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OVERVIEW

Disorders involving are frequently found among our patients. Anxiety makes one feel tension, apprehension and uneasiness. The physical symptoms of anxiety may cause symptoms such as tachycardia, sweating, trembling, and palpitations.

Most case of anxiety do NOT require medications however, if the anxiety is severe and chronic medications can be used.

Many of our anxiolytics also cause sedation and can be used for sleep.

BENZODIAZEPINES

Benzodiazepines, have for the most part replaced barbiturates and meprobamate in the treatment of anxiety and insomnia due to a higher therapeutic index.

Today, antidepressents with anxiolytic actions such as serotonin reuptake inhibitors for anxiety while antihistamines may be preferred for insomnia.

The benzodiazepines bind the γ-aminobutyric acid (GABA-A) receptors, GABA-A receptors are the most abundant inhibitory receptors in the nervous system.

GABA-A RECEPTOR

The GABA-A receptor is composed of five subunits 2α 2β and 1γ subunit. For each, there are subtypes. The binding of the GABA-A receptor by γ-aminobutyric acid (GABA) causes the pore to open and Cl- rushes in causing hyperpolarization of the neuron and decreasing neurotransmission.

Benzodiazepines by a specific site separate from γ-aminobutyric acid located at the intersurface of the of the α and γ subunit.

Benzodiazepines increase the frequency of channel openings when the channel is bound to GABA.

ACTIONS OF BENZODIAZEPINES

At low doses , benzodiazepines reduce the neurotransmission of neurons have the α2 subunit involved with the limbic system of the brain. This reduces anxiety. High levels of α2 binding will cause muscle relaxation by inhibiting the spinal cord/

At higher doses the benzodiazepines bind the α1 receptor which will produce hypnosis – artificially induced sleep.

Binding the α1 receptor helps mediate the anticonvulsant activity of benzodiazepines.

Unfortunately, by binding the α1 receptor new memory formation is impaired and retrograde amnesia can occur.

THERAPEUTIC USESBenzodiazepines as a class show little differences in their sedative,

anticonvulsant and sedative properties , their half – lives are different however and the difference in half life is often is what determines the selection of a particular benzodiazepine.

THERAPEUTIC USE - ANXIETY DISORDERBenzodiazepines are effective for the treatment of the anxiety

component of panic disorder, performance anxiety, generalize anxiety disorder, social anxiety disorder, post-traumatic stress disorder, phobias, and obsessive compulsive disorder. They are useful for anxiety associated with schizophrenia and depression.

There is mild cross- tolerance between the benzodiazepines.

Lorazepam or diazepam are usually given for prolonged treatment.

Alprazolam may be given in panic disorder though usage causes withdrawal symptoms in 30% of those who take it.

THERAPEUTIC USE – SLEEP DISORDERSBenzodiazepines may be useful as hypnotic agents. These drugs

decrease the latency for sleep onset and increase stage II sleep while decreasing REM sleep and slow wave sleep.

Intermediate acting drugs are given for sleep in an attempt to limit daytime drowsiness. Among them Temazepam which should be given 1-3 hours prior to sleep and this also helps people stay asleep and Triazolam for those who need to go to sleep.

These drugs should not be given for more than 2-4 weeks as tolerance develops and rebound insomnia can occur with withdrawal.

THERAPEUTIC USE - AMNESIA

The shorter acting agents are used for anxiety producing procedure's such as endoscopy, dental procedures and angioplasty. They are used at low doses to allow for conscious sedation.

Midazolam is used prior to anesthesia.

THERAPEUTIC USE – SEIZURES AND MUSCULAR DISORDERS

Clonazepam is occasionally used as an adjuvant for some forms of seizure. Lorazepam and diazepam are the drugs of choice for terminating status epilepticus.

Due to cross resistance clorazepate, diazepam, lorazepam, with alcohol these drugs are useful for the treatment of acute withdrawal and to reduce the risk of withdrawal related seizures.

Diazepam is useful in the treatment of muscle spasms from strains and degenerative neurological conditions.

PHARMACOKINETICSBenzodiazepines are lipophilic and they distribute throughout the

body and penetrate into the CNS.

The benzodiazepines are classified according to their half-lives. The longer acting benzodiazepines have active metabolites.

In some benzodiazepines the half-life does not correlate well with the clinical duration. This may have to do with receptor dissociation rates in the CNS and subsequent redistribution to fatty tissues.

Benzodiazepines are excreted in the urine as glucuronides or oxidized metabolites. Benzodiazepines can be passed in breast milk.

DEPENDENCE

High doses and prolonged use of benzodiazepines are most likely to cause psychological and physical dependence.

Abrupt discontinuation of the drugs can cause withdrawal symptoms inclusive of the following symptoms:

ADVERSE EFFECTS OF BENZODIAZEPINES

CNS depression – Tolerance

Blurring of Vision

Cognitive impairment – retrograde amnesia

Hallucinations

Paradoxical Reactions – Excitement

GI / Blood dyscrasia’s – Rare

Overdose is seldom fatal UNLESS taken with alcohol or other medications.

