ANTI-FUNGAL DRUGS
AGENTS
A. Subcutaneous and Systemic Anti-fungal
Agents
– Amphotericin B
– Caspofungin
– Flucytosine
– Imidazoles: Ketoconazole,
Itraconazole, Fluconazole,
Miconazole, Voriconazole
– Nystatin
– Terbinafine, Amorolfine
B. Topical Anti-fungal Agents
– Amphotericin B, Butenafine,
Butoconazole, Griseofulvin,
Ciclopirox, Clioquinol,
Clotrimazole, Econazole, Gentian
violet, Ketoconazole, Miconazole,
Naftifine, Nystatin, Oxiconazole,
Sulconazole, Terbinafine,
Terconazole, Tolnaftate
Antifungal Antibiotics
– Amphotericin B
– Nystatin
– Griseofulvin
MECHANISM OF ACTION OF SOME ANTI-
FUNGAL DRUGS
AMPHOTERICIN B
• A polyene antibiotic derived from
Streptomyces nodosus.
• Broad spectrum of activity (C. albicans,
H. capsulatum, C. neoformans, C.
immitis, aspergillus) both fungistatic and
fungicidal activity.
• MOA: Binds to sterols (ergosterol) in the
cell membranes, forming pores or
channels which increase membrane
permeability, making the cell more
susceptible to destruction.
• MOR: Decreased ergosterol content of
the fungal membrane.
• Active in growing and resting cells; not
highly selective and will interfere with
membrane function of mammalian host
cell.
Pharmacokinetic profile:
– Given by slow IV injection, topical,
intrathecal (meningitis) or oral.
– Highly CHON-bound; excreted very
slowly through the urine.
ADR:
Infusion reactions:
Fever, shaking chills, hypotension, anorexia,
NAV, headache, dyspnea, tachypnea.
Others:
Renal toxicity (potentiated by sodium
depletion), electrolyte impairment
(hypokalemia, hypomagnesemia,
hypocalcemia), normocytic normochromic
anemia, impaired hepatic function, local
thrombophlebitis; intrathecal à neurotoxicity;
topical à skin rash.
Therapeutic Uses:
Acute, severe, systemic fungal infections
(primary drug – DOC).
Local dermatophytic and mucocutaneous
infections (topical).
Fungal infections of the GIT (oral).
NYSTATIN
• Isolated from Streptomyces; first
antimycotic antibiotic.
• Polyene antibiotic with broad spectrum
of activity.
• MOA: Binds to sterols in fungal cell
membranes, thereby increasing
membrane permeability and making the
cell more susceptible to destruction.
Pharmacokinetic profile:
– Given by oral or topical route.
• ADR: Local burning and itching (topical).
 GI upset (NAV, diarrhea), renal toxicity.
• Therapeutic Uses: Prevention and topical
treatment of superficial candidal
infections of the skin and mucous
membranes (gums, GIT, rectum, vagina).
GRISEOFULVIN
• Fungistatic in activity.
• MOA: Inhibits fungal cell mitosis by being
accumulated in the newly-synthesized
keratin-containing tissue, thus producing
multinucleated defective cells that bind
to the microtubules, thereby disrupting
mitotic spindle.
• Pharmacokinetic profile:
– Orally administered; t1/2: 24
hours.
– Distributes to growing nails and
skin, binding to keratin and
making the cells resistant to
fungal infection.
– Biotransformed in the liver to 6-
methyl-griseofulvin; urinary excr.
• ADR: Headache, lethargy, fatigue,
blurred vision,
insomnia, GI upset, hepatotoxicity.
Drug Interactions:
– With anticoagulants à reduced
effectiveness of anticoagulants
because of enhanced metabolism.
– With barbiturates à enhanced
metabolism of griseofulvin.
– With alcohol à tachycardia and
flushing; potentiation of
intoxicating effects of alcohol.
– With oral contraceptives à
amenorrhea, increased
breakthrough bleeding.
Therapeutic Use:
For tinea infections of the skin, hair, nails
including athlete’s foot and ringworm caused
by Microsporum, Epidermophyton, and
Trichophyton (oral).
FLUCYTOSINE
• Fluorinated pyrimidine derivative for
candidiasis, cryptococcosis, and
chromomycosis.
• Fungistatic, synergistic effect with
Amphotericin B.
• MOA: Converted to 5-FU in sensitive
fungi à biotransformed to 5-fluoro-
deoxyuridylic acid that inhibits
thymidylate synthetase, thus depriving
the organism of thymidilic acid (essential
DNA component) à disrupts DNA
synthesis.
• MOR: Decreased level of the enzymes in
the conversion of flucytosine to 5-FU.
Pharmacokinetic profile:
– Administered by oral route; t1/2:
3-6 hours. Excretion: Urine.
• ADR: NAV, diarrhea, rash, anemia,
leukopenia, thrombocytopenia;
increased liver enzymes, BUN, &
creatinine.
SYSTEMIC IMIDAZOLE
Ketoconazole
• Broad antifungal activity; fungistatic
activity.
• MOA: Selectively increases fungal cell
membrane
permeability by blocking the
demethylation of lanosterol to ergosterol.
(effective only in growing cells)
• MOR: Mutation in the C14 a-
demethylase
gene à decreased azole binding; fungi’s
ability to pump the azole out of the cell.
• Orally given; readily absorbed under
acidic pH.
• ADR: NAV, diarrhea, rash, itching,
dizziness,
constipation, fever, chills, and
headache; gynecomastia and
impotence; hepatocellular toxicity.
Therapeutic Uses:
Rx of systemic and vaginal candidiasis,
mucocandidiasis, oral thrush, histoplamosis,
chromomycosis. coccidioidomycosis,
dermatophytosis.
Other Azoles
• Fluconazole
– Administered PO or IV.
– May produce teratogenic effects.
– DOC for Cryptococcus
neoformans.
• Itraconazole
– DOC for blastomycosis,
aspergillosis, sporotrichosis,
histoplasmosis, and
paracoccidioidomycosis.
– Orally administered.
– With teratogenic capability.
• Voriconazole
– Administered orally and effective
for invasive aspergillosis and
serious infections caused by
Scedosporium apiospermum and
fusarium species.
– ADR: Transient visual disturbance.
Caspofungin
• First of the echinocandins class of
antifungal drugs.
• MOA: Interferes with the synthesis of the
