GROUP NUMBER 8.

NAME OF STUDENT REGISTRATION NUMBER

GETRUDE LEINA T/UDOM/2020/07049

FEDRIC LAMBATI T/UDOM/2020/06952

HAPPINESS MUCHA T/UDOM/2020/00019

KELVIN MYAMBA T/UDOM/2020/06979

ALVIN JOHN T/UDOM/2020/06970

DEOGRATIUS MLUGE T/UDOM/2020/06966

ERIC MAKOLE T/UDOM/2020/06918

FELIX MWENDA T/UDOM/2020/07018

PASCHAL SABASABA T/UDOM/2020/06893

KASIMU GULAMU T/UDOM/2020/00031

ROSEMARY MDAMA T/UDOM/2020/00025

JEREMIAH HATARI T/UDOM/2020/06956

ANXIOLYTICS/SEDATIVES AND
HYPNOTICS.
 DEFINITIONS OF SOME KEY TERMS.
• Sedation: Reduction of anxiety.
• Addiction: The state of response to a drug whereby the drug taker
feels compelled to use the drug and suffers anxiety when
separated from it.
• Anesthesia: Loss of consciousness associated with absence of
response to pain.
• Dependence: The state of response to a drug whereby removal of
the drug evokes unpleasant, possibly life-threatening symptoms,
often the opposite of the drug’s effects.
• Hypnosis: Induction of sleep.
• Sedative (anxiolytic) agent is a drug that subdues excitement or
anxiety and calms the subject without inducing sleep.

• Anxiety is an unpleasant state of tension, apprehension, or

uneasiness (a fear that arises from either a known or an
unknown source).

• Anxiety involves sympathetic activation.

• The physical symptoms of severe anxiety are similar to those of

fear (such as tachycardia, sweating, trembling, and palpitations).
• Sedative(Anxiolytic) agents/drugs are therefore sometimes
referred to as antianxiety drugs.

• Hypnotics are drugs that induces and/or maintains sleep,

similar to normal arousable sleep.

• The sedatives and hypnotics are more or less CNS depressants

with somewhat differing time-action and dose-action
relationships.

• Based on time-action, when CNS depression with quicker

onset, shorter duration is required, hypnotics are used.
• Also when CNS depression with more slow onset is required,
Sedatives are used.
• Based on dose-action, these CNS depressants at lower dose has
anxiolytic/sedative effect.
• While at higher doses, the same CNS depressant can have
hypnotic effect.
• However, some newly discovered medicines have separated the
effects.
• Example: Buspirone, Tracazolate, Zopiclone and Fenobam are
some anxiolytics without sedative effects.
A GRAPH SHOWING SEDATIVE-HYPNOTICS DOSE-ACTION
• Sedative-hypnotic drugs act preferentially on midbrain
ascending reticular formation (which maintains wakefulness)
and on limbic system (thought and mental functions).
• The drugs are highly lipid soluble and hence penetrate easily
to access the CNS.
• Metabolism is mainly by hepatic enzymes with many sedative-
hypnotics converted to active metabolites, with exception of
few barbiturates.
• Drug effects are terminated not only by excretion but also by
redistribution.
• No single mechanism of action for sedative-hypnotics has
been identified.
• Different chemical subgroups/classes may have different
actions.
 CLASSIFICATION
There are Three main classes of Sedative-Hypnotic drugs namely:
• Benzodiazepines: Examples:
-Triazolam, Alprazolam, Flurazepam.
• Barbiturates: Examples:
-Thiopental, Secobarbital, Phenobarbital.
• Miscellaneous/Non-Benzodiazepine Hypnotics: Examples:
-Buspirone, Chloral hydrate, Eszopiclone, Ramelteon,
Zolpidem, Zaleplon.
CLASSES OF SEDATIVE-HYPNOTIC DRUGS
 1. BENZODIAZEPINES
• They are widely used anxiolytic drugs.
• The benzodiazepines can be roughly divided into short-,
intermediate-, and long-acting groups.
• Long acting Benzodiazepines( 1-3 days): Clorazepate,
Chlordiazepoxide, Diazepam, Flurazepam, Quazepam
• Intermediate acting Benzodiazepines( 10-20 hours): Alprazolam
Estazolam Lorazepam Temazepam
• Short acting Benzodiazepines( 3-8 hours): Oxazepam, Triazolam.
• Most benzodiazepines are metabolized by the hepatic
microsomal system to compounds that are also active.
• The benzodiazepines are excreted in the urine as glucuronides or
oxidized metabolites.
• Benzodiazepines have largely replaced barbiturates and other
drugs in the treatment of anxiety and insomnia, because of the
following advantages:
1. Benzodiazepines produce a lower degree of neuronal
depression than barbiturates.
-They have a high therapeutic index.
2. Benzodiazepines cause less distortion of sleep architecture;
rebound phenomena on discontinuation of regular use are less
marked.
3. Benzodiazepines do not alter disposition of other drugs by
microsomal enzyme induction.
4. They have lower abuse liability: tolerance is mild, psychological
and physical dependence, drug seeking and withdrawal
syndrome are less marked
5. A specific Benzodiazepine antagonist flumazenil is available
which can be used in case of poisoning.
• In contrast to barbiturates, Benzodiazepines are not general
depressants, but exert relatively selective anxiolytic, hypnotic,
muscle relaxant and anticonvulsant effects in different
measures.
• There are prominent differences in selectivity for different
facets of action, and in their time-course of action. Different
members are used for different purposes.
• However, the overall mechanism of action of all
Benzodiazepines is qualitatively similar.
 MECHANISM OF ACTION OF BENZODIAZEPINES.
• The target for benzodiazepines are the Gamma aminobutyric
acid(GABA) receptors.
• The GABA receptors are composed of combination of five
subunits a,b,g,d,r that spans post synaptic membrane.

