Sedative Hypnotics and anxiolytics

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Sedative Hypnotics and anxiolytics
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Terminology

• Tranquilizers (anxiolytics) Treat excitment and
  anxiety
• Sedative-Hypnotics (sleeping pills) Sedation and
  sleep

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Sedative hypnotics are drugs used for the
treatment of anxiety and sleep disorders.

• A sedative
• Sometimes called anxiolytic, or minor
  tranquilizer, reduces anxiety and exerts a
  calming effect

• A hypnotic drug produces drowsiness and
  encourage the onset and maintenance of sleep

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Anxiety disorders
Generalized anxiety disorder (GAD) excessive anxiety lacking any clear reason Panic disorder (sudden attacks of severe fear accompanied by sweating, tachycardia, chest pains,.) Phobias (strong fears of snakes, open spaces, flying) Post-traumatic stress disorder (anxiety triggered by recall of past stressful experiences) Obsessive compulsive disorder (OCD) e.g. fear of contamination
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Examples of Sedative-Hypnotic drugs

• 1- Benzodiazepines
• 2- Buspirone
• 3- Zolpidem
• 4- Barbiturates
• 5- Ethyl alcohol

• NB BZs and barbiturates share very similar
  properties but BZs have a much safer
  pharmacological profile
• All have the same
• Mechanism of action (acting on GABA)
• except Buspirone

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• Graded dose-dependent depression of the CNS
  function
• is a characteristic of sedative-hypnotics.
• Individual drugs differ in the relationship
  between the dose and the degree of CNS depression

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BENZODIAZEPINES
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• Benzodiazepines (BZs) are the most widely used
  sedative-hypnotic drugs
• They have replaced barbiturates for most uses,
  particularly for treatment of anxiety and sleep
  disorders

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How Do BZ Work?
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A model of the GABAA receptor-chloride ion
channel The receptor consists of five or more
membrane-spanning subunits. GABA interact with
alpha or beta subunits triggering chloride
channel opening with resultant membrane
hyperpolarization. Binding of BZs to gamma
subunits potentiates effects of GABA, facilitates
the process of channel opening.
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• BZs increases the frequency of channel opening
  by a given concentration of GABA, but no change
  in the mean open time

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Pharmacokinetics

• absorption well absorbed if given orally , Cmax
  reached in about 1 h
• strongly bound to plasma proteins
• distribution high lipid solubility
• metabolism hydroxylation conjugation with
  glucuronic acid

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Pharmacological Actions
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The main effects of BZs are
1- Reduction of anxiety and aggression 2-
Sedation induction of sleep 3- Reduction of
skeletal muscle tone and coordination 4-
Anticonvulsant (antiepileptic) effect 5-
Anterograde amnesia ., they obliterate memory of
events experienced while under their influence
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Therapeutic uses
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1) as anxiolytic

• Short-term treatment of acute anxiety states

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2) for insomnia

• BZs decrease rapid eye movement (REM) sleep,
  which is associated with dreaming
• For short-term courses, as tolerance ,
  dependence, hangover may occur

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3) Reduction of muscle tone and coordination

• Increased muscle tone is a common feature of
  anxiety states in humans and may contribute to
  the aches and pains, headache
• The relaxant effect of BZs may therefore be
  clinically useful

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• 4) As anticonvulsants
• Clonazepam has selective anticonvulsant action (
  epilepsy)
• Diazepam i.v. in status epilepticus

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5) Muscular disorders

• strong muscle-relaxing properties
• In cases of
• - muscle spasm
• - spastic disorders (MS, cerebral palsy)

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6) Ttreatment of alcohol withdrawal symptoms

• By ameliorating the alcohol withdrawal syndrome
• The commonly used drug is Diazepam

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7) as a pre-ansthetic medication

• for
• i) Anxiolytic effects
• ii) Amnesia
• (impair short-term memory)
• 7) To control extreme
• mania

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Pharmacokinetics
BZS are well absorbed orally, giving a peak plasma concentration in about 1 hour They bind strongly to plasma protein, and their high lipid solubility causes many to accumulate in body fat given by mouth or i.v. (e.g. diazepam in status epilepticus, midazolam in anaesthesia) BZs are all metabolized and excreted in the urine
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Classificaion of BZs

