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61 Cards in this Set

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Explain Aminoglycosides
Aminoglycosides (Amikacin, Tobramycin) act synergistically with penicillins.

They inhibit protein synthesis by binding to the 30s ribosomal subunit, causing misreading of the mRNA. They are a broad-spectrum bacteriocidal antibiotic.

They are not orally active b/c they are not abosrbed by the GIT. They can cause nephrotoxicity, ototoxicity, and neuromuscular blockade.

Their concentrations in the renal cortex are much higher than in the serum.

Resistance includes: Ribosomal alteration (30s), production of inactivating enzymes (encoded by R factors), and inhibition of active transport. Amikacin is the least susceptible and is used to treat resistant gram-negative bacteria.
Explain Tetracyclines
Tetracyclines are inhibitors of protein systhesis by binding to the 30s subunit thus blocking the binding of the tRNA, stopping protein synthesis.

Tetracycline is a YELLOW compound due to a phenolic diketone system in their chemical structure. They are amphoteric, meaning both acidic and basic functional groups are present.

Tetracyclines are a broad-spectrum bacteriostatic antibiotic. They absorb light and Demeclocycline is the most phototoxic. They bind to calcium and can cause yellowing of the teeth.

They should not be taken with antacids, iron supplements, or dairy products.

They can cause superinfections (due to being broad-specturn), nephrotoxicity, hepatotoxicity, and GI irritation.

Mechanisms of resistance include: Ribosomal alteration, Decreased cellular premeability, nad increased active efflux.
Explain Macrolides
Macrolides (Erythromycin, Azithromycin) inhibit bacterial protein synthesis by binding to the 50s subunit.

Macrolides are medium-spectrum bacteriostatic antibiotics. They are well distributed through out the body but do not enter the CSF.

All macrolides (except Dirithromycin) are potent inhibitors of cyt. P450, which will increase other drugs concentrations.

Erythromycin must be either enteric coated or salt based to be given orally.

Macrolides may cause superinfections (PMC), hepatotoxicity, and GI upset. Pregnant women should not take Clarithromycin.
Explain Lincosamides
Lincosamides (Clindamycin) are inhibitors of protein synthesis by binding to the same 50s subunit as macrolides causing cross-resistance.

Lincosamides are a narrow-spectrum bacteriostatic antibiotic. Clindamycin is the best to use b/c it causes less GI upset and food does not interfere with absorption.

Toxicities include: hepatotoxicity and GI irritation (colitis).
Explain Chloramphenicol
Chloramphenicol inhibits protein synthesis by binding to a 50s subunit near the site of action of macrolides/lincosamides, causing cross-resistance. (The combination of the two would be antagonistic)

Chloramphenicols are broad-spectrum bacteriostatic antibiotics.

Toxicities include: bone-marrow depression, immunosuppression, alpastic anemia (could be fatal), inhibition of Vitamin K, and alcohol intolerance.

It can cuase Gray Baby Syndrome, and is contraindicated in patients with hepatic dysfunction and neonates b/c they cannot metabolize the drug.
Explain Streptogramins
Streptogramins (Quinupristin & Dalfopristin) (Synercid) are inhibitors of protein systhesis by binding to the 50s subunit.

Quinupristin (streptogramin B) binds at the same site as the macrolides and lincosamides (cross-resistance). Dalfopristin (Streptogramin A) binds at a site nearby, resulting in a conformational change in the 50s ribosome, synergistically enhancing the binding of quinupristin at its target site. The net result of the two binding is a bactericidal effect.

Streptogramins are used to treat Vancomycin-resistant Enterococcus faecium infections (VREF). The combination is an inhibitor of CYP3A4 isoenzyme increasing the effect of other drugs.

Toxicities include: Nausea Vomiting Diarrhea, PMC, rash, arthralgia/myalgia, and venous irritation and pain at infusion site.

Resistance to quinupristin includes: The production of a ribosomal methylase that prevents binding of the drug to its target (by placing an AA in the binding site of the receptor) (similar to the main resistance mechanism against erythromycin). And the production of lactonases the are capable of inactivating quinupristin.

Resistance to dalfopristin includes: The production of acetyltransferases that are capable of inactivating dalfopristin and other type A streptogramins. And the production of ATP-binding efflux proteins that pump type A streptogramins out of the cell. (these pumps are nonspecific).

Resistance genes are located on plasmids. Resistance to quinupristin/dalfopristin is always associated with a resistance gene for type A streptogramins. Genes encoding resistance to type B may also be present, but are not sufficient to produce resistance alone. Methylase-encoding genes, however, can render the combination bacteriostatic instead of bactericidal, rendering it ineffective in certain infections in which bactericidal activity is necessary for cure, such as endocarditis.
Explain Oxazolidinones (Linezolid)
Linezolid (Zyvox) inhibits protein synthesis by binding to the 50s subunit, inhibiting the formation of the 70s complex.

Linezolid is a bacteriostatic antibiotic that is active mainly against gram-POSITIVE bacteria. It is indicated for the treatment of VREF and community-acquired pneumonia.

Toxicities include PMC and thrombocytopenia. Linezolid is a MAOI and has potential interactions with adrenergic and serotonergic agents.

Resistance to linezolid is due to mutation of the ribosomal binding site (target modification).
Explain Rifamycins
Rifamycins (Rifampin, Rifabutin, Rifapentine) are inhibitors of Nucleic Acid Synthesis. They inhibit RNA synthesis in bacterial cells by inhibiting bacterial DNA-dependent RNA polymerase (they do not inhibit the mammalian enzyme)(making them very selective).

Rifamycins are medium-spectrum bactericidal antibiotics. They are highly conjugated and orange-red in color.

They are indicated for the prevention and/or treatment of mycobacterial infections (TB; atypical mycobacterial infections). And there is NO cross-resistance with other drugs.

Toxicities include: discoloration of urine, hepatotoxicity, skin rash, and GI upset.

Rifamycins are INDUCERS of cyt. P450 (Rifampin and Rifapentine are potent, Rifabutin is less potent). As a result they decrease blood levels of other drugs.
Explain Quinolones
First generation quinolones are only used to treat UTI's. Secong generation fluoroquinolones (ciprofloxacin) are used to treat systemic infections (mycobacterial infections: TB).

Quinolones inhibit DNA synthesis in bacterial cells. They inhibit DNA Gyrase in Gram-Negative bacteria, and Topoisomerase IV in Gram-Positive. Quinolones are bacteriacidal.

Quinolones should not be taken with Calcium due to decreased bioavailability. Quinolones have the potential to cause Arthropathy, a chronic degenerative disease of the joints, and are not recommended for use in pregnant women and children under the age of 16.

Phototoxicity is more common with Sparfloxacin and Lomefloxacin than with other fluoroquinolones. Patients should avoid sunlight and artificial UV-light. Quinolones are inhibitors of cyt. P450 enzymes in the liver and have been reported to increase blood levels of Theophylline, Digoxin, Caffeine, Warfarin, and Cyclosporine.

Resistance to Quinolones include: Expression of an altered DNA Gyrase or Topoisomerase IV with low binding affinity to the drug. Active efflux of the drug.
Explain Polymyxins
Polymyxins/Gramicidins are disruptors of bacterial cell membrane permeability. They bind to phospholipids of the outer membrane of Gram-negative bacteria, penetrating the cell wall through porin channels. Once inside they act as cationic detergents.

Polymyxins are not active against Gram-positive bacteria, Gram-negative cocci (N. gonorrhea, N. meningitides), and fungi. They are not absorbed from the GIT and they are rarely administered parenterally (IM, IV, or Intrathecal) to treat severe systemic infections caused by susceptible Gram-negative bacteria.

They are nephrotoxic and neurotoxic when administered parenterally. They should not be used with other nephrotoxic or neurotoxic agents
Explain Daptomycin
Daptomycin (Cubicin) is a bacteriocidal lipopeptidolactone antibiotic.

Daptomycin binds to bacterial membranes and causes a rapid depolarization of membrane potential; this leads to inhibition of bacterial protein, DNA, and RNA synthesis. They also inhibit lipoteichois acid, found in the outer membranes of Gram-Positive bacteria.

Daptomycin is used for the treatment of serious Gram-positive bacterial infections. It is administered as an IV infusion. Because of its unique mode of action, daptomycin retains potency against Gram-positive bacteria that are resistant to other antibiotics including methicillin, vancomycin, and linezolid.

Possible toxicities include: superinfection (e.g., pseudomembranous colitis, Candida infections), peripheral or cranial neuropathy, and muscle pain or weakness.
Explain Sulfonamides
1. Short-Acting Sulfonamides with a serum half-life of 5-9 hours (e.g., sulfisoxazole, sulfamethizole).

