NOTRE DAME OF DADIANGAS UNIVERSTY (NDDU)

College of Pharmacy
COURSE TITLE PHARMACOLOGY II COURSE CODE Pharm36
Course Placement 3rd yr, 1st SEM CONTACT HOURS 3 hours/week, 54 hours/sem
Date for this topic 2020 Sept. 21 SME: Melba M. Roma, RPh, MSPh
MODULE 4: PHARMACOLOGY OF AGENTS THAT TARGET PATHOGENIC
ORGANISMS
Reading Assignment: Katzung , B.G., Basic Clinical Pharmacology, 14th ed. Section VIII
Online resources: http://www.chem.uzh.ch/zerbe/MedChem/MedChem9_Antibac.pdf

Content Demonstrate knowledge and understanding on the classification of

Standards antimicrobial agents.

Functional Identify the antibacterial agents:

Knowledge a. cell wall inhibitors
b. cell membrane inhibitors
c. other cell-wall or membrane-active agents
d. protein synthesis inhibitors
e. antimycobacterial agents

Introduction

(Flip) Vid watch: https://www.youtube.com/watch?v=IVBCrzjOl40

Bacteria are simple one‐celled organism, which were first identified in the 1670s by van
Leeuwenhoek. Though small, bacteria are powerful and complex, and they can survive in
extreme conditions. Bacteria have a tough protective coating that boosts their resistance to
white blood cells in the body.

Bacteria reproduce by binary fission. In this process the bacterium, which is a single cell, divides
into two identical daughter cells. Binary fission begins when the DNA of the bacterium divides
into two (replicates). The bacterial cell then elongates and splits into two daughter cells each
with identical DNA to the parent cell. Each daughter cell is a clone of the parent cell.

Classification of Anti‐Bacterial Agents and Their Functions

1. Classification based on type of action.
Generally, antibacterials can be classified on the basis of type of action: bacteriostatic and
bactericidal. Antibacterials, which destroy bacteria by targeting the cell wall or cell membrane
of the bacteria, are termed bactericidal and those that slow or inhibit the growth of bacteria
are referred to as bacteriostatic.

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2. Classification based on source of antibacterial agents.
Antibacterials are the subclass of antibiotics, which can be naturally obtained from fungal
sources, semi‐synthetic members which are chemically altered natural product and or
synthetic. Cephalosporins, cefamycins, benzylpenicillin, and gentamicin are well‐known
examples of natural antibiotics/antibacterials; they often exhibit high toxicity than synthetic
antibacterials. Ampicillin and amikacin are semi‐synthetic antibiotics, which were developed to
show low toxicity and increase effectiveness. Synthetic antibiotics are also designed to have
even greater effectiveness and less toxicity and, thus, have an advantage over the natural
antibiotics that the bacteria are not exposed to the compounds until they are released.
Moxifloxacin and norfloxacin are promising synthetic antibiotics

3. Classification based on spectrum of activity.

In this category, the antibacterials may be either narrow or broad spectrum. The narrow
spectrum antibacterials are considered to be those which can work on a narrow range of
microorganisms, that is, they act against Gram‐positive only or Gram‐negative only bacteria,
while broad spectrum antibacterial affects a wide range of pathogenic bacteria, including both
Gram‐positive and Gram‐negative bacteria. Usually, the narrow spectrum antibacterials are
considered ideal antibacterials and are preferred over the broad‐spectrum antibacterials.

4. Classification based on chemical structure

Different skeleton‐containing antibiotics display different therapeutic behaviour; therefore, it is
an ultimate need to classify antibacterials on the basis of their chemical structure. This
classification is also very important as similar structural units have similar patterns of toxicity,
effectiveness, and other related properties. Usually on a structural basis, antibacterials have
been classified into two groups: group A (β‐lactams) and group B (aminoglycosides). However,
in a more elaborated way, the antibacterials can be classified into β‐lactams, β‐lactam/β‐
lactamase inhibitor combinations, aminoglycoside, macrolides, quinolones, and
flouroquinolones.

