Antiviral Drugs

General principles: Viruses are parasitic, i.e. they utilize: Host metabolic enzymes Host ribosome for protein synthesis Structure of viruses: Nucleic acid “Core”: DNA or RNA Often contain crucial virus-specific “Enzymes” Surrounded by “Protein”: “Capsid” … and sometimes an outer lipid “Envelope” Complete viral particle = “Virion” “ Often visible by electron microscopy”

HIV-1

DNA viruses: General principles: Based on viral genomic ds-DNA Life cycle of a generic DNA virus: Virion often contains specialized enzymes viral DNA/RNA polymerases etc.

General principles RNA viruses: Based on viral genomic ss-RNA Example HIV-1: HIV virion contains enzymes: Reverse transcriptase Integrases Proteases But note: NOT all RNA viruses are retroviruses (e.g. influenza)

DNA-based viruses Resultant disease Herpes simplex types 1, 2 herpes (skin); encephalitis (brain) Varicella zoster chickenpox (children) Herpes zoster shingles (adult) Human papillomavirus warts (plantar, genital), cancer Epstein-Barr virus Mononucleosis Burkitt’s lymphoma; nasopharyngeal carcinoma Poxvirus smallpox; chickenpox

RNA-based viruses Resultant disease HIV-1, HIV-2 HIV; AIDS Rhinovirus respiratory/GI infections (“common cold”) Hepatitis A, B, C viruses Hepatitis Influenza A, B, C viruses Influenza A, B, C

Approaches to treat viral diseases: As viruses are intracellular parasites (utilizing host machinery), there are “Very few unique targets” in viruses This distinguishes viruses from other infectious organisms: (Bacteria, protozoa, fungi) Challenges in designing anti-viral treatments: 1-Host cell must be Immune to treatment. (to limit off-target toxicity) 2-Viral infection disease symptoms often associated with latency period.

General anti-viral strategies are to inhibit: 1-Viral “Attachment” to host cell, penetration, and uncoating. 2-Viral “Enzymes”: DNA/RNA polymerases, etc Reverse transcriptase, proteases, etc. 3-Host “Expression” of viral proteins. 4-”Assembly” of viral proteins. 5-”Release” of virus from cell surface membranes.

General anti-viral approaches: 1-Targeting influenza virus 2-Specifically targeting DNA viruses (e.g. HSV) 3-Specifically targeting RNA viruses (e.g. HIV)

Antiviral drugs for influenza: Are effective for both early treatment and Chemoprophylaxis of influenza infections. Likely the only virus-specific interventions available during the initial pandemic response, as a suitable vaccine is unlikely to be available for at least 6-8 months.

Adamantanes (M2 inhibitors) Classes of Influenza Antiviral Drugs Adamantanes (M2 inhibitors) Amantadine Rimantadine Neuraminidase inhibitors Oseltamivir Zanamivir

Amantadine, Rimantadine Chemically related Orally administered (100 mg tablets and syrup for children) Activity against Influenza A viruses only, through inhibiting replication Have comparable antiviral and clinical activities when used for prophylaxis or treatment

Amantadine, Rimantadine Mechanism of Action: 1-Interfere with the function of the transmembrane domain of the M2 protein of influenza A viruses. 2-Interfere with virus assembly during replication of influenza A viruses. 3-Decrease the release of influenza A viral particles into the host cell.

Amantadine, Rimantadine Treatment (3-5 days) Decreases length of illness due to influenza A by about 1 day. Reduces shedding of influenza A viruses Must be started within 2 days of illness Placebo-controlled studies: both reduced fever, symptom severity, and time to resumption of normal activities

Amantadine Metabolism Well-absorbed, half-life 12-16 hours Excreted largely unchanged in the urine by glomerular filtration and tubular secretion Has the narrowest toxic to therapeutic ratio of available antivirals Dose adjustments required for relatively small decreases in renal function creatinine clearance <50-80 ml/min including those typically observed with aging

Commonly associated with dose-related minor CNS side effects Amantadine Adverse Effects Commonly associated with dose-related minor CNS side effects anxiousness, difficulty concentrating, insomnia, lightheadedness Less often with severe CNS toxicities delirium, hallucinosis, acute psychosis, seizures, coma most often in older persons and those with pre-existing renal insufficiency, seizure disorders, or psychiatric illness

Amantadine, Rimantadine Resistance Rapid development of resistance to amantadine and rimantadine in 30% of treated patients (can develop in 2-5 days). Cross-resistance: viruses resistant to amantadine are also resistant to rimantadine

Chemically related, but have different routes of administration Neuraminidase Inhibitors Oseltamivir, Zanamivir Newer medications: became available in 1999 Have activity against both influenza A and influenza B viruses Chemically related, but have different routes of administration

