CHEMOTHERAPEUTIC DRUGS

ANITA Q. SANGALANG, MD, FPOGS DEPARTMENT OF MEDICAL TECHNOLOGY COLLEGE OF PHARMACY UNIVERSITY OF SANTO TOMAS

MICROORGANISMS & ANTIMICROBIALS

1. Bacteria 2. Viruses 3. Fungi 4. Parasites - Antibacterial - Antiviral - Antifungal - Antiparasitic

OBJECTIVES
1. 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 Action
Broad: wide range of bacteria Narrow: limited to subset of bacteria

Action
Bacteriostatic: stop bacteria from multiplying Bactericidal: kills bacteria

Bacterial vulnerability:
Susceptibility: presence of antimicrobial targets Sensitivity: necessary effective concentration Resistance: target not present, mutation prevents antimicrobial activity

ANTIBACTERIAL DRUGS
MECHANISMS 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

BETABETA-LACTAM ANTIBIOTICS
Penicillins Cephalosporins Monobactams Carbapenems -lactamase inhibitors

BETABETA-LACTAM ANTIBIOTICS
Basic structure: 6-aminopenicillanic acid 6Thiazolidine ring, -lactam ring (secondary amino group), substituents (R group) Structural integrity essential for the biologic activity If -lactam ring is cleaved by bacterial lactamases penicilloic acid no antibacterial activity

BETABETA-LACTAM ANTIBIOTICS
Penicillin G (benzylpenicillin) g(+)>g(g(+)>g(-) acid labile; destroyed by -lactamase -lactamase resistant acid stable lactamase resistant

Oxacillin Cloxacillin Dicloxacillin Flucloxacillin Nafcillin (ethoxynaphthami dopenicillin)

BETABETA-LACTAM ANTIBIOTICS
Ampicillin destroyed by -lactamase acid stable g(-) > g(+) g(G(G(-) aerobes

Ticarcillin Piperacillin Mezlocillin Amoxicillin

Like ampicillin but better absorbed

BETABETA-LACTAM ANTIBIOTICS
(mechanism of action)
inhibit cell wall synthesis
Plasma membrane
gram positive bacterium

Cell wall

cross-linked Peptidoglycans if damaged: cell lysis(bactericidal)

BETABETA-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 Effects 1) Hypersensitivity - mild allergy to anaphylactic 2) Colitis penicillins can disturb gut flora

BETABETA-LACTAM ANTIBIOTICS
4 General Mechanisms of Resistance 1. Inactivation of antibiotic by lactamase
2. Modification of target penicillin binding proteins (PBP) 3. Impaired penetration of drug to target PBPs 4. Presence of efflux pump

BETABETA-LACTAM ANTIBIOTICS
Penicillin G Not acid stable @ must be injected Effective against gram (+) anaerobic bacteria Why gram (+) and not gram (-) ? (1) have difficulty penetrating outer membrane (2) beta-lactamases in periplasmic space of gram (-) bacteria

BETABETA-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-lactamases

BETABETA-LACTAM ANTIBIOTICS Penicillins

Units and Preparations Crystalline sodium penicillin G 1600 units/mg (1 unit=0.6Qg; 1 million units of unit=0.6Q penicillin=0.6g) Potassium penicillin G benzanthine/ procaine parenteral form Penicillin V oral: 250, 500mg tabs

BETABETA-LACTAM ANTIBIOTICS
Penicillins Cloxacillin Acid stable @ given orally; Beta-lactamase resistant Effective against beta-lactamase producing staphylococcal Infections (e.g.. toxic shock syndrome)

BETABETA-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)

BETABETA-LACTAM ANTIBIOTICS
Cephalosporins

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

BETABETA-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

BETABETA-LACTAM ANTIBIOTICS
Cephalosporins

1st generation (early cephalosporins): gram (+) e.g. cefazolin (used as prophylactic following surgery) 2nd generation: gram (+) & gram (-)

BETABETA-LACTAM ANTIBIOTICS
Cephalosporins 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 betalactamases

BETABETA-LACTAM ANTIBIOTICS Cephalosporins

1ST GENERATION Cephalexin, Cefazolin, Cephalexin, Cefadroxil, Cephalotin, Cephadrine, Cephapirin Cefuroxime, Cefoxitin, Cefuroxime, Cefotetan, Cefamandole Ceftriaxone, Cefotaxime, Cefoperazone, Ceftazidime Cefepime

