Introduction to Antiviral, Antifungal and Antiprotozoal Drugs PDF

Introduction to Antiviral, Antifungal and Antiprotozoal drugs Medical Microbiology MD320 Charalampos Filippou PgCert, MSc, PhD, FHEA, FIBMS By the end of this practical the students should be able; ✓ To give major groups and specific examples of the antiviral, antifungal and antiprotozoal drugs....

Introduction to Antiviral, Antifungal and Antiprotozoal drugs Medical Microbiology MD320 Charalampos Filippou PgCert, MSc, PhD, FHEA, FIBMS By the end of this practical the students should be able; ✓ To give major groups and specific examples of the antiviral, antifungal and antiprotozoal drugs. ✓ To describe the mechanisms of action the drugs including their pharmacological effects. ✓ To outline clinical applications of the drugs in medicine. What is a virus? Are viruses living organisms? ANTIVIRAL DRUGS TREATMENT APPROACHES • ULTIMATE EXPRESSION OF PARASITISM • TAKES NUTRITION FROM HOST • HIJACKER - DIRECT HOST`S METABOLIC PATHWAYS TO SYNTHESIZE VIRUS PARTICLES CHALLENGES IN DESIGNING ANTI-VIRAL TREATMENTS: • HOST CELL MUST BE IMMUNE TO TREATMENT! (TO LIMIT OFF-TARGET TOXICITY) • VIRAL INFECTION DISEASE SYMPTOMS OFTEN ASSOCIATED WITH LATENCY PERIOD (REPLICATION AT PEAK WHEN SYMPTOMS APPEAR) – INCUBATION PERIOD THERAPY – IMMUNE SYSTEM MOST IMPORTANT ANTI-VIRAL STRATEGIES ARE TO INHIBIT: 1. VIRAL ENZYMES: • • DNA/RNA POLYMERASES, ETC. REVERSE TRANSCRIPTASES, PROTEASES, ETC. 2. PENETRATION AND UNCOATING 3. REVERSE TRANSCRIPTION 4. ASSEMBLY AND MATURATION 5. RELEASE OF VIRUS Classification • Anti-herpes: ✓ Idoxuridine, acyclovir, valacyclovir, famciclovir, ganciclovir, foscarnet. • Anti-retrovirus ✓ Nucleoside reverse transcriptase inhibitor NRTI: Zidovudine AZT, Didanosine, zalcitabine, abacavir ✓ Nonnucleoside reverse transcriptase inhibitors NNRTI: nevirapine, efavirenz, delavirdine. ✓ Protease inhibitors: Ritonavir, indinavir, nelfinavir, lopinavir • Anti-influenza: Amanatadine, rimantadine • Non selective: Ribavirin, Lamivudine, adefovir, dipdvoxil interferon α. ACYCLOVIR • An acyclic guanosine derivative with clinical activity against HSV-1, HSV-2, and VZV. • 10 times more potent against HSV-1 and HSV-2 than against VZV. • Requires three phosphorylation steps for activation ✓ Firstly converts to the monophosphate derivative by the virus specified thymidine kinase. ✓ Then to the di- and tri-phosphate compounds by host cell enzymes Acyclovir Virus specific enzyme thymidine kinase Resistance to acyclovir can develop in HSV or VZV through alteration in either the viral thymidine kinase or the DNA polymerase Inhibition of viral DNA polymerase → Inhibition of viral replication Monophosphate Host kinases Diphosphate Triphosphate Clinical Use • First episodes of HSV acyclovir (Zovirax) shortens the duration of ✓ Symptoms by approx. 2 days, ✓ Time to healing by 4 days, ✓ Duration of viral shedding by 7 days • Recurrent HSV, the time course is shortened by 1–2 days. • Decreases the frequency of symptomatic recurrences and of asymptomatic viral shedding • VZV is less susceptible to acyclovir than HSV, higher doses are required (oral route). • 400 mg twice daily: may reduce the plasma viral load of HIV-1 and the risk of HIV-associated disease ACYCLOVIR AND CONGENERS Antiviral spectrum : • Acyclovir: HSV-1, HSV-2, VZV, Shingles. • Ganciclovir / Cidofovir : CMV • Famciclovir : Herpes genitalis and shingles • Foscarnet : HSV, VZV, CMV, HIV • Penciclovir : Herpes labialis • Trifluridine : Herpetic keratoconjunctivitis • Uninfected cells do not Phosphorylate acyclovir. Therapeutic uses : Acyclovir is the drug of choice for: • HSV Genital infections • HSV encephalitis • HSV infections in immunocompromised patient Ganciclovir is the drug of choice for: • CMV retinitis in immunocompromised patient (Cidofovir as well) • Prevention of CMV disease in transplant patients