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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5265_Библиотеки_им_академика_М_И_Перельмана.pdf
Anti-infective Agents 287
Types of Tuberculosis
➢ Latent TB: In the latent TB infection, the bacteria remain in the body in an inactive state.
They cause no symptoms and are not contagious, but they can become active.
➢ Active TB: In the active TB, bacteria are active and rapidly multiplying and invading
different organs of the body, and make the person sick.
Signs and symptoms of active TB include: cough, chest pain, and pain with breathing or
coughing, fatigue, phlegm, weakness, weight loss, fever, chills and sweating at night. A person
with active pulmonary TB disease may spread TB to others by airborne transmission of infectious
particles coughed into the air.
Anti-tubercular or antimycobacterial medications are a group of drugs used to treat
tuberculosis. These drugs are used either alone or in combinations to treat Mycobacterium
infections, including tuberculosis and leprosy. Tuberculosis can be treated by taking several anti-
tubercular drugs for 6 to 9 months. These drugs include Rifampin, Isoniazid, Ethambutol,
Streptomycin, and Kanamycin.
Classification of Anti-tubercular Agents
First-line Drugs
Second-line Drugs
Third-line Drugs
Isoniazide
Rifampicin
Pyrazinamide
Ethambutol
Streptomycine
Ethionamide
Cycloserine
Para aminosalicylic acis (PAS)
Rifabutin
Rifapentine
Terizidon
Fluoroquinolones:
Moxifloxacin
Levofloxacin
Ofloxacin
Ciprofloxacin
Amikacin
Injectable:
Capreomycin
Amikacin
Kanamycin
Newer drug
Bedaquiline
Pretomanid
Amoxicillin/Clavulanate
Meropenem
Imipenem
Clarithromycin
Linezolid
Thioacetazone
Thioridazine
288 Text Book of Pharmaceutical Chemistry
11.3.1 Isoniazid
Brand Names: Isonarif, Isotamine, Isotamine B, Rifamate, Rifater
Isoniazid is a synthetic derivative of nicotinic acid. It inhibits the biosynthesis of mycolic
acids, important constituents of the mycobacterial cell wall.
IUPAC Name: 4-Pyridinecarboxylic acid hydrazide
Properties: Isoniazid appears as odorless, colorless or white crystals or white crystalline powder
with slightly sweet taste at first and then bitter. It is soluble in alcohol, chloroform; practically
insoluble in ether, benzene; and soluble in methyl ethyl ketone and acetone.
Uses: Isoniazid is a bactericidal agent, active against organisms of the genus Mycobacterium,
specifically M. tuberculosis, M. bovis and M. kansasii. It is a highly specific agent, ineffective
against other microorganisms.
➢ Isoniazid is an antimycobacterial agent is often used to treat latent and active tuberculosis
infections.
➢ It is bactericidal for both extracellular and intracellular organisms.
➢ For latent tuberculosis, it is used alone. For active TB, it is used together
Dosage Forms: The usual adult dose of INH is a single dose of 5 mg/kg/day up to a maximum of
300 mg daily (PO, IM or as a slow infusion).
➢ Powder: Oral solution: 50 mg/5 ml isoniazid syrup
➢ Tablets: 100 mg and 300 mg.
➢ Parenteral Injection: 100 mg/mL, Nydrazid (Sandoz).
Storage Conditions: It should be stored in a tight, light-resistant container. It should be protected
from freezing. Preparations should be stored below 40°C (104°C), preferably between 15°C and
30°C unless otherwise specified by manufacturer.
Officials:
➢ Isoniazide. I.P., B.P.
➢ Isoniazide Injection, B.P., U.S.P.
➢ Isoniazide Tablet, I.P., B.P.
Anti-infective Agents 289
11.3.2 Ethambutol
Brand Names: Argentina, Myambutol
Ethambutol is a derivative of ethylene diamine, i.e., ethane-1,2-diamine in which one
hydrogen attached to each of the nitrogens is substituted by a 1-hydroxybutan-2-yl group.
