Sedative-Hypnotic Drugs

Prepared by professor Berdiyeva

Dilnavoz, PhD
 Overview of the chapter
Introduction (Sedatives, Hypnotics).
Salient features of Sedatives and Hypnotics.
Classification of Hypnotic- Sedatives
Barbiturates
Benzodiazepines (advantages over barbiturates,
MOA)
Cloralhydrates
Paraldehyde
Methaqualone
Glutithimide
Xylazine hydrochloride
Detomidine hydrochloride
Medetomidine hydrochloride
 Sedative-Hypnotics & Anxiolytics

❖Sedative: Drug that

calm behavior but
produces drowsiness.
❖Hypnotics: Drugs that
induce state like sleep.
 Ideal Hypnotic

Should cause a transient decrease in the level of

consciousness for the purpose of sleep without
lingering effect.
Have no potential for decreasing or arresting
respiration
Produce no abuse, addiction, tolerance or dependence
Classification:
1- Barbiturates.
2 Benzodiazepines (BZ).
3 Non-barbiturates hypnotics.
4 Non-BZ anxiolytics.
BARBITURATES CLASSIFIED ACCORDING TO THEIR
DURATIONS OF ACTION

Short acting Ultra-Short

Long acting acting
1- Barbiturates.
Pharmacodynamics:
 BARBITURATES

PHARMACOLOGICAL ACTIONS

1. CNS

2. Other actions
CNS: Barbiturates
produce dose-
dependent effects:

sedation → sleep
→ anaesthesia →
coma.
 Actions of barbiturates
A)C.N.S: Non-selective C.N.S depressant from sedation to anesthesia
&coma:
1) Sedative action but produces drowsiness.
2) Hypnotic: but abnormal sleep due to ↓↓↓ REM sleep leads to:
a.Hang over.
b.Rebound paradoxical sleep (night mare) after tolerance or
stoppage of
drug.
3) Amnesia.
4) Potentiate analgesics e.g. morphine but not used alone.
5) Anticonvulsant: all barbiturates treat all types of convulsions but
as anti-
epileptic only phenobarbitone treats grand mal & status
epilepticus.
6) Anesthesia (thiopental): but → hang-over & large dose →
depresses RC.
7) Large doses: depress vital medullary centers:
a)RC → hypoventilation & hypoxia.
b)VMC → hypotension.
C)HRC → hypothermia.
 B)CVS: by large dose & by IV
route → hypotension due to
(depression VMC, decrease
cardiac contraction & decrease
sympathetic tone→ VD).

C)Hormones: increase ADH

release. D)Liver: hepatic
microsomal enzyme inducer:
tolerance, cross tolerance &
drug interactions.N.B. The
dose of barbiturates as
sedative is 1\3 of the
hypnotic dose.
 Therapeutic uses
1. Antianxiety agents in
emotional strain
2. Anticonvulsant
3. Muscle relaxants
4. General Anaesthetics
5. Potentiation of analgesic
agents
6. Adjuvants to anaesthesia
7. In hypertension
•Phenobarbital – This drug is most commonly prescribed as an
anti-epileptic drug and to help treat those with severe traumatic
brain injury. It helps with preventing seizures or treating them
when they happen.
•Methohexital – This drug has been used clinically for sedation
for short periods of time during pediatric outpatient surgeries.
•Butalbital – This drug is used for the treatment of headache
disorders. Butalbital is a combination of aspirin, acetaminophen,
caffeine and codeine.
•Pentobarbital – This drug is often used as a pre-anesthetic
medication.
•Primidone – This drug is commonly prescribed to treat seizure
disorders and essential tremors.
•Amobarbital – This drug is often prescribed for treating sleep
disorders such as insomnia.
Contraindications:

