Anti Anxiety Agents

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Anti-Anxiety Agents and Sedative-Hypnotics: 

Anti-Anxiety Agents and Sedative-Hypnotics

Anti-Anxiety Agents: 

Anti-Anxiety Agents

Anti-Anxiety Agents: 

Anti-Anxiety Agents Benzodiazepines (BZDs) Buspirone Antihistamines Antidepressants Anti-epileptic drugs (AEDs) Atypical antipsychotics

Drugs No Longer Used As Anti-Anxiety Agents: 

Drugs No Longer Used As Anti-Anxiety Agents Typical antipsychotics (e.g., thioridazine) Barbiturates Meprobamate* *Carisoprodol is metabolized to meprobamate.

Advantages of BZDs (Vs. Barbiturates, Meprobamate): 

Advantages of BZDs (Vs. Barbiturates, Meprobamate) Greater dose margin between Anxiolysis Sedation Higher LD50:ED50 ratio Less tolerance and dependence Less abuse potential Arana & Rosenbaum, Handbook of Psychiatric Drug Therapy, 2000

BZD Pharmacodynamics: 

BZD Pharmacodynamics BZDs increase the efficiency of GABA at GABAA receptors via allosteric modulation. So do barbiturates and alcohol. Barbiturates and alcohol can open the chloride channel independent of GABA—BZDs can’t.

BZD Dependence: 

BZD Dependence BZDs cause dependence, i.e., withdrawal symptoms on discontinuation of long-term use. Dependence is not the same as addiction. Addiction is Compulsive (out of control) use of a substance Despite negative consequences.

Unsubstantiated Beliefs About BZDs: 

Unsubstantiated Beliefs About BZDs Therapeutic effects diminish over time. Long-term users tend to escalate their doses. Dependence is the usual reason for long-term use. BZDs produce euphoria in most people. BZDs are commonly abused by people who do not otherwise abuse substances. Silberman, Primary Psychiatry 1998

Effects of BZDs: 

Effects of BZDs Anxiolytic Sedative-hypnotic Anticonvulsant Muscle relaxant

BZD Pharmacokinetics: 

BZD Pharmacokinetics “Of all of the drugs used in psychiatry, benzodiazepines are the class in which pharmacokinetic considerations play the greatest role in selecting a drug …” Arana & Rosenbaum, Handbook of Psychiatric Drug Therapy, 2000

Anti-Anxiety BZDs: 

Anti-Anxiety BZDs Alprazolam (Xanax) Chlordiazepoxide (Librium) Clonazepam (Klonopin) Clorazepate (Tranxene) Diazepam (Valium) Lorazepam (Ativan) Oxazepam (Serax)

BZD Pharmacokinetics: 

BZD Pharmacokinetics Arana & Rosenbaum, Handbook of Psychiatric Drug Therapy, 2000

Active Metabolite: 

Active Metabolite Chlordiazepoxide, clorazepate, and diazepam are all metabolized to desmethyldiazepam.

Practically Speaking: 

Practically Speaking If given IV, BZDs should be given Slowly (over 1-2 min) Only if ready to deal with respiratory arrest. Antacids and food interfere with absorption po. After a single dose, BZDs lose effect by distribution more rapidly than by elimination. With repeated dosing, distribution is saturated and elimination half-life determines drug behavior. Arana & Rosenbaum, Handbook of Psychiatric Drug Therapy, 2000

Long Half-Life Vs. Short Half-Life: 

Long Half-Life Vs. Short Half-Life Pro Less frequent dosing No interdose rebound Less severe withdrawal Con Accumulation Con More frequent dosing Interdose rebound More severe withdrawal Pro No accumulation

More On Metabolism: 

More On Metabolism Most BZDs are metabolized by hepatic microsomal enzymes. Lorazepam and oxazepam are metabolized only by glucuronidation, which is less affected by aging and liver disease. They are the BZDs of choice in elderly or cirrhotic patients.

BZD Indications: 

BZD Indications Situational anxiety Anxiety due to medical condition or medication Preoperative sedation Insomnia Restless legs syndrome Muscle spasm / tension Epilepsy Panic disorder Social anxiety disorder Generalized anxiety disorder Anxiety / agitation due to other Axis I disorders Alcohol withdrawal Akathisia Catatonia

Before Starting a BZD: 

Before Starting a BZD A history of alcohol or other substance abuse is a relative contraindication. Warn patients about potential sedation —on starting or restarting the drug. Instruct patients to take BZD on an empty stomach and without antacids. Start low, go slow.

