17 6

SECTION II

M I C RO B I O LOGY

MIC R O BIO L O G Y - ANTIMIC R O BIA L S

MIC R O BIO L O G Y - ANTIMIC R O BIA L S

Antimicrobial therapy

MECHANISM OF ACTION

DRUGS

0 Block cell wall synthesis by inh ibition of

Penicillin, methicillin, ampicillin, piperacillin,

cephalosporins, aztreonam, i mipenem

peptidoglycan cross-l inking

f) Block peptidoglycan synthesis

Bacitracin, vancomycin

E) Block nucleotide synthesis by inhibiting folic

Sulfonamides, trimethopri m

acid synthesis (involved in methylation)

0 Block DNA topoisomerases

Fluoroqui nolones

0 Block m RNA synthesis

Rifampin

0 Damage DNA

Metronidazole

0 Block protein synthesis at 50S ribosomal

Chloramphenicol, macrol ides, cl indamycin,

streptogramins (qui nupristin , dalfopristin),
l i nezol id

subunit

(l) Block protein synthesis at 30S ribosomal

Ami noglycosides, tetracycl i nes

subunit
E) SMX, TMP
0 - lacta ms
f) Vancomycin

and bacitraci n

Penicillin

Tetracycli nes,
a m i noglycosides

Macrolides, c h lora m p h e n icol,

clindamycin, linezolid, streptogra m i n s

Pen icillin G (IV and I M form), pen icillin V (oral) . Prototype P-lactam antibiotics.

MECHANISM

Bind penicill in-binding proteins (transpeptidases)

Block transpeptidase cross-l inking of peptidoglycan
Activate autolytic enzymes

CLINICAL USE

Mostly used for gram-positive organisms (S. pneumoniae, S. pyogenes, Actinomyces) . Also used for
Neisseria meningitidis, Treponema pallidum, and syphilis. Bactericidal for gram-positive cocc i ,
gram-positive rods, gram-negative cocci, an d spirochetes. N ot pen icillinase resistant.

TOXICITY

Hypersensitivity reactions, hemolytic anem ia.

RESISTANCE

P-lactamases cleave P-lactam ring.

M I C R O B I O LOGY

MIC R O BI O L O G Y -ANTI MI C R O BIA L S

SECTION II

1 77

Oxacillin, nafcillin, dicloxacillin (penicillinase-resistant penicillins)

MECHANISM

Same as pen icil l i n . Narrow spectrum;

pen icillinase resistant because bulky R group
blocks access of -lactamase to -lactam ring.

CliNICAL USE

S. au reus (except MRSA; resistant because of

altered penicill in-binding protein target site) .

TOXICITY

Hypersensitivity reactions, interstitial nephritis.

"Use naf (nafcillin) for staph."

Ampicillin, amoxicillin (aminopenicillins)

MECHANISM

Same as penicillin. Wider spectrum ;

penicill inase sensitive. Also combine with
clavulanic acid to protect against -lactamase.
Am Oxicillin has greater Oral bioavai labil ity
than ampicillin.

AMinoPenicillins are AMPed-up penicill in .

CliNICAL USE

Extended-spectrum penicillin Haemophilus

influenzae, E. coli, Listeria monocytogenes,
Proteus mirabilis, Salmonella, Shigella,
enterococci.

Coverage : ampici l l i n /amoxicillin HELPSS kill

enterococci .

TOXICITY

Hypersensitivity reactions ; ampicillin rash ;

pseudomembranous colitis.

RESISTANCE

-lactamases cleave -lactam ring.

Ticarcillin, piperacillin (antipseudomonals)

MECHANISM

Same as penicillin. Extended spectrum.

CliNICAL USE

Pseudomonas spp. and gram-negative rods; susceptible to penicil l i nase; use with clavulanic acid.

TOXICITY

Hypersensitivity reactions.

-ladamase inhibitors

Include Clavulanic Acid, Sulbactam ,

Tazobacta m . Often added to penici llin
antibiotics to protect the antibiotic from
destruction by -lactamase (pen icill inase) .

CAST.

l 78

SECTION II

MI CROBI OLO G Y

MICROBIOLOGY-ANTIMICROBIALS

Cephalosporins
MECHANISM

-lactam drugs that inhibit cell wall synthesis

but are less susceptible to pen icill inases.
Bactericidal .

Organisms typically not covered by

cephalosporins are LAME : Listeria, Atypicals
(Chlamydia, Mycoplasma) , M RSA, and
Enterococci. Exception : ceftarol ine covers
MRSA.

CliNICAl USE

1 st generation (cefazol in, cephalexin) -grampositive cocci, Proteus mirabilis, E. coli,

Klebsiella pnewnoniae. Cefazol in used prior to
surgery to prevent S. aureus wound infections.
2nd generation (cefoxitin, cefaclor,
cefuroxime) -gram-positive cocci ,
Haemophilus influenzae, Enterobacter
aerogenes, Neisseria spp., Proteus mirabilis,
E. coli, Klebsiella fJneumoniae, Serratia
marcescens.
3rd generation (ceftriaxone, cefotaxime,
ceftazidime) - serious gram-negative infections
resistant to other -lactams.
4th generation (cefepime) - t activity against
Pseudomonas and gram-positive organisms.

1 st generation - PEcK.

TOXICITY

2nd generation - HEN PEcKS.

Ceftriaxone-meningitis and gonorrhea.

Ceftazid i me-Pseudomonas.

Hypersensitivity reactions, vitamin K deficiency.

Low cross-reactivity with pen icillins.
t nephrotoxicity of aminoglycosides.

Aztreonam
MECHANISM

A monobactam resistant to -lactamases. Prevents peptidoglycan cross-l inking by binding to PBP3.

Synergistic with aminoglycosicles. No cross-allergenicity with penicillins.

CliNICAl USE

Gram-negative rods only-No activity against gram-positives or anaerobes. For penicill in-allergic
patients and those with renal insufficiency who cannot tolerate aminoglycosicles.

TOXICITY

Usually nontoxic ; occasional GI upset.

lmipenem/ cilastatin, meropenem

MECHANISM

Im ipenem is a broad-spectrum, -lactamase

resistant carbapenem . Always adm inistered
with cilastatin (inh ibitor of renal
cl e hyclropepticlase I) to ! inactivation of drug
in renal tubules.

CliNICAl USE

Gram-positive cocci, gram-negative rods, and

anaerobes. Wiel e spectru m , but the sign ificant
side effects l i m it use to life-threatening
infections, or after other drugs have failed.
Meropenem, however, has a reduced risk of
seizures and is stable to dehyclropepticlase I.

TOXICITY

GI d istress, ski n rash, and CNS toxicity

(seizures) at high plasma levels.

With im ipenem, " the kill is lastin' with

cilastatin."
ewer carbapenems i nclude ertapenem and
cloripenem.

M I C R O B I O LO G Y

MICRO BIOLO G Y - ANTI MICRO BIAL S

SECTION I I

Vancomycin
MECHANISM

Inhibits cell wall peptidoglycan formation by binding 0-ala 0-ala portion o f cell wall precursors.
Bactericidal .

CLIN ICAL USE

Cram positive only- serious, amulticlru g-resistant organisms, including M RSA, enterococci, and
Clostridium diffi.cile (oral close for pseudomembranous colitis) .

TOXICITY

Nephrotoxicity, Ototoxicity, Thrombophlebitis, diffuse flushing- red m a n syn d ro m e (can largely

prevent by pretreatment with antihistam ines and slow infusion rate ) . Well tolerated in genera l
does N OT have many problems.

RESISTANCE

Occurs with amino acid change of D-ala D-ala to 0-ala 0-lac. " Pay back 2 D-alas (dollars) for
vandalizing (vancomycin) ."

Protein synthesis
inhibitors

Specifically target smaller bacterial ribosome

(70S, made of 30S and 50S subun its), leaving
human ribosome ( 80S) unaffected.

"Buy AT 3 0, CCEL (sell) at 50."

3 05 i n h i b itors

A = Am inoglycosicl e s [bactericidal ]
T Tetracycl i nes [bacteriostatic]
=

5 05 i n h i b itors

C = Chloramphen icol, Clinclamycin [bacteriostatic]

E Erythromycin (macrol icl e s) [bacteriostatic]
L Li nezol icl [variable]
=

l i nezolid
(50S)

mRNA

Z.l
J

I n itiator tRNA

Ribosomal A&P site

,-A---.,
PA

I n itiation
com plex
formation

t-0--

PA

Macrolides (erythromycin ) (505)

aAlso causes misreading of mRNA.

Clindamycin (50S)

A m 1 n og lycos1de s ( 3 0S) a

1 79

1 80

S E CTI O N I I

M I C RO B I O LO G Y

M I C R O B I O LO G Y - A N T I M I C R O B I A L S

Gentamicin, Neomycin, Am ikacin ,

Tobramyci n, Streptomycin.

"Mean" (arninoglyc oside) GNATS caNNOT

kill anaerobes.

MECHANISM

Bactericidal ; inhibit formation of in itiation

complex and cause m isreading of m RNA. Also
block translocation. Require 02 for uptake ;
therefore ineffective against anaerobes.

A " i nitiates" the Alphabet.

CLINICAL USE

Severe gram-negative rod infections. Synergistic

with P-lactam antibiotics.
Neomycin for bowel surgery.

TOXICITY

Nephrotoxicity (especially when used with

cephalosporins ) , Neuromuscular blockade,
Ototoxicity (especially when used with loop
d iuretics) . Teratogen.

RESISTANCE

Transferase enzymes that inactivate the drug by

acetylation , phosphorylation, or adenylation.

Aminoglycosides

Tetracyclines

Tetracycline, doxycycline, demeclocycl ine,

m i nocycl ine.

MECHANISM

Bacteriostatic; bind to 30S and prevent

attachment of aminoacyl-tRNA; lim ited CNS
penetration. Doxycycline is fecally el iminated
and can be used i n patients with renal failure.
Do not take with milk, antacids, or iron
containing preparations because divalent
cations inhibit its absorption in the gut.

CLINICAL USE

Borrelia burgdorferi, M. pnewnoniae. Drug's

abil ity to accumulate intracellularly makes
it very effective against Rickettsia and
Chlamydia .

TOXICITY

Gl distress, discoloration of teeth and inh ibition

Demeclocycl i ne-ADI-1 antagonist; acts as a

Diuretic in SIAD H . Rarely used as antibiotic.

of bone growth in children, photosensitivity.

Contraindicated in pregnancy.
RESISTANCE

Macrolides

! uptake into cells or t efflux out of cell by

plasmid-encoded transport pumps.

Azithromycin, clarithromycin, erythromycin.

MECHANISM

I n h ibit protein synthesis by blocking translocation ( "macroslides" ) ; bind to the 23S rRNA of the
50S ribosomal subunit. Bacteriostatic.

CLINICAL USE

Atypical pneumonias (Mycoplasma, Chlamydia, Legionella) , STDs (for Chla mydia), and gram
positive cocci (streptococcal infections in patients allergic to penici l l i n ) .

TOXICITY

MACRO : Moti lity issues, Arrhythmia caused b y prolonged QT, acute Cholestatic hepatitis, Rash,
eOsinophil ia. I ncreases serum concentration of theophyll ines, oral anticoagulants.

RESISTANCE

Methylation of 23S rRNA binding site.

M I C RO B I O LOGY

M I C R O BIO L O G Y - A N T I MIC R O BIA L S

SECTI O N I I

1 81

Chloramphenicol
MECHANISM

Blocks peptidyltransferase a t 50S ribosomal subunit. Bacteriostatic.

CLINICAL USE

Meningitis (Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae) .

C onservative use owing to toxicities but often still used in developing countries because of low
cost.

TOXICITY

Anemia (close dependent) , aplastic anem ia (close independent) , gray baby syndrome (in premature
infants because they lack liver UDP-glucuronyl transferase) .

RESISTANCE

Plasmid-encoded acetyltransferase that inactivates drug.

Clindamycin
MECHANISM

Blocks peptide transfer (transpeptidation) at 50S

ribosomal subunit. Bacteriostatic.

CLINICAL USE

Anaerobic infections (e.g., Bacteroides fragilis,

Clostridium perfringens) in aspiration
pneumonia or lung abscesses. Also oral
infections with mouth anaerobes.

TOXICITY

Pseudomembranous colitis ( C . difficile

overgrowth) , fever, diarrhea.

Sulfonamides

Treats anaerobes above the diaphragm vs.

metronidazole (anaerobic infections below
diaphragm) .

Sulfa methoxazole ( SMX), sulfisoxazole, sulfadiazine.

MECHANISM

PABA anti metabol ites inhibit dihydropteroate synthase. Bacteriostatic.

CLINICAL USE

Gram-positive, gram-negative, Nocardia, Chlamydia. Triple sulfas or SMX for simple UTI .

TOXICITY

Hypersensitivity reactions, hemolysis if G6PD deficient, nephrotoxicity (tubulointerstitial

nephritis) , photosensitivity, kernicterus in infants, d isplace other drugs from album i n (e.g.,
warfarin) .

RESISTANCE

Altered enzyme (bacterial d ihydropteroate synthase), uptake, or t PABA synthesis.

tI

PABA

Dihydropteroate
synthase

Pteridine

. Su lfo n a m ides I

Dihydropteroic acid

D i hyd rofolic acid

Dihydrofolate
reductase

'----___--'
lir i m e th o p r i m ,
pyrimet h a m i n e

Tetrahydrofolic acid (THF)

N 5 N 1 0 -methylene T H F

/ 1

Pu rines

Thymi d i n e

Methionine

DNA

P rotein

DNA, RNA

(Adapted, with permission, from Katzung BG. Basic and Clinical Pharmacology, 7th ed. Stamford, Cf: Appleton & lange, 1 99 7 : 762.)

1 82

SECTION II

MI C R OBI OLO G Y

MICROBIOLOGY-ANTI MICROBIALS

Trimethoprim
MECHANISM

Inh ibits bacterial dihydrofolate reductase.

Bacteriostatic.

CLI N I CAL USE

Used i n combination with sulfonamides

(trimethoprim-sulfamethoxazole [TMP
SMX] ) , causing sequential block of folate
synthesis. Combination used for UTis,
Shigella, Salmonella, Pneumocystis jirovecii
pneumonia (treatment and prophylaxis).

TOXICITY

Megaloblastic anem ia, leukopenia,

granulocytopenia. ( May alleviate with
supplemental fol inic acid [leucovorin rescue ] . )

Fluoroquinolones

Abbreviated TMP.
TMP: Treats Marrow Poorly.

CiproAoxaci n , norAoxacin, levoAoxacin, oAoxacin, sparAoxaci n , moxiAoxacin, gatiAoxaci n,

enoxacin (Auoroquinolones), nalidixic acid (a quinolone).

MECHAN ISM

Inhibit DNA gyrase (topoisomerase I I ) and

topoisomerase IV Bactericidal. Must not be
taken with antacids.

CLINICAL USE

Gram-negative rods of urinary and GI tracts

(including Pseudomonas), Neisseria, some
gram-positive organisms.

TOXICITY

GI upset, superinfections, skin rashes,

headache, dizziness. Less common ly, can
cause tendon itis, tendon rupture, leg cramps,
and myalgias. Contraind icated in pregnant
women and in children because animal
studies show damage to cartilage. Some may
cause prolonged QT i nterval. May cause
tendon rupture i n people > 60 years old and in
patients taking predn isone.

RESISTANCE

Chromosome-encoded mutation i n DNA

gyrase, plasm id-mediated resistance, efflux
pumps.

Fluoroquinolones hurt attachments to your

bones.

Metronidazole
MECHAN ISM

Forms free radical toxic metabol ites in the

bacterial cell that damage DNA. Bactericidal,
antiprotozoal.

CLIN ICAL U S E

GET GAP on the Metro with metron idazole !

