Pharm Exam 3

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Pharm Exam 3
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  1. Antibiotic Dynamics
    Bact growth inhibited by antibiotic [] above MIC

    MIC of antibiotic can vary 100-fold depending on bact species - higher MIC = greater likelihood of resistance.
  2. Antibiotic Dynamic - 1st Gen Cephalosporins: Cefazolin

    EXAMPLE
    • Resistance breakpoint >8 mg/L
    • MIC of E coli (8) > S. aureus (1) > S. pyogenes (0.1)

    Can use cefazolin for E. coli UTIs because of high concentration in urine, but NOT systemically
  3. Empiric Therapy
    No gram stain or culture taken

    • Best guess therapy - antibiotic choice depends on:
    • Infection
    • Most likely organisms
    • Resistance patterns
    • Severity
    • Location
    • Immune Status
    • USE MORE BROAD SPECTRUM
    • Greater chance of failure/adverse events
  4. Targeted Therapy
    Identify organisms by gram stain or culture
  5. Case 1: Strep Throat

    Tx for Group A Strep Pharyngitis Tx
    • Oral: Penicillin V x 10 days
    • Amoxicillin 50mg/kg/day x 10 days
    • (DEPENDENT ON AGE + WEIGHT)

    IM: Benzathine Penicillin G x 1 dose

    • If penicillin allergy: azithromycin, clarithromycin, clindamycin
    • OR
    • Oral 1st gen cephalosporin x 10 days if no hx of IgE mediated rxn
  6. Penicillin Allergy - Cause, Alternate Agents, Different Reactions, Desensitization
    Rxn to b-lactam ring structure

    Use aztreonam or any non b-lactam antibiotic for ANAPHYLACTIC rxn

    Must differentiate between immediate-onset IgE or delayed onset (rash): use penicillin skin test to differentiate

    Cephalosporins OK as long as not IgE rxn

    If penicillin absolutely necessary (syphilis), can desensitize with increasing amounts of antibiotic in hospital
  7. Case 2: Abrasion at softball tournament
    Leg is painful, tight
    Non-purulent cellulitis: Strep A/B or MSSA
    • Mild to moderate inf:
    • Oral therapy: dicloxacillin or cephalexin

    If significant penicillin allergy: oral macrolide (azithromycin) or clindamycin

    • Severe infection: IV nafcillin or cefazolin
    • If severe allergy: vancomycin
  8. Case 3: 5 days after Case 2 tx, cellulitis worsened, purulent discharge occurring: MRSA
    MRSA: mecA gene codes for new PBP2a, MRSA resistant to ALL b-lactams
  9. CA-MRSA
    If cultured in outpatient or in hopsital setting less than 72 hrs post-admittance

    Incision and Drainage (I&D) tx of choice for ISOLATED cutaneous abcess

    • If severe disease, rapid progression, co-morbidities:
    • Oral antibiotics for mild-moderate:
    • Clindamycin
    • Doxycycline
    • TMP-SMX (bactrim)
    • Linezolid

    Children: topical mupirocin for impetigo from CA-MRSA OR oral clindamycin
  10. HA-MRSA
    Usually MDR

    IV Vancomycin (MIC slowly creeping up, fear of VRSA/VISA)

    Alternative Agents:DaptomycinLinezolidMupirocin ointment (bactroban)
  11. Case 4: 36 y/o HIV+ IV drug user
    Infective endocarditis
    All for at least 4, some as long as 6 weeks of tx

    • Depends on organism
    • Viridans Strep (low MIC): Penicillin G or ceftriaxone

    Viridans Strep (high MIC): Penicillin G OR  ceftriaxone + high-dose gentamicin

    Viridans Strep (very high MIC): Vancomycin + low-dose gentamicin

    MSSA: Nafcillin +/- low-dose gentamicin

    MRSA: Vancomycin

    Enterococcus (ampicillin sens): Ampicillin + low-dose gentamicin

    Enterococcus (ampicillin res): Vancomycin  + low-dose gentamicin
  12. Case 5: Acute Otitis Media (AOM)

    Usually Strep pneumo, H. flu or Moraxella catarrhalis
    Tx: amoxicillin +/- clauvanate (augmentin) at twice-normal doses for potential penicillin resistant strains
  13. AOM: New guidelines (2013)
    Severe AOM: antibiotic therapy in children 6 months and older

    Non severe bilateral AOM: antibiotic therapy in 6-23 months

    Non-severe unilateral AOM: antibiotic therapy OR observation and close follow up in ALL children

    Antibiotic of choice: high dose amoxicillin IF patient has not received amoxicillin within previous 30 days OR does not have concurrent purulent conjunctivitis

    NO ANTIBIOTIC IF OLDER THAN 2 Y/O
  14. Rhinosinusitis: Adults
    5th most common diagnosisn for which antibiotics are prescribed

    Antibiotics NOT recommended for initial tx of sinusitis in adults: Use OTC for pain, fever, cough, nasal congestion

    Bact infection more likely if symptoms > 7 days, with maxillary pain/purulent discharge
  15. Rhinosinusitis: Children
    Antibiotics recommended for acute bact sinusitis: usually strep pneumo, h flu or moraxella catarrhalis

    Use same antibiotics as for AOM:

    Double dose of amoxicillin or augmentin
  16. Case 6: 72 y/o woman, flu like symptoms:
    CA-Pneumonia--Causative organisms
    • 43% Strep pneumo
    • 29% Mycoplasma pneumo
    • 18% Chlamydolpha pneumo
    • 16% Legionella pneumo
    • 11% resp viruses
    • 6% H flu
    • 1-5% S. aureus
  17. Drug Resistanst Strep Pneumo (DRSP):
    Risk Factors
    43% incidence of DRSP at Sentara

