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Transcript
Chapter 22: Sedative-hypnotic Drugs 1 Introduction • A sedative drug (anxiolytic) reduce anxiety and exert a calming effect • A hypnotic drug produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep • Most anxiolytic and sedative–hypnotic drugs produce dose-dependent depression of CNS function 2 CNS depression: dose-response curve Coma DRUG A CNS effects Anesthesia DRUG B Hypnosis Sedation Increasing dose 3 Sedative-hypnotics Benzodiazepines Short action Intermediate action Long action Barbiturates Miscellaneous agents Buspirone Ramelteon Zaleplon Zolpidem 4 Other drugs with sedative-hypnotic effects 1) β-blockers (e.g. Propranolol) 2) Antipsychotics 3) Antidepressants (e.g. SSRIs, venlafaxine, duloxetine & MAOIs) TCAs, 4) Antihistamines (e.g. Hydroxyzine, diphenhydramine, & doxylamine) 5 Benzodiazepines • Benzodiazepines are the most widely used anxiolytic drugs • They have largely replaced barbiturates and meprobamate in the treatment of anxiety, b/c they are safer and more effective • The most prominent of these effects are sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia, and anticonvulsant activity 6 Benzodiazepines- Mechanism of action • The targets for bzds actions are the γaminobutyric acid (GABAA) receptors • Bzds enhance the response to GABA by facilitating the opening of GABA-activated chloride channels • They bind specifically to a regulatory site of the receptor, distinct from the GABA-binding site, and act allosterically to increase the affinity of GABA for the receptor 7 GABA receptors • GABA receptors are membrane-bound proteins that can be divided into two major subtypes: GABAA and GABAB receptors • The ionotropic GABAA receptors are composed of five subunits that assembled from five subunits selected from multiple polypeptide classes (α, β, γ, δ, ε, ρ etc) to form an integral chloride channel • The GABAA-receptor (or recognition site), when coupled with GABA, induces a shift in membrane permeability, primarily to chloride ions, causing hyperpolarization of the neuron 8 GABA receptors • GABA receptor appears to be part of a macromolecule that contains, in addition to the GABAA-receptor, bzds and barbiturate binding sites and the chloride ionophore (chloride channel) • The bzds, barbiturates, alcohols, and general anesthetics appear to facilitate GABA transmission • Vigabatrin, an anticonvulsant, elevates brain GABA by inhibiting the breakdown enzyme GABA-T 10 Benzodiazepines- Mechanism of action • Bzds increase the efficiency of GABAergic synaptic inhibition • The enhancement in chloride ion conductance induced by the interaction of benzodiazepines with GABA takes the form of an increase in the frequency of channel-opening events 11 Benzodiazepines- Mechanism of action • Two benzodiazepine receptor subtypes commonly found in the CNS have been designated as BZ1 and BZ2 receptor depending on whether their composition includes the α1 subunit or the α2 subunit, respectively 12 Benzodiazepine Binding Site Ligands 1. Agonists: • Benzodiazepines: multiple BZ binding sites • Zolpidem, zaleplon, and eszopiclone: selective agonists at the BZ1 2. Antagonists: Flumazenil 3. Inverse agonists: β-carbolines, eg, nbutyl- β -carboline-3-carboxylate (β -CCB) 13 Benzodiazepines • The PK properties of the bzds affect their clinical utility • Bzds vary greatly in duration of action and can be roughly divided into: a. Short-acting b. Medium-acting c. Long-acting 14 Short acting (3-8 hours) :Oxazepam ,Triazolam Intermediate (6-24 hours):Alprazolam ,Lorazepam , Estazolam,Temazepam Long acting ( 24-72 hours):Chlorazepate ,Diazepam Chlordiazepoxide,Flurazepam ,Quazepam Benzodiazepines • Bzds are all metabolised both by dealkylation (phase 1) & conjugation (phase 2) reactions • The longer acting agents are converted in the liver to one or active metabolite, some with long halflives than the parant drug • The t1/2 of flurazepam in plasma is ∼2 hours, but that of a major active metabolite N-desalkylflurazepam is ∼50 hours • The short-acting compounds are metabolised directly by conjugation with glucuronide (e.g. oxazepam) 16 • Diazepam desmathyldiazepam oxazepam conjugation active