A 60-year-old man comes to the physician’s office with jaundice. Liver ultrasound reveals a shrunken liver and biopsy reveals cirrhosis. Hepatitis serologies are below: Anti-HAV: negative HBsAg: negative HBsAb: positive HBeAg: negative Anti-HBe: negative Anti-HBc: negative Anti-HCV: positive The hepatitis C viral load is 1,000,000 copies/mL. The patient is started on an antiviral regimen including sofosbuvir. What is the mechanism of action of this drug?

Inhibits RNA-dependent RNA polymerase

Inhibits synthesis of DNA-dependent DNA polymerase

A 53-year-old woman comes to the physician in February because of a 1-day history of fever, chills, headache, and dry cough. She also reports malaise and generalized muscle aches. She works as a teacher at a local high school, where there was recently an outbreak of influenza. She has a history of intermittent asthma, for which she takes albuterol as needed. She declined the influenza vaccine offered in the fall because her sister told her that a friend developed a flulike illness after receiving the vaccine. She is worried about possibly becoming ill and cannot afford to miss work. Her temperature is 37.9°C (100.3°F), heart rate is 58/min, and her respirations are 12/min. Physical examination is unremarkable. Her hemoglobin concentration is 14.5 g/dL, leukocyte count is 9,400/mm3, and platelet count is 280,000/mm3. In addition to analgesia, which of the following is the most appropriate next step in management?

Live attenuated influenza vaccine

A 66-year-old woman with chronic obstructive pulmonary disease is brought to the emergency department because of fever, body aches, malaise, and a dry cough. She has smoked one pack of cigarettes daily for 30 years but quit smoking 1 year ago. She lives with her daughter and her granddaughter, who attends daycare. Her temperature is 38.1°C (101°F). Physical examination shows bilateral conjunctivitis, rhinorrhea, and erythematous tonsils without exudates. Further testing confirms infection with an enveloped orthomyxovirus. Administration of a drug with which of the following mechanisms of action is most appropriate?

Inhibition of proton translocation

Inhibition of nucleoside reverse transcriptase

A 49-year-old woman presents to her primary care doctor in late December with malaise. She reports worsening fatigue, myalgias, headache, and malaise that started 1 day ago. She works as a lunch lady at an elementary school. Her past medical history is notable for a distal radius fracture after a fall 2 years ago, but she is otherwise healthy and takes no medications. She does not smoke or drink alcohol. She is married and has 3 adult children who are healthy. Her temperature is 102.9°F (39.4°C), blood pressure is 101/61 mmHg, pulse is 112/min, and respirations are 21/min. On exam, she appears lethargic and uncomfortable but is able to answer questions appropriately. Breath sounds are normal bilaterally. She is started on intravenous fluids and a pharmacologic agent for treatment. Which of the following is the most likely mechanism of action of the drug being used to treat this patient?

Reverse transcriptase inhibitor

RNA-dependent polymerase inhibitor

A 26-year-old G1P0 woman is brought to the emergency room by her spouse for persistently erratic behavior. Her spouse reports that she has been sleeping > 1 hour a night, and it sometimes seems like she’s talking to herself. She has maxed out their credit cards on baby clothes. The patient’s spouse reports this has been going on for over a month. Since first seeing a physician, she has been prescribed multiple first and second generation antipsychotics, but the patient’s spouse reports that her behavior has failed to improve. Upon examination, the patient is speaking rapidly and occasionally gets up to pace the room. She reports she is doing “amazing,” and that she is “so excited for the baby to get here because I’m going to be the best mom.” She denies illicit drug use, audiovisual hallucinations, or suicidal ideation. The attending psychiatrist prescribes a class of medication the patient has not yet tried to treat the patient’s psychiatric condition. In terms of this new medication, which of the following is the patient’s newborn most likely at increased risk for?

Right ventricular atrialization

Attention deficit hyperactivity disorder

An 8-year-old boy is brought to the emergency department by his parents because of sudden onset of abdominal pain beginning an hour ago. The parents report that their son has also had an episode of dark urine earlier that morning. Three days ago, he was diagnosed with a urinary tract infection and was treated with trimethoprim-sulfamethoxazole. He emigrated from Liberia to the US with his family 3 years ago. There is no personal history of serious illness. His immunizations are up-to-date. Vital signs are within normal limits. Examination shows diffuse abdominal tenderness and scleral icterus. The spleen is palpated 1–2 cm below the left costal margin. Laboratory studies show: Hemoglobin 10 g/dL Mean corpuscular volume 90 μm3 Reticulocyte count 3% Serum Bilirubin Total 3 mg/dL Direct 0.5 mg/dL Haptoglobin 20 mg/dL (N=41–165 mg/dL) Lactate dehydrogenase 160 U/L Urine Blood 3+ Protein 1+ RBC 2–3/hpf WBC 2–3/hpf Which of the following is the most likely underlying cause of this patient's symptoms?

