3What type of antimicrobial drugs inhibit cell wall synthesis? General Questions:What is an antibiotic?A substance produced by a microbe that suppresses the growth of or kills other microbesWhat type of antimicrobial drugs inhibit cell wall synthesis?β lactams, glycopeptides, and bacitracinWhat type of antimicrobial drugs inhibit DNA gyrase?FluoroquinilonesWhat type of antimicrobial drugs inhibit the ribosomal 50s unit and thus protein synthesis?Macrolides, streptogramins, ketolides, chloramphenicol, and oxazolidinonesWhat type of antimicrobial drugs inhibit the ribosomal 30s unit and thus protein synthesis?Aminoglycosides, tetracyclines, aminocyclitolsWhat drugs interfere with folic acid metabolism?Sulfonamides and trimethoprimWhat type of drugs inhibit RNA polymerase?RifamycinsThese cationic detergents dissolve the cell membrane. (what are they?)polymyxinsThese ergosterol specific compounds are commonly used as antifungals.Amphotericin B, nystatin, azole antifungals
4More General StuffName and define the four ways extrachromasomal (plasmid mediated) resistance can be spread.TransductionPlasmid DNA enclosed in bacteriophage, transferred to another bacteriumTransformationNaked DNA diffuses from one bacterium to anotherConjugationTransfer DNA or plasmids by sex with the use of piliTranspositionJumping of short DNA sequences, (the movement of short DNA sequences within the bacterial chromosome)What are 3 reasons from lecture why someone might reasonably be put on prophylactic antibiotics?Sugical procedures or trauma, sexual contact with a person with gonorrhea or syphilis, and recurrent infectionsWhat is the most common “superinfection” caused by antibiotic-induced changes in the normal flora?C. difficile (which causes pseudomembranous colitis)By weight, what are most antibacterial drugs used for?Agriculture (farm animals)
5ResistanceWhat are the five general ways bacteria resist antibacterial drugs?Destruction of the drugReduce permeability to the antibacterial component or create efflux pumpsAlter the structure of the drug targetAlter the target enzyme, retaining functionAlter the metabolic pathway affected by the drugWhat is the most important “non-genetic” resistance factor?Growth rate- that is, some drugs only affect actively dividing cellsWhat is the MIC?The minimum inhibitory concentration is the minimum concentration required to prevent visible growth in a 24 hr periodWhat is the MBC?The minimum bactericidal concentration is the minimum concentration of drug that results in a 99.9% decline in a pathogen
6What are the five most common microbial causes of bronchitis? What is the causative agent in most upper respiratory tract infections?VirusesWhat are the five most common microbial causes of bronchitis?Strep. Pneumoniae, mycoplasma pneumoniae, H. influenzae, M. catarrhalis, Chlamydia pneumoniaeWhat is Rifamycin used for?On this testtuberculosisDOC (drug of choice) for M. tuberculosis (w/isoniazid), M. leprae (w/dapsone), and N. meningitidisAlso active against most gram+ and many gram-
7β Lactams Describe the Mechanism of action of the β-lactams. These drugs bind the penicillin-binding proteins (PBP), Inhibiting transpeptidase and cross-linking of peptidoglycan precursorsInactivate inhibitors of autolytic bacterial enzymes, leading to cell death.Considered bactericidalSee link below for detailsWhat are the three mechanisms (from this lecture) of resistance to β-lactams?Intrinsically altered PBPs with decreased β-lactam affinityAcquisition of (plasmid) genes for altered PBPs (basically the same as number one but with plasmids)β-lactamases (plasmid mediated)Why might you use penicillin V instead of penicillin G?V is better absorbed orally compared with GWhat respiratory bugs are the natural penicillins (pen V and G) good for?S. pyogenes (and S. pneumoniae (from Micro #49))What is S. pyogenes?Any Group A β hemolytic streptococcusWhat are two generic aminopenicillins? What resp. bugs are they used for?Ampicillin and amoxicillinS. pyogenes, S. pneumoniae, H. influenzaeWhat is piperacillin particularly useful for?Pseudomonas (also works for Klebsiella and many Gram negatives)
8β-lactams (continuned) What are the β-lactamase inhibitor containing drugs for which we are responsible? And what are the components of each? Give an example of a bug treated by each.AugmentinAmoxicillin and clavulanateTreats Hemophilus InfluenzaeZosynPiperacillin and TazobactamΒ-lacatamase producing Klebsiellatazobactam does not improve activity of piperacillin against Pseudomonas, but does extend spectrum of piperacillin to include beta-lactamase producing strains of Klebsiella pneumoniae.Why don’t β-lactams hurt human cells?Eukaryotic cells utilize collagen, laminin, elastin, and other ECM proteins (not peptidoglycan). These properties impart a remarkable selectivity of beta-lactams for bacterial cells
9CephalosporinsWhat are two specific adverse reactions with some cephalosporins (drugs containing methylthioetrazole side chains)?Disulfiram-like reaction when mixed with alcoholBy inibiting aldehyde dehydrogenaseHypoprothrombinemia and thrombocytopenia/platelet dysfunctionWhat two rings do cephalosporins have? What substance is used to make them?They have a dihydrothiazine ring and a beta-lactam ring.7-aminocephalosporanic acid: this is used to make all of the semi-synthetic derivatives we know today. It imparts some resistance to penicillinases. There are some beta-lactamases that can still hydrolyze its beta-lactam ring though.