Antidote – Flumenazil - May cause withdrawal symptoms

BARBITURATES

In the past, barbiturates were the main stay of inducing sleep in insomnia. The have been replaced by the benzodiazepines due to the severe withdrawal symptoms of barbiturates and the tolerance and physical dependence that they cause. Barbiturates can be fatal alone with overdose unlike benzodiazepines.

Barbiturates act at a different site than the benzodiazepines and cause a prolonged opening of the GABA-A channel. In addition, barbiturates can block the excitatory glutamate receptors.

BARBITURATES

Barbiturates are also classified by their half-lives like benzodiazepines: short acting, medium action and long acting.

Phenobarbital 1-2 days half life

Pentobarbital

Secobarbital 3-8 hours half life

Amobarbital

Thiopental 20 minutes half life

BARBITURATESBarbiturates DO NOT raise the pain thresh hold and have no analgesic

properties. They may even exacerbate pain. At low dose barbiturates cause sedation , as we increase the amount this is followed by hypnosis , then coma then death. This occurs in an almost linear fashion. These medications also decrease respiration.

PHARMACOKINETICS/DYNAMICS

Like the benzodiazepines barbiturates will distribute to most of the tissues of the body. Again the half life of the drugs may not exactly correspond to the clinical effect as the drug can redistribute from the brain to elsewhere, keeping in mind the brain get a large supply of the blood.

Barbiturates are excreted inactively in the urine unlike benzodiazepines which may frequently be active.

Barbiturates induce the p450 system. Thus, the metabolism of other drugs may increase if a patient is on barbiturates.

THERAPEUTIC INDICATIONS

The ultra-short acting barbiturates such as thiopental are given intravenously to induce anesthesia but have largely been replaced by other agents.

Phenobarbital has specific anticonvulsant activity and is used in long term management of tonic-clonic seizures. Phenobarbital can also be used to treat refractory status epilepticus.

Long term use in children can stunt cognitive development in children and impede cognitive performance in adults.

Barbiturates have been used as sedatives to relieve anxiety, tension and insomnia. They suppress REM sleep however.

OTHER ANXIOLYTICS - ANTIDEPRESSANTS

Many of the antidepressants are effective in the treatment of chronic anxiety disorders and should be considered first line agents especially in those with addiction issues.

Selective Serotonin Reuptake Inhibitors such as paroxetine or escitoprolam or serotonin/norepinephrine reuptake inhibitors venlafaxine and duloxetinewhen taken after 4-6 weeks tend to have an anxiolytic effect. These drugs are very useful for general anxiety disorder.

OTHER ADVERSE EFFECTS

Barbiturates cause drowsiness, impaired concentration, mental and physical sluggishness. They synergize with alcohol.

Hypnotic does of barbiturates produce a drug hangover that ay lead to functional impairment many hours after waking. Barbiturates are contraindicated in patients with intermittent porphyria.

Abrupt withdrawal can lead to tremors, anxiety, weakness, restlessness, nausea, vomiting , seizures, respiratory depression and death. The withdrawals from barbiturates are worse than from Opioids.

OTHER ANXIOLYTICSBuspirone: is used in the treatment of generalized anxiety disorder and has an

efficacy similar to benzodiazepines. It has a slow onset of action (about 4 weeks) and is not effective for short term or as-needed therapy.

Buspirone’s action is mediated by the 5-HT-1A receptor (serotonin receptor) both pre an and post synaptically and it displays some affinity for the D2 and 5-HT-2A receptor. The net result of buspirone actions is that serotonergic activity is suppressed while noradrenergic and dopaminergic cell firing is enhanced

Sedation , psychomotor and cognitive dysfunction are minimal. It also lacks anti-convulsant properties.

Headaches, dizziness, nausea, and light headedness are the usual side effects.

Buspirone does NOT potentiate the effects of alcohol.

OTHER ANXIOLYTICS

Zolpidem: Is not structurally related to benzodiazepines but it does bind to the same site as benzodiazepines. This drug has No anticonvulsant or muscle relaxing properties. The drug also shows few withdrawal effects, exhibits minimal rebound insomnia and has little tolerance with prolonged use.

This drug is used for sleep and does not significantly alter the REM cycle.

Side Effects: agitation, anterograde amnesia, headache, GI upset, dizziness and daytime drowsiness.

Zaleplon: The side effects are less intense than Zolpidem however, it has a half life of only 1 hour compared to 2-3 hours of Zolpidem.

OTHER ANXIOLYTICS

Eszopicione: is a nonbenzodiazepine hypnotic which shortens time to sleep by 15 minutes. Eszopiclone may lead to physical and psychological dependence. Side effects: day time drowsiness, headaches , flu like symptoms, decreased sexual desire.

Ramelteon: is the first in a new class of sleep agents that selectively binds to the Melatonin type I and II (MT1 and MT2) receptors in the suprachiasmatic nucleus (SCN).

Side effects: somnolence, dizziness, nausea, fatigue, headache, and insomnia

ANTIHISTAMINES/TCA’S

Some antihistamines have sedating properties such as diphenylhydramine, hydroxyzine and doxylamine are all useful in treating mild to moderate insomnia.

These all have anticholinergic effects which in some cases make them less useful than bezodiazepines.

The old tricyclic antidepressants mirtazapine and trazadone have strong antihistamine properties and have been used for insomnia.