Treats Giardia, Entamoeba, Trichomonas,
Treats
anaerobic infection below the diaphragm
Gardnerella vagina/is, Anaerobes (Bacteroides,
vs. clindamyci n (anaerobic infections above
C. difficile) . Used with a proton pump inhibitor
diaphragm ) .
and clarithromycin for " triple therapy" against
H. Pylori.

TOXICITY

Disulfiram-like reaction with alcohol ; headache,

meta II ic taste.

M I CROBI O L O G Y

MICROBIOLOGY-ANTI MICROBIALS

SE CTI O N I I

1 83

Antimycobaderia l d rugs
BACTERIUM

PROPHYLAXIS

TREATMENT

M. tuberculosis

I son iazid

Rifampin , Ison iazid , Pyrazinamide,

Ethambutol ( R IPE for treatment)

M . avium-intracellulare

Azithromycin

Azithromycin, rifampin, ethambutol ,

streptomycin

M. leprae

N/A

Long-term treatment with dapsone and rifampin

for tuberculoid for m. Add clofazim ine for
lepromatous for m.

l synthesis of mycol ic acids . Bacterial catalase

INH Injures Neurons and Hepatocytes.

Isoniazid (I N H)
MECHAN ISM

peroxidase ( KatG) needed to convert INH to

active metabolite.
CLINICAL USE

Mycobacterium tuberculosis. The only agent

used as solo prophylaxis against TB.

TOXICITY

Neurotoxicity, hepatotoxicity. Pyridoxine

(vitamin B 6 ) can prevent neurotoxicity, lupus.

Different I H half-lives in fast vs. slow

acetyla tors.

Rifampin
MECHANISM

Inh ibits DNA-dependent R A polymerase.

CLINICAL USE

Mycobacterium tuberculosis; delays resistance

to dapsone when used for leprosy. Used
for meningococcal prophylaxis and
chemoprophylaxis in contacts of children with
Haemophilus inf/.uenzae type B .

TOXICITY

M inor hepatotoxicity a n d drug interactions

( t P-4 5 0 ) ; orange body Auids (nonhazardous
side effect) .

Rifampin's 4 R's :
RNA polymerase inh ibitor
Revs up m icrosomal P-45 0
Red /orange body Auids
Rapid resistance i f used alone

Pyrazinamide
MECHAN ISM

Mechanism u ncertain. Thought to acid ify intracel lular environ ment via conversion to pyrazinoic
acid. Effective in acidic pH of phagolysosomes, where TB engulfed by macrophages is found.

CLINICAL U S E

Mycobacterium tuberculosis.

TOXICITY

Hyperuricem ia, hepatotoxicity.

Ethambutol
MECHANISM

l carbohyd rate polymerization of mycobacterium cell wall by blocking arabinosyltransferasc.

CLINICAL USE

Mycobacterium tuberculosis.

TOXICITY

Optic neuropathy (red-green color blindness ) .

1 84

SECTI O N I I

Antimicrobial
prophylaxis

M I C RO B I O LOGY

MIC RO BIO LO G Y - ANTIMIC ROBIA L S

CONDITION

MEDICATION

Meningococcal infection

Ciprofloxacin (drug of choice) , rifampin for

children

Gonorrhea

Ceftriaxone

Syphilis

Benzathine pen icillin G

H istory of recurrent UTis

TMP-SMX

Endocarditis with surgical or dental procedures

Pen icillins

Pregnant woman carrying group B strep

Ampicillin

Prophylaxis of strep pharyngitis in child with

prior rheumatic fever

Oral penicillin

Prevention of postsurgical infection clue to

S. aureus

Cefazol i n

Prevention of gonococcal or chlamydia!

conjunctivitis in newborn

Erythromycin ointment

H IV prophylaxis
PROPHYLAXIS

I N FECTION

CD4 < 200

cel ls/m m3

TMP-SMXa

Pneumocystis pneumon ia

CD4 < 1 00

cel ls/m m3

TMP-SMXa

Pnewnocystis pneumonia and toxoplasmosis

Azithromycin

Mycobacterium aviwn complex

CELL COUNT

C D 4 < 50
a

cel l s/mm3

Aerosolized pentam idine may be used if patient is unable to tolerate TMP-SMX, but this may not prevent toxoplasmosis
infection concurrently.

Treatment of highly
resistant baderia

Antifungal therapy

MRSA-vancomycin.
VRE -linezol icl and streptogramins ( quinupristin/dalfopristin) .

Cell w a ll synthesis
Membrane function

Caspofungin
Anidu lfu n gi n

E rgosterol
synthesis

N ucleic acid
synthesis

5-Fiucytosine
Lanosterol synthes is

Fluconazole
ltraconazole
Voriconazole

Naftifine
Terbi nafine
(Adapted, with permission, from Katzung BG, Trevor AJ . USMLE Rood Mop: Phormocology, l st e d . New York: McGraw-Hill, 2003 : 1 20.)

M I CRO B I O L O G Y

Amphotericin

MIC R O BIO LO G Y - ANTI MIC R O BIA L S

SECT I O N I I

1 85

MECHANISM

Binds ergosterol (unique to fungi) ; forms

membrane pores that allow leakage of
electrolytes.

CLINICAL USE

Serious, systemic mycoses. Cryptococcus

(amphotericin B with/without Aucytosine
for cryptococcal men ingitis) , Blastomyces,
Coccidioides, Histoplasma, Candida,
Mucor. l ntrathecally for fungal men ingitis.
Supplement K and Mg because of altered
renal tubule permeabil ity.

TOXICITY

Fever/chills ( "shake and bake"), hypotension,

nephrotoxicity, arrhythm ias, anemia, IV
phlebitis ( "amphoterrible" ) . Hydration
reduces neph rotoxicity. Liposomal
amphotericin reduces toxicity.

Amphotericin " tears" holes i n the fungal

membrane by forming pores.

Nystatin
MECHANISM

Same as amphotericin B. Topical form because too toxic for systemic use.

CLINICAL USE

" Swish and swallow" for oral candidiasis (thrush); topical for d i aper rash or vaginal candidiasis.

Azoles

Fluconazole, ketoconazole, clotrimazole, m iconazole, itraconazole, voriconazole.

MECHANISM

I n h ibit fungal sterol (ergosterol) synthesis, by inhibiting the P-45 0 enzyme that converts lanosterol
to ergosterol.

CLINICAL USE

Local and less serious systemic mycoses. Fluconazole for chronic suppression of cryptococcal
meningitis in AIDS patients and candidal infections of all types. Itraconazole for Blastomyces,
Coccidioides, Histoplasma. Clotrimazole and miconazole for topical fungal infections.

TOXICITY

Testosterone synthesis inh ibition (gynecomastia, esp. with ketoconazole), l iver dysfunction (inhibits
cytochrome P-4 5 0 ) .

Flucytosine
MECHAN ISM

Inh ibits DNA a n d RNA biosynthesis b y conversion t o 5-Auorouracil b y cytosine deaminase.

CLIN ICAL USE

Used i n systemic fungal infections (esp. men ingitis caused by Cryptococcus) i n combination with
amphotericin B .

TOXICITY

B one marrow suppression.

Caspofungin, micafungin
MECHANISM

Inh ibits cell wall synthesis by inh ibiting synthesis of -glucan.

CLINICAL USE

Invasive aspergillosis, Candida.

TOXICITY

GI upset, Aushing (by histam ine release) .

1 86

SECTION II

MI CROBI OLO G Y

MICROBIOLOGY-ANTI MICROBIALS

Terbinafine
MECHANISM

Inhibits the fungal enzyme squalene epoxidase.

CLINICAL USE

Used to treat dermatophytoses (especially onychomycosis-fungal infection of finger or toe nails).

TOXICITY

Abnormal LFTs, visual d isturbances.

Griseofulvin
MECHANISM

Interferes with m icrotubule function ; disrupts m itosis. Deposits i n keratin-containing tissues (e.g.,
nail s ) .

CLINICAL USE

Oral treatment of superficial infections; inhibits growth of derm atophytes (tinea, ri ngworm) .

TOXICITY

Teratogenic, carcinogenic, confusion , headaches, t P-450 and warfarin metabol ism.

Antiprotoz:oan therapy

Pyrimethamine (toxoplasmosis), suramin and melarsoprol (Trypanosoma brucei) , nifurtimox

(T cruzi), sodium stibogluconate (leishmaniasis) .

Chloroquine
MECHAN ISM

Blocks detoxification of heme into hemozoin. Heme accumulates and is toxic to plasmodia.

CLIN ICAL USE

Treatment of plasmodial species other than P. falciparum (frequency of resistance i n P. falciparwn

is too high) . Resistance due to membrane pump that i ntracellular concentration of d rug. Treat
P. falciparwn with artemether/lumifantrine or atovaquone/proguan i l. For life-threatening malaria,
use quinidine i n U. S . (quinine elsewhere) or artisunate.

TOXICITY

Retinopathy.

Antihelminthic therapy

Mebendazole, pyrantel pamoate, ivermecti n, diethylcarbamazine, praziquantel ; i mmobil ize

helminths. Use praziquantel against flukes (trematodes) such as Schistosoma.

M I C R O B I O LOGY

MIC R O BIO LOGY -ANTI MIC R O BIAL S

SECTI O N I I

1 87

Antiviral therapy

-::l

ati n g

Early p rotei n
synthesis

Blocked by
neuraminidase
i n h ibitors
( i nfluenza)

Mammalian
cell

N u cleic acid
synthesis

Packaging
Late p rotei n
--->.;"'-- and _ synthesis and
assembly
processing

Blocked by purine
and pyri m id i n e
analogs, a n d
reverse transcriptase
i n h ibitors

--r--; Blocked by

p rotease
i n h ibitors

Blocked by f---
rifampin
(vaccinia)
(Adapted, with permission, from Katzung BG, Trevor AJ. USMLE Road Map: Pharmacology, 1 st ed. New York: McGraw-Hill, 2003 : 1 20.)

Zanamivir, oseltamivir
MECHAN ISM

Inhibit influenza neur a m i n idase, decreasing the release of progeny virus.

CLINICAL USE

Treatment and prevention of both influenza A and B.

Ribavirin
MECHAN ISM

Inhibits synthesis of guanine nucleotides by competitively i n h ibiting IMP dehydrogenase.

CLIN ICAL USE

RSV, chronic hepatitis C.

TOXICITY

Hemolytic anemia. Severe teratogen.

Acyclovir
MECHANISM

Monophosphorylated by H SV/VZV thymidine kinase. Guanosine analog. Triphosphate formed by

cellular enzymes. Preferentially inh ibits viral DNA polymerase by chain term ination .

CLINICAL USE

H SV and VZV. Weak activity against EBV. No activity against CMV. Used for H SV
induced mucocutaneous and gen ital lesions as wel l as for encephalitis. Prophyl axis in
im munocompromised patients. No effect on latent forms of H SV and VZV. Valacyclovir, a
prodrug of acyclovir, has better oral bioavailability.
For herpes zoster, use a related agent, famciclovir.

TOXICITY

Few serious adverse effects.

MECHANISM OF RESISTANCE

Mutated viral thym idine kinase.

1 88

SECTI O N I I

M I C R O B I O LO G Y

MIC RO BIOLOG Y - A N TI MIC RO BIA L S

Cianciclovir
MECHANISM

5'-monophosphate formed by a CMV viral kinase. Guanosine analog. Triphosphate formed by

cellular kinases. Preferentially inh ibits viral DNA polymerase.

CliNICAL USE

CMV, especially in im munocomprom ised patients. Valganciclovir, a prodrug of ganciclovir, has

better oral bioava ilabil ity.

TOXICITY

Leukopenia, neutropenia, thrombocytopenia, renal toxicity. More toxic to host enzymes than
acyclovir.

MECHANISM OF RESISTANCE

Mutated CMV DNA polymerase or lack of viral kinase.

Foscamet
MECHANISM

Viral DNA polymerase inhibitor that binds to

the pyrophosphate-binding site of the enzyme.
Does not require activation by viral kinase.

CLINICAL USE

CMV retinitis in immunocomprom ised patients

when ganciclovir fa ils; acyclovir-resistant HSV.

TOXICITY
MECHANISM OF RESISTANCE

Foscarnet

pyrofosphate analog.

ephrotoxicity.
Mutated DNA polymerase.

Cidofovir
MECHANISM

Preferentially inhibits viral DNA polymerase. Does not require phosphorylation by viral kinase.

CLINICAL USE

CMV retinitis in immunocomprom ised patients ; acyclovir-resistant H SV. Long half-life.

TOXICITY

Nephrotoxicity (coadminister with probenecid and IV saline to reduce toxicity) .

M I C R O B I O LO G Y

H IV therapy

DRUG

M I C R O B I O LO G Y- A N T I M I C R O B I A L S

S ECTI O N I I

1 89

H ighly active antiretroviral therapy ( HAART) : in itiated when patients present with A I D S -defining
illness, low C D4 cell counts (< 500 cells/m m 3 ) , or h igh viral load. Regimen consists of 3 d ru gs to
prevent resistance :
[2 nucleoside reverse transcriptase inh ibitors ( N RTis)] +
[ l non-nucleoside reverse transcriptase inh ibitor ( N N RTI) OR l protease inh ibitor OR l
i ntegrase i nh ibitor]
M ECHANISM

TOXICITY

Assembly of virions depends on HIV-l protease

(pol gene), wh ich cleaves the polypeptide
products of HIV mR A into their functional
parts. Thus, protease i nh ibitors prevent
maturation of new viruses.
Ritonavir can "boost" other drug concentrations
by inh ibiting cytochrome P-450.
All protease inh ibitors end in -navir.
Navir ( never) tease a protease.

Hyperglycemia, G I i ntolerance (nausea,

diarrhea) , l ipodystrophy.
Neph ropathy, hematuria (indinavir) .

Competitively inhibit nucleotide binding to

reverse transcriptase and terminate the D A
chai n ( lack a 3' OH group) . Tenofovir is a
nucleotide analog and does not have to be
activate d ; the others are nucleoside analogs
and do need to be phosphorylated to be active.
ZDV is used for general prophylaxis and during
pregnancy to reduce risk of fetal transm ission .
Have you dined (vudine) with my nuclear
( nu cleo sides) fam i ly?

Bone marrow suppression (can be reversed

with G-CSF and erythropoieti n ) , peripheral
neuropathy, lactic acidosis (nucleosides ) , rash
(non-nucleosides), anemia (ZDV ) .

Bind to reverse transcriptase at site different

from RTis. Do not require phosphorylation
to be active or compete with nucleotides.

S a m e as N RTJs.

Inh ibits HIV genome integration i nto host cell

chromosome by reversibly inhibiting HTV
integrase.

I-Iypercholesterolem ia.

Protease inhibitors
Lopinavir
Atazanavir
Darunavi r
Fosamprenavir
Saquinavir
R itonavi r
l n d inavir

N RTis
Tenofovir (TDF)
Emtricitabine (FTC)
Abacav i r (ABC)
Lamivudine (3TC)
Zidovudine (ZDV,
formerly AZT)
Didanosine (ddl)
Stavud i n e (d4T)

N N RTis
Nevirapine
Efavi renz
Delavirdine

lntegrase inhibitors
Ra ltegravi r

Interferons
MECHANISM

Glycoproteins synthesized by virus-infected cells ; block repl ication of both RNA and DNA viruses.

CLINICAL USE

I FN-a - chronic hepatitis B and C , Kaposi 's sarcoma. I FN- - M S . I FN-y- NADPH oxidase
deficiency.