2ND GENERATION

3RD GENERATION

4TH GENERATION

BETABETA-LACTAM ANTIBIOTICS
MONOBACTAMS BETABETA-LACTAMASE INHIBITORS (CLAVULANIC ACID, SULBACTAM & TAZOBACTAM) CABAPENEMS VANCOMYCIN TEICOPLANIN FOSFOMYCIN BACITRACIN CLYCLOSERINE

CHLORAMPHENICOL, TETRACYCLINE, MACROLIDES, CLINDAMYCIN AND STREPTOGRAMINS

ANITA Q. SANGALANG, MD, FPOGS DEPARTMENT OF MEDICAL TECHNOLOGY COLLEGE OF PHARMACY UNIVERSITY OF SANTO TOMAS

Chloramphenicol
Effective bacteriostatic broad-spectrum aerobic and anaerobic gram (+) and gram (-) organisms Use is limited due to side effects An almost ideal antibiotic

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

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 -lactam antibiotics Dose: 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 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

TETRACYLINES
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

TETRACYLINES
RESISTANCE widespread most common: efflux pump -removes drug from bacterial cell ribosome protection -production of proteins that prevent tetracycline binding enzymatic inactivation (tetracyclinase)

MACROLIDES - ERYTHROMYCIN
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 - ERYTHROMYCIN
useful as penicillin substitute in penicillinallergic individuals MOA: inhibits protein synthesis by binding to 50S subunit prevents tRNA from accessing donor site bacteriostatic; at high doses bactericidal

MACROLIDES - ERYTHROMYCIN
Absorption: destroyed by stomach acid (enteric coated) Distribution: most tissues, except CNS Elimination: mainly excreted in bile

MACROLIDES - ERYTHROMYCIN
Drug of choice: diphtheria, community-acquired pneumonia, penicillin substitute Resistance: reduced permeability of bacteria enzyme inactivation modification of ribosomal binding unit

MACROLIDES - ERYTHROMYCIN
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 - CLARITHROMYCIN
derived from erythromycin by addition of

methyl group improved acid stability more active against Mycobacterium avium

MACROLIDES - CLARITHROMYCIN

longer half-life (6 hrs) twice daily dosing 250- 500mg major metabolite has antibacterial activity: 14-hydroxyclarithromycin lower frequency of GI intolerance

MACROLIDES - AZITHROMYCIN
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 - AZITHROMYCIN
slightly more active against H influenzae highly active against chlamydia tissue half-life 2-4 days for 3-5 days once daily dosing

AMINOGLYCOSIDES
- effective against gram (-) enteric bacteria Enteric bacteria - facultative anaerobes that can grow in presence or absence of oxygen

AMINOGLYCOSIDES
- enter outer membrane of gram (-) bacteria by passive diffusion - cross cytoplasmic membrane by oxygendependent active transport - transport inhibited in anaerobic conditions - transport may be enhanced by cell-wall active drugs (penicillins)

AMINOGLYCOSIDES
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

AMINOGLYCOSIDES
Clinical Uses: gentamicin by far most important severe infections caused by gram (-) aerobic bacteria topical administration for infections resulting from burns or wounds Most gentamicin resistant bacteria will be susceptible to amikacin

AMINOGLYCOSIDES
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

AMINOGLYCOSIDES
STREPTOMYCIN GENTAMICIN TOBRAMYCIN AMIKACIN NETILMICIN NEOMYCIN KANAMYCIN

SULFONAMIDES, TRIMETHOPRIM & QUINOLONES

ANITA Q. SANGALANG, MD, FPOGS DEPARTMENT OF MEDICAL TECHNOLOGY COLLEGE OF PHARMACY UNIVERSITY OF SANTO TOMAS

ANTIFOLATE DRUGS SULFONAMIDES

Structural analog of p-aminobenzoic acid (PABA) that competitively inhibit dihydropteroate synthase inhibits folic acid synthesis g(+), g(-) bacteria, nocardia, chlamydia g(trachomatis, some protozoa, some enteric bacteria (E. coli, klebsiella, salmonella, shigella, enterobacter bacteriostatic

ANTIFOLATE DRUGS SULFONAMIDES

Drug of choice for infections of Pneumocystis carinii pneumonia, toxoplasmosis, nocardiosis For UTI 1g of sulfixazole 4x daily For ulcerative colitis, enteritis and Inflammatory bowel disease Bacterial conjuctivitis Silver sulfadiazine burn wound infection

