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Antimicrobial Therapy

Chemotherapeutic agent (drug): any chemical substance used in medical practice.

Fleming observation 1928!

Antibiotic: chemical substances produced by microorganisms that inhibits & destroys other microorganisms when used at low concentration. (synthetic drug or semisynthetic)

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• Properties that an AB should have (ideal drug):1. Selective toxicity: the drug should harm the microbe without

significant harm on the host. This means the toxic dosage level (the dose that causes damage to the host) should be much higher than the therapeutic dosage level (the dose needed to destroy the microbe).

To evaluate toxicity of the drug, chemotherapeutic index is used: the ratio between the conc. at which the drug causes harm to the host (toxic dose) & that at which it is required to be clinically effective (therapeutic dose)

2. Soluble in body fluids in order to penetrate body tissues

3. Should not be metabolized so quickly so that they are excreted before having time to exert their effect

4. Minimal side effects e.g allergy

5. Long shelf life with convenient storage conditions requirement & low cost

6. Stable in body fluids to have therapeutic activity over long hours.e.g oral drugs should withstand acidic environment of the stomach.

7. Has no significant effect on normal microflora

8. Resistance to it not easily acquired

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Broad spectrum Vs narrow spectrum antibiotics• Broad spectrum AB: effective against a wide range of

microorganisms of different taxonomic groups including G+ve & G-ve bacteria. e.g tetracycline

• Narrow spectrum AB: effective against small no. of microorganisms or single group e.g Penicillin

• If the microorganism is identified, use narrow spectrum AB, because narrow spectrum reduce the possibility of producing resistance in microorganism, also using broad spectrum will destroy microflora(normal flora). Normal flora is the indigenous microbes that live in/on the host & prevent the growth of infectious microbes.

• If the patient is seriously ill & the microbe is not identified, broad spectrum AB is useful in this case.

Modes of actionAntibiotics could have bactericidal effect (killing effect) or bacteriostatic

effect (inhibit bacterial growth) where in this case the host immune response destroys & eliminate the microbe.

5 major modes of action through which antibiotics act on microbes

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1. Inhibition of Cell wall synthesis2. Inhibition of protein synthesis3. Disruption of cell membrane4. Inhibition of nucleic acid synthesis5. Action as antimetabolite

• Cell wall inhibitors:Many bacteria & fungi have external rigid cell walls, while animal cells don’t, therefore antibiotics that disrupt cell wall synthesis will cause the bacteria cells to burst when present in low osmotic pressure in body fluids.

The main group of AB that act on cell wall is the beta lactams. So called due to presence of β-lactam ring. It includes penicillins, cephalosporins & others.

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� β-lactams are analogues to D-alanyl-D-alanine residue of the peptidoglycan chain which is the substrate for the enzyme transpeptidase. They bind irreversibly to transpeptidase & inhibit it from cross linking the peptidoglycan chains,

so the cell wall continues to form but become weaker, then the cell swells & lyses. • https://www.youtube.com/watch?v=qBdYnRhdWcQ

• PenicillinsThe 1st naturally isolated AB was benzylpenicillin or penicillin-G. Isolated from moldPenicillium notatum. It is administered

parenterally (IV or IM) because it is degradedby stomach acids. It is effective against G+ve

bacteria only because it is unable to penetrate G-ve cell wall.

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• Penicillin-V is naturally occurring, similar to Penicillin-G but is less acid labile i.e can be taken orally.

• Semisynthetic penicillins: they have the same nucleus of penicillin but with side chains added chemically.

– Ampicillin: acid stable with broader spectrum of activity than Penicillin-G, i.e acts on G-ve bacteria.

– Amoxicillin: acid stable, broad spectrum.– Carbenicillin, ticarcillin, Pipercillin: broad spectrum,

especially useful against Pseuodomonas infections. Used parenterally.

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• A problem that faces penicillins is that they are degraded by naturally occurring bacterial b-lactamase enzyme (a group of it called penicillinase) which breaks b-lactam ring & inactivates the drug.

