Pharma Lecture with Dr. Maria Yña Eluisia T.

Pereyra-Borlongan 1

DRUG METABOLISM
Sites of Drug Metabolism
Drug Metabolism  LIVER (most important organ for drug metabolism)
 metabolic pathways alter drug activity and their  KIDNEYS
susceptibility to excretion  TISSUE COMPARTMENTS
 Two phases o few drugs (eg. esters) are metabolized in many
o Phase 1 or Functionalization Rxn tissues (eg. liver, blood, intestinal wall)
o Phase 2 or Conjugation Rxn because of the broad distribution of their
enzymes
Phase I Reactions
 convert the parent drug to a more polar (water-soluble) or Drug Biotransformation
more reactive product by unmasking or inserting a polar  most often due to genetic or drug-induced differences
functional group  gender is important for only a few drugs
 EXAMPLES: oxidation, reduction, deamination, hydrolysis o first-pass metabolism of alcohol (M > F)
 primary determinant of clearance
MNEMONICS – Phase I Reactions o variations must be considered carefully when
A HORDe of PHASE I REACTIONS designing or modifying a dosage regimen
Hydrolysis Reduction
Oxidation Deamination Genetic Factors
 drug-metabolizing systems differ among families or
Cytochrome P450 Enzymes populations in genetically determined ways
 Also called mixed-function oxidases  recent advances in genomic techniques allow screening
 High concentrations in the smooth endoplasmic reticulum for a huge variety of polymorphisms
of the liver (pharmacogenomics)
 Not highly selective in their substrates
 Approximately 75% are metabolized by: CYP3A4 or Examples in Pharmacogenomics
CYP2D6  HYDROLYSIS OF ESTERS
succinylcholine metabolism by pseudocholinesterase
Examples of Phase I Reactions  ACETYLATION OF AMINES
fast and slow acetylation of isoniazid, hydralazine and
procainamide
 OXIDATION
debrisoquin,
Enzyme Inductionsparteine, phenformin,
 dextromethorphan,
results metoprolol,
from increased and
synthesis of tricyclic P450
cytochrome
antidepressants
enzymes and heme
 several days are usually required to reach maximum
induction
 most common strong inducers are carbamazepine,
phenobarbital, phenytoin, and rifampin

MNEMONIC - CYTOCHROME P450 INDUCERS

Ethel Booba takes Phen-Phen and Refuses Greasy Carb Shakes
Ethanol (Chronic ingestion) Griseofulvin
Barbiturates exc. SECOBARBITAL Carbamazepine
Phase 2 Reactions Phenytoin St. John’s Wort / Smoking
 involve conjugation of subgroups to –OH, –NH2, and –SH Rifampicin
functions on the drug molecule
o makes the drug more polar and less lipid-soluble OTHER ENZYME INDUCERS:
than the original drug molecule Glutethimide Phenylbutazone
o EXAMPLES: glucuronate, acetate, glutathione, Ritonavir (on chronic or repeated administration)
glycine, sulfate, and methyl group ** SECOBARBITAL is an INHIBITOR **
 phase II enzymes are not very selective ** Phenylbutazone (induces the metabolism of Aminopyrine,
 drugs may undergo phase II metabolism before or after Cortisol, Digitoxin) **
phase I
Enzyme Inhibition
Examples of Phase 2 Reactions  most significant inhibitors are amiodarone, cimetidine,
furanocoumarins present in grapefruit juice, azole
antifungals, and the HIV protease inhibitor ritonavir
 metabolism may be decreased by reduction in blood flow
to the metabolizing organ
EXAMPLE: propranolol reduces hepatic blood
flow

MNEMONICS – CYTOCHROME P450 INHIBITORS

Inhibitors Stop Cyber Kids from Eating GRApefruit QV
Isoniazid Grapefruit Juice
Pharma Lecture with Dr. Maria Yña Eluisia T. Pereyra-Borlongan 2

Sulfonamides Ritonavir (on acute ingestion) initiation of drug treatment before

o
Cimetidine Amiodarone identification of a specific pathogen
Ketoconazole Quinidine  ANTIMICROBIAL PROPHYLAXIS
Erythromycin Valproic Acid o use of antimicrobial drugs to decrease the risk
of infection

BACTERIAL CELL WALL SYNTHESIS INHIBITORS

PENICILLINS

OTHER CYP450 INHIBITORS

MOA of Beta-Lactam Antibiotics
Allopurinol Chloramphenicol
 binds to penicillin-binding proteins (PBPs) located in the
bacterial cytoplasmic membrane
Chlorpromazine Dicumarol
Disulfiram Ethanol (acute toxicity)
 inhibits the transpeptidation reaction that cross-links the
linear peptidoglycan chain constituents of the cell wall
Itraconazole Nortriptyline
 activates autolytic enzymes that cause lesions in the
Oral contraceptives Phenylbutazone
bacterial cell wall
Saquinavir Secobarbital
 Bactericidal
Spironolactone Troleandromycin
 Excreted unchanged in the urine
** Phenylbutazone (inhibits the metabolism of phenytoin &
tolbutamide) **
 Capable of entering the blood brain barrier

Penicillin Resistance
Suicide Inhibitors  enzymatic hydrolysis of beta-lactam ring by formation of
 bind irreversibly to metabolizing enzymes beta-lactamases (penicillinases)
EXAMPLES: ethinyl estradiol, norethindrone, o EXAMPLE: Staphylococcus aureus
spironolactone, secobarbital, allopurinol,
o beta-lactamase inhibitors (clavulanic acid,
fluroxene, PTU
sulbactam, tazobactam) prevent inactivation
 structural change in target PBPs
o EXAMPLES: MRSA, pneumococci,
ANTIBIOTIC AGENTS enterococci
 changes in the porin structures in outer cell wall
impeding access of penicillins to PBPs
OVERVIEW
o EXAMPLE: Pseudomonas aeruginosa

Types of Antibiotic Agents

 BACTERICIDAL NATURAL PENICILLIN
o can eradicate an infection in the absence of host
defense mechanisms PENICILLIN G [B]
o kills bacteria SimD PENICILLIN V [B]
 BACTERIOSTATIC Class Penicillin (Narrow spectrum)
o inhibits microbial growth but requires host MOA Binds to penicillin-binding proteins. Inhibits
defense mechanisms to eradicate the infection transpeptidation in bacterial cell walls.
o does not kill bacteria Uses DOC for syphillis, for streptococcal, pneumococcal,
meningococcal, G+ bacilli, spirochete infection
SE Hypersensitivity, Complete cross-allergenicity
with other penicillins, Gastrointestinal
MNEMONICS – Bactericidal VS Bacteriostatic Antibiotics disturbances, seizures
What antibiotics are BACTERICIDAL? Notes Renal tubular reabsorption inhibited by
Very Finely Proficient At Murder! probenecid
Vancomycin Aminoglycosides Inactivated by beta-lactamase (penicillinase)
Fluoroquinolones Metronidazole Benzathine Penicillin & Procaine Penicillin: long-
Penicillins acting intramuscular preparations
Given IM but Pen V can be given PO
What antibiotics are BACTERIOSTATIC? Increased activity against enterococci when
We’re ECSTaTiC about bacteriostatics. given together with aminoglycosides
Erythromycin Trimethoprim
Clindamycin Tetracycline ISOXAZOLYL PENICILLIN (ANTI-STAPHYLOCCAL)
Sulfamethoxazole Chloramphenicol
METHICILLIN [B]
Minimum Inhibitory Concentration SimD NAFCILLIN [B], OXACILLIN [B], CLOXACILLIN [B],
 lowest concentration of antimicrobial drug capable of DICLOXACILLIN [B]
inhibiting growth of an organism in a defined growth Class Penicillin (Very-Narrow spectrum)
medium MOA Binds to penicillin-binding proteins. Inhibits
transpeptidation in bacterial cell walls.
Antibacterial Therapy Uses Staphylococcal infections
 EMPIRIC THERAPY SE Hypersensitivity, Complete cross-allergenicity
with other penicillins, Gastrointestinal
Pharma Lecture with Dr. Maria Yña Eluisia T. Pereyra-Borlongan 3