• According to duration of action
• Very short (lt 6 h) Triazolam , midazolam
• Short (12-18) Lorazepam (Ativan)
• Medium (24 h) Alprazolam (Xanax),
• Long (24-48 h) Diazepam (Valium)
• The longer acting agents form active metabolites
  with long half-lives

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Classificaion of BZs

• According to therapeutic uses
•   Hypnotic- Temazepam, Nitrazepam
  Anti-anxiety- Diazepam, Oxazepam
• For panic attacks Alprazolam Anticonvulsant-
  Diazepam, Lorazepam,

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Advantages
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• Why BZ have replaced barbiturates ??
• 1- Less tolerance physical dependence
• 2- They cause less disturbance in sleep patterns
• 3- Barbiturates causes drug interaction because
  they are enzyme inducers
• e.g. They increase metabolism of warfarin
• due to induction of cytochrome P450
• thus making it less effective

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• 4- BZ are Safe in overdose while Barbiturates
  have lower therapeutic index (easily overdosed)
• They dont produce marked and fatal CNS
  depression
• Symptoms of overdose of BZ are less than of
  barbiturates
• 5- BZs produce minimal sedation and motor
  impairment
• 6- A Benzodiazepine antagonist is available
  (Flumazenil)

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Advanges as Hypnotics

• REM sleep ( rapid eye movement) is less affected
  if compared with the same effect of other
  hypnotics
• artificial interruption of REM sleep causes
  irritability and anxiety even if the total amount
  of sleep is not reduced

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BZ antagonist Flumazenil

• Mechanism of action
• Flumazenil acts as a competitive antagonist to
  the binding of BZs to their receptors
• Flumazenil is a short-acting drug while, most BZs
  have longer half-lives, therefore, repeated i.v.
  administration of flumazenil is required to avoid
  relapse into the sedative state

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Side Effects
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• Drowsiness and confusion, amnesia
• BZ may paradoxically produce an increase in
  irritability and aggression in some individuals
  (particularly if short- acting drugs are given
  (triazolam)
• Hypotension in old patients
• Ataxia occurs at high doses and interfere with
  motor coordination (e.g. driving a car)
• BZs enhance the depressant effect of other drugs
  alcohol, in a more than additive way

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• Tolerance and dependence
• If high doses of BZs are given over a prolonged
  period, weight gain as well as physical
  dependence may develop
• Abrupt discontinuation of BZs causes withdrawal
  symptoms, including confusion, anxiety,
  restlessness ,tremor and dizziness
• Short-acting BZs (triazolam) cause more
  withdrawal effects
• Less than Barbiturates

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Contraindications
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• 1.Pregnancy, labour and lactation
• During pregnancy
• Late in pregnancy or around the time of labor and
  delivery
• During the period of breast feeding
• 2. In patients with myasthenia gravis due to the
  muscle relaxing effect of BZs
• 3.Pre-existing CNS depression

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II. BUSPIRONE

• Mechanism of action
• Buspirone is a 5HT1A receptor agonist
• with anxiolytic activity but little sedation
• 5-HT1A receptors are inhibitory receptors that
  reduce the release of 5-HT and other mediators
• Advantages of buspirone
• 1.Unlike BZs, buspirone has no sedative hypnotic,
  anticonvulsant, or muscle relaxant properties
  (anxiolytic only)
• 2. It has minimal abuse liability

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• 3.Buspirone causes less psychomotor impairment
  than BZs and does not affect driving skills
• 4. The drug does not potentiate the CNS
  depressant effects of other sedative-hypnotics
  e.g. ethyl alcohol
• Disadvantages of buspirone
• Its anxiolytic effect takes days or weeks to
  develop . (useful in chronic anxiety states)
• Buspirone is ineffective in controlling panic
  attacks or severe anxiety states

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Side effects

• Buspirone has side effects quite different from
  those of BZs. It does not cause sedation or motor
  incoordination, nor have withdrawal effects been
  reported.
• Main side effects are nausea, dizziness,
  headache and restlessness
• Less troublesome than the side effects of BZs

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IV. BARBITURATES

• Barbiturates are non-selective CNS
  depressants. They can produce varying degrees of
  CNS depression ranging from mild sedation to
  general anesthesia

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Barbiturates have been largely replaced by BZs,
because of the following

