Anxiolytic and hypnotic drugs 2

Other anxiolytic agents

A. Buspirone
Useful in the treatment of generalized anxiety disorder, it s efficacy comparable to that of the BZDs. It is not effective for short-term or “as-needed” treatment of acute anxiety states.
• Buspirone s actions appear to be mediated by 5-HT1A receptors, although other receptors could be involved, such DA2 dopamine receptors & 5-HT2A receptors. Thus, its mode of action differs from that of BZDs.
• Unlike BZDs, buspirone lacks the anticonvulsant & muscle-relaxant properties & causes only minimal sedation.
• Most common adverse effects are headaches, dizziness, nervousness & light-headedness. Sedation & psychomotor & cognitive dysfunction are minimal & dependence is unlikely.
• It does not potentiate the CNS depression of alcohol.
• Buspirone has the disadvantage of a slow onset of action.
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B. Hydroxyzine
• Antihistamine with antiemetic activity.
• Has a low tendency for habituation thus, is useful for patients with anxiety who have a history of drug abuse.
• Used for sedation prior to dental procedures or surgery.

C. Antidepressants
• Many antidepressants should be seriously considered as first-line agents in patients with concerns for addiction or dependence or a history of addiction or dependence to other substances.
• SSRIs, TCAs, (eg. escitalopram), SNRIs (Venlafaxine & Duloxetine) & MAOIs all have potential usefulness in treating anxiety.

Barbiturates
• They were the mainstay to sedate patients or to induce & maintain sleep. But today they have been largely replaced by BZDs because they induce tolerance, drug-metabolizing enzymes & physical dependence & are associated with very severe withdrawal symptoms,.
• Foremost is their ability to cause coma in toxic doses.
• Very short-acting barbiturates, such as the thiopental, are still used to induce anesthesia.

Mechanism of action
• Interact with GABAA receptors, enhancing GABAergic transmission (note: the binding site is distinct from that of the BZDs).
• Prolong chloride-channel openings.
• Block excitatory glutamate receptors.
• pentobarbital in anesthetic concentrations also block high-frequency sodium channels.
• All of these molecular actions lead to decreased neuronal activity.

Actions
Barbiturates are classified according to their duration of action. For example:
• Thiopental, acts within seconds & has a duration of action of about 30 minutes, it is used in the IV induction of anesthesia.
• Phenobarbital duration of action is greater than a day, it is useful in the treatment of seizures.
• Pentobarbital, secobarbital & amobarbital are short-acting barbiturates, which are effective as sedative & hypnotic (but not anti-anxiety) agents.



1. Depression of CNS:
• At low doses, the barbiturates produce sedation (have a calming effect & reduce excitement).
• At higher doses, they cause hypnosis, followed by anesthesia and finally coma & death.
• Barbiturates do not raise the pain threshold & have no analgesic properties. They may even exacerbate pain.
• Chronic use leads to tolerance.

2. Respiratory depression:
They suppress the hypoxic & chemoreceptor response to CO2 & overdosage is followed by respiratory depression & death.

3. Enzyme induction:
They induce CYP450 microsomal enzymes in the liver. Therefore, chronic barbiturate use diminishes the action of many drugs that are dependent on CYP450 metabolism.

Therapeutic uses
1. Anesthesia:
Selection of a barbiturate is strongly influenced by the desired duration of action. The ultrashort-acting barbiturates, such as thiopental, are used IV to induce anesthesia.

2. Anticonvulsant:
• Phenobarbital is used in long-term management of tonic-clonic seizures, status epilepticus & eclampsia.
• Phenobarbital is the drug of choice for treatment of young children with recurrent febrile seizures, however, it can depress cognitive performance in children thus, it should be used cautiously.
• Phenobarbital has specific anticonvulsant activity that is distinguished from the nonspecific CNS depression.

3. Anxiety:
• Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension & insomnia (when used as hypnotics, they suppress REM sleep more than other stages).

Pharmacokinetics
• They redistribute, from the brain to the splanchnic areas, skeletal muscle, and, finally, adipose tissue. This movement is important in causing the short duration of action of thiopental & similar short-acting derivatives.
• They readily cross the placenta & can depress the fetus.

Adverse effects
1. CNS:
• Drowsiness, impaired concentration & mental & physical sluggishness.
• The CNS depressant effects of barbiturates synergize with those of ethanol.

2. Drug hangover:
Hypnotic doses of barbiturates produce a feeling of tiredness well after the patient wakes. This drug hangover may lead to impaired ability to function normally for many hours after waking. Occasionally, nausea & dizziness can occur.