Structure of the ethambutol is given below:
IUPAC Name: (2S)-2-[2-[[(2S)-1-hydroxybutan-2-yl]amino]ethylamino]butan-1-ol
Properties: Ethambutol appears as white color, odorless or almost odorless, bitter taste
crystalline hygroscopic powder. Melting point is between 199°C to 204°C. It is soluble in water,
alcohol, chloroform, and methyl alcohol; and very slightly soluble in ether.
Uses:
➢ Ethambutol may be used alone or with other anti-tubercular drugs for the treatment of
extra pulmonary and pulmonary tuberculosis.
➢ Resistant strains of M. tuberculosis are readily produced if ethambutol is used alone.
It has a role as an anti-tubercular agent, an environmental contaminant and a xenobiotic.
➢ Ethambutol is used in the treatment of atypical mycobacterial infections, such as
Mycobacterium avium complex.
Mechanism of Action: Ethambutol interferes with the biosynthesis of a polysaccharide of the
mycobacterial cell wall called arabino galactan and halting multiplying bacilli.
Ethambutol works by obstructing the formation of cell wall. Mycolic acids attach to the
5'-hydroxyl groups of D-arabinose residues of arabinogalactan and form mycolyl-
arabinogalactan-peptidoglycan complex in the cell wall. It disrupts arabinogalactan synthesis by
inhibiting the enzyme arabinosyl transferase. Disruption of the arabinogalactan synthesis inhibits
the formation of this complex and leads to increased permeability of the cell wall. It is
bacteriostatic against actively growing TB bacilli.
Dosage Forms: Oral tablet (100 mg and 400 mg).
Marketed Preparations:
Drug
Brand Name
Company
Ethambutol Tablet I.P.
Combutol 800
Lupin
Ethambutol Tablet
Ethambutol Hydrochloride
Tablet, U.S.P.
STI Pharma, LLC
Storage: Ethambutol tablets should be protected from light, moisture, and excessive heat and
should be stored in well-closed containers at 15°C to 30°C.
290 Text Book of Pharmaceutical Chemistry
11.3.3 Pyrazinamide
Brand Names: Pezetamid, Rifater, Tebrazid, Unipyranamide, Zinamide
Pyrazinamide is a derivative of pyrazinoic acid amide with bactericidal property. It is the
pyrazine analogue of nicotinamide, an anti-tuberculous agent. Structure of the pyrazinamide is
given below:
IUPAC Name: Pyrazine-2-carboxamide
Properties: It occurs as a white crystalline powder, stable at room temperature. It is sparingly
soluble in water; soluble in chloroform and methylene chloride; and less soluble in benzene.
Uses: Pyrazinamide is used with other medications to treat tuberculosis (TB). Tuberculosis can
become resistant to treatment if pyrazinamide is used alone.
Dosage Form: Pyrazinamide Tablets USP contains Pyrazinamide 500 mg. They are supplied as
white, round; scored tablets debossed “VP/012”.
Orally; 15 to 30 mg/kg once daily.
Marketed Preparations:
Drug
Brand name
Company
Pyrazinamide Tablets, I.P. 750 mg
Kenamide-750
Florencia Healthcare
Pyrazinamide Tablets, I.P. 750 mg
PZA CIBA Tablet
Oaknet
Storage: Pyrazinamide tablets should be stored in well-closed containers at a temperature less
than 40°C, preferably between 15°C to 30°C.
11.3.4 p-Aminosalicylic Acid
Brand Names: Paser, Rezipas
p-aminosalicylic acid is an aminobenzoic acid that is salicylic acid substituted by an amino
group at position 4. It is practically insoluble in benzene. It is soluble in dilute nitric acid or dilute
sodium hydroxide. Melting point is 150.5ºC. The structural formula of p-aminosalicylic acid is:
IUPAC Name: 4-amino-2-hydroxybenzoic acid; PAS, 4-Aminosalicylic acid
Anti-infective Agents 291
Properties: It occurs as a white, or nearly white, bulky, reddish-brown crystalline powder,
odorless, or has slight acetous odor obtained on recrystallization from ethanol-ether. It is slightly
soluble in alcohol; freely soluble in water; and virtually insoluble in benzene, chloroform, or
carbon tetrachloride.
