Pulmonary.

Pulmonary

Principles of Antimicrobial Drug Action

What 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 microbes What type of antimicrobial drugs inhibit cell wall synthesis? β lactams, glycopeptides, and bacitracin What type of antimicrobial drugs inhibit DNA gyrase? Fluoroquinilones What type of antimicrobial drugs inhibit the ribosomal 50s unit and thus protein synthesis? Macrolides, streptogramins, ketolides, chloramphenicol, and oxazolidinones What type of antimicrobial drugs inhibit the ribosomal 30s unit and thus protein synthesis? Aminoglycosides, tetracyclines, aminocyclitols What drugs interfere with folic acid metabolism? Sulfonamides and trimethoprim What type of drugs inhibit RNA polymerase? Rifamycins These cationic detergents dissolve the cell membrane. (what are they?) polymyxins These ergosterol specific compounds are commonly used as antifungals. Amphotericin B, nystatin, azole antifungals

More General Stuff Name and define the four ways extrachromasomal (plasmid mediated) resistance can be spread. Transduction Plasmid DNA enclosed in bacteriophage, transferred to another bacterium Transformation Naked DNA diffuses from one bacterium to another Conjugation Transfer DNA or plasmids by sex with the use of pili Transposition Jumping 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 infections What 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)

Resistance What are the five general ways bacteria resist antibacterial drugs? Destruction of the drug Reduce permeability to the antibacterial component or create efflux pumps Alter the structure of the drug target Alter the target enzyme, retaining function Alter the metabolic pathway affected by the drug What is the most important “non-genetic” resistance factor? Growth rate- that is, some drugs only affect actively dividing cells What is the MIC? The minimum inhibitory concentration is the minimum concentration required to prevent visible growth in a 24 hr period What is the MBC? The minimum bactericidal concentration is the minimum concentration of drug that results in a 99.9% decline in a pathogen

What are the five most common microbial causes of bronchitis?
What is the causative agent in most upper respiratory tract infections? Viruses What are the five most common microbial causes of bronchitis? Strep. Pneumoniae, mycoplasma pneumoniae, H. influenzae, M. catarrhalis, Chlamydia pneumoniae What is Rifamycin used for? On this testtuberculosis DOC (drug of choice) for M. tuberculosis (w/isoniazid), M. leprae (w/dapsone), and N. meningitidis Also active against most gram+ and many gram-

β 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 precursors Inactivate inhibitors of autolytic bacterial enzymes, leading to cell death. Considered bactericidal See link below for details What are the three mechanisms (from this lecture) of resistance to β-lactams? Intrinsically altered PBPs with decreased β-lactam affinity Acquisition 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 G What 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 streptococcus What are two generic aminopenicillins? What resp. bugs are they used for? Ampicillin and amoxicillin S. pyogenes, S. pneumoniae, H. influenzae What is piperacillin particularly useful for? Pseudomonas (also works for Klebsiella and many Gram negatives)

β-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. Augmentin Amoxicillin and clavulanate Treats Hemophilus Influenzae Zosyn Piperacillin and Tazobactam Β-lacatamase producing Klebsiella tazobactam 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

Cephalosporins What are two specific adverse reactions with some cephalosporins (drugs containing methylthioetrazole side chains)? Disulfiram-like reaction when mixed with alcohol By inibiting aldehyde dehydrogenase Hypoprothrombinemia and thrombocytopenia/platelet dysfunction What 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.

For 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 Generation Group A strep and Klebsiella Good G+, less G-, good oral anaerobe killer, Cephalexin (Keflex) 2nd Generation Hemophilus Influenzae, Klebsiella, M. catarrhalis Decreased G+, better G- Cefuroxime (IV, Zinacef) and cefaclor (Ceclor, oral) 3rd Generation Enterobacteriaceae (including β-lactamase producing strains) Poor G+ coverage, but “much improved” G- coverage Ceftriaxone (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-lactamases 4th 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”

Carbapenems What is this drug class’s nickname? Why?
The cannon Carbapenems are some of the most active antibacterial agents against a wide variety of organisms, including many G+ and many anaerobes What 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 strep Overly broad for common use on any of these. In each case, more specific drugs are available

Tetracyclines For what bugs (respiratory/overall) are tetracyclines used? mycoplasma and chlamydiae Good for arthropod-borne disease (Rocky Mountain Spotted Fever, erhylyciosis) What two drugs are important in this class Tetracycline 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 teeth Other adverse effects include gastrointestinal problems, photosensitivity, and nephrtoxicity Who shouldn’t receive Tetracyclines? Pregnant women and children under 8 What 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.