    • Risk Factors: B-lactam therapy within prev. 3 months
    • Age <2 or >65
    • Alcoholism
    • Co-morbidities: heart, lung, liver, renal disease
    • Diabetes
    • Immunosuppressive illness/therapy
    • Exposure to child in day care center
  18. Outpatient Tx of CA-Pneumonia
    Cover for S. pnuemo and atypical

    Azithromycin (1st choice) or doxycycline (2nd choice) - if previously healthy, no risk factors for DRSP

    Resp fluoroquinolones (levofloxacin or moxifloxacin) if comorbidities or other risks for DRSP

    • High dose amoxicillin-clauvante  + macrolide:
    • If co-morbidities AND other risks for DRSP
    • Can sub 2nd gen cephalosporin for amoxicillin
  19. Antibiotics for DRSP
    • Intermed penicillin resistance:
    • High dose amoxicillin or amox-clauvanate
    • Resp. fluoroquinolone
    • Ceftriaxone or cefotaxime for meningitis

    • High penicillin resistance:
    • Ceftriaxone or cefotaxime
    • Resp fluoroquinolone
    • Vancomycin and rifampin for meningitis
  20. Antiarrhythmics: Classifications
    By electrophysiological effects on usually normal cardiac cells (traditional approach): Vaughn-Williams classification

    • By type of arrhythmia (fairly new but more common sense approach):
    • Supraventricular arrhythmias
    • Ventricular arrhythmias
  21. Cardiac Conduction Cycle (5 phases of Action Potential)
    Phase 0: Vent depol (QRS) due to Na+ entry into cell via fast sodium channels

    Phase 1: overshoot phase due to Ca2+ entering cell and contraction

    Phase 2: plateau phase with balance between inward currents through slow Na+ and Ca2+ channels and OUTWARD K+ current

    Phase 3: repolarization (T wave) due to outward K+ current

    Phase 4: Na+ moves out of cell and K+ into cell via active pump
  22. Anti-arrhythmic Agents:
    Vaughn-Williams Classifications
    Class I: block SODIUM channels -> slower depolarization

    • 1a: intermediate block duration (also reduce K+ current)
    • 1b: rapid block duration (only ischemic cells)
    • 1c: long block duration

    Class II: block B1 receptors in AV node

    Class III: block POTASSIUM channels -> prolonged QT interval (most-used currently)

    Class IV: block L-type Ca2+ channels in AV node
  23. Anti-arrhythmic Agents
    Class I
    Block sodium channels -> slower depol

    • 1a - intermediate block duration (also reduce K current):
    • Quinidine
    • procainamide
    • disopyramide

    • 1b - rapid block duration (only in ischemic cells):
    • lidocaine (only in cardiac arrest)
    • mexiletine

    • 1c - long block duration: A-fib
    • flecainide
    • propafenone

    Class I can induce own arrhythmias
  24. Anti-arrhythmic agents
    Class II
    • Block B1 receptors in AV node:
    • B-blockers
  25. Anti-arrhythmic agents
    Class III
    • Block potassium channels resulting in prolonged action potential duration (prolonged QT interval):
    • ibutilide
    • dofetilide

    • Mixed Class III:
    • amiodoraone
    • sotalol

    • Increases risk of Torsades de Pointe, sudden death
    • Most used currently
    • Mixed Class III agents also have minor class I and II properties
  26. Anti-arrhythmic agents
    Class IV
    • Block L-type calcium channels in AV node:
    • verapamil
    • diltiazem
  27. Indications for Anti-arrhythmic Agents
    • Supraventricular:
    • Ia
    • Ic
    • II slows ventricular response
    • III
    • IV slows ventricular response

    • Ventricular:
    • Ia
    • Ib
    • Ic
    • II slows ventricular response
    • III
    • IV slows ventricular response
  28. Supraventricular arrhythmias
    Sinus bradycardia

    Sinus tachycardia

    • Paroxysmal supraventricular tachy:
    • Adenosine, class IV agents

    Atrial flutter

    • Atrial fibrillation:
    • Class Ic, II, III, and IV agents and digoxin

    • Wolf-Parkinson-White Syndrome:
    • Class Ia and Ic agents

    Premature atrial contractions (PACs)
  29. Ventricular arrhythmias
    • Premature ventricular complexes (PVCs):
    • Class II agents, amiodoraone

    • Non-sustained ventricular tachy:
    • Class II agents

    • Sustained ventricular tachy:
    • IV amiodarone, sotalol, procainamide

    • Ventricular fibrillation:
    • IV amiodarone or lidocaine after defibrillating shock
  30. Classification of Atrial Fibrillation
    Look at chart on slide 12
  31. Management of A-fib
    • Ventricular Rate Control:
    • Drug therapy, AV node catheter ablation
    • OR
    • Conversion to and maintenance of normal sinus rhythm:
    • No tx
    • Drug therapy
    • Ablation or pacemake
    • PLUS
    • Prevention of thromboembolism
  32. AFFIRM Study: indications for best management of Afib
    Rate control preferred over rhythm control - fewer adverse events
  33. A-fib: Agents for rate control
    • B-Blockers (Class II): considered slightly safer than others
    • Esmolol (IV) - in hospital, fast-acting
    • Propanolol
    • Metoprolol

    • Non-DHP Ca-channel blockers (Class IV):
    • Diltiazem
    • Verapamil

    Digoxin
  34. B-Blockers: Class II Anti-Arrhythmic Agents
    • Esmolol (IV only), half life 9 min.
    • Propanolol (IV + PO)
    • Metoprolol (IV + PO)

