Drug/Application
Antibiotics
Clinical
Uses

Drugs used to treat
infectious agents
 Dosing: Antibiotics with
low PAE – optimize the
duration of time the serum
is > MIC; Those with high
PAE – peak conc. is
important
Used in three ways:
 Empirical therapy
1. Determine if infected
2. Identify site of infection
3. Ascertain possible
pathogens
4. Predict susceptibility
5. Obtain specimens for
testing
 Definitive therapy
 Prophylactic therapy
Possible routes of
administration: IM, SC, IV,
topical
Mechanism
 Pharmacokinetics: successful
therapy depends on the drug’s
ability of killing the pathogen
without causing harm
 Distribution: Difficult sites to
access: brain, eye, prostate – contain
permeability barriers
 Elimination: Most eliminated by
kidney unless otherwise noted
 Post-antibiotic effect (PAE):
suppression of bacterial growth after
removal of antibiotic. PAE usually
seen in gram (+) bugs, sporadically
in (-) bugs.
 Antibiotics that inhibit cell wall
synthesis (β-lactams and
glycopeptides) have minimal or no
PAE against gram (-) bugs
 Aminoglycosides- PAEconcentration-dependent killing
 -lactams- no PAE-time above MIC
determines efficacy
Drug Interactions/
Side Effects
 Direct effects: the result of
direct interaction b/w the
drug and/or one its
metabolites and a specific
tissue or organ in the body.
 Hypersensitivity – Type I HS
rxn, Coomb’s (+) hemolytic
anemia, serum sickness, and
Stevens-Johnson syndrome
 Changes in microbial flora all antibiotics may lead to
pseudomembranous colitis
 Drug interactions – esp. with
Warfarin – enhances anticoagulation
 Host factors – genetics, age
 Pregnancy
Comments
 Minimum inhibitory conc.
(MIC) – the smallest conc.
of the drug that inhibits the
growth
 Minimum bactericidal
conc. (MBC) – the conc. of
the drug that will kill the
bacterium
 Bactericidal: achievable
blood concentration is >
MBC
 Bacteriostatic: achievable
concentration > MIC, but
below MBC
1
Drug/Application
INHIBITORS OF CELL
WALL SYNTHESIS
-lactams
Bactericidal
Penicillin
* Standard penicillins
Clinical
Uses
Mechanism
Drug Interactions/
Side Effects
Comments




Non-competitive inhibitors of
transpeptidases (penicillinbinding proteins-PBPs)
Resistance mechanisms:
 Inactivation of antibiotics
by β-lactamase – most
common mechanism, those
produced by S. aureus,
hemophilus, and E. colo
are relatively narrow in
substrate specificity and
woll hydrolyze penicillins
but NOT cephalasporins
 Modification of target
PBP’s – mech for MRSA
and penicillin resistance in
pneumococci
 Impaired penetration of
drug to target PBP’s –
presence of impermeable
membram (gram neg)
 Presence of an efflux pump

 Possess a four member nitrogencontaining beta lactam ring
 Inhibit bacterial growth by
interfering with a specific step in
bacterial cell wall synthesis.
 Β-lactam antibiotics are structural
analogs of the natural D-Ala-D-Ala
substrate and are covalently bound
by PBP’s at the active site.
 Binding leads to inactivation of
the transpeptidase reaction –
inhibiting peptidoglycan synthesis.
 High therapeutic index
 Type I – mediated by IgE –
urticaria, rhinitis,
angioedema, conjuctivits, or
systemic anaphylaxis
 Type II – rare, interaction of
IgG or IgM with antigen 
complement activiation, eg.
Hemolytic anemia
 Type III – most common –
serum sickness, arthralgia,
rash, fever,
lymphadenopathy, or
vasculitis
 Type IV – CMI: cutaneous
eruptions or
thrombocytopenia
 Cell wall is composed of a
complex cross-linked
polymer, peptidoglycan,
consisting of
polysaccharides and
polypeptides
 PBP in bacteria catalyze
the transpeptidase reaction
that removes the terminal
alanine to form cross link
with a nearby peptide
 Beta-lactam ring fused to a 5member, sulfur containing
thiazolidine
 Modification of side chain 
differing properties
 Inhibitor of cell wall synthesis

 Penicillin allergy occurs in
0.5% of patients


 Probenecid-inhibits tubular
secretion of penicillinused therapeutically

Targets gram (+)
2
Drug/Application
*Penicillin G
(benzylpenicillin - IV)
(crystaliine penicillin G – IM)
(Benzathine penicillin G – long
lasting – 1 mo)
*Penicillin V
(phenoxymethylpenicillin)
*Antistaphylococcal penicillins
(Methicillin – allegic intestinal
nephritis)
(Nafcillin – IV, preferred to above,
metabolized by liver)
(Oxacillin)
*Dicloxacillin
*Aminopenicillins
*Amoxicillin
*Ampicillin
Clinical
Uses
Mechanism
Drug Interactions/
Side Effects
Comments
 Route – IV, IM
 Syphilis – treated with
Benzathine penicillin G
 Rheumatic fever – treated
with Benzathine penicillin
G
 Neurosyphilis and
meningitis due to S.
Pneumoniae and Neisseria
meningitides.
 Meningococcal infection
 Streptococci (S. pnemo)
 Route - Oral
 Pharmacokinetics – penetrates CNS
in high doses
 Elimination: Primarily renal (10%
by glomerular filtration and 90%
tubular secretion)
 HS reaction: rash, serum
sickness, and rare
anaphylaxis
 Hematologic – Coombs (+)
hemolytic anemia, rare
 Neuromuscular
irritability/seizures –
associated with high dose
penicillin therapy in patients
with renal failure
 Probenecid - inhibits
tubular secretion, can be
used to increase blood
concentration and prolong
the half-life
 Resistance – in S.
pneumoniae and
meningococci in some
parts of the world


 Penicillin resistant
staphylococci (S. aureus)
 Treat methicillin-sensitive
staphylococcal infections
(not active against MRSA)
 Stable to staphylococcal betalactamase


 Antistaphylococcal penicillin
Structural analog of oxacillin
 Well absorbed after oral
administration
 Addition of an amino group to the
penicillin side chain
 Inhibitor of cell wall synthesis
 Not -lactamase resistant
 Distribution – Similar to other betalactams, can reach CSF in presence
of inflamed meninges
 Elimination – primarily kidney,
biliary excretion also occurs
 Hematologic – esinophilia
 Neutropenia may occur with
long course (>21d) of
nafcillin
 Hepatic dysfunction with
high dose oxacillin

 More stable in the presence
of acid than Penicillin G

Minor staphylococcal
infections
 Enhanced activity against
gram (-) bacilli
 Some streptococci
 Enterococci and L.
monocytogenes – has
more activity against than
Pen G
 E. coli, proteus mirabilis,
H. in fluenza, samonella,
and shgella
 Broad spectrum
 Route – oral
 Route – IV
 Meningitis
 Aminopenicillin
 Aminopenicillin
 Large dose – enters CSF

 Macropapular rash in patients
with mononucleosis, Chronic
Lymphocytic Leukemia, or
on allopurinol








Spectrum:
Gram (+)
Gram (-) bacilli
Formulated with betalactamase inhibitors to
increase the spectrum of
activity
3
Drug/Application
*Antipseudomonal penicillins
-lactamase inhibitors
*Clavulanate (Augmentin)
*Sulbactam (Unasyn)
Clinical
Uses
 Same spectrum as
aminopenicillins plus
additional activity against
gram (-) bacilli including
Pseudomonas aeruginosa
(used in combo with
aminoglycoside)
 IV
 Available only in fixeddose combination with
beta-lactamase sensitive
penicillins
 Inhibit beta-lactamases
produce by staphylococci,
gonococci, H. influenza,
B. fragilis, and some
enterobacteriaceae
 Used in the treatment of
intra-abdominal
infections, bite wound
infection and infected
cutaneous ulcers
 Used in combination with
AMOXICILLIN
 See above for uses
 Used in combination with
AMPICILLIN
 See above for uses
Mechanism
Drug Interactions/
Side Effects
Comments
 Exteded spectrum aminopenicillins
 Not stable against beta-lactamase
 Inhibitor of cell wall synthesis

 Subclasses
 Carboxypenicillins:
ticarcillin
 Ureidopenicillins:
piperacillin
 Beta-lactamase inhibitor
 Contain beta-lactam ring
 Covalently bind bacterial lactamase w/o intrinsic antibiotic
activity
 Non-competitive inhibition

 Other combinations:
Ticarcillin/clavulanate
Piperacillin/tazobactam
 Beta-lactam antibiotic with a betalactamase inhibitor

 Beta-lactam antibiotic with a betalactamase inhibitor

4
Drug/Application
Cephalosporins
First Generation Cephalosporin
*Cefazolin
*Cephalexin (Keflex)
Clinical
Uses
 Activity against gram (-)
bacteria increases from 1st
gen. to 3rd gen.
 Antistaphylococcal
activity decreases from 1st
gen. To 3rd gen.
 No loss of
antistreptococcal activity
 Activity against
enterobacteriaceae
superior to that of
aminopencillins
 Resistant to most lactamases
Activity against
 Streptococci
 Staphylococci
 E. coli
 P. mirabilis
 Klebsiella pneumoniae
 Useful against skin and
soft tissue infections due
to streptococcus pyogens
or S. aureus
 Prophylaxis against
infection following
surgical procedures
 IV only
 Skin/soft tissue infections
 Oral
Mechanism
 Beta-lactam ring fused to a sixmember sulfur-containing
dihydrothiazine ring
 Individual cephalosporins are
created by side-chain substitutions
 Inhibitor of cell wall synthesis
Drug Interactions/
Side Effects
Comments
 Approximately 10% crossallergenicity between
cephalosporin and penicillin
 Avoided in patients who
show IgE-mediated penicillin
allergy
 Classified into different
generations based on their
spectrum

 Used as alternatives to
penicillins in
penicillin=allergic
individuals
 1st generation


 1st generation


5
Drug/Application
*Second Generation
Cephalosporin
*Third Generation
Cephalosporin
- look for the “t” for third
*Cefotaxime
*Ceftriaxome
*Ceftazidime
Clinical
Uses
 Genrally used against
mixed aerobic/anaerobic
infections
 Against B. fragilis (ONLY
2nd gen)
 Activity against H.
influenzae (β-lactamase
producers or not)
 Community-acquired
respiratory tract infections
due to S. pneumoniae or
H. influenzae
 Against
enterobacteriaceae
 Children infections:
streptococci, S. aureus,
and H. influenzae
 Increased activity against
aerobic gram (-) bacilli
 Esp. against
Enterobacteriaceae and H.
influenza
 Reduced activity against
S. aureus
 Treat nosocomial
pneumonia: gram - bacilli
 IV
 Activity against
meningeal pathogens (S.
pneumoniae, N.
meningitidis, and H.
influenzae)
 Activity against
meningeal pathogens (S.
pneumoniae, N.
meningitidis, and H.
influenzae)
 Active against P.
aeruginosa
Mechanism
Drug Interactions/
Side Effects
Comments


 Not used for meningitis
 Cefuroxime
 Cefprozil
 Stable to beta-lactamases that are
produced by H. influenza and N.
gonorrhoeae, and many of those
produced by enterobacteriaceae

 3rd generation
 Enters CNS

 NOT effective against type
I chromosome mediated
inducible cephalosporinase
produced by Enterobacter
sp., citrobacter freundii,
serratia marcescens, and P.
aeruginosa
 Oral form is available but
has reduced activity, only
used for enterobacteriaceae

 3rd generation
 Enters CNS


 3rd generation


6
Drug/Application
Clinical
Uses
Mechanism
Drug Interactions/
Side Effects
Comments
*Fourth Generation
Cephalosporin
 Excellent activity against
enterobacteriaceae and P.
aeruginosa
 Good activity against S.
aureus


Carbapenems
 Broadest spectrum of all
antibiotic
 Beta-lactam ring fused with a 5member carbon containing penem
ring
 Inhibitor of cell wall synthesis

 Very broad spectrum
 IV only
Used against
 Streptococci
 Enterobacteriaceae
 P. aeruginosa
 Hemophilus species
 Anaerobic bacteria, inc. B.
fragilis

 Has better penetration and access
(through pore channels) to the
periplasmic space in gram (-)
bacteria
 Resistant to -lactamases
 Pharmacokinetics: low oral
bioavailability, well distributed to
most tissue, and excreted by the
kidneys
 Seizures
 Elimination: broken down by
the kidney by human betalactamase (dehydropeptidase1) to a nephrotoxic
metabolite
 Monocyclic beta-lactam – single
ring structure attached to a sulfonic
acid group
 Only binds transpeptidases of gram
(-)


 Essentially nonallergic

*Imipenem
‘Rambocillin- blows everything
away, including your kidney’
Monobactams
*Aztreonam
‘A bullet through an AZ tree is a
negative thing’
 Targets aerobic gram (-)
bacilli inc. P. aeruginosa
 No activity against gram
(+) bacteria or anaerobes
 IV only
 Cefepime – IV
 NO activity against:
MRSA
Enterococci
Listeria
B. fragilis
 Meropenum – similar
activity as imipenem but
does not produce toxic
metabolite and is slightly
more active against aerobic
gram (-) bacilli and less
active against gram (+)
cocci
 ALWAYS co-administered
with Cilastatin, a
dehydropeptidase-1
inhibitor
 NOT active against
enterococcus faecium,
legionella, mycoplasma, or
chlamydia sp.
7
Drug/Application
Glycopeptides
*Vancomycin
- Bactericidal
‘Vanquishes gram (+)’
Clinical
Uses

 Targets gram (+) bacteria
-esp. those resistant to lactams
 MRSA
 β-lactam resistant strains
of coagulase (-)
staphylococci,
enterococci, and
pneumococci
 Serious infections with S.
aureua, enterococci in pts.
intolerant of β-lactam
antibiotics
 Given orally for C. dificile
 Used as an IV
 Endocarditis prophylaxis
for selected GU or GI
procedures in β-lactam
intolerant pts.
Mechanism

 Inhibits cell wall synthesis
 Covalently binds terminal two Dalanine residue at the free carboxyl
end of pentapeptide
 Sterically hinders the elongation
of peptidoglycan backbone
 Unable to penetrate the cell
membrane of gram (-) bacteria
 Low oral availability
 Excreted unchanged by the kidneys,
half-life = 6 hrs
 Diffuses across serous membranes
into pleural, pericardial, synovial,
and ascitic fluid
 Enters CNS only at high doses
 Unaffected by beta-lactamase
production or PBR alteration
Drug Interactions/
Side Effects

 No cross-reactivity between
beta-lactams and vancomycin
 Patients with anuria, half-life
= 7 days
 Nephrotoxicity
 Ototoxicity
 ‘Redneck’ or ‘red-man’
syndrome- histamine release
w/ rapid infusion-slow
infusion better
Comments

