inhibitor of Folic Acid Metabolism.pdf

Sulfonamides
Are similar to p-aminobenzoic acid (PABA)
Sulfonamides with varying physical, chemical, pharmacologic, & antibacterial properties are produced by attaching substituents to amido group (–SO2–NH–R) or to amino group (–NH2) of sulfanilamide nucleus.
Trimethoprim & trimethoprim+ sulfamethoxazole mixtures
Trimethoprim
Its a trimethoxybenzylpyrimidine
Mechanism of action
Selectively inhibits bacterial dihydrofolic acid reductase that converts dihydrofolic acid to tetrahydrofolic acid

1. Dr. NDAYISABA CORNEILLE
CEO of CHG
MBChB,DCM,BCSIT,CCNA
SupportedBY
INHIBITOR OF
FOLIC ACID
METABOLISM

2. Inhibitors of Folic Acid
Metabolism
Dr Ndayisaba Corneille

3. Classification of Drugs
Step 1:Inhibit (DHFS)
⚫Sulphonamides
⚫Dapsone
⚫Methtrexate
⚫Tremetrexate
⚫Step 2:Inhibit (DHFR)
⚫Pyrimethamine
⚫Trimethoprim
Dr Ndayisaba Corneille

4. INHIBITS
BACTERIAL
DIHYDROPTEROATE
SYNTHASE(DHFS)

5. Sulfonamides
oAre similar to p-aminobenzoic acid (PABA)
oSulfonamides with varying physical, chemical,
pharmacologic, & antibacterial properties are
produced by attaching substituents to amido
group (–SO
2–NH–R) ortoamino group (–NH
2) of
sulfanilamide nucleus.
Dr Ndayisaba Corneille

6. Sulfonamides
1) Topical sulphonamides
⚫Sulphacetamide
⚫Silver sulphadiazine
⚫Silver sulphacetamide
⚫Mefanide
2) Systemic sulphonamides
a) Short acting systemic
⚫Sulfadiazine
⚫Sulfisoxazole
⚫Sulfamethizole
⚫Sulphadimidine
b) Long acting
⚫Sulphasalazine
⚫Sulfamethoxazole
c) Very long acting
⚫Sulphadoxine
⚫Sulphamethopyrazine
Dr Ndayisaba Corneille

7. Mechanism of action
oSulfonamidesusceptible organisms, unlike mammals,
cannot use exogenous folate but must synthesize
folate(folic acid) frm PABA.
oThis pathway is thus essential for production of
purines &nucleic acid synthesis.
oCozsulfonamides are structural analogs of PABA,
they inhibit;
⚫Dihydropteroate synthase &folate production.
Dr Ndayisaba Corneille

8. Antimicrobial Activity
oInhibit both gram+ve &gram-ve bacteria
oNocardia
oChlamydia trachomatis
oSome protozoa.
oSome enteric bacteria;
⚫E coli,
Dr Ndayisaba Corneille

9. ⚫klebsiella,
⚫salmonella,
⚫shigella,
⚫enterobacter
oIt is interesting that rickettsiae are not inhibited by
sulfonamides but are actually stimulated in their
growth.
oActivity is poor against anaerobes.
Dr Ndayisaba Corneille

10. oCombination of a sulfonamide with an inhibitor
of dihydrofolate reductase (Trimethoprim or
pyrimethamine) provides synergistic activity
bcozof sequential inhibition of folate synthesis .
Resistance
oMammalian cells (& some bacteria) lack
enzymes required for folate synthesis frm PABA
thusdepend on exogenous sources of folate
oHence they are not susceptible to
sulfonamides.
Dr Ndayisaba Corneille

11. oSulfonamide resistance may occur as a result of
mutations that;
⚫Cozoverproduction of PABA
⚫Cozproduction of a folic acid-synthesizing
enzyme that has low affinity for sulfonamides
⚫Impair permeability to sulfonamide.
oDihydropteroate synthase with low sulfonamide
affinity is often encoded on a plasmid that is
transmissible a can disseminate rapidly & widely.
Dr Ndayisaba Corneille

12. Pharmacokinetics
oSulfonamides can be divided into 3major groups:
⚫Oralabsorbable;
⚫Oralnonabsorbable
⚫Topical.
Oralabsorbable sulfonamides
oCan be classified as short, intermediate, or long
acting on the basis of their half-lives.
Dr Ndayisaba Corneille

