A-Sedative-Hypnotics

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Therapeutic Uses of Sedative-hypnotics

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Anxiety
Short-term txt of insomnia
Epilepsy/seizure
Control of ethanol withdrawal
Pre-anesthesia
Spasticity

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Drugs that can reduce anxiety

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Sedatives

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Drugs that encourage sleep

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Hypnotics

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Sedatives effects

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Exert a calming effect
Reduce anxiety (antiolytics)
Minimal CNS depression

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Hypnotics

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Produce drowsiness
Encourage onset/maintenance of sleep
More pronounced CNS depression

*Dose dependance sedation*

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Achieving hypnotic (and anesthetic) effects

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May be achieved by increasing the dose of a sedative

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Linear CNS Depression

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the level of CNS depression is directly related to the dose
Higher relevance of AE's in these patients such as coma
EX: Barbiturates
Bottom line:
Linear: As you progress beyond above hypnosis you do not have to have large dose increases to get to anesthesia and coma

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Non-linear CNS depression

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Sedatives that require proportionately greater increase in dose to achieve hypnotic and anesthesia
EX: benzodiazepines
Bottom line:
Non-linear: To progress past sedation/hypnosis you need a higher dose increase to reach anesthesia or may never reach anesthesia, very difficult to get to coma stage (Non-linear = safer)

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Benzodiazepine Structure

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Built around a common nucleus
Substitutions in R group affect: lipophilicity, absorption, half-life, metabolism

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MOA benzodiazepines

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Act by activation of receptors for γ-aminobutyric acid (GABA) causing hyperpolarization
ALLOSTERIC ACTIVATORS of GABAa: increasing the efficiency of GABAergic synaptic inhibition by increasing the frequency of Cl- channel opening

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GABA

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Inhibitor neurotransmitter in CNS
3 subtype of GABA receptors: GABAa,b and c
contains 5 subunits (2-alpha, 2-beta, 1 gamma), and a center pore (calcium channel)

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GABAa

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Ligand-gated ionotropic channel

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GABAb

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G-protien GPCR (Gi)

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GABAc

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Ligand gated ionotroic channel

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Benzodiazepine CNS Actions

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Sedation
Hypnosis
Decreased anxiety
Anterograde amnesia (forget what is happening/coming)
Anticonvulsant actions
Muscle relaxation

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Benzodiazepine CV Actions

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Minor
Coronary artery dilation with IV doses
At higher doses (dec. BP, inc. HR)

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Benzodiazepine Muscle relaxation actions

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Relax skeletal muscle to varying degres
Depress motor neurotransmission
Depress the neuromuscular junction at high doses

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Benzodiazepine Respiratory Systems

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Minimal at therapeutic doses and in people with normal liver function
Slight depression of alveolar ventilation, respiratory acidosis
Effects may be exaggerated in patients with pulmonary disease (COPD)

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Benzodiazepine's effect on sleep apnea

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May worsen sleep apnea b/c they affect control of the upper airway muscles

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Short-acting benzodiazepine usual treatments

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Pre-anesthesia
Anxiolytic
Insomnia

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Intermediate-long benzodiazepine usual treatment

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Anticonvulsant
Anxiolytic
Beware of hangover when used for sleep maintenance

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Benzodiazepine PK (Absorption)

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Complete absorption from the GI
Circulate 70-90% bound to plasma proteins (does not seem to be clinically important)

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Benzodiazepine PK (Distribution)

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Large Vd: distributes to adipose due to their lipophilic
Penetrate the CNS: this is where we need them to work
Crosses placenta, excreted in breast milk (CI in preg)

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Benzodiazepine PK (metabolism)

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Phase I: microsomal oxidation by 3A4, many phase I active metabolites, they may accumulate, inducers/inhibitors of cyps's, genetic variation (2C19)
Phase II: glucuronide conjugation (inactivated and excreted in urine)

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What Benzodiazepine's produce and active metabolite?

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Chlordiazepoxide (desmethylchlordiazepoxide)
Diazepam, Prazepam, Clorazepate (desmethyldiazepam)
Alprazolam and triazolam (alpha-hydroxy metabolites

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What Benzodiazepine is a prodrug?

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Chloazepate

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Which Benzodiazepine's do not go through phase I metabolism and therefore do not have active metabolites?

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Oxazepam
Lorazepam

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Tolerance

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Chronic benzodiazepine use is associated with tolerance

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What are possible molecular/cellular mechanisms for development of tolerance to benzodiazepines?

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Decreased expression of GABAa receptors
"uncoupling" of benzodiazepines allosteric site from GABAa receptor

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What will happen if a patient who has been taking benzo just stops taking them?

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insomnia
agitation
anxiety
withdrawal
*it causes the symptoms they are treating... not life threatening

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How do you avoid withdrawal symptoms?

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always taper the dose

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Adverse effects of benzodiazepines

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CNS depression: lightheadedness, motor and mental impairment, confusion, daytime sleepiness if used for insomnia
risk worsens when used in combination with other CNS depressants (alcohol, opioids, tricyclic antidepressants, barbiturates)

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Benzodiazepine overdose culprets

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oxycodone, hydrocodone, diazepam, alprazolam, temazepam, doxylamine

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treatment for benzodiazepine overdose

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Flumazenil: GABAa antagonist (competitive antagonist)
AE's: agitation, confusion, dizziness, N/V

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What will happen if a patient who has been on benzodiazepines for a long time is given flumazenil?

