Sedative-Hypnotic Drugs PDF

Sedative-Hypnotic Drugs  Sedative (Anxiolytic) Exert a calming effect. Reduce tension, nervousness, fear and apprehension. A sedative drug decreases activity, moderates excitement and calms the recipient. little or no effect on motor or mental function. Anxiolytic : A...

Sedative-Hypnotic Drugs  Sedative (Anxiolytic) Exert a calming effect. Reduce tension, nervousness, fear and apprehension. A sedative drug decreases activity, moderates excitement and calms the recipient. little or no effect on motor or mental function. Anxiolytic : A drug that reduces anxiety, Is a sedative  Hypnosis Promote onset and maintenance of sleep. A hypnotic drug produce state of drowsiness and facilitates the onset and maintenance of sleep. Patient can be awakened readily.  Drug Classification The sedative-hypnotic drugs have dose-dependent CNS depressant effects ❖ The followings are sedative hypnotics: 1) Barbiturates 2) Benzodiazepines 3) Miscellaneous agents  Miscellaneous agents Buspiron (the anxiolytic) Alcohols Zalpelon, Zolpidem (the hypnotics) Melatonin agonists (used in sleep disorders)  1) Barbiturates Duration Of Action Drug Typical Indication Ultra-short acting Thiopental Anesthesia (20 min) Short acting Secobarbital Insomnia (3-8 h) Long acting Phenobarbital Seizures (1-2 days) Anesthesia: Loss of consciousness associated with absence of response to pain  2) Benzodiazepines They vary greatly in duration of action, and can be roughly divided into: – Short-acting compounds: (3-8 hours) Triazolam, Oxazepam, Midazolam – Medium-acting compounds: (10-20 hours) Nitrazepam, Alperazolam – Long-acting compounds: (1-3 days) Diazepam, Flurazepam, Chlordiazepoxide, Clonazepam  Pharmacodynamics ▪ Receptors for benzodiazepines (BZ receptors) are present in many brain regions, including the thalamus, limbic structures, and the cerebral cortex. ▪ The BZ receptors form a part of GABA-A receptor (chloride ion channel macromolecular complex in a cell membrane)  Pharmacodynamics Both enhance action of GABA by binding to different site of GABAA receptor/chloride channel Barbiturates are less specific than Benzodiazepines. Barbiturates increase the duration but Benzodiazepines increase the frequency of GABA-mediated chloride ion channel opening. Cl - GABA+Bz Complex Bz GABA Receptor Receptor Profoundly Exterior Hyperpolarized! Interior GABAA receptors  Pharmacokinetics ▪ Most sedative-hypnotic drugs are lipid-soluble and are absorbed well from the gastrointestinal tract, with good distribution to the brain. ▪ Oral absorption of Benzodiazepines depend on lipophilicity (Triazolam and Diazepam more rapid than others) ▪ Drugs with the highest lipid solubility (thiopental) enter the CNS rapidly and can be used as induction agents in Anesthesia.  Pharmacokinetics Are metabolized by hepatic enzymes and converted to active metabolites with long half-life, before elimination from the body. Many benzodiazepines are converted initially to active metabolites, with long half-lives. Prototype drug is diazepam (Valium), which has active metabolites (desmethyl-diazepam and oxazepam) and is long acting (t½ = 20-80 hr). After several days of therapy with some drugs (diazepam, flurazepam), accumulation of active metabolites can lead to excessive sedation.  Pharmacokinetics Lorazepam and Oxazepam undergo extrahepatic conjugation and do not form active metabolites. All BDZs cross the placenta ➔ detectable in breast milk ➔ may exert depressant effects on the CNS of the lactating infant. In the elderly and in those with limited hepatic function, dosages should be reduced.  Pharmacokinetics With the exception of phenobarbital, which is excreted partly unchanged in the urine, the barbiturates are extensively metabolized. however, there are no active metabolites. Phenobarbital is excreted unchanged. Its excretion can be increased by alkalinization of the urine. Phenobarbital is an potent enzyme inducer drugs by induction of liver enzymes. may lead to drug interactions.  Pharmacological effects and uses Sedation (relief of anxiety) ✓ Alprazolam and clonazepam have greater efficacy than other benzodiazepines, in panic and phobic disorders (the longer term treatment).  Pharmacological effects and uses Hypnosis ✓ Sedative-hypnotics can promote sleep onset and also increase the duration of the sleep state. ✓ Rapid eye movement (REM) sleep duration is usually decreased at high doses ✓ Benzodiazepines, including flurazepam, and triazolam, have been widely used in primary insomnia and for the management of certain other sleep disorders. ✓ Lower doses should be used in elderly patients (who are more sensitive to their CNS depressant effects).  Pharmacological effects and uses Anesthesia ✓ For loss of consciousness and absence of response to pain (suppression of reflex and amnesia). Thiopental is commonly used for the induction of anesthesia, and certain benzodiazepines (diazepam and midazolam) are used as components of anesthesia protocols.  Pharmacological effects and uses Anticonvulsant action ✓ Suppression of seizure activity occurs with high doses of most of the barbiturates and some of the benzodiazepines. ✓ Benzodiazepines: clonazepam, diazepam ✓ Barbiturates: phenobarbital  Anticonvulsant and Antiseizure used to treat Epilepsy Clonazepam High Doses of : DIAZ, LORAZ in status epilepsy They can enhance GABA-mediated synaptic systems and inhibit excitatory transmission.  