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Source: http://www.doksinet Antifungal and Antiviral Agents Source: http://www.doksinet Mycoses  Systemic   Candidiasis, aspergillosis, blastomycosis, histoplasmosis, coccidiomycosis, Superficial  Dermatomycoses   Trychophyton, Microsporum, Epidermophyton, Tinea (capitis, cruris, pedis, corporis) Candidiasis Source: http://www.doksinet Antifungal Agents  Three groups: Polyenes (nystatin, amphotericin)  Azoles (imidazoles, triazoles)  Others (5-flurocytosine)  Source: http://www.doksinet Fungi Fungi have rigid cell walls which contain chitin and polysaccharides  Most of these organisms are resistant to the drugs used to treat bacteria and vice versa  Source: http://www.doksinet Polyenes  Amphotericin – B (Fungizone) Broad spectrum antifungal  Consider the gold standard which all new antifungal agents are compared for efficacy, safety, and fungal activity  Source: http://www.doksinet Source: http://www.doksinet

Model for Amphotericin B induced Pore in Cell Membrane Source: http://www.doksinet Polyenes  Mode of action Affect the integrity of fungal cell membranes by binding to ergosterol, fungisterol, and other sterols in fungal cell membrane  They can bind to cholesterol and may affect mamalian cell membranes  Source: http://www.doksinet Amphotericin B Source: http://www.doksinet  Mode of action Binds to ergosterol altering the cell membrane permeability in susceptible fungi. Mammalian cells contain cholesterol!  Forms a pore in the membrane, the hydrophilic core creating a transmembrane ion channel  Loss of K+. Leakage of cell components ultimately leads to cell death  Source: http://www.doksinet Can be fungicidal or fungistatic depending upon the concentration and the specific organism  Resistance is rare but has been reported with some Candida species resulting in a need to check species identification and MICs  Source: http://www.doksinet

Influence of Amphotericin B on intracellular Ca++ levels in glomerular mesangial cells Theory Pore ↑ Na entry Depolarization Voltage-dep. Ca channels Contraction Source: http://www.doksinet ADME    Must be given intravenously for disseminated disease because inadequate amounts of the drug are absorbed from the gastrointestinal tract Oral adm for GI fungal infections IV with sodium deoxycholate slowly       With Beta-cyclodextrin, liposomes, nanospheres Binds highly to plasma albumin, high cc in exudates BBB penetration is poor (but in meningitis the penetration is increased). (Amphotericin + flucytosine in cryptococcal meningitis) Very slowly excreted by the kidneys Half life – 15 - 48 hours Exhibits non-linear kinetics (Volume of distribution and clearance from the blood increases with increasing doses) Source: http://www.doksinet Toxicity           Renal failure Hypokalaemia Hypomagnesaemia Anaemia Impaired

hepatic function Thrombocytopenia Anaphylactic reactions (chills, fever, tinnitus, headache, vomitus) Local thrombophlebitis in iv injection Seizures Cardiac arrhythmias Source: http://www.doksinet Calcium channel blockers are protective against AmB- nephrotoxicity in-vivo in rats Salt loading is protective against nephrotoxicity in vivo in animals Source: http://www.doksinet Salt loading or Supplements Protect Against AmBNephrotoxicity In Humans Source: http://www.doksinet VLBW infants may experience thrombocytopenia, changes in renal function tests, changes in liver function studies  Drug interactions may increase the risk of toxicity: aminoglycosides  Increase risk for digitalis toxicity and prolonged neuromuscular blockade  Source: http://www.doksinet Nephrotoxicity Correlates with the total dose  Occurs from drug induced renal vasoconstriction and from direct action of the drug on the renal tubules  May result in increases in serum creatinine, BUN,

renal tubular acidosis and necrosis, and nephrocalcinosis  Source: http://www.doksinet Toxicity Determines Administration Generally administer a test dose (0.25 mg/kg over 4 to 6 hours) to determine response to the drug  Gradually increase the dose (increase by 0.25 mg/kg) until the maximum daily dose is achieved (1 mg/kg/day)  Source: http://www.doksinet     Speed of increasing dose is influenced by the side effects experienced Drug dose can be altered daily or every other day to manage side effects Daily dose is administered over a minimum of 4 to 6 hours mixed in dextrose (precipitates in normal saline) Maximum daily dose and duration of therapy determined by patient response to the drug, focus and extent of fungal infection and drug MIC Source: http://www.doksinet Total dose is given over 2 to 6 weeks and may be expressed as a total mg/kg dose versus a time frame (example: 15 to 20 mg/kg total dose)  Meningitis often requires intrathecal

