MBR 2019 - Pharmacology Handouts

ANTIBIOTICS
DENNIS S. FLORES, MD
GENERAL PRINCIPLES OF ANTIBIOTIC  severity of infection

THERAPY  inoculum size, virulence, re-growth &
susceptibility pattern of infecting
LEARNING OBJECTIVES: pathogens
At the end of the lecture, students should be able to  infection at sequestered sites
learn the general principles governing antimicrobial  previous antimicrobial therapy
therapy, namely:  local factors: presence of pus, foreign
 factors to consider in the choice of body, devitalized tissues, pH changes,
antibiotic(s) impaired penetration into affected areas
 antibiotic pharmacodynamics
 antibiotic pharmacokinetics 2. HOST-RELATED FACTORS
 antibiotic combination therapy  age
 general mechanisms of acquired antibiotic  genetic factors
resistance  renal and hepatic functions
 prophylactic antibiotic therapy  pregnancy and nursing status
 misuse/abuse practices in antimicrobial  host defense mechanism, both humoral
therapy and cellular (immunocompetent vs.
immunocompromised host)
ANTIMICROBIALS  co-morbid conditions: CNS, atopy,
 Ligands whose active chemical moiety binds metabolic abnormalities, pre-existing
with microbial protein receptors which are dysfunction in other organs, obesity
essential components of biochemical  previous history of drug reaction
reactions in the microbes
 Interference with physiological pathways 3. DRUG-RELATED FACTORS
inhibits growth and multiplication or kill  pharmacodynamics: antimicrobial
microorganisms spectrum, bacteriostatic vs. bactericidal;
 Biochemical processes commonly inhibited: concentration- dependent vs. time-
cell wall synthesis, cell membrane function, dependent bacterial killing
synthesis of 30’s and 50’s ribosomal  pharmacokinetics: concentration at the
subunits, nucleic acid synthesis. site of infection, the major determinant
of successful therapy
CHARACTERISTICS OF AN IDEAL  adverse effects: risk/benefit ratio
ANTI-INFECTION AGENT  drug interactions
1. Selective toxicity; effective anti-infective  cost/benefit ratio
activity (preferably bactericidal rather than  others: ease and accuracy of dosing,
bacteriostatic). stability, acceptability
2. Capable of penetration in concentration that
exceeds several folds the MIC/MBC of CLASSIFICATION OF ANTIBACTERIAL AGENTS
potential pathogen, high affinity for site of  Based on spectrum of activity
action. ◦ narrow or broad
3. Resistant to inactivation by microbial  Based on antimicrobial action
enzymes, tissue fluid or products of ◦ bactericidal or bacteriostatic
inflammation and must not readily stimulate  Based on mechanism of action
microbial resistance. ◦ Inhibition of cell wall synthesis
4. Orally active ◦ Inhibition of cell membrane function
5. Long elimination half-life ◦ Inhibition of protein synthesis
6. Devoid of adverse drug-drug interaction ◦ Inhibition of nucleic acid synthesis
7. Absence of major organ system toxic effect  Direct inhibition of DNA
8. Absence of developmental or behavioral synthesis
toxic effects  Inhibition of synthesis of
essential metabolites for
FUNDAMENTAL QUESTIONS IN ANTIMICROBIAL DNA synthesis
THERAPY
• WHAT am I treating? ANTIBIOTIC PHARMACODYNAMICS
• WHO am I treating?
• WHICH antibiotic (or antibiotic combination) PHARMACODYNAMICS OF BACTERIAL KILLING
is most appropriate? 1. CONCENTRATION-DEPENDENT OR DOSE-
• HOW do I administer the antibiotic(s) ? DEPENDENT KILLING
 the higher the concentration, the greater
FACTORS TO CONSIDER IN THE CHOICE OF THE the bactericidal effect
ANTIBIOTIC(S)  most important determinant of efficacy:
1. DISEASE / CLINICAL SYNDROME & LIKELY Cmax/MIC ratio – e.g. aminoglycosides
PROVEN PATHOGEN(S) (MICROBIAL AUC/MIC ratio – e.g. fluoroquinolones
FACTORS)  prolonged PAE, significant PALE even at
 site of infection subminimal inhibitory concentration
UST FMS MEDICAL BOARD REVIEW 2019 1 | PHARMACOLOGY

ANTIBIOTICS
 less frequent dosing is more effective  rifampicin

 others: streptogramins, daptomycin,  sulfisoxazole
metronidazole  tetracyclin
2. TIME-DEPENDENT KILLING
 bactericidal effect is dependent on the INCREASED BIOAVAILABILITY (take with
length of time the bacteria are exposed to food)
serum concentrations of at least 4x the MIC  cefuroxime axetil
 most important determinant of efficacy:  fusidic acid
time >MIC  griseofulvin
 goal: attain serum concentration of at least  nitrofurantoin
4x MIC of infecting organism at all times for
at least 40-50% of the dosing interval UNCHANGED BIOAVAILABILITY (take with or
without food)
Classes:  amoxicillin, coamoxiclav
2.1 No persistent effect – e.g.  cefalexin, cefadroxil
betalactams  cefixime
- most have negligible PAE  chloramphenicol
- most cost-effective manner of  ciprofloxacin, ofloxacin, levofloxacin,
administration by continuous IV moxifloxacin and gemifloxacin
infusion or intermittent IV infusion or  clarithromycin
choose an antibiotic with long half-life  clindamycin
2.2 Moderate to long persistent effect  cotrimoxazole
- e.g. clindamycin, erythromycin,  dapsone
linezolid, tetracycline, vancomycin  doxycycline/minocycline
- goal: enhanced amount of drug; 24h  fluconazole
AUC/MIC  flucytosine
 ketoconazole
 linezolid
ANTIBIOTIC PHARMACOKINETICS  metronidazole
1. ABSORPTION  pyrazinamide
 to be effective the antibiotic has to be absorbed
and penetrate into the infected compartment 2. DISTRIBUTION
/organ; a crucial consideration is whether the  effectiveness of antimicrobial therapy is
drug can penetrate to the site of infection determined by the relationship of the
 oral administration for mild to moderate concentration of drug reaching the site of
infection infection and the MIC of the infecting
 IV therapy for serious infections where organism
predictable plasma concentrations of the drug  tissue concentration equilibrates with plasma
must be achieved free drug concentration
 in hemodynamically stable patients, enteral or  poor antimicrobial penetration of the blood
IM administration may be considered brain barrier, intraocular tissues and prostate;
 developments have led to greater use of oral increased diffusion with inflammation; as
therapy in infectious diseases; availability of infection is controlled and inflammation
improved oral agents that achieve higher or subsides, penetration reverts back to normal
more persistent serum and tissue concen-
trations (oral as effective as parenteral, less CSF concentration greater than 10-fold above MBC is
expensive, fewer complications) - necessary for maximal bactericidal effect
cotrimoxazole, flouroquinolone, clindamycin,
chloramphenicol, metronidazole, rifampicin, BLOOD BRAIN BARRIER PENETRATION
linezolid, fluconazole Excellent with or Good with
without inflammation inflammation
INFLUENCE OF FOOD AND DIET ON -chloramphenicol -3rd generation
GASTROINTESTINAL DRUG ABSORPTION -ethionamide parenteral
DECREASED BIOAVAILABILITY -fluconazole cephalosporins (except
(take on “empty stomach” i.e. 1 h before or 2h -flucytosine cefoperazone)
after a meal for better oral absorption) -isoniazid -cefepime (9-10% of
 ampicillin -metronidazole peak plasma
 azithromycin -pyrazinamide concentration)
 didanosine, efavirenz, indinavir -rifampicin -aztreonam
 erythromycin base/ester -sulfonamides -ciprofloxacin,
 isoniazid -trimethoprim moxifloxacin
 itraconazole -linezolid
 norfloxacin -meropenem
 cloxacillin -penicillins
 phenoxymethylpenicillin (penicillin V) -vancomycin

ANTIBIOTICS
Minimal or not good No passage even with -moxifloxacin fluoroquinolones

even with inflammation -nafcillin in general
inflammation -quinupristin -penicillins in
-aminoglycosides (CSF -amphotericin B (?) +dalfopristin general
levels reach 25% of -1st , 2nd gen -rifampicin -sulfonamides/
plasma levels in cephalosporins (except cotrimoxazole
meningitis and even cefuroxime), -tetracyclines
higher in neonates) cefoperazone & in general
-lincosamides ceftaroline -vancomycin
-macrolides -Polymixin E (colistin)
-streptogramins
-tetracyclines PHARMACODYNAMIC / PHARMACOKINETIC
CORRELATES
3. METABOLISM 1. MIC and MBC: indicators of the potency of
 relatively few commonly used antibiotics the antibiotic against infecting bacterial
undergo significant metabolism pathogen.
 some antibiotics are administered as 2. Potency not synonymous to efficacy
prodrugs and have to undergo 3. Optimal antibiotic dosing requires
biotransformation to become active integration of a drug’s pharmacokinetic
(chloramphenicol succinate/palmitate; profile with its in-vitro pharmacodynamic
cefetamet pivoxil, cefodoxime proxetil, correlates
isoniazid, pyrazinamide)
 some active antibiotics undergo RATIONALE FOR ANTIBIOTIC COMBINATION
biotransformation to form still active THERAPY
metabolites (clarithromycin  1. Provide broad spectrum empiric therapy in
14hydroxyclarithromycin; rifampicin  severe life-threatening infections - beta-
diacetylrifampicin) lactams and aminoglycosides for sepsis in
 several antibiotics (erythromycin, neonates
clarithromycin, ciprofloxacin, isoniazid, 2. Treat polymicrobial infection - anti-aerobes
chloramphenicol, ketoconazole, and anti-anaerobes for intraabdominal
fluconazole, metronidazole, cotrimoxazole) abscess
inhibit metabolism of other drugs 3. Prevent/delay emergence of resistance -
 some antibiotics (e.g. rifampicin, disease due to M. tuberculosis, M. leprae,
rifapentin, nafcillin) may enhance P. aeruginosa, etc.
metabolism of other drugs 4. Decrease dose-related toxicity - flucytosine
and amphotericin B in cryptococcal
4. EXCRETION meningitis
 most antibiotics are eliminated via the 5. Obtain enhanced inhibition/killing
kidney (synergism) - penicillin & aminoglycoside
 some important antibiotics undergo non- combination in enterococcal endocarditis;
renal elimination FDC of sulfamethoxazole -trimethoprim, etc.
 some betalactams are secreted as well as
filtered and a few eliminated by non-renal MECHANISM OF ANTIMICROBIAL SYNERGISM
mechanisms 1. Blockade of sequential steps in metabolic
 probenecid impairs renal tubular secretion of sequence
weak acids e.g. beta-lactams e.g. sulfamethoxazole + trimethoprim
sulfadoxine +pyrimethamine
MAJOR ELIMINATION PATHWAYS OF 2. Inhibition of enzymatic inactivation
ANTIMICROBIALS e.g. beta lactamase inhibitor + beta-
Hepatobiliary Renal & Renal lactam antibiotic
Biliary clavulanate K + amoxicillin
-cefoperazone/ -ampicillin -aciclovir sulbactam + ampicillin
ceftriaxone -cefixime - tazobactam + piperacillin
- -isoniazid aminoglycosides 3. Enhancement of antimicrobial uptake
chloramphenicol -oxacillin & -amphotericin B e.g. penicillins and aminoglycoside
-clindamycin related drugs -aztreonam ampicillin and gentamicin
-doxycycline/ pyrazinamide -carbapenems ceftazidime and amikacin
-tigecycline telithromycin -cephalosporins *marked by fourfold or greater reduction in MIC or
-erythromycin/ in general MBC when used in combination
azithromycin -clarithromycin
-linezolid -colistin MECHANISM OF ANTIMICROBIAL ANTAGONISM
-metronidazole -daptomycin 1. Inhibition of bactericidal activity by
-most azoles -ethambutol bacteriostatic antibiotic
(but not -fluconazole -betalactams and tetracycline
fluconazole) -

ANTIBIOTICS
2. Induction of enzymatic inactivation -

imipenem, cefoxitin and ampicillin as
potent inducers of betalactamase
production; combination with piperacillin
may result in antagonism
- rifampicin + protease inhibitors
* the combined inhibitory or killing effect of 2 or
more antibiotics is significantly less than expected
when drugs are used individually
MECHANISMS OF ACQUIRED DRUG RESISTANCE

1. Decreased drug uptake or increased efflux of
the drug - tetracyclines, quinolones,
aminoglycosides, macrolides,
chloramphenicol PENICLLINS
2. Enzymatic inactivation of the drug - penicillins,
aminoglycosides, chloramphenicol
3. Decreased conversion of a drug to the active
growth inhibitory compound - flucytosine
4. Increased concentration of metabolite
antagonizing the drug action -
sulfonamides  A – thiazolidine ring
5. Altered amount of drug receptor -  B – β-lactam ring
trimethoprim  A + B – amino penicillanic acid nucleus (for
6. Decreased affinity of receptor for the drug - antibacterial activity)
sulfonamides, streptomycin, rifampicin,  Penicilloic acid – product of hydrolysis of β-
erythromycin, penicillins (structural lactam ring
change in target PBPs e.g. PRSP, Penicillin Anti- Extended
MRSA, enterococci), vancomycin s staphylococca Spectrum
(Penicillin l (Methicillin, (Ampicillin,
GENERAL STEPS IN APPROPRIATE ANTIMICROBIAL G) Oxacillin)* Piperacillin
THERAPY )
1. Formulate a clinical diagnosis of microbial Gram
infection positive + + +
2. Obtain appropriate specimens for laboratory cocci except
examination, when applicable. Enterococci
3. Formulate a specific microbiologic diagnosis Gram
4. Determine the need for empiric therapy negative 0 0 +
5. Institute pharmacologic treatment bacilli but limited
considering microbial, host and drug factors Anaerobe + 0 +
and using EFFICACY, SAFETY, SUITABILITY
s except
and COST of the antimicrobial options in the
B. fragilis
selection process and following the “Rules of
+susceptible; +variable; 0 resistant
Right”.
*Resistant to staphylococcal β-lactamases
6. Institute adjuvant and non-pharmacologic
therapy.
MECHANISM OF ACTION
7. Adjust antimicrobial regimen according to
• Bind with PBP causing selective inhibition of
the isolated organism and its susceptibility
transpeptidase
pattern correlated with the patient’s clinical
response (directed or targeted antimicrobial
MECHANISMS OF RESISTANCE
therapy)
 Inactivation by β-lactamase – most common
 Modification of target PBP
SPECIFIC ANTIBIOTICS
 Impaired entry to target PBP
 Efflux
OUTLINE
PHARMACOKINETICS
BETA-LACTAM ANTIBIOTICS
• Penicillins
-Penicillins + Betalactamase inhibitors
– Penicillin G (Benzylpenicillin G)
-Cephalosporins
• Crystalline/Aqueous (IV)
-Carbapenems
• Procaine, Benzathine (IM;
-Monobactam (Aztreonam)
repository)
– Penicillin V
Other Cell Wall & Membrane-Active Antibiotics
(Phenoxymethylpenicillin; oral)
-Glycopeptides
• Anti-staphylococcal penicillins
-Lipopeptide (Daptomycin)
– Methicillin (no longer manufactured)
-Polymixins
ANTIBIOTICS
– Nafcillin, Oxacillin (IV) • Penicillin V

– Dicloxacillin, cloxacillin, flucloxacillin – Streptococcus pyogenes
(oral; acid-stable) (pharyngitis)
• Extended-spectrum penicillins • Replaced by amoxicillin due
– Aminopenicillins to poor oral bioavailability
• Amoxicillin (oral; absorption
NOT impaired by food) CLINICAL USES – ANTI-STAPHYLOCOCCAL
• Ampicillin (IV; oral has PENICILLINS
lower bioavailability • Drug of choice for infections caused by
compared to amoxicillin) Methicillin-sensitive S. aureus (MSSA)
– Ureidopenicillins • NOT active against Enterococci and gram-
• Piperacillin (IV) negative organisms
• Mezlocillin, Azlocillin (not
available) CLINICAL USES – AMINOPENICILLINS
– Carboxypenicillins • Most active oral β-lactam antibiotics for
• Ticarcillin (IV) susceptible Streptococcus pneumoniae
• Carbenicillin (no longer • Other uses of ampicillin (NOT amoxicillin)
manufactured) – Shigella spp.
• High protein-binding – Salmonella typhi (increasing
• Widely distributed in body fluids and tissues amoxicillin-resistance)
(except in uninflamed meninges, brain, eye – E. coli but NOT for other
and prostate) Enterobacteriaceae (Klebsiella
• Poor intracellular concentrations pneumoniae, Enterobacter spp.)
• Excreted in urine except – Listeria monocytogenes
– Nafcillin (bile) – Enterococcus faecalis but NOT E.
– Oxacillin, dicloxacillin, cloxacillin faecium
(urine and bile) • NOT active against Pseudomonas
aeruginosa
PHARMACODYNAMICS
• Time-dependent killing CLINICAL USES – CARBOXYPENICILLINS
– Efficacy is directly related to time • Pseudomonas aeruginosa (nosocomial
above MIC, and becomes infections)
independent of concentration once • Compared to aminopenicillins
the MIC has been reached – Broader coverage against
– Requires multiple dosing (or as Enterobacteriaceae
infusion) to maintain serum – NOT active against Enterococci
concentration above MIC
CLINICAL USES – UREIDOPENICILLINS
CLINICAL USES – PENCIILLIN G • Pseudomonas aeruginosa (nosocomial
• Drug of choice for infections caused by infections)
– Streptococcus pyogenes (skin and – More active than carboxypenicillins
soft tissue infection) • Compared to aminopenicillins
– Susceptible Streptococcus – Broader coverage against
pneumoniae Enterobacteriaceae (including
– Non-β-lactamase-producing Klebsiella spp.)
Staphylococcus aureus • Compared to carboxypenicillins
– Enterococcus faecalis (NOT E. – Active against Enterococcus faecalis
faecium)
– Neisseria meningitidis (NOT N. ADVERSE REACTIONS
gonorrhoeae) • Common
• Drug of choice for infections caused by – Hypersensitivity (cross-sensitizing,
– Treponema pallidum cross-reacting)
– Leptospira spp. • Due to major determinants:
• Other uses penicilloyl (most important),
– Clostridium tetani penicillanic acid derivatives
– Actinomyces – Rash (maculopapular)
• NOT active against Bacteroides fragilis • Occurs after 72hrs; not IgE-
mediated
CLINICAL USES – OTHER PENICILLINS – GI disturbance e.g. diarrhea
• Procaine and Benzathine Penicillin G (ampicillin), nausea/vomiting, oral
– Streptococcus pyogenes candidiasis
(pharyngitis, prophylaxis for • Occasional
reinfection) – Hematologic disturbance e.g.
– Treponema pallidum bleeding due to platelet dysfunction
(ticarcillin)

ANTIBIOTICS
– Pseudomembranous colitis - High doses may cause diarrhea

(ampicillin)
• Rare CEPHALOSPORINS
– Anaphylactic shock (0.05%)
• IgE-mediated
• Due to minor determinants:
benzylpenicillin, benzyl
penicilloate (acid hydrolysis
product)
– Serum sickness (penicillin G) • A – dihydrothiazine ring
– Muscle irritability, seizure (penicillin • B – β-lactam ring
G) • A + B – amino cephalosporanic acid nucleus
– Hemolytic anemia (penicillin G) (for antibacterial activity)
– Interstitial nephritis (methicillin) • More stable to β-lactamases than penicillin
– Hepatitis (oxacillin)
1st 2nd 3rd 4th 5th
– Agranulocytosis, neutropenia
Gen Gen Gen Gen Gen
(nafcillin)
Gram positive + + + + +*
Cocci
BETA LACTAMASE INHIBITORS
MRSA 0 0 0 0 +
• Competitive inhibition of many β-lactamases
Gram + + + + +
– Bind irreversibly to the catalytic site
negative
of β-lactamases rendering them
bacilli
inactive
• Very weak antibacterial action Pseudomonas 0 0 + + +
Anaerobes 0 + + 0 0
Amoxicilli Amoxicillin Ampicillin
n/ - - + susceptible; + variable; 0 resistant
Ampicillin Clavulanic Sulbacta *includes coverage for Enterococcus faecalis NOT
Acid m E. faecium
Klebsiella 0 + +
pneumonia PHARMACOKINETICS – ORAL
E. coli + + + 1st Gen 2nd Gen 3rd Gen
Proteus spp. + + + Cephalexin Cefuroxime Cefixime
Salmonella + + + Cefadroxil Cefaclor Cefpodoxime
typhi Cefprozil* Cefdinir
Acinetobacter 0 0 + Loracarbef* Cefditoren*
baumannii Ceftibuten*
Pseudomona 0 0 0 *Not available
s aeruginosa  Absorption enhanced by ester
Bacteroides 0 + + formulations (axetil, proxetil)
fragilis  Very high urine concentration
+ susceptible; + variable; 0 resistant  Tissue levels lower than the serum
concentration
 Exctreted in urine
Ticarcillin Ticarcillin Piperacillin
/ / -
Piperacilli Clavulani Tazobacta PHARMACOKINETICS – INTRAVENOUS
n c Acid m 1st Gen 2nd Gen 3rd Gen
Klebsiella 0 + + Cefazolin Cefuroxime Ceftriaxone
pneumonia Ceftazidime
Serratia spp. 0 + + cephamycins Cefotaxime
E. coli + + + Cefotetan Cefoperazone
Acinetobacte 0 + + Cefoxitin Ceftizoxime
r baumannii Cefmetazole* Ceftibuten*
Pseudomona + + + Moxalactam*
s aeruginosa *Not available
Bacteroides 0 + +
fragilis 4th Gen 5th gen
+ susceptible; + variable; 0 resistant Cefepime Ceftaroline
Cefpirome Ceftobiprole
PHARMACOKINETICS
• CSF penetration is unreliable PHARMACOKINETICS – INTRAVENOUS
– NOT recommended for meningitis • Widely distributed in body fluids and tissues
• Coamoxiclav (except in the eye, prostate, brain and
– IV formulation very unstable meninges for 1st and 2nd gen)
– 125mg (clavulanate) not to exceed • Poor intracellular penetration
TID • Excreted in urine except

ANTIBIOTICS
– Ceftriaxone and Cefoperazone (bile) – Pseudomonas aeruginosa

(nosocomial infections)
CLINICAL USES – NOT active against Enterococci, Acinetobacter spp.
1ST GEN CEPHALOSPORINS and anaerobes
• Streptococci and Staphylococci (minor skin
and soft tissue infections) CLINICAL USES –
• Surgical prophylaxis (cefazolin) 5TH GEN CEPHALOSPORINS
– NOT recommended for colorectal Ceftaroline Ceftobiprole
procedure MRSA + +
• E. coli (uncomplicated cystitis) Streptococci + +
– NOT active against Enterococci, Enterococcus + +
Pseudomonas aeruginosa, and faecalis
Acinetobacter spp. Enterobacteriaceae + +
(including E. coli,
CLINICAL USES – Klebsiella spp.,
2ND GEN CEPHALOSPORINS Enterobacter spp.)
• Compared to 1st gen cephalosporins Pseudomonas 0 +
– Broader coverage against gram- aeruginosa
negative organisms [including β- Acinetobacter spp. 0 0
lactamase-producing Haemophilus Anaerobes 0 0
influenzae, Moraxella catarrhalis, *No longer manufactured; +susceptible; +variable
Klebsiella spp. (sinusitis, otitis 0 resistant
media, pneumonia, NOT
meningitis)]
ADVERSE REACTIONS
• Bacteroides fragilis (intraabdominal/pelvic • Common
infections – cephamycins)
– GI disturbance e.g. diarrhea
– NOT active against Enterococci,
(cefoperazone), nausea/vomiting
Pseudomonas aeruginosa, and – Thrombophlebitis
Acinetobacter spp. • Occasional
– Hypersensitivity
CLINICAL USES –
• Cross-allergenicity with
3RD GEN CEPHALOSPORINS
penicillins ~5-10%
• Drug of choice for meningitis caused by – Serum sickness-like reactions
Penicillin-resistant Streptococcus
(cefaclor)
pneumoniae (ceftriaxone or cefotaxime) – Bile sludging, pseudocholelithiasis
• Pseudomonas aeruginosa (ceftazidime,
(ceftriaxone)
cefoperazone)
– Hematologic disturbances e.g.
• Compared to 1st and 2nd gen cephalosporins
bleeding due to antagonism of
– Broader coverage against
vitamin K (cefamandole,
Enterobacteriaceae [including cefoperazone, cefmetazole,
Citrobacter spp. Serratia cefotetan)
marcescens, Providencia spp. – Disulfiram-like reactions
(pneumonia, pyelonephritis)]
• Rare
• Drug of choice for infections caused by
– Anaphylactic shock
– Neisseria gonorrhoeae (ceftriaxone) – Interstitial nephritis and tubular
– MDR Salmonella typhi (ceftriaxone)
necrosis (cephalotin)
• Other uses – Pseudomembranous colitis
– Burkholderia cepacia (ceftazidime)
– Hepatitis
– Bacteroides fragilis
– Seizure
(intraabdominal/pelvic infections –
ceftizoxime)
MONOBACTAM
– NOT active against Enterococci and
Acinetobacter spp.
– Some are NOT very active against
Staphylococci and Streptococci
(cefixime, ceftibuten, ceftazidime)
– Some do NOT cross blood-brain
barrier (cefoperazone and all oral
forms) • B – β-lactam ring
CLINICAL USES – • Aztreonam – only monobactam available
4TH GEN CEPHALOSPORINS
• Compared to 1st to 3rd gen cephalosporins PHARMACOKINETICS
– Broader coverage against • Poor oral absorption
Enterobacteriaceae (including • Widely distributed in body fluids and tissues
Enterobacter spp.) (including inflamed meninges)

ANTIBIOTICS
• Excreted in urine MECHANISM OF RESISTANCE

• NO cross-resistance with other β-lactams
CLINICAL USES • NO class resistance
Aztreonam Ceftazidime – Imipenem
Staphylococci 0 0 • OprD efflux pump
Streptococci 0 + – Meropenem, Doripenem, Ertapenem
Enterococci 0 0 • MexA-MexB-OprM efflux
Enterobacteriaceae + + system
(including E. coli,
Klebsiella spp., PHARMACOKINETICS
Enterobacter spp.) • Intravenous preparation
NOT ESBLS – Ertapenem may also be given
Pseudomonas + + intramuscularly (with 1% lidocaine)
aeruginosa • Imipenem inactivated by dehydropeptidases
Acinetobacter spp. 0 0 • Meropenem, Doripenem and Ertapenem
Anaerobes 0 + NOT degraded by dehydropeptidases
+susceptible; +variable; 0resistant • High urinary concentration
• Widely distributed in body fluids and tissues
(including inflamed meninges for
ADVERSE REACTIONS
meropenem and imipenem)
• Occasional
• Excreted in urine
– Hypersensitivity
• NO cross-allergenicity with
penicillins CLINICAL USES
• Drug of choice for infections caused by
– GI disturbances e.g.
– ESBLs
nausea/vomiting, diarrhea
– Serious mixed aerobic and
– Transaminitis
anaerobic infections
– Local reaction e.g. pain at injection
site – Enterobacter spp.
• NOT active against MRSA, Enterococci
• Rare
– Hematologic disturbance e.g. (except imipenem), and Stenotrophomonas
thrombocytopenia
maltophila
– Pseudomembranous colitis
ADVERSE REACTIONS
• Common
CARBAPENEMS
– GI disturbance e.g. diarrhea,
nausea/vomiting
• Occasional
– Hypersensitivity (cross-sensitizing,
cross-reacting)
– Hematologic disturbances e.g.
anticoagulation abnormalities
• B – β-lactam ring – Local reaction e.g. pain at injection
• site
Imi Mero Dori Erta • Rare
Staphylococcal + + + + – Seizure esp. among renal failure
NOT MRSA patients
Streptococci + + + + • Most epileptogenic –
Enterococcus + + + 0 imipenem
faecalis NOTE E. • Least epileptogenic –
faecium doripenem
Enterobacteriaceae + + + + – Hallucination (ertapenem)
(E. coli, Klebsiella – Anaphylactic shock
spp., Enterobacter – Serum sickness
spp.) – Pseudomembranous colitis
Extended- + + + +
spectrum beta- GLYCOPEPTIDES
lactamase (ESBLS) • VANCOMYCIN – only glycopeptide locally
Acinetobacter spp. + + + 0 available
Pseudomonas + + +* 0 Vancomycin* Teicoplanin
Aeruginosa MRSA + +
Anaerobes + + + + VRSA 0 0
+susceptible; +variable; 0resistant VISA 0 0
*lowest MIC (4ug/mL vs 32 for imipenem and 16 Streptococci + +
for meropenem) Enterococcus + +
faecalis

ANTIBIOTICS
E. faecium + + – NOT recommended for serious S.

VRE 0 0 aureus infection if susceptible to
Gram- 0 0 penicillins
nergative • Drug of choice for coagulase-negative
Bacilli staphylococci
C. difficile + + – Prosthetic device infections, CSF
*Available locally; +susceptible; +variable: 0 shunt infections, catheter-related
resistant infections
• Other uses
Telavancin Dalbavancin – Enterococci
MRSA + + – Penicillin-resistant Streptococcus
VRSA 0 0 pneumoniae (meningitis)
VISA + + – Metronidazole-resistant C. difficile
(colitis)
Streptococci + +
– Surgical prophylaxis for centers with
Enterococcus + +
high prevalence for MRSA
faecalis
E. faecium + +
ADVERSE REACTIONS
VRE 0 0
• Common
Gram- 0 0 – “Red man” or “Red neck” syndrome
nergative – Phlebitis to injection site
Bacilli – GI disturbance e.g. diarrhea,
C. difficile + + nausea/vomiting
*Available locally; +susceptible; +variable: 0 • Occasional
resistant – Ototoxicity
– Nephrotoxicity
MECHANISM OF ACTION • Rare
 Inhibits cell wall synthesis by binding to the – Macular rash
D-Ala-D-Ala terminus – Hematologic disturbance e.g.
 Inhibits transglycosylase (prevents neutropenia, thrombocytopenia
elongation and cross-linking)
TEICOPLANIN
METHICILLIN-RESISTANT S. aureus (MRSA) • Compared to Vancomycin
• β-lactam antibiotics cannot bind to PBP – High protein binding and highly
(altered PBP) bound in tissues
– mecA gene produces PBP2a • Slowly released from tissues
 Vancomycin does NOT target the PBP (t½ 3-7days); low clearance
– Less nephrotoxicity and ototoxicity
PHARMACOKINETICS – More common macular rash and
• Vancomycin drug-related fever
– Poor oral absorption
• Administered orally only for LIPOPEPTIDE
treatment of C. difficile • Daptomycin – only lipopeptide available
colitis Daptomyci Vancomyci
– Widely distributed in body fluids and n n
tissues (including inflamed MRSA + +
meninges) VRSA + 0
– Excreted in urine
VISA + 0
• Trough level should be
Streptococci + +
obtained 30mins prior to the
Enterococcus faecalis + +
4th or 5th dose
E. faecium + +
• Other glycopeptides have the same PK as
VRE + 0
vancomycin except for longer half-lives
– Teicoplanin (45-70hrs) Gram-negative bacilli 0 0
– Televancin (8hrs) Clostridium difficile 0 +
– Dalbavancin (6-11days) +susceptible; + variable; 0 resistant
• Time-dependent killing
MECHANISM OF ACTION
CLINICAL USES – VANCOMYCIN • Bind to the cell membrane via Ca-dependent
• Drug of choice for infections caused by insertion of its lipid tail
MRSA (including pneumonia, bacteremia • Depolarization of cell membrane with K
and endocarditis) efflux and rapid cell death
– Target trough for serious infections:
15-20µg/mL

ANTIBIOTICS
PHARMACOKINETICS • Widely distributed in tissues except bone,

• Poor oral absorption CSF, synovial fluid, pleural fluid, and
• Distributed mainly into plasma and pericardial fluid
interstitial fluid; little CNS and bone • Excreted in urine
penetration
• Excreted in urine PHARMACODYNAMICS
PHARMACODYNAMICS • Concentration-dependent killing
• Concentration-dependent killing
– As the serum concentration is CLINICAL USES
increased above the MIC, • Infections caused by Multidrug-resistant
bactericidal activity is also increased organisms (unresponsive to other
and at a more rapid rate antibiotics)
– Pneumonia
CLINICAL USES – Skin and soft tissue infections
• Drug of choice for Vancomycin-resistant – Intraabdominal infections
strains of S. aureus and Enterococci – Bacteremia
(including bacteremia) • NOT recommended as monotherapy
• Alternative drug for Vancomycin for
treatment of MRSA bacteremia ADVERSE REACTIONS
• NOT recommended for pneumonia • Common
– Inactivated by lung surfactant – Nephrotoxicity
• Occasional
ADVERSE REACTIONS – Neurotoxicity – peripheral
• Common neuropathy, paresthesias
– Muscle toxicity (myopathy) – Neuromuscular blockade
• Occasional • Rare
– Allergic pneumonitis (prolonged use - Hypersensitivity
>2weeks)
AMINOGLYCOSIDES
POLYMIXINS
• Polymyxin B
• Polymixin E (Colisthemethate/ Colistin)*
Colistin
Gram-positive organisms 0
Enterobacteriaceae except Serratia spp, +
Proteus spp., Providencia spp.,
Morganella spp.
Extended-spectrum β-lactamases +
(ESBLs)
Klebsiella pneumoniae Carbapenemases +
(KPCs) • Aminocyclitol structure
• Protein synthesis inhibitors
New Delhi metallo-β-lactamase (NDM- +
• More active in alkaline pH
1)
Acinetobacter baumannii including MDR +
Strep Genta Amik Tobra*
Pseudomonas aeruginosa including +
S. aureus NOT + + + +
MDR
MRSA
Anaerobes 0
Streptococci 0 0 0 0
+ = susceptible; + variable; 0 = resistant
Enterococcus + + + +
faecalis
MECHANISM OF ACTION
Enterococcus 0 + 0 0
faecium
• Attach and disrupt bacterial cell membrane
– Act as “cationic detergent” Enterobacteriaceae + + + +
– Bind to anionic lipopolysaccharide Pseudomonas + + + +#
molecules leading to permeability aeruginosa
changes in cell membrane Atypical organisms 0 0 0 0
– Leakage of intracellular metabolites Anaerobes 0 0 0 0
and nucleosides, causing cell death + susceptible; + variable; 0 resistant
*Not locally available
#
PHARMACOKINETICS Lowest MIC
• Polymyxin B (topical)
• Polymyxin E (IV) MECHANISM OF ACTION
• Poor oral absorption • Transported to the cytoplasm by an oxygen-
dependent process

ANTIBIOTICS
– Inhibited by low extracellular pH • Contraindicated during pregnancy due to

and anaerobic condition risk of deafness in the newborn
• Bind to 30s subunit
1. Block formation of the initiation complex ADVERSE REACTIONS
2. Block translocation • Common
3. Misreading of the mRNA – Ototoxicity – Pregnancy Risk
– incorporation of incorrect amino acids into Category D
the growing peptide chain • Auditory/cochlear damage
(up to 62%) – tinnitus,
MECHANISM OF RESISTANCE sensation of “fullness in the
• Inactivation by transferase enzymes ears”
(adenylation, acetylation, phosphorylation) – • Most common with
most important neomycin (most
– NO class resistance toxic)
• Impaired entry into the cell • Vestibular damage (up to
• Modification of ribosomal binding site/ 19%) – ataxia, loss of
Ribosomal protection balance, vertigo
• Most common with
PHARMACOKINETICS streptomycin
• Very poorly absorbed from intact GI tract – Nephrotoxicity (up to 50%)
• Poorly distributed in tissues, and non- • Most common with
inflamed meninges except in neonates (even neomycin
if given IV) • Rare
• Excreted in urine (if given parenteral) – Hypersensitivity, anaphylaxis
• Synergism with β-lactam antibiotics if given – Local reaction e.g. pain at injection
sequentially site
– Do NOT mix with β-lactam in the – Neuromuscular blockade
same solution • Results in respiratory
paralysis
PHARMACODYNAMICS • Risk factors: bolus/fast
• Concentration-dependent killing infusion, large dose,
– As the serum concentration is hypocalcemia,
increased above the MIC, succinylcholine
bactericidal activity is also increased • Antidote: calcium gluconate
and at a more rapid rate
– Better efficacy when given as a PROTEIN SYNTHESIS INHIBITORS
single large dose than multiple
smaller doses except OUTLINE
• Staphylococcal and • Tetracyclines
enterococcal endocarditis • Glycylcycline (Tigecycline)
• Pregnancy • Macrolides
• Neonates • Lincosamide (Clindamycin)
– Post-antibiotic effect • Chloramphenicol
• Killing action continues • Oxazolidinone (Linezolid)
when serum concentration • Streptogramins (Quinupristin-Dalfopristin)
has declined below
measurable levels TETRACYCLINES
• Short-acting (t½ 6-8hrs)
CLINICAL USES – Chlortetracycline
• Used in combination with β-lactam – Tetracycline*
antibiotics for serious infections – Oxytetracycline
– Gram-negative septicemia • Intermediate-acting (t½ 12hrs)
– Staphylococcal and enterococcal – Demeclocycline
endocarditis (gentamicin, – Methacycline
streptomycin) – Lymecycline*
• NOT recommended as monotherapy for • Long-acting (t½ 16-18hrs)**
Pseudomonas aeruginosa pneumonia – Doxycycline*
– Poor penetration to infected lung – Minocycline*
tissue *Locally available
– Low oxygen tension **Second generation tetracycline
• NOT recommended for anaerobic infections
e.g. abscess Tetracyclines
• Other uses Gram-positive cocci +
– M. tuberculosis (streptomycin – Enterobacteriaceae +
most active, amikacin) Pseudomonas aeruginosa 0

ANTIBIOTICS
Legionella spp. +  Avoid during pregnancy and

Chlamydophila spp. + children <8yrs
Mycoplasma pneumoniae +  Occasional
Ricketssiae + o Hepatitis (tetracycline), liver failure
Anaerobes + o Photosensitivity (demeclocycline)
+ = susceptible; + variable; 0 = resistant o Esophageal ulceration
o Pancreatitis (tetracycline)
MECHANISM OF ACTION o Visual disturbance (tetracycline)
• Susceptible organisms concentrate the drug o Vestibular toxicity, vertigo
intracellularly (minocycline)
• Bind to the 30s subunit o Pseudomembranous colitis
• Prevent binding of incoming charged tRNA o Aggravate pre-existing renal failure
unit to the acceptor site  Rare
o Hypersensitivity, drug eruption
MECHANISM OF RESISTANCE o Pseudotumor cerebri (increased
• Efflux pump – most important intracranial pressure in infants)
• Modification of ribosomal binding site/ o Diabetes insipidus (demeclocycline)
Ribosomal protection o Interstitial nephritis (minocycline)
o Lupus-like syndrome (minocycline)
PHARMACOKINETICS o Black pigmentation of thyroid
• Absorption impaired by food (except (minocycline)Gray pigmentation of
doxycycline, minocycline), antacids, dairy nail, skin, sclera (minocycline)
products, and divalent cations (Ca2+, Mg2+,
Fe2+), or Al3+ GLYCYCYCLINE
• High protein-binding • Tigecycline – only glycylcycline available
• Widely distributed to tissues except CSF • Third generation tetracycline
• Excellent intracellular penetration
• Excreted in bile and urine except Gram (+) Gram (-) Others
– Doxycycline (bile) Staphylococc Enterobacteriacea Atypical
 Can pass the placenta; excreted in milk i including e (except Proteus organisms
MRSA, VRSA, spp., Providencia (Legionella
PHARMACODYNAMICS VISA spp., Morganella spp.,
• Time-dependent killing spp.) including Mycoplasma
ESBL, KPC, NDM-1 pneumoniae,
CLINICAL USES – DOXYCYCLINE Chlamydophil
• Drug of choice for infections caused by a spp.)
Rickettsiae Streptococci MDR Rickettsiae
• Other uses Acinetobacter spp.
– Mycoplasma pneumoniae Enterococci Anaerobes
– Chlamydophila pneumoniae and C. including
psittaci VRE
• NOT recommended for *NOT active against Pseudomonas aeruginosa
Legionella spp.
– Chlamydia trachomatis MECHANISM OF ACTION
• NOT recommended for N. • Bind to the 30s subunit
gonorrhoeae • Prevent binding of incoming charged tRNA
• Other uses unit
– Leptospira spp. (mild infection, • NO cross-resistance with 1st and 2nd
prophylaxis) generation tetracyclines
– Vibrio spp. • NOT affected by efflux pumps and
– Borellia burgdorferi (Lyme Disease) ribosomal protection
– Plasmodium falciparum
(prophylaxis) PHARMACOKINETICS
• Tigecycline (IV)
ADVERSE REACTIONS • Poorly absorbed after oral administration
• Common • Widely distributed to tissues except CSF
o GI disturbance e.g. • Excellent intracellular penetration
nausea/vomiting, diarrhea • Low urinary concentration
(minocycline) • Excreted in bile and urine
o Local reaction e.g. thrombophlebitis – Adjust dose if with liver disease
o Oral candidiasis (Childs–Pugh C)
o Permanent teeth discoloration and
enamel hypoplasia CLINICAL USES
o Bone deformity/ growth retardation • Infections caused by Multidrug-resistant
Pregnancy Risk Category D organisms

ANTIBIOTICS
– Skin and soft tissue infections • Widely distributed to tissues except CSF
– Intraabdominal infections • Good intracellular/ tissue penetration
• NOT recommended as 1st line treatment for • Excreted in bile
pneumonia • Can pass the placenta; excreted in milk
 NOT recommended for bacteremia • Inhibit cytochrome P450
– Increases serum concentration of
ADVERSE REACTIONS theophylline, warfarin,
• Same as tetracyclines – Pregnancy Risk methylprednisolone, carbamazepine
Category D
• Hematologic disturbances e.g. PHARMACODYNAMICS
thrombocytopenia, prolonged partial • Time-dependent killing
thromboplastin time and
prothrombin time CLINICAL USES – ERYTHROMYCIN
• Pancreatitis • Drug of choice for infections caused by
• Transaminitis – Legionella pneumophila,
• Somnolence Mycoplasma pneumoniae,
• Chlamydophila spp. (atypical
MACROLIDES pneumonia)
• Macrocyclic lactone ring – Corynebacterium spp. (diphtheria)
– Bordetella pertussis
MECHANISM OF ACTION • Other uses
• Susceptible organisms concentrate the drug – Chlamydia trachomatis
intracellularly • Penicillin substitute for Streptococcus
• Bind to the 50s subunit pyogenes to those with penicillin-allergy
• Block peptide chain elongation
ADVERSE REACTIONS – ERYTHROMYCIN
Erythro Clarithro Azithro • Common
Gram-positive + + + – GI disturbance e.g. diarrhea,
cocci abdominal cramps, flatulence,
Moraxella + + + nausea/vomiting
catarrhalis • Occasional
Haemophilus + + + – Acute cholestatic hepatitis (estolate)
influenzae – Stomatitis
Some 0 0 + – Thrombophlebitis
Enterobacteriaceae • Rare
(E. coli, Klebsiella – Hypersensitivity
spp.) – Infantile hypertrophic pyloric
Legionella spp. + + + stenosis
Chlamydophila + + + – QTc interval prolongation,
spp. arrhythmia (torsades de pointes,
ventricular tachycardia)
Mycoplasma + + +
– Transient hearing loss
pneumoniae
– Pseudomembranous colitis
Pseudomonas 0 0 0
aeruginosa
CLARITHROMYCIN
Anaerobes 0 0 0
• Compared to Erythromycin
– Most active against H. influenzae
and Mycobacterium avium complex
MECHANISM OF RESISTANCE – Longer half-life
• Modification of ribosomal binding site/ – Absorption less affected by food
ribosomal protection (by production of – Excreted in urine
methylase) – Less GI disturbance
– Confers resistance to structurally
related compounds (clindamycin and AZITHROMYCIN
streptogramin B) • Similar spectrum of activity with
• Efflux pump Clarithromycin with additional coverage for
• Production of esterases Salmonella spp. and Shigella spp.
• Drug of choice for infection caused by
PHARMACOKINETICS – ERYTHROMYCIN Bartonella henselae (cat scratch disease)
• Absorption impaired by food • Compared to other macrolides
– Stearates and esters promotes • Absorption impaired by food
better absorption; estolate best • Best tissue penetration (>10 to 100-
absorption fold than serum)
– IV formulation (gluceptate, • Slowly released from tissues
lactobionate) (t½ 2-4days)

ANTIBIOTICS
• Concentration-dependent killing ADVERSE REACTIONS

• Does not inhibit cytochrome P450 • Common
• Less GI disturbance – GI disturbance e.g. diarrhea (more
common with oral preparation),
LINCOSAMIDE nausea/vomiting
• Clindamycin – derivative of lincomycin – Hypersensitivity
• Occasional
MECHANISM OF ACTION – Pseudomembranous colitis, toxic
• Bind to the 50s subunit megacolon
– Block peptide bond formation • Rare
– Block translocation – Esophageal ulceration
– Transaminitis, hepatitis
Clindamycin Vancomycin Hematologic disturbance e.g. neutropenia,
Staphylococci + + agranulocytosis, thrombocytopenia
including CA- including HA- CHLORAMPHENICOL
MRSA MRSA Chloramphenic
Streptococci + + ol
Enterococci 0 + Staphylococci +
Gram- 0 0 Enterococci 0
negative Streptococci +
bacilli Neisseria meningitidis +
Anaerobes + + Haemophilus influenzae +
+ = susceptible; + variable; 0 = resistant Enterobacteriaceae +
Pseudomonas aeruginosa 0
MECHANISM OF RESISTANCE Atypical organisms +
• Modification of ribosomal binding site/ Anaerobes +
ribosomal protection (by production of + = susceptible; + variable; 0 = resistant
methylase)
– Confers resistance to structurally MECHANISM OF ACTION
related compounds (macrolides and • Bind to the 50s subunit
streptogramin B; also called MLSB) – Block peptide bond formation
• Enzymatic inactivation
MECHANISM OF RESISTANCE
PHARMACODYNAMICS • Production of chloramphenicol
• Time-dependent killing acetyltransferase
PHARMACOKINETICS
• Clindamycin (oral, IV) PHARMACOKINETICS
– Absorption not affected by food • Available as prodrug
• High protein binding – Succinate (IV)
• Good distribution to tissues (including bone) – Palmitate (oral)
except CSF • Produces higher blood level
• Can penetrate abscesses of free drug than IV
• Excreted in bile and urine • Low protein binding
• Can pass the placenta • Widely distributed to tissues including CSF
• Good intracellular penetration
CLINICAL USES • Metabolized in the liver (glucuronic acid
• Drug of choice for infections caused by conjugation)
Community Acquired MRSA (skin and soft • Excreted in urine and bile
tissue infection) • Can pass the placenta; excreted in milk
– NOT recommended for Hospital • Inhibit cytochrome P450
Acquired MRSA – Increases serum concentration of
– NOT recommended for bacteremia phenytoin, warfarin
and meningitis
• Other uses PHARMACODYNAMICS
– Anaerobic infections ABOVE the • Time-dependent killing
level of diaphragm (e.g. lung
abscess) except CNS CLINICAL USE
• NOT recommended for • Alternative drug for β-lactam for treatment
Bacteroides fragilis of bacterial meningitis
(intraabdominal infection) • Other uses
– Alternative treatment for – Salmonella typhi
staphyloccal infections – Shigella spp.
(osteomyelitis, septic arthritis) to – Ricketssia spp.
those with penicillin-allergy