VIDARABINE • Its use is limited to HSV keratitis only FOSCARNET • Does not require phosphorylation for antiviral activity Amantadine and Rimantadine : • Prevention & Treatment of influenza A • Inhibition of viral uncoating by inhibiting the viral membrane protein M2 • Influenza A virus • Amantadine cross BBB whereas Rimantadine does not. • Administration: Oral Neuraminidase inhibitors : Influenza Oseltamivir / Zanamavir • Influenza contains an enzyme neuraminidase which is essential for the replication of the virus. • Neuraminidase inhibitors prevent the release of new virions and their spread from cell to cell. • Oseltamivir is orally administered. • Zanamavir is given intranasal. Ribavirin • Is a guanosine analog. • Inhibition of RNA polymerase • Antiviral spectrum : DNA and RNA viruses are susceptible, including influenza, parainfluenza viruses, RSV, Lassa virus RSV • Administration : Oral, IV, Inhalational in RSV. • Anemia and jaundice are adverse effects • Not advised in pregnancy. Therapeutic uses Ribavirin Ribavirin is the drug of choice for: • RSV bronchiolitis and pneumonia in hospitalized children (given by aerosol) • Lassa fever Ribavirin is an alternative drug for: • Influenza, parainfluenza, measles virus, Ebola, Hanta, HCV infections Antivirals for Hepatitis C encompass various drug classes. • Previous treatment involved interferon alfa (IFN-α) and ribavirin targeting viral entry, immune modulation, and viral replication. • New direct-acting antiviral (DAV) agents focus on specific nonstructural (NS) proteins of the hepatitis C virus (HCV) crucial for replication. • DAV categories: NS3A/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors. • Combination therapy with DAVs is common and is the preferred management for hepatitis C. • DAVs have a high success rate and typically lead to milder side effects compared to older treatments. Viral structure of hepatitis C and the proteins that are translated from its genome: • Structural proteins include core, envelope 1 (E1), and E2. NS2, NS3, NS4A, NS4B, NS5A, and NS5B are nonstructural (NS) proteins, most of which are the targets for direct-acting antiviral therapy. Hepatic Viral infections : • Interferons • Lamivudine – cytosine analog – HBV • Entecavir – guanosine analog – HBV – lamivudine resistance strains • Ribavirin – Hepatitis C (with interferons) What are interferons? What are the three classes of interferons? Mechanism of action of Interferons : • Induction of the following enzymes: 1. a protein kinase which inhibits protein synthesis 2. an oligo-adenylate synthase which leads to degradation of viral mRNA 3. a phosphodiesterase which inhibit t-RNA • The action of these enzymes leads to an inhibition of translation Antiviral spectrum of Interferon α: • Includes HBV, HCV and HPV. Antiretroviral Drugs HAART - Highly active antiretroviral therapy Includes at least three medications – “cocktails” • These medications work in different ways to reduce the viral load Anti-Fungal Drugs Classification of antifungal drugs • Based on chemical structures: ✓ The classes include Polyene macrolides, Imidazoles, Fluorinated pyrimidines, Benzo-furans and Iodides • Based on their sites of action: ✓ Either systemic or topical antifungal drugs. • Miscellaneous classifications: ✓ Organic acids and their salts and other inorganic salts Classification based on mechanism of action 1. Fungal cell wall synthesis inhibition: Caspofungin. 2. Bind to fungal cell membrane ergosterol: Amphotercin–B, Nystatin. 3. Inhibition of ergosterol + lanosterol synthesis: Terbinafine, Naftifine, Butenafine. 4. Inhibition of ergosterol synthesis: Azoles 5. Inhibition of nucleic acid synthesis: 5–Flucytosine. 6. Disruption of mitotic spindle and inhibition of fungal mitosis: Griseofulvin. 