Antivirals for Herpes Virus

Antiviral agents against human herpesviruses (HHVs) include acyclovir, cidofovir, and foscarnet. Human herpesviruses are DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure viruses in the Herpesviridae family. Herpes simplex virus ( HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2), varicella-zoster virus Varicella-Zoster Virus Varicella-zoster virus (VZV) is a linear, double-stranded DNA virus in the Herpesviridae family. Varicella-zoster infections are highly contagious and transmitted through aerosolized respiratory droplets or contact with infected skin lesions. Varicella-Zoster Virus/Chickenpox (VZV), cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus (CMV), Epstein-Barr virus Epstein-Barr Virus Epstein-Barr virus (EBV) is a linear, double-stranded DNA virus belonging to the Herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus (EBV), and HHV-8 belong to the Herpesviridae family. Antivirals against the group generally act via inhibition of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase. Acyclovir (the prototypical nucleoside analog) requires viral kinase for phosphorylation to become a triphosphate, which is incorporated in viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure. Cidofovir requires phosphorylation by host cellular kinase, which allows cidofovir to have activity against mutated viruses and become deficient in viral kinase. Foscarnet (a pyrophosphate analog) does not require phosphorylation. Nephrotoxicity is a shared adverse effect in the agents. Acyclovir can also cause obstructive crystalline nephropathy and foscarnet carries a risk of electrolyte abnormalities and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. The nephrotoxic effect of cidofovir can be reduced with IV saline and probenecid.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Human herpesviruses (HHVs)

  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure viruses (a similar infection process):
    • Viruses enter the nucleus of the host cell.
    • Viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure is transcribed into mRNA via host-cell polymerase.
    • Subsequently, the mRNA is translated into virus-specific proteins. 
  • Herpesviridae family:
    • Subfamily: Alphaherpesvirinae:
      • Herpes simplex virus ( HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2)-1 and HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2-2 (mucocutaneous and genital lesions)
      • Varicella-zoster virus (VZV) ( chickenpox Chickenpox Varicella-zoster virus (VZV) is a linear, double-stranded DNA virus in the Herpesviridae family. Chickenpox is the primary infection and occurs most commonly in children. The typical clinical presentation includes prodromal symptoms and a generalized, intensely pruritic vesicular rash. Varicella-Zoster Virus/Chickenpox)
    • Subfamily: Betaherpesvirinae:
      • Cytomegalovirus (CMV)
      • HHV-6 HHV-6 Human herpesvirus (HHV)-6 and HHV-7 are similar double-stranded DNA viruses belonging to the Herpesviridae family. Human herpesviruses are ubiquitous and infections are commonly contracted during childhood. Human Herpesvirus 6 & 7 and HHV-7 HHV-7 Human herpesvirus (HHV)-6 and HHV-7 are similar double-stranded DNA viruses belonging to the Herpesviridae family. Human herpesviruses are ubiquitous and infections are commonly contracted during childhood. Human Herpesvirus 6 & 7 (roseola)
    • Subfamily: Gammaherpesvirinae:
      • Epstein-Barr virus Epstein-Barr Virus Epstein-Barr virus (EBV) is a linear, double-stranded DNA virus belonging to the Herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus (EBV) (Burkitt lymphoma and infectious mononucleosis Mononucleosis Infectious mononucleosis (IM), also known as "the kissing disease," is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Mononucleosis)
      • HHV-4
      • HHV-8 (Kaposi sarcoma)

Antiherpes agents

  • Target viral nucleic acid synthesis by inhibiting DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase
  • Groups of drugs:
    • Nucleoside analogs:
      • Acyclovir
      • Valacyclovir
      • Famciclovir
      • Ganciclovir
      • Penciclovir
    • Cytidine nucleotide analog: cidofovir
    • Pyrophosphate analog: foscarnet
Antivirals for herpesviruses

Antiviral drug mechanism:
Antivirals for herpesviruses (right side) generally inhibit nucleic acid synthesis.

Image by Lecturio.

