chemotherapeutic drugs
TRANSCRIPT
![Page 1: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/1.jpg)
CHEMOTHERAPEUTIC CHEMOTHERAPEUTIC DRUGSDRUGS
ANITA Q. SANGALANG, MD, FPOGSANITA Q. SANGALANG, MD, FPOGSDEPARTMENT OF MEDICAL TECHNOLOGYDEPARTMENT OF MEDICAL TECHNOLOGY
COLLEGE OF PHARMACYCOLLEGE OF PHARMACYUNIVERSITY OF SANTO TOMASUNIVERSITY OF SANTO TOMAS
![Page 2: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/2.jpg)
MICROORGANISMS & ANTIMICROBIALS
1. Bacteria - Antibacterial
2. Viruses - Antiviral
3. Fungi - Antifungal
4. Parasites - Antiparasitic
![Page 3: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/3.jpg)
OBJECTIVES1. Mechanisms of action
2. Pharmacokinetics
3. Clinical uses
4. Resistance
5. Adverse effects
•main classes of drugs used to treat pathogens provide examples of some specific drugs from each class that are used clinically
![Page 4: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/4.jpg)
ANTIMICROBIAL DRUGS
1. Beta-Lactam Antibiotics & Other Inhibitors of Cell Wall Synthesis
Penicillins, Cephalosporins & Cephamycins
2. Chloramphenicol, Tetracylines, Macrolides, Clindamycin & Streptogramins
3. Aminoglycosides and Spectinomycin
4. Sulfonamides, Timethoprim, & Quinolones
![Page 5: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/5.jpg)
ANTIBACTERIAL DRUGS
Spectrum of ActionBroad: wide range of bacteriaNarrow: limited to subset of bacteria
ActionBacteriostatic: stop bacteria from multiplyingBactericidal: kills bacteria
Bacterial vulnerability:Susceptibility: presence of antimicrobial targetsSensitivity: necessary effective concentrationResistance: target not present, mutation prevents
antimicrobial activity
![Page 6: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/6.jpg)
ANTIBACTERIAL DRUGSMECHANISMS OF ACTION
1) Disruption of cell wall synthesis
2) Inhibition of protein synthesis
3) Inhibition of DNA synthesis or damage to DNA
4) Disruption of cell membrane
5) Metabolism
BACTERIAL CELL ENERGY
Aerobic : with oxygen
Anaerobic: without oxygen
![Page 7: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/7.jpg)
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICS
PenicillinsPenicillins
Cephalosporins Cephalosporins
MonobactamsMonobactams
CarbapenemsCarbapenems
ß-lactamase inhibitorsß-lactamase inhibitors
![Page 8: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/8.jpg)
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICS
Basic structure: 6-aminopenicillanic Basic structure: 6-aminopenicillanic acidacidThiazolidine ring, ß-lactam ring Thiazolidine ring, ß-lactam ring (secondary amino group), substituents (secondary amino group), substituents (R group)(R group)Structural integrity essential for the Structural integrity essential for the biologic activity biologic activity If ß-lactam ring is cleaved by bacterial If ß-lactam ring is cleaved by bacterial ß-lactamases ß-lactamases penicilloic acid penicilloic acid no no antibacterial activityantibacterial activity
![Page 9: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/9.jpg)
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICSPenicillin G Penicillin G (benzylpenicillin)(benzylpenicillin)
g(+)>g(-)g(+)>g(-)
acid labile; acid labile; destroyed by destroyed by ß-lactamase ß-lactamase
OxacillinOxacillin
CloxacillinCloxacillin
DicloxacillinDicloxacillin
FlucloxacillinFlucloxacillin
ß-lactamase ß-lactamase resistantresistant
acid stableacid stable
Nafcillin Nafcillin (ethoxynaphthami(ethoxynaphthamidopenicillin)dopenicillin)
ß lactamase ß lactamase resistantresistant
![Page 10: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/10.jpg)
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICSAmpicillinAmpicillin destroyed by destroyed by
ß-lactamaseß-lactamase
acid stableacid stable
g(-) > g(+) g(-) > g(+)
TicarcillinTicarcillin
Piperacillin Piperacillin MezlocillinMezlocillin
G(-) aerobesG(-) aerobes
AmoxicillinAmoxicillin Like ampicillin Like ampicillin but better but better absorbedabsorbed
![Page 11: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/11.jpg)
(mechanism of action)
• inhibit cell wall synthesis
cross-linked Peptidoglycans
if damaged: cell lysis(bactericidal)
gram positive
bacterium
Cell wallPlasma membrane
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICS
![Page 12: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/12.jpg)
Absorption: variable/impaired by food
Distribution: most tissues except CNS, prostate (unless inflamed)
Elimination: mainly excreted unchanged in urine Penicillins (adverse reactions)
Main Adverse Effects1) Hypersensitivity - mild allergy to
anaphylactic 2) Colitis –penicillins can disturb gut flora
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICS
![Page 13: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/13.jpg)
4 General Mechanisms of Resistance
1. Inactivation of antibiotic by ß lactamase
2. Modification of target penicillin binding proteins (PBP)
3. Impaired penetration of drug to target PBPs
4. Presence of efflux pump
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICS
![Page 14: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/14.jpg)
Penicillin G
• Not acid stable must be injected
• Effective against gram (+) anaerobic bacteriaWhy gram (+) and not gram (-) ?(1) have difficulty penetrating outer
membrane(2) beta-lactamases in periplasmic space
of gram (-) bacteria
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICS
![Page 15: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/15.jpg)
Penicillin G
• Penicillin destroyed before it can bind to transpeptidases• Drug of choice for streptococcal (eg. pharyngitis, scarlet fever, pneumonia) and meningococcal (eg. meningitis) infections
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICS
![Page 16: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/16.jpg)
beta-lactamases