TOXICITY

Neutropenia, myopathy.

l 90

SECTION I I

Antibiotics to avoid i n
pregnancy

M I C RO B I O LO G Y

MIC R O BIO L O G Y - ANTI MIC R O BIA L S

ANTIBIOTIC

ADVERSE EFFECT

Sulfonam ides

Kern icterus

Am inoglycosides

Ototoxicity

Fl uoroqui nolones

Cartilage damage

Clarithromycin

Embryotoxic

Tetracyclines

D iscolored teeth, inhibition of bone growth

Ribavirin (antiviral )

Teratogenic

Griseofulvin (antifungal)

Teratogenic

Chloramphenicol

"Gray baby"

--------------------------------------------

SAFe Children Take Really Good Care.

IMMUNOLOGY

IMMUNOLOGY-IMMUNOSUP PRESSANTS

SECTION II

209

IM MUNOLOGY-IM M UNOSUPPRESSANTS
Cyclosporine
MECHANISM

Binds to cycloph il ins. Comp l ex blocks the d i fferentiation and activation of T ce lls by i n h ibiting
ca l cineurin, thus preventing the production of i L-2 and its receptor.

CLINI C AL USE

Suppresses organ rejection after transplantation ; selected autoimmune d isorders.

TOXICITY

Nephrotoxicity, hypertension, hyperlipidemia, hypergl ycemia, tremor, gingiva l hyperplasia,

h i rsutism .

Tacrolimus {FK-506)
MECHANISM

Similar to cyclosporine; binds to FK-binding protein, inhibiting ca l cineur i n and secretion of I L-2
and other cytokines.

CLINICAL USE

Potent immunosuppressive used in organ transplant recipients.

TOXICITY

S i m ilar to cyclosporine except no gingival hyperplasia and h i rsuti sm.

Sirolimus (rapamycin)
MECHANISM

Inh ibits mTOR. Inh ibits T-ce ll prol iferation in response to I L-2 .

CLINI C AL USE

I m munosuppression after kidney transplantation in combination with cyclosporine and

corticosteroids. Also used with drug-e l uting stents.

TOXICITY

Hyperl ipidemia, thrombocytopenia, l eukopen ia.

Azathioprine
MECHANISM

CLINICAL USE

TOXICITY

Antimetabol ite precursor of 6-mercaptopurine that i nterferes with the metabo l ism and synthesis of
nucleic acids. Toxic to prol iferating l ymphocytes.
Kidney transplantation, autoim mune disorders (inc l uding glomeru lonephritis and hemolytic
anemia) .
Bone marrow suppression. Active metabol ite mercaptopurine is metabol ized by xanth ine oxidase ;
thus, toxic effects may be increased by allopurinol.

Muromonab-CD3 {OKT3)
MECHANISM

Monoclona l antibody that binds to CD3 (epsilon chain) on the surface of T ce l ls. Blocks cel l u l ar
i nteraction with C D 3 protein responsibl e for T-ce l l signa l transduction.

CLINICAL USE

I mmunosuppression after kidney transp l antation .

TOXICITY

Cytokine re l ease syndrome, hypersensitivity reaction.

210

SECTION II

I M MUN O LOGY

IMMUNOLOGY-IMMUNOSU P PRESSANTS

N
T
AG
Recombinant cytokines
E

CLI NI C A L U S ES

---------------------------

______
__
__
__
__
________
__
__
__
__
__

and clinical uses

Aldesleukin (interleukin-2 )

Renal cell carcinoma, metastatic melanoma

Epoetin alfa (erythropoietin)

Anem ias (especially in renal fai lure)

Filgrastim (granulocyte colony-stimulating

Recovery of bone marrow

factor)
Sargramostim (granulocyte-macrophage colony

Recovery of bone marrow

stimulating factor)
a-interferon

Hepatitis B and C, Kapos i 's sarcoma, leukemias,

mal ignant melanoma

-interferon

Multiple sclerosis

y-interferon

Chron ic granulomatous d isease

O prelvekin (interleu kin- l l )

Thrombocytopen ia

Throm bopoietin

Thrombocytopenia

TARGET

CL I NI C AL USE

Muromonab-CD3
(OKT3)

CD3

Prevent acute transplant rej ection

Digoxin I m mune Fab

Digoxin

Antidote for d igoxi n i ntoxication

lnfliximab

TNF-a

Crohn's disease, rheumatoid arthritis, psoriatic

arthritis, ankylosing spondyl itis

Adalimumab

TNF-a

Crohn's d isease, rheumatoid arthritis, psoriatic

arthritis

Abciximab

Glycoprotein Jib/Ilia

Prevent card iac ischem ia in unstable angina and

i n patients treated with percutaneous coronary
intervention

Trastuzumab
( Herceptin)

HER2

H E R2-overexpressing breast cancer

Rituximab

CD20

B-cell non-Hodgkin's lymphoma

O malizumab

IgE

Add itional l ine of treatment for severe asthma

Therapeutic antibodies
A GENT

EN DOCRINE

ENDOCRINE-PHA R M ACOLOGY

SECTION Ill

305

ENDOCRINE-PHA R M ACOLOGY
Diabetes drugs

Treatment strategy for type l DM -low-sugar diet, insulin replacement.

Treatment strategy for type 2 DM-dietary modification and exercise for weight loss; oral
hypoglycemics and insulin replacement.

DRUG CLASSES

ACTION

Insulin :

Bind insulin receptor (tyrosine

kinase activity).
Liver: t glucose stored as glycogen.
Muscle : t glycogen and protein
synthesis, K+ uptake.
Fat: aids TG storage.

Lispro (rapid-acting)
Aspart (rapid-acting)
Glulisine (rapid-acting)
Regular (short-acting)
NPH (intermediate)
Glargine (long-acting)
Detemir (long-acting)
Biguanides :

M etformin

Sulfonylurea s :

First generation :
Tol butamide
Chlorpropamide
Second generation:
G lyburide
Glimepiride
G l ipizide
G litazones/
thiazolidinediones :

Piogl itazone
Rosiglitazone
a-glucosidase
inhibitors :

Acarbose
M igl itol

CLINICAL USE

Type l DM, type 2 DM,

gestational diabetes, life
threatening hyperkalemia,
and stress-induced
hyperglycemia.

TOXICITIES

Hypoglycemia, very rarely

hypersensitivity reactions.

Exact mechanism is unknown.

gluconeogenesis, t glycolysis,
t peripheral glucose uptake
(insulin sensitivity).

Oral. First-line therapy in

type 2 DM.
Can be used in patients
without islet function.

GI upset; most serious

adverse effect is
lactic acidosis (thus
contraindicated in renal
failure).

Close K+ channel in -cell

membrane, so cell depolarizes
triggering of insulin release via
t Ca 2+ influx.

Stimulate release of
endogenous insulin in type
2 DM. Require some islet
function, so useless in type
l DM.

First generation : disulfiram

like effects.
Second generation :
hypoglycemia.

Used as monotherapy in type

2 DM or combined with
above agents.

Weight gain, edema.

Hepatotoxicity, heart failure.

Used as monotherapy in type

2 DM or in combination
with above agents.

GI disturbances.

-+

t insulin sensitivity in peripheral

tissue. Binds to PPAR-y nuclear
transcription regulator."
Inhibit intestinal brush-border
a-glucosidases.
Delayed sugar hydrolysis
and glucose absorption
postprandial hyperglycemia.
-+

Amylin analogs:

glucagon.

Type l and type 2 DM.

t insulin, glucagon release.

Type 2 DM.

Nausea, vomiting;
pancreatitis.

t insulin, glucagon release.

Type 2 DM.

Mild urinary or respiratory

infections.

Pra m lintide
GLP-1 analogs :

Exenatide
Liraglutide
DPP-4 inhibitors :

Linagliptin
Saxagliptin
Sitagliptin

Hypoglycemia,
nausea, diarrhea.

"Genes activated by PPAR-y regulate fatty acid storage and glucose metabolism. Activation of PPAR-y t insulin sensitivity and
levels of adiponectin.

30 6

SECTION Il l

ENDOCRINE

ENDOC R I NE- P H A R M ACO LOG Y

Propylthiouracil. methimazole
MECHANISM

Block peroxidase, thereby inhibiting organification of iodide and coupling of thyroid hormone
synthesis. Propylthiouracil also blocks 5 '-deiodinase, which peripheral conversion of T4 to T 3 .

CLINICAL USE

Hyperthyroidism.

TOXICITY

Skin rash, agranulocytosis (rare), aplastic anemia, hepatotoxicity (propylthiouracil). Methimazole is

a possible teratogen.

Levothyroxine. triiodothyronine
MECHANISM

Thyroxine replacement.

CLINICAL USE

Hypothyroidism, myxedema.

TOXICITY

Tachycardia, heat intolerance, tremors, arrhythmias.

Hypothalamic/pituitary d rugs
DRUG

CLINICAL USE

GH

GH deficiency, Turner syndrome.

Somatostatin
(octreotide)

Acromegaly, carcinoid, gastrinoma, glucagonoma, esophageal varices.

Oxytocin

Stimulates labor, uterine contractions, milk let-down; controls uterine hemorrhage.

ADH (desmopressin)

Pituitary (central, not nephrogenic) DI.

Demeclocycline
MECHANISM

ADH antagonist (member of the tetracycline family).

CLINICAL USE

SIADH.

TOXICITY

Nephrogenic DI, photosensitivity, abnormalities of bone and teeth.

Glucocorticoids
MECHANISM

Hydrocortisone, prednisone, triamcinolone, dexamethasone, beclomethasone.

the production of leukotrienes and prostaglandins by inhibiting phospholipase A 2 and expression

of COX-2.

CliNICAl USE

Addison's disease, inflammation, immune suppression, asthma.

TOXICITY

Iatrogenic Cushing's syndrome -buffalo hump, moon facies, truncal obesity, muscle wasting, thin
skin, easy bruisability, osteoporosis, adrenocortical atrophy, peptic ulcers, diabetes (if chronic).
Adrenal insufficiency when drug stopped abruptly after chronic use.

CAR D I O VASC U LAR

C A R D I OVA S C U LAR- P H A R M A C O LOGY

SE C T I O N I l l

2 79

C A R D I OVAS C U L A R- P H A R M A COLOGY
Antihypertensive therapy
Essential hypertension

Diuretics, ACE inh ibitors, angiotensin I I

receptor blockers (ARBs) , calcium channel
blockers.

See the Ren a l chapter for more deta ils about

diuretics and ACE inh ibitors/ARBs.

CHF

Diuretics, AC E inh ibitors/ARBs, -blockers

(compensated C H F ) , K+ -sparing d iuretics.

-blockers must be used cautiously in

decompensated C H F, and are contraindicated
in cardiogen ic shock.

Diabetes mellitus

AC E inhibitors/ARBs, calcium channel

blockers, d iuretics, -blockers, a-blockers.

AC E i n h ibitors are protective aga inst diabetic

nephropathy. See the Pharmacology chapter
for more details about a-blockers.

Calcium channel
blockers

Nifedipine, verapamil, diltiazem, amlodipine.

MECHAN ISM

Block voltage-dependent L-type calcium chan nel s of card iac and smooth muscle and thereby
reduce muscle contractil ity.
Vascular smooth muscle -amlodipine = nifed ipine > d iltiazem > verapamil.
Heart-verapamil > diltiazem > amlodipine = nifedipine (verapam il = ventricle) .

CliNICAL USE

Hypertension, angina, arrhythm ias (not nifed ipine) , Prinzmeta l 's angina, Raynaud's.

TOXICITY

Cardiac depression, AV block, peripheral edema, flush ing, d i zziness, and constipation.

Hydralazine
MECHAN ISM

t cGMP

-+

smooth muscle relaxation. Vasodilates arterioles > veins; afterload reduction .

CliNICAL USE

Severe hypertension, C H F. First-l ine therapy for hypertension in pregnancy, with methyldopa.
Frequently coadmin istered with a -blocker to prevent reflex tachycardia.

TOXICITY

Compensatory tachycardia (contra ind icated in angina/CAD ) , fluid retention, nausea, headache,
angina. Lupus-like syndrome.

Malignant
hypertension treatment

Commonly used d rugs include n itroprusside, n icard ipine, clevidipine, labetalol , and fenoldopam.

Nitroprusside

Short acting; t cGMP via direct release of NO. Can cause cyanide toxicity (releases cyanide) .

Fenoldopam

Dopamine D 1 receptor agon ist- coronary, peripheral, renal, and splanchnic vasodilation. BP and
t natriuresis.

280

SECT I O N I l l

CAR D I OVASC U L A R

C A R D I OVASC U L A R- P H A R M A COLOGY

Nitroglycerin, isosorbide dinitrate

MECHANISM

Vasodilate by releasing n itric oxide in smooth muscle, causing t i n cGM P and smooth muscle
rel axation . Dilate veins >> arteries. ! preload.

CLIN ICAL USE

Angina, pulmon ary edema.

TOXICITY

Reflex tachycardia, hypotension , Hushing, headache, " Monday disease" i n industrial exposur e :
development o f tolerance for the vasod ilating action during the work week a n d loss o f tolerance
over the weekend results in tachycardia, dizziness, and headache upon reexposure .

Antianginal therapy

COMPONENT

Goal- reduction o f myocard ial 02 consumption (MV02 ) b y decreasing 1 or more of the

determinants of MV0 2 : end-diastol ic volume, blood pressure, heart rate, contractility, ej ection
time.
N ITRATES (AFFECT PRELOAD)

End-diastolic volume

-BLOCKERS (AFFECT AFTERLOAD)

N ITRATES + -BLOCKERS

No effect or !

Blood pressure
Contractility

t (reflex response)

Heart rate

t (reflex response)

Little/no effect

Ejection time

Little/no effect

MV02

!!

Calcium channel blockers - n ifedipine is similar to nitrates in effect; verapamil is similar to -blockers i n effect.
Pindolol and acebutolol - partial -agonists contraindicated in angina.

CARD I O VASC U LAR

C A R D I OV ASC U L A R - P H A R M A C O LOGY

SECT I O N I l l

28 1

Lipid-lowering agents
EFFECT ON HDl
EFFECT ON lDl
"BAD CHOlESTEROL" "GOOD CHOlESTEROl'

DRUG

EFFECT ON
TRIGlYCERIDE$

HMG -CoA reductase

inhibitors (lovastatin,
pravastatin,
simvastatin,
atorvastatin,
rosuvastatin)
Niacin (vitamin

83)

Bile acid resins

(cholestyramine,

tt

Slightly t

Slightly t

colestipol,
colesevelam)

Cholesterol absorption
blockers (ezetimibe)

Fibrates (gemfibrozil,
clofibrate,
bezafibrate,
fenofibrate)

MECHANISMS O F ACTION

SIDE EFFECTS/PROBlEMS

I n h ibit conversion
of H MG-CoA
to mevalonate, a
cholesterol precursor

Hepatotoxicity
(t LFTs),
rhabdomyolysis

I n h ibits l ipolysi s
in ad ipose tissue ;
reduces hepatic
VLDL secretion i nto
circulation

Reel , flushed face,

which is by aspirin
or long-term use
Hyperglycemia
(acanthosis
n i gricans)
Hyperuricemia
(exacerbates gout)

Prevent i ntestinal
reabsorption of bile
acids; l iver must use
cholesterol to make
more

Patients hate it- tastes

bad and causes
GI discomfort,
absorption of fatsoluble vitam ins
Cholesterol gal l stones

Prevent cholesterol
reabsorption at small
i ntesti n e brush border

Rare t LFTs, diarrhea

Upregulate LPL
t TG clearance

Myositis,
hepatotoxicity
(t LFTs), cholesterol
gallstones

--+

Endothelial
cells

B lood

Gut

Hepatocytes

Ac-CoA

Ezetl mlbe

HMG

oA

HMG-CoA

:J

reductase

bitors

I
/Li)L\

T"'
]'"'
Nla::..

-r

L[

Reslns

""'

e
@

rr-

Gemfibrozil

,------2-.,

/}'

._/

Lipid
oxidation

(Adapted, with permission, from Katzung B G , Trevor AJ. USMLE Rood Map: Pharmacology, I st e d . N e w York: McGraw-Hill, 2003 : 56.)

