2. Fungi and Mycosis
• Infectious diseases caused by fungi are
called mycoses
• They are often chronic in nature
• Mycotic infections can be superficial and
involve only the skin (cutaneous
mycoses extending into the epidermis)
• Mycotic infections may also penetrate
the skin, causing subcutaneous or
systemic infections
2
3. Fungi and Mycosis
• Unlike bacteria, fungi are eukaryotic, with rigid cell
walls composed largely of chitin rather than
peptidoglycan.
• Fungal cell membrane contains ergosterol rather
than the cholesterol found in mammalian
membranes.
• These structural characteristics are useful in targeting
chemotherapeutic agents against fungal infections J
3
4. Fungi and Mycosis
• Fungal infections are generally resistant to antibiotics, and,
conversely, bacteria are resistant to antifungal agents
• The risk of fungal infections increases with
immunosuppression cases, such as in organ transplantation,
cancer chemotherapy, or HIV.
4
8. Amphotericin B
• a naturally occurring polyene antifungal produced by
Streptomyces nodosus
• In spite of its toxic potential, amphotericin B remains
the drug of choice for the treatment of several life-
threatening mycoses
8
9. Mechanism of action of Amphotericin B
• Amphotericin B binds to ergosterol in the
plasma membranes of sensitive fungal
cells.
• There, it forms pores (channels) that
require hydrophobic interactions between
the lipophilic segment of the polyene
antifungal and the sterol.
• The pores disrupt membrane function,
allowing electrolytes (particularly
potassium) and small molecules to leak
from the cell, resulting in cell death
9
10. Antifungal spectrum
It is effective against a wide range of fungi, including
• Candida albicans
• Histoplasma capsulatum,
• Cryptococcus neoformans
• Coccidioides immitis,
• Many strains of Aspergillus.
• Treatment of the protozoal infection leishmaniasis
10
11. Pharmacokinetics of Amphotericin B
• Administered by slow IV infusion.
• Amphotericin B is insoluble in water and must be co-
formulated with either sodium deoxycholate
(conventional) or a variety of artificial lipids to form
liposomes.
• The liposomal preparations have the primary
advantage of reduced renal and infusion toxicity.
11
12. Pharmacokinetics of Amphotericin B
• However, due to high cost, liposomal preparations
are reserved mainly as salvage therapy for patients
who cannot tolerate conventional amphotericin B.
• Amphotericin B is extensively bound to plasma
proteins and is distributed throughout the body.
• Inflammation favors penetration into various body
fluids, but little of the drug is found in the CSF,
vitreous humor, or amniotic fluid.
• However, amphotericin B does cross the placenta. 12
13. Pharmacokinetics of Amphotericin B
• Low levels of the drug and its metabolites appear in
the urine over a long period of time, and some are
also eliminated via the bile.
• Dosage adjustment is not required in patients with
hepatic dysfunction
• When conventional amphotericin B causes renal
dysfunction, the total daily dose is decreased by 50%.
13
14. Adverse effects of Amphotericin B
• Amphotericin B has a low therapeutic index
• The total adult daily dose of the conventional
formulation should not exceed 1.5 mg/kg/d,
whereas lipid formulations have been given safely in
doses up to 10 mg/kg/d
14
15. Adverse effects of Amphotericin B
• Fever and chills: most commonly 1 to 3 hours after starting
the IV administration, usually subside with repeated
administration.
• Renal impairment:
Ø Decrease in glomerular filtration rate and renal tubular
function.
Ø Renal function usually returns with discontinuation of the
drug, but residual damage is likely at high doses.
Ø Azotemia is exacerbated by other nephrotoxic drugs, such
as aminoglycosides, cyclosporine, and vancomycin,
Ø Adequate hydration can decrease its severity.
15
16. Adverse effects of Amphotericin B
• Hypotension: accompanied by hypokalemia
• Thrombophlebitis: Adding heparin to the infusion
can alleviate this problem.
16
17. Antimetabolite antifungals (Flucytosine [5-FC])
• Synthetic pyrimidine antimetabolite that is often
used in combination with amphotericin B
• Administered for the treatment of systemic mycoses
and for meningitis caused by C. neoformans and C.
albicans
17
18. Mechanism of action of Flucytosine
• Well absorbed by the oral
• 5-FC enters the fungal cell via a cytosinespecific permease, an
enzyme not found in mammalian cells.
