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Sedative-Hypnotic Drugs

Dr.Peer Mohamed.MD Asst Professor, Dept. of Medicine, Madurai Medical College

Anxiolytic: drug that reduce anxiety Sedatives: drugs that have an inhibitory effect on the CNS; reduce nervousness, excitability and irritability without causing sleep Hypnotics: drugs that have more potent effects than sedatives; cause sleep

Sedative hypnotics: drugs that can act in the body either as a sedative or hypnotic

Sedative Hypnotics: Classification

1.

Barbiturates

2.

Benzodiazepines

3.

Newer Agents: zolpidem, zaleplon, eszopiclone, ramelteon, buspirone

Sedative Hypnotics: Clinical Uses


for relief of anxiety for insomnia

for sedation and amnesia before and during medical and surgical procedures
for treatment of epilepsy and seizure states

Sedative Hypnotics: Clinical Uses


as component of balanced anesthesia for control of ethanol or other sedative-hypnotic withdrawal states for muscle relaxation in specific neuromuscular disorders as diagnostic aids

Barbiturates
introduced into clinical use in 1903 derivatives of barbituric acid produce many unwanted side effects: habit-forming and have a narrow therapeutic range

Barbiturates: Classes
Ultrashort onset: <15 minutes duration: <2 hours mephobexital, thiamylal, thiopental Intermediate onset: 20 30 minutes duration: 2 4 hours aprobarbital, butabarbital

Short onset: 15 20 minutes duration: 2 -4 hours pentobarbital, secobarbital

Long onset: 30 60 minutes duration: 6 8 hours phenobarbital

Barbiturates
Pharmacokinetics most barbiturates are absorbed rapidly following oral administration all sedative-hypnotics cross the placental barrier; are also detectable in breast milk Biotransformation only phenobarbital is excreted unchanged in the urine

Barbiturates
Mechanism of Action inhibit nerve impulse transmission by potentiating GABA (increase the duration of the GABA-gated chloride channel openings; direct activation of the GABA-chloride channels) CNS depressant act primarily on the reticular formation

Barbiturates
Therapeutic Uses 1. 2. 3. 4. 5. 6. hypnotics sedatives anticonvulsant anesthesia adjuncts reduction of intracranial pressure in neurosurgical patients (ultrashort) treatment of neonatal hyperbilirubinemia (long)

Barbiturates
Side Effects and Adverse Effects CNS: drowsiness, lethargy, dizziness, excitement, paradoxical restlessness, headache, depression CVS: vasodilatation and hypotension (if given rapidly) Blood: decreased rbc, wbc and platelets GIT: nausea, vomiting, diarrhea, constipation Respiratory: respiratory depression, laryngospasm, bronchospasm, coughing Other: allergic reactions: rashes, fever, Stevens Johnson syndrome

Barbiturates
Toxicity and Management of Overdose overdose: 1. respiratory depression respiratory arrest 2. CNS depression: sleep coma and death treatment: symptomatic and supportive

activated charcoal to help eliminate the drug

Barbiturates
Interactions produces additive CNS depression with: 1. alcohol 2. antihistamines 3. benzodiazepines 4. opioids prolonged effect if given with: 1. MAOIs 2. anticoagulants

Barbiturates
Drug Profiles dosage forms: tablets, capsules, elixirs, injections, suppositories

pregnancy category: D
all are considered as controlled substances

contraindications: hypersensitivity, significant liver dysfunction, known previous addiction

Phenobarbital
Luminal most frequently prescribed barbiturate long acting agent Uses: 1. seizures 2. hyperbilirubinemia 3. Gilberts syndrome Contraindications: 1. preexisting CNS depression 2. severe pain 3. severe respiratory disease Routes of Administration 1. PO 2. IM 3. IV

Phenobarbital
Lifespan Considerations readily crosses placenta; distributed in breast milk may cause postpartum hemorrhage or hemorrhagic disease in newborns

elderly may exhibit confusion, excitement

Pentobarbital
Nembutal Uses: 1. hypnotic (insomnia) 2. preop med 3. anticonvulsants 4. treatment for withdrawal symptoms

Secobarbital
Seconal Uses: 1. hypnotic agent 2. status epilepticus 3. anesthetic adjunct

Benzodiazepines

most frequently prescribed sedativehypnotic

safe
anxiolytic or sedativehypnotic

Benzodiazepines
Long Acting flurazepam quazepam

(Dalmane) (Doral)