Nucleoside Analogs

Chemical structure

  • Acyclovir: an acyclic guanosine nucleoside analog (the prototypical drug of the group)
  • ​​Valacyclovir: the L-valyl ester prodrug of acyclovir
  • Penciclovir, famciclovir, and ganciclovir are related agents.

Pharmacodynamics

Acyclovir:

  • Sequential phosphorylation of viral kinase (e.g., dependent on thymidine kinase (TK)) and host kinase convert the drug to a monophosphate and then to a triphosphate moiety.
  • Since the initial step requires viral kinase, only infected cells are affected.
  • The steps allow the drug to become triphosphate inhibitors of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase.
  • Inhibits viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis:
    • The triphosphate competes with deoxyguanosine triphosphate (dGTP) for viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase.
    • The triphosphate incorporates into the viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
    • Chain termination occurs due to the lack of a 3’-hydroxyl group and prevents attachment of nucleosides. 
  • Mechanism of resistance: 
    • Change in viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase 
    • Absence or impairment of TK (caused by viral mutations)
Mechanism of action of acyclovir

Mechanism of action of acyclovir:
The drug undergoes sequential phosphorylation, which is facilitated by thymidine kinase (TK) of the herpesvirus and host kinases. Since viral TK is required for phosphorylation of acyclovir, only cells infected with the virus are affected by the drug. Host enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes convert the monophosphate to acyclovir triphosphate, which subsequently competes with deoxyguanosine triphosphate (dGTP) for the viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase. The triphosphate gets incorporated into the template of the viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure. Chain termination follows because a 3′-hydroxyl group is lacking.

Image: “OSC Microbio 14 03 Acyclovir” by CNX OpenStax. License: CC BY 4.0

Pharmacokinetics

  • Absorption: 
    • Acyclovir:
      • Available as oral, IV, and topical 
      • Poor oral bioavailability (10%–30%)
    • Valacyclovir: higher bioavailability 
    • Penciclovir: topical
  • Distribution: 
    • High distribution rate (including CSF)
    • Good tissue and fluid penetration 
    • Multiple doses per day are required because of the short half-life
  • Metabolism: minimally metabolized (> 80% excreted unchanged)
  • Excretion: 
    • Renal via glomerular filtration Glomerular filtration The kidneys are primarily in charge of the maintenance of water and solute homeostasis through the processes of filtration, reabsorption, secretion, and excretion. Glomerular filtration is the process of converting the systemic blood supply into a filtrate, which will ultimately become the urine. Glomerular Filtration rate and tubular secretion 
    • Dose modification is required in renal impairment. 
    • Elimination half-life varies between 2–4 hours.

Indications

Acyclovir (and other related agents): 

  • HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2
  • VZV
  • Prevention of herpes viruses in immunocompromised individuals 
  • Off-label: Bell palsy and CMV prevention in individuals with low-risk hematopoietic stem cell transplant

Adverse events and contraindications

Acyclovir:

  • Notable adverse events:
    • Acute kidney injury Acute Kidney Injury Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury:
      • Obstructive uropathy (formation of acyclovir crystals)
      • Interstitial nephritis
      • Rental tubular acidosis
    • Neurotoxicity:
      • Confusion, agitation, and hallucination
      • Myoclonus and tremor
    • Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of ADAMTS-13, a metalloproteinase that cleaves multimers of von Willebrand factor (VWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura (TTP) and hemolytic uremic syndrome (HUS)
  • Contraindications: hypersensitivity to acyclovir

