Unit-II Anti-fungal Drugs By Aurangzeb.pdf

Very Important and to the point according to BS nursing Curriculum

1. Unit-II/Lecture-VI
Anti-fungal Drugs
By: Muhammad Aurangzeb
Pharm-B, BSN, MSPH, MSN
Assistant Professor-INS/KMU

2. Objectives
Atthecompletionofthisunitthestudentswillbeableto;
•Definethemostcommonlyusedcategoriesofanti-fungal
drugsthatareusedtopreventandtreatfungalinfections.
•Brieflydiscussactionandeffectsofselecteddrugcategory
•Listsomeofthemostcommonlyuseddrugsforeachdrug
category
•Discussthenursingmeasures/patienteducationwhichcanbe
takenifpatientisusingtotreatandpreventinfections.

3. Fungal Infections
•Infectious diseases caused by fungi are called mycoses, and
they are often chronic in nature.
•Fungal infectious occur due to :
1-Abuse of broad spectrum antibiotics
2-Decrease in the patient immunity

4. Fungal Cell
•TheyhaverigidcellwallscomposedlargelyofapolymerofN-
acetylglucosamineratherthanpeptidoglycan(acharacteristic
componentofmostbacterialcellwalls).
•Thefungalcellmembranecontainsergosterolratherthanthe
cholesterolfoundinmammalianmembranes.
•Thesechemicalcharacteristicsareusefulintargeting
chemotherapeuticagentsagainstfungalinfections

5. Cont…
•Human fungal infections have increased dramatically , owing
mainly to advances in surgery, cancer treatment, and critical
care accompanied by increases in use of broad-spectrum
antimicrobials and the HIV epidemic.

6. Types of fungal infections
I.Mucocutaneous (superficial)
infections:
A.Dermatophytes:
•Cause infection of skin, hair,
and nails e.g. tinea capitis
(scalp), tinea cruris (groin),
tinea pedis (foot),
onychomycosis (nails).

7. Types of Fungal Infections
B.Yeasts:
•Cause infections of moist skin
and mucous membranes e.g.
Candida albicans causing oral,
pharyngeal, vaginal, &
bladder infections
7

8. Types of fungal infections
II.Systemic mycoses: are
fungal infections affecting
internal organs. It occurs in
immunocompromized
patients e.g. cryptococcosis,
and aspergillosis (lung).

9. Azolesinhibit
Polyenes (Disrupt membrane structure &function)
Flucytosine inhibits DNAsynthesis

10. Caspofungin inhibits
cell wallsynthesis

11. Sites of Actions of Antifungal Drugs

12. Classification of AntifungalAgents
Antifungals
ERGOSTEROL SYNTHESIS
INHIBITORS
Voriconazole
Itraconazole
Posaconazole
Fluconazole
Caspofungin

13. Classification of Antifungal Drugs
•Classification of Antifungal Drugs based on mechanism of
action
1.Fungal cell wall synthesis inhibition:Caspofungin.
2.Bindto fungalcellmembraneergosterol: Amphotericin-B,
Nystatin.
3.Inhibition of ergosterol synthesis:Azoles
4.Inhibition of lanosterol synthesis:Terbinafine
5.Disruption of mitotic spindle and inhibition of fungal
mitosis: Griseofulvin.
6.Nucleic Acid synthesis inhibitors: Flucytosine

14. Amphotericin B
•AmphotericinBisanaturallyoccurringpolyeneantifungal
producedbyStreptomycesnodosus.Inspiteofitstoxic
potential,amphotericinBremainsthedrugofchoiceforthe
treatmentofseverallife-threateningmycoses.
•Itisamacromoleculeandconsistsofbothlipophilicand
hydrophilicgroupsi.e.,itisamphiphilicinnature
•Theamphiphilicityofthedrugisresponsibleforitsunique
mechanismofaction

15. Pharmacokinetics
•Poorly absorbed orally, is effective for fungal infection of
gastrointestinal tract.
•For systemic infections given as slow I.V. Infusion.
•Highly bound to plasma protein .
•Poorly crossing BBB.
•Metabolized in liver
•Excreted slowly in urine over a period of several days.
•Half-life 16 days.

16. Cont…
•Inflammationfavorspenetrationintovariousbodyfluids,but
littleofthedrugisfoundintheCSF,vitreoushumor,or
amnioticfluid.However,amphotericinBdoescrossthe
placenta.
•Accumulatesinrenalcellscausingnephrotoxicityleadingto
AzotemiacharacterizedbydecreasedGFR,Urinaryoutput,
CreatinineclearanceandincreasedSerumcreatinineand
BUN

17. Mechanism ofAction
AMPHOTERICIN B
HYDROPHILICPART
LIPOPHILICPART
Binds with ergosterol andbilipid
layer
Forms pores in the cellmembrane
Cell contents such as Na
+
and K
+
leak trough the
spores from thecytoplasm
FUNGICIDALACTION

18. Mechanism of Action
•It is a selective fungicidal drug.
•Disruptfungalcellmembranebybindingtoergosterol,so
altersthepermeabilityofthecellmembraneleadingto
leakageofintracellularions&macromolecules(celldeath).

