Unit 3 - Cology 3

COURSE: B.
PHARMACY SUBJECT: PHARMACOLOGY-III, CODE: BP602

Module 03 CHEMOTHERAPY
COURSE: B.PHARMACY SUBJECT: PHARMACOLOGY-III, CODE: BP602 Module 03

CHEMOTHERAPY
COURSE: B.PHARMACY
SEMESTER: 6TH
SUBJECT: PHARMACOLOGY-III
CODE: BP602T
SUBJECT TEACHER: MS. KIRAN SAINI
Chemotherapy
Antitubercular agents
Antileprotic agents
Antifungal agents
Antiviral drugs
Anthelmintics
Antimalarial drugs
Antiamoebic agents
ASBASJS MEMORIAL COLLEGE OF PHARMACY, BELA Page 1

COURSE: B.PHARMACY SUBJECT: PHARMACOLOGY-III, CODE: BP602
Antitubercular Drugs
Tuberculosis is a chronic granulomatous disease and a major health problem in developing

countries. A new dimension got added in the 1980s due spread of HIV with high prevalence of
tuberculosis and Mycobact. avium complex (MAC) infection among these patients. India has a
large Load of HIV infected subjects, and these patients are especially vulnerable to severe forms
of tubercular /MAC infection
According to their clinical utility the anti-TB drugs can be divided into:
First line: These drugs have high antitubercular efficacy as well as low toxicity; are used
routinely.
Second line: These drugs have either low antitubercular efficacy or high toxicity or both;
are used in special circumstances only.
First line drugs
1. Isoniazid (H) 4. Ethambutol (E)
2. Rifampin (R) 5. Streptomycin (S)
3. Pyrazinamide (Z)
Second line drugs
1 . Thiacetazone (Tzn) Newer drugs
2. Paraaminosalicylic 1. Ciprofloxacin
acid (PAS) 2. Ofloxacin
3. Ethionamide (Etm) 3. Clarithromycin
4. Cycloserine (Cys) 4. Azithromycin
5. Kanamycin (Kmc) 5. Rifabutin
6. Amikacin (Am)
7. Capreomycin (Cpr)
Mechanism of action: Isoniazid, often referred to as INH, is a prodrug that is activated
by a mycobacterial catalase-peroxidase (KatG). Genetic and biochemical evidence has implicated
at least two different target enzymes for isoniazid within the unique Type II fatty acid
synthase system involved in the production of mycolic acids.

Antibacterial spectrum: For bacilli in the stationary phase, isoniazid is bacteriostatic, but for
rapidly dividing organisms, it is bactericidal. It is effective against intracellular bacteria.
Isoniazid is specific for treatment of M. tuberculosis, although Mycobacterium kansasii (an
organism that causes three percent of the clinical illness known as tuberculosis) may be
susceptible at higher drug levels. When it is used alone, resistant organisms rapidly emerge.
Resistance: This is associated with several different chromosomal mutations, each of which
results in one of the following: mutation or deletion of KatG (producing mutants incapable of
prodrug activation), varying mutations of the acyl carrier proteins, or overexpression of InhA.
Cross-resistance does not occur between isoniazid and other antitubercular drugs.
Rifampin (Rifampicin, R) It is a semisynthetic derivative of rifamycin B obtained from
Streptomyces mediterranei. Rifampin is bactericidal to M. tu berculosis and many other gram-
positive and gram-negative bacteria. Rifampin inhibits DNA dependent RNA
synthesis. Probably, the basis of selective toxicity is that mammalian RNA polymerase does not
avidly bind rifampin
Mechanism of action: Rifampin blocks transcription by interacting with the subunit of bacterial
but not human DNA-dependent RNA polymerase.
Pyrazinamide
Pyrazinamide is a synthetic, orally effective, bactericidal, antitubercular agent used in
combination with isoniazid, rifampin, and ethambutol. It is bactericidal to actively dividing
organisms, but the mechanism of its action is unknown.
Mechanism of action Pyrazinamide must be enzymatically hydrolyzed to pyrazinoic acid,
which is the active form of the drug. Some resistant strains lack the
pyrazinamidase. Pyrazinamide is active against tubercle bacilli in the acidic environment of
lysosomes as well as in macrophages. Pyrazinamide distributes throughout the body,
penetrating the CSF. It undergoes extensive metabolism.
Ethambutol
Ethambutol is bacteriostatic and specific for most strains of M. tuberculosis and M. kansasii.
Mechanism of action: Ethambutol inhibits arabinosyl transferase an enzyme that is important for
the synthesis of the mycobacterial arabinogalactan cell wall. Resistance is not a serious