10For each class of cephalosporins, give the respiratory bugs for which they are useful and then the specific drugs that Dr. Melchert wants us to know:1st GenerationGroup A strep and KlebsiellaGood G+, less G-, good oral anaerobe killer,Cephalexin (Keflex)2nd GenerationHemophilus Influenzae, Klebsiella, M. catarrhalisDecreased G+, better G-Cefuroxime (IV, Zinacef) and cefaclor (Ceclor, oral)3rd GenerationEnterobacteriaceae (including β-lactamase producing strains)Poor G+ coverage, but “much improved” G- coverageCeftriaxone (meningitis), cefoperazone and cefixime (oral, Suprax)cefoperazone is good for Pseudomonas aeruginosa (a G- aerobic rod).What else did Melchert say about 3rd gens (bad things)?They are broad spectrum and can cause superinfections, they are expensive and can induce chromosomal expression of β-lactamases4th Generation? Group A strep and Psuedomonas (?maybe?)“more active against β-lactamase producing strains of many gram(-) organisms”Cefepime (IV, Maxipime)What is the most important thing about 4th generation Cephalosporins?They are “much less likely to induce chromosomal production of β-lactamase”
11Carbapenems What is this drug class’s nickname? Why? The cannonCarbapenems are some of the most active antibacterial agents against a wide variety of organisms, including many G+ and many anaerobesWhat does the cilastatin in Primaxin do?Cilastatin is a renal dipeptidase inhibitor that keeps this enzyme from breaking down the active agent, imipenem.For what bugs is Imipenem/cilastatin (Primaxin) used?Klebsiella, Pseudomona, and Group A strepOverly broad for common use on any of these. In each case, more specific drugs are available
12TetracyclinesFor what bugs (respiratory/overall) are tetracyclines used?mycoplasma and chlamydiaeGood for arthropod-borne disease (Rocky Mountain Spotted Fever, erhylyciosis)What two drugs are important in this classTetracycline and doxycycline-they’re useful alternatives if not the Drug Of Choice for:mycoplasma pneumoniae or chlamydiae.The poor safety profile of doxycycline makes macrolides more preferable. The usefulness of TCN is not so great.What are the major adverse effects with these drugs?pseudomembranous colitis and discoloration of teethOther adverse effects include gastrointestinal problems, photosensitivity, and nephrtoxicityWho shouldn’t receive Tetracyclines?Pregnant women and children under 8What is Melchert’s rule of less than a brick?If it’s not a brick, it crosses the placenta and gets into the breast milk.
13Macrolides and Ketolides What is the mechanism of Macrolides?Reversibly bind to 50s ribosomal subunit at MLSB site, inhibiting peptide bond formation by preventing translocation of aa-tRNA from the A to the P site on the ribosome complex.MLSB site= macrlodie/lincomycin/streptogramin B binding siteAll of these drugs compete and bind at the same site, so you should not add combined macrolide treatment because the drugs will compete with each other for the binding site.What are the three major plasma-mediated mechanisms of resistance?Macrolide efflux pumps- mrsA, mefA, mefE genesErm- erythromycin resistant methylasemethylates the TARGET (the 50s subunit) not the drug, therefore changing the affinity of the drug for the binding sitePlasmid-mediated production of esterases which hydrolyze the drugWhat chromosomal resistance sometimes occurs?Chromosomal mutations with altered 50s ribosomal subunitsFor what bugs are macrolides useful?Four most important: Legionella pneumophila, B. pertussis, Chlamydiae, and MycobacteriaOthers: pretty much every other bugGroup A strep., Strep. pneumoniae,the gram negative bacilli: H. influenzae, legionella pneumophila (DOC) and bordeetella pertuss (DOC), mycoplasma pneumoniae, and chlamydiae pneumoniae,the gram negative cocci: moraxella catarrhalis
14What are the main adverse effects of Macrolides? increased gastric motility (diahrrea, abdominal cramps), superinfection/psuedomembranous colitis, cholestatic jaundiceAlso (rarely): transient auditory impairment, prolonged QT intervalWhat is important to know about these drugs with regard to drug-drug interactions? Why is this so important?Macrolide antibiotics inhibit cytochorme P-450, especially CYP 3A4CYP3A4 is responsible for the metabolism of 50-70% of all orally administered medications (maybe you should take these drugs with grapefruit juice (not seriously))What are the two drugs in this class for which we are responsible?Erythromycin and ClarithromycinFor what type of bacteria is Clarithromycin especially good?Clarithromycin is good for MAC (Mycobacterium avium complex)
15Fluoroquinolones What is the mechanism of action of fluroquionolones? They inhibit the topoisomerases, subsequently inhibiting DNA replication.Topoisomerase IIformerly called DNA Gyrase, this enzyme is required to unwind the superwound DNA for replication.Topo IV –Topo 4 is responsible for separation of chromosomal DNA into respective daughter cells during cell divisionWhy does Dr. Melchert say these aren’t antibiotics?They’re not antibiotics because they aren’t natural products of microorganisms. They’re made by humans in an attempt to kill a bacterium. Subsequently, there are no naturally made enzymes produced by bacteria that impart resistance.There are no enzymes that impart resistance to these drugs, so how does resistance occur?Point mutations in DNA gyrase or topoisomerase IV.bacterial efflux pumps/mutations reducing cell wall permeabilityThese drugs actually inhibit pasmid-mediated resistance to other antibacterial agents.Describe the Toxicity of these agents.They will accumulate in tissues high in calcium, and calcium in the gastric contents reduces absorption (just like with TCN).Few organ systems are immune to the toxic effects, toxicity includes: GI, Photosensitivity, CNS, connective tissue, and hematopoietic.
