Antifungal Drugs for Oral Candidiasis PDF

Pharmacology II Antifungal Drugs Dr. Dina Abdel Hamid Oral Surgery Division Learning outcomes: 1) Classify different types of Oral Candidiasis. 2) Enumerate the most commonly used antifungal drugs in the dental clinic and describe its pros and cons. 3) Discuss the pharmacokinetics and therapeutic us...

Pharmacology II Antifungal Drugs Dr. Dina Abdel Hamid Oral Surgery Division Learning outcomes: 1) Classify different types of Oral Candidiasis. 2) Enumerate the most commonly used antifungal drugs in the dental clinic and describe its pros and cons. 3) Discuss the pharmacokinetics and therapeutic uses of different antifungals used in treatment of Oral Candidiasis. OUTLINE: -Introduction -Oral Candidiasis -Antifungal drugs: Amphotericin-B (AMB) Nystatin Azoles: Topical: Clotrimazole - Miconazole Systemic: Ketoconazole – Fluconazole Griseofulvin Flucytosine -Management of oral candidiasis Introduction Fungi are group of organisms that include yeasts, molds, and mushrooms. Their cells contain a nucleus enclosed with membranes. The fungal cell structure is similar to that of human cells, except that the cell membrane contains ergosterol instead of cholesterol. Oral Candidiasis The Most Common Fungal Infections Encountered In Dental Practice Oral Candidiasis Oral Candidiasis Candidiasis (Moniliasis) is the most frequently occurring opportunistic fungal infection to affect humans that is produced by the yeast like fungus Candida albicans. Oral Candidiasis Candida albicans is the only fungus that can be a member of human normal flora. It is normally exists in a commensal state in the skin, oral cavity, GIT & vagina of humans. C. albicans is typically well tolerated, and is viewed as being non-pathogenic. The shift from a state of commensalism to a pathogenic infection is almost always associated with an underlying predisposing factor that may include: Systemic Factors (Immunosuppression): 1) 2) 3) 4) AIDS Malignancy Diabetes mellitus (DM) Medications Broad-spectrum antibiotics Local Factors: 1) Poor oral hygiene 2) Acrylic dentures 3) Decreases in salivary flow (xerostomia) Classification of oral candidiasis 1. Pseudomembranous Candidiasis (Thrush) 2. Erythematous (atrophic) candidiasis 3. Chronic Hyperplastic Candidiasis (Candidal leukoplakia) Diagnosis of oral candidiasis: It is based on clinical signs (variety of clinical presentations) and symptoms (burning sensation, dysgeusia (taste alteration), or dysphagia (difficulty of swallowing). ▪ In some cases, culture or biopsy may be necessary. 1-Pseudomembranous Candidiasis (Thrush): The most commonly seen form of oral candidiasis. It is characterized by the presence of soft friable and creamy white plaques on the mucosa that can be wiped off, leaving a red raw or bloody and painful mucosal surface. It may be painless or associated with burning sensation and/or dysgeusia (sense of taste abnormalities). It affects buccal and labial mucosa, palate, tongue, and oropharynx. 2-Erythematous (atrophic) candidiasis It manifests as a flat raw-looking painful red patches that devoid of the pseudomembranous coating. ▪ It is commonly associated with burning sensation. Common clinical presentations: 1. Median rhomboid glossitis that is characterized by depapillation for the dorsal surface of the tongue. 2. Kissing lesion in the hard/soft palates. 3. Angular cheilitis (inflamed corner of the mouth) is common in patients wearing dentures. 4. Denture stomatitis: an erythematous candidiasis may occur in a patient wearing a dental prosthesis, in which case the erythema is usually limited to the denture-bearing surface. 3-Chronic Hyperplastic Candidiasis It presents as white papules or plaques that cannot be easily scraped off or wiped off. ▪ It represents the least commonly observed form. ▪ It commonly affects the corners of the mouth and on the dorsal surface of the tongue. ANTIFUNGAL DRUGS Antifungal Drugs: Antifungal agents are characterized by their antifungal spectrum and antifungal activities. The antifungal spectrum of an antifungal indicates the range of fungi that are inhibited by the agent. If an antifungal agent inhibits a large variety of fungi, including yeasts and molds, it is considered a broad-spectrum antifungal. If it inhibits a limited range of fungi, it is considered a narrow-spectrum antifungal. Antifungal drugs Activities can be: Fungistatic (inhibiting the growth of fungi). Fungicidal (causing cytotoxicity in fungi = kill fungi). Classification of Antifungal drugs: 1. Drugs that disrupt the fungal cell membrane: ▪ Polyenes: Amphotericin B (AMB), Nystatin. ▪ Azoles: Topical: Clotrimazole - Miconazole Systemic: Ketoconazole – Fluconazole 2. Drugs that inhibit mitosis: ▪ Griseofulvin 3. Drugs inhibiting the DNA synthesis: ▪ Flucytosine Amphotericin-B (AMB) Amphotericin-B (AMB) Amphotericin-B Chemistry: − It is a polyene antibiotic. (Antifungal Antibiotic) - It is naturally derived from a strain of bacterium streptomyces nodosus. Spectrum of Activity: − It has a broad spectrum antifungal activity. Mechanism of Action − It is fungistatic at low concentrations and fungicidal at high concentrations. − Amphotericin B has a high affinity to bind to the ergosterol, which is present in the fungal cell membrane, this bind forms micropores through which the cell contents like electrolytes, ions and water leak out resulting in cell death. What is the cause of the severe toxicity in host cells associated with Amphotericin-B “AMB”? Cholesterol present in the host cell closely resembles ergosterol and that accounts for severe toxicity in host cell.(it kills host cell and the fungal cell) Amphotericin-B Pharmacokinetics: ▪ Absorption: -It is not absorbed from the skin or mucous membranes into blood stream. − It is not absorbed from the gastrointestinal tract (so, it can be given orally to treat intestinal candidiasis without systemic toxicity). − For dangerous systemic fungal infections, Amphotericin B is administered intravenously because it is not absorbed via the gastrointestinal tract. Distribution: -If given IV, it has wide distribution in the body except CSF. − It is relatively toxic as it can interact with cholesterol in human cell membranes. − It causes fever, chills, myalgias (muscle pain), hypotension and headache. − It can cause renal dysfunction. Excretion: − Slowly excreted in the urine and bile. Amphotericin-B Therapeutic Uses: − Topical treatment of oral, cutaneous and vaginal candidiasis. (locally) − AMB is the most effective drug for dangerous systemic fungal infections. However, because of higher toxicity, azoles are preferred now. Available Preparations: ▪ Parenteral: 50 mg powder for IV-injection. ▪ Topical: Gel Nystatin Nystatin Chemistry:. − It is a polyene antibiotic. (Antifungal Antibiotic) -It is naturally derived from a strain of bacterium streptomyces noursei. Spectrum of Activity: − It is a narrow spectrum antifungal drug. Mechanism of Action − It is structurally similar to amphotericin B, and its mechanism of action and pharmacokinetics are the same. What is the cause of the severe toxicity in host cells associated with Nystatin? Cholesterol present in the host cell closely resembles ergosterol and that accounts for severe toxicity. Nystatin Therapeutic Uses: − Topical treatment of mucocutaneous, oropharyngeal, and vaginal candidiasis Available Preparations: − Pastille / lozenge/ Troche: 500.000 units. (It is designed to dissolve slowly in the mouth to deliver the medication directly to the mucous membranes of the mouth and throat). − Oral suspension: 100,000 units/ml. − Ointment - Cream: 100,000 units/g. N.B: No IV administration (as it has a toxic effect), no tablets form as it has poor absorption from GIT. Azoles Azoles -It is a synthetic compounds and have a broad spectrum antifungal activity. Topical: Clotrimazole - Miconazole Systemic: Ketoconazole – Fluconazole Mechanism of Action: − They inhibit enzymes involved in the biosynthesis of ergosterol, a major component of the fungal membrane, so disruption of the structure of the cell membrane. CLOTRIMAZOLE & MICONAZOLE: (Topical) They are used topically in the treatment of oropharyngeal candidiasis and denture stomatitis. Azoles ▪ KETOCONAZOLE: (Systemic) − It is the first orally effective azole (tablets) used in the treatment of systemic fungal infection. − It is well absorbed from GIT and distributed widely in all tissues except CSF. Adverse Effects: 1) Decreased libido in men secondary to impairment of testosterone synthesis. 2) Hepatotoxicity. 3) Teratogenicity. Therapeutic Uses: 1) Antidandruff shampoo (Nizoral). 