Hypnotics

1. HYPNOTICS

2. Insomnia is characterized by the complaint of poor
sleep, with difficulty either in initiating sleep or
maintaining sleep throughout the night. It can
occur exclusively in the course of another physical
disorder such as pain, mental disorder, e.g. depres-
sion, or sleep disorder, e.g. sleep apnoea. In a large
proportion of patients it is a primary sleep disorder
and causes significant impairment in social, occu-
pational or other important areas of functioning.
One survey showed similar deficits in quality of life
in insomniacs as in patients with long-term disorders
such as diabetes. About 60% of patients with insomnia
have abnormal sleep.

4. Transmitters: waking state and sleep.
During the sleep dominates GABA.
Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)
Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)

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6. Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)
Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)

7. Normal hypnogram

8. Effect of hypnotics on proportion of REM/NREM
Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)
Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)

9. Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)
Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)
Transmitters: waking state and sleep

10. Sleep hygiene
(adapted from Bennett and Brown, 2003)
• keep regular bedtimes and rising times
• daytime (but not evening) exercise and exposure
to daylight
• avoid stimulants, alcohol and cigarettes in the
evening
• establish bedtime routine — “wind down” —
milk drink may be helpful
• avoid dwelling on problems in bed
• bed should be comfortable and not too warm or
too cold.

11. In the treatment of long-term insomnia the most
important factor is the anxiety about sleep, arising from
conditioning behaviors that predispose to heigh-
tened arousal and tension at bedtime. Thus the
bedroom is associated with not sleeping and auto-
matic negative thoughts about the sleeping process
occur in the evening. Cognitive behavioral therapy
is helpful in dealing with “psychophysiological”
insomnia and together with education and sleep
hygiene measures as above is the treatment of
choice for long-term primary insomnia. Cognitive
behavioral therapists are specially trained in
changing behavior and thoughts about sleep, parti-
cularly concentrating on learned sleep-incompatible
behaviors and automatic negative thoughts at bedtime.

12. TREATMENT OF INSOMNIA
Timely treatment of short-term insomnia is valu-
able, as it may prevent progression to a chronic
condition, which is much harder to alleviate. Psy-
chological treatments are effective and pharmaco-
therapy may be either unnecessary or used as a
short-term adjunct. The approaches are to:
1. Treat any precipitating cause
2. Educate about trigger factors for sleep
and reassure that sleep will improve
3. Establish good sleep hygiene
4. Consider hypnotic medication

14. 1. Benzodiazepines (euhypnotics) – on the green Rp blank
Bromazepam, Flurazepam, Flunitrazepam,
Nitrazepam, Midazolam, Triazolam etc.
2. Benzodiazepine like drugs (euhypnotics,
Z-drugs): Zaleplon, Zolpidem, Zopiclone
3. Barbiturates
•Very short-acting (i.v. anaesthetics): Methohexital, Thiopental
•Intermediate-acting: Cyclobarbital, Secobarbital (out of date)
•Long-acting: Phenobarbital (t1/2 96 h)
4. H1-blockers – I generation: Diphenhydramine, Promethazine
CLASSIFICATION OF HYPNOTICS

15. 7. Melatonergic hypnotics: Ramelteon®
8. Combinations: Reladorm®
(cyclobarbital/diazepam)
9. Herbal preparations: Benosen®
, Valerian,
Dormiplant®
, ReDormin®
5. Piperidinеdiones:
Gluthetimide
6. Some Phenothiazines:
Thioridazine

16. Gamma aminobutyric acid (GABA) is probably
the most important inhibitory transmitter in
the CNS. GABA-ergic neurons are distributed
widely in the CNS. GABA controls the state of
excitability in all brain areas and the balance
between excitatory inputs (mostly glutamatergic)
and the inhibitory GABA-ergic activity. If the balance
swings in favour of GABA, then sedation, amnesia,
muscle relaxation, and ataxia appear and nervous-
ness and anxiety are reduced. The mildest reduction
of GABA-ergic activity elicits arousal, anxiety, rest-
lessness, insomnia, and exaggerated reactivity.

17. Most drugs used in insomnia act as agonists
at the GABAA-receptor
and have effects other than their direct
sedating action, including muscle relaxation,
memory impairment, and ataxia, which can impair
performance of skills such as driving. Clearly those
drugs with onset and duration of action confined to
the night period will be most effective in insomnia
and less prone to unwanted effects during the day.
Those with longer duration of action are likely to
affect psychomotor performance, memory and
concentration; they will also have enduring
anxiolytic and muscle-relaxing effects.

