Antifolate Drugs 17970

Antifolate drugs
Drug class:
Sulfonamides
 sulfonamides are similarity to p-aminobenzoic
 antibacterial properties of Sulfonamides are produced by
attaching substituents to
– the amido group (⎯SO2 ⎯NH ⎯R) or
– the amino group (⎯ NH2) of the sulfanilamide nucleus
Figure: Structures of some sulfonamides and p-aminobenzoic
acid
Mechanism of Action & Antimicrobial Activity
 Sulfonamide-susceptible organisms, cannot use exogenous

folate
– must synthesize it from PABA.
 sulfonamides inhibit dihydropteroate synthase and folate
production.
Spectrum of activity
 Rickettsiae are not inhibited by sulfonamides but stimulated
Gram (+) Gram (-)
Staphylococcus E.coli Nocardia sp
K. pneumoniae Chlamydia trachomatis
Salmonella,
Shigella,
Enterobacter sp
Mechanism of Action & Antimicrobial Activity
Figure: Actions of sulfonamides and trimethoprim.

 sulfonamide with an inhibitor of dihydrofolate reductase
(trimethoprim or pyrimethamine)
– provides synergistic activity because of sequential inhibition of folate
synthesis
Resistance
 Some bacteria lack the enzymes required for folate synthesis
from PABA and depend on exogenous sources of folate;
– not susceptible to sulfonamides.
 Sulfonamide resistance may also occur as a result of
– cause overproduction of PABA,
– cause production of a folic acid-synthesizing enzyme that has low
affinity for sulfonamides
– impair permeability to the sulfonamide..
Pharmacokinetics
Sulfonamides can be divided into three major groups:

– oral, absorbable;
– oral, non-absorbable; and
– topical.
Oral absorbable sulfonamides
 absorbed from the stomach and small intestine
 Protein binding …..20% to over 90%.
Metabolism… acetylated or glucuronidated in the liver.
 Excretion,,,, excreted in the urine, mainly
– must be reduced in patients with significant renal failure.
Clinical Uses
 Sulfonamides are infrequently used as single agents.

 The combination of trimethoprim-sulfamethoxazole is the
drug of choice for
– Pneumocystis jiroveci (formerly P carinii) pneumonia,
toxoplasmosis, and
– nocardiosis.
Oral absorbable
Oral absorbable sulfonamides
 absorbed from the stomach and small intestine
 Protein binding …..20% to over 90%.
Metabolism… acetylated or glucuronidated in the liver.
 Excretion,,,, excreted in the urine, mainly
– must be reduced in patients with significant renal failure
Sulfamethoxazole and Sulfisoxazole is a commonly
– For treatment of UTI
Sulfadiazine + pyrimethamine
– first-line therapy for treatment of acute toxoplasmosis.
Sulfadoxine + pyrimethamine (Fansidar)
– used as a second-line treatment for malaria
.
Oral nonabsorbable agents
Sulfasalazine (salicylazosulfapyridine) is widely used in ulcerative

colitis,
– enteritis, and
– other inflammatory bowel disease
Topical Agents
Sodium sulfacetamide ophthalmic solution
– For treatment of bacterial conjunctivitis and
– as adjunctive therapy for trachoma.
Mafenide acetate
– Topically used but can be absorbed from burn sites.
– parent drug and its metabolite inhibit carbonic anhydrase
• metabolic acidosis…..limits its usefulness.
Silver sulfadiazine is a less toxic
– preferred to mafenide for prevention of infection of burn
wounds.
Adverse Reactions
The most common adverse effects are

 fever, skin rashes, exfoliative dermatitis, photosensitivity,
urticaria, nausea, vomiting, diarrhea,
Stevens-Johnson syndrom… uncommon (<1% ) but
– serious and potentially fatal.
 Other unwanted effects include
 stomatitis, conjunctivitis, arthritis, hematopoietic disturbances),
hepatitis, and, rarely, polyarteritis nodosa and psychosis.
Adverse Reactions…
Urinary Tract Disturbances
Sulfonamides urine at neutral or acid pH,
– producing crystalluria, hematuria, or obstruction.
• But rare with the more soluble sulfonamides (eg, sulfisoxazole).
– Sulfadiazine and sulfamethoxazole ..relatively insoluble in

