FOLIC ACID ANTAGONISTS
(Sulfonamides and Related Drugs)
Outline

Overview

• Sulfanilamide was first successful antibacterial, 1935
• Older sulfonamides
  • poor water solubility
  • low potency
  • combination led to
    • crystallization in renal tubules
    • few dose forms
• Both sulfonamides & 2,4-diaminopyrimidines act in folic acid pathway
  • Synergistic combination -- commonly used today
  • Combination is Cidal!
  • Sulfonamides and trimethoprim alone -- Static!
  • Humans: Sulfamethoxazole + trimethoprim
  • Animals: Sulfadiazine + trimethoprim -- (Tribrissen^R, Di-Trim^R)
  • Animals: Sulfadimethoxine + ormetoprim (Primor^R)
  • Often called "Potentiated" sulfas

Structure and chemical characteristics

• Sulfonamides
  • [PABA] [Sulf] Functional group resembles p-Aminobenzoic acid (PABA)
  • Precursor for dihydropteroyl glutamic acid (Folic acid)
  • Poorly water soluble
  • Commonly available as alkaline sodium salts
• Trimethoprim (Proloprim^R, Trimpex^R)
  • [pic] a 2,4-diaminopyrimidine
  • weakly basic
  • Also has antiprotozoal activity

Mechanism of action

• Sulfonamides
  • Competes with PABA to inhibit synthesis of dihydrofolic acid (DHF)
    • Enzyme: Dihydropteroate synthase
  • False synthesis
    • Some sulfonamides can be incorporated into DHF-like compound
    • DHF-like compound can inhibit dihydrofolic acid reductase (DHFR)
  • Sequential blockade
    • Blocking sequential steps improves action, but sulfas alone not strong
• Trimethoprim (TMP)
  • Trimethoprim (TMP) strong inhibitor of DHFR
  • Thus, blocks conversion & recycling of DHF --> THF --> DHF --> THF --> ...
• Combination
  • Sequential blockade strong and synergistic
  • Cidal
  • Blocks synthesis of DHF (sulfa)
  • Thus, blocks conversion & recycling of DHF --> THF --> DHF --> THF --> ...
• Tetrahydrofolic acid (THF, FH-4)
  • Methyl donor in dUMP --> thymidine synthesis
    • Decreased DNA & RNA synthesis
    • Eventually decreased protein synthesis
  • Depleted by sequential blockade
• Selectivity
  • Sulfonamide
    • Bacteria must make own DHF
    • Vertebrates require as vitamin
  • Trimethoprim
    • Different binding affinity for DHFR of vertebrates vs microorganisms
    • Table compares affinity for mammalian , protozoan, and bacterial enzyme

Resistance

• Common
• Cross-resistance common in group
• Plasmid-borne
• Change in organism's DHPt synthase to decrease affinity for sulfa
• By-pass reaction by using "preformed" folic acid
• Abscesses
  • Action decreased by pus / debris
  • Bind to proteins
  • Too much PABA, thymidine, purines, methionine

Sulfonamide Pharmacokinetics

Dose forms

• Nearly every route
• Ophthalmic
  • Sulfacetamide
  • Sulfisoxazole diolamine
• Vaginal sulfonamides no proven efficacy (USPDI10th90)
• Intestinal sulfas
  • For local effect, poorly absorbed
  • Pthalylsulfathiazole as example
    • Note "prefix" typical of these
    • Use of this category is decreasing
  • Sulfasalazine
    • Inflammatory bowel disease (Ulcerative colitis)
    • 33% absorbed
    • 67% metabolized to --
      • sulfapyridine and
      • mesalamine (5-aminosalicylic acid; 5-ASA)
      • These absorbed
      • MOA unknown, but may be antiinflammatory action
      • MOA -- NOT antibacterial
• Systemic sulfas
  • Given IV and mostly PO
  • Few IM -- sterile abscesses -- high pH of solution
  • Human medicine -- USPDI11th91 mentions 3
    • sulfacytine (Renoquid^R)
    • sulfamethoxazole (Gantanole^R)
      (also with trimethoprim; Co-Trimoxazole^R, Bactrim^R, Septra^R)
    • sulfisoxazole [Gantrisin^R]
    • Mostly for urinary tract infections
  • Veterinary medicine
    • sulfadiazine
    • sulfadiazine plus trimethoprim
      (Tribrissen^R, Di-Trim^R)
    • sulfamethazine (Calfspan^R, Span bolet^R)
    • sulfadimethoxine (Albon^R)
      has IM dose form (strongly buffered to neutrality)
    • sulfadimethoxine plus ormetoprim (Primor^R)
    • sulfathiazole
    • Drugs such as sulfamerazine mentioned in older literature no longer available

