Drug Treatment: Anxiolytics, Hypnotics and Antiepileptics

This class of drugs is commonly abused, and tolerance develops over time. Dependence occurs unless they are properly prescribed with users receiving appropriate guidance. Benzodiazepines exhibit the following actions on the body:

• Anxiolytic property
• Sedative and hypnotic effects
• Muscle relaxation
• Anticonvulsant activity

Mechanism of Action: The pharmacological actions are mediated through specific receptor sites located in a supramolecular complex with gamma-amino butyric acid (GABA) receptors. BZDs enhance GABA neurotransmission throughout the entire brain, with a greater impact in cortical and limbic areas.

Benzodiazepines differ in potency concerning their interaction with BZD-receptors and plasma half-life. High-potency BZDs and those with a short half-life are more likely to be associated with dependence and withdrawal symptoms.

Half-Lives of BZDs:

The following benzodiazepines have varying half-lives:

• Diazepam
• Chlordiazepoxide
• Clonazepam
• Chlorazepate
• Flurazepam
• Prazepam
• Quazepam
• Halazepam

These are longest acting with a half-life ranging from 30 to >100 hours.

Lorazepam, oxazepam, temazepam, and estazolam have a half-life of 8-30 hours.

Alprazolam has a half-life of 10-15 hours. It is a highly potent drug and is effective in treating panic disorder. An equivalent dose of clonazepam can also be used for panic disorder.

Triazolam has a half-life of 2-3 hours.

All BZDs, except clorazepate, are absorbed unchanged in the gastrointestinal tract. Lorazepam and midazolam have good effects when given intramuscularly, but other BZDs are either administered orally or intravenously.

BZDs that have quick action and are used in episodic bursts of anxiety to achieve rapid sedation include diazepam, lorazepam, alprazolam, triazolam, and estazolam.

In cases of BZD overdose, the BZD receptor antagonist Flumazenil is used intravenously to counter BZD toxicity.

Elimination half-life	Benzodiazepine
Short (2 to 5 hours)	Triazolam, Midazolam, Brotizolam
Intermediate (6 to 24 hours)	Alprazolam, Lorazepam, Lormetazepam, Oxazepam, Temazepam
Long (> 24 hours)	Clonazepam, Clorazepate, Diazepam, Flunitrazepam, Flurazepam, Prazepam

Pharmacokinetics:

Benzodiazepines (BZDs) are rapidly absorbed and strongly bound to plasma proteins, but they cross the blood-brain barrier due to their lipophilicity. They undergo metabolism to several compounds that are also therapeutically active. For example, the metabolites of diazepam include temazepam and oxazepam. Diazepam and clorazepate can be metabolized to long-acting derivatives, such as desmethyldiazepam, which is metabolically active. Excretion primarily occurs as conjugates in the urine.

Clinical Indications of BZDs:

• Insomnia
• Generalized anxiety disorders (for brief period treatment)
• Panic disorder (alprazolam and clonazepam). Note that SSRIs are also indicated, but they have sexual dysfunction and weight gain as side effects compared with BZDs.
• Social phobia - use clonazepam
• Akathisia - 1st line drug in its management
• Mixed anxiety and depressive disorder - alprazolam
• Bipolar I disorder - clonazepam, lorazepam, and alprazolam in acute manic episodes and as adjuvant maintenance treatment to Lithium or lamotrigine.
• Other anxiety disorders, e.g., in OCD and PTSD.
• Alcohol withdrawal - chlordiazepoxide and clorazepate.
• Psychosis induced by hallucinogens
• Muscle relaxant
• Abreactive technique
• In modified ECT procedure
• Acute agitation
• Status epilepticus

Side Effects (S.Es):

• Sedation
• Ataxia/lack of motor coordination
• Cognitive blunting (be careful when treating elderly patients)
• Memory impairment, especially in the elderly
• Apnea in I.V bolus, which can result in laryngeal muscle spasm (administer over minutes while engaging with the patient until they fall asleep)
• Respiratory depression, especially in patients with obstructive airway disease
• Dependence
• Amnesia in large doses
• Confusion in the elderly

Withdrawal Problems with BZDs:

• Rebound insomnia
• REM rebound
• Tremor
• Anxiety
• Restlessness
• Weight loss
• Appetite disturbances
• Sweating
• Convulsion – long use and sudden stoppage
• Depression and suicidal ideation
• Perceptual disturbances

NB: In prescribing benzodiazepines, there is a need to be cautious to prevent patients from becoming dependent when placed on these drugs. It is not advisable to have more than a two-week prescription at a time.

The barbiturate class has a high abuse and addictive tendency. It possesses a narrow therapeutic window, accounting for serious side effects, which is a major drawback. Common examples include phenobarbitone, methohexital, thiopental, amobarbital, etc.

