L-27- Anti-Folate Drugs and DNA Synthesis

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Questions and Answers

Which of the following is NOT a typical use of intravenous trimethoprim-sulfamethoxazole?

Treatment of shigellosis and typhoid fever when oral administration is not feasible

Management of severe _P. jirovecii_ pneumonia in AIDS patients

First-line treatment for uncomplicated cystitis (correct)

Treatment of gram-negative bacterial sepsis, including multi-drug resistant species

What is the primary mechanism of action of the active metabolite of proguanil?

Inhibition of plasmodial mitochondrial oxidative phosphorylation

Prevention of DNA replication in protozoa

Selective inhibition of the bifunctional dihydrofolate reductase-thymidylate synthetase enzyme of plasmodia (correct)

Direct damage to the cell wall of Gram-negative bacteria

Why is the prophylactic use of sulfadoxine, in combination with pyrimethamine for falciparum malaria, restricted to high-risk cases?

The long half-life of sulfadoxine requires constant clinical monitoring

The combination is not suitable for children.

High prevalence of resistance to sulfadoxine

The risk of a serious adverse reaction such as Steven-Johnson syndrome (correct)

Which adverse effect associated with trimethoprim-sulfamethoxazole would permanently preclude a patient from ever receiving the drug again?

Steven-Johnson syndrome (D) Signup and view all the answers

Besides P. jirovecii pneumonia in AIDS patients, what other conditions are typically treated using intravenous trimethoprim-sulfamethoxazole?

Gram-negative bacterial sepsis caused by multi-drug resistant species (C) Signup and view all the answers

Which sulfonamide is characterized by a rapid absorption and rapid excretion, coupled with low renal toxicity and a low incidence of crystalluria?

Sulfisoxazole (D) Signup and view all the answers

Which of the following is a long-acting sulfonamide, with a serum half-life between 100 to 230 hours?

Sulfadoxine (A) Signup and view all the answers

In newborns, the half-life of which sulfonamide is significantly longer compared to that of older children and adults?

Sulfamethoxazole (A) Signup and view all the answers

Which sulfonamide is known to potentially enhance the effects of warfarin?

Sulfadiazine (A) Signup and view all the answers

The combination of sulfisoxazole with which other drug is marketed for use in children with otitis media?

Erythromycin (C) Signup and view all the answers

Which sulfonamide is poorly absorbed in the gastrointestinal tract and primarily used for treating ulcerative colitis and regional enteritis?

Sulfasalazine (B) Signup and view all the answers

Which of the following sulfonamides is commonly used in ophthalmic infections?

Sulfacetamide (B) Signup and view all the answers

Crystalluria is a known side effect associated with which of these medications due to its acetylated, insoluble form?

Sulfamethoxazole (C) Signup and view all the answers

A patient's urine has turned orange-red following medication intake. This is a known side effect of which combination drug?

Sulfisoxazole-Phenazopyridine (A) Signup and view all the answers

Which of the following statements is true about sulfadiazine's pharmacokinetics?

It is rapidly absorbed from the GI tract, with peak concentrations reached within 3-6 hours. (D) Signup and view all the answers

Which of the following best describes the primary advantage of using silver sulfadiazine in treating microbial colonization?

Its non-irritating nature to the eye, even at high concentrations. (B) Signup and view all the answers

A patient with a severe burn injury requires prophylactic treatment to prevent infection. Which sulfonamide is most appropriate for this patient?

Silver sulfadiazine. (B) Signup and view all the answers

Which of the following best characterizes the limitation of using both silver sulfadiazine and mafenide?

Their use is limited to superficial infections. (C) Signup and view all the answers

A patient is diagnosed with a Plasmodium falciparum infection resistant to mefloquine. Which sulfonamide is most appropriate for their treatment?

Sulfadoxine. (B) Signup and view all the answers

Which of the following is a common adverse effect associated with the use of mafenide?

Intense pain at the site of application. (B) Signup and view all the answers

What is the primary mechanism by which sulfonamides inhibit bacterial growth?

By acting as competitive antagonists of para-aminobenzoic acid (PABA), preventing folic acid synthesis. (A) Signup and view all the answers

Which of the following conditions can be effectively treated with oral trimethoprim-sulfamethoxazole (TMP-SMZ)?

Pneumocystis jirovecii pneumonia. (A) Signup and view all the answers

Why is trimethoprim particularly effective in treating bacterial prostatitis?

It concentrates in prostatic fluid due to its weak base nature. (A) Signup and view all the answers

Why is trimethoprim often used in combination with sulfonamides?

To achieve a sequential blockade of folic acid synthesis, leading to a bactericidal effect. (C) Signup and view all the answers

Which of the following best describes how bacteria develop resistance to sulfonamides?

Through mutation of the enzyme dihydro-pteroate synthase, increased destruction of the drug, or alternative metabolic pathways. (C) Signup and view all the answers

A patient has a respiratory infection known to be caused by Moraxella catarrhalis. Which of the following medications would be an appropriate alternative if beta-lactam antibiotics are not suitable?

