Transcript Adverse Effects

Antiviral Drugs
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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”
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HIV-1
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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
Herpes simplex types 1, 2
Varicella zoster
Human papillomavirus
Epstein-Barr virus
Poxvirus
Resultant disease
herpes (skin); encephalitis (brain)
chickenpox (children)
Herpes zoster shingles (adult)
warts (plantar, genital), cancer
Mononucleosis
Burkitt’s lymphoma;
nasopharyngeal carcinoma
smallpox; chickenpox
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RNA-based viruses
HIV-1, HIV-2
Rhinovirus
Hepatitis A, B, C viruses
Influenza A, B, C viruses
Resultant disease
HIV; AIDS
respiratory/GI infections
(“common cold”)
Hepatitis
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.
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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
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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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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.
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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
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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
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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
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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
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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
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Oseltamivir (Tamiflu)
Zanamivir
(Relenza)
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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
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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
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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
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Oseltamivir, Zanamivir
Treatment: 5 Days
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
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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
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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
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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
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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:
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
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Prophylaxis of Influenza A & B
Oseltamivir:
Age  13 years:
75 mg per day
Zanamivir
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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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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
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Two types of nucleotides:
Purine nucleotides
Guanine
Adenine
Pyrimidine nucleotides
Thymine
Cytosine
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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?
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Acyclovir: Mechanism of action
Step 2: incorporation into growing DNA chain
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Note similarity to 2-deoxythymidine: with iodxouridine base
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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)
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Antiherpes Agents
Clinical Uses:
Genital herpes treatment and suppression varicellaZoster
Anti-CMV prophylaxis in organ transplants
Herpes encephalitis
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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).
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Anti-cytomegalovirus Agents
1-Ganciclovir
2-Foscarnet
3-Cidofovir
4-Valganciclovir
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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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Non-nucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
Nevirapine
Delavirdine
Efavirenz
Reverse transcriptase inhibitors
Inhibit RNA- and DNA- dependent DNA polymerases
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Adverse Effects:
Severe skin rashes,
Hepatitis,
Nausea,
Headache.
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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
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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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Protease Inhibitors
Adverse Effects
Altered body Fat distribution (buffalo lump and
truncal obesity, facial and peripheral atrophy).
Insulin resistance.
Hyperlipidemia.
GI intolerance.
Nephrolithiasis (Indinavir)
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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).
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Treatment of AIDS
HAART
This combination produces profound suppression
of viral replication and results in useful
restoration of immune system.
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Anti-Malarial Drugs
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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).
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1.
2.
3.
4.
5.
6.
Quinine
Chloroquine
Sulfadoxine + pyrimethamine (fansidar)
Primaquine
Mefloquine
Proguanil
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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
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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
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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”
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When should we start the
prophylaxis?
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1 week before entering
4 weeks after leaving
The endemic area
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1-Chloroquine resistance absent or low:
Chloroquine tablet 150 mg 2 tab. weekly
Or
Proguanil 100 mg tab daily
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2-Chloroquine resistance is high
Mefloquine 250 mg week
(neuro psychiatric symptoms conductive disorders)
Or
Doxycyclin 100 mg daily
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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
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Corneal deposits:
Asymptomatic.
Halos around light.
Photophobia.
Reversible on stopping the treatment
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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
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Ophthalmoscope
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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
Hypotension
Disturbed AV conduction
Cardiac arrest