L-28 Anti Anxiety Drugs and Hypnotics.xml

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Lecture 28. Antianxiety Drugs and Hypnotics


Lecture 28 Antianxiety Drugs and Hypnotics

R. apek

References

1. Katzung, 10th ed., Section V., Chapter 22 and 32.2. Goodman and Gilman, 11th ed., Section III. Chapters 16, 17 and 23.3. NEJM 351: 675-682, 2004 (Clinical review of generalized anxiety disorder.)4. Treatment Guidelines from The Medical Letter 4: 35-46, 2006 (Concise clinical review of

Drugs for Psychiatric Disorders)5. Treatment Guidelines from The Medical Letter 4; 5-10, 2006 (Brief outline of Treatment

of Insomnia). 3, 4 and 5 are available on-line through the Health Science Library.

Objectives

1. To know basic pharmacologic properties of prototype benzodiazepines and non-

benzodiazepine hypnotics-antianxiety agents.2. To recognize why benzodiazepines are considered better therapeutic agents thanbarbiturates and other hypnotics and antianxiety drugs.

3. To get acquainted with the place of antidepressants in the treatment of anxiety disorders.4. To understand the principles of treatment of anxiety and insomnia by drugs.

Drugs to Be Discussed

Benzodiazepines: chlordiazepoxide, diazepam, flurazepam, oxazepam,lorazepam, triazolam, alprazolam;flumazenil (antagonist);

Miscellaneous other drugs: buspirone, propranolol;

zolpidem, zaleplon; eszopiclone, ramelteonbarbiturates, chloralhydrate,

Non-prescription hypnotics: antihistaminics, melatonin, valerian root.

Key Points to Understand1. Clinical importance of the pharmacokinetic profile of various benzodiazepines.2. The involvement of GABA in the effects of benzodiazepines and barbiturates.3. The role of pharmacotherapy in the treatment of anxiety and insomnia.


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Antianxiety Drugs (Anxiolytics, Sedatives)

Anxiety is a ubiquitous symptom. Mild anxiety could mobilize; severe anxiety can hinder allproductive effort. Anxiety is a subjective symptom; the accompanying tension is manifested byobjective signs: fatigue, dizziness, vague pains, palpitations, headache, irritability, indigestion, etc.

Anxiety may accompany physical illness, such as hypertension, asthma, irritable colon, pepticulcer, etc. Anxiety may be present in schizophrenics and depressed patients are frequentlyanxious.

BENZODIAZEPINES

1.Pharmacokinetics:

1.1Absorption from GI tract is almost complete. Absorption of diazepam, triazolam andflurazepam is rapid, of chlordiazepoxide and lorazepam is intermediate, and of oxazepam is slow.Some benzodiazepines are available for parenteral administration. Absorption of diazepam orchlodiazepoxide after i.m. injection is slow and erratic, avoid this route. Lorazepam can be

administered i.m.

1.2Plasma protein binding is very high (diazepam 96% bound).

1.3Distribution

1.Early stage (non-equilibrium). "Free" drug distributes to all tissues. Blood flow determines therate at which various tissue compartments take up the drug, e.g., a single i.v. injection of diazepamyields rapidly high concentrations in the brain (a high perfusion organ), which declinessubsequently because of extensive redistribution to low perfusion organs.

2.Late stage (equilibrium). Apparent volume of distribution (AVD) of highly lipid soluble

benzodiazepines may exceed several folds the body weight. AVD is larger in females and inelderly.

1.4Metabolic degradation- occurs in liver by complex pathways. Many compounds arebiotransformed by oxidative reactions, primarily N-demethylation and hydroxylation yieldingoften active metabolites, some of which are available as drugs in their own right. Oxidativereactions may be influenced by various factors such as old age, liver disease, or co-administrationof other drugs which may induce or depress hepatic drug-oxidizing enzymes. Position of a givencompound in the metabolic path determines the duration of action (diazepam is demethylated andhydroxylated to oxazepam - diazepam is longer acting than oxazepam). All active metaboliteshave to be considered when relating plasma concentrations to therapeutic effect. Benzodiazepines

are poor inducers of drug metabolizing enzymes. The active metabolites and somebenzodiazepines, such as oxazepam or lorazepam, undergo conjugation with glucuronic acid.Conjugation results in a loss of activity and is much less influenced by aging, liver disease or druginteractions.

