ANTIANXIETY AGENTS Dr. Sanjita Das

(Spielberger & Rickman, 1991) What is anxiety? “Anxiety has been defined as an unpleasant emotional state or reaction that can be distinguished from others, such as anger or grief, by a unique combination of experiential qualities and physiological changes.” “An anxiety state consists of feelings of tension, apprehension, nervousness, and worry, and activation of the autonomic nervous system.” “Physiological manifestations generally include increased blood pressure, rapid heart rate…, sweating, dryness of mouth, vertigo, irregularities in breathing, and muscular skeletal disturbances.” (Spielberger & Rickman, 1991)

Explanations of Anxiety Psychological theories Freud’s theory Cognitive Behavioral Biological theories Genetics Neural and neuroendocrine pathways involved in body’s normal stress response (fight or flight) Specific action by neurotransmitters and other neurochemicals

Anti-anxiety Medications (i.e., anxiolytics) Benzodiazepines Atypical benzodiazepines Busipirone Antidepressants Antihistamines Beta blockers Clonidine Tiagabine

Major Uses – Anxiety state – Insomnia – Epilepsy – Muscle spasticity – Induction of amnesia – As preanesthetic medication – Adjunct in alcohol withdrawal – For differential psychiatric diagnosis

Classification – Benzodiazepines: Chlordiazepoxide, diazepam, xazepam – Non-benzodiazepines: Buspirone, β-adrenergic blocker-propranolol, some antidepressants (imipramine, fluoxetine, MAOIs), zolpidem, zaleplon, clonidine – Older and less commonly used: Barbiturates, meprobamate, chloral hydrate

Benzodiazepines Benzodiazepines are the most commonly used antianxiety agents. They are neither analgesics nor anesthetics. 􀂄 Alprazolam Xanax 􀂄 Clonazepam Klonopin 􀂄 Diazepam Valium 􀂄 Lorazepam Ativan 􀂄 Oxazepam Serax

Mechanism of Action 􀂋 Increases neurotransmitter GABA 􀂋 Depresses CNS 􀂋 Produces skeletal muscle relaxation 􀂋 Anticonvulsant properties Potentiate GABA-induced inhibition (GABA is the major inhibitory neurotransmitter in the CNS)(inhibitory neuron) GABAA receptor (Ionotropic receptor– a cl- channel)

Benzodiazepines 􀂄 Crosses blood-brain barrier – absorption: Rapidly absorbed from GI tract – distribution & redistribution of benzodiazepines is effected by • blood flow: brain, heart, kidney > skeletal muscles > > fat tissue 􀂄 Crosses blood-brain barrier 􀂄 Crosses placenta and enters breast milk • concentration gradient • Lipophilicity – more lipophilic drugs have faster onset of action and short duration of action – biotransformation in liver: benzodiazepines form • active compounds 􀂄 Metabolites active as CNS depressant

Side Effects 􀂄 Central Nervous System Depressant 􀂄 Cardiovascular Side Effects 􀂄 Blood 􀂄 Gastrointestinal 􀂄 Other 􀂄 Dependence 􀂄 Tolerance 􀂄 Physical addiction 􀂄 Psychological addiction 􀂄 Withdrawal syndrome 􀂄 Xanax, Valium and Ativan should only be used short-term. Dependence and tolerance develop quickly 􀂄 Signs and symptoms of withdrawal 􀂋 Anxiety, tremors, insomnia 􀂋 Grand mal seizures,delirium 􀂋Respiratory depression and death

Diazepam – anticonvulsant - Short term treatment of anxiety - May be useful in acute stage of panic – amnesic agent – alcohol withdrawal – status epilepticus • Oxazepam – metabolite of diazepam – short duration of action

Drug Interactions – additive with CNS depressants such as alcohol, opioids, antihistamines, phenothiazines – cimetidine decreases diazepam metabolism -Day time sedation and drowsiness, synergistic depression of CNS with other sedatives and alcohol, likelihood of physical and psychological dependence has led to the development of non-benzodiazepine antianxiety agents

Nonbenzodiazepines Buspirone HCL BuSpar 􀂄 Nonbenzodiozepine BuSpar 􀂄 Non addicting 􀂄 No significant sedation, drowsiness or hypnotic action 􀂄 Absent or minimal mental confusion, psychomotor impairment 􀂄 No physical or psychological dependence 􀂄 Can be used for long periods of time 􀂄 Useful in generalized anxiety disorderBuspirone HCL BuSpar

Mechanism of action of Buspirone - Partial 5-HT1A receptor agonist at postsynaptic sites and agonist at 5-HT1A presynaptic receptors – Additionally, it functions as a dopamine D2, as well as α1, and α2-adrenergic receptor antagonist to a lesser degree - no direct effect on GABA system – little interaction with depressants

Interactions Grapefruit, grapefruit juice, grapefruit extract, kool-aid: Drastically increased plasma levels of buspirone. Grapefruit juice considerably increased plasma buspirone concentrations. The probable mechanism of this interaction is delayed gastric emptying and inhibition of the cytochrome P450 3A4-mediated first-pass metabolism of buspirone caused by grapefruit juice. Haloperidol: Increased plasma levels of haloperidol. Rifampicin: Decreased plasma levels of buspirone. Carbamazepine: Increased plasma levels of buspirone

Contraindications Myasthenia gravis. Acute, closed-angle glaucoma. Severely compromised liver and/or renal function. Pre-existing heart conditions (e.g., myocardial infarction). Epilepsy

Other Anti-Anxiety Agents Antihistamines Mechanism: Block histamine receptors in the CNS associated with anxiety and agitation. Rapid effect – within 20-30 min. May cause drowsiness, impaired performance, and develop tolerance to anxiolytic effects. Beta Blockers Mechanism: Block the effects of norepinephrine at the receptor in the brain and the peripheral nervous system. Originally developed to treat hypertension. Effective at reducing physical symptoms of anxiety (i.e., rapid heart beat, muscle tension, dry mouth). Beta blockers have been used with some benefit for PD and social phobia. Beta blockers have brief effect only a few hours. (Preston et al., 2005; Walsh, 1999)

Other Anti-Anxiety Agents Clonidine Mechanism: alpha-2 adrenergic agonist; presynaptic inhibitor of norepinephrine release Originally used to treat hypertension Tiagabine Mechanism: GABA reuptake inhibitor Originally an anticonvulsant May be useful in treating PTSD and PD. (Preston et al., 2005)

ZOLPIDEM, ZALEPLON -Non-benzodiazepine but interact with benzodiazepine receptors; produce less amnesia; in high doses, may produce insomnia; potentiate ethanol effect; little anticonvulsant and muscle relaxant effects

Antidepressants – Imipramine in panic disorder. The dose is higher than used in the treatment of depression – MAO inhibitors in agoraphobia, panic disorder, social phobia, post-traumatic stress –Selective serotonin reuptake inhibitors (SSRIS) and TCAS such as clomipramine in obsessive compulsive disorder

Special Considerations Concerning Antianxiety Agents : – Choice of drug should be based on: • Desired onset of action. • Desired duration of action. • Desired period of treatment. • Presence or absence of pain. • Personality of patient including age. • Risk of drug interactions. – Avoid • Use of short-acting agents for long periods. • Combine with other sedative-hypnotic agents, alcohol, antihistamines, anticholinergics, and phenothiazines.