• For each subunit many subtypes exists: for example there are
six subtypes of alpha subunits.
• Binding of GABA to its receptors trigger an opening of central ion
channel allowing chloride ions through the pore.
• The influx of chloride ions causes hyperpolarization of neurons
and decrease neurotransmission by inhibiting formation of
action potential.
• Benzodiazepines modulate GABA effect by binding to a specific
high affinity site(distinct from GABA binding site) located at the
interphase of the alpha subunits and the gamma subunits on
the GABA receptor.
• The binding sites are sometimes called ‘’BZ receptors”
• Common BZ receptor subtypes in CNS are designed as BZ1 and
BZ2 depending on whether the binding site includes an alpha1
or alpha2 subunits respectively.
• Benzodiazepines increases the frequency of channel openings
produced by GABA hence increases the affinity of GABA to its
binding site.(GABA facilitatory action)
• For this reason benzodiazepines are considered as a safer than
barbiturates drugs that can direct mimic GABA.
 THERAPEUTIC USES OF BENZODIAZEPAMS
1. Treating Anxiety Disorders.
• At low dose the benzodiazepines are anxiolytic.
• They reduce anxiety by selectively enhancing GABAergic
transmission in neuron having alpha2 subunits in their GABA
receptors.
• The result is inhibition of neuronal circuit in limbic system of the
brain.
• Donezepam, Lorazepam and Diazepam are longer acting often
preferred in prolonged treatment.
• For both short and long-term treatment alprazolam is preferred.
2. Treating sleeping disorders.
• At high doses some benzodiazepines may produce
hypnosis(artificially produced sleep).
• This effects is mediated by alpha1 GABA receptors.
• Temazepam; for patients experiencing frequent wakening.
• Triazolam; used for insomnia caused by inability to stay asleep,
short acting triazolam is effective in treating individuals who
have difficult in going to sleep.
3. Inducing temporary conscious sedation.
• Temporary impairment of memory with the use of
benzodiazepines is also mediated by alpha1 GABA receptors.
• The shorter acting agents are often employed as medication of
unpleasant procedures such as endoscopy, dental procedure and
angioplasty.
• They cause a form of conscious sedation allowing the person to
be receptive to instruction during those procedures.
• Example: Midazolam.
4. As an anti-seizure
• Several benzodiazepines have antiseizures activity, this is
mediated by alpha1 GABA receptors.
• Clonazepam is occasionally used as adjunctive therapy for certain
type of seizures where as Diazepam and Lorazepam are drug of
choice in treating status epilepticus.

5. Treating Muscular disorders.

• At high doses benzodiazepines relax the spasticity of skeletal
muscle
• They increase presynaptic inhibition in the spinal cord where
alpha2 GABA receptors are largely located, the common used
drug is Diazepam.
6. Alcoholic withdraw symptoms.
• Diazepam and other benzodiazepines may be administered to
easy withdraw from alcohol.
• Benefits derives cross-dependence with alcohol which enable
benzodiazepines to suppress symptoms brought on by alcohol
abstinence.
 ADVERSE EFFECTS OF BENZODIAZEPINES
1. When taken to promote sleep benzodiazepines may cause
drowsiness, light headedness, and difficult in concentrating.

