number Done by Corrected by Doctor Ashraf

Size: px

Start display at page:

Download "number Done by Corrected by Doctor Ashraf"

Eugenia Barker
5 years ago
Views:

1 number 6 Done by حسام أبو عوض Corrected by Doctor Ashraf 1

3 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 2

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

4 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 3

5 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]. 4

6 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% 5

7 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. Cidofovir: - Nephrotoxicity (crystalluria, haematuria, renal insufficiency) - Myelosuppression (bone-marrow suppression) (neutropenia and thrombocytopenia) (only ganciclovir). - Nephrotoxicity (a major disadvantage for the drug). Therapeutic Uses Acyclovir is the Drug of Choice for: HSV genital infections (oral, also in notso-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 قيصرية),(والدة 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. 6

8 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 7

9 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. 8

10 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). 9

11 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 الشهية) (فقدان and arthralgia (joint pain). Another drug, maraviroc (Selzentry, outside the US: Celsentri), inhibits the coreceptor (CCR5) instead of the receptor on the T-cells (as mentioned in page 3). This drug was approved by the FDA in 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) 10

12 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 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. 11

13 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).(أخيرا!) This is the final group of drugs for today 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 antiproliferative 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. 12

14 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: 13

15 The following table is the one that shows the drugs of the NRTIs group: Drug Toxicity Special Considerat ions 3TC (Lamivudine / Epivir) Few Hepatitis B exacerbation Dosing Hepatitis B 150mg bid or 300mg qd. Renal dosing available Adverse Effects Few; class effect Combination with AZT D4T (Stavudine / Zerit) AZT (Zidovudine / Retrovir) DDI (Didanosine / Videx) stomach 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. 14 Lipoatrophy Peripheral neuropathy Pancreatitis Lactic acidosis Anemia Neutropenia Thrombocytopenia Myopathy Lactic acidosis Peripheral neuropathy Pancreatitis Lipodystrophy - 40mg bid (if >60kg) 30mg bid (if <60kg) Gen welltolerated H/N/V - 300mg bid Nausea / vomiting Headache Dizziness - If EC, 400mg QD (<60kg: 250mg qd) If reg tabs, 200mg bid (<60kg:125 bid/250qd) Empty GI Combination only Combination Only Combination Only

Anti-viral drugs. Certain viruses multiply in the cytoplasm but others do in the nucleus Most multiplication take place before diagnosis is made

Anti-viral drugs. Certain viruses multiply in the cytoplasm but others do in the nucleus Most multiplication take place before diagnosis is made Anti-viral Drugs Viruses have no cell wall and made up of nucleic acid components Viruses containing envelope antigenic in nature Viruses are obligate intracellular parasite They do not have a metabolic