20. Adverse Effects
1-Immediate reactions(Infusion –related toxicity).
•Fever, muscle spasm, vomiting, headache, hypotension. Can
be avoided by:
–Slowing the infusion
–Decreasing the daily dose
–Premedication with antipyretics, antihistamines or
corticosteroids.
–A test dose.

21. Adverse Effects
2-Slower toxicity
•Most serious is renal toxicity (nearly in all patients ).
•Hypokalemia
•Hypomagnesaemia
•Impaired liver functions
•Thrombocytopenia
•Anemia

22. Clinical uses
•Has a broad spectrum of activity & fungicidal action.
•The drug of choice for life-threatening mycotic infections.
•Also, for chronic therapy &preventive therapy of relapse.
•Intestinal candidiasis
•Topical candidiasis
•Febrile neutropenia
•Leishmaniasis –kala Azar

23. Liposomal preparations of Amphotericin B
•Amphotericin B is packaged in a lipid-associated delivery
system to reduce binding to human cell membrane , so
reducing:
•Nephrotoxicity
•Infusion toxicity
•Also, more effective
•More expensive

24. Nystatin
•It is a polyene macrolide, similar in structure & mechanism to
amphotericin B.
•Too toxic for systemic use.
•Used only topically.
•It is available as creams, ointment, suppositories & other
preparations.
•Not significantly absorbed from skin, mucous membrane, GIT

25. Clinical uses
•Preventor treat superficial candidiasis of mouth, esophagus,
intestinal tract.
•Vaginal candidiasis
•Can be used in combination with antibacterial agents &
corticosteroids.

26. Ergosterol Synthesis Inhibitors (Azoles)
•A group of synthetic fungistatic or fungicidal agents with a
broad spectrum of activity .
•Azoles are made up of two different classes of drugs
–Imidazole
–Triazoles
•Althoughthesedrugshavesimilarmechanismsof
action andspectra of activity, their pharmacokinetics and
therapeutic uses vary significantly.

27. Azoles
Triazoles
Voriconazole
Itraconazole
Posaconazole
Fluconazole
Imidazoles
Systemic
Ketoconazole
Topical
Clotrimazole
Oxiconazole
Moconazole
Econazole
Butoconazole

28. AzoleMechanism ofAction
•Inhibit the fungal cytochrome P450 enzyme, (α-
demethylase) which is responsible for converting
lanosterol to ergosterol
Lanosterol
Lanosterol 14demethylase
(CYP 450enzyme)
Azoles
Ergosterol

29. Imidazoles
•Imidazoles includes:
–Ketoconazole
–Miconazole
–Clotrimazole
•They lack selectivity, they inhibit human gonadal and steroid
synthesis leading to decrease testosterone & cortisol
production.
•Also, inhibit human P-450 hepatic enzyme.

30. Ketoconazole
•Well absorbed orally
•Bioavailability is decreased with antacids, H2 blockers, proton
pump inhibitors & food .
•Cola drinks improve absorption in patients with achlorhydria.
•Half-life increases with the dose, it is (7-8 hrs).
•Inactivated in liver & excreted in bile (feces ) & urine.
•Does not cross BBB

31. Ketoconazole Clinical Uses
•Used topically or systematic (oral route only ) to treat :
1.Oral & vaginal candidiasis
2.Dermatophytosis.
3.Systemic mycoses.

32. Ketoconazole Adverse Effects
•Nausea, vomiting, anorexia
•Hepatotoxic
•Inhibits human P 450 enzymes
•Inhibits adrenal & gonadal steroids leading to:
–Menstrual irregularities
–Loss of libido
–Impotence
–Gynaecomastia in males

33. Triazoles
•Triazoles includes:
–Fluconazole
–Itraconazole
–Voriconazole
•They are :
–Selective
–Resistant to degradation
–Causing less endocrine disturbance

34. Itraconazole
•Lacks endocrine side effects
•Has a broad spectrum activity
•Given orally & IV
•Food increases its absorption
•Metabolized in liver to active metabolite
•Highly lipid soluble, well distributed to bone, sputum, adipose
tissues.
•Can not cross BBB

35. Itraconazole (cont.)
•Half-life 30-40 hours
Clinical uses:
•Used orally indermatophytosis & vulvo-vaginal candidiasis.
•IV only in serious infections.
•Effective in AIDS-associated histoplasmosis
Side effects:
•Nausea, vomiting, hypokalemia, hypertension, edema,
inhibits the metabolism of many drugs as oral anticoagulants

36. Fluconazole
•Water soluble
•Completely absorbed from GIT
•Excellent bioavailability after oral administration
•Bioavailability is not affected by food or gastric PH
•Concentrated in plasma is same by oral or IV route
•Hasthe least effect on hepatic enzymes

37. Fluconazole (cont.)
•Drug interactions are less common
•Penetrates well BBB so, it is the drug of choice of cryptococcal
meningitis
•Safely given in patients receiving bone marrow transplants
(reducing fungal infections)
•Excreted mainly through kidney
•Half-life 25-30 hours
•Resistance is not a problem

