Sedatives / Hypnotics

  1. Neuropharmacology of GABA
    • γ-aminobutyrate
    • 4-aminobutyrate
    • Inhibitor of presynaptic transmission in the CNS and retina
  2. GABA Synthesis
    • Decarboxylation of glutamate catalyzed by glutamate decarboxylase (GAD) in GABAergic neurons
    • GAD is present in nerve endings of the brain and β-cells of the pancreas
    • GAD requires pyridoxal phosphate (PLP) as a cofactor
    • → PLP is generated from the B6 vitamins through pyridoxal kinase which requires zinc for activation
    • → Zinc deficiency or defects in pyridoxal kinase leads to seizures, especiallt in seizure-prone preeclamptic patients
  3. GABAergic Receptor
    • GABA-A (ion channels)
    • → Chloride channels associated with in the receptor
    • → Modulated by GABA, Benzodiazepines, Barbiturates
    • → sedative, anxiolytic, hypnotic effect
    • GABA-B (GPCR)
    • → Agonist- Baclofen
    • → muscle relaxant effect
  4. GABA-A receptor-chloride ion channel macromolecular complex
    • A hetero-oligomeric glycoprotein, the complex consists of five or more membrane-spanning subunits
    • → Multiple forms of α, β, and γ subunits are arranged in different pentameric combinations so that GABA-A receptors exhibit molecular heterogeneity
  5. GABA-A Receptor
    • A major isoform of the GABA-A receptor that is found in many regions of the brain (CNS) consists of two α1 subunits, two β2 subunits, and one γ2 subunit
    • In this isoform, the two binding sites for GABA are located between adjacent α1 and β2 subunits, and the binding pocket for benzodiazepines (the BZ site of the GABA-A receptor) is between an α1 and the γ2 subunit
    • GABA-A receptors in different areas of the central nervous system consist of various combinations of the essential subunits, and the benzodiazepines bind to many of these, including receptor isoforms containing α2, α3, and α5 subunits
  6. GABA-A Receptor Binding Sites
    • BZD binding site (between α1 and γ2 subunits)
    • → Need binding of GABA to work
    • Barbiturate binding site (on α1 subunit)
    • Separate binding site for GABA-A receptor containing α1 subunits such as zolpidem, zaleplon, and eszopiclone
    • Besides GABA-A receptors these drugs may some affinity of GABAB receptors (activated by baclofen) FYI
  7. GABA-A Receptor Heterogeneity & Pharmacologic Selectivity
    • α1 subunit in GABA-A receptors mediates sedation, amnesia, and ataxic effects of BZDs
    • α2 and α3 subunits are involved in BZDs anxiolytic and muscle-relaxing actions
    • α5 subunit is involved in at least some of the memory impairment caused by BZDs
  8. BZDs and GABA (GABA-A): MOA
    • GABA: Major inhibitory neurotransmitter in spinal cord, hypothalamus, hippocampus, substantia nigra, cerebellar cortex and cerebral cortex
    • BZDs increase synaptic inhibition of GABA
    • BZDs enhance GABAergic effect without directly activating GABAA receptor not by opening of chloride channels, but by increasing frequency of chloride opening events and enhancing chloride ion conductance
    • Enhance membrane hyperpolarization
  9. Benzodiazepine Binding Site Ligands
    • BZD site agonists: all BZDs
    • GABA-A (containing α1 subunit) agonist- Zolpidem, Zaleplon, and Eszopiclone
    • Antagonist- Flumazenil blocks actions of Benzodiazepines, zolpidem, zaleplon, and eszopiclone but not of barbiturates, meprobamate or ethanol
    • Inverse agonists: β-carbolines, e.g., n-butyl-β-carboline-3-carboxylate (β -CCB) FYI
    • → Produce anxiety, seizures but block actions of benzodiazepines
  10. α1 Subunits in GABA-A Agonists
    • Zolpidem, Zaleplon, and Eszopiclone
    • Enhance membrane hyperpolarization similar to BZs (sedative hypnotics)
    • → Anxiolytic effect
    • → Muscle relaxant effect
    • → Amnesia effect
  11. GABA-A and barbiturates
    • Barbiturates enhance membrane hyperpolarization via increase the duration of the GABA-gated chloride channel openings
    • At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride channels
    • Barbiturates are less selective in their actions than benzodiazepines, because they also depress the actions of the excitatory neurotransmitter glutamic acid via binding to the AMPA receptor
    • This multiplicity of sites of action of barbiturates may be the basis for their ability to induce full surgical anesthesia and pronounced central depressant effects (which result in their low margin of safety)
  12. Sedative and Hypnotics
    • Sedatives (Anxiolytics): Calming effect
    • → The degree of central nervous system depression caused by a sedative should be the minimum consistent with therapeutic efficacy

