Antivirals, antihelminths, antifungals

1. MBSM 713: BIOCHEMISTRY OF ANTI
MICROBIAL AGENTS
Lecture Three:
1.1.AntiviralsAntivirals
2.2.AntifungalsAntifungals
3.3.Antihelmitic drugsAntihelmitic drugs
Dr. G. Kattam Maiyoh
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3. Understanding VirusesUnderstanding Viruses
They are different from other MicrobesThey are different from other Microbes
Viral replicationViral replication
• A virus cannot replicate on
its own
• It must attach to and enter
a host cell
• It then uses the host cell’s
energy to synthesize DNA,
RNA and protein.
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4. Understanding VirusesUnderstanding Viruses
Viruses are
difficult to kill
because they live
inside the cells
• Any drug that kills
a virus MAY also kill
cells
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5. Anti-viral drugsAnti-viral drugs
• Certain viruses
multiply in the
cytoplasm but
others do in the
nucleus
• Most multiplication
take place before
diagnosis is made
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6. Anti-Viral drugs
• Many antiviral drugs are Purine or
Pyrimidine analogs.
• Many antiviral drugs are Prodrugs. They
must be phosphorylated by viral or cellular
enzymes in order to become active.
• Most anti-viral agents inhibits active
replication so the viral growth resumes
after drug removal.
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7. Antivirals how they act
Key characteristics of antiviral drugs
Able to enter the cells infected with virus
Interfere with viral nucleic acid synthesis and/or
regulation
Some drugs interfere with ability of virus to bind to
cells
Some drugs stimulate the body’s immune system
Best responses to antiviral drugs are in patients with
competent immune systems
A healthy immune system works synergistically with
the drug to eliminate or suppress viral activity
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8. Antiviral Medications
Antiviral drugs
 Used to treat infections caused by
viruses other than HIV
Antiretroviral drugs
 Used to treat infections caused by HIV,
the virus that causes AIDS
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9. Antiviral Drugs: Nonretroviral
Mechanism of action
 Inhibit viral replication (Does not necessarily mean
viral DNA replication.)
Used to treat non-HIV viral infections
 Influenza viruses
 HSV (herpes simplex virus), VZV (vericella zoster virus)
 CMV (cytomegalovirus)
 Hepatitis A, B, C (HAV, HBV, NCV)
Adverse Effects
 Vary with each drug
 Healthy cells are often killed also, resulting in serious toxicities
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10. Anti-viral drugs
• Current anti-viral agents do not eliminate non-
replicating or latent virus
• Effective host immune response remains
essential for the recovery from the viral
infection
• Clinical efficacy depends on achieving
inhibitory conc. at the site of infection within
the infected cells
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11. Anti-viral drugsAnti-viral drugs
Stages of viral replication
• Cell entry – attachment
- penetration
• Uncoating
• Transcription of viral genome
• Translation
• Assembly of virion components
• Release
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13. Anti-viral drugs
Anti-herpes virus agents
• Acyclovir / Valacyclovir
• Famciclovir / Penciclovir
• Ganciclovir / Cidofovir
• Foscarnet
• Trifluridine / Idoxuridine / Vidarabine
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14. • Valacyclovir is a prodrug of Acyclovir
with better bioavailability.
• Famciclovir is hydrolyzed to
Penciclovir and has greatest
bioavailability.
• Penciclovir is used only topically
whereas Famciclovir can be
administered orally.
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Features