Pharmacological effects and uses Muscle Relaxation Relaxation of skeletal muscle occurs only with high doses of most sedative-hypnotics. Diazepam is effective at sedative dose levels for specific spasticity states  Pharmacological effects and uses Medullary Depression of sedative-Hypnotics ✓ High doses, especially alcohols and barbiturates, can cause depression of medullary neurons, leading to respiratory arrest, hypotension, and cardiovascular collapse. ✓ These effects are the cause of death in suicidal overdose. Action Profiles of Benzodiazepines Relief of anxiety Anticonvulsant Sedation action Induction of sleep Muscle relaxation  SEDATIVE-HYPNOTIC DRUGS Coma BARBITURATES Medullary depression BENZODIAZEPINES Anesthesia Hypnosis Sedation DOSE = CNS DEPRESSION Greater Margin Of Safety  CLINICAL USES OF SEDATIVE-HYPNOTICS A. Anxiety States B. Sleep Disorders C. Anesthesia protocols D. Management of seizure disorders E. Treatment of muscle spasticity A. Longer acting benzodiazepines (chlordiazepoxide and diazepam) are used in the management of withdrawal states in persons physiologically dependent on ethanol and other sedative-hypnotics.  TOLERANCE AND DEPENDENCE A decrease in responsiveness—occurs when sedative-hypnotics are used chronically or in high dosage. Tolerance Reduction in drug effect requiring an increase in dosage to maintain the same response. Cross-tolerance may occur among different chemical subgroups. Psychological dependence occurs frequently with most sedative- hypnotics and is manifested by the compulsive use of these drugs to reduce anxiety.  TOLERANCE AND DEPENDENCE ✓ Physiologic dependence constitutes an altered state that leads to an abstinence syndrome (withdrawal state) when the drug is discontinued. ✓ Withdrawal signs, which may include anxiety, tremors, hyperreflexia, and seizures, occur more commonly with shorter-acting drugs. ✓ Serious withdrawal syndrome can include convulsions and death. ✓ The dependence liability of zolpidem and zaleplon may be less than that of the benzodiazepines since withdrawal symptoms are minimal after their abrupt discontinuance.  ADVERSE DRUG REACTION TOXICITY Psychomotor Dysfunction This includes cognitive impairment, decreased psychomotor skills, and unwanted daytime sedation. These adverse effects are more common with benzodiazepines that have active metabolites with long half-lives (diazepam, flurazepam), but can also occur after a single dose of a short-acting benzodiazepine such as triazolam.  ADVERSE DRUG REACTION The dosage of a sedative-hypnotic should be reduced in elderly patients, who are more susceptible to drugs that cause psychomotor dysfunction. In such patients excessive daytime sedation has been shown to increase the risk of falls and fractures. Anterograde amnesia may also occur with benzodiazepines, especially when used at high dosage. Anterograde amnesia is a type of memory loss that occurs when you can't form new memories.  ADVERSE DRUG REACTION Additive CNS Depression This occurs when sedative-hypnotics are used with other drugs in the class as well as with alcoholic beverages, antihistamines, antipsychotic drugs, opioid analgesics, and tricyclic antidepressants. This is the most common type of drug interaction involving sedative-hypnotics.  Toxicity/Overdose with Benzodiazepines Overdosage of sedative-hypnotic drugs causes severe respiratory and cardiovascular depression; these potentially lethal effects are more likely to occur with alcohols, barbiturates, and carbamates than with benzodiazepines or the newer hypnotics such as zolpidem.  Toxicity/Overdose with Benzodiazepines Management of intoxication requires maintenance of a patent airway and ventilatory support. Flumazenil is Benzodiazepine competitive Antagonist. Flumazenil reverses the CNS depressant effects of benzodiazepines, zolpidem and zaleplon, but has no beneficial actions in overdosage with other sedative-hypnotics.  Sedative-Hypnotic Drugs ▪ Replaced Barbiturates ▪ Benzodiazepine Advantages - Safer- higher therapeutic index - Tolerance- lower - Addictive liability- lower - Less drug interactions  Benzodiazepines vs. Barbiturates Criteria BZ Barb Relative Safety High Low Maximal CNS depression Low High Respiratory Depression Low High Suicide Potential Low High Abuse Potential Low High Antagonist Available? Yes No  ZOLPIDEM Not a benzodiazepine but binds to BZ receptor (BZ receptor agonists). Good hypnotic, with less effects on stages of sleep. Minimal muscle relaxing & anticonvulsant effect. Tolerance less than Benzodiazepines. Low incidence of rebound insomnia, daytime sedation Actions are antagonized by flumazenil.  ZOLPIDEM It has rapid onset with minimal effects on sleep patterns and cause less daytime cognitive impairment than benzodiazepines. Adverse effects of Zolpidem: ✓ Nightmares, Agitation, Headache, GIT upset, Dizziness, Daytime drowsiness.  BUSPIRON Buspirone is a selective anxiolytic, with minimal CNS depressant effects (it does not affect driving skills) and has no anticonvulsant, no hypnotic or muscle relaxant properties. Acts at 5-HT1A (partial agonist) and Dopamine receptors. Does not produce tolerance and physical dependence. Side effects of buspirone include tachycardia, nausea, dizziness, headache, paresthesias, pupillary constriction, and gastrointestinal distress.  Use of Sedative/Hypnotics All of the anxiolytics/sedative/hypnotics should be used only for symptomatic relief. ************* All the drugs used alter the normal sleep cycle and should be administered only for days or weeks, never for months. ************ USE FOR SHORT-TERM TREATMENT ONLY!! Thank you Receptor regulation. Desensitization, tachyphylaxis Down-regulation Up-regulation