Drugs Flashcards
Strategies toward development of new antibiotics
- Combat bacterial resistance mechanisms: develop inhibitors of drug inactivating proteins and efflux transporters, develop drug analogs that are resistant to drug-inactivating proteins
- ID new targets for chemotherapy for chemotherapy
Aminoglycosides
Antibiotics that inhibit protein synthesis
Includes streptomycin, tobramycin, gentamicin, amikacin, neomycin, kanamycin
Targets 30S ribosomal subunit to irreversibly interfere with protein synthesis by either blocking initiation, blocking ribosomal translocation, or causing mistranslation
Post-antibiotic effect
Bactericidal against many aerobic gram negative bacteria
Streptomycin
Aminoglycoside
Used as second-line treatment for TB (in combo with other agents to inhibit resistance)
Tobramycin
Most clinically used aminoglycoside
Used for severe infections caused by aerobic Gram- bacteria that are resistant to other drugs
Often used in combo with beta-lactam antibiotics because synergystic
More expensive than gentamycin
Gentamicin
Most clinically used aminoglycoside
Used for severe infections caused by aerobic Gram- bacteria that are resistant to other drugs
Often used in combo with beta-lactam antibiotics because synergystic
More cheaper than tobramycin
Amikacin
Aminoglycosides
Only really used in cases of resistance to tobramycin and gentamicin (there are many bacterially-produced enzymes that cause inactivate tobramycin and genamicin)
Neomycin
Aminoglycoside
Restricted to topical use only because very toxic (neosporin)
Kanamycin
Aminoglycoside
Restricted to topical use only because very toxic
Adverse Effects from Aminoglycosides
Reversible nephrotoxicity
Irreversible ototoxicity (auditory damage and/or vestibular damage)
Auditory damage include tinnitus, high frequency hearing loss
Vestibular damage includes vertigo and ataxia
More likely to occur with use of aminoglycosides longer than 5 days
Tetracyclines
Inhibit protein synthesis
By blocking 30s ribosomal subunit, inhibit peptide elongation
Bacteriostatic for many aerobic Gram+ and -, including rickettsiae, chlamydiae, and mycoplasmas
Used for rickettsial infections (RMSF, typhus, and Q fever), STIs (chlamydia, urethritis, cervicitis, and epididymititis), respiratory tract infections (pneumonia), Lyme’, anthrax, malaria, and skin/soft tissue infections
Absorption is impaired by food and multivalent cations (Ca2+, Mg2+, Fe2+, and Al3+) cause chelation
Includes tetracycline, oxytetracycline, demeclocycline, minocycline, doxycycline, and tigecycline (first two have VERY short half life)
Adverse Effects from Tetracyclines
GI problems (nausea, vommitting, diarrhea)
Tooth discoloration and deformity, especially in children
Photosensitization (easily sunburn)
Hepatoxicity during pregnancy
Doxycycline
Tetracycline used for treatment and prevention of malaria, anthrax, and treatment of Lyme
Tigercycline
An IV tetracycline with a long half life used for treatment of community acquired pneumonia, intra-abdominal, skin and soft tissue infections cause by MDR bacteria (MRSA, VRE, etc)
Macrolides
Inhibit protein synthesis
Bind to the 50S subunit to inhibit ribosomal translocation
Bacteriostatic against aerobic Gram+ and some Gram- bacteria
Used for community acquired pneumonia, bronchitis, otitis media, strep throat, chlamydia, diptheria, pertussiss
Erythromycin, carithromycin, azithromycin, and telithromycin
Can cause GI problems and hepatotoxicity
Azithromycin
Macrolide with long half life
Aka Z-Pak
Lincosamide
Inhibits protein synthesis
Binds to 50S subunit and interferes with protein synthesis by blocking ribosomal translocation
Bacteriostatic ONLY against aerobic and anaerobic Gram+ bacteria
Used for soft tissue and skin infections
Can cause diarrhea, pseudomembranous colitis caused by C. dif, and skin rash
Adverse effects from macrolides
Hepatotoxicity-through hypersensitivity reaction
GI Effects-stimulate gut motility-anorexia, nausea, vomiting, and diarrhea accompanying oral administration
Strepogramins
Protein synthesis inhibitors
Bind to 50S ribosomal subunit to inhibit ribosomal translocation
For VRE and MSSA (not MRSA)
Used against Gram+ bacteria
Quinupristin and dalfopristin
Oxazolidinone
Protein synthesis inhibitors
