pharm exam 2

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pharm exam 2
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  1. Virchow's Triad
    • = 3 things that inc risk of thromboembolism :
    • 1. hypercoaguabte state
    • 2. circulatory stasis
    • 3. endoth injury
  2. Ex of Risk factors for thromboembolism: Abnormalities of bld flow
    • Atrial fibrillation
    • immobilization/bed rest
    • Venous obstruction from tumor/preg

    (i.e. situations of blood stasis)
  3. Ex of Risk factors for thromboembolism: Abnormalities of Clotting components
    • (most = hereditary )
    • Prot C or S deficiencies
    • Malignancy- thrombo embolism out of the blue
    • preg
    • thrombocytosis
    • estrogen therapy
  4. Ex of Risk factors for thromboembolism: Abnormalities of surf in contact w/ bld
    • vasc injury / trauma
    • heart Valve replacement
    • indwelling Catheters
    • atherosclerosis
    • fractures
  5. Endogenous Anticoagulants
    • 》Circulating in plasma:
    • Anti-thrombin Ill
    • Prot C
    • Prot S
    • Tissue fact pthwy inhibitor ( TFPI)
    • ------------------------------------------------
    • 》Released by vasc endoth:
    • Prostacyclin (PGI 2)
    • NO
    • Thrombomodulin
    • Heparin Sulfate
  6. formation of fibrin clot
    • expose vWF → platelet adhesion ⇒ Release Platelet factors → platelet aggregation ⇒ Release of tiss fact & fibrin clot formation
    • fibnnolysis & removal of clot after Vess repair
  7. loc of action in clot formation: anti-Platelet vs. anti-coagulants
    • 》Anti-Platelets: act on platelet aggregation pthwy
    • 》anti-coagulants: act on intrinsic/extrinsic pthwys that → thrombin formation
  8. Intrinsic Coagulation Cascade / Pthwy
    • initiating / first step: factor Xll activ by vess injury or exposure to foreign body
    • Meets extrinsic pthwy at factor X
  9. Extrinsic Coagulation Cascade / pthwy
    • initiating/ first step: factor Vll activ by exposure to Tiss fact (TF) on endoth cells & leukocytes @ injury site
    • Meets intrinsic pthwy @ fact X
  10. Common Pthwy of coagulation Cascade
    • starts w/factor X - activated by BOTH intrinsic & extrinsic coag pthwy
    • X→Xa ⇒ activ prothrmbin → thrombin ( lla) ⇒ activ fibrinogen → fibrin
    • * a = activated
  11. Thrombin
    • potent activator of platelets
    • activated by factor Xa
    • activates fibrinogen → fibrin
  12. Arterial Thrombi
    • = white thrombi
    • = platlet rich, held together w/ fibrin
    • *to prevent & treat acute coronary synd ( ACS ) use anti-platelet agents
  13. Venous thrombi
    • = red thrombi
    • = platlet poor, 1°ly fibrin
    • * anti - coagulant to tx & prevent venous thromboembolism & embolic events 2° to Afib
  14. Indications of Anti-Platlet Drugs
    • 》Prevention:
    • ACS ( Acute coronary synd )
    • 2° prevention of Stroke
    • stroke 2° to Afib (Only low risk pts. Hi risk pts get anticoag)
    • -----------------------------------------------------------------
    • 》Tx:
    • unstable angina & NSTEMI
    • STEMI
    • Post coronary stent placement
    • ( usually use 2 antiplatlet agents)
  15. NSTEMI
    non-ST segment elevation myocardial infarction
  16. STEMI
    ST- elevation myocardial infarction
  17. Anti-Platlet Drugs & Mech of action
    • 》COX-1 inhibitors :
    • Asprin ⇒ irrev, = Why use So much ( can take less)
    • NSAIDs ⇒ rev.
    • -------------------------------------------------------------------------------
    • 》Inhibitors of intracell phosphodiesterase & uptake of adenosine ( don't use much)
    • Dipyridamole ⇒ Usually use this
    • Cilostazol
    • -------------------------------------------------------------------------------
    • 》Inhibitors of P2Y12 adenosine diphosphate (ADP) platelet rec ⇒ most common after aspirin
    • Clopidogrel (Plavix) ⇒ irrev→ prolonged effect
    • Prasugrel ( effient) ⇒ irrev
    • Ticagrelor (Brilinta) ⇒ rev
    • -------------------------------------------------------------------------------
    • 》Glycoprot llb/Illa antagonists

    * irrev usually = good EXCEPT w/Surgery
  18. Aspirin
    • AKA: ASA ( acetylsalicylic acid)
    • ------------------------------------------------------------------------------- -
    • = NSAID;= anti-platlet agent
    • *irrev inhib of platlet func
    • @ hi doses (like for pain)→ gastric bleeding & bad side effects⇒ not used for pain now (replaced by acetaminophen)
    • * use lo dose for ant-platlet effect
    • -------------------------------------------------------------------------------
    • Mech: inhibits COX-1 → prevent Synth of TXA2 (thromboxane A2 )
    • -------------------------------------------------------------------------------
    • Uses: angina, post-MI, 2° prevention of stroke
    • -------------------------------------------------------------------------------
    • Dose as prophylactic = 81 mg = baby aspirin
    • * single dose lasts the 8-10 day life of platlet
  19. Dipyridamole
    • * most commonly used as: Dipyridamole 200mg + ASA 25mg [ = Aggrenox ]
    • less effective than ASA when used alone
    • -------------------------------------------------------------------------------
    • Mech: inhibits platelet func by inhibiting Phosphodiesterase & inc's in plasma adenosine levels ⇒ inc intracell conc of cAMP
    • Also vasodil
    • -------------------------------------------------------------------------------
    • Advers: headache (40% ) -b/c Vasodil
    • -------------------------------------------------------------------------------
    • rarely Used by itself: effects <ASA w/ more side effects b/c of Vasodil
  20. Aggrenox brand
    • = Dipyridamole 200 mg + ASA 25mg
    • slightly More effective than ASA alone BUT not that diff & still Controvertial
    • given 2× day orally *2× = hard
    • $$$ (200$/month)
    • * anti-platlet med
  21. Thienopyridines
    • Mech: irrev inhibtor of P2Y12 ADP platlet rec
    • -------------------------------------------------------------------------------
    • given orally once/ day
    • -------------------------------------------------------------------------------
    • Thienopyridine drugs:
    • CIopidogrel (plavix)
    • Prasugrel ( Effient)
    • Ticlopidine ( Ticlid ) -prototype
  22. Clopidogrel
    • AKA: plavix ( just became generic)
    • -------------------------------------------------------------------------------
    • mech: irrev. inhibitor of P2Y12 ADP platelet Rec (= thienopyridine)
    • = prodrug ⇒ met by CYP 2C19
    • ⇒ *** beware of polymorphisms (esp Asians) ⇒ rec genotyping ⇒ poor / intermed met req diff therapy
    • ⇒ drug interactions W/ CYP 2C19 inhibitor-ie PPI (proton Pump inhib) drugs
    • -------------------------------------------------------------------------------
    • USE:
    • use alone if ASA allergy
    • use w/ lo dose aspirin after acute coronary synd ( ACS ) OR stent replacement up to 1 yr
    • * usually use clopidogrel + ASA
    • * stop AT LEAST 5 days before Surgery
    • -------------------------------------------------------------------------------
    • Adverse: bleeding, Purpura
    • * safer than ticlopodine
    • -------------------------------------------------------------------------------
    • given orally once daily after loading dose
    • * most widely used thienopyridine
  23. Prasugrel
    • AKA: Effient
    • -------------------------------------------------------------------------------
    • mech: irrev. inhibitor of P2Y12 ADP platlet Rec (= thienopyridine)
    • (similar to Clopidogrel, just diff met)
    • Pro drug BUT lo risk of interaction w/ PPIs b/c diff met
    • -------------------------------------------------------------------------------
    • given orally once daily
    • -------------------------------------------------------------------------------
    • only indication: prevention of post-PCI events in ACS pt + aspirin
    • -------------------------------------------------------------------------------
    • * sig Black box warning ( > risk than Clopidogrel )
    • Contra Ind: TIA or > 75 y.o.
    • $$$
    • must start in hospital (loading dose)
  24. Ticlopidine
    • AKA: Ticlid
    • mech: irrev. inhibitor of P2Y12 ADP platlet Rec (= thienopyridine)
    • given orally once daily
    • ( = prototype)
    • * Not used b/c hi insidence of thrombotic thrombocytopinic Purpura (TTP)
  25. PPI (proton pump inhibitor )
    • Use: GERD, peptic Ulcer dz
    • -------------------------------------------------------------------------------
    • Met by CYP 2C19
    • Drug interaction w/ Clopidogrel (which req CYP 2C19 for activation) → inc problems for pts
    • * try not to use PPI when unnecessary (use H2 antagonists instead)
    • -------------------------------------------------------------------------------
    • Drugs:
    • omeprezole (Prilosec) - strong CYP 2C19 inhibitor
    • Iansoprazole - strong CYP 2C19 inhibitor
    • Esomeprazole (Nexivm)-moderate CYP 2C19
  26. Ticagrelor
    • AKA: Brilinta
    • -------------------------------------------------------------------------------
    • = anti-platelet drug
    • Mech: rev inhibition of P2Y12 ADP rec
    • * faster, more consistent inhibition of rec than Clopidogrel
    • -------------------------------------------------------------------------------
    • indication: ACS & unstable angina
    • -------------------------------------------------------------------------------
    • Down Side:
    • Dose: loading ⇒ 2x day
    • $$$
    • black box warning: use aspirin <100 mg
    • Adverse: dyspnea, bradycardia
    • met by CYP 3A4 → active metabolite
    • * common drug interactions
    • inhibits CYP 3A4 & P-glycoprot ( ⇒ can inc plasma conc of simvastatin & digoxn etc )
  27. Glycoprotein llb/llla Antagonists
    • mech: prevent fibrinogen from binding to platelets → directly block platelet aggregation
    • * work immed'ly
    • -------------------------------------------------------------------------------
    • Drugs:
    • Abciximab (ReoPro)
    • Tirofiban (Aggrastat)
    • Eptifibatide (Integrelin)
    • -------------------------------------------------------------------------------
    • indication: ACS, prep for percutaneous coronary intervention ( PCI )
    • sig'ly dec risk of death & acute MI
    • -------------------------------------------------------------------------------
    • IV in 1st 24 hrs post-PCI + aspirin + heparin
    • -------------------------------------------------------------------------------
    • Adverse: bleeding, thrombocytopenia
    • -------------------------------------------------------------------------------
    • $$$ biologics
  28. Abciximab
    • AKA: ReoPro
    • -------------------------------------------------------------------------------
    • mech: prevent fibrinogen from binding to platelets → directly block platelet aggregation

    • Fab fragment of Monoclonal Ab to GP IIb/IIIa rec
    • binds activated & non-activated platelets
    • platlet inhibition 24-48 hrs
    • * work immed'ly
    • -------------------------------------------------------------------------------
    • indication: ACS, prep for percutaneous coronary intervention ( PCI )
    • sig'ly dec risk of death & acute MI
    • -------------------------------------------------------------------------------
    • IV in 1st 24 hrs post-PCI + aspirin + heparin
    • -------------------------------------------------------------------------------
    • Adverse: bleeding, thrombocytopenia
    • -------------------------------------------------------------------------------
    • $$$ biologics
  29. Tirofiban
    • AKA: Aggrastat
    • -------------------------------------------------------------------------------
    • mech: prevent fibrinogen from binding to platelets →directly block platelet aggregation
    • competitive, rev inhibitor
    • * work immed'ly
    • -------------------------------------------------------------------------------
    • indication: ACS, prep for percutaneous coronary intervention ( PCI )
    • sig'ly dec risk of death & acute MI
    • -------------------------------------------------------------------------------
    • IV in 1st 24 hrs post-PCI + aspirin + heparin
    • -------------------------------------------------------------------------------
    • Adverse: bleeding, thrombocytopenia
    • -------------------------------------------------------------------------------
    • $$$ biologics
  30. Eptifibatide
    • AKA: Integrelin
    • derived from rattlesnake venom
    • -------------------------------------------------------------------------------
    • mech: prevent fibrinogen from binding to platelets → directly block platelet aggregation
    • competitive, rev inhibitor
    • * work immed'ly
    • -------------------------------------------------------------------------------
    • indication: ACS, prep for percutaneous coronary intervention ( PCI )
    • sig'ly dec risk of death & acute MI
    • -------------------------------------------------------------------------------
    • IV in 1st 24 hrs post-PCI + aspirin + heparin
    • -------------------------------------------------------------------------------
    • Adverse: bleeding, thrombocytopenia
    • -------------------------------------------------------------------------------
    • $$$ biologics
  31. When to Stop & Restart anti-platlet agents perioperatively?
    • * dep on type of agent
    • -------------------------------------------------------------------------------
    • STOP -For low risk pt (no prev Ml, angioplasty, Stent)
    • 》Aspirin: ( irrev platlet inhib, aggrenox too)
    • → stop 7-10d before surgery
    • 》NSAIDs: (rev platelet inhib)
    • ⇒ short acting (ibuprofen) - stop 24 hr
    • ⇒ long acting (naprosyn) - stop 2-3d before
    • ⇒ Celecoxib = ONLY NSAID w/ minimal platelet effect
    • 》clopidogrel & prasugrel:( irrev inhib)
    • → stop 5-7d before surgery
    • -------------------------------------------------------------------------------
    • Restart
    • ⇒ after surgery once there = adequate hemostasis
  32. Indications for Anti-coagulant drugs
    • Prevention:
    • > venous thromboembolism
    •       -hospitalized pts
    •       -gen & ortho surgery (any jt replacements)
    • > stroke 2˚ to Afib (hi risk pts)
    • _______________________________________
    • TX:
    • > vv thromboembolism
    •       -DVT
    •      - Pulmonary embolism
    • >Acute Coronary Syndrome (ACS)
    • >PCI
  33. Anti-coagulants: Mechanism of action
    • Indirect Factor Xa inhibitors (perenteral)--act by activation of anti-thrombin III
    • > unfractioned heparin - IV, SC
    • > low molecular wt heparins - SC
    •        -Enoxaparin (Lovinox)
    • >Fondaparinux (Arixtra) - SC 
    • ____________________________________
    • Direct Factor Xa inhibitors--new, oral
    • >Rivaroxiban (Xarelto) - oral
    • >Apixaban (Eliquis) - oral
    • ____________________________________
    • Direct thrombin inhibitors
    • >Dabigatran (Pradaxa) - oral (new)
    • > Lepirudin (Refludan) - IV
    • > Argatroban (Argatroban) - IV
    • ____________________________________
    • Vitamin K antagonist:
    • > warfarin - oral (aka: cumadin = brand name)
  34. Indirect Factor Xa inhibitors
    • = anticoagulant drugs
    • = heparin derived factors
    • given perenteral
    • ___________________________________
    • Mech: act by activation of anti-thrombin III
    • __________________________________
    • > unfractioned heparin - IV, SC
    • > low molecular wt heparins - SC
    •        -Enoxaparain (Lovinox)
    • >Fondaparinux (Arixtra) - SC
  35. Direct Factor Xa inhibitor
    • = anti-coagulant
    • = new & oral
    • ______________________________________
    • >Rivaroxiban (Xarelto)
    • >Apixaban (Eliquis)
  36. Direct Thrombin inhibitors
    • = anti-coagulant
    • ------------------------------------------------------
    • >Dabigatran (Pradaxa) - oral (new)
    • > Lepirudin (Refludan) - IV
    • > Argatroban (Argatroban) - IV
  37. Vitamin K antagonist
    • = anti-coagulant
    • > warfarin - oral (aka: cumadin = brand name)
  38. Unfrationated Heparin (UFH)--Pharmacokinetics
    • not absorbed orally
    • IV and (sometimes) SC (for prophylaxis)
    • T 1/2 varies
    • cleared by reticuloendothelial system & eliminated by kidneys
  39. Unfractionated Heparin (UFH)--general
    • = indirect factor Xa inhibitor and thrombin inhibitor
    • = heparin derived factor
    • ---------------------------------------------------
    • mech:bind and activate of anti-thrombin III --> inactivate Factor Xa & thrombin
    • >immediate effect
    • ---------------------------------------------------
    • natural product of bovine ==> het mix of polysaccharide chains (largest chain link of heparin derived factors) ==> somewhat variable response
    • ---------------------------------------------------
    • *monitor w/ aPTT & platelet counts
  40. Low Molecular Weight Heparin (LMWH)
    • = indirect factor Xa inhibitor (little activity vs thrombin)
    • = heparin derived factor
    • ---------------------------------------------------
    • mech: activation of anti-thrombin III (like UFH) BUT less activity vs thrombin (unlike UFH, b/c of short chian length)
    • immediate effect
    • ---------------------------------------------------
    • fragments of UFH --> medium chain link --> more predictable dose and response ==> can send people home w/ LMWH
    • --------------------------------------------------
    • i.e. Enoxaparin
  41. Fondaparinux (Arixtra)
    • = indirect factor Xa inhibitor (no activity vs thrombin)
    • = synthetic analog of heparin pentasaccharide seq
    • ---------------------------------------------------
    • mech: activation of anti-thrombin III
    •           *no effect on thrombin
    • ---------------------------------------------------
    • similar in efficacy to LMWH w/ longer T 1/2
    • most predictable response of the heparin derived factors b/c no chain link
    • --------------------------------------------------
    • Use:
    • > prevention of DVT post-ortho & ab surgery
    • >tx of acute DVT & pulmonary embolism
    • > safe with HIT hx
    • Off Label use:
    • >in place of LMWH for unstable angina & acute coronary sndrome
    • --------------------------------------------------
    • contraindicated: if ClCr < 30 ml/min (imp: hi'est incidence of bleeds in renal failure pt)
    • --------------------------------------------------
    • Sentara reccom: use Arixtra instead of LMWH
  42. Unfractionated Heparin (UFH)--variable responses
    • chain length determines activity
    • clearance affected by chain size