Oseltamivir (Tamiflu) Zanamivir (Relenza)

Oseltamivir, Zanamivir Mechanism of Action Block the active site of Neuraminidase, present in all influenza A and B viruses Reduce the number of viral particles released from infected cells

Oseltamivir Orally administered: 75 mg capsules and syrup for children Approved for treatment and prophylaxis of influenza A and B Treatment  1 year Chemoprophylaxis  13 years

Zanamivir Inhalational delivery of dry powered drug (5 mg per package) in a lactose carrier. A proprietary device is used to deliver drug (Diskhaler) Approved for treatment of influenza A & B Among those aged  7 years

Oseltamivir, Zanamivir Treatment: 5 Days Must be administered < 48 hours after onset of illness Reduce symptoms and decrease length of illness due to influenza A & B virus infections by approximately 1 day Decrease viral shedding

Oseltamivir, Zanamivir Prophylaxis Oseltamivir and zanamivir are both approximately 80% effective in preventing illness. Can prevent influenza in family members after one family member in the home has influenza. Uncontrolled studies of both oseltamivir and zanamivir report termination of nursing home outbreaks that continued despite the use of amantadine

Oseltamivir Adverse Effects Mild-to-moderate nausea/vomiting in 10-15% of adults; symptoms are not usually dose-limiting Fewer GI symptoms if given with food Only 1-2% stop because of adverse events Headache reported in older adults Cases of hypersensitivity reactions, rash, hepatotoxicity, and thrombocytopenia reported rarely

Zanamivir Adverse Effects Gastrointestinal (nausea, diarrhea) Headache Cough Use in influenza-infected persons with pre-existing lower airway tract disease associated infrequently with bronchospasm Rarely with a severe or fatal outcome Not recommended in those with obstructive lung disease

Prophylaxis of Influenza A Amantadine: Ages 1-9 years: 5 mg/kg/day divided twice daily (not to exceed 150 mg per day) Ages 10-64 years: 100 mg twice daily Ages  65 years:  100 mg per day Rimantadine: (not to exceed 150 mg Ages 10-64 years: 100 mg twice daily Ages  65 years: 100 mg per day

Prophylaxis of Influenza A & B Oseltamivir: Age  13 years: 75 mg per day Zanamivir

Herpes simplex virus (HSV) Specifically Targeting DNA viruses (HSV) Herpes simplex virus (HSV) Cause of several painful skin/eye infections The two most common types: HSV-1: orofacial (cold sores on the mouth and lips) HSV-2: genital herpes Both types: can have dormancy periods (often for several year periods) are infectious, but the potential is greatest during an outbreak currently incurable but generally not fatal Neonatal HSV (transmission from mother to child)

Antiherpes Agents Acyclovir Valacyclovir Famciclovir Penciclovir Idoxuridine These are Nucleoside derivatives Mechanism of Action: Competitive inhibition of deoxy GTP for viral DNA polymerase Chain termination of viral DNA after incorporation Resistance mutants can develop

Two types of nucleotides: Purine nucleotides Guanine Adenine Pyrimidine nucleotides Thymine Cytosine

Step 1: Activation Specifically Targeting DNA viruses (HSV) Acyclovir: Mechanism of action Step 1: Activation

…so will “normal” (non-infected) cells be sensitive to this drug?

Acyclovir: Mechanism of action Step 2: incorporation into growing DNA chain

Note similarity to 2-deoxythymidine: with iodxouridine base

Antiherpes Agents Spectrum of Activity : HSV-1, HSV-2, VZV Oral, intravenous, topical formulation (Acyclovir) Excretion primarily by glomerular filtration and tubular secretion. Good tissue penetration 50 - 100%; CSF - 50% (Acyclovir)

Antiherpes Agents Clinical Uses: Genital herpes treatment and suppression varicella- Zoster Anti-CMV prophylaxis in organ transplants Herpes encephalitis

Antiherpes Agents Adverse Effects: GIT disturbances (orally). IV use →local inflammation if there is extravasations renal dysfunction (high doses or dehydrated patients) due to crystalluria (adequate hydration + slow infusion rate). Topically on the eye →stinging sensation. Headache & CNS effects (confusion, lethargy & tremors).