13. oAre absorbed from stomach &small intestine
oDistributed widely to tissues +body fluids
(including CNS &CSF), placenta& fetus.
oProtein binding varies frm 20% -90%.
Dr Ndayisaba Corneille

14. Short acting sulphonamides
oSulfacytine,prompt absorption frm gut
oSulfisoxazole,(T ½ = 6hrs),Promptabsorption
frm gut
oSulfamethizole ,(T ½ = 9 hrs) ,Promptabsorption
frm gut
Dr Ndayisaba Corneille

15. Intermediateacting sulphonamides
oSulfadiazine, T ½ = 10–17 hrs
oSulfamethoxazole, T ½ = 10–12 hrs
oSulfapyridine,T ½ = 17 hrs
* All are slowly absorbed frm gut
Long acting sulphonamides
oSulfadoxine, T ½ = 7–9 days
*Intermediateabsorption frm gut
Pyrimidines
oTrimethoprim, T ½ = 11 hrs
*Promptabsorption frm gut
Dr Ndayisaba Corneille

16. Metabolism
oA portion of absorbed drug is acetylated or
glucuronidated in liver.
oSulfonamides &inactive metabolites are then
excreted into the urine, mainly by GF.
oIn renal failure, dosemust be reduced.
Dr Ndayisaba Corneille

17. Clinical UsesofSulfonamides
oInfrequently used as single agents.
oMany strains of formerly susceptible spp, including;
⚫Meningococci,Pneumococci,Streptococci
Staphylococci&Gonococci, are now resistant.
.Urinary tract infections, Pneumocyctiscarinii
pneumonia in AIDS,
.Prophylaxis: Otitis, meningitis, burns
Dr Ndayisaba Corneille

18. oFixed-drug combination of trimethoprim-
sulfamethoxazoleis drug of choice for;
⚫Pneumocystis jiroveci (formerly P
carinii) pneumonia
⚫Toxoplasmosis
⚫Nocardiosis
⚫Occasionally other bacterial infections.
Dr Ndayisaba Corneille

19. Oral absorbable agents
Sulfisoxazole & sulfamethoxazole
oShort-medium-acting agents.
Indications
oAlmost exclusively to RxUTIs.
Adult dosage is;
o1 g of sulfisoxazole QIDor
o1 g of sulfamethoxazole 2-3times daily.
Dr Ndayisaba Corneille

20. Sulfadiazine +pyrimethamine
o1
st
-line therapy for Rxof acute toxoplasmosis.
⚫Sulfadiazine + pyrimethamine
⚫pyrimethamine a potent inhibitor of
dihydrofolate reductase,
⚫This is synergistic bcozthese drugs block
sequential steps in folate synthesis.
Dr Ndayisaba Corneille

21. Dosage regimen inof acute toxoplasmosis
oSulfadiazine 1 g QID
oPyrimethamine 75-mg loading dose followed by a
25mg o.ddose.
oFolinic acid10 mg POo.d minimizesbone marrow
suppression.
Dr Ndayisaba Corneille

22. Sulfadoxine
olong-acting sulfonamide
Indications
Sulfadoxine + pyrimethamine (Fansidar)
o2
nd
-line agent in Rxfor malaria
oMalaria prophylaxis
Dr Ndayisaba Corneille

23. Oral nonabsorbable agents
Sulfasalazine(salicylazosulfapyridine)
Indications
⚫ulcerative colitis
⚫enteritis
⚫other inflammatory bowel disease
Dr Ndayisaba Corneille

24. Topical agents
Sodium sulfacetamide
oAn ophthalmic solution or ointment
Indications
oBacterial conjunctivitis
oAdjunctive therapy for trachoma.
Dr Ndayisaba Corneille

25. Mafenide acetate
⚫Another sulfonamideis used topically
⚫Can be absorbed from burn sites.
⚫Drug & its 1°metabolite inhibit carbonic anhydrase
and can cause metabolic acidosis, a S/Ethat limits
its usefulness.
Dr Ndayisaba Corneille

26. Silver sulfadiazine
oless toxic topical sulfonamide
oPreferred to mafenide for prevention of infection of
burn wounds.
Indications
oPrevention of infection of burn wounds.
Dr Ndayisaba Corneille