disturbances, Interstitial nephritis (methicillin), SimD CEFADROXIL [B], CEPHALEXIN [B],

Neutropenia (nafcillin) CEPHALOTHIN, [B] CEPHAPIRIN [B],
Notes Resistant to inactivation by beta-lactamase CEPHRADINE [B]
(penicillinase) Class Cephalosporin (First Generation)
Biliary clearance MOA Binds to penicillin-binding proteins. Inhibits
transpeptidation in bacterial cell walls.
AMINO PENICILLIN (EXTENDED SPECTRUM PENICILLIN) Uses Surgical prophylaxis, Bone infections, Infections
due to gram-positive cocci (staphylococci and
AMPICILLIN common streptococci), Escherichia coli and
SimD AMOXICILLIN Klebsiella pneumoniae, Skin and soft tissue
Class Penicillin (Extended spectrum) infections, Urinary Tract infections
MOA Binds to penicillin-binding proteins. Inhibits SE Hypersensitivity, Cross-allergenicity (partial with
transpeptidation in bacterial cell walls. penicillins, complete with cephalosporins),
Injection site reactions, Phlebitis, GI upset
Uses Infections due to enterococci, Listeria
Notes Increases nephrotoxicity of aminoglycosides
monocytogenes, Escherichia coli, Proteus mirabilis,
Do not cross the BBB
Haemophilus influenzae and Moraxella catarrhalis
Minimal activity against G- cocci, enterococci,
(HELPSE)
MRSA and most G- rods
SE Hypersensitivity, Cross-allergenicity, GI upset,
Pseudomembranous colitis and Rash (ampicillin)
Notes Inactivated by beta-lactamase (penicillinase) MNEMONICS – First Generation Cephalosporins
Enhanced effect when used with beta-lactamase Which microbes are covered by the spectrum of activity of
inhibitors (clavulanic acid, sulbactam) first generation cephalosporins?
Synergistic effect with aminoglycosides FIRST GENERATION CEPHALOSORINS
Ampicillin undergoes enterohepatic recirculation PEcKs FIRST
Proteus mirabilis
MNEMONICS – Ampicillin/Amoxicillin Escherichia coli
 AMPicillin = AMPed up penicillin Klebsiella pneumoniae
 amOxicillin = greater Oral bioavailability
How do you remember first generation cephalosporins?
Describe the antimicrobial coverage of extended spectrum FIRST GENERATION CEPHALOSPORINS
penicillins (HELPSE): Amoxicillin HELPS kill Enterococci FADer, help me FAZ my PHarmacology boards!
Haemophilus influenza Salmonella sp. CeFADroxil
Escherichia coli Enterococci CeFAZolin
Listeria monocytogenes CePHalothin
Proteus mirabilis CePHapirin
CePHradine
CePHalexin
ANTIPSEUDOMONAL PENICILLIN
CEFACLOR [B - all]
PIPERACILLIN [B]
SimD CEFAMANDOLE, CEFMETAZOLE, CEFONICID,
SimD TICARCILLIN [B], CARBENICILLIN [B]
CEFUROXIME, CEFPROZIL, CEFORANIDE, CEFOXITIN,
Class Penicillin (Antipseudomonal)
CEFOTETAN, LORACARBEF
MOA Binds to penicillin-binding proteins. Inhibits
transpeptidation in bacterial cell walls. Class Cephalosporin (Second Generation)
Uses Greater activity against G(-) infections. Infections MOA Binds to penicillin-binding proteins. Inhibits
due to Pseudomonas, Enterobacter and Klebsiella transpeptidation in bacterial cell walls.
SE Hypersensitivity, Complete cross-allergenicity Uses Added coverage for infections due to Haemophilus,
with other penicillins, Gastrointestinal Enterobacter and Neisseria
disturbances SE Hypersensitivity, Cross-allergenicity (partial with
Notes Inactivated by beta-lactamase (penicillinase) penicillins, complete with cephalosporins), Injection
Enhanced effect when used with beta-lactamase site reactions, Phlebitis, GI upset, Disulfiram reaction
inhibitors (clavulanic acid, tazobactam) (cefamandole, cefotetan)
Synergystic with aminoglycosides against Notes Increases nephrotoxicity of aminoglycosides
Pseudomonas Do not cross the BBB
Slight less activity against G+ but extended G- activity
MNEMONICS – Antipseudomonal Penicillins Cefuroxime has improved action against
TCP: Takes Care of Pseudomonas pneumococcus and H. influenza
Ticarcillin Carbenicillin Piperacillin Cefotetan and Cefoxitin have good activity against B.
fragilis and thus are used for abdominal and pelvic
infections
CEPHALOSPORINS
ALL ARE PREGNANCY CATEGORY B
** Bactericidal ; mostly IV ; all have renal excretion EXCEPT
Cefoperazone and Ceftriaxone **
MNEMONICS – Second Generation Cephalosporins
Which microbes are covered by the spectrum of activity of
CEFAZOLIN [B]
second generation cephalosporins?
SECOND GENERATION CEPHALOSORINS
HEN PEcKS
Pharma Lecture with Dr. Maria Yña Eluisia T. Pereyra-Borlongan 4

Haemophilus influenzae, Enterobacter aerogenes, Neisseria SE Hypersensitivity, Cross-allergenicity (partial with

spp. penicillins, complete with cephalosporins), GI
Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae, upset
Serratia marcescens Notes Resistant to beta-lactamase. Broad G(-) activity
In some sources, Ceftaroline belongs to the 5th
How do you remember second generation cephalosporins? generation of Cephalosporin
SECOND GENERATION CEPHALOSPORINS More resistant to beta-lactamase produced by
In a FAMily gathering, you see your FOXy cousin wearing a Enterobacter, Haemophilus, Neisseria and
FUR coat and drinking TEA. Pneumococcal
CeFAMandole, CeFOXitin, Has improved stability to chromosomal lactamase
CeFURoxime, CefoTEtan Ceftaroline used for MRSA
SECOND GENERATION CEPHALOSPORINS
FAC! LORA the PROfessional AZhOLE is still on the FONe. MNEMONICS – Anti-Pseudomonal Cephalosporins
CeFAClor, LORAcarbef, CefPROzil, ANTI-PSEUDOMONAL CEPHALOSPORINS
CefmetAZOLE, CeFONicid Ceftazidime Cefepime Cefoperazone

