Mycobacterium leprae Mycobacterium tuberculosis

Mycobacteria
intrinsically resistant to most antibiotics → they grow slowly compared with
other bacteria → Antibiotics ineffective

can also be dormant → completely resistant to many drugs or killed only very
slowly

The lipid-rich mycobacterial cell wall is impermeable to many agents

Mycobacterial species are intracellular pathogens, and organisms residing within

macrophages are inaccessible to drugs that penetrate these cells poorly
DRUGS USED IN TUBERCULOSIS
 ISONIAZID Isoniazid penetrates into macrophages and is active against
both extracellular and intracellular organisms.

Isoniazid inhibits synthesis of mycolic acids, which are

essential components of mycobacterial cell walls.

Adverse Reactions
Fever and skin rashes

Isoniazid-induced hepatitis
Isoniazid promotes excretion of pyridoxine, and this
Peripheral neuropathy toxicity is readily reversed by administration of
pyridoxine in a dosage as low as 10 mg/d.

pyridoxine deficiency → memory loss, psychosis, and

seizuresanemia, tinnitus, and gastrointestinal discomfort.
RIFAMYCINS RIFAMPIN Rifapentine Rifabutin

Inhibits DNA-dependent RNA

polymerase, thereby blocking
production of RNA

Bactericidal activity against susceptible bacteria and

mycobacteria
• resistance rapidly emerges when used as a single drug in the
treatment of active infection

Toxicity: Rash, nephritis, thrombocytopenia, cholestasis,

flu-like syndrome with intermittent dosing
ETHAMBUTOL
Inhibits mycobacterial arabinosyl
transferases, which are involved in the
polymerization reaction of arabinoglycan →
an essential component of the mycobacterial
cell wall

Bacteriostatic activity against susceptible

mycobacteria

Toxicity: Retrobulbar neuritis

PYRAZINAMIDE
Not fully understood
• pyrazinamide is converted to the
active pyrazinoic acid under acidic
conditions of macrophage lysosomes

Bacteriostatic activity against susceptible

strains of M tuberculosis

Toxicity: Hepatoxicity, hyperuricemia

STREPTOMYCIN
Prevents bacterial protein synthesis by
binding to the S12 ribosomal subunit

Bactericidal activity against susceptible

mycobacteria

Used in tuberculosis when an injectable drug is needed or

desirable and in treatment of drug-resistant strains

Toxicity: Nephrotoxicity, ototoxicity

Antifungal
Agents
POLYENE MACROLIDE Amphotericin B

PYRIMIDINE ANALOG Flucytosine

AZOLES Ketoconazole Itraconazole Fluconazole

ECHINOCANDINS Caspofungin Micafungin

ALLYLAMINE Terbinafine
POLYENE MACROLIDE

produced by Streptomyces nodosus

Amphotericin B binds to ergosterol and alters the
permeability of the cell

Forms pores in fungal membranes (which contain ergosterol) Loss of intracellular contents through pores is
but not in mammalian (cholesterol-containing) membranes fungicidal

Localized and systemic Infusion-Related Toxicity

• Candidemia Oral but not absorbed →effective only on
• Cryptococcus fungi within the lumen of the tract toxicity
• Histoplasma • IV for systemic use
• Blastomyces • intrathecal for fungal meningitis
• Coccidioides • topical for ocular and bladder infection
Cumulative Toxicity
• Aspergillus
PYRIMIDINE ANALOG

Flucytosine is a water-soluble pyrimidine analog related to the

chemotherapeutic agent fluorouracil
(5-FU)

Interferes with DNA and RNA synthesis selectively in

fungi

Cryptococcus and chromoblastomycosis infections

Toxicity: Myelosuppression
AZOLES

The imidazoles consist of ketoconazole, miconazole, and clotrimazole

The triazoles include itraconazole, fluconazole, voriconazole, and posaconazole.

Blocks fungal P450 enzymes and interferes with ergosterol synthesis

The selective toxicity of azole drugs results from their greater affinity for fungal than for
human cytochrome P450 enzymes

Imidazoles exhibit a lesser degree of selectivity than the triazoles, accounting for their
higher incidence of drug interactions and side effects.
KETOCONAZOLE
Ketoconazole was the first oral azole introduced into clinical use

It is distinguished from triazoles by its greater propensity to inhibit mammalian cytochrome

P450 enzymes → As a result, systemic ketoconazole has fallen out of clinical use in the USA

ITRACONAZOLE
Itraconazole is available in oral and intravenous formulations and is used at a dosage of 100–400
mg/d

It does not affect mammalian steroid synthesis, and its effects on the metabolism of other
hepatically cleared medications are much less than those of ketoconazole

Itraconazole is used extensively in the treatment of dermatophytoses and onychomycosis.

