Sedatives - Pharm Exam 2

Sedatives Overview ○ Sedative-hypnotic drugs are extremely common Sedative– calm, reduce anxiety Hypnotic – induce drowsiness and promote sleep ○ Causes sedation at regular doses, hypnosis at higher doses ○ Some agents only have a...

Sedatives Overview ○ Sedative-hypnotic drugs are extremely common Sedative– calm, reduce anxiety Hypnotic – induce drowsiness and promote sleep ○ Causes sedation at regular doses, hypnosis at higher doses ○ Some agents only have anxiolytic effects without sedation or hypnosis (e.g., buspirone aka BuSpar) Drug classes ○ Benzodiazepines (e.g., alprazolam aka Xanax) ○ Barbiturates (e.g., pentobarbital aka Nembutal) ○ Antihistamines (e.g., diphenhydramine aka Benadryl) ○ Misc, sedative-hypnotics (e.g., zolpidem aka Ambien) ○ Non-sedating anxiolytic drugs (e.g., buspirone aka BuSpar) Classification of anxiety ○ Acute anxiety ○ Panic disorder ○ Phobic disorders ○ obsessive - compulsive disorder (OCD) ○ Generalized anxiety disorder (GAD) ○ Post-traumatic stress disorder (PTSD) Panic disorders ○ Acute episodes of severe anxiety with marked psychological and physiologic symptoms ○ May feel impending sense of doom accompanied by sweating, tachycardia, tumor, etc ○ Often responds to treatment with benzodiazepine or an antidepressant (SSRIs) Alprazolam (Xanax®) and clonazepam (Klonopin®) are the most common benzodiazepines used. Fluoxetine (Prozac®) is the most common SSRI used OCD ○ Obsessions, which are recurring or persistent thoughts and impulses, as well as compulsions ○ Compulsions are repetitive behaviors in response to obsessions ○ Treated effectively with an antidepressant drug and psychotherapy Generalized anxiety disorder ○ Chronic worry and apprehension concerning future events ○ Benzodiazepines are used for short-term therapy, can be used intermittently, SSRIs and SNRIs are often used as well ○ Severity often fluctuates over time  ○ Buspirone (BuSpar®) provides a non-sedating alternative to benzodiazepines Sleep disorders Sleep stages ○ High-frequency, low-amplitude activity gradually diminishes during stages 1 and 2, gets replaced by low-frequency, high-amplitude activity of slow-wave sleep during stages 3 and 4 ○ Overtime, return to stage 1 and eventually REM stage ○ REM stage also called paradoxical, EEG pattern is similar to awake state A normal adult cycles through the sleep stages every 90 mins Sleep patterns ○ Drugs that treat insomnia ○ Benzodiazepines and most other hypnotics decrease sleep latency (time required to go to sleep) and increase sleep duration ○ Newer agents do not significantly impact sleep architecture and don’t cause as much tolerance and dependence Zolpidem (Ambien®), zaleplon (Sonata®), eszopiclone (Lunesta®), and ramelteon (Rozarem®) are the drugs of choice to treat most types of insomnia Other sleep disorders ○ Hypersomnia – difficulty awakening ○ Narcolepsy – sleep attacks ○ Enuresis – bedwetting during sleep ○ Somnambulism – sleepwalking ○ Nightmares/night terrors Sedative-hypnotic drugs Benzodiazepines have fewer adverse reactions and interactions than barbiturates, are safer in cases of overdose Barbiturates still used when benzodiazepines are ineffective or contraindicated Sedating antihistamines are occasionally used to treat mild insomnia and anxiety, have less potential for abuse  ○ Many OTC sleep aids contain antihistamines as their effective ingredient Benzodiazepines ○ Alprazolam aka Xanax® ○ Chlordiazepoxide aka Librium® ○ Clonazepam aka Klonopin® ○ Diazepam aka Valium® ○ Lorazepam aka Ativan® ○ Midazolam aka Versed® ○ Triazolam aka Halcion® ○ Flumazenil aka Romazicon® → reversal Mechanism of actions ○ Benzodiazepines (and barbiturates) exert effect on consciousness and sleep by facilitating activity of GABA at various sites ○ Benzodiazepines increase affinity of GABA for its binding site by increasing the frequency at which the ion channel opens (barbiturates increase the length of time the channel remains open) ○ Also inhibit neuronal reuptake of adenosine, may explain why these drugs dilate coronary arteries and decrease total peripheral resistance Pharmacologic effects ○ Can produce anterograde amnesia (i.e., won’t remember what happens from time drug is administered to time drug has dissipated) Occurs because they interfere with formation of new memory Doesn’t affect ability to recall past events ○ Useful for patients undergoing stressful procedures like endoscopy or outpatient surgery (e.g., wisdom tooth extraction ) Dependence ○ Long-term use can produce physical dependence ○ Severity of which is proportional to the dosage and duration of administration ○ After several months of use, most patients develop some degree of physical dependence ○ Withdrawal syndrome usually mild, not life threatening Abrupt withdrawal from alprazolam (Xanax®) has been associated with seizures. Gradually taper doses of benzodiazepines to prevent seizure Flumazenil (Romazicon) ○ Competitive benzodiazepine receptor antagonist ○ Counteracts adverse effects of benzodiazepines (i.e., respiratory depression resulting from IV administration or overdose of oral pills) ○ Given IV, has a rapid onset and short duration of action ○ Adverse effects include seizures, arrythmias, blurred vision, emotional lability, and dizziness  Alprazolam (xanax) ○ Medium duration of action, used primarily in management of anxiety ○ Special utility in treatment of panic disorder (larger doses required), so most patients will be treated with anti-depressants and behavioral therapy instead ○ Useful as short-term measure to relieve acute symptoms while other therapies are instituted Lorazepam (Ativan), oxazepam, temazepam ○ Short or medium duration of action ○ Preferable in treatment of elderly patients ○ Lorazepam can be administered orally or IV, used to treat anxiety and to control seizures ○ Oxazepam is a short-acting drug used to treat anxiety ○ Temazepam is used primarily to treat insomnia Other benzodiazepines ○ Clonazepam (Klonopin®) used to treat panic disorder and other anxiety disorders, as well as seizure disorders; doesn’t have active metabolites ○ Midazolam (Versed®) is used IV as an anesthetic for patients undergoing endoscopy or other diagnostic procedures, or minor surgery Barbiturates ○ Drug properties Onset and duration determined by lipid solubility and rate of inactivation Highly lipid-soluble drugs (e.g., amobarbital, pentobarbital, and thiopental) are well absorbed from gut, rapidly redistribute from brain to peripheral tissues as conc fall Phenobarbital is slowly absorbed from gut, has a longer duration of action ○ Mechanism of action Bind to site on GABA receptor chloride ion channel, distinct site from where benzodiazepines bind Increase affinity of receptor for GABA and the duration of time the channel remains open Also act to directly increase chloride influx in absence of GABA, so they don’t have a ceiling effect Higher doses increasingly depress CNS, causing respiratory depression, coma, and death. Greater toxicity and smaller TI than benzodiazepines. ○ Specific agents Amobarbital and pentobarbital have been used primarily to treat insomnia Phenobarbital is used occasionally to treat seizure disorders Thiopental is administered IV to induce anesthesia High degree of lipid solubility, has very fast onset of action  Antihistamines ○ Tolerance Some tolerance can occur during long-term use Not associated with physical dependence or significant drug abuse ○ Specific drugs Diphenydramine is the active ingredient in several nonprescription sleep preparations Hydroxyzine has been used to treat mild anxiety, sometimes used as sedative before surgery Doxepin recently approved for treatment of insomnia, has high affinity for H1 receptors Non-benzodiazepine sedative hypnotics ○ Other Zolpidem (Ambien®), zaleplon (Sonata®), and eszopiclone (Lunesta®) have replaced older benzodiazepines for tx of insomnia Fewer adverse effects (i.e., don’t affect REM or slow wave sleep, less potential for tolerance and dependence) Shorter duration of action precludes daytime sedation and hangover effects ○ Melatonin Available OTC, may be accelerate “resetting” the biologic clock May be effective in tx jet lag in individuals who have rapidly traveled across several time zones Sometimes used to treat insomnia in shift-change workers May also be effective in treating insomnia in elderly patients who don’t secrete enough melatonin Appears to be effective in treating delayed sleep-phase syndrome and non-24-hour sleep-wake disorder Non-sedating anxiolytic drugs Buspirone aka BuSpar ○ Unique anxiolytic drug, not similar to any other drugs ○ Partial agonist at serotonin 5-HT1A receptors, causes up-regulation of postsynaptic serotonin receptors but takes 3-4 weeks before onset of anxiolytic effect ○ Used to treat chronic anxiety and produces anxiolytic effect without causing sedation, amnesia, tolerance, dependence, or muscle relaxation