Macrolides 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 site All 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 genes Erm- erythromycin resistant methylase methylates the TARGET (the 50s subunit) not the drug, therefore changing the affinity of the drug for the binding site Plasmid-mediated production of esterases which hydrolyze the drug What chromosomal resistance sometimes occurs? Chromosomal mutations with altered 50s ribosomal subunits For what bugs are macrolides useful? Four most important: Legionella pneumophila, B. pertussis, Chlamydiae, and Mycobacteria Others: pretty much every other bug Group 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

What are the main adverse effects of Macrolides?
increased gastric motility (diahrrea, abdominal cramps), superinfection/psuedomembranous colitis, cholestatic jaundice Also (rarely): transient auditory impairment, prolonged QT interval What 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 3A4 CYP3A4 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 Clarithromycin For what type of bacteria is Clarithromycin especially good? Clarithromycin is good for MAC (Mycobacterium avium complex)

Fluoroquinolones What is the mechanism of action of fluroquionolones?
They inhibit the topoisomerases, subsequently inhibiting DNA replication. Topoisomerase II formerly 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 division Why 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 permeability These 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.

Fluoroquinolones What 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 psuedomonas Also good for many G- and G+ organism we don’t have to know about For what are 3rd generation or group 3 Fluoroquinolones used? H. influenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae, L. pneumonophilia, P. aeruginosa in trials for MAC and TB Moxifloxacin is good for pneumococcus (Strep. pneumoniae) Spectrum includes 2nd generation spectrum with better G+ and, as mentioned a slide ago, ideal pharmacokinetics

Asthma and COPD

General Asthma facts you need to know.
Define asthma. Chronic reversible airway obstruction that with increased airway responsiveness to a variety of stimuli Often has recurrent wheezing, dyspnea, chest tightness and coughing, particularly at night and early morning In asthma pulmonary function tests, peak expiratory flow rate is < ____% of predicted, and ____ is normal 80 Forced vital capacity What 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 agents In Emergency Room: systemic corticosteroids when necessary Describe the major non-pharmacologic treatment of asthma Patient 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.

Bronchodilators: β2 agonists
β2 Agonsits Mechanism Activation of pulmonary β2 receptors results in relaxation of bronchial smooth muscle and a subsequent decrease in airway resistance May also modulate mediator release from mast cells Long term administration does not reduce bronchial hyperreactivity Pharmacokinetic problems Tachyphylaxis 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 receptors Overcome by increasing the dose or using corticosteroids Selective β2 agonists become less “selective” at higher doses Adverse effects Tachycardia, palpitation, and (transient) hypokalemia Drugs Short acting: Albuterol, Pirbuterol, Levalbuterol and Terbutaline Long acting: Formoterol and Salmeterol

LABA (Long acting beta agonists)
What are the two long acting β2 agonists? What is the problem with these drugs? Formoterol and Salmeterol When used for long periods of time they can increase the risk of deadness What commonly used anti-asthma drug has salmeterol as one of it’s components? Advair is Fluticasone and salmeterol

Bronchodilators: Methylxanthines and anticholinergics
Methylxanthines (Theophylline) Mechanism Stimulates the respiratory center and improves respiratory muscle function Inhibition of phosphodiesterase increases cAMP Antagonizes adenosine receptors, relaxing smooth muscle of the bronchi and pulmonary blood vessles. (adenosine antagonism also affects the heart) Pharmacokinetics Metabolized in the liver, interacts with many other drugs Adverse effects >20mg/L Nausea, vomiting, diarrhea, headache, irritability, insomnia, tremor >35 mg/L Hyperglycemia, hyperkalemia, hypotension, cardiac arrhythmias, hyperthermia, seizures, brain damage, and deadness Anticholinergics (Ipratropium) Block muscarinic receptors in airway smooth muscle, reducing airway resistance and blocking cholinergic reflex bronchoconstriction Usefulness Better for COPD than asthma

Anti-Inflammatory agents: Mast Cell Stabilizers
Mechanism Inhibit degranulation of pulmonary mast cells, which inhibits the release of inflammatory mediators Does not produce bronchodilation When are they useful? For prophylactic management of severe bronchial asthma, exercise-induced bronchospasm, or acute bronchospasm from environmental pollutants Allergic rhinits

