number Done by Corrected by Doctor

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1 number 34 Done by حسام ابو عوض Corrected by Waseem Alhaj Doctor مالك الزحلف

2 Antiviral Chemotherapy (chemotherapy is another way of saying drugs بنحب نتفلسف وهيك.(بس When dealing with viruses we are entering into a totally different category than that of bacteria due to the different mechanisms with which these two cause their respective infections. Unlike bacteria, viruses need to enter INTO the cell to replicate and increase in number. When the viruses do so, they take control over the cell s machinery and use it for their own benefit to be able to replicate and increase in number. Just like bacteria, when the number of viruses increases over the limit with which the body s immune system can deal then infection occurs and symptoms start to appear. For DNA viruses to replicate they must first get adsorbed to the receptors of their host cell then they need to penetrate into the cell (similar to endocytosis). After entering the cell, the viruses release their active material (genome and proteins) by an uncoating process either in the cytosol or the nucleus of the host s cell. Next, the virus uses the cell s machinery to replicate its genome and proteins and then re-assemble itself. Finally, the virus (if enveloped) gets its envelope and leaves the cell (gets released) in a process similar to exocytosis. RNA viruses have a slightly different life-cycle as they often have a reverse transcriptase enzyme to produce DNA from their RNA and some of them (like HIV) have an integrase enzyme (integrates the viral genome into the cellular genome) which makes dealing with them way more difficult than DNA viruses. Initially, when scientists began to understand viruses and their mechanisms of replication, all the viral treatments were circling over the idea of killing the infected cell (the one in which too much replication is occurring; the virus forces the cell to enter its replicative phase) and so getting rid of the viruses contained within it. The main mechanism in which this was done was by giving a drug that contains a false nucleoside (a nucleoside that looks very similary to the normal nucleosides used by the virus and the cell, but with slight adjustments in its structure) which gets activated (changed to a nucleotide) in the infected cell and so, when the virus uses this adjusted nucleotide in its replication it won t be able to add another nucleotide after our adjusted one, resulting in the

3 failure of the replicative mechanism of the viruse and its death (the cell is also affected) (this false nucleoside we gave is called an anti-metabolite ). Despite the obvious benefit of such treatment, there are simply too many side effects as it is very difficult to target ONLY the infected cells. This means that normal cells also get destroyed which is quite bad. Our bone marrow produces at least 13 billion new cells daily; with anti-viral drugs the bone marrow is being targeted as well (as a side effect) which means that the bone marrow won t be able to function normally resulting in bone marrow suppression, which is seen as leukopenia (decrease in WBCs count in the blood), thrombopenia (decrease in platelets count in the blood), anemia (decrease in RBCs count in the blood), etc. A scientist insisted that there must be a way for us to become selective to the viruses (or the infected cells) and then came up with the drug Acyclovir (commercial name: Zovirax). This drug is also a false nucleoside, but ONLY the virus can change it to a nucleotide and therefore, this drug will only get activated in the infected cells (the ones in which the viruses are found). Adminstered orally, this is one of the safest drugs ever. After that, other selective drugs were made including a drug that acts on the neuraminidase (related to the release step in influenza virus) and another one that inhibits the penetration step of the virus. Generally, anti-viral drugs are only present for viruses for which no vaccines are available. Following is a list of viruses and the diseases they cause:

