hypotonic

• Sedative & Hypnotic Drugs

  A chemically heterogeneous class of drugs classified based on clinical use for anxiety states and sleep disorders, that produce dose-dependent CNS depressant effects causing sedation or hypnosis

  
• Sedative-Hypnotic Drugs


  • An effective sedative agent should reduce anxiety and exert a calming effect
  • The degree of CNS depression caused by a sedative should be the minimum consistent with therapeutic efficacy
  • A hypnotic drug produces drowsiness and encourages the onset and maintenance of a state of sleep, involving more pronounced depression of the CNS than sedation
  • Graded dose-dependent depression of CNS function is a characteristic of most sedative-hypnotics, with individual drugs differing in the relationship between dose and degree of CNS depression

  
• Absorption


  The rates of oral absorption of sedative-hypnotics differ by their lipophilicity
• Distribution


  Lipid solubility plays a major role in determining the rate a particular sedative-hypnotic enters the CNS, responsible for the rapid onset of effects of some drugs
• Metabolism - Benzodiazepines


  1. Hepatic metabolism via Phase I and Phase II reactions

  2. Many Phase I metabolites are active and have long half-lives, more likely to cause cumulative effects with multiple doses

  3. Drugs with relatively short half-lives and metabolized directly to inactive glucuronides have less cumulative and residual effects
• Metabolism - Barbiturates


  1. Oxidation by hepatic enzymes to form alcohols, acids, and ketones, which appear in the urine as glucuronide conjugates

  2. The overall rate of hepatic metabolism is usually slow, except for thiobarbiturates

  3. The elimination half-lives vary, and multiple dosing can lead to cumulative effects
• Metabolism - Newer Hypnotics

  1. Zolpidem: Rapidly metabolized to inactive metabolites via oxidation and hydroxylation by hepatic CYP3A4

  2. Zaleplon: Metabolized to inactive metabolites mainly by hepatic aldehyde oxidase and partly by CYP3A4

  3. Eszopiclone: Metabolized by CYP3A4 to inactive and weakly active metabolites

  4. Suvorexant: A substrate of CYP3A4, with half-life prolonged by inhibitors of the enzyme
• Excretion


  Mainly through the kidney as water-soluble metabolites, with changes in renal function not having a marked effect on the elimination of parent drugs in most cases
• Factors affecting biodisposition


  • Alterations in hepatic function due to disease or drug-induced changes in microsomal enzyme activities can affect the elimination half-lives and lead to excessive CNS effects
  • Barbiturates and meprobamate can induce hepatic drug-metabolizing enzymes, increasing their own metabolism and that of other drugs, while benzodiazepines and newer hypnotics do not change enzyme activity with continuous use
• GABAA receptor


  The benzodiazepines, barbiturates, zolpidem, zaleplon, eszopiclone, and many other drugs bind to molecular components of the GABAA receptor in neuronal membranes in the CNS, which functions as a chloride ion channel activated by GABA
• GABAA receptor structure


  • A major isoform consists of two α1 subunits, two β2 subunits, and one γ2 subunit, with the GABA binding sites located between adjacent α1 and β2 subunits and the benzodiazepine binding pocket between an α1 and the γ2 subunit
  • GABAA receptors consist of various combinations of subunits, with benzodiazepines binding to many isoforms, barbiturates binding to multiple isoforms at different sites, and zolpidem, zaleplon, and eszopiclone binding more selectively to isoforms containing α1 subunits
• Benzodiazepines


  Potentiate GABAergic inhibition at all levels of the neuraxis, increasing the efficiency of GABAergic synaptic inhibition without directly activating GABAA receptors or opening the associated chloride channels, but enhancing GABA's effects allosterically
• Barbiturates


  Facilitate the actions of GABA at multiple sites in the CNS, increasing the duration of the GABA-gated chloride channel openings, and at high concentrations may also be GABA-mimetic, directly activating chloride channels, while also depressing the actions of the excitatory glutamate
• Benzodiazepine binding site ligands

  • Agonists facilitate GABA actions at multiple BZ binding sites, while selective agonists like zolpidem, zaleplon, and eszopiclone act at BZ sites containing an α1 subunit
  • Antagonists like flumazenil block the actions of BZs, eszopiclone, zaleplon, and zolpidem, but not barbiturates, meprobamate, or ethanol
  • Inverse agonists act as negative allosteric modulators of GABA-receptor function, producing anxiety and seizures
• Sedation


  • Benzodiazepines, barbiturates, and most older sedative-hypnotic drugs have calming effects with concomitant reduction of anxiety at relatively low doses, accompanied by some depressant effects on psychomotor and cognitive functions
  • Disinhibition, equated with the antianxiety effects, can lead to euphoria, impaired judgment, and loss of self-control, and these drugs also exert dose-dependent anterograde amnestic effects

