22 sedative hypnotic drugs

SEDATIVE-HYPNOTIC DRUGS


Anita Q. Sangalang, MD, FPOGSFACULTY OF PHARMACY

UNIVERSITY OF SANTO TOMAS



SEDATIVE-HYPNOTICS

Benzodiazepines Barbiturates Miscellaneous agents

Short Ultra

action action

Intermediate Short Buspirone

action action Chloral hydrate

Long Long Zaleplon

action action Zolpidem



SEDATION• Reduction of anxiety• Calming effectANXIOLYTIC• Drug that reduces anxiety• SedativeHYPNOSIS• Induction of sleep



• Lipid soluble

• Absorbed well from the GIT

• Good distribution to the brain

• Metabolized before elimination from the body by hepatic enzymes



BENZODIAZEPINES

• Converted initially to active metabolites with long half-lives

• Diazepam and flurazepam After several days of therapy

accumulation of active metabolites can lead to excessive sedation



BENZODIAZEPINES

• Lorazepam and oxazepam Undergo extrahepatic conjugation

and do not form active metabolites



BENZODIAZEPINES

• Bz receptors Form part of GABAA receptor-chloride

ion channel macromolecular structure Binding facilitates the inhibitory actions

of GABA Increased GABA mediated chloride ion

conductance



BENZODIAZEPINES

• Flumazenil Reverses the CNS effects of

benzodiazepines Antagonist at the Bz receptor



BENZODIAZEPINES

• Beta-carbolines High affinity for Bz receptors Can elicit anxiogenic and convulsant

effects Inverse agonists



BENZODIAZEPINES

• Diazepam

desmathyldiazepam active

oxazepam metabolites

conjugation



BENZODIAZEPINES

• Chlorazepam

• Estazolam immediately converted to • Oxazepam inactive metabolites



BARBITURATES

• Extensively metabolized

• Depress the neuronal activity

• Facilitates and prolongs the inhibitory effects of GABA and glycine



BARBITURATES

• Bind to multiple isoforms of GABAA

receptor but at different sites from those with which benzodiazepines interact



BARBITURATES

• Not antagonize by flumazenil

• Increase the duration of GABA- mediated chloride ion channel opening



BARBITURATES

• Block the excitatory transmitter glutamic acid and at high concentration, sodium channels



BARBITURATES

• Thiopental Drug with highest lipid solubility enter

the CNS rapidly Used as induction agents in anesthesia



BARBITURATES

• Thiopental CNS effects are terminated by rapid

redistribution of the drug from the brain to other highly perfused tissues (skeletal muscles)



BARBITURATES

• Thiopental Metabolism occur via oxidation

and glucoronidation Converted to active metabolite



BARBITURATES

• Phenobarbital Goes to the liver to be oxidized Excreted partly unchanged in the urine Alkalinizes the urine Half-life of 4-5 days Requires loading dose



OTHER DRUGS

• Buspirone Partial agonist at serotonin receptor

(5-HT receptor) Impairment of mental activity Psychomotor impairment Selective with minimal depressant

effects on the CNS



OTHER DRUGS

• Zolpidem and zaleplon Exert their CNS effects via interaction

with benzodiazepine receptors Bind more selectively Antagonize by flumazenil



DRUG A - BARBITURATES dose = CNS depression

DRUG B - BENZODIAZEPINES - flatter dose response curve - greater margin of safety

DRUG A

DRUG B



ORGAN SYSTEM EFFECTS1. Sedation2. Hypnosis• Promote sleep onset• Increase the duration of the sleep stateSTAGES OF SLEEPa. REM (Rapid eye movement)• Dream• Decreases at high dosesb. Non-REM• 70-75%



ORGAN SYSTEM EFFECTS3. Anesthesia• Thiopental (barbiturate)• Midazolam (benzodiazepine)• Loss of consciousness, amnesia

and suppression of reflexes



ORGAN SYSTEM EFFECTS4. Anticonvulsant actions• Phenobarbital, clonazepam

Suppression of seizure activity Selective because they do not

cause severe sedation



ORGAN SYSTEM EFFECTS4. Anticonvulsant actions• Diazepam, lorazepam and phenobarbital

Given IV Used in status epilepticus Heavy sedation is needed



ORGAN SYSTEM EFFECTS5. Muscle relaxation• Diazepam

Spasticity states Cerebral palsy



ORGAN SYSTEM EFFECTS6. Medullary depression• High doses can lead to

Respiratory arrest Hypotension CVS collapse Death in suicidal overdose



ORGAN SYSTEM EFFECTS

7. Tolerance and dependence

• Tolerance Decrease in responsiveness Used chronically or in high dosage





• Tolerance Metabolic tolerance

Occurs with phenobarbital Induces its own metabolism Decreases CNS response to the

drug itself





• Dependence

Physiologic State of response to a drug Removal of the drug evokes

unpleasant symptoms Opposite of the drug’s effects





• Dependence

Physiologic Leads to abstinence syndrome

(withdrawal state) when the drug is discontinued



ORGAN –SYSTEM EFFECTS7. Tolerance and dependence• Dependence

Physiologic Withdrawal signs

Anxiety Tremors Hyperreflexia Seizures





• Dependence

Physiologic Occur more commonly with short-

acting drugs Pentobarbital and secobarbital Dependence is unlikely to occur

with buspirone



ORGAN SYSTEM EFFECTS7. Tolerance and dependence• Dependence

Psychological State of response to a drug Drug taker feels compelled to use

the drug Suffers anxiety when separated

from the drug



CLINICAL USES1. Anxiety states• Benzodiazepines with intermediate or

long durations of action are favored• Buspirone

Used for generalized anxiety disorders• Alprazolam

Phobic and panic attacks



CLINICAL USES2. Sleep disorders• Used to treat primary insomnia and

other sleep disorders



CLINICAL USES3. Sedation • Prior to medical/surgical procedures• Conscious sedation-anterograde

amnesia4. Treatment of seizures and convulsions



CLINICAL USES4. Detoxification of alcoholics• Chlordiazepoxide• Diazepam6. Muscle relaxation7. Manias, major depression, phobias



TOXICITY

1. Psychomotor dysfunction

• Cognitive impairment

• Decreased psychomotor skills

• Unwanted daytime sedation



TOXICITY

2. Additive CNS depression

• When used with Alcoholic beverages Antihistamines Antipsychotic drugs Opioid analgesics Tricyclic antidepressants



TOXICITY

3. Overdosage causes severe respiratory and cardiovascular depression

4. Terratogenic



TOXICITY

3. Induce formation of liver microsomal enzymes

• Metabolize drugs multiple drug interactions

• Chloral hydrate displaces coumarin from protein binding sites and increases anticoagulant effects

22 sedative hypnotic drugs

Education

sedativehypnotic drugs

inhibitory effects of

serotonin receptor

oxazepam inactive metabolites

mediated chloride ion

duration of gaba

minimal depressant effects

long halflives diazepam