fungal cell wall by inhibiting the
synthesis of b-D-glucan à cell lysis and
death.
• ADR: Fever, rash, nausea, phlebitis,
flushing.
SYSTEMIC & TOPICAL IMIDAZOLE:
Miconazole
• Administered both parenterally and
topically.
• Therapeutic Uses: For Rx of candidal and
dermatophytic infections of the skin and
for vaginal candidiasis (topical).
For severe systemic fungal infections
unresponsive or not tolerant to
Amphotericin B (IV)
• ADR: Local burning, itching, and rash
(topical).
NAV, anemia, anaphylactoid reactions,
CNS toxicity, hyponatremia, phlebitis
(IV).
TOPICAL IMIDAZOLE
Clotrimazole
• Broad antifungal activity.
• Therapeutic Uses: Vulvovaginal
candidiasis (topical) Oropharyngeal
candidiasis (topical oral)
• ADR: Erythema, blistering, edema,
pruritus, urticaria.
TOPICAL IMIDAZOLES
Econazole and Butoconazole
ECONAZOLE
– Derivative of miconazole.
– Used for the treatment of tinea pedis,
tinea cruris, tinea corporis, tinea
versicolor, and cutaneous candidiasis.
– ADR: Burning, itching, rash.
– BUTOCONAZOLE
– Azole cream for vaginal use and is
effective against vaginal infections
caused by Candida albicans and
Candida tropicalis.
– May cause vulvovaginal burning and
itching.
OTHER TOPICAL ANTIMYCOTIC AGENTS
– Undecylenic acid, haloprogin.
• TERBINAFINE, NAFTIFINE, AMOROLFINE
TERBINAFINE
• Fungicidal agent that acts by selectively
inhibiting squalene epoxidase that is
involved in the synthesis of ergosterol
from squalene in the fungal cell wall à
accumulation of squalene à toxicity to
organism.
• Given orally or topically for fungal
infections of the nails.
• ADR: GI disturbances, rashes, pruritus,
headache,
dizziness, joint and muscle pains,
hepatitis.
Related drug: Naftifine
AMOROLFINE
• A morpholine derivative that interferes
with fungal sterol synthesis.
 • Given orally for fungal infections of the
nails.
BUTENAFINE
• A synthetic benzylamine.
• MOA
– Alters fungal membrane
permeability and growth inhibition.
– Interferes with sterol biosynthesis
by allowing squalene to
accumulate within the cell.
• Therapeutic Uses
– Dermatophytoses, including tinea
corporis, tinea cruris, and tinea
pedis (1% cream).
CICLOPIROX
• MOA:
– Intracellular depletion of amino acids
and ions necessary for normal cellular
function.
– Therapeutic Uses:
– Tinea pedis, tinea cruris, tinea
corporis, tinea versicolor, cutaneous
candidiasis (topical).
• Clioquinol
– Available in 3% ointment for tinea
pedis and cruris.
– May cause local irritation, rash, and
sensitivity reactions.
• Oxiconazole
– Available in 1% cream or lotion for
tinea cruris, corporis, mannum, and
pedis and tinea versicolor.
• Sulconazole
– Imidazole derivative available in
1% cream or solution and used for
tinea corporis, cruris, pedis,
versicolor and impetigo.
• Terconazole
– Imidazole derivative available in
vaginal cream and suppository
and used for vulvovaginal
candidiasis.
ANTIVIRAL DRUGS
• STAGES OF VIRUS MULTIPLICATION
Phase 1: Adsorption, penetration, and
uncoating as the virus enters the host cell and
sheds its protective coating.
Phase 2: Synthesis of viral components.
Phase 3: Assembly and release of the virus
which can destroy or permanently change the
cell.
INHIBITORS OF VIRAL CELL
MULTIPLICATION
• Phase 1 and phase 3 inhibitor:
Amantadine.
• Phase 2 inhibitors: Acyclovir, Ganciclovir,
Vidarabine, Trifluoridine, Idoxuridine,
Ribavirin, Zidovudine.
Drugs for Respiratory Virus Infections
– Amantadine, Oseltamivir, Ribavirin,
Rimantadine, Zanamirvir
Drugs for Hepatic Viral Infections
– Adefovir, Entecavir, Interferon,
Lamivudine
Drugs for Herpes and Cytomegalovirus
Infections
– Acyclovir, Cidofovir, Famciclovir,
Fomivirsen, Foscarnet, Ganciclovir,
Penciclovir, Valacyclovir,
Valgancyclovir, Vidarabine
Drugs for HIV Infections
– Abacavir, Amprenavir, Atazanavir,
Delavirdine, Didanosine,
Emtricitabine, Enfuvirtide, Efavirenz,
Indinavir, Lamivudine, Lopinavir,
Nelfinavir, Nevirapine, Ritonavir,
Saquinavir, Stavudine, Tenofovir,
Zalcitabine, Zidovudine
Treatment of Respiratory Virus Infections
 Neuraminidase Inhibitors: Oseltamivir,
Zanamivir
– Sialic acid analogues
– MOA: Inhibits the neuraminidase
enzyme à preventing the release
of new virions and their spread
from cell to cell.
– MOR: Mutation of the
neuraminidase.
– Oseltamivir: Orally active
prodrug à active metabolite in
 liver; ADR: GI discomfort and
nausea.
– Zanamavir: Inhalation or
intranasal administration; avoided
in severe reactive asthma or
COPD.
– Effective for influenza A and B
infections.
 Inhibitors of Viral Uncoating:
Amantadine, Rimantadine, Ribavirin
AMANTADINE & RIMANTADINE
• Adamantadine derivatives.
• Synthetic tricyclic amine with a narrow
spectrum of activity.
• Therapeutic Uses: Treatment or
prophylaxis of influenza A virus and for
Parkinson’s disease.
• MOA: >Inhibits the adsorption of viral
particles to host cells, resulting in
delayed penetration of the virus into the
cell and/or inhibition of uncoating.
> Inhibits virus assembly.
• MOR: Change in one amino acid of the
M2 matrix protein.
• Given orally; t1/2: 12-36 hours; peak
effects in 2-4 hours.
• ADR: Dizziness, insomnia, and slurred
speech;
confusion, ataxia, sleep disorders,
tumors, hallucinations; anorexia, NAV,
orthostatic hypotension; edema.
RIBAVIRIN
• A synthetic nucleoside analog.
• MOA: Interferes with guanidine
monophosphate, thereby reducing
nucleic acid synthesis.
• Therapeutic Uses: RSV infections, herpes
simplex infections, influenza A and B
infections.
• ADR:Rash, headache, fatigue.
TREATMENT OF HEPATIC VIRAL
INFECTIONS
• Hepatitis B: Rx with interferon-a and