administration  Source: http://www.doksinet Pharmacokinetics Half life – 15 - 48 hours  Exhibits non-linear kinetics (Volume of distribution and clearance from the blood increases with increasing doses)  90% protein bound  2 to 4% eliminated in the urine unchanged  Source: http://www.doksinet Lipid-Amphotericin Agents Source: http://www.doksinet Lipid formulations: 20-50 times more expensive than AmB-deoxycholate Source: http://www.doksinet     Amphotericin B lipid complex (Abelcet) Liposomal amphotericin (AmBisome) Amphotericin colloidal dispersion (Amphotec) Amphotericin is encased or bound to a lipid to make the drug less toxic, yet with the same efficacy Source: http://www.doksinet Typically used for patients who are refractory or intolerant to conventional amphotericin B  Refractory or intolerant refers to serum creatinine > 1.5 mg/dl during therapy  Cost is significant and may not be worth using routinely (unless conventional

amphotericin B is contraindicated)  Source: http://www.doksinet Abelcet (A.-B lipid complex) Half life -173 hours  Exhibits non-linear kinetics, volume of distribution and clearance from the blood increases with increasing doses  Source: http://www.doksinet AmBisone (Liposomal) Volume of distribution 0.1 – 016 L/kg  Half life – 100 to 150 hours  Exhibits non-linear kinetics – greater than proportional increase in serum concentration with an increase in dose  Source: http://www.doksinet Source: http://www.doksinet Source: http://www.doksinet Nystatin      Polyene antibiotic similar to amphotericin B; active against Candida Binds to sterols in the fungal cell membrane, changing the cell wall permeability allowing leakage of cellular contents Use restricted to topical treatment because it is too toxic to give parenterally Minimal absorption from the GI tract Cutaneous, vaginal, mucosal and esophageal Candida infections usually

respond well to treatment with nystatin. Source: http://www.doksinet     Duration of therapy is several days after disappearance of the lesions In case of re-lapse continue for an additional 7 to 10 days Equal efficacy between combination (skin cream and oral solution versus topical only) Dose: 100,000 units 4 times a day or 50,000 units to each side of the mouth (Remember to “paint” the mouth for best effectiveness) Source: http://www.doksinet Azoles -ketoconazole Source: http://www.doksinet Imidazoles – Miconazole (Monistat)  Active against many species of fungi including Candida  Technical problems with finding a good vehicle for this drug – reports of adverse CV problems  Limited use with newborns – most reports of cardiac toxicity or heart failure  Source: http://www.doksinet Mechanism of Action   Inhibits biosynthesis of ergosterol, damaging the fungal cell wall membrane with increases permeability and causes leaking of

nutrients Lanosterol – ergosterol conversion     CYP3A Lanosine 14α-demethylase Decrease the number of amphotericin-B binding sites! Inhibits the C17-20 lyase activity of CYP450 17alpha (steroid biosynthesis) Source: http://www.doksinet Pharmacokinetics          Needs acidic environment for absorption Only available PO Distributes into epidermis, synovial fluid, saliva, and lungs. Poor distribution into CSF and eye. Metabolized in the liver Half life – Multiphasic degration Alpha – 40minutes Beta – 126 minutres Terminal – 24 hours Dose  200 to 400 mg once daily  Decrease dose for severe liver failure Source: http://www.doksinet Adverse Effects     GI distress (17-43%) Rash (4-10%) Increased transaminases (2-10%) Hepatitis (1 in 10,000)        Dose-dependent inhibition of synthesis of testosterone (521% of patients will have symptoms such as impotence or gynecomastia) Menstrual