Mechanism of Action: There are two mechanisms responsible for aminosalicylic acid’s
bacteriostatic action against Mycobacterium tuberculosis. Firstly, aminosalicylic acid inhibits
folic acid synthesis (without potentiation with antifolic compounds). The binding of para-
aminobenzoic acid to pteridine synthetase acts as the first step in folic acid synthesis.
Uses: p-aminosalicylic acid is indicated for the treatment of tuberculosis with other anti-
tuberculosis drugs for the treatment of all forms of active tuberculosis due to susceptible strains
of tubercle bacilli. It is most commonly used in patients with Multi-drug Resistant TB (MDR-TB)
or in situations when therapy with Isoniazid and Rifampin is not possible due to a combination of
resistance and/or intolerance.
Dose: Tablet 500 mg; dose is 8-12 g daily in 2-3 doses.
Storage: Store below 59°F (15°C) in a refrigerator. Patients are urged to store PASER in a
freezer. Its packets may be stored at room temperature for short periods of time.
11.3.5 Rifampicin
Brand Names: Rimactan, Rifadin, Rifocine, Rifadin, Rimycin, Rifadine, Rofact, Rifoldine,
Rimactane, Rifampin, Rimactazide, Rifater
Rifampicin is a semi-synthetic antibiotic produced from Streptomyces mediterranei. It has a
wide spectrum of antibacterial activity against several forms of Mycobacterium. It is a
macrocyclic antibiotic commonly used in combination with other agents as therapy of
tuberculosis.
IUPAC Name: 3-[[(4-methyl-1-piperazinyl)imino]methyl)] rifamycin
Properties: Rifampicin appears as red to orange odorless crystalline powder. It is very slightly
soluble in water acetone, carbon tetrachloride, ethanol, and ether; freely soluble in chloroform
and (DMSO); and soluble in ethyl acetate, methanol and tetrahydrofuran. It has a melting point of
138°C to 188°C. Rifampicin has a complex structure. It exists as various combinations of form I,
form II, and amorphous, solid-state. The antibacterial activity of rifampicin is due to its inhibition
of transcription.
292 Text Book of Pharmaceutical Chemistry
Uses: Rifampicin is used for treatment of tuberculosis (pulmonary and extrapulmonary) and for
leprosy. It is also indicated for elimination of Neisseria meningococci in carriers (but not
recommended for active meningococcal infection), and for gram positive (Staphylococcus aureus
and epidermidis, Streptococcus pyogenes, viridans and pneumoniae) and gram negative bacteria
(Haemophilus influenzae type B).
Dosage Forms and Strengths:
➢ Capsule: 150 mg, 300 mg
➢ Injectable powder: 600 mg
Rifampin 1% Nasal Drop (100g) Ingredients
Rifampin 1 gm
Hydroxymethylcellulose 1.25 gm
Polysorbate-80 300 mg
Ascorbic acid 100 mg
Sodium sulphite 400 mg
Purified water q.s.
Marketed Preparations:
Drug
Brand Name
Company
Rifampicin and Isoniazid Tablets
450 mg + 300 mg
RIWELL-IS
Wellona Pharma Pvt. Ltd.
Rifaximin 550 mg Tablet
Rcifax 550 mg
Lupin
Storage: Store at temperature not exceeding 40°C (preferably between 15°C to 30°C) in airtight
containers in an atmosphere of nitrogen.
11.3.6 Bedaquiline
Brand Name: Sirturois
Bedaquiline is a quinoline-based diaryl quinoline antimycobacterial drug used in combination
with other antituberculosis medications in the treatment of multi-drug resistant tuberculosis.
