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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 α Lanosine 14 -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) Can be fatal Usually occurs within first 4 months of treatment 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 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: CrCl >50 ml/min, give full dose CrCl<50 ml/min, give 50% of dose Dialysis: replace full dose after each session Drug Interactions Minor inhibitor of CYP 3A4 Moderate inhibitor of CYP 2C9 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) 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 Drug Interactions Oral solution is 60% more bioavailable than the capsules 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 6 mg/kg IV for 2 doses, then 3 to 4 mg/kg IV every 12 hours > 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 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 Increase caspofungin dose Cyclosporine Increases AUC of caspofungin Hepatotoxicity Tacrolimus 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 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, Coxsackie's 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
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 α Lanosine 14 -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) Can be fatal Usually occurs within first 4 months of treatment 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 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: CrCl >50 ml/min, give full dose CrCl<50 ml/min, give 50% of dose Dialysis: replace full dose after each session Drug Interactions Minor inhibitor of CYP 3A4 Moderate inhibitor of CYP 2C9 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) 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 Drug Interactions Oral solution is 60% more bioavailable than the capsules 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 6 mg/kg IV for 2 doses, then 3 to 4 mg/kg IV every 12 hours > 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 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 Increase caspofungin dose Cyclosporine Increases AUC of caspofungin Hepatotoxicity Tacrolimus 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 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, Coxsackie's 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
