1. Nucleoside reverse transcriptase inhibitors (NRTIs) work by inhibiting the reverse transcriptase enzyme and terminating viral DNA chain. Common NRTIs include abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine.
2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind directly to reverse transcriptase and block its activity. Common NNRTIs are nevirapine, efavirenz, and delavirdine.
3. Protease inhibitors (PIs) inhibit the viral protease enzyme and prevent maturation of viral particles. Common
1. Nucleoside reverse transcriptase inhibitors (NRTIs) work by inhibiting the reverse transcriptase enzyme and terminating viral DNA chain. Common NRTIs include abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine.
2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind directly to reverse transcriptase and block its activity. Common NNRTIs are nevirapine, efavirenz, and delavirdine.
3. Protease inhibitors (PIs) inhibit the viral protease enzyme and prevent maturation of viral particles. Common
1. Nucleoside reverse transcriptase inhibitors (NRTIs) work by inhibiting the reverse transcriptase enzyme and terminating viral DNA chain. Common NRTIs include abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine.
2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind directly to reverse transcriptase and block its activity. Common NNRTIs are nevirapine, efavirenz, and delavirdine.
3. Protease inhibitors (PIs) inhibit the viral protease enzyme and prevent maturation of viral particles. Common
GROUP OF ANTI-VIRAL MOA DRUGS COMMENTS PHARMACOKINETICS A/E
NRTIs -prodrugs: phosphorylation by intracellular kinases-->active triphosphate
Abacavir forms (ABC) -add w 3TC -good oral bioavailibility -hypersensitivity rx -compete for HIV-1 reverse transcriptase (RT) -slowly develop resistance -renal elimonation -avoid use w d4T: overlapping mitochondrial toxicities--> -inhibit its DNA polymerisation Didanosine (ddl) peripheral neuropathy, pancreatitis & hyperlactatemia -mitochondrial toxicity & myopathy -chain terminator in growing viral DNA Emtricitabine (FTC) -activity vs HBV -C/I in children & pregnant, renal/hepatic dysfx pt Lamivudine (3TC) -exacerbation of HBV -mild A/E: gut disturbances, headache, fatigue -avoid use w FTC -synergistic effect w ZDV&d4T -avoid use w ZDF: d/t they antagonize each other effect Stavudine (d4T) on HIV-1 -mitochondrial toxicity & myopathy -fat atrophy (lipoatrophy) Tenofavir (TDF) -add w FTC -nephrotoxicity -reduce renal elimination of acyclovir & ganciclovir -decrease bone marrow density Zidovudine (AZT,ZDF) -add w 3TC and ddl -mitochondrial toxicity & myopathy -prevent vertical transmission HIV-1 -bone marrow suppression -azole antifungals & PIs increases plasma level -rifampicin increases the clearance NNRTIs -not a prodrug Nevirapine (NVP) -single dose: a)during onset of labor -good oral bioavailability -fatal hepatotoxicity -bind directly to hydrophobic near catalytic site on HIV-1 RT--> *not effective vs HIV-2 blockade of RNA & DNA-dependent DNA polymerase activity b)to newborn after delivery -good penetration -CYP 3A4 inducer -hepatic metabolism by CYP34A *2-NNRTIs combo (NOT recommended): high incidence of A/E -increase by enzyme inhibitors (macrolide&cimetidine) -reduce by enzyme inducers (rifampim) Efavirenz (EFV) -mixed inducers/inhibitors of CYP3A4 -fatty food enhances oral bioavailibility -CNS effect (dizziness, headache, nightmare, -reduce PIs, simvastatin, methadone -penetrates CNS delusion, euphoria, insomnia, amnesia) -teratogenicity (avoid in 1st trimester) -avoid use w PI, saquinavir Delavirdine (DLV) -CYP 3A4 inhibitor -antacids reduces oral bioavailability *Generally: 1)GI tolerance -enzyme inhibitors reduced it -less penetration to CNS 2)Skin rashes-->C/I in pt w hx of severe rash -azole, antifungals & macrolides increase it -hepatic metabolism by CYP3A & CYP 2D6 3)Teratogenicity -benzodiazepines, PIs increase it -HIV-1 protease cleaves precusor polyprotein to form proteins of PIs mature virions Atazanavir (ATV) -potent inhibitor of CYP 3A4 & CYP 2C9 *Generally: 1)exacerbate emergence of resistant HIV strain -no lipodystrophy -hyperbilirubinemia w overt jaundice: inhibit hepatic -avoid use w IDV: d/t it will exacerbate A/E 2)varying bioavailability UGT1A1 glucuronidation enzyme -PIs inhibit protease active site-->immature, non-infectious viral particles Darunavir (DRV,TMC114) -resistance is common Fosamprenavir (FPV) -always combined! Indinavir (IDV) -inhibitor of CYP 3A4 -kidney stones & renal failure (d/t x soluble in urine) Lopinavir (LPV) -inhibitor of CYP 3A4 Nelfinavir (NFV) Ritonavir (RTV) -add with other PIs & act as PI booster -higher oral bioavailability (by fatty meal&increase gastric pH) *Generally: 1)Hyperglycaemia - insulin resistance -inhibitor of CYP 3A4 2)High cholesterol & TG levels -inhibit metabolism of drugs (erythromycin, ketoconazole, prednisolone, rifampin & squamavir) 3)GI side effect - bloating, nausea, diarrhoea Saquinavir (SQV) -inhibitor of CYP 3A4 -oral bioavailability (by fatty meal&increase gastric pH) Tipranavir (TPV) Booster -inhibit P 450 isozymes, act as booster for HIV-1 PIs Cobicistat -inhibit CYP 3A4,CYP 2D6 & transporter(p-glycoprotein) -metabolized by CYP 3A4 & CYP 2D -increase systemic exposure of ATV/DRV -binds integrase--> interferes w integration of RT HIV DNA into the IIs chromosome of host cell Raltegravir (RAL) -for resistant strains tx -metabolized by glucuronidation Diarrhoea, nausea, dizziness, headache -caution use w antacids: Ca, Mg, Fe bind to IIs & interfere w absorption -not interact w P450 -rifampin reduce it level Entry Inhibitors (EIs) -binds to gp41 subunit of viral envelope glycoprotein Enfurvirtide (ENF,T-20) -combine w other anti-HIV in pt w persistent HIV-1 replication -metabolized by protein hydrolysis -local injection site rx -prevents confirmational changes necessary for viral fusion -S/C injection -hypersensitivity & eosinophilia -cough, URTI, muscle pain, diarrhoea, increased hepatic -binds selectively to CCR5 coreceptor Maraviroc (MVC) -tx of tx-expereinced adult pt infected w CCR5-tropic HIV-1 transaminase activity -CYP 3A4 substrate -MI & infarction
GROUP OF ANTI-FUNGAL MOA DRUGS COMMENTS/CLINICAL USES PHARMACOKINETICS A/E
-bind w sterols in fungal cell membrane (ergosterol) --> -infusion-related: 1)fever, chills, muscle spasm, Polyenes leak out of cell's contents & the cell dies Amphotericin B -tx for systemic fungal disease -poorly absorbed orally shake & bake syndrome -also bind to humam membrane sterols --> prominent toxicity -broad antifungal -synergistic effect w flucytosine -given by IV/intrathecal 2)hypotension w hypokalemia -vs molds & yeast -systemic candidiasis -liposomal formulation: for intolerant pt 3)local thrombophlebitis -cumulative toxicity: 1)renal toxicity --> acidosis & severe K -initial induction for immunosuppressed pt w: -penetrates poorly into CNS & Mg wasting 1)severe fungal pneumonia, severe cryptococcal meningitis/ disseminated histoplasmosis & coccidioidomycosis -excreted in urine 2)neurotoxicity--> seizure, paresthesia 2)continue w maintenance therapy w azole 3)reduce erythropoietin -mycotic corneal ulcers & keratitis -aminoglycosides,vancomycin,furosemide reduce renal fx -corticosteroids, skeletal muscle relaxants, thiazole cause hypokalemia -hypokalemia & digoxin will increase risk of digoxin toxicity -bind w sterols in fungal cell membrane (ergosterol) --> leak out of cell's contents & the cell dies Nyastin -candidal infection of vagina, skin & mouth -used topically -mycostatin -oralpharyngeal trush, vaginal candidiasis -little toxicity -nilstat -nystex -inhibit CYP450 14alpha-demethylase(convert lanosterol-->ergosterol) Imidazole required in fungal cell