ANTIBIOTICS
ADVERSE REACTIONS – Pneumonia

• Common • NOT recommended for MRSA bacteremia
– Dose-related anemia • Other use
• Common – MDR M. tuberculosis
– Gray baby syndrome (gray
color/cyanosis, vomiting, flaccidity, ADVERSE REACTIONS
hypothermia, shock) – Pregnancy • Common
Risk Category C – Hematologic disturbance
• Due to lack of effective • Thrombocytopenia (most
glucuronic acid conjugation common)
in newborn infants • Anemia, neutropenia
• Not recommended during • Occasional
term pregnancy and – GI disturbance e.g.
lactation, and in neonates nausea/vomiting, diarrhea
• Occasional – Optic and peripheral neuropathy
– GI disturbance e.g. diarrhea, – Lactic acidosis
nausea/vomiting, anorexia – Serotonin syndrome (fever,
– Oral candidiasis agitation, confusion, tremors,
• Rare diaphoresis)
– Aplastic anemia (idiosyncratic;
IRREVERSIBLE) STREPTOGRAMINS
– Hypersensitivity • Streptogramin B – Quinupristin
– Peripheral neuropathy • Streptrogramin A – Dalfopristin
– Optic neuritis • Displays synergism
– Pseudomembranous colitis – Bactericidal unlike other protein
synthesis inhibitors
OXAZOLIDINONE
• Linezolid – only oxazolidinone available Quinupristin- Linezolid
Dalfopristin*
Linezoli Vancomyci Daptomyci MRSA + +
d n n VRSA + +
MRSA + + + VISA + +
VRSA + 0 + Streptococci + +
VISA + 0 + Enterococcus 0 +
Streptococci + + + faecalis
Enterococcu + + + E. faecium + +
s faecalis VRE + +
E. faecium + + + Gram-negative 0 0
VRE + 0 + bacilli
Gram- 0 0 0 Anaerobes 0 +
negative *Not locally available
bacilli + susceptible; + variable; 0 resistant
Anaerobes + + 0
+ susceptible; + variable; 0 resistant MECHNAISM OF ACTION
• Bind to the 50s subunit
MECHANISM OF ACTION • Interfere with peptidyl transferase
• Bind to 50s subunit (dalfopristin)
• Inhibit formation of ribosome complex that • Inhibit peptide chain elongation
initiates protein synthesis (quinupristin)
• NO cross-resistance with other drug classes
MECHANISM OF RESISTANCE
PHARMACOKINETICS • Modification of ribosomal binding site/
• Linezolid (oral, IV) ribosomal protection (by production of
– 100% bioavailability after oral methylase)
administration – Confers resistance to structurally
• Widely distributed to tissues including CSF related compounds (macrolides and
• Excreted in urine clindamycin)
• Efflux pump
PHARMACODYNAMICS
• Time-dependent killing PHARMACOKINETICS
• Quinupristin-Dalfopristin (IV), 30:70 ratio
CLINICAL USES • Widely distributed in tissues except CSF
• Infections caused by Multidrug-resistant • Excreted in stool
Gram-positive cocci (MRSA, VRE) • Inhibit CYP3A4
– Skin and soft tissue infections

ANTIBIOTICS
– Increases serum concentration of MECHANISM OF RESISTANCE

warfarin, diazepam • SMX
– Overproduction of PABA
PHARMACODYNAMICS – Overproduction of dihydropteroate
• Concentration-dependent killing synthase with reduced drug binding
– Impaired entry into the cell
CLINICAL USES • TMP
• Infections caused by Multidrug-resistant – Overproduction of dihydrofolate
Gram-positive cocci except Enterococcus reductase with reduced drug binding
faecalis – Impaired entry into the cell
– Skin and soft tissue infections
– Pneumonia PHARMACOKINETICS
– Bacteremia • TMP-SMX (oral, IV), 1:5 ratio
– Single strength (SS): 80/400mg
ADVERSE REACTIONS (well-absorbed)
• Common – Double strength (DS): 160/800mg
– Infusion-related reactions e.g. • Widely distributed in body fluids and tissues
phlebitis including CSF and prostate
– Arthralgia-myalgia syndrome • Metabolized in the liver (glucuronic acid
– Direct hyperbilirubinemia conjugation)
NUCLEIC ACID SYNTHESIS INHIBITORS • Can pass the placenta
OUTLINE
• Antifolate Drugs PHARMACODYNAMICS
– Trimethoprim-Sulfamethoxazole • Time-dependent killing
(Cotrimoxazole)
• DNA Gyrase Inhibitors CLINICAL USES
– Fluoroquinolones • Drug of choice for infections caused by
Stenotrophomonas maltophilia
COTRIMOXAZOLE • Other uses
– Susceptible MRSA
– Burkholderia cepacia
– Salmonella typhi
– Shigella spp.
– Nocardia spp.
• May be used for prostatitis
• NOT recommended empiric therapy for
pneumonia
• SMX – sulfanilamide nucleus (similar to p- • Other uses
aminobenzoic acid [PABA]) – Drug of choice for Pneumocystis
• TMP – benzypyrimidine jiroveci pneumonia (PCP)
• Combination is bactericidal – Alternative treatment for
Toxoplasma gondii encephalitis
TMP-SMX Drug of choice is pyrimethamine-
sulfadiazine
S. aureus including MRSA +
Streptococci +
ADVERSE REACTIONS
Enterococci 0
• Common
Enterobacteriaceae +
– Rash, exfoliative dermatitis,
Pseudomonas aeruginosa 0 photosensitivity (SMX)
Burkholderia cepacia + • Occasional
Stenotrophomonas maltophilia + – Hematologic disturbances
Anaerobes 0 • SMX: aplastic anemia,
+ = susceptible; + variable; 0 = resistant hemolytic anemia (those
with G6PD deficiency),
MECHANISM OF ACTION granulocytopenia,
• SMX (structural analog of PABA) inhibit thrombocytopenia
dihydropteroate synthase • TMP: megaloblastic anemia,
- Inhibit production of dihydrofolic leukopenia,
acid granulocytopenia
• TMP inhibit dihydrofolate reductase – Kernicterus (SMX) – Pregnancy Risk
– Inhibit production of tetrahydrofolic Category C
acid (essential for purine/ DNA) • Due to lack of effective
• TMP-SMX blocks sequential step in folic acid glucuronic acid conjugation
synthesis (synergism) in newborn infants

ANTIBIOTICS
• NOT recommended during • Inhibit topoisomerase IV

term pregnancy and – Interferes with separation of
lactation, and in neonates replicated chromosomal DNA into
– Urinary tract disturbances e.g. respective daughter cells during cell
crystalluria, hematuria, obstruction division
– Hyperkalemia
– Pseudomembranous colitis MECHANISM OF RESISTANCE
• Rare • Modification of target enzyme (DNA gyrase)
– Stevens-Johnson syndrome (SMX) • Impaired entry into the cell
– Hepatitis, cholestasis
– CNS disturbances e.g. confusion, PHARMACOKINETICS
depression, hallucinations, ataxia • Oral, IV
– Methemoglobinemia – 80-95% bioavailability after oral
– Pancreatitis administration
– Lupus-like syndrome (SMX) – Absorption impaired by divalent
cations (Ca2+, Mg2+, Fe2+), or Al3+
FLUOROQUINOLONES • Widely distributed in body fluids and tissues
• Analogs of nalidixic acid including CSF and prostate
• 1st generation • High intracellular/ tissue penetration
– Norfloxacin* • Excreted in urine except
• 2nd generation – Gemifloxacin (urine, bile),
– Ciprofloxacin*, Ofloxacin*, moxifloxacin (bile)
Pefloxacin
• 3rd generation PHARMACODYNAMICS
– Levofloxacin*, Gatifloxacin, • Concentration-dependent killing
Gemifloxacin*, Moxifloxacin*
CLINICAL USES
Nor Oflo Cipro • Oral step-down therapy for Pseudomonas
Staphylococci + + + aeruginosa infections (ciprofloxacin,
Streptococci + + + levofloxacin)
Enterococcus 0 0 0 • Other uses
faecalis – Salmonell typhi
N. gonorrhoeae + + + – Shigella spp.
Enterobacteriaceae + + + – E. coli (cystitis, pyelonephritis)
Pseudomonas spp. 0 0 +* – Neisseria meningitidis (post-
Atypical organisms + + + exposure prophylaxis)
Anaerobes 0 0 0 • NOT recommended for Neisseria
+ susceptible; + variable; 0 resistant
gonorrhoeae
• Other use
*Lowest MIC
Atypical organisms – Legionell spp., – MDR M. tuberculosis (ciprofloxacin,
ofloxacin, levofloxacin, moxifloxacin)
Chlamydophila spp., Mycoplasma spp.
• Moxifloxacin – most active
Levo Moxi Gemi
ADVERSE REACTIONS
Staphylococci + + +
• Occasional
Streptococci + + +*
Enterococcus + + + nausea/vomiting, diarrhea,
faecalis abdominal pain
N. gonorrhoeae + + + – CNS disturbances e.g. insomnia,
Enterobacteriaceae + + + headache, dizziness, tremors,
Pseudomonas spp. +* 0 0 restlessness, confusion
Atypical organisms + + + – Rash (macular)
Anaerobes 0 + 0 – Oral candidiasis
+ susceptible; + variable; 0 resistant – Transaminitis, hepatitis
*Lowest MIC (trovafloxacin*, sparfloxacin*)
Atypical organisms – Legionell spp., • Occasional
Chlamydophila spp., Mycoplasma spp. – Hematologic disturbance e.g.
leukopenia, neutropenia,
MECHANISM OF ACTION eosinophilia, anemia (norfloxacin)
• Inhibit bacterial topoisomerase II (DNA – Hyperglycemia in diabetics;
gyrase) hypoglycemia when combined with
– Prevents relaxation of positively oral hypoglycemic agents
supercoiled DNA i.e. required for (gatifloxacin*)
normal transcription Arthropathy (reversible),
damages growing cartilage –
Pregnancy Risk Category C
ANTIBIOTICS
• Not routinely recommended – Clostridium tetani

for children <18yrs and – Entamoeba histolytica
during pregnancy – Trichomonas vaginalis
– Rare – Giardia lamblia
– Tendinitis, tendon rupture
– Retinal detachment ADVERSE REACTIONS
– Anaphylaxis (often fatal) • Common
– CNS disturbances e.g. – GI disturbances e.g.
hallucinations, delirium, convulsions nausea/vomiting, diarrhea
– Peripheral neuropathy – Dry mouth, furry tongue
– Pseudomembranous colitis – Metallic taste
– Interstitial nephritis • Occasional
– Vasculitis – Insomnia
– QTc prolongation, torsades de – Urethral burning
pointes, ventricular tachyarrhytmias – Darkening of urine
(levofloxacin, moxifloxacin, – Phlebitis
gemifloxacin, gatifloxacin, – Disulfiram-like effect
grapefloxacin*) • Rare
– CNS disturbances e.g. seizure,
MISCELLANEOUS ANTIBIOTICS ataxia, dysarthria, encephalopathy
OUTLINE (reversible)
• Metronidazole – Peripheral and optic neuropathy
• Nitrofurantoin – Pancreatitis
• Fosfomycin
TINIDAZOLE
METRONIDAZOLE
• Same coverage as metronidazole but NOT
Metronidazole yet approved by U.S. FDA for anaerobic
Gram-positive organisms 0 infection
Gram-negative organisms 0 • Advantage of once daily dosing
Anaerobes including B. fragilis +
and Clostridium difficile NITROFURANTOIN
+ = susceptible; + variable; 0 = resistant Nitrofurantoin
Staphylococci including MRSA +
MECHANISM OF ACTION Streptococci +
• Nitro group reduced intracellularly by Enterococci +
reacting with reduced ferredoxin E. coli +
– Catalyzed by pyruvate:ferredoxin Other Enterobacteriaceae 0
oxidoreductase Pseudomonas aeruginosa 0
– This process only happens in Anaerobes 0
anaerobic bacteria + = susceptible; + variable; 0 = resistant
• Produce toxic metabolites which are taken
up into bacterial DNA MECHANISM OF ACTION
– Loss of helical DNA structure and • Rapid intracellular conversion to highly
strand breakage reactive intermediates by bacterial
reductases
PHARMACOKINETICS – Intermediates react non-specifically
• Oral, IV, rectal (suppository) to many ribosomal proteins
– Approaches 100% oral – Disrupt the synthesis of proteins,
bioavailability (not affected by food) RNA and DNA
• Widely distributed in body fluids and tissues
including CSF PHARMACOKINETICS
• Penetrate abscesses including those in the • Well absorbed after oral administration
brain • Very rapid excretion in urine
• Excreted in urine and feces – No systemic antibacterial effect
PHARMACODYNAMICS CLINICAL USE

• Concentration-dependent killing • Urinary antiseptic (uncomplicated acute
cystitis)
CLINICAL USES • NOT recommended during renal failure
• Drug of choice for Clostridium difficile colitis (creatinine clearance <60mL/min)
• Anaerobic infections BELOW the level of – Urine levels are insufficient for
diaphragm (e.g. intraabdominal infection) antibacterial action
• Brain abscess – High blood levels may produce
• Other uses toxicity

ANTIBIOTICS
• NOT recommended for upper urinary tract

infection (pyelonephritis)
ADVERSE REACTIONS
• Common
nausea/vomiting, diarrhea
• Occasional
– Neuropathy
– Hemolytic anemia (those with G6PD
deficiency)
– Rash
– Pulmonary infiltration, fibrosis
FOSFOMYCIN
Fosfomycin
Staphylococci including MRSA +
Streptococci +
Enterococcus faecalis NOT E. +
faecium
Enterobacteriaceae +
Extended-spectrum β-lactamases +
(ESBLs)
Klebsiella pneumoniae +
Carbapenemases
(KPCs)
Pseudomonas aeruginosa 0
Anaerobes +
MECHANISM OF ACTION
• Inhibit the very early stage of cell wall
synthesis
– Inhibit enolpyruvate transferase
– Block the addition of
phosphoenolpyruvate to UDP-N-
acetylglucosamine (first step in the
formation of N-acetylmuramic acid)
PHARMACOKINETICS
• 40% bioavailability after oral administration
• Poorly distributed in tissues
– Urinary concentration exceeding
MICs for most urinary tract
pathogens
CLINICAL USE
• Uncomplicated acute cystitis
• NOT recommended as 1st line agent for
treatment for MDR infections

ANTIBIOTICS
ANTIBIOTICS ______9. The following is true concerning

Choose the best answer: sulfonamides EXCEPT:
A. They are more likely to produce
______1. Which of the following would be MOST crystalluria in alkaline urine in which
effective in the treatment of a gram negative they are less soluble
infection? B. They are primarily metabolized by
A. Amoxicillin acetylation
B. Daptomycin C. They may exert bactericidal action in the
C. Vancomycin urinary tract
D. Gentamycin D. Used alone, they have become
therapeutically unreliable for serious
______2. The main problem (s) with the use of beta infections
lactams is/are:
A. narrow therapeutic index ______10. Ciprofloxacin is not active against
B. renal impairment which organism?
C. allergic reactions A. H. influenza
D. neutropenia B. E. coli
C. Enterobacter sp.
______3. Which of the following is true regarding D. Bacteroides fragilis
vancomycin?
A. Covers gram negative bacteria only ______11. A 58 year old patient develops
B. inhibits protein synthesis palpitations. ECG showed prolonged QT
C. it is potentially nephrotoxic interval. Which one of the following
D. produces red man syndrome when given fluoroquinolones most likely caused this adverse
by slow IV infusion effect?
A. ciprofloxacin
______4. By what mechanism does MRSA achieve B. norfloxacin
resistance to standard beta lactam antibiotics? C. levofloxacin
A. beta lactamases D. ofloxacin
B. penicillin efflux pump
C. altered penicillin binding protein ______12. A patient with watery stools is
D. altered peptide sequence in diagnosed as suffering from amebic dysentery.
peptidoglycan He is given a drug that causes a metallic taste
A. diloxanide furoate
______5. Adverse effect of aminoglycosides include B. metronidazole
the following EXCEPT: C. emetine
A. hypersensitivity reactions D. iodoquinol
B. neuromuscular blockade
C. pseudomembranous colitis ______13. A 25 year old female arrives at the
D. nephrotoxicity ER with high fever, flank pains, and painful
urination. Urine culture grew E. coli heavy
______6. A patient with a blood culture result of S. growth. A diagnosis of acute pyelonephritis was
aureus resistant to Cefazolin, Oxacillin, and given. The decision is made to use a beta
Cefuroxime, may likely respond to which antibiotic? lactam antibiotic that has both an appropriate
A. Ceftriaxone antibacterial spectrum of activity, and good
B. Meropenem tissue penetration, yet is more resistant to beta
C. Linezolid lactamases than narrow spectrum penicillins.
D. Chloramphenicol The drug that fits these characteristics is:
A. ceftriaxone
______7. Which antibiotic is primarily bacteriostatic B. cefoxitin
but becomes bactericidal at higher concentrations? C. cefazolin
A. Erythromycin D. vancomycin
B. Tetracycline
C. Chloramphenicol ______14. A patient was diagnosed to have
D. Ampicillin sepsis with blood culture growth of E. coli –
Extended Spectrum Beta Lactamases (ESBLs).
______8. A patient presents with kidney injury . Which type of beta lactam drug is structurally
Select the antibiotic whose dose must be reduced in different enough to other beta lactams to
this patient: remain effective in treating most infections
A. Ceftriaxone caused by this type of bacteria?
B. Clindamycin A. extended spectrum penicillins
C. Clarithromycin B. fourth generation cephalosporins
D. chloramphenicol C. carbapenems
D. monobactams
UST FMS MEDICAL BOARD REVIEW 2019 | PHARMACOLOGY

ANTIBIOTICS
______15. A 48 year old male develops

hypotension, marked flushing and itching of face
and chest. He was just given an antibiotic by
infusion. The antibiotic most likely responsible
for this reaction is:
A. aztreonam
B. linezolid
C. vancomycin
D. cotrimoxazole
______16. Among the antibiotics that act by

inhibiting protein synthesis, several members of
this drug class are known to produce side
effects related to both drug interactions caused
by inhibition of P-450 and cardiac effects (QT
prolongation/torsade de pointes). Which drug
class is this?
A. aminoglycosides
B. fluoroquinolones
C. macrolides
D. tetracyclines
______17. Aztreonam is an unusual beta lactam

drug that most drug formularies would include
because:
A. it has good activity against methicillin
sensitive S. aureus
B. it is excellent for empiric therapy for
bronchitis
C. if does not cross react with penicillins to
elicit an allergic reaction
D. it is effective PO and IV
______18. The following antibiotic should be

avoided in pregnancy:
A. Amikacin
B. Cefuroxime
C. Azithromycin
D. Clindamycin
______19. A patient presents with deep seated

purulent wound. Scrapings showed MRSA.
Which of the following antibiotics may effectively
cover this organism?
A. Clarithromyin
B. Clindamycin
C. Chloramphenicol
D. Cefepime
______20. The fluoroquinole with the highest

activity vs P. aeruginosa is:
A. Levofloxacin
B. Ciprofloxacin
C. Norfloxacin
D. Moxifloxacin

RESPIRATORY PHARMACOLOGY
KRISTINE MARIE F. GUTIERREZ, MD
RESPIRATORY PHARMACOLOGY Table 3. PK/PD of Epinephrine

PK PD Indications Adverse
ANTI-ASTHMA DRUGS
effects
Table 1. Classification of anti-asthma drugs by MOA:
Bronchodilators Anti-inflammatory Given • ß2 In severe • fear,
IM/SC receptor asthma not anxiety,
SYMPATHOMIMETICS CORTICOSTEROIDS only as stimulatio responding tenseness,
 Catecholamines:epinep  Systemic: it is n to restlessness
hrine - rapidly bronch inhalational , headache,
 ß2-agonists: Hydrocortisone, conjugat odilator agents & / tremor,
- SABA: - Prednisone ed & action; severe pallor,
Salbutamol, - oxidized • alpha bronchospa palpitation;
Terbutaline Methylprednisolone in the receptor sm • cardiac
- LABA:  Inhaled: gut stimulatio especially arrhythmias
Salmeterol, - mucosa n  dec. those , cerebral
Formoterol Beclomethasone & liver mucosal associated hemorrhag
ANTICHOLINERGICS: - Budesonide by edema with es
 Ipratropium - Fluticasone COMT & anaphylaxis
 Tioptropium LEUCOTRIENNE (LT) MAO
METHYLXANTHINES: ANTAGONISTS: when
 aminophylline MAST CELL given po
 theophylline STABILIZER
LAGUNDI METHYLXANTHINES
Table 4. Adverse effects of ß2-agonists on different
LAGUNDI
organ systems & their mechanism:
ANTI-IgE
(Omalizumab) Organs Adverse Mechanism
system effects
Table 2. Classification of anti-asthma drugs Skeletal Tremors Stimulation of ß2-
according to whether they are relievers or muscle receptors in skeletal
controllers (GINA) muscle
Relievers: quickly reverse Controllers: Taken
bronchoconstriction continuously on a CV system Tachycar Reflex cardiac
during acute maintenance basis to dia, stimulation due to ß2-
exacerbations or control asthma palpitatio receptors induced
breakthrough symptoms; n vasodilation, direct
taken prn stimulation of atrial ß2
receptors & stimulation
1. Bronchodilators 1. Anti-inflammatory of myocardial ß1
1.1 Epinephrine agents receptors at higher
1.2 SABA 1.1 LT antagonists doses
1.3 LABA: Formoterol 1.2 Mast cell
only stabilizers Metabolic  FFA ß3 receptors activation
1.4 Methylxanthines 1.3 effects in adipose tissue
1.5 Anticholinergics Methylxanthines
2. Anti-inflammatory: (long acting) glucose ß2 receptor activation 
systemic steroids 1.4 Anti-IgE  glycogenolysis
2. Bronchodilators
2.1 LABA insulin ß2 receptor activation
2.2
lactate
Methylxanthines
K+, ß2 receptors activation
Mechanisms of action of ß2-agonists: Activation of ß Mg++  K+ entry into skeletal
receptors  activation of Gs coupled protein, muscles; Note:
adenylyl cyclase,  ATP, cAMP (2nd messenger)  Hypokalemia +
 protein kinase  phosphorylation of target hypoxemia  dysarrhyt
enzymes  bronchial smooth muscle relaxation, hmias
and enhanced mucociliary function.
Respirator  V-P Pulmonary vasodilation
Structure activity relationship: Increasing the size of y mismatch in blood vessels
alkyl substitution of the terminal amino group in the previously contracted by
catechol ring confers ß2-receptor selectivity. ß2- hypoxia  shunting of
selective agonists are not catecholamines, so they blood to poorly
are not substrates for COMT and metabolism by ventilated areas
MAO is slower, so they can be given orally.

Organs Adverse Mechanism
Table 6. Comparison between ß2 agonist vs
system effects
anticholinergics inhalational agents
CNS Headache ß2 receptor activation Inhalation Onset of Peak Duration of
, Drugs action effect action
restlessne
ss, SABA 0.8 min 2 hrs 4-8 hrs
tension,
dizziness, LABA 1.7 - 5 1-4 12-24 hrs
nervous, min hrs
insomnia
Anticholinerg 15-30 2 hrs Ipratropim:
ß2 Tachyphy downregulation of ß2 ic min 4-5 hr
receptor laxis receptors Tiotropium:
24 hr
Indications for ß2 agonists:
- SABA: METHYXANTHINES: Theophylline, Aminophylline
 treatment of asthma exacerbation, COPD; (consists of 80% theophylline)
prevention of EIA MOA: exact mechanism unclear
 treatment of hyperkalemia; for premature •Bronchodilator actions
labor (tocolytic) - High level inhibits PDE4  cAMP smooth
- LABA: muscle relaxation
 Prophylaxis vs EIA, nocturnal asthma; - Competitive antagonist at adenosine receptor
 Adjunct to anti-inflammatory medications for •Anti-inflammatory actions
asthma control; - Activates histone deacetylases in the nucleus
 Only Formoterol is approved for transcription of proinflammatory genes.
symptomatic relief of asthma Interaction with corticosteroid which recruits
histone deacetylases to the site of
ANTICHOLINERGIC DRUGS: inflammatory gene transcription
MOA: Competitive antagonist to Ach receptors on - Low level  late response to Ag challenge affecting
smooth muscles  bronchodilation & mucus lymphocyte & eosinophil trafficking
secretion
Pharmacokinetics: both Ipra- & Tiotropium act Table 7. Pharmacodynamic actions of theophylline
topically because of their quaternary ammonium
Organ Effects/actions
side chain system
Table 5. Comparison between Ipratropium vs CNS mild-mod dose arousal &
Tiotropium alertness, large
Ipratropium Tiotropium dose nervousness, tremors;
very high dose  medullary
M3 selective No, binds to Yes, binds to stimulation, convulsion,
both M2 & M3; M3 and vasoconstriction of cerebral
blocking M2 at dissociates vessels
postganglionic from M3 100x
parasympatheti more slowly CV + direct chronotropic & inotropic
c nerves may than effect on heart, relaxation of
increase release ipratropium vascular sm muscles;  blood
of Ach viscosity & improve blood flow
(pentoxyphylline)
Duration of shorter, given longer, given
action every 4-6 hrs once daily GIT  secretion of gastric acid and
digestive enzymes
Drug interaction: In combination with ß-agonist Eosinophil  inflammatory response

addition in  bronchodilation effect s
Indications:
1. in combination with ß2-agonist - quick relief of GUT weak diuretic action by  GFR &
acute asthma attack  tubular Na+ reabsorption
2. nasal spray for vasomotor rhinitis
relief medication for COPD patients Smooth relaxation, no tolerance
muscle
Skeletal improves diaphragm contractility

muscle in COPD patients

Pharmacokinetics - Theophylline: Table 9. ICS adverse effects:

1. metabolized in the liver by cytochrome P450,
local adverse effects systemic adverse
subject to multiple drug interactions
(more common) effects
plasma clearance varies depending on age,
concurrent drug intake, diet, medical conditions, - hoarseness/dysphonia, Any systemic adverse
needs serum level monitoring oral effects are possible.
candidiasis, throat (see section on CS)
Table 8. Factors affecting theophylline clearance irritation & cough
Factors that  Factors that  - these can be minimized
clearance clearance by using spacer and
asking patients to gargle
1. Enzyme induction 1. Enzyme inhibition after inhalation
• Drugs: • Drugs:
Rifampicin, (Cimetidine,
Indications for CS:
Phenobarbital, Erythromycin,
1. Systemic steroids: for both asthma reliever &
alcohol ciprofloxacin,
controller
• Smoking: allopurinol)
2. ICS: controller/maintenance of all levels of
tobacco, • high carb diet
persistent asthma
marijuana 2. CHF, liver disease,
• Diet: high pneumonia, viral
LT ANTAGONISTS:
protein, low infections,
MOA:
carb diet, vaccination
1. Inhibits 5-lipoxygenase  cyst-LTs & LTB4
barbecued 3. extreme age: early
(ex. Zileuton- not available here)
meat infancy and old
2. inhibits binding of LTD4 to cyst-LT1 receptors
2. Age: 1-9 y/o with age
on target tissues: ex. Montelukast
highest clearance
Pharmacodynamics:
1. Attenuate the acute airway response to
Adverse effects of theophylline allergen & EIA & improve asthma control when
 nausea & vomiting taken chronically
 GIT disturbance, GERD 2. Anti-inflammatory actions are less than those
 headache of ICS
 restlessness 3. Clinical trials with anti-LT drugs have shown
 dieresis heterogeneity in response to therapy, with
 cardiac arrhythmias patients falling into “responders” &
 convulsions “nonresponders”
Indications of theophylline: Adverse effect: Churg-Strauss syndrome ?

1. as reliever & adjunct therapy for control of Indications:
persistent asthma 1. Alternative controller for mild asthma & allergic
2. apnea of prematurity rhinits
2. Excellent for those with Aspirin/NSAIDs
LAGUNDI: (Vitex negundo): 1 of 10 herbal drugs induced asthma
endorsed by DOH as effective herbal medicine with
proven therapeutic value. It contains Chrysophenol MAST CELL STABILIZERS: Sodium cromoglycate /
D which possesses antihistamine & muscle relaxant cromolyn, Nedocromil (not available)
properties. It can also prevent LT production. MOA:
1. Alters function of delayed Cl- channels on cell
CORTICOSTEROIDS (CS): membrane, inhibiting cellular activation,
MOA: modulating mast cell mediator release,
1.  production of proinflammatory cytokines & eosinophil recruitment or function of airway
chemokines  trafficking of lymphocytes, nerves in airway mucosa
eosinophils & other leucocytes into the airways 2. Inhibits cough on airway nerves
 bronchial hyperreactivity 3. On mast cells,  early & late phase responses
2. Potentiates ß2 agonist effect by  synthesis of to Ag challenge by inhibiting mediator release
ß2 receptors Indications:
3.  mucus production -Controller for mild-mod persistent asthma in
Pharmacokinetics: young children, prevention of EIA, Treatment of AR
Majority of swallowed inhaled CS (ICS) undergo & AC
extensive 1st pass effect in the liver, decreasing
systemic toxicity. But ICS deposited in the KETOTIFEN:
respiratory tract are absorbed systemically and may MOA:
potentially cause systemic adverse effects • H1 receptor antagonist
• Membrane stabilizer inhibiting cellular
degranulation & histamine release

Adverse effects: wt gain from increased appetite & 2. IM absorption is rapid with water soluble
sedations succinate and PO4, slower with lipid soluble
Indications: acetate & acetonide esters
1. adjunct therapy of asthma 3. CS are absorbed from sites of local application
2. treatment of AR & AC 4. > 90% are reversibly bound to plasma
proteins, CBG, transcortin & albumin
ANTI-IGE (OMALIZUMAB): 1st biological drug 5. only unbound portion is pharmacologically
approved for treatment of asthma. It is a active
recombinant humanized monoclonal Ab (IgG1) 6. crosses placenta & maybe distributed to milk
targeted vs IgE 7. metabolism mostly in the liver with resulting
MOA: metabolites undergoing sulfation or
1. binds to Fc portion of IgE, preventing IgE from glucoronidation before being excreted in the
binding to FceR1 on mast cells, basophils, kidneys
eosinophils & Ag presenting cells (APC),
preventing allergic rxn at very early step, Pharmacodynamcis:
free IgE by > 95% 1. Gene-active drugs, with most effects mediated
2. FceRI expression on cell surface of basophils by glucocorticoid receptors (GR) in the cell
& mast cells by > 95% due to  turnover of 2. In the absence of hormonal ligand, GRs are in
unbound receptors complexes with heat shock protein (hsp) in the
Pharmacokinetics: cytoplasm
1. Given as single sc injection q 2-4 wks with 3. Free GCS enters cell & binds to GR, inducing
bioavailability of ~60%, reaching peak serum conformational changes in the GR leading to
levels after 7-8 days, T1/2 = 26 days hsp release. The ligand bound receptor
2. Elimination of omalizumab-IgE complexes complexes dimerize & are transported into the
occurs in liver RES nucleus, interacting with DNA, binding to GC
Adverse effects: receptor elements (GRE) in the promoter
1. local effects: redness, stinging, bruising, region of responsive genes. This interaction is
induration facilitated or inhibited by coactivators or
2. anaphylaxis corepressors respectively, leading in turn to
3. slight increased frequency of malignancy? activation or inhibition of transcription of mRNA
Indication: for patients ≥ 12 y/o with moderate - by polymerase II & associated transcription
severe persistent atopic asthma, AR & food allergies factors & subsequent translation to protein
synthesis. Thus there is a lag period of hew hrs
FIXED DOSE COMBINATIONS IN ASTHMA THERAPY: to days before steroid effects are noted
1. Salbutamol + Ipratropium Bromide: additive 4. Feedback suppression of ACTH occurs in
effect, for relief of asthma attacks & COPD minutes probably from direct effects of GC-GR
2. LABA + ICS: Salmeterol + Fluticasone, Formoterol complexes on cell membrane receptors or from
+ Budesonide; nongenomic effects.
 Synergistic actions: LABA induced sustained
bronchodilation enhancing penetration of Table 1, Effects of GC-GR on Gene transcription
ICS, ICS
Genes whose Genes whose
prevents down-regulation of ß2 agonist
transcriptions transcriptions are
receptors;
are promoted inhibited
 LABA + ICS in fixed dose combination
obviates the need for doubling ICS dose in 1. lipocortin 1. cytokines
patients with 2. ß2-agonist 2. 5-lipoxygenase
partially controlled asthma receptors 3. endothelin-1
 enhance compliance by combining 2
3. endonucleas 4. collagenase,
medicines in 1 gadget es stromelysin
4. stromelysin
CORTICOSTEROIDS
ADRENOCORTICOSTEROIDS: Hormones produced &
secreted from the adrenal cortex and their Physiologic effects of GCS:
analogues Cortisol are produced 10 mg daily & in times of
stress, there is 10 fold increased secretion
1. glucocorticoids (GCS): those with important
effects on intermediary metabolism & immune
functions, ie., Cortisol
2. mineralocorticoids (MC): those with salt-
retaining property, ie. Aldosterone
3. sex steroids: with either androgenic or
estrogenic activity
Pharmacokinetics:
1. most are absorbed readily

Table 2: Physiologic effects of GCS Table 4. Relative potencies & equivalent doses of
representative CS
Permissive effects: Metabolic effects
responses  in the anti- Na durati Equi
absence of cortisol & inflam retainin on of -
restored by physiologic mator g action vale
amount y potency * nt
dose
1. vascular & bronchial 1. formation of
smooth muscle glucose, glycogen Cortisol 1 1 S 20
response to storage &
catecholamines gluconeogenesis by cortisone 0.8 0.8 S 25
2. lipolytic response of mobilizing AA
fat cells to 2. peripheral Prednisone 4 0.8 I 5
catecholamines, utilization, glucose
ACTH, GH uptake in adipose Prednisolone 4 0.8 I 5
tissue, skin
fibroblasts, methylpredn 5 0.5 I 4
thymocytes, PMNs isolone
3. Redistributes body
Triamcinolon 5 0 I 4
fat (truncal obesity),
e
 lipolysis of
triglycerides of
Betamethaso 25 0 L 0.75
adipose tissues, 
ne
lipogenesis net in
fat deposition Dexamethas 25 0 L 0.75
4. Catabolic effects: one
lymphoid tissue,
connective tissue, Fludrocortiso 10 125 - -
muscles, fat & skin ne
Effects on electrolyte & water balance: h •Biologic half-life: S = short acting (8-12 hrs), I
reabsorption of Na from tubular fluid, h urinary = intermediate (12-36 hrs); L = long acting (36-
excretion of K, Ca, & H 72 hrs)
Table 3. Effects on formed elements of the blood Table 5. Structure-Activity relationships of CS

Hgb & Polymorphs Lympho, Ring Carbon # Effect
RBC mono, baso-
eosinophil A C1-2 double bond GC > MC
C3 ketone  GC & MC
  from influx from BM,   C4-5 double bond  GC & MC
rate of removal from
circulation,  B Fl at C9  GC & MC
demargination from
vascular walls,  migration C C11-OH needed for GC
from blood vessels, thus  activity
count
D -CH3 at C16 MC
-OH at C17 GC optimally
Anti-inflammatory & immunosuppressive effects:
1.  IL-1, IL-2, IL-3, IL-6, TNF-a, IFN-g, GM-CSF, -OH at C21 essential for
Macrophage, lymphos, CMI, T cell proliferation MC activity
2.  Ig & complements conc.,  reactivity of
tissue to Ag-Ab interaction,  microbicidal
effects of monocytes,  macrophage
accumulation in inflamed areas
3. Stabilize leucocyte lyzozomal membranes, 
capillary wall permeability & edema formation
4. Antagonizes histmine activity & release of
kinins from substrates
5.  fibroblast proliferation, collagen deposition &
subsequent scar tissue formation
6.  productions of lipocortin which inhibits PA2

Organ Adverse effects
CORTICOSTEROID STRUCTURE
system
Metabolic 1. hyperglycemia, DM ( 
gluconeogenesis in liver &
degradation of proteins to free
amino acid in muscles)
2. metabolic alkalosis (from  K+ &
H+ losses in the kidneys)
3. dyslipidemia (from  lipolysis)
CV HPN ( Na+ reabsorption, H2O

retention; potentiation of vasopressor
responses to angiotensin (AT) &
catecholamines through induction of
AT II receptors & potentiation of
downstream a1 receptors signaling
respectively)
Immunity Impaired (See PD)
HPA axis Prolonged suppression by CS 

withdrawal syndrome (fever, myalgia,
Table 6. Adverse effects of CS by system
arthralgia, malaise, hypotension, GIT
Organ Adverse effects sxs, dehydration, lethargy, weakness
system
Therapeutic uses of CS:
CNS Psychosis, pseudotumor cerebri 1. Substitution therapy in deficient states like
Addison’s disease, at 20-30 mg of cortisol
Eyes glaucoma, posterior subcapsular (hydrocortisone) or equivalent daily,  dose in
cataracts times of stress.
2. Anti-inflammatory uses in various conditions
Skin 1. ulcers, striae, 3. As part of anti-cancer regimen
hypo/hyperpigmentation, acne, 4. Treatment of graft rejection in organ
facial plethora, hirsutism, alopecia transplantation
2. poor wound healing through 
synthesis of matrix metalloprotein- General Principles in CS therapy
ases & collagen important for 1. High dose CS tx of < 1-2 wks is unlikely to
wound healing cause HPA axis suppression & significant
adverse effects
Skeletal 1. osteoporosis (  transcription of 2.  risks with prolonged duration of treatment,
osteocalcin important for bone long acting steroids, & frequent dosing/day
mineralization,  osteoblasts,  3. Anti-inflammatory effects are only palliative,
apoptosis of osteoblasts & not curative, and are closely tied in with their
 osteoclast activity;  renal Ca++ toxic effects
loss &  GIT Ca++ absorption 4. Abrupt cessation of prolonged high CS dose
2. fractures esp in postmenopausal  risks for adrenal insufficiency &
women exacerbation / relapse of underlying diseases
3. osteonecrosis (formerly known as for which CS was used
aseptic necrosis) 5. Adrenals of patients who had been on chronic
4. vertebral compression fracture systemic steroid tx will take a long time to fully
5. In children, growth stunting by  recover (~9 months - 2 yr)
proliferation &  apoptosis of 6. In chronic steroid therapy,
chondrocytes  Start with high daily split dose during acute
phase
Muscular Myopathy, atrophy (from protein  Use short or intermediate acting steroids
catabolism) (prednisone, prednisolone,
methylprednisolone)
GIT hyperacidity, peptic ulcer disease,  After the acute phase of illness is controlled,
perforation, pancreatitis the steroid dose can be consolidated into
single daily
Reproducti Amenorrhea, infertility, loss of libido breakfast dose to simulate normal diurnal
ve rhythm of cortisol.
 Switch to alternate day regimen with
gradual tapering to the lowest possible
dose to allow the
HPA axis to recover on the off day

REVIEW TEST
REVIEW TEST: ASTHMA DRUGS

______9. The general safety of ICS is due to the ff
Choose the best answer: pharmacokinetic or pharmacodynamic property:
A. Almost none of the ICS is absorbed
______1. A 5 y/o boy was given epinephrine systemically
because of anaphylaxis after peanut intake. He B. Systemically absorbed ICS are
developed tachycardia & tremors thereafter. The tightly bound to serum proteins
tremors are mediated by which receptor? C. Systemically absorbed ICS undergo
A. a1 1st-pass effect in the liver
B. a2 D. Most of the systemically absorbed
C. ß1 ICS are rapidly excreted in the
D. ß2 urine on their 1st pass through the
kidneys
______2. An asthmatic patient in exacerbation was
given ß2 nebulization q 20 min. As his asthma ______10. What is the mechanism of action of
improves, he started to feel muscle cramps. This is steroids as an anti-inflammatory agent?
most likely caused by: A. Gene active
A. Respiratory acidosis B. Activates G protein coupled
B. Hypocalcemia receptors
C. Hypokalemia C. Activates protein kinases
D. Hyponatremia D. Activates ligand gated channel
______3. Which of the ff anti-asthma drugs is NOT ______11. The following steroid preparation is a
suitable for monotherapy of asthma pro-drug. Its C-11 ketone needs to be hydroxylated
A. Montelukast in the liver before it becomes active.
B. LABA A. Prednisone
C. ICS B. Prednisolone
D. Theophylline C. Methylprednisolone
D. Dexamethasone
______4. This is the bronchodilator of choice for
patients with COPD. ______12. In the long term treatment of chronic
A. Salbutamol autoimmune disorders with prednisone, it is best to
B. Tiotropium give steroids at this time of the day to minimise
C. Formoterol adverse effects.
D. Theophylline A. 6 – 8 am
B. 12 noon
______5. Which subtype of muscarinic receptors is C. 3 pm
blocked by tiotropium D. 6 – 8 pm
A. M1
B. M2 ______13. The steroid preparation of choice for a
C. M3 patient in Addisonian crisis:
D. M4 A. Hydrocortisone
B. Prednisolone
______6. Which of the ff anti-asthma drugs C. Methylprednisolone
possesses both bronchodilator & anti-inflammatory D. Dexamethasone
properties
A. Formoterol ______14. The most potent mineralocorticosteroid
B. Montelukast recommended in the treatment of salt losing
C. Theophylline adrenogenital syndrome:
D. Ipratropium A. Hydrocortisone
B. Prednisolone
______7. Clearance of theophylline is enhanced by C. Methylprednisolone
concurrent administration of the ff drug or D. Fludrocortisone
substance
A. Cigarette smoke ______15. In adopting “every other day” steroid
B. Grapefruit juice therapy for persistent severe asthma, which of the
C. Macrolides following is most suitable for long term use.
D. Cimetidine A. Hydrocortisone
B. Prednisone
______8. Which of the ff is best for reducing C. Methylprednisolone
bronchial hyperreactivity of persistent asthma? D. Dexamethasone
A. ICS
B. Inhaled LABA
C. Methylxanthines
D. LTRA

REVIEW TEST
______16. A patient with severe asthma needs to be

on methylprednisolone 16 mg qod but can no
longer afford it. How much prednisone does he need
to get the equivalent dose of methylprednisolone?
A. 10
B. 15
C. 20
D. 25
______17. A patient diagnosed with bronchial

asthma, partly controlled on maintenance
medication developed oral candidiasis and throat
irritation. The most likely drug given
A. Fluticasone inhaler
B. Salbutamol inhaler
C. Theophylline
D. Montelukast
______18. This drug is a H1 receptor antagonist and

a membrane stabilizer inhibiting cellular
degranulation & histamine release used as adjunct in
the treatment of asthma
A. Montelucast
B. Ketotifen
C. Cetirizine
D. Theophylline
______19. This corticosteroid has the greatest Na

retaining potency
A. Hydrocortisone
B. Dexamethasone
C. Methylprednisolone
D. Fludrocortisone
______20. This drug can be taken continuously on a

maintenance basis to control asthma
A. Epinephrine
B. Salbutamol
C. Montelukast
D. Terbutaline

THYROID AND ANTI-THYROID DRUGS
JEAN UY-HO, MD
INSULIN. ORAL HYPOGLYCEMIC AGENTS REGULATION OF GLUCOSE TRANSPORT BY

AND OTHER AGENTS USED IN DIABETES INSULIN
MELLITUS 1. Translocation of glucose transporter from
sequestered site to exposed locations on the
GOALS OF THERAPY cell membrane
 Achieve and maintain normal or near normal 2. Stimulation of the intrinsic activity of the
metabolic and biochemical parameters transporters (muscle)
 Eliminate the symptoms of hyperglycemia 3. Regulation of synthesis of glucose
 To prevent occurrence of acute transporters
complications
 To prevent or delay long-term complications GLUCOSE TRANSPORTERS – facilitate diffusion of
 To prevent progression to diabetes mellitus glucose into the cells
in prediabetics  GLUT 1:
• all tissues especially red cells, brain
ANTIDIABETIC DRUGS (MECHANISM TO INDUCE • basal up-take of glucose, transport
BLOOD GLUCOSE LOWERING ACTION ) refer to across the blood-brain
Table 1 Appendix A)  GLUT 2:
• B cells of pancreas; liver, kidney;
I. INSULIN gut
INSULIN CHEMISTRY • regulation of insulin release, other
 composed of 2 polypeptides aspects of glucose homeostasis
o A chain (21AA)  GLUT 3:
o B chain (30 AA) • brain, placenta, other tissues
( A & B ) joined covalently by 2 interchain • uptake into neurons, other tissues
disulfide bonds; a third intrachain disulfide
 GLUT 4:
bridge is present in the A chain.
• muscle, adipose
 Human insulin – produced by recombinant • Insulin mediated uptake of glucose
DNA techniques
 GLUT 5:
o Regular
• gut, kidney
o NPH
• transport of fructose
 insulin analogs:
a) Rapid acting
 Insulin lispro DISTRIBUTION, FATE AND EXCRETION
 Insulin aspart
 Circulates as free hormone and taken up by
 Insulin glulisine
tissues or metabolized rapidly. Plasma half-
b) Long acting
life = 3-5 minutes in normal subjects &
 Insulin glargine
patients with uncomplicated diabetes
 Insulin detemir
 Sites of degradation: Liver 60% Kidney
40%
 In solution, it can exist as monomer, dimer
or hexamer  Ratio is reversed in diabetics receiving
exogenous insulin
REGULATION OF INSULIN SECRETION
(refer to Table 2 Appendix A) HUMAN INSULIN
Biosynthetic (Recombinant DNA technology)
INSULIN SECRETION OF PANCREATIC BETA CELLS  prepared by inserting human proinsulin
ENDOCRINE EFFECTS OF INSULIN gene into plasmids of E.coli.
(refer to Table 3 Appendix A)  separate production of the A and B chains
with 2 fermentations and subsequent sulfur
OTHER METABOLIC EFFECTS OF INSULIN linkage of the chains by chemical means
 Transport into cells of K+ , Ca++,  more soluble than porcine insulin in aqueous
nucleosides and inorganic phosphate solutions, due to presence of threonine,
with its extra hydroxyl group
INSULIN RECEPTOR
 Membrane glycoproteins composed of 2 INSULIN ANALOGS
protein subunits.  Recombinant chemical modifications of
 2 Alpha - extracellular, carry the insulin naturally occurring insulin
binding site  Alteration of specific AA residues yields
novel derivatives that vary in their pK
 2 Beta - transmembrane proteins with  Rapid acting insulin
tyrosine kinase activity
o Insulin lispro – differs from human
insulin at B28 and B29 where the AA
has been reversed : does not self-
associate