CEFOPERAZONE [B] CEFTOLOZANE A novel Cephalosporin, usually

SimD CEFOTAXIME, CEFTAZIDIME, CEFTIZOXIME, [B] combined wit Tazobactam, used for
CEFTRIAXONE, CEFIXIME, CEFPODOXIME the treatment of complicated urinary
PROXETIL, CEFDINIR, CEFDITOREN PIVOXIL, tract and intraabdominal infections;
CEFTIBUTEN, MOXALACTAM very good activity against Gram
Class Cephalosporin (Third Generation) negative organisms including
MOA Binds to penicillin-binding proteins. Inhibits Pseudomonas aeruginosa, most
transpeptidation in bacterial cell walls. extended-spectrum-B-lactamase-
Uses Decreased gram-positive coverage. Increased producing organisms and some
gram-negative activity (Pseudomonas, anaerobes
Bacteroides), against Providencia, Serratia,
Neiserria, Haemophilus; DOC for gonorrhea OTHER BETA LACTAM ANTIBIOTICS
(Ceftriaxone and Cefixime)
SE Hypersensitivity, Cross-allergenicity (partial with
IMIPENEM-CILASTATIN [C]
penicillins, complete with cephalosporins), GI
SimD ERTAPENEM [B], MEROPENEM [B], DORIPENEM
upset, Disulfiram reaction (cefoperazone)
[B]
Notes Synergistic effect with aminoglycosides
Class Carbapenem
All have renal excretion EXCEPT Cefoperazone
MOA Binds to penicillin-binding proteins. Inhibits
and Ceftriaxone
transpeptidation in bacterial cell walls.
All can penetrate the BBB EXCEPT
Uses Wide coverage against gram-positive and gram-
Cefoperazone and Cefixime
negative bacteria. For serious infections such as
Ceftriaxone and Cefotaxime are the most active
peneumonia and sepsis
Cephs against Penicillin resistant Streptococcus
SE Hypersensitivity, Cross-allergenicity (partial with
pneumoniae
penicillins), GI upset, CNS toxicity (confusion,
Ceftizoxime is commonly used against
encephalopathy, seizures)
Bacteroides
Notes Reserved for serious life-threatening infections
Should be reserved against serious infection
Cilastatin inhibits renal metabolism (Hydrolysis) of
EXCEPT ceftriaxone and cefixime ; Ceftriaxone
imipenem by Dihydropeptidase
has very good CNS penetration
Given IV
Ceftazidime has very good action on
Low susceptibility to B-lactamases
Pseudomonas
Active against Pseudomonas and Acinetobacter
ALL ARE PREGNANCY CATEGORY B
EXCEPT Ertapenem
Imipenem given with Cilastatin which acts as
MNEMONICS – Third Generation Cephalosporins Dehydropeptidase enzyme inhibitor
How do you remember third generation cephalosporins? Partial cross-allergenicity with Penicillins
THIRD GENERATION CEPHALOSPORINS Ertapenem has longer t1/2 but less active against
FEnge PO ng PERA to FIX my TTTTTV! Enterococci and Pseudomonas
CeFEtamet CefTazidime
CefPOdoxime CefoTaxime AZTREONAM [B]
CefoPERAzone CefTizoxime Class Monobactam
CeFIXime CefTibuten MOA Binds to penicillin-binding proteins. Inhibits
CefTriaxone transpeptidation in bacterial cell walls.
Uses Infections resistant to beta-lactamases produced
CEFEPIME [B] by gram-negative rods, including Klebsiella,
SimD CEFTAROLINE [B], CEFPIROME [B] Pseudomonas and Serratia
Class Cephalosporin (Fourth Generation) SE Gastrointestinal upset, Superinfection, Vertigo,
MOA Binds to penicillin-binding proteins. Inhibits Headache, Hepatotoxicity, Skin rash
transpeptidation in bacterial cell walls. Notes Resistant to beta-lactamase
Uses Wide coverage against gram-positive and gram- No cross-allergenicity with penicillins
negative bacteria, MRSA (Ceftaroline)
Pharma Lecture with Dr. Maria Yña Eluisia T. Pereyra-Borlongan 5

No activity against gram-positive bacteria or MOA Interferes with a late stage in cell wall synthesis in
anaerobes gram-positive organisms
Given IV Uses Infections due to gram-positive bacteria
Synergistic with AG SE Nephrotoxicity
Renal excretion Notes Reserved for topical use only due to marked
nephrotoxicity
MISCELLANEOUS
CYCLOSERINE [C]
CLAVULANIC ACID [B] MOA Blocks incorporation of D-Ala into the
SimD SULBACTAM [B], TAZOBACTAM [B] pentapeptide side chain of the peptidoglycan
Class Beta-lactamase inhibitor Uses Drug-resistant tuberculosis (2nd line drug)
MOA Inhibits inactivation of penicillins by bacterial SE Neurotoxicity (tremors, seizures, psychosis)
beta-lactamase (penicillinase) Notes Only used as a second-line agent in TB
Uses Infections against beta-lactamase producing
gonococci, streptococci, E. coli and H. influenzae DAPTOMYCIN [B]
SE Hypersensitivity, Cholestatic jaundice MOA Binds to cell membrane causing depolarization
Notes Usual combinations include Amoxicillin- and rapid cell death
Clavulanate, Ampicillin-Sulbactam, Piperacillin- Uses Infections caused by G(+) bacteria including
Tazobactam sepsis and endocarditis
Most active against plasmid encoded B SE Myopathy
lactamases (Gonococci, Streptococci, E coli and Notes More rapidly bacteridicidal than Vancomycin
H. Influenzae) Inactivated by pulmonary surfactants so cannot
Not good inhibitor of inducible chromosomal B be used against pneumonia
lactamases (Enterobacter,Pseudomonas, Monitor Creatine Phosphokinase weekly to
Serratia) check for severity of myopathy
NOT Bactericidal (only destabilizes bacterial cell
VANCOMYCIN [C if parenteral, B if per orem] membrane)
SimD TEICOPLANIN [B], DALBAVANCIN [C[,
TELAVANCIN [C] OTHER DRUGS ACTING ON CELLWALL
Class Glycopeptide FOSFOMYCIN Inactivates the enzyme UDP-N-
MOA Inhibits cell wall synthesis by binding to the D- [B] acetylglucosamine-3-
Ala-D-Ala terminus of nascent peptidoglycan  enolpyruvyltransferase which is
inhibit transglycosylation  prevent elongation important in peptidoglycan synthesis (very
and cross-linking of peptidoglycan chain early stage of bacterial cell wall synthesis)
Uses Serious infections caused by drug-resistant gram-  prevents formation of N-
positive organisms (MRSA), sepsis, endocarditis & acetylmuramic acid (a peptidoglycan
meningitis, Pseudomembranous colitis precursor molecule); for uncomplicated
SE Red Man syndrome, Nephrotoxicity, Ototoxicity, UTI; safe for pregnant patients; renal
Chills, Fever, Phlebitis excretion; resistance emerges rapidly;
Notes Reserved for serious life-threatening infections synergistic with Beta lactam and
Treat red man syndrome by slowing the rate of quinolones
infusion
Use oral formulation for Pseudomembranous BACTERIAL PROTEIN SYNTHESIS INHIBITORS
colitis
Narrow spectrum Treat red man syndrome by
MNEMONIC - Protein Synthesis Inhibitors
slowing the rate of infusion
A = Aminoglycosides
VRSA and VRE are due to D-Ala-D-Lactate
T = Tetracyclines
formation
C = Chloramphenicol
Teicoplanin and telavancin are not absorbed in
E = Erythromycin (Macrolides)
the GIT thus used for bacterial enterocolitis, L = Lincosamides (Clindamycin)
they are also eliminated unchanged in the urine L = Linezolid
Decrease dose for renally impaired patients S = Streptogramins
Dalbavancin has very long t1/2 (6-11 days) which
permits once-weekly dosing and is more active
than Vancomycin