2. Intermediate-Acting Sulfonamides with a serum half-life of 10-17 hours (e.g., sulfadiazine, sulfamethoxazole).

3. Long-Acting Sulfonamides with a serum half-life of 7-9 days (e.g., sulfadoxine).

4. Poorly Absorbed Sulfonamides (active in bowel lumen; e.g., sulfasalazine).

5. Topical Sulfonamides (e.g., sulfacetamide, silver sulfadiazine, mafenide acetate). (Used to treat skin infections)

Sulfonamides are structural analogs and competitive antagonists of p-aminobenzoic acid (PABA), thus preventing normal bacterial utilization of PABA for the synthesis of folic acid. They are competitive inhibitors of Dihydropteroate Synthase, the bacterial enzyme responsible for the incorporation of PABA into dihydropteroic acid, the immediate precursor of folic acid.

Sulfonamides are bacteriostatic antibiotics and are usually administered with sodium bicarbonate to help increase urine pH. Increasing urine pH helps decrease the formation of crystalluria, since the metabolized form (N4-acetates) of sulfonamides are less soluble in urine.

Sulfonamides are readily absorbed from the GIT and have a wide range of bacteriostatic activity against Gram-Positive and Negative bacteria. However they are rarely used as single agents.

Toxicities include: Hemolytic anemia (individuals with a genetic deficiency in glucose-6-phosphate dehydrogenase enzyme). Aplastic anemia, Agranulocytosis.

Resistance to Sulfonamides include: Expression of altered dihydropteroate synthase with lower affinity. Decreased bacterial permeability / Active efflux. Developing an alternative pathway for the synthesis of THF (using folic acid of host cell). Increased production of PABA.
Explain Trimethoprim
Sulfamethoxazole & Trimethoprim (Bactrim or Septra) act on sequential steps in the pathway of THF, therfore they are synergistic.

Trimethoprim is a potent and selective competitive inhibitor of microbial Dihydrofolate Reductase (DHFR), the enzyme that reduces dihydrofolic acid to tetrahydrofolic acid (THF).

Trimethoprim is usually 20 to 100 times more potent than sulfamethoxazole. Therefore to achieve destruction of the greatest number of bacterial species, the most synergistic concentration ratio of the two drugs in the combination is 20:1 (sulfamethoxazole : trimethoprim). Trimethoprim does cross into the CSF, middle ear fluid, and placenta.

Trimethoprim (in Bactrim®) can cause leukopenia, megaloblastosis, and thrombocytopenia in patients with folate deficiency due to inhibition of human DHFR. In addition, Bactrim® may cause permanent renal damage in patients with renal disorders.

Although resistance is lower than it is to either of the agents alone. Resistance is often due to the acquisition of a plasmid that encodes for an altered DHFR.
Explain Polyene Antifungal Antibiotics
Two polyene antifungal antibiotics are used to treat fungal infections: Amphotericin B and Nystatin. Only amphotericin B is used parenterally to treat systemic fungal infections. Nystatin is too toxic for parenteral administration; it is used only topically.

Polyene antibiotics are large water-insoluble amphoteric (can react as either an acid or base) molecules.

They are fungicidal and are active against yeast infections. The presence of conjugated trans double bonds in these molecules has been associated with increased potency and decreased toxicity to humans. Amphotericin B, which has more conjugated trans double bonds than nystatin, is 10 times more potent (and is less toxic) than nystatin. UV-light can break these double bonds and render the drug inactive.

Amphotericin B remains the antifungal agent with the broadest spectrum of activity. It is not absorbed from the GIT. Nystatin is not absorbed from the skin, mucous membranes, or the GIT. It is active against most candida species (yeast) and is most commonly used for the treatment of local candidal infections. It is used orally to treat intestinal candidiasis.

The polyenes bind to ergosterol and alter the permeability of the fungal cell by forming polyene-associated pores in the cell membrane. The polyene molecule combines with the ergosterol molecules (found only in fungi) along the double bond-rich side of the polyene structure and associates with water molecules along the hydroxyl-rich side.

The polyene’s amphipathic characteristic facilitates pore formation by multiple polyene molecules, with the lipophilic portions around the outside of the pore and the hydrophilic regions lining the inside. The pore allows the leakage of intracellular ions and macromolecules, leading to cell death.

Fungal resistance to the polyenes occurs if binding to ergosterol is inhibited, either by decreasing the concentration of ergosterol in the membrane or by altering the chemistry of the ergosterol molecule to reduce its affinity for binding to the polyene.

Nystatin is used only topically and is not well absorbed well, so it has little toxicity besides having an unpleasant taste.

The most significant toxic reaction to amphotericin B therapy is a dose-dependent nephrotoxicity; the irreversible form of its nephrotoxicity usually occurs as a result of prolonged administration (> 4 g cumulative dose). Other amphotericin B toxicities include occasional abnormalities of liver function tests and a varying degree of anemia. Neurotoxicity has also been reported following intrathecal therapy with amphotericin B.

Patients who are intolerant or not responding to conventional amphotericin B treatment can be given an liposomal amphotericin B preparation. This allows for a reduction in toxicity without sacrificing efficacy and permits the use of a larger dose. The binding of Amphotericin B to the lipids causes the Amphotericin B to decrease it's binding to human cholesterol. Although some fungi produce lipases that seperate Amphotericin B from the lipid vehicles directly at the site of injection.
Explain Flucytosine (5-FC)
Flucytosine (or 5-FC) is a water-soluble pyrimidine analog related to the anticancer drug Fluorouracil (5-FU) (active form of the drug). 5-FC has a much narrower antifungal spectrum of activity than that of amphotericin B (amphotericin B has the widest (broadest) spectrum for treating fungal infections). 5-FC is used only in combination therapy, with amphotericin B or the azole antifungals, because of its demonstrated synergy with other antifungals and to avoid the emergence of resistance. It is given orally.

5-FC is taken up by fungal cells via the enzyme cytosine permease. It is converted intracellularly first to 5-FU by fungal cytidine deaminase enzyme. 5-FU is then converted to 5-fluorodeoxyuridine monophosphate (F-dUMP) and fluorouridine triphosphate (FUTP). F-dUMP inhibits DNA synthesis, while FUTP is an inhibitor of RNA synthesis. The overall effect of 5-FC is fungistatic. Human cells are unable to convert 5-FC to its active metabolites (selectivity).

Synergy with amphotericin B is attributed to enhanced penetration of 5-FC through the fungal cell membrane that was damaged by the antifungal action of amphotericin B. Synergy with the azole antifungals has also been reported, although the mechanism is unclear.

 Fungal resistance to 5-FC is mediated through altered metabolism of 5-FC. Resistance develops rapidly in the course of 5-FC monotherapy. (that is why it is given in combination)

Toxicity of 5-FC results from its metabolism, possible by microflora, to the toxic 5-FU. Bone marrow toxicity with anemia, leucopenia, and thrombocytopenia are the most common adverse effects of 5-FC. Other toxicities include hepatotoxicity and enterocolitis.
Explain Azoles
Azoles are classified into Imidazoles (2 nitrogen atoms) and Triazoles, depending on the number of nitrogen atoms in the five-membered azole ring which is present in their chemical structures.

The imidazoles consist of Ketoconazole, Miconazole, and Clotrimazole. The latter two antifungals are now used only topically. Ketoconazole is given orally.

The triazoles include Itraconazole, Fluconazole, Voriconazole, and Posaconazole. They are administered orally and IV; Posaconazole is available for oral administration only.

They are broad-spectrum antifungal agents. Fluconazole is eliminated predominantly unchanged in urine. The other azoles are extensively metabolized in the liver. Fluconazole is the azole of choice for the treatment and secondary prophylaxis of cryptococcal meningitis; unlike the other azoles, fluconazole displays good CSF penetration. Fluconazole and voriconazole display high oral bioavailability; the oral bioavailability of itraconazole and ketoconazole is variable. Posaconazole displays low oral bioavailability; administration of posaconazole with food (high-fat meal) increases (up to 4-fold) its absorption and oral bioavailability.

Imidazoles and triazoles inhibit the biosynthesis of fungal ergosterol by inhibiting fungal cyt. P450 (all P450 bind to iron) 14a-demethylase enzyme. They are also inhibitors of the mammalian (human) cyt. P450 14a-demethylase enzyme; however, they have greater affinity for the fungal enzyme. The overall effect is fungistatic.

