PHARMACOLOGY

5.01 CHEMOTHERAPEUTIC DRUGS

DR. LOUELLA SANGALANG | JULY 2022

OUTLINE Factors to consider for a particular patient:

I. Chemotherapeutic VII. Antifolate Drugs o Signs and symptoms
Drugs A. Sulfonamides o Severity
II. Objectives B. Trimethoprim and o Allergy to drugs
III. Antimicrobial Drugs TMP- o Age group of patients
IV. Antibacterial Drugs Sulfamethoxazole
V. Beta-Lactam Drugs Mixture The gold standard for knowing that the antibiotic is
A. Penicillin G VIII.DNAse Gyrase recommended for a particular area is blood culture
B. Cloxacillin Inhibitors and sensitivity which gives a result in 5 to 10 days.
C. Amoxicillin A. Fluoroquinolones This process is only done if the antibacterial drug
D. Cephalosporin IX. Antimycobacterial is available in the laboratory if not, you can derive
E. Extended spectrum Drugs from the other drugs available.
penicillins. A. Isoniazid Minimum inhibitory concentration: With just
VI. Protein Synthesis B. Rifampin lesser amount of antibiotics killing occur, choose
Inhibitors C. Pyrazinamide the drug with the lowest MIC.
A. Chloramphenicol D. Ethambutol For example:
B. Tetracyclines E. Streptomycin MIC of Penicillin:14, Cefuroxime:17, Co-Amoxiclav:
C. Macrolides X. Role of New Drugs 20
D. Aminoglycosides XI. Policies on Case - If this is the case, PENICILLIN is used for
Finding that organism.
XII. Anti-tuberculous • Action
Medications ® Bacteriostatic: stop bacteria from multiplying
® Bactericidal: kills bacteria
LEGENDS • Bacterial Vulnerability:
Remember Lecturer Book Presentation ® Susceptibility: presence of antimicrobial targets
§ It is a general term
® Sensitivity: necessary effective concentration
I. CHEMOTHERAPEUTIC DRUGS § It is more specific
• Microorganisms and Antimicrobials ® Resistance: target not present, mutation prevents
® Bacteria: Antibacterial antimicrobial activity
® Viruses: Antiviral • Mechanisms of Action
® Fungi: Antifungal ® Disruption of cell wall synthesis
® Parasites: Antiparasitic ® Inhibition of protein synthesis
® Inhibition of DNA synthesis or damage to DNA
II. OBJECTIVES ® Disruption of cell membrane
• Mechanisms Of Action ® Metabolism
• Pharmacokinetics • Bacterial Cell Energy
• Clinical Uses ® Aerobic: with oxygen
• Resistance ® Anaerobic: without oxygen
• Adverse effects § It is harder to kill, so we give higher dose of a drug
• Main classes of drugs used to treat pathogens provide because they are fastidious.
examples of some specific drugs from each class that are § If you think that a patient has acquired nosocomial
used clinically infections, you must consider an anaerobic infection.
V. BETA-LACTAM ANTIBIOTICS
III. ANTIMICROBIAL DRUGS • Penicillin
• Beta-Lactam Antibiotics and Other Inhibitors of Cell Wall • Cephalosporins
Synthesis Penicillins, Cephalosporins and Cephamycins ® The higher the generation the higher the effect
• Chloramphenicol, Tetracylines, Macrolides, Clindamycin ® 1st generation: G+
and Streptogramins
® 2nd generation: G+ and some G – (Cefuroxime)
• Aminoglycosides and Spectinomycin
® 3rd generation: has more penetration in the BBB
• Sulfonamides, Timethoprim, and Quinolones
® 4th generation: Never start with this generation
unless the lower generations are already
IV. ANTIBACTERIAL DRUGS
resistant.