    chain size of UFH is variable

    *dose dependent kinetics
  43. Unfractionated Heparin (UFH)--adverse reactions
    • > hemorrhage:
    •        -inc risk with hi dose, recent surgery, trauma, peptic ulcer dz, platelet dysfunc
    • > Antidote for hemorrhage: Protamine sulfate
    • >Osteoporosis
    •        -w/ long term use
    • >Heparin-Induced Thrombocytopenia (HIT)
  44. Heparin-Induced Thrombocytopenia (HIT)
    • idiosyncratic late allergic drug rxn, 5-14d after start heparin (Type 2)
    • in 1-3% pt (pretty hi)
    • dec platlet count by 50%
    • **must monitor platlets every other day w/ heparin IV
    • HIT causes hypercoagulable state & 50% chance of thrombus
    • D/C heparin & start direct thrombin inhibitors
    • *lower incidence w/ LMWH (BUT contraindicated once HIT dev with UFH)
  45. Unfractionated Heparin (UFH)--Dosing
    • wt-based dosing = more effective AND less bleeding
    • avg: 80 units/kg/hr
    • ave maintenance does: 18 units/kg/hr
  46. Unfractionated Heparin (UFH)--monitoring
    • aPTT (activated partial thromboplastin time)
    •        -normal: 24-36 sec
    •        -heparinization: 1.5-2.5 x normal
    • *get aPTT 6 hrs after 1st dose ==> with subsequent dosage changes
  47. Unfractionated Heparin (UFH)--clinical uses
    • initially tx vv thrombosis & pulomnary embolism b/c of rapid onset of action
    • during/after coronary angioplasty or stent
    • cardiopulmonary bypass surgery
    • **safe to use during pregnancy (category B)
    •       -does NOT cross placenta
    •       -not assoc w/ fetal malformations
    •        - (one of few anticoagulants can = used in preg)
  48. Low molecular Weight Heparin (LMWH)--available agents
    • Enoxaprin (Lovenox) - Aventis
    •       -used most often
    • Dalteparin (Fragmin) - Pharmacia
    • Tinzaparin (Innohep) - Dunpont
    •        -approved ONLY for tx of DVT
    • ---------------------------------------------------
    • admin SC
    • *agents NOT interchangeable
    • (1-2x per day)
  49. Low molecular Weight Heparin (LMWH)--advantages
    • dec binding to plasma prot, endoth cell surf, & macrophages
    •       -less heparin res
    •       -predictable & reproducible response
    • *no lab monitoring necessary
    • given QD or BID SC as outpatient
    • longer T 1/2 b/c not cleared by liver w/macrophages (renal elimination)
    • LESS HIT (1%)
    • *almost same indications as UFH, including use in preg
  50. Low molecular Weight Heparin (LMWH)--disadvantages
    • onset of action = slower than UFH ==> NOT indicated for life threatening thromboembolism
    • req SC self injection
    • excess bleeding not completely reversed by protamine
    • may NOT be covered by some insurance
    •        $$$
  51. Enoxaparin (Lovenox)--indications
    • = LMWH used most often
    • prevent DVT (set dose)
    •        -post-surgery
    • Tx of DVT when given w/ warfarin
    • ST-elevation MI (STEMI)
    • prevention of ischemic complications of unstable angina & NSTEMI (w/ ASA)
  52. Rivaroxiban (Xarelto)
    • = direct factor Xa inhibitors (1st)
    • -----------------------------------------------------
    • approved 2011 (new) ==> be careful
    • -----------------------------------------------------
    • Uses:
    • DVT prophylaxis post-hip & knee replacement
    • prevention of stroke in non-valvular Afib
    • ----------------------------------------------------
    • Met:
    • CYP 3A4
    • ----------------------------------------------------
    • Contraindications:
    • dec dose if CrCl = 15-50 ml/min
    • avoid in preg
    • ---------------------------------------------------
    • "Bottom Line":
    • too soon to tell, no big red flags
    • 1st oral alt to warfarin or LMWH for DVT prophylaxis
    • oral alt to warfarin or dobigatran for Afib
    • No INR monitoring, std single dose
    • sig drug interaction potential --> bleeding
    • **No antidote or coagulation monitoring test (for any Xa inhibitors)
  53. Apixaban (Eliquis)
    • = direct factor Xa inhibitor
    • = newest anticoagulant (2012) - took a while to come out b/c FDA kept rejecting
    • -----------------------------------------------------
    • Uses:
    • prevention of stroke in pt w/ nonvalvular Afib
    • *AVOID in preg
    • -----------------------------------------------------
    • 2x day
    • no method to determine potency (extent of anitcoagulation)
    • no antidote
    • ----------------------------------------------------
    • Met:
    • CYP 2A4 and p-glycoprotein (avoid drug interactions)
  54. Dabigatran Etexilate (Pradaxa)
    • *slightly different than other direct thrombin inhibitors
    • = competitive, direct thrombin inhibitor
    • --------------------------------------------------------
    • Met:
    • oral prodrug (convert to dabigatran in plasma)
    • substrate of p-glycoprotein
    • renal Cl (adjust dose accordingly)
    • -----------------------------------------------------
    • Use:
    • to dec risk of stroke & systemic embolism in pt w/ non-valvular Afib
    • -----------------------------------------------------
    • *AVOID in preg
    • no antidote
    • no way to monitor
    • *in study, shown to be "non-inferior" vs warfarin
  55. Dabigatran Etexilate (Pradaxa)--advantages
    • as effective as warfarin in preventing stroke in pt with Afib
    • oral
    • no therapeutic monitory of INR & dose adjustment
    • *less food interactions (ie vitamin K)
    • less drug interactions (ie P450 enzymes)
    • no genetic polymorphisms of met enzymes
    • fast onset of action
  56. Dabigatran Etexilate (Pradaxa)--disadvantages
    • bioavailability inc by 75% if capsule chewed/broken open
    • must = in original container w/ dessicant
    • $$$$
    • BID
    • *dyspepsia (mb --> non-adherence)
    • possible hi'er rate of GI bleed ??
    • *drug interactions: any that induce/inhibit p-glycoprotein (rifampin, amiodarone, varapamil)
    • *no antidote (for severe bleeds)
  57. direct thrombin inhibitors for Pt w/ HIT
    • IV
    • -----------------------------------------------------
    • Lepirudin (Refludan) - prototype
    • Argatroban (Argatroban)
  58. Lepirudin (Refludan)
    • IV only
    • = direct thrombin inhibitor for pt w/ HIT
    • prototype
    • recombinant derivative of anticoagulant from leechs (hirudin)
    • Use: replacement for heparin after HIT develops
    • $$$$
    • (same indications and cost as argatroban)
  59. Argatroban (Argatroban)
    • IV only
    • direct thrombin inhibitor for pt w/ HIT
    • synthetic derivative fo L-arginine
    • Use: replacement for heparin after HIT develops
    • $$$$
    • (same indications and cost as lepirudin)
  60. Warfarin (Coumadin)
    • = vitamin K anatagonist
    • ------------------------------------------------------
    • Mech: inhibits vitamin K epoxide reductase enzyme (normally converts inactive vitamin K --> active vitamin K)
    • *clotting factors dependent on vitamin K for carboxylation/activity: facotrs VII, IX, X & prothrombin (II)
    • effectively warfarin inhibits synthesis of usable clotting factors
    • delayed antithrombotic effect unrelated to warfarin serum levels:
    •           -warfarin inhibits formation of clotting factors
    •          -factors already made/active are NOT affected
    • inhibits endogenous anti-coagulants Protein C & protein S (normally promote fibrinolysis) ==> can PARADOXICALLY --> hyper-coagulable state
    • ----------------------------------------------------
    • structually related to vitamin K
    • S and R enantiomers
    •        - activity S >>> R
    • ------------------------------------------------------
  61. Warfarin enantiomers
    • activity S >>>> R
    • S met: CYP 2C9
    • R met: CYP 1A2, 2C19, 3A4
    • both act on vitamin K reductase
  62. vitamin K dependent clotting factors
    • Factor VII
    • Factor IX
    • Factor X
    • Prothrombin
    • Protein C
    • Protein S
    • ---------------------------------------------------
    • range of T 1/2: 5hr - 12 days
    • **each factor has a different T 1/2 ==> see warfarin anticoagulant effects on each factor at different times after first dose
    • ----------------------------------------------------
    • warfarin decreases synthesis of usable clotting factors, which = produced in the liver ==>
    •       *warfarin effects w/ INR = affects by liver dz (liver dz --> dec synthesis of clotting factors)
  63. Warfarin pharmacokinetics
    • well absorbed
    • hi'ly protein bound (lo Vd)
    • racemic mix of R & S isomers
    •          -70% warfarin activity = S isomer
    • Met:
    • hepatic met
    • S-warfarin = CYP 2C9 (genetic variation, 25% pop w/ dec met)
    • R-warfarin = CYP 1A2, 2C19, & 3A4
    • T 1/2 longer if elderly or dec rate of met (~ 40 hr)
    • *variability in effective dose and it takes a while to figure out the dose
  64. Warfarin: Factors Affecting Bleeding Control
    • Clotting factor production: Reduced in liver disease, chronic illness
    • ------------------------------------------------
    • Inadequate patient education and monitoring: Need frequent lab monitoring
    • ------------------------------------------------
    • Drug Interactions
  65. Warfarin - Drug Interactions (Non-CYP)
    • Drugs with synergistic bleeding potential:
    • Antiplatelets (aspirin, clopidogrel)
    • NSAIDs
    • Ethanol
    • Corticosteroids
    • ---------------------------------------------------
    • Drugs that decrease protein binding:
    • Phenytoin
    • High dose aspirin
    • ---------------------------------------------------
    • Drugs that decrease absorption:
    • Cholestyramine
    • ---------------------------------------------------
    • Herbals that potentiate warfarin effect:
    • Garlic
    • Ginger
    • Ginko
    • Feverfew
  66. Warfarin - Drug Interactions (CYP Enzymes)
    • Inhibits CYP 2C9:
    • Amiodarone
    • Fluconazole
    • Fluoxetine
    • Metronidazole
    • Paroxetine
    • Sulfonamides
    • Omeprazole
    • -------------------------------------------
    • Drugs that induce CYP 2C9:
    • Carbamazepine
    • Phenobarbital
    • Rifampin
    • -------------------------------------------
    • Drugs that inhibit CYP 1A2, 2C19, 3A4:
    • Macrolides
    • Azole
    • Antifungals
    • Diltiazem
    • Ciprofloxacin
    • -------------------------------------------
    • Drugs that induce CYP 1A2, 2C19, 3A4:
    • Phenytoin
    • St. John's wort
  67. Warfarin: INR
    • Mathematical "correction" of PT time
    • ----------------------------------------
    • Relies upon reference thromboplastins with known sensitivity to antithrombotic effects of oral anticoagulants
    • ----------------------------------------
    • INR is PT ration one would have obtained if "reference" thromboplastin had been used
    • ----------------------------------------
    • Allows for comparison of results between labs and standardizes reporting of prothrombin time
    • ----------------------------------------
    • Goal INR: 2.0-3.0 for most indications
  68. Warfarin: INR Indications
    • Everything between 2.0 and 3.0
    • EXCEPT
    • Prosthetic Heart Valve
  69. Warfarin: Dosing
    • Dose individualized according to patient response
    • ------------------------------------------------
    • Loading dose = controversial
    • ------------------------------------------------
    • Low initiation doses recommended for elderly, frail, hepatic failure, malnourished
    • ------------------------------------------------
    • Start low: 5-10mg first 2 days, then 5 mg/day
    • ------------------------------------------------
    • Stabilize: Titrate to appropriate INR
    • Monitor INR freq (daily then weekly)
    • ------------------------------------------------
    • Adjust as necessary (increase/decrease daily dose by 10-20%)
    • ------------------------------------------------
    • Monitor INR regularly (every 1-4 weeks) and adjust
  70. Contraindications to Warfarin Therapy
    • Pregnancy: fetal hemorrhage
    • ------------------------------------------------
    • There are situations where risk of hemorrhage is greater than the potential clinical benefits of therapy:
    • Uncontrolled alcohol or drug abuse
    • Unsupervised dementia or psychosis
  71. Heparin to Warfarin Conversion
    • Begin concomitantly in hospital
    • ------------------------------------------------
    • Heparin continued for minimum of 4 days
    • ------------------------------------------------
    • When INR reaches desired therapeutic range, discontinue heparin (after minimum 4 days)
  72. Warfarin Overdose: Signs
    • Any unusual bleeding:
    • Blood in stools/urine
    • Excessive menstrual bleeding
    • Bruising
    • Excessive nose bleeds/bleeding gums
    • Persisten oozing from superficial injuries
    • Bleeding from tumor, ulcer, other lesion
  73. Managing Patients with High INR Values - Minor or No Bleeding
    • INR >therapeutic range but <5.0, no clinically significant bleeding, rapid reversal not indicated for reasons of surgical intervention:
    • Lower the dose or omit the next
    • dose; resume warfarin therapy at a lower dose when the INR approaches desired
    • range
    • If the INR is only minimally above
    • therapeutic range, dose reduction may not be necessary
    • --------------------------------------------
    • INR >5.0 but <9.0, no clinically significant bleeding:
    • Patients with no additional risk factors for bleeding; omit the next dose or two of warfarin, monitor INR more frequently, and resume warfarin therapy at a lower dose when the INR is in therapeutic range
    • Patients at increased risk of bleeding: omit the next dose of warfarin, and give vitamin K1 (1.0 to 2.5 mg orally)
    • Patients requiring more rapid reversal before urgent surgery or dental extraction: vitamin K1 (2–4 mg orally); if the INR remains high at 24 h, an additional dose of 1–2 mg
    • --------------------------------------------
  74. Managing Patients with High INR Values - Serious Bleeding
    • INR >9.0, no clinically significant bleeding:
    • Vitamin K1 (3–5 mg orally); closely monitor the INR; if the INR is not substantially reduced by 24–24 h, the vitamin K1 dose can be repeated
    • Serious bleeding, or major warfarin overdose (e.g., INR >20.0) requiring very rapid reversal of anticoagulant effect: Vitamin K1 (10 mg by slow IV infusion), with fresh plasma transfusion or prothrombin complex concentrate, depending upon urgency; vitamin K1 injections may be needed q12h
    • ---------------------------------------------------
    • Life-threatening bleeding or serious warfarin overdose:
    • Prothrombin complex concentrate, with vitamin K1 (10 mg by slow IV infusion); repeat if necessary, depending upon the INR
    • --------------------------------------------
    • Continuing warfarin therapy indicated after high doses of vitamin K1:
    • Heparin, until the effects of vitamin K1 have been reversed, and patient is responsive to warfarin
  75. Bridge Therapy
    • Temporary use of heparin perioperatively is chronic anticoagulant use interrupted
    • -----------------------------------------
    • Heparin Use/Dose dependent on risk of thromboemboism:
    • High Risk - use therapeutic doses of LMWH or IV UFH
    • Moderate Risk - depends on individual patient and surgery related factors
    • Low Risk - no bridging
  76. Warfarin: When to Stop and Restart Perioperatively
    • Stop 5 days pre surg
    • Start LMWH 36 hours after last Warfarin dose, give last dose 24 hrs pre surg
    • Restart LMWH 24-48 post surg
    • Restart warfarin at preop dose 1 day post surg, discontinue LMWH when INR 2-3
  77. Dabigatran: When to Stop/Restart Perioperatively
    • Stop 1-2 days, up to 3-5 days before procedure
    • Consider longer period if major surg or epidural catheter
    • Restart 1-3 days post op depending on bleeding risk (NO ANTIDOTE)
  78. Rivaroxiban: When to Stop/Restart Perioperatively
    No guidelines yet - can increase stroke risk if stopped suddenly
  79. Fibrinolytic Drugs (Thrombolytics)
    • Mech:
    • Catalyze conversion of plasminogen to plasmin
    • Plasmin then breaks down fibrin and fibrinogen to degradation products
    • --------------------------------------------
    • Indication:
    • Dissolve thrombus causing acute MI or pulm embolism
    • --------------------------------------------
    • Adverse: Cerebral hemorrhage
    • --------------------------------------------
    • Drugs:
    • Streptokinase
    • Alteplase (recombinant form of Human t-PA)
    • Retaplase (similar to t-PA but longer T 1/2)
  80. Classifications of Anemias
    • Pathophysiologic:
    • Blood Loss, Inadequate RBC Production, Excessive RBC Destruction
    • --------------------------
    • Morphologic:
    • Microcytic, hypochromic; Normocytic, normochromic; Macrocytic
  81. Iron Deficiency Anemia – Lab Values
    • Lab Values:
    • Serum Iron:
    • Male
    • 75-175 mcg/dL
    • Female
    • 65-165 mcg/dL
    • Toxic
    • >300 mcg/dL
  82. Iron Deficiency Anemia – Causes
    • Blood Loss:
    • Menstruation, GI Bleeding, Trauma
    • ---------------------------
    • Decreased absorption:
    • Medication, Gastrectomy, Enteritis
    • --------------------------           
    • Increased requirement:
    • Pregnancy, Lactation, Infancy
    • --------------------------
    • Impaired utilization:
    • Hereditary
  83. Location, Amount, Type of Iron
    Absorption
    • Best Absorbed in Duodenum and proximal Jejunum
    • --------------------------
    • 1-2mg/day if normal iron stores
    • --------------------------
    • Ferrous (animal sources) (2+) better than Ferric (vegetable) (3+) for absorption
    • --------------------------
    • Absorption increased if iron depleted or epo accelerates
    • --------------------------
    • Less absorption further down GI tract
  84. Iron Transporation
    Via Transferrin
  85. Iron Binding Capacity
    Measure saturation of transferrin with iron, usually 30-50% saturated
  86. Iron Taken up by _____, Stored as
    ______, Used for ________
    • Reticulocytes
    • ---------------
    • Ferritin
    • ---------------
    • Other compounds like CYP enzymes
  87. Iron Loss
    Lose 1-2mg iron/day from desquamation of epithelia
  88. Factors Promoting Iron Absorption
    • Inorganic iron – Ferrous Iron, heme
    • -----------------
    • Ascorbic Acid (Vitamin C)
    • -----------------
    • Gastric Acid – promotes conversion of dietary iron to ferrous form
    • -----------------
    • Clinical States – Iron deficiency, increased erythropoiesis, pregnancy, anoxia
  89. Factors Reducing Iron Absorption
    • Alkaline environment – Pancreatic secretions may promote formation of insoluble iron
    • ----------------
    • Dietary factors – Dairy products (chelate iron, prevent absorption); Grains, cereals, tea, coffee, soy (contain inhibitors of absorption)
    • ----------------
    • Medications – Acid Reducing (H2 blockers, PPIs, Antacids including Ca2+); Antibiotics
    • (tetracyclines, fluroquinolones); Fiber Supplements
    • ----------------
    • Clinical States – Adequate iron stores, chronic diarrhea, decreased epo, inflammation
  90. Low Iron Anemia Treatment Options
    • Control Underlying Cause
    • ------------------
    • Increase dietary consumption
    • ------------------
    • Iron supplementation
  91. Iron Supplmentation Sources
    • Oral: Ferrous sulfate, fumarate, gluconate; Polysaccharide iron complex (niferex); Carbonyl iron (Ferralet)
    • Parenteral:
    • Iron dextran, sucrose, gluconate
  92. Oral Iron Therapies
    • Ferrous Sulfate
    • Ferrous Fumarate
    • Ferrous Gluconate
    • Carbonyl Iron

