Anxiolytic/Sedative Hypnotic drugs

Question 1

Benzodiazepine - anxiolytics

Answer 1

alprazolam, chlordiiazepoxide, diazepam, lorazepam, oxazepam, clonazepam

Question 2

Benzodiazepine - hypnotic action

Answer 2

Flurazepam, temazepam, triazolam

Question 3

Benzodiazepine- anesthetic

Answer 3

Midazolam.

Question 4

Mechanism of action

Answer 4

GABAA receptors are ligand-gated ion channels. Binding of GABA (the most important inhibitor neurotransmitter in CNS) opens up a chloride channel, which is part of the protein structure; GABAA receptors also contain binding sites for the barbiturates and benzodiazepines; benzodiazepines bind to specific, high affinity sites on the cell membrane, which are separate from (but adjacent to) the receptor for GABA; benzodiazepine binding is rapid, reversible and saturable; the binding of benzodiazepines enhances the affinity of GABA receptors for this neurotransmitter, resulting in a more frequent opening of adjacent chloride channels; this in turn results in enhanced hyperpolarization and further inhibition of neuronal firing;
benzodiazepine and GABA bind at different sites within the GABAA receptor complex; the consequences of GABA binding are: opening of chloride channel and increased chloride influx; neuronal membrane hyperpolarization.

Question 5

Pharmacokinetics

Answer 5

Absorption: benzodiazepines are lipophilic and are rapidly and completely absorbed after oral administration; all benzodiazepines should be given on an empty stomach for best absorption; food and antacids slow absorption;
Biotransformation and elimination: the t1/2 of the benzodiazepines (see table) are very important clinically, since the duration of action may determine the therapeutic usefulness; the benzodiazepines can be divided into short–, intermediate– and long–acting groups; the longer acting agents form active metabolites with long t1/2; most benzodiazepines, including Chlordiazepoxide and Diazepam are converted to active metabolites in the liver, which prolongs their t1/2.
see chart

Question 6

Pharmacodynamic effects

Answer 6

reduction of anxiety;
sedative and hypnotic actions:
sedative properties;
at higher doses, certain benzodiazepines produce hypnosis;
anticonvulsant;
muscle relaxant (relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord).

Question 7

Indications

Answer 7

anxiety (Diazepam) - the antianxiety effects of benzodiazepines are less subject to tolerance than the sedative and hypnotic effects;
panic attacks (Alprazolam) - physical dependence can occur;
sleep disorders (Flurazepam, Temazepam, Triazolam);
seizure disorders (Clonazepam - in the chronic treatment of epilepsy, Diazepam - the drug of choice in terminating grand mal epileptic seizures and status epilepticus);
as central skeletal muscle relaxants (Diazepam);
anesthetic premedication (Midazolam);
treatment of alcohol withdrawal syndromes (Diazepam, Oxazepam, Chlordiazepoxide).

Question 8

Adverse effects

Answer 8

CNS depression: drowsiness, sedation and confusion;
reversible confusion in elderly;
paradoxically excitement in children;
menstrual irregularities, including anovulation;
tolerance and dependence: psychological and physical dependence on benzodiazepines can develop if high doses of the drug are given over a prolonged period; abrupt discontinuation of the benzodiazepines results in withdrawal symptoms (confusion, anxiety, agitation, restlessness, insomnia and tension); because of the long t1/2 of some of the benzodiazepines, withdrawal symptoms may not occur until a number of days after discontinuation of therapy; benzodiazepines with a short elimination t1/2, such as Triazolam, induce more abrupt and severe withdrawal reactions than those seen with drugs that are slowly eliminated, such as Flurazepam.

Question 9

Therapeutic notes

Answer 9

Flurazepam (long-acting) significantly reduces both sleep-induction time and the number of awakenings, and increase the duration of sleep; Flurazepam and its active metabolites have a t1/2 of approximately 85 hours, which may result in daytime sedation and accumulation of the drug;
Temazepam (intermediate-acting) is useful in patients who experience frequent wakening; however, the peak sedative effect occurs 2-3 hours after an oral dose, and therefore it may be administered several hours before bedtime;
Triazolam: (short-acting) is used to induce sleep in patients with recurring insomnia;
whereas Temazepam is useful for insomnia caused by the inability to stay asleep, Triazolam is effective in treating individuals who have difficulty in going to sleep; tolerance frequently develops within a few days, and withdrawal of the drug often results in rebound insomnia, leading the patient to demand another prescription; therefore, this drug is best used intermittently rather than daily;
in general, hypnotics should be given for only a limited time, usually less than 2-4 weeks;
Midazolam is a parenteral benzodiazepine that will replace Diazepam for perioperative use; its advantages include less tissue irritation, faster onset of action and more rapid elimination;
treatment in case of benzodiazepine overdoses: gastric lavage, activated charcoal, Flumazenil (a GABA receptor antagonist that rapidly reverses the effects of benzodiazepines; onset is rapid, but duration is short (t1/2 is 50 minutes) and frequent administration may be necessary to maintain reversal of a long-acting benzodiazepine), IV fluids.

Question 10

Zolpidem

Answer 10

Mechanism of action
it acts on a subset of the benzodiazepine receptor family.
Pharmacodynamic action
hypnotic;
no anticonvulsant or muscle relaxing properties.
Pharmacokinetics
Absorption: rapidly absorbed from GI tract;
Biotransformation and elimination: it has a short elimination t1/2 (~ 3 hours).
Adverse effects
nightmares;
headache, daytime drowsiness.
Therapeutic notes
it has no withdrawal effects, exhibits minimal rebound insomnia and little or no tolerance occurs with prolonged use.

