1. Metabolic & Nucleic Acid Inhibitors
Reading assignments:
Katzung’s Basic & Clinical Pharmacology,
13th Edi ,Ch-46,p ;

2. D. Inhibitors of folate-dependent pathways
LEARNING OBJECTIVES
D. Inhibitors of folate-dependent pathways
Understand the production and use of folate derivatives in bacterial systems
1. Sulfonamides
Know the mechanism of action of sulfonamides
Understand the concept of "antimetabolite"
Appreciate the role of pharmacokinetics in the action and uses of sulfonamides
Know the pharmacokinetic and pharmacodynamic differences among various sulfonamides
Know the adverse effects of sulfonamides
2. Trimethoprim
Know the mechanism of action of trimethoprim
Understand the rationale of combined sulfonamide-trimethoprim chemotherapy
Know the clinical uses and adverse effects associated with trimethoprim
E. DNA gyrase inhibitors
Understand the function of DNA gyrases, and the effects of their inhibition
Know the clinical uses of quinolones and fluoroquinolones
Know the adverse effects and potential drug-drug interaction for quinolones
F. Nitroimidazoles
Understand the mechanism of action of Metronidazole & tinidazole
Know the clinical uses
Know the adverse effects and potential drug-drug interaction
G. Urinary tract antiseptics
Understand the role of pharmacokinetics in the treatment of urinary tract infections

4. D. Inhibitors of folate-dependent pathways 1. Sulfonamides
SULFISOXAZOLE
SULFAMETHOXAZOLE (1)
SULFASALAZINE (SALICYLAZOSULFAPYRIDINE)(2)
SODIUM SULFACETAMIDE
SILVER SULFADIAZINE (3)
CO-TRIMOXAZOLE (SULFAMETHOXAZOLE/TRIMETHOPRIM) (7)
2. Dihydrofolate reductase inhibitors
TRIMETHOPRIM (bacteria) (4)
PYRIMETHAMINE (protozoa) (5)
METHOTREXATE (mammalian) (6)

5. Anti-Metabolites: Anti-Folates
Two Classes—
Inhibitors of folate synthesis
p-Aminobenzoic acid analogs
(PABA)
Inhibitors of folate use
dihydrofolate reductase inhibitors
Trimethoprim – bacterial
Pyrimethamine – protozoa
Methotrexate - mammalian
#Folic acid requirement is for1. methylation required for the conversion of uracil to thymine 2. adenine & 3.guanine synthesis (indirect effect on NA synthesis)
#Bacteria synthesizes FA from junk through Dihydropteroate synthase enzyme which is absent in human.Hence sufonamide donot cause toxicity that stems from inhibition of Folic acid in human beings eg.bone marrow depression etc
#Human has DHFR like bacteria, protozoa therefore drugs that are designed to inhibit DHFR in bacteria or protozoa may cross inhibit DHFR in human ,may cause BMS etc.
1.A 25-year-old female with a sinus infection caused by Haemophilus influenzae is treated with trimethoprim-sulfamethoxazole.What is the Mechanism of action of those drugs?

6. Sulfonamides Mechanism PABA analogs
Enter into a normal metabolic pathway, but then block that pathway
Competitive inhibitor of dihydropteroate synthase
Bacteriostatic
Pharmacokinetics
Oral, some topical (burns), rarely IV
Well absorbed from GI, high PPB, well distributed including to CNS
Variable metabolism, depending on drug and patient
Acetylation yields inactive metabolite (less water soluble)→ Crystalluria
Excreted in urine (90% by glomerular filtration)
10-20x blood concentration in urine

7. Sulfonamides: Clinical Aspects
Clinical Use--
Topical for burns--Silver sulfadiazine
Ophthalmic preparations – Sodium sulfacetamide
Urinary Tract Infections-- Uncomplicated, untreated, acute
Ulcerative colitis-- Sulfasalazine, Mesalamine
Not absorbed-- split by gut bacteria reductase to release 5-aminosalicylate
Sulfonamides now are seldom used as single agents-- combine with trimethoprim
Adverse Effects--
Allergic reactions-- fever, rash, etc.
Up to 5% incidence
Cross-reactivity with other sulfonamides-- carbonic anhydrase inhibitors, thiazides, furosemide, sulfonylurea hypoglycemics
Crystalluria
Sulfonamide alone is almost never used as an antibiotic
1.A 26-year-old woman presents to the emergency department with a third-degree burn on her right forearm. She states that she accidentally spilled boiling water on her arm. Which of the following topical medications would be the most appropriate treatment of her condition?
Betamethasone cream
Calcipotriene ointment
Erythromycin solution
Metronidazole cream
Silver sulfadiazine cream

