Herpesvirus medications

Definitions & Key takeaways

Herpes medications are antiviral agents used to treat herpes infection. They mainly work by interfering with DNA replication of Herpes simplex viruses. Commonly prescribed herpes medications include acyclovir, cidofovir, foscarnet, and valacyclovir. Side effects include nephrotoxicity, electrolyte imbalances, headaches, hallucinations, and seizures.

Chapters:

Watch video only

Introduction0:00–0:26

Anti-herpes medications are a group of antiviral agents that treat herpes infections including herpes simplex virus, or HSV, but they can also treat other viral infections like varicella zoster virus, or VZV, and cytomegalovirus, or CMV.
They act by inhibiting viral DNA synthesis and thus, inhibiting viral proliferation. Alright, now let’s start with HSV, which infects skin and mucosal epithelial cells.

Herpes simplex virus0:26–1:51

There are two types of HSV, HSV1 and HSV2. Generally speaking, HSV1 tends to cause infections “above the waist” mostly involving the lips, or labia, which is referred to as herpes labialis, and the mouth and the gingiva, which is called gingivostomatitis.
In rare cases, HSV1 can spread to the esophagus, causing esophagitis, or to the central nervous system, causing meningitis or encephalitis, typically affecting the temporal lobe.
On the other hand, HSV2 tends to cause infections “below the waist” affecting the genital organs, which is referred to as herpes genitalis.
HSV can also pass from a mother to a baby usually when the baby passes through the infected maternal vaginal secretions and can cause severe neonatal infections.
The typical presentation of a herpes infection is clusters of small, painful, fluid-filled blisters, that ooze and ulcerate.
They eventually heal after a few weeks. However, HSV also infects the nearby sensory neurons, which aren’t destroyed, but instead, they become a permanent home for the herpes virus.
This is referred to as the latent phase of the infection and is typically asymptomatic. From time to time, the herpes virus from the sensory neurons make a few viral copies of itself which can get released and infect the epithelial cells.
Alright, now let’s move on to varicella zoster virus. VZV causes a primary infection called varicella or chickenpox, which is characterized by a rash on the scalp, face, and trunk that contains macules, papules, vesicles, and scabs at the same time.
Now, from the neurons in the skin, VZV travels retrogradely to the nerve ganglia, where it remains dormant. Later on, if the immune system weakens, due to aging, stress, or immunosuppressive therapy, the virus can be reactivated.

Varicella zoster virus1:51–2:33

It can then travel back up through the sensory nerves, anterogradely to the skin and cause an infection in the innervated dermatome - that’s called herpes zoster or shingles.
Now, let’s talk a bit about cytomegalovirus. CMV causes mononucleosis, commonly known as “mono,” which presents with sore throat, fever, lymphadenopathy, malaise, headache, and resolves over a few weeks.
Now, in immunocompromised individuals, CMV can cause more severe infections including pneumonia, esophagitis, and retinitis which can lead to vision loss.

Cytomegalovirus2:33–3:16

CMV can also pass from a mother to a baby via the placenta causing a potentially life-threatening congenital infection. Alright, now depending on their mechanism of action, anti-herpes medications can be divided into two categories: the guanosine analogs, and the viral DNA polymerase inhibitors.
Let’s start with the guanosine analogs which include acyclovir; medications that are similar to acyclovir such as valacyclovir, penciclovir, famciclovir, ganciclovir, and valganciclovir.
Once they’re inside an infected cell, they get phosphorylated to a monophosphate form by a viral enzyme, which is called viral kinase.
For example, acyclovir is converted to the acyclovir monophosphate by the viral thymidine kinase, while ganciclovir is initially phosphorylated by the enzyme UL-97 kinase, which is found in CMV infected cells.

Guanosine analogs3:16–5:30

Next, the monophosphate form is phosphorylated twice to the active triphosphate form by cellular enzymes. This triphosphate form acts as a guanosine analog which means that it’s similar in structure with the normal guanosine nucleotide.
When this analog is inserted into the replicating viral DNA, it causes the growing DNA chain to terminate and DNA synthesis is halted.
Okay, now resistance to these medications can be developed if there is a mutated form of the viral kinase which won’t phosphorylate the medication.
Alright, now let’s move on to indications. Acyclovir is active against HSV and VZV.
When it’s used orally it’s only partially absorbed and so oral acyclovir is used for mild mucocutaneous lesions and genital lesions or for herpes prophylaxis in immunocompromised individuals such as individuals with AIDS.
Now, intravenous acyclovir is the treatment of more severe herpes infections, such as HSV encephalitis. Acyclovir has no effect on latent forms of HSV and VZV.
Valacyclovir is the prodrug of acyclovir that gets converted to acyclovir in the liver and has better bioavailability than acyclovir when given orally.
Famciclovir is the prodrug of penciclovir that gets converted to penciclovir in the liver and is used for HSV and VZV. Now, ganciclovir and its prodrug valganciclovir are active against HSV and CMV, and they’re typically used for prophylaxis and treatment of cytomegalovirus, or CMV infections, and especially CMV retinitis in immunocompromised individuals.
Okay, now let’s move on to side effects. Acyclovir needs the viral thymidine kinase in order to become active and so it cannot act in uninfected cells.
That explains why it causes only minimal side effects which typically include gastrointestinal disturbances like nausea and headache.
Now, if acyclovir rises to toxic levels when given intravenously, it can cause symptoms from the central nervous system including delirium, seizures and tremor; hypotension; and nephrotoxicity.