Anti-infective Agents 293
IUPAC Name: (1R, 2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-naphthalen-
1-yl-1-phenylbutan-2-ol
Uses: Bedaquiline is used (as its fumarate salt) for the treatment of pulmonary multi-drug
resistant tuberculosis. It is active against both Mycobacterium tuberculosis and the drug-resistant
TB bacteria that cause MDR-TB.
Mechanism of Action: Bedaquiline (BDQ) inhibits the proton pump of mycobacterial ATP
(adenosine 5'-triphosphate) synthase, an enzyme that is essential for the generation of energy in
Mycobacterium tuberculosis is bactericidal.
Dosage Forms: Tablet; 20 mg (functionally scored), 100 mg
11.3.7 Delamanid
Brand Name: Deltyba
Delamanid is a nitro-dihydro-imidazooxazole class of compounds and have antimycobacterial
activity. It has been developed by Otsuka Pharmaceutical for the treatment of multi-drug resistant
tuberculosis. It is a nitroimidazo-oxazole antimycobacterial prodrug that is activated through
bioreduction of its nitro group by Mycobacterium tuberculosis.
IUPAC Name: (2R)-2-methyl-6-nitro-2-[[4-[4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl]
phenoxy]methyl]-3H-imidazo [2,1-b][1,3]oxazole
Mechanism of Action: Delamanid is a prodrug, activated via the mycobacterial F420 coenzyme
system to form a reactive intermediate metabolite that inhibits the synthesis of the mycobacterial
cell wall components methoxy-mycolic and keto-mycolic acid.
Uses:
➢ Delamanid is given to person with tuberculosis and which is resistant to at least isoniazid
and rifampicin drugs.
➢ It is a novel agent for the treatment of pulmonary multi-drug resistant Mycobacterium
tuberculosis infections, in combination with other agents.
Dosage Forms:
➢ Pulmonary multi-drug resistant tuberculosis.
➢ Adult: 100 mg bid for 24 weeks, in combination with other drug.
294 Text Book of Pharmaceutical Chemistry
Storage: It should be stored in a tight light-resistant container with an expiration date not to
exceed 3 months. Store at 25°C; excursions permitted to 15°C to 30°C.
11.3.8 Pretomanid
Brand Name: Pretomanid
Pretomanid is a nitroimidazole-based antibiotic used for the treatment of multi-drug resistant
pulmonary tuberculosis. It prevents the growth of tuberculosis in the body. The structural formula
of Pretomanid is as follows:
IUPAC Name: (6S)-2-nitro-6-[[4-(trifluoromethoxy) phenyl] methoxy]-6,7-dihydro-5H-imidazo
[2,1-b][1,3]oxazine
Properties: Pretomanid is a white to off-white oval shaped, immediate-release, uncoated tablet,
debossed with M on one side and P200 on the other side, containing 200 mg Pretomanid.
Uses: Pretomanid FGK is indicated as a part of combination dosing regimen in combination with
Bedaquiline and Linezolid, in adults, for the treatment of pulmonary extensively drug resistant
(XDR), or treatment-intolerant or non-responsive multi-drug resistant (MDR) tuberculosis (TB).
Dosage Form: Pretomanid tablets, 200 mg, are white to off-white oval tablets debossed with M
on one side and P200 on the other side.
Storage: 200 mg tablet is packed in either white, round, high-density polyethylene bottles with
polypropylene child-resistant closure or child-resistant blister packages comprised of a
polyvinylchloride film with foil and paper backing.
11.4 ANTIVIRAL AGENTS
Virus is a small (microscopic), infectious agent that can only multiply in living cells of
animals, plants, or bacteria. The simplest virus contains a piece of genetic material, such as DNA
or RNA that is enclosed in a coat of protein called a ‘Capsid’. Sometimes, the capsid is
surrounded by an additional spikey coat called the envelope. Viruses are capable of latching onto
host cells and getting inside them.
A viral infection is the growth and multiplication of a harmful virus within the body. The
symptoms of the viral infection are caused by tissue damage and the host’s immunological
response.