27. Adverse Reactions; Occur with all sulfonamides;
⚫Antimicrobial sulfas
⚫Diuretics
⚫Diazoxide
⚫Sulfonylurea hypoglycemic agents
oAll have been considered to be partially cross-
allergenic.
oHoweverevidence for this is not extensive.
Dr Ndayisaba Corneille

28. Most common S/Es are
oFever
oSkin rashes
oExfoliative dermatitis
oPhotosensitivity
oUrticaria
oNausea
oVomiting& Diarrhea
Dr Ndayisaba Corneille

29. oStevens-Johnson syndrome
⚫Relatively uncommon (< 1% of Rxcourses),
⚫Particularly serious
⚫Potentially fatal
⚫Its a type of skin &mucous membrane
eruption associated with sulfonamide use.
Dr Ndayisaba Corneille

30. OtherS/E;
⚫Stomatitis
⚫Conjunctivitis
⚫Arthritis
⚫Hematopoietic disturbances
⚫Hepatitis
⚫Rarelypolyarteritis nodosa
⚫Psychosis.
Dr Ndayisaba Corneille

31. oUrinary tract disturbances
⚫Sulfonamides may ppt in urine, esp at neutral or
acid pH, producing;
⚫Crystalluria
⚫Hematuria
⚫Even obstruction.
⚫This is rarely a problem with more soluble
sulfonamides (egsulfisoxazole).
.
Dr Ndayisaba Corneille

32. oSulfadiazine in large doses& if fluid intake is poor,
can cozcrystalluria.
Mgt
⚫NaHCO3 to alkalinize the urine
⚫Fluids to maintain adequate hydration.
oSulfonamides are implicated in various types of;
⚫Nephrosis
⚫Allergic nephritis
Dr Ndayisaba Corneille

33. oHematopoietic disturbances
⚫Sulfonamides can coz;
⚫Hemolytic anemia
⚫Aplastic anemia
⚫Granulocytopenia
⚫Thrombocytopenia
⚫leukemoid reactions
Dr Ndayisaba Corneille

34. oCan provoke hemolytic reactions in pts with
glucose-6-phosphate dehydrogenase deficiency
oWhen taken near end of preg increase risk of
kernicterus innew borns
Contraindications
oAllergic pts to sulphonamides
oNeonates
o1
st
trimester of pregnancy
Dr Ndayisaba Corneille

35. INHIBITS
BACTERIAL
DIHYDROFOLIC
ACID REDUCTASE
(DHFR)
Dr Ndayisaba Corneille

36. Dr Ndayisaba Corneille

37. *
*
Dr Ndayisaba Corneille

38. Trimethoprim & trimethoprim+ sulfamethoxazole
mixtures
Trimethoprim
⚫Its a trimethoxybenzylpyrimidine
Mechanism of action
oSelectively inhibits bacterial dihydrofolic acid
reductasethat converts dihydrofolic acid to
tetrahydrofolic acid
Dr Ndayisaba Corneille

39. oThis step leadsto synthesis of purines &ultimately
to DNA .
oTrimethoprime is 50,000 times less efficient in
inhibition of mammalian dihydrofolic acid
reductase.
Dr Ndayisaba Corneille

40. Pyrimethamine
oAnother benzylpyrimidine,
Mechanism of action
oSelectively inhibits dihydrofolic acid reductase of
protozoathan that of mammalian cells.
Dr Ndayisaba Corneille

41. oThus trimethoprim or pyrimethamine in
combination with sulfonamide blocks sequential
steps in folate synthesis,
oThis resultsin marked enhancement (synergism)
ofactivity of both drugs.
oThe combination often is bactericidal, compared
with bacteriostatic activity of a sulfonamide alone.
Dr Ndayisaba Corneille

42. Cozes of resistance to trimethoprim
oReduced cell permeabilityto drug
oOverproduction of dihydrofolate reductase
oProduction of an altered reductase with reduced
drug binding.
⚫Resistance can emerge by mutation, although
more commonly its due to plasmid-encoded
trimethoprim-resistant dihydrofolate
reductases.
Dr Ndayisaba Corneille

43. Pharmacokinetics of trimethoprim
Route of administration
oPO alone or in combination with sulfamethoxazole,
that has a similar half-life.
oIV Trimethoprim+sulfamethoxazole
Dr Ndayisaba Corneille