Anti-Inflammatory agents: Corticosteroids
(Corticosteroid) Mechanism Inhibits formation of various vasoactive substances inhibits WBC and macrophage response to chemotactic products Inhibit phospholipase, which prevents the formation of arachidonic acid, leukotrienes, and prostaglandins Works synergistically with β2 agonists by restoring β2 receptor density Why 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 inhibition What are the adverse effects of the inhalation route? Oropharyngeal candidiasis, dysphonia, and mild adrenal suppression

Anti-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 edema What is the most potent LT? LTD4 What are the three LT inhibitors? What does each do? Zafirlukast (Accolate) Potent, selective reversible antagonist of cysteine LT receptor Zileuton (Zyflo) Selective inhibitor of 5-lipoxygenase Montelukast (Singulair) “giant in this group” good for exercise/aspirin induced asthma Very expensive ($300/month)

DNA gyrase inhibitors These are synthetic fluorinated analogs of nalidixic acid Active against gram-positive and gram-negative bacteria Block bacterial DNA synthesis by inhibiting: topoisomerase II (DNA gyrase), which prevents transcription and replication topoisomerase IV, which interferes with separation of chromosomal DNA into respective daughter cells during cell division

COPD Define COPD What spirometry values are expected in COPD?
A preventable and treatable progressive disease state that is characterized by non-reversible airflow limitation What 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 COPD What 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 exacerbations COPD is pathologically mediated by structural lung damage which is neither prevented nor cured by steroid treatment

COPD Treatment What are the five non-pharmacologic therapies for COPD listed in the syllabus? Describe each Smoking cessation Smoking is the main cause of COPD, cessation greatly delays progression of symptoms Pulmonary rehabilitation Improves muscle function and oxygen utiliation, decreasing dyspnea However, does not effect lung function. Vaccination Influenza and pneumovax Oxygen therapy For severe COPD associated hypoxemia, use the lowest possible O2 supplement to keep SpO2>90%. This therapy can reduce respiratory drive and worsen hypercapnia Surgery Lung volume reduction or lung transplant What are the four treatments for COPD exacerbations? Systemic antibiotics (Tetracycline, bactrim, macrolides, fluoroquinolones), systemic steroids tapered over 2 weeks, bronchodilators, and O2 therapy

Alpha 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 Zemaira Treatments are given weekly by IV

Sulfonamides and Trimethoprim
11/21/2007

Objectives Learn how chemical structure affects the function of sulfonamides Learn 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.

General Structure What’s the structure on the left? On the right? Why is it significant Prontosil (Prodrug) Sulfanilamide (active form) Prontisil is metabolised to sulfanilamide in the body Prontosil was the first sulfonamide drug developed and the first example of a known pro-drug.

Structural requirements
What group at what position “appears to be essential” for sulfonamides? A para NH2 group This 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 ring Substitions of the N atom of this group makeup most of the currently used sulfonamides What groups are substituted for the N on the sulfanyl group? Heterocyclic rings heterocyclic 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 carbon What 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

Sulfanilamide Therapeutic Use and Mechanism
Therapeutic Uses Inhibit both Gram- and Gram+s High 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)

Sulfanilamide Properties
General Properties Absorption Many 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 drugs Sodium sulfacetamide What is the name of the long acting sulfonamide? What is it usually combined with? What does this combination treat? Sulfadoxine Pyrimethamine (an inhibitor of parasitic digydrofolate reductase) Plasmodium falciparum (malaria) Adverse Effects Hypersensitivity reactions, urinary tact disturbances, and hematopoietic disturbances

Trimethoprim 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 effect What are three major uses of this combination? AIDS-associated Pnuemocystis Jiroveci (carinii) Chronic and reccurrent urinary tract infections Parasitic infections (leishmaniasis, toxoplasmosis, falciparum malaria)

Antiviral Drugs 11/21/06

Learning Objectives Learn 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.

General Principles What are three problems with current antiviral therapy? There are two few agents The agents that do exist are only active against one or a few viruses To be effective most antiviral drugs should be taken before or during the arly stages of infection Why 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.

Learning Objectives Learn 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.

Viral Life Cycle What are the (5) steps of viral replication, as listed in this lecture? Adsorption to and penetration of susceptible cells Synthesis of early, nonstructural proteins such as acid polymerases Synthesis of RNA or DNA Synthesis of late, structural proteins Assembly (maturation) of viral particles and their release from the cell

Drugs and the Viral life cycle
What drugs inhibit adsorption and penetration of viruses? Amantadine, gamma globulin, and Fuzeon What 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), Foscarnet Pyrimidine and purine analogues Idoxuridine, vidarabine, trifluorothymidine What drugs work by inhibition of late protein synthesis and assembly and release of viral particles? Protease inhibitors (saquinavir, ritonavir, lopinavir/ritonavir, indinavir)

Learning Objectives Learn 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.