7. Miscellaneous: Ciclopirox, Tolnaftate, Haloprogin, Undecylenic acid, Topical azoles Azoles • Ketoconazole, Miconazole, Fluconazole, Itraconazole, Voriconazole • • • • • Synthetic antifungals Broad spectrum Fungistatic or fungicidal depending on conc of drug Most commonly used Classified as imidazoles & triazoles Azoles • Imidazoles: Two nitrogen in structure ✓ Topical: econazole, miconazole, clotrimazole ✓ Systemic : ketoconazole ✓ Newer : butaconazole, oxiconazole, sulconazole • Triazoles : Three nitrogen in structure ✓ Fluconazole, itraconazole, voriconazole ✓ Fluconazole can reach the Cerebrospinal fluid (CSF) with good concentrations. The other drugs cannot. ✓ Fluconazole is excreted in the urine mostly unchanged Mechanism of action ❑ Azoles inhibit fungal cytochrome P450 (14 α demthylase )necessary for ergosterol synthesis, a major component of fungal cell membrane. This will alter membrane permeability and disrupt its function. ❑ Are broad spectrum fungistatic against many dermatophytes and candida. Therapeutic uses I. Superficial fungal infections: [ketoconazole – itraconazole – miconazole] 1. Dermatophytes infection of the skin (tinea), hair, and nails (onychomycosis): • For skin infection: treatment continued for 2-4 weeks. • For hair infection: treatment continued for 6-8 weeks. • For nail infection: treatment continued for 3-6 months. 2. Mucocautaneous candidiasis: oropharyngeal, vulvovaginal, etc. II. Systemic fungal infections: [itraconazole – fluconazole – voriconazole] • Itraconazole (orally or IV) is the drug of choice for systemic blastomycosis. • Fluconazole (orally or IV) is the drug of choice for systemic candidiasis, and cryptococcal meningitis (because it is the only azole that can cross to CSF with good concentration). • Voriconazole is the drug of choice for invasive aspergillosis of the lung. Amphotericin-B • Is polar compound that cannot be absorbed from the GIT or cross the CSF. • It should be administered IV or intrathecal. • Half-life is 15 days. • Bind preferentially to ergosterol in the fungal cell membrane with lower affinity to mammalian cell membranes. Mechanism of action • Amphotericin B is polyene macrolide that binds to ergosterol of fungal cell membranes and forms “pores” that alter membrane stability and allow leakage of cellular contents. Therapeutic uses ▪ Amphotericin B has the broadest spectrum of activity. ▪ Treat severe Systemic fungal infections, including those caused by Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis and Aspergillus spp. OTHER ANTIFUNGAL DRUGS Flucytosine I. Mechanism of action • Flucytosine is actively transported into fungal cells and is converted to the uracil form 5-fluorouracil (5-FU) which inhibits nucleic acid synthesis. Human cells lack the ability to convert large amounts of flucytosine into 5-FU. II. Uses • Used in combination with other antifungal agents (because of rapid development of resistance) to treat Severe systemic fungal infections. Griseofulvin I. Mechanism of action • Griseofulvin binds to microtubules and prevents spindle formation and mitosis in fungi. • It is fungistatic and requires long duration of therapy. • The drug binds to keratin structures and accumulates in skin, hair, and nails. II. Therapeutic uses • Used orally for long-term therapy of dermatophyte infections of the hair and nail. Nystain • Nystatin is polyene macrolide very similar in kinetics and mechanism to amphotericin B. • It is too toxic for parenteral administration and is used only topically. • It is active mainly against Candida, and is used topically for oralpharyngeal and vaginal candidiasis. Caspofungin (Cancidas) • It is large cyclic peptide that disrupts the fungal cell wall resulting in cell death. • Works by inhibiting β(1,3)-D-Glucan of the fungal cell wall. • Used by IV route for therapy in i. Severe invasive aspergillosis and candidiasis ii. Esophageal candidiasis who failed to respond to amphotericin B (second line drug). Ciclopirox • Broad-spectrum