Pharmacology - An Illustrated Review

30. Antiviral Drugs

Viruses are obligate intracellular parasites that have no energy-generating enzymes. They require the metabolic processes and activities of the host cell; thus, virus reproduction requires the virus particle to infect a cell and use the cytoplasmic machinery to synthesize the macromolecules necessary for assembly of new virus particles. They contain DNA or RNA, not both, and range in size from 20 nm (parvoviruses) to 300 nm (poxviruses); the largest virus approximates the size of the smallest bacterial cells (chlamydiae and mycoplasma). They are not susceptible to antibacterial agents.

Viral replication begins with attachment whereby specific ligands (antireceptors) on the virus recognize and bind to specific receptors on the host cell surface. This interaction is temperature and energy independent and is also related to the tropism of the virus, i.e., the specificity of the virus to a particular host tissue. For example, poliovirus receptors exist on anterior horn cells of the spinal cord but not on kidney cells. The virus then penetrates the host cell by endocytosis (e.g., polyomaviruses), direct fusion with the host cell membrane (e.g., HIV and measles), or receptor-mediated endocytosis (e.g., influenza and Epstein—Barr virus). Penetration is also temperature and energy dependent. Once inside the host cell, there is viral uncoating or dismantling, which is the removal of the viral nucleic acid from the capsid. The last stage in viral replication is genome expression. Viruses adapt host cell machinery to transcribe viral RNA from a viral DNA template, producing key proteins for new virus synthesis. Release of daughter viruses results in the spread of the virus, both within and outside the host (Fig. 30.1).

Antiviral drugs are used to treat susceptible viral infections, which include herpes simplex virus, varicella zoster virus, cytomegalovirus (CMV), influenza viruses, respiratory syncytial virus (RSV), hepatitis B, hepatitis C, and human immunodeficiency virus (HIV). Antiviral drugs target an essential viral enzyme or protein to inhibit a pathway unique to the virus but not the cell (Fig. 30.1).

Fig. 30.1 image Viral multiplication and mechanism of action of antiviral agents.

Viruses can be destroyed by cytotoxic T lymphocytes, which are part of the specific immune response. These lymphocytes detect the virus via proteins on the viral membranes. They may also be inactivated by antibodies. Interferons are glycoproteins that are released from virus-infected cells. They stimulate the production of antiviral proteins in neighboring cells, which destroy or suppress viral DNA and thus prevent viral protein synthesis.


Table 30.1 is included for reference.

  Table 30.1 image Selected Viruses


Typical Example(s)

Nucleic Acid Polarity and Structure


DNA viruses


Human parvovirus

ssDNA (+ or −)



Hepatitis B

dsDNA/ss portions



JC virus

dsDNA circular



Human adenovirus




Herpes simplex 1 (α)

Herpes simplex 2 (α)

CMV (β)

Epstein–Barr (γ)




Vaccinia virus

dsDNA closed ends


RNA viruses


Rubella virus

ssRNA (+)




ssRNA (+)



Yellow fever virus (hepatitis C virus)

ssRNA (+)



Rabies virus

ssRNA (−)




ssRNA (+)



Measles virus

ssRNA ()



Influenza virus

ssRNA (−) segments



Encephalitis virus

ssRNA (− circular)



Lymphocytic choriomen

ssRNA (− circular)




ssRNA (+ identical)




dsRNA (segments)



Norwalk virus

ssRNA (+)



Ebola, Marburg



Abbreviations: CMV, cytomegalovirus; ds, double-stranded; HIV, human immunodeficiency virus; ss, single-stranded.

30.1 Inhibitors of Nucleic Acid Synthesis

Most inhibitors of nucleic acid synthesis are nucleoside analogues that must be phosphorylated intracellularly to exert their antiviral effects. They act by inhibiting viral replication by acting as false nucleosides (Fig. 30.2).

Acyclovir, Famciclovir, Penciclovir, and Valacyclovir

Mechanism of action. These agents inhibit DNA polymerase and, once incorporated into viral DNA, terminate chain elongation. They exhibit remarkable selective toxicity due to action on virus-specific thymidine kinase and viral DNA polymerase (Fig. 30.3).


