PHARMACOLOGY- BLOCK 4 REVIEW Anti-microbials Antibiotic: A substance that is produced by one microbe and inhibits the growth or viability

ty of other microbes. Bacteriostatic: inhibit the growth of bacteria but does not kill them. The number of bacteria remains relatively constant in the presence of a bacteriostatic drug. All protein synthesis inhibitors (Tetracyclines, Sulfonamides) except Aminoglycosides are bacteriostatic drugs. These drugs inhibit a protein that is needed for cell growth but is not necessary for cell survival. Note that these drugs can be used in patients with good immunity (non-immunocompromised) because the drug inhibits the growth of the bacteria and then the persons immune system can kill the rest of the bacteria. Bactericidal: kills the organism and the number of viable organisms falls rapidly after exposure to the drug. These include cell wall synthesis inhibitors and Aminoglycosides (irreversible protein synthesis inhibitors). Note that bactericidal drugs are preferred in immunocompromised patients such as AIDS patients, elderly, diabetics and cancer patients receiving chemotherapy because these people do not have their immunity to fight the infection so a drug is needed to kill all the bacteria. ** Note that using a bacteriostatic drug with a bactericidal drug would have an Antagonistic effect because bactericidal drugs are more effective against rapidly dividing bacteria, and their effect is reduced if bacterial growth is slowed by a bacteriostatic drug. ** Narrow-spectrum Drugs: Active against a single species or a limited group of pathogens, such as grampositive bacteria. Broad-spectrum Drugs: Active against a wide-range of pathogens gram positive and gram-negative bacteria. Use of a narrow-spectrum drug is the logical choice for treatment of an infection where the responsible specific pathogen is known. In cases of serious infection where the responsible pathogen is not yet known, a broad-spectrum bactericidal drug is often used for initial treatment. Extended spectrum: these are narrow spectrum drugs that have an intermediate range of action and can also be active against a few other species Minimum Inhibitory Concentration (MIC) is the lowest concentration of a drug at which bacterial growth is inhibited. On the basis of MIC, the organism is classified as having Susceptibility, Intermediate Sensitivity, or Resistance. Peak serum concentration of a drug should be 2-4 X greater than the MIC in order for a pathogen to be susceptible to a drug. Pathogens with intermediate sensitivity may respond to treatment with maximum doses of an antimicrobial agent. A bacterium is very susceptible to a drug if it can be eradicated with a single dose of MIC. Post-Antibiotic Effect (PAE): Antibacterial effect persisting even after the removal of the antibiotic from the culture bacterial growth is inhibited but not reduced after the antibacterial is removed. ** Fluoroquinolones (Ciprofloxacin) Aminoglycosides (Tobramycin) against gram-negative bacilli and Penicillins against gram-positive cocci ** CDKR: concentration-dependent killing rate the higher the concentration of the drug (drug conc. greater than MIC) the lower the number of viable gram-negative bacteria. ** Tobramycin and Ciprofloxacin ** In contrast, Penicillins and other Beta-Lactam Antibiotics usually do not exhibit a CDKR. The drug has to be delivered to the site of infection and is normally done so by the blood, therefore organs that have more blood flow (liver) will receive the drug faster as opposed to organs with low blood flow (bone) in which case the drug would take a longer time to reach and the infection would be harder to treat. Bacterial resistance to drugs can be innate or acquired. Acquired resistance is due to mutation or selection. Microbes can spontaneously mutate to a form that is resistant to a certain drug. There is an increased chance of bacterial mutation to a resistant form when the bacteria is exposed to a sub-optimal conc. of anti-biotic because at this conc. the drug is not enough to kill the bacteria or inhibit its growth but it is enough for the bacteria to realize that the conditions are unfavorable and it should do something to elongate its survival so it decides to mutate. This can also occur during prolonged exposure of an anti-biotic to the bacteria. Page 1 of 29

Selection of the resistant form of the bacteria can also occur when a mutation is taking place and the bacteria is exposed to sub-optimal drug conc. because that will kill all the susceptible, non-mutated bacteria but the few bacteria that were able to mutate will be resistant to the anti-biotic and will then start replicating so that all the new bacteria that is produced is of the resistant type. Transferable Resistance: Bacterial conjugation and transfer of plasmids (extra-chromosomal DNA). Bacterial conjugation enables a bacterium to donate a plasmid containing genes that encode proteins responsible for resistance to an antibiotic. These genes are called Resistance factors (R factors). R factors can be transferred not only within a particular species but also between different species, so they confer Multi-Drug Resistance (MDR). Transformation (uptake of naked DNA), Transduction (transfer of bacterial DNA by a bacteriophage) or Translocation may also mediate resistance. Primary mechanisms of microbial resistance to an antibiotic are: Inactivation of the drug by microbial enzymes ** B-lactamases ** o ** This is the major mechanism for Penicillin resistance ** o -lactamases may be inhibited by Clavulanic acid, Sulbactam, and Tazobactam. These drugs are given in conjunction with B-lactams to prevent the inactivation of the B-lactam drug. Decreased intracellular accumulation of the drug by the microbe o Increased drug efflux is mediated by membrane proteins that transport anti-microbial drugs out of bacterial cells o Decreased uptake of antimicrobial drugs may result from altered bacterial porins. o Both these mechanisms contribute to resistance of microbes to Tetracyclines and Fluoroquinolones. Reduced affinity of the target macromolecule for the drug change in PBP or binding site o Main mechanism of methicillin resistance in staphylococci and Pen G. in pneumococci Certain G- bacteria contain porins in their outer membrane, which function to let drugs pass through the outer membrane; alterations in the structure of these porins can lead anti-biotic resistance. Example: resistance against Imipenem. Resistance to Aminoglycosides is partly due to elaboration of drug-inactivating enzymes that acetylate, adenylate, or phosphorylate these antibiotics. Selection of an anti-microbial agent is based on: o Type of infection, status of the patient, pharmacological properties of the drug Antimicrobial drugs can cross placenta and may affect fetus. Use of Tetracyclines by a pregnant woman may cause damage to the teeth and bones of the fetus because the Tetracyclines deposit in areas that are high in calcium. Cephalosporins and Penicillins cause very little fetal toxicity and may be safely given to pregnant women. Note that penicillins are safest antibiotics and have the least adverse effects; they are also safe to give to pregnant women. However, penicillins are also the antibiotics, which can cause a hypersensitivity reaction and anaphylactic shock. Note that drugs such as trimethoprim (weak bases) can more readily cross the cell membrane at a blood pH of 7.4 and dissociate to the ionized form inside the cell due to the acidic pH, therefore are better to treat infections such as prostatitis due to the acidic pH of the prostate fluid. Two bactericidal drugs, acting by two different mechanisms, used concurrently exhibit a synergistic effect against susceptible bacteria. Penicillins (cell wall synthesis inhibitors) and Aminoglycosides (irreversible protein synthesis inhibitors) show synergistic effects when used together against a gram-negative bacillus such as Pseudomonas aeruginosa. Patients with heart valve problems that are undergoing dental procedures are given Amoxicillin as prophylactic treatment. If the patient cannot take Amoxicillin then they are given Erythromycin or Clindamycin. Patients undergoing surgical procedures are given Cefazolin as prophylactic treatment. Cefoxitin can also be used. Page 2 of 29

