Brody's Human Pharmacology: With STUDENT CONSULT

APPENDIX Answers to SELF-ASSESSMENT QUESTIONS

Chapter 1

1. B.

Binding usually involves multiple weak bonds. It is rarely covalent, is usually stereoselective, and may or may not occur with a high affinity (KD).

2. A.

Chronic antagonist exposure will often increase receptor sensitivity. The other answers all decrease receptor sensitivity.

3. B.

The affinity of drugs for receptors varies by many orders of magnitude. All other answers are correct.

4. E.

Hormone receptor signaling can occur through any of the mechanisms listed.

5. B.

Based on the information given, one can conclude only that the potencies are different. No conclusions can be made about structure, types of receptors involved, whether they are directly acting agonists, or whether they cause the same extent of relaxation.

6. D.

The affinity constant is the concentration of a drug that occupies half of available receptor sites, is the ratio of the rate constants, and is important in determining fractional occupancy.

Chapter 2

1. D.

There is no DNA in cell membranes.

2. B.

Renal tubular reabsorption increases plasma drug concentrations.

3. D.

pH - pKa = log [A]/[HA] = 7.4 − 5.4 = 2. Therefore the antilog of 2 is 100, and [HA] is 1%.

4. E.

Highly polar and quaternary nitrogen compounds do not easily diffuse across cell membranes.

5. D.

All of the answers listed are involved except esterases.

6. E.

Conjugation reactions require drug-metabolizing enzymes and activation by high-energy phosphates, can occur with a variety of amino acids, and can also involve acids and weak bases.

Chapter 3

1. E.

See equation 7.

2. A.

Clearance is an independent pharmacokinetic parameter.

3. E.

See discussion on protein binding.

4. D.

Glomerular filtration rate (GFR) may slow, which alters the clearance of drugs.

5. D.

Phase two drug metabolism such as glucuronidation does not change significantly with aging.

Chapter 4

1. D.

The FDA restricts only drugs that are Schedule 1. It does not restrict how it is used or whether or not a generic form exists.

2. C.

Safe dosage on a small number of human volunteers and pharmacokinetics of the drug are determined by Phase I studies.

3. A.

See Table 6-3.

4. B.

q.i.d. means four times a day.

5. D.

1 grain equals about 65 mg, so 5 grains is about 325 mg.

Chapter 5

1. D.

A non-mutant gene is added to the cell in so-called complementation therapy. Optimized, this strategy is more efficient than adding RNA or protein to the cell. Current technology does not permit efficient repair of mutant DNA.

2. B.

Transfer of genes in human gene therapy must be safe and nontoxic. Delivery of foreign DNA in a plasmid or viral vector may induce an immune response, which should be monitored. The success of gene transfer should be determined by evaluating the expression of the added DNA. The target cell for gene delivery should be a somatic cell, because transfer to germ cells is not ethical.

3. B.

Microsomes (phospholipids) have not been used for gene transfer in clinical trials. Lipids in the form of liposomes are widely used. Many other viral and nonviral vehicles have been used.

4. C.

Oligonucleotide antisense therapy depends on complementary binding of the delivered oligonucleotide and mRNA. RNaseH attacks this heteroduplex to degrade the mRNA. The effect is transient and depends on continued availability of antisense. Antisense oligonucleotides can be generated by a viral vector, but production of new mRNA is not the therapeutic mechanism.

Chapter 6

1. B.

Corticosteroids suppress immune and inflammatory responses.

2. D.

Cyclosporine is considered to be more selective than the antiproliferative immunosuppressive agents (azathioprine and cyclophosphamide) by inhibiting cytokine synthesis in T-lymphocytes.

3. B.

Cyclosporine does not produce bone marrow suppression.

4. B.

Cyclosporine prevents graft rejection by inhibiting several T-lymphocyte-dependent immune responses—the cytotoxic T-lymphocyte response, delayed-type hypersensitivity response, and antibody response.

Chapter 7

1. B.

Randomized controlled clinical trials provide the most-solid evidence.

2. B.

The Dietary Supplement Health Education Act (DHSEA) provides the regulatory framework for herbal and dietary supplements.

3. C.

Echinacea is used to modulate immune function.

4. D.

St. John’s wort is used as an antidepressant.

5. C.

No claims about efficacy can be made without sufficient scientific evidence.

6. A.

Middle-aged people are most likely to use dietary supplements.

Chapter 8

1. A.

Only extremely small particulates remain airborne and penetrate all the way to the alveolus.

2. B.

The kidney, which receives 25% of cardiac output, filters, concentrates and eliminates toxicants. The kidney does synthesize metallothioneins, which have a protective effect by binding to metals, not by metabolizing organic solvents.

3. C.

Lead tends to concentrate in red blood cells, and the blood lead concentration is an index of the degree of lead exposure.

Chapter 9

1. B.

ACh is the neurotransmitter for preganglionic neurotransmission.

2. B.

The neurotransmitter for postganglionic sympathetic neurons is NE.

3. A.

Only the nicotinic receptors are ligand-gated, whereas all the others act on GPCRs.

4. D.

The stimulation by NE and any other agonist of prejunctional α2 adrenergic receptors on postganglionic sympathetic neurons results in inhibition of NE release.

5. D.

Phenylethanolamine-N-methyltransferase is a key enzyme in the synthesis of epinephrine.

6. C.

Activation of the parasympathetic system results in constriction of airway smooth muscle.

Chapter 10

1. C.

Pyridostigmine is orally administered on a chronic basis for myasthenia gravis and, unlike physostigmine, does not pass the blood-brain barrier.

2. B.

Pilocarpine is a cholinergic agonist that acts on ACh receptors to constrict the pupil.