2) Oral ketoconazole (tablets) was used in treatment of systemic candidiasis. Azoles FLUCONAZOLE: (Diflucan) − It is available for oral and intravenous administration. − It is well absorbed from GIT and distributed widely in all tissues including CSF. − Therapeutic Uses: 1) Treatment of systemic fungal infection (e.g., Candida) 2) Prophylaxis against candidiasis in immunocompromised patients (e.g., AIDS patients). AVOID AZOLES IN THE FOLLOWING CASES: − Patients on warfarin, as Azoles interact with warfarin, increase the effect of Warfarin (risk of bleeding) − Pregnant women. − Babies younger than 6 months. − Patients on statin (Cholesterol reduction medication), increased risk of muscle- related side effects. Griseofulvin Griseofulvin Chemistry: − It is a benzofuran antibiotic (naturally derived from Penicillium griseofulvum). Spectrum of Activity: − It is a broad spectrum antifungal. Mechanism of Action : − It is fungistatic antifungal drug. − It interferes with mitosis. Therapeutic Uses: It is used orally for superficial candidiasis, superficial skin ring worm and tinea pedis. tinea pedis Griseofulvin Pharmacokinetic: Absorption: Absorbed in the intestine following oral administration. Distribution: It has wide distribution in the body. Excretion: Most of the drug is eliminated in the urine. Dose for Oral Candidiasis: Rx: Griseofulvin 250 mg tablet four times per day “QID” for 3 weeks Flucytosine Flucytosine Mechanism of Action −Flucytosine interferes with DNA synthesis leading to fungal cell death. -Therapeutic Uses: − It is used orally for the treatment of systemic infections caused by Candida. MANAGEMENT OF ORAL CANDIDIASIS Management of Oral Candidiasis In all cases, the goals of therapy are: 1) Management of the predisposing factor(s). 2) Administration of symptomatic relief. (Analgesic) 3) It is highly recommended for patients affected by oral candidiasis to: -Follow strict oral hygiene guidelines. (brushing teeth-limit sugary and yeast containing food-proper hydration-mouth wash). -Replace their contaminated oral hygiene devices (toothbrushes, denture brushes). -The prosthesis should not be worn during sleep. − The prosthesis should be soaked in a commercial denture solutions that exhibit antifungal properties, such as Nystatin solution, Chlorhexidine Gluconate, and Sodium Hypochlorite. 4) Antifungal drugs. Primary line of therapy of Oral Candidiasis For mild localized lesions the use of a topical antifungal agent such as nystatin or clotrimazole is usually effective. ▪Clotrimazole 10-mg troches ▪Disp: 70 troches ▪Sig: Let 1 troche slowly dissolve in mouth 5 times per day. Topical therapy should be continued for another 5 days after the improvement. N.B: Disp: stands for dispense and followed by specific instructions for the pharmacist regarding: quantity dosage and form. Sig: followed by instructions for patients regarding how to take medication dosage, frequency, duration. Secondary line of therapy For patients nonresponsive to topical treatment: Available drugs include ketoconazole and Fluconazole Fluconazole is usually the drug of choice as it is readily absorbed and exhibits a better safety than ketoconazole. ▪Fluconazole (Diflucan), 100-mg tablets ▪Sig: Take 2 tablets start, then take 1 tablet daily until gone Pharmacology II Antiviral Drugs Dr. Dina Abdel Hamid Oral Surgery Division LEARNING OUTCOMES: 1)Describe the reason for the difficulty associated with the treatment of viral infections. 2) Enumerate the most commonly used antiviral drug in the dental clinic and describe its pros and cons. 3) Discuss the pharmacokinetics of different antivirals used in treatment of herpes simplex. OUTLINE: -Introduction -Types of Human Herpes Viruses -Antiviral drugs: Acyclovir Penciclovir Ganciclovir Famciclovir -Home message INTRODUCTION Viruses Viruses are tiny (microscopic) infectious agents that grow and multiply only inside living cells of an organism. The virus is an obligate intracellular organism. (i.e. it depends upon the host cells for their growth and multiplication). It attaches itself to the host cell membrane, penetrates the cell, releases its nucleic acid into the host cell where it is duplicated. Antivirals can interfere with any of these steps. Therefore, to kill the virus, the host’s cell must also be harmed. Viruses Herpes simplex viruses are the most common and can usually be managed with supportive therapy. Management of oral viral infections is usually involves: (supportive measures) Rest Plenty of fluids Soft diet Antipyretic analgesics (to reduce pain and fever). Antimicrobial mouthwash to reduce secondary infection. Chlorhexidine or hydrogen peroxide are suitable agents. Antiviral drugs Types of Human Herpes Virus Types of Human Herpes Virus Herpes Simplex Virus (HSV): Herpes simplex virus HSV-1: -Primary herpes simplex infections -Secondary (recurrent) Herpes Labialis Herpes simplex virus HSV-2: Genital Herpes Simplex Virus Varicella Zoster Virus (VZV): Herpes zoster virus (HZV) shingles. Herpes Simplex Virus Herpes Simplex Virus (HSV) There are two herpes simplex virus (HSV-1 or HSV-2) that are distinguished by DNA hybridization (a technique