Sedative-hypnotic drugs

Sedative-hypnotics are a group of drugs that cause central nervous system (CNS) depression.
Benzodiazepines and barbiturates are the most commonly used agents in this class. Other agents
include the nonbarbiturate nonbenzodiazepine sedative-hypnotics. Most cases of severe sedative-
hypnotic poisoning are deliberate (suicidal). These agents are also commonly abused as recreational
drugs.

Indications:
• Benzodiazepines are commonly prescribed for anxiety and panic disorder.
• Nonbenzodiazepine hypnotics may be used for the treatment of insomnia based on their
short duration of action.
• Anxiolytics - for the treatment of spasticity.
• Barbiturates are rarely prescribed due to risk of respiratory depression, although
occasionally used for migraines, spasticity, and seizure disorder.

Mechanisms of action:
• All facilitate inhibitory neurotransmission via gamma-aminobutyric acid (GABA) receptor
chloride channel, modifying the frequency or duration of channel opening.
• Sedative-hypnotics may also decrease excitatory glutamate transmission, affect alpha-
amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, and
interact with N-methyl D-aspartate (NMDA) receptors.

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Pharmacokinetics
• Rapidly absorbed when administered orally.
• Rate of central nervous system (CNS) penetration determines onset of effects.
• Nearly all commonly encountered agents are hepatically metabolized.
• Half-life information is misleading due to active metabolites and drug-specific effects, and
correlate poorly with duration of clinical effect.
• Duration of action is variable:
o Short-acting agents: zolpidem, zaleplon, eszopiclone.
o Intermediate-acting agents: lorazepam and diazepam.
o Long-acting agents: baclofen, phenobarbital, and clonazepam.

Benzodiazepines
Benzodiazepines are one of the most commonly prescribed medications to treat anxiety,
insomnia, and other conditions. Benzodiazepine core chemical structure is composed of diazepine
fused to a benzene ring. Different benzodiazepines have different side chains, which determine their
pharmacokinetic profile. Benzodiazepines are used for their anxiolytic, antiepileptic, muscle
relaxant, and hypnotic effects. Apart from their medical benefit, they have the potential for abuse
and misuse.

Mechanism of action
Benzodiazepines affect a key neurotransmitter in the brain called gamma-amino butyric acid
(GABA). This neurotransmitter has an inhibitory effect on motor neurons, thus the presence of
GABA slows or stops neuronal activity. Benzodiazepines enhance the activity of GABA,
effectively slowing nerve impulses throughout the body. The human nervous system has two
different types of benzodiazepine receptors: one that causes the anti-anxiety effect, and one that
elicits the sedative effect.

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 Figure. Diagram of mechanism of action of the natural neurotransmitter GABA (gamma-
aminobutyric acid) and benzodiazepines on nerve cells (neurons) in the brain
1,2 - Nerve impulse causes release of GABA from storage sites on neuron 1
3 - GABA released into space between neurons
4 - GABA reacts with receptors on neuron 2; the reaction allows chloride ions (CI–) to enter the
neuron
5 - This effect inhibits further progress of the nerve impulse
6,7 - Benzodiazepines react with booster site on GABA receptors
8 - This action enhances the inhibitory effects of GABA; the ongoing nerve impulse may be
completely blocked

As a consequence of the enhancement of GABA's inhibitory activity caused by benzodiazepines,

the brain's output of excitatory neurotransmitters, including norepinephrine (noradrenaline),
serotonin, acetyl choline and dopamine, is reduced. Such excitatory neurotransmitters are necessary
for normal alertness, memory, muscle tone and co-ordination, emotional responses, endocrine gland
secretions, heart rate and blood pressure control and a host of other functions, all of which may be
impaired by benzodiazepines. Other benzodiazepine receptors, not linked to GABA, are present in
the kidney, colon, blood cells and adrenal cortex and these may also be affected by some
benzodiazepines. These direct and indirect actions are responsible for the well-known adverse
effects of dosage with benzodiazepines.