JEAN UY-HO, MD
o Insulin aspart – proline at B28 is  Effect appears within 30 minutes, peak between
replaced with aspartic acid 2-3h and lasts 5-8h
o Insulin glulisine – glutamic acid  Given 30 min SC before a meal to control
replaces lysine at B29, and lysine postprandial hyperglycemia
replaces asparagine at B3
 Preparation of choice for IV therapy during
 Long Acting Analogs
surgery, acute infections, diabetic ketoacidosis ;
o Insulin glargine
the only type that can be administered IV
2 arginine are attached to B chain
carboxyl terminal; glycine is
INTERMEDIATE ACTING INSULIN
substituted for asparagine at A21
NPH ( Isophane Insulin )
o Insulin detemir
Threonine is dropped from B30 and  Onset of action is delayed by mixing insulin and
myristic acid is attached to B29 lysine protamine in an equal ratio at neutral pH with
small amount of zinc
PHARMACOKINETICS OF AVAILABLE INSULIN  Converts the normally rapidly absorbed insulin
PREPARATIONS (refer to Table 4 Appendix A) to a preparation with longer duration of action
 Can be mixed with regular, lispro, aspart or
INDICATIONS FOR INSULIN glulisine insulin and given 2-4 times daily
1. Persons with Type 1 (insulin dependent)  Dose regulates the action profile; small doses
diabetes or postpancreatectomy diabetes have lower, earlier peaks and a short duration of
2. Acutely decompensated diabetes (with action
diabetic ketoacidosis or hypersmolar,  Variability of absorption is >50%
hyperglycemic coma)
3. Hyperglycemic pregnant diabetic not RAPID ACTING INSULIN ANALOGS
controlled by diet alone - Very fast onset, short duration
4. Short-term treatment of type 2 or impaired Insulin Analogs
glucose tolerance during intercurrent events 1. Insulin Lispro
(operations, infections, myocardial
infarction)
 Same AA as human insulin except
B28 contains lysine and B29
5. Persons with Type 2 diabetes but good
contains proline
blood glucose control can not be achieved
and maintained by diet, exercise and/or oral  The switching results in insulin
hypoglycemics molecule that resists formation of
6. Emergency treatment of hyperkalemia; hexamers and tends to remain
insulin is given with glucose to lower ECF K+ monomeric, thus promoting a more
via distribution into cells. rapid rate of absorption from SC
injection sites reaching peak serum
CHARACTERISTICS OF INSULIN values as early as 1 hour, and has
PREPARATION shorter duration of action (2-4 hrs)
 No advantage over regular insulin if  Injection immediately before a meal
given intravenously affords hypoglycemic control similar
2. Insulin Aspart to regular insulin given 30 min.
before the meal
 Substitution of the B28 proline with
aspartic acid  Lowest variability of absorption;
duration of action is not prolonged
 The modification reduces ProB28
by increasing the dose
and GlyB23 monomer -monomer
interaction inhibiting self –  These unique characters allow a
aggregation better match of the rise in
circulating insulin concentration with
 Rapidly breaks into monomers after
glucose excursions after meals
SC injection
 Absorption and activity profile LONG ACTING BASAL INSULIN ANALOGS
similar to insulin lispro. Provide a more constant low-level release of insulin
3.Insulin glulisine 1. Insulin Glargine - An insulin analog
 Asparagine is substituted for lysine
at B3 and glutamic acid for lysine at
 2 arginine are attached to the
carboxyl terminal of B; glycine is
B29
substituted for asparaginase at A21
SHORT ACTING INSULIN  Soluble in solution but precipitates in the more
Regular or Soluble Crystalline Zinc Insulin neutral body pH after SC injection, absorption
is thus prolonged; avoids insulin peaks
 Predominantly dimeric and hexameric causing
delay in onset and prolong time to peak action  Provides constant basal insulin supply and
mimic physiological post-absorptive basal
 Has to be diluted by interstitial fluid to change to
insulin secretion
monomers

JEAN UY-HO, MD
 Used in conjunction with short acting insulin SOME DRUGS THAT MAY PROMOTE
– Lower post absorptive plasma glucose but HYPOGLYCEMIA
reduce the risk of night time hypoglycemia β Adrenergic antagonists
*Due to its acidic pH, it should not be Ethanol
mixed with short acting or rapid acting Salicylates
insulin Lithium chloride
*Must be given as separate injections Theophylline
ACE inhibitors
2. Insulin - detemir NSAIDs
 Terminal threonine is dropped from B30 & Pentamidine
myristic acid (C-14 FA chains) is attached to Bromocriptine
the terminal B29 lysine Mebendazole
 This modification prolong the availability of the
injected analog by promoting binding to serum
COMPLICATIONS OF INSULIN THERAPY
and tissue albumin
1. Hypoglycemia
 Dose dependent onset of action of 1-2h and 2. Weight gain
duration of action of more than 24h 3. Insulin lipodystrophy (atrophy and/or
hypertrophy)
INSULIN MIXTURES 4. Insulin allergy and resistance
 Combination of intermediate acting & rapid or
short acting insulin in premixed ratio II. ORAL ANTIDIABETIC AGENTS
 Useful for patients with physical impairments A. Insulin Secretagogues
(visual or manual) who are on mixed insulin 1. Sulfonylureas (SUR)
regimens. 2. Rapid-Acting Prandial Insulin
 Not ideal for most diabetics who may achieve Releasers (Glinides)
better control by separately mixing short-acting B. Biguanides (MET)
and intermediate acting insulins to arrive at a C. Thiazolidinediones(Tzds)
ratio that is better suited to manage their D. Alpha Glucosidase Inhibitors (AGIs)
diabetes.
A. INSULIN SECRETAGOGUES
FACTORS THAT AFFECT THE ABSORPTION OF
INSULIN 1. SULFONYLUREAS
1. Site of injection – abdominal wall > arm >
buttocks > thigh
2. Type of insulin
3. Subcutaneous blood flow
4. Altered volume or concentration of injected
insulin
5. Regional muscular activity at site of injection
6. Depth of injection The effective compounds are arysulfonylureas with
7. Species source – human insulin is absorbed substitution on the benzene and the urea group
faster
Mechanisms of Action
EFFECTS OF SELECTED HORMONES ON ENERGY  Stimulate release of preformed insulin
HOMEOSTASIS (refer to Table 5 Appendix B  Reduce serum glucagon concentration
(chronic)
SOME DRUGS THAT MAY PROMOTE
HYPERGLYCEMIA PHARMACOKINETICS OF SULFONYLUREAS refer to
Glucocorticoids Table 6 Appendix B)
Epinephrine SECOND GENERATION SULFONYLUREAS
Thyroid hormones  100-200 x more potent by weight than first
β 2 Adrenergic agonists generation agents
Diuretics (thiazide, loop)  Similar mechanism of action as first generation
Hydantoins (phenytoin, others) agents
Antipsychotics (atypical,others)  May be effective in patients who experience
Diazoxide secondary failure with first generation
Oral contraceptives
 Fewer adverse effects and drug interactions
Pentamidine
Interferons
INDICATIONS FOR SULFONYLUREAS
Amphotericin B
Asparaginase  In type 2 DM who can not achieve appropriate
Protease inhibitors control with diet and exercise alone
Opioids (morphine fentanyl)

JEAN UY-HO, MD
 Type 2 DM whose disease is controlled with  Result in plasma insulin levels that
relatively low doses of insulin (<40 u/d) and are peak within 2 hrs; returns to
> 40 yrs of age baseline by 4 hrs.
 Clinical presentation warrants immediately  Hepatically metabolized (CYP2C9,
beginning oral agent along with diet and CYP3A4), t ½ = 1.5 hrs, duration
exercise. of action < 4 hrs
 Dose: 60-120 mg before each meal
CONTRAINDICATIONS  Side effect :Hypoglycemia
 Type I DM
 Pregnancy and Lactation B. BIGUANIDES: METFORMIN
 Significant hepatic or renal insufficiency MECHANISMS OF ACTION
 Decreases hepatic glucose
ADVERSE EFFECTS: production thru activation of AMPK
 Hypoglycemia (adenosine 5’ monophosphate –
 GIT upsets activated protein kinase)inhibits
gluconeogenesis, fatty acid
 Cholestatic jaundice synthesis, . cholesterol synthesis
 Agranulocytosis  Increase peripheral glucose uptake
 Aplastic & hemolytic anemias and utilization in skeletal muscle &
 Disulfiram-like reactions (chlorpropamide) adipose tissues
 Dilutional hyponatremia (chlorpropamide)  Increases insulin signaling (inc.
 Hypersensitivity reactions activity of insulin receptor)
 Slows glucose absorption from the
DRUG INTERACTIONS GIT
Concomitant intake of drugs
(a) that affect: Added benefits:
(1) protein binding - Improvement in the adverse lipid
(2) hepatic metabolism profile found in DM: inc. HDL, dec.
(3) urinary excretion Tg
(b) that has opposite action / suppress insulin - suppresses appetite & causes less
secretion weight gain than SUR
Absorption, Fate and Excretion
2. GLINIDES. Rapid-acting prandial insulin Metformin is partially absorbed from
secretagogues the GIT not bound to plasma
proteins, not metabolized and is
Repaglinide excreted by the kidney as the active
 a derivative of benzoic acid, lack the compound. It has a half-life of 1.5
SUR moiety to 3 hours.
 stimulates insulin release by closing
KATP channels in β cells CLINICAL USE
 rapidly absorbed from gut, peak 1. Firstline therapy for mild to
blood level is obtained in 1 hr, moderate type 2 obese diabetic with
metabolized in the liver (CYP3A4) insulin resistance
2. Combination with sulfonylurea
 t1/2 = 1 hour, duration of action 5- 3. Prevention of T2DM in middle-aged
9 hrs
obese with IGT and fasting
 Indicated for use in controlling hyperglycemia
postprandial glucose excursions 4. Polycystic ovarian syndrome (off-
 Dose: 0.25-4 mg taken just before label use)
each meal
 Side effect: hypoglycemia if meal is CONTRAINDICATIONS
delayed or skipped 1. Decreased renal or hepatic function
2. Myocardial infarction
Nateglinide 3. Septicemia
 D-phenylalanine derivative 4. Prolonged fasting
 Same M.A. as SUR and repaglinide
UNTOWARD EFFECT
 Binds with higher affinity; 1. GIT disturbances – metallic taste,
 Faster onset, shorter duration anorexia, nausea diarrhea
 Restores initial insulin release in 2. Lactate accumulation and acidosis
response to glucose 3. Long-term use may interfere with
 Absorbed within 20 min. after oral absorption of Vit. B12 and folate
administration peak effect < 1 hr.

JEAN UY-HO, MD
C. THIAZOLIDINEDIONES (Tzds)  Excreted in the urine and feces

 Selective agonist for peroxisome  Maximum clinical effect requires
proliferator-activated receptor gamma several weeks (6-12 wks)
(PPARγ )
-PPAR receptors are found in muscle, liver
 Adverse effects:
- inc. plasma volume: dilutional
and fat; affect adipose cell differentiation
anemia / edema / CHF
and lipid metabolism
- weight gain
 Require insulin to be present for their action
- macular edema (rosiglitazone)
 Increase insulin sensitivity in target tissues
- demineralization and inc.
 Euglycemia
 Mechanisms of action:
(1) increase insulin mediated glucose  bone fracture in women
transport into muscle and adipose tissue  Pre-treatment liver function tests
(inc. glucose transporter expression) and periodically thereafter
(2) decreased hepatic glucose output  Contraindications: liver disease,
(3) promote fatty acid uptake and storage CHF
in adipose tissue
(4) regulates the release of adipokines from D. ALPHA-GLUCOSIDASE INHIBITORS
dipocytes Acarbose, Miglitol
(4-a) stimulate secretion of  Carbohydrate analogues that bind to α-
adipomectin  sensitizes tissues to glucosidase
the effects of insulin  Competitive inhibitors of alpha-
(4-b) inhibit resistin secretion  glucosidases (final enzyme in the
reduces insulin resistance digestion of CHO)
 Long term therapy  dec. Tg, inc.  has higher affinity for the enzymes (
HDL, inc. LDL (less dense) 1000 x ) than natural CHO
 Readily absorb from the GIT, highly  Reduce postprandial peak in blood
protein bound rapidly metabolized glucose by delaying the digestion and
by the liver absorption of starch and dissacharides
 Half-life <7 hours for parent drug  Prevent progression to diabetes mellitus
but up to 150 hrs and 24 hrs for the in prediabetics (STOP-NIDDM)
metabolites of rosiglitazone and  Reduce CV events in diabetics
pioglitazone respectively.
Pioglitazone:
 Poorly absorbed from GIT, extensively
degraded in the bowel and excreted in
 with PPAR-α and PPAR-y
the feces and urine
activity
 food delays absorption but  Should be administered at the start of a
total bioavailability is not meal
affected;  Prominent adverse effects: diarrhea,
 absorption is decreased if flatulence, abdominal bloating
taken with bile acid  Contraindicated in patients with
sequestrants inflammatory bowel disease
 metabolized by CYP2C8 and
CYP3A4 III. GLP-1-BASED AGENTS
 Tg lowering effect greater
than rosiglitazone A. GLP-1- Receptor Agonists
 Approved as monotherapy 1. Exenatide
and in combination with  Synthetic analog of GLP-1
MET, SUR and insulin for  ACTIONS:
T2DM -Potentiates glucose-mediated
  risk of bladder cancer insulin secretion
when used for >1 yr. -Suppresses postprandial glucagon
release
Rosiglitazone: -Slows gastric emptying
 PPAR-y agonist -Decreases appetite
 Rapidly absorbed; highly  An injectable adjunctive therapy
protein bound in T2DM on MET and/or SUR
 Metabolized by CYP2C8 and who still have suboptimal
CYP2C9 glycemic control
 Appears to carry more  Injected SC within 60 min
cardiovascular risk than before a meal
pioglitazone  Associated with weight loss
 Adverse effects:
-Nausea (44%)

JEAN UY-HO, MD
-Vomiting  Adverse reactions: GIT: constipation,

-Diarrhea indigestion, flatulence
-Necrotizing & hemorrhagic May impair absorption of fat-soluble
pancreatitis vitamins and other drugs
2. Liraglutide
 Pharmacodynamic profile COMBINATION DRUG THERAPY IN DIABETICS
mimics exenatide Advantages:
 Has an extended t1/2 permitting  target more than one therapeutic area and
once a day administration provide synergistic effect of individual drugs
 Adjunctive therapy in T2DM on  reduce adverse effects because lower dose
MET, SUR who still have of each drug is used
inadequate control
B. Dipeptidyl Peptidase-4 Inhibitors PRINCIPLES IN CHOOSING COMBINATION
(Sitagliptin, Saxagliptin, Linagliptin) ANTIHYPERGLYCEMIC DRUGS:
 The drugs must have complementary
 inactivate the enzyme that degrades mechanisms of action.
incretins & other GLP-1-like molecules  The drugs must have compatible
thus prolonging the half-life of pharmacokinetic profiles.
endogenous GLP-1  The drugs must have different adverse
 Actions: effect profiles.
↑ GLP-1 & GIP - ↓ post prandial
glucose excursions by increasing TREATMENT OF HYPOGLYCEMIA
glucose-mediated insulin secretion and  Mild hypoglycemia in a patient who is
decreasing glucagon level conscious and able to swallow:
 Adjunctive therapy to diet and exercise The preferred treatment is glucose 15-20g,
MET, Tzds, SUR in T2DM although any form of carbohydrate that
 Oral bioavailability of over 85%; t/2 12h contains glucose may be use
 Well tolerated; weight neutral  Unconscious or stuporous patient
 Adverse effects: nasopharyngitis, URTI, a. 20-50 ml of 50% glucose solution IV
headache, acute pancreatitis, severe infusion over a period of 2-3
allergic and hypersensitivity reactions minutes
b. If IV therapy is not available 1 mg
IV. PRAMLINTIDE of glucagon SC or IM
 Synthetic analog of amylin
 Glucagon should be prescribed for all
Amylin (Islet Amyloid Polypeptide)
individual at significant risk of severe
-Produced in the β cells and co-
hypoglycemia
secreted with insulin
 Actions:
HYPERGLYCEMIC AGENTS
-Suppresses glucagon release, delays
Glucagon
gastric emptying, promotes satiety
 Given to supplement insulin in  Secretion of A cells of the pancreas
individuals unable to achieve the desired  A poypeptide with MW of 3485
postprandial blood glucose (Type I and  Degraded in the liver, kidney, plasma
Type 2 insulin-requiring) and tissue receptor sites
 Results in modest weight loss  Half-life 3-6 minutes, proteolytic
 Injected subcutaneously immediately removal of the amino-terminal histidine
after eating residue leads to loss of biological activity
 Adverse effects
-Nausea PHARMACOLOGIC EFFECTS
-Hypoglycemia when administered with 1. Metabolic Effects
insulin  Stimulates adenylcyclase
 activation of phosphorylase
The dose of short-acting or premixed insulin should
be reduced by 50% when pramlintide is started.  breakdown of liver glycogen to
glucose
V. BILE ACID SEQUESTRANTS (BASS)  increase gluconeogenesis and
Colesevelam ketogenesis
 prevent reabsorption of bile acids in the 2. Cardiac Effects
intestinal lumen  Potent inotropic and chronotropic
 endogenous ligands of FX( farsenoid x effect
receptor) R  play an important role in bile  Tx of acute heart failure pptd by
acids, cholesterol and glucose metabolism injudicious use of B-Blockers
 Clinical use: add-on therapy for T2DM who 3. Effects on Smooth Muscle
are on MET, SUR or insulin, who have not  relaxation of intestine
achieved adequate control.

JEAN UY-HO, MD
DIAZOXIDE
 It inhibits insulin release from β cells and
causes hyperglycemia lasting 4-8 hours.
 Its action on ATP sensitive K+ channels is
opposite to that of sulfonylureas.
 Other actions which may contribute to
hyperglycemia are decreased peripheral
utilization of glucose and release of
catecholamines.
 It has been used to prevent hypoglycemia in
insulinomas.
Adverse Effects: sodium or water retention

 hyperuricemia
 thrombocytopenia
OCREOTIDE
 somatostatin analogue
 blocks hormone release from insulinomas,
glucogonomas and thyrotropin secreting
pituitary adenomas

JEAN UY-HO, MD
THYROID HORMONES SYNTHETIC LEVOTHYROXINE (T4)

 Thyroxine (4)  Preparation of choice for replacement
 Triiodothyronine (T3) therapy
 Reverse Triiodothyronine (rT3)  Stability
 Follicular cells produce T4 and T3 (T4 >  Content uniformity
T3) which are iodine containing  Low cost
derivatives of thyronine.  Lack allergenic foreign protein
 C cells (parafollicular cells) produces  Easy laboratory measurement
calcitonin (calcium metabolism)  Long plasma half-life (7 days)
 T4 converted to T3 intracellularly
THYROID HORMONE SECRETION AND
SYNTHESIS SYNTHETIC LIOTHYRONINE (T3)
 Active transport of iodide Not recommended for routine replacement therapy;
 Organification of iodide (MIT / DIT) best used for short-term suppression of TSH:
 Coupling (T4 / T3)  Short half-life
 Storage and release  More expensive
 Peripheral conversion of T4 to T3  Greater difficulty in monitoring its
therapeutic and toxic effects with
SUMMARY OF THYROID HORMONE KINETICS conventional thyroid function tests
T4 T3  Greater hormone activity and consequent
From thyroid 100% 20% greater risk of cardiotoxicity
secretion
Plasma concentration 99.9% 99.6% LIOTRIX
Amount bound 0.02% 0.4  Combined synthetic T4 and T3 in 4:1 ratio
Free 85.47 33.6 mg/day  Stable, predictably potent but more
Total production rate mg/day 0.75 days expensive
Plasma half-life 6.7 days 40 L
Volume of 10L 24 L/day NATURAL HORMONE EXTRACTS
distribution 1.1 L/day 4 -Dessicated thyroid
Metabolic clearance 1 95%  No longer recommended for the treatment
rate 75.90% of hypothyroidism
Biologic potency  protein antigenicity
Oral absoprtion  product instability
 variable hormone concentrations
MAJOR ROUTE OF ELIMINATION:  difficulty in laboratory monitoring
 Metabolism – deiodination to either T3 or  significant amounts of T3 in some
reverse T3 preparations thus, greater toxicity
 The liver is the major non-thyroidal site of  The only apparent advantage of dessicated
conversion of T4 to T3 thyroid is its low cost.
INDICATIONS: TOXICITY OF THYROXINE

 Simple non-toxic goiter, due to dietary  Directly related to hormone level
iodine deficiency usually with normal thyroid  Manifests as hyperthyroidism
function
 Hypothyroidism DRUGS THAT DECREASE EFFECTS OF T3&T4
- Myxedema MECHANISMS PRECIPITANT DRUGS
- Cretinism Decreased T3 and T4 Aluminum hydroxide
absorption or Calcium carbonate
ACTIONS: enterohepatic cycling Ferrous sulfate
 Essential for growth & development of Sucralfate
nervous, skeletal & reproductive tissues Cholestipol
 Increase carbohydrate, fats and protein Cholestyramine
metabolism Increased serum TBG Estrogens
 Calorigenic effect concentration Tamoxifen
Raloxifene
THYROID PREPARATIONS Heroin
A. Synthetic Mathadone
 Levothyroxine (T4) Mitotane
 Liothyronine (T3) 5-Fluorouracil
 Liotrix Increased hepatic Phenobarbital
B. Natural Hormone Extracts metabolism of T3, T4 Rifampicin
 Dessicated thyroid Phenytoin
 Thyroglobulin Carbamazepine
Decreased T4- Iopanoic acid

JEAN UY-HO, MD
deiodination activity Ipodate hepatic first pass

Beta-adrenergic effect
blockers Protein binding 75% Nil
Glucocorticoids Plasma half-life 1.5 hrs. 6 hrs.
Amiodarone Dose 100 mg every 6 30-40 mg
Decreased thyroid Lithium hrs. once daily
hormone secretion Iodides & iodide Dose response Rapid-brings down Slower
containing agents activated thyroid
Amiodarone hormone levels
Aminoglutethimide faster due to
inhibition of T4
DRUGS THAT INCREASE EFFECTS OF conversion to T3
T3 &T4 Pregnancy Preferred as its
MECHANISMS DRUGS strong protein
Increased thyroid Iodide binding prevents
hormone secretion Amiodarone ready crossing of
Displacement from Salicylates placenta
protein binding sites Furosemide
Mefenamic acid TOXICITY:
Heparin  Frequency of adverse effects 3-12%
Phenytoin  Maculopapular pruritic rash (most common
Sulfonylureas 4-6%) agranulocytosis (most serious 0.3-
Decreased serum Androgens 0.6%); reversible upon discontinuation
TBG Anabolic steroids
Slow release nicotinic acid (2) IODIDES
Glucocorticoids
MECHANISMS OF ACTION:
THE ANTITHYROID AND THYROID INHIBITOR  Inhibit organification & hormone release (>
DRUGS 6 mg/d major action) through possible
inhibition of thyroglobulin proteolysis.
INDICATIONS: Usually effects are seen in 2-7 days.
 Hyperthyroidism  Decreases the size and vascularity of the
 Thyroid CA (radioactive iodine hyperplastic gland (preoperative preparation
MECHANISMS: for surgery)
 Interfere directly with the synthesis of
thyroid hormones (true anti-thyroids) INDICATIONS:
 Block iodide transport mechanisms (ionic  Rarely used as monotherapy
inhibitors)  Thyroid storm
 Pre-operative preparation for thyroid
 Decrease the release of thyroid hormones
surgery
from the gland & may decrease hormone
 Protection of thyroid against fallout in
Synthesis (iodine)
the event of nuclear accident
 Damages the thyroid gland with ionizing
radiation (radioactive I131)
DISADVANTAGES OF IODIDES:
 Because of increase in intraglandular
THE ANTI-THYROID DRUGS
stores of iodine there is a delay in the
onset of thioamide effects
(1) THE THIOAMIDES
 Prevent use of radioactive iodine
-Prophylthiouracil (PTU)
therapy for several weeks
-Methimazole
-Carbimazole
TOXICITY OF IODINE: (UNCOMMON)
MECHANISMS OF ACTION:
 Acneiform rash
 Prevent hormone synthesis by blocking  Swollen salivary glands
iodide organification through inhibition of  Mucous membrane ulcerations
thyroid peroxidase catalyzed reactions  Conjunctivitis
 Block coupling of iodothyronines  Drug fever
 Metallic taste
CHARACTERIS PROPHYLTHIOURA METHIMAZO  Bleeding
TIC CIL LE *In susceptible individuals, it can induce
Relative 1 10 hyperthyroidism (jod-Basedow phenomenon) or
potency / precipitate hypothyroidism
activity
Absorption Rapid Complete
Bioavailability
50-80% due to Variable
incomplete
absorption or
JEAN UY-HO, MD
(3) RADIOACTIVE IODINE REDNISONE

 Rapidly absorbed, concentrated in the  blocks conversion of T4 to T3
thyroid  anti-inflammatory
 Incorporated into thyroid follicles  use is presently controversial but may be
 Beta emission is the basis of the therapeutic useful for thyroid storm, myxedema coma
effects and ophthalmopathy in Graves’ disease
MECHANISM OF ACTION: ANTI-THYROID COMPOUNDS:

Advantages Disadvantages Process affected Examples of Inhibitors
 Safe  High incidence of  Active transport of Complex anions;
 No tissue other than delayed iodide perchlorate, thiocyanate
thyroid is exposed in hypothyroidism
sufficient ionizing  Long period of  Iodination of Thionamides:
radiation time is required thyroglobulin propylthiouracil,
 Absence of pain before methimazole,
 Relatively cheaper hyperthyroidism Carbimazole
 Hospitalization not is controlled Iodide
required 
 Patients can indulge  Coupling reaction Thionamides
in their customary
activities during the  Hormone release Lithium salts / Iodide
procedure
 Peripheral Thiouracil derivatives (PTU)
INDICATIONS: iodothyronine Amiodarone
It is the preferred drug for: deiodination
 all patients above 21 years of age who are
not pregnant or breast-feeding
 debilitated, cardiac or elderly patients who AGENTS THAT AFFECT BONE HOMEOSTASIS
are poor surgical risks
 patients failing to respond to drug therapy Calcium Preparations:
 patients who had ADRs with other  Calcium gluconate
treatments - IV 10% solution – 1 gram Ca gluconate in
 patients with recurrence after thyroid 10 mL solution, contains 9% elemental
surgery calcium or 90 mg Ca
-treatment of choice for severe
(4) ANION INHIBITORS: hypocalcemic tetany
 perchlorate - preferred IV form
 pertechnectate  Calcium lactate - 13% calcium
 thiocyanate  Calcium carbonate – 40% calcium
- preferred oral preparation
MECHANISM OF ACTION:
 Block thyroid gland re-uptake of iodide THE FACTORS THAT CONTROL BONE MINERAL
through competitive inhibition of iodide HOMEOSTASIS
transport mechanism PARATHYROID HORMONE
 an 84-AA peptide synthesized in the
ADJUNCT DRUGS: parathyroid gland
 biologic activity related to the presence of
BETABLOCKERS N-terminal AA
 block the peripheral effects of thyroid
hormone
 secreted in response to low serum ionized
calcium
 block the peripheral conversion of T4 to T3
 may be used as preoperative preparation for  phosphate regulates PTH secretion
thyroid surgery indirectly
 effective adjunct in the management of  half-life = 2-5 minutes
thyroid storm  90% clearance - by liver and kidney
LITHIUM Actions:
 blocks the release of thyroid hormone 1. Kidney
 last-resort alternative to iodides and - stimulates the synthesis of calcitriol
thioamides - promotes tubular calcium and
when these are contraindicated magnesium reabsorption and
enhances urinary phosphate excretion

JEAN UY-HO, MD
2. Bone OSTEOPOROSIS
- enhances calcium and phosphate  Disease characterized by loss of bone mass
mobilization by stimulating bone due to reduced organic bone matrix and
resorption consequently, mineral content which
reduces the mechanical strength of the
Net Effect: to increase serum calcium bone.
concentration and to lower the serum  Once established, it is extremely difficult to
phosphate concentration reverse.
VITAMIN D
 Types: Postmenopausal, senile or
glucocorticoid-induced osteoporosis
 prohormone
 secosteroid produced in the skin from 7- ANTI-OSTEOPOROSIS DRUGS
dehydrocholesterol under the influence of A. Anti-resorptive :
UV radiation Bisphosphonates
 undergoes metabolic activation in the liver & Estrogens/HRT
kidneys Selective Estrogen Receptor Modulators
 2 sources: the natural form (vitamin D3, (SERMs)
cholecalciferol) and the plant-derived form Calcitonin
(vitamin D2, ergocalciferol) Denosumab
 stored in the body, mostly in adipose tissue B. Vitamins and minerals
Calcium
 plasma half-life : 22 h Vitamin D3
C. Bone-forming :
Actions:
Teriparatide (Recombinant PTH)
1. GIT: stimulates intestinal absorption of
C. Both anti-resorptive and Bone-forming
calcium & phosphate
Strontium ranelate
2. Bone: enhances calcium and phosphate
mobilization
BISPHOSPHONATES
3. Kidney: promotes tubular reabsorption
of calcium & phosphate  enzyme resistant analogues of
pyrophosphate that directly bind to
Net effect: to increase serum calcium and hydroxyapatite in bone
phosphate concentrations  oral bioavailability is low and is impaired by
food and iron
Drug interactions:  50% excreted unchanged by the kidney in
 Cholestyramine can decrease vitamin D 24 hours; the rest is bound to tissues
absorption  Amino bisphosphonates such as alendronate
 Phenytoin, phenobarbital, carbamazepine and risedronate inhibit farnesyl
and rifampicin increase vitamin D pyrophosphate synthase, an enzyme in the
metabolism mevalonate pathway that is important for
Preparations: osteoclast survival
Cholecalciferol (D3)
Calcitriol or 1,25 dihydroxy vitamin D 3 – Effects:
active vitamin D  provide the greatest BMD increases and
Ergocalciferol (D2) fracture risk reductions
CALCITONIN Therapeutic Use:

 A 32-AA polypeptide produced by the  drug of choice for the prevention and
parafollicular cells of the thyroid treatment of postmenopausal osteoporosis,
 secretion is determined mainly by plasma osteoporosis in men and corticosteroid-
calcium concentration induced osteoporosis
 short plasma half-life (10 minutes)
Adverse Effects:
 renal clearance
 esophageal/gastric irritation and ulceration
Actions:
1. Bone: inhibits osteoclastic bone Preparations:
resorption Oral -Alendronate, Risedronate, Ibandronate
2. Kidney: decreases the tubular IV – Zoledronic acid
reabsorption of calcium and phosphate
Net effect: to decrease serum calcium and

phosphate concentrations

JEAN UY-HO, MD
ESTROGEN and HORMONAL REPLACEMENT CALCITONIN

THERAPY  powerful inhibitor of osteoclastic bone
Estrogen: resorption
 plays an important role in the maintenance  human calcitonin: half-life of 10 mins,
of bone integrity during reproductive life of broken down to inactive fragments by
female enzymatic degradation in plasma and in the
 suppresses bone resorption by decreasing kidney
osteoclast recruitment and activity  Salmon Calcitonin: half-life of 40-50 mins.
 opposes the bone-resorbing action of PTH
Effects:
Effects:  increases spine BMD and reduces fracture
 the enhanced BMD effects from estrogen risks
therapy (ET) and combined estrogen-  may provide minimal pain relief to some
progestin hormonal therapy (HRT) are < patients with vertebral fracture
those from bisphosphonates or teriparatide
but > those from raloxifene Preparation:
 oral and transdermal estrogens and  Salmon calcitonin, intranasal or SC
continuous or cyclic HRT regimens have
similar BMD effects Adverse Effects:
 bone loss acceleration noted immediately  vomiting, facial flushing, tingling of hands
after discontinuation of therapy
 beneficial bone benefits do not outweigh Therapeutic Use:
their negative effects  2nd line treatment for osteoporosis in
women
Adverse effects:
 increase in coronary heart disease, stroke CALCIUM and VITAMIN D (CALCITRIOL)
and venous thromboembolism  an adjunct to other anti-resorptive drugs
 increased risk of breast cancer  combination of calcium and vitamin D
decreases the risk of fractures when added
SELECTIVE ESTROGEN RECEPTOR to anti-resorptive drugs
MODULATORS  has been shown to increase bone mineral
 Raloxifene density (BMD)
 compounds whose estrogenic activities are
tissue-selective STRONTIUM RANELATE
 estrogen agonist in bone tissue but an  Composed of two atoms of strontium bound
antagonist in the breast and uterus to an organic ion, ranelic acid.
 bioavailability : 2% ;  Blocks differentiation of osteoclasts while
promoting their apoptosis, thus inhibiting
 half-life : 32 h bone resorption.
 Also promote bone formation.
 Increases bone formation markers while
Effects:
inhibiting bone resorption markers.
 increases spine and hip BMD and decreases  Decreases fractures in the spine and hip.
fracture risks
 discontinuation results in immediate TERIPARATIDE
decrease in BMD  contains the 1st 34 AA in human PTH
 associated with decreased breast and  therapeutic doses for intermittent, shorter
uterine cancer risk periods improve BMD and reduce fracture
 associated with decreases in total risk
cholesterol and LDL, neutral effects on HDL  anabolic activity may result from decreased
but slight increase in triglycerides osteoblast apoptosis and increased bone
 no beneficial cardiovascular effects formation from the longer-lived osteoblasts
Therapeutic Use: Effects:

 prevention and treatment of  useful among postmenopausal women with
postmenopausal osteoporosis osteoporosis and pre-existing fractures
 increases BMD and decreased risk of
Adverse effects: aggravate hot flushes of vertebral and non-vertebral fracture
menopause, leg cramps, venous thromboembolism
 should not be combined with
bisphosphonates

JEAN UY-HO, MD
Therapeutic Use:
 for treatment of postmenopausal
osteoporosis and osteoporosis in men at
high risk of osteoporosis-related fracture
who cannot or have failed bisphosphonate
therapy
Adverse Effects:
 nausea, esophageal reflux, postural
hypotension, dizziness
DENOSUMAB
 Human monoclonal antibody to RANKL
preventing its binding to RANK receptor
leading to osteoclast inhibition ( both in
number and function )
 Reduces bone resorption
 Reduces risk of spine, hip and nonvertebral
fractures
 Used for postmenopausal osteoporosis,
prostate CA, breast CA
 No dose adjustment for decreased kidney
function
 ADR: increased risk of infection (RANKL also
present in immune system), Osteonecrosis
of the jaw, Subtrochanteric fractures

REVIEW TEST
JEAN UY-HO, MD
THYROID AND ANTI-THYROID DRUGS ______9. When taking this drug for osteoporosis,
the patient should remain upright position for 30
Choose the best answer: min to prevent esophageal ulceration:
A. Teriparatide
______1. The major mechanism of action of PTU is B. Alendronate
to: C. Raloxifene
A. Block iodide transport mechanism D. Calcitriol
B. interfere directly with the synthesis of
thyroid hormones ______10. A 60 year old male recently fell and
C. decrease the release of thyroid hormones sustained hip fracture. What is the best agent that
from the gland will promote bone healing?
D. Destroy the thyroid gland A. Zoledronic acid
B. Teriparatide
______2. This is a pharmacokinetic property of PTU: C. Denosumab
A. slowly absorbed, reaching peak serum D. Alendronate
levels after 6 hours
B. excreted in urine conjugated to ______11. A patient with uncontrolled
glucuronide within 24 hours hyperglycemia was managed with insulin therapy.
C. has a 100% bioavailability What correct metabolic process will take place?
D. long half-life A. Intracellular lipase will be activated
favoring ketone body formation as
______3. This is an advantage of methimazole over energy source
PTU in the treatment of hyperthyroidism: B. Both muscle and liver glycogenolysis will
A. higher oral bioavailability be stimulated
B. longer duration of action C. Muscle ribosomal protein synthesis is
C. higher protein binding stimulated
D. lower incidence of drug-drug interaction D. Lipoprotein lipase is inhibited to inhibit
hydrolysis of chylomicrons
______4. The serious toxicity that maybe associated
with thioamides (methimazole): ______12. This is an advantage of insulin lispro over
A. SLE syndrome regular insulin:
B. myopathy A. more effective in lowering blood glucose
C. Torsades de pointes B. longer duration of action
D. Agranulocytosis C. faster onset of action
D. less immunogenicity
______5. Saturated solution of potassium iodide can
be administered 1 hour after initiation of thioamide ______13. Which of the following is a
in thyroid storm patients for this purpose? pharmacokinetic property of insulin glargine?
A. To inhibit thyroid hormone release A. neutral pH in solution
B. To replenish depleted iodine stores B. protaminated insulin
C. To replace sodium loss due to sweating C. bound to albumin
D. To replace potassium D. Forms stable aggregates in
subcutaneous tissue
______6. Which of the following is used to reduce
the size and vascularity of the thyroid prior to ______14. This is the proper technique of insulin
surgery? administration:
A. Propylthiouracil A. Exercise the muscle adjacent to the
B. Levothyroxine injection site
C. Saturated solution of Potassium iodide B. rotate injection sites in a single region of
D. Radioactive iodine (I 131) the body
C. Inject into the muscle tissue
______7. Iodides cannot be used long term to D. preferred injection site is the thigh
control thyrotoxicosis (hyperthyroidism) because of
this effect? ______15. The glucose lowering effect of this drug
A. Wolff-Chaikoff requires functioning beta cells:
B. Thyroid storm A. Sulfonylurea
C. Jod-Basedow B. Biguanide
D. Iodism C. Thiazolidinedione
D. alpha glucosidase inhibitor
______8. The mechanism of action of this agent is
inhibiton of osteoclastic bone resorption: ______16. Which of the following is a correct pairing
A. Teriparatide of class and specific agent?
B. glucocorticoid A. Sulfonylurea – repaglinide
C. Calcitonin B. SGLT2 inhibitor – Sitagliptin
D. calcitriol C. Alpha-glucosidase inhibitor – voglibose
D. Biguanide – pramlintide
REVIEW TEST
JEAN UY-HO, MD
______17. Nateglinide produces less hypoglycemia

than sulfonylurea because of this pharmacokinetic or
pharmacodynamic property:
A. Metabolized by the liver cyp3A4 to
inactive metabolite
B. Closes the potassium channel and opens
the calcium channel
C. High plasma protein binding than
sulfonylurea
D. Peak effect within an hour, duration
lasting for 4 hours
______18. A 70 year old diabetic male was recently

diagnosed with bladder cancer. Which of the
following oral antidiabetic drug should be avoided?
A. Gliclazide
B. Linagliptin
C. Pioglitazone
D. Acarbose
______19. Possible adverse reactions of TZD

thiazolidinedione
A. urinary tract infection
B. hypoglycemia
C. congestive heart failure
D. nausea and vomiting
______20. The most important reason why DPP-4

inhibitor does not cause hypoglycemia:
A. glucose dependent stimulation of insulin
secretion
B. delays gastric emptying
C. promotes satiety
D. decreases glucagon

CARDIOVASCULAR DRUGS
CLARISSA M. MENDOZA, MD
REVIEW OF CARDIOVASCULAR DRUGS
Q1. A 30-year-old male was found to have elevated

BP at 1150/100 during an annual checkup. On
monitoring at home, his BP readings were in the
range of 150-160/100. Which of the following drugs
may be started?
A. Thiazides
B. ARB/ACEI
C. CCB
D. Any of the above
(refer to Annex A)
Q2. Blood pressure reduction can be achieved
either by decreasing the total peripheral resistance
or by decreasing cardiac output. Which of the
following drugs can achieve both?
A. Hydrochlorothiazide
B. Carvedilol
C. Metopolol Classes of Antihypertensive Drugs
D. A and B only • Diuretics
• Drugs Acting on the Adrenergic
Goal: to lower blood pressure by decreasing cardiac Nervous System
output and/or peripheral resistance – Alpha-blockers (alpha 1)
BP = CO x TPR – Beta-blockers (beta 1)
CO= SV x HR – Centrally Acting Adrenergic
o Antihypertensive drug classification based Blockers (alpha 2)
on mechanism of action • Peripheral Vasodilators
Decrease CO Decrease TPR – Calcium Channel Blockers
o Diuretics o Diuretics • Drugs Acting on the Renin-Angiotensin
o Betablockers o Alpha-blockers System
o Adrenergic blockers – Angiotensin Converting
o Ca Channel blockers Enzyme Inhibitors
o ACE Inhibitors - Angiotensin Receptor Blockers
o A-II Receptor
blockers Q4. Antihypertensive drugs that decrease the total
peripheral resistance do so through vasodilation.
Q3. Which of the following statements is true? Which of the following produce vasodilation by
A. Methyldopa block peripheral sympathetic releasing nitric oxide?
nerve endings A. Amlodipine
B. Nifedipine lowers blood pressure by blocking B. Nitroprusside
the T type calcium channels C. Methydopa
C. Valartan blocks the AT2 receptor D. Carvedilol
D. Captopril inhibits the angiotensin converting
enzyme MECHANISMS OF VASODILATION
• Fall in intracellular calcium
– hydralazine
– CCBs
• K-ATP channel openers leading to
hyperpolarization & relaxation of smooth
muscles
– Minoxidil
– Diazoxide
• Release of nitric oxide –inc cGMP
– nitroprusside
– Nitrates

• Blocking the effect of Ang II Pharmacological Effects of CCBs

– ACEI Nifedipine Verapamil Diltiazem
– ARBs Heart Rate +++ + ++
 Blocking of alpha 1 AV-Node 0 ++ +
– Prazosin Systemic VR +++ ++ +
 Alpha 2 agonism in the CNS Coronary VS +++ ++ ++
– Methyldopa Myocardial 0 or + ++ 0 or +
 Alpha 2 agonism in the brainstem Contractility
– Clonidine Improvement of 0 ++ 0 or +
Diastolic
Q5. SG, a bank executive is a known hypertensive Function
for 5 years on Valsartan. She consulted because of VS- Vascular Resistance
palpitation. Runs of SVT were seen on the 24-hour Clinical Uses of CCBs
Holter. You will shift to:  Hypertension
A. Verapamil  Supraventricular Tachyarrhythmias
B. Diltiazem  Hypertrophic Cardiomyopathy
C. Amlodipine  Migraine
D. Any of the above  Raynaud’s phenomenon
 Atherosclerosis
Group First Second Third
(Specificity) generat Generation Genera Q6. A 50-year-old consults because of palpitation
ion ______________ tion and headache after initiation of an antihypertensive
New active drug given when he consulted in the ER 2 days ago.
principles and/or Which of the following is the most likely drug that
novel she took?
formualtions A. Verapamil
Dihydro- Nife- Nife- Beni- Amlo- B. Losartan
pyridine dipine dipine dipine dipine C. Amlodipine
(artery>car SR/ Laci- D. Metoprolol
diac) Nicar- GITS Isra- dipine
dipine dipine Lercani Non-Cardiac Side Effects of CCBs
Felo- -dipine Nifedipine Verapamil Diltiazem
dipine Mani- Headache +++ + ++
ER dipine Postural 0 ++ +
dizziness
Nicar- Nilva- Flushing +++ ++ +
dipine dipine
Peipheral +++ ++ ++
SR
edema
Nimo-
Constipation 0 or + ++ 0 or +
dipine
Other GI 0 ++ 0 or +
Nisoldi
complaints
pine
Paresthesias
Nitren-
+= rarely seen; ++ Occasionally seen; +++
dipine
Commonly seen.
Benzothiaze Diltiaze Diltia-
pine m zem
Q7. Which of the following antihypertensive drugs
(artery=car SR
can prevent ventricular remodeling in a post MI
diac)
patient?
Phenylalkyla Verapa Vera-
A. Losartan
mine mil pamil
B. Captopril
(artery<car SR
C. Bisoprolol
diac) Gallopa
D. All of the above
mil
Abreviations: ER = extended release; GITS =
gastrointestinal therapeutic system;
SR = sustained release
Zanchetti, 1997

Action of Angiotensin II on the Heart, Kidney

& Blood Vessel
Blood- RA System Tissue- RA System
(Short-term Effect) (Long-term Effect)
Vascular
Vascular
Constriction
Hypertrophy
AngiotensinII
Positive Inotropic
Action
Increase in Myocardial
Afterload/Preload Hypertrophy
Intra-glomerular
Increase of Sodium Hypertension
Re-absorption by Aldosterone
A II Plays a Central Role in

Organ Damage Q9. Which of the following are side effects of ACE
inhibitors?
Stroke A. Hyperkalemia
Atherosclerosis* B. Cough
Vasoconstriction Hypertension C. Angioedema
Vascular hypertrophy D. All of the above
LV hypertrophy
A II Fibrosis Heart failure DEATH
Remodeling MI Side Effects of ACEIs:
Apoptosis • Dry Cough: common (3-15%)
GFR • Hypotension: variable (care with renal artery
AT1 receptor Proteinuria stenosis; severe heart failure)
Renal failure
Aldosterone release
• Deterioration of renal function (related in
Glomerular sclerosis
part to hypotension)
• Angioedema (rare, but potentially fatal)
• Renal failure (rare, risk with bilateral renal
*preclinical data artery stenosis)
LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate • Hyperkalemia (in renal failure, especially
Adapted from Willenheimer R et al Eur Heart J 1999;20(14):997-1008; Dahlöf B J Hum Hypertens 1995;9(suppl 5):S37-
S44; Daugherty A et al J Clin Invest 2000;105(11):1605-1612; Fyhrquist F et al J Hum Hypertens 1995;9(suppl 5):S19- with K-retaining diuretics)
S24; Booz GW, Baker KM Heart Fail Rev 1998;3:125-130; Beers MH, Berkow R, eds. The Merck Manual. 17th ed.
Whitehouse Station, NJ: Merck Research Laboratories, 1999:1682-1704; Anderson S Exp Nephrol 1996;4(suppl 1):34- • Skin reactions (especially with captopril)
40; Fogo AB Am J Kidney Dis 2000;35(2):179-188.
• Fetal Teratogenicity: Contraindicated in
Side Effects of ARBs: Pregnancy
• Cough: much much less than with ACE
inhibitors ACEI and ARBs in Hypertension:
• Deterioration of renal function (related in - Monotherapy/combination drug for uncomplicated
part to hypotension) hypertension
• Renal failure (rare, risk with bilateral renal
artery stenosis) ACE Inhibitors ARBs
• Hyperkalemia (in renal failure, especially Hypertension with Hypertension with
with K-retaining diuretics) compelling indications compelling indications:
• Fetal Teratogenicity: Contraindicated in - Heart failure - Heart failure
Pregnancy - After myocardial - Diabetes
infarct mellitus
Q8. The added benefit of ACE inhibitors over the - High CHD risk - Chronic
ARBs when given to patients with heart failure - Diabetes kidney disease
is/are: mellitus (incl. DM
A. They increase bradykinin. - Chronic kidney nephropathy)
B. They increase substance P. disease (incl.
C. They completely block the effect of DM
angiotensin II. nephropathy)
D. All of the above. - Recurrent stroke