• Some drugs are resistant to penicillinase:– Methicillin: semisynthetic, narrow spectrum (G+ve)used

for bacteria that are resistant to penicillin. In the past it was the ultimate solution for treating resistant bacteria mainly Staphylococcus aureus, until Methicillin Resistant Staph. aureus emerged (MRSA).

– Oxacillin: semisynthetic, narrow spectrum, G+ve, antistaphylococcal drug.

– Nafcillin: G+ve , Antistaphylococcal drug

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• To overcome the inactivation caused by β-lactamase, inhibitors to β-lactamase are given in combination with the drug e.g Clavulanic acid (Amoxicillin/Clavulanic acid= Augmentin ®)& tazobactam (Tazobactam/ piperacillin) effective against G+ve &G-ve including Pseudomonas). These inhibitors have no antimicrobial activity but increase the activity of antibiotics.

• Procaine penicillin is long acting, procaine slows excretion & prolongs duration.

• Penicillins generally are non toxic, but 1-5% of adults are allergic to them (penicillin allergy is rare among children), inextreme cases death may result from anaphylactic shock.

• Penicillins may be used prophylactically (to prevent infections) before surgeries.

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• Cephalosporins

• Naturally occurring ones produced from fungus Cephalosporium, have little antimicrobial action. Cephalosporins have broader specificity than penicillins & more resistance to β-lactamase. But still cephalosporins are degraded by cephalosporinase enzymes (a group of b-lactamases)

• Semisynthetic cephalosporins differ by their side chains. They are divided into generations (1st, 2nd, 3rd, 4thgeneration). When resistance appeared to old generations new generation was produced. The aim of these generations was to broaden spectrum of activity & to include many G-ve bacteria.

• In general, 1st generation have better activity against G+ve bacteria, • 2nd generation: more active on G-ve, some G+ve, more resistant to β-

lactamase• 3rd generation (with some exceptions) more G-ve activity, • 4th generation have both G+ve & G-ve activity (used for hospital

acquired infections)

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Antibiotic Route Spectrum

1st generation G +ve

Cephalexin (Keflex) Oral

Cephradine Oral

Cefadroxil (Duricef) Oral

Cefazolin Parenteral

2nd generation Broad spectrum (mainly G-ve)

Cefaclor (Ceclor) Oral

Cefuroxime (Zinnat) Oral

3rd generation

Cefixime (Suprax) Oral

Cefdinir Oral

Cefpodoxime (Cefodox) Oral

Cefotaxime (Claforan) P Very good G-ve, some G+ve

Ceftriaxone (Rocephin) P Very good G-ve, some G+ve

Ceftazidime (Fortum) P G-ve including Pseudomonas

4th generation G+ve, G-ve, Pseudomonas

Cefpirome, cefepime P

5th generation ? Skin & soft tissue infections, MRSA, Gram +ve, G -ve

Ceftaroline P

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• Ceftaroline : 5th generation??, active against MRSA for skin & soft tissue infections.

• Cephalosporins usually are not the first drugs considered in treatment of an infection, they are used when toxicity or allergy prevents the use of other drugs.

• Since Cephalosporins are structurally similar to penicillins, 4-15% of patients who are allergic to penicillins are also allergic to cephalosporins.

• Penicillins & cephalosporions exert their activity against growing bacteria

Other cell wall inhibitors

• Monobactam includes the drug Aztreonam• The β-lactam ring is alone not fused with other ring. It resists β-

lactamases, effective against G-ve bacteria including Pseudomonasaeruginosa, used for meningitis, UTI & kidney infections

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• CarbapenemsA group of β-lactams that are resistant to β-lactamase. e.gImipenem, meropenem (Meronem®).

Imipenem: active against G+ve & G-ve bacteria including Pseudomonas aerogenosa & Enterococcus. Usually coadministeredwith Cilastatin (Tynam®), (a compound which inhibits imipinemdegradation in kidneys, not needed with meropenem).