Bind to 50S to inhibit initiation step of protein synthesis
Used against aerobic and anaerobic Gram+
Used for treatment of infections caused by MDR gram+ bacteria (MRSA, VRE, and penicillin resistant streptococci)
Sulfonamides
Inhibit DNA synthesis (anti-folate)
Competitive antagonist of dihydropteroate synthase needed for purine synthesis; act as PABA analogs
Bacteriostatic when used as single agent; bactericidal when used with tripmethoprim (which inhibits DNA synthesis further downstream)
Sulfisoxazole, sulfamethoxazole, and sulfasalazine
Sulfisoxazole
Sulfonimide (antifolate DNA synthesis inhibitor)
Used for UTIs
Sulfamethoxazole
Sulfonimide (antifolate DNA synthesis inhibitor)
Used for UTIs
Sulfasalazine
Sulfonamide (anti-folate DNA synthesis inhibitor)
Used for ulcerative colitis, enteritis, and other IBD
Has anti-inflammatory properties
Adverse effects of sulfonamides
Hypersensitivity/allergic reactions-fever, rash,
Most serious=crystalluria, hematuria, or obstruction
TMP-SMX
Combination of trimethoprim and sulfamethoxazole
Both are anti-folates that, when used together, are bactericidal
Used for UTIs, pneumonia, Shigellosis, Salmonella, prostatitis, and acute bronchitis
Treatment less than 5 days can cause allergic reaction
Treatment longer than 5 days can cause megaloblastic anemia and leukopenia
Trimethoprim
Inhibits DNA synthesis
Blocks DHFR needed to make purines
Fluroquinolone
Inhibit DNA synthesis
Inhibit DNA gyrase and topoisomerase
Bactericidal against Gram- and Gram+
Used for UTIs, diarrhea caused by Shigella or Salmonella or E. Coli, soft tissue and bone and joint infections, intra-abdominal infections, respiratory tract infections
Levofloxacin, gemifloxacin, and moxifloxacin effective for respiratory tract infections
Cipro used for anthrax (caused by Gram+)
Ciprofloxacin, lomefloxacin, levofloxacin, ofloxain, gemifloxacin, moxifloxacin
Beta-Lactam Antibiotics
Antibiotic that targets cell wall
Inhibit cross linking of peptidoglycan units by mimicking D-Ala-D-Ala to bind to Ser-enzyme
Without cell wall, bacteria bursts
Combined with beta-lactamase inhibitors
4 types, but all share core ring: penicillin, cephalosporin, monobactam, and carbepenems
Beta-lactamase
Action and drug names
Gram- response to beta-lactam antibiotics
Clavulanic acid
Avibactam-broad spectrum inhibitor
Act like transpeptidases, but use water to hydrolyze serine-lactam linkage to irreversibly inactivate beta-lactams and allow for peptidoglycan cross linking
Two types: serine and metallo
Penicillin
Details and drug names
Beta-lactam antibiotic
Use with probenecid to increase half life (prevent excretion)
Oral, IV, or IM administration
Common: pencillin G
Antistaphlycoccal pencillin: oxacillin, cloxacillin, dicloxacillin
Extended spectrum: amoxicillin
Resistance=MRSA
Penicillin G
Beta-lactam antibiotic, Common penicillin
Acid labile, beta-lactamase susceptible
Gram+, and Gram- cocci
Anti-staphylococcal Penicillins
Beta-lactam antibiotic
Includes oxacillin, cloxacillin, and dicloxacillin
Acid stable, beta-lactamase resistant
not suitable for enterococci, anaerobes, and Gram- cocci and rods
Amoxicillin
Beta-lactam antibiotic, extended spectrum penicillin
Acid stable, beta-lactamase sensitive
Greater activity against Gram- because able to penetrate outer membrane
With clavulanate=augmentin
Cephalosporins
Beta-lactam antibiotic
Greater spectrum because increased resistance to beta-lactamases
5 generations
Cefazolin
First generation cephalosporin
Best for Gram+
Given for surgery prophylaxis
Cefamandole
Second generation cephalosporin
Gram + and -
No allergic cross reactivity with penicillin
Ceftazidime
Third generation cephalosporin
Extend Gram- at expense of Gram+
Can cross BBB
Cefepime
Fourth generation cephalosporin
Broad spectrum
Penetrates BBB
Ceftaroline
Fifth generation cephalosporin
Used for MRSA because has high affinity for transpeptidase found in MRSA
Monobactams
Beta-lactam antibiotic
Active ONLY against Gram-rods
Given by IV and excreted rapidly
Resistant to beta-lactamases
No cross reactivity with pencillin
Aztreonam
Beta-lactam antibiotic, Monobactam
Only active against Gram- rods
Carbapenems
Beta-lactam antibiotic, Imipenem
Broad spectrum
Cilastatin used to block excretion.
