PRESENTED BY MADAM IRINA , KSMU

1. Slide-lecture N 8
1. Sedative-hypnotic drugs
2. Antianxiety (anxiolytic, minor
tranquillizer) drugs

2. Sleep
• is a process of physiological consciousness
inhibition when activity of hypnogenic
(responsible for sleep) structures (anterior
hypothalamus, reticular formation of posterior
section of truncus cerebri) is increased and
awakening action of аctivating ascending
reticular formation is decreased.

3. Phases of sleep
• Non-REM sleep
• REM-sleep

4. NREM sleep (orthodoxal, forebrain, synchronized slow-
waved of high amplitude EEG sleep)
• During non-REM sleep:
• Slow movement of eyeballs
• HR, BP and respiration are steady
• Muscles are moderately relaxed (awakened person states
that he was relaxed)
• Parasympathetic tone is increased
• Endogenic sunstances level, that have hypnogenic
activity, increases («delta» peptide of sleep, serotonin,
GABA)
• Growth hormone and prolactin secretion are increased
• Duration of non-REM sleep 90 min (75% of total sleep)

5. NREM sleep
Complications during non-REM sleep:
• - Bronchial asthma
• - Apnoe
• - Epileptic fits (attacks)
• - “Sudden death”
Complications at deficiency of NREM sleep
phase:
- fatigue (tiredness)
- depression
- anxiety (alarm)
- decrease in the mental abilities
- somatic discomfort

6. REM sleep (paradoxical,
Hind brain, desynchronized fast-waved irregular low
amplitude EEG sleep)
• REM-sleep:
• Rapid eye movements
• Vivid dreams (awakened person states that
he was dreaming)
• Cerebral blood flow is increased
• HR, BP and respiration are fluctuant
• Skeletal muscle are profoundly relaxed
• The penis is erect
• Sympathetic tone is increased
• Duration 20 min (25% of total sleep
duration)

7. REM sleep
• Normally the REM stage is entered only after a
preceeding non-REM cycle
• Frequent interruption of sleep will decrease the
REM portion
• Shortening of REM sleep results in increased
irritability and restlessness during the daytime.
• With undisturbed night rest, REM deficits are
compensated by increased REM sleep on
subsequent nights.
• Acute attacks of cardiovascular diseases and
peptic ulcer are possible as a complication
during REM sleep phase

8. Localization and function of basic subtypes of BDZ
receptors
• Оmega-1 (ω-1)
• hypnoselective action
• are located in cortical
and subcortical areas
• Zolpidem
∀ ω-2 and ω-5
• Miorelaxant
• Sedative action
• Benzodiazepines,
tranquilazers

9. Causes of insomnia
• Include emotional problems (grief, anxiety, stress),
physical complaints (cough, pain), or the ingestion
of stimulant substances (caffeine-containing
beverages, sympathomimetics, theophylline, or
certain antidepressants). These factors cause an
imbalance in favor of excitatory influences. As a
result, the interval between going to bed and falling
asleep becomes longer, total sleep duration
decreases, and sleep may be interrupted by several
waking periods.

10. Treatment of sleep problems
• The complaint of insomnia embraces a wide variety of sleep
problems that include difficulty in falling asleep, frequent
awakenings, short duration of sleep, and “unrefreshing” sleep.
• Nonpharmacological therapies sometimes useful include
proper diet and exercise, avoiding stimulants before retiring,
ensuring a comfortable sleeping place, and retiring at a regular
time each night. In some cases, however, the patient will need
and should be given a sedative-hypnotic for a limited period. It
should be noted that the discontinuance of any drug in this
class can lead to rebound insomnia.
• Note: Long-term use of hypnotics is irrational and
dangerous medical practice.

11. Requirements of an ideal hypnotic
• 1. It should be effective orally
• 2. It should produce sleep resembling natural
sleep
• 3. The onset of action must be quick and the
duration adequate
• 4. It should not produce hangover effects such as
drowsiness, dysphoria, and mental or motor
depression.
• 5. It should not produce tolerance, habituation, or
addiction
• 6. The drug should be non-toxic (favorable
therapeutic index)

12. Classification of sleep disorders
• 1) Difficulty in falling asleep: drugs with short
t 1/2 ( 5 hrs) – Zopiclon, Zolpidem, Triazolam,
Midazolam.
• 2) Daytime activity requires increased
concentration and speed of reaction:
see above
• 3) Frequent awakenings, short duration of
sleep and unrefreshing sleep: drugs with
intermediate duration of action (ТЅ 5-10 hrs) -
Nitrazepam, Oxazepam, Temazepam

13. Classification of barbiturates based on
duration of action
1. Ultra-short acting (duration of action 30 min)
Thiopental sodium
2. Short acting (about 2 hrs)
Pentobarbital, Hexobarbital, Secobarbital
3. Intermediate acting (3-5 hrs)
Butobarbital, Secobarbital, Methohexital
4. Long acting (greater than 6 hrs)
Phenobarbital