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 Pharmacology
There are major differences in potency between different benzodiazepines, so that equivalent
doses vary as much as 20-fold. For example, 0.5 milligrams (mg) of alprazolam is approximately
equivalent to 10mg of diazepam.
Benzodiazepines also differ markedly in the speed at which they are metabolised (in the liver
benzodiazepines undergo hepatic oxidation and reduction (by cytochrome P450) and glucuronide
conjugation) and eliminated from the body (in the urine). For example, the "half-life" (time taken
for the blood concentration to fall to half its initial value after a single dose) for triazolam is only 2-
5 hours, while the half-life of diazepam is 20-100 hours, and that of an active metabolite of
diazepam (desmethyldiazepam) is 36-200 hours. Most of benzodiazepine metabolites are
pharmacologically active.

Figure. Benzodiazepines metabolic pathways

Although most benzodiazepines trigger the same physical effects, their dosage and absorption
time into the bloodstream can vary widely. The medications are broken into two separate categories
for classification-short-acting and long-acting. A short-acting benzodiazepine is cleared from the
body in a short period of time, whereas long-acting benzodiazepines may either accumulate in the
bloodstream or take a much longer period of time to leave the body. There is modest evidence that
benzodiazepines with a shorter half-life are associated with a greater risk of dependence, so
benzodiazepine abstinence occurs more rapidly with the use of short-acting benzodiazepines.
Benzodiazepines with short half-lives (less than 12 hours) include lorazepam and temazepam.
Because of problems with dependence, long-acting compounds are preferable for the management
of anxiety. A particular benzodiazepine's classification determines what it is prescribed for, as well
as its potential for tolerance, dependence, and abuse.

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Table. Metabolism and elimination of select benzodiazepines
Parent drug Approximate Time to peak Metabolic Elimination Metabolites Detection
equivalent plasma level pathway halflife of window in
dose following oral parent drug urine drug
administration (hours) screening
(hours) (days)
Diazepam 5mg 0.5-2 Demethylation 20-80 Desmethyldiazepam (major) 10-30 days
Hydroxylation Temazepam (minor)
Oxazepam (minor)
Alprazolam 0.5mg 1-2 Hydroxylation 12-15 α-hydroxyalprazolam 5 days
Clonazepam 0.25mg 1-4 Nitroreduction 30-40 7-amino-clonazepam 5 days
Acetylation
Oxazepam 15 mg 2-4 Conjugation 5-20 Oxazepamglucuronide 5 days
Temazepam 15 mg 1-2 Conjugation 3-13 Oxazepam 1-4 days
Lorazepam 1 mg 2-4 Conjugation 10-20 Lorazepam glucuronide 5 days
Midazolam 5 mg Hydroxylation 1-4 4- Hydroxymidazolam 0.5-2 days

1- Hydroxymidazolam
Chlordiazepoxide 25 mg 1-4 N-demethylation 6.5-28 Desmethylchlordiazepoxide 5-30 days
Hydroxylation Desmethyldiazepam (active)
Oxazepam (active)

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 Therapeutic actions of benzodiazepines
Regardless of their potency, speed of elimination or duration of effects, the actions in the body
are virtually the same for all benzodiazepines. This is true whether they are marketed as anxiolytics,
hypnotics or anti-convulsants. All benzodiazepines exert five major effects which are used
therapeutically: anxiolytic, hypnotic, muscle relaxant, anticonvulsant and amnesic (impairment of
memory).

Effects on the body and toxicity

Short Term Effects. Benzodiazepines are prescribed for relaxation, calmness, and relief from
anxiety and tension. In some cases side effects will occur; these vary widely depending on the type
of benzodiazepine, the dose, and the person. They can include:
• Impaired motor coordination
• Drowsiness, lethargy, fatigue
• Impaired thinking and memory
• Confusion
• Depression
• Altered vision
• Slurred speech, stuttering
• Vertigo
• Tremors
• Respiratory depression
• Nausea, constipation, dry mouth, abdominal discomfort, loss of appetite, vomiting,
diarrhea
At high doses benzodiazepines can cause extreme drowsiness. In addition to the adverse effects
listed above, the following are also observed:
• Slowed reflexes
• Mood swings
• Hostile and erratic behavior
• Euphoria
Long Term Effects. Some benzodiazepines are eliminated from the body slowly. Thus, ingesting
multiple doses over long periods of time can lead to significant accumulation in fatty tissues. The
symptoms of over-sedation may not appear for a few days. Some include:
• Impaired thinking, memory, and judgment
• Disorientation
• Confusion
• Slurred speech
• Muscle weakness, lack of coordination

Oversedation is a dose-related extension of the sedative/hypnotic effects of benzodiazepines.