Question 11

Buspirone

Answer 11

Mechanism of action
in general is unknown;
can bind to dopamine and serotonine receptors;
does not bind to benzodiazepine receptors and does not have muscle-relaxant, anticonvulsant or hypnotic activity.
Indications
short term treatment of generalized anxiety.
Adverse effects
headaches, dizziness, nervousness;
little potential to develop dependence.
Therapeutic notes
it may require 1-2 weeks for a therapeutic effect to take place.

Question 12

Hydroxyzine

Answer 12

it has a little potential to develop dependence; thus it is useful for patients with anxiety, who have a history of drug abuse.

Question 13

Propranolol

Answer 13

it is usually used in varying doses (40-240 mg/day); so far it has only proved useful in reducing the somatic symptoms of anxiety (e.g., palpitations, sweating, tachycardia).

Question 14

Meprobamate

Answer 14

Mechanism of action
it depresses the CNS in a similar way to that of barbiturates, especially Phenobarbital, but Meprobamate is shorter acting;
it is capable of promoting sleep.
Indications
anxiety.
Adverse effects
drowsiness;
blood dyscrasias;
physical dependence.

Question 15

Barbiturates - ultra short duration of action (30 minutes)

Answer 15

thiopental

Question 16

Barbiturates - short duration of action (2 hours)

Answer 16

hexobarbital, pentobarbital, secobarbital

Question 17

Barbiturates intermediate (3-5 hours)

Answer 17

amobarbital, butobarbital

Question 18

Barbiturates long (more than 6 hours)

Answer 18

barbital, phenobarbital

Question 19

Barbiturate mechanism of action

Answer 19

barbiturates have a GABA-like action or enhance the effects of GABA (an inhibitory neurotransmitter); when GABA receptors are activated, chloride channels open; chloride enters the cell, hyperpolarizes it and produces decreased excitation;
they also antagonize glutamate-induced excitation (glutamate and aspartate are excitatory neurotransmitters);
overall the net effect is to stabilize neuronal membranes.

Question 20

Barbiturate pharmacodynamic effects

Answer 20

depression of CNS: barbiturates depress the CNS at all levels and in a dose-dependent fashion; at low doses, the barbiturates produce sedation (calming effect, reducing excitement); at higher doses, the drugs cause hypnosis, followed by anesthesia (loss of feeling or sensation) and finally coma and death; thus, any degree of depression of the CNS is possible, depending on the dose; a barbiturate plus another CNS depressant (e.g. ethanol, phenothiazine, antihistamine) can result in marked depression;
as hypnotics, barbiturates decrease the amount of time spent in rapid eye movement (REM) sleep;
suppress convulsant activity if given in sufficient doses;
are not analgesic and, at low doses, are thought to exacerbate pain;
suppress the hypoxic and chemoreceptor response to C02 and overdosage is followed by respiratory depression and death;
especially Phenobarbital, can induce hepatic microsomal drug-metabolizing enzymes; this results in increased degradation of the barbiturate, ultimately leading to barbiturate tolerance; it also causes increased inactivation of other compounds, such as the anticoagulants, Phenytoin, Digitoxin, Theophylline and glucocorticoids, leading to potentially serious problems with drug interactions.

Question 21

Barbiturate pharmacokinetics

Answer 21

Absorption: barbiturates are absorbed from the stomach, small intestine, rectum and IM sites;
Distribution: ultra-short-acting barbiturate’s high lipid solubility allows rapid transport across the BBB; removal of the ultra-short-acting barbiturates from the brain occurs via redistribution to other tissues (splanchnic areas, skeletal muscle, adipose tissue); this removal is responsible for the short duration of action of Thiopental and similar short-acting derivatives.
Biotransformation and elimination: long-acting barbiturates are metabolized principally in the liver; more polar derivatives with low lipid solubility are produced; ultra-short-acting barbiturates are highly lipid-soluble and, thus, have a short onset and duration of action; barbiturates and their metabolites are principally excreted via the renal route; alkalinization of the urine profoundly enhances the excretion of barbiturates with lower lipid solubility, such as Phenobarbital.

Question 22

Barbiturate indications

Answer 22

long-term management of tonic-clonic seizures, status epilepticus, eclampsia, children with recurrent febrile seizures;
to induce anesthesia (Thiopental IV);
hyperbilirubinemia and icterus in the neonate.

Question 23

Barbiturate adverse effects

Answer 23

oversedation (drug hangover), decrease in REM sleep;
skin eruptions;
porphyria;
physical and psychological dependence; withdrawal of a barbiturate may result in grand mal seizures, severe tremors, hallucinations, anxiety, weakness, restlessness, nausea and vomiting;
an overdose can result in coma, diminished reflexes, severe respiratory depression, hypotension leading to cardiovascular collapse.

Question 24

Barbiturate therapeutic notes

Answer 24

treatment of acute overdosage:
supporting respiration and circulation;
gastric lavage if the drug has been recently taken;
alkalinization of the urine and promoting diuresis often aids in the elimination of long-acting barbiturates (Phenobarbital);
hemodialysis is useful and often needed.