16FluoroquinolonesWhat makes 3rd generation fluoroquinolones pharmacokinetically “ideal”?Their distribution is extremely wide and are even present in respiratory secretions. They have low protein binding, good oral bioavailability, and long half lives.For what are first generation or group 1 Fluoroquinolones used?Genitourinary tract infections (GUTI) (norfloxacin)For what are 2nd generation or group 2 Fluoroquinolones used?Ciprofloxacin is good for psuedomonasAlso good for many G- and G+ organism we don’t have to know aboutFor what are 3rd generation or group 3 Fluoroquinolones used?H. influenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae, L. pneumonophilia, P. aeruginosain trials for MAC and TBMoxifloxacin is good for pneumococcus (Strep. pneumoniae)Spectrum includes 2nd generation spectrum with better G+ and, as mentioned a slide ago, ideal pharmacokinetics
18General Asthma facts you need to know. Define asthma.Chronic reversible airway obstruction that with increased airway responsiveness to a variety of stimuliOften has recurrent wheezing, dyspnea, chest tightness and coughing, particularly at night and early morningIn asthma pulmonary function tests, peak expiratory flow rate is < ____% of predicted, and ____ is normal80Forced vital capacityWhat percent of inhaled drugs reach and affect the lungs? He said this 87 times.10%What is the primary agent in the treatment of Asthma?Inhaled corticosteroids (ICS)What is used for short term relief of asthma attacks?Short acting β2 agonists (DOC) or anticholinergic agentsIn Emergency Room: systemic corticosteroids when necessaryDescribe the major non-pharmacologic treatment of asthmaPatient education including: avoiding attack provoking stimuli, home use of a Peak Flow Monitor to asses treatment success, and occasionally relocation to an environment with fewer environmental contributory factors.
19Bronchodilators: β2 agonists β2 AgonsitsMechanismActivation of pulmonary β2 receptors results in relaxation of bronchial smooth muscle and a subsequent decrease in airway resistanceMay also modulate mediator release from mast cellsLong term administration does not reduce bronchial hyperreactivityPharmacokinetic problemsTachyphylaxis and tolerance occur, the latter being a function of down-regulation of β2 receptors as well as a decrease in binding affinity of the remaining receptorsOvercome by increasing the dose or using corticosteroidsSelective β2 agonists become less “selective” at higher dosesAdverse effectsTachycardia, palpitation, and (transient) hypokalemiaDrugsShort acting: Albuterol, Pirbuterol, Levalbuterol and TerbutalineLong acting: Formoterol and Salmeterol
20LABA (Long acting beta agonists) What are the two long acting β2 agonists? What is the problem with these drugs?Formoterol and SalmeterolWhen used for long periods of time they can increase the risk of deadnessWhat commonly used anti-asthma drug has salmeterol as one of it’s components?Advair is Fluticasone and salmeterol
21Bronchodilators: Methylxanthines and anticholinergics Methylxanthines (Theophylline)MechanismStimulates the respiratory center and improves respiratory muscle functionInhibition of phosphodiesterase increases cAMPAntagonizes adenosine receptors, relaxing smooth muscle of the bronchi and pulmonary blood vessles. (adenosine antagonism also affects the heart)PharmacokineticsMetabolized in the liver, interacts with many other drugsAdverse effects>20mg/LNausea, vomiting, diarrhea, headache, irritability, insomnia, tremor>35 mg/LHyperglycemia, hyperkalemia, hypotension, cardiac arrhythmias, hyperthermia, seizures, brain damage, and deadnessAnticholinergics (Ipratropium)Block muscarinic receptors in airway smooth muscle, reducing airway resistance and blocking cholinergic reflex bronchoconstrictionUsefulnessBetter for COPD than asthma
22Anti-Inflammatory agents: Mast Cell Stabilizers MechanismInhibit degranulation of pulmonary mast cells, which inhibits the release of inflammatory mediatorsDoes not produce bronchodilationWhen are they useful?For prophylactic management of severe bronchial asthma, exercise-induced bronchospasm, or acute bronchospasm from environmental pollutantsAllergic rhinits
23Anti-Inflammatory agents: Corticosteroids (Corticosteroid) MechanismInhibits formation of various vasoactive substancesinhibits WBC and macrophage response to chemotactic productsInhibit phospholipase, which prevents the formation of arachidonic acid, leukotrienes, and prostaglandinsWorks synergistically with β2 agonists by restoring β2 receptor densityWhy do drug developers try to reduce the absorption of inhaled corticosteroids?Systemic adverse effects are severe, lower systemic absorption reduces side effects and allows higher doses.Systemic side effects (usually seen with oral or IV therapy) include: adrenal suppression, GI, Psychogenic, Immune, electrolyte, and dermatologic problems, osteoporosis, Cataracts, and growth inhibitionWhat are the adverse effects of the inhalation route?Oropharyngeal candidiasis, dysphonia, and mild adrenal suppression