28 2

SECTI O N I l l

Cardiac glycosides
MECHAN ISM

CAR D I OVASC U LAR

D igoxin-7 5 % bioavailability, 20-40% protein bound, t 1 12

TOXICITY

ANTIDOTE

40 hours , u rinary excretion .

D i rect inh ibition of Na+fK+ ATPase leads to indirect inhibition of Na+fCa2 + exchanger/antiport.
t [Ca 2 +] i positive inotropy. Stimulates vagus nerve ! H R .
-+

CLIN ICAL USE

C A R D I OVASC U L A R - P H A R M A COLOGY

-+

C H F ( t contractil ity) ; atrial fibrillation ( ! conduction a t AV node a n d depression of SA node) .

Chol i nergi c - nausea, vom iting, diarrhea, blurry yel low vision (th ink Van Gogh) .
E C G - t PR, ! QT, ST scooping, T-wave inversion, arrhythm ia, AV block.
Can lead to hyperkalem ia, a poor prognostic indicator.
Factors predisposing to toxicity- renal fai l ur e ( ! excretion), hypokalemia (permissive for digoxin
binding at K+ -binding site on Na+fK+ ATPase), quinidine ( ! digoxin clearance ; d isplaces d igoxin
from tissue-binding sites) .
Slowly normalize K+, l i docaine, cardiac pacer, anti-digoxin Fab fragments, Mg 2 +.

CAR D I O VASC U LAR

Antiarrhythmics
Na+ channel blockers
(class I)

C A R D I OVAS C U L A R- P H A R M A COLOGY

SECT I O N I l l

283

Local anesthetics. Slow or block ( ! ) conduction (especially in depolarized cells). ! slope of phase 0
depolarization and t threshold for firing in abnormal pacemaker cells. Are state dependent
(selectively depress tissue that is frequently depolarized [e.g., tachycardia] ) .
Hyperkalemia causes t toxicity for all class I d rugs.

Class lA

Qu i n idine, Procainam ide, Disopyramide.

t AP duration, t effective refractory period
( ERP) , t QT interval. Affect both atrial and
ventricular arrhythmias, especially reentrant
and ectopic supraventricular and ventricular
tachycard ia.
Toxicity: quinidine (ci nchon ism- headache,
tinn itus) ; procainam ide (reversible SLE-l ike
syndrome) ; d isopyram ide (heart failur e ) ;
thrombocytopen i a ; torsades d e pointes d u e to
t QT interval.

"The Queen Proclai ms D iso's pyramid ."

Class IB

Lidocaine, Mexiletine, Tocainide.

! AP duration . Preferentially affect ischem ic or
depolarized Purkinje and ventricular tissue.
Usefu l i n acute ventricular arrhythmias
(especially post-MI) and in digital is-induced
arrhythmias.
Toxicity: local anesthetic. C S stimulation /
depression, cardiovascular depression .

'T cl

Class IC

Flecai nide, propafenone.

No effect on AP duration. Useful in ventricular
tachycardias that progress to VF and in
intractable SVT. Usually used only as last
resort i n refractory tachyarrhythm ias. For
patients without structural abnormalities.
Toxicity: proarrhythm ic, especially post-MI
(contraind icated) . Significantly prolongs
refractory period in AV node.

IC is C ontra ind icated in structural heart d isease

and post-M I .

Buy Lidy's Mexican Tacos."

Phenytoin can also fal l into the I B category.
IB is B est post- M I .

All class I drugs

O mV
Phase 0
I Na
Phase 3 ( I K)
-85 mV

Phase 4

(Adapted, with permission, from Katzung BG, Trevor AJ. Pharmacology: Examination & Board Review, 5th ed. Stamford, G: Appleton & Lange, 1 99 8 : 1 1 8.)

284

SECT I O N I l l

Antiarrhythmics

CARD I O VASC U LAR

C A R D I OVAS C U LA R -PH A R M A COLO G Y

Metoprolol , propranolol , esmolol , atenolol , timolol.

-blockers (class I I)
MECHANISM

Decreases SA and AV nodal activity by ! cAM P, ! Ca 2 + currents. Suppress abnormal pacemakers by

! slope of phase 4.
AV node particularly sensitive - t PR interval . Esmolol very short acting.

CliN ICAl USE

Ventricular tachycard ia, SVT, slowing ventricular rate during atrial fibrillation and atrial flutter.

TOXICITY

I mpotence, exacerbation of asthma, cardiovascular effects (bradycard ia, AV block, C H F) , CNS

effects (sedation, sleep alterations) . May mask the signs of hypoglycem i a .
Metoprolol c a n cause dysl ipidemia. Treat overdose with glucagon . Propranolol c a n exacerbate
vasospasm i n Prinzmetal 's angina.

Antiarrhythmics
K+ channel blockers
(class I l l)
MECHANISM

TOXICITY

Am iodarone, Ibutil ide, Dofetil ide, Sotalol .

"AIDS."

t AP duration, t ERP. Used when other

antiarrhyth m ics fai l . t QT interval.
Sotalol - torsades de pointes, excessive block;
ibutilide - torsades; am iodarone -pulmonary
fibrosis, hepatotoxicity, hypothyroidism/
hyperthyroidism (am iodarone is 40% iodine by
weight) , corneal deposits, skin deposits (blue/
gray) resulting in photodermatitis, neurologic
effects, constipation, cardiovascular effects
(bradycard ia, heart block, C H F ) .
Amiodarone h a s class I , I I , I I I , a n d IV effects
because it alters the lipid membrane.

Remember to check PFTs, LFTs, and TFTs

when using am iodarone.

C lass I l l act ion

(Adapted, with permission, from Katzung BG, Trevor AJ. Pharmacology: Examination & Boord Review, 5th ed. Stamford, a: Appleton & Lange, 1 99 8 : 1 20.)

Antiarrhythmics

Verapam i l , diltiazem.

Cal+ channel blockers

(class IV)
MECHANISM
TOXICITY

! conduction velocity, t ERP, t PR interval. Used in prevention of nodal arrhythmias (e.g., SVT) .
Constipation , flushing, edema, CV effects ( C H F, AV block, sinus node depression ) .

Other antiarrhythmics
Adenosine

t K + out o f cells --+ hyperpolarizing t h e cell + !

lea D r u g o f choice in d iagnosing/abol ishing

supraventricular tachycard ia. Very short acting ( 1 5 sec) . Toxicity includes flushing, hypotension,
chest pai n . Effects blocked by theophylline and caffeine.

Effective in torsades de pointes and digoxin toxicity.

53 8

SECTION Ill

R EPRODUCTIVE-PHARMACOLOGY

REPRODUCTIVE

REPRODUCTIVE-PHARMACOLOGY
Control of reproductive

Hypothalamus

hormones

Hypothalamus

$
H

Anterior

---0- GnRH antagonists

---0- 0ral
contraceptives,
danazol

pituitary

-&-- GnR H a ntagonists

+--G)- GnRH agonists

Ovary

GnRH agonists
Pituitary
gonadotrophs

Testis

Progesterone
(luteal phase)
'-7------.r'

------e-- Ketoconazole,

danazol

A ndrostenedione

Estrone -- Estriol

'

Expression in estrogen-responsive cells

Control of female hormones

+-0--- Finasteride

Flutamide,
cyproterone,
spironolactone

Androgen-receptor complex

:.---=--cB- SEAMs
Estrogen
response
element

Sareductase

Dihydrotestostero ne

Fulvestrant

m {/\\ rf\
, W W

Ketoconazole,
spironolactone

Testosterone

Testosterone

Estradiol

l --0-

Androgen
response
element

Expression of appropriate
genes in androge n-responsive cells

Control of androgen secretion

(Adapted, with permission, from Katzung BG. Basic & Clinical

(Adapted, with permission, from Katzung BG. Basic & Clinical

Pharmacology, I Oth ed. New York: McGraw,Hill, 2006, Fig. 40-5.)

Pharmacology, I Oth ed. New York: McGraw-Hill, 2006, Fig. 40-6.)

REPRODUCTIVE

REPRODUCTIVE-PHARMACOLOGY

SECTION Ill

53 9

Leuprolide
MECHANISM

GnRH analog with agon ist properties

when used i n pulsatile fashion ; antagon ist
properties when used in continuous fashion
(downregulates GnRH receptor in pituitary
F S H /L H ) .

Leuprol ide can be used i n lieu of G n R H .

....

CliNICAl USE

Infertil ity (pulsatile) , prostate cancer

(continuous- use with flutamide), uterine
fibroids (continuous), precocious puberty
(continuous) .

TOXICITY

Antiandrogen, nausea, vom iting.

Testosterone, methyltestosterone
MECHANISM
CliNICAl USE

TOXICITY

Antiandrogens

Agon ist at androgen receptors.

Treats hypogonadism and promotes development of zo sex characteristics ; stimulation of anabol ism
to promote recovery after burn or injur y.
Causes masculinization in females; reduces intratesticular testosterone in males by inh ibiting
release of LH (via negative feedback) , leading to gonadal atrophy. Premature closure of epiphyseal
plates. t LDL, H DL .

Testosterone

) a-reductase

DHT (more potent) .

Finasteride

A 5 a-reductase inh ibitor ( ! conversion of

testosterone to DHT). Useful in BPH . Also
promotes hair growth - used to treat male
pattern baldness.

Flutamide

A nonsteroidal competitive inh ibitor of

androgens at the testosterone receptor. Used in
prostate carcinoma.

Ketoconazole

I n h ibits steroid synthesis (inhibits

1 7, 20-desmolase ) .

Spironolactone

I n h ibits steroid binding.

To prevent male-pattern hair loss, give a drug

that will encourage female breast growth .

Ketoconazole and spironolactone are used in

the treatment of polycystic ovarian syndrome
to prevent h i rsutism. B oth h ave side effects of
gynecomastia and amenorrhea.

Estrogens (ethinyl estradiol, DES, mestranol)

MECHANISM

Bind estrogen receptors.

CliNICAl USE

Hypogonadism or ovarian failure, menstru al abnormal ities, H RT in postmenopausal women ; use

in men with androgen-dependent prostate cancer.

TOXICITY

t risk of endometrial cancer, bleeding in postmenopausal women, clear cell adenocarcinoma of

vagina in females exposed to DES in utero, t risk of thrombi . Contraind ications - E R-positive
breast cancer, history of DVTs.

540

SECTION Ill

REPRODUCTIVE

REPRODUCTIVE-PHARMACOLOGY

Selective estrogen receptor modulators-SERMs

Clomiphene

Partial agonist at estrogen receptors in hypothalamus. Prevents normal feedback inh ibition and
t release of LH and FSH from pituitary, which stimulates ovulation. Used to treat infertil ity and
polycystic ovarian syndrome. May cause hot flashes, ovarian enlargement, multiple simultaneous
pregnancies, and visual disturbances.

Tamoxifen

Antagonist on breast tissue ; used to treat and prevent recurrence of E R-positive breast cancer.

Raloxifene

Agon ist on bone ; reduces resorption of bone ; used to treat osteoporosis.

Hormone replacement
therapy

Anastrozole/

Used for rel ief or prevention of menopausal symptoms (e.g., hot flashes, vaginal atrophy) and
osteoporosis (t estrogen, osteoclast activity) .
Unopposed estrogen replacement therapy (ERT) t the risk of endometrial cancer, so progesterone
is added. Possible t CV risk.

Aromatase i n hibitors used in postmenopausal women with breast cancer.

exemestane

Progestins
MECHANISM
CLINICAL USE

Bind progesterone receptors, reduce growth and t vasculari zation of endometrium.

Used in oral contraceptives and in the treatment of endometrial cancer and abnormal uterine
bleeding.

Mifepristone (RU-486)
MECHANISM

Competitive inh ibitor of progestins at progesterone receptors.

CLINICAl USE

Termination of pregnancy. Administered with m isoprostol ( PGE 1 ) .

TOXICITY

Heavy bleed ing, G I effects (nausea, vom iting, anorexia) , abdom inal pa i n .

Oral contraception
(synthetic progestins.
estrogen)

Estrogen a n d progestins inhibit LH/FSH a n d thus prevent estrogen surge. o estrogen surge no
LH surge
no ovulation.
Progestins cause th ickening of the cervical mucus, thereby l i m iting access of sperm to uterus.
Progestins also inhibit endometrial prol iferation , thus making endometrium less suitable for the
implantation of an embryo.
Contra ind ications- smokers > 35 years of age (t risk of cardiovascular events ) , patients with h istory
of thromboembol ism and stroke or history of estrogen-dependent tumor.
-+

-+

Terbutaline

Tagonist that relaxes the uteru s ; reduces premature uterine contractions.

Tamsulosin

a 1 -antagonist used to treat BPH by inhibiting smooth muscle contraction. Selective for a 1A,D
receptors (found on prostate) vs. vascular a 1 B receptors.

REPRODUCTIVE

REPRODUCTIV E-PHARMACOLOGY

SECTION Ill

Sildenafil, vardenafil
MECHANISM

Inh ibit phosphodiesterase 5, causing t cGM P,

smooth muscle relaxation in the corpus
cavernosu m , t blood flow, and penile erection .

CLINICAL USE

Treatment of erectile dysfunction .

TOXICITY

Headache, flushing, dyspepsia, impaired blue

green color vision. Risk of l i fe-threatening
hypotension i n patients taking nitrates.

Sildenafil and vardenafil fill the pen is.

"Hot and sweaty," but then Headache,

Heartburn, Hypotension .

Danazol
MECHANISM

Synthetic androgen that acts as partial agon ist at androgen receptors.

CLINICAL USE

Endometriosis and hereditary angioedema.

TOXICITY

Weight gai n , edema, acne, hirsuti sm, masculinization, ! HDL levels, hepatotoxicity.

54 1

RENAL

RENAL-PHARM ACOLOGY

SECTION Ill

RENAL-PHARM ACOLOGY

Diuretics: site of adion

Acetazolam ide
D i stal convoluted

Th iazides

ca 2 +
(+ PTH )

tubule

Potassi u m-spa r i n g
d i u retics

NaCI

Cortex

(+aldoste ron e)

Outer med u l l a

M a n n itol

t
I n n e r med u l l a

ADH
antagon i sts
C o l l ecti n g
d uct

(Adapted, with permission, from Katzung BG. Basic and Clinical Pharmacology, 7th ed. Stamford, G: Appleton & Lange, 1 997: 243.)

499

500

SECTION Ill

R ENAL

RENAL-PHARM ACOLOGY

Mannitol
MECHANISM

Osmotic diuretic, t tubular fluid osmolarity,

producing t urine flow, * intracranial/
intraocular pressure.

CliNICAl USE

Drug overdose, elevated intracranial/intraocular

pressure.

TOXICITY

Pulmonary edema, dehydration.

Contraindicated in anuria, CHF.

Acetazolamide
MECHANISM

Carbonic anhydrase inhibitor. Causes self

limited NaHC0 3 diuresis and reduction in
total-body HC0 3 - stores.

CliNICA l USE

Glaucoma, urinary alkalinization, metabolic

alkalosis, altitude sickness, pseudotumor
cerebri.

TOXICITY

Hyperchloremic metabolic acidosis,

paresthesias, NH 3 toxicity, sulfa allergy.

"ACID"azolamide causes ACIDosis.

Loop diuretics
Furosemide
MECHANISM

Sulfonamide loop diuretic. Inhibits cotransport

system (Na+, K+, 2 CJ-) of thick ascending
limb of loop of Henle. Abolishes hypertonicity
of medulla, preventing concentration of urine.
Stimulates PGE release (vasodilatory effect
on afferent arteriole); inhibited by NSAIDs.
t Ca2 + excretion. Loops Lose calcium.

CliNICAl USE

Edematous states (CHF, cirrhosis, nephrotic

syndrome, pulmonary edema), hypertension,
hypercalcemia.