College students who are going to be living on campus are required to get a vaccine against meningitis and are given Rifampin as prophylactic treatment. Elderly people are given Amantadine as prophylactic for the flu during winter time Chloroquine is given as prophylactic treatment for malaria Isoniazid is given as prophylactic treatment for Tuberculosis

Mechanisms of action for different drug groups Penicillins disrupt cell wall synthesis by inhibiting transpeptidation (cross-linking) of the peptidoglycan and activation of autolytic enzymes. Aminoglycosides irreversibly inhibit protein synthesis by binding to the 30S subunit and blocking the formation of the initiation complex Chloramphenicol binds to the 50S subunit and blocks peptidyl transferase to inhibit protein synthesis Macrolides / Lacosamides bind to the 50S subunit to inhibit translocation inhibiting the formation of the initiation complex to stop protein synthesis Tetracyclines bind to the 30S subunit to block the attachment of aminoacyl-tRNA to inhibit protein synthesis Sulfonamides / Trimethoprim, inhibit folic acid synthesis. Quinolones / Fluoroquinolones inhibit bacterial DNA gyrase. Polyenes / Imidazoles disrupt fungal cell membranes. Daptomycin / Fosfomycin / Polymyxin B: act directly on the cytoplasmic cell membrane to increase membrane permeability causing the cell contents to leak out. CELL WALL SYNTHESIS INHIBITORS Penicillins MOA: Cell wall synthesis inhibitor. Bind to the PBPs in the cytoplasmic membrane and inhibit the transpeptidation reaction, which is responsible for the cross-linking of peptidoglycan. They also activate meurein hydrolases (autolytic enzymes) that destroy the cell wall. Penicillins are Beta Lactam drugs, meaning they have a Beta Lactam ring. This B-Lactam ring can be cleaved by B-lactamase enzymes (penicillinase), which are produced by the bacteria to make Penicillic Acid. This penicillic acid acts as an antigen and is responsible for the hypersensitivity reaction resulting in anaphylactic shock. This is also the major mechanism by which bacteria develop resistance to penicillins. Because of this, inhibitors of B-lactamases (Clavulanic acid, Sulbactam, Tazobactam) are given in conjunction with penicillins to prevent their inactivation. Note that having a larger, bulkier group with the B-Lactam ring makes it less susceptible to hydrolysis by the B-lactamases. Penicillins can cross the blood-brain barrier but only when the meninges are inflamed so penicillins can be administered via IV for the treatment of meningitis. Note that penicillins have a very short half-life and are mainly excreted unchanged in the proximal tubule of the kidney. Probenecid inhibits this excretion of penicillin and Cephalosporins by competing for secretion by the proximal tubule therefore can be added to retain the drug in the body for longer periods of time. Ampicillin and Nafcillin are excreted by the liver, in the bile, so they can be used in patients with renal insufficiency. Overall Penicillins are relatively safe and have the least side effects, they can however cause hypersensitivity reactions resulting in anaphylactic shock in susceptible individuals. Penicillins are safe to use during pregnancy. Narrow-Spectrum Penicillins Penicillin G Procaine and Benzathine (Oral or Parenteral) o Administered intramuscularly and slowly released in the body Benzathine however is hydrolyzed slowly over a period of weeks and provides low plasma concentrations whereas Procaine is hydrolyzed more rapidly and provides higher plasma concentrations for 24 hours. o ** DOC for Syphilis Page 3 of 29

** DOC for gas gangrene due to Clostridium Perfringens ** DOC for meningococcal infections ** DOC for Actinomycosis Procaine has to be given every 24 hours (once daily) but Benzathine can be given between longer time intervals o Not very acid-stable but can be given orally in high doses Penicillin V (Oral) o Penicillin VK+ form can release Na+ and K+ into the blood causing hypertension, hyperkalemia, which has drug interactions. ACE inhibitors also cause hyperkalemia and it can decrease the effect of Digoxin because it competes with K+ for binding site on the enzyme. o More acid-stable and can be given oral b/c it will have higher bioavailability o o o o

Penicillinase ( -lactamase)-Resistant Penicillins have a large, bulky R group that protects them from hydrolysis by B-lactamase enzymes. These agents are used to treat serious Staphylococcal infections, such as Acute Endocarditis and Osteomyelitis. Dicloxacillin (Oral) Cloxacillin (Oral) Nafcillin (Oral or Parenteral) o Excreted by the liver in bile so can be used in patients with renal insufficiency o Can cause neutropenia Oxacillin (Oral) Methicillin o can cause interstitial nephritis Extended-Spectrum Penicillins Amoxicillin (Oral) o Used as prophylaxis treatment for patients with heart valve problems undergoing dental work o Used to treat Otitis media o Can be used to treat Lyme disease o Combined with Clavulanic acid to prevent inactivation by penicillinases Ampicillin (Oral or Parenteral) o Highly active against Listeria Monocytogenes induced meningitis o Excreted by the liver in bile so can be used in patients with renal insufficiency o Combined with Sulbactam to prevent inactivation by penicillinases o Frequently causes a maculopapular rash o Ampicillin may cause Pseudomembranous Colitis o Other side effects are nausea and vomiting Piperacillin and Ticarcillin (Parenteral) o Anti-pseudomonal o Active against G- rods such as Pseudomonas and Klebsiella o Piperacillin combined with Tazobactam and Ticarcillin combined with Clavulanic acid Indanyl Carbenicillin (Oral) Acid-stable Penicillins Amoxicillin, Ampicillin, Cloxacillin, Oxacillin, Nafcillin, Dicloxacillin and Penicillin V & G are effective orally. Note that Pen. G and Nafcillin can be used orally but they are not as stable as the others. Acid-labile Penicillins: Piperacillin and Ticarcillin must be administered parenterally. Page 4 of 29

Penicillin adverse effects: diarrhea due to disruption of normal flora, increased effect of anti-coagulant drugs due to disruption of normal flora which produce vitamin K, increased bleeding in the joints due to decreased vitamin K, hypersensitivity reaction leading to hives and anaphylactic shock, serum sickness, hepatitis, interstitial nephritis (methicillin), maculopapular skin rash (ampicillin), neurotoxicity can lead to seizures, cation toxicity (elevated Na+ or K+) seen with Pen VK+, Pseudomembranous colitis (ampicillin), nausea, vomiting. Clavulanic acid, Sulbactam, and Tazobactam are -lactamase inhibitors that act as suicide inhibitors of -lactamase enzymes by serving as a surrogate substrate for these enzymes. Used in conjunction with Blactam drugs to prevent the inactivation of these drugs.