Symptoms include drowsiness, poor concentration, incoordination, muscle weakness, dizziness and
mental confusion. When benzodiazepines are taken at night as sleeping pills, sedation may persist
the next day as "hangover” effects, particularly with slowly eliminated preparations. Oversedation
persists longer and is more marked in the elderly and may contribute to falls and fractures. Acute
confusional states have occurred in the elderly even after small doses of benzodiazepines.
Memory impairment. Benzodiazepines have long been known to cause amnesia, an effect which
is utilised when the drugs are used as premedication before major surgery or for minor surgical
procedures.

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 Paradoxical stimulant effects. Benzodiazepines occasionally cause paradoxical excitement with
increased anxiety, insomnia, nightmares, hallucinations at the onset of sleep, irritability, hyperactive
or aggressive behaviour, and exacerbation of seizures in epileptics.
Depression, emotional blunting. Long-term benzodiazepine users, like alcoholics and
barbituratedependent patients, are often depressed, and the depression may first appear during
prolonged benzodiazepine use. Benzodiazepines may both cause and aggravate depression, possibly
by reducing the brain's output of neurotransmitters such as serotonin and norepinephrine
(noradrenaline). However, anxiety and depression often co-exist and benzodiazepines are frequently
prescribed for mixed anxiety and depression. Sometimes the drugs seem to precipitate suicidal
tendencies in such patients.
Adverse effects in the elderly. Older people are more sensitive than younger people to the central
nervous system depressant effects of benzodiazepines. Benzodiazepines can cause confusion, night
wandering, amnesia, ataxia (loss of balance), hangover effects and “pseudodementia” (sometimes
wrongly attributed to Alzheimer’s disease) in the elderly and should be avoided wherever possible.
Increased sensitivity to benzodiazepines in older people is partly because they metabolise drugs less
efficiently than younger people, so that drug effects last longer and drug accumulation readily
occurs with regular use. However, even at the same blood concentration, the depressant effects of
benzodiazepines are greater in the elderly, possibly because they have fewer brain cells and less
reserve brain capacity than younger people. For these reasons, it is generally advised that, if
benzodiazepines are used in the elderly, dosage should be half that recommended for adults, and use
(as for adults) should be short-term (2 weeks) only. In addition, benzodiazepines without active
metabolites (e.g. oxazepam, temazepam) are tolerated better than those with slowly eliminated
metabolites (e.g. chlordiazepoxide, nitrazepam).
Adverse effects in pregnancy. Benzodiazepines cross the placenta, and if taken regularly by the
mother in late pregnancy, even in therapeutic doses, can cause neonatal complications. The foetus
and neonate metabolise benzodiazepines very slowly, and appreciable concentrations may persist in
the infant up to two weeks after birth, resulting in the "floppy infant syndrome" of lax muscles,
oversedation, and failure to 10 suckle. Withdrawal symptoms may develop after about two weeks
with hyperexcitability, high-pitched crying and feeding difficulties. Benzodiazepines in therapeutic
doses appear to carry little risk of causing major congenital malformations. However, chronic
maternal use may impair foetal intrauterine growth and retard brain development. There is
increasing concern that such children in later life may be prone to attention deficit disorder,
hyperactivity, learning difficulties, and a spectrum of autistic disorders.

