2023 Pharmacology Slides (PDF)

Protein Synthesis Inhibitors / Clindamycin • • • • • • • • • Clindamycin Chlorine-substituted derivative of lincomycin MOA same as macrolides Resistance mechanisms as macrolides To treat infections caused G +ve, such as MRSA, streptococcus, and anaerobic bacteria (treatment of skin and soft-tissue...

Protein Synthesis Inhibitors / Clindamycin • • • • • • • • • Clindamycin Chlorine-substituted derivative of lincomycin MOA same as macrolides Resistance mechanisms as macrolides To treat infections caused G +ve, such as MRSA, streptococcus, and anaerobic bacteria (treatment of skin and soft-tissue infections) Oral and IV Distributes well to all body fluids but poor entry into CSF Extensive oxidative metabolism to active and inactive metabolites – excreted into bile and urine C. difficile is resistant – treatment with vancomycin or metronidazole Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 100 Chapter 31 Quinolones, Folic Acid Antagonists, and Urinary Tracy Antiseptics (Antibacterial Drugs) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 101 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 102 Quinolones • Fluoroquinolones ➢Overview: • 1st generation - Nalidixic acid (prototype) • Further modifications of quinolone nucleus – expanded spectrum of activity, improved PK, and stable against common mechanisms of resistance – Fluoroquinolones (fluorinated nucleus) • 2nd generation (e.g. ciprofloxacin) / 3rd generation (levofloxacin) / 4th generation (moxifloxacin, gemifloxacin, delafloxacin) • Became 2nd line options for various indications due to resistance to G –ve and G +ve organisms and increased frequency of C. difficile Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 103 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 104 Quinolones • Fluoroquinolones ➢MOA: • Bind to and inhibiting bacterial DNA gyrase and topoisomerase IV • DNA gyrase – reducing torsional stress ahead of replicating forks by breaking double-strand DNA • Topoisomerase IV – separating daughter chromosomes once replication is completed • Fluoroquinolones interfere with DNA ligation – rapid cell death Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 105 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 106 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 107 Quinolones • Fluoroquinolones ➢Spectrum and Clinical Uses: • G +ve and G –ve organisms / anaerobic organisms • Ciprofloxacin – anthrax / UTIs / GIT infections / traveler’s diarrhea / typhoid fever • Levofloxacin – UTIs / respiratory infections – community-acquired pneumonia • Moxifloxacin – anaerobic infections / respiratory infections – communityacquired pneumonia • Gemifloxacin – community-acquired respiratory infections Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 108 Quinolones • Fluoroquinolones ➢Resistance: • Altered target binding • Decreased accumulation – permeability and efflux pumps • Enzymatic degradation – acetylation Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 109 Quinolones • Fluoroquinolones ➢PK: • Absorption • Well absorbed after oral administration • Levofloxacin and moxifloxacin – highest bioavailability • Al- or Mg-containing antacids + Fe or Zn containing supplements + Ca and other divalent cations – interfere with their absorption • Distribution • Distribute well into all tissues and body fluids • High concentrations in bone, urine (except moxifloxacin), kidney, prostatic tissue, lungs • Penetrate into CSF – considered in certain CNS infections Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 110 Quinolones • Fluoroquinolones ➢PK: • Elimination • Excreted renally • Moxifloxacin – metabolized primarily by the liver ➢Adverse reactions: • Nausea, vomiting, diarrhea • Headache • Dizziness • CNS effects (hallucinations, anxiety, insomnia, confusion, seizures) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 111 Quinolones • Fluoroquinolones ➢Adverse reactions: • • • • • Tendinitis, tendon rupture Peripheral neuropathy Phototoxicity – sunscreen Arrhythmia – QTc interval prolongation Drug-drug interactions Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 112 Folate Antagonists ➢Overview: • Folic acid – coenzyme essential for the synthesis of RNA, DNA, and certain amino acids • Absence of folate – cells cannot grow or divide • Critical folate derivative – tetrahydrofolic acid • Humans (dietary folate) vs. bacteria (de novo folate synthesis) • Sulfonamides (sulfa drugs) – inhibit de novo synthesis of folate • Trimethoprim – prevents microorganisms from converting dihydrofolic acid to tetrahydrofolic acid • Combination – synergistic effect Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 113 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 114 Folate Antagonists / Sulfonamides • Sulfonamides (e.g. sulfamethoxazole, sulfadiazine, sulfasalazine) ➢MOA: • Synthetic analogs of PABA • Compete with PABA • Bacteriostatic ➢Spectrum: • G +ve and G –ve Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 115 Folate Antagonists / Sulfonamides • Sulfonamides (e.g. sulfamethoxazole, sulfadiazine, sulfasalazine) ➢Resistance: • Some bacteria obtain folate from their environment – naturally resistant • Acquired mechanisms: • Altered dihydropteroate synthetase • Decreased cellular permeability • Enhanced production of PABA Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 116 Folate Antagonists / Sulfonamides • Sulfonamides (e.g. sulfamethoxazole, sulfadiazine, sulfasalazine) ➢PK: • Absorption • • • • Well absorbed after oral administration Sulfasalazine not absorbed – used for chronic inflammatory bowel diseases – act locally IV available Silver sulfadiazine (safer) or mafenide – topically for burn associated sepsis –prevent colonization of bacteria • Distribution • Binds to serum albumin and distributed widely in body tissues • Penetrates well into CSF and placental barrier Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 117 Folate Antagonists / Sulfonamides • Sulfonamides (e.g. sulfamethoxazole, sulfadiazine, sulfasalazine) ➢PK: • Metabolism • Acetylation + conjugation in liver • Acetylated metabolite – ppt. at neutral or acidic pH – crystalluria + kidney damage • Excretion • Unchanged sulfa drugs and metabolites are eliminated via glomerular filtration and secretion • May be eliminated in breast milk Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 118 