SEDATIVES, HYPNOTICS, ANXIOLYTICS

Sedatives are drugs used to calm anxious and restless patients thus allowing sleep without actually producing it while hypnotics are drugs used to induce drowsiness and sleep. Small doses of hypnotics can be used as sedatives.

CLASSES OF ANXIOLYTIC AND HYPNOTIC DRUGS
• Benzodiazepines: the most important class, used for treating both anxiety states and insomnia • 5-HT1A-receptor agonists: recently introduced, show anxiolytic activity with little sedation. • Barbiturates: now largely obsolete as anxiolytic/sedative agents, though amobarbital is still occasionally prescribed. • β-adrenoceptor antagonists: used mainly to reduce physical symptoms of anxiety (tremor, palpitations, etc.); no effect on affective component. • Miscellaneous other agents are still used occasionally to treat insomnia (eg chloral hydrate)

Dose-response curves for two hypothetical sedative-hypnotics

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BENZODIAZEPINES
• BENZODIAZEPINES now the most commonly used drugs in this class and have largely replaced barbiturates. • Benzodiazepines, at low doses are useful anxiolytics and at high doses produce a hypnotic effect. • They produce fewer and less serious sideeffects than barbiturates. • Dependence liability is lower.

CLASSIFICATION OF BENZODIAZEPINES
Classification is based on the duration of action • Short acting (t1/2 < 5hr) eg. Midazolam and Triazolam 2. Intermediate acting (t1/2 = 5-24hr) eg. Alprazolam, Clonazepam, Oxazepam, Lorazepam 3. Long acting (t1/2 > 24hr) eg Chlordiazepoxide, clorazepate, diazepam, flurazepam

MECHANISM OF ACTION
Benzodiazepines enhance GABA-mediated inhibition of neuronal activity. This they do by binding to specific benzodiazepine receptor sites that are part of but distinct from the GABAA receptor-chloride channel complex. As a result the ability of GABA to open chloride channels is increased. Activity of the benzodiazepines requires the presence of GABA. They act on polysynaptic pathways throughout CNS.

Schematic diagram of benzodiazepine-GABA-chloride ion channel complex.

PHARMACOKINETICS
• Benzodiazepines are administered orally when used as sedatives and hypnotics. The rate of absorption is variable and some are rapidly redistributed from the brain to the peripheral tissues. This redistribution is important for terminating the action of the highly soluble benzodiazepines. • Benzodiazepines bind to a variable extent to plasma proteins (3-4% Flurazepam 99% Diazepam) to a variable extent.

PHARMACOKINETICS
• Benzodiazepines are metabolized mostly in the liver by microsomal oxidation and glucuronidation. Some metabolites are pharmacologically active. • Benzodiazepines have only weak effects on hepatic drug-metabolizing enzymes.

PHARMACOLOGICAL ACTIONS
It is assumed that all benzodiazepines produce qualitatively similar actions and that virtually all their effects result from actions on CNS. These include: • sedation • hypnosis • decreased anxiety • muscle relaxation • anticonvulsant

OTHER ACTIONS
• Benzodiazepines have very slight effects on respiration, cardiovascular system and the gastrointestinal tract. • They potentiate the effect of ethanol • Large doses of benzodiazepines taken before labour may cause hypothermia, hypotonia and mild respiratory depression in the neonate. Heavy use (or abuse) by pregnant mother may produce withdrawal syndrome in newborn.

THERAPEUTIC USES
1. Anxiety states 2. Insomnia 3. Seizures 4. Pre-anaesthetic medication 5. Muscle relaxation – spontaneous spasms 6. Withdrawal from CNS depressants

ADVERSE EFFECTS
2. May cause rebound insomnia 3. Ataxia 4. Daytime drowsiness 5. Confusion in the elderly 6. Blurred vision 7. Hypotension and constipation

TOLERANCE AND DEPENDENCE

• Tolerance develops to sedative and hypnotic but not anxiolytic effects of the benzodiazepines. Benzodiazepines confer cross-tolerance to barbiturates and ethanol.

• Withdrawal syndrome depends on benzodiazepine of abuse and can be severe.

BARBITURATES

These are classified according to t duration of action

3. Ultra-short acting barbiturates suc thiop

2. Short acting barbiturates suc pentobarbital, secobarbital and amoba

3. Long acting barbiturates suc Phenoba

MECHANISM OF ACTION
Block conduction in reticular activating system. Interact with binding sites on GABA receptor-chloride channel complex that is separate from the benzodiazepine binding site. Barbiturates increase chloride channel activation. They can act independently of GABA. Affect mono- and polysynaptic pathways.