15. PHARMACOLOGY OF
ACYCLOVIR AND
CONGENERS
• Acyclovir,
Valacyclovir,
Ganciclovir,
Famciclovir,
Penciclovir
• All are guanine
nucleoside analogs.
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16. Mechanism of action of Acyclovir and
congeners :
• All drugs are phosphorylated by a viral
thymidine-kinase, then metabolized by host
cell kinases to nucleotide analogs.
• The analog inhibits viral DNA-
polymerase
• Only actively replicating viruses are
inhibited
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17. • Acyclovir is thus
selectively activated
in cells infected with
herpes virus.
• Uninfected cells do
not phosphorylate
acyclovir.
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18. Mechanism of Action of Acyclovir
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19. Antiviral spectrum :
• Acyclovir: HSV-1, HSV-2, VZV, Shingles.
• Ganciclovir / Cidofovir : CMV
• Famciclovir : Herpes genitalis and shingles
• Foscarnet : HSV, VZV, CMV, HIV
• Penciclovir : Herpes labialis
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20. Pharmacokinetics of Acyclovir :
–Oral bioavailability ~ 20-30%
–Distribution in all body tissues including
CNS
–Renal excretion: > 80%
–Half lives: 2-5 hours
–Administration: Topical, Oral , IV
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21. Adverse effects of Acyclovir /
Ganciclovir
• Nausea, vomiting and diarrhea
• Nephrotoxicity - crystalluria,
haematuria, renal insufficiency
• Myelosuppression – Neutropenia and
thrombocytopenia – Ganciclovir
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22. Therapeutic uses :
Acyclovir is the drug of choice for:
• HSV Genital infections
• HSV encephalitis
• HSV infections in immunocompromised patient
Ganciclovir is the drug of choice for:
• CMV retinitis in immunocompromised patient
• Prevention of CMV disease in transplant patients
CMV = Cytomegalovirus is a serious eye infection
of the retina
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23. Cidofovir :
• It is approved for the treatment of CMV
retinitis in immunocompromised patients
• It is a nucleotide analog of cytosine – no
phosphorylation required.
• It inhibits viral DNA synthesis
• Available for IV, Intravitreal inj, topical
• Nephrotoxicity is a major disadvantage.
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24. PHARMACOLOGY OF FOSCARNET
• Foscarnet is an inorganic
pyrophosphate analog
• It directly inhibits viral DNA and RNA
-polymerase and viral reverse
transcriptase (it does not require
phosphorylation for antiviral activity)
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25. Foscarnet
• HSV-1, HSV-2, VZV, CMV and
HIV.
• Oral bioavailability ~ 10-20%
• Distribution to all tissues
including CNS
• Administration: IV
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26. Adverse effects of Foscarnet
• Hypocalcemia and hypomagnesemia (due
to chelation of the drug with divalent
cations) are common.
• Neurotoxicity (headache, hallucinations,
seizures)
• Nephrotoxicity (acute tubular nephrosis,
interstitial nephritis)
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27. Therapeutic uses of Foscarnet
• It is an alternative drug for
• HSV infections (acyclovir resistant /
immunocompromised patient )
• CMV retinitis (ganciclovir resistant /
immunocompromised patient )
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28. Respiratory viral infections
Influenza –
• Amantadine / Rimantadine
• Oseltamivir / Zanamavir
RSV bronchiolitis –
• Ribavirin
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29. Amantadine and Rimantadine :
Influenza
• Prevention & Treatment of influenza A
• Inhibition of viral uncoating by
inhibiting the viral membrane protein
M2
• Amantadine has anti-parkinsonian
effects.
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30. Pharmacokinetics of Amantadine
• Oral bioavailability ~ 50-90%
• Amantadine cross extensively
BBB whereas Rimantadine
does not cross extensively .
• Administration: Oral
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31. Neuraminidase inhibitors : Influenza
Oseltamivir / Zanamavir
• Influenza contains an enzyme neuraminidase
which is essential for the replication of the virus.
• Neuraminidase inhibitors prevent the release
of new virions and their spread from cell to cell.
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32. Neuraminidase inhibitors : Influenza
Oseltamivir / Zanamavir
• These are effective against both types of
influenza A and B.
• Do not interfere with immune response to
influenza A vaccine.
• Can be used for both prophylaxis and acute
treatment.
Administration
• Oseltamivir is orally administered.
• Zanamavir is given intranasal.
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33. Viru
s
Diseases
Drug(s) of
choice
Alternative
drugs
FLU
A
Influenza Amantadine
Rimantadine
RSV
Pneumonia,
bronchiolitis
Ribavirin
(aerosol)
HSV
Genital herpes Acyclovir Foscarnet
Keratitis
Conjunctivitis
Trifluridine
Idoxuridine
Vidarabine
Encephalitis Acyclovir
Neonatal HSV
infection
Acyclovir Vidarabine
Herpes infections in
immuno-
compromised host
Acyclovir Foscarnet
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34. VZV
In normal host No therapy
In immunocompro-
mised host, or during
pregnancy
Acyclovir Foscarnet
CMV Retinitis Ganciclovir Foscarnet
HIV
AIDS
HIV antibody
positive with CD4
count < 500/mm3
Zidovudine ±
protease
inhibitors
Didanosine,
Stavudine
HBV
HCV
Hepatitis B, C Interferons
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35. Antiretroviral Drugs
HAART - Highly active
antiretroviral therapy
• Includes at least
three medications
–“cocktails”
• These medications
work in different
ways to reduce the
viral load
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36. Antiretroviral Drugs
• Reverse transcriptase inhibitors (RTIs)
– Block activity of the enzyme reverse transcriptase, preventing
production of new viral DNA
• Include:
– Nucleoside RTIs (NRTIs)
– Nonnucleoside RTIs (NNRTIs)
– Nucleotide RTIs (NTRTIs)
• Examples
abacavir (Ziagen) delavirdine (Rescriptor)
didanosine (Videx) lamivudine (Epivir)
stavudine (Zerit) tenofovir (Viread)
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37. Antiretroviral Drugs
• Protease inhibitors (PIs)
– Inhibit the protease a
retroviral enzyme,
preventing viral replication
– Examples:
amprenavir (Agenerase)
indinavir (Crixivan)
nelfinavir (Viracept)
ritonavir (Norvir)
saquinavir (Invirase)
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38. Antiretroviral DrugsAntiretroviral Drugs
• Fusion inhibitors
– Inhibit viral fusion,
preventing viral
replication
– Newest class of
antiretroviral drugs
– Example: enfuvirtide
(Fuzeon)
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39. Antiretroviral Drugs
• Combinations of multiple antiretroviral
medications are common
• Adverse effects vary with each drug
and may be severe−monitor for dose-
limiting toxicities
• Monitor for signs of opportunistic
diseases
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40. Antiretroviral Drugs:Antiretroviral Drugs:
Adverse EffectsAdverse Effects
 Numerous and varyNumerous and vary
with each drugwith each drug
Drug therapy may need
to be modified because
of adverse effects
Goal is to find the
regimen that will best
control the infection
with a tolerable
adverse effect profile
 Medication regimens change
during the course of the illnessduring the course of the illness
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Antiviral DrugsAntiviral Drugs