Cephalosporins MOA: Cell wall synthesis inhibitor. Bind to the PBPs in the cytoplasmic membrane and inhibit the transpeptidation reaction, which is responsible for the cross-linking of peptidoglycan. They also activate autolytic enzymes that destroy the cell wall. 1st generation Cephalosporins are primarily active against gram-positive cocci and a limited number of gram-negative bacilli. Subsequent generations have increased activity against gram-negative bacilli and less activity against some species of gram-positive cocci. Therefore, as they move from 1st generation 4th generation, their activity against G- bacteria increases and they become more resistant to B-lactamase enzymes. Resistance is due to decrease in membrane permeability or changes in the penicillin binding protein, but note that Cephalosporins are not very susceptible to B-lactamase enzymes. Cephalosporins exhibit cross-sensitivity with Penicillins. So, if a patient is allergic to penicillin they are most probably also going to be allergic to Cephalosporins. First-generation Cephalosporins Good activity against most G+ bacteria such as Streptococci and Methicillin-sensitive Staphylococci Cefazolin (Parenteral) o ** Used as prophylaxis treatment during surgery to prevent infections ** o Used parenterally to treat more serious infections due Staphylococci or Streptococci; UTI due to E. coli or other enteric bacilli. Cephalexin (Oral) Cephradine Second-generation Cephalosporins Cefotetan (Parenteral) o ** Can cause a Disulfiram-like reaction (like Metronidazole) if taken with alcohol ** o ** Causes platelet dysfunction increased bleeding and will increase the effect of anti-coagulant drugs such as Warfarin ** o Used against infections caused by Bacteroides Fragilis o Used for the treatment of diverticulitis and pelvic inflammatory disease Cefoxitin (Parenteral) o ** Can induce B-lactamase enzymes ** o Used against infections caused by Bacteroides Fragilis o Used for the treatment of diverticulitis and pelvic inflammatory disease Cefaclor o Active against infections caused by H. Influenzae and M. catarrhalis Cefprozil (Oral) o Can be used to treat Otitis media caused by H. Influenzae Cefuroxime (Oral or Parenteral) o Can be used to treat Otitis media caused by H. Influenzae Page 5 of 29

o Can be used to treat community acquired pneumonia Third-generation Cephalosporins 3rd generation Cephalosporins are active against Otitis media and can be used in children but since giving a child a parenteral drug is difficult, an oral drug is preferred such as Cefixime. Note that these 3rd generation Cephalosporins can cross the Blood brain barrier (except Cefoperazone and Cefixime) so they can be used to treat meningitis. These drugs are normally reserved for patients with severe infections such as immunocompromised patients. Cefixime (Oral) o Can be given to children for the treatment of Otitis media because it can be taken orally o Cannot cross the BBB o ** DOC for Neisseria Gonorrhea ** Ceftriaxone (Parenteral) o Most commonly used 3rd generations Cephalosporin o ** Excreted by the liver can be used in patients with renal insufficiency ** o ** DOC for Neisseria Gonorrhea ** o A single injection is effective in the treatment of Otitis media o Has a much longer half life because it is excreted by the kidney Cefoperazone o ** Excreted by the liver can be used in patients with renal insufficiency ** o Cannot cross the BBB Cefotaxime (Parenteral) o ** DOC for Neisseria Gonorrhea ** Ceftazidime (Parenteral) o active against Pseudomonas Aeruginosa Fourth-generation Cephalosporins Cefepime (Parenteral) o Primarily indicated for the treatment of infections due to multidrug-resistant bacteria Monobactams Aztreonam o ** Only active against G bacteria ** o Gram + bacteria are innately resistant to Aztreonam because their PBPs do not bind to this drug. o MOA: binds to PBP3 and inhibits cell wall synthesis o Resistant to B-lactamases produced by G- bacteria therefore can be used to treat Pseudomonas, Klebsiella, and Serratia. o Used with Aminoglycosides for synergistic effect o Aztreonam is used to treat serious infections, and is particularly useful for multidrug-resistant strains of Pseudomonas aeruginosa. o Does not have any cross-reactive allergic reactions with penicillin meaning it can be used in a pt. that is allergic to penicillin o Aztreonam is excreted through the kidney so does should be adjusted in patients with renal failure o May cause seizures, leukopenia, vertigo, headache, skin rash Carbapenems These are also monobactam rings that contain a B-lactam ring that has C in it. These drugs are active against both G- and G+ bacteria and are mainly used to treat nosocomial infections. Imipenem o MOA: binds to PBP2 and inhibits cell wall synthesis Page 6 of 29

o ** DOC for Enterobacter infections ** o ** Imipenem is rapidly metabolized by Renal Dehydropeptidase I therefore is administered with Cilastatin, an inhibitor of this enzyme ** o Cilastatin increases the plasma half life of Imipenem and inhibits the formation of a potentially nephrotoxic metabolite o At high doses Imipenem can cause CNS toxicity seizures, confusion, encephalopathy

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Meropenem o MOA: binds to PBP2 and PBP3 to inhibit cell wall synthesis o ** DOC for Enterobacter infections ** o Since it binds to PBP3 it is more active against Enterobacter o Not metabolized by Renal Dehydropeptidase o Less likely to cause seizures

Other drugs that also inhibit the cell wall synthesis but are not B-lactam drugs because they do not have Blactam rings and cannot be inactivated by B-lactamases. Bacitracin o MOA: inhibits cell wall synthesis by inhibiting dephosphorylation of bactoprenol pyrophosphate o ** Very nephrotoxic so it is limited to topical use only ** o Combined with Neomycin or Polymyxin B in ointments and creams o Active against G+ bacteria Polymyxin B o ** Very nephrotoxic so it is limited to topical use only ** o MOA: disrupts the cell membrane causing the cell contents to leak out and cell death o Combined with Bacitracin or Neomycin in ointment form o Used as ointment for skin or ophthalmic infections Fosfomycin o MOA: inhibits cell wall synthesis at a very early stage by inhibiting enolpyruval transferase this action prevents the formation of N-acetylmuramic acid o Binds to cytoplasmic cell membrane causing cell contents to leak out of the cell o FDA approved for use during pregnancy o Excreted by the kidney so it is to treat lower UTIs due to E. Coli o MIC is exceeded to treat many UTI pathogens o Administered orally as a single dose o Resistance is due to decreased intracellular concentrations of the drug Vancomycin o MOA: binds to D-Ala D-Ala terminal and inhibits trans-glycosylation o Vancomycin is a narrow-spectrum drug and is active only against G+ bacteria o Used for MRSA (methicillin-resistant staphylococci) but if Vancomycin wont work either then use Linezolid o Used orally for the treatment of Pseudomembranous Colitis if Metronidazole cannot be used o Can cause ** nephrotoxicity, ototoxicity, and phlebitis ** -- should not be combined with other drugs that cause nephrotoxicity such as Amphotericin B and Aminoglycosides. o Rapid IV infusion can result in the release of Histamine causing flushing and an erythematous rash on the face and neck known as the Red Man Syndrome therefore it is always diluted with saline. o For systemic infections vancomycin is always given via IV, but for infections such as Pseudomembranous colitis it is give orally o Note that Vancomycin is not susceptible to penicillinases Cycloserine o * Exclusively used as a second line drug to treat TB when first line drugs dont work * o ** NEUROTOXICITY seizures, tremors, psychosis ** o MOA: blocks the incorporation of D-Ala into the peptidoglycan Daptomycin o Can cause Myopathy elevated serum creatinine kinase levels o MOA: disrupts the cell membrane causing the cell contents to leak out and cell death Page 8 of 29