Trimethoprim-sulfamethoxazole. (A) Signup and view all the answers

Which of the following is NOT a primary target for trimethoprim?

Mycoplasma species. (A) Signup and view all the answers

What is the distinguishing characteristic of bacterial dihydrofolate reductase that makes trimethoprim a selective antibacterial agent?

It is about 4 to 5 orders of magnitude more sensitive to inhibition by trimethoprim than the mammalian enzyme. (C) Signup and view all the answers

In addition to genetic changes, what mechanism can some Staphylococci use to develop resistance to sulfonamides?

Increased PABA production, which overcomes competitive inhibition by sulfonamides. (C) Signup and view all the answers

What is a significant consideration when using mafenide, beyond its adverse effects?

It can cause Candida superinfections. (B) Signup and view all the answers

Which of the following best describes the mechanism of action of trimethoprim?

It inhibits synthesis of purines and pyrimidines by blocking the reduction of dihydrofolate to tetrahydrofolate. (C) Signup and view all the answers

How are sulfonamides distributed in the body?

They are distributed throughout all tissues and present in pleural, synovial, peritoneal, ocular fluids in unbound form. (A) Signup and view all the answers

What is the significance of sulfonamide resistance being persistent and irreversible?

It implies that once resistance develops, the sulfonamides will likely be permanently ineffective against the bacteria. (D) Signup and view all the answers

What is the specific role of dihydropteroate synthase in bacterial folic acid synthesis?

It incorporates PABA into dihydropteroic acid. (B) Signup and view all the answers

Which of the following is NOT a mechanism of sulfonamide resistance?

Increased bacterial cell wall thickness to prevent drug entry. (B) Signup and view all the answers

Which characteristic of sulfonamides is MOST crucial for their antimicrobial action?

A sulfur atom directly linked to a benzene ring, along with a para-amino group. (C) Signup and view all the answers

Why are sulfonamides considered antibacterial and antiprotozoal agents?

They inhibit folate synthesis but do so in a manner that selectively affects bacteria and protozoa because eukaryotes do not synthesize folate. (D) Signup and view all the answers

What is the primary distinction between anti-folate drugs targeting synthesis and those targeting reduction?

Synthesis inhibitors exclusively target bacteria, whereas reduction inhibitors have broader effects including on the host. (C) Signup and view all the answers

A patient has a burn and is prescribed Mafenide. What is the MOST LIKELY reason for this treatment?

To prevent infection by bacteria as a form of prophylaxis. (D) Signup and view all the answers

A patient experiencing bacterial infection is prescribed Co-trimoxazole, how does this work at a mechanistic level?

It inhibits folic acid synthesis and its subsequent reduction to tetrahydrofolate (THF) (C) Signup and view all the answers

Which structural aspect of sulfonamides is key in determining its mechanism of action?

The direct bonding of the sulfur to the benzene ring together with a para-amino group. (A) Signup and view all the answers

What is the therapeutic rationale for using a combination of Sulfadoxine and Pyrimethamine?

To use a synergistic method of blocking folate production. (A) Signup and view all the answers

Why are silver sulfadiazine and mafenide primarily used topically instead of intravenously or orally?

They need to have direct contact with the infected area for a direct effect. (C) Signup and view all the answers

Study Notes

Drugs That Cause DNA Synthesis Inhibition: Anti-Folates

Anti-folate drugs inhibit DNA synthesis by targeting folate synthesis
These drugs primarily affect bacteria, not eukaryotes

Folate Synthesis Inhibitors

Sulfonamides: These are antibacterial and antiprotozoal agents
Targets bacteria only, cannot be synthesized by eukaryotes

Folate Reduction Inhibitors

Trimethoprim: Antibacterial
Pyrimethamine: Antiprotozoal
Proguanil: Antiprotozoal

Combinational Drugs

Co-trimoxazole (sulfamethoxazole-trimethoprim, TMP-SMX): Effective antibacterial agent
Sulfadoxine plus Pyrimethamine: Antiprotozoal combination

Folate Synthesis Inhibitors List

Sulfamethoxazole
Sulfisoxazole
Sulfacytine
Sulfadiazine
Sulfamethizole
Mafenide
Sulfadoxine
Sulfasalazine
Sulfacetamide
Silver sulfadiazine

Sulfonamides and PABA Structure

Sulfonamides are structurally similar to p-aminobenzoic acid (PABA)
Sulfonamides act as competitive antagonists of PABA

Folate Reduction Inhibitors List

Trimethoprim

Folate Synthesis and Reduction Combinations

Trimethoprim-sulfamethoxazole (TMP-SMX): Combination antibacterial drug
Pyrimethamine-Sulfadoxine (Fansidar): Used in malaria prophylaxis and treatment

Chemistry of Sulfonamides

Sulfonamides are derivatives of sulfanilamide, often insoluble in water but soluble as sodium salts
The para-amino group and sulfur directly linked to the benzene ring are key to antimicrobial action
Replacing the amide group (-SO₂NH₂) with heterocyclic aromatic nuclei enhances potency

