CAM Exam #5

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  1. Deaths from malaria occur because of:
    • failure to take chemoprophylaxis (compliance)
    • inappropriate chemoprophylaxis (wrong drugs)
    • delay in seeking medical care
    • misdx
  2. Clinical Presentation both initailly and during erythrocytic phase
    • Initial:  nonspecific fever, chills, rigors +/- maliase
    • Prodrome:  HA, anorexia, fatigue, myalgias
    • Cold Phase:  severe pallor, cyanosis of lips and nail bed
    • Hot Phase:  fever resulting in death
    • Sweating Phase:  Follows hot phase by 2-6 hrs, fever resolves, marked fatigue eventually with warm dry skin
    • Anemia
    • Splenomegaly
    • P. falciparum (most severe form):  thrombocytopenia, hypoglycemia, ARF, etc
  3. Milaria has three stages
    • 1- chills and uncontrollable shaking
    • 2- high fever
    • 3- profuse sweating
  4. What two milarial species are enountered most frequently?
    faciparum and vivax
  5. What two milarial species have dormant hepatic stage (hypnozite) that causes recurrent infections and relapses?
    ovale and vivax
  6. Milarial Stages (definitions)
    • sporozite:  infectious stage in life cycle of sporozoan
    • merozite:  asexual division of a protozoan in body of host
    • hypnozites:  dormant hepatic stage that can cause relapses
    • trophozoites:  young, ameboid, undivided stage
    • schizont:  adult asexual form of milarial parasite in man
  7. Classification of Antimilarials by Life Cycle Stage
    • Group 1:  Target blood asexual blood stages
    • Group 2 (atovaquone/proguanil):  primary liver and asexual blood stages
    • Group 3 (primaquine):  effective against primary liver, and both blood stages
  8. Which stage is the easiest to kill malaria?  Hardest to kill?
    • erythroctic stages are kiled most easily
    • exoerythrocytic (hepatic) stages are more difficult to kill
    • sporozoites don't respond to drugs at all - no prevention, just tx
    • 3 Objectives:  tx acute attack (clinical cure), prevent relapse (radical cure), suppressive therapy
  9. When tx acute attack (clinical cure) of malaria...
    • need drugs that are active against erythrocytic forms of malaria and eliminate parasites from blood cells
  10. When preventing relapse (radical cure) of malaria...
    • want drugs to act on latent tissue forms
  11. When having suppressive care of malaria...
    • drugs can't prevent primary infection of liver, can prevent infection of erythrocytes
    • prevents only sxs and not invasion of liver
  12. Inhibitors of Heme Metabolism (antimalarials - Q-CAM)
    • Quinine/Quinidine
    • CQ
    • Artemisinin
    • Mefloquine
  13. Inhibitors of electron transport (anitmalarials - AP)
    • atovaquone
    • primaquine
  14. Inhibitors of Folate metabolism (anitmalarials - PSp)
    • proguanil
    • sulfadoxine-pyrimethamine
  15. Malarial Tx for CQ Sensitive Areas (Americas)
    Prophylatic:  Chloroquine 300 mg once weekly starting 1 week prior to depature, continuing 4 weeks after return + DEET +/- thiamine + mosquito nets
  16. Malarial Tx for CQ-Resistant Areas (Kenya/Ghana, Africa)
    • Acute Tx:  Coartem (artemether + lumefantrine) - artemisinin based combo
    • Severe Acute Illness:  quinine/quinidine can be added to Coartem
    • Prophylactic Tx:  mefloquine 250 mg once weekly starting 1 week prior to departure continuing for 4 weeks after returning OR doxycyline 100 mg daily starting 1-2 days prior to departure and continuing for 4 weeks after returning + DEET +/- thiamine + mosquito nets
  17. Chloroquine (CQ)
    • MOA:  blood schizonticide that inhibits malarial heme polymerase
    • weak base and uncharged a physiologic pH that goes through erythrocyte and malarial trophozoite to reach the acidic vacuole; charged CQ shifts equilibrium back towards the erythrocyte causing heme degradation
    • only intraerythrocytic trophozites that are actively degrading hemoglobin are CQ-susceptible
    • CQ is not toxic to humans b/c it's pH dependent
    • SE are dose dependent
    • will not effect a complete cure of P. vivax or ovale (must give primaquine concurrently to eradicate the hypnozoites)
    • decrease CQ in food vacuole will cause transporters to pump CQ out
  18. Quinine/Quinidine
    • blood schizonticide
    • severe acute attacks b/c faster onset
    • SE:  cinchonism and hemolytic anemia in G6PD deficient patients
  19. Mefloquine
    • blood schizonticide for P. falciparum and P. vivax
    • resistance can develop rapidly
    • SE of epilespy/psychiatric disorder
  20. Artermether/lumefantrine (Coartem)
    • blood schizonticides providing synergistic antimaliarial activity while preventing the development of resistance
    • has extremely short half life which leads to increase resistance
    • recommended combining an atremisinin with a slowly eliminated blood schizonticidal agent (lumefantrine)
  21. Lumefantrine
    • long acting blood schizonticide
    • inhibits parasite's ability to detoxify free heme, which is necessary step afer parasite's degradation of human hemoglobin
    • SE:  HA, dizziness, QT prolongation
  22. Primaquine
    • MOA:  severely disrupts metabolic processes of plasmoidal mitochondria
    • quinone- a primaquine metabolite that interferes with the function of ubiquinone as an electron carrier