 15% of enterococci
resistant to vancomycin
 Vancomycin-resistant
enterococci (VRE) is often
resistant to all other
antibiotics  incurable
 VanA – Genes are carried
on Transposable elements
thant encode enzymes
responsible for resistance
 D-Ala-D-Ala terminal is
converted to D-Ala-Dlactate on resistant
enterococci
 S. aureus strains gaining
enterococcal transposon
8
Drug/Application
Clinical
Uses
Mechanism
Drug Interactions/
Side Effects
Comments
INHIBITOR OF PROTEIN
SYNTHESIS

 Ribosomes are the site of protein
synthesis in both prokaryotic and
eukaryotic
 The differences in ribosomes
between bacteria and humans
provide a useful target for antibiotics
 Selective toxicity for bacteria

*Aminoglycosides
 Bactericidal for aerobic
gram (-) bacteria,
staphylococci (in combo),
and mycobacteria (in
combo)
 Used only in serious
infections due to
enterobacteriaceae and P.
aeruginosa and in a
hospital setting
 IV only
 Once daily dosing/ single
large dose – conc.
dependent killing
therefore the peak
conc./MIC ration is the
best predictor of bacterial
killing
 Significant post antibiotic
effect (PAE)
 Synergistic w/ penicillins
 Irreversible inhibitors of protein
synthesis
 Crosses outer membrane through
porin channels (passive diffusion)
 Then actively transported across the
cell membrane by an oxygen
dependent mechanism
 Binds IRREVERSIBLY to the 30S
ribosomal subunit
 Blocks initiation of protein synthesis
 Blocks further translation and elicits
premature termination
 Incorporation of incorrect amino
acid
 Absorbed poorly for GI
 Highly polar compounds – don’t
enter cell readily
 Low intracellular conc. except in
proximal renal tubule
 Do NOT enter CSF
 Excreted by kidneys – glomerular
filtration
 Half-life = 2-3 hr
 Consist of two or more amino sugars
linked by glycosidic linkage to a
hexose nucleus
 Aminoglycoside
 Nephrotoxicity –
concentrates in renal tubules Reversible
- Increased when combined
with another nephrotoxic
drug
 Ototoxicity (auditory and
vestibular) - permanent
 Risk of toxicities are dose
and duration dependent
 Control with MONITORING
 Neuromuscular paralysis
 Half-life in renal impairment
= 24 – 48 hr
 Ribosomes:
 Bacteria – total 70S
Small: 30S = 16S + 21
proteins
Large: 50S = 23S 5S rRNA’s
+ 21 proteins
 Humans – total 80S
Small: 40S
Large: 60S
 Resistance:
 Bacteria produce
transferases enzymes that
inactivate the
aminoglycoside
 Mutation of porin or of the
30S subunit
 Aminoglycosidemodifying enzymes
(AMEs) differ among
aminoglycosides – so
bacteria may be resistant to
one but not to another
 Anerobic bacteria are
innately resistant to
aminoglycosides - lack the
oxygen dependent
transport
 Other aminoglycoside: Amikacin – contains
structural change that
prevents its inactivation by
many bacterial enzymes
- Neomycin


‘A mean guy hits his opponent in
the ear and kidney. He drops,
paralyzed.’
*Streptomycin
 Activity against
mycobacterium
tuberculosis
9
Drug/Application
*Gentamicin
*Tobramycin
*Macrolides
Clinical
Uses
 Hospital use
 Anti-Tb drug
 Used in combo with
penicillin, ampicillin or
vancomycin to treat
enterococci and Listeria
monocytogenes
 IV
 Opthalmic prep available
 Most active against P.
aeruginosa
 IV
 Opthalmic prep.available
 Treat respiratory tract
infections
 Alternate to penicillin to
treat streptococcal
pharyngitis
 Atypical strains of TB
 Mild community acquired
pneumonia
 Treat hospitalized
community acquired
pneumonia (with IV 3rd
gen. cephalosporin),
Active against:
- Pneumococci
- M. Pneumoniae
- C. pneumoniae
- Legionella species
 Drug of choice to treat
pertussis and Legionella
Mechanism
Drug Interactions/
Side Effects
Comments
 Most active aminoglycoside for
synergy in combo therapy


 Aminoglycoside


 Inhibits prokaryotic protein
synthesis
 Do not affect the donor acceptor
transfer reaction
 Prevent translocation of peptidyl
tRNA from the acceptor site to the
donor site, thus halting protein
synthesis
 Macrocyclic lactone ring to which
deoxy sugars attach
 SEE BELOW
Resistance:
 Reduced permeability or
reduced active efflux of
drug
 Production of esterases that
hydrolyze macrolides
 Ribosomal binding site
mutation
 NOT active against
enterobacteriaceae or
P.aeruginosa
10
Drug/Application
*Erythromycin
‘Someone with diarrhea and
whooping cough laying a wreath on
a Legionnaire’s cross (gram +)
Clinical
Uses
Mechanism
Group A streptococci
Staphylococci
Bordetella pertussis
Corynebacterium
Diphtheriae
Campylobacter jejuni
Mycoplasma
pneumoniae
 Legionella species
 Chlamydia species
 Macrolide
 Contains two sugars moieties
attached to 14-atom lactone ring
 Administered with enteric coating
due to destruction by stomach acid
 Partly metabolized by the liver by
N-demethylation
 Mainly excreted unchanged in the
bile
 Only 5% excreted in the urine
 Do not penetrate the CSF
 Macrolide
 Semi-synthetic derivatives of
erythromycin – addition of a methyl
group
 Increased absorption
 Increased half-life
 Metabolized in the liver to 14hydroxyclarithromycin (also has
antibacterial activity)
 Eliminated via hepatic metabolism
and urinary excretion of intact drug
 Macrolide
 Semi-synthetic derivatives of
erythromycin – adds methylated
nitrogen to the lactone ring
 Increased absorption
 Increased half-life – slow
elimination
 Produces lower serum conc.
 Has a large volume of distribution,
tissue conc exceeds serum conc by
10 to 100-fold
 Penetrates most tissue
 Does NOT penetrate CSF
 Better absorption
 Eliminated in urine and feces







*Clarithromycin
 Increase spectrum of
activity
 See above plus against H.
influenza
 Active against
Mycobacterium avium
complex (pathogen in pts.
with AIDS)
 Very active against H.
pylori
*Azithromycin
 Increase spectrum of
activity
 See above plus against H.
influenza
 Active against
Mycobacterium avium
complex (pathogen in pts.
with AIDS)
 Treat urethritis and
cervicitis caused by C.
trachomatis
 Once daily therapy
Drug Interactions/
Side Effects
Comments
 High incidence of GI upsetbinds to motilin receptors
 Poorly tolerated - dyspepsia,
nausea, and vomiting
 Elevates serum theophylline
 Prolong QT interval when
combined with non-sedating
antihistamines- caution b/c of
Torsades de Pointe risk
 Interferes with the
metabolism of other drugs
 Less GI effects than
erythromycin
 Prolongs QT interval – see
above
 Available as erythromycin
base and various salts and
esters
 Weak activity against H.
influenza
 Less GI effects than
erythromycin
 Fewer drug interactions

 Primarily hepatic
metabolism
 Spectrum: extended
beyond erythromycin
11
Drug/Application
Clinical
Uses
C. Lincosamides

*Clindamycin







*Tetracyclines

‘T-A-G 30S’






Oral or IV administration
Active against:
Streptococci
Staphylococci (not
MRSA)
Anaerobic bacteria, inc. B.
fragilis
Several protoza
Used as an alternative to
beta-lactams
Inhibits prokaryotic
protein synthesis
Chlamydiae
Mycoplasmas
Spirochetes
Rickettsial infections
Legionella
Brucella
*Tetracycline
 Administered qid
*Doxycyline
 Once – twice a day
administration
Mechanism
Drug Interactions/
Side Effects
Comments
 Inhibits prokaryotic protein
synthesis
 Binds to the 50S ribosome at the
same site as macrolides
 Prevent translocation of peptidyl
tRNA from the acceptor site to the
donor site, thus halting protein
synthesis
 Do not affect the donor acceptor
transfer reaction
 Metabolized by liver


 Higher risk of
pseudomembranous colitis by
C. difficile
 Resistance due to mutation
of the ribosomal binding
site
 Causes cross-resistance to
macrolides
 NO activity against
enterococci or aerobic
gram (-) bacilli
 Binds 30S rRNA, directly blocking
the binding of the AA-charged
tRNA to the acceptor site of the
ribosome-mRNA complex
 Excreted by kidneys and in the bile
 Do not penetrate CSF
 Strong affinity for developing
bone and teeth - Yellowbrown discoloration
 GI adverse effects – nausea,
vomiting, and diarrhea
 Photsensitization
 Vestibular reactions (with
minocycline)
 CONTRAINDICATION:
pregnancy, children < 8 yrs
 Chelated by divalent or
trivalent cations - ↓
absorption with Ca, Mg, Alcontaining antacid, dairy
products, Ca supplements or
sucralfate
 See above
 Resistance- due to changes
in the transport mechanism
 decrease accumulation
of tetracycline in the
bacteria
 Widespread use 
resistance among
pneumococci, group A
streptococci, and
staphylococci
 See above

 Binds 30S rRNA, directly blocking
the binding of the AA-charged
tRNA to the acceptor site of the
ribosome-mRNA complex
 Short acting
 Binds 30S rRNA, directly blocking
the binding of the AA-charged
tRNA to the acceptor site of the
ribosome-mRNA complex
 Long half-life

12
Drug/Application
*Chloramphenicol
‘Like pouring chlorine bleach on
organisms/baby/bones’
*F. Streptogramins
*Oxazolidinones- Linezolid
Clinical
Uses
Mechanism
 Inhibits prokaryotic
protein synthesis
 NOT used as 1st line
therapy in US
 Alternative tx. for
bacterial meningitis
 Used for meningitis (S.
pneumoniae, N.
meningitidis, and H.
influenzae)
 Treat brain abscess
 Broad spectrum
 IV
 Twice daily dosing
 Gram (+) bacteria
 Against Staphylococci
(inc. MRSA),
streptococci, and
enterococcus facecium
(inc. resistant forms)
 Binds to the 50S subunit at the
peptidyltransferase site to prevent
transpeptidation
 Enters CSF and brain parenchyma
 Conjugated in liver to its inactive
form glucuronide (neonates are less
able to conjugate)
 Serious toxicity  virtually
obsolete in US
 Gray baby syndrome - ↑
serum chloramphenicol:
abdominal distension,
vomiting, cyanosis, and
circulatory collapse.
 Myelosuppression – dose
dependent (reversible)
 Irreversible aplastic anemia
(rare but fatal)
 Huge use in 3rd world
 Not effective against
enterobacteriaceae
 B form binds to the 50S ribosome
at the same site as macrolides
 Prevent translocation of peptidyl
tRNA from the acceptor site to the
donor site, thus halting protein
synthesis
 Do not affect the donor acceptor
transfer reaction
 Streptogramins A and B act
synergistically
 Rapidly cleared by nonrenal
mechanisms
 Large PAE
 Inhibitor of bacterial ribosomal
protein synthesis
 Binds to the 50S subunit near its
interface with the 30S subunit 
preventing the formation of the
70S subunit
 100% oral bioavailability
 Distribution volume of >0.8L/kg
 Good tissue penetration
 Clearance is nonrenal and
nonhepatic
 Metabolized by nonenzymatic
oxidation

Types:
 Quinpristin/dalfopristin
(Synercid) – IV

 To be approved
 Resistance is infrequent
 Gram (+) pathogens
 Inc. MRSA, penicillinresistant pneumococci,
macrolide-resistant
streptococci, and
vancomycin-resistant
enterococci
 Saved for the treatment of
resistant bugs
Drug Interactions/
Side Effects
Comments
13
Drug/Application
INHIBITORS OF DNA
SYNTHESIS
*Fluoroquinolones
Bactericidal
*Ciprofloxacin
‘Flock of sinners gyrating’
*Metronidazole
Bactericidal
‘An underground metro-no air’
Clinical
Uses
Mechanism
Drug Interactions/
Side Effects
Comments




 Oral – use in outpatient
 Broad-spectrum
 Against aerobic gram (-)
bacilli
 Enterobacteriaceae
 Hemophilus species
 Moraxella catarrhalis
 Respiratory
fluoroquinolones (newer)
– improved activity
against S. pneumoniae,
inc. penicillin resistant
strains
 The addition of fluorine atom to the
quinolone nucleus enhances activity
against gram (-) bacteria
 Inhibits both:
 DNA gyrase in gram (-) by binding
to DNA-enzyme complexes –
interfering with DNA replication
 Topoisomerase IV- gram (+)
 High oral bioavailability
 Divalent cations interfere w/
absorption
 Large volume of distribution –
penetrate prostate, lung, bile, and
ascitic fluid
 Penetrates CSF – but little clinical
use for meningitis
 Elimination by kidneys
 Others: Levofloxacin,
moxifloxacin, and
gatifloxacin
 Overuse has eroded utility
 Resistance due to 1)
mutations in DNA gyrase
and Topoisomerase IV 2)
decrease permeability
 DNA-gyrase – responsible
for introducing neg.
supercoils into the DNA
 Topoisomerase IV –
separates interlinked
daughter DNA molecules
following replication





 See above
 Generally well-tolerated
 Common: nausea, vomiting,
and diarrhea
 Occasional: HA, dizziness,
insomnia, skin rash
 Photosensitivity
 Abnormal liver function test
 Hallucinations/Delirium
 Seizures, increase risk with
NSAIDS
 Prolonged QT
 Damage growing catilage Arthropathy/tendonitis
 CONTRAINDICTION:
pregnancy, younger then 18
 Inhibits eukaryotic
topoisomerase II at high
conc.
 Increase serum theophylline
levels
 No prolonged QT
 Nausea and vomiting
 Disulfiram-like reaction with
ethanol (avoid EtOH up to 48
hrs after administration)
 Psychosis w/ disulfiram
 Aerobic bacteria –
inherently resistant, lack
nitroreductase
 Acquired resistance can
develop  decreased
uptake or decreased
nitroreductase production
Oral
Broad spectrum
Pseudomonas aeruginosa
Anthrax
Anaerobic bacteria, esp.
against B. fragilis
 Choice for C. difficile
associated diarrhea/colitis
 Certain protozoa:
giardiasis, ambiasis, and
trichomoniasis
 Acne rosacea
 Nitroimidazole
 Enters bacterial cell by passive
diffusion
 Reduced by nitroreductase 
Produce short-lived intermediate
compounds or free radicals that
interact with DNA and possibly
other macromolecules leading to the
disruption of DNA and inhibition
of nucleic acid synthesis
 Large volume of distribution
 Enter CSF and brain
 Metabolized by liver, metabolite has
antibacterial activity
 Excreted primarily in urine
 Weak activity against S.
pneumoniae
14
Drug/Application
INHIBITORS OF RNA
SYNTHESIS
*Rifamycins
*Rifampin
*Antifolates
Sulfonamides (sulfa drugs)
Bacteriostatic
Trimethoprim
Bacteriostatic
Clinical
Uses
Mechanism
Drug Interactions/
Side Effect
Comments





