🗊Презентация Anti-anxiety drugs

Anti-anxiety drugs

תרופות נוגדות חרדה.. Benzodiazepines (BZDs) Buspirone Antihistamines Antidepressants Anti-epileptic drugs (AEDs) Atypical antipsychotics

תרופות שלא משומשות יותר לחרדה Typical antipsychotics (e.g., thioridazineמלריל -) Barbiturates

Benzodiazepines (BZDs) The Problem About 2 per cent of the adult population of the US (around 4 million people) appear to have used prescribed benzodiazepine hypnotics or tranquillisers regularly for 5 to 10 years or more. Similar figures apply in the UK, over most of Europe and in some Asian countries. Surveys of general practices show that there are over 180 long-term prescribed users per general practice. Despite repeated recommendations to limit benzodiazepines to short-term use (2– 4 weeks), doctors in the UK and worldwide are still prescribing them for months or years. Dependence upon prescribed benzodiazepines is now recognised as a major clinical problem and the National Performance Assessment Framework for the NHS makes it a national priority to reduce this within each health board area.

History of benzodiazepines 1912 phenobarbital 1961 chlordiazepoxide (Librium): 1st BDZ 1963 diazepam 1970 highest level of use 1980s reduced use because of social concerns

BZD Alprazolam (Xanax) Clonazepam (clonex) Diazepam (Valium,Assival) Lorazepam (Lorivan) Oxazepam (Vaben) Clorazepate (Tranxal) Chlordiazepoxide (Librium)

History The first benzodiazepine (benzo) was synthesized by an Austrian scientist - Dr. Leo Sternbach in the mid 1950’s while working at Hoffman-La Roche. The new compound’s potential as a pharmaceutical was not initially recognized, however, Dr. Sternbach’s persistent research eventually uncovered it’s efficacy as a tranquilizer. In 1959, chlordiazepoxide (Librium) was introduced as the first of many benzos to come. Just four years later, in 1963, diazepam (Valium) came on the market. Clinicians quickly recognized the potential of benzos as a safer alternative to the barbiturate class of anxiolytics.

Structure 2-Keto Benzos Some administered as prodrug All have active metabolites (commonly desmethyldiazepam) Long half-lives (most in excess of 60 hours) 3-hydroxy Benzos No active metabolites Not metabolized in the liver Intermediate half-lives (most ~ 8-20 hours) Triazolo Benzos Additional heterocyclic ring attached at the 1 and 2 positions Some active metabolites Short to intermediate half-lives (anywhere from 3-14 hours)

2-Keto Benzos First isolated benzo Oxidized to desmethyldiazepam in the liver Indicated for treatment of anxiety and insomnia

2-Keto Benzos Longest half-life of any benzo (~ 40-250 hours) Indicated primarily for treatment of insomnia, may also serve as an anxiolytic

2-Keto Benzos The original date-rape drug, and the origin of the term “roofie” Pharmacologically very similar to clonazepam, but possesses much stronger amnesic properties. One of only two drugs in the U.S. for which a first possession charge is a mandatory felony. The other of the two is crack cocaine.

3-hydroxy Benzos Indicated for treatment of anxiety, seizure, insomnia, panic disorder, and alcohol withdrawal. Unique among benzos in it’s use as an adjunctive anti-emetic

Triazolo Benzos First benzo approved by FDA for treatment of panic disorder. Also used as an adjunctive treatment for depression while adjusting to SSRIs.

Mechanism of Action Benzodiazepines act as GABA (γ-aminobutyric acid) potentiators. They bind to BZ receptors on the GABA-BZ receptor complex, which allows them to allosterically modulate and enhance the activity of GABA. This results in increased hyperpolarization at target neurons, making them less responsive to excitatory stimuli.