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 PROTEIN SYNTHESIS INHIBITORS Aminoglycosides MOA: irreversibly inhibit protein synthesis by binding to the 30S subunit and preventing the formation of the initiation complex. In addition to this, Aminoglycosides cause miscoding in the peptide chain and can cause the insertion of a premature stop codon and block translocation, which also inhibit protein synthesis. Note that Aminoglycosides are poorly absorbed from the gut and must be administered parenterally for systemic infections. Aminoglycosides do not penetrate the meninges, even when they are inflamed so they cannot be used to treat meningitis, but note that Aminoglycosides can be administered intrathecally in conjunction with Cephalosporins to treat meningitis. Aminoglycosides are not metabolized, and are excreted primarily by renal glomerular filtration, with little reabsorption. *** AMINOGLYCOSIDES ARE NEPHROTOXIC AND OTOTOXIC should not be given during pregnancy can cause ototoxicity in the growing baby!!! *** Patients may suffer from both vestibular (dizziness, vertigo, N/V, nystagmus, impaired vision) and cochlear (tinnitus, impaired hearing) toxicity. Should not be used in conjunction with other drugs that can cause ototoxicity such as Loop diuretics, Vancomycin, and Amphotericin B. ** Aminoglycosides are the most common cause of drug-induced renal failure! ** The drugs accumulate in proximal tubular cells causing tubular necrosis, reducing renal function and leading to a rise in plasma concentrations and further impairing renal function and contributing to the ototoxicity. Bacterial resistance to Aminoglycosides is primarily due to inactivation of drugs by bacterial acetylase, adenylase, and phosphorylase enzymes. These enzymes attach acetyl, adenyl, or phosphoryl groups to the amino groups on the antibiotics, and prevent inhibition of bacterial protein synthesis. Resistance may also occur due to decreased binding to 30S ribosomal subunit or to decreased uptake of the drug via porins in bacterial membranes. Aminoglycosides are more active against G- bacilli such as Pseudomonas and Enterobacter. Aminoglycosides exhibit concentration-dependent killing rate (CDKR). As the concentration of the drug is increased, more bacteria are killed. Aminoglycosides also exhibit Post-Antibiotic Effect (PAE) even after the drug has been removed from the body, its effect persists for hours. ** Aminoglycosides are contraindicated in Myasthenia Gravis b/c they can cause neuromuscular block and decrease release of ACh, can potentiate the effect of neuromuscular blocking drugs respiratory paralysis can be counteracted with Neostigmine or Calcium. ** Amikacin o Expensive drug and is reserved for serious infections which are resistant to other Aminoglycosides because it is more resistant to inactivation by acetylases, adenylases, and phosphorylases o Causes more cochlear toxicity o 2nd line drug for TB Gentamicin o Least expensive and most commonly used and can be used in combination with penicillins o Causes more vestibular toxicity and is the most nephrotoxic Neomycin and Kanamycin o Used as an ointment for skin or ophthalmic bacterial infections o ** MOST NEPHROTOXIC so it is limited to topical use only ** o Can be used GIT sterilization o Used to in hepatic coma to suppress coliform bacteria reducing ammonia (nitrogen) intoxication Streptomycin o Used to treat multi-drug resistant Tuberculosis o Used in combination with Pen. G for the treatment of enterococcus carditis o Causes more vestibular toxicity Tobramycin o Has CDKR and PAE activity and is the most nephrotoxic Page 10 of 29

 Netilmycin o Can be used as ophthalmic ointment for ocular infections, but not used for systemic infections Spectinomycin o It is an aminocyclitol structure drug related to aminoglycosides o MOA: binds to the 30S subunit and inhibits the formation of the initiation complex o ** Used to treat Neisseria Gonorrhea in patients allergic to 3rd generation Cephalosporins * Tetracyclines MOA: inhibit protein synthesis by binding to 30S subunit and blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA complex. This prevents the addition of new amino acids to the growing peptide chain. ** DO NOT USE DURING PREGNANCY can get deposited in the growing TEETH and BONES of the fetus ** Tetracyclines are used to treat Lymes disease, Vibrio Cholera, Rocky Mountain Spotted Fever due to Rickettsiae, Chlamydia Trachomatis, Relapsing Fever, and Acne. Tetracyclines enter microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport (pump). Main mechanism for resistance is efflux of the drug out of the cell. Tetracycline-resistant strains remain susceptible to Doxycycline or Minocycline because these drugs are not transported out of the cell as fast as the others. Note: oral absorption of these drugs may be impaired by food, multivalent cations (Ca+, Fe, Al), dairy products, and antacids that cause alkaline pH (except Doxycycline and Minocycline) Adverse effects: nausea, vomiting, diarrhea, hepatotoxicity, nephrotoxicity (Fanconis Syndrome), tooth enamel dysplasia, gray mottling of teeth, irregularities of bone growth, phototoxicity, dizziness and vertigo Doxycycline o Still active against resistant strains because it is not pumped out of the cell as fast o ** Can be used in patients with renal insufficiency because it goes thru entero-hepatic cycling ** o Absorption is not impaired due to any of the above o ** DOC for Lymes disease ** o ** DOC for Chlamydia Trachomatis ** o May cause dizziness and vertigo Minocycline o Still active against resistant strains because it is not pumped out of the cell as fast o Absorption is not impaired due to any of the above o May cause dizziness and vertigo Tetracycline o ** Used for the treatment of Helicobacter Pylori related gastric ulcers ** Demeclocycline o ** Used for the treatment of SIADH or ADH secreting tumor ** o MOA: inhibits the action of ADH o ** Can cause phototoxicity due to deposition in the skin and sensitivity to UV light erythema ** Methacycline Tigecycline o This drug is useful for strains that are resistant to other Tetracyclines Macrolides MOA: inhibits protein synthesis by binding to 50S subunit and blocking aminoacyl translocation to inhibit formation of initiation complex. Macrolides are not very effective against Klebsiella. Page 11 of 29

 Resistance is due to the efflux pumps kicking the drug out of the cell and production of methylene adds a methyl group to the ribosomal binding site.

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 Erythromycin o ** Enzyme inhibitor ** o ** Safe to use in patients with renal failure ** o Erythromycin estolate can produce ** acute cholestatic hepatitis ** as a hypersensitivity reaction, resulting in fever, jaundice and impaired liver function. o Destroyed by stomach acid so it is administered with enteric coating o ** DOC for corynebacterium, diptheria ** o ** DOC for respiratory, neonatal, ocular or genital Chlamydia infections ** o ** DOC for community-acquired pneumonia due to Chlamydia pneumoniae ** o Given as prophylaxis for people with valve heart disease undergoing dental work o I.V. Erythromycin may cause Thrombophlebitis and Ototoxicity resulting in tinnitus or impaired hearing o Should not be used during pregnancy Clarithromycin o ** Enzyme inhibitor ** o ** Used for the treatment of Helicobacter Pylori related gastric ulcers ** o Note that it is more active against H. Pylori than other drugs because it can be used for only 7-10 days and have the same effect whereas the other drugs have to be used for at least 2 weeks o Should not be used during pregnancy Azithromycin o Safer to use during pregnancy o Absorption is inhibited by food o Can be used as single-dose treatment of uncomplicated Chlamydia urethritis o Prophylactic against M. avium in AIDS patients Dirithromycin Telithromycin o More stable than Erythromycin and is less likely to get kicked out of the cell because it binds more tightly to the ribosomes and is a poor substrate for bacterial efflux pumps that mediate resistance o FDA approved for mild community-acquired pneumonia o ** Contraindicated in patients with Myasthenia Gravis because it blocks the neuromuscular junction inhibiting the release of ACh so it can exacerbate the effects of Myasthenia Gravis ** o Can cause hepatotoxicity leading to liver failure, visual disturbances, and fainting episodes Chloramphenicol MOA: inhibits protein synthesis by binding to 50S subunit and blocking peptidyl transferase. Note that Chloramphenicol can cross the BBB even when the meninges are not inflamed. Therefore it is effective in Pneumococcal-, Meningococcal or H. influenzae induced ** meningitis ** Also used as a back up drug for severe infections caused by Salmonella species It is conjugated w/ glucuronide by hepatic glucuronosyltransferase and is excreted 90% in the urine unchanged; only 10% is excreted as an inactive compounds. Note that neonates do not have glucuronide transferase activity, that leads to higher Chloramphenicol concentrations causing Gray Baby Syndrome decreased RBCs, cyanosis, cardiovascular collapse Note that doses do not need to be adjusted in patients with renal failure but must be reduced in patients with liver failure Chloramphenicol is a CYP450 enzyme inhibitor 2 types of adverse effects are seen o Dose-dependent inhibition of red cell maturation leading to a decrease in RBCs (reversible) o Dose-independent ** aplastic anemia ** (irreversible and may be fatal) Page 13 of 29

