Fundamentals

1. Distinguish between a competitive inhibitor and allosteric inhibitor

l Competitive antagonist - pharmacologic antagonist that can be overcome by increasing

concentration of agonist. (HYT). Drugs that bind to, or very close to, the agonist receptor site in
a reversible way without activating the effector system for that receptor. (p.16)

antagonists bind to the agonist site and prevent access of the agonist. High concentrations of
agonist displace or prevent the binding of a pharmacologic antagonist but not an allosteric
antagonist. (stillkeeper, p21)

l Allosteric inhibitor/antagonist - drug that binds to receptor molecule without interfering with
normal agonist binding but alters the response to normal agonist. (HYT)

They do not bind to the agonist receptor site; they bind to some other region of the receptor
molecule that results in inhibition of the response to agonists. They do not prevent binding of the
agonist. (Stillkeeper p21)

2. List and discuss the common routes of drug administration and excretion

Common routes of drug administration (p.5)

l Oral (swallowed) - Offers maximal convenience; absorption is often slower. Subject to the first-
pass effect, in which a significant amount of the agent is metabolized in the gut wall, portal
circulation, and liver before it reaches the systemic circulation.

l Buccal and sublingual (not swallowed) - Direct absorption into the systemic venous circulation,
bypassing the hepatic portal circuit and first-pass metabolism.

l Intravenous- Instantaneous and complete absorption (by definition, bioavailability is 100%).

Potentially more dangerous.

l Intramuscular- Often faster and more complete (higher bioavailability) than with oral
administration. Large volumes may be given if the drug is not too irritating. First-pass
metabolism is avoided.

l Subcutaneous- Slower absorption than the intramuscular route. First-pass metabolism is avoided.

l Rectal (suppository)- The rectal route offers partial avoidance of the first-pass effect. Larger
amounts of drug and drugs with unpleasant tastes are better administered rectally than by the
buccal or sublingual routes.

l Inhalation Route offers delivery closest to respiratory tissues (eg, for asthma). Usually very rapid
absorption (eg, for anesthetic gases).

l Topical - The topical route includes application to the skin or to the mucous membrane of the eye,
ear, nose, throat, airway, or vagina for local effect.

l Transdermal - The transdermal route involves application to the skin for systemic effect.
Absorption usually occurs very slowly (because of the thickness of the skin), but the first-pass
effect is avoided.
Drug Elimination (p.7)

l First order elimination - The term first-order elimination implies that the rate of elimination is
proportional to the concentration (ie, the higher the concentration, the greater the amount of drug
eliminated per unit time). Drugs with first-order elimination have a characteristic half-life of
elimination that is constant regardless of the amount of drug in the body. The concentration of
such a drug in the blood will decrease by 50% for every half-life. Most drugs in clinical use
demonstrate first-order kinetics

l Zero-Order Elimination - The term zero-order elimination implies that the rate of elimination is
constant regardless of concentration. As a result, the concentrations of these drugs in plasma
decrease in a linear fashion over time.

A 60-year-old patient with severe cancer pain is given 10 mg of morphine by mouth. The plasma
concentration is found to be only 30% of that found after intravenous administration of the same dose.
Which of the following terms describes the process by which the amount of active drug in the body is
reduced after administration but before entering the systemic circulation?
(A) Excretion
(B) First-order elimination
(C) First-pass effect
(D) Metabolism
(E) Pharmacokinetics

Rationale: First-pass effectis the term given to elimination of a drug before it enters the systemic
circulation (ie, on its first pass through the portal circulation and liver). The first-pass effect is usually,
but not always, due to metabolism in the gut, the portal blood, or the liver. The answer is C.

3. Draw graphs of the blood level versus time for drugs subject to zero-order elimination and
for drugs subject to first order elimination. Label the axes appropriately
 5. Ampicillin is eliminated by first-order kinetics. Which of the following statements best describes
the process by which the plasma concentration of this drug declines?
(A) There is only 1 metabolic path for drug elimination
(B) The half-life is the same regardless of the plasma concentration
(C) The drug is largely metabolized in the liver after oral administration and has low bioavailability
(D) The rate of elimination is proportional to the rate of administration at all times
(E) The drug is distributed to only 1 compartment outside the vascular system

Rationale: First-ordermeans that the elimination rate is proportional to the concentration perfusing
the organ of elimination. The half-life is a constant. The rate of elimination is proportional to the rate
of administration only at steady state. The order of elimination is independent of the number of
compartments into which a drug distributes.

8. The pharmacokinetic process that distinguishes the elimination of ethanol and high doses of
phenytoin and aspirin from the elimination of most other drugs is called
(A) Distribution
(B) Excretion
(C) First-pass effect
(D) First-order elimination
(E) Zero-order elimination

Rationale: The excretion of most drugs follows first-order kinetics. However, ethanol and, in higher
doses, aspirin and phenytoin follow zero-order kinetics; that is, their elimination rates are constant
regardless of blood concentration

4. Predict the effect of a partial agonist in a patient in the presence and in the absence of full
agonist.

Partial agonist - a drug that binds to its receptor but produces a smaller effect at full dosage than a full
agonist. In presence of full agonist it acts as an inhibitor. (HYT, p.16)

4. A study was carried out in isolated, perfused animal hearts. In the absence of other drugs, pindolol,
a -adrenoceptor ligand, caused an increase in heart rate. In the presence of highly effective
stimulants, however, pindolol caused a dose-dependent, reversible decrease in heart rate. Which of the
following expressions best describes pindolol?
(A) A chemical antagonist
(B) An irreversible antagonist
(C) A partial agonist
(D) A physiologic antagonist
(E) A spare receptor agonist

Rationale: Choices involving chemical or physiologic antagonism are incorrect because pindolol is
said to act at receptors and to block stimulants. The drug effect is reversible, so choice B is
incorrect. Spare receptor agonistis a nonsense distracter.

5. Give examples of competitive and irreversible pharmacologic antagonists and of physiologic

and chemical antagonists.

Competitive and irreversible antagonist - drugs that bind to, or very close to, the agonist receptor site
in a reversible way without activating the effector system for that receptor.
Physiologic antagonist - binds to a different receptor molecule, producing an effect opposite to that
produced by the drug it antagonizes. Familiar examples of physiologic antagonists are the antagonism
of the bronchoconstrictor action of histamine by epinephrine s bronchodilator action and glucagon s
antagonism of the cardiac effects of propranolol.

Chemical antagonist - interacts directly with the drug being antagonized to remove it or to prevent it
from binding to its target. A chemical antagonist does not depend on interaction with the agonists
receptor (although such interaction may occur). Common examples of chemical antagonists are
dimercaprol, a chelator of lead and some other toxic metals, and pralidoxime, which combines avidly
with the phosphorus in organophosphate cholinesterase inhibitors.

7. Sugammadex is a new drug that reverses the action of rocuronium and certain other skeletal
muscle-relaxing agents. It appears to interact directly with the rocuronium molecule and not at all with
the rocuronium receptor. Which of the following terms best describes sugammadex?

(A) Chemical antagonist

(B) Noncompetitive antagonist
(C) Partial agonist
(D) Pharmacologic antagonist
(E) Physiologic antagonist

Rationale: Sugammadex interacts directly with rocuronium and not with the rocuronium receptor;
therefore, it is a chemical antagonist.

6. Compare the efficacy and the potency of 2 drugs on the basis of their graded dose-response curves.

Rationale: No information is presented regarding the safety of these drugs. Similarly, no information
on efficacy (maximal effect) is presented; this requires graded dose-response curves. Although both
drugs are said to be producing a therapeutic effect, no information on their receptor mechanisms is
given. Since no data on toxicity are available, the therapeutic index cannot be determined. The
answer is D because the ED50 of drug Y (20 mg/d) is less than that of drug X (50 mg/d).