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withdrawal

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What are the potential benefits of drugs like oxazepam and lorazapam?

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not metabolized by cyp's
not active metabolites
not interactions
no phase I
do not have to worry about a patients liver function

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What are some of the drawbacks to using benzodiazepine for insomnia?

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Daytime sedation
Tolerance
Anterograde amnesia
Dependance

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Buspirone MOA

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BuSpar
Relieves anxiety w/o marked sedation
*Partial 5-HT1a agonist in brain
*Central dopamine receptor effects
DOES NOT AFFECT GABA signaling directly

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Buspirone benefits/drawbacks

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Minimal abuse liability, no rebound withdrawal, agitation
limitation: slow onset of action (not good for short term anxiety)

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Buspirone PK

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Rapid oral absorption
Extensive 1st pass metabolism
Alpha antagonist metabolite

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Buspirone AE's

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dizziness
Nervousness
GI distress
Tachycardia

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Buspirone advantages

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Less sedating
Less impairment of cognitive function
Less psychomotor impairment

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List the "Z" Drugs

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Zolpidem (Ambien)
Zaleplon (Sonata)
Eszopiclone (Lunesta)

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Z Drug approved treatment

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treatment of insomnia

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Z drug MOA

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Benzodiazepine-like
Interact with GABAa site that s adjacent to the benzodiazepine Binding site
*These drugs have weaker anticonvulsant/muscle relaxant effects compared to benzo's

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Z drug absorption

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readily absorbed from GI tract

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Z Drug metabolism

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Zolpidem/Zaleplon: primarily 3A4
Eszopiclone: 3A4(60%), 2E1(40%)
*Heavily dependent on liver metabolism so age is an issue

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Z drug excretion

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primarily urine

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Zolpidem

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Ambien
Z drug
Used for short-term txt of insomnia
Short t1/2 (1.5-3.5)
Plasma levels peak at 1.6 hours
*Less daytime sleepiness compared to the benzo's

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Zaleplon

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Sonata
Z drug
Used for short-term txt of insomnia
Shorter t1/2 (1-2 hours) than zolpidem
Peak plasma levels in ~1 hour

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Zaleplon benefits/drawbacks

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drawbacks to half-life: staying asleep might be a problem
Benefit of half-life: dec. risk of daytime sedation

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What type of patient benefits from Zaleplon

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people who have trouble falling asleep

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Eszopiclone

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Lunesta
Z drug
longer t1/2 (6 hours)
can be used for chronic txt of insomnia
NO EVIDENCE OF TOLERANCE after 6 months
No rebound insomnia
No next day residual effects in most patients

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Z drug Adverse effects

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Mostly mild and similar to benzodiaazepines
Sleep-related behaviors
Less potential for abuse compared to barbiturates and some benzo's

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Z drug overdose txt

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May be reversed with flumazenil

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Ramelteon uses

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Rozerem
First non-scheduled agent approved for long-term txt of insomnia
Synthetic analogue of melatonin
Used for insomnia characterized by difficulty with sleep onset

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Ramelteon MOA

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agonist at melatonin receptors MT1 and MT2
No direct effects on GABAegic neurotransmission

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Melatonin

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endogenous molecule synthesized from the amino acid tryptophan in the pineal gland (Darkness stimulates melatonin secretion, light inhibits melatonin secretion
Exerts its effect by interacting with the melatonin (MT) GPCR

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What processes is melatonin involved with

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circadian rhythm/ sleep-wake cycle
Immune system regulation
Anti-aging effects? (antioxidant effects)

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Ramelton PK

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Rapidly absorbed after oral administration
Metabolized in the liver by 1A2 to an active metabolite that has a longer t1/2 than the parent drug (parent drug: 2 hours, metabolite drug: 2-4 hours)
Rebound insomnia/withdrawal

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Ramelteon Adverse Effects

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Dizziness, somnolence, and fatigue
Decreased testosterone and increased prolactin (sexual affects)

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Barbiturates

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thiopental (pentothal)
Methohexital (Brevital)
Pentobarbital (Nembutal)
Secobarbital (seconal)

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Barbiturate uses

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older group of sedative-hypnotics
Use as sedative-hypnotic is rapidly decking
pronounced non-selective CNS depression, low, TI, rapid tolerance, and Development of better drugs

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Barbiturate MOA

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Multiple MOA's
*Facilitate the actions of GABA at GABAa: binds to GABAa at a site that is distinct from the benzo's, increased the duration of GABAa Cl- channel opening, directly activate GABAa at high (barbiturate), and promote benzo binding
*Extra-GABA effects: depress the actions of excitatory NT's through effects on AMPA-R
REVERSIBLY DEPRESS ALL EXCITABLE CNS TISSUES

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Barbiturate PK

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Rapidly and completely absorbed orally
Large Vd: distributed in fat
Extensive hepatic metabolism (oxidation vis microsomal enzymes in the liver)
Elimination (Metabolites excreted by the kidneys)

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Barbiturate adverse effects

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hangover (24 hours)
Dizziness, nausea, vomiting
"Paradoxical excitement" in elderly, children
Increased perception of pain
Hypersensitivity in asthma pts
Respiratory system (powerful central respiratory depressant, also depresses both neural and rhythm of respiration)
CV system (little effect at sedative doses)
Drug interactions (powerful cyp inducer, severe CNS depression with ethanol, antihistamines, benzo's, and others)

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Barbiturate overdose txt

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NONE
flumazenil is not effective as a barbiturate overdose