inhibitor of Folic Acid Metabolism.pdf

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

Inhibitors of Folic Acid
Metabolism
Dr Ndayisaba Corneille

Classification of Drugs
Step 1: Inhibit (DHFS)
⚫ Sulphonamides
⚫ Dapsone
⚫ Methtrexate
⚫ Tremetrexate
⚫ Step 2: Inhibit (DHFR)
⚫ Pyrimethamine
⚫ Trimethoprim

INHIBITS
BACTERIAL
DIHYDROPTEROATE
SYNTHASE(DHFS)

Sulfonamides
o Are similar to p-aminobenzoic acid (PABA)
o 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.

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

Mechanism of action
o Sulfonamide susceptible organisms, unlike mammals,
cannot use exogenous folate but must synthesize
folate(folic acid) frm PABA.
o This pathway is thus essential for production of
purines & nucleic acid synthesis.
o Coz sulfonamides are structural analogs of PABA,
they inhibit;
⚫ Dihydropteroate synthase & folate production.

Antimicrobial Activity
o Inhibit both gram+ve & gram-ve bacteria
o Nocardia
o Chlamydia trachomatis
o Some protozoa.
o Some enteric bacteria;
⚫ E coli,

⚫ klebsiella,
⚫ salmonella,
⚫ shigella,
⚫ enterobacter
o It is interesting that rickettsiae are not inhibited by
sulfonamides but are actually stimulated in their
growth.
o Activity is poor against anaerobes.

o Combination of a sulfonamide with an inhibitor
of dihydrofolate reductase (Trimethoprim or
pyrimethamine) provides synergistic activity
bcoz of sequential inhibition of folate synthesis .
Resistance
o Mammalian cells (& some bacteria) lack
enzymes required for folate synthesis frm PABA
thus depend on exogenous sources of folate
o Hence they are not susceptible to
sulfonamides. Dr Ndayisaba Corneille

o Sulfonamide resistance may occur as a result of
mutations that;
⚫ Coz overproduction of PABA
⚫ Coz production of a folic acid-synthesizing
enzyme that has low affinity for sulfonamides
⚫ Impair permeability to sulfonamide.
o Dihydropteroate synthase with low sulfonamide
affinity is often encoded on a plasmid that is
transmissible a can disseminate rapidly & widely.

Pharmacokinetics
o Sulfonamides can be divided into 3 major groups:
⚫ Oral absorbable;
⚫ Oral nonabsorbable
⚫ Topical.
Oral absorbable sulfonamides
o Can be classified as short, intermediate, or long
acting on the basis of their half-lives.

o Are absorbed from stomach & small intestine
o Distributed widely to tissues + body fluids
(including CNS & CSF), placenta & fetus.
o Protein binding varies frm 20% - 90%.

Short acting sulphonamides
o Sulfacytine ,prompt absorption frm gut
o Sulfisoxazole ,(T ½ = 6 hrs ), Prompt absorption
frm gut
o Sulfamethizole ,(T ½ = 9 hrs ) ,Prompt absorption
frm gut

Intermediate acting sulphonamides
o Sulfadiazine , T ½ = 10–17 hrs
o Sulfamethoxazole, T ½ = 10–12 hrs
o Sulfapyridine,T ½ = 17 hrs
* All are slowly absorbed frm gut
Long acting sulphonamides
o Sulfadoxine, T ½ = 7–9 days
*Intermediate absorption frm gut
Pyrimidines
o Trimethoprim, T ½ = 11 hrs
*Prompt absorption frm gut

Metabolism
o A portion of absorbed drug is acetylated or
glucuronidated in liver.
o Sulfonamides & inactive metabolites are then
excreted into the urine, mainly by GF.
o In renal failure, dose must be reduced.

Clinical Uses of Sulfonamides
o Infrequently used as single agents.
o Many strains of formerly susceptible spp, including;
⚫ Meningococci,Pneumococci,Streptococci
Staphylococci &Gonococci, are now resistant.
.Urinary tract infections, Pneumocyctis carinii
pneumonia in AIDS,
.Prophylaxis: Otitis, meningitis, burns

o Fixed-drug combination of trimethoprim-
sulfamethoxazole is drug of choice for;
⚫ Pneumocystis jiroveci (formerly P
carinii) pneumonia
⚫ Toxoplasmosis
⚫ Nocardiosis
⚫ Occasionally other bacterial infections.

