2012 Sedative Hypnotic Drugs

8/3/2019 2012 Sedative Hypnotic Drugs

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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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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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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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2012 Sedative Hypnotic Drugs

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