– Herpes simplex virus (HSV) and varicella zoster virus

Pharmacokinetics. Although oral bioavailablity of acyclovir is low, this compound is effective after oral administration, by injection, or topically applied. The other agents are available for oral administration and have longer half-lifes that require one or two doses daily.

Fig. 30.2 image Chemical structure of virustatic antimetabolites.

Nucleosides consist of a base (e.g. thymine) and deoxyribose. Virustatic antimetabolites act as false nucleosides or sugars. In the body, they are incorporated into viral DNA and terminate replication. Acyclovir and ganciclovir also inhibit viral DNA polymerase.


Fig. 30.3 image Activation of acyclovir and inhibition of viral DNA synthesis.

In an infected cell, viral thymidine kinase performs the initial phosphorylation step then cellular kinases attach the remaining phosphate residues. This bioactivation of acyclovir occurs only in infected cells, which gives it high specificity and tolerability. Furthermore, the polar phosphate residues render acyclovir unable to diffuse across cell membranes and cause it to accumulate in infected cells. Acyclovir triphosphate is a preferred substrate of viral DNA polymerase and inhibits its activity. Following incorporation of acyclovir triphosphate into viral DNA, it induces strand breakage because it lacks the 3′-OH group of deoxyribose that is required for the attachment of additional nucleotides.



– Genital herpes

– Herpes simplex encephalitis

– Neonatal herpes

– Herpetic infections in immunocompromised patients

Herpes zoster (shingles)

Chickenpox is the primary infection with varicella zoster virus. Following the initial infection the virus remains dormant in the dorsal root ganglia. Reactivation of the virus causes shingles. Shingles starts with pain, tingling, or burning in a dermatomal distribution (often the ophthalamic division of the trigeminal nerve and lower thoracic dermatomes are affected). This is a ccompanied by fever and malaise. Later, a vesicular rash develops involving the same dermatome. Complications of shingles include post-herpetic neuralgia of the affected dermatome. This pain can range from mild to very severe and can persist for months or years. Treatment of shingles may involve the early use of antiviral medications, e.g., acyclovir, to shorten the course of the infection and to reduce pain and complications. Pain may also be treated with oxycodone (a narcotic analgesic), amitryptyline (a tricyclic antidepressant), gabapentin (an anticonvulsant), or lidocaine (a local anesthetic). Post-herpetic neuralgia can be treated with carbamazepine or phenytoin and prednisone. If these are unsuccessful, surgical ablation of the appropriate ganglion may be tried but this too is often unsuccessful and may leave the patient with numbness of the dermatome supplied.


Herpes simplex virus

Herpes simplex virus (HSV) type 1 is the most common HSV infection and usually produces cold sores and other blisters around the mouth, lips, and face. These may be accompanied by fever, sore throat, and lymphadenopathy. It is spread via saliva. HSV type 2 is usually responsible for genital herpes and is sexually transmitted. Symptoms include blisters around the vagina, anus, buttocks, penis shaft/glans, or scrotum that may be accompanied by itching, pain, dysuria (difficult or painful urination), and fever. Complications of HSV infections include herpetic whitlow (vesicles develop on an infected digit), herpetic simplex keratitis (corneal ulcers), herpetic simplex meningitis (rarely occurs but is usually due to HSV type 2), and herpetic simplex encephalitis (usually HSV type 1). Treatment of HSV may include the use of antiviral medications, e.g., acyclovir, and analgesics. Herpes simplex encephalitis has a high risk of mortality and requires urgent care.


Ganciclovir and Valganciclovir

Mechanism of action. The mechanism and structure are similar to acyclovir.

Spectrum. Ganciclovir and valganciclovir are 100 times more active against CMV than is acyclovir.

Pharmacokinetics. Ganciclovir is administered by intravenous (IV) infusion or as an intravitreal implant (for CMV retinitis). Valganciclovir is an orally active prodrug.


– Limited to treating CMV infection in immunocompromised patients

Side effects

– Bone marrow depression


Cytomegalovirus is an infection that is often asymptomatic and therefore goes unnoticed. It is spread by a variety of routes, e.g., saliva, blood, semen, urine, and breast milk. Like herpes simplex virus (HSV), it lies dormant after the initial infection and may become reactivated. Symptoms, if any, are similar to mononucleosis and include fever, fatigue, weakness, sore throat, swollen glands, muscle and joint aches, and a feeling of generally being unwell. Treatment with gancyclovir is generally reserved for immunocompromised patients.