Q10. Alpha 1 blockers are generally indicated for: Important PK Properties

A. hypertension Lipid-Soluble Water-Soluble
B. Heart failure Absorption Almost Incomplete
C. Bladder outlet obstruction sec to BPH complete
D. Hair loss Bioavailability Highly variable Less variable
Half-life Short Longer
Alpha-Blockers: Mechanism of Action
Metabolism Hepatic, first No
• Blocks post-synaptic alpha-1 receptors considerable
pass effect
located on vascular smooth muscle metabolism
• Relaxes both arteriolar and venous smooth
Elimination GI/Kidney Unchanged:
muscles
kidney
• Peripheral resistance decreases
Side-effects CNS: lethargy,
• Cardiac output remains unchanged
confusiton
• Example: Prazosin, Terazosin, Doxazosin
Examples Propranolol, Atenolol,
Metoprolol, Nadolol,
Side Effects of Peripherally Acting Anti-Adrenergic
Bisoprolol, Timolol
Agents (notably -blockers):
Carvedilol
• Postural dizziness
• Orthostatic hypotension
Q12. Which of the following is a cardioselective
• CNS side effects – drowsiness, nausea,
betablocker?
dry mouth, headache
A. Bisoprolol
• Rash, fluid retention, urinary incontinence,
B. Propranolol
polyarthralgia
C. Carvedilol
D. Labetalol
Beta-Adrenergic Receptors Blockers
By blocking the action of the sympathetic nervous
Classification of beta-blockers
system on the heart:
I. Noncardioselective
- Depress the sinus node = slow the heart
Propranolol, Carteolol, Nadolol, Sotalol,
beat (negative chronotropic)
Timolol
- lessen the force with which the heart muscle
II. Cardioselective MABBE
contracts (negative inotropic)
Acebutolol, Atenolol, Betaxolol, Bisoprolol,
- Prevent ventricular remodeling
Metoprolol, Esmolol
- Indicated in Class I-II heart failure
III. Vasodilatory-blockers, Nonselective
- Prolong AVN conduction and refractoriness
Labetolol, Pindolol, Carvedilol
(decrease the ventricular response in AF)
IV. Vasodilatorybetablockers, Selective
- Decrease renin secretion and FFA release
Celiprolol, Nebivolol
Beta2 blockade:
- Vasocontstriction
Adverse Effects of Betablockers
- Bronchoconstriction
Bradycardia, heart block,
- Increase glycogenoslysis, gluconeogenesis Cardiac
hypotension, heart failure
and hypokalemia
Pulmonary Bronchospasm
Q10. True of the use of betablockers in heart Insomnia, depression
CNS
failure: (propranolol)
A. They are absolutely contraindicated Peripheral
Intermitent claudication
B. They up-regulate the beta receptors Vasculature
C. They can decrease the preload. Inc. triglycerides, dec HDL,
Metabolic
D. They can be used in CHF Functional Class hypokalemia, glucose intolerance
IV.
Contraindications of Beta blockers
Q11. True of Atenolol  Asthma and other bronchospastic conditions
A. Lipid soluble  Severe bradycardia
B. Long half life  AV blockade
C. Hepatic metabolism  Sick Sinus Syndrome
D. Complete absorption  Severe Unstable LV Failure

3rd Generation Beta blockers: VASODILATORS:

 Block both β1 and β2 receptors Drug Indications:
 Block α1 receptors Hydralazine Hypertensive
 Reduce cardiac and/or systemic adrenergic urgency/emergency in
drive pregnant women, CHF patients
 Do not upregulatedownregulatedβ1 who cannot tolerate ACEI and
receptors ARBs
 Endothelium-dependent vasodilating Nitroprusside Hypertensive emergencies,
properties specifically related to the Acute aortic dissection, CHF,
microcirculation. Acute MI, controlled
hypotension to reduce bleeding
Q13. Which of the following is true about in surgery
nebivolol? Mehyldopa Hypertension in pregnancy
A. It is a β1selective beta blocker
Imidazoline Receptor Agonists
B. Its vasodilatory effect is through the
Clonidine Patients with metabolic
generation of nitric oxide by the endothelial
syndrome (dec insulin
cells
resistance)
C. It has an antioxidant effect
Moxonidine
D. All of the above.
or
monoxidine
Q14. Aliskerin is a
and
A. β1selective beta blocker
rlmenidine
B. ARB
C. Diuretic
Diuretics
D. Renin inhibitor
Q15. A 50-year-old male presents in the emergency
room because of dyspnea. Physical examination
SARA: Specific Aldosterone Receptor Antagonist
showed crackles over both lungfields. Which of the
Spironolactone Eplerenone
following is the most appropriate to give?
Less specific More specific for A. Furosemide
aldosterone B. Hydrochlorothiaze
receptors C. Indapamide
More progestational and Lesser D. Mannitol
anti-androgenic action
Inhibit P450 enzymes in No effect CLASSES OF DIURETICS
endocrine organs • Carbonic anhydrase inhibitors
Induce P450 enzymes in the Minimal increase – Acetazolamide
liver • Osmotic diuretics
Partial affinity to – Mannitol, Urea, Glycerin, Isosorbide
glucocorticoid receptors • Loop diuretics
– Furosemide, Ethacrynic Acid,
Q15. A 38-year-old primi was admitted due to Bumetanide, Torsemide
headache. Her blood pressure is 170/100. Which of • Thiazides
the following must be given: – Hydrochlorothiazide
A. IV hydralazine – indapamide
B. IV Nitroprusside • Potassium sparing
C. IV Nitroglycerine – Amiloride, Triamterene
D. Sublingual nifedipine • Aldosterone antagonists
– Spironolactone, Eplerenone

Electrolyte and ph Changes

Drug Urine Blood
electrolytes
Acetazolamide Na, K, Hyperchloremic
++HCO3 Metabolic
Acidosis
Ethacrinicaicd, ++Na, Ca, Hypokalemic
bumetanide, Mg. Cl Metabolic
furosemide Alkalosis
HCTZ, Na, K, Cl, low Alkalosis
Indapamide Ca
Spironolactone, Na, low K Hyperchloremic
Eplerenone Metabolic
Acidosis
Q18. A 30-year-old male with chronic heart failure

has frequent attacks of gout. Which of the following
may have caused this?
A. Chlorothiazide
B. Bumetanice
C. Mannitol
D. Spironolactone
Q16. Which of the following diuretics can be given
to patients with acute mountain sickness? Side Effects of Diuretics
A. Furosemide Drug Side Effects
B. Acetazolamide
Acetazolamide Renal stones from:
C. Mannitol
hyperphosphaturia and
D. Spironolactone
hypercalciuria
Calcium salts insoluble in
Indications:
alkaline urine
Drug Indications Drowsiness and paresthesias
Carbonic Glaucoma Hypersensitivity reaction
anhydrase Urinary alkalinization Ethacrinic acid, Hyperuricemia
inhibitors Metabolic alkalosis bumetanide, Hypomagnesemia
Acute Mountain Sickness furosemide Allergic reactions
Adjuvant in epilepsy, Severe dehydration
hypokalemic periodic paralysis Hypocalcemia
Severe hyperphospahatemia Paresthesias
Osmotic Intcaacranial hypertension Hepatid dysfunction
diuretics Intraocular hypertension - HCTZ, Glucose intolerance due to
glaucoma Indapamide impaired pancreatic insulin
Loop diuretics Hyperkalemia release and dec. utilization of
Acute renal failure glucose
Pulmonary edema Hyperlipidemia
Anion overdose: fluoride, Hyponatremia
bromide,iodide Allergic reactions
Thiazides Hypertension Weakness, fatigability,
CHF paresthesias
Nephrolithiasis due to idiopathic Impotence
hypercalciuria Hyperuricemia
Nephrogenic diabetes insipidus Spironolactone, Gynecomastia (spironolactone)
Aldosterone Mineralocorticoid excess Eplerenone Acute renal failure
antagonists Secondatry aldosteronism: CHF, Kidney stone (triamterene is
cirrhosis, nephrotic syndrome poorly soluble)

ANTIANGINAL DRUGS  Post PCI

Q19. Nitrates decrease oxygen demand by o Anticoagulants in MI
A. Decreasing preload  Heparin
B. Decreasing arterial pressure  Post clot-specific fibrinolysis
C. Decreasing ejection time  AF
D. All of the above  Large anterior wall MI
o Fibinolytics: lyse thrombi by
Q20. In patients with Prinzmetal angina, chest pain catalyzing the formation of plasmin
relief may be obtained with from plasminogen
A. Nitroglycerine Non-clot specific – streptokinase,
B. Verapamil urokinase, APSAC
C. Diltiazem Clot-specific: t-PA, alteplase,
D. All of the above reteplase
 STEMI
PRINCIPLES OF THERAPY o PCI and stenting
 Risk factor modification
o Smoking cessation Q21. A 50-year-old male presented in the
o Control hypertension emergency room because of chest pain of 40
o Treat hyperlipidemia minutes duration. The 12 lead ECG showed ST
 Decrease myocardial oxygen demand segment elevation in II, III and avF. The BP is
o Decrease preload 110/70. Which of the following is possibly
 Nitrates contraindicated?
 IV nitroglycerine – Acute MI A. ASA
except inferior wall with RV B. Streptokinase
infarct C. Nitrates
 Isosorbidemononitrate– Chronic D. Diltiazem
Stable Angina
 SL ISDN, Nitroglycerine – acute Contraindications for nitrate use:
angina relief  Systolic BP < 90 mm Hg
o Decrease afterload  Severe bradycardia or severe tachycardia
 Nitrates  RV Infarction
 Betablockers  Use of sildenafil within 24 hours
 CCBs
o Decrease contractility Q21. A 45-year-old hypertensive and diagnosed to
 Betablockers have coronary artery disease was brought to the ER
 Non-dihydropyridine CCBS because of lightheadedness and loss of
Verapamil consciousness. The 12 lead ECG showed 3rd degree
Diltiazem AV block. Which of the following drug combinations
o Decrease heart rate may have caused this?
 Betablockers without ISA A. Metoprolol and felodipine
 Non-dihydropyridine CCBS B. Metoprolol and Diltiazem
 If Na channel blocker C. Metoprolol and isosrbidemononitrate
 Ivabradine D. None of the above
 Increase myocardial supply
o Vasodilators –incl Variant Angina Toxicity of CCBs
 Nitrates Cardiac depression –
 CCBS  Cardiac arrest
o PCI with stenting – Unstable Angina,  Bradycardia
Acute MI  AV Block
o CABG  CHF
 Alter myocardial metabolism
o Trimetazidine Q22. Antiplatelets must be given to patients with:
o Ranolazine A. Chronic stable angina
 Prevent MI and death B. Unstable angina
o Antiplatelet C. Acute Myocardial Infarction
 Stable, Unstable Angina, D. All of the above
NSTEMI, STEMI

Antiplatelet Agents D. A 35-year-old male with chest pain since an

hour ago with T wave in version in V1-6
Inhibition of prostaglandin metabolism- inhibits
synthesis of thromboxane A2 through irreversible Indications for thrombolysis:
acetylation of cyclooxygenase 1. Chest pain suggesting MI
 Aspirin 2. ST segment elevation >0.1 mV (1mm) in 2 or
o Precautions: active PUD, history of more contiguous ECG leads or new or
allergy, bleeding disorders presumably new LBBB, strongly suspicious for
Inhibition of ADP-induced platelet activation injury (BBB obscuring ST segment analysis
 Clopidogrel 3. Time to therapy <12 hours
 Ticlopidine 4. Age <75 years (age>75 years Class IIa)
 Prasugrel
 Ticagrelor – allosteric antagonist of ADP Absolute contraindications for thrombolysis:
receptors of subtype P2Y12 1. Previous hemorrhagic stroke
Blockade of GP IIb/IIIa receptors on platelets 2. Other stroke or CVA within 1 year
 Abciximab 3. Active internal bleeding (menses excluded)
 Tirofiban 4. Suspected aortic dissection
 Eptifibatide
Cautions for fibrinolysis/thrombolysis
Phosphodiesterase inhibitors: with vasodilator 1. Severe uncontrolled hypertension on
properties presentation (BP.180/110 mm Hg); history of
 Dipyridamole – diagnostic, used with severe chronic hypertension
stress thallium 2. Current use of anticoagulants (INR>2.5);
 Cilostazol – for intermittent claudication known bleeding disorder
3. Recent trauma (within 2-4 weeks), including
Q23. Which of the following has a reversible anti- head and traumatic CPR or major surgery (<3
platelet effect? weeks)
A. Clopidogrel 4. Recent (2-4 weeks) internal bleeding; active
B. ASA peptic ulcer
C. Prasugrel 5. Pregnancy
D. Ticagrelor 6. For streptokinase: allergy or prior exposure
(esp 5 days to 2 years)
Q24. Glycoprotein IIb/IIIa Antagonists are indicated
in: Classification Drug Specific Drugs
A. ST elevation myocardial infarction
B. Immediately after PCI
Indirect High Molecular UFH or
C. ACS without ST elevation
Thrombin Weight Heparin unfractionated
D. All of the above
Inhibitors heparin
E. B and C only
Low Molecular Enoxaparin
Weight Heparin Fraxiparin
Q25. A patient with peripheral arterial occlusive
Dalteparin
disease is best given
Tinzaparin
A. Aspirin
Synthetic Fondaparinux
B. Clopidogrel
Pentasaccharide
C. Cilostazol
Direct Parenteral Hirudin
D. Prasugrel
Thrombin direct thrombin Lepirudin
Inhibitors inhibitors Bivalirudin
Q26. Which of the following MI patients must be
Argatroban
given a fibrinolytic agent?
Oral Dabigatran
A. A 35-year-old male with chest pain since 4
Direct Xa Oral Rivaroxaban
hours ago, with 3 mm ST segment elevation
Inhibitors Apixaban
in V1-V6
Vit. K Warfarin
B. A 35-year-old male with chest pain a day
Antagonist
before lasting for 4 hours and 2mm ST
elevation with Q wave in V1-6
C. A 35-year-old male with chest pain since 2
hours ago with 3 mm ST depression in V3-6

Q27. A 24-year-old woman was previously Q28. A 50-year-old male was previously diagnosed
diagnosed to have Severe Mitral Stenosis. She to have dyslipidemia. He consults because of
underwent valve replacement using a metallic flushing. Which of the following drugs is he
prosthetic valve. She has been on warfarin since probably taking?
then. She plans to start a family soon. What advise A. Clofibrate
should be given to her? B. Rosuvastatin
A. Stop warfarin when she gets pregnant. C. Ezetimibe
B. She may continue the warfarin even when D. Niacin
she gets pregnant.
C. Stop the warfarin and start IV heparin Q29. A 50-year-old male with history of
D. Stop the warfarin and start low molecular dyslipidemia develops acute renal failure. He was
weight heparin on simvastatin for more than a month until he
consulted, and another drug was added. Which of
Q28. The dose of warfarin must be decreased if the following drug combination was responsible for
given with the following drugs this?
A. Amiodarone A. Simvastatin and ezetimibe
B. Metronidazole B. Simvastatin and nicotinic acid
C. Fluconazole C. Simvastatin and omega 3 fatty acid
D. All of the above D. Simvastatin and gemfibrozil
Drug Interaction with Warfarin Drug Effect Adverse Effects

Increased prothrombin time
PK PD Niacin Dec VLDL, Cutaneous
Amiodarone Drugs LDL, Inc HDL vasodilation, pruritus,
Cimetidine ASA acanthosisnigrican,
Disulfiram Cephalosporins, third hyperuricemia,
Metronidazole generation carbohydrate
Fluconazole Heparin intolerance, elevations
Phenylbutazone Body Factors of transainases and
Sulfinpyrazone Hepatic disease alkaline phosphatase,
Trimethoprim-Sulfa Hyperthyroidism atrial arrhythmias
Decreased prothrombin time Fibric Acid Dec Rashes, myopathy,
Barbiturates Drugs Derivatives Triglycerides, arrhythmias,
Cholestyramine Diuretics Gemfibrozil inc HDL hypokalemia, inc in
Rifampin Chlorthalidone Fenofibrate through inc transferases and alk
Spirononolactone Clofibrate in APOA-I phosphatase,
Vitamin K Bezafibrate and APO, rhabdomyolysis if
Body Factors A-II gemfibrozil is given
Hereditary resistance production with statins
Hypothyroidism Bile acid Decrease Constipation
binding LDL Heartburn and
resins – diarrhea
Lipid- lowering Drugs colestipol, Malabsorption of Vit
1. Niacin cholesty- K, folic acid
2. Fibric acid derivatives – activates PPAR-a ramine, Dry flaking skin
3. Bile acid binding resins – bind bile acids in the colesvelam Impairs absorption of
intestinal lument and prevent their reabsorption. digitalis, thiazides,
4. HMG-CoA Reductase inhibitors – structural warfarin, tetracycline,
analog of HMG Co-A intermediate, cause partial thyroxine, iron salts,
inhibition of the enzyme; decrease oxidative pravastatin,
stress and increased stability of atherosclerotic fluvastatin, folic acid,
lesions. phenylbutazone,
5. Ezetimibe – inhibit intestinal absorption f aspirin, ascorbic acid
phytosterols and cholesterol; synergistic with HMG-CoA Dec LDL, Elevation of
reductase inhibitors Reductase modest dec aminotransferase,
Inhibitors in Tg, small minor inc in creatine
Lovastatin, increase in kinase activitiy,

Pravastatin, HDL myopathy, o Argenine-Vasopressin Antagonists

atorvastatin hypersensitivity • Tolvaptan
Rosuvastatin syndromes, peripheral • Conivaptan
– most neuropathy
potent Q31. A 56-year-old male, post MI 1 month ago,
Ezetimie Dec LDL complains of palpitation which started a week
earlier. On presentation at the emergency room,
Q30. A 50-year-old male presents with an acute ST the ECG shows atrial fibrillation with rapid
elevation myocardial infarction. To stabilize the ventricular response. If his BP is 90/60, which of
plaque, this drug must be started: the following is the most appropriate drug to give?
A. Ezetimibe A. Verapamil
B. Atorvastain B. Digoxin
C. Niacin C. Diltiazem
D. Fenofibrate D. Amiodarone
CHF Principles of Pharmacolgy Management Q32. Digitalis toxicity is enhanced by the following
1. Decrease the preload electrolyte abnormalities:
2. Decrease the afterload A. hypocalcemia
3. Increase myocardial contractility B. hyperkalemia
o Digitalis – inhibits NaK ATPase; at physiologic C. hyponatremia
doses= parasympathomimetic; at high doses = D. hypomagnesemia
sympathomimetic
• Digoxin – renal excretion Q33. An acute MI patient complains of dyspnea.
• Digitoxin – hepatic excretion The BP is 130/80, LV filling pressure >20 mmHg and
For acute heart failure: CI >2.5. He must be given:
o PhosphdiesteraseIII A. Dopamine
o inhibitors – inotropic and vasodilators through B. Dobutamine
increase in cAMP and cGMP C. Furosemide
• Amrinone D. Digoxin
• Milrinone
o Beta-adrenoceptor stimulants – for acute heart Therapeutic Classification of Subsets in Acute MI
failure or exacerbation of chronic heart failure Subset SBP LV Cl Therapy
• Dopamine mmH Filling
1-2ug/kg/min = dopaminergic g pressure
receptors Hypovolemi <100 <10 <2. Volume
2-10ug/kg/min = alpha and beta a 5 replacemen
>20ug/kg/min = alpha, similar to NE t
• Dobutamine = inotropic and Pulmonary 100- >20 >2. Diuretics
vasodilator, B1 agonist and alpha1 Congestion 150 5
antagonist Peripheral <100 10-20 >2. None, or
4. Attenuate the adverse effects of chronic vasodilation 5 vasoactive
neurohumoral stimulation drugs
o ACEi Power <100 >20 <2. Vasodilator
o ARBs failure 5 s, Inotropic
o Betablockers drugs
o ARNI – angiotensin receptor neprilysin Severe <90 >20 <2. Vasoactive
inhibitor; neprilysin degrades BNP – shock 0 drugs,
valsartan/sacubitril Inotropic,
5. Prevent ventricular remodeling Vasodilator
o ACEi s,
o ARBs circulatory
o Betablockers assist
o Spironolactone RV <100 RVFP>1 <2. Provide
6. Relieve the congestion Infarction 0 5 volume
o Furosemide LVFP<1 replacemen
o Other Loop 0 t for LVFP,
o HCTZ Inotropic.
Avoid Clinical Generalizations by Class

diuretics. Vaughan Location General End- Potential
MR with <100 >20 <2. Vasodilator Williams of Level Organ for Pro-
VSD 5 s, Inotropic Class Activity of Toxicity Arrhythmia
drugs, Efficacy
circulatory Class IA A, V 2+ 3+ 2+
assist, Class IB V 1+ 1+ 1+
surgery Class IC A, V 3+ 1+ 3+
Class II AVN, V 1+ 1+ 0
Antiarrhythmic Drugs Class III A, V 2+ 1+ 2+
Class I Sodium-channel blocking drugs (amlo (amlo (amlo 4+)
IA Markedly slow conduction, markedly 4+) 4+)
prolong action potential duration Class IV AVN 1+ 1+ 0
• Quinidine, Procainamide,
Disopyramide Q33. A 44-year-old female presents in the ER
IB Minimally slow conduction, shorten action because of palpitation. The cardiac monitor shows
potential duration supraventricular tachycardia (SVT). Which of the
• Lidocaine, Mexiletine, Tocainide, following is true?
Phenytoin A. Adenosine can terminate the arrhythmia.
IC Markedly slow conduction, minimally B. Verapamil can be given to prevent recurrent
prolonged action potential duration SVTs
• Flecainide, Encainide, Moricizine C. Betablockers can also be given to prevent
recurrence
Class II Beta Blocking Drugs D. All of the above
Class III Potassium Channel Blocking Drugs Q34. A 45-year-old male was admitted because of
• Amiodarone chest pain. The initial ECG is normal. While in the
• Bretyllium ER he complains of palpitation and the monitor
• Sotalol shows atrial fibrillation with rapid ventricular
• Ibutilide response. The BP is 130/80. What is the most
appropriate drug to give?
Class IV Calcium Channel Blocking Drugs A. Amiodarone
• Verapamil B. Digoxin
• Diltiazem C. Verapamil
D. Esmolol
Miscellaneous Agents:
1. Adenosine – inhibits AV nodal conduction and Principles of Drug Use
increases AV nodal refractory perior 1. Define a benefit for therapy.
Use: Paroxysmal SVT Goals of therapy in AF:
2. Magnesium – for Torsades de Pointes Acute AF – cardiovert
3. Potassium Chronic AF – rate control
2. Define an end point for therapy.
Increasing serum K will result in In AF: 1) cardioversion: Class1A, 1C, III
• Resting potential depolarizing action 2) rate control: AV nodal blocking
• Membrane potential stabilizing action drugs: Class II, IV, digitalis
• Depress ectopic pacemakers 3. Minimize the risks (and ensure that these do
• Severe hyperK will suppress the SA node not outweigh the expected benefits).
4. Define the need for therapy.
Hypokalemia results in Asymptomatic PVCs in normal hearts – no
• Increased risk of EAD and DAD treatment required.
• Increased ectopic pacemaker activity 5. Consider alternative therapies
VTach stable: drug
Vtach with pulse, low BP: electrical
synchronized cardioversion
Vtach without pulse and Vfib: defibrillation

PROARRHYTHMIA: RELATIVE RISK

Risk of Risk of Torsades
Exacerbations de Pointes
of Reentry
Class IA
Quinidine ++ ++
Procainamide ++ ++
Disopyramide ++ ++
Class IB
Lidocaine + 0
Mexiletine + 0
Phenytoin + 0
Class IC
Flecainide +++ 0
+++ 0
Propafenone +++ +
Moricizine
Class III
Amiodarone + +
Bretyllium + +
Sotalol + +++
Ibutilide ++ +++
Memory Tip: The greater the K+ blocking, the

higher the risk for Torsades de Pointes, the greater
the Na+ blocking, the greater the risk for re-entry.

REVIEW TEST
CARDIOVASCULAR QUESTIONS: 7. A post MI hypertensive and diabetic patient

must be given this drug to prevent ventricular
1. A 65-year-old female consults in the OPD remodeling through inhibition of the production
because of blood pressure of 160/100. For the of angiotensin II
past months, she has been noted on several A. Losartan
occasions to have hypertension. Based on the B. Captopril
JNC 8 guidelines, which of the following drugs C. Bisoprolol
may be started. D. Felodipine
A. Thiazides
B. ARB/ACEI 8. Which of the following antihypertensive drugs is
C. CCB contraindicated in pregnant women?
D. Any of the above A. Nifedipine
B. Losartan
2. Which of the following drugs decrease both the C. Metoprolol
cardiac output and the total peripheral D. Alphamethyldopa
resistance?
A. Thiazides 9. Which of the following are side effects of ACE
B. ARBs inhibitors?
C. CCBs A. Hyperkalemia
D. ACEIs B. Cough
C. Angioedema
3. Which of the following statements is true? D. All of the above
A. Clonidine blocks peripheral sympathetic
nerve endings 10. Orthostatic hypotension is a common side effect
B. Nifedipine lowers blood pressure by of:
blocking the T type calcium channels A. Betablockers
B. Alpha1 blockers
C. Valsartan blocks the AT1 receptor
C. Calcium Channel Blockers
D. Enalapril inhibits renin release in the D. Angiotensin Receptor Blockers
kidneys
11. True of metoprolol:
4. Antihypertensive drugs that decrease the total A. Lipid soluble
peripheral resistance do so through vasodilation. B. Short half life
Which of the following is true regarding their C. Hepatic metabolism
mechanism of vasodilation? D. All of the above
A. Hydralazine and CCBs induce a fall in
intracellular calcium 12. Which of the following is a non-selective
B. Nitroprusside releases nitric oxide vasodilator betablocker used in heart failure?
C. Prazosin blocks alpha 1 receptors A. Nebivolol
D. All of the above B. Carvedilol
C. Metorpolol
5. A 68-year-old teacher, hypertensive and D. Bisoprolol
asthmatic for 10 years complains of frequent
palpitation which started a month ago. The ECG 13. Which of the following is the most appropriate
showed atrial fibrillation with rapid ventricular drug to give in patients with pulmonary edema?
response. Which of the following is the best one A. Spironolactone
to give? B. Indapamide
A. Verapamil C. Hydrochlorothiazide
B. Diltiazem D. Furosemide
C. Amlodipine
D. Any of the above 14. Which of the following diuretics should be used
with caution in patients with diabetes?
6. A 60-year-old hypertensive complains of bipedal A. Indapamide
edema. Which of the following is the most likely B. Spironolactone
antihypertensive agent that she is currently C. Furosemide
taking? D. Acetazolamide
A. Verapamil
B. Losartan 15. A 50-year-old male presents in the emergency
C. Amlodipine room because of chest pain of 4 hours duration.
D. Metoprolol Which of the following drugs is the best to give
that will address his chest pain?
A. Nitroglycerine
B. Morphine
C. Aspirin
D. Streptokinase
REVIEW TEST
16. Which of the following diuretics act at the

ascending limb of the loop of Henle?
A. Acetazolamide
B. Indapamide
C. Bumetanide
D. Eplerenone
17. A 45-year-old male, chronic metamphetamine

user, presents with intractable heart failure. You
think he will benefit from a neprilysin inhibitor.
You will give:
A. Eplerenone
B. Sacubitril
C. Candesartan
D. Conevaptan
18. A 50-year-old female consults because of

recurrent palpitation. A 24-hour Holter has been
previously done and shows paroxysmal
supraventricular tachycardia. She is hypertensive
on amlodipine. She is also a known asthmatic.
You will:
A. Change amlodipine to metoprolol
B. Change amlodipine to carvedilol
C. Change amlodipine to verapamil
D. Change amlodipine to diltiazem
19. A 30-year-old known hypertensive missed his

medications for 2 days. He presents in the
emergency room with headache and vomiting.
His BP is 230/140. Which of the following is the
most appropriate drug to give, if you want to
tightly titrate the lowering of the BP to not more
than 20% decrease in mean arterial pressure in
the first hour?
A. IV nicardipine
B. IV esmolol
C. IV nitroglycerine
D. IV nitropusside
20. 40-year-old male is brought to the ER due to

loss of consciousness. Her has no BP no pulses
and the monitor is showing ventricular
tachycardia. Aside from doing CPR, what will
you do?
A. Give IV bolus of amiodarone
B. Give IV adenosine
C. Do synchronized cardioversion
D. Deliver electrical defibrillation

ANTI-NEOPLASTIC AGENTS
FLORDELUNA Z. MESINA, MD
ANTI-NEOPLASTIC AGENTS  activation of proto-oncogenes affects signal

transduction mechanisms for cell division by
NEOPLASIA producing abnormalities in the production of
 “new growth” autocrine growth factors, receptors for
 abnormal mass of tissue the growth of which growth factors, receptor-linked signaling
exceeds and is uncoordinated with that of normal pathways (cytosolic and nuclear
tissues and persists in the same excessive transducers), cell cycle transducers
manner after the cessation of the stimuli which  inactivation of tumor suppressor genes
evoked the change
 may be benign or malignant (cancerous) Six fundamental changes in cell physiology leading
 consists of parenchyma and supporting host- to cancer
derived non-neoplastic stroma  self-sufficiency in growth signals
o growth factors, growth factor receptors,
BIOLOGY OF CANCER CELLS signal-transducing proteins, nuclear
1. differentiation: extent to which they resemble transcription factors, cyclins and cyclin-
their normal forebears morphologically and dependent kinases
functionally  insensitivity to growth inhibitory signals
2. anaplasia: lack of differentiation, dedifferentiation o Rb gene, transforming growth factor beta
or loss of structural and functional differentiation pathway (TGF-beta), APC gene (adenosis
of normal cells; hallmark of malignancy polyposis coli)-Beta catenin pathway,
3. rapid rate of growth: good correlation with level TP53 gene,
of differentiation  evasion of apoptosis
4. local invasion: progressive infiltration, invasion,  limitless replicative potential
destruction and penetration of surrounding o telomeres and telomerase
tissues  sustained angiogenesis
5. metastasis: development of secondary implants o necessary biologic correlate of
discontinuous with the primary tumor possibly in malignancy
remote tissues; most reliable feature of o balance of angiogenic and anti-
malignancy angiogenic factors
a. pathways of spread  ability to invade and metastasize
i. seeding within body cavities o invasion of extracellular matrix
ii. lymphatic route o vascular dissemination and homing of
iii. hematogenous route (liver and lungs) cells
EPIDEMIOLOGICAL FACTORS IN CANCER ETIOLOGY OF CANCER: CARCINOGENIC

1. environmental factors: environmental AGENTS
carcinogens, diet, cigarette smoking, alcohol  chemicals (direct acting and indirect acting
consumption agents)
2. age  radiation (UV rays of sunlight, nuclear fission,
3. heredity nucleotides)
a. inherited cancer syndromes  microbial agents (RNA oncogenic virus, DNA
b. familial cancers oncogenic virus, Helicobacter pylori)
c. autosomal recessive syndromes of
defective DNA repair HOST DEFENSE AGAINST TUMORS: TUMOR
IMMUNITY
CARCINOGENESIS: THE MOLECULAR BASIS  tumor antigens (cancer-testis antigens,
OF CANCER tissue-specific antigens, antigens resulting
 non-lethal genetic damage lies at the heart from mutational change in proteins,
of carcinogenesis overexpressed antigens, viral antigens,
 three classes of normal regulatory genes are oncofetal antigens, differentiation-specific
the principal targets of genetic damage antigens)
o growth promoting proto-oncogenes  anti-tumor effector mechanisms (cytotoxic T
o growth inhibiting cancer suppressor genes lymphocytes, NK cells, macrophages,
(anti-oncogenes) humoral mechanisms)
o genes that regulate programmed cell  immunosurveillance (selective outgrowth of
death or apoptosis antigen-negative variants, loss or reduced
 genes that regulate DNA repair are pertinent expression of histocompatibility antigens, lack
to carcinogenesis of co-stimulation, immunosuppression
 multi-step process at both the phenotypic
and genetic levels CLINICAL FEATURES OF NEOPLASIA
 effects of tumor on host (cancer cachexia,
GENESIS OF CANCER CELL parameoplastic syndromes)
A normal cell turns into a cancer cell as a result of  grading: estimate of aggressiveness or level
DNA mutation which can be inherited or acquired. of malignancy based on cytologic
Two main categories of genetic changes which lead differentiation of tumor cells and the number
to cancer formation: of mitoses within the tumor
 staging: size of the primary lesion, extent of I. CYTOTOXICS

spread to regional lymph nodes, presence or A. Antimetabolites
absence of metastases  folate antagonists (methotrexate)
Laboratory Diagnosis of Cancer  purine antagonists (6-mercaptopurine,
o morphologic methods (fine needle 6-thioguanine)
aspiration biopsy, cytologic smears,  pyrimidine antagonists (5-FU,
immunocytochemistry, flow cytometry) cytarabine, hydroxyurea)
o biochemical assays (CEA, AFP) B. Alkylators
o molecular diagnosis (PCR, FISH)  nitrogen mustards (mechlorethamine,
o molecular profiling of tumors cyclophosphamide, ifosfamide,
melphalan, chlorambucil, thiotepa)
FACTORS AFFECTING DRUG SELECTION IN  platinum analogs (cisplatin, carboplatin)
CANCER TREATMENT  nitrosoureas (carmustine,
- curability of the cancer streptozotocin)
- previous chemotherapy  imidazoles (dacarbzine)
- previous radiotherapy  miscellaneous (procarbazine)
- bone marrow reserve C. Anti-tumor Antibiotics
- nutritional status  anthracyclines (doxorubicin, idarubicin,
- performance status epirubicin, daunoribicin)
- organ dysfunction  bleomycin
- concurrent problems (infections and malignant  mitomycin C
effusions)  plicamycin (mithramycin)
- tumor resistance D. Vinca Alkaloids (vincristine, vinblastine,
- psychosocial aspects vinorelbine)
E. Epipodophyllotoxins (etoposide, teniposide)
Cancer Treatment Regimens and Scheduling F. Anthracenes (mitoxantrone)
- log kill concept G. Protein inhibitors (L-asparaginase)
- pharmacologic sanctuaries (CNS, testes and eyes)
- treatment protocols (combination chemotherapy) II. HORMONES
a) estrogens (diethylstilbestrol,
Problems associated with cancer treatment ethinylestradiol)
- inherent resistance b) anti-estrogens (tamoxifen)
- multi-drug resistance c) androgens (fluoxymesterone, testosterone)
- toxicity d) progestins (medroxyprogesterone acetate,
- treatment induced tumors megestrol)
e) glucocorticoids (prednisone,
CLASSIFICATION OF ANTI-NEOPLASTIC dexamethasone)
AGENTS f) LHRH antagonists (leuprolide)
The major categories of anti-neoplastic agents g) anti-androgens (flutamide, megestrol)
according to cell cycle specificity:
CELL-CYCLE SPECIFIC III. BIOLOGIC RESPONSE MODIFIERS

S-Phase Specific Agents a) BCG vaccine
- anti-metabolites b) Interferon alpha
- hydroxyurea c) Interferon beta
- topoisomerase I inhibitors d) Interferon gamma
- topoisomerase II inhibitors e) Interleukin-2
f) Levamisole
G2-M Phase Specific Agents g) Tumor necrosis factor
- vinca alkaloids
- taxanes ANTIMETABOLITES
- bleomycim FOLATE ANTAGONISTS
NON-CELL CYCLE SPECIFIC AGENTS Methotrexate

- alkylating agents  interferes with the availability of normal
- platinum alkaloids purine or pyrimidine nucleotide precursors
- antitumor antibiotics: dactinomycin, either by inhibiting their synthesis or by
mitomycin competing with them in DNA or RNA
- campthotecins synthesis
 maximal cytotoxic effects are S-phase (cell-
CLASSIFICATION OF ANTI-NEOPLASTIC cycle) specific
AGENTS MOA:
Three major categories of anti-cancer drugs 1) MTX  inhibition of dihydrofolate reductase
according to mechanism of action: (DHFR) which catalyzes the reduction of
dihydrofolate (DH2) to tetrahydrofolate
(DH4) which is the coenzyme form of folic
acid  rapid depletion of intracellular folate  administered intravenously because of

coenzymes needed for thymidylate and severe toxicity to the GIT
purine biosynthesis  blockage of DNA  short metabolic half-life: 15 minutes
replication  cessation of cell replication  distributes freely into third spaces
2) MTX  blockage of reduced folate uptake  metabolized in the liver producing
 impairment of folate restoration dihydrofluorouracil
3) intracellular retention of MTX is due to
enzymatic reaction (folypolyglutamate  ADVERSE EFFECTS:
synthetase or FPGS) which adds - myelosuppression and GI toxicity
polyglutamates to the anti-folate  (dose-limiting toxicities)
inhibition of DHFR - occur 4-7 days after chemotherapy and
 well absorbed orally in low doses (5-10 mg) recovery noted in 14 days
but oral bioavailability decreases at high  CLINICAL USES: colon CA, breast CA, head
doses (30 mg) and must be delivered by and neck CA
intramuscular, intravenous and
subcutaneous routes. Cytosine arabinoside (Cytarabine, Ara-C)
 antimetabolite analog of 2-deoxycytidine
 half-life of MTX is triphasic with a with a D-arabinose
distribution phase of 30-45 mins, clearance  S-phase specific antimetabolite
phase of 3-4 hours and a terminal phase of  Isolated from the sponge Cryptothethya
6-20 hrs. crypta
 excreted primarily unchanged through the
kidneys by glomerular filtration and active MOA: Ara-C  ara-CTP (triphosphate) intracellularly
tubular secretion.  inhibition of DNA polymerase  DNA
 adverse effects: myelosuppression and GI incorporation  defective elongation of newly
toxicity (dose-limiting toxicities) mucositis: synthesized fragments of DNA  cessation of DNA
early sign of MTX toxicity diarrhea: severe replication
toxicity due to small intestinal irritationrenal,  poorly absorbed orally due to deamination
hepatic, pulmonary and neurologic to the non-cytotoxic uracil arabinoside (ara-
toxicitiesoccurs 7-10 days after treatment U) by cytidine deaminase in the intestines
- Leucovorin: antidote for MTX-induced and liver
toxicity and usually given 24-36 hours  administered intravenously but does not
after MTX Infusion (“leucovirin rescue”) penetrate the blood brain barrier
N5-formyl-FH4 (substrate) in large amounts  distributes freely into the body water and
can bypass the inhibited may be administered intrathecally
DHFR  short half-life: 7-20 minutes
- clinical Uses: ALL, lymphomas, breast CA,  excreted in the urine as its inactive
head and neck CA, osteogenic sarcoma, metabolite, ara-U
bladder CA; given intrathecally to treat CNS  adverse effects:
leukemia, lymphoma; non-neoplastic o myelosuppression (dose-limiting
applications include treatment of psoriasis, toxicity)
RA, autoimmune diseases, abortifacient, - nadir of BM suppression: 10
prevention of GVHD in organ transplantation days
- reversible
PYRIMIDINE ANTAGONISTS - directly proportional with
5-Fluorouracil (5-FU) and 5- duration of treatment
fluorodeoxyuridine (floxuridine) o GIT disturbances: nausea, vomiting,
 pyrimidine analog diarrhea
 interfere with the conversion of o neurological (esp. when given
deoxyuridylic acid to thymidylic acid intrathecally) and hepatic toxicities
depriving the cell of precursors for DNA noted
synthesis  clinical uses:
o DRUG OF CHOICE for AML
MOA: o administered intrathecally to treat
5-FU  5-FUMP  5-FUDP  5-FdUMP + meningeal leukemia
thymidylate synthase + N5-N10 methylene
FH4  inhibition of DNA synthesis Gemcitabine
(“thymineless death”) - novel pyrimidine nucleoside analog structurally
5-FU  5-FUTP  RNA incorporation  similar to cytarabine
inhibition of RNA processing and translation MOA:
5-FU  5-FdUTP  DNA incorporation  (1) gemcitabine  difluorodeoxycytidine
inhibition of DNA synthesis and function triphosphate  DNA incorporation  disruption
 erratic absorption after oral administration of DNA chain elongation  inhibition of DNA
due to high levels of the breakdown enzyme synthesis
dihydropyrimidine dehydrogenase in the GIT
mucosa
(2) inhibition of DNA polymerases  impairment of o myelosuppression

DNA repair o GIT toxicity: nausea, vomiting, diarrhea
(3) inhibition of ribonucleotide reductase  o fever, edema and neurologic toxicity
reduction of deoxyribonucleoside triphosphates  o progressive encephalopathy, cortical blindness
inhibition of DNA synthesis and death in high doses
- administered intravenously
- excreted in the urine as the non-cytotoxic - clinical uses:
metabolite - difluorodeoxyuridine o single most active agent in CLL
- adverse effects: -myelosuppression (dose-limiting o antitumor activity in lymphomas an
toxicity) macroglobulinemia
- transient elevation in transaminases, flu-like
syndrome, severe hypotension, bronchospasm, skin Ribonucleotide reductase inhibitor
rashes Hydroxyurea
- clinical uses: -analog of urea
chiefly for pancreatic CA -S-phase specific antimetabolite
non-small lung cell CA, bladder CA
MOA: inhibition of ribonucleotide reductase 
PURINE ANTAGONISTS inhibition of conversion of ribonucleotides to
6-Mercaptopurine (6-MP) and 6-Thioguanine deoxyribonucleotides  depletion of
(6-TG) deoxyribonucleotide pools  inhibition of DNA
- thiol analog of hypoxanthine synthesis
- first of the thiopurines to be used as an anticancer  well absorbed orally even in large doses
agent  plasma concentrations reach a maximum
MOA-6-MP: (1) thiol group substitution in after 1 hour and fall rapidly
hypoxanthine and xanthine  6-MP ribose  excreted unchanged by the kidneys
monophosphate (6-thioinosinic acid or TIMP)   adverse effects:
inhibition of de novo purine synthesis  decreased o bone marrow suppression chiefly
DNA and RNA synthesis leucopenia
MOA-6-MP: (2) thiol group substitution in - nadir in leukocyte count
hypoxanthine and xanthine  6-MP ribose occurs 6-7 days after
monophosphate (6-thioinosinic acid or TIMP)  6- treatment
MP ribose triphosphate  DNA and RNA - recovery is thereafter rapid
incorporation  non-functional DNA and RNA o nausea, vomiting, diarrhea, mucositis
MOA-6-TG: (3) thiol substitution in hypoxanthine o headache, increased lethargy
and xanthine  6-thioguanilyic acid  DNA o maculopapular rash
incorporation  inhibition of DNA synthesis  clinical uses:
o myeloproliferative disease chiefly CML
Other MOA’s for 6-TG: o blast crisis in AML to rapidly lower the
 inhibition of purine blast count
- catabolism and excretion of 6-MP but o adjunct with radiation therapy for head
NOT 6-TG involves oxidation by and neck CA, essential thrombocytosis
xanthine oxidase to 6-thiouric acid or S- and polycythemia vera
methylation by TPMT (thiopurine
methyltransferase) and is inhibited by MICROTUBULIN INHIBITORS
allopurinol Vinca Alkaloids (Vinblastine, Vincristine and
- administered orally Vinorelbine)
- adverse effects:  alkaloids isolated from the leaves of the
o myelosuppression Madagascar periwinkle plant (Catharantus
o GIT toxicity (less with 6-TG because roseus/ Vinca rosea)
of its metabolism in the GIT  asymmetric dimeric compounds
mucosa)  both cell-cycle specific and phase-specific
o mild reversible increase in hepatic
transaminases MOA: binding of vinca alkaloids to tubulin 
 clinical uses: ALL and AML inhibition of assembly and dissolution of the mitotic
spindle  dysfunctional spindle apparatus  arrest
Fludarabine in metaphase  inhibition of chromosomal
- purine nucleotide/ adenosine analog segregation  termination of cell replication
MOA: fludarabine  fluoro-arabinofuranosyladenine - administered intravenously
 fludarabine triphosphate  inhibition of DNA - rapid distribution phase
polymerase and ribonucleotide reductase  - metabolized by the hepatic CYP450-3A
inhibition of DNA synthesis - excreted in the feces
- administered intravenously because intestinal - VINORELBINE, a synthetic vinca alkaloid is a
bacteria split off the sugar to yield the toxic non-specific inhibitor of AZT used in the
metabolite “fluoroadenine” treatment of AIDS-related Kaposi sarcoma
- adverse effects: - adverse events: VINCRISTINE

 neurotoxicity (dose-limiting toxicity) Taxanes (Paclitaxel and Docetaxel)

o initial signs of toxicity: paresthesias of Paclitaxel
distal fingers and lower extremities and  obtained from extracts of Pacific yew (Taxus
loss of deep tendon reflexes brevifolia)
o late signs of toxicity: profound decrease  other sources: Taxomyces andreanae
in motor strength particularly (fungal endophyte isolated from the bark of
dorsiflexion of the foot the yew) Taxus baccata (needles of the
o cranial nerve palsies, jaw pain European yew)
o high doses: autonomic neuropathy  active in G2/M phase of the cell cycle
leading to obstipation and paralytic ileus
o sensory changes and reflex MOA: binding to the beta-tubulin subunit 
abnormalities slowly improve when stabilizes microtubule structure  inhibition of
treatment is stopped depolymerization  overly stable microtubules
o motor impairment reversible but produced are non-functional, so chromosome
improves more slowly desegregation does not occur  arrest in
 SIADH: hyponatremia metaphase  cell death
 phlebitis or cellulites: severe pain and local  insoluble in aqueous solution, formulated in
toxicity upon extravasation a castor oil and alcohol vehicle (50%
 some myelosuppression Cremophor EL) which is responsible for
producing histamine stimulated acute
VINORELBINE: more selective for non-neuronal hypersensitivity reactions
microtubules, more lipophilic, and rapidly  administered by intravenous bolus or
metabolized by hepatocytes  less neurotoxicity continuous infusion
 neutropenia (dose-limiting toxicity)  predominantly metabolized by the hepatic
 nadir occurs 7-10 days after treatment and CYP450 enzyme
recovery by 14 days  excreted by the biliary route
 mild sensory neuropathy  adverse effects:
 GIT toxicity: constipation, nausea, vomiting, o neutropenia (principal toxicity)
diarrhea, stomatitis o transient asymptomatic bradycardia
 Vesicant o heart blocks, ischemia, infarction
o peripheral neuropathy (stock and glove
VINBLASTINE: leucopenia (primary toxicity) distribution)
 nadir occurs 6-7 days after treatment o acute hypersensitivity within the first 2-3
 reversible minutes of infusion
 mucositis at higher doses  clinical uses: ovarian CA, breast CA, head
and neck CA, esophageal CA. non-small lung
clinical uses: CA
o Vinblastine: testicular CA, bladder CA, Hodgkin’s
disease Docetaxel
o Vincristine: ALL, lymphoma, Wilm’s tumor - semisynthetic taxoid derivative
o Vinorelbine: non-small cell lung CA, breast CA MOA: binding to the beta-tubulin subunit 
stabilizes microtubule structure  inhibition of
Estramustine depolymerization  overly stable microtubules
 structurally an estradiolmolecule linked to a produced are non-functional, so chromosome
nitrogen mustard through a carbamate desegregation does not occur  arrest in
 ester group metaphase  cell death
 exploits the alkylating activity of the  more soluble in water
nitrogen mustard and the estrogen binding  does not use Cremophor EL as a vehicle 
qualities of the estradiol moiety less HPS reaction
 inhibits growth of many cell lines including  metabolized by the hepatic microsomal
those that lacked estrogen receptors enzyme system
 administered intravenously
MOA: binding to MAP (microtubule associated  adverse effects:
proteins)  dissociation of MAP from tubulin  o severe neutropenia
inhibition of microtubule assembly and disassembly o peripheral neuropathy, stomatitis,
adverse events: myalgias, nausea and vomiting, severe
 nausea and vomiting (dose-limiting toxicity) asthenia, fluid retention
 gynecomastia, nipple tenderness,  clinical uses:
exacerbation of congestive heart failure o anthracycline resistant advanced breast
secondary to the mineralocorticoid effect of CA
the steroid molecule o non-small cell lung CA, ovarian CA, head
clinical uses: metastatic prostatic CA and neck CA