• Bacitracin: a mixture of polypeptide produced by Bacillus bacteria, has bactericidal activity. It inhibits cell wall synthesis by interfering with the molecules that carry peptidoglycan subunits across cell membrane to their site in the cell wall. It is highly effective against G+ve bacteria, but with high toxicity, therefore used topically (skin, mucus membranes)

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• Vancomycin (administered only IV in hospitals)

• A large complex glycopeptideproduced by soil actinomycetes. Its large size prevents its penetrationthrough G-ve pores in the outer membrane,

therefore, it is not effective against most G-ve bacteria.

• It acts by binding to the D-alanyl-D-alanine residue & forming a complex with it which inhibits peptidoglycan synthesis. It is effective against streptococci & Staphylococci & due to its toxicity used as last resort for organisms resistant to methicillin & cephalosporins e.gMRSA & enterococci.

• It was used for 40yrs without having resistance against it until strains of Vancomycin resistant Staphylococcus aureus (VRSA) emerged.

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It is the drug of choice for treating pseudomembranous colitis (enteritis with formation of false membranes on stool), an infection (super infection) by Clostridium difficile that results from the use of broad spectrum antibiotics

It is given IV. It is fairly toxic, causes hearing loss, kidney damage.

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•Protein synthesis inhibitors• These drugs act on bacterial ribosomes. Since bacterial ribosomes

are (30S+50S= 70S) while animal ribosomes are (60S+40S =80S), these antibiotics act selectively on 70S ribosomes.

• mRNA translation

(protein synthesis)

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• These drugs include many groups:

• Aminoglycosides: obtained from different species of Streptomyces & Micromonospora. They act on 30S subunit & interferes with mRNA translation.

• Aminoglycosides act synergistically with other drugs e.gcephalosporins, penicillins. Therefore in most cases are used in combination with other drugs.

• They have varying degree of toxicity to kidneys (damage kidney cells causing protein excretion) & (ototoxicity) inner ear (damaging 8th cranial nerve).

• They are active against G+ve & G-ve bacteria including Pseudomonas & Enterobacter.

• Due to their toxicity ,they are used in treating complicated infections (urinary tract infections, peritonitis -infection of the lining of abdomen-, joint & bone infections) or to treat bacteria resistant to other drugs

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• They are not absorbed in GIT, administered IV or IM or topically

They include:– Streptomycin: v. toxic causes damages to the kidneys & ringing

in the ear. Usually used in combination with other drugs to treat TB & plague.

– Neomycin – Kanamycin– Tobramycin– Gentamicin– Netilmicin– Amikacin: for hospital acquired infections resistant to other drugs

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�Tetracyclines: produced from Streptomyces species & some are semisynthetic. They act on 30S ribosomal subunit. They are absorbed from GIT.

• They have the widest spectrum of activity (G+ve, G-ve, mycoplasma)& can enter the cell host, therefore useful for intracellular infections (ricketssia & Chlamydia).

• Because of their wide spectrum, they destroy the intestinal normal flora causing severe GI disorders. Superinfections by Staphylococcus & Pseudomonas & yeast also occur.

• Tetracycline form complexes with calcium & become inactive, therefore milk & dairy product should not be taken. Due to reaction with Ca, they cause coloration to the teeth (under age of 5 or by mother during last half of pregnancy)& abnormal bone formation (abnormal skull of infants) if taken by pregnant women.

• Tetracyclines include– Tetracycline– Chlortetracycline– Minocycline– doxycycline

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tetracycline

macrolide

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• Tigecycline (approved 2005): belongs to new class of drugs, glycylcycline (a derivative of minocycline) inhibits proteins synthesis by binding to 30S ribosome. Has broad spectrum activity (Except Pseudomonas), mainly used against MRSA

• Chloramphenicol: it is bacteriostatic agent. Acts on 50S ribosomal subunit in a way to prevent amino acid assembly in a chain. Nowadays produced synthetically.

