Pharmacodynamics of Antifungal Drugs
Session 19: Pharmacodynamics of Antifungal Drugs
Total Session Time: 120 minutes
Prerequisites
None
Learning Tasks
By the end of this session students are expected to be able to:
Describe mechanism of action of antifungal drugs
Describe drug interactions associated with antifungal drugs
Describe side effects of antifungal drugs
Describe contraindications of antifungal drugs
Resources Needed:
Flip charts, marker pens, and masking tape
Black/white board and chalk/whiteboard markers
Computer and projector
SESSION OVERVIEW
Step
Time
Activity/
Content
Step
Time
Activity/
Content
Step
Time
Method
Content
Method
Method
1
1
05 minutes
05 minutes
Presentation
Introduction, Learning Tasks
Introduction, Learning Tasks
2
2
45 minutes
45 minutes
Presentation/
Mechanism of Action of Antifungal Drugs
Mechanism of Action of Antifungal Drugs
2
2
45 minutes
45 minutes
Buzzing
Mechanism of Action of Antifungal Drugs
Mechanism of Action of Antifungal Drugs
Buzzing
3
3
20 minutes
20 minutes
Presentation/
Drug Interactions Associated With Antifungal
Drug Interactions Associated With Antifungal
3
3
20 minutes
20 minutes
brainstorming
Drugs
Drugs
brainstorming
Drugs
Drugs
4
4
20 minutes
20 minutes
Presentation
Side Effects of Antifungal Drugs
Side Effects of Antifungal Drugs
5
5
20 minutes
20 minutes
Presentation/
Contraindications of Antifungal Drugs
Contraindications of Antifungal Drugs
5
5
20 minutes
20 minutes
Brainstorming
Contraindications of Antifungal Drugs
Contraindications of Antifungal Drugs
Brainstorming
6
6
05 minutes
05 minutes
Presentation
Key Points
Key Points
7
7
05 minutes
05 minutes
Presentation
Evaluation
Evaluation
PST 05104 Pharmacology & Therapeutics 154 NTA Level 5 Semester 1 Facilitator Guide
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)
READ or ASK students to read the learning tasks and clarify
ASK students if they have any questions before continuing.
STEP 2: Mechanism of Action of Antifungal Drugs (45 minutes)
Activity: Buzzing (5 minutes)
ASK students to pair up and buzz on the following question for 2 minutes
How do antifungal drugs produce their pharmacological effects?
ALLOW few pairs to respond and let other pairs add on points not mentioned
WRITE their response on the flip chart/board
CLARIFY and SUMMARIZE by using the content below
Polyenes
Amphotericin B
o Is a polyene macrolide with a hydroxylated hydrophilic surface on one side of the molecule and an unsaturated conjugated lipophilic surface on the other side.
o The lipophilic surface has a higher affinity for fungal sterols than for cholesterol in mammalian cell membranes and increases membrane permeability by creating a
‗membrane pore‘ with a hydrophilic centre which causes leakage of small molecules, e.g. glucose and potassium ions.
Nystatin
o Nystatin works in the same way as amphotericin B, but its greater toxicity precludes systemic use.
Azoles (imidazoles and Triazoles)
Fluconazole (a triazole)
o Imidazoles and Triazoles competitively inhibit lanosterol 14-α-demethylase (a fungal cytochrome-haem P450 enzyme), which is a major enzyme in the pathway that synthesizes ergosterol from squalene.
o This disrupts the acyl chains of fungal membrane phospholipids, increasing membrane fluidity and causing membrane leakage and dysfunction of membrane-bound enzymes.
PST 05104 Pharmacology & Therapeutics 155 NTA Level 5 Semester 1 Facilitator Guide
Triazole drugs work by the same mechanism as imidazoles but have a wider antifungal spectrum and are more specific for fungal CYP450.
The imidazoles have considerable specificity/affinity for fungal cytochrome-haem P450 enzymes.
Ketoconazole (an imidazole)
Mechanism of action is as discussed above
Imidazoles are fungistatic at low concentrations and fungicidal at higher
concentrations.