Irregularities (16% of women) Alopecia (8%) Dose-related decrease in cortisol synthesis Hypermineralocorticoid state   Can be fatal Usually occurs within first 4 months of treatment Can cause HTN in patients on long-term high dose ketoconazole Teratogenic in animals Source: http://www.doksinet Drug Interactions  Antacids, H2 blockers, proton pump inhibitors, sucralfate    Decreases absorption of ketoconazole Rifampin decreases ketoconazole concentrations by 33% CYP inhibition         Cyclosporine levels increased Warfarin Phenytoin Methylprednisolone Isoniazid Terfenadine Astemizole Cisapride Source: http://www.doksinet Triazoles Source: http://www.doksinet Triazoles  MOA: Inhibits 14-αsterol demethylase, which is a microsomal CYP450 enzyme. This enzyme is responsible for conversion of lanosterol to ergosterol, the major sterol of most fungal cell membranes Source: http://www.doksinet Fluconazole (Diflucan)  Active

against many species of fungi including Candida  Oral or intravenous preparations available with equal pharmacokinetics  Crosses blood-brain barrier effectively (CSF, ocular fluid)  Candida krusei is resistant!  Source: http://www.doksinet Pharmacokinetics Protein binding: 11 to 12%  Half life: 73.6 hours  80% of the dose eliminated unchanged in the urine  Fungistatic effect  Source: http://www.doksinet Dose < 29 Weeks 0 to 14 days – 5-6 mg/kg/dose every 72 hours  > 14 days – 5-6 mg/kg/dose every 48 hours  Source: http://www.doksinet Dose 30 to 36 Weeks  0 – 14 days – 3-6 mg/kg/dose every 48 hours Source: http://www.doksinet Fluconazole Itraconazole Voriconazole Posaconazole C. albicans +++ ++ +++ +++ C. glabrata + + ++ ++ C. krusei -- + +++ ++ C. tropicalis +++ ++ +++ +++ C. parapsilosis +++ ++ +++ +++ C. lusitanae ++ ++ +++ +++ Aspergillus -- ++ +++ +++ Cryptococcus +++ +++ +++ +++

Coccidioides +++ +++ +++ +++ Blastomyces ++ +++ ++ +++ Histoplasma + +++ ++ +++ Fusarium -- -- ++ ++ Scedosporium -- +/- + +/- Zygomycetes - - - ++ Triazoles - ADME Source: http://www.doksinet Fluconazole Absorption IV and PO Good bioavailability Itraconazole PO Capsule ≠ Suspension Capsules best absorbed with food. Suspension best absorbed on empty stomach. Voriconazole Posaconazole IV and PO 90% oral bioavailability PO--Absorption enhanced with high fat meal Distribution Wide. Good CNS penetration Low urinary levels Poor CNS penetration Wide. Good CNS penetration Widely distributed into tissues Metabolism Hepatic/Renal Hepatic CYP 2C9, 2C19, 3A4 Saturable metabolism Not a substrate of or metabolized by P450, but it is an Inhibitor of 3A4 Minimal renal excretion Minimal renal excretion of parent compound 66% excreted in feces Elimination 80% excreted Excreted in feces unchanged in the urine Source: http://www.doksinet

Fluconazole  Dose   100 to 400 mg daily Renal impairment:     Drug Interactions   Minor inhibitor of CYP 3A4 Moderate inhibitor of CYP 2C9   CrCl >50 ml/min, give full dose CrCl<50 ml/min, give 50% of dose Dialysis: replace full dose after each session Warfarin, phenytoin, cyclosporine, tacrolimus, rifampin/rifabutin, sulfonylureas Adverse Drug Reactions    Well tolerated Nausea Elevated LFTs Source: http://www.doksinet Itraconazole  Dose  200 to 400 mg/day (capsules)     Oral solution is 60% more bioavailable than the capsules Drug Interactions     doses exceeding 200 mg/day are given in 2 divided doses Loading dose: 200 mg 3 times daily can be given for the first 3 days Major substrate of CYP 3A4 Strong inhibitor of CYP 3A4 Many Drug Interactions Adverse Drug Reactions       Contraindicated in patients with CHF due to negative inotropic effects QT prolongation,