• It is subsequently converted to a series of compounds,
including 5-fluorouracil and 5-fluorodeoxyuridine
5ʹ-monophosphate, which disrupt nucleic acid and protein
synthesis
• Note: Amphotericin B increases cell permeability, allowing
more 5-FC to penetrate the cell and leading to synergistic
effects
18
20. Adverse effects of Flucytosine
• 5-FC causes reversible neutropenia,
thrombocytopenia, and dose-related bone marrow
depression
• Gastrointestinal disturbances (nausea, vomiting, and
diarrhea)
20
21. Azole antifungals
• Two classes:
I. Triazole antifungals include Fluconazole, Itraconazole and others
II. Imidazole antifungals (are discussed in the section on agents for
cutaneous mycotic infections)
• These drugs have similar mechanisms of action and spectra of
activity, but their pharmacokinetics and therapeutic uses vary
significantly
• Imidazoles are given topically for cutaneous infections
• Triazoles are given systemically for the treatment or prophylaxis of
cutaneous and systemic fungal infections 21
22. Mechanism of action of Azole drugs
• Predominantly fungistatic
• They inhibit ergosterol biosynthesis
via inhibiting C-14 α-demethylase ( a
CYP450 enzyme)
• This causes disruption of membrane
structure and function, which, in
turn, inhibits fungal cell growth
22
23. Mechanism of Resistance of Azole drugs
• Resistance to azole antifungals is becoming a
significant clinical problem.
• Resistance is due to mutations in the C-14 α-
demethylase gene and developing of efflux pumps
23
24. Drug interactions of Azole drugs
• All azoles inhibit the hepatic CYP450 3A4 isoenzyme to varying
degrees.
• Thus increases the risk of toxicity for other drugs
24
Contraindications
• Azoles are considered teratogenic, and they should
be avoided in pregnancy unless the potential benefit
outweighs the risk to the fetus
25. Clinical uses of Fluconazole
• Prophylaxis against invasive fungal infections in
recipients of bone marrow transplants
• Treatment of candidemia and coccidioidomycosis
• Fluconazole is effective against most forms of
mucocutaneous candidiasis.
• Commonly used as a single-dose oral treatment for
vulvovaginal candidiasis
25
26. Clinical uses of Itraconazole
• It is rarely used for treatment of infections due to Candida and
Aspergillus species because of the availability of newer and more
effective agents.
• Can be used for the treatment of onychomycoses (fungal
infections of nails)
• It is the drug of choice for the treatment of blastomycosis,
sporotrichosis, paracoccidioidomycosis, and histoplasmosis
26
28. CUTANEOUS MYCOTIC INFECTIONS
• Mold-like fungi that cause cutaneous infections are called
dermatophytes or tinea
• Tinea infections are classified by the affected site (for example,
tinea pedis, which refers to an infection of the feet, athlete's
feet)
28
29. CUTANEOUS MYCOTIC INFECTIONS
• Common dermatomycoses, such as tinea infections that appear
as rings or round red patches with clear centers, are often
referred to as “ringworm.”
29
31. Terbinafine
• Oral terbinafine is the drug of choice for treating
dermatophyte onychomycoses (fungal infections of nails)
• It is better tolerated, requires a shorter duration of therapy,
and is more effective than either Itraconazole or Griseofulvin
31
32. Terbinafine
• Therapy is prolonged (usually about 3 months) but
considerably shorter than that with Griseofulvin
• Oral terbinafine may also be used for tinea capitis (infection of
the scalp). [Note: Oral antifungal therapy (griseofulvin,
terbinafine, itraconazole) is needed for tinea capitis, Topical
antifungals are ineffective]
32
tinea capitis infection
33. Terbinafine
• Topical Terbinafine (1% cream, gel or solution) is used to treat
tinea pedis, tinea corporis (ringworm), and tinea cruris
(infection of the groin).
• Duration of treatment is usually 1 week.
• Terbinafine is an inhibitor of the
CYP450 2D6 isoenzyme, and
concomitant use with substrates
of that isoenzyme may result in
an increased risk of adverse
effects with those agents.
33
34. Griseofulvin
• Causes disruption of the mitotic spindle and inhibition of
fungal mitosis
• It has been largely replaced by oral terbinafine for the
treatment of onychomycosis, although it is still used for
dermatophytosis of the scalp and hair
• Griseofulvin is fungistatic and requires a long duration of
treatment (for example, 6 to 12 months for onychomycosis)
• Duration of therapy is dependent
on the rate of replacement of
healthy skin and nails
34
35. Griseofulvin
• Ultrafine crystalline preparations are absorbed
adequately from the gastrointestinal tract, and
absorption is enhanced by high-fat meals
• The drug concentrates in skin, hair, nails, and adipose
tissue
• Griseofulvin induces hepatic CYP450 activity, which
increases the rate of metabolism of a number of drugs
• The use of griseofulvin is contraindicated in pregnancy
35
36. Nystatin
• Its structure, chemistry, mechanism of action,
and resistance profile resemble those of
amphotericin B.
• It is used for the treatment of cutaneous and
oral Candida infections.