Comparison of nucleoside analogs

Table: Comparison of nucleoside analogs against herpesviruses
Agent Characteristics and mechanism of action Pharmacokinetics Approved indication Adverse drug effects
Acyclovir
  • Nucleoside analog
  • Polymerase inhibitor
Poor oral bioavailability
  • Herpes simplex virus ( HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2)-1
  • HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2-2
  • Varicella zoster virus (VZV)
  • Acute renal injury
  • Neurotoxicity
  • Thrombotic microangiopathy
Valacyclovir
  • Nucleoside analog
  • Prodrug of acyclovir
  • Polymerase inhibitor
Good oral bioavailability
Penciclovir
  • Nucleoside analog
  • Polymerase inhibitor with a 3’-hydroxyl group (not an obligate chain terminator)
Topical HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2 (herpes labialis) Mild side effects
Famciclovir
  • Nucleoside analog
  • Prodrug of penciclovir
  • Polymerase inhibitor
Better oral bioavailability than penciclovir
  • HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2
  • Shingles Shingles Varicella-zoster virus (VZV) is a linear, double-stranded DNA virus in the Herpesviridae family. Shingles (also known as herpes zoster) is more common in adults and occurs due to the reactivation of VZV. Varicella-Zoster Virus/Chickenpox
  • Headache
  • Nausea, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
Ganciclovir
  • Nucleoside analog
  • Phosphorylation catalyzed by the virus protein kinase phosphotransferase UL97
  • Polymerase inhibitor
  • IV
  • Poor oral bioavailability
Cytomegalovirus (CMV) infections
  • Hematological toxicity (↓ platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets, leukopenia)
  • Nephrotoxicity
  • In animal studies, associated with birth defects, ↓ spermatogenesis, and carcinogenesis Carcinogenesis Carcinogenesis is the development of cancer by transforming healthy cells into cancer cells. This complex process occurs because of mutations in DNA that prevent the normal process of cell division. Normal cells have programmed cell death, but cancer cells proliferate without regulation. Carcinogenesis
Valganciclovir
  • Nucleoside analog
  • Phosphorylation catalyzed by the virus protein kinase phosphotransferase UL97
  • Prodrug of ganciclovir
  • Polymerase inhibitor
Better oral bioavailability than ganciclovir

Cidofovir

Chemical structure

Cidofovir is a cytidine nucleotide analog.

Pharmacodynamics

  • Targets viral replication by inhibiting viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase: 
    • Unlike nucleoside analogs, cidofovir is phosphorylated by cellular (host kinase), not viral, enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes.
    • Competes with deoxycytidine triphosphate (dCTP) for incorporation into viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure by viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase.
    • Disruption of further chain elongation occurs when the drug is incorporated.
  • Cidofovir has activity against TK-deficient or TK-altered viruses because viral enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes are not required.
  • Mechanism of resistance: mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase

Pharmacokinetics

  • Absorption:
    • IV administration
    • Low oral bioavailability
  • Distribution:
    • Poor CSF penetration
    • The active metabolite (cidofovir diphosphate) is slowly eliminated → long intracellular half-life
  • Metabolism: Most of the drug is excreted unchanged in the urine.
  • Excretion:
    • Renal 
    • Glomerular filtration and tubular secretion

Indications

  • CMV retinitis (in AIDS)
  • Activity against:
    • Herpesviruses
    • Adenovirus Adenovirus Adenovirus (member of the family Adenoviridae) is a nonenveloped, double-stranded DNA virus. Adenovirus is transmitted in a variety of ways, and it can have various presentations based on the site of entry. Presentation can include febrile pharyngitis, conjunctivitis, acute respiratory disease, atypical pneumonia, and gastroenteritis. Adenovirus
    • Polyomavirus ( BK virus BK Virus BK virus (BKV) is a small, nonenveloped, single-stranded DNA virus belonging to the Polyomaviridae family, which are ubiquitous in the human population. While the primary infection is usually asymptomatic, the infection leads to lifelong latency in the kidneys and lymphoid organs. JC Virus and BK Virus nephropathy)
    • Papillomavirus (e.g., warts, molluscum contagiosum Molluscum contagiosum Molluscum contagiosum is a viral infection limited to the epidermis and is common in children below 5 years of age. Lesions appear as grouped, flesh-colored, dome-shaped papules with central umbilication. Molluscum Contagiosum)
    • Poxvirus 
  • Active against mutant viruses resistant to acyclovir and ganciclovir:
    • TK-negative HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2
    • UL97 phosphotransferase-negative CMV 

