1. Antiviral Drugs

2. 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”

3. HIV-1

4. 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.

5. 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)

8. DNA-based viruses Resultant disease
Herpes simplex types 1, 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

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

10. 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.

11. 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.

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

14. 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.

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

16. 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

17. 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.

18. 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

19. Amantadine Metabolism
Well-absorbed, half-life 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

20. 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

21. 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

22. 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

23. Oseltamivir (Tamiflu)
Zanamivir (Relenza)

26. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

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

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

36. 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)

37. 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

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

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

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

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

43. Note similarity to 2-deoxythymidine: with iodxouridine base

44. 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 %; CSF - 50% (Acyclovir)

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

46. 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).

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

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

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

52. Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Lamivudine
Zidovudine
Didanosine
Stavudine

53. 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”

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

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

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

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

58. 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

59. “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.

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

61. 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).

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

63. Anti-Malarial Drugs

64. Life cycle of malarial parasite

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

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

68. 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

69. 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

70. 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”

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

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

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

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

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

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

77. 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

78. Ophthalmoscope

82. 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

83. Acute overdose of Quinine
Hypotension Disturbed AV conduction Cardiac arrest