Anxiolytics, Hypnotics and Sedative Medicines

Classification and key concepts

A. Benzodiazepines (BZDs)

Anxiolytics:

• Diazepam – long-acting benzodiazepine, also used for muscle spasms and as an anticonvulsant; high lipophilicity and active metabolites lead to prolonged effects and risk of accumulation in chronic use.
• Alprazolam – rapid onset, short duration of action, effective in panic attacks and acute anxiety episodes.
• Lorazepam – intermediate-acting, often used in acute severe anxiety and for inpatient use; lacks active metabolites and is less dependent on hepatic oxidative metabolism.

Hypnotics (benzodiazepine type):

• Midazolam – very short duration, used primarily for preoperative sedation and short procedures.
• Nitrazepam – long-acting, used in difficulties maintaining sleep, with a higher risk of residual next-day sedation.

B. Non‑benzodiazepine “Z‑drugs” – sedative‑hypnotics

• Zolpidem – selective for the α1 subtype of the GABAa_aa​ receptor, with pronounced hypnotic effect and relatively less muscle relaxation and anticonvulsant activity.
• Zopiclone, Eszopiclone – similar Z‑drugs with longer half‑life, used mainly for sleep maintenance problems.

C. Sedating antihistamines

• Diphenhydramine, Doxylamine – H1_11​ receptor antagonists in the central nervous system, acting as weak hypnotics with anticholinergic adverse effects.

D. Melatonin and melatonergic receptor agonists

• Melatonin – hormone that regulates the sleep–wake cycle and circadian rhythm; used for insomnia and circadian rhythm disorders.
• Ramelteon – selective MT1_11​/MT2_22​ receptor agonist without GABAergic activity, used for sleep‑onset insomnia.

E. Other agents

• Buspirone – non‑sedating anxiolytic, partial agonist at 5‑HT1A_{1A}1A​ receptors, without significant risk of dependence and without relevant anticonvulsant or muscle‑relaxant properties.
• Barbiturates (rarely used for anxiety/insomnia) – e.g. phenobarbital, with high risk of dependence, respiratory depression and overdose toxicity; currently reserved mainly for epilepsy and specific indications.

Mechanism of action

Benzodiazepines and Z‑drugs:

• Potentiate GABAa_aa​ receptors, increasing the frequency of opening of chloride channels, leading to neuronal hyperpolarisation and reduced excitability of the central nervous system.
• BZDs bind to all major GABAa_aa​ receptor subtypes, whereas Z‑drugs are more selective for α1 subunits (mainly hypnotic effect), while α2/α3 subunits are more associated with anxiolysis and myorelaxation.

Sedating antihistamines:

• Block H1_11​ receptors in the brain, leading to sedation; additional anticholinergic effects contribute to adverse events such as dry mouth and constipation.

Buspirone:

• Acts as a partial agonist at 5‑HT1A_{1A}1A​ serotonin receptors, reducing anxiety without causing clinically significant sedation, respiratory depression or withdrawal syndrome.

Melatonin and melatonergic agonists:

• Regulate the circadian rhythm via activation of MT1_11​/MT2_22​ receptors in the suprachiasmatic nucleus of the hypothalamus, improving sleep initiation and alignment of the sleep–wake cycle.

Indications

Typical indications for these drug groups include:

• Anxiety disorders (generalised anxiety disorder, panic disorder, social anxiety).
• Insomnia (difficulties with sleep onset and/or sleep maintenance).
• Preoperative and procedural sedation (e.g. midazolam).
• Acute severe anxiety states (e.g. intravenous lorazepam).
• Alcohol and benzodiazepine withdrawal syndromes (e.g. diazepam in detoxification protocols).

Adverse effects

Benzodiazepines and Z‑drugs:

• Sedation, dizziness and ataxia, with increased risk of falls and fractures, especially in older adults.
• Cognitive impairment (anterograde amnesia, impaired attention), “hangover” effect with residual drowsiness, paradoxical reactions such as agitation and aggression, and development of tolerance and dependence with prolonged use.

Sedating antihistamines:

• Dry mouth, constipation, urinary retention and fatigue due to anticholinergic and sedative effects, particularly problematic in older patients and those with comorbidities.

Buspirone:

• Headache and dizziness are the most common adverse effects, with minimal risk of dependence or significant withdrawal symptoms.

Melatonin:

• Headache, vivid or intense dreams and, occasionally, mild next‑day drowsiness; overall a favourable safety profile compared with classical hypnotics.