Folate Antagonists / Sulfonamides • Sulfonamides (e.g. sulfamethoxazole, sulfadiazine, sulfasalazine) ➢Adverse effects: • Crystalluria • Hypersensitivity • Hematopoietic disturbances • Kernicterus • Drug potentiation • Contraindications – newborns and infants less than 2 months of age / pregnant women / patients receiving methenamine (crystallize in presence of formaldehyde) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 119 Folate Antagonists / Trimethoprim • Trimethoprim ➢MOA: • Potent inhibitor of bacterial dihydrofolate reductase • Binds to bacterial enzyme more readily than human enzyme – selective toxicity • Prevents the formation of metabolically active form of folic acid (tetrahydrofolic acid) ➢Spectrum: • G +ve and G –ve / 20- to 50-fold more potent than sulfonamides • May be used alone for UTIs and bacterial prostatitis Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 120 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 121 Folate Antagonists / Trimethoprim • Trimethoprim ➢Resistance: • Altered dihydrofolate reductase • Decreased permeability ➢PK: • Rapidly absorbed after oral administration • Widely distributed into body tissues and fluids including CSF • Undergoes some O-demethylation • 60% to 80% - renally excreted Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 122 Folate Antagonists / Trimethoprim • Trimethoprim ➢Adverse effects: • Produce effects of folic acid deficiency – megaloblastic anemia, leukopenia, granulocytopenia (especially pregnant patients and those with nutrient-poor diets) – reversed by folinic acid (leucovorin) • Hyperkalemia Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 123 Folate Antagonists / Cotrimoxazole • Cotrimoxazole ➢Overview: • Combination of trimethoprim + sulfamethoxazole // Synergistic activity • Spectrum, resistance, PK, and adverse effects – similar to individual drug • Uses: • • • • • • MRSA Respiratory infections – H. influenzae Septicemia and meningitis caused by Listeria monocytogenes Prostate and UT infections GI infections (shigellosis and nontyphoid salmonella) Toxoplasmosis gondii (sulfadiazine + pyrimethamine = preferred) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 124 Urinary Tract Antiseptics ➢Overview: • High resistance to fluoroquinolones and cotrimoxazole in common pathogen as E. coli – new drugs needed • Methenamine / Nitrofurantoin • For treatment or suppression of recurrence • High efficacy against common pathogens and high concentrations in urine Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 125 Urinary Tract Antiseptics ➢Methenamine: • MOA • Hydrolyzed to ammonia + formaldehyde in acidic urine (pH ≤ 5.5) • Formaldehyde denatures proteins and nucleic acids – bacterial cell death • Combines with weak acid (hippuric acid/mandelic acid) – maintain acidity Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 126 Urinary Tract Antiseptics ➢Methenamine: • Spectrum • Used for chronic suppressive therapy to reduce frequency of UTIs • E. coli, Enterococcus spp., Staphylococcus spp., some activity against Proteus and Pseudomonas aeruginosa. • Lack of selection for resistant organisms • PK • Orally absorbed / enteric coating is needed to avoid 30% decomposition • Reaches urine through tubular secretion and glomerular filtration • Ammonia production – avoid use in hepatic insufficiency Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 127 Urinary Tract Antiseptics ➢Methenamine: • Adverse effects • GI distress • High doses – albuminuria, hematuria, rashes • Methenamine mandelate is contraindicated in patients with renal insufficiency – precipitation of acid • Methenamine taken with sulfonamides are contraindicated – high risk of crystalluria Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 128 Urinary Tract Antiseptics ➢Nitrofurantoin: • 1st line therapy for uncomplicated cystitis • Inhibits DNA and RNA synthesis • Orally • Rapid absorption – and then 40% excreted unchanged in the urine • Adverse effects: nausea, vomiting, and diarrhea Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 129 Chapter 32 Antimycobacterial Drugs (Antibacterial Drugs) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 130 Antimycobacterial Drugs ➢Overview: • Mycobacteria are rod-shaped aerobic bacilli • Multiply slowly and high ability to develop resistance • Intracellular pathogens – can reside within macrophages • Cell wall contains mycolic acid – long-chain, β-hydroxylated fatty acids – essential component • Lipophilic lipid-rich cell wall • Mycobacterial infections – slow-growing, granulomatous lesions – tissue destruction throughout the body • Lungs – mostly affected – disease = tuberculosis (TB) – caused by Mycobacterium tuberculosis Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 131 Antimycobacterial Drugs ➢Overview: • Lungs – mostly affected – disease = tuberculosis (TB) – caused by Mycobacterium tuberculosis • Latent tuberculosis infection (LTBI) – patient is infected with M. tuberculosis without signs and symptoms – dormant mycobacteria within macrophages • TB treatment: • Four 1st line drugs – (e.g. Isoniazid / rifampin / pyrazinamide / ethambutol) • 2nd line drugs used when 1st line drugs ineffective (resistant TB) or patient cannot tolerate 1st line drugs (e.g. aminoglycosides / fluoroquinolone / cycloserine / macrolides) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 132 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 133 Antimycobacterial Drugs ➢Overview: • TB treatment: • Due to slow growth of M. tuberculosis – treatment ranges from months to years • LTBI can be treated for 9 months with isoniazid monotherapy • TB – at least 6 months // multidrug-resistant TB (MDR-TB) – 2 years • TB or MDR-TB – must be treated with multiple drugs • Standard regimen = see figure • MDR-TB – 2nd line drugs + any effective drug from 1st line Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 134 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 135 Antimycobacterial Drugs ➢Isoniazid: • MOA • Most active drug for the treatment of TB caused by susceptible strains • Prodrug – activated mycobacterial catalaseperoxidase (KatG) • Active form targets enzymes required for mycolic acid synthesis [acyl carrier protein reductase (InhA) + β-ketoacyl-ACP synthase (KasA)] • Inhibit mycolic acid synthesis • Active against rapidly growing cells + intracellular organisms - bactericidal Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 136 Antimycobacterial Drugs ➢Isoniazid: • Resistance: • Mutation or deletion of KatG • Mutations of acyl carrier proteins • Overexpression of InhA • PK: • Readily absorbed after oral administration • Taken on empty stomach • Diffuses into all body fluids and cells including CSF • Undergoes n-acetylation and hydrolysis – excreted through glomerular filtration and secretion Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 137 Antimycobacterial Drugs ➢Isoniazid: • Adverse effects: • Hepatitis (most serious) • Peripheral neuropathy • Convulsions • Rashes • Fever • Drug-drug interaction – inhibit metabolism of carbamazepine and phenytoin – causing ataxia and nystagmus Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 138 Antimycobacterial Drugs ➢Rifamycins (e.g. rifampin, rifabutin, and rifapentine) ➢Rifampin • Broader spectrum than isoniazid – different bacterial infections • MOA • Blocks RNA transcription – interacting with mycobacterial DNAdependent RNA polymerase • Spectrum • Bactericidal • Intracellular and extracellular mycobacteria • G +ve and G –ve organisms Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 139 Antimycobacterial Drugs ➢Rifamycins (e.g. rifampin, rifabutin, and rifapentine) ➢Rifampin • Resistance • Mutations in RNA polymerase • PK • Adequate absorption after oral administration • Distribution to all body fluids and organs (CSF concentrations are between 10% to 20% of blood concentrations) • Taken up by liver and undergoes enterohepatic recycling • Elimination of rifampin and its metabolites mainly through the bile and into feces / small percentage in urine Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 140 Antimycobacterial Drugs ➢Rifamycins (e.g. rifampin, rifabutin, and rifapentine) ➢Rifampin • Adverse effects • Nausea, vomiting, rash • GI upset • Flu-like syndrome (fever, chills, myalgia) • Hepatitis and death (rare) • Drug interactions • See figure / rifabutin may be used Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 141 Antimycobacterial Drugs ➢Pyrazinamide • Used for short period in combination with other drugs / taken orally • Prodrug – activated to pyrazinoic acid by mycobacterial pyrazinamidase • Taken up by macrophages and exerts its activity against mycobacteria residing within the acidic environment of lysosomes • Active at low pH (5.5) • Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport functions • Act as “sterilizing” agent active against residual intracellular organisms that may cause relapse • Adverse effects: nausea, hepatitis, hyperuricemia, rash, joint ache, gout (rare) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 142 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 143 Antimycobacterial Drugs ➢Ethambutol • Bacteriostatic / specific for mycobacteria • Inhibits arabinosyl transferases – required for synthesis of cell wall – involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall • Distributes well throughout the body (not adequate concentrations for tuberculous meningitis) • Parent drug and its hepatic metabolites are excreted in the urine • Adverse effects: optic neuritis – diminished visual acuity (blurred vision) + red-green color blindness / uric acid excretion is decreased Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 144 Chapter 33 Antifungal Drugs Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 145 Antifungal Drugs ➢Overview: • Infectious diseases caused by fungi – mycoses • Mycotic infections: Cutaneous mycoses (skin-extending into the epidermis) or subcutaneous or systemic infections • Fungi: Eukaryotic, rigid cell wall (chitin), cell membrane (ergosterol) // targets for chemotherapeutic agents • Medications are selective (antifungal drugs; antibiotics are ineffective) • Increased incidence of mycoses due to various reasons: e.g. cancer chemotherapy, HIV, organ transplantation. (Immune suppression) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 146 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 147 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 148 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 149 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 150 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Amphotericin B: • Amphoteric polyene macrolide • Naturally occurring – produced by Streptomyces nodosus • Drug of choice for several life-threatening mycoses • Water insoluble - colloidal suspension of amphotericin B and sodium deoxycholate or liposomes – parenterally (slow IV infusion) • Oral amphotericin B – local GI tract treatment Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 151 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Amphotericin B: • MOA: • Fungicidal • Binds to ergosterol – forming pores – disrupt membrane function – leakage – cell death • Antifungal Spectrum: • Wide • Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, and many strains of Aspergillus Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 152 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 153 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Amphotericin B: • Resistance: • Ergosterol content and structure • PK: • Water insoluble - colloidal suspension of amphotericin B and sodium deoxycholate or liposomes – parenterally (slow IV infusion) • Extensively bound to plasma proteins • High distribution – but little of drug is found in CSF (intrathecal administration), vitreous humor, peritoneal fluid, synovial fluid • Excreted in the urine over a long period of time Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 154 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Amphotericin B: • Adverse effects: • Fever, chills, kidney failure, hypotension, anemia, thrombophlebitis • Infusion-related toxicity: • Fever, chills, muscle spasm, headache, hypotension, vomiting • Subside with repeated administration / ameliorated by decreasing infusion rate or daily dose • Prevented with premedication: corticosteroid, antipyretic • Cumulative toxicity: • Renal damage (most significant toxicity) • Decreased glomerular filtration rate + decreased renal tubular function Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 155 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Amphotericin B: • Adverse effects: • Cumulative toxicity: • Creatinine clearance decrease • K and Mg wasting • Renal tubular acidosis • Reversible, but