• Spectrum of Action
• Monobactams
® Broad: wide range of bacteria
• Carbapenems
® Narrow: limited to subset of bacteria
• ß-lactamase inhibitors
• Basic structure: 6-aminopenicillanic acid

TRANS Adawe, Callueng, Gervacio, Llanto, Mago, Novero, Pagunuran, Pattaguan, Singh, Talaue, Villafuerte 1 of 9
5.1 Chemotherapeutic Drugs
® Thiazolidine ring attached to the ß-lactam ring Destroyed by ß-
(secondary amino group), substituents (R group) lactamase; acid stable; G
® If ß-lactam ring is cleaved by bacterial ß-lactamases → → Ampicillin (-) > G (+)
penicilloic acid → no antibacterial activity → It was previously used as Not used in beta
® Structural integrity of the 6-aminopenicillanic acid drops and in capsules but lactamase producing
nucleus (rings A plus B) is essential for the biologic later on stopped because pseudomonas aeruginosa
activity of these compounds. it was found out that only and Enterobacter spp.
• MOA: Inhibit cell wall synthesis. 20% is absorbed
® Inhibit bacterial growth by interfering with the therefore, it is no longer Retain antibacterial
transpeptidation reaction of bacterial cell given orally, it is given in spectrum of penicillin and
wall(peptidoglycan) synthesis. IV either for pediatrics or has improved activity
• GASTRIC ACID STABLE SUITABLE FOR ORAL adults. against Gram(-)
INGESTION: → Half life: 1 hr
® Penicillin V, Dicloxacillin, Amoxicillin. Effective against
• Administration should be 1-2 hours after meal except for shigellosis.
Amoxicillin Ticarcillin
Piperacillin G (-) anaerobes
® Due to inactivation by food.
Mezlocillin
• Clinical uses:
Like ampicillin but better
® Blood levels of all penicillins can be raised by Amoxicillin
absorbed
simultaneous administration of probenecid, 0.5 g (10
Methicillin
mg/kg in children) every 6 hours orally, which impairs
- Beta lactamase
renal tubular secretion of weak acids such as β-lactam
resistant
compounds.
® Never be used against viral infection.

Table 1. Beta-Lactam Drugs and Spectrum of Activity

Penicillin G
(Benzylpenicillin)
→ Acid labile: easily disturbed destroyed by ß-lactamase
by acidic environment
Oxacillin (Parenteral form)
Cloxacillin (Oral form)
Dicloxacillin
Flucloxacillin
- These 2 last drugs are
much stronger than the → For mild to moderate
first 2 for very stubborn
staphylococcal
infections.
→ ß-lactamase resistant;
acid stable
→ 0.25–0.5 g orally every
4–6 hours (15–25
mg/kg/d for children)
→ Excretion: Kidney and
biliary excretion.
Nafcillin
(ethoxynapthamidopenicillin)
Commercially known as
Unipen
→ Beta lactamase resistant. staphylococcal infections
→ Absorption: erratic GI
absorption, hence not for
oral administration.
Distribution: Highly
protein bound.
→ Excretion: Biliary
excretion.
G (+) > G(-); acid labile;
They are not affected by
the acidic GI mucosa
therefore they are not
degraded, and they reach
the absorption area.
staphylococcal
infection.
→ For serious systemic
staphylococcal
infections, oxacillin or
nafcillin, 8–12 g/d, is
given by intermittent
intravenous infusion
of 1–2 g every 4–6
hours (50–100
mg/kg/d for children).
but for very stubborn
you already need
Linezolid for MRSA.
For Staph and strep that
acquired resistance.
Figure 1. Mechanism of Action of Beta-Lactam Antibiotics
• Absorption: Variable/impaired by food
• Distribution: Most tissues except CNS, prostate (unless
inflamed)
• Elimination: Mainly excreted unchanged in urine
• Main Adverse Effects (Penicillins):
® Hypersensitivity - mild allergy to anaphylactic
® Colitis - penicillins can disturb gut flora
• Four General Mechanisms of Resistance
® Inactivation of antibiotic by ß lactamase
® Modification of target penicillin binding proteins (PBP)
Because b-lactam antibiotics inhibit many different
PBPs, their affinity for several PBPs must decrease to
confer resistance
® Impaired penetration of drug to target PBPs In gram-
negative bacteria, the inner membrane is covered by the
outer membrane, lipopolysaccharide, and capsule,
which block access of some antibiotics.