1) Allergy to barbiturates.
2) Idiosyncrasy (porphyria).
3) Head injury.
4) Hypotension (shock).
5) Liver & kidney diseases.
6) Depressed RC.
7) Respiratory: emphysema,
bronchial asthma
 Benzodiazepines
Benzodiazepines are commonly used as sedatives or hypnotics in man
and dog.
These compounds have several advantages over barbiturates as
hypnotic and sedatives. ---
Benzodiazepines have high therapeutic index. Ingestion of even 20
hypnotic doses does not usually endanger life—there is no loss of
consciousness.
Hypnotic doses do not affect respiration or cardiovascular
function.
BZDs have practically no action on other body systems. Only on
i.v. injection the BP falls and cardiac contractibility decreases.
BZDs do not alter disposition of other drugs by microsomal
enzyme induction.
Their toxicity (due to higher dosage) can be overcome by giving
specific benzodiazepine receptor antagonist flumazenil.
COMPARISON OF THE DURATIONS OF ACTION OF
THE BENZODIAZEPINES
Pharmacokinetics:
A) Absorption:
Well absorbed orally: Clorazepate (inactive &
prodrug) converted by gastric HCL into active metabolite
(nordiazepam).
B)Metabolism: Mainly by hepatic microsomal enzymes:
1-Activation (drug to active metabolite) e.g. diazepam,
chloridiazepoxide, flurazepam, alprazolam & triazolam.
2-Inactivation by oxidation & conjugation: most of Bzd.
C)Excretion: renal excretion of inactive hydrophilic
metabolites.
N.B. Duration of actions of Bzd: duration of parent drug +
active metabolite.
Pharmacodynamics:
Mechanism of action:
o Bzd binds to specific binding site (BZ receptor = ω
receptor ; ω1& ω2) on GABA receptors → facilitate
binding of GABA to its binding site on GABA receptor →
increase frequency of opening of Cl- channels
→increase Cl- influx → hyperpolarization & post synaptic
inhibition.
N.B. GABA binds to 2 specific sites between α & β subunits
of GABA receptor (GABA binding sites).
o Bzd & newer hypnotic (zolpidem) bind to site between
α & γ subunits of the GABA receptor → increase the
frequency of opening of Cl- channels.
Pharmacological actions:
1-Anxiolytic = anti-anxiety = minor tranquilizer
Due to inhibition of neurons in limbic system.
2 Hypnotic action
3Antiepileptics: e.g. diazepam & clonazepam in status
epilepticus & grand mal epilepsy.
4-Antispasticity = skeletal muscle relaxant:
e.g. diazepam so used in multiple sclerosis & cerebral
palsy.
5-Induction of anesthesia: by I.V administration of:
Long acting: diazepam.
Short acting: midazolam.
Advantages of Bzd over barbiturates as hypnotics:
Adverse effects of Bzd:
1 Daytime sedation (long acting) or Daytime anxiety (short
acting).
2 Dependence → addiction → sudden withdrawal → anxiety,
confusion, agitation & insomnia.
3 Affect mental, psycho-motor & sexual functions.
4 Amnesia especially short acting triazolam.
5 Ataxia.
6 Allergy.
7Amenorrhea, inhibit ovulation & ejaculation even
teratogenic.
8 Stimulates appetite → increase body weight.
9 Acute toxicity: rare unless if used with alcohol.
Treatment of acute toxicity: flumazenil + supportive
treatment.
HyPNOTIC BENZODIAZEPINES:
Flumazenil: NINDRAL, FLURAZ 15 mg cap.
o Selective & competitive Bzd receptor blocker →
antagonizes all Bzd actions.
o Given by repeated I.V injections or by I.V infusion.
o Uses:
1 Acute Bzd toxicity.
2 Awake patients from anesthesia.
3Under trial in hepatic coma to block endozepine
present in high concentrations in patients with hepatic
coma.
 Diazepam
Generic name: diazepam (oral) [ dye-AZ-e-
pam ]
Brand name: Valium
Dosage forms: oral concentrate (5 mg/mL),
oral solution (5 mg/5 mL), oral tablet (10 mg;
2 mg; 5 mg)
Drug classes: Benzodiazepine
anticonvulsants, Benzodiazepines
Uses: It is the oldest and all purpose
BZD, used as anxiolytic, hypnotic, muscle
relaxant, premedicant, anaesthetic and for
emergency control of seizures due to its
broad spectrum activity
Diazepam
III- Other hypnotics
Zolpidem:
o Not Bzd but acts as Bzd receptor agonist.
o No anticonvulsant, no muscle
relaxation, no tolerance.
o Uses: hypnotic with rapid onset &
short duration (3hrs).
o Side effects: nightmares, confusion,
drowsiness & GIT upset.
o N.B. Flumazenil antagonizes zolpidem
action.
o Dose: 5–10 mg (max 20 mg) at bedtime; ½
dose in elderly and liver disease patients.
o NITREST, ZOLDEM, DEM 5, 10 mg tabs.
Zaleplon:
Very similar to zolpidem in its hypnotic
action but zaleplon causes fewer
residual effects on psychomotor and
cognitive functions compared to
Dose: 5–10 mg (max
zolpidem or the benzodiazepines, this 20 mg) at bed time.
may be due to its rapid elimination ZAPLON, ZALEP, ZASO
5, 10 mg tabs.
(t1/2 1 hour).
Zaleplon is used on a short-term basis to treat
insomnia (difficulty falling asleep). Zaleplon does
not help you to stay asleep longer or decrease the
number of times that you awaken during the night.
Zaleplon is in a class of medications called
hypnotics. It works by slowing activity in the brain
to allow sleep.
Eszopiclone:
o It is BZ1 receptor agonist,
similar to zolpidem and
zaleplon , used for
insomnia.
o Side effects:
anxiety, dry
Dose: 2–3 mg at bed time,
mouth and elderly and liver disease
patient 1 mg:
peripheral FULNITE, ZOLNITE 1 mg, 2
mg tabs.
oedema.
Ramelteon:
o It is a selective agonist at the MT1 and MT2
subtypes of melatonin receptors in supra-chiasmatic
nucleus.
o There is no evidence of dependence or withdrawal
effects.
o Side effects: dizziness, fatigue and somnolence.
CATEGORIES OF INSOMNIA