ANTIFOLATE DRUGS SULFONAMIDES

Adverse Effects Common: fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea Stevens-Johnson syndrome Stevens Hematopoietic: aplastic anemia, granulocytopenia, thrombocytopenia

ANTIFOLATE DRUGS
TRIMETHOPRIM & TRIMETHOPRIMTRIMETHOPRIMSULFAMETHOXAZOLE MIXTURES Trimethoprim inhibits bacterial dihydrofolic acid reductase TrimethoprimTrimethoprim-Sulfamethoxazole mixtures (1:5 ratio) synergistic, bactericidal Trimethoprim more lipid soluble, absorbed in the gut and CNS efficiently

ANTIFOLATE DRUGS
TRIMETHOPRIM & TRIMETHOPRIMTRIMETHOPRIMSULFAMETHOXAZOLE MIXTURES Uses: pneumonia, shigellosis, salmonella, diarrhea, urinary tract infection Dose: TMP-SXZ 160mg/800mg q 12 hrs TMP(UTI) 8mg/kg for children shigellosis & UTI

DNA GYRASE INHIBITORSINHIBITORSFLUOROQUINOLONES

Synthetic fluorinated analogs of nalidixic acid MOA: blocks bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV prevents the relaxation of positively supercoiled DNA (required for normal transcription and replication)

DNA GYRASE INHIBITORSINHIBITORSFLUOROQUINOLONES

Effective against g(-) bacteria, limited activity g(against g(+) organisms Norfloxacin least active Ciprofloxacin, enoxacin, lomefloxacin, levofloxacin, ofloxacin, pefloxacin (2nd group) : g(-)>g(+) g(-

DNA GYRASE INHIBITORSINHIBITORSFLUOROQUINOLONES

Ciprofloxacin - most effective against P aeruginosa Levofloxacin superior against g(+), S pneumoniae A/E: nausea, vomiting, diarrhea, headache, dizziness, damage growing cartilage (arthropathy) Not routinely given to under 18 years of age

ANTIANTI-MYCOBACTERIAL AGENTS

ANTITUBERCULOSIS DRUGS
FIRST LINE AGENTS Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin
SECONDSECOND- LINE AGENTS Amikacin Aminosalicylic acid Capreomycin Ciprofloxacin Clofazimine Cycloserine Ethionamide Levofloxacin Rifabutin Rifapentine

ISONIAZID
WellWell-absorbed after oral administration Good distribution including CSF Acetylated (fast acetylators> slow acetylators) Inhibits mycolic acid synthesis (myobacterial cell walls) Dose: Adult 300mg ; Pedia 5mkd OD Peak plasma conce 3-5Qg/mL in 1-2 hrs 31-

ISONIAZID
May cause peripheral neuritis (treated with pyridoxine 25-50mg/day) 25May cause optic neuritis (must monitor vision) Teratogenic Used prophylactically in tuberculin converters Used alone or in combination in the treatment of most cases of TB)

RIFAMPICIN
Well absorbed after oral administration Good distribution Metabolized in the liver and excreted via the bile Inhibits RNA synthesis by binding strongly to the F subunit of bacterial DNADNA-dependent RNA polymerase

RIFAMPICIN
Bactericidal for mycobacteria Readily penetrates most tissues and into phagocytic cells Kill organisms poorly accessible to many drugs, like intracellular organisms, sequestered in abscess and lung cavities Decrease effectiveness of oral contraceptive

RIFAMPICIN
Dose: 600mg/day (10mkd) Prophylaxis for meningococcal carriage: 600mg BID for 2 days Hepatotoxic Cytochrome P450 inducer

PYRAZINAMIDE
Administered orally HalfHalf-life: 8-11 hours 8Taken up by macrophages and kills bacilli residing within the acidic environment M. tuberculosis only organism susceptible to this drug Hepatotoxic Dose: 25mkd; or 50-70mg/kg/dose for twice50twiceweekly or thrice-weekly treatment regimen thrice-

ETHAMBUTOL
Well absorbed after oral administration Crosses the blood brain barrier only if the meninges are inflamed. Excreted in the urine Inhibitor of mycobacterial arabinosyl transferase (involved in the polymerization reaction of arabinoglycan, essential to mycobacterial cell wall May cause a decrease in visual acuity (optic neuritis 25mkd)

ETHAMBUTOL
Dose: 15-25mg/kg/day 15for tuberculous meningitis 50mg/kg twice weekly dosing Blood peak level 2-5Qg/mL in 2-4hrs 22Adverse Effects: hypersensitivity C/I: children less than 6 years old because cannot assess visual acuity and red-green color discrimination red-

