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First Line Drugs in TB Therapy

TUBERCULOSIS (Mycobacterium tuberculosis)
This is the leading cause of morbidity in developing countries where 90%
of TB cases occur
n the pre-chemotherapy era, mortality was approximately 50-60%.
Today death rates are considerably lower because a significant
proportion of cases are detected and treated.
Complexity of TB
1. nfection tend to be chronic but may also give rise to
hyperacute lethal complication
2. Organisms are frequently intracellular and exhibit
long periods of metabolic inactivity, and tend to
develop resistance to any one drug
Mycobacterium tuberculosis
- Classification based on staining properties difficult to stain because
of the presence of an outer coat of mycolic acid
- Cause serious infections of the lungs, GUT, Skeleton, and meninges
- Because strains are resistant to a particular agent emerge during
treatment, multiple drug therapy is employed to delay or prevent
their emergence
- Should always include a minumum of 2 cidal drug. (eg Short
course chemotx include RP for 2 months, R for the next 4 months)
- hydrazide of isonicotinic acid
- Synthetic analog of pyridoxine
- Most potent
- believed to target the enzyme responsible for assembly of mycotic
acids into the outer layer of the mycobacteria.
- Resistance inability of the organism to accumulate the drug
- SE Peripheral neuritis ( need Vit B6 supplementation);
Hepatotoxicity, Seizures, Optic Neuritis
- Derived from mold Streptomyces
- Broader antimicrobial activity than soniazid
- Blocks transcription by interacting with the B-subunit of bacterial
DNA-Dependent RNA polymerase thus inhibiting RNA synthesis by
suppressing the initiation step
- Specific for Prokaryotes
- Bactericidal for Mycobacteria; G(+) and G(-) ; prophylaxis for
meningococci or H. influenzae
- To delay emergence of resistant strains it is given in combination
with other drugs
- Urine orange red color
- SE- N/V; rash, fever

- Synthetic orally effective bactericidal anti-TB agent
- Must be actively hydrolyzed to pyrazinoic acid which is the active
form of the drug
- MOA is unknown
- SE- liver dysfunction, urate retention precipitates gouty attack
- Bacteriostatic, and specific for most strains of M. tuberculosis and
M. kansasii
- Penetrates the CSF tb meningitis
- SE- optic neurits (diminished visual acuity and loss of ability to
discriminate between red and green); exacerbation of gout
- An aminoglycoside
- more serious toxicities
1. Amikacin
2. Capreomycin
3. Ciprofloxacin/ Levofloxacin
4. p-Aminosalicylic acid
5. Cycloserine
6. Ethionamide
7. Rifabutin
LEPROSY (Hansen's Disease) M. Ieprae
Bacteria from skin lesions or nasal discharges of infected patients
enter susceptible individuals via the skin or respiratory tract
WHO recommends triple drug regimen dapsone, clofazimine, and
rifampin for 6 to 24 months
- Structurally related to sulfonamides
- Bacteriostatic
- Also used for P. carinii pneumonia in HV patients
- Acts a PABA antagonist.
- Adverse Reaction: hemolysis especially in patients with peripheral
neuropathy and possibility of developing erythyma nodosum
a phenazine dye
ts redox properties may lead to the generation of cytotoxic oxygen
radicals that are also toxic to the bacteria
Patients may develop red-brown discoloration of the skin
Adverse Effect: Eosinophilic Enteritis
Drugs for Subcutaneous and Systemic Mycoses
Amphotericin B
Drugs for Superficial Mycoses
Miconazole, Clotrimazole, Econazole
nfectious diseases caused by fungi are called mycoses and are
often chronic in nature.
Common mycotic infections are superficial and only involve the skin
but may also penetrate the skin, causing subcutaneous infections.
Fungal infections that are most difficult to treat are the systemic
Fungi are eukaryotic.
Drugs for Subcutaneous and Systemic Mycotic Infections
A. Amphotericin
Drug of choice to treat systemic mycoses.
Sometimes used with flucytosine so that lower levels of
amphotericin are possible.
Action: Enters fungal cells via a cytosine-specific permease.5-FC is
then conveted by a series of steps to 5-fluorodeoxyuridylic acid;
this false nucleotide inhibits thymidylate synthetase, thus depriving
the organism of thymidylic acid. The unnatural pyrimidine is also
metabolized to the nucleotide and incorporated into fungal RNA, to
disrupt nucleic acid and protein synthesis.
