PHARMACOLOGICAL PROPERTIES OF BENZODIAZEPINE

 An effective sedative (anxiolytic) agent should reduce anxiety

and exert a calming effect.
 A hypnotic drug should produce drowsiness and encourage the
onset and maintenance of a state of sleep.
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 Hypnotic effects involve more pronounced depression of the

central nervous system than sedation, and this can be achieved by
increasing the dose.

 Graded dose-dependent depression of central nervous system

function is a characteristic of most sedative-hypnotics.

PHARMACOKINETIC

ABSORBTION AND DISTRIBUTION

 Lipid solubility plays a major role in determining the rate at which a particular
sedative-hypnotic enters the central nervous system responsible for the rapid onset
of central nervous system effect.
 All sedative-hypnotics cross the placental barrier during pregnancy.
 If sedative-hypnotics are given during the predelivery period, they may contribute
to the depression of neonatal vital functions.
 Sedative-hypnotics are also detectable in breast milk and may exert depressant
effects in the nursing infant.

BIOTRANSFORMATION
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Metabolic transformation to more water-soluble metabolites by microsomal drug-
metabolizing enzyme systems of the liver  for clearance from the body.
 Hepatic metabolism accounts for the clearance of all benzodiazepines.
 Most benzodiazepines undergo microsomal oxidation (phase I reactions),
including N-dealkylation and aliphatic hydroxylation catalyzed by cytochrome P450
isozymes, especially CYP3A4.
 The metabolites are subsequently conjugated (phase II reactions) to form
glucuronides that are excreted in the urine.

EXCRETION

 The water-soluble metabolites of sedative-hypnotics are excreted mainly via the

kidney.

MOLECULAR PHARMACOLOGY OF THE GABAA RECEPTOR

 The benzodiazepines bind to molecular components of the GABAA receptor in

neuronal membranes in the central nervous system.
 The GABAA receptor has a pentameric structure assembled from five subunits.
 A major isoform of the GABAA receptor that is found in many regions of the
brain consists of two α 1 and two β 2 subunits and one γ 2 subunit.
 The binding sites for GABA are located between adjacent α 1 and β 2 subunits,
and the binding pocket for benzodiazepines (the BZ site of the GABAA receptor) is
between an α 1 and the γ 2 subunit.

 Benzodiazepines and other sedative-hypnotics have a low affinity for GABAB

receptors.
 GABA (gamma-aminobutyric acid) is the major inhibitory neurotransmitter in the
central nervous system.
 Benzodiazepines appear to increase the efficiency of GABAergic synaptic
inhibition.
 The benzodiazepines do not substitute for GABA but appear to enhance GABA's
effects allosterically (by conformational change) without directly activating GABAA
receptors or opening the associated chloride channels. The enhancement in chloride
ion conductance induced by the interaction of benzodiazepines with GABA takes the
form of an increase in the frequency of channel-opening events.
 Barbiturates also facilitate the actions of GABA butin contrast to
benzodiazepinesthey appear to increase the duration of the GABA-gated chloride
channel openings. At high concentrations, the barbiturates may also be GABA-
mimetic, directly activating chloride channels. Barbiturates are less selective in their
 actions than benzodiazepines, because they also depress the actions of excitatory
neurotransmitters (eg, glutamic acid).

