Sedative-Hypnotics DSA Flashcards
Define sedative
Drug that decreases CNS activity, moderates excitement, and calms the recipient
Anxiolytic because sedative reduces anxiety
Sedation is a SE of many drugs that are not general CNS depressants
Agents that produce sedation as a SE can intensify effects of depressants and usually produce more specific therapeutic effects at conc lower than those causing substantial depression
Define hypnotic
Drug that produces drowsiness and facilitates onset and maintenance of state of sleep
Induced sleep resembles natural sleep in its EEG characteristics
Induces sleep from which recipient can be aroused easily
Hypnotic effects involve more pronounced depression of CNS, which can be achieved with many sedative-hypnotics by increasing dose
Describe MOA and effects of benzodiazepines
MOA: promote binding of major inhibitory neurotransmitter gamma-aminobutyric acid to GABAa receptor and enhance GABA-induced ion currents (increase frequency of channel openings by shifting dose-response curve to left)
Capable of causing sedation, hypnotic effects, muscle relaxation, and anxiolytic and anticonvulsant effects
High anxiolytic potency in relation to their depression of CNS function
Because of their low capacity to produce fatal CNS depression, these have displaced barbiturates as preferred agents
Describe MOA and effects of barbiturates
MOA: bind to GABAa receptors and potentiate GABA-induced chloride currents (increase duration of channel openings)
Can activate channel directly by acting as a GABA-mimetic at high concentrations
Capable of causing mild sedation to anesthesia and anxiolytic, hypnotic and anticonvulant effects
Possess a narrow therapeutic index and often not possible to achieve desired effect without evidence of general depression on CNS
Describe absorption and distribution of sedative-hypnotics
Lipid solubility plays role. MOst are rapidly absorbed into blood after oral administration
All cross CNS, placental barrier, and breast milk
Describe biotransformation of benzodiazepines
Hepatic metabolism: most undergo phase I reactions, mostly CYP3A4, then glucuronidation (phase II)
Many phase I metabolites are pharm active (desmethydiazepam with half-life 40 hrs)
Triazolam short half-life 2-3 hrs, so hypnotic rather than sedative
Cumulative toxicity: those with long half-lives are more likely to cause cumulative effects (excessive drowsiness) with multiple doses
Those that are extensively metabolized by liver are poor choice in pts with hepatic insufficiency (oxazepam and lorazepam better choices)
Describe biotransformation of barbiturates
Except for phenobarbital (20-30%), most ingested undergo hepatic metabolism and are excreted in urine as glucuronide conjugates
Elimination half-lives are relatively long, and multiple dosing can lead to cumulative effects
Describe biotransformation of newer hypnotics
CYP3A4 enzymes play major role in biotransformation of eszopiclone, zolpidem, and zaleplon
Half-lives relatively short (<6 hrs, well suited for sleep aids)
Describe excretion of sedative-hypnotics
Primarily via kidney. Changes in renal function do not have marked effect on elimination of parent drug
20-30% of phenobarbital is excreted unchanged in urine. Alkalinization of urine can increase its elimination rate
Describe the GABAa receptor
Ligand-gated ion channel (ionotropic) made up of 5 subunits that, when activated by GABA, allows chloride ions to enter cell
Receptors in brain made up of 2a, 2b, 1g
Under normal phys conditions, activation causes normal chloride influx and polarization and reduces number of action potentials
Responsible for most inhibitory transmission in CNS
Describe the neuropharm of benzodiazepines
Increase efficiency of GABAergic synaptic inhibition (shift GABA conc-response curve to left with less GABA required to activate receptor)
Do not substitute for GABA but enhance effects of GABA allosterically without directly activating GABAa receptors
Leads to increase in frequency of channel-opening events, causing increased chloride influx, hyperpolarization of neurons, and reduced number of APs (depressed state of CNS)
Describe neuropharm of barbiturates
MOA: increase duration of GABA-gated chloride channel openings (channel open longer)
At high conc, may also directly activate receptor
Increased channel openings or activation leads to increase of chloride ions, hyperpolarization of neurons, and reduced number of APs
Barbiturates are less selective in their actions (also depress actions of excitatory neurotransmitters such as glutamic acid) and exert nonsynaptic membrane effects in parallel with their effects on GABA neurotransmission
Describe sedation effects of sedative-hypnotics
Exert calming effects with concomitant reduction of anxiety
