Table of Contents
Overview
Antiviral pharmacology on the USMLE focuses on a limited set of drugs, most of which you will see again and again in questions. The key is to link each drug to its viral target, mechanism of action, major clinical use, and a few classic adverse effects. This chapter assumes you already know general pharmacology principles and focuses only on what is specific to antivirals.
Antivirals are usually grouped by the type of virus they target, such as herpesviruses, HIV, hepatitis viruses, and respiratory viruses. Many work by interfering with viral nucleic acid synthesis or viral enzymes that are unique to the virus, which increases selectivity and limits toxicity to human cells.
Antiherpesvirus Drugs
The classic USMLE antivirals are those that target herpesviruses, including HSV-1, HSV-2, VZV, CMV, and sometimes EBV. Most of them are nucleoside analogs that must be activated and ultimately inhibit viral DNA polymerase.
Acyclovir, Valacyclovir, and Famciclovir
Acyclovir is a guanosine analog used primarily for HSV and VZV. Valacyclovir is the prodrug of acyclovir with better oral bioavailability, and famciclovir is related and used for VZV and HSV as well.
These drugs must be phosphorylated to become active. The first phosphorylation step is usually done by a viral thymidine kinase, followed by further phosphorylation by host cell kinases. The active triphosphate form inhibits viral DNA polymerase and causes chain termination.
Because they require viral thymidine kinase for initial activation, these drugs preferentially act in infected cells, which improves selectivity. Resistance often develops through mutations that decrease viral thymidine kinase activity or alter viral DNA polymerase.
Clinically, acyclovir and related drugs are used for genital herpes, mucocutaneous HSV infections, HSV encephalitis, and varicella zoster, including shingles. Valacyclovir is often favored for oral dosing because of better absorption, and famciclovir is a common choice for shingles.
Renal toxicity is important. Acyclovir can cause crystalluria and acute kidney injury, especially if patients are dehydrated or receive rapid intravenous infusions.
Acyclovir, valacyclovir, and famciclovir are guanosine analogs that require viral thymidine kinase activation and inhibit viral DNA polymerase, leading to chain termination. Renal toxicity is a classic adverse effect of high-dose or intravenous acyclovir.
Ganciclovir, Valganciclovir, Foscarnet, and Cidofovir
Ganciclovir is a guanosine analog like acyclovir but is more active against CMV. Valganciclovir is its oral prodrug. In CMV infected cells, ganciclovir is activated by a viral kinase (commonly UL97 in CMV) then further phosphorylated by host kinases. The active form inhibits viral DNA polymerase.
These drugs are used for CMV infections, especially CMV retinitis and other severe CMV diseases in immunocompromised patients, such as AIDS or transplant patients.
Bone marrow suppression is a very important toxicity of ganciclovir. Neutropenia, thrombocytopenia, and anemia can occur and are especially problematic in already immunosuppressed patients. Renal toxicity can also occur.
Foscarnet is not a nucleoside analog. It is a pyrophosphate analog that directly inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase at the pyrophosphate binding site. Foscarnet does not require phosphorylation and is active even when viral kinases are absent, which is very important in drug resistance.
Foscarnet is used for CMV retinitis, especially when ganciclovir fails due to resistance, and for acyclovir resistant HSV infections. Its major toxicity is nephrotoxicity with electrolyte disturbances such as hypocalcemia, hypomagnesemia, and hypokalemia, which can provoke seizures.
Cidofovir is a cytidine analog that already has one phosphate group and mainly requires host kinases for further activation. It also does not depend on viral kinases, so it can be used in cases resistant to acyclovir or ganciclovir due to kinase mutations. Cidofovir also causes significant nephrotoxicity, which is often mitigated with aggressive hydration and coadministration of probenecid.
For CMV:
- Ganciclovir / valganciclovir need viral UL97 kinase and cause bone marrow suppression.
- Foscarnet and cidofovir do not require viral kinases and are used for drug resistant CMV or HSV, but both have marked nephrotoxicity.
Anti-HIV Drugs: General Principles
USMLE questions on antiretrovirals usually test mechanisms and toxicities. Antiretroviral therapy combines multiple drugs to suppress viral replication and prevent resistance. The details of regimens are covered elsewhere. Here, focus on identifying drug classes and key adverse effects.