7. Estimate the half-life of a drug based on its clearance and volume of distribution of from a
graph of its plasma concentration over time

10. Which of the curves in the graph describes the percentage of binding of the partial agonist whose
effect is shown by Curve 4 if the system has many spare receptors?
(A) Curve 1
(B) Curve 2
(C) Curve 3
(D) Curve 4
(E) Curve 5

Rationale: Partial agonists, like full agonists, bind 100% of their receptors when present in a high
enough concentration. Therefore, the binding curve (but not the effect curve) will go to 100%. If the
effect curve is Curve 4 and many spare receptors are present, the binding Curve must be displaced to
the right of Curve 4 (Kd > EC50). Therefore, Curve 3 fits the description better than Curve 2.
The answer is C.
8. Estimate clearance and volume of distribution from a table or graph of plasma concentration
of a drug over time following a single known dose

Rationale: Drug A produces 50% of its maximal effect at a lower dose than either B or C and thus is
the most potent; drug C is the least potent. However, drug A, a partial agonist, is less efficacious than
drugs B and C. The answer is D.

9. Calculate the dosage adjustment required for a patient with impaired renal fxn.

10. Gentamicin, an aminoglycoside antibiotic, is sometimes given in intermittent intravenous

bolus doses of 100 mg 3 times a day to achieve target peak plasma concentrations of about 5 mg/L.
Gentamicin s clearance (normally 5.4 L/h/70 kg) is almost entirely by glomerular filtration. Your
patient, however, is found to have a creatinine clearance one third of normal. What should your
modified dosage regimen for this patient be?

(A) 20 mg 3 times a day

(B) 33 mg 3 times a day
(C) 72 mg 3 times a day
(D) 100 mg 2 times a day
(E) 150 mg 2 times a day
Rationale: If the drug is cleared almost entirely by the kidney and creatinine clearance is reduced to
one third of normal, the total daily dose should also be reduced to one third. The answer is B.

10. List 3 drugs that inhibit the metabolism of other drugs

3. Which of the following factors is likely to increase the duration of action of a drug that is
metabolized by CYP3A4 in the liver?

(A) Chronic administration of phenobarbital before and during therapy with the drug in question
(B) Chronic therapy with cimetidine
(C) Displacement from tissue-binding sites by another drug
(D) Increased cardiac output (E) Chronic administration of rifampin

Rationale: Phenobarbital and rifampin can induce drug-metabolizing enzymes and thereby may
reduce the duration of drug action. Displacement of drug from tissue may transiently increase the
intensity of the effect but decreases the volume of distribution. Cimetidine is recognized as an
inhibitor of P450 and may also decrease hepatic blood flow under some circumstances. The answer is
B.

11. List 3 drugs for which there well-defined, genetically determined differences in metabolism

5. Which of the following drugs is genetically associated with slower metabolism in European
Americans and African Americans than in most Asians?
(A) Cimetidine
(B) Hydralazine
(C) Propranolol
(D) Rifampin
(E) Succinylcholine

Rationale: Hydralazine, like procainamide and isoniazid, is metabolized by N-acetylation, an

enzymatic process that is slow in about 20% of Asians and in about 50% of European Americans and
African Americans. The answer is B.

12. List the major phase I and phase II metabolic reactions

Phase I - oxidation (especially cytochrome P450), reduction, deamination, hydrolysis

Phase II - reactions that involve addition (conjugation) of subgroups to -OH, -NH2, -SH functions.
Glucuronidation, acetylation, glutathione conjugation, glycine conjugation, sulfation, methylation.
13. FDA ratings of drug safety in pregnancy

The FDA uses a 5-level descriptive scale to summarize information regarding the safety of drugs in
pregnancy
14. Define carcinogenesis, mutagenesis, and teratogenesis

l Carcinogenesis is the induction of malignant characteristics in cells.

l Mutagenesis is induction of changes in the genetic material of animals of any age and therefore
induction of heritable abnormalities.
l Teratogenesis can be defined as the induction of developmental defects in the somatic tissues of
the fetus (eg, by exposure of the fetus to a chemical, infection, or radiation).

15. Describe the major animal and clinical studies carried out in drug development.

Tests done with animals usually include general screening tests for pharmacologic effects,
hepatic and renal function monitoring, blood and urine tests, gross and histopathologic examination of
tissues, and tests of reproductive effects and carcinogenicity. (p.43)

RESPIRATORY

1. Describe the strategies of drug treatment of asthma and COPD.

Acute bronchospasm must be treated promptly and effectively with bronchodilators ( relieverdrugs).
Beta2 agonists, muscarinic antagonists, and theophylline and its derivatives are available for this
indication. Long-term preventive treatment requires control of the inflammatory process in the
airways ( controllerdrugs). The most important anti-inflammatory drugs in the treatment of chronic
asthma are the corticosteroids. Long-acting 2 agonists can improve the response to corticosteroids.
Anti-IgE antibodies also appear promising for chronic therapy. The leukotriene antagonists have
effects on both bronchoconstriction and inflammation but are used only for prophylaxis. (p.184)

2. List the major classes of drugs used in asthma and COPD

Drugs useful in asthma include bronchodilators (smooth muscle relaxants) and anti-inflammatory
drugs.

l Bronchodilators include sympathomimetics, especially 2-selective agonists, muscarinic

antagonists, methylxanthines, and leukotriene receptor blockers.

l Anti-inflammatory drugs used in asthma include corticosteroids, mast cell stabilizers, and an
antiIgE antibody. Leukotriene antagonists play a dual role.
Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is less
reversible than in asthma and by a progressive course. However, many of the same drugs are used.
3. Describe the mechanisms of action of these drug groups
4. List the major adverse effects of the drugs used in airways disease
CARDIOVASCULAR

1. List the major sites of action of sympathoplegic drugs in clinical use, and give examples of
drugs that act at each site. Note safety in pregnancy.

Sympathoplegic drugs interfere with sympathetic (SANS) control of cardiovascular function. The
result is a reduction of one or more of the following: venous tone, heart rate, contractile force of the
heart, cardiac output, and total peripheral resistance.

l Baroreceptor-Sensitizing Agents - natural products, such as veratrum alkaloids, appear to

increase sensitivity of baroreceptor sensory nerves and reduce SANS outflow while increasing
vagal tone to the heart. These agents are toxic and no clinically available drugs act at this site.

l Central Nervous System- Active Agents Alpha2-selective agonists (eg, clonidine, methyldopa)
cause a decrease in sympathetic outflow by activation of 2 receptors in the CNS.

l Ganglion-Blocking Drugs - Nicotinic blockers that act in the ganglia are very efficacious, but
because their adverse effects are severe, they are now considered obsolete. Hexamethonium and
trimethaphan are extremely powerful blood pressure-lowering drugs.

l Postganglionic Sympathetic Nerve Terminal Blockers - Drugs that deplete the adrenergic nerve
terminal of its norepinephrine stores (eg, reserpine) or that deplete and block release of the stores
(eg, guanethidine, guanadrel) can lower blood pressure.

l Adrenoceptor Blockers - Alpha1-selective agents (eg, prazosin, doxazosin, terazosin) are

moderately effective antihypertensive drugs. Alpha blockers reduce vascular resistance and
venous return.

1. A 32-year-old woman with hypertension wishes to become pregnant. Her physician informs her
that she will have to switch to another antihypertensive drug. Which of the following drugs is
absolutely contraindicated in pregnancy?
(A) Atenolol
(B) Captopril
(C) Methyldopa
(D) Prazosin
(E) Propranolol

Rationale: Methyldopa is often recommended in pregnant patients because it has a good safety record.
Alpha (choice D) and blockers (choices A and E) are not contraindicated. In contrast, ACE
inhibitors (choice B) and ARBs have been shown to be teratogenic. The answer is B.
2. List the major toxicities of the prototype antihypertensive agents.
5. A significant number of patients started on ACE inhibitor therapy for hypertension are intolerant
and must be switched to a different class of drug. What is the most common manifestation of this
intolerance?
(A) Diarrhea
(B) Glaucoma
(C) Incessant cough
(D) Lupus-like syndrome
(E) Vomiting

Rationale: Chronic, intolerable cough is an important adverse effect of captopril and other ACE
inhibitors. It may be relieved by prior administration of aspirin. These drugs are very commonly used
in hypertensive diabetic patients because of their proven benefits in reducing diabetic renal damage.
The ACE inhibitors do not cause glaucoma or gastrointestinal disturbances. The answer is C.