lamivudine
• Hepatitis C: Rx with interferon-a and
ribavirin
INTERFERON
– Immunomodulator.
– Inducible proteins synthesized by
mammalian cells and now
produced by recombinant DNA
technology.
– MOA: Induces, in the ribosomes of
the host cells, the production of
enzymes that inhibit translation of
viral mRNA into viral CHON à
stops reproduction of viruses.
– Given IV; t1/2 of 2-4 hours.
– Therapeutic Uses: Hepatitis B
infection and AIDS-related Kaposi
sarcoma (a interferon)Hepatitis C
infection (a2b interferon)
– ADR: Fever, lassitude, headache,
myalgia, bone marrow depression,
rashes, alopecia.
Other Drugs for Hepatic Viral Infections
• Lamivudine
– Cytosine analog that inhibits both
hepatitis B virus (HBV) DNA
polymerase and human
immunodeficiency (HIV) reverse
transcriptase.
– Oral administration with t1/2 of 9
hours.
• Adefovir
– Nucleotide analog that is
phosphorylated into adefovir
diphosphate and incorporated into
the viral DNA à terminates further
synthesis à prevents viral
replication.
• Entecavir
– Guanosine analog that is
converted into entecavir
triphosphate which competes for
viral reverse transcriptase.
ACYCLOVIR
• Acycloguanosine, 9-2-OH-
ethoxymethylguanine.
• A nucleoside analog of the pyrimidine,
guanosine.
• MOA: Its triphosphate (acyclo GTP)
competitively inhibits viral DNA
 polymerase and is also incorporated into
viral DNA where it functions as a chain
terminator, thus preventing the further
elongation of the DNA molecule and
therefore viral replication.
• MOR: Changes in the viral genes coding
for DNA
polymerase.
• Given orally, topically, and intravenously;
t1/2 of 2.5 - 3.5 hrs.
• Related drugs: Valaciclovir (prodrug
of aciclovir)
Famciclovir (met. to penciclovir -
active)
• Therapeutic Uses: > Rx of
mucocutaneous herpes and genital and
disseminated adult herpes simplex.
> Mgt. of initial herpes genitalis and in
non-
life-threatening cutaneous simplex virus
infections in immunocompromised
px.
>Rx or suppression of recurrent episodes
of genital herpes infection and in
varicella zoster.
• ADR: Mild pain, transient burning and
stinging, pruritus, and rash (ointment);
NAV, headache, diarrhea, dizziness,
anorexia, fatigue, edema, skin rash, leg
pain, adenopathy, sore throat (oral);
phlebitis, transient elevation of serum
creatinine, rash (IV).
GANCICLOVIR
• A synthetic purine nucleoside analog.
• Therapeutic Use: Cytomegalovirus
infections (IV) and for maintenance
therapy in AIDS patients (oral).
• MOA: Activated to its triphosphate form
which competes with guanosine
triphosphate for incorporation into the
viral DNA.
• Given intravenously and orally with t1/2
of 4 hours.
• ADR: Bone marrow depression,
carcinogenicity.
• Drug Interactions:
– With Probenecid à increased
ganciclovir level à toxicity.
– With Imipenem-Cilastatin à
generalized seizures.
– With Zidovudine and cytotoxic
drugs à neutropenia.
VIDARABINE
• Adenine arabinoside.
• MOA: Its triphosphate inhibits viral DNA
polymerase, thus reducing DNA
synthesis.
• Administered topically or intravenously
(slow infusion).
• T1/2: 4 hours.
• Undergoes deamination to arabinosyl-
hypoxanthine.
• Therapeutic Uses:
 Herpes simplex keratitis
(ophthalmic).
 Herpes simplex encephalitis,
 other severe
systemic herpes infections, and
varicella zoster (IV).
• ADR: NAV, anorexia, diarrhea;
decreased Hgb and Hct, increased SGOT,
tremors, dizziness, hallucinations.
TRIFLURIDINE
• Trifluorothymidine; a halogenated
thymidine derivative used as ophthalmic
solution for herpes simplex-induced
keratoconjunctivits.
• MOA: Converted to its triphosphate
which inhibits DNA polymerase.
• ADR: Local burning or stinging.
IDOXURIDINE
• Halogenated derivative of deoxyuridine.
• MOA: Inhibits the replication of of DNA
viruses by its incorporation into the
virus.
• Given topically.
• Used for the treatment of herpes simplex
keratitis.
• ADR: Inflammatory edema of the eyelids,
photophobia, lacrimal duct occlusion,
and contact dermatitis.
FOSCARNET
• Trisodium phosphonoformate
hexahydrate or PFA
• A synthetic non-nucleoside analog of
pyrophosphate; given IV.
 • MOA: Inhibits viral DNA polymerase by
binding directly to the
pyrophosphate binding site.
• ADR: Nephrotoxicity;
hyper/hypocalcemia, seizures.
ZIDOVUDINE
• Azidothymidine or AZT.
• Therapeutic Indication: Rx of AIDS
patients with P. carinii pneumonia or
advanced AIDS-related complex.
• Given orally or by IV; t1/2: 1 hour.
• MOA: Interferes with HIV replication by
being converted to triphosphate and
inhibiting the DNA polymerase.
• MOR: Rapid mutation of the virus;
decreased activation of the drug to its
triphosphate; increased virus load due
to reduction in immune mechanisms.
• ADR: Insomnia, myalgia, nausea, severe
headache, anemia, and neutropenia.
DIDANOSINE
• Dideoxyinosine, ddI.
• A synthetic purine analog.
• MOA: Phosphorylated to triphosphate
which acts as a chain terminator and
inhibitor of the viral reverse
transcriptase.
• Given orally with plasma t1/2 of 30 mins.
and intracellular t1/2 of 12 hours.
• Used to treat AIDS.
• ADR: Pain and sensory loss in the feet;
dose-related pancreatitis.
ZALCITABINE
• Dideoxycytidine, ddC.
• A synthetic nucleoside analog.
• MOA: Inhibits the reverse transcriptase
enzyme.
• Given orally with a plasma t1/2 of 20
mins. and intracellular t1/2 of 3 hours.
• Used in the Rx of AIDS in combination
with Zidovudine.
• ADR: Dose-related neuropathy, GI
disturbances,
headache, mouth ulcers, edema of the
lower limbs, general malaise,
pancreatitis.
NUCLEOSIDE REVERSE TRANSCRIPTASE
INHIBITORS
