Anxiolytics: types, mechanism of action, clinical effects, adverse effects, indications, and monitoring

01Drug classification

Anxiolytics are drugs that relieve anxiety. Only some do it at once; the antidepressants, now the main long-term treatment of the anxiety disorders, take weeks. Many anxiolytics also cause sleep, so the line between anxiolytics and hypnotics is blurred.

1. 1903 to 1950s

   Barbiturates

   Barbital, then phenobarbital, become the sedatives of their age, but they cause dependence, and an overdose often kills.

2. 1960 to 1963

   The first benzodiazepines

   Leo Sternbach at Roche makes chlordiazepoxide, then diazepam, far safer in overdose. Diazepam becomes one of the most prescribed drugs in the world.

3. 1980s

   Dependence recognised

   Patients and doctors describe withdrawal even after normal doses. In 1988 the UK's Committee on Safety of Medicines limits benzodiazepines to 2 to 4 weeks for severe, disabling anxiety.

4. 1990s to 2000s

   Antidepressants and pregabalin

   SSRIs and SNRIs are licensed for the anxiety disorders, and pregabalin, in the EU, for generalised anxiety disorder.

5. 2019

   Pregabalin controlled

   With misuse and deaths rising, the UK makes pregabalin and gabapentin Class C controlled drugs.

02Pharmacokinetics

Benzodiazepines are fat-soluble and well absorbed by mouth, diazepam fastest, so a dose acts within 30 to 60 minutes. After a single dose diazepam's effect wears off as it spreads into fat, even though its half-life is long; with regular doses it, and its active metabolite desmethyldiazepam, build up over days to a week or more.

Liver disease and old age slow the oxidation of diazepam and most other benzodiazepines, but not glucuronidation, which is why lorazepam, oxazepam and temazepam are chosen there, at low doses. In severe liver disease any of them can bring on hepatic encephalopathy.

03Pharmacodynamics

The GABA-A receptor is a chloride channel of five subunits, usually two α, two β and one γ. GABA, the brain's main inhibitory transmitter, binds between α and β subunits and opens it; chloride flows in and the neuron becomes harder to fire. Benzodiazepines bind at a different site, between the α and γ subunits, and make the channel open more often when GABA binds: they are positive allosteric modulators, with little effect without GABA.

Tolerance, dependence and withdrawal

1. 1

   Days to weeks

   Tolerance to sedation and the anticonvulsant effect comes quickly; to the relief of anxiety more slowly and less completely.
2. 2

   Four weeks

   Taken regularly for more than about 4 weeks, a benzodiazepine causes physical dependence in many people, even at normal doses, as receptors adapt.
3. 3

   On stopping

   Within a day or two of a short-acting drug, or up to 1 to 3 weeks of a long-acting one: rebound anxiety and insomnia, irritability, tremor, sweating, palpitations, and sensitivity to light, sound and touch, with depersonalisation.
4. 4

   Abrupt stop of high doses

   Seizures, delirium and psychosis, which can be life-threatening.

Some people have symptoms for months after stopping, and for some anxiety returns that the drug had held back, which is hard to tell from withdrawal.

The others

• Buspirone is a partial agonist at 5-HT1A receptors. At first it damps the firing of serotonin neurons through their autoreceptors; anxiety eases over 2 to 4 weeks as these adapt, by a route not fully known. It does not act at the GABA-A receptor, so it neither sedates nor helps benzodiazepine withdrawal.
• Pregabalin binds the α2δ subunit of voltage-gated calcium channels in overactive neurons and lowers their release of glutamate, noradrenaline and substance P. It relieves anxiety within a week, sooner than an SSRI.
• Propranolol blocks β1 and β2 receptors, so adrenaline no longer drives the fast heart, tremor and sweating that feed anxiety. The worry itself is unchanged.
• Hydroxyzine blocks histamine H1 receptors in the brain, sedating and calming.
• SSRIs and SNRIs relieve anxiety over 2 to 6 weeks, as they do depression.
• Flumazenil is a competitive antagonist at the benzodiazepine site, acting within minutes but lasting only about an hour, so sedation can return.

04Clinical indications

Benzodiazepines are used for alcohol withdrawal, catatonia and acute disturbance, while the long-term treatment of anxiety rests on psychological therapy and SSRIs.