    • Most effective drug class for rate control in Afib
    • Decreased AV node conduction and slow AV node refractory period
    • Rapid onset IV
    • Esp useful with high adrenergic tone (hyperthyroidism/post-op)
    • Can use digoxin for synergy (monitor heart rate, BP)
    • Caution: use in asthma, untreated heart failure, COPD
  35. B-blockers: Indications
    Esp. Useful with high adrenergic tone (hyperthyroidism/post-op)

    A-fib, FIRST LINE
  36. B-Blockers: Mech of Action
    Decreased AV node conduction, slow AV node refrac period
  37. Calcium Channel Blockers: Class IV Anti-arrhythmic Agents
    • Verapamil - IV + PO
    • Diltiazem - IV + PO

    • Only NON-DHP CCBs have antiarrhythmic activity
    • Decrease AV node conduction, slow AV node refrac period by blocking Ca channels in AV node
    • Rapid onset IV
    • More likely to cause hypotension than B-blockers
    • -------------------------------
    • Drug Interactions:
    • Increase digoxin concentrations
    • Potent inhibitors of CYP 3A4
    • Monitor: HR, BP
    • Avoid use in heart failure: negative inotropic effect
    • Contraindicated in Wolf-Parkinson-White Syndrome (WPW): may accelerate conduction down accessory pathway and cause V-tachy
  38. NON DHP CCBs: Indications
    A-fib
  39. NON DHP CCBs: Mech of Action
    Decrease AV node conduction, slow AV node refrac period by blocking Ca channels in AV node
  40. Digoxin
    • Digitalis glycoside primarily used in HF - positive inotropic agent
    • Narrow therapeutic index drug - req periodic plasma drug level monitoring
    • No longer first line therapy for rate control of A-fib

    May be used if patient in heart failure or has LV dysfunction

    • Slow onset, less effective than B-blockers or CCBs
    • A-Fib caused by high adrenergic tone is often digoxin resistant

    • Not effective in controlling rate during exercise
    • Proarrhythmic with high doses: causes AV block and V-tachy
    • Drug interaction with Non-DHP CCBs -> higher plasma levels, but can be used for synergy

    Contraindicated in WPW syndrome like CCBs

    Monitor: digoxin levels, HR, EKG
  41. Digoxin: Indications
    • Heart failure - positive inotropic agent
    • Second line/synergistic for A-fib
  42. Digoxin: Mech of Action
    Digitalis glycoside
  43. A-fib: Rate control drugs
    • B-blockers:
    • Esmolol
    • Propanolol
    • Metoprolol

    • Ca-Channel Blockers (NON DHP ONLY):
    • Diltiazem
    • Verapamil

    Digoxin
  44. A-Fib: Sinus Rhythm Control Agents
    • Class III:
    • Block potassium rectifier channels responsible for repolarizing myocardial tissue during phase 3 of AP
    • Prolong ventricular repolarization
    • Prolong QT interval on EKG (QTc refers to QT interval corrected for heart rate)

    • Mixed Class III:Amidoranone, Dronedarone, Sotalol
    • Class III: Dofetilide, Ibutilide
    • -----------------------------------
    • Class Ic:
    • Bind sodium channels when in open/inactivated state, dissociate during resting state
    • Very slow rate of dissociation (different from class Ia/Ib)

    Greater effect on conduction rate throughout heart, esp His-Purkinje system

    Flecainide, Propafenone
  45. Amiodarone
    • Red Flag Drug
    • Mixed Class III anti-arrhythmic drug
    • Blocks potassium currents during Phase 3 of AP, also blocks sodium and calcium channels, B-receptors
    • Causes prolongation of PR, QRS, QT interval

    Considered first-line agent for most cases of AF requiring rhythm control

    Anti-arrhythmic agent of choice in heart failure

    More effective than Sotalol or Class Ic agents in preventing recurrence of A-Fib

    Therapy complicated by adverse effect and drug interaction profile
  46. Amiodarone: Mech of Action
    Blocks potassium currents during Phase 3 of AP, also blocks sodium and calcium channels, B-receptors
  47. Amiodarone: Indications
    • Considered first-line agent for most cases of AF requiring rhythm control
    • Anti-arrhythmic agent of choice in heart failure
    • FDA Approved: Sustained V-tachy, V-fib
    • Off-label: Maintenance of sinus rhythm in A-Fib
  48. Amiodarone: Adverse Effects
    Long T 1/2 - may take one year to eliminate drug, stop adverse effect

    • Pulmonary toxicity
    • Hypo/Hyper-thyroidism
    • Liver Toxicity
    • GI effects
    • Ocular effects
    • Dermatologic effects
    • Neurologic toxicity
    • Cardiovasular effects: bradycardia, heart block, QT prolongation, Torsades de Pointes (1%)
  49. Amiodarone: Drug Interactions
    Inhibits CYP 1A2, 2C9, 2D6, 3A4

    • Must decrease Warfarin dose
    • Doubles Digoxin levels
    • B-blockers - bradycardia, heart block
    • CCBs - bradycardia, heart block
    • Anti-arrhythmic drugs - increased serum levels of quinidine, disopyramide, flecainide, propadenone, dofetilide
    • Additive with drugs that lengthen QT interval
  50. Amiodarone: Dose
    • Loading dose of 800mg/day until 10gm reached
    • Maintenance dose of 200-400mg/day for V-arrhythmias and 200 mg/day for A-fib
  51. Amiodarone: Monitoring
    Need extensive baseline assessment, freq monitoring during outpatient loading dose period, evaluations every 6 months
  52. Dronedarone
    • Mixed Class III - structurally related to amiodarone
    • Indicated for prevention of hospitalization in patients with a-fib or a-flutter
    • Does not contain iodine (amiodarone contains iodine, causes adverse thyroid rxns)
    • Considerably shorter half-life (1 day vs 50 for amiodarone)
    • No loading dose req

