Buspirone, Zolpidem, Zaleplon and other Sedative/Hypnotic Drugs

In addition to benzodiazepines, already mentioned, the following are also used as anxiolytics:

Buspirone

–          Non Benzodiazepine

–          Non – sedating anxiolytic

–          Onset of action slow

–          No hypnotic, anti convulsant or muscle relaxant properties

Mechanism of Action:

Act as partial agonist at brain 5-HT_1A receptors

–          Rebound anxiety after sudden cessation of high doses

–          Minimal abuse liability.

 Pharmacokinetics

–Rapidly absorbed orally, undergoes Ist pass metabolism

-Active metabolites are formed after hydroxylation & dealkylation

-Active metabolite (I-PP) has alpha2 ADRENERGIC action in CNS

–       t ½  of Buspirone  is 2-4 hrs.

Advantages

1. no rebound anxiety
2. no withdrawal symptoms
3. minimal abuse liability
4. cause less psychomotor impairment than benzodiazepines and do not effect driving skills
5. does not potentiate effects of sedatives/hypnotics of ethanol and TCAs
6. elderly people do not appear to be more sensitive to its actions

Drawback

Onset of action is delayed. It takes about 7 days. In generalized anxiety disorders, although action is comparable to benzodiazepines, so may be used. It does not interact with other CNS depressants except ethanol.

Acts by inhibiting presynaptic receptors, increasing serotonin.

Toxicity:

Less troublesome than benzodiazepines

–       Palpitation

–       Tachycardia

–       Nervousness

–       Parasthesias

–       GI distress

–       Dose dependent pupillary constriction

Drug Interactions

–          Monoamine oxidase inhibitors antidepressants + Buspirone  increase B.P

–          Macrolyte antibiotics (Erythromycin [enzyme inhibitor], Ketoconazole) increase plasma levels

–          Rifampin decrease plasma level

 Zolpidem :

Imadazopyridine derivative- (Non BDZ)

Mechanism of action:

Binds with benzodiazepine receptor (omega 1)

Facilitates GABA mediated neuronal inhibition

Acts as sedative/hypnotic & antagonized by Flumazenil  

– Has minimal anti Convulsant & muscle relaxant properties

– Affects sleep pattern & respiration at  higher doses.
– Metabolized in liver, t ½ is 1-5 – 3-5 hrs.

Advantages

1. Improves sleep
2. Increases sleep time
3. Tolerance is less
4. Short term insomnia –usually administered for short term effect which persists for 4-5 days, after 1-2 doses drug is stopped and effect persists for about a week

Disadvantages

1. In chronic insomnia, with initial doses, chances of rebound insomnia are there when drug is discontinued
2. Patients suffering from obstructive apnea are not given as may increase hypoxia.
3. Patients of respiratory distress, COPD, cardiac patients are not administered as aggravate.

Available as biphasic formulation, which provides sustained drug levels.

Chloral Hydrate

-First hypnotic, trichloroethanol.

It is one of the oldest hypnotic, used since 18^th century.

Present is liquid form, irritant to skin and gastric mucosa, producing a burning sensation when taken orally.

It is converted to trichloroethanol in liver.

Tolerance develops.

It is occasionally used in children and elderly undergoing painful diagnostic procedures.

Onset of action occurs within 5-10 minutes. Duration of action is about 4 hours.

-High P. Protein binding & displace oral anticoagulant.

May be used for dental extraction but not preferred.

Disadvantages

1. Forms active metabolite trichloroacetic acid, which is cardio toxic
2. Idiosyncratic reaction occurs in some individuals and person shows disorientation and incoherent and paranoid behavior.

Urochloric acid is excreted in urine, which is the third metabolite.

 Meprobamate

Has muscle relaxant activity and blocks inter-nuncial neurons in spinal cord.

It is not used now because of abuse liability and hypnotic actions, safer drugs are available

Paraldehyde

– Cyclic ether, a polymer of acetaldehyde. It has a strong aromatic smell and disagreeable taste. If given orally, it causes burning sensation, irritation of mouth, throat and stomach. After oral administration, it is rapidly absorbed and sleep occurs within 10-15 minutes. It is never administered I/V  and never in plastic syringe, as is corrosive.

Anticonvulsant

-70-80% is metabolized in liver, 20-30% is exhaled from lungs.

Thus, if liver is compromised, alternative route is used.

Used;

1. In retention enema, via rectum
2. Also given in delirium tremors

 Zaleplon

–          Selectively bind  to benzodiazepines receptors

–          GABA-ergic

–          Rapid onset & shorter duration (short half life).

–          Not antagonized by flumazenil   

–          Effective for management of patients who woke up early in sleep cycle.

Eszopiclone

Has longer half life than Zaleplon.

Is associated with less dizziness, less insomnia and drowsiness.

Continue Reading

Sedatives and Hypnotics -An Introduction

Benzodiazepines

Flumazenil -Benzodiazepines Antagonist

Barbiturates