On Stopping a BZD: 

On Stopping a BZD Relapse = return of original symptoms Rebound = return of original symptoms at a greater intensity than before Withdrawal = occurrence of symptoms not previously experienced

Withdrawal Symptoms: 

Withdrawal Symptoms Confusion Clouded sensorium Heightened sensory perception Dysosmia (abnormal taste and smell) Paresthesias Muscle cramps Muscle twitches Blurred vision Diarrhea Decreased appetite Weight loss Pecknold et al, Arch Gen Psychiatry 1988

Severe Withdrawal (DTs): 

Severe Withdrawal (DTs) Hallucinations Other psychotic symptoms Delirium Seizures

Discontinuation Effects: 

Discontinuation Effects 126 patients with panic disorder Assigned to alprazolam or placebo for 8 wks Average of 4.8 mg/day alprazolam Medication then tapered over 4 wks  Relapse: % panic-free decreased from 60 to 48 Rebound: 27% Withdrawal (mild-moderate): 35% Pecknold et al, Arch Gen Psychiatry 1988

Authors’ Recommendations: 

Authors’ Recommendations Treat panic disorder for at least 6 months. Taper medication over at least 8 weeks. Pecknold et al, Arch Gen Psychiatry 1988

Risk Factors for Dependence: 

Risk Factors for Dependence Longer-term treatment Higher dosage Higher-potency drugs Shorter-half-life drugs More abrupt discontinuation

Highest Abuse Liability (Reinforcing/Subjective Effects) Among BZDs*: 

Highest Abuse Liability (Reinforcing/Subjective Effects) Among BZDs* Diazepam Alprazolam Lorazepam Sellers et al, J Clin Psychiatry 1993 *Found among alcoholics, but not among control subjects without a personal or family history of alcoholism.

Side Effects of BZDs: 

Side Effects of BZDs Sedation Impairment of Memory (anterograde amnesia) Other cognitive functions Motor function (falls, MVAs) Disinhibition Depression (except alprazolam?)

BZDs and Depression: 

BZDs and Depression Among 30 patients treated for at least 6 wks with lorazepam (average dose < 4 mg/day) for panic disorder 8 (> 25%) developed major depression over 9 months of BZD treatment 4 had past history of MDD, 1 of dysthymia 4 improved with dose reduction 4 required a TCA Lydiard et al, Am J Psychiatry 1989

Drug Interactions of BZDs: 

Drug Interactions of BZDs Increased CNS depression Alcohol Other anti-anxiety / sedative-hypnotic drugs Increased BZD levels Cimetidine (diazepam) Nefazodone, other CYP3A4 inhibitors (alprazolam, triazolam) Decreased BZD levels Carbamazepine (alprazolam, triazolam) Zaleplon levels increased by cimetidine, decreased by rifampin.

CYP 3A4: 

CYP 3A4 Substrates Alprazolam, midazolam, triazolam Buspirone Calcium-channel blockers Carbamazepine Clarithromycin, erythromycin Clozapine, haloperidol, pimozide, quetiapine, ziprasidone Cyclosporine Estradiol Methadone Nefazodone, trazodone Protease inhibitors Sertraline Tertiary TCAs Zaleplon, Zolpidem Inducers Carbamazepine St. John’s wort Inhibitors Grapefruit juice Cimetidine Clarithromycin, erythromycin Itraconazole, ketoconazole Fluvoxamine Methadone Nefazodone Protease inhibitors

Buspirone: 

Buspirone Partial agonist at the 5-HT1A receptor Indicated in generalized anxiety disorder May augment SSRIs in depression Dosage: 15-30 mg bid 4-6 week delay in therapeutic effect Side effects: dizziness (9% > placebo)

Insomnia and Sedative-Hypnotics: 

Insomnia and Sedative-Hypnotics

Insomnia: 

Insomnia Initial (difficulty falling asleep) Middle (difficulty maintaining sleep) Terminal (early morning waking) or Un-refreshing sleep Plus impairment in daytime function < 4 weeks = transient (50% of gen. pop.) > 4 weeks = chronic (15% of gen. pop.) Black & Loewy, CNS News 2002

Slide33: 

after Walsh et al, NIH publication 98-4088, available at www.nhlbi.nih.gov/health/prof/sleep/insom_pc.htm/

Slide34: 

after Walsh et al, NIH publication 98-4088, available at www.nhlbi.nih.gov/health/prof/sleep/insom_pc.htm/

Some Causes of Secondary Insomnia: 

Some Causes of Secondary Insomnia Shift work Jet lag Stress Pain GERD Nocturia Substance use or withdrawal Axis I disorders Medications Sleep disorders Treat the underlying cause!