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 Clindamycin MOA: inhibits protein synthesis by interfering with formation of initiation complex and aminoacyl translocation reactions ** Most common cause of drug-induced Pseudomembranous colitis ** Active against Pneumocystis pneumonia when used with primaquine for AIDS patients Used as prophylaxis treatment in patients with valvular defects undergoing dental work Streptogramins Quinupristin-Dalfopristin o Act synergistically to inhibit bacterial protein synthesis when administered in a ratio of 30 parts of Quinupristin and 70 parts of Dalfopristin o Used in cases of Bacteremia, Peritonitis, Endocarditis, or Aortic Graft infections caused by Vancomycin-resistant organisms o Used to treat severe life-threatening infections o CYP450 enzyme inhibitors Linezolid MOA: binds to 23S site ** Used against Vancomycin resistant Staphaureus ** Can cause thrombocytopenia can potentiate the effect of anti-coagulants *** Only approved for G+ bacteria *** Patients treated with Linezolid had a higher chance of death than those treated with comparator drugs INHIBITION OF NUCLEIC ACID SYNTHESIS Sulfonamides MOA: inhibit folic acid synthesis by binding and blocking Dihydropteroate Synthase. Sulfonamides are bacteriostatic PABA analogs so they compete with PABA for binding to this enzyme Note that Sulfonamide drugs are weakly acidic compounds that are more soluble at alkaline pH Solubility is decreased at acidic pH causing the drugs to crystallize, so in acidic urine the drug will precipitate to form crystal like stones crystalluria Local anesthetic esters are metabolized to PABA and sunscreen contains PABA so using these with Sulfonamides can reduce the effect of Sulfonamides because remember that Sulfa drugs compete with PABA for binding to Dihydropteroate Synthase so if PABA conc. is increased it will have more chances of binding to the enzyme Sulfonamides can cross the BBB even when the meninges are not inflamed These drugs are not active on human cells because eukaryotic cells do not synthesize folic acid, it is taken in the diet Sulfonamides are heavily protein bound and can displace Warfarin Adverse effects: The most common adverse effect of Sulfonamides is skin rashes and urticaria; because they inhibit the formation of folic acid, they can cause aplastic anemia. Acute hemolysis may occur in people with Glucose-6-Phosphate Dehydrogenase deficiency. ** Can cause Kernicterus in neonate because it can displace Bilirubin from plasma proteins ** Oral, absorbable Sulfisoxazole o Has a good taste so can be given to children to treat Otitis media o More soluble at acidic pH and less likely to cause crystalluria o Used to treat uncomplicated simple Urinary Tract infection

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 Sulfamethoxazole o Sulfamethoxazole + Trimethoprim Spectra of Bactrim o More soluble at acidic pH and less likely to cause crystalluria o Used to treat uncomplicated simple Urinary Tract infection o But can treat complicated UTI when combined with Trimethoprim Sulfadiazine o Used with Pyrimethamine to treat Toxoplasmosis o Used with Pyrimethamine to treat Chloroquine-resistant malaria Oral nonabsorbable Sulfasalazine o Used to treat Ulcerative Colitis, and Rheumatoid Arthritis Topical Sulfacetamide o Used topically as ophthalmic ointment for Ocular infections Blepharitis, conjunctivitis, Trachoma Silver Sulfadiazine o Used topically for Burn infections Trimethoprim MOA: inhibits folic acid synthesis by blocking Dihydrofolate Reductase Weakly basic drug that crosses the cell membrane and gets trapped inside the cell due to its acidic environment and has high concentrations in prostatic and vaginal fluids Used in combination with Sulfamethoxazole for synergistic activity by sequential blockade of folate synthesis. Sulfamethoxazole + Trimethoprim: complicated UTI and URTIs ** DOC for Pneumocystis jiroveci pneumonia ** Sulfamethoxazole + Trimethoprim: used for prevention and treatment of toxoplasmosis in AIDS patients DOC for Nocardiosis Can be used for Prostatitis due to its high concentration in prostatic fluid Also used for Shigella infections and systemic Salmonella infections Note that Pyrimethamine and Methotrexate also inhibit DHF Adverse effects: megaloblastic anemia (need to give folic acid supplements), leukopenia Resistance due to reduced cell permeability, overproduction of dihydrofolate reductase, or altered reductase with reduced drug binding. FLUOROQUINOLONES MOA: inhibit bacterial DNA synthesis by blocking DNA gyrase (topoisomerase II) in gram-negative bacteria and DNA gyrase (topoisomerase IV) in gram-positive bacteria. this blocks the relaxation of supercoiled DNA note that this does not effect eukaryotic cells because they do not have the same topoisomerase. Fluoroquinolones are bactericidal and exhibit concentration-dependent killing rate (CDKR). As the concentration of the drug is increased, more bacteria is killed. Fluroquinolones also exhibit Post-Antibiotic Effect (PAE) even after the drug has been removed from the body, its effect persists for hours. Note that as the generations increase, activity against G+ bacteria increases. These drugs are more suitable for female infections endometrium, ovaries, fallopian tubes Like Tetracyclines, the absorption of these drugs is inhibited by cations (Ca+, Fe, Mg+, Zn+) Tubular secretion can be blocked by Probenecid ** Fluoroquinolones should not be used in children under 18 because they can damage the cartilage causing arthralgia, tendonitis, and tendon rupture ** contraindicated in pregnancy because they can cause cartilage defects in growing fetus Page 16 of 29