§ Only in gram negative spp. Due to impermeable cell
membrane.

PHARMACOLOGY 2 of 9
5.1 Chemotherapeutic Drugs
® Presence of efflux pump Active efflux pumps also can
remove the antibiotic before it can act.
§ Gram negative spp.
§ Cytoplasmic and periplasmic protein components that
efficiently transport some β-lactam antibiotics from the
periplasm back across the outer membrane.
A. Penicillin G
• Not acid stable (it readily gets denatured by the stomach
acid) therefore must be injected
• Most penicillins are formulated as the sodium or potassium
salt of the free acid.
Penicillin V is the oral Penicillin.
• Effective against gram (+) organism, gram (-) cocci and
non-beta lactamase producing anaerobes.
• Effective against gram (+) anaerobic bacteria
® Why gram (+) and not gram (-) ?
§ Have difficulty penetrating outer membrane
§ Beta-lactamases in periplasmic space of gram (-)
bacteria
• Penicillin destroyed before it can bind to transpeptidases
Readily hydrolyzed by penicillinase and therefore
ineffective against most strains of S. aureus.
• Drug of choice for streptococcal (eg. pharyngitis,
pneumonia) and meningococcal (eg. meningitis)
infections, some enterococci, pneumococci, non beta
lactamase producing staphylococci, treponema
pallidum, other spirochetes, Clostridium spp.,
actinomyces, other gram positive rods, and non beta
lactamase producing gram negative anaerobic
organisms.
• Administration of Penicillin V (oral).
® 4x a day
• A single intramuscular injection of benzathine penicillin, 1.2
million units, is effective treatment for β-hemolytic
streptococcal pharyngitis, given intramuscularly once
every 3–4 weeks, it prevents reinfection.
• Benzathine penicillin G, 2.4 million units intramuscularly
once a week for 1–3 weeks, is effective in the treatment of
syphilis.
• Units and Preparations
® Crystalline sodium penicillin G 1600 units/mg (1
unit=0.6ug; 1 million units of penicillin=0.6g)
® Potassium penicillin G benzathine/procaine – parenteral
form
® Penicillin V – oral: 250, 500mg tabs
• Serum concentrations 30 minutes after an intravenous
injection of 1 g of a penicillin are 20–50 mcg/ mL.
• Half-life: 30 mins, w/ Renal failure: 10 hrs.
• Excretion: Via kidneys
® 10% GFR
® 90% tubular secretion.
B. Cloxacillin
• Acid stable therefore given orally
• Beta-lactamase resistant
• Effective against beta-lactamase producing
staphylococcal infections (e.g.. toxic shock syndrome
PHARMACOLOGY
C. Amoxicillin
• Acid stable - given orally
• Extended spectrum: gram (+) and some gram (-) bacteria
(eg. E.Coli)
• Used to treat infections caused by penicillin resistant
bacteria (eg. S. pneumonia)
• Degraded by beta-lactamase
® More effective when given with beta-lactamase inhibitor
(eg. Clavulanic acid)
• 250–500 mg three times daily, is equivalent to the same
amount of ampicillin given four times daily.
• Given orally to treat urinary tract infections, sinusitis, otitis,
and lower respiratory tract infections.
• Ampicillin and Amoxicillin: the most active oral abx against
pneumococci.
•
D. Cephalosporin
• Similar to penicillins (mechanism of action, distribution,
elimination, adverse effects).
• More stable to beta lactamases, hence broader spectrum.
• Most not acid stable therefore cannot be given orally
• Not as sensitive as penicillins to degradation by beta-
lactamases
• Only 5 to 10 % of individuals with penicillin allergies are
also allergic to cephalosporins
• Should be avoided in individuals with history of
anaphylaxis to penicillins
The generation depends on the degree of coverage of the
cephalosporin
• Not active against listeria and enterococci.
• Nucleus: 7-aminocephalosphoranic acid.
• Cephalosporins divided into 4 generations.
• Refer to the table 43-2 (appendix)
® 1st generation (early cephalosporins):
§ Gram (+) e.g. cefazolin (used as prophylactic
following surgery)
§ Have oral forms
§ cefadroxil, cephalexin, cephradine.