44. Absorption
oWell absorbed frm gut
oDistributed widely in body fluids &tissues,
including CSF.
oMore lipid-soluble than sulfamethoxazolethus has
alarger volume of distribution.
oThus 1 part of trimethoprim is given with 5 parts of
sulfamethoxazole in formulations
Dr Ndayisaba Corneille

45. Excretion
o30–50% of sulfonamide &50–60% of trimethoprim
(or their respective metabolites) are excreted in
urine within 24 hours.
oDose shld be reduced by ½ for pts with creatinine
clearances of 15–30 mL/min.
oTrimethoprim [ ]s in prostatic &vaginal fluids,
which are more acidic than plasma.
Dr Ndayisaba Corneille

46. oThus itshas more antibacterial activity in prostatic
&vaginal fluids than many other antimicrobial
drugs.
Clinical Uses
Oral trimethoprim
oAcute UTIs,100 mg bid
Dr Ndayisaba Corneille

47. Oraltrimethoprim+ sulfamethoxazole (TMP-SMZ)
Indications
oP jirovecipneumonia
oOtitis media
oshigellosis
oSystemic salmonella infections
oUrinary tract infections
oProstatitis
oSome nontuberculous mycobacterial infections. Dr Ndayisaba Corneille

48. oStaph aureus infections
oRespiratory infections
Antibacterial activity
oS aureusstrains
⚫Methicillin-susceptible S aureus
⚫Methicillin-resistant S aureus
Dr Ndayisaba Corneille

49. ⚫Respiratory tract pathogens such as;
⚫pneumococcus,
⚫Haemophilusspecies,
⚫Moraxella catarrhalis
⚫Klebsiella pneumoniae
⚫but not active against Mycoplasma
pneumoniae
Dr Ndayisaba Corneille

50. Dosage
oAdults ; 960 mg BD using one double-strength
tablet (@ tab trimethoprim 160 mg +
sulfamethoxazole 800 mg)
oChildren;8 mg/kg trimethoprim & 40 mg/kg
sulfamethoxazole bid .
Dr Ndayisaba Corneille

51. oInfections with P jiroveci& some other pathogens
⚫High doses of cotrimoxazole
⚫Dosed on basis of trimethoprim component at
15–20 mg/kg
⚫Immunosuppressed pts given prophylaxis
with cotrimoxazole 960 mg bid or 3times
wkly.
Dr Ndayisaba Corneille

52. Intravenous trimethoprim-sulfamethoxazole
oA solution mixture ; 80 mg trimethoprim+400 mg
Sulfamethoxazole
Indications
oModerately severe to severe pneumocystis
pneumonia.
oShigellosis
oTyphoid fever
Dr Ndayisaba Corneille

53. ourinary ,respiratory tract infection cozed by a
susceptible organism whn pt is unable to take drug
PO
oGram-vebacterial sepsis, including that caused by
some multidrug-resistant sppsuch as enterobacter
&serratia
⚫Prostatitis
⚫Traveller’s diarrhoea
Dr Ndayisaba Corneille

54. Oral pyrimethamine + sulfonamide
Pyrimethamine + sulfadiazine
Indications
oleishmaniasis
oToxoplasmosis
Pyrimethamine+ sulfadoxine (Fansidar)
Indication
oIn falciparum malaria
Dr Ndayisaba Corneille

55. Adverse Effects
oTrimethoprim produces predictable S/Es of an
antifolate drug, esp
⚫Megaloblastic anemia,
⚫Leukopenia
⚫Granulocytopenia.
Dr Ndayisaba Corneille

56. oTrimethoprim+sulfamethoxazole may cozall
S/Es associated with sulfonamides.
⚫Nausea & vomiting,
⚫Drug fever
⚫Vasculitis
⚫Renal damage
⚫CNSdisturbances
Dr Ndayisaba Corneille

57. oPts with AIDS & pneumocystis pneumonia have a
particularly high frequency ofS/Es to trimethoprim-
sulfamethoxazole, esp
-Fever, -Rashes,
-Leukopenia, -Diarrhea,
-Hyperkalemia -Hyponatremia.
-Elevations hepatic enzymes
Dr Ndayisaba Corneille

58. END
BY
DR NDAYISABA CORNEILLE
MBChB,DCM,BCSIT,CCNA,CyberSecurity
contact: [email protected] ,
[email protected]
whatsaps:[phone] /[phone]
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