 ** Fluoroquinolones inhibit the metabolism of methylxanthine (caffeine, Theophylline) leading to their toxicity tachycardia, convulsion, nausea, vomiting, sleeplessness ** First generation Norfloxacin o Mainly used to treat UTIs because it does not achieve sufficient concentrations in blood and tissues so it cannot be used to treat systemic infections Second Generation Ciprofloxacin o Treat Travelers diarrhea caused by E. Coli o Prophylactic treatment for anthrax o 2nd line drug for TB Ofloxacin o Effective against Chlamydia Trachomatis Third Generation Levofloxacin o Treats Prostatitis o Treats community-acquired pneumonia o 2nd line drug for TB Moxifloxacin o ** Causes severe hepatotoxicity ** o Contraindicated in hepatic failure patients Sparfloxacin o ** QT interval Torsade de pointes ** o * Can cause phototoxicity * Fourth Generation Trovafloxacin o ** Causes sever hepatotoxicity ** o Contraindicated in hepatic failure patients Nitrofurantoin Antibacterial activity is localized to the urinary bladder only used for UTI!!! At lower concentrations it is bacteriostatic but at higher concentrations is it bactericidal MOA: decomposed to a highly reactive intermediate that causes damage to bacterial DNA Nitrofurantoin (100 mg/d) can be given for months for the suppression of chronic UTI Contraindicated in patients with renal failure ** Neuropathies and hemolytic anemia occur in patients with G6PD deficiency **

Methamine For urinary tract infections Methamine Formaldehyde lethal to bacteria This conversion can only occur in acidic pH so methamine is given with Mendalic Acid to keep the urine acidic Metronidazole ** Treats Pseudomembranous Colitis ** Well absorbed from gut and widely distributed to tissues and fluids, including the liver and CSF. Extensively metabolized in the liver before renal excretion. ** DOC for Entamoeba histolytica, Giardia lamblia, Trichomonas vaginalis ** Page 17 of 29

 Selectivity for anaerobes is due to highly reactive nitro molecules that produce a cytotoxic effect by affecting DNA and protein synthesis. ** Metronidazole also causes a Disulfiram-like rxn with ethanol, patients should be instructed to avoid alcohol Metronidazole increases the anticoagulant effect of Warfarin, Warfarin dose should be adjusted Antimycobacterial Drugs Therapy is usually initiated with a four-drug regimen of Isoniazid, Rifampin, Pyrazinamide, and either Ethambutol or Streptomycin the primary reason for the use of drug combinations is to prevent resistance Pregnant women should be treated with INH, RIF and EMB do not use Pyrazinamide in pregnant women Directly observed therapy (DOT) is recommended in non-compliant patients and in drug-resistant Tuberculosis First-line Drugs: Initially used to treat most patients with T.B. Isoniazid o MOA: inhibits the synthesis of mycolic acids o Bactericidal prodrug that is activated by catalase peroxidase which is expressed by the katG gene, so people with deletion of the katG gene are innately resistant to Isoniazid o Active against intracellular and extracellular bacteria o ** Age-related hepatotoxicity patient under 35 will most probably not develop hepatic problems but patient over 35 will ** o Acetylhydrazine is considered to be responsible for the drugs hepatotoxicity o Acetylated to Acetyl-Isoniazid (Arabs are fast acetylators, Japanese are slow acetylators) o Can cause neurotoxicity peripheral neuritis, restlessness, muscle twitching, insomnia o Neuropathy can be due to vitamin B6 (pyridoxine) deficiency o Can cause RBC hemolysis in people with glucose-6-phosphate dehydrogenase deficiency o Can inhibit the metabolism of Phenytoin Rifampin o ** ENZYME INDUCER ** (if Cyclosporine is given to a transplant patient who is also on Rifampin, pt. may have a graft rejection) o MOA: inhibits DNA-dependent RNA polymerase and inhibits RNA synthesis o Active against intracellular and extracellular bacteria o Never used alone o Prophylaxis to prevent meningitis o Can be used to treat osteomyelitis and endocarditis o Recommended with Vancomycin or Ceftriaxone to treat meningitis o Adverse effects: orange color to urine, sweat, tears and contact lenses o Can cause a hypersensitivity rxn with flu-like symptoms Pyrazinamide o MOA: lowers the pH inside the cell causing the death of the bacteria o Taken up macrophages and is active against intracellular bacteria o It a prodrug that is activated inside the cell by Pyrazinamidase o ** Do not use in pregnant women ** o Can also cause hyperuricemia leading to an acute gout attack Streptomycin o Only active against extracellular bacteria o An aminoglycoside so it is nephrotoxic and ototoxic Ethambutol o MOA: inhibits arabinosyl transferase to stop mycobacterial cell wall synthesis o Adverse effects: visual disturbances red-green color blindness, optic neuritis, retinal damage o Can also cause hyperuricemia leading to an acute gout attack Page 18 of 29

Second-line Drugs (plus Ciprofloxacin, Levofloxacin, Amikacin, and Clofazimine) Cycloserine o ** NEUROTOXICITY seizures, tremors, psychosis ** Capreomycin o AMG so nephrotoxic and ototoxic

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 Ethionamide o MOA: blocks mycolic acid synthesis o Causes extreme gastric irritation and neurological problems Aminosalicylic acid (PABA) o Treats Multi-drug resistant TB o Structure similar to PABA o Can cause epigastric pain Rifapentine, Rifabutin o MOA: inhibit DNA-dependent RNA polymerase o Used to prevent atypical mycobacterial (MAC) infection in AIDS patients Leprosy Drugs MOA: inhibit the synthesis of folic acid Dapsone o Used with Rifampin o Heavily concentrated in the skin and can stay in the skin even after treatment is stopped o Can cause a Lupus-like syndrome o People with glucose-6-phosphate dehydrogenase deficiency can develop hemolytic anemia due to oxidation of erythrocyte membranes by Dapsone Diaminodiphenylsulfone Clofazimine o Has anti-inflammatory effect o MOA: enhances the phagocytic activity of macrophages and neutrophils o ** Can cause brownish-black discoloration of the skin ** o Use is chiefly limited to Sulfone-resistant patients or intolerance to sulfone o Can cause Erythema Nodosum o May elevate hepatic enzyme levels and may cause hepatitis ANTI- FUNGAL DRUGS Polyene Antibiotics MOA: bind to ergosterol in fungal membranes, forming pores and increasing fungal membrane permeability. Increased cell permeability allows cytoplasmic contents to escape from the cell leading to cell death. Amphotericin B o IV to treat severe systemic and subcutaneous mycoses o ** DOC for life-threatening mycotic infections ** o Amphotericin B lipid complex protects kidneys and other organs from drugs toxicity while preserving its antifungal activity but alone it can cause severe nephrotoxicity! o Used in combination with Flucytosine to treat Cryptococcal meningitis and Aspergillosis because they have a synergistic effect, Amphotericin B disrupts the cell membrane so Flucytosine can get inside the cell. o 2 types of adverse effects: Immediate and Late. Immediate reactions may be due to Histamine release and include chills, fever, flushing, vomiting, headache and hypotension. These can be minimized by pre-medication with anti-pyretics, acetaminophen, aspirin, anti-histamines, Meperidine or corticosteroids. Long-term effects include, azotemia (accumulation of Nitrogenous substances in the body), hypokalemia and hypomagnesemia which can lead to cardiac arrhythmias and interfere with Digoxin activity. Natamycin o Topically to treat superficial Candida infections Page 20 of 29

