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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
1.
Barbiturates
2.
Benzodiazepines
3.
for sedation and amnesia before and during medical and surgical procedures
for treatment of epilepsy and seizure states
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
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
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
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
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
safe
anxiolytic or sedativehypnotic
Benzodiazepines
Long Acting flurazepam quazepam
(Dalmane) (Doral)
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
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
Benzodiazepines
Drug Profiles C IV controlled substances pregnancy category X agents contraindications: hypersensitivity and pregnancy
Flurazepam
Dalmane Long acting hypnotic agent
Temazepam
Restoril indication: short-term treatment of 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
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
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