Sedative Hypnotics.docx

An effective sedative reduces anxiety and exerts calming effect. A hypnotic drug induces drowsiness and encourages the onset and maintainence of sleep. A sedative hypnotic then , as you will see, all kinds of cns depression. One of the most widely used sedative hypnotic is benzodiazepines.  ‘pam’ suffix of benzodiazepines (eg diazepam, lorazepam,oxazepam) o Benzodiazepines can be classified as either short acting or long acting agents depending on their onset and duration of action o Oxazepam- short acting benzodiazepine  ‘olam’ suffix common to many of the other short acting benzodiazepines (triazolam, alprazolam, midazolam)  Because of their short serum half life , these short acting agents are morelikely to lead to physical dependence , therefore they are more likey to cause addiction.  Short acting benzodiazepine such as oxazopam , alprazolam , triazolam exert such short lived pharmalogical effects because they are rapidly metabolized and inactivated by liver. Infact hepataic metabolism accounts for clearance of all benzodiazepines but here is the key difference to keep in mind , the long acting agents such as diazepam chlordiazepoxide form active metabolites at the liver . these biological active molecules have half life upto a 100 hours and exert lasting pharmacological effects. Also multiple doses can lead to cumulative effects leading to increased risk of toxicity so be careful when prescribing benzos to very old pt? or pt with liver disease.  Altered hepatic function can cause significantly increased serum half lives of these drugs o Benzodiazepines work by binding to an allosteric site on the gaba A receptor facilitiating its action.  Gaba slong with glycine is a major inhibitory neurotransmitter in the cns .  Benzodiazepine potentiate gaba a transmission thoughout the cns including the spinal cord, cerebellum, cerebral cortex. Remember u are enhancing gaba activity , u are not blocking it . but gaba is an inhibitory neurotransmitter , so overall benzodiazepines have a depressive effect on cns function.  The gaba a receptor once activated functions as a chloride ion channel (gaba a rec is a chloride channel)  Increased chloride conductance inhibits synaptanse transmission throughout cns, leading to cns depression  Increased chloride permeability at the cns neurons hyperpolarizes and stabilizes the membrane , rendering them less excitable.  Remember benzodiazepines do not substitute for gaba but instead enhance gaba s effectby binding to a separate allosteric site on the gaba a receptor  We will soon see that numerous sedative hypnotic agents are able to modulate the activity of gaba by binding to this receptor.

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When benzodiazepines bind to their unique sites, the resulting enhancement in chloride ion channel conductance is due to an increase in frequency of ion channel opening not an increase in duration. Gaba receptors are divided into 3 subtypes :gaba A,B,C rec.  gaba a site of benzo- its composed of 5 subunits that together form a chloride channel which primarily mediates neuronal excitability, mood changes, anxiety and sleep. You know what other agent affects this cns functions- alcohol > prob the most widely used sedative hypnotic- alcohol is a cns depressanat that also binds to the gaba a receptor complex at ANOTHER allosteric site > enhancing the inhibitory tone of gaba .  chronic alcohol consumption leads to decreased gaba sensitivity and alcohol tolerance develops> meaning u need to increase intake to get the same effect . and abrupt sessation of alcohol causes decreased gaba mediated inhibitory tone resulting in the opposite tone > cns excitation – this is what characterizes alcohol withdrawal o alcohol withdrawal symptoms typically start 8-12 hours after the last drink and include insomnia,trmulusnous, anxiety and autonomic hyperactivity which includes variable blood pressure,diaphoresis and tachycardia. o Within 12-48 hours of withdrawal – seizures can occur o 48-96 hours- delirium tremens . keep in mind the delirium part of delirium tremens because this syndrome includes fever,disorientation, and sever agitation Benzodiazepines are first line therapy for the psychomotor agitation associated with alcohol withdrawal and to prevent progression to seizures and delirium. Long acting benzos with active metabolites such as diazepam or chlordiazopoxide are preffered in majority of pt due to their self tapering effect which results in a smoother course of withdrawal- so these are useful in tx of alcohol withdrawal. Remember however that all benzos are metabolized by liver and it’s the long acting agents that form the active metabolite prolonging their pharmacologic effects. In pt with cirrhosis or alcoholic hepatitis , these active metabolites tend to accumulate leading to oversedation therefore short acting benzos that are more rapidly inactivated and have no active metabolite are preferred in the setting of hepatic indufficiency such as lorazepam or oxazopam As u can see treatment and prevention of seizures is an important component of management of alcohol withdrawal . infacr alcohol withdrawal is one of the most common causes of seizures in adults and when given iv , benzodiazepines are able to provide rapid treatment severe withdrawal reactions . (iv benzo is useful for alcohol withdrawal , seizures, anesthesia) . benzodiazepines when given iv arehighly affective in stopping continues seizure activity esp status epilepticus which is when recurrent or continuous generalized tonic clonic seizures last for more than 30 minutes without

