книга / 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

Chapter 7 λ Cardiac and Renal Drug List and Practice Questions

16.Answer: C. ACE inhibitors prevent the conversion of angiotensin I to angiotensin II and lower blood pressure by decreasing both the formation of aldosterone formation and the vasoconstrictive action of AII at AT-1 receptors. ACEIs also inhibit the metabolism of bradykinin, and this leads to additional hypotensive effects, because bradykinin is an endogenous vasodilator. Unfortunately, increases in bradykinin are associated with side effects, including cough and angioedema. Losartan, which blocks AT-1 receptors, does not increase bradykinin levels.

17.Answer: B. Supraventricular tachycardias (SVTs) are treated effectively by class II and class IV antiarrhythmics. In addition, adenosine is indicated for SVTs and nodal tachycardias but only acutely since it must be administered IV and has an extremely short duration. The primary actions of both beta blockers (esmolol) and CCBs (diltiazem) are at the AV node, but esmolol is too short-acting to be useful as prophylaxis. Lidocaine and mexilitene are both class Ib drugs that are used in ventricular arrhythmias.

18.Answer: A. ACEIs slow the progression of diabetic nephropathy and are indicated for management of HTN in such patients. Nitroprusside is used IV in severe HTN or hyper¬tensive crisis, not for management of mild-to- moderate HTN. Losartan, which blocks AT-1 receptors, is associated with teratogenic effects during fetal development, as are the ACEIs. Nonselective beta blockers are not ideal for patients who suffer from peripheral vascular disease, diabetes, or asthma. Milrinone, like most inotropes, is not useful long-term in CHF patients. The drug has been shown to increase mortality with chronic use, and thus is indicated for acute CHF. Digoxin is currently the only inotrope used chronically.

19.Answer: E. The sublingual administration of a drug avoids its absorption into the portal circulation and hence eliminates the possibility of first-pass metabolism, which can often have a major impact on oral bioavailability. Given sublingually, nitroglycerin is more effectively absorbed into the systemic circulation and has improved effectiveness in angina by this mode of administration. Effective absorption is unlikely to decrease reflex tachycardia or propensity toward methemoglobinemia. There is no bypass of the coronary circulation—nitrates actually decrease coronary vasospasm, which makes them effective in variant angina.

20.Answer: D. An increase in AV conduction is characteristic of quinidine, which exerts quite marked blocking actions on muscarinic receptors in the heart. Thus, an atrial rate, formerly transmitted to the ventricles in a 2:1 ratio, may be transmitted in a 1:1 ratio after quinidine. This effect of quinidine can be offset by the prior administration of an antiarrhythmic drug that decreases AV nodal conduction, such as digoxin or verapamil. All of the drugs listed (except quinidine) slow AV nodal conduction, but adenosine and esmolol (a beta blocker) are very short-acting agents used IV only.

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SECTION IV

CNS 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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