Pharmacology (Dr.

Albatross)
Anti-Folates and Urinary Antiseptics

8-10 January 2008

ANTI-FOLATE DRUGS  Folinic Acid

I. Sulfonamides - added to combo to minimize one
- inhibitors of folate synthesis marrow suppression
- action is dependent on Sulfanylamide group c. Sulfadoxine
(composed of an amide group)  Only long-acting sulfonamide
Sulfadiazine  Urinary excretion is very slow, resulting to
Sulfodoxine prolonged drug serum level
Sulfamethoxazole  Fansidar = Sulfadoxine + Pyrimethamine
Sulfone - used as second-line Tx for Malaria
Silver suldiazine
Mafenide 2. Oral, Non-Absorbable Agents
II. Trimethoprim a. Sulfasalazine (salicylazosulfapyridine)
- Inhibitors of folate reductase - Used in ulcerative colitis, enteritis and other
Trimetoprim inflammatory bowel disease
Pyrimethamine
Chlorguanide 3. Topical Agents
III. Co-trimoxazole; co-trimazine a. Sodium sulfacetamide ophthalmic solution or ointment
- Effective Tx for bacterial conjunctivitis and as
- inhibitors of folate synthesis and reduction adjunctive therapy for trachoma
DNA GYRASE INHIBITORS b. Mafenide acetate
Floroquinolones - Used topically to prevent bacterial colonization
and infection of burn wounds
Action of Anti-Folate Drugs - Absorbed from burn site and systemic levels are
PABA produced
Dihydropteroate Synthase SULFONAMIDE - Inhibit carbonic anhydrase and can cause
metabolic acidosis
Dihydrofolic acid c. Silver sulfadiazine
Dihydrofolate Reductase TRIMETHOPRIM - Much less toxic topical sulfonamide
- Preferred than mafenide for prevention of
Tetrahydrofolic acid infection of burn wounds because mafenide can
cause metabolic acidosis

Purine According to Duration of Action

1. Short Acting
Sulfasoxazole and sulfamethoxazole
DNA synthesis 2. Intermediate
Sulfadiazine sulfamethoxazole
• Not used along, bacteriostatic only. But combined 3. Long Acting
bacteriocidal Sulfadoxine

SULFONAMIDES Pharmacokinetics
• Structural analogs of PABA that competitively inhibit • Will become bound to protein
dihydropteroate synthase • Reach peak concentration 15 hour
• Inhibit growth by reversibly blocking folic acid • Metabolized in the liver
synthesis • Excreted in the urine
• Inhibit both gram (+) and (-) bacteria, Staphylococci,
ADR
Nocardia, C.trachomatis and some protozoa
(Pneumocystis carinii, Toxoplasma gondii) • Nausea, vomiting, diarrhea, fever, skin rashes,
exfoliative dermatitis, photosensitivity, urticaria
• Some enteric bacteria like E.coli, Klebsiella and
• Steven-Johnson Syndrome
Enterobacter are inhibited
o Particularly serious and potentially fatal type of skin
• Rickettsiae are not inhibited but are actually and mucous membrane eruption
stimulated in their growth • Urinary tract disturbances:
• Varying physical, chemical, pharmacological and o Crystalluria, hematuria, obstruction
antibacterial properties are produced by attaching o Crystalluria is treated by administration of sodium
substituents to the amido group and the amino group bicarbonate to alkalinize the urine and fluids to
• Much more soluble in alkaline than acid pH maintain adequate hydration; advice px to drink
plenty of water
Pharmacokinetics • Hematopoietic disturbances:
1. Oral, Absorbable Agents
a. Sulfisoxazole and Sulfamethoxazole
o Hemolytic or aplastic anemia, granulocytopenia,
 Short to medium acting agents thrombocytopenia, or leukomoid reactions (WBC too
high)
 Used almost exclusively to treat UTI
o Hemolytic reaction in patients with G6PD
b. Sulfadiazine
o Kernicterus in newborns if taken near pregnancy
 Achieves therapeutic concentration in CSF
 Sulfadiazine + Pyrmethamine + Folinic acid Resistance
- first line therapy for Tx of acute • Mammalian cells and some bacteria which lack
toxoplasmosis and leishmaniasis enzymes required for folate synthesis are not
 Pyrimethamine susceptible to sulfonamides
- antiprotozoal agent • Occur as a result of mutations that cause:
- Potent inhibitor of dihydrofolate reductase o Overproduction if PABA