8. Sulfonamides: Clinical Aspects
Adverse Effects–
Stevens-Johnson syndrome—(Type IV)
Fever, malaise, . . .
Rare, but can be fatal
Hematopoietic effects
Hemolytic anemias-- G6PDH deficiency
Drug Interactions
Kernicterus in newborns
Resistance--
Mutations causing overproduction of PABA
Loss of permeability
New form of dihydropteroate synthetase-discriminates between PABA and sulfonamide
Sulfonamide-Sulfur(S)+Amide(PABA analogue)=hence so much allergic
Therapeutic Rationale for Kernicterus : Treatment of neonatal meningitis (m/c organism E.Coli or St.Agalactae)
1.A jaundiced one-day-old premature infant with an elevated free bilirubin is seen in the premature-baby nursery. The mother received an antibiotic combination preparation containing sulfamethizole for a urinary tract infection (UTI) one week before delivery. You suspect that the infant’s findings are caused by the sulfonamide because of the following mechanism:
a. Enhanced synthesis of bilirubin
b. Competition between the sulfonamide and bilirubin for binding sites on albumin
c. Inhibition of bilirubin degradation
d. Inhibition of urinary excretion of bilirubin
The answer is b. Sulfonamides should not be used in pregnant women who are at term because of their ability to cross the placenta and enter the fetus in concentrations sufficient to produce
toxic effects. Sulfonamides should also not be given to neonates, especially premature infants, because they compete with bilirubin for serum albumin binding, resulting in increased levels of free bilirubin, which cause kernicterus.

9. Dihydrofolate Reductase Inhibitors
Trimethoprim-- blocks bacterial enzyme
Pyrimethamine-- protozoan enzyme
Methotrexate-- mammalian enzyme
Trimethoprim--
Readily absorbed from GI
Wide distribution, including CNS
Excreted in urine
Can be used alone for UTI, but usually combined with a sulfonamide

10. Trimethoprim-Sulfamethoxazole (Co-trimoxazole)
Combination is often bactericidal
DOC in Nocardia
Mycobacteria
Gm-ve Infections
(E.Coli, Salmonella,Shihella)
Gm+ve Infections
( Staph, Strepto, H. Influenzae )
Fungus: Pneumocystis jiroveci pneumonia (PCP)-both for prophylaxis (when CD4 count <200) & treatment in HIV infection.
Protozoa : Toxoplasma Gondii (Sulfadiazine + Pyrimethamine) both for prophylaxis (when CD4 count <200) & treatment in HIV infection & in T of STORCH infection.
Note: Pneumocystis jiroveci used
to be called Pneumocystis carinii (PCP)

11. Adverse Effects of Trimethoprim
Trimethoprim is 10,000x more effective against bacterial DHFR than against the mammalian enzyme, but still may see "anti-folate" effects
Megaloblastic anemia, leukopenia, granulocytopenia
Treat with folinic acid
Co-trimoxazole-- Add typical sulfonamide effects
AIDS patients with Pneumocystis pneumonia (PCP) receiving Co-trimoxazole--
Much higher incidence of adverse effects
Fever, rashes, leukopenia, diarrhea
1.A newborn boy is diagnosed with a disorder caused by high levels of unconjugated bilirubin. Which of the following drugs administered to the infant’s mother during the last trimester of pregnancy might account for this presentation?
Acetaminophen
Azithromycin
Chloramphenicol
Diethylstilbestrol
Trimethoprim-sulfamethoxazole

12. Common ending with ‘floxacin’
E. DNA gyrase inhibitors
NALIDIXIC ACID
NORFLOXACIN
CIPROFLOXACIN
LEVOFLOXACIN
GATIFLOXACIN
SPAROFLOXACIN
MOXIFLOXACIN
TROVAFLOXACIN
Common ending with ‘floxacin’
Flo-fluorine

