Lecture 03.2014

MBSM 713: BIOCHEMISTRY OF ANTI MICROBIAL AGENTS

Lecture Three:

1.1.AntiviralsAntivirals

2.2.AntifungalsAntifungals

3.3.Antihelmitic drugsAntihelmitic drugs

Dr. G. Kattam Maiyoh

01/23/15

GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC03

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Understanding VirusesUnderstanding VirusesThey 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.


Understanding VirusesUnderstanding Viruses

Viruses are difficult to kill because they live inside the cells• Any drug that kills a virus MAY also kill cells


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


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.


Antivirals how they act Key characteristics of antiviral drugsAble to enter the cells infected with virusInterfere with viral nucleic acid synthesis and/or

regulationSome drugs interfere with ability of virus to bind to

cellsSome drugs stimulate the body’s immune systemBest responses to antiviral drugs are in patients with

competent immune systemsA healthy immune system works synergistically with

the drug to eliminate or suppress viral activity


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


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


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


Anti-viral drugsAnti-viral drugs

Stages of viral replication• Cell entry – attachment

- penetration • Uncoating• Transcription of viral genome• Translation • Assembly of virion components• Release



Anti-viral drugs

Anti-herpes virus agents• Acyclovir / Valacyclovir• Famciclovir / Penciclovir • Ganciclovir / Cidofovir • Foscarnet • Trifluridine / Idoxuridine / Vidarabine


• 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.


Features

PHARMACOLOGY OF ACYCLOVIR AND CONGENERS

• Acyclovir, Valacyclovir, Ganciclovir, Famciclovir, Penciclovir

• All are guanine nucleoside analogs.


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


• Acyclovir is thus selectively activated in cells infected with herpes virus.• Uninfected cells do

not phosphorylate acyclovir.


Mechanism of Action of Acyclovir


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


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


Adverse effects of Acyclovir / Ganciclovir • Nausea, vomiting and diarrhea • Nephrotoxicity - crystalluria,

haematuria, renal insufficiency• Myelosuppression – Neutropenia and

thrombocytopenia – Ganciclovir


Therapeutic uses :Acyclovir is the drug of choice for:• HSV Genital infections• HSV encephalitis • HSV infections in immunocompromised patientGanciclovir 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


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.


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)


Foscarnet • HSV-1, HSV-2, VZV, CMV and

HIV.• Oral bioavailability ~ 10-20%• Distribution to all tissues

including CNS• Administration: IV


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)


Therapeutic uses of Foscarnet • It is an alternative drug for• HSV infections (acyclovir resistant /

immunocompromised patient )• CMV retinitis (ganciclovir resistant /

immunocompromised patient )


Respiratory viral infectionsInfluenza –• Amantadine / Rimantadine• Oseltamivir / Zanamavir

RSV bronchiol it is –• Ribavirin01/23/15 GKM/KISIIU/MBSM713

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Amantadine and Rimantadine : Influenza• Prevention & Treatment of influenza A• Inhibit ion of viral uncoating by

inhibiting the viral membrane protein M2• Amantadine has anti-parkinsonian

effects.


Pharmacokinetics of Amantadine

• Oral bioavailability ~ 50-90%• Amantadine cross extensively

BBB whereas Rimantadine does not cross extensively . • Administration: Oral


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.


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.


Virus

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 IdoxuridineVidarabine

Encephalitis

Acyclovir

Neonatal HSV

infection

Acyclovir

Vidarabine Herpes infections in

immunocompromised host

Acyclovir

Foscarnet01/23/15 GKM/KISIIU/MBSM713

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VZV

In normal host

No therapy

In immunocompro-mised host, or during pregnancy

Acyclovir

Foscarnet

CMV

Retinitis

Ganciclovir

Foscarnet

HIV

AIDSHIV antibody positive with CD4 count < 500/mm3

Zidovudine ± protease inhibitors

Didanosine,Stavudine

HBVHCV

Hepatitis B, C

Interferons


Antiretroviral DrugsHAART - Highly active

antiretroviral therapy

• Includes at least three medications– “cocktails”

• These medications work in different ways to reduce the viral load


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)

• Examplesabacavir (Ziagen) delavirdine (Rescriptor)didanosine (Videx) lamivudine (Epivir)stavudine (Zerit) tenofovir (Viread)


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)


Antiretroviral DrugsAntiretroviral Drugs• Fusion inhibitors– Inhibit viral fusion,

preventing viral replication

– Newest class of antiretroviral drugs

– Example: enfuvirtide (Fuzeon)


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


Antiretroviral Drugs:Antiretroviral Drugs:Adverse EffectsAdverse Effects

Numerous and vary Numerous 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


Antiviral Drugs Antiviral Drugs

ANTIFUNGAL DRUGS

Systemic & Topical

Some are fungistatic, while others are fungicidal

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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


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


Antifungal AgentsImidazole 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 • Thiabendazole Tiaconazole 01/23/15 60GKM/KISIIU/MBSM713

/BIOC.AMIC.AGENS.LEC03

Antifungal Agents

• The triazoles are newer, and are less toxic and more effective:• Fluconazole • Itraconazole • Ravuconazole • Posaconazole • Voriconazole


Antifungal Agents

Allylamines• Allylamines inhibit the enzyme squalene

epoxidase, another enzyme required for ergosterol synthesis:– Terbinafine - marketed as Lamisil – Amorolfine – Naftifine

– Butenafine


Antifungal AgentsEchinocandin• Echinocandins inhibit the synthesis of

glucan in the cell wall, probably via the enzyme 1,3-β glucan synthase:– Anidulafungin – Caspofungin

– Micafungin


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


ANTHELMINTIC DRUGS


Helminth Infections1-Tapeworms ( cestodes)

Beef tapeworm / fish tapeworm2- Intestinal round worms ( nematodes)

Ascaris, pinworm ,whipworm, strongyloides, ancylostoma ( hookworm ).

A skin infection is termed cutaneous larva migrans

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.

• 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

Ascaris lumbricoids ( common round worm)

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

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

Pharmacokinetics

• Formulated as Benzimidazole carbamate• Administered orally , absorption

increased with a fatty meal• Metabolized in the liver to the active

metabolite called albendazole sulfoxide

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

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

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.

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 .

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

Clinical uses

• Pin worm given orally with or without food.

• Ascariasis • Hookworm

Pinworm male ,female

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

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.

Adverse Effects• GI disturbance

• Neurotoxicity ,allergic reactions .

• Contraindications

• Epilepsy or a history of epilepsy

• Impaired liver or kidney functions

• pregnancy

• Chronic neurologic disease

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.

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.

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.

DIETHYL CARBAMAZINE

• Drug of choice for the treatment of filariasis and tropical eosinophilia.


• 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.

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

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

Contraindications & Cautions

• * Hypertension

• * Renal disease

* Patient with lymphangitis

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.

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.

Clinical uses

• Drug of choice for cutaneous larva migrans & strongyloidiasis.

• Onchocerciasis

• It is also used for scabies , lice .

• Filariasis.

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.

Contraindications & Cautions

• Concomitant use with other drugs that enhance GABA

e.g Barbiturates, bnzodiazepines, valproic acid.

• pregnancy

• Meningitis

• Children under 5 years of age.

BITHIONOL

• Drug of choice for the treatment of fascioliasis ( sheep liver fluke)


• It is orally administered and excreted in urine.

Adverse Effects

• GI disturbance ( N., V., D., A.)Dizziness, headacheSkin rashes , urticaria, Leucopenia

• Contraindications and precautions:Hepatitis , leucopeniaUsed with caution in children under 8 years of age.

Health & Medicine

Lecture 03.2014