5. Function‐based classification of antibacterial drugs

Function means how a drug works or what is its mode of action. This is one of the most
important factors related to each antibacterial. Bacterial growth undergoes major processes or
functions; these are cell wall synthesis, cell membrane function, protein synthesis, nucleic
acid synthesis, and so on. All such processes are targets for antibiotics; therefore,
antibacterials, which interfere or disturb these processes in different ways, can be subdivided
into four groups: such as cell wall synthesis inhibitors, inhibitors of membrane function,
inhibitors of protein synthesis, and inhibitors of nucleic acid synthesis.

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ANTIBACTERIAL AGENTS
(Flip) Vid watch: (series)
1. https://www.youtube.com/watch?v=omovOv3DFz8
2. https://www.youtube.com/watch?v=Q2B35HB78bE
3. https://www.youtube.com/watch?v=bViytsc7vnQ
4. https://www.youtube.com/watch?v=OZSXXTNfpqs
Adverse effects: https://www.youtube.com/watch?v=5HQmvQJWzNY

A. Cell Wall Inhibitors

Structurally, the bacterial cell wall is different from that of all other organisms by the presence
of polysaccharide backbone, called peptidoglycan. The most important process for avoiding
bacterial growth is to stop cell wall synthesis by inhibiting the peptidoglycan layer of bacterial
cell walls. The agents used to work against this function are called cell wall synthesis inhibitors
and the cell wall of new bacteria growing in the presence of these agents is deprived of
peptidoglycan.

B. Cell Membrane Inhibitors

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The cytoplasmic membrane, which covers the cytoplasm, serves as a selective barrier and
controls the internal composition of the cell. Whenever these functional roles of the
cytoplasmic membrane get disturbed, macromolecules and ions will outflow, which will result
in cell destruction or death. Additionally, changes like discharge of the molecules from interior
of the cell, inhibition of respiration, and increased water uptake lead to the cell death.

C. Protein synthesis inhibitors

Protein synthesis is one of the most important functions in the bacterial cell and humans as
well. Therefore, to cure infectious disease caused by pathogenic bacteria, it is the most
important target for the drugs, which are called protein synthesis inhibitor antibiotics. Since
both human and bacterial cells synthesize proteins, due to the slow synthesis of human
proteins, it has remained a comfortable task for the development of the selective antibiotics.
Only the side effects from toxicity and resistance phenomenon are taken seriously during
antibiotic development. Mechanistically, protein synthesis inhibitors act to disturb any stage of
the protein synthesis such as initiation and elongation stages.

D. Inhibition of nucleic acid synthesis

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One of the most important targets for antibiotic to cure infectious diseases is nucleic acid
synthesis, and the antibiotics used are called nucleic acid synthesis inhibitors. The
antibacterials of this class can be subdivided into DNA inhibitors and RNA inhibitors. RNA
inhibitors interfere with the bacterial transcription process in which messenger RNA transcripts
of genetic material are produced for later transformation into proteins. DNA synthesis is also
achieved by initiation, elongation, and termination stages; therefore, antibacterial drugs target
any one of these processes to inhibit DNA synthesis.

E. Antimycobacterial agents
Antimycobacterial antibiotics are a class of antimicrobial drugs that target mycobacterium, a
genus of Actinobacteria that includes pathogens known to cause serious and infectious disease.
The types of pathogens considered to be mycobacterium include Mycobacterium tuberculosis
(tuberculosis) and Mycobacterium leprae (leprosy). Mycobacterium grow in a mold-like
manner on the surface of liquids when cultured. Antiomycobacterial antibiotics specifically
target these types of microbes.