![Page 17: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/17.jpg)
Units and PreparationsUnits and Preparations
Crystalline sodium penicillin G 1600 Crystalline sodium penicillin G 1600 units/mg (1 unit=0.6units/mg (1 unit=0.6g; 1 million units of g; 1 million units of penicillin=0.6g)penicillin=0.6g)
Potassium penicillin G benzanthine/ Potassium penicillin G benzanthine/ procaine – parenteral formprocaine – parenteral form
Penicillin V – oral: 250, 500mg tabsPenicillin V – oral: 250, 500mg tabs
BETA-LACTAM ANTIBIOTICS BETA-LACTAM ANTIBIOTICS Penicillins
![Page 18: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/18.jpg)
Cloxacillin
• Acid stable given orally; Beta-lactamase resistant
• Effective against beta-lactamase producing staphylococcal Infections (e.g.. toxic shock syndrome)
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICS Penicillins
![Page 19: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/19.jpg)
Amoxicillin• Acid stable - given orally• Extended spectrum: gram (+) and some gram (-) bacteria (eg. E.Coli)• Used to treat infections caused by penicillin resistant bacteria (eg. S. pneumonia)• Degraded by beta-lactamase \ more effective when given with beta-lactamase inhibitor (eg. clavulanic acid)
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICS Penicillins
![Page 20: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/20.jpg)
• Similar to penicillins (mechanism of action, distribution, elimination, adverse effects)
• Most not acid stable cannot not be given orally
• Not as sensitive as penicillins to degradation by beta-lactamases
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICS Cephalosporins
![Page 21: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/21.jpg)
• Only 5 to 10 % of individuals with penicillin allergies are also allergic to cephalosporins • Should be avoided in individuals with history of anaphylaxis to penicillins• Cephalosporins divided into 4 generations
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICS Cephalosporins
![Page 22: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/22.jpg)
1st generation (early cephalosporins):
gram (+) e.g. cefazolin (used as prophylactic following surgery)
2nd generation:
gram (+) & gram (-)
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICS Cephalosporins
![Page 23: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/23.jpg)
3rd generation:
good against gram (-) aerobes some cross into CNS readily e.g. cefotaxime used to treat meningitis
4th generation:
like 3rd generation but more resistant to beta-lactamases
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICS Cephalosporins
![Page 24: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/24.jpg)
BETA-LACTAM ANTIBIOTICS BETA-LACTAM ANTIBIOTICS Cephalosporins
11STST GENERATION GENERATION CephalexinCephalexin, Cefazolin, , Cefazolin, Cefadroxil, Cephalotin, Cefadroxil, Cephalotin, Cephadrine, CephapirinCephadrine, Cephapirin
22NDND GENERATION GENERATION CefuroximeCefuroxime, Cefoxitin, , Cefoxitin, Cefotetan, CefamandoleCefotetan, Cefamandole
33RDRD GENERATION GENERATION Ceftriaxone, Cefotaxime, Ceftriaxone, Cefotaxime, Cefoperazone, Cefoperazone, CeftazidimeCeftazidime
44THTH GENERATION GENERATION CefepimeCefepime
![Page 25: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/25.jpg)
BETA-LACTAM ANTIBIOTICS BETA-LACTAM ANTIBIOTICS
MONOBACTAMSMONOBACTAMSBETA-LACTAMASE INHIBITORS BETA-LACTAMASE INHIBITORS (CLAVULANIC ACID, SULBACTAM & (CLAVULANIC ACID, SULBACTAM & TAZOBACTAM)TAZOBACTAM)CABAPENEMSCABAPENEMSVANCOMYCINVANCOMYCINTEICOPLANINTEICOPLANINFOSFOMYCINFOSFOMYCINBACITRACINBACITRACINCLYCLOSERINECLYCLOSERINE
![Page 26: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/26.jpg)
CHLORAMPHENICOL, CHLORAMPHENICOL, TETRACYCLINE, MACROLIDES, TETRACYCLINE, MACROLIDES,
CLINDAMYCIN AND CLINDAMYCIN AND STREPTOGRAMINSSTREPTOGRAMINS
ANITA Q. SANGALANG, MD, FPOGSANITA Q. SANGALANG, MD, FPOGSDEPARTMENT OF MEDICAL TECHNOLOGYDEPARTMENT OF MEDICAL TECHNOLOGY
COLLEGE OF PHARMACYCOLLEGE OF PHARMACYUNIVERSITY OF SANTO TOMASUNIVERSITY OF SANTO TOMAS
![Page 27: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/27.jpg)
Chloramphenicol
•Effective bacteriostatic broad-spectrum
• aerobic and anaerobic gram (+) and gram (-) organisms
• Use is limited due to side effects
• An almost ”ideal” antibiotic
![Page 28: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/28.jpg)
Chloramphenicol
MOA:
• inhibits protein synthesis by reversibly binding to 50S of the bacterial ribosome
• inhibits peptidyl transferase step of protein
synthesis
Absorption: rapid and complete
Distribution: virtually all tissues (including CNS)
Elimination: metabolized in liver (conjugation), excreted in urine
![Page 29: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/29.jpg)
Chloramphenicol• Drug of choice for typhoid fever and eye infection, except chlamydia
• Considered for treatment of rickettsial infection
• alternative drug for meningococcal infection in cases of hypersensitivity reaction to ß-lactam antibioticsDose: 50-100mg/kg/d in 4 divided doses
![Page 30: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/30.jpg)
Chloramphenicol•Adverse effects
nausea, vomiting, diarrhea,
oral or vaginal candidiasis
aplastic anemia – suppress red cell production
Gray baby syndrome – newborns lack effective
glucoronic acid conjugation for degradation and
detoxification (vomiting, flaccidity, hypothermia,
gray color, shock, collapse)
![Page 31: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/31.jpg)
Chloramphenicol
•Drug Interactions inhibits liver enzymes that metabolize other drugs e.g. warfarin
![Page 32: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/32.jpg)
TETRACYLINES•Effective bacteriostatic against many aerobic and anaerobic gram (+) and gram (-) bacteria
•Enter bacteria in part by passive diffusion in part by active transport accumulate in susceptible cells