Deficient glucose-6-phosphate dehydrogenase

Defective RBC membrane proteins

Broad-spectrum antivirals for USMLE Step 3: High-Yield Pharmacology Lessons

Broad-Spectrum Antivirals - Viral Villains Vanquished

Broad-spectrum antivirals (BSAs) inhibit multiple viral species by targeting conserved viral enzymes or host-cell factors essential for viral replication. This strategy circumvents narrow-spectrum limitations and can combat emerging viruses.

Major Classes:
- Nucleoside/Nucleotide Analogs: Mimic natural building blocks, causing DNA/RNA chain termination.
- Polymerase Inhibitors: Directly block viral RNA or DNA polymerase activity.

Host cell factors targeted by broad-spectrum antivirals

⭐ Cidofovir is effective against numerous DNA viruses (CMV, adenovirus, poxviruses) as it bypasses the need for viral thymidine kinase activation, a common resistance mechanism.

Ribavirin - The Reckless Ribonucleoside

Mechanism: A guanosine analog pro-drug.
- Inhibits inosine monophosphate (IMP) dehydrogenase → ↓ GTP synthesis.
- Integrates into viral RNA, causing lethal hypermutations.
- Directly inhibits viral RNA polymerase.
Clinical Use:
- Chronic Hepatitis C (in combination, largely historical).
- Severe RSV bronchiolitis (aerosolized).
- Hemorrhagic fevers (Lassa, CCHF).
Toxicity:
- ⚠️ Hemolytic Anemia: Severe, dose-dependent.
- ⚠️ Teratogenicity: Extreme risk. Contraindicated in pregnancy (patient or partner).

⭐ Exam Favorite: Due to its profound teratogenicity, effective contraception is required for at least 6 months after discontinuing therapy for both male and female patients.

📌 Mnemonic: RIBA

Ribs (teratogen)
Inhibits IMP dehydrogenase
Bone marrow suppression
Anemia (hemolytic)

Ribavirin mechanism of action in HCV infection

Modern Viral Warriors - Polymerase & Endonuclease Blockers

These agents disrupt viral replication at critical enzymatic steps, offering broad-spectrum activity against various RNA viruses.

Drug	Mechanism	Key Spectrum	Key Adverse Effect
Remdesivir	Adenosine analog; inhibits viral RNA-dependent RNA polymerase (RdRp) → premature chain termination.	SARS-CoV-2, Ebola	↑ LFTs, nephrotoxicity
Favipiravir	Purine analog; inhibits RdRp → lethal mutagenesis.	Influenza, various RNA viruses	↑ Uric acid, teratogenicity ⚠️
Baloxavir marboxil	Inhibits cap-dependent endonuclease → blocks viral mRNA transcription ("cap-snatching").	Influenza A & B	Diarrhea, chelation with cations

⭐ Baloxavir marboxil is notable for its single-dose oral regimen, offering a significant advantage in compliance for treating acute uncomplicated influenza.

Antiviral Spectrum - Rogues' Gallery

A summary of key broad-spectrum agents against clinically important viruses. Choice depends on viral target, host factors, and resistance patterns.

Virus	First-line / Notable Agent(s)
Influenza	Neuraminidase Inhibitors (Oseltamivir), Endonuclease Inhibitor (Baloxavir)
SARS-CoV-2	Protease Inhibitor (Nirmatrelvir/r), RdRp Inhibitor (Remdesivir)
RSV	Guanosine Analog (Ribavirin), mAb (Palivizumab for prophylaxis)
HCV	DAA Cocktails (e.g., Sofosbuvir/Velpatasvir)
Ebola Virus	Monoclonal Antibody Combo (Inmazeb, Ebanga)
Lassa Fever	Ribavirin (most effective within first 6 days)

High‑Yield Points - ⚡ Biggest Takeaways

Ribavirin inhibits inosine monophosphate dehydrogenase, is used for HCV and RSV, and causes hemolytic anemia and teratogenicity.

Foscarnet, a pyrophosphate analog, treats ganciclovir-resistant CMV and does not require intracellular phosphorylation.

Foscarnet's main toxicities are nephrotoxicity and electrolyte disturbances (especially Ca & Mg), which can cause seizures.

Cidofovir, a nucleotide analog, also treats CMV and bypasses viral kinases.

Its dose-limiting toxicity is nephrotoxicity; always co-administer with probenecid and IV fluids.

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