3. A.

The patient exhibits typical parasympathetic symptoms with little neuromuscular involvement; consequently the muscarinic antagonist atropine is administered to antagonize the actions of the anticholinesterase insecticide. Atropine is preferred over the quaternary ammonium muscarinic antagonist propantheline, which does not enter the brain. In the presence of more neuromuscular symptoms, atropine plus pralidoxime would be the appropriate treatment. The reversible carbamate cholinesterase inhibitor physostigmine is sometimes administered as an antidote to organophosphorus cholinesterase poisoning; however, this treatment is not as effective as pralidoxime. The short-acting competitive inhibitor of cholinesterase, edrophonium, has no use in treatment of cholinesterase poisoning.

4. D.

The cause of death from anticholinesterase poisoning is usually respiratory failure, resulting from bronchoconstriction, excessive bronchial secretions, and paralysis of the diaphragm. Cholinesterase inhibitors do not cause hypertension or congestive heart failure. Although cholinesterase inhibitors cause hypotension, it usually is not the cause of death.

5. B.

The mechanism of action of botulinus toxin is inhibition of vesicular release of acetylcholine. It does not block nicotinic receptors or peristalsis, nor does it stimulate the vagus nerve or cause circulatory collapse.

6. D.

Bethanechol activates muscarinic receptors, causing a decrease in heart rate, peripheral vasodilation, and constriction in the airways of the lung. Bethanechol does not activate nicotinic receptors at the neuromuscular junction.

Chapter 11

1. B.

Metoprolol is a relatively selective β1 adrenergic receptor antagonist; the other responses to epinephrine are mediated by different adrenergic receptor subtypes (a, α2; c, β2; d, α1; and e, α1).

2. C.

Labetalol has α1 adrenergic receptor antagonist properties in addition to its β receptor-blocking actions. Propranolol and nadolol are β receptor antagonists that lack α1-blocking properties. Dobutamine and methoxamine are β1 and α1 agonists, respectively, and do not reduce sympathetic output to the vascular system.

3. E.

Nadolol is more effective in blocking β2 adrenergic receptors on bronchial smooth muscle than atenolol, which tends to be more specific in blocking β1 adrenergic receptors. The other three drugs are β2 agonists that would reduce airway resistance.

4. C.

Phenylephrine, by activating α1 adrenergic receptors, increases blood pressure, resulting in reflex bradycardia. The other drugs would be expected to have little effect or increase heart rate by acting directly on the heart (a and e) or by causing reflex tachycardia (b and d).

5. A.

Terbutaline is a β2 adrenergic receptor agonist, and all effects are produced by activation of β2 receptors (reflex tachycardia) except mydriasis, which can be caused by activating α1 adrenergic receptors on the radial smooth muscle of the iris.

6. C.

After blockade of α1 and α2 adrenergic receptors by phentolamine, epinephrine activates β1 and β2 adrenergic receptors and thus most closely resembles the β12 agonist isoproterenol. The other drugs have α- (a and e), α/β1- (norepinephrine), or β2-(b) agonist properties.

Chapter 12

1. D.

Tubocurarine causes noncytotoxic degranulation of mast cells, which induces release of histamine.

2. E.

Although competitive nicotinic receptor blockers such as doxacurium may affect other targets, at therapeutic concentrations their predominant action is to cause a nondepolarizing block of the acetylcholine receptor.

3. C.

Succinylcholine has the fastest onset and the shortest duration of action of any of the agents listed.

4. A.

Awareness of pain during surgery occurs rarely but is devastating because the patient is unable to move or speak due to skeletal muscle paralysis, but the patient is not anesthetized and can be subjected to extreme pain.

5. B.

Control of ventilation during surgery, insertion of endotracheal tubes, and prevention of muscle movements during surgery are major reasons why these agents are used. The use of these agents in myasthenia gravis patients is dangerous, because they are extremely sensitive to neuromuscular block. These agents have no effect on pain and are not useful in spastic disorders. They would be useful in producing low-pressure airways in intensive care.

Chapter 13

1. B.

Blockade of activity-dependent Na+ channels is the mechanism of action of local anesthetics.

2. E.

Local anesthetics are weak bases (pKa -8 to 9), thus existing primarily in the protonated, cationic form in solutions at physiological pH (-7.4). Whereas the protonated species blocks Na+ channels with higher affinity, the neutral species passes more readily across the membrane to reach its site of action.

3. D.

Type A subtype δ nerve fibers are the ones affected at the lowest dose and with the earliest onset.

4. B.

Involves metabolic breakdown primarily by plasma cholinesterase with ester type agents.

Chapter 14

1. D.

First-generation antihistamines penetrate the CNS quite well and mainly differ from the second-generation agents by producing more sedation. None has partial agonist activity or much affinity for H3receptors.

2. E.

L-Histidine decarboxylase is the enzyme that mediates the conversion of dietary histidine to histamine

3. B.

H2 receptor agonists exert their major effects on gastric secretion. Histamine-induced bronchoconstriction is mediated by H1 receptors. The inhibition of norepinephrine release can be mediated by H3receptors. Neither a stimulation of basophil degranulation nor a decreased inotropy is an action of histamine.

4. A.

Release of histamine from mast cells is often induced by antibodies.

Chapter 15

1. A.

All eicosanoids are unsaturated fatty acids.

2. C.

Prostaglandins are products of cyclooxygenase activity.

3. B.

PGI2 possesses vasodilator activity.

4. A.

Leukotrienes are products of lipoxygenases.

5. C.

A leukotriene receptor antagonist such as montelukast or zafirlukast.

Chapter 16

1. B.

The cromones are recommended for prevention of exercise-induced bronchospasm and have an onset of action of 10 to 15 minutes. None of the other agents listed is indicated as preventive therapy for exercise-induced bronchospasm.

2. A.

The bronchoconstrictive component of COPD has been shown to respond better to antimuscarinic agents than β2 adrenergic selective agonists.

3. B.

The only drugs shown to reduce recruitment of eosinophils are the glucocorticoids. They decrease bone marrow production of eosinophils and enhance their removal from the circulation.

4. C.

Of the β2 selective agonists, salmeterol has the longest duration of action, approximately 12 hours.

