47. Antianxiety and hypnotic drugs

Anxiolytic and hypnotic drugs (often called sedative-hypnotic drugs) are those that induce sedation, decrease consciousness, and prevent seizures. They have a general inhibitory effect on the brain. They’re used on a wide range of indications, like anxiety and agitation, insomnia, status epilepticus, to induce anaesthesia, etc. Hypnotic drugs (sleeping pills) are those that induce sleep.

It’s not easy to draw a clear line between anxiolytic and hypnotic drugs. Mostly the same types of drugs are used in both conditions and only the dose determines whether the drug only has an anxiolytic effect or an anxiolytic and hypnotic effect. With an even higher dose these drugs can stop epileptic seizures or act as general anaesthetics.

Most of these drugs act by similar mechanisms and their effects are additive, so they should not be combined.

The most important drug types used for these purposes are the barbiturates, benzodiazepines, nonbenzodiazepines (“z-drugs”), and a few miscellaneous types. Some drugs from other classes may be used as sedative-hypnotics as well.

SSRIs have long-term anxiolytic effect (but not short term) and will not be covered by this topic.

Benzodiazepines

Benzodiazepines (often called benzos, BZDs, or BDZs) are drugs with anxiolytic, sedative, hypnotic and muscle relaxing effects. They act by binding to GABAA receptors in the CNS. They are very frequently used drugs.

These drugs are highly effective in the short term, but long term use is associated with adverse effects and tolerance. Short-term use is also associated with severe side effects.

Benzodiazepines have a very high addictive potential, and so they should be used with care. Many people suffer from benzodiazepine use disorder due to inappropriate prescription of these drugs, often due to either or both the patient and the physician wanting a “quick fix” for the patient’s anxiety or insomnia.

Compounds

• Short acting
  • Midazolam
• Intermediate acting
  • Alprazolam (Xanax®, Xanor®)
  • Oxazepam (Sobril®, Serax®)
• Long acting
  • Diazepam (Stesolid®, Valium®, Vival®)
  • Nitrazepam (Apodorm®)
  • Clonazepam (Rivotril®)
  • Lorazepam (Ativan®)

These drugs differ in their onset of action and duration of action.

Indications

• Anxiety
• Panic disorders
• Status epilepticus and epilepsy
• Preoperative sedation
• General or light anaesthesia
• Insomnia
• Alcohol withdrawal

Benzodiazepines are not a first-line treatment for long-term treatment, due to their risk of abuse and adverse effects. They’re better suited for short-term treatment of anxiety, like before procedures or during flights (in case of flight anxiety).

Dosage

Benzodiazepine exist in a variety of formulation, including p.o., IV, rectal solution, rectal suppository, and buccal solution. Rectal and buccal formulations are especially useful for status epilepticus, in which case administration of oral tablets or IV injections may be difficult.

Mechanism of action

Benzodiazepines binds to an allosteric site (not the ligand-binding site!) on the GABAA receptor in the CNS, which increases the receptor’s affinity for GABA. GABA is an inhibitory neurotransmitter, so this produces CNS depression.

The GABAA receptor is a ligand-gated chloride channel with five subunits. When benzos bind to the allosteric binding site the chloride channel opens more frequently, allowing more chloride to enter the cells. This hyperpolarizes the membrane and therefore inhibits synaptic transmission in the CNS.

Pharmacokinetics

The benzodiazepines differ in their rate of absorption and their half-life, which influences their onset of action and duration of action, respectively.

All benzodiazepines are metabolized by the liver. The long-acting ones produce active metabolites.

Contraindications

These drugs should be given with care to elderly and people with decreased liver function as their potency is increased in these populations. In these patients short-acting benzos are preferred, as they don’t have active metabolites. They should also be avoided in patients with history of substance abuse, due to the abuse potential.

Interactions

Alcohol binds to a different allosteric site on the GABAA receptor which also increases influx of chloride ions. This means that alcohol and benzos potentiate each other’s effects on CNS depression. They should not be used with other CNS depressants like barbiturates, alcohol or first-generation antihistamines.

Side effects

Short-term side effects are common and include somnolence, confusion, coordination problems (which may lead to falls), and many more. Overdose can cause respiratory depression.

Long-term use causes tolerance by downregulating the GABAA receptor. Long-term use is also neurotoxic, causing a long list of problems:

• Impaired cognition
• Depression and other psychiatric disorders
• Memory problems
• Sleep problems
• Mood swings

Addiction is more commonly seen in the rapid-onset benzodiazepines, like diazepam, alprazolam, and clonazepam.

Elderly are especially prone to both short and long-term adverse effects of benzodiazepines.

A significant dose is necessary for intoxication (they’re dosed at 10 – 100 mg daily but several hundred mg are necessary to cause severe intoxication). However, when combined with other CNS depressants, a significantly lower dose is necessary.

Antidote – flumazenil

Flumazenil is a competitive antagonist for the allosteric binding site on GABAA receptors where benzos bind to. It reverses benzo-induced sedation. However, it has a very short duration of action, shorter than the benzodiazepine. If the intention is to reverse benzodiazepine intoxication, administration of flumazenil should be repeated. Flumazenil is mostly used to diagnose benzodiazepine intoxication, rather than to treat it. If the drug reverses the patient’s CNS depression, the diagnosis is clear and the patient can be managed by supportive measures.