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Page 6 of 23
 Side effects of antibiotics
Allergic reactions All antibiotics, predominantly penicillins
Nephrotoxicity Aminoglycosides, cephalosporins
Ototoxicity Aminoglycosides
Dysbiosis Cephalosporins, penicillines, Macrolides
Pseudomembranous colitis Penicillins, cephalosporins
Hepatotoxicity Tetracyclines, cephalosporins
Cholistasis Macrolides
Leucopoesis supression Chloramphenicol
Osteogenesis disturbances Tetracyclines, lincomycin
ANTIFUNGAL AGENTS

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(flip) vidwatch: https://www.youtube.com/watch?v=uU_OeL40E-E

Fungal Infections
http://courses.washington.edu/medch401/pdf_text/401_06_VI_Antifungal.pdf

Fungal infections are caused by microscopic organisms that can invade the epithelial tissue.
The fungal kingdom includes yeasts, molds, rusts and mushrooms. Most fungi are beneficial
and are involved in biodegradation, however, a few can cause opportunistic infections if they
are introduced into the skin through wounds, or into the lungs and nasal passages if inhaled.

Diseases caused by fungi include superficial infections of the skin by dermatophytes in the
Microsporum, Trichophyton or Epidermophyton genera. These dermophytic infections are
named for the site of infection rather than the causative organism. Systemic infections are
caused by the inhalation of spores and cause fungal pneumonia. This pneumonia cannot be
transmitted from human to human. These infections can occur in otherwise healthy individuals.
Many of the organisms that cause systemic fungal infections are confined to specific geographic
locations due to favorable climates for their proliferation.

Organisms that cause opportunistic infections will not gain a foothold in healthy individuals, but
in the immunocompromised they can cause serious, sometimes life-threatening infections.
Patients especially susceptible to these infections include individuals with leukemia and other
blood diseases, cancer, HIV and other immunodeficiencies, and diabetes.

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Antifungal Agents

1. AMPHOTERICIN B Class of Antifungal: Polyene

Mechanism of Action: Binds to ergosterol in fungal membrane causing membrane to become
leaky.
Products
a. Fungizone (Bristol Myers Squibb) 50 mg/vial with 41mg of sodium deoxycholate.
Several months of therapy is usually needed.
b. Abelcet (Liposome Co.) 1:1 mixture of amphotericin and lipid complex, 100 mg/20 ml.
Rationale for this lipid preparation is that amphotericin B should have a greater affinity
for the lipid vehicle than for cholesterol in cell membranes, thus lower toxicity
c. Aphotec (Sequus Pharmaceuticals) cholesterol colloidal dispersion, 50 or 100 mg/20 ml.
Supplied in variety of topical forms including a 3% cream, lotion or ointment and
100mg/mL oral suspension to treat cutaneous and mucocutaneous mycoses caused by
Candida albicans
d. AmBiosome (Fujisawa) liposomal, 50mg/vial.

2. NYSTATIN Class of Antifungal: Polyene

Mechanism of Action: Binds to ergosterol in fungal membrane causing membrane to
become leaky
Indications: Nystatin was originally isolated from Streptomyces noursei in 1951. A
conjugated tetraene, it was the first clinically useful polyene antifungal antibiotic.
Products
a. Mycostatin ® and other generic products.

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3. NATAMYCIN (Pimaricin, Natacyn) Class of Antifungal: Polyene
Mechanism of Action: Binds to ergosterol in fungal membrane causing membrane to
become leaky
Indications: Natamycin was first isolated from cultures of Streptomyces natalensis
suspension intended for the treatment of fungal conjunctivitis, blepharitis and keratitis.
Products
Natamycin is supplied as a 5% ophthalmic suspension intended for the treatment of fungal
conjunctivitis, blepharitis and keratitis.
Adverse Effects: Eye irritation, redness and swelling not present prior to use.

4. Azoles and Triazole Antifungal Agents: Ergosterol Biosynthesis Inhibitors

Azole antifungal agents are the largest class of synthetic antimycotics. About 20 agents on
the market today. Some used topically to treat superficial dermatophytic and yeast
infections. Others used systemically to treat severe fungal infections. Antifungal activity
stems from the presence of an aromatic five member heterocyclic, either an imidazole or a
triazole. The first members of the class were highly substituted imidazoles (clotrimazole,
miconazole) were not absorbed orally. Ketoconazole introduced in 1984 was the first
effective oral therapy for Candida.