    See Slide 17 in Hematopoietic Disorders
  93. Adverse Effects of Oral Iron
    • Constipation
    • Nausea/Vomiting
    • Stomach cramping
    • Heartburn                          
    • Black tarry stools
    • --------------------------
    • Liquids can stain teeth
    • --------------------------
    • Related to amount of elemental iron ingested
    • --------------------------
    • With persistent GI intolerance – may do better with FeSO4 elixir
  94. Iron Therapy – Dosing, Time to
    Effect
    • 150-200mg Fe/day, FeSO4 325mg 3x/day
    • ----------------
    • Give between meals
    • ----------------
    • Reticulocytosis in 7 days, rise in Hg in 3 weeks
  95. Iron Therapy Failure - Causes
    • Ongoing Blood Loss
    • Non-compliance
    • Not being absorbed: (food, meds, GI disease)
    • Concurrent folate/B12 defic
    • Incorrect diagnosis
  96. Parenteral Iron Indications
    • Sig blood loss
    • Intolerance to Oral Therapy
    • Noncompliance with Oral Therapy
    • Abnormal absorption secondary to gastric resection, gastric bypass, GI disease
    • Prep for EPO therapy
  97. Parenteral Iron Products
    • Dose determined by baseline Hb/Hb goal level
    • Ferric gluconate complex
    • Iron sucrose
    • Iron dextran (INFeD, Dexferrum)
  98. Ferric gluconate complex
    (ferrlecit)
    • 12.5 mg/mL of elemental iron
    • IV use in hemodialysis pts in conjunction with EPO
    • Delivered to transferrin within 24 hours
  99. Iron sucrose (Venofer)
    • 20 mg/mL of elemental iron
    • IV use in hemodialysis pts in conjunction with EPO
  100. Iron dextran (INFeD, Dexferrum)
    • 50 mg/mL elemental iron – IM/IV
    • 6-10 injections of 100mg or 500-2000mg in 500mL NS
    • Z-track if IM
    • Approved for pts unable to take oral iron
    • Test dose req’d
    • Usually not recommended
  101. Parenteral Iron Dose – Adverse Rxns
    • Injection site rxns
    • Diarrhea
    • Nausea
    • Anaphylactoid – uticaria, rash, dyspnea, hypotension – shock/death in severe cases
    • ----------------
    • Highest risk of anaphylaxis with iron dextran
  102. Megaloblastic (Macrocytic) Anemias
    • From impaired DNA syn, primary affects rapidly growing cells – RBCs/GI Epi
    • -----------------
    • Cobalamin/Folate cofactors for DNA
    • -----------------
    • Caused by Vit B12/Folic Acid Defic
    • -----------------
    • Develops slowly – more slowly
    • -----------------
    • Vit B12 defic also prevents myelin syn resulting in neuro disorders
  103. Causes of Vit B12 Defic
    • Pernicious anemia – lack of IF (necessary for B12 absorption)
    • Achlorhydria – lack of gastric acid
    • Atrophic gastritis, H. pylori infection
    • Gastric surgery
    • Medications – PPIs, metformin (colchicine, neomycin, H2 receptor blockers)
    • Ethanol abuse
    • Nitrous Oxide  – avoid in patients over 60
  104. Treatment of B12 Defic
    • Correct cause
    • Replenish depleted stores
    • Maintenance Therapy
  105. Methods of Vit B12 Deficiency Tx
    • Dietary changes
    • Vit B12 supplementation – oral, intranasal, parenteral
  106. Oral Vit B12 Therapy
    • If due to diet – 1-10 mcg/day
    • ---------------
    • If due to Pernicious Anemia/Gastrectomy: 1% can be absorbed w/o IF
    • Dose
    • – 1000 mcg/day (after giving parenteral dose of 100mcg/day x 1 week)

    1mg oral dose available OTC
  107. Parenteral Vit B12 Therapy
    • Given IM or SC (cyanocobalamin, hydroxycobalamin)
    • ----------------------------
    • Dose regimens:
    • 100 mcg/day for 1 week, then QOD for 2 weeks, then every month
    • 100 mcg/day for 1 week, than 1000 mcg every 1-3 months
    • --------------------------
    • Half life in plasma – 6 days
    • Half life in liver – 400 days
  108. Intranasal B12 Therapy
    • Intranasal gel (Nascolbal)
    • 500 mcg 3x/week
    • More expensive
  109. Causes of Folic Acid Deficiency
    • Malnutrition:
    • Alcoholics – 60% incidence
    • Heating foods decreases folate availability by over 50%
    • Folate-rich foods – raw spinach, broccoli, cauliflower, peanuts, peas
    • ---------------------
    • Increased requirements:
    • Pregnancy (folate needs triple)
    • Malignancy
    • Infancy
    • Increased hematopoiesis
    • --------------------
    • Malabsorption
    • -------------------
    • Drug-induced
  110. Drug-Induced Folic Acid Deficiency
    • Reduced Absorption:
    • Ethanol
    • Metformin
    • Cholestyramine
    • Sulfasalazine
    • Sulfamethoxazole
    • Oral Contraceptives
    • -------------------
    • Altered metabolism:
    • Anticonvulsants (carbamazepine, phenytoin, phenobarbital)
    • Methotrexate
    • Trimethoprim
    • Triamterene
    • Pentamidine
    • Ethanol
  111. Treatement of Folic Acid Deficiency
    • Dietary Sources
    • ------------------
    • Oral Therapy: Folic acid 400 mcg (OTC) for women preg or trying for preg
    • 1 mg (Rx) daily for deficiency
    • ----------------
    • Parenteral therapy: Available as folic acid 5mg/mL, can be given IV, IM, SC
    • ----------------
    • Folic acid supplementation – presence of undiagnosed and untrated B12 defic corrects
    • megaloblastic anemia, but neuro damage will continue
  112. Anemia of Chronic Kidney Disease
    • EPO – Growth factory necessary for erythropoiesis, 90% synthesized by kidney
    • -----------------
    • In CKD, kidneys unable to produce erythropoietin
    • Develops early, worsens as CKD progresses
    • Normochromic, normocytic anemia
    • -----------------
    • Shortened life span of RBCs
    • Worsened in CKD by destruction of RBCs during hemodialysis
  113. Factors Necessary for Erythropoiesis
    • EPO
    • Iron
    • Vit B12
    • Folic Acid
    • Ascorbic Acid
    • Pyridoxine (B6)
    • Amino Acids
  114. Regulation of Erythropoiesis
    • Kidneys receive 25% of CO, only 0.5% of body weight
    • Amount of oxygen/min received by the kidneys  = same as req’d by body tissues/min
    • If renal tissue = hypoxic, EPO is produced by renal peritubular interstitial cells
  115. EPO Preparations
    • Epoetin alfa (Epogen, Procrit):
    • Recombinant human EPO
    • Preferably given SC but also IV
    • Must be given 2-3x/week for dialysis pts
    • Dosed in units/kg
    • --------------------
    • Darbepoetin alfa (Aranesp):
    • Extra CHO chains -> half life 3x longer than epoetin alfa
    • Give once weeks SC or IV
    • Dosed in mcg/kg
    • ---------------------
    • Weekly cost of both is similar – $125-500
    • --------------------
    • Peginesatide (Omontys):
    • Administered IV or SC 1x/month
    • Monthly cost almost half of above
    • Too soon to tell long-term
  116. EPO Warnings
    • For CKD pts w or w/o dialysis:
    • Increase in death/CV complications if target HB levels >11 g/dL
    • Black Box Warning for all EPO
    • --------------------
    • For Cancer patients with anemia secondary to chemo:
    • Increase in tumor progression, thromboembolic complications, death if target Hb >12 g/dL
  117. Abuse of EPO
    Athletes – blood doping – increases RBCs – athletes have died – is banned
  118. Colony Stimulating Factors
    Tx of neutropenia 2ndary to chemo, BM transplant
  119. Granulocyte CSF
    • Stimulates neutrophil production:
    • Filgrastim
    • Pegfilgastrim – increased T ½ allowing for fewer doses compared to filgastrim
    • -----------------------------------------------
    • Stimulates both neutrophil and macrophage production:
    • Sagramostim
  120. Antibiotic vs. Anti Microbial
    • Antibiotic
    • = natural substance produced by microbe to kill other microbes 