• It is broad spectrum (G+ve & G-ve excluding pseudomonas & enterococcus), but has serious side effect that it damages bone marrow which could be fatal. therefore, its use is considered as last choice when other effective agents are available. Its main use is to treat typhoid fever & to treat meningitis for patients with allergy to cephalosporins & penicillins.

�Macrolides:• A group of compounds have macrolide ring. They are bacteriostatic

agents. Act on 50S ribosomal subunit in a way to prevent amino acid assembly in a chain (elongation). They are readily absorbed.

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• They are active against most G+ve bacteria: streptococci, pneumococci, staphylococci, corynebacteria & also mycoplasma. Macrolides have variable activity against G-ve bacteria.

• Macrolides include:– Erythromycin: one of the safest commonly used drugs.– Roxithromycin– Azithromycin– Clarithromycin: a member of the triple therapy used to treat Helicobacter

pylori responsible for stomach & duodenal ulcers.

• Macrolides main use: for penicillin resistant infections & as alternative to penicillin for patients allergic to them.

• Very important for treating Legionnaires’ disease (pneumonia like disease) caused by Legionella pneumophila

� Lincosamides• Bacteriostatic agents, bind to 50S ribosomal subunit & inhibit polypeptide

elongation.

• Include Clindamycin & lincomycin. Clindamycin is less toxic than lincomycin.

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• Clindamycin is used to treat Bacteroids & other anaerobic bacteria except Clostridium defficile. Also used for G+ve cocci(except enterococci), in topical preparations for acne.

• Long term use of clindamycin causes pseudomembranous colitis due to toxins from Clostridium difficile

� Streptogramins• Relatively new drugs. A group of macromolecules produced by

streptomyces sp., includes Streptogramin A & B.

• Quinopristin/Dalfopristin (30/70 ratio): derivatives of Streptogramin B (Quinopristin) & Streptogramin A (Dalfopristin).

• Both interact with the ribosome at different sites & act synergistically to inhibit protein synthesis. Dalfopristin inhibits early stages of protein synthesis while quinopristin prevents polypeptide elongation & causes early release of the polypeptidechain.

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• Given IV. They are effective against G+ve bacteria resistant to other antibiotics including vancomycin.

• Used for life threatening infections caused by vancomycin resistant Enterococcus faecium (G+ve bacteria that cause skin, blood &abdominal infections), MRSA, & Streptococcus pyogenes.

� Disrupters of cell membrane• Animal cells have cell membranes that differ than bacterial or fungal

membranes, this allows for selective action of antibiotics.

• These drugs include:– Polyenes– Cyclic lipopeptides (polymyxins & Daptomycin)

� Polyenes:• e.g amphotericin B & Nystatin: they bind to certain sterols present in the

fungal membrane, but their therapeutic index is low.

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� Cyclic lipopeptides

• Polymyxins: designated A, B, C, D, E: are polypeptides act as detergent. (Polymexin E= colistin). They bind to the membrane phospholipids & cause distortion to it, thus, the cytoplasm & cell contents are lost. Since G-ve bacteria has outer membrane which is rich in phospholipids, polymyxins are especially effective against them.

– Causes serious side effects if taken systemically ( administered by injection & needs monitoring).

– Generally, they are used topically for skin infections caused by G-vebacteria like Pseudomonas, wounds & burns.

• Daptomycin:

– It is inserted into the cell membrane forming aggregates which results in membrane disruption and depolarization

– Active against G+ve bacteria (including multidrug-resistant strains such as VRE and MRSA). Given parenterally, but induce serious side effects

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�Nucleic acid synthesis inhibitors

– DNA synthesis inhibitors

• Quinolones: a group of synthetic AB, They act by inhibiting DNA gyrase, the enzyme which unwinds DNA double helix preparing it to replication, thus inhibiting DNA synthesis.