TOPOISOMERASE I INHIBITORS o non-classical alkylators (procarbazine,

Irinotecan and Topotecan dacarbazine)
MOA: inhibition of topoisomerase I  induction of  most toxic to rapidly dividing cellsdo not
single strand breaks  inhibition of DNA synthesis discriminate between cycling and resting
 administered intravenously cells
 excreted in the urine  cytotoxic, mutagenic and carcinogenic
 adverse effects: (secondary malignancy)
o diarrhea - principal toxicity of irinotecan
- occurs within 24 hours of treatment MOA: (1) intramolecular cyclization of alkylating
lasting 4-8 days agents  ethyleneimonium ion  carbonium ion 
- nausea, vomiting, alopecia, headache transfer of an alkyl group to a cellular constitutent
- myelosuppression (neutropenia)- dose-  DNA cross linking  cell death
limiting toxicity of topotecan MOA (2) carbamoylation of lysine  isocyanates
anemia, thrombocytopenia -major site of alkylation within DNA: N7 position of
 clinical uses: guanine
o advanced colorectal CA
Nitrogen Mustards
TOPOISOMERASE II INHIBITORS Mechlorethamine
Epipodophyllotoxins (Etoposide and  highly reactive unstable compound
Teniposide)  potent vesicant
 blocks cells in the late S-G2 phase of the cell
cycle MOA: (1) alkylation of N7 nitrogen in guanine in 1 or
 semisynthetic derivatives extracted from the both strands of DNA  cross linking between DNA
mayapple root (podophyllum peltatum) guanine residues and/ or depurination  DNA
strand breakage
MOA: inhibition of topoisomerase II  induction of MOA: (2) alkylation  miscoding mutations in DNA
double strand breaks  inhibition of DNA synthesis  inhibition of DNA synthesis
 administered orally or intravenously adverse reactions:
 half-life: 2.8-15.1 hours o severe nausea and vomiting
 excreted by the kidneys o alopecia
 water insoluble and uses Cremophor vehicle o phlebitis and cellulites if extravasated
 adverse effects: o myelosuppression
o myelosuppression (principal toxicity) - nadir occurs 10-14 days
o hypotension (slow IV infusion required) clinical uses
o nausea, vomiting o Hodgkin’s disease
o alopecia o Mycosis fungoides: control of pleural and
o fever, mild elevations of liver function pericardial effusion via intracavitary
tests, peripheral neuropathy administration
 clinical uses: Hodgkin’s disease, lymphomas,
leukemias, small lung cell CA, testicular CA Cyclophosphamide
 wide spectrum anti-tumor activity
ALKYLATING AGENTS  immunosuppressant
 DNA damaging compounds  most commonly used alkylating agent
 not cell cycle-specific but exerts its effect
during the late G1-S phases of the cell cycle MOA: cyclophosphamide  hydroxylation  4-
and express block in G2 hydroxycyclophosphamide + aldophosphamide 
 classified as phosphoramide mustard + acrolein
o bifunctional (2-reactive sites, double  administered orally or intravenously
strand breaks with cross-linking) or  high oral doses produce nausea and
monofunctional (1 reactive site, single vomiting
strand breaks with no cross-linking)  DOES NOT produce tissue extravasation
alkylators  excreted in the feces and urine
o bifunctional alkylators:  adverse effects:
cyclophosphamide, nitrogen mustard, o myelosuppression: leucopenia (dose-
thiotepa, melphalan, busulfan, limiting toxicity)
chlorambucil, nitrosoureas - nadir occurs 10-14 days after
o monofunctional alkylators: procarbazine, treatment
dacarbazine - platelet-sparing
 Classification of Alkylating Agents o HEMORRHAGIC CYSTITIS
o nitrogen mustards (mechloethamine, - accumulation of ACROLEIN in the
melphalan, chlorambucil, urine and bladder
cyclophosphamide, ifosfamide) - vigorous hydration
o aziridines (thiotepa) - antidote: N-acetylcysteine and
o alkyl alkane sulfonates (busulfan) sodium-2-mercaptoethanesulfonate
o nitrosoureas (carmustine, lomustine) (MESNA)

 nausea and vomiting Nitrosoureas

o high doses (> 500 mg/m2): nausea and Carmustine (BCNU) and Lomustine (CCNU)
vomiting 8-12 hours after treatment - high lipid solubility
o delayed nausea and vomiting due to - can cross the blood-brain barrier (treatment
conversion of cyclophosphamide to for tumors of the brain and meninges)
more emetegonic metabolites - chloroethylnitrosoureas
o pulmonary toxicity (fibrosis) - administered intravenously
o cardiac toxicity (acute hemorrhagic - initial half-life: 6 minutes
carditis) - elimination half-life: 68 minutes
o alopecia - adverse effects
o veno-occlusive disease of the liver o myelosuppression
o SIADH  nadir occurs 4-5 weeks after
o long term toxicity: infertility and treatment
secondary malignancies o nausea and vomiting
 clinical uses: o nephrotoxicity
o lymphoma, breast CA, small-cell lung o hepatotoxicity
CA, ovarian CA o secondary leukemias
o BM transplantation - clinical uses: brain tumors, lymphoma,
o Immunosuppression - GI cancer (colorectal metastasis)
Ifosfamide Streptozotocin
MOA: ifosfamide hydroxylation  ifosfamide - methylnitrosourea isolated from
mustard  acrolein + chloroacetic acid Streptomyces sp.
- excreted in the urine - short plasma half-life: 35 minutes
- adverse effects: - excreted in the urine
o bladder toxicity (dose-limiting - selectively lethal to the beta-islet cells of the
toxicity) pancreas
 vigorous hydration required - adverse effects:
 antidote: MESNA (nausea and o nephrotoxicity (dose-limiting toxicity)
vomiting) o mild glucose tolerance
o nausea and vomiting o nausea and vomiting
o alopecia o minimal myelosuppression
o veno-occlusive disease of the liver - clinical uses:
o myelosuppression o carcinoid and islet cell tumors of the
o CNS toxicity (changes in mental pancreas
status, cerebellar dysfunction, o Hodgkin’s disease, colon CA
seizures)
- clinical uses: lymphoma, ovarian CA, Non-Classical Alkylating Agents
sarcoma, testicular CA Dacarbazine
- methylating agent
Melphalan - activated by hepatic CYP450 microsomal
- bifunctional alkylator enzyme system
- causes interstrand, intrastrand DNA protein - elimination half-life: 5 hours
cross link - administered intravenously
- active orally - excreted unchanged in the urine as
- adverse effects: diazomethane
o myelosuppression (dose-limiting toxicity) - adverse effects:
o alopecia o severe nausea and vomiting
o pulmonary fiborosis o myelosuppression is uncommon
o GI toxicity in high doses (nausea, o flu-like syndrome
vomiting, diarrhea, mucositis) o facial flushing
- clinical uses: multiple myeloma, ovarian CA, o occasional hepatotoxicity
breast CA o severe pain and necrosis when
extravasated
Chlorambucil - clinical uses: Hodgkin’s disease, soft tissue
- administered orally sarcoma, malignant melanoma
- well-tolerated with minimal nausea and
vomiting Procarbazine
- given as pulse treatment (5 days a month) MOA: inhibition of DNA, RNA and protein synthesis
or continuous infusion  prolongs interphase  chromosome breaks
- adverse effect: - activated by the hepatic CYP450 microsomal
o myelosuppression (dose-limiting toxicity) enzyme system to produce azoprocarbazine
o liver abnormalities which causes DNA scission
o pulmonary fibrosis - administered orally
o secondary malignancies and leukemias - equilibrates rapidly between plasma and CSF
- half-life: 10 minutes
- excreted in the urine - has synergistic cytotoxicity with radiation

- adverse events: and other anti-neoplastic agents
o myelosuppression (principal toxicity) - kills all cells in all stages of the cell cycle
o GI toxicity (nausea, vomiting,
diarrhea) MOA: (1) formation of inter and intra-strand DNA
o neurotoxicity (dizziness, ataxia, cross-links  inhibition of DNA synthesis
paresthesia, headache, insomnia, MOA: (2) cross-linking of DNA with proteins 
nightmares) inhibition of DNA synthesis
o weak MAO inhibitor which reacts - administered intravenously with forced
with tyramine rich food (aged hydration and high chloride containing IV
cheese, beer, wine) and produce fluids to keep it in its neutral/ inactivated
severe headache state and allows use of higher doses
o interaction with sympathomimetic - rapidly bound to protein and persists in
amines, TCA, alcohol serum over long periods of time
o leukemogenic, teratogenic, - high levels in the liver, intestines, testes,
carcinogenic potential ovaries and kidneys
- clinical uses: - adverse effects:
o Hodgkin’s disease o nephrotoxicity due to tubular injury
o Non-Hodgkin’s disease, lung CA, (dose-limiting toxicity)
brain CA o hypomagnesemia due to tubular
damage
Ethyleneimine and Alkyl-Alkane Sulfonate o severe nausea and vomiting
Based Alkylating Agents o anemia in multiple courses
Thiotepa o neurotoxicity (peripheral neuropathy,
- lipophilic and can cross the blood brain ototoxicity: high frequency hearing loss
barrier and tinnitus)
- administered both orally, intravenously, o immunoglobulin-mediated
intravesically, intra-arterially and hypersensitivity reactions
intramuscularly - clinical uses: ovarian CA, testicular CA, lung
- administered by local instillation to treat CA, bladder CA, head and neck CA
superficial bladder cancer and malignant
effusions Carboplatin
- not a vesicant - second generation platinum analog
- adverse effects: - vigorous intrahydration not required
o myelosuppression (dose-limiting toxicity) - relatively well-tolerated
o high doses: mucositis, skin rash, CNS - less reactive and less bound to plasma
toxicity proteins
o gonadal dysfunction - adverse effects:
- clinical uses: o myelosuppression (dose-limiting toxicity)
o superficial bladder CA o less renal and GI toxicity
Busulfan Oxaliplatin
o alkyl sulfonate alkylator - third generation platinum analog
o metabolized by the hepatic CYP450 enzyme - adverse effects:
microsomal system o neurotoxicity (dose-limiting toxicity)
o excreted in the urine  peripheral neuropathy worsened by
o administered orally and well-absorbed cold
o elimination half-life: 2-5 hours  cumulative and reversible
o adverse effects: - clinical uses: second line therapy for
o myelosuppression chiefly of the myeloid metastatic colorectal CA
elements (dose-limiting toxicity)
o nausea and vomiting ANTI-TUMOR ANTIBIOTICS
o gynecomastia, hyperpigmentation, transient - isolated from soil microbes Streptomyces
elevation of transaminases - cytotoxicity due to DNA interactions leading to
o pulmonary fibrosis (long term treatment) disruption of DNA function
- clinical uses: - cell-cycle specific
o CML (rapid reduction of leukocytosis and
splenomegaly) Anthracyclines: Doxorubicin and Daunorubicin -
o myeloablation treatment produced by the fungus Streptomyces peucetius var.
o myeloproliferative disorders caesius
o gonadal dysfunction MOA: (1) inhibition of topoisomerase II  induction
of single strand DNA breaks 
PLATINUM COMPOUNDS inhibition of DNA synthesis
Cisplatin, Carboplatin and Oxaliplatin MOA: (2) high affinity binding to DNA through
- platinum coordination complex intercalation  blockade of DNA synthesis and RNA
- inorganic metal complex
MOA: (3) binding to cellular membranes to alter - administered by subcutaneous,

fluidity and ion transport intramuscular, intravenous, intracavitary
MOA: (4) generation of semiquinone free radicals routes
and oxygen free radicals through - excreted in the urine
an enzyme-mediated reductive process - elimination half-life: 2-3 hours
- administered intravenously due to - selectively exerts anti-tumor effects with
inactivation in the GIT little or no bone marrow toxicity
- half-life: rapid distribution phase lasts 15 - bleomycin-inactivating enzyme (bleomycin
minutes, elimination phase lasting several hydrolase) is high in the liver and spleen but
hours and elimination phase in 24-48 hours is low in the lungs and absent in the skin
- metabolized in the liver to daunomycinol - adverse effects:
and doxorubicinol o PULMONARY FIBROSIS (dose-limiting
- excreted in bile toxicity)
- no penetration in the blood brain barrier  Pneumonitis with cough, dyspnea,
- bound to plasma proteins and tissues dry inspiratory crackles and
- imparts red color in the urine radiologic infiltrates
- adverse effects:  related to cumulative dose > 450
o myelosuppression (neutropenia) mg or a high single dose of >25
 nadir occurs 10 days after treatment mg/m2
with recovery in 3 weeks
o phlebitis and cellulitis due tissue
 toxicity high for individuals > 70
years old
necrosis when extravasated
o SKIN CHANGES
o alopecia
o nausea and vomiting  dose related
o mucositis  apparent when administered for >
o RADIATION RECALL REACTION: 2-3 weeks
erythema and desquamation in  erythema, hyperkeratosis and
previously irradiated areas appearing 3 ulceration
weeks before or after radiation  affect the skin of the hands, fingers,
o CARDIAC TOXICITY joints
2 forms:  nail changes, hyperpigmentation,
 Acute: arrhythmias, conduction hypertrophy, alopecia
abnormalities, ECG changes, o fever and malaise
pericarditis, myocarditis, transient, o hypersensitivity reactions
asymptomatic o idiosyncratic cardiovascular collapse
 Chronic: dose-dependent dilated - clinical uses
cardiomyopathy associated with o Hodgkin’s disease, non-Hodgkin’s
congestive heart failure due to lymphoma, germ cell tumors, head and
increased production free radicals neck CA
within the myocardium o squamous cell CA of the skin, cervix,
 Cumulative dose: 450-550 mg/m2 vulva
 Antidote: dexrazoxane –an iron o malignant pleural effusion and ascites
chelating agent started when
anthracycline dose > 300 mg/m2 Dactinomycin
 adverse effects: pain at the injection - isolated from Streptomyces parvullus
site, modest neutropenia, - has a phenoxazone ring structure
thrombocytopenia MOA: binds to DNA through intercalation
- clinical uses: between adjacent guanine-cytosine base
o AML, ALL, Hodgkin’s disease, non- pairs  dactinomycin-DNA complex 
Hodgkin’s lymphoma inhibition of DNA-dependent RNA
o breast CA, lung CA, bladder CA polymerase  inhibition of DNA-dependent
RNA synthesis
Bleomycin - administered intravenously
- isolated from the fungus Streptomyces - minimally metabolized and does not enter
verticillius the CSF
- copper chelating glycopeptides - excreted unchanged in the bile and urine
- cell-cycle specific - rapid initial half-life in minutes followed by
- cell killing is maximal in G2 phase an elimination half-life of 36 hours
- adverse effects:
MOA: oxidation DNA-bleomycin-ferrous o myelosuppression chiefly leucopenia and
complex  toxic free radicals (superoxide or thrombocytopenia (dose-limiting
hydroxide radicals)  single and double toxicity)
strand DNA breaks (DNA fragmentation) 
inhibition of DNA synthesis + cell death
 nadir occurs 2-3 weeks after
treatment

o nausea and vomiting  remedy: switch to PEG-

o GI toxicity (stomatitis, cheilitis, glossitis, asparaginase or to enzyme
proctitis) purified from Erwininia
o RADIATION RECALL carotovora
o phlebitis and cellulitis when o inhibition of protein synthesis in
extravasated tissues especially the liver
o alopecia and severe skin toxicity  low albumin
- clinical uses:
o Wilm’s tumor, gestational
 low clotting factor synthesis
choriocarcinoma, embryonal  low serum lipoproteins
rhabdomyosarcoma o neurologic toxicity: confusion,
o Osteosarcoma stupor, coma
o acute hemorrhagic pancreatitis
Mitomycin o hyperglycemia
- quinine antibiotic o minimal or no myelosuppression nor
- isolated from Streptomyces caespositus GI toxicity
MOA: metabolic activation by biochemical - clinical uses: ALL, T-cell leukemia, T-cell
reduction  cross-linking of DNA strands  lymphomas
inhibition of DNA synthesis
- administered intravenously ENDOCRINE AGENTS
- little or no systemic toxicity Estrogens (Diethystilbestrol)
- elimination half-life: 25-90 minutes MOA: inhibition of the growth of prostatic tissue by
- adverse effects: blocking production of LH  decreased synthesis of
o myelosuppression (dose-limiting toxicity) androgen in the testes
- adverse effects:
 nadir occurs 3-5 weeks after
o acute: nausea, vomiting, hypercalcemia,
treatment
uterine bleeding
o nausea and vomiting
o chronic: hypecoagulable state
o phlebitis and cellulitis when
(thromboemboli), premature coronary
extravasated
disease (myocardial infarction, stroke),
o hemolytic uremic cyndrome, interstitial
feminization
pneumonitis, cardiomyopathy
- clinical uses prostatic CA, breast CA
- clinical uses:
o adenocarcinoma of the lungs, pancreas,
Anti-Estrogens (Tamoxifen)
stomach
MOA: (1) competitive partial agonist-inhibitor of
o head and neck CA
estrogen and binding to estrogen receptors of
o squamous cell CA of the anus, cervix
estrogen-sensitive tumors + inhibition of autocrine
o intravesical administration for superficial
and paracrine growth factor stimulation decreased
bladder CA
estrogen levels + depletion of estrogen receptors
- administered orally and is rapidly absorbed
ENZYMES
- estrogen antagonist
L-asparaginase
- longer half-life than estrogen
- isolated from bacteria, Escherichia coli,
- metabolized in the liver by the hepatic
Erwinia carotovora 5
CYP450 microsomal enzyme system
MOA: catalysis of the conversion of L-
- excreted in the bile
asparaginase  aspartic acid + ammonia 
- well-tolerated
rapid depletion of L-asparagine  inhibition
- adverse effects:
of protein synthesis
o acute: hot flashes, weight gain due to
- administered intramuscularly or
fluid retention, mild nausea
intravenously
o chronic: thromboembolic disease,
- half-life: 14-24 hours
retinitis (rare)
- PEG-asparaginase (polyethylene glycol-
- clinical uses:
conjugated) decreases probability of
o early stage and metastatic breast CA
antibody formation against the enzyme and
o chemopreventive agent for women at
increases serum half-life
high risk of breast CA with hormone-
- adverse effects:
receptor-positive disease
o hypersensitivity (principal toxicity)
 uncommon in the first dose, Androgens (Testosterone propionate,
common in the second or fluoxymesterone, testosterone enanthate)
subsequent doses - contraindicated in prostatic CA
 allergic reaction: urticaria to - adverse effects:
anaphylaxis o acute: cholestatic jaundice (oral
 skin testing required halogenated androgens-
 hypersensitive patients may fluoxymesterone), fluid retention
develop secondary antibodies to o chronic: virilization (hirsutism,
L-asparaginase deepening of voice, changes in libido)

- clinical use: metastatic breast CA with AROMATASE INHIBITORS

hormone-receptor-positive disease Aminogluthetimide
MOA (1): non-steroidal inhibition of corticosteroid
Anti-Androgens (Flutamide and Bicalutamide) synthesis  conversion of cholesterol to
MOA: binding to androgen receptor  inhibition of pregnenolone  decreased estrogen
translocation of androgen receptor from cytoplasm MOA (2): inhibition of extra-adrenal synthesis of
to nucleus  inhibition of androgen effects estrone from estradiol
- Flutamide: blocks the inhibitory effects of MOA (3): inhibition of aromatase enzyme  less
testosterone on gonadotropin secretion  conversion of adrenal androgen androstenedione to
increased LH and testosterone levels estrone
o Administered with GnRH agonists - requires hydrocortisone co-administration
- administered orally and rapidly absorbed in due to inhibition of hydrocortisone synthesis
the GIT - adverse effects:
- adverse effects: o acute: dizziness
o gynecomastia, GI distress o chronic: rash
o liver failure (flutamide) - clinical uses: breast CA, prostate CA
- clinical use: early stage and metastatic
prostate CA Anastrazole and Letrozole
MOA: selective non-steroidal inhibitor of aromatase
Progestins (Megestrol acetate, with no inhibitory effects on adrenal glucocorticoid
hydroyprogesterone caproate) or mineralocorticoid synthesis
- adverse effects: Versus aminogluthetimide:
o acute: increased appetite, fluid retention - more potent
o chronic: weight gain, thromboembolism - more selective
- clinical use: - no need for supplemental hydrocortisone
o palliative management of metastatic - no predisposition to endometrial CA
breast CA or endometrial CA - no androgenic side effects
o prostate CA - administered orally
- administered intramuscularly - metabolized in the liver
- clinical uses:
Glucocorticoids (Prednisone, o first line treatment of post-menopausal
Methylprednisolone, Dexamethasone) women with metastatic breast CA that is
- potent, synthetic anti-inflammatory with less ER (+) and has progressed despite anti-
mineralocorticoid activity estrogen treatment
- lympholytic and non-myelosuppressive
- can induce cell death by apoptosis Exemestane
- administered orally, intramuscularly, steroidal irreversible inhibitor of aromatase
intravenously - widely distributed
- adverse effects: - administered orally
o acute: fluid retention, hyperglycemia, - metabolized in the liver using the CYP34A
mood changes (euphoria and microsomal enzyme system
depression), hypokalemia, acute - adverse effects:
confusional states o nausea, fatigue, hot flashes
o chronic: osteoporosis, o acne and hair changes
immunosuppression, GI ulcers,
cushingoid appearance, cataracts BIOLOGIC THERAPY (Biologic Response
- clinical use: Modifiers)
o ALL, lymphoma, multiple myeloma, Interferons
o breast CA - antiviral proteins
o brain metastasis - 3 types: alpha, beta, gamma
o spinal cord compression due to - MOA: Interferon alpha and beta bind to the
malignancy same cell surface receptor whereas a
second cell surface receptor mediates the
Gonadotropin-Releasing Hormone Agonists action of interferon gamma  synthesis of
(Leuprolide and Goserelin) enzymes, suppression of cell proliferation,
MOA: initial stimulation of the pituitary gland to activation of macrophages, increased
release FSH and LH followed by long-term inhibition cytotoxicity of lymphocytes
of FSH and LH  reduction of testicular androgen - well absorbed after intramuscular or
and ovarian estrogen production subcutaneous administration
- available in long-acting parenteral depot - metabolized in the liver
formulations - adverse effects:
- more potent than natural GnRH antagonists o fever, chills (low doses)
- adverse effects: o cardiac arrhythmias, nausea, vomiting,
o acute: transient flare of symptoms leucopenia, myalgias, proteinuria,
o hot flushes, impotence, gyncecomastia hepatic dysfunction
- clinical use: prostate CA, breast CA - clinical uses:
o CML, multiple myeloma, low grade non- dependent process releasing

Hodgkin’s lymphoma, renal cell CA, cytochrome C and activating caspase
metastatic melanoma, hairy cell - administered intravenously
leukemia (IF-alpha) - adverse effects:
o ECG changes, (QT prolongation),
Interleukins arrhythmias, fever, dyspnea, skin
- IL-2 rash, fluid retention and weight gain
- immunomodulatory cytokine that acts - clinical use: acute promyelocytic leukemia
on T-cell progenitors
- adverse effects:
o lymphoid infiltration of organs Monoclonal Antibodies
o capillary leak syndrome Rituximab
o tachychardia MOA: monoclonal antibody directed against the
o hypotension CD20 antigen found on the surface of normal and
o fluid retention with weight gain malignant B lymphocytes  rapid depletion of B
o oliguria and azotemia lymphocytes
- clinical use: pulmonary metastases - administered intravenously
- adverse effects:
Levamisole o hypotension,
- antihelminthic agent with o bronshospasm, angioedemachills and
immunopotentiating properties fever
- clinical use: Hodgkin’ disease, adjuvant o arrhythmias
treatment for colon CA o tumor lysis syndrome
- clinical uses: CLL, post-transplant
Imatinib lymphoma
- MOA: tyrosine kinase inhibitor in the
BCr-ABL oncoprotein preventing Trastuzumab
phosphorylation of the kinase substrate MOA: monoclonal antibody directed against human
by ATP epidermal growth factor receptor 2 (HER)  down
- administered orally and is well-absorbed regulation of HER-2 receptor expression + induction
- metabolized in the liver of antibody dependent cytotoxicity + decrease
- clinical use: angiogenesis due to effect on the vascular
o CML chronic phase endothelial growth factor
o CML blast crisis - administered intravenously
o GI tumors - does not penetrate the blood brain barrier
- adverse effects:
Mitotane o congestive heart failure
- dichloro analog of the insecticide DDT o infusion related fever, chills, headache,
- MOA: production of tumor regression dizziness, nausea, vomiting, abdominal
and reduces excessive adrenal steroid pain, back pain
secretion - clinical uses: metastatic breast CA
- clinical use: adrenocortical CA
LONG TERM TOXICITIES ASSOCIATED WITH
Retinoic Acid Derivatives CANCER TREATMENT
- ATRA (all-trans retinoic acid) or tretinoin - Pulmonary fibrosis/ pulmonary insufficiency:
- MOA: induction of terminal bleomycin, cyclophosphamide, carmustine,
differentiation of leukemic radiotherapy to lung fields
promyelocytes - Coronary artery disease/ valvular heart
- adverse effects: disease: radiation therapy
- retinoic acid syndrome: fever, - Cardiomyopathy: anthracyclines
leukocytosis, dyspnea, weight gain, (doxorubicin, mitoxantrone), mitomycin C
diffuse pulmonary infiltrates, pleural - Secondary malignancies: alkylating agents
or pericardial effusion, elevated (procarbazine, dacarbazine,
serum cholesterol and triglycerides, mechlorethamine, melphalan,
CNS toxicity, abdominal pain and cyclophosphamide), etoposide and
diarrhea, abnormalities in liver teniposide, tamoxifen, radiation therapy
function tests - Gonadal dysfunction (infertility): alkylating
- clinical use: acute promyleocytic agents (mechlorethamine,
leukemia cyclophosphamide, chlorambucil,
procarbazine, busulfan), cisplatin, radiation
Arsenic Trioxide to the gonads
- MOA: induction of differentiation
through degradation of the abnormal
fusion protein and induction of
apoptosis through a mitochondrion-

MECHANISMS OF RESISTANCE TO ANTI-

NEOPLASTIC AGENTS
- Methotrexate: - impaired transport,
amplification of DHFR
- Cytosine arabinoside: - decreased
deoxycytidine kinase, increased cytidine
deaminase
- 5-FU: - increased thymidylate synthase,
nucleoside salvage, dihydropyrimidine
dehydrogenase
- Cisplatin: decreased uptake, increased DNA
repair
- Taxol and Vinca Alkaloids: multi-drug
resistance (MDR) phenotype, mutations in
tubulin resulting in decreased binding
- Doxorubicin: MDR expression, decreased
alterations in toposisomerase II
- Irinotecan and topotecan: decreased
topoisomerase I
CYTOTOXIC AGENTS THAT PRODUCE FEBRILE

REACTIONS
L-asparaginase, azathioprine, bleomycin,
chlorambucil, cyclophosphamide, cytarabine,
dacarbazine, dactinomycin, daunorubicin,
doxorubicin, 6-mercaptopurine, methotrexate,
procarbazine, vinblastine, vincristine
VESSICANT ANTI-NEOPLASTIC AGENTS

Dactinomycin, daunorubicin, doxorubicin,
mechlorethamine, mitomycin-C, vinblastine,
vincristine
NAUSEA AND VOMITING ASSOCIATED WITH

- SEVERE: carmustine, cisplatin, dacarbazine,
dactinomycin, mechlorethamine,
streptozotocin,
- MODERATE: cyclophosphamide, cytarabine,
daunomycin, doxorubicin, procarbazine
- MILD: L-asparaginase, busulfan, etoposide,
5-FU, hydroxyurea, melphalan, 6-
mercaptopurine, methotrexate, mitomycin,
mitoxantrone, tamozxifen, 6-thioguanine,
thiotepa, vinblastine, vincristine
- NONE: bleomycin
NEUROTOXICITY ASSOCIATED WITH ANTI-

NEOPLASTIC AGENTS
- Central Nervous System: L-asparaginase,
cytarabine, methotrexate, procarbazine
- Peripheral Nervous System: cisplatin
- Central, peripheral and autonomic nervous
systems: vinblastine, vincristine
HEPATOTOXICITY ASSOCIATED WITH ANTI-

NEOPLASTIC AGENTS
- Hepatocellular: carmustine,
cyclophosphamide, dacarbazine, etoposide,
methotrexate, Streptozotocin
- Cholestatic: L-asparaginase, azathioprine,
bleomycin, daunoribicin, doxorubicin,
Mitomycin-C, 6-mercaptopurine

PHARMACOLOGY
JUDE P. GUIANG, MD
ANTI-MYCOBACTERIAL AGENTS RIFAMPICIN: inhibits DNA dependent RNA

DRUG RAPIDLY SLOWLY SLOWLY polymerase
GROWING GROWING GROWING  most potent sterilizing drug
EXTRACELLULAR EXTRACELLULAR INTRACELLULAR  resistance is due to mutation in rpo B gene
(NEUTRAL PH) (NEUTRAL PH) (ACIDIC PH)  complete absorption in the fasting state
 bioavailability dependent on formulation
h +++ + +
 highly lipophilic and distributes into body
r ++ ++ ++
tissues and fluids
z 0 0 +++
 penetrates cavities and caseous masses
e +/- 0 +/-  metabolism is via deacytilation
 side effects: discoloration of body fluids,
MAIN PROPERTIES OF ANTI-TB DRUGS proteinuria, hepatitis,thrombocytopenia
1. Bactericidal activity: rapid killing of actively  drug interactions: anti-hypertensives,
multiplying organisms analgesics, oral contraceptives
2. Sterilizing activity: ability to kill all remaining
organism PYRAZINAMIDE: disrupts cell membrane
3. Ability to prevent or delay emergence of metabolism and transport functions
resistance  widely distributed in body tissues
4. Relatively low toxicity  hydrolyzed in the liver to 5-hydroxy
pyrazinoic acid by xanthine oxidase
DRUG BACTERICIDAL  resistance: impaired uptake of Z or
ACTIVITY mutations in pncA gene
H 0.50-.054  side effects: hyperuricemia, hepatotoxicity,
R 0.17-0.20 hypersensitivity
P 0.004
E 0.246 ETHAMBUTOL: inhibition of arabinosyl transferase
S 0.043  both bacteriostatic (15mg/kg) and
bactericidal (.25mg/kg)
ANTI-TB DRUGS BACTERICIDAL ACTIVITIES  no effect on non-replicating bacilli
WORKS IN COMPLEMENT  resistance: mutation in emb B gene
PERIOD 1 PERIOD 11 PERIOD III  good oral absorption
(2-3 DAYS) (4-8 WEEKS) (4-6 MONTHS)  distributed to most tissues
H R&Z R&H  half-life is prolonged in renal failure
 side effects: retrobulbar neuritis,
FIRST LINE ANTI-TB DRUGS hypersensitivity, hyperuricemia
ISONIAZID: inhibits synthesis of mycolic acid TREATMENT MODIFICATIONS FOR SPECIAL

 hydrazide of isonicotinic acid SITUATIONS
 prodrug activated by mycobacterial catalase  breastfeeding
peroxidase (kat g)  use of oral contraceptives
 active drug forms a covalent complex with acyl  liver disease or history of liver disease
carrier protein (AcpM) and beta-keto-acyl carrier  co-infection with HIV
protein synthetase (KasA) blocking mycolic acid
synthesis SECOND LINE ANTI-TB DRUGS
 resistance occurs via: STREPTOMYCIN: inhibits protein synthesis by
1. overexpression of inhA binding to 30s ribosomal subunit
2. mutation or deletion of katG gene  active against extracellular rapidly
3. promoter mutation with overexpression multiplying bacilli, caseous and cavitary
of ahpc gene lesions
4. mutations in kasA gene  resistance: mutation in S12 gene or gene
 metabolism is via acetylation encoding 16s ribosomal rRNA
 half-life depending whether slow or fast  distributed to most tissues; no GIT
acetylator absorption
 monoacetyl hydrazine (metabolite) is associated  side effects: ototoxicity, nephrotoxicity,
with hepatotoxicity paresthesias, hypersensitivity
 absorption is complete in the fasting state *amikacin/kanamycin: NO cross resistance with
 diffuses to all tissues and penetrates well into streptomycin
caseous material
 side effects: peripheral neuropathy, seizures, ETHIONAMIDE: blocks mycolic acid synthesis
hepatotoxicity, rash, drug-induced lupus,  remains active when INH resistance is due
hemolysis to Kat G gene mutation
 drug interactions: antacids, carbamazepines,  ineffective if resistance is due to inh A gene
oral contraceptives, theophylline, phenytoin mutation
 concentration in the CSF is equal to plasma
1|PHARMACOLOGY
PHARMACOLOGY
JUDE P. GUIANG, MD
 side effects: hepatotoxicity, GI irritation ANTI-FUNGAL DRUGS

A. POLYENE ANTIBIOTICS: binds to ergosterol
CAPREOMYCIN: peptide protein synthesis inhibitor creating pores causing increased cell
 alternative to streptomycin and amikacin permeability and loss of cellular contents
resistance
 resistance: rrs mutation 1. AMPHOTERICIN B
 side effects: nephrotoxicity, ototoxicity  Selective in its fungicidal effects (ergosterol
vs. cholesterol)
CYCLOSERINE/TERIZODONE: inhibits cell wall  90% plasma protein binding
synthesis  with poor meningeal penetration with or
 NO cross resistance with other 2nd line drugs without inflammation
 CSF concentration is equal to plasma  eliminated via hepatic metabolism
 Side effects: peripheral neuropathy, CNS  resistance:
dysfunction 1. decrease membrane concentration of
 Pyridoxine should be given concomitantly ergosterol
2. modifying sterol target molecule
FLUOROQUINOLONES: reducing drug affinity
 Inhibits bacilli at conc. <2mcg/ml INFUSION-RELATED CUMULATIVE
 Gatifloxacin/moxifloxacin have better in-vitro TOXICITY TOXICITY
activity than ciproflioxacin Fever, chills, muscle Nephrotoxicity, seizures,
 Side effects: prolonged QT interval spasms anemia
Vomiting, headache, Elevated transaminases,
DRUGS FOR NON-TUBERCULOUS hypotension arachnoiditis
MYCOBACTERIA (MOTT)  new formulations:
DAPSONE: competitive inhibitor or dihydropteroate 1. Amphotericin B lipid complex (ABLC)
synthase inhibiting folate synthesis 2. Amphotericin B colloidal dispersion
 Bacteriostatic against M. leprae (ABCD)
 Indications: 3. Liposomal Amphotericin B
1. All forms of leprosy  Indications: Cryptococcus, blastomyces,
2. Dermatitis herpetiformis Histoplasma, aspergillus, candida
3. Prophylaxis and treatment of
pneumocystis jiroveci NYSTATIN
 Slowly and completely absorbed and widely  Candida infection
distributed to allbody tissues and fluids  Oropharyngeal thrush, vaginal candidiasis
 Metabolized in the liver, excreted into the  SWISH AND SPIT AND SWISH AND
bile then reabsorbed in the intestines then SWALLOW
excreted in the urine
 Retained in the skin, muscle, liver and B. AZOLES: binds and inhibits cytochrome
kidneys: half-life 1-2 days P450 enzyme lanosterol 14-demethyl
 Side effect: hypersensitivity, hemolysis, decreasing ergosterol synthesis
peripheral neuropathy, leukopenia,
agranulocytosis  Has greater affinity to fungal than human
 SULFONE SYNDROME: development of cytochrome P450
erythema nodosum leprosum after initial
therapy with multibacillary leprosy 1. IMIDAZOLES: lesser selectivity, more drug
interaction and side effects
CLOFAZIMINE: preferential binding to A. KETOCONAZOLE
mycobacterial DNA inhibiting growth; exerts anti- o Greater propensity to inhibit
inflammatory effect mammalian cytochrome P450
 Indications: o Good oral absorption in an acidic
1. Sulfone-resistant leprosy gastric environment
2. Erythema nodosum leprosum o Highly protein bound
3. Mycobacterium avium intracellulare o Extensively metabolized in the liver
 Accumulates in tissues for prolonged periods and excreted in bile but with
(treatment interruption every 4 weeks) negligible CSF penetration
 Stored in the RES and skin; does not cross o Side effects: decreases testosterone
the BBB synthesis and blocksk adrenal
 Side effects: hypersensitivity, skin corticotropin response
discoloration, GI intolerance o Drug interactions:
 Precautions: 1. Decrease ketoconazole
1. Avoid dose >100mg/day absorption: H2 blockers, PPI,
2. Breastfeeding antacids
3. Avoid during the 1st trimester 2. Induces ketoconazole
metabolism decreasing efficacy:
2|PHARMACOLOGY
PHARMACOLOGY
JUDE P. GUIANG, MD
rifampicin, phenobarbital, o Broadest spectrum against candida

phenytoin and aspergillus
3. Increases blood levels of drugs o ONLY azole with significant activity
due to inhibition of CYP34A: against mucormycosis
warfarin, diazepam, indinavir
4. Torsades de Pointes: PYRIMIDINE ANALOG;
terfenadine, cisapride 1. FLUCYTOSINE: conversion of 5-FC to 5-
FU by cytosine permease then to 5-
2. TRIAZOLES: lower affinity, less toxicity fluorodeoxyuridylic acid inhibiting DNA
A. FLUCONAZOLE and RNA synthesis
o Fluorinated bistriazole o Well absorbed >90%
o LEAST effect on hepatic microsomal o Poorly protein bound but with good
enzymes tissue penetration including CSF
o High oral bioavailability, high degree o Human cells cannot convert parent
of water solubility and good CSF drug to its active metabolite
penetration o Given in synergism with
o Absorption does not require an amphotericin B
acidic environment o Resistance: altered metabolism to
o Does not inhibit steroid synthesis flucytosine
o Drug of choice: treatment and o Toxicity: metabolism to an
secondary prophylaxis for antineoplastic compound
cryptococcal meningitis, systemic o Trough levels need to monitor (50-
and mucosal candidiasis 100ug/ml)
o Side effects: reversible alopecia, o Side effects: aplastic anemia,
rash, diarrhea, GI upsets elevated transaminases,
enterocolitis
B. ITRACONAZOLE E. HETEROCYCLIC BENZOFURAN
o Lipid soluble; absorption is o Fungistatic against dermatophytes
increased by food and low gastric o Mechanism of action:
pH 1. Binds to microtubules causing
o Highly protein bound but with poor defective cell wall
CSF penetration and interacts with 2. Binds to newly formed keratin
hepatic microsomal enzymes protecting skin from new
o Does not affect mammalian steroid infection
synthesis o Better absorption if taken with fatty
o Has a potent antifungal activity but meals or in the microcrystalline form
limited effectiveness due to reduced o CYP inducer
bioavailability o Side effects: peripheral neuritis,
o Drug interaction (decreases blurring of vision, stomatitis,
bioavailability): rifampin, rifabutin, leukopenia, neutropenia,
rifepentine albuminuria, photosensitivity,
o Indications: Histoplasma, vesicular and morbiliform eruptions,
aspergillus, blastomycosis, vaginal estrogen-like effects
candidiasis, dermatophytosis
F. ALLYLAMINE: TERBINAFINE
C. VORICONAZOLE o Reversible noncompetitive inhibition
o 90% bioavailability and less protein of squalene monooxygenase
binding than itraconazole o Keratophilic and fungicidal
o metabolism is predominantly hepatic o 99% plasma protein bound and
and inhibits mammalian CYP3A4 accumulates in skin, nails, fats
o drug of choice for Invasive o DOES NOT inhibit CYP450
Aspergillosis o Side effects: headache, SJS,
o trough levels need to be monitored hepatotoxicity, GI distress,
(1-5ug/ml) neutropenia
o side effects: rash, elevated hepatic
enzymes, blurring and G. ECHINOCANDINS
o changes in color vision or brightness o Inhibits synthesis of B (1-3) glucan
resulting to cell disruption and death
D. POSACONAZOLE o Well tolerated
o Enhanced absorption when taken o Side effects: GI upsets, flushing,
with high fat meal elevated liver enzymes
o Rapidly distributed to tissues but
low blood levels
o Trough levels need to monitor (0.5-
1.5ug/ml)
3|PHARMACOLOGY
PHARMACOLOGY
JUDE P. GUIANG, MD
ANTI-HERPES AGENTS  Triphosphate intracellular conc:

Need to be converted into the triphosphate form to penciclovir > acyclovir
inhibit DNA synthesis and chain termination  Food slows absorption but does not
1. ACYCLOVIR reduce overall bioavailability
 15%-20% bioavailability after  Side effects: headache diarrhea,
absorption and is not affected by food nausea, burning sensation
 CSF conc. Is 50% that of plasma; conc.  Testicular toxicity with repeated
In breast milk, amniotic fluid, placenta exposures but NO evidence of increased
 Resistance: alteration in thymidine birth defects
kinase or DNA polymerase; develops
croos-resistance with valacyclovir, 4. DOCOSANOL
famciclovir, ganciclovir  Inhibits fusion between host cell plasma
 Side effects: nausea, diarrhea, mucosal membrane and envelope preventing
irritation, reversible renal insufficiency viral entry and replication
and neurologic effects  Recurrent orolabial herpes
 High doses result to chromosomal
changes and testicular atrophy but NO 5. TRIFLURIDINE
evidence of teratogenicity  Fluorinated pyrimidine nucleoside
 Drug interaction: nephrotoxic drugs,  Inhibits viral DNA synthesis
probenecid and cimetidine decreases  Incorporation to host and infected cells
acyclovir clearance prevents its systemic use
 Clinical outcome: decreases  Uses: primary keratoconjunctivitis,
1. Total number of lesions recurrent keratitis
2. Duration of symptoms
3. Viral shedding ANTI-CMV AGENTS
4. Time to lesion healing 1. GANCICLOVIR
5. reactivation  Acyclic guanosine nucleoside analog
 Uses:  Bioavailability: IV > oral
1. First episode genital herpes  Activity against CMV is 100x greater
2. Recurrent genital herpes than acyclovir
3. Varicella  Uses: CMV retinitis, colitis, esophagitis,
4. Recurrent herpes labialis pneumonitis
5. Post organ transplant  Resistance: mutation in UL 97 and UL
54 in DNA polymerase
2. VALACYCLOVIR  Toxicities:
 L-valyl ester prodrug of acyclovir 1. Myelosuppression, infusion-related
 Rapidly and completely converted to phlebitis, retinal detachment,
acyclovir via enzymatic hydrolysis vitreous hemorrhage
 Serum concentration 3x-5x higher than 2. Mutagenic
acyclovir 3. Carcinogenic
 Uses: 4. Embrytoxic
1. First or recurrent genital herpes and 5. Aspermatogenesis
VZ infection 2. VALGANCICLOVIR
2. Orolabial herpes  L-valyl ester prodrug of ganciclovir
3. Herpetic neuralgia:  Rapidly hydrolyzed by intestinal
valacyclovir>acyclovir esterases to ganciclovir
4. Prevention of CMV infection post-  60% oral bioavailability, should be taken
transplant with food
5. Prevention of VZV reactivation after  <2% protein bound
BMT
 Side effect: nausea, vomiting, 3. FOSCARNET
confusion, hallucination, seizures at  Directly inhibits viruses without
high doses activation by phosphorylation
 NO evidence of increased birth  Blocks the pyrophosphate binding site
defects and inhibits cleavage of pyrophosphate
 Uses: end-organ CMV disease,
3. FAMCICLOVIR/PENCICLOVIR ganciclovir resistant disease, acyclovir
 Acyclic guanosine analog resistant HSV and VZV
 Famciclovir is rapidly deacylated and  Side effects: nephrotoxicity and
oxidized to penciclovir via first-pass electrolyte imbalance (Ca, P04, K, Mg),
metabolism genital ulceration, infusion-related
 NO chain termination in penciclovir thrombophlebitis
 Triphosphate affinity for viral DNA  Poor solubility requires large volumes of
polymerase: penciclovir < acyclovir fluid
4|PHARMACOLOGY
PHARMACOLOGY
JUDE P. GUIANG, MD
 Resistance: point mutation in DNA 1,000x

polymerase gene due to repeated or Nausea, vomiting, Cough, bronchospasm,
prolonged drug exposure headache, diarrhea, transient nasal and
fatigue throat irritation
4. CIDOFOVIR
 Phosphorylation to the active ANTI-HEPATITIS B AGENTS
diphosphate is independent of viral HBV INFECTION HBV INFECTION +
enzymes HIV
 Acts as a potent inhibitor and alternative Lamivudine Tenofovir
substrate to viral DNA polymerase Adefovir dipivoxil Lamivudine
 Contains 2 active metabolites: cidofovir tenofovir Adefovir dipivoxil
diphosphate (17-65hrs) and cidofovir Entecavir
phosphocholine (87hrs) telbivudine
 Poor CSF penetration Interferon alfa-2b
 Administered with high dose probenecid Pegylated interferon
to block active tubular secretion and alfa-2a
decrease nephrotoxicity
 Toxicities:
1. ADEFOVIR DIPIVOXIL
1. dose dependent proximal tubule
 Competitive inhibition of HBV DNA
2. nephrotoxicity,
polymerase causing chain termination of
3. uveitis, ocular hypotonia
DNA synthesis
4. neutropenia, Fanconi’s syndrome
 Rapidly and completely hydrolyzed to
5. mutagenic, gonadotoxic, embrytoxic
parent compound by intestinal and
6. hypospermia, mammary
blood esterases
adenocarcinoma
 Can be administered in decompensated
ANTI-INFLUENZA AGENTS
liver disease
1. AMANTADINE/RIMANTADINE
 Slower to suppress HBV DNA and least
 Influenza A infection
likely to induce HBeAg seroconversion
 Tricyclic amines that blocks the M2
 Resistance involves rt233 HBV gene; NO
proton ion channel and inhibits
cross resistance between Lamivudine and
uncoating of viral RNA within infected
Entecavir
host cells preventing replication
 Side effects: dose-dependent
 NO longer recommended for the
nephrotoxicity, headache, diarrhea,
prevention and treatment of influenza
asthenia, abdominal pain
due to high rates of resistance of H1N1
 if co-administered with NRTI:
and H3N2 viruses
mitochondrial dysfunction (lactic
 Rimantadine is 4x-10x more active in
acidosis and hepatic steatosis)
vitro
 Levels of Rimantadine in nasal
2. INTERFERONS: inhibits viral penetration,
secretions and saliva approximates that
uncoating, mRNA synthesis, translation,
in serum and CSF levels is 52%-96%
assembly and release
 Side effects:
 Anti-viral, immunomodulating and anti-
1. nausea, anorexia, nervousness,
proliferative activities
insomnia
 Alpha, beta, gamma
2. seizures: more common with
Amantadine and is due to alteration in
INTERFERON ALFA PEGYLATED
dopamine neurotransmission
INTERFERON ALFA-
3. teratogenic, embryotoxic
2A
Half-life: 2-5 hours Longer terminal half lives
2. OSELTAMIVIR AND ZANAMIVIR
Undergoes rapid Slower clearance and
 Neuraminidase inhibitors
proteolytic degradation steadier concentration
 Influenza A and B infection
 Early administration is crucial; Liver metabolism and Renal elimination
1. Decreases duration of symptoms biliary excretion
2. Decreases viral shedding and
ttransmission INTERFERON INDICATION
3. Decreases rate of complications Interferon alfa-2b Chronic Hepatitis B
4. Decreases hospitalization and Acute Hepatitis C
mortality Pegylated interferon Chronic Hepatitis B and
alfa-2a C
OSELTAMIVIR ZANAMIVIR Pegylated interferon Chronic Hepatitis C
Prodrug activated by Administered via alfa-2b
hepatic esterases inhalation
80% oral bioavailability Conc. In the lungs is
5|PHARMACOLOGY
PHARMACOLOGY
JUDE P. GUIANG, MD
 Side effects/Toxicities:  Side effects/toxicities: fatigue,