24Anti-Inflammatory agents: Leukotriene inhibitors Why would we want to inhibit leukotrienes (LTs) in asthma patients?Because LTs are very potent bronchoconstrictors ( times histamine), they are long lasting and also cause mucous secretion and airway edemaWhat is the most potent LT?LTD4What are the three LT inhibitors? What does each do?Zafirlukast (Accolate)Potent, selective reversible antagonist of cysteine LT receptorZileuton (Zyflo)Selective inhibitor of 5-lipoxygenaseMontelukast (Singulair)“giant in this group” good for exercise/aspirin induced asthmaVery expensive ($300/month)
25DNA gyrase inhibitorsThese are synthetic fluorinated analogs of nalidixic acidActive against gram-positive and gram-negative bacteriaBlock bacterial DNA synthesis by inhibiting:topoisomerase II (DNA gyrase), which prevents transcription and replicationtopoisomerase IV, which interferes with separation of chromosomal DNA into respective daughter cells during cell division
26COPD Define COPD What spirometry values are expected in COPD? A preventable and treatable progressive disease state that is characterized by non-reversible airflow limitationWhat spirometry values are expected in COPD?Airflow limitation (reduced FEV1) and hyperinflation (increased residual volume)What are “the most important agents in the pharmacologic management of patients with COPD?”Bronchodilators, especially anticholinergics (Ipratropium and Tiotropium)What is the mechanism of theophylline? When is it used?Theophylline (a methylxanthine class drug) works in a variety of ways. Most importantly for COPD patients, it stimulates the respiratory center.It also inhibits phosphodiesterase, decreases pulmonary arterial pressure, improves respiratory muscle function, and causes many adverse cardiac effects.It is used rarely in severe COPDWhat is the only inhaled corticosteroid approved for COPD? When is it recommended? Why aren’t steroids as useful in COPD?Advair (fluticasone—corticosteroid & salmetrol—long acting β agonist)The corticosteroid anti-inflammatory properties are useful in preventing exacerbations of COPD and are thusly recommended in patients with frequent exacerbationsCOPD is pathologically mediated by structural lung damage which is neither prevented nor cured by steroid treatment
27COPD TreatmentWhat are the five non-pharmacologic therapies for COPD listed in the syllabus? Describe eachSmoking cessationSmoking is the main cause of COPD, cessation greatly delays progression of symptomsPulmonary rehabilitationImproves muscle function and oxygen utiliation, decreasing dyspneaHowever, does not effect lung function.VaccinationInfluenza and pneumovaxOxygen therapyFor severe COPD associated hypoxemia, use the lowest possible O2 supplement to keep SpO2>90%.This therapy can reduce respiratory drive and worsen hypercapniaSurgeryLung volume reduction or lung transplantWhat are the four treatments for COPD exacerbations?Systemic antibiotics (Tetracycline, bactrim, macrolides, fluoroquinolones), systemic steroids tapered over 2 weeks, bronchodilators, and O2 therapy
28Alpha 1-antitrypsin deficiency What is Alpha 1-antitrypsin deficiency?An autosomal co-dominantly transmitted genetic disease in which leaves the lungs particulary susceptible to damage by neutrophil elastase.What percentage of COPD patients are afflicted with this disorder?1%What are the treatment options?Along with other symptomatic treatments for the existing lung damage, protein replacement therapy is available in three forms: Aralast, Prolastin, and ZemairaTreatments are given weekly by IV
30ObjectivesLearn how chemical structure affects the function of sulfonamidesLearn the therapeutic uses, mechanism of action, general properties, and adverse effect of sulfonamides.Learn how the combined use of sulfonamides with other drugs can increase the effectiveness of the therapy.
31General StructureWhat’s the structure on the left? On the right? Why is it significantProntosil (Prodrug)Sulfanilamide (active form)Prontisil is metabolised to sulfanilamide in the bodyProntosil was the first sulfonamide drug developed and the first example of a known pro-drug.
32Structural requirements What group at what position “appears to be essential” for sulfonamides?A para NH2 groupThis group may only be replaced by groups which can be converted in vivo by the host to the free amino group (as prontosil is)Is the sulfanyl group (-SO2NH2) essential?No, but the S atom is essential and must be linked directly to the benzene ringSubstitions of the N atom of this group makeup most of the currently used sulfonamidesWhat groups are substituted for the N on the sulfanyl group?Heterocyclic ringsheterocyclic ring (n.)—a ring of atoms of more than one kind : especially a ring of carbon atoms containing at least one atom that is not carbonWhat structural characteristic of some sulfonamide compounds makes them more toxic?Compounds with only a single benzene ring are generally more toxic than those with heterocyclic sulfanyl-N substitutions
33ObjectivesLearn how chemical structure affects the function of sulfonamidesLearn the therapeutic uses, mechanism of action, general properties, and adverse effect of sulfonamides.Learn how the combined use of sulfonamides with other drugs can increase the effectiveness of the therapy.