Absorption: Good absorption following oral use.

Half-life: 1-120 hours.

Metabolism: Metabolized in the liver.

Excretion: Excreted in the kidneys.

Cytochrome P450 Inducer.

Mechanism of Action: GABA receptor - BZD receptor - Chloride channel complex.

Uses:

• ECT: Used as an anaesthetic agent to decrease cardiac risk. In prolonged ECT seizure, give IV methohexital 0.7-1.2mg/kg or in post-ictal agitation.
• Seizure
• Narcoanalysis (Abreaction): Amobarbital (truth serum) given in conversion disorder, catatonia, hysterical stupor, unexplained muteness, etc.
• Insomnia: Barbiturates reduce sleep latency and prevent intermittent awakening during sleep.

Drugs used to improve sleep are called hypnotics. Many anxiolytics are hypnotics. Hypnotics are prescribed for a prolonged period for insomnia, and it is important to address the root of the sleep problem. Psychological treatment has clinical relevance in this regard.

The ideal hypnotic drug is expected to increase the length and quality of sleep, causing no daytime somnolence, no withdrawal effects. Unfortunately, no single drug meets all these criteria. The most prescribed hypnotics enhance the action of GABA via interaction with the BZD receptor or other adjacent sites located on the GABA macromolecular complex. Antihistamines, low-dose antidepressants such as amitriptyline and trazodone, and non-BZD hypnotics called the "Z drugs" (zopiclone, zolpidem, and zaleplon) are commonly used.

"Z Drugs"

The "Z drugs" are chemically unrelated to BZDs but share many pharmacologic effects. Flumazenil can reverse their effects or toxicities.

Mechanism of Action of 'Z Drugs': It is by selective interaction with only one GABA-BZD receptor complex leading to sedation.

• T/2 of Zaleplon: 1 hour.
• T/2 of Zolpidem: 2.6 hours.
• T/2 of Zopiclone: 3.5-6.0 hours.

NB: None of the Z drugs has an active metabolite.

Zopiclone is a cyclopyrrolone and produces fewer changes in sleep architecture than BZDs. Side effects include a bitter after-taste, confusion, amnesia, and depression.

Zolpidem and zaleplon have shorter half-lives. Zaleplon is the most marketed of all and is used as needed in patients who wake in-between sleep.

Other Hypnotic Drug - Chloral Hydrate

Chloral hydrate is another hypnotic drug that is effective in the elderly and pediatrics. Common side effects include gastric irritation, necessitating copious dilution.

Hypnotics' Side Effects:

• Residual effects
• Slowness and drowsiness
• Tolerance
• Rebound insomnia

(A) Adrenergic Agents (e.g., Clonidine)

Mechanism of Action: Central alpha adrenoceptor stimulation leading to reduced sympathetic outflow.

Uses:

• Opioid withdrawal
• Adjunct treatment of ADHD for highly activated child
• Aggression in children
• Akathisia
• Tic disorder
• Post-traumatic stress disorder (PTSD)
• Hypertension

Side Effects of Alpha-Agonists:

• Sedation
• Dry mouth
• Hypotension
• Headaches
• Constipation
• Dizziness
• Rebound hypertension

Contraindications: CVD, poor drug compliance, autonomic hyperarousal with sudden stoppage, and co-administration with other drugs.

(B) Beta-Blockers

Propranolol: B1=B2 in terms of activity

Labetalol: B1=B2 in terms of activity

In acebutalol, atenolol, and maprotolol, B2>B1 activity

Uses of Beta-Blockers:

• Anxiolytic
• Impulse dyscontrol
• Akathisia
• Opiate withdrawal
• Familial and other tremors
• Hypertension

(C) Buspirones

Introduced in 1986 as the first non-sedating drug specifically for the treatment of generalized anxiety disorder but not for panic disorder. It has no dependence compared to BZDs and barbiturates. Buspirone is a member of the azapirone class. Anxiolytic effects take several days compared to BZDs, and it cannot treat BZD withdrawal. It has good GIT absorption but is delayed by food ingestion.

Peak Plasma Level: 40-90 minutes following oral use.

Mechanism of Action: Stimulates 5HT1A receptor. Buspirone lowers firing 5HT neurotransmission in certain brain regions, which may be the basis of its anxiolytic effect.

Side Effects:

• Lightheadedness
• Nervousness
• Headache

(D) Antidepressants

Tricyclic Antidepressants (TCAs): Good for the treatment of Generalized Anxiety Disorder (GAD) and panic disorders.

Selective Serotonin Reuptake Inhibitors (SSRIs) and Monoamine Oxidase Inhibitors (MAOIs): Effective for treating panic disorder. SSRIs are also used for social phobia and Obsessive-Compulsive Disorder (OCD).