PHARMACOLOGICAL ACTIONS
• sedation • hypnosis • decreased anxiety • anticonvulsant

OTHER ACTIONS
• Barbiturates can have marked respiratory depressant action. • Barbiturates also depress transmission in sympathetic ganglia - may account for fall in blood pressure. • Barbiturates greatly induce DME systems. Therefore are responsible for many adverse drug interactions. • They enhance porphyrin synthesis and so are absolutely contraindicated in porphyria - can be fatal.

THERAPEUTIC USES
2. Anaesthesia 3. Seizures 4. Anxiety 5. Sleep disorders

ADVERSE EFFECTS
• Drowsiness, tiredness, impaired judgement • Enzyme induction – cause of many drug interactions • Addiction – withdrawal symptoms Barbiturate poisoning – severe respiratory and cardiovascular depression results in shock-like state. Treatment includes gastric lavage, haemodialysis, artificial respiration and alkalinization of the urine.

HT-51A agonists as anxiolytic drugs

• Buspirone is an azapirone derivative (others include ipsapirone and gepirone). It is a partia agonist at inhibitory presynaptic 5-HT1A

receptors and reduces 5-HT neurotransmission It has no hypnotic properties. It has no action on GABA-benzodiazepine receptor complex and canno be used to treat benzodiazepine withdrawal syndrome Anxiolytic effects take days or weeks to develop

• Side effects include dizziness, nervousness and headache

ZOLPIDEM AND ZOPICLONE
• These are non-benzodiazepine hypnotics but act through a subset of the benzodiazepine receptors. • They are rapidly acting but with a short duration (approximately 2hrs) of action. They are therefore used for sleep-onset insomnia • They produce minimal hangover effect. • They have no anticonvulsant action and do not relax skeletal muscles.

β-ADRENOCEPTOR ANTAGONISTS
These are used to reduce heart rate and other manifestations of anxiety related to hyperactivity of the sympathetic nervous system.

ETHANOL
Ethanol acts as a general CNS depressant, similar to volatile anaesthetic agents. The exact mechanism of action is not known but several cellular mechanisms have been postulated. These include: 6. inhibition of calcium channel opening 7. enhancement of GABA action and 8. inhibition of NMDA-type glutamate receptors.

PHARMACOKINETICS
• Ethanol is absorbed throughout the gastrointestinal tract. It is subject to significant first pass in the stomach and liver. It is quickly distributed to other parts of the body at a rate determined by blood flow to that organ. It is eventually distributed throughout the body water. High concentrations in the brain are rapidly reached because of the high blood flow to the brain. • Ethanol is metabolized in the liver by alcohol dehydrogenase to yield acetaldehyde which in turn is converted into acetate by aldehyde dehydrogenase. Acetate is oxidized into carbon dioxide and water. Excretion is via the lungs, urine milk and sweat.

PHARMACOLOGICAL ACTIONS
Acute effects - Low-moderate doses: general CNS depression – disinhibition of inhibitory CNS pathways leading to impaired judgement, euphoria, ataxia - Moderate-toxic doses – further CNS depression – sedative effect with further decrease in mental acuity and motor function - Toxic dose – CNS depression resulting in anaesthesia with profound respiratory depression

PHARMACOLOGICAL ACTIONS
Acute effects - Cutaneous vasodilation – action on vasomotor center as well as a direct action on vascular smooth muscle - Diuresis – increase in fluid volume and decreased release of ADH - Relaxation of uterine smooth muscle - Reduced cardiac contractility

CONSEQUENCES OF CHRONIC ETHANOL USAGE 1. Cirrhosis of the liver 2. Fetal alcohol syndrome – retarded growth, congenital heart abnormalities 3. Pancreatitis and Gastritis (increased secretions) 4. Increased gastrointestinal bleeding and incidence of peptic ulcer 5. Cardiomyopathy 6. Cancer of upper gastrointestinal tract and liver

Ethanol is used: 3. topically to reduce body temperature and also as an antiseptic agent 4. by injection to produce irreversible nerve block 5. by inhalation to reduce foaming in pulmonary oedema 6. orally for sedative effect 7. orally to increase appetite 8. to treat methanol and ethylene glycol poisoning.

Effective plasma concentration: • Threshold effects: about 40 mg/100 ml (5mmol/l) • Severe intoxication: about 150 mg/100 ml • Death from respiratory failure: about 500 mg /100 ml

Chloral Hydrate
• This is similar to ethanol in its mechanism of action. It has a rapid onset and short duration of action. It is metabolized in the liver into trichloroethanol which is the active form. Trichloroethanol is highly bound to plasma proteins. It is used to treat insomnia in children and the elderly. Tolerance develops to the hypnotic effect of chloral hydrate. • Chloral hydrate has an unpleasant taste and odor (bad breath). It also causes gastric irritation and occassionally, cardiac arrhythmias

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