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Anesthesia Pharmacology Chapter 11: Pharmacology of Anxiolytics and Sedative-Hypnotics
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Stages of central nervous system depression: Non-benzodiazepine (e.g. barbiturates) sedative-hypnotic drugs produce a dose-dependent sequence of CNS depression
With increasing dosage:
Calming or drowsiness {sedation}
Sleep {pharmacological hypnosis}
Unconsciousness
Coma
Surgical anesthesia
Fatal respiratory/cardiovascular depression
Classification of central nervous system depressants
Benzodiazepines (e.g.,diazepam (Valium), midazolam (Versed), clonazepam (Klonopin)
Barbiturates (amobarbital, pentobarbital (Nembutal), thiopental (Pentothal))
Miscellaneous agents (e.g. paraldehyde (Paral), meprobamate (Miltown), ethchlorvynol (Placidyl))
Benzodiazepines
Benzodiazepines act on GABAA receptors
GABA receptor: a pentameric protein, consists of several subunits designated alpha (mainly responsible for the pharmacology of the receptor) ,beta and gamma which is required for high affinity benzodiazepine binding.
Electrophysiological Effects: Benzodiazepines enhance GABA-activated hyperpolarizing chloride currents.
Ethanol
Several sites and mechanisms may be responsible for ethanol-mediated CNS depression:
Direct membrane effects:
Dissolves into lipid membranes affecting the function of membrane proteins, such as receptors and ion channels.
Decreases GABA-receptor mediated synaptic inhibition
Inhibits the NMDA glutamate receptor (inhibits an excitatory effect)
Potentiates the action of serotonin (5-HT) at excitatory 5-HT3 receptors.
Since these receptors are often localized on inhibitory interneurons, ethanol-enhanced activation results in increased inhibition.
Barbiturates
Barbiturates activate inhibitory GABAA while inhibiting excitatory AMPA receptors.
AMPA receptors are the subtype of glutamate receptors sensitive to kainate or quisqualate.
Barbiturates interact differently than benzodiazepines at GABA receptors. For example, the gamma subunit is not required for barbiturate activity.
The combination of these receptor effects may result in the profound central nervous system depression that occurs with higher barbiturate doses.
[Hobbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives: Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 361-383.]
Benzodiazepine Effects on cardiovascular, respiratory and central nervous systems
Cardiovascular System
Except in overdosage, cardiovascular effects of benzodiazepines in normal subjects are minor.
If used as preanesthetic medication, benzodiazepines decrease blood pressure and increase heart rate.
Respiratory System
At pharmacological hypnotic doses, benzodiazepines do not affect respiration in normal subjects.
Severely benzodiazepine-intoxicated patients may require assistance in breathing if other CNS depressant drugs have been taken
If a patient, however, has a sleep-related breathing syndrome such as obstructive sleep apnea (OSA), benzodiazepines may be contraindicated.
In patients with obstructive sleep apnea, hypnotic doses of benzodiazepines may decrease muscle tone in the upper airway and accentuate or worsen the impact of apneic episodes on alveolar hypoxia, pulmonary hypertension and cardiac demand.
At higher doses, such as those used for endoscopy or when given as preanesthetic medication, benzodiazepines somewhat depress alveolar ventilation causing a respiratory acidosis secondary to a decrease in hypoxic drive (rather than hypercapnic drive).
These effects are more severe in patients with COPD (chronic obstructive pulmonary disease) and maybe sufficiently detrimental to induce alveolar hypoxia and/or CO2 narcosis.
Central Nervous System
With increasing doses, benzodiazpines can progressive cause sedation, then hypnosis and then stupor.
Benzodiazepines do not cause general anesthesia since awareness persists.
These agents have anti-anxiety / sedative-hypnotic properties.
Some benzodiazepines (clonazepam (Klonopin)) are effective muscle relaxants, whereas most others are not.
[Hibbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives: Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 364-367.]
Barbiturates: Effects on the cardiovascular and central nervous system
Cardiovascular System
In sedative or doses for pharmacological hypnosis, barbiturates have minimal cardiovascular effects.
When thiopental is used in general anesthesia, following pre-anesthetic medication:
plasma renal flow decreases
cerebral blood flow decreases
CSF pressure decreases
Significant depression of myocardial contractility occurs in barbiturate poisoning.