residual damage at high doses (> 4g cumulative dose; prolonged) • Azotemia – might require dialysis / hydration might decrease its severity • Risk of nephrotoxicity minimized by normal saline infusion prior amphotericin B administration Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 156 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Antimetabolite antifungals (Flucytosine) (5-FC): • Synthetic pyrimidine • Combined with other antifungal agents (Amphotericin B + 5-FC – synergistic effect + safer) • MOA: • Fungistatic • Selective toxicity; no effect on human cells (lack of enzymes) • Disrupting nucleic acid and protein synthesis Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 157 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 158 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Antimetabolite antifungals (Flucytosine) (5-FC): • Antifungal spectrum: • Restricted (narrow) • Combined with amphotericin B (for treatment of systemic mycoses and for meningitis caused by C. neoformans and C. albicans) or itraconazole (a triazole, for the treatment of chromoblastomycosis) • Not used alone; high susceptibility of resistance • Resistance: • Altered metabolism of 5-FC Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 159 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Antimetabolite antifungals (Flucytosine) (5-FC): • PK • Well-absorbed orally • Distributes throughout body water and penetrates into CSF • 5-FU detectable in patients due to metabolism by intestinal bacteria • Excretion (parent drug + metabolites) in the urine via glomerular filtration • Adverse effects: • Due to formation of 5-FU by intestinal bacteria • Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia • Nausea, vomiting, diarrhea, severe enterocolitis, reversible hepatic dysfunction with elevation of serum transaminases Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 160 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Azole antifungals (imidazoles + triazoles): • Similar MOA and spectra of activity • Differ in PK properties and therapeutic use • Imidazoles: applied topically for cutaneous infections • Triazoles: administered systemically for the treatment or prophylaxis of cutaneous and systemic mycoses • Triazoles: e.g. fluconazole, itraconazole, posaconazole, voriconazole, isavuconazole Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 161 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 162 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Azole antifungals (imidazoles + triazoles): • MOA: • Fungistatic • Reduce ergosterol synthesis • Inhibit 14 α-demethylase – blocking demethylation of lanosterol to ergosterol – disrupts fungal membrane function and structure – inhibit fungal cell growth • Resistance: • Mutations in the 14 α-demethylase gene • Efflux pumps Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 163 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 164 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Azole antifungals (imidazoles + triazoles): • Drug interactions: • All azoles inhibit the hepatic CYP450 3A4 isoenzyme to varying degrees • Concomitant medications that are substrate for the above enzymes – result in high concentrations and toxicity – drug-drug interactions • Several azoles, such as itraconazole and voriconazole, are metabolized by CYP450 3A4 and other CYP450 isoenzymes – drug-drug interactions with CYP450 inhibitors (ritonavir) and inducers (rifampin, phenytoin) will occur • Imidazoles exhibit a lesser degree of selectivity than the triazoles, accounting for their higher incidence of drug interactions and adverse effects Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 165 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Azole antifungals (imidazoles + triazoles): • Contraindications: • Azoles are teratogenic – avoided in pregnancy (unless benefit > risk to fetus) • Fluconazole: • 1st triazole • Least active of all triazoles • Spectrum: yeast and some dimorphic fungi • No role in the treatment of aspergillosis or zygomycosis • Activity against: Cryptococcus neoformans, Candia albicans, Candida parapsilosis Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 166 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Azole antifungals (imidazoles + triazoles): • Fluconazole: • Prophylactic – against invasive fungal infections in recipients of bone marrow transplants • Drug of choice for Cryptococcus neoformans after induction therapy with amphotericin B and flucytosine • Used for candidemia and coccidiomycosis • Active against mucocutaneous candidiasis – vulvovaginal candidiasis • Oral (high distribution) / IV • Excreted in the urine • Adverse effects: nausea, vomiting, headache, skin rashes Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 167 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Azole antifungals (imidazoles + triazoles): • Itraconazole: • Broader spectrum than fluconazole • Drug of choice for the treatment of blastomycosis, sporotrichosis, paracoccidioidomycosis, and histoplasmosis • Capsule, tablets: taken with food + acidic beverage • Solution: on empty stomach • High distribution in the body • Metabolized in liver – drug + inactive metabolites excreted in urine and feces • Adverse effects: nausea, vomiting, rash, hypokalemia, HTN, edema, headache // has negative inotropic effect = avoided in patients with HF Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 168 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Azole antifungals (imidazoles + triazoles): • Voriconazole: • Broad-spectrum of activity • Oral / IV • Drug of choice for invasive aspergillosis • Used for invasive candidiasis and infections caused by Scedosporium and Fusarium species • Drug-drug interactions; metabolized and inhibits various CYP450 isoenzymes • High doses – visual and auditory hallucinations, hepatotoxicity Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 169 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 170 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Echinocandins (caspofungin, micafungin, anidulafungin): • Newest class of antifungal agents • Fungicidal / act on cell wall • Large cyclic peptides linked to a long-chain fatty acid – IV • Caspofungin and anidulafungin require loading dose • Potent activity against Aspergillus and most Candida species, including those resistant to azoles • MOA: • Inhibiting the