    • causes oxidative damage to plasmodial mitochondria
    • TISSUE SCHIZONTICIDE and gametocide
    • SE:  methemoglobinemia, graulocytopenia, agranulocytosis (rare)
    • Use for all plasmoidal speicies
  23. Atovaquone
    MOA:  inhibits activity of plasmoidal cytochrome bc1 and NOT USED AS A SINGLE AGENT
  24. Proguanil
    • MOA:  interfere with 2 different pathways involved in biosynthesis of pyrimidines required for nucleic acid replication and primarily exerts effects by cycloguanil metabolite
    • Cycloguanil selectively inhibits bifunctional DHFR- thymidylate syntetase enzyme of palsmoida resulting in DNA synthesis inhibition & depletion of folate cofactors
    • GISE and CI in severe renal impairment
  25. Pyrimethamine-sulfadoxine
    • blood schizonticide
    • Use:  combo is not longer routinely recmmended for malaria prophylaxis due to possibility of fatal toxic epidermal necrolysis (TEN)
    • prophylatic therapy should only be considered for travelers to areas where CQ-resistant p. falciparum is endemic and sensitive
  26. Metronidazole
    • MOA:  nitro group receives electrons from ferredoxin (present in anerobic parasites) in redox reaction; binds to proteins and DNA is cytotoxic; mixed amebicide = effective against lumenal and systemic disease
    • SE:  CNS disturbances, potentiation of warfarin's anticoagulation effects, teratogenic
  27. Amebiasis (Entamoeba hystolytica) pathology
    • amoeba invades mucosal cells of colonic epithelium and causes ulceration through toxin
    • left untreated, may invade portal cirulation and cause liver abscesses and then get into brain and lung
    • must differentiate between ambiasis and ulcerative colitis (UC) b/c UC may be tx w/ CS which can cause toxic megacolon if it's actually ambiasis
  28. Amebiasis (Entamoeba hystolytica) Clinical Presentation
    • mild-severe ab cramps +/- flatulence
    • diarrhea w/ blood & mucus (heme + in 100% of cases)
    • Liver abscess:  high fever, leukocytosis, liver tenderness, RUQ pain in shoulder, hepatomegaly
  29. Amebiasis (Entamoeba hystolytica) intestinal infection Tx
    Metronidazole 2.4 g/d PO x 2 days for intestinal disease (may cuase urine to be brown, metallic taste; disulfiram rxn)
  30. Amebiasis (Entamoeba hystolytica) Liver Abscess Tx
    Metronidazole 750 mg PO TID x 10 days followed by an intestinal agent
  31. Giardiasis pathology
    • intestinal protozona that is the most common intestinal parasite in US
    • found in fecally contaminate food and water
  32. Giardiasis Presentation
    • diarrhea (no blood/mucus), flatulence, belching, ab pain
    • Chronic - foul smelling, copious, light-colored fatty stools
  33. Giardiasis Tx
    Metronidazole 250 mg PO TID x 7 days
  34. Leishmaniasis pathology
    • Three forms are visceral, cutaneous, mucocutaneous
    • spread by dogs, squirrels, and rodents by sandfly vector
    • found in US around Mexican border
  35. Leishmaniasis presentation
    • Visceral:  ulcerative papules w/ late dz of fever, chills, hepatosplenomegaly
    • Mucocutaneous:  mutilation of nose, soft palate, trachea
  36. Leishmaniasis Tx
    stibogluconate sodium (antimony sodium gluconate)
  37. Trypanosomias/ African "sleeping sickness"/ American "chagas" disease pathology
    cause by "tsetse" fly bite from sucking blood of infected animals
  38. Trypanosomias presentation
    • unilateral orbital edema (Romana's sign)
    • granuloma/chagoma
    • fever, hepatosplenomegaly, lymphadenopathy
    • Chronic dz - cardiomyopathy, heart failure
  39. Trypanosomias Tx
  40. Hookworm pathology
    • ingestion of contaminated food and water; may penetrate skin; at risk patients include:
    • institutionalized patients
    • preschool children
    • residents of Indian reservations
    • homosexuals
  41. Hookworm Presentation
    • worms attach to SI mucosa causing mechanical & lytic destruction of tissue (inflammation)
    • anemia & hypoproteinemia (blood in stool)
    • eosinophilia
  42. Hookworm Tx
    mebendazole (Vermix) PO 100 mg BID x 3 days
  43. Ascariasis (Roundworm) Presentation
    • larva migrate through lungs
    • pneumonitis, fever, cough, eosinophilia, pulmonary infiltrates, ab discomfort w/ or w/o appendicitis
    • Dx made through charateristic egg in stool
  44. Ascariasis (Roundworm) Tx
    mebendazole (Vermix) PO 100 mg BID x 3 days
  45. Enterobiasis (Pinworm) pathology
    • small, thread-like spindle shaped worm
    • most widespread helminthic infection in world
    • mostly children
  46. Enterobiasis (Pinworm) Presentation
    cutaneous irritation in perianal region made by migrating females → intense itiching → dermatitis and secondary bacterial infection

    Dx:  perianal swab using scotch (adhesive) tape
  47. Enterobiasis (Pinworm) Tx
    Mebendazole (Vermox) 100 mg once and repeated in 2 wks OR Albendazole (Zentel) 400 mg once and repeated in 2 wks OR pyrental pamoate
  48. Head Lice Tx
    • eggs (nits) deposited on hair; hatched nits suck on host blood causing itching and secondary bacterial infection
    • Tx:  permethrin (Nix) 1% OR spinosad (Natroba) 0.9% topical suspension (Rx only) - apply to dry scalp and hair, wait 10 min & rinse; no need to comb out nits
    • wash all clothing, bedding, etc.