- 500mg oral dose (15-20mcg/ml serum level) 4x a
day.
§ Cefazolin is the only first-generation parenteral
cephalosporin still in general use.
- Also a drug of choice for surgical prophylaxis.
- Alternative antistaphylococcal for penicillin allergic
patients.
§ Cannot cross BBB hence not used for meningitis.
§ Blood Concentration is increased by probenecid.
® 2nd generation:
§ Gram (+) & gram (-) extended gram negative
coverage.
§ Have oral forms.Ex: Cefuroxime (for UTI)
§ Cefoxitin, cefmetazole, and cefotetan are active
against B fragilis and some serratia strains but are
less active against H influenzae
§ Cefamandole, cefuroxime, cefonicid, ceforanide, and
cefaclor are active against H influenzae but not
against serratia or B fragilis.
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5.1 Chemotherapeutic Drugs
® 3rd generation:
§ Good against gram (-) aerobes some cross into CNS
readily e.g. cefotaxime used to treat meningitis)
§ Hydrolyzed by extended spectrum beta lactamases.
§ No oral forms
§ Active against Citrobacter , S marcescens , and
Providencia
§ They are also effective against β-lactamase-
producing strains of haemophilus and neisseria.
§ Third-generation cephalosporins should be avoided in
treatment of enterobacter infections even if the clinical
isolate appears susceptible in vitro—because of
emergence of resistance.
® 4th generation:
§ Like 3rd generation but more resistant to beta-
lactamases
§ However like 3rd generation, it is hydrolyzed by
extended spectrum beta lactamases.
§ Cefepime has good activity against P aeruginosa,
Enterobacteriaceae , S aureus , and S pneumoniae. It
is highly active against Haemophilus and Neisseria
sp. It penetrates well into cerebrospinal fluid.
§ Half life:2 hrs
§ Cleared by the kidneys.
§ No oral forms:
Not usually used unless warranted by the patient
Ex. Cefipime
Table 2. Classification of Cephalosporins
1st Generation Cephalexin, Cefazolin, Cefadroxil,
Cephalotin, Cephadrine, Cephapirin
2nd Generation Cefuroxime, Cefoxitin, Cefotetan,
Cefamandole
3rd Generation Ceftriaxone, Cefotaxime,
Cefoperazone, Ceftazidime
4th Generation Cefepime
The higher the generation the more extensive the
cephalosporin
E. Extended spectrum penicillins.
• Aminopenicillins, Carboxypenicillins and
Uridopenicillins.
• Have greater activity than penicillin against gramnegative
bacteria because of their enhanced ability to penetrate the
gram-negative outer membrane.
• Inactivated by beta lactamases.
VI. PROTEIN SYNTHESIS INHIBITORS
A. Chloramphenicol
• Effective bacteriostatic broad-spectrum
• Aerobic and anaerobic gram (+) and gram (-) organisms
• Use is limited due to side effects
• An almost “ideal” antibiotic (inexpensive)
• Has good penetration
• MOA
® Inhibits protein synthesis by reversibly binding to 50s
of the bacterial ribosome
® Inhibits peptidyl transferase step of problem
synthesis - specific step
• Absorption: rapid and complete
PHARMACOLOGY
• Distribution: virtually all tissues (including CNS)
• Elimination: metabolized in liver (conjugation), excreted in
urine
• Drug of choice for typhoid fever and eye infection
except chlamydia
• Considered treatment of rickettsial infection
• Alternative drug for meningococcal infection in cases
of hypersensitivity reaction to ß-lactam antibiotics
• Dose: 50-100mg/kg/d in 4 divided doses
• For blood-brain barrier infections - 100mg/kg/d
• Adverse Effects
® Nausea and vomiting
® Diarrhea
® Oral or vaginal candidiasis
® Aplastic anemia- suppress red cell production
® Gray baby syndrome – newborns who lack effective
glucuronic acid conjugation for degradation and
