SEDATIVE-HYPNOTIC DRUGS

sedatives or anxiolytics

• agents that reduce anxiety and exerts a calming effect

• no effect in sleep cycle

hypnotics

• aents that produces drowsiness and encourage the onset of maintenance of state of sleep

• alters sleep wake cycle

absorption of sedative-hypnotic drugs depend on similar factors, primarily on __

degree of lipophilicity

degree of lipophilicity

determines the rate a drug can enter the CNS and is responsible for its rapid onset of action (easily absorbed, rapid distribution)

sedative-hypnotic drugs

can cross placental barrier and may contribute to depression of neonatal vital signs when taken pre delivery period

sedative-hypnotic drugs

detectable in breast milk which may also cause depressant effect in the nursing infant

sedative-hypnotic drugs

drug classes

• benzodiazepines

• barbiturates

• newer hypnotics

• melatonin-receptor agonists

• orexin antagonists

• 5-ht receptor agonist

benzodiazepines

widely used class with their effects attributed to the presence of halogen or nitro grp at c7

benzodiazepines

metabolism is highly dependent on presence of 3-hydroxyl grp

benzodiazepines

with 3-oh

easily metabolized; shorter doa

benzodiazepines

without 3-oh

• long-acting; longer half-life

• not easily metabolized

benzodiazepines

metabolism

primary carried out by CYP 3A4, glucuronidation and urinary excretion

benzodiazepines

many phase 1 metabolites stay active and some have longer half-lives (40 hrs)

short half-life bzd

rapidly conjugated and are more useful as hypnotics than sedative

short half-life bzd

midazolam

Drugs included in BZD

• alprazolam

• chlordiazepoxide

• clonazepam

• clorazepate diazepam

• estrazolam

• flurazepam

• lorazepam

• midazolam

• oxazepam

• quazepam

• temazepam

• triazolam

barbiturates

effects are attributed to the 5,5-substitution of the barbituric acid structure

barbiturates

currently used less as anxiolytics due to numerous ADRs, drug effects, drug interactions, and high degree of tolerance noted (now used as anticonvulsants)

barbiturates

metabolism

primarily metabolized via hepatic metabolism through oxidative reactions leading to alcohols, acids, and ketone metabolites. glucuronidation takes place in phase ii, then slow urinary excretion

barbiturates follow same metabolism except

thiobarbital

20-30% phenobarbital

is excreted unchanged and elimination can be via urinary alkalinization

urinary alkalinization

treatment for phenobarbital toxicity/overdose (give sodium bicarbonate)

drugs included in barbiturates

• amobarbital

• butabarbital

• mephobarbital

• pentobarbital

• phenobarbital

• secobarbital

bzd and barbiturates

traditional sedative-hypnotics (many adrs and drug interactions)

newer hypnotics

agents with novel chemical structure that are not related to bzd but exhibit similar moa

drugs included in newer hypnotics

• zolpidem

• zaleplon

• eszopiclone

zolpidem

imidazopyridine

zaleplon

pyrazolopyrimidine

eszopiclone

cyclopyrrolone

newer hypnotics

metabolism

• CYP3A4 is primarily involved in metabolism via oxidative and hyroxylation reactions

• glucuronidation takes place in phase ii and then urinary excretion

melatonin receptor agonists

acts on melatonin receptors found in the suprachiasmic nuclei (SCN) in the anterior part of the hypothalamus

SCN

Responsible of regulating the circadian rhythm of the body (sleep wake cycle)

melatonin receptor agonists

activates receptors to inhibit arousal signaling and promote sleep

drugs included in melatonin receptor agonists

• ramelteon

• tasimelteon

orexin antsgonists

blocks orexin and other neuropeptides that are responsible for promoting wakefulness

drugs included in orexin antagonists

• suvorexant

• lemoborexant

orexin antagonists

metabolism

primarily metabolized by CYP3A4 but no glucuronidation

suvorexant

metabolism

mainly excreted in the feces and less in urine

serotonin receptor agonists

action is uncertsin but hypothesized as partial 5HT receptor agonists with possible affinity of D3 receptors (central inhibitory)

all sedative hypnotics will produce

inhibition; sedation, hypnotic and anxiolytic effect

BZD, barbiturates and newer hypnotics

• bind to components of GABA receptor which functions as Cl channel and is activated by GABA NTs

