SEDATIVE/HYPNOTICS ANXIOLYTICS Martha I. Dávila-García, Ph.D. Howard University Department of Pharmacology

Optimal Performance Nervous Breakdown Sedated Performance Anxiety GOAL

_________  _________________ Normal  Relief from Anxiety _________  _________________ SEDATION (Drowsiness/decrease reaction time) HYPNOSIS Confusion, Delirium, Ataxia Surgical Anesthesia  Depression of respiratory and vasomotor center in the brainstem COMA DEATH

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).

Causes of Anxiety 1). Medical: Respiratory Endocrine Cardiovascular Metabolic Neurologic.

Causes of Anxiety 2). Drug-Induced: Stimulants Amphetamines, cocaine, TCAs, caffeine. Sympathomimetics Ephedrine, epinephrine, pseudoephedrine phenylpropanolamine. Anticholinergics\Antihistaminergics Trihexyphenidyl, benztropine, meperidine diphenhydramine, oxybutinin. Dopaminergics Amantadine, bromocriptine, L-Dopa, carbid/levodopa.

Causes of Anxiety 3). Drug Withdrawal: Miscellaneous: Baclofen, cycloserine, hallucinogens, indomethacin. 3). Drug Withdrawal: BDZs, narcotics, BARBs, other sedatives, alcohol.

Anxiolytics Strategy for treatment Reduce anxiety without causing sedation.

Anxiolytics Benzodiazepines (BZDs). Barbiturates (BARBs). 5-HT1A receptor agonists. 5-HT2A, 5-HT2C & 5-HT3 receptor antagonists. If ANS symptoms are prominent: ß-Adrenoreceptor antagonists. 2-AR agonists (clonidine).

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). Novel drugs. (Most of these are still on clinical trials). CCKB (e.g. CCK4). EAA's/NMDA (e.g. HA966).

Sedative/Hypnotics A hypnotic should produce, as much as possible, a state of sleep that resembles normal sleep.

Sedative/Hypnosis By definition all sedative/hypnotics will induce sleep at high doses. Normal sleep consists of distinct stages, based on three physiologic measures: electroencephalogram, electromyogram, electronystagmogram. Two distinct phases are distinguished which occur cyclically over 90 min: 1) Non-rapid eye movement (NREM). 70-75% of total sleep. 4 stages. Most sleep  stage 2. 2) Rapid eye movement (REM). Recalled dreams.

Properties of Sedative/Hypnotics in Sleep 1) The latency of sleep onset is decreased (time to fall asleep). 2) The duration of stage 2 NREM sleep is increased. 3) The duration of REM sleep is decreased. 4) The duration of slow-wave sleep (when somnambulism and nightmares occur) is decreased. Tolerance occurs after 1-2 weeks.

Other Properties of Sedative/Hypnotics Some sedative/hypnotics will depress the CNS to stage III of anesthesia. Due to their fast onset of action and short duration, barbiturates such as thiopental and methohexital are used as adjuncts in general anesthesia.

Sedative/Hypnotics Benzodiazepines (BZDs): Alprazolam, diazepam, oxazepam, triazolam 2) Barbiturates: Pentobarbital, phenobarbital 3) Alcohols: Ethanol, chloral hydrate, paraldehyde, trichloroethanol, 4) Imidazopyridine Derivatives: Zolpidem 5) Pyrazolopyrimidine Zaleplon

Sedative/Hypnotics 6) Propanediol carbamates: Meprobamate 7) Piperidinediones Glutethimide Azaspirodecanedione Buspirone 9) -Blockers** Propranolol 10) 2-AR partial agonist** Clonidine

Sedative/Hypnotics Others: TCAs, SSRIs Dephenhydramine 11) Antyipsychotics ** Ziprasidone 12) Antidepressants ** TCAs, SSRIs 13) Antihistaminic drugs ** Dephenhydramine

Sedative/Hypnotics USE FOR SHORT-TERM TREATMENT ONLY!! ************* 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 Barbiturates Benzodiazepines Glutethimide Zolpidem Relationship between Older vs Newer Drugs Barbiturates Benzodiazepines Glutethimide Zolpidem Meprobamate Zaleplon **All others differ in their effects and therapeutic uses. They do not produce general anesthesia and do not have abuse liability.