(E) Antipsychotics

Major tranquilizers for a rapid calming effect of agitation. Used in low doses for anxiolytic purposes in some instances.

In conclusion, various drugs can serve different purposes, but treatment modality is individualized when a psychiatrist reviews a patient and prescribes the one that is most suitable for the patient's needs. It's essential to consider gradual tapering when weaning off these drugs to prevent withdrawal rebound or discontinuation symptoms, which can be potentially fatal.

This anticonvulsant is used across all age groups and has mood-stabilizing properties.

Mechanism of Action: Possibly increases GABA levels by inhibiting its degradation and enhances GABA synthesis.

Valproic acid has a moderate therapeutic index. The therapeutic level for bipolar illness in acute mania and the maintenance phase is 50-100µg.

Route of Administration: Oral

Side Effects:

• G.I symptoms including nausea, vomiting, diarrhea, pancreatitis, and rare instances of liver damage
• Neurological symptoms such as headache, tinnitus, neural tube defects
• Other side effects may include weight gain, hair loss, and polycystic ovarian syndrome.

Uses:

• Acute mania
• Maintenance therapy for bipolar illness
• Rapid cycling and mixed episodes
• Treatment-resistant bipolar illness
• Epilepsy
• Migraine

Mechanism of Action: Blocks frequent use-dependent and voltage-gated dependent Na+ channels, thereby limiting repetitive firing of action potentials.

Metabolism: Liver

Excretion: Kidney

It has a low therapeutic index of 8-12 µg.

Contraindications: Not recommended when the patient is already placed on MAOIs.

Uses:

• Acute mania
• Bipolar illness prophylaxis
• Rapid cycling mania (better than Lithium in this condition)
• Trigeminal neuralgia
• Seizure disorder
• Alcohol withdrawal syndrome

Side Effects:

• Common side effects include nausea, vomiting, headache, diplopia, dizziness, and ataxia.
• Other side effects: sedation, dry mouth, Steven Johnson Syndrome, leucopenia/agranulocytosis during early treatment, and decreased body sodium.
• Sexual dysfunction by increasing prolactin and decreasing dehydroepiandrosterone.
• In pregnancy, neural tube defects can occur.

Mechanism of Action: Possibly neuron stabilization via inhibition of Na+ and Ca2+ channels in presynaptic cell membranes.

It does not require serum level determination, unlike lithium, carbamazepine, and valproic acid.

NB*: Sodium valproate increases lamotrigine levels while carbamazepine lowers it. No weight gain associated with its use.

Uses:

1. For maintenance therapy in bipolar disorders. Delays the onset of hypomania and mania and also depressive episodes.
2. Epilepsy

Side Effects:

• Headache
• Nausea
• Insomnia
• Rash, especially with higher titrating doses in the young.

All are considered mood stabilizers, but not fully supported by studies, though some clinicians prescribe them in certain circumstances.

(A) Tiagabine:

It is a selective reuptake inhibitor of GABA. It blocks 5HT1B and Cl-1 channel receptors.

Uses:

• As a mood stabilizer
• For anxiolytic and hypnotic purposes

Side Effects:

• Ataxia
• Tremor
• Confusion
• Sedation
• SLE sometimes too

(B) Topiramate

Mechanism of Action:

1. Selective Glu AMPA receptor inhibitor.
2. Blocks sodium receptors and also has indirect GABAergic effects by potentiating GABA at non-BZD and non-barbiturate sensitive GABAA receptors.

Uses:

• Mood stabilizer
• Self-mutilation
• Alcoholism
• Post-traumatic stress disorder
• Used as an indirect weight control drug

(C) Gabapentin

Mechanism of Action: Increases brain GABA level

Absorption: Oral, not affected by food.

Excretion: Unchanged in urine.

Uses:

• Mood stabilizer
• Anxiolytic property
• Panic and social phobia
• Decreases alcohol craving
• Adjunct to standard stabilizer
• Post-herpetic neuralgia
• Pain syndromes
• Compression neuropathy (e.g., carpal tunnel syndrome)
• Radiculopathies

(D) Zonisamide

Mechanism of Action: Inhibits carbonic anhydrase, and there is also evidence of calcium channel blockade.

Uses:

• Alternative treatment of acute mania
• Weight loss agent
• Epilepsy

Side Effects:

• Increases BUN
• Increases creatinine and alkaline phosphatase
• Fatal rash and blood dyscrasias can occur

(E) Levetiracetam

Uses:

• Acute mania
• Antidepressant to prevent mania or cycling
• Anxiolytic agent

Side Effects:

• Drowsiness
• Dizziness
• Ataxia
• Diplopia
• Memory impairment
• Apathy
• Paresthesia
• Suicidality in few patients

In conclusion, one needs to use discretion when placing patients on these drugs, as common ones should be given priority unless otherwise specified.