    • Hypnotics: Drowsiness and encourage the onset and maintenance of a state of sleep
    • → Pronounced depression of the central nervous system than sedation, and this can be achieved with many drugs in this class simply by increasing the dose
  13. Sedation-Hypnosis
    • Graded dose-dependent depression of central nervous system function with most sedatives and hypnotics
    • Older sedative/hypnotics such barbiturates have linear dose relationship for CNS depression leading to general anesthesia vasomotor and respiratory center depression
    • → Euthanasia
    • Such linear relationship does not exist in case of benzodiazepines and newer sedatives
  14. Absorption of Hypnotics and Sedatives
    • The rates of oral absorption of sedative-hypnotics differ depending on a number of factors, including lipophilicity
    • → Absorption of triazolam is extremely rapid
    • Diazepam and the active metabolite of clorazepate (prodrug) is more rapidly absorbed than other commonly used benzodiazepines
    • Clorazepate, a prodrug, is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach
    • → Most of the barbiturates and other older sedative-hypnotics, as well as the newer hypnotics (eszopiclone, zaleplon, zolpidem), are absorbed rapidly into the blood following oral administration
  15. Distribution of Hypnotics and Sedatives
    • Most of hypnotics and sedatives are lipid soluble and thus have rapid onset of central nervous system effects
    • All sedative-hypnotics cross the placental barrier during pregnancy
    • → DO NOT USE in pregnant women- neonatal depression
    • → If sedative-hypnotics are given during the predelivery period, they may contribute to the depression of neonatal vital functions
    • Sedative-hypnotics are also detectable in breast milk and may exert depressant effects in the nursing infant
  16. Biotransformation of Barbiturates
    • With the exception of phenobarbital, only insignificant quantities of the barbiturates are excreted unchanged
    • Slow rate of hepatic metabolism in humans depends on the individual drug but (with the exception of the thiobarbiturates)
    • → CYP 450 drug induction
    • The major metabolic pathways involve oxidation by hepatic enzymes to form alcohols, acids, and ketones, which appear in the urine as glucuronide conjugates
    • The elimination half-lives
    • → Secobarbital and pentobarbital range from 18 to 48 h
    • → Phenobarbital in humans is 4–5 days thus multiple dosing with these agents can lead to cumulative effects
  17. BZDs Biotransformation
    • Metabolic transformation to more water-soluble metabolites is necessary for clearance of sedative-hypnotics from the body
    • Hepatic Microsomal enzyme metabolism
    • → Phase 1: N-dealkylation and aliphatic hydroxylation catalyzed by cytochrome P450 isozymes, especially CYP3A4
    • → Phase 2: conjugation
    • → Affects half-life due to active metabolites
  18. Factors Affecting Biodisposition
    • Drug induced increase or decrease of hepatic microsomal enzymes, CytoP450 (CYP3A4)
    • Geriatric patients: elimination half-life is prolonged
    • Microsomal enzyme induction: Barbiturates and mebrobamate
  19. Long Acting BZDs (24-48 h)
    • Diazepam
    • Chlordiazepoxide
    • Flurazepam
    • Clonazepam
    • Clorazepate
  20. Medium Acting BZDs (24 h)
  21. Short acting drugs: (12-18 h)
    • Alprazolam
    • Lorazepam
    • Oxazepam
    • Temazepam
  22. Ultrashort acting drugs: (6 h)
    • Triazolam
    • Midazolam
  23. Short Acting Non-Benzodiazepine
    • Zolpidem (t½ ~2 h)
    • Eszopiclone (t½ 5-6 h)
    • Zaleplon (t½  ~2 h)
  24. Sedation
    • Calming effects with concomitant reduction of anxiety at relatively low doses
    • Psychomotor and cognitive function depression
    • Euphoria, impaired judgment, and loss of self-control
    • Dose-dependent anterograde amnesia (inability to remember events occurring during the drug's DOA)
  25. Hypnosis
    • All of the sedative-hypnotics induce sleep if high enough doses are given depending upon the dose, and the frequency of its administration.
    • The latency of sleep onset is decreased (time to fall asleep);
    • The duration of stage 2 NREM (nonrapid eye movement) sleep is increased
    • The duration of REM (rapid eye movement) sleep is decreased
    • The duration of stage 4 NREM slow-wave sleep is decreased.
    • The newer hypnotics all decrease the latency to persistent sleep. 
    • Zolpidem decreases REM sleep but has minimal effect on slow-wave sleep. 