    • Contraindicated in HF with EF < 35%
  53. Dronedarone: Indications
    Prevention of hospitalization in patients with a-fib or a-flutter
  54. Dronedarone vs Amiodarone
    Dronedarone doubling of death rate compared to amiodarone in patients with Class II/IV heart failure

    Dronedarone less effective in maintaining sinus rhythm but better safety profile
  55. Sotalol
    • Mixed Class III
    • Non selective B-blocker - also blocks potassium rectifier currents, prolongs QT interval
    • Uses: maintenance of sinus rhythm in A-fib, suppression of other supraventricular tachys
    • Kinetics: Oral only, renal elimination unchanged
    • Adverse Effects:
    • Dose related QT interval prolongation
    • Proarrhythmias at higher doses (torsades - higher than amiodarone)
    • Bradycardia
    • Exacerbation of asthma or COPD
    • Dosing:
    • Slow titration of dose with QTc interval monitored 2-4 hrs after each dose change
    • Contraindication: CrCl < 40mL/min
    • Monitoring: EKG monitored for 3 days in hospital when starting therapy
  56. Sotalol: Mech of Action
    Non-selective B-blocker, also blocks potassium rectifier currents, prolongs QT interval
  57. Sotalol: Uses
    • Maintenance of sinus rhythm in a-fib
    • Suppressin of other supraventricular tachys
  58. Sotalol: Adverse Effects
    • Dose related QT interval prolongation
    • Proarrhythmias at higher doses: incidence of Torsades higher than amiodarone
    • Bradycardia
    • Exacerbation of asthma or COPD
  59. Dofetilide (Tikosyn)
    • Class III agent
    • Prolongs QT interval and ventricular repolarization
    • Uses: ONLY class III agent for both conversion and maintenance of sinus rhythm in AF
    • Education program mandatory
    • Oral Only
    • Adverse: Dose related QT interval prolongation
    • Torsade de pointes in 3% of patients
    • Drug Interactions: Drugs also prolonging QT interval contraindicated
    • Use caution with drugs depleting potassium (diuretics) or Mg, also with CYP 3A4 inhibitors
    • Dosing: Reduce dose if CrCl < 60mL/min
    • Monitoring: EKG monitoring over first 3 days in hospital
  60. Dofetilide (Tikosyn): Mech of action
    Prolongs QT interval and ventricular repolarization
  61. Dofetilide (Tikosyn): Adverse Effects
    • Dose related QT interval prolongation
    • Torsade de Pointes in 3% of patients
  62. Ibutilide
    • Class III agent
    • IV use only
    • Indication: conversion of a-flutter or a-fib to normal sinus rhythm
    • Precautions: prolongs QT interval
    • EKG monitoring for 4 hrs post-infusion
  63. Flecainide (Tambocor)
    • Class Ic
    • Prolongs PR and QRS intervals
    • Uses: conversion and maintenance of sinus rhythm in AF, suppression of other supraventricular tachys
    • Adverse Effects: may increase ventricular rate
    • Dizziness, visual disturbances, dyspnea, hadache, fatigue, tremor, nausea
    • Drug Interactions: Inhibitors of CYP 2D6, drugs with negative inotropic effects, alkalinizing agents may increase serum levels
    • Pill in the Pocket Dose: 300mg x 1 dose after onset of palpitations as outpatient

    Avoid if coronary artery disease, structural heart disease, or heart failure - potent negative inotropic effects

    Monitoring
    : EKG, pulse, BP, serum levels
  64. Flecainide: Mech of Action
    Prolongs PR and QRS intervals
  65. Flecainide: Adverse Effects
    • May increase ventricular rate
    • Dizziness, visual disturbances, dyspnea, headache, fatigue, tremor, nausea
  66. Flecainide: Indications
    • Conversion and maintenance of sinus rhythm in AF
    • Suppression of other supraventricular tachys
  67. Flecainide: Pill in the Pocket Dose
    300mg x 1 dose after onset of palpitations as outpatient
  68. Flecainide: Contraindications
    • Avoid if:
    • Coronary artery disease
    • Structural heart disease
    • Heart failure

    Drug has potent negative inotropic effects
  69. Propafenone
    • Class Ic
    • Prolongs PR and QRS intervals - some nonselective B-blocking properties

    Uses: conversion and maintenance of sinus rhythm in AF, suppression of other supraventricular tachys

    Kinetics: Oral only, NONLINEAR KINETICS - serum levels may increase tenfold as dose is slowly increased

    Adverse Effects: Bradycardia, heart failure, nausea, taste disturbances, dizziness, fatigue, bronchospasm, constipation

    Drug Interactions: Inhibits CYP 2D6

    Pill-in-the-Pocket Dose: 600mg x 1 dose after onset of palpitations as outpatient

    Same precautions and contraindications as flecainide

    Monitoring:
    EKG, pulse, BP
  70. Propafenone: Mech Of Action
    Prolongs PR and QRS intervals, also some nonselective B-blocking properties
  71. Propafenone: Uses
    Conversion and maintenance of sinus rhythm in AF, suppression of other supraventricular tachys
  72. Propafenone: Kinetics
    Nonlinear kinetics
  73. Propafenone: Adverse Effects
    • Bradycardia
    • Heart Block
    • Heart failure
    • Nausea
    • Taste disturbances
    • Dizziness
    • Fatigue
    • Bronchospasm
    • Constipation
  74. Propafenone: Pill in the Pocket Dose
    600mg x 1 dose for palpitations in outpatient
  75. Propafenone: Contraindications
    • Avoid if:
    • Coronary artery disease
    • Structural heart disease
    • Heart failure

