16. Antianxiety and hypnotic drugs

Last updated on June 13, 2019 at 17:41

Anxiolytic and hypnotic drugs

Anxiolytic drugs are those that reduce anxiety and calm down the patient. 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 act as general anaesthetics.

We can imagine these drugs as existing on a spectrum. In a low dose they act as anxiolytics. In a higher dose they act as sleeping pills. In even higher doses they act as general anaesthetics (although not all these drugs are used for that purpose).

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 and nonbenzodiazepines. There are some other drugs as well, as is discussed at the end.

Benzodiazepines

Benzodiazepines (often called benzos) 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.

Many drugs are in this class, like diazepam, lorazepam, oxazepam

Indications:

  • Anxiety
  • Panic disorders
  • Seizures
  • General or light anaesthesia
  • Insomnia
  • As muscle relaxants
  • Alcohol withdrawal (the long-acting ones)

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.

Duration of action:

Benzodiazepines can be classified according to their onset and duration of action:

  • Short acting (mostly -olams)
    • Oxazepam
    • Triazolam
    • Alprazolam
    • Midazolam
  • Long acting
    • Diazepam

Metabolism:

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, as these drugs have abuse potential.

They should also not be used with other CNS depressants like barbiturates, alcohol or first-generation antihistamines.

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.

Side effects:

Somnolence, confusion, coordination problems, respiratory depression.

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

Addiction is more commonly seen in the short-acting benzodiazepines.

Antidote:

Flumazenil is a competitive antagonist for the allosteric binding site on GABAA receptors where benzos bind to. It reverses benzo-induced sedation, but may induce seizures.

Barbiturates

Barbiturates are old drugs. They’ve been mostly replaced nowadays by more effective or safer drugs. In general, they’re similar to benzodiazepines but they have longer half-life and more side-effects. Their side-effects limit their clinical use.

The most important barbiturates are phenobarbital and thiopental.

Indications:

Phenobarbital is used to treat seizures.

Thiopental is used for rapid induction of anaesthesia.

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.

Side effects:

The clinical use of barbiturates is limited due to their significant sedative effects. They cause hypotension, cardiac depression, respiratory depression and CNS depression.

Phenobarbital is not the first-line treatment of seizures as it causes respiratory depression.

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 avoided in elderly. They should also not be used with other CNS depressants like benzos, alcohol or first-generation antihistamines.

Duration of action:

Most barbiturates have long duration of action (80-100 hours half-life), except thiopental.

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.

Interactions:

Barbiturates induces several CYP450 enzymes, like CYP3A4, which causes them to interact with many other medications.

Nonbenzodiazepines

These drugs are similar to benzodiazepines in clinical behaviour, but their structure is different. The important drugs here are zolpidem and zopiclone. Due to their name they’re often called “Z-drugs”.

Their anxiolytic and anticonvulsive effect is smaller than that of benzo’s, so they’re mainly used as hypnotic drugs. Z-drugs are the preferred drugs to treat insomnia as they have fewer side effects than benzos and barbiturates.

Indications:

Insomnia. It may be more effective for people who have problems falling asleep rather than people who have problems staying asleep, due to their short duration.

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.

Duration of action:

Zolpidem has rapid onset of action and short duration of action. Zopiclone has a longer duration of action.

Contraindications:

These drugs should not be combined with other CNS depressants.

Metabolism:

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

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.

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 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. Ramelteon is a melatonin receptor agonist that acts on the same receptors. Melatonin and ramelteon have fewer side-effects than the GABA-acting drugs in this topic and can be used to treat insomnia. They can also be used in elderly.

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.

First generation antihistamines have CNS depressing effect.


Previous page:
15. Immunosuppressants, immunomodulators, treatment of rheumatoid arthritis

Next page:
17. Alcohols. Pharmacology, toxicology

Leave a Reply

Only the "Comment" field must be filled in. It is not compulsory to fill out your name; you can remain anonymous. Do not fill out e-mail or website; if you do, your comment will not be published.