MOA:
• inhibits protein synthesis by binding to 30S subunit
• inhibits binding of tRNA to mRNA
![Page 33: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/33.jpg)
TETRACYLINES
Absorption:
• variable, depends on specific drug
Distribution:
• most tissues, low levels in CNS, crosses placenta, excreted in milk, bind calcium
Elimination:
•some excreted unchanged in urine, others metabolized by liver, excreted in bile
![Page 34: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/34.jpg)
Clinical Uses:
• drug of choice for rickettsia, chlamydia, cholera
• sometimes used for acne
• formerly used for urinary tract infections, pneumonia (bacteria resistant)
TETRACYLINES
![Page 35: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/35.jpg)
TETRACYLINES
Adverse effects:
• nausea, vomiting, diarrhea• bones and teeth, bind with calcium and deposit in newly formed bones (impaired long bone formation ) & teeth (discolouration of teeth)not given to children under age 8• other systems affected: liver toxicity, kidney toxicity, photosensitivity
![Page 36: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/36.jpg)
RESISTANCE
• widespread
• most common: efflux pump
-removes drug from bacterial cell
• ribosome protection
-production of proteins that prevent tetracycline binding
• enzymatic inactivation (tetracyclinase)
TETRACYLINES
![Page 37: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/37.jpg)
Effective against variety of gram positive (pneumococci, streptococci, staphylococci, corynebacteria, mycoplasma, legionella, chlamydia trachomatis, C. psittaci, C. pneumoniae, helicobacter, listeria, and certain mycobacterium) and gram negative bacteria (neisseria, bordetella pertussis, Bartonella henselae, B. quintana)
MACROLIDES - ERYTHROMYCINMACROLIDES - ERYTHROMYCIN
![Page 38: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/38.jpg)
• useful as penicillin substitute in penicillin-allergic individuals
MACROLIDES - ERYTHROMYCINMACROLIDES - ERYTHROMYCIN
MOA:
• inhibits protein synthesis by binding to 50S subunit
• prevents tRNA from accessing donor site
• bacteriostatic; at high doses bactericidal
![Page 39: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/39.jpg)
Absorption:
• destroyed by stomach acid (enteric coated)
Distribution:
• most tissues, except CNS
Elimination:
• mainly excreted in bile
MACROLIDES - ERYTHROMYCINMACROLIDES - ERYTHROMYCIN
![Page 40: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/40.jpg)
Drug of choice: • diphtheria, community-acquired pneumonia, penicillin substituteResistance: • reduced permeability of bacteria• enzyme inactivation• modification of ribosomal binding unit
MACROLIDES - ERYTHROMYCINMACROLIDES - ERYTHROMYCIN
![Page 41: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/41.jpg)
Adverse Effects:
• nausea, vomiting, diarrhea
•hypersensitivity reactions - likely contributes to acute hepatitis - fever and rash
Drug interactions:
• inhibits cytochrome P450s can increase concentration of some drugs e.g., anticoagulants
MACROLIDES - ERYTHROMYCINMACROLIDES - ERYTHROMYCIN
![Page 42: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/42.jpg)
• derived from erythromycin by addition of methyl group
• improved acid stability
• more active against Mycobacterium avium
MACROLIDES - CLARITHROMYCINMACROLIDES - CLARITHROMYCIN
![Page 43: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/43.jpg)
• longer half-life (6 hrs) – twice daily dosing 250- 500mg
• major metabolite has antibacterial activity: 14-hydroxyclarithromycin
• lower frequency of GI intolerance
MACROLIDES - CLARITHROMYCINMACROLIDES - CLARITHROMYCIN
![Page 44: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/44.jpg)
• 15-atom lactone macrolide ring compound
• active against M avium complex and T gondii
• slightly less active than erythromycin and clarithromycin against staphylococci and streptococci
MACROLIDES - AZITHROMYCINMACROLIDES - AZITHROMYCIN
![Page 45: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/45.jpg)
•slightly more active against H influenzae
• highly active against chlamydia
• tissue half-life 2-4 days once daily dosing for 3-5 days
MACROLIDES - AZITHROMYCINMACROLIDES - AZITHROMYCIN
![Page 46: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/46.jpg)
AMINOGLYCOSIDESAMINOGLYCOSIDES
- effective against gram (-) enteric bacteria
Enteric bacteria
- facultative anaerobes that can grow in presence or absence of oxygen
![Page 47: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/47.jpg)
AMINOGLYCOSIDESAMINOGLYCOSIDES
- enter outer membrane of gram (-) bacteria by passive diffusion
- cross cytoplasmic membrane by oxygen-dependent active transport
- transport inhibited in anaerobic conditions
- transport may be enhanced by cell-wall active drugs (penicillins)
![Page 48: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/48.jpg)
AMINOGLYCOSIDESAMINOGLYCOSIDES
MOA: inhibits protein synthesis by binding irreversibly to 30S ribosomal
subunit
- bactericidal
Absorption: poor oral absorption - injected
Distribution: “levels not high in most tissues except renal cortex; “largely excluded from CNS (slight with inflammation) and eye
Elimination: kidney
![Page 49: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/49.jpg)
Clinical Uses:
– gentamicin by far most important
– severe infections caused by gram (-)
aerobic bacteria
– topical administration for infectionsresulting from burns or wounds
Most gentamicin resistant bacteria will be
susceptible to amikacin
AMINOGLYCOSIDESAMINOGLYCOSIDES
![Page 50: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/50.jpg)
Adverse Effects:
1) Nephrotoxicity
enhance free-radical formation following accumulation in renal tubular cells
ordinary dose can be very damaging to kidneys of patients with renal disease, dehydrated patients
2) Ototoxicity
