1

number 6

Done by أبو عوضحسام

Corrected by

Doctor Ashraf

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Antiviral Drugs

When dealing with drugs, it is always important to keep an eye on what you

want to target (viruses here), so here is a reminder of some of the main

features of viruses:

- Viruses have no cell wall.

- All viruses contain nucleic acids (RNA or DNA).

- Viruses may be enveloped or naked.

- The antigens of the viruses are their spikes or glycoproteins.

- Viruses are obligate intracellular parasites.

- Most of the viruses rely mainly on the host’s mechanisms for their

replication.

- Some viruses replicate in the cytoplasm while others do so in the nucleus.

- Usually, at the time of diagnosis, most of the viral replication would have

already occurred.

By relying on the above noted points (and some others), many antiviral

drugs were developed and the following was noted:

- Many antiviral drugs are purines (A & G) or pyrimidines (C & T)

analogues (anti-metabolites) (Molecularly, the drug looks very similar to

one of the normal nucleosides (A, T, G, C or U), but slight variations on

the structure were made resulting in our drug being able to join the

DNA/RNA synthesis process, but not allowing it to continue. After

activation (changing to nucleotide), the drug joins the DNA/RNA strand

being synthesised (by binding to one other nucleotide) it stops further

synthesis as it can only bind unilaterally (from one-sid) stopping further

synthesis of that DNA or RNA strand).

- Many antiviral drugs are “prodrugs”, i.e. their structures get changed

when they enter the body (by viral or cellular enzymes) resulting in their

activation.

- Ant-viral drugs inhibit the viral replication, so once they are removed the

replication resumes.

- As you can tell from the first point, most antiviral drugs work on the

replicative step of the viral life-cycle, therefore, they can ONLY work

against replicating viruses not latent viruses (see pathogenesis sheet for

different ways in which the viruses infect the body).

- Antiviral drugs only help the immune system in dealing with the virus,

this means that the immune system remains the main factor in dealing

with the infection [that’s why antiviral drugs are rarely prescribed in

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acute infections, in fact they are only supposed to be prescribed (in acute

infections) to immunocompromised patients] (in viral infections, the

cellular immunity (T-cells) is of greater importance than the humoral

immunity(B-cells); B-cells produce antibodies specific to certain

antigens, these antigens may simply change later on by a mutation, so it

is often that a new immune reaction has to occur to the invading virus

(i.e. no memory cells present) and in such immune reactions T-cells are

of a greater importance, especially the CD8+ T-cells which “kill” the

virus after identifying the infected cell, see the end of the sheet for a

small note about immunity).

- For the drug to be effective clinically it is important for the minimum

inhibitory concentration of the drug to reach the infected cells.

Stages of Viral Replication

I- Cell entry

➢ Attachment (Adhesion)

➢ Penetration

II- Uncoating

III- Transcription of viral genome

IV- Translation

V- Assembly of virion components

VI- Release

There are antiviral drugs that target each one of the steps mentioned above, but

this is not for all viruses (for example, some viruses may have drugs that are

only active on their

uncoating stage, other

viruses may have no active

drugs against them at all

and others, like HIV, have

active drugs for each stage

of their replication cycles).

The following diagram

shows some antiviral drugs

and the stages that they

work on. [Note: the HIV

drug (enfuvirtide) blocks

the CD-4 receptor on the

T-cell, another drug

(Maraviroc) blocks the CCR5 co-receptor on the T-cell, both give the same

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result, work on the same virus and at the same stage of the replication cycle].

[Early protein synthesis for the CMV is targeted by the drug (fomivirsen)].

From now on, we will be discussing the antiviral drugs by mentioning a virus

(or a family of viruses) and the drugs against it.

Anti-Herpes Virus Agents

There are 8 genera of the family herpesviridae and they are called human herpes

1 to 8 (human herpes 1 is herpes simplex virus 1 (HSV-1), human herpes 2 is

herpes simplex virus 2 (HSV-2), human herpes 3 is varicella zoster virus (VZV)

and human herpes 5 (5 not 4) is cytomegalovirus (CMV).

The drugs used against the herpesviridae are:

A- Acyclovir / Valacyclovir

B- Famciclovir / Penciclovir

C- Ganciclovir / Cidofovir

D- Foscarnet

E- Trifluridine / Idoxuridine / Vidarabine

The first three groups (A, B and C) are categorised as a single group

pharmacologically as they all have similar mechanisms of action. Vidarabine

makes a second group, trifluridine a third group and foscarnet a fourth group.