MOst produce some depressant effects on psychomotor and cognitive functions
Benzodiazepines exert dose-dependent anterograde amnesiac effects
Describe hypnosis effects of sedative-hypnotics
Given in high doses (higher than used for sedation/anxiety), agents induce sleep
Newer agents decrease time to fall asleep, while eszopiclone increases total sleep time
Describe anesthesia effects of sedative-hypnotics
High doses esp of barbiturates and older agents depress CNS to stage III general anesthesia
Thiopental and methohexital are lipid soluble and penetrate brain tissue rapidly after IV admin
Benzodiazepines (diazepam, lorazepam, midazolam) are used for IV anesthesia in combo with other drugs
If certain agents are given in high doses, may contribute to persistent postanesthetic respiratory depression
Describe anticonvulsant effects of sedative-hypnotics
Some benzodiazepines (clonazepam, nitrazepam, lorazepam, diazepam) and barbiturates (phenobarbital) are sufficiently selective for management of seizures Zolpidem, zaleplon, and eszopiclone lack anticonvulsant activity
Describe muscle relaxation effects of sedative-hypnotics
Benzodiazepines (diazepam) and carbamates (meprobamate) can exert inhibitory effects on polysynpatic reflexes and internuncial transmission and may also depress transmission at skeletal neuromuscular junction at high doses
Zolpidem, zaleplon, and eszopiclone do not cause muscle relaxation
Describe effects of sedative-hypnotics on respiration and CV function
Can produce significant dose-dependent respiratory depression in pt with pulmonary disease
Depression of medullary respiratory center is usual cause of death due to overdose of sedative-hypnotics
At normal doses, agents can cause CV depression in pts with disease that impair CV function (HF, hypervolemia), most likely a result of depression of medullary vasomotor centers
At toxic doses, myocardial contractility and vascular tone may both be depressed and could lead to circulatory collapse
Effects on respiration and CV function more marked when agents given IV
Define tolerance
Decrease in responsiveness to drug following repeated exposure and common feature of sedative-hypnotics
Define cross-tolerance
When repeated use of a drug in a given category confers tolerance not only to that drug, but also to other drugs in the same structural and mechanistic category (example: between sedative-hypnotics and ethanol)
Give pharmacodynamic example of tolerance
Benzodiazepine tolerance associated with down regulation of GABA receptors
This leads to hyperexcitability of CNS during withdrawal
Give pharmacokinetic example of of tolerance
Barbiturates stimulate production of higher hepatic CYPs, causing more rapid removal and breakdown of barbiturates from circulation
Results in decrease in efficacy
Describe flumazenil
Binds to benzodiazepine binding sites on GABA receptors and acts as competitive antagonist
Blocks actions of benzodiazepines, zolpidem, zaleplon, and eszopiclone.
Does not block CNS effects of barbiturates, meprobamate, buspirone, RA meltdown, ethanol, opioids, or general anesthetics
Reverses CNS depressant effects of benzodiazepine overdose and shortens recovery following benzodiazepine in anesthetic and diagnostic procedures
Short half-life due to hepatic clearance (1 hr). Longer half-lives of benzodiazepines cause recurrence of sedation and requires repeated admin of flumazenil
Adverse effects: agitation, confusion, dizziness, nausea
Can precipitate abstinence syndrome in pts who have developed physiologic benzodiazepine dependence
Describe clinical uses of sedative-hypnotics
Relief of anxiety
Insomnia,
Sedation and amnesia before and during medical procedures
Treatment of epilepsy and seizure states
Component of balanced anesthesia (IV admin)
Control of ethanol or other sedative-hypnotic withdrawal states
Muscle relaxation in specific neuromuscular disorders
Diagnostic aids or for treatment in psychiatry
Describe treatment of anxiety states
Benzodiazepines used in management of acute anxiety states (situational anxiety) and rapid control of panic attack and long-term management of generalized anxiety disorder and panic disorders
Alprazolam is effective in treatment of panic disorders and agoraphobia and appears to be more selective in these conditions than others (lorazepam and clonazepam useful for acute panic disorders)
Currently, use of newer antidepressants (SSRIs) are preferred in treatment of generalized anxiety disorders and certain phobias, although benzodiazepines still used for acute anxiety states
Concomitant treatment of anxiety on short-term basis with benzodiazepines and SSRIs is useful until SSRIs become effective (4-6 weeks)
What are benzodiazepine advantages in treating anxiety ?