Distribution

• Widely distributed -- even eye and CSF
  • CSF - 10-50% of plasma
  • Not sulfisoxazole -- only ECF
• Protein binding
  • Some very high
  • Classic for DRUG INTERACTION
    • other drugs
    • bilirubin -- kernicterus in newborn
  • Causes under estimate of Vd
    • sulfamethoxazole Vd = 0.36 L/Kb

Elimination

• Primarily glomerular filtration
• Some tubular secretion (esp those with short half-lives!)
• Alkalinzation of urine
  • Decreases back-diffusion to hasten elimination
  • Increases solubility to decrease crystalization
• Elimination half-lives
  • Human (Dose intervals)
    • sulfacytine -- 4 hr (q6h)
    • sulfamethoxazole -- 6-12 hr (q8h to q12h) if /w tmp (q12h)
      20-50 end-stage renal failure
    • sulfisoxazole -- 3-7 hr (q6h)
      6-12 hr end-stage renal failure
  • Animals -- sulfadiazine
    • cattle -- 10.1 hr
    • sheep -- 7.2 hr
    • swine -- 2.9 hr
    • dogs -- 3.9 hr
    • horses -- 2.7 (with trimethoprim)
  • Dogs do not acetylate sulfonamides
    (Cribb'89)

Sulfonamide Adverse Reactions

Biological

• Disturbances of GI flora

Allergies

• Immunogenic as haptens
• Idiosyncratic reactions
  • Dogs, especially Dobermans
  • Sulfadiazine plus trimethoprim
  • Manifests as
    • polyarthritis
    • fever syndrome
  • Hydroxylamine -- reactive intermediate metabolite of sulfas
    • Intermediate may form haptens
    • Dobermans less ability to detoxify
• Nearly every type of hypersensitivity reaction has been described
• One of more frequent (up to 3%)
  • rarely serious
  • fever, itching, skin rash
• Stevens-Johnson syndrome is less frequent
  • arthralgia and myalgia
  • redness to blistering of skin
  • weakness

Direct toxicity

Miscellaneous

• "more" frequently (USPDI)
• dizziness, headache
• gastrointestinal disturbances
  • anorexia
  • diarrhea
  • nausea, and/or vomiting

Renal crystalluria

• Major problem older sulfonamides
• Rare with newer derivatives
• All sulfas -- Drink copious quantities of water
• Older sulfas -- could also alkalinize urine
• Triple sulfas (historical information) -- now inappropriate
  • Antibacterial action -- additive
  • Solubility -- independent
  • Increase safety margin by 3-fold

Keratitis sicca

• Common in dogs

Decreased Thyroid Function

• dogs (Hall, et al., 1993)
• Maximum Rx 2-3 weeks
• Trimethoprim/sulfa may cause hypothyroidism
• Sulfas impair thyroglobulin iodination and coupling of tyrosines
• Trimethoprim/sulfa, 30 mg/kg, po q12h for 6 weeks to 21 dogs.
  • Decreased T4(serum), NOT T3(serum)
  • 3 of 12 had decreased response to TSH
  • 2 dogs had increased uptake of Technetium 99m suggesting interference with iodide metabolism.
• Primary adverse effect Primor^R
  (Roche FDA file)

Photosensitivity

• Avoid sunlight

Cardiovascular collapse

• If too rapid IV aministration

Tissue necrosis

• Solutions strongly alkaline
• Avoid perivascular leakage
• Avoid IM/SC unless specific product approval

Blood dyscrasias

• USPDI states
  "More often than rarely!"
• Newer sulfonamides
• Fever, paleness, sore throat, unusual bleeding or bruising, and unusual tiredness and weakness.

Hematuria

• rare with newer derivatives
• Related to hemolysis
• Especially likely if reduced Glucose-6-phosphate Dehydrogenase activity
  • Tendency follows sickle cell trait in blacks
    10% of US Blacks have trait
  • People from Eastern Mediterranean

Drug interaction

• Bacteriostatic vs cidal
• High protein binding -- potential for displacement of other drugs
• Enhance action of carbonic anhydrase inhibitors
  • furosemide (not its primary MOA)
  • thiazide diuretics
  • sulfonylureas (antidiabetics)

Clinical Applications Sulfonamides

• Broad range
• Spectrum rivals tetracyclines
• First line alone or in combo with TMP
  • pneumonias
  • meningitis
  • UTI
• With TMP for HIV - Pneumocystis carinii pneumonia.
• Some for chloroquine-resistant malaria in conjunction with chloroquine and/or other agents
• Sulfadimethoxine (Albon^R) is the only sulfonamide approved for cattle
• Swine -- long withdrawal times -- use only young animals
• Claims for sulfonamide plus tetracycline synergy
  No sensitivity testing to support combination (Bowersock'95)
• Intrauterine
  • Alone or with urea
  • Evidence for this application is not strong
• Some names of preps formerly or currently available in veterinary medicine
  • sulfathiazole
  • sulfamethazine (CalfSpan^R, Spanbolet II^R, Sulkamycin^R)
  • sulfamerazine
  • sulfabromomethazine (Sulfabrom^R)
  • sulfadimethoxine (Albon^R, Bactrovet^R)
  • sulfachlorpyridazine (Nefrosul^R, Vetisulid^R, Sonilyn^R)
  • sulfamethoxypyridazine (Midicel^R, S.E.Z.sol'n^R)
  • Triple sulfas (now illegal in USA)
    commonly contained sulfathiazole, sulfamerazine, sulfamethazine, sulfadiazine