Abacavir, Adefovir, Lamivudine, Stavudine,
Zalcitabine, Didanosine, Zidovudine.
• Competitive inhibitors of reverse
transcriptase à chain termination when
incorporated into the viral DNA chain.
NON-NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS
Delavirdine, Efavirenz, Nevirapine
• Competitive inhibitors of reverse
transcriptase à chain termination when
incorporated into the viral DNA chain.
PROTEASE INHIBITORS
Amprenavir, Indinavir, Nelfinavir, Ritonavir,
Saquinavir.
• Competitively inhibit the viral protease
enzyme, preventing the enzyme from
cleaving the polyprotein necessary for
the production of the infectious virions.
Viral Fusion Inhibitor
• Enfuvirtide
– Antiretroviral drug.
– A 36 AA peptide that binds to
gp41, preventing the
conformational change of the viral
transmembrane that is necessary
for the fusion of the HIV
membrane with that of the host
cell
– Subcutaneous administration.
NATIONAL GUIDELINES FOR ANTI-HIV
TREATMENT
• When to begin treatment
– Treat any symptomatic patient.
– Offer treatment to asymptomatic
patients with CD4 <500 or HIV-
RNA >20,000 or recommend
observing patients with CD4 350-
500 and RNA <20,000.
– Observe or treat asymptomatic
patients with CD4 >500 and HIV-
RNA <20,000.
• Preferred Regimen
– Choose from one of the protease
inhibitors and one of the
 nucleoside reverse transcriptase
inhibitor combinations (NRTI)
(zidovudine + lamivudine,
zidovudine + didanosine,
zidovudine + zalcitabine,
stavudine + lamivudine)
• Alternative Regimen
– Choose 2 NRTI combinations + 1
non-nucleoside RTI, either
nevirapine or delavirdine.
• Monitoring
– Monitor HIV-RNA level; if HIV-RNA
does not fall more than 10-fold by
week 8, change drug regimen and
use 2-3 new agents.
– Consider changing if CD4 is falling
or if there is clinical deterioration.
ANTI-PROTOZOAL DRUGS
ANTI-MALARIAL DRUGS
DRUG CLASSIFICATION
>Blood schizonticides
• Drugs for suppressive or clinical cure.
• Affect the erythrocytic stage of life cycle.
• Suppress the symptoms of actual attack
by destroying the schizonts and
merozoites in the erythrocytes.
• CHLOROQUINE, AMODIAQUINE,
MEFLOQUINE, QUININE, HALOFANTRINE.
>Tissue schizonticides
• Effects radical cure by acting on the
malarial hepatic stage.
• Destroys gametocytes, thus reducing the
spread of infection.
• PRIMAQUINE.
•
>Drugs that affect both exo- and
erythrocytic forms
• Anti-folate drugs or dihydorfolate
reductase inhibitors.
• CHLOROGUANIDE, PYRIMETHAMINE,
TRIMETHOPRIM.
GAMETOCIDES
• Prevent infection in mosquitoes by
destroying the gametocytes in the blood.
• PRIMAQUINE, CHLOROQUINE.
SPORONTICIDES
• Render the gametocytes non-infective in
the mosquito.
• PYRIMETHAMINE, PROGUANIL.
• BLOOD SCHIZONTICIDES
• 4-AMINOQUINOLINES: Chloroquine,
Amodiaquine.
• QUINOLINE METHANOLS: Quinine,
Mefloquine.
• PHENANTHRENE METHANOL:
Halofantrine.
CHLOROQUINE (Aralen)
• MECHANISMS OF ACTION
– Blocks the enzymatic synthesis of
DNA and RNA in humans and
protozoal cells à forms a complex
with DNA à prevents DNA from
acting as template for the
replication and transcription to
RNA.
– Forms a complex with
ferriprotoporphyrin à damage to
cell membrane à lysis of the
parasite and RBC.
• MECHANISM OF RESISTANCE
– Impaired mechanism of drug
transport across the parasite cell
wall à concentration of drug in
resistant schizonts never reaches
a level sufficient to arrest nucleic
acid synthesis.
• PHARMACOKINETICS
– Formulation: Phosphate,
hydrochloride.
– PPB: 50-65%.
 – High concentrations in the
erythrocytes, liver, spleen,
kidneys, lungs, leukocytes.
– Penetrates the CNS and crosses
the placenta.
– T1/2: 3-5 days.
• PHARMACOLOGIC EFFECTS
– Antimalarial effect.
– Quinidine-like effect on the heart
à depresses the cardiac function.
– Distinct anti-inflammatory
capability especially in rheumatoid
arthritis and chronic discoid LE.
– CHLOROQUINE (Aralen)
• THERAPEUTIC USES
– Acute malarial attacks.
• Terminates fever in 24-48
hours.
• Terminates parasitemia in
48-72 hours.
– Chemophophylaxis vs all forms of
malaria except P. falciparum
resistant to 4-aminoquinolines.
– Amoebiasis, autoimmune
disorders as DMARD.
• ADR
– Mild: GI complaints (nausea,
epigastric distress), skin rash,
headache.
– High dosage: Alopecia, graying of
the hair, skin eruptions and
desquamations, keratopathy,
retinopathy.
– Overdosage: Visual disturbances,
hyperexcitability, convulsions, AV
block, death.
QUININE
• Alkaloid from the cinchona bark.
• MECHANISM OF ACTION
– Complexes with double-stranded
DNA to prevent strand separation,
transcription, and CHON synthesis.
• PHARMACOLOGIC EFFECTS
– Peripheral vosodilation.
– Quinidine-like depression of
myocardial excitability and
conduction velocity.
– Direct relaxant effect on the
smooth muscles à severe or
lethal hypotension.
– Distinct curare-like action.
– Contraction of the pregnant
uterus.
– Hypoglycemia.
• PHARMACOKINETICS
– Administration: PO, IV, IM (7-
day course).
– PPB: 70-80%.
– T1/2: 7-12 hours.
– Highest concentrations in the
liver, lungs, kidneys, spleen.
– Metabolism in the liver; excretion
through the urine.
• THERAPEUTIC USES
– Parenteral treatment of severe
falciparum malaria.
– Oral Rx of falciparum malaria
resistant to Chloroquine.
– Prophylaxis for Chloroquine-
resistant falciparum strains.
– Relief of nighttime leg cramps.
– Severe babesiosis with
Clindamycin.
• Adverse Reactions
• GI: Irritation à NAV, epigastric pain.
• Cinchonism: At a drug plasma level of
7-10 mg/ml.
– GI distress, tinnitus, vertigo,
headache, blurred vision.
• Hematologic effects
– Hemolysis, leukopenia,