 Inhibit bacterial RNA synthesis by
inhibiting DNA-dependent RNA
polymerase
 Metabolized by liver
 See above
 Enters CSF
 Potent inducer of hepatic
microsomal enzymes
 Impart an orange color to all
body fluids, esp. urine
 Resistence: Mutation in the
DNA-dependent RNA
polymerase
 Hepatotoxicity
 Flu-like syndrome/ Drug
fever
 Drug Interactions: increases
the metabolism of many
drugs, e.g. glucosteroids,
oral contraceptives,
quinidine, phenytoin,
barbiturates, theophylline,
clarithromycin, ketoconazole,
intraconazole, cyclosporine,
warfarin


 Most allergenic of all
antibiotics-macropapular
rash
 Greater risk in HIV pts.
Life Threatening
 Stevens-Johnson syndrome:
flu-like syndrome involving
rash, cardiac, renal, GI, and
pulmonary complications
 Toxic epidermal necrolysis

 Resistance: organisms that
use pre-formed folic acid,
altered DHPS, increased
PABA production,
decreased permeability
 Anti-tuberculous
therapy
 Activity against
staphylococci, N.
meningiditis, H. influenza,
and Legionella
pneumophila
 Eliminate nasal carriage
state of N. meningiditis
and S. aureus
 Used orally, IV form is
also available

 Rarely used due to high
rates of bacterial
resistance and superiority
of other drugs
 Active against
Enteriobacteriaceae
 Rarely used alone
 Antagonize folate syntetic pathway
by 1) inhibition of dihydropteroate
synthetase (DHPS) 2) or
dihydrofolate reductase (DHFR)
 Antifolates
 Inhibits dihydropteroate synthase
(DHPS)- blocking bacterial
dihydrofolate synthesis from PABA
 Excreted unchanged by kidney
 Antifolate
 Inhibit dihydrofolate reductase
 Excreted unchanged by kidney


15
Drug/Application
*SulfamethoxazoleTrimethoprim
(TMP/SMZ)
Bacteriocidal
Other
*Nitrofurantoin
Anti-TB drugs
Clinical
Uses
 Oral and IV form
 UTI
 Prevention and treatment
of Pneumocystis carinii
 Enterobacteriaceae
 H. influenzae
 Many strains of
streptococci and
staphylococci

 Oral
 UTI
 Active against most
Enteriobacteriaceae and
enterococci
 Use in combination
 Duration of therapy
- Isoniazid + rifampin = 9 mo
course
- Addition of pyrazinamide
for 1st two mo, permits
shortening of total duration to
six months
 If drug resistant organism,
use 4 drugs (ethambutol or
streptomycin)
 If sputum (+) after 3 mo,
use DOT, and conduct
susceptibility studies
Mechanism
Drug Interactions/
Side Effects
Comments
 Sulfonamide and Trimethoprim
 Combination targets both steps in
folate synthesis
 Results in antibacterial activity that
is 20 –100 x greater than
sulfonamide alone
 Excreted unchanged by kidney
 Penetrates CNS – but not used
 See sulfonamides
 Not active against P.
aeruginosa or anaerobic
bacteria

 Mechanism of action unknown
 High oral bioavailability
 Low blood conc. – not adequate to
treat infection
 High urinary and renal conc.
 Activity reduced in an alkaline pH
 Empiric therapy: isoniazid, rifampin,
pyrazinamide, streptomycin, and
ethambutol
 Isoniazid and rifampin are the most
active
 Susceptibility testing is performed,
then:
 Pyrazinamide (1st 2 mos.), rifampin,
isoniazid (6 mos) if susceptible

 No cross-resistance
 Long-term use  peripheral
neuropathy and pulmonary
fibrosis
 Hemolytic anemia in pts.
with G6PD deficiency


 Not active against P.
aeriginosa
 Not effective to treat a UTI
caused by proteus species
due to alkaline pH
Difficulties with treating
Tuberculosis:
 Mycobacteria are slow
growing organisms
 Very resistant to antibiotics
 Have a lipid rich
mycobacterial cell wall,
very impermeable
 Organism mostly resides
intrcellularly, poor
penetration
 Develop drug resistance
16
Drug/Application
*Isioniazid (INH)
Bactericidal
*Rifampin
Bactericidal
*Pyrazinamide (PZA)
*Ethambutol
Bacteriostatic
Clinical
Uses
 -M. Tuberculosis
 Less active against
atypical mycobacteria
 As a single agent used for
latent infections
(prophylaxis)
 Prevention of TB in close
contacts of active cases of
pulmonary TB
 Single drug therapy
 Access poorly accessible
organisms, such as
intracellular organisms
and those sequestered in
abscesses and lung
cavities
 See antibacterials
 First-line drug used in
conjunction with INH and
rifampin in short course (6
mo) regimens
 Kills intracellular M.
tuberculosis
 Enhances uptake of
rifampin into bacteria
Mechanism
 Inhibits mycolic acid synthesis,
which are a componet of the cell
wall
 Acts on actively growing TB
 Penetrates all tissues, including CSF
 Penetrate phagocytic cells, so active
against extracellular and
intracellular organisms
 Prodrug- activated by mycobacterial
catalase-peroxidase (katG)
 Metabolized by liver Nacetyltransferase

 Inhibits RNA synthesis
 Inhibit bacterial RNA synthesis by
inhibiting DNA-dependent RNA
polymerase
 Readily penetrates most tissues and
into phagocytic cells
 Mechanism of action is unknown
 Activated by mycobacterial
pyrazinamidase
 Taken up by macrophages and
exerts its activity against
intracellular organisms residing here
 Inhibits mycobacterial arabinosyl
transferase, which is involved in
the polymerization reaction of
arabinoglycan
 Essential component of
mycobacterial cell wall
 Alters cell wall permeability
 Well absorbed, eliminated in feces
and urine in unchanged form
Drug Interactions/
Side Effects
Comments
 Genetics determines if
rapid/slow acetylators 
adjust dose
 INH-induced Hepatitis
 Peripheral neuropathy at high
doses or in slow acetylators
and in pts with predisposing
conditions (associated with
pyridoxine deficiency) –
treated with pyridoxine
 Resistance develops with
mutations in the katG
enzyme and in pther
proteins
 Single drug therapy  10
– 20% prevalence of
isoniazid resistance in
clinical isolates
 Metabolized in liver, turn
body fluids red-orange
 Hepatotoxicity
 Flu-like syndrome
 Induces microsomal
Cytochrome p450- increases
metabolism of many drugsprotease inhibitors, etc.
 Hyperuricemia that may
precipitate acute gout
(common)
 Hepatotoxicity
 No cross-resistance to
other antimicrobial drugs,
but cross-reactivity to other
rifamycin
 Resistance: altered RNA
Pol
 Dose-related: Retrobulbar
(optic) neuritis which causes
loss of acuity and red-green
color blindness
 Monitoring at high doses
 Resistance develops
quickly, so always
administered in
combination
 Resistance due to
mutations that impair
conversion of PZA to its
active form
 No cross-resistance with
INH or other
antimycobacterial drugs
17
Drug/Application
*Streptomycin
Clinical
Uses
 Active against
extracellular TB
Antivirals
* Oseltamavir/Zanamavir
 Anti-influenza
*Amantidine/Rimantidine
 Anti-influenza
 No activity against
Influenza B.
 Prophylactic and lessen
severity of symptoms
 Must be started within 48
hrs. of onset
Mechanism
Drug Interactions/
Side Effects
 Aminoglycoside antibiotic (see
under AB section)
 Binds IRREVERSIBLY to the 30S
ribosomal subunit
 Blocks initiation of protein synthesis
 Blocks further translation and elicits
premature termination
 Incorporation of incorrect amino
acid
 Penetrates cell poorly
 Inhibit steps in viral replication: 1.
absorption to and penetration into
susceptible host cell
2.
uncoating of viral nucleic adic 3.
synthesis of early regulatory
proteins 4. synthesis of RNA or
DNA 5. Synthesis of late, structural
proteins 6. Assembly of viral
particles 7. release from cell
 Neuraminidase inhibitor for both
influenza A & B-prevents binding
 Ototoxic
 Nephrotoxic
 Inhibit un-coating of viral RNA of
influenza A by binding M2
protein.
 GI intolerance
 CNS complaint –
nervousness, difficulty in
conc., lightheadedness
 Reduced dose in pts > 65 and
in pts with renal insufficiency
Comments
 serf
Non-HIV viral infections
 Influenza
 Herpes virus (HSV, VZV,
CMV)
 Hep C, RSV
 DNA viruses: ASH B
(adenovirus, small pox,
herpes, Hep. B)

 Prophylaxis
 Lessen duration of illness
by 1 day

18
Drug/Application
Clinical
Uses
*Acyclovir
 Antiherpes agent
 Oral, IV and topical
formulation
 Primary and recurrent
genital herpes
 ORAL: Shortens duration
of symptoms, time of viral
shedding, and time of
resolution of lesions
 IV: tx for herpes simplex
encephalitis and neonatal
HSV infection
 Higher doses for VZV –
shortens duration and
lesions
*Ganciclovir
 Anti-herpes
 IV and oral
 Potent activity against
cytomegalovirus (CMV)
 IV use: CMV retinitis,
colitis, and esophagitis in
AIDS pts.
 IV use: Reduces incidence
of symptomatic CMV
disease of administered
before organ
transplantation
 IV use: CMV pneumonitis
in immunocompromised
pts. in combo w/ CMV Ig
Mechanism
 Acyclic guanosine derivative that
lacks a 3’-OH on the side chain
 Converted to monophosphate
derivative by virus-specified
thymidine kinase – therefore only
active in infected cells
 Then cellular enzyme convert it to
the di and tri- compounds
 Inhibits viral DNA syn. by 2
mechanisms: 1) Competitive
inhibition of deaxyGTP for the viral
DNA polymerase 2) Chain
termination following incorporation
into the viral DNA
 Elimination: Glomerular filteration
and tubular secretion
 Enters CNS
 Acyclic guanosine analog
 Phosphorylated (activated) by CMV
protein kinase phosphotransferase or
HSV thymidine kinase
 Competitively inhibits viral DNA
polymerase
 Incorporated into DNA- chain
terminator
 Enters CNS
 Clearance related to creatine
clearance
Drug Interactions/
Side Effects
Comments
 Generally well-tolerated
 Nausea, diarrhea, and HA
 IV infusion associated with
renal insufficiency or
neurologic toxicity (may
include tremors and delirium)
 Resistance - via mutation
of viral thymidine kinase
or DNA Pol.
 Valcyclovir – L-valyl form
of acyclovir – achieves
plasma levels 3 –5 times
higher
 Myelosuppression,
particularly neutropenia

19
Drug/Application
Anti-HIV (p.44)
*Nucleoside Reverse
Transcriptase Inhibitors
(NRTI)
Clinical
Uses
 Multi-drug regimens
essential b/c resistance
develops
 Active against HIV-2 and
HIV-1
 Important component of
multi-drug regimens
*AZT (Zidovudine) / Didanosine
(ddI), Zalcitabine (ddC), Abacavir,
3TC
 Nucleoside
ReverseTranscriptase
Inhibitors (NRTI)
*Nonnucleoside Reverse
Transcriptase Inhibitors
(NNRTI)
 Specific activity against
HIV-1
*Protease Inhibitors
 Combination therapy is
necessary to combat
resistance
Mechanism
Drug Interactions/
Side Effects
Comments



 Substrate for reverse transcriptase,
which converts viral RNA into
proviral DNA before its
incorporation into the host cell
chromosome
 Pro-drug –phosphorylated by cell
enzymes
 Incorporation into DNA terminates chain elongation
 See above
 Chain terminators; viral RT is
‘sloppier’ than host enzymes, more
susceptible
 Bind directly to a site on the viral
reverse transcriptase (not same as
NRTI)
 Blockade of RNA- and DNAdependent DNA polymerase
activities
 Metabolized in liver by CYP450
enzymes
 Bind reversibly to the active site of
HIV protease, preventing cleavage
of gag-pol polyproteins into mature
products
 Prevent a new wave of infection
 High affinity for HIV proteases
 Poor systemic bioavailability
 Undergo oxidative metabolism by
CYP3A4 – occurs in liver
 Lactic acidosis
 Severe hepatomegaly with
steatosis

 See Above

 Multiple drug interactions,
including protease inhibitors
 Rapid resistance develops
– need to use as a multiregimen
 No cross resistance b/w
NNRTIs and NRTIs or
protease inhibitors
 Nausea, vomiting, diarrhea,
and paresthesias
 Glucose intolerance
 Diabetes
 Hypercholesterolemia
 Hypertriglyceridemia
 Prolonged administration –
Cushingoid syndrome: fat
redistribution, esp. central fat
accumulation, buffalo hump,
breast enlargement, and
subcutaneous lipomas
 Drug interactions occur with
other protease inhibitors,
NNRTIs and non-HIV drug
 Protease is essential for the
production of mature
infectious virions during
HIV replication
 Drugs:
Saquinavir/Indinavir/Nelfi
navir/Ritonavir/Amprenavi
r/Lopinavir
20
Drug/Application
Clinical
Uses
*Antifungals
 Systemic drugs (oral or IV)
for systemic infection
 Oral drugs for
mucocutaneous infections
 Topical drugs for
mucocutaneous infection
*Amphotericin B
Flucytosine
 IV (colloid suspension
w/bile salt, and
deoxycholate)
 First line therapy for lifethreatening mycotic
infection
 Broad spectrum, inc.
Candida albicans and
Cryptococcus neoformans
 Organisms causing
endemic mycoses
 Pathogenic molds
 Used for systemic
infections
 Intrathecal therapy for
fungal meningitis
 Lipid drug formulation
(Liposomal Amphotericin
B) – created to decrease
toxicity ($$$)
 Active only against yeasts
Griseofulvin
Fungicidal
“Ampho-terrible”
Drug Interactions/
Side Effects
Comments
 MODE OF ACTION (4 classes):
- Polyene macrolides that lead to an
alteration of membrane funtion
- DNA and RNA synthesis inhibitors
- Azole derivatives that inhibit sterol
14-α-demethylase, a key enzyme in
ergosterol biosynthesis
- 1,3-β-glucan synthase inhibitors
 Binds ergosterol (cell membrane
sterol specific for fungi) and alters
the permeability of the cell by
forming pores
 Leads to cell death
 Poorly absorbed from GI
 Large tissue distribution
 2-3% reach CNS
 Mostly metabolized, excreted slowly
in urine
 Half-life = 15 days
 No adjustment required in
hepatic/renal failure


 Binds to human membrane
sterols  toxicity
 Immediate infusion reaction:
fever, chills, vomiting, HA,
muscle spasms (prevented w/
slowing infusion rate of
decreasing dose OR by premedication with antipyretics
or meperidine)
 Renal toxicity, presents with
renal tubular acidosis, severe
K and Mg wasting
 Resistance occurs when
ergosterol binding is
imparied
 Initial therapy for serious
fungal infection, then
replaced w/ azole drug
 Facilitates entry of
flucytosine
 Converted to 5-fluoruracil
 Myelosuppression

 Concentrates in keratinized
epithelium, blocking fungal
microtubules and preventing growth.
Prevents infection of new cells.