34Sulfanilamide Therapeutic Use and Mechanism Therapeutic UsesInhibit both Gram- and Gram+sHigh urinary concentration of some of the soluble drugs allows effective treatment of urinary tract infections (usually the short acting drugs)More on therapeutic uses of specific sulfonamides on the next slide (under ‘general properties’)Mechanism of Action (*emphasized*)These drugs are structural analogs of PABA (para-aminobenzoic acid) which act as competitive inhibitors of PABA in the production of folic acid.They inhibit synthesis of folic acid by inhibiting dihydropteric acid synthetase, the enzyme which incorporates PABA into dihydropteric acid (en route to becoming folic acid)
35Sulfanilamide Properties General PropertiesAbsorptionMany are poorly absorbed from the intestinal tract and hence produce local changes in bacterial flora (good for sterilizing the gut for surgical procedures)Which ones are used for IV administration? For topical?Sodium salts of these drugsSodium sulfacetamideWhat is the name of the long acting sulfonamide? What is it usually combined with? What does this combination treat?SulfadoxinePyrimethamine (an inhibitor of parasitic digydrofolate reductase)Plasmodium falciparum (malaria)Adverse EffectsHypersensitivity reactions, urinary tact disturbances, and hematopoietic disturbances
36ObjectivesLearn how chemical structure affects the function of sulfonamidesLearn the therapeutic uses, mechanism of action, general properties, and adverse effect of sulfonamides.Learn how the combined use of sulfonamides with other drugs can increase the effectiveness of the therapy.
37Trimethoprim What is Trimethoprim’s mechanism of action? Trimethoprim inhibits bacterial dihydrofolate reductase, preventing the enzymatic reduction of dihydrofolic acid to tetrahydrofolic acid.Why is it useful to administer Trimethoprim with Sulfamethoxazole?This combination inhibits two unrelated but sequential steps in the same metabolic pathway, producing a synergistic effectWhat are three major uses of this combination?AIDS-associated Pnuemocystis Jiroveci (carinii)Chronic and reccurrent urinary tract infectionsParasitic infections (leishmaniasis, toxoplasmosis, falciparum malaria)
39Learning ObjectivesLearn the general principles for the use of chemotherapy for viral infections.Learn the steps in viral replication and the points at which specific drugs act.Learn the clinical uses, mechanism of action, major side effects, and dosing considerations for antiviral agents.
40General PrinciplesWhat are three problems with current antiviral therapy?There are two few agentsThe agents that do exist are only active against one or a few virusesTo be effective most antiviral drugs should be taken before or during the arly stages of infectionWhy is it so hard to develop antiviral drugs?By definition, viruses are obligate intracellular parasites that utilize the metabolic processes of infected cells. This it has proven difficult to develop drugs with selective toxicity against viral components.
41Learning ObjectivesLearn the general principles for the use of chemotherapy for viral infections.Learn the steps in viral replication and the points at which specific drugs act.Learn the clinical uses, mechanism of action, major side effects, and dosing considerations for antiviral agents.
42Viral Life CycleWhat are the (5) steps of viral replication, as listed in this lecture?Adsorption to and penetration of susceptible cellsSynthesis of early, nonstructural proteins such as acid polymerasesSynthesis of RNA or DNASynthesis of late, structural proteinsAssembly (maturation) of viral particles and their release from the cell
43Drugs and the Viral life cycle What drugs inhibit adsorption and penetration of viruses?Amantadine, gamma globulin, and FuzeonWhat drugs inhibit early protein synthesis?resistant mutants emerge too quickly to make current drugs useful at this stage (so… none)What drugs inhibit viral nucleic acid synthesis?Ribavirin, Acyclovir, Ganciclovir, Azidothymidine (AZT), Dideoxyinosine (ddI), Dideoxycytidine (ddC), FoscarnetPyrimidine and purine analoguesIdoxuridine, vidarabine, trifluorothymidineWhat drugs work by inhibition of late protein synthesis and assembly and release of viral particles?Protease inhibitors (saquinavir, ritonavir, lopinavir/ritonavir, indinavir)
44Learning ObjectivesLearn the general principles for the use of chemotherapy for viral infections.Learn the steps in viral replication and the points at which specific drugs act.Learn the clinical uses, mechanism of action, major side effects, and dosing considerations for antiviral agents.Now, the hard part. When in doubt, guess herpes.