2. Paradoxical effect.
• Certain Beta-carbolines have a high affinity for BZ receptors
and can elicit anxiogenic and convulsant effects. These drugs
are classified as inverse agonists.
3. Respiratory depression.
• Benzodiazepines can cause respiratory depression when
administered intravenously, depression with oral therapy is
rare.
4. Ataxia.
• occurs at high doses and precludes activities that require fine
motor coordination, such as driving an automobile.

5. Anterograde amnesia.
• It has been especially troublesome with Triazolam.
6. Congenital malformations when used during pregnancy.
• Since benzodiazepines are highly lipid soluble can rapidly cross
the placental barrier.
• The use of benzodiazepines during the 1st trimester is associated
with increased risk of congenital malformation.
• Also it easily enter breast milk and may accumulate to toxic
levels in breast feeding infant.
 BENZODIAZEPINES ANTAGONIST.
• Flumazenil is GABA receptor antagonist that can rapidly
reverse the effect of benzodiazepines in case of overdose.
• The drug is available for intravenously only.
• Its onset is rapid but duration is short with half life about one
hour
• Hence frequent administration may be necessary
 2. BARBITURATES.
• Barbiturates form the second class of sedative-hypnotics drugs.
• Barbiturates have been largely replaced by the benzodiazepines
these days.
• Primarily because barbiturates induce tolerance and physical
dependence and are associated with very severe withdrawal
symptoms.
• Like benzodiazepines, barbiturates can also be further divided
based on their time of action.
• Long acting Barbiturates(1-2 days) include phenobarbital
• Short acting Barbiturates ( 3-8 hours) include Pentobarbital
Secobarbital Amobarbital
• Ultra short acting Barbiturates( 20 minutes) include Thiopental
 MECHANISM OF ACTION OF BARBITURATES.
• Barbiturates bind to GABAergic receptors which are the main
inhibitory receptor.
• After binding to the GABA-A receptor( which are different
from those of benzodiazepines) , it prolongs the period by
which chloride channels stays open.
• Prolonged opening of chloride channels allow large amount
of chlorine ions to enter the cell and this leads to
hyperpolarization.
• Hyperpolarization leads to blockage of transmission of the
impulse.
• Barbiturates also blocks the excitatory receptors of glutamate
and therefore hinder transmission of sympathetic signal in the
brain including wakefulness and alertness.
• They also tend to block the sodium channels especially when
in high concentrations.
• For example pentobarbital at high dose block the sodium
channels and hence no depolarization and therefore block the
transmission of impulse with in brain.
• The action of Barbiturates cannot be antagonized by
Flumazenil

.
 THERAPEUTIC USES OF BARBITURATES
1.Anticonvulsant
• Phenobarbital has specific anticonvulsant activity that is
distinguished from the nonspecific CNS depression.
• It is used in long-term management of tonic–clonic seizures.
• Similarly, phenobarbital may be used for the treatment of
refractory status epilepticus.
2. Sedative/hypnotic.
• Barbiturates have been used as mild sedatives to relieve anxiety,
nervous tension, and insomnia.
• Butalbital is commonly used in combination products (with
acetaminophen and caffeine or aspirin and caffeine) as a sedative
to assist in the management of tension-type or migraine
headache

3. Anesthesia.
The ultra–short-acting barbiturates, such as thiopental, have been
used intravenously to induce anesthesia
 ADVERSE EFFECTS OF BARBITURATES.
1. Barbiturates cause drowsiness, impaired concentration, and
mental and physical sluggishness.
• The CNS depressant effects of barbiturates synergize with those
of ethanol.
2. Hypnotic doses of barbiturates produce a drug “hangover”
that may lead to impaired ability to function normally for many
hours after waking.
• Occasionally, nausea and dizziness occur
3. Barbiturates induce cytochrome P450 (CYP450) microsomal
enzymes in the liver.
• Therefore, chronic barbiturate administration diminishes the
action of many drugs that are metabolized by the CYP450
system.
4. Barbiturates are contraindicated in patients with acute
intermittent porphyria.
• Because porphyrin synthesis is increased due to induction of d-
ALA synthase; rate limiting enzyme in porphyrin synthesis, by
barbiturates).

