Anxiolytics Rashida Manzoor Mphil Uos

ANXIOLYTICS

By Rashida Manzoor Roll # 18 2nd semester

SEDATIVE/HYPNOTICS ANXIOLYTICS • Major therapeutic use is to relief anxiety (anxiolytics) or induce sleep (hypnotics). • Hypnotic effects can be achieved with most anxiolytic drugs just by increasing the dose. • The distinction between a "pathological" and "normal" state of anxiety is hard to draw, but in spite of, or despite of, this diagnostic vagueness, anxiolytics are among the most prescribed substances worldwide.

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 and often 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: Simple phobias. Agoraphobia, fear of animals, etc. Social phobias. Panic disorders: Characterized by acute attacks of fear as compared to the chronic presentation of GAD. Obsessive-compulsive behaviors: These patients show repetitive ideas (obsessions) and behaviors (compulsions).

Anxiolytics

Strategy for treatment Reduce anxiety without causing sedation.

Anxiolytics – Benzodiazepines (BZDs). – Barbiturates (BARBs). – 5-HT1A receptor agonists. 4) 5-HT3 receptor antagonists.

Anxiolytics • Other Drugs with anxiolytic activity. – TCAs (Fluvoxamine). Used for Obsessive compulsive Disorder. – MAOIs. Used in panic attacks. – Antihistaminic agents. Present in over the counter medications. – Antipsychotics (Ziprasidone).

Sedative/Hypnotics All of the anxiolytics/sedative/hypnotics should be used only for symptomatic relief. ************* All the drugs used alter the normal sleep cycle and should be administered only for days or weeks, never for months. ************

USE FOR SHORT-TERM TREATMENT ONLY!!

SEDATIVE/HYPNOTICS ANXYOLITICS B E N Z O D IA Z E P IN E S

B A R B IT U R A T E S

GABAergic SYSTEM

Benzodiazepines • Diazepam • Chlordiazepoxide • Triazolam • Lorazepam • Alprazolam • Clorazepate => nordiazepam • Halazepam • Clonazepam • Oxazepam • Prazepam

Barbiturates • • • • • •

Phenobarbital Pentobarbital Amobarbital Mephobarbital Secobarbital Aprobarbital

NORMAL  ANXIETY

_________  _________________ SEDATION



HYPNOSIS  Confusion, Delirium, Ataxia

 Surgical Anesthesia



COMA

 DEATH

Respiratory Depression

BARBS

RESPONSE

Coma/

BDZs

Anesthesia Ataxia ETOH Sedation

Anticonvulsant Anxiolytic

DOSE

Respiratory Depression

BARBS

RESPONSE

Coma/

BDZs

Anesthesia Ataxia Sedation

Anticonvulsant Anxiolytic

DOSE

GABAergic SYNAPSE glucose

glutamate GABA

GAD

Cl

-

GABA-A Receptor BDZs

BARBs

GABA AGONISTS

γ α

δ β

ε

• Oligomeric (αβδγεπρ) glycoprotein. • Major player in Inhibitory Synapses. • It is a Cl- Channel. • Binding of GABA causes the channel to open and Cl- to flow into the cell with the resultant membrane hyperpolarization.

Mechanisms of Action 1) Enhance GABAergic Transmission  frequency of openings of GABAergic channels. Benzodiazepines  opening time of GABAergic channels. Barbiturates  receptor affinity for GABA. BDZs and BARBS

2) Stimulation of 5-HT1A receptors. 3) Inhibit 5-HT3 receptors.

Benzodiazepines PHARMACOLOGY • BDZs potentiate GABAergic inhibition at all levels of the neuraxis. • BDZs cause more frequent openings of the GABA-Cl- channel via membrane hyperpolarization, and increased receptor affinity for GABA. • BDZs act on BZ1 (α1 and α2 subunit-containing) and BZ2 (α5 subunit-containing) receptors. • May cause euphoria, impaired judgement, loss of cell control and anterograde amnesic effects.

Pharmacokinetics of Benzodiazepines • Although BDZs are highly protein bound (60-95%), few clinically significant interactions.* • High lipid solubility  high rate of entry into CNS  rapid onset. *The only exception is chloral hydrate and warfarin

Pharmacokinetics of Benzodiazepines • Hepatic metabolism. Almost all BDZs undergo microsomal oxidation (Ndealkylation and aliphatic hydroxylation) and conjugation (to glucoronides). • Rapid tissue redistribution  long acting  long half lives and elimination half lives (from 10 to > 100 hrs). • All BDZs cross the placenta  detectable in breast milk  may exert depressant effects on the CNS of the lactating infant.

Pharmacokinetics of Benzodiazepines • Many have active metabolites with halflives greater than the parent drug. • Prototype drug is diazepam (Valium), which has active metabolites (desmethyldiazepam and oxazepam) and is long acting (t½ = 20-80 hr). • Differing times of onset and elimination half-lives (long half-life => daytime sedation).

Properties of Benzodiazepines • BDZs have a wide margin of safety if used for short periods. Prolonged use may cause dependence. • BDZs have little effect on respiratory or cardiovascular function compared to BARBS and other sedative-hypnotics. • BDZs depress the turnover rates of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in various brain nuclei.