Short Acting estazolam temazepam triazolam

(Prosom) (Restoril) (Halcion)

Benzodiazepines
Pharmacokinetics rate of oral absorption depends on lipophilicity; triazolam extremely rapid lipid solubility also determines the rate of entry into the CNS Metabolism metabolic transformation to more water-soluble metabolites major site of metabolism is the liver Excretion via the kidneys

Benzodiazepines
Mechanism of Action binding to GABA receptors potentiation of GABAergic inhibition depress specific areas of the brain: 1. hypothalamus 2. thalamus 3. limbic system no suppression of REM

Benzodiazepines
Drug Effects calming effect on the CNS Therapeutic Uses sedation

controlling agitation and and anxiety


skeletal muscle relaxation

sleep induction
anxiety relief

alcohol withdrawal
epilepsy

Benzodiazepines
Effects on Patterns of Normal Sleep 1. the latency (time to fall asleep) of sleep onset is decreased 2. the duration of stage 2 NREM sleep is increased 3. the duration of REM is decreased 4. the duration of stage 4 NREM slow-wave sleep is decreased

Benzodiazepines
Side/Adverse Effects drowsiness headache paradoxical excitement/ nervousness dizziness vertigo lethargy palpitations dry mouth nausea and vomiting Toxicity and Overdose somnolence confusion coma diminished reflexes

Treatment symptomatic and supportive gastric lavage Flumazenil

Benzodiazepines
Drug Profiles C IV controlled substances pregnancy category X agents contraindications: hypersensitivity and pregnancy

Flurazepam
Dalmane Long acting hypnotic agent

For short term treatment of insomnia (may be used up to 4 weeks)


hangover effect: lethargy or grogginess

Temazepam
Restoril indication: short-term treatment of glaucoma

contraindication: patients with glaucoma

Newer Agents
Zolpidem (Ambien) imidazopyridine absorbed rapidly into the blood following oral administration reaches peak plasma levels in 1.6 hours metabolized in the liver mechanism of action: similar to benzodiazepines (binds selectively to GABA receptors uses: short-term treatment of insomnia (7-10 days) toxicity: extension of CNS depressant effect interaction: ethanol

Ramelteon
Rozerem mechanism of action: agonist at MT1 and MT2 melatonin receptors in the suprachiasmatic nuclei of the brain no direct effect on GABA neurotransmission rapidly absorbed after oral administration and undergoes extensive first-pass metabolism prescribed specifically for patients who have difficulty in falling asleep adverse effects: dizziness, somnolence, fatigue, decreases in testosterone and increases in prolactin not a controlled substance

Buspirone
BuSpar relieves anxiety without marked sedative, hypnotic or euphoric effects has no anticonvulsant or muscle relaxant properties anxiolytic effect may take more than one week to become established not suited for management of acute anxiety states does not interact directly with the GABAergic system rapidly absorbed orally and undergoes extensive first pass metabolism does not potentiate effects of conventional sedativehypnotics

BZD-ADVERSE DRUG REACTION


Acute toxicity:
Benzodiazepines in acute overdose are considerably less dangerous than other sedative-hypnotic drugs. Cause prolonged sleep,without serious depression of respiration or cardiovascular. The availability of an effective antagonist, flumazenil.

BZD-ADVERSE DRUG REACTION


Side-effects during therapeutic use: drowsiness, confusion, amnesia,
impaired coordination. Main disadvantages are interaction with alcohol, long-lasting hangover and the development of dependence.

Tolerance and dependence:

induction of hepatic drug-metabolising enzymes; a change at the receptor level;

Barbiturates-Adverse effects
After effect: hangover---dizzy, drowsiness, amnesia, impaired judgment, disorientation.
Tolerance: decreased responsiveness to a drug following repeated exposure because of down-regulation of receptors and induction of hepatic drug-metabolising enzymes.

Barbiturates-Adverse effects
Dependence: including psychologic and physiologic dependence. Withdrawal symptoms: excitation, insomnia, tremor, anxiety, hallucinations and sometimes convulsions. Depressant effect on respiration: can cross the placental barrier during pregnancy and secrete to breast milk. Others: Skin eruptions and porphyria

Treatment of acute overdosage


An overdose can result in coma, diminished reflexes, severe respiratory depression, hypotension leading to cardiovascular collapse, and renal failure. Treatment (A.B.C): (1) supporting respiration and circulation. (2) alkalinizing the urine and promoting diuresis. (3) Hemodialysis or peritoneal dialysis.

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