1.5Excretion- Benzodiazepines are excreted as conjugated metabolites in urine. Biliary excretionis insignificant.


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Table 1. Pharmacokinetic classification of benzodiazepines and new hypnotics.Parent compound Clinically Important

Active Metabolites

-

l

i

f

e

*

*

(

Long-actingChlordiazepoxideDiazepamFlurazepam*

DesmethyldiazepamDesmethyldiazepam)Desalkylflurazepam

20-8020

8040-100

Intermediate -LorazepamOxazepam

NoneNone

102

010-20

Ultrashort-actingTriazolamEscozopicloneZaleplonZolpidem

Ramelteon

NoneDesmethylescozopicloneNoneNoneM II

2361

21.53.5


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2-5

* Does not reach systemic circulation as such in clinically important amounts.** Includes half-lives of active metabolites

2.Effects:

2.1CNS- Benzodiazepines produce CNS depression of varying degree, qualitatively similar withother depressants.

2.1.1Antianxiety - sedative- Small doses produce emotional calming and relief of anxiety. Motorco-ordination impairment may occur.

2.1.2Hypnotic. (See Hypnotics).

2.1.3Anticonvulsant. These drugs are very effective in controlling existing convulsions of allorigin. Some (e.g. clonazepam-see Antiepileptic Drugs) are also useful in chronic treatment ofcertain epilepsies or as adjuvant with other antiepileptics.

2.1.4Amnesic. Anterograde amnesia is produced by higher doses of benzodiazepines.

2.1.5Muscle relaxant. Benzodiazepines depress, to slight extent, systems in the CNS regulatingmuscle tone along with sedation (distinguish central muscle relaxants from neuromuscularblocking agents, such as tubocurarine!).

2.2Respiratory. Significant depression of respiration in a normal individual can occur only afteri.v. injection or very large oral doses.

3.Mechanism of action:

Benzodiazepines enhance GABA mediated inhibition postsynaptically by interacting with abinding site in the CNS, the benzodiazepine binding site (receptor). The binding is saturable,specific and reversible. The affinity of various benzodiazepines for the site correlates withbiological and therapeutic potency.

The benzodiazepine binding site is a part of the GABAA receptor that also contains chloridechannel, and the barbiturate, picrotoxinin and steroid binding sites (see Figs.1 and 2). In thepresence of a benzodiazepine agonist (see below), a given GABA concentration produces greaterincrease in chloride conductance than in the absence of the drug. Single channel recordingrevealed that benzodiazepines increase the frequency of single channel opening events induced by

GABA. However, benzodiazepines are unable to produce any change in chloride conductancewithout GABA.

Most benzodiazepines in routine clinical use to date are agonists (positive modulators). Two othertypes of benzodiazepine receptor ligands have been described: the inverse agonists (negativemodulators) diminish the GABA mediated inhibition; the antagonists (null modulators) preventthe action of both, the agonists and inverse agonists, without having any action of their own.


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These three prototypes of ligands of benzodiazepine receptor represent maximal positive efficacy(full agonist), zero efficacy (antagonist), and maximal negative efficacy (full inverse agonist).Partial agonists and partial inverse agonists lie within this spectrum of efficacy.

Existence of endogenous ligands is likely but remains unproven.

Barbiturates enhance GABA mediated inhibition postsynaptically by interacting with specificbinding sites in the CNS. This site is also associated with the GABAA receptor, benzodiazepinebinding site and chloride channel protein. The enhanced GABA- induced chloride conductance inthe presence of barbiturates is due to a prolonged duration of the single channel opening events.Unlike benzodiazepines, barbiturates in higher concentrations are able to increase the chlorideconductance even in the absence of GABA. Additional effects of barbiturates on excitatorysynaptic transmission have been described: depression of the release of excitatory transmitters anddepression of the postsynaptic action of excitatory transmitters.