The imidazoles have considerable specificity/affinity for fungal cytochrome-haem P450 enzymes but less specific when compared to Triazoles.
Itraconazole and Voriconazole ( Triazoles)
Have a similar mechanism of action to fluconazole
Echinocandins
Caspofungin and micafungin
o Echinocandins are non-competitive inhibitors of 1, 3-β-D glucan synthase, an enzyme necessary for synthesis of a glucose polymer crucial to the structure and integrity of the cell walls of some fungi.
o Fungal cells unable to synthesize this polysaccharide cannot maintain their shape and lack adequate rigidity to resist osmotic pressure, which results in fungal cell lysis.
Allylamines
Terbinafine
o Terbinafine acts by inhibiting the enzyme squalene epoxidase, which is involved in fungal ergosterol biosynthesis.
Other antifungals
Griseofluvin
o This drug is concentrated in fungi and binds to tubulin, blocking polymerization of the microtubule, disrupting the mitotic spindle.
Flucytosine (5-Fluorocytosine)
o This drug is deaminated to 5-fluorouracil in the fungus and converted to an antimetabolite 5-FdUMP.
o This inhibits thymidylate synthetase, impairing fungal DNA synthesis.
PST 05104 Pharmacology & Therapeutics 156 NTA Level 5 Semester 1 Facilitator Guide
STEP 3: Drug Interactions Associated with Antifungal Drugs (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What drug interactions associated with antifungal drugs?
ALLOW few students to respond
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
Azoles (imidazoles and Triazoles)
Fluconazole (a triazole)
o Fluconazole reduces the metabolism of several drugs by inhibiting CYP3A, including benzodiazepines, calcium channel blockers, ciclosporin, docetaxel and, importantly, warfarin.
o The plasma concentrations and toxicity of these drugs will increase during concomitant treatment with fluconazole.
o Rifampicin enhances the metabolism of fluconazole.
Itraconazole and Voriconazole ( Triazoles)
Echinocandins
Caspofungin and micafungin
o These are minimal compared to the azoles. Ciclosporin increases Caspofungin AUC by 35% and micafungin increases the bioavailability of sirolimus and nifedipine.
o The pharmacokinetics of micafungin do not appear to be affected by other drugs; however, micafungin has been shown to increase levels of amphotericin B.
o Because of their complementary MOA, these two antifungal agents might be combined.
Other antifungals
Griseofluvin
o Griseofluvin induces hepatic CYP450s and consequently can interact with many drugs.
PST 05104 Pharmacology & Therapeutics 157 NTA Level 5 Semester 1 Facilitator Guide
STEP 4: Adverse Effects of Antifungal Drugs (20 minutes)
Polyenes
Amphotericin B
o Nephrotoxicity: Reversible kidney dysfunction, sometimes leading to chronic kidney dysfunction, can result. The mechanism is incompletely understood but thought to be mediated in part by both renal tubular injury and renal vasoconstriction.
o Infusion reactions: Fever, chills, hypotension, vomiting, dyspnoea, and headaches may occur. The mechanism of these reactions is unknown.
o Electrolyte abnormalities: Because of increases in the distal tubular permeability, potassium and magnesium wasting, leading to Hypokalemia and hypomagnesemia, can occur.
Nystatin
Nystatin is not administered systemically because of high toxicity
Azoles (imidazoles and Triazoles)
Ketoconazole (imidazole)
o Hepatotoxicity (has occurred rarely)
Echinocandins
Caspofungin and micafungin
o Infusion reactions: Swelling and rash occur and may be an allergic-type reaction mediated by histamine
o Elevated liver enzymes: This side effect occurs mainly in patients receiving both cyclosporine and caspofungin. Cyclosporine is an immunosuppressant, and patients who are immunosuppressed are more likely to develop fungal infections and therefore are more likely to be treated with antifungals.