The main classes you must recognize are:
| Class | Main Target |
|---|---|
| Nucleoside / nucleotide RT inhibitors (NRTIs) | HIV reverse transcriptase |
| Non-nucleoside RT inhibitors (NNRTIs) | HIV reverse transcriptase |
| Protease inhibitors (PIs) | HIV protease |
| Integrase strand transfer inhibitors (INSTIs) | HIV integrase |
| Fusion / entry inhibitors | Viral entry into CD4 cells |
NRTIs
NRTIs are nucleoside or nucleotide analogs that get phosphorylated by host cell kinases and then compete with natural nucleotides for incorporation into viral DNA by reverse transcriptase. Once incorporated, they cause chain termination and block DNA synthesis.
Common NRTIs include zidovudine (AZT), lamivudine, emtricitabine, abacavir, didanosine, stavudine, and the nucleotide analog tenofovir.
A frequent theme is mitochondrial toxicity. NRTIs can inhibit mitochondrial DNA polymerase, leading to lactic acidosis, hepatic steatosis, and peripheral neuropathy. Stavudine and didanosine are especially associated with neuropathy and pancreatitis.
Zidovudine is notable for myelosuppression, leading to anemia and neutropenia. It is also used in pregnant women and newborns to reduce vertical transmission of HIV.
Abacavir is classically associated with a hypersensitivity reaction that is strongly linked to the HLA-B*57:01 allele. Patients must be screened before starting abacavir to avoid severe reactions.
Tenofovir is a nucleotide analog that has renal toxicity and can cause decreased bone mineral density. Questions may link tenofovir to Fanconi-like proximal renal tubulopathy.
NRTIs are phosphorylated by host kinases, act as chain terminators for reverse transcriptase, and are associated with mitochondrial toxicity (lactic acidosis, hepatic steatosis), myelosuppression (especially zidovudine), and HLA-B*57:01 dependent abacavir hypersensitivity.
NNRTIs
NNRTIs, such as efavirenz, nevirapine, and delavirdine, bind directly to HIV reverse transcriptase at a site distinct from the active site and cause noncompetitive inhibition. Unlike NRTIs, they do not require phosphorylation and do not mimic nucleosides.
They are metabolized hepatically and can cause hepatotoxicity and skin rash. Efavirenz is also linked with vivid dreams, neuropsychiatric symptoms, and teratogenicity in early pregnancy. Nevirapine can cause severe hepatotoxicity and Stevens Johnson syndrome or toxic epidermal necrolysis.
Resistance to NNRTIs arises quickly when these drugs are used alone. For USMLE purposes, remember that genetic mutations in reverse transcriptase decrease their binding.
Protease Inhibitors
Protease inhibitors, such as lopinavir, atazanavir, ritonavir, and darunavir, inhibit the HIV-1 protease. This protease cleaves viral polypeptide precursors into functional proteins. Inhibition prevents maturation of virions, so newly produced virions remain noninfectious.
An important characteristic is their role in drug interactions. Many protease inhibitors, especially ritonavir, are potent inhibitors of cytochrome P450. Ritonavir is often used at low doses to boost levels of other protease inhibitors.
Metabolic adverse effects are a high-yield topic. These drugs can cause hyperglycemia, insulin resistance, dyslipidemia, fat redistribution, and increased cardiovascular risk. Atazanavir can cause indirect hyperbilirubinemia with jaundice.
Integrase Inhibitors
Integrase strand transfer inhibitors, such as raltegravir, elvitegravir, and dolutegravir, block HIV integrase. This prevents the insertion of viral DNA into host cell chromosomal DNA, an essential step in the HIV lifecycle.
They are generally well tolerated. Reported adverse effects include increased creatine kinase, myopathy, and rarely rhabdomyolysis. Weight gain has also been associated with newer integrase inhibitors in some studies.
Fusion and Entry Inhibitors
Fusion and entry inhibitors target the early step of HIV entry into CD4 cells.
Enfuvirtide is a peptide that binds to gp41 and prevents the conformational change required for fusion of the viral and cell membranes. It is given subcutaneously and commonly causes injection site reactions.