problem if the drug is employed with other antitubercular agents. Ethambutol can be used
in combination with pyrazinamide, isoniazid, and rifampin to treat tuberculosis. Absorbed on oral
administration, ethambutol is well distributed throughout the body. Penetration into the centra
nervous system (CNS) is therapeutically adequate in tuberculous meningitis.
Streptomycin: This is the first antibiotic effective in the treatment of tuberculosis and is
discussed with the aminoglycosides. Its action is directed against extracellular organisms.
Infections due to streptomycin-resistant organisms may be treated with kanamycin or amikacin,
to which these bacilli remain sensitive.
Capreomycin: This is a peptide that inhibits protein synthesis. It is administered parenterally.

Capreomycin is primarily reserved for the treatment of multidrug-resistant tuberculosis. Careful
monitoring of the patient is necessary to prevent its nephrotoxicity and ototoxicity.
Cycloserine: is an orally effective, tuberculostatic agent that appears to antagonize the steps in
bacterial cell wall synthesis involving D-alanine. It distributes well throughout body fluids,
including the CSF. Cycloserine is metabolized, and both parent and metabolite are excreted in
urine. Accumulation occurs with renal insufficiency. Adverse effects involve CNS disturbances,
and epileptic seizure activity may be exacerbated.
Ethionamide: This is a structural analog of isoniazid, but it is not believed to act by the same
mechanism. Ethionamide can inhibit acetylation of isoniazid. It is effective after
oral administration and is widely distributed throughout the body, including the CSF. Metabolism
is extensive, and the urine is the main route.
Daily dose 3 x per week dose
DRUG mg/kg For > 50 kg mg/kg For > 50 kg
Isoniazid (H) 5 (4-6) 300 mg 10 (8-12) 600 mg
Rifampin (R) 10 (8-12) 600 mg 10 (8-12) 600 mg

Pyrazinamide (Z) 25 (20-30) 1500 mg 35 (30-40) 2000 mg

Ethambutol (E) 15 (15-20) 1000 mg 30 (25-35) 1600 mg
Streptomycin (S) 15 (12-18) 1000 mg' 15 (12-18) 1000 mg
Category I This category includes:

• New ( untreated) smear-positive pulmonaty TB.
• New smear-negative pulmonary TB with extensive parenchymal involvement.
• New cases of severe forms of extra pulmonary TB, viz . meningitis, miliary,
pericarditis, peritonitis, bilateral or extensive pleural effusion, spinal, intestinal, genitourinary
TB.
Initial phase Four drugs HRZ + E or S are given daily or thrice weekly for 2 months.
 The revised national tuberculosis control programme (RNTCP) has been launched in
India in 1997, which is implementing DOTS*. Out of the WHO recommended
regimens, the RNTCP has decided to follow thrice weekly regimen, since it is equally
effective, saves drugs and effort, and is more practical.
 The RNTCP recommends that if the patient is still sputum-positive at 2 months, the
intensive phase should be extended by another month; then continuation phase is
started regardless of sputum status at 3 months.

Antileprotic Drugs
Leprosy caused by Mycobacterium leprae, has been considered incurable Due to availability of
effective antileprotic drugs now, it is entirely curable, but deformities/ defects already incurred
may not reverse.
CLASSIFICATION
Sulfone:Dapsone (DDS)
Phenazine derivative Clofazimine
Antitubercular drugs Rifampin, Ethionamide
Other antibiotics :Ofloxacin, Minocycline,, Clarithromycin
Dapsone (DDS)
It is diamino diphenyl sulfone (DDS), the simplest, oldest, cheapest, most active and
most commonly used member of its class.
DAPSONE
Activity and mechanism Dapsone is chemically related to sulfonamides and has the same
mechanism of action, i.e. inhibition of PABA incorporation into folic acid; its antibacterial action
is antagonized by PABA It is leprostatic at low concentrations, and at relatively higher
concentrations arrests the growth of many other bacteria sensitive to sulfonamides. Specificity for
M. leprae may be due to difference in the affinity of its folate synthase.
Clofazimine (Cio)
It is a dye with leprostatic and anti-inflammatory properties; acts probably by interfering with
template function of DNA in M. leprae. When used alone, resistance to clofazimine develops in
1-3 years. Dapsone-resistant M. leprae respond to clofazimine, but apparently after a lag period
of about 2 months. Clofazimine is orally active (40-70% absorbed). It accumulates in many
tissues, especially in fat, in crystalline form. However, entry in CSF is poor. The t half is 70 days
so that intermittent therapy is possible

