Rang & Dale's Pharmacology, 6 Edition, 2007, Chapter 37 Objectives

Kenny J. Simansky, Ph.D.Anti-Anxiety AgentsReading: Rang & Dale’s Pharmacology, 6 th Edition, 2007, Chapter 37Objectives:1. List examples drugs used currently for treating different symptoms and syndromesof anxiety;2. Review the GABA A supramolecular receptor complex and the cellular actions ofGABA and the benzodiazepines that influence chloride conductance via this complex;3. Distinguish benzodiazepines having active metabolites that are clinically significantfrom those that are eliminated without biotransformation to anxiolytic agents;4. List major therapeutic actions of benzodiazepines other than anxiolytic treatment;5. Explain the major clinical issues involved in using benzodiazepines, including thoserelated to aging; and6. Explain the proposed mechanism of action of nonbenzodiazepine anxiolytics thatinteract with serotonergic receptors.DRUGSDiazepam Flurazepam Buspirone FluoxetineChlordiazepoxide Clonazepam (and related drugs) SertralineLorazepam Alprazolam Chlorimipramine ParoxetineOxazepam Temazepam Imipramine FluvoxaminePhenelzineI. Pharmacological Treatment of AnxietyAnxiety is a component of every major psychiatric disorder. Consequently, anxiolytic agentsmay be used adjunctively with other classes of psychotherapeutic drugs. However, the greatestnumber of prescriptions of anxiolytic drugs is targeted for treating the various symptoms associatedwith specific anxiety disorders as described in the nosology of the Diagnostics and StatisticsManual. Until the 1960's, anxiety was generally treated by relatively nonselective, sedating agentssuch as barbiturates (e.g., amobarbital); alcohols (e.g., chloral hydrate); piperidinediones (e.g,glutethimide); and carbamates (e.g., meprobamate). Antihistaminic sedatives (e.g, hydroxyzine)are still used in this manner. Beginning in the 1960's, benzodiazepines (e.g., diazepam andchlordiazepoxide) rapidly and dramatically supplanted these other agents because thebenzodiazepines (BZD) were generally safer and more efficacious. During the past decade, otheragents increasingly gained use in managing situational anxiety, phobic disorders accompanied bypanic attacks, and obsessive-compulsive disorder (OCD). Also, a nonsedating, nonbenzodiazepineanxiolytic, buspirone (Buspar ® ) became the first new anxiolytic based upon a specific serotonergictarget for developing new psychotherapeutic agents.

Therapeutic Indications for PharmacotherapyA. Classes of drugs previously or currently in common use for treating generalized anxiety1. Barbiturates (e.g., amobarbital; phenobarbital; butabarbital)2. Propanediol carbamates (e.g., meprobamate [Miltown®; Equanil®])3. Piperazines (hydroxyzine [Atarax®; Vistaril®; other names])4. Benzodiazepines (Chlordiazepoxide [Librium®]; diazepam [Valium®])*5. Azapirones (buspirone [Buspar®])*6. Serotonin reuptake inhibitors (SNRI, SSRI)**currently indicated anxiolytic preparations for generalized anxiety syndromeB. Somatic symptoms of anxiety (in situational anxiety)1. Beta-blockers (e.g., propranolol [Inderal®])C. Obsessive-Compulsive Disorder1. Chlorimipramine (also called clomipramine)(Anafranil®)2. Nontricyclic, selective serotonin reuptake inhibitors (SSRIs)(e.g., fluoxetine [Prozac®]; fluvoxamine [Dumirox®]; paroxetine [Paxil®];sertraline [Zoloft®])D. Phobic anxiety and panic attacks; agoraphobia1. SSRIs and SNRI’s (serotonin and norepinephrine reuptake inhibitors)2. Tricyclic antidepressants (e.g., imipramine [Tofranil®])3. Monoamine oxidase inhibitors (MAO inhibitors) (e.g., phenelzine[Nardil®])4. Triazolobenzodiazepines (i.e., alprazolam [Xanax®])II.GABAergic Synapses and the Mechanism of Action of BenzodiazepinesBenzodiazepines (BZD) remain among the most commonly prescribed drugs in the worldand certainly used frequently for treating anxiety. BZDs are thought to exert their anxiolytic,sedative-hypnotic, anticonvulsant, and skeletal muscle relaxant actions largely by virtue of theirability to enhance the inhibitory action of the neurotransmitter γ-aminobutyric acid (GABA)in the central nervous system. Please see handout on GABA and glutamate.

III.Structure and Pharmacokinetics of BenzodiazepinesStructure. Fundamentally, BZDs consist of a phenyl group linked to the 5-position of afused two-ring structure containing the 1,4-diazepine moiety. Substitutions of chloride or NO 2 atthe 7-position, or addition of a ring across the 1- and 2- positions alter various properties of theagents. All of these drugs, however, are believed to exert their therapeutic actions by interactingwith the BZD receptor on one of the subtypes of GABA A complex. The structure of diazepam, andthe ring addition for triazolobenzodiazepines, are shown above.