Oral benzodiazepine overdoses, without co-ingestions, rarely result in significant morbidity (eg,
aspiration pneumonia, rhabdomyolysis) or mortality. In mixed overdoses, they can potentiate the
effect of alcohol or other sedative-hypnotics. Acute intravenous administration of benzodiazepines
is associated with greater degrees of respiratory depression.
Patients receiving prolonged parenteral administration of benzodiazepines are at risk for
propylene glycol poisoning (the diluent used in parenteral formulations of diazepam and
lorazepam). Although rare, this may result in hypotension, cardiac dysrhythmias, lactic acidosis,
seizures, or coma.
Symptoms of benzodiazepine overdose may include the following:
• Dizziness
• Confusion
• Drowsiness
• Blurred vision
• Unresponsiveness
• Anxiety
• Agitation

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 Findings on physical examination may include the following:
• Nystagmus
• Hallucinations
• Slurred speech
• Ataxia
• Coma
• Hypotonia
• Weakness
• Altered mental status, impairment of cognition
• Amnesia
• Paradoxical agitation
• Respiratory depression
• Hypotension

Treatment of overdose
As with any overdose, the first step is an assessment of the patient's airway, breathing, and
circulation, and these should be addressed rapidly as needed. In any patient with an altered mental
status, a blood glucose level should be obtained immediately. The cornerstone of treatment in
benzodiazepine overdoses is good supportive care and monitoring. Single-dose activated charcoal is
not routinely recommended as the risks far outweigh the benefit. Benzodiazepines are very rarely
fatal in overdoses, although the resulting altered mental status greatly increases the risk of
aspiration following oral charcoal dose.
Flumazenil is a specific antidote for benzodiazepine poisoning, although its use in acute
benzodiazepine overdose is controversial and its risks usually outweigh any possible benefit. In
long-term benzodiazepine users, flumazenil may precipitate withdrawal and seizures; in patients
taking benzodiazepines for a medical condition, flumenazil may result in exacerbation of the
condition.

Diagnosis
Immunoassay screening techniques are performed most commonly. These tests typically detect
benzodiazepines that are metabolized to desmethyldiazepam or oxazepam; thus, a negative
screening result does not rule out the presence of a benzodiazepine.

Tolerance
Tolerance to benzodiazepines develops at different rates and to different degrees for the various
actions. Tolerance to hypnotic effects develops rapidly, within a few days or weeks of regular use.
Studies in elderly patients indicate that, when taken over long periods, benzodiazepines have little
effect on sleep. Tolerance to the anxiolytic effects of benzodiazepines develops more slowly, over a
few months, and clinical observations show that long-term use does little to control, and may even
aggravate, anxiety.
Tolerance to the anticonvulsant effects of benzodiazepines occurs within a few weeks in a high
proportion of patients with epilepsy and also to the muscular relaxant effects when used in patients
with spastic disorders. Of particular clinical importance, however, is the finding that little tolerance
develops to the amnesic effects and other cognitive impairments caused by benzodiazepines.
Studies of long-term users have shown deficits in learning, memory, attention and visuospatial
ability.

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 Escalation of dosage and chronic use of benzodiazepines cause additional adverse effects
including depression, excessive sedation, leading to falls and fractures, road traffic and other
accidents (especially when combined with alcohol), and the insidious development of increasing
psychological and physical symptoms.

Dependence
The key signs of benzodiazepine dependence are withdrawal symptoms on dosage reduction or
discontinuation. However, dependence can often be inferred in continuing benzodiazepine users
from a history of longterm use, reliance on regular prescriptions, dosage escalation, unsuccessful
attempts to cut down or stop drug use, and high anxiety levels. Chronic benzodiazepine users with a
history of other drug or alcohol dependence are also likely to be dependent.
How to identify benzodiazepine abuse:
• Often times, Benzo abusers will initially deny their problem by blaming their drug use on
work or family stress or by playing down the extent of their use.
• Benzo abusers tend to show a detachment from life events, goals, and/or family.
• Benzo abusers may obtain prescriptions from multiple doctors or may have one or more
visits to the emergency room.
• Benzo abuse can cause both physical and psychological dependence.