The various types of interactions within the complex of GABA A receptor, chloride channel,benzodiazepine and barbiturate/picrotoxinin binding sites and the various types of benzodiazepine

receptor ligands are shown in Fig. 2. Several other depressants of the CNS, such as generalanesthetics, hypnotics and, notably, ethanol, have been also shown to enhance the GABAmediated inhibition


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Figure 1. A: Generic GABAA receptor protein subunit structure and topological sequence. N,amino terminal; 10 and 110 asparagine glycosylation sites; 138-152 cystine bridge; M1, M2, M3,M4, four membrane spanning domains; C, carboxy terminal. B: Model of the GABAA receptor -chloride ion channel complex. The channel is probably formed by the second transmembranedomains of the five subunits. (Modified from Olsen & Tobin, 1990.) C: Model of the GABAAreceptor - chloride ionophore complex. The heteropentameric structure of the protein with twoGABA and one benzodiazepine (BDZ) binding sites are shown. (Modified from Zorumski &Isenberg, 1991.) The naturally occurring oligomers are composed of , , and subunits. GABAinteracts with the subunit. Receptors containing and subunits respond to barbiturates and

subunit is necessary for benzodiazepine sensitivity. There is a significant brain regional variationin unit composition of these receptors. This is consistent with the biochemical andpharmacological evidence for the GABAA receptor heterogeneity. Based on relative affinities ofvarious ligands; two types of benzodiazepine receptors have been classified in the CNS, BZ 1 andBZ2. Clinically used benzodiazepines bind to both types but some agonists, such as zolpidem, (seeHypnotics) are more selective for the BZ1 type. On the molecular level, the pharmacologicaldifference between BZ1 and BZ2 is related to the subtype of the subunit of the GABAA receptor.


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Figure 2.

Hypothetical model of the complex of GABAA receptor (GABA-R), benzodiazepine binding site(BDZ-R) and chloride channel protein. This complex contains a binding domain for GABAagonists and antagonists (GABA), for benzodiazepine receptor agonists, antagonists, and inverseagonists (BDZ), and for barbiturates, picrotoxinin and 5-3663 (BARB), respectively. The largearrow indicates that activation of the GABA receptor leads to chloride channel opening.Activation of the benzodiazepine receptor by agonists enhances and activation by inverse agonistsdiminishes this coupling function; pure competitive antagonists do not affect the couplingfunction, but block the effects of both agonists and antagonists. The arrows 4 and 5 indicate thatbenzodiazepine receptor agonists enhance GABA binding and GABA agonists enhance binding ofbenzodiazepine agonists. (From: Naunyn-Schmiedeberg's Arch. Pharmacol. (1982) 321, 260-264.)

4.Therapeutic use

4.1Anxiety. Generalized anxiety disorder, other types of anxiety and anxious depression areameliorated by these drugs.

4.2Disorders of initiation and maintenance of sleep. - See Hypnotics

4.3Convulsive disorders. Diazepam is the drug of choice in status epilepticus and for control ofexisting seizures of any origin. Some benzodiazepines are also used for chronic treatment ofmyoclonic and some other types of epilepsies frequently in combination with otheranticonvulsants (see Antiepileptic Drugs).

4.4Chronic alcoholism and other drug abuse. Long acting benzodiazepines, diazepam orchlordiazepoxide, control well the withdrawal syndrome of ethanol and other general CNSdepressants. This use is based on the existence of cross dependence among various depressants.Severe anxiety and agitation associated with the withdrawal symptoms of other abused drugs canbe ameliorated by benzodiazepines.

4.5Neuromuscular disorders. Spasticity associated with cerebral palsy, tetanus and some otherdisorders is relieved by diazepam.