Maraviroc binds to CCR5 on the host cell surface and blocks interaction with viral gp120. It is only effective against CCR5-tropic HIV strains, so tropism testing is necessary before use.
Antihepatitis Drugs
USMLE questions often focus on the difference between hepatitis B and C antivirals, and the unique targets of these drugs.
Hepatitis B
Hepatitis B virus uses reverse transcription in its replication cycle. Therefore, some NRTIs that also treat HIV are active against HBV, such as tenofovir, lamivudine, and entecavir. These drugs inhibit the HBV reverse transcriptase or polymerase and reduce viral DNA synthesis.
Entecavir is not used for HIV but is an HBV nucleoside analog that inhibits the viral DNA polymerase. As with other NRTIs, lactic acidosis and hepatic flares can occur when treatment is stopped abruptly.
In chronic HBV, interferon alpha is sometimes used. It exerts antiviral and immunomodulatory effects, enhances host immune response, and inhibits viral protein synthesis. Side effects include flu like symptoms, depression, bone marrow suppression, and autoimmune phenomena.
Hepatitis C
Modern treatment of hepatitis C relies on direct acting antivirals. These drugs target specific viral proteins that are essential for HCV replication. Unlike older interferon based regimens, direct acting antivirals have high cure rates and better tolerance.
Key targets include:
| Target protein | Drug class | Function blocked |
|---|---|---|
| NS3 / 4A | Protease inhibitors | Cleavage of HCV polyprotein |
| NS5A | NS5A inhibitors | Viral replication complex and assembly |
| NS5B | RNA dependent RNA polymerase inhibitors | Viral RNA synthesis |
Examples you may see include sofosbuvir, which is a nucleotide analog that inhibits NS5B RNA polymerase, and ledipasvir, an NS5A inhibitor. Often these drugs are combined, such as sofosbuvir plus ledipasvir.
Adverse effects of direct acting antivirals are usually mild, including fatigue and headache, but drug interactions via CYP metabolism can be important, especially when combined with other drugs. Some older regimens used ribavirin, a guanosine analog associated with hemolytic anemia and teratogenicity.
HCV therapy now centers on direct acting antivirals that target NS3/4A protease, NS5A, or NS5B RNA polymerase. Sofosbuvir is a nucleotide NS5B inhibitor, and combinations with NS5A inhibitors provide very high cure rates.
Anti-Influenza and Other Respiratory Antivirals
Respiratory viruses on the exam are usually influenza and RSV. The focus is on recognizing neuraminidase inhibitors, M2 inhibitors, and RSV specific drugs.
Neuraminidase Inhibitors
Oseltamivir and zanamivir are neuraminidase inhibitors that target influenza A and B. Viral neuraminidase cleaves sialic acid to release newly formed virions from infected cells. Inhibition prevents viral release and reduces spread in the respiratory tract.
Oseltamivir is given orally, while zanamivir is inhaled. These drugs are most effective when started early in infection, typically within 48 hours of symptom onset. Adverse effects include gastrointestinal upset for oseltamivir and bronchospasm for zanamivir, which is especially relevant in patients with asthma or COPD.
M2 Ion Channel Inhibitors
Amantadine and rimantadine inhibit the M2 proton channel of influenza A, which is required for uncoating of the virus inside host cells. They have no activity against influenza B. Due to widespread resistance, they are rarely used for influenza treatment now, but they still appear on exams.
Amantadine also increases dopamine release and decreases dopamine reuptake in the CNS, which explains its use in Parkinson disease. Toxicities include CNS effects, such as confusion and hallucinations, and anticholinergic effects.
RSV Antivirals
Respiratory syncytial virus can be treated with ribavirin in certain severe cases, though its use has declined. Ribavirin is a guanosine analog that interferes with synthesis of guanosine nucleotides and impairs viral RNA synthesis. It is teratogenic and can cause hemolytic anemia.
Palivizumab is used for prophylaxis, not treatment, of RSV. It is a monoclonal antibody against the F protein of RSV. The F protein mediates fusion of the viral envelope with host cell membranes. By binding F protein, palivizumab prevents fusion and entry of the virus into cells. It is used in high risk infants, such as those with prematurity or congenital heart disease.