membrane synthesis Miconazole -local fungal infection: vaginal & vulvar candidiasis -topical fungal infection: chronic candidiasisof skin & mucous membranes -used topically -orally given for GIT infection Ketoconazole -not use for systemic infection -used topically -hepatic toxicity & antiandrogenic, anaphylaxis -tx for dermatophytosis & candidiasis -astemizole w ketoconazole is C/I --> cause long QT -tx of seborrheic dermatitis, pityriasis versicolor (shampoo) -inhibit liver enzyme Clotrimazole -tx for oral trush (clotrimazole troche) -inhibit CYP450 14alpha-demethylase(convert lanosterol-->ergosterol) Triazoles required in fungal cell membrane synthesis Fluconazole -2ndary prophylaxis of cryptococal meningitis -given orally / IV -well tolerated -greater specificity for fungal P450 -mouth, throat, oesophageal candidiasis -good oral bioavailability -minor GI upset -serious systemic candidal infection -good CNS penetration -abnormalities in liver enzyme -fewer hepatic enzyme interaction compared to ketoconazole -hepatic metabolism -clinical hepatitis -inhibitors of CYP 3A4 & CYP 2C9 -renal elimantion -increase saquinavir, tipranavir, nevirapine & etravirine Itraconazole -blastomycosis -given orally / IV -minor GI upset -histoplasmosis -absorption increased by food & low gastric pH -quinidine coadministration --> QT prolongation -aspergillosis: for pt intolerent to amphotericin B -absorption reduced by ranitidine / antacid tx -onychomycosis d/t dermatophytes -poor CSF penetration -rifampin, NNRTIs reduce it bioavailability -hepatic metabolism -PIs increase its level -biliary excretion -increase itraconazole, PIs & statins level Echinocandins *Generally: fungal cell wall distruption Caspofungin -tx of invasive Aspergillus in pt who can't tolerate amphotericin B -given IV *Generally: 1)lesser than amphotericin B & triazoles -non-competitive inhibition of B-(1,3)-D-glucansynthase -tx of oral candidiasis refractory to azoles & amphotericin B -increase protein bound 2)infusion-related A/E -blockade of this enzyme complex Micafungin -tx of invasive candida infection in bone marrow transplant pt -excreted via gut & kidneys 3)increase in hepatic enzyme -inability of the fungal cell to synthesise B-(1,3)-D-glucan Anidulafungin *Generally: 1)fungicidal activity vs candida sp 4)pregnancy (category C) -osmotic instability & cell death 2)fungistatic activity vs aspergillus sp 3)vs molds, given w ampB / broad spectrum triazole Flucytosine *Generally: inhibit DNA synthesis -tx of serious candida and/or cryptococcus infection -given orally -close monitoring of hematologic, renal & hepatic status -anti-metabolite -excreted via kidneys (extreme ⚠ in impaired renal fx) -reversible bone marrow toxicity -narrower spectrum than ampB -hepatotoxicity Griseofulvin -inhibit mitosis -tx vs dermatophyte (ring worm)
TYPE OF FUNGAL TYPE OF INFECTION/THERAPY TYPE OF DRUGS
Candidiasis Oral candidiasis -topical tx: 1)clotrimazole troches -nyastin suspension (nyastin swish & swallow) Oropharyngeal candidiasis -systemic anti-fungal drug: 1)fluconazole 2)itraconazole Candida esophagitis -oral/IV fluconazole -oral itraconazole -amphotericin B (in severe/azole resistant) Genitourinary tract candidiasis -topical antifungal -single dose of oral fluconazole Disseminated candidiasis w end organ infection -fluconazole -echinocandins Crytococcosis Initial therapy -amphotericin B (2 weeks) -w/ or w/out flucytosine (2 weeks) -followed by fluconazole (8-10 weeks) Alternative initial therapy -lipid formulation of amphotericin B (3 weeks) -fluconazole/flucytosine (amphotericin B intolerance pt) Maintenance therapy -fluconazole for life Fungal Severe histoplasmosis -itraconazole Chronic histoplasmosis -itraconazole Disseminated histoplasmosis -itraconazole Coccidioidomycosis -fluconazole -itraconazole -amphotericin B Coccidioidal meningitis -fluconazole