Sedative Hypnotics

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With increasing dose all sed hypnotics can produce

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Relief of anxiety, sedation, euphoria-disinhibition, hypnosis, anesthesia, death

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All sed/hyp also have a potential for dependence and abuse

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abuse liability

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Benzo have a much flatter what compared to barbituates

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flatter dose response curve than barbs ie. Ceiling effect

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Benzo preclude what

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Severe depression

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What do benzos have that barbs don't

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a large TI

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Is it hard to overdose from benzo alone

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yes
Hard to produce true anesthesia and death, easy with combined with other CNS depressants

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Benzo pharmacokinetics
Absorption and distribution
oral

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Oral: BZ are lipophilic, rapidly completely absorbed after oral use and distribute throughout body

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Absorption IM

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Chlordiazepoxide and diazepam are not well absorbed; lorazepam and midazolam are well abs IM

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Abs IV

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Diazepam & Lorazepam for  STATUS EPILEPTICUS

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All BZs undergo hepatic metab

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. Many benzodiazepines (e.g. diazepam,
chlordiazepoxide, flurazepam, etc) are oxidized in the liver to active metabolites with longer half- lives than the parent drug.
b. Some benzodiazepines (e.g. alprazolam, triazolam, and midazolam) are oxidized to short-acting or inactive metabolites.
c. Oxazepam, lorazepam, and temazepam are all directly conjugated with glucuronate to inactive metabolites which are eliminated in urine-- may be safer to use IN ELDERLY

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Long duration Benzos

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chlordiazepoxide (Librium, generic)
diazepam (Valium, generic)
flurazepam (Dalmane, generic)

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Intermediate duration Benzo

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alprazolam (Xanax, generic) lorazepam (Ativan, generic) temazepam (Restoril, generic) clonazepam (Klonopin)

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Short acting benzo

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Triazolam
midazolam

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Benzo MOA

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Benzodiazepines (BZ) act on polysynaptic pathways throughout the CNS e.g. cortex, limbic system etc. They appear to selectively ↑ the inhibitory effects of GABA

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Benzo MOA: where does it bind

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Bz bind to specific binding sites on the GABAa R which fxns as a Cl- ion channel complex consists of 5 membrane-spanning subunits.

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How are different BZ receptors made

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Multiple forms of α, β & γ subunits (e.g. α1, α2, β1, β2, γ1, γ2, etc.) are arranged in different pentameric combinations to form multiple isoforms of GABAA R in many regions of the brain.

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Whats a major isoform of GABAaR is

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Two alpha, two b2, and one gamma 2

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Where does GABA bind

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GABA binds to 2 sites between α & β subunits
→ Cl- Channel opening & hyper-polarization

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Where does BZ bind

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between alpha and gamma

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Where do Barbs bind

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to an allosteric site between alpha and gamma subunit- both in presence and absence of GABA

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Where does Ethanol bind

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Ethanol binds to a distinct site on the ionophore and ↑ Cl- influx. The ionophore also contains binding sites for steroids & inhalational anesthetics

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Benzo Effects on CNS

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Relief of Anxiety (Anxiolytic):
Low doses can relieve anxiety that produce very little sedation and drowsiness
Sedation & Hypnosis: BZ will induce SLEEP
↓ latency of sleep onset**-- induce sleep
↑ duration of stage 2 sleep (NREM)**
↓ duration of REM sleep
↓ duration of slow-wave sleep (stage 3 & 4)
-- Tolerance develops with continued use.

“REM Rebound”--↑ REM sleep and/or insomnia can occur following discontinuation of chronic drug use.--WITHDRAWAL

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BZ anesthesia

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can be produced IV with midazolam with good anterograde amnesia

Not capable of producing surgical anestehsia alone

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BZ anticovulsants

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decrease seizure
all BZ have varying degrees of anticonvulsant activity

Clonazepam (Klonopin)-- very selective.
Diazepam,Lorazepam-- Tolerance ↑ readily

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BZ central muscle relaxant

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↓ Transmission at skeletal NMJ

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Clinical use

Alprazolam
Clonazepam

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Panic disorders
GAD
situational axiety

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Longer acting anxiety relief

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diazepam; lorazepam & oxazepam prefer for elderly

not that important

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Treatment for insomnia short acting

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Triazolam

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insomnia intermediate

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temazepam

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insomnia long

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Flurazepam

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SE of insominia drugs

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Symptomatic treatment only; long-term use is irrational and dangerous: Tolerance ↑; REBOUND INSOMNIA during withdrawal, esp. triazolam– amnesia, confusion in elderly.