• The basic drug of this group is Nalidixic acid, the majority of drugs in clinical use belong to the subgroup, fluoroquinolones, e.g ciprofloxacin, norfloxacin, enoxacin.

• They are active against G+ve & G-ve bacteria including Pseudomonas aeuroginosa. Used mainly for traveler’s diarrhea & urinary tract infections caused by multipley resistant bacteria

• Levofloxacin: new generation (3rd generation). Used mainly for community acquired pneumonia, sinusitis & acute exacerbations of chronic bronchitis

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• Inhibitors of nucleic acid synthesis

• Rifampin/Rifampicin: a semisynthetic drug belongs to Rifamycins (produced by Streptomyces sp).

• Rifampin binds to RNA polymerase & blocks mRNA synthesis. It penetrates tissues therefore used against Mycobacteria to treat TB as part of the cocktail treatment.

• Unlike other antibiotics, it interacts with other drugs reducing or nullifying their effect like oral contraceptives, anticoagulants & the reason is that it stimulates liver enzymes that metabolize these drugs.

• At high doses it turns the secretions like tears, sweat, saliva, breast milk & urine to orange red color, even the skin, this is called red man syndrome. Also high doses result in liver damage.

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�Antimetabolites• A group of compounds that are structurally similar to

normal microbial metabolites, therefore they interfere with microbial metabolic reactions. They act by 2 ways:

– Competitive inhibition to the enzyme. They resemble the substarte of metabolic enzyme, thus they bind to the active site of the enzyme & prevent the substrate of the enzyme from binding, this slows or ceases the metabolic reaction.

– By being incorporated into important molecules (e.gnucleic acids), thus inhibiting their function.

• Antimetabolites include:– Antifolates (sulfa drugs & trimethoprim)– Purines analogues – Pyrimidines analogues

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• Sulfonamides (sulfa drugs): a group of synthetic compounds that are bacteriostatic, the first one known Sulfanilamide.

• They act by competitive inhibition to the enzymes that acts on Para amino benzoic acid needed for folic acid, which is important for synthesizing nucleic acids & other metabolic products. Sulfonamides are chemically similar to (PABA).

• When sulfonamides rather than PABA bind to the enzyme, the bacterium can not make folic acid. Animal cells can not produce folic acids & should obtain it from diet, on the other hand, bacteria can not use folic acid from diet & should synthesize it, thus sulfonamides are selective in activity.

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sulfanilamide PABA

• Used to treat some kinds of meningitis as they pass cerebrospinal fluid easily.

• e.g sulfamethoxazole & sulfadiazine. These are usually given in combination with Trimethoprim (sulfa powder used in world war II).

• Cotrimoxazole is a combination of sulfamethoxazole & Trimethoprim. Trimethoprim inhibits another enzyme in the pathway of synthesizing folic acid.

NH2

COOH

NH2

SO2NH2

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• Cotrimoxazole (Bactrim®,Septrin ® ):used for urinary tract infections& considered drug of choice for Pnemocystis pneumonia(fungal complication of AIDS patients). Both drugs are toxicto bone marrow .

• Trimethoprim-sulfonamides are broad spectrum effective against most G-ve bacteria & skin Staphylococci.

• Isoniazid: also called isonicotinyl hydrazine (INH) antimetabolite for 2 vitamins nicotinamide (niacin) & Vit B6 (pyridoxal). It binds to the enzymes that converts the vitamins to other molecules. This results in inhibiting the synthesis of mycolic acid a component of Mycobacteriacell wall (responsible for acid fastness).

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• Isoniazid is absorbed from GIT & reaches all body tissue &fluids. It is effective against Mycobacteria & has little effect on other bacteria. As such it is inactive (prodrug) & should be transformed by bacterial enzyme to the active form.

• Resistant mycobacteria does not produce the activating enzyme thus INH remains inactive. Since resistance to INH is high, it is usually given in combination with other 2 or 3 drugs e.g Rifampin & ethambutol.

