfortable feeling of vague fear or apprehension accompanied
by characteristic physical sensations.
❖Anxiety is the most commonly observed symptom of mental illness but also
occurs in normal individuals.

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❖The normal fear response to threatening stimuli comprises several
components, including defensive behaviors, autonomic reflexes,
arousal and alertness, corticosteroid secretion, and negative
emotions.
❖In anxiety states, these reactions occur in an anticipatory manner,
independently of external events.
❖The distinction between a 'pathological' and a 'normal' state of
anxiety is not clear-cut but represents the point at which the
symptoms interfere with normal productive activities.
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❖Normal anxiety is of short duration, usually event related, not under
conscious control, and is characterized by dis-satisfaction, somatic
complaints, or apprehension
❖If the anxiety is not due to an external cause such as a medical illness
or a medication, and it is out of proportion to the actual threat or when
the anxiety lasts far beyond the presence of the threat, anxiety may
impair normal functioning they are considered pathological and
require treatment (anxiety disorder).

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❖ Anxiety disorders as recognized clinically include:
1. Generalized anxiety disorder: an ongoing state of excessive anxiety
lacking any clear reason or focus.
2. Panic disorder: sudden attacks of overwhelming fear occur in
association with marked somatic symptoms, such as sweating,
tachycardia, chest pains, trembling, and choking.
3. Phobias: strong fears of specific objects or situations, e.g. snakes,
open spaces, flying, and social interactions.
4. Post-traumatic stress disorder: anxiety triggered by recall of past
stressful experiences.
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5. Obsessive compulsive disorder: compulsive ritualistic behaviors
driven by irrational anxiety, e.g. fear of contamination.
6. Common medical illness associated with anxiety symptoms
7. Drugs associated with anxiety symptoms.
8. Social anxiety disorder.
✓The treatment of such disorders generally involves psychological
approaches as well as drug treatment.

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• An effective sedative (anxiolytic) agent should reduce
anxiety and exert a calming effect with little or no effect
on motor or mental functions. The degree of central
nervous system depression caused by a sedative should
be the minimum consistent with therapeutic efficacy.
• A hypnotic drug should produce drowsiness and
encourage the onset and maintenance of a state of sleep
that as far as possible resembles the natural sleep state
(used for the treatment of insomnia).
• Hypnotic effects involve more pronounced
• depression of the CNS than sedation, and this can be
achieved with most sedative drugs simply by increasing
the dose.

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❖ Classification of anxiolytics and hypnotics drugs:
1- Benzodiazepines:
This is the most important group used as an anxiolytic and hypnotic
agents.
2- 5-HT1A-receptor agonists (e.g. buspirone):
These agents, recently introduced, are anxiolytic but not appreciably
sedative.
3- Barbiturates:
These are now largely obsolete, superseded by benzodiazepines.
Their use is now confined to anesthesia and the treatment of epilepsy.

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4- β-adrenoceptor antagonists (e.g. Propranolol):
➢These are used to treat some forms of anxiety, particularly where physical
symptoms, such as sweating, tremors, and tachycardia, are troublesome. Their
effectiveness depends on a block of peripheral sympathetic responses rather than
on any central effects.
5- Miscellaneous:
➢Other drugs (e.g. chloral hydrate, meprobamate, and paraldehyde);
They are no longer recommended.
➢Sedative antihistamines such as diphenhydramine, are sometimes used as
sleeping pills, particularly for wakeful children.

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(1) Benzodiazepines:
➢The term benzodiazepine refers to the portion of the structure composed of a
benzene ring fused to a seven-membered diazepine ring.
➢The benzodiazepines (BZ) are the most effective and safe medications for the
treatment of acute anxiety symptoms.
▪Examples: chlordiazepoxide, diazepam, oxazepam, lorazepam, clorazepate,
halazepam, parazepam and alprazolam.
❖Efficacy and Safety measures:
✓All BZs are equally effective anxiolytics, and most of the improvement occurs in
the first 2 weeks of therapy.