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Preanesthetic medication

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increase sedation and amnesia

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Diazapam use

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Status epilepticus, IV
Alcohol withdrawal *b/c replaces the same depressant effects that alcohol has
Muscle spasm **CENTRAL MUSCLE RELAXANT**
Chronic epilepticus

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IV anesthesia

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Diazepam, Midazolam

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Anticonvulsant acute, status epilepticus

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Diazepam, Lorazepam

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Chronic anticonvulsant

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Diazepam, clonazepam

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Alcohol withdrawal

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Chlordiazepoxide, diazepam

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Chlordiazepoxide
(Librium) Indication

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first introduced BZD


Alcohol withdrawal

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Cholrdiazepoxide metab

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Oxidized  active metabolites w/ longer half-life (Phase I)
 long acting

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Chlordiazeproxide SE

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Avoid long-term use  Tolerance & Rebound Insomnia

Drowsiness, dizziness, ataxia, impaired performance & judgment, anterograde amnesia

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skeletal muscle spasm and spasticity from degenerative disease, MS, CP

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Diazepam

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Bz CNS side effects

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Most common: Drowsiness, sedation, ataxia, impaired motor coordination, driving & judgment; anterograde amnesia

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How do you prevent Bz SE

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start lower move gradually high

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Who are more suceptible to BZ SE CNS

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Elderly patients are more susceptible: Confusion; anterograde amnensia; ↑ incidence of falls & hip fractures; cumulative effects - - CAUTION

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Bz psychological effects

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excitement, anxiety, mild euphoria and even hallucinations -- ‘Disinhibitory’ effect

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BZ allergic rxns

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rash, anphylaxis-rare

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Teratogenic effects Bz

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Diazepam (Valium) - cleft lip and palate: It is now assumed that all BZ are potentially teratogenic. (Debated!)

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Over dose toxicity Bz

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not common when not combined. Combined with ROH and CNS depressants maybe

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Over dose trt

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Flumazil a competitive Bz receptor antag--antidote

Β-carboline derivatives act as inverse agonists & allosteric modulators of GABA-R function → bind to BZ sites & ↓ Cl- conductance
. → anxiety & seizures.

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BZ drug dependence and abuse: ie tolerance

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Psychological dependence: relief of anxiety can want more

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Other dependence

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physical: An altered physiological state which necessitates continued administration of the drug to prevent appearance of withdrawal symptoms.

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all S-H have potential for ......

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All S-H have potential for PSYCHOLOGICAL AND PHYSICAL DEPENDENCE –and therefore, ABUSE.

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BZ are a contolled substance T/F bec

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T because abuse potential
Schedule IV

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Which are more prone for abuse

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rapid onset like diazapam

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Withdrawal symptoms occur when...

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after abrupt discontinuation of BZ
Confusion, anxiety, agitation, restlessness, insomnia, tremor, tachycardia, convulsions -- potentially life-threatening.
Symptoms are more intense with the short-to-intermediate acting BZ, e.g. triazolam, than with long-acting drugs e.g. flurazepam
Do not ABRUPTLY discontinue.
↓ DOSE BY 10-15%/wk over 4-8 wks.
Treatment of withdrawal: substitute with diazepam or chlordiazepoxide

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What are the drugs that are likely to cause severe withdrawal

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The drugs that are more potent and rapidly eliminated have more frequent and severe withdrawal

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The less potent and more slowly eliminated drugs

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Continue to improve sleep even after discontinuation

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Contraindication and Cautions of BZ

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Hypersensitivity, alcoholism/drug abuse, pregnancy, respiratory disease, liver impairment

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Drug interactions of BZ

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Alcohol: ↑ CNS depressant effects

Other CNS depressants

Cimetidine (Tagament): decrease METABOLISM

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Zolpidem (ambien) MOA

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Selective Benzodiazepine R Agonists

Structurally unrelated to the BZ; Selective BZ-R agonists.
Selectively bind to BZ sites on GABAА R

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Attribute of Zolpidem

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Possesses minimal anticonvulsant and muscle relaxant activity

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Zolpidem indication

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Used as hypnotic agents for insomnia; Schedule IV – Replaced older BZ.

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Zolpidem alpha 1,2,3

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1- α1 subunits – mediate sedation, amnesia
α2 & α3– mediate anxiolytic, muscle relaxation

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Selective Benzodiazepine R Agonists
Zolpidem (Ambien
Zaleplon (Zonata)
Eszopiclone (Lunesta)

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Rapid onset of 30 minutes; half-life is 1 hr for zaleplon, 2.5 hrs for zolpidem and 6 hrs for eszopiclone

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Zolpidem metab

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Undergo hepatic oxidation to inactive metabolites; eszopiclone is extensively metab by CYP3A4

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Pharm effects
Zolpidem/ Zaleplon

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↓ sleep latency and has little effect on total sleep time.
Minimal rebound insomnia and no withdrawal symptoms
Little or no tolerance

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Eszopiclone

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↓ sleep latency and nighttime awakenings;
↑ total sleep time
Rebound insomnia can occur
NO tolerance, dependence or abuse

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Zolpidem SE

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Headache, somnolence, dizziness, malaise, lethargy-- less w/ Zaleplon.
Impaired coordination and memory--mild

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Zolpidem Rx interaction

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Cautions with other CNS depressants.
Potent CYP3A4 inhibitors, such as itraconazole, clarithromycin, ritonavir: ↑ [ESZ]
Rifampin: ↓ [ESZ]

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Ramelteon MOA

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A melatonin receptor agonist; approved for treatment of sleep-onset insomnia

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Ramelteon MOA

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A highly effective agonist for melatonin type 1 (MT1) and melatonin type 2 (MT2) receptors located in the hypothalamus
→
MT1 R regulates sleepiness while MT2 R may mediate the phase shifting effects of melatonin on 24-hr biological clock.– Day-shift to Night–shift.