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return to consciousness. Ivy benzo such as diazepam and lorazepam used for the acute control of seizure activity (tx status epilepticus). Benzodiazepines such as diazepam, lorazepam and midazolam are also used iv for general anesthesia (muscle relaxant,amnesia) , usually in combination with other agents. Heres the thing tho, many diagnostic and minor procedures can be performed without general anesthesia using sedation based anesthetic technique during a colonoscopy for example, iv benzo can be used to induce a state of conscious sedation when the pt is able to maintain a patent airway and even follow commands during a procedure. ( lite anesthesia accomplished with iv benzo) Alright we have gone over sedation .but a sedative hypnotic wouldn’t be called a sedative hypnotic, unless it could also cause hypnosis or sleep. Benzodiazepines are commonly used for the short term treatment of insomnia ( not first line due to sside of physical dependence and tolerance) Benzodiazepines can also be useful in treating parasomnias in children ( sleepwalking,night terrors) Benzodiazepines are also used as central muscle relaxant - diazepam for example can stop the spasticity that is caused by umn disorders like ms, stroke , spinal cord trauma, tetanus . gotta be careful tho, benzos will also produce sedation at the doses req to reduce muscle tone Benzos also used widely for the management of acute anxiety states, for eg they can be used to treat the symptoms associated with generalized anxiety disorder or GAD – gad involves excessive or unreasonable anxiety about life circumstances such as anticipation of a freightening medical or dental procedure, illness in fam , etc . acute anxiety can also be accompanied by other symptoms such asheadaches, muscle tension, incomnia.and benzos can be used to reduce the emotional and somatic symptoms of GAD within minutes to hours Benzos also used for management of panic disorder . pt with panic disorder experience recurrent panic attacks typically presenting with spontaneous episodes of intense fear that begin abruptly and last for several minutes to an hour. Pt may also present with other symptoms such as chest pain and sob and they ususally have excessive worry about future attack . but heres the thing tho , the first line pharmacologic treatment for generalized anxiety disorderand other condition such as panic disorder and agoraphobia is not a benzo but usually a serotonin reuptake inhibitor such as an ssri or an snri and the rest of the sketch is dedicated to showing u why. There are numerous disadvantages that limit the use of benzos as a long term therapy for pt with anxiety  Lets start with tolerance- decreased sensitivity to a drug effect after long term use. Chronic benzo use results in downregulation of the gaba a receptor complex . this leads to decreased gaba sensitivity and tolerance develops, meaning ull need to increase the dose of benzos to produce the same pharmacological effect.

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Not only that, physical dependence can develop, which means that your body adapts to chronic use of a drug and if a drug is stopped abruptly, youll start experiencing some withdrawal symptoms, so because alcohol works in much the same way as benzos , when u are trying to remember the withdrawal symptoms of benzos or any sedative hypnotic , just think of alcohol withdrawal symptoms. Withdrawal can include tremors , anxiety , perceptual disturbance , dysphoria, psychosis and even seizures. All in all because of tolerance to increased dosages and physical dependence to the drug effect , pt are an increased riskof developing addiction.  So if your pt has a history of substance abuse disorder, benzos are probably not your best offer  The most common side effect of benzos result from their dose dependant depression of cns – being sedative an all – even low doses benzo can lead to drowsiness , impairese judgement , diminished motor skills, job performance and driving ability  May also cause significant dose related anterograde amnesia , impairing the ability to learn new information ( this is useful during conscious sedation thoduring uncomfortable procedures like endoscopy , benzo are used to create a level of sedation where the pt is able to cooperate in a procedure but is amnestic to it afterwards-‘so it was uncomfortable but u just don’t remember it was comfortable  Elderly pt are more sensitive to the effects of benzo. Infact the most common reversible cause of confusional states- somnolence, confusion, disorientation) in elderly is the overuse of sedative hypnotics  Benzo may also impair coordination and balance leading to central ataxia( causes fall in elderly so these drugs are usually avoided in elderly)  As a class benzo should not be administered with other cns depressant including alcohol, barbiturates, neuroleptics, 1st gen antihistamine.so when u get an old pt with depressed cns , look at drugs and interactions between agents.  Barbiturates also bind to a different allosteric rec on gaba a If u need to rapidly reverse the sedative actions of benzodiazepines, flumazenil is your antidote. Flumanezil is a competitive antagonist of the benzodiazepine receptor.flumanezil can be used to reverse benzo induced sedation following general anesthesia, procedural sedation, or overdose. However, use of flumanezil in the setting of overdose remains highly contrevertial . administration of flumanezil can precipitate withdrawal seizures in pt who developed a tolerance to benzo through chronic use or abuse

