Sedative-Hypnotic Drugs

Subclass, Drug Mechanism of Action Effects Clinical Applications P, T, I

Benzodiazepines: Binds to specific GABAa Enhance membrane Dose-dependent depressant Extensions of CNS depressant
receptor subunits at central hyperpolarization effects on the CNS including effects, dependence liability
nervous system (CNS) sedation and relief of anxiety,
Alprazolam neuronal synapses facilitating amnesia, hypnosis,
GABA-mediated chloride ion anesthesia, coma, respiratory
channel opening frequency depression
Same Same Same Same
Chlordiazepoxide
Same Same Same Same
Clonazepam
Same Same Acute anxiety states, panic Same
attacks, generalized anxiety
Clorazepate disorder, insomnia and other
sleep disorders, relaxation of
skeletal muscle, anesthesia
(adjunctive), seizue disorders
Same Same Same Same
Diazepam
Same Same Same Same
Estazolam
Same Same Same Same
Flurazepam
Same Same Same Same
Lorazepam
Same Same Same Same
Midazolam
Same Same Same Same
Oxazepam
Same Same Same Same
Quazepam
Same Same Same Same
Temazepam
Same Same Same Same
Triazolam
Benzodiazepine
Antagonist:

1
 Antagonist at Blocks actions of Management of Agitation, confusion, possible
benzodiazepine-binding sites benzodiazepines and benzodiazepine overdose withdrawal symptoms in
Flumazenil on the GABAa receptor zolpidem but not other benzodiazepine dependence
sedative-hypnotic drugs
Barbiturates: Binds to specific GABAa Dose-dependent depressant Anesthesia (thiopental) Extensions of CNS depressant
receptor subunits at CNS effects on the CNS including Insomnia (secobarbital) effects, dependence liability
neuronal synapses facilitating sedation and relief anxiety, Seizure disorders > benzodiazepines
GABA-mediated chloride ion amnesia, hypnosis, (phenobarbital)
channel opening duration anesthesia, coma and
Amobarbital Enhances hyperpolarization respiratory depression,
steeper close-response
relationship than
benzodiazepines
Same Same Same
Butabarbital
Same Same Same
Mephobarbital
Same Same Same
Pentobarbital
Same Same Same
Phenobarbital
Same Same Same
Secobarbital
Newer Hypnotics: Binds selectively to a Rapid onset of hypnosis with Sleep disorders, especially Extensions of CNS depressant
subgroup of GABAa few amnestic effects of day- those characterized by effects, dependence liability
receptors, acting like after psychomotor difficulty in falling asleep
Eszopiclone benzodiazepines to enhance depression or somnolence
mebrane hyperpolarization
Same Same Same Same
Zaleplon
Same Same Same Same
Zolpidem
Orexin Receptor Sleep-enabling drug
Antagonists:
Almorexant
Same
Suvorexant
Melatonin Receptor
Agonists:

2
 Activates MT1 and MT2
receptors in suprachiasmatic
Ramelteon nuclei in the CNS (both)
Orally active MT1 and MT2
agonist, recently approved
Tasimelteon for non-24 hour sleep
disorder
5-HT-Receptor Agonist: Mechanism uncertain: partial
agonist at 5-HT receptors but
affinity for D2 receptors also
possible
Slow-onset anxiolytic agent
Buspirone whose actions are quite
different from those of
conventional sedative-
hypnotics
Alcohols and Associated Multiple effects on
Drugs: neurotransmitter receptors,
ion channels, and signaling
Alcohols: pathways
Ethanol
Poisonings result in toxic
levels of formate, which
Methanol causes characteristic visual
[Methyl alcohol, Wood disturbance plus coma,
alcohol] seizures, acidosis, and death
due to respiratory failure
Poisoning creates toxic
aldehydes and oxalate, which
Ethylene Glycol causes kidney damage and
[Polyhydric alcohol] severe acidosis
Drugs Used in Acute
Ethanol Withdrawal:
Rapid onset of sleep with
minimal rebound insomnia or
withdrawal symptoms
Slow-onset (1-2 weeks) of
anxiolytic effects, minimal
psychomotor impairment
Antidote in methanol and
ethylene glycol poisoning
Widely used in the industrial
production of synthetic
organic compounds and as a
constituent of many
commercial solvents
Used as heat exchanger, in
antifreeze formulations, and
as industrial solvents
IV ethanol is an alternative to
fomepizole in ethylene glycol
poisoning
Sleep disorders especially
those characterized by
difficulty in falling asleep, not
a controlled substance
Generalized anxiety states
Dizziness, fatigue, endocrine
changes
Tachycardia, paresthesias,
gastrointestinal distress
Acutely CNS depression and
respiratory failure,
chronically damage to many
systems, including liver,
pancreas, GIT, and central
and PNSs
Visual disturbance (“like
being in a snowstorm”)
3
 BDZ receptor agonists that
Benzodiazepines facilitate GABA-mediated
[Chlordiazepoxide, Diazepam, activation of GABAa
Lorazepam] receptors
Essential vitamin required for
