sedative

Slide-lecture N 8

1. Sedative-hypnotic drugs2. Antianxiety (anxiolytic, minor tranquillizer) drugs

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.

Phases of sleep

• Non-REM sleep

• REM-sleep

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)

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

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)

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

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

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.

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.

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)

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

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

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

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)

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).

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

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

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.


• 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.

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

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.

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

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.


• 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

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


• 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.


• 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.

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.

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.

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

Imidazopyridines

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

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).

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

ANTIANXIETY DRUGS1.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.

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.

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.

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.

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sedative