TOXICITY

Ototoxicity, Hypokalemia, Dehydration, Allergy

(sulfa), Nephritis (interstitial), Gout.

Ethacrynic acid
MECHANISM

Phenoxyacetic acid derivative (not a

sulfonamide). Essentially same action as
furosemide.

CliNICAl USE

Diuresis in patients allergic to sulfa drugs.

TOXICITY

Similar to furosemide; can cause

hyperuricemia; never use to treat gout.

OH DANG!

RENAL

RENAL - PHARM ACOLOGY

SECTION Ill

50 1

Hydrochlorothiazide
MECHANISM

Thiazide diuretic. Inhibits aCl reabsorption in

early distal tubule, reducing diluting capacity
of the nephron. ! Ca2+ excretion.

CLINICAL USE

Hypertension, CHF, idiopathic hypercalciuria,

nephrogenic diabetes insipidus.

TOXICITY

Hypokalemic metabolic alkalosis,

hyponatremia, hyperGlycemia,
hyperLipidemia, hyperUricemia, and
hyperCalcemia. Sulfa allergy.

HyperGLUC.

Spironolactone and eplerenone; Triamterene,

and Amiloride.

T he K+ STAys.

K+sparing diuretics
MECHANISM

Spironolactone and eplerenone are competitive

aldosterone receptor antagonists in the cortical
collecting tubule. Triamterene and amiloride
act at the same part of the tubule by blocking
Na+ channels in the CCT.

CLINICAL USE

Hyperaldosteronism, K+ depletion, CHF.

TOXICITY

Hyperkalemia (can lead to arrhythmias),

endocrine effects with spironolactone (e.g.,
gynecomastia, antiandrogen effects).

Diuretics: electrolyte changes

Urine NaCI

t (all diuretics). Serum NaCl may ! as a result.

Urine K+

t (all except K+ -sparing diuretics). Serum K+ may ! as a result.

Blood pH

! (acidemia) : carbonic anhydrase inhibitors- ! HC0 3 - reabsorption. K+ sparing-aldosterone

blockade prevents K+ secretion and H+ secretion. Additionally, hyperkalemia leads to K+ entering
all cells (via H+fK+ exchanger) in exchange for J-I+ exiting cells.
t (alkalemia) : loop diuretics and thiazides cause alkalemia through several mechanisms:
Volume contraction -+ t AT II .... t Na+fJ-I+ exchange in proximal tubule
t HC0 3 reabsorption ("contraction alkalosis")
K+ loss leads to K+ exiting all cells (via J-I+fK+ exchanger) in exchange for f-I+ entering cells
In low K+ state, f-I+ (rather than K+) is exchanged for Na+ in cortical collecting tubule, leading
to alkalosis and "paradoxical aciduria"
t with loop diuretics: ! paracellular Ca2+ reabsorption hypocalcemia.
! with thiazides : Enhanced paracellular Ca2+ reabsorption in proximal tubule and loop of Henle.
....

Urine Cal+

-+

502

SECTION Ill

ACE inhibitors
MECHANISM

RENAL

RENAL-PHARM ACOLOGY

Captopril, enalapril, lisinopril.

Inhibit angiotensin-converting enzyme (ACE)
-+ angiotensin II GF R by preventing
constriction of efferent arterioles. Levels
of renin t as a result of loss of feedback
inhibition. Inhibition of ACE also prevents
inactivation of bradykinin, a potent vasodilator.
-

CLINICAL USE

Hypertension, CHF, proteinuria, diabetic renal

disease. Prevent unfavorable heart remodeling
as a result of chronic hypertension.

TOXICITY

Cough, Angioedema, Teratogen (fetal renal

malformations), Creatinine increase U GF R),
Hyperkalemia, and Hypotension. Avoid in
bilateral renal artery stenosis, because ACE
inhibitors will further GF R -+ renal failure.

Angiotensin II receptor blockers (-sartans) have

effects similar to ACE inhibitors but do not
t bradykinin -+ no cough or angioedema.

Captopril's CATCHH.

47 2

SECTION I l l

Alcoholism

Wernicke- Korsakoff
syn d rome

Mallory-Weiss
synd rome

Delirium tremens (DTs)

PSYCHI ATRY

PSYCHIATRY-PHAR MACOLOGY

Physiologic tolerance and dependence with symptoms of withdrawal (tremor, tachycard ia,
hypertension, malaise, nausea, DTs) when intake is interrupted.
Complication s : alcohol ic cirrhosis, hepatitis, pancreatitis, peripheral neuropathy, testicular atrophy.
Treatment: disulfiram (to condition the patient to abstai n from alcohol use), supportive care.
Alcoholics Anonymous and other peer support groups are helpful i n sustaining abstinence.
Caused by th iamine deficiency. Triad of confusion, ophthal moplegia, and ataxia (Wernicke's
encephalopathy) . May progress to irreversible memory loss, confabulation, personal ity change
( Korsakoff's psychosis) . Associated with periventricular hemorrhage/necrosis of mamm illary
bodies. Treatment: IV vitamin B1 (thiamine).
Longitudinal lacerations at the gastroesophageal junction caused by excessive vom iting. Often
presents with hematemesis. Associated with pain (vs. esophageal varices).

Life-threatening alcohol withdrawal syndrome that peaks 2-5 clays after last drink.
Symptoms in order of appearance : autonom ic system hyperactivity (tachycardia, tremors, anx iety,
seizures), psychotic symptoms (halluci nations, delusions), confusion .
Treatment: benzodiazepines.

PSYCHIATRY-PHAR MACOLOGY

Treatment for selected

psychiatric condit ions

CNS

stimulants

PSYCHIATRIC CONDI TION

PREFERRED DRUGS

Alcoho l withdr awal

Benzocliazepines

Anxiety

SSRis, SNRis, buspirone

ADHD

Methylphen idate, ampheta m i nes

Bipolar d isorder

"Mood stabilizers" (e.g., l ithium, valproic acid,

carbamazepine), atypical antipsychotics

Bulimia

SSRis

Depression

SSRis, SNRis, TCAs, buspi rone, m irtazapine

(especially with insomnia)

Obsessive-compulsive d isorder

SSRis, clomipra m i ne

Panic disorder

SSRis, venlafaxine, benzodiazepines

PTSD

SSRis

Sch izophrenia

Antipsychotics

Social phobias

SSRis

Tourette's syndrome

Antipsychotics (e.g., haloperidol, rispericlone)

-------

Methylphenidate, dextroamphetamine, methamphetamine.

MECHANISM

t catecholamines at the synaptic cleft, especially NE and dopamine.

CliNICAL USE

ADHD, narcolepsy, appetite control.

 PSYCHIATRY-PHAR MACOLOGY

PSYCHIATRY

Antipsychotics
(neuroleptics)

All typical antipsychotics block dopamine D 2

receptors ( t [cAMP]).

C LINICAL USE

Schizophren ia (primarily positive symptoms),

psychosis, acute man ia, Tourette's syndrome.

OTHER TOXICITIES

H ighly lipid soluble and stored in body fat; thus,

very slow to be removed from body.
Extrapyram idal system (EPS) side effects (e.g.,
clyski nesias).
Endocrine side effects (e.g., dopamine receptor
antagonism .... hyperprolactinem ia ....
galactorrhea).
Side effects arising from blocking muscarinic
(dry mouth, constipation), a 1 (hypotension),
and h ista m i ne (sedation) receptors.
N e u roleptic m a l ignant syndrome ( N M S )

rigid ity, myoglobinuria, autonomic instability,

hyperpyrexia. Treatment: clantrolene, 0 2
agonists (e.g., bromocriptine).
stereotypic oral
facial movements as a result of long-term
antipsychotic use. Often irreversible.

Ta rdive dysk i nesia

Atypical antipsychotics

4 73

Haloperidol, trifluoperazine, fluphenazine, thioriclazine, chlorpromazine (haloperidol + "-azines").

MECHANISM

TOXICITY

SECTION I l l

Olanzapine, clozapine, quetiapine ris per icl o ne,

aripiprazole, ziprasiclone.
,

MECHANISM

Not completely u nderstood. Varied effects on

5-HT 2 , dopami ne, and a- and H 1 -receptors.

C LINICAL USE

Sch izophrenia- both positive and negative

symptoms. Also used for bipolar disorder,
OCD, anxiety disorder, depression, man ia,
Tourette's syndrome.

TOXICITY

Fewer extrapyram idal and antichol inergic

side effects than trad itional antipsychotics.
Olanzapine/clozapine may cause significant
weight gai n . Clozapine may cause
agranulocytosis (requ ires weekly WBC
mon itoring) and seizu re. Ziprasiclone may
prolong the QT i nterval.

potency: Trifluoperazine, Fluphenazine,

Haloperidol (Try to Fly H igh) -neurologic
side effects (extrapyram idal symptoms).

High

Low potency: Chlorpromazine, Thioridazine

(Cheating Thieves are low) -non-neurologic
side effects (antichol inergic, antihistami ne,
and a 1 -blockacle effects).
Chlorpromazine- C orneal deposits ;
Th ioriclazine - reT inal deposits ; halopericl o l
N M S, tard ive dyskinesia.
Evolution of EPS side effects :
4 hr acute dystonia (muscle spasm, stiffness,
oculogyric crisis)
4 clay akath isia (restlessness)
4 wk bradykinesia (parki nsonism)
4 mo tard ive dyskinesia
For N M S, think FEVER:
Fever
Encephalopathy
Vitals unstable
Elevated enzymes
Rigidity of muscles

It's atypical for old closets to quietly risper from

A to Z .

Must watch clozapine clozely !

47 4

SECTION I l l

P SYCHI ATRY

PSYCHIATRY-PHAR MACOLOGY

Lithium
MECHANISM

Not establ ished ; possibly related to inh ibition of

phosphoinositol cascade.

C LINICAl USE

Mood stabil izer for bipolar disorder; blocks

rel apse and acute manic events . Also SIAD H .

TOXICITY

Tremor, sedation, edema, heart block,

hypothyroidism, polyuria (ADH antagon ist
causing nephrogenic diabetes insipidus),
teratogenesis. Fetal cardiac defects include
Ebstein anomaly and malformation of the
great vessels. Narrow therapeutic window
requires close monitoring of serum levels.
Almost exclusively excreted by the kidneys ;
most is reabsorbed at the proximal convoluted
tubules fol lowing Na+ reabsorption.

LMNOP:
Lith ium side effects
Movement (tremor)
Neph rogenic diabetes i nsipidus
HypOthyroid ism
Pregnancy problems

Buspirone
MECHANISM

Stimulates 5-HT 1 A receptors.

C LINICAl USE

General ized anxiety disorder. Does not cause

sedation, addiction, or tolerance. Takes 1-2
weeks to take effect. Does not interact with
alcohol (vs. barbiturates, benzodiazepines).

I 'm always anxious if the bus will be on ti me, so

I take buspirone.

Antidepressants
Norad renergic
neuron

Serotonergic
n e u ron

receptor

receptor

Postsynaptic
neuron

(Adapted, with permission, from Katzung B G , Trevor A J . USMLE Road Map: Pharmacology, 2nd ed. N e w York: McGraw-Hill, 2006: Fig. 5-7.)

PSYCHIATRY

PSYCHIATRY-PHAR MACOLOGY

SECTION Il l

47 5

Fluoxetine, paroxetine, sertraline, citalopram.

Flashbacks paralyze senior citizens .

MECHANISM

Serotonin-specific reuptake inh ibitors.

C LINICAL USE

Depression, general ized anxiety disorder, panic

disorder, O C D, bulim ia, social phobias,
PTSD.

It normally takes 4-8 weeks for antidepressants

to have an effect.

TOXICITY

Fewer than TCAs . CI distress, sexual

dysfunction (anorgasm ia and ! l ibido) .
Serotonin syndrome with any drug that t
seroton i n (e.g., MAO inhibitors, SNRis,
TCAs) - hypertherm ia, confusion, myoclonus,
cardiovascular collapse, Hushing, di arrhea,
seizures. Treatment: cyproheptadine (5 -HT 2
receptor antagon ist) .

SSRis

SNRis

Venlafaxine, cluloxetine.

MECHANISM

I n h ibit seroton i n and NE reuptake.

C LINICAL USE

Depression. Venlafaxine is also used in general ized anxiety and panic d isorders ; cluloxetine is also
ind icated for diabetic peripheral neuropathy. Duloxetine has greater effect on N E .

TOXICI TY

Tricyclic
antidepressants

t B P most common ; also stimulant effects, sedation, nausea.

Am itriptyl i ne, nortriptyl ine, im ipramine, desipramine, clomipra m ine, cloxepin, amoxapine (all
TCAs end i n -iptyl ine or -ipramine except cloxepin and amoxapine ) .

MECHANISM

Block reuptake o f NE a n d seroton in.

C LINICAL USE

Major depression, becl wetting (im ipramine), OCD (clomipram ine), fibromyalgia.

TOXICI TY

Sedation, a 1 -blocki ng effects including postural hypotension, and atropi ne-like (antichol inergic)
side effects (tachycardia, urinary retention, dry mouth ) . 3 TCAs (am itriptyl ine) have more
antichol i nergic effects than 2 TCAs (nortriptyl ine) have. Desipramine is less sedating and has
higher seizure threshold.
Tri-C 's : C onvulsions, Coma, Carcliotoxicity (arrhythm ias); also respiratory depression,
hyperpyrexia. Confusion and hallucinations in elderly clue to anticholinergic side effects (use
nortriptyl ine) . Treatment: NaHC03 for card iovascular toxicity.

Monoamine oxidase
(MAO) inhibitors

Tranylcyprom ine, Phenel zine, Isocarboxazicl, Selegi line (selective MAO-B inh ibitor) .
(MAO Takes Pride In Shanghai) .

MECHANISM

Nonselective MAO inh ibition t levels of amine neurotransm itters (NE, seroton in, dopamine) .

C LINICAL USE

Atypical depression, anxiety, hypochondriasis.

TOXICITY

Hypertensive crisis (most notably with ingestion of tyram i ne, which is found i n many foods such
as wine and cheese); CNS stimulation . Contraind icated with SSRis, TCAs, St. John's Wort,
meperidine, and clextromethorphan (to prevent seroton i n syndrome) .

47 6

SECTION Ill

PSYCHI ATRY

PSYCHIATRY-PHAR MACOLOGY

Atypical antidepressants
B upropion

Also used for smoking cessation . t N E and

dopa m i ne via unknown mechanism. Toxicity:
stimulant effects (tachycardia, insomnia),
headache, seizure in bulimic patients. No
sexual side effects.

M i rtazapine

a2-antagon ist ( t release of N E and seroton in)

and potent 5-HT2 and 5-HT 3 receptor
antagonist. Toxicity: sedation (wh ich may be
desirable in depressed patients with insom nia),
t appetite, weight ga in (wh ich may be
desirable i n elderly or anorexic patients), dry
mouth .

Maprotiline

Blocks N E reuptake. Toxicity: sedation,

orthostatic hypotension.

Trazodone

Primarily inh ibits seroton in reuptake. Used

primarily for insomn ia, as high doses are
needed for antidepressant effects. Toxicity:
sedation, nausea, priapism, postural
hypotension.

Called trazobone due to male-specific side

effects.