Mechanism of Action

Sulfonamides and trimethoprim act as antimetabolites
They are structural analogues of PABA, competing for the enzyme, preventing normal bacterial utilization of PABA for folate synthesis
Sulfonamides inhibit dihydropteroate synthase, critical for folate synthesis

MOA Diagram Summary

Sulfonamides compete with PABA for dihydropteroate synthase
Trimethoprim blocks dihydrofolate reductase
Both prevent the formation of tetrahydrofolic acid a critical precursor for nucleotide synthesis

Synergists of Sulfonamides

Trimethoprim is a dihydrofolic acid analogue that inhibits dihydrofolate reductase
This sequential inhibition of folic acid synthesis leads to a bactericidal action due to its potency and high sensitivity compared to mammalian enzymes

Resistance

Bacterial resistance to sulfonamides is attributed to several mechanisms
- Random mutations and selection
- Plasmid-mediated resistance
- Increased capacity to destroy or inactivate the drug
- Alternate pathways to synthesize essential metabolites
- Increased PABA synthesis in some resistant strains
- Reduced permeability leading to decreased uptake

Pharmacokinetics and Classification

Sulfonamides are classified into oral absorbable, oral non-absorbable, topical, and parenteral types
They distribute throughout the body and are present in unbound forms in body fluids like pleural, synovial, peritoneal, and ocular fluids
Different sulfonamides have varying half-lives influencing their duration of action.

Specific Sulfonamide Properties

Sulfisoxazole (Gantrisin): Rapid absorption and excretion, high solubility
Sulfamethoxazole (Gantanol): Slower absorption and excretion than sulfisoxazole, some crystalluria possible
Sulfadiazine: Rapid absorption, attained in CSF within 4 hours, excreted through the kidneys

Sulfasalazine (Azulfidine)

Poorly absorbed from the GI tract, used in ulcerative colitis and regional enteritis however relapses are common
Preferred over corticosteroids for ulcerative colitis and also used in granulomatous colitis

Topical Sulfonamides

Sulfacetamide (Isoptocetamide): Used in ophthalmic infections, non-irritating to the eyes
Silver sulfadiazine (Silvadene): Used to prevent burn infections, not in established deep infection
Triple combinations are used for bacterial vaginosis

Long-Acting Sulfonamides (Sulfadoxine)

Half-life of 7-9 days
Frequently used in combination with pyrimethamine (Fansidar) for prophylaxis and treatment of malaria, particularly in cases of mefloquine resistance

Oral Trimethoprim-sulfamethoxazole (TMP-SMX)

Effective against various infections, including Pneumocystis jirovecii pneumonia, UTIs, bacterial prostatitis, some mycobacterial infections
More concentrated in prostatic fluids and vaginal fluids enhancing efficacy compared to plasma
Effective against pathogens like Haemophilus, Moraxella, Klebsiella, and certain strains of E. coli, and Staphylococcus resistant strains

IV Trimethoprim-sulfamethoxazole

Used for severe Pneumocystis infections in AIDS patients, and gram-negative bacterial sepsis due to multi-drug resistant species
Effective for Shigellosis, typhoid fever, and UTIs when oral administration isn't possible

Oral Pyrimethamine with Sulfonamide

Used for Leishmaniasis and toxoplasmosis (a protozoan infection); sulfadoxine combination (Fansidar) shows effectiveness especially in mefloquine-resistant strains
Prophylactic use is crucial in high-risk cases due to potential for Steven Johnson Syndrome

Proguanil & Atovaquone

Proguanil's activity is mediated by cycloguanil, an active metabolite, inhibiting dihydrofolate reductase-thymidylate synthetase
Malarone (Atoquone/proguanil) is a combination drug used in malaria treatment and prophylaxis

Adverse Reactions

Hypersensitivity reactions (fever, dermatitis, Stevens-Johnson syndrome) are common side effects
GI upset (nausea, vomiting) and liver dysfunction are often encountered
Hematological effects (granulocytopenia, thrombocytopenia) and nephrological problems (crystaluria, hematuria) can also occur

Synopsis of Major Diseases Treated with TMP-SMZ

UTIs (chronic/recurrent), respiratory infections, GI infections, infections in AIDS patients, and prophylaxis in neutropenic patients

Other Uses

Effective against a broad range of gram-positive and gram-negative organisms
Used in ocular diseases targeting Chlamydia, Nocardia, and protozoa
Used in prophylaxis of burn infections
Effective in treating ulcerative colitis and granulomatous colitis
Also effective in treating malaria and other infections

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Description

This quiz focuses on anti-folate drugs and their mechanisms in inhibiting DNA synthesis. It covers key topics such as sulfonamides, their antibacterial properties, and combinational therapies like co-trimoxazole. Test your knowledge on how these drugs impact bacterial infections and protozoal diseases.