3. Precautions:
• They may decrease the duration of action of drugs that are metabolized by CYP450 hepatic enzymes.
• Barbiturates increase porphyrin synthesis & are contraindicated in patients with acute intermittent porphyria.

4. Physical dependence:
• Barbiturates abrupt withdrawal may cause tremors, anxiety, weakness, restlessness, nausea & vomiting, seizures, delirium & cardiac arrest.
• Withdrawal is much more severe than that associated with opiates & can result in death.


5. Poisoning:
• Barbiturate poisoning has been a leading cause of death resulting from drug overdoses.
• Severe depression of respiration is coupled with central CV depression & result in a shock-like condition with shallow, infrequent breathing.
• Treatment includes artificial respiration & purging the stomach of its contents if the drug has been recently taken.
Note: No specific barbiturate antagonist is available.
• Hemodialysis may be necessary if large quantities have been taken.
• Alkalinization of the urine often aids in the elimination of Phenobarbital.

Other hypnotic agents

A. Zolpidem
• It is not a BZD in structure, but it acts on BZD1 receptor.
• Has no anticonvulsant or muscle-relaxing properties.
• Shows few withdrawal effects & exhibits minimal rebound insomnia & little or no tolerance occurs with prolonged use.
• Has rapid onset of action & short elimination half-life (2-3 hours). An extended- release formulation is now available
• Metabolized into inactive products, thus Zolpidem half-life is shortened by some drugs eg. Rifampin, while increased by others that inhibit CYP 3A 4 isoenzyme.
• Nightmares, agitation, headache, GI upset, dizziness & daytime drowsiness may occur.
B. Zaleplon
• Very similar to Zolpidem in its hypnotic actions, but compared to Zolpidem or BZDs it causes fewer residual effects on psychomotor & cognitive functions. This may be due to its rapid elimination,.

C. Eszopiclone
• An oral non BZD hypnotic (like Zolpidem & Zaleplon it also utilizes the BZD1).
• Effective for up to 6 months compared to a placebo.
• Elimination half-life is 6 hours.
• It may cause anxiety, dry moth, headache, peripheral edema, somnolence & unpleasant taste.

D. Ramelteon
• Selective agonist at the MT1 & MT2 subtypes of melatonin receptors found in the suprachiasmatic nucleus (SCN) of the hypnothalamus.
Note: normally melatonin is able to induce & promote sleep.
• Ramelteon is indicated for falling asleep insomnia (increased sleep latency).
• Potential for abuse is minimal with no evidence of dependence or withdrawal effects.
Therefore, ramelteon can be administered long term.

E. Chloral hydrate
• Trichlorinated derivative of acetaldehyde, in the body it is converted into trichloroethanol an active metabolite.
• Effective sedative & hypnotic that induce sleep in about 30 minutes & the duration of sleep is about 6 hours.
• It is irritating to the GIT & causes epigastric distress; also it produces an unusual, unpleasant taste sensation.

E. Antihistamines
• Some antihistamines with sedating properties, eg. diphenhydramine, hydroxyzine & doxylamine are effective in treating mild types of insomnia.
• Have numerous undesirable side effects (eg. anticholinergic effects).


F. Ethanol
• Ethanol (ethyl alcohol) has anxiolytic & sedative effects, but its toxic potential outweighs its benefits.
• Produce sedation & ultimately, hypnosis with increasing dosage.
• Metabolized primarily in the liver, first to acetaldehyde by alcohol dehydrogenase & then to acetate by aldehyde dehydrogenase.
• Chronic consumption can lead to severe liver disease, gastritis & nutritional deficiencies.
• Heavy drinking cause cardiomyopathy.
• BZDs are the treatment of choice for alcohol withdrawal, carbamazepine is effective in treating convulsive episodes during withdrawal.

G. Drugs to treat alcohol dependence

1. Disulfiram:
• It blocks the oxidation of acetaldehyde to acetic acid by inhibiting aldehyde dehydrogenase, results in the accumulation of acetaldehyde in the blood, causing flushing, tachycardia, hyperventilation & nausea.
• So that the patient abstains from alcohol to prevent the unpleasant effects of disulfiram-induced acetaldehyde accumulation.

2. Naltrexone:
• Long-acting opiate antagonist that should be used in conjunction with supportive psychotherapy.
• It is better tolerated than disulfiram & does not produce the aversive reaction that disulfiram does.

3. Acamprosate:
• Used in alcohol dependence treatment programs.
• Its mechanism of action is understood.
• It should also be used in conjunction with supportive psychotherapy.