Sedative-Hypnotic Drugs PDF

Central Nervous system pharmacology for medical students Sedative-hypnotic drugs 1 Abenezer Aklog (B.Pharm, MSc.) Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic Drugs 2  A sedative drug...

Central Nervous system pharmacology for medical students Sedative-hypnotic drugs 1 Abenezer Aklog (B.Pharm, MSc.) Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic Drugs 2  A sedative drug (aka Anxiolytic) decreases activity, moderates excitement, and calms the recipient  Commonly used in the management of Anxiety  Anxiety is an unpleasant state of tension, apprehension, or uneasiness mostly to perceived threat GAD, Panic Disorder, SAD, PTSD, OCD  A hypnotic drug produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep  Hypnotic effects involve more pronounced depression of the CNS than sedation  This can be achieved simply by increasing the dose of sedative- hypnotic drug Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 3  Sedatives produce therapeutic effects at concentrations lower than those causing substantial CNS depression  E.g. Benzodiazepine sedative-hypnotics do not produce generalized CNS depression (like surgical anesthesia, or respiratory depression) Important exception is midazolam (dec. tidal volume and RR)  Whereas, older sedative-hypnotics, like barbiturates, produce a dose dependent generalized depression that may even lead to Dose-response curves for two death hypothetical sedative-hypnotics. Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 4  Benzodiazepines (BZDs)  Promote the binding of the major inhibitory neurotransmitter GABA to the GABAA receptor  A number of distinct mechanisms of action, reflecting involvement of specific subunits of the GABAA receptor  Likely contribute to distinct effects of various benzodiazepines Sedative-hypnotic, Muscle-relaxant, Amnesic, and Anticonvulsant effects Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 5  Benzodiazepines (BZDs) Examples of BZDs o “Azepam”s o “Azolam”s Chlordiazepoxide Diazepam Midazolam Clorazepate Lorazepam Alprazolam Clonazepam Triazolam Flurazepam Estazolam Oxazepam Quazepam Temazepam Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 6  Benzodiazepines (BZDs)  Mechanism of Action  Are allosteric modulators of GABAA receptor function  Enhance GABA binding and increase Cl- conductance resulting in hyperpolarization and decrease in synaptic transmission  BZDs intensify GABA mediated increase in Cl- conductance (by inc frequency of channel opening)  GABAA R has 5subunits (most are composed of 2α1, 2β2, and 1γ2)  GABA binds between adjacent α1 and β2 subunits  BZDs bind between adjacent α1 and γ2 subunits Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 7  Benzodiazepines (BZDs)  Mechanism of Action  In pharmacodynamic terms, agonists at the BZD binding site shift the GABA concentration-response curve to the left  BZD effects depend on the presynaptic release of GABA;  In the absence of GABA, BZDs have no effects on GABAA receptor function Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 8  Benzodiazepines (BZDs)  Pharmacokinetics  All BZDs are absorbed completely except clorazepate  Clorazepate, a prodrug, is converted to its active form nordiazepam by acid hydrolysis in the stomach which is then absorbed  Rate of oral absorption is affected by many factors including lipophilicity  Absorption of triazolam, diazepam, and nordiazepam is more rapid  Lipid solubility also plays a major role in determining the rate at which a BZDs enters the CNS  Highly lipophilic agents have rapid onset of action Sedative-Hypnotic Drugs Abenezer Aklog 9 Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 10  Benzodiazepines (BZDs)  Pharmacokinetics  Hepatic metabolism accounts for the clearance of all BZDs  Metabolism takes place both by dealkylation (phase 1 especially by CYP 3A4) and conjugation (phase 2) reactions  Oxazepam, lorazepam are directly conjugated by phase2 enzymes  Many phase I metabolites of BZDs are pharmacologically active, some with long half-lives  Desmethyldiazepam (t1/2>40hrs) is an active metabolite of diazepam, chlordiazepoxide, prazepam, and clorazepate Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 11  Benzodiazepines (BZDs)  Pharmacokinetics Biotransformation of benzodiazepines. Boldface, drugs available for clinical use in various countries;*, active metabolite. Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 12  Benzodiazepines (BZDs)  System effects o CNS effects  Reduction of anxiety and aggression- at low doses  Induction of sleep- at high doses  Reduction of muscle tone and coordination  Anticonvulsant effects o CVS  When BZPs are given per orally –no effect on HR and BP  However, after IV route they cause profound hypotension and cardiac arrest Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 13  Benzodiazepines (BZDs)  System effects o Respiratory effects  They have little respiratory depression when used alone w/out CNS depressant  However, it exacerbate some respiratory disorder such: Hypoventilation and hypoxemia-in patients with COPD Apnea (pause in breathing) o Skeletal muscle  They cause relaxation of skeletal muscle Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 14  Benzodiazepines (BZDs)  Clinical Uses o Anxiety  Effective in the management of acute anxiety states  They reduce anxiety through their effects on the limbic system, a neuronal network associated with emotionality o Insomnia  Decrease latency time to falling asleep, reduce awakenings, and increase total sleeping time  Promote sleep through effect on cortical areas and the sleep- wakefulness clock  Triazolam, Temazepam, Flurazepam, Estazolam Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 15  Benzodiazepines (BZDs)  Clinical Uses o Amnesia  Shorter-acting agents are often employed as premedication for anxiety-provoking and unpleasant procedures (e.g. Endoscopy)  Resulted from effect on hippocampus and cerebral cortex o Acute alcohol withdrawal- Alleviate the withdraw syndromes  BZDs’ benefits derived from cross-tolerance with alcohol  Reduce the risk of withdrawal-related seizures  Chlordiazepoxide, Clorazepate, Diaz, Loraz, and Oxazepam Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 16  Benzodiazepines (BZDs)  Clinical Uses o Seizure/Epilepsy  Inhibit the development and spread of epileptiform electrical activity in the CNS  Clonazepam (seizure), Lorazepam, and Diazepam (Status Epilepticus) o Muscular disorders  Relaxing the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord and cerebellum  Diazepam Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 17  Benzodiazepines (BZDs)  Side Effects  Hypnotic doses of cause varying degrees of  Light-headedness, lassitude, increased reaction time  Motor incoordination, impairment of mental and motor functions, confusion, and anterograde amnesia Impair driving and other psychomotor skills, especially if combined with ethanol  Other common side effects  Weakness, headache, blurred vision, vertigo, nausea and vomiting, epigastric distress Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 18 Novel Benzodiazepine Receptor Agonists  Hypnotics in this class are commonly referred to as “Z compounds” Zolpidem, Zaleplon, and EsZopiclone  Z compounds are structurally unrelated to each other and to BZDs  But therapeutic efficacy as hypnotics is due to agonist effects at the BZD site of the GABAA receptor  Z compounds are less effective as anticonvulsants or muscle relaxants  May be due to selectivity for GABAA receptors containing the α1 subunit  Have replaced BZDs for the treatment of insomnia Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 19 Novel Benzodiazepine Receptor Agonists  Zaleplon  Bind to GABAA receptors containing the α1 receptor subunit  Decreases the latency of sleep onset with little effect on total sleep time (t1/2 is short)  FDA-approved for use up to 7–10 days at a time  Has sustained hypnotic efficacy without occurrence of rebound insomnia on abrupt discontinuation  Not associated with morning sedation, delayed reaction time, and anterograde amnesia at therapeutic doses Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 20 Novel Benzodiazepine Receptor Agonists  Zaleplon  Pharmacokinetics  Absorbed rapidly and reaches peak plasma conce. in about 1h  Presystemic metabolism limits its bioavailability (BA-30%)  Metabolized largely by aldehyde oxidase and to a lesser extent by CYP3A4 and has shorter t1/2 (~1hr)  Cimetidine increases the peak plasma conce. of Zaleplon  Dosage should be reduced in patients with hepatic impairment and in the elderly Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 21 Novel Benzodiazepine Receptor Agonists  Zolpidem  Effective in shortening sleep latency and prolonging total sleep time in patients with insomnia (t1/2 is relatively long)  After D/C, the beneficial effects on sleep reportedly persist for up to 1week (with mild rebound insomnia on the 1st day of D/C)  Approved only for the short-term treatment of insomnia (7-10days)  Differ from Zaleplon in that late night admin. results in residual effects  Morning sedation, delayed reaction time, and anterograde amnesia Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 22 Novel Benzodiazepine Receptor Agonists  Zolpidem  Pharmacokinetics  Absorbed readily from the GI tract;  First-pass hepatic metabolism results in an bioavailability of ~70%  BA may decrease when the drug is ingested with food  Eliminated almost entirely by conversion to inactive products in the liver (CYP3A4)  Has a t1/2 of ~2hrs, which is sufficient to cover most of a typical 8hr sleep period Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 23 Novel Benzodiazepine Receptor Agonists  Eszopiclone  Used for the long-term (~12 months) treatment of insomnia, for sleep maintenance, and to decrease the latency to onset of sleep  No tolerance