Side Effects of Benzodiazepines • Related primarily to the CNS depression and include: drowsiness, excess sedation, impaired coordination, nausea, vomiting, confusion and memory loss. Tolerance develops to most of these effects. • Dependence with these drugs may develop. • Serious withdrawal syndrome can include convulsions and death.

Toxicity/Overdose with Benzodiazepines • Drug overdose is treated with flumazenil (a BDZ receptor antagonist, short half-life), but respiratory function should be adequately supported and carefully monitored. • Seizures and cardiac arrhythmias may occur following flumazenil administration when BDZ are taken with TCAs. • Flumazenil is not effective against BARBs overdose.

Drug-Drug Interactions with BDZs • BDZ's have additive effects with other CNS depressants (narcotics), alcohol => have a greatly reduced margin of safety. • BDZs reduce the effect of antiepileptic drugs. • Combination of anxiolytic drugs should be avoided. • Concurrent use with ODC antihistaminic and anticholinergic drugs as well as the consumption of alcohol should be avoided. • SSRI’s and oral contraceptives decrease metabolism of BDZs.

Pharmacokinetics of Barbiturates • Rapid absorption following oral administration. • Rapid onset of central effects. • Extensively metabolized in liver (except phenobarbital), however, there are no active metabolites. • Phenobarbital is excreted unchanged. Its excretion can be increased by alkalinization of the urine.

Pharmacokinetics of Barbiturates • In the elderly and in those with limited hepatic function, dosages should be reduced. • Phenobarbital and meprobamate cause autometabolism by induction of liver enzymes.

Properties of Barbiturates Mechanism of Action. • They increase the duration of GABA-gated channel openings. • At high concentrations may be GABAmimetic. Less selective than BDZs, they also: • Depress actions of excitatory neurotransmitters. • Exert nonsynaptic membrane effects.

Toxicity/Overdose • Strong physiological dependence may develop upon long-term use. • Depression of the medullary respiratory centers is the usual cause of death of sedative/hypnotic overdose. Also loss of brainstem vasomotor control and myocardial depression.

Toxicity/Overdose • Withdrawal is characterized by increase anxiety, insomnia, CNS excitability and convulsions. • Drugs with long-half lives have mildest withdrawal (. • Drugs with quick onset of action are most abused. • No medication against overdose with BARBs..

Miscellaneous Drugs • • • •

Buspirone Chloral hydrate Hydroxyzine Meprobamate (Similar to BARBS) • Zolpidem (BZ1 selective) • Zaleplon (BZ1 selective)

BUSPIRONE • Most selective anxiolytic currently available. • The anxiolytic effect of this drug takes several weeks to develop => used for GAD. • Buspirone does not have sedative effects and does not potentiate CNS depressants. • Has a relatively high margin of safety, few side effects and does not appear to be associated with drug dependence. • No rebound anxiety or signs of withdrawal when discontinued.

BUSPIRONE Side effects: • Tachycardia, palpitations, nervousness, GI distress may occur. • Causes a dose-dependent pupillary constriction.

BUSPIRONE Mechanism of Action: • Acts as a partial agonist at the 5-HT1A receptor presynaptically inhibiting serotonin release. • The metabolite 1-PP has α2 -AR blocking action.

Pharmacokinetics of BUSPIRONE • Not effective in panic disorders. • Rapidly absorbed orally. • Undergoes extensive hepatic metabolism (hydroxylation and dealkylation) to form several active metabolites (e.g. 1-(2pyrimidyl-piperazine, 1-PP) • Well tolerated by elderly, but may have slow clearance. • Analogs: Ipsapirone, gepirone, tandospirone.

Zolpidem • Structurally unrelated but as effective as BDZs. • Minimal muscle relaxing and anticonvulsant effect. • Rapidly metabolized by liver enzymes into inactive metabolites. • Dosage should be reduced in patients with hepatic dysfunction, the elderly and patients taking cimetidine.

Properties of Zolpidem Mechanism of Action: • Binds selectively to BZ1 receptors. • Facilitates inhibition.

GABA-mediated

neuronal

• Actions are antagonized by flumazenil

OTHER USES 1. Generalized Anxiety Disorder Diazepam, lorazepam, alprazolam, buspirone 2. Phobic Anxiety a. Simple phobia. BDZs b. Social phobia. BDZs

3. Panic Disorders TCAs and MAOIs, alprazolam

4. Obsessive-Compulsive Behavior Clomipramine (TCA), SSRI’s 5. Posttraumatic Stress Disorder (?) Antidepressants, buspirone

ANXYOLITICS

HYPNOTICS

Alprazolam Chlordiazepoxide Buspirone Diazepam Lorazepam Oxazepam Triazolam Phenobarbital Halazepam Prazepam

Chloral hydrate Estazolam Flurazepam Pentobarbital Lorazepam Quazepam Triazolam Secobarbital Temazepam Zolpidem

References: • Katzung, B.G. (2001) Basic and Clinical Pharmacology. 7th ed. Appleton and Lange. Stamford, CT. • Brody, T.M., Larner,J., and Minneman, K.P. (1998) Human Pharmacology: Molecular to Clinical. 2nd ed. Mosby-Year Book Inc. St. Louis, Missouri. • Rang, H.P. et al. (1995) Pharmacology . Churchill Livingston. NY., N.Y. • Harman, J.G. et al. (1996) Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. McGraw Hill.