3. Describe the differences between the 2 types of angiotensin antagonist

The two primary groups of angiotensin antagonists are the angiotensin-converting enzyme (ACE)
inhibitors and the angiotensin II receptor blockers (ARBs).

l ACE inhibitors (eg, captopril), which inhibit the enzyme variously known as
angiotensinconverting enzyme, kininase II, and peptidyl dipeptidase, cause a reduction in blood
levels of angiotensin II and aldosterone and an increase in endogenous vasodilators of the kinin
family (bradykinin.

l The second group of angiotensin antagonists, the receptor blockers, is represented by the orally
active agents losartan, valsartan, irbesartan, candesartan, and other ARBs, which competitively
inhibit angiotensin II at its AT1 receptor site.

Which one of the following is characteristic of captopril treatment in patients with essential
hypertension?

(A) Competitively blocks angiotensin II at its receptor

(B) Decreases angiotensin II concentration in the blood
(C) Decreases renin concentration in the blood
(D) Increases sodium and decreases potassium in the blood
(E) Decreases sodium and increases potassium in the urine

Rationale: Converting enzyme inhibitors act on the enzyme, not on the angiotensin receptor. The
plasma renin level may increase as a result of the compensatory response to reduced angiotensin II.
ACE inhibitors increase blood potassium and urine sodium. The answer is B.

4. List the major antihypertensive vasodilator drugs and describe their effects.
Refer to Cardio table.
10. Which of the following is very short-acting and acts by releasing nitric oxide?
(A) Atenolol (B) Captopril (C) Diltiazem (D) Fenoldopam (E) Hydrochlorothiazide
(F) Losartan (G) Minoxidil (H) Nitroprusside (I) Prazosin

Rationale: The two agents in this list that act via a nitric oxide mechanism are hydralazine and
nitroprusside. However, hydralazine has a duration of action of hours, whereas nitroprusside acts for
seconds to minutes and must be given by intravenous infusion. The answer is H.

5. Explain why the combination of a nitrate with a beta blocker or a calcium channel blocker
may be more effective than either alone.

Nitrates release nitric oxide (NO) within smooth muscle cells, probably through the action of the
mitochondrial enzyme aldehyde dehydrogenase-2 (ALD2). NO stimulates guanylyl cyclase and
causes an increase of the second messenger cGMP (cyclic guanosine monophosphate); the latter
results in smooth muscle relaxation by dephosphorylation of myosin light-chain phosphate. Smooth
muscle relaxation by nitrates leads to an important degree of venodilation, which results in reduced
cardiac size and cardiac output through reduced preload

3. One year later, the patient returns complaining that his nitroglycerin works well when he takes it for
an acute attack but that he is now having more frequent attacks and would like something to prevent
them. Useful drugs for the prophylaxis of angina of effort include (A) Amyl nitrite
(B) Diltiazem
(C) Esmolol
(D) Sublingual isosorbide dinitrate
(E) Sublingual nitroglycerin

Rationale: The calcium channel blockers and the blockers are generally effective in reducing the
number of attacks of angina of effort, and most have durations of 48 h. Oral and transdermal nitrates
have similar or longer durations. Amyl nitrite, the sublingual nitrates, and esmolol (an intravenous
blocker) have short durations of action and are of no value in prophylaxis. The answer is B

6. Toxicity of nitrate and nitrites

The most common toxic effects of nitrates are the responses evoked by vasodilation. These include
tachycardia (from the baroreceptor reflex), orthostatic hypotension (a direct extension of the
venodilator effect), and throbbing headache from meningeal artery vasodilation.

Nitrites 0 cause methemoglobinemia at high blood concentrations.

The nitrates do not cause methemoglobinemia. In the past, the nitrates were responsible for several
occupational diseases in munitions factories in which workplace contamination by these volatile
chemicals was severe. The most common of these diseases was Monday disease,that is, the
alternating development of tolerance (during the work week) and loss of tolerance (over the weekend)
for the vasodilating action and its associated tachycardia and resulting in headache (from cranial
vasodilation), tachycardia, and dizziness (from orthostatic hypotension) every Monday.

6. A man is admitted to the emergency department with a brownish cyanotic appearance, marked
shortness of breath, and hypotension. Which of the following is most likely to cause
methemoglobinemia?
(A) Amyl nitrite
(B) Isosorbide dinitrate
(C) Isosorbide mononitrate
(D) Nitroglycerin
(E) Sodium cyanide

Rationale: Read carefully! Nitrites, not nitrates, cause methemoglobinemia in adults.

Methemoglobinemia is deliberately induced in one of the treatments of cyanide poisoning. The
answer is A.

7. Explain why the combination of a nitrate and sildenfil is potentially dangerous.

Nitrates interact with sildenafil and similar drugs promoted for erectile dysfunction. These agents
inhibit a phosphodiesterase isoform (PDE5) that metabolizes cGMP in smooth muscle. The increased
cGMP in erectile smooth muscle relaxes it, allowing for greater inflow of blood and more effective
and prolonged erection. This effect also occurs in vascular smooth muscle. As a result, the
combination of nitrates (through increased production of cGMP) and a PDE5 inhibitor (through
decreased breakdown of cGMP) causes a synergistic relaxation of vascular smooth muscle with
potentially dangerous hypotension and inadequate perfusion of critical organs.

10. Certain drugs can cause severe hypotension when combined with nitrates. Which of the following
interacts with nitroglycerin by inhibiting the metabolism of cGMP?
(A) Atenolol
(B) Hydralazine
(C) Isosorbide mononitrate
(D) Nifedipine
(E) Ranolazine
(F) Sildenafil
(G) Terbutaline

Rationale: Sildenafil inhibits phosphodiesterase 5, an enzyme that inactivates cGMP. The nitrates (via
nitric oxide) increase the synthesis of cGMP. This combination is synergistic. The answer is F.

8. Describe the strategies and list the major drug groups used in the treatment of acute heart
failure and chronic failure

Pharmacologic therapies for heart failure include the removal of retained salt and water with diuretics;
reduction of afterload and salt and water retention by means of angiotensin-converting enzyme (ACE)
inhibitors; reduction of excessive sympathetic stimulation by means of blockers; reduction of
preload or afterload with vasodilators; and in systolic failure, direct augmentation of depressed
cardiac contractility with positive inotropic drugs such as digitalis glycosides.

l Current clinical evidence suggests that acute heart failure should be treated with a loop diuretic;
if very severe, a promptacting positive inotropic agent such as a a agonist or phosphodiesterase
inhibitor, and vasodilators should be used as required to optimize filling pressures and blood
pressure.

l Chronic failure is best treated with diuretics (often a loop agent plus spironolactone) plus an
ACE inhibitor and, if tolerated, a a blocker. Digitalis may be helpful if systolic dysfunction is
prominent. Nesiritide, a recombinant form of brain natriuretic peptide, has vasodilating and
diuretic properties and has been heavily promoted for use in acute failure.

An 82-year-old woman has long-standing heart failure. Which one of the following drugs has been
shown to reduce mortality in chronic heart failure?
(A) Atenolol
(B) Digoxin
(C) Dobutamine
(D) Furosemide
(E) Spironolactone

Rationale: Of the drugs listed, only spironolactone has been shown to reduce mortality in this highly
lethal disease. Digoxin, dobutamine, and furosemide are used in the management of symptoms. The
answer is E.
9. List some positive inotropic drugs other than digitalis that have been used in heart failure
Positive inotropic agent such as a a agonist or phosphodiesterase inhibitor for acute heart failure
Which one of the following drugs is associated with clinically useful or physiologically important
positive inotropic effect?
(A) Captopril
(B) Dobutamine
(C) Enalapril
(D) Losartan
(E) Nesiritide
Rationale: Although they are extremely useful in heart failure, ACE inhibitors (eg, captopril, enalapril)
, and angiotensin receptor blockers (ARBs, eg, losartan) have no positive inotropic effect on the heart.
Nesiritide is a vasodilator with diuretic effects and renal toxicity. The answer is B

10. Describe the nature and mechanism of digitalistoxic effects on the heart

The major signs of digitalis toxicity are arrhythmias, nausea, vomiting, and diarrhea. Rarely,
confusion or hallucinations and visual or endocrine aberrations may occur. Arrhythmias are common
and dangerous. Chronic intoxication is an extension of the therapeutic effect of the drug and is caused
by excessive calcium accumulation in cardiac cells (calcium overload). Severe, acute intoxication
caused by suicidal or accidental extreme overdose results in cardiac depression leading to cardiac
arrest rather than tachycardia or fibrillation.