18. Cl−
Barbitu-
rate sate
GABAA-
site
GABA
BDZs
site
+
+
+
Benzodiazepines (BDZs)
Zolpidem, Zopiclone
Barbiturates
Ethanol
+
Adapted from Bennett and Brown,
Clinical Pharmacology – 9th
Ed. (2003)
Adapted from Bennett and Brown,
Clinical Pharmacology – 9th
Ed. (2003)

19. The most used
BENZODIAZEPINES
•Bromazepam
(t1/2 20 h)
•Flurazepam
(t1/2 > 40 h)
•Flunitrazepam
(t1/2 15 h)
•Nitrazepam
(t1/2 26 h
tab. 5 mg)
•In anesthesiology
•Diazepam (long t1/2)
•Midazolam
(t1/2 2 h)
•Triazolam
(t 3 h)

20. When GABA binds with the GABAA-receptor,
the permeability of the central pore of
the receptor to chloride ions increases
(hyperpolaritization), allowing more ions into
the neuron and decreasing excitability.
Benzodiazepines in clinical use enhance
the effectiveness of GABA by increasing the
frequency of the opening of the chloride
ions. These drugs are agonists at the
receptor and the flumazenil (antagonist)
prevents agonists from binding at the receptor site.

21. A model of the GABAA
receptor-chloride ion
channel macromole-
cular complex
Basic & Clinical
Pharmacology –
10th
Ed. (2007)
Basic & Clinical
Pharmacology –
10th
Ed. (2007)

22. BDZs enhance GABA-ergic inhibition.
Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)
Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)

23. Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)
Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)

24. All BDZs and newer benzodiazepine-like drugs
are safe and effective for insomnia, if the
compound with the right timing of onset of action
and elimination is chosen. However, care should
be taken in prescribing them to patients with
co-morbid sleep-related breathing disorders such
as obstructive sleep apnoea syndrome,
which is exacerbated by BDZs.
Objective measures of sleep show that BDZs
decrease time to sleep onset and waking during
the night; subjective effects of improved sleep are
usually greater than the objective changes,
probably because of their anxiolytic effects.

25. Pharmacokinetics
BDZs are effective after administration
by mouth but enter the circulation at very different
rates that are reflected in the speed of onset of
action, e.g. alprazolam is rapid, oxazepam is slow.
The liver metabolizes them, usually to inactive
metabolites, but some compounds produce active
metabolites, some with long t1/2 which greatly
extends drug action, e.g. chlordiazepoxide,
clorazepate and diazepam.

26. Biotransformation of benzodiazepines
Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)
Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)

27. Uses
•Benzodiazepines are used for: insomnia,
anxiety, alcohol withdrawal states, muscle spasm
due to a variety of causes, including tetanus and
cerebral spasticity, epilepsy (clonazepam),
anaesthesia and sedation for endoscopies
and cardioversion.
•The choice of drug as hypnotic and anxiolytic
is determined by pharmacokinetic properties.

28. Tolerance to the anxiolytic effects does not seem
to be a problem. In sleep disorders the situation is not
so clear; studies of subjective sleep quality show
enduring efficacy but about half of the objective
(EEG) studies indicate decreased effects after
4–8 weeks, implying that some tolerance develops.
The necessity for dose escalation in sleep disorders
is rare.
Dependence. Animal and human research has
shown that brain receptors do change in character
in response to chronic treatment with BDZs
and therefore will take time to return to premedication
levels after cessation of medication.

29. Features of withdrawal and dependence vary.
Commonly there is a kind of psychological depend-
ence based on the fact that the treatment works to
reduce patients' anxiety or sleep disturbance and
therefore they are unwilling to stop. If they do stop,
there can be relapse, where original symptoms return.
Withdrawal of BDZs should be gradual after
as little as 3 weeks' use but for long-term users
it should be very slow, e.g. about 6–12 weeks. With-
drawal should be slowed if marked symptoms occur
and it may be useful to substitute a long t1/2 drug (e.g.
diazepam) to minimize rapid fluctuations in plasma
concentrations. In difficult cases withdrawal may be
assisted by concomitant use of an antidepressant.

30. Green
Reception
Form

31. Adverse effects
In addition to those given above, BDZs can affect
memory and balance. Hazards with car driving
or operating any machinery can arise from am-
nesia and impaired psychomotor function,
in addition to sleepiness (warn the patient).
Amnesia for events subsequent to administration
occurs with i.v. high doses, for endoscopy, dental
surgery (with local anaesthetic), cardioversion, and
in these situations it can be regarded as a blessing.
Women (1 in 200), may experience sexual fantasies,
including sexual assault, after large doses of BDZs
as used in some dental surgery, and have brought
charges in lawsuits against male staff.