Contraindications

Absolute contraindications (mainly for BZDs and Z‑drugs):

• Severe respiratory insufficiency due to risk of further respiratory depression.
• Myasthenia gravis, in which benzodiazepines may aggravate muscle weakness.
• Acute alcohol intoxication, where co‑administration markedly increases the risk of respiratory depression and coma.

Relative contraindications:

• Severe hepatic insufficiency, which reduces metabolism of benzodiazepines and increases bioaccumulation.
• Depressive disorders, where benzodiazepines may worsen symptoms or mask depression and increase suicide risk.
• Pregnancy, especially the first trimester, due to potential risk of congenital malformations and neonatal toxicity.

Long‑term use considerations

With chronic use of benzodiazepines and Z‑drugs:

• Tolerance develops, necessitating progressively higher doses to achieve the same clinical effect and increasing the risk of adverse reactions.
• Dependence arises, both physical (withdrawal symptoms on abrupt discontinuation) and psychological (difficulty stopping despite harm).

Withdrawal syndrome may present with:

• Rebound insomnia and anxiety, tremor, irritability and, in severe cases, seizures, especially after high doses or prolonged use.
• Gradual dose reduction (tapering) is mandatory to minimise withdrawal risk and to support successful discontinuation.

Practical prescribing tips

Choice of drug:

• Short‑acting agents (e.g. alprazolam, zolpidem) are more suitable for sleep‑onset insomnia and short‑term relief of acute anxiety.
• Long‑acting agents (e.g. diazepam) are preferred when the goal is maintenance of sleep or management of withdrawal syndromes due to smoother plasma level profiles.

Risk minimisation strategies:

• Avoid concomitant use of alcohol and other central nervous system depressants to reduce the risk of respiratory depression, overdose and accidents.
• Limit benzodiazepine use to 2–4 weeks whenever possible, and always use the lowest effective dose for the shortest feasible duration.

Non‑pharmacological and pharmacological alternatives:

• Cognitive behavioural therapy for insomnia (CBT‑I) is an evidence‑based first‑line non‑pharmacological approach, and selective serotonin reuptake inhibitors (SSRIs) or serotonin–noradrenaline reuptake inhibitors (SNRIs) are preferred for chronic anxiety disorders.
• Overall, benzodiazepines and Z‑drugs are effective but carry a high dependence risk, whereas non‑benzodiazepine options such as buspirone and melatonin are generally safer for long‑term use.

Lactation‑related considerations

General principles in lactation:

• Most benzodiazepines and Z‑drugs are excreted into breast milk to varying degrees; the risk to the breastfed infant depends on maternal dose, half‑life, active metabolites and infant maturity (especially preterm or medically fragile infants).
• When anxiolytic or hypnotic therapy is unavoidable in breastfeeding women, short‑acting agents without active metabolites, used at the lowest effective dose for the shortest possible time, are generally preferred to minimise infant exposure, and timing of dosing immediately after breastfeeding can further reduce peak levels in milk at the next feed.

Benzodiazepines during breastfeeding:

• Long‑acting benzodiazepines such as diazepam and nitrazepam may accumulate in the breastfed infant and are associated with higher risk of sedation, hypotonia and poor suck, particularly with chronic maternal use; therefore, they should be avoided or used only when safer alternatives are not suitable.
• Intermediate‑acting drugs like lorazepam, given intermittently and at low doses, are often considered more compatible with breastfeeding, but infants should still be monitored for excessive sleepiness, feeding difficulties and weight gain issues, especially in the neonatal period.

Z‑drugs and sedating antihistamines in lactation:

• Zolpidem and related Z‑drugs, due to their short half‑life and primarily nocturnal use, may be an option for occasional treatment of severe insomnia in breastfeeding women, provided that the mother can safely care for the infant and that the infant is monitored for unusual drowsiness or hypotonia.
• Sedating antihistamines such as diphenhydramine and doxylamine can reduce milk production at higher or repeated doses and may cause infant drowsiness; therefore, they should be avoided for chronic insomnia management in lactating women, particularly in the early postpartum period when lactogenesis and milk supply are still stabilising.

Buspirone, melatonin and safer approaches in lactation:

• Buspirone, as a non‑sedating anxiolytic without significant GABAergic activity, may represent a lower‑risk alternative for chronic anxiety in breastfeeding women, especially when combined with non‑pharmacological interventions such as psychotherapy and sleep hygiene.
• Melatonin and melatonergic agonists, used at physiological or low pharmacological doses, have limited but generally reassuring data in lactation; they may be considered for circadian rhythm–related insomnia under specialist supervision, prioritising non‑drug measures first and closely observing the infant for changes in sleep patterns or behaviour.