synthesis of β(1,3)-D-glucan (cell wall component forming chitin) – lysis – cell death Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 171 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 172 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Echinocandins (caspofungin, micafungin, anidulafungin): • Adverse effects: • Fever, rash, nausea, phlebitis at infusion site • Should be administered via a slow IV infusion – prevent histamine-like reaction (flushing) if infused rapidly • Caspofungin: • 1st line option for patients with invasive candidiasis, including candidemia • 2nd line option for invasive aspergillosis in patients who have failed or cannot tolerate amphotericin B or an azole • Metabolized via CYP450 enzymes – drug-drug interactions Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 173 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Echinocandins (caspofungin, micafungin, anidulafungin): • Micafungin and anidulafungin: • 1st line option for the treatment of invasive candidiasis, including candidemia • Not substrates for CYP450 enzymes – NO drug-drug interactions Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 174 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Overview: • Mold-like fungi cause cutaneous infections = dermatophytes / tinea • Infections = dermatophytosis / e.g. tinea pedis, tinea corporis (ringworm), tinea capitis, tinea cruris, tinea versicolor, onychomycoses • Majority of dermatophytosis caused by: • Trichophyton, Microsporum, and Epidermophyton fungi Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 175 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Squalene epoxidase inhibitors: • E.g. terbinafine, naftifine, butenafine • Inhibiting squalene epoxidase – block synthesis of ergosterol • Accumulation of squalene – increased membrane permeability – cell death Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 176 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 177 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Squalene epoxidase inhibitors: • Terbinafine: • Fungicidal • Orally – drug of choice – onychomycosis • Better tolerated, short duration of therapy, more effective compared to itraconazole or griseofulvin • Therapy is prolonged – 3 months (shorter than griseofulvin) • Tinea capitis – require oral formulation • Topically (1% cream, gel or solution) – 1 week treatment – tinea pedis, tinea corporis, tinea cruris, tinea versicolor Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 178 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Squalene epoxidase inhibitors: • Terbinafine: • PK: • Oral/topical administration • 40% bioavailable – first-pass metabolism • Highly protein-bound and deposited in skin, nails and adipose tissue // keratophilic • Prolonged half-life – 200 to 400 hrs • Oral terbinafine - metabolized in liver and excreted in the urine – avoided in patients with moderate to severe renal impairment or hepatic dysfunction • Inhibitor of CYP450 2D6 isoenzyme – drug-drug interaction Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 179 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Squalene epoxidase inhibitors: • Terbinafine: • Adverse effects: • Diarrhea, dyspepsia, nausea, headache, rash • Taste and visual disturbances reported • Elevations in serum hepatic transaminases Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 180 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Griseofulvin: • Fungistatic / keratophilic • Causes disruption of mitotic spindle – inhibition of fungal mitosis • Deposited in newly forming skin where it binds to keratin • Used to be used for onychomycosis (6-12 months of treatment) • Still used for dermatophytosis of the scalp and hair – taken with high-fat meals • Induces hepatic CYP450 – drug-drug interactions • Contraindicated in pregnancy and patients with porphyria. Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 181 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Nystatin: • Resembles amphotericin B • Treatment of cutaneous and oral Candida infections • Not absorbed from GI tract / systemic toxicity if given parenterally • Oral agent – “swish and swallow” or “swish and spit” – oropharyngeal candidiasis (thrush) • Intravaginally – vulvovaginal candidiasis • Topically – cutaneous candidiasis Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 182 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Imidazoles: • E.g.: butoconazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sertaconazole, sulconazole, terconazole, and tioconazole • Uses: tinea corporis, tinea cruris, tinea pedis, and oropharyngeal and vulvovaginal candidiasis • Oral ketoconazole has historically been used for the treatment of systemic fungal infections but is rarely used today due to the risk for severe liver injury, adrenal insufficiency, and adverse drug interactions. Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 183 Chapter 34 Antiviral Drugs Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 184 Antiviral Drugs ➢Overview: • Viruses are obligate intracellular parasites • NO cell wall, NO cell membrane, NO organelles • Clinical symptoms appear late in the course of the disease • Antiviral drugs are virustatic • Antiviral drugs could be used as prophylactic agents Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 185 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 186 Antiviral Drugs / Treatment of Respiratory Viral Infections ➢Overview: • Viral respiratory tract infections caused by: • Influenza A virus (infect variety of animal hosts) • Influenza B virus (infect only people) • Respiratory syncytial virus (RSV) • Immunization – preferred approach • Allergies or outbreaks – antiviral drugs • Influenza A causes pandemics (e.g. H1N1); have surface proteins (neuraminidase (N) / hemagglutinin (H)) • H for attachment / N for viral release Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 187 Antiviral Drugs / Treatment of Respiratory Viral Infections ➢A) Neuraminidase inhibitors (e.g. Oseltamivir and Zanamivir) • NO interference with vaccines • Activity against Influenza A and B viruses • Administered prior to exposure or within 48 hrs after onset of symptoms • 5-day course • MOA: • Selectively inhibit neuraminidase – prevent the release of new virions • PK: • Oseltamivir: prodrug, administered orally, activated by hepatic esterases • Zanamivir: active, administered via inhalation • Both excreted in the urine Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 188 Antiviral Drugs / Treatment of Respiratory Viral Infections ➢A) Neuraminidase inhibitors (e.g. Oseltamivir and Zanamivir) • Adverse effects: • Oseltamivir: nausea and vomiting (minimized with food), headache • Zanamivir: respiratory discomfort; caution in patients with airway diseases • Resistance: • Mutations of the neuraminidase enzyme Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 189 Antiviral Drugs / Treatment of Respiratory Viral Infections ➢B) Adamantane antivirals (e.g. Amantadine and Rimantadine) • Activity against Influenza A viruses only • Administered prior to exposure or within 48 hrs after onset of symptoms • Due to high resistance – no longer recommended • MOA: • Block M2 proton ion channel – block viral uncoating • Use of amantadine in Parkinson? • PK: • Amantadine: excreted unchanged in the urine • Rimantadine: extensive metabolism before urinary excretion Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 190 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 191 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 192 Antiviral Drugs / Treatment of Respiratory Viral Infections ➢C) Ribavirin • Guanosine analogue • Active against a broad spectrum of RNA and DNA viruses • Activity against RSV infections (and HCV, when combined with other medications) • Used for the treatment of severe RSV bronchiolitis or pneumonia in children and infants Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 193 Antiviral Drugs / Treatment of Respiratory Viral Infections ➢C) Ribavirin • MOA: • Inhibits the replication of RNA and DNA viruses • Ribavirin – 5’-phosphate derivative formation – triphosphate derivative formation – inhibiting GTP formation, preventing viral messenger RNA (mRNA) capping, blocking RNA-dependent RNA polymerase • PK: • Orally and inhalation • Aerosolized ribavirin via nebulizer for RSV infection • Drug and its metabolites excreted in the urine Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 194 Antiviral Drugs / Treatment of Respiratory Viral Infections ➢C) Ribavirin • Adverse effects: • Dose-dependent transient anemia • Aerosol: may cause conjunctival or bronchial irritation • Contraindicated in pregnancy / patients exposed to the drug should not conceive children for at least 6 months Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 195 Antiviral Drugs / Treatment of Hepatic Viral Infections ➢Overview: • Hepatitis viruses (A, B, C, D, E) • Destruction of hepatocytes • Most common causes of chronic diseases: hepatitis B (a DNA virus) (HBV) and hepatitis C (an RNA virus) (HCV) • Goals of chronic HBV therapy – suppression of HBV DNA to undetectable levels, seroconversion of HBeAg from +ve to –ve, and reduction in elevated hepatic transaminase levels. • Goal of treatment in patients with HCV infection – viral eradication Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 196 Antiviral Drugs / Treatment of Hepatic Viral Infections ➢Overview: • Interferon alpha used for the treatment of HBV and HCV infections • Interferons are glycoproteins – bind to specific cell membrane receptors – inducing various intracellular signals – resulting in inhibition of viral RNA translation – degradation of viral mRNA and tRNA • Use of interferon alpha uncommon; more effective and better tolerability agents available Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 197 Antiviral Drugs / Treatment of Hepatitis B ➢Lamivudine: • Cytidine analogue • Activity against HBV and human immunodeficiency virus (HIV) • Inactive • Phosphorylated (activated) by host cell kinases into triphosphate form • Inhibits HBV DNA polymerase and HIV reverse transcriptase – competition with deoxycytidine triphosphate Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 198 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 199 Antiviral Drugs / Treatment of Hepatitis B ➢Lamivudine: • Chronic therapy is limited due to emergence of lamivudine-resistant HBV • Headache, nausea, diarrhea, myalgia, and malaise are rare at doses used for HBV infection Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 200 Antiviral Drugs / Treatment of Hepatitis B ➢Adefovir dipivoxil: • Diester prodrug of adefovir • Adefovir is acyclic phosphonated adenine nucleotide analog • Adefovir is activated by host cell kinases into the active diphosphate metabolite • Inhibit HBV DNA polymerase • Prodrug administered once daily – oral – rapidly and completely hydrolyzed to adefovir Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 201 Antiviral Drugs / Treatment of Hepatitis B ➢Adefovir dipivoxil: • Well-tolerated • Adefovir excreted in the urine • Nephrotoxicity (increased serum creatinine) is dose-dependent • Other adverse effects: headache, diarrhea, asthenia and abdominal pain • Have activity against lamivudine-resistant strains of HBV Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 202 Antiviral Drugs / Treatment of Hepatitis B ➢Entecavir: • Guanosine nucleoside analog • Activated by host cell kinases into triphosphate form • Inhibit HBV DNA polymerase • Has weak anti-HIV activity (on reverse transcriptase) • Suppression of HBV DNA is higher than lamivudine or adefovir • Cross-resistance with lamivudine Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 203 Antiviral Drugs / Treatment of Hepatitis B ➢Entecavir: • Orally / well-tolerated • Excreted in the urine • Adverse effects: headache, fatigue, dizziness, nausea, rash, and fever Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 204 Antiviral Drugs / Treatment of Hepatitis B ➢Tenofovir: • Nucleotide analogue of adenosine • Activity against lamivudine- and entecavir-resistant strains of HBV • Activity against HBV DNA polymerase • Activity against HIV reverse transcriptase • Activated by host cell kinases to diphosphate form • Higher rate of virologic response, histologic improvement, and lower rate of emergence of resistance • Adverse effects: nausea, diarrhea, abdominal pain, dizziness, fatigue, rash Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 205 Antiviral Drugs / Treatment of Hepatitis B ➢Telbivudine: • Thymidine nucleoside analogue • Activated by host cell kinases to the triphosphate form • Inhibit HBV DNA polymerase • Greater rate of virologic response compared to lamivudine or adefovir • There are emergence of resistance