Central Nervous System
Barbiturates depress respiratory drive
At doses somewhat (three times) higher than required for pharmacological hypnosis, neurogenic is abolished and the hypoxic respiratory drive is reduced and the chemoreceptor drive is attenuated.
At still higher doses, the hypoxic drive is abolished.
[Hibbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives: Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 377.]
Advantages and disadvantages of each class relative to the others (Benzodiazepines vs Barbiturates)
Benzodiazepines have proven far safer than barbiturates for pharmacological hypnosis and both safer and more effective in management of generalized anxiety disorder.
The use of barbiturates therefore has declined as a result of more favorable pharmacological properties associated with benzodiazepines.
Tolerance to barbiturates occurs more often than that observed with benzodiazepines
Barbiturate abuse liability is greater than with benzodiazepines.
Barbiturate use may be accompanied by significant drug-drug interaction.
Barbiturates lack CNS specificity
Prominent barbiturate use:
Barbiturates are used as therapeutic/diagnostic aids in psychiatry
Barbiturates also are effective in reducing cerebral edema following surgery, head injury or cerebral ischema.
Barbiturates are also effective antiepileptic medications
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Major drugs and drug classes used to treat anxiety
Chlordiazepoxide (Librium), Diazepam (Valium), Oxazepam (Serax), Clorazepate (Tranxene), Lorazepam (Ativan),Alprazolam (Xanax), Halazepam (Paxipam), barbiturates (rarely), buspirone
Benzodiazepines are commonly used for management of generalized anxiety disorder. Most, but not all, clinical research studies have shown that benzodiazepines are more effective than placebo in treating anxiety.
Factors that have promoted the popularity of these drugs include:
Safety
Pharmacology
Patient demand.
Benzodiazepines may be more efficacious and certainly safer in management of anxiety compared to barbiturates.
Barbiturates and non-barbiturates such as meprobamate have been used in the past to manage anxiety. However, these drugs are now rarely used.
Barbiturates are also infrequently used for this indication because of:
Excessive sedation/intoxication at anxiolytic dosages
Tolerance
Physical dependence
Potentially life-threatening withdrawal reactions
Life-threatening toxicity with overdosage.
Buspirone
Buspirone,which has selective affinity of 5-HT1A, is a relatively new anxiolytic.
Buspirone seems most effective in mild anxiety and is not effective compared to benzodiazepines and certain antidepressant agents in treatment of panic disorder.
Buspirone does not exhibit cross-tolerance with benzodiazepines or other sedative-hypnotics.
Baldessarini, R. J., Drugs and the Treatment of Psychiatric Disorders, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 421-427]
Pharmacological hypnosis: major drugs /drug classes
Introduction
If non-pharmacological treatment of insomnia (such as moderate exercise) is not effective, drugs may have to be used.
Untreated chronic insomnia may have many adverse effects including a four-fold increase in serious accidents.
In addition to use of pharmacological agents, management of insomnia should include (a) a search for an underlying cause, elimination of "performance anxiety" related to falling asleep, adjusting the patient's biological clock such that sleepiness corresponds to the time of attempted sleep, and suppression of the use of alcohol or over-the-counter sleep aids
Ethanol
Ethanol should not be used to manage insomnia because of numerous adverse effects.
For insomnia, despite reducing sleep latency, it may cause sleep fragmentation.
Barbiturates and non-barbiturates for hypnosis
Barbiturates and non-barbiturates such as meprobamate have been used in the past for pharmacological hypnosis.
However, these drugs should be avoided:
Liabilities associated with barbiturate use include abuse potential, physical potentially life-threatening withdrawal reactions, dependence, and life-threatening toxicity with overdosage.
Benzodiazepines
Hypnotics that act at benzodiazepine receptors and newer agents such as zolpidem (Ambien) are preferable to barbiturates because of: greater therapeutic index, less disruption of sleep patterns, less danger of overdosage toxicity, less abuse liability
In the absence of daytime anxiety benzodiazepines with short half-lives (no active metabolites or only short-acting metabolites) are preferable.
Triazolam (Halcion) is an example of a short-acting agent that has been used as a hypnotic.
Short acting benzodiazepines may, however cause amnesia, early morning awakening, rebound daytime anxiety
Some patients who have insomnia also have daytime anxiety.