o Ophthalmic suspension for treatment of fungal Blepharitis, Conjunctivitis, or Keratitis Nystatin (nasty tasting) o Topically to treat superficial Candida infections Azole Derivatives MOA: inhibit ergosterol synthesis by blocking 14--demethyalse which converts lanosterol to ergosterol Note that all Azoles are enzyme inhibitors but Ketoconazole is the most potent enzyme inhibitor Azoles are used for mild to moderate fungal infections Clotrimazole (diazole) o Treat oral thrush because it has a better taste compared to Nystatin o For Vulvovaginal Candidiasis Econazole (diazole) Ketoconazole (diazole) o ** Most potent enzyme inhibitor ** o Lipophilic so it is better absorbed when taken with fatty foods o ** Requires acidic pH for absorption which can be inhibited by antacids ** o ** Inhibits testosterone and cortisol so it is used in patients with prostatic carcinoma ** Miconazole (diazole) o For Vulvovaginal Candidiasis Fluconazole (triazole) o ** Highest CSF concentration ** used to treat Cryptococcus fungal meningitis o Fluconazole has high CNS concentrations, so can be used prophylaxis treatment for fungal meningitis, so after pts condition is controlled give Fluconazole to prevent re-infection o ** Not active against dermatophytes (tineas) or aspergillosis ** o Fluconazole is excreted by the kidney so it can be used to treat ** fungal UTI ** o DOC for oropharyngeal and esophageal candidiasis o DOC for Coccidioides o Single oral dose is sufficient for vaginal candidiasis Itraconazole (triazole) o ** Requires acidic pH for absorption which can be inhibited by antacids ** o ** DOC for Sporothrix and Blastomycoses infections ** Voriconazole (triazole) o Can cause visual disturbances o Active against Fluconazole resistant Candidiasis Echinocandins Caspofungin o MOA: inhibits cell wall synthesis by inhibiting the synthesis of -glucan o Salvage therapy for Aspergillosis if patient does not respond to Amphotericin B and Flucytosine o Can cause flushing due to histamine release Allylamine Drugs MOA: inhibit ergosterol synthesis by blocking squalene monooxygenase epoxidase leading to the accumulation of the sterol squalene, which interferes with ergosterol synthesis Primarily used to treat ** dermatophytes ** Naftifine Terbinafine o DOC for Onychomycosis (finger nail fungal infection) o * Can cause severe hepatotoxicity * Page 21 of 29

Fungicidal

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 Other Antifungal Drugs Ciclopirox o MOA: bind to ergosterol in fungal membranes, forming pores and increasing fungal membrane permeability. Increased cell permeability allows cytoplasmic contents to escape from the cell leading to cell death. Flucytosine o MOA: permeates the cell membrane by cytosine permease and is deaminated to 5-FU in the cell by cytosine deaminase. 5-FU is then converted to 5-fluorodeoxyuridine monophosphate (F-dUMP) and fluoruridine triphosphate (FUTP). F-dUMP inhibits thymidylate synthase and interferes with DNA synthesis, while FUTP incorporates into fungal RNA and disrupts protein synthesis. o Note that human eukaryotic cells do not have cytosine deaminase. o ** Used with Amphotericin B to treat cryptococcal meningitis ** o 5-FU can cause bone marrow toxicity anemia, leukopenia, and thrombocytopenia Griseofulvin o MOA: disrupts microtubules o ** Enzyme inducer ** o ** Lipophilic take with fatty meal to increase absorption ** o Should NOT be used in patients with porphyria o Can cause a Disulfiram-like rxn with alcohol Tolnaftate o Effective topically against dermatophytes o Tolnaftate is available as a cream, solution, powder or powder aerosol for application twice daily to infected areas ANTI-VIRAL DRUGS Drugs used for Herpes and CMV MOA: nucleoside analog prodrugs that enter the cell and are phosphorylated by viral and host cell kinases to form active triphosphate metabolites. First they are converted to monophosphate metabolites by thymidine kinase produced by the virus in the infected host cells, contributing to selective toxicity of the analogues. Host cell kinases then convert monophosphates to active triphosphate metabolites. Active metabolites then compete with endogenous nucleoside triphosphates to competitively inhibit viral DNA polymerase and Acyclovir, Ganciclovir, and Cidofovir incorporate into the viral genome to cause premature chain termination. Inhibition of DNA polymerase prevents synthesis of viral DNA Note: Ganciclovir is activated by viral produced phosphotransferase Loss of thymidine kinase activity is the major cause of innate and acquired resistance to Acyclovir Foscarnet, Cidofovir, and Trifluridine do not require activation by thymidine kinase so they are only activated by host kinases to diphosphates Cidofovir and Foscarnet are very nephrotoxic Acyclovir used orally for Herpes Simplex o Guanosine analog that acts as a competitive substrate for DNA polymerase and incorporates into the viral DNA causing premature chain termination ** o ** DOC for Herpes Encephalitis ** can cross the BBB and is used via IV o DOC for neonatal Herpes Simplex infections o DOC for serious Varicella-Zoster infections Valacyclovir used orally for Herpes Simplex o Converted to Acyclovir in the intestines o Is converted to Acyclovir, it inhibits DNA polymerase and causes premature chain termination Page 23 of 29

o 1-day treatment of oro-labial herpes o Effective in preventing CMV disease after organ transplantation Famciclovir used orally for Herpes Simplex o Converted to Penciclovir in the intestines o Has the highest bioavailability o Inhibits DNA polymerase o Orally for genital herpes and Acute Herpes-Zoster (Shingles) Penciclovir used topically as an ointment for Herpes Simplex o Inhibits DNA polymerase Trifluridine used topically for Herpes Simplex o Less selective and incorporates into both viral and host DNA so if used systemically it can cause damage to human cells so it is only used topically for the treatment of keratitis and keratoconjunctivitis Cidofovir used for CMV o Treats CMV retinitis in patients who do not respond to Ganciclovir o Does NOT require thymidine kinase so it is activated to Cidofovir diphosphate o Acts as a competitive substrate for DNA polymerase and incorporates into the viral DNA causing premature chain termination o Probenecid blocks renal tubular secretion and decreases nephrotoxicity of Cidofovir Fomivirsen used for CMV o Anti-sense oligonucleotide that binds to mRNA of CMV and inhibits protein synthesis Ganciclovir used for CMV o ** DOC for CMV ** o DOC for CMV retinitis in AIDS patients o Intraocular implant form can be used in CMV retinitis o DOC for CMV esophagitis and colitis o Activated by viral phosphotransferase o Acts as a competitive substrate for DNA polymerase and incorporates into the viral DNA causing premature chain termination o Adverse effects: nephrotoxicity, retinal detachment, vitreous hemorrhage, neutropenia Foscarnet used for CMV, HSV, HIV o ** Very nephrotoxic ** Saline preloading helps to prevent nephrotoxicity or used w/ Probenecid o Pyrophosphate that has a specific binding site on DNA polymerase o Inhibits DNA polymerase, RNA polymerase, and HIV reverse transcriptase o Can cause penile ulcers due to high levels of ionized form in the urine HIV Drugs HAART highly active retroviral therapy Reverse Transcriptase RNA dependent DNA polymerase HIV is an RNA virus that is classified as Retrovirus. Once HIV enters CD4+ cell, viral RNA serves as a template to produce a complementary double-stranded DNA catalyzed by reverse transcriptase (RNA-dependent DNA polymerase). This viral DNA then enters host cell nucleus and is incorporated into host genome in a reaction catalyzed by HIV integrase. Eventually, viral DNA is transcribed and translated to produce large, nonfunctional polypeptides called polyproteins. Polyproteins are packaged into immature virions at cell surface. As these virions are released into plasma, an enzyme called HIV protease cleaves polyproteins into smaller, functional proteins in a process called viral maturation. Reverse Transcriptase inhibitors and Protease Inhibitors are the major drugs used to treat HIV. CCR-5 and HIV integrase are mainly given to treatment-experienced patients Page 24 of 29