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4.6Miscellaneous. Use of these drugs for sedation and amnesia before medical or surgicalprocedures or as a component of balanced anesthesia is common. Benzodiazepines are also used,in combination with other psychotropic drugs, for panic disorder (alprazolam), anxiousdepression, mania and psychotic agitation.

5.Side effects and hazards:

5.1Oversedation. Tiredness, lethargy, impairment of motor coordination, and ataxia are extensionof the therapeutic effects. They tend to wane within a few days of treatment because ofdevelopment of tolerance.

5.2Memory impairment. Whereas anterograde amnesia commonly seen in anesthetic applicationsof benzodiazepines is desirable, impairment of memory and judgment seen in some patientsduring the first week or two of treatment is an unwanted effect. Short acting drugs are more proneto produce it.

5.3Other adverse reactions. Paradoxical reactions, such as hostility, aggression, irritability oruncontrollable giggling or weeping, are rare. They are usually confined to the beginning oftreatment or can be controlled by lowering the dose.

5.4Tolerance. Whereas tolerance develops readily to the sedative and anticonvulsant effects ofbenzodiazepines, there is no clinically important tolerance to their antianxiety effects.

5.5Physical dependence. Withdrawal symptoms, indicative of physical dependence, includeincreased anxiety, insomnia, agitation, sweating, tremor, nausea and occasionally convulsions.They are more frequent, more intense and occur earlier after discontinuation of a rapidlymetabolized benzodiazepine. Abuse of benzodiazepines is now a subject of much concern.Nevertheless, the number of convincingly documented case reports is low in relation to theextensive use of benzodiazepines.

5.6Acute toxicity. Overdosage with the benzodiazepines occurs frequently but deaths are rare. It isalmost impossible to commit suicide with benzodiazepines taken orally without any other drug.Drowsiness, stupor and deep sleep are the main symptoms of overdose. Respiration and bloodpressure are minimally affected; general supportive measures are usually not required. Thebenzodiazepine antagonist, flumazenil, can hasten the awakening.

5.7Drug interaction. Benzodiazepines interact additively with other CNS depressants, alcohol inparticular. They enhance the sedative effects of antipsychotics, antidepressants, antihistaminicsand opioid analgesics. Benzodiazepines are not effective inducers of liver microsomal enzymes.Their metabolism can be altered by drugs that inhibit or induce P450 enzymes but, in general,interactions with other drugs because of changed drug disposition are of little clinical significance.

MISCELLANEOUS OTHER DRUGS

Buspirone

Originally developed as a potential antipsychotic agent, buspirone is a representative of a newclass of drugs whose chemical structure and pharmacological properties are distinct from those ofbenzodiazepines.


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Buspirone is well absorbed, is highly protein bound in the plasma, and undergoes extensive firstpass metabolism in the liver. It is metabolized to several hydroxylated metabolites, one of themactive. Elimination half-life is about 2 - 3 hours. The drug is excreted mainly in urine almostentirely as metabolites.

Similarly to benzodiazepines, buspirone has anxiolytic and general tranquilizing properties.

However, unlike benzodiazepines, this drug has no muscle relaxant, anticonvulsant or hypnoticactivity. Mechanism of action is not known, the monoamine neurotransmitter systems appear to bethe primary targets, in particular, the 1A subtype of the serotonin receptor where buspirone acts asan agonist. This drug does not bind to the benzodiazepine receptors and does not increase GABAeffects.

Clinical trials indicate that the antianxiety effects of buspirone are usually equivalent but notsuperior to those of benzodiazepines. However, the onset of the therapeutic effect of buspirone isdelayed by 1 - 2 weeks. Patients who have previously been treated by benzodiazepines may lesslikely respond to buspirone than those who have not.

Adverse effects are relatively rare. Buspirone does not impair daytime wakefulness andperformance, including driving, interfere with cognitive functions or have additive effects withalcohol and other CNS depressants. There is little if any propensity for abuse, no euphoria orwithdrawal symptoms have been observed.

