Pharmacology II Exam 2: Infectious disease

antifolate DNA/RNA synthesis inhibitors

• Cotrimoxazole

• Sulfonamides

• Trimethoprim

Cotrimoxazole is a

folate antagonist

sulfonamide that is orally absorbable, short acting, used in UTI

Sulfisoxazole

sulfonamide that is orally absorbable, intermediate acting, used in UTI

Sulfamethoxazole

sulfonamide that is orally absorbable, long acting, used in malaria

Sulfadioxine

sulfonamide that is oral but non absorbable, used in ulcerative colitis

Sulfasalazine

topical sulfonamides

• sodium sulfacetamide: ophthalmic conjunctivitis

• silver sulfacetamide: burn wound prophylaxis

Sulfamethoxazole/Trimethoprim MOA

• sulfamethoxazole: inhibits dihydropteroate synthase

• trimethoprim: inhibits dihydrofolate reductase (DHFR)

Quinolones suffix

-floxacin

MOA of quinolones

inhibits topoisomerase IV and gyrase to inhibit bacterial DNA synthesis

RNA polymerase inhibitors

• Fidaxomicin - inhibits sigma subunit, GI infections

• Rifampin - inhibits beta subunit, TB, mycobacterium

Rifampin increases efficacy of

Isoniazid

Inhibitors of 30S ribosomal subunit

• Aminoglycosides - Tobramycin, Gentamycin, Amikacin

• Tetracyclines (-cycline)

Inhibitors of 50S ribosomal subunit

• Macrolides (-omycin)

• Streptogramins - Quinupristin/Dalfopristin

• Mupirocin

• Chloramphenicol

• Lincosamides - Clindamycin

• Oxazolidinones - Linezolid, Tedezolid

• Pleuromutilins - Lefamulin, Retapamulin

MOA of aminoglycosides

• bactericidal - causes leakage of cytoplasm due to polycationic properties

• irreversible inhibition of 30S, causes mRNA codon to be misread

• interferes with the initiation complex of 30S and 50S with mRNA

• used against aerobic gram - microbes

aspects of Aminoglycosides

• ototoxicity

• poor oral absorption due to polycations, poor CSF penetration

• used against aerobic gram - microbes

• bactericidal

• do not combine with penicillins

aspects of tetracyclines

• reversible binding to “A” site of 30S and interferes with binding of tRNA to ribosome

• commonly used in animal feed

• binds to calcium - tooth discoloration

• avoid in children < 8 yrs and in pregnancy/lactation

• photosensitive rashes

aspects of Macrolides

• reversible binding to 50S ribosomal subunit near P site - blocks exit channel to inhibit transpeptidation

• bactericidal at high concentrations - complete block of ribosomal activity

• effective against gram + bacteria

Levofloxacin is a

Quinolone - DNA synthesis inhibitor

Ciprofloxacin is a

Quinolone - DNA synthesis inhibitor

fidaxomycin is a

RNA polymerase inhibitor

Rifampin is a

RNA polymerase inhibitor

Amikacin is a

aminoglycoside - 30S ribosomal inhibitor

Tobramycin is a

aminoglycoside - 30S ribosomal inhibitor

Gentamycin is a

aminoglycoside - 30S ribosomal inhibitor

Doxycycline is a

tetracycline - 30S ribosomal inhibitor

Tigecycline is a

tetracycline - 30S ribosomal inhibitor

Azithromycin is a

Macrolide - 50S ribosomal inhibitor

Clarithromycin is a

Macrolide - 50S ribosomal inhibitor

Erythromycin is a

Macrolide - 50S ribosomal inhibitor

Quinipristin/Dalfopristin is a

Streptogramin - 50S ribosomal inhibitor

aspects of Streptogramins

• bactericidal

• overlaps with macrolide binding site - 50S ribosomal subunit near P site - blocks exit channel to inhibit transpeptidation

• bilirubin elevations

Mupirocin is a

50S ribosomal inhibitor

Chloramphenicol is a

50S ribosomal inhibitor

aspects of Chloramphenicol

• aerobic and anaerobic bacteria

• binding site overlaps with macrolides and clindamycin - used to inhibit formation of peptide bond

• gray baby syndrome

• DDI: warfarin, phenytoin

Clindamycin is a

Lincosamide - 50S ribosomal inhibitor

Linezolid is a

• Oxazolidinone - 50S ribosomal inhibitor

• prevents formation of 30/50S complex

Tedizolid is a

Oxazolidinone - 50S ribosomal inhibitor

Lefamulin is a

Pleuromutilin - 50S ribosomal inhibitor

Retapamulin is a

Pleuromutilin - 50S ribosomal inhibitor

Beta lactams

• Penicillins (-illin)

• Cephalosporins

• Monobactams - Aztreonam

• Carbapenems (-penem)

Penicillins:

