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Sedative-Hypnotic Drugs
Dr. Hiwa K. Saaed, BSc, HD, MSc. PhD
Department of Pharmacology & Toxicology
College of Pharmacy/ University of Sulaimani
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Sedative-Hypnotic Drugs
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Sedative-Hypnotic drugsThe sedative-hypnotics belong to a
chemically heterogeneous class of drug.
The most important are:
Benzodiazepines (BZs), 1963
Barbiturates, (1963)
New drugs: buspirone, zolpidem, andZaleplon
Miscellaneous: carbamates, alcohol
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Anxiety
Is tension or apprehension which is a
normal response to certain situations in life.
It is a universal human emotion, but when it
becomes excessive and disproportionate to
the situation, it becomes disabling and
needs treatment.
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Sedatives (anxiolytics)is a drug that produces calming or
quietening effect and reduces excitement
Drugs that have an inhibitory effect on the
CNS to the degree that they reduce: Nervousness
Excitability
Irritability without causing sleepWith as little effect on motor or mental functions as possible
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Hypnotics
Hypnotic is a drug that induces sleep
resembling natural sleep. Both sedation and hypnosis may be
considered as different grades of CNS
depression.
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Dose-dependent depression of CNS
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Tolerance: reduction in drug effect requiring
an increase in dosage to maintain the same
response.
Physiological dependence: removal of thedrug evokes unpleasant symptoms, usually
the opposite of the drugs effects
Psychological dependence: the drug taker
feels compelled to use the drug & suffersanxiety when separated from drug.
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The pentapeptide structure of the GABAA receptor has
binding sites for BZs and for other drugs, includingBarbiturates and ethanol.
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BZs potentiate GABA
increase frequency of Cl- ion channel
opening,
causes hyperpolarization
raise firing threshold
and thus inhibits the formation of action
potentials.
BZs Mechanism of action
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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.
BarbituratesMechanism of action
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In addition, barbiturates can blockexcitatory glutamate receptor.
at high doses (anesthetics conc. Ofpentobarbital), also open Cl- ion channels
directly and block high frequency Na+
channels). Flumazenil does not block the effects of
barbiturates.
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Barbiturates Mechanism of action
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Benzodiazepines:
Are the most commonly used
anxiolytic drugs.
They have largely replaced
barbiturates & meprobamet,
because the BZs are safer andmore effective
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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
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Actions and therapeutic doses:BZs have neither antipsychotic activity nor analgesic. They
dont affect ANS
Therapeutic Uses Sedation
Sleep induction Skeletal muscle relaxation
Anxiety relief: alprazolam is the DOC
Treatment of alcohol withdrawal
A
gitation Depression
Epilepsy: clonazepam
Balanced anesthesia
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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
not all, three most commonly prescribed BZs are:
long acting flurazepam,
intermediate temazepam short acting triazolam.
and Two non BZs: Zolpidem & Zaleplon.
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Actions and therapeutic doses:
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Anterograde amnesia; short acting BZs
used in premedication for endoscopic,
bronchoscopic, angioplasty
Anticonvulsant; clonazepam is useful inchronic Rx of epilepsy,
Alcohol withdrawal symptoms:
chlordiazepoxide, chlorazepate,diazepam & oxazepam are useful in the
Rx of alcohol withdrawal.
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Actions and therapeutic doses:
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Muscle relaxant at higher doses; diazepam
is useful in the Rx of skeletal muscle spasm
Other actions: in higher doses BZsdecrease BP and increase HR. diazepam
decreases nocturnal gastric acid secretion
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Actions and therapeutic doses:
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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.
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Dependence & Withdrawal symptoms
Abrupt discontinuation, particularly if high dosesused for prolong period.
1. Confusion,
2. anxiety,
3. agitation,
4. restlessness,
5. insomnia
6. tension WD symptoms with BZs are less intense than
with ethanol or barbiturates;
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Adverse effects ofBZs:
Drowsiness and confusion
Ataxia at high doses-precludes activities
like driving
Cognitive impairment:
long term recall,
acquisition of knowledge
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BZs antagonist
Flumazenil: I.V only, reverses the effect of
the BZs (competitive antagonist), onset is
rapid, and duration is short.
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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, for seizure
disorders, or for muscle relaxing.
Possibly less tolerance occur with prolong use
and lower abuse liability and dependence thanBZs.
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Zolpidem and Zaleplon
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
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Buspirone:
totally different anxiolytic from BZs, noeffects 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.
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Buspirone lucks anticonvulsant and Musclerelaxant property of BZs and cause minimal
sedation. No additive CNS depression with other
drugs.
Adverse effects:hypothermia,
increase prolactin,
headache,dizziness,
nervousness
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Barbiturates:
Formerly used as sedative hypnotic
replaced by BZs, because barbiturates
induce:
1. tolerance,
2. drug metabolizing enzyme,
3. physical dependence4. and very severe withdrawal symptom.
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Classification
Long acting (1-2 days)Phenobarbital; anticonvulsant
Short (3-8hrs) Pentobarbital,secobarbital and amobarbital Use:sedative & Hypnotic
Ultrashort (20 min) ThiopentalUse: I.V induction of anesthesia
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Adverse effects ofBarbiturates:
Dose-dependent CNS depression, with
nystagmus and ataxia progressing to
respiratory depression, coma, andpossible mortality.
no specific antidote in overdose.
Additive CNS depression with other drugs.
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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.
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Non barbiturate sedative:
Chloral hydrate: is a trichlorinated
derivative of acetaldehyde that is
converted to the active metabolite,
trichloroethanol in the body.
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