    Drug has potent negative inotropic effects
  76. Pill-In-The-Pocket Dose
    Flecainide, Propafenone
  77. Rate vs. Rhythm Control
    Rate control first

    • Rhythm control if:
    • persistently symptomatic w rate control
    • Rate control not maintained
    • heart failure
  78. CHADS2
    • Congestive heart failure - 1
    • Hypertension - 1
    • Age > 75 - 1
    • Diabetes - 1
    • Prior stroke or TIA - 2
  79. Warfarin Alternatives for Stroke Prevention in A-Fib
    Clopidogrel + aspirin - intermediate results between aspirin and warfarin

    Dabigatran - twice daily, non-inferior

    Rivaroxiban - once daily, non-inferior

    Apixaban - twice daily, non-inferior
  80. Supraventricular Tachycardias (Normal QRS)
    • Sinus bradycardia
    • Sinus tachycardia
    • Paroxysmal supraventricular tachy (PST)
    • Atrial flutter
    • Atrial fibrillation
    • Wolf-Parkinson-White (WPW) syndrome
    • Premature atrial contractions
  81. Adenosine
    Uses: acute paroxysmal supraventricular tachy (PST)

    Ultrashort acting IV agent - T1/2 = 9 seconds

    Opens potassium channels in AV nodal cells -> hyperpolarization

    Low toxicity profile

    Reduces conductance along slow anterograde pathway
  82. Adenosine: Mech of Action
    Blocks conduction in AV node

    Opens potassium channels in AV nodal cells resulting in hyperpolarization
  83. Ventricular Arrhythmias
    Non-pharma therapy predominates

    Premature Ventricular Complexes: Class II agents, amiodarone

    Non-sustained ventricular tachycardia: Class II agents

    Sustained ventricular tachycardia: IV amidoarone, sotalol, procainamide

    Ventricular fibrillation: IV amiodarone, or lidocaine after defibrillating shock

    DRUGS ARE SECOND CHOICE
  84. Class Ia and Ib Antiarrhythmic Agents
    Now used infrequently

    • Ia:
    • Block both fast sodium channels and potassium channels
    • Decrease ventricular conduction velocity and prolong action potential
    • Some anticholinergic effects on SA/AV nodes
    • Quinidine, porcainamide, disopyramide

    • Ib:
    • More pronounced effect on ischmic tissue

    Lidocaine, mexiletine, tocainide
  85. Quinidine
    • IV for malaria
    • D-isomer of quinine
    • Adverse: diarrhea, torsade de pointes, cinchonism

    = Class Ia anti-arrhythmic
  86. Procainamide
    Converted to active metabolite in liver

    Adverse: can cause drug-induced lupus with positive ANA titers after chronic use, hypotension, torsade

    = Class Ia anti-arrhythmic
  87. Dyspyramide
    Greater neg inotropic and anticholinergic effects that quinidine or procainamide

    Adverse: urinary retention, blurred vision, torsades

    = Class Ia anti-arrhythmic
  88. Lidocaine
    • Class Ib
    • Only IV for Ventric arrhythmias

    Local Anesthetic

    CNS toxicity with higher serum levels - alternative to amiodarone for pharmacologic treatment of v-fib
  89. Mexiletine
    Oral congener of lidocaine

    nausea, tremor common
  90. Drug-Induced Arrhythmias
    Sympathomimetic Drugs: Increase automaticity of SA node, AV node, Purkinje fibers

    • Digoxin: Heart block, Ventric-tachyarrhythmias
    • Use digoxin-immune Fab (Digibind) as primary antidote

    TORSADE DE POINTES
  91. Torsade de Pointes
    Secondary to anti-arrhythmic, other drugs

    Extension of QT interval

    Polymorphic ventricular-tachy

    Eventually leads to v-fib, sudden death
  92. Drugs removed from market for Torsades
    • Terfenadine (Seldane)
    • Astemizole
    • Cisapride
    • Grepafloxacin
  93. Torsades - Risk Factors
    Using drugs, esp in combination, known to prolong QT interval