antifungal effective against dermatophytes and yeasts. • Mechanism is unclear. (Has high affinity for trivalent metal cations which inhibit essential co-factors in enzymes). • Used topically for skin and nail infections. Terbinafine • Act by inhibiting squalene epoxidase, thereby blocking the biosynthesis of ergosterol. • Accumulation of toxic amounts of squalene results in increased membrane permeability and death of the fungal cell. • The drug of choice for treating dermatophyte onychomycoses • Better tolerated, requires a shorter duration of therapy, and is more effective than either itraconazole or griseofulvin Anti-protozoal drugs Antimalarial Drug Drug Principle • In P falciparum and P malariae infection, only one cycle of liver cell invasion and multiplication occurs. ➢ Treatment that eliminates erythrocytic parasites will cure these infections. • In P vivax and P ovale infections, a dormant hepatic stage hypnozoite, is not eradicated by most drugs ➢ Subsequent relapses can therefore occur after therapy directed against erythrocytic parasites. ➢ Eradication of both erythrocytic and hepatic parasites is required to cure these infections ➢ It usually requires two or more drugs Classification: Antimalarial Drug • It can be classified on the basis of action ✓ Tissue schizonticides ✓ Blood schizonticides ✓ Gametocides CHLOROQUINE • Drug of choice for both treatment and chemoprophylaxis of malaria since the 1940s • Usefulness against P falciparum has been seriously compromised by drug resistance • Chemistry & Pharmacokinetics ✓ Synthetic 4-aminoquinoline phosphate salt for oral use ✓ Rapidly and almost completely absorbed from the gastrointestinal tract, ✓ Reaches maximum plasma concentrations in about 3 hours Antimalarial Action & Resistance • Highly effective against blood schizonticide • Moderately effective against gametocytes of P vivax, P ovale, and P malariae but not against those of P falciparum. Treatment • Drug of choice in the treatment of non-falciparum and sensitive falciparum malaria • Rapidly terminates fever (in 24–48 hours) and clears parasitemia (in 48–72 hours) • Replaced by other drugs, principally artemisinin-based • Does not eliminate dormant liver forms of P vivax and P ovale, • Primaquine must be added for the radical cure of these species. • Chemoprophylaxis Contraindications & Cautions • Psoriasis or porphyria: may precipitate acute attacks of these diseases • Retinal or visual field abnormalities or myopathy • History of liver disease or neurologic or hematologic disorders. • Antidiarrheal agent kaolin and calcium- and magnesium-containing antacids interfere with the absorption of chloroquine and should not be co-administered with the drug. • Safe in pregnancy and for young children Artemisinin Antimalarial • Artemisinin monotherapy for the treatment of uncomplicated malaria is now strongly discouraged. • Rather, co-formulated artemisinin-based combination therapies are recommended to improve efficacy ✓ oral combination regimen Coartem • Prevent the selection of artemisinin-resistant parasites • Rapidly acting blood schizonticides against all human malaria parasites. • No effect on hepatic stages Clinical Uses • Standard for treatment of uncomplicated falciparum malaria. • WHO recommends five artemisinin-based combinations for the treatment of uncomplicated falciparum malaria QUININE & QUINIDINE • Important therapies for falciparum malaria ✓ especially severe disease ✓ Resistance is uncommon but may be increasing • Derived from the bark of the cinchona tree Antimalarial Action • Rapid-acting, highly effective blood schizonticide against the four species of human malaria parasites • Gametocidal against P vivax and P ovale but not P falciparum. • Not active against liver stage parasites • Mechanism of action of quinine is unknown. Clinical Uses I. Parenteral Dose ✓ Quinine dihydrochloride