After your patient has been receiving digoxin for 3 wk, he presents to the emergency department with
an arrhythmia. Which one of the following is most likely to contribute to the arrhythmogenic effect of
digoxin?
(A) Increased parasympathetic discharge
(B) Increased intracellular calcium
(C) Decreased sympathetic discharge
(D) Decreased intracellular ATP
(E) Increased extracellular potassium

Rationale: The effects of digitalis include increased vagal action on the heart (not arrhythmogenic)
and increased intracellular calcium, including calcium overload, the most important cause of toxicity.
Decreased sympathetic discharge and increased extracellular potassium and magnesium reduce
digitalis arrhythmogenesis. The answer is B.

11. Describe the mechanism of selective depression by local anesthetic antiarrhythmic agents

Selective depression - The ability of certain drugs to selectively depress areas of excitable membrane
that are most susceptible, leaving other areas relatively unaffected (HYT)

Mechanism: Useful sodium channel-blocking drugs bind to their receptors much more readily when
the channel is open or inactivated than when it is fully repolarized and resting. Therefore, these
antiarrhythmic drugs block channels in abnormal tissue more effectively than channels in normal
tissue. They are use dependent or state dependent in their action (ie, they selectively depress tissue
that is frequently depolarizing, eg, during a fast tachycardia; or tissue that is relatively depolarized
during rest, eg, by hypoxia).

A 57-year-old man is admitted to the emergency department with an irregular heart rate. The ECG
shows an inferior myocardial infarction and ventricular tachycardia. Lidocaine is ordered. When used
as an antiarrhythmic drug, lidocaine typically
(A) Increases action potential duration
(B) Increases contractility
(C) Increases PR interval
(D) Reduces abnormal automaticity
(E) Reduces resting potential

Rationale: Lidocaine reduces automaticity in the ventricles; the drug does not alter resting potential or
AP duration and does not increase contractility. The answer is D.
12. Drugs for arrhythmias in thyrotoxicosis
Group 2: Propranolol

A 36-year-old woman with a history of poorly controlled thyrotoxicosis has recurrent episodes of
tachycardia with severe shortness of breath. When she is admitted to the emergency department with
one of these episodes, which of the following drugs would be most suitable?
(A) Amiodarone
(B) Disopyramide
(C) Esmolol
(D) Quinidine
(E) Verapamil

Rationale: Beta blockers are the most effective agents in acute thyrotoxic arrhythmias. Esmolol is a
parenteral, rapid-acting blocker. The answer is C.

13. Describe the distinguishing electrophysiologic and ECG effects of the 4 major groups of
antiarrhythmic drugs and adenosine

Which of the following drugs slows conduction through the AV node and has its primary action
directly on L-type calcium channels?
(A) Adenosine
(B) Amiodarone
(C) Diltiazem
(D) Esmolol
(E) Flecainide
(F) Lidocaine
(G) Mexiletine
(H) Procainamide
(I) Quinidine

Rationale: Diltiazem is the calcium channel blocker in this list. (Beta blockers also slow AV
conduction but have much smaller effects on calcium channels.) The answer is C.

GENITOURINARY

1. List the 5 major types of diuretics and relate them to their sites of action
 2. Describe 2 drugs that reduce potassium loss during sodium diuresis.

POTASSIUM-SPARING DIURETICS

l Spironolactone and eplerenone are steroid derivatives and act as pharmacologic antagonists of
aldosterone in the collecting tubules. By combining with and blocking the intracellular
aldosterone receptor, these drugs reduce the expression of genes that code for the epithelial
sodium ion channel (ENaC) and Na+/ K+ ATPase. Spironolactone and eplerenone have slow
onsets and offsets of action (2472 h).

l Amiloride and triamterene act by blocking the epithelial sodium channels in the same portion of
the nephron. (These drugs do not block INa channels in excitable membranes.) Amiloride and
triamterene have durations of action of 1224 h.

Effects All drugs in this class cause an increase in sodium clearance and a decrease in potassium and
hydrogen ion excretion and therefore qualify as potassium-sparing diuretics. They may cause
hyperkalemic metabolic acidosis.

3. Describe a therapy that reduces calcium excretion in patients who have recurrent urinary
stones.

Chronic renal calcium stone formation can sometimes be controlled with thiazides because they
reduce urine calcium concentration.

4. Describe a treatment for severe acute hypercalcemia in a patient with advanced carcinoma.

A less common but important application of loop diuretics is in the treatment of severe
hypercalcemia. This life-threatening condition can often be managed with large doses of furosemide
together with parenteral volume and electrolyte (sodium and potassium chloride) replacement.

5. Describe a method for reducing urine volume in nephrogenic diabetes insipidus.

Salt restriction, water restriction, thiazides, and loop diuretics may be used. These therapies reduce
blood volume, a very strong stimulus to proximal tubular reabsorption. The proximal tubule thus
substitutesin partfor the deficient concentrating function of the collecting tubule in nephrogenic
diabetes insipidus.

6. List the major applications and the toxicities of acetazolamide, thiazides, loop diuretics, and
potassium-sparing diuretics.
Drug Application Toxicity

Acetazolamide Glaucoma, Metabolic acidosis; sedation, paresthesias.

mountain sickness Hyperammonemia in cirrhosis
edema with alkalosis

Thiazides
Hydrochlorothiazide, many Hypertension, Metabolic hypokalemic alkalosis
other thiazides Mild heart failure Early hyponatremia
Hypercalciuria with stones Increased serum glucose, lipids, uric acid
SIADH Efficacy is reduced by NSAIDs
Sulfonamide allergy (rare)
Loop Diuretics

Furosemide, also bumetanide, Heart failure, Metabolic hypokalemic alkalosis

torsemide Pulmonary edema, Ototoxicity
Severe hypertension, Hypovolemia
other forms of edema Efficacy is reduced by NSAIDs
Sulfonamide allergy (rare).

Potassium-sparing diuretics

Spironolactone, eplerenone Excessive K+ loss when using Hyperkalemia Gynecomastia

other diuretics aldosteronism (spironolactone only)

Amiloride Excessive K+ loss when using Hyperkalemia

other diuretics usually in
combination with thiazides

GASTROINTESTINAL

1. Identify the 5 different groups of drugs used in peptic ulcer disease.

2. List 7 different drugs used in the prevention of chemotherapy or radiation induced emesis
and identify the receptors with which they interact.

In addition to metoclopramide and other D2 dopamine receptor antagonists, useful antiemetics

are drugs with H1 histamine blocking activity including diphenhydramine and several
phenothiazines, antimuscarinic drugs (scopolamine), the corticosteroid dexamethasone, and the
cannabinoid receptor agonists dronabinol and nabilone.

Ondansetron, granisetron, dolasetron, and palonosetron are 5-HT3 antagonists particularly

useful in preventing nausea and vomiting after general anesthesia and in patients receiving cancer
chemotherapy.

Aprepitant a newer antiemetic is an antagonist of the neurokinin 1 (NK1) receptor.

3. Describe the mechanism of action, clinical uses, and adverse affects of metoclopramide

4. Identify 2 drugs commonly used as antidiarrheal agents and 4 drugs with different
mechanisms that are used as laxatives

The most effective antidiarrheal drugs are the opioids and derivatives of opioids that have been
selected for maximal antidiarrheal and minimal CNS effect.