    Drugs that inhibit CYP enzymes responsible for metab of QT prolonging drugs

    • Advanced age
    • Hypokalemia
    • hypomagnesemia
    • Bradycardia
    • Coronary artery disease
    • LV hypertrophy, dysfunction
  94. Prevention of Torsades
    • EKG at baseling, regular intervals after
    • Avoid drugs if baseline QTc > 440msec
    • Reduce dose or discontinue drug if QTc > 500msec on therapy
    • Monitor electrolytes
  95. Drugs Causing Prolonged QT interval or TdP
    • Class Ia
    • Class III
    • Azole antifungals
    • Fluoroquinolones
    • Macrolides
    • Tricyclic antidepressants
    • Typical/atypical antipsychotics
    • Droperidol
    • Indapamide
    • Methadone
    • Ranolazine
    • Tamoxifen
    • TMP-SMX
  96. Tx of TB: Goals & organization/supervision
    • 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
  97. 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
  98. 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 enzymes
    • 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)
  99. Acetylation of INH
    • ~50% of US pop = slow acetylators of INH
    • = AR
  100. Rifampin
    • MOA: inhibits bacterial RNA polymerase
    • --------------------------------------------------
    • Uses:
    • alternative single agent for LTBI (2nd choice)
    • combo therapy for active TB infeciton
    •      never used as single agent for active infection --> res
    • ---------------------------------------------
    • Adverse Effects:
    • flu-like illness (</= 5%)
    • potential hepatic toxicity (esp with alcohol use)
    • reddish orange color of urine, tears, saliva, contact lens (body fluids)
    • -----------------------------------------------
    • Drug interactions:
    • potent inducer of CYP 450 enzymes
    • inc metabolism of many drugs, incld many for HIV
    • biggest drawback of rifampin
    • -------------------------------------------------
    • Monitoring:
    • liver function tests (LFT)
  101. Newer Rifampins
    • derivatives of rifampin w/ similar MOA & adverse effects
    • ------------------------------------------------
    • Drugs:
    • Rifabutin
    • Rifapentine
  102. Rifabutin
    • derivative of rifampin w/ similar MOA & adverse effects
    • ------------------------------------------------
    • least potent inducer of CYP 450 enzymes of the different rifampins
    • preferably used in HIV pt
  103. Rifapentine
    • derivative of rifampin w/ similar MOA & adverse effects
    • ----------------------------------------------------
    • intermediate between rifampin & rifabutin in drug interaction potential (bc of effects on CYP 450)
    • can be given 1x week in select pt (vs 1x day, others)
  104. Pyrazinamide
    • MOA: exact mech unknown
    • ----------------------------------------------------
    • Use:
    • combo therapy for active TB infections allows reduction in tx duration
    • ------------------------------------------------
    • Adverse Effects:
    • hepatotoxicity, esp in combo w/ rifampin
    • hyperuricemia & gout
    • -------------------------------------------------
    • Drug Interactions:
    • blocks hypouricemic action of allopurinol
    • ----------------------------------------------
    • Monitoring:
    • LFT, uric acid
  105. Ethambutol
    • MOA: impairs bacterial metabolism
    • --------------------------------------------------
    • Use:
    • Combo therapy for active TB infection
    • --------------------------------------------
    • Adverse Effects:
    • optic neuritis @ higher doses
    • red-green color blindness
    • ---------------------------------------------
    • Drug interactions: none
    • -------------------------------------------
    • Monitoring:
    • visual acuity tests before tx and every month
  106. Recommended Tx for Latent TB infection (LTBI)
    • > First line therapy:
    • Isoniazid (INH) (1xday or 2xweek for 9 mo)
    • --------------------------------------------
    • >Alternative first line therapy:
    • Isoniazid + rifampin 1xweek for 12 weeks w/ DOT (= less time and fewer doses)
    • -----------------------------------------------
    • > Second line therapy:
    • Rifampin (if INH res is suspected) (1xday, 4 mo)
  107. Recommended Tx for active TB infection: drug susceptible
    • > For drug susceptible organisms:
    • Initial phase: isoniazid, rifampin, pyrazinamide, & ethambutol (2 mo)
    • Continuation: isoniazid & rifampin (4-7 mo, duration dep on presence of cavitary dz initially & positive sputum @ 2mo)
    • completion determined by total # doses taken, not duration of therapy
    • lots of variations of therapy
  108. Reccomended Tx for active TB: drug resistant
    • > For drug res organisms:
    • refer to clinical specialist, regiment based on expert opinion
    • drugs can include: aminoglycoside (streptomycin, kenamycin, or amikacin), fluoroquinolones, capreomycin, aminosalicylic acid, cycloserine or ethionamideif suspect tx failure, never add a single drug (or res will be acquired quickly)
    • ----------------------------------------------
    • > Multi drug resistant TB (MDRTB):
    • res to at least isoniazid & rifampin
    • typically tx incld 5-7 drugs
    • Tx cont for 18-24 mo OR 12-18 mo after culture becomes neg (LONG TIME)
    • -----------------------------------------------
    • > Extensively drug-resistance TB (XDRTB):
    • Res to isoniazid, rifampin, any fluoroquinolone & either capreomycin, kenamycin, or amikacin
    • Tx cont for 18-24 mo OR 12-18 mo after culture becomes neg (LONG TIME)
  109. Adverse effects of TB tx (overview)
    • GI upset very common in 1st few weeks--give with food
    • drug interactions, esp w/ rifampin
    • drug indiced hepatitis:
    •      can occure w/ INH, RIF, & PZA
    •      @ hi'er risk if previous hx of hepatitis, alcohol abuse
    • Other:
    •       Rifampin: thrombocytopenia & acute remal failure
    •       Ethambutol: optic neuritis
  110. Diuretic
    Agent which increases the flow of urine. 

    Inhibit normal xport of sodium from filtrate into renal tubular cells OR block transcellular water absorption (V2 receptors)--> retention of H2O in tubule--> loss of water in urine

    Most diuretics act on Na+ reabsorption
  111. Natriuretic
    Any agent which increases the excretion of sodium in the urine
  112. Diuretics Mechanism of Action
    • 1. Inhibit enzymes --> carbonic anhydrase, Acetazolamid
    • 2. Osmotic effect --> mannitol
    • 3. Block membrane transport proteins--> loop diuretics, thiazides, Aldosterone antagonists
    • 4. Interfere with hormone receptors --> Aldosterone, V2 (ADH) receptor inhibitor
  113. Tubular secretion
    Process of diuretic delivery to apical membrane

    Diuretic delivered to glomerulus on albumin and filtered by an ACTIVE process into the nephron
  114. Clinical uses diuretics
    • 1. Treatment of increased ECF --> cardiac disease, cirrhosis, renal failure (Acute/Chronic), hypoalbuminemia states, nephrotic syndrome, hormonal imbalance, SIADH
    • 2. HTN
    • 3. Maintenance of Urine output
    • 4. Prevention of bladder irritation, especially during chemo
    • 5. Prevention of precipitation of substances (Ca2+) in urine
    • 6. Enhanced secretion of toxic cmpds --> salycilic acid
  115. Diuretics that act on the PCT
    Carbonic anhydrase inhibitors --> acetazolamide, dorzolamide

    Osmotic Diuretics --> mannitol, glycerol
  116. Diuretics that act on the DCT
    Loop diuretics --> furosemide, butmetanide, torsemid