ORGAN LEVEL EFFECTS

1. Sedation
 Exert calming effects with associated reduction of anxiety at relatively low doses.
 In most cases, however, the anxiolytic actions of sedative-hypnotics are
accompanied by some depressant effects on psychomotor and cognitive functions.
 The benzodiazepines also exert dose-dependent anterograde amnesic effects
(inability to remember events occurring during the drug's duration of action).
2. Hypnosis
 All of the sedative-hypnotics induce sleep if high enough doses are given.
3. Anesthesia
 Benzodiazepinesincluding diazepam, lorazepam, and midazolamare used
intravenously in anesthesia.
 Benzodiazepines given in large doses as addition to general anesthetics may
contribute to a persistent postanesthetic respiratory depression, such depressant
actions of the benzodiazepines are usually reversible with flumazenil
(benzodiazepine antagonist).
4. Anticonvulsant effects
 Several benzodiazepinesincluding clonazepam, nitrazepam, lorazepam, and
diazepamare sufficiently selective to be clinically useful in the management of
seizures.
5. Muscle relaxation
 Benzodiazepine groups, exert inhibitory effects on polysynaptic reflexes and
interneuronal transmission and at high doses may also depress transmission at the
skeletal neuromuscular junction.
6. Effects on respiration and cardiovascular function
 Even at therapeutic doses, sedative-hypnotics can produce significant respiratory
depression in patients with pulmonary disease.
 Effects on respiration are dose-related, and depression of the medullary
respiratory center is the usual cause of death due to overdose of sedative-
hypnotics.
 In condition that impair cardiovascular function  normal doses of sedative-
hypnotics may cause cardiovascular depression, probably as a result of actions on
the medullary vasomotor centers. At toxic doses, myocardial contractility and
vascular tone may both be depressed, leading to circulatory collapse.
 Respiratory and cardiovascular effects are more marked when sedative-hypnotics
are given intravenously.

CLINICAL PHARMACOLOGY OF SEDATIVE-HYPNOTICS

TREATMENT OF ANXIETY STATES

  The psychic awareness of anxiety is accompanied by enhanced vigilance (careful
watch for danger), motor tension, and autonomic hyperactivity.
 Anxiety is often secondary to organic disease statesacute myocardial infarction,
angina pectoris, gastrointestinal ulcers, etcwhich themselves require specific
therapy.
 Situational anxiety results from circumstances that may have to be dealt with only
once or a few times, including anticipation of frightening medical or dental
procedures and family illness or other stressful event.
 The use of a sedative-hypnotic as premedication prior to surgery or some
unpleasant medical procedure is rational and proper.
 The benzodiazepines continue to be widely used for the management of acute
anxiety states and for rapid control of panic attacks, also used in the long-term
management of GAD (Generalized Anxiety Disorder) and panic disorders.
 The choice of benzodiazepines for anxiety is based on several sound
pharmacologic principles: (1) a relatively high therapeutic index (2) a low risk of
drug interactions based on liver enzyme induction; (3) minimal effects on
cardiovascular or autonomic functions.
 Disadvantages of the benzodiazepines include the risk of dependence, depression
of central nervous system functions, and amnestic effects.
 The advantages of long half-life drugs include less-frequent dosing, less variation
in plasma concentration, and less-severe withdrawal phenomena. The disadvantages
include drug accumulation, increased risk of daytime psychomotor impairment and
daytime sedation.
 The advantages of the short half-life drugs include no drug accumulation and less
daytime sedation. The disadvantages include more-frequent dosing and earlier and
more-severe withdrawal syndromes. Rebound insomnia and anterograde amnesia are
thought to be more of a problem with the short half-life drugs than with the long half-
life drugs.
INSOMNIA
 Temazepam, flurazepam, and triazolam are benzodiazepines with a sole (only)
indication for insomnia.

Table 22-2. Clinical uses of sedative-hypnotics.

Relief of anxiety
Insomnia
For sedation and amnesia before and during medical and surgical procedures
For treatment of epilepsy and seizure states
As a component anesthesia (intravenous administration)
For control of ethanol or other sedative-hypnotic withdrawal states
For muscle relaxation in specific neuromuscular disorders
As diagnostic aids or for treatment in psychiatry