Effective against Candida albicans, Histoplasma capsulatum,
Cryptococcus neoformans immitis
Adverse effect: fever and chills, renal impairment, hypotension,
anemia, neurological effects, thrombophlebitis.
B. FIucytosine
Used only in combination with amphotericin for the treatment of
systemic mycoses and meningitis caused by Cryptococcus
neoformans and Candida.
Action:same as amphotericin
Adverse Effects: Hematologic toxicity, hepatic dysfunction,
gastrointestinal disturbances
C. KetoconazoIe
Substituted imidazole.
Should not be used with amphotericin
Action: blocks demethylation of lanosterol to ergosterol. This
inhibition disrupts membrane function and increase permeability.
Effective against nonmeningeal coccidiomycosis and blastomycosis.
Adverse Effects: gastrointestinal distress, endocrine effects (
gynecomastia, decreased libido, impotence, and menstrual
irregularities), hepatic dysfunction.
D. FIuconazoIe
Clinically important because of its lack of the endocrine side effects
of ketoconazole, and its excellent penetrability into the CSF.
Action: nhibits the synthesis of fungal membrane ergosterol in the
same manner as ketoconazole.
Drug of choice for cryptococcus neoformans, candidemia, and
Adverse effects: nausea and vomiting, rashes.
E. ItraconazoIe
ts action is the same with ketoconazole.
Drug of choice for blastomycosis.
t is effective in ADS-associated histoplasmosis.
Adverse Effects: nausea and vomiting, rash,
hypokalemia,hypertension, edema and headache.
Drugs for SuperficiaI Mycotic Infections
A. GriseofuIvin
Action: enters susceptible fungal cells by an energy-dependent
process. t is believed to interact with the microtubules within the
fungus to disrupt the miotic spindle and inhibit mitosis. t
accumulates in the infected, newly synthesized, keratin-containing
tissues, making them unsuitable for the growth of the fungi.
Therapy must be continued until normal tissue replaces infected
Effective only against dermatophytes.
Adverse effects: headache, nausea, hepatotoxicity.
B. Nystatin
ts mode of action resemble those of amphotericinB.
ts use is restricted to the topical treatment of Candida infections
because of its systemic toxicity.
Adverse effects are rare because of its lack of absorption, but
occasionally nausea an vomiting occur.
C. MiconazoIe, CIotrimazoIe, EconazoIe
are topically active drugs and are only rarely administered
parenterally because of their severe toxicity.
Their action is the same as ketoconazole.
Chemotherapy of Amebiasis
Chemotherapy of Malaria
Chemotherapy of Plasmosis
Chemotherapy of Giardiasis
ProtozoaI Infections
Are common among people in countries where sanitary conditions,
hygienic practices, and control of the vectors of transmissions are
Protozoal diseases are less easily treated than bacterial infections,
and many of the antiprotozoal drugs cause serious toxic effects in
the host, particularly on cells showing high metabolic activity.
Chemotherapy of Amebiasis
Amebiasis is an infection of the intestinal tract caused by
Entamoeba hystolytica.
Diagnosis is made by isolating E. hystolica in fresh feces.
Classification of Antiprotozoal drugs: mixed (effective against both
the luminal and systemic forms of disease), luminal (act on parasite
in the lumen of the bowel), or systemic (effective against amebae in
the intestine wall and the liver).
A. MetronidazoIe (Mixed Amebicide)
Amebiasis is generally treated with a combination of metronidazole
plus a luminal amebicidal drug such as diloxanide furoate. This
combination provides cure rates of greater than 90%.
s selectively toxic not only for amebae but also for anaerobic
Action: the nitro group of metronidazole is able to serve as an
electron acceptor, forming reduced cytotoxic compounds that bind to
proteins and DNA to result in cell death
Adverse effects: nausea, vomiting, epigastric distress, and
abdominal cramps.
B. Choroquine (Systemic Amebicide)
Used in conjunction with metronidazole and diloxanide furoate to
treat and prevent amebic liver abscesses,
t eliminates trophozoites in liver abscesses, but it is not useful in
treating luminal amebiasis.
Effective in the treatment of malaria.
Chemotherapy of MaIaria
Malaria is an acute infectious disease caused by four species of the
protozoal genus plasmodium.
!lasmodium falciparum is the most dangerous species, causing an
acute, rapidly fulminating disease characterized by persistent high
fever, orthostatic hypotension, and massive erythrocytosis.