Oseltamivir and zanamivir inhibit neuraminidase and prevent release of influenza A and B virions. Amantadine and rimantadine block M2 uncoating of influenza A but face widespread resistance and are rarely used.
Anti-Coronavirus and Other Emerging Antivirals
Exam content continues to evolve, but some drugs against coronaviruses or other emerging viruses may be tested conceptually, especially regarding mechanism.
Remdesivir is a nucleotide analog that inhibits viral RNA dependent RNA polymerase and was used in severe COVID 19. It mimics adenosine nucleotides and causes premature termination of viral RNA chains.
Favipiravir is another RNA polymerase inhibitor investigated for various RNA viruses. It also acts as a purine analog that is incorporated into viral RNA, leading to faulty replication.
Monoclonal antibodies directed against viral surface proteins may appear in questions more for their conceptual basis than for specific drug names. They neutralize the virus by binding the protein required for receptor binding or fusion, similar in concept to palivizumab for RSV.
Nucleoside / Nucleotide Analogs: A Unifying Pattern
A large portion of antiviral drugs are nucleoside or nucleotide analogs. Although details vary, they often share a similar logic. Many are prodrugs that must be phosphorylated to become active triphosphates. Once activated, they either cause chain termination or inhibit viral polymerases by competing with natural nucleotides.
The key variables you should recognize are:
- Which kinase performs the first phosphorylation, viral or host.
- Which polymerase or reverse transcriptase is targeted.
- Whether chain termination occurs or the effect is more subtle inhibition.
- Which virus or virus family is susceptible.
- What forms of resistance occur, such as mutations in kinases or polymerases.
For example, acyclovir depends on viral thymidine kinase and targets herpesvirus DNA polymerase. Ganciclovir depends on CMV UL97 kinase and targets CMV DNA polymerase. NRTIs use host kinases and target HIV reverse transcriptase or HBV polymerase.
Most antiviral nucleoside / nucleotide analogs are prodrugs that require phosphorylation and then inhibit viral polymerases or reverse transcriptase, often by chain termination. Differences in activating kinase and target enzyme determine viral selectivity and resistance patterns.
Adverse Effects and Drug Interactions
Adverse effects of antivirals frequently appear in USMLE questions and can determine the correct choice among similar drugs. Certain toxicities are considered classic and must be memorized with the associated drug or class.
Examples include:
| Drug / Class | Classic adverse effect |
|---|---|
| Acyclovir | Crystalluria, acute kidney injury |
| Ganciclovir | Bone marrow suppression |
| Foscarnet | Nephrotoxicity, electrolyte abnormalities, seizures |
| Cidofovir | Dose limiting nephrotoxicity |
| NRTIs | Mitochondrial toxicity, lactic acidosis |
| Zidovudine | Anemia, neutropenia |
| Abacavir | HLA-B*57:01 dependent hypersensitivity |
| Tenofovir | Renal toxicity, decreased bone density |
| NNRTIs | Rash, hepatotoxicity |
| Efavirenz | CNS / psychiatric symptoms, vivid dreams |
| Protease inhibitors | Hyperglycemia, dyslipidemia, lipodystrophy |
| Ribavirin | Hemolytic anemia, teratogenicity |
| Interferon alpha | Flu like symptoms, depression, bone marrow suppression |
Many antiretrovirals interact with cytochrome P450 enzymes. Protease inhibitors and some NNRTIs can be strong inhibitors or inducers, which changes levels of many concurrent drugs. Ritonavir is especially known as a CYP inhibitor used to boost other protease inhibitors.
Monitoring of renal function, liver function, and blood counts is often required during antiviral therapy, especially in patients with existing comorbidities or polypharmacy.
Summary
Antiviral pharmacology is highly mechanistic. For USMLE purposes, you should be able to match each key antiviral to its viral target, mechanism of action, and a small number of hallmark adverse effects or resistance mechanisms. Once you learn the patterns of nucleoside analog activation, polymerase or protease targeting, and characteristic toxicities, you can rapidly identify the correct drug in clinical vignettes involving specific viral infections.