Chapter 22: Sedative-Hypnotic Drugs 2024 PDF

CHAPTER 22: SEDATIVE-HYPNOTIC DRUGS Second-Semester-2024 Anxiolytic Normal CNS activity Sedative Hypnotic General Anaesthetic...

CHAPTER 22: SEDATIVE-HYPNOTIC DRUGS Second-Semester-2024 Anxiolytic Normal CNS activity Sedative Hypnotic General Anaesthetic Coma 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 ❑ Hypnosis involves more pronounced CNS depression…achieved by increasing the dose Most anxiolytic and sedative–hypnotic drugs produce dose-dependent depression of CNS function Sedative-Hypnotics The main group of drugs are as follows: o Benzodiazepines (anxiolytic and hypnotic) o Barbiturates (their used is now confined to anesthesia and epilepsy) o Miscellaneous agents Dose-response curves for Barbiturates vs BZD Other drugs with sedative-hypnotic effects 1) β-blockers (e.g. Propranolol) 2) Antipsychotics 3) Antidepressants (e.g. SSRIs, TCAs, venlafaxine, duloxetine & MAOIs) 4) Antihistamines (e.g. Hydroxyzine, diphenhydramine, & doxylamine) 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 Mechanism of action Their targets of actions are the γ-aminobutyric acid (GABAA) receptors (bzns, barbs, eszopiclone, zolpidem, zaleplon) 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 (α1 & β2 subunits) (α1 & γ2 subunits) 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  No change in the conductance or mean open time  Bzds do not affect receptors for other amino acids such as glycine and glutamate  GABA receptors  GABA receptors are membrane-bound proteins divided into two major subtypes: GABAA and GABAB receptors  The ionotropic GABAA receptors has a pentameric structure assembled from five subunits selected from multiple polypeptide classes (α, β, γ, δ, ε, ρ etc) to form an integral chloride channel  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 Benzodiazepines- Mechanism of action  Major isoform of the GABAA receptor found in many regions of the brain consists of two α1 subunits, two β2 subunits, and one γ2 subunit  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 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)  zolpidem, zaleplon, and eszopiclone bind more selectively because these drugs interact only with GABAA-receptor isoforms that contain α1 subunits  In contrast to GABA itself, sedative-hypnotics have a low affinity for GABAB receptors (spasmolytic baclofen) Benzodiazepine Binding Site Ligands 1. Agonists: ◼ Benzodiazepines: multiple BZ binding sites ◼ Zolpidem, zaleplon, and eszopiclone: selective agonists at the BZ1 2. Antagonists: Flumazenil (blocks the actions of bzd, zolpidem, zaleplon….but not that of barbiturates) 3. Inverse agonists: negative allosteric modulators of GABA-receptor function can produce anxiety and seizures….β-carbolines, (eg, n-butyl- β -carboline-3- carboxylate (β -CCB)) Benzodiazepines….PK  The PK properties of the bzds affect their clinical utility  Bzds vary greatly in duration of action and can be roughly divided into: long, intermediate and short acting  Benzodiazepines…..PK  Absorption:Bzds with greater lipid solubility tend to enter the CNS more rapidly and thus tend to produce their effect quickly  Distribution:These drugs cross the placental barrier and are secreted into breast milk…..depression of neonatal vital functions if given during pre-delivery period  Tissue redistribution (e.g., muscle and fat) is more rapid for drugs with the highest lipid solubility  Metabolism and Excretion: Biotransformation to more water- soluble metabolites is necessary for clearance of sedative- hypnotics…..metabolised by dealkylation (phase 1) & conjugation (phase 2) reactions  Benzodiazepines…..PK  The longer acting agents are converted in the liver to one or active metabolite, some with long half-lives than the parent drug…..  The t1/2 of desmethyldiazepam (Nordazepam)in plasma is ∼40 hours  Alprazolam & triazolam…are short-acting compounds metabolized directly by glucuronidation  Benzodiazepines with long half-lives are more likely to cause cumulative effects with multiple doses…..less a problem with short half-lives drugs (estazolam, oxazepam, and lorazepam) Benzodiazepines…..PK  The metabolism of several commonly used benzodiazepines is affected by inhibitors and inducers of hepatic P450 isozymes  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  Organ Level Effects….. 