damages cranial nerve VIII
permanent deafness and / or vertigo
AMINOGLYCOSIDESAMINOGLYCOSIDES
![Page 51: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/51.jpg)
AMINOGLYCOSIDESAMINOGLYCOSIDES
STREPTOMYCIN STREPTOMYCIN
GENTAMICINGENTAMICIN
TOBRAMYCINTOBRAMYCIN
AMIKACINAMIKACIN
NETILMICINNETILMICIN
NEOMYCINNEOMYCIN
KANAMYCINKANAMYCIN
![Page 52: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/52.jpg)
SULFONAMIDES, SULFONAMIDES, TRIMETHOPRIM & QUINOLONESTRIMETHOPRIM & QUINOLONES
ANITA Q. SANGALANG, MD, FPOGSANITA Q. SANGALANG, MD, FPOGSDEPARTMENT OF MEDICAL TECHNOLOGYDEPARTMENT OF MEDICAL TECHNOLOGY
COLLEGE OF PHARMACYCOLLEGE OF PHARMACYUNIVERSITY OF SANTO TOMASUNIVERSITY OF SANTO TOMAS
![Page 53: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/53.jpg)
ANTIFOLATE DRUGS - ANTIFOLATE DRUGS - SULFONAMIDESSULFONAMIDES
Structural analog of Structural analog of p p-aminobenzoic acid -aminobenzoic acid (PABA) that competitively inhibit (PABA) that competitively inhibit dihydropteroate synthase dihydropteroate synthase inhibits folic inhibits folic acid synthesisacid synthesisg(+), g(-) bacteria, nocardia, chlamydia g(+), g(-) bacteria, nocardia, chlamydia trachomatis, some protozoa, some enteric trachomatis, some protozoa, some enteric bacteria (E. coli, klebsiella, salmonella, bacteria (E. coli, klebsiella, salmonella, shigella, enterobactershigella, enterobacterbacteriostaticbacteriostatic
![Page 54: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/54.jpg)
ANTIFOLATE DRUGS - ANTIFOLATE DRUGS - SULFONAMIDESSULFONAMIDES
Drug of choice for infections of Drug of choice for infections of Pneumocystis carinii pneumonia, Pneumocystis carinii pneumonia, toxoplasmosis, nocardiosistoxoplasmosis, nocardiosis
For UTI – 1g of sulfixazole 4x dailyFor UTI – 1g of sulfixazole 4x daily
For ulcerative colitis, enteritis and For ulcerative colitis, enteritis and Inflammatory bowel diseaseInflammatory bowel disease
Bacterial conjuctivitisBacterial conjuctivitis
Silver sulfadiazine – burn wound infectionSilver sulfadiazine – burn wound infection
![Page 55: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/55.jpg)
ANTIFOLATE DRUGS - ANTIFOLATE DRUGS - SULFONAMIDESSULFONAMIDES
Adverse EffectsAdverse Effects
– Common: fever, skin rashes, exfoliative Common: fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrheanausea, vomiting, diarrhea
– Stevens-Johnson syndromeStevens-Johnson syndrome
– Hematopoietic: aplastic anemia, Hematopoietic: aplastic anemia, granulocytopenia, thrombocytopeniagranulocytopenia, thrombocytopenia
![Page 56: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/56.jpg)
ANTIFOLATE DRUGS – ANTIFOLATE DRUGS – TRIMETHOPRIM & TRIMETHOPRIM-TRIMETHOPRIM & TRIMETHOPRIM-SULFAMETHOXAZOLE MIXTURESSULFAMETHOXAZOLE MIXTURES
Trimethoprim – inhibits bacterial Trimethoprim – inhibits bacterial dihydrofolic acid reductasedihydrofolic acid reductase
Trimethoprim-Sulfamethoxazole mixtures Trimethoprim-Sulfamethoxazole mixtures (1:5 ratio) – synergistic, bactericidal(1:5 ratio) – synergistic, bactericidal
Trimethoprim – more lipid soluble, Trimethoprim – more lipid soluble, absorbed in the gut and CNS efficientlyabsorbed in the gut and CNS efficiently
![Page 57: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/57.jpg)
ANTIFOLATE DRUGS – ANTIFOLATE DRUGS – TRIMETHOPRIM & TRIMETHOPRIM-TRIMETHOPRIM & TRIMETHOPRIM-SULFAMETHOXAZOLE MIXTURESSULFAMETHOXAZOLE MIXTURES
Uses: pneumonia, shigellosis, salmonella, Uses: pneumonia, shigellosis, salmonella, diarrhea, urinary tract infection diarrhea, urinary tract infection
Dose: TMP-SXZ 160mg/800mg q 12 hrs Dose: TMP-SXZ 160mg/800mg q 12 hrs (UTI) (UTI)
8mg/kg for children – shigellosis & UTI 8mg/kg for children – shigellosis & UTI
![Page 58: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/58.jpg)
DNA GYRASE INHIBITORS-DNA GYRASE INHIBITORS-FLUOROQUINOLONESFLUOROQUINOLONES
Synthetic fluorinated analogs of nalidixic Synthetic fluorinated analogs of nalidixic acidacid
MOA: blocks bacterial DNA synthesis by MOA: blocks bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IVgyrase) and topoisomerase IV prevents prevents the relaxation of positively supercoiled the relaxation of positively supercoiled DNA (required for normal transcription and DNA (required for normal transcription and replication)replication)
![Page 59: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/59.jpg)
DNA GYRASE INHIBITORS-DNA GYRASE INHIBITORS-FLUOROQUINOLONESFLUOROQUINOLONES
Effective against g(-) bacteria, limited activity Effective against g(-) bacteria, limited activity against g(+) organismsagainst g(+) organisms
Norfloxacin – least activeNorfloxacin – least active
Ciprofloxacin, enoxacin, lomefloxacin, Ciprofloxacin, enoxacin, lomefloxacin, levofloxacin, ofloxacin, pefloxacin (2levofloxacin, ofloxacin, pefloxacin (2ndnd group) : group) : g(-)>g(+) g(-)>g(+)
![Page 60: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/60.jpg)
DNA GYRASE INHIBITORS-DNA GYRASE INHIBITORS-FLUOROQUINOLONESFLUOROQUINOLONES
Ciprofloxacin - most effective against Ciprofloxacin - most effective against P P aeruginosaaeruginosa
Levofloxacin – superior against g(+), Levofloxacin – superior against g(+), S S pneumoniaepneumoniae
A/E: nausea, vomiting, diarrhea, headache, A/E: nausea, vomiting, diarrhea, headache, dizziness, damage growing cartilage dizziness, damage growing cartilage (arthropathy)(arthropathy)
Not routinely given to under 18 years of ageNot routinely given to under 18 years of age
![Page 61: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/61.jpg)
ANTI-MYCOBACTERIAL ANTI-MYCOBACTERIAL AGENTSAGENTS
![Page 62: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/62.jpg)
ANTITUBERCULOSIS DRUGSANTITUBERCULOSIS DRUGS
FIRST LINE AGENTSFIRST LINE AGENTS
IsoniazidIsoniazid
RifampicinRifampicin
PyrazinamidePyrazinamide
EthambutolEthambutol