5. Hypersensitivity.
• Rashes, swelling of eyelids, lips, etc. more common in atopic
individuals.
6. Tolerance and dependence.
• Both cellular and pharmacokinetic (due to enzyme induction)
tolerance develops on repeated use.
• Abrupt withdrawal from barbiturates may cause tremors, anxiety,
weakness, restlessness, nausea and vomiting, seizures, delirium,
and cardiac arrest
• Death may also result from overdose(There is no specific antidote
for barbiturates poisoning) (reason why Benzodiazepines replaced
them)
 3.MISCELLANEOUS/NON-BENZODIAZEPINE
SEDATIVE-HYPNOTICS.
• This is a group of hypnotics which are chemically different from
Benzodiazepines, but act as agonists on a specific subset of
Benzodiazepine receptors.
• Exert their CNS effects via interaction with
benzodiazepine receptors, classified as BZ1 or w1 subtypes.
• Their action is competitively antagonized by the
Benzodiazepines antagonist flumazenil, which can be used
to treat their overdose toxicity.
• The non-benzodiazepines hypnotics act selectively on alpha1
subunit containing Benzodiazepine receptors and produce
hypnotic amnesic action with only weak antianxiety, muscle
relaxant and anticonvulsant effects.
• They have lower abuse potential than hypnotic
Benzodiazepines.
• Given their shorter duration of action, they are being preferred
over Benzodiazepines for the treatment of insomnia.
• Some commonly used non-benzodiazepines include:
1. Zopiclone
• This is the first of the non-benzodiazepines hypnotics.
• Acts as an agonist at a subtype of benzodiazepine receptor
involved in the hypnotic action.
• The effect on sleep resemble those of benzodiazepines
• However it is reported not to disturb sleep architecture, but
some degree of next morning impairment can occur.
• Zopiclone is indicated for short term (< 2 weeks) treatment of
insomnia.
• Side effects are metallic or bitter after-taste, impaired
judgement and alertness, psychological disturbances, dry
mouth and milder dependence.
• Safety in overdose is similar to benzodiazepines.

2. Zolpidem.
• it selectively binds to the benzodiazepine receptor subtype
BZ1.
• Zolpidem has no anticonvulsant or muscle-relaxing properties.
• It shows few withdrawal effects, exhibits minimal rebound
insomnia, and little tolerance occurs with prolonged use.
• Adverse effects of zolpidem include nightmares, agitation,
anterograde amnesia, headache, GI upset, dizziness, and
daytime drowsiness.
• Unlike the benzodiazepines, at usual hypnotic doses, the
nonbenzodiazepine drugs, zolpidem do not significantly alter
the various sleep stages and, hence, are often the preferred
hypnotics.
3. Zaleplon
• It is an oral nonbenzodiazepine hypnotic similar to zolpidem.
• Zaleplon causes fewer residual effects on psychomotor and
cognitive function compared to zolpidem or the
benzodiazepines.
• This may be due to its rapid elimination, with a half-life of
approximately 1 hour.
• The drug is metabolized by CYP3A.
4. Buspirone.
• Buspirone is a selective anxiolytic, with minimal CNS depressant
effects and has no anticonvulsant or muscle relaxant properties.
• The drug interacts with the 5-HT1A subclass of brain serotonin
receptors as a partial agonist, but the precise mechanism of its
anxiolytic effect is unknown.
• Tolerance development is minimal with chronic use, and there is
little rebound anxiety or withdrawal symptoms on
discontinuance.
• Side effects of buspirone include tachycardia, paresthesias.
5. Eszopiclone
• nonbenzodiazepine hypnotic that also acts on the BZ 1
receptor.
• It has been shown to be effective for insomnia for up to 6
months.
• Adverse events with eszopiclone include anxiety, dry mouth,
headache, peripheral edema, somnolence, and unpleasant
taste.
6. Ramelteon.
• Activates melatonin receptors in the suprachiasmatic nuclei of
the CNS decreases the latency of sleep onset with minimal
rebound insomnia or withdrawal symptoms.
• Ramelteon has no direct effects on GABAergic neurotransmission
in the CNS.
• ramelteon appears to have minimal abuse liability, and it is not a
controlled substance.

• The adverse effects of the drug include dizziness, fatigue, and

endocrine changes including decreased testosterone and
increased prolactin.
• Other less commonly used non-benzodiazepines sedatives-hypnotics
include Alpidem, Necopidem, Saripidem, Divaplon, Fasiplon, Pagoclone,
Suriclone etc.
REFERENCES.
• Rang and Dale’s Pharmacology, 7th edition: Flashcards updated
edition 2012.
• Lippincott Illustrated Reviews: Pharmacology 6th Edition
• Essentials of Medical Pharmacology 7th Edition KD TRIPATHI MD
• Pharmacology Examination & Board Review 10th Edition
THANK YOU!