 Resistance: Mutant
permease prevents entry
into cell





‘A grease covering the skin,
blocking further infection’
- Nystatin (topical/ ‘swish and
swallow for thrush’
Mechanism
21
Drug/Application
*Azoles
*Ketoconazole
Clinical
Uses






Broad spectrun
Candida species
Cryptococcus neoformans
Endemic mycoses
Aspergillus infections
Limited use due to toxicity
Mechanism
 Reduction of ergosterol synthesis
by inhibiting 14--demethylase
(cytochrome P450 dependent
enzyme system), inhibiting growth
 Increased affinity for fungal cP450
 See above
 Less selective for fungal P450
Drug Interactions/
Side Effects









*Fluconazole
Polyenes
 Oral
 Treatment and secondary
prophylaxis of cryptococcal
and coccidiodal meningitis
 Alters fungal cell
membrane permeability
 See above
 Enters CNS
 Good bioavailability


 Binds ergosterol, disrupting
membrane structure; causes
leakage and cell death

Relatively non-toxic
GI: nausea and vomiting
Abnormal liver enzymes
Clinical hepatitis (rare)
CP450 metabolism
Inhibition of human cP450
interferes with biosynthesis
of adrenal and gonadal
steroid hormones
Endocrine effects:
Gynecomastia, infertility, and
menstrual irregularities
Alter the metabolism of other
drugs
Other drugs can influence its
blood levels (H2 blockers and
rifamycins)
Less drug interactions
Least effect on human
cytochrome P450 system
Comments
 Other: Itraconazole

 Poor activity against
aspergillus

22
Drug/Application
Clinical
Uses
Mechanism
Drug Interactions/
Side Effects
Anesthetics
 Depth of anesthesia: ↑ BP
indicates patient is feeling
pain (too little anesthesia),
↓ BP indicates excessive
anesthesia (respiratory
depression).


Inhaled anesthetics

 Organ effects:
CNS: - Depressed
-  ICP with intracranial
masses
Respiration: -  ventilation
CV: - Depressed
- Dose-related, (-)
inotrophic effects
- Peripheral vasodilation
- Decreased blood pressure
- Nodal arrhythmia
- PVC’s
Uterus: - Inhibit contraction
Hepatic/Metabolic: - Blood
flow is diminished
- Decreased renal fxn.
Nausea and vomiting
 Nausea and vomiting
  temperature
Nitrous oxide
 Non-volatile (anesthetic)
 Quickly gets in, quickly gets out via
lungs.
 Important actions at sites in the
brain and the spinal cord.
 Act at the synapse. Interact with
the hydrophobic regions of the
membrane protein.
 Inhibition of AA GABAA and
glycine receptors by interacting
with specific sites in the
transmembrane domain 2 and 3 of
the receptor protein.
 The most hydrophobic anesthetics
are the most potent.
 Blood-gas partition coefficient: if
low, less affinity for blood, gets into
brain more easily (lower MAC).
Also leads to faster emergence from
anesthesia.
 Oil-gas partition coefficient: if high,
more affinity for CNS, less likely to
remain in blood (lower MAC). Little
effect on emergence.
 MAC = 105
 Blood-gas coefficient = 0.4
 Oil gas coefficient = 1.4

Comments
 General anesthetic:
produces unconsciousness
 Objectives of general
anesthesia: (1)
Unconsciousness (2)
Analgesia (3) SKM
relaxation (4) ↓ reflexes
(gag, etc.)
 Anesthetic activity depends
on partial pressure.
 Volume % = partial
pressure/ atmospheric
pressure
 Minimum alveolar
concentration (MAC):
conc. of anesthetic in
alveolar gas that prevents
the response to pain in
50% of patients.

23
Drug/Application
Clinical
Uses
Mechanism
Halothane/ Enflurane/Isoflurane/
Desflurane/Sevoflurane
 Volatile

IV anesthetics
 Induction or maintenance
of anesthesia
Barbiturates
 Most commonly used:
thiopental and
methohexital
 Enhance inhibitory
neurotransmission or inhibit
excitatory neurotransmission
 IV: depends on renal/hepatic
clearance. Specific antagonists may
be available.
 GABAA receptor agonist
*Sodium pentothal
Methohexital
 Thiopental
 Most commonly used IV
induction of anesthesia
 Administered by infusion
for cerebral protection
 Oxybarbiturate
 Administered rectally for
induction in children
 Highly alkaline – tissue damage if
injected extravenously

Drug Interactions/
Side Effects
Comments
 Halothane- Bradycardia
 Other volatile – mild
tachycardia
 Desflurane and isofluraneexcite CNS when inhaled
amount is sharply increased
 HTN and tachycardia
 Malignant hyperthermia:
Produces SER dumping of
Ca++, ↑ metabolism/
contraction leads to excessive
heat generation, ↑ CO2 leads
to acidosis. Fever,
tachycardia, tachypnea,
dysrhythmia, muscle rigidity,
mottled skin, cyanosis, CV
instability
 Treatment: dantrolene
(muscle relaxant).
 Dose-dependent respiratory
depression
 Cause apnea for 30 – 90 sec
after induction of anesthesia
 All volatile gases have
much lower MAC’s than
NO, this means less drug is
needed for induction
 Cardiovascular depression by
↓ myocardial contractile and
↓ systemic vascular
resistance
 May precipitate episodes of
acute intermittent porphyria





 ‘Truth serum’
 Used for cerebral
protection
24
Drug/Application
Benzodiazepines
*Midazolam
*Etomidate
*Propofol
‘Milk of amnesia’
*Ketamine
Clinical
Uses
Mechanism
 Most common: Midazolam
 Anxiolytic
 Sedation
 GABAA receptor agonists
 Administered
intramuscularly
 Administered orally as a
sedative premedication in
pediatric patients
 Used for intravenous
induction in pts. With CV
compromise
 Water soluble – less local irritation
 At physiological pH, it rearranges to
a more active lipid soluble form
 Induction and maintenance
of anesthesia or for
sedation
 Antiemetic
 Rapid emergence and a
feeling of well-being
 Ambulatory surgery
 Intramuscular induction in
children or in
uncooperative patient.
 Dissociative anesthetic
used in veterinary medicine
 2,6- diisopropylpylphenol
 GABAA receptor agonist
 Carboxylated imidazole derivative
 Pain on injection
 GABAA receptor agonist
 Structurally related to PCP
 NMDA (glutamate) receptor
blocker
 Stimulates the sympathetic NS and,
therefore, stimulates the CV system
 Direct myocardial depressant
Drug Interactions/
Side Effects
Comments
 Cardiovascular depression by
↓ myocardial contractile and
↓ systemic vascular
resistance

 Diazepam and Larazepam
also used
 Indirectly cause myoclonic
movements during induction
 Produces no CV depression
in HEALTHY patients
 CV depression in
compromised pts compensatory ↑ in
sympathetic activity
 Adrenal suppression
 Pain on injection – egglecithin emulsion
 Cardiovascular depression by
↓ myocardial contractile and
↓ systemic vascular
resistance
 Used in cardiaccompromised patients
 Increases cerebral
metabolism and intracranial
pressure
 Changes in mentation
 Catatonia, hallucinations
 Bronchodilation
 CONTRAINDICTION:
- pts. at risk for cerebral
ischemia
- Intracranial
hypertension
- Careful: critically ill
pts. with depleted
catecholamine reserves,
pts. with CAD
 Cerebroprotective action
by preventing excitatory
AA-mediated neurotoxicity
through its blockade of the
NMDA receptor
 Little respiratory
depression


25
Drug/Application
Neuromuscular blockers
*Succinylcholine
Non-depolarizing
Mivacurium
Clinical
Uses
Mechanism
 Muscle relaxants
 Tracheal intubation
 When rapid onset is
required

 Depolarizing neuromuscular
blocker, acts at NMJ
 Initially causes fasciculation
 Desensitization of Ach receptor
 Broken down by plasma
cholinesterase
 Onset within 1 min.
 Clinical duration 2-3 min.
 Full recovery 10-12 min.
 Selected on 1. Onset and
duration 2. Route of
metabolism and/or
elimination 3.
Cardiovascular side effects.
 Competitively inhibits Ach
receptor
 Partial to complete blockade occurs
over the narrow range of 75% 100% of receptor occupancy.
 Short acting
 Motor end plate acetycholine
receptor antagonist
 Duration of action 20 min.
 Metabolized by plasma
cholinesterase
 Motor end plate acetycholine
receptor antagonist
 Duration of action 30 – 45 min.
 Atracurium and cis-atracurium are
metabolized by a nonenzymatic
mechanism (Hoffman elimination)
and by ester hydrolysis
 Motor end plate acetycholine
receptor antagonist
Atracurium, cis-Atrcurium,
Vecuronium, and rocuronium
 Intermediate acting
 Rocuronium – most rapid
onset and succinylcholine
is contraindicated
*d-tubocurarine (curare),
pancuronium, doxacurium, and
pipecuronium
Long-acting
Drug Interactions/
Side Effects
Comments

 Bradycardia + asystole: rare
 Myalgias 24 to 48 hours after
administration
  IOP, ICP
 Hyperkalemia – in pts. with
UMN and LMN lesions,
major crush injuries, burns or
prolonged immobility
 Phase II block- prolonged
neuromuscular block
 Metabolism and elimination
is important in pts. with
impaired organ clearance
 CV effects:
- Vagolytic effects ↑ HR
- Autonomic block  ↓ HR
- Histamine release  ↑ HR
and hypotension
- or NO CV effects
 Histamine release

 Cholinesterase SNPs or
long-term succinylcholine
infusion can lead to phase
II block
 Vecuronium, cis-Atrcurium,
rocuronium: NO
cardiovascular effect
 Atracurium: Histamine
relaease
 Atracurium and cisatracurium are independent
of hepatic or renal function
 Pipecuronium: NO
cardiovascular effects
 Pancuronium: Vagolytic
effect
 D-tubocurarine: Autonomic
ganglionic blockade and
Histamine release

 Antagonized by
neostigmine.
 Neostigmine side effects
blocked by atropine
 Blockade is monitored by
electrical stimulation of
nerve

26
Drug/Application
Clinical
Uses
Mechanism
Drug Interactions/
Side Effects
Comments
 Produce a transient and
reversible loss of sensation
in a circumscribed area of
the body
 Topical anesthesia
 Blockade of peripheral
nerves
 Spinal or epidural
blockades
 Intravenous regional
anesthesia
 Systemic uses: Antiarrhythmic, pain syndromes
 Interfere with nerve conduction, by
blocking the influx of Na+ ions,
thereby preventing the
depolarization of the nerve
 Binds to sodium channels at site
exposed during activity
- More active neurons are more
quickly blocked
- Blocks both sensation and motor
function
- Conformational change
 80% block required for anesthesia
 Does not alter resting membrane
potential or threshold potential
Systemic Toxicity
 Initial symptoms: CNSlightheadness, dizziness,
seizures, tinnitus
 Higher serum conc.: ↓
myocardial contractility and
systemic vasodilatation 
hypotension (blocks
sympathetic conduction)
 High systemic conc.: Cardiac
arrhythmia (inc. VF)

 Mostly hydrolyzed by plasma
cholinesterase

*Procaine
 Route – infiltration, spinal
Chloroprocaine
 Route – epidural
 Peripheral nerve block


Tratrcaine
 Route – topical, spinal














 Allergenic reactions can
occur
- Skin rashes
- Bronchspasms



 Allergic reactions: RARE
 Stable in solution


Local anesthetics
Esters
Amides
*Lidocaine

 Route – topical, infiltration,
spinal, epidural
 Peripheral nerve block
 IV regional anesthsia
Sodium channel blocker
Slow onset
Short duration
Sodium channel blocker
Fast onset
Short duration
Sodium channel blocker
Slow onset
Long duration
Metabolized in the liver
Sodium channel blocker
Fast onset
Moderate duration





PHYSIOCHEMICAL
CHARACTERISTICS:
The more lipid soluble, the
more potent
The lower the pKa and the
greater the lipid solubility
 greater rate of onset
The lower the pKa  more
anesthetic in unionized
form
The uncharged form (base)
diffuses more readily than
charged form (acid)
Duration of action
correlates with the degree
of binding to generalized
proteins in vitro

27
Drug/Application
Clinical
Uses
Mechanism
Drug Interactions/
Side Effects
Opioids
 Narcotic analgesic
 Opium-like drugs
 Cross tolerance occurs to all
members of opioid class
 Opioid poisoning: coma,
pinpoint pupils, respiratory
depression
*Morphine
 Pain management
 Given parenterally, but in
large doses it is effective
orally
 Hospice Mix – morphine +
flavored syrup
 Antitussive (rarely used)
 Antidirrheal (rarely used)
 Major active ingredient in opium
 opioid receptor agonist
 Receptors located on nerve cells in
the brain, spinal cord, digestive
system, etc
 Low oral bioavailability
 Metabolism – inactivated by
glucuronide formation in the liver
then excreted in urine
 0.02% of dose crosses BBB
 Crosses placenta
 Ion trapping in stomach
 Duration of action: 4 –6 hours
 Effects:
- CNS: Inhibitory: Analgesia,
Euphoria, Drowsiness,
Respiratory depression,
Depression of cough reflex,
Decreased sympathetic outflow
Stimulatory: Stimulation of CTZ,
Release of PRL and ADH,
Miosis
- Cardiovascular: Bradycardia,
Decrease BP, Postural
hypotension, Release Histamine
 peripheral vasodilatation,
Cerebral vasodilatation due to
increased pCO2  Increased ICP
-Constipation, Inhibits gastric
emptying, Inhibits flow of bile,
Enhances absorption of fluid
 OPIOID POISONING Triad:
Respiratory Depression,
coma, miosis
 Nausea and vomiting
 Constipation
 Orthostatic hypotension
 Dependence develops after
long term therapy
 Opioid withdrwal syndrome
- 8-12 hr: lacrimination,
rhinorrhea, yawning,
sweating
- 10-16 hr: Restless sleep
- 16-24 hr: anorexia, dilated
pupils, restlessness, tremor,
gooseflesh
- 48-72 hr: PEAK- anorexia,
severe sneezing, irritability,
insomnia, diarrhea,
chills/sweats, abdominal
cramps, orgasm, muscle pain,
leg muscle spasms, waves of
gooseflesh
- 7-10 days: recovery form
acute phase of withdrawal
- Months: Narcotics huger
Comments
 Physical dependence:
desire to avoid withdrawal
 Psychological dependence:
preference for drugged
state
 Alcohol extract of opium –
Laudanum
 Deodorized camphorated
tincture of opium –
Paregoric
 Acute withdrawal state can
be stopped with an
opioid agonist
28
Drug/Application
Clinical
Uses
*Heroin
 Not medically used
*Codeine
 Antitussive
 Antidiarrheal
 Pain management – not as
effective as morphine
*Meperidine (Demerol)
 Analgesics
Methadone (Dolophine)
 Oral analgesic
 Antitussive
 Heroin addict rehab –
prevents withdrawal
Mechanism
 Diacetylmorphine
 Opioid receptor agonist
 3 – 5 times more potent then
morphine
 Crosses BBB much more effectively
than morphine, where it is converted
rapidly to morphine in brain.
 Methylmorphine
 Opiod receptor agonist
 1/6 – 1/10 as potent as morphine
 Demethylated in brain to form
morphine
 Orally active – resists hepatic
metabolism
 Phenylpiperidine derivative
 Opioid receptor agonist
 10% as potent as morphine
 Short duration of action (2 –4 hr)
 Not antitussive or constipating




