Antiviral Drugs pptx - د.عمر

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

General principles:

DNA viruses:

Based on viral genomic ds-DNA

Life cycle of a generic DNA virus:

Virion often contains specialized enzymes

viral DNA/RNA polymerases etc.
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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)
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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
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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
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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.
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General anti-viral approaches:

1-Targeting influenza virus

2-Specifically targeting DNA viruses (e.g. HSV)

3-Specifically targeting RNA viruses (e.g. HIV)
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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.

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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

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• 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
Mechanism of Action:

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• 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, RimantadineTreatment (3-5 days)

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• 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
Amantadine Metabolism

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• 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 Adverse Effects

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• 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
Amantadine, Rimantadine Resistance

Newer medications: became available in 1999

Have activity against both influenza A and influenza B viruses

Chemically related, but have different routes of administration

Neuraminidase Inhibitors Oseltamivir, Zanamivir

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Oseltamivir (Tamiflu)

Zanamivir (Relenza)

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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, Zanamivir
Mechanism of Action

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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
Oseltamivir

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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

Zanamivir

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Treatment

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, ZanamivirTreatment: 5 Days

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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, Zanamivir

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• 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
Oseltamivir Adverse Effects

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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
Zanamivir
Adverse Effects

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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:

Ages 1-9 years: 5 mg/kg/day divided twice daily
(not to exceed 150 mg
Ages 10-64 years: 100 mg twice daily
Ages  65 years: 100 mg per day

Prophylaxis of Influenza A

Oseltamivir:

Age  13 years: 75 mg per day

Zanamivir

Prophylaxis of Influenza A & B

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)

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• 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
Antiherpes Agents

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Two types of nucleotides:

Purine nucleotides

Guanine
Adenine
Pyrimidine nucleotides
Thymine
Cytosine

Specifically Targeting DNA viruses (HSV)

Acyclovir: Mechanism of action

Step 1: Activation
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…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

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• 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

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

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• 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).
Antiherpes Agents

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

Drugs used to treat HIV viruses
Anti-Retroviral Drugs

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Classes if anti retroviral drugs:

1-Neucloeside reverse transcriptase inhibitors. (NRTIs)

2- Non-Nucleoside reverse transcriptase inhibitors. (NNRTIs)

3-Protease inhibitors. (PI)

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Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Lamivudine

Zidovudine
Didanosine
Stavudine

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• 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”

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

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

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

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

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

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

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

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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).

HAART

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

Treatment of AIDS

Anti-Malarial Drugs

Life cycle of malarial parasite

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1-Treatment of malaria:

A- initial treatment.
B- prevention of relapse(radical cure).

2-Prevention of malaria (chemoprophylaxis).

Drugs used in malaria
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• Quinine

• Chloroquine
• Sulfadoxine + pyrimethamine (fansidar)
• Primaquine
• Mefloquine
• Proguanil
Therapeutic options
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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
Treatment of plasmodium falciparum
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Chloroquine 150 mg tab.

600 mg initially
300 mg after 6 hours
150 mg 12 hourly for 2 days

10 tablets

Plasmodium vivax , ovale ,malariae
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Primaquine 15 mg daily for 14 days

Haemolysis in patients with G6PD deficiency
Methaemoglobinaemia leading to cyanosis is more common but
“Not dangerous”
Prevention of relapse
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When should we start the prophylaxis?

chemoprophylaxis
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1 week before entering

4 weeks after leaving

The endemic area

Malaria prophylaxis
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1-Chloroquine resistance absent or low:

Chloroquine tablet 150 mg 2 tab. weekly

Proguanil 100 mg tab daily

Malaria prophylaxis
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2-Chloroquine resistance is high

Mefloquine 250 mg week
(neuro psychiatric symptoms conductive disorders)

Or

Doxycyclin 100 mg daily
Malaria prophylaxis
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Half life = 50 days

Safe in short treatment
pruritus headache nausea ….etc

Adverse effects in long term:
Corneal effect
Retinal effects
Chloroquine Adverse reactions
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Corneal deposits:

Asymptomatic.
Halos around light.
Photophobia.
Reversible on stopping the treatment

Corneal effects

More serous

Irreversible
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
Retinal toxicity
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Ophthalmoscope

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
Quinine:

Hypotension

Disturbed AV conduction
Cardiac arrest
Acute overdose of Quinine