Resistant to serine bet-lactamases, but NOT metallo beta-lactamases
Cross BBB
Cross reactivity with penicillin allergies
Imipenem
Beta lactam antibiotic, carbapenem
Broad spectrum and can cross BBB
Vancomycin
Glycopeptide; Non-beta lactam cell wall inhibitor
For Gram+ bacteria, especially staphylococci
Too big to affect Gram-
Binds tightly to D-Ala-D-Ala to block transglycosylase and transpeptidase action
Used for MRSA and methicillin-resistant endocarditis or sepsis
Resistance: bacteria switches from D-Ala-D-Ala to D-Ala-D-Lactate, which decreases Vancomycin affinity by 1000x
Requires IV administration
Dalbavancin
Glycopeptide non-beta lactam antibiotic
Derivative of Vancomycin, but only need two doses
Oritavancin
Glycopeptide non-beta lactam antibiotic
Derivative of Vancomycin, but only need one dose
Daptomycin
Lipopeptide non-beta lactam antibiotic
Drills pores in inner membrane of Gram+ that allow K+ loss WITHOUT cell rupture
Polymyxins
A lipopeptide non-beta lactam antibiotic
Binds to a liposaccharide only on outer membrane of GRAM- bacteria and makes perforation leading to permeability of the inner and outer cell membrane
Used topically; in neosporin
Fosfomycin
Antibiotic inhibitor of peptidoglycan precursors
Inhibits MurA, which is needed to catalyze the first committed step (NAG-UDP –> NAM-UDP)
Used for Gram+ and-
Commonly used for UTIs
Bacitracin
Antibiotic inhibitor of peptidoglycan precursors
Inhibits dephosphorylation of lipid carrier of peptidoglycan subunits
Active only against Gram+
Only used topically
D-Cycloserine
Antibiotic inhibitor of peptidoglycan precursors
D-Ala analog so inhibits enyzmes needed to convert Ala–>D-Ala (racemase) and glue D-Ala subunits together (D-alanine ligase)
Used in combination with other antibiotics as a second line drug to treat TB, but otherwise toxic
First line TB drugs
Rifampin
Isoniazid
Pyrazinamide
Ethambutol
Features of Second-line TB drugs
Given for MDR-TB
Less effective than first line drugs with significant side effects
Expensive
Isoniazid
First line treatment for TB; targets mycolic acid biosynthesis at FAS-II
Bactericidal against both extracellular and intramacrophage mycobacteria
Taken orally
High probability of resistance, so used with other drugs
Pro-drug activated by bacterial enzyme KatG
Side effects: hepatitis and peripheral neuropathy (because competitive inhibitor of vitamin B6)
Supplement administration with B6
Metabolism varies by genetics; drug inactivated by acetylation
Rifampin
First line treatment for TB
Inhibits bacterial transcription elongation by inhibiting RNA from interacting with RNApol
Bactericidal
Administer orally
Side effects: flu-like symptoms; increases P450 members including CYP3A which increases elimination of other drugs
Harmless red or purple urine
Rifabutin
Rifapentine
Derivative of rifampin used as first line treatment for TB
Have higher potency, longer half life, and less CYP interference
Pyrazinamide
First line treatment for TB that inhibits protein synthesis
Bactericidal; pro-drug activated by PZase
Oral
Inhibits trans-translation so there is a defect in rescue of stalled ribosome and depletion of available ribosomes for protein synthesis
Works synergistically with rifampin
Rapid emergence of resistance
Ethambutol
First line treatment for TB
Inhibits incorporation of arabinose in cell wall; cell wall is too weak
Oral
Side effects: optic neuritis and red green color blindness
High probability of resistance