Of the latter group, the most important are diphenoxylate and loperamide, meperidine analogs with
very weak analgesic effects. Diphenoxylate is formulated with antimuscarinic alkaloids to reduce the
likelihood of abuse; loperamide is formulated alone.

Kaolin, a naturally occurring hydrated magnesium aluminum silicate, is combined with pectin, an
indigestible carbohydrate derived from apples in a popular nonprescription preparation that absorbs
toxins and fluid, resulting in decreased stool liquidity. They can cause constipation and interfere with
absorption of other drugs.
bacterial
Endocrine

1. Describe the drugs used for treatment of acromegaly and hyperprolactinemia

Growth Hormone Antagonist

Somatostatin analogs (Octreotide and Lanreotide) - inhibits release GH
Pegvisomant - GH receptor antagonist

Bromocriptine - Dopamine D2 receptor agonist effective in inhibiting prolactin

A 27-year-old woman with amenorrhea, infertility, and galactorrhea was treated with a drug that
successfully restored ovulation and menstruation. Before being given the drug, the woman was
carefully questioned about previous mental health problems, which she did not have. She was advised
to take the drug orally. Which of the following is most likely to be the drug that was used to treat this
patient?
(A) Bromocriptine
(B) Desmopressin
(C) Human gonadotropin hormone
(D) Leuprolide
(E) Octreotide

Rationale: Bromocriptine, a dopamine receptor agonist, is used to treat the amenorrhea-galactorrhea

syndrome, which is a consequence of hyperprolactinemia. Because of its central dopaminergic effects,
the drug should not be used in patients with a history of schizophrenia or other forms of psychotic
illness. The answer is A.

A 47-year-old man exhibited signs and symptoms of acromegaly. Radiologic studies indicated the
presence of a large pituitary tumor. Surgical treatment of the tumor was only partially effective in
controlling his disease. At this point, which of the following drugs is most likely to be used as
pharmacologic therapy?
(A) Cosyntropin
(B) Desmopressin
(C) Leuprolide
(D) Octreotide
(E) Somatropin

Rationale: Octreotide, a somatostatin analog, has some efficacy in reducing the excess GH production
that causes acromegaly. The answer is D.

2. Describe the major toxicities for thyroxine and the antithyroid drugs.

l Thyroxine toxicity is that of thyrotoxicosis.

l Antithyroid drugs: Toxic effects include skin rash (common) and severe reactions (rare) such as
vasculitis, agranulocytosis, hypoprothrombinemia, and liver dysfunction. These effects are
usually reversible.
Which of the following is a sign or symptom that would be expected to occur in the event of chronic
overdose with exogenous T4?
(A) Bradycardia
(B) Dry, puffy skin
(C) Large tongue and drooping of the eyelids
(D) Lethargy, sleepiness
(E) Weight loss

Rationale: In hyperthyroidism, the metabolic rate increases, and even though there is increased
appetite, weight loss often occurs. The other choices are symptoms seen in hypothyroidism. The
answer is E.

3. List the principal drugs for the treatment of hyperthyroidism and compare the onset and
duration of their action.

ANTITHYROID DRUGS
l Thioamides: Methimazole and propylthiourcil (PTU)- their onset of activity is usually slow,
often requiring 34 wk for full effect.

l Iodide Salts and Iodine - their onset of action occurs rapidly, within 27 d.

l Beta blockers (Propranolol) - rapid onset of activity.

The decision is made to begin treatment with methimazole. Methimazole reduces serum concentration
of T3 primarily by which of the following mechanisms?
(A) Accelerating the peripheral metabolism of T3
(B) Inhibiting the proteolysis of thyroid-binding globulin
(C) Inhibiting the secretion of TSH
(D) Inhibiting the uptake of iodide by cells in the thyroid
(E) Preventing the addition of iodine to tyrosine residues on thyroglobulin

Rationale: The thioamides (methimazole and propylthiouracil) act in thyroid cells to prevent
conversion of tyrosine residues in thyroglobulin to MIT or DIT. The answer is E.
4. List the indications for the use of corticosteroids in adrenal and nonadrenal
disorders.

Clinical Uses:

l Adrenal disordersGlucocorticoids are essential to preserve life in patients with chronic

adrenal cortical insufficiency (Addison s disease) and are necessary in acute adrenal
insufficiency associated with life-threatening shock, infection, or trauma. Glucocorticoids are
also used in certain types of congenital adrenal hyperplasia, in which synthesis of abnormal
forms of corticosteroids are stimulated by ACTH.

l Nonadrenal disordersMany disorders respond to corticosteroid therapy. Some of these are

inflammatory or immunologic in nature (eg, asthma, organ transplant rejection, collagen
diseases, rheumatic disorders). Other applications include the treatment of hematopoietic
cancers, neurologic disorders, chemotherapy-induced vomiting, hypercalcemia, and
mountain sickness. Betamethasone, a glucocorticoid with a low degree of protein binding, is
given to pregnant women in premature labor to hasten maturation of the fetal lungs.

Glucocorticoids have proved useful in the treatment of which of the following medical conditions?
(A) Chemotherapy-induced vomiting
(B) Essential hypertension
(C) Hyperprolactinemia
(D) Parkinson s disease
(E) Type II diabetes

Rationale:Glucocorticoids are used in combination with other antiemetics to prevent chemotherapy-

induced nausea and vomiting, which are commonly associated with anticancer drugs. The answer is A.

5. Name 3 drugs that interfere with the action or synthesis of corticosteroids, and, for each,
describe its mechanism of action.

Which of the following is a drug that, in high doses, blocks the glucocorticoid receptor? (A)
Aminoglutethimide
(B) Beclomethasone
(C) Ketoconazole
(D) Mifepristone
(E) Spironolactone

Rationale: Mifepristone is a competitive antagonist of glucocorticoid and progesterone receptors.

Ketoconazole and aminoglutethimide also antagonize corticosteroids; however, they act by inhibiting
steroid hormone synthesis. The answer is D.

6. List the benefits and hazards of hormonal contraceptives

Clinical uses and beneficial effects

l Prevent estrogen deficiency.

l To treat acne, hirsutism, dysmenorrhea, and endometriosis.
l Reduced risks of ovarian cysts, ovarian and endometrial cancer, benign breast disease, and pelvic
inflammatory disease as well as a lower incidence of ectopic pregnancy, iron deficiency anemia,
and rheumatoid arthritis.

Toxicity

l Thromboembolism increase in the risk of thromboembolic events (myocardial infarction, stroke,

deep vein thrombosis, pulmonary embolism)
l Breast cancer
l Other toxicities of the hormonal contraceptives include nausea, breast tenderness, headache, skin
pigmentation, and depression.
l Preparations containing older, more androgenic progestins can cause weight gain, acne, and
hirsutism.

A 23-year-old woman desires a combined oral contraceptive for pregnancy protection. Which of the
following patient factors would lead a health professional to recommend an alternative form of
contraception?
(A) Evidence of hirsutism
(B) H istory of gastroesophageal reflux disease and is currently taking omeprazole
(C) History of pelvic inflammatory disease
(D) History of migraine headache that is well controlled by sumatriptan
(E) She plans to use this contraceptive for about 1 yr and will then attempt to become pregnant

Rationale: Estrogen-containing hormonal contraceptives increase the risk of episodes of migraine

headache. The answer is D.

7. Name 2 SERMs and describe their unique properties

A 50-year-old woman with a positive mammogram undergoes lumpectomy and a small carcinoma is
removed. Biochemical analysis of the cancer reveals the presence of estrogen and progesterone
receptors. After this procedure, she will probably receive which of the following drugs?
(A) Danazol
(B) Flutamide
(C) Leuprolide
(D) Mifepristone
(E) Tamoxifen

Rationale: Tamoxifen has proved useful in adjunctive therapy of breast cancer; the drug decreases the
rate of recurrence of cancer. The answer is E.