metabolites 17 • Estazolam • Oxazepam immediately converted to inactive metabolites 18 Benzodiazepines • In very old patients and in patients with severe liver disease, the elimination half-lives of these drugs are often increased significantly • In such cases, multiple normal doses of these sedative-hypnotics can result in excessive CNS effects 19 Benzodiazepines • The distribution of the bzds from blood to tissues and back again is a dynamic process with considerable influence on the onset and duration of the action • Bzds having greater lipid solubility tend to enter the CNS more rapidly and thus tend to produce their effect quickly • Tissue redistribution (e.g., muscle and fat) is more rapid for drugs with the highest lipid solubility • These drugs cross the placental barrier and are secreted into breast milk 20 Organ Level Effects • The main effects of benzodiazepines are: 1) Reduction of anxiety (BZ2) 2) Sedation and induction of sleep (BZ1) 3) Reduction of muscle tone and coordination (BZ2 in the spinal cord) 4) Anticonvulsant effect (BZ1) 5) Anterograde amnesia (BZ1) 21 Clinical uses of benzodiazepines a. Treatment of anxiety state • The bzds are the most widely used drugs for the management of acute and chronic anxiety b/c of their: 1) Rapid onset of action 2) Relatively high therapeutic 3) Availability of flumazenil for treatment of overdose 4) Low risk of drug interactions 5) Minimal effects on CV or ANS 22 Clinical uses of benzodiazepines a. Treatment of anxiety state • For most types of anxiety, none of the bzds is therapeutically superior to any other • They should be reserved for continued severe anxiety, and then should only be used for short periods of time because of their addiction potential • The antianxiety effects of the bzds are less subject to tolerance than the sedative and hypnotic effects 23 Clinical uses of benzodiazepines a. Treatment of anxiety state • Choice of a particular agent is usually made on the basis of pharmacokinetic: The longer-acting agents: preferred when anxiety is intense and sustained/ prolonged The short-acting agents: advantageous when the anxiety is provoked by clearly defined circumstances and is likely to be of short duration 24 Clinical uses of benzodiazepines A. Treatment of anxiety state • Alprazolam is particularly effective in treatment of panic disorders & agoraphobia & is more selective in than other BDZs 25 Clinical uses of benzodiazepines B. Treatment of sleep disorders • An ideal hypnotic agent would have: 1) A rapid onset of action when taken at bedtime 2) A sufficient duration of action to facilitate sleep throughout the night 3) A minimal "hangover" effects the following day • Commonly prescribed bzds for sleep disorders include long-acting flurazepam, intermediateacting temazepam, and short-acting triazolam 26 Clinical uses of benzodiazepines B. Treatment of sleep disorders • The choice of a particular bzd to treat a sleep disturbance is generally based on PK criteria: Long-acting compounds (e.g. flurazepam) may ensure that a patient will sleep through the night, they also may cause cumulative effects resulting in daytime sluggishness or drug hangover Short-acting compounds (e.g. triazolam) avoid the hangover problem, but their use may be associated with early awakening and an increase in daytime anxiety 27 Clinical uses of benzodiazepines C. Other Therapeutic Uses 1. Seizures 2. Anesthesia & Amnesia (Midazolam) • Bzds have the capacity to cause anterograde amnesia and often used as premedication for anxiety-provoking and unpleasant procedures, such as endoscopic, bronchoscopic, and certain dental procedures as well as angioplasty • They also cause a form of conscious sedation, allowing the person to be receptive to instructions during these procedures 28 Clinical uses of benzodiazepines C. Other Therapeutic Uses 3. Alcohol and Sedative–Hypnotic Withdrawal • Cross-dependence, defined as the ability of one drug to suppress abstinence symptoms from discontinuance of another drug, is quite marked among sedative-hypnotics • Longer-acting drugs such as chlordiazepoxide, diazepam, and phenobarbital can be used to alleviate withdrawal symptoms of shorter-acting drugs, including ethanol 29 