Pharmacology: Antiviral Agents (PDF)

Pharmacology: Antiviral agents (non-retroviral, non-hepatitis agents) Dhara Surati, PharmD, BCPS Clinical Associate Professor University of Houston College of Pharmacy PHAR 5338 (ID 2 module) November 6, 2023 [email protected] 1 Learning Objectives • Identify mechanism of action and key compon...

Pharmacology: Antiviral agents (non-retroviral, non-hepatitis agents) Dhara Surati, PharmD, BCPS Clinical Associate Professor University of Houston College of Pharmacy PHAR 5338 (ID 2 module) November 6, 2023 [email protected] 1 Learning Objectives • Identify mechanism of action and key components involved • Identify the general spectra of activity • Know the types of formulations available • Apply basic pharmacokinetic (ADME)/pharmacodynamics knowledge from a pharmacologic perspective • Recognize key adverse effects and drug-drug interactions – where applicable, possible pharmacologic reasoning 2 Format • Slide based • Interactive/active learning questions 3 Primary Reference • Acosta EP. Chapter 62: Antiviral Agents (Nonretroviral). In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e. McGraw Hill; 2017. https://accesspharmacy.mhmedical.com/cont ent.aspx?bookid=2189&sectionid=172486085 4 Additional References • The Sanford Guide to Antimicrobial Therapy (latest digital content 2023) • The Johns Hopkins POC-IT ABX Guide. (latest online version) • Gallagher JC, MacDougall C. Antibiotics simplified. 5e Burlington, MA: Jones & Bartlett Learning • Online.lexi.com • www.cdc.gov 5 Drugs – Influenza 6 Influenza virus: key players ~20% http://micro.magnet.fsu.edu/cells/viruses/influenzavirus.html ~80% Attachment of virus to host cell 7 Activity of neuraminidase (NA) Facilitates the release of newly produced virus particles from the host cell Moscona A. NEJM. 2005, September;353:1363-1373 8 Types of influenza Feature Influenza A Influenza B Major protein M2 (unique) NB (unique) 9 Anti-influenza agents Drug Trade Name Target oseltamivir Tamiflu® NA* zanamivir Relenza® NA* peramivir Rapivab® NA* baloxavir marboxil Xofluza® Inhibits endonuclease amantadine Symmetrel® M2 protein rimantadine Flumadine® M2 protein N Eng J Med 2000;343:1778; www.online.lexi.com; http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm Influenza Type NA* = neuraminidases 10 Mechanism of action Anti-influenza agents 11 MOA – Neuraminidase inhibitors Moscona A. NEJM. 2005, September;353:1363-1373 12 Types of formulations Anti-influenza agents Drug Oseltamivir Oral IV Yes Zanamivir Yes Peramivir Baloxavir marboxil Inhalation Yes Yes 13 Formulation-dependent caution • Oseltamivir oral suspension – Contains sorbitol – Concern: diarrhea and dyspepsia – Caution: in patients with hereditary fructose intolerance 14 ADME Overview – key points Anti-influenza agents oseltamivir zanamivir peramivir baloxavir Dose adjustment for renal impairment? Yes or No 15 Common adverse effects Anti-influenza agents Drug Common Adverse Effects All four • GI side effects – N/V/D Oseltamivir / Peramivir/ Baloxavir • Hypersensitivity / serious skin reactions • transient neuropsychiatric events reported (self-injury; delirium) • sinusitis, cough, headache, and ear, nose, throat infections Zanamivir http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm 16 Drug-drug interactions Drug: Interacts with Details: All four agents Live/attenuated influenza vaccine Concern: Diminish the effect of the live influenza vaccine Baloxavir Polyvalent cationscontaining products/dairy Concern: May decrease the absorption of baloxavir 17 Active learning question #1 Which of the following is available as an IV formulation in the US? A. Oseltamivir B. Peramivir C. Baloxavir D. Zanamivir 18 Active learning question #2 Which of the following has a different target against the influenza virus? A. Oseltamivir B. Peramivir C. Baloxavir D. Zanamivir 19 Drugs – COVID-19 20 Anti-COVID-19 agents Drug Trade Name Target Remdesivir Veklury® Nirmatrelvir and ritonavir Paxlovid® SARS-CoV-2 RNA-dependent RNA polymerase (RdrP) Main protease(Mpro) Molnupiravir Lagevrio® Viral mutagenesis 21 Types of formulations Anti-COVID-19 agents Drug Oral remdesivir IV Yes nirmatrelvir and ritonavir Yes molnupiravir Yes 22 Overview ADME – key points Anti-COVID-19 agents Drug remdesivir nirmatrelvir and ritonavir molnupiravir Dose adjustment for renal impairment? Yes or No Other