14. Barbiturates
• Effect on liver
• Induce hepatic microsomal drug-metabolizing enzyme system.
This results in:
• (a) inc. degradation of barbiturates leading to barbiturate
tolerance
• (b) inc. inactivation of anticoagulants, phenytoin, digitoxin,
theophylline and glucocorticoids.
• Effect on blood: Barbiturate-induced porphyria can occur
• Withdrawal symptoms:
• Grand mal seizures, tremors, vivid hallucinations, psychosis

15. Clinical uses of barbiturates
• Anxiety
• Hypnosis
• Convulsions
• As IV adjuncts to surgical anaesthetics (ultra-
short acting barbiturates)
• Cerebral edema due to surgery or trauma
• During cerebral ischemia to protect cerebral
infarction
• Hyperbilirubinemia and kernicterus in the
neonate (due to ability of barbiturates to
stimulate hepatic glucuronyl transferase)

16. Barbiturates
• Were extensively used but are now obsolete as
hypnotics and anxiolytics because they readily
lead to psychological and physical dependence,
induce microsomal enzymes, and relatively
small overdosage may be fatal. In contrast, huge
overdoses of BDZs have been taken without
serious long-term effects. Barbiturates (e.g.
thiopentone) remain important in anaesthesia
and are still used as anticonvulsants (e.g.
phenobarbitone).

17. Acute barbiturate overdosage
• Results in:
• Coma, decr. reflexes, severe respiratory depression,
circulatory collapse, renal failure
Treatment:
• Support respiration and circulation
• Alkalinize urine and promote diuresis (to inc.
elimination of drug)
• Hemodialysis or peritoneal dialysis

18. BDZs
Hypnotic BDZs:
- Midazolam, Triazolam (ТЅ 1-8 hrs);
- Nitrazepam, Oxazepam, Temazepam (ТЅ 5-15 hrs);
- Flunitrazepam, Flurazepam (ТЅ 20-50 hrs).
Most dangerous side effects of BDZs are anterograde amnesia (loss of
memory of events after administration of the drug), tolerance, withdrawal
symptoms and dependence, daytime sleep (except short-acting drugs)
– 5mg diazepam=15 mg chlordiazepoxide=0,5 mg lorazepam=5mg nitrazepam
= 15 mg oxazepam =10mg temazepam
– To avoid withdrawal syndrome (especially with short-acting BDZs) therapy
discontinuation shoul be gradual – decrease dose to 1/8 (from 1/10 to ¼) every 2
weeks

19. Benzodiazepines (BDZs)
• Drug treatment of sleep disorders (hypnotics) and
acute anxiety states (anxiolytics) is dominated by the
BDZs. In general, these drugs will induce sleep when
given in high doses at night and will provide
sedation and reduce anxiety when given in low,
divided doses during the day.
• BDZs have anxiolytic, hypnotic, muscle relaxant and
anticonvulsant actions.

20. Benzodiazepines (BDZs)
• Active orally and although most are
metabolized by oxidation in the liver, they do
not induce hepatic enzyme systems. They
are central depressants, but when given
orally does not normally cause respiratory
depression. Respiratory depression may
occur in patients with bronchopulmonary
disease or with I.V. administration.

21. Mechanism of action of BDZs
1. Benzodiazepines bind to BDZ receptors that are
separate from from but adjacent to the GABA
receptor
2. It potentiates the binding of GABA to its own receptor
3. Increased chloride ion coductance
4. Cell membrane hyperpolarization
5. Decreased initiation of action potentials (reduce
neural excitability)
Remember, that BDZs do not bind to GABA receptors –
they bind adjacent to them

22. Benzodiazepines (BDZs)
• The popularity of BDZs arose from their apparently
low toxicity, but it is now realized that chronic BDZ
treatment may cause cognitive impairment,
tolerance and dependence. For these reasons BDZs
should only be used for 2-4 weeks to treat severe
anxiety and insomnia.
• Since BDZs depress responsivity to external stimuli,
automotive driving skills and other tasks requiring
precise sensorimotor coordination will be impaired.

23. Therapeutic uses of BDZ:
• Anxiety
• Insomnia
• Acute agitation, aggression in some forms of
depression and schizophrenia.
• For sedation and amnesia before medical and
surgical procedures
• Anesthetic premedication
• Epilepsy and status epilepticus
• Night terrors
• As muscle relaxants
• Acute treatment of alcohol withdrawal

24. Benzodiazepines (BDZs)
• BDZs used as hypnotics can be divided into short acting and
longer acting. A rapidly eliminated drug (e.g.temazepam) is
usually preferred to avoid daytime sedation. A longer acting
drug (e.g. nitrazepam) might be preferred where early morning
waking is a problem and where a daytime anxiolytic effect is
needed.
• Intravenous BDZs (e.g. diazepam, clonazepam) are used in
status epilepticus. Midazolam, unlike other BDZs, forms water-
soluble salts and is used as an I.V. sedative during endoscopic
and dental procedures. When given intravenously BDZs have
an impressive amnesic action and patients may remember
nothing of unpleasant procedures.