N E U ROLOGY

N E U ROLOGY- PHA RMACOLOGY

SECTI O N I l l

44 9

NE U ROLOGY- PHA RMACOLOGY

Glaucoma drugs

l intraocular pressure via l amount of aqueous humor ( i n h ibit synthesis/secretion or increase

drainage ) .
DRUG

MECHANISM

SIDE EFFECTS

a-agonists

Epinephrine
Brimonidine ()

l aqueous humor synthesis via vasoconstriction

l aqueous humor synthesis

Mydriasis; do not use i n closed-angle glaucoma

Blurry vision, ocular hyperem ia, foreign body
sensation , ocular allergic reactions, ocular
pruritus

l aqueous humor synthesis

No pupillary or vision changes

l aqueous humor synthesis via inh ibition of

No pupillary or vision changes

-blockers

Timolol, betaxolol,
carteolol
D i uretics

Acetazolamide

carbonic anhydrase
Cholinomimetics

Direct (pilocarpine,
carbachol)
Indirect
(physostigmine,
echothiophate)

t outflow of aqueous humor via contraction

of cil iary muscle and open ing of trabecular
meshwork
Use pilocarpine in emergencies-very effective
at opening meshwork into canal of Schlemm

M iosis and cyclospasm (contraction of cili ary

muscle)

Prostaglandin

Latanoprost (PG F2a)

Opioid analgesics
MECHANISM

t outflow of aqueous humor

Darkens color of iris ( brow n ing)

Morphine, fentanyl, codeine, heroin, methadone, meperidine, dextromethorphan, d iphenoxylate.

Act as agonists at opioid receptors (mu = morph ine, delta = en kephalin, kappa = dynorph in)
to modulate synaptic transmission- open K+ channels, close C a 2 + channels
l synaptic
transmission. I n h ibit release of ACh, NE, 5-HT, glutamate, substance P.
--+

CliNICAL USE

Pain, cough suppression (dextromethorphan), diarrhea ( lopera m ide and d iphenoxylate ) , acute
pulmonary edema, maintenance programs for add icts (methadone ) .

TOXICITY

Addiction , respi ratory depression , constipation , m iosis (pinpoint pupils), add itive CNS depression
with other drugs. Tolerance does not develop to miosis and constipation . Toxicity treated with
naloxone or naltrexone (opioid receptor antagon ist) .

Butorphanol
MECHANISM

Mu-opioid receptor partial agon ist and kappa-opioid receptor agon ist; produces analgesia.

CliNICAL USE

Severe pain (migraine, labor, etc . ) . Causes less respiratory depression than full opioid agon ists.

TOXICITY

Can cause opioid withdrawal symptoms if patient is also taking full opioid agonist (competition for
opioid receptors ) . Overdose not easily reversed with naloxone.

4 50

SE C T IO N I l l

N E U R O LO G Y

NEUROLOGY- PHARMACOLOGY

Tramadol
MECHANISM

Very weak opioid agonist; also inh ibits seroton in and NE reuptake (works on mu ltiple
neurotransm itters-" tram it all " in with tramadol) .

CliNICAL USE

Chron ic pa i n .

TOXICITY

Similar t o opioids. Decreases seizur e threshold.

 NEUROLOGY- PHARMACO LOGY

N E U R O LO G Y

SECTION Ill

45 1

Epilepsy drugs
GENERALIZED

PARTIAL (FOCAL)

STATUS
SIMPLE

Phenytoin
Carbamazepine

./

l st line

COMPLEX

./

l st l i ne

TONIC-CLONIC

ABSENCE

lst l ine

EPILEPTICUS

MECHANISM

NOTES

l st l ine for
prophylaxis

t Na+ channel

Fosphenytoin for
parenteral use

in activation

t Na+ channel

l st l ine

inactivation
./

Lamotrigine

Gabapentin

./

./

Topiramate

./

./

Phenobarbital

./

Valproic acid

./

./

lst line for

trigeminal
neuralgia

Blocks voltagegated Na+

channels
Designed as GABA
analog, but
primarily i n h ibits
h igh-voltageactivated C a 2 +
channels

Also used for

peripheral
neuropathy,
postherpetic
neuralgia,
m tgrame
prophylaxis,
bipolar d isorder

./

Blocks a+
channels,
t GABA action

Also used for

mtgrame
prevention

./

./

l st l i ne i n children

./

lst l ine

t GABA A action
t Na+ channel

./

inactivation,
t GABA
concentration
Blocks thalamic
T-type C a 2 +
channels

l st l ine

Ethosuximide

l st l ine for
acute

Benzodiazepines
(diazepam or
lorazepam)

t GABA A action

Tiagabine

./

./

Inh ibits GABA

reuptake

Vigabatrin

./

./

Irreversibly
inh ibits GABA
transaminase
..... t GABA

Levetiracetam

./

./

Also used for

myoclon ic
setzures

Unknow n ; may
modulate GABA
and glutamate
release

Also used for

seizures of
eclampsia ( l st
l ine is MgS0 4 )

4 52

SECTION I l l

N E U R O LOGY

NEURO LOGY- PHARM ACO LOGY

Epilepsy drug toxicities

Benzodiazepines

Sedation, tolerance, dependence.

Carbamazepine

Diplopia, ataxia, blood dyscrasias

(agranulocytosis, aplastic anem ia) , l iver
toxicity, teratogenesis, i nduction of cytochrome
P-450, SIADH , Stevens-Johnson syndrome.

Ethosuximide

GI d istress, fati gue, headache, urticaria,

Stevens-Johnson syndrome.

Phenobarbital

Sedation, tolerance, dependence, i nduction of

cytochrome P-450.

Phenytoin

Nystagmus, d iplopia, ataxia, sedation , gingival

hyperplasia, h i rsutism, megaloblastic anem ia,
teratogenesis (fetal hydantoin syndrome) , SLE
l ike syndrome, i nduction of cytochrome P-450,
lymphadenopathy, Stevens-Johnson syndrome,
osteopenia.

Valproic acid

GI d istress, rare but fatal hepatotoxicity

(measure 1FT's), neural tube defects in
fetus (spina bifida), tremor, weight ga in.
Contraindicated i n pregnancy.

Lamotrigine

Stevens-Johnson syndrome.

Gabapentin

Sedation, ataxi a .

Topiramate

Sedation , mental dulling, kidney stones, weight

loss.

Stevens-Johnson syndrome -prodrome of

malaise and fever followed by rapid onset of
erythematous/purpuric macules (oral, ocular,
gen ital ) . Skin lesions progress to epidermal
necrosis and sloughing.
EFGH - Ethosuxim ide, Fatigue, GI , Headache.

Phenytoin
MECHANISM

Use-dependent blockade of Na+ channels; inh ibition of glutamate release from excitatory
presynaptic neuron.

CLINICAL USE

Ton ic-clon ic seizures. Also a class I B antiarrhythm ic .

TOXICITY

Nystagmus, ataxia, d iplopia, sedation, SLE-l ike syndrome, i nduction o f cytochrome P-4 5 0 . Chronic
use produces gingival hyperplasia in children, peripheral neuropathy, h i rsutism, megaloblastic
anem ia U folate absorption) . Teratogen ic (fetal hydantoin syndrome) .

Barbiturates
MECHANISM

Phenobarbital, pentobarbital, thiopental , secobarbital.

Facil itate GABAA action by t duration of CJ- chan nel open ing, thus ! neuron firing (barbidurates
t duration) . Contraindicated in porphyria.

CLINICAL USE

Sedative for anxiety, seizures, insomnia, i nduction of anesthesia (th iopental ) .

TOXICITY

Respiratory and card iovascular depression (can b e fatal ) ; CNS depression (can b e exacerbated by
EtOH use) ; dependence; drug interactions (i nduces P-4 5 0 ) .
Overdose treatment is supportive (assist respiration a n d mainta i n BP) .

N E U R O LOGY

Benzodiazepines

MECHANISM

NE UROLOGY- PHARMACOLOGY

4 53

Diazepam, lorazepam, triazolam, temazepam , oxazepam , m idazolam, chlord iazepoxide,

alprazolam.
Facilitate GABA A action by t frequency of
Cl- chan nel opening. ! REM sleep. Most
have long half-l ives and active metabol ites
(exception s : triazolam, oxazepam, and
m idazolam are short acting ....higher
.
addictive
potential ) .

CLINICAL USE

Anxiety, spasticity, status epilepticus (lorazepam

and d iazepam) , detoxification (especially
alcohol withd rawal-DTs), n ight terrors,
sleepwalking, general anesthetic (amnesia,
muscle relaxation ) , hypnotic (insomn ia) .

TOXICITY

Dependence, add itive CNS depression effects

with alcohol . Less risk of respiratory depression
and coma than with barbiturates.
Treat overdose with flumazenil (competitive
antagonist at GABA benzodiazepine receptor) .

Nonbenzodiazepine

S E C TI O N I l l

Frenzodiazepines t frequency.
Benzos, barbs, and EtOH all bind the
GABA A receptor, which is a l igand-gated
chloride channel .

Zolpidem (Ambien) , zaleplon, eszopiclone.

hypnotics
MECHANISM

Act via the B Z l subtype of the GABA receptor. Effects reversed by flumazen i l .

CLINICAL USE

Insomnia.

TOXICITY

Ataxia, headaches, confusion. Short duration because of rapid metabol ism by l iver enzymes. Unlike
older sedative-hypnotics, cause only modest day-after psychomotor depression and few am nestic
effects. Lower dependence risk than benzodiazepines.

Anesthetics-general
principles

CNS drugs must be l ipid soluble (cross the blood-brain barrier) or be actively transported.
Drugs with ! solubility in blood = rapid induction and recovery times.
Drugs with t solubi l ity i n l ipids = t potency =

_
_

MAC

MAC = m i n imal alveolar concentration at which 5 0 % of the population is anesthetized. Varies

with age .
Examples: N 2 0 has ! blood and l ipid solubility, and thus fast induction and low potency.
Halothane, in contrast, has t lipid and blood solubi lity, and thus h i gh potency and slow induction.

Inhaled anesthetics

Halothane, enflurane, isoflurane, sevoflurane, methoxyflurane, n itrous oxide.

MECHANISM

Mechanism unknown .

EFFECTS

Myocard ial depression, respiratory depression , nausea /emesis, t cerebral blood flow ( ! cerebral
metabol ic demand) .

TOXICITY

Hepatotoxicity (halothane), neph rotoxicity (methoxyflurane), proconvu lsant ( enflurane) , mal ignant
hyperthermia (all but nitrous oxide; rare, life-threatening, inherited susceptibility) , expansion of
trapped gas in a body cavity (n itrous oxide ) .

4 54

SE C T IO N I l l

N E U R O LO G Y

NEU ROLOGY- PHARMACOLOGY

Intravenous anesthetics

Barbiturates

Th iopental-h igh potency, high l ipid solubility,

rapid entry into brain. Used for induction
of anesthesia and short surgical procedures.
Effect term inated by rapid redi stribution into
tissue (i.e., skeletal muscle) and fat. ! cerebral
blood Aow.

Benzodiazepines

Midazolam most com mon dru g used for

endoscopy; used adjunctively with gaseous
anesthetics and narcotics. May cause severe
postoperative respiratory depression, ! BP (treat
overdose with Aumazen il), and amnesia.

Arylcyclohexyla mines
(Ketamine)

PCP analogs that act as dissociative anesthetics.

Block M DA receptors. Cardiovascular
stimulants. Cause disorientation ,
hallucination , and bad dreams. t cerebral
blood Aow.

Opioids

Morphine, fentanyl used with other CNS

depressants during general anesthesia.

Propofol

Used for sedation in ICU, rapid anesthesia

induction, and short procedures. Less
postoperative nausea than thiopental.
Potentiates GABA A '

Local anesthetics

B . B. Ki ng on OPIOIDS PROPOses
FOOLishly.

Not recommended for home use by pop stars.

Esters -procaine, cocai ne, tetracaine.

Amides -l ldocalne, meplvacalne, buplvacalne (amldes have 2 I's in name) .

MECHANISM

Block a+ channels by binding to specific receptors on inner portion of channel. Preferentially

bind to activated Na+ channels, so most effective i n rapidly firing neurons. 3 amine local
anesthetics penetrate membrane in uncharged form, then bind to ion channels as charged form.

PRINCIPLE

Can be given with vasoconstrictors (usually epi nephrine) to enhance local action- ! bleedi ng,
t anesthesia by ! systemic concentration.
In infected (acidic) tissue, alkaline anesthetics are charged and cannot penetrate membrane
effectively need more anesthetic.
Order of nerve blockade: small-diameter fibers > large diameter. Myel inated fibers > un myel inated
fibers. Overall, size factor predominates over myel ination such that small myel inated fibers
> small unmyel inated fibers > large myel inated fibers > large unmyel inated fibers.
Order of loss : ( l ) pain, (2) temperature, ( 3 ) touch, (4) pressure.
--+

CliNICAL USE

M inor surgical procedures, spinal anesthesia. If allergic to esters, give am ides.

TOXICITY

CNS excitation, severe card iovascular toxicity (bupivacaine), hypertension, hypotension, and
arrhythm ias (cocaine) .

N E U R O LO G Y

Neuromuscular
blocking drugs

NEUROLOGY- PHARMACOLOGY

SECTION I l l

455

Used for muscle paralysis in surgery or mechanical ventilation. Selective for motor (vs . autonomic)
nicotinic receptor.

Depo l arizing

Succinylcholine- strong ACh receptor agonist; produces sustained depolarization and prevents
muscle contraction .
Reversal of blockade:
Phase I (prolonged depolari zation) -no antidote. Block potentiated by chol inesterase inh ibitors.
Phase I I (repolarized but blocked; ACh receptors are ava ilable, but desensitized) -antidote
consists of chol inesterase inhibitors (e.g., neostigm ine) .
Complications include hypercalcemia, hyperkalemia, and malignant hyperthermia.

Nondepo l arizing

Tubocurarine, atracurium, mivacurium, pancuronium, vecuronium, rocuronium. C ompetitive

antagonists - compete with ACh for receptors.
Reversal of blockade-neostigmine, ecl r ophon ium, and other cholinesterase inh ibitors.

Dantrolene
MECHANISM
CLINICAL USE

Parkinson's disease

Prevents the release of Ca 2 + from the sarcoplasmic reticulum of skeletal muscle.

Used in the treatment of mal ignant hyperthermia, a rare but l i fe-threatening side effect of
inhalation anesthetics (except N 2 0) and succinylchol ine. Also used to treat neuroleptic mal ignant
syndrome (a toxicity of antipsychotic drugs).

Parkinsonism is clue to loss of cloparninergic neurons and excess chol inergic activity.

drugs
STRATEGY

AGENTS

Dopamine agonists

Bromocriptine (ergot) , pram ipexole, ropinirole

(non-ergot) ; non-ergots are preferred

dopamine

Amantadine (may t dopamine release) ; also

used as an antiviral against influenza A and
rubella; toxicity = ataxia
L-clopa/carbidopa (converted to dopamine in
CNS)

Prevent dopamine
breakdown

Selegiline (selective MAO type B inh ibitor) ;

entacapone, tolcapone (COMT inh ibitors
prevent L-clopa clegraclation , thereby increasing
dopamine availabil ity)

Curb excess chol inergic

activity

Benztropine (Antimuscarinic ; improves

tremor and rigidity but has l ittle effect on
bradykinesia)

BALSA :
Bromocriptine
Am antad ine
Levocl o pa (with carbiclopa)
Selegiline (and COMT inh ibitors)
Antimuscarin ics
For essential or fam i l ial tremors, use a -blocker
(e.g., propranolol ) .

Park your Mercedes-Benz.

456

SECTI O N I l l

N E UROLOGY

NEUROLOGY- PHARMACOLOGY

Ldopa (levodopa)/ carbidopa

MECHANISM

t level of dopamine in brain. Unl ike dopamine, L-clopa can cross blood-brai n barrier and is
converted by dopa decarboxylase in the CNS to dopamine. Carbiclopa, a peripheral decarboxylase
inhibitor, is given with L-clopa to t the bioavailabil ity of L-clopa i n the bra i n and to l i m it peripheral
s i cl e effects.

CliNICAL USE

Parkinson's disease.

TOXICITY

Arrhythmias from increased peripheral formation of catecholamines. Long-term use can lead
to dyskinesia following administration, akinesia between clo ses.