1.Anti-anxiety and Sedation: exert calming effects with concomitant reduction of anxiety at relatively low doses. Accompanied by some depression on psychomotor and cognitive functions 2. Hypnosis: by definition, all of the sedative-hypnotics induce sleep if high enough doses are given BZD decrease the latency of sleep onset Organ Level Effects….. ❖ Anxiolytic effects are mediated by GABAA receptors containing the α2 subunit, while hypnosis and anticonvulsant occur through those with the α1 subunit. 3. Anesthesia: at higher doses depress the CNS causing general anesthesia Thiopental and methohexital very lipid-soluble, penetrate brain tissue rapidly used IV for the induction of anesthesia Diazepam (LA), lorazepam(IA), midazolam (SA)(BZD)—used IV in anesthesia Such depressant actions of benzodiazepines are usually reversible with flumazenil  Organ Level Effects ….. 4. Anticonvulsant Effects: capable to inhibit the development and spread of electrical activity in the CNS Bzd (Clonazepam-absence seizure) and barbiturates (Phenobarbital-Tonic-Clonic seizure) are effective in tx of seizures 4. Muscle Relaxation: exert inhibitory effects on polysynaptic reflexes and at high doses may also depress transmission at the skeletal neuromuscular junction Observed with meprobamate, Bzd 5. Anterograde amnesia: Benzodiazepines prevent memory of events experienced while under their influence, an effect not seen with other CNS depressants Organ Level Effects ….. This point is exclusive to Barbiturates 6. Generalised CNS inhibition and Effects on Respiration and Cardiovascular Function (including medullary centre): At therapeutic doses can produce significant respiratory depression in patients with pulmonary disease….depression of the medullary respiratory center….common cause of death in overdoses In hypovolemic states, heart failure, and other diseases that impair cardiovascular function, normal doses of sedative- hypnotics may cause cardiovascular depression Unwanted effects of BZD These may be divided into:  Tolerance and dependence  Toxic effects resulting from acute overdosage  Unwanted effects occurring during normal therapeutic use (memory disturbances, some depression on psychomotor and cognitive functions)  Tolerance and Dependence  Tolerance: decrease responsiveness to a drug following repeated exposure – a common feature of sedative-hypnotics  It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep  Tolerance is less marked than it is with barbiturates  The development of tolerance has been associated with the down- regulation of brain benzodiazepine receptors (PD tolerance- decrease the sensitivity of GABA-A receptor OR increases sensitivity of excitatory transmitters such as NMDA glutamate receptor)  An increase in the rate of drug metabolism (PK/metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates Tolerance and Dependence  Dependence can develop if high doses of the drugs are given over prolonged period  The consequences of abuse of these agents can be defined in both psychologic and physiologic terms  Abrupt withdrawal is associated with withdrawal symptoms: rebound insomnia & anxiety, and central nervous system excitability that may progress to convulsions……gradual tapering of the dose  Hangover: (Residual effect) A state of psychomotor depression occurs in the following day after the use of a long-acting (LA) drug.  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 slowly with few physical symptoms and last several days after discontinuation ❖ Bzds with short half-lives (e.g. Triazolam): induce more abrupt and severe withdrawal reactions Tolerance and Dependence  Abrupt withdrawal from BZD/barbiturates may cause tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest  Abrupt cessation of zolpidem, zaleplon, or eszopiclone may also result in withdrawal symptoms, though usually of less intensity than those seen with bzds Adverse effects  Dose-dependents CNS depression:  This is the most common adverse effects  Include: drowsiness, impaired judgment, and diminished motor skills, sometimes with a significant impact on driving ability, job performance, and personal relationships  Barbiturates increase porphyrin synthesis, and are contraindicated in patients with acute intermittent porphyria  Toxic effects resulting from acute overdosage Overdoses  Overdoses of barbitutares are associated with severe respiratory and central CV depression  Overdoses with the bzds occur commonly, but fatal toxic occurrences are rare…..  …..more likely to occur in children, in individuals with respiratory difficulties, or have consumed another CNS depressant (e.g. Alcohol) Toxic effects resulting from acute overdosage Flumazenil: Benzodiazepine antagonist  Flumazenil is a competitive antagonist of bzds that can rapidly reverse the sedative effects of benzodiazepines, zolpidem, zaleplon, and eszopiclone (overdose)  The drug is available for IV administration only  Onset is rapid, but duration is short, with a half-life of about 1 hour due to extensive hepatic clearance  Frequent administration may be necessary to maintain reversal of a long-acting bzd Flumazenil: Benzodiazepine antagonist  Adverse effects: o Agitation, confusion, dizziness, and nausea o Severe precipitated abstinence syndrome in patients who have developed physiologic benzodiazepine dependence o Precipitation of seizures and cardiac arrhythmias may follow flumazenil administration Drug interactions 1) PD interactions: Additive effect with other CNS depressants, which can lead to serious consequences, including enhanced CNS depression (ethanol)  Drug interactions 2. PK interactions:  Many bzds are metabolized by the CYP3A4  CYP3A4 inhibitors (e.g. grapefruit juice, ketoconazole, itraconazole, erythromycin) result in intensification and prolongation of the bzd  CYP3A4 inducers (e.g. rifampin, carbamazepine, and phenytoin) can reduce the therapeutic effect of bzds  Barbiturates induce hepatic CYP450: chronic administration diminishes the action of many drugs dependent on CYP450 metabolism (e.g. dicumarol, phenytoin, digitalis compounds, & griseofulvin) Barbiturates Dose-response curves for Barbiturates vs BZD  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  Barbiturates- Mechanism of action  Barbiturates are less selective in their actions, they also depress the actions of the excitatory neurotransmitter glutamic acid via binding to the glutamate 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  Barbiturates…..PK  Metabolism in the liver --→ inactive metabolite unlike BZD  The major metabolic pathways involve oxidation by hepatic enzymes and glucuronidation….the conjugates appear in the urine  The overall rate of hepatic metabolism in humans depends on the individual drug but (except the thiobarbiturates) is usually slow  T1/2 of secobarbital and pentobarbital range 18-48hrs in different individuals. Phenobarbital T1/2 is 4–5 days Contraindications 1. Severe respiratory insufficiency 2. Sleep apnea syndrome 3. Acute narrow-angle glaucoma 4. Pregnancy Other Sedative-Hypnotic Agents  Other Sedative-Hypnotic Agents 1. Non-Benzodiazepine- (Z Hypnotics)  Agents: Zolpidem, zaleplon, & eszopicolone (used for insomnia)  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  Z-Hypnotic Agents  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  Z-hypnotic…..PK  Zolpidem and Zaleplon are rapidly metabolized to inactive metabolites by hepatic CYP3A4  Eszopiclone is metabolised by hepatic cytochromes to form the inactive derivative and weakly active desmethyleszopiclone (longer duration of action)  Dosage should be reduced in patients with hepatic impairment and in elderly  Inhibitors of CYP3A4 (eg, ketoconazole) may prolong t1/2 while inducers of CYP3A4 (eg, rifampin) increase the hepatic metabolism  Adverse effect of Z-Hypnotic Agents  ADEs: GIT upset and CNS (dizziness, drowsiness, nightmares, headache, agitation)  Eszopiclone ADEs: dry mouth, peripheral edema, and unpleasant taste  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 hypnotic effect and lacks anticonvulsant or muscle relaxant properties of bzds  Other Sedative-Hypnotic Agents 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 (3–4 weeks), making the drug unsuitable for management of acute anxiety states  Other Sedative-Hypnotic Agents Buspirone  It does not potentiate effects of conventional sedative-hypnotic drugs, ethanol, or TCA, and is the anxiolytic of choice for elderly patients  The frequency of ADEs is low, with the most common effects being headaches, dizziness, nervousness, and light-headedness  Buspirone-PK  It is rapidly absorbed orally but undergoes extensive first-pass metabolism (CYP3A4 ).  