Sulfonamides

Front 1

MOA of sulfonamides

Back 1

Folate is made up of Pteridine, para-aminobenzoic acid (PABA), and glutamic acid.

Sulfonamides are competitive antagonists of PABA --> prevent formation of folic acid

Front 2

Why are sulfonamides selective?

Back 2

Folic acid is an essential vitamin. We dont make it as we do not have dihydropteroate synthetase.

Bacteria cannot uptake folic acid so they make it. So disrupting it --> decrease in DNA replication and protein synthesis

Front 3

Which bacteris are resistant to sulfonamides and trimethoprim? and why?

Back 3

Enterococcus faecalis and Enterococcus faecium.

They can absorb folic acid from the enviroment.

Front 4

sulfonamides bacteriostatic or bacteriocidal?

Back 4

bacteriostatic

Front 5

sulfonamides inhibit which enzyme?

What is this enzymes function?

Back 5

dihydropteroate synthase

bacterial enzyme responsible for incorporation of PABA into dihydropteroic acid the immediate precursor of folic acid.

Front 6

Trimethoprim are...

Back 6

Is a structural analog of the pteridine portion of dihydrofolate

Front 7

Sulfonamides are...

Back 7

structural analogues and competitive antagonists of para-aminobenzoic acid (PABA),

Front 8

Trimethoprim in hibits which enzyme?

What is this enzymes function?

Back 8

dihydrofolate reductase (DHFR).

DHFR is the enzyme responsible for conversion of dihydrofolate to tetrahydrofolate (hence to purines then to DNA).

Front 9

What classification are Sulfonamides

Back 9

Broard spectrum

Front 10

Where are Sulfonamides absorbed after oral admin?

Back 10

Mainly in the small intestine, some in the stomach.

Vagina, resp. tract, abradded skin - variable and unreliable

Front 11

Sulfonamides peak plasma levels?

Back 11

2-6hrs

Front 12

How are Sulfonamides distributed in the body?

Back 12

Widely through all tissue

Front 13

Can you administer Sulfonamides parentally?

Back 13

No, due to soluble sulfonamide salts are highly alkaline and irritating to the tissues.

Front 14

Give 5 resistance mechanisms for sulfonamides

Back 14

-Mutation allows synthesis of large amounts of PABA.
Some bacteria produce an DHPS (Dihydropteroate synthetase) with a lower affinity for sulfonamides.
-Mutant enzyme - binds sulfonamides less well.
-Decreased uptake of sulfa drugs.
-Resistance is persistent and irreversible.
-Resistance is class specific i.e. does not impart cross resistance to other antimicrobials.

Front 15

Give an example of synergistic therapy of sulfonamides

Back 15

Sulfa + DHFR inhibitor

Used today to treat P. carinii pneumonia in HIV

Front 16

Give exmaples of species sulfonamides are effective against

Back 16

Strept. pneumoniae, Strept. pyogenes, some strains of Staph. aureus, Cl. welchii, H. influenzae, H. ducreyi, Y. pestis, Nocardia asteroides, Chlamydiae (e.g. C. trachomatis).

Plasmodium, Pneumocystis and Toxoplasma spp.
Neisseria, Shigella and other enterobacteria give variable results.

E. coli in acute UTI may be sensitive.

Front 17

Do sulfonamides have G-ve &/or G+ve effects?

Back 17

Both

Front 18

How are sulphonamides metabolished?

Back 18

Varying proportions of sulfonamides are conjugated, usually with acetate, and in such a state are antibacterially inactive.

All sulfonamides that are absorbed are excreted, together with the conjugated forms. Some achieve high concentrations in the urine.

Front 19

What happens with acetylated sulfonamides?

Back 19

They tend to crystallise (CRYSTALLURIA) in the kidney if the urine is acidic.

Front 20

List some toxicity and side effects of sulfonamides

Back 20

-5% of all patients have some degree of hypersensitivity: Drug fever, skin rashes, photosensitivity, allergic myocarditis, anaphylaxis
-Patients deficient in glucose-6-phosphate - hemolytic anemia
-Headache, dizziness, gastric and intestinal upsets.
-Haematuria and anuria
-Stevens-Johnson syndrome
-Blood dyscrasias such as Aplastic anemia, Agranulocytosis
-Crystalluria if normal adequate fluid intake is not sufficient (2-3 liters per day),alkalinisation.