Stopping a benzodiazepine

1. 1

   Agree it

   The patient wants to stop and sets the pace. Short-term use of under a few weeks can be tapered over a week or two; long-term use over months.
2. 2

   Change to diazepam

   A short-acting benzodiazepine or Z-drug is changed to an equivalent dose of diazepam, in one step or in stages, as its long half-life smooths the fall.
3. 3

   Lower it slowly

   By about an eighth of the current dose every 1 to 2 weeks, in smaller steps once below about 20 mg, and more slowly near the end. Pauses are allowed; the dose is not raised again.
4. 4

   Support

   Psychological help for anxiety and sleep, and treatment of depression if it emerges. High doses or a past withdrawal seizure call for a specialist and sometimes admission.

05Adverse drug reactions

• Life-threatening
  Slowed breathing with opioids, alcohol and other depressants, with benzodiazepines, Z-drugs and pregabalin, which can be fatal; pregabalin has done it even without them. Combined only when nothing else will do, at the lowest doses for the shortest time, with the patient and family told the signs; worse in COPD, sleep apnoea, kidney disease and old age.
• Life-threatening
  Propranolol overdose: low blood pressure, a slow heart, heart block, seizures and cardiac arrest, within hours.
• Life-threatening
  Seizures and delirium on stopping a benzodiazepine suddenly after regular use, above all at high doses.
• Serious
  Dependence and misuse, after regular use for more than about 4 weeks, with benzodiazepines and pregabalin, more often in people who use alcohol or opioids.
• Serious
  Falls and hip fractures in older people, from drowsiness, unsteadiness and slowed reactions; the risk is high with long-acting drugs.
• Serious
  Confusion and delirium in older people and those with dementia, and poorer memory and attention in anyone on long-term use.
• Serious
  Paradoxical disinhibition: agitation, aggression and loss of control, more often in children, older people and those with brain injury or intellectual disability.
• Serious
  Amnesia for the hours after a dose, used deliberately in sedation for procedures.
• Serious
  Accidents: driving, machinery and next-day impairment, worse with alcohol.
• Serious
  Complex sleep behaviours with Z-drugs: sleepwalking, sleep-driving and eating while asleep, with no memory of it; the drug is stopped.
• Serious
  Bronchospasm with propranolol in asthma, and heart failure, heart block and cold peripheries in those at risk.
• Serious
  A long QT and arrhythmias with hydroxyzine, mostly in people with other risks.
• Serious
  Withdrawal on stopping pregabalin suddenly: insomnia, headache, nausea, anxiety, sweating, and seizures in some.
• Serious
  Swollen ankles and heart failure with pregabalin, mostly in older people with heart disease.

Monitoring

Benzodiazepine overdose

A benzodiazepine overdose alone causes drowsiness, slurred speech, unsteadiness and, at most, coma with mild slowing of breathing, and supportive care is usually enough (benzodiazepine intoxication). Deaths come from mixtures with alcohol, opioids, tricyclics or other depressants, from aspiration, and in older people and those with lung disease.

06Side effects

• Mild
  Drowsiness and slowed reactions, worse at the start and with alcohol, with benzodiazepines, Z-drugs, pregabalin and hydroxyzine.
• Mild
  A hangover the next morning with long-acting benzodiazepines and higher doses of Z-drugs.
• Mild
  Unsteadiness and slurred speech at higher doses.
• Mild
  Rebound anxiety or insomnia between doses or after a short course of a short-acting drug.
• Mild
  A bitter taste with zopiclone.
• Mild
  Dizziness, nausea, headache and nervousness with buspirone.
• Mild
  Dizziness, drowsiness, weight gain, blurred vision and a feeling of drunkenness with pregabalin.
• Mild
  Tiredness, cold hands and feet, vivid dreams and poor sleep with propranolol.
• Mild
  Dry mouth, drowsiness and headache with hydroxyzine.