  49. Body lice (crabs)
    • inhabit genital, eyelash, beard, axillae areas
    • Tx:  Permethrin (Nix) 1%
  50. Scabies
    • extreme itching and inability to sleep
    • Dx made by skin scrappings of burrowed areas
    • Tx:  permethrin (Elimite) 5% applies once and washed off 8-14 hours after
  51. Benzimidazoles: Mebendazole, Albendazole, Thiabendazole
    • MOA:  inhibit mitosis by 1) inhibiting mitochondrial fumurate 2) decrease GLU transport 3) uncouple oxidative P 4) inhibits microtuble polymerization by binding beta-tubulin
    • anti-nematodal
    • albendazole can also tx cysicercosis and echinococcosis (larva forms of nematodes)
    • resistance is a problem for animals NOT humans
    • All CI in pregnancy
  52. Pyrantel pamoate
    • MOA:  depolarizing neuromuscular blockade agent in helminths causing persistent activation of nicotinic receptors that leads to spastic paralysis of worm
    • DOC for treating Ascaris (giant roundworm)
  53. Diethylcarbamazine
    • MOA:  unknown but decreases muscular activity and immobilizes parasites; alters microfilarial surface membranes so they're more susceptible to host defenses
    • DOC for lympatic filarisis - thickening of skin and underlying tissues (legs & male genitalia)
    • ADE:  Mazotti rxn - SE from worms dying enlarged lymph nodes, HTN, tachycardia
  54. Ivermectin
    • bind glutamate-gated channels
    • bind GABA-gated chloride channels
    • Avoid BZDs & barbituates
    • selectivity:  glutamate-gated chloride channels have only been found in invertebrates; affintiy for invertebrate GABA receptors 100x greater than for vertebrates; ivermectin doesn't corss BBB
    • drug target for RIVER BLINDNESS
    • has less severe Mazzotti rxn
    • only for microfiliaria and takes drug 10-15 years
  55. Praziquantel
    • MOA:  increases parasite's cell membrane permeability to calcium, causing marked muscle contraction, followed by spastic paralysis of worm musculature; vacuolization & disintegration of tegument and ultimate parasite death
    • Anti-trematode (Fluke) + Cestode
  56. Mycobacterium characteristics
    • aerobic gram +
    • acid fast, non-motile, rod-shaped
    • slow growing; requires lengthy tx
    • complex, waxy outer layer
    • can spontaneously and randomly become resistant to drug tx
    • Cell Wall contains:  extractable phospholipids, mycolic acids, arabinogalactan, murein (petidoglycan)
    • Cell wall of mycobacteria is thick, asymmetric, and highly impermeable to both hydrophillic and hydrophobic substances
  57. Primary infection of TB
    • inhale infected sputum that has been aersolized by coughing/sneezing
    • infection can spread via lymphatic and circulatory systems
  58. Reactivation of TB
    • active infection cause by dormant tubercle bacilli following control of a primary infection by host defenses
    • necorsis & cavitation of lung tissue
    • lung tissue may become caseous (cheeselike in appearance)
    • since phagocytes don't fxn at necrosis site, cellular immunity is unable to suppress active infection
    • absence of tx, progressive tissue destruction may result in death
  59. What makes TB difficult to tx?
    • It's an intracellular organism
    • cell grows slowly (difficult to kill) and lengthy tx time (6 mos w/ multiple agents)
    • resistance due to subotimal doses for long periods of time
    • #1 cause is poor compliance
  60. How do ATB promote resistance?
    • If a drug-resistant microbe is present, ATB will create an environment for that microbe to thrive in by:
    • killing off sensitive microbes and toxins produced by the microbes
    • making more nutrients available to the suriving drug-resistant microbe
  61. TB:  Mechanisms which resistance is acquired
    • Intrinsic Resistance:  fundamental properities like cell wall of a microbe
    • Spontaneous Mutation (and selection):  results in random changes in microbe's DNA; as a rule, spontaneous mutation confers resistance to only one drug; development of multiple drug resistance would require multiple mutations, a rare phenomenon
    • Conjugation:  plasmid-mediated resistance, transferable resistance
  62. Rationale for Multi-Drug Therapy in TB
    • delay and prevent the emergence of resistant strains:  use multiple agents for a long period of time ("kill them all" approach)
    • to target different populations of mycobacterial cells
  63. TB basics
    • disproportionately higher in ethnic minorities in US reflecting greater transmission
    • co-infection w/ HIV patients accelerates the progression of both diseases
    • atypical s/s in infants, elderly, immunocompromised patients
    • LTBI leads to reactivation disease years after primary infection
    • isolation procedures must be done for patients suspected of TB
    • isoniazid & rifampin are most important TB drugs
    • NEVER add only a single drug to a failing regimen; must add two more drugs
    • use Direct Observational Therapy (DOT)
  64. TB Typical S/S
    • weight loss
    • fatigue
    • productive cough leading to Frank hemoptysis (bright red blood in cough)
    • fever
    • night sweats
    • Labs:  elevated WBC (left shift) and does not gram stain well (acid fast)
  65. TB Dx
    • Heaf and Tine test are less accurate than the Mantoux test
    • PPD (purified protein derivative)/Mantoux test:  standard 5 tuberculin units of ppd injected intradermally → TB infected pt produce small, raised, blanched wheal in 48-72 hrs → raised area (induration) more significant than redness
    • some pts previously infected or have recieved BCG vaccine may test postively with one test, BUT will test negatively (booster effect) w/ another test a week later
    • sputum culture/chest x-ray is next
  66. LTBI Tx
    • INH 300 mg QD for 9 mos w/ Vit B6 10-50 mg OR
    • INH 900 mg twice weekly for 9 mos by DOT w/ Vit B6 OR
    • rifampin 600 mg daily for 4 mos when INH resistance is suspected
  67. Active TB infection Tx for INITIAL phase
    • INH/RIF/PZA/EMB daily for 8 weeks (2 mos)
    • all first line
    • PIE (PZA/INH/EMB) are all cell wall inhibitors
    • RIF is a nucleic acid agent
    • EMB - Static
    • PZA - CIDAL?