Mechanism of Action: These imidazoles and triazoles inhibit CYP P450 14 α- demethylase in
fungi. This enzyme is involved in the conversion of lanosterol to ergosterol.
Five azole antifungals, miconazole, econazole, oxiconazole, sulconazole and tioconazole
are used in topical application only.
a. MICONAZOLE (developed by Janssen Pharmaceutica) is used for skin infections such as
tinea pedis, tinea cruris and vulvovaginitis. It comes in cream, lotion, powder, spray liquid
and spray powder, and also in suppository form for vaginal use. Miconazole is used once
or twice a day for one month for tinea pedis or two weeks for other skin infections. For
vaginal infections it is used once a day at bedtime for three or seven days.
Adverse effects include: increased burning, itching or irritation of the skin or vagina,
stomach pain, fever or foul-smelling vaginal discharge.
Products: Micatin, Monistat-3, Monistat-7, Monistat-Derm, Monistat Dual-Pak.

b. ECONAZOLE (developed by Janssen Pharmaceutica) is a topical cream applied to the skin

to treat fungal infections including: tinea corporis, tinea pedis, tinea cruris, and
superficial candidiasis.
Adverse effects include: Burning, itching, stinging, redness and skin rash.
Products: Spectrazole, Ecostatin

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c. OXICONAZOLE (developed by F. Hoffmann-LaRoche and Siegfried AG) is a cream or lotion
applied to the skin in the treatment of tinea corporis, tinea pedis and tinea cruris.
Adverse effects include: Burning, itching, blistering, crusting, dryness or flaking of the
skin, scaling, severe redness, soreness, swelling and pain in hairy areas with pus at the
root of hair.
Products: Oxistat, Oxizole

d. SULCONAZOLE (developed by Syntex Research) is a topical cream or solution to treat

tinea corporis, tinea pedis and tinea cruris.
Adverse effects include: Burning, stinging, itching and redness of the skin.
Products: Exelderm

e. TIOCONAZOLE (developed by Pfizer U.K.) is a cream to treat tinea corporis, tinea pedis,
tinea cruris and cutaneous candidiasis.
Adverse effects include: Burning, itching, redness, skin rash and swelling.
Products: Trosyd AF, Trosyd J

f. KETOCONAZOLE is supplied as a cream or in shampoos at one- or two-percent, for the

treatment of tinea pedis, tinea corporis, tinea cruris and cutaneous candidiasis.
Adverse effects include: itching, stinging, skin rash, dry skin, and dry or oily scalp.
Products: Nizoral Cream, Nizoral A-D Shampoo (1%), Nizoral Shampoo (2%)

g. ITRACONAZOLE is taken orally in capsule form to treat fungal infections that start in the
lungs and spread throughout the body. Itraconazole can also be used to treat fungal
infections of the nails, although it is important to point out that treatment of nail fungal
infections does not result in healthier looking nails. Normal nail appearance will occur
only with new growth, which can take up to six months for full nail growth. Oral solutions
of this antifungal agent can be used to treat oral candidiasis.
Drug Interactions: Patients on proton pump inhibitors should take itraconazole with a
cola soft drink to aid in bioavailability.
Adverse effects include: diarrhea, constipation, gas, stomach pain, heartburn, sore or
bleeding gums, sores in and around the mouth, headache, dizziness, sweating, muscle
pain, decreased sexual desire or ability, nervousness, depression and runny nose. More
severe side effects can include: excessive tiredness, loss of appetite, upset stomach,
vomiting, tingling or numbness in the extremities, fever, chills, rash, hives and difficulty
breathing or swallowing. HEPATOXICITY: yellowing of the eyes or skin, dark urine or pale
stools.
Product: Sporanox