1. Flu-like syndrome headache, cough, nausea, diarrhea,
2. Neurotoxicities: mood disorder, myopathy/myalgia, peripheral
depression, somnolence, confusion neuropathy, lactic acidosis and steatosis
3. Myelosuppression, fatigue, weight loss
4. Tinnitus, reversible hearing loss 6. TENOFOVIR
5. Cardiotoxicity  Nucleotide analog of adenosine
6. Abortifacient  Virologic response: tenofovir > adefovir
7. Increases risk of hepatic failure with  Histologic improvement: tenofovir >
didanosine adefovir
8. Increase risk of BM suppression with  Rates of HBV resistance: tenofovir <
zidovudine adefovir
 Side effects: nausea, abdominal pain,
3. LAMIVUDINE diarrhea, dizziness, fatigue, rash
 Inhibition of HBV DNA polymerase by
competing with deoxycytidine HEPATITIS C AGENTS
triphosphate inhibiting replication and A. NS5B RNA POLYMERASE INHIBITOR
chain termination 1. SOFOSBUVIR
 80% oral bioavailability; increased if co-  Given in combination with pegylated alfa
administered with trimethoprim + ribavirin, declastavir, simeprevir,
sulfamethoxazole ledipasvir
 poor CSF penetration and freely crosses  61%-65% protein bound
the placenta  a substrate of drug transporter P-gp (P-
 discontinuation may cause flare of glycoprotein)
hepatitis in HBV + HIV co-infection  side effect: fatigue, headache
 prolonged treatment may decrease
clinical progression of HBV infection and 2. DASABUVIR
development of HCC  Non-nucleoside inhibitor
 prevents vertical transmission of HBV  Used in combination with ombitasvir,
when given in the last 4 weeks of paritrapevir, ritonavir
gestation  Bioavailability is 70%; >99.5% protein
 can be given as FDC with zidovudine bound
and abacavir  Metabolized by CYP2C8 & CYP3A
 Side effects: nausea, pruritus, insomnia,
4. ENTACAVIR elevated ALT
 Inhibits base printing, reverse
transcription and synthesis of HBV DNA B. NS3A/4A PROTEASE INHIBITOR
polymerase 1. GRAZOPREVIR
 100% oral bioavailability but decreased  98.8% protein bound
with food  partially eliminated by oxidative
 weak anti-HIV activity metabolism via CYP3A and excreted via
 suppression of HBV DNA: the feces
entecavir > lamivudine or adefovir  should not be administered with
 higher barrier to resistance (S202G moderate to severe hepatic impairment,
gene) entecavir > lamivudine concomitant inducers and inhibitors and
 side effects/toxicities: efavirenz
1. headache fatigue, dizziness, nausea,  side effects: fatigue, headache, nausea
rash, fever
2. lung adenoma and carcinoma 2. PARITAPREVIR
3. hepatic adenoma and carcinoma  Given in combination with ombistavir
4. glioma and fibroma and ritonavir for genotype 4 hepatitis C
 Given in combination with dasabuvir for
5. TELBIVUDINE genotype 1 hepatitis C
 Competitively inhibits HBV DNA  Metabolized via CYP3A5
polymerase causing chain termination  Contraindicated in severe hepatic
 Oral bioavailability is not affected by impairment
food  Side effects: pruritus, nausea, insomnia,
elevated alt/ast
 Virologic response:
telbivudine > lamivudine or adefovir 3. SIMEPREVIR
 Resistance: M204I mutation and may  2nd generation inhibitor due to enhanced
cause virologic rebound if >1-year binding affinity and specificity to NS3/4A
therapy  used in combination with sofosbuvir
 Not effective with lamivudine resistant with or without ribavirin or with
HBV pegylated interferon alfa and ribavirin
6|PHARMACOLOGY
PHARMACOLOGY
JUDE P. GUIANG, MD
 taken with meals to maximize  Accumulates in body tissues including

absorption CSF due to increased cellular uptake and
 substrate and mild inhibitor of CYP3A, P- conc. In rbc’s
gp and OATP1B/13 (organic anion  Side effects/toxicities:
transporting polypepetide) 1. Fatigue, irritability, rash, cough
 screening for Q80L mutation is required insomnia, nausea, pruritus
 side effects: photosensitivity and rash, 2. Hemolytic anemia, depression
nausea, elevated bilirubin levels 3. Teratogenic and embryotoxic
C. NS5A INHIBITOR ANTI-HIV AGENTS

A. NUCLEOSIDE AND NUCLEOTIDE
1. DACLATASVIR REVERSE (NRTI)
 Used in combination with sofosbuvir for
genotypes 1,2,3 Hepatitis C 1. ZIDOVUDINE
 Taken with or without food
 Metabolized by CYP3A  A deoxythymidine analog
 Inhibitor of P-gp, OATP, BCRP (breast  Underfoes rapid first pass hepatic
cancer resistance protein) metabolism
 Side effects: headache, fatigue,  Well absorbed; good distribution in body
bradycardia tissues and fluids
 Used in combination with lamivudine
2. ELBASVIR alone or lamivudine and abacavir
 Used in combination with grazoprevir for  Decreases rate of clinical progression
genotype 1,4 Hepatitis C and prolongs survival
 Baseline testing for NS5A gene is  Reduces rate of vertical transmission
needed (first line agent for pregnant women)
 Absorption is not food dependent  Side effects: myelosuppression, GI
 Drug interaction: CYP3A, OATP1B/13, intolerance, insomnia, lipoatrophy,
efavirenz thrombocytopenia, hyperpigmentation,
 Side effects: headache, nausea, myopathy
elevated alt/ast
 Increases zidovudine levels: phenytoin,
3. LEDIPASVIR methadone, fluconazole, valproic acid
 Used in combination with sofosbuvir
 Not recommended for genotype 2,3 2. DIDANOSINE
Hepatitis C
 Absorption not affected by food  Synthetic analog of deoxyadenosine
 99.8% protein bound  Oral bioavailability is 30%-40%;
 inhibitor of drug transporter P-gp and buffered formulation prevents
BRCP inactivation by gastric acid
 side effects: fatigue, headache,  Avoid combining with:
asthenia, bradycardia 1. Zalcitabine, stavudine, ribavirin,
hydroxyurea (pancreatitis)
4. OMBITASVIR 2. Stavudine, INH, vincristine, ribavirin
 Used in combination with paritaprevir (peripheral distal sensory
and ritonavir for genotype 6 Hepatitis C neuropathy)
 Used in combination with dasabuvir,  Side effects/toxicities:
parittrapevir, ritonavir for genotype 1 1. Pancreatitis
Hepatitis C 2. Distal peripheral sensory neuropathy
 Bioavailability is 48% and 99.9% protein 3. Optic neuritis, lipoatrophy
bound 4. Hepatotoxicity, cardiotoxicity,
 Inhibitor of UGT1A1 but NOT cardiomyopathy,
metabolized by CYP2A hypertriglyciredemia
 Side effects: nausea, pruritus, insomnia.  Buffer preparation interferes absorption
of: indinavir, delavirsine,
OTHER ANTI-HEPATITIS C AGENTS atazanavir, dapsone, itraconazole,
1. RIBAVIRIN fluoroquinolone
 Interferes with synthesis of guanosine  increases didanosine levels: allopurinol,
triphosphate inhibiting capping of viral tenofovir, ganciclovir
messenger RNA and inhibits viral RNA-  decreases didanosine levels: atazanavir,
dependent polymerase delavirdine, ritonavir, tipranavir
 Rapid oral absorption with extensive 3. STAVUDINE
first pass metabolism  synthetic thymidine analog
 Bioavailability increases with high fat  80% oral bioavailability
meal and decreases with antacids  crosses the placenta
7|PHARMACOLOGY
PHARMACOLOGY
JUDE P. GUIANG, MD
 avoid combining with:  Used in combination with tenofovir or

1. didanosine, vincristine, INH, efavirenz and rilpivarine or elvitegrair
ribavirin (peripheral neuropathy) plus cobicistat
2. stavudine, didanosine (pancreatitis)  Together with tenofovir for pre-
 side effects: arthralgia, fat atrophy, exposure prophylaxis to rduce HIV
 toxicity: lactic acidosis, hepatic acquisition
steatosis, lipodystrophy  Resistance: M184V/1 gene mutation
common in lamivudine and emticitabine
4. ZALCITABINE combination
 80% oral bioavailability  Side effects: headache, insomnia, rash,
 CSF conc. Is 20% of plasma level hyperpigmentation of the palms and
 Side effects: dose-dependent peripheral soles
neuropathy, oral and esophageal
ulcerations, nausea, rash, NON-NUCLEOSIDE REVERSE
cardiomyopathy TRANSCRIPTASE INHIBITORS
 Metabolized by CYP450
5. ABACAVIR  All are substrates for CYP3A4: inducers
 Guanosine analog that undergoes (nevirapine), inhibitors (delavirdine, mixed
hepatic glucoronidation and inducers-inhibitors (efavirenz, etravirine)
carboxylation
 Bioavalability not affected by food 1. NEVIRAPINE
 Resistance develops SLOWLY because it  90% oral bioavailability
requires 2-3 concomitant mutations  highly lipophilic and achieves CSF conc.
 Used in combination with lamivudine or 45% of plasma levels
with zidovudine and lamivudine  crosses the placenta
 Screening for HLA-B*5701 for abacavir-  extensively metabolized by CYP3A
associated hypersensitivity reaction isoform to hydroxylated metabolites
 Fatal hypersensitivity syndrome: fever,  prevents vertical transmission of HIV at
abdominal pain, maculopapular rash, the onset of labor and repeated dose 3
respiratory and musculoskeletal days after delivery to the newborn
coplaints, headache, paresthesias o non-teratogenic
 side effects/toxicities: rash sparing the
6. TENOFOVIR palms and soles, pruritus, hepatitis,
 Acyclic nucleotide phosphonate analog headache, fatigue, SJ syndrome, toxic
 Requires 2/3 intracellular epidermal necrolysis
phosphorylation to inhibit DNA synthesis  nevirapine decreases the levels of
 Bioavailability increases after a high fat amprenavir, indinavir, lopinavir,
meal saquinavir, efavirenz, methadone
 Used in combination with entricitabine  rifampin and rifabutin decreases the
or efavirenz or rilpivirine or with levels of nevirapine
emtricitabine and cobicistat  fluconazole, ketoconazole,
 Used in combination with emtricitabine clarithromycin increases the levels of
for pre-exposure prophylaxis for HIV nevirapine
transmission
 Resistance: mutation in K65R/N and 2. EFAVIRENZ
K70E gene  Risk of toxicity increased when taken
 Side effects: GI symptoms, headache, after a high fat meal
rash, dizziness, osteomalacia  Principally metabolized by CYP3A4 and
 Increases tenofovir levels: atazanavir, CYP2B5
lopinavir, ritonavir  Side effects/toxicities: dizziness,
drowsiness, insomnia, headache,
7. EMTRICITABINE depression, diarrhea, elevated
 Fluorinated analog of lamivudine transaminases and cholesterol, neural
 Low CSF penetration and plasma tube defects
binding protein  Decreases conc. of the ff: drugs:
 Oral preparation contains propylene phenobarbital, phenytoin,
glycol (NOT given in young children, carbamazepine, indinavir, saquinavir,
women, renal and hepatic failure, amprenavir
metronidazole, disulfiram)
 LEAST toxic of the NRTIs 3. DELAVIRDINE
 Side effects: headache, diarrhea,  Extensively metabolized by CYP3A and
nausea, hyperpigmentation with sun CYP2D6 enzymes and inhibits CTP3A4
exposure and CYP2C9 enzymes
8|PHARMACOLOGY
PHARMACOLOGY
JUDE P. GUIANG, MD
 Side effects/toxicities: rash, headache, 1. SAQUINAVIR

fatigue, nausea, diarrhea, neutropenia,  Given in combination with low dose
teratogenic ritonavir
 Decreases delavirdine levels:  Taken within 2 hours after a fatty meal
fosamprenavir, rifabutin, didanosine,  97% protein bound; with large volume
lopinavir, nelfinavir, ritonavir of distribution except CSF
 Prolongs elimination half-life of indinavir  mainly CYP3A4 inhibitor
and saquinavir  nelfinavir, omeperazole, digoxin
increases levels of saquinavir
4. ETRAVIRINE
 Alternative drug in patients who 2. RITONAVIR
developed resistance to the 1st  98% protein bound
generation NNRTIs (efavirenz,  metabolized to an active metabolite via
nevirapine, delavirdine) CYP3A and CYP2D^ isoforms
 Taken with meals to increase systemic  recommended for pregnant patients
exposure  given in escalated doses over 1-2 weeks
 Highly protein bound and metabolized in to decrease dose limiting side effects
the liver  a potent inhibitor of CYP3A4 that
 Substrate and inducer of CYP3A4, increases the levels of digoxin,
inhibitor of CYP2C9 and CYP2C19 theophyllines, saquinavir
 Should not be given with other NNRTIs,
unboosted protease inhibitors, 3. INDINAVIR
atazanavir/ritonavir,  Requires an acidic environment for
fosamprenavir/ritonavir, optimum solubility (taken on an empty
tripanavir/ritonavir stomach or small, low fat, low protein
meal)
5. RILPIRIVINE  With high CSF penetration
 Used in combination with emtricitabine  More common causing insulin resistance
and tenofovir than any other PIs
 Preferably taken with high fat meals of  Combining with ritonavir has a higher
>400kcal meal risk for nephrolithiasis
 Used with caution when taking antacids
and H2 blockers; contraindicated if 4. NELFINAVIR
taking PPI  70%-80% high absorption rate in the
 Highly protein bound, half-life of 50 fed state
hours, metabolized by CYP3A4  98% protein bound
 Resistance due to EI38K and M184I  inhibits CYP3A requiring to increase
substitution; develops cross-resistance dose if co-administered with rifabutin
with other NNRTIs and increases levels of saquinavir, but
 Side effects/toxicities: rash, depression, efavirenz decreases nelfinavir level
insomnia, headache, elevated liver
enzymes/cholesterol, fat redistribution
5. FOSAMPRENAVIR/AMPRENAVIR
syndrome, prolonged QT interval
 Fosamprenavir is a phosphonooxy
prodrug of amprenavir with greater
PROTEASE INHIBITORS
water solubility and oral bioavailability
 Prevents the processing of viral proteins into
 Co-administered in combination low
functional conformations producing
dose ritonavir
immature, noninfectious viral particles
 High fat meal decreases its absorption
 Do not need intracellular activation
 Both an inducer and inhibitor of CYP3A4
 Resistance is due to substitution at
10,46,54,82,84,90 codons  Contains propylene glycol
 Side effects/toxicities: nausea, diarrhea,
dyslipidemia, central obesity, buffalo hump, 6. LOPINAVIR
peripheral and facial wasting, breast  Inhibits the CYP3A mediated metabolism
enlargement, cushingoid facies, prolonged of lopinavir
PR and QT interval, hepatitis  98%-99% protein bound
 All are metabolized by CYP3A4  recommended for use in pregnant
 Ritonavir has more pronounced inhibitory patients
effect and acts as a pharmacokinetic  increase dose if co-administered with
enhancer efavirenz or nevirapine
 Saquinavir has the least inhibitory effect  avoid taking metronidazole and
difulfiram (propylene glycol),
fosamprenavir decreases its plasma
level, rifampin (hepatotoxicity)
9|PHARMACOLOGY
PHARMACOLOGY
JUDE P. GUIANG, MD
7. DARUNAVIR INTEGRASE STRAND TRANSFER INHIBITORS

 Must be co-administered with ritonavir  Binds to integrase inhibiting strand transfer
 Should be taken with meals thus interfering with the integration of
 Contains a sulfonamide moiety reverse-transcribed HIV DNA into host cell
(hypersensitivity) chromosomes
1. DOLUTEGRAVIR
8. ATAZANAVIR  Taken with or without food but should
 Requires an acidic medium for be taken 2 hours before or 6 hours after
absorption; exhibits ph-dependent taking antacids or laxatives, sucralfate,
aqueous solubility iron and calcium supplements or
 If taken with antacids must be 12 hours buffered medications
apart; contraindicated with PPI  Primarily metabolized via UGT1A1 and
 Penetrates CSF and seminal fluid CYP3A
 Recommended in pregnant patients  Used in raltegravir and elvitegravir
 Should not be co-administered with resistance
tenofovir or efavirenz unless ritonavir is  Side effects: insomnia, headache,
added hypersensitivity, fat redistribution
syndrome
9. TIPRANAVIR
 Used in patients resistant to PIs 2. ELVITEGRAVIR
 Poor bioavailability but increased when  Used in combination with cobicistat,
taken with high fat meal emtricitabine, tenofovir taken with food
 Avoided in patients with head trauma or  Side effects: insomnia, headache, renal
bleeding (risk for intracranial bleeding failure
with tipranavir/ritonavir)
 It decreases levels of valproic acid and 3. RALTEGRAVIR
omeprazole  Variable oral bioavailability
 It increases levels of statins  Taken at least 4 hours after taking
antacids
ENTRY INHIBITORS  Does not interact with CYP450 but
 Inhibits binding of the viral envelope metabolized by UGT1A1
glycoprotein complex gp160 to its cellular o Resistance: single point
receptor CD4 mutation involving codons 148
1. ENFUVIRTIDE or 155
 Given to patients with evidence of viral  Side effects/toxicities: insomnia,
replication despite on ART headache, diarrhea, fatigue, increase
 Only parenterally administered ART (SQ) pancreatic amylases and transaminases,
 Metabolized by proteolytic hydrolysis SJ syndrome, toxic epidermal necrolysis
 Resistance: mutations in gp41 gene
 Side effects/toxicities: local reaction at
injection site, insomnia, headache,
eosinophilia, lymphadenopathy,
pneumonia
 No drug-drug interaction requiring dose
adjustment
2. MARAVIROC
 With rapid and variable absorption
 Dose depends on renal function and
concomitant use of CYP3A inducers or
inhibitors
 High conc. in the cervicovaginal fluid
than plasma
 Resistance: V3 loop of gp120; NO cross
resistance with other ART
 Levels increases if co-administered with
delavirdine, ketoconazole, itraconazole,
clarithromycin
 Levels decreases if co-administered with
efavirenz, etravirine, rifampin,
carbamazepine
10 | P H A R M A C O L O G Y
REVIEW TEST
JUDE P. GUIANG, MD
ANTI-TB, ANTI FUNGAL, ANTI-VIRAL
______1. A 30year old smear (+) was started on ______9. A 2nd line anti-TB drug that interferes with
quadruple anti-Koch’s. Which among the following folic acid synthesis?
agent has the most sterilizing property? A. Ethionamide
A. Isoniazid B. Cycloserine
B. Rifampicin C. Stretomysin
C. Ethambutol D. Para-amino-salicyclic acid (PAS)
D. Pyrazinamide
______10. Which among the fluoroquinolones has a
______2. A 30-year old on his 5th month of anti-TB higher in vitro activity against Mycobacterium TB?
treatment remains smear (+). Culture revealed A. Levofloxacin.
rifampicin resistance. The mechanism is due to: B. Moxifloxacin.
A. point mutation in rpoB gene. C. Ciprofloxacin.
B. point mutation in rpsL gene. D. Gatifloxacin.
C. overexpression of rpoB gene.
D. overexpression of pncA gene. ______11. Aside from leprosy, this drug is also used
in the prevention or treatment of Pneumocystis
______3. Mutation in one of the following gene jiroveci pneumonia in AIDS patients?
expresses high level of resistance to isoniazid? A. Clofazimine.
A. ahpC. B. Dapsone.
B. KatG. C. Thalidomide.
C. inhA. D. Ethionamide.
D. kras.
______12. True of the pharmacokinetic profile of
______4. A patient on anti-TB drugs developed flu dapsone:
like symptoms. CBC done showed A. absorption is unpredictable.
thrombocytopenia. The agent most likely responsible B. widely distributed in fluids and tissues.
is? C. excretion is primarily thru the kidneys.
A. Pyrazinamide. D. it has a short half-life.
B. Ethambutol.
C. Rifampicin. ______13. Discoloration of the skin and
D. Isoniazid. conjunctivae, nausea and vomiting are side effects
associated with?
______5. An 18 year-old developed hypersensitivity A. Ethionamide
reaction 3 weeks after starting his anti-TB B. Dapsone
medications. This reaction is rarely seen in patients C. Clofazimine
taking? D. Thalidomide
A. pyrazinamide.
B. rifampicin. ______14. Incorporation of the triphosphate form of
C. ethambutol. this anti-herpes agent into both viral and host DNA
D. streptomycin. polymerase prevents its systemic use?
A. Acyclovir
______6. Which of these agents inhibits B. Trifluridine
mycobacterial arabinosyl transferases? C. Valacyclovir
A. Rifampicin. D. Valgancyclovir
B. Ethambutol.
C. Pyrazinamide. ______15. Which of the following anti-CMV agent
D. Isoniazid has poor CNS penetration and a prolonged
intracellular half-life of 17-65 hours?
______7. A 50-year old 1 month after starting anti- A. Valganciclovir
TB medications consulted because of joint pains. B. Cidofovir
Blood tests shows hyperuricemia. Which of the C. Ganciclovir
following most likely caused his symptoms? D. Foscarnet
A. Fluoroqinolone.
B. Ethambutol. ______16. Bioavailability of this nucleoside reverse
C. Pyrazinamide. transcriptase inhibitor is increased if co-administered
D. Isoniazid. with one of the following drugs?
A. Probenecid
______8. Which agent has good bactericidal activity B. Colchicine
on rapidly growing extracellular bacilli used in C. Co-trimoxazole
patients with MDR-TB? D. Cimetidine
A. Cycloserine.
B. Streptomycin
C. Fluoroquinolone.
D. Ethionamide.
REVIEW TEST
JUDE P. GUIANG, MD
______17. A 30year old male, currently on his 3rd

month of a nonnucleoside reverse transcriptase
inhibitor develops a maculopapular rash sparing the
palms and soles. The drug most likely responsible is?
A. Saquinavir
B. Nevirapine
C. Lopinavir
D. Rilviripine
______18. One of the following agents for Hepatitis

B infection is effective in preventing vertical
transmission when given in the last 4 weeks of
gestation?
A. Tenofovir
B. Telbivudine
C. Lamivudine
D. Entecavir
______19. Myelosuppression, lipoatrophy and

hyperpigmentation of the nails are common side
effects of one of the following anti-retroviral agents?
A. Zidovudine
B. Stavudine
C. Nelfinavir
D. Ritonavir
______20. Prolonged PR or QT interval is a side

effect of which nucleoside reverse transcriptase
inhibitor?
A. Abacavir
B. Atazanavir
C. Didanosine
D. Lamivudine

AUTONOMIC DRUGS
MARIA MINERVA P. CALIMAG, MD
AUTONOMIC DRUGS  Sympathetic

 Parasympathetic
Goal of the lecture
 To allow the students to build a framework Sympathetic Nervous System
of understanding to properly predict the  Sympathetic innervations usually consist of
effects and side effects of the different one short preganglionic fiber synapsing with
autonomic nervous system drugs simply by several (one or more) long postganglionic
knowing the receptors they interact with. o fibers in the sympathetic ganglia
 Sympathetic preganglionic neurons exit the
THE PERIPHERAL NERVOUS SYSTEM spinal cord at the thoraco-lumbar level to
Subdivisions of the Peripheral Nervous system synapse with postganglionic nerves at the
 Somatic nervous system paravertebral ganglia (22 pairs on each side
• (voluntary) of spinal cord and are connected to form the
 Autonomic nervous system sympathetic chain or trunk): 3 in the
 (involuntary) cervical region, 10 to 11 in the thoracic
region, 4 in the lumbar region, 4 in the
THE ANATOMIC CLASSIFICATION OF THE sacral region, and a single, unpaired
PERIPHERAL NERVOUS SYSTEM ganglion lying in front of the coccyx called
SOMATIC NERVOUS SYSTEM the ganglion impar
 The somatic nervous system (SNS) regulates  The three cervical sympathetic ganglia are
activities which are under conscious control the superior cervical ganglion, the middle
 It consists of sensory and motor nerve cervical ganglion, and the cervicothoracic
divisions ganglion (also called the stellate ganglion).
 The sensory division, also called the  the superior ganglion innervates
afferent division, contains neurons that viscera of the head;
receive signals from the tendons, joints,  the middle and stellate ganglia
skin, skeletal muscles, eyes, nose, ears innervate viscera of the neck,
and tongue, and many other tissues and thorax (i.e., the bronchi and heart),
organs. These signals are conveyed to and upper limb;
the cranial and spinal nerves.  the thoracic sympathetic ganglia
 The motor division, also called the innervate the trunk region; and
efferent division, contains pathways that  the lumbar and sacral sympathetic
go from the brain stem and spinal cord ganglia innervate the pelvic floor
to the lower motor neurons of the and lower limb
cranial and spinal nerves. Stimulation of  All the paravertebral ganglia provide
this pathway cause voluntary sympathetic innervation to blood vessels in
contraction of the skeletal muscles. muscle and skin, arrector pili muscles
 Acetylcholine is the neurotransmitter attached to hairs, and sweat glands.
released at the neuromuscular junction.  The adrenal medulla is considered to be a
modified sympathetic ganglion; the medulla
AUTONOMIC NERVOUS SYSTEM is embryonically and anatomically
 Releases acetylcholine (Ach) homologous to the sympathetic ganglia
 Functional considerations:  There is a greater ramification of
- mediates control of vegetative sympathetic fibers compared to the
or involuntary functions parasympathetic system (the ratio of pre- to
- innervation of cardiac muscle, postganglionic fibers = 1:20)
vascular and non-vascular  Diffuse action: “fight or flight responses
smooth muscle and exocrine (i.e., stress)
glands  This system is normally active with the
- functions in these systems degree of activity varying from moment to
often occur without conscious  moment and organ to organ
control  This system constantly adjusts to a
 Anatomical considerations changing environment, especially during
- in contrast to somatic rage or fright
efferents, autonomic
innervations consist of 2 Typical sympathetic responses include:
sequential neurons  Increase in heart rate
- these sequential neurons are  Shift in blood flow in muscles
the preganglionic and  Increase in blood glucose levels
postganglionic neurons which  Dilation of the pupils
synapse at autonomic ganglia
 Anatomical considerations  Parasympathetic Nervous System
- The autonomic nervous Preganglonic neurons originate in the cranial
system consist of two nerves of the brain stem and the sacral
divisions: portion of the spinal cord

AUTONOMIC DRUGS
 These parasympathetic preganglionic  The major means of inactivation of

neurons synapse with postganglionic acetylcholine is degradation in the synapse
neurons in ganglia very close or in the using the enzyme acetylcholine esterase
organs innervated. They are called  Acetylcholine (Ach or Cholinergic) synapses
prevertebral or preaortic ganglia. include:
 The three preaortic ganglia are the celiac,  All preganglionic fibers outside CNS
superior mesenteric, and inferior mesenteric. (sympathetic & parasympathetic)
Lying on the anterior surface of the aorta,  All parasympathetic postganglionic nerve
they provide axons that are distributed with endings (ACh is the neurotransmitter)
the three major gastrointestinal arteries
arising from the aorta. The three ganglia  Exception: sympathetic postganglionic nerve
retain a pattern of innervation that endings of sweat glands
originates in the embryo.  Somatic motor neurons innervating skeletal
 the celiac ganglion innervates muscle
structures derived from the embryonic
foregut, including the stomach, liver, Norepinephrine
pancreas, duodenum, and the first Chemistry
part of the small intestine;  Norepinephrine is ultimately synthesized
 the superior mesenteric ganglion from tyrosine using the enzyme tyrosine
innervates the small intestine, which is hydroxylase which converts tyrosine to
derived from the embryonic midgut; DOPA
and  Aromatic L-amino acid decarboxylase
 the inferior mesenteric ganglion converts DOPA to dopamine
innervates embryonic hindgut  Dopamine b-hydroxylase converts dopamine
derivatives, which include the to norepinephrine
descending colon, sigmoid colon,  Phenylethanolamine N-methyl-transferase
rectum, urinary bladder, and sexual converts norepinephrine to epinephrine
organs.  The major means of inactivation of
 Parasympathetic innervations typically norepinephrine is reuptake back into the
consist of on e long preganglionic fiber presynaptic neuron from which it was
synapsing with one short post-ganglionic released
fiber in the parasympathetic ganglia.
 This system is more circumscribed than the  Noradrenergic (NE) synapses”
sympathetic system, although a 1:1 ratio of  All postganglionic sympathetic fibers (except
pre to postganglonic fibers is not always the those to sweat glands)
case  Adrenal medulla (norepinephrine &
 Discrete action; conservation and restoration epinephrine)
of energy, localized control of discrete
functions AUTONOMIC RECEPTORS
 1. G protein coupled receptors
Typical parasympathetic responses include:  Acetylcholine muscarinic receptors
 Slowing the heart rate  Adrenergic receptors
 Lowering blood pressure  Dopamine receptors
 Protecting the retina from light  Adenosine receptors
 Emptying the bladder  2. Ligand-gated ion channels
 Acetylcholine nicotinic receptors
Physiological antagonism
 The sympathetic and parasympathetic Receptors: Affinity and Efficacy
systems usually do not function  Agonist – binding to receptors triggers a
independently; i.e., they are physiological pharmacologic response 9 with affinity and
antagonists. intrinsic efficacy)
 Often when one system inhibits a process,  Full agonist produces maximum
the other system will augment the level of response (intrinsic activity = 1)
activity so that the total response depends  Partial agonist cannot produce
on the influence of both systems, although maximum response (intrinsic activity
this is not always the case. <1)
 The integration of these system regulates  Antagonist – binding to receptor does
functions below the level of consciousness not trigger a pharmacologic response (
with affinity but no intrinsic efficacy);
NEUROCHEMICAL CLASSIFICATION OF THE Antagonists (intrinsic activity = 0)
PERIPHERAL NERVOUS SYSTEM  Competitive antagonist block of receptor can
 Acetylcholine Chemistry be overcome by increasing the
Acetylcholine is synthesized from acetyl co- concentration of the agonist
enzyme A and choline using the enzyme  Noncompetitive antagonist block of the
choline acetyl transferase receptor cannot be overcome by increasing

AUTONOMIC DRUGS
 the concentration of the agonist  Effects blocked with neuromuscular blockers

 Inverse agonist – ligand binding produces (e.g., curare)
opposite effects to those of an agonist. They  Muscarinic
are not the same as antagonists, which  Muscarinic receptors are part of the
block the effects of both Agonists and transmembrane G protein coupled
inverse agonists receptors (5 subtypes)
 M1 - found in the autonomic
THE SYMPATHETIC RECEPTORS AND SUBTYPES ganglia and CNS
 M2 - supraventricular parts of the
Norepineprine (noradrenergic) receptors heart
 Alpha receptors are found in smooth  M3 – smooth muscles and glands,
muscles and glands and on endothelial cells in the
 Alpha1are postsynaptic receptors vasculature.
which are excitatory  M1 and M3 receptors generally mediate
 Alpha2 are presynaptic receptors excitatory responses in effector cells.
that cause feedback inhibition on  M1 receptors promote
the release of NE depolarization of postganglionic
 Beta receptors autonomic nerves, and
 Beta1 are excitatory to the heart and  M3 receptors mediate contraction
fat cells of all smooth muscles and
 Beta2 are inhibitory to smooth increased secretion in glands,
muscles and glands except for the effect of ACh on
blood vessels. Ach causes
α1 (alpha 1) vasodilation and decreased blood
 vascular smooth muscle, genitourinary pressure. This is mediated by an
smooth muscle, liver (contraction) effect of ACh on the endothelial
 intestinal smooth muscle (hyperpolarization cells of the vasculature.
and relaxation)  Postganglionic parasympathetic fibers
 heart (increased contractile force, innervating heart, smooth muscle and
arrhythmias) exocrine glands
α 2 (alpha 2)  Exception: postganglionic sympathetic fibers
 pancreatic islets (b cells, decreased insulin innervating sweat glands
secretion)  Effects Blocked by antimuscarinic agents
 platelets (aggregation) (e.g., atropine)
 vascular smooth muscle (contratin)
β 1 (beta 1) THE ANS DRUGS
 heart (increased force and rate of The Sympathetic Drugs
contraction, AV nodal conduction velocity)
 juxtraglomerular cells (increased renin  Adrenergic Agonists (Sympathomimetic)
secretion)  Direct acting
β 2 (beta 2)  Mixed alpha and beta (NE, EPI)
 smooth muscle (vascular, bronchial,  Alpha2 selective (clonidine)
gastrointestinal, genitourinary) {relaxation}  Beta2 selective (terbutaline,
 skeletal muscle (glycogenolysis; uptake of K- isoproterenol)
+
)  Indirect acting – (amphetamine, cocaine)
 liver (glycogenolysis; gluconeogenesis)  Dual-acting – (ephedrine)
THE PARASYMPATHETIC RECEPTORS AND  Adrenergic Antagonists (Sympatholytic)

SUBTYPES  Alpha blockers
 Acetylcholine (cholinergic) Receptors  Nonselective (phenoxybenzamine,
 Nicotinic phentolamine)
 Nicotinic receptors are ligand-gated ion  Selective alpha1 (prazosin)
channels  Beta blockers
 Nicotinic muscle-subtype found in the  Nonselective (propanolol)
NM junction  Selective beta1 (metoprolol)
 Nicotinic neuronal-subtype in the
autonomic ganglia STRUCTURE-ACTIVITY RELATIONSHIPS OF
 Classically a biphasic response is observed SYMPATHOMIMETIC DRUGS
with stimulation at low doses and inhibition
at high doses  Substitution of the benzene ring
 Sympathetic and parasympathetic autonomic  Substitution of hydroxyl groups at the 3-
ganglia and the adrenal medulla and 4-positions of the benzene ring
 Effects blocked with ganglionic blockers (e.g., converts benzene to catechol, and thus
trimethapahan, hexamethonium) the dihydroxylated phenylethylamine
 Neuromuscular junction of skeletal muscle compounds are known as catecholamines
with maximal α and β effects.
AUTONOMIC DRUGS
 Absence of one or the other substituent

particularly at the 3-position causes
marked diminution in potency. α effect is
decreased a 100-fold and β effect is
negligible.
 Substitution of hydroxyl groups at the 3-
and 5-positions of the benzene ring
imparts β2 selectivity
 Unsubstituted benzene ring

 The catecholamines are primarily
metabolized by COMT. Loss either of the
two hydroxyl groups enhances oral
effectiveness and duration of action
because the drug is no longer metabolized
by COMT. It also causes increased CNS
effects.
 Noncatecholamines (also called
sympathomimetic amines) are primarily
metabolized by MAO.
 Substitution at the α carbon
 Noncatecholamines that have a
substituted α-carbon have a longer
duration of action because they are not
metabolized by either COMT or MAO.
 Substitution at the β carbon
 Typical of direct acting agonists,
important for storage of
sympathomimetic amines in neural
vesicles
 Substitution at the amine side chain
 Substitution of bulky structures to the
catecholamine amino group increases
β2-selectivity, decreases affinity for α-
receptors, and protects against
metabolism by COMT.
 Epinephrine – 1 methyl
substituent
 Isoproterenol – 2 methyl
substituents
 Terbutaline – 3 methyl
substituents
The Parasympathetic Drugs

 Cholinergic Agonists (parasympathomimetic)
 Direct-acting muscarinic
- Naturally occurring alkaloids
(muscarine, arecoline,
pilocarpine)
- Synthetic alkaloids (carbachol
betanechol)
 Indirect-acting muscarinic (AchE
inhibitors)
- Short Acting (edrophonium)
- Medium Acting (neostigmine,
physostigmine)
- Long Acting
(organophosphates)
 Direct Acting Nicotinic depolarizing
NMB
 Cholinergic Antagonists (parasympatholytic)
 Antimuscarinic – belladona alkaloids
 Antinicotinic – nondepolarizing NMB
and ganglionic blockers

AUTONOMIC DRUGS
ADRENERGIC AGONISTS (SYMPATHOMIMETIC DRUGS)
Drug Mechanism of Action Indications
Act directly on both alpha and beta Used in asthma and other allergic diseases; it
Epinephrine
receptors relaxes airways and reduces swelling
Pseudoephedrine Used as treatment for rhinitis and colds as a
Causes release of noradrenaline
decongestant
Acts directly on alpha receptors.
Phenylephrine Used as decongestant in rhinitis and colds
Selective alpha 1 agonist
No longer used clinically except for treatment
Causes accumulation of
Amphetamines of narcolepsy and attention deficiency
noradrenaline at the synapses
hyperkinesis
Acts indirectly on both alpha and Used as vasopressor
Ephedrine beta receptors. Causes release of
endogenous catecholamines
Used as a bronchodilator in asthma and as a
Terbutaline Selective beta 2 agonist
tocolytic agent in premature labor.
Clonidine Selective alpha2 agonist Used for the treatment of hypertension.
Dopamine alpha1 agonist with Used for hemodynamic support in patients
Dopexamine
beta2 agonist activity with low cardiac output as in heart failure
ADRENERGIC ANTAGONISTS (SYMPATHOLYTIC DRUGS)

Reserpine Blocks the synthesis and Used in the management of some types of
storage of norepinephrine hypertension. Sedation is a side effect.
Phenoxybenzamine Noncompetitively blocks alpha Used in the management of malignant
receptors hypertension secondary to pheochromocytoma.
Phentolamine Competitively blocks alpha Used for the management of malignant
receptors hypertension during operations for
pheochromocytoma
Prazosin Selectively blocks alpha 1 Used in the management of some types of
receptors hypertension. No reflex tachycardia and
postural hypotension.
Propanolol Nonselectively blocks beta Used in hypertension, angina, migraine
receptors headaches and mitral valve prolapse.
Metoprolol Selectively blocks beta 1 Predominant effects are cardiac
receptors
Metoclopramide Selectively blocks dopamine2 Used as a powerful antiemetic; acts by
receptors increasing lower esophageal sphincter pressure
and increasing the rate of gastric emptying
CHOLINERGIC AGONISTS (PARASYMPATHOMIMETIC DRUGS) At Muscarinic Sites

Acetylcholine Acts directly on muscarinic receptors Used as eye drops in Ophthalmology to
constrict the iris of the eye.
Pilocarpine Acts directly on muscarinic receptors Used as eye drops in ophthalmology to
constrict the iris of the eye. Used in the
treatment of acute angle closure glaucoma
Betanechol Acts directly on muscarinic receptors Used for the treatment of GI and bladder
atony.

AUTONOMIC DRUGS
CHOLINERGIC AGONISTS (PARASYMPATHOMIMETIC DRUGS) At Nicotinic Sites

Acts directly on nicotinic NMJ
receptors. Causes continuous
stimulation of nicontinic NMJ
Succinylcholine Depolarizing NMJ blocker
receptors. Fasciculations
followed by paralysis is a
hallmark.
Acetylcholinesterase Acts indirectly on nicotinic receptors. Causes inhibition of
Inhibitors acetylcholinesterase, thereby increasing acetylcholine that stimulates
nicotinic NMJ receptors.
a. Quaternary ammonium
Used as a diagnostic aid in myasthenia
compounds Short-acting reversible
gravis.
Endrophonium
b. Carbamates
Used to reverse nondepolarizing NMJ
neostigmine, Moderately reversible
blockers.
physostigmine
c. Organophosphates Irreversible Used as insecticides. Poisoning with
organophosphates is treated with
anticholinergic drugs.
CHOLINERGIC ANTAGONISTS (PARASYMPATHOLYTIC DRUGS) At Muscarinic Sites

A. Tertiary Tertiary Compounds are lipid-soluble and can easily penetrate the brain.
1. Naturally-occuring alkaloids
a. Atropine Acts directly as competitive Used as anticholinergic agent to reduce
antagonist at muscarinic salivation, increase heart rate, decrease gastric
receptors. motility, cause mild bronchodilatation, and in
the treatment of organophosphate poisoning.
b. Scopolamine Acts directly as competitive Same as atropine, but with more central effect,
antagonist at muscarinic may cause mild sedation.
receptors.
2. Synthetic esters
a. Dicyclomine Acts directly as competitive Same as atropine
antagonist at muscarinic
receptors
B. Quaternary Quaternary compounds are water-soluble and do not penetrate the CNS well
Acts directly as competitive Used as mild bronchodilator in asthma therapy
a. Ipratropium antagonist at muscarinic
receptors
Acts directly as competitive Used as an antispasmodic by decreasing gastric
b. Propantheline antagonist at muscarinic motility
receptors
Acts directly as competitive Used as preoperative medication to reduce
c. Glycopyrrolate antagonist at muscarinic salivation and maintain heart rate during
receptors surgery
CHOLINERGIC ANTAGONISTS (PARASYMPATHOLYTIC DRUGS) At Nicotinc Sites

Nondepolarizig NMJ Competitively inhibits Causes nondepolarizing block of the NMJ. Block
blockers (Gallamine, acetylcholine at nicotinic NMJ can be reversed by increasing the amount of
Pancuronium, receptor sites acetylcholine at the NMJ
Atracurium,
Vecuronium,
Rocuronium)

REVIEW TEST
NSAID
____10. A drug with analgesic and antipyretic
Choose the best answer: properties but devoid of anti-inflammatory effects
A. etoricoxib
____1. A uricostatic medication that is not B. acetaminophen
recommended for acute attacks of gout C. aspirin
A. diclofenac D. Ibuprofen
B. allopurinol
C. colchicine ____11. Among the NSAIDS, aspirin is unique
D. prednisone because it
A. irreversibly inhibits its target enzyme
____2. Drug indicated for the acute attacks of gout B. prevents episodes of gouty arthritis
A. diclofenac C. reduces fever
B. prednisone D. selectively inhibits COX-2 enzyme
C. allopurinol
D. colchicine ____12. Patient characteristic that is the most
compelling reason for avoiding the use of celecoxib
____3. Patients with gouty nephropathy will benefit in the treatment of arthritis
from this alternative drug that decreases uric acid A. History of peptic ulcer disease
A. allopurinol B. History of myocardial infarction
B. colchicine C. History of gout
C. methyprenisolone D. History of alcohol abuse
D. feboxustat
____13. Celecoxib is an analgesic that
____4. The preferred drug for osteoarthritic pain in A. Reversibly inhibits COX-1 and COX-2
an elderly patient who also presents with gastritis. B. Reversibly inhibits COX-2
A. ibuprofen C. Irreversibly inhibits both COX-1 and
B. acetaminophen COX-2
C. celecoxib D. Irreversibly inhibits COX-3
D. aspirin
____14. The most likely cause of death associated
____5. DMARDs used to reduce inflammation and to with acetaminophen overdose is
decrease joint damage in rheumatoid arthtitis A. arrhythmia
A. gold B. hemorrhagic stroke
B. metothrexate C. respiratory failure
C. sulfasalazine D. hepatic failure
D. hydroxychloroquine
____15. Action of aspirin on platelets
____6. The preferred drug for closure of Persistent A. Duration of effect is reversible in 1-2
Ductus Arteriosus days
A. ibuprofen B. Blocks PGE2
B. indomethacin C. Reversibly inhibits platelet COX-1
C. aspirin D. Blocks Thromboxane A2
D. acetaminophen
____16. Advantage of giving a COX-2 selective
____7. COX-2 selective and non-selective NSAIDS inhibitor with an opiate in severe pain
share this untoward side effect A. Analgesic effect of both drugs is
A. antiplatelet effects decreased
B. gastric mucosal effects B. Side effect of both drugs is decreased
C. renal effects C. Dose and side effect of COX-2 selective
D. hepatic effects inhibitor is increased
D. Dose and side effect of opiate is
____8. A uricosuric drug that acts on the kidneys to decreased
help the body eliminate uric acid
A. probenecid ____17. Overdose of aspirin can be treated by
B. feboxustat A. Induce vomiting
C. allopurinol B. Alkalinization of the urine increases the
D. prednisone rate of excretion
C. Enhanced hydrolysis
____9. Celecoxib is an analgesic that D. Increase the albumin concentration in
A. Reversibly inhibits COX-1 and COX-2 the plasma
B. Irreversibly inhibits both COX-1 and COX-
2
C. Reversibly inhibits COX-2 only
D. Irreversibly inhibits COX-3

REVIEW TEST
____18. Drug interaction between opiates and

NSAIDs in the treatment of pain
A. additive
B. potentiation
C. synergism
D. antagonism
____19. A drug that predisposes to Reye’s

Syndrome when given to children with viral
infections
A. acetaminophen
B. aspirin
C. Ibuprofen
D. celecoxib
____20. Treatment for paracetamol overdose

A. ammonium chloride
B. naloxone
C. sodium bicarbonate
D. n-acetylcysteine

PSYCHOPHARMACOLOGY
ALEJANDRO C. BAROQUE II, MD
PSYCHOPHARMACOLOGY Receptor Binding Profile of Low Potency

Antipsychotics
PSYCHOPHARMACOLOGIC AGENTS:  Mesolimbic Pathway
o Antipsychotics o Antipsychotic effect
o Antidepressants o Efficacy on positive symptoms
o Mood stabilizers o Efficacy on agitation
o Sedative-hypnotics  Mesocortical Pathway
o Heightened Negative Symptoms
ANTIPSYCHOTICS  Nigrostriatal Pathway
 drugs that reduce psychotic symptoms seen in o Extrapyramidal movement disorders
variety of conditions including: schizophrenia, (EPS), (dystonia, parkinsonism,
bipolar disorder, psychotic depression, senile akathisia, tardive dyskinesia)
psychoses, various organic psychoses  Tuberoinfundibular Pathway
o Endocrine changes (prolactin
Schizophrenia – model for psychosis; elevation causing galactorrhoea,
conglomeration of positive and negative symptoms gynecomastia, menstrual changes,
sexual dysfunction)
Dopamine Hypothesis of Schizophrenia
 neurotransmitter-based concept to be developed High potency Antipsychotic
that explains the major aspect of schizophrenia  (ex. Haloperidol) are more likely to cause
(positive and negative symptoms) and also the parkinsonian adverse effects
mechanism of action of APs Low potency Antipsychotic
 Excessive limbic dopaminergic activity: produces  (ex. chlorpromazine) are more likely to
psychosis interact with nondopaminergic receptors
o Dopamine Overactivity in the Mesolimbic
Pathway = Positive Symptoms Serotonin-Dopamine Antagonist Mechanism of
o Dopamine Deficiency in the Mesocortical Action
Pathway = Negative Symptoms  Serotonin opposes the release of dopamine
 The clinical potency of antipsychotic drugs is in the nigrostriatal, tuberoinfundibular,
related to their binding to post-synaptic D2 mesocortical pathways
receptors in the CNS o Leads to less adverse effects due to
dopamine deficiency in these
4 Dopamine Pathways in the CNS pathways caused by typical
 Nigrostriatal antipsychotics
 Mesolimbic  D2 Blockade in the mesolimbic pathway
 Mesocortical o Antipsychotic efficacy
 Tuberoinfundibular
Third Generation Atypical Antipsychotic
2 Classes of Antipsychotics  D2 receptor partial agonist
 Typical/Conventional/First Generation
 Atypical Antipsychotics: Pharmacokinetics
o Second Generation /Serotonin-  Readily but erratically absorbed – oral
Dopamine Antagonist (SDA)  First-pass effect
o Third Generation  High plasma protein binding: 92 – 99%
 High lipid solubility
Typical Antipsychotics  High volumes of distribution >7 L/kg
 Phenothiazines – chlorpromazine,  Long clinical duration of action is related to
thioridazine, trifluoperazine prolonged D2 receptor occupancy in the
 Butyrophenones – haloperidol brain
 Thioxanthenes – thiothixene  Injectable preparations may have prolonged
actions for several months
2nd Generation Atypical  Completely metabolized - microsomal P450
 dihydroindolones - ziprazidone enzymes (CYP2D6, CYP1A2, CYP3A4)
 dibenzoxazepines - loxapine  Typical doses do not interfere with
 dibenzodiazepines - clozapine metabolism of other drugs
 benzisoxazole – risperidone, paliperidone
 arylpiperidylindole – sertindole Antipsychotics: Pharmacodynamics
 thienobenzodizepines - olanzapine  Efficacy is related to D2 blocking effects and
 dibenzothiazepine – quetiapine adverse effects are secondary to blockade of
 benzamide – sulpride, amisulpiride variety of receptors: α adrenoreceptors,
muscarinic H1 receptors and 5HT2 (see
3rd Generation Atypical table)
 dihydrocarbostyril – aripiprazole  D2 blockade reduce production of cAMP by
Clinical Implications of D2 Receptor Blockade in the adenyl cyclase and production of secondary
Different Dopamine Pathways messengers in the mesolimbic pathway.