Allylamines
Terbinafine
o Stevens-Johnson syndrome is a life-threatening condition whereby the dermis and epidermis separate. It is commonly caused by drugs (there is a long list). It is mediated by a hypersensitivity reaction. It occurs in about 2 to 3 per million people per year.
o Toxic epidermal necrolysis is a less severe form of Stevens-Johnson syndrome. o Liver failure: Liver enzymes must be measured before patients start terbinafine.
o Neutropenia and lymphopenia: Neutrophil and lymphocyte counts can be severely decreased. The drug should be discontinued if the counts are very low. The effect is reversible.
PST 05104 Pharmacology & Therapeutics 158 NTA Level 5 Semester 1 Facilitator Guide
Other antifungals
Griseofluvin
o The drug potentiates the intoxicating effects of alcohol. Griseofluvin is teratogenic in laboratory animals
o Headache: can sometimes be very severe and force discontinuation of the drug
o Peripheral neuropathy: tingling of the hands and feet o Sleep disturbances and fatigue
o Dermatologic: Skin rashes: Remember that the drug is in high concentrations in the keratin. Different rash types can include the following: Urticaria (hives),Erythema (red rash)
Flucytosine (5-Fluorocytosine)
o There is a risk of infection. Avoid treating patients with nonfungal infections. o Liver damage can rarely occur. Liver enzymes should be routinely measured.
o Bone marrow suppression: Anemia, low WBC count, and low platelet counts can occur. This is due to inhibition of rapidly dividing cells, as 5-DUMP can inhibit DNA synthesis
o Toxic epidermal necrolysis is a severe skin reaction with a mortality rate around 30%.
STEP 5: Contraindications of Antifungal Drugs (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are the contraindications of antifungal drugs? ALLOW few students to respond?
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
Polyenes
Amphotericin B
o Renal dysfunction, because amphotericin B is nephrotoxic
Nystatin
o None of significance
Azoles (imidazoles and Triazoles)
Fluconazole (a triazole)
o Fluconazole is contraindicated in pregnancy because of fetal defects in rodents and humans.
PST 05104 Pharmacology & Therapeutics 159 NTA Level 5 Semester 1 Facilitator Guide
Breast milk concentrations are similar to those in plasma and fluconazole should not be used by nursing mothers.
Ketoconazole (imidazole)
Ketoconazole and amphotericin B should not be used together
Echinocandins
Caspofungin and micafungin o None of major significance
Other antifungals
Griseofluvin
o Griseofulvin may cause hepatotoxicity and is contraindicated in patients with acute intermittent porphyria.
o Pregnancy: Griseofulvin is a potential teratogen.
Flucytosine (5-Fluorocytosine)
o Pregnancy is a contraindication because of the conversion to 5-FU, which is an antimetabolite for human DNA and a potential teratogen.
STEP 6: Key Points (5 minutes)
Systemic toxicity (especially nephrotoxicity) of amphotericin is reduced by using the liposomal/ lipid/micellar formulations.
Antifungals may be used for topical or systemic conditions
Some antifungals like amphotericin B have some toxicities
STEP 7: Evaluation (5 minutes)
What are the common adverse effects of ketoconazole?
What is the mechanism of action of Echinocandins?
What are advantages of using fluconazole versus fluconazole in systemic conditions?
PST 05104 Pharmacology & Therapeutics 160 NTA Level 5 Semester 1 Facilitator Guide
References
Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.
Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.
Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:
Jaypee Brothers Medical P.
Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.
Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.
School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).
Dar es Salaam, ARDHI University press.
The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.
The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary (59th ed). London, BMJ Group and RPS Publishing.
PST 05104 Pharmacology & Therapeutics 161 NTA Level 5 Semester 1 Facilitator Guide
Unataka kutumiwa notes hizi kupitia WhatsApp?Kwa notes zilizopangiliwa vizuri kwa kusoma offline au PDF, bonyeza kitufe hapa chini. Ujumbe wenye Level, Semester, Module na Topic utaandaliwa moja kwa moja.TUMIWA NOTES WHATSAPP