was observed, and no signs of serious withdrawal, such as seizures or rebound insomnia, were seen on D/C of the drug  Pharmacokinetics  Absorbed rapidly after oral administration (BA~80%)  50%–60% bound to plasma proteins (has large Vd)  Metabolized by CYPs 3A4 and 2E1, and has a t1/2 of about 6hr Sedative-Hypnotic Drugs Abenezer Aklog 24 Onset and duration of action of the commonly used nonbenzodiazepine hypnotic agents Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 25 Benzodiazepine Receptor Antagonist  Flumazenil  Binds with high affinity to the BZD binding site on the GABAA R  It competitively antagonizes the binding and allosteric effects of BZDs and other ligands (like “Z Cpds”)  Antagonizes both the electrophysiological and behavioral effects of agonist and inverse-agonist (β-Carboline)  Available only for intravenous administration (Oral BA only 25%)  Eliminated almost entirely by hepatic metabolism to inactive products with a t1/2 of about 1hr  Duration of clinical effects usually is only 30–60 min Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 26 Benzodiazepine Receptor Antagonist  Flumazenil  Primarily indicated for  Management of suspected benzodiazepine overdose and  Reversal of sedative effects produced by benzodiazepines  Because all BZDs have a longer duration of action than flumazenil  Sedation commonly recurs, requiring repeated administration  Seizures or other withdrawal signs may be precipitated in patients in whom tolerance or dependence may have developed  ADRs- Agitation, confusion, dizziness, and nausea Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 27 Benzodiazepine Overdose  May be intentional or secondary to accumulation of doses  Symptoms: somnolence, impaired coordination, slurred speech, diminished reflexes, confusion, respiratory depression, hypotension  Treatment options  Supportive and symptomatic care  Gastric lavage (removing poison from GIT)  Activated Charcoal (adsorb poisonous substance)  IV hydration and maintain adequate airway  IV Flumazenil:-1mg infused over 1-3min Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 28 Barbiturates  Once used extensively as sedative-hypnotic drugs  Largely replaced by much safer BZDs and Z cpds  Barbiturates induce Tolerance, Drug-metabolizing enzymes, Physical dependence, and Very severe withdrawal symptoms  Increase in lipid solubility of barbs decrease latency to onset of activity, Decrease duration of action Accelerate metabolic degradation, and increase hypnotic potency Sedative-Hypnotic Drugs Abenezer Aklog  THERAPEUTIC USES OF BARBITURATES 29 Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 30 Barbiturates  Pharmacological properties  Reversibly depress the activity of all excitable tissues in CNS  Direct effects on peripheral excitable tissues are weak  Pharmacokinetics  For sedative-hypnotic use, they usually are administered orally  Na+ salts are absorbed more rapidly than the corresponding free acids  Onset of action varies from 10 to 60 min and is delayed by the presence of food Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 31 Barbiturates  Pharmacokinetics  Intravenous route usually is reserved for  Management of status epilepticus (phenobarbital sodium) or  Induction/maintenance of general anesthesia (thiopental/methohexital)  Distribute widely in the body and readily cross the placenta  Can injure developing fetus and may cause dependence (3rd trimester)  Except for the less lipid-soluble aprobarbital and phenobarbital  Nearly complete metabolism or conjugation of barbiturates in the liver precedes their renal excretion Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 32 Barbiturates  Pharmacokinetics  Oxidation of radicals at C5 is the most important biotransformation that terminates biological activity  About 25% of phenobarbital and nearly all of aprobarbital are excreted unchanged in the urine  Renal excretion can be increased greatly by osmotic diuresis or alkalinization of the urine  t1/2 of biotransformable barbs increase in cirrhosis pts, elderly, infants, and pregnant woman  Repeated administration, especially of phenobarbital, shortens the t1/2 of barbiturates (b/c of induction of enzymes) Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 33 Barbiturates  Pharmacodynamics  Bind to a distinct allosteric site on the GABAA R and enhance inhibition of synaptic transmission mediated by GABA  Binding leads to an increase in the mean open time of Cl- channel  At higher conce., barbs directly activate channel opening, even in the absence of GABA  Also reportedly inhibit excitatory AMPA/kainate R and inhibit glutamate release (Via effect on VG Ca2+ channel) These multiple actions, may explain the potent CNS depressant effects of barbs compared to BZDs Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 34 Barbiturates  Pharmacodynamics o Effects in the CNS  Can produce all degrees of depression of the CNS, ranging from