FLUCONAZOLE
Fluconazole displays a high degree of water solubility and good cerebrospinal fluid
penetration

oral bioavailability is high

Drug interactions are also less common because fluconazole has the least effect of all
the azoles on hepatic microsomal enzymes

Fluconazole is the azole of choice in the treatment and secondary prophylaxis of

cryptococcal meningitis

Fluconazole is the agent most commonly used for the treatment of mucocutaneous candidiasis

Fluconazole displays no activity against aspergillus or other filamentous fungi.

Antifungal topical
miconazole clotrimazole ketoconazole

Oral clotrimazole troches are available for treatment of oral thrush and are a pleasant-tasting alternative to
nystatin
Miconazole &clotrimazole cream, both agents are useful for dermatophytic infections, including tinea corporis,
tinea pedis, and tinea cruris
Topical and shampoo forms of ketoconazole are also available and useful in the
treatment of seborrheic dermatitis and pityriasisversicolor
Antifungal topical
Nystatin is a polyene macrolide much like amphotericin B

It is too toxic for parenteral administration and is only used topically

Nystatin is currently available in creams, ointments, suppositories, and other forms for
application to skin and mucous membranes

it is not absorbed to a significant degree from skin, mucous membranes, or the gastrointestinal tract →
has little toxicity

Nystatin is active against most Candida Sp

indications : oropharyngeal thrush, vaginal candidiasis, and intertriginous candida infections.

ECHINOCANDINS Caspofungin anidulafungin
IV only Micafungin

Blocks glucan synthase →

Prevents synthesis of fungal cell
wall Toxicity:
Minor gastrointestinal effects,
flushing
• Interactions:
Increases cyclosporine
Fungicidal Candida sp also levels (avoid combination)

used in aspergillosis
ALLYLAMINE Terbinafine

Inhibits epoxidation of squalene in fungi

→Reduces ergosterol → prevents synthesis of
fungal cell membrane

Mucocutaneous fungal infections

Gastrointestinal upset, headache,

hepatoxicity
Antiviral
Agent
 DNA viruses: poxviruses (smallpox), herpesviruses
(chickenpox, shingles, cold sores, glandular fever),
adenoviruses (sore throat, conjunctivitis) and
papillomaviruses (warts)

RNA viruses: orthomyxoviruses (influenza), paramyxoviruses

(measles, mumps, respiratory tract infections), rubella virus
(German measles), rhabdoviruses (rabies), picornaviruses
(colds, meningitis, poliomyelitis), retroviruses (AIDS, T-cell
leukaemia), arenaviruses (meningitis, Lassa fever),
hepadnaviruses (serum hepatitis) and arboviruses (various
arthropod-borne illnesses, e.g. encephalitis, yellow fever)
 HERPES VIRUS / VARICELLA ZOSTER

INFLUENZA VIRUS

CHRONIC HEPATITIS/HEPATITIS B/HEPATITIS C

HIV
HERPES
SIMPLEX

aciclovir

ganciclovir

valaciclovir

foscarnet
Aciclovir The bioavailability of oral acyclovir is low (15–20%) and is unaffected by food.
An intravenous formulation is available.
Topical formulations produce high concentrations in herpetic lesions, but
systemic concentrations are undetectable by this route

Acyclovir is cleared primarily by glomerular filtration and tubular secretion

The half-life is 2.5–3 hours in patients with normal renal function and 20 hours
in patients with anuria.

Acyclovir diffuses readily into most tissues and body fluids.

Cerebrospinal fluid concentrations are 20–50% of serum values.

Acyclovir is generally well tolerated. Nausea, diarrhea, and headache have

occasionally been reported
INFLUENZA VIRUS
INFLUENZA VIRUS
neuraminidase inhibitors
The neuraminidase inhibitors oseltamivir and zanamivir, analogs of sialic acid, interfere with
release of progeny influenza virus from infected to new host cells, thus halting the spread of
infection within the respiratory tract

These agents competitively and reversibly interact with the active enzyme site to inhibit
neuraminidase activity at low nanomolar concentrations and destroy the receptors
recognized by viral hemagglutininon cells, newly released virions, and respiratory tract mucins

oseltamivir and zanamivir have activity against both influenza A and influenza B viruses.

Early administration is crucial because replication of influenza virus peaks at 24–72

hours after the onset of illness.
 OSELTAMIVIR
Oseltamivir is FDA-approved for patients 1 year and older,

Oseltamivir is an orally administered prodrug that is activated by hepatic

esterases and widely distributed throughout the body.