PSYCHOPHARMACOLOGY
 In vivo imaging:
o Antipsychotic effects: 60% receptor
occupancy, > 80% EPS
o This level is not required for atypical
APs (~30-50%) due to their effect
on 5-HT2A
Generic name (class) Dose D2/ Histamine EPS Anticholinergic α-1
equivalent in 5HT2A blockade blockade
mg
Chlorpromazine 100 ++++ ++++ ++ +++ ++++
(Phenothiazines,
alipathic)
Thioridazine 100 ++++ ++++ + ++++ ++++
(Phenothiazines,
piperidine)
Triflupromazine 25 ++++ +++ ++ +++ ++
(Phenothiazines,
aliphatic)
Clozapine 50 + +++ 0 ++++ +
(Dibenzodiazepine)
Quetiapine 150 + ++ 0 ++ +
(Dibenzothiazepine)
 Aripiprazole has a very high D2 receptor
occupancy, but it does not cause EPS being
a partial D2 agonist and also with high 5-
HT2A antagonism and 5-HT1
partial agonism
Receptor Binding Profile of High Potency

Antipsychotics
Generic name (class) Dose D2/ Histamine EPS Anticholinergic α-1

equivalent in 5HT2A blockade blockade
mg
Perphenazine 10 ++++ +++ +++ ++ +++
(Phenothiazines,
piperazine)
Trifluoroperazine 5 ++++ + +++ ++ ++
(Phenothiazines,
piperidine)
Haloperidol 2 +++ + ++++ + +
(Butyrophenone)
Fluphenazine 2 ++++ ++ ++++ ++ ++
(Phenothiazine,
piperazine)
Risperidone 2 + ++ + ++ +++
(Benzosoxazole)
Aripirazole 10 +++ + 0 + +
(Dihydrocarbostyril)

PSYCHOPHARMACOLOGY
Receptor Binding Profile of Antipsychotics
Receptor Positive Negative

D2 antagonist Efficacy on positive symptoms EPS; prolactin increase; cognitive side
effects; worsen negative symptoms
D3 antagonist D3 antagonists enhance cognition; inhibit -
EPS; not antipsychotic
D4 antagonist Improve cognition? No EPS Several D4 failed in clinic
5-HT 1A agonist Less EPS; some anxiolytic effect; improve
cognition; reduce weight gain
5-HT 2A antagonist Efficacy contribution negative sx; some
anxiolytic effect; less EPS
α1-NA antagonist - Orthostatic hypotension; sedation, rhinitis;
dry ejaculation
Histamine antagonist - Sedation; weight gain
Muscarinic antagonist M2 antagonists treat EPS; Cognitive deficit; confusion; dry mouth;
(anticholinergic) constipation, blurred vision, urinary
retention

PSYCHOPHARMACOLOGY
Antipsychotics: Clinical Indications ANTIDEPRESSANTS

 Psychotic Disorder  Monoamine Hypothesis of depression
o Schizophrenia o Depression caused by perturbations of
o Schizoaffective Disorder
serotonin (5-HT), norepinephrine and
o Schizophreniform Disorder
o Brief reactive psychosis dopamine transmission
o Mood Disorder with Psychotic features
Antidepressant Drugs
o Delusional disorder
 Potentiates monoamine neurotransmission
o Psychosis associated with organic brain
 Inhibition of NT reuptake (SERT, NET or both)
disease
 Inhibition of NT metabolism (MAOIs)
 Blockade of presynaptic inhibitory receptors
 Non-psychotic disorders
 Blockade of postsynaptic receptors
o Behavioral and Psychological Symptoms of
Dementia
Classes of Antidepressant Drugs
o Gilles dela Tourette
 Reuptake Inhibitors
o Tetanus
 Enzyme Inhibitors
o Antiemetic
 Receptor Blockers
o Intractable cingultus
 Multimodal Antidepressants
o Pre-operative medication
o Mood disorder
I. Reuptake inhibitors
 Tricyclic antidepressants (TCA)
Antipsychotics: Contraindications
o amitriptyline, dothiepen, trimipramine,
 Depressed sensorium
clomipramine, imipramine
 Parkinsonism
 Selective serotonin reuptake inhibitor (SSRI)
 Pregnancy
o citalopram, escitalopram, paroxetine,
 Respiratory depression
fluoxetine, sertraline
 Medically ill geriatric patients
 Noradrenaline reuptake inhibitor (NARI)
o raboxetine, atomoxetine
Antipsychotics: Non-Neurologic Adverse Effects
 Selective serotonin & noradrenaline reuptake
 Sedation
inhibitor (SNRI)
 Orthostatic hypotension
o venlafaxine, desenlafaxine, duloxetine
 Peripheral anticholinergic responses
 Noradrenaline & dopamine reuptake inhibitor
 Central anticholinergic reactions
(NDRI)
 Endocrine effects
o bupropion
Antipsychotics: Neurologic Adverse Effects
Tricyclic Antidepressants
 Epileptogenic
 Advantages
 Dystonias
o Equal or greater efficacy than the SSRIs
 Parkinsonism
o Mechanism via NE and 5-HT
 Akathisia
o Proven efficacy in pain symptoms
 Tardive dyskinesia
 Disadvantages
o Late-occuring abnormal choreoathetoid
o Poor receptor site selectivity
movements seen in 20-40% of patient who
 Alpha-Adrenergic blockade:
are chronically treated; lower rate with
hypotension
atypical APs
 Anticholinergic side effects:
Mechanism: relative cholinergic deficiency
tachycardia, dry mouth, urinary
due to supersensitivity of dopamine
retention
receptors in the caudate-putamen
 Antihistaminic side effects: sedation,
 Neuroleptic Malignant Syndrome
increase in weight
o Life-threatening complication of AP use
o Cardiotoxicity in overdose
resulting from extreme sensitivity with the
EP effects of APs manifesting as marked
SSRIs
rigidity, rapid rise in temperature, autonomic
 Advantages
instability, and elevated muscle CK
o Improved tolerability compared to TCAs
o Treatment
 Disadvantages
 Anti-Parkinson drugs
o Lower remission rate than with dual acting
 Muscle relaxants
agents
 Dopamine agonists
o Weight gain and sexual side effects
 Physical cooling
o Questionable efficacy on painful physical
 Switching to atypical APs
symptoms of depression

PSYCHOPHARMACOLOGY
SNRIs Antidepressants: Adverse Effects

 Advantages
o Dual action on both 5-HT and NE  Common to all AD: Increased risk of suicidality
o Newer SNRIs has balanced (duloxetine) o Under age 25
o Higher reported remission rates than SSRIs o Suicidal ideation and gestures 2x more than
 Disadvantages placebo
o Old SNRIs are less balanced (venlafaxine) o Some minority, experience treatment
o Titration may be necessary to achieve emergent increase in suicidal ideation with
optimal therapeutic effects AD
o Adverse events may be increased by
titrating to higher doses (e.g., nausea)  SSRIs:
o GIT symptoms early in the course, improve
II. Enzyme inhibitors after first week
 Monoamine oxidase inhibitor (MAOI) - o Diminished sexual function
isocarboxazid, phenelzine, tranylcypromine o Headache
 Reversible inhibitor of MAO-A (RIMA) - o Insomnia or hypersomnia
moclobemide o Discontinuation syndrome
III. Mix Receptor Blockers  SNRIs

 Noradrenergic & specific serotonin o Noradrenergic effects:
antidepressant (NaSSA) – mirtazapine, o Increased BP, heart rate
mianserin o CNS activation: insomnia, anxiety and
 Serotonin antagonist & reuptake inhibitor (SARI) agitation
– trazodone, nefazodone o Discontinuation syndrome
 Noradrenaline & dopamine reuptake inhibitor
(NDRI) – bupropion  TCAs
o Anticholinergic effect
IV. Multimodal Antidepressant o Alpha blocking property: orthostatic
 Vortioxetine hypotension
 MOA: o H1 antagonism: sedation and weight gain
o Inhibits serotonin re-uptake
o Agonist at serotonin receptor 1A  MAOIs
o Partial agonist at serotonin receptor o Orthostatic hypotension, weight gain,
1B highest sexual effects of all
o Antagonist at serotonin receptors o Anorgasmia is common with therapeutic
1D, 3, 7 doses
 Advantages o Amphetamine like effects in some agents
o Can be stopped without gradual o Dangerous drug and food interaction (block
removal metabolism of tyramine)
o Proven efficacy in cognitive o Sudden discontinuation syndrome
symptoms (psychosis, excitement and confusion)
o No clinically relevant weight change
o Placebo level sexual side effects  NaSSA
o Mirtazapine: highly sedating (potent H1
Antidepressants: Pharmacokinetics blocking effects)
 Most are fairly rapidly absorbed
 Peak plasma: 2-3 hours  Vortioxetine
 Tightly plasma bound o Nausea, headache
 Hepatic metabolism
 Renally cleared Serotonin Syndrome
 Slight variation in PK properties per class  Excessive serotonin level that leads to mental
status changes, neuromuscular hyperactivity and
FDA Approved Indications autonomic instability
 Depression  Often caused by combinations of SSRIs with
 Anxiety Disorder other proserotonergic agents
 Obsessive-compulsive disorder
 Posttraumatic stress disorder BENZODIAZEPINES
 MOA: enhance GABA mediated synaptic
 Premenstrual syndrome inhibition
 Eating disorders (Fluoxetine)  Well absorbed after oral administration
 Pain disorders (TCA, SNRI)  Concentrations in plasma usually maximal in 1-4
 Enuresis in children hours
 Vasomotor symptoms in perimenopausal  Hepatic metabolism accounts for clearance of all
syndrome (SSRI, SNRI) benzodiazepines
 Smoking cessation (bupropion)

PSYCHOPHARMACOLOGY
 Many of the metabolites of benzodiazepines are

pharmacologically active, some with long half-
lives
 Limitations
 Pronounced sedation
 Development of tolerance
 Adverse Effects
 Drowsiness, dizziness and lethargy
(tolerance with continued administration)
 Muscular incoordination, ataxia, dysarthria
 Cardiovascular and respiratory depression
with IV administration
 In children, behavioural disturbances such
as aggression, hyperactivity, irritability
Diazepam
 N-desmethyldiazepam, major metabolite that is

less active than parent drug and may behave as
partial agonist
 Widely distributed to tissues
 Plasma protein binding 99%
 Effective agent for status epilepticus (given IV)
but has short duration of action due to rapid
redistribution of the drug from the brain; rectal
administration possible
 Immediate onset of action within 2-6 mins with
parenteral administration
Not useful as an oral agent for treatment of seizure
 disorder
Clonazepam
 Useful in the therapy of myoclonic seizures,

absence and infantile spasms
 Only oral preparation available
Lorazepam
 Rapidly and extensively distributed to tissues

 Less lipid-soluble than diazepam, with a
distribution half-life of two to three hours versus
15 minutes for diazepam and binds GABA
receptor more tightly
 longer duration of clinical effect.

PSYCHOPHARMACOLOGY
CYCLIC AND RELATED ANTIDEPRESSANTS
Generic name Dopamine Ach blockade Histamine α blockade

reuptake blockade blockade
Amitriptyline 1 4 3 3
Cloimipramine 1 2 0 2
Doxepine 0 3 4 3
Imipramine 0 3 2 3
Trimipramine 0 3 4 3
Desipramine 0 2 1 2
Nortriptyline 0 2 2 1
Proptriptyline 0 3 2 2
Maprotiline 1 2 3 2
Brupropion 2 1 1 1
Trazodone 0 0 1 3
Amoxapine 1 1 2 2
Fluoxetine 1 1 0 1
Paroxetine 1 2 0 1
Sertraline 1 1 0 1
Venlaflaxine 0 0 0 1

MOOD STABILIZERS
MOOD STABILIZERS  Benzodiazepines (BZ)

 Barbiturates (BB)
Bipolar Disorder  Newer hypnotics (ZZ)
 Indication of mood stabilizers
 Biological substrate Graded dose-dependent depression of the CNS
o Abnormal neurotransmission  Show linear relation
o Altered intracellular signal transduction  BZ and ZZ require higher graded dose
o Altered gene expression increments to produce depression more
o Chronic neuronal damage profound than hypnosis
Mood Stabilization Chemical Classification: Sedative-Hypnotics

 Amelioration of affective and psychotic  Benzodiazepines
symptoms during acute manic episodes o Alprazolam, clonazepam, estazolam,
 Improvement in depression episodes during midazolam
acute bipolar depressive episodes o enhance GABAergic synaptic transmission
 Prevention of future mood episodes with resulting to increased chloride conductance
sustained treatment at therapeutic levels by increasing frequency of channel-opening
(prophylactic benefit)  Barbiturates
o Phenobarbital, pentobarbital, secobarbital
Mood Stabilizers o increase duration of chloride channel
 Lithium opening. At high dose, it is GABA-mimetic
 Antiepileptics - CBZ,oxCBZ, lamotrigine, valproic (directly opening the channel)
acid, gabapentin, topiramate  Newer drugs – mainly for sleep disorders
 Atypical antipsychotics – quetiapine, olanzapine, (hypnotics); structurally unrelated to BZ but with
ziprazidone, risperidone, aripiprazole (FDA similar mechanism of action
approved) o Zolpidem, zaleplon, eszopiclone, zopiclone
cyclopyrrolone, ramelteon
Lithium
 Inhibit 2 signal transduction pathways Pharmacokinetics
o Suppress inositol signaling – depletion of  Absorption and Distribution
intracellular inositol. Lithium depletes all are rapidly absorbed and mostly lipophilic
inositol-1,4,5-triphosphate (IP3) and  all S-H cross the placenta and breast milk
diacylglycerol (DAG) through depletion of (contribute to fetal depression)
precursors in the membrane: free inositol
and phosphatidylinositol-4,5-biphosphate Biotransformation
(PIP2), as well as other intermediates  metabolic transformation to more water-soluble
o Inhibition of glycogen synthase kinase-3 metabolites
(GSK-3) a multi-function protein kinase  liver microsomal drug-metabolizing enzyme
 Monovalent ion systems
 Complete absorption within 6-8 hours o BZ - All undergo hepatic metabolism
 Peak plasma: in 30min to 2 hours (CYP3A4); some metabolites (metabolically
 Some sequestration to bone active) with long half-lives (e.g.
 Target plasma concentration is 0.6 – 1.4 mEq/L desmethyldiazepam, t ½ 40 hours)
 NOT bound to plasma proteins o BB - Insignificant quantities are excreted
 NO metabolism unchanged (except PB)
 Eliminated entirely through renal route  Major pathway: oxidation by hepatic
 Adverse effects enzymes to form alcohols, acids and
o Nausea, vomiting, diarrhea ketones (as glucoronides in the urine)
o Weight gain & edema  Hepatic metabolism is generally slow
o Tremors (except thiobarbital)
o Fatigue  t ½: generally long, e.g. phenobarbital
o Mild cognitive impairment (PB) - 4-5 days
o Polyuria & polydipsia Goiter & o Newer hypnotics (ZZ)
hypothyroidism  Short half-life with rapid time to peak,
o T-wave flattening rapid metabolism in the liver by hepatic
o Alopecia, worsens psoriasis, acneiform CYP3A4
rashes Excretion
o Ebstein’s anomaly  Conjugated metabolites (Phase I) are excreted
in the kidneys
SEDATIVE HYPNOTIC (S-H) DRUGS o PB excreted unchanged in the urine (20-
30%)
 Sedative -anxiolytic, calming effect o Increased significantly by alkalization of the
 Hypnotic - produce drowsiness; encourage urine (pKa 7.4)
onset and maintains sleep

MOOD STABILIZERS
Factors affecting Biodisposition Drug Interaction

 Hepatic function  Additive effect with use of other CNS
 Age depressants: alcohols, opioids, anticonvulsants,
 Auto-induction of hepatic metabolism antihypertensives, phenothiazines and TCAs
Tolerance and dependence

 Tolerance
o refers to decreased responsiveness to a
drug following repeated exposure
 Dependence
o Psychological
 secondary to neurotic behavior
o Physiologic
 altered physiologic state that requires
continuous administration of the drug to
prevent abstinence and withdrawal
syndrome
 Withdrawal syndrome -
characterized by increased anxiety,
insomnia, excitability to convulsions
commonly seen with abrupt
withdrawal of the drug
Therapeutic Indications of S-H Drugs

 Treatment of Anxiety states
 Treatment of Sleep disorders
 Other indications
o Premedication for surgical anesthesia
(sedative and amnesic effect)
o Alcohol withdrawal
o BZ are useful in treatment of central origin
spasticity
o Other uses of BZ in psychiatry include initial
treatment of mania and other drug-induced
hyperexcitability
Adverse Effects of S-H Drugs

 Direct Toxic Action
o Dose related CNS depression
 Drowsiness
 Impaired judgment
 Diminished motor skills - FDA warning
 Sleep driving and somnambulism – FDA
warning
o Dose related anterograde amnesia
 Impaired ability to learn new
information
 Intact retrieval of old learned memo
 Useful in premedication with
uncomfortable clinical procedures
 Criminal use: “date rape” drug
o S-H are the most common cause of acute
confusional states in elderly
o Exacerbate chronic obstructive pulmonary
disease
o Disinhibitory reactions
 Others
o Hypersensitivity reactions
o Teratogenicity
o Barbiturates - exacerbate intermittent
porphyria

REVIEW TEST
PSYCHOPHARMACOLOGY ____6. If an information stating that there were

distinct periods of hearing demeaning voices
Choose the best answer: interspersed with the symptoms presented in
this recent episode, which of the following
____1. Which of the following molecular targets diagnostic classification will be considered?
for interventions in psychiatric models of A. dysthymic disorder
biological illnesses will prove to be the least B. unipolar depression or major
pharmacologically rational? depressive disorder
A. blockade of substrate C. double depression
transportation D. bipolar mood disorder with
B. inhibition of transporter proteins psychotic features
C. those that will block the
presynaptic channels ____7. Which of the following clinical conditions
D. degradative enzyme inhibitors will not be responsive at all to antidepressant
medications?
____2. Quetiapine has which of the following A. generalized anxiety disorder
specific mechanisms of action associated with B. mood disorder – unipolar
2nd generation antipsychotic? C. mood disorder – bipolar
A. readily dissociating D2 antagonist D. acute panic disorder
B. partial D2 agonist
C. tightly D2 binding antagonist ____8. Which of the following will discriminate
D. D2 transporter protein inhibition major depressive disorders from dysthymic?
A. sadness
Case: A 23-year-old female medical student has B. feelings of self- pity and guilt
been up and awake all night for the past several C. disturbance in activities of daily
days saying she’s got full of energy. She’s been living
very talkative jumping from one topic to the D. hopelessness
other with grandiose thought contents that at
times are becoming impertinent. Her parents ____9. The pharmacodynamic properties of
have to settle six figure credit card current debts tricyclic antidepressants are contraindicated in
on account of the patient’s just recent which of the following clinical conditions?
department store purchases. Personal hygiene A. diabetic neuropathic pain
has not been attended to and she has not been syndromes
attending her classes. Parents were compelled B. attention deficit hyperactivity
to seek consultation because of disruptive disorder
behavior. C. benign prostatic hypertrophy
D. nocturnal enuresis
____3. Which of the following will be most
appropriate clinical impression of the case as ____10. Aripiprazole is an ideal atypical
presented? antipsychotic which has demonstrated efficacy
A. cyclothymic disorder for both positive and negative symptom
B. bipolar mood disorder schizophrenia due to which of the following
C. double depression mechanism of action?
D. bipolar mood disorder with A. dopamine 2 antagonism
psychotic features B. serotonergic antagonism
C. fast dissociating dopamine 2
____4. Which of the following pharmacologic antagonism
strategies have been demonstrated to provide D. partial dopamine agonism
control for the symptoms?
A. increase dopaminergic activity ____11. Negative, affective and cognitive
B. promote GABAergic symptoms are prominent manifestations for
C. increase synthesis of disturbance in which of the following
phosphokinase C enzymes dopaminergic pathways?
D. activated cytoplasmic GSK3 A. mesocortical
enzymes B. mesolimbic
C. nigrostriatal
____5. Which of the following class of mood D. tuberoinfundibular
stabilizing drugs will be the drug of choice?
A. mood stabilizer – lithium ____12. Which of the following core-symptom
carbonate domains of schizophrenia will flat affect, reduced
B. antipsychotic - quetiapine social interaction, anhedonia, avolition and
C. benzodiazepine - diazepam catatonia be described?
D. selective serotonin reuptake A. positive symptoms
inhibitor - escitalopram B. negative symptoms
C. cognitive symptoms
D. mood symptoms
REVIEW TEST
____13. An individual with schizophrenia when ____20. If a patient on the other hand is manic,
presenting with disorganised speech, the term which of the following clinical impressions can
'clanging' refers to which of the following? be conveniently eliminated?
A. individuals only communicate A. major depressive disorder
with words that rhyme B. cyclothymic disorder
B. answers to questions may not be C. bipolar I mood disorder
relevant D. bipolar II mood disorder
C. individuals communicate without
completing their sentences
D. speech may be neither structured
nor comprehensible
____14. Dry mouth, blurred vision, constipation

and urinary retention are side effects due to
blockade of:
A. 5HT1 serotoninergic receptors
B. Dopaminergic receptors
C. H1 histaminic receptors
D. Muscarinic-cholinergic
____15. The characteristic of “ATYPICALITY”

imparted on 2nd generation antipsychotics is/are
defined by which of the following?
A. partial receptor intrinsic activity
B. high affinity with D2 receptor
C. high ratio of 5-HT2A to D2
receptor affinity
D. all are correct
____16. Which of the following clinical

presentation of depression should be present,
out of the 5 required in the new DSM 5 criteria,
for at least the past 2 weeks?
A. insomnia
B. hopelessness
C. loss of interest or pleasure in
doing daily activities
D. recurrent thoughts of death
____17. Which of the following stressors have

been shown to be associated with the onset of
an episode of depression?
A. death of a spouse
B. losing a parent before the age
of 11
C. unemployment
D. frequent moving from one place
of residence to another
____18. Which of the following symptom

specifiers in depressive disorder is a poor
prognostic indicator and reflects a severe
disease?
A. atypical
B. chronic
C. melancholic features
D. psychotic features
____19. If the patient presents with depressive

symptoms, which of the following clinical types
of mood disorder can be entertained?
A. major depressive disorder
B. cyclothymic disorder
C. bipolar mood disorder
D. all are correct

ANTIPROTOZOAL DRUGS
ANTIPROTOZOAL DRUGS • Exoerythrocytic Phase : stage of

MALARIA development of malaria parasite within the
 Caused by Plasmodium sp. liver cells (P. vivax and P. ovale have
 Transmitted by the bite of an infected dormant stage for a fixed interval before
female Anopheles mosquito maturing to hepatic schizonts)
• Sporozoites : motile malaria parasites that
LIFE CYCLE OF MALARIA PARASITE are infective to humans, transmitted during
the blood-meal feeding of a female
Anopheles mosquito; they invade and reside
within the mosquito’s salivary glands where
they increase in numbers
• Hypnozoites : persistent liver stages of P.
vivax and P. ovale that remain dormant in
host hepatocytes for fixed interval before
maturing to hepatic schizonts; they burst
and release merozoites
• Merozoites : parasites released into the
bloodstream when a hepatic or erythrocytic
schizont bursts; they invade RBCs
• Schizonts : mature malaria parasites in host
liver cells or RBCs that are undergoing
nuclear division
• Gametocytes : sexual stages of malaria
parasites present in the host RBCs which are
infective to Anopheles mosquito
• Zygotes : formed within the gut of a
mosquito by fusion of ingested male and
female gametocytes; initiates the sexual
reproductive cycle (sporogony) which
produces the sporozoites that invade
humans via mosquito saliva
AIMS OF TREAMENT:
• To prevent and treat clinical attack of
malaria
• To completely eradicate the parasite from
the patient’s body
• To reduce the human reservoir of infection –
Courtesy of CDC cut down transmission
TREATMENT:
DEFINITION OF TERMS: Factors that influence treatment:
 Cure/Clinical Cure : elimination of malarial 1. Infecting Plasmodium species
symptoms caused by asexual erythrocytic stage 2. Clinical status of the patient
Radical Cure : elimination of malarial symptoms plus 3. Drug susceptibility of the infecting parasites as
prevention of relapse; can be achieved by determined by the geographic area where the
eliminating both erythrocytic and dormant hepatic infection was acquired
(exoerythrocytic) stages
• Recrudescence : recurrence of asexual ANTI-MALARIAL DRUGS:
parasitaemia after treatment of the infection with 1. Drugs used to treat acute attack
the same species of Plasmodium that caused the chloroquine, quinine, mefloquine,
original infection due to failure to completely halofantrine, lumefantrine, artemisinins,
eradicate the parasite because of resistance atovaquone, antifolates,
• Relapse : recurrence of asexual doxycycline/clindamycin (in combination
parasitaemia in P. vivax and P. ovale infections due with other agents)
to failure to eradicate the persistent hepatic stage 2. Drugs that effect radical cure
• Treatment failure : failure to clear malarial • primaquine
parasitemia and/or resolve clinical symptoms despite 3. Drugs used for chemoprophylaxis
the administration of an antimalarial drug • drugs given to individuals who intend to
• Chemoprophylaxis : prevention of the travel to malaria endemic areas
development of symptomatic malaria caused • chloroquine, mefloquine, atovaquone-
by asexual erythrocytic stage proguanil (malarone), doxycycline
• Pre-erythrocytic Phase : life cycle of malaria 4. Drugs used to prevent transmission
parasite when it first enter the host • primaquine & artemisinins(against all 4
• Erythrocytic Phase : stage of development sp.); chloroquine & quinine(against P.
of malaria parasite within the host RBCs vivax, P. ovale and P. malariae)
from the ring stage and before nuclear
division
ANTIPROTOZOAL DRUGS
CHLOROQUINE Mechanism of Action: acts by concentrating in

• Synthetic 4-aminoquinoline plasmodial food vacuoles preventing the
• Rapidly acting blood schizonticide polymerization of toxic free heme into harmless
against all 4 sp. hemozoin resulting in build-up of toxic free
• Moderately effective against P. vivax, P. heme that damages the parasite’s membrane
ovale and P. malariae gametocytes leading to its death
Mechanism of Action: acts by concentrating in Pharmacokinetics:

plasmodial food vacuoles preventing the Quinine:
polymerization of toxic free heme into harmless • Rapidly & almost completely absorbed
hemozoin resulting in build-up of toxic free from the GIT
heme that damages the parasite’s membrane • Peak plasma levels in 1-3h
leading to its death • Protein binding and half-life increase in
proportion to the severity of malaria
Pharmacokinetics: • High levels of alpha1-acid glycoprotein
• Rapidly & completely absorbed; peak produced in severe malaria may
plasma concentrations in 3h prevent toxicity
• Protein binding : 50 – 65% • Widely distributed to body tissues
• Extensively distributed to body tissues including CSF
• Very large Vd (100-1000L/Kg) • Metabolized in the liver via CYP3A4
• Slowly released from tissues and • Metabolites are excreted in the urine
metabolized in the liver within 24h
• Eliminated slowly via the kidneys • Half-life: 7-12h (healthy persons); 18h
• Initial half-life of 3-5 days and a (those with severe malaria)
terminal half-life of 1-2 months Quinidin: Has shorter half-life as a
result of lower protein binding
Therapeutic Indications:
• Drug of choice for the treatment of Therapeutic Indications:
non-falciparum and sensitive falciparum • Q/Q(parenteral) – treatment of severe
malaria falciparum malaria
• Chemoprophylaxis in malarious areas • Quinine- oral treatment of
without resistant falciparum malaria uncomplicated falciparum malaria in
• Treatment of amebic liver abscess that areas with documented chloroquine
failed initial metronidazole treatment resistance
• Treatment of rheumatic diseases as *Quinine is commonly used with a 2nd drug
DMARD (doxycycline or clindamycin) for a shorter
Adverse Effects: and better tolerated course of quinine
• Common – unpleasant taste, pruritus
• Uncommon - vomiting, urticaria, Adverse Effects:
blurring of vision • Common (at therapeutic doses) –
• Rare – impaired hearing, psychosis, tinnitus, headache, dizziness, vomiting,
seizures, hemolysis in those with G6PD flushing, visual disturbances
deficiency, QT interval prolongation (cinchonism)
• Long term/high dose – irreversible • Hypoglycemia at therapeutic doses
ototoxicity, retinopathy, peripheral • Hypersensitivity reactions - skin rash,
neuropathy, myopathy angioedema, bronchospasm, black-
*Considered safe in pregnancy and young water fever
children • Hematologic abnormalities: hemolysis in
Drug Interactions: G6PD deficiency
• Reduced absorption when given with • Quinine can stimulate mild uterine
antacids contractions esp. in the 3rd trimester of
• Increased risk of convulsions with pregnancy
mefloquine • IV Quinidine – thrombophlebitis, QTc
• Increased risk of arrhythmias with prolongation; too rapid - hypotension;
halofantrine and drugs that prolong the should be administered under cardiac
QT interval monitoring
Drug Interactions:
QUININE / QUINIDINE • Prolongation of QT interval when given
• Synthetic 4-quinoline methanol concurrently with or shortly after
• Rapidly acting blood schizonticides mefloquine administration
against all 4 sp. • Oral absorption decreased by aluminum-
• Gametocidal against P. vivax , P. ovale containing antacids
and P. malariae • Quinine increases plasma warfarin and
• Quinidine is more potent as an digoxin levels
antimalarial but more toxic than quinine • Antagonize the action of physostigmine
on skeletal muscles
ANTIPROTOZOAL DRUGS
MEFLOQUINE • Plasma half-life : 3-8h

• Synthetic 4-quinoline methanol, • Excreted in the urine
chemically related to quinine
• Blood schizonticide against all 4 sp.( Therapeutic Indications:
slower acting than chloroquine and • For radical cure of P. vivax and P. ovale
quinine) malaria, in combination with
chloroquine
Mechanism of Action : acts by concentrating in • Terminal prophylaxis of P. vivax and P.
plasmodial food vacuoles preventing the ovale malaria (primaquine is given for
polymerization of toxic free heme into harmless 14 days after leaving the malarious
hemozoin resulting in build-up of toxic free area to decrease the likelihood of
heme that damages the parasite’s membrane relapse)
leading to its death • A single dose of primaquine can be used
as a control measure to render P.
Pharmacokinetics: falciparum gametocytes non-infective to
• Well absorbed after an oral dose; mosquito , thus disrupting the
plasma levels rise in a biphasic manner transmission of the disease
to their peak in about 18h
• Undergoes enterohepatic recirculation Adverse Effects:
• Protein binding – 98% • Most common : hemolytic anemia or
• Widely distributed to all tissues methemoglobinemia in G6PD deficiency
including the CSF • High dose: GI distress, headache,
• Eliminated slowly  single-dose agranulocytosis
treatment regimen *Should be avoided during pregnancy
• Terminal elimination half-life : 20 days
 weekly prophylactic dosing ARTEMISININ and derivatives
• Parent drug and its acid metabolites are • Sesquiterpene lactone with
slowly excreted mainly in the feces endoperoxide linkage
• Artemisinin is insoluble and can only be
Therapeutic Indications: used orally
• Chemoprophylaxis in malarious areas • Analogs: artesunate (water soluble)
with documented chloroquine resistance artemether (lipid soluble)
• Treatment of uncomplicated falciparum dihydroartemisinin (water
malaria (in combination with artesunate) soluble)
• Potent & very rapidly acting blood
Adverse Effects : schizonticides against all 4 sp. with no
• Vomiting, dizziness, sleep and clinical evidence of resistance yet
behavioral disturbances, confusion, • Active against gametocytes of all 4 sp.
psychosis/seizures (at treatment  reduction in malaria transmission
doses), prolongation of QT interval rates (most potent gametocidal drugs)
• Produce rapid and substantial reduction
Drug Interactions: of the parasite biomass resulting in
• Prolongation of cardiac conduction with rapid parasite clearance & rapid
quinine , quinidine and halofantrine resolution of symptoms
PRIMAQUINE Mechanism of Action: * production of highly

• Synthetic 8-aminoquinoline reactive free radicals that follows heme iron-
• The only drug active against the catalyzed cleavage of the artemisinin
dormant hepatic stage of P. vivax and endoperoxide bridge in the parasite food
P. ovale vacuole. These free radicals bind to the
• Gametocidal against all 4 sp. parasite membrane proteins causing lipid
peroxidation, damage to the endoplasmic
Mechanism of Action: production of oxygen free reticulum and ultimately lysis of the parasite.
radicals that interfere with the plasmodial electron
transport chain during respiration Pharmacokinetics:
• Rapidly absorbed after an oral dose
Pharmacokinetics: • Peak plasma levels in 1-2h
• Almost completely absorbed; peak • Rapidly metabolized via CYP2B6 to
plasma levels in 1-2h dihydroartemisinin
• Widely distributed to tissues • Short half-life(1-3h) – limits their
• Rapidly metabolized; its 3 major efficacy
metabolites have less antimalarial • Rapidly eliminated via the kidney
activity but with more potential for
inducing hemolysis than the parent Therapeutic Indication: (ideal partners for other
drug drugs)

ANTIPROTOZOAL DRUGS
• Standard treatment for uncomplicated quinine, chloroquine, pyrimethamine,

falciparum malaria, in combination with proguanil, mefloquine, FDC of sulfadoxine-
lumefantrine or mefloquine or with pyrimethamine
FDC of sulfadoxine-pyrimethamine  Chemoprophylaxis : chloroquine or
Adverse Effects: mefloquine
• Most common : mild GI symptoms  Uncomplicated chloroquine-sensitive malaria
Drug Interactions: : chloroquine
 Concurrent administration with  Uncomplicated falciparum malaria during
astemizole, anti-arrhythmics, TCAs and all trimesters of pregnancy : quinine(3d)
phenothiazines increases the risk of plus clindamycin(7d )
cardiac conduction defects  Uncomplicated falciparum malaria during
the 2nd and 3rd trimesters of pregnancy:
ANTI-MALARIAL DRUGS artesunate + clindamycin or quinine +
(refer to Table 1 APPENDIX A) clindamycin
 Uncomplicated P. vivax & P. ovale malaria:
COMPARATIVE PROPERTIES OF ANTIMALARIAL chloroquine; maintained on chloroquine
DRUGS prophylaxis for the duration of pregnancy;
(refer to Table 2 APPENDIX A) primaquine should be given only after
delivery if the woman is not G6PD deficient
ANTIMALARIAL DRUG RESISTANCE  Severe malaria during the 1st trimester: IV
 The ability of a parasite to survive and artesunate or quinine plus clindamycin
/or multiply despite the administration  Severe malaria during the 2nd & 3rd
of an antimalarial drug in doses equal to trimester: IV artesunate plus clindamycin
or higher than those usually
recommended
 Resistance to an antimalarial drug DRUGS USED FOR CHEMOPROPHYLAXIS OF
arises because of the selection of MALARIA
parasites with genetic mutations or gene (refer to Table 3 APPENDIX B)
amplifications that confer reduced
susceptibility. DRUGS USED FOR TREATMENT OF MALARIA
(refer to Table 4 APPENDIX B)
ANTIMALARIAL COMBINATION THERAPY
Objectives: SUMMARY:
- To improve therapeutic efficacy  The various stages of malaria life cycle that
- To prevent or delay the emergence of occur in humans differ in their drug
resistance sensitivity.
 The simultaneous use of 2 or more  None of the available anti-malarial drugs kill
blood schizonticidal drugs with different sporozoites on entry into the host (true
modes of action causal prophylaxis), therefore it is not truly
 WHO recommends Artemisinin-based possible to prevent infection
Combination Therapy(ACT) as the  However, prevention of the development of
optimal treatment for falciparum clinical attacks caused by the asexual
malaria: Artemisinin derivative erythrocytic stages can be achieved by
combined with a longer-acting chemoprophylactic drugs
antimalarial partner drug  No chemoprophylactic regimen is 100%
effective
ARTEMISININ-BASED COMBINATION THERAPY  None of the anti-malarial drugs, given
(ACT) alone, is effective against both hepatic and
Advantages : erythrocytic stages of malaria parasites that
 Rapid and substantial reduction of the occurs in P. vivax and P. ovale infections.
parasite biomass Radical cure, therefore, requires the use of
 Rapid parasite clearance more than one antimalarial drug, a blood
 Rapid resolution of clinical symptoms and a tissue schizonticide
 Effective action against multidrug-  Artemisinin-based combination therapies
resistant P. falciparum have been shown to improve treatment
 Reduction of disease transmission efficacy and delay the emergence of
resistance to the partner drug
MALARIA IN PREGNANCY
 Associated with high risk of both maternal
and perinatal morbidity and mortality
 Pregnant women less effectively clear the
infection and tend to have more severe
disease
 Antimalarial drugs that can be safely given
during the 1st trimester of pregnancy –

ANTIPROTOZOAL DRUGS
Life Cycle of E. histolytica • Tinidazole has similar activity, better

toxicity profile and offers simpler
dosing regimen than metronidazole
Mechanism of Action: its nitro group is chemically

reduced in sensitive protozoa and the reductive
products react with various intracellular molecules of
protozoal cells to cause inhibition of protein
synthesis leading to cell death
Pharmacokinetics:
• Well absorbed after an oral dose;
peak plasma concentration in 1-3h
• Low plasma protein binding (<20%)
• Distributed to all body fluids
including CSF
• Freely penetrates protozoal and
bacterial cells
• Metabolized in the liver
• Half-life of 7.5h
• Excreted in the urine as
metabolites(>75%), as
unchanged(10%)
• Drug of choice in the
treatment of all symptomatic
amebiasis ( including amebic
colitis and amebic liver abscess) in
conjunction with a luminal
amebicide
• Drug of choice in the
treatment of giardiasis,
trichomoniasis, and Clostridium
difficile-induced pseudomembranous
Courtesy of DPD/CDC colitis
DRUGS FOR AMEBIASIS • Drug of choice for reducing the
1. Tissue amebicides – act on organisms in vegetative form of C. tetani in
the bowel wall, liver and other conjunction with Tetanus Immune
extraintestinal tissues Globulin
A. For both intestinal and • Treatment of anaerobic
extraintestinal amebiasis infections particularly B. fragilis
- nitroimidazoles: metronidazole, • In combination with other
tinidazole antibiotics and PPI to treat H. Pylori-
- alkaloids: emetine, associated peptic
dehydroemetine ulcer disease
B. For extraintestinal amebiasis
only Adverse Effects:
- chloroquine • Most frequent: nausea, headache,
2. Luminal amebicides dry mouth, metallic taste
- act on organisms in the bowel • Infrequent: vomiting, diarrhea,
lumen insomnia, dark urine
- diloxanide furoate • Rare: pancreatitis, CNS toxicity
- iodoquinol Drug Interactions:
- paromomycin • Potentiates anti-coagulant effect of
Tetracycline / erythromycin – bowel coumarin
amebicides • Elimination increased by phenytoin
and phenobarbital
METRONIDAZOLE / TINIDAZOLE • Elimination decreased by cimetidine
• Prodrug • Disulfiram-like reaction with ethanol
• Kills trophozoites but not cysts of E.
histolytica EMETINE / DEHYDROEMETINE
• Effectively eradicates intestinal and • Effective against tissue trophozoites
extraintestinal tissue infections • Use is limited to severe amebiasis
• Not effective against luminal in patients in whom metronidazole
parasites
ANTIPROTOZOAL DRUGS
is contraindicated or cannot be • Excreted mainly in the urine

tolerated asmetabolites; small amount excreted
in the bile
LUMINAL AMEBICIDES
(refer to Table 5 APPENDIX B) Therapeutic Indications:
• Treatment of GI nematode infections-
Alternative Drugs & Adult Dosage ascaris, trichuris, hookworm and
(refer to Table 6 APPENDIX C) pinworm for 2 yrs old and above
• Used for annual deworming of Filipino
OTHER ANTI-PROTOZOAL DRUGS children 1 to 14 yrs of age (DOH/PPS)
(refer to Table 7 APPENDIX C) • Albendazole - treatment of choice for
medical therapy and adjunct to surgical
removal or aspiration of hydatid cyst
ANTI-HELMINTHIC DRUGS • Albendazole – drug of choice for
neurocysticercosis, in combination with
HELMINTHIC INFECTIONS steroids
Ascaris lumbricoides • Albendazole – drug of choice in the
Necator americanus treatment of cutaneous & visceral larva
Strongyloides stercolaris migrans and intestinal capillariasis
Trichinella spiralis • Mebendazole – alternative drug for
treatment of strongyloidiasis and
ANTI-HELMINTHIC DRUGS cutaneous larva migrans
Drugs that act either locally to expel worms from the
GIT or systemically to eradicate adult helminths or Adverse Effects:
developmental forms that invade organs or tissues • Infrequent: transient & mild GI
1. Drugs for common roundworm infections: symptoms, insomnia
Albendazole • Rare: high dose & prolonged use:
Mebendazole hypersensitivity reactions, elevated liver
Thiabendazole enzymes
Oxantel / Pyrantel pamoate *Safety in pregnancy and children less than 2 yrs old
2. Drugs for filariasis not established. However, the summary
Diethylcarbamazine recommendation of the technical updates on the
Ivermectin Guidelines on IMCI states that Albendazole and
3. Drug for schistosomiasis and fluke infection Mebendazole can be safely used inchildren 12
Praziquantel months and older
BENZIMIDAZOLES PYRANTEL PAMOATE

• Broad spectrum oral antihelminthics • Broad-spectrum tetrahydropyrimidine
particularly against GI nematodes antihelminthics
• Albendazole, Mebendazole, • Highly effective against pinworm,
Thiabendazole ascaris, hookworm and Trichostrongylus
Selectively toxic orientalis
• Pyrantel is not effective against
Mechanism of Action: inhibit microtubule Trichuris and Strongyloides
polymerization by binding to the parasite’s beta- • Oxantel – analog of pyrantel ; effective
tubulin, thus interfering with microtubule-dependent against Trichuris
glucose uptake by the parasite leading to glycogen
consumption and ATP depletion Mechanism of Action: depolarizes the
neuromuscular junction of most intestinal
Pharmacokinetics: nematodes resulting in their irreversible paralysis
• Poorly absorbed(<10%); absorption and allowing their natural expulsion
increased when taken with a fatty
meal Pharmacokinetics:
• Extensive first pass hepatic metabolism • Poorly absorbed; peak plasma levels in
• Peak plasma levels reached 2-3h after 1-3h
an oral dose • Excreted unchanged in the feces (85%)
• Highly protein-bound and in urine(15%)
• Widely distributed to all tissues
(including CSF & hydatid cyst for Therapeutic Indication:
albendazole) • Treatment of ascaris, pinworm and
• Plasma half-life : hookworminfections as alternative to
2 – 6 h for mebendazole mebendazole
8 – 12h for albendazole • Oxantel pamoate – for treatment of
1.2h – for thiabendazole trichuriasis

ANTIPROTOZOAL DRUGS
Adverse Effects: (infrequent/mild • When used in onchocerciasis treatment:

• Nausea, vomiting, diarrhea, abdominal Mazotti reaction
cramps, headache, dizziness, transient * Avoid concomitant use of drugs that
elevation of liver enzymes enhance GABA activity
*Safety in pregnant women and children below * Safety in children below 5 yrs not
2 yrs old not established established
DIETHYLCARBAMAZINE CITRATE DOXYCYCLINE : has significant microfilaricidal

• Synthetic piperazine derivative actitvity against W.bancrofti(adult form) and against
Mechanism of Action: immobilizes microfilariae O. volvulus
and alters their surface structure, displacing
them from tissues and making them more PRAZIQUANTEL
susceptible to destruction by host defense • Broad spectrum synthetic isoquinoline-
mechanisms pyrazine derivative
Pharmacokinetics: Mechanism of Action: increases the permeability of