torsades de pointes, ventricular tachycardia, cardiac arrest in the setting of drug interactions Hepatotoxicity Rash Hypokalemia Nausea and vomiting Source: http://www.doksinet Voriconazole  Dose  IV   PO    > 40 kg200-300 mg PO every 12 hours < 40 kg100-150 mg PO every 12 hours Cirrhosis:  IV   PO    6 mg/kg IV for 2 doses, then 3 to 4 mg/kg IV every 12 hours 6 mg /kg IV for 2 doses, then 2 mg/kg IV every 12 hours > 40 kg100 mg PO every 12 hours < 40 kg 50 mg PO every 12 hours Renal impairment:  if CrCl<50 ml/min, use oral formulation to avoid accumulation of cyclodextrin solubilizer Source: http://www.doksinet Voriconazole Drug Interactions Major substrate of CYP 2CD and 2C19 Minor substrate of CYP 3A4 Weak inhibitor of CYP 2C9 and 2C19 Moderate inhibitor of CYP 3A4  Dose Adjustments Efavirenz Phenytoin Cyclosporine Warfarin Tacrolimus Common Adverse Effects        Peripheral

edema Rash (6%) N/V/D Hepatotoxicity Headache Visual disturbance (30%) Fever  Serious Adverse Events  Stevens-Johnson Syndrome  Liver failure  Anaphylaxis  Renal failure  QTc prolongation Source: http://www.doksinet Posaconazole  Dosing (only available PO)  Prophylaxis of invasive Aspergillus and Candida species   Treatment of oropharyngeal candidiasis   800 mg/day in divided doses Drug Interactions   400 mg twice daily Treatment of refractory invasive fungal infections (unlabeled use)   100 mg twice daily for 1 day, then 100 mg once daily for 13 days Treatment or refractory oropharyngeal candidiasis   200 mg 3 times/day Moderate inhibitor of CYP3A4 Adverse Reactions    Hepatotoxicity QTc prolongation GI: Diarrhea Source: http://www.doksinet Miconazole Half life short: needs to be given in every 8 hours  Bones, joints, lungs – high cc  Do not cross BBB  Liver metabolizes it  Allergic

reactions  Source: http://www.doksinet Other azoles Clotrimazole  Econazole  Tioconazole  Sulconazole  Source: http://www.doksinet Echinocandins MOA Irreversibly inhibits B-1,3 –D glucan synthase, the enzyme complex that forms glucan polymers in the fungal cell wall. Glucan polymers are responsible for providing rigidity to the cell wall. Disruption of B-1,3-D glucan synthesis leads to reduced cell wall integrity, cell rupture, and cell death. Source: http://www.doksinet Echinocandins – spectrum of activity Zygomycetes Scedosporidium Fusarium Histoplasma Blastomyces Coccidioides Cryptococcus Aspergillus guilliermondii lusitanae parapsilosis tropicalis krusei glabrata albicans Candida -++ ++ -+++ + +++ + +++ +++ +++ +++ Source: http://www.doksinet Echinocandins ADME Caspofungin Micafungin Anidulafungin Absorption Not orally absorbed. IV only Distribution Extensive into the tissues, minimal CNS penetration Metabolism Elimination spontaneous

degradation, hydrolysis and N-acetylation Chemical degradated Not hepatically metabolized Limited urinary excretion. Not dialyzable Half-life 9-23 hours 11-21 hours 26.5 hours Dose 70 mg IV on day 1, then 50 mg IV daily thereafter 100 mg IV once daily 200 mg IV on day 1, then 100 mg IV daily thereafter Dose Adjustment Child-Pugh 7-9 70 mg IV on day 1, then 35 mg IV daily thereafter CYP inducers 70 mg IV daily None None Source: http://www.doksinet Echinocandin – drug interaction  Caspofungin   Not an inducer or inhibitor of CYP enzymes CYP inducers (i.e phenytoin, rifampin, carbamazepine)  Reduced caspofungin levels   Cyclosporine   Increases AUC of caspofungin Hepatotoxicity   Reduced tacrolimus levels by 20%  Micafungin   Increased AUC (18%) and Cmax (42%) of nifedipine Sirolimus   Monitor levels of tacrolimus Minor substrate and weak inhibitor of CYP3A4 Nifedipine   Avoid or monitor LFTs Tacrolimus