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Ramelton Pharmacoknets

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Orally active; undergoes extensive first- pass metabolism in the liver by CYP1A2.
Plasma half-life is 1-3 hrs.

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Ramelteon effects

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↓ latency to sleep by 8-15 min and ↑ total sleep time by 12-19 min.

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Ramelteon SE

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Somnolence, dizziness & fatigue; hallucination & bizarre behavior.
↑ serum prolactin can result in infertility & ↓ libido.
Angioedema & anaphylaxis-- dyspnea, nausea.
NOT a controlled substance and has no abuse potential.
NO Rebound insomnia and withdrawal symptoms; teratogenic in rats.

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Ramelteon Rx interaction

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CYP1A2 inhibitors e.g. ciprofloxacin: ↑ level
Rifampin: ↓ Level

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Barbiturates long acting

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phenobarbital

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Short to intermediate

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pentobarbital

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Ultrashort acting barb

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thiopental

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Barb pharmkinetics

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Barbiturates are well absorbed orally and
distributed widely throughout the body.

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Barb pharmkinetcis

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. All barbiturates redistribute from the brain to splanchnic areas, to skeletal muscle and finally, to adipose tissue. Redistribution is important for short duration of action of thiopental and other short-acting drugs.

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Barb do they cross the placenta

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yes and depress the fetus

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Barb except phenobarbital

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metabolized in the liver and inactive metabolites are excreted in the urine

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Barb MOA

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a. Barbiturates bind to an allosteric site on the GABAA R-Cl- Channel  →b. Also act to Directly inc. Cl- influx in the absence of GABA→ do NOT exhibit a “Ceiling Effect”

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Barb CNS

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General CNS depressants - - with ↑ in dose, can elicit all stages of anesthesia from mild sedation to disinhibition, anesthesia and finally respiratory depression with CV collapse and death.– Small T.I.

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Barb tolerance PB

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Drug-disposition tolerance  (“pharmacokinetic tolerance”) increase CYTOCHROME P-450 enzymes • Pharmacodynamic tolerance (“functional tolerance”) • Cross-tolerance among CNS depressant drugs

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Barb Clinical use

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Anxiety: largely replaced by BZ. Anticonvulsant -- PB Anesthesia– IV Thiopental

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Barb SE s

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Similar to BZ but more pronounced

1. Acute: a. Side-effects: pronounced drowsiness, rebound insomnia, confusion, ataxia, paradoxical excitement. b. Overdose toxicity: Barbiturate Poisoning - - was the leading causes of death in the past.
c. Allergic reactions: Skin rash, fever.

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Barb chronic

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Barbiturates have a high potential for dependence and abuse, Esp. SHORT-ACTING barbiturates

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Barb physical dependence

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Physical dependence - - Withdrawal Syndrome: 1) Rebound hyperexcitability of CNS can result in convulsions followed by CV collapse and death. 2) Treatment (“detoxification”) • Re-introduced a sedative-hypnotic— preferably a long-acting agent: e.g. Diazepam • Gradually decrease dose by 10-15% /week over 4-8 weeks.

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Chloral hydrate what is it

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VI.OTHER NON-BENZODIAZEPINE, NON-BARBITURATE SEDATIVE-HYPONOTICS- - Almost OBSOLETE

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Chloral hydrate MOA

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Short-acting, lipid-soluble sedative-hypnotic
with unpleasant taste; primarily used as a
hypnotic.
Acts as a prodrug - - converted to trichloroethanol in liver.
Irritating to the GI & causes epigastric distress

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Carbamates: meprobamate

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Meprobamate was introduced in 1954 - - prototype of the dicarbamates. • Acts very similar to the intermediate-acting barbiturates (e.g. amobarbital).

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Buspirone: what is it

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Nonsedating Anxiolytic Drugs:

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Busiprone MOA

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- May also interact with dopamine D2 R

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Buspirone Effects

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- Lacks hypnotic muscle relaxant and anticonvulsant properties of the other sedative-hypnotic drugs.  • Does not potentiate the depressant effects of alcohol & other CNS depressants • Does not have abuse potential or physical dependence liability.  - No rebound anxiety or withdrawal symptoms.

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Busiprone Clinical use

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Anxiolytic effect may require up to 7 to10 days and optimal effects may take 3 to 4 weeks.– DELAYED onset. b. May be the DOC in chronic anxiety, esp. in elderly pts and in anxious pts with a history of substance abuse.

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Buspirone SE

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a. Less sedating than sedative-hypnotics: Minimal impairment of cognitive and psychomotor function. b. Most common: dizziness, nausea, headache and nervousness.