agranulocytosis,
thrombocytopenia purpura,
Henoch-Schonlein purpura,
hypoprothrombinemia.
• Hypoglycemia, thrombophlebitis,
moderate-severe hypotension, seizures,
ventricular fibrillation, death.
• Severe toxicity
– Fever, skin eruptions, GI
symptoms, deafness, visual
abnormalities, CNS effects
(syncope, confusion), quinidine-
like effects.
• Blackwater fever
– Characterized byexcessive
intravascular hemolysis followed
 by hemoglobinuria, dark urine, • GI disturbances, fatigue,
azotemia, renal failure. neuropsychiatric symptoms,
pruritus, skin rash, myalgia.
• DRUG INTERACTIONS (QUININE) • CONTRAINDICATIONS
– + aluminum-containing antacids – History of epilepsy, psychiatric
à delayed absorption of Quinine. illness, arrhythmias, cardiac
– + Digoxin à decreased renal conduction defects, or sensitivity
clearance of Digoxin à increased to quinidine or related drugs.
serum concentration of Digoxin. – Concurrent use with quinine,
– + Warfarin and other quinidine, or halofantrine.
anticoagulants à enhanced action – Pregnancy.
of these anticoagulants. – Persons whose work requires fine
coordination and spatial
– + Cimetidine à slowed elimination
discrimination.
of Quinine.
– With anti-convulsant drugs à
MEFLOQUINE breakthrough seizures.
 Synthetic 4-quinoline methanol
HALOFANTRINE
derivative chemically related to quinine.
• Active against strains of P. falciparum
• MECHANISM OF ACTION
resistant to chloroquine, pyrimethamine,
– Inhibition of heme polymerase
or quinine and the erythrocytic form of P.
(enzyme that polymerizes toxic
vivax.
free heme to hemozoin) à
• PHARMACOKINETICS
parasite becomes harmless.
– Administered PO with peak plasma
• PHARMACOKINETICS
concentration 4-6 hours after
– Administered by oral route; highly
ingestion.
protein-bound, concentrated in the
– Main metabolite: N-debutyl-
RBC and extensively distributed to
halofantrine; excretion: feces.
the tissues; t1/2 of > 6 days.
– T1/2: 4-5 days.
• PHARMACOLOGIC EFFECT
• ADR
– Quinidine-like effects on the heart
– Abdominal pain, GI disturbances,
à BP reduction and depression of
headache, cough, transient rise in
cardiac function.
hepatic enzymes, pruritus,
• THERAPEUTIC USES
syncope, dysrhythmias, hemolytic
– Prophylaxis and treatment of
anemia, convulsions.
Chloroquine-resistant strains of P.
falciparum.
PRIMAQUINE
• ADVERSE REACTIONS
 An 8-aminoquinoline drug.
– Prophylactic dose:
• MECHANISM OF ACTION
• GI disturbances, headache,
– Forms quinoline-quinone
dizziness, syncope,
metabolites which interfere with
extrasystoles.
electron transport causing
• Transient leukocytosis,
oxidative damage to mitochondrial
thrombobocytopenia,
enzyme system in the parasite à
aminotransferase
swelling and vacuolation of the
elevations.
• Transient neuropsychiatric mitochodria à lysis of the
events as convulsions, parasite.
depression, and psychosis. • PHARMACOKINETICS
– Treatment dose: – Administered PO.
 – Concentrated in the liver, lungs,
brain, heart, and skeletal muscles.
– Rapidly biotransformed (liver) to
carboxyprimaquine.
– T1/2: 3-5 hours.
• THERAPEUTIC USES
– Terminal prophylaxis of vivax and
ovale malaria.
– Radical cure of acute vivax and
ovale malaria.
– Gametocidal action.
– Pneumocystis carinii pneumonia.
– ALTERNATIVE ANTIMALARIAL DRUG:
• ADVERSE REACTIONS
– Abdominal discomfort, nausea,
headache, changes in visual
accommodation.
– Leukopenia, agranulocytosis,
leukocytosis, pruritus,
arrhythmias.
– Primaquine sensitivity
• Intravascular hemolysis
accompanied by the
formation of
methemoglobin in G6PD-
deficient patients.
ANTIFOLATE DRUGS OR FOLATE
METABOLISM INHIBITORS OR
DIHYDROFOLATE REDUCTASE INHIBITORS
• DRUGS: Chloroguanide/Proguanil,
Pyrimethamine, Trimethoprim
• MECHANISM OF ACTION
– Inhibits plasmodial dihydrofolate
reductase (DHFR) à reduction of
dihydrofolic acid to
tetrachydrofolic acid (folinic acid)
is inhibited.
PHARMACOKINETICS
• Chloroguanide
– Slowly absorbed from the GIT;
activated by conversion to the
triazine compound; t1/2 of 16
hours.
• Pyrimethamine/Trimethoprim
– Rapidly absorbed in the GIT; tissue
concentration is high; t1/2 of 4
days.
• THERAPEUTIC USES
– Prophylaxis against malaria and in
Chloroquine-resistant falciparum
malaria (Chloroguanide.)
– Treatment of Chloroquine-resistant
P. falciparum malaria (with sulfone
or sulfonamide).
– ADVERSE REACTIONS
– Anorexia (Chloroguanide).
– Folic acid deficiency manifested as
bone marrow depression and
megaloblastosis (Pyrimethamine).
QINGHAOSU
• Also known as Artemisinin.
• Sesquiterpene lactone endoperoxide.
• Extract from a Chinese herbal medicine
(Artemisia amma).
• Other derivatives: Artesunate,
artemether, artether.
• PHARMACOKINETICS
– Administered PO, IV, IM, rectal
insertion.
– Converted into dihydroqinghaosu
or dihydroartemisinin.
– T1/2: Artemisinin - 4 hours;
artesunate - 45 minutes;
artemether - 4-11 hours.
• CLINICAL USES
– Effective blood schizonticide
against all malarial forms and
Chloroquine-resistain falciparum
malaria; cerebral falciparum
malaria.
• ADVERSE REACTIONS
– Abdominal pain, diarrhea;
depression of reticulocyte ct;
transient heart block.
ALTERNATIVE ANTIMALARIAL DRUGS
• QUINACRINE
– A blood schizonticide that
suppresses all types of human
malaria; effects radical cure of P.
malariae and non-resistant strains
of falciparum malaria.
– ADR: yellowish discoloration of
the skin, psychotic rxns
– Also used in the treatment of
giardiasis.
 • DOXYCYCLINE
– A tetracycline used vs multidrug
resistant P. falciparum. THERAPEUTIC OPTIONS FOR THE
TREATMENT AND
CONDITION DRUG
PREVENTION OF MALARIA