  Increase caspofungin dose Increased concentration of sirolimus Anidulafungin  No clinically significant interactions Source: http://www.doksinet Echinocandins adverse effects Generally well tolerated  Phlebitis, GI side effects, Hypokalemia  Abnormal liver function tests  Caspofungin  Tends to have higher frequency of liver related laboratory abnormalities  Higher frequency of infusion related pain and phlebitis  Source: http://www.doksinet Others Flucytosine (5-flucytosine, F-FC)  Used in combination treatment with amphotericin b  Synthetic pyrimidine antimetabolite (flourine analog of cytosine) which is fungistatic NOT fungicidal  Has narrow spectrum of activity (Candida albicans, some Candida species and Crytococcus)  Converted to 5-FU antimetabolite  Source: http://www.doksinet Resistance can develop even during therapy-never use as sol therapy  Oral agent only: penetrates CSF well  Dose 50 to 100 mg/kg/day divided

every 12 to 24 hours  Source: http://www.doksinet Mechanism of Action Drug enters the cell via a specific enzyme (permease) where it is converted by a series of steps to a product which inhibit the production of an essential DNA component  Some drug is metabolized into nucleotide (5-FUTP) which is incorporated into fungal RNA disrupting protein and DNA synthesis  Source: http://www.doksinet  Synergistic with Amphotericin B (amphotericin b alters cell membrane allowing Flucytosine into the cell) Source: http://www.doksinet Pharmacokinetics Half life – 4 to 34 hours  75 to 90% excreted unchanged in the urine  Source: http://www.doksinet Toxicity Relatively safe drug with little toxicity  Side effects include transient neutropenia and hepatic dysfunction  Used in caution in presence of renal failure since is excreted by the kidneys  Source: http://www.doksinet Terbinafine Highly lipophilic  Keratinofilic  Fungicidal  Squalene epoxidase

is inhibited – aacumulation of squalene is toixic for the fungus  Topical, po adm  Source: http://www.doksinet New drugs Ravuconazole  Pradimicin  Nikkomycins  Sordarins  Source: http://www.doksinet Gentian Violet 0.25% Source: http://www.doksinet Used topically for thrush  Not well accepted because of the purple staining  Apply to lesions 2 or 3 times daily for 3 days  Don’t apply to ulcerative lesions  Source: http://www.doksinet Mechanism of Action Topical antiseptic/germicide effective against some vegetative gram positive bacteria, particularly Staphylococcus species, and some yeast  Less effective against gram negative bacteria  Ineffective against acid-fast bacteria  Source: http://www.doksinet Antiviral Agents Source: http://www.doksinet Viruses are obligate intracellular parasites who depend upon host cell metabolic processes for their survival  Since they do not possess a cell wall or membrane, they do not

respond to antibiotics  Source: http://www.doksinet Early drugs were not specific often resulting in damage to the host  Rapidly developing area of drug development in light of recent advances in rapid diagnosis of viral infection and molecular biology  Source: http://www.doksinet Approach to Treatment  Based on targeting viral specific steps in the replication process Source: http://www.doksinet Source: http://www.doksinet Replication Process     Adsorption of virus to the cell membrane Penetration Un-coating of viral nucleic acid Transcription of viral proteins (early gene expression) Synthesis of nucleic acid strands Source: http://www.doksinet Transcription of mRNA and late proteins (late gene expression)  Maturation and assembly of new virions  Release of new virions  Source: http://www.doksinet  Because of the intracellular parasitic nature of viruses, most agents have a high “in vivo” toxicity and low therapeutic index

especially in rapidly growing hosts such as infants Source: http://www.doksinet Chemotherapy Approach Inhibit attachment and penetration (amantadine, rimantadine)  Inhibit reverse transcriptase (zidovudine)  Inhibit transcription and translocation (acyclovir, ganciclovir, Ara-A)  Inhibit assembly and release (interferon)  Source: http://www.doksinet Sites of drug action Source: http://www.doksinet Antiherpes agents Acyclovir- prototype  Valacyclovir  Famciclovir  Penciclovir  Trifluridine  Vidarabine  Source: http://www.doksinet Acyclovir Source: http://www.doksinet Source: http://www.doksinet Mechanism of Action Nucleoside analog which incorporates into viral DNA or RNA nucleic acids resulting in abnormal transcription and translation and loss of viral infectivity  Inhibit DNA and RNA polymerases  Source: http://www.doksinet  Inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral

DNA polymerase and by incorporating into viral DNA Source: http://www.doksinet Source: http://www.doksinet  Possesses clinical activity against herpes viruses including HSV-1 and 2, Varicella zoster virus (VZV), CMV, Hepatitis b virus, and Epstein Barr virus Source: http://www.doksinet Available as an oral, IV, and topical preparation  Drug of choice for the treatment of neonatal herpes simplex infections  Source: http://www.doksinet Pharmacokinetics Protein binding < 30%  Half life – terminal phase: 4 hours  Eliminated primarily through the kidney with 30 to 90% of the dose excreted unchanged  Source: http://www.doksinet Dose Prematures 20 mg/kg/day divided every 12 hours for 14 to 21 days IV  Terms 30 mg/kg/day divided every 8 hours for 14 to 21 days IV  Longer dosage regime intended for those with CNS involvement and disseminated disease  Source: http://www.doksinet Mechanisms of resistance - acyclovir  Alteration in viral

thymidine kinase  Alteration in viral DNA polymerase  Cross-resistance with valacyclovir, famciclovir, and ganciclovir Source: http://www.doksinet Herpes Infants with ocular involvement should be treated with topical medications as well as intravenous therapy  Trifluorothymidine (Viroptic)  Vidarabine opthalmic  Idoxuridine (Stoxil)  Source: http://www.doksinet Source: http://www.doksinet Method of Action  Inhibits viral DNA synthesis by blocking DNA polymerase or virus-induced ribonucleotide reductase Source: http://www.doksinet Ribavarin Source: http://www.doksinet Synthetic nucleoside analog effective against a variety of RNA and DNA viruses although used most often for RSV  Antiviral activity against HSV-1, and 2, vaccinia, Para influenza, influenza A and B, measles virus, HIV-1, some adenoviruses, Coxsackies virus b and poliovirus  Source: http://www.doksinet Mechanism of Action Inhibits replication of RNA and DNA viruses 

Inhibits influenza virus RNA polymerase activity and interferes with the expression of messenger RNA resulting in inhibition of viral protein synthesis  Source: http://www.doksinet Pharmacokinetics Absorbed systemically from the respiratory tract following nasal and oral inhalation  Half life – 2 hours respiratory tract secretions  Source: http://www.doksinet Available for administration as oral, intravenous amd aerosol agent  Delivery to mechanically ventilated infants requires skill with the drug  Aerosols must be administered via SPAG (small particle aerosol generator) to create appropriate size droplet, drug may crystallize in the apparatus and occlude ventilator circuits  Source: http://www.doksinet    Controversy over its use in the neonatal population Infants with congenital heart disease, chronic lung disease, immunodeficiency, and severe respiratory failure are at increased risk for RSV and thought to benefit from therapy Rarely used at

this time in the neonatal patient population Source: http://www.doksinet Anti-cytomegalo virus agents Gancyclovir  Valgancyclovir  Cidofovir  Foscarnet  Fomivirsen  Source: http://www.doksinet Gancyclovir Source: http://www.doksinet  Nucleoside analog of acyclovir developed specifically for the treatment of cytomegalovirus (CMV) infections in immune-compromised hosts Source: http://www.doksinet Mechanism of Action   Ganciclovir is phosphorylated to a substrate which competitively inhibits the binding of deoxguanosine triphosphate to DNA polymerase Ganciclovir triphosphate competes with deoxyguanosine triphosphate for incorporation into viral DNA and interferes with viral DNA chain elongation resulting in inhibition of viral replication Source: http://www.doksinet Method of Action Competitive inhibitor of human CMV polymerase  Investigational drug for use in patients with AIDS and transplant recipients  Source: http://www.doksinet