Immune 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 rabies Mechanism of action Antibodies neutralize viral infectivity Dosage considerations IM; protection for 2-3 weeks after a single dose. (repeat every 2-3 weeks)

Enfuvirtide (Fuzeon) Clinical use Mechanism of action
HIV—works outside the cell to prevent HIV virus from infecting healthy CD4 cells Mechanism of action Binds to HIV gp41 subunit of viral envelope Prevents HIV confirmation change needed for cellular penetration Disrupts structural rearrangement, which is necessary for viral fusion with a healthy CD4 cell

Amantadine HCL Clinical use Mechanism of action Dosage considerations
Prophylaxis for influenza a virus infection, especially with high-risk patients Possible therapeutic value if given within hours of onset of Influenza A Also used in Parkinson’s disease Mechanism of action Inhibits 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 considerations Rapidly and completely absorbed orally Side effects CNS (insomnia, confusion, hallucinations, seizures) and GI Contraindications Pregnancy, epilepsy, psychosis, cerebral atherosclerosis, anticholinergic drugs, renal insufficiency

Vidarabine (adeninine arabinoside, ara-A)
Clinical use IV for Herpes Simplex (neonatal and otherwise) and varicella zoster (immunocompromised patients) Topical for herpes simplex keratoconjunctivits and recurrent epithelial keratitis Mechanism of action This 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 considerations IV infusion enters the CNS and is metabolized rapidly to arabinosyl hypoxanthine which retains some antiviral activity Opthalmic (topical) use causes little systemic absorption Side effects Weakness, hypokalemia, CNS effects, blood dyscrasias (anemia etc.) Topical opthalmic: some local irritation and photophobia Contraindications Pregnancy, renal insufficiency, concurrent use with allopurinol

Idoxuridine 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 action An 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 observed Dosage considerations Topical use only, no longer the DOC. Side effects Local irritation, mild edema and photophobia Teratogenic even as a topical application Trifluorothymidine (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.”

Acyclovir (acycloguanosine)
Clinical use Herpes Simplex and Herpes Genitalis (see sylabus for excrutiating detail) Mechanism of action Viral-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 drugs Dosage considerations Available by IV, topical, and oral (though oral is poorly absorbed) Readily enters CSF Side effects “relatively rare” edema, hematuria, diaphoresis, hypotension, renal dysfunction, lethargy, headache, nausea, encephalopathy Contraindicated with (shockingly!!) pregnancy and renal insufficiency

Ganciclovir Clinical use Mechanism of action Dosage considerations
Treatment of cytomegalovirus retinitis in immunocompromised patients Currently being evaluated for potential use in colitis, esophagitis, and pneumonia caused by CMV Mechanism of action A 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 considerations IV, excreted by the kidney, CNS penetration is variable Side effects Are common and limit clinical use CNS (including seizures and coma), neutropenia, thrombocytopenia, GI symptoms, and hepatic abnormalities

Interferons 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., Rhinovirus Mechanism 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 understood Dosage considerations Injectable (SubQ, IM, Intralesional), 5 hour half life with continued biologic effects after reduced serum concentrations Side effects Effects everything. Intralesional injection: Fever, chills, nausea, myalgia, headache, leukopenia, thrombocytopenia, neurotoxicity, seizures, elevated hepatic enzymes, renal insufficiency, cardiotoxicity.

Zidovudine (AZT; Azidothymidine)
Clinical use Reduces progression in AIDS patients with a history of Pneumocystis Carinii pneumonia or low CD4 count Activity is enhanced by coadministration of ddI, acyclovir, interferon, granulocyte-macrophage colony-stimulating factor, and neutralizing antibody More effective when administered with a protease inhibitor Mechanism of action This thymidine analogue prodrug is phosphorylated to AZT triphosphate in cells. AZT triphosphate competes with thymidine triphosphate as well as causing chain termination Competitive Inhibition AZT triphosphate bins to reverse transcriptase at a site which ordinarily binds endogenous nucleoside triphosphates. Chain termination Reverse 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 considerations Well absorbed orally, crosses into CSF, metabolized by the liver. Resistance occurs More effective with a protease inhibitor Side effects Anemia, granulocytopenia, headache, insomnia, myalgia, seizures Drug interactions Activity is antagonized by Ribavirin

Ribavirin 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 B Mechanism of action Purine analogue inhibits the synthesis of guanine nucleotides, inhibits viral RNA polymerase, and inhibits GTP-dependent enzymes needed for capping viral mRNA. Dosage considerations Aerosol every 12 hours for 3-7 days Side effects Decreased pulmonary function, rash and conjunctivits, anemias Contraindicated in pregnancy and with AZT use.