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h. FLUCONAZOLE is a one-a-day tablet or suspension to treat yeast infections of the vagina,
mouth, throat, esophagus, abdomen, lungs, blood and other organs. Fluconazole is also
used to treat meningitis and can prevent yeast infections in patients who are likely to
become infected due to chemotherapy or radiation therapy before a bone marrow
transplant.
Adverse effects include: headache, dizziness, diarrhea, stomach pain, heartburn and
changes in the ability to taste food. More severe side effects can include: excessive
tiredness, loss of appetite, upset stomach, vomiting, tingling or numbness in the
extremities, fever, chills, rash, hives and difficulty breathing or swallowing.
HEPATOXICITY: yellowing of the eyes or skin, dark urine or pale stools.
Product: Diflucan

i. VORICONAZOLE is formulated in an oral suspension, tablets or parenteral injection. It is

used to treat different kinds of serious fungal infections and may be used in patients who
have not responded to other antifungal agents.
Drug interactions: Xanax, Versed, Halcion, Agenernase, Viracept, Invirase, Hismanal,
barbiturates, cyclosporine, ergot alkaloids, HMG CoA reductase inhibitors and warfarin.
Adverse effects include: rash, bloating or swelling of face, arms, hands, lower legs or
feet, stomach pain, blurred vision, chills, convulsions, dizziness, dry mouth, headache and
muscle pain. HEPATOXICITY: dark urine or pale stools.
Product: VFEND

j. BUTOCONAZOLE is a cream suppository used to treat vulvovaginitis. It is used either

once or in a seven-day regimen at bedtime.
Adverse effects include: burning or irritation in the vagina when cream is inserted,
stomach pain,fever or foul-smelling vaginal discharge.
Product: Gynazole-1

k. TERCONAZOLE is supplied as a cream or suppository to treat vulvovaginitis. It is usually

used daily at bedtime for either three or seven days.
Adverse effects include: headache, missed menstrual periods, burning or irritation in
vagina when cream or suppository is inserted, stomach pain, fever, or foul-smelling
vaginal discharge.
Product: Terazol 3, Terazol 7.

l. POSACONAZOLE (Schering-Plough) is a novel triazole in Phase II clinical trials to be used

as an oral suspension to treat invasive fungal infections caused by Candida and
aspergillus.

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Antifungal Agents Targeting Squalene Epoxidase: Ergosterol Biosynthesis Inhibitors
The allylamines have a more limited spectrum of activity than the azoles and triazoles and
are only effective against dermatophytes. They are employed in the treatment of fungal
infections of the skin and nails.
Mechanism of Action: These antifungal agents are reversible, noncompetitive inhibitors of
the first step in ergosterol biosynthesis; the conversion of squalene to squalene-2,3- epoxide
by squalene epoxidase. The buildup of squalene in the cell membrane is toxic to the cell,
causing pH imbalances and malfunction of membrane bound proteins.
a. TERBINAFINE comes as a tablet to take orally or as a topical cream It is used to treat
fungal infections of the nails.
Drug interactions: warfarin, antidepressant drugs, beta-blockers, proton pump inhibitors
and drugs to suppress the immune system.
Adverse effects include: headache, dizziness, diarrhea, stomach pain, heartburn and
changes in the ability to taste food.
More severe side effects can include: excessive tiredness, loss of appetite, upset
stomach, vomiting, tingling or numbness in the extremities, fever, chills, rash, hives and
difficulty breathing or swallowing. HEPATOXICITY: yellowing of the eyes or skin, dark
urine or pale stools.
Product: Lamisil

b. TOLNAFTATE is a topical cream to treat tinea infections of the skin.

