ANTI-FUNGAL DRUGS

Dr Abid Laghari
 FUNGI
– Also known as mycoses
– Very large and diverse group of microorganisms
– Broken down into yeasts and molds
• Yeasts
– Single-cell fungi
– Reproduce by budding
– Very useful organisms, used in
• Baking
• Alcoholic beverages
• Molds
– Multicellular
– Characterized by long, branching filaments called
hyphae
 Fungal Infections
• Develop due to a loss of mechanical barriers (i.e.
burns,major surgery) or immunodeficiency
(chemotherapy,organ transplant, AIDS)

• Fungal infections may be superficial or systemic

• Fungi possess different ribosomes, cell wall

components, and discrete nuclear membrane
 MOST COMMON FUNGAL
PATHOGENS

Dermatophytes

Candida

Aspergillus

Cryptococcus

Rhizopus
 Mycotic Infections

Four General Types

– Cutaneous
– Subcutaneous
– Superficial
– Systemic*
• *Can be life-threatening
• *Usually occur in immunocompromised
host
 Antifungal Drugs
• Polyene antibiotics: Amphotericin B, nystatin

• Antimetabolites: 5-Fluorocytosine

• Azoles:
Imidazoles: Ketoconazole, miconazole (topical)
Trizoles: Itraconazole, Fluconazole

• Griseofulvin

• Topical antifungal agents: imidazoles, polyenes and

others.
 ANTIFUNGAL DRUGS
--by mode of action
Drugs: Alter cell membrane permeability
Amphotericin B, Nystatin (polyenes)
Azoles
Terbinafine

Nucleic acid inhibitor

Flucytosine

Anti-mitotic (spindle disruption)

Griseofulvin
 Amphotericin B
Mechanism of Action
– Bind to sterols (Ergosterol) in the fungal cell
membrane and causes formation of artificial
pores
– Allow K+ & Mg++ to leak out, altering
fungal cell metabolism
– Resulting in fungal cell death
 Clinical uses
• It has widest anti-fungal spectrum, it is drug of
choice for most systemic infections caused by
aspergillus, Candida albicans, Cryptococcus,
histoplasma, and Mucor.

• It is usually given by slow intravenous infusion,

but in fungal meningitis, it is given by intrathecal
route.
 Adverse Effects
• Acute: Infusion-related
– Chills, fever, nausea, vomiting, muscle
spasm, hypotension

– These effects can be prevented by slow

infusion rate and by premedication with
Antihistamine, Antipyretic, Meperidine
or Glucocorticoids
 Adverse Effects
• Chronic
– Nephrotoxicity
It decreases the glomerular filtration rate, so
causes azotemia, impaired concentration,
renal tubular acidosis with K & Mg wasting
(Nephrotoxic effect of drug is dose related
and can be reduced by concomitant saline
infusion)
 Adverse Effects
• Chronic (continue)
– Normochromic, Normocytic anemia
(due to ↓ erythropoietin)

– Neurotoxicity : Its intrathecal

administration may cause seizure and
neurological damage
 5-Fluorocytosine
A fluorinated pyrimidine
• Converted to 5 fluorouracil by a deaminase,
which inhibits thymidylate synthase and DNA
synthesis
• Selective toxicity to fungal cells (no deaminase
in mammalian cells)
• Resistance is common. Do not use alone, but in
combination with AmB cryptococcal meningitis
• Bone marrow toxicity – pancytopenia
-reversible
 The Azoles
Imidazoles and Triazoles
• Triazoles newer with fewer side effects
• Impair synthesis of ergosterol; inhibit sterol 14
α-demethylase (of cyt. P450). Acumulation of
precursors which inhibit growth.
• Mammalian cells can incorporate already
formed cholesterol; fungi have to synthesize
• Adverse effects due to inhibition of mammalian
steroid synthesis
• Drug interactions due to inbibition of cyt. P450
enzymes.
 Ketoconazole
(older, more toxic, replaced by itraconazole, but less costly)

• Absorption variable (better in acidic medium)