MNEMONICS – Drugs of Last Resort

Which antibiotics are considered drugs of last resort?
I AM your Last Shot at Victory
Imipenem Linezolid
Amikacin Streptogramins
Meropenem Vancomycin

BACITRACIN [C]
Class Peptide antibiotic
Pharma Lecture with Dr. Maria Yña Eluisia T. Pereyra-Borlongan 6

CHLORAMPHENICOL [C] T = TeTracyclines = Block aTTachment of T-RNA to

Class Protein synthesis inhibitor (broad spectrum) acceptor site
MOA Inhibits transpeptidation (catalyzed by peptidyl
transferase) at 50S subunit. Bacteriostatic. ERYTHROMYCIN [B]
Uses Meningitis (Streptococcus pneumoniae, SimD AZITHROMYCIN [B], CLARITHROMYCIN [C],
Haemophilus influenzae, Neisseria meningitidis), TELITHROMYCIN [C], ROXITHROMYCIN [B]
Backup for Salmonella, Rickettsia and Bacteroides Class Macrolide
SE Gastrointestinal disturbance, Aplastic anemia MOA Binds 50S ribosomal subunit. Bacteriostatic.
(idiosyncratic), Gray baby syndrome, dose-related Uses Community-acquired pneumonia, Pertussis,
anemia Diphtheria, Chlamydial infections
Notes Inhibits hepatic drug-metabolizing enzymes SE Gastrointestinal upset, Cholestatic hepatitis,
causing many drug interactions Hepatotoxicity, QT prolongation, Drug
given PO and IV interactions, rare fulminant hepatic failure
Able to cross the placenta and BBB (Telithromycin)
Inhibits hepatic drug-metabolizing enzymes Notes All macrolides inhibit CYP450 EXCEPT
causing many drug interactions Azithromycin
Resistance is due to the formation of Azithromycin has highest Vd and slowest
acetyltransferase that inactivates drug elimination
Usually used as topical agent Telithromycin is used for macrolide-resistance
Chloramphenicol Palmitate and Chloramphenicol Good oral bioavilability but azithromycin
Na Succinate absoprtion is impeded by food
Half-lives: Erythromycin (2hrs), Clarithromycin
Gray Baby Syndrome (6hrs), Azithromycin (24-48hrs)
 characterized by decreased red blood cells, cyanosis and Resistance is due to development of efflux
cardiovascular collapse pumps and production of methylase enzyme
 characteristic ashen gray skin Cross-resistance among macrolides: complete or
 premature neonates are deficient in hepatic partial resistance with drugs acting on the 50S
glucuronosyltransferase
 very sensitive to doses of chloramphenicol CLINDAMYCIN [B]
SimD LINCOMYCIN [C]
TETRACYCLINE [D -ALL] Class Lincosamide
SimD DOXYCYCLINE, MINOCYCLINE, TIGECYCLINE, MOA Binds 50S subunit. Bacteriostatic.
DEMECLOCYCLINE, LYMECYCLINE Uses Skin and soft tisuue infection, Anaerobic
Class Tetracycline infections, Backup drug against gram-positive
MOA Binds 30S ribosomal subunit. Bacteriostatic. cocci, Endocarditis prophylaxis (penicillin-
Uses Infections caused by M. pneumoniae, chlamydiae, allergy), PCP pneumonia, Toxoplasmosis
rickettsiae and Vibrio, Peptic ulcer disease, Lyme SE Gastrointestinal disturbance, Skin rash,
disease, Malaria prophylaxis, Amebiasis, SIADH Neutropenia, Hepatic dysfunction,
(demeclocycline), Acne, CAP and bronchitis Pseudomembranous colitis (C. difficile
(Doxycycline) overgrowth)
SE GI disturbance, Teratogen (tooth enamel
dysplasia/discoloration), Hepatotoxicity, Notes Cross-resistance between clindamycin and
Nephrotoxicity, Photosensitivity, reversible macrolides is common
Vestibulotoxicity (esp Minocycline) Resistance is due to methylation of binding sites
Notes Divalent cations impair oral absorption (minimal and enzymatic inactivation
for Doxycycline) G(-) aerobes are resistant because of poor
Tigecycline has the broadest spectrum and has penetration through th eouter membrane
the longest t1/2 (30-36hrs)
Do not drink with milk (decreased absorption MNEMONICS – Clindamycin VS Metronidazole
with divalent cations like calcium)  CLINDAMYCIN for anaerobic infections ABOVE the
High Vd, cross the placenta, enterohepatic diaphragm.
recycling  METRONIDAZOLE for anaerobic infections BELOW
All are excreted renally EXCEPT Doxycycline the diaphragm.
(bile)
Resistance is due to development of efflux
QUINUPRISTIN-DALFOPRISTIN [B]
pumps for active extrusion of tetracyclines and
Class Streptogramin
the formation of ribosomal protection proteins
MOA Binds 50S subunit. Bactericidal.
that interfere with tetracycline binding (but not
Uses Infections caused by drug-resistant gram-positive
present with Tigecycline EXCEPT in Proteus and
cocci such as Staphylococci and E. faecium (MRSA,
Pseudomonas)
VRSA, VRE)
Tigecycline is given IV only and is unaffected by
SE Injection site reactions, severe Arthralgia-myalgia
common tetracyclie resistace mechanisms
syndrome
GROUP PREGNANCY CATEGORT: D
Notes Inhibits CYP450 enzymes, causing multiple drug
interactions
MNEMONICS – Tetracycline
LINEZOLID [C]
Pharma Lecture with Dr. Maria Yña Eluisia T. Pereyra-Borlongan 7