Ribavirin is a deoxyguanosine analogue that contains a fraudulent base.

Mechanism of action. Ribavirin is phosphorylated to mono-, di-, and triphosphate forms that interfere with viral RNA polymerases.


– Effective against respiratory syncytial virus (RSV) and hepatitis C

Pharmacokinetics. Ribavirin is administered by aerosol for RSV to prevent systemic toxicity. It is given orally for hepatitis C.

Uses. For RSV, its use is limited to infants and children with severe lower respiratory tract infections. For hepatitis C, it is used in combination therapy with interferon alfa.


– Hemolytic anemia (if taken systemically)

Respiratory syncytial virus

Respiratory syncytial virus (RSV) is a virus that causes infections of the respiratory tract and lungs. It gains entry to the body through the eyes, nose, or mouth and is typically spread by droplets via coughing or sneezing or direct contact (e.g., shaking hands). Symptoms are usually mild and include congested or runny nose, cough, sore throat, headache, fever, and a generally feeling of being unwell. Treatment is usually limited to over-the-counter drugs, e.g., acetaminophen to reduce fever. Treatment with ribavirin is reserved for infants and children with severe RSV infections.



Foscarnet is a pyrophosphate analogue.

Mechanism of action. Foscarnet inhibits viral DNA and RNA polymerases.


– CMV infections resistant to other drugs


Foscarnet is infused IV or by intravitreal injection (for retinitis).


– CMV infections resistant to other drugs or in patients with HIV


– Renal toxicity leading to electrolyte imbalances


Cidofovir is a cytosine analogue.

Mechanism of action. Cidofovir interferes with viral DNA polymerases.


– CMV infections resistant to other drugs

Pharmacokinetics. Cidofovir is infused IV or by intravitreal injection.


– CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) after ganciclovir and foscarnet therapy have failed


– Renal toxicity and neutropenia


Fomivirsen is an antisense oligonucleotide.

Mechanism of action. Fomivirsen is a synthetic RNA with a sequence that is complementary to and binds to the messenger RNA (mRNA) of the immediate-early transcriptional unit (IE2) of human CMV. This inhibits translation of IE2 proteins necessary for CMV replication.

Spectrum. Fomivirsen was approved for intravitreal treatment of CMV retinitis in HIV-infected patients who could not tolerate or did not respond to other therapies, but it is no longer commercially available in the United States.


Mechanism of action. Trifluridine is an analogue of thymidine that acts by inhibiting viral DNA polymerase.


– Herpes simplex keratitis (applied topically to the cornea of infected eyes)

Side effects

– Local stinging and irritation around the eyes

30.2 Viral M2 Protein Blockers

Amantadine and Rimantadine

Mechanism of action. These agents are highly selective antiviral drugs that inhibit the growth of influenza A viruses by acting as ion channel blockers of the viral M2 protein, thus preventing viral uncoating (Fig. 30.4).


– Influenza A

Pharmacokinetics. Completely absorbed from the gastrointestinal (GI) tract and excreted unchanged in the urine.


– Prophylaxis and treatment of influenza A virus infections

Side effects. Central nervous system side effects (nervousness, confusion, insomnia, light-headedness, and hallucinations) are the most common.

Fig. 30.4 image Prophylaxis for viral flu.

Amantadine specifically prevents uncoating of influenza A viruses. Influenza A is endocytosed into cells, but they require protons, supplied by the endosome, to penetrate the virus and allow it to release its RNA. Amantadine prevents this influx of protons into the virus. Neuraminidase inhibitors are effective against influenza A and B. Normally, viral neuraminidase splits off N-acetylneuraminic (sialic) acid residues on the cellular cell surface coat, thereby enabling newly formed virus particles to be detached from the host cell.


30.3 Selective Neuraminidase Inhibitors for Influenza A and B

Oseltamivir and Zanamivir

Mechanism of action. These agents are inhibitors of influenza neuraminidase. Without neuraminidase, the hemagglutinin of the virus binds to sialic acid, forming clumps and preventing virus release (Fig. 30.4).


– Influenza A and B

Pharmacokinetics. Oseltamivir is given orally. Zanamivir is inhaled.