mild sedation to general anesthesia  Those containing a 5-phenyl substituent (e.g., phenobarbital and mephobarbital), have selective anticonvulsant activity  Except for anticonvulsant activity, they show low degree of selectivity and have low therapeutic index  Barbiturates increase reactions to painful stimuli Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 35 Barbiturates  Pharmacodynamics o Effects on stages of sleep  Hypnotic doses increase the total sleep time and alter the stages of sleep in a dose-dependent manner  Tolerance to the effects on sleep occurs within a few days  Rebound insomnia may occur up on discontinuation o Tolerance, Abuse, and Dependence  With chronic administration of gradually increasing doses, pharmacodynamics tolerance continues to develop over months  Readily to sedative, hypnotic, and euphoric effects than toxic effects Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 36 Barbiturates  Pharmacodynamics o Tolerance, Abuse, and Dependence  Pharmacodynamic tolerance to barbiturates confers cross-tolerance to all general CNS depressant drugs, including ethanol  Pharmacokinetic tolerance reaches its peak in a few days to a week  Increase in the rate of drug metabolism (metabolic tolerance)  Like other CNS depressant drugs, barbiturates are abused, and some individuals develop physical dependence  Perceived relief of anxiety, euphoria, disinhibition, and promotion of sleep Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 37 Barbiturates  Pharmacodynamics o Respiration  Only slightly depress protective reflexes until the degree of intoxication is sufficient to produce severe respiratory depression  Coughing, sneezing, hiccoughing, and laryngospasm may occur  Doses three times greater than that used normally to induce sleep  Eliminate neurogenic, hypoxic, and chemoreceptor drive for respiration o Cardiovascular system  Sedative/hypnotic doses don’t produce significant overt CV effect Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 38 Barbiturates  Pharmacodynamics o Cardiovascular system  Barbiturates can blunt cardiovascular reflexes by partial inhibition of ganglionic transmission  Other CV effects include a decrease in renal and cerebral blood flow with a marked fall in CSF pressure o GI Tract  Decrease the tone of the GI musculature and the amplitude of rhythmic contractions  A hypnotic dose doesn’t significantly delay gastric emptying Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 39 Barbiturates  Pharmacodynamics o Liver  Acutely, they inhibit the biotransformation of other drugs (Compete)  Chronic Admn. Increases the metabolism of drugs (Induction)  Glucuronic transferases and CYPs 1A2, 2C9, 2C19, and 3A4 o Kidney  Severe oliguria or anuria may occur in acute barbiturate poisoning largely as a result of the marked hypotension Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 40 Barbiturates  Side Effects  Residual CNS depression sometimes is evident the following day  Distorted Mood, impaired judgment and fine motor skill  Vertigo, N,V,D, and sometimes excitement  Allergic reactions occur, especially in persons with asthma, urticaria, angioedema, or similar conditions  Attributed to Histamine release from the mast cells  Absolutely contraindicated in pts with acute intermittent porphyria or porphyria variegata  Barbiturates enhance porphyrin synthesis Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 41 Barbiturates  Drug Interactions  Cause severe depression when combined with other CNS depressant  Ethanol, 1st gen. Antihistamine, and Antipsychotics  Isoniazid, Methylphenidate, MAOIs increase CNS depressant effect  Greatest number of DIs results from induction of hepatic CYPs  Endogenous steroid hormones- Endocrine disturbance  Oral contraceptives- unwanted pregnancy  Barbiturates also induce the hepatic generation of toxic metabolites of chlorocarbons  Facilitates periportal necrosis of the liver Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 42 Barbiturates  Barbiturate Poisoning  Most of the cases are the result of attempts at suicide  But some are from accidental poisonings in children or drug abusers  Severe poisoning likely occurs when >10 times the full hypnotic dose has been ingested at once  In severe intoxication  Patient is comatose; respiration is affected early (shallow breathing)  BP falls (Depression of cardiac contractility and sympathetic ganglia)  Pulmonary complications (atelectasis, edema, and bronchopneumonia)  Renal failure- fatal complications of barbs poisoning Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 43 Barbiturates  Treatment of acute Barbiturate Poisoning  Is based on general supportive measures  Use of CNS stimulants is contraindicated (inc. mortality rate)  Hypovolemia must be corrected, and if necessary, the BP can be supported with dopamine  If renal and cardiac functions are satisfactory, and the patient is hydrated  Forced diuresis and