Acyclovir5:30–6:18

Moving on to ganciclovir. Ganciclovir is more toxic to host enzymes than acyclovir and so it causes more serious side effects including suppression of the bone marrow, which manifests as leukopenia, thrombocytopenia, and anemia.
Other side effects include nephrotoxicity, hepatotoxicity, mucositis, and seizures. Alright, now let’s switch gears and move on to viral DNA polymerase inhibitors, which include cidofovir and foscarnet.
Cidofovir is exclusively phosphorylated by cellular kinases to the active diphosphate form, which directly binds to and inhibits viral DNA polymerases.
However, foscarnet, unlike the rest of the herpes medications, doesn’t require phosphorylation to become active. It competitively inhibits several viral enzymes involved in viral proliferation such as DNA polymerase, RNA polymerase, but also HIV reverse transcriptase.

Viral DNA polymerase inhibitors6:18–7:38

Resistance to foscarnet can develop due to mutated forms of DNA polymerase. Moving on to indications.
Cidofovir and foscarnet are indicated for the treatment of acyclovir-resistant HSV infections. They are also used as an alternative to ganciclovir for the prophylaxis and treatment of CMV infections in immunocompromised individuals.Moving on to side effects.
The main side effect of cidofovir and foscarnet is nephrotoxicity. That’s why cidofovir is usually given along with probenecid and IV saline to decrease toxicity.
Nephrotoxicity due to foscarnet can be severe and manifest with electrolyte disturbances usually affecting the balance of calcium, phosphate, and magnesium.
Furthermore, these electrolyte imbalances can lead to headache, hallucinations, and seizures. Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts about herpes medications.
So first let’s go to an office where there’s a big pile of paper with the letter G on them for the guanosine analogs, and there’s a copy machine making copies of DNA, which is where we’ll put the DNA polymerase inhibitors.

Memory palace7:38–10:11

Now, for the viruses, let’s use a chicken with blisters to represent varicella virus, which causes chicken pox, a harpy for herpes, and an owl to represent cytomegalovirus, since it causes an “owl’s eye” appearance in infected cells.
We’ll put all 3 birds in top of the stack of paper since guanosine analogs can treat all 3 viruses, and only an owl and a harpy by the copier, since DNA polymerase inhibitors are used for these two.For the drugs, we can start with the guanosine analogs which will be the office workers.
Let’s put an alpha male on a unicycle for Acyclovir and he’s standing between the chicken and the harpy since he treats VZV and HSV.
Next, we have a worker who brought his family into the office and they’re carrying a giant pencil for penciclovir and famciclovir.
This family is standing directly in front of the chicken and the harpy since they are mainly used to treat HSV and VZV. Finally we have a gangster who runs the office for ganciclovir, and he’s standing between the harpy and the owl since it’s used to treat HSV and CMV.
For the DNA polymerase inhibitors, we have a fox in a car for foscarnet, and he crashed into the office since he’s drunk on cider, or cidofovir.
The crashed car is between an owl and a harpy to help you remember both drugs treat HSV and CMV. Let’s also put a suit of armor on the harpy since these drugs are used to treat acyclovir-resistant HSV infections.
Okay for some of the more important side effects, the alpha male has his brain exposed to represent neurotoxicity and he’s wearing kidney shaped headphones for nephrotoxicity.
The gangster also has an exposed brain and kidney headphones since ganciclovir is also neuro and nephrotoxic, but in addition, he wants to look intimidating, so there’s a big liver by his feet with broken bones sticking out of it, which represents hepatotoxicity and bone marrow suppression.
Finally he’s wearing lipstick for mucositis.Now foscarnet and cidofovir both cause nephrotoxicity so let’s put kidney shaped headphones on the fox, and a tiny kidney in the cider.
Since foscarnet can also cause an electrolyte imbalance, let’s have the car knock over a bottle of milk, representing calcium.
The bottle is shaking to help you remember that electrolyte imbalances can lead to seizures. ##SummaryAll right, as a quick recap… Herpes medications are a group of antiviral agents that act by inhibiting viral DNA replication either by acting as guanosine analogs or by competitively inhibiting viral DNA polymerase.
Guanosine analogs include acyclovir and its prodrug valacyclovir, penciclovir and its prodrug famciclovir, and ganciclovir with its prodrug valganciclovir.
Acyclovir and penciclovir are active against HSV and VZV, while ganciclovir is active against HSV and CMV. Side effects of low doses of acyclovir are minimal and include GI symptoms and headache.

Review10:11–11:38

If acyclovir rises to toxic levels, it can cause neurotoxicity, hypotension, and nephrotoxicity. Side effects of ganciclovir are more serious and include bone marrow suppression, nephrotoxicity, hepatotoxicity, mucositis, and seizures.
The viral DNA polymerase inhibitors are cidofovir and foscarnet, which are used for acyclovir-resistant HSV infections and as an alternative to ganciclovir for the prophylaxis and treatment of CMV infections in immunocompromised individuals.
The main side effect of cidofovir and foscarnet is nephrotoxicity. Foscarnet also causes calcium and other electrolyte imbalances which can lead to headaches, hallucinations, and seizures.
effects of ganciclovir are more serious and include bone marrow suppression nephrotoxicity hepatotoxic mucositis and seizures The viral DNA polymerase inhibitors are cyto Favier and Foscarnet which are used for Acyclovir resistant HSV infections And as an alternative to ganciclovir for the prophylaxis and treatment of CMV infections in immunocompromised individuals The is a is a side effect of the of the vir and Foscarnet is nephrotoxicity P Foscarnet also causes calcium and other electrolyte imbalances which can lead to headaches hallucinations and seizures But wait there's more here's a mind map with all the mnemonics Go ahead and pause the video so you can test yourself to see what you remember and