• group 1: Penicillin G, + and -

• group 2: Oxacillin, + only

• group 3: Amoxicillin, Ampicillin, + and -

• group 4: Ticarcillin, + and -

• group 5: Piperacillin/Tazobactam, + and -

beta lactamase inhibitors

• clavulanate acid

• sulbactam

• tazobactam

Cephalosporins

• group 1: Cephalexin, Cefazolin

• group 2: Cefuroxime

• group 3: Ceftriaxone

• group 4: Cefepime

• group 5: Ceftaroline

MOA of beta lactams

suicide inhibition of transpeptidase - bactericidal

Aztreonam is a

monobactam

Meropenem is a

carbapenem

Imipenem is a

carbapenem

Vancomycin is a

glycopeptide/lipoglycopeptide

MOA of vancomycin

binds terminal D-ala-D-ala dipeptide to prevent joining of murein

Daptomycin is a

lipopeptide

MOA of daptomycin

binds and depolarizes bacterial inner membrane - bactericidal

MOA of Bacitracin

inhibits peptidoglycan precursor trafficking

Bacitracin is a

cell wall synthesis inhibitor

Polymixin is a

cell wall synthesis inhibitor

MOA of Polymixin

• binds to LPS on gram - microbes and disrupts cell wall integrity

• alters membrane potential

• too toxic - topical only

Mycobacterial therapeutics

• Rifampin

• Isoniazid

• Pyrazinamide

• Ethambutol

Treatment of drug resistant TB

• Bedaquiline

• Clofazimine

• Delamanid

• Pretomanid

MOA of Triazole and Imidazole antifungals

inhibits activity of 14-a-sterol demethylase reducing ergosterol synthesis, fungistatic

Triazoles

• fluconazole

• itraconazole

• voriconazole

imidazole

ketoconazole

Caspofungin is a

echinocandin

MOA of Caspofungin

non-competitive inhibition of fungal enzyme to prevent linkage of glucan to chitin, rupture of fungal cell wall - fungicidal

Polyenes

• Amphotericin B

• Nystatin

MOA of polyenes

complexes with ergosterol and extracts it from cell membrane - fungicidal

Allyamines

Terbanifine

MOA of Terbanafine

inhibits squalene epoxidase to decrease lanosterol production, increased levels of toxic squalene - fungicidal

What is used in combination with Amphotericin B to enhance uptake

5-Flucytosine

5-Flucytosine MOA

creates suicide inhibitor of thymidylate synthase blocking DNA synthesis

treatment of influenza:

• M2 ion channels - no longer used

• Neuraminidase inhibitors - Oseltamivir, Zanamivir

Treatment of Hepatitis B

• chain terminators - Tenofovir, Entecavir, Lamivudine

• interferon-a

Treatment of Hepatitis C

• NS5B - Sofosbuvir

• NS5A - Velpatsvir, Ledipasvir, Pibrentasvir

• NS3/4A - Glecaprevir

• Ribavirin

prophylactic treatment of RSV

Palivizumab

Palivizumab is a

mAb against RSV fusion protein

Glecaprevir is a

NS3/4A serene protease - treats HCV

Velpatasvir, Ledipasvir, Pibrentasvir are

NS5A inhibitor - Treats HCV

Sofosbuvir is a

NS5B RNA polymerase inhibitor - treats HCV

interferon-a is a

transcription inhibitor - treats HBV

Entecavir, Lamivudine are

nucleoside analogues - treats HBV

Tenofovir is a

nucleoside analogue - treats HBV

Zanamivir is a

neuraminidase inhibitor - treats influenza

Oseltamivir is a

neuraminidase inhibitor - treats influenza

HSV-1

oral herpes

HSV-2

genital herpes

HSV-5

cytomegalovirus

treatment of herpes viruses

• Acyclovir/valacyclovir

• Ganciclovir

• Foscarnet

• Cidofovir

Acyclovir, Valaciclovir are

DNA polymerase inhibitor/chain terminator - treats HSV

Foscarnet is a

DNA polymerase inhibitor - treats acyclovir resistant HSV and VZV, cytomegalovirus

biologic treatment of COVID-19

• Casirivimab

• Imdevimab

Treatment of COVID-19

• Paxlovid: Nirmatrelvir/Ritonavir

• Remdesivir

Nirmatrelvir/Ritonavir is a

protease inhibitor - treats COVID-19

Remdesivir is a

COVID-19 RNA polymerase inhibitor

treatment of HIV:

• attachment/fusion inhibitors - Maraviroc, Enfuvirtide

• NRTI - Abacavir, Lamivudine, Tenofovir, Zidovudine (AZT), Emtricitabine (FTC)

• Non-NRTI - Efavirenz, Nevirapine

• Integrase inhibitors - Dolutegravir, Raltegravir

• Protease inhibitors - Atazanavir (ATV), Ritonavir (RTV)

HAART therapy for HIV

2 NRTI + 1 Non-NRTI + 1 Protease Inhibitor

PK enhancer for HIV treatment

Cobicistat

Maraviroc is a

attachment/fusion inhibitor, prevents gp120/CCR5 binding - treats HIV

Enfuvirtide is a

attachment/fusion inhibitor, mimics gp41 to prevent fusion - treats HIV

Abacavir is a

NRTI, ddNTP, guanosine analogue, chain terminator - treats HIV

Lamivudine is a

NRTI, ddNTP, chain terminator, mitochondrial DNA polymerase inhibition - treats HIV

Zidovudine (AZT) is a

NRTI, ddNTP, chain terminator, mitochondrial DNA polymerase inhibition - treats HIV