Inhibition of the biosynthesis of fungal ergosterol results in decreased sterol content of the fungal cell membrane, leading to altered physical and chemical properties of the fungal cell, increased cell permeability, and malfunction of membrane proteins. The imidazoles are less selective than the triazoles in their binding to fungal cyt. P450 14-demethylase enzyme (ie, the imidazoles have a higher affinity for binding to the human P450 enzyme than the triazoles); this accounts for the higher incidence of drug interactions and side effects associated with the use of the imidazoles.

Fungal resistance to the azoles occurs via a number of mechanisms, including the production of an altered fungal P450 14-demethylase (which has a very low affinity for binding to the azoles) and active efflux of the azoles from fungal cells.

The azoles are relatively nontoxic. The most common adverse reaction is GI upset. All azoles cause abnormalities in liver enzymes and, very rarely, clinical hepatitis. All azoles inhibit human cyt. P450 enzymes in the liver, particularly CYP3A4. Consequently, they are prone to drug interactions (they increase the efficacy of many drugs which are metabolized by these enzymes). Fluconazole has the least inhibitory effect of all the azoles on hepatic cyt. P450 enzymes; as a result, drug interactions are less common with fluconazole therapy. Fluconazole also has the widest therapeutic index of all the azoles, permitting more aggressive dosing in a variety of fungal infections.

Toxicities of voriconazole also include rash and transient visual disturbances. Visual disturbances (blurring and changes in color vision or brightness) are common and resolve within 30 min after a dose of voriconazole.
Explain Echinocandins (Caspofungin)
Echinocandins are large cyclic peptides linked to a long-chain fatty acid. (They are fungicidal). Caspofungin (Cancidas) is given IV. It is active against candidal (yeast) infections (in addition to its antifungal activity).

Caspofungin is metabolized in the liver by CYP enzymes. Dosage adjustments are required only in the presence of severe hepatic insufficiency. Its metabolism is increased by inducers of CYP enzymes (e.g., rifampin). Micafungin and Anidulafungin are not metabolized by CYP enzymes. In addition, they do not induce/inhibit CYP enzymes. As a result, they are not expected to have clinically significant drug interactions (unlike caspofungin).

Echinocandins inhibit the enzymeB(1,3)-glucan synthase which is responsible for the synthesis of (1,3)-B-D-glucan. As a result, they inhibit the synthesis of (1,3)-B-D-glucan which is an important polysaccharide component of the fungal cell wall. This results in the rupture of the fungal cell wall and cell death.

Caspofungin is well tolerated, with minor GI side effects and flushing reported infrequently. Elevated liver enzymes have been reported in patients receiving caspofungin in combination with cyclosporine (the combination should be avoided).
Explain Griseofulvin
Griseofulvin is a water insoluble, fungistatic antifungal antibiotic derived from a penicillium species. It is administered orally and used only for the systemic treatment of infections caused by dermatophytes (localized superficial fungal infections of the skin, hair, and nails) (It affects anything with keratin).

It is not active against yeast infections; it is also not active against systemic fungal infections. It is an inducer of liver cyt. P450 enzymes; as a result, it decreases the efficacy of many drugs which are metabolized by these enzymes (drug interactions).

The mechanism of action of griseofulvin at the cellular level is unclear; however, it is deposited in newly forming skin/hair/nail (in keratin precursor cells) where it binds to keratin, protecting the keratinized tissue from new infection. Since its antifungal activity is attributed to its keratophilic properties and to preventing infection of the new skin/hair/nail structures, it must be administered for 2-6 weeks for skin and hair infections to allow the replacement of infected keratin by the resistant structures. Nail infections may require therapy for months to allow regrowth of the new protected nail and is often followed by relapse.

Toxicities of griseofulvin include hepatitis and an allergic syndrome (much like serum sickness).
Explain Allylamines (Terbinafine)
Terbinafine is a highly lipophilic, synthetic allylamine derivative. It is given orally. It is fungicidal against dermatophytes and other filamentous fungi; it is fungistatic against yeasts (candida species).

Like griseofulvin, it is keratophilic; it is indicated for the treatment of onychomycosis of the nail due to dermatophytes. The optimal clinical effect of terbinafine is seen only after several months following curing of the infection and cessation of treatment (a period of time is required for the outgrowth of healthy nails).

It is more effective (cure rate of up to 90%) than griseofulvin or itraconazole for the treatment of onychomycosis and it does not seem to affect the cyt. p450 enzyme system in humans.

Terbinafine inhibits the biosynthesis of fungal ergosterol by inhibiting squalene epoxidase enzyme, which is a key enzyme in sterol biosynthesis in fungal cells. Inhibition of fungal squalene epoxidase leads to a deficiency in ergosterol and accumulation of the sterol squalene which is toxic to fungal cells. Terbinafine has no significant effect on cholesterol biosynthesis in human cells (it is a weak inhibitor of the mammalian squalene epoxidase).

Adverse effects are rare, consisting mainly of GI upset and headache.
Explain the steps involved in viral replication
 Adsorption to and penetration into susceptible host cells

 Uncoating of viral nucleic acid

 Synthesis of early regulatory proteins (e.g., nucleic acid polymerases)

 Synthesis of RNA or DNA

 Synthesis of late, structural proteins

 Assembly (maturation) of viral particles

 Release from the cell (Viral Exit)
Explain Acyclovir (Anti-HSV and Anti-VZV)
Three orally administered agents are available for the treatment of Herpes Simplex Virus and Varicella Zoster Virus infections: acyclovir, valacyclovir, and famciclovir. They have similar mechanisms of action and are well tolerated. Acyclovir has been the most extensively studied and is the only anti-HSV agent available for IV use. It is an acyclic guanosine derivative.

Acyclovir requires three phosphorylation steps for activation. It is converted first to the monophosphate derivative by viral thymidine kinase, and then to the di- and triphosphate (active form) derivatives by the host’s cellular enzymes (host cell kinases) (Therefore it only affects cells that are infected by virus). Because viral kinase is required for its initial phosphorylation, acyclovir is selectively activated and accumulates only in infected cells.

Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms:

1. Competitive inhibition with deoxyGTP for the viral DNA polymerase, resulting in binding to the DNA template as an irreversible complex.

2. Chain termination following incorporation of the triphosphate into the viral DNA.

Resistance to acyclovir can develop in HSV or VZV through alteration in either the viral thymidine kinase or the DNA polymerase. Most resistant clinical isolates are deficient in thymidine kinase activity (activates the drug) and thus are cross-resistant to valacyclovir, famciclovir, and ganciclovir. Agents such as foscarnet, cidofovir, and trifluridine do not require activation by viral thymidine kinase. As a result, they are active against the most prevalent acyclovir-resistant strains.

Acyclovir is generally well tolerated. Nausea, diarrhea, and headache have occasionally been reported. IV infusion of acyclovir may cause reversible renal dysfunction, due to crystalline nephropathy, or neurologic toxicity (e.g., tremors, seizures); however, these are uncommon with adequate hydration and avoidance of rapid infusion rates.
Explain Granciclovir (Anti-CMV)
Ganciclovir is an acyclic guanosine analog. It has in vitro activity against Cytomegalovirus, HSV, VZV, EBV, and human herpesvirus-8 (HHV-8). Its activity against CMV is up to 100 times greater than that of acyclovir.

Ganciclovir requires triphosphorylation for activation prior to inhibiting the viral DNA polymerase. Initial phosphorylation is catalyzed by the viral protein kinase phosphotransferase UL97 in CMV-infected cells. The other two phosphorylations are catalyzed by host cell kinases. Ganciclovir triphosphate competitively inhibits viral DNA polymerase and causes termination of viral DNA elongation.

Mutations in UL97, resulting in decreased levels of the active triphosphorylated form of ganciclovir. Isolates with these mutations are not cross-resistant to cidofovir or foscarnet. Mutations in UL54, resulting in a mutant DNA polymerase; these mutations occur less frequently. Isolates with these mutations may exhibit cross-resistance to cidofovir and, less frequently, to foscarnet.

Toxicity includes:
 Myelosuppression (bone marrow suppression), particularly neutropenia (more common with IV than with oral administration)
 CNS toxicity (rare)
 Fever
 Abnormal liver function
 Retinal detachment (in patients with CMV retinitis)
Explain Cidofovir (Anti-CMV)
Cidofovir is a cytosine nucleotide analog. It has in vitro activity against a number of viruses including CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8, adenovirus, poxviruses, and human papillomavirus.