• Nitrofurans: synthetic drug. Interferes with bacterial respiration. Nitrofurantoin, used for UTI,

• Ethambutol:• It inhibits cell wall synthesis of mycobacteria. Since

resistance to it emerges rapidly, it is used in combination with other drugs for TB treatment

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Antifungal agents• Since fungi & human cells are eukaryotes, these drugs cause toxic

side effects. Their use is increasing due to emergence of resistant strains & to the increase in immunosuppressed patients, especially AIDS patients.

• Imidazoles & triazoles

imidazole triazole• These form a large group of fungicides. Imidazoles (e.g clotrimazole,

ketoconazole, miconazole) & Triazoles e.g fluconazole, voriconazole.

• These drugs interfere with plasma membrane of the fungus by disrupting the synthesis of membrane sterols.

• Ketoconazole & fluconazole are used orally to treat systemic fungal infections.

N

NNN

N

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• Voriconazole (new drug given orally & IV) activity is compared to amphotericin B used for aspergillosis & candidemia(candida in blood).

• Imidazoles & triazoles are used topically to control skin infections (dermatomycoses) & Candida skin infections.

• Polyenes: family of antifungal agents that has at least 2 double bonds, e.g Amphotericin B & Nystatin.

• Amphotericin B: derived from Streptomyces sp., it binds to a sterol (ergosterol) present in fungal plasma membrane & some protozoa but not humans. Amphotericin B thus increases permeability of plasma membrane & causes leak of glucose, potassium & other substances from the cell.

• It is the drug of choice to treat most systemic fungal infections like aspergillosis, coccidioidomycosis & cryptococcosis (fatal fungal infection)

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• Amphotericin B has poor absorption so it is given IV. It has many side effects some are severe like kidney damage, depression anemia & blindness.

• Nystatin: same mode of action like amphotericin B, but also used topically to treat Candida yeast skin infections. Since it is not absorbed from intestines, it is given orally to treat fungal superinfection in intestines.

• Griseofulvin: it interferes with fungal mitosis by disrupting

the mitotic spindle used in cell division. It is given orally to treat skin, nails & scalp infections. Treatment may take from 4wks to 1year if the infection was recalcitrant associated with fingernails or toenails.

• it is not effective against most systemic fungal infections.• Due to its mode of action could be potential drug for cancer.

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• Flucytosine: in the body it is transformed to fluorouracil, an analogue of uracil, therefore it interferes with nucleic acid & protein synthesis. It is less toxic than Amphotericin B & its use should be considered instead of Amphotericin B whenever possible.

• Tolnaftate: a topical fungicide, available OTC. Used for fungal skin infections like athlete’s foot (flaking, itching & scaling).

• Terbinafine: relatively new fungicide for topical infections & cutaneous candidiasis. It is absorbed through skin & reaches therapeutic levels faster than the orally administered griseofulvin

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Antiviral agents• The difficulty in finding antiviral drugs is that the drug should attack

viruses inside cells without affecting host cell.

• Antiviral agents act by interfering on some phase of viral replication but they don’t kill viruses.

� Purines & pyrimidines analoguesThese agents are considered anti-metabolites because they are similar to purines & pyrimidinesof nucleic acids so the virusincorporate wrong information (the analogue) into nucleic acid leading to incorrect base pairing thus,

interfering with its replication.

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• Pyrimidines analogues: Idoxuridine & trifluridine.

– Both drugs are analogues of thymine, used in eye drops to treat infection of the cornea by herpesvirus. Not used internally due to toxicity (suppress bone marrow).

• Azidothymidine =Zidovudine (AZT): analogue of thymine. It interferes with reverse transcriptase the enzyme which synthesizes DNA from RNA e.g HIV virus. It is one of the first drugs approved for treating HIV.

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• Purines analogues include Vidarabine, Ribavirin, Acyclovir, Ganciclovir.