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 Pharmacology – Antimycobacterial Drugs by Dra Alabastro Page 2 of 4

o Production of a folic acid synthesizing enzymes that prostatitis, some nontuberculous mycobacterial
has low affinity for sulfonamides infections
o Loss of permeability to the sulfonamides - Active against many respiratory tract pathoges,
• Oral, absorbable sulfonamides are absorbed from the including pneumococcus, Haemophilus sp.,
stomach and small intestine and distributed widely to Moraxella catarrhalis and Klebsiella pneumoniae,
tissues and body fluids (including CNS and CSF), making it potentially useful alternative to β-
placenta and fetus lactam drugs for Tx of upper respiratory tract
• Bound to serum proteins infections and community-acquired bacterial
• Portion of absorbed drug is acetylated or pneumonia
glucoronidated in the liver C. IV Trimethoprim-sulfamethoxazole
• Excreted in the urine by glomerular filtration - Agent of choice for moderately severe to severe
pneumocystis pneumonia
Clinical Uses - May e used for Gr (-) bacterial sepsis, shigellosis,
• Infrequently used as a single agent typhoid fever or UTI caused by a susceptible
• Former DOC for infections such as P.jiroveci organism when the patient is unable to take
pneumonia, toxoplasmosis, nocardosis and anything by mouth
occasionally other bacterial infections but have D. Oral Pyrimethamine with Sulfonamide
supplanted by fixed combo of trimethoprim- - Used for Tx of Leishmaniasis and toxoplasmosis
sulfamethoxazole
• Useful for Tx of UTI due to susceptible organisms Resistance
• Can result from reduced cell permeability,
TRIMETHOPRIM & TRIMETHOPRIM-SULFAMETHOXAZOLE overproduction of dihydrofolate reductase, or
MIXTURES production of an altered reductase with reduced drug
Trimethoprim binding
- inhibits bacterial dihydrofolic acid reductase • Can emerge by mutation, though more commonly it
Pyrimethmine is due to plasmid-encoded trimethoprim-resistant
- inhibits activity of dihydrofolic acid reductase of dihydrofolate reductases
protoa more than mammalian cells
FLUOROQUINOLONES • Synthetic fluorinated analogs of Nalidixic Acid (a
Chlorguanide Quinolone but not fluorinated)
• Active against variety of Gr (+) and (-) bacteria
Pharmacokinetics
• Absorbed efficiently from GI • MOA: Blocks DNA synthesis by inhibiting bacterial
• More lipid soluble topoisomerase II (DNA gyrase) and topoisomerase IV