  68. Active TB infection Tx for CONTINUATION phase
    INH/RIF daily for 4 mos
  69. Special Pops w/ TB
    • extrapulmonary TB
    • miliary TB:  infiltration of granulomas at extrapulmonary sites
    • children:  may need higher doses of RIF/INH
    • pregnancy: INH and EMB relatively safe w Vit B6; RIF rarely w/ birth defects; pyrazinamide not been studied; streptomycin causes hearing loss
    • HIV pts:  many drug interaction w/ various HIV meds
    • Renal Failure:  INH & RIF DON'T require dose reductions
  70. Pyrazinamide (PZA)
    • Chemistry:  nicotinamide analog
    • Mechanistic Class:  mycobacterial cell wall inhibitor
    • MOA:  targets FAS1 invovled in mycolic acid biosynthesis
    • Resistance:  pyrazinamidase (PncA protein) necessary to hydrolyze drug for activity; pyrazinamide must be hydrolyzed to active form (pyrazinoic acid)
    • Resistant organisms lack functional form of pyrazinadmidase to activate drug
    • BACTERIOCIDAL (sometimes STATIC)
    • SE:  hepatic damage, arthralgia, myalgia, darkened urine, yellow discolartion of skin/eyes
    • used in combination therapy - MUST NEVER BE GIVEN ALONE W/O RIF & INH
    • take w/ or w/o food
  71. Isoniazid (INH)
    • Chemistry:  nicotinic acid derivative
    • Mechanistic Class:  mycobacterial cell wall inhibitor
    • antimycobacterial
    • MOA:  inhibits synthesis of mycolic acid
    • pro-drug activated by catalase-peroxidase (KatG protein) of tubercle bacillus
    • activated drug's target is Enoyl-ACP reductase (InhA protein) of FAS2, which is essential for FA elongation
    • Resistance:  mutations in KatG or InhA (gene; gene product)
    • w/ TB, intracellular & extracellular levels are similar
    • plasma drug levels in liver by N-acetylation; rate of N-acetylation alters conc. of drug in plasma and it's half-life
    • INH is relatively nontoxic, sufficient amount of drug can be administered to fast acetylators to achieve therapeutic effect = to slow acetylators
    • SE:  peripheral neuritis (can be reversed by vit B6 supplements) and crosses placenta, yellowing skin and eyes and darkening urine ~ liver involvement
    • inhibits CYP450
    • take on empty stomach
  72. Ethambutol (EMH)
    • Chemistry:  semisynthetic
    • Mechanisitc Class:  mycobacterial cell wall inhibitor
    • MOA:  inhibits arabinsoyl transferase (EmbA protein) which is involved in synthesis of arabinogalactan, an essential component of mycobacterial cell wall; may also affect RNA synthesis/stabilization
    • Resistance:  overproduction and/or mutation of target arabinosyl transferase (EmbA protein)
    • SE:  optic neuritis/visual distrubances (decreased visual acuity, red-green color blindness); inhibits uric acid excretion (dose-dependent)
    • take with food
  73. Rifampin
    • Chemistry:  macrocyclic
    • Mechanistic Class:  nucleic acid agent
    • MOA:  inhibits bacterial and mycobacterial DNA-dependent RNA polymerase; suppresses RNA synthesis by blocking chain initiation
    • Resistance:  spontaneous mutations in RNA polymerase
    • limited penetration into CSF
    • Braod Spectrum 
    • SE:  red-orange secretions that may permanently discolor soft contact lenses, darkened urine/yellowish discoloration of skin or eyes
    • CYP450 (3A4) DIs
  74. HIV pts vs. non-HIV pts w/ TB
    • Diseminated infection is common in HI V patients:  fever, night sweats, weight loss, lethargy, anemia, abnormal liver fxn tests
    • Non-HIV patients have disease limited to lung and presents with a chornic productive cough and chest roentgenorgram showing limited, diffuse, and/or cavitary disease
  75. Rifabutin
    • MOA:  inhibits mycobacterial DNA-dependent RNA polymerase; suppesses RNA synthesis by blocking chain initiation
    • used for MAC seen in HIV positive patients
    • shouldn't be used in pts w/ active TB
    • SE:  nausea and rash
    • *** can also use macrolides (bacteriocidal) for tx of MAC***
  76. Rifapentine
    85% of RIF's activity
  77. Rifater
    RIF/INH/PZA combo
  78. Rifamate
    RIF/INH combo
  79. Second Line Drugs for TB
    • more toxic and less effective than 1st line drugs
    • principal use is tx of TB caused by organisms that are resistant to 1st line drugs
  80. Streptomycin
    • Chemistry:  AMG
    • Mechanistic Class:  interferes with protein synthesis
    • MOA:  binds to several ribosomal sites, usually at 30S/50S interface; interferes with bacterial protein synthesis (primary site of action is 16S rRNA of 30S subunit)
    • doesn't penetrate into cells or CNS (lipid-insoluble); will not kill intracellular microbes
    • SE:  otoxocity affecting balance and hearing (permanent with continued use); nephrotoxicity (mild & reversible)
    • used for life-threatening TB in combo with first line drugs
    • could subsitute with amikacin/kanamycin
  81. Capreomycin
    • bacteriostatic
    • can cause neuromuscular blockade
    • second line agent for TB
  82. Cycloserine
    • MOA:  amino acid D-alanine; cycloserine competes with D-alanine for 2 enzymes (L-alanine racemase & D-alanine synthetase); inhibits both enzymes and peptidoglycan synthesis, resulting in weak cell wall and eventually cell lysis
    • CNS effects/toxicity
    • only used to tx MDR-TB
  83. Ethionamide
    • MOA:  inactive pro-drug that's activated by mycobacterial enzyme (EtA) and inhibits the enoyl-ACP reductase of FAS2 resulting in inhibition of mycolic acid biosynthesis