StreptomycinStreptomycin
SECOND- LINE AGENTSSECOND- LINE AGENTS
AmikacinAmikacin
Aminosalicylic acidAminosalicylic acid
CapreomycinCapreomycin
CiprofloxacinCiprofloxacin
ClofazimineClofazimine
CycloserineCycloserine
EthionamideEthionamide
LevofloxacinLevofloxacin
RifabutinRifabutin
RifapentineRifapentine
![Page 63: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/63.jpg)
ISONIAZIDISONIAZIDWell-absorbed after oral administrationWell-absorbed after oral administration
Good distribution including CSFGood distribution including CSF
Acetylated (fast acetylators> slow Acetylated (fast acetylators> slow acetylators)acetylators)
Inhibits mycolic acid synthesis (myobacterial Inhibits mycolic acid synthesis (myobacterial cell walls)cell walls)
Dose: Adult – 300mg ; Pedia – 5mkd ODDose: Adult – 300mg ; Pedia – 5mkd OD
Peak plasma conce 3-5Peak plasma conce 3-5g/mL in 1-2 hrsg/mL in 1-2 hrs
![Page 64: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/64.jpg)
ISONIAZIDISONIAZID
May cause peripheral neuritis (treated with May cause peripheral neuritis (treated with pyridoxine 25-50mg/day)pyridoxine 25-50mg/day)
May cause optic neuritis (must monitor May cause optic neuritis (must monitor vision)vision)
TeratogenicTeratogenic
Used prophylactically in tuberculin Used prophylactically in tuberculin convertersconverters
Used alone or in combination in the Used alone or in combination in the treatment of most cases of TB)treatment of most cases of TB)
![Page 65: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/65.jpg)
RIFAMPICINRIFAMPICIN
Well absorbed after oral Well absorbed after oral administrationadministration
Good distributionGood distribution
Metabolized in the liver and excreted Metabolized in the liver and excreted via the bilevia the bile
Inhibits RNA synthesis by binding Inhibits RNA synthesis by binding strongly to the strongly to the subunit of bacterial subunit of bacterial DNA-dependent RNA polymeraseDNA-dependent RNA polymerase
![Page 66: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/66.jpg)
RIFAMPICINRIFAMPICIN
Bactericidal for mycobacteriaBactericidal for mycobacteria
Readily penetrates most tissues and Readily penetrates most tissues and into phagocytic cellsinto phagocytic cells
Kill organisms poorly accessible to Kill organisms poorly accessible to many drugs, like intracellular organisms, many drugs, like intracellular organisms, sequestered in abscess and lung sequestered in abscess and lung cavitiescavities
Decrease effectiveness of oral Decrease effectiveness of oral contraceptivecontraceptive
![Page 67: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/67.jpg)
RIFAMPICINRIFAMPICIN
Dose: 600mg/day (10mkd)Dose: 600mg/day (10mkd)
Prophylaxis for meningococcal Prophylaxis for meningococcal carriage: 600mg BID for 2 days carriage: 600mg BID for 2 days
HepatotoxicHepatotoxic
Cytochrome P450 inducerCytochrome P450 inducer
![Page 68: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/68.jpg)
PYRAZINAMIDEPYRAZINAMIDEAdministered orallyAdministered orally
Half-life: 8-11 hoursHalf-life: 8-11 hours
Taken up by macrophages and kills bacilli Taken up by macrophages and kills bacilli residing within the acidic environmentresiding within the acidic environment
M. tuberculosis only organism susceptible to M. tuberculosis only organism susceptible to this drugthis drug
HepatotoxicHepatotoxic
Dose: 25mkd; or 50-70mg/kg/dose for twice-Dose: 25mkd; or 50-70mg/kg/dose for twice-weekly or thrice-weekly treatment regimenweekly or thrice-weekly treatment regimen
![Page 69: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/69.jpg)
ETHAMBUTOLETHAMBUTOL
Well absorbed after oral administrationWell absorbed after oral administrationCrosses the blood brain barrier only if the Crosses the blood brain barrier only if the meninges are inflamed.meninges are inflamed.Excreted in the urineExcreted in the urineInhibitor of mycobacterial arabinosyl Inhibitor of mycobacterial arabinosyl transferase (involved in the transferase (involved in the polymerization reaction of arabinoglycan, polymerization reaction of arabinoglycan, essential to mycobacterial cell wall essential to mycobacterial cell wall May cause a decrease in visual acuity May cause a decrease in visual acuity (optic neuritis 25mkd)(optic neuritis 25mkd)
![Page 70: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/70.jpg)
ETHAMBUTOLETHAMBUTOL
Dose: 15-25mg/kg/dayDose: 15-25mg/kg/day
for tuberculous meningitis 50mg/kg for tuberculous meningitis 50mg/kg twice –weekly dosingtwice –weekly dosing
Blood peak level 2-5Blood peak level 2-5g/mL in 2-4hrsg/mL in 2-4hrs
Adverse Effects: hypersensitivityAdverse Effects: hypersensitivity
C/I: children less than 6 years old C/I: children less than 6 years old because cannot assess visual acuity because cannot assess visual acuity and red-green color discriminationand red-green color discrimination
![Page 71: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/71.jpg)
STREPTOMYCINSTREPTOMYCIN
Administered intramuscularyAdministered intramuscularyAntimicrobial activity typical of other Antimicrobial activity typical of other aminoglycosidesaminoglycosidesPenetrates into cells poorly, active against Penetrates into cells poorly, active against extracellular tubercleextracellular tubercleResistant strains develop so must be used Resistant strains develop so must be used in combinationin combinationDose; 15mkd IM or 20-40mkd for weeksDose; 15mkd IM or 20-40mkd for weeksOtotoxicityOtotoxicity
![Page 72: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/72.jpg)
![Page 73: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/73.jpg)
![Page 74: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/74.jpg)
POLICIES ON CASE FINDINGPOLICIES ON CASE FINDINGDirect sputum smear microscopy shall be Direct sputum smear microscopy shall be