Adverse effects and contraindications

  • Adverse effects:
    • Nephrotoxicity: 
      • Most important adverse effect
      • Decreased when administered with IV saline and probenecid (blocks active renal tubular secretion)
    • Nausea, vomiting
    • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia
    • Acute iritis and ocular hypotony
    • In animal studies: hypospermia, carcinogenesis Carcinogenesis Carcinogenesis is the development of cancer by transforming healthy cells into cancer cells. This complex process occurs because of mutations in DNA that prevent the normal process of cell division. Normal cells have programmed cell death, but cancer cells proliferate without regulation. Carcinogenesis, and teratogenesis
  • Contraindications:
    • Proteinuria ≥ 2+ or urine protein ≥ 100 mg/dL
    • Baseline serum creatinine > 1.5 mg/dL

Foscarnet

Chemical structure

Foscarnet is a pyrophosphate analog.

Pharmacodynamics

  • Inhibits viral nucleic acid synthesis: 
    • No intracellular phosphorylation required for antiviral activity
    • Reversibly binds to the pyrophosphate-binding site of viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase (or reverse transcriptase)
    • Inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates → stops DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure chain elongation 
  • Mechanism of resistance: point mutations in the viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase

Pharmacokinetics

  • Absorption: 
    • Poor oral bioavailability
    • IV form
  • Distribution: 
    • Vitreous levels similar to plasma
    • CSF levels approach 66% of plasma.
  • Metabolism: minimally metabolized
  • Excretion:
    • Tubular secretion and glomerular filtration Glomerular filtration The kidneys are primarily in charge of the maintenance of water and solute homeostasis through the processes of filtration, reabsorption, secretion, and excretion. Glomerular filtration is the process of converting the systemic blood supply into a filtrate, which will ultimately become the urine. Glomerular Filtration 
    • Approximately 20% of foscarnet may be taken up in bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones.
    • Decreased excretion in individuals with kidney disease

Indications

  • Ganciclovir-resistant CMV infections (AIDS or transplant recipients)
  • Mucocutaneous acyclovir-resistant HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2 infections

Adverse effects and contraindications

  • Adverse effects:
    • Nephrotoxicity (reduced by IV saline)
    • Hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia, hypomagnesemia, and hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia
    • Ulcer formation in the genitals
    • Neurologic:
      • Seizures
      • Paresthesia
      • Irritability
      • Headache
      • Hallucinations
    • QT prolongation
  • Contraindications: hypersensitivity to foscarnet

Nonsystemic Agents

Docosanol

  • A saturated 22-carbon aliphatic alcohol
  • Inhibits fusion between the host-cell plasma membrane and the HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2 envelope → prevents viral entry into cells 
  • Topical docosanol 10% cream:
    • Over the counter
    • Reduces healing time if applied within 12 hours of prodromal symptom onset 

Trifluridine

  • Trifluorothymidine
  • Mechanism of action: 
    • Inhibition of viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis ( HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2-1, HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2-2, CMV)
    • Undergoes intracellular phosphorylation by host cell enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes → competes with thymidine triphosphate for incorporation by the viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase 
  • 1% solution:
    • Treatment for keratoconjunctivitis and recurrent epithelial keratitis due to HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2-1 or HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2-2
    • Off-label: topical application for acyclovir-resistant HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2 infections

Comparison of Medications

Table: Comparison of medications
Antiviral agent Mechanism of action Indications Major adverse effects
Acyclovir (nucleoside analog) Polymerase inhibitor requiring phosphorylation by viral kinase
  • HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2-1
  • HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2-2
  • VZV
Acute kidney injury Acute Kidney Injury Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury (obstructive nephropathy)
Cidofovir (nucleotide analog) Polymerase inhibitor requiring phosphorylation by host kinase (not viral kinase) Approved for CMV retinitis with activity against other viruses* Nephrotoxicity (risk decreased by IV saline and probenecid)
Foscarnet (pyrophosphate analog) Polymerase inhibitor not requiring phosphorylation Resistant CMV and HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2
  • Nephrotoxicity
  • Electrolyte abnormalities
  • Seizures
*Herpesviruses, adenovirus, polyomavirus, papillomavirus, poxvirus, TK-negative HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2, UL97 phosphotransferase-negative CMV

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