STREPTOMYCIN
Administered intramusculary Antimicrobial activity typical of other aminoglycosides Penetrates into cells poorly, active against extracellular tubercle Resistant strains develop so must be used in combination Dose; 15mkd IM or 20-40mkd for weeks 20Ototoxicity

POLICIES ON CASE FINDING

Direct sputum smear microscopy shall be the primary NTP diagnostic tool
1. It provides definitive diagnosis of

active TB. 2. The procedure is simple 3. It is economical 4. A microscopy center would be organized even in remote areas

POLICIES ON CASE FINDING

All TB symptomatics must undergo sputum examination prior to initiation of treatment, w/ or w/o X-ray results XContraindication: Contraindication: massive hemoptysis

No diagnosis of TB shall be made based on the result of x-ray examinations alone x-

PROGRAM COMPONENTS
Types of TB cases
based on history of anti-TB treatment antiimportant in determining Tx regimen
1. 2. 3. 4. 5. 6.

New: no Tx or < 1month Tx Relapse: cured & Sm (+) again TransferTransfer-in: change Tx facility Return after default (RAD): interrupted Tx; Sm (+) Treatment Failure: still (+) on 5th month Others: became (+) on 2nd month : interrupted Tx; Sm (-) (-

ANTIANTI-TUBERCULOSIS MEDICATIONS

H = ISONIAZID R = RIFAMPICIN Z = PYRAZINAMIDE E = ETHAMBUTOL S = STREPTOMYCIN TREATMENT STRATEGY: DOTS

CATEGORIES OF TREATMENT
REGIMEN Regimen I: 2HRZE/4HR TB PATIENT TO BE GIVEN TX New pulmonary smear (+) cases New seriously ill pulmonary smear (-) with (extensive parenchymal involment New severely ill extrapulmonary TB cases Failure cases Relapse cases RAD (smear +) Other (smear +) New smear (-) but with minimal pulmonary TB (on radiography as confirmed by a medical officer New extra-pulmonary TB (not serious) extra-

Regimen II: 2HRZES/1HREZ/ 5HRE

Regimen III: 2HRZE/4HR

ANTIFUNGAL AGENTS

Antifungal Drugs
Polyenes AMPHOTERICIN NYSTATIN Flucytosine Imidazoles KETOCONAZOLE FLUCONAZOLE Voriconazole MICONAZOLE ITRACONAZOLE Griseofulvin Terbinafine

SUPERFICIAL INFECTIONS
Griseofulvin oral Amphotericin B topical Nystatin topical Clotrimazole - topical Miconazole topical Terginafine oral and topical

SYSTEMIC INFECTIONS
flucytosine Amphotericin B topical Itraconzole Ketoconazole fluconazole

A.

Polyenes 1. amphotericin B

(Fungizone)

Chemical properties - amphoteric aqueous insolubility at neutral pH

AMPHOTERICIN B
ergosterol

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.
ergosterol with pore

+ a polyene

AMPHOTERICIN B
Poorly absorbed orally (5%), therefore administered IV Distribution: large, slow distribution; tissue is a reservoir over time, very slow CNS penetration Terminal half-life: 15 days halfSlowly excreted in the urine and bile (5-10%) (5-

AMPHOTERICIN B
Alters membrane permeability characteristics Used for systemic fungal infections Many side effects- requires effectshospitalization Nephrotoxic, hypokalemia, fever, chills, thrombophlebitis Drug Interactions: potentiates other renal toxins

Nystatin
similar to amphotericin B used topically and for GI use used against candida and dermatophytes (Epidermophyton, Trichophyton, Microsporum) Side effects: minimal

Chemistry
H N O N F NH2

Flucytosine

FLUCYTOSINE
Orally effective Readily passes into the CNS Resistance develops fairly rapidly Relatively low toxicity Used mainly in combination with amphotericin B in the treatment of cryptococcal meningitis Flucytosines use has declined significantly since the release of fluconazole 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 thymidylate synthetase synthesized to 5-FUTP incorporated into RNA.

5-flucytosine permease 5-flucytosine (outside) (inside)

Cytosine deaminase

5dUMP (inhibits thymidylate synthase) RNA 5-FUMP

5-fluorouracil

Phosphoribosyl transferase

FLUCYTOSINE -Uses
systemic fungi, mainly candida, and cryptococcus. fungistatic. used with amphotericin B (cryptococcal meningitis) and with itraconazole (chromoblastomyosis).