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✓They are considered to be more effective for somatic and
autonomic symptoms of GAD, while antidepressants are considered
more effective for psychic symptoms (e.g., apprehension and worry).
✓The dose must be individualized.
✓Duration of therapy usually should not exceed 4 months. Some
patients require longer treatment.
✓The elderly have an enhanced sensitivity to BZs and may
experience falls when on BZ therapy.
✓Benzodiazepines have only a limited capacity to produce profound
and potentially fatal CNS depression.
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✓Although coma may be produced at very high doses,
benzodiazepines cannot induce a state of surgical anesthesia by
themselves and virtually are incapable of causing fatal respiratory
depression or cardiovascular collapse unless other CNS depressants
also are present.
➢Because of this measure of safety, benzodiazepines and their newer
analogs have largely replaced older agents for the treatment of
insomnia or anxiety.

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❖ Mechanism of action:
➢ Benzodiazepines act very selectively on
GABAA-receptors, which mediate the fast
inhibitory synaptic response produced by activity
in GABA-ergic neurons.
➢ The effect of benzodiazepines is to enhance the
response to GABA, by facilitating the opening of
GABA-activated chloride channels. ( frequency
of opening)
➢ Benzodiazepines bind specifically to a
regulatory site (benzodiazepine receptor) in the
receptors, is between an α and the γ subunit.
distinct from the GABA Binding site, and act
allosterically to increase the affinity of GABA for
the receptor.
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❖ Pharmacological effects:
✓They are basically similar in their pharmacological actions,
though some degree of selectivity has been reported (e.g.
clonazepam shows anticonvulsant activity with less marked
sedative effects).
✓From a clinical point of view, differences in pharmacokinetic
behavior among different benzodiazepines are more
important than differences in profile of activity.

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❖Effect on the central nervous system:
[1] Reduction of anxiety and aggression:
✓Benzodiazepines have anxiolytic effects.
✓With the possible exception of alprazolam, benzodiazepines do not have
antidepressant effects.
✓Benzodiazepines may paradoxically produce an increase in irritability and
aggression in some individuals. This appears to be particularly pronounced with
the ultra-short-acting drug triazolam and is generally more common with short-
acting compounds. "It is probably a manifestation of the benzodiazepine
withdrawal syndrome".

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[2] Sedation and induction of sleep:
✓Benzodiazepines decrease the time taken to get to sleep, and increase
the total duration of sleep, Both effects tend to decline when
benzodiazepines are taken regularly for 1-2 weeks.
✓"The use of sedative-hypnotics for more than 1-2 weeks leads to some
tolerance to their effects on sleep patterns".

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[3] Muscle relaxation:
✓Benzodiazepines reduce muscle tone by a central action that is independent of
their sedative effect. (muscle tone is a common feature of anxiety states)
[4] Anticonvulsant effects:
✓All of the benzodiazepines have anticonvulsant activity in experimental animal
tests.
✓Clonazepam, because of its selective anticonvulsant action, is used to treat
epilepsy.
✓Diazepam is given intravenously to control life-threatening seizures in status
epilepticus.

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[5] Anterograde amnesia:
✓Benzodiazepines obliterate the memory of events experienced while under
their influence, an effect not seen with other CNS depressants. Minor surgical
procedures can thus be performed without leaving unpleasant memories.
❖Effect on the Cardiovascular system:
✓The cardiovascular effects of benzodiazepines are minor in normal
subjects except in severe intoxication.
✓In preanesthetic doses, all benzodiazepines decrease blood
pressure and increase heart rate.

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❖Effects on the respiratory system:
✓ Sedative hypnotics even at therapeutic doses can produce
significant respiratory depression in patients with pulmonary disease.
❖Effect on Gastro-Intestinal Tract:
✓Benzodiazepines are thought to improve a variety of “anxiety-related “ GIT
disorders.

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❖ Pharmacokinetics of benzodiazepines:
A- Absorption and Distribution:
• Well absorbed when given orally, usually giving a peak plasma
concentration in about 1 hour. The rates of absorption differ
depending on lipophilicity.
• They bind strongly to plasma protein, and their high lipid
solubility causes many of them to accumulate gradually in body
fat.
• Can also given intravenously (e.g. diazepam in status epilepticus,
midazolam in anesthesia). Intramuscular injection often results in
slow absorption.
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• All sedative-hypnotics cross the placental barrier during pregnancy.
Thus, if they are given in the pre-delivery period, they may
contribute to depression of neonatal vital functions.
• Sedative hypnotics are detectable in breast milk and may exert
depressant effects on CNS function in nursing infants.