Mechanism of Action: The exact mechanism unknown; however, it has been reported to
distort the hyphae and to stunt mycelial growth in susceptible organisms. Inhibition of
squalene epoxidation has also been reported.
Adverse effects are rare. Skin irritation has been reported.
Products:Aftate, Tinactin, Ting, Breezee

Other Antifungals Affecting Cell Membrane Stability

CICLOPIROX is a topical solution used to treat fungal infections of the nails and hair. It is
a broad-spectrum antifungal medication that also has antibacterial and anti-
inflammatory properties.
Mechanism of Action: Its main mode of action is thought to be its high affinity for
trivalent cations, which inhibit essential co-factors in enzymes.
Adverse effects: redness, irritation, burning, blistering or swelling at the site of
application and discoloration of the nails or surrounding area. Treated nails may become
ingrown.
Product: Loprox, Penlac nail lacquer

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 Inhibitors of Cell Division
a. GRISEOFULVIN is an antifungal produced from Penicillium griseofulvin. Therapy must
continue until new tissue replaces old diseased tissue. When given orally, plasma-borne
griseofulvin becomes incorporated into keratin precursor cells and ultimately into
kearatin that cannot support fungal growth.
Mechanism of Action: Griseofulvin inhibits microtubule polymerization thus inhibiting
the formation of the mitotic spindle.
Adverse effects: Headache is a common adverse effect. May cause aplastic anemia.
Being gradually replaced by newer agents.
Products: Fulvicin-U/F, Grifulvin V, Gris-PEG

Cell Wall Inhibitors

a. UNDECYLENIC ACID is widely used topically as the zinc salt in OTC preparations for
topical treatment of infections by dermatophytes.
Mechanism of Action: This organic acid will interact non-specifically with components in
the cell membrane. It can be used in concentrations up to 10% in solution, powder and
emulsions. Traditionally used for athlete’s foot (tinea pedis) although cure rates are low.
Adverse effects are rare. Skin irritation has been reported.
Products: Desenex, Cruex, Decylenes Powder, Caldesene, Gordochom Solution
Summary of drug–drug interactions for systemic antifungal agents
 Amphotericin B has few significant drug–drug interactions. The main concerns arise from
drugs with the potential for additive nephrotoxicity.
 Absorption of 2 triazole formulations—the itraconazole oral capsules and the posaconazole
oral solution—is affected by gastric acidity. Medications that alter gastric pH, such as
proton pump inhibitors and histamine-2 blockers, should be avoided.
 The azole drugs act as substrates and inhibitors of the CYP450 enzymes (CYP3A4, CYP2C19,
CYP 2C9) and the affinities for each enzyme vary significantly by individual drug.
 Given the hundreds of potential drug–drug interactions for azoles, a patient’s medication
list should be carefully examined with initiation and discontinuation of azoles.
 Some of the common drug–drug interactions for azoles include antiarrhythmics,
antipsychotics, immunosuppressants, migraine medications, antibiotics, anticoagulants,
antidepressants, antiepileptics, antiretrovirals chemotherapeutics, antihypertensives,
lipidlowering agents, narcotics, sedatives, hormonal therapies, and medications for
diabetes.

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ANTIVIRAL AGENTS
(Flip) Vid watch:
https://www.youtube.com/watch?v=DLTbpTXox08
MOA- https://www.youtube.com/watch?v=IOXEAAHmzT4&ab_channel=AlilaMedicalMedia

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CORONAVIRUS infection and test
(Flip) vidwatch
https://www.youtube.com/watch?v=j4Xiow30bGo
https://www.youtube.com/watch?v=akiXEfWW-V0

HIV/AIDS infection and REPLICATION

(Flip ) Vidwatch:
https://www.youtube.com/watch?v=ng22Ucr33aw
https://www.youtube.com/watch?v=hdgNnXLY8LU

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ANTI HIV DRUGS
https://www.youtube.com/watch?v=a-D43q_URkE
Vidwatch https://www.youtube.com/watch?v=VLEe5A74evo

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HIV treatment involves taking medicines that slow the progression of the virus in your body.
HIV is a type of virus called a retrovirus, and the combination of drugs used to treat it is called
antiretroviral therapy (ART).
Retroviruses are a type of virus in the viral family called Retroviridae. They use RNA as their
genetic material and are named for a special enzyme that's a vital part of their life cycle —
reverse transcriptase.