In contrast to ganciclovir, phosphorylation of cidofovir to the active diphosphate is independent of viral enzymes (making it less selective b/c it is only activated by human cells). Following phosphorylation, cidofovir acts both as a potent inhibitor of and as an alternative substrate for viral DNA polymerase, competitively inhibiting DNA synthesis and becoming incorporated into the viral DNA chain. Isolates with resistance to cidofovir tend to be cross-resistant to ganciclovir but retain susceptibility to foscarnet.

Toxicities include:
 Dose-dependent nephrotoxicity
 Decreased intraocular pressure
 Neutropenia and metabolic acidosis (rare)
 Cidofovir caused mammary adenocarcinomas in rats and is embryotoxic
Explain Foscarnet (Anti-CMV)
Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate analog. It has in vitro activity against HSV, VZV, CMV, EBV, HHV-6, HHV-8, and HIV.

Foscarnet inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase directly, without requiring activation by phosphorylation.

Resistance to foscarnet in HSV and CMV is due to point mutations in the DNA polymerase gene and is associated with prolonged or repeated exposure to the drug. Mutations in the HIV-1 reverse transcriptase gene have also been reported. Foscarnet-resistant CMV isolates are cross-resistant to ganciclovir. Ganciclovir- and cidofovir-resistant isolates of CMV, on the other hand, are susceptible to foscarnet.

Toxicities include:
 Renal insufficiency
 Hypo- or hypercalcemia
 Hypo- or hyperphosphatemia
 Anemia
 Nausea, vomiting, and fatigue
 CNS toxicity (headache, hallucinations, seizures)
Explain Fomivirsen (Anti-CMV)
Fomivirsen is used to treat CMV retinitis (injected intravitreally) in patients with AIDS who are intolerant of or unresponsive to alternative therapies. Concurrent systemic anti-CMV therapy is recommended to protect against extraocular and contralateral retinal CMV disease. Potential side effects include changes in vision and increased intraocular pressure.

Fomivirsen is an oligonucleotide that inhibits human CMV through an antisense mechanism. Binding of fomivirsen to target mRNA results in inhibition of immediate early region 2 protein synthesis, thus inhibiting viral replication.

Clinical resistance to fomivirsen has not been observed to date. Cross-resistance between fomivirsen and other anti-CMV agents (ganciclovir, cidofovir, foscarnet) would not be expected.
Explain Zidovudine (Azidothymidine; AZT) (NUCLEOSIDE Reverse Transcriptase Inhibitors)(NRTIs)
Zidovudine is a deoxythymidine analog. It was the first antiretroviral drug to be approved.

It has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals. When administered during pregnancy, during labor, and to the neonate, zidovudine has also been shown to reduce the rate of vertical (mother-to-newborn) transmission of HIV by up to 23%.

The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase and can also be incorporated into the growing viral DNA chain to cause termination. Each one of the NRTIs requires intracytoplasmic activation by phosphorylation to the triphosphate form. Phosphorylation of the NRTIs is catalyzed by host cell kinases. Most NRTIs are active against both HIV-1 and HIV-2.

As with other NRTIs, viral resistance to AZT may limit its clinical efficacy. High-level resistance to AZT is generally seen in strains with three or more mutations. Withdrawal of AZT exposure may permit the reversion of AZT-resistant HIV-1 isolates to the susceptible wild-type phenotype.

Lactic acidemia and severe hepatomegaly have been reported with the use of the NRTIs, alone or in combination with other antiretroviral drugs.

Toxicities for Azidothymidine include:

 Myelosuppression (bone marrow suppression) (resulting in anemia or neutropenia) is the most common adverse effect of AZT.

 GI intolerance, headaches, and insomnia may occur but tend to resolve during therapy.
Explain Tenofovir (NUCLEOTIDE Reverse Transcriptase Inhibitor)
Tenofovir is an acyclic nucleoside phosphonate (nucleotide) analog of adenosine.

• Like the NRTIs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination following its incorporation into viral DNA.

Remember, each one of the NRTIs requires intracytoplasmic activation by phosphorylation to the triphosphate form. Phosphorylation of the NRTIs is catalyzed by host cell kinases.

GI upset is the most common side effect of tenofovir. Studies in animals have demonstrated bone toxicity (e.g., osteomalacia); however, to date there has been no evidence of bone toxicity in humans. As with the NRTIs, lactic acidosis and hepatomegaly may occur.

Elimination of tenofovir occurs mainly by a combination of glomerular filtration and active tubular secretion. Consequently, tenofovir may compete with other drugs that are actively secreted by the kidneys, such as cidofovir, acyclovir, and ganciclovir.

Varying degrees of cross-resistance between tenofovir and the NRTIs have been reported; these appear to depend on the number of specific mutations present. Cross-resistance with the protease inhibitors is unlikely.
Explain Nevirapine (Nonnucleoside Reverse Transcriptase Inhibitors) (NNRTI)
Nevirapine is used mainly as a component of a combination antiretroviral regimen. Recently, a single dose of nevirapine has been shown to be effective in preventing transmission of HIV from mother to newborn (vertical transmission) when administered to women at the onset of labor and followed by an oral dose given to the neonate within 3 days after delivery.

The NNRTIs bind directly to a site on the HIV-1 reverse transcriptase, resulting in inhibition of RNA- and DNA-dependent DNA polymerase activities. The binding site for the NNRTIs is near to but distinct from that of the NRTIs. Unlike the NRTIs, the NNRTIs do not compete with nucleoside triphosphates and do not require phosphorylation to be active.

Nevirapine is extensively metabolized by CYP3A4 in the liver (ie, it is a substrate for CYP3A4). It is also an inducer of CYP3A metabolism (drug interactions) (lowers plasma levels of other drugs). Because it is a substrate for CYP3A4, nevirapine levels may increase during coadministration with inhibitors of CYP3A metabolism, and decrease in the presence of CYP3A inducers. Other NNRTIs also affect CYP3A4 metabolism. Delavirdine is a substrate and an inhibitor of CYP3A4; efavirenz is also a substrate and an inhibitor of CYP3A4.

Resistance to a NNRTI is rapid with monotherapy and is associated with specific viral mutations. Cross-resistance among the NNRTIs, although observed in vitro, is of unknown clinical significance. There is no cross-resistance between the NNRTIs and the NRTIs or the protease inhibitors.

Severe and life-threatening skin rashes, including toxic epidermal necrolysis, have occurred during nevirapine therapy; in such cases, nevirapine therapy should be discontinued. Fulminant hepatitis may occur within the first 6 weeks of initiation of therapy; serial monitoring of liver function tests is recommended.
Explain Ritonavir (Protease Inhibitor)
Ritonavir is an inhibitor of HIV-1 and HIV-2 proteases.

The protease inhibitors prevent cleavage of the Gag-Pol polyprotein by inhibiting the protease enzyme. Inhibition of the protease enzyme results in the production of immature, noninfectious viral particles. Specific genotypic mutations that confer viral resistance to the protease inhibitors are common. As a result, monotherapy is contraindicated.

All protease inhibitors are substrates for CYP3A4 in the liver (ie, they are metabolized by CYP3A4 in the liver). As a result, there is a great potential for drug-drug interactions. In addition, protease inhibitors are CYP3A4 inhibitors as well. Consequently, these agents can cause decreased clearance and increased plasma levels of other substrate drugs. Protease inhibitors should not be administered concurrently with agents that are extensively metabolized by CYP3A4.

Since ritonavir is an inhibitor of CYP3A4, concurrent administration of ritonavir with other protease inhibitors results in increased plasma levels of these agents.

For example, administration of saquinavir in combination with a low dose of ritonavir has allowed clinicians to decrease the frequency of saquinavir dosing and resulted in improved antiviral efficacy of saquinavir and decreased GI side effects that are typically associated with saquinavir therapy. In this combination, the subtherapeutic dose of ritonavir inhibits the CYP3A4-mediated metabolism of saquinavir, thereby resulting in increased exposure (blood levels) to saquinavir. The high saquinavir plasma levels that are produced by this combination maintain potent viral suppression as well as provide a pharmacologic barrier to the emergence of resistance. Another example of the use of ritonavir in a combination with another protease inhibitor is the lopinavir/ritonavir combination.

The most common adverse effects of ritonavir are GI disturbances, elevated serum aminotransferase levels, redistribution of body fat, altered taste, and hypertriglyceridemia. The use of protease inhibitors has been associated with increased spontaneous bleeding in patients with hemophilia A or B.
Explain Enfuvirtide (T-20) (Fusion Inhibitor)
• Enfuvirtide is a synthetic 36-amino-acid peptide. Enfuvirtide is administered subcutaneously, in combination with other antiretroviral agents, in patients with persistent HIV-1 replication despite ongoing therapy.