• Poor concentration in CSF
• Metabolized by Cyt. P450 enzymes
• Therapeutic Use: coccidiomycosis,
histoplasmosis if not severely ill or
immunocompromized. Oral, esophageal,
mucocutaneous candidiasis
• Adverse effects:
- Nausea, anorexia, vomiting
- Endocrine: menstrual abnormalities,
gynecomastia, azoospermia, decreased
libido and potency
- Hepatitis (rare-fatal)
- Drug Interactions (inhibition of cyt.
P450)
 Triazoles
Itraconazole Fluconazole
• Varied absorption. • Completely absorbed
Metabolized by cyt and better tolerated
P450
• Renal excretion
• Has less endocrine
effects but occur at • Less endocrine effects
high doses • Penetrates well into
• Less hepatitis CSF
• Histoplasmosis and • Cryptococcal,
blastomycosis coccidial meningitis.
• Many drug Candidiasis.
interactions (due to • Drug Interactions
 Other Antifungal Agents
Griseofulvin Topical Antifungals
• Binds to • For stratum corneum,
microtubules/ disrupts mucosa, cornea by
mitosis dermatophytes &
• Deposits in keratin Candida.
layers • Not for subcutaneous,
• Dermatophytes nail or hair infections.
actively concentrate it • Many azoles;
• Infections of skin, Tolnaftate; nystatin
hair, nails; Prolonged (Candida only);
therapy. naftifine; terbinafine;
• Toxicity: headache, miconazole;
BACKGROUND
 CANCER

• Cancer is a disease in which there is

uncontrolled multiplication and spread within the
body of abnormal forms of body’s own cells
• One of major cause in the developed countries
(about 1:5)
• Malignant tumors differ from benign by the
properties of differentiation, invasiveness and
ability to metastasize
 TYPES OF CANCER
• Carcinoma – 85% of cancers
– Organs, skin, nerves, membranes
• Sarcomas – 2% of cancers
– Bone, blood, connective tissue
• Lymphomas – lymphatic cells
– Hodgkin's disease
• Leukemia – blood and blood forming tissue
• Melanomas – skin cancer
 HOW CANCER SPREADS

• Metastasis –
cancerous cells
break away from
the primary tumor
and spread to other
organs
– Lymphatic system
– Blood stream
 GENERAL TREATMENT
• Surgery
– Removal of cancerous tissue
• Radiation therapy
– High energy doses to kill cancer cells
• Chemotherapy
– Medicine that kills the cancer cells
• May block blood supply to tumor and prevent
development of new blood vessels
– Unpleasant side effects
• Immunotherapy
– Bolster immune system to destroy the cancer cells
 CANCER CHEMOTHERAPY

• Depending on the type of tumor and the stage

of its development cancer can be treated by
surgical excision, irradiation and
chemotherapy
• The aim of chemotherapy is cure, if not
possible, then palliation
CLASSIFICATION OF
ANTICANCER DRUGS
 (A)ALKYLATING AGENTS
Busulfan
Carmustine
Chlorambucil
Cyclophosphamide
Dacarbazine
Ifosfamide
Lomustine
Mechlorethamine
Melphalan
Temazolamine
Thiopeta
 (B) ANTIMETABOLITES

• Capecitabine
• Cladribine
• Fludarabine
• 5-fluorouracil
• Gemcitabine
• 6-mercaptopurine
• Methotraxate
• 6-thioguanine
 (C) PLANT ALKALOIDS

• Camptothecins (topotecan, Irinotecin)

• Podophyllotoxins (etoposide, teniposide)
• Taxanes (peclitaxel, docataxel)
• Vinblastin
• Vincristine
• Vinorelbine
 (D) ANTIBIOTICS

• Anthracyclines (doxorubicin, daunorubicin)