Propranolol and other adrenergic receptor antagonists

These drugs were shown to be effective in acute anxiety states associated with prominentautonomic symptoms, usually induced by a stressful situation, such as stage fright, and improveperformance. Peripheral block of palpitations, tremor and other symptoms, which tend toreinforce anxiety, is the most likely mechanism of this action.

Anxiety without prominent autonomic symptomatology and chronic anxiety are unlikely torespond to adrenergic blockade.

Antidepressants

Antidepressants have been tried in the treatment of anxiety and were shown to be effective. Newerantidepressants are often used as first line drugs for generalized anxiety disorder. The delayedonset of their therapeutic effect limits their usefulness in acute anxiety states (see Antidepressantand Mood-stabilizing Drugs).

Anticonvulsants

Some anticonvulsants (gabapentin, tiagabine) may be helpful in combination with antidepressants(see Antiepileptic Drugs).

Antihistaminics

Sedative antihistaminics, hydroxyzine in particular, have been frequently used for the treatment ofanxiety. However, the doses that produce marked sedation must be used to be effective.

Older sedatives


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Many drugs which have been used for daytime sedation became obsolete with the advent ofbenzodiazepines. Such drugs include barbiturates, methaqualone. For any given degree ofantianxiety effect, they produce more unwanted sedation and other signs of general depression ofthe CNS. They are more liable to induce tolerance, physical dependence and severe withdrawalsymptoms. Acute intoxication is difficult to treat and frequently fatal. As good inducers of drugmetabolizing enzymes, these drugs are prone to cause drug interactions from alteredpharmacokinetics. Their use is not advisable.

Principles of treatment of anxiety

1. Use drugs only for good reasons - severe symptoms, disability, discomfort. Drug therapyis symptomatic and should be adjunctive to other therapeutic approaches.

2. Benzodiazepines and antidepressants are widely used for treatment of common anxietydisorders.

3. Benzodiazepines are more selectively anxiolytic than other sedative drugs and are thesafest. It appears that various benzodiazepines are about equally effective in treatment ofanxiety.

4. Differences in pharmacokinetics of various benzodiazepines are of clinical importance.

Compounds biotransformed to active metabolites (e.g. diazepam) are longer acting andprone to produce cumulative effects during repeated dosage. Those metabolized to aninactive product (e.g. oxazepam, lorazepam) have shorter duration of action andcumulative effects are much less important. They are preferred for the elderly.

5. Treatment should follow the intensity of symptoms, preferably with interrupted coursesproposed at the onset.

6. Doses should be individualized and dosage schedule should be flexible; avoidoversedation.

7. Constantly assess efficacy. Poor efficacy usually indicates another diagnosis.8. Favorable non-drug influences should be exploited.9. An antidepressant (e.g., paroxetine, venlafaxine) is the treatment of choice for most

patients with generalized anxiety disorder, even in the absence of depression.10. Buspirone or antidepressants are preferred for anxious patients with a history of alcohol

or other drug abuse.11. Panic disorders can be treated with a benzodiazepine (e.g., clonazepam, alprazolam) or

antidepressants; social phobias with antidepressants (SSRIs, MAOIs); obsessive-compulsive disorder with antidepressants; posttraumatic stress disorder withantidepressants, and performance anxiety (stage fright) with adrenergic blockers.

Hypnotic Drugs

Insomnia

Hypnotics are widely used for adjunctive treatment of disorders of initiating and maintainingsleep (DIMS, insomnia). Although a symptom of psychiatric and medical disorders or situationaldisturbances, insomnia is often perceived as a primary disorder. It is characterized by a relativedeficiency in the amount or quality of sleep: inability to induce sleep, inability to stay asleep,premature awakening, interrupted sleep, sleep that is not refreshing.

Sleep architecture


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Neither sleep nor wakefulness is considered a unitary state. Electrographic parameters of theelectroencephalogram (EEG), electrooculogram (EOG) and electromyogram (EMG) are used todistinguish the following stages:

Waking. Relaxed wakefulness is characterized on the EEG by low-amplitude, high-frequency betaactivity accompanied by alpha rhythm which increases with increased relaxation and reduced

visual input.