• Combination ration Trimetoprim:Sulfa 1:5 • DNA gyrase

• Concentrates in prostatic fluid - for relaxation of positively supercoiled DNA
• Reach peak in 2hrs • Topoisomerase IV
• 2-5% (70% of combine drug) is protein bound - for separation of replicated chromosomal DNA into
• Trimethoprim respective daughter cells during cell division
- Given orally, alone or in combo with sulfamehtoxazole • Excellent activity against Gr(-) aerobic bacteria,
- Absorbed efficiently in the gut and distributed widely limited actively against Gr(+) organisms
in body fluids and tissues • Effective against bacteria is dose-dependent
- Concentrates in prostatic fluid and vaginal fluid
• Trimethoprim-sulfamethoxazole Pharmacokinetics
- Used for UTI • Well absorbed orally and distributed widely in the
- Given IV body fluids and tissues
- Trimethoprim is more lipid soluble so ratio of • Half-lives:
formulation is 1:5 o 3 hrs Norfloxacin, Ciprofloxacin
•
o 10 hrs Pefloxacin, Flerofloxacin
ADR o Longer Sparfloxacin, Levofloxacin, Moxifloxacin,
• Same with Sulfas except more prominent vasculitis, renal Trovafloxacin
damage, CNS disturbances • Significance of half life = longer T½: ↓ dosing
• Megaloblastic anemia, leucopenia, granulocytopenia regimen/less frequently
• Nausea, vomiting, drug fever, vasculitis, renal • Excreted in kidney except by tubular secretion or
damage, CNS disturbances glomerular filtration except Travafloxacin and
o Prevented by administration of Folinic Acid Moxifloxacin which are eliminated by the liver and
• Fever, rash, leucopenia diarrhea, elevation of hepatic Sparfloxacin whose elimination is 50% (kidney) and
aminotransferase, hyperkalemia and hyponatremia 50% (feces)
o Px with AIDS and pneumocystis pneumonia
• Concentration dependent killing
Clinical Uses (Trimetoprim-Sulfas) • Oral absorption is impaired by divalent cations,
including antacids
• Primarily for UTI
• Serum concentration is equal for moral and IV
But due to resistant cases, use of other drugs administration
• First line drug for pneumonia • Alatrovalfloxacin
• Shigellosis - inactive prodrug form of Trovafloxacin for parenteral
• Systemic salmonella (DOC: cloramphenicol) administration
• Prostatis - Rapidly converted to active compound
• Otitis Media - Concentration in prostate, kidney, neutrophils and
macrophages exceed serum concentration
A. Oral Trimethoprim
- can be given alone in acute UTI Resistance
B. Oral Trimethoprim-sulfamethoxazole • Due to one or more point mutations in the quinolone
- Effective Tx for P.jiroveci pneumonia, shigellosis, binding region of the target enzyme
systemic salmonella infection, complicated UTI,
 Pharmacology – Antimycobacterial Drugs by Dra Alabastro Page 3 of 4