41. ANTIFUNGAL DRUGS
Systemic & Topical
Some are fungistatic,
while others are fungicidal
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42. Fungal Infection in Humans =
Mycosis
Fungal Infection in Humans =
Mycosis
• Major Types of Mycoses
– superficial
– cutaneous
– subcutaneous
– systemic
– opportunistic
• Symptoms vary from cosmetic to life
threatening
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43. Antifungal Agents
• Polyene antibiotic
• The polyene antibiotics bind with sterols in the fungal cell
membrane, principally ergosterol. This causes the cell's
contents to leak out and the cell dies. Animal cells contain
cholesterol instead of ergosterol and so they are much less
susceptible.
– Nystatin
– Amphotericin B (may be administered liposomally)
– Natamycin
– Rimocidin
– Filipin
– Pimaricin
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44. Antifungal Agents
Imidazole and triazole
• The imidazole and triazole groups of antifungal drugs
inhibit the enzyme cytochrome P450 14α-
demethylase. This enzyme converts lanosterol to
ergosterol, and is required in fungal cell membrane
synthesis. These drugs also block steroid synthesis in
humans.
• Imidazoles:
• Miconazole Bifonazole
• Ketoconazole Butoconazole
• Clotrimazole Econazole
• Mebendazole Fenticonazole
• Isoconazole Oxiconazole
• Sertaconazole Sulconazole
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45. Antifungal Agents
• The triazoles are newer, and are less
toxic and more effective:
• Fluconazole
• Itraconazole
• Ravuconazole
• Posaconazole
• Voriconazole
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46. Antifungal Agents
Allylamines
• Allylamines inhibit the enzyme squalene
epoxidase, another enzyme required for
ergosterol synthesis:
– Terbinafine - marketed as Lamisil
– Amorolfine
– Naftifine
– Butenafine
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47. Antifungal Agents
Echinocandin
• Echinocandins inhibit the synthesis of
glucan in the cell wall, probably via the
enzyme 1,3-β glucan synthase:
– Anidulafungin
– Caspofungin
– Micafungin
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48. Antifungal Agents
• Others:
–Flucytosine is an antimetabolite.
–Griseofulvin binds to polymerized microtubules
and inhibits fungal mitosis; It is derived from
the mold Penicillium griseofulvum.
–Fluocinonide
–Salicylic Acid (topical)
–Tinactin or Tolnaftate
–Potassium Iodide
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49. ANTHELMINTIC DRUGS
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50. Helminth Infections
1-Tapeworms ( cestodes)
Beef tapeworm / fish tapeworm
2- Intestinal round worms ( nematodes)
Ascaris, pinworm ,whipworm,
strongyloides, ancylostoma (
hookworm ).
A skin infection is termed cutaneous larva
migrans