4 Acyclovir [We treat some common diseases with our anti-viral drugs caused by the DNA viruses: Herpes simplex, Varicella-Zoster, Cytomegalovirus]. This diagram shows the action of the metabolites we previous talked about. The first row shows how we previously used to treat the viruses (the one that used to affect uninfected cells too) by changing a single substituent on the (pyrimidine) ring of Thymine (can be other pyrimidines or purines) (the R groups shown at the top right of the diagram are the possible substituents instead of the original methyl group). Later, when acyclovir was made, we noticed that if the sugar chain was altered instead of the purine/pyrimidine ring(s) then the drug becomes specific to the infected cells only (can only be activated by the virus). [notice the Acyclovir (contains adenine) and its close relative Ganciclovir (contains guanine) drugs which simply have a non-ring containig structure of their ribose sugar]. When producing acyclovir (for example) the first step of activating the nucleoside (adding the first phosphate to make it a nucleotide) MUST be done by the virus (the affinity of the viral kinase is 200X that of the cellular kinase, so practically the activity is all viral), but the following steps (adding the 2 nd and 3 rd phosphates) can be done by the host cell. Viruses are beginning to become resistant to our drugs by either decreasing the activity of their viral kinase and so not activating many false-nucleosides (most common) or (less common) getting their DNA polymerase to be able to work with false-nucleotides as if they were correct ones. Acyclovir has a high first pass metabolism if taken orally and only 15% of the given dose reaches the cells, therefore we give a high dose (400mg, 4 times daily) or prevent the first pass metabolism by giving Valacyclovir (a valine

5 group is added to acyclovir. This valine group protects acyclovir from the CYP- 450 enzymes that metabolise acyclovir, instead of acyclovir increasing its bioavailability to 50%. With acyclovir the dose is adjusted be given just twice daily and even with a lower mass (<400mg). The herpes simplex virus type I causes encephalitis (can cause encephalopathy and meningitis) and this is a life threatening situation, we must administer our acyclovir intravenously here [side note: meningitis can be bacterial, viral or fungal so it is not uncommon for one to see in the hospital a patient on vancomycin (and other antibiotics) AND acyclovir as it could be difficult sometimes to tell if the infection is bacterial or viral]. This virus can also cause the Herpes Labialis (see diagram) which is not a serious situation, so unless the infection is recurrent (at least infected 4 times in a single year) then there is no need for the drug, because it only reduces the duration of the infection by one and a half day. If the infection is recurrent we begin by giving acyclovir (or valacyclovir) for two weeks at full dose; that is 400mg for 4 times per day (or two times per day and <400mg for valacyclovir) then half-dose is given for two to three months (this is called postsuppression therapy, very similar to prophylactic therapy except that postsuppression therapy is preceeded by a full dose for a certain period of time while the prophylactic therapy is not). If the patient was a neonate (may be caused by breastfeeding) you MUST give them the drug even if it is not a recurrent therapy. Note: topical acyclovir has no real effect in reducing the infection duration. The herpes simplex virus type II causes the genital herpes which has to be treated regardless if it is recurrent or not since this disease already has a high recurrence rate (give the drug for one to two weeks, usually it would only shorten the infection duration by two days, but still it is important to give the drug). If the infection becomes recurrent then, again, begin by giving the drug for two weeks at full dose then for two to three months at half-dose. [In all cases valacyclovir or acyclovir, but taking into account their differences in dosing is a must].

6 Acyclovir is also used in treating chickenpox (caused by varicella zoster virus) in immunocompromised patients. Vericella zoster virus can also cause shingles الناري) (الحزام which is also treated with acyclovir. Important Note: We describe the effectiveness of an anti-viral drug by mentioning how many days of the infection does it cut. E.g. giving the acyclovir for a recurrent genital herpes disease cuts the infection by 1-2 days only. Side Effects As an oral drug, acyclovir has almost no side effects (maybe just some headache rarely), but when given intravenously.. everything chages. When given IV, acyclovir can cause renal insufficiency (kidney failure) and neurologic toxicity (dizziness or seizures can be seen). These side effects are very dangerous and they occur due to the accumulation of the drug. To prevent this accumulation from occurring we need to give the drug over a long period of time (infusion) instead of giving it as a bolus dose, and hydration (giving normal saline) is also needed (remember how we prevented the redman syndrome with vancomycin by giving it over 1-2 hours? We are doing the same here, and the same is done with almost all the drugs that can cause damage to the kidneys). The hydration forces the drug to be excreted out of the body with urine once it enters the kidneys preventing its accumulation, so the drug just does its job and is quickly excreted (and only small amounts of the drug are given per unit time) [Some other examples: cisplatin and cyclophosphamide are some other kidney-toxic drugs. When giving these drugs (as infusions of course), 2-3 litres of normal saline must be given to the patient to prevent their accumulation in the body].