Chapter 17

1. C.

The longer terbutaline (or other β adrenergic agonists) is used, the less effective it becomes, an effect called tachyphylaxis. Even selective β2 adrenergic agonists can still stimulate all β adrenergic receptors to some degree. As a result, cardiovascular complications may occur. Hyperglycemia is also a side effect. β adrenergic agonists do not act on the COX enzymes. PGs are commonly used to treat primary dysmenorrhea.

2. B.

Indomethacin is an NSAID, which inhibits PG synthesis by blocking COX.

3. D.

A combination of the two treatments is preferred, with an appropriate interval to prevent adverse effects.

4. C.

OT is a peptide with a very short half-life. It does not readily cross the placenta, does not cause cervical ripening, has an increased sensitivity in late pregnancy, and cannot be administered orally.

5. D.

Like OT, ergot alkaloids increase uterine contractions. In fact, they cause severe, sustained contractions that are sometimes required to stop severe uterine bleeding. They cannot be administered orally. PG effects are more similar to OT.

6. C.

Magnesium sulfate promotes smooth-muscle relaxation by blocking elevation in intracellular Ca++ and is commonly used between 20 and 36 weeks of gestation. As such, phosphorylation of MLCK is inhibited. It is a fast-acting choice.

Chapter 18

1. C.

Cimetidine is one of currently marketed H2 antagonists that inhibit histamine-stimulated secretion of acid. Because of the important role of histamine in the regulation of acid secretion, H2 antagonists are highly effective inhibitors of gastric secretion.

2. D.

The prokinetic and antiemetic effects of metoclopramide result primarily from antagonism at D2 receptors on neurons in the enteric nervous system and in the brainstem.

3. A.

Although not extensively metabolized itself, cimetidine binds to certain isoforms of cytochrome P450 and can decrease activity of the enzyme in the metabolism of several other drugs.

4. E.

Metoclopramide, because it is a D2 receptor antagonist and crosses the blood-brain barrier, can act in brain nigrostriatal pathways to induce extrapyramidal motor dysfunction characteristic of Parkinson’s disease.

5. C.

Aluminum ions avidly bind phosphate, and chronic use of aluminum salts as antacids can diminish absorption of phosphate from the small intestine, thus depleting phosphate from the body. Bone resorption can result.

6. A.

Muscarinic receptor antagonists are notorious for producing these and other side effects because acetylcholine, acting at muscarinic receptors, is the principal neurotransmitter at many different sites. It is hoped that improved definitions of multiple subtypes of muscarinic receptors will lead to more selective and thus more specific drugs.

Chapter 19

1. E.

Activation of the sympathetic nervous system causes all of the effects listed.

2. B.

Skin is the tissue that is least influenced by the baroreceptor reflex, because it is relatively unimportant in such critical physiological processes as maintaining an upright posture.

3. A.

The nucleus of the tractus solitarius located in the dorsomedial brainstem represents the first central synapse for afferents.

Chapter 20

1. B.

The directly acting vasodilator drugs produce rapid and marked reduction in arterial pressure that engages the baroreceptor reflex to produce sympathetically mediated tachycardia and renin release. This would not occur with the other drug types listed because they all reduce sympathetic nervous system function and/or activation of β adrenergic receptors.

2. B.

Only clonidine acts on the central nervous system to produce sedation.

3. A.

α1 Receptor blockers are not the preferred drugs for patients older than 55 years of age.

4. E.

Many clinical trials have demonstrated the effectiveness of thiazide diuretics in reducing hypertension and associated cardiovascular sequelae, and based on these results, thiazide diuretics are recommended as initial therapy for treatment of uncomplicated hypertension.

5. B.

Enalapril is an ACE inhibitor that prevents the formation of angiotensin II from angiotensin I. Because this individual appears to respond well to a compound that prevents the action of angiotensin, substitution with losartan, which is an angiotensin receptor blocker and does not have a great propensity to induce a hacking cough, should work well.

Chapter 21

1. A.

Loop diuretics such as furosemide or bumetanide inhibit the Na+/K+/2Cl cotransporter present in the apical cell membrane of the ascending limb of the loop of Henle.

2. D.

Transepithelial Na+ transport involves two steps. (1) The basolateral Na+/K+ ATPase actively (ATP dependent) extrudes Na+ from the cell interior to the interstitial fluid. (2) The activity of this pump provides the electrochemical gradient for apical Na+ entry across the apical membrane.

3. E.

Spironolactone blocks aldosterone receptors. Aldosterone increases Na+ conductance in the apical membrane of principal cells of the late distal tubule and collecting tubule and increases Na+/K+-ATPase activity. The net result is an increase in the electrochemical gradient for K+ secretion. By blocking aldosterone receptors, spironolactone abolishes the effect of aldosterone on K+ secretion.

4. A.

Hypokalemia, hyperglycemia, and hyperlipidemia are known consequences of thiazide use.

Chapter 22

1. C.

Amiodarone is a Class III antiarrhythmic.

2. C.

The plateau of action potential of a nonpacemaker cardiac cell is characterized by a low-conductance state in which Ca++ influx is balanced by K+ efflux.

3. E.

Propranolol has negative inotropic effects and slows conduction, which can be detrimental to patients with congestive heart failure or AV conduction disturbances. Because propranolol lacks cardioselectivity, it also blocks β2 adrenergic receptors on bronchi and bronchioles, thereby increasing airway resistance.

4. D.

Ibutilide is the only agent listed likely to precipitate this effect.

Chapter 23

1. B.

Digitalis glycosides bind directly to the Na+/K+-ATPase and inhibit its electrogenic function.

2. D.

Both nitrovasodilators and loop diuretics will decrease preload.

3. B.

An ACE inhibitor, such as captopril, is most likely to reduce afterload.

4. F.

Digoxin and milrinone act through mechanisms that do not involve β adrenergic receptor activation, whereas dobutamine and isoproterenol stimulate these receptors. Thus the effects of the latter two will be blocked by a β receptor blocker.

5. C.

Milrinone is a type III phosphodiesterase inhibitor; the other drugs act by different mechanisms.