alkalinization of the urine will hasten the excretion of phenobarbital  Mechanical ventilation and hemodialysis –used when indicated Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 44 Miscellaneous Sedative-Hypnotic Drugs  Except ramelteon and meprobamate, the pharmacological action of paraldehyde and chloral hydrate resembles that of barbiturates  Are general CNS depressants that can produce profound hypnosis  Effects on the stages of sleep are similar to those of the barbiturates  Therapeutic indices are low, and acute intoxication, which produces respiratory depression and hypotension, are managed same as barbs  Chronic use can result in tolerance and physical dependence  Syndrome after chronic use can be severe and life threatening Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 45 Miscellaneous Sedative-Hypnotic Drugs  Buspirone  Has selective anxiolytic effects (mainly chronic treatment of GAD)  Relieves anxiety without causing marked sedative, hypnotic, or euphoric effects (has no muscle relaxant/anticonvulsant effect)  Exert its anxiolytic effects by acting as a partial agonist at brain 5- HT1A receptors (also has affinity for D2 R)  Has a slow onset of action and is not effective for acute anxiety state  Rapidly absorbed orally but undergoes extensive first-pass metabolism  Elimination half-life is 2-4hrs but increase with liver dysfunction Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 46 Melatonin Congeners  Melatonin is serotonin derivative (N-acetyl-5-methoxytryptamine)  Produced and released primarily at night from pineal gland  Play a role in the sleep-wake behavior of humans  In the brain, MT1 and MT2 receptors are found in the suprachiasmatic nucleus of the hypothalamus  Are seven-transmembrane Gi protein-coupled receptors  Activation of the MT1 receptor results in sleepiness,  Whereas the MT2 receptor may be related to the light-dark synchronization of the biologic circadian clock Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 47 Melatonin Congeners  Ramelteon  Synthetic tricyclic analogue of melatonin, approved in the U.S. for the treatment of insomnia, specifically difficulties of sleep onset  Has agonistic effect on both MT1 and MT2 R  Clinical Pharmacology  Prescribing guidelines suggest that an 8-mg tablet be taken about 30min before bedtime  Rapidly absorbed from the GI tract but has high first-pass effect Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 48 Melatonin Congeners  Ramelteon  Clinical Pharmacology  Largely metabolized by hepatic CYPs 1A2, 2C, and 3A4, with a t1/2 of about 2h  Fluvoxamine, strong inhibitors of CYP1A2, can increase the levels of ramelteon  Tolerance doesn’t develop to the sleep induction effect even after long periods of admn. (~6months)  No evidence of rebound insomnia and withdrawal effect  Ramelteon is not a controlled substance (no risk of dependence) Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 49 Miscellaneous Sedative-Hypnotic Drugs  Meprobamate  An antianxiety and sedative-hypnotic agent  Pharmacological actions resemble those of BZDs, although it can cause CNS depression, it cannot produce anesthesia  Have a mild analgesic effect in pts with musculoskeletal pain  Well absorbed when administered orally  Metabolized in the liver by hydroxylation and glucuronidation  Abrupt D/c evokes a withdrawal syndrome usually characterized by anxiety, insomnia, and tremors Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 50 Miscellaneous Sedative-Hypnotic Drugs  Other Agents  Etomidate- an IV anesthetic  Clomethiazole- has sedative, muscle relaxant, and anticonvulsant properties. High therapeutic index but affected by alcohol  Propofol- has profound use in intensive care sedation in adults  Non-prescription Hypnotic Drugs  Antihistamines diphenhydramine and doxylamine are FDA- approved as OTC sleep aids Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 51 Miscellaneous Sedative-Hypnotic Drugs  New and Emerging Agents  Suvorexant  Inhibitor of orexin 1 and 2 receptors (GPCRs) used to treat insomnia  Orexins are peptide NTs found in specific hypothalamic neurons  Involved in the control of wakefulness and that are silent during sleep  Orexins promote wakefulness, while antagonists at orexin receptors enhance REM and non-REM sleep  Should be taken within 30min of going to bed  Common adverse reaction is daytime somnolence Sedative-Hypnotic Drugs Abenezer Aklog  Sedative-Hypnotic cont... 52 Miscellaneous Sedative-Hypnotic Drugs  New and Emerging Agents  Doxepine- a tricyclic antidepressant  Indicated for the treatment of difficulties with sleep maintenance  Acts presumably via antagonism of H1 R function at low doses  Can worsen suicidal ideation and depression  Pregabalin  Anxiolytic agent that binds to Ca2+ channel  Used to manage insomnia in pts with GAD  For induction and maintenance of sleep Sedative-Hypnotic Drugs Abenezer Aklog 53 Sedative-Hypnotic Drugs Abenezer Aklog