    Antimicrobial= antibacterial, antifungal, andiviral

    *terms used interchangably
  121. a. When choosing a drug
    b. when choosing an antimicrobial
    • a. drug toxicity, drug kinetics,
    • and cost
    • b. dynamics, susceptibility,
    • infection, host defense, kinetics, toxicity
  122. Mechanism of Action of
    Antimicrobial agents
    • Cell wall synthesis inhibitors, cell membrane inhibitors, protein synthesis inhibitors,
    • DNA gyrase inhibitors, RNA polymerase inhibitors, Folic acid synthesis inhibitors
  123. Folate synthesis inhibitors
    Sulfonamindes, Trimethoprim
  124. RNA polymerase inhibitor
    Rifampin
  125. Cell membrane inhibitors
    Amphotericin, Ketoconazole, Polymyxin
  126. Cell wall synthesis inhibitors
    Beta-lactam antibiotics (carbapenems, cephalosporins, monobactams, and penicillins) 

    Other antibiotics, bacitracin, fosfomycin, and vancomycin
  127. DNA gyrase inhibitors
    Fluroquinolones
  128. Protein Synthesis inhibitors
    • Aminoglycosides, Chloramphenicol, Clindamycin, Macrolides, Mupirocin, Streptogramins,
    • Tetracyclines
  129. Bacteriostatic Agent
    • Inhibits growth of microbe
    • Does NOT reduce number of viable
    • microbes 
    • Need functional immune system(neutrophils) to reduce remaining microbes 
    • Drugs that reversibly inhibit bacterial protein synthesis
  130. Bactericidal Agent
    • Kills
    • Susceptible microbe
    • Reduces number of viable microbes

    --> @ low concentractions: may only be bacteriostatic

    • --> some antibicrobials are bactericidal against some microbes, but
    • bacteriostatic against others
  131. Time dependent killing rate
    Mechanism for most Antimicrobial agents 


    • Ability to kill microbes
    • depends on the length of time concentration of antimicrobial is abvoe the
    • minimum bactericidal concentration (MBC) 

    • Ability to inhibit further microbe growth depends on the length of time
    • concentration of antimicrobial is above the minimum inhibitory concentration at
    • site of infection
  132. Concentration dependent killing rate
    Ability to kill microbes increases as concentration of antimicrobial increases

    (Aminoglycosides, flurorquinolones, and daptomycin)
  133. Post antibiotic effect
    Microbial death or inhibition of growth continues for a period of time after concentration of drug drops below the MBC or MIC at site of infection

    Depends on antimicrobial and specific bacterial species
  134. MBC
    minimum bactericidal concentration
  135. MIC
    minimum inhibitory concentration
  136. Combination Antimicrobial Therapy
    Two or more agents with different mechanisms of action used
  137. Combination therapy for single microbe infections
    • Syngerism of effect
    • Particularly resistant microbes 
    • infections at difficult to reach sites
    • decreases emergence of resistance
  138. Combination therapy for polymicrobial infections
    Infection involving gram+, gram-, or anaerobic bacteria

    • diabetic foot infections, intra-abdominal
    • wounds, etc
  139. How to identify pathogens
    • Site of infection
    • Gram stain
    • adequate structure
    • Host factors --> community, nosocomial (hospital), age, immune status
  140. Susceptibility testing of microbes
    • Disk diffusion, broth dilution, Etest method
    • Susceptibility usually based on MIC
    • Only obtain MBC by special request
  141. Inoculum effect
    Susceptibility testing done on standard concentration (inoculum) of bacterial isolate

    Actual infection (usually severe) may have > concentration

    • Actual MIC at site of infection may be much higher than reported by lab and
    • lead to antibiotic failure
  142. Susceptibility reporting
    Reports list sensitivity vs. resistance to antibiotics tested (no MIC listed) 

    Bacteria is reported to be sensitive (usually)
  143. Choosing a drug based on Susceptibility
    Select agent and does that provides wide margin between acheivable serum concentrations and the MIC or MBC

    ALWAYS TRY TO SELECT MOST NARROW SPECTRUM AGENT
  144. Bacterial Resistance Categories
    • 1. Intrinsic Resistance
    • 2. Acquired Resistance
  145. Intrinsic Resistance
    • Vancomycin vs. gram-negative bacteria
    • Penicillin vs. Enteric Bacteria
    • Aminoglycosides vs. anaerobic bacteria
  146. Aquired Resistance
    • Many bacterial species over the last 50 years of antibiotic era via gene transfer
    • --> new gene pool created

    Ex. subtherapeutic levels of oxytetracycline fed to chickens caused MDR in E. Coli in both chickens and humans
  147. Genetics of Bacterial Resistance
    • 1. Point mutation
    • 2. Plasmids
    • 3. Transposons
  148. Point mutations in Resistance
    Point mutations on chromosomes --> slowly developing resistance
  149. Plasmids in Resistance
    • Fast Process
    • Strands of DNA with 100-300 genes able to duplicate and pass between cells of like or unlike species
  150. Transposons in Resistance
    • Transposons --> small gene strands able to jump from chromosome to plasmid and from cell
    • to cell

    MDR genes link together on transposons
  151. Mechanisms of Antibiotic Resistance
    • 1. Decreased drug entry to cell
    • 2. Inactivation of drug
    • 3. Alteration of drug target site
  152. Decreased Drug Entry into Cell (resistance mechanism)
    less penetration through porons/greater efflux of antibiotic from cell --> tetM
  153. Inactivation of drug (resistance mechanism)
    Beta-lactamase enzymes in periplasmic space --> acytylating enzymes against aminoglycosides
  154. Alteration of drug target site (resistance mechanism)
    • 1. Penicillin binding proteins 
    • 2. Ribosomes
    • 3. DNA gyrase
  155. Antimicrobial Pharmacokintetics--> categories
    • 1. Route of administration
    • 2. Distribution
    • 3. Metabolism
    • 4. Excretion
  156. Route of Administration for Antimicrobials (pharmacokinetics)
    • 1.Oral 
    • 2. Parenteral

    Ideally effective parenteral agents can also be converted to oral form-->some antibiotics can be given parenterally or orally
  157. Oral administration of antimicrobials
    • Safest route
    • Limitations: bioavailability, drug/nutrient
    • interactions, preventing absorption, GI irritability
  158. Parenteral administration of antimicrobials
    • Fastest Route
    • Limitations: toxicity, complexity of care cost
  159. Distribution of Antimicrobials (Pharmacokinetics)
    • High antimicrobial concentrations and successful treatment can be expected in well
    • perfused tissues (plasma, muscle, kidney, etc) 

    • Low antimicrobial concentrations and increased failure rates can be expected at
    • infection sites not readily penetrated by most antimicrobials (bone, brain, prostate gland, abscesses, infected heart valves)
  160. Metabolism of microbials (Pharmacokinetics)
    -->some are metabolized by the liver

    --> many are excreted unchanged via the biliary tract or the kidney

    • --> some antimicrobials may induce or inhibit the metabolism on the CYP 450
    • enzyme system for metabolism
    •     -macrolide antibiotics, Azole antifungals
  161. Excretion of Antimicrobials (pharmacokinetics)
    -->adjust dose in renal failure for renally excreted <-- preferred for treating UTIs at lower doses
  162. Antimicrobial toxicity
    • 1. Ideally none
    • 2. Hypersensitivity reactions are common
    • 3. Toxicity usually related to dose 
    •        -->phelbitis from parenteral agents
    •        -->photosensitivity
    •        -->GI interolerance <-- most common
    •        -->renal failure possible
  163. Superinfection
    • Secondary to use of broad spectrum agents over time
    • Usually fungal infections
  164. Idiosyncratic reactions
    • Hepatotoxicity
    • Serum sickness
  165. How to determine dose/ route/ combination therapy?
    Type of infection
  166. Localized vs. Systemic Treatement
    • Localized = topical 
    • Systemic = greater area of infection so greater area of administration of antimicrobials
    • --> more agressive treatment for blood, brain, and bone infections
  167. Signs of Sepsis
    Sepsis due to endotoxins produced by bacteria

    Fever, chills, hypotension, shock, organ failure
  168. Host defense considerations
    • 1. Immune competency
    • 2. Concomitant disease states
    • 3. Prosthesis
    • 4. Catheter
  169. Immune Competency
    May determine success or failure of treatment
  170. Immuno incompetency
    Absolute neutrophil count (ANC) < 500/ml3 (after chemo) 

    Patient on immunosuppressive drugs 

    Must use bactericidal agents +/- combination therapy
  171. Concomitant disease states
    Ex. Diabetics more prone to infections
  172. Prosthesis
    • Infected prostheses (joint replacements, etc), usually need to be removed - difficult to
    • sterilize w/ antimicrobials
  173. Catheter Infections
    • Infected catheters need to be removed --> difficult to sterilize, provide entry site
    • for surface bacteria
  174. Cost of antimicrobials
    1. Direct --> acquisition cost, depends on units and duration of therapy, up to 1000s 

    2. Indirect --> labor cost for parenteral administration, monitoring, and adverse reactions
  175. Causes of Antimicrobial Failure
    • Drug Resistance
    • Drug Selection
    • Subtherapeutic dosing
    • Monotherapy
    • Poor penetration at site of infection
    • Inadequate duration
  176. Prophylactic Antibacterial Therapy
    1. Prevention of infections during invasive procedures --> dental and oral to prevent endocarditis in pts with valvular heart disease/surgical to prevent infection --> always give before procedures 

    • 2. Prevent disease transmission to close contacts of infected persons 
    • Meningococcal infection, TB, influenza
  177. Gram-Negative Bacteria
    • G- Cocci
    • Neisseria meningitidis, Moraxella catarrhalis
    • -------------------------------------
    • G- bacilli
    • Enteric Pathogens
    • Proteus sp, E. coli, Klebsiella sp - PEK group (usually community acquired)
    • Enterobacter, Serratia, Bacteroides (Nosocomial - hospital acquired)

    • Pulmonary pathogens
    • Hemophilus influenza

    • Highly Resistant
    • Pseudomonas aerugniosa
    • Acinetobactor
  178. Gram Negative Cocci
    • Neisseria meningitidis
    • Moraxella catarrhalis
  179. Gram Neg Bacilli (3 categorizations)
    Enteric, Pulmonary, Highly Resistant
  180. G- Bacilli - Enteric Pathogens
    Proteus sp, E. Coli, Klebsiella sp (PEK, community acquired)

    Enterobacter, Serratia, Bacteroides (hospital acquired)
  181. G- Bacilli - Pulmonary pathogens
    Hemophilus influenza
  182. G- Bacilli: Highly Resistant
    • Pseudomonas aeruginosa
    • Acinetobactor
  183. Atypical Bacteria
    • Mycoplasma pneumonia
    • Smallest free living organism, no cell wall, incubation period of 3 weeks
    • -----------------------------------
    • Chlamydophyla pneumoniae
    • Intracellular G- parasite
    • related to Chlamydia
    • -----------------------------------
    • Legionella pneumophila
    • In acquatic reservoirs
    • G-, hard to visualize, grow on media
  184. Antibacterial Classification
    • Inhibit bacterial cell wall syn
    • B-lactams (Penicillins, Cephalosporins, Monobactams, Carbapenems)
    • Bacitracin
    • Daptomycin
    • Vancomycin
    • -------------------------------------
    • Inhibit bacterial DNA gyrase
    • Fluroquinolones
    • -------------------------------------
    • Inhibit bacterial folic acid synthesis
    • Trimethoprim-sulfamethoxazole
    • -------------------------------------
    • Inhibit bacterial protein synthesis
    • Macrolides + ketolides
    • Tetracyclines
    • Aminoglycosides
    • Clindamycin
    • Quinupristin-dalfopristin
    • Linezolid
    • Mupirocin
    • ------------------------------------
    • Antitubercular agents
    • Isoniazid
    • Rifampin
    • Pyrazinamide
    • Ethambutol
  185. Inhibitors of Bacterial Cell Wall Syn: B-Lactam Antibiotics
    • Penicillins
    • Natural penicillins, aminopenicillins, extended-spectrum penicillins, beta-lactamase inhibitor combination, pencillinase-resistant penicillins
    • ----------------------------------------
    • Cephalosporins
    • Gen 1-5
    • ----------------------------------------
    • Monobactams
    • Aztreonam
    • ----------------------------------------
    • Carbapenems
    • Imipenem-cilistatin
    • Meropenem
    • Ertapenem
    • Doripenem
  186. Penicillins
    • Action: Bind to penecillin-binding protein (PBPs) on cell wall to inhibit further synthesis
    • ---------------------------------------
    • Resistance: Production of B-lactamase enzymes (destroys B-lactam ring of penicillin molecule)
    • Mutation of PBP to prevent penicillin binding
    • ---------------------------------------
    • Activity depends on affinity to PBPs or degree of resistance to B-lactamase enzymes
    • ---------------------------------------
    • Pharmacokinetics: Relatively short t1/2, most eliminated by kidneys unchanged
    • ---------------------------------------
    • Important adverse rxns:
    • Hypersensitivity: Immediate - anaphylaxis, uticaria, edema
    • Accelerated (1-72 hrs) urticaria
    • Delayed (days to weeks) rash, fever, serum sickness
    • -----------------------------------
    • Cross sensitivity exists between all penicillins - avoid if hx of immediate/accelerated rxn w any of penicillin group
  187. Natural Penicillins
    • G & V
    • Originally active against all staph/strep
    • Staph resistance by early 50's (acquired penicillinase)
    • No staph sensitive strains exist today
    • ------------------------------------
    • Use: Narrow spectrum
    • Strep (pyogenes + pneumoniae)
    • Neisseria
    • Clostridium
    • Treponema pallidum (syphilis)
  188. Penicillin G
    • 1st penicillin
    • Very acid labile (IV, t1/2 30 min)
    • Dosed in units (1 million units = .6 gm)
  189. Procaine penicillin G
    Suspension given IM - lasts 1-4 days
  190. Benzathine penicillin G
    Suspension given IM - can last several weeks
  191. Penicillin V
    Oral form - more acid stable
  192. To Extend Duration of Penicillins:
    Add probenecid (prevents renal secretion)
  193. Aminopenicillins
    First of semisynthetic penicillins - all produced from 6-aminopenicillinamic

    • Ampicillin
    • Amoxicillin

    • Idiosyncratic rxns: Ampicillin rash (up to 10% of individuals)
    • Up to 60% incidence of rash if mononucleosis present or taking allopurinol for gout

    • Uses: Active against UR tract pathogens (S. pyogenes, S. pneumoniae, H. influenza)
    • Some activity against Enterococcus, common community G- bact (E. Coli, Proteus sp)