CLINICAL TOXICOLOGY OF SEDATIVE-HYPNOTICS

  The most common adverse effect of benzodiazepines is drowsiness, which occurs
in about 10 percent of all persons  persons should be advised to be careful while
driving or using dangerous machinery when taking the drugs.
 Drowsiness can be present during the day after the use of a benzodiazepine for
insomnia the previous night, so-called residual daytime sedation.
 Some persons also experience ataxia (less than 2 percent) and dizziness (less than
1 percent)  These symptoms can result in falls and hip fractures, especially in
elderly persons.
 High-potency benzodiazepines, especially triazolam, and zolpidem can cause
anterograde amnesia; they can significantly impair ability to learn new information,
particularly that involving effortful cognitive processes.
 At higher doses, toxicity may present as lethargy or a state of exhaustion.
 An increased sensitivity to sedative-hypnotics is more common in patients with
cardiovascular disease, respiratory disease, or hepatic impairment and in older
patients.
 In very old patients and in patients with severe liver disease, the elimination half-
lives of these drugs are often increased significantly.
 Persons with hepatic disease and elderly persons are particularly likely to have
adverse effects and toxicity from the benzodiazepines, including hepatic coma,
especially when the drugs are administered repeatedly or in high dosages.
 Benzodiazepines can produce clinically significant impairment of respiration in
persons with chronic obstructive pulmonary disease and sleep apnea.
 Alprazolam can exert a direct appetite stimulant effect and may cause weight
gain.
 Benzodiazepines should be used with caution by persons with a history of
substance abuse, cognitive disorders, renal disease, hepatic disease, porphyria, central
nervous system (CNS) depression, or myasthenia gravis.
 Allergic reactions to the drugs are rare, but a few studies report maculopapular
rashes and generalized itching.
 The symptoms of benzodiazepine intoxication include confusion, slurred speech,
ataxia, drowsiness, dyspnea, and hyporeflexia.
 Some data indicate that benzodiazepines are teratogenic  their use during
pregnancy is not advised. Use of benzodiazepines in the third trimester can precipitate
a withdrawal syndrome in the newborn.
 The drugs are secreted in breast milk in sufficient concentrations to affect the
newborn. Benzodiazepines can cause dyspnea, bradycardia, and drowsiness in
nursing babies.

Drug Interactions
 The most common and potentially serious benzodiazepine receptor agonist
interaction results in excessive sedation and respiratory depression occurring when
benzodiazepines are administered concomitantly with other CNS depressants, such as
alcohol, barbiturates, tricyclic and tetracyclic drugs, dopamine receptor antagonists
(DRAs), opioids, and antihistamines.
  Ataxia and dysarthria may likely occur when lithium, antipsychotics, and
clonazepam are combined.
 Cimetidine (Tagamet), disulfiram (Antabuse), isoniazid, estrogen, and oral
contraceptives increase the plasma concentrations of diazepam.
 Antacids and food can decrease the plasma concentrations of benzodiazepines.
 Smoking can increase the metabolism of benzodiazepines.

Tolerance, Dependence, and Withdrawal

 The short-acting benzodiazepines  some persons have reported increased
anxiety the day after taking a single dosage of the drug  tolerance for the anxiolytic
effects of benzodiazepines  require increased dosages to maintain the clinical
remission of symptoms.
 The appearance of a withdrawal syndrome (discontinuation syndrome) depends
on the length of time the person has been taking a benzodiazepine, the dosage the
person has been taking, the rate at which the drug is tapered, and the half-life of the
compound.
 Abrupt discontinuation of benzodiazepines, particularly those with short half-
lives, is associated with severe withdrawal symptoms.
 Symptoms are more likely to occur if flumazenil is used for rapid reversal of the
benzodiazepine effects.
 The development of a severe withdrawal syndrome is seen only in persons who
have taken high dosages for long periods.
 The appearance of the syndrome can be delayed for 1 or 2 weeks in persons who
had been taking benzodiazepines with long half-lives.
 Benzodiazepine seems to be particularly associated with an immediate and severe
withdrawal syndrome  should be tapered gradually.
Table 36.9-1 Signs and Symptoms of Benzodiazepine
Withdrawal
Anxiety Tremor
Irritability Depersonalization
Insomnia Hyperesthesia
Hyperacusis Myoclonus (spasm jerky of
muscle)
Nausea Delirium
Difficulty concentratingSeizures