32. Plainly a court of law has, in the absence of a witness,
great difficulty in deciding whom to believe.
Paradoxical behavior effects and perceptual disorders,
e.g. hallucinations, can occur.
Headache, giddiness, GI upset, skin rashes, and
reduced libido can occur. Extrapyramidal reactions,
reversible by flumazenil, are rare.
The PRC of BDZs is D. BDZs cross the placenta and
can cause fetal cardiac arrhythmia and muscular
hypotonia, suckling hypothermia, and respiratory
depression in the newborn.

33. Interactions
All BDZs potentiate the effects of alcohol
and other central depressants, and all are likely
to exacerbate breathing difficulties where this is
already compromised, e.g. in obstructive sleep
apnoea. BDZs potentiate the action of analgetics too.
The fluoroquinolones block BDZs receptors and
decrease the action of BDZs.
Overdose. Flumazenil (Anexate®
) selectively
reverses benzodiazepine effects and is useful in
diagnosis and in treatment of intoxication with them.
Flumazenil is a competitive partial agonist.

34. Fluoroquinolones
Adapted from Bennett and Brown (2003)Adapted from Bennett and Brown (2003)

35. Nonbenzodiazepine hypnotics that act
at the GABAA-benzodiazepine receptor
Zopiclone is a cyclopyrrolone in structure. It has a
fairly fast (about 1 h) onset of action which lasts
for 6–8 h, making it an effective drug both for
initial and maintenance insomnia. It may cause
fewer problems on withdrawal than BDZs.
Its duration of action is prolonged in the elderly
and in hepatic insufficiency. About 40% of patients
experience a metallic aftertaste. Care should be
taken with concomitant medication that affects its
metabolic pathway. The dose is 3.75–7.5 mg p.o.
Zolpidem is an imidazopyridine in structure and has a fast
onset (30–60 min) and short duration of action.
Patients over 80 years have slower clearance of this drug.

37. Barbiturates have a low therapeutic index.
(relatively small overdose may endanger life);
they also cause dependence and have been popular
drugs of abuse.
Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)
Lüllmann, Color Atlas of Pharmacology – 2nd
Ed. (2000)

38. The use of intermediate-acting drugs (cyclobarbital, secobarbital)
is now limited to severe intractable insomnia in patients already
taking barbiturates (they should be avoided in the elderly).
The long-acting phenobarbital is used for epilepsy, and
very short-acting thiopental and methohexital for anaesthesia.
The barbiturates are enzyme inducers. They can cause rachitis
in children and osteomalacia in elderly. They cross the placenta
and have teratogenic activity (PRC: D). The phenobarbital
may produce tolerance and drug dependence.
Overdose following self-poisoning by barbiturates may have
severe features including hypotension (may lead to renal failure),
hypothermia, respiratory depression, and coma. Supportive mea-
sures may suffice with i.v. fluid to restore central venous pressure
and also cardiac output and, if that fails, use a cardiac drug.

39. A good urine volume (e.g. 200 ml/h) promotes
elimination of the drug. Urine alkalinisation accele-
rates removal of phenobarbital (an acid, pKa 7.2)
as do repeated doses of activated charcoal. Active
elimination by haemoperfusion or dialysis may be
needed in particularly severe and complicated cases.
Antihistamines. Promethazine has a slow
(1–2 h) onset and long (t1/2 12 h) duration of action.
It reduces sleep onset latency and awakenings
during the night after a single dose but there have
been no studies showing enduring action.
It is sometimes used as a hypnotic in children.

40. Barbiturates, glutethimide, and
meprobamate should be avoided for the
management of insomnia. They have
high abuse potential and are dangerous
in overdose (Charney et al.: GOODMAN &
GILMAN'S THE PHARMACOLOGICAL
BASIS OF THERAPEUTICS. 11th
Ed. (2006)

41. Melatonin is the hormone produced by the pineal
gland during darkness, has been investigated
for insomnia. The impressive nature of the diurnal
rhythm in melatonin secretion has stimulated
interest in its use therapeutically to reset circadian
rhythm to prevent jet-lag on long-haul flights and
for blind or partially sighted people who cannot
use daylight to synchronize their natural rhythm.

42. Ramelteon – analogue of melatonin

43. Herbal preparations
Randomized clinical trials
have shown some effect of valerian in mild to
moderate insomnia, and hops, lavender and other
herbal compounds show promise in pilot studies
that are presently being pursued more fully.
The valerian extract contains valeopotriates, which
possess GABA-mimetic action.
Dormiplant®
(coat tabl.) contain ethanol extract:
Rad. Valerianae 160 mg and fol. Mellissae 80 mg.
It possesses sedative and hypnotic effect.
ReDormin®
, Benosen®

44. Valeriana officinalis Leonurus cardiaca
Humulus
lupulus
(Hop – хмел)