– Used to reduce the severity and prevent the spread of influenza

Side effects

– Nausea and vomiting (oseltamivir)

– Cough, and nasal and throat symptoms (zanamivir)


Influenza (or “flu”) is a viral infection that affects the respiratory tract and lungs. The virus has three types: A, B, and C. It is spread by droplets that are either inhaled following coughing or sneezing or directly transferred from an infected person. Symptoms of flu may mimic the common cold initially with nasal congestion or runny nose, sneezing, and sore throat. However, these symptoms rapidly become worse and progress to include fever, chills and sweats, aching muscles, headache, fatigue, weakness, and a general feeling of being unwell. Complications include pneumonia, otitis media, sinusitis, and bronchitis.Treatment for influenza usually involves bed rest, fluids, and NSAIDs. However, antiviral medications such as oseltamivir and zanamivir may sometimes be used to shorten the course of the infection.


30.4 Drugs for Hepatitis B and Hepatitis C

Interferon alfa

Several forms of interferon, including alfa-1, alfa-2a, and alfa-2b, are available.

Mechanism of action. Interferons are endogenous cytokine proteins that interfere with viral replication. They also activate immune responses.


– Injected subcutaneously

– Peginterferons, interferon formulated with polyethylene glycol, have longer half-lifes and can be given once weekly.


– Hepatitis B therapy

– Hepatitis C therapy when used in combination with ribavirin

Side effects. Flulike syndrome with headache, chills, fever, and muscle pain is common within hours of injection. Adverse effects on all systems may be observed with chronic use, including

– Alopecia, pruritis (itching), and rash

– Weight loss

– Bone marrow suppression

– GI upset

– Joint and muscle pain

– Dizziness, headache, and insomnia

– Anxiety, irritability, and depression

Hepatitis A, B, and C

Hepatitis is a viral infection that causes inflammation and dysfunction of the liver. The three main types are hepatitis A, B, and C (although D and E exist). Hepatitis A is spread by the fecal–oral route, often via contaminated food or water. Symptoms tend to appear one month following the initial infection and include nausea and vomiting, loss of appetite, fever, abdominal pain, muscle aches, fatigue, itching, and jaundice. Hepatitis A usually resolves with no treatment. Hepatitis B is spread via blood, semen, or saliva. Symptoms are the same as hepatitis A but itching and joint pain are more prominent. Chronic infection with hepatitis B may lead to cirrhosis and/or liver cancer. Antiviral drugs such as interferon alfa may be used to slow liver damage but treatment is usually limited to supportive measures. Hepatitis C is spread in the same manner as hepatitis B. It is typically asymptomatic initially and may remain so for many years. Symptoms, when they do occur, are the same as those listed for hepatitis A and B but are generally more mild. Like hepatitis B, chronic hepatitis C may lead to cirrhosis and liver cancer. Treatment may involve the use of interferon alfa. If hepatitis B or C lead to liver failure then liver transplantation may be indicated.


Adefovir Dipivoxil, Entecavir, Lamivudine, Telbivudine, and Tenofovir

Mechanism of action. These agents are nucleoside/nucleotide analogues that inhibit viral DNA polymerase.


– Orally effective

Side effects

– Asthenia and nephrotoxicity (adefovir dipivoxil [dose-dependent])

– Dizziness, fatigue, headache, and nausea (entecavir)

– Dizziness, headache, and nausea (lamivudine)

– Headache, cough, fatigue, flu, and increased serum creatine kinase level (telbivudine)

– Asthenia, rash, and GI upset (tenofovir)


Mechanism of action. Ribavirin is a guanosine analogue that inhibits viral RNA polymerases.


– Orally effective


– Used in the therapy of hepatitis C in combination with interferon alfa

Side effects

– Hemolytic anemia

– Pruritis and rash

– Headache, fatigue, irritability, and insomnia

– Nausea

Table 30.2 summarizes the drugs used to treat non-HIV viral infections.

  Table 30.2 image Drugs Used to Treat Viral Infections (non-HIV)


Antiviral Activity



Influenza A


Neuraminidase inhibitors

Influenza A and B


Acyclovir and analogues

Herpes viruses


Ganciclovir and valganciclovir

CMV in HIV patients



CMV, HSV (resistant)



RSV, hepatitis C



Hepatitis B, C; papillomavirus


Imiquimod, podoflox

Topical agents for papillomavirus


Abbreviations: CMV, cytomegalovirus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; RSV, respiratory syncytial virus.