Two polar types-lepromatous (LL) and tuberculoid (TT) with 4 intermediate formsborderline
(BB), borderline lepromatous (BL),
For operational purposes, leprosy has been divided into:

Paucibacil/ary leprosy (PBL) (Non-infectious): This includes TT, BT, I and polyneuritic.
Multibacillary leprosy (MBL) (Infectious): This includes LL, BL and BB

Reactions in leprosy
Lepra reaction These occur in LL, usually with institution of chemotherapy and/ or intercurrent
infection. It is a Jarish Herxheimer (Arthus) type of reaction due to release of antigens from the
killed bacilli. It may be mild, severe or lifethreatening (erythema nodosum leprosum).
Sulfone syndrome It is the reaction which develops 4-6 weeks after dapsone treatment: consists of
fever, malaise, lymph node enlargement, desquamation of skin, jaundice and anaemia. It is
generally seen in malnourished patients. Lepra reaction is of abrupt onset; existing lesions enlarge,
become red, swollen and painful; several new lesions may appear. Malaise, fever and other
constitutional symptoms generally accompany and may be marked. Temporary discontinuation of
dapsone is recommended only in severe cases. Clofazimine (200 mg daily) is highly effective in
controlling the reaction (except the most severe one), probably because of its antiinflammatory
property.
Reversal reaction:This is seen in TT -is a manifestation of delayed hypersensitivity to M leprae

antigens. Cutaneous ulceration, multiple nerve involvement with pain and tenderness occur
suddenly even after completion of therapy. It is treated with clofazimine or corticosteroids.

. Module 03 CHEMOTHERAPY
Antifungal Drugs
These are drugs used for superficial and deep (systemic) fungal infections. A disquietening trend
after 1950s is the rising prevalence of more sinister type of fungal infections which are, to a large
extent, iatrogenic. These are associated with the use of broad-spectrum antibiotics,
corticosteroids, anticancer immunosuppressant drugs, dentures, indwelling catheters and
implants, and emergence of AIDS.
Many topical antifungals have been available since the antiseptic era. Two important antibiotics:
amphotericin B-to deal with systemic mycosis, and griseofulvin-to supplement attack on
dermatophytes were introduced around 1960.
CLASSIFICATION
1. Antibiotics
A. Polyenes:AmphotericinB (AMB),Nystatin, Hamycin, Natamycin (Pimaricin)
B. Heterocyclic benzofuran: Griseofulvin
2. Antimetabolite Flucytosine (5-FC)
3 Azofes
A. lmidazoles (topical): Clotrimazole,Econazole, Miconazole, Oxiconazole (systemic):
Ketoconazole
B. Triazoles (systemic): Fluconazole, Itraconazole, Voriconazole
4. Allylamine Terbinafine
5. Other topical agents Tolnaftate, Undecylenic acid, Benzoic acid, Quiniodochlor,
Ciclopirox olamine, Butenafine, Sod. thiosulfate.
POLYENE ANTIBIOTICS
The name polyene is derived from their highly double-bonded structure. Amphotericin B
is described as the prototype.
Amphotericin B (AMB)

It is obtained from Streptomyces nodosus. Chemistry and mechanism of action The polyenes
possess a macrocyclic ring, one side of which has several conjugated double bonds and is highly
lipophilic, while the other side is hydrophilic with many OH groups. Several amphotericin B
molecules bind to ergosterol in the plasma membranes ofsensitive fungal cells. There, they form
pores (channels) that require hydrophobic interactions between the lipophilic segment of the
polyene antibiotic and the sterol. The pores disrupt membrane function, allowing electrolytes
(particularly potassium) and small molecules to leak from the cell, resulting in cell death.
HETEROCYCLIC BENZOFURAN
Griseofulvin
It was one of the early antibiotics extracted from Penicillium griseofulvum. However, because of
lack of antibacterial activity, little attention was paid to it: clinical utility in dermatophytosis was
demonstrated only around 1960. Griseofulvin is active against most dermatophytes, including
Epidermophyton, Trichophyton, Microsporum.
Griseofulvin interferes with mitosis-multinucleated and stunted fungal hyphae result from its
action. It also causes abnormal metaphase configurations. However, unlike the typical mitotic
inhibitors (colchicine, vinca alkaloids), it does not cause metaphase arrest; rather the daughter
nuclei fail to move apart or move only a short distance.