Diphenylheptane derivative
Opioid receptor agonist
Orally bioavailable
Does not induce euphoria
Drug Interactions/
Side Effects
Comments
 High abuse potential

 Low abuse potential

 Respiratory depression
 Convulsions – toxic
metabolite (normeperidine)
 Does NOT suppress cough
reflex
 NON-constipating
 Abuse potential = morphine
 Antitussive
 Constipation
 Withdrawal – more rapid
time course than for
morphine and heroin
 Rehabilitation- eliminates
needle fixation, prevents
withdrawal for 24+ hrs,
given in doses large
enough to induce tolerance
to heroin, allows for
stabilization, pts become
addicted to methadone vs.
heroin
29
Drug/Application
Other Opioid Agonist
d-Propoxyphene (Darvon)
Fentanyl (Sublimaze)
*Dextromethorphan (Romilar)
Diphenoxylate and Loperamide
Opioid Antagonist
*Naloxone (Narcan)
Clinical
Uses

 Analgesic
 Anesthesia
 Epiduraly following
abdominal or pelvic
surgery
 Antitussive (OTC)
 Antidiarrheal
 Reverse effects of opioid
agonist drugs
 Reverse opioid agonist
effects during an overdose
Naltrexone (Trexan)
 Prevent opioid readdiction
in detoxified patients
Opioid Agonist-Antagonist
 Analgesics
Pentazocine (Talwin)
 Analgesic
*Buprenorphine (Temgesic)
 Analgesic
 Treatment for opioid
dependent persons
Mechanism
Drug Interactions/
Side Effects
Comments

 Weak opioid agonist
 Strength between aspirin and
morphine
 Potent opioid receptor agonist
 80x more potent than morphine
 Short duration of action

 Moderate abuse potential


 High abuse potential

 Specific opioid receptor agonist
 Not analgesic
 Opiod receptor agonist

 Vey low abuse potential





  receptor competitive
antagonist
 Contains a bulky allyl group
substitution at the nitrogen function
of the piperidine ring
 Poor oral bioavailability
 Short duration of action (1 – 4 hrs)
  receptor competitive
antagonist
 High oral bioavailability
 Antagonist effects at  opioid
receptor
 Agonist actions at opioid
receptor
 Weak antagonist effects at 
opioid receptor
 Agonist actions at opioid
receptor
 Non-toxic – but must be
administered slowly to avoid
triggering a opiod withdrawal
syndrome
 IV


 Less abuse potential than
opioids

 Respiratory depression at low
dose BUT has ceiling effect
i.e. not dose dependent
 Low abuse potential
 High doses – dysphoria and
psychomimetic effects
 May precipitate withdrawal
symptoms in a person with
opioid tolerance dependence


 Potent partial opioid agonistantagonist
 Schedule III drug
 Does NOT replace
methadone therapy
30
Drug/Application
Anti-inflammatory Drugs
NSAIDS
Clinical
Uses
Mechanism

 Analgesic (esp. HA and
Somatic pain)
 Antipyretic
 Anti-inflammatory
(alleviate symptoms)

 COX-1 and COX-2 inhibitors
 Anti-inflammatory/Antipyretic:
blocks synthesis of TNF- and IL-1,
which normally act on anterior
hypothalamus to synthesize PGE2.
PGE2 raises the ‘set-point’ and
causes edema.
 Analgesic: Somatic pain results from
inflammation that triggers paininducing PGs.
Drug Interactions/
Side Effects

 Due to the inhibition of
COX-1
 Blocking PGI2: GI
intolerance/ulceration- PGs
maintain blood flow and
reduce acid secretion
 Blocking PGI2 and PGE2:
Renal insufficiency/
hypertension- PGs increase
renal blood flow; can lead to
fluid retention. Caution in
those with hypertension or
CHF using ACE inhibitors or
diuretics.
 Blocking PGF2: Inhibits
uterine contraction-prolongs
pregnancy, increases
perinatal mortality and risk of
postpartum hemorrhage
(contraindicated in 3rd
trimester)
 Blocking TXA2: Decreases
platelet aggregation
 Aspirin induced
asthma/allergy: due to
shunting to LOX pathway
 Reye’s syndrome- associated
febrile illness/ viral infection,
do not give salicylates to
children
Comments

 General Properties of
NSAIDS:
 Most are effective against
fever, pain, and
inflammation
 Gastrointestinal upset is a
frequent side effect
 Most show cross
sensitivity in aspirin
sensitivity
 Most are highly bound to
plasma proteins
 Symptoms of inflammation
are affected more than the
underlying cause.
31
Drug/Application
Clinical
Uses
Mechanism
*Aspirin
 Reduce fever
 Diminish pain (dull, aching
pain)
 Anti-inflammatory
 RA
Ibuprofen

 Irreversibly acetylates COX-1
(which is constituently expressed)
 Blocks COX-2 (responsible for
inflammatory actions)
 ↓edema: Decreased pathological
movement of fluid and cellular
elements from the vasculature
 Decreased migration of leukocytes
into tissue by decreasing adhesion
molecule expression, and, therefore,
decreased release of lytic enzymes
 Antipyretic: Leukocytes release IL1, which causes the formation of
PGE2 by the COX enzyme (blocked
by aspirin )that acts on the
thermoregulatory region of the
anterior hypothalamus, raising the
set point. Suppress the production
of TNF and IL-1B
 Analgesic: Inhibition of the
synthesis of PG’s, mainly peripheral
pain
 Anti-inflammatory: Blocks
expression of leukocyte adhesion
molecules. Induces synthesis of
lipoxins and adenosine release (both
anti-inflammatory).
 Metabolized in liver; 1st order at low
conc., zero order kinetics at high
conc.
 COX-1 and COX-2 inhibitor
*Celecoxib (Celebrex)
 Arthritic conditions
 Selective COX-2 inhibitor
Rofecoxib

 Selective COX-2 inhibitor
Drug Interactions/
Side Effects
Comments
 See above
 Most effective anti-platelet
NSAID because of
irreversible acetylation
 Gastrointestinal toxicity
 Reversible renal failure in pts.
with intrinsic renal disease
who are > 65, HTN, CHF,
using diuretics and ACE
inhibitors
 No gastrointestinal side
effects

 Use with misoprostol (PG
analog) – provide
gastrointestinal protection
 Not used prophylatively
against MI
 Not used prophylatively
against MI
32
*Acetaminophen (Tylenol)
 Analgesic
 Antipyretic
 Less effective in reducing
inflammation
 Not effective in reducing
peripheral inflammation or
producing endogenous
antipyretics
 Inhibits COX-3, located in brain
tissue
 3 Metabolic Pathways: Metabolized
by glucuronidation (60%), sulfation
(35%), and oxidation mediated by
cytochrome P450s (3%)
 Oxidation products are toxic but are
detoxified by glutathione (limited
amount in liver)
Corticosteroids
 Glucocorticoid activityincrease glycogen
deposition, antiinflammatory
 Mineralocorticoid activitymimics aldosterone:
sodium retention
 USES: anti-inflammatory,
Immunosuppresion
 Oral
 Inhalation: Asthma
 IV or IM
 Topical
 Endogenous cortisol- Hypothalamus
secretes CRH, stimulates ACTH in
anterior pituitary, regulated by
negative feedback from cortisol.
 Carbohydrate metabolism – Increase
gluconeogenesis by converting AA
to glucose and glycogen; induce
hepatic enzymes that increase
formation of glucose from pyruvate
 Lipid metabolism – redistribution
that causes buffalo hump and moon
face

 Anti-inflammatory: 1. Promotes
transcription of the gene encoding
IκBα, which inhibits transcription of
inflammatory cytokines (IL-6 and
IL-8) by binding to the transcription
factor NF-κB. 2. Produce peptides
that stabilize membranes and
reduce release of arachidonic acid.
 Anti-inflammatory activity: 1
 Mineralocorticoid activity: 1
 Short duration of action
Hydrocortisone (cortisol)
 Well tolerated
 Hepatic injury (centrilobular
necrosis) with doses > 4g/day
 Interactiion with ethanol:
Acutely: EtOH induced
cytochromes (no effect
because cytochromes are
occupied with EtOH met.)
Chronic followed by
abstinence: Now
cytochromes metabolize
acetaminophen →toxic
metabolite
 Exacerbated by glutathione
depletion seen in alcoholics
 Muscle atrophy due to
gluconeogensis
 Glycogen deposition in liver
 Exacerbates peptic ulcers
 Painless perforation
 CNS toxicity: Insomnia,
changes in mood, irritability,
psychopathy
 Immunosuppressive
 Glaucoma, lens opacities
 Osteopenia/osteonecrosis
 Acute adrenal insufficiency
after abrupt withdrawal
 Diabetes mellitus

 Treat hepatotoxicity with
acetylcysteine- helps
replenish glutathione
 Considerations when
selecting a steroid:
- Anti-inflammatory effects
- Sodium retention
- Deposition of liver
glycogen
 Doesn’t stop RA disease
progression
 Prototype natural
glucocorticoid
33
Drug/Application
Clinical
Uses
Mechanism
Dexamethasone




Asthma
AI disorders
Inhalation, oral
Anti-inflammatory
activity: 25
 Mineralocorticoid activity:
0
 Long duration of action






Betamethasone





*Prednisone
Migraine-treatment
*Ergotamine and DHE
 Ergot based
 Chronic use of NSAIDs
can lead to headache
syndrome
 Moderate to severe
Migraine treatment
Anti-inflammatory activity: 5
Mineralocorticoid activity: 1
Intermediate duration of action
Anti-inflammatory activity: 25
Mineralocorticoid activity: 0
Long duration of action
Anti-inflammatory activity: 25
Mineralocorticoid activity: 0
Long duration of action
Vascular phase: triggered by
changes in serotonergic brain stem
function  constriction then dilation
of vessels (due to spreading cortical
excitation-aura)  activation of CN
V nocieoceptive pathways with
neurogenic inflammation
 Complex 5-HT, DA, NE partial
agonist/antagonist
 Constriction of arteries and veins
Drug Interactions/
Side Effects
Comments

 Prototype synthetic
glucocorticoid


 Cushing’s Disease test:
 Pituitary (ACTHproducing) tumor is
cortisol resistant: 
cortisol,  ACTH but
ACTH inhibited by
exogenous (high dose)
dexamethasone
 Adrenal (cortisolproducing) tumor: 
cortisol, significantly 
ACTH- will show no
further ACTH drop
 Ectopic ACTH-producing
tumor:  cortisol, 
ACTH, non-responsive to
dexamethasone challenge



 Nausea
 Induce abortion
 Contraindication in
pregnancy, HTN, coronary,
cerebral, and peripheral
vascular disease
 DHE is a more efficacious
vasoconstrictor
34
Drug/Application
*Sumatriptan (Imitrex)
Prophylactic therapy
*Methysergide
Clinical
Uses
Mechanism
 Moderate to severe
Migraine treatment
 Available in US: subcu,
oral (IV elsewhere)
 Selective agonist 5HT-R1 located in
extracranial circ. to cause
vasoconstriction.
 More than 2-3 attacks/mo
 Last longer than 48 hrs
 Significant functional
impairment
 Inadequate relief for tx or
have unacceptable side
effects
 Attacks occur after a
prolonged aura
 Prophylactic prevention of
migraine
 Given intermittently with
monitoring for fibrotic
complications







Drugs used:
Beta-blockers
TCA
Calcium channel blockers
Anticonvulsants
Combo of above
MAO inhibitors – interactions with
many foods (COUNSEL!!!)
 Ergot derrivative
 Complex 5-HT, DA, NE
agonist/antagonist
Drug Interactions/
Side Effects
Comments
 Anaphylaxis
 Contraindication in
pregnancy, CAD,
postmenopausal, men >40,
diabetes, obesity, HTN,
smokers, hyperlipidemia,
family hx. of vascular disease

 First does given under
medical supervision
 Retroperitoneal fibrosis with
ureteral obstruction
 Contraindiction in CAD,
gastritis, HTN, connective
tissu disease and pregnancy


35
Drug/Application
Anti-Rheumatic Drugs
*NSAIDS
*Corticosteroids (Low dose)
Clinical
Uses
 Rheumatoid Arthritis:
morning stiffness >1 hour
 Swelling in hands and 3
other joints
 Erosion on X-ray
 Rheumatoid
nodules/pannus:
inflammatory exudate
overlying synovium
 Rheumatoid factor (IgM 
IgG)
 See anti-inflammatory
 RA
 See anti-inflammatory
 RA
- low dose (< 7.5 mg/d)
- Intra-articular injections
can be used for individual
joint flares
Mechanism
Drug Interactions/
Side Effects
Comments


Goals of therapy:
 1. Relieve pain and
inflammation
 2. Prevent joint destruction
 3. Maintain function






 Does not affect disease
progression
 GI toxicity common
 Renal complications
 CNS toxicity
 Does not affect disease
progression
 Tapering and d/c of use is
often unsuccessful
 Low dose result in skin
thinning, ecchymoses, and
Cushinoid appearance
 Osteopenia, osteoporosis,
osteonecrosis
 Endocrine: Adrenal
insufficiency, hyperglycemia,
DM and
hypercholesterolemia
 GI: PUD with NSAIDS
 Muscle: Myopathy

COX-1 and COX-2 inhibitor
Help control inflammation and pain
Improve mobility, flexibility, ROM
Improve quality of life
Relatively low-cost
Modify gene transcription of
inflammatory and noninflammatory mediators
 Bridge gap between initiation of
DMARD therapy and onset of action
 Anti-inflammatory and
immunosuppressive effects

36
Drug/Application
Clinical
Uses
Mechanism
Drug Interactions/
Side Effects
 Anti-inflammatory
 Slow inflammatory disease
progression