• Bleomycin
• Dactinomycin
• Idarubicin
• Mitomycin
• Plicamycin
 (E) HORMONAL AGENTS
 Androgens(testosterone propionate, fluxymesterone)
Antiandrogens (flutamide)
Estrogens (diethyl stilbestrol, ethinyl estradiol)
Progestins (hydroxyl progesterone, medroxy
progesterone, megesterol acetate)
Adrenocorticosteroids ( hydrocortisone, prednisolone)
Gonado-releasing hormone agonists (goserelin acetate,
leuprolide)
Aromatase inhibitors (aminoglutethimide, anastrozole)
Peptide hormones (octreolide)
 (F) MISCELENEOUS ANTICANCER
DRUGS
• Asparaginase
• Hydroxyurea
• Mitoxantrone
• Mitotane
• Retinoic acid derivatives
• Bone marrow growth factors
• Amifostine
Cell Cycle Specific Cell Cycle Non-
Agents Specific Agents
• Antimetabolites • Alkylating Agents
• Bleomycin • Antibiotics
• Podophyllin • Cisplatin
Alkaloids
• Nitrosoureas
• Plant Alkaloids
BASIC PHARMACOLOGY OF CANCER
CHEMOTHERAPEUTIC AGENTS
(A) POLYFUNCTIONAL
ALKYLATING AGENTS
Cell Cycle Specific Cell Cycle Non-
Agents Specific Agents
• Antimetabolites • Alkylating Agents
• Bleomycin • Antibiotics
• Podophyllin • Cisplatin
Alkaloids
• Nitrosoureas
• Plant Alkaloids
BASIC PHARMACOLOGY OF CANCER
CHEMOTHERAPEUTIC AGENTS
(A) POLYFUNCTIONAL
ALKYLATING AGENTS
 (A)POLYFUNCTIONAL
ALKYLATING AGENTS
• Contain a bis(chloro-ethyl)amine,
ethylenimine or nitrosuoreas moiety
• They exert cytotoxic effect by
transferring their alky group to
various cellular constituents
• Cause cell death probably by
alkylations of DNA within the
nucleus
 (A)POLYFUNCTIONAL
ALKYLATING AGENTS:
MECHANISM OF ACTION
Intramolecular cyclization to form enemonium ion
that transfers an alkyl group to a cellular constituent
either directly or by formation of carbonium ion
 Nitrosuoreas act through carbomoylation of lysine
residues of proteins, in addition to alkylation
Major site of alkylation within DNA is N7 position
of guanine
Alkylation can result in miscoding through abnormal
base pairing with thymine or in depurination by
excision of guanine residues
 (1)MECLORETHAMINE

PHARMACOKINETICS

• Very unstable
• Given only I/V
 (1)MECLORETHAMINE

CLINICAL USES

• Used primarily in the Hodgkin’s disease

as MOPP regimen
• Also used in some solid tumors
 (1)MECLORETHAMINE

DRUG RESISTANCE

• May be due to decreased permeability of the

drug, increased conjunction with thiols and
possibly increased DNA repair
 (1)MECLORETHAMINE
ADVERSE EFFECTS

• Severe nausea and vomiting

• Severe bone marrow depression on
chronic use
• Immunosuppression may lead latent viral
infection
• Extravasation, if occurs should be
infiltrated with isotonic sodium thiosulfate
to inactivate the drug
(2) CYCLOPHOSPHAMIDE AND
IFOSFAMIDE

PHARMACOKINETICS

• Preferentially administered orally

• Small amounts are excreted in feces or urine
(2) CYCLOPHOSPHAMIDE AND
IFOSFAMIDE
CLINICAL USES

Widely used singly or as a part of regimen

Used in many neoplastic diseases
eg: Burkitt’s lymphoma and breast cancer
Cyclophosphamide is also used in non-
neoplastic conditions like nephrotic
syndrome and rheumatoid arthritis
(2) CYCLOPHOSPHAMIDE AND
IFOSFAMIDE
DRUG RESISTANCE

• Results from increased DNA repair,

decreased drug permeability, and reaction
of the drug with thiols (eg: glutathione) but
cross-resistance usually does not occur
(2) CYCLOPHOSPHAMIDE AND
IFOSFAMIDE
ADVERSE EFFECTS

Alopecia
Nausea
Vomiting
Diarrhea
Bone marrow depression
Hemorrhagic cystitis
Amenorrhea
Testicular atrophy
Sterility
Neurotoxicity
Secondary malignancies after many years of therapy
 (3) NITRSOUREAS

• Carmustine and lomustine are closely

related nitrsoureas

• Streptozotocin is specifically toxic to β-

cells of the islets of Langerhans, used in
insulinomas
 (3) NITRSOUREAS
MECHANISM OF ACTION

• Exert cytotoxic effect by alkylation, that

cross links strands of DNA to inhibit its
replication and eventually RNA and protein
synthesis

• Cytotoxicity is only expressed on cell

division
 (3) NITRSOUREAS
DRUG RESISTANCE

• Probably results from DNA repair and

reaction of drugs with thiols
 (3) NITRSOUREAS

CLINICAL USES

• Primarily used in brain tumors, because

they can penetrate into the CNS
• Limited use in other cancer
 (3) NITRSOUREAS
PHARMACOKINETICS

Peak plasma levels reach in 1-4 hours

Half-life initial 6 hours and secondary 1-2 hrs
Carmustine is administered I/V, while
lomustine is given orally
Readily enters CNS due to their high lipid
solubility
Undergoes extensive metabolism
Lomustine is metabolized to active products
 (3) NITRSOUREAS