SimD TEDIZOLID [C] MNEMONICS - Aminoglycosides

Class Oxazolidinone AminOglycosides require O2 for transport.
MOA Bindsto the 23S ribosomal RNA of 50S subunit. They won’t work under anaerobic conditions.
Bacteriostatic.
Uses Infections caused by drug-resistant gram-positive Resistance to Aminoglycosides
cocci such as Staphylococci and Enterecoccus  plasmid-mediated formation of inactivating enzymes
(MRSA, VRSA, VRE), Listeria, Corynebacteria (group transferases)
SE Bone marrow suppressioin, Thrombocytopenia, o AMIKACIN is often resistant to many enzymes
Neutropenia, Serotonin syndrome (when given that inactivate other aminoglycosides
together with serotonergic drugs such as SSRIs),  resistance to STREPTOMYCIN develops due to changes
Neuropathy, Optic neuritis in the ribosomal binding site
Notes Resistance is due to decreasedaffinity of drug to
binding site
MNEMONICS – Aminoglycosides
Mean GNATS canNOT kill anaerobes.
AMINOGLYCOSIDES Gentamicin Nephrotoxicity
Neomycin Ototoxicity
Modes of Antibacterial Action Amikacin Teratogen
 CONCENTRATION-DEPENDENT KILLING ACTION Tobramycin
o as the plasma level is increased above the MIC, Streptomycin
an increasing proportion of bacteria are killed
and at a more rapid rate GENTAMICIN [D]
o EXAMPLE: aminoglycosides
SimD TOBRAMYCIN [B if ophthalmic drop]
 TIME-DEPENDENT KILLING ACTION
Class Aminoglycoside
o efficacy is directly related to time above MIC
MOA Inhibit protein synthesis by binding to 30S
o efficacy independent of concentration once
subunit. Bactericidal.
the MIC has been reached
Uses Infections caused by aerobic gram-negative
o EXAMPLES: penicillins, cephalosporins
bacteria (E. coli, Enterobacter, Klebsiella, Proteus,
Providencia, Pseudomonas, Serratia), Endocarditis
Post-antibiotic Effect (caused by staphylococci, streptococci and
 seen in aminoglycosides enterococci), Ocular infections
 killing action continues when their plasma levels have SE Nephrotoxicity (reversible), Ototoxicity
declined below measurable levels (irreversible), Neuromuscular blockade
 greater efficacy when administered as single large dose Notes SYNERGISTIC effect with cell wall synthesis
 toxicity depends on a critical plasma concentration and (Beta Lactam and Vancomycin) inhibitors due to
on the time such a level is exceeded enhancement of transport to the inside of the
o shorter with single large dose than multiple small bacterial cell
doses AG are given IM or IV only
 basis for once-daily aminoglycoside Have concentration dependent killing
dosing protocols Are not capabale of penetrating the blood brain
barrier
Pharmacokinetics of Aminoglycosides Low tissue penetration
 not absorbed after oral administration Mechanism of resistance of AG: plasmid-
o must be given IM or intravenously for systemic mediated formation of inactivating enzymes
effect "group transferase" --> catalyze the acetylation of
 limited tissue penetration amine functions and the transfer of phosphoryl
o do not readily cross the blood-brain barrier or adenylyl groups to the oxygen atoms of the
 glomerular filtration is the major mode of excretion hydroxyl groups of AG
o plasma levels greatly affected by changes in renal Gentamicin and tobramycin are the most
function vestibulotoxic and nephrotoxic
 Amikacin has the narrowest therapeutic window among Gentamicin and Tobramycin are the most
aminoglycosides vestibulotoxic and nephrotoxic aminoglycosides
 Mostly given parenterally
 GROUP PREGNANCY CATEGORY: D AMIKACIN [D]
Class Aminoglycoside
MOA of Aminoglycosides
MOA Inhibit protein synthesis by binding to 30S
 bactericidal inhibitors of protein synthesis
subunit. Bactericidal.
 aminoglycoside transport can be enhanced by cell wall
Uses Infections caused by aerobic gram-negative
synthesis inhibitors (synergistic effect)
bacteria (E. coli, Enterobacter, Klebsiella, Proteus,
 require oxygen for uptake Providencia, Pseudomonas, Serratia), Multi Drug-
o ineffective against anaerobes Resistant Tuberculosis (2nd line drug)
 bind to the 30S ribosomal subunit and interfere with SE Nephrotoxicity (reversible), Ototoxicity
protein synthesis: (irreversible), Neuromuscular blockade
o block formation of the initiation complex
Notes Synergistic effect with beta-lactam antibiotics
o cause misreading of the code on the mRNA
Least resistance but narrowest therapeutic
template
window
o inhibit translocation
Pharma Lecture with Dr. Maria Yña Eluisia T. Pereyra-Borlongan 8

STREPTOMYCIN [D] FUSIDIC ACID or Inhibits translocation process

Class Aminoglycoside Na FUSIDATE during protein synthesis; an
MOA Inhibit protein synthesis by binding to 30S (Group: Fusidane) antibiotic isolated from the
subunit. Bactericidal. fermentation broth of Fusidium
Uses Tuberculosis, Tularemia, Bubonic plague, coccineum; used as topical
Brucellosis, Enterococcal endocarditis antimicrobial against most common
SE Hypersensitivity, Nephrotoxicity (reversible), skin pathogens including S. aureus
Ototoxicity (vestibulotoxic, irreversible),
Neuromuscular blockade, Teratogen (congenital NUCLEIC ACID SYNTHESIS INHIBITORS
deafness), Injection site reactions
Notes Synergistic effect with beta-lactam antibiotics
Administered intramuscularly
Has widespread resistance
For Streptomycin, resistance is due to changes in
the ribosomal binding site
If given together with Pens can be used for
enterococcal endocarditis, TB plague and
tularemia

NEOMYCIN
SimD KANAMYCIN, PAROMOMYCIN
Class Aminoglycoside
MOA Inhibit protein synthesis by binding to 30S
subunit. Bactericidal.
Uses Skin infections, Bowel preparation for elective Antifolate Drugs
surgery (to decrease aerobic flora), Hepatic
encephalopathy, Visceral leishmaniasis Sulfonamides
(paromomycin)  weakly acidic compounds that have a common chemical
SE Hypersensitivity, Nephrotoxicity (reversible), nucleus resembling p-aminobenzoic acid (PABA)
Ototoxicity (irreversible), Neuromuscular  solubility may be decreased in acidic urine
blockade
o combination of 3 separate sulfonamides (triple
Notes Limited to topical and oral use (Neomycin) sulfa) to reduce the likelihood that any one
Reverse neuromuscular blockade with calcium
drug will precipitate
gluconate and neostigmine
 classification
Kanamycin is most ototoxic
Short Acting Intermediate Long Acting
Acting
SPECTINOMYCIN
Sulfacytine Sulfadiazine Sulfadoxine
Class Aminoglycoside
Sulfisoxazole Sulfamethoxazole * Pyrimethamine
MOA Inhibit protein synthesis by binding to 30S
Sulfamethizole Sulfapyridine
subunit. Bactericidal.
* Trimethoprim
Uses Drug-resistant gonorrhea, Gonorrhea in penicillin-
allergic patients
Trimethoprim
SE Nephrotoxicity (reversible), Ototoxicity
 structurally similar to folic acid
(irreversible), Neuromuscular blockade, Anemia
 weak base that is trapped in acidic environments
Notes No cross-resistance with other drugs used in
 reaches high concentrations in prostatic and vaginal
gonorrhea
Given Intramuscularly fluids