Modulatory interactions at GABAA receptor

Benzodiazepines Mechanism of action Increase GABA-mediated inhibition: - spinal cord - cuneate nucleus - cerebellum - brain stem - hippocampus - neocortex

Clinical Applications Anxiolytic GAD, PTSD, OCD, etc. Panic Disorder Specific Phobias Anticonvulsant Status epilepticus Myoclonic epilepsy Muscle relaxant Sleep aid Pre-operative anesthesia Alcohol withdrawal

Benzodiazepines CNS - Antianxiety, sedative - Hypnotic - Amnesic - Anticonvulsant - Muscle relaxant

Benzodiazepines Antianxiety - sedative effects - relief of anxiety and tension - emotional calming - drowsiness (tolerance) - motor incoordination (tolerance)

Benzodiazepines Hypnotic effects - ↓ latency of sleep onset - ↓ awakenings - ↑ stage 2 NREM sleep - ↓ stage 3 & 4 NREM sleep - ↓ REM sleep - ↑ total sleep time

Benzodiazepines Anticonvulsant effects - interrupt status epilepticus or any existing seizures – diazepam (i.v.) - prevent infantile myoclonus, absence seizures – clonazepam (orally) tolerance → escape from seizure control

Benzodiazepines Muscle relaxant effects ! No effect on NMJ (neuromuscular junction); a CNS effect! Diazepam: i.v. - tetanus - stiff-man syndrome - endoscopy, orthopedic manipulations orally - not well documented

Benzodiazepines Effects on respiration and cardiovascular system -usually insignificant Preexisting respiratory failure can be aggravated by any hypnotic - sedative drug

Enhancement of GABAergic inhibition GABA agonistic action enhancement of GABA release enhancement of synthesis depression of metabolism depression of GABA uptake allosteric enhancement of action at GABAA receptor

Potentiation of GABA-induced Cl- conductance conductance of open channels BARBITURATES life-time of channel openings BENZODIAZEPINES frequency of channel openings

Benzodiazepines Binding sites - 3H-diazepam binding: saturable, reversible, specific - sites unevenly distributed; parallel to GABAA receptors cortex high striatum cerebellum spinal cord low - affinity of various BDZ derivatives for the receptor correlates with biological and therapeutic potency

Benzodiazepine binding site ligands Agonists (positive modulators) benzodiazepines Antagonists (null modulators) flumazenil for BZD overdose - ( 0.5 mg ½ min repaid after ½ min (max 3 mg) Inverse agonists (negative modulators) β-carbolines

Future therapeutic trends of benzodiazepine binding site (BDZ R) ligands Drugs for a given binding site subtype: BDZ R1 agonist sedative, amnesic, (anticonvulsant) BDZ R2 agonist anxiolytic, muscle relaxant BDZ R partial agonist ↓ dependence BDZ R inverse agonist ↓ ethanol intake abnormal BDZ R specific disorder

Benzodiazepine pharmacokinetics Absorption rapid: diazepam, triazolam, flurazepam intermediate: lorazepam slow: oxazepam Plasma protein binding high Distribution non-equilibrium: blood flow, lipid solubility equilibrium: lipid solubility

Benzodiazepine pharmacokinetics Metabolism Oxidative reactions: active metabolites, long half-life, influenced by age, disease and other drugs - diazepam Conjugation: loss of activity, far less influenced by age, disease and other drugs - lorazepam, oxazepam, active metabolites

Benzodiazepines: pharmacokinetics Drug Important differences Diazepam Mean half-life 35-50 h (desmethyldiazepam) metabolites have long half-life Lorazepam Mean half-life 12-20 h, rapid oral absorption, disposition not altered appreciably by liver disease, aging or inhibitors of drug metabolism Oxazepam Mean half-life 6-10 h, slower absorption than lorazepam, disposition not altered appreciably by liver disease, aging or inhibitors of drug metabolism Triazolam Mean half life 2-3 h, rapid absorption, disposition not altered appreciably by liver disease, aging or drugs

Benzodiazepine metabolism

Benzodiazepine metabolism