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B- Biotransformation (metabolism):
✓Many phase I metabolisms of benzodiazepines produce active
metabolites, with half-lives greater than the parent drugs. (e.g. N-
desmethyl diazepam "nor diazepam" which has a half-life of about 60
hours).
✓Benzodiazepine can be roughly divided into short, medium-and
long-acting compounds.
✓Desmethyl diazepam is an active metabolite of chlordiazepoxide,
diazepam, prazepam, and clorazepate; Desmethyl diazepam in turn is
biotransformed to the active compound oxazepam.
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❖ Unwanted effects of benzodiazepines:
1- Toxic effects resulting from acute overdosage:
• cause prolonged sleep, without serious depression of respiration or
cardiovascular function, which could be more severe in the presence of other
CNS depressants, particularly alcohol.
These toxic effects can be counteracted by an effective antagonist "flumazenil".
2- Unwanted effects occurring during normal therapeutic use:
• Drowsiness, confusion, and impaired coordination, which considerably
affects manual skills such as driving performance.
• Benzodiazepines enhance the depressant effect of other drugs, including
alcohol, in a more than additive way.
3- Tolerance, psychological and physiological dependence:

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❖Benzodiazepine Discontinuation:
➢When regular users "of sedative-hypnotic" stop using large doses of these drugs
suddenly, they may develop physical withdrawal symptoms ranging from
restlessness, insomnia, and anxiety, to convulsions and death.
✓After BZs are abruptly discontinued, three events can occur:
* Rebound symptoms are an immediate, but transient, return of original
symptoms with an increased intensity compared with baseline.
* Recurrence or relapse is the return of original symptoms at the same intensity
as before treatment.
* Withdrawal is the emergence of new symptoms and a worsening of preexisting
symptoms.
✓The onset of withdrawal symptoms is 24 to 48 hours after discontinuation of
short-t1/2 and 3 to 8 days after discontinuation of long-t1/2 drugs.
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❖Discontinuation strategies include the following:
✓A 25% per week reduction in dosage until 50% of the dose is
reached, then dosage reduction by one-eighth every 4 to 7 days.
✓A BZ with a long-t1/2 (e.g., diazepam, clonazepam) may be
substituted for a drug with a short-t1/2 (e.g., lorazepam, oxazepam,
alprazolam). The substituted drug should be given for several weeks
before gradual tapering begins.
✓Adjunctive use of imipramine, valproic acid, or buspirone can help
to reduce withdrawal symptoms during the BZ taper.

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❖Benzodiazepine inverse agonists:
✓The term "inverse agonist" is applied to drugs that bind to
benzodiazepine receptors and exert the opposite effect to that
of conventional benzodiazepines, producing signs of
increased anxiety and convulsions. (e.g. Diazepam-binding
inhibitor (BDI) and some benzodiazepine analogs act
similarly).

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❖Benzodiazepine antagonists: (e.g. Flumazenil):
✓Flumazenil has a high affinity for the benzodiazepine receptor that acts as a
competitive antagonists.
✓Flumazenil is approved for use in reversing the central nervous system
depressant effects of benzodiazepine overdose and to hasten recovery following
the use of these drugs in anesthetic and diagnostic procedures.
✓When given intravenously, flumazenil acts rapidly but has a short half-life (0.7 -
1.3 hours) due to rapid hepatic clearance.
✓Since all benzodiazepines have a longer duration of action than flumazenil,
sedation commonly recurs, requiring repeated administration of the antagonist.

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❖Adverse effects of flumazenil include:
✓Agitation, confusion, dizziness, and nausea.
✓Flumazenil may cause a severe precipitated withdrawal syndrome in
patients who have developed physiologic benzodiazepine dependence.

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(2) Barbiturates:
➢Examples: amobarbital, pentobarbital, phenobarbital, secobarbital, thiopental.
➢Barbiturates have depressant activity on the central nervous system, producing
effects similar to those of inhalation anaesthetics.
➢They cause death from respiratory and cardiovascular depression if given in
large doses for this reason they are now little used as anxiolytic and hypnotic
agents.
➢Barbiturates which have specific use include "phenobarbitone" used for its
anticonvulsant activity, and thiopentone, which is widely used as an intravenous
anaesthetic agent.