the primary NTP diagnostic toolthe primary NTP diagnostic tool
1.1. It provides definitive diagnosis of It provides definitive diagnosis of active TB.active TB.
2.2. The procedure is simpleThe procedure is simple3.3. It is economicalIt is economical4.4. A microscopy center would be A microscopy center would be
organized even in remote areasorganized even in remote areas
![Page 75: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/75.jpg)
POLICIES ON CASE FINDINGPOLICIES ON CASE FINDING
All TB symptomatics must undergo All TB symptomatics must undergo sputum examination prior to initiation of sputum examination prior to initiation of treatment, w/ or w/o X-ray resultstreatment, w/ or w/o X-ray results ContraindicationContraindication: massive hemoptysis: massive hemoptysis
No diagnosis of TB shall be made based on No diagnosis of TB shall be made based on the result of x-ray examinations alonethe result of x-ray examinations alone
![Page 76: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/76.jpg)
PROGRAM COMPONENTSPROGRAM COMPONENTS
Types of TB casesTypes of TB cases based on history of anti-TB treatmentbased on history of anti-TB treatment
important in determining Tx regimenimportant in determining Tx regimen
1.1. New:New: no Tx or < 1month Tx no Tx or < 1month Tx
2.2. Relapse:Relapse: cured & Sm (+) again cured & Sm (+) again
3.3. Transfer-in:Transfer-in: change Tx facility change Tx facility
4.4. Return after default (RAD):Return after default (RAD): interrupted Tx; Sm (+) interrupted Tx; Sm (+)
5.5. Treatment Failure:Treatment Failure: still (+) on 5 still (+) on 5thth month month
6.6. Others:Others: became (+) on 2 became (+) on 2ndnd month month
: interrupted Tx; Sm (-): interrupted Tx; Sm (-)
![Page 77: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/77.jpg)
ANTI-TUBERCULOSIS MEDICATIONSANTI-TUBERCULOSIS MEDICATIONS
H = ISONIAZIDH = ISONIAZIDR = RIFAMPICINR = RIFAMPICINZ = PYRAZINAMIDEZ = PYRAZINAMIDEE = ETHAMBUTOLE = ETHAMBUTOLS = STREPTOMYCINS = STREPTOMYCINTREATMENT STRATEGY: DOTSTREATMENT STRATEGY: DOTS
![Page 78: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/78.jpg)
CATEGORIES OF TREATMENTCATEGORIES OF TREATMENTREGIMENREGIMEN TB PATIENT TO BE GIVEN TXTB PATIENT TO BE GIVEN TX
Regimen I:Regimen I:
2HRZE/4HR2HRZE/4HR
New pulmonary smear (+) casesNew pulmonary smear (+) cases
New seriously ill pulmonary smear (-) withNew seriously ill pulmonary smear (-) with
extensive parenchymal involmentextensive parenchymal involment
New severely ill extrapulmonary TB casesNew severely ill extrapulmonary TB cases
Regimen II:Regimen II:
2HRZES/1HREZ/ 2HRZES/1HREZ/ 5HRE5HRE
Failure casesFailure cases
Relapse casesRelapse cases
RAD (smear +)RAD (smear +)
Other (smear +)Other (smear +)
Regimen III:Regimen III:
2HRZE/4HR2HRZE/4HR
New smear (-) but with minimal pulmonary TB New smear (-) but with minimal pulmonary TB on radiography as confirmed by a medical on radiography as confirmed by a medical officerofficer
New extra-pulmonary TB (not serious)New extra-pulmonary TB (not serious)
![Page 79: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/79.jpg)
![Page 80: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/80.jpg)
![Page 81: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/81.jpg)
![Page 82: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/82.jpg)
ANTIFUNGALANTIFUNGALAGENTSAGENTS
![Page 83: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/83.jpg)
Antifungal Drugs
Polyenes • AMPHOTERICIN • NYSTATIN
FlucytosineImidazoles • KETOCONAZOLE
• FLUCONAZOLE • Voriconazole
• MICONAZOLE • ITRACONAZOLE • Griseofulvin
• Terbinafine
![Page 84: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/84.jpg)
SUPERFICIAL INFECTIONSSUPERFICIAL INFECTIONS
Griseofulvin – oralGriseofulvin – oral
Amphotericin B – topicalAmphotericin B – topical
Nystatin – topicalNystatin – topical
Clotrimazole - topicalClotrimazole - topical
Miconazole – topicalMiconazole – topical
Terginafine – oral and topicalTerginafine – oral and topical
![Page 85: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/85.jpg)
SYSTEMIC INFECTIONSSYSTEMIC INFECTIONS
flucytosineflucytosine
Amphotericin B – topicalAmphotericin B – topical
ItraconzoleItraconzole
KetoconazoleKetoconazole
fluconazolefluconazole
![Page 86: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/86.jpg)
A. Polyenes1. amphotericin B (Fungizone)
Chemical properties - amphoteric aqueous insolubility at neutral pH
![Page 87: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/87.jpg)
AMPHOTERICIN BAMPHOTERICIN B
Mechanism of action
It binds to fungal membrane sterols (ergosterol) and alters permeability selectively to K+
and Mg2+. Resistance may develop from altered sterols or decreased sterols. It is cidal.
