CHEMOTHERAPEUTIC CHEMOTHERAPEUTIC DRUGS DRUGS ANITA Q. SANGALANG, MD, FPOGS ANITA Q. SANGALANG, MD, FPOGS DEPARTMENT OF MEDICAL TECHNOLOGY DEPARTMENT OF MEDICAL TECHNOLOGY COLLEGE OF PHARMACY COLLEGE OF PHARMACY UNIVERSITY OF SANTO TOMAS UNIVERSITY OF SANTO TOMAS
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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
MICROORGANISMS & ANTIMICROBIALS
1. Bacteria - Antibacterial
2. Viruses - Antiviral
3. Fungi - Antifungal
4. Parasites - Antiparasitic
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
ANTIMICROBIAL DRUGS
1. Beta-Lactam Antibiotics & Other Inhibitors of Cell Wall Synthesis
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
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
BETA-LACTAM ANTIBIOTICSBETA-LACTAM ANTIBIOTICS
PenicillinsPenicillins
Cephalosporins Cephalosporins
MonobactamsMonobactams
CarbapenemsCarbapenems
ß-lactamase inhibitorsß-lactamase inhibitors
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
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
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
(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
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
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
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
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
beta-lactamases
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
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)
• 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
•Drug Interactions inhibits liver enzymes that metabolize other drugs e.g. warfarin
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
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
Clinical Uses:
• drug of choice for rickettsia, chlamydia, cholera
• sometimes used for acne
• formerly used for urinary tract infections, pneumonia (bacteria resistant)
TETRACYLINES
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
RESISTANCE
• widespread
• most common: efflux pump
-removes drug from bacterial cell
• ribosome protection
-production of proteins that prevent tetracycline binding
• enzymatic inactivation (tetracyclinase)
TETRACYLINES
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)
Drug of choice: • diphtheria, community-acquired pneumonia, penicillin substituteResistance: • reduced permeability of bacteria• enzyme inactivation• modification of ribosomal binding unit
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
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
8mg/kg for children – shigellosis & UTI 8mg/kg for children – shigellosis & UTI
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)
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
Peak plasma conce 3-5Peak plasma conce 3-5g/mL in 1-2 hrsg/mL in 1-2 hrs
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)
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
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
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
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
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)
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
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
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
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
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
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
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)
ANTIFUNGALANTIFUNGALAGENTSAGENTS
Antifungal Drugs
Polyenes • AMPHOTERICIN • NYSTATIN
FlucytosineImidazoles • KETOCONAZOLE
• FLUCONAZOLE • Voriconazole
• MICONAZOLE • ITRACONAZOLE • Griseofulvin
• Terbinafine
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
SYSTEMIC INFECTIONSSYSTEMIC INFECTIONS
flucytosineflucytosine
Amphotericin B – topicalAmphotericin B – topical
ItraconzoleItraconzole
KetoconazoleKetoconazole
fluconazolefluconazole
A. Polyenes1. amphotericin B (Fungizone)
Chemical properties - amphoteric aqueous insolubility at neutral pH
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.
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%)
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
Nystatin
• similar to amphotericin B • used topically and for GI use• used against candida and dermatophytes (Epidermophyton, Trichophyton, Microsporum)
•Side effects: minimal
Chemistry
N
HN
F
NH2
O
Flucytosine
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
Mechanism of action
• taken up into the fungal cell by means of permease
• converted to 5-fluorouracil (5-FU) by cytosine deaminase
• Uses – cryptococcal meningitis, candidiasis,coccidioidomycosis; prophylactive use for bone-marrow transplant patients
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
Griseofulvin (Chemistry)
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
• inhibit squalene-2,3-epoxidase – for dermatophytes
N
Terbinafine
Acetyl CoA
Squalene
Lanosterol
(ergosterol)
Allylaminedrugs
Azoles
Squalene-2,3 oxide
Squalene monooxygenase
14--demethylase
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
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,
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.