6. B.

Eplerenone is an aldosterone antagonist.

Chapter 24

1. A.

Of the drugs listed, only hydralazine is selective for arterioles. All the other agents affect either venuoles or both arterioles and venuoles.

2. E.

Activator Ca++ for contraction of smooth muscle can either enter through voltage-operated channels or be released from intracellular sites by IP3. Ca++ combines with calmodulin to activate myosin light-chain kinase and promote cross-bridge formation, leading to vascular contraction.

3. D

Minoxidil relaxes arterioles through activation of K+ channels, leading to a hyperpolarization.

4. B

Sexual stimulation releases NO via the parasympathetic nerves innervating the penile corpus cavernosum. The NO increases cGMP, which causes smooth-muscle relaxation, and this effect is prolonged by the PDE5 inhibitors.

Chapter 25

1. B.

The major vehicle for transporting cholesterol from peripheral tissues to the liver is HDL.

2. C.

Fibric acids decrease both fasting and postprandial triglycerides by reducing VLDL, VLDL remnants, and IDL. They also increase LDL particle size and HDL particle number and decrease the cholesterol content of LDL-C.

3. D.

The statins decrease circulating cholesterol content by increasing LDL receptor number and activity, thereby increasing the clearance of LDL particles.

4. E.

Ezetimibe is a cholesterol absorption inhibitor that decreases cholesterol absorption by the small intestine, thereby decreasing the delivery of cholesterol to the liver.

Chapter 26

1. C.

In contrast to warfarin, heparin must be given by injection, has a short half-life, and may cause platelet aggregation and thrombocytopenia. It acts by binding to antithrombin, thereby increasing the activity of this serine protease inhibitor.

2. D.

Warfarin, which can be taken orally, acts by inhibiting vitamin K regeneration, thus preventing the posttranslational modification of clotting factors. Warfarin metabolism is accelerated by barbiturates and other drugs that stimulate the activity of cytochrome P450.

3. B.

Aspirin and other drugs that inhibit platelet function increase the risk of bleeding in patients receiving other types of anticoagulants.

4. D.

Aspirin and clopidogrel increase the antithrombotic effect by inhibiting platelet aggregation; chloral hydrate does so by displacing warfarin from binding sites on plasma albumin, and heparin does so by increasing antithrombin activity. Cholestyramine decreases warfarin absorption.

5. A.

Aspirin inhibits platelet cyclooxygenase, thereby preventing the formation of TXA2, a powerful platelet- aggregating agent. Inhibition of platelet aggregation lengthens the bleeding time without affecting the coagulation mechanism.

Chapter 27

1. A.

ACh is the only neurotransmitter whose action is terminated by hydrolysis via the action of acetylcholinesterase; the actions of all the other amine neurotransmitters listed are terminated by reuptake.

2. A.

All of the biogenic amine neurotransmitters are synthesized in nerve terminals and transported into vesicles by an active process; their concentration in vesicles is 10 to 100 times that in the cytosol.

3. C.

The long-term administration of agonists leads to a down regulation of receptors in the postsynaptic cell membrane.

4. C.

Dopaminergic neurons originate in the substantia nigra and hypothalamus; the other types of neurons listed originate in other brain regions.

5. B.

A high degree of lipophilicity will facilitate the ability of drugs to cross the blood-brain barrier; the other choices would hinder it.

6. C.

Ethanol, a CNS depressant, produces an initial stage of excitation by reducing the activity of tonically active inhibitory brain systems. It has none of the other effects listed.

Chapter 28

1. B.

Bromocriptine is the only DA agonist listed. Administration of any of the other drugs results in an indirect activation of D2 receptors: l-DOPA enhances DA synthesis and release; amantadine facilitates DA release; selegiline enhances DA action by preventing its metabolism.

2. D.

A cardinal sign of Parkinson’s disease is tremor at rest, often consisting of a “pill-rolling” tremor. This should be distinguished from essential tremor, which occurs with the use of a limb. Tremor at rest is often treated with antimuscarinic agents.

3. B.

Carbidopa is an inhibitor of aromatic L-amino acid decarboxylase and does not cross the BBB; thus carbidopa does not influence l-DOPA metabolism in the brain.

4. A.

Peripheral cholinergic effects are common with the use of these compounds.

Chapter 29

1. C.

Neuroleptic malignant syndrome is a life-threatening complication associated with antipsychotic drug treatment. It involves a near-complete collapse of the autonomic nervous system. Immediate hospitalization is required.

2. E.

The efficacy of typical antipsychotic drugs is essentially the same. The potency of these agents differs and is correlated with their affinity for the D2-receptor. Acute (but not chronic) treatment with antipsychotic drugs increases the firing rate of dopamine neurons. Chronic treatment results in an up regulation or supersensitivity of D2 dopamine receptors.

3. A.

The actions of antipsychotics include production of depolarization blockade and some anticholinergic effects, but these are unrelated to tardive dyskinesia. Tardive dyskinesia is a late-onset movement disorder that is thought to be related to the delayed induction of D2-receptor supersensitivity that occurs with chronic antipsychotic drug treatment.

4. D.

Clozapine, the prototypic atypical antipsychotic, is characterized by its failure to produce parkinsonian symptoms, tardive dyskinesia, or hyperprolactinemia. It does produce the potentially fatal complication of agranulocytosis.

5. E.

The pharmacological profile of newer antipsychotic drugs is that they are relatively weak antagonists of dopamine at D2-receptors. Consequently they have a smaller propensity to produce extrapyramidal symptoms and hyperprolactinemia. For unknown reasons these agents appear to selectively affect limbic dopamine neurons.

Chapter 30

1. B.

Fluoxetine is approximately 15-fold more potent in blocking the uptake of serotonin than norepinephrine and has negligible effects on the other neurotransmitters.

2. E.

Fluoxetine does not cause the side effects listed.

3. B.

Imipramine, diazepam, and buspirone are not used to treat mania, and renal disease is a contraindication for the use of lithium.