Withdrawal symptoms of acute drug abuse include:

• drowsiness
• confusion
• poor coordination
• difficulty breathing
• blurred vision
• amnesia
• weakness
• impaired judgment
• reduced inhibition

Withdrawal symptoms of chronic drug abuse include:

• elevated anxiety
• rebound insomnia
• headaches
• weakness
• panic attacks
• tremors
• sweating/flushing
• seizures
• hallucinations
• psychosis

Treatment of withdrawal symptoms and dependence

The overall consensus is that benzodiazepines should be discontinued gradually over a period of
several weeks (e.g., 4 to 6 weeks or more for diazepam doses >30 mg per day), to prevent seizures
and avoid severe withdrawal symptoms. The withdrawal rate is often determined by a person’s
capacity to tolerate symptoms. Recommendations range from reducing the initial benzodiazepine
dose by 50% every week or so to reducing the daily dose by between 10% and 25% every 2 weeks.
A period of 4 to 6 or 4 to 8 weeks is suitable for withdrawal for most patients. If possible,
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prolonged reductions over a period of many months should be avoided in order to prevent the
withdrawal treatment from becoming the patient’s “morbid focus.”
Whether switching to a long-acting agent such as diazepam has fundamental advantages is
unclear, as is the question of whether hospital admission is required for a “blind reduction” (i.e., the
patient is not told the exact dose). The use of several benzodiazepines should be converted to the
use of one, preferably diazepam.

Barbiturates

Barbiturates are the earliest class of sedative-hypnotic agents to be developed and were first used
in medicine in the early 1900s and remained widely prescribed prior to the development of the less
toxic hypnosedative drug class known as benzodiazepines. Their popularity peaked in the 1960s and
1970s for treatment of insomnia, anxiety, and seizures. Also known by street names such as, “reds”,
“downers”, “barbs”, “yellow jackets”, “blue heavens”, and “nenbies”, barbiturates’ owe their
various effects to a combination of a pyrimidinetrione ring structure and the overall size and
structure of the C-5 position substituents.

Barbiturates may be grouped functionally into long- and short-acting agents (consisting of
ultrashort-, short-, and intermediate-acting agents). However, the relevance of this classification
system in terms of prognosis remains to be well defined as the agents’ duration of action is only
partially correlated with half-life (the remaining differences are accounted for with tissue binding
and distribution). All of the drugs in this class are derivatives of barbituric acid, which was the
original compound developed in 1864. However, the structure of each barbiturate differs and can be
related to its effective duration of action.

Mechanism of action
The molecular site of action for the barbiturates is nearly the same as for the benzodiazepines.
Like benzodiazepines, barbiturates bind at a unique site on the GABA-A receptor. However, there
is a significant difference in the effect of barbiturates at these receptors that is dependent on the
dose administered. At lower doses, barbiturates act like benzodiazepines, and simply increase the
effect of GABA at the GABA-A receptor. However, at higher doses, barbiturates may act as direct

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agonists at GABA-A receptors in the place of GABA, producing profound CNS depression. This
partially explains the increased risk associated with barbiturate use relative to benzodiazepine risk.

Pharmacokinetics
Compared with long-acting agents, short-acting agents are more lipid soluble, more protein
bound, have a higher pKa, a more rapid onset, shorter duration of action, and are metabolized
almost entirely in the liver to inactive metabolites (which are excreted as glucuronides in the urine).
Long-acting agents are less lipid soluble, accumulate more slowly in tissue, and are excreted more
readily by the kidney as active drug. For instance, urinary excretion accounts for 20-30% of
phenobarbital and 15-42% of primidone elimination (both long-acting agents). Specifically, the
duration of action depends mainly on the alkyl groups attached to C-5. The structure of these alkyl
groups determine lipid solubility of the drug in that the duration of action decreases as the total
number of carbons at C-5 increases.
Short-acting agents have an elimination half-life of less than 40 hours compared with long-acting
agents, which have an elimination half-life of longer than 40 hours. The elimination half-life of
barbiturates can be greatly shortened in infants and children and very prolonged in the elderly and
in patients with liver or renal disease. Most barbiturates are metabolized in the liver to inactive
metabolites.