45Immune Serum Globulin Clinical use Mechanism of action Given during early stages of infection to confer passive immunity and thereby partially or completely alleviate the progression of hepatitis, measles, poliomyelitis, and other infections.Used as prophylaxis for rabiesMechanism of actionAntibodies neutralize viral infectivityDosage considerationsIM; protection for 2-3 weeks after a single dose. (repeat every 2-3 weeks)
46Enfuvirtide (Fuzeon) Clinical use Mechanism of action HIV—works outside the cell to prevent HIV virus from infecting healthy CD4 cellsMechanism of actionBinds to HIV gp41 subunit of viral envelopePrevents HIV confirmation change needed for cellular penetrationDisrupts structural rearrangement, which is necessary for viral fusion with a healthy CD4 cell
47Amantadine HCL Clinical use Mechanism of action Dosage considerations Prophylaxis for influenza a virus infection, especially with high-risk patientsPossible therapeutic value if given within hours of onset of Influenza AAlso used in Parkinson’s diseaseMechanism of actionInhibits the uncoating, and therefore the replication, of some myxoviruses, particularly influenza A (but not B), rubella, and some tumor viruses“…Weak bases like this drug probably also act by buffering the pH of the endosomes, which are membrane-bound vesicles that surround the virus as it is taken into a cell. Prevention of the acidification of these vacuoles blocks the fusion of the virus envelope with the endosomal membrane. This prevents the transfer of the viral genetic material into the cytoplasm of the cell. The drug may also inhibit viral particle release”Dosage considerationsRapidly and completely absorbed orallySide effectsCNS (insomnia, confusion, hallucinations, seizures) and GIContraindicationsPregnancy, epilepsy, psychosis, cerebral atherosclerosis, anticholinergic drugs, renal insufficiency
48Vidarabine (adeninine arabinoside, ara-A) Clinical useIV for Herpes Simplex (neonatal and otherwise) and varicella zoster (immunocompromised patients)Topical for herpes simplex keratoconjunctivits and recurrent epithelial keratitisMechanism of actionThis analogue of adenosine is phosphorylated to the nucleotide in the cell and acts to inhibit viral DNA polymerase. It is also incorporated into viral and cellular DNA.Dosage considerationsIV infusion enters the CNS and is metabolized rapidly to arabinosyl hypoxanthine which retains some antiviral activityOpthalmic (topical) use causes little systemic absorptionSide effectsWeakness, hypokalemia, CNS effects, blood dyscrasias (anemia etc.)Topical opthalmic: some local irritation and photophobiaContraindicationsPregnancy, renal insufficiency, concurrent use with allopurinol
49Idoxuridine Clinical use Mechanism of action Dosage considerations Topical treatment of Herpes Simplex virus infection of eyelid, conjunctiva, and cornea. Epithelial infections respond much better than stromal infections.Mechanism of actionAn iodinated analogue of deoxyuridine, this drug is phopshorylated and incorporated into viral and mammalian DNA making the DNA more susceptible to breakage; faulty transcription may also occur.Resistance has been observedDosage considerationsTopical use only, no longer the DOC.Side effectsLocal irritation, mild edema and photophobiaTeratogenic even as a topical applicationTrifluorothymidine (trifluridine)“A fluorinated pyrimidine which is more selectively incorporated into viral DNA than idoxuridine, topical use of this drug may be the coice for primary keratoconjunctivitis and recurrent epithelial keratitis due to Herpes Simplex 1 and 2. Viral resistance does occur.”
50Acyclovir (acycloguanosine) Clinical useHerpes Simplex and Herpes Genitalis (see sylabus for excrutiating detail)Mechanism of actionViral-specific thymidine kinase converts this guanine derivative to its monophosphate form which is subsequently converted to the tripohosphate by host kinases; the triphosphate inhibits viral DNA polymerase and may serve as a substrate of the enzyme to cause termination of the DNA chain.More virus-selevtive than other drugsDosage considerationsAvailable by IV, topical, and oral (though oral is poorly absorbed)Readily enters CSFSide effects“relatively rare” edema, hematuria, diaphoresis, hypotension, renal dysfunction, lethargy, headache, nausea, encephalopathyContraindicated with (shockingly!!) pregnancy and renal insufficiency
51Ganciclovir Clinical use Mechanism of action Dosage considerations Treatment of cytomegalovirus retinitis in immunocompromised patientsCurrently being evaluated for potential use in colitis, esophagitis, and pneumonia caused by CMVMechanism of actionA deoxyguanosine analogue that is phosphorylated to the triphosphate in the host cell. The triphosphate competes with deoxyguanosine triphosphate for binding to viral DNA polymerase and thus acts as a competitive inhibitor, incorporation of the phosphorylated drug into DNA.Also prevents elongation.Dosage considerationsIV, excreted by the kidney, CNS penetration is variableSide effectsAre common and limit clinical useCNS (including seizures and coma), neutropenia, thrombocytopenia, GI symptoms, and hepatic abnormalities
52Interferons Clinical use Mechanism of action Dosage considerations Interferon alpha-2a and alpha-2b are approved for intralesional treatment of genital warts (HPV), hairy cell leukemia, and AIDS related Kaposi Sarcoma.Experimentally: Herpes Zoster, Varicella Zoster, Herpes Simplex, CMV, Hep B., RhinovirusMechanism of action(Primarily) Inhibit viral protein synthesis.Host cell ribosomes are induced to produce cellular enzymes that block viral reproductin by inhibiting the translation of viral mRNA into viral protein.Not fully understoodDosage considerationsInjectable (SubQ, IM, Intralesional), 5 hour half life with continued biologic effects after reduced serum concentrationsSide effectsEffects everything.Intralesional injection: Fever, chills, nausea, myalgia, headache, leukopenia, thrombocytopenia, neurotoxicity, seizures, elevated hepatic enzymes, renal insufficiency, cardiotoxicity.