4. B.

Mirtazapine is the only drug that enhances noradrenergic and serotonergic neurotransmission in the brain by blocking α2 adrenergic receptors.

Chapter 31

1. C.

Benzodiazepines act indirectly on chloride-inhibitory mechanisms through modulating GABAA-receptor activity.

2. E.

Buspirone is least likely to induce sedation.

3. C.

Buspirone is a partial agonist at brain 5-HT1A-receptors.

4. D.

General CNS depressant drugs have common mechanisms of action to a considerable extent.

Chapter 32

1. E.

Cardiac toxicity, increased caloric intake, and disturbed lipid metabolism caused by alcohol use contribute to cardiovascular disease. Ethanol is metabolized in the liver, and this leads to a myriad of biochemical disturbances via increased NADP and acetaldehyde concentrations. Alcohol is associated with cancer of the larynx and pharynx. Fetal alcohol syndrome (intake of ethanol by the mother during pregnancy) is the leading preventable cause of mental retardation.

2. A.

Obstructed hepatic venous return causes increased venous pressure and leakage of fluid. Increased osmolality of blood would decrease ascites, and just the opposite happens because of decreased serum protein synthesis by the liver.

3. B.

However, recent evidence indicates that the genetic risk for women is greater than first thought. Dopamine is important to the rewarding effects of ethanol, but there is no evidence that increased concentrations are related to the risk for developing alcoholism.

4. D.

The interaction of estrogens may be responsible for the nearly twofold increase in the risk of liver damage in women compared with men.

5. D.

Disulfiram (via a metabolic product) inhibits high Km ALDH enzymes in the liver. The mitochondrial enzyme (low Km enzyme) is inactive in some Asians because of a genetic abnormality. The end result in either case is increased acetaldehyde concentrations in the liver and blood, and a flushing reaction results.

6. E.

Induction of cytochrome P450 2E1 is independent of ethanol oxidation. When it is present with other substrates for the enzyme, it competes with them for the enzyme, thus inhibiting their metabolism. When ethanol is absent, the increased enzyme content and activity lead to increased metabolic activity.

Chapter 33

1. C.

Orlistat is the one agent for the treatment of obesity that has no cardiovascular side effects. Because the patient has a history of hypertension and angina, this would be the preferred treatment.

2. A.

Underweight patients are extremely sensitive to cardiovascular side effects of drugs. Of the agents listed, fluoxetine is a selective serotonin reuptake inhibitor that has minimal risk of these adverse effects.

3. D.

Orlistat acts locally within the intestines to reduce the absorption of dietary fat via inhibition of intestinal lipase, which decreases the production of free fatty acids from triglycerides.

4. C.

Dronabinol, which is used for cachexia, stimulates appetite through agonist actions at the cannabinoid receptor located in both the eating centers in the brain and in the gastrointestinal tract.

Chapter 34

1. E.

The 3-per-second spike and wave activity on the EEG and the clinical presentation are classic for absence seizures. The drug of choice for absence seizures is ethosuximide. Valproic acid also can be used but is not listed as a choice.

2. B.

Phenytoin is one of few drugs that convert from first-order kinetics to zero-order kinetics in the therapeutic dose range. Therefore it is impossible to estimate a serum concentration based on a direct relationship to dose. When phenytoin becomes zero-order, the serum concentration will be higher than predicted from the dose.

3. C.

This patient should be treated with antiepileptic drugs because she is having repeated (daily) seizures. The choice of drug is based on her generalized tonic-clonic seizures. Phenytoin and carbamazepine are effective for tonic-clonic seizures, but phenytoin has side effects of hirsutism and coarsening of facial features. Therefore the best choice for this young girl is carbamazepine.

4. C.

A specific feature of generalized tonic-clonic seizures is repetitive action potentials in the cortex. Therefore a drug that blocks repetitive action potentials would be desirable.

5. D.

Carbamazepine causes autoinduction of its own metabolism over the first several weeks of treatment. As the patient continues to take the same dose, the half-life shortens and the average plasma concentration falls, possibly below the therapeutic level.

Chapter 35

1. B.

None of the other drugs reduces cardiac output significantly at doses usually used, and effects on blood pressure are small compared with those of halothane. Ketamine often increases blood pressure.

2. E.

All volatile anesthetics and morphine-like opioids decrease the sensitivity of chemoreceptors in the respiratory centers of the brainstem to CO2, thus blunting the ventilatory response to increases in CO2 tension in blood and cerebrospinal fluid.

3. C.

As an ED50, MAC is unaffected by the size of the patient (although it takes longer to anesthetize a large patient than it does a smaller one), the patient’s gender, or the length of time over which the anesthetic is administered. Morphine depresses the CNS so that less anesthetic is required (i.e., the MAC is lowered). Because of their high basal metabolism, infants have a higher anesthetic requirement than do older patients.

4. D.

The competitive antagonist flumazenil binds only to the benzodiazepine recognition site on GABAA receptors, and thus, can reverse the effects of the benzodiazepine midazolam. Although the inhalational anesthetics may affect ligand-gated ion channels, they do not bind to the benzodiazepine site on GABAA receptors.

5. E.

All morphine-like opioids, including fentanyl, have similar spectra of pharmacological activity; most differences of clinical significance are due to pharmacokinetic characteristics.

Chapter 36

1. D.

Naloxone is a short-acting antagonist that is selective for opioid receptors. It does not antagonize the effects of nonopioid drugs such as barbiturates. As a “pure” antagonist it has no intrinsic efficacy. It does not activate opioid receptors and produces no effects by itself.

2. E.

All opioid analgesics decrease the sensitivity of chemoreceptors in the brainstem to CO2, which is a stimulant of respiration. After an analgesic dose of any opioid, the ventilatory response to CO2 is blunted and respiration is depressed, albeit not to a clinically significant extent in a patient with otherwise normal pulmonary function.