• Vidarabine: Analogue of adenine. Used to treat viral encephalitis (inflammation of the brain) caused by herpesviruses or cytomegaloviruses.

• Ribavirin: analogue of guanine. Blocks viral replication. Has activity against wide range of unrelated viruses which makes it potential broad spectrum antiviral drug. Used in aerosol for influenza viruses, in ointments to heal herpes lesions. Also used with interferons to treat Hepatitis C. Has low toxicity but may induce birth defects.

• Acyclovir: analogue of guanine. Used topically, orally & IV. It is most commonly used to treat herpes simplex virus infections, HV 1, 2 (cold sores, genital herpes) & herpes zoster virus (shingles). Effective in reducing pain & promoting healing of genital herpes lesions. – It doesn’t prevent establishment of latent virus in the nerve cells– It is more effective than vidarabine against herpes encephalitis.

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• Shingles Shingles

Cold sores

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– Acyclovir has 100 times more affinity to viral DNA polymerase than to the human one (therefore it is less toxic than other analogues), so it interacts with the virus DNA polymerase & blocks its action.

• Ganciclovir: analogue to guanine, similar to acyclovir. Active against several herpes viruses mainly cytomegalovirus eye infections in AIDS patient.

� Amantadine: tricyclic amine, it is used to treat Parkinson disease in addition to its antiviral activity although mechanism of actions are not related.

Amantadine prevents Influenza A virus from entering the host cell by interfering with viral protein. It is given orally & should be given days to a week earlier before the exposure to the virus. It has many side effects.

� Rimantadine: similar to amantadine but with less side effects.

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�Antiprotozoan agents• Drugs used to treat infections caused by protozoa. Protozoa are

unicellular animal like organisms.• Examples: giardia, amoeba, plasmodium, leishmania, toxoplasma

• Giradiasis: (transmission by fecal-oral route); caused by Giardia lamblia;complications: gastrointestinal disorders (irritable bowel syndrome, biliary tract dysfunction).

• Amoebiasis: (transmission: fecal-oral route); caused by Entamoebahistolytica; severe form is amoebic dysentery characterized by severe diarrhea, abdominal pain, loss of appetite, wt loss. May reach the liver & form abscess.

• Malaria (caused by plasmodium)

• Leishmaniasis: (transmitted by sand fly) caused by Leishmania. It results in skin lesions& ulcers (cutaneous form), mucucutaneous forms causes deformation to the affected region, visceral form leads to death.

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• Antimalarial drugs• Malaria is caused by Plasmoidum vivax, P. ovale, P. malariae; P. falciparum (the most deadly one) • Occurs in more than 100 countries throughout Africa, Asia, Latin America.• 2-3 billion inhabitants at risk • 300-500 million clinical cases • 1-2 million per year• It affects cardiovascular system (hypotension, tachycardia, P falciparum causes blocking in heart capillaries), Anemia; GI: nausea vomiting; pulmonary system; blood; kidneys, enlargementof liver& spleen & other serious effects.

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• Quinine: from the bark of cinchona trees. The first effective drug for malaria, used for centuries. Nowadays used to treat malaria resistant to other drugs.

• Chloroquine & Primaquine: synthetic drugs, most widely used antimalarial drugs.

• Chloroquine:– it enters red blood cells & accumulates in the parasite

vacuole & interferes with protozoan enzyme that convert heme (toxic to the parasite) to nontoxic molecule, thus, toxic heme will accumulate in the parasite.

• Primaquine: is essential co-drug with chloroquine. It is effective against dormant forms in tissue. It is given in combination with chloroquine as prophylaxis to people visiting places where malaria occurs.

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• Mefloquine: antimalarial drug, effective against resistant strains of parasite (falciparum malaria).

• Pyrimethamine: interferes with folic acid synthesis needed for purines & pyrimidine synthesis. Used in combination with sulfa drugs (2 step blockage of folic acid synthesis) to treat some resistant forms of malaria & for some protozoan infections like toxoplasmosis.

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