All Plasmodium Chloroquine

species except AMOEBIASIS: E. histolytica
Chloroquine- • DRUG CLASSIFICATION
resistant P. – Mixed amoebicidal drug
falciparum • Effective against both
Chloroquine- Quinine + Pyrimethamine- luminal and systemic forms.
resistant P. sulfadoxine or Doxycycline • METRONIDAZOLE.
falciparum or Clindamycin – Luminal amoebicides
Alternate drug: • Act on the parasite in the
Mefloquine lumen of the bowel.
• Dichloroacetamides:
Prevention of Primaquine
DILOXANIDE FUROATE,
relapses: P.
TECLOZAN, ETOFAMIDE.
vivax and P.
• Halogenated
ovale only
hydrogquinolines:
Prevention of In Chloroquine-sensitive IODOQUINOL, CLIOQUINOL.
malaria geographic areas: • Antibiotics: TETRACYCLINE,
Chloroquine PAROMOMYCIN.
In chloroquine-resistant – Systemic amoebicides
geographic areas: • Effective against amoebae
Mefloquine in the intestine and liver.
In pregnancy Chloroquine or Mefloquine • EMETINE,
DEHYDROEMETINE,
–Also for blood stages of the other CHLOROQUINE.
Plasmodium species. NITROIMIDAZOLES:
– With quinine for acute malaria. >Metronidazole (Flagyl, Anerobia)
– ADR: GI symptoms, candidal >Tinidazole (Fasigyn)
vaginitis, photosensitivity. • MECHANISM OF ACTION
• DAPSONE – Undergoes reductive bioactivation
– 4,4-diaminodiphenylsulfone (DDS) of its nitro group by ferredoxin to
used in the prophylaxis of malaria form reactive cytotoxic products.
usually combined with • PHARMACOKINETICS
Pyrimethamine. – Administered PO, IV, rectal
insertion.
POTENTIAL NEW ANTIMALARIAL DRUGS – Peak plasma concentration 1-3
• PYRONARIDINE hours after administration.
– Synthetic schizonticidal agent – T1/2: Metronidazole - 7 hours;
derived from mepacrine; Tinidazole - 12-14 hours.
developed in China. • Drug of choice in severe intestinal wall
– ATOVAQUONE disease and in hepatic abscess and other
– Hydroxynapthoquinone for P. extra-intestinal amoebic disease.
carinii penumonia. • CLINICAL USES: Mild-severe intestinal
disease, liver abscess, amoeboma, extra-
intestinal infections.
 • TOXICITY: Bitter metallic taste, GI • ADVERSE REACTIONS
irritation, headache, discoloration of the – Mild: Diarrhea, NAV, gastritis,
urine, leukopenia, dizziness, ataxia. CLINICAL DRUG
• DRUG INTERACTION: Disulfiram-like rxn SYNDROME
with ethanol and potentiation of
coumarin anticoagulant effect. Asymptoma Iodoquinol or
tic cyst Paromomycin or
DILOXANIDE FUROATE carriers Diloxanide furoate
• Drug of choice in the treatment of
asymptomatic passers of cysts and in Diarrhea / Metronidazole +
the treatment of intestinal amoebiasis. dysentery Iodoquinol or
• Direct amoebicidal action, affecting the Extraintesti Paromomycin or
amoeba before encystment. nal Diloxanide furoate
• Administered PO; converted in the gut to Amoebic Chloroquine +
diloxanide-free base which is active. liver Metronidazole or
• ADR: Flatulence, dryness of the mouth, abscess Emetine
nausea, pruritus, urticaria. headache, malaise.
• CI in pregnant women and children under – Large doses and prolonged use:
2 years old. SMON (subacute myelo-
optic neuropathy.
EMETINES:
Emetine, Dehydroemetine OTHER DRUGS
 Alkaloid obtained from Brazil root. • CHLOROQUINE
• MECHANISM OF ACTION – Active against amoebas in the
– Inhibits protein synthesis by liver especially when given with
blocking ribosomal movement Emetine.
along the messenger RNA. – Used in combination with
• Used as back-up drugs for the treatment Metronidazole and Diloxanide
of severe intestinal or hepatic furoate to treat and prevent
amoebiasis in hospitalized patients. amoebic liver abscesss.
• Given parenterally (IM); widely – PAROMOMYCIN (Humagel)
distributed; excreted slowly by the – Aminoglycoside antibiotic used as
kidneys. a 2nd-line amoebicide (luminal
• TOXICITY: Pain, tenderness, GI distress, type).
muscle weakness, CV dysfunction – Reduces the population of the
(arrhythmias and CHF with dyspnea and intestinal flora.
hypotension. – ADR: GI distress, diarrhea,
• CLINICAL USES: Amoebic dysentery, headache, rashes, arthralgia.
amoebic liver abscess, amoebomas, and – For mild intestinal disease à
extra-intestinal amoebiasis. combine with Doxycycline.