    NO ACTIVITY AGAINST STAPH
  194. Ampicillin
    • = Aminopenicillins
    • Only IV - T1/2 80 min (give 4x/day)
  195. Amoxicillin
    • = Aminopenicillins
    • Most common antibiotic prescribed
    • Oral equiv of ampicillin because of better absorption
    • Can be given 2-3x/day
    • Higher doses used if suspicion of penicillin-resistant pneumococcus
  196. Extended-Spectrum Penicillins (Anti-pseudomonal penicillins)
    • Piperacillin (Pipracil)
    • Carbenicillin, ticarcillin, mezlocillin
    • Adverse effects: Sodium overload w high doses (contraindicated in pt with HF)
    • Thrombocytopenia with high doses
  197. Piperacillin (Pipracil)
    • = Extended-Spectrum Penicillins (Anti-pseudomonal penicillins)
    • Most common agent in class
    • Only given IV
    • Usually used in combination with tazobactam (Zosyn)
    • Excreted via biliary tract
  198. B-lactamase Inhibitor/Penicillin Combinations
    • Clavulanic acid - with amoxicillin = Augmentin
    • For diabetic foot wounds, bites, Staph infections
    • -----------------------------
    • Sulbactam with ampicillin = Unasym
    • -----------------------------
    • Tazobactam with piperacillin = Zosyn
    • Most widely used antibiotic in hospitals
    • Active against most G+, G-, and anaerobic bacteria
  199. B-Lactamse Inhibitor/Penicillin Combinations
    Mech of Action
    • B-Lactamase inhibitors prefer combine w B-lactamase enzyme produced by bact, inactiate them
    • -------------------------------
    • Make penicillin more active against previously resistant bact (increases activity against Staph, gram-, anaerobic bact)
    • -------------------------------
    • Does NOT increase activity against bact resistant because of altered PBPs (MRSA)
    • -------------------------------
    • Same kinetics, adverse eff, as penicillins alone
  200. Penicillinase-Resistant Penicillins
    • Semisynthetic penicillins specifically designed to treat Staph-resistant to penicillins
    • ---------------------------------
    • First - methicillin
    • Removed because of interstitial nephritis
    • ---------------------------------
    • Nafcillin
    • Dicloxacillin
    • Best single agents for susceptible Staph
  201. Methicillin resistance
    • Methicillin introduced in 1960
    • First case of resistance in 1961, London
    • mecA gene codes for new PBP2a
    • Now, 55% of S.aureus in hospitals/community is MRSA
  202. Nafcillin
    • = Penicillinase-Resistant Penicillins
    • Only used IV - 4-6x/day - can cause severe phlebitis at IV site
  203. Dicloxacillin
    • = Penicillinase-Resistant Penicillins
    • Oral equivalent of nafcillin
  204. Cephalosporins (general, mech, res, pharmacokinetics)
    • similar to penicillins (Beta-lactam ring), more stable
    • semi-synthetic drug from Cephalosporium
    • _____________________________________
    • Mech:
    • bind to penicillin-binding proteins (PBPs) on cell wall --> inhibit cell wall synthesis
    • ---------------------------------------------------
    • Pharmacokinetics:
    • >range of t1/2
    • >most eliminated from kidney
    • _____________________________________
    • Bacterial Res:
    • > Beta -lactamase enzymes (destroy Beta-lactam ring)
    • > no activity vs MRSA
    • > no activity vs Enterococcus sp or Listeria (but penicillins do)
    • --------------------------------------------------
    • 5 major grps/generations--based on spectrum of activity:
    • > each succeeding generation has MORE gram (-) activity but LESS gram (+) activity.
  205. Cephalosporins: Adverse reactions
    • hypersensitivity rxn = LESS common than penicillins
    • cross sensitivity w/ penicillins = minimal unless hx of anaphylactic rxn w/ penicillins
    • Bacterial resistance tends to develop quickly w/ use ==> why so many cephalosporins were developed
  206. Generations of cephalosporins
    • 1st Generation:
    • >cefazolin (Kefzol, Ancel)-IV
    • > Cephalexin (Velocef)- oral
    • > Cephradine (Velocef)- oral
    • > Cefadroxil (Duracef)- oral
    • ---------------------------------------------------
    • 2nd Generation:
    • > Cefuroxime (Ceftin) - IV/oral
    • > Cefoxitin - IV
    • > Cefaclor - oral
    • > Cefprozil - oral
    • ----------------------------------------------------
    • 3rd Generation:
    • > Cefotaxime (Claforan) - IV
    • > Ceftriaxone (Rocephin) - IV
    • > Ceftazidime (Fortaz) - IV
    • > Cefixime (Suprax) - Oral
    • > Cefpodoxime (Vantin) - Oral
    • ---------------------------------------------------
    • 4th Generation:
    • Cefepime (Maxipime) - IV
    • --------------------------------------------------
    • 5th Generation:
    • none listed
  207. 1st Generation Cephalosporins
    • cefazolin (Kefzol, Ancel) - IV, every 8 hrs
    • Cephalexin (Keflex)- oral, short t1/2
    • Cephradine (Velocef)- oral
    • Cefadroxil (Duracef)- oral, long t 1/2
    • ---------------------------------------------------
    • Uses:
    • active vs Streptococcus sp & methicillin-sensitive Staphylococcus (MSSA)
    • active vs strains of E. coli (UTI) & Klebsiella sp
    • Cefazolin widely used in hospitals for wound infections & surgical prophylaxis
    • Cephalexin widely used in community for Staphylococcal & Streptococcol infections
    • *(often used for cellulitis of Staph and Strep)
    • --------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  208. cefazolin
    • (Kefzol, Ancel)
    • IV
    • every 8 hrs
    • 1st generation cephalosporin
    • ---------------------------------------------------
    • Uses:
    • active vs Streptococcus sp & methicillin-sensitive Staphylococcus (MSSA)
    • active vs strains of E. coli (UTI) & Klebsiella sp
    • Cefazolin (only) widely used in hospitals for wound infections & surgical prophylaxis
    • --------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  209. Cephalexin
    • (Keflex)
    • oral
    • short t1/2
    • 1st generation cephalosporin
    • ---------------------------------------------------
    • Uses:
    • active vs Streptococcus sp & methicillin-sensitive Staphylococcus (MSSA)
    • active vs strains of E. coli (UTI) & Klebsiella sp
    • Cephalexin (only) widely used in community for Staphylococcal & Streptococcol infections
    • --------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  210. Cephradine
    • (Velocef)
    • oral
    • 1st generation cephalosporin
    • ---------------------------------------------------
    • Uses:
    • active vs Streptococcus sp & methicillin-sensitive Staphylococcus (MSSA)
    • active vs strains of E. coli (UTI) & Klebsiella sp
    • --------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  211. Cefadroxil
    • (Duracef)
    • oral
    • long t1/2
    • 1st generation cephalosporin
    • ---------------------------------------------------
    • Uses:
    • active vs Streptococcus sp & methicillin-sensitive Staphylococcus (MSSA)
    • active vs strains of E. coli (UTI) & Klebsiella sp
    • --------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  212. 2nd Generation Cephalosporins
    • *(not going to see often)
    • -----------------------------------------------------
    • Cefuroxime (Ceftin) - IV/oral
    • Cefoxitin - IV
    • Cefaclor - oral
    • Cefprozil - oral
    • -----------------------------------------------------
    • Uses:
    • Inc activity vs gram (-) bacteria, including Kelbsiella pneumoniae, Hemophilus influenzae, & Moraxella catarrhalis
    • for community-acquired pneumonia & more res upper respiratory infections (ie otitis media)
    • *(dec use b/c quick bacterial res)
    • -------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  213. Cefuroxime
    • (Ceftin)
    • IV & oral
    • *for upper respiratory infections
    • 2nd generation cephalosporin
    • -----------------------------------------------------
    • Uses:
    • Inc activity vs gram (-) bacteria, including Kelbsiella pneumoniae, Hemophilus influenzae, & Moraxella catarrhalis
    • for community-acquired pneumonia & more res upper respiratory infections (ie otitis media)
    • *(dec use b/c quick bacterial res)
    • -------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  214. Cefoxitin
    • IV
    • *for abdominal & gynecologic infections b/c of inc'd anaerobic activity
    • 2nd generation cephalosporin
    • -----------------------------------------------------
    • Uses:
    • Inc activity vs gram (-) bacteria, including Kelbsiella pneumoniae, Hemophilus influenzae, & Moraxella catarrhalis
    • for community-acquired pneumonia & more res upper respiratory infections (ie otitis media)
    • *(dec use b/c quick bacterial res)
    • -------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  215. Cefaclor
    • oral
    • 2nd generation cephalosporin
    • -----------------------------------------------------
    • Uses:
    • Inc activity vs gram (-) bacteria, including Kelbsiella pneumoniae, Hemophilus influenzae, & Moraxella catarrhalis
    • for community-acquired pneumonia & more res upper respiratory infections (ie otitis media)
    • *(dec use b/c quick bacterial res)
    • -------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  216. Cefprozil
    • oral
    • 2nd generation cephalosporin
    • -----------------------------------------------------
    • Uses:
    • Inc activity vs gram (-) bacteria, including Kelbsiella pneumoniae, Hemophilus influenzae, & Moraxella catarrhalis
    • for community-acquired pneumonia & more res upper respiratory infections (ie otitis media)
    • *(dec use b/c quick bacterial res)
    • -------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  217. 3rd Generation Cephalosporins
    • IV: Much more active than oral forms
    • Cefotaxime (Claforan) - short t 1/2
    • Ceftriaxone (Rocephin) - long t 1/2, 1xday IM/IV
    • Ceftazidime (Fortaz)
    • *(will see a lot in hospital)
    • -------------------------------------------------
    • Oral:
    • Cefixime (Suprax)
    • Cefpodoxime (Vantin)
    • -------------------------------------------------
    • Uses:
    • IV forms w/ wide range of activity vs gram (-) & gram (+) bacteria
    • for nosocomial infections, pneumonia, meningitis, advanced Lyme dz
    • *Ceftazidime ONLY 3rd gen w/ activity va Pseudomonas (useful alternative to piperacillin)
    • NO activity vs anaerobic bacteria
    • --------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  218. Cefotaxime
    • (Claforan)
    • IV = Much more active than oral forms
    • short t 1/2
    • 3rd Generation Cephalosporin
    • -------------------------------------------------
    • Uses:
    • IV forms w/ wide range of activity vs gram (-) & gram (+) bacteria
    • for nosocomial infections, pneumonia, meningitis, advanced Lyme dz
    • NO activity vs anaerobic bacteria
    • --------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  219. Ceftriaxone
    • (Rocephin)
    • IV = Much more active than oral forms
    • long t 1/2
    • 1xday IM/IV
    • 3rd Generation Cephalosporin
    • -------------------------------------------------
    • Uses:
    • IV forms w/ wide range of activity vs gram (-) & gram (+) bacteria
    • for nosocomial infections, pneumonia, meningitis, advanced Lyme dz
    • NO activity vs anaerobic bacteria
    • --------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  220. Ceftazidime
    • (Fortaz)
    • IV = Much more active than oral forms
    • 3rd Generation Cephalosporin
    • -------------------------------------------------
    • Uses:
    • IV forms w/ wide range of activity vs gram (-) & gram (+) bacteria
    • for nosocomial infections, pneumonia, meningitis, advanced Lyme dz
    • *Ceftazidime ONLY 3rd gen w/ activity va Pseudomonas (useful alternative to piperacillin)
    • NO activity vs anaerobic bacteria
    • --------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  221. Cefixime
    • (Suprax)
    • Oral
    • 3rd Generation Cephalosporin
    • -------------------------------------------------
    • Uses:
    • for nosocomial infections, pneumonia, meningitis, advanced Lyme dz
    • NO activity vs anaerobic bacteria
    • --------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  222. Cefpodoxime
    • (Vantin)
    • Oral
    • 3rd Generation Cephalosporin
    •  -------------------------------------------------
    • Uses:
    • for nosocomial infections, pneumonia, meningitis, advanced Lyme dz
    • NO activity vs anaerobic bacteria
    • --------------------------------------------------
    • Mech:
    • bind to PBPs on cell wall --> inhibit cell wall synthesis
  223. 4th Generation Cephalosporin
    • Cefepime (Maxipime)
    • IV only
    • more resistant to chromosomal Beta-lactamase enzymes (from Enterobacter sp)
    • Good activity vs Enterobacteriaceae & Pseudomonas aeruginosa
    • Unlike ceftazidime, GOOD activity vs penicillin-resistant Strep pneumoniae
  224. Cefepime
    • (Maxipime)
    • = 4th generation cephalosporin
    • IV only
    • more resistant to chromosomal Beta-lactamase enzymes (from Enterobacter sp)
    • Good activity vs Enterobacteriaceae & Pseudomonas aeruginosa
    • Unlike ceftazidime, GOOD activity vs penicillin-resistant Strep pneumoniae
  225. Monobactam
    • Aztreonam (Azacctam) - only given IV
    • -----------------------------------------------------
    • has monocyclic Beta-lactam ring
    • no cross sensitivity in pts w/ hx of severe penicillin or cephalosporin hypersensitivity rxns
    • activity similar to ceftazidime (3rd gen) w/ activity vs many gram (-) bacteria & Pseudomonas
    • no activity vs gram (+) bacteria
    • *Used for pts with Beta-lactam allergies
  226. Aztreonam
    • (Azacctam)
    • = Monobactam
    • only given IV
    • -----------------------------------------------------
    • has monocyclic Beta-lactam ring
    • no cross sensitivity in pts w/ hx of severe penicillin or cephalosporin hypersensitivity rxns
    • activity similar to ceftazidime (3rd gen) w/ activity vs many gram (-) bacteria & Pseudomonas
    • no activity vs gram (+) bacteria*Used for pts with Beta-lactam allergies
  227. Carbapenems
    • *all end in -penem
    • ---------------------------------------------------
    • broadest spectrum antibacterial drug available
    • *reserved for life threatening or multi-res infections
    • structurally related to other Beta-lactam antibiotics
    • all given IV
    • ------------------------------------------------
    • Dugs:
    • Imipenem-cilistatin (Primaxin)
    • Meropenem (Merrem)
    • Ertapenem (Invanz)
    • Doripenem (Doribax)
    • ---------------------------------------------------
    • Uses:
    • serious polymicrobial & nosocomial infections due to highly res bacteria
    • imipenem, doripenem & meropenem (NOT ertapenem) also have activity vs pseudomonas
    • (beware of fungal infections w/ long tx's)
    • --------------------------------------------------
    • Down side:
    • can = neurotoxic @ higher doses (seizures)
    • greater chance of superinfections (very res bacteria)
    • hi cost
    • some cross sensitivity in penicillin-allergic pts
  228. Imipenem-cilistatin
    • (Primaxin)
    • *end in -penem --> = Carbapenem
    • ---------------------------------------------------
    • broadest spectrum antibacterial drug available
    • *reserved for life threatening or multi-res infections
    • structurally related to other Beta-lactam antibiotics
    • IV
    • ------------------------------------------------
    • Mech:
    • cilistatin inhibits enzyme that hydrolyzes imipenem in kidney --> helps inc t 1/2 but still give every 8 hrs
    • ------------------------------------------------
    • Uses:
    • serious polymicrobial & nosocomial infections due to highly res bacteria
    • activity vs pseudomonas
    • (beware of fungal infections w/ long tx's)
  229. Meropenem
    • (Merrem)
    • *end in -penem --> = Carbapenem
    • ---------------------------------------------------
    • broadest spectrum antibacterial drug available
    • *reserved for life threatening or multi-res infections
    • structurally related to other Beta-lactam antibiotics
    • IV
    • --------------------------------------------------
    • Uses:
    • serious polymicrobial & nosocomial infections due to highly res bacteria
    • have activity vs pseudomonas
    • (beware of fungal infections w/ long tx's)
  230. Ertapenem
    • (Invanz)
    • *end in -penem --> = Carbapenems
    • ---------------------------------------------------
    • broadest spectrum antibacterial drug available
    • *reserved for life threatening or multi-res infections
    • structurally related to other Beta-lactam antibiotics
    • IV
    • ------------------------------------------------
    • longest t 1/2
    • given 1 x daily
    • ------------------------------------------------
    • Uses:
    • serious polymicrobial & nosocomial infections due to highly res bacteria
    • NO activity vs pseudomonas (unlike imipenem, doripenem & meropenem)
    • (beware of fungal infections w/ long tx's)
  231. Doripenem
    • (Doribax)
    • *all end in -penem --> = Carbapenem
    • ---------------------------------------------------
    • broadest spectrum antibacterial drug available
    • *reserved for life threatening or multi-res infections
    • structurally related to other Beta-lactam antibiotics
    • IV
    • ------------------------------------------------
    • more active vs Pseudomonas than other Carbapenums
    • -------------------------------------------------
    • Uses:
    • serious polymicrobial & nosocomial infections due to highly res bacteria
    • has activity vs pseudomonas
    • (beware of fungal infections w/ long tx's)
  232. Bacitracin
    • bacterial cell wall inhibitor
    • active vs gram (+) bacteria ONLY
    • hi'ly nephrotoxic if given systemically
    • poorly absorbed if given orally
    • ONLY used in topical preparations to tx skin infections due to Strep and Staph (not MRSA)
  233. Daptomycin
    • (Cubicin)
    • bacterial cell wall inhibitor
    • unique cyclinc lipopeptide active vs gram (+) bacteria
    • ONLY IV
    • = old drug making comeback for vancomycin-res bacteria
    • conc-dep activity
  234. Vancomysin (General, mech, route, pharmacokinetics)
    • = glycopeptide molecule w/ hi molecular wt
    • ------------------------------------------------
    • Mech: inhibits cell wall synthesis by blocking elongations of peptoglycan molecule
    • -------------------------------------------------
    • Route:
    • IV usually
    • NOT absorbed orally
    • use orally to tx Clostridium difficile colitis b/c it remains in GI
    • --------------------------------------------------
    • Pharmacokinetics:
    • eliminated via kidney, proportional to creatinine clearance (=> variable, dep on renal function)
    • narrow therapeutic index (monitor peaks/troughs)
  235. Vancomysin: Bacterial Susceptibility
    • bactericidal vs most gram (+) bacteria (including those res to Beta-lactam antibiotics)
    • NO activity vs gram (-) bacteria
    • some enterococci have become res = vancomycin-res enterococci (VRE)      worry res mut will pass to Staph
  236. Vancomysin: Adverse reactions
    • Red Man Syndrome:
    • = infusion rxn
    • due to massive histamine release if given too fast or too high a dose
    • Tx w/ antihistamine
    • --------------------------------------------------
    • Ototoxicity @ hi'er doses => get blood levels
  237. Vancomysin: Uses
    • *Reserved for known or suspected infections due to MRSA
    • also, use in combo with aminoglycoside for serious Enterococcus infections
    • Oral vancomysin: tx pseudomembranous colitis secondary to toxin of Clostidium difficile infections
  238. Inhibitors of Bacterial Protein Synthesis (Antibiotics)
    • Macrolides:
    • Erythromycin
    • Clarithromycin
    • Azithromycin
    • Ketolides:
    • Telithromycin
    • Tetracyclines:
    • Tetracycline
    • Doxycycline
    • Tigecycline
    • Aminoglycosides:
    • Gentamicin
    • Tobramycin
    • Amikacin
    • Streptomycin
    • Neomycin
    • Miscellaneous:
    • Clindamycin
    • Quinupristin-dalfopprstin
    • Linezolid
    • Mupirocin
  239. Macrolides Antibiotics (just drugs in this category)
    • = inhibitors of bacterial protein synthesis
    • -----------------------------------------------------
    • Drugs:
    • Erthromycin
    • Clarithromycin
    • Azithromycin
  240. Ketolides Antibiotics (just drugs in this category)
    • = inhibitors of bacterial protein synthesis
    • -----------------------------------------------------
    • Drugs:
    • telithromycin
  241. Tetracyclines Antibiotics (just drugs in this category)
    • = inhibitors of bacterial Protein synthesis
    • -----------------------------------------------------
    • Drugs:
    • Tetracycline
    • Doxycycline
    • Tigecycline
  242. Aminoglcosides Antibiotics (just drugs in this category)
    • = inhibitors of bacterial protein synthesis
    • -----------------------------------------------------
    • Drugs:
    • Gentamicin
    • Tobramycin
    • Amikacin
    • Streptomycin
    • Neomycin
  243. Macrolide Antibiotics
    • = inhibitors of bacterial protein synthesis
    • -----------------------------------------------------
    • Mech: reversibly bind 50S ribosomal subunit
    • ----------------------------------------------------
    • Bacterial Susceptibility:
    • usually bacteriostatic effect
    • Strep sp & Staph (res gradually inc)
    • *Activity vs some atypical bacteria (Mycoplasma, Legionella, Chlamydophyla) that cause pneumonia
    • -------------------------------------------------
    • Uses:
    • for upper and lower respiratory tract infections due to atypical bacterial (esp IV azithromycin for pneumonia)
    • for penicillin-allergic pt
    • for Chlamydia trachomatis STD infections
    • Clarithromycin for Mycobacterium Avian Complex (MAC)
  244. Erythromycin
    • = Macrolide antibiotic (inhibit bacterial protein synthesis-50s ribosome subunit)
    • -----------------------------------------------------
    • IV - rarely used
    • oral (as base, stearate, estolate, & ethylsuccinate salts)
    • give 3-4 x day
    • --------------------------------------------------
    • Adverse Effects:
    • Oral form has hi dose-dep effect on intestinal peristalsis --> *abdominal pain diarrhea
    • high IV dose --> ototoxicity
    • ---------------------------------------------------
    • Drug Interactions:
    • *Inhibits CYP450 3A4 enzyme responsible for metabolizing 50% of drugs
    • will inc serum levels of statins, benzodiazepines, calcium channel blockers, cyclosporine, etc
  245. Clarithromycin
    • (Biaxin) - now generic
    • = macrolide antibiotic (inhibit bacterial protein synthesis-50s ribosome subunit)
    • -----------------------------------------------------
    • very similar to erythromycin but better absorbed
    •         --> hi'er serum levels & lower GI levels
    • Not available IV
    • can give 2 x day
    • has less GI adverse effects
    • --------------------------------------------------
    • *same drug interactions as erythromycin:
    • Drug Interactions:
    • *Inhibits CYP450 3A4 enzyme responsible for metabolizing 50% of drugs
    • will inc serum levels of statins, benzodiazepines, calcium channel blockers, cyclosporine, etc
  246. Azithromycin
    • (Zithromax)
    • = macrolide antibiotic (inhibits bacterial protein synthesis- 50s ribosome subunit)
    • ----------------------------------------------------
    • most popular & safest macrolide antibiotic
    • given oral & IV
    • T 1/2 = 60 hrs (hi Vd): require loading dose & 1 x day (Z-pack)
    • only give for 3-5 days
    • *minimal adverse rxns
    • *no drug interactions
  247. Tetracyclines Antibiotics (general, bacterial susceptibility, uses)
    • = inhibitors of bacterial protein synthesis
    • -----------------------------------------------------
    • Mech: reversibly bind 30s ribosomal subunit of bacteria
    • ----------------------------------------------------
    • Bacterial Susceptibility:
    • usually bacteriostatic effect
    • activity vs many gram (-) and gram (+) bacterua
    • activity vs rickettsiae, chlamydiae, mycoplasma, & some protozoa
    • ------------------------------------------------
    • Uses:
    • Lyme dz
    • erlichiosis
    • Rocky Mountain Spotted Fever
    • Atypical pneumonia
    • pelvic inflammatory dz
    • tetracycline & minocycline for acne
  248. Tetracyclines Antibiotics (adverse rxn, drug interactions)
    • Important Adverse Rxns:
    • GI irritation
    • photo-sensitivity rxn
    • *discoloration of tooth enamel in kids/fetus
    • Hepatotoxicity possible w/ extended use
    • --------------------------------------------------
    • Imp Drug Interactions:
    • cations such as calcium will bind to tertracyclines & prevent absorption (don't take w/ dairy or antacids)
  249. Tertracycline [Drug]
    • = tetracycline antibiotic (inhibit bacterial protein synthesis--30s ribosome subunit)
    • -----------------------------------------------------
    • rarely used now b/c of lower bioavailability & short T 1/2 (must give 4 x day)
  250. Docycycline
    • = tetracycline antibiotic (inhibit bacterial protein synthesis--30s ribosome subunit)
    • ---------------------------------------------------
    • *Most popular tetracycline
    • IV & oral (good bioequivalence)
    • lont T 1/2, given 1-2 x day (depends on infection)
  251. Minocycline
    • = tetracycline antibiotic (inhibit bacterial protein synthesis--30s ribosome subunit)
    • ----------------------------------------------------
    • popular for acne due to hi distribution in skin
    • very expensive
  252. Tigecycline
    • (Tygacil)
    • = new tetracycline antibiotic (inhibit bacterial protein synthesis--30s ribosome subunit)
    • ----------------------------------------------------
    • derivative of minocycline
    • (2005)
    • IV drug: for complicated skin & intra-abdominal infections
    • not affected by 2 major mechanisms of tetracycline res
    •      *sill only bacteriostatic activity
    • *active vs gram (+) [incld MRSA], gram (-) ad anaerobic bacteria
    • not active va Pseudomonas or Proteus species
    • *Reserve for antibiotic-res infections
    • adverse effect profile: frequent nausea & vomiting
  253. Aminoglycoside Antibiotics (general, mech, bacterial susceptibility, uses)
    • = inhibitors of bacterial protein synthesis
    • -----------------------------------------------------
    • Mech: irreversibly bind 30s ribosomal subunit of bacteria
    • ---------------------------------------------------
    • Bacterial Susceptibility:
    • bactericidal activity vs most gram (-) bacteria, including Pseudomonas
    • Strep = res to aminoglycosides when used alone
    •     synergistic activity w/ B-lactam antibiotics
    • ---------------------------------------------------
    • Uses:
    • bacteremia, pneumonia, intra-abdominal infections & other serious infections due to gam (-) bacteria
    • --------------------------------------------------
  254. Aminoglycoside Antibiotics (Pharmocokinetics, adverse rxns)
    • Pharmacokinetics:
    • only IV or IM (can't absorb orally)
    • short T 1/2 (2-3 hr)
    • *give hi dose daily due to conc-dep effect on bacterial killing (more effect & less toxic)
    • eliminated renally (accumulates in renal failure)
    • *narrow therapeutic index (measure peak/troughs)
    • ------------------------------------------------
    • Important adverse rxns:
    • very nephrotoxic (can accumulate in renal tubules & cause *acute renal failure)
    • ototoxic at high doses for extended periods of use
  255. Gentamicin
    • = aminoglycoside antibiotic (inhibit bacterial protein synthesis - 30s ribosome)
    • ---------------------------------------------------
    • Im or IV
  256. Tobrammycin
    • = aminoglycoside antibiotic (inhibit bacterial protein synthesis - 30s ribosome)
    • ---------------------------------------------------
    • Im or IV
    • also available as inhales form for CF pt w/ Pseudomonas pneumomniae (unlike other aminoglycoside antibiotics)
  257. Amikacin
    • = aminoglycoside antibiotic (inhibit bacterial protein synthesis - 30s ribosome)
    • ---------------------------------------------------
    • Im or IV
  258. Neomycin
    • = aminoglycoside antibiotic (inhibit bacterial protein synthesis - 30s ribosome)
    • ---------------------------------------------------
    • = most toxic aminoglycoside antibiotic
    • NEVER given IV
    • used topically in combo w/ other antibiotics
    • oral for sometimes for prophylaxis before elective bowel surgery
  259. Streptomycin
    • = aminoglycoside antibiotic (inhibit bacterial protein synthesis - 30s ribosome)
    • ---------------------------------------------------
    • 1st aminoglycoside antibiotic
    • IV or IM as 2nd line therapy for active TB (still worry about toxicity)
  260. Clindamycin
    • Mechanism
    •  Binds to same 50s ribosomal subunit as macrolide antibiotics. (bacteriostatic activity) 
    • ----------------------------------------------------
    • USES
    • - inhibits steptococci, staphylococci, and Penumococci and anaerobic bacteria such as bacteroides fragilis and Clostridium perfringes 
    •  
    • -used for Anaerobic infections (intrabdominal wounds, gynecologic infections, abscesses, and aspiration pneumonia), gram + infxns in penicillin allergic patients, newly discovered community acquired MRSA 

