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Antiviral Exam 1
Infectious Disease Drug List Exam 1
| Generic | Brand | MOA | Uses | Side Effects | Ramsinghani Notes | Resistance | Shah dose/notes | Shah dose/notes |
|---|---|---|---|---|---|---|---|---|
| Acyclovir (PO, topical, IV), capsule, buccal tablet, suspension | Acyclo-G; Zovirax | Inhibition of viral genome replication; ACYCLIC NUCLEOSIDE; Competitive inhibition of viral DNA pol by acyclovir triphosphate; insertion into vDNA --> termination of vDNA synthesis | HSV-1. HSV-2. VZV infections | dose-limiting; nephrotoxicity, crystalluria, (drug is insoluble in urine) Neurotoxicity, N/V. Pancytopenia (lowering of blood cells) | Acyclic--> attached is a sugar but not a full cyclized sugar. Acyclic structure inhibt DNA chain elongation--> missing the 3'OH so it can't make the Phosphodiester bond -Which drug is a nucleotide? based on if it has a phsophate group | reduction of virus encoded thymine kinase (If virus is not creating this, the drug will not be able to get phosphorylated and the drug would become inactive); no mono-->di--triphosphate | Herpes Labialis: Initial: 200 mg 5x/day or 400 TID x 7-10 days; Recurrence: 400 mg TID x 5-10 days; Chronic supp: 400 mg BID; Severe IV acyclovir (5-10 mg/kg q8h (IBW); renal impair (<50 ml/min--> decrease dose to 10mg/kg--> 8mg/kg or increase dosing interval q8h--> q12h | Genital Herpes: (First episode)--> 400 mg PO TID or 200 mg 5x/day; Duration: 7-10 days; Suppressive Therapy: 400 mg PO BID; Episodic Tx: 800(2)/800(3)/400 (3); 5/2/5 days; Severe HSV DOT: 10-21 days |
| Valacyclovir (Prodrug); (only PO) | Valtrex | Inhibition of viral genome replication; ACYCLIC NUCLEOSIDE; Conversion--> loss of valine-ester (esterified to Acyclovir)--> ester removed by hydrolysis to--> 9-Carbaroxymethoxy methylguanine and Acyclo-G monophosphate--> Acyclo-G triphosphate (Active form) | HSV-1. HSV-2. VZV infections | not given; may be similar to acylcovir | Determining if cross-resistance of the drugs? similar structure and MOA within a class (resistance to 1= resistance to whole class); Valcyclovir--> better oral BA (70%) compared to acylcovir. due to lipophilic valine ester | reduction of virus encoded thymine kinase (If virus is not creating this, the drug will not be able to get phosphorylated and the drug would become inactive); no mono-->di--triphosphate | Initial: 1 g BID; Recurrence: 2 g BID x 1 day Chronic supp: 500 mg or 1 g daily | Genital Herpes: (First episode)--> 1 g PO BID; Duration: 7-10 days; Suppressive Therapy: 500-1000 mg PO daily; Episodic Tx: 500 BID- 3 days; 1g qd- 5 days |
| Famciclovir (Prodrug) | No brand indicated | Inhibition of viral genome replication; ACYCLIC NUCLEOSIDE; removal of ester and double bond O group--> Penciclovir | HSV, VZV | not given | Oral BA: 75% | Initial: 250 mg TID or 500 mg BID; Recurrence: 1.5g x 1 dose; Chronic supp: not approved for chronic suppression | Genital Herpes: (First episode)--> 250 mg PO TID; Duration: 7-10 days Suppressive therapy: 250 mg PO BID; Episodic tx: 1g BID-1day; 500+250BID x 2days-->3 days; 125 mg PO BID-->5 days | |
| Penciclovir (used topically) | Denavir | Inhibition of viral genome replication; ACYCLIC NUCLEOSIDE | HSV, VZV; used topically; cream for herepes labialis (lips and face only) | not given | OH group (3'OH) is not constrained in a sugar making it not effective for the phosphodiester bond formation | |||