Acyclovir and Related Compounds

Valacyclovir is the same as acyclovir except that a “valine” group is added in

valacyclovir. This valine group allows for a better bioavailability than when

using acyclovir. Valacyclovir is a prodrug of acyclovir (apparently, the drug

metabolism results in deactivation of lots of the acyclovir, with valacyclovir,

however, it seems that the metabolism simply removes the valine group leaving

us with acyclovir as is which means that more acyclovir molecules remain

active after the first pass metabolism).

The same concept applies to famciclovir and penciclovir (famciclovir gets

hydrolysed to penciclovir resulting in a higher bioavailability than if

penciclovir was directly used). [In the slides it is written that penciclovir is

given topically while famciclovir is given orally… To me, this makes no

sense, how do you administer a drug with a lower bioavailability in a way

that will decrease its bioavailability even more! (even Wikipedia says that

topical penciclovir has a “negligible” bioavailability!! But I guess we better

follow what is in the slides for exam purposes].

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Pharmacology of this group: Acyclovir, valacyclovir, ganciclovir,

famciclovir and penciclovir are all guanine analogues (the nucleoside they

look similar to is guanine). Cidofovir is a cysteine analogue.

Mechanism of Action: All the drugs in this group (except cidofovir which

needs no phosphorylation and inhibits viral DNA synthesis) get

phosphorylated by the viral thymidine-kinase (ganciclovir is activated by

UL-97 enzyme by CMV) changing them from nucleosides to nucleotides,

monophosphate though (it must be a triphosphate to be used in nucleic acids

synthesis). Further phosphorylations are done by the kinases of the host cell

producing the required nucleotides. When the drug molecule adds to the

DNA strand being synthesised viral DNA-polymerase cannot add more

nucleotides (so it inhibits DNA-polymerase). As you can see (also

mentioned in page 2), the drug can only work on replicating viruses (not

latent).

These drugs are selective to the virus (as their activation has to be done by

the viral thymidine-kinase), therefore, only infected cells are affected by the

drug (the drug affects both, the infected cells and the viruses, but not in an

equal proportion (i.e. not 1:1 ratio) since the viral replication is faster and

the virus has a higher affinity to the drug (a drug with a 1:1 ratio of affecting

the viruses and the infected cells does more damage to the tissue and so

makes the situation worse) [some drugs are not selective (not mentioned

here) and damage uninfected cells and often cause bone marrow

suppression].

Spectrum: Following is the spectrum for all the drugs mentioned in this

group:

i- Valacyclovir / Acyclovir: HSV-1, HSV-2, VZV [VZV causes

Shingles in adults (chickenpox in kids) by travelling in a dermatome

(a superficial nerve that circles around the body (e.g. T1 dermatome))

and blisters appear in the area that the dermatome innervates].

ii- Ganciclovir / Cidofovir: CMV (Cidofovir is approved for treating

CMV retinitis in immunocompromised patients and adenovirus

infections, it is not specific to these, but a fine effect is seen here).

iii- Famciclovir: Herpes genitalis and shingles (diseases).

iv- Penciclovir: Herpes labialis (a disease).

Pharmacokinetics of Acyclovir (I don’t know if the list is for the entire

group or only acyclovir)

Oral bioavailability: 20-30%

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Distribution: All the tissues including the CNS.

Renal excretion: >80%

Half-lives: 2-5 hours

Administration: Topical, oral or IV (cidofovir is available topically,

intravenously and as an intravitreal injection (vitreus is a structure in the

eye, so intravitreal injection = an injection in the eye).

Adverse Effects:

Acyclovir and Ganciclovir: - Nausea, vomiting and diarrhea.

- Nephrotoxicity (crystalluria, haematuria,

renal insufficiency)

- Myelosuppression (bone-marrow

suppression) (neutropenia and

thrombocytopenia) (only ganciclovir).

Cidofovir: - Nephrotoxicity (a major disadvantage for the

drug).

Therapeutic Uses

Acyclovir is the Drug of Choice for: HSV genital infections (oral, also in not-

so-serious shingles you can give oral acyclovir, if too serious you must give the

acyclovir IV), HSV encephalitis [needs to be given IV as this is a very

dangerous situation; a pregnant mother with encephalitis can only give a

caesarean delivery (والدة قيصرية), it’s too dangerous otherwise] and HSV

infections in immunocompromised patients.

Ganciclovir is the Drug of Choice for: CMV retinitis in immunocompromised

patients and in prevention of CMV in transplant patients.

Vidarabine

It is also a nucleoside analogue, but this time of adenosine (so its mechanism of

action is similar to acyclovir).

Pharmacokinetics

Bioavailability: ~2% (oral)

Administration: Ophthalmic (eye) ointment.