NREM sleep - stages 1 through 4. From stage 1 to 4 of the non-rapid eye movement (NREM)sleep, there is a progressive slowing of frequency and increase in amplitude of the EEG activity.Muscle tone gradually decreases. Eye movements are rare. Stages 3 and 4 are often collectivelycalled slow-wave or delta-wave sleep.

REM sleep. In the rapid-eye-movement (REM) sleep, the EEG activity is of mixed fast frequencyand low voltage, similar to the stage 1 NREM sleep. Rapid conjugate eye movements occurintermittently. All major muscle groups are atonic. Heart rate, respiratory rate and blood pressureare irregular and elevated. Cerebral blood flow, brain oxygen consumption and brain temperatureare increased. Dreaming probably occurs during such REM periods.

REM and NREM stages of sleep cyclically alternate. The NREM - REM cycle lasts between 70and 120 minutes. There are 3 to 6 cycles per night. Stage 2 NREM sleep represents about 50 %,stages 3 and 4 NREM sleep combined 10 to 20 %, and REM sleep 20 to 25 % of the total sleepingtime. Studies with selective REM or stage 3 and 4 NREM sleep deprivation suggest that both arerequired for emotional stability and normal performance. However, the clinical importance of thedrug-induced changes in various sleep stages has not been unequivocally established.

Neurotransmitters in sleep

Many animal and human studies indicate that a complex interplay of serotoninergic,

catecholaminergic and cholinergic neuronal systems regulate the sleep cycles. The sleeppromoting property of the serotonin precursor l-tryptophan detected in several clinical studies isbelieved to be related to enhancement on serotoninergic synaptic mechanisms.

Involvement of other neurotransmitters and neuromodulators, GABA and adenosine, in particular,in sleep regulation is very likely. Existence of several putative circulating sleep factors has beensuggested. Initial clinical studies of two such peptides (arginine vasotocin - AVT, delta sleep-inducing peptide - DSIP) support their role in sleep regulation in man.

BENZODIAZEPINES AND NEWER HYPNOTICS

Benzodiazepines are currently the most widely used hypnotics. They decrease the sleep latency,

diminish awakenings, increase stage 2 and decrease stages 3 and 4 of NREM sleep. REM sleep isalso slightly reduced and the number of sleep cycles increased. The net effect is an increase intotal sleep time. Flurazepam, triazolam and other benzodiazepines labeled as hypnotics do nothave any unique hypnogenic properties not shared by all other benzodiazepines. The short actingbenzodiazepines which are not converted to active metabolites (e.g. lorazepam, triazolam) are lesslikely to produce daytime drowsiness than the long acting ones (e.g. diazepam, flurazepam), butcan produce early morning insomnia and daytime anxiety during use and rebound insomnia after


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discontinuation. The long acting benzodiazepines have lesser tendency to produce reboundinsomnia on discontinuation (Table 2). The most significant advantage of these drugs over otherhypnotics is their remarkable safety record with respect to overdose.

Table 2. Comparison of short-acting and long-acting benzodiazepine hypnotic drugs

Characteristics short-acting long-actingAccumulation with repeated use No MarkedHangover effects next day, sedation Mild ModerateTolerance Moderate MildAnterograde amnesia Moderate MildRisk of rebound insomnia Moderate NoRisk of early-morning insomnia Mild NoRisk of day-time anxiety Mild NoAntianxiety effects next day No ModerateFull benefits on first night Moderate Moderate

Several novel benzodiazepine receptor agonists, zolpidem, escozopiclone and zaleplon, althoughchemically unrelated to benzodiazepines, are similar to benzodiazepines in the mechanism ofaction, in therapeutic efficacy in insomnia and in most of the side effects. They bindpreferentially to the BZ1 binding site and increase the GABA-mediated synaptic inhibition. Theyhave minimal muscle relaxant and anticonvulsant effects. In therapeutic doses, they shorten thesleep latency with minor effects on sleep architecture. Amnesia and psychomotor impairment theday after use are rare and little tolerance during chronic administration of these drugs has beenreported. Zaleplon has a shorter duration of action than the other two drugs; it does not decreaseearly morning awakenings or increase the total sleep time; the risk of residual effects next day islow even when used in the middle of night.