    • --------------------------------------------------
    • kinetics
    • -given IV or orally, metabolized by the liver
    • ---------------------------------------------------
    • adverse reactions
    • GI upset (N/V/D)
    • - primary antibiotic to cause antibiotic-associated pseudomembranous colitis
  261. Quinupristin/Dalfopristin
    • Trade name: Synercid
    • -----------------------------------------------
    • Mechanism 
    • Unique streptogramin molecules that act synergistically to inhibit bacterial protein synthesis at 50s ribosomal subunit
    • ------------------------------------------------
    • Uses 
    • Bactericidal -Streptococcic and Staphylococci
    • Bacteriostatic- Enterococcus faecium

    Reserved for use in serious infections caused by multidrug resistant streptococci, MRSA and VRE

    • ----------------------------------------------------
    • Kinetics 
    • Only given IV every 8-12 hrs , metabolized by the liver
    • -------------------------------------------------
    • Adverse Reactions 

    Infusion related pain and myalgias 

    • ------------------------------------------------
    • Drug interactions 

    Inhibits CYP 450 3A4 enzyme that metabolizes many drugs
  262. Linezolid
    Trade Name: Zyvox

    • Mechanism
    • Oxazolidinedione with unique activity agains bacterial 50s subunit of bacteria 
    • Bacteriostatic 
    • -----------------------------------------------
    • Uses
    • Active against most gram + bacteria, most strains resistant to other antibiotics

    • Reserved for infections caused by multidrug-resistant bacteria such as VRE and MRSA
    • -----------------------------------------------
    • Kinetics
    • Given oral or IV with 100% bioavailability
    • Metabolized b ythe liver with T1/2 of 4-6 hrs
    • ----------------------------------------------------
    • Adverse reactions 
    • Hematologic toxicity- thrombocytopenia and neutropenia with extended use
    • Resistance may occur with overuse 
    • ----------------------------------------------
    • Cost
    • $1000/week of oral therapy
  263. Mupirocin
    Trade name: Bactroban

    • Mechanism
    • -Unrelated to other antibiotics 
    • -----------------------------------------------
    • Uses
    • Topical for treating staphylococcal infections
    • Reserved for suspected or definite MRSA to avoid developing resistance
    • Also used to impetigo caused by Streptococci or Staphylococci
    • Special nasal formulation available to eliminate carriage of MRSA
  264. Fluroquinolone antibiotics
    • DNA gyrase inhibitors 
    • Divided into Generations 

    • 1st Generation
    • Nalidixic acid 

    • 2nd Generation
    • Norfloxacin
    • Ciprofloxacin
    • Ofloxacin
    • Lomefloxacin
    • Enoxacin

    • 3rd Generation
    • Levofloxacin
    • Moxifloxacin
    • Gemifloxacin
  265. Fluoriquinolone antibiotics (Mechanism and Uses)
    • Mechanism
    • Inhibit DNA gyrase and topoisomerase that are essential for maintaining bacterial DNA structure and function

    • - Bactericidal against most gram negative bacteria 
    • - Active against atypical bacteria
    • - 3rd generation agents have good gram + bacteria (except staphylococci) 