Enfuvirtide is a fusion inhibitor that blocks entry of the virus into the cell. It binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes.

Viral resistance to enfuvirtide can occur and it is being investigated. However, there is no cross-resistance between enfuvirtide and the other currently available antiretroviral drug classes.

The most common side effects of enfuvirtide therapy are local injection site reactions. Hypersensitivity reactions of varying severity may occur and recur on rechallenge. No interactions have been identified that would require alteration of other antiretroviral therapies.
Explain Adefovir (Anti-Hepatitis)
Adefovir has been approved for the treatment of HBV infection. Studies have shown that adefovir therapy results in significant suppression of HBV replication and improvement in liver histology and fibrosis. However, as with lamivudine, serum HBV DNA reappeared following discontinuous of therapy.

Like tenofovir, adefovir is a nucleotide analog of adenosine monophosphate. It is phosphorylated by cellular kinases to the active diphosphate metabolite. Following activation, it competitively inhibits HBV DNA polymerase and results in chain termination after incorporation into the viral DNA.

No resistance to adefovir was detected in patients who had received continuous treatment for up to one year. In addition, it is active against lamivudine-resistant strains of HBV.

Adefovir therapy is associated with a dose-dependent nephrotoxicity. The risk of nephrotoxicity may rise in patients with preexisting renal dysfunction or in those treated for longer durations. As with the antiretroviral nucleoside analogs (NRTIs), lactic acidosis and severe hepatomegaly may occur.
Explain Interferon Alfa (IFN-a) (Anti-Hepatitis)
Interferon alfa preparations are available for the treatment of both HBV and HCV infections; they are administered SC or IM. Interferon alfa-2b is used for the treatment of chronic HBV infection and acute HCV infection. Interferon alfa-2b and other preparations, such as interferon alfa-2a, interferon alfacon-2, and pegylated interferon alfa-2a and -2b, are used for the treatment of chronic HCV infection. Combination therapy with oral ribavirin is more effective in treating chronic HCV infection than monotherapy with either interferon or ribavirin alone. Monotherapy is recommended only in patients who cannot tolerate ribavirin.

Interferons are a group of cytokines. They are endogenous proteins that exert complex antiviral, immunomodulatory, and antiproliferative activities through cellular metabolic processes involving the synthesis of both RNA and protein. They bind to specific membrane receptors on the cell surface and initiate a series of intracellular events that include enzyme induction, suppression of cell proliferation, immunomodulatory activities, and inhibition of viral replication.

Common side effects include a flu-like syndrome within 6 hours after dosing that tends to resolve upon continued administration. Other potential adverse effects include thrombocytopenia, elevation in serum aminotransferase levels, induction of autoantibodies, hypotension, and edema. Severe neuropsychiatric side effects may occur.

There are many contraindications to interferon therapy, including psychosis, severe depression, symptomatic heart disease, and uncontrolled seizures. Alfa interferons are abortifacient in primates and should not be administered during pregnancy.
Explain Pegylated Interferon Alfa (Anti-Hepatitis)
Pegylated interferon alfa preparations are available. In these preparations, a linear or branched polyethylene glycol (PEG) moiety is attached to the interferon molecule by a covalent bond. Adding a PEG moiety to interferon results in reduced clearance and sustained absorption.

In comparison with the nonpegylated interferon alfa compounds, the pegylated products have substantially longer half-lives, slower clearance, and steadier serum concentrations, allowing for less frequent dosing.

As with the nonpegylated interferon alfa products, combination therapy of the pegylated products with ribavirin is more effective than monotherapy.

Adverse effects are similar to those of the nonpegylated interferon alfa products. PEG is a nontoxic polymer that is readily excreted in urine.
Explain Ribavirin (Anti-Hepatitis)
Ribavirin triphosphate inhibits the replication of a number of DNA and RNA viruses, including influenza A and B, respiratory syncytial virus (RSV), HCV, and HIV-1.

In addition to its oral use in combination with interferon alfa for the treatment of HCV infection, aerosolized ribavirin is administered by nebulizer (inhalation) to children and infants with severe RSV bronchiolitis or pneumonia.

It is a guanosine (Nucleoside) analog that requires intracellular activation. It is phosphorylated by host cell enzymes to the active triphosphate.

Its mechanism of action has not been fully elucidated. However, it appears to be involved in the following:

1. It interferes with the synthesis of guanosine triphosphate.
2. It inhibits capping of viral mRNA.
3. It inhibits the viral RNA-dependent RNA polymerase of certain viruses.

IV ribavirin has been shown to decrease mortality in viral hemorrhagic fevers if administered early; clinical benefit has also been reported in cases of severe measles pneumonitis and lower respiratory tract influenza infections.

Side effects of ribavirin include a dose-dependent hemolytic anemia, depression, rash, insomnia, and pruritus. Contraindications to therapy include anemia, renal failure, severe heart disease, and pregnancy. Ribavirin is teratogenic in animals and mutagenic (causes mutations) in mammalian cells.
Explain Amantadine & Rimantadine (Anti-Influenza)
Amantadine and its derivative rimantadine are cyclic amines. Rimantadine is four to ten times more active than amantadine.

Amantadine is excreted unchanged in urine; rimantadine is extensively metabolized in the liver before urinary excretion. Dose reductions are required for both agents in the elderly, in renal insufficiency, and for rimantadine in patients with marked hepatic insufficiency.

Amantadine and rimantadine inhibit the uncoating of the viral RNA of influenza A virus within infected host cells, thus preventing its replication. (Not Affective against Influenza B)

The primary target for both agents is the M2 protein within the viral membrane, which makes these two agents highly specific against influenza A virus (influenza B virus contains a different protein in its membrane). Cross-resistance to zanamivir and oseltamivir does not occur.

Due to resistance, these drugs are no longer used in the US. They posses activity against avian strains but not against the H5N1 strain found in Asia.

The most common adverse effects of amantadine and rimantadine are GI intolerance and CNS complaints (e.g., nervousness, lightheadedness, difficulty in concentrating). The CNS side effects are less frequent with rimantadine than with amantadine.

CNS toxicity of amantadine may be enhanced with concomitant antihistamines and anticholinergic drugs. Serious neurotoxic reactions, occasionally fatal, may be associated with high amantadine plasma levels (1-5 g/mL). Amantadine is teratogenic in rodents; birth defects have been reported after exposure during pregnancy.
Explain Zanamivir & Oseltamivir (Anti-Influenza)
Unlike amantadine and rimantadine, zanamivir and oseltamivir are active against both influenza A and influenza B. Zanamivir is administered via oral inhalation; oseltamivir is an orally administered prodrug that is activated in the gut and liver.

Both agents have been approved for prophylaxis or treatment of acute uncomplicated influenza infection. When administered for a 5-day course within 36-48 hours after the onset of symptoms, use of either agent shortens the severity and duration of illness and may decrease the incidence of respiratory complications in children and adults. A single daily dose of oseltamivir may also be effective in preventing influenza.

Both agents are active against avian strains of influenza and are options for prophylaxis and early treatment of suspected H5N1 infection in humans; however, resistance to oseltamivir has been reported. Higher doses and longer courses of treatment than those used for seasonal influenza may be needed.

Inactivated flu vaccines are not affected by antiviral drug therapy. However, antivirals may interfere with the efficacy of the live-attenuated intranasal flu vaccine (FluMist); they should be stopped at least 48 hours before and should not be started for at least 2 weeks after FluMist administration.

Zanamivir and oseltamivir are inhibitors of the viral neuraminidase enzyme. Neuraminidase is an essential viral glycoprotein for viral replication and release. Resistance to zanamivir and oseltamivir is associated with viral mutations.

Zanamivir can cause nasal and throat irritation; bronchospasm in patients with reactive airway disease has also been reported. Potential side effects of oseltamivir include nausea and vomiting.
Explain Palivizumab (Treats Respiratory Syncytial Virus)
Palivizumab is a humanized monoclonal antibody directed against the F glycoprotein on the surface of RSV.

It has been approved for the prevention of RSV infection in high-risk infants and children.

The major side effect of palivizumab is elevation in serum aminotransferase levels.
Explain Imiquimod
Imiquimod is an immune response modifier.

It is used topically for the treatment of external genital and perianal warts (condyloma acuminatum). Local skin reactions are the most common side effects.