| Ganciclovir (IV, Intravitreal implant, ophthamic gel/jelly) | No brand indicated | Inhibition of viral genome replication; ACYCLIC NUCLEOSIDE; Same as acyclovir but uses UL97 gene encoded phosphotransferase instead of thymidine kinase for conversion to monophosphate in CMV | treatment and maitenance/ prophylaxis (shah); Greater activity aginst CMV and EBC; Treatment of Cytomegalovirus (HCMV) retinitis in immunocompromised pts; Prevention of HCMV disease after trasnplant | Boxed warning: BLOOD DYSCRASIAS (abnormalities of blood); Carcinogenic; teratogenic; N/V/D; CNS toxicity; Myelosuppression | Transplant pts are at risk of getting infections such as HCMV; Shah (avoid PO use in CMV colitis due to absorption variability) | Mutations in viral phosphotransferase (enzyme needed for the conversion to mono-phosphate) and DNA pol | IV injection only; for treatment and maint/ppx; 5mg/kg IV BID for tx; 5mg/kg IV daily for maint/ppx; IV ganciclovir 5mg/kg= PO Valganciclovir 900 mg | |
| Valganciclovir (prodrug); (PO) | Valcyte | Inhibition of viral genome replication; ACYCLIC NUCLEOSIDE; Same as acyclovir but uses UL97 gene encoded phosphotransferase instead of thymidine kinase for conversion to monophosphate in CMV | Greater activity aginst CMV and EBC; Treatment of Cytomegalovirus (HCMV) retinitis in immunocompromised pts; Prevention of HCMV disease after trasnplant | Boxed warning: BLOOD DYSCRIASIS (abnormalities of blood); Carcinogenic; teratogenic; N/V/D; CNS toxicity | Transplant pts are at risk of getting infections such as HCMV | Mutations in viral phosphotransferase (enzyme needed for the conversion to mono-phosphate) and DNA pol | Uses: tx and maint/ppx; 900 mg PO BID x 21 days for tx; 900 mg PO daily for maint/ppx; Prodrug of ganciclovir (better BA) -avoid PO use in CMV colitis due to absorption variability | |
| Cidofovir (IV) IV due to phsophate group (+) so not absorbed PO | No brand indicated | Inhibition of viral genome replication; ACYCLIC PYRIMIDINE NUCLEOTIDE analog of CYTOSINE; active form--> **Cidofovir diphosphate (3 PO4) (already comes with initial phosphate) | Effective agaisnt acyclovir-resistant HSV, and gancilcovir-resistant HCMV infections; Treatment of CMV retinitis in HIV pts only | Boxed warning: nephropathy, neutropenia, carcinogenic, teratogenic, myelosuppression Adv. effect: Nephrotoxicity (**pre-hydrate) | Does not require viral-specific thymidine kinase *Prehydrate w/ NS and can also use probenacid (inhibits the tubular secretion of Cidofovir (keeping it in culrcualrion and not accum. in nephron; ** when you see "fo" it indicates a Phosphate group | uses: treatment; not approved for maintenance; ADE: nephro, myelosuppression, neutropenia, carcinogenic/teratogenic; Clincal pearls: hazardous agent (special handling); Hydrate before infusion to minimize nephrotoxicity | **Reserved for refractory cases, as an alternative when treatment limiting toxicities occur with ganciclovir and/or when CMV is resistant | |
| Foscarnate (IV) *trisodium phosphormate hexahydrate | No brand indicated | Inhibition of Viral genome replication; Non-nucloside inhibitor; Inhibition of viral DNA polymerase | -Treatment of CMV retinitis in AIDS pts -Treatment of acyclovir-resistant HSV and VZV infections | Neurotoxicity, phlebitis, hematologic abnormalities, N/V, electrolyte imbalances (wasting can lead to neurotoxicity specifically seizures; Pt must be monitored | triple Na+; 6 H2O (Very charged; cannot be given PO | IV only; for tx; not approved for maintenance; ADE: renal impairment, including electrolyte abnormalities (K,Ca, Mg, PO4, QTc prolong.; Clinical pearls: faster infusions lead to increased toxicity | ** Reserved for refractory cases, as an alternative when treatment limiting toxicities occur with ganciclcovir and/or CMV is resistant | |