• High incidence of tolerance and physical
  dependence following chronic use
• Barbiturates have a low therapeutic index (they
  are dangerous in overdose)
• Barbiturates are enzyme inducers especially
  cytochrome P450 system, they increase the rate of
  metabolic degradation of many other drugs, so
  liable to cause drug interactions
• They dont have an antagonist

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Mechanism of Action

• Barbiturates like BZs, cause activation of GABAA
  receptor and opening of the Cl- channel
  associated with the receptor
• The neuronal membrane is hyperpolarized and less
  likely to fire

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Actions

• At low doses, barbiturates produce sedation
• At higher doses, they cause hypnosis followed by
  anesthesia
• Overdosage may cause respiratory depression and
  death

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Classification

• Ultra-short acting Thiopental Na is an i.v.
  anesthetic that acts within seconds with short
  duration of action
• Short-acting Pentobarbital and secobarbital act
  for 3-8 hours
• Long-acting Phenobarbital (gt than 24 h)

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Therapeutic Uses
1- Anesthesia Thiopental Na is used iv to induce
anesthesia 2- As sedative-hypnotic agents
Barbiturates have been replaced by BZs
3-Anticonvulsants Emergency treatment of
convulsions in status epilepticus by thiopental
as the last approach
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4-Phenobarbital is used in long-term management
of tonic-clonic seizures and eclampsia 5- To
lower serum bilirubin in Neonatal jaundice
(kernicterus) Barbiturates such as
phenobarbital can increase the conjugation of
bilirubin and reduces this risk by inducing the
activity of glucuronyl transferase enzyme
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Side effects

• 1-CNS effects drowsiness can interfere with
  motor mental performance hangover. In large
  doses, barbiturates cause marked depression of
  CNS (may be fatal)
• 2- Induction of P450 thus the rate at which they
  are metabolized increases over the first few days
  of administration. Also, it leads to increased
  metabolism of other drugs e.g. estrogen and
  warfarin ( oral contraceptives and oral
  anticoagulants)
• 3-Tolerance and physical dependence with
  prolonged use
• 4-Teratogenicity

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III. ZOLPIDEM, Z drugs

• Mechanism of action
• Zolpidem is a non-benzodiazepine hypnotic that
  binds selectively to a subset of the BZs receptor
  family and facilitates GABA-mediated neuronal
  inhibition
• Zolpidem has a rapid onset and a short duration
  of action (about 4 hours)
• Its action is antagonized by flumazenil
• Zopiclone is similar to zolpidem

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Advantages Disadvantages

• Short duration of action
• Nightmares
• GIT upset
• Respiratory depression occurs only if large doses
  of zolpidem are ingested together with other
  central depressants

• Rapid onset
• less daytime sleepiness
• Less tolerance or dependence with prolonged use
• It has no effect on psychomotor skills
• Antagonized by flumazenil
• Least effect on REM

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Hypnotic drugs

• Benzodiazepines (e.g. Temazepam , nitrazepam)
• Related drugs working on the BZ receptor (e.g.
  zolpidem, zopiclone)
• Sedating antihistamines (e.g. promethazine),
  which cause drowsiness and are used for
  occasional insomnia. They can impair performance
  the day after

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V. ETHYL ALCOHOL (Ethanol)

• Ethyl alcohol (ethanol) is the most
• abused drug in the world. Ethyl alcohol in low to
  moderate amounts relieves anxiety and causes
  euphoria
• Large dose causes hypnosis and respiratory
  depression which may be fatal

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Mechanism of action

• Ethanol enhances GABA-mediated synaptic
  inhibition
• Ethanol inhibits excitatory NMDA glutamate
  receptors

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Treatment of Chronic Alcoholism

• Hospitalization, psychotherapy and nutritional
  therapy may be needed.
• Drug therapy includes
• BZs (e.g. diazepam) are used to prevent alcohol
  withdrawal symptoms. They are preferred over
  barbiturates because of their wide margin of
  safety. The dose must be tapered slowly over
  several weeks

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Disulfiram
The drug given by itself to nondrinkers has
little effects however, it causes extreme
discomfort to patients who drink alcohol
(Flushing, throbbing headache, nausea, vomiting,
sweating, hypotension and confusion)
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Mechanism of action
Disulfiram acts by inhibiting aldehyde
dehydrogenase thus, alcohol is metabolized as
usual but acetaldehyde accumulates. Acetaldehyde
will form the toxic intermediates methanol and
formaldehyde
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