Flucytosine
Flucytosine [floo-SYE-toe-seen] (5-FC) is a synthetic pyrimidine antimetabolite that is
often used in combinationwith amphotericin B. This combination of drugs is administered
for the treatment of systemic mycoses and for meningitis caused by Cryptococcus
neoformans and Candida albicans.
Mechanism of action: 5-FC enters fungal cells via a cytosine-specific permease an enzyme not
found in mammalian cells. 5-FC is then converted by a series of steps to 5
fluorodeoxyuridine 5'-monophosphate. This false nucleotide inhibits thymidylate synthase, thus
depriving the organism of thymidylic acid an essential DNA component.
Pharmacokinetics: 5-FC is well absorbed by the oral route. It distributes throughout the body
water and penetrates well into the CSF. 5-FU is detectable in patients and is probably the result
of metabolism of 5-FC by intestinal bacteria. Excretion of both the parent drug and its
metabolites is by glomerular filtration, and the dose must be adjusted in patients
with compromised renal function.
Adverse effects: 5-FC causes reversible neutropenia, thrombo-cytopenia, and dose-related bone
marrow depression.
Ketoconazole
Ketoconazole was the first orally active azole available for the treatment of systemic mycoses.
Mechanism of action: Azoles are predominantly fungistatic. They inhibit C-14 ±-demethylase
(a cytochrome P450 enzyme), thus blocking the demethylation of lanosterol to ergosterol the
principal sterol of fungal membranes This inhibition disrupts membrane structure and function
and, thereby, inhibits fungal cell growth.
For example, in addition to blocking fungal ergosterol synthesis, the drug also inhibits human
gonadal and adrenal steroid synthesis, leading to decreased testosterone and cortisol production.
Pharmacokinetics: Ketoconazole is only administered orally. It requires gastric acid for
dissolution and is absorbed through the gastric mucosa. Drugs that raise gastric pH, such
as antacids, or that interfere with gastric acid secretion, such as H2-histamine receptor blockers
and proton-pump inhibitors, impair absorption.
Adverse effects: In addition to allergies, dose-dependent gastrointestinal disturbances, including
nausea, anorexia, and vomiting, are the most common adverse effects of ketoconazole treatment.
Endocrine effects, such as gynecomastia, decreased libido, impotence, and menstrual

irregularities, result from the blocking of androgen and adrenal steroid synthesis by
ketoconazole.
Antiviral Drugs
Viruses are the ultimate expression of parasitism: they not only take nutrition from the host cell
but also direct its metabolic machinery to synthesize new virus particles. Viral
chemotherapy, therefore, is difficult, as it would require interference with cellular
metabolism in the host. However, virus directed enzymes have been identified in the infected
cell and some viruses have few enzymes of their own which may have higher affinities for
some antimetabolites or inhibitors than the regular cellular enzymes.
CLASSIFICATION
Anti-Herpes virus
Idoxuridine, Acyclovir, Valacyclovir, Famciclovir, Ganciclovir*, Foscarnet*
Anti-Retrovirus
(a) Nucleoside reverse transcriptase inhibitors (NRTis): Zidovudine ((AZT), Didanosine,
Zalcitabine*, Stavudine, Lamivudine, Abaca vir
(b) Nonnucleoside reverse transcriptase inhibitors (NNRTis): Nevirapine, Efavirenz,
Delavirdine*
(c) Protease inhibitors: Ritonavir, Indinavir, Nelfinavir, Saquinavir, Amprenavir*, Lopinavir
Anti-Influenza virus Amantadine, Rimantadine*
NonselectiVe antiviral drugs Ribavirin, Lamivudine, Adefovir dipivoxil, Interferon a * Not yet
marketed in India.

ANTI-HERPES VIRUS DRUGSModule 03 CHEMOTHERAPY
ldoxuridine It is 5-iodo-2-deoxyuridine (IUDR); acts as a thymidine analogue. It was the first
pyrimidine antimetabolite to be used as antiviral drug. It competes with thymidine, gets
incorporated in DNA so that faulty DNA is formed which breaks down easily. It is effective only
against DNA viruses.
Acyclovir
This deoxiguanosine analogue antiviral drug requires a virus specific enzyme for conversion to
the active metabolite that inhibits DNA synthesis and viral replication.
Use
1 . Genital Herpes simplex
2. Mucocutaneous H.
3. H. simplex encephalitis (type I virus):
4. H. simplex (type I) keratitis:
5. Herpes zoster
6. Chickenpox:
Adverse effects
Topical: stinging and burning sensation after each application.
Oral: The drug is well tolerated; headache, nausea, malaise and some CNS effects are reported.
Intravenous: rashes, sweating, emesis and fall in BP occur only in few patients.