51. Mechanism of action
• May act by causing :
• 1- paralysis of the worm.
• 2- damaging the worm leading to partial digestion or
rejection by immune mechanisms.
• 3- interfere with the metabolism of the worm.
*Worms or larvae live in tissues of host
body like muscles , viscera , menninges ,
subcutaneous tissues.

52. • Adult filariae live in the lymphatics,
connective tissue or mesentery of host and
produce live embryos or microfilariae, which
goes to blood stream.
• They are ingested by mosquitoes or similar
insects, they develop to larvae this secondary
host and pass to mouth parts of insect and
re-injected to humans

53. Ascaris lumbricoids ( common round worm)

54. ANTHELMINTIC DRUGS
ALBENDAZOLE
• Broad spectrum oral anthelmintic
• Drug of choice for treatment of hydatid
disease (tapeworm) and cysticercosis (pork
tapeworm)
• It is also used for the treatment of ascariasis
,tricurasis and strongyloidiasis, pinworm,
hookworm

55. Mechanism Of Action
1. Inhibits microtubule synthesis by binding to β –
tubulin.
2. Inhibits mitochondrial reductase causing reduced
glucose transport. Intestinal parasites are immobilized
and die slowly.
• Larvicidal in hydatid ,cysticercosis , ascariasis and
hook worm infections.
• Ovicidal in ascariasis, hookworm ,trichuriasis

56. Pharmacokinetics
• Formulated as Benzimidazole
carbamate
• Administered orally , absorption
increased with a fatty meal
• Metabolized in the liver to the active
metabolite called albendazole sulfoxide

57. Pharmacokinetics
• Plasma half life is 8-12 hours
• sulfoxide is mostly protein bound
distributes well to tissues and enters
bile,CSF & hydatid cysts.
• Metabolites are excreted in urine

58. Clinical uses
• Used on empty stomach when used against
intraluminal parasites but with a fatty meal when
used against tissue parasites.
1. In ascariasis ,trichuriasis ,hookworm, pin worm
infections :
2. Hydatid diseases

59. Albendazole (con’)
3. Neurocysticercosis:
Used with corticosteroid to decrease the
inflammation caused by dying organism and
it also reduces the duration of course for 21
days
4. Other infections: Drug of choice in
cutaneous and visceral larva migrans ,
intestinal capillariasis, giardiasis & taeniasis.

60. Adverse Effects
• In short term(1-3 days): Mild epigastric pain,diarrhea,
nausea, headache & insomnia.
• In long term use : for hydatid cyst and cysticercosis :
abdominal pain, headache ,fever ,fatigue, alopecia ,
increased liver enzymes , pancytopenia. Blood counts and
liver enzymes should be followed.
• Not given during pregnancy, hypersensitive people to
benzimidazole drugs & children under 2 years .