Front 21

Contraindications of sulfonamides

Back 21

-Hypersensitivity
-In patients with impaired renal functions
-In patients with impaired hepatic functions
-Pregnancy
-Lactation

Front 22

Drug interactions with sulfonamides

Back 22

-Oral anticoagulants NB Warfarin
-Sulfonylurea
-Hydantoin anticonvulsants (sulfonamides potentiate their effect)

Front 23

Trimethoprim MOA

Back 23

A synthetic anti-folate acting as a dihydrofolate reductase (DHFR) inhibitor.

a structural analogue of the pteridine portion of DHF so competitively inhibits DHFR catalyzing the reduction of DHF to THF.

Front 24

Which m/o are sensitive to Trimethoprim alone?

Back 24

Escherichia, Klebsiella and H. influenzae.

Front 25

Uses of Trimethoprim

Back 25

-The first and still its major use is in combination with sulfamethoxazole.
-The combination (Co-trimoxazole) has been demonstrated to act synergistically. The potentiation is between 2X and 64X.
-The mixture has been shown in some cases to be bactericidal.
-The single-entity product is promoted for UTI.
-and for long-term prophylaxis against UTI.
-It may also be useful against respiratory tract infections.
-It has been suggested that the use of the single drug may lead to an increase in the number of organisms resistant to TMP.
-Prostatitis (extended courses).
-Treatment and prophylaxis for pneumocystosis (plus steroids to avoid inflammation).
-Well tolerated.

Front 26

ADME of Trimethoprim

Back 26

-It is well absorbed orally reaching 1-2 mcg/mL two hours after a 160 mg dose.
-It is widely distributed in the tissues, reaches the prostate, lung and the sputum in high concentrations.
-Penetrates the csf to give 20-44% of blood levels.
63% of the dose appears in the urine with only a small proportion conjugated (8%).
-It is also excreted in breast milk and crosses the placenta.

Front 27

What is Co-trimoxazole

Back 27

Trimethoprim with Sulfamethoxazole

SMX/TMP, SXT, TMP-SMX, TMP-SMZ or TMP-sulfaSeptrin (GSK), Bactrim (Roche)

The introduction of trimethoprim with combination of sulfamethoxazole is a clinically effective antimicrobial agent. The combination is SYNERGISTIC and the drug becomes Bactericidal.

Front 28

Adverse effects of Trimethoprim

Back 28

-TMP/SMX can cause true and pseudo renal failure
-Crystalluria by SMX causes acute renal
-By blocking creatine secretion TMP may cause an increase in serum creatine but with no true decline in glomerular filtration rate (pseudo).
-TMP may cause hyperkalemia.
-TMP/SMX fairly insoluble so for i.v. use large volumes of diluent needed. Be aware with volume overloaded patients i.e. heart failure.
-Rash mostly due to SMX (in HIV patients more common)
-Toxic epidermal necrosis and Stevens-Johnson syndrome reported.
-Haematological -dose dependent bone marrow suppression. Especially at higher conc’s in Pneumocystic infections.

Front 29

Therapeutic use of Co-trimoxazole

Back 29

-Urinary Tract Infections:
-Treatment of uncomplicated lower urinary tract infections
-Bacterial Respiratory tract infections:
-Gastrointestinal infections
-Infections by Pneumocytis carinii (an opportunistic infection in patients with AIDS)
-Prophylaxis in Neutropenic patients.
-Dosage depends on individual infection.

Front 30

Adverse effects of Co-trimoxazole

Back 30

-Permanent impairment of renal function (crystal urea, urinary obstruction)
-In recommended doses the combination does not induce folic acid deficiency in normal persons, but can precipitate megaloblastosis, leukopenia or thrombocytopenia
-In routine 75% of adverse effects involve skin as described in sulfonamides.
-GIT – mostly nausea and vomiting – diarrhea is rare.
-Mild jaundice (transient)
-headache, depression and hallucinations.
-Various types of anemia.
-AIDS patients more susceptible to adverse effects.