53Zidovudine (AZT; Azidothymidine) Clinical useReduces progression in AIDS patients with a history of Pneumocystis Carinii pneumonia or low CD4 countActivity is enhanced by coadministration of ddI, acyclovir, interferon, granulocyte-macrophage colony-stimulating factor, and neutralizing antibodyMore effective when administered with a protease inhibitorMechanism of actionThis thymidine analogue prodrug is phosphorylated to AZT triphosphate in cells. AZT triphosphate competes with thymidine triphosphate as well as causing chain terminationCompetitive InhibitionAZT triphosphate bins to reverse transcriptase at a site which ordinarily binds endogenous nucleoside triphosphates.Chain terminationReverse transcriptase is tricked into incorporating AZT triphosphate into a growing chain of viral DNA. The AZT lacks the essential hydroxyl group needed to form the bond with the next deoxynucleoside triphosphate. The virus cannot repair this mistake, and DNA synthesis is stopped.Dosage considerationsWell absorbed orally, crosses into CSF, metabolized by the liver.Resistance occursMore effective with a protease inhibitorSide effectsAnemia, granulocytopenia, headache, insomnia, myalgia, seizuresDrug interactionsActivity is antagonized by Ribavirin
54Ribavirin Clinical use Mechanism of action Dosage considerations Approved for use as an aerosol to treat severe lower respiratory tract infections caused by Respiratory Syncytial virus.May be effective in Influenza A and BMechanism of actionPurine analogue inhibits the synthesis of guanine nucleotides, inhibits viral RNA polymerase, and inhibits GTP-dependent enzymes needed for capping viral mRNA.Dosage considerationsAerosol every 12 hours for 3-7 daysSide effectsDecreased pulmonary function, rash and conjunctivits, anemiasContraindicated in pregnancy and with AZT use.
55Foscarnet Clinical use Mechanism of action Dosage considerations Not available in U.S.Cytomegalovirus retinitis and Herpes Simplex 2 in AIDS patients, and for other HIV infectionsMechanism of actionThis “phosphorate” (?phosphate) analogue inhibits viral DNA polymerase and reverse transcriptaseDifferent site of action from acyclovir and AZTDosage considerationsIV, penetrates CNS, renal eliminationSide effectsReduced renal function, anemia, headache, fatigue, hypocalcemia, seizures
56Didanosine (Dideoxyinosine, ddI) Clinical useApproved for treatment of advanced HIV infection in patients intolerant of or already taking AZT.Increases CD4 count, decreases p24 antigen levels, and decreased AIDS symptoms.Can be used with AZTMechanism of actionThis synthetic dideoxynucleoside inhibits viral reverse transcriptaseSide effectsPainful peripheral neuropathy and (sometimes fatal) pancreatitis are dose limiting.Others: Headache, insomnia, emesis, abdominal pain, fever, rash, confusion, hyperuricemia, leukopenia, thrombocytopenia.Zalcitabine (dideoxycytidine, ddC)Similar to AZT and ddI. Causes peripheral neuropathy even at low doses. Administered with AZT.
57Protease Inhibitors Clinical use Mechanism of action Active against viral strains that are resistant to reverse transcriptase inhibitorsMore effective for AIDS than AZT, often used with AZT. It’s the third drug in “triple therapy”Mechanism of actionHIV protease is necessary for cleavage of polypeptide precursors that generate structural proteins and enzymes for the virus.These drugs inhibit HIV protease activity and prevent in vitro HIV replication. They do this by either (1) acting as transition state mimics of peptide substrates or (2) by interacting with catalytic residues, displacing a sructural water molecule.Has resistance been observed?yesDosage considerationsLow oral availability, short half life, and almost 100% protein boundSide effectsFew and less severe than other AIDS drugs. However, nephrolithiasis (kidney stones) has occurred.
59Learning ObjectivesLearn the therapeutic strategies and important factors for treating tuberculosis and leprosy.Learn the first-line drugs for treating tuberculosis, their major side effects, general properties, metabolism, mechanism of action, and use.Learn the names of second-line drugs and the special uses and considerations for these drugs.
60General TuberculosisTuberculosis is currently the ___ leading cause of death among infectious diseases worldwide.3rdIt is also the leading cause of death in AIDS patients.How long is a “short course” of TB therapy? A “long course?”Short course is 6-9 monthsLong course is monthsHow is resistance overcome in Tuberculosis?Resistance to first line therapy is very common (especially Isoniazid), but cross-resistance does not usually occur. Therefore, multiple drug therapy is most effective. Standard treatment includes four drugs.When is the only time that a single drug can be used in regard to Tuberculosis?For prophylaxis in healthy exposed indidividualsWhy are “first-line” drugs best? When are second-line drugs used?“First-line agents combine the greatest level of efficacy and activity with an acceptable level of toxicity.”“Second-line drugs are used only in cases of bacterial resistance or patient-related problems with the first line drugs.”