Its mechanism of action against the human papillomavirus (HPV) that causes these lesions is unknown.
Explain Polyfunctional Alkylating Agents (Cell-Cycle Nonspecific) (Anti-Cancer)
The alkylating agents exert cytotoxic effects via transfer of their alkyl groups to various cellular constituents, particularly DNA; alkylation of DNA and other cellular constituents lead to cell death. The general mechanism of action of these drugs involves intramolecular cyclization to form an ethyleneimonium ion that may directly or through formation of a carbonium ion transfer an alkyl group to a cellular constituent (e.g., DNA).

In addition to DNA alkylation, the nitrosoureas are also capable of carbamoylating lysine residues of cellular proteins through the formation of isocyanate species (Cl-CH2-CH2-N=C=O). The major site of alkylation within DNA is the N7 position of guanine; however, other bases are also alkylated to lesser degrees as well as phosphate atoms and proteins associated with DNA.

Covalent binding interactions of the alkylating agents with DNA can occur on a single strand (Monofunctional – cannot cross-link DNA) or on both strands of DNA through cross-linking (most major alkylating agents are bifunctional). The higher efficacy of bifunctional alkylating agents in cancer chemotherapy, as compared to monofunctional agents, is attributed to their ability to cross-link DNA. (Cells have trouble repairing cross-linked DNA, making bifunctional alkylating agents the most affective).  Although alkylating agents are CCNS, replicating cells (ie, cells in late G1 and S phases) are most susceptible to alkylation.

Cyclophosphamide is the most widely used alkylating agent. It is administered orally. It is relatively a less reactive alkylating agent; it requires activation to its cytotoxic forms by the cyt. P450 enzyme system in the liver.

The active metabolites of cyclophosphamide are first delivered by the general circulation to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic (electrophilic) forms (phosphoramide mustard & acrolein) occurs. The liver protects itself from the cytotoxic effect of cyclophosphamide by further metabolizing the active metabolites to inactive metabolites.

Resistance includes:
 Increased capability to repair DNA.

 Decreased permeability of the cell to the drug.

 Increased production of glutathione which inactivates the electrophilic alkylating agent via conjugation.

 Increased glutathione S-transferase (an endogenous peptide that inactivates the enzymatic activation of the drug) activity (the enzyme that catalyzes the glutathione conjugation reaction).

Cross-resistance exists among the alkylating agents; however, there are exceptions to the rule depending on the specific type of tumor. Cross-resistance to the nitrosoureas is less likely. The most common toxicities of the alkylating agents include nausea, vomiting, and bone marrow depression.
Explain Methotrexate (Antimetabolite) (Cell-Cycle Specific)
Methotrexate is a folic acid antagonist that binds to the active catalytic site of dihydrofolate reductase (DHFR) enzyme, inhibiting the enzyme and interfering with the synthesis of tetrahydrofolic acid (THF).

The lack of THF inhibits the synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine, thereby inhibiting the formation of DNA, RNA, and proteins. (Inhibits DNA synthesis in cancer and normal cells)

Intracellular formation of polyglutamate derivatives during methotrexate therapy is important for its anticancer activity. The polyglutamates are selectively retained in cancer cells and have increased inhibitory effects on enzymes involved in folate metabolism, resulting in an increase in the duration of action of methotrexate.

Tumor cell resistance to methotrexate has been attributed to:

1. Decreased drug transport into the cell.

2. Decreased polyglutamate formation.

3. Synthesis of increased levels of DHFR via gene amplification.

4. Altered DHFR with reduced affinity for methotrexate.

5. Active efflux through activation of a MDR P170 glycoprotein transporter. (All anticancer drugs are susceptible to this)

Toxicities of methotrexate include diarrhea and bone marrow depression with leucopenia and thrombocytopenia.

Methotrexate inhibits the synthesis of purines and DNA in normal cells. To reverse these effects and rescue normal cells, one particular agent is administered: Leucovorin. Leucovorin prevents the lethal effects of methotrexate on normal cells by overcoming the blockade of THF production and rescuing the biosynthesis of purines in normal cells. In addition, leucovorin inhibits the active transport of methotrexate into normal cells and stimulates its efflux. Leucovorin does not reach adequate concentrations in tumor cells; as a result, it will not rescue tumor cells. (This is known as rescue therapy)
Mercaptopurine (6-MP) (Antimetabolite) (Cell-Cycle Specific)
6-MP must be bioactivated first by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to the nucleotide form 6-thioinosinic acid, which in turn inhibits a number of the enzymes involved in purine nucleotide interconversions. Consequently, DNA synthesis is inhibited.

Resistance to 6-MP is most commonly attributed to a decrease in HGPRT activity (This enzyme is needed to bioactivate the drug). Another mechanism of resistance involves increased levels of alkaline phosphatase which inactivates 6-MP by dephosphorylation.

Toxicities of 6-MP include myelosuppression (bone marrow suppression), immunosuppression, and hepatotoxicity. 6-MP is converted in the body to an inactive metabolite, 6-thiouric acid, by xanthine oxidase enzyme. The purine analog allopurinol is a potent inhibitor of xanthine oxidase; as a result, allopurinol is capable of enhancing the activity and toxicity of 6-MP. (Increasing the plasma levels and half-lifes of 6-MP) (If allopurinol is administered with 6-MP, then the dose of 6-MP must be reduced).

Allopurinol is frequently administered with chemotherapy to cancer patients in order to prevent hyperuricemia (which is caused by the release of purines into the general circulation following tumor cell lysis).
Explain Fluorouracil (5-FU) (Antimetabolite) (Cell-Cycle Specific)
5-FU must be bioactivated first to ribosyl and deoxyribosyl nucleotide metabolites. Its cytotoxicity is attributed to effects on both DNA- and RNA-mediated events. (It is a uracil analog)

5-FU is bioconverted to fluorodeoxyuridine monophosphate (FdUMP), which inhibits thymidylate synthase enzyme and the synthesis of thymidylate. This results in inhibition of DNA synthesis.

5-FU is also bioconverted to fluorouridine triphosphate (FUTP), which is incorporated into RNA, where it interferes with RNA processing and mRNA translation.

In addition, 5-FU is bioconverted to fluorodeoxyuridine triphosphate (FdUTP), which can be incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function.

5-FU is normally given IV. It is not administered orally because of decreased bioavailability due to high levels of the enzyme dihydropyrimidine dehydrogenase present in the gut mucosa; this particular enzyme inactivates 5-FU following oral administration.

Toxicities of 5-FU include nausea, diarrhea, myelosuppression, and neurotoxicity.
Explain Vinca Alkaloids (Vinblastine, Vincristine, Vinorelbine) (Plant Product) (Cell-Cycle Specific)
Vinblastine and vincristine are plant alkaloids derived from the periwinkle plant (Vinca rosea). Vinorelbine is a semisynthetic vinca alkaloid. All vinca alkaloids exhibit the same mechanism of action and are closely related in their chemical structures.

The vinca alkaloids cause depolymerization of microtubules, which are an important part of the cytoskeleton and the mitotic spindle. They bind specifically to the microtubule protein tubulin in dimeric form. The drug-tubulin complex adds to the forming end of the microtubules to terminate assembly, and depolymerization of the microtubules then occurs.

Depolymerization of the microtubules results in mitotic arrest at metaphase (the M phase), dissolution of the mitotic spindle, and interference with chromosome segregation.

Toxicities of vinblastine include nausea, vomiting, bone marrow suppression, and alopecia. The main dose-limiting toxicity of vincristine is neurotoxicity (including neuropathy, ataxia, seizures, coma). While myelosuppression can occur, it is generally milder and much less significant than with vinblastine.

The dose-limiting toxicity of vinorelbine is myelosuppression with neutropenia. Other toxicities include nausea, vomiting, transient elevations in liver function tests, and neurotoxicity.
Explain Epipodophyllotoxins (Etoposide & Teniposide) (Plant Product) (Cell-Cycle Specific)
Etoposide and teniposide are semisynthetic derivatives of podophyllotoxin, which is extracted from the mayapple root (Podophyllum peltatum). Both agents exhibit the same mechanism of action and are closely related in their chemical structures.

Etoposide and teniposide block cell division in the late S-G2 phase of the cell cycle.

They inhibit topoisomerase II enzyme, which results in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme.

Toxicities of the epipodophyllotoxins include nausea, vomiting, alopecia, and bone marrow depression.
Explain Camptothecins (Topotecan & Irinotecan) (Plant Product) (Cell-Cycle Specific)
The camptothecins are natural products derived from a tree, Camptotheca acuminata.

Irinotecan is a prodrug; it is converted mainly in the liver by a carboxylesterase enzyme to the active metabolite.

They inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands. Inhibition of Topo I results in DNA damage.