    • static/cidal depending on dose
  84. Para-aminosalicyclic acid
    • MOA:  competitive inhibitor of DHFR, which inhibits synthesis of folic acid 
    • children accept drug somewhat better
  85. New Drugs and Delivery systems
    • nitromidazopyran PA-824 drug
    • liposlam delivery to enhance efficacy
  86. MDR-TB
    • never add a single drug to a failing regimen
    • drug resistance should be suspected in:  pts who have received prior tx for TB and pts from areas with a high prevalence for resistance
    • patients who are homeless, institutionalize, IV drug abusers or infected with HIV
    • pts who still have (+) AFB smears after 1-2 mos of tx and who still have (+) cultures after 2-4 mos of tx
    • pts failing tx of relapse post tx
    • pts known to be exposed to MDR-TB cases
  87. Monitoring Tx Care Plan for TB
    • Most serious problem with TB tx is NON-ADHERENCE
    • DOT greatly improves adherence rates in unreliable patients
    • homeless and other underprivledged individuals are considered unreliable patients
    • patients who complete all their tx for drug-susceptible TB have cure rates approaching 100%
    • patients who have AFB positive stains, should have AFB stains performed every 1-2 weeks until 2 consecutive smears are negative
    • if sputum cultures continue to be (+) after 2 mos, drug suscpetibility should be tested and serum drug conc. should be confirmed
    • Baseline labs should be performed periodically and more often in special pops
    • patients recieving streptomycin should have Snellen visual acutiy and Ishihara color discrimination tests performed
    • all pts dx with TB should be tested for HIV infection
  88. Dapsone
    • Chemistry:  4,4-diaminodiphenysulfone
    • Mechanistic Class:  energy metabolism agent
    • Therapeutic:  antimycobacterial; leprostatic
    • MOA:  competitive inhibitor of dihydorpteroate synthetase; inhibits synthesis of folic acid; bacteriostatic
    • SE:  hemolytic anemia & methemoglobinemia
    • Use:  combo w/ RIF and clofazimine to tx leprosy
  89. Clofazimine
    • Chemistry:  phenazine dye
    • Mechanistic:  nucleic acid agent
    • Therapeutic:  antimycobacterial
    • MOA:  binds to GC-rich mycobacterial DNA and inhibit its template fxn (interfering iwth reproduction and growth)
    • SE:  distincitive reddish-brown discoloration of skin
    • Use:  combo chemotherapy; often for sulfone-resistant leprosy
  90. Endothelial cells
    • scavenge lipoproteins via the apoE receptor
    • secrete cytokines, prostanoids, NO, endothelins
    • can fxn as APC
  91. Kuppfer cells
    • resident macrophages of liver
    • Primary fxn:  ingest and degrade particulate matter
    • major source of cytokines and eicosinoids
    • acts as APCs
  92. Stellate cells
    • vitamin A storage
    • activated, these cells synthesize and excrete collagen and other extracellular matrix proteins and express smooth muscle actin
  93. Microcystin fxn
    • large doses of microcystin leads to marked deformation of hepatocytes due to collaspe of microtubular actin scaffold into a spiny aggregate
    • small doses don't produce deformities, but diminishes uptake and secretory fxns of hepatocytes through hyperphosphorylation of dynein
    • can be inhibited by bile salts and organic anions
  94. Zone 1 of hepatocyte
    • high oxygen levels
    • iron overload
    • more GSH
  95. Zone 3 of hepatocyte
    • less oxygen levels
    • more P450 enzyme
    • less GSH
  96. DILI proposed two pathways
    • Direct hepatotoxicity:
    • protein dysfunction
    • lipid peroxidation
    • DNA damage
    • oxidative stress
    • Adverse Immune Rxns:  innate and adaptive immune responses
  97. Innate Immune System DILI
    hepatocyte stress and/or damage result in release of signals stimulating activation of other cells (Kpuffer cells, NK cells, NKT cells) → progress liver injury by producing proinflammatory mediators & secreting chemokines for futher inflammatory cell recruitment (TNFα, INF-γ, IL-1β) → tissue damage

    innate immune cells also have protective role (IL-10,6, certain prostglandins)
  98. Adaptive Immune System DILI
    • Clinical Characteristics include:
    • rash, fever, eosiophilia
    • delay of initial rxn (1-8 wks) or requirement of repeated exposure to culprit drug
    • rapid recurrence of toxicity on re-exposure to drug
    • presence of antibodies specific for native or drug-modified hepatic proteins
    • solely based on Hapten Hypothesis
    • can only happen when tolerance mechanism is deficient or abrogated in susceptible people
  99. Hapten Hypothesis w/ Adapative Immune System DILI
    • IN SUPPORT:  patients with halothane hepatitis or patients w/ liver injury caused by ethanol, antibodies against drug-modified proteins were detected
    • NOT IN SUPPORT:  APAP forms reactive metabolite and drug-modified proteins, does not trigger an immune response which suggests additional activating factors may be necessary to induce immune-mediated liver injury
  100. Danger Hypothesis w/ Adapative Immune System DILI
    • damaged cells release danger signals, which induce the upregulation of B7 on APCs (costimulation)
    • cytotoxic immune response when TCR stimulation w/ antigen is accompanied by an indpendent co-stimulation of T-cell
    • Liver sinusoidal endothelial cells and Kuppfer cells can functions as APCs in liver