61. PYRANTEL PAMOATE
• Broad spectrum
• Pharmacokinetics:
– Poorly absorbed from GIT
– Half of the drug is excreted unchanged in the feces.
• Mechanism of action:
– result in paralysis of worms. It is a neuromuscular
blocking agent
Efficacy
– Very effective against luminal organisms( mature or
immature forms).
– Not effective against migratory stages in the tissues or
against ova

62. Clinical uses
• Pin worm given orally with or without food.
• Ascariasis
• Hookworm
Pinworm male ,female

63. Adverse Effects
Infrequent mild transient GI disturbance
– Drowsiness , headache ,insomnia.
– Rash ,fever
Contraindications & Cautions
– Should be used with caution in liver
dysfunction.
– Pregnancy
– Children under 2 years of age

64. PIPERAZINE
• Only recommended for the treatment of ascariasis
• Cure rate 90% for 2 days treatment.
• Readily absorbed orally and excreted mostly unchanged
in urine
• Mechanism of action:
Causes paralysis of ascaris by blocking acetylcholine at
myoneural junction , the live worms expelled by normal
peristalsis.
• Treatment
• Treatment is continued for 3-4 days or repeated after
one week in case of heavy infections.

65. Adverse Effects
• GI disturbance
• Neurotoxicity ,allergic reactions .
• Contraindications
• Epilepsy or a history of epilepsy
• Impaired liver or kidney functions
• pregnancy
• Chronic neurologic disease

66. NICLOSAMIDE
• Second-line drug for treatment of most
tapeworm infections.
• Mechanism of action:
• Adult worm( not ova) is rapidly killed by
inhibition of oxidative phosphorylation .
• Pharmacokinetics:
• Poorly absorbed from gut & excreted in urine.

67. Clinical Uses
• Treatment of most forms of tapeworms.
• Not effective against cysticercosis or hydatic
disease.
• Given in the morning on empty stomach.
• Purgative is necessary to purge all dead
segments& prevent liberation of ova.

68. Adverse effects &
Contraindications
• Mild ,infrequent and transitory GI disturbance
• Alcohol consumption should be avoided
• Not indicated in children under 2 years of age
or in pregnancy.

69. DIETHYL CARBAMAZINE
• Drug of choice for the treatment of filariasis and
tropical eosinophilia.
• Pharmacokinetics:
• Rapidly absorbed from gut
• Half- life is 2-3 hours
• The drug should be given after meals
• It is excreted in urine as unchanged or metabolite.
• Dosage is reduced in urinary alkalosis and renal
impairment.

70. Mechanism Of Action
• Immobilizes microfilariae and alters their
surface structure ,displacing them from tissues
& making them susceptible to destruction by
host defense mechanism
• It has immunosuppressive effects

71. Adverse Effects
• Fever , malaise, papular rash, headache, GI
disturbance,cough. Chest,muscle,joint pain
• Leucocytosis
• Retinal hemorrhage
• Encephalopathy
• lymphangitis and lymphadenopathy.
• *It is not teratogenic

72. Contraindications & Cautions
• * Hypertension
• * Renal disease
* Patient with lymphangitis

73. IVERMECTIN
• Drug of choice for treatment of
strongyloidiasis
• Macrocyclic lactone ring
• Given only orally
• Rapidly absorbed
• Does not cross BBB.
• Half- life is 16 hrs
• Excretion is mainly in feces.

74. Mechanism Of Action
• Acts on the parasitte,
s glutamate-gated Cl-
channel receptors . Chloride influx increased ,
hyperpolarization occurs , resulting in
paralysis of the worm.
Or
• Paralyze nematodes by intensifying GABA-
mediated transmission of signals in peripheral
nerves.

75. Clinical uses
• Drug of choice for cutaneous larva migrans &
strongyloidiasis.
• Onchocerciasis
• It is also used for scabies , lice .
• Filariasis.

76. Adverse Effects
• Fatigue ,dizziness, GI disturbance
• Killing of microfilaria result in a Mazotti
reaction ( fever, headache, dizziness,
somnolence, hypotension , tachycardia,
peripheral edema……).
• Corneal opacities & other eye lesions.

77. Contraindications & Cautions
• Concomitant use with other drugs that
enhance GABA
e.g Barbiturates, bnzodiazepines, valproic acid.
• pregnancy
• Meningitis
• Children under 5 years of age.

78. BITHIONOL
• Drug of choice for the treatment of
fascioliasis ( sheep liver fluke)
• Pharmacokinetics:
• It is orally administered and excreted in urine.

79. Adverse Effects
• GI disturbance ( N., V., D., A.)
Dizziness, headache
Skin rashes , urticaria, Leucopenia
• Contraindications and precautions:
Hepatitis , leucopenia
Used with caution in children under 8 years of age.