Nucleoside reverse transcriptase inhibitors

(NRTis)
Zidovudine It is a thymidine analogue (azidothymidine, AZT), the prototype NRTI. After
phosphorylation in the host cell-zidovudine triphosphate selectively inhibits viral
reverse transcriptase (RNA-dependent DNA polymerase) in preference to cellular DNA
polymerase.
On the template of single-stranded RNA genome of HIV a double-stranded DNA copy is
produced by viral reverse transcriptase. Finally, viral particles are assembled and matured.
Zidovudine thus prevents infection of new cells by HIV, but has no effect on virus
directed DNA that has already integrated into the host chromosome
Non-nucleoside reverse transcriptase inhibitors (NNRTis)

Nevirapine (NVP) and Efavirenz (EFV): These are nucleoside unrelated compounds which
directly inhibit HlV reverse transcriptase without the need for intracellular phosphorylation.
Retroviral protease Inhibitors (Pis)
An aspartic protease enzyme encoded by HIV is involved in the production of structural proteins and
enzymes (including reverse transcriptase) of the virus. The large viral polyprotein is broken into
various functional components by this enzyme. This protease acts at a late step in HIV
replication, i.e. maturation of the new virus particles when the RNA genome acquires the core
proteins and enzymes. Five protease inhibitors-Indinavir (IDV), Nelfinavir (NFV), Saquinavir
(SQV), Ritonavir (RTV) and Lopinavir.
ANTI-INFLUENZA VIRUS DRUGS
Amantadine
Chemically, it is a tricyclic amine unrelated to any nucleic acid precursor, but inhibits replication
of influenza A virus (a myxovirus). It appears to act at an early step (possibly uncoating) as well
as at a late step (viral assembly) in viral replication.

Antimalarial Drugs
These are drugs used for prophylaxis, treatment and prevention of relapses of malaria.
Malaria, caused by 4 species of the protozoal parasite Plasmodium, is endemic in most parts of
India and other tropical countries.
CLASSIFICATION
4-Aminoquino/ines Chloroquine, Amodiaquine, Piperaquine.
Quinoline-methanol Mefloquine.
Cinchona alkaloid Quinine, Quinidine
Biguanides Proguanil, (Chloroguanide), Chlorproguanil
Diaminopyrimidines Pyrimethamine
8-Aminoquino/ine Primaquine, Bulaquine
Sulfonamides Sulfadoxine and sulfone Sulfamethopyrazine, Dapsone
Tetracyclines Tetracycline, Doxycycline
Sesquiterpine lactones Artesunate, Artemether, Arteether
Amino alcohols Halofantrine, Lumefantrine
Mannich base Pyronaridine
Naphthoquinone Atovaquone

CHLOROQUINE
It is a rapidly acting erythrocytic schizontocide against all species of plasmodia; controls most
clinical attacks in 1-2 days with disappearance of parasites from peripheral blood in 1-3 days.
Therapeutic plasma concentrations are in the range of 15-30 ng/ml.
The mechanism of action of chloroquine is not completely known. It is actively concentrated
sensitive intraerythrocytic plasmodia: higher concentration is found in infected RBCs. By
accumulating in the acidic vesicles of the parasite and because of its weakly basic nature,
it raises the vesicular pH and thereby interferes with degradation of haemoglobin by
parasitic lysosomes. Polymerization of toxic haeme to nontoxic parasite pigment hemozoin is
inhibited by formation of chloroquine-heme complex. Heme itself or its complex with
chloroquine then damages the plasmodial membranes

Blood schizonticide: Mefloquine

Mefloquine [MEF-lo-kween] appears to be promising as an effective single agent
for suppressing and curing infections caused by multidrug-resistant forms of P. falciparum. Its
exact mechanism of action remains to be determined, but like quinine, it can apparently damage
the parasite's membrane.
Mefloquine is absorbed well after oral administration and concentrates in the liver and lung. It has
a long half-life (17 days) because of its concentration in various tissues and its continuous
circulation through the enterohepatic and enterogastric systems. The drug undergoes extensive
metabolism. Its major excretory route is the feces.
Adverse reactions at high doses range from nausea, vomiting, and dizziness to disorientation,
hallucinations, and depression. Electrocardiographic abnormalities and cardiac arrest are possible
if mefloquine is taken concurrently with quinine or quinidine.
Blood schizonticides: Quinine and quinidine