30.5 Management of HIV and AIDS

HIV is a retrovirus transmitted by free viral particles or infected immune cells (e.g., CD4 [T helpe rcells], macrophages, and dendritic cells) in blood, semen, vaginal fluid, preejaculate, and breast milk. It causes acquired immunodeficiency syndrome (AIDS). The goal of HIV/AIDS therapy is to increase CD4 cell counts, suppress viral load, and reconstitute the immune system.

Highly active antiretroviral therapy (HAART) is combination therapy used in the treatment of HIV/AIDS to decrease the development of resistance. It usually involves using three agents from two different classes.

Replication of the HIV virus

There are several steps involved in the replication of the HIV virus:

1. Proteins (gp120 protein) on the surface of the HIV virus cell are fused to CD4+ receptors (glycoproteins) found on the surface of helper T cells, monocytes, and macrophages.

2. HIV RNA, reverse transcriptase, HIV integrase, and other viral proteins are released into the host cell.

3. Single-stranded viral RNA is transcribed to double-stranded DNA in the cytoplasm by the action of reverse transcriptase.

4. New viral DNA migrates into the nucleus and becomes spliced into host DNA by the action of HIV integrase.

5. DNA is transcribed into new viral RNA, which is then translated into viral proteins.

6. New viral RNA and proteins congregate near the cell membrane and become enclosed in the membrane, forming immature (not yet infective) HIV virus cells, which bud off from the host cell.

7. The virus is cleaved by proteases into its mature, infective form.


Nucleoside Reverse Transcriptase Inhibitors

Mechanism of action. Nucleoside reverse transcriptase inhibitors (NRTIs) are unnatural nucleoside analogues that decrease viral DNA synthesis by inhibiting viral reverse transcriptase (Fig. 30.5).

Abacavir (ABC), Didanosine (ddI), Emtricitabine (FTC), Lamivudine (3TC), Stavudine (d4T), Tenofovir, and Zidovudine (Azidothymidine, AZT),

– AZT is the first antiretroviral drug approved by the U.S. Food and Drug Administration for the treatment of HIV.


– Orally effective

Side effects. Serious adverse effects for NRTIs include pancreatitis, fatty liver, lactic acidosis, and peripheral neuropathy. See Table 30.3 for the side effects of individual agents.

  Table 30.3 image Side Effects of Nuceloside Reverse Transcriptase Inhibitor Drugs


Side Effects


Abacavir (ABC)

Hypersensitivity, liver disease


Emtricitabine (FTC)

Nausea, vomiting, headache, fatigue


Lamivudine (3TC)

Nausea, vomiting, headache, fatigue


Stavudine (d4T)

Peripheral neuropathy, diarrhea, nausea, vomiting



Rash, mild GI upset


Zidovudine (azidothymidine, AZT)

Asthenia (lack of energy and strength), headache, fatigue, insomnia, anorexia, constipation, nausea, vomiting


Abbreviations: GI, gastrointestinal; NRTI, nucleoside reverse transcriptase inhibitor.


Nonnucleoside Reverse Transcriptase Inhibitors

Mechanism of action. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) also interfere with viral DNA synthesis but bind near the active site of the viral reverse transcriptase to inhibit its activity (Fig. 30.5).

Side effects

– Hypersensitivity reactions and liver disease


– Orally effective

– These drugs are substrates of cytochrome P-450 enzymes and may induce or inhibit the metabolism of other drugs metabolized by the liver.

Fig. 30.5 image AIDS drugs.

Inhibitors of reverse transcriptase are nucleosides containing an abnormal sugar moiety and require phosphorylation for activation. As triphosphates, they inhibit reverse transcriptase (RT) and induce strand breakage following incorporation into DNA. Nonnucleoside inhibitors inhibit RT without requiring prior activation. Protease inhibitors prevent polyprotein cleavage, which is necessary for the maturation of viral cells. Fusion inhibitors prevent the change in conformation of viral fusion proteins that allows them to attach to host CD4 cells. SC, subcutaneous.