3. A.

Butorphanol is a low efficacy agonist at the μ-opioid receptor, which mediates the effects of morphine-like opioids, including analgesia, respiratory depression, and physical dependence. It is a higher-efficacy agonist at the κ-opioid receptor, which also mediates analgesia, particularly in the spinal cord. This profile of activity results in analgesic efficacy that is roughly comparable to that of morphine and a ceiling on those side effects that results primarily from activation of the μ- opioid receptor. Naloxone has a lower affinity for the κ-opioid receptor than it does for the μ-opioid receptors and therefore is less potent in reversing effects mediated by the μ-opioid receptor.

4. E.

Surmountable tolerance develops to the analgesic effect of all morphine-like opioids such as methadone and meperidine, and there is cross-tolerance to this effect among all drugs of this group. However, tolerance does not develop to the same extent to every effect of these drugs. For example, little or no tolerance develops to their constipating effect and their effect on pupil size.

5. E.

Aspirin decreases body temperature and should not be used in children because of the possibility of Reye’s syndrome; it does not affect PG receptors in the hypothalamus.

6. C.

All the drugs listed, with the exception of codeine, work by inhibiting COX; one can only achieve a greater effect by using drugs with different mechanisms.

Chapter 37

1. C.

The ability of one drug to completely prevent the onset of withdrawal signs and symptoms during abstinence from another drug is evidence of cross-dependence between them.

2. B.

The withdrawal syndrome from depressant drugs such as alcohol and barbiturates may include severe tremors and convulsions that can be life threatening.

3. B.

There is a very large therapeutic index for benzodiazepines, and they can be administered quite safely over a very wide range of doses. This is not true for barbiturates.

4. C.

Cocaine is a psychomotor stimulant with actions similar to amphetamines. Their patterns of abuse are also very similar.

5. E.

Alcohol, barbiturates, and benzodiazepines belong to the CNS depressant class. They produce a similar withdrawal syndrome after chronic use, which reflects CNS hyperexcitability. They show cross-dependence to each other. Because benzodiazepines have a long duration of action, the withdrawal syndrome after their discontinuation is generally milder than that seen in alcoholics and barbiturate abusers.

Chapter 38

1. E.

When reduction of body fluid and increased salt intake are inadequate to prevent hyponatremia, blockade of the ADH receptor becomes a next best step, although considerably more expensive. The treatment of SIADH with a receptor antagonist is effective regardless of source of ADH.

2. B.

Because the anterior pituitary dysfunction was acquired, that is, related to a history of head trauma rather than inheritance, the most likely option is hypothyroidism, which can retard growth. The other options are less likely to be associated with a recent head trauma. In addition, this situation would be revealed by laboratory values of all hormone regulated by the anterior pituitary.

3. C.

The advantage of receptor antagonists is that their action is independent of the responsiveness of the hypersecreting tissue to somatostatin analogs.

4. B.

Desmopressin is a complex ADH analog that is resistant to hepatic metabolism and excretion. The increased duration of action was accomplished by blockade of the C and N terminus of the peptide and the use of D-amino acids.

Chapter 39

1. A.

Patients who have been chronically treated with adrenocorticosteroids have sustained reduction of ACTH production, which leads to an atrophied adrenal cortex. The regeneration of the atrophied adrenal cortex is the limiting factor in weaning a patient from exogenous sources of cortisol. Of the options, only the ACTH stimulation test will directly test adrenal responsiveness to ACTH.

2. A.

The 11-hydroxyl group on cortisol conveys maximum activation of the steroid receptor complex and its effect on gene activity.

3. C.

Alternate-day therapy is not used to replace physiological levels of cortisol, because this technique uses pharmacological levels of an adrenocorticosteriod and does not replicate the diurnal cycling of cortisol.

4. D.

Of this group of disorders that could be associated with salt imbalance, only the forms of congenital hyperplasia associated with the loss of aldosterone production will clearly benefit from mineralocorticoid replacement. The drug to use would be fludrocortisone. Adrenal hyperplasia is due to failure to make adrenocorticosteroids, which suppress the release of ACTH.

5. B.

Clinical epidemiological studies indicate that the administration of adrenocorticosteroids to treat autoimmune diseases, inflammation, and following organ transplants is the most common cause of the symptoms of Cushing’s syndrome.

6. B.

The goal leading to identification of elevated ACTH is to determine its source to rationally treat the problem. Overproduction of ACTH can originate from a hyperplastic pituitary, pituitary adenoma, pituitary tumor, or ectopic production. Metyrapone inhibition of 11β hydroxylase blocks the synthesis of cortisol, which would stimulate ACTH secretion from the anterior pituitary but not from ectopic sources. Of these options, only the pituitary source of ACTH will increase if blood cortisol levels are decreased. With focal problems of the pituitary, there is adequate cortisol-responsive tissue to exhibit a response to decreased cortisol levels.

Chapter 40

1. D.

The blockade of aromatase reduces the conversion of circulating androgens to estrogens, which has proven useful to reduce the systemic effects. This has proven to be beneficial in treatment of polycystic ovary disease and estrogen-dependent neoplasms.

2. B.

The configuration of a SERM and estrogen receptor complex is the primary determinant of its ability to alter gene activity.

3. C.

A medical history of DVT is considered one of the contraindications for estrogen use because this significantly increases the risk of recurrence.

4. B.

The inclusion of a progestin with estrogen administration is known to significantly reduce the incidence of endometrial cancer.

5. C.

The addition of the ethinyl side chain at the carbon 17 position to synthetic estrogens and progestins blocks hydroxylation at this position, which decreases its elimination and extends its duration of action.

Chapter 41

1. B.

This combination chemotherapeutic management of metastatic prostatic cancer is dependent on the testosterone dependency of the cancer cells. Flutamide is a competitive androgen receptor antagonist, which blocks the androgenic effects of testicular and adrenal androgens and their active metabolites. The depot analogs of GnRH have extended duration of action in the suppression of testicular androgen production.