Increase in use in the neonatal population  Decreased morbidity of hearing deficit with use and as a result may be utilized more in our patient population  Source: http://www.doksinet Clinical Trials Data suggest high drug toxicity including severe neutropenia, NEC, worsening liver function, retinal hemorrhage, and bacterial infection  May benefit infants with CNS disease  Known reduction of hearing defects  Source: http://www.doksinet Pharmacokinetics 1-2% protein binding  Half life – 2 to 49 days of age 2 to 4 hours  Source: http://www.doksinet Dose Depends upon reference  15 mg/kg/day divided every 12 hours  Treatment effect is that is decreases the viral load which MAY limit morbidity  Has been shown to be carcinogenic in animal studies  Source: http://www.doksinet Source: http://www.doksinet Anti-influenza agents Amantadine  Rimantadine  Zanamivir  Source: http://www.doksinet Amantadine / Rimantadine Source:

http://www.doksinet  Used for prophylaxis in selected populations for outbreaks of influenza A, although not generally used in neonates Source: http://www.doksinet Mechanism of Action Blocks the uncoating of influenza A viral RNA and prevents penetration of the virus into host cell  Inhibits M2 protein in the assembly of progeny virions  Source: http://www.doksinet Pharmacokinetics Protein binding – 40%  Half life children 4 to 8 years – 13 to 38 hours  Source: http://www.doksinet Dose  Children < 10 5 mg/kg daily Source: http://www.doksinet Reverse transcriptase inhibitors Zidovudine (AZT)  Didanosine- causes pancreatitis*  Lamivudine- causes pancreatitis  Zalcitabine- causes peripheral  neuropathy* Stavudine- causes peripheral neuropathy*  Abacavir  Source: http://www.doksinet Zidovudine (AZT) Source: http://www.doksinet Thymidine analog originally developed as an anti-cancer drug in the 1960s  Active against the

human immunodeficiency virus by interfering with viral multiplication and slowing progression of the disease  Available as oral and intravenous preparation with short half-life  Easily crosses into the CSF  Source: http://www.doksinet Relatively safe drug which does cross the placental barrier  Newborns treated with AZT demonstrate improvement in neurodevelopmental outcomes  Major impact on the prevention of maternal-fetal HIV-1 transmission  Source: http://www.doksinet Mechanism of Action Enters the cell and is phosphorylated by cellular kinases to the active metabolite zidovudine triphosphate which serves as an alternative substrate to deoxythymidine triphosphate for incorporation by reverse transcriptase  Inhibits HIV viral polymerases and DANA synthesis  Source: http://www.doksinet Pharmacokinetics Well absorbed orally  Extensive first pass effect  Metabolized in the liver via glucuronidation to inactive metabolites  Half life – terminal:

60 minutes  Premature infants – 6.3 hours  Term infants – 3.1 hours  Source: http://www.doksinet Dose 2 mg/kg/dose every 6 hours oral (give 30 minutes before or 1 hour after a meal)  1.5 mg/kg/dose every 6 hours IV  Initial dose should be give within 6 hours of birth  Dosing continued for 6 weeks  Source: http://www.doksinet Other AIDS Drugs Didanosine (ddI)  Similar to ddC  Infants have shown improved neurodevelopmental function on this therapy  Source: http://www.doksinet Other AIDS Drugs Zalcitabine (ddC)  In vitro effects are 100 times higher than that of ZDV in HIV-1 infected macrophage and t cells  Well tolerated in children at low doses  Source: http://www.doksinet Protease inhibitors    HIV-1 encodes an aspartate protease, which required for cleavage of polypeptide precursors that generate structural proteins and enzymes (reverse transcriptase, integrase, protease itself). Alpha-1 acid glycoprotein binds them

intensively and the plasma elimination half life is short. Saquinavir, low oral bioavail = 4%!! but it has antiretroviral effect and well torelable. Indinavir Source: http://www.doksinet Acyclic nucleosid phosphonates    They are not dependent on viral enzymes for their initial phosphorylation. Cidofovir � cytosine anlogue, in itro it is active against acyclovir-resistant HSV and gancyclovir-resistant CMV. Iv treatment of CMV retinitis in AIDS patient. Topically to mucocutaneous HSV infections. Adefovir, adenine analogue, in HSV and retroviral infections. Poor oral bioavail