 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) MOA: inhibit reverse transcriptase and incorporate into the viral DNA to cause premature chain termination ** Require phosphorylation to triphosphate form for activation ** ** Adverse effects: Lactic acidosis and severe hepatomegaly with Steatosis ** Note: Lamivudine and Abacavir do not cause that much lactic acidosis Note that diabetes, obesity, and alcohol can contribute to the lactic acidosis ** NRTIs are all excreted after conjugation with glucoronide ** Abacavir o Does NOT cause that much lactic acidosis o Metabolized by alcohol dehydrogenase, so if patient is consuming alcohol it may increase the concentration of Abacavir leading to toxic concentrations o Can cause a hypersensitivity rxn that can recur and be fatal if drug is re-administered Didanosine o ** Should be taken on empty stomach because food can inhibit its absorption ** o ** Can cause pancreatitis and neuropathy ** o Should not be used with Zalcitibine b/c it also causes pancreatitis and neuropathy Lamivudine o Does NOT cause that much lactic acidosis o ** Has longer half life in Hepatitis B infected cells used to treat Hepatitis B ** o ** Used with Zidovudine in case of accidental pin prick for 4 weeks ** Stavudine o Zidovudine may reduce the phosphorylation of Stavudine, these two drugs should not be used together Zalcitabine o ** Can cause pancreatitis and neuropathy ** o Should not be used with Didanosine b/c it also causes pancreatitis and neuropathy Zidovudine (AZT) can be used via IV o ** Prevention of vertical HIV transmission to baby during child birth ** o ** With Lamuvidine in case of accidental pin prick for 4 weeks ** o Zidovudine may reduce the phosphorylation of Stavudine, these two drugs should not be used together o Can be used for HIV-associated dementia and thrombocytopenia o Adverse effects: myelosuppression which may increase if used with Ganciclovir o Withdrawal of AZT exposure may cause the reversion of a previously Zidovudine-resistant HIV strain to be susceptible Emtricitabine Non-Nucleoside Reverse Transcriptase Inhibitors(NNRTIs) ** NNRTIs do not require phosphorylation to become active ** ** MOA: NNRTIs inhibit the reverse transcriptase but do not get incorporated into the viral dna ** Adverse effects: skin rash Steven Johnson syndrome Delavirdine o Do not use during pregnancy Efavirenz o Do not use during pregnancy o ** Highly protein bound ** Nevirapine Page 25 of 29

o ** Prevention of vertical HIV transmission to baby during child birth ** o Enzyme inhibitor and enzyme inducer Etravirine o Can bind reverse transcriptase in various conformations so this drug has a higher chance of binding mutated or resistant strains approved for treatment experienced patients Nucleotide Reverse Transcriptase Inhibitors Tenofovir o MOA: competitively inhibits HIV reverse transcriptase and is incorporated into DNA causing chain termination Protease Inhibitors (navirs are protease inhibitors) MOA: inhibit the formation of functional viral protein by inhibiting aspartyl protease. By preventing cleavage of polyproteins, protease inhibitors produce immature, noninfectious viral particles. p-glycoproteins can pump the drug out of the cell which can be inhibited by Verapamil, Ca+ channel blockers, Quinidine, and Phenothiazenes. ** PIs Lipodystrophy syndrome causing redistribution of fat causing central obesity, buffalo hump, breast enlargement ** PIs also cause increase in glucose intolerance due to insulin resistance and increase in Triglyceride levels Give with fatty food to increase their absorption All protease inhibitors are enzyme inhibitors but Ritonavir is the most potent enzyme inhibitor o o o o o o o o o o o o Fosamprenavir ** Contains propene glycol and is contraindicated in pregnancy and young children ** ** Contraindicated in patients with hepatic insufficiency ** Atazanavir can be used once daily, this is a major advantage and increases patient compliance Less likely to cause lipodystrophy Chemically unrelated to other PIs so it may not be cross-resistant Indinavir ** Should be taken on empty stomach because food can inhibit its absorption ** ** Highest CSF concentration ** can be used HIV related CNS diseases Causes hyperbilirubinemia and nephrolithiasis due to crystallization of the drug (crystalluria) Lopinavir can cause sever diarrhea Nelfinavir ** Highly protein bound ** Ritonavir ** Enzyme inhibitor ** added with other HIV drugs to increase their duration of action Unpalatable taste, usually taken with chocolate milk Can cause severe diarrhea Saquinavir Least enzyme inhibitory effect

Fusion Inhibitor Enfuvirtide o MOA: binds to gp41 and blocks the fusion of the virus with the cell membrane o No drug-drug interaction and no cross resistance because it does not share MOA with any drug CCR5 Inhibitor Maraviroc Page 26 of 29

o CCR5 receptor antagonist o Contraindicated in patients with hepatitis HIV Integrase Inhibitor Raltegravir o Prevents incorporation of viral DNA into host genome

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 Hepatitis Drugs Hepatitis B drugs Lamivudine o Chronic Hepatitis B o Has a higher half-life in Hepatitis cells and can be used in lower doses and will be effective without causing too many adverse effects o Can cause liver fibrosis and liver failure Adefovir o Chronic Hepatitis B o MOA: inhibits Hepatitis B DNA polymerase and incorporates into viral DNA chain o Can cause lactic acidosis, steatosis, and hepatomegaly Interferon alfa-2b o ** Acute Hepatitis C ** o Chronic Hepatitis B o Chronic Hepatitis C Hepatitis C drugs These are immune modulating drugs. Adverse effects: flu-like symptoms chills, fever, myalagia, and neuropsychological symptoms DO NOT USE IN PATIENTS WITH DEPRESSION/PSYCHOSIS Interferon alfa-2b o Acute Hepatitis C o Chronic Hepatitis C Interferon alfa-2a o Chronic Hepatitis C Interferon alfacon-1 o Chronic Hepatitis C Pegylated interferon alfa-2a polyethylene glycol reduces excretion and increases half-life o Chronic Hepatitis C Pegylated interferon alfa-2b polyethylene glycol reduces excretion and increases half-life Ribavirin used for RSV MOA: inhibits GTP synthesis Influenza drugs Amantadine o MOA: inhibits uncoating of viral RNA of influenza o Anti-cholinergic effects and is also used for Parkinsons disease o Crosses into the CNS neurotoxicity o Excreted unchanged o CNS toxicity of Amantadine may be increased with co-administration with antihistamines, anticholinergic drugs, Hydrochlorothiazide, and Trimethoprim-Sulfamethoxazole. Rimantadine o MOA: inhibits uncoating of viral RNA of influenza o Extensively metabolized by the liver do not use in patient with liver insufficiency Neuraminidase Inhibitors MOA: Neuraminidase enzyme allows the influenza virus to exit the cell so these drugs prevent the release of new virions to inhibit their spread from cell to cell by inhibiting neuraminidase Oseltamivir o Can cause severe psychological problems children can become suicidal Page 28 of 29

Zanamivir

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