8. List the prototypes and describe the mechanisms of action, key pharmacokinetic features,
and toxicities of the major classes of agents used to treat type 2 diabetes.
Which of the following is an important effect of insulin?
(A) Increased conversion of amino acids into glucose
(B) Increased gluconeogenesis
(C) Increased glucose transport into cells
(D) Inhibition of lipoprotein lipase
(E) Stimulation of glycogenolysis

Rationale: Insulin lowers serum glucose concentration in part by driving glucose into cells,
particularly into muscle cells. The answer is C.

9. Give 3 examples of rational drug combinations for treatment of type 2 diabetes mellitus.

Because type 2 diabetes involves both insulin resistance and inadequate insulin production, it makes
sense to combine an agent that augments insulin s action (metformin, a thiazolidinedione, or an -
glucosidase inhibitor) with one that augments the insulin supplies (insulin secretagogue or insulin).
Long-acting drugs (sulfonylureas, metformin, thiazolidinediones, exenatide, sitagliptin, some insulin
formulations) help control both fasting and postprandial blood glucose levels, whereas short-acting
drugs (-glucosidase inhibitors, repaglinide, pramlintide, rapid-acting insulins) primarily target
postprandial levels.

Exetanide + Metformin + Sulfonylurea

Sitaglipin + Metformin + Thiazolidinediones

Which of the following drugs is taken during the first part of a meal for the purpose of delaying the
absorption of dietary carbohydrates?
(A) Acarbose
(B) Exenatide
(C) Glipizide
(D) Pioglitazone
(E) Repaglinide
Rationale: To be absorbed, carbohydrates must be converted into monosaccharides by the action of -
glucosidase enzymes in the gastrointestinal tract. Acarbose inhibits -glucosidase and, when present
during digestion, delays the uptake of carbohydrates. The answer is A.

10. Describe the clinical uses of glucagon.

Glucagon is used to treat severe hypoglycemia in diabetics, but its hyperglycemic action requires
intact hepatic glycogen stores. The drug is given intramuscularly or intravenously. In the
management of severe -blocker overdose, glucagon may be the most effective method for
stimulating the depressed heart because it increases cardiac cAMP without requiring access to
receptors.

Which of the following patients is most likely to be treated with intravenous glucagon?

(A) An 18-year-old woman who overdose of cocaine and now has a blood pressure of 190/110 mm
Hg
(B) A 27-year-old woman with severe diarrhea caused by a flare in her inflammatory bowel disease
(C) A 57-year-old woman with type 2 diabetes who has not taken her glyburide for the last 3 d
(D) A 62-year-old man with severe bradycardia and hypotension resulting from ingestion of an
overdose of atenolol
(E) A 74-year-old man with lactic acidosis as a complication of severe infection and shock

Rationale: Glucagon acts through cardiac glucagon receptors to stimulate the rate and force of
contraction of the heart. Because this bypasses cardiac adrenoceptors, glucagon is useful in the
treatment of -blocker-induced cardiac depression. The answer is D.

11. Compare and contrast the clinical uses and effects of the major forms of vitamin D and its
active metabolites

Vitamin D, a fat-soluble vitamin, can be synthesized in the skin from 7-dehydrocholesterol under the
influence of ultraviolet light or absorbed from the diet in the natural form (vitamin D3, cholecalciferol)
or the plant form (vitamin D2, ergocalciferol). Active metabolites are formed in the liver (25-
hydroxyvitamin D or calcifediol) and kidney (1,25dihydroxyvitamin D or calcitriol plus other
metabolites).
Which of the following drugs is most likely to lower this patient
s serum PTH concentration?
(A) Calcitriol
(B) Cholecalciferol
(C) Furosemide
(D) Gallium nitrate
(E) Risedronate

Rationale: In patients with chronic kidney disease that requires dialysis, the impaired production of
active vitamin D metabolites compounded with elevated serum phosphate due to renal impairment
leads to secondary hyperparathyroidism. Administration of the active vitamin D metabolite calcitriol
acts directly on the parathyroid to inhibit PTH production. Cholecalciferol, a form of vitamin D, is not
effective in patients with advanced renal disease who cannot form adequate amounts of active
vitamin D metabolites. The answer is A.

12. Describe the agents used in the treatment of hypercalcemia and the agents used in the
treatment of osteoporosis

Hypercalcemia
Pamidronate, zoledronic acid, etidronate - parenteral treatment of hypercalcemia associated
with Pagets disease and malignancies.
Cinacalcet - treatment for hypercalcemia in parathyroid carcinoma
Biphosphonates (alendronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate,
zoledronic acid) - hypercalcemia in Paget
s disease and malignancies
Plicamycin (mithramycin) - short-term treatment of serious hypercalcemia

Osteoporosis
Teriparatide - recombinant truncated form of PTH, parenteral treatment osteoporosis
Calcitonin
Raloxifene - in postmenopausal women
Denosumab

Which of the following conditions is an indication for the use of raloxifene?

(A) Chronic kidney failure
(B) Hypoparathyroidism
(C) Intestinal osteodystrophy
(D) Postmenopausal osteoporosis
(E) Rickets

Rationale: Raloxifene, a SERM, is approved for use in postmenopausal women with osteoporosis. The
answer is D

NEUROMUSCULOSKELETAL

1. Describe the effects and the major toxicity of acetaminophen

Which of the following is an analgesic and antipyretic drug that lacks an anti-inflammatory action?
(A) Acetaminophen
(B) Celecoxib
(C) Colchicine
(D) Indomethacin
(E) Probenecid

Rationale: Acetaminophen is the only drug that fits this description. Indomethacin is a nonselective
COX inhibitor and celecoxib is a COX-2 inhibitor; both have analgesic, antipyretic, and
antiinflammatory effects. Colchicine is a drug used for gout that also has an anti-inflammatory action.
Probenecid is a uricosuric drug that promotes the excretion of uric acid. The answer is A.

An 18-month-old boy dies from an accidental overdose of acetaminophen. Which of the following is
the most likely cause of this patient
s death?
(A) Arrhythmia
(B) Hemorrhagic stroke
(C) Liver failure
(D) Noncardiogenic pulmonary edema
(E) Ventilatory failure

Rationale: In overdose, acetaminophen causes fulminant liver failure as a result of its conversion by
hepatic cytochrome P450 enzymes to a highly reactive metabolite. The answer is C.

2. Compare the actions and toxicity of aspirin, the older non-selective NSAIDs, the COX-2-
selective drugs.
Among NSAIDs, aspirin is unique because it
(A) Irreversibly inhibits its target enzyme
(B) Prevents episodes of gouty arthritis with long-term use
(C) Reduces fever
(D) Reduces the risk of colon cancer (E) Selectively inhibits the COX-2 enzyme

Rationale: Aspirin differs from other NSAIDs by irreversibly inhibiting cyclooxygenase. The answer
is A.

3. Describe the toxic effects of aspirin

Gastrointestinal (GI) toxicity, nephrotoxicity, and increased bleeding time at therapeutic levels
hypersensitivity reaction due to increased leukotrienes tinnitus,
hyperventilation metabolic acidosis, hyperthermia, coma in overdose.

A 16-year-old girl comes to the emergency department suffering from the effects of an aspirin
overdose. Which of the following syndromes is this patient most likely to exhibit as a result of this
drug overdose?
(A) Bone marrow suppression and possibly aplastic anemia
(B) Fever, hepatic dysfunction, and encephalopathy
(C) Hyperthermia, metabolic acidosis, and coma
(D) Rapid, fulminant hepatic failure
(E) Rash, interstitial nephritis, and acute renal failure

Salicylate intoxication is associated with metabolic acidosis, dehydration, and hyperthermia. If these
problems are not corrected, coma and death ensue.
The answer is C.

4. Describe the proposed mechanisms of action of benzodiazepines, barbiturates, and zolpidem

l Benzodiazepines increase the frequency of GABA-mediated chloride ion channel opening.

