ANXIOLYTICS

1
ANXIOLYTICS

• Dr.HAZAR
• Department of Pharmacology
• College of Pharmacy
• King Saud University

2
Fear response

• The normal fear response to threatening stimuli
  comprises several components, including
• defensive behaviors,
• autonomic reflexes,
• arousal and alertness,
• corticosteroid secretion and
• negative emotions.

3
Anxiety

• In anxiety states, these reactions occur in
  anticipatory manner, independently of external
  stimuli
• Characterized by worry, apprehension plus
  physical symptoms
• More prevalent in women than in men.

4
Diagnostic and Statistical Manual of Mental
Disorders, defines the five major anxiety
disorders as

• generalised anxiety disorder
• panic disorder
• phobias disorder
• obsessive compulsive disorder
• post-traumatic stress disorder.

5
Anxiety disorders

• Generalized anxiety disorder (GAD)
• an ongoing state of excessive anxiety
  lacking any clear reason or focus.
• Lifelong tendency to experience tension
• Panic disorder (PD)
• Sudden unpredictable anxiety attack
  physical symptoms
• (sudden attacks of overwhelming fear occur in
  association with marked somatic symptoms, such as
  sweating, tachycardia, chest pains, trembling and
  choking). Such attacks can be induced even in
  normal individuals by infusion of sodium lactate
  , and the condition appears to have a genetic
  component

6
Anxiety disorders cont

• Phobia or Social anxiety disorder (SAD)
• Anxiety triggered by a single stimulus. It
  could be agoraphobia, social phobia or simple
  phobia
• (strong fears of specific objects or situations,
  e.g. snakes, open spaces, flying, social
  interactions)
• Obsessive-compulsive disorder (OCD)
• Unwanted thoughts, impulses, or images that
  cause great anxiety
• (compulsive ritualistic behaviour driven by
  irrational anxiety, e.g. fear of contamination).
• Posttraumatic stress disorder (PTSD)
• Exposure to a life-threatening or traumatic
  event that is persistently reexperienced (anxiety
  triggered by recall of past stressful experiences)

7

• It should be stressed that the treatment of such
  disorders generally involves psychological
  approaches as well as drug treatment.
  Furthermore, other types of drug, particularly
  antidepressants and sometimes antipsychotic drugs
  are often used to treat anxiety disorders

8
Etiology

• Genetic 15 of patients
• Environmental factors stress, difficulties in
  child-parent relationship or learning problems

9
Pathophysiology of anxiety

• Levels of GABA appear to be decreased in the
  cortex
• Release of corticotropin-releasing factor (CRF),
  which, in turn, stimulates the release of
  corticotropin, leading to release of the stress
  hormones (glucocorticoids and epinephrine) from
  the adrenal gland
• Dysfunction of serotonin neurotransmission in
  hippocampal (5-HT1A receptors)

10
Symptoms of anxiety

• Physical symptoms
• GI dry mouth, swallowing difficulty, flatulence
  diarrhea
• Respiratory over breathing, difficulty in
  inhaling, feeling of chest constriction
• CVS palpitation, pain over the heart
• GU increased frequency of urination
• Head blurred vision, dizziness, headache and
  tinnitus

11
Symptoms of anxiety cont.

• Psychological symptoms
• Fear apprehension
• Irritability
• Difficulty in concentrating
• Restlessness
• Sensitivity to noise
• Obsession symptoms
• Distractibility

12
Animal human models of anxiety

• Animal models
• Behavioral suppression elevated cross maze
• Conflict tests
• Aggressive behavior
• Social interaction
• Human models
• Galvanic skin response (GSR)
• Conflict tests

13
Treatment of anxiety

• Cognitive behavioral therapy (CBT) breathing
  retraining
• Desensitization exposure to fear
• Supportive and interpersonal psychotherapy
• Pharmacotherapy anxiolytics