Clinical uses of sedative-hypnotics C. Other Therapeutic Uses 4. Muscle Relaxation • Diazepam is useful in the treatment of skeletal muscle spasms, such as occur in muscle strain, and in treating spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy (CP) 30 Tolerance and Dependence • Tolerance: decrease responsiveness to drug following repeated exposure • It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep • Tolerance is barbiturates less marked than it is • The development of tolerance has associated with down-regulation of benzodiazepine receptors (PD tolerance) with been brain 32 Tolerance and Dependence • Dependence on bzds can develop if high doses of the drugs are given over prolonged period • Abrupt withdrawal is associated with withdrawal symptoms, including rebound insomnia & rebound anxiety, which may even exceed that which preceded the treatment • A gradual tapering of the dose until it is eventually discontinued lessens the likelihood of a withdrawal reactions 33 Tolerance and Dependence • Differences in the severity of withdrawal symptoms resulting from individual bzds relate in part to half-life: Bzds with long half-lives (e.g. Flurazepam): withdrawal symptoms occur slowely with few physical symptoms and last a number of days after discontinuation Bzds with short half-lives (e.g. Triazolam): induce more abrupt and severe withdrawal reactions 34 Adverse effects • • Dose-dependents CNS depression: Most common adverse effects associated with use of bzds • Include: drowsiness, excessive sedation, impaired motor coordination, ataxia, confusion, and memory loss, and cognitive impairment 35 Adverse Effect • Overdoses with the bzds occur commonly, but fatal toxic occurrences are rare • Fatal intoxications are more likely in children, in individuals with respiratory difficulties, and in individuals who have consumed another CNS depressant (e.g. Alcohol) 36 Drug interactions 1. Pharmacodynamic interactions: • Additive effect with other CNS depressants which can lead to serious consequences, including enhanced depression 37 Drug interactions 2. Pharmacokinetic interactions: • Many bzds are metabolized by the CYP3A4 • Coadministration of CYP3A4 inhibitors (e.g. grapefruit juice, ketoconazole, itraconazole, erythromycin) result in intensification and prolongation of the bzd • Coadministration of CYP3A4 inducers (e.g. rifampin, carbamazepine, and phenytoin) can reduce the therapeutic effect of bzds 38 Flumazenil: Benzodiazepine antagonist • Flumazenil is a competitive antagonists of bzds that can rapidly reverse the effects of benzodiazepines • The drug is available for IV administration only • Onset is rapid but duration is short, with a half-life of about 1 hour • Frequent administration may be necessary to maintain reversal of a long-acting bzd 39 Flumazenil: Benzodiazepine antagonist • Adverse effects: oAgitation, confusion, dizziness, and nausea oSevere precipitated abstinence syndrome in patients who have developed physiologic benzodiazepine dependence oIn patients who have ingested bzds with TCA, seizures and cardiac arrhythmias may follow flumazenil administration 40 Barbiturates • The barbiturates were formerly the mainstay of treatment to sedate the patient or to induce and maintain sleep • Today, they have been largely replaced by the bzds, primarily because they: a) b) c) d) Induce tolerance Induce drug-metabolizing enzymes Physical dependence Associated with very severe withdrawal symptoms e) Ability to cause coma in toxic doses 41 Barbiturates- Mechanism of action • Barbiturates—in contrast to bzds— appear to increase the duration of the GABA-gated chloride channel openings • At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride channels • These effects involve a binding site or sites distinct from the bzd binding sites 42 Barbiturates- Mechanism of action • Barbiturates are less selective in their actions than bzds, because they also depress the actions of the excitatory neurotransmitter glutamic acid via binding to the AMPA receptor • The multiplicity of sites of action of barbiturates may be the basis for their ability to induce full surgical anesthesia and for their more pronounced central depressant effects compared