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 Antiparasitic Agents: Antiprotozoals, Anthelmintics and Others
https://www2.med.wayne.edu/elab/lectures/mic01web/lecture/kerns/antpar.pdf

Protozoa are single celled organisms. They come in many different shapes and sizes ranging
from an Amoeba which can change its shape to Paramecium with its fixed shape and complex
structure. They live in a wide variety of moist habitats including fresh water, marine
environments and the soil.
Some are parasitic, which means they live in other plants and animals including humans, where
they cause disease. Plasmodium, for example, causes malaria.
They are motile and can move by:
Cilia - tiny hair like structures that cover the outside of the microbe. They beat in a regular
continuous pattern like flexible oars.
Flagella - long thread-like structures that extend from the cell surface. The flagella move in a
whip-like motion that produces waves that propel the microbe around.
Amoeboid movement - the organism moves by sending out pseudopodia, temporary
protrusions that fill with cytoplasm that flows from the body of the cell.
I. Antiprotozoal Agents
Protozoa are one-celled eukaryotes which typically afford disease as a consequence of
replicating in large numbers in the host
A. Antimalarial Agents
 Malaria is caused by a class of red blood cell parasites (protozoa) called Plasmodium
(falciparum, Pmalariae, P. vivax, P. ovale, >100 other minor strains). P. falciparum most .
common and severe.

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 Mosquitoes pass sporozoites to humans where they enter the blood stream and travel
to the liver where hepatocytes are infected (we will not discuss life cycle and
replication)
 Resistance to antimalarial agents, particularly Chloroquine, is a problem
1. Quinine and 4-Quinoline Methanols
 Quinine original from Cinchona bark (used by Inca's pre 16th century)
 Quinidine gluconate and sulfate salts given IV and may be used alone or in
combination with other agents where chloroquine resistance occurs.
a. Mefloquine approved in 1989: is a synthetic analog of quinine
 Kills Plasmodia at 'blood stage' of life cycle
 Not prescribed to patients with history of depression, psychosis, convulsions.
 Used for Prophylaxis where chloroquine resistance to P. falciparum occurs.

2. Aminoquinolines
a. Chloroquine is the most versatile (oral) used to treat acute attacks and prophylactic
where resistance not reported.
b. Primaquine used to prevent relapse (more adverse effects)
"Other agents developed/used because of resistance to chloroquine"

3. 9-Methanthrene Methanols (Halofantrine)

 FDA approved in 1992
 Contraindicated in heart disease and for use with mefloquine

4. Mechanism of Action for the Quinoline-Based Antimalarials

 Exact mechanism is not known: A number of molecular mechanisms are proposed
for how these agents act and whether they have 'identicle' or just similar
mechanisms of action. Generally, the following is accepted.
 These agents are weak bases which are uncharged at neutral pH. When the agents
enter the protozoa and subsequently the lysosomes, a more acidic environment, the
agents are converted to their 'charged' salt form and trapped in the lysosome. Thus,
high concentration of drug are accumulated in the protozoa food vacuoles
(lysosomes). It is then believed that when the parasite feeds on hemoglobin in red
blood cells the digestion of protein results in an insoluble precipitate in the
lysosome. (eg. Chloroquine complexes with these protein digest products (heme)) In
the end, degradation of hemoglobin by the malaria parasite is adversely effected by
these agents and the ultimate result is their death. Exactly how this happens is still
debated.

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 This general mechanism also explains why resistance to these agents is associated
with impaired uptake of the drug by the malarial protozoa and that cross-resistance
has been observed among these agents.
5. Diaminopyrimidine/Dihydrotriazine Antimalaria Agents
(Inhibitors of folate metabolism, DHFR)
 These agents inhibit dihydrofolate reductase, which interferes with folic acid synthesis,
and thus ultimately as a folic acid antagonist results in interference of nucleotide
synthesis. High affinity for Plasmodia DHFR and low affinity for human DHFR.