13. DNA Gyrase Inhibitors Quinolones Nalidixic Acid-- Fluoroquinolones--
Prototype quinolone antibiotic
Inhibits DNA replication
[by inhibiting DNA gyrase (Topoisomerase II)& IV]
Pharmacokinetics
Oral administration
Rapidly absorbed, metabolized (Glucuronidated)
and excreted in urine
Fluoroquinolones--
Norfloxacin
Ciprofloxacin
Ofloxacin
Levofloxacin
Gatifloxacin
Moxifloxacin
Gemifoxacin
Fluorinated analogues of nalidixic acid
Well absorbed and distributed after oral administration (Iron,Calcium limit absorption )
Only 20% is metabolized (liver)
Excreted in urine, blocked by probenecid
Effective systemically after oral dose, parenteral forms also available
Note: -floxacin ending
#Topoisomerase are required for supercoiling (over & under twisting of DNA called +ve & -ve super coiling respectively). All Topoisomerases decreases supercoiling allowing other enzymes to express for replication.Particularly Topoisomerase II helps in –ve supercoinling (opening DNA to help processing of replication & gene expression).All fluroquinolone prevent introduction of negitive supercoiling.
#Topoisomerase II keeps the recently separated DNA stands in position (by inhibiting cystochromatids) until G2 phase starts in.
1.A 36-year-old female with a chronic UTI treated with ciprofloxacin is not responsive to the antibiotic. Which of the following agents that she might have been taking for other reasons would decrease the effectiveness of ciprofloxacin?
a. An antacid
b. An antihistamine
c. A nonsteroidal anti-inflammatory
d. An anxiolytic
e. A multivitamin not containing iron
2.A 39-year-old female with a history of chronic UTI develops a new infection with Escherichia coli that is sensitive to levofloxacin.What is the Mechanism of action of Levofloxacin (or any quinolone)?

14. Fluoroquinolones
Example 1st Generation: norfloxacin; activity against common pathogens that cause urinary tract infections; similar to nalidixic acid
Examples of 2nd Generation: ciprofloxacin, ofloxacin; excellent activity against gram-negative bacteria, including gonococcus, Chlamydia, many gram-positive cocci, mycobacteria, and Mycoplasma pneumoniae
Examples of 3rd Generation: levofloxacin, gatifloxacin; less activity against gram-negative bacteria but greater activity against some gram-positive cocci, such as S. pneumoniae, entercocci, and MRSA; good for many drug-resistant respiratory tract infections
Examples of 4th Generation: moxifloxacin, Gemifloxacin; broadest spectrum fluoroquinolones with good activity against anaerobes

15. Activity & Clinical Uses
-UTIs particularly when resistant to Cotrimoxazole
-STDs/PIDs:Chlamydia (Ofloxacin), Gonorrhea (Cipro,Ofloxacin)
-Skin, soft tissue & bone infection by gm-ve organisms (all except norfloxacin)
-Diarrhea due to Shigella ,Salmonella, E.coli, Campylobacter (any quinolone)
-PNSP (Levofloxacin)

16. Fluoroquinolones Adverse Effects-- Nausea and vomiting
Phototoxicity & rashes (other drugs?)
All quinolone ↑ QT interval
Headaches, dizziness, insomnia
Abnormal liver function tests
Blocks theophylline clearance-- cannot be co-administered
Connective tissue disorders including tendonitis or tendon rapture (in adults),
myalgia & leg cramps (in children)
Do not use during pregnancy or in children (Fluorine is the culprit )
Resistance--
Altered (mutated) DNA gyrase
Especially Pseudomonas, Staph, Serratia
No longer recommended for gonococcus because of resistance
#Connective tissue disorder as an a/e of FQ occurs due to inhibition of host DNA gyrase responsible for replication in connective tissue
1.Which of the following may cause damage to growing cartilage?
a. Fluoroquinolones
b. Sulfonamides
c. Aminoglycosides
d. Cephalosporins
e. Tetracyclines
The answer is a. Fluoroquinolones are not recommended in patients less than 18 years old. They have a tendency to damage growing cartilage and cause arthropathy. The arthropathy is generally reversible. Tendinitis may occur, and in rare instances in adults, this finding may lead to tendon ruptures.

17. Discuss about the rationality of long term use of fluoroquinolones in children , adults or in pregnancy.

18. F. Urinary tract antiseptics
NITROFURANTOIN
SYSTEMIC AGENTS

19. Urinary Tract Antiseptics
Use systemic agents, which are efficiently cleared in the urine:
Penicillins
Aminoglycosides
Sulfonamides
Resistance and re-infection are common
May need to suppress bacteria for a long time
Common UTI bugs are
E.Coli(m/c), staphylococcus saprophyticus ,enterobacter cloacae, proteus mirabilis,klebsiella pneumonae, pseudomonus aeruginosa and serriatia .