  
• Hypnosis


  • All sedative-hypnotics induce sleep if high enough doses are given, with effects on normal sleep patterns including decreased latency of sleep onset, increased duration of stage 2 NREM sleep, decreased duration of REM sleep, and decreased duration of stage 4 NREM slow-wave sleep, with tolerance developing to these effects with prolonged use
  • Secretion of pituitary or adrenal hormones is not disturbed when either barbiturates or benzodiazepines are used as hypnotics

  
• Anesthesia


  • High doses of certain sedative-hypnotics depress the CNS to the point of general anesthesia, with the suitability of a particular agent depending on its rapidity of onset and duration of effect
  • Barbiturates like thiopental and methohexital are very lipid-soluble, penetrating brain tissue rapidly for inducing anesthesia, while benzodiazepines like diazepam, lorazepam, and midazolam are used as adjuncts and may contribute to persistent postanesthetic respiratory depression
• Flumazenil


  A benzodiazepine antagonist with high affinity for the BZ binding site on the GABAA receptor, blocking many of the actions of BZs, zolpidem, zaleplon, and eszopiclone, but not the CNS effects of other sedative-hypnotics, used to reverse the CNS depressant effects of BZ overdose and to hasten recovery following their use in anesthetic and diagnostic procedures
• Anticonvulsant effects


  • Most sedative-hypnotics are capable of inhibiting the development and spread of epileptiform electrical activity, with some groups exerting anticonvulsant effects without marked CNS depression, and barbiturates and certain benzodiazepines being clinically useful in the management of seizures, while the newer sedative-hypnotics like zolpidem, zaleplon, and eszopiclone lack anticonvulsant activity

  
• Effects on muscles and cardiorespiratory system

  • Muscle relaxation occurs only with high doses of most sedative-hypnotics, with diazepam being effective at sedative dose levels for specific spasticity states, while the newer hypnotics lack this effect
  • In therapeutic doses, there are no significant effects on the cardiorespiratory system in patients without respiratory or cardiovascular conditions, but high doses can cause depression of medullary neurons leading to respiratory arrest, hypotension, and cardiovascular collapse
• Tolerance and Dependence


  Decreased responsiveness when used chronically or in high dosage, with cross-tolerance occurring among different sedative-hypnotics, and dependence developing with prolonged use
• Relaxation of skeletal muscle

  • Occurs only with high doses of most sedative-hypnotics
• Diazepam


  Effective at sedative dose levels for specific spasticity states, including cerebral palsy
• Meprobamate


  Also has some selectivity as a muscle relaxant
• Muscle relaxation is not a characteristic action of zolpidem, zaleplon, and eszopiclone
• Cardiorespiratory system effects of sedative-hypnotics

  • No significant effect in therapeutic doses in patients without respiratory or CV condition
  • Significant respiratory depression in patients with pulmonary disease
  • CV depression in hypovolemic states, heart failure, or impaired CV functions
• High doses of conventional sedative-hypnotics, especially alcohols and barbiturates, can cause depression of medullary neurons
• Respiratory arrest, hypotension, and cardiovascular collapse: the cause of death in suicidal overdose
• Tolerance


  Decreased responsiveness when used in chronically or in high dosage
• Cross-tolerance may occur among different chemical subgroups
• Psychological dependence


  Frequently with most sedative-hypnotics & manifested by the compulsive use to decrease anxiety
• Physiologic dependence


  An altered state that leads to an abstinence syndrome when the drug is abruptly discontinued (withdrawal signs)
• Anxiety, tremors, hyperreflexia, & seizures; more commonly with shorter-acting drugs
• The dependence of zolpidem, zaleplon, and eszopiclone is less than BZs with minimal withdrawal
• Buspiron


  • Selective anxiolytic, minimal CNS depression
  • 5HT1A partial agonism
  • No anticonvulsant or muscle-relaxing effect
  • Used in generalized anxiety disorders
  • Tolerance & withdrawal is minimal
  • Side effects: tachycardia, paresthesias
• Melatonin receptor agonists (Ramelteon, tasimelteon)


  • Decreases latency of sleep onset
  • No effect on GABAergic neurotransmission
  • Tasimelteon used in non-24-hour sleep-wake disorder in totally blind cases
  • Side effects include dizziness, fatigue
• Orexin antagonists (Suvorexant)


  • Antagonist of orexin receptors (OX1R & OX2R) found in hypothalamus
  • Involved in wakefulness
  • Used in insomnia
  • Promotes sleep onset & duration
• Clinical uses of sedative-hypnotics

  • Relief of anxiety
  • Insomnia
  • Sedation & amnesia before/during medical/surgical procedures
  • Treatment of epilepsy and seizure states
  • As a component of balanced anesthesia (IV use)
  • Control of alcohol or other sedative-hypnotic withdrawal states
  • Muscle relaxation in specific neuromuscular disorders

  
• Acute anxiety states and rapid control of panic attacks

  Benzodiazepines are favored for pharmacological management
• Alprazolam and clonazepam


  Have greater efficacy than other BZs in the longer term treatment of panic and phobic disorders