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