Recently introduced ramelteon is particularly suitable for treatment of insomnia characterized by

difficulty falling asleep. Unlike the other hypnotics, this drug has no direct effect on GABAergicsynaptic transmission. It is an agonist of the melatonin type 1 (MT1) and type 2 (MT2) receptorson the neurons in the suprachiasmatic nuclei that regulate the circadian rhythm. It has a rapidonset of action and short duration of action. In addition to the common side effects such assomnolence, dizziness and fatigue, increase in serum prolactin and decrease in cortisol andtestosterone has been reported.

BARBITURATES AND OTHER OLDER HYPNOTICS

1.Pharmacokinetics

Barbiturates are well absorbed from the GI tract and are widely distributed throughout the body.Except phenobarbital which is partly excreted unchanged by the kidney, all clinically usedbarbiturates are metabolized in the liver by drug metabolizing microsomal enzymes to inactiveand more soluble compounds. Barbiturates are very effective inducers of the drug metabolizingenzymes.

2.Effects:

2.1CNS. Barbiturates can produce all degrees of CNS depression from mild sedation to coma.


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2.1.1Hypnotic. These drugs increase the total sleep time but also alter sleep architecture bydecreasing stage 3 and 4 of NREM sleeps and the REM sleep.

2.1.2Anesthetic. High doses of barbiturates produce surgical anesthesia. Short acting barbituratesadministered i.v. are used as general anesthetics (see General Anesthetics).

2.1.3Anticonvulsant. All barbiturates can arrest existing convulsions in anesthetic doses, only afew are useful antiepileptics preventing occurrence of generalized tonic-clonic and other types ofseizures (see, Antiepileptic Drugs).

2.2Respiratory. With increasing dose, the respiratory drives are depressed in the following order:neurogenic, chemical (pCO2) and hypoxic.

2.3Hemodynamic. Effects of hypnotic doses of barbiturates on cardiovascular system areunimportant. Anesthetic doses impair circulatory compensation, especially in hypovolemicpatients.

3.Therapeutic use:

As daytime sedatives and hypnotics, barbiturates have been largely replaced by benzodiazepines.They continue to be used as general anesthetics (e.g., thiopental) and antiepileptics (e.g.,phenobarbital).

4.Side effects and hazards:

4.1Daytime sedation. It can be minimized by dose adjustment.

4.2Tolerance. Barbiturates can accelerate their own metabolism by induction of the drugmetabolizing enzymes in the liver. In addition to this metabolic or drug disposition tolerance,pharmacodynamic tolerance also develops during chronic administration. This adaptation issubstantial to the sedative doses of barbiturates but minimal to the lethal doses. Thus, the marginof safety in an addict is narrower than in a normal person.

4.3Physical dependence. Intensity from the withdrawal symptoms which are indicative of physicaldependence depends on the dose, duration and continuity of chronic administration, andelimination half-life of the drug. They include tremulousness, insomnia, fever, agitation, delirium,convulsive seizures and cardiovascular collapse. They are more severe after discontinuation of ashort-acting drug. Abuse potential of barbiturates is high.

4.4Acute toxicity. Apart from accidental intoxication in children, most cases of acute barbituratepoisoning are suicidal attempts. The signs and symptoms of acute overdose include slurred

speech, ataxia, nystagmus, depressed respiration, depressed tendon reflexes, shock and coma.Treatment consists of general supportive measures. Hemodialysis is very efficient in speeding updrug elimination. CNS stimulants should never be used.

4.5Drug interaction. Barbiturates are additive with other CNS depressant drugs, including alcohol.Most drug interactions result from accelerated metabolism of various drugs includinganticoagulants, phenylbutazone, antiepileptics, oral contraceptives, certain vitamins, etc.