Quinine and its stereoisomer, quinidine interfere with heme polymerization, resulting in death of
the erythrocytic form of the plasmodial parasite. These drugs are reserved for severe infestations
and for malarial strains that are resistant to other agents, such as chloroquine. Taken orally,
quinine is well distributed throughout the body and can reach the fetus. Alkalinization of the
urine decreases its excretion.
The major adverse effect of quinine is cinchonisma syndrome causing nausea, vomiting,
tinnitus, and vertigo. These effects are reversible and are not considered to be reasons for
suspending therapy. However, quinine treatment should be suspended if a positive Coombs' test for
hemolytic anemia occurs.
Drug interactions include potentiation of neuromuscular-blocking agents and elevation of
digoxin levels if taken concurrently with quinine. Quinine absorption is retarded when the drug is
taken with aluminum-containing antacids. Quinine is fetotoxic.
Blood schizonticide: Artemisinin Artemisinin is derived from the qinghaosu plant, which
has been used in Chinese medicine for more than two millennia in the treatment of
fevers and malaria. Artemisinin (or one of its derivatives) is available for the treatment of

severe, multidrug-resistant P. falciparum malaria. Its antimalarial action involves the production of
free radicals within the plasmodium food vacuole, following cleavage of the drug's endoperoxide
bridge by heme iron in parasitized erythrocytes. It is also believed to covalently bind to and
damage specific malarial proteins. Oral, rectal, and intravenous preparations are available, but the
short half-lives precludetheir use in chemoprophylaxis. They are metabolized in the liver and are
excreted primarily in the bile. Adverse effects include nausea, vomiting, and diarrhea, but
overall, artemisinin is remarkably safe. Extremely high doses may cause neurotoxicity and
prolongation of the QT interval.

ANTIAMOEBIC DRUGS
These are drugs useful in infection caused by the protozoa Entamoeba histolytica.
INTESTINAL LUMEN ULCER

(Dysentery) which occurs by faecal contamination of food and water. Amoebic cysts reaching the
intestine transform into trophozoites which either live on the surface of colonic mucosa as
commensalsform cysts that pass into the stools (luminal cycle) and serve to propagate the
disease, or invade the mucosa-form amoebic ulcers and cause acute dysentery (with blood and
mucus in stools) or chronic intestinal amoebiasis (with vague abdominal symptoms, amoeboma).
CLASSIFICATION
1. Tissue amoebicides
(a) For both intestinal and extraintestinal amoebiasis: Nitroimidazoles: Metronidazole,
Tinidazole, Secnidazole, Ornidazole, Satranidazole
Alkaloids: Emetine, Dehydroemetine
(b) For extraintestinal amoebiasis only: Chloroquine
2. Luminal amoebicides
(a) Amide : Diloxanide furoate, Nitazoxanide
(b) 8-Hydroxyquinolines: Quiniodochlor (Iodochlorohydroxyquin, Clioquinol),
Diiodohydroxyquin (Iodoquinol)

(c) Antibiotics: Tetracyclines
METRONIDAZOLE
It is the prototype nitroimidazole introduced in 1959 for trichomoniasis and later found to be a
highly active amoebicide. It has broad-spectrum cidal activity against protozoa, including
Giardia Iamblia in addition to the above two. Many anaerobic bacteria, such as Bact.
fragilis, Fusobacterium, Clostridium perfringens, Cl. difficile, Helicobacter pylori,
Campylobacter, peptococci, spirochetes and anaerobic Streptococci are sensitive.
Metronidazole is selectively toxic to anaerobic microorganisms. After entering the cell by