To manage those patients a longer-acting benzodiazepine may be appropriate.
Use of these agents may result in: next-day cognitive impairment or delayed cognitive impairment as metabolites accumulate
[Hobbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives: Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 385-386
Ethanol
Ethanol: absorption, metabolism of ethanol, its effects on major organs system, contraindications, acute and chronic toxicities, the mechanism of action of disulfiram
*Note: Chronic ethanol abuse has anesthesia implications. In consideration of a variety of surgeries including colonic surgery, prostatectomy, ankle surgery, and surgical intervention to treat subdural hematoma, perioperative morbidity increases by 200%-300%. (*Mushlin, P.S. and S. Gelman, "Anesthesia and the Liver", in Clinical Anesthesia (4/e), edited by Paul G. Barish, Bruce F. Cullen and Robert K. Stoelting, Lippincott Williams and Wilkins, p 1084, 2001)
Frequently observed complications include bleeding, cardiopulmonary insufficiency, and infection.
Underlying mechanisms for the is complications include:
subclinical cardiac insufficiency, hemostatic imbalance, immune system deficiencies, and possibly in accentuated stress response to surgery or alcohol abstinence (withdrawal).
Ethanol is rapidly absorbed from stomach, small intestine and colon but the rate of absorption from the stomach is influenced by the food content.
Ethanol evenly distributed throughout all fluids and tissues, after absorption.
Placental permeability ensures access of ethanol to the fetus.
Most ethanol molecules are oxidized, with the rate of oxidation insensitive to ethanol concentration (zero-order kinetics).
Most ethanol oxidation occurs in the liver and is catalyzed by alcohol dehydrogenase.
The product is acetaldehyde which is then converted to acetyl CoA.
To a limited extent, in humans, ethanol is also oxidized by mixed function oxidases in liver microsomal membranes.
Genetic polymorphisms occur for both alcohol and aldehyde dehydrogenase.
Mechanism of Action
Ethanol (along with anesthetics) enhances GABA-mediated synaptic inhibition.
Ethanol inhibits glutamate-activated ion channels (excitatory) (predominately the NMDA glutamate receptors at mild intoxicating ethanol concentrations.)
Ethanol may also act by affecting 5-HT3 receptors.
Activation of these receptors results in excitation of inhibitory interneurons.
Serotonin's action at the 5-HT3 receptor subtype is enhanced by ethanol.
Drug-Drug Interactions
Ethanol enhances CNS depression caused by other sedative-hypnotics.
Ethanol interferes with metabolism of drugs that utilize the same hepatic oxidase system.
For example the clearance of phenytoin is prolonged due to competition with ethanol for the same mixed-function hepatic oxidase system.
By contrast, with chronic use, ethanol causes induction of hepatic metabolizing enzymes and can, in this case, increase clearance of many drugs (e.g. phenytoin (Dilantin), Tolbutamide (Orinase)).
Chronic consumers of ethanol are susceptible to acetaminophen hepatoxicity probably due to accumulation of toxic metabolites and glutathione depletion.
Contraindications for ethanol use: Hepatic disease, gastrointestinal ulcer, cardiac or skeletal myopathy, pregnancy, individuals previously addicted to ethanol
Ethanol: Organ Systems: Pharmacological Effects
Central Nervous System
Acute effects
Ethanol is a CNS depressant.
Depression of inhibitory CNS systems may be responsible for apparent stimulation that is observed initially.
With moderate intoxication, mood swings, outgoing, and expansive behavior occur.
General impairment of statements function becomes evident with increased intoxication.
Large amounts of ethanol may lead to severe (even lethal) respiratory depression.
Chronic effects
Chronic and excessive ethanol use results in brain damage, memory loss, sleep disturbances.
Increased risk of seizures.
Neuropsychiatric disturbances including Wernicke's encephalopathy.
(Wernicke's encephalopathy is due to a nutritional thiamine deficiency. This syndrome is not observed only in alcoholics. Common causes include chemotherapy-associated prolonged vomiting with lack of nourishment, eating disorders, elderly patients who had been living alone and who have not been maintaining adequate nutrition [Wernicke's may be precipitated in the hospital by glucose administration to patients who is deficient in thiamine.]