2. C.

The specific α1 adrenergic receptor antagonists that are used to treat the symptoms of BPH promote relaxation of the bladder and urethra. Finasteride antagonizes 5 α-reductase reducing formation of DHT, which apparently fosters prostate hyperplasia by IGF-1.

3. E.

The predominance of cGMP phosphodiesterase type 5 (PDE5) in the corpus canaverosa increases the sensitivity and selectivity of agents used to treat ED. Blockade of the in situ degradation cGMP by inhibition of PDE5 leads to increased cellular levels of cGMP, which promotes activation of cGMP-dependent protein kinase and reduced intracellular Ca++ levels.

4. E.

Esterification of the 17 hydroxyl group of testosterone with fatty acids creates a fully active form of testosterone that is administered subcutaneously and has duration of action from 2 to 4 weeks.

5. C.

The development of azospermia is a result of suppression of the anterior pituitary production of gonadotropins, leading to lack of formation of sperm by the testes.

Chapter 42

1. B.

Hashimoto’s disease is a common form of hypothyroidism, which is diagnosed by decreased thyroid hormone, increased TSH, and elevated thyroglobulin antibodies.

2. A.

Graves’ disease is a common form of hyperthyroidism, which is diagnosed by increased thyroid hormone, suppressed TSH, and elevated thyroglobulin antibodies.

3. C.

Propranolol is used acutely to treat the cardiovascular symptoms caused by increased sensitivity to circulating catecholamines. This is a secondary measure that requires further management of this patient.

4. B.

Patients who have a history of cardiovascular complications must have their thyroid hormones increased slowly to high normal values to relieve the effects of the increased thyroid hormone levels on their cardiovascular system.

5. B.

Of these options, only the functioning of the thyroid gland dictates the need and extent of treatment for hypothyroidism.

Chapter 43

1. E.

The primary factor leading to reduced incidence of hypoglycemia using this type of combination therapy is the reduced overlap of the biological activity of both types of modified human insulin.

2. D.

Although this patient is likely to need K+ and HCO3, only saline administration is warranted without more information and the laboratory results.

3. B.

This patient has hypoglycemia caused by insulin administration. Depending on the severity of the hypoglycemia, restoration of blood glucose levels should quickly improve this problem.

4. D.

This woman has an HbA1c of <7%, indicating that her blood glucose levels are fairly well controlled. Metformin is indicated because the other agents may decrease HbA1c to near-normal levels, which could precipitate hypoglycemic episodes.

5. A.

Acarbose will minimize postprandial hypoglycemia; the others will not.

Chapter 44

1. D.

Raloxifene is a SERM that is used to reduce bone loss resulting from postmenopausal osteoporosis.

2. D.

The human parathyroid hormone analog, teriparatide, is capable of both actions at different concentrations.

3. E.

The second-generation bisphosphonates are released from their association with bone during resorption, which allows them to exert cytotoxic effects on osteoblasts, and they do not have inhibitory effects on the attraction of osteoblasts and the recalcification of bone.

4. B.

Increased intestinal Ca++ absorption contributes to the hypercalcemia associated with primary hyperparathyroidism.

Chapter 45

1. A.

All methicillin-resistant S. aureus or MRSA resists β-lactams because of the acquisition of a novel protein called PBP2a.

2. A.

The prophylactic antibiotic should be administered just before the procedure, because limiting exposure minimizes the selection of resistant bacteria.

3. D.

Sulfonamides are known to induce hemolytic anemia in patients deficient in glucose-6-phosphate dehydrogenase.

4. A.

Beta-lactams (cell wall synthesis inhibitors) and aminoglycosides (protein synthesis inhibitors) are synergistic when administered in combination.

5. D.

An enhanced efflux of drug is the main mechanism of resistance for the tetracyclines.

Chapter 46

1. E.

Patients who have experienced an allergic reaction in the form of a rash to a penicillin are at low risk of a serious reaction to other beta-lactam antibiotics. However, the patient is asthmatic with a documented allergic reaction. Therefore all beta-lactams should be avoided if possible. Vancomycin is the drug of choice for this patient.

2. C.

Imipenem binds to brain tissue better than the other beta-lactams and is therefore more likely to induce seizures.

3. C.

Increased numbers of cell wall binding sites is the most common cause of bacterial resistance to vancomycin.

4. C.

After the concentration of meropenem decreases below MIC, the bacteria that have not been killed do not resume growth for another 2 to 4 hours.

5. A.

Lysis of gram-positive bacteria treated with β-lactams is ultimately dependent on autolysins, which are normally involved in new cell wall synthesis when cells divide. There are bacteria that lack these autolysins, which are termed “tolerant” because the β-lactams inhibit their growth and division but do not kill them.

Chapter 47

1. B.

Chloramphenicol can be used to treat bacterial meningitis. It has pronounced hematological adverse effects, including bone marrow depression and aplastic anemia.

2. C.

Linezolid has been known to interact with serotonergic agents, resulting in an increased risk of serotonin syndrome when administered with serotonergic agents. It is also a weak and reversible inhibitor of monoamine oxidase.

3. D.

Bacterial protein synthesis is inhibited by sequential binding of each component to the 50S ribosomal subunit. This forms a stable drug-ribosome complex that interferes with peptide chain elongation and peptidyl transferase.

4. D.

The aminoglycosides exhibit a postantibiotic effect, in that the drug is still detectable after completion of therapy, and still exerts a therapeutic effect.

5. A.

Azithromycin is the only macrolide that does not inhibit the cytochrome P450 enzymes.

Chapter 48

1. E.

The symptoms described are characteristic of Stevens-Johnson syndrome, which is a potential adverse effect of the sulfonamides.

2. D.

First-time urinary tract infections are treated empirically with the trimethoprim/sulfamethoxazole combination. Cultures should be obtained before initiating therapy in the event the organism is resistant to the TMP/SMX regimen.

3. D.

The sulfonamide sulfamethoxazole exerts its bacteriostatic action by inhibiting folate synthesis by microorganisms. Unlike mammalian cells, microorganisms must synthesize their own folic acid to maintain growth.

