ANXIOLYTICS

Dr.HAZAR

Department of PharmacologyCollege of PharmacyKing Saud University

Fear response

The normal fear response to threatening stimuli comprises several components, including:

1. defensive behaviors,

2. autonomic reflexes,

3. arousal and alertness,

4. corticosteroid secretion and

5. negative emotions.

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.

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.

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

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)

• 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

Etiology

• Genetic: 15% of patients

• Environmental factors: stress, difficulties in child-parent relationship or learning problems

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)

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

Symptoms of anxiety; cont.

Psychological symptoms

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

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

Treatment of anxiety

• Cognitive behavioral therapy (CBT); breathing retraining

• Desensitization: exposure to fear• Supportive and interpersonal psychotherapy • Pharmacotherapy; anxiolytics

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

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)

BZD: pharmacological actions

• reduction of anxiety and aggression

• sedation and induction of sleep

• reduction of muscle tone and coordination

• anticonvulsant effect

• anterograde amnesia

Clinical uses

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

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

Metabolism of BZD

The metabolism of BZD

• 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.

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

•

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.

•toxic effects resulting from acute overdosage •unwanted effects occurring during normal therapeutic use •tolerance and dependence.

UNWANTED EFFECTS

These may be divided into:• toxic effects resulting from acute over

dosage • unwanted effects occurring during normal

therapeutic use • tolerance and dependence.

Side effects of BZD

1. Drowsiness, confusion, amnesia and impaired coordination .

2. Agitation and excitement 3. 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

4. BDZ enhance the depressant effect of other drugs, including alcohol .

Contraindication: acute narrow-angle glaucoma

Acute toxicity• Prolonged sleep • Respiratory depression only with CNS

depressant

Treatment: Flumazenil

Tolerance and dependence

• Tolerance is less marked than it is with barbiturates

• Dependence: withdrawal syndrome

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

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.

Benzodiazepines(Summary) ..Cont

• Anxiolytic effects are mediated by GABAA receptors containing the α2 subunit, while sedation occurs through those with the α1 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.

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.

• 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).

• 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.

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.

•

• 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.

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.

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

Barbiturates

• Non-selective CNS depressants that produce effects ranging from

1. sedation 2. reduction of anxiety3. unconsciousness 4. death from respiratory and

cardiovascular failure-therefore dangerous in overdose.

• Act partly by enhancing action of GABA, but less specific than BDZ.

• Mainly used in1. anaesthesia 2. 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.

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

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.

• 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.

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.

• 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.

• 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.

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.