  101. Why is it difficult to explain hypothesis about Adaptive Immune System?
    • default response of liver to antigens is immunological tolerance
    • tolerance - following antign exposure, activated T cells undergo apoptosis after a transient accumulation within liver
  102. Idiosyncratic Liver Injury
    • Idiosyncratic drug reaction:  uncommon drug response resutling from a genetic predisposition
    • Idiosyncratic drug hepatoxicity:  rare but potentially serious ADE; not dose-dependent; unpredictable; affects very few pts exposed to drug
    • Idiosncratic hepatoxicity:  observed after consumption of herbal remedies and food supplements
  103. What must be present in order for APAP toxicity to occur?
    binding to NAPQI to mitochondrial proteins is considered a critical initiating event of toxicity that requires amplification
  104. anti-infective
    any agent used to control an infectious disease process
  105. antibiotics
    chemical substances produced by micoorganism as well as their synthetic/semi-synthetic analogs that have the capacity to selectively inhibit/destro bacteria in lon concentration
  106. antimetabolites
    • chemical substances that have capacity in LOW CONCENTRATIONS to inhibit normal growth processes of cell, effects which can be reversed by administration of one or more common biochemicals (nutrients)
    • Ex. anti-folates, sulfonamides, NRTI, nucleosides and nucleoside like drugs
  107. antimicrobial
    substances other than ATBs wholly synthetic that inhibit growth or survival of microorganisms in HIHGER concentrations (antibacterials, antifungals, antivirals)
  108. germicides/antiseptics
    • chemical substances that inhibit microbial growth in relatively LARGE concentrations, without selective toxicity
    • Ex. phenols, alcohols, hydrogen peroxide and iodine
  109. Anti-infective Targets:  Receptors
    CCR5 receptor - maraviroc
  110. Anti-infective Targets:  Enzymes
    • dihydropteroate synthase - sulfonamides
    • DHFR - trimethoprim
    • DNA gyrase (bacterial Toposiomerase I) & Top IV - quinolones
    • cell wall transamidases & transglycoslases - β-lactams
    • bacterial DNA-dependent RNA polymerase (DDRP) - rifampin
    • reverse transcriptase - NRTI NNRTI
    • HIV protease - azatanvir, ritonavir, etc
    • Integrase - raltegravir
    • neuramindase - olsetamivir
    • mycobacterial desaturase - isonicotinic and hydrazide (INH)
    • squalene epoxidase - allyamine antifungals
    • 14α-demethylase - antifungal azoles
  111. oxazolidinones (Ox)
    binds to 23S portion of 50S ribosomal subunit to prevent formation of 70S initiation complex
  112. streptogramin A (dalfopristin)
    binds to 50S inhibiting aa-tRNA binding to "A" site
  113. streptogramin B (quinupristin)
    binds to 70S inhibiting proper translocation ("P" site)
  114. macrolides
    binds to 50S inhibiting proper translocation ("P" site)
  115. tetracyclines
    binds to 30S inhibiting aa-tRNA binding to "A" site
  116. aminoglycosides
    binds to 30S at interface of 30S and 50S
  117. lincosamides
    binds to 50S at a site overlapping macrolides and SGMB
  118. choloramphenicol
    binds to 50S at a site similar to but different than macrolides, lincosamides, and SGMB
  119. Calcineurin Inhibitors (CNIs)
    • MOA:  block T-cell proliferation by inhibiting IL-2 and other cytokines by T-cells
    • drug binds to immunophillin and complex then inhibits calcineurin blocking IL-2 PRODUCTION
    • sometimes delay initiation of CNIs to avoid ADE early post-transplant
  120. Cyclosporine
    • CNI that binds to cyclophillin
    • used in autoimmune disorders
    • stay with same manufacturer once on drug
    • PK:  absorption sporadic & variable, difficulty switching dosage formulations, very hydrophobic, high protein binding, levels difficult to interpret so adjust doses
    • metabolized by CYP3A4 and excreted in bile and feces
    • ADE:  hyperglycemia, HTN, histuism, gingival hyperplasia
  121. Tacrolimus
    • CNI binds FKBP12
    • steroid sparing effect and cost reduction
    • more potent immunosuppressant than cyclosporine, but increase ADE
    • PK:  crosses the placenta and in breast milk, high liphophilicity and protein binding, clearance increased in peds (BID dosing)
    • CY3A4 inhibitor and substrate
  122. Corticosteroids
    • methlprednisolone and prednisone
    • signifcant party of tx, increased chance of rejection if not part of combo therapy
    • inhibit t-cell proliferation by blocking gene transcription of cytokines
  123. mycophenolate
    • MOA:  antimetabolite that inhibits monophosphate dehydrogenase (de novo synthesis) of human lymphocytes and proliferation of lymphocytes
    • MPA active metabolite - via hepatic and GI