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4.6Other hazards. Barbiturates are absolutely contraindicated in patients with acute intermittentporphyria because they enhance porphyrin synthesis. In the presence of pulmonary insufficiency,a serious respiratory depression may occur even with moderate doses.

The non-barbiturate hypnotics, glutethimide and methylprylon, which were popular before thedevelopment of benzodiazepines, are comparable with an intermediate acting barbiturate in all

respects. They share all the drawbacks of barbiturates: narrow therapeutic ratio, enzyme induction,hangover, abuse liability including for suicidal purposes, physical dependence and tolerance.

Chloral hydrate, once popular for institutional use, is reduced in the body to trichloroethanolwhich is the active substance. This drug is a good enzyme inducer. The possibility ofcardiotoxicity is most likely remote with the use of therapeutic doses.

Miscellaneous other drugs

Some antidepressants, in particular, trazodone, have been used effectively to relieve insomniaeven in non-depressed patients. Sedative antihistaminics are available as "sleep aids" without

prescription but daytime sedation and the antimuscarinic effects limit their usefulness. Althoughalcohol may decrease sleep latency, it is an ineffective hypnotic disrupting sleep and causingrebound excitation. Adequate controlled studies of melatonin are lacking and the purity, hypnoticdose and side effects have not been established (but see above). Valerian root may improve qualityof sleep but optimal dosage and purity is a concern as with other herbal products.

An ideal hypnotic drug should:

1. promote sleep quickly2. alter the architecture and patterns of sleep only toward the norm3. ensure a complete night's sleep4. produce no residual daytime sedation5. influence no other body system or drug action

6. have a wide margin of safety7. be without danger of producing habituation, tolerance and dependence

Principles of treatment of insomnia


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1. Insomnia is a symptom. It may well be a symptom without recognizable disease, but oneshould be alert to underlying causes that may require more specific treatment. Theseinclude pain (e.g., arthritis, dyspepsia), dyspnea (left ventricular failure, bronchospasm),high frequency of micturition, mood disorders, anxiety.

2. Common prescription drugs and over-the-counter medication known to cause insomniainclude antihypertensives (clonidine, -blockers), anticholinergics (ipratropium), CNSstimulants (methyphenidate), hormones (thyroid preparations, cortisone)sympathomimetic amines (bronchodilators), xanthine derivatives (caffeine, theophylline),decongestants in cough and cold preparations.

3. Treatment with hypnotics should be on short-term or intermittent basis.4. Benzodiazepines and the newer benzodiazepine receptor agonists (e.g. zaleplon) should

be considered to be hypnotic drugs of choice for most insomniacs; one or two standarddrugs can manage majority of cases.

5. The smallest dose suitable for obtaining the desired effects should be used.6. Hypnotic effect of drug should be exploited by association with habitual activities; habit

alone may substitute for the drug or enhance its effect.7. Sleep apnea syndrome, heavy use of alcohol, pregnancy and necessity of alert night time

performance precludes the use of hypnotics.8. Advanced age, heavy snoring, lung disease (preexisting respiratory failure in patientswith severe pulmonary insufficiency can be aggravated by a usual dose of any hypnotic),liver disease, tendency of drug abuse, suicidal risk and special job requirements (pilot,driver) constitute relative contraindications of the use of hypnotics.


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SAMPLE EXAM QUESTIONS

CHOOSE THE MOST APPROPRIATE ANSWER

Among the drugs shown to be therapeutically effective in various anxiety states, the following

do(es) not enhance the GABA-mediated inhibition:1. oxazepam2. buspirone3. phenobarbital4. propranolol5. 2 and 4 of the above

ANSWER (5)

A 34 year old female complains about difficulty to fall asleep after it was announced that theoffice where she works will be soon reorganized. During the day, she does not feel apprehensiveabout this change. She is concerned about residual drowsiness in the morning because she has to

get up early and drive her car to work. Which of the following drugs would be suitable for short-term treatment of her sleep disturbance?

1. Flurazepam2. Phenobarbital3. Zaleplon4. Zopiclon5. Diazepam

ANSWER (3)

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