Flumazenil reverses the CNS effects of benzodiazepines and is classified as an antagonist at BZ
receptors. Certain -carbolines have a high affinity for BZ receptors and can elicit anxiogenic
and convulsant effects. These drugs are classified as inverse agonists.

l Barbiturates depress neuronal activity in the midbrain reticular formation, facilitating and
prolonging the inhibitory effects of GABA and glycine. Barbiturates also bind to multiple
isoforms of the GABAA receptor but at different sites from those with which benzodiazepines
interact. Their actions are not antagonized by flumazenil. Barbiturates increase the duration of
GABA-mediated chloride ion channel opening. They may also block the excitatory transmitter
glutamic acid, and, at high concentration, sodium channels.

l The hypnotics zolpidem,zaleplon, and eszopiclone are not benzodiazepines but appear to exert
their CNS effects via interaction with certain benzodiazepine receptors, classified as BZ1 or 1
subtypes. In contrast to benzodiazepines, these drugs bind more selectively, interacting only with
GABAA receptor isoforms that contain 1 subunits. Their CNS depressant effects can be
antagonized by flumazenil.

5. Sketch the biochemical pathways for ethanol metabolism and indicate where fomepizole and
disulfiram act.
The combination of ethanol and disulfiram results in nausea and hypotension as a result of the
accumulation of which of the following?
(A) Acetaldehyde
(B) Acetate
(C) Methanol
(D) NADH
(E) Pyruvate

Rationale: Nausea, hypotension, and ill feeling that result from drinking ethanol while also taking
disulfiram stems from acetaldehyde accumulation. Disulfiram inhibits acetaldehyde dehydrogenase,
the enzyme that converts acetaldehyde to acetate. The answer is A.

6. Relate blood alcohols levels in a nontolerant person to CNS depressant effects of acute
alcohol ingestion

The major acute effects of ethanol on the CNS are sedation, loss of inhibition, impaired judgment,
slurred speech, and ataxia.In nontolerant persons:
Blood level (Ethanol) Effects
60-80 mg/dL Impairment of driving ability
120-160 mg/dL Gross drunkenness
>300 mg/dL Loss of consciousness, anesthesia, coma
with fatal respiratory and cardiovascular
depression
> 500mg/dL Lethal

A freshman student (weight 70 kg) attends a college party where he rapidly consumes a quantity of an
alcoholic beverage that results in a blood level of 500 mg/dL. Assuming that this young man has not
had an opportunity to develop tolerance to ethanol, his present condition is best characterized as
(A) Able to walk, but not in a straight line
(B) Alert and competent to drive a car
(C) Comatose and near death
(D) Sedated with increased reaction times
(E) Slightly inebriated

Rationale: The blood level of ethanol achieved in this individual is extremely high and likely to result
in coma and possibly death due to respiratory arrest in a person who lacks tolerance to ethanol. The
answer is C.

7. Name the inhalation anesthetic agents and identify their pharmacodynamic and
pharmacokinetic properties.

Questions 7 and 8. A 20-year-old male patient scheduled for hernia surgery was anesthetized with
halothane and nitrous oxide; tubocurarine was provided for skeletal muscle relaxation. The patient
rapidly developed tachycardia and became hypertensive. Generalized skeletal muscle rigidity was
accompanied by marked hyperthermia. Laboratory values revealed hyperkalemia and acidosis.

7. This unusual complication of anesthesia is most likely caused by

(A) Acetylcholine release from somatic nerve endings at skeletal muscle
(B) Activation of brain dopamine receptors by halothane
(C) Block of autonomic ganglia by tubocurarine
(D) Pheochromocytoma
(E) Release of calcium from the sarcoplasmic reticulum

Rationale: Malignant hyperthermia is a rare but life-threatening reaction that may occur during
general anesthesia with halogenated anesthetics and skeletal muscle relaxants, particularly
succinylcholine and tubocurarine. Release of calcium from skeletal muscle leads to muscle spasms,
hyperthermia, and autonomic instability. Predisposing genetic factors include clinical myopathy
associated with mutations in the gene loci for the skeletal muscle ryanodine receptor or L-type
calcium receptors. The answer is E.

8. The patient should be treated immediately with

(A) Atropine
(B) Baclofen
(C) Dantrolene
(D) Edrophonium
(E) Flumazenil

Rationale: The drug of choice in malignant hyperthermia is dantrolene, which prevents release of
calcium from the sarcoplasmic reticulum of skeletal muscle cells. Appropriate measures must be taken
to lower body temperature, control hypertension, and restore acid-base and electrolyte balance. The
answer is C.

8. Identify the commonly used intravenous anesthetics and point out their main
pharmacokinetic and pharmacodynamic characteristics.

For which of these drugs is the following true? Postoperative vomiting is uncommon with this
intravenous agent, and patients are often able to ambulate sooner than those who receive other
anesthetics.
(A) Enflurane
(B) Etomidate
(C) Propofol
(D) Remifentanil
(E) Thiopental

Rationale: Propofol is used extensively in anesthesia protocols, including those for day surgery. The
favorable properties of the drug include an antiemetic effect and recovery more rapid than that after
use of other intravenous drugs. Propofol does not cause cumulative effects, possibly because of its
short half-life (28 min) in the body. The drug is also used for prolonged sedation in critical care
settings. The answer is C.

9. Describe the mechanism of action of local anesthesics

MECHANISM OF ACTION

Local anesthetics block voltage-dependent sodium channels and reduce the influx of sodium ions,
thereby preventing depolarization of the membrane and blocking conduction of the action potential.
Local anesthetics gain access to their receptors from the cytoplasm or the membrane.

Characteristic properties of local anesthetics include all of the following EXCEPT

(A) An increase in membrane refractory period
(B) Blockade of voltage-dependent sodium channels
(C) Effects on vascular tone
(D) Preferential binding to resting channels
(E) Slowing of axonal impulse conduction

Rationale: Local anesthetics bind preferentially to sodium channels in the open and inactivated states.
Recovery from drug-induced block is 101000 times slower than recovery of channels from normal
inactivation. Resting channels have a lower affinity for local anesthetics. The answer is D.

10. Describe the major toxic effects of the local anesthetics

TOXICITY

A. CNS Effects:

The important toxic effects of most local anesthetics are in the CNS. All local anesthetics are capable
of producing a spectrum of central effects, including light-headedness or sedation, restlessness,
nystagmus, and tonic-clonic convulsions. Severe convulsions may be followed by coma with
respiratory and cardiovascular depression.

B. Cardiovascular Effects:

With the exception of cocaine, all local anesthetics are vasodilators. Patients with preexisting
cardiovascular disease may develop heart block and other disturbances of cardiac electrical function at
high plasma levels of local anesthetics.

C. Other Toxic Effects

Prilocaine is metabolized to products that include o-toluidine, an agent capable of converting

hemoglobin to methemoglobin. Though tolerated in healthy persons, even moderate
methemoglobinemia can cause decompensation in patients with cardiac or pulmonary disease. The
ester-type local anesthetics are metabolized to products that can cause antibody formation in some
patients. In high concentrations, local anesthetics may cause a local neurotoxic action that includes
histologic damage and permanent impairment of function.
The most important effect of inadvertent intravenous administration of a large dose of an amide local
anesthetic is
(A) Bronchoconstriction
(B) Hepatic damage
(C) Renal failure
(D) Seizures
(E) Tachycardia

Rationale: Of the effects listed, the most important in local anesthetic overdose (of both amide and
ester types) concern the CNS. Such effects can include sedation or restlessness, nystagmus, coma,
respiratory depression, and seizures. Intravenous d iazepam is commonly used for seizures caused by
local anesthetics. The answer is D.

11. Describe the therapeutic and toxic effects of the major antiparkinsonism agents
Bradykinesia has made drug treatment necessary in a 60-year-old male patient with Parkinson s
disease, and therapy is to be initiated with levodopa. The prescribing physician will (or should) know
that levodopa
(A) Causes less severe behavioral side effects if given together with a drug that inhibits hepatic dopa
decarboxylase
(B) Fluctuates in its effectiveness with increasing frequency as treatment continues
(C) Prevents extrapyramidal adverse effects of antipsychotic drugs
(D) Protects against cancer in patients with melanoma
(E) Has toxic effects, which include pulmonary infiltrates

Rationale: Levodopa causes less peripheral toxicity but more CNS or behavioral side effects when its
conversion to dopamine is inhibited outside the CNS. The drug is not effective in antagonizing the
akinesia, rigidity, and tremor caused by treatment with antipsychotic agents. Levodopa is a precursor
of melanin and may activate malignant melanoma. Use of levodopa is not associated with pulmonary
dysfunction. The answer is B.