Anti-infective Agents 295
Antiviral Agents
Antiviral are medications that are approved by the (FDA) for the treatment or control of viral
infections. Available antiviral agents mainly target stages in the viral life cycle. Antiviral agents
are also preventive. These drugs can protect the person from getting viral infections or spreading
a virus to others.
Classification of Antiviral Agents
I. Based on mode of action:
1. DNA Polymerase Inhibitors –
➢ Purine Nucleoside Analogues (interfere with viral nucleic acid replictation) –
Acyclovir, Ganciclovir, Famiciclovir, Valacyclovir, Penciclovir, Cidofovir
➢ Pyrimidine Nucleoside Analogues – Idoxuridine
➢ Non-nucloside Foscarnet
2. Inhibitors of Viral Penetration Uncoating – Amantadine, Rimantadine
3. m-RNA Synthesis Inhibitors – Ribvirin, Fomivirsen
4. Neuraminidase Inhibitors – Zanamivir, Oseltamivir
5. Immunomodulators – Immunoglobulins, Interferns, Palivizumab, Imiquimod
II. Based on inhibition of viruses:
1. Anti-herpes – Acyclovir, Valacyclovir, Ganciclovir, Penciclovir, Cidofivir, Fomivirsen,
Idoxuridine Trifluridine, Docosanol
2. Anti-influenza – Amantadine, Rimantadine, Oseltamivir, Zanamivir
3. Anti-hepatitis – Adefovir, Ribavirin, Lamivudin, Palivizumab
4. Anti-retroviral – Zidovudine, Stavudine, Didanosine, Lamivudine, Zalcitabine,
Efavirenz, Nevirapine Delavirdine, Tenofovir, Saquinavir, Indinavir, Nelfinavir,
Lopinavir
11.4.1 Amantadine Hydrochloride
Brand Names: Symadine, Gocovri, Osmolex ER, Symmetrel
Amantadine is a member of the class of adamantanes, a synthetic tricyclic amine with
antiviral, antiparkinsonian, and antihyperalgesic activities. Amantadine hydrochloride is the
hydrochloride salt of amantadine. It is a primary aliphatic amine and a conjugate base of
an adamantan-1-aminium. It derives from a hydride of an adamantane.
296 Text Book of Pharmaceutical Chemistry
IUPAC Name: adamantan-1-amine; hydrochloride
Properties: Amantadine hydrochloride is a stable white or nearly white, odorless and bitter taste
crystalline powder. It is freely soluble in water; soluble in alcohol and chloroform; and practically
insoluble in ether. Its melting point is > 360°C.
Uses:
➢ Amantadine is indicated in the treatment of idiopathic Parkinsonism (paralysis agitans
and shaking palsy) and post-encephalitic Parkinsonism.
➢ It is used for the chemoprophylaxis, prophylaxis, and treatment of signs and symptoms of
infection caused by various strains of influenza A virus.
➢ It is used in the management of certain aspects of fatigue associated with multiple
sclerosis.
Mechanism of Action: Amantadine hydrochloride inhibits penetration of RNA viral particles
into the host cell. It also inhibits the early stages of viral replication by blocking the uncoating of
the viral genome and the transfer of nucleic acid into the host cell.
Storage: Store the drug in a closed container at room temperature, away from heat, moisture, and
direct light. Protect from freezing.
Officials:
➢ Amantadine Hydrochloride, I.P.
➢ Amantadine Hydrochloride Capsule, I.P.
11.4.2 Idoxuridine
Brand Names: Dendrid, Herplex, Stoxil
Idoxuridine is an iodinated thymidine analogue. It is a topical antiviral medication used to
treat viral infections of the eye. It comes as eye drops. It is a pyrimidine 2'-deoxyribonucleoside,
an iodinated analogue of deoxyuridine, with antiviral activity against herpes simplex virus (HSV)
and potential radio-sensitizing activities. The triphosphorylated metabolite of idoxuridine inhibits
both viral and cellular DNA synthesis, and is also incorporated into DNA.
IUPAC Name: 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodopyrimidine-2,4-
dione