Oral bioavailability is approximately 80%, plasma protein binding is low, and

concentrations in the middle ear and sinus fluid are similar to
those in plasma

The half-life of oseltamivir is 6–10 hours, and excretion is by glomerular filtration

and tubular secretion in the urine
Potential adverse effects include nausea, vomiting, and abdominal pain, which occur
in 5–10% of patients early in therapy but tend to resolve spontaneously

Taking oseltamivir with food does not interfere with absorption and may decrease
nausea and vomiting.
 ZANAMIVIR
zanamivir is approved in patients 7 years or older.

Zanamivir is delivered directly to the respiratory tract via

inhalation

Ten to twenty percent of the active compound reaches the

lungs, and the remainder is deposited in the oropharynx.

Potential adverse effects include cough, bronchospasm

(occasionally severe), reversible decrease in pulmonary
function, and transient nasal and throat discomfort
CHRONIC HEPATITIS/
HEPATITIS B/HEPATITIS C
CHRONIC HEPATITIS/
HEPATITIS B/HEPATITIS
C
INTERFERON Interferons are host cytokines that exert complex antiviral, immunomodulatory,
and antiproliferative actions
ALFA
Interferon alfa appears to function by:
• induction of intracellular signals following
binding to specific cell membrane receptors,
• resulting in inhibition of viral penetration,
translation, transcription, protein processing,
maturation, and release,
• increased expression of major histocompatibility
complex antigens
• enhanced phagocytic activity of macrophages
• augmentation of the proliferation and survival of
cytotoxic T cells.
Injectable preparations

Interferon alfa-2a and interferon alfa-2b may be administered subcutaneously or intramuscularly, whereas
interferon alfacon-1 is administered subcutaneously

T ½ elimination :
interferon alfa-2a and -2b, depending on the route of administration.
interferon alfacon-1 in patients with chronic HCV ranges from 6 to 10 hours

adverse effects : flu-like syndrome (ie, headache, fevers, chills, myalgias, and malaise)

Contraindications : hepatic decompensation, autoimmune disease, and history of cardiac arrhythmia

Alfa interferons are abortifacient in primates and should not be administered in pregnancy
 Lamivudine inhibits HBV DNA polymerase and HIV reverse
LAMIVUDIN transcriptase by competing with deoxycytidine triphosphate for
incorporation into the viral DNA, resulting in chain termination

In the doses used for HBV infection, lamivudine has an

excellent safety profile. Headache, nausea, and dizziness are
rare.
Oral bioavailability exceeds 80% and is not food-dependent.

Serum half-life is 2.5 hours, whereas the

intracellular half-life of the triphosphorylated compound is
11–14 hours
ADEFOVIR It is phosphorylated by cellular kinases to the active diphosphate
metabolite and then competitively inhibits HBV DNA polymerase to result
in chain termination after incorporation into the viral DNA

Oral bioavailability of adefovir dipivoxil is about 59% and is unaffected by meals

The intracellular half-life of the diphosphate is prolonged, ranging from 5 to 18 hours

in various cells; this makes once-daily dosing feasible

well tolerated, ADR → increased serum creatinine, headache, diarrhea, asthenia,

and abdominal pain
ENTECAVIR
competitively inhibits all three functions of HBV DNA polymerase, including base
priming, reverse transcription of the negative strand, and synthesis of the positive
strand of HBV DNA.

Oral bioavailability approaches 100% but is decreased by food; therefore,

entecavir should be taken on an empty stomach.

The intracellular halflife of the active phosphorylated compound is 15 hours

The most frequently reported adverse events are headache, fatigue, dizziness,
and nausea
 The phosphorylated compound competitively inhibits HBV DNA
TELBIVUDINE polymerase, resulting in incorporation into viral DNA and chain termination

Oral bioavailability is unaffected by food

Plasma proteinbinding is low (3%) and distribution wide

The serum halflife is approximately 15 hours and excretion is renal

Adverse effects in clinical trials were mild, including fatigue, headache, abdominal
pain, upper respiratory infection, increased creatine phosphokinase levels, and nausea
and vomiting
RIBAVIRINE guanosine analog that is phosphorylated intracellularly by host cell enzymes.

interfere with the synthesis of guanosine triphosphate, to inhibit capping of viral

messenger RNA, and to inhibit the viral RNA-dependent polymerase of certain
viruses.

The absolute oral bioavailability of ribavirin is 45–64%,

increases with high-fat meals, and decreases with co-administration of antacids

Plasma protein binding is negligible, volume of distribution is large, and

cerebrospinal fluid levels are about 70% of those in plasma

Ribavirin elimination is primarily through the urine

Other potential adverse effects are depression, fatigue, irritability, rash, cough,
insomnia, nausea, and pruritus.

Contraindications to ribavirin therapy include uncorrected anemia, end-stage

renal failure, ischemic vascular disease, and pregnancy