| Letermovir (**Concatemer drug) | Prevymis | Inhibition of viral terminase complex; Drug inhibits terminase complex and prevents the concatemers from being released by targeting pUL56 | Prevention of CMV infection in BONE MARROW TRANSPLANT | Not given | Remember Viral genome replication--> DNA CONCATEMERS; multiple repeated gene sequences; terminase complex--> cleaves DNA concatemers (pUL56, pUL89, and others); Oral BA increases w/ cyclosporine (CYP3A4 inhib) | Is there cross-resistance? No because this is a unique drug with no similar MOA | ||
| Zanamavir (oral inhalation) | Relenza | Anti-influenza; inhibition of viral release Drug: inhibtion of neuraminidase prevents cleavage of sialic acid (host cell) from hemagglutinin sugars (glycoprotein present on virus)--> prevents release of infectious virus | Anti-influenza; enhanced interaction of drug with target: -Guanidino grp w/ Glu 119 and Glu 227 | cough, nasal congestion | *Tx most effective when started w/in 48h of onset of symptoms; *Substitution of 4-hydroxy with GUANIDINO group; given by oral inhalation (ionized at phys. pH) | |||
| Oseltamivir (PO) (Suspension or capsule) | Tamiflu | Anti-influenza; inhibition of viral release Drug: inhibtion of neuraminidase prevents cleavage of sialic acid (host cell) from hemagglutinin sugars (glycoprotein present on virus)--> prevents release of infectious virus | Anti-influenza; enhanced interaction of drug with target: -amino grp w/ Glu 119; 3-pentyloxy grp w/ hydrophobic pocket | Nausea/Vomiting | *Tx most effective when started w/in 48h of onset of symptoms; hydrophobic interactions at C-6; Ester at C-2 | binding requires a conf. change in NA (neuraminidase); needs rotation of Glu276 (needs to move away to allow Tamiflu binding--> His274Tyr mutation in NA prevents the conf. change to move Glu 276 for Tamiflu to bind | For tx and prophylaxis; 75 mg PO BID x 5days for tx; 75 mg PO daily x 10 days for ppx; ADR: D/skin rash, hypersensitivity rxn, delirium, hallucination; Clinical P: tx is most effective when started w/in 48h of illness; can extend the course of tx | |
| Baloxavir marboxil (Prodrug) (PO only, suspension) | No brand indicated | Cap-snatching mechanism of the influenza virus; drug inhibits the ENDONUCLEASE activity of the PA subunit | Treatment: UNCOMPLICATED influenza infection; SINGLE DOSE DRUG (79h 1/2 life); tx and POST-EXPOSURE prevention | Drug interaction with Di- and poly-valent metal ion containing meds (i.e. Antacids, Ca2+, Iron containing products) | Baloxavir chelates the Mn2+ ions--> Cap-dependent Endonuclease (CEN) inactive; *Tx most effective when started w/in 48h of onset of symptoms | ILE38Tyr | For tx and POST-EXPOSURE PREVENTION; <80 kg: 40 mg PO x 1; >80 kg: 80 kg PO x 1; ADE: N/V/abd. pain, HA; Clinical Pearls: Tx is most effective when started w/in 48h of illness | |
| Remdesivir (Prodrug) (IV) | Veklury | Broad Spectrum Antiviral Drug; Nucleoside monophosphate-like structure; MOA: inhibits vRdRP (viral RNA dependent RNA polymerase) | Influenza, Ebola, SARS-CoV-2; Uses: adults and children >12yo w/ COVID-19 in the inpatient setting | nausea, increase LFT, infusion rxn | Undergoes activation by 1. esterase and 2. Phosphamidase; releases monophosphate form of the drug to further metabolism (Mono-di-triphosphate form) | Dosing: 200 mg IV on day 1, then 100 mg on days 2-3; Clincal P: must start w/in 7 days of symptom onset; can extend to 10 days based on clinical improvement | ||