diffusion its nitro group is reduced by certain redox proteins operative only in anaerobic
microbes to highly reactive nitro radical which exerts cytotoxicityThe energy metabolism of
anaerobes is, thus, disrupted Metronidazole has been found to inhibit cell mediated
immunity, to induce mutagenesis and to cause radiosensitization.
Pharmacokinetics Metronidazole is almost completely absorbed from the small intestines; little
unabsorbed drug reaches the colon. It is widely distributed in the body, attaining
therapeutic concentration in vaginal secretion, semen, saliva and CSF. It is metabolized in liver
primarilyby oxidation and glucuronide conjugation, and excreted in urine. Plasma t half is 8 hrs.
Adverse effects Side effects to metronidazole are relatively frequent and unpleasant, but mostly
nonserious. Anorexia, nausea, metallic taste and abdominal cramps are the most
common. Looseness of stool is occasional.
AMIDES
Diloxanide furoate
It is a highly effective luminal amoebicide: directly kills trophozoites responsible for production
of cysts. The furoate ester is hydrolysed in intestine and the released diloxanide is
largely absorbed Diloxanide is a weaker amoebicide than its furoate ester : no systemic
antiamoebic activity is evident despite its absorption. It is primarily metabolized by
glucuronidation and is excreted in urine. Diloxanide furoate exerts no antibacterial action. It is
less effective in invasive amoebic dysentery, because of poor tissue amoebicidal action.
However, a single course produces high (80-90%) cure rate in mild intestinal amoebiasis and in
asymptomatic cyst passers.
Luminal amebicides
After treatment of invasive intestinal or extraintestinal amebic disease is complete, a
luminal agent, such as iodoquinol, diloxanide furoate, or paromomycin, should be
administered for treatment of asymptomatic colonization state.
Iodoquinol: Iodoquinol a halogenated 8-hydroxy quinolone, is amebicidal against E.
histolytica, and is effective against the luminal trophozoite and cyst forms. Side effects from
iodoquinol includerash, diarrhea, and dose-related peripheral neuropathy, including a rare
optic neuritis. Long-term use of this drug should be avoided.
Paromomycin: Paromomycin an aminoglycoside antibiotic, is only effective against the

intestinal (luminal) forms of E. histolytica and tapeworm, because it is not significantly
absorbed from the gastrointestinal tract. It is an alternative agent for
cryptosporidiosis. Although directly amebicidal, paromomycin also exerts its antiamebic actions
by reducing the population of intestinal flora. Its direct amebicidal action is probably due to the
effects it has on cell membranes, causing leakage.

ANTI HELMINTIC
Three major groups of helminths (worms) the nematodes, trematod, and cestodes ”infect
humans. As in all antibiotic regimens, the anthelmintic drugs are aimed at metabolic targets that
are present in the parasite but are either absent from or have different characteristics than those of
the host.
II. Drugs for the Treatment of Nematodes
Nematodes are elongated roundworms that possess a complete digestive system, including both a
mouth and an anus. They cause infections of the intestine as well as the blood and tissues.
A. Mebendazole
Mebendazole a synthetic benzimidazole compound, is effective against a wide spectrum of
nematodes. It is a drug of choice in the treatment of infections by whipworm (Trichuris trichiura),
pinworm (Enterobius vermicularis), hookworms (Necator americanus and Ancylostoma
duodenale), and roundworm (Ascariasis lumbricoides).
Mebendazole acts by binding to and interfering with the assembly of the parasites'
microtubules and also by decreasing glucose uptake.
Affected parasites are expelled with the feces. Mebendazole is nearly insoluble in aqueous
solution. Little of an oral dose (that is chewed) is absorbed by the body, unless it is taken
with a high-fat meal. It undergoes first-pass metabolism to inactive compounds.
Mebendazole is relatively free of toxic effects,although patients may complain of abdominal
pain and diarrhea. It is, however, contraindicatedin pregnant women because it has been shown to
be embryotoxic and teratogenic in experimental animals.
B. Pyrantel pamoate
Pyrantel pamoate along with mebendazole, is effective in the treatment of infections
caused by roundworms, pinworms, and hookworms. Pyrantel pamoate is poorly absorbed
orally and exerts its effects in the intestinal tract.
It acts as a depolarizing, neuromuscular-blocking agent, causing persistent activation of
the parasite's nicotinic receptors. The paralyzed worm is then expelled from the host's intestinal
tract. Adverse effects are mild and include nausea, vomiting, and diarrhea.