    • Dose separated by 12 hours on empty stomach
    • ADE:  increased risk for cancers, diarrhea, leukopenia, nausea
    • doesn't cause nephrotoxicity/HTN
  124. azathioprine
    • prodrug of 6-MP disrupting salvage and de novo pathways of DNA, RNA, and protein synthesis
    • ADE:  dose-limiting (lekopenia, anemia, thrombocytopenia)
  125. mTOR inhibitors
    • Block RESPONSE of IL-2, NOT production
    • MOA:  bind to FKBP12 forming a complex that binds to mTOR, inhibiting response to ciruclating cytokines
    • sirolimus & everolimus
  126. sirolimus
    • MOA:  binds to FKBP12 forming a complex that binds to mTOR, inhibiting response to circulating cytokines
    • can be used directly after kindey transplant
    • ADE:  hyperlipidemia, thrombocytopenia, leukopenia
    • increased HSV risk
    • no increase risk for CMV, fungal/bacterial
    • CYP3A4 inhibitor and substrate
    • used in hepatic artery thrombosis, graft failure in liver tx, bronchial anastomotic dehiscence (fatal) in lung transplant
  127. everolimus
    • MOA:  binds to FKBP12 forming a complex that binds to mTOR, inhibiting response to circulating cytokines
    • used for rejection prophylaxis for renal transplatn (unlabled for heart transplant)
    • adjust dose with hepatic dysfxn, not renally cleard
    • CYP3A4 inhibitor and substrate
    • BBW:  increased risk of RAS & VT, infection, malignancy
  128. antithymocyte globulin
    • antibody agent that use lymphocyte receptors to activate complement-mediated lysis and lymphocyte depletion
    • ADE:  myelosuppression, anaphylaxis
    • Dose for 7-14 days
  129. muromonab-CD3 (OKT3)
    • antibody agent that acts at CD3 to deplete t-cells and alter fxn
    • ADE:  cytokine release syndrome
  130. alemutuzumab
    • antibody agent that acts at CD52 to induce abdy-dependent lysis of both T and B-cells, depleting them from blood, bone marrow, and organs
    • ADE - pancytopenia
  131. basiliximab
    MOA:  IL-2RA that binds to α-chain (CD24) on activated Tcells which blocks IL-2 from binding (ultimately stopping activation/proliferation of Tcells)
  132. belatacept
    • prophylaxis of kidney rejection intially and as maintence
    • only in combo with other agents and in seropositive for EBV
    • selective T-cell costimulation blocker by binding to CD80 and CD86 receptors on APCs which block CD28 mediated interaction b/t APCs and T-cells required for activation
  133. Who are the fastest growing populations receving heart transplant?
    elderly ≥55 yoa
  134. Heart Transplant Indications
    • Class III/IV
    • intolerable sxs
    • lack of reversible factors
    • 1 year life expectancy of <50%
    • <20% EF - not indication alone for heart transplant
  135. Comorbid conditions affecting selection for heart transplant
    • irreversible renal, hepatic, or pulmonary disease
    • severe PVD/PE
    • current malignancy/GI disease
    • DM or morbid obesity
  136. Post-Operative Mgmt of heart transplant
    • minimize infection complications through:
    • early ambulation
    • vigorous pulmonary support
    • removal of all lines and catheters
    • CO largely rate dependent - milrinone often used instead of dobutamine
    • HTN common
  137. Cardiac Transplant Preoperative Immunosuppression Regimen
    • mycophenolate mofetil PO
    • cyclosporine/tacrolimus IV
    • administered 2-6 hrs prior to surgery
  138. Tripe immunosuppressive regimen Post cardiac transplant
    • methylprednisolone IV immediately after bypass removed 
    • mycophenolate mofetil PO BID
    • CNIs
  139. Immunosuppressive Induction for Heart Transplant
    • may use in combo w/ low dose CNI or alone until renal fxn recovers
    • may also allow for more rapid D/C of maintenance CS
    • OKT3 IV
    • antithymocyte globulin
    • regimens given for 10 days (5-7 as effective)
    • infection and malignancy risk is higher
  140. Acute Rejection in cardiac transplantation
    • high-dose CS
    • Rescue therapy - OKT3 (if not use before) or ATG (no induction meds b/c you have risk of autoimmune rxn)
  141. Chronic Rejection in cadiac transplant
    • cardiac allograft vaculopathy (CAV) or transplant CAD
    • leading causing of death after 1 year post-transplant
    • drugs have been pointed at for prevention (treat diseases)
  142. GVHD
    • problem with allogenic HSCT
    • marrow purgingin:  used to eliminate Tcells to reduce risk of acute GVHD
    • Acute = first 3-4 mos and involves three organs:  skin, liver, GI
    • rash w/i 21 days on palsm and soles to start, face and trunk later
    • liver GVHD - increase LFTs and bilirubin with janudice
    • GI - severe diarrhea possibly bloody, ab pain, N/V
  143. Acute GVHD Tx is unsatisfactory