HALOGENATED HYDROQUINOLINES:
Iodoquinol, Clioquinol
• Orally active luminal amoebicides used
as alternative drugs for mild to severe
intestinal infections.
• CLINICAL USES
– Intestinal amoebiasis, T. vaginalis
vaginitis, other intestinal parasites Therapeutic options for amoebiasis
as B. coli, G. lamblia.

Treatment for trypanosomiasis
• African sleeping sickness
– Caused by Trypanosoma brucei
gambiense and Trypanosoma
brucei rhodiense.
– Live and grow in the blood à
invade CNS à inflammation of the
brain and spinal cord à lethargy
and continuous sleep.
• American sleeping sickness
– Chagas’ disease.
– Caused by Trypanosoma cruzi.
– Occurs in South America.
Melarsoprol
– A derivative of mersalyl oxide that
is used for the treatment of late
stage of the infection with CNS
involvement.
– MOA: Reacts with sulfhydryl
groups of various substances,
including the enzymes à toxic
compounds.
– MOR: Decreased permeability of
the drug.
– Administered by IV; short t 1/2;
rapidly oxidized into nontoxic
pentavalent arsenic compound.
– DOC in the Rx of T. brucei
rhodiense and for
meningoencephalitis caused by T.
brucei gambiense.
– ADR: Encephalopathy;
hypersensitivity reactions; GI
disturbances, such as severe
vomiting and abdominal pain;
hemolytic anemia in G-6-PD
deficiency.
Pentamidine isethionate
– Administered IM or by aerosol; no
metabolized but excreted very
slowly into the urine; t1/2 of 5
days.
– Used to prevent and treat the
organism’s hematologic stage.
Nifurtimox
– Used for Chagas’ disease.
– Undergoes reduction into
intrecellular oxygen radicals
(superoxide and hydrogen
peroxide radicals) à toxic to
organism.
– Administered orally.
– ADR (elderly): Hypersensitivity
reaction and GI problems;
peripheral neuropathy.
Suramin
– Used for African trypanosomiasis.
– MOA: Inhibits many enzymes
involved in energy metabolism.
– Given IV.
Treatment for other protozoal infections
 LEISHMANIASIS
o Sodium stibogluconate
 TOXOPLASMOSIS
o Pyrimethamine
o Sulfadiazine + Pyrimethamine
 GIARDIASIS
– Metronidazole
BACILLARY POPULATION (IN LUNG
FIELDS)
• population A
– bacilli lining the cavity wall
– rapid growth and multiplication due to abundant
supply of O2
– reside in neutral or slightly alkaline [pH]
environment
 – source of infectiousness, communicability, and Given for the next 4 months – Maintenance
resistant mutants
• population B (Persisters) – INH
– bacilli in caseous nodules and inner linings of – RFP Same dose as mentioned above
cavitary lesions
– slow or intermittent metabolism [persisters]
– environment contains little O2 and pH is slightly • Total number of Rx= 6 months
acidic
– source of relapse à difficult to eradicate
• population C (Intracellular Bacilli) CONTRAINDICATIONS TO SCC
– bacilli inside macrophages [intracellular
population] • History of liver disease (SGPT, SGOT, alcoholics)
– slow metabolizers [persisters] • History of chronic and acute renal disease
– environment is poorly oxygenated and frankly • History of gout or predisposition to gout (PZA)
acidic • Patients taking steroids for more than 6 months –
– source of relapse Immunosuppression

VITAL FACTORS IN THE CHEMOTHERAPY OF TB

S**M Streptomycin
(Oldest, 1944)
active
• Correct dosage
• Regularity of administration
Pop. A • Adequate duration
Most active
Second most active • Proper drug combination
Weakly active Most active