C. Thiabendazole
Thiabendazole, like the other benzimidazoles, affects microtubular aggregation. Although nearly
insoluble in water, the drug is readily absorbed on oral administration. It is
hydroxylated in the liver and excreted in the urine. The adverse effects most often encountered
are dizziness, anorexia, nausea, and vomiting. There have been reports of central nervous
system (CNS) symptomatology.
D. Ivermectin
Ivermectin [eye-ver-MEK-tin] is the drug of choice for the treatment of onchocerciasis
(river blindness) caused by Onchocerca volvulus and is a drug of first choice for cutaneous
larva migrans and strongyloides. Ivermectin targets the parasite's glutamate-gated Cl-
channel receptors.
Chloride influx is enhanced, and hyperpolarization occurs, resulting in paralysis of the worm. The
drug is given orally. It does not cross the blood-brain barrier and, thus, has no pharmacologic
effects in the CNS. However, it is contraindicated in patients with meningitis, because their
blood-brain barrier is more permeable and CNS effects might be expected.
E. Diethylcarbamazine
Diethylcarbamazine [dye-eth-il-kar-BAM-a-zeen] is used in the treatment of filariasis because of its
ability to immobilize microfilariae and render them susceptible to host defense mechanisms. It is
rapidly absorbed following oral administration with meals and is excreted primarily in the urine.
Urinary alkalosis or renal impairment may require dosage reduction. Adverse effects are primarily
caused by host reactions to the killed organisms. The severity of symptoms is related to the parasite
load and include fever, malaise, rash, myalgias, arthralgias, and headache.
III. Drugs for the Treatment of Trematodes
The trematodes (flukes) are leaf-shaped flatworms that are generally characterized by the tissues
they infect. For example, they may be categorized as liver, lung, intestinal, or blood flukes
A. Praziquantel
Trematode infections are generally treated with praziquantel. This drug is an agent of choice for the
treatment of all forms of schistosomiasis and other trematode infections and for cestode infections
like cysticercosis. Permeability of the cell membrane to calcium is increased, causing contracture
and paralysis of the parasite.

Praziquantel is rapidly absorbed after oral administration and distributes into the cerebrospinal
fluid. High levels occur in the bile. The drug is extensively metabolized oxidatively, resulting in
a short half-life. The metabolites are inactive and are excreted through the urine and bile.
Common adverse effects include drowsiness, dizziness, malaise, and anorexia, as well as
gastrointestinal upsets.
IV. Drugs for the Treatment of Cestodes
The cestodes, or tapeworms typically have a flat, segmented body and attach to the host's intestine
Like the trematodes, the tapeworms lack a mouth and a digestive tract throughout their life cycle.
A. Niclosamide
Niclosamide is the drug of choice for most cestode (tapeworm) infections. Its action has been
ascribed to inhibition of the parasite's mitochondrial phosphorylation of adenosine
diphospate, which produces usable energy in the form of adenosine triphospate. Anaerobic
metabolism may also be inhibited. The drug is lethal for the cestode's scolex and segments of
cestodes but not for the ova. A laxative is administered prior to oral administration of niclosamide.
This is done to purge the bowel of all dead segments and so preclude digestion and liberation of
the ova, which may lead to cysticercosis. Alcohol should be avoided within 1 day of niclosamide.
B. Albendazole
Albendazole is a benzimidazole that, like the others, inhibits microtubule synthesis and glucose
uptake in nematodes. Its primary therapeutic application, however, is in the treatment of cestodal
infestations, such as cysticercosis (caused by Taenia solium larvae) and hydatid disease (caused by
Echinococcus granulosis).
Albendazole is erratically absorbed after oral administration, but absorption is enhanced by a high-
fat meal. It undergoes extensive first-pass metabolism, including formation of the sulfoxide, which
is also active. Albendazole and its metabolites are primarily excreted in the urine.


Unit 3 - Cology 3

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COURSE: B.

PHARMACY SUBJECT: PHARMACOLOGY-III, CODE: BP602

COURSE: B.PHARMACY SUBJECT: PHARMACOLOGY-III, CODE: BP602 Module 03

SUBJECT TEACHER: MS. KIRAN SAINI

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Tuberculosis is a chronic granulomatous disease and a major health problem in developing

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Capreomycin: This is a peptide that inhibits protein synthesis. It is administered parenterally.

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Pyrazinamide (Z) 25 (20-30) 1500 mg 35 (30-40) 2000 mg

Category I This category includes:

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For operational purposes, leprosy has been divided into:

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Reversal reaction:This is seen in TT -is a manifestation of delayed hypersensitivity to M leprae

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Endocrine effects, such as gynecomastia, decreased libido, impotence, and menstrual

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Nucleoside reverse transcriptase inhibitors

Non-nucleoside reverse transcriptase inhibitors (NNRTis)

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Blood schizonticide: Mefloquine

Blood schizonticides: Quinine and quinidine

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INTESTINAL LUMEN ULCER

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(c) Antibiotics: Tetracyclines

Metronidazole is selectively toxic to anaerobic microorganisms. After entering the cell by

Paromomycin: Paromomycin an aminoglycoside antibiotic, is only effective against the

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