Figure. Barbiturates metabolic pathways

Barbiturates readily distribute throughout the body to most tissues, crossing the blood–brain
barrier and placenta and being excreted in breast milk.
Chronic barbiturate use induces activity of the cytochrome P-450 enzymes and may accelerate
the metabolism of other therapeutic drugs, such as oral contraceptives, anticoagulants, and
corticosteroids, when taken concurrently

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 Effects on the body
Central nervous system effects. Barbiturates mainly act in the CNS, though they may indirectly
affect other organ systems. Direct effects include sedation and hypnosis at lower dosages. The CNS
depressant effect mimics that of ethanol. The lipophilic barbiturates, such as thiopental, cause rapid
anesthesia because of their tendency to penetrate brain tissue quickly. Elderly people have
proportionally more adipose tissue and therefore are more susceptible to this narrow therapeutic
index. Barbiturates all have anticonvulsant activity because they hyperpolarize cell membranes.
Therefore, they are effective adjuncts in the treatment of epilepsy.
Pulmonary effects. Barbiturates can cause a depression of the medullary respiratory center and
induce a respiratory depression. Patients with underlying chronic obstructive pulmonary disease
(COPD) are more susceptible to these effects, even at doses that would be considered therapeutic in
healthy individuals. Fatality from barbiturate overdose is usually secondary to respiratory
depression and subsequent pneumonia and one must respect its narrow therapeutic index as even a
slight overdose can cause coma or death.
Cardiovascular effects. Cardiovascular depression may occur following depression of the
medullary vasomotor centers; patients with underlying congestive heart failure (CHF) are more
susceptible to these effects. At higher doses, cardiac contractility and vascular tone are
compromised, which may cause cardiovascular collapse. The combination of the decreased vascular
resistance by means of peripheral dilation and inherent negative ionotropic properties of
barbiturates yields to the development of another recognized complication, hypotension.

Treatment
In barbiturate overdose, treatment starts with airway management and supportive care. Once
pulmonary and cardiovascular function has been stabilized, options for increasing drug clearance
are considered. Airway assessment and stabilization are the first management priorities. Intubation
with mechanical ventilation in severe sedative-hypnotic overdose is often required and should take
priority. Barbiturate toxicity also results in decreased cardiac output and vascular tone, often
resulting in profound hypotension. Volume expansion is the mainstay of circulatory support in the
absence of cardiac failure. If fluid resuscitation fails to correct hypotension, vasopressors such as
dopamine and norepinephrine should be initiated. Hypothermia between 30°C and 36°C is common
and should be treated with rewarming measures.
A single dose of activated charcoal should be given to cooperative, clinically stable patients who
present with in 1 hour of acute oral overdose. Multi-dose activated charcoal is beneficial in reducing
serum phenobarbital concentrations.
Hemodialysis, hemoperfusion, and hemodiafiltration have all been used to enhance elimination
of phenobarbital; however, they are reserved for patients who are deteriorating despite aggressive
supportive care. These modalities are not useful for poisoning from barbiturates other than
phenobarbital.

Barbiturate Abstinence Syndrome

Barbiturates are notorious for their rapid development of tolerance, high liability for physical
dependence and abuse, and multiple drug interactions. Abrupt discontinuation of barbiturates in a
chronically dependent user will produce minor withdrawal symptoms within 24 hours and major
life-threatening symptoms within 2 to 8 days. The severity of the withdrawal reflects the degree of
physical dependence and drug half-life. Cessation of short-acting barbiturates results in more severe
abstinence symptoms than stopping long-acting barbiturates. This is consistent with the clinical
observation that the brain has more time to adapt to gradually declining drug concentrations.
Clinical manifestations of barbiturate abstinence mimic those described for alcohol withdrawal.
Minor symptoms include anxiety, restlessness, depression, insomnia, anorexia, nausea, vomiting,

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muscle twitching, abdominal cramping, and sweating. Major symptoms include psychosis,
hallucinations, delirium, generalized seizures, hyperthermia, and cardiovascular collapse.
Priorities in the treatment of major abstinence symptoms are cardiovascular stabilization and
seizure control. Seizures may be treated with benzodiazepines, but are more effectively treated with
barbiturates. Due to the mortality associated with barbiturate abstinence, gradual in-hospital
withdrawal of the addicting agent is recommended.
Infants who are born to mothers physically dependent on barbiturates are at risk for being
dependent and subsequently going through withdrawal. This may manifest within the first to third
days of life. Signs and symptoms may include high-pitched crying, vomiting, diarrhea, tremors,
and, possibly, seizures. Withdrawal is treated with gradually decreasing doses of phenobarbital.

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