or quinidine gluconate ✓ Administered slowly intravenously or, in a dilute solution, intramuscularly in divided doses or by continuous intravenous infusion; II. Cardiac toxicity and the relative unpredictability of its pharmacokinetics, ✓ Treatment should begin with a loading dose ✓ Therapy should be changed to an effective oral agent as soon as the patient has improved III. Oral Treatment ✓ Quinine sulfate ✓ Commonly used with a second drug (most often doxycycline or in children, clindamycin) ✓ Less effective than chloroquine against other human malarias and is more toxic. ✓ Babesiosis: first-line therapy, in combination with clindamycin, in Babesia microti or other human babesial infections. Currently, only two drugs, primaquine and tafenoquine, have been approved for the elimination of P. vivax hypnozoites in the treatment of malaria relapses Tables of antivirals Table: Pharmacokinetics of neuraminidase inhibitors Category Oseltamivir Absorption • Oral • IV • Absorbed rapidly • Single 600-mg dose • Bioavailability not decreased by food • Low plasma protein binding • 30% protein-bound • Half-life: 20 hours Distribution • Peramivir Zanamivir Inhalation • On inhalation, drug reaches oropharynx and lungs • Half-life: 2–3 hours Half-life: 6–10 hours Metabolism No significant metabolism Excretion • Renal • Renal • Unchanged in urine • Unchanged in urine • Requires dose adjustment in renal insufficiency • Requires dose adjustment in renal insufficiency Up to 15% absorbed and excreted in the urine Table: Adverse effects and contraindications of neuraminidase inhibitors Oseltamivir Adverse effects Contraindications Peramivir Zanamivir • Nausea, vomiting • Diarrhea • Sore throat • Headache • • • Hallucination, delirium, confusion Hypersensitivity reactions (SJS, EM) Cough, bronchospasm • Hallucinations, delirium • Hypersensitivity reactions (SJS, EM) • Renal and hepatic function abnormalities • Hypersensitivity to oseltamivir • Hypersensitivity to peramivir • Hypersensitivity to zanamivir • Precaution with cardiovascular, hepatic and renal diseases • Precautions with renal disease • Precautions with COPD and asthma Table: Pharmacokinetics of adamantanes Category Amantadine Rimantadine Absorption Good oral bioavailability Good oral bioavailability Distribution • Half-life: 12–18 hours • Half-life: 24–36 hours • 67% protein-bound • 40% protein-bound Metabolism No significant metabolism Undergoes hepatic metabolism Excretion Renal (excreted unchanged) Renal Table: Major classes of antiretroviral drugs Type of drug Mechanism of action Reverse transcriptase inhibitors • Interfere with the translation of viral RNA into DNA • NRTIs: nucleoside reverse transcriptase inhibitors • Affect reverse transcription • NtRTIs: nucleotide reverse transcriptase inhibitors • NNRTIs: non-nucleoside reverse transcriptase inhibitors • Prevent the insertion of the viral genome into the host DNA • Affect integration • Block the cleavage of protein precursors (by protease) necessary to produce mature infectious viral particles • Affect budding and maturation • Inhibit virion binding via gp120 (attachment inhibitor) or CCR5 receptor (CCR5 antagonist), and virion-host cell fusion (fusion inhibitor) • Affect viral entry Integrase strand transfer inhibitors (INSTIs) Protease inhibitors (PIs) Entry inhibitors: • CCR5 antagonists • Fusion inhibitors • Attachment inhibitors Post-attachment inhibitor Binds CD4 molecule, blocking entry but not the attachment Table: NRTIs and NtRTIs Drug Adverse effects Interactions/contraindications Zidovudine (AZT): • Lactic acidosis, hepatomegaly, hepatic steatosis • Azole antifungals, valproic acid, atovaquone increase plasma levels • Bone-marrow suppression: anemia and neutropenia • • GI: vomiting, diarrhea Caution in anemia, neutropenia, liver dysfunction (requires dose adjustment) • Headache, myopathy, insomnia, nail