| Nirmatrelvir + Ritonavir (PO) | Paxlovid | -Nirmatrelvir inhibits 3C-like protease (3CL^pro)--> inhibits production of non-structural proteins (virus can't finish replication and life cycle); -Ritonavir--> used as a boosting agent and has no inhibition effect on the virus/ increases level of Nirmatrelvir by inhibiting metabolism) | Broad Spectrum Antiviral; Uses: adults and children >12 yo w/ COVID-19 in the outpatient setting | Contraindication: drugs primarily metabolized by CYP3A4 for which elevated conc. can be serious or life-threatening; strong inducer of CYP3A4 | Ritonavir: CYP3A4 inhibitor; remember that the virus uses the 3C-like protease to activate some of the large proteins by cutting them into smaller active proteins | Dosing: 300 mg nirmaltrelvir + 100 mg ritonavir PO BID x 5 days; Clinical P: renal dose adj. in CrCl <60; Ritonavir is a strong CYP3A4 inhib; interaction checker! | ||
| Molnupiravir (Prodrug) | Lagevrio | isopropylester of N4-hydroxycytidine (NHC); drug causes mutation in RNA by causing INCORRECT BASE pairing of G->A and C->U | Active against positive and negative sense viruses, MERS-CoV, SARS-CoV, SARS-COV-2 | Not given | *Molupiravir contains a isopropyl ester group *Broad Spectrum antiviral | |||
| Maraviroc | No brand indicated | Inhibition of viral attachment and entry; Inhibits HIV-1 gp 120 binding to CCR5-> prevents gp160-CCR5 mediated cell-cell fusion | HIV | Not given | remember that Maraviroc only binds to CCR5; Pt must undergo Trofile test (determine receptor expression either CCR5 or CXCR4 or sometimes both (dual-tropism) | Mutations in the HIV genome; RT, Protease, Integrase; Resistance: CXCR4 (different co-receptor; so if CD4 cells are expressing lots of CXCR4 (inactive drug) | ||
| Fostemsavir (Prodrug) | No brand indicated | Inhibition of viral attachment and entry; Directly binds to gp120 subunit; prevent viral attachment to CD4 cells | HIV | QTc Prolongation; Drug interaction: CI w/ strong inducers of CYP3A4, QTc prolonging drugs | * prodrug is activated by alkaline phosphatase--> removes phosphate group and gives the active drug--> Temsavir which is further metabolized to inactive metabolites. | Mutations in the HIV genome; RT, Protease, Integrase; | ||
| Enfuvirtide (SQ) | No brand indicated | Inhibition of viral attachment and entry; binds to gp41 subunit and traps the virion in a confirmation that prevents fusion with the host cell membrane | for treatment-experienced adults (* other HIV treatments have been TRIED and not worked effectively so this is a 2nd or 3rd option) | injection-site rxn; counsel to rotate injection site | **why cant this be given SQ? peptide bonds would be broken by GI making drug ineffective | Mutations in the HIV genome; RT, Protease, Integrase; mutation in enfuvirtide--> binding domain of gp41 | ||
| General NRTI (Nucleoside reverse transcriptase inhibitors) | No brand indicated; remember MOA (2 ways)--> 1. either compete with native nucleotides (bind directly to active site inhibiting RT) 2. inserted into DNA that is being synthesized (stopping futher elongation of DNA (*lack of 3'OH) | Class MOA: Nucleoside--> N-MP--> N-DP--> N-TP--> block proviral DNA replication | NRTI's compete with native nucleotides (adeonise TP, deoxy TP, guanosine, cytidine, etc; Terminate elongation of proviral DNA | Adverse effects as a class--> inhibit host DNA pol y(gamma); anemia, granulocytopenia, myopathy, peripheral neuropathy, pancreatitis; BW--> Precaution: lactic acidosis, severe hepatomegaly w/ steatosis; all adv effects linked to inhibition of DNA pol gamma | Precautions due to newer drugs dont cause these much. *lactic acidosis (mitochondria affected by these drugs switch to anaerobic glycolysis--> lactic acid production; hepatomegaly (large liver, filled with fat globules) | *Drug interaction is not significant, why? B/c we don't have the CYP mediated interactions** | ||