25. Benzodiazepines (BDZs)
• Day tranquillizers:
• Medazepam
• Tofisopam
• Prominent anxyolitic effect, but miorelaxant and
sedative effects are less than for other BDZs.
Psychostimulant effect is present
• They are effective in somatic symptoms of
anxiety

26. Adverse effects of BDZs:
• CNS: drowsiness (except short-acting), impaired
alertness, agitation and ataxia, especially in the
elderly.
• Paradoxically inc. anxiety including psychosis
esp. with high doses
• CVS: myocardial depression
• Respiration: respiratory depression
• Hypersensitivity reactions: skin rashes

27. Benzodiazepines (BDZs)
• Flumazenil is a competitive BDZ
antagonist that has a short duration of
action and is given I.V. It can be used to
reverse the sedative effects of BDZs in
anaesthetic, intensive care, diagnostic
procedures, and in overdoses.

28. Benzodiazepines (BDZs)
• Dependence. A physical withdrawal syndrome
may occur in patients given BDZs for even short
periods. The symptoms, which may persist for
weeks or months, include anxiety, insomnia,
depression, nausea and perceptual changes.
• Drug interactions. BDZs have additive or
synergistic effects with other central depressants
such as alcohol, barbiturates and
antihistamines.

29. Ethanolamines
• Doxylamine is H1-histamine receptor blocker
• Donormil (trade name) is manufactured in form
of soluble hissing tablets in dose 15 mg
• ТЅ doxylamine is 11-12 hrs; it has daytime
hangover. Efficacy is similar to BDZs.

30. Chlormethiazole
• Has no advantage over short-acting BDZs,
except in the elderly, where it may cause
less hangover. It is given by I.V. infusion in
cases of acute alcohol withdrawal and in
status epilepticus.
• Causes dependence and should be used
only for a limited period.

31. Cyclopyrrolones
• Zоpiclon (ТЅ 5-6 hrs)
• Interferes with GABA-complex, bounds only
with receptors of CNS
• Оptimal therapeutic dose – 7.5 mg, overdosage
is relatively safe

32. Imidazopyridines
• Zolpidem blocks a selective omega1
receptors of GABA-complex. Doesn’t
produce tolerance, аnterograde amnesia
and daytime hangover.

33. Antianxiety drugs
Minor tranquillizers (from Latin word
tranquillius – cool, imperturbable,
unruffled) are drugs used for the
treatment of anxiety and phobic states
(neuroses). Nowadays they are called
аnxiolytics (anxius – uneasy, troubled,
disturbed, full of fear; lysis - dissolving).

34. Effects of tranquillizers
• The anxiolytics differ markedly from the
neuroleptics (antipsychotics). They –
• Have anticonvulsant and miorelaxant properties
• Have no therapeutic effect to control psychosis
• Don’t affect on autonomic nervous system
• Don’t produce extrapyramidal side effects
• Produce physical dependence and carry abuse
liability

35. ANTIANXIETY DRUGS
1.Benzodiazepines:Diazepam,Oxazepam,
Chlordiazepoxide, Lorazepam, Alprazolam;
2. Venlafaxine (antidepressant)
3. 5-HT1A-receptor agonists (e.g. buspirone). It is
relatively anxiolytic without marked hypnotic,
anticonvulsant or muscle relaxant properties.
4. β-blockers (Propranolol) are used mainly to reduce
physical symptoms of anxiety (tremor, palpitations,
sweating, diarrhea); no effect on affective component.
5. Miscellaneous drugs (e.g. chloral hydrate,
meprobamate and paraldehyde). Sedative antihistamines,
such as diphenhydramine, are sometimes used as sleeping
pills, particularly for wakeful children.

36. Chloral hydrate
• It is converted in the body to
trichloroethanol, which is an effective
hypnotic. It is cheap but may cause gastric
irritation. Dichloralphenazone is a
derivative of chloral hydrate that is not a
gastric irritant. These drugs are useful in
the young and elderly. They can cause
tolerance and dependence.

37. Drugs acting at serotonergic (5-HT)
receptors
• 5HT cell bodies are located in the raphe nuclei of the
mid brain and project to many areas of the brain
including those thought to be important in anxiety
(hippocampus, amygdala, frontal cortex).
• Buspirone, a 5HT1A partial agonist, has anxiolytic
actions by acting as an antagonist at postsynaptic
5HT1A sites in the hippocampus.
• Buspirone is not sedative and does not cause
dependence. Unfortunately, it is only anxiolytic after
2 weeks’ administration and the indications for
buspirone are unclear.

38. Antidepressants
• Tricyclic antidepressants, such as
amitriptyline, have anxiolytic effects. They
are used in patients with depression and
anxiety, and for patients who require long-
term anxiolytic drugs where BDZs would
result in dependence. MAO-inhibitors may
be especially useful in phobic anxiety
disorders.