hyperpigmentation • Diabetes, acute cholestatic hepatitis • Minimal toxicity • Palmoplantar hyperpigmentation, headache, diarrhea, rash • Severe hepatitis in those infected with HBV, if medication is discontinued • Generally well tolerated • Pancreatitis in children • Severe hepatitis in those with HBV, if medication is discontinued • First ARV drug for HIV • Crosses the placenta (prevents mother-to-child transmission) Emtricitabine: structurally similar to lamivudine Lamivudine: active against the hepatitis B virus Abacavir Tenofovir (NtRTI): TAF and TDF (TAF: Hypersensitivity reaction (potentially fatal): fever, rash, abdominal pain, vomiting, dyspnea • GI symptoms Do not combine with lamivudine (the drugs compete with intracellular phosphorylation). Do not combine with emtricitabine (the drugs compete with intracellular phosphorylation). • Contraindicated in patients who are HLAB*5701 positive (risk of hypersensitivity reaction) • Associated with CV events • Concurrent use of didanosine Table: NNRTI drugs Drug Adverse effects Interactions/contraindications Etravirine: most commonly used NNRTI in resistant HIV cases • Rash • Nausea Can interact with other antiretroviral drugs (e.g., if in combination, dose of maraviroc should be doubled) Efavirenz • CNS/psychiatric effects: ↓ concentration, dizziness, dysphoria • Rash • QT prolongation • Hepatitis Avoid in long QT syndrome, liver disease, psychiatric illness Doravirine CNS/psychiatric effects similar to efavirenz (but much less common) Use with rifampin contraindicated (↓ doravirine exposure) Rilpivirine • QT prolongation • • Rash Absorption is pH dependent, so, it should not be administered with PPIs, H2 inhibitors/antacids. • Depression, insomnia, headache • Avoid in long QT syndrome • Hepatic necrosis • • Rash, serious cutaneous reactions If considered, avoid in patients in moderate to severe hepatic disease. • If considered, avoid in women with CD4 count > 250 cells/mL or in men with CD4 count > 400 cells/mL (threshold for Nevirapine: not initial treatment of treatment-naive patients (↑ toxicity) Table: Protease inhibitors Drug Adverse effects Interactions/contraindications Atazanavir • • Food increases absorption and bioavailability. • Avoid PPIs, antacids (reduce atazanavir concentration) • Given with low-dose ritonavir/cobicistat; combination drug increases maraviroc levels (the dose of which needs to be reduced) • Avoid in severe liver disease Darunavir Ritonavir: booster Lopinavir: coformulated with ritonavir Hyperbilirubinemia (indirect), cholestasis/cholecystitis, abnormal LFTs • ↑ Risk of kidney stones • Lower risk of hyperlipidemia than other protease inhibitors • GI symptoms • Hepatotoxicity • Rash • GI symptoms • Paresthesias • Lipid abnormalities • GI symptoms • Lipid abnormalities One of the most potent known inhibitors of CYP3A4; avoid taking drugs with narrow therapeutic index. Not for initial treatment (related to potency and toxicity) Table: Integrase strand transfer inhibitors Drug Adverse effects Interactions/contraindications Raltegravir • Usually well tolerated • GI symptoms most common Enzyme inducers (e.g., rifampin) increase its metabolism by inducing UDP-glucuronosyltransferase. • Dizziness, headache, potential myopathy, depression (suicidal ideation) • Rash Dolutegravir Mild reversible creatinine elevation (inhibits the renal transporter, OCT2) • Contraindicated in patients with Q148 mutation • Enzyme inducers (e.g., rifampin) increases its metabolism by inducing UDPglucuronosyltransferase. Elvitegravir: administered with cobicistat or ritonavir GI symptoms Currently available only in a fixed-dose combination with tenofovir, emtricitabine, and cobicistat (which ↑ drug-drug interactions) Bictegravir: coformulated with emtricitabine and TAF • Diarrhea • Headache Intake with rifampin or dofetilide contraindicated • Weight gain Bibliography