!lasmodium vivax causes milder form of the disease.
!lasmodium malariae is common to many tropical regions.
!lasmodium ovale is rarely encountered.
A. Primaquine ( Tissue Schizonticide)
s often used in conjunction with a schizonticide.
Action: believed to act as oxidants that are responsible for the
schizonticidal action as well as for hemolysis and
methemoglobinemia encountered as toxicities.
Effective only against the exoerythrocytic(tissue) stages and not the
erythrocytic stage of malaria.
Adverse effects: drug-induced hemolytic anemia, abdominal
discomfort, granulocytopenia
B. ChIoroquine (BIood Schizonticide)
Action: kills the organism after accumulating in the organism.
t decreases DNA synthesis.
Drug of choice in the treatment of erythricytic falciparum malaria.
Adverse effects:gastrointestinal upset, pruritus, headaches, and
visual disturbances.
C. Quinine (BIood Schizonticide)
s now reserved for malarial strains resistant to other agents.
The drug can affect DNA synthesis.
Adverse effects: cinchonism (a syndrome causing nausea, vomiting,
tinnitus, and vertigo.
t should be suspended if a positive drug interactions are 1)
retardation of absorption when quinine is taken with aluminum-
containing antacids, 2)potentiation of neuro-muscular blocking
agents, and 3) elevation of digoxin levels.
C. MefIoquine (BIood Schizonticide)
Action remains to be determined, but apparently can damage the
parasite's membrane like quinine does.
Adverse effects: nausea, vomiting, and dizziness to disorientation,
hallucinations, and depression.
Electrocardiographic abnormalities and cardiac arrest are possible if
mefloquine is taken concurrently with quinine.
D. Pyrimethamine (BIood Schizonticide)
act as a strong sporonticide in the mosquito's gut when the mosquito
ingest it with the blood of the human host.
Action: inhibits plasmodial dihydrofolate reductase at much lower
concentrations than those that inhibit the mammalian enzyme.
Chemotherapy for ToxopIasmosis
nfections caused by Toxoplasma gondii,which is transmitted to
humans when they consume raw or inadequately cooked, infected
The treatment of choice is antifolate drug, pyrimethamine.
Note: appearance of rash, discontinue pyrimethamine since
hypersensitivity to this drug can be severe.
Chemotherapy for Giardiasis
Giardia lamblia is the most commonly diagnosed intestinal parasite
in the US.
t has only two life-cycle stages: the binucleate trophozoite with
flagellae, and the drug-resistant 4-nucleate cyst.
ngestion, usually contaminated drinking water, leads to infection.
Quinacrine is used in the treatment of giardiasis, but is also
effective against tapeworm and malaria.
Action: bind to membrane phospholipids, blocking phospholipase A
activity. t also bind to acetylcholine receptor.
Adverse effects: dizziness, headaches and vomiting to more serious
psychosis, urticaria,and pigmintation of the skin.
PyranteI pamoate
Elongated Roundworms
Possess a complete digestive system including a mouth and anus
Cause infections of the intestine, blood and tissues
- Synthetic Benzimidazole Compound
- DOC for infections caused by whipworm (%richuris trichura), pinworm
(Enterobius vermicularis), hookworm (Necator americanus &
Ascariasis lumbricoides)
- Acts by binding to and interfering with the synthesis of the parasite's
microtubules and also by decreasing glucose uptake
- Affected parasites are expelled with the feces
- SE abdominal pain, diarrhea
- C- pregnant women (teratogenic)
- For infections caused by roundworms, pinworms, and hookworms
- Acts as a depolarizing neuromuscular blocking agent, causing
persistent activation of the parasite's nicotinic receptors and
paralyzing the worm expelled from intestinal tract
- SE N/V/D
- Another synthetic benzimidazoles
- Effective against $trongyloides stercoralis (threadworm), cutaneous
larva migrans (creeping eruption) , & early stages of tricinosis
- Also affects microtubular aggregation
- SE: dizziness, anorexia, CNS symptoms, erythema multiforme,
Steven-Johnson syndrome
- DOC for onchocerciasis (river blindness) by nchocerca volvulus
and scabies
- Targets GABA receptors resulting in enhanced chloride influx and
hyperpolarization resulting in paralysis of the worm
- C- Meningitis px, pregnancy