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Insomnia is common in the elderly population and can significanatly impair quality of life . non pharmacological intervention such as sleep hygene measures and cognitive behaivioral therapy are recommended for initial treatment. Pharmacological treatment can provide immediate relief and should generally be limited to short management. Several drugs with novel chemical structures have been introduced more recently for use in sleep disorders. zolpidem, zaleplon , eszopiclone ( nonbenzodiazepine hypnotics). Although these agents are structurally unrelated to benzodiazepines, they share a similar MOA . these 3 work by binding to an allosteric site at gaba a receptor ( the same gaba a rec with allosteric site for alcohol , benzo , barbiturate) The gaba a complex function as an ionotropic channel selectively permeable to chloride ( basically gaba a rec is a chloride channel) , so when these bind to receptor , they fascilitate gaba action at the receptor , thereby permitting an increased flow of chloride ions across the membrane. This causes neuronal hyperpolarization inhibiting synaptic transmission throughout the cns . the reason why nonbenzodiazepine hypnotics are so similar to benzodiazepines> BOTTH BIND TO THE SAME PORTION (allosteric site) OF THE GABA A REC. These are selective at the benzodiazepine binding site, so the net neurophysiological effects are similar Nonbenzodiazepine receptor agonist have a structure that is different from benzodiazepines and includes a more targeted action at the gaba a receptor. A consequence of their greater specificity is less anxiolytic and anticonvulsant activity; therefore they are mainly used for the short term treatment of insomnia. Zaleplon and zolpidem have a rapid onset of action . they also have a relatively short duration of action . zaleplon and zolpidem are rapidly metabolized in liver (p450) so they have very short serum half lives about 1-2 hours . as a result of their short duration of action , these agents are effective for pt who have difficulty falling asleep but may not be effective for people who have difficulty maintaining sleep . dur to the very short half life of these drugs the potential for residual hangover effects is minimal after normal sleep periods Zaleplon and zolpidem treat sleep onset insomnia ( eszoplicone has the longest half life of the approved non benzos , approx. 5-7 hours, and is effective for both sleep onset and sleep maintainance insomnia) Generally speaking the adverse effect associated with non benzodiazepines are similar to those ass with benzodiazepines but their frequency and severity maybe less , this is prob from their shorter half lives.nevertheless the serum half lives of these agents may be greatly extended in elderly pt – just like with benzos and barbs, older adults have a particularly have a high risk of adverse effects including excessive sedation , cognitive impairement and delirium , night wandering and agitation. Even these safer Nonbenzo hypnotics can lead to balance problems (central ataxia) > falls and fractures and impaired performance of daily activity Should not combine zolpidem , zaleplon or eszoplicone with other cns depressants , this includes all the gaba fascilitating sedative hypnotics including alcohol , benzos and barbs. Watch out too for the first generation antihistamine that cross bbb. One of the important diff between benzos and non benzos – o Non benzos are less likely to cause tolerance