    • cylosporine + MTX/CS
    • tacrolimus + MTX/CS
  144. Chronic GVHD
    • >100 days post-BMT
    • can involve skin, mouth, liver, eyes, pulmonary
    • no effective prophylactic regimens
    • prednisone + CNI
    • very poor Px in those that fail initial tx:  thalidomide, UV radiation, total lymphoid irradiation
    • infection is primary cause of death - antimicrobial prophylaxis for immunocompromised patient
  145. Liver Transplant Indications
    • 1- chronic viral hep B/C
    • 2- alcoholic liver disease
  146. Liver Transplant indications for referral (work-up)
    • serum albumin <2.5 g/dL
    • PT > 5 sec
    • serum bilirubin > 5 mg/dL
    • hepatorenal syndrome
    • SBP
    • intractable/refractory ascites
    • severe encephalopathy
    • severe fatigue
    • bleeding from esophogeal/gastric varices
  147. CI for Liver Transplant
    • AIDS (not HIV)
    • active illicit drug use
    • extrahepatic malignancy
    • cholangiocarcinoma
    • infection outside biliary tract
    • advanced cardiopulmonary disease
  148. Relative CI for Liver Transplant
    • inadequate family/social support
    • advanced age
    • hepatopulmonary syndrome with partial pressure of oxgen in arterial blood < 50 mmHg
    • intrahepatic tumor > 5 cm
    • HIV positive
    • renal failure
    • severe obesity/undernutrition
    • uncontrolled psychiatric disorder
  149. Model for End-stage Liver Disease (MELD)
    the way we categorize liver transplants/liver disese
  150. Prevention of Liver Transplant
    • CNI + mycophenolate
    • may need CS/OKT3 in actue rejection
    • lungs and heart have are more immunogeic than liver
  151. Lung Allocation Score (LAS)
    score based on survival probability and pathophysiology of underlying disease
  152. Lung Transplant
    infection leading cause of death in first 60 days post-transplant, not rejection
  153. Immunosuppression for lung transplant
    • CNI
    • mycophenolate
    • CS
  154. Acute Rejection of lung transplant
    • CS
    • refractory cases may require OKT3, ATG, tacrolimus
  155. Chronic Rejection of lung transplant
    • bronchiolitis obliterans - progressive airway obstruction
    • irrversible- CS
  156. Aboslute CI for Renal Transplant
    • current malignancy
    • active infection
    • active liver dz and/or substance abuse
    • severe symptomatic CV and/or pulmonary disease
    • abnormal psychosocial/compliant behavoir
  157. Relative CI for Renal Transplant
    • chronic liver disease
    • positive for HCV/HIV
    • morbid obesity
    • >70 yoa
  158. Physiologic Consequence of Renal Transplant
    • GFR may be near normal almost immediately after transplant
    • BUN and sCr may remain elevated for several days
    • resolution of anemia, Ca/PO4 imbalance, lipid abnormalities may take several weeks
    • erythropoeitin and hydroxylation of vit D may also be delayed
  159. Renal Transplant Regimens
    • Most rely on 3-4 agents
    • CNI
    • mycophenolate/sirolimus/azathioprine
    • prednisone
    • +/- monoclonal (OKT3, basiliximab) or polyclonal (ATG) (induction therapy)
  160. CNI in renal transplants
    • CNI cause dealyed graft fxn so may not use during 1-2 wks
    • use monoclonals/polyclonals instead
  161. Renal Transplant Induction tx
    • should include steroid + antiproliferative agent (AZA/mycophenolate) w/ or w/o antibody therapy
    • OKT3/ATG
    • basiliximab
  162. Transplant Tx Summar
    • Heart:  CNI + antiproliferative (antimetabolite) + CS
    • BMT:  CNI + CS/MTX
    • Liver:  CNI + antiproliferative (antimetabolite) +/- CS/monoclonal
    • Lung:  CNI/antiproliferative (antimetabolite)/CS
    • Kidney:  CNI + antiproliferative + CS +/- monoclonal/polyclonal
  163. Which organisms have a polysaccharide capsule?
    • Strep. pneumoniae
    • N. meningitidis
    • Klebsiella pneumoniae
    • Bacteroides fragilis
    • Haemophilus influenzae
    • Bortedella pertussis
  164. Which organisms are oxidative anaerobes?
    • Peptococci
    • Clostridium
    • Actinomyces israeli (filamentous)
    • Bacteroides fragilis
  165. Which organisms are oxidative aerobes?
    • Bacillus (spore forming)
    • Corynebacterium diphtheria (non-spore forming)
    • Listeria monocytogenes (non-spore forming)
    • Pseudomonas aeruginosa
    • Haemophilus
    • Legionella
    • Bortedella pertussis
  166. Which organisms are aerobic acid-fast?
    • Nocardia asteroides
    • Moraxella catarrhalis
    • Mycobacteria
  167. Not readily gram-stained organisms?
    • Mycobacteria
    • Mycoplasma
    • Treponema pallidum 
    • Borrelia burgdorferi 
    • Chlamydia sp.
Card Set:
CAM Exam #5
2013-05-03 05:36:42
Parasitic Disease

Parasitic Diseases
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