FLUCYTOSINE Pharmacokinetics
Given orally T ~ 3-6 hours Penetrates into CNS Excreted in urine-80% unchanged

FLUCYTOSINE Untoward effects

nausea, vomiting, colitis bone marrow suppression thrombocytopenia alopecia decreased liver function

Azoles Imidazoles ketoconazole, miconazole, clotrimazole Triazoles- itraconazole, fluconazole, voriconazole

chemistry

Mechanism of Action
inhibit the synthesis of ergosterol by blocking demethylation (14-demethylase) of lanosterol also inhibit cytochrome activity.

Acetyl CoA Squalene

Squalene monooxygenase

Allylamine drugs

Squalene-2,3 oxide Lanosterol

14-E-demethylase

Azoles
(ergosterol)

Spectrum of imidazoles
systemic fungi, dermatophytes fungistatic

Specific drugsketoconazole
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.

MICONAZOLE
Used topically to treat superficial infections Inadequate CSF penetration Many significant side effects Increases the anticoagulant effect of coumarin drugs Blocks 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 t - 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

FLUCONAZOLE
Antifungal spectrum is broader than other azole antifungals More resistant to first pass metabolism and has lower lipophilicity and protein binding than ketoconalzole Unlike ketoconazole, its oral absorption is not affected by the absence of stomach acid It is equivalent to amphotericin b in the treatment of candidemia in nonnonneutorpenic patient

Griseofulvin (Chemistry)

GRISEOFULVIN
Orally effective for superficial infections absorption enhanced by fatty meals Inhibits the growth of fungal hyphae of dermatophyte infections which grow beneath the skin (fungistatic) by inhibiting mitosis by binding to microtubules comprising the spindles and

GRISEOFULVIN
HalfHalf-life: 9-21 hrs 9Metabolism: hepatic Elimination: urine 2/3; fecal 1/3 Spectrum: dermatophytes only Dose: 10-20mkd x 4-8 wks 104S/E: Headache, nausea, headache hepatoxicity, renal toxicity, photosensitivity, can precipitate acute intermittent porphyria, possibly teratogenic Drug interactions: rare

Topical Azoles
Clotrimazole Miconazole Econazole Oxiconazole Terconazole Sulconazole Tioconazole Butoconazole

Allylamines (fungicidal)
inhibit squalene-2,3-epoxidase for dermatophytes
N

Terbinafine

Acetyl CoA Squalene

Squalene monooxygenase

Allylamine drugs

Squalene-2,3 oxide Lanosterol

14-E-demethylase

Azoles
(ergosterol)

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 to griseofulvin and to its itraconazole for onychomycosis

TERBINAFINE
Used for the treatment of tinea infections due to susceptible organisms Adverse effects include hepatitis and rashes. Both are rare. metabolized then excreted in urine Side effects associated with oral terbinafine include gastrointestinal symptoms such as:
Abdominal pain, diarrhea, nausea/vomiting, dyspepsia Rare blood dyscrasia reported

Antiviral Drugs
AMANTIDINE and Rimantadine FOSCARNET Lamivud ine

ACYCLOVIR

Didanosine

ir r r

Zanamiv

ZIDOVUDINE GANCICLOVIR

Valacyclovir Efavirenz

Ribavirin Lopinavi

Nevirapine

Indinavir

Nelfinavi

Interferon alpha

Enfuvirtide

Stavudi ne

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 MEFLOQUINE Quinine PRIMAQUINE PYRIMETHAMINE-SULFASOXINE (Fansidar) atovaquone

Antiprotozoal Drugs Amebiasis and Trichomonas

METRONIDAZOLE Diloxanide Iodoquinol pentamidine

Pneumocystis
TRIMETHOPRIM - SUFAMETHOXAZOLE Clindamycin plus primaquine PYRIMETHAMINE plus sulfadiazine Pyrimethamine plus clindamycin METRONIDAZOLE

Toxoplasmosis Trichomonas

Antihelminthic Drugs
Flatworms
PRAZIQUANTEL

Fluke and Tapeworm Infections Schistosomiasis

PRAZIQUANTEL diethylcarbamazine ivermectin mebendazole Albendazole mebendazole pyrantel pamoate

Filariasis Intestinal Roundworms (Ascaris), Enterobius (Pinworm) and Hookworm Angiostroglyliasis

Trichurius (Whipworm) Hookworm

mebendazole albendazole

Trypanosomiasis
nifurtimox or suramin pentamidine

Giadiasis
metronidazole