| Key examples of NRTI drugs: *2-50h 1/2 life; Most NRTI require dose adjustment in renal dysfunction | ZidovuDINE is a Thymidine analog derivative--> competes with dTTP; ***What is the critical structural piece missing in the NRTI drug that will prevent HIV DNA synthesis? 3'-OH; 5'-OH is not present but added in the bio-activation process. | Inhibition of viral genome replication; (NRTI) | LamivuDINE and EmtricitaBINE are both derivatives of: Deoxycytidine analogs; these corresponds to chemical structure | NRTI AE? Class Notes: Abacavir and Tonofovir are derivatives of: Purine analogs; TenoFovir (phosphorylated nucleotide) | NRTI Notes: Abacavir can cause hypersensitivity in pts who harber the HLAB*5701 allele (Boxed warning); pts must get tested for allele. | Mutations in the HIV genome; RT, Protease, Integrase; | ||
| TenoFOvir (Prodrug) | Vemlidy | Acyclic nucleoTIDE analog;--> metabolites TDF/TAF; TDF--> hydrolyzed by plasma esters | HIV | TDF:Nephrotoxicity, REDUCTION IN BONE MINERAL DENSITY; TAF--> more stable in plasma/higher conc. in virus infected cells | TAF has reduced adverse effects; TDF--> Tenofovir--> Tenofovir diphsophate (1/2 life 17h so once daily dosing) | Mutations in the HIV genome; RT, Protease, Integrase; | ||
| NNRTI (Non-nucleoside reverse transcriptase inhibitor | No brand indicated | MOA: bind RT at an ALLOSTERIC site--> confirmational change in RT--> vDNA elongation terminated | HIV | Adverse effects: RASH, SJS; CYP enzymes--> potenial for DI | ***The inhibition of RT by NNRTI is? non-competitive inhibition | Mutations in the HIV genome; RT, Protease, Integrase; NNRTI resistance develops quickly so these are used in combination. resistance could occur based on change in amino acid causing the drug not to bind effectively | ||
| Efavirenz | Sustiva | First generation NNRTI | HIV | Adverse effects of First generation: CNS (abnormal/vivid dreams), teratogen | **The inhibition of RT by NNRTI is? non-competitive inhibition | Mutations in the HIV genome; RT, Protease, Integrase; | ||
| Nevirapine | Viramune | First generation NNRTI | Has been used for preventing HIV transmission from mother-newborn | Crosses placenta: | **The inhibition of RT by NNRTI is? non-competitive inhibition | Mutations in the HIV genome; RT, Protease, | ||
| Etravirine, Rilpivirine, Doravirine | Intelence, Edurant, Pifeltro | 2nd generation NNRTIs | High potency against HIV resistant to first gen NNRTI | Rilpivirine requres acidic environment for getting absorbed (potential for DI; give with food) | ** Structure on Etravirine that gives flexibility? Oxygen | Mutations in the HIV genome; RT, Protease, | ||
| Integrase Strand Transfer inhibitors (INSTI) Class: | INSTI brand? Notes: Common Feature--> Oxol groups (carbonyl or OH groups), with close groups, opportunity for intermolecular H-bonding; can also chelate with integrase active site | MOA: inhibit integrase--> inhibit incorporation of vDNA into host cell genome | HIV integrase inhibitor; notes: Virus requires binding to the metal ion for activity; INSTIs chelate with metal ion--> inactivate integrase since metal isn't available | INSTI AE? No adverse effects since nothing like it in our cells hence well-tolerated | *These are FIRST LINE TREATMENT for HIV | Resistance: mutations in integrase gene--> Combo with NRTI, NNRTI, or PI | ||
