Chemotherapeutic Drugs

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

Penicillins, Cephalosporins & Cephamycins

2. Chloramphenicol, Tetracylines, Macrolides, Clindamycin & Streptogramins

3. Aminoglycosides and Spectinomycin

4. Sulfonamides, Timethoprim, & Quinolones

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

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

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

OxacillinOxacillin

CloxacillinCloxacillin

DicloxacillinDicloxacillin

FlucloxacillinFlucloxacillin

ß-lactamase ß-lactamase resistantresistant

acid stableacid stable

Nafcillin Nafcillin (ethoxynaphthami(ethoxynaphthamidopenicillin)dopenicillin)

ß lactamase ß lactamase resistantresistant

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

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

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

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

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-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

BETA-LACTAM ANTIBIOTICS BETA-LACTAM ANTIBIOTICS Penicillins

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

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

• 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

• 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

1st generation (early cephalosporins):

gram (+) e.g. cefazolin (used as prophylactic following surgery)

2nd generation:

gram (+) & gram (-)

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 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

BETA-LACTAM ANTIBIOTICS BETA-LACTAM ANTIBIOTICS

MONOBACTAMSMONOBACTAMSBETA-LACTAMASE INHIBITORS BETA-LACTAMASE INHIBITORS (CLAVULANIC ACID, SULBACTAM & (CLAVULANIC ACID, SULBACTAM & TAZOBACTAM)TAZOBACTAM)CABAPENEMSCABAPENEMSVANCOMYCINVANCOMYCINTEICOPLANINTEICOPLANINFOSFOMYCINFOSFOMYCINBACITRACINBACITRACINCLYCLOSERINECLYCLOSERINE

CHLORAMPHENICOL, CHLORAMPHENICOL, TETRACYCLINE, MACROLIDES, TETRACYCLINE, MACROLIDES,

CLINDAMYCIN AND CLINDAMYCIN AND STREPTOGRAMINSSTREPTOGRAMINS

Chloramphenicol

•Effective bacteriostatic broad-spectrum

• aerobic and anaerobic gram (+) and gram (-) organisms

• Use is limited due to side effects

• An almost ”ideal” antibiotic

Chloramphenicol

• 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

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

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)

Chloramphenicol

•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

• 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

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)

MACROLIDES - ERYTHROMYCINMACROLIDES - ERYTHROMYCIN

• useful as penicillin substitute in penicillin-allergic individuals

• inhibits protein synthesis by binding to 50S subunit

• prevents tRNA from accessing donor site

• bacteriostatic; at high doses bactericidal

Absorption:

• destroyed by stomach acid (enteric coated)

Distribution:

• most tissues, except CNS

Elimination:

• mainly excreted in bile

Drug of choice: • diphtheria, community-acquired pneumonia, penicillin substituteResistance: • reduced permeability of bacteria• enzyme inactivation• modification of ribosomal binding unit

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

• derived from erythromycin by addition of methyl group

• improved acid stability

• more active against Mycobacterium avium

MACROLIDES - CLARITHROMYCINMACROLIDES - CLARITHROMYCIN

• 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

• 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

•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

AMINOGLYCOSIDESAMINOGLYCOSIDES

- effective against gram (-) enteric bacteria

Enteric bacteria

- facultative anaerobes that can grow in presence or absence of oxygen

- 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)

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

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

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

STREPTOMYCIN STREPTOMYCIN

GENTAMICINGENTAMICIN

TOBRAMYCINTOBRAMYCIN

AMIKACINAMIKACIN

NETILMICINNETILMICIN

NEOMYCINNEOMYCIN

KANAMYCINKANAMYCIN

SULFONAMIDES, SULFONAMIDES, TRIMETHOPRIM & QUINOLONESTRIMETHOPRIM & QUINOLONES

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

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

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

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

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

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)

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(+)

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

ANTI-MYCOBACTERIAL ANTI-MYCOBACTERIAL AGENTSAGENTS

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

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

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

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

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

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

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

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

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

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 (-)

ANTI-TUBERCULOSIS MEDICATIONSANTI-TUBERCULOSIS MEDICATIONS

H = ISONIAZIDH = ISONIAZIDR = RIFAMPICINR = RIFAMPICINZ = PYRAZINAMIDEZ = PYRAZINAMIDEE = ETHAMBUTOLE = ETHAMBUTOLS = STREPTOMYCINS = STREPTOMYCINTREATMENT STRATEGY: DOTSTREATMENT STRATEGY: DOTS

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)

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.

+ a polyene

ergosterol

ergosterol withpore

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%)

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

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

• 5-FU eventually inhibits thymidylatesynthetase

• synthesized to 5-FUTP• incorporated into RNA.

5-flucytosine(outside)

permease5-flucytosine(inside)

Cytosinedeaminase

5-fluorouracil

5-FUMPRNA

Phosphoribosyltransferase

5dUMP(inhibits thymidylatesynthase)

FLUCYTOSINE -Uses

• systemic fungi, mainly candida, andcryptococcus.

• fungistatic.

• used with amphotericin B (cryptococcal meningitis) and with itraconazole (chromoblastomyosis).

FLUCYTOSINE -Pharmacokinetics

• Given orally

• T ½ ~ 3-6 hours

• Penetrates into CNS

• Excreted in urine-80% unchanged

FLUCYTOSINEUntoward effects

• nausea, vomiting, colitis

• bone marrow suppression

• thrombocytopenia

• alopecia

• decreased liver function

Azoles

• Imidazoles – ketoconazole, miconazole, clotrimazole

• Triazoles- itraconazole, fluconazole, voriconazole

chemistry

Mechanism of Actioninhibit the synthesis of ergosterol by blockingdemethylation (14-demethylase) of lanosterol -also inhibit cytochrome activity.

Acetyl CoA

Squalene

Lanosterol

(ergosterol)

Allylaminedrugs

Azoles

Squalene-2,3 oxide

Squalene monooxygenase

14--demethylase

Spectrum of imidazoles

systemic fungi, dermatophytes -fungistatic

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.

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

Triazoles (a type of azole)

Itraconazole: uses

• Histoplasmosis

• Sporotrichosis

• Aspergillosis

• Blastomycosis

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.

Itraconazole: untoward effects

• Nausea, vomiting

• Liver dysfunction

• Hypokalemia

• Hypertriglyceridemia

• Drug-drug interactions, similiar to ketoconazole but to lesser degree

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

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

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

Topical Azoles

• Clotrimazole

• Miconazole

• Econazole

• Oxiconazole

• Terconazole

• Sulconazole

• Tioconazole

• Butoconazole

Allylamines (fungicidal)

• inhibit squalene-2,3-epoxidase – for dermatophytes

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,

dyspepsiadyspepsia– Rare blood dyscrasia reportedRare blood dyscrasia reported

Antiviral Drugs • AMANTIDINE and Rimantadine

• FOSCARNET • Lamivudine

• ACYCLOVIR • Didanosine • Zanamivir

• ZIDOVUDINE • Valacyclovir • Ribavirin

• GANCICLOVIR • Efavirenz • Lopinavir

• Nevirapine • Indinavir • Nelfinavir

• Interferon alpha • Enfuvirtide • Stavudine

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.

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

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

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