synthesis of the coenzyme
thiamine pyrophosphate
Thiamine
(Vitamin B1)
Drugs Used in Chronic Nonselective competitive
Alcoholism: antagonist of opioid
receptors
Relatively long-acting opioid
antagonist, blocks the effects
Naltrexone at mu-opioid receptors
Poorly understood NMDA
receptor antagonist and
Acamprosate GABAa agonist effects
Inhibits aldehyde
dehydrogenase, resulting in
Disulfiram aldehyde accumulation
during ethanol ingestion
Drugs Used in Acute Inhibits alcohol
Methanol or Ethylene dehydrogenase, prevents
conversion of methanol and
Glycol Toxicity: ethylene glycol to toxic
Fomepizole metabolites
Higher affinity than methanol
Ethanol or ethylene glycol for alcohol
Prevention and tx of acute
ethanol withdrawal
syndrome
Administered to patients
suspected of having
alcoholism (those exhibiting
acute alcohol intoxication or
alcohol withdrawal
syndrome) to prevent
Wernicke-Korsakoff
syndrome
Reduced risk of relapse in Tx of alcohol dependence GI effects and live toxicity;
individuals with alcoholism will precipitate a withdrawal
reaction in individuals
physically dependent on
opioids and will prevent the
analgesic effect of opioids
Reduced risk of relapse in GI effects and rash
individuals with alcoholism
Multiple effects on
neurotransmitter receptors,
ion channels and signaling
pathways
Deterrent to drinking in Little effect alone but severe
individuals with alcohol and potentially dangerous
dependence flushing, headache, nausea,
Extreme discomfort to vomiting, and hypotension
individuals who drink when combined with ethanol
alcoholic beverages
Methanol and ethylene glycol Headache, nausea, dizziness,
poisoning rare allergic reactions
Used to reduce metabolism
of methanol and ethylene
4
 dehydrogenase
Antiseizure Drugs: Block high-frequency firing of
Cyclic Ureids: neurons through action on
Hydrantoin: voltage-gated (VG) sodium
channels
Phenytoin, Decrease synaptic release of
glutamate
Fosphenytoin
2 desoxyphenobarbital
Primidone Similar to phenytoin but
converted to phenobarbital
Enhances phasic GABAa
receptor responses
Phenobarbital Reduces excitatory synaptic
responses
Reduces low-threshold
calcium currents (T-type)
Ethosuximide
Tricyclics: Similar to carbamazepine;
shorter half-life but active
metabolite with longer
Oxcarbazepine duration and fewer
interactions reported
Similar to oxcarbazepine but
shown to be effective when
Eslicarbazepine give once daily and may be
more rapidly converted to
Acetate the active metabolite
Blocks high frequency firing
of neurons through action on
Carbamazepine voltage-gated sodium
channels
glycol to toxic products
Absorption is formulation
dependent highly bound to
plasma proteins
No active metabolites
Dose-dependent elimination
Fosphenytoin is for IV, IM
routes
Independent antiseizure
action independent of its
conversion to phenobarbital
DOC for seizure in infants
Inhibit calcium currents
which provide a pacemaker
current in thalamic neurons
responsible for generating
rhythmic cortical discharge of
an absence attack
DOC for partial and
generalized tonic-clonic
seizures
Decreases high frequency
repetitive firing of neurons
Adjunctive therapy in adults
with partial-onset seizures,
with or without secondary
generalization
Bipolar depression
DOC for partial seizures +
used in bipolar disorders
Generalized tonic-clonic
seizures, partial seizures
Grand mal seizure
Oldest non-sedating
antiseizure drug
Generalized tonic-clonic
seizures, partial seizures
Complex partial seizure
Generalized tonic-clonic
seizures, partial seizures,
myoclonic seizures,
generalized seizures,
neonatal seizures, status
epilepticus
Absent seizures
DOC for pure petit mal
seizure
Generalized tonic-clonic
seizures, partial seizures
Diplopia, ataxia, gingival
hyperplasia, hirsutism,
neuropathy, nystagmus,
sedation, megaloblastic
anemia
Sedation, cognitive issues,
ataxia, hyperactivity
Sedation, cognitive issues,
ataxia, hyperactivity
Nausea, diplopia, ataxia,
hyponatremia, headache
Unsteadiness, drowsiness,
agranulocytosis
Nausea, diplopia, ataxia,
hyponatremia, headache,
idiosyncratic blood dyscrasias
5
 Decreases synaptic release of
glutamate
Benzodiazepines: Potentiates GABAa responses
Safer parenteral agent for
Diazepam the tx of status epilepticus
As for diazepam
Clonazepam
GABA Derivatives: Decreases excitatory
transmission by acting on
voltage-gated calcium
Gabapentin channels presynaptically
(alpha2delta subunit)
Analog of GABA (amino acid)
As for gabapentin
Pregabalin
Irreversibly inhibits GABA-
Vigabatrin transaminase
Enhances GABA action
Other Drugs: Blocks high-frequency firing
of neurons
Modifies amino acid