4. D.

The synthesis of dihydropteroate synthetase can be modified by a chromosomal mutation or by a plasmid leading to resistance to trimethoprim.

Chapter 49

1. D.

Rifampin is a potent inducer of the cytochrome P450 enzymes and will result in decreased plasma levels of many drugs, including the oral contraceptives.

2. E.

All newly diagnosed active TB cases are initially treated with four first-line agents: isoniazid, rifampin, pyrazinamide, and ethambutol. Multidrug therapy is required to prevent development of resistance.

3. B.

Patients who have been exposed to tuberculosis with a positive PPD skin test and negative chest x-ray are classified as having latent tuberculosis infection (LTBI). They may be treated with isoniazid alone for 9 to 12 months, which has been shown to be effective in preventing progression of the disease.

4. C.

Dapsone may cause hemolytic anemia. Patients who are deficient in glucose-6-phosphate dehydrogenase are especially susceptible. This patient is of Mediterranean descent, where G-6-PD is more prevalent.

5. D.

Isoniazid has multiple mechanisms of action, including inhibition of mycolic acid synthesis.

Chapter 50

1. B.

Colloidal amphotericin B is nephrotoxic.

2. B.

Fluconazole is the drug of choice for prophylactic therapy against Cryptococcus neoformans and is often used for maintenance therapy in immunocompromised patients. It is not appropriate for treatment of an acute infection, but because of its lower toxicity, it is preferred over amphotericin as a prophylactic drug.

3. E.

Terbinafine is highly lipophilic and keratophilic, resulting in high concentrations in the stratum corneum, sebum, hair, and nails. The drug may be detected in nails for up to 90 days after treatment is discontinued.

4. E.

Voriconazole results in blurred vision and color disturbances. These are transient and typically resolve within 30 minutes.

5. B.

Capsofungin is the only echinocandin currently approved for use in the United States. This class of drugs inhibits glucan synthesis.

Chapter 51

1. C.

Famciclovir is indicated for the treatment of herpes zoster virus (shingles).

2. B.

Although NRTIs and NNRTIs bind at different sites on the HIV reverse transcriptase enzyme, cross-resistance can occur. The second regimen contained abacavir, an NNRTI.

3. E.

The herpes simplex virus encodes a thymidine kinase that monophosphorylates acyclovir significantly better than does the host cell enzyme. Because acyclovir monophosphate is trapped in cells, it becomes highly concentrated there.

4. C.

Oseltamavir is indicated for either influenza A or influenza B. Amantadine and rimantadine are effective only against influenza A.

5. B.

All protease inhibitors may inhibit the cytochrome P450 enzymes, but ritonavir is the most potent inhibitor of the liver metabolizing enzymes.

Chapter 52

1. C.

The child has an infection of hookworms, commonly acquired through bare feet and also the leading cause of iron-deficiency anemia. Mebendazole is indicated.

2. E.

The couple have contracted tapeworms from eating undercooked pork. Praziquantel is effective for treatment.

3. D.

Reinfection from an untreated partner is the most common reason for recurrence of trichomoniasis.

4. B.

The hypnozoite stage of P. ovale and P. vivax can form cysts that remain dormant in the liver for extended periods of time, and then present as a recurrence of disease. Only primaquine is effective in eradicating this stage.

5. D.

Primaquine is a well-known cause of hemolysis in persons who have G6PD deficiency. Chloroquine, mefloquine, pyrimethamine, and doxycycline do not cause G6PD deficiency-related hemolysis, although pyrimethamine can cause anemia by inhibiting human dihydrofolate reductase.

Chapter 53

1. C.

Hodgkin’s disease is curable with chemotherapy even in situations in which the liver and lung are involved by metastatic disease. Breast, colon, lung, and stomach cancer are curable only with surgery.

2. E.

Generally, when patients fail to respond to first-line chemotherapy, the chances of a meaningful response to second-line drugs are small, particularly for solid tumors, for all of the reasons indicated. The higher the performance status of a patient is, the greater the likelihood is of an objective response to chemotherapy.

3. C.

Of the drugs listed, cisplatin has the greatest tendency to induce nausea and vomiting.

4. A.

Adjuvant therapy is administered after surgery/radiation with the goal of killing small metastases that may be clinically undetectable.

Chapter 54

1. B.

Tumor cells are killed by chemotherapeutic agents according to a first-order process. This means that the same fraction of cells is killed with each drug dose. Therefore to reduce a tumor burden from 1028 cells to 104, with a regimen that has a 4 log kill, 6 courses of therapy are required.

2. D.

Many chemotherapeutic agents are transported out of tumor cells via a p-glycoprotein transporter. If the transporter is overexpressed, it will affect the transport of multiple drugs, resulting in multidrug resistance.

3. D.

The ABVD regimen for Hodgkin’s disease (doxorubicin, bleomycin, vinblastine, and dacarbazine) contains only one alkylating agent (dacarbazine) as compared with two in the MOPP routine (mechlorethamine, vincristine, procarbazine, and prednisone). Furthermore ABVD consists of two synergistic combinations (doxorubicin and darcabazine; bleomycin and vinblastine), minimizing need doses.

4. D.

Mercaptoethane sulfonate-Na+ (MESNA) binds to the toxic metabolite acrolein, rendering it inert.

Chapter 55

1. A.

Anastrazole is an aromatase inhibitor that inhibits conversion of androstenedione to estrogen.

2. A.

Through inhibition of vascular endothelial growth factor, bevacizumab can severely impair wound healing and lead to potentially fatal outcomes.

3. E.

Sunitinib inhibits tyrosine kinase activity associated with both vascular endothelial growth factor and platelet-derived growth factor. It has been approved as an adjuvant agent in the treatment of advanced renal cell carcinoma.

4. A.

Flutamide binds to intracellular androgen receptors and blocks the binding of testosterone. Testosterone levels will increase in the patient, but the effects are blocked by the presence of the flutamide.


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