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Spectrum: HSV-1, HSV-2 and VZV.

Therapeutic Uses: Only for HSV keratitis (inflammation of the cornea) and for

HSV keratoconjunctivitis in immunocompromised patients (inflammation of

both, the cornea and the conjunctiva).

Adverse Effects: Anemia and SIADH (Syndrome of Inappropriate Antidiuretic

Hormone secretion).

Trifluridine

This drug is a pyrimidine nucleoside analogue which inhibits viral DNA

synthesis (similar mechanism to acyclovir).

Spectrum: HSV-1, HSV-2 and VZV.

Therapeutic Uses: Only for topical-ocular HSV keratitis and herpetic

keratoconjunctivitis.

Foscarnet

Mechanism of Action: It is an analogue for the inorganic pyrophosphate and so

it directly inhibits viral DNA and RNA polymerases and viral reverse

transcriptase (it does not need phosphorylation to produce its antiviral activity).

Spectrum: HSV-1, HSV-2, VZV, CMV and HIV

Pharmacokinetics

Bioavailability: 10-20% (oral).

Distribution: All the tissues including the CNS.

Administration: IV

Therapeutic Uses: It is an alternative drug for acyclovir in HSV infections (if

the patient is resistant to acyclovir or is immunocompromised) and for

ganciclovir in CMV retinitis (if the patient is resistant to ganciclovir or is

immunocompromised).

Respiratory Viral Infections

There are two viruses to deal with in this group; Influenza and RSV

(Respiratory Syncytial Virus) (often causes bronchiolitis).

Influenza

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There are two groups of drugs for the influenza virus: Amantadine and

rimantadine and oseltamivir and zanamivir (neuraminidase inhibitors).

Amantadine and Rimantadine

These work against influenza A only because they inhibit the viral membrane

protein M2 which is only present in influenza A.

Mechanism of Action: by blocking the M2 protein channel, these drugs disrupt

hydrogen transport and, therefore, disrupt viral uncoating in the host cell

(remember that uncoating often occurs by hydrogen ions transport leading to a

change in the pH resulting in dissolving the vesicle that is carrying the virus,

thus letting the virus release its genome and proteins) (so viral RNA

transcription is prevented) (90-95% of influenza A are now resistant to these

drugs) [when the patient visits the doctor, the infection would have already

happened and most of the viral replication would have been done, so the

treatment is more of a symptomatic treatment (Panadol and things similar to it)

rather than a curative one].

Pharmacokinetics

Bioavailability: ~50-90%.

Distribution: Amantadine extensively crosses the blood brain barrier whereas

rimantadine does not cross it extensively.

Administration: Oral.

Oseltamivir and Zanamivir

These drugs are neuraminidase inhibitors and they affect influenza A and B.

Mechanism of Action: Neuraminidase is an enzyme present within the

influenza virus which is essential for its replication (during the release process a

bit of the virion remains attached with the cellular membrane, neuraminidase

enzyme “cuts” this final attachment setting the virion free). Therefore, these

neuraminidase inhibitors keep the virions “stuck” and unable to leave the cell’s

surface preventing their release and not allowing them to spread from cell to

cell. These two drugs do not interfere with the immune response to the influenza

A vaccine and they can be used prophylactically and for treating an acute

infection.

Pharmacokinetics: Oseltamivir is an oral drug while zanamivir is an intranasal

drug.

Adverse effects: There is a risk of bronchospasm with zanamivir.

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RSV

This virus often causes bronchiolitis (an upper respiratory tract infection that

often catches new-borns and children less than 2 years old) and it is treated with

“Ribavirin”.

Mechanism of Action: Ribavirin is a guanosine analogue and it requires

phosphorylation to its mono- di- and tri- phosphate forms. Its triphosphate

inhibits RNA polymerase, depletes the cellular storages of guanine (inhibits

IMDH) and decreases the synthesis of the mRNA 5’ cap (by interfering with the

guanylation and the methylation of the nucleic acid bases).

Spectrum: RNA viruses including influenza, parainfluenza, RSV and Lassa

virus.

Pharmacokinetics

Distribution: All body tissues except the CNS.

Administration: Oral, IV and inhalation in RSV.

Adverse Effects: Anaemia and jaundice (contraindicated in pregnant women).

Therapeutic Uses: RSV bronchiolitis and pneumonia in hospitalized children

(given by aerosol) and Lassa fever. Ribavirin serves as an alternative drug for

infections caused by influenza, parainfluenza and measles virus infection in

immunocompromised patients.

Hepatic Viral Drugs

These are viral infections caused to the liver and we’ll only mention a bit about

them.