Foscarnet 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 infections Mechanism of action This “phosphorate” (?phosphate) analogue inhibits viral DNA polymerase and reverse transcriptase Different site of action from acyclovir and AZT Dosage considerations IV, penetrates CNS, renal elimination Side effects Reduced renal function, anemia, headache, fatigue, hypocalcemia, seizures

Didanosine (Dideoxyinosine, ddI)
Clinical use Approved 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 AZT Mechanism of action This synthetic dideoxynucleoside inhibits viral reverse transcriptase Side effects Painful 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.

Protease Inhibitors Clinical use Mechanism of action
Active against viral strains that are resistant to reverse transcriptase inhibitors More effective for AIDS than AZT, often used with AZT. It’s the third drug in “triple therapy” Mechanism of action HIV 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? yes Dosage considerations Low oral availability, short half life, and almost 100% protein bound Side effects Few and less severe than other AIDS drugs. However, nephrolithiasis (kidney stones) has occurred.

Antimycobacterial Drugs
11/26/2007

Learning Objectives Learn 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.

General Tuberculosis Tuberculosis is currently the ___ leading cause of death among infectious diseases worldwide. 3rd It 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 months Long course is months How 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 indidividuals Why 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.”

More 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? Streptomycin Ototoxicity and Nephrotoxicity Which first line drug is commonly used alone in prophylaxis for family members? Isoniazid

Isoniazid Mechanism of action General properties Metabolism
Inhibits biosynthesis of mycolic acid and subsequently reduces the integrity of the cell wall Bactericidal for actively growing bacilli and at high concentrations; bacteriostatic at lower concentration General properties Is 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. Metabolism Is 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 effects Central and peripheral nervous system toxicities Caused 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 use Used in combination with 1-3 other first line drugs Used alone for prophylaxis of family members Always coadministered with pyridoxine 10mg/100mg.

Rifampin Mechanism of action General properties Metabolism
Binds strongly to DNA-dependent RNA polymerase, inhibiting RNA synthesis (transcription). Suppression of initiation of chain formation Bactericidal General properties Well absorbed and widely distributed in body fluids and tissues Metabolism Not mentioned for this or any other drug except isoniazid. Major side effects Causes orange color to urine and other body fluids. Rarely causes other effects includingrashes, thrombocytopenia, nephritis and impaired liver funciton Clinical use Effective against atypical mycobacteria Used in combination with other first lines for TB

Ethambutol Mechanism of action General properties Major side effects
Unknown General properties Well absorbed after oral doses, good CSF penetration Works for TB and M. kansasii, but resistance would appear quickly if used alone Major side effects Few if any. Hooray! Clinical use Many atypical mycobacteria are sensitive Used in combination with other first lines for TB

Pyrazinamide Mechanism of action General properties Major side effects
Not known, Awesome. General properties Inactive 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 problem Major side effects Hepatotoxicity/impaired liver function. Clinical use Well absorbed from GI and distributed widely Used in combination with other first lines for TB

Streptomycin Mechanism of action General properties Major side effects
Not listed General properties Penetrates 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 effects Ototoxic and nephrotoxic Clinical use As stated above, it is important as an IV for patients with severe TB symptoms.

All 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 therapy What 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

Leprosy 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 therapy What three drugs are listed in the treatment of leprosy? Dapsone, Rifampin, Clofazimine Rifampin and dapsone are usually given together (due to resistance), clofazimine is an alternative to dapsone.

Dapsone (and other sulfones)
Mechanism Probably inhibits folate synthesis Structurally similar to sulfonamides Bacteriostatic General Properties More effective against M. leprae than tuberculi Slowly absorbed from GI Adverse effects High incidence of side effects: hemolysis, methemaglobinemia, GI disturbance, allergic responses. Use Treatment may require several years. Patients must be monitored for side effects and require an array of supportive and rehabilitation measure (sounds scary).

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