    • Zaleplon decreases the latency of sleep onset with little effect on total sleep time, NREM, or REM sleep. 
    • Eszopiclone increases total sleep time
  26. Rebound REM
    • Abrupt interruption of sedation by sedatives can cause rebound REM sleep specially with triazolam and drugs with shorter duration of action
    • Newer drugs such as zolpidem do not affect rebound REM
    • Rebound insomnia occurs with Zolpidem and zaleplon at higher doses
    • Drugs used for longer duration leads to Tolerance to sleep patterns
  27. Anesthesia
    • Barbiturates:
    • → thiopental and methohexital are very lipid-soluble, and penetrate brain tissue rapidly -thus favor their use for induction of anesthesia
    • → Rapid tissue redistribution (not rapid elimination) accounts for the short duration of action of these drugs
    • Diazepam, lorazepam, and midazolam in combination with other agents—are used intravenously in anesthesia
    • → Benzodiazepines given in large doses as adjuncts to general anesthetics may contribute to a persistent post anesthetic respiratory depression.
    • ¤ Due long half-lives and the formation of active metabolites
    • → Such depressant actions of the benzodiazepines are usually reversible with flumazenil
  28. Muscle Relaxation
    • Inhibitory effects on polysynaptic reflexes and internuncial transmission
    • At high doses may also depress transmission at the skeletal neuromuscular junction
    • Muscle relaxant effects are seen in experimental animal models-advocate their use in muscular spasm
  29. Cardiovascular System
    • No significant effect in healthy subjects
    • In CHF patients, may cause cardiac depressions due to depressed medullary vasomotor center
    • At toxic doses: may circulatory collapse due to decrease myocardial contractility
  30. Respiration
    • At hypnotic doses in healthy patients, the effects of sedative-hypnotics on respiration are comparable to changes during natural sleep
    • Even at therapeutic doses, sedative-hypnotics can produce significant respiratory depression in patients with pulmonary disease
    • Effects on respiration are dose-related, and depression of the medullary respiratory center is the usual cause of death due to overdose of sedative-hypnotics
  31. Tolerance
    • → Decreased responsiveness to a drug following repeated exposure
    • → Result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep
    • → Partial cross-tolerance occurs between the sedative-hypnotics

    • The mechanisms responsible for tolerance:
    • → An increase in the rate of drug metabolism (metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates
    • → Changes in responsiveness of the central nervous system to sedatives and hypnotics
  32. Psychological Dependence
    • An altered physiologic state that requires continuous drug administration to prevent an abstinence or withdrawal syndrome
    • Compulsive misuse of virtually all sedative-hypnotics due to anxiety, euphoria, disinhibition, and promotion of sleep properties
    • Schedule III: Barbiturates except phenobarbital (barbital)
    • Schedule IV: all newer GABA-A agonists, BZs and barbital
  33. Withdrawal Syndrome
    • Characterized by states of increased anxiety, insomnia, and central nervous system excitability that may progress to convulsions
    • Severity of withdrawal symptoms differs among individual drugs and depends also on the magnitude of the dose used immediately before cessation of use
    • → The use of drugs with very short half-lives for hypnotic effects may lead to signs of withdrawal even between doses [Triazolam]
  34. Flumazenil
    • Competitive antagonist with high affinity for the BZD binding site
    • It blocks many of the actions of benzodiazepines, zolpidem, zaleplon, and eszopiclone
    • Flumazenil is approved for use in reversing the central nervous system depressant effects of benzodiazepine overdose and to hasten recovery in anesthetic and diagnostic procedures
    • Acts rapidly but has a short half-life (0.7–1.3 hours) due to rapid hepatic clearance
    • Requires repeated administration IV
    • Adverse effects of flumazenil: agitation, confusion, dizziness, and nausea.
    • → Flumazenil may cause a severe precipitated abstinence syndrome in patients who have developed physiologic benzodiazepine dependence
  35. Clinical Uses of Sedative-Hypnotics
    • For relief of anxiety
    • For insomnia
    • For sedation and amnesia before and during medical and surgical procedures
    • For treatment of epilepsy and seizure states
    • As a component of balanced anesthesia (intravenous administration)
    • For control of ethanol or other sedative-hypnotic withdrawal states
    • For muscle relaxation in specific neuromuscular disorders
    • As diagnostic aids or for treatment in psychiatry
  36. Drug Interactions
    • The most common drug interactions involving sedative-hypnotics are interactions with other central nervous system depressant drugs, leading to additive effects. These interactions have some therapeutic usefulness when these drugs are used as adjuvants in anesthesia practice.