Oral absorbable agents
Sulfisoxazole & sulfamethoxazole
o Short-medium-acting agents.
Indications
o Almost exclusively to Rx UTIs.
Adult dosage is;
o 1 g of sulfisoxazole QID or
o 1 g of sulfamethoxazole 2-3 times daily.

Sulfadiazine + pyrimethamine
o 1st -line therapy for Rx of acute toxoplasmosis.
⚫ Sulfadiazine + pyrimethamine
⚫ pyrimethamine a potent inhibitor of
dihydrofolate reductase,
⚫ This is synergistic bcoz these drugs block
sequential steps in folate synthesis.

Dosage regimen in of acute toxoplasmosis
o Sulfadiazine 1 g QID
o Pyrimethamine 75-mg loading dose followed by a
25mg o.d dose.
o Folinic acid 10 mg PO o.d minimizes bone marrow
suppression.

Sulfadoxine
o long-acting sulfonamide
Indications
Sulfadoxine + pyrimethamine (Fansidar)
o 2nd -line agent in Rx for malaria
o Malaria prophylaxis

Oral nonabsorbable agents
Sulfasalazine (salicylazosulfapyridine)
Indications
⚫ ulcerative colitis
⚫ enteritis
⚫ other inflammatory bowel disease

Topical agents
Sodium sulfacetamide
o An ophthalmic solution or ointment
Indications
o Bacterial conjunctivitis
o Adjunctive therapy for trachoma.

Mafenide acetate
⚫ Another sulfonamide is used topically
⚫ Can be absorbed from burn sites.
⚫ Drug & its 1° metabolite inhibit carbonic anhydrase
and can cause metabolic acidosis, a S/E that limits
its usefulness.

Silver sulfadiazine
o less toxic topical sulfonamide
o Preferred to mafenide for prevention of infection of
burn wounds.
Indications
o Prevention of infection of burn wounds.

Adverse Reactions ; Occur with all sulfonamides;
⚫ Antimicrobial sulfas
⚫ Diuretics
⚫ Diazoxide
⚫ Sulfonylurea hypoglycemic agents
o All have been considered to be partially cross-
allergenic.
o However evidence for this is not extensive.

Most common S/Es are
o Fever
o Skin rashes
o Exfoliative dermatitis
o Photosensitivity
o Urticaria
o Nausea
o Vomiting & Diarrhea

o Stevens-Johnson syndrome
⚫ Relatively uncommon (< 1% of Rx courses),
⚫ Particularly serious
⚫ Potentially fatal
⚫ Its a type of skin & mucous membrane
eruption associated with sulfonamide use.

Other S/E;
⚫ Stomatitis
⚫ Conjunctivitis
⚫ Arthritis
⚫ Hematopoietic disturbances
⚫ Hepatitis
⚫ Rarely polyarteritis nodosa
⚫ Psychosis.

o Urinary 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 (eg sulfisoxazole).
.

o Sulfadiazine in large doses & if fluid intake is poor,
can coz crystalluria.
Mgt
⚫ NaHCO3 to alkalinize the urine
⚫ Fluids to maintain adequate hydration.
o Sulfonamides are implicated in various types of;
⚫ Nephrosis
⚫ Allergic nephritis

o Hematopoietic disturbances
⚫ Sulfonamides can coz;
⚫ Hemolytic anemia
⚫ Aplastic anemia
⚫ Granulocytopenia
⚫ Thrombocytopenia
⚫ leukemoid reactions

o Can provoke hemolytic reactions in pts with
glucose-6-phosphate dehydrogenase deficiency
o When taken near end of preg increase risk of
kernicterus in new borns
Contraindications
o Allergic pts to sulphonamides
o Neonates
o 1st trimester of pregnancy

INHIBITS
BACTERIAL
DIHYDROFOLIC
ACID REDUCTASE
(DHFR)

Trimethoprim & trimethoprim+ sulfamethoxazole
mixtures
Trimethoprim
⚫ Its a trimethoxybenzylpyrimidine
Mechanism of action
o Selectively inhibits bacterial dihydrofolic acid
reductase that converts dihydrofolic acid to
tetrahydrofolic acid

o This step leads to synthesis of purines & ultimately
to DNA .
o Trimethoprime is 50,000 times less efficient in
inhibition of mammalian dihydrofolic acid
reductase.