to it • Taken orally • Adverse effects: nausea, diarrhea, rash, fever, fatigue, headache, cough Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 206 Antiviral Drugs / Treatment of Hepatitis C ➢HCV: • RNA virus • Attach to specific receptor and enter host cell • HCV RNA serves as template for viral RNA replication and as messenger RNA for protein production (translation) • Protein produced (polyprotein) is cleaved by proteases • Drugs targeting HCV RNA polymerase and HCV RNA protease Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 207 HCV Life Cycle Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 208 Antiviral Drugs / Treatment of Hepatitis C ➢NS5B Polymerase inhibitors: • Sofosbuvir • Nucleotide analog • Inhibits HCV NS5B RNAdependent RNA polymerase • Activated by host cell kinases to triphosphate form • Combined with ribavirin and peginterferon alfa / taken with or without food • Eliminated in the urine Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 209 Antiviral Drugs / Treatment of Hepatitis C ➢NS5B Polymerase inhibitors: • Dasabuvir • Nonnucleoside analog • Inhibits HCV NS5B RNAdependent RNA polymerase • Binds to allosteric site Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 210 Antiviral Drugs / Treatment of Hepatitis C ➢NS3/4A Protease inhibitors: • NS3/4A serine protease cleaves polyprotein encoded by HCV RNA into active proteins (NS4A, NS4B, NS5A, and NS5B) • If it is inhibited – NO RNA replication – HCV life cycle disrupted • e.g. paritaprevir, grazoprevir, voxilaprevir, glecaprevir, boceprevir, simeprevir, telaprevir // administered with ribavirin • Drug-drug interactions – metabolized by CYP3A enzymes • Adverse effects: rash, pruritis, nausea, fatigue, anemia ➢NS5A replication complex inhibitors: • e.g. ledipasvir, ombitasvir, elbasvir, velpatasvir, pibrentasvir, daclatasvir • Drug-drug interactions – metabolized by CYP450 isoenzymes ➢Ribavirin (discussed before) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 211 Antiviral Drugs / Treatment of Herpes Simplex Virus (HSV) and Varicella-Zoster Virus (VZV) Infections ➢Overview: • HSV and VZV cause broad spectrum of diseases: • Cold sores • Viral encephalitis • Genital herpes • Shingles • The drugs are effective during the acute phase of viral infections not during the latent phase Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 212 Antiviral Drugs / Treatment of Herpes Simplex Virus (HSV) and Varicella-Zoster Virus (VZV) Infections ➢Acyclovir: • Prototypic antiherpetic agents • Active against HSV-1, HSV-2, and VZV (less potency than on HSVs) • May be administered prophylactically • Acyclic guanosine analogue • Selective drug – acts only in infected cells (due to its activation); initial activation (1st phosphorylation) is performed via viral thymidine kinase Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 213 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 214 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 215 Antiviral Drugs / Treatment of Herpes Simplex Virus (HSV) and Varicella-Zoster Virus (VZV) Infections ➢Acyclovir: • MOA: • Inhibits viral DNA synthesis (as discussed before) • PK: • Oral, IV, topical • Partially metabolized to an inactive drug / drug and metabolites excreted in the urine • Oral acyclovir has low bioavailability (15-20%) / absorption not affected by food • No systemic concentrations are detected by topical route Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 216 Antiviral Drugs / Treatment of Herpes Simplex Virus (HSV) and Varicella-Zoster Virus (VZV) Infections ➢Acyclovir: • PK: • Diffuses readily into most tissues and body fluids (20-50% of serum values inside CSF) • IV: herpes simplex encephalitis, neonatal HSV infections, and serious HSV or VZV infection • Topical (less effective than oral for primary HSV infection): cold sores, genital herpes, ophthalmic / no benefit in treating recurrent genital herpes Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 217 Antiviral Drugs / Treatment of Herpes Simplex Virus (HSV) and Varicella-Zoster Virus (VZV) Infections ➢Acyclovir: • Adverse effects: • Topical route: local irritation • Oral: headache, nausea, diarrhea • IV: reversible renal toxicity (crystalline nephropathy, intestinal nephritis), neurologic effects (tremors, delirium, seizures) • Resistance: • Develops in HSV or VZV due to (mostly in immunocompromised patients): • Alterations in viral thymidine kinase • Alterations in DNA polymerase Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 218 Antiviral Drugs / Treatment of Herpes Simplex Virus (HSV) and Varicella-Zoster Virus (VZV) Infections ➢Valacyclovir: • L-valyl ester of acyclovir • Rapidly converted into acyclovir after oral administration (intestine and liver) • 50-70% oral bioavailability / 50% of those in serum in CSF • Amino acids/peptide transporters? Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 219 Antiviral Drugs / Treatment of Herpes Simplex Virus (HSV) and Varicella-Zoster Virus (VZV) Infections ➢Ganciclovir/Valganciclovir: • Acyclovir analogue • Similar to acyclovir/valacyclovir • Similar MOA as acyclovir • Used for cytomegalovirus (CMV) infections / immunocompromised patients • CMV retinitis, colitis, esophagitis, pneumonitis • IV and intravitreal Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 220 Antiviral Drugs / Treatment of HIV Infection ➢Overview: • Human Immunodeficiency Virus (HIV) • HIV is a retrovirus – RNA virus – has reverse transcriptase enzyme • HIV causes Acquired Immunodeficiency Syndrome (AIDS) • Anti-HIV agents = Antiretroviral agents • Target cells = CD4 cells (T cells; WBCs) • HIV causes immunosuppression state (patients are immunocompromised) • Drugs – restore the umber of CD4 cells and immunocompetence to the host • Goals: maximally and durably suppress HIV RNA replication, restore and preserve immunologic function, reduce HIV-related morbidity and mortality, and to improve quality of life. Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 221 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 222 Antiviral Drugs / Treatment of HIV Infection ➢Overview: • There are 5 groups of antiretroviral drugs and combination therapy (not all 5 groups) is essential: 1. Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) 2. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) 3. Protease Inhibitors (PIs) 4. Entry Inhibitors 5. Integrase Inhibitors • Initial therapy: 2 NRTIs + NNRTI or Integrase inhibitor or boosted PI Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 223 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 224 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 225 Antiviral Drugs / Treatment of HIV Infection ➢NRTIs: • e.g. zidovudine, lamivudine, emtricitabine, tenofovir, didanosine, stavudine, abacavir (underlined commonly used; safer) • Tenofovir disoproxil combined with emtricitabine = preexposure prophylaxis in individuals • MOA: • Lack 3’-hydroxyl group • Activated to the triphosphate form by host cell kinases • Inhibit HIV reverse transcriptase enzyme • Low affinity to host cell DNA polymerase / have affinity to mitochondrial DNA polymerase gamma - mitochondrial toxicity Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 226 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 227 Antiviral Drugs / Treatment of HIV Infection ➢NRTIs: • PK: • Administered orally (zidovudine available also as IV) • Renally excreted (except abacavir; hepatically eliminated; hepatic glucuronidation and carboxylation) • Adverse effects: • Toxicities due to inhibition of mitochondrial DNA polymerase gamma • Lactic acidosis with hepatic steatosis, lipodystrophy • Abacavir – hypersensitivity (fever, fatigue, rash, GI disturbances, respiratory distress) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 228 Antiviral Drugs / Treatment of HIV Infection ➢NRTIs: • Resistance: • Alterations of viral RT • Cross-resistance occurs between agents of the same analog class Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 229 Antiviral Drugs / Treatment of HIV Infection ➢NNRTIs: • e.g. nevirapine, delavirdine, efavirenz, etravirine, rilpivirine (underlined; commonly used) • Efavirenz (in patients coinfected with TB due to lower drug-drug interactions with rifamycins) and rilpivirine (small tablet; patient convenience in patients with swallowing difficulty) are recommended in initial antiretroviral regimens • Etravirenz, 2nd generation NNRTI active against HIV strains resistant to 1st generation NNRTIs. • MOA: • Highly selective, noncompetitive inhibitor of HIV RT • NO activation is required Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 230 Antiviral Drugs / Treatment of HIV Infection ➢PIs: • e.g. atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir • MOA: • Reversible inhibitors of HIV aspartyl protease (retropepsin) • Inhibition results in immature of released new virions / release of noninfectious virions • Adverse effects: • Nausea, vomiting, diarrhea, disturbances in lipid and glucose metabolism, paresthesia, fat redistribution, breast enlargement • Drug-drug interactions/contraindications Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 231 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 232 Antiviral Drugs / Treatment of HIV Infection ➢PIs: • Require boosters – potent inhibitors of CYP3A isoenzymes (PIs metabolizing enzymes) – increase bioavailability of PIs • e.g. of boosters: ritonavir and cobicistat Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 233 Antiviral Drugs / Treatment of HIV Infection ➢Entry Inhibitors: • Enfuvirtide: • Fusion inhibitor • Polypeptide that binds to viral gp41 required for entry into CD4 cells • Administered via SC injection causing pain, erythema, induration, nodules • Maraviroc: • Entry inhibitor • Blocks the CCR5 coreceptor that works with viral gp41 to facilitate HIV entry • Hepatotoxic Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 234 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 235 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 236 Antiviral Drugs / Treatment of HIV Infection ➢Integrase Inhibitors: • e.g. raltegravir, elvitegravir, dolutegravir, bictegravir • Inhibiting the insertion of proviral DNA into the host cell genome • Adverse effects: nausea, diarrhea Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 237 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 238 Chapter 52 + 53 Antiprotozoal Drugs + Antihelminthic Drugs Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 239 Antiprotozoal Drugs ➢Overview: • Protozoa = single-celled eukaryotes • Sexual and asexual (schizogony – producing schizonts) reproduction • Parasites = their proliferation depends on the host (human cells) • Examples of diseases = Malaria, Amebiasis, Giardiasis, Trichomoniasis, Leishmaniasis Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 240 Antiprotozoal Drugs / Malaria ➢Malaria: • Caused by plasmodium species: Plasmodium falciparum (majority of serious complications and illness), P malariae, P vivax, P ovale • Transferred to humans by female anopheline mosquito • Life cycle involves: liver, RBCs, and mosquito (sexual) • Infective Sporozoite – then Merozoite (exoerythrocytic-tissue schizonts-liver) – then Erythrocytic parasites (Trophozoite) and Gametocyte (sexual) • Gametocytes (taken up by mosquitoes) – Infective Sporozoites in mosquito’s gut • Hypnozoite – dormant hepatic stage from P vivax and P ovale Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 241 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 242 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 243 Antiprotozoal Drugs / Malaria ➢Malaria: • Erythrocytic parasites cause clinical illness (high fever, orthostatic hypotension, massive erythrocytosis, capillary obstruction, and death • P falciparum and P malariae – eradication of erythrocytic parasites (liver?) • P vivax and P ovale – eradication of both erythrocytic and hepatic parasites • Treatment involves: tissue schizonticides, blood schizonticide, gametocides • Chemoprophylaxis and treatment Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 244 Drug Use (chemoprophylaxisprevention) Chloroquine Areas without resistant P falciparum Mefloquine Areas with chloroquineresistant P falciparum Doxycycline Areas with multidrug-resistant P falciparum Primaquine (if G6PD is normal) Terminal prophylaxis of P vivax and P ovale infections; alternative for primary prevention Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 245 Drug Chloroquine (Blood schizonticide) Mefloquine (Blood schizonticide) Doxycycline Chloroquine + Primaquine (Tissue schizonticide used if G6PD is normal) Use (clinical settings) Chloroquine-sensitive P falciparum and P malariae Chloroquine-resistant P falciparum (not in individuals with severe or complicated