    Thiazide and related diuretics--> HCTZ, metolazone, Indepamide
  117. Drugs that act on the cortical collecting duct
    Aldosterone antagonists--> spironolactone, eplerenone (receptor blockers) 

    Potassium sparing diuretics --> amiloride, tramterine (block eNAC channels) 

    ADH (aka: vasopressin) antagonists

    Selective V2 receptor antagonists --> tolvaptan

    Combined V1a/V2 --> Conivaptan  *useful in SIADH
  118. Carbonic Anhydrase inhibitors --> Acetazolamide, dorzolamide
    MOA: reversibly inhibit carbonic anhydrase, decrease hydration of carbonic acid--> decrease Na+/H+ exchange by shutting down NHE3 pump, no HCO3- reabsorbed --> lost Na+

    Clinical uses --> glaucoma, epilepsy, acute mountain sickness, urinary alkalinization, salycylate poisoning

    Adverse reactions --> fatigue, HA, parasthesias, hypokalemia, renal stones, METABOLIC ACIDOSIS
  119. Osmotic Diuretics --> mannitol, glycerol, urea
    MOA: pharmacologically inert, filtered at glomerulus, minimally reabsorbed in tubules --> prevent movement of water trans/paracellularly --> RAPIDLY EFFECTIVE

    Clinical uses: cerebral edema, glaucoma, oliguria or acute renal failure (increased urinary output), ENHANCE URINARY EXCRETION OF TOXINS

    Adverse Reactions --> cellular dehydration, overly rapid fluid loss (esp in pts with normal renal function) and electrolyte abnormalities (hypernatremia, hypokalemia)
  120. Loop diuretics --> Furosemide, bumetanide
    • MOA: inhibit Na/K/2CL transport--> stops 20-25% Na+ reabsorption. Rapid onset of action (Oral <1hr; IV = 2-10 mins) with short duration of action
    •     1. Give furosemide Q12 oral, Q 4-6 IV
    • High ceiling diuretics --> continue to increase dose and still get a response but has a 'breaking phenomenon' with magnitude of natriuresis of diuretic declines over time

    Clinical uses --> HTN (when CrCl <30 ml/min in association with metazolone) Edema, Acute renal failure, hyperkalemia, anion overdose (bromide, fluoride, iodide) 

    • Adverse reactions --> hypovolemia, electrolyte abnormalities (hypokalemia, hypochloremia, hypomagnesmia, and hypocalcemia), hyperuricemia (gout), oxotoxicity (hearing and balance), impaired platelet aggregation, tolerance
    • ALSO similar adverse reactions as sulfonamide derivatives --> skin rash, eosinophilia, interstitial nephritis, allergic cross reactivity
  121. Thiazides--> hydrochlorothiazide (HCTZ), chlorithalidone, Metolazone, indapamide
    • MOA: inhibit NCC symporter in distal tubule
    •   --> HCTZ most commonly used 70% bioavailability, t1/2=9 hrs, duration of action = 12 hrs, 12.5-25 mg given once daily with flat dose response curve

    --> chlorithalidone better than HCTZ for decreased M&M and increased potency, t1/2=60 hrs, given 12.5-25 mg once daily

    •   --> Metazolone 65% bioavailability, t1/2=8hrs, duration of action= 8 hrs
    •   --> Indapamide 90% bioavailabilty, t1/2=16 hrs, duration of action = 24 hrs 

    Clinical uses:

    HTN (preferred use for HCTZ and chlorthalidone)--> decrease in SBP by 10-15 and DBP by 5-10. Works much better for HTN with decreased Na intake. May use metolazone for HTN for low CrCl with loop diuretic

    • Other clinical uses:
    • heart failure (chronic), Edema (less effective than loop diuretics), nephrolithiasis (hypercalciniuria), nephrogenic diabetes insipidus

    Adverse reactions --> hypokalemia (keep K >4.0), hyperglycemia (minor), hyperuricemia, metabolic alkalosis, decreased Ca2+ excretion, hyperlipidemia (minor increased cholesterol and LDL)
  122. Aldosterone Antagonists --> spironolactone, eplerenone
    • MOA --> competitive inhibition of MR aldosterone receptor acts at distal renal tubule
    • Spironolactone = non-selective, give 25 mg QD, increased NaCl excretion while conserving K+ Eplerenone= selective, very new, give 50-100 mg/day, contraindicated with CrCl < 50 ml/min, expensive but useful for males unable to tolerate spironolactone

    Clinical uses: prevent or treat hypokalemic alkalosis esp in combo with thiazide diuretic, heart failure (eplerenone), cirrhosis with ascites (spironolactone), resistant HTN, hyperaldosteronism

    Adverse effects: hyperkalemia --> increased risk in chronic kidney disease, receiving K+ supplements, ACE inhibitors, angiotensin receptor blockers, NSAIDs, beta-blockers, gynecomastia, BPH, loss of libido, impotence, menstrual irregularities ( endocrine effects less with eplerenone)
  123. Potassium sparing diuretics--> triamterene, amiloride
    MOA: block ENaC directly from apical membrane (aldosterone function antagonists) 

    Clinical uses: Prevent or treat hypokalemic alkalosis, esp in combo with a thiazide diuretic, HTN (most commonly combined with HCTZ to make Dyazide, not as a monotherapy), hyperaldosteronism

    Adverse rxns: Hyperkalemia, nausea, vomiting, dizziness, leg cramps, acute renal failure (triamterene+indomethacin), kidney stones (triamterene)

    Caution: with ACEIs, ARBs, and renal failure that also raise K levels
  124. ADH antagonists (vaptans) --> conivaptan, lixivaptan, tolvaptan
    MOA: selective non-peptide V2 receptor antagonists (V2RA) 