14
Anxiolytics and hypnotic drugs

• Anxiolytics vs hypnotic. Overlapping
• Benzodiazepine
• Buspirone
• Zolpidem. This hypnotic acts similarly to
  benzodiazepines, although chemically distinct,
  but lacks appreciable anxiolytic activity
• Beta-blockers
• Miscellaneous e.g. chloralhydrate
• Barbiturate (obsolete)
• Antidepressants e.g. (TCA) or venlafazine

15
(No Transcript)
16
Benzodiazepines (BZD)

• Act by binding to a specific regulatory site on
  the GABAA-receptor, thus enhancing the inhibitory
  effect of GABA.
• They facilitate opening of chloride channels
• Act by causing allosteric changes in receptors
• Examples
• 1- triazolam midazolam (ultrashort acting
• 2- alprazolam (medium acting)
• 3- diazepam clonazepam (long acting)

17
BZD pharmacological actions

• reduction of anxiety and aggression
• sedation and induction of sleep
• reduction of muscle tone and coordination
• anticonvulsant effect
• anterograde amnesia

18
Clinical uses

• Anxiolytic
• Antidepressant (alprazolam)
• Muscle relaxant (diazepam)
• Anticonvulsant (clonazepam)
• Hypnotic (midazolam)

19
Pharmacokinetics of BZD

• BDZ are well absorbed when given orally
• Highly bind to plasma protein
• Given PO or IV
• BDZ are all metabolized excreted as glucuronide
  conjugates in the urine
• Some are converted to active metabolites e.g.
  nordazepam which has a half-life of about 60
  hours, and which accounts for the tendency of
  many BDZ to produce cumulative effects and long
  hangovers when they are given repeatedly

20
Metabolism of BZD
Drug Half-life of parent compound (h) Active metabolite Half-life of metabolite (h) Overall duration of action Main uses
Triazolam  ,a midazolam 2-4 Hydroxylated derivative 2 Ultra-short (lt6 h) Hypnotic Midazolam used as intravenous anaesthetic
Zolpidemb 2 No   Ultra-short ( 4 h) Hypnotic
Lorazepam  , oxazepam  , temazepam  , lormetazepam 8-12 No   Short (12-18 h) Anxiolytic, hypnotic
Alprazolam   6-12 Hydroxylated derivative 6 Medium (24 h) Anxiolytic, antidepressant
Nitrazepam 16-40 No   Medium Hypnotic, anxiolytic
Diazepam  , chlordiazepoxide 20-40 Nordazepam 60 Long (24-48 h) Anxiolytic, muscle relaxant Diazepam   used intravenously as anticonvulsant
Flurazepam 1 Desmethyl-flurazepam 60 Long Anxiolytic
Clonazepam   50 No   Long Anticonvulsant, anxiolytic (especially mania)
aTriazolam   has been withdrawn from use in UK on account of side-effects.bZolpidem is not a benzodiazepine but acts at the same site.

• The metabolism of BZD

21

• Advancing age affects the rate of oxidative
  reactions more than that of conjugation
  reactions. Thus the effect of the long-acting
  BDZ, which may be used regularly as hypnotics or
  anxiolytic agents for many years, tends to
  increase with age, and it is common for
  drowsiness and confusion to develop insidiously
  for this reason.

22

• The short-acting compounds are those that are
  metabolised directly by conjugation with
  glucuronide. The main pathways are shown

23
Figure 4. shows the gradual build-up and slow
disappearance of nordazepam from the plasma of a
human subject given diazepam daily for 15 days.
Body_ID HC037019
Body_ID P037028
Body_ID None
Body_ID P0541
Body_ID P037029
UNWANTED EFFECTS
These may be divided into
toxic effects resulting from acute overdosage unwanted effects occurring during normal therapeutic use tolerance and dependence.
page 540

page 541
24
UNWANTED EFFECTS

• These may be divided into
• toxic effects resulting from acute over dosage
• unwanted effects occurring during normal
  therapeutic use
• tolerance and dependence.