used to detect and analyze viral DNA). Herpetic Lesions of Interest To The Dentist 1-Herpetic Gingivostomatitis: Primary herpes simplex infections (HSV-1) : -It is a combination of gingivitis and stomatitis (inflammation of oral mucosa). - Affects mainly children. - The incubation period is approximately five days. - Sores and ulcers inside the cheeks or gingiva. - Not able to chew or swallow. - Halitosis (bad breath). - Management is primarily with supportive measures as outlined above. Herpetic Lesions of Interest To The Dentist 2-Herpes Labialis: Secondary (recurrent) herpes simplex infections (HSV-1) : - Cold sores typically affect the lips. - Following a primary herpetic gingivostomatitis infection, herpes simplex virus remains latent in the trigeminal ganglion. Approximately one third of people develop herpes labialis and a secondary infection from reactivation of the virus. Herpetic Lesions of Interest To The Dentist 3-Herpetic Whitlow: -Typically on a finger or thumb. -Swelling, reddening and tenderness of the infected Part, fever and swollen lymph nodes. -In children, it is transferred by cutting, sucking of fingernail. -In adults, it is more common for the primary source to be the genital region. 4-Herpetic conjunctivitis Herpetic Lesions of Interest To The Dentist Orofacial varicella zoster infections (VZV) Synonyms: shingles (herpes zoster virus HZV) -It is a viral infection that causes a painful rash, it is caused by Varicella Zoster Virus (VZV), which is the same virus that causes Chickenpox. After a person recovers from chickenpox, the virus can lie dormant in the body and reactivate years later causing shingles (painful rash with blisters often on one side of the body). Chickenpox shingles ANTIVIRAL DRUGS Acyclovir Penciclovir Ganciclovir Famciclovir Acyclovir [ay-SYE-kloe-veer] (Zovirax®) (Zovirax®) (Zovirax®) Acyclovir (Zovirax®) Acyclovir is an antiviral medication that works by interfering with the viral DNA synthesis. Acyclovir is effective and exerts its action on infected cells. It is non toxic to normal non infected cells. Pharmacokinetics: Absorption: When acyclovir is taken orally, it has a poor absorption. Distribution: Acyclovir is distributed widely throughout the body and CSF “crosses BBB”. Metabolization and Excretion: Drug is excreted without change “unmetabolized” by the kidney. Acyclovir (Zovirax®) (Treatment of HSV): Treatment of HSV: Primary herpetic infection: Moderate to severe primary herpetic gingivostomatitis is treated with Oral & Topical Acyclovir along with symptomatic measures (Antipyretics “Acetaminophen”). Secondary (recurrent) herpetic infection (Herpes Labialis): Acyclovir doesn't prevent recurrence nor the transmission of infection. Acyclovir doesn’t cure HSV infection but it decreases signs and symptoms associated with HSV infection and shortening the duration. Acyclovir should be limited to immunocompromised patients. In severe cases IV injection of Acyclovir is administered. Rx: 400mg tab PO TID / 5 Days Rx: 1 gm vial IV TID / 5 Days Penciclovir [pen-CY-klo-veer] (Denavir®) (Denavir®) (Zovirax®) (Zovirax®) PENCICLOVIR It is only administered topically. It reduces the duration and pain of the herpes labialis lesions. Advantages over the Acyclovir: 1. It achieves a higher intracellular concentration. 2. It remains longer in the cells. PENCICLOVIR Herpes labialis GANCICLOVIR (Cymevene®) GANCICLOVIR Clinical Uses: It is an analog of Acyclovir. It has a greater activity against management of Cytomegalovirus CMV retinitis (serious eye infection) in HIV/AIDS patients and immunocompromised patients such as organ transplant patients. ▪ Pharmacokinetics: It is administered intravenously and distributed throughout the body including the CSF. Adverse effects: -Neutropenia (lower number of neutrophils which is a type of white blood cells that play role in fighting infection). -Carcinogenic. -Teratogenic (causes malformation in a developing fetus). FAMCICLOVIR [fam-CY-klo-veer] (Famvir®) FAMCICLOVIR ▪ The drug is effective orally and is similar to acyclovir but has better absorption rate, which allows for less frequent dosing. ▪ It is a prodrug that is converted to penciclovir and acyclovir, as it passes through the intestinal wall. ▪ Clinical Uses: Management of Varicella Zoster Virus Infection shingles (Herpes Zoster). Recurrent Herpes Genitalis Acute Herpes Zoster Home Message Home Message ACYCLOVIR ----- Herpes Simplex Virus “HSV” PENCICLOVIR ---- Herpes Simplex Virus “HSV” GANCICLOCIR----- Cytomegalovirus “CMV” FAMCICLOVIR ---- Herpes zoster HZV Reference Reference Thank you