 Myelosuppression
*Methotrexate





 Folic acid analog
 Antimetabolite
 Inhibits dihydrofolate reductaselimiting ‘active THF’ productionalso directly blocks DNA, RNA,
and protein synthesis
 Dosing: initial- 7.5 mg/wk,then
increase, max dose 20mg/wk
 Short half-life, renal tubular secreted
non-metabolized in urine
Sulfasalazine
 Mild-moderate RA
 Broken down to 5-aminosalicylate
(anti-inflammatory properties) and
sulfapyridine (which has some
immune modulatory affects)
 Dosing: Maintenance dose – 1 gm
BID, max. is 4 gm/day
Azathioprine
 Used for moderate to
severe RA
 Prodrug form of 6-mercaptopurine
 Inhibits nucleic acid synthesispurine analog
 Pulmonary pneumonitis
and/or fibrosis
 GI: nausea, anorexia, dirrhea,
LFTs ↑
 Skin: mucositiis
 Heme: ↓ blood counts, bone
marrow suppression
 Other: nodulosis,
opportunistic infections
 Renal tubular dysfunction
 Hepatic cirrhosis in RA
dosing
 Contraindication: EtOH
abuse, pregnancy, hepatitis,
severe hepatic, renal,
hematologic or interstitial
lung disease
 Contraindication:
Documented allergic rxn to
sulfa drugs or aspirin, severe
hepatic or hematologic
disease.
 GI: nausea, vomiting,
anorexia, LFTs
 Skin: rash, urticaria, StevenJohnsons syndrome (rare)
 Heme: neutropenia, anemia,
thrombocytopenia

DMARDs (Disease-modifying antirheumatic drugs)
The “Gold Standard”
Psoriasis
Rheumatoid arthritis
Graft vs. host disease
Wegener’s granulomatosis
Comments
 Choice of DMARD:
Cost, convenience of
administration, convenience
of toxicity monitoring,
compliance, comorbid
disease, toxicity, severity and
prognosis of patient
 Monitoring:
Initial – CBC, LFTs, alb,
hepatitis B and C serology,
consider CXR, PFT’s
F/U – CBC, LFTs, alb q 6-8
wks, creatine periodically
 Gold standard DMARD
 S-phase specific, but
effects on protein and RNA
synthesis may ‘self-limit’
this effect
 Monitoring:
Initial – CBC, LFTs, G6PD
F/U – CBC, LFTs, every 6 –8
wks.
 Not to be used in
conjunction with
allopurinol
 Rarely used
37
Drug/Application
Clinical
Uses
Mechanism
Hydroxychloroquine
 Mild RA, alone or in
combination with other
drugs (esp. Methotrexate)
 Dosing: Start 200 mg BID and keep
under 5.0 mg/kg
 Not shown to prevent erosion

 New generation DMARD
 RA
 Taken orally

 Inhibits dihydroorotate
dehydrogenase, an intermediate in
the pyrimidine synthetic pathway
(decrease synthesis)
 Reduces pain and inflammation
 Retartds structural damage evidence
by x-ray, e.g. erosions and joint
space narrowing
 Selectively targets autoimmune
lymphocytes (T helper cells)
 Early onset of action
 Binds to TNF-α to prevent binding
to receptor
 Slow radiologic progression of joint
damage (more than MTX?)
Newer DMARDs
*Leflunomide
*Etanercept
*Infliximab
 RA
 Given every 2 wks
 RA
 Given once a month
 Chimeric IgG 1K monoclonal
antibody
 Binds specifically to human TNFα
 Neutralizes TNFα biologic activity
by binding both soluble and
transmembrane forms, thus
inhibiting binding of TNFα with its
natural receptor
 Shown to prevent erosion (w/ MTX)
Drug Interactions/
Side Effects
Comments
 Contraindication: Preexisting
retinopathy
 GI: nausea, vomiting,
anorexia
 CNS: irritability, nervousness
 Heme: anemia
 Eye: retinopathy, macular
atrophy

 Hepatotoxicity
 gastrointestinal
 Monitoring:
Initial – Ophtamological
exam, G6PD (if suspected)
F/U: Ophth exam q 6 – 12
mo.













Multiple sclerosis
Aplastic anemia
Systemic infection/sepsis
Worsening of CHF
Reactivation of prior
granulomatous disease
Long-term effects unknown
Multiple sclerosis
Aplastic anemia
Systemic infection/sepsis
Worsening of CHF
Reactivation of prior
granulomatous disease
Long-term effects unknown

 Fast acting (~ 4 weeks)
 Expensive
 Better than methotrexate

38
Drug/Application
*Anakinra
Clinical
Uses
 RA
Gout treatment
Gout Characteristics:
 Acute attacks of crystal
induced arthritis
 Chronic deposits of
monosodium urate in and
around joints and cartilage
and in the renal
parenchyma
 Uric acid kidney stones
 Hyperuricemia
*Colchicine
 Acute gout – no longer
used
 Prophylaxis – low oral dose
Mechanism
 Recombinant human IL-1ra
produced in E. coli
 Identical to human IL-1ra except
with an additional 1 n-termainal
methionine
 Half-life = 6 hrs
 Reduce radiologic progression of
joint damage
 Hyperuricemia is secondary to
increased uric acid production or
decreased renal clearance.
 Causes:
Increased ProductionGout
Lesch-Nyhan syndrome
Lymphoproliferative disease
Cytotoxic drugs
Sickle cell anemia
Decreased Renal ClearanceIntrinsic renal disease
Renal failure
Gout
Lead nephropathy
Decreased excretion due to
competition
Organic acids
Increased lactate
Increased ketone bodies
Other- HTN, CAD
 Interrupts the inflammation
triggered by the phagocytosis of
urate crystals by inhibiting the
release of a chemotactic
glycoprotein from PMN and
synoviocytes
 Spindle poison
 Metaphase arrest
 Microtubular poison
Drug Interactions/
Side Effects
Comments





Multiple sclerosis
Aplastic anemia
Systemic infection/sepsis
Worsening of CHF
Reactivation of prior
granulomatous disease
 Long-term effects unknown



Oral:
 Nausea
 Vomiting
 Diarrhea
 Severe abdominal pain
IV:
 Increased morbidity and
mortality

39
Drug/Application
Clinical
Uses
Mechanism
NSAID:
 Acute Gout
 Prophylaxis
 COX-1 and COX-2 inhibitors
 Decrease the inflammation
associated with gout
*Allopurinol
 Gout prophylaxis
 Overproducers
Oxypurinal
 Gout prophylaxis
 Overproducers
 Competitive inhibitor of xanthine
oxidase
 Xanthine oxidase converts
hypoxanthine to xanthine and
converts xanthine to uric acid
 Lowers production of uric acid,
lowers serum uric acid, and
decreases uric acid excretion
 Also inhibits de nova production
of purines
 Metabolite of allopurinol
 Inhibitor of xanthine oxidase
 Also inhibits de nova production
of purines
*Sulfinpyrazone/ *probenecid
 Gout prophylaxis
 Under-excretors
 Diminish renal tubular
reabsorption of uric acid
 Promotes uricosuria
 Lowers serum uric acid
Drug Interactions/
Side Effects
Comments
 Newer drugs have fewer side
effects
 Do NOT use aspirin or other
salicylates
Immunologic
 Bone marrow depression
 Skin rash
 Vasculitis
Drug Interaction
 6-mercaptopurine and
azathioprine – cancer drug
that is metabolized by
xanthine oxidase
 Opioids and intra-articular
glucocorticoids are useful
in persons who cannot take
NSAIDs
 Transiently increases
serum uric acid levels as
uric acid is mobilized- can
lead to attack of acute gout
Immunologic
 Bone marrow depression
 Skin rash
 Vasculitis
Drug Interaction
 6-mercaptopurine and
azathioprine – cancer drug
that is metabolized by
xanthine oxidase
 Contraindication in
hyperuricemia associated
with uric acid nephropathy
 Transiently increases
serum uric acid levels as
uric acid is mobilized- can
lead to attack of acute gout
 Transiently increases
serum uric acid levels as
uric acid is mobilized-can
lead to attack of acute gout
40
Drug/Application
Ethanol
*Ethanol
Clinical
Uses
Mechanism

 Used socially
 Treat methanol poisoning
(IV)
 Treat ethylene glycol
intoxication

 Mechanism of action: Bind to
GABA type A receptors
facilitating the entrance of Cl- into
the cell thereby causing cellular
depression
 Metabolism: In the liver 1)
Metabolized by alcohol
dehydrogenase to acetaldehyde 2)
Metabolized by aldehyde
dehydrogenase to acetate 3) which is
activated to acetyl CoA in peripheral
tissues
 Both reactions are redox reactions
that increases the NADH/NAD+
ration, affecting other metabolic
pathways that require NAD+:
glycolysis, CAC, pyruvate
dehydrogenase, fatty acid oxidation,
and gluconeogenesis
 Distribution: Tissues with a high
water content and that are highly
perfused receive the most amount of
EtOH
Drug Interactions/
Side Effects

Side Effects
 Glucose intolerace
 Alcoholic hypoglycemia
 Alcoholic ketoacidosis
 Lactic acidosis
 CNS: Behavioral syndrome,
cerebellar syndrome,
Wernick-korsakoff syndrome,
cerebellar atrophy, central
pontine myelinosis,
demylination of corpus
callosum, mamillary body
destruction
 GI: local irritant, stimulate
gastric acid production,
gastric and duodenal ulcers,
vomiting, acute and chronic
pancreatitis, hepatic steatosis,
hepatitis, cirrhosis
 Withdrawal syndrome:
psychologic and physical –
treat physical with
benzodiaepines
Interactions
 Acute – Metabolized by
CYP2E1, so increases
sensitivity of drugs
metabolized by this enzyme
 Chronic – Induces CYP2E1
so the metabolism of drugs is
increased in the absence of
EtOH
 Alcoholics - develop
metabolic tolerance due to
increased CYP2E1
Contraindications
 Pregnancy – FAS
 Breast feeding
Comments

Factors influencing the BAC:
 Conc. of EtoH
 Irritant properties
 Type of beverage
 Blood flow at site of
absorption
 Rate of ingestion
 Food
41
Drug/Application
Clinical
Uses
Mechanism
Drug Interactions/
Side Effects
*Methanol

 Metabolized to formaldehyde and
formic acid
 Visual damage
 Acidosis
*Pyrazole
 Methanol intoxication

*Disulfiram
 Aversion therapy for
alcoholism




*Ethylene glycol
 Ingredient in antifreeze
Drugs of Abuse
Motives for Using
 Obtain perceived
therapeutic benefit (not
abuse)
 Improve performance
 Obtain a rewarding
subjective effect

Hallucinogens
 AKA: Psychedelics and
psychotomimetic
*Lysergic Acid Diethlamide
(LSD)
 AKA: Acid, boomers,
yellow sunshine
 Important neurotransmitters: NE,
dopamine, serotonin (5-HT)
 Induce altered states of
consciousness
 Antagonist and agonist effects on
5-HT receptors- Synesthesia
 5-HT2 on post-synaptic side, 5-HT1A
on both pre and post synaptic
neurons
 Raphe nuclei – involved in sleep,
exerts presynaptic actions at 5-HT1A
receptor to decrease function of 5HT neuron
 Agonist effects on presynaptic 5HT1A autoreceptors to decrease
release of 5-HT
Inhibits alcohol dehydrogenase
Decreases the metabolism of EtOH
Inhibits aldehyde dehydrogenase
Leads to the build up of
acetaldehyde to the point of causing
noxious effects
 ADH mediates its metabolism to
glycolic and oxalic acids






Comments
 Treated with hemodialysis,
ADH inhibitor, or IV
ethanol

Nausea
Sweating
Vomiting
Increased heart rate
Severe CNS depression
Renal damage (due to build
up of oxalic acid)
 Meabolic acidosis (due to
build up of glycolic acid)
 Psychological dependence –
results from craving for the
drugged state in preference to
the undrugged state
 Physical dependence- the
appearance of a withdrawal
syndrome in the absence of
the drug


 Produces altered perception
without clouded
consciousness
 Perceptual sphere: visual
hallucinations
 Affective sphere: extreme
emotional lability
 Cognitive sphere: variation in
logic
 Revelation: special insight
 Chronic effects – flashbacks
which are transient, chronic
abuse → depression/suicide
 Treatment: “Talk-downs”,
maintenece of a quiet
environment, subdued
lighting; Diazepam,
haloperidol, risperdone
PRN
 Treated with hemodialysis,
ADH inhibitor, or IV
ethanol


42
Drug/Application
Dimethyltryptophan
Bufotenin
Clinical
Uses
 Synthetic hallucinogen
 AKA: Business man trip
(BMT)
 Dose: 1mg
 Rarely seen in US
Pilocybin
 Magic mushrooms of
Mexico
Psychomotor stimulants
*Amphetamine

 Management of ADD or
hyperkinesis in children –
has paradoxical calming
effect
Mechanism
Drug Interactions/
Side Effects
Comments
 Same as above
 Short duration of action (30 min)
 Lethal: 10 – 15 mg/kg

 Same as above
 10 times less potent than LSD
 Same as above – acts on S-5HT1A
receptor
 10 times less potent than LSD

 Release of newly synthesized
monoamines: epinephrine,
dopamine, and NE from brain
neurons
 Rewarding effects are mediated
through the mesolimbic and
mesocortical dopamine systems















Alertness
Wakefulness
Increased vigilance
Increases physical and mental
energy
Tolerance develops rapidly
Large dose: induces euphora,
improved self-confidence,
increased speech activity, and
improved ability to
concentrate
Amphetamine-induced
paranoia
Secondary depression
Physiological effects:
increased BP, increased
temp, and appetite
suppression
Toxicity: Seizures, cardiac
arrhythmias, CVA, HTN and
severe anxiety

 Treatment of overdose:
Induce emesis, gastric
lavage, urine acidification,
haloperiodol
 Similar drugs: mescaline,
dimethoxymethylampheta
mine, and methylene dioxy
amphetamine
43
Drug/Application
Clinical
Uses
Mechanism
*Methylated Amphetamine
(MDMA)
 AKA: Adam, ecstasy,
XTC, clarity, lover’s speed
 Previously used for
psychotherapy
 Street form: MDA
 Acts at alpha receptors –
stimulating both adrenergic and
noradrenergic neurons
 Increases 5-HT release and blocks
uptakes
 MDA- metabolite
*Cocaine
 Routes of administration:
topical- nasal mucosa, IV,
smoked
 Local anesthetic
 Ingredient in Brompton’s
mixture for cancer pts
 Causes a massive release of
dopamine at the synaptic cleft
 Prevents the re-uptake of
dopamine, NE, and serotonin
 Acts on pleasure centers of brain
 Rapid onset of action when inhaled
*Phenyclidine (PCP)
 AKA Angel dust
 Often used as an adulterant
to marijuana or sold as
LSD, mescaline, etc.
 Chemically related to ketamine
 Psychotomimetic
 Open channel blocker: Noncompetitive antagonist at the
NMDA glutamate receptor (blocks
the excitatory NT)
 Reabsorbed through the
enterohepatic circulation
 Persist for days to weeks