SEDATIVE/HYPNOTICS ANXYOLITICS GABAergic SYSTEM

Sedative/Hypnotics The benzodiazepines are the most important sedative hypnotics. Developed to avoid undesirable effects of barbiturates (abuse liability).

Clorazepate => nordiazepam 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

RESPONSE DOSE Respiratory Depression BARBS BDZs Coma/ Anesthesia Ataxia RESPONSE ETOH Sedation Anticonvulsant Anxiolytic DOSE

RESPONSE DOSE Respiratory Depression BARBS Coma/ BDZs Anesthesia Ataxia RESPONSE Sedation Anticonvulsant Anxiolytic DOSE

GABAergic SYNAPSE glucose glutamate GAD GABA Cl-

GABA-A Receptor   d  e Oligomeric (abdgepr) 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. BDZs BARBs GABA AGONISTS   d  e

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-HT2A, 5-HT2C, and 5-HT3 receptors.

Patch-Clamp Recording of Single Channel GABA Evoked Currents From Katzung et al., 1996

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 (1 and 2 subunit-containing) and BZ2 (5 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

(Rate of Onset) CNS Effects Lipid solubility

Pharmacokinetics of Benzodiazepines Hepatic metabolism. Almost all BDZs undergo microsomal oxidation (N-dealkylation 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 half-lives greater than the parent drug. Prototype drug is diazepam (Valium), which has active metabolites (desmethyl-diazepam and oxazepam) and is long acting (t½ = 20-80 hr). Differing times of onset and elimination half-lives (long half-life => daytime sedation).

Biotransformation of Benzodiazepines From Katzung, 1998

Biotransformation of Benzodiazepines Keep in mind that with formation of active metabolites, the kinetics of the parent drug may not reflect the time course of the pharmacological effect. Estazolam, oxazepam, and lorazepam, which are directly metabolized to glucoronides have the least residual (drowsiness) effects. All of these drugs and their metabolites are excreted in urine.

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.

Sedative/Hypnotics They produce a pronounce, graded, dose-dependent depression of the central nervous system.

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 GABA-mimetic. 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. Contraindicated in patients with porphyria.

Sedative/Hypnotics CONTROL WITHDRAWAL SLEEP PER NIGHT (%) Tolerance and excessive rebound occur in response to barbiturate hypnotics. NIGTHS OF DRUG DOSING SLEEP PER NIGHT (%) CONTROL WITHDRAWAL REM NREM III and IV 1 2 3

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 and paresthesias 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 2 -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-(2-pyrimidyl-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 GABA-mediated neuronal inhibition. Actions are antagonized by flumazenil

GABA ? (-) (-) (-) (-) (-) ACh NE 5-HT DA ANTICONVULSANT/ MUSCLE RELAXANT ? ANXIOLYTIC ? SEDATION ?

Properties of Other drugs. Chloral hydrate Is used in institutionalized patients. It displaces warfarin (anti-coagulant) from plasma proteins. Extensive biotransformation.

Properties of Other Drugs 2-Adrenoreceptor Agonists (eg. Clonidine) Antihypertensive. Has been used for the treatment of panic attacks. Has been useful in suppressing anxiety during the management of withdrawal from nicotine and opioid analgesics. Withdrawal from clonidine, after protracted use, may lead to a life-threatening hypertensive crisis.

Properties of Other Drugs -Adrenoreceptor Antagonists (eg. Propranolol) Use to treat some forms of anxiety, particularly when physical (autonomic) symptoms (sweating, tremor, tachycardia) are severe. Adverse effects of propranolol may include: lethargy, vivid dreams, hallucinations.

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

Other Properties of Sedative/Hypnotics BDZs on the other hand, with their long half-lives and formation of active metabolites, may contribute to persistent postanesthetic respiratory depression. Most sedative/hypnotics may inhibit the development and spread of epileptiform activity in the CNS. Inhibitory effects on multisynaptic reflexes, internuncial transmission and at the NMJ.

ANXYOLITICS HYPNOTICS Alprazolam Chlordiazepoxide Buspirone Diazepam Lorazepam Oxazepam Triazolam Phenobarbital Halazepam Prazepam HYPNOTICS 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.