    • → Depressant drugs: antihistaminics, antidepressants, antipyschotics, anticonvulsants
    • However, if not anticipated, such interactions can lead to serious consequences, including enhanced depression with concomitant use of many other drugs.
    • Additive effects can be predicted with concomitant use of alcoholic beverages, opioid analgesics, anticonvulsants, and phenothiazines.
    • Less obvious but just as important is enhanced central nervous system depression with a variety of antihistamines, antihypertensive agents, and antidepressant drugs of the tricyclic class.
  37. Agents that do not act through GABA-BZ mechanisms
    • Ramelteon
    • Buspirone
  38. Ramelteon
    • Melatonin receptors (MT1 and MT2 ) are thought to be involved in maintaining circadian rhythms underlying the sleep-wake cycle
    • Located in suprachiasmatic nuclei of the brain
    • No direct effect on GABA ergic neurotransmission
    • Ramelteon agonist at MT1 and MT2 melatonin receptors
  39. Ramelteon Absorption
    Rapidly absorbed after oral administration and undergoes extensive first-pass metabolism, forming an active metabolite with longer half-life (2–5 hours) than the parent drug
  40. Ramelteon Biotransformation
    CYP1A2 isoform of cytochrome P450 is mainly responsible for the metabolism of Ramelteon, but CYP2C9 isoform is also involved
  41. Ramelteon Interactions
    • Should not be used in combination with inhibitors of CYP1A2 (e.g., ciprofloxacin, fluvoxamine, tacrine, zileuton) or CYP2C9 (e.g., fluconazole) and should be used with caution in patients with liver dysfunction
    • The CYP inducer rifampin markedly reduces the plasma levels of both Ramelteon and its active metabolite
  42. Ramelteon Pharmacological Effects
    • In polysomnography studies of patients with chronic insomnia, Ramelteon reduced the latency of persistent sleep with no effects on sleep architecture and no rebound insomnia or significant withdrawal symptoms
    • Adverse effects: Dizziness, somnolence, fatigue, and endocrine changes as well as decreases in testosterone and increases in prolactin Ramelteon is not a controlled substance
  43. Buspirone MOA
    • Does not interact directly with GABAergic system
    • No action on BZ sites or at GABAA receptors site
    • Partial agonist at brain presynaptic 5-HT1A receptors in the dorsal raphe and on postsynaptic neurons in the hippocampus, thus inhibiting the firing rate of 5-HT-containing neurons in the dorsal raphe
    • The net result of buspirone actions is that serotonergic activity is suppressed while noradrenergic and dopaminergic cell firing is enhanced
  44. Buspirone PK
    • Rapidly absorbed orally but undergoes extensive first-pass metabolism via hydroxylation and dealkylation reactions to form several active metabolites
    • The major metabolite is 1-(2-pyrimidyl)-piperazine (1-PP), which has  an α2-adrenoceptor-blocking actions and enters in the central nervous system to reach higher levels than the parent drug
    • The elimination half-life of buspirone is 2–4 hours, and liver dysfunction may slow its clearance
    • Rifampin, an inducer of cytochrome P450, decreases the half-life of buspirone
    • Inhibitors of CYP3A4 (e.g., erythromycin, ketoconazole, grapefruit juice, nefazodone) can markedly increase its plasma levels
  45. Buspirone Pharmacological/Clinical Effects
    • Less psychomotor impairment than benzodiazepines and does not affect driving skills
    • No potentiation of conventional sedative-hypnotic drugs, ethanol, or tricyclic antidepressants
    • Unlike BZDs, elderly patients do not appear to be more sensitive to its actions
    • Nonspecific chest pain, tachycardia, palpitations, dizziness, nervousness, tinnitus, gastrointestinal distress, and paresthesias and a dose-dependent pupillary constriction may occur
    • Blood pressure may be significantly elevated in patients receiving MAO inhibitors
    • FDA category B drug in terms of its use in pregnancy
    • Selective anxiolytic effects, without causing marked sedative, hypnotic, or euphoric effects
    • No anticonvulsant or muscle relaxant properties
    • No rebound anxiety or withdrawal signs on abrupt discontinuance
    • Not effective in blocking the acute withdrawal syndrome resulting from abrupt cessation of use of BZDs or other sedative-hypnotics
    • Minimal abuse liability
    • In marked contrast to the BZDs, the anxiolytic effects of buspirone may take more than a week to become established, making the drug unsuitable for management of acute anxiety states
    • Used in generalized anxiety states but is less effective in panic disorders
Card Set
Sedatives / Hypnotics
IT 2 (MT 3): Sedatives / Hypnotics