• The drug is negligibly absorbed from the GIT
36
37. Nystatin
• It is not used parenterally due to systemic toxicity
(nephrotoxicity)
• It is administered as an oral agent (“swish and
swallow” or “swish and spit”) for the treatment of
oropharyngeal candidiasis (thrush)
• Administered intravaginally for vulvovaginal
candidiasis, or topically for cutaneous candidiasis.
37
38. Imidazoles
• Common examples: Clotrimazole, Ketoconazole and Miconazole
• The topical imidazoles have a variety of uses, including tinea
corporis, tinea cruris, tinea pedis, and oropharyngeal and
vulvovaginal candidiasis
• Topical use is associated with contact dermatitis, vulvar irritation,
and edema
• Clotrimazole is also available as a troche (lozenge), and
miconazole is available as a buccal tablet for the treatment of
thrush
38
39. Imidazoles
• Oral ketoconazole has historically been used for the
treatment of systemic fungal infections but is rarely
used today due to the risk for
Ø severe liver injury
Ø adrenal insufficiency
Ø adverse drug interactions
39
40. Tolnaftate
• Tolnaftate distorts the hyphae and stunts
(suppresses) mycelial growth in susceptible fungi.
• Tolnaftate is used to treat tinea pedis, tinea cruris,
and tinea corporis.
• It is available as a 1% solution, cream, and powder.
40
44. Drugs that prevent the virus entering or leaving
the host cells
1. Immunoglobulins
• Specific antibodies against superficial antigens of
viruses and can interfere with their entry into host
cells.
• Used to give protection against hepatitis A,
measles and rubella.
2. Enfuvirtide
– is the first antiretroviral drug to act by preventing
the entry of HIV-1 virus into host cells.
44
45. 3. Palivizumab
– is a monoclonal antibody that binds to a glycoprotein on the
surface of respiratory syncytial virus (RSV) and prevents
attachment to host cells.
– It is given monthly by intramuscular injection to infants at high
risk of RSV infections.
4. Amantadine
• interferes with the replication of influenza A by inhibiting the
transmembrane M2 protein that is essential for uncoating the
virus.
• It has a narrow spectrum and influenza vaccine is usually
preferable.
Drugs that prevent the virus entering or leaving
the host cells
45
46. 5. Neuraminidase inhibitors: Zanamivir and Oseltamivir
• Interfere with release of progeny influenza virus from
infected to new host cells, thus halting the spread of
infection within the respiratory tract .
• Zanamivir (Relenza) is given by inhalation
• Oseltamivir (Tamiflu) is given orally and can be used for
prophylaxis.
Drugs that prevent the virus entering or leaving
the host cells
46
47. Drugs that inhibit nucleic acid synthesis
1. Acyclovir
– Acyclovir is active against herpes viruses e.g. herpes
simplex (HSV) and varicella zoster (VZV), but does not
eradicate them.
– It is effective topically, orally and parenterally
– Acyclovir is widely used in the treatment of HSV genital
infections and high oral doses are effective in treating
severe shingles by VZV
47
HSV
HSV VZV
shingles
48. Mechanism of action of Acyclovir
• Acyclovir, a guanosine analog, is monophosphorylated
in the cell by the herpes virus-encoded enzyme
thymidine kinase
• Therefore, virus-infected cells are most susceptible.
• The monophosphate analog is converted to the di- and
triphosphate forms by the host cell kinases.
• Acyclovir triphosphate competes with deoxyguanosine
triphosphate as a substrate for viral DNA polymerase
and is itself incorporated into the viral DNA, causing
premature DNA chain termination
48
49. 2. Valacyclovir
– a prodrug that after oral administration releases
Acyclovir.
– It has a higher bioavailability than Acyclovir and is used
for treating HSV and VZV infections of the skin and
mucous membranes.
3. Ganciclovir
– must be given intravenously and, because of its toxicity
(neutropenia), it is used only to treat severe
cytomegalovirus (CMV) infections in
immunocompromised patients.
– CMV is resistant to Acyclovir because it does not code for
thymidine kinase.
49
50. 4. Zidovudine
• Inhibits the reverse transcriptase of HIV
• Used orally in the treatment of AIDS.
• Some patients cannot tolerate the severe side-effects, which
include anemia, neutropenia, myalgia, nausea and
headaches.
• Other Nucleoside/Nucleotide Reverse Transcriptase
Inhibitors
(NRTIs) include stavudine, didanosine and zalcitabine.
• Newer NNRTIs that act by denaturing reverse transcriptase
include nevirapine and efavirenz.
50
51. Protease inhibitors
• Saquinavir and Ritonavir.
• In HIV, mRNAs are translated into inert polyproteins.
• These are then converted into essential mature proteins (e.g.
reverse transcriptase) by a virus-specific protease.
• Inhibitors of ‘HIV protease’ prevent the maturation of virions,
resulting in the production of non-infectious particles.