key points --Severe hepatic impairment (ChildPugh Class C) – not recommended --23 Common adverse effects Anti-COVID-19 agents Drug Common Adverse Effects remdesivir • Infusion-related reaction • Bradycardia • Elevated LFTs • hepatotoxicity Nirmatrelvir and ritonavir • Dysgeusia, diarrhea • Elevated LFTs • Hepatitis Molnupiravir • N/V/D 24 Drug-drug interactions Drug: Interacts with Remdesivir Chloroquine/ Concern: Diminish the effect of hydroxychloroquine _____________________ Nirmatrelvir Many drugs and ritonavir Details: Interaction: CYP450 3A4; please check for specific interaction and details 25 Active learning question #3 All of the following are indicated for COVID-19, EXCEPT: A. Peramivir B. Remdesivir C. Paxlovid® D. Molnupiravir 26 Active learning question #4 Select all that apply: Which of the following has a drug interaction with calcium carbonate PO? A. Baloxavir marboxil B. Paxlovid® C. Remdesivir D. Levofloxacin PO 27 Drugs - RSV 28 Potential options for RSV Drug Ribavirin Key Points Inhibits replication of RNA and DNA viruses Palivizumab Monoclonal antibody against RSV Nirsevimab (July 2023) 29 Ribavirin FOR RSV Basic information • For RSV: usually aerosol inhalation • Special equipment required: – Small-particle aerosol generator – Specially trained personnel 30 Drugs – Herpesviruses 31 In the spotlight: Herpes simplex virus (HSV) Varicella zoster virus (VZV) Cytomegalovirus (CMV) 32 General spectra of activity Drug HSV acyclovir valacyclovir (Valtrex®) famciclovir VZV Yes Yes prodrug Yes Yes prodrug Yes Yes CMV penciclovir Yes ganciclovir Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes valganciclovir (Valcyte®) cidofovir foscarnet letermovir prodrug Yes 33 Mechanism of Action – Anti-HSV / Anti- VZV agents 34 Types of formulations Anti-HSV / Anti-VZV agents Drug Oral IV Ophthalmic Topical acyclovir Yes Yes Yes Yes valacyclovir (Valtrex®) prodrug famciclovir prodrug Yes penciclovir Yes Yes 35 ADME Overview – key points Anti-HSV / Anti-VZV agents acyclovir Absorption valacyclovir famciclovir Poor Better^ Better^ More frequently* Less frequently^ Less frequently^ Distribution Well Well No data about CSF Excretion Renal Renal Renal Frequency of dosing penciclovir Dose adjustment for renal impairment? Yes or No *compared to valacyclovir ^compared to acyclovir 36 Adverse effects Anti-HSV / Anti-VZV agents Abdominal headache pain nausea Confusion Agitation Hallucination Seizures Tremors Crystallization AIN* acyclovir Yes Yes Yes Yes valacyclovir (Valtrex®) Yes Yes Yes famciclovir Yes Yes penciclovir Local-site: erythema *AIN – acute interstitial nephritis 37 Mechanism of Action – Anti-CMV agents 38 Types of formulations Anti-CMV agents Drug Oral ganciclovir valganciclovir (Valcyte®) prodrug IV Ophthalmic Yes Yes Yes cidofovir Yes foscarnet Yes letermovir Yes Yes 39 ADME Overview – key points Anti-CMV agents ganciclovir Absorption Excretion valganciclovir cidofovir foscarnet letermovir Better^ Renal Renal Renal Renal Non-renal Dose adjustment for renal impairment? Yes or No ^compared to ganciclovir 40 Adverse effects Anti-CMV agents Ganciclovir and valganciclovir: nephrotoxicity Foscarnet and letermovir: myelosuppression Letermovir: peripheral edema *US Boxed Warning ganciclovir valganciclovir Myelosuppression *Yes *Yes Nephrotoxicity cidofovir letermovir *Yes (neutropenia) *Yes Seizures *Yes *Yes Impairment of fertility *Yes *Yes Fetal toxicity *Yes *Yes *Yes Carcinogenic *Yes *Yes *Yes Appropriate use foscarnet *Yes *Yes 41 Drug – drug interactions Drug: Interacts with Details: foscarnet Or cidofovir letermovir Other nephrotoxic medications With many medications Concern: Greater risk of nephrotoxicity Interaction: CYP450; transporter interactions; please check for specific interaction and details 42 Active learning question #5 Which of the following has activity against CMV? A. Acyclovir B. Valganciclovir D. Oseltamivir E. Palivizumab 43 Activity learning question #6 Medication Toxicity 1. Paxlovid® A. BBW – nephrotoxicity 2. Tamiflu B. Transient neuropsychiatric event 3. Remdesivir C. BBW – pancytopenia 4. Valganciclovir D. Bradycardia 5. Foscarnet E. Dysgeusia 44 Pharmacology: Antiviral agents (non-retroviral, non-hepatitis agents) Dhara Surati, PharmD, BCPS Clinical Associate Professor University of Houston College of Pharmacy PHAR 5338 (ID 2 module) November 6, 2023 [email protected] 45