Toxicities of Aminoglycosides MOA of Antifolates

 OTOTOXICITY  SULFONAMIDES
o MOST OTOTOXIC: kanamycin, amikacin o bacteriostatic inhibitors of folic acid synthesis
o MOST VESTIBULOTOXIC: tobramycin, o competitive inhibitors of dihydropteroate
gentamicin synthase
o cumulative ototoxicity when used with loop o selective toxicity of sulfonamides results from
diuretics the inability of mammalian cells to synthesize
 NEPHROTOXICITY folic acid
o acute tubular necrosis o must use preformed folic acid that is present in
o MOST NEPHROTOXIC: tobramycin, gentamicin the diet
 Toxicities of Aminoglycosides  TRIMETHOPRIM (intermediate acting)
 NEUROMUSCULAR BLOCKADE o selective inhibitor of bacterial dihydrofolate
o curare-like effect (nondepolarizing NMJ block) reductase
reversible with calcium and neostigmine o bacterial dihydrofolate reductase is 4–5x more
sensitive to inhibition by trimethoprim
 SKIN REACTIONS
o commonly from Neomycin and Streptomycin  TRIMETHOPRIM PLUS SULFAMETHOXAZOLE
o when the 2 drugs are used in combination,
antimicrobial synergy results from the sequential
OTHER PROTEIN SYNTHESIS INHIBITOR
blockade of folate synthesis
o drug combination is bactericidal
Pharma Lecture with Dr. Maria Yña Eluisia T. Pereyra-Borlongan 9

 Trimethoprim: used for lower UTI, may be safely given

to patients with sulfonamide allergy
 Pyrimethamine: co-administered with Leucovorin to limit
bone marrow toxicity

Toxicity of Sulfonamides
 HYPERSENSITIVITY
o spectrum: EM, SJS/TEN, PAN, exfoliative
dermatitis
o most common drug triggers
o cross-allergenicity should be assumed
 GASTROINTESTINAL DISTRESS
o nausea, vomiting, diarrhea and mild hepatic
dysfunction
 HEMATOTOXICITY
o granulocytopenia, thrombocytopenia, aplastic
anemia
Resistance to Antifolate Drugs
o cause acute hemolysis in G6PD deficient patients
 plasmid-mediated and results from:
o Toxicity of Sulfonamides
o decreased intracellular accumulation of the
 NEPHROTOXICITY
drugs
o crystalluria, hematuria
o increased production of PABA by bacteria
 DRUG INTERACTIONS
o decrease in the sensitivity of dihydropteroate
o displace protein binding affecting levels of
synthase to sulfonamides
warfarin and methotrexate
o displace bilirubin binding sites leading to
SILVER SULFADIAZINE [B] kernicterus
SimD MAFENIDE ACETATE [C] o
Class Sulfonamide Kernicterus
MOA Inhibit dihydropteroate synthase. Bacteriostatic.  caused by increased levels of unconjugated bilirubin
Uses Burn infections  due to immaturity of fetal blood brain barrier
SE GI upset, Acute hemolysis in G6PD deficiency,  histopathology
Nephrotoxicity, Hypersensitivity (assume cross- o bilirubin deposits in subcortical nuclei and basal
hypersensitivity, SJS/TEN), Hematotoxicity, Drug ganglia
interactions, Kernicterus  clinical presentation
Notes Displaces protein binding of other drugs/bilirubin o hypo/hypertonia, lethargy, high-pitched cry,
opisthotonos
CO-TRIMOXAZOLE [D]
Class Sulfonamide Quinolones
MOA Sequential blockade of dihydropteroate synthase
MOA of Quinolones
(Sulfamethoxazole) and dihydrofolate reductase
 interfere with bacterial DNA synthesis by inhibiting:
(Trimethoprim). Bactericidal.
o topoisomerase II (DNA Gyrase) in gram-negative
Uses Urinary tract, respiratory, ear and sinus infections
organisms
(Haemophilus, Moraxella, Aeromonas), P jiroveci
 prevents relaxation of supercoiled DNA
pneumonia, Toxoplasmosis, Nocardiosis, Cholera
o topoisomerase IV in gram-positive organisms
(backup), Typhoid fever, Shigellosis
 interferes with the separation of
SE GI upset, Acute hemolysis in G6PD deficiency, replicated chromosomal DNA during
Nephrotoxicity, Hypersensitivity (assume cross- cell division
hypersensitivity, SJS/TEN), Hematotoxicity, Drug
 usually bactericidal against susceptible organisms
interactions, Kernicterus
 exhibit postantibiotic effect
Notes Displaces protein binding of other drugs/bilirubin
 should not be taken with other preparations containing
Low solubility in acidic urine causing formation
cations (should be taken 2 hours before or 4 hours after
of stones
any product containing cations)
Resistance is due to plasmin-mediated (decreased
 may damage growing cartilage and cause arthropathy
intracellular accumulation of the drug, increased
production of PABA by bacteria, decreased
Resistance to Fluoroquinolones
sensitivity of dihydropteroate synthetase to
 decreased intracellular accumulation of the drug via the
sulfas and production of dihydrofolate
production of efflux pumps
reductase that has decreased affnity for the
 changes in porin structure
drug
 changes in the sensitivity of the target enzymes via point
Sulfonamides are formulated in a 5:1 ratio with
mutations in the antibiotic binding regions
trimethoprim
Classification of Fluoroquinolones
Other Sulfonamides and Antifolate Drugs:  1ST GENERATION
 Sulfisoxazole : only for lower UTI o Nalidixic acid, Cinoxacin, Rosoxacin, Oxolinic
 Sulfadiazine-Pyrimethamine: DOC for Toxoplasmosis
acid
 Sulfadoxine-Pyrimethamine: 2nd line agent for Malaria  2ND GENERATION
Pharma Lecture with Dr. Maria Yña Eluisia T. Pereyra-Borlongan 10