o Modification of bacterial DNA gyrase in the amino acid Clinical Uses of Quinolones
at the A subunit; B subunit rarely mutated • Pseudomonas
• Due to change in permeability of the organism Ciprofloxacin, Ofloxacin, Norfloxacin
o Decrease number of porin protein in the outer
membrane of resistant cell • Prostatitis
o Impaired accumulation of drugs to intracellular gyrase Norfloxacin, Ciprofloxacin, Ofloxacin
• Bacterial diarrhea caused by Shigella, Salmonella, ETEC or
• Exhibits cross resistance between quinolones
campylobacter
Any
1st Generation Quinolones
• Soft Tissue infection
o Cinoxacin, Oxolinic Acid, Nalidixic Acid,
Any except Norfloxacin
Pipenidic Acid • Intraabdominal infection
o Non-fluorinated Any except Norfloxacin
o Effective against Gr(-) organisms that causes UTI • Chlamydia
o Gr(+) bacteria are resistant Gonococcal Ciprofloxacin, Ofloxacin
o Use is limited by rapid emergence of resistant • Legionellosis
strains Ciprofloxacin
o Well absorbed; 90% is protein bound
o Excreted rapidly, not for systemic use • TB and atypical mycobacteria
o Therapy lasting more than 2 weeks adversely Ciprofloxacin, Levofloxacin, Ofloxacin
affect liver function (HEPATOTOXIC) • Prophylaxis for meningococcal carrier especially in
o ADR: nausea, vomiting, photosensitivity, neutropenic Px
urticaria, headache, malaise Ciprofloxacin, Levofloxacin
• Atypical pneumonia
2nd Generation Quinolones Levofloxacin, Gatifloxacin, Moxifloxacin
o Ciprofloxacin, Enofloxacin, Flenofloxacin,
Lomefloxacin, Norfloxacin, Ofloxacin,
• UTI caused by multi-drug resistant bacteria
Perfloxacin Ciprofloxacin
o not for patients with pneumonia
o Active against aerobic Gr(-) bacteria particularly
o not used in patients below 18 years old
Enterobacter and Haemophilus sp., N.gonorrhea, o not used for respiratory infections
M.catarrhalis, P.aeuginosa and Campylobacter
o Excellent Gr(-) activity and moderate to good
Adverse Effects
activity against Gr(+) bacteria
• Nausea, vomiting, diarrhea
o Inactive against anaerobes
• Headache, dizziness, insomnia, skin rash, abnormal
o Minimun inhibitory concentrations for Gr(-) cocci
liver function test
and bacilli
• Trovafloxacin
o Methicillin-susceptuble strains of S.aureus are
- restricted indication due to hepatotoxicity
susceptible to these fluoroquinolones, but - associated with acute hepatitis and hepatic failure
methicillin-resistant Staphylococcus are often • Lemofloxacin, Pefloxacin
resistant - photosensitivity
o Nofloxacin
• Grepafloxacin, Sparfloxacin, Gatifloxacin,
- Least active against both Gr(-) and Gr(+)
Levofloxacin, Moxifloxacin
organisms
- CARDIOTOXIC (Q-T prolongation)
o Ciprofloxacin
• Gatifloxacin
- prototype drug
- associated with hyperglycemia in diabetic patients and
- Most active agent against Gr(-), particularly hypoglycemia in patients receiving oral hypoglycemic
P.aeruginosa agents
o Levofloxacin • May damage growing cartilage and cause as
- L-isomer of Ofloxacin and twice as potent arthropathy (reversible)
- Superior activity against Gr(+) organisms, • Not recommended for patients below 18 years old
including S.pnemoniae (destroy bone in growing children)
o Ciprofloxacin and Ofloxacin
• Tendinitis in adults
- moderately active against C.trachomatis,
H.ducreyi, M.tuberculosis(secondary drug),
M.fortiutum URINARY ANTISEPTICS
• Oral agents that exert antibacterial action in the
urine but little or no systemic effect
3rd Generation Quinolones • Used in lower UTI
o Cinafloxacin (IV and PO), Grepafloxacin (PO),
Levofloxacin (PO), Tosulfloxacin (PO) 1. NALIDIXIC ACID
o Broaden activity against anaerobic organism, - same MOA of quinolones
intracellular pathogens and some Gr(+) and (-)
aerobic bacteria 2. NITROFURATION
o No activity against Enterococci - antagonizes action of Nalidixic acid
- Bactriostatic and bactericidal for many Gr(-) and
4th Generation Quinolones (+) bacteria
o Gatifloxacin (IV,PI) and Moxifloxacin (IV), - Pseudomonas and Proteus are resistant
Trovofloxacin, Gemifloxacin - Clinical drug resistance emerges slowly
o Trovofloxacin – very good for anaerobic bacteria - Well absorbed after digestion
o Active in vitro against both typical and atypical - Well absorbed with food or milk
bacterial respiratory pathogen - Metabolized and excreted rapidly so no systemic
antibacterial action is achieved
o Highly active in Enterobacter
- Excreted into urine by both glomerular filtration
o Marginal or no activity against P.aerugiosa and tubular secretion
o Given IV or PO - Enhanced drug activity if urine pH is less than
5.5 (acidic)
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- Can be given for months for the suppression of

chronic UTI
- A single daily dose can prevent recurrent UTI in
women
- No cross resistance to other organism
- Side Effects: anorexia, nausea, vomiting
- Causes neuropathy and hemolytic anemia to
those with G6PD deficiency
- CI: severe urinary insufficiency

3. METHENAMINE MANDELATE
- Decomposes to generate formaldehyde
- Salt of mandelic acid and methenamine
- Distributed throughout body fluids but
decomposition at pH 7.4
- No systemic toxicity
- Rapid metabolism and excretion
- Below pH 5.5, methenamine releases
formaldehyde, which is antibacterial
- Mandelic acid is excreted unchanged in the urine
and bactericidal for some Gr(-) when pH is less
than 5.5
- Proteus is resistant because it makes a strongly
alkaline urine
- CI: hepatic and renal insufficiency
- ADR: GI
- DI: sulfonamides for which they form insoluble
compounds
- Product is ammonia therefore not given with
hepatic insufficiency, renal insufficiency

4. PHENAZOPYRIDINE
- Analgesic action
- Not a urinary antiseptic
- Alleviate dysuria, frequency, burning and
urgency
- The compound azo dye causes orange to red
urine
- Combined with sulfisoxazole
- Overdose causes methemoglobinemia
- Causes GI upset (10%)
- Combine with sulfisoxazole (Azo-Gantrisisn)
- Combine with sulfamethoxazole (Azo-Gantanol)