Valproate metabolism
Blocks NMDA-receptor
mediated excitation
Prolongs inactivation of
voltage-gated sodium
channels
Acts presynaptically on
Lamotrigine voltage-gated calcium
channels, decreasing
glutamate release
Action on synaptic protein
SV2A
Levetiracetam Prominent activity in kindling
model
Binds avidly to the voltage N-
type calcium channels
Spasmolytic
Tx of neuropathic pain and
postherpetic neuralgia
Tx of neuropathic pain,
including painful diabetic
peripheral neuropathy, and
postherpetic neuralgia
DOC for juvenile myoclonic
epilepsy
Suppresses sustained rapid
firing of neurons and
produces a voltage and use
dependent blockade of
sodium channels
Ineffective in seizures
induced by maximum
electroshock or
pentylenetetrazol
Status epilepticus, seizure Sedation
clusters
Absence seizures, myoclonic Sedation
seizures, infantile spasms
Generalized tonic-clonic Somnolence, dizziness,
seizures, partial seizures, ataxia, drowsiness, muscle
generalized seizures pain, eyesight problems
Has analgesic property
Fibromyalgia
partial seizures with or Somnolence, dizziness, ataxia
without secondary
generalization
Partial seizures, infantile Drowsiness, dizziness,
spasms psychosis, visual field loss
Generalized tonic-clonic Nausea, tremor, weight gain,
seizures, partial seizures, hair loss, teratogenic,
generalized seizures, absence hepatotoxic, spina bifida
seizures, myoclonic seizures
Bipolar disorders
Migraine
Generalized tonic-clonic Dizziness, headache, diplopia,
seizures, partial seizures, rash, nausea, somnolence
generalized seizures, absence
seizures,
Bipolar disorders
Lenox-Gastaut syndrome
Generalized tonic-clonic Nervousness, dizziness,
seizures, partial seizures, depression, seizures
generalized seizures
6
 Enhances potassium channel
opening
Retigabine Potassium channel facilitator
Prolongs inactivation of
Rufinamide voltage-gated sodium
channels
Blocks GABA reuptake in
forebrain by selective
Tiagabine blockade of GAT-1
Derivative of nipecotic acid
Multiple actions on synaptic
function, probably via actions
Topiramate on phosphorylation
Blocks high-frequency firing
via action on voltage-gated
Zonisamide sodium channels
Acts on sodium and voltage-
gated calcium channels
Enhances slow activation of
Lacosamide sodium channels
Binds to AMPA receptors at
noncompetitive site with
high selectivity
Orally active AMPA
Perampanel antagonist
Causes use-dependent block
Felbamate of the NMDA receptor
Inhibits calcium channels and
Brivaracetam release from intracellular
An inhibitor of GABA uptake
in both neurons and glia
Prolongs the inhibitory action
of synaptically released GABA
AMPA receptor blocker
Binds to an allosteric site on
the glutamate-gated sodium-
potassium AMPA channel
Causes barbiturate-like
potentiation of GABA
receptor responses
Adjunctive tx of partial
seizures
Adjunctive tx of the Lenox-
Gastaut syndrome
4 years old
Partial seizures
Generalized tonic-clonic
seizures, partial seizures,
generalized seizures, absence
seizures, migraine, infantile
spasms, absence seizure,
Lenox-Gastaut syndrome
Generalized tonic-clonic
seizures, partial seizures,
myoclonic seizures
Generalized tonic-clonic
seizures, partial seizures
Partial seizures with or
without secondary
generalization
Partial seizures
rd
3 -line drug for refractory
cases
Myoclonic seizures of
juvenile myoclonic epilepsy
Dizziness, somnolence,
confusion, blurred vision,
asthenia, blue pigmentation
in the skin and lips
Somnolence, vomiting,
pyrexia, diarrhea
Nervousness, dizziness,
depression, seizures
Somnolence, cognitive
slowing, confusion,
paresthesias
Drowsiness, cognitive
impairment, confusion, skin
rashes
Dizziness, headache, nausea,
small increase in PR interval,
diplopia
Dizziness, somnolence,
headache, psychiatric
syndromes, serious and life-
threatening behavioral
changes (aggression,
hostility, irritability, and
anger)
Aplastic anemia, severe
hepatitis
Ataxia, dizziness, mood and
behavioral changes,
7
 stores
Enhances GABAergic
transmission in the brain,
partly through a barbiturate-
like effect
Stiripentol Prolonged opening of the
chloride in GABA receptors
Raises threshold for seizure
Trimethadione discharge after repetitive
thalamic discharge
Carbonic anhydrase inhibitor
Acetazolamide diuretic
Increases GABA levels in the
brain
Potent inhibitor of CYP3A4,
CYP1A2, and CYP2C19
Causes metabolic acidosis
responsible for its antiseizure
activity
psychotic reactions are rare
Used with clobazam and
valproate in the adjunctive
therapy of refractory
generalized tonic-clonic
seizures in patients with
severe myoclonic epilepsy of
infancy
Absence seizures Sedation