BZD, barbiturates and newer hypnotics

bind with the allosteric site of GABA receptors inducing opening of Cl channels. Cl ions will enter the cell making it negative leading to hyperpolarization (decreased neuron firing)

Zolpidem, zaleplon, eszopiclone

binds more selectively to GABA-a

BZD and other sedative hypnotics

have low affinity to GABA-b

BZD moa

potentiate GABAergic inhibition at all lvls

BZD potentiate GABAergic inhibition at all levels of the CNS

increases the efficacy of GABAergic synaptic inhibition but do not substitute GABA, only enhancing Cl ion conductance by increasing frequency of channel opening events

Barbiturates moa

interacts with GABA at multipls site similar to BZD

barbiturates interacts with GABA at multipls site similar to BZD

• increases the duration of GABA-gates d cl-channel openings

Barbiturates moa

depress the action of excitatory nt glutamic acid making it less selective than bzd but can lead to more pronounce CNS depressant effect and even induced full surgical anesthesia

drug effects

• sedation

• hypnosis

• anesthesia

• anticonvulsant

• muscle relaxation

• respiratory and cv function

sedation

• BZDs, barbiturates and older agents exert calming/ anxiolytic effect (low doses)

• BZDs exhibit dose-dependent anterograde amnesia

BZDs, barbiturates and older agents

exert calming/ anxiolytic effect (low doses)

BZDs exhibit

dose-dependent anterograde amnesia

hypnosis

varying effects on the latency and onset of non-rem and rem sleep

anesthesia

• thiopental and methohexital- good agents (fast onset and tissue distribution

• BZDs (diazepam, lorazepam, midazolam)- IV agents used as adjuncts

• newer agents lack anesthetic activity

thiopental and methohexital

- good agents for anesthesia (fast onset and tissue distribution

BZDs (diazepam, lorazepam, midazolam)

- IV agents used as adjuncts for anesthesia

newer agents lack

anesthetic activity

anticonvulsant

• BZDs (clonazepam, nitrazepam, diazepam, lorazepam)

• Barbiturates (phenobarbital, metharbital) for generalized tonic-clonic seizures

• zolpidem, zaleplon, eszopiclone lack anticonvulsant activity (more on sedative)

BZDs used as anticonvulsant

(clonazepam, nitrazepam, diazepam, lorazepam)

Barbiturates (phenobarbital, metharbital)

for generalized tonic-clonic seizures

zolpidem, zaleplon, eszopiclone lack

anticonvulsant activity (more on sedative)

muscle relaxation

high dose meprobamate, bzd- inhibit transmission at skeletal neuromuscular junction

high dose meprobamate, bzd

- inhibit transmission at skeletal neuromuscular junction (muscle relaxation)

respiratory and cv function

• may cause respiratory depression and orthostatic hypotension

• effects are more significant when agents are given as IV drugs

clinical usses

• anxiety relief (secondary and GAD)

• insomnia

• surgical sedation/ anesthesia (short-acting agents are preferred)

• epilepsy and seizure states

• balanced anesthesia

• alcohol/sedaive-hypnotic withdrawal states

• diagnostic aid in psychiatric conditions

BZD

adverse effect

• cns depression

• drowsiness

• ataxia

• confusion

• dysarthria

• nausea

• vomiting

• diarrhea

• potential for abuse and dependence

flumazenil

gaba receptor antagonist; antidote for bzd toxicity

barbiturates adr

• cns effects

• respiratory depression

• bradycardia

• orthostatic hypotension

• exfoliatve dermatitis

• headache

• fever

• hepatotoxicity

• megaloblastic anemia (phenobarbital)

buspirone adr

• restlessness

• dizziness

• headache

• diarrhea

• paresthesia

other effects

teratogenicity

SJS and toxic epidermal necolysis

• rare; immuned

• mucocutaneous

• type 4 hypersensitivity

• associated with barbiturates and azaspirodecanediones