" Wernicke-Korsakoff encephalopathy. Note pigmentation of gray matter around third ventricle. Occurs with Vitamin B1 deficiency, most often in chronic alcoholics."--image from educational materials (pathology) University of Texas (Houston) (http://medic.med.uth.tmc.edu/edprog/path/path-10.htm)
"Mammillary Gross Wernicke's encephalopathy. Note bodies black mammillary body from acute congestion and hemorrhage indicating the acute form of Wernicke's" --image from educational materials (pathology) University of Texas (Houston)
Cardiovascular System
Acute Effects:
Ethanol causes a generalized vasodilation (due to both central effects and effects on the vascular bed)
Moderate doses, however, can cause a vasoconstrictive effect in the heart and brain.
In severe intoxication, cardiovascular depression occurs secondary to central vasomotor effects and respiratory depression.
Chronic Effects:
With chronic use, significant and irreversible damage to the myocardium may occur.
This effect is one of the most important causes of cardiomyopathy.
Gastrointestinal Tract
Ethanol increases gastric secretions by (a) direct action on the stomach (may increase gastrin), (b) psychological mechanism (if the individual likes it), (c) stimulating sensory endings in the buccal and gastric mucosae.
At high ethanol concentrations (80 proof [40% alcohol]), direct gastric mucosal irritation occurs resulting in congestive hyperemia and inflammation.
These concentrations can result in an erosive gastritis.
Gastric damage caused by aspirin is significantly worsened by ethanol.
Chronic, excessive ethanol consumption may cause either diarrhea or constipation.
Ethanol may also predispose to chronic pancreatitis because of both increased secretion and pancreatic ductal obstruction.
Liver
Chronic use of ethanol promotes hepatic cirrhosis and is associated with an increased risk of cancer and drug toxicity (acetaminophen).
Acute use probably does not produce lasting hepatic changes.
Miscellaneous organ effects
Teratogenic effects:
Fetal alcohol syndrome consists of many dysfunction. including low IQ, microcephaly, facial abnormalities.
Ethanol appears to be the most frequent cause of teratogenically-caused mental deficiency in the West.
Sexual Functions:
Inebriation interferes with coitus, decreasing sexual responsiveness in both men and women.
Chronic ethanol abuse may lead to impotence, sterility, testicular atrophy, and gynecomastia.
Feminization in males is due to both hyperestrogenization with reduced rate of testosterone production (due to hepatic damage) and by ethanol's induction of hepatic metabolizing enzymes, increasing the rate of testosterone inactivation.
Renal: Increased diuresis due to reduction in ADH and hence a decrease in tubular water reabsorption.
Disulfiram (Antabuse) inhibits aldehyde dehydrogenase which results, following ethanol ingestion, in an increased acetaldehyde concentration.
The resulting "acetaldehyde syndrome" consists of facial flush, headache, hypotension, marked uneasiness, confusion, vomiting and other symptoms.
These unpleasant effects are the basis of the use of disulfiram as part of the treatment of chronic alcoholism.
Disulfiram is converted to ethyldithiocarbamate a very effective chelator of copper and other metals. As a result, ethyldithiocarbamate inhibits the activity of dopamine beta-hydroxylase, alcohol dehydrogenase, and other metalloenzymes.
Hobbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives: Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 386-392.
Mechanism of action
Molecular: Barbiturates activate inhibitory GABAA while inhibiting excitatory AMPA receptors.
AMPA receptors are the subtype of glutamate receptors sensitive to kainate or quisqualate.
Barbiturates interact differently than benzodiazepines at GABA receptors. For example, the gamma subunit is not required for barbiturate activity.
The combination of these receptor effects may result in the profound cns depression that occurs with higher barbiturate doses.
Pharmacokinetics/Redistribution
Barbiturates are usually orally administered and are rapidly and well absorbed.
Intravenous administration is used for:
Treatment of status epilepticus (phenobarbital)
Anesthesia induction/maintenance (methohexital (Brevital), thiopental (Pentothal)).
Barbiturates are highly lipid soluble and the i.v. barbiturate anesthesia induction agent are the most lipid soluble.
After i.v. injection these agents undergo rapid redistribution from the brain to other tissues.
Redistribution is the major mechanism for termination of CNS action.