oCiprofloxacin, Ofloxacin, Norfloxacin, Notes Avoid use in young children and pregnant women
Lomefloxacin, Enoxacin Enhance toxicity of methylxanthines
 3RD GENERATION (theophylline)
o Levofloxacin, Gemifloxacin, Moxifloxacin, Grepafloxacin withdrawn due to severe
Sparfloxacin, Grepafloxacin, Gatifloxacin, cardiotoxicity (arrhythmias), Gatifloxacin has
Pazufloxacin, Tosufloxacin, Balofloxacin also been withdrawn due to Diabetes mellitus
 4TH GENERATION Moxifloxacin ha shepatice clearance  lower
o Trovafloxacin, Alatrofloxacin, Prulifloxacin, urinary levels, so use in UTI is not recommended
Clinafloxacin High resistance esp for C. jejuni, gonococci, G+
cocci like MRSA, Pseudomonas and Serratia
Antimicrobial Spectrum of Fluoroquinolones Are used as alternative to Ceftriaxone and
 1st Generation: urinary tract infections Cefixime in gonorrhea
 2nd Generation: gram negatives, gonococci, gram positive Ofloxacin can be used against C. trachomatis
cocci and Mycoplasma "Respiratory Quinolones"
 3rd Generation: less gram negative and more gram positive Moxifloxacin and Gemifloxacin are the newest
activity, streptococci and enterococci members of this family and are condisered to
 4th Generation: broad spectrum, including anaerobes have the broadest spectrum of activity with
o with increasing generation, increasing gram increased activity aginst anaerobes ang atypical
positive activity agents
o unlike cephalosporins where increasing FQ elimination is via kidneys by tubular secretion
generation leads to increasing gram negative (may compete with probenecid for excretion)
activity EXCEPT Moxifloxacin
NEVER use moxifloxacin in UTI
CIPROFLOXACIN [C] Levofloxacin is used in CAP caused by
SimD OFLOXACIN [C], NORFLOXACIN[C], Chlamydia, Mycoplasma and Legionella
LOMEFLOXACIN [C], ENOXACIN [C] Gemifloxacin, Levofloxacin and Moxifloxacin
Class Fluoroquinolone (2nd Generation) can prolong Q
MOA Inhibits DNA replication by binding to DNA gyrase Levofloxacin has superior activity against G(+)
and topoisomerase IV. Bactericidal. bacteria including S. pneumoniae ; All have
Uses Urinary tract infections and GIT infections (gram- relatively long t1/2 permitting once daily dosing
negative rods (such as Shigella, Salmonella, ETEC Oral absorption is impaired by cations
& Campylobacter), gonococci, gram positive Gatifloxacin can cause hyperglycemia in DM Px
cocci), Atypical pneumonia, Tuberculosis (2nd and hypoglycemia in patients also receiving OHA
line drug), Infection of soft tissue, bones and joints and was withdrawn from the market in 2006
; Intra-abdominal MDR organisms (such as
(USA)
Pseudomonas Enterobacter)
SE Gastrointestinal distress, CNS effects (dizziness,
TROVAFLOXACIN [C]
headache), insomnia, skin rash, abnormal LFTs,
SimD ALATROFLOXACIN [C], PRULIFLOXACIN,
Tendonitis and Tendon rupture
CLINAFLOXACIN
Notes Avoid use in young children and pregnant women
Class Fluoroquinolone (4th Generation)
Enhance toxicity of methylxanthines
MOA Inhibits DNA replication by binding to DNA gyrase
(theophylline)
and topoisomerase IV. Bactericidal.
Ciprofloxacis is the most active agent against
Uses Broad spectrum activity (gram-negatives, gram-
Gram Negative orgamisms esp. Pseudomonas
positives), Enhanced activity against anaerobes
General properties of quinolones: good oral
SE Gastrointestinal distress, CNS effects (dizziness,
bioavailability, high Vd, t1/2 3-8hrs, absorption is
headache), Tendinitis, QTc prolongation,
impeded by antacids, elimination is via kidneys by
Hepatotoxicity (trovafloxacin)
tubular secretion (may compete with probenecid
Notes Avoid use in young children and pregnant women
for excretion) EXCEPT for MOXIFLOXACIN
Enhance toxicity of methylxanthines
Norfloxacin does not achieve adequte plasma
(theophylline)
levels for use in systemic infections
Widest spectrum of activity among
fluoroquinolones
LEVOFLOXACIN [C]
SimD SPARFLOXACIN [C], MOXIFLOXACIN [C],
Miscellaneous
GEMIFLOXACIN [C], PAZUFLOXACIN,
TOSUFLOXACIN, BALOFLOXACIN
METRONIDAZOLE [B]
Class Fluoroquinolone (3rd Generation)
SimD TINIDAZOLE [C], SECNIDAZOLE [C]
MOA Inhibits DNA replication by binding to DNA gyrase
and topoisomerase IV. Bactericidal. Class Nitroimidazole, Antiprotozoal
Uses Lung infections caused gram-positive cocci, MOA Reactive reduction by ferredoxin forming free
Atypical pneumonia (Chlamydia, Mycoplasma), radicals that disrupt electron transport chain.
Tuberculosis (2nd line drug) Bactericidal.
SE Gastrointestinal distress, CNS effects (dizziness, Uses Anaerobic or mixed intra-abdominal infections,
headache), Tendinitis, QTc prolongation Vaginitis (Trichomonas, Gardnerella),
Pseudomembranous colitis, Brain abscess,
Protozoal infections
Pharma Lecture with Dr. Maria Yña Eluisia T. Pereyra-Borlongan 11

SE Gastrointestinal irritation, Metallic taste,

Headache, Dark urine, Leukopenia, Dizziness,
Ataxia, Neuropathy, Seizures, Disulfiram reaction
Notes DOC for amoebiasis, giardiasis and
Pseudomembranous colitis

NITROFURANTOIN [B, CI at term]

Class Nitrofuran
MOA Forms multiple reactive intermediates when acted
upon by bacterial nitrofuran reductase  disrupt Drug Therapy for Mycobacterial Infections
protein, RNA and DNA synthesis. Bactericidal.  chemotherapy is complicated by numerous factors
Uses Uncomplicated Urinary tract infections (EXCEPT o limited information about mechanisms of drug
Proteus and Pseudomonas) action
SE Anorexia, Nausea, Vomiting, Skin rashes, o development of resistance
Pulmonary infiltrates, Phototoxicity, o intracellular location of mycobacteria
Neuropathies, Hemolysis in patients with G6PD o chronic nature of mycobacterial disease
deficiency o patient compliance
Notes Proteus and Pseudomonas are resistant  chemotherapy always involves the use of drug
Contraindictaed in Renal insufficiency combinations to delay the emergence of resistance and
to enhance efficacy
MUPIROCIN [B]
Class Topical anti-infective. Pseudomonic Acid Drugs Used in Tuberculosis
MOA Inihibits Staphylococcal isoleucyl tRNA
synthetase. Bactericidal. ISONIAZID [C]
Uses Gram positive cocci including methicillin- Class Antimycobacterial (nicotinic acid derivative)
susceptible and MRSA, for minor skin infections MOA Inhibits mycolic acid synthesis. Bactericidal.
such as Impetigo Uses Tuberculosis (active, latent, prophylaxis)
SE Epistaxis, Stinging or burning sensation on the SE Hepatitis, Neurotoxicity (seizures, neuritis,
skin, mild skin rash, headache insomnia), Acute hemolysis in G6PD deficiency,
Notes Only used topically (available as intranasal Drug-induced lupus, Drug interactions
ointment) Notes Most important drug used in tuberculosis (FIRST
Do not used over large infected areas such as LINE AGENT)
Decubitus ulcers or open surgical wounds (may Prevent neurotoxicity by co-administering
lead to resistance) Pyridoxine (vitamin B6)
Single OD dose can prevent recurrent UTI Liver metabolism by acetylation (Filipinos are fast
Acidification of urine enhances activity acetylators)
Adjust dose in renal patients Potent CYP450 inhibitor
Less Active against other Mycobacteria
POLYMYXIN B [C] Structural congener of pyridoxine
SimD POLYMYXIN E [C] High level resistance due to deletion of KatG
Class Polymyxins. Cationic detergents gene whichh codes for catalase-peroxidase
MOA Attach to and disrupt bacteirla cell membrane, enzyme involved in bioactivation of INH, low
bind and inactivate endotoxin. Bactericidal. level resistance due to deletion og inhA gene
Uses Gram-negative bacteria. For salvage therapy of which encodes the target enzyme which is an
Acinetobacter, Enterobacteriaceae and acyl protein reductase
Pseudomonas aeruginosa. Best taken 1 hour before or 2 hours after meals
SE Eosinophilia, fever, Nephrotoxicity,
Neurotoxicity, Rash, Urticaria MNEMONICS - Isoniazid
Notes Proteus and Neisseria are resistant INH Injures Neurons and Hepatocytes
For Topical use only (to limit toxicity)
RIFAMPICIN (RIFAMPIN) [C]
FIDAXOMICIN [B] SimD RIFABUTIN [B], RIFAPENTINE [C], RIFAXIMIN [C]
Class Macrocyclic, Narrow-spectrum Class Antimycobacterial (rifamycin)
MOA Inhibits bacterial protein synthesis by binding to MOA Inhibits DNA-dependent RNA polymerase 
the sigma subunit of RNA polymersase. inhibits RNA production. Bactericidal.
Bacteriostatic. Uses Tuberculosis (active, latent), Atypical
Uses Gram positive bacteria only, C. difficle colitis in Mycobacterial Infections, Leprosy, Prophylaxis for
adults meningococcal and staphylococcal carriers states,
SE Nausea, Vomiting, Abdominal pain, GI bleeding, Drug-resistant infections (MRSA, PRSP)
Anemia, Neutropenia SE Red-orange Body Fluids, Light chain proteinuria,
Notes Granted Orphan Drug Status for C difficile in Skin rash, Thrombocytopenia, Nephritis,
children Hepatotoxicity, Flulike Syndrome, Anemia,
Cholestasis
Notes Also considered a FIRST LINE AGENT for PTB
ANTIMYCOBACTERIAL DRUGS Potent CYP450 inducer
Rapid development of resistance if used alone
Pharma Lecture with Dr. Maria Yña Eluisia T. Pereyra-Borlongan 12