(low pH) cause….crystalluria,
 Crystalluria is treated by administration of sodium bicarbonate
and fluids
Adverse Reactions…
Hematopoietic Disturbances
 Sulfonamides can cause
– hemolytic or aplastic anemia,
– granulocytopenia,
– thrombocytopenia, or
– leukemoid reactions.
 Sulfonamides may provoke hemolytic reactions in G-6-P
dehydrogenase deficiency.
 Sulfonamides ….. increase the risk of kernicterus in
newborns.
Trimethoprim & trimethoprim-sulfamethoxazole combination
Trimethoprim is a much less efficient inhibitor of mammalian

dihydrofolic acid reductase.
 combination of trimethoprim and sulfamethoxazole is often
bactericidal,
 But sulfonamide alone is bacteriostatic
.
Pharmacokinetics
Trimethoprim given orally/IV, alone or in combination with

sulfamethoxazole
Both has a similar half-life.
Given as (1:5 ration) TMP-SMX
1 part of trimethoprim is given with 5 parts of sulfamethoxazole
30–50% of the sulfonamide and 50–60% TMP of the ..excreted in the

urine within 24 hours.
– Dose be reduced by 50 % with creatinine clearances of 15–30 mL/min.
Trimethoprim concentrates in prostatic fluid and in vaginal fluid,

– has more antibacterial activity in this areas.
Clinical uses
Oral Trimethoprim
 Trimethoprim 100 mg twice daily in acute UTI
Oral Trimethoprim-Sulfamethoxazole (TMP-SMZ)
effective treatment for a wide variety of infections
 PCP ⸻ Respiratory infections
 UTI ⸻ uncomplicated skin and soft tissue
 Prostatitis ⸻ nontuberculous mycobacteria.
 Shigella
 Salmonella
 MSSA and MRSA
In UTI……UP to 30% in E.coli pneumococci
consider to resistance before using as an empiric
Clinical uses…
 Infections with P jiroveci, Nocardia or Stenotrophomonas maltophilia
 Treated with high doses of the either the PO or IV (15–20 mg/kg/d).
 in immunosuppressed patients Prophylaxis P jiroveci …..one double-

strength tablet daily or three times weekly.
Intravenous Trimethoprim-Sulfamethoxazole
 for moderately severe to severe pneumocystis pneumonia
 for Gram-negative bacterial sepsis

– replaced by extended spectrum β-lactams and fluoroquinolones.
 Used as an alternative for multidrug-resistant infection

 serious Listeria infections (unable to tolerate ampicillin).
– 10–20 mg/kg/d of the trimethoprim component.
Oral Pyrimethamine with Sulfonamide
They are used in the treatment of toxoplasmosis.

Dosage…..sulfadiazine is 1–1.5 g (4X) +
pyrimethamine 200-mg loading followed by 50-
75 mg QD
 Leucovorin (folinic acid)….10 mg orally each
day
– to minimize bone marrow suppression
trimethoprim-sulfamethoxazole as an alternate
option if pyrimethamine is not available.
.
Adverse Effects
Trimethoprim
megaloblastic anemia,
leukopenia, and
Granulocytopenia
Nausea and vomiting, drug fever, vasculitis, renal
damage,
CNS disturbances occasionally
Patients with AIDS + PCP
– have a particularly high frequency of untoward reactions to
trimethoprim-sulfamethoxazole, especially fever, rashes,
leukopenia, diarrhea, elevations of hepatic
aminotransferases, hyperkalemia, and hyponatremia.
Adverse Effects
 Trimethoprim inhibits secretion of creatinine

– mild elevation of serum creatinine without
impairment of GFR.
• important to distinguish from true nephrotoxicity that
may be caused by sulfonamides.

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Antifolate drugs

 Sulfonamide-susceptible organisms, cannot use exogenous

Figure: Actions of sulfonamides and trimethoprim.

Sulfonamides can be divided into three major groups:

 Sulfonamides are infrequently used as single agents.

Sulfasalazine (salicylazosulfapyridine) is widely used in ulcerative

The most common adverse effects are

– Sulfadiazine and sulfamethoxazole ..relatively insoluble in

Trimethoprim is a much less efficient inhibitor of mammalian

Trimethoprim given orally/IV, alone or in combination with

Both has a similar half-life.

Given as (1:5 ration) TMP-SMX

1 part of trimethoprim is given with 5 parts of sulfamethoxazole

30–50% of the sulfonamide and 50–60% TMP of the ..excreted in the

Trimethoprim concentrates in prostatic fluid and in vaginal fluid,

 in immunosuppressed patients Prophylaxis P jiroveci …..one double-

 for Gram-negative bacterial sepsis

 Used as an alternative for multidrug-resistant infection

They are used in the treatment of toxoplasmosis.

 Trimethoprim inhibits secretion of creatinine

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