Drugs

Interferons

Lamivudine (a cytosine analogue used against the hepatitis B virus)

Entecavir (a guanosine analogue used against the lamivudine resistant strains

of the hepatitis B virus)

Ribavirin (used with interferons against the hepatitis C virus)

SOFOSBUVIR (a nucleotide analogue used in combination with ribavirin and

interferons for the treatment of the hepatitis C viral infection. It’s a 12-week

course that costs a total of 84,000$ (1000$ for each pill).

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Retroviruses

We treat the retroviruses (the family of the HIV) using the “HAART” (Highly

Active Anti-Retroviral Therapy) which is simply a “cocktail” of at least three

medications that work via different mechanisms to reduce the viral load.

(As we mentioned in the second page, every single step of the viral life-cycle

for the HIV has a drug that was made to inhibit it).

Cell Entry Inhibitors

The drugs that inhibit this stage are called “Fusion inhibitors” (or “Entry

Inhibitors”) (i.e. they do not allow the virus to “fuse” with the cell membrane).

This is the newest class of antiretroviral drugs. Enfuvirtide (Fuzeon) is a good

example (we talked a bit about it in the second page).

These drugs are used in combination with other drugs active against HIV.

Adverse Effects: Peripheral neuropathy (damage to peripheral nerves),

insomnia (sleeplessness), depression, cough, dyspnea (shortness of breath),

anorexia (فقدان الشهية) and arthralgia (joint pain).

Another drug, maraviroc (Selzentry, outside the US: Celsentri), inhibits the co-

receptor (CCR5) instead of the receptor on the T-cells (as mentioned in page 3).

This drug was approved by the FDA in 2007. This drug is used in combination

with other drugs active against HIV. (HIV can use other co-receptors like

CXCR4 so an HIV tropism test (e.g. trofile assay test) is needed to prove the

drug’s efficacy for this patient).

There are some safety issues in blocking the CCR5 co-receptor as its function

(in a normal situation) is yet to be known.

Important Note: in the slides, maraviroc is placed in a separate group called

“Entry inhibitors” and the first group is called “Fusion inhibitors”, but a quick

search on google showed that “Entry Inhibitors” and “Fusion Inhibitors” are just

two names for the same group of drugs, still, if a question like (Under which

group does maraviroc fall?) was asked and you had both “Fusion Inhibitors”

and “Entry Inhibitors” present in the choices, I guess you must go with “Entry

Inhibitors” (if the question was about enfuvirtide then go with “Fusion

inhibitors”).

Reverse Transcriptase Inhibitors (RTI)

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These drugs block the activity of the reverse transcriptase enzyme preventing

the production of new viral DNA (from RNA). Below are the sub-groups of

reverse transcriptase inhibitors and the associated examples [the doctor said that

he won’t ask about the sub-groups’ examples (I don’t know if he will ask about

the following explanations about each subgroup), but he might bring a drug

name from one of the examples below and ask to which group (not sub-group) it

belongs (the answer would be reverse transcriptase inhibitors].

a- Nucleoside RTIs (NRTIs): Azidothymidine (AZT), Didanosine (ddI),

Stavudine (D4T), Lamivudine (3TC).

b- Nonnucleoside RTIs (NNRTIs): Nevirapine, delavirdine, efavirenz.

c- Nucleotide RTIs (NTRTIs): Tenofovir, Adefovir

NRTIs: These drugs require phosphorylation by the host cellular kinases to

become in their active (triphosphate) forms. Still, selectivity is noted with AZT

as HIV’s reverse transcriptase has a higher affinity to AZT than the DNA

polymerase of the host cell. (A table showing all the information about each of

the drugs in this group is found at page 14, the doctor said that he won’t ask

about the side effects of these drugs).

NNRTIs:

➢ They are active against HIV-1 and do not require cellular enzymes to be

phosphorylated.

➢ They do not inhibit the human DNA polymerase.

➢ They are relatively safe (noncytotoxic).

➢ They are highly prone to drug resistance.

➢ They are used with other drugs that are active against HIV.

Integrase Inhibitors

The drugs of this group block the action of the enzyme integrase (an enzyme

that allows the virus to insert its genome into the DNA of the host cell). The

drugs are: Raltegravir, Elvitegravir, Dolutegravir and MK-2048.

Protease Inhibitors

These drugs inhibit the action of the protease retroviral enzyme (remember that

HIV produces a “poly-protein” after the translation of its mRNA; the protease

enzyme cuts this “poly-protein” to individual proteins) preventing viral

replication. So, inhibition of the protease enzyme prevents the re-assembly and

the release steps from occurring.