Pyrimethamine
o Another benzylpyrimidine,
Mechanism of action
o Selectively inhibits dihydrofolic acid reductase of
protozoa than that of mammalian cells.

o Thus trimethoprim or pyrimethamine in
combination with sulfonamide blocks sequential
steps in folate synthesis,
o This results in marked enhancement (synergism)
of activity of both drugs.
o The combination often is bactericidal, compared
with bacteriostatic activity of a sulfonamide alone.

Cozes of resistance to trimethoprim
o Reduced cell permeability to drug
o Overproduction of dihydrofolate reductase
o Production 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

Pharmacokinetics of trimethoprim
Route of administration
o PO alone or in combination with sulfamethoxazole,
that has a similar half-life.
o IV Trimethoprim+sulfamethoxazole

Absorption
o Well absorbed frm gut
o Distributed widely in body fluids & tissues,
including CSF.
o More lipid-soluble than sulfamethoxazole thus has
a larger volume of distribution.
o Thus 1 part of trimethoprim is given with 5 parts of
sulfamethoxazole in formulations

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

o Thus its has more antibacterial activity in prostatic
& vaginal fluids than many other antimicrobial
drugs.
Clinical Uses
Oral trimethoprim
o Acute UTIs,100 mg bid

Oral trimethoprim + sulfamethoxazole (TMP-SMZ)
Indications
o P jiroveci pneumonia
o Otitis media
o shigellosis
o Systemic salmonella infections
o Urinary tract infections
o Prostatitis
o Some nontuberculous mycobacterial infections.

o Staph aureus infections
o Respiratory infections
Antibacterial activity
o S aureus strains
⚫ Methicillin-susceptible S aureus
⚫ Methicillin-resistant S aureus

⚫ Respiratory tract pathogens such as;
⚫ pneumococcus,
⚫ Haemophilus species,
⚫ Moraxella catarrhalis
⚫ Klebsiella pneumoniae
⚫ but not active against Mycoplasma
pneumoniae

Dosage
o Adults ; 960 mg BD using one double-strength
tablet (@ tab trimethoprim 160 mg +
sulfamethoxazole 800 mg)
o Children;8 mg/kg trimethoprim & 40 mg/kg
sulfamethoxazole bid .

o Infections 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 3 times
wkly.

Intravenous trimethoprim-sulfamethoxazole
o A solution mixture ; 80 mg trimethoprim + 400 mg
Sulfamethoxazole
Indications
o Moderately severe to severe pneumocystis
pneumonia.
o Shigellosis
o Typhoid fever

o urinary , respiratory tract infection cozed by a
susceptible organism whn pt is unable to take drug
PO
o Gram-ve bacterial sepsis, including that caused by
some multidrug-resistant spp such as enterobacter
& serratia
⚫ Prostatitis
⚫ Traveller’s diarrhoea

Oral pyrimethamine + sulfonamide
Pyrimethamine + sulfadiazine
Indications
o leishmaniasis
o Toxoplasmosis
Pyrimethamine + sulfadoxine (Fansidar)
Indication
o In falciparum malaria

Adverse Effects
o Trimethoprim produces predictable S/Es of an
antifolate drug, esp
⚫ Megaloblastic anemia,
⚫ Leukopenia
⚫ Granulocytopenia.

o Trimethoprim+sulfamethoxazole may coz all
S/Es associated with sulfonamides.
⚫ Nausea & vomiting,
⚫ Drug fever
⚫ Vasculitis
⚫ Renal damage
⚫ CNS disturbances

o Pts with AIDS & pneumocystis pneumonia have a
particularly high frequency of S/Es to trimethoprim-
sulfamethoxazole, esp
-Fever, -Rashes,
-Leukopenia, -Diarrhea,
-Hyperkalemia -Hyponatremia.
-Elevations hepatic enzymes

END
BY
DR NDAYISABA CORNEILLE
MBChB,DCM,BCSIT,CCNA,Cyber Security
contact: amentalhealths@gmail.com ,
ndayicoll@gmail.com
whatsaps :+256772497591 /+250788958241
THANKS FOR LISTENING

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