+ a polyene
ergosterol
ergosterol withpore
![Page 88: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/88.jpg)
AMPHOTERICIN BAMPHOTERICIN B
Poorly absorbed orally (5%), Poorly absorbed orally (5%), therefore administered IVtherefore administered IV
Distribution: large, slow Distribution: large, slow distribution; tissue is a reservoir distribution; tissue is a reservoir over time, very slow CNS over time, very slow CNS penetrationpenetration
Terminal half-life: 15 daysTerminal half-life: 15 days
Slowly excreted in the urine and Slowly excreted in the urine and bile (5-10%)bile (5-10%)
![Page 89: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/89.jpg)
AMPHOTERICIN BAMPHOTERICIN B
Alters membrane permeability Alters membrane permeability characteristicscharacteristicsUsed for systemic fungal infectionsUsed for systemic fungal infectionsMany side effects- requires Many side effects- requires hospitalizationhospitalizationNephrotoxic, hypokalemia, fever, chills, Nephrotoxic, hypokalemia, fever, chills, thrombophlebitisthrombophlebitisDrug Interactions: potentiates other Drug Interactions: potentiates other renal toxinsrenal toxins
![Page 90: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/90.jpg)
Nystatin
• similar to amphotericin B • used topically and for GI use• used against candida and dermatophytes (Epidermophyton, Trichophyton, Microsporum)
•Side effects: minimal
![Page 91: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/91.jpg)
Chemistry
N
HN
F
NH2
O
Flucytosine
![Page 92: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/92.jpg)
FLUCYTOSINEFLUCYTOSINE
Orally effectiveOrally effectiveReadily passes into the CNSReadily passes into the CNSResistance develops fairly rapidlyResistance develops fairly rapidlyRelatively low toxicityRelatively low toxicityUsed mainly in combination with Used mainly in combination with amphotericin B in the treatment of amphotericin B in the treatment of cryptococcal meningitiscryptococcal meningitisFlucytosine’s use has declined Flucytosine’s use has declined significantly since the release of significantly since the release of fluconazole in the 1990fluconazole in the 1990
![Page 93: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/93.jpg)
Mechanism of action
• taken up into the fungal cell by means of permease
• converted to 5-fluorouracil (5-FU) by cytosine deaminase
• 5-FU eventually inhibits thymidylatesynthetase
• synthesized to 5-FUTP• incorporated into RNA.
![Page 94: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/94.jpg)
5-flucytosine(outside)
permease5-flucytosine(inside)
Cytosinedeaminase
5-fluorouracil
5-FUMPRNA
Phosphoribosyltransferase
5dUMP(inhibits thymidylatesynthase)
![Page 95: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/95.jpg)
FLUCYTOSINE -Uses
• systemic fungi, mainly candida, andcryptococcus.
• fungistatic.
• used with amphotericin B (cryptococcal meningitis) and with itraconazole (chromoblastomyosis).
![Page 96: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/96.jpg)
FLUCYTOSINE -Pharmacokinetics
• Given orally
• T ½ ~ 3-6 hours
• Penetrates into CNS
• Excreted in urine-80% unchanged
![Page 97: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/97.jpg)
FLUCYTOSINEUntoward effects
• nausea, vomiting, colitis
• bone marrow suppression
• thrombocytopenia
• alopecia
• decreased liver function
![Page 98: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/98.jpg)
Azoles
• Imidazoles – ketoconazole, miconazole, clotrimazole
• Triazoles- itraconazole, fluconazole, voriconazole
![Page 99: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/99.jpg)
chemistry
![Page 100: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/100.jpg)
Mechanism of Actioninhibit the synthesis of ergosterol by blockingdemethylation (14-demethylase) of lanosterol -also inhibit cytochrome activity.
![Page 101: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/101.jpg)
Acetyl CoA
Squalene
Lanosterol
(ergosterol)
Allylaminedrugs
Azoles
Squalene-2,3 oxide
Squalene monooxygenase
14--demethylase
![Page 102: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/102.jpg)
Spectrum of imidazoles
systemic fungi, dermatophytes -fungistatic
![Page 103: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/103.jpg)
Specific drugs-ketoconazole
• blastomycosis, coccidioidomycosis, ringworm, candidiasis; given orally.
• acid environment is needed to dissolve drug, does not enter the CNS well.
• metabolized and has a half-life of 3-6 hrs. Mostly fecal excretion after metabolism.
![Page 104: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/104.jpg)
MICONAZOLEMICONAZOLE
Used topically to treat superficial infectionsUsed topically to treat superficial infections
Inadequate CSF penetrationInadequate CSF penetration
Many significant side effectsMany significant side effects
Increases the anticoagulant effect of Increases the anticoagulant effect of coumarin drugscoumarin drugs
Blocks biosynthesis of fungal lipidsBlocks biosynthesis of fungal lipids
![Page 105: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/105.jpg)
Triazoles (a type of azole)
![Page 106: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/106.jpg)
Itraconazole: uses
• Histoplasmosis
• Sporotrichosis
• Aspergillosis
• Blastomycosis
![Page 107: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/107.jpg)
Itraconazole
• variable absorption when given orally, metabolized (one active metabolite) approx. 30 hr. half-life.
• fecal and renal excretion after extensive metabolism
• hydroxyitraconazole - an active metabolite.