Most barbiturates undergo extensive hepatic metabolism prior to renal excretion.
Renal excretion is favored by osmotic diuresis and/or alkalinization of the urine.
Barbiturate metabolism is more rapid in young adults compared to children or the elderly.
Half-lives may be increased in pregnancy (due to increased volume of distribution)
Barbiturate half-lives can be increased in patients with chronic liver disease, such as cirrhosis.
Effects of barbiturates on major organ systems
Cardiovascular System
In sedative or doses for pharmacological hypnosis, barbiturates have minimal cardiovascular effects
When thiopental (Pentothal) is used in general anesthesia, following pre-anesthetic medication, plasma renal flow, cerebral blood flow, and CSF pressure decrease.
Significant depression of myocardial contractility occurs in barbiturate poisoning
Central Nervous System
Barbiturates depress respiratory drive.
At doses somewhat (three times) higher than required for pharmacological hypnosis, neurogenic drive is abolished and the hypoxic respiratory drive is reduced and the chemoreceptor drive is attenuated.
At still higher doses, the hypoxic drive is abolished.
Liver
Acutely, barbiturates combine with cytochrome P-450 and produce competitive inhibition of metabolism of a number of drugs and endogenous agents (such as steroids)
Chronically, barbiturates increase activities of cytochrome P-450 oxidases and glucuronyl transferases and therefore increase the metabolism (due to enzyme induction) of many drugs, steroids, vitamins K and D, cholesterol, bile salts. The extent of the increase is about two fold
Part of barbiturate tolerance is due to increased hepatic metabolism of barbiturates, induced by barbiturates.
Non-microsomal enzyme system are also induced, including:
d -aminolevulinic acid (ALA) synthetase. The effect of barbiturates on ALA synthetase that produces exacerbation in patients with intermittent porphyria.
aldehyde dehydrogenase
Barbiturate Overdosage/Adverse Effects
Adverse Effects:
Drowsiness, impaired judgment, impaired motor skills
Significant CNS/respiratory depression with high dosage.
Paradoxical excitement
If barbiturates are given for pain, restlessness, excitement, or delirium may result
Hypersensitivity: allergic reaction in patients who are predisposed to angioedema, urticaria, and asthma
Drug interactions: combination with other sedative agents can result in severe CNS depression.
Untoward effects:
Absolutely contraindicated in acute intermittent porphyria or porphyria variegata because barbiturates increase porphyrin synthesis.
i.v. administration can produce cardiovascular collapse; overdosage can cause severe respiratory depression.
Management of barbiturate poisoning
Severe intoxication is associated with coma and depressed respiration
Treatment is supportive with CNS stimulants contraindicated (increases mortality)
Hemodialysis or hemoperfusion may be needed
Complicating factors include:
circulatory collapse
shock
dehydration
renal failure.
Therapeutic Uses
IV anesthesia: Thiopental (Pentothal) and methohexital (Brevital)
Convulsions: emergency treatment (eclampsia, tetanus, status epilepticus), but benzodiazepines are preferable.
Epilepsy
Rarely used as a sedative due to the availability of safer benzodiazepine agents.
[Hibbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives: Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 374-377.]
Diazepam (Valium)
Alprazolam (Xanax)
Chlordiazepoxide (Librium)
Clonazepam (Klonopin)
Clonazepam is used (a) in seizure disorders: absence seizures, myoclonic seizures in children (b) as adjunctive treatment in acute mania and in (c) certain movement disorders.
Adverse Effects:
Common: Drowsiness, lethargy
Less common: Muscular incoordination, ataxia
Other: hypotonia, dysarthria, dizziness, behavior disturbances including hyperactivity, irritability, difficulty in concentration.
Seizures may occur if drug is discontinued abruptly.
Flurazepam (Dalmane)
Flurzepam has been prescribed for insomnia.
Flurazepam has long-acting metabolites.
Adverse Effects:
Presence of long-acting metabolites may cause daytime sedation, which may be undesirable.
Triazolam (Halcion)
Triazolam is used to induce sleep.
Triazolam is short-acting with no active metabolites
Adverse Effects: Tolerance may develop and rebound insomnia has been reported.