Anti-cytomegalovirus Agents 1-Ganciclovir 2-Foscarnet 3-Cidofovir 4-Valganciclovir

Anti-Retroviral Drugs Drugs used to treat HIV viruses Anti-Retroviral Drugs

Classes if anti retroviral drugs: 1-Neucloeside reverse transcriptase inhibitors. (NRTIs) 2- Non-Nucleoside reverse transcriptase inhibitors. (NNRTIs) 3-Protease inhibitors. (PI)

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Lamivudine Zidovudine Didanosine Stavudine

These are Nucleoside derivatives Competitive inhibitors of reverse transcriptase Incorporated in DNA leading to chain termination Effective against HIV-1 & HIV-2 “Resistance develops with monotherapy”

Clinical Uses: HIV-infection with features of AIDS. Prophylaxis for contacts (Zidovudine) Prevent maternal to fetal transmission (Zidovudine).

Adverse Effects: Zidovudine: Myelosuppression, Anemia, Neurpenia, GI intolerance, Headaches, Insomnia, Myopathy, Lactic Acidosis, Hepatotoxicity. Didanosine: Pancreatitis, Peripheral Neuropathy, Diarrhoea, Hyperuricemia Stavudine: Peripheral Neuropathy

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Nevirapine Delavirdine Efavirenz Reverse transcriptase inhibitors Inhibit RNA- and DNA- dependent DNA polymerases

Adverse Effects: Severe skin rashes, Hepatitis, Nausea, Headache.

Protease Inhibitors (PI) Saquinavir Ritonavir Indinavir Nelfinavir Inhibitors of viral protease which are essential for production of mature infectious virions Resistance and cross-resistance develops

“Drug - drug interactions common’ Good Oral bioavailability Metabolized by CYP450 isoenzymes like CYP3A4, CYP2D6 “Drug - drug interactions common’ Uses: Antiretroviral therapy in combination with NRTIs and NNRITs.

Protease Inhibitors Adverse Effects Altered body Fat distribution (buffalo lump and truncal obesity, facial and peripheral atrophy). Insulin resistance. Hyperlipidemia. GI intolerance. Nephrolithiasis (Indinavir)

Treatment of AIDS The most effective combinations so called highly active anti- retroviral therapy (HAART) This comprises 1-Two nucleoside reverse transcriptase inhibitors (NRTIS). 2- With either: Non-nucleoside reverse transcriptase inhibitor (NNRTI) Or Protease inhibitor (PI).

Treatment of AIDS HAART This combination produces profound suppression of viral replication and results in useful restoration of immune system.

Anti-Malarial Drugs

Life cycle of malarial parasite

Drugs used in malaria 1-Treatment of malaria: A- initial treatment. B- prevention of relapse(radical cure). 2-Prevention of malaria (chemoprophylaxis).

Therapeutic options Quinine Chloroquine Sulfadoxine + pyrimethamine (fansidar) Primaquine Mefloquine Proguanil

Treatment of plasmodium falciparum Quinine 600 mg 3 times daily for 3-5 days Reduce to twice if toxicity appears. Followed by single dose of sulfadoxine 1.5gm with pyrimethamine 75 mg(Fansidar) (3 tablets) Or Doxycycline 100 mg daily for 7 days

Plasmodium vivax , ovale ,malariae Chloroquine 150 mg tab. 600 mg initially 300 mg after 6 hours 150 mg 12 hourly for 2 days 10 tablets

Prevention of relapse Primaquine 15 mg daily for 14 days Haemolysis in patients with G6PD deficiency Methaemoglobinaemia leading to cyanosis is more common but “Not dangerous”

When should we start the prophylaxis? chemoprophylaxis When should we start the prophylaxis?

Malaria prophylaxis 1 week before entering 4 weeks after leaving The endemic area

Malaria prophylaxis 1-Chloroquine resistance absent or low: Chloroquine tablet 150 mg 2 tab. weekly Or Proguanil 100 mg tab daily

Malaria prophylaxis 2-Chloroquine resistance is high Mefloquine 250 mg week (neuro psychiatric symptoms conductive disorders) Or Doxycyclin 100 mg daily

Chloroquine Adverse reactions Half life = 50 days Safe in short treatment pruritus headache nausea ….etc Adverse effects in long term: Corneal effect Retinal effects

Corneal effects Corneal deposits: Asymptomatic. Halos around light. Photophobia. Reversible on stopping the treatment

Retinal toxicity Irreversible More serous Early visual field defects. Late macular pigmentation. Ring of pigment “Bull’s eye macula” Scotomas, photophobia, defects in vision Blindness Acute Overdose is rapidly fatal

Ophthalmoscope

Quinine: Hale life = 9 hours but increase to 18 hours in malaria Adverse effects: Tinnitus Reduced auditory acuity Headache blurred vision nausea diarrhea “Acute cinchonism” Quinine, Quinidine, Salicylate Hypoglycemia

Acute overdose of Quinine Hypotension Disturbed AV conduction Cardiac arrest