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❖Mechanism of action of barbiturates:
➢ Barbiturates share with benzodiazepines the ability to enhance the
action of GABA, but they bind to a different site on the GABA-
receptor/chloride channel, and their action seems to be much less
specific.
➢ The effect of barbiturate is to enhance the response to GABA, by
increasing the duration of opening of GABA-activated chloride
channels. And thus increase the chloride influx.
➢ Barbiturates bind specifically to a regulatory site (Barbiturates
receptor) in the receptors, between adjacent α1 and β2 subunits
. distinct from the GABA Binding site, and act allosterically to increase
the affinity of GABA for the receptor.
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❖Pharmacokinetics of Barbiturates:
➢The barbiturates are usually absorbed very rapidly into the blood following oral
administration.
➢The thiobarbiturates (e.g. thiopental) are very lipid soluble, and a high rate of
entry into the CNS contributes to the rapid onset of their central effects.
➢The major metabolic pathways involve oxidation by hepatic enzymes. With very
few exceptions, the metabolites of the barbiturates lack pharmacologic activity.
➢The elimination half-life of Phenobarbital in humans is 4-5 days.
➢Phenobarbital is excreted unchanged in the urine to a certain extent (20-30% in
humans), and its elimination rate can be increased significantly by alkalinization of
the urine.

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❖Adverse effects of barbiturates:
➢They induce a high degree of tolerance and dependence.
➢They strongly induce the synthesis of hepatic cytochrome P450 and
conjugating enzymes and thus increase the rate of metabolic
degradation of many other drugs "cause drug interaction".

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(3) Newer drugs for anxiety and sleep disorders:
A. Buspirone:
✓Buspirone relieves anxiety without causing marked sedative or euphoric
effects.
✓Unlike benzodiazepines, the drug has no hypnotic, anticonvulsant, or
muscle relaxant properties.
✓Buspirone-treated patients show no rebound anxiety or withdrawal signs on
abrupt discontinuance.
✓Buspirone has minimal abuse liability.
✓In contrast to benzodiazepines, the anxiolytic effects of buspirone may take
more than a week to become established.

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❖Mechanism of action of buspirone:
✓Buspirone is a potent agonist at 5- HT1A-receptors.
❖Pharmacokinetics:
✓Buspirone is rapidly absorbed orally but undergoes extensive first-
pass metabolism.
✓The elimination half-life of buspirone is 2-4 hours, and liver
dysfunction may decrease its clearance.

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❖Side effects:
✓Buspirone does not cause sedation or motor incoordination and does not
affect driving skills.
✓The main side effects are nausea, dizziness, headache and restlessness.
✓Tachycardia, palpitations, nervousness, gastrointestinal distress, and
paresthesia may occur more frequently than with benzodiazepines.
✓Buspirone also causes a dose-dependent pupillary constriction.
❖Buspirone analogs:
✓ Some buspirone analogs have been developed (e.g. Ipsapirone, gepirone,
tandospirone) and are under study.

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B. Zolpidem:
✓An imidazopyridine derivative structurally unrelated to
benzodiazepines, has hypnotic actions.
✓The drug binds selectively to the BZ1 subtypes of benzodiazepine
receptors and facilitates GABA-mediated neuronal inhibition.
✓Respiratory depression may occur if large doses of zolpidem are
ingested with other CNS depressants, including ethanol.

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C. Zaleplon:
✓Zaleplon resembles zolpidem. The drug binds selectively to the BZ1
receptor subtype, facilitating the inhibitory actions of GABA.
✓Zaleplon is rapidly absorbed from the G.I.T and has an elimination
half-life of about 1 hour.
✓Zaleplon decreases sleep latency but has little effect on total sleep
time or sleep architecture.
✓Rapid onset and short duration of action are favorable properties for
those patients who have difficulty falling asleep.

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(4) Older sedative-hypnotics:
• These drugs include alcohols, chloral hydrate, piperidinediones
(glutethimide, methyprylon), and carbamates (meprobamate).
• They are rarely used in therapy.
• Trichloroethanol is the pharmacologically active metabolite of chloral
hydrate and has a half-life of 6-10 hours. However, its toxic
metabolite, trichloroacetic acid, is cleared very slowly.
• Recurrent concerns regarding the possible carcinogenicity of chloral
hydrate itself or its metabolites- suggest that this drug should not be
used until more data are available.

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 Have A Nice Day

Next: Antiepileptic drugs (Anti-seizure drugs)

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