stimuli include defensive behaviors autonomic reflexes arousal and alertness corticosteroid secretion negative emotions In anxiety states, these reactions occur in an anticipatory manner, independently of external events Manifestations of anxiety Verbal complaints The patient says he/she is anxious, nervous, edgy Somatic and autonomic effects The patient is restless and agitated has tachycardia increased sweating weeping gastrointestinal disorders Social effects Interference with normal productive activities Pathological Anxiety Generalized anxiety disorder (GAD) People suffering from GAD have general symptoms of motor tension, autonomic hyperactivity, etc. for at least one month Phobic anxiety Strong fears of specific things or situations, e.g. snakes, open spaces, flying, social interactions Post-traumatic stress disorder Anxiety triggered by insistent recall of past stressful experiences Pathological Anxiety Panic disorders Attacks of overwhelming fear occurring in association with marked somatic symptoms, such as sweating, tachycardia, chest pains, trembling, choking Genetic?
Obsessive-compulsive behaviors These patients show repetitive ideas (obsessions) and behaviors (compulsions) Pathology of anxiety The stress response in humans involves a cascade of hormonal events
release of corticotropin-releasing factor (CRF)
release of corticotropin
release of the stress hormones from the adrenal cortex (glucocorticoids and epinephrine)
glucocorticoids exert negative feedback to the hypothalamus
decreasing the release of CRF Corticotropin-releasing factor, - key mediator of autonomic, behavioral, immune, and endocrine stress responses The peptide appears to be anxiogenic, depressogenic, and proinflammatory and leads to increased pain perception GABA inhibits CRF release Benzodiazepines facilitate GABA neurotransmission and therefore can improve anxiety
Prolonged exposure of the CNS to glucocorticoid hormones eventually depletes norepinephrine levels in the locus ceruleus As norepinephrine is an important neurotransmitter involved in attention, vigilance, motivation, and activity, the onset of depression may subsequently occur Anxiolytic drugs Benzodiazepines 5-HT 1A -receptor agonists: Buspirone -adrenoceptor antagonists Others - Hydroxyzine, Methaqualone, Chloral hydrate Barbiturates Classes of anxiolytic drugs Benzodiazepines- used for treating both anxiety states and insomnia
5-HT 1A -receptor agonists - anxiolytic activity with little sedation
-adrenoceptor antagonists - reduce physical symptoms of anxiety (tremor, palpitations, etc.); no effect on the affective component
Methaqualone, chloral hydrate - still used occasionally to treat insomnia
Barbiturates - obsolete as anxiolytic/sedative agents Classes of anxiolytic drugs Benzodiazepines: Diazepam, Chlordiazepoxide, Oxazepam, Lorazepam, Alprazolam
Azapirones: Buspirone, Gepirone,
- blocker: Propranolol
Sedative antihistaminics: Hydroxyzine BZDs in anxiety Minimal effects on other body systems Lower dependence producing liability Safe in gross overdosage Chlordiazepoxide Slow oral absorption Long lasting effects t 1/2 :5-15 hrs
Diazepam Dose: 5-30 mg
Oxazepam Preferred in elderly and patients with liver disease as hepatic metabolism is negligible Lorazepam Shorter t 1/2 : 10-20 hrs Very sedative and marked amnesia OCD, tension syndromes
Alprazolam High potency anxiolytic Mood elevating action in mild depression t 1/2 : 12 hrs
Adverse effects of BZDs in anxiolytic doses Sedation Lightheadedness Psychomotor or cognitive impairment Vertigo Increased appetite and weight gain Alteration in sexual function Failure in ovulation Dependence Buspirone Used in various anxiety disorders Ineffective in controlling panic attacks No significant sedation No cognitive/ functional impairment Doesn't interact with BDZ receptor or modify GABAergic transmission Doesn't produce tolerance or physical dependence No muscle relaxant activity No anticonvulsant activity Analogs: Ipsapirone, gepirone, tandospirone Buspirone: MOA Buspirone is a partial agonist at presynaptic 5-HT 1A receptors - inhibitory autoreceptors that reduce the release of 5-HT and other mediators
5-HT 1A subtype is important in the brain in relation to mood and behaviour
Inhibition of the activity of noradrenergic locus coeruleus neurons - interferes with arousal reactions
Weak D 2 blocking action: No mood elevation, EPS
Buspirone takes days or weeks to produce its effect in humans Pkinetics Rapid absorption Extensive first pass metabolism (BA<5%) One active metabolite Excretion: urine and faeces
Side-effects Less troublesome than with BDZs They include Dizziness Nausea Headache -adrenoceptor Antagonists Used mainly to reduce physical symptoms of anxiety due to sympathetic overactivity tremor, palpitations, rise in BP
Effectiveness depends on block of peripheral sympathetic responses rather than on any central effects