    • Uses
    • -Complicated UTIs and prostatitis 
    • - Serious infxns secondary to gram - bacteria such as bacteremia and intra-abdominal infections 
    • - 3rd generation agents used to severe pneumonia
    • - infectious diarrhea secondary to Salmonella and Shigella
    • - for penicillin resistant anthrax
  266. Fluorquinolone Antibiotics (Pharmacokinetics, adverse reactions, and drug interactions)
    • Kinetics
    • -most available as both IV and oral 
    • -distribute very well into most tissues 
    • -most excreted renally 

    • Adverse reactions
    • -Causes arthropathy in developing animals - avoid in children less than 18 yrs and pregnant women
    • -Achilles tendon rupture
    • -Neurotoxic in high doses (irritability, seizures) 

    • Drug interactions
    • -absorption of oral dosage forms inhibited by cations such as calcium, magnesium, iron, and zinc (found in multivitamins and antacids) 
    • -inhibit metabolism of caffeine and theophylline
  267. Ciprofloxacin
    • -Most commonly used 2nd generation fluoroquinolone agent
    • ----------------------------------------------------
    • Advantage 
    • only quinolone with activity agains pseudomonas aeruginosa
    • ----------------------------------------------------
    • Disadvantages
    • Poor activity against gram (+) bacteria
    • Shorter T1/2--> requires twice daily dosing IV or oral
  268. Norfloxacin
    -1st fluoroquinolone, 2nd generation

    -still used for UTIs, does not acheive high enough serum levels for systemic infections
  269. 3rd Generation Fluoroquinolone Antibiotics (uses)
    • "respiratory fluoroquinolones" --> active against most bacteria responsible for respiratory infections 
    •     -including atypical bacteria and multidrug
    •      resistant Streptococcus pneumoniae
  270. Levofloxacin
    Trade name: Levaquin

    • L-isomer of ofloxacin
    • = 3rd generation fluoroquinolone
    • - most common fluoroquinolone used for variety of serious infections 
    • ----------------------------------------------
    • Kinetics
    • -renal elimination with normal T1/2=7hrs
    • -given once daily IV or oral
  271. Moxifloxacin
    • - 3rd generation fluoroquinolone
    • - better activity against anaerobic bacteria than levofloxacin
    • -Metabolized by the liver <-- DON'T use for UTI
    • - Given once daily IV or oral
  272. Gemifloxacin
    • Trade name: Factive
    • - 3rd generation fluoroquinolone 
    • - Newest fluoroquinolone
    • ---------------------------------------------------
    • Kinetics
    • -Oral dosing only
    • -Hepatic Metabolism
    • ---------------------------------------------------
    • Adverse effects
    • -increased incidence of rash (32% vs 4% with Cipro in women < 40 yrs) 
    • -Twice as expensive as other 2nd generation agents
  273. Trimethoprim-Sulfamethoxazole
    Trade-Name- Bactrim

    • Mechanism: combination drug --> sulfamethoxazole is only oral sulfonamide still used as an antibacterial agen and is only available in cimbination with trimethoprim
    • - Sequential inhibition of bacterial folic acid synthesis preventing DNA synthesis (human cells do no synthesize folic acid) 
    • ---------------------------------------------------
    • Kinetics
    • For maximal synergy, drugs are dosed in ratio of 5 parts SMX of 1 part TMP 
    • -can be given both oral and IV
    • -Well distributed in tissues including CSF
    • -50% excreted by kidneys
    • -T1/2 = 12 hrs, so can be dosed twice daily
    • ----------------------------------------------------
    • Uses
    • -Primary drug for UTIs 
    • -Secondary drug for upper and lower respiratory tract infections, sepsis, meningitis, travelers diarrhea, typhoid, cholera
    • -Bacterial activity against most gram (+) and gram (-) bacteria including CA-MRSA
    • -Active against nocardiam pneumocystisis jiroveci
    • -No activity against enetrococci, atypical bacteria, anaerobic bacteria, or Pseudomonas aeruginosa
    • ---------------------------------------------------
    • Adverse Reactions
    • -Hypersensitivity to SMX --> may use TMP alone for UTI 
    • -Severe hypersensitivity includes exfoliative dermatitis and Stevens-Johnson syndrome
    • -high doses of TMP-SMX for P. jiroveci infections in AIDS --> thrombocytopenia, neutropenia, allergic rxns, hyperkalemia 
    • -------------------------------------------------
    • Drug interactions
    • -Increased serum levels and toxicity of wafarin, phenytoin, and oral sulfonylureas (for DM)
  274. Nitrofuantoin
    Trade Name: Mcrodantin 

    • Uses
    • -Lower UTIs
    • -bactericidal against E. coli, Enterococcus, and other common UTI organisms
    • ------------------------------------------------
    • Adverse Reactions
    • -commonly causes GI irritation, nausea, and vomiting
    • -avoid in the elderly due to increased risk of pneumonitis and neuropathy
    • --------------------------------------------------
    • Contraindications
    • -renal failure
  275. Metronidazole
    Trade name: Flagyl

    • Mechanism
    • Antiprotozoal
    • -----------------------------------------------------
    • Uses
    • -best single agent to treat anaerobic infections including intra abdominal infectsion and C. diff. colitis 
    • ----------------------------------------------------
    • Kinetics
    • -Oral and IV
    • -----------------------------------------------------
    • Contraindications
    • -Alcohol use (disulfiram like effect)
  276. Colistin or polymyxin E
    -Old antibiotic being revived --> used in the 1920s

    • Uses
    • -MDR resistant bacteria such as CRE (carbapenemase-resistant Enterobacteriaceae)
    • --------------------------------------------------
    • Adverse Reactions
    • -Nephrotoxic like aminoglycosides
    • ---------------------------------------------------
    • Kinetics
    • Intravenous
  277. Fosfomycin
    -A phosphonic antibiotic discovered in 1969 

    Oral agent now recommended for gram negative UTIs --> use if suspected or known resistance to sulfa and fluoroquinolone antibiotics
  278. Antibiotics and Pregnancy
    • Category B 
    • beta-lactams
    • clindamycin
    • azithromycin

    • Category C
    • Clarithromycin
    • Fluroquinolones
    • TMP-SMX (1st and 2nd) 
    • Nitrofurantoin (1st and 2nd) 
    • Vancomycin

    • Category D
    • Aminoglycosides
    • Tetracyclines
    • TMP-SMX (3rd) 
    • Nitrofurantoin (3rd)

    • A & B = safest
    • D = worst for pregnancy
  279. Ischemic Heart Disease
    Categories 

    Angina --> unstable vs. Stable 

    ACS (acute coronary syndrome) = unstable angina + MI
  280. Acute Coronary Syndrome Classification
    • Non-ST-segement elevation ACS 
    •    1. Unstable Angina = Cardiac enzymes 
    •        negative
    •    2. Non-ST-segment elevation MI = Cardiac 
    •        enzymes positive

    • ST-segment elevation ACS 
    •    1. STEMI
  281. Stable Angina Pathophysiology
    • -Chronic
    • -angina episodes precipitated by increase in myocardial O2 demand in a setting of fixed decrease in myocardial O2 supply
    • -due to atherosclerotic plaques in coronary arteries
  282. Variant Angina
    • -coronary artery spasms
    • -uncommon
    • -Angina episodes precipitated by acute narrowing or coronary artery secondary to vasospasm
    • -May or may not be CAD or usual risk factors for angina 
    • -may occur at rest w/o exertion
    • -usually see ST elevation on EKG <--- secondary to MI
  283. Clinical presentation of Angina
    • Sx
    • -short duration
    • - crushing/tightness/burning/ vice-like/aching
    • - over the sternum or b/w epigastrum and pharynx, sometimes L shoulder and arm --> radiates into L shoulder/arm/jaw
    • -stops when exertion stops --> may occur in excercise, cold weather, walking after heavy meal, emotions, sex
    • EKG
    • generally no ST-segement changes, T wave inversion
    • Relief
    • nitroglycerin must provide pain relief quickly to categorize as unstable angina
  284. Treatment Goals for CP/Angina
    • 1. Relief of anginal sx/episodes
    • 2. Reduction of ischemia
    • 3. Prevention of major complications of CAD such as ACS and death
  285. Determinants of MVO2 (myocardial O2 demand)
    • 1. Heart rate --> more contraction = more O2 needed
    • 2. Myocardial contractility --> sympathetic nerve stimulation --> more contraction --> more O2 needed
    • 3. Intramyocardial wall tension (most important) 
    •      - mostly talking about the L ventricle. Size of ventricular cavity (bigger = more O2 needed) and blood pressure (residual pressure heart has to pump against)
  286. Drug effects on O2 supply and demand
    • O2 supply
    • 1. Regional flow is improved by nitrates, CCBs and beta-blockers
    • 2. Coronary blood flow is increased by nitrates and CCBs
    • 3. Can't do much about O2 extraction

    • O2 demand
    • 1. Heart rate decreased by beta-blockers and some CCBs
    • 2. Cardiac contractility decreased by beta-blockers and CCBs
    • 3. Myocardial wall tension <---determined by ventricular volume and pressure. 
    •       a. Preload decreased by nitrates
    •       b. afterload decreased by CCBs
    •       c. basically anything that decreases BP
  287. Drugs that affect myocardial ischemia
    -Prototype drugs 

    • 1. Nitrates
    •     nitroglycerin and isosorbide dinitrate
    • 2. Beta-blockers
    •      the olols
    • 3. Calcium channel blockers (CCP) 
    •      Amlodipine, nifedipine, diltiazem,       verapamil
    • 4. Modify mycardial metabolism (fairly new) 
    •      ranolazine
    • 5. Antiplatelet drugs 
    •      aspirin and clopidogrel
  288. Regulation of Vascular Tone
    -many of the drugs for angina and ACS do this

    • 1. Calcium channel blockers --> prevent release of Ca2+ from intercellular stores and therefore prevent promotion of contraction by myosin light chain kinase 
    • 2. Beta blockers --> prevent adenylate cyclase release and therefore prevent further promotion of contraction by myosin light chain kinase 
    • 3. Organic nitrates --> release NO for activation of guanylate cyclase --> cyclic GMP --> phosphatase breaks down myosin light chain kinase
  289. Nitrates
    Prototype is nitroglycerin

    • Mechanism
    • release of endogenous NO from vascular smooth muscle, or breaks down directly to NO. Metabolized by mitochondrial aldehyde dehydrogenase to NO (we don't know all intermediate steps) --> stimulates guanylyl cyclase to relax vascular SM

    • Pharmacological effects
    • relaxation of smooth muscle (vascular/other) 
    • indirectly increases heart rate through sympathetic reflex
    • antiplatelet effect --> weakly inhibits platelet aggregation 

    Coronary arteries - relief of spasm, opening of collaterals, improved subendocardial flow by reduced left ventricular end diastolic pressure (LVEDP) 

    Peripheral venous effects -->  peripheral blood pooling, decreased venous return, decreased LVEDP and LVEDV (decreased preload) <--- most important! 

    Peripheral arterial effects --> decreased arterial pressure (decreased afterload) 


    Adverse effects 

    • headache 
    • syncope --> immediate acting forms causes fainting
    • flushing
    • tachycardia

    • Drug interactions 
    • Drugs for erectile dysfunction <-- increase cGMP 
    • when nitrates are added there is too much cGMP --> potentiate effects of nitrate, syncope, hypotension, MI and sudden death reported with combination
  290. Vasodilation and Vasodilation effects
    Arteries that are occluded may dilate

    • 1. At the very lowest dose of nitroglycerin venous capacitance increases <--- more blood to venous system means heart size decreases 
    • 2. Increased doses of nitroglycerin will dilate arteries and arterioles 
    • 3. Venous effects are maximum
  291. Multiple doses forms of Nitroglycerin
    • 1. IV form --> hypertensive crisis, NOT ANGINA
    • 2. Oral sublingual/buccal --> tablets that break apart and dissolves quickly, do not go through the liver (faster effects and delivery) <-- onset of relief within 30 seconds, lasts 2-4 hours) 
    • 3. Transdermal ointment - not used very often, spread on and cover with plastic wrap 
    • 4. Transdermal patch --> stable nitrate rate for 12-24 hours but only provides relief for 2-4 hours. Tolerance to any form of nitro given continuously. Take patch off for at least 10 hrs/day
    • 5. Oral/nasal spray 
    • 6. Tablets that are swallowed and break down in the liver. 

    • Immediate relief forms are used to abort attack (sublingual tablets) 
    • Other forms used to decrease number of attacks (oral tablets or patches)
  292. Tolerance of nitroglycerin
    • 1. mtALDH enzyme --> free radicals --> inactivate mtALDH <-- sulfur-nitrothiol cofactor
    • 2. Need 10-14 hr nitrate free interval every day for all chronic nitrate products (usually at night) 
    • 3. not applicable to immediate relief nitrates
    • 4. Night-time angina can be helped with beta blockers or CCB therapy
  293. Isosorbide dinitrate
    • Slower onset and longer duration (T1/2 = 60 mins) 
    • First pass effect to active metabolite --> isosorbide mononitrate
    • Administer BID or TID
    • Sublingual or oral
  294. Isosorbide mononitrate
    Trade name: Imdur, Monoket