Trimethoprim Pharmacokinetics

• Oral only as single agent
• High bioavailability; F= 90-100%
• Distribution -- broad, all tissues
  • Apparently not well in bone
  • CSF -- 30-50% of plasma
  • Vaginal fluids -- 3-fold plasma
  • Fetus
  • Vd (humans) = 1.2 to 2.0 L/Kg (weak base)
• Primarily renal
  • Glomerular filtration
  • tubular section
  • Acidification of urine hastens elimination
    Not do with sulfas!
• Half-life
  • 8-10 hr -- Normal renal function (human)
  • 20-50 hr -- anuric patients

Adverse Effects Trimethoprim

• Safe drug
• See refs for rare effects
• Unusual taste
• Headache
• Mild hypersensitivity

Clinical Application of Trimethoprim

• Number of gram(+) and gram(-) bacteria
• Skin (staph)
• Urinary tract infections (E. coli, Staph, etc.), Bordetella bronchiseptica and others.
• Enteric infections (Expensive) (Bowersock 95)
• NO Pseudomonas aeruginosa
• With dapsone for Pneumocystis carinii pneumonia

Ormetoprim

• Similar to trimethoprim

References

• Bowersock, T. 1995, Personal communication
• USPDI11th. Factual information on trimethoprim is heavily based on this reference and its predecessor, the 10th edition.
• Bevill, R.F., (1988). Sulfonamides. in Veterinary Pharmacology and Therapeutics, eds N.H. Booth and L.E. McDonald, Iowa State University Press, Ames, IA. Chapter 48.
• GG7th, 1985. Chapters on antimetabolites and sulfonamides.
• Cribb, H.E., 1989. Idiosyncratic reactions to sulfonamides in dogs. JAVMA 195(11):1612-1614.
• Hall, I.A., K.L. Campbell, M.D. Chambers, C.N. Davis, 1993. Effect of trimethoprim/sulfamethoxazole on thyroid function in dogs with pyoderma. JAVMA 202(12):1959-1962. (Decreases Thyroid function)

Study Questions

1. You should be able to name and discuss how the sulfonamides combined with trimethoprim exemplify three general mechanisms of drug action. What is the basis of selectivity in each of these mechanisms?
2. Why are the sulfonamides and trimethoprim synergistic? Does their combination change their action from being bacteriostatic to bactericidal?
3. How reasonable would it be to switch from one sulfonamide to another in therapy of an organism that is resistant to the first? Note that in vitro sensitivity testing of the sulfonamides is often misleading. Some authorities claim MICs derived from such tests often underestimate the concentration truely needed.
4. How does the spectrum of activity of sulfonamides compare to that of the tetracyclines?
5. Is the distribution of newer, systemic sulfonamides and trimethoprim similar to that of chloramphenicol? If so, why might the apparent Vd of a sulfonamide like sulfamethoxazole be so low?
6. Why do pharmacists nearly always encourage patients to drink a lot of water when taking sulfonamides?
7. Why does alkalinization of urine (what could you use?) enhance elimination and safety of sulfonamides?
8. How do the "Law of Independent Solubility", additive antibacterial action, and "triple sulfas" related to each other? What place did these occupy in the history of sulfonamide use?
9. How likely is one to use an oral dose form to treat a pneumonia caused by Pneumocystis carinii in patients with AIDS? What rule was presented earlier in the course that might speak to this issue?
10. Name a couple of drugs with which the sulfonamides might interact and explain the basis of the interaction. Include two categories (mechanisms) of interactions. Examples: Protein binding and kernicterus; renal secretion and competitiors; cidal/static considerations.
11. Why are sulfonamides generally not given by IM injection?
12. Is it likely that sulfasalazine acts solely or primarily as an antibacterial? Give a reason for your conclusion.
13. Under what conditions might one consider using sulfadoxine plus pyrimethamine as an antimalarial?
14. What are the major adverse effects of the sulfonamides?
15. Note that Primor[R] is a q1d "potentiated" sulfa that is equivalent to Tribrissen[R]. Ormetoprim is the pyrimidine in Primor[R] whereas trimethoprim is in Tribrissen[R].