• Rapidly absorbed from the GIT; peak trematode and cestode cell membrane to calcium
plasma levels in 1-2h resulting spastic paralysis and death
• Widely distributed to all tissues except
fatty tissues Pharmacokinetics:
• Plasma half-life= 2-3h(acidic urine), • Rapidly & completely absorbed from the
10h(alkaline urine) GIT
• Excreted mainly in the urine in • Bioavailability increased with high
unchanged form and as N-oxide carbohydrate meal or with cimetidine
metabolite and reduced with antiepileptics and
steroids
Therapeutic Indications: • Peak plasma levels reached in 1-3h
• Drug of choice in the treatment of • Highly protein-bound (80%)
filariasis, loiasis and tropical • Widely distributed to tissues including
eosinophilia CSF
• Chemoprophylaxis against L.loa, • Rapidly metabolized to inactive mono-
W.bancrofti and B.malayi infections and poly-hydroxylated metabolites
• Plasma half-life: 0.8 – 3h
Adverse Effects: • Excreted in the urine (60-80%) and
• Headache, malaise, anorexia, weakness, bile(15-35%)
dizziness, vomiting
• Mazotti reaction- fever, papular rash, Therapeutic indications:
pruritus, GI upset, cough, chest pain, • Drug of choice for all forms of
muscle or joint pain, proteinuria, schistosomiasis
eosinophilia, leukocytosis • Drug of choice for H. nana infections
• Treatment of Taeniasis and
IVERMECTIN Diphyllobothriasis
• Semisynthetic macrocyclic lactone • Treatment of clonorchiasis,
Mechanism of Action: paralyzes the parasite paragonimiasis and opistorchiasis
by intensifying GABA-mediated transmission of • Alternative drug in the treatment of
signals in the parasite’s peripheral nerves neurocysticercosis
Pharmacokinetics:
• Rapidly absorbed from the GIT Adverse Effects: mild/transient
• Maximum plasma concentrations within • Most common: headache, dizziness,
4–5h drowsiness, vomiting, abdominal pain,
• Widely distributed to all tissues, large Vd urticaria, arthralgia, pruritus, myalgia,
(50L) low fever, elevation of liver enzymes
• Plasma half-life – 16h • Mazotti reaction (fever, pruritus and
• Excreted mainly in the feces skin rash with eosinophilia
• *Safety in children <4 yrs old not
Therapeutic Indications: established
• Drug of choice in the treatment of • Should be avoided in pregnancy, if
onchocerciasis and strongyloidiasis possible
• Used with Diethylcarbamazine for the
control of filariasis NICLOSAMIDE
 Salicylamide derivative
Adverse Effects:
• Infrequent: when used in the treatment Mechanism of Action: inhibition of oxidative
of strongyloides: fatigue, dizziness, phosphorylation or stimulation of ATPase activity
vomiting, abdominal pain, rash rapidly killing the adult worms
ANTIPROTOZOAL DRUGS
 2nd-line drug for the treatment of most

tapeworm infections
 Alternative drug in the treatment of F.buski
and other intestinal fluke infections
Adverse Effects:
 Nausea, vomiting, diarrhea, abdominal
discomfort
 Safety in pregnancy and children below
2 years not established
ATERNATIVE DRUGS
(refer to Table 8 Annex G)

ANTIPROTOZOAL DRUGS
APPENDIX A: TABLE 1: ANTI-MALARIAL DRUGS
DRUG MECHANISM OF PHARMACOKINETICS ADVERSE THERAPEUTIC

ACTION EFFECTS INDICATIONS
Pyrimethamine/ Inhibits plasmodial Slow, adequate Gastric FDC Proguanil-
Proguanil – slow- DHFR-inhibition absorption, high protein discomfort Chloroquine:
acting blood of folic acid binding, extensive High dose: folic malaria
schizonticides synthesis metabolism; excreted in acid deficiency chemoprophylaxi
against all 4 urine Pregnancy Risk s as alternative
Plasmodium sp Pyrimethamine half-life Category: C to mefloquine
=3.5d
Proguanil half-life= 16h
Sulfadoxine – Analog and Rapidly absorbed, FDC of FDC
slow-acting blood competitive widely distributed to all pyrimethamine- Sulfadoxine-
schizonticide antagonist of PABA tissues incldg. CSF; sulfadoxine : pyrimethamine:
 inhibition of folic high protein binding; erythema 2nd-agent for
acid synthesis acetylated in liver; multiforme, treatment of
slowly excreted with Steven’s falciparum
extensive tubular Johnson malaria
reabsorption of the free Syndrome
form; t1/2= 7-9d Pregnancy Risk
Category:C
Atovaquone – Inhibits the Poor oral absorption, Mild GI FDC
blood parasite’ high protein binding; symptoms atovaquone-
schizonticide mitochondrial excreted unchanged in Pregnancy Risk proguanil : for
against all 4 electron transport feces; t1/2= 2-3d Category: C treatment &
Plasmodium sp. chain by mimicking chemo-
the natural prophylaxis of
substrate falciparum
ubiquinone malaria
Halofantrine/ Formation of Variable oral absorption Halofantrine: FDC

Lumefantrine – cytotoxic but enhanced with GIT upset, lumefantrine-
potent blood complexes with food; plasma levels elevated liver arthemeter :
schizonticides ferritophorphyrin achieved after 16h; enzymes, dose- treatment of
against all 4 sp XI that cause excreted mainly in related uncomplicated
plasmodial feces prolongation of falciparum
membranedamage Lumefantrine t1/2 QT interval malaria
=4.5h Lumefantrine:
Halofantrine t1/2 = 1- mild GIT upset
5d
Doxycycline/ Inhibits protein Oral absorption variable GI upset, bone Given with
clindamycin – synthesis & impaired by food, growth quinine for
slow-acting blood antacids, divalent & retardation, treatment of
schizonticides trivalent cations, dairy permanent falciparum
against all 4 sp products; wide pigmentation & malaria
distribution except hypoplasia of Doxycycline :
Not used alone in CNS, bound to teeth, teeth chemoprophy-
the treatment of spleen & bone; Not given to laxis in areas
malaria hepatobiliary excretion children <8yrs with multi-drug
old resistance(as
Pregnancy Risk alternative to
category: D mefloquine)

ANTIPROTOZOAL DRUGS
TABLE 2: COMPARATIVE PROPERTIES OF ANTIMALARIAL DRUGS
Drugs Erythrocytic Phase ExoErythro Gametocytes
All 4 species P. viv./P.ovale P. fal. P. viv./P.ov/P.

mal
1. Chloroquine + - - +
2. Mefloquine + - - -
3. Quinine + - - +
4. Proguanil + ± * *
5.Pyrimethamine + - * *
6. Primaquine ± + + +
7. Sulfadoxine ± - - -
8. Doxycycline + - - -
9. Artemisinin + - + +
10. Halofantrine + - - -
 Do not kill gametocytes but inhibit development in mosquito
APPENDIX B: TABLE 3: DRUGS USED FOR CHEMOPROPHYLAXIS OF MALARIA
DRUG USE ADULT DOSAGE
Chloroquine Areas without resistant P. falciparum 500 mg (base) weekly starting 1-2 weeks
before entering an endemic area &
continued for 4 weeks after leaving the
endemic area
Atovaquone- Areas with chloroquine-resistant P. (250 mg atovaquone & 100 mg proguanil)

proguanil falciparum 1 tablet daily beginning 2 days before
(Malarone) entering an endemic area & continuing for
7 days after leaving
Mefloquine Areas with chloroquine-resistant P. 250 mg weekly starting 1-2 wks before
falciparum entering an endemic area & continued for
4 weeks after leaving
Doxycycline Areas with multidrug-resistant P. 100 mg daily. Begin 2 days before travel
falciparum to an endemic area & continued for 4
weeks after leaving

ANTIPROTOZOAL DRUGS
TABLE 4: DRUGS USED FOR TREATMENT OF MALARIA
DRUG CLASS USE
Chloroquine 4- Aminoquinoline Treatment & chemoprophylaxis of infection with

sensitive parasites
Quinine Quinoline methanol Oral & intravenous treatment of P. falciparum

infections
Quinidine Quinoline methanol Intravenous therapy of severe infections with P.

falciparum
Mefloquine Quinoline methanol Chemoprophylaxis & treatment of infections with

P. falciparum
Primaquine 8-Aminoquinoline Radical cure & terminal prophylaxis of infections

with P. vivax & P. ovale; alternative
chemoprophylaxis for all sp
FDC Sulfadoxine- Folate antagonist Treatment of infections with some chloroquine-

Primethamine combination resistant P. falciparum including combination with
artesunate
Doxycycline Tetracycline Treatment (with quinine) of infections with P.

falciparum; chemoprophylaxis in areas where
multi-drug resistance occurs
Halofantrine Phenanthrene methanol Treatment of P. falciparum infections

Lumefantrine Aryl alcohol Treatment of P.falciparum malaria in fixed
combination with artemether(Coartem)
Artemisinins(arte- Sesquiterpene lactone Treatment of P. falciparum infections; oral

sunate, arteme- endoperoxides combination therapies for uncomplicated disease;
ther) IV artesunate for severe disease
TABLE 5: LUMINAL AMEBICIDES
DRUG MECHANIS PHARMACOKINETICS ADVERSE THERAPEUTIC

M OF EFFECTS INDICATIONS
ACTION
Diloxanide Unknown Good oral absorption;hydrolyzed to Flatulence Drug of choice for
furoate furoic acid & diloxanide( 90% of asymptomatic
diloxanide is absorbed,conjugated & intestinal amebic
excreted in urine, only the 10% infections
unabsorbed exerts anti-amebic (asymptomatic cyst
activity passers)
Used with
metronidazole in the
treatment of
intestinal and
extraintestinal
amebic infections
Iodoquinol Unknown 90% retained in the intestine then Diarrhea, Used with
excreted in the feces, remaining vomiting, metronidazole in the
10% enters the circulation with half- abdominal treatment of
life of 11-14h then excreted in urine pain; high dose intestinal and
as glucuronide in children extraintestinal
associated with amebic infections
optic
atrophy/perma
nent loss of
vision
Paromomy Inhibits Following oral dose, 100% of the Rare: GIT Used with
cin protein drug is recovered in feces upset metronidazole in the
synthesis treatment of
intestinal and
extraintestinal
amebic infections

ANTIPROTOZOAL DRUGS
APPENDIX C: TABLE 6: ALTERNATIVE DRUGS & ADULT DOSAGE
Clinical Setting Drug of Choice and Adult Dosage Alternative Drugs and Adult
Dosage
Luminal agent: Diloxanide furoate,
500 mg tid for 10 days
Asymptomatic intestinal or–
infection Iodoquinol, 650 mg tid for 21 days
or–
Paromomycin, 10mg/kg tid for 7 days
Luminal agent
Metronidazole, 750 mg tid (or 500 mg
plus either–
IV q 6h) for 10 days
Tetracycline, 250 mg tid for
Mild to moderate intestinal or–
10 days
infection Tinidazole, 2 g daily for 3 days
or–
plus–
Erythromycin, 500 mg qid for
Luminal agent
10 days
Luminal agent
Metronidazole, 750 mg tid (or 500 mg
plus either–
IV q 6h) for 10 days
Tetracycline, 250 mg tid for
or–
Severe intestinal infection 10 days
Tinidazole, 2 g daily for 3 days
or–
plus–
Dehydroemetine or emetine, 1
Luminal agent
mg/kg SC or IM for 3–5 days
Dehydroemetine or emetine, 1
Metronidazole,750 mg tid(or 500 mg mg/kg SC or IM for 8-10
IV q 6h) for 10 days days, followed by (for liver
Hepatic abscess, ameboma
or– abscess only) chloroquine,
and other extraintestinal
Tinidazole, 2 g daily for 3 days 500 mg bid for 2 days, then
disease
plus– 500 mg daily for 21 days
Luminal agent plus–
Luminal agent
TABLE 7: OTHER ANTI-PROTOZOAL DRUGS

THERAPEUTIC
DRUG MOA PHARMACOKINETICS ADVERSE EFEFCTS INDICATIONS
Pentamidine unknown Given parenterally, is Highly toxic, DOC for early

bound avidly to severe stage of West
tissues, eliminated hypotension, African
very slowly, terminal tachycardia, trypanosomiasis;
half-life of 12d, dyspnea after alternative Tx for
excreted in urine rapid IV; visceral
pancreatic & renal leishmaniasis &
toxicity pneumocytosis
Suramin unknown Given IV, tight Early: fatigue, DOC for early
protein binding, nausea, vomiting; stage East African
short initial half-life, Late: fever, rash, trypanosomiasis
terminal half-life of renal abnormalities
50d, renal neuropathies
elimination
Sodium Unknown Rapidly absorbed & GI symptoms, 1st line agent for
stibogluconate distributed, initial fever, myalgias, cutaneous &
half-life of 2h; arthralgias, rash, visceral
terminal half-life of QT interval leishmaniasis
24h prolongation
Nifurtimox Unknown Well absorbed after Vomiting, Treatment of acute
oral administration Rash, fever, American
and eliminated with abdominal pain, trypanosomiasis
a plasma half-life of insomnia, (Chaga’s disease)
3h neuropathies,
seizures

ANTIPROTOZOAL DRUGS
Infecting Organism Drug of Choice Alternative Drugs
RoundWorms (nematodes)
Albendazole or mebendazole or Ivermectin or
Ascaris lumbricoides (roundworm)
Pyrantel pamoate Piperazine
Trichuris Trichiura (whipworm) Mebendazole or Albendazole Ivermectin
Necator americanus (hookworm); Albendazole or Mebendazole or

Ancylostoma duodenale (hookworm) Pyrantel pamoate
Albendazole or
Strongyloides stercoralis (threadworm) Ivermectin
thiabendazole
Enterobius vermicularis (pinworm) Mebendazole or Pyrantel pamoate Albendazole
Mebendazole or Albendazole
Trichinella spiralis (trichinosis)
add corticosticosteroids for severe infection
Visceral larva migrans Albendazole Mebendazole
Wuchereria bancrofti (filariasis);

Brugia malayi (filariasis); Diethylcarbamazine Ivermectin
Tropical eosinophilia; Loa loa (loiasis)
Onchocerca volvulus (onchocerciasis) Ivermectin
Capillaria philippinensis
Albendazole Mebendazole
(intestinal capillariasis)
Flukes (trematodes)
Schistosoma Praziquantel Metrifonate
Clonorchis sinensis (liver fluke) Praziquantel Albendazole
Paragonimus westermani (lung fluke) Praziquantel Bithionol
Fasciolopsis buski (large intestinal fluke) Praziquantel or niclosamide
Tapeworm (cestodes)
Taenia saginata & solium Praziquantel or niclosamide Mebendazole
Diphyllobothrium latum (fish tapeworm) Praziquantel or niclosamide
Cysticercosis (pork tapeworm larva

Albendazole Praziquantel
stage)
Hymenolepis nana (dwarf tapeworm) Praziquantel Niclosamide
Echinococcus granulosus (hydatid

disease); Albendazole
Echinococcus multilocularis

AUTACOIDS
ANNEX A
Table 1 Histamine receptors & their distribution, functions
H1 R H2 R H3 R H4 R
Distribution Vascular smooth muscle, endothelium, Presynaptic (auto Eφ PMNs, CD4 T
brain, brains, epithelial cells, DC, Eφ. receptor), brain, cells
MO, T & B cells myenteric plexus,
Airway sm muscle Gastric mucosa, other neurons
muscle, mast
cell,
Post receptor Gq,  IP3, DAG Gs,  cAMP Gi,  cAMP Gi, cAMP
mechanism
Histamine  pruritus, pain,  gastric acid  pruritus (no mast  pruritus (no
general vasodilation, production, cell involvement), mast cell
functions vascular vascular nasal congestion; involvement),
permeability, permeability, prevents excessive nasal
hypotension, CR, hypotension, bronchoconstriction congestion;
bronchoconstriction, CR, chrono- & differentiation of
stimulation of a/w inotropic myeloblasts &
vagal afferent activity, promyeloblasts
nerves & cough bronchodilation,
receptors; AV node a/w mucus
conduction time production
Histamine  histamine & other Eφ & PMN che- Inhibition of Selective
function in mediator release, motaxis, TH1 histamine release recruitment of
allergic CAMs, chemotaxis of & TH2 cells, Eφ in humans,
inflammation Eφ & PMNs, induces chemotaxis of
tolerance mast cells
Histamine Sleep/wakefulness, Neuroendocrine Modulate release
function in the food intake, thermal of other
brain regulation, neurotransmitters
emotions/aggressive
behavior,
locomotion,
memory, learning
Table 2 Comparisons between 1st & 2nd generation H1 blockers:

1st generation 2nd generation
Passes through BBB Yes No
Occupancy of CNS H1 receptors >70% <20%
Molecular weight low High
Lipophilicity/solubility ratio High Low
Recognition by P-glycoprotein efflux pump no Yes
Sedating property Yes Usually no
Anticholinergic actions Yes No
Metabolized by liver microsomal enzymes Yes Yes & no
Duration of action Slightly shorter Longer
Table 3 Chemical classification of H1-blockers

Chemical group Examples Characteristics
Alkylamines Chlorphenamine Tend to produce paradoxical CNS stimulation in
children, slight sedation
Ethanolamines Diphenhydramine Marked sedation & anti-muscarinic & anti-motion
clemastine sickness action
Ethylendiamines Antazoline, Tripolidine Moderate sedation
Phenothiazines Promethazine Marked sedation; anti-emetic & anti-muscarinic
actions
Piperazines Hydroxyzine*, *Marked sedation;
Meclozine^, ^Anti-emetic & anti-motion sickness;
Cetirizine+ +
Less sedation.
Levocetirizine+
+
Piperidines Ketotifen , Non-sedating.
+
Fexofenadine 
Used topically
Loratadine+ 
May cause sedation if taken orally

AUTACOIDS
Desloratadine+
Ebastine+
Levocabastine
unclassified Azelastine+ +
Non-sedating
Olopatadine+ 
used topically

may cause sedation if taken orally
+ nd
2 generation H1-blockers
Table 7 Comparison between AT1 & AT2
AT1 AT2
Sites Most vascular tissues  level seen in fetal tissues; in
adults, high conc is found in
adrenal medulla, reproductive
tissues, parts of brain; upregulated
in CHF & MI
Affinity for Yes No
Losartan
Receptor GqPCR
Activation  phospholipase C leading to  IP3 & Causes vasodilation that is nitric
DAG, resulting in smooth muscle oxide dependent involving
contraction; it also stimulates vascular bradykinin-NO-cGMP pathway
& cardiac growth
ANNEX B
Table 8 Drugs inhibiting the RAS

Components Blocked by Mechanism
of RAS
Renin Clonidine Centrally mediated  in renal sympathetic nerve activity + direct renal
effect
Aliskiren Inhibits renin action on angiotensinogen
Propranolol Blocks intra & extra renal ß receptors that control neural control of
renin release
ACE ACE Blocks conversion of ANG I to ANG II; also inhibits degradation of
inhibitors bradykinins, substance P & enkephalins which explains the adverse
(ACEI) effects of cough & angioedema; the inhibition of bradykinin
metabolism also contributes to hypotensive effect
AT1 Saralasin Partial agonist
ARBs Competitive antagonist; prolonged treatment disinhibits renin
(losartan) secretion &  circulating AG II which may stimulate AT2 which
mediates vasodilation & other beneficial effects
Table 9 Comparison of ACEI vs ARBs

ACEI ARBs
/
Permits activation of AT2 /
/
/
Table 13 Differentiation between COX-1 & COX-2

COX-1 COX-2
Expression Expressed constitutively in most Inducible, varies depending on stimulus; an
cells immediate early response gene product,
upregulated by shear stress, growth factors,
tumor promoters, cytokines
Function / Generates prostanoids for - Inflammation & cancer
role housekeeping function like - Endothelial COX-2 is the primary source of
cytoprotection for GIT vascular PGI2
- Renal derived PGI2s are important for renal
development & maintenance of function

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Table 14 COX-1 vs COX-2 inhibitors

NSAIDs COX-1 inhibitor COX-2 inhibitor
Indomethacin & sulindac / (slightly selective)
Meclofenamate & Ibuprofen & high / /
doses Aspirin (ASA)
Low dose ASA (<100mg/day) / (preferentially)
COXIBS /
(celecoxib=diclofenac <
rofecoxib=lumiracoxib <
etoricoxib)
Table 16 Prostanoids & derivatives & their indications

Prostanoids or derivative Commercial preparation Indications
PGE1 Alprostadil To maintain patency of ductus
arteriosus in cyanotic congenital
heart disease before
cardiacsurgery
Misoprostol Cytoprotective agent for peptic
ulcer; “misused” for terminating
pregnancy
PGE2 & PGF2α To induce labor
PGF2α Latanoprast (topical) Open angle glaucoma
PGI2 Epoprostenol for treatment of pulmonary HPN
& portopulmonary HPN

AUTACOIDS
AUTACOIDS
to H1 R, but act mostly as inverse agonist.
Autacoids: Physiologically active substances (see chemical structure of Histamine and
produced by many cell types, released by various Anti-histamine – Katzung book)
stimuli, & acting within the body & consist of the
following: 1.4.1. Pharmacodynamics:
 biologically active amines like histamine,  competitive antagonist (traditional view)
serotonins at H1 receptors (HR1) of bronchiolar &
 ergot alkaloids GIT smooth muscles;
 endogenous peptides  partial block of H receptors of the
 prostaglandins cardiovascular system which have both H1 &
 leukotriennes H2 receptors;
1. Histamine: a natural body constituent synthesized  H1 blockers (current view) act as inverse
from L-histidine by histidine decarboxylase, an agonist which has a preferential affinity for
enzyme expressed throughout the body cells. the inactive state, stabilizing the receptor in
1.1. Major sources of histamine: this conformation and consequently inducing
 mast cells, basophils, gastric an inactive state characterized by blocked
enterochromaffin-like cells, platelets & signal transduction through HR1, thus, 
histaminergic neurons NF-kB expression & subsequently 
 Mast cell & basophils are the major sources generation of proinflammatory cytokines,
of granule stored histamine where it is growth factors, chemokines, adhesion
associated with proteoglycans & chondroitin molecules. These effects occur with low
SO4 concentrations of H1 blockers in vitro & with
 Histamine is released when mast cells & usual doses of H1 blockers in vivo.
basophils degranulate in response to both  H1 receptor independent anti-inflammatory
immunologic & non-immunologic stimuli. actions of antihistamines include  release
 Non-mast cell histamine are found in of preformed mediators of inflammation
neurons in the brain from mast cells & basophils after
1.2. Histamine plays diverse roles in human immunologic & non-immunologic stimuli, 
health by exerting its effects through 4 types inflammatory cell activation & de novo
of receptors. generation & release of pro-inflammatory
products. These effects require high H1
Table 1 Histamine receptors & their distribution, blocker concentration in vitro & in vivo &
functions (refer to Annex A) have no direct relationship with H1 blocker
potency).
1.3. All histamine receptors exist in active &
inactive forms & have constitutive activity in - Other effects of H1 blockers:
the absence of agonist, histamine  sedation with old generation H1 blockers
Histamine (agonist) binds  anti-nausea & anti-emetic actions of some
preferentially to the active receptor old generation H1 blockers
(R), stabilizing the R in active  antimuscarinic effects on peripheral
state, leading to continuous muscarinic receptors: drying of secretions,
activating signals, thus  urinary retention, blurring of vision (esp with
upregulation of transcription factor ethanolamines & ethylendiamines); anti-
NF-kB, results of which is  Parkinson’s effect
production of the following which  adrenoceptor blockade  hypotension
further propagate allergic (phenothiazine)
inflammation:  serotonin blocking effects  appetite
 proinflammatory cytokines (IL-1a, IL-1b, IL-  blocks Na+ channels in excitable
6), membranes like procaine & lidocaine,
 growth factors (GM-CSF, IL-3), (diphenhydramine, promethazine)
 chemotactic factors (RANTES, IL-8)
 adhesions molecules (ICAM-1, VCAM-1, p- 1.4.2 Classifications of H1 blockers:
selectin).  1st generation H1-blockers
 An inverse agonist like antihistamine  2nd generation H1-blockers
preferentially bind to inactive R, stabilizing
the R in this state, thus, blocking Table 2 Comparisons between 1st & 2nd generation
downstream activation signals from the H1 blockers: (refer to Annex A)
active R. Low dose H1-blocker with cetirizine Some of the new generation H1 blockers in use are
& azelastine has been shown downregulate derivatives of other old & new generation H1
NF-kB & pro-inflammatory cytokine blockers:
production.  Cetirizine: metabolite of hydroxyzine
 Fexofenadine: end metabolite of terfenadine
1.4. Antihistamines or H1-blockers: bind  Desloratadine: metabolite of loratadine
competitively  Levocetirizine: enantiomer of cetirizine

AUTACOIDS
Table 3 Chemical classification of H1-blockers (refer motility, urinary retention,  CR.

to Annex A)  Alpha blocking effect: hypotension
 Miscellaneous: GIT upset,  appetite & wt
1.4.3 Pharmacokinetics of H1 blockers: gain, pancytopenias, jaundice (methdilazine,
 Most are well absorbed orally trimeprazine)
 Peak plasma concentration in 1-3 hrs after  Astemizole & Terfenadine may  QTc
administration on fasting state. interval with drug interactions or overdose,
 Vd values range from 0.33 L/Kg  serum levels cardiac arrest from
(levocetirizine), to 0.5 L/Kg (cetirizine), to > ventricular arrhythmias (Torsades de
100L/Kg (for ebastine). Pointes).
 Protein binding values range from 50%  Topical antihistamines: associated with high
(ebastine) to > 90% for cetirizine, risk of skin sensitization; topical
levocetirizine & desloratadine. diphenhydramine has rarely been associated
 Many are extensively distributed into body with toxic encephalopathy in patients with
tissues epidermal breakdown from varicella.
 Mean terminal T½ of 1st generation H1
blockers range from 21-24 hrs 2. Serotonin or 5-hydroxytryptamine is a
(chlorphenamine) to 2-27 hrs for new neurotransmitter, a vasoconstrictor that plays an
generation H1 blockers. (based on adult important role in migraine & platelet clotting
studies). system, a smooth muscle stimulant in the small
 Drug-drug interactions may occur with H1 intestine. It is the major mediator in carcinoid
blockers that undergo extensive hepatic syndrome where it is secreted by the
CYP450 system. If H1 blocker metabolism is enterochromaffin cells of the gastric mucosa.
 by CYP450 inhibitors (EES, ketoconazole),
plasma & tissue levels of H1 blocker ,  2.1. Major source & sites of synthesis/storage &
potential toxicity like Torsades de pointes, metabolism:
as had occurred with terfenadine &  Found in plants & animal tissues, in
astemizole, both of which have been venoms & stings.
phased out.  Synthesized from L-tryptophan by
 Azelastine, ebastine, desloratadine, hydroxylation of indole ring ffd by
loratadine & mizolasatine are extensively decarboxylation.
metabolized by hepatic CYP450 system.  After synthesis, it is stored or rapidly
 50% of a dose of acrivastive, cetirizine or inactivated by MAO.
levocabastine is excreted unchanged in the  In the pineal gland, it serves as
urine; > 85% of levocetirizine & precursors of melatonin, a melanocyte
fexofenadine is excreted unchanged. stimulating hormone.
 In mammals, >90% is found in
1.4.4 Indications for antihistamines: enterochromaffin cells of the gastric
 Allergic rhinitis & allergic conjunctivitis mucosa, which are the site of synthesis &
 Acute & chronic urticaria storage of 5-HT in the body.
 Anaphylaxis/anaphylactoid reactions  In platelets & serotonergic nerves, it is
 Atopic dermatitis concentrated by means of serotonin
 Hypersensitivity reactions to drugs, food, transporter mechanism (SERT) & stored
physical agents in vesicles by vesicle associated
 Premedication for prophylaxis against RCM transporter (VAT), which process is
induced anaphylactoid reactions blocked by reserpine.
 Prophylaxis against motion sickness & anti-  Serotonergic neurons in raphe nuclei of
emesis, including those related to Meniere’s brain stem synthesize, store & release
disease serotonin as a neurotransmitter
 Pre-op medication: promethazine  Serotonergic neurons are also present in
 Anti-extrapyramidal symptoms induced by the enteric nervous system of the GIT &
antipsychotic drugs: Diphenhydramine around the blood vessels
 Short term management of insomnia  Serotonins are found in mast cells of
 Local anesthesia: diphenhydramine, rodents but not in humans.
phenothiazine  Serotonins are metabolized by MAO into
5-Hydroxylindole-acetic acid (HIAA).
1.4.5. Adverse effects of antihistamines:
 CNS depressive effects: fatigue, lassitude, 2.2. Functions & actions in the physiologic
drowsiness, sedation, weakness system:
 CNS stimulating effects: insomnia,  Brain serotonergic neurons are involved in
irritability, hyperreflexia, headaches, muscle the regulation of mood, sleep, temperature
twitching, nervousness, tremor, dyskinesia, control, blood pressure, vomiting &
dystonia, seizures perception of pain.
 Anticholinergic effects: dry mouth, fever,  Serotonins are also involved in the
flushed face (overdose), mydriasis,  GIT pathogenesis of depression, anxiety,
migraine & carcinoid syndrome
AUTACOIDS
2.3. Pharmacodynamic actions: retroperitoneal space, pleural cavity &

 Actions of serotonin are mediated by 7 endocardial tissue of the heart occurring
families of serotonin receptors, 6 of which insidiously; phased out from the market
are G-protein coupled R & 1 is ligand-gated  Other effects: drowsiness, hallucinations
channel (5-HT3R is a member of the (from methylsergide & LSD)
nicotinic/GABAA family of Na+ K+ channels)
 Most of the 5 HT-Rs are constitutively active 4. Vasoactive peptides: consist of
2.4. 5-HT Rs & their actions, agonist &  Vasoconstrictors: angiotensin II,
antagonist drugs & indications. vasopressin, endothelins, neuropeptide Y,
urotensins
3. Ergot alkaloids:  Vasodilators: bradykinins & other related
3.1. Source & effects: produced by a fungus, kinins, natriuretic peptides, vasoactive
Claviceps purpurea, which infects grasses & peptides (VIP), substance P, neurotensin,
grains under damp growing or storage calcitonin-gene related peptide (CGRP)
conditions. Ergot alkaloids act on several 4.1. Renin-angiotensin system:
(refer to Fig. 1 The RAS pathway – Katzung
5HT-R & others. Accidental ingestion leads Book)
to ergot poisoning or ergotism, the most 4.1.1. Renin:
dramatic form is called St. Anthony’s fire,  An aspartyl protease that catalyze
consisting of dementia, florid hallucinations, the hydrolytic release
prolonged painful vasospasm leading to ofdecapeptide angiotensin (ANG)
gangrene, stimulation of uterine smooth I from angiotensinogen;
muscle leading to abortion.  It is synthesized, stored &
released from the JGA of the
3.2. 2 major groups of ergoline derivative /ergot nephrons.Release of renin is
alkaloids regulated by the degree of stretch
Table 5 2 major groups of ergot alkaloids in the renal vascular receptor,
Amine ergot Peptide alkaloids with stretch leading to  renin
alkaloids release;  delivery of Na+ & K+ in
- LSD - Ergotamine the distal tubules also  renin
- Ergonovine - Bromocriptine release;  renal nerve activity 
renin secretion; ANG II  renin
3.3. Pharmacokinetics: release.
 variably absorbed from the gut  Drugs that  renin release:
 oral dose > 10 x IM dose vasodilators, ß-agonists, diuretics,
 speed & extent of absorption can be α-adrenoceptor antagonists,
enhanced by administration with phosphodiesterase inhibitor &
caffeine anesthetics
 the amine alkaloids can also be  renin released is mediated mainly
absorbed from the rectum, buccal cavity by cAMP.
& aerosol inhaler
 bromocriptine is well absorbed orally 4.1.2. Angiotensinogen:
 extensively metabolized in the body  synthesized in the liver with
production  by corticosteroids,
3.4. Pharmacodynamics: estrogens, thyroid hormones & ANG
 on α- & HT1A/1D receptors: agonist, partial II; (all partly contribute to
agonist (PA), & antagonist effects mechanism for HPN)
 on CNS Dopamine receptors: agonist or PA  it is the circulating protein substrate
effects from which renin cleaves ANG I
 some have high affinity for presynaptic
receptors, other on postjunctional 4.1.3. ANG I:
 on HT2 receptors in uterus, agonist or PA  inert by itself
effects leading to powerful stimulant effect  converted to ANG II by converting
on uterus enzyme (ACE)
3.6. Toxicity 4.1.4. ACE: also known as peptidyl

 GIT: diarrhea, nausea, vomiting from dipeptidase or kininase II
activation of medullary vomiting center &  widely distributed in the body,
GIT serotonin receptor mostly along the luminal surfaces
 Prolonged vasospasm from ergonovine & of vascular endothelial cells.
ergotamine that may lead to gangrene;  catalyzes the cleavage of
treatment requires the use of high dose IV dipeptides from the carboxyl
nitroprusside or nitroglycerin terminal of certain peptides, most
 Chronic methylsergide therapy is associated importantly, ANG I, converting it
with connective tissue proliferation in to ANG II

AUTACOIDS
 other substrates: bradykinin, intercellular junctions, & by

enkephalins, substance P venous pressure caused by
venoconstriction
4.1.5. ANG II:  antiproliferative effect by
 A very potent vasopressor agent, preventing vascular smooth muscle
40 x > than norepinephrine (NE), cell growth & proliferation
by direct contraction of vascular  contraction of visceral smooth
smooth muscle, esp arteriolar. muscles
 Through actions on the brain, BP is  IV infusion does not cause
, with baroreceptor reflex control sustained fall in BP
of CR reset to a higher pressure,  Bradykinins can produce the 4
thus, there is no associated classic symptoms of inflammation
tachycardia.  Kinins are generated in acute tissue
 It stimulates the autonomic ganglia, injury
release of NE & E from the  Kinins elicit pain by eliciting
adrenal medulla, facilitating nociceptive afferents in the skin &
sympathetic transmission by an viscera
action at the adrenergic nerve
endings, release & reuptake of 4.3. Vasopressin or antidiuretic hormone:
NE 4.3.1. Action: increases H2O reabsorption in
 On the zona glomerulosa of the the kidneys; has important role in BP
adrenal cortex, it  synthesis & control
release of aldosterone
 At higher levels, it  glucocorticoids 4.4. Natriuretic hormones: Atrial natriuretic peptide
synthesis (ANP), brain natriuretic peptide (BNP), c-type
 On the kidneys, it causes renal natriuretic peptide (CNP)
vasoconstriction, proximal tubule 4.4.1. Actions and PK:
Na+ reabsorption,  renin release  natriuretic (by  GFR & filtration
 It has + dipsogenic effect,  fraction), diuretic, vasorelaxant.
vasopressin & ACTH  very short T½ in circulation
4.1.6. ANG receptors: 2 major classes are AT1 4.4.2. Uses: in decompensated heart failure,
& AT2. cirrhosis with Na+ retention
Table 7. Comparison between AT1 &
AT2 (refer to Annex A) 4.5. Endothelins (ET): vasoconstrictor peptides
from endothelial cells; widely distributed in
4.1.7. Drugs that inhibit the renin- the body.
angiotensin 4.5.2. ET receptors: ETA & ETB receptors are
system both GPCR
Table 8 Drugs inhibiting the RAS
(refer to Annex B) 4.6. Vasoactive peptide (VIP):
4.2. Kinins: potent vasodilator peptides formed 4.6.1. Actions:
enzymatically by  a major neuropeptide transmitter in
kallikreins/kininogenases acting on both the central & peripheral
protein substrates kininogens (refer to nervous system
Fig. 3. The Kinin System – Katzung  exerts smooth muscle relaxation on
book) CV system  vasodilation
4.2.1. Actions:  + inotropic & chronotropic effects
 vasodilation of the vascular beds of on the 
the heart, kidneys, intestine,
skeletal muscle & liver from a direct 4.7. Tachykinin family of peptides: Substance P,
inhibitory effect of kinins on neurokinin A, Neurokinin B.
arteriolar smooth muscle, or by 4.7.1. Actions: Substance P is present in
release of NO, or vasodilator PGs the CNS as neurotransmitter, in the
like PGE2 & PGI2; ~ 10 x more GIT, as transmitter in the enteric
potent than histamine. nervous system.
 contraction of veins by direct
stimulation or by venoconstrictor 4.8. Neurotensins (NT)
PGF2α.  Neurotransmitter in the CNS 
 arteriolar dilation induced by kinins hypothermia, antinociception,
causes  pressure & flow in the modulation of dopamine
capillary bed  efflux of fluid from neurotransmission, maybe involved in
blood into tissues facilitated by  schizophrenia, Parkinson’s disease &
capillary permeability which in turn drug abuse
is caused by contraction of  In peripheral circulation, causes
endothelial cells & widening of vasodilation, hypotension,  vascular

AUTACOIDS
 permeability, secretion of anterior

pituitary hormones, hyperglycemia, 
gastric acid production & pepsin
secretion, gastric motility.
4.9. Calcitonin gene related peptide (CGRP):

Most potent vasodilator; plays a central role in
the pathogenesis of migraine
4.10. Adrenomedullin: causes hypotension, Na+

excretion in the kidneys, in the CNS,
sympathetic flow
4.11. Neurotensin Y (NPY): most abundant

neuropeptides in the CNS & PNS
4.12. Urotensin (U-11): potent vasoconstrictor

5. Eicosanoids:
 are oxygenated products of polyunsaturated
long chain fatty acids & include
prostaglandins (PGs), thromboxanes (TX),
leukotriennes (LTs)
 very short T½; act in autocrine or paracrine
fashion
 receptors for eicosanoids are all GPCR
( refer to Fig 4. Pathways of Arachidonic acid

release & metabolism – Katzung book)
( refer to Fig 5. Prostanoid biosynthesis)
5.1. Components & products of prostanoid

biosynthesis:
5.1.1 Cyclooxygenase (COX)/PGH synthase:
converts AA to PG endoperoxides
 2 isoforms COX-1 & COX-
Table 9 Comparison of ACEI vs ARBs

(refer to Annex B)
Table 13 Differentiation between COX-1 &
COX-2
(refer to Annex B)
5.1.2. Drugs that inhibit COX: NSAIDs

Table 14. COX-1 vs COX-2 inhibitors
(refer to Annex B)
5.1.3. Prostanoids
Table 16. Prostanoids & derivatives
& their indications
(refer to Annex B)
5.1.4. 5-Lipoxygenase (5-LOX) products

(refer to Fig. 6. Leukotriene (LT)
biosynthesis – Katzung book)

REVIEW TEST
ANTIPROTOZOAL DRUGS
Choose the best answer: ______8. A patient diagnosed with Filariasis
developed fever, papular rash, pruritus, chest
______1. This antimalarial is a synthetic 4- pain, muscle or joint pain, proteinuria,
aminoquinolone and is a rapidly acting blood eosinophilia, leukocytosis . The most likely drug
schizonticide against all 4 species: that caused this
A. Chloroquine A. Diethylcarbamazine Citrate
B. Primaquine B. Praziquantel
C. Clindamhycin C. Pyrantel pamoate
D. Co-trimoxazole D. Thiabendazole
______2. A patient diagnosed with Falciparum ______9. This drug has a mechanism of action
malaria had impaired consciousness, respiratory of this drug against roundworms: depolarizes
distress and jaundice. The most appropriate the neuromuscular junction of most intestinal
treatment of choice: nematodes resulting in their irreversible
A. Primaquine paralysis and allowing their natural expulsion
B. Quinidine A. Albendazole
C. Mefloquine B. Pyrantel pamoate
D. Doxycycline C. Ivermectin
D. Praziquantel
______3. This drug acts against the dormant
hepatic stage of P. vivax and P. ovale ______10. Drug of choice for all forms of
A. Chloroquine schistosomiasis:
B. Primaquine A. Albendazole
C. Quinidine B. Pyrantel pamoate
D. Mefloquine C. Ivermectin
D. Praziquantel
______4. A patient on anti malarial drug developed
tinnitus, headache, dizziness, vomiting, flushing, ______11. Which of the ff H1 blockers is
visual disturbances. The most likely drug that available in IV formulation?
caused this is: A. Hydroxyzine
A. Chloroquine B. Chlorphenamine
B. Primaquine C. Diphenhydramine
C. Quinidine D. Brompherinamine
D. Mefloquine
______12. An elderly man received
______5. This drug acts for both intestinal and Diphenhydramine in the ER due to severe
extraintestinal amebiasis: urticaria & angioedema. Thereafter he
A. Chloroquine complained of urinary retention. This adverse
B. Metronidazole effect is due to blockade of which receptors:
C. Tetracycline A. Muscarinic
D. Iodoquinol B. Serotonin
C. Histamine
______6. A 70 year old was diagnosed with D. alpha-agonist
amoebiasis. Metronidazole was given. Which of the
following drugs should have dose adjustment? ______13. Which of the ff H1 blockers can be
A. Losartan given safely and once daily to a pilot?
B. Coumarin A. Clemastine
C. Simvastatin B. Hydroxyzine
D. Metformin C. Loratadine
D. Chlorphenamine
______7. Treatment for ascaris lumbricoides
infection: ______14. A child has history of severe motion
A. Metronidazole sickness. What can you give her before her
B. Mebendazole plane flight?
C. Praziquantel A. Cetirizine
D. Ivermectin B. Meclizine
C. Desloratadine
D. Loratadine

REVIEW TEST
______15. Which of the ff H1 blockers is available

as a topical nasal spray for the treatment of allergic
rhinitis?
A. Cetirizine
B. Meclozine
C. Azelastine
D. Loratadine
______16. Which of the ff serotonin agonists is

useful for the treatment of acute migraine?
A. Buspirone
B. Sumatriptan
C. Cisapride
D. Fluoxetine
______17. Which of the ff serotonin antagonists is

useful for prophylaxis against nausea & vomiting
induced by cancer chemotherapy?
A. Cyproheptadine
B. Ketanserin
C. Meclozine
D. Ondansetron
______18. This acts as a dopamine agonist & is

useful in the treatment of hyperprolactinemia &
Parkinson’s disease:
A. Bromocriptine
B. Ergotamine
C. Ergonovine
D. Methylsergide
______19. ACE inhibitors may indue severe cough.

This adverse effect is because ACEIs:
A. directly stimulate cough receptors in
the bronchial tree
B. directly stimulate cough center in
the CNS
C. inhibit the breakdown of kinins,
enkephalins & substance P which
enhance cough reflex
D. stimulate the release of histamine
from the mast cells & basophils
leading to bronchospasm & cough
______20. Which of the ff can be given to maintain

patency of the ductus arteriosus in a neonate with
TGA?
A. indomethacin
B. PGE1 analogue
C. Thromboxane
D. PGF2a

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ANTIBIOTICS

GENERAL PRINCIPLES OF ANTIBIOTIC  severity of infection

UST FMS MEDICAL BOARD REVIEW 2019 1 | PHARMACOLOGY

 less frequent dosing is more effective  rifampicin

UST FMS MEDICAL BOARD REVIEW 2019 2 | PHARMACOLOGY

Minimal or not good No passage even with -moxifloxacin fluoroquinolones

UST FMS MEDICAL BOARD REVIEW 2019 3 | PHARMACOLOGY

2. Induction of enzymatic inactivation -

MECHANISMS OF ACQUIRED DRUG RESISTANCE

– Nafcillin, Oxacillin (IV) • Penicillin V

UST FMS MEDICAL BOARD REVIEW 2019 5 | PHARMACOLOGY

– Pseudomembranous colitis - High doses may cause diarrhea

UST FMS MEDICAL BOARD REVIEW 2019 6 | PHARMACOLOGY

– Ceftriaxone and Cefoperazone (bile) – Pseudomonas aeruginosa

UST FMS MEDICAL BOARD REVIEW 2019 7 | PHARMACOLOGY

• Excreted in urine MECHANISM OF RESISTANCE

UST FMS MEDICAL BOARD REVIEW 2019 8 | PHARMACOLOGY

E. faecium + + – NOT recommended for serious S.

UST FMS MEDICAL BOARD REVIEW 2019 9 | PHARMACOLOGY

PHARMACOKINETICS • Widely distributed in tissues except bone,

UST FMS MEDICAL BOARD REVIEW 2019 10 | PHARMACOLOGY

– Inhibited by low extracellular pH • Contraindicated during pregnancy due to

UST FMS MEDICAL BOARD REVIEW 2019 11 | PHARMACOLOGY

Legionella spp. +  Avoid during pregnancy and

UST FMS MEDICAL BOARD REVIEW 2019 12 | PHARMACOLOGY

UST FMS MEDICAL BOARD REVIEW 2019 13 | PHARMACOLOGY

• Concentration-dependent killing ADVERSE REACTIONS

UST FMS MEDICAL BOARD REVIEW 2019 14 | PHARMACOLOGY

ADVERSE REACTIONS – Pneumonia

UST FMS MEDICAL BOARD REVIEW 2019 15 | PHARMACOLOGY

– Increases serum concentration of MECHANISM OF RESISTANCE

UST FMS MEDICAL BOARD REVIEW 2019 16 | PHARMACOLOGY

• NOT recommended during • Inhibit topoisomerase IV

• Not routinely recommended – Clostridium tetani

PHARMACODYNAMICS CLINICAL USE

UST FMS MEDICAL BOARD REVIEW 2019 18 | PHARMACOLOGY

• NOT recommended for upper urinary tract

UST FMS MEDICAL BOARD REVIEW 2019 19 | PHARMACOLOGY

ANTIBIOTICS ______9. The following is true concerning

UST FMS MEDICAL BOARD REVIEW 2019 | PHARMACOLOGY

______15. A 48 year old male develops

______16. Among the antibiotics that act by

______17. Aztreonam is an unusual beta lactam

______18. The following antibiotic should be

______19. A patient presents with deep seated

______20. The fluoroquinole with the highest

UST FMS MEDICAL BOARD REVIEW 2019 | PHARMACOLOGY

RESPIRATORY PHARMACOLOGY Table 3. PK/PD of Epinephrine

UST FMS MEDICAL BOARD REVIEW 2019 1 | PHARMACOLOGY

Drug interaction: In combination with ß-agonist Eosinophil  inflammatory response

Skeletal improves diaphragm contractility

UST FMS MEDICAL BOARD REVIEW 2019 2 | PHARMACOLOGY

Pharmacokinetics - Theophylline: Table 9. ICS adverse effects:

Indications of theophylline: Adverse effect: Churg-Strauss syndrome ?

UST FMS MEDICAL BOARD REVIEW 2019 3 | PHARMACOLOGY

UST FMS MEDICAL BOARD REVIEW 2019 4 | PHARMACOLOGY

Table 3. Effects on formed elements of the blood Table 5. Structure-Activity relationships of CS

UST FMS MEDICAL BOARD REVIEW 2019 5 | PHARMACOLOGY

CV HPN ( Na+ reabsorption, H2O

Immunity Impaired (See PD)

HPA axis Prolonged suppression by CS 

UST FMS MEDICAL BOARD REVIEW 2019 6 | PHARMACOLOGY

REVIEW TEST: ASTHMA DRUGS

UST FMS MEDICAL BOARD REVIEW 2019 1 | PHARMACOLOGY