Reported associations of triazolam with psychotic reactions,
dependency, anterograde amnesia are some factors that
contributed to triazolam removal from the market in some
European countries.5
Flumazenil (Romazicon, benzodiazepine antagonist*)
Primary use is for management of benzodiazepine overdosage.
Additional use in the reduction of benzodiazepine effects in general anesthesia or diagnostic procedures.Competitively antagonizes the binding and allosteric effects of benzodiazepines.
Benzodiazepine-induced electrophysiological and behavioral effects are antagonized.
Fumazenil is available only for intravenous administration (because of high first-pass effect)
Adverse Effects:
in comatose patients, intoxicated with alcohol, flumazenil may increase risk of seizures.
in comatose patients due to tricyclic antidepressant agents, flumazenil increases seizure risk.
[[Hobbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives: Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp. 372-373.;
McNamara, J.O. Drugs Effective in the Therapy of the Epilepsies, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp. 479];
Dopheide, J.A.. Sleep Disorders, In, Applied Therapeutics: The Clinical Use of Drugs, (Young, L.Y. and Koda-Kimble, M.A.,eds) Applied Therapeutics, Inc., 1995, p 74-5);
[Harvery, R.A, Champe, P.C., Mycek, M.J., Gertner, S.B. and Perper, M.M., Anxiolytic and Hypnotic Drugs, In: Lippincott's Illustrated Reviews: Pharmacology, J.B. Lippincott Co, 1992, p 94]
Eisendrath SJ and Lichtmacher JE "Psychiatric Disorders" in 2008 Current Medical Diagnosis and Treatment, (McPhee SJ, Papadakis MA and Tierney LM, eds) Lange 2008, McGraw Hill Medical, New York, 47th edition, 2008.
Benzodiazepines: Effects on Organ Systems and Side Effects
Cardiovascular System
Except in overdosage, cardiovascular effects of benzodiazepines in normal subjects are minor.
If used as preanesthetic medication, all benzodiazepines decrease blood pressure and increase heart rate.
In this setting diazepam increases coronary flow (perhaps by increasing adenosine concentration).
Respiratory System
At pharmacological hypnotic doses, benzodiazepines do not affect respiration in normal subjects.
At higher doses, such as those used for endoscopy or when given as preanesthetic medication, benzodiazepines somewhat depress alveolar ventilation due to a decrease in hypoxic drive. (as noted above)
These effects are worse in patients with COPD (chronic obstructive pulmonary disease).
In the presence of other CNS depressant drugs, severely benzodiazepine intoxicated patients may require assisted respiration.
If a patient, however, has a sleep-related breathing syndrome such as obstructive sleep apnea (OSA), benzodiazepines may be contraindicated.
In this setting benzodiazepines may decrease muscle tone in the upper airway and accentuate the effect of apneic episodes on:
alveolar hypoxia
pulmonary hypertension
cardiac demand.
Central Nervous System
With increasing doses, benzodiazpines can progressive cause sedation, then hypnosis and then stupor.
Since awareness persists, benzodiazepines do not cause general anesthesia
Anti-anxiety / sedative-hypnotic properties
Some benzodiazepines are effective muscle relaxants (clonazepam (Klonopin)) , whereas most others ( diazepam (Valium)) are not.
Other Agents--further comments about buspirone
Buspirone is a non-benzodiazepine anxiolytic drug.
Site of action: 5-HT1A receptor subtype.
No anticonvulsant activity.
No interaction with benzodiazepine binding sites
No influence on interaction of GABA with the GABA receptor.
Not effective in management of severe anxiety/panic disorder.
No cross-tolerance with other sedative-hypnotic drugs
No muscle relaxant properties.
Minimal adverse effects
[Hibbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives; Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 364-367.];
Baldessarini, R. J., Drugs and the Treatment of Psychiatric Disorders, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 425]
Anxiolytic-Sedative Hypnotic Drug List
Alprazolam (Xanax)j
Clonazepam (Klonopin)
Diazepam (Valium)
Lorazepam (Ativan)
Triazolam (Halcion)
Flumazenil* (Romazicon) *receptor antagonist
Non-Depressant Anxiolytic
Buspirone (BuSpar)
Treatment of alcoholism
Disulfiram
Barbiturates/Anesthetics
Pentobarbital (Nembutal)
Phenobarbital (Luminal)
Thiopental (Pentothal)
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