Anxiolytics, Sedatives, and Hypnotics Study Notes

Anxiolytics (Antipanic or Antianxiety Agents): Drugs used for the treatment of symptoms of anxiety.
Sedatives: Drugs that reduce anxiety, stress, irritability, and excitement; they calm, ease agitation, and allow for sleep.
Hypnotics: Drugs that induce sleep.

Anxiolytics are primarily used to relieve anxiety.
Sedatives/Hypnotics are used to induce sleep.
Few drugs specifically classified as anti-anxiety; most anxiolytic drugs can also induce hypnotic effects by increasing the dosage.

Gamma-Aminobutyric Acid (GABA): - The primary inhibitory neurotransmitter in the brain. - Most clinically used anxiolytics and sedatives are GABA receptor agonists. - Suggests that anxiety circuits might be more sensitive to GABAergic stimulation than other brain circuits.

Increasing GABAergic signaling can lead to various states, including: - Normal: Relief from anxiety - Sedation: Drowsiness and decreased reaction time - Hypnosis: May cause confusion, delirium, ataxia - Surgical Anesthesia: Depression of the respiratory and vasomotor centers in the brainstem - Coma: Prolonged state due to high sedation levels - Death: Resulting from overdose

GAD (Glutamic Acid Decarboxylase): Synthesizes GABA from glutamate.
GAT (GABA Transporter): Pumps GABA out of the synaptic cleft into glia and presynaptic terminals, terminating the signal.
GABA-T (GABA-Transaminase): Inactivates GABA to help terminate the signal in the synapse.
VGAT (Vesicular GABA Transporter): Responsible for packaging GABA into vesicles.

GABA-A Receptor: An ionotropic receptor functioning as a chloride ion channel.
GABA-B Receptor: A metabotropic receptor, functioning through G proteins. - Example: Baclofen is a GABA-B agonist with anxiolytic properties but less potency than GABA-A agonists.

Structure: - Composed of multiple binding sites: - GABA sites - Barbiturates binding site - Benzodiazepines binding site - Site for other compounds (e.g., steroids, picrotoxin)
Functionality of the complex is altered by various ligands.

Molecular Structure: Similar ring structure with distinct side-chains affecting lipid solubility, which influences how drugs enter the brain and metabolize.
Mechanism of Action: Barbiturates can directly gate (open) GABAA receptors, leading to varied physiological effects.
Indications: - Seizure prophylaxis and treatment (long-acting) - Anxiety (short to intermediate-acting) - Insomnia (short to intermediate-acting) - Surgical anesthesia (ultra-short acting for induction)
Physiological Effects: Dose-dependent: - Sedation to coma and respiratory depression with increasing doses - High risk of depression and overdose

Duration of Action: Depends on lipid solubility and method of administration: - Ultrashort (e.g., Thiopental): High lipid solubility, rapid onset (10-20 s), short duration (20-30 min) - Short/Intermediate (e.g., Amobarbital, Secobarbital): Moderate lipid solubility - Long (e.g., Phenobarbital): Low lipid solubility, slower onset (> 1 h), longer duration (10-12 h)

Development of cognitive side effects with anxiolytic effects.
Intoxication and impaired thinking at higher doses, with serious risks of respiratory depression and death at overdose levels.
Cross-tolerance and pharmacokinetic tolerance develop.
Significantly dangerous when alcohol is involved due to potentiation effects.
Abuse potential: notable figures have had fatal overdoses related to barbiturates.

Introduced as a safer alternative to barbiturates: - Lower tolerance incidence - Less severe withdrawal syndrome - Higher therapeutic index.
Safety Profile: Generally safe but can cause respiratory depression, mainly when combined with other CNS depressants.
Mechanism of Action: Allosteric enhancers of GABAA receptors, requiring GABA to activate them; thus, their maximum effect is limited to the level of endogenous GABA.

Actions: - Anxiolytic at low doses - Sedative and hypnotic effects - Anticonvulsant properties - Muscle relaxant effects at high doses
Metabolism: - Phase I involves active metabolites; Phase II leads to excretion with glucuronide conjugation.

CNS depression-related effects: muscle relaxation, impaired coordination, nausea, vomiting, confusion, memory loss, and anterograde amnesia.
Risks of dependence and potential for addiction are lower than barbiturates, but withdrawal can include convulsions.

Short-acting non-BDZ hypnotics: - Include Zolpidem, Zaleplon, and Eszopiclone - Not structurally related to BDZ but claim an improved therapeutic profile. - Act as allosteric activators of the GABAA receptor complex, with specificity for hypnotic effects.

Properties: Alcohol acts as an amphiphile, readily crosses biological membranes, and has various molecular interactions, primarily influencing neurotransmitter systems.
Meyer-Overton Relationship: Describes the potency of alcohol and anesthetics correlating with lipid solubility.
Metabolism: Involves conversion from ethanol to acetaldehyde and then to acetic acid via enzymes ADH and ALDH, where inhibitors like Disulfiram can exacerbate reactions post-consumption.

Most selective anxiolytic available, with effects not accompanied by sedation.
Acts gently on serotonin pathways, enhancing serotonin release in the long-term, unlike BDZs that are more immediate in action.

Melatonin receptor agonist, implicated for its role in promoting sleep without a high risk for abuse or dependence, making it a long-term option for insomnia treatments.

With the spectrum from least to most anxiety-selective agents, various medications exhibit differing levels of selectivity and side effect profiles, with the locus coeruleus being critical for noradrenergic control in CNS anxiety responses.

The understanding of the mechanisms, effectiveness, and side effects of various anxiolytics, sedatives and hypnotics is vital for informed clinical practice and patient safety. Knowledge of the pharmacological properties assists in guiding treatment choices and managing the complexities associated with anxiety disorders.