12. Identify 4 receptors blocked by antipsychotic drugs

13. Identify an opoid receptor antagonist and a mixed agonist-antagonist

Pure opioid receptor antagonists

l Naloxone,
l Nalmefene,
l Naltrexone

Mixed agonist-antagonist
l Buprenorphine
l Nalbuphine

Which drug does not activate opioid receptors, has been proposed as a maintenance drug in treatment
programs for opioid addicts, and with a single oral dose, will block the effects of injected heroin for
up to 48 h?
(A) Amphetamine
(B) Buprenorphine
(C) Naloxone
(D) Naltrexone
(E) Propoxyphene

Rationale: The opioid antagonist naltrexone has a much longer half-life than naloxone, and its effects
may last 2 d. A high degree of client compliance would be required for naltrexone to be of value in
opioid dependence treatment programs. The same reservation is applicable to the use of naltrexone in
alcoholism. The answer is D.

IMMUNOLOGY AND HEMATOLOGY

1. Name the 2 most common types of nutritional anemia, and, for each, describe the most likely
biochemical causes.

l Microcytic hypochromic anemia, caused by iron deficiency, is the most common type of anemia.

l Megaloblastic anemias are caused by a deficiency of vitamin B12 or folic acid, cofactors
required for the normal maturation of red blood cells. Pernicious anemia, the most common type
of vitamin B12 deficiency anemia, is caused by a defect in the synthesis of intrinsic factor.

Questions 13. A 23-year-old pregnant woman is referred by her obstetrician for evaluation of anemia.
She is in her fourth month of pregnancy and has no history of anemia; her grandfather had pernicious
anemia. Her hemoglobin is 10 g/dL (normal, 1216 g/dL).

1. If this woman has macrocytic anemia, an increased serum concentration of transferrin, and a
normal serum concentration of vitamin B12, the most likely cause of her anemia is deficiency of
which of the following?
(A) Cobalamin
(B) Erythropoietin
(C) Folic acid
(D) Intrinsic factor
(E) Iron

Rationale: Deficiencies of folic acid or vitamin B12 are the most common causes of megaloblastic
anemia. If a patient with this type of anemia has a normal serum vitamin B12 concentration, folate
deficiency is the most likely cause of the anemia. The answer is C.

3. The laboratory data for your pregnant patient indicate that she does not have macrocytic anemia
but rather microcytic anemia. Optimal treatment of normocytic or mild microcytic anemia associated
with pregnancy uses which of the following?
(A) A high-fiber diet
(B) Erythropoietin injections
(C) Ferrous sulfate tablets
(D) Folic acid supplements
(E) Hydroxocobalamin injections

Rationale: Iron deficiency microcytic anemia is the anemia that is most commonly associated with
pregnancy. In this condition, oral iron supplementation is indicated. The answer is C.
2. List acute and chronic toxicites of iron

Acute iron overdose results:

l necrotizing gastroenteritis,
l abdominal pain,
l bloody diarrhea,
l shock,
l lethargy,
l and dyspnea

Chronic iron overload results:

l hemochromatosis, with damage to the heart, liver, pancreas

If this patient has a young child at home and is taking iron containing prenatal supplements, she
should be warned that they are a common source of accidental poisoning in young children and
advised to make a special effort to keep these pills out of her child
s reach. Toxicity associated with
acute iron poisoning usually includes which of the following?
(A) Dizziness, hypertension, and cerebral hemorrhage
(B) Hyperthermia, delirium, and coma
(C) Hypotension, cardiac arrhythmias, and seizures
(D) Necrotizing gastroenteritis, shock, and metabolic acidosis
(E) Severe hepatic injury, encephalitis, and coma

Rationale: Acute iron poisoning often causes severe gastrointestinal damage resulting from direct
corrosive effects, shock from fluid loss in the gastrointestinal tract, and metabolic acidosis from
cellular dysfunction. The answer is D.

3. Explain the major hazard involved in the use of folic acid as sole therapy for megaloblastic
anemia and indicate on a sketch of the dTMP cycle the biochemical basis of the hazard

Folic acid supplements correct the anemia but not the neurologic deficits of vitamin B12 deficiency.
Therefore, vitamin B12 deficiency must be ruled out before one selects folic acid as the sole
therapeutic agent in the treatment of a patient with megaloblastic anemia. Folic acid has no recognized
toxicity.

The megaloblastic anemia that results from vitamin B12 deficiency is due to inadequate supplies of
which of the following?
(A) Cobalamin
(B) dTMP
(C) Folic acid
(D) Homocysteine
(E) N 5-methyltetrahydrofolate

Rationale: Deficiency of vitamin B12 (cobalamin) leads to a deficiency in tetrahydrofolate and

subsequently a deficiency of the dTMP required for DNA synthesis. Homocysteine and N 5-
methyltetrahydrofolate accumulate. The answer is B.

4. Compare the oral anticoagulants, standard heparin, and LMW heparins with respect to
pharmacokinetics, mechanisms, and toxicity.
During the next week, the patient was started on warfarin and her heparin was discontinued. Two
months later, she returned after a severe nosebleed. Laboratory analysis revealed an INR
(international normalized ratio) of 7.0 (INR value in such a warfarin-treated patient should be 2.03.0).
To prevent severe hemorrhage, the warfarin should be discontinued and this patient should be treated
immediately with which of the following?
(A) Aminocaproic acid
(B) Desmopressin
(C) Factor VIII
(D) Protamine
(E) Vitamin K1

Rationale: The elevated INR indicates excessive anticoagulation with a high risk of hemorrhage.
Warfarin should be discontinued and vitamin K1 administered to accelerate formation of v itamin K-
dependent factors. The answer is E

5. Compare the pharmacokinetics, clinical uses, and the toxicities of the major antiplatelet drugs.

Over the next 2 d, the patient s symptoms resolved completely. To prevent a recurrence of this disease,
the patient is most likely to be treated indefinitely with which of the following?
(A) Aminocaproic acid
(B) Aspirin
(C) Enoxaparin
(D) Lepirudin
(E) Warfarin

Rationale: Aspirin, an irreversible inhibitor of platelet cyclooxygenase, prevents recurrence of TIAs

and ischemic stroke. The answer is B.
6. Name the 3 types of anticoagulants and describe their mechanism of action

Three major types of anticoagulants:

l Heparin and related products

Complexes with antithrombin III and irreversibly inactivates the coagulation factors
thrombin and factor Xa.

l Direct thrombin and factor X inhibitors

Direct thrombin: Binds to thrombin s active site and inhibits its enzymatic action
Factor X inhibitors: Binds to the active site of factor Xa & inhibits its enzymatic action

l Orally active coumarin derivatives (eg, warfarin).

Inhibits vitamin K poxide reductase and thereby interferes with production of functional
vitamin K-dependent clotting and anticlotting factors.

A 58-year-old business executive is brought to the emergency department 2 h after the onset of severe
chest pain during a vigorous tennis game. She has a history of poorly controlled mild hypertension
and elevated blood cholesterol but does not smoke. ECG changes confirm the diagnosis of
myocardial infarction. The decision is made to attempt to open her occluded artery.

Which of the following drugs accelerates the conversion of plasminogen to plasmin?

(A) Aminocaproic acid
(B) Heparin
(C) Lepirudin
(D) Reteplase
(E) Warfarin

Rationale: Reteplase is the only thrombolytic drug listed. Heparin and warfarin are anticoagulants.
Lepirudin is a direct inhibitor of thrombin, and aminocaproic acid is an inhibitor, not an activator, of
the conversion of plasminogen to plasmin. The answer is D