The elimination half-life 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 (eg, erythromycin, ketoconazole, grapefruit juice, nefazodone) can markedly increase its plasma levels. Melatonin Ramelteon and Tasimelteon  Ramelteon and Tasimelteon are novel hypnotic drugs prescribed specifically for patients who have difficulty falling asleep.  It is an agonist at MT1 and MT2 melatonin receptors located in the suprachiasmatic nuclei of the brain Ramelteon and Tasimelteon  These drugs have no direct effects on GABAergic neurotransmission in the central nervous system.  The drug is 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 Ramelteon and Tasimelteon  Ramelteon 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  ADR: dizziness, somnolence, fatigue, and endocrine changes.  Clinical uses of BZD and Barbiturates a. Treatment of anxiety state (BDZ>>>>Barbiturates)  The BZDs are widely used for the management of acute anxiety states and for rapid control of panic attacks. They are also used, though less commonly, in the long-term management of generalised anxiety disorder (GAD).  They replaced the barbiturates because: 1) Rapid onset of action 2) Relatively high therapeutic index 3) Availability of flumazenil for treatment of overdose 4) Low risk of drug interactions 5) Minimal effects on CV or ANS Clinical uses Treatment of anxiety state  Although it is difficult to demonstrate the superiority of one drug over another, alprazolam and clonazepam have greater efficacy than other benzodiazepines in the longer term treatment of panic and phobic disorders.  These drugs should be reserved for severe anxiety only and not used to manage the stress of everyday life. Because of their addiction potential, they should only be used for short periods of time.  The antianxiety effects of the bzds are less subject to tolerance than the hypnotic effects Clinical uses 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 Clinical uses a. Treatment of anxiety state  In the treatment of generalized anxiety disorders and certain phobias, newer antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are now considered by many authorities to be drugs of first choice. However, these agents have a slow onset of action and thus minimal effectiveness in acute anxiety states. Clinical uses  Sedative-hypnotics should be used with appropriate caution so as to minimize adverse effects  The patient should be warned of the possibility to avoid impairment of performance of any task requiring mental alertness and motor coordination  Some patients may tolerate the drug better if most of the daily dose is given at bedtime for the shortest period (2 months)  Combinations of antianxiety agents should be avoided.  Cautious with consumption of alcohol or concurrent use of OTC antihistaminic or anticholinergic drugs Clinical uses B. Treatment of sleep disorders  True primary insomnia is rare  Useful non-pharmacologic therapies include proper diet and exercise, avoiding stimulants before retiring, ensuring a comfortable sleeping environment, and retiring at a regular time each night Clinical uses…. B. Treatment of sleep disorders  In some cases, however, the patient will need and should be given a sedative-hypnotic for a limited period.  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  Clinical uses 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 ❖ Note that sedative-hypnotic drugs are not recommended for breathing-related sleep disorders, eg, sleep apnea  Clinical uses B. Treatment of sleep disorders ❖ More recently there has been increasing use of zolpidem, zaleplon, and eszopiclone in insomnia, since they have rapid onset with minimal effects on sleep patterns and cause less daytime cognitive impairment than benzodiazepines Clinical uses  Anticonvulsant: Phenobarbital has specific anticonvulsant activity that is distinguished from the nonspecific CNS depression  Anesthesia: Selection is strongly influenced by the desired duration of action. The ultrashort-acting barbiturate, thiopental, is used IV to induce anesthesia Clinical uses  Amnesia (Midazolam)  Bzds have the capacity to cause anterograde amnesia and often used as premedication for anxiety-provoking and unpleasant procedures, such as endoscopic, 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  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 Clinical uses of benzodiazepines 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)