61More Generalities What is the most common first-line therapy? A combination of isoniazide, rifampin, pyrazinamide, and (sometimes) ethambutol are typically used empirically until the anti-bacterial sensitivity tests are completed.Once antibacterial sensitivity testing is complete, two appropriate drugs may be selected and used for the duration of therapy. However, for disseminated TB, Meningitis-TB, or AIDS-TB, the original four drugs are continued for 9-12 months or longer.Which first line drug was the first effective treatment for Tuberculosis? What are two of it’s dangerous adverse effects?StreptomycinOtotoxicity and NephrotoxicityWhich first line drug is commonly used alone in prophylaxis for family members?Isoniazid
62Learning ObjectivesLearn the therapeutic strategies and important factors for treating tuberculosis and leprosy.Learn the first-line drugs for treating tuberculosis, their major side effects, general properties, metabolism, mechanism of action, and use.Learn the names of second-line drugs and the special uses and considerations for these drugs.
63Isoniazid Mechanism of action General properties Metabolism Inhibits biosynthesis of mycolic acid and subsequently reduces the integrity of the cell wallBactericidal for actively growing bacilli and at high concentrations; bacteriostatic at lower concentrationGeneral propertiesIs the most active drug against TB species and M. kansasii, but not active against most atypical mycobacteria.Penetrates most body fluids and accumulates in casseous lesions. Also enters host cells and has access to intracellular pathogens.MetabolismIs a prodrug that is activated by KatG (a mycobacterial enzyme). The activated form inhibits mycolic acid synthesis.Acetylated in the liver.Half life for fast acetylators is less than 1.5 hours, for slow acetylators is about 3 hours.Major side effectsCentral and peripheral nervous system toxicitiesCaused by inhibition of pyridoxal kinase; can be prevented by coadministering pyridoxine (B6)Also may cause some allergic (skin) type reactions and may inhibit the breakdown of some drugs (diphenylhidantoin)Clinical useUsed in combination with 1-3 other first line drugsUsed alone for prophylaxis of family membersAlways coadministered with pyridoxine 10mg/100mg.
64Rifampin Mechanism of action General properties Metabolism Binds strongly to DNA-dependent RNA polymerase, inhibiting RNA synthesis (transcription).Suppression of initiation of chain formationBactericidalGeneral propertiesWell absorbed and widely distributed in body fluids and tissuesMetabolismNot mentioned for this or any other drug except isoniazid.Major side effectsCauses orange color to urine and other body fluids. Rarely causes other effects includingrashes, thrombocytopenia, nephritis and impaired liver funcitonClinical useEffective against atypical mycobacteriaUsed in combination with other first lines for TB
65Ethambutol Mechanism of action General properties Major side effects UnknownGeneral propertiesWell absorbed after oral doses, good CSF penetrationWorks for TB and M. kansasii, but resistance would appear quickly if used aloneMajor side effectsFew if any. Hooray!Clinical useMany atypical mycobacteria are sensitiveUsed in combination with other first lines for TB
66Pyrazinamide Mechanism of action General properties Major side effects Not known, Awesome.General propertiesInactive at neutral pH, but exhibits bactericidal activity at slightly acidic pH.Like every other first line drug, resistance develops rapidly but cross-resistance is not a major problemMajor side effectsHepatotoxicity/impaired liver function.Clinical useWell absorbed from GI and distributed widelyUsed in combination with other first lines for TB
67Streptomycin Mechanism of action General properties Major side effects Not listedGeneral propertiesPenetrates cells poorly, so most useful for extracellular tubercle forms.Important as an IV drug for patients with life threatening TB presentations like meningitis and disseminated disease.Major side effectsOtotoxic and nephrotoxicClinical useAs stated above, it is important as an IV for patients with severe TB symptoms.
68Learning ObjectivesLearn the therapeutic strategies and important factors for treating tuberculosis and leprosy.Learn the first-line drugs for treating tuberculosis, their major side effects, general properties, metabolism, mechanism of action, and use.Learn the names of second-line drugs and the special uses and considerations for these drugs.
69All you need to know about 2nd line drugs: What are the four second-line TB drugs?para-Aminosalicylic acid, Ethionamide, Cycloserine, and Capreomycin.What two conditions warrant their use?Resistance to the drugs of first choice (increasing problem)Failure of clinical response to conventional therapyWhat other requirment should be met when using these drugs?An Infectious Disease doc or other expert on these medicines should be consulted to deal with the toxic effects of these drugs that can occur
70Leprosy Which type of leprosy is the more severe? What makes it worse? Lepromatous leprosy is more severe because it is characterized by decreased cell mediated immunity.Requires longer course of therapyWhat three drugs are listed in the treatment of leprosy?Dapsone, Rifampin, ClofazimineRifampin and dapsone are usually given together (due to resistance), clofazimine is an alternative to dapsone.
71Dapsone (and other sulfones) MechanismProbably inhibits folate synthesisStructurally similar to sulfonamidesBacteriostaticGeneral PropertiesMore effective against M. leprae than tuberculiSlowly absorbed from GIAdverse effectsHigh incidence of side effects: hemolysis, methemaglobinemia, GI disturbance, allergic responses.UseTreatment may require several years. Patients must be monitored for side effects and require an array of supportive and rehabilitation measure (sounds scary).