Selegiline
MECHANISM

Selectively inh ibits MAO-B, which preferentially metabol izes dopamine over N E and 5-HT,
thereby increasing the availability of dopamine.

CLINICAL USE

Adjunctive agent to L-clopa in treatment of Parkinson's disease.

TOXICITY

May enhance adverse effects of L-cl o pa .

Alzheimer's drugs

Memantine
MECHANISM

N M DA receptor antagon ist; helps prevent excitotoxicity (mediated by Ca 2 +) .

TOXICITY

Dizziness, confusion, hallucinations.

Donepezil, galantam ine, rivastigmine

MECHANISM

Acetylchol inesterase inh ibitors.

TOXICITY

Nausea, dizziness, insomnia.

Huntington's drugs

Neurotransmitter changes in Huntington's d isease : GABA, ACh, t dopamine.

Treatments :
Tetrabenazine and reserpine - inhibit VMAT; l i m it dopamine vesicle packaging and release.
H aloperidol - dopa m i ne receptor antagonist.

Sumatriptan
MECHANISM

5-HT J B/ID agonist. Inh ibits trigem inal nerve

activation ; prevents vasoactive peptide release ;
i nduces vasoconstriction. Half-life < 2 hours.

C liNICAL USE

Acute m igraine, cluster headache attacks.

TOXICITY

Coronary vasospasm (contraindicated in

patients with CAD or Prinzmetal's angina),
mild tingling.

A SUMo wrestler TRIPs ANd falls on your

head.

404

MUSCULOSKELETAL, SKIN, AND CONNECTIVE T ISSUE

SECTION Ill

PHAR M ACOLOGY

M U S C U LOS K EL E TAL, S K I N , AN D C O N N E C T I V E TI S S U E - PHAR M ACOLOGY

Lipoxygenase pathway yields Leukotrienes.

LT B 4 is a neutrophil chemotactic agent.
LTC 4 , 0 4 , and E4 function in
bronchoconstriction, vasoconstriction ,
contraction of smooth muscle, and t vascular
permeabil ity.
PGI2 inhibits platelet aggregation and promotes
vasod ilation.

Arachidonic acid
products

L for Lipoxygenase and Leukotriene.

Neutrophils arrive " B4" others.

Platelet-Gathering Inhibitor.

Membrane lipid (e.g . , phosphatidylinositol)

N SAI DS, aspirin,

acetaminophen,
Endoperoxides COX-2 inhibitors
(PGG2, PGH2)

Hydroperoxides
(HPET Es)

Leu ko enes
(LTC4 . LT D4)
(LT B4)

=!

.)

It Bronchial tone I
.

Prostacycli
(PG I 2)

t Platelet aggregation
t Vascular tone
t Bronchial tone
t Uterine tone

{Ada pted, with permission, from Katzung BG, Trevor

CT: Appleton & Lange, 1 998: 1 5 0 )

AJ.

omboxane
A

t Uterine tone

(TX 2)

Prostaglandins
(PGE2, PGF2a)

t Vascular tone
t Bronchial tone

t Platelet aggregation
t Vascular tone
t Bronchial tone

----

Pharmacology: Examination & Board Review, 5th ed. Sta mford,

Aspirin
MECHANISM

Irreversibly inh ibits cyclooxygenase (both COX- I and C OX-2 ) by acetylation, which synthesis of
both thromboxane A 2 (TXA 2 ) and prostaglandins. t bleed ing time. No effect on PT, PTT. A type
of NSAID.

CLINICAL USE

Low close (< 300 mg/clay) : platelet aggregation. Intermediate close ( 3 0 0 -240 0 mg/clay) : antipyretic
and analgesic. H igh close (2400-4000 mg/clay) : anti-inflammatory.

TOXICITY

Gastric ulceration, tinn itus (CN V I I I ) . Chron ic use can lead to acute renal fa i lure, interstitial
nephritis, and upper GI bleeding. Risk of Reye's syndrome i n children treated with aspirin for
viral infection . Also stimulates respiratory centers, causing hyperventilation and respiratory
alkalosis.

M USCULOSKELETAL, SKI N, AND CONNECTIVE TISS U E

NSAI Ds

PHA R M ACOLO G Y

SECT ION Ill

40 5

I buprofen, naproxen, indomethacin, ketorolac, diclofenac.

MECHANISM

Reversibly inhibit cyclooxygenase (both COX- 1 and C OX-2 ) . Block prostaglandin (PC) synthesis.

CLINICAL USE

Antipyretic, analgesic, anti-inflam matory. Indomethacin is used to close a PDA.

TOXICITY

I nterstitial neph ritis, gastric ulcer ( PGs protect gastric mucosa ) , renal ischemia ( PGs vasodilate
afferent arteriole) .

COX-2 inhibitors (celecoxib)

MECHANISM

Reversibly inhibit specifically the cyclooxygenase (COX) isoform 2 , which is found in inflammatory
cells and vascular endothelium and med iates inflammation and pain; spares COX- 1 , which helps
mainta i n the gastric mucosa. Thus, should not have the corrosive effects of other NSAIDs on the
GI l i n ing. Spares platelet function as TXA 2 production is dependent on COX- I .

CLINICAL USE

Rheumatoid arthritis and osteoarthritis; patients with gastritis o r u lcers.

TOXICITY

t risk of thrombosis. Sulfa allergy.

Acetaminophen
MECHANISM

Reversibly inh ibits cyclooxygenase, mostly in C N S . Inactivated peripherally.

CLINICAL USE

Antipyretic, a nalgesic, but not anti-inflammatory. Used i nstead of aspirin to avoid Reye's syndrome
i n children with viral infection .

TOXICITY

Overdose produces hepatic necrosis; acetami nophen metabol ite depletes glutathione and forms
toxic tissue adducts i n l iver. N-acetylcysteine is antidote - regenerates glutath ione.

Bisphosphonates

Alendronate, other -d ronates.

MECHANISM

Pyrophosphate analogs; bind hydroxyapatite in bone, inh ibiti ng osteoclast activity.

CLINICAL USE

Osteoporosis, hypercalcemia, Paget's d isease of bone.

TOXICITY

C orrosive esophagitis, osteonecrosis of the jaw.

4 () b

S E CT I O N I l l

PHAR M ACOLOG Y

M USCULOSK E L E TAL, S K I N, AND C ONN E C T I V E T I SSUE

Ciout drugs
Chronic gout drugs

Allopurinol

I n h ibits xanthine oxidase, conversion of

xanth ine to uric acid. Also used in lymphoma
and leukemia to prevent tumor lysis
associated urate nephropathy. t concentrations
of azathioprine and 6-MP (both normally
metabolized by xanth ine oxidase) .
Do not give sal icylates; all but the highest
closes depress uric acid clearance. Even h igh
closes ( 5 -6 g/clay) have only m inor uricosuric
activity.

Febuxostat

Inh ibits xanthine oxidase.

Probenecid

Inh ibits reabsorption of uric acid in PCT (also

inh ibits secretion of penicillin) .

Colchicine

Diet --- Purines -- Nucleic acids

Hypoxanthine

l
Xanthine

Xanthine
oxidase

>

Allopurinol

Plasma --- Urate crystals --- Gout

uric acid
deposited
in j oints

T
Probenecid and

Binds and stabil izes tubulin to inhibit

polymerization, impa iring leukocyte
chemotaxis and degranulation .
GI side effects, especially if given orally.

high-dose salicylates
----=,.------

+-\

T
Diuretics and

Tubular
reabsorption
Tubular
secretion

low-dose salicylates
Urine

Acute gout drugs

NSAI Ds

Naproxen , indomethacin.

Cilucocorticoids

Oral or i ntraarticular.

TN F-a inhibitors

Xanthine
oxidase

All TNF-a inhibitors predispose to infection including reactivation of latent TB since TNF
blockade prevents activation of macrophages and destruction of phagocytosed m icrobes.

DRUG

MECHANISM

CLINICAL USE

Etanercept

Fusion protein (receptor for TNF-a + IgG 1 Fe) ,

produced b y recombinant DNA.
Etanercept is a TNF decoy receptor.

Rheumatoid arthritis, psoriasis, ankylosing

spondyl itis

lnfliximab,
adalimumab

Anti-TNF-a monoclonal antibody

Crohn's disease, rheumatoid arthritis, ankylosing

spondyl itis, psoriasis

HEMATOLOGY AND ONCOLO GY

H E M AT O L O G Y A N D O N C O LO G Y-P H A R M A C O LO G Y

SECTION Ill

3 67

H E M AT O L O G Y A N D O N C O L O G Y-P H A R M A C O L O G Y
Heparin
MECHAN ISM

Cofactor for the activation of antithrombin, ! thrombin, and ! factor Xa. Short half-l i fe .

CliNICAl USE

Immediate anticoagulation for pulmonary embol ism, acute coronary syndrome, M I , DVT. Used
during pregnancy (does not cross placenta ) . Follow PTT.

TOXICITY

Bleeding, thrombocytopenia ( H IT), osteoporosis, drug-dru g i nteractions. For rapid reversal

(antidote), use protamine sulfate (positively charged molecule that binds negatively charged
hepari n ) .

NOTES

Low-molecular-weight heparins (e.g., enoxaparin, dalteparin) a c t more on factor X a , h ave better

bioavailabil ity and 2-4 times longer half-l ife. Can be adm i n i stered subcutaneously and without
laboratory mon itoring. Not easily reversible.
Heparin-induced thrombocytopenia ( H IT) - development of IgC antibodies against heparin
bound to platelet factor 4 ( PF4 ) . Antibody-heparin-PF4 complex activates platelets -+ thrombosis
and thrombocytopenia.

Lepirudin, bivalirudin

Derivatives of hirudin, the anticoagulant used by leeches ; i n h ibit thrombin. Used as an alternative
to heparin for anticoagulating patients with H IT.

Warfarin (Coumadin)
MECHAN ISM

Interferes with normal synthesis and

y-carboxylation of vitamin K-dependent
clotting factors I I , V I I , IX, and X and proteins
C and S . Metabol ized by the cytochrome
P-450 pathway. In laboratory assay, has effect
on EXtrinsic pathway and t PT. Long halflife.

CliNICAl USE

Chronic anticoagulation (after STE M I , venous

thromboembolism prophylaxis, and prevention
of stroke i n atrial fibrillation ) . Not used in
pregnant women (because warfarin, unl ike
heparin, can cross the placenta ) . Follow PT/
I N R values.

TOXICITY

Bleeding, teratogenic, skin/tissue necrosis, drug

drug interactions.

The EX-PresidenT went to war (farin) .

For reversal of warfarin overdose, give vitamin

K. For rapid reversal of severe warfarin
overdose, give fresh frozen plasma.

368

SECTI O N Ill

HEMATOLOGY AND ONC OLOGY

H E M AT O L O G Y A N D O N C O L O G Y-P H A R M A C O L O G Y

Heparin vs. warfarin

Heparin

Warfarin

STRUCTURE

Large anionic, acidic polymer

Small l ipid-soluble molecule

ROUTE O F ADMIN ISTRAT I O N

Parenteral (IV, S C )

Oral

S ITE O F ACTION

Blood

Liver

ONSET OF ACTION

Rapid (seconds)

Slow, l i m ited by half-l ives of normal clotting

factors

Activates antithrombin, which the action of

I la (thrombin) and factor Xa

Impairs the synthesis of vita m i n K-clepenclent

clotti ng factors II, VII, IX, and X (vita m i n K
antagon ist)

DURATION O F ACTI O N

Acute ( hours)

Chronic (clays)

I N H IBITS COAGULATION

Yes

No

Protamine sulfate

IV vita m i n K and fresh frozen plasma

MONITO R I N G

PTT (intrinsic pathway)

PT/INR (extrinsic pathway)

CROSSES PLACENTA

No

Yes (teratogenic)

MECHAN I SM OF ACTION

I N VITRO
TREATMENT O F ACUTE
OVERDOSE

Thrombolytics

Alteplase (tPA) , reteplase (rPA) , tenecteplase (TN K-tPA) .

MECHANISM

Directly or indirectly a iel conversion of plasm inogen to plasm i n , which cleaves thrombin and fibrin
clots. t PT, t PTT, no change in platelet count.

CLINICAL USE

Early Ml, early ischemic stroke, direct thrombolysis of severe pul monary embol ism.

TOXICITY

Bleeding. Contra ind icated in patients with active bleeding, h istory of i ntracranial bleeding, recent
s urgery, known bleeding diatheses, or severe hypertension . Treat toxicity with a minocaproic acid,
an inhibitor of fibrinolysis.

Aspirin (ASA)
MECHAN ISM

CLI N ICAL USE

TOXICITY

ADP receptor inhibitors

MECHANISM

Irreversibly inh ibits cyclooxygenase (both COX-I and C OX-2) enzyme by covalent acetylation.
Platelets cannot synthesize new enzyme, so effect lasts until new platelets are produced :
t bleeding time, TXA2 and prostaglandins. No effect on PT or PTT
Antipyretic, analgesic, anti-inflammatory, antiplatelet ( aggregation ) .
Gastric ulceration, tinnitus (CN V I I I ) . Chronic use can lead to acute renal failure, i nterstitial
nephritis, and upper GI bleeding. Reye's syndrome in children with viral infection . Overdose
causes respiratory alkalosis and metabol ic acidosis.

Clopiclogrel, ticlopicline, prasugrel , ticagrelor.

Inhibit platelet aggregation by irreversibly blocking ADP receptors. I n h ibit fibrinogen binding by
preventing glycoprotein l ib/lila from binding to fibrinogen .

CLIN ICAL USE

Acute coronary syndrome; coronary stenting. incidence or recurrence of thrombotic stroke.

TOXICITY

Neutropen ia (ticlopid ine) .

HEMATO LOGY AND ONC O LOGY

H E M ATO L O G Y A N D O N C O L O G Y-P H A RMA C O LO G Y

SECTION Ill

3 69

Cilostazol, dipyridamole
MECHANISM

Phosphodiesterase I I I inh ibitor; t cAM P in platelets, thus i n h ibiting platelet aggregation ;

vasodilators.

CliN ICAL USE

I nterm ittent claudication, coronary vasodilation, prevention of stroke or TIAs (combined with
aspirin), angina prophylaxis.

TOXICITY

Nausea, headache, facial flushing, hypotension, abdom inal pain.

GP l i b/ l i la inhibitors

Abciximab, eptifibatide, tirofiban.

MECHANISM

Bind to the glycoprotein receptor lib/Ilia on activated platelets, preventing aggregation . Abciximab
is made from monoclonal antibody Fab fragments .

CliN ICAL USE

Acute coronary syndromes, percutaneous transluminal coronary angioplasty.

TOXICITY

Bleeding, thrombocytopenia.

Cancer drugs-cell cycle

G2

Synthesis
of components
needed for
mitosis

G,

Synthesis
of components
needed for
DNA synthesis

Go

'

'\\

Resting ;

s
DNA

Anti metabolites

(Adapted, with permission, from Katzung BG, Trevor AJ. USMLE Road Map: Pharmacology, I st ed. New York:
McGraw-Hill, 200 3 : 1 33.)

3 70

SECTION Ill

HE MATOLOGY AND ONCOLOGY

H E M ATO L O G Y A N D O N C O LO G Y-P H A R M A C O L O G Y

Antineoplastics
Nucleotide synthesis

...- DNA ---- RNA ---- Protei n --- Ce llular d i v i s i o n

---

J
Methotrexate, 5-FU:

J.. t h y m i d i n e synthesis

_
Alkylating agents, cisplatin :
cross-link DNA

6 - M P:

J.. p u r i n e synthesis

Dactinomycin, doxoru bicin :

DNA i ntercalators
Etoposide:
i n h i b i ts topoisomerase I I

Vinca alkaloids:
i n h i b i t m i c rotu b u le formation
Paclitaxel:
i n h i bits m i c rotu b u le d i sassem bly

3 40

S E CTI O N I l l

G A ST R O I N T E ST I N A L

GASTROINTESTINAL-PHARMA COLOGY

Chronic pancreatitis

Chronic inflammation,atrophy,calcification of the pancreas. Major causes are alcohol abuse and
idiopathic.
Can lead to pancreatic insufficiency-+ steatorrhea,fat-soluble vitamin deficiency,diabetes mellitus,
and t risk of pancreatic adenocarcinoma.
Amylase and lipase are less elevated (compared to levels in acute pancreatitis).