    • Active metabolite of isosorbide dinitrate
    • T1/2 = 5 hrs
    • 100% bioavailability 
    • Sustained release from in a once daily dose
  295. B-Adrenergic Antagonists for Angina/myocardial ischemia (general)
    • metoprolol (Lopressor)
    • pindolol (Visken)
    • atenolol (Tenormin)
    • propranolol (Inderal)
    • ----------------------------------------------------
    • = Drugs of choice for management of chronic stable angina  (esp due to exertion)
    • better @ dec anginal episodes compared to nitrates or CCBs
    •               (dec # of episodes/prevent)
    • dec morbidity and mortality in patients w/ HTN, acute MI, and heart failure (= added benefit)
  296. Why use B-adrenergic Antagonists to Tx Angina?
    • BOTH dec O2 demand and inc O2 supply:
    • > improves subendocardial flow (*subendocardiium is not well perfused to begin with) by:
    •                dec HR
    •                dec L ventricular systolic press (assoc w/ wall tension)
    •                dec velocity of contraction (dec O2 need and inc O2 delivered)
    • > balance with effects that ­ myocardial work
    • > additive effects with nitrates
    • --------------------------------------------------
    • Note:
    • Adjust dose until heart rate = 55-60 beats/min
    • DO NOT DISCONTINUE SUDDENLY – withdraw dose slowly over 1-2 weeks to prevent precipitation of angina and acute
    • MI (b/c of rebound effect)
  297. Ca Channel Blockers for Angina/myocardial ischemia (list of drugs)
    • Dihydropyridines: all end in -ipine
    • nifedipine (Procardia)
    • amlodipine (Norvasc)
    • nicardipine (Cardene)
    • felodipine (Plendil)
    • [little/no efficacy on cardiac tissue and
    • NORMAL doses]
    • ------------------------------------------------
    • Non-dihydropyridines:
    • verapamil (Calan) 
    • diltiazem  (Cardizem)
    • [do affect cardiac tissue: dec SA/AV node conduction/HR; dec CO]
    • -------------------------------------------------
    • *both groups dec blood pressure (dec Ca influx in sm mm of vessels)
  298. Dyhydropyridine CCBs v Non-dihydopyridine CCBs (diltiazem/verapamil)
    • Effects on Cardiac Tissue:
    • dihydropyridine CCBs: have relatively little/no effect on cardiac tissue @ NORMAL doses. Diltiazem/verapamil: suppress SA/AV nodal
    • conduction --> dec HR & dec CO
    • => Diltiazem/verapamil = contraindicated w/ heart failure b/c of neg inotropic effect
    • => Diltiazem/verapamil combo w/ beta-blockers can have synergistic effect
    • on HR --> sig bradycardia or heart block.
    • -----------------------------------------------
    • Effects on Peripheral Vasculature:
    • BOTH --> peripheral vasodilation
    • -------------------------------------------------
    • Drug interactions/Metabolism:
    • diltiazem/verapamil (nondihydropyridines) = potent inhibitors of enzyme CYP3A4 => assoc w/ a # of sig drug interactions (many imp drugs rely on CYP3A4 for inactivation)
    • dihydropyridine CCBs: metabolized by CYP3A4 (so potential druginteractions, BUT doesn't inhibit it)
  299. Ca Channel Blockers: Mechanism of Actions
    • Overall Effects:
    • Bind L-type Ca channels/block -->
    • > decreased afterload (dec BP)
    • > inc diastolic filling time (dec HR)
    • > dec preload (dec myocardial contraction)
    • > inhibition of coronary vasospasm (vascular sm mm relaxation)
    • Effective for BOTH exertional and variant angina (dec spasms)
    • -------------------------------------------------
    • Mechanisms:
    • Bind to L-type calcium channels
    • Vascular smooth mm dep on Ca influx via  L-type Ca channels for resting tone and
    • contractility (Ca comes in ch --> release of intracellular Ca stores)
    • Cardiac muscle, SA and AV nodes have   L-type calcium channels: for HR upstroke
    • All CCBs relax vascular smooth muscle --> can reduce blood pressure &
    • intramyocardial wall tension
    •              May also dilate coronary aa & reduce vasospasm
    • ----------------------------------------------
    • Secondary Effects:
    • delayed adenosine breakdown
    • dec platelet aggregation
    • inhibition of adrenergic neurotransmission (which dep a little on Ca influz to release NT vessicles)
    • protection vs anoxia (utilizes a Na/Ca pump that doesn't need ATP to pump Na out of cell in preparation for next contraction even w/o O2/ATP)
    • -----------------------------------------------
    • *dihydropyridine CCBs have little/no efficacy on cardiac tissue and NORMAL doses (DIFFERENT from non-dihydropyridines, which do affect cardiac tissue)
  300. Dihydropyridines (just the drugs in category)
    • nifedipine (Procardia)
    • amlodipine (Norvasc)
    • nicardipine (Cardene)

    all end in -ipine
  301. Dihydropyridine CCB
    • Most have relatively short T ½ (Amlodipine = longest; 40 hrs => once daily)
    •           only sustained release forms used
    • All = metabolized by CYP 3A4
    •         Drug interactions: inhibitors/inducers of CYP 3A4 enzyme
    • *relatively little/no effect on cardiac tissue at NORMAL doses
    • ------------------------------------------------
    • Adverse effects:
    • fatigue
    • headache
    • flushing
    • tachycardia: big vasodil --> SNS reflex --> inc HR and overcome loac effects of CCB (which normally dec HR)
    • *peripheral edema
  302. nifedipine (Procardia)
    • = Prototype Dihydropyridine CCB
    • Originally marketed as short acting product, T ½ =3 hr
    • Incr sudden deaths b/c of rapid vasodilation & reflex tachycardia in patients w/ CAD and hypertension
    • Now only use sustained release form; also improves compliance
  303. Non-Dihydropyridine CCBs (list of drugs in category)
    • verapamil (Calan)
    • diltiazem  (Cardizem)
  304. Verapamil (Calan)
    • Usually given as sustained release product
    • *suppress SA & AV nodal conduction --> dec HR & dec CO
    •       in addition to peripheral distillation effects
    • -----------------------------------------------
    • Adverse effects:
    • same as DHP CCBs PLUS bradycardia (no SNS reflex) and constipation
    • [fatigue
    • headache
    • flushing
    • *peripheral edema*]
    • --------------------------------------------------
    • Drug interactions:
    • *inhibits CYP 3A4 enzyme
    • p-glycoprotein (will increase digoxin levels)
    • -------------------------------------------------
    • Contraindications:
    • LV dysfunction & heart failure due to negative
    • inotropic effect
    •             Ca req'd for contraction => pre-existing contraction probalen = bad
  305. Diltiazem (Cardizem)
    • Similar to verapamil but tends to be better tolerated
    • Same adverse effects, drug interactions, and contraindications
    •           *BUT does not usually cause constipation
    • -------------------------------------------------
    • Adverse effects:
    • same as DHP CCBs PLUS bradycardia (no SNS reflex) 
    • [fatigue
    • headache
    • flushing
    • *peripheral edema*]
    • --------------------------------------------------
    • Drug interactions:
    • *inhibits CYP 3A4
    • enzyme p-glycoprotein (will increase digoxin levels)
    • -------------------------------------------------
    • Contraindications:
    • LV dysfunction & heart failure due to negativeinotropic effect           
    •             Ca req'd for contraction => pre-existing contraction probalen = bad
  306. Ranolazine (Ranexa) [everything but MOA]
    • = medication for tx of angina
    • *3rd line, consider as add on therapy
    • How: modification of mycardial metabolism (only one)
    • Improves cardiac diastolic function
    • with NO change in HR or BP (good)
    • short t1/2 ~1.5 hr  → sustained release
    • formulation
    • -------------------------------------------------
    • metabolism:
    • CYP3A4/2D6 and p-glycoprotein
    • -------------------------------------------------
    • adverse effects:
    • prolongs QT interval
    •             potential for torsades de pointe (= lethal arrhythmia; = polymorphic ventricular tachycardia) [not good]
    • dizziness, syncope, headache, nausea, constipation (pt don't feel well)
    • -------------------------------------------------
    • Contraindications:
    • concomitant use with:
    •              strong inhibitors of CYP3A4
    •             *other QT prolonging drugs (mb --> Torsades de pointes)
    • --------------------------------------------------
    • Warnings:
    • can increase QT interval in dose-dependent manner [not good]
  307. Ranolazine Mechanism of Action
    • MOA: inhibits late cardiac Ina (= inward Na current)
    • ---------------------------------------------------
    • Theory:
    • ischemia → ↓adenylyl cyclase → ↓Na/K pump → ↑[Na] in cell →  ↑Ca/Na pump → ↑Ca in cell → mechanical dysfunction

    • --> longer AP AND cell doesn't repolarize as fast
    • don't contact as well
  308. Antiplatelet Drugs for angina/mycoardial ischemia
    • Cyclooxygenase inhibitors
    • aspirin/NSAIDS
    • --------------------------------------------------
    • P2Y12 receptor blockers:
    • clopidogrel (Plavix)
    • prasugrel (Effient)
    • ticagrelor (Brilinta)
  309. Cyclooxygenase inhibitors for angina/myocardial ischemia
    • aspirin (irreversible)
    • NSAIDS (reversible)
    • *only inhibition by aspirin is irreversible
    • platelets may be more sensitive
    • than the vessel wall
    • high dose/low dose controversy
    • aspirin resistance (not everyone gets an effect w/ aspirin)
    • ----------------------------------------------
    • *there is only one receptor cyclooxygenase inhibitors => all compete for same receptor
    • => if want to take NSAID (ie for pain) w/ apririn either:
    •     1) DON'T take them together
    •     2) take aspirin 1st to make sure it is working
    • -----------------------------------------------
    • *GI bleeds with too much aspirin (much more than dose to get anti-angina effects)
  310. Apsirin Resistance
    • Causes:
    • Cellular factors:
    • insuff inhib of COX-1
    • overexpression of COX-2 mRNA
    • erythrocyte induced platelet activation
    • inc NE
    • Generation of PGF2 isozymes
    • Clinical factors:
    • no Rx
    • noncompliance
    • nonabsorbtion
    • interaction w/ibuprofen (use same receptor as ASA)
    • Genetic polymorphism:
    • COX-1 (extra)
    • GPIIIa, collagen or vWF receptors => not enough ASA for clinical effect
  311. Who is a candidate for antiplatelet therapy? (for mycoardial ischemia)
    • *risk factors (have serious risk factors => take drug):
    • previous coronary heart disease
    • previous stroke
    • medical history
    • *great prophylactic for people with serious risk factors)
    • ---------------------------------------------------
    • adverse effects of drug vs efficacy
    • 1° GI
    • hemorrhage
    • --------------------------------------------------
    • men and/or women - doesn't differentiate candidate or not
    • resistance
  312. Aspirin vs Placebo for angina/myocardial ischemia: clinical study
    • Swedish Angina Pectoris Aspirin Trial (SAPAT)-slide 40, Lect Angina/ACS for more detail
    • --------------------------------------------------
    • Aspirin v placebo
    • study = several yrs (50 mo)
    • -------------------------------------------------
    • Results:
    • RRR with aspirin
    • Aspirin NNT = 22 (pretty good)
    • ------------------------------------------------
    • Recommendation:
    • aspirin for all patients w/ chronic stable angina
    •             Clopidogrel (Plavix; = P2Y12) for patients with allergy or intolerance to aspirin
    • *true aspirin allergy = rare; pt get upset stomach (not true allergy)
  313. Review of angina drug effects on supply vs demand of O2
    • see table, slide 41, lecture Angina/ACS
    • To Note:
    • Nitrates dec wall tension, systolic BP, & ventricular vol AND B-blockers dec HR & contractility (and systolic BP) ==> they complement each other b/c they do different things
    • B-blockers and non-dihydropyridines shouldn't be used together without the consult of a cardiologist b/c they can have synergistic effects on HR --> significant baradycardia or heart block.
  314. Angina Tx - Risk Factor Modification
    • Smoking
    • Hypertension
    • Hyperlipidemia
    • Physical inactivity
    • Obesity
    • Diabeetus
  315. Angina Tx - Start with?
    Aspirin!
  316. Look at chart on slides 44-45
  317. 10 Point Plan for Chronic Stable Angina (ABCDE)
    • A - aspirin, anti-anginal agents
    • B - Beta-blocker, blood pressure
    • C - cholesterol, cigarettes
    • D - diet and diabetes
    • E - education and exercise
  318. ACE Inhibitors - HOPE Trial
    End Result - All patients w CAD (esp those w diabetes/LV dysfunction) should be started on ACE inhibitor
  319. Medical vs Interventional Therapy for CSA
    COURAGE trial
    • No difference in outcome between anti-platelet, anti-ischemic, lipid lowering therapy
    • PCI should be considered 2nd line therapy for treating stable angina
  320. Acute Coronary Syndrome (ACS)
    • Patient presents with anginal chest pain at read, new-onset severe anginal chest pain, or increasing angina
    • ---------------------
    • Symptoms secondary to plaque rupture, erosion with thrombus formation in coronary arteries
    • ---------------------
    • Triggered by acute pressure surge, vasoconstriction, increased coagubility
    • ---------------------
    • Obtain EKG, biochem markers for myocardial necrosis
  321. Classifications of Acute Coronary Syndromes
    • ST Seg elevation ACS - Troponin + - Myocardial infarction
    • ----------------------------------
    • Non-ST Seg elevation ACS - Troponin + - Myocardial Infarction
    • ----------------------------------
    • Non-ST Seg elevation - Troponin (-) - Unstable angina
  322. Classification of Recommendations
    • Class I - Benefit >>>> Risk
    • Class II - Benefit >> Risk
    • Class IIb - Benefit >/= risk
    • Class III - No Benefit or Harm
  323. Unstable Angina + NSTEMI: Anti-ischemic Therapy - Class I Recommendations
    • Bed Rest + EKG Monitoring
    • Supplemental oxygen is features of hypoxemia
    • SL NTG followed by IV NTG if persistent ischemia
    • Oral B-blocker w/in 24 hours
    • Non-DHP CCB if contraindications to B-blocker and no LV dysfunction
    • ACE inhibitor if hypertension persists in patients with heart failure/diabetes
  324. Unstable Angina + NSTEMI: Anti-ischemic Therapy - Class II Recommendations
    • Morphine IV if uncontrolled ischemic pain
    • Long-acting oral CCB if recurring ischemia on B-blocker and no contraindications
    • ACE inhibitor in all post-ACS patients
  325. Unstable Angina + NSTEMI: Anti-ischemic Therapy - Class III Recommendations (Avoid)
    • Avoid nitrates w/in 24 hrs of ED drugs
    • Avoid immediate release DHP CCB's in absense of b-blocker
    • Avoid NSAIDs (except aspirin)
  326. Unstable Angina + NSTEMI: Antiplatelet/Anticoag Therapy - Class I Recommendations
    • Aspirin as soon as possible (clopidogrel for patients unable to take aspirin)
    • Clopidogrel/ticagrelor added to aspirin if no CABG planned
    • Continue aspirin indef
    • If no CABG, continue clopidogrel/ticagrelor for up to 12 months
    • IV UFH, enoxaprin, or fondaparinux added to antiplatelet therapy in hospital
    • Continue anticoagulants for duration of hospitalization
    • GP IIb/IIIa antagonist added to patients for whom cath or PCI planned
    • Clopidogrel/ticagrelor withheld 5 days before CABG
  327. Unstable Angina + NSTEMI: Antiplatelet/Anticoag Therapy - Class II Recommendations
    • Consider platelet function testing to determine response to P2Y12 receptor blockers
    • Consider genotyping for CYP 2C19 variants for patients on P2Y12 receptor blockers
  328. Unstable Angina + NSTEMI: Antiplatelet/Anticoag Therapy - Class III Recommendations
    • Avoid all IV fibrinolytic therapy
    • Avoid abciximab in patients in whom PCI not planned
  329. Look at Chart on Slide 59
  330. Clinical Case on Slides 60-62 - quiz from lecture
  331. Tx of TB
    • Goals:
    • cure patient
    • minimize transmission to M. tuberculosis
    • -------------------------------------------------
    • Organization & supervision of Tx:
    • tailored to patient clinical & social circumstances
    • emphasis on directly observed therapy (DOT) to ensure adherence
  332. TB screening
    • Mantoux Tuberculin Skin Test = standard
    •         uses tuberculin purified protein derivative (PPD) (w/ 5 tuberculin units in injection)
    • pos PPD does NOT distinguish btw latent and active infection
  333. Isoniazid (INH)
    • derivative of nicotinic acid
    • -------------------------------------------
    • MOA: inhibit synthesis of mycolic acid, necessary for cell wall structure
    • ------------------------------------------
    • Use:
    • drug of choice for latent TB infection (LTBI)
    • combo TX for active infection
    • -------------------------------------------
    • Adverse Effects:
    • inc liver enxymes
    • hepatitis (rare)
    • peripheral neuropathy (esp in slow acetylators), caused by B6 deficiency (need to supplement)
    • ----------------------------------------------
    • Drug interactions:
    • inhibit CYP 2C9 & 2C19
    • inc serum warfarin, phenytoin, benzodiazapenes
    • -------------------------------------------
    • Monitoring:
    • periodic measurement of serum transaminase levels (w/ LFT)
  334. Acetylation of INH
    • ~50% of US pop = slow acetylators of INH
    • = AR

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