with bzds and the newer hypnotics 43 Organ Level Effects • The main effects of barbiturates are: 1) 2) 3) 4) Reduction of anxiety Sedation and induction of sleep Anticonvulsant effect Dose -dependent respiratory depression espically in patients with pulmonary disease 5) CV depression1,which is most evident in patients hypovolemic states, HF, and other diseases that impair CV function • Respiratory and CV effects are more marked when are given IV 44 Clinical uses 1) Anesthesia: Selection is strongly influenced by the desired duration of action. The ultrashortacting barbiturate, thiopental, is used IV to induce anesthesia 2) Anticonvulsant: Phenobarbital has specific anticonvulsant activity that is distinguished from the nonspecific CNS depression 3) Antxiety and hypnosis (secobarbital): most have been replaced by the bzds 45 Tolerance and Dependence • Metabolic tolerance: an increase in the rate of drug metabolism in the case of chronic administration of barbiturates contributes to the decreased effect • Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest • Withdrawal is much more severe than that associated with opiates and can result in death 46 Adverse effects 1) CNS: Barbiturates cause drowsiness, impaired concentration, and mental and physical sluggishness 2) Poisoning: associated with severe depression of respiration is coupled with central CV depression, and results in a shock-like condition with shallow, infrequent breathing • Barbiturates increase porphyrin synthesis, and are contraindicated in patients with acute intermittent porphyria 47 Drug interactions 1) PD interactions: barbiturates combine with other CNS depressants cause severe CNS depression, especially ethanol 2) PK interactions: • Barbiturates induce hepatic CYP450: chronic administration diminishes the action of many drugs that are dependent on CYP450 metabolism to reduce their concentration (e.g. dicumarol, phenytoin, digitalis compounds, & griseofulvin) 48 Other Sedative-Hypnotic Agents 1. Benzodiazepine-Receptor Agonists • Agents: Zolpidem, zaleplon, & eszopiclone • Are structurally unrelated to bzds but share a similar mechanism of action • They act on a subset of the benzodiazepine receptor family, BZ1 • Compared with the bzds, they have relatively weak anxiolytic, anticonvulsant, and skeletal muscle relaxant properties at therapeutic doses 49 Other Sedative-Hypnotic Agents 1. Benzodiazepine-Receptor Agonists • They have efficacies similar to those of the hypnotic bzds in the management of sleep disorders, with few withdrawal effects and minimal rebound insomnia • Little or no tolerance and dependence with prolonged use 50 Other Sedative-Hypnotic Agents 1. Benzodiazepine-Receptor Agonists • ADEs: GIT upset and CNS (dizziness, drowsiness, nightmares, headache, agitation) • Eszopiclone ADEs: dry mouth, peripheral edema, and unpleasant taste 51 Other Sedative-Hypnotic Agents 2. Buspirone • Buspirone exert its anxiolytic effects by acting as a partial agonist at brain 5-HT1A • In therapeutic doses, buspirone relieves anxiety with little or no sedative effect and lacks anticonvulsant or muscle relaxant properties of bzds 52 Other Sedative-Hypnotic Agents 2. Buspirone • Buspirone-treated patients show no withdrawal signs on abrupt discontinuance • Buspirone causes less psychomotor impairment than bzds, and does not affect driving skills • Buspirone has the disadvantage of a slow onset of action, making the drug unsuitable for management of acute anxiety states 53 Other Sedative-Hypnotic Agents 2. Buspirone • It does not potentiate effects of conventional sedative-hypnotic drugs, ethanol, or TCA, and elderly patients do not appear to be more sensitive to its actions • The frequency of ADEs is low, with the most common effects being headaches, dizziness, nervousness, and light-headedness • BP may be significantly elevated in patients receiving MAO inhibitors 54 Other Sedative-Hypnotic Agents 3. Ramelteon • It is a selective agonist at the MT1 and MT2 subtypes of melatonin receptors • It is indicated for the treatment of insomnia in which falling asleep is the primary complaint • ADRs: dizziness, somnolence, fatigue, decreases in testosterone and increases in prolactin 55