Drug Interactions/
Side Effects
 Stimulant and psychedelic
effects
 Neronal toxicity in animal
models – destroys dorsal
neurons
 Muscle tension
 Nausea
 Blurred vision
 Chills
 MDA – Serenity, joy, insight,
and self-awareness; toxicity:
profuse sweating, skin
reactions, and confusion
 Intense euphoria
 Increased self-confidence
 Increased energy
 Chronic use: disruption of
sleeping and eating,
psychological disturbance
 Strong psychological
dependence
 Toxicity: HTN< tachycardia,
diaphoresis, mydriasis,
vasospasms  MI and CVA
 Euphoria
 Hallucinations (often
auditory)
 Can induce (+) and (-)
symptoms of schizophrenia
 R – rage
 E – erythemia
 D – dilated pupils
 D – delusions
 A – amnesia
 N – horizontal nystagmus
 E – excitation
 S – dry skin
Comments
 Treatment: talk down, and
diazepam (rarely used)
 Brompton’s mixture:
cocaine, methadone, and
alcohol
 Treatment: Acute anxiety
with Diazepam, seizures
with chlordiazepoxide,
cocaine psychosis with
haloperidol
 Treatment: Stabilization of
CV and respiratory system
and protection for selfinflicted harm. HTN –
diazoxide; Convulsions –
Diazepam; mechanical
respiratory assistance;
activated characoal
 Clinical presentation:
HTN, convulsions
 With alcohol – respiratory
depression
44
Drug/Application
Clinical
Uses
Mechanism
Marijuana
 Prepared from the leaves
and flowering tops
 Anti-emetic in cancer
 Decrease IOP
 Appetite stimulation
Chemotherapeutic agents
 Cell cycle specific (CCS): schedule-dependent
cytotoxicity (repetitive/
prolonged administration
better)
-Majortiy are active in S
phase
OR
 Cell cycle non-specific
 Active ingredient: deltatetrhydrocannabinol (THC)
 Acts on cannabinoid receptor
which is a G-protein coupled to
cyclase
 THC receptors are concentrated in
the hippocampus (memory),
substantia nigra (reticulata), and
cerebellum (motor and balance)
 No receptors in the medulla
 Fat soluble
 Slow excretion - half-life = 56 hrs,
can be detected up to 120 hrs after
last use.
 More rapidly growing tumors
(embryonal>lymphomas>sarcomas>
squamous cell
carcinomas>adenocarcinomas) are
more susceptible to
chemotherapeutic agents
 Larger tumors have central
ischemia- less blood-borne delivery
of anti-cancer agents; less O2 to
form radicals from radiation
Antiemetic
 Prevent nausea and
vomiting
 Antiemetic
 Antiemetic
 Antiemetic
*Ondansetron
Prochlorperazine
Lorazepam and Dexamethasone
Drug Interactions/
Side Effects
Comments
 Improve mood and alter
cognitive ability
 Exaggerated perception of
time
 Sense of well-being or
euphoria
 Vivid visual imagery with
novel sight and sound
 Munchies
 Motivational syndrome with
chronic use
 Chronic use - ↓ imuune
system
 Withdrawal syndrome:
restlessness, agitation,
insomnia, sleep ECG
disturbance, nausea,
cramping
 Each individual treatment
can reduce the tumor
burden by 99%
 Prevent alopecia by scalp
cooling- vasoconstriction
leads to less drug delivery

 Bone marrow: Leukopenia
and lymphocytopenia,
immunosuppression,
thrombocytopenia
 GI: Nausea and vomiting,
oral and intestinal
ulcerations, diarrhea
 Hair: Alopecia
 Gonads: Ammenorrhea,
infertility, impaired
spermatogenesis, sterility
 Kidney: Depends on cancer
 Fetus: Teratogenesis
 Nadir- low point of
myelosuppression
 Majority produce:
 - Myelosuppression
- Alopecia (reversible)

 5-HT-3 inhibitor
 Dopamine antagonist
 CNS-targeting agent







45
Drug/Application
Alkylating Agents
*Mechlorethamine
*Cyclophosphamide (Cytoxan)
*Carmustine (Nitrosurea)
Platinum Analogs
*Cisplatin
*Carboplatin
Clinical
Uses
Mechanism
Drug Interactions/
Side Effects

 Lymphomas, esp.
Hodgkin’s disease
 IV

 Alkylation of DNA
 Nitrogen mustard





 Solid tumors (lung, breast)
 Hematologic cancers
(myeloma, acute leukemia,
non-Hodgkin’s)
 IV or PO
 Also used as a DMARD
 Alkylating agent- cross-links
guanines-CCNS
 Metabolized to active form by
cytochrome P450
 Hepatically cleared, slowly excreted
in urine

 CNS tumors
 Multiple myeloma
 IV
 Alkylating agent (carbonium
ions)-CCNS
 CNS penetration
 Metabolized to active form by
cytochrome P450
 Toxic products:
-DNA alkylating corbonium –
crosslink DNA
- Isocyanates- inactivate proteins (not
anti-tumor)
 Excretion via hepatic inactivation
with urinary elimination

 Platinum analog-alkylating agentCCNS
 Binds DNA nucleophiles following
the loss of Cl- side group to the low
Cl- intracellular environment – intrastrand guanosine crosslinks most
toxic
 Platinum analog-alkylating agentCCNS
 Binds DNA nucleophiles following
the loss of carboxyl side group





Testicular cancer
Ovarian cancer
Head and neck cancer
Limited myelosuppression
 Ovarian cancer
 (Head and neck)
 Slowly activated






Phlebitis
Nausea and vomiting
Alopecia
Myelosuppression (rapid
nadir, granulocytes and
platelets)
Bladder toxin: Acrolein, a
toxic metabolite, accumulates
and causes fibrosis, acute
ulceration, ↑ risk for cancer
Myelosuppression – rapid
Nadir, ↓ thrombocytopenia
Alopecia – transient
Emetic potential – low - mod
Hepatotoxicity
Profound and delayed
myleosuppression – 6 wk.
Nadir, 8 wk recovery
Phlebitis due to ethanol
diluent

 Heavy metal damage to renal
tubular epithelium due to
reduced creatinine clearance
and BUN elevation
 Severe emesis
 Peripheral neuropathy
 Rare HS: ototoxicity
 No neurotoxic effects
 Greater myelotoxicities –
thrombocytopenia
 Decreased vomiting
Comments


 To prevent acrolein
toxicity:
 Hydrate – high urine flow
 Frequent voiding
 Nucleophilic thiols to
conjugate acrolein
 Mesna forms monomer
that inactivates acrolein


Avoid renal damage by:
 High urine flow
 Diuretic use
46
Drug/Application
Clinical
Uses
DNA Intercalating Agents

Doxorubicin (Adriamycin)
 Broad spectrum
 Heamatologic cancers
 Solid tumors, esp. sarcomas
and breast cancer
Topoisomerase Inhibitors

 Small cell lung cancer
 Refractory lymphomas
 Testicular cancer
*Etoposide
*Irinotecan
 Pro-drug
 Refractory solid tumors
 Non-small cell lung cancer

Mechanism
 DNA binding antibiotics –CCNS
 Derived from streptomoycetes
 Plana chromophore slides b/w
stacked nucleotides in DNA helix –
distorts helix
 Anthracycline Antibiotic
 Intercalation of DNA blocks both
DNA and RNA synthesis
 Quinone moiety promotes radical
formation
 Inhibition of DNA Topoisomerase
II – Accentuates strand breaking
activity of topo II while inhibiting
ligase activity, leading to cell lysis
 Long half life (24 –36 hrs)
 Biliary secretion

 Epipodophyllotoxin derivative
 DNA Topoisomerase II inhibitor
 CCS for G2 phase
 Results in the production of DNA ds
breaks
 Topoisomerase I inhibitor
 CCS for late S/early G2 phase
 Stabilizes TOPI –I nicked DNA
‘cleavable complex’ causing strand
breaks to persist
 Hydrolyzed to active product
 Half-life: 11 hrs
 Glucuronidated in liver
Drug Interactions/
Side Effects
Comments
 Myelosuppression
 Myelosuppression – short
Nadir (8 – 10 d)
 Moderate nausea and
vomiting
 Alopecia – prevent w/ scalp
cooling
 Congestive heart failure-heart
has low antioxidant activity –
prevent w/ continuous drug
infusion
 Colors urine red

 Myelosuppression:
granulocytopenia, short nadir
(8 – 10 d)

 Diarrhea
 Myelosuppression:
Neutropenia
 Topiomerase I – alter the
topology of DNA during
transcription and
replication
 Schedule-dependent
toxicity – frequent
administration to increase
toxicity


47
Drug/Application
Clinical
Uses
Antimetabolites

*6-Mercaptopurine
 Oral adminstration to organ
allograft pts.
 Oral admin: remission of
ALL in children
*Cladribine (2-cda)
 Hairy cell leukemia –
curative
 Non-Hodgkins lymphomas
 CLL
 Infusion for 7 d
 Remission induction and
maintenance of acute
myelogenous leukemia
 Infuse for 5 – 10 d
*Cytarabine
*Gemcitabine (Gemzar)
 Palliative care of pancreatic
cancer – reduces pain,
maintenance of wt,
increased energy level
*5-Fluorouracil
 Colon cancer
 Solid tumors: breast, head
and neck
 IV – constant infusion
Mechanism
 Structurally similar to DNA and
RNA
 Needs metabolic activation
 Schedule dependent toxicity
 Dose-limiting myelosuppression
 Purine antimetabolite-CCS for S
phase
 Inhibits de novo purine
biosynthesis
 Blocking the amination of
phosphoribosyl pyrophosphate by
glutamine
 DNA miscoding by direct insertion
of metabolite of 6-MP into
DNA/RNA
 Inactivated by xanthine oxidase
 New purine antimetabolite- CCS for
S phase
 Inhibits adenosine deamininase leads to lethal accumulation of
deoxyribonucleosides in cells
 Cytidine (pyrimidine) analog-CCS
for S phase
 Inserted in growing DNA chain
 DNA chain terminator
 Inactivation by deaminase (liver)
 Cytidine (pyrimidine) analog-CCS
for S phase
 Inhibit deoxycytidin synthesis
 Insertion into chain – premature
DNA chain termination
 Uracil (pyrimidine) analog- partially
CCS for S phase
 Inhibits DNA synthesis by
inhibiting thymidine biosynthesis
– forms complex: FdUMP-reduced
folate-thymidylate synthetase
 RNA chain terminator by insertion
 Plasma half-life: 10-20 min
Drug Interactions/
Side Effects
Comments


 Granulocytopenia
 Do not use w/ allopurinol
 Azathioprine is prodrug
form of mercaptopurine
 Myelosuppression

 Myelotoxicity
 Conjunctivitis – acute
 Cerebellar dysfunction –
chronic

 Well-tolerated – low toxicity
 Does not increase survival
 Myelosuppression – minor
with continuous infusion,
major w/ intermittent tx
 Stomatitis
 Diarrhea

48
Drug/Application
Clinical
Uses
Mechanism
*Imatinib (Gleevec)
 Chronic myelogenous
leukemia
 Gastrointestinal stromal
tumors
 Dose and schedule
dependent
*Methotrexate
 Cancers: ALL, osteogenic
sarcoma, breast, head and
neck, cervical
 Non-malignant: psoriasis,
RA, GVHD, Wegener’s
 Can be administered
directly into CNS
*Leucovorin
 Treat MTX toxicity
Microtubular Inhibitors
*Vincristine

 Hematologic cancers
*Vinblastin
 Solid tumors
 Inhibits t(9;22) bcr-abl tyrosine
kinase, stopping cell proliferation
and inducing apoptosis
 Metabolized by CYP3A4,
eliminated in feces
 Half life 18 hr (parent), 40 hr
(metabolite)
 CCS for S phase – self limited
 Folic acid antagonist
 Inhibit DHFR – blocks conversion
to THF (active form)
 Inhibition of thymidylate synthetase
– blocks DNA syn.
 Half-life: 2-4 hrs
 Renal tubular secretion
 Fully reduced folate
 Given 24 – 48 hrs after high dose
MTX

 Vinca alkaloid
 CCS- M-phase microtubule
inhibitor, binds in S phase
 Bind tubulin subunits, capping the
microtubule and preventing
elongation, disrupting chromosome
segregation
 Long half-life – 30 hrs
 Excreted in bile
 Vinca alkaloid
 CCS- M-phase microtubule
inhibitor, binds in S phase
 Bind tubulin subunits, capping the
microtubule and preventing
elongation, disrupting chromosome
segregation
 Long half-life – 30 hrs
 Excreted in bile
Drug Interactions/
Side Effects





Unusually well-tolerated
Nausea
Fluid retention
Muscle cramp
Chronic tx: suppression of
WBC and platelets
Comments
 Resistance: Point mutation
or c-abl overexpression
 Bcr-abl tyrosine kinase –
only in tumor cells
 Lethal myelosuppressionreversed by Leucovorin –
fully reduced folate – given
24 – 48 hrs. high dose MTX
 Mocositis
 Dermatitis
 Renal tubular dysfuction
 Daily doses: cirrhosis

 Resistance: DHFR gene
amplification

 Peripheral neuropathy –
Parethesis, ↓ reflexes,
paralytic ileus, jaw pain
 SIADH – rare
 Management- delay or reduce
next dose
 NOT myelotoxic

Tubulin fxn:
 1) Intracellular solute
transport
 2) Cell movement
 3) Nuclear scaffolding
 4) Formation of mitotic
spindles
 Myelotoxic: granulocyte and
platelet suppression
 Short Nadir: 8-10 d
 Infection and bleeding
 Tumor pain – rare
 Management – Antibiotics or
platelet transfusion


49
Drug/Application
Clinical
Uses
*Paclitaxel (Taxol)
 Solid tumors
 Advanced and refractory
ovarian cancer
 IV
Steroid Hormones

 Breast cancer
 Suppressive but notcurative in estrogenresponsive tumors
 May be efficacious in
tumors that are estrogen
receptor negative (rarely)
*Tamoxifen
*Megestrol
 Breast cancer
*Anastrozole
 Breast cancer
*Leuprolide
 Prostate cancer
 Palliative care inc.
decreased bone pain
 Subcu pellet in abdomen
Monoclonal Antibodies

 HER2-/Neu (+) Breast
cancers
 Highly effective in combo
with cytotoxic drugs
*Trastuzumab (Herceptin)
*Rituximab (Rituxan)
 B cell non-Hodgkin’s
lymphoma
Mechanism
Drug Interactions/
Side Effects
Comments
 CCS- M-phase microtubule
inhibitor
 Binds complete microtubules,
causing clumping and disrupting
mitosis
 Short half-life 6-8 hrs
 Excreted in bile