20. Nitrofurantoin Mechanism Unknown, but may involve oxidative stress
Bacteriostatic or bactericidal (depends on microbe)
Pharmacokinetics--
Rapidly absorbed (oral), metabolized , and excreted in urine (50% as active drug)
Even IV nitrofurantoin does not have a systemic effect
Clinical Use--
UTI, gram positive or gram negative microbes
Most effective if urine pH < 5.5
Adverse Effects--
Anorexia, GI disturbances common, headaches
Occasional hemolytic anemia (oxidative) especially if G6PDH deficient, leukopenia, hepatotoxicity
In renal insufficiency, see systemic toxicity
Resistance--
All Pseudomonas, some Proteus are resistant

21. Spectrum coverage of Antibiotics covered in a chart.

22. Antibiotic Sensitivity Overview

23. Antibiotics of Choice for Various Infections
Drug Organism (Disease)
Amoxicillin, clarithromycin (omeprazole*) Helicobacter pylori (peptic ulcer)
Ampicillin Listeria (meningitis)
Ceftriaxone, Cefexime Neisseria gonorrhoeae (gonorrhea)
Cephalosporins (third-generation) Haemophilus influenzae
(pneumonia, meningitis)
Klebsiella (meningitis)
Doxycycline Borrelia burgdorferi (Lyme disease)
Rickettsiae (Rocky Mountain spotted fever)
Erythromycin Legionella (legionnaires’ disease)
Fluconazole, miconazole, nystatin Candida (candidiasis)
Isoniazid, rifampin, ethambutol, Mycobacterium tuberculosis
pyrazinamide (tuberculosis)
*Omeprazole is not an antibiotic but is used in combination with antibiotics for treatment of H. pylori.

24. Antibiotics of Choice for Various Infections
Drug Organism (Disease)
Macrolides Mycoplasma pneumoniae (atypical pneumonia)
Legionella (legionnaires’ disease)
Corynebacterium diphtheriae; Chlamydia
Metronidazole Trichomonas (trichomoniasis)
Penicillin G Neisseria meningitidis (meningitis)
Treponema pallidum (syphilis)
Infections caused by streptococci, pneumococci, other meningococci,
Bacillus anthracis,
Clostridium,
Bacteroides (except B. fragilis)
Fluroquinolones Campylobacter (diarrhea); Shigella
Tetracycline Vibrio cholerae (cholera)
Other tetracyclines Chlamydia (pneumonia, lymphogranuloma venereum)
Trimethoprim-sulfamethoxazole Salmonella; Shigella (diarrhea)
Metronidazole or vancomycin (oral) Clostridium difficile (diarrhea)
1. A man is with fever, chills, and a productive cough with sputum Gram's stain reveals numerous gram-positive diplococci. Which of the following antibiotics would be the most appropriate choice for empiric therapy of this man's infection?

25. Prophylactic Use of Anti-infective Drugs
Drug Use
Cefazolin Surgical procedures
Cefoxitin, Cefotetan Surgical procedures where anaerobic infections are common
Ampicillin or penicillin Group B streptococcal infections
Trimethoprim-sulfamethoxazole Pneumocystis carinii pneumonia (PCP)
UTIs
Rifampin Haemophilus influenzae type B
Meningococcal infection
Chloroquine Malaria
Isoniazid Tuberculosis
Azithromycin Mycobacterium avium complex (MAC) in patients with AIDS
Ampicillin or azithromycin
or clindamycin Dental procedures in patients with valve abnormalities
Prophylaxis for a patient w/murmur attending a dentist for tooth extraction ?
AIDS = Acquired immunodeficiency syndrome; UTI = urinary tract infection.

26. Pyrimethamine
Methotrexate
-floxain

27. A 44-year-old woman recently exposed to influenza experiences a headache, fever, malaise and a cough. These symptoms subside after 5 days but on the 8th day her cough worsen and she again has a fever. Physical examination reveals signs of pneumonia. Which of the following medications would be most appropriate for the treatment of pneumonia in this patient?
Amantadine
Levofloxacin
Palivizumab
Ribavirin
Sulfamethoxazole
Answer: B
Levofloxacin is a
respiratory fluoroquinolone

28. PowerPoint Slides
Several of the PowerPoint slides are Copyright © , the  American Society for Pharmacology and Experimental Therapeutics (ASPET). All rights reserved.
Some of slides in this session are from the above mentioned format and are free for use by members of ASPET. 
Some others are from various sources like text book, recommended books, slides of Dr. S. Akbar (ex. professor, Pharmacology ,MUA).
Core concepts of various USMLE High yield review series like Kaplan ,BRS etc. are thoroughly explored & integrated whenever necessary