Pancreatic
adenocarcinoma

Prognosis averages 6 months or less; very aggressive tumor arising from pancreatic ducts; usually
already metastasized at presentation; tumors more common in pancreatic head (-+ obstructive
jaundice). Associated with CA-1 9-9 tumor marker (also CEA,less specific).
Risk factors:
Tobacco use (but not EtOH)
Chronic pancreatitis (especially > ZO years)
Age > 5 0 years
Jewish and African-American males
Often presents with:
Abdominal pain radiating to back
Weight loss (clue to malabsorption and anorexia)
Migratory thrombophlebitis-redness and tenderness on palpation of extremities (Trousseau's
syndrome)
Obstructive jaundice with palpable,nontender gallbladder (Courvoisier's sign)
Treatment: Whipple procedure,chemotherapy,radiation therapy.

GASTROINTESTINAL-PHARMA COLOGY
Cil

therapy

Somatostatin
(octreotide)
Enteric

ST2

Fundus

Antrum

G (CCK-B)

- ,......_

Antacids

Stomach lumen

(Adapted, with permission, from Katzung BG, Trevor AJ . USMLE Road Mop: Pharmacology, I st ed. New York: McGraw-Hill, 2003 : 1 59.)

G A S T R O I N T E ST I N A L

H2 blockers

GASTRO INTEST INAL-PHARMA COLOGY

Cimetidine,ranitidine,famotidine,nizatidine.

SECTION I l l

Take H z blockers before you dine. Think "table

for 2" to remember H2 .

MECHANISM

Reversible block of histamine Hrreceptors

CLINICAL USE

Peptic ulcer,gastritis,mild esophageal reflux.

TOXICITY

Cimetidine is a potent inhibitor of cytochrome P-45 0 (multiple drug interactions); it also has
antiandrogenic effects (prolactin release,gynecomastia,impotence, libido in males); can
cross blood-brain barrier (confusion,dizziness,headaches) and placenta. Both cimetidine and
ranitidine renal excretion of creatinine. Other H z blockers are relatively free of these effects.

Proton pump inhibitors

-+

34 1

H+ secretion by parietal cells.

Omeprazole,lansoprazole,esomeprazole,pantoprazole,dexlansoprazole.

MECHANISM

Irreversibly inhibit H+fK+ ATPase in stomach parietal cells.

CLINICAL USE

Peptic ulcer,gastritis, esophageal reflux,Zollinger-Ellison syndrome.

TOXICITY

Increased risk of C. difficile infection,pneumonia. Hip fractures, serum MgZ+ with long-term use.

Bismuth, sucralfate
MECHANISM

CliNICAl USE

Misoprostol
MECHANISM

Bind to ulcer base,providing physical protection and allowing HC0 3 - secretion to reestablish pH
gradient in the mucous layer.
t ulcer healing, traveler's diarrhea.

A PGE 1 analog. t production and secretion of gastric mucous barrier, acid production.

CLINICAL USE

Prevention of NSAID-induced peptic ulcers; maintenance of a patent ductus arteriosus. Also used
to induce labor (ripens cervix).

TOXICITY

Diarrhea. Contraindicated in women of childbearing potential (abortifacient).

Odreotide
MECHANISM

Long-acting somatostatin analog.

CliNICAl USE

Acute variceal bleeds,acromegaly,VIPoma,and carcinoid tumors.

TOXICITY

Nausea,cramps,steatorrhea.

Antacid use

Can affect absorption,bioavailability,or urinary excretion of other drugs by altering gastric and
urinary pH or by delaying gastric emptying.
All can cause hypokalemia.
Overuse can also cause the following problems.

Aluminum hydroxide

Constipation and hypophosphatemia; proximal

muscle weakness, osteodystrophy,seizures

Aluminimum amount of feces.

Magnesium hydroxide

Diarrhea,hyporeflexia,hypotension,cardiac
arrest

Mg = Must go to the bathroom.

Calcium carbonate

Hypercalcemia,rebound acid t

Can chelate and effectiveness of other drugs

(e.g.,tetracycline).

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SECTION I l l

Osmotic laxatives

G A ST R O I N T E S T I N A L

GASTROINTESTINAL-PHARMACOLOGY

Magnesium hydroxide,magnesium citrate,polyethylene glycol,lactulose.

MECHANISM

Provide osmotic load to draw water out.

Lactulose also treats hepatic encephalopathy since gut flora degrade it into metabolites (lactic acid
and acetic acid) that promote nitrogen excretion as NH4 +.

CLINICAL USE

Constipation.

TOXICITY

Diarrhea,dehydration; may be abused by bulimics.

lnfliximab
MECHANISM

Monoclonal antibody to TNF-a.

CLINICAL USE

Crohn's disease,ulcerative col itis,rheumatoid arthritis.

TOXICITY

Infection (including reactivation of latent TB),fever,hypotension.

Sulfasalazine
MECHANISM

A combination of sulfapyridine (antibacterial) and 5 -aminosalicylic acid (anti-inflammatory).

Activated by colonic bacteria.

CLINICAL USE

Ulcerative colitis,Crohn's disease.

TOXICITY

Malaise,nausea,sulfonamide toxicity,reversible oligospermia.

Ondansetron
MECHANISM

5 - H T 3 antagonist. Powerful central-acting

antiemetic.

CLINICAL USE

Control vomiting postoperatively and in patients

undergoing cancer chemotherapy.

TOXICITY

Headache,constipation.

Metoclopramide
MECHANISM

CLINICAL USE
TOXICITY

At a party but feeling queasy? Keep on dancing

with ondansetron !

D2 receptor antagonist. t resting tone,contractility, LES tone, motility. Does not influence colon
transport time.
Diabetic and post-surgery gastroparesis,antiemetic.

t parkinsonian effects. Restlessness,drowsiness,fatigue,depression,nausea,diarrhea. Drug

interaction with digoxin and diabetic agents. Contraindicated in patients with small bowel
obstruction or Parkinson's disease.

EN DOCRINE

ENDOCRINE-PHA R M ACOLOGY

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305

ENDOCRINE-PHA R M ACOLOGY
Diabetes drugs

Treatment strategy for type l DM -low-sugar diet, insulin replacement.

Treatment strategy for type 2 DM-dietary modification and exercise for weight loss; oral
hypoglycemics and insulin replacement.

DRUG CLASSES

ACTION

Insulin :

Bind insulin receptor (tyrosine

kinase activity).
Liver: t glucose stored as glycogen.
Muscle : t glycogen and protein
synthesis, K+ uptake.
Fat: aids TG storage.

Lispro (rapid-acting)
Aspart (rapid-acting)
Glulisine (rapid-acting)
Regular (short-acting)
NPH (intermediate)
Glargine (long-acting)
Detemir (long-acting)
Biguanides :

M etformin

Sulfonylurea s :

First generation :
Tol butamide
Chlorpropamide
Second generation:
G lyburide
Glimepiride
G l ipizide
G litazones/
thiazolidinediones :

Piogl itazone
Rosiglitazone
a-glucosidase
inhibitors :

Acarbose
M igl itol

CLINICAL USE

Type l DM, type 2 DM,

gestational diabetes, life
threatening hyperkalemia,
and stress-induced
hyperglycemia.

TOXICITIES

Hypoglycemia, very rarely

hypersensitivity reactions.

Exact mechanism is unknown.

gluconeogenesis, t glycolysis,
t peripheral glucose uptake
(insulin sensitivity).

Oral. First-line therapy in

type 2 DM.
Can be used in patients
without islet function.

GI upset; most serious

adverse effect is
lactic acidosis (thus
contraindicated in renal
failure).

Close K+ channel in -cell

membrane, so cell depolarizes
triggering of insulin release via
t Ca 2+ influx.

Stimulate release of
endogenous insulin in type
2 DM. Require some islet
function, so useless in type
l DM.

First generation : disulfiram

like effects.
Second generation :
hypoglycemia.

Used as monotherapy in type

2 DM or combined with
above agents.

Weight gain, edema.

Hepatotoxicity, heart failure.

Used as monotherapy in type

2 DM or in combination
with above agents.

GI disturbances.

-+

t insulin sensitivity in peripheral

tissue. Binds to PPAR-y nuclear
transcription regulator."
Inhibit intestinal brush-border
a-glucosidases.
Delayed sugar hydrolysis
and glucose absorption
postprandial hyperglycemia.
-+

Amylin analogs:

glucagon.

Type l and type 2 DM.

t insulin, glucagon release.

Type 2 DM.

Nausea, vomiting;
pancreatitis.

t insulin, glucagon release.

Type 2 DM.

Mild urinary or respiratory

infections.

Pra m lintide
GLP-1 analogs :

Exenatide
Liraglutide
DPP-4 inhibitors :

Linagliptin
Saxagliptin
Sitagliptin

Hypoglycemia,
nausea, diarrhea.

"Genes activated by PPAR-y regulate fatty acid storage and glucose metabolism. Activation of PPAR-y t insulin sensitivity and
levels of adiponectin.

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SECTION Il l

ENDOCRINE

ENDOC R I NE- P H A R M ACO LOG Y

Propylthiouracil. methimazole
MECHANISM

Block peroxidase, thereby inhibiting organification of iodide and coupling of thyroid hormone
synthesis. Propylthiouracil also blocks 5 '-deiodinase, which peripheral conversion of T4 to T 3 .

CLINICAL USE

Hyperthyroidism.

TOXICITY

Skin rash, agranulocytosis (rare), aplastic anemia, hepatotoxicity (propylthiouracil). Methimazole is

a possible teratogen.

Levothyroxine. triiodothyronine
MECHANISM

Thyroxine replacement.

CLINICAL USE

Hypothyroidism, myxedema.

TOXICITY

Tachycardia, heat intolerance, tremors, arrhythmias.

Hypothalamic/pituitary d rugs
DRUG

CLINICAL USE

GH

GH deficiency, Turner syndrome.

Somatostatin
(octreotide)

Acromegaly, carcinoid, gastrinoma, glucagonoma, esophageal varices.

Oxytocin

Stimulates labor, uterine contractions, milk let-down; controls uterine hemorrhage.

ADH (desmopressin)

Pituitary (central, not nephrogenic) DI.

Demeclocycline
MECHANISM

ADH antagonist (member of the tetracycline family).

CLINICAL USE

SIADH.

TOXICITY

Nephrogenic DI, photosensitivity, abnormalities of bone and teeth.

Glucocorticoids
MECHANISM

Hydrocortisone, prednisone, triamcinolone, dexamethasone, beclomethasone.

the production of leukotrienes and prostaglandins by inhibiting phospholipase A 2 and expression

of COX-2.

CliNICAl USE

Addison's disease, inflammation, immune suppression, asthma.

TOXICITY

Iatrogenic Cushing's syndrome -buffalo hump, moon facies, truncal obesity, muscle wasting, thin
skin, easy bruisability, osteoporosis, adrenocortical atrophy, peptic ulcers, diabetes (if chronic).
Adrenal insufficiency when drug stopped abruptly after chronic use.

56 2

SECTION Ill

RESPIRATORY

RESPIRATORY-PHARMACOLOGY

RESPIRATORY-PHARMACOLOGY
H1 blockers

Reversible inhibitors of H1 histamine receptors.

1st generation

Diphenhydramine, dimenhydrinate,
chlorpheniramine.

CLINICAL USES

Allergy, motion sickness, sleep aid.

TOXICITY

Sedation, antimuscarinic, anti-a-adrenergic.

2nd generation

Loratadine, fexofenadine, desloratadine,

cetirizine.

CLINICAL USES

Allergy.

TOXICITY

Far less sedating than lst generation because of

entry into CNS.

Names contain "-en/-ine" or "-en/-ate."

Names usually end in "-adine."

RESPIRATORY

Asthma drugs

RESPIRATORY-PHAR M A CO lOGY

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5 63

Bronchoconstriction is mediated by ( l) inflammatory processes and (2) parasympathetic tone;

therapy is directed at these 2 pathways.

-agonists

Albuterol -relaxes bronchial smooth muscle W2 ). Use during acute exacerbation.

Salmeterol, formoterol -long-acting agents for prophylaxis. Adverse effects are tremor and
arrhythmia.

Methylxanthines

Theophylline -likely causes bronchodilation by inhibiting phosphodiesterase, t hereby ! cAM P

hydrolysis. Usage is limited because of narrow t herapeutic index (cardiotoxicity, neurotoxicity);
metabolized by P-450. Blocks actions of adenosine.

Muscarinic
antagonists

lpratropium -competitive block of muscarinic receptors, preventing bronchoconstriction. Also

used for COPD, as is tiotropium, a long-acting muscarinic antagonist.

Corticosteroids

Beclomethasone, fluticasone -inhibit the

synthesis of virtually all cytokines. Inactivate
N F-KB, t he transcription factor that induces
the production of T F-a, among other
inflammatory agents. lst-line therapy for
chronic asthma.

Antileukotrienes

Montelukast, zafirlukast-block leukotriene

receptors. Especially good for aspirin-induced
asthma.
Zileuton -a 5 -lipoxygenase pathway inhibitor.
Blocks conversion of arachidonic acid to
leukotrienes.

Omalizumab

Monoclonal anti-IgE antibody. Binds mostly

unbound serum IgE. Used in allergic asthma
resistant to inhaled steroids and long-acting
z-agonists.

Bcoochodllatloo

+-0--Bro n c h i a l tone

+---0-- Theophy l l i ne
AMP

ACh

M usca ri n c

---0-7 Adenosine

ff

antagom sts

Theophyl l i ne

Moldoo

Antigen and lgE f--Omalizumab

on mast cells

Mediators
(leukotrienes, histamine, etc.)

-agonists
Theophylline
Muscarinic
antagonists

Steroids
Antileukotrienes

!l-ago o l "

cAM P

POE

c:p

Exposure to antigen
(dust, pollen, etc.)

Late response:
inflammation

Early response:
bronchoconstriction

Bronchial
hyperreactivity

Symptoms

T reatment strategies in asthma

Bronchoconstriction
(Adapted, with perm ission, from Katzung BG, Trevor AJ. Pharmacology: Examination 8 Board Review, 5th ed. Stamford, 0: Appleton & Lange, 1 9 9 8 : 1 59 and 1 6 1 .)

Expedorants

Guaifenesin

Expectorant-thins respiratory secretions; does not suppress cough reflex.

N-acetylcysteine

Mucolytic-can loosen mucous plugs in CF patients. Also used as an antidote for acetaminophen
overdose.

56 4

SECTION Ill

RESPIRATORY

RESPIRATORY-PHARMACOLOGY

Bosentan

Used to treat pulmonary arterial hypertension. Competitively antagonizes endothel in-l receptors,
decreasing pulmonary vascular resistance.

Dextromethorphan

Antitussive (antagonizes N M DA glutamate receptors). Synthetic codeine analog. Has mild opioid
effect when used in excess. aloxone can be given for overdose. Mild abuse potential.

Pseudoephedrine, phenylephrine
MECHANISM

Sympathomimetic a-agonistic nonprescription nasal decongestants.

CLINICAL USE

Reduce hyperemia, edema, and nasal congestion; open obstructed eustachian tubes.
Pseudoephedrine also used as a stimulant.

TOXICITY

Hypertension. Can also cause CNS stimulation/anxiety (pseudoephedrine).

Methacholine

Muscarinic receptor agonist. Used in asthma challenge testing.