Side effects. A rash develops on the upper body and arms within the first 1 to 3 weeks after taking the medication. This rash usually goes away within ~2 weeks. Other side effects include

– Severe skin rash accompanied by blisters, fever, joint or muscle pain, redness and swelling of the eyes, sores in the mouth, and swelling

— Serious kidney problems

– Anemia

– Liver

– Muscle problems


Side effects

– Abnormal thinking, confusion, depression, hallucinations, memory loss, paranoid thinking, and thoughts of suicide

– Convulsions

– Liver complications

– Increase in cholesterol, fat accumulation, and fat redistribution


Side effects

– Mild to moderate rash sometimes occurs in the second week of therapy and generally resolves within 1 to 2 weeks of continued therapy.

– Serious side effects may include a severe skin rash with or without an accompanying fever, muscle or joint aches, blistering, oral lesions, facial swelling, and swelling and reddening of the eye.


Side effects

– Severe skin rash, chills, fever, sore throat, and other flulike symptoms. These may be signs of liver disease.

Protease Inhibitors

Saquinavir, Ritonavir, Lopinavir, Indinavir, Nelfinavir, Amprenavir, Atazanavir, Tipranavir, and Darunavir

Mechanism of action. Protease inhibitors inhibit viral assembly and release from the host CD4 cells (Fig. 30.5).

Pharmacokinetics. These drugs are substrates for CYP3A4. Thus, they may inhibit the metabolism of other drugs that are CYP3A4 substrates.

Side effects. The general side effects of these drugs include the following:

– Changes in body fat distribution (central obesity, buffalo hump, gynecomastia)

– Increased bleeding in patients with hemophilia

– High sugar levels in the blood; onset or worsening of diabetes

The additional side effects of individual drugs are listed in Table 30.4.

  Table 30.4 image Side Effects of Protease Inhibitor Drugs


Side Effects



Inflammation of the pancreas, which can cause severe stomach pain, nausea, or vomiting; heart dysrhythmias (this may happen when ritonavir is used alone or when used with other drugs that affect the heart)



Disease of the pancreas; dizziness, lightheadedness, fainting, or sensation of abnormal heartbeats



Kidney stones



Severe rash



Yellowing of the eyes or skin; change in heart rhythm; diarrhea, infection, nausea, and blood in the urine



Increased cholesterol and triglyceride levels; serious liver problems; bleeding in the brain; rash



Inflammation of the liver and abnormal liver function tests (liver injury, specifically drug-induced hepatitis, may occur when darunavir and ritonavir are taken together); severe skin rash; fever; abnormally high cholesterol and triglyceride levels; hypersensitivity; metabolic disturbances


Entry (Fusion) Inhibitor


Mechanism of action. Enfuvirtide binds to the transmembrane glycoprotein subunit (gp41) of the viral envelope and prevents the fusion of viral envelope and cell membrane (Fig. 30.5).

Chemokine coreceptor antagonist


Mechanism of action. Maraviroc blocks certain strains of HIV from binding to chemokine receptor type 5 (CCR5) thus preventing the virus from entering target cells. This agent can only be used when the virus is CCR5-tropic. If the patient's virus is chemokine receptor type 4 (CCR4)-tropic or has a mixed population, as seen in later stages of the disease, maraviroc will not be effective.

Integrase Inhibitor


Mechanism of action. Raltegravir inhibits the viral integrase that mediates the integration of the newly synthesized viral DNA into host cell DNA.

CD4 and CD8 cells

CD4 cells (T helper cells) play an important role in the immune system by alerting other immune cells—B cells and cytotoxic T cells (CD8)—to kill pathogens or tumor cells. The normal range for CD4 cells in a blood sample is 500 to 1500; for CD8 cells, it is ~1200.


Highly Active Antiretroviral Therapy (HAART)

HAART is combination therapy used in the treatment of HIV/AIDS to decrease the development of resistance. It usually involves using three agents from two different classes.

  Table 29.4 image External Antiseptics and Disinfectants

Class of Substance




Anionic: ordinary soaps

Cationic: benzalkonium chloride


Phenols (probably also act as detergents)

Phenol: hexylresorcinol

Cresol: hexachlorophene



Ethanol and isopropyl alcohol



Chlorine, chloramines, and iodine



Silver (used in combination with sulfadiazine) and mercury (thimerosal)



Hydrogen peroxide, permanganate, sodium peroxide, and perborate