38. Clinical uses
•Candidiasis (is effective in all forms of cutaneous candidiasis)
•Cryptococcus meningitis
•Histoplasmosis, blastomycosis, ring worm

39. Side effects
•Nausea, vomiting, headache, skinrash, diarrhea, abdominal
pain, reversible alopecia.
•Hepatic failure may lead to death
•Highly Teratogenic ( as other azoles)
•Inhibit cytochrome P450
•No endocrine side effects

40. Inhibition of Lanosterol Synthesis:
Terbinafine
•Mechanism of action:
•It inhibits squalene epoxidase thus blocking the biosynthesis
of ergosterol, an essential component of fungal cell
membranes.
•This inhibition also results in an accumulation of squalene,
result in the death of the fungal cell.

42. Terbinafine
•Fungicidal ,its activity is limited to candida albicans &
dermatophytes.
•Effective for treatment of onychomycoses
•6 weeks for finger nail infection & 12 weeks for toe nail
infections .
•Well absorbed orally , bioavailability decreases due to first
pass metabolism in liver.

43. Therapeutic uses
•It is fungicidal and drug of choice for treating dermatophytoses
and, especially, onychomycoses (fungal infections of nails).
•It is better tolerated, requires shorter duration of therapy, and
is more effective than either itraconazole or griseofulvin

44. Adverse effects
•Thedrugiswelltolerated,withalowincidenceof
gastrointestinaldistressheadache,orrash
•Contraindicated in pregnancy

45. Nucleic Acid synthesis inhibitors
Flucytosine
•Flucytosine(5-FC)isasyntheticpyrimidineanalogthatis
oftenusedincombinationwithamphotericinB.
•Thiscombinationofdrugsisadministeredforthetreatment
ofsystemicmycosesandformeningitiscausedby
CryptococcusneoformansandCandidaalbicans.

46. Mechanism of Action
•Converted within the fungal cell to 5-fluorouracil (Not in
human cell), that inhibits thymidylate synthetase enzyme that
inhibits DNA synthesis.
•(Amphotericin B increases cell permeability , allowing more
5-FC to penetrate the cell, they are synergistic).

47. Pharmacokinetics
•Rapidly & well absorbed orally
•Widely distributed including CSF.
•Mainly excreted unchanged through kidney
•Half-life 3-6 hours

48. Clinical Uses
•Severe deep fungal infections as in meningitis
•Generally given with amphotericin B
•For cryptococcal meningitis in AIDS patients

49. Adverse Effects
•Nausea, vomiting, diarrhea, severe enterocolitis
•Reversible neutropenia, thrombocytopenia, bone marrow
depression
•Alopecia
•Elevation in hepatic enzymes

50. Fungal Cell Wall Synthesis Inhibitors
Caspofungin
•Inhibits the synthesis of fungal cell wall, leading to lysis & cell
death.
•Given by IV route only
•Highly bound to plasma proteins
•Half-life 9-11 hours
•Slowly metabolized by hydrolysis
•Elimination is nearly equal between the urinary & fecal
routes.

51. Caspofungin Mechanism of Action
•Inhibit synthesis of glucan in the cell wall via noncompetitive
inhibition of enzyme 1,3-β glucan synthase
•Beta glucans are carbohydrate polymers that are cross-linked
with other fungal cell wall components .

52. Clinical Uses
•Effective in aspergillus & candida infections.
•Second line for those who have failed or cannot tolerate
amphotericin B or itraconazole.
Adverse effects:
•Nausea, vomiting
•Flushing (release of histamine from mast cells)

53. Anti-Mitotic (Griseofulvin)
•Fungistatic, has a narrow spectrum
•Given orally (Absorptionincreases with fatty meal)
•Half-life 26 hours
•Taken selectively by newly formed skin & concentrated in the
keratin.
•Should be given for 2-6weeks for skin & hair infections to
allow replacement of infected keratin by the resistant
structure

54. Griseofulvin(cont.)
•MOA: Inhibits fungal mitosis by interfering with microtubule
function
•Clinical uses:
–Used to treat dermatophyte infections ( ring worm of skin,
hair, nails ).
–Highly effective in athlete's foot.
•Adverse effects:
–Peripheral neuritis, mental confusion, fatigue, vertigo,
–GIT upset, enzyme inducer, blurred vision.

55. Nursing Considerations
•Assess for the contraindications
•Obtain a culture of the infected area
•Instruct patient for correct method of administration, to
improve effectiveness and decrease the risk of adverse effects
•Advise patient to stop the drug if a severe rash occurs
•Educate client on drug therapy to promote understanding and
compliance.
•Monitor patient response to therapy (resolution of fungal
infections).
•Monitor for adverse effects

56. References
•Harvey, R.A and Champe, P.C. Lippincott’s Pharmacology.4th
edidtion.(2006)
•Katzung, B.G. and Masters, S.B. Basic and clinical
pharmacology 12th edition.(2012)
•Brunton.L, Chabner. B, and Knollman. B. Goodman and
Gillman’s The Pharmacological Basis of Therapeutics.12th
eidtion.(2011)