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Examples: Amprenavir (Agenerase), Indinavir (Crixivan), Nelfinavir

(Viracept), Ritonavir (Norvir), Saquinavir (Invirase). [Hepatotoxicity is noted].

These drugs are used in combination with other drugs active against HIV.

(Combining multiple antiretroviral drugs is common).

Adverse Effects: vary from drug to drug and may be severe (the patient must be

monitored to avoid dose-limiting toxicities and for signs of opportunistic

diseases).

Interferons (IFNs)

This is the final group of drugs for today (!أخيرا).

Interferons are natural proteins produced by the cells of the immune system in

response to any foreign agents they face (viruses, bacteria, fungi, tumour, etc.).

These interferons result in some antiviral, immune modulating and anti-

proliferative actions.

There are three classes of interferons (α, β and γ).

Interferons α and β are produced by all the cells in response to viral infections

while interferon γ is only produced by the T-lymphocytes and by the NK-cells

in response to cytokines (interferon γ is more into immune regulation, while

interferons α and β are more into producing antiviral effects).

Mechanism of Action: The interferons induce some enzymes including a

protein kinase (inhibits protein synthesis), an oligo-adenylate synthase (leads

to degradation of viral mRNA) and a phosphodiesterase (inhibits tRNA),

together, these three enzymes lead to the inhibition of translation.

Spectrum: Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) [pegylated

interferons (pegylation: addition of polyethylene glycol to the interferons) are

used to prolong the duration (increase half-life) for which the interferons remain

inside the body] and Human Papilloma Virus (HPV).

Anti-proliferative actions (of the interferons) may inhibit the growth of some

cancers (E.g. Kaposi sarcoma and hairy cell leukemia).

Pharmacokinetics

Bioavailability: <1% (Oral).

Administration: Intralesional, Sub-cutaneous and IV.

Distribution: All the tissues except the CNS.

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Half-lives: 1-4 hours.

Adverse Effects

➢ Acute Flu-like syndrome (fever, headache).

➢ Bone-marrow suppression (granulocytopenia, thrombocytopenia).

➢ Neurotoxicity (confusion, seizures).

➢ Cardiotoxicity (arrhythmia).

➢ Impairment of fertility.

Therapeutic Uses

➢ Chronic hepatitis B and C (complete disappearance in 30% of the patients).

➢ Herpes Zoster viral (HSV) infection in cancer patients (prevent

dissemination of the infection).

➢ CMV infections in renal transplant patients.

➢ Condylomata acuminate (genital wart caused by some subtypes of HPV)

(intralesional injection, complete clearance is seen in 50%).

➢ Hairy cell leukemia (in combination with zidovudine).

➢ AIDS related Kaposi’s sarcoma.

The following table summarizes some of what was said in this sheet:

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The following table is the one that shows the drugs of the NRTIs group:

The note about immunity: All cells have a protein called “MHC-I” (Major

histocompatibility complex -1) and antigen presenting cells (macrophages, B-

cells and dendritic cells) have MHC-II. When a pathogen invades a cell, the cell

uses its proteasomes to “cut” the pathogen into pieces and take its “antigen”.

The MHC (I or II) binds to that antigen and takes it to the surface of the cell

presenting it. A T-cell, which has receptors to MHC-I and II, binds to that

antigen and begins the immune response [CD4+ T-cells are the ones that do this

job (also known as T-helper cells)]. This process initiates the production of T-

killer cells (or CD8 + T-cells) which release substances that kill the invading

pathogen.

Drug Toxicity Special

Considerat

ions

Dosing Adverse

Effects

3TC

(Lamivudine

/ Epivir)

Few

Hepatitis B

exacerbation

Hepatitis B 150mg bid

or 300mg

qd.

Renal

dosing

available

Few; class

effect

Combination

with AZT

D4T

(Stavudine /

Zerit)

Lipoatrophy

Peripheral

neuropathy

Pancreatitis

Lactic acidosis

- 40mg bid (if

>60kg)

30mg bid (if

<60kg)

Gen well-

tolerated

H/N/V

Combination

only

AZT

(Zidovudine /

Retrovir)

Anemia

Neutropenia

Thrombocytopenia

Myopathy

- 300mg bid Nausea /

vomiting

Headache

Dizziness

Combination

Only

DDI

(Didanosine /

Videx)

Lactic acidosis

Peripheral

neuropathy

Pancreatitis

Lipodystrophy

- If EC,

400mg QD

(<60kg:

250mg qd)

If reg tabs,

200mg bid

(<60kg:125

bid/250qd)

Empty

stomach

GI Combination

Only