- SE: Mazotti-like reaction (fever, HA, dizziness, somnolence,
Leaf-shaped flatworms
- DOC of schistosomiasis and cestode infections like cysticercosis
- ncrease permeability of CM to calcium causing contracture and
paralysis of parasite
- Rapidly absorbed after oral administration and distributes into the
- SE- drowsiness, dizziness, malaise, anorexia, G upsets
- C- pregnant and nursing mothers
True tapeworms
Flat segmented body and attach to the host's intestine
- nhibition of mitochondrial anaerobic phosphorylation of ADP which
produces usable energy in the form of ATP
- Not lethal to the ova
- Administer laxative prior to oral administration to purge the bowel of
all dead segments in order to get rid of ova
- Avoid alcohol intake
AtTlvlRAl 0Ru6S
- Obligate intracellular parasites
- Lack a CW, CM, and do not carry out metabolic processes
- nfluenza, Respiratory Syncytial Virus
- MOA: blockage of the viral matrix protein, M2, which functions as an
ion channel
- Effective on nlfluenza A
- Vaccination is preffered
- Useful for high risk patients who have not been vaccinated, or
during epidemics
- SE: insomnia, dizziness, ataxia
- C: pregnancy - teratogenic
- Synthetic guanosine analog
- Effective against broadspectrum RNA viruses
- nhibits viral mRNA synthesis
- For infants and children infected with RSV; Acute hepatitis A & B
- SE: transient anemia
- C: Pregnancy
- Cold sores, viral encephalitis, genital infections
- Gaunosine analog
- Acyclovir triphosphate competes with deoxyguanosine triphosphate
(dGTP) as a substrate for viral DNA polymerase and is incorporated
into the viral genome causing premature DNA chain termination
- Herpesviruses
- SE: HA, diarrhea, N/V, Transient renal dysfunction
- Dihydroxypropoxymethylguanine
- Acyclovir analog
- Like acyclovir, competitively inhibits viral DNA polymerase and is
incorporated into the DNA to decrease the rate of chain elongation
- SE: severe dose dependent neutropenia
- A phosphonoformate, a pyrophosphate derivative
- Only approved for tx for cytomegalic retinitis in immunocompromised
HV- infected px, especially if infection is resistant to Ganciclovir
- Reversibly inhibits viral DNA and RNA polymerases termination
chain elongation
- SE: Nephrotoxicity, anemia, nausea, fever
- Arabinofuranosyl adenine, adenine arabinoside
- One of the most effective nucleoside analogs and the least toxic
- nhibits viral DNA synthesis
- Treatment of immunocompromised px with herpes simplex keratitis or
encephalitis, or VZV nfections
- Presently there are 6 drugs approved
- Not curative but interfere in the multiplication of virus and slow
progression of the disease to prolong survival
ZIDOVUDINE (3'-Azido-3'-Deoxythymidine, AZT)
- mprovement in immunologic status has been reported
- Protection of fetuses from becoming infected
- ncorporated into the growing chain of viral DNA by reverse
transcriptae resulting in termination of DNA chain
- SE: bone marrow toxicity severe anemia and leukopenia
- Used for AZT-resistant HV infections
- Also cause termination of chain elongation
- For retroviruses- HV-1
- SE: pancreatitis
- Analog of thymidine
- Must be converted by intracellular kinases to the triphosphate
(d4TTP) which inhibits reverse transcriptase to cause DNA chain
- Also inhibits cellular enzymes reducing mitochondrial DNA synthesis
- SE : peripheral neuropathy
- Approved in conjugation with zidovudine
- Terminates the synthesis of the proviral DNA chain and also inhibits
reverse transcriptase of both HV and Hep B
- SE: pancreatitis
- Analog of deoxycytidine
- Used in conjugation with AZT or as monotherapy in px who cannot
tolerate AZT
- SE: peripheral neuropathy, pancreatitis
- Targets HV protease
- Leads to assembly of nonfunctional virions
- Saquinavir, Ritonavir, ndinavir, Nelfinavir, Amprenavir
- Frequently given in combination with zidovudine or lamivudine
- Family of naturally occuring inducible glycoproteins that interfere
with the ability of viruses to infect cells
- nterferon d,,y
- Treatment of HBV, HCV, Hairy cell leukemia, Kaposi's sarcoma
- nduction of host cell enzymes that inhibit viral RNA trnaslation
- SE: fever, letahrgy, bone marrow depression, Cardiovascular
problems, acute hypersensitiviity reacitons