Sleep Disorders: 

Sleep Disorders Obstructive sleep apnea Snoring Witnessed pauses in breathing during sleep Shortness of breath at night Excessive daytime sleepiness Restless legs syndrome Creeping sensation in legs before bed Periodic leg movement syndrome Reported kicking or jerking of legs during sleep

Primary Insomnia: 

Primary Insomnia Poor sleep hygiene Psychophysiologic (conditioned) insomnia Sleep state misperception Idiopathic (childhood onset) insomnia Circadian rhythm disturbances Phase delay among teens Phase advance among elderly Black & Loewy, CNS News 2002

Non-Pharmacologic Interventions: 

Non-Pharmacologic Interventions Maintain a regular AM rising time. No daytime naps. Exercise regularly (4-6 hours before bedtime). Schedule worry time earlier in the evening. No alcohol or stimulants near bedtime. Eliminate the bedroom clock. Curtail time in bed to what is needed for sleep (and sex). Don’t focus on the inability to sleep (read or watch TV). Hauri & Cleveland-Hauri, Primary Psychiatry 1999

Sedative-Hypnotics: 

Sedative-Hypnotics Benzodiazepines Non-BZD Type 1 BZD receptor agonists Antihistamines Antidepressants Anti-epileptic drugs (AEDs) Atypical antipsychotics

Drugs No Longer Used Often As Sedative-Hypnotics: 

Drugs No Longer Used Often As Sedative-Hypnotics Typical antipsychotics (e.g., thioridazine) Barbiturates Chloral hydrate

Sedative-Hypnotic GABAA Agonists: 

Sedative-Hypnotic GABAA Agonists Estazolam (ProSom) Flurazepam (Dalmane) Quazepam (Doral) Temazepam (Restoril) Triazolam (Halcion) Zaleplon (Sonata) Zolpidem (Ambien)

Sedative-Hypnotic Pharmacokinetics: 

Sedative-Hypnotic Pharmacokinetics

More On Metabolism of BZD Sedative-Hypnotics: 

More On Metabolism of BZD Sedative-Hypnotics Flurazepam and quazepam are metabolized to N-desalkylflurazepam. Temazepam is metabolized only by glucuronidation.

Long Half-Life Vs. Short Half-Life: 

Long Half-Life Vs. Short Half-Life Pro Less early AM waking Less daytime anxiety No rebound anxiety Less rebound insomnia on discontinuation Con Daytime drowsiness / cognitive impairment Accumulation Con No less early AM waking No less daytime anxiety Rebound anxiety More rebound insomnia on discontinuation Pro No daytime drowsiness / cognitive impairment No accumulation

Zaleplon & Zolpidem: 

Zaleplon & Zolpidem Non-BZD Type 1 BZD receptor agonists Less anxiolytic, anticonvulsant, muscle relaxant effects Less rebound, risk for dependence No REM suppression

Dose-Related Side Effects of Short Half-life Sedative-Hypnotics (triazolam, zolpidem): 

Dose-Related Side Effects of Short Half-life Sedative-Hypnotics (triazolam, zolpidem) Impairment of Memory (anterograde amnesia) Other cognitive functions Motor function (falls, MVAs) Disinhibition Hallucinations, delusions

Using Sedative-Hypnotics: 

Using Sedative-Hypnotics It is suggested that nightly use of sedative-hypnotics be limited to < 3 weeks. However, many patients seem to need and to benefit from continuous use over years. The need for continued use should be reevaluated at regular intervals.

Contraindication to BZDs: 

Contraindication to BZDs Sleep apnea

Antihistamines: 

Antihistamines Less effective than BZDs Daytime drowsiness Strong anticholinergic effects

Antidepressants : 

Antidepressants Sedating TCAs Trazodone Dosage 25-200 mg/hs Risk of priapism Nefazodone Mirtazapine

Effects of Psychotropics on Sleep Architecture: 

Effects of Psychotropics on Sleep Architecture See Gonzalez et al, “Comorbidity of insomnia with medical and psychiatric disorders,” TEN 3:48-57, 2001