 Anti-estrogen-CCNS
 Breast estrogen receptor
antagonist
 Bone, endometrium estrogen
receptor agonist
 HS rxn to Cremophor EL –
bronchospsms, dyspnea,
hypotension
 Myelosuppression – short
Nadir (10-14d)
 Peripheral neuropathy
 Cremophor EL (vehicle) –
premedicate with
dexamethasone,
diphenhydramine, or
ranitidine, cimetidine

 Acute disease flare
 Menopause symptoms inc.
hot flashes













 Hormonally dependent
breast cancers:
 Post menopausal
 ↑ estrogen and
progesterone receptors
 Response to hormonal
manipulation
 Long disease-free period
after 1º tx

Progestin agent
Decreases Estrogen receptors
Enhances estrogen metabolism
Reversible selective aromatase
inhibitor – blocks estrogen syn.
 GnRH derivative
 Acutely: agonist - ↑ FSH and sex
hormones
 Chronically: antagonist - ↓ FSH and
sex hormones (castration levels)

 Humanized murine Ab binds to
erb-b2 receptor (HER-2/Neu),
member of EGFR family.
 Leads to antibody dependent cellular
cytotoxicity
 Humanized murine monoclonal
Ab binds to CD20
 Blocks cell signaling (proliferation)
→ apoptosis
Appetite and weight gain
Fluid retention
Vaginal bleeding
Lethargy
Adrenal insufficiency
Dermatitis
Well-tolerated
Hot flashes
 Give w/ dexamethasone
and mineralocorticoids


 First infusion rxn – fever,
chills, and rigors
 Enhanced antracyclineinduced cardiotoxicity

 Erb-b2 receptor –overexpressed in 20-25% of
breast cancers- poor
prognosis
 First infusion rxn
 CD-20: on immature B
cells
50
Drug/Application
Clinical
Uses
Mechanism

 Decrease Parkinson signs
 Initial improvement
 Chronic use: effectiveness
decreases due to
progression of disease

 Dopamine precursor - restores
dopamine conc. in the basal ganglia
 Low bioavailability due to
decarboxylation and MAO in gut
*Pergolide
 Parkinson
 Used in combo w/ levdopa
 Dopamine receptor agonist –
mimics endogenous dopamine
*Seligiline
 Effective in early Parkinson
 Can be used in combo with
levodopa
*Benztropine
 Useful in patients taking
neuroleptics
 Selectively inhibits MAO-B, in
dopaminergic neurons
 Increases Dopamine by preventing
metabolism
 Muscarinic receptor antagonist
*Amantidine
 Parkinson’s
 Benefit decreases with
long-term use
Parkinson’s Drugs
*Levodopa (w/ Carbidopa)
 Antiviral drug
 Releases endogenous dopamine (?)
Drug Interactions/
Side Effects

 Choreiform movements of
face and limb – limits dose
 On-off effect
 Nausea and anorexia –
treated w/ peripheral
dopamine antagonist
 Hypotension
 High doses: psychotic effects
– confusion, insomnia, and
nightmares
 Paranoia
 Hallucinations
 Confusion and Nightmares
 Dyskinesia
 Vomiting
 Less wine-cheese effect
 Fatal hyperthermia in combo
w/ meperidine, fluoxetine, or
cocaine
 Dry mouth
 Heat stroke
 Impaired vision
 Urinary retention
 Constipation
 Drowsiness
 Confusion
 Minor
Comments

 Administered with
peripheral dopa
decarboxylase inhibitor
(carbidopa)
 Decreases levadopa side
effects
 Does not retard
neurodegenerative process


51
Drug/Application
Anti-anxiety Drugs
*Buspirone
*Diazepam
Clinical
Uses

 Anti-anxiety
 Takes 1 wk to work
 Oral
 Anti-anxiety and insomnia
 Sedation in mania
 Spastic due to CP or
tetanus
 Anesthesia – milk of
amnesia
 EtOH detox
 Seizures – status
epilepticus
 Block sedating effects of
benzos
 Schizophrenia
 Intractable hiccups
 Huntington’s chorea
 Ballism
 Tourette’s syndrome
 Acute psychotic depression
Mechanism







Mechanism unknown
Serotonin 1a receptor agonist (?)
Half-life 2-4 hrs
Metabolized in liver
Long-acting benzodiazepine
GABA-A receptor agonist – binds
to alpha-2 subunit plus others to
increase Cl channel opening thereby
hyperpolarizing the cell
Half-life 20-80 hrs
Penetrates CNS
Liver metabolism, renal excretion
Active metabolite
Benzodiazepine receptor
antagonist
Act mainly on D2 receptors, with
the atypicals also acting on serotonin
receptors
Also have limited action at αadrenergic, cholinergic, histamine
Higly lipophilic
Metabolism by cP450
Drug Interactions/
Side Effects

 Mild sedation
 No withdrawal syndrome






 Gradual withdrawal to
avoid seizure
 Alpha-2 subunit – binding
here causes anti-anxiety
effects
 Other subunits are
responsible for anesthetic
effects

*Haloperidol
 (+) Symptoms of
schizophrenia
 Typical anti-psychotic
 Blocks D2 receptors in the limbic
and mesocortical areas – need to
block > 75%
 High potency


Sedation
Ataxia
Dependence
Death when combined with
EtOH
Amnesia
Withdrawal effect: seizures
and agitation
Crosses placenta
Precipitate withdrawal
symptoms
SEE NOTES
Occupancy > 85% → extrapyramidal movements due to
increased sensitization of
unoccupied receptors to
dopamine
Cross placenta
Neuroleptic malignant
syndrome – needs immediate
care
Extra-pyramidal movements
Sedation
*Chlorpromazine
 Schizophrenia
 Typical anti-psychotic
 Block D2 receptors
 Low potency




Photosensitivity
Large autonomic effects
Sedation
Extrapyramidal movements
*Flumazenil
Anti-psychotics









Comments









 α-adrenergic – control
excitement, postural
hypotension
 Cholinergic – atropine side
effects
 Histamine - sedation

52
Drug/Application
Clinical
Uses
Mechanism
*Thioridazine
 Schizophrenia
 Typical anti-psychotic
 Block D2 receptors
 Low potency
*Clozapine
 (-) and (+) Symptoms of
schizophrenia
*Dantrolene
 Neuroleptic malignant
syndrome
 Malignant hyperthermia
 Serotonin syndrome
 Depression
 Panic or phobic disorders
 OCD
 Enuresis
 Anorexia and bulimia
 Treat for 1 – 6 mo
 Depression
 Atypical anti-psychotic
 Block Serotonin receptors and D2
receptors
 Low potency – blocks 35% of D2
receptors
 Direct muscle relaxant
Anti-depressants
*Fluoxetine (Prozac)
 Depression: Dysregulation of NE
and 5-HT leads to alterations in the
NE and 5-HT receptors
 Antidepressants re-regulate receptor
sensitivity
 Takes 2 wks for re-regulation
 SSRI
 Potent blockers of serotonin
reuptake
 Active metabolite w/ half-life of 128
hrs.
Drug Interactions/
Side Effects
Comments
 Pigmentary degeneration of
retina – browning of vision
 Large autonomic effects
 Abnormal cardiogram –
prolong Q-T
 Sedation
 Mild Extrapyramidal
movements
 Agranulocytosis in 1%
 Large autonomic effect
 Sedation
 No extrapyramidal movement


 All characterized by having
a labile system
 Non-compliance due to oversedation, anticholinergic side
effects, or sexual dysfunction
 Drug selection is based on
past response to drug,
susceptibility to side
effects, compatibility w/
other drugs pt. is taking
 Nausea, HA, nervousness,
and insomnia
 Some sedation
 Anorganism, impotence, ↓
libido (30-40%)
 Fatal interaction w/ MAOI →
Serotonin Syndrome
 Treat serotonin syndrome
with Dantrolene, avoid by
spacing out tx. switch
(4wk. For Prozac)

53
Drug/Application
Clinical
Uses
Mechanism
*Tranylcypromine
 Depression
 MOAI
 Prevent the metabolism of
monoamime NT – increasing the
conc. at nerve terminal
*Setraline (Zoloft)
 Depression
 SSRI
 Potent blockers of serotonin
reuptake
*Imipramine
 Depression
 TCA – tertiary
 Blocks reuptake of
norepinephrine and serotonin
Drug Interactions/
Side Effects
 Wine-cheese effect
 Dry mouth, constipation,
difficult urination (no direct
anticholinergic effects)
 Sedation
 Weight gain
 Sexual dysfuction
 CV: orthostatic hypotension
 Monoclonic jerks in sleep
 Serotonin syndrome w/SSRI
 Enhances depressive effects
of EtOH
 Nausea, HA, nervousness,
and insomnia
 Some sedation
 Anorganism, impotence, ↓
libido (30-40%)
 Fatal interaction w/ MAOI →
Serotonin Syndrome
 Anticholinergic – dry mouth,
blurred vision, constipation,
urinary retention and speech
blocking
 Postural hypotension
 Tachycardia, arrhythmia,
ECG abnormalities, A-V
block
 Sedation – take QHS
 Weight gain
 Tremor and akathisia
 Lowers seizure’s threshold
 Sexual dysfunction: resolves
Comments
 Wine-cheese effect:
Tyramine, usually broken
down by GI MAOI’s, is
taken into nerve endings
where it causes massive
NE release → HTN crisis,
tachycardia, HA< chest
pain, dilated pupils, nausea
and sweating
 Treat w/ α-adrenergic
blocker
 Treat serotonin syndrome
with Dantrolene, avoid by
spacing out tx. switch (2
wks)

 Treat tremor w/
propranolol
 Used for SUICIDE
54
Drug/Application
Clinical
Uses
Mechanism
*Lithium
 Mood stabilizer
 Acute mania
 Manic episode of bi-polar
disorder
 Slow onset – intiate tx. w/
benzo or anti-psychotic
 Severe recurrent depression
 Substitutes sodium in generating
action potentials
 Pumped out slowly → accumulates
→ partial ndepolarization
 Enhancement of serotonin effects
 Inhibition of NE and dopamine
release
 Augmentation of Ach synthesis
 2nd messenger systems → reduced
response to muscarinic and αadrenergic stimulation
 Renal clearance
Anti-convulsants
 Steady plasma conc. must
be reached before changing
dose
*Ethosuximide
 Uncomplicated absence
seizures
 Epilepsy is a chronic brain disorder
 10-30% don’t respond to therapy
 General site of action: Sodium
channels, GABA
 Inhibiting low threshold voltage
dependent (T-type) calcium
channels in thalamocortical neurons
*Topiramate
 Adjunctive or monotherapy
for all types of seizures
*Lamotrigine
 Adjunctive or monotherapy
for all seizures
 3 mechanisms of action:
 Na channel blocker
 Enhancement of GABA at GABA-A
receptors
 AMPA receptor antagonist
 Inhibits release of excitatory
amino acids
Drug Interactions/
Side Effects
Comments
 Narrow therapeutic index
(0.8-1.2 meq/L) – check
serum conc. regularly
 Tremor – alleviate w/
propranolol
 Decreased thyroid function
 Polydipsia and polyuria
 Edema
 ECG abnormalities depressed T wave
 Excreted in breast milk
 Therapeutic overdose – treat
w/ hemodialysis, peritoneal
dialysis

 Physical work-up and renal
function before prescribing
 Drowsiness
 GI distress: nausea and
vomiting
 HA
 Somnolence and fatigue
 Dizzyness
 Difficulty concentrating
 Speech disorders and ataxia

 Some dizziness, ataxia,
somnolence, and fatigue
 Rash in 5%
 Increased elimination when
taken with carbamazepine,
phenytoin, and pheno
 Decreased elimination with
valproic acid



55
Drug/Application
Clinical
Uses
Mechanism
*Phenobarbital
 Suppress seizure activity,
elevate seizure threshold,
and limit spred from a
focus
 Generalized tonic/clonic
 Partial seizures
 Status epilepticus
 Barbiturate
 Enhance GABA inhibition by
increasing Cl channel opening
 Bind to BZD binding → increase the
frequency of opening but not the
time
*Phenytoin (Dilantin)




Generalized tonic/clonic
Partial seizures
Status epilepticus
Oral
 Na channel blocker
 Maintains Na channel in inactive
state for a prolonged perion
 Follows Zero-ordered kinetics –
small changes in dose → large
changes in plasma level
 Metabolized in liver, half life is 24
hrs.
*Carbamazepine




Generalized tonic/clonic
Partial seizures
Status epilepticus
Focal epilepsy in children





*Valprocic Acid
 Absence seizures
 Myoclonic seizures
 Partial seizures: complex



Na channel blocker
Increase central NE transmission
Adenosine partial agonist (?)
Metabolism: 95% hepatic, half life
is 12 hrs
Induces own metabolism by
increasing microsomal enzymes
Inhibits metabolism of GABA
Prolongs recovery of Na channels
Some inhibition of low threshold
voltage dependent (T-type) calcium
channels
Drug Interactions/
Side Effects
Comments
 Sedation and impaired
cognitive function
 Ataxia
 Withdrawal syndrome
 Osteomalacia
 Paradoxical hyperactivity in
some children
 Agitation and confusion in
elderly pts.
 May WORSEN absence
seizures
 Dizzyness, ataxia,
nystagmus, diplopia
 Gingival hyperplasia
 Hirsutism
 Skin rash
 Mental confusion
 Altered vit. D and Ca
metabolism
 Tetratogenic
 Drowsiness
 Disequilibrium
 Blurred vision
 Ataxia
 Used in children










Anorexia
Nausea
Vomiting
Hand tremor at high doses
Alopecia
Weight gain
Hepatoxic
Neural tube defects
Increase Phenobarbitol levels
in blood
 Minmal drowsiness and
general depression
 Use w/ caution in liver
disease
 Fosphenytin – used for
Status epilepticus (IV)
 Need to increase dose over
time
56
Drug/Application
Clinical
Uses
*Gabapentin
 Partial seizures
 Neuropathic pain
 Psychiatric conditions
*Tiagabine
 Adjunctive therapy in
adults and children (>12)
for tx of partial seizures
 Absence seizures
 Myoclonic seizures
 Atonic seizures
*Diazepam
Mechanism
 Unknown
 Indirectly increases CNS GABA
levels, ↑release (?)
 Absorption shows saturability from
GI
 Renal elimination
 Interfers with GABA reuptake
 96% protein bound, half-life is 7-9
hrs
 Benzodiazepine
 Enhances GABA actions by
increasing the frequency of Cl
channel opening → hyperpolarized
Drug Interactions/
Side Effects
Comments
 No drug interactions
 Mild: somnolence, fatigue,
ataxia, and dizzyness









 Drugs effecting micrsomal
enzymes will increase its
metabolism
 Side effects may lessen w/
long term use
Impaired concentration
Somnolence and fatigue
Dizzyness and nervousness
CNS depression
Drowsiness
Ataxia
Dysarthria
Respiratory depression and
bronchial hypersecretion
57