Delays the emergence of resistance to dapsone Dose adjustment id needed in renal patients
RIFAXIMIN is a Rifampin derivative that is not Always used in combination with other drugs for
absorbed in the GIT, and so is used for the TB
prevention of hepatic encephalopathy, for Take with meals
treatment of traveler’s diarrhea, (off-label use:
for IBS and Pseudomembranous colitis) STREPTOMYCIN [D]
Resistance is due to changes of drug sensitivity Class Antimycobacterial (aminoglycoside)
of the polymerase enzyme MOA Inhibit protein synthesis by binding to S12
Undergoes enterohepatic recirculation ribosomal subunit. Bactericidal.
Orange-colored metabolites Uses Tuberculosis (for Drug-resistant strains),
Delay emergence of resistance to dapsone Tularemia, Bubonic plague, Brucellosis
Rifabutin is equally effective as anti- SE Hypersensitivity, Nephrotoxicity (reversible),
mycobacterial agent with less drug interaction Ototoxicity (vestibulotoxic, irreversible),
and it is the preferred anti-TB for AIDS patients Neuromuscular blockade, Teratogen (congenital
Rifamixin is not absorbed in the GIT and is used deafness), Injection site reactions
for traveler's diarrhea Notes Synergistic effect with beta-lactam antibiotics
Best taken 1 hour before or 2 hours after meals Administered intramuscularly

MNEMONICS - Rifampicin Alternative Antimycobacterial Drugs

R = Rifampicin  AMIKACIN
RNA polymerase inhibitor o streptomycin-resistant or multidrug-resistant
Red-orange body fluids mycobacterial strains
Rapid development of resistance  CIPROFLOXACIN, OFLOXACIN
Revs up cytochrome P450 (inducer) o active against strains of M tuberculosis
resistant to first-line agents
 ETHIONAMIDE
PYRAZINAMIDE [C]
o no cross-resistance with INH
Class Antimycobacterial (pyrazine derivative)
o SE: severe gastrointestinal irritation and
MOA Unknown. Converted to active pyrazinoic acid
neurotoxcity
under acidic conditions of macrophage lysosomes.
Bacteriostatic but can be bacteriocidal on actively  P-AMINOSALICYLIC ACID (PAS)
dividing mycobacteria. o rarely used because primary resistance is
common
Uses Tuberculosis (active)
o SE: gastrointestinal irritation, peptic ulcers,
SE Hepatotoxicity, Nongouty polyarthralgia,
Asymptomatic hyperuricemia, Myalgia, GIT hypersensitivity reactions, effects on kidney,
irritation, Rash, Porphyria, Photosensitivity liver, and thyroid function
Notes Also known as “sterilizing agent” used during the  CAPREOMYCIN
first 2 months of therapy o SE: ototoxicity, renal dysfunction
Most hepatotoxic anti-TB drug  CYCLOSERINE
Require metabolic conversion via o SE: peripheral neuropathy, CNS dysfunction
pyrazinamidases in MTb
Resistance is via mutation in pncA gene which Drugs Used in Leprosy
codes for pyrazinamidases and increased efflux
systems DAPSONE [C]
Decrease dose in hepatic and renal patients SimD ACEDAPSONE [C]
Take with meals Class Antimycobacterial (sulfone)
MOA Inhibition of folic acid synthesis. Bacteriostatic.
MNEMONICS – Hepatotoxicity of Anti-TB Drugs Uses Leprosy, PCP pneumonia (backup)
Which anti-TB drugs are hepatotoxic? SE Gastrointestinal irritation, Fever, Skin rashes,
ISO a Red PYRe! Methemoglobinemia, Acute hemolysis in patients
(I saw a red fire!) with G6PD deficiency
Isoniazid < Rifampin < Pyrazinamide Notes Most active drug against M. leprae
Usually used in combination with rifampicin and
clofazimine
ETHAMBUTOL [B]
Acedapsone is a repository form of dapsone
Class Antimycobacterial (butanol derivative)
which has drug action that can last for several
MOA Inhibits arabinosyl transferases involved in the
months
synthesis of arabinogalactan in mycobacterial cell
wall. Bacteriostatic.
Uses Tuberculosis (active) , atypical mycobacterial CLOFAZIMINE [C]
infections Class Antimycobacterial (phenazine dye)
SE Visual disturbances (decreased visual acuity, red- MOA Binds to guanine bases in bacterial DNA.
green color blindness, retrobulbar neuritis, retinal Bactericidal.
damage), Headache, Confusion, Hyperuricemia, Uses Leprosy (sulfone-resistance)
Peripheral neuritis SE Gastrointestinal irritation, Skin discoloration
Notes Perform baseline opthalmologic examination (ranging from orange to red brown to nearly
before starting antimycobacterial therapy black)
Resistance is due to mutation in emb gene
Pharma Lecture with Dr. Maria Yña Eluisia T. Pereyra-Borlongan 13

Drugs Used for Atypical Mycobacteria

Drugs for Atypical Mycobacteria

 PROPHYLAXIS
o clarithromycin or azithromycin with or without
rifabutin in patients with CD4 counts less than
50/L
 TREATMENT
o azithromycin or clarithromycin with ethambutol
and rifabutin