| INSTI Class: Ral/Dolu/CaboTEGRAVIR | Ral--> Isentress; Tivicay; Vocalbria/Apretude | These are well absorbed orally, RAL/DOLU/CABO are metabolozed by UGT1A1; Elvitegravir by CYP3A; Bictegravir: CYP3A, UGT1A1 | These are used and blocking the normal activity of the virus (incorporating proviral DNA into the human DNA into the chromosome | DI: Avoid concomitant use of divalent cations, i.e antacids; Inducers of UGT1A1, CYP3A4; Rifampin contranindicated w/ bictegravir, elvitegravir, cabotegravir | Elvi--> combination w/ Cobicistat (used as a booster, inhib of 3A4; Area of Cabotegravir that is responsible for its activity? Oxole group | Mutations in the HIV genome; RT, Protease, | ||
| Protease Inhjibitors (PI) Class -PI drugs "navir" | PI Virus brand? | Virus MOA: HIV protease cleaves gag and gag-pol gene precursor proteins to produce active proteins (-p7, p9, p17, p24 *Transistion state inhibitors | HIV protease inhibitor | PI Virus AE: may cause selective toxicity due to presnce of aspartic protease in our cells. (**different from HIV monomers since humans dont have 2 amino acids phe | pro close together. | Virus Notes: HIV protease: aspartic protease (means it has aspartic acid at its active site; Dimer of 2 different units (Asp 25/Asp 25) Cleaves at the N-terminal side of proline in the polypeptide seq (phe | pro); PI drugs designed on the Transistion state of the proteolytic action | Resistance: amino acid mutations in HIV protease; mostly given in combination with other drugs. | ||
| Saquinavir | No brand indicated | contains phenyalanine (tetrahedral carbon that mimics the Transistion state on the proteolytic action; mimic and inhibti the protease; phenylalanine structure mimics proline. | HIV protease inhibitor | may cause selective toxicity due to presence of aspartic proteinases in our cells | All PI are Navir drugs and they have peptidic structures; Drugs will have something similar to a hydroxyethylamine | Resistance: amino acid mutations in HIV protease; mostly given in combination with other drugs. | ||
| Protease inhibitor (PI) Class Drugs | No brand indicated | Our drugs will have something similar to a hydroxyethylamine; (HO-CH2-NH) | HIV protease inhibitor | may cause selective toxicity due to presence of aspartic proteinases in our cells | Fosamprenavir (prodrug--> removal of PO4---> amprenavir; Ampre/Daru--> avoid in sulfa allergy; Atazanavir--> needs intragastric acidity for absorb.; Tipranavir (non-peptide PI); Lopinavir/Ritonavir based on hydroxyethelene (No Nitrogen) | |||
| Tipranavir | No brand indicated | Protease Inhibitor | improved interaction w/ HIV Protease; More frequent bioactive conformations; Strong network of H-bonds (**not only binding to Asp 25 but also Asp30 | Class effect: Metabolic syndrome; metabolized by CYP3A4; inhibitor of CYP3A4--> Potential for DI | Direct binding to conserved ILE (in the HIV protease); Enhanced contacts w/ protease through hydrophobic interactions | |||
| Pharmacokinetic Boosting PIs: Ritonavir, Cobicistat | No brand indicated | Combo PI drug MOA: Ritonavir: low dose ritonavir combo; Cobicistat: No PI activity (job to inhibit metabolism) | COMBO use for PI | Combo AE not stated | Ritonavir--> contains hydroxyethylamine; Cobicistat: does not contain classic structure for mimicking trans state | COMBO resistance: not stated |
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