07Contraindications

• Contraindicated
  Benzodiazepines in respiratory depression, acute respiratory failure, sleep apnoea, myasthenia gravis, severe liver failure and acute porphyria; and alone in depression or anxiety with depression, phobic and obsessional states, and chronic psychosis.
• Contraindicated
  Z-drugs in respiratory failure, severe sleep apnoea, myasthenia gravis and severe liver failure, and again after complex sleep behaviour on one.
• Contraindicated
  Propranolol in asthma or past bronchospasm, uncontrolled heart failure, cardiogenic shock, second- or third-degree heart block, sick sinus syndrome, a very slow heart or low blood pressure, severe peripheral arterial disease and untreated phaeochromocytoma.
• Contraindicated
  Hydroxyzine with a long QT, from birth or acquired, or its risks: heart disease, low potassium or magnesium, a slow heart, a family history of sudden cardiac death, or other drugs that lengthen the QT; and in porphyria.
• Contraindicated
  Buspirone in epilepsy, severe kidney or liver disease, and acute intoxication with alcohol, hypnotics, analgesics or antipsychotics.
• Avoid
  Benzodiazepines and pregabalin in people with a history of drug or alcohol misuse, unless under specialist care with small supplies.
• Avoid
  Long-term benzodiazepines and Z-drugs in older people; if needed, a short-acting one at half the adult dose, briefly.
• Avoid
  Buspirone with an MAOI, which can raise the blood pressure.
• Avoid
  Hydroxyzine in older people, at most 50 mg a day if it can't be avoided; adults at most 100 mg a day.
• Avoid
  Large supplies of propranolol, or tricyclics, to anyone at risk of self-harm.
• Caution
  Opioids, alcohol, gabapentinoids, sedating antihistamines, antipsychotics and other depressants, with benzodiazepines, Z-drugs and pregabalin.
• Caution
  CYP3A4 inhibitors, clarithromycin, azole antifungals, HIV protease inhibitors and grapefruit, which raise midazolam, alprazolam, diazepam, zopiclone and buspirone; and inducers, such as rifampicin and carbamazepine, which lower them.
• Caution
  Clozapine with a benzodiazepine by injection, and olanzapine by injection within an hour of one, for collapse and slowed breathing (Antipsychotics).
• Caution
  Liver and kidney disease: lorazepam, oxazepam or temazepam at low doses in liver disease, and a lower dose of pregabalin in kidney disease.
• Caution
  COPD and neuromuscular disease, with any sedative.
• Caution
  Diabetes with propranolol, which hides the warning signs of a low blood sugar; and verapamil or diltiazem, with which it can stop the heart.

08Pregnancy and lactation

• Caution
  Benzodiazepines in pregnancy. Large studies have not confirmed the cleft lip and palate once linked to them, but used regularly late in pregnancy they cause a floppy, cold, sleepy baby who feeds and breathes poorly, and withdrawal after birth. The lowest dose is used, for the shortest time, and the baby is watched; a dependent woman is not stopped suddenly.
• Caution
  Z-drugs in pregnancy, not linked to malformations, with the same effects on the newborn after late use.
• Avoid
  Pregabalin in pregnancy. In a large Nordic study major malformations were slightly more common, about 5.9 against 4.1 per cent, though the difference was not significant once other factors were allowed for, and other studies disagree. It is used only if clearly needed, at the lowest dose, with high-dose folic acid, and the newborn is watched for withdrawal; women who could become pregnant use effective contraception.
• Caution
  Propranolol in pregnancy, which can slow the baby's growth and cause a slow heart and a low blood sugar after birth; growth is watched.
• Avoid
  Buspirone and hydroxyzine in pregnancy, for want of data; hydroxyzine's licence rules it out, and taken late in pregnancy it has left newborns floppy and drowsy, with abnormal movements.
• Compatible
  Breastfeeding with lorazepam or oxazepam, short-acting and without active metabolites, or zolpidem or zopiclone for sleep; the baby is watched for sleepiness, and the mother does not share a bed with it.
• Caution
  Breastfeeding with diazepam, probably compatible for single or occasional low doses, but with regular use it builds up in the baby, who becomes sleepy and feeds poorly; a short-acting drug is preferred.
• Compatible
  Breastfeeding with propranolol, which passes into milk in tiny amounts.
• Caution
  Breastfeeding with pregabalin, probably compatible by e-lactancia, with the baby watched for sleepiness; its licence advises against it.
• Caution
  Breastfeeding with hydroxyzine, probably compatible for short courses by e-lactancia, though it may reduce the milk supply in the first weeks; its licence rules it out.
• Caution
  Breastfeeding with buspirone, probably compatible by e-lactancia, with very few data; its licence advises against it, and a better-known drug is preferred for a newborn.