Материал: 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

Section IV λ CNS Pharmacology

λPharmacokinetics of BZs:

−Liver metabolites are also active compounds, except for oxazepam, temazepam, and lorazepam

λUses of barbiturates:

−Phenobarbital is used for seizures

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Chapter 1 λ Sedative-Hypnotic-Anxiolytic Drugs

λPharmacokinetics of barbiturates:

−Liver metabolized, sometimes to active compounds

−General inducers of cytochrome P450s

−Contraindication in porphyrias

λTolerance to and dependence on sedative-hypnotics:

−Chronic use leads to tolerance

−Cross-tolerance occurs between BZs, barbiturates, and ethanol

−Psychologic and physical dependence occur

−But abuse liability of BZs is < ethanol or barbiturates

−Withdrawal signs of BZs:

ºRebound insomnia

ºAnxiety

ºSeizures when BZs were used as antiepileptic or in high doses

−Withdrawal signs of barbiturates and ethanol:

ºAnxiety

ºAgitation

ºLife-threatening seizures (delirium tremens with alcohol)

−Management of withdrawal: supportive and long-acting BZs

λDrug interactions

−GABAA drugs are:

ºAdditive with other CNS depressants (possible life-threatening

respiratory depression), such as anesthetics, antihistamines, opiates, β-blockers, etc.

ºBarbiturates induce metabolism of most lipid-soluble drugs, such as oral contraceptives, carbamazepine, phenytoin, warfarin, etc.

λNon-BZ drugs:

−Zolpidem and zaleplon

ºBZ1 receptor agonist

ºLess effect on cognitive function (BZ2-mediated)

ºOverdose reversed by flumazenil

ºUsed in sleep disorders

ºLess tolerance and abuse liability (sleepwalking)

−Buspirone

ºNo effect on GABA

º5-HT1A partial agonist

ºUsed for generalized anxiety disorders

ºNonsedative

ºTakes 1 to 2 weeks for effects

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Section IV λ CNS Pharmacology

Chapter Summary

λSedative-hypnotic-anxiolytic drugs include the benzodiazepines, barbiturates, and alcohols.

λS-H drugs ideally should reduce anxiety without affecting mental or motor function. However, most do affect mental or motor function. Figure IV-1-1 illustrates the relative effects on these functions of classes of S-H drugs at increasing concentrations.

λMost S-H drugs facilitate GABA action by binding to the GABAA receptor, which has one binding site for barbiturates and alcohol and another for benzodiazepines (Figure IV-1-2). The binding of these drugs at these sites leads to increased Cl– influx, potentiating the inhibitory transmitter effects of GABA. The differences in action of the various S-H drugs relate to the differences in the binding site used. Further heterogeneity is introduced by the existence of two subtypes of benzodiazepine receptors, BZ1 and BZ2.

λThe benzodiazepines are used to treat anxiety states and sleep disorders.

Dose-dependent CNS depression does occur but can be reversed by flumazenil. Chronic use can lead to tolerance and dependency with rebound effects upon withdrawal. Table IV-1-1 summarizes the various benzodiazepines and their indications.

λPhenobarbital is used to treat seizures, and thiopental is used as an IV anesthetic. Barbiturates induce deep CNS depression at high doses, and there is no antidote.

λThe barbiturates induce drug-metabolizing enzymes, including the P450 system, leading to potential drug interactions. They also stimulate heme synthesis and are contraindicated in porphyrias.

λTolerance, dependence, and severe withdrawal symptoms are associated with chronic barbiturate use.

λZolpidem and zaleplon are nonbenzodiazepines that bind to the BZ1 receptors and therefore are more specific hypnotics. Buspirone is an anxiolytic that does not work through the GABA system. It is nonsedating and does not cause dependence but takes a week or two to show antianxiety effects.

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Alcohols 2

Learning Objectives

Answer questions about the mechanism of action and metabolism of alcohol

λAll alcohols cause CNS depression, in part through GABA mimetic activity.

λAll alcohols cause metabolic acidosis.

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Section IV λ CNS Pharmacology

Chronic Alcoholism

1.Hypoglycemia

2.Fatty liver and lipemia

3.Muscle wasting (long-term alcoholic, poor food intake)

4.Gout (lactate competes with urate for excretion)

Figure IV-2-1. Metabolism and Pharmacologic Actions of the Alcohols

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