25
Side effects of BZD

• Drowsiness, confusion, amnesia and impaired
  coordination .
• 2. Agitation and excitement
• BDZ may paradoxically produce an increase in
  irritability and aggression in some individuals.
  This appears to be particularly pronounced with
  the ultrashort-acting drug triazolam (and led to
  its withdrawal in the UK and some other
  countries), and is generally more common with
  short-acting compounds
• BDZ enhance the depressant effect of other drugs,
  including alcohol .
• Contraindication acute narrow-angle glaucoma

26

• Acute toxicity
• Prolonged sleep
• Respiratory depression only with CNS depressant
• Treatment Flumazenil

27
Tolerance and dependence

• Tolerance is less marked than it is with
  barbiturates
• Dependence withdrawal syndrome

28
BZD withdrawal symptoms

• Restlessness
• Worsening of anxiety and insomnia
• Agitation
• Irritability
• Unsteadiness
• Muscle tension
• Depressive symptoms
• Photophobia
• Increased pulse
• Dilated pupils
• Tremors

29
Benzodiazepines(Summary)

• Act by binding to a specific regulatory site on
  the GABAA receptor, thus enhancing the inhibitory
  effect of GABA. Subtypes of the GABAA receptor
  exist in different regions of the brain and
  differ in their functional effects.
• Anxiolytic BDZ are agonists at this regulatory
  site. Other BDZ (e.g. flumazenil ) are
  antagonists and prevent the actions of the
  anxiolytic benzodiazepines. A further class of
  inverse agonists is recognised, which reduce the
  effectiveness of GABA and are anxiogenic they
  are not used clinically.

30
Benzodiazepines(Summary) ..Cont

• Anxiolytic effects are mediated by GABAA
  receptors containing the a2 subunit, while
  sedation occurs through those with the a1
  subunit.
• Endogenous ligands for the BDz-binding site are
  believed to exist. They include peptide and
  steroid molecules, but their physiological
  function is not yet understood.

31
Benzodiazepines cause

• reduction of anxiety and aggression
• sedation, leading to improvement of insomnia
• muscle relaxation and loss of motor coordination
• suppression of convulsions (antiepileptic effect)
  
• anterograde amnesia.

32

• Differences in the pharmacological profile of
  different BDZ are minor clonazepam appears to
  have more anticonvulsant action in relation to
  its other effects.
• BDZ are active orally and differ mainly in
  respect of their duration of action. Short-acting
  agents (e.g. lorazepam temazepam , half-lives
  8-12 hours) are metabolised to inactive compounds
  and are used mainly as sleeping pills.
• Some long-acting agents (e.g. diazepam
  chlordiazepoxide) are converted to a long-lasting
  active metabolite (nordazepam).

33

• Some are used I.V, for example diazepam in
  status epilepticus, midazolam in anaesthesia.
• Zolpidem is a short-acting drug that is not a BDZ
  but acts similarly and is used as a hypnotic.
• BDZ are relatively safe in overdose. Their main
  disadvantages are interaction with alcohol,
  long-lasting 'hangover' effects, withdrawal
  symptoms and the development of dependence.

34
Buspirone

• is a partial agonist at 5-HT1A receptors and is
  used to treat various anxiety disorders. It also
  binds to dopamine receptors, but it is likely
  that its 5-HT-related actions are important in
  relation to anxiety suppression, because related
  compounds (e.g. ipsapirone and gepirone, neither
  of which are approved for clinical use, which are
  highly specific for 5-HT1A receptors show
  similar anxiolytic activity in experimental
  animals.

35

• 5-HT1A receptors are inhibitory autoreceptors
  that reduce the release of 5-HT and other
  mediators. They also inhibit the activity of
  noradrenergic locus ceruleus neurons and thus
  interfere with arousal reactions. However,
  buspirone takes days or weeks to produce its
  effect in humans, suggesting a more complex
  indirect mechanism of action.
• Buspirone is ineffective in controlling panic
  attacks or severe anxiety states.