The most common toxicities of irinotecan are diarrhea and myelosuppression. Toxicities of topotecan include nausea, vomiting, myelosuppression, and arthralgias.
Explain Taxanes (Paclitaxel & Docetaxel) (Plant Product) (Cell-Cycle Specific)
Paclitaxel (Taxol®) is a natural product derived from the pacific yew tree (Taxus brevifolia). Docetaxel is a semisynthetic taxane derived from the European yew tree (Taxus baccata). Both agents exhibit the same mechanism of action and are structurally related.

The taxanes function as mitotic spindle poisons through high-affinity binding to microtubules with enhancement of tubulin polymerization. (Work the opposite way of Alkaloids) (Alkaloids promote depolymerization)

This promotion of microtubule assembly by the taxanes can occur in the absence of microtubule-associated proteins and guanosine triphosphate and results in inhibition of mitosis and cell division.

Toxicities of paclitaxel include nausea, vomiting, arrhythmias, hypersensitivity reactions, bone marrow depression, and peripheral sensory neuropathy.
Explain Anthracyclines (Cell-Cycle Nonspecific)
The anthracyclines are among the most widely used cytotoxic anticancer drugs. Daunorubicin and doxorubicin were the first agents in this class to be introduced. Idarubicin is a semisynthetic analog of daunorubicin. Epirubicin is a doxorubicin analog.

Daunorubicin is used in the treatment of acute myeloid leukemia. Doxorubicin has a broad spectrum of clinical activity against hematologic malignancies as well as a wide range of solid tumors.

The anthracyclines exert their cytotoxic effect through four major mechanisms (because the molecules are so flat, they can bind to the bases (intercalation) and inhibit DNA synthesis):

1. Inhibition of topoisomerase II. (This causes DNA damage)

2. High-affinity binding to DNA through intercalation, leading to inhibition of the synthesis of DNA and RNA as well as DNA strand breakage.

3. Binding to cellular membranes to alter fluidity and ion transport.

4. Generation of semiquinone free radicals and oxygen free radicals through an enzyme-mediated reductive process. Generation of free radicals (superoxide) has been shown to be the cause of the cardiac toxicity of the anthracyclines.

The main dose-limiting toxicity of the anthracyclines is myelosuppression with neutropenia.

Two forms of cardiotoxicity are observed during anthracycline therapy:

1. Acute Cardiotoxicity which occurs within the first 2-3 days of therapy and is characterized by arrhythmias and myocarditis. This form of cardiotoxicity is usually transient and is asymptomatic in most cases.

2. Chronic Cardiotoxicity which results in a dose-dependent, dilated cardiomyopathy associated with heart failure. This form of cardiotoxicity is caused by increased production of free radicals within the myocardium.

A decrease in the dose or the use of continuous infusion appear to reduce the incidence of cardiac toxicity.
Explain Mitomycin (Mitomycin C) (Anti-Tumor Antibiotic) (Cell-Cycle Nonspecific)
Mitomycin is a CCNS alkylating agent. It is the best available drug for use in combination with radiation therapy to kill hypoxic tumor stem cells of solid tumors. It is used in combination chemotherapy for the treatment of squamous cell carcinoma of the anus and cervix as well as adenocarcinomas of the stomach, pancreas, and lung.

Mitomycin is metabolically activated via an enzymatic reduction reaction to generate an alkylating electrophilic species that is capable of cross-linking DNA. (They form covalent bonds that make it very strong) (It is a bi-functional drug that forms two covalent bonds)

Hypoxic tumor stem cells of solid tumors exist in an environment conducive to reductive reactions and, as a result, are more sensitive to the cytotoxic effects of mitomycin than normal cells and oxygenated tumor cells.

Toxicities of mitomycin include nausea, anemia, thrombocytopenia, and leucopenia.
Explain Bleomycin (Anti-Tumor Antibiotic) (Cell-Cycle Specific)
Bleomycin is a peptide that contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule. (Bonding to the two forms a complex)

It acts by binding to DNA, which results in single-strand and double-strand breaks following free radical formation, and inhibition of DNA synthesis.

The fragmentation of DNA is due to oxidation of a DNA-bleomycin-Fe (II) complex and leads to chromosomal aberrations.

Bleomycin is a CCS anticancer drug that causes accumulation of cells in the G2 phase of the cell cycle. (Less efficient than the other two drugs)

Toxicities of bleomycin include allergic reactions, fever, alopecia, and pulmonary fibrosis.

The dose-limiting toxicity for bleomycin is pulmonary toxicity which is characterized by pneumonitis with cough, dyspnea, and infiltrates. The incidence of pulmonary toxicity is increased in patients older than 70 years of age and with cumulative doses greater than 400 units; in rare cases, pulmonary toxicity can be fatal.(The symptoms are dose related)
Explain Tamoxifen (Hormonal Agent)
Tamoxifen is a selective estrogen-receptor modulator (SERM). Tamoxifen has estrogen-agonist effects on bone and uterus; it has anti-estrogen effects on the breast tissue.

The anti-estrogen tamoxifen has proved to be extremely useful for the treatment of both early-stage and metastatic breast cancer. It is also used as a chemopreventive agent in women at high risk for breast cancer. It is given orally.

Raloxifene, a related SERM, differs from tamoxifen mainly in having anti-estrogen effects on the uterus (acts as an antagonist). Preliminary results from a new NCI study (STAR) suggest that raloxifene might be a better choice than tamoxifen for prevention of breast cancer in high-risk postmenopausal women. The study showed a lower incidence of uterine (mainly endometrial) cancer with raloxifene; however, the incidence of non-invasive breast cancer was lower with tamoxifen. The study also showed a lower incidence of deep vein thrombosis or pulmonary embolism (known toxicities of SERMs) with raloxifene. Longer studies (> 4 years) are needed to evaluate mortality and the efficacy or risk of switching from tamoxifen to raloxifene. (Tamoxifen increases the risk of endometrial cancer) (Raloxifene has a lower chance for cancer) (Tamoxifen is the drug of choice against breast cancer)

Tamoxifen acts as a competitive partial agonist (ie, an antagonist) of estrogen and binds to the estrogen receptors of estrogen-sensitive tumors. It has a much longer biologic half-life (7-14 days) than estradiol.

Tamoxifen has a tenfold lower affinity for the estrogen receptor than does estradiol, indicating the importance of ablation (removal) of endogenous estrogen for optimal antiestrogen effect.

Tamoxifen is well tolerated; its toxicities are generally mild and include menopausal symptoms, fluid retention and edema, and thromboembolic events. Tamoxifen therapy increases the risk/incidence of estrogen-sensitive endometrial hyperplasia and cancer
Explain Fulvestrant (Hormonal Agent)
Fulvestrant is a selective estrogen-receptor downregulator (SERD). SERDs, unlike SERMs, are devoid of any estrogen-agonist activity. SERDs are ‘pure anti-estrogens’ or ‘pure ER-antagonists’. (This will not feed the tumor). SERDs are expected to have a better safety profile, faster onset, and longer duration of action than the SERMs.

Fulvestrant was approved for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that has progressed despite first-line anti-estrogen therapy such as tamoxifen. Fulvestrant is at least as effective in this setting as the aromatase inhibitor anastrozole.

Fulvestrant is a steroidal anti-estrogen that binds to the ER with an affinity more than 100 times that of tamoxifen. Binding of fulvestrant to the ER sterically hinders receptor dimerization, leading to inhibition of receptor dimerization, an increase in ER degradation (turnover), and disruption of nuclear localization.

Unlike tamoxifen, which stabilizes or even increases ER expression, fulvestrant reduces the number of ER molecules in cells, both in vitro and in vivo (ie, downregulation of ER). ER downregulation abolishes ER-mediated transcription, completely suppressing the expression of estrogen-dependent genes. This likely explains why fulvestrant is effective against tamoxifen-resistant breast cancer.

The mechanism of action suggests that fulvestrant should provide more effective anti-estrogen activity than tamoxifen; however, this was not confirmed by comparative clinical trials.

Fulvestrant is generally well tolerated. Most common adverse effects of fulvestrant include nausea, vasodilation (hot flushes), and headache.
Explain Flutamide & Bicalutamide (Hormonal Agents)
Flutamide and bicalutamide are nonsteroidal antiandrogen agents that bind to the androgen receptors of androgen-sensitive tumors and block androgen effects. (They antagonize androgens)

They are used orally, in combination with radiation therapy, for the treatment of early-stage prostate cancer; they are also used in the treatment of metastatic prostate cancer.