![Page 108: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/108.jpg)
Itraconazole: untoward effects
• Nausea, vomiting
• Liver dysfunction
• Hypokalemia
• Hypertriglyceridemia
• Drug-drug interactions, similiar to ketoconazole but to lesser degree
![Page 109: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/109.jpg)
Fluconazole• A triazole
• Well absorbed orally, enters CNS; may be given intravenously
• t½ - 25 – 30 hours, excreted unchanged
• Adverse effects- headache, N&V, rash, alopecia, rarely liver failure
• Least effect of all azoles on liver enzymes
• Uses – cryptococcal meningitis, candidiasis,coccidioidomycosis; prophylactive use for bone-marrow transplant patients
![Page 110: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/110.jpg)
FLUCONAZOLEFLUCONAZOLEAntifungal spectrum is broader than other Antifungal spectrum is broader than other azole antifungalsazole antifungalsMore resistant to first pass metabolism and More resistant to first pass metabolism and has lower lipophilicity and protein binding has lower lipophilicity and protein binding than ketoconalzolethan ketoconalzoleUnlike ketoconazole, its oral absorption is Unlike ketoconazole, its oral absorption is not affected by the absence of stomach not affected by the absence of stomach acidacidIt is equivalent to amphotericin b in the It is equivalent to amphotericin b in the treatment of candidemia in non-treatment of candidemia in non-neutorpenic patientneutorpenic patient
![Page 111: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/111.jpg)
Griseofulvin (Chemistry)
![Page 112: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/112.jpg)
GRISEOFULVINGRISEOFULVIN
Orally effective for superficial Orally effective for superficial infections –absorption enhanced by infections –absorption enhanced by fatty mealsfatty mealsInhibits the growth of fungal hyphae Inhibits the growth of fungal hyphae of dermatophyte infections which of dermatophyte infections which grow beneath the skin (fungistatic) grow beneath the skin (fungistatic) by inhibiting mitosis by binding to by inhibiting mitosis by binding to microtubules comprising the microtubules comprising the spindles andspindles and
![Page 113: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/113.jpg)
GRISEOFULVINGRISEOFULVINHalf-life: 9-21 hrsHalf-life: 9-21 hrs
Metabolism: hepaticMetabolism: hepatic
Elimination: urine 2/3; fecal 1/3Elimination: urine 2/3; fecal 1/3
Spectrum: dermatophytes onlySpectrum: dermatophytes only
Dose: 10-20mkd x 4-8 wksDose: 10-20mkd x 4-8 wks
S/E: Headache, nausea, headacheS/E: Headache, nausea, headache
hepatoxicity, renal toxicity, photosensitivity, hepatoxicity, renal toxicity, photosensitivity, can precipitate acute intermittent porphyria, can precipitate acute intermittent porphyria, possibly teratogenicpossibly teratogenic
Drug interactions: rareDrug interactions: rare
![Page 114: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/114.jpg)
Topical Azoles
• Clotrimazole
• Miconazole
• Econazole
• Oxiconazole
• Terconazole
• Sulconazole
• Tioconazole
• Butoconazole
![Page 115: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/115.jpg)
Allylamines (fungicidal)
• inhibit squalene-2,3-epoxidase – for dermatophytes
N
Terbinafine
![Page 116: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/116.jpg)
Acetyl CoA
Squalene
Lanosterol
(ergosterol)
Allylaminedrugs
Azoles
Squalene-2,3 oxide
Squalene monooxygenase
14--demethylase
![Page 117: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/117.jpg)
Terbinafine
• Inhibits squalene 2, 3- epoxidase, a key enzyme in sterol biosynthesis
• Squalene is cidal to sensitive organisms
• Given either orally or topically
• Excellent for onychomycosis because it concentrates within the nail; superior togriseofulvin and to its itraconazole for onychomycosis
![Page 118: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/118.jpg)
TERBINAFINETERBINAFINE
Used for the treatment of tinea infections Used for the treatment of tinea infections due to susceptible organismsdue to susceptible organismsAdverse effects include hepatitis and Adverse effects include hepatitis and rashes. Both are rare.rashes. Both are rare.metabolized then excreted in urinemetabolized then excreted in urineSide effects associated with oral terbinafine Side effects associated with oral terbinafine include gastrointestinal symptoms such as:include gastrointestinal symptoms such as:– Abdominal pain, diarrhea, nausea/vomiting, Abdominal pain, diarrhea, nausea/vomiting,
dyspepsiadyspepsia– Rare blood dyscrasia reportedRare blood dyscrasia reported
![Page 119: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/119.jpg)
Antiviral Drugs • AMANTIDINE and Rimantadine
• FOSCARNET • Lamivudine
• ACYCLOVIR • Didanosine • Zanamivir
• ZIDOVUDINE • Valacyclovir • Ribavirin
• GANCICLOVIR • Efavirenz • Lopinavir
• Nevirapine • Indinavir • Nelfinavir
• Interferon alpha • Enfuvirtide • Stavudine
![Page 120: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/120.jpg)
Drug Organization. Drugs Effective Against DNA Viruses. Drugs Effective Against RNA Viruses. Drugs for the Treatment of RNA Retroviral Diseases. Drugs for the Treatment of RNA Non-retroviral Diseases. Prospects for Future Antiviral Drugs.
![Page 121: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/121.jpg)
Antimalarial • CHLOROQUINE • PYRIMETHAMINE-SULFASOXINE (Fansidar) • MEFLOQUINE • atovaquone • Quinine • PRIMAQUINE
Antiprotozoal Drugs Amebiasis and Trichomonas • METRONIDAZOLE • Diloxanide • IodoquinolPneumocystis • TRIMETHOPRIM - SUFAMETHOXAZOLE • pentamidine • Clindamycin plus primaquine Toxoplasmosis • PYRIMETHAMINE plus sulfadiazine • Pyrimethamine plus clindamycinTrichomonas • METRONIDAZOLE
![Page 122: Chemotherapeutic Drugs](https://reader034.vdocument.in/reader034/viewer/2022051610/547e9504b4af9f7a5d8b4587/html5/thumbnails/122.jpg)
Antihelminthic Drugs Flatworms • PRAZIQUANTEL Fluke and Tapeworm InfectionsSchistosomiasis • PRAZIQUANTEL Filariasis • diethylcarbamazine • ivermectin Intestinal Roundworms (Ascaris), Enterobius (Pinworm) and Hookworm • mebendazole • pyrantel pamoate • Albendazole Angiostroglyliasis • mebendazole
Trichurius (Whipworm)Hookworm • mebendazole • albendazole
Trypanosomiasis • nifurtimox or suramin • pentamidine
Giadiasis • metronidazole