INH Pop. B RFP

PRIMARY HEALTH CARE [PHILIPPINES]
Less active than RFP 2nd most active

• For 2 months daily Rx -intensive

Pop. C – Rifampicin 450mg
Most active – INH 300mg
2 – Pyrazinamide 1000mg to 15000mg
PZA

ETHAMBUTOL • For 4 months -maintenance

– Rifampicin 450mg
• Bacteriostatic to populations A and C – INH 300mg
• Inhibits the growth of mutants resistant to INH and
RFP
• Not hepatotoxic but causes optic neuritis, give to • Pyrazinamide 500mg/ tab (aka Para amino salicylic
adults only, not in children. acid)
• Hepatotoxic: • Above 50 kilos – 3tabs (1,500 mg)
– Isoniazid • 50 kilos and below – 2tabs (1,000 mg)
• Rifater, Pyrina – RNZ (Rifampicin, INH, PZA)
– Pyrazinamide ß Causes gout
– For 2 months
– Rifampicin
• Rifinah – RN (Rifampicin, and INH)
– For 4 months

REASONS FOR RX FAILURE

SHORT COURSE THERAPY OR SHORT COURSE
CHEMOTHERAPY [AUGUST 19, 1986] 1. Non-observance of vital factors of Rx by either
physician or px
Given for the first 2 months - Intesnsive 2. Very extensive disease
3. Uncontrolled DM and alcoholism
– INH [Isoniazid] 300 mg PO daily
4. Primary resistance to drugs
– PZA [Pyrazinamide] 500 mg PO daily
5. Inherent of cellular immunity in the px
– RFP [Rifampicin] 450 mg PO AC OD
ADVERSE DRUG REACTIONS [ADR] – 1ST MONTH

• Loss of appetite and tiredness without reason - INH • 4 drugs given initially [2 months]
• Unexplained nausea and vomiting, collapse - INH – Big bacillary population especially cavitary
• Rash and persistent itchiness - INH lesion
• Yellowish discolorations of skin and eyeballs - – Previous use of anti-TB drugs
Rifamp – High primary resistance to H ?
• Flu-like syndrome- fever, chills, pain – Close contact with resistant source case
• When R is given intermittently in high dose - Rifamp
• Tingling and burning sensation of hands and feet
• Swelling and generalized edema
• Shortness of breath - INH
MDT FOR LEPROSY [WHO]
Disease Paucibacillary Multibacillary
• Petechiae and ecchymoses – Rifampicin
Other Name Tuberculoid, Lepromatous, mid
Indeterminate type borderline (Serious,
fingerless)
• Advice- stop medication for few days and do
Rx Rifampicin 600mg once -Same
desensitization a month, Dapsone 100
– Dose- 1/10, ¼, ½ à average dose mg 1-2 mg/kg/d -Same
-Clofazimine
(Lamprene) 300mg
once a month AND 50
DRUG DOSE ADJUSTMENT mg/d

Rx duration 6 months 2 years or until skin

• INH – 5-10mg/kg, up to 400mg/ day smears are negative
• Rifampicin – 10mg/kg, up to 600mg/day Surveillance after Rx Annual exams for at Annual exams for at
• Pyrazinamide – 25-35 mg/kg, not to exceed 2grams completion least 2 years least 5 years
14

daily
• irrespective of serum uric and level for as long as px
is asymptomatic SIDE NOTES
• Ethambutol – 25mg/ kg/ day for 1st 2 months
– 15mg/ kg for next 4 months • Give Vitamin B complex (Pyridoxine) to prevent INH
• Streptomycin – 15-20mg/ kg up to 1 gram daily by (Isoniazid H) toxicity
IM • DOT – Direct Observance Therapy
• Streptomycin – Only anti TB drug administered IM
• Increased dose in INH causes convulsions
INH PROPHYLACTIC USE • 2 months is INTENSIVE, 4 months is
MAINTENANCE
– Infants and children up to 6 years who converts to [+] • Myrin P – Combination of the following drugs, 2
PPD [without previous BCG] months: (INTENSIVE)
– PPD [–] medical personnel and students who are in – R = Rifampicin
close contact with active cases in wards – I = Isoniazid
– Recent tuberculin converters in close contact with – P = Pyrazinamide
open cases of TB – E = Ethambutol
– Px on corticosteroid, anti-metabolite therapy with • Myrin (4 months), only R I E
previous TB history • Rifampicin has PAE against leprosy, it is leprocidal
• dose- 10mg/kg/ day • PHILCAT – Philippine Coalition Against tuberculosis
- 300-400mg daily

Rx regimen
Best recommended Rx regimen for pulmonary TB I. 2 HRZE (2 RIPE) / 4HR (4 RI)
[MDRTB ?] I. New pulmonary smear (+) cases
II. New seriously ill pulmonary smear negative
– RHZE or RHZS daily [2 months] cases with parenchymal involvement
– RH [4 months] daily III. New seriously ill extrapulmonary TB cases

• Chemoprophylaxis of adult patient [13-35 years] II. 2 HRZES (2 RIPES) / 1 HREZ (1 RIPE) / 5 HRE
– INH + Ethambutol daily for 6 months; (5 RIE)
– Or INH + Rifampicin daily for 4 months
 I. Failure cases
II. Relapse cases
III. X-ray smear (+)

III. 2 HRZ (2 RIP) / 4 HR (4 RI)

I. New cases, smear (--) but with minimal
pulmonary TB on x-ray confirmed by medical
officer
II. New extrapulmonary TB (Not serious)

• H = Isoniazid H
• R = Rifampicin
• Z = Pyrazinamide
• E = Ethambutol

• INH & rifampicin- hepatotoxic

• Streptomycin & ethambutol- parenteral route
• Rifampicin- nephrotoxic
• Pyrazinamide- increase uric acid- gout
• Ethambutol- cause optic neuritis in chidren