6. Other Agents with Antimalarial Activity

 sulfa drugs as shown above for combination therapy with DHFR inhibitors (synergistic)
 Artemisinin
 tetracycline, chloramphenicol

B. Other Antiprotozoal Agents

 There are many other agents with a variety of mechanisms of action to treat protozoal
infections such as trypanosomiasis, leishmaniasis, amebiasis, giardiasis, trichomoniasis
and others.
1. Metronidazole
 Metronidazole is metabolically reduced to reactive metabolites in the protozoa. These
reactive metabolites bind DNA of the protozoa affording a lethal effect.
 Generally low toxicity in humans.
 widely used for variety of protozoal infections in North America
 Adverse Effects: nausea, dry mouth, metalic taste, disulfuram-like reaction with alcohol
2. Other agents typically used in North America
a. Paromycin (aminoglycoside)
b. Combinations of sulfa drugs (sulfamethazole) and DHFR inhibitor
(trimethoprim/pyrimethamine)
c. Tetracycline
3. Other agents available from CDC (for Leishmaniasis, Trypanosomiasis and other
protozoal infections not common in North America)
a. Pentamidine,
b. Suramin,
c. Sodium Stibogluconate,
d. melarsoprol,
e. nifurtimox

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II. Anthelminthic Agents
Helminths (worms) are multicellular animals that are much larger than protozoa. Many
types of worms (tapeworms, roundworms and flatworms (flukes))
1. The Benzimidazoles
a. Mebendazole (Vermox) used in the U.S.
 Cimetidine may inhibit liver metabolism of Mebendazole (roundworms and
tapeworms)
Mechanism of Action:
The benzimidazoles bind to beta-tubulin which results in the inhibition of microtubule assembly
involved in cell division. Therefore, cell division processes are arrested. Glucose uptake is also
depleted. The benzimidazoles have high affinity for beta-tubulin in the parasite (worm) but low
affinity for mammalian betatubulin affording 'selective toxicity'.

2. Pyrantel
Pyrantel pamoate acts on the nervous system of pinworm, roundworm and hookworm.
It is a depolarizing neuromuscular blocking agent that causes spastic paralysis in
susceptible helminths.
3. Niclosamide (a salicylanilide) –
 used for tapeworms
 kills on cantact by uncoupling oxidative phosphorylation (energy depletion)
4. Praziquantel
 Broad spectrum
 well tolerated
 Mechanism of Action: Appears to effect helminth membranes ultimately
stimulating the action of hosts antibodies. (expose/release antigen(s))

5. Other Antihelminths with various applications

a. Ivermectin
b. Diethylcarbamazine
c. Piperazine
III. Pediculocides and Miticides (Lice and Scabies)
1. Lindane (Kwell®)
 Effect on insects is similar to DDT but lower toxicity to humans
 Adverse effects: rash, conjunctivitis (rare: convulsions, aplastic anemia)
 Insecticidal against lice

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2. Malathion - Another insecticide that has limited use for lice. (local irritation and foul
smelling)
3. Pyrethrins
 Pyrethrins are natural extracts from Chrysenthemum (A-200, RID, Pronto)
 Only major adverse effect is possible allergic reaction
 for lice (pyrethrin + piperonyl butoxide)
a. Permethrin is a synthetic pyrethrin which is chemically more stable
 Mechanism of Action: Disrupts sodium conductance of nerve cell membranes
of the parasite.
 Adverse Effects: burning, numbness, rash

i. (Eliminate®) 5% permethrin for scabies, alternative is 1% lindane or 10%

crotamilton
ii. (Nix®) 1% permethrin for lice

4. Crotamiton- Scabicide (Eurax®)

---END OF MODULE 4---

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