Pharmacokinetics. The clinical applications and adverse effects of individual BZDs aredetermined greatly by their pharmacokinetics. After oral administration, the benzodiazepinesgenerally are completely absorbed although their rates of absorption differ (e.g., see Table 1). Thebenzodiazepines are highly bound to plasma proteins.• BZDs are metabolized either by:(a) the hepatic P-450 system via N-dealkylation and/or hydroxylation followed byconjugation. The products of glucuronidation are inactive. Examples arediazepam (Valium), chlordiazepoxide (Librium®) and flurazepam (Dalmane®); oror(b) glucuronidation. Examples are oxazepam (Serax®) and lorazepam (Ativan®);(c) conversion to active metabolites of uncertain clinical significance. Examplesare alprazolam (Xanax®), triazolam (Halcion®)and temazepam (Restoril®).• BZDs do not induce hepatic microsomal enzymes.• Old age, hepatic damage (as after chronic ethanol abuse or hepatitis) and other drugs(e.g., cimetidine) can reduce the rate of oxidative biotransformation of certain BZDsthereby increasing their accumulation and prolonging their duration of action.Chlordiazepoxide* Diazepam * Clorazepate(prototype)(inactive)P-450 P-450FlurazepamP-450Desalkylflurazepam*Desmethyldiazepam*P-450Oxazepam*GlucuronidationAcidhydrolysisLorazepam*UrinaryExcretionBiotransformation of Benzodiazepines

PHARMACOKINETIC PROPERTIES OF SOME BENZODIAZEPINESAGENT ABSORPTION METABOLITES ELIMINATIONHALF-LIFE(Range in hrs)Diazepam fast active 27-37; desmethyldiazepam,50-100.Chlordiazepoxide intermediate active 10, parent24-100, metabolitesFlurazepam intermediate active 75-160 (metabolites,parent drug convertedalmost immediately)Clonazepam intermediate probably inactive 18-50Alprazolam fast active; uncertainclinical significanceTemazepam slow active; unlikelyclinical significance11-198-12Lorazepam intermediate inactive 10-18Oxazepam slow inactive 8-12IV.Some Considerations About the Therapeutic Use and Adverse Effects of BZDsBenzodiazepine agonists have a diverse range of therapeutic indications. Besides their useas anxiolytic agents, BZDs are used as:• hypnotic agents for inducing sleep (see specific lecture on this topic);• adjunctive agents in surgical anesthesia and sometimes as the primary sedative/amnestic agents in certain nonsurgical procedures (lorazepam, diazepam, midazolam);• anticonvulsants in treating status epilepticus (diazepam, lorazepam) , petit maland myoclonus (clonazepam, nitrazepam);• muscle relaxants in treating spasticity (diazepam); and• controlled replacement drugs in withdrawing patients from ethanol toxicity.Sedation is a prominent effect of BZDs in each of these applications and is generally doserelated.Besides initial dose, the magnitude and duration of the sedation are determined by the halflivesof the parent compound and any active metabolites that are produced. With prolonged,repeated administration, tolerance develops to the sedative and anticonvulsant actions of BZDs.Little if any tolerance has been noted for the anxiolytic effect in clinical usage. This distinctionamong different responses to chronic administration of BZDs is highly significant both for its

Pharmacokinetic and therapeutic considerations with buspirone. Buspirone is rapidlyabsorbed after oral administration and is highly bound to plasma proteins (>90 percent). It ismetabolized by hepatic oxidation to 1-pyrimidinyl piperazine, which is active. The half-life of theparent drug is less than 3 hours; the parent compound accounts for less than half of the urinaryexcretion of a dose. Buspirone does not pose problems for drug interactions with ethanol.However, patients who have been maintained on benzodiazepines for anxiolytic therapy frequentlyreport dissatisfaction with buspirone and discontinue its use. One possibility is that anxiouspatients who are experienced with benzodiazepines miss some of the overt drug cues associatedwith BZDs but not with buspirone.VI.Treatment of Obsessive-Compulsive Disorder and Panic Attack DisorderObsessive-Compulsive Disorder. The tricyclic "antidepressant" chlorimipramine(clomipramine; Anafranil®) was the first drug to demonstrate reliable therapeutic activity intreating OCD. Chlorimipramine is a halogenated derivative of imipramine which is more potent asa serotonin (5-HT) reuptake inhibitor than the parent compound although chlorimipramine retainssignificant activity in blocking norepinephrine (NE) reuptake. Chlorimipramine also retains thepotential cardiac toxicity associated with tricyclics. The selective serotonin reuptake inhibitors,such as fluoxetine, sertraline, paroxetine and fluvoxamine are equally effective withchlorimipramine in treating OCD and generally safer because they lack the anticholinergic actionsand quinidine-like effects on cardiac conduction. To date, other agents, such as buspirone, havenot displayed therapeutic benefits in ameliorating the defining (stereotyped, ritualistic) symptoms ofthis disease. Benzodiazepines may be used as adjunctive drugs to reduce the high levels of anxietyroutinely experienced by OCD patients.Panic Disorder. Panic disorder is characterized by recurrent panic attacks which mayoccur spontaneously and/or elicited by phobic stimuli. Recurrent panic attacks generally lead to astate of anticipatory anxiety and often to avoidance behavior, especially agoraphobia. Panicdisorders have been reported in as many as 6% of primary care patients. Selective serotoninreuptake inhibitors (also, SNRI’s) are now the primary agents for treating panic disorder.Originally, the tricyclic antidepressant imipramine, the irreversible monoamine oxidase A/Binhibitor phenelzine and the triazalobenzodiazepine alprazolam were used and they may beemployed if the SSRIs do not help. The doses of alprazolam that are used for treating panicdisorder are 2-10 times higher than the doses that are used for generalized anxiety disorder. Thesehigher doses of alprazolam pose more serious problems for adverse effects and withdrawal. Thenewer, reversible and selective MAO-A inhibitors appear to be efficacious without the toxicitydue to tyramine potentiation associated with the irreversible MAO inhibitors.