Transient insomnia Short-term insomnia Long-term insomnia

•Lasts <3 days •3 days to 3 weeks •lasted for >3 weeks

•---Caused by a brief •--- Caused by a personal •---No specific stressor may

environmental or situational stressor such as illness, grief, be identifiable.
stressor. or job problems.
•---A more complete medical
•---Respond to attention to •---Sleep hygiene education evaluation is necessary in
sleep hygiene rules. is the first step. these patients, but most do
not need an all-night sleep
•--- Hypnotics should be •---Hypnotics may be used study.
used at the lowest dose and adjunctively for 7-10 nights.
for only 2-3 nights.
•---- Hypnotics are best used
intermittently during this
time, with the patient
skipping a dose after 1-2
nights of good sleep.
 LONG-TERM INSOMNIA
Nonpharmacological treatments are important for all patients with long-
term insomnia.These include
Reduced caffeine intake
Avoidance of alcohol
Adequate exercise
Relaxation training
Behavioral-modification approaches, such as sleep-restriction and stimulus-
control therapies.
Nonpharmacological treatments for insomnia have been found to be
particularly effective in reducing sleep-onset latency and time awake after
sleep onset.
Management of Patients after Long-Term Treatment with
Hypnotic Agents

If a benzodiazepine has been used regularly for >2 weeks, it

should be tapered rather than discontinued abruptly.

In some patients on hypnotics with a short t1/2, it is easier to

switch first to a hypnotic with a long t1/2 and then to taper.

The onset of withdrawal symptoms from medications with a

long t1/2 may be delayed.

Consequently, the patient should be warned about the

symptoms associated with withdrawal effects.
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