Flumazenil may precipitate seizures.

Abuse

Benzodiazepine abuse is a big problem in society. They create severe physical dependence, and they can produce severe withdrawal if not tapered properly. Withdrawal may cause depression, tremor, anxiety, and in severe cases seizures. Long-term use causes tolerance.

Benzodiazepines produce a relaxing effect similar to that of alcohol.

Barbiturates

Barbiturates are old drugs with similar mechanism of action, effect, and addictive potential as benzodiazepines, but with more adverse effects and higher addictive potential. Benzodiazepines have replaced most of the use of barbiturates, but there are still some uses for them.

Compounds

• Phenobarbital
• Thiopental

Indications

Phenobarbital is used to treat seizures.

Thiopental is used for anaesthesia and sedation.

Mechanism of action

Barbiturates binds to an allosteric site on the same receptor as benzodiazepines, the GABAA receptor, but it binds to a different allosteric site than the benzos. Except for this fact the mechanism of action for the two drug types is almost the same.

While benzos cause the chloride channel to open more frequently, the barbiturates cause the channel to stay open for longer. The effect on the neurons in both drugs is similar despite these small differences, so both cause similar CNS depression.

Pharmacokinetics

Phenobarbital has a long duration of action (80-100 hours half-life).

Thiopental is highly lipid soluble so it can enter the CNS rapidly. This gives it an onset of action of just 1 minute. However, thiopental soon starts to redistribute to other tissues, which causes its level in the CNS to decrease rapidly. This gives it a short duration of action of just about 10 minutes, making it good for anaesthesia and sedation.

Side effects

The clinical use of barbiturates on the same indications as benzodiazepines is limited due to their significant sedative effects. They cause hypotension, cardiac depression, respiratory depression and CNS depression more easily than benzodiazepines.

Long-term use causes tolerance by downregulating the GABAA receptor. Physical dependence also occurs with long-term use.

Contraindications

Due to the side effects barbiturates should be used with care. They should also not be used with other CNS depressants like benzos, alcohol or first-generation antihistamines.

Barbiturates are strong CYP450 inducers, especially of CYP3A4, which causes them to interact with many other medications.

Benzodiazepine receptor agonists (“Z-drugs”)

The benzodiazepine receptor agonists act similarly to benzodiazepines, but their structure is different. Due to their name they’re often called “Z-drugs”. Their anxiolytic and anticonvulsive effect is smaller than that of benzodiazepines, but they retain the hypnotic effect, so they’re used as hypnotic drugs.

Compounds

• Zolpidem (Stilnoct®)
• Zopiclone (Imovane®)

Indications

Insomnia.

Z-drugs are the preferred drugs to treat insomnia as they have fewer side effects than benzos and barbiturates. However, these drugs have the same issues as benzodiazepines, including addictive potential, development of tolerance, and side effects. For these reasons, they should only be used for short-term treatment of insomnia. Long-term treatment of insomnia includes sleep hygiene and cognitive behavioural therapy.

Mechanism of action

These drugs bind to the same allosteric binding site at the GABAA receptor as benzodiazepines and therefore have the same mechanism of action as those drugs. Nonbenzodiazepines have higher specificity to this binding site than the benzo’s though.

Pharmacokinetics

Zolpidem has rapid onset of action and short duration of action. Zopiclone has a slightly longer duration of action (but still short).

These drugs are metabolized quickly by the liver, which is what gives them the relatively short duration of action. The metabolism of these drugs is severely slowed down in elderly.

Contraindications

These drugs should not be combined with other CNS depressants.

Side effects

The side effects are the same as for benzodiazepines. Side effects are more severe in elderly.

These drugs are less likely to cause tolerance and dependence than benzodiazepines and barbiturates.

A significant dose is necessary for intoxication (they’re dosed at 5 – 10 mg but several hundred mg are necessary to cause severe intoxication). However, when combined with other CNS depressants, a significantly lower dose is necessary.

Antidote

Because these drugs act on the same binding site as benzodiazepines flumazenil can work as an antidote for these drugs as well.

Other anxiolytic and hypnotic drugs

Melatonin

Melatonin is an endogenous hormone that is involved in the circadian rhythm. Melatonin binds to MT1 and MT2 melatonin receptors in the suprachiasmatic nucleus of the hypothalamus. Melatonin has fewer side-effects than the GABA-acting drugs in this topic and can be used to treat insomnia and jet lag. They can also be used in elderly. However, they’re less efficacious than benzodiazepines or z-drugs.

Melatonin has few side effects and no addictive potential.

Buspirone

Buspirone is a serotonin agonist that acts on 5-HT1A receptors. It is used to treat generalized anxiety disorders.

It has no sedative potential and less severe side-effects than other anxiolytics.

Clomethiazole

Clomethiazole (Heminevrin®) is a barbiturate-like sedative-hypnotic drug. It is indicated for delirium tremens, alcohol withdrawal, and insomnia. Clomethiazole has the same issues as benzodiazepines and barbiturates (CNS depression, addictive potential) and should be used with care.

First generation antihistamines

First generation H1 antihistamines have CNS depressing effect. Hydroxyzine (Atarax®) and alimemazine (Vallergan®) are the antihistamines most frequently used on this indication. They also have anticholinergic effects and should therefore be used with care in elderly.