Toxicities of the antiandrogen agents include mild nausea, hot flushes, and transient elevations in liver function tests.
Explain Leuprolide & Goserelin (Hormonal Agent)
Leuprolide and goserelin are synthetic peptide analogs of gonadotropin-releasing hormone (GnRH).

They function as GnRH agonists and are more potent than the natural hormone. They stimulate a transient release of the follicle-stimulating hormone (FSH) and luteinizing hormone (LH), followed by inhibition of the release of FSH and LH.

In men, 2-4 weeks of GnRH agonist therapy results in castration levels of testosterone. (Very low levels). Both agents are used for the treatment of advanced prostate cancer and as part of neoadjuvant therapy of early-stage prostate cancer.

Toxicities of the GnRH agonists include hot flushes, impotence, and gynecomastia.
Explain Aminoglutethimide (Aromatase Inhibitor)
Aminoglutethimide is a nonsteroidal inhibitor of the aromatase enzyme. As a result, it inhibits estrogen synthesis in adipose tissue. Aminoglutethimide also inhibits adrenal steroidogenesis (corticosteroid synthesis) and the extra-adrenal synthesis of estrone and estradiol.

Since estrogens promote the growth of breast cancer, estrogen synthesis in adipose tissue can be important in breast cancer growth in postmenopausal women.

It is mainly used in the treatment of metastatic breast cancer in women whose tumors express significant levels of estrogen or progesterone receptors. In addition, it has activity in advanced hormone-responsive prostate cancer.

It is normally administered with hydrocortisone to prevent symptoms of adrenal insufficiency.

Toxicities of aminoglutethimide include mild nausea, skin rash, adrenal insufficiency, and myelosuppression.
Explain Anastrozole (Aromatase Inhibitor)
Anastrozole is a selective nonsteroidal inhibitor of aromatase. (They do not cause adrenal insufficiency) (Don’t need to be combined with a corticosteroid)

Unlike aminoglutethimide, anastrozole has no inhibitory effect on adrenal glucocorticoid or mineralocorticoid synthesis.

It is used as a first-line treatment of postmenopausal women with metastatic breast cancer that is ER-positive (ER = estrogen receptor), as well as women whose tumors have progressed while on tamoxifen therapy. It is also used as adjuvant therapy of postmenopausal women with hormone-positive, early-stage breast cancer.

Toxicities of anastrozole include mild nausea, hot flushes, and arthralgias.

Letrozole is another selective aromatase inhibitor that has the same mechanism of action, toxicities, and clinical indications as anastrozole.
Explain Exemestane (Aromatase Inhibitor)
Exemestane is a steroidal hormonal agent that binds to and irreversibly inactivates the aromatase enzyme.

There is no cross-resistance between exemestane and the nonsteroidal aromatase inhibitors.

It is indicated for the treatment of advanced breast cancer in postmenopausal women whose tumors have progressed on tamoxifen therapy.

Toxicities of exemestane include mild nausea, headache, and hot flushes.
Explain Protein Kinase Inhibitors (Imatinib, Gefitinib, Erlotinib)
Protein kinases are critical components of signal transduction pathways that transmit information concerning extracellular or cytoplasmic conditions to the nucleus, thereby influencing gene transcription and/or DNA synthesis.

Tyrosine kinases are classified into proteins that have an extracellular ligand binding domain (receptor tyrosine kinases) and enzymes that are confined to the cytoplasm and/or nuclear cellular compartment (nonreceptor tyrosine kinases). (Only affective against a certain Tyrosine Kinase)

Abnormal activation of specific protein tyrosine kinases has been demonstrated in many human cancers, making them attractive molecular targets for cancer therapy.

Imatinib has inhibitory activity against the platelet-derived growth factor receptor (PDGFR) tyrosine kinase, the cytoplasmic ABL tyrosine kinase, and the receptor tyrosine kinase KIT.

Imatinib is effective in treating cancers in which the ABL, KIT, or PDGFR have dominant roles in driving the proliferation of the tumor. This dominant role is defined by the presence of a mutation that results in constitutive activation of the kinase, either by fusion with another protein or point mutations.

Imatinib shows remarkable therapeutic efficacy in patients with chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs), chronic myelomonocytic leukemia (CMML), and hypereosinophilic syndrome (HES). It is given orally.

Acquired resistance to imatinib results predominantly from mutations in the kinase domain. The most frequently reported adverse effects of imatinib are nausea, vomiting, edema, and muscle cramps.
Explain Trastuzumab (Herceptin) (Monoclonal Antibody)
Trastuzumab (HERCEPTIN) is the first monoclonal antibody to be approved for the treatment of a solid tumor. It is a humanized monoclonal antibody against the HER2/neu (ErbB-2) member of the epidermal growth factor (EGF) family of cellular receptors.

HER2/neu is overexpressed in up to 30% of breast cancers and is associated with clinical resistance to cytotoxic and hormone therapy. The internal domain of the HER2/neu glycoprotein encodes a tyrosine kinase that activates downstream signals, resulting in increased metastatic potential and inhibition of apoptosis.

Trastuzumab therapy results in downregulation of HER2/neu expression, which leads to antiangiogenetic effects and the inhibition of cell proliferation. Trastuzumab can also initiate FC-receptor-mediated antibody-dependent cellular cytotoxicity and directly induce apoptosis.

Trastuzumab is approved for HER2/neu overexpressing metastatic breast cancer in combination with paclitaxel as initial treatment or as monotherapy following chemotherapy relapse.

Adverse effects of trastuzumab therapy include fever, chills, nausea, dyspnea, and rashes. Allergic reactions and cardiomyopathy may also occur.
Explain B-Lactam Antibiotics (Penicillin, Cephalosporin, Carbapenem, Monobactam)
PBPs catalyze the transpeptidation (penicillin binding protein) reaction (cross-linking) in the biosynthesis of peptidoglycan by removing the terminal D-alanine residue from a peptide side chain to form a crosslink with another nearby peptide side chain. This cross-linking reaction is inhibited by B-lactam antibiotics.

A ‘PBP’ is a D-alanyl-D-alanine carboxypeptidase/transpeptidase enzyme that creates a cross-link between two linear chains in the peptidoglycan net. PBPs are found in the cell membrane of all bacteria.

B-lactam antibiotics are structural analogs of the natural [D-Ala-D-Ala] substrate for the PBPs. -lactams bind covalently to the active site of PBPs, inhibiting the transpeptidation reaction. Consequently, peptidoglycan synthesis is inhibited and the bacterial cell dies. The exact mechanism responsible for cell death is not completely understood, but autolysins (bacterial enzymes that remodel and break down the cell wall) are involved.

B-lactam antibiotics and the other inhibitors of bacterial cell wall synthesis are bactericidal only if bacterial cells are actively growing (multiplying/dividing) and synthesizing cell wall.
Explain B-Lactamases
B-Lactamase is a ‘protease’ capable of inactivating a B-lactam antibiotic. The reaction between a B-lactamase and a B-lactam antibiotic is reversible via hydrolysis (the reaction between a PBP and a B-lactam antibiotic, on the other hand, is irreversible).

A small amount of the B-lactamase enzyme can destroy a very large amount of the B-lactam antibiotic.

The synthesis of B-lactamases is R-Factor mediated (Extrachromasomal Resistance) and, in some cases, induced by the presence of B-lactam antibiotics.
Explain Cephalosporins
Classification of the cephalosporins is based on kinetic parameters, spectrum of antimicrobial activity, and the ability to resist B-lactamase activity. Progression from the First to the Third Generation cephalosporins reveals the following:

 Decrease in efficacy against Gram-positive bacteria.
 Increase in efficacy against Gram-negative bacteria.
 Increase in resistance to B-lactamase activity.
 Increase in cost.

Cefepime is an example of the Fourth Generation cephalosporins. Although its clinical use is very similar to that of the Third Generation, cefepime is more resistant to extended-spectrum B-lactamases that inactivate many of the Third Generation cephalosporins. In addition, cefepime is active against most penicillin-resistant Strep. infections.

They are less allergenic than the penicillins.

Cross-allergenicity between the penicillins and the cephalosporins occurs in about 5-10% of individuals allergic to penicillins.

Renal toxicity, including interstitial nephritis and tubular necrosis, has been demonstrated.

Cephalosporins that contain a methylthiotetrazole group (e.g., cefmetazole, cefotetan, cefoperazone, cefamandole) frequently cause hypoprothrombinemia and bleeding disorders. They can also cause severe disulfiram-like reactions (Nausea and vomiting) with alcohol consumption; consequently, alcohol must be avoided in patients who are taking one of these particular cephalosporins.

Superinfection, particularly with the use of many of the Second and Third Generation cephalosporins.