ADVERSE EFFECTS

• Delayed hematopoietic depression

• Bone marrow aplasia on prolonged use
• Renal toxicity
• Pulmonary fibrosis
 RELATED DRUGS PROBABLY
ACTING AS ALKYLATING AGENTS

• Procarbazine
• Dacarbazine
• Altretamine (hexamethylmelamine)
• Cisplatin
• Carboplatin
 (1)PROCARBAZINE
A methyl hydrazine derivative
Mainly used in Hodgkin’s disease
Also leukemogenic, and have teratogenic
and mutagenic properties
Inhibits the RNA, DNA and protein
synthesis, prolongs interphase and produce
chromosome break
Adverse effects include nausea, vomiting,
myelosuppression, hemolytic anemia and
pulmonary reaction
 (2) DACARBAZINE
A synthetic compound, act as alkylating agent
after metabolic activation by liver
microsomal enzyme by oxidative N-
demethylation to 5-amino imidazole 4-
carboxamide and diazomethane
Administered parenterally
Mainly used in melanoma, Hodgkin’s disease
and some soft tissue sarcomas
Adverse effects include nausea, vomiting and
myelosuppression
 (3) ALTRETAMINE
• Relatively insoluble, available only in oral
form
• Metabolized by demethylation, probably to
active intermediates
• Used in ovarian carcinoma
• Adverse effects include nausea, vomiting,
neuropathies and mild myelosuppression
(4) CISPLATIN AND CARBOPLATIN

• Cause cell death in all stages of cell cycle

• Inhibits DNA synthesis, and binds DNA by
forming interstrand cross-links
• Administered I/V
• Cisplatin is mainly used in genitourinary
cancer especially testicular and bladder
cancer
• Adverse effects include nausea and vomiting
(B) ANTIMETABOLITES
 (B) ANTIMETABOLITES
MECHANISM OF ACTION

• They interfere with the availability of normal

purine or pyrimidine nucleotide precursors
either by inhibiting their synthesis, or by
competing with them in DNA or RNA
synthesis
• Their maximal cytotoxic effects are on
• S-phase therefore they are cell-cycle specific
 METHOTRAXATE
• A folic acid antagonist, binding to active
catalytic site of dihydrofolate reductase
(DHFR), interfering with the synthesis of
the reduced from that accept one-carbon
units
 METHOTRAXATE
MECHANISM OF ACTION
• Folic acid is reduced to TH4 by DHFR
• Methotraxate enters the cell by active transport
• MTX has strong affinity for DHFR, and it effectively inhibit
DHFR
• MTX becomes polyglutameted within a cell
• MTX polyglutamates also potently inhibit DHFR, so folate
coenzymes are lacked leading to decreased production of
compound depending on these enzymes including NAD,
guanine and thymine
• It results in decreased synthesis of DNA, RNA and proteins and
leads ultimately to cell death
 MTX

5-FU
X

Figure 2. This figure illustrates the effects of MTX and 5-FU on the
biochemical pathway for reduced folates.
 METHOTRAXATE
DRUG RESISTANCE

Results from:

• Decreased drug transport

• Altered DHFR with lower affinity for methotraxate
• Decreased polyglutamete formation and
• Synthesis of increased levels of DHFR 
• It occur through gene amplification and results in a marked
increase in DHFR messenger RNA
 METHOTRAXATE
CLINICAL USES

• Acute lymphocytic leukemia

• Choriocarcinoma
• Burkitt’s lymphoma in children
• Some inflammatory condition like psoriasis
and rheumatoid arthritis and in Crohn
disease as single dose therapy
 METHOTRAXATE
PHARMACO KINETICS
• On oral administration, absorbed at low doses from
GIT
• Also administered I/M, I/V, and intrathecally
• Does not penetrate BBB
• Distributed highly in the intestinal epithelium, liver
and kidney as well as in the ascites and pleural
effusion, and also distributed to the skin
• Metabolized to polyglutamated derivations, and
polyglutamates also remain in the cell even when
drug in absent extracellularly  
 METHOTRAXATE
DOSAGE

• Oral:2.5 -5 mg/d
• Intrathecal 10mg once or twice weekly
 METHOTRAXATE
TOXICITY
• Nausea
• Vomiting
• Diarrhea
• Stomatitis
• Myelosuppression
• Erythema
• Rash
• Urticaria
• Alopecia
• Renal damage
• Fibrosis and cirrhosis of liver
 METHOTRAXATE
CONTRAINDICATIONS

• Pregnancy, because it is teratogenic and

abortifacient
Thanks for your kind attention