• They are used in combination with other drugs
• Adverse effects: nausea, vomiting, diabetes and lipodystrophy.
51
52. D.Immunomodulators
Interferons (INFs)
• Are protective glycoproteins that are synthesized in the body in
response to virus infection.
• They are classified as α, β or γ.
• Interferons have a wide spectrum.
• They prevent viral replication by binding to specific ganglioside
receptors on the host cells and induce the production of enzymes
that inhibit the translation of viral mRNA into viral proteins.
52
53. • IFN-α
• for chronic myelogenous leukemia, Kaposi's sarcoma
and chronic hepatitis B and C.
• IFNs conjugated with polyethylene glycol (pegylated
INFs) have a longer action and are more effective.
53
54. Drugs for Hepatitis infections
• Lamivudine: Nucleoside Reverse Transcriptase Inhibitor (NRTI)
• Lamivudine is active against HBV but resistant strains may
develop.
• Some newer drugs, e.g. adefovir, are effective in lamivudine-
resistant infections.
• Antiviral suppression of HBV for 2–5 years reverses hepatic
fibrosis and prevents cirrhosis.
• Hepatitis C (HCV) is treated with pegylated INF-α and
ribavirin and successfully clears the virus in more than 50% of
patients. 54
56. Antiretroviral drugs
• Are used to suppress the replication of HIV in
patients with AIDS.
• Resistance to single drugs develops rapidly and this
unfortunate fact led to the introduction of highly
active antiretroviral treatments (HAART).
56
60. Common Helminths
• Roundworm: Ascaris lumbricoides
• Hookworm: Ancylostoma duodenale and Necater americanus
• Threadworm: Enterobius vermicularis and Strongyloides stercoralis
• Whipworm: Trichuris trichiuria and Trichinella spiralis
• Filaria: Wuchereria bancrofti, Brugia malayi
• Tapeworms: T. saginata, T. solium, H. nana
• Hydatid disease: E granulosus and E multilocuralis
60
61. Mebendazole
• Synthetic benzimidazole derivative
• Action:
– 100% cure rate for round worm, hook worm, enterobius and
trichuris
– 75% effective for tape worms
– Hydatid cyst: prolonged treatment
– Hatching of nematode eggs and larva inhibited and Ascaris eggs
are killed
61
62. Mechanism of action of Mebendazole
– Slow in action, takes 2-3 days to develop
– Blocks glucose uptake in the parasite and depletion of
glycogen store
– Site of action: microtubular protein “ß-tubulin” – inhibits
polymerization
– Intracellular mictotubules are gradually lost
62
63. Mebendazole
• Pharmacokinetics: Minimal absorption, 75-90% is passed
unabsorbed in the feces. Excreted mainly in urine as
inactive metabolite
• Adverse effects:
– No adverse effects with short term therapy, mild GIT
disturbanes-nausea, diarrhea and abdominal pain
– Allergic reactions, granulocytopenia, loss of hair and
elevation of liver enzymes
63
64. Mebendazole
• Uses: Available as 100 mg chewable tablet and
100mg/ml suspension
– Common indications: 100 mg twice daily for 3 days
– Enterobius 100 mg single dose + repeat after 2-3
weeks
– Trichinella spiralis – 200 mg twice daily for 4 days
– Hydatid cyst: 200-400 mg twice daily for 3-4 weeks
64
65. Metronidazole
• Highly active amoebicide.
• Selectivity of nitro group containing antibacterial,
antiamoebic, antitrypanosomal arises from absence
of nitroreudctase in human and presence of it in the
invading organism.
• It has broad spectrum cidal activity against protozoa,
including Giardia lamblia.
65
66. Mechanism of Action of Metronidazole
• Metronidazole is selectively toxic to anaerobic
microorganisms.
• It enters the cell by diffusion then its nitro group is reduced
by redox proteins (nitroreudctase) to highly reactive nitro
radical which exerts cytotoxicity by damaging DNA & other
critical biomolecules.
66
67. Pharmacokinetics of Metronidazole
• Completely absorbed from intestine.
• Widely distributed in the body.
• Metabolized in liver & excreted in urine.
• Plasma t1/2 is 8 hrs.
67
68. Adverse Effects of Metronidazole
• Anorexia
• Nausea
• Metallic taste
• Abdominal cramps
• Loose stool is occasional
• Headache
• Dryness of mouth
68
70. Interactions
• A disulfiram like intolerance to alcohol occurs;
patients should avoid drinking.
• When metronidazole is given with alcohol
abdominal distress, nausea, vomiting, flushing, or
headache, tachycardia, hyperventilation
1.Enzyme inducer (phenobarbitone, rifampicin)
2.Cimetidine reduce metabolism.
3.It decrease renal metabolism of lithium.
70