36
Buspirone

• has side effects quite different from those of
  BDZ. It does not cause sedation or motor in
  coordination, nor have withdrawal effects been
  reported. Its main side effects are nausea,
  dizziness, headache and restlessness, which
  generally seem to be less troublesome than the
  side effects of BDZ.

37
Buspirone

• Buspirone is a partial agonist at
  5-HT1A-receptors
• It also inhibits the activity of noradrenergic
  locus ceruleus neurons
• Buspirone takes days or weeks to produce its
  effect
• SE dizziness, nausea, headache and restlessness

38
Barbiturates

• Non-selective CNS depressants that produce
  effects ranging from
• sedation
• reduction of anxiety
• unconsciousness
• death from respiratory and cardiovascular
  failure-therefore dangerous in overdose.
• Act partly by enhancing action of GABA, but less
  specific than BDZ.

39

• Mainly used in
• anaesthesia
• treatment of epilepsy use as sedative/hypnotic
  agents is no longer recommended.
• Potent inducers of hepatic drug-metabolizing
  enzymes, especially cytochrome P450 system, so
  liable to cause drug interactions. Also
  precipitate attacks of acute porphyries in
  susceptible individuals.
• Tolerance and dependence occur.

40
Barbiturates

• They act by enhancing action of GABA
• They cause death from respiratory and
  cardiovascular depression
• Barbs. induce a high degree of tolerance and
  dependence
• They strongly induce the synthesis of hepatic
  cytochrome P450 and conjugating enzymes

41
Other anxiolytics

• Beta-blockers, e.g. propranolol, are used to
  relieve physical symptoms
• Selective serotonin reuptake inhibitors SSRIs
  e.g. sertraline, fluoxetine paroxetine are used
  to treat certain anxiety disorders, including
  obsessive compulsive disorder and panic. Their
  action in this context appears to be independent
  of their antidepressant effects.

42

• Venlafaxine (serotonin-norepinephrine reuptake
  inhibitor)
• Mirtazapine ( alpha2-antagonist/5-HT2 and 5-HT3
  antagonists)
• MAO inhibitors, and the tricyclic antidepressants
• Various drugs that enhance the effects of GABA,
  developed primarily as antiepileptic drugs may
  also be effective in treating anxiety disorders .
• They include gabapentin , vigabatrin, tiagabine
  and valproate.

43
Potential

• Besides the GABAA and 5-HT1A receptor mechanisms
  discussed above, many other transmitters and
  receptors have been implicated in anxiety and
  panic disorders ,particularly noradrenaline, and
  neuropeptides such as cholecystokinin (CCK) and
  substance P. Anxiolytic drugs aimed at these
  targets are in development, but none are so far
  available for clinical use.

44

• 5-HT3 receptor antagonists such as ondansetron
  show anxiolytic activity in animal models but
  have not proved efficacious in controlled human
  trials. As mentioned earlier, 5-HT uptake
  inhibitors, such as fluoxetine, and mixed
  5-HT/noradrenaline uptake inhibitors, which are
  used as antidepressant drugs also show efficacy
  in anxiety disorders.

45

• Antagonists of the neuropeptide CCK have been
  tested as anxiolytic drugs. CCK, which is
  expressed in many areas of the brain stem and
  midbrain that are involved in arousal, mood and
  emotion, has been considered as a possible
  mediator of panic attacks, but non-peptide CCK
  antagonists have proved ineffective in clinical
  trials.

46
Conclusion

• Anxiety is a persistent state of excessive
  fear. Pathology of anxiety involves abnormalities
  in GABA, noadrenaline serotonin transmissions.
• Drugs that enhance GABA action, like BDZ , are
  commonly used to treat anxiety. Beside using them
  as anxiolytic, BDZ are used as hypnotic. Some
  antidepressant ( e.g. SSRI and TCA) drugs have
  anxiolytic activity and are used in the treatment
  of anxiety disorder.