High therapeutic index
Availability of flumazenil for overdose
Low risk of drug interactions based on liver enzyme induction
Minimal effects on CV or autonomic functions
What are benzodiazepine disadvantages?
Risk of dependence
Depression of CNS functions
Amnesties effects
Additional CNS depression when combined with other drugs (including ethanol)
Describe benzodiazepines and treatment of sleep
Used but cause daytime sedation due to slow elimination times and biotransformation to active metabolites
Pts run risk of developing tolerance and anterograde amensia
Describe newer agents for sleep problems
Rapid onset of activity and modest day-after psychomotor depression with few amnestied effects
Zolpidem available in biphasic release formulation that provides sustained drug levels for sleep maintenance
Zaleplon acts rapidly and has value in management of pts who awaken early in sleep cycle
Zaleplon and eszopiclone may cause less amnesia or day-after somnolence than zolpidem or benzodiazepines at recommended doses
Half-lives of zaleplon and zolpidem are similar (1-2 hrs and 1.5-3.5 hrs0 and are good for pts who have trouble going to sleep
Eszopiclone has half life 6 hrs and more effective treating pts who awaken early and have difficulty sleeping through night
Describe long-termm use of hypnotics for sleep
Irrational and dangerous
Failure of insomnia to remit after 7-10 days of treatment may indicate presence of primary psychiatric or medical illness that should be evaluated
Nonpharm therapies like proper diet and exercise, avoiding stimulants before retiring, ensuring comfortable sleep environment, retiring at a regular time each night
Describe misc uses for sedative-hypnotics
Seizures and IV agents in anesthesia
Oral of short acting agents for sedative and amnestic effects during procedures
Long acting chlordiazepoxide, diazepam, and phenobarbital for pts in withdrawal from dependence on ethanol or other drugs
Diazepam approved for muscle spasticity
Describe direct toxic actions of sedative-hypnotics
Low doses may lead to drowsiness, impaired judgement, and diminished skills that can lead to impacts on driving, job performance, and personal relationships
Increased sensitivity more common in pts with CV disease, respiratory disease, or hepatic impairment and in older pts (doses half of those in younger pts usually effective)
Most frequently involved in deliberate overdoses (benzodiazepines safer because flatter dose response curves)
With severe toxicity, respiratory depresssion from central actions of drug may be complicated by aspiration of gastric contents in unattended pt
Barbiturates enhance porphyria synthesis and are contraindicated in pts with history of acute intermittent porphyria, variegated porphyria, hereditary coproporphyria, or symptomatic porphyria
Describe drug interactions with sedative-hypnotics
With alcohol, opioids, anticonvulsants, phenothiazines, antihistamines, antiHTN, antidepressants of TCAs
Cytochrome P450 induction: phenobarbital and meprobamate can induce P450 induction wiht long term use
Cytochrome P450 inhibition: many benzodiazepines and newer hypnotics are metabolized by P450s (CYP3a4). Coadministration of agents that inhibit P450s will cause a marked increase in concentrations of theses sedative-hypnotics
Describe ramelteon
Treatment of insomnia characterized by difficulty with sleep onset MOA: agonist at MT1 and MT2 melatonin receptors located in suprachiasmatic nuclei of brain Oral bioavailability less than 2% because of first-pass metabolism. Use with caution in pts with hepatic impairment Parent drug (1-2.5 hrs) metabolized by CYP1A2 to active with longer half life 2-5 hrs Avoid coadministration with fluvoxamine (SSRI) because it's inhibitor of CYP1A2 Adverse effects include dizziness, somnolence, fatigue, and endocrine changes (decreases in testosterone and increases in prolactin)
Describe buspirone
Treatment of generalized anxiety disorder (anxiolytic effects may take more than week to become established. Less effective in acute panic disorders)
Does not cause sedation, hypnotic, euphoric, anticonvulsant, or muscle relaxant effects
Oral bioavailability 4% because of first pass
Extensive metabolism by CYP3A4. Caution with hepatic impairment
May act on serotnergic, dopaminergic, Cholinergic, and a-adrenergic systems
Adverse effects: tachycardia, palpitations, nervousness, GI distress, parestheisa, and dose-dependent papillary constriction
Describe meprobamate
Short-term relief of anxiety
Effective preoperative agent used to relieve anxiety and provide sedation. Effective in promoting sleep in anxious and tense pt
CNS depressant
High potential for tolerance, psychological, and physical dependence, and abuse
Active metabolite of drug carisoprodol (centrally-acting muscle relaxant 0