    Clinical uses: SIADH, heart failure, cirrhosis
  125. Urinary Tract Infections: General guidelines
    • Uncomplicated cystitis: usual pathogen = Escherichia coli, tx for 3-5d w/ appropriate antibiotic w/o urine culture
    • Complicated cystitis: tx for 7d, culture + f/u culture
    • pyelonephritis: tx for 10-14d, ideally w/ cultures (blood & urine) + f/u culture
    • asymptomatic bacteriuria in elderly should NOT be tx'd
    • patients w/ indwelling catherter w/o sx of UTI should NOT be cultured or tx'd
  126. Drugs of Choice for uncomplicated cystitis
    • > 1st line:
    • Nitrofurantoin (BID for 5d): old agent, only UTI (not hi enough plasma conc for other)
    • TMP-SMX DS (BID for 3d)
    •          if local res rates <20%
    • --------------------------------------------------
    • > 2nd line:
    • Ciprofloxacin (BID for 3d): lo dose, res develops fast
    • B-lactam (ie cephalexin) (3-7d): 1st generation cephalosporin, conc in urine
  127. Drugs of choice for pyelonephritis
    • Ciprofloxacin (BID for 7d): hi'er dose than uncomplicated b/c it's systemic (= full dose)
    • TMP-SMX DS (BID for 14 d) if pathogen susceptible
  128. Trimethoprim-Sulfamethoxazole
    • Synonyms:
    • co-trimoxazole
    • TMP-SMX
    • SMX-TMP
    • Bactrim SS, Bactrim DS
    • Septra SS, Septra DS
    • -------------------------------------------
    • Dosage:
    • 5:1 ratio of SMX-TMP
    • single strength (SS) = SMX 400mg:TMP 80 mg
    •      for elderly or if dec renal func
    • Double strength (DS) = SMX 800mg:TMP 160mg
  129. Sulfa Allergy
    • sulfonamide antibiotic allergy in 3 % pop
    •        controversy about whether other drugs containing sulfonamide moiety will cross react w/ sulfa antibiotic allergy
    •       pt w/sulfa antibiotic allergy can usually take other sulfa drug categories
    •       rxn to non-antibiotic sulfa drugs seems ass with general susceptibility to allergies
    • 3 sulfa drug classifications:
    •        sulfonylarylamines (incld sulfa antibiotics) [= true sulfa drug]
    •        non sulfonylarylamines
    •        sulfonamide moiety containing drugs
  130. Chronic UTI prophylaxis
    • > 3 episodes of cystitis per yr
    • give low, once daily dose of antibiotic for 6 mo - 1 yr
    • Drug of choice: TMP-SMX
    • Alt drugs:
    •       TMP alone (SMX intolerance)
    •       Fluoroquinolones (if res to TMP-SMX)
    •       Nitrofurantoin
    •           -nausea more common, must take w/ food
    •           ->'er change of long-term effects (ie pneumonitis, drug-induced liver injury
    •           -active vs Enterococcus in urine, unlike other drugs
  131. Urinary analgesics
    • symptomatic relief of pain, urgency, burning, & freq ass with lower UTI
    • does NOT tx infection
    • > Drugs:
    • phenazopyridine
    •       colors urine/clothes red-orange
    •       OTC
    • Flavoxate (Urispas)
    •       anti-cholinergic side effects
  132. TX of Acute Prostatitis
    • pathogens usually similar to those of UTI
    • ID pathogens by urine culture
    • therapy for 4 wks
    • TMP-SMX usually drug of choice unless contraindicated by allergy or drug interaactions
    • fluoroquinolones for G- bacteria not sensitive to TMP-SMX
  133. Tx of Chronic Prostatitis
    • common cause of recurrent UTI in men
    • inflammation < acute prostatitis
    • penetration of antibiotics into prostatic tissue can = difficult
    • drugs: TMP-SMX (usually) or fluoroquinolones (same as for acute prostatitis) but must give for 6 - 12 weeks (= longer than acute prostatitis)
    • usually try TMP-SMX first, then try fluoroquinolones
  134. Usual suspects for intra-abdominal infections (case 2, G- lecture)
    • G-:
    •    Escherichia cole
    •    Klebsiella spp
    •    Proteus spp
    •    Pseudomonas aeruginosa (if hospital-acquired)
    • G +:
    •     Enterococcus
    • Anaerobic
    •    lots*
    • ----------------------------------------------
    • Presumptive Tx:
    • Make sure cover for all of these until get cultures
    • *esp bacteroides fragilis
  135. Recommended Agents for Intra-abdominal (mixed) infections
    • > single agents w/ G+/- & anaerobic coverage
    • Piperacillin-tazobactam
    •      incld Enterococcus activity
    • Doripenem
    •     Imipenem derivative, longer T1/2
    •     most res of B-lactams to extended spectrum B-lactamases
    •     NO Enterococcus activity
    • -----------------------------------------------
    • > Combo therapy (no Enterococcus activity)
    • Ceftriaxone or cefotaxime + metronidazole
    • Levofloxacin or moxifloxacin + metronidazole
    • Aztreonam + metronidazole
    •      no G+ activity
  136. Anaerobic infections
    • GI:
    • Bacteriodes fragilis: common bacterium in distal small bowel & colon
    •      always assume lower GI tract infections involve it
    • Respiratory:
    • Peptostrptococcus: can cause aspiration pneumonia from inhalation of upper GI bacterial flora
    • Skin & soft tissue:
    • Clostridium perforinges: causative agent of gas gangrene
  137. Clostridium difficile infection & tx
    • AKA: antibiotic-associated colitis, pseudomembranous colitis
    • --> severe diarrhea