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Also physical dependace is much lower than the benzos> so less likely to cause withdrawal symptoms and the potential for addiction is much lower  If u need to rapidly reverse the actions of non benzos – flumanezil is the antidote - is a competitive antagonist of the benzo receptor receptor , so because zolpidem zaleplon eszoplicone all bind to the same sites ( as benzos) , flumanezil will reverse the agnets as well . o Remember though , the use of lfumanezil in the setting of overdose remains controvertial – administration of flumanezil can precipitate withdrawal seizures  --- Melatonin o An endogenous molecule produces by the brain that regulates your sleep cycle . o Ramelteon and tazamelteon are newer hypnotic drugs that act as melatonin receptor agonist o Melatonin receptors are thought to be involved in maintaining circadian receptors that are underlying the sleep wake cycle o Ramelteon has no direct effect on gaba ergic neurotransmission in the cns, instead its an agonist at the mt1 and mt2 melatonin receptors located in the suprachiasmatic nucleus of the hypothalamus o As you know medication selection of elderly pt require special attention to this populations increased sensitivity to adverse affects . ramelteon is one of the few medication with demonstrated safety and efficacy in older adults. Ramelteon dosent affect sleep architecture and dosent cause rebound insomnia or significanta withdrawal symptoms . o Overall ramelteon has few side effects , no dosafe adjustment is necessary in geriatric pt. Onto our last class of sedative hypnotics  Barbiturates – they are some of the oldest antiseizure drug . and when used as sedaatives , they have serious cns, cvs and pulm depression and potential to cause addictiton . the clinical uses of the barbiturates are pretty slim limited to sedation for critically ill pt and the occational use as antiseizure agent . on the exam u only have to know a few important facts about barbiturates. Mostly concerning their side effect profile .  Barbiturate work by binding toan allosteric site of the gaba a receptor – so barbiturate such as phenobarbital bind to their special site on complex of gaba a .  Gaba a complex works as an ionotropic channel selectively permeable to chloride.  Heres the thing to remember tho , barbiturates work by prolonging the duration of channel opening In response to gaba NOT the frequency of channel opening . at the beginning od the chapter, we highlighted how benzodiazepen enhance chloride conductance by increasing the frequency of ion channel opening  Although barbiturates bind to a different site than benzodiazepine , the net neurophysiological effect are similar , however barbiturates usually have longer half lives than the relatively short acting benzodiazepines and residual sedation or hangover effects occur frequently following

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hypnotic doses. Theres one important exception to that rule tho . theopentol is an ultra short acting barbiturate , most commonly used for induction(IV) in rapid sequence intubation. Has a time to effect in less than 30 seconds- has rapid onset and short duration of action . its highly lipid soluble and immediately enters the cns to take effect , thiopental equilibrates in the brain tissue within 1 minute after administration and causes loss of consciousness . but not only is it quick to act , itsduration of action is pretty quick too – only about 5-10 minutes > this is not due to drug metabolism but due to drug redistribution . it turns out after thiopental is given iv , blood levels begin to decrease rapidly and that’s because the accumulation of thiopental in the brain is followed by its rapid redistribution into skeletal muscles and adipose tissues. So remember the rapid plasma decay of thiopental is not due to drug metabolism but redistribution of drug to other tissues throughout the body esp skeletal muscle and adipose tissue. This rapid brain clearance leads to recovery from anesthesia o Rapid decay of plasma thiopental levels due to redistribution o Drug conc in brain rapidly rising , then equilibrating , and then immediately falling as the drug anters body tissues o Last rising line representa redistribution as the drug rapidly accumulates in skeletal muscle and adipose tissue “iv administration of barbiturates is useful for induction of anesthesia (thiopental) and management of seizures (phenobarbital)” Phenobartibitol – iv – also causes clinical useful depression of cns activity – this time tho we are going to suppress seizures . phenobarbital is among the oldest antiseizure drug still in use. Its effective for generalized and focal seizures and itll stop any seizures at high enough doses can stop pretty much any seizures .BUT. despite its efficacy , phenobarbital is generally not used as a first line antiseizure treatment in adults, though it remains the first line agent in neonates. So usually reserved as 2nd or 3rd line agent since administration is slow, causes prolonges sedation and it may involve a higher risk of hypoventilation and hypotension than other first line agents. Primidone – a barbiturate used for seizures and essential tremor – one of the active metabolites of primidone is phenobarbital and so it can likewise be used to manage partial or tonic-clonic seizures. Primidone is also a first line therapy with a beta blocker propranolol to treat essential tremor – but in much lower dose than used to treat seizures. Since phenobarbital is onr of the active metabolite , it has similar adverse effects. The clinical utility of barbiturates is limited by their significant sedating effect . keep in mind the long serum half life of phenobarbital for example is 75 – 100 hours and during this time, multiple doses can lead to accumulative effect resulting in profound hypotension (cardiac depression) and respiratory depression. Also barbiturates exert potent cns depressive effects and are more likely to cause coma compared to other sedative agents such as benzos, for these reasons barbiturates should ALWAYS be avoided in elderly pt . and just like we emphasized with other sedative hypnotics, these effects are exacerbated by other agents that depress cns function such as benzos, alcohol, 1st gen antihistamine. Just like with benzodiazepines, long term (chronic) use of barbiturates leads to tolerance. Physical dependace also develops with chronic use – which means your body adapts to chronic use off drug and if the drug is stopped abruptly , ull start experiencing withdrawal symptoms .

 Barbiturates ( eg phenobarbital) is a potent inducer of cyp450 in liver > so it can increase the metabolism of other agents eliminated by this pathway including warfarin and statins.