detoxification (vomiting, flaccidity, hypothermia, gray
color, shock, collapse)
• Drug Interactions: Inhibits liver enzymes that metabolize
other drugs
• Results in toxicity
® Warfarin - lowers the number of clotting factors
B. Tetracycline
• Effective bacteriostatic against many aerobic and
anaerobic gram (+) and gram (-) bacteria
• Enter bacteria in part by passive diffusion in part by active
transport
• Accumulate in susceptible cells
• MOA
® Inhibits protein synthesis by binding to 30s subunit
® Inhibits binding of tRNA to mRNA
• Absorption: variable, depends on specific drug
• Distribution: most tissues, low levels in CNS, crosses
placenta, excreted in milk, bind calcium (no quality that it
can go through the CNS)
• Elimination: some excreted unchanged in urine, others
metabolized by liver, excreted in bile
• Clinical Uses
® Drug of choice for rickettsia, chlamydia, cholera
® Sometimes used for acne
® Formerly used for urinary tract infections, pneumonia
(bacteria resistant)
® Prophylaxis for Leptospirosis
• Adverse Effects
® Nausea, vomiting
® Diarrhea
® Bones and teeth, bind with calcium and deposit in newly
formed bones (impaired long bone formation)
® Teeth discoloration
® Other systems affected: liver toxicity, kidney toxicity,
photosensitivity
® Not given to children under age of 8
• Resistance
® Widespread
® Most common: efflux pump, removes drug from
bacterial cell
® Ribosome protection: production of proteins that
prevent tetracycline binding
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5.1 Chemotherapeutic Drugs
® Enzymatic inactivation (tetracyclinase) • Enteric bacteria
® Facultative anaerobes that can grow in presence or
C. Macrolides absence of oxygen.
Erythromycin • Enter outer membrane of gram (-) bacteria by passive
• Effective against variety of diffusion
® Gram positive: Pneumococci, Streptococci, • Cross cytoplasmic membrane by oxygen-dependent
Staphylococci, Corynebacteria, Mycoplasma, active transport
Legionella, Chlamydia trachomatis, C. psittaci, C. • Transport inhibited in anaerobic conditions
pneumoniae, Helicobacter, Listeria, and certain • Transport may be enhanced by cell-wall active drugs
Mycobacterium (penicillins)
® Gram negative: Neisseria, Bordetella Pertussis, • MOA
Bartonella henselae, B. quintana ® Inhibits protein synthesis by binding irreversibly to 30s
• Useful as penicillin substitute in penicillin-allergic ribosomal subunit
individuals • Bactericidal
• MOA • Absorption: poor oral absorption – injected
® Inhibits protein synthesis by binding to 50s subunit • Distribution: levels not high in most tissues except renal
® Prevents tRNA from accessing donor site cortex
® Bacteriostatic; at high doses bactericidal • Elimination: kidney
• Absorption: • Clinical Uses:
® Destroyed by stomach acid (enteric coated) ® Severe infections caused by G (-) aerobic bacteria
• Distribution: ® Topical administration for infections
® Most tissues, except CNS (do not penetrate BBB) ® Gentamicin by far most important
• Elimination: ® Most gentamicin resistant bacteria will be susceptible to
® Mainly excreted in bile amikacin
• Drug of choice: • Adverse effects
® Diphtheria, community-acquired pneumonia, ® Nephrotoxicity
penicillin substitute § Enhance free-radical formation following
• Resistance: accumulation in renal tubular cells
® Reduced permeability of bacteria § Ordinary dose can be very damaging to kidneys of
® Enzyme inactivation patients with renal disease
® Modification of ribosomal binding unit ® Ototoxicity
• Adverse effects: ® Damages cranial nerve VIII (vertigo, sensorineural
® Nausea, vomiting, diarrhea hearing loss
® Hypersensitivity reactions - likely contributes to acute ® Permanent deafness and/ or vertigo
hepatitis - fever and rash • Aminoglycosides
• Drug interactions: ® Streptomycin
® Inhibits cytochrome P450s ® Gentamicin
® Can increase concentration of some drugs e.g. ® Trobramycin
anticoagulants ® Amikacin
Clarithromycin ® Netilmicin
• Derived from erythromycin by addition of methyl group ® Neomycin
• Improved acid stability ® Kanamycin
• More active against mycobacterium avium
• Longer half-life (6hrs)- twice daily dosing 250-500mg VII. ANTIFOLATE DRUGS
• Major metabolite has antibacterial activity: 14- A. Sulfonamides
hydroxyclarithromycin • Structural analog of p-aminobenzoic acid (PABA) that
• Lower frequency of GI intolerance competitively inhibit dihydropteroate synthase which
Azithromycin inhibits folic acid synthesis
• 15-atom lactone macrolide ring compound • Folic acid - Vitamin B9 - important in red blood cell
• Active against M.avium complex and T. gondii formation
• Slightly less active than erythromycin and clarithromycin • G(+), G(-) bacteria, Nocardia, Chlamydia trachomatis,
against staphylococci and streptococci some protozoa, some enteric bacteria (E. coli, Klebsiella,
• Slightly more active against H. influenza Salmonella, Shigella, Enterobacter
• Highly active against chlamydia • Bacteriostatic - keeps bacteria in the stationary phase of
• Tissue half-life 2-4 days → once daily dosing for 3-5 days growth
D. Aminoglycosides • Pharmacokinetics:
• Include streptomycin, neomycin, kanamycin, ® Oral absorbable
amikacin, gentamicin, tobramycin, sisomicin, § Short, intermediate/ long acting
netilmicin § Absorbed: stomach and small intestines
• Effective against gram (-) enteric bacteria ® oral, nonabsorbable,

PHARMACOLOGY 5 of 9
5.1 Chemotherapeutic Drugs
§ sulfasalazine- ulcerative colitis, enteritis and other topoisomerase IV à prevents the relaxation of positively
inflamm. bowel dx. supercoiled DNA (required for normal transcription and
® Topical replication)
§ Sodium sulfacetamide ophthalmic solution/ointment is • Effective against g(-), limited activity against G (+)
effective in the treatment of bacterial conjunctivitis and • Norfloxacin: least active - once a day
as adjunctive for trachoma • Ciprofloxacin, enoxacin, lomefloxacin, levofloxacin,
® sulfonamides and inactive metabolites are the excreted ofloxacin, pefloxacin (2nd group): G(-) > G (+)
into the urine, mainly by GLOMERULAR FILTRATION • Ciprofloxacin
• Drug of choice for infections of pneumocystis carinii ® Most effective against P aeruginosa (G (-) anaerobic,
pneumonia, toxoplasmosis, nocardiosis fastidous) - causes UTI, respiratory system infection,
• Treatment for bacterial conjunctivitis dermatitis
• Sulfixazole: for UTI, 1g 4x daily ® Given among very severe
• Silver sulfadiazine: for burn wound infection ® Once a day dosing
• Adverse Effects • Levofloxacin
® Common: fever, skin rashes, exfoliative dermatitis, ® Superior against G (+), S pneumonia
photosensitivity, urticaria, nausea, vomiting, diarrhea • Adverse effects
® Stevens-Johnson Syndrome - rare disorder of the skin ® Nausea, vomiting
and mucous membrane ® Diarrhea
® Urinary tract: sulfonamides may precipitate in urine- ® Headache
producing crystalluria, hematuria, or even ® Dizziness
obstruction ® Damage growing cartilage (arthropathy)
® Hematopoietic: aplastic anemia, granulocytopenia, ® Not routinely given to under 18 years old
thrombocytopenia ® Not given to immunocompromised person
B. Trimethoprim and TMP-SMX Mixtures ® Photosensitivity (lomefloxacin and pefloxacin)
• Trimethoprim ® QTc prolongation (gatifloxacin, levofloxacin,
® Inhibits bacterial dihydrofolic acid reductase which gemifloxacin and moxifloxacin)
converts dihydrofolic acid to tetrahydrofolic acid, - a ® Fluoroquinolones
step leading to the synthesis of purines and
ultimately to DNA IX. ANTIMYCOBACTERIAL DRUGS
• More lipid soluble, absorbed in the gut and CNS efficiently • First line: For TB DOTS
• Trimethoprim(TMP)-Sulfamethoxazole(SMX) mixture (1:5 ® Rifampicin
ratio) - best absorbed in gut
® Isoniazid
® Synergistic and bactericidal - kills bacteria
® Pyrazinamide
• Pharmacokinetics:
® Ethambutol
® Orally, alone/combination w/ sulfamethoxazole, IV(w/
® Streptomycin
sulfamethoxazole)
• Second line: Add-ons depending on the patient case
® Well absorbedfrom the gut and distributed widely in body
® Amikacin
fluids and tissues, including CSF
® Aminosalicylic acid
® Trimethoprim (weak base) concentrates in prostatic fluid
and in vaginal fluid ® Capreomycin
• Uses: ® Ciprofloxacin
® Pneumonia ® Clofazimine
® Shigellosis ® Cycloserine
® Salmonella ® Ethionamide
® Diarrhea ® Levofloxacin
® Urinary tract infection ® Rifabutin
• Dose ® Rifapentine
® TMP-SXZ 160mg/800mg q 12 hrs (UTI)
A. Isoniazid
® 8mg/kg for children, shigellosis and UTI
• Inhibits mycolic acid synthesis (myobacterial cell walls)
• Adverse effects:
• Well-absorbed after oral administration
® Antifolate drugs – megaloblastic anemia, leukopenia and
• Good distribution including CSF
granulocytopenia
• Given usually 30 minutes before breakfast, if not, 2 hours
® Nausea and vomiting, drug fever, vasculitis, renal
after breakfast
damage and CNS disturbances
• Acetylated (fast acetylators> slow acetylators)
• Dose
VIII. DNAse Gyrase Inhibitors ® Adult – 300mg
A. Fluoroquinolones ® Pedia – 5mg/kg/day OD (usually 10mg)
• Synthetic fluorinated analogs of nalidixic acid • Peak Plasma Conc: 3-5 ug/mL in 1-2 hrs
• MOA: blocks bacterial DNA synthesis by inhibiting • Side effects
bacterial topoisomerase II (DNA gyrase) and ® Peripheral neuritis

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5.1 Chemotherapeutic Drugs
§ Treated with pyridoxine (Vit B6) 25- 50mg/day
® Optic neuritis (must monitor vision)
® Teratogenic
• Used prophylactically in tuberculin converters
• Used alone or in combination in the treatment of most
cases of TB
B. Rifampicin
• Well-absorbed after oral administration
• Good distribution
• Metabolized in the liver and excreted via the bile
• Inhibits RNA synthesis by binding strongly to the ß subunit
of bacterial DNA-dependent RNA polymerase
• Bactericidal for mycobacteria
• Readily penetrates most tissues and into phagocytic cells
• Kill organisms poorly accessible to many drugs, like
intracellular organisms
• Decreases effectiveness of oral contraceptive (decreasing
the birth control hormone levels)
• Can induce enzymes in your liver that will break down
estrogen faster than normal
• Dose: 600mg/day (10mkd- pedia)
• Prophylaxis for meningococcal carriage: 600mg BID for
2 days
• Hepatotoxic
• Cytochrome P450 inducer
• Adverse reactions:
® Orange color to urine, sweat and tears
® Rashes, thrombocytopenia and nephritis
® May cause cholestatic jaundice and occasionally
hepatitis
C. Pyrazinamide
• Relative of nicotinamide
• Administered orally
• Half-life: 8-11 hours
• Taken up by macrophages and kills bacilli residing
within the acidic environment
• MOA: pyrazinamide is converted to pyrazinoic acid
® Specific target is unknown, but pyrazinoic acid disrupts
mycobacterial cell membrane metabolism and transport
fxns.
• M. tuberculosis only organism susceptible to this drug
• Hepatotoxic
• Dose: 25mkd; or 50-70mg/kg/dose for twice-weekly or
thrice-weekly treatment regimen
• Well-absorbed after oral administration
D. Ethambutol
• Well-absorbed after oral administration
• Crosses the blood brain barrier only if the meninges are
inflamed
• Excreted in the urine
• Inhibitor of mycobacterial arabinosyl transferase
® Involved in the polymerization reaction of aminoglycan,
essential to mycobacterial cell wall
• May cause a decrease in visual acuity (optic neuritis
25mkd)
• May lead to permanent vision loss by inducing a dose- and
duration-dependent optic neuropathy
• Dose: 15-25mg/kg/day
• For tuberculous meningitis 50mg/kg twice – weekly dosing
• Blood peak level 2-5 ug/mL in 2-4hrs
PHARMACOLOGY
• Adverse Effects: hypersensitivity, upset stomach and loss
of appetite
• C/I: children less than 6 y.o. because cannot assess
visual acuity and red-green color discrimination
E. Streptomycin
• Administered intramuscularly
• Antimicrobial activity typical of other aminoglycosides
• Penetrates into cells poorly, active against extracellular
tubercle
• Resistant strains develop so must be used in combination
• Dose: 15mkd IM for weeks or 20-40 mkd for weeks
• Ototoxicity - resulting in hearing loss, ringing in the ear
and or balance disorder
X. ROLE OF NEW DRUGS
• Rifabutin:
® For patients receiving medications having unacceptable
interactions with Rifampin (e.g. persons with HIV/AIDS).
• Rifapentine:
® Used in once-weekly continuation phase for HIV-
negative adults with drug-susceptible noncavitary TB
and negative AFB smears at completion of initial phase
of treatment
• Fluoroquinolones
® Levofloxacin, Moxifloxacin, Gatifloxacin
® Used when:
§ First-line drugs are not tolerated
§ Strains resistant to RIF, INH, or EMB; or
§ Evidence of other resistance patterns with
fluoroquinolone susceptibility
XI. POLICIES ON CASE FINDINGS
• Direct sputum smear microscopy shall be the primary
NTP diagnostic tool.
® It provides definitive diagnosis of active TB.
® The procedure is simple
® It is economical
® A microscopy center would be organized even in remote
areas
• All TB symptomatics must undergo sputum
examination prior to initiation of treatment, w/ or w/o X-ray
results.
• Contraindication: massive hemoptysis - used to
describe a large amount of expectorated blood or rapid rate
of bleeding
• No diagnosis of TB shall be made based on the result of X-
ray examinations alone.
• Program Components
® Types of TB Cases
§ Based on history of antiTB treatment
§ Important in determining Tx regimen
® New: no Tx or < 1month Tx
® Relapse: cured & Sm (+) again
® Return after default (RAD): interrupted Tx; Sm (+)
® Treatment Failure: still (+) on 5th month
® Others: became (+) on 2nd month
® Interrupted Tx; Sm (-)
XI. ANTITUBERCULOUS MEDICATIONS
• H = ISONIAZID
• R = RIFAMPICIN
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• Z = PYRAZINAMIDE • Ringing in
• E = ETHAMBUTOL the ears
• S = STREPTOMYCIN • Abnormal
• Treatment Strategy: DOTS kidney
function
Table 3. Common Adverse Reactions to Drug Treatment test
Signs and • Easy
Caused By Adverse Reaction
Symptoms bruising
Any drug Allergy Skin rash • Slow blood
Blurred or clotting
Ethambutol Eye damage changed color • stomach
vision upset
• Abdominal • Interferes
pain Rifamcyin with
• Thrombocytopeni
• Abnormal • Rifabutin certain
a
liver • Rifapentin medication
• GI intolerance
function e s such as
• Drug interactions
test results • Rifampin birth
Isoniazid, • Fatigue control
Pyrazinamide, or Hepatitis • Lack of pills, birth
Rifampin Appetite control
• Nausea implants,
• Vomiting and
• Yellowish methadone
skin or treatment
eyes
• Dark urine REFERENCES
Tingling • Dra Sangalang’s PPT
Peripheral sensation in
Isoniazid
neuropathy hands and
feet
• Upset
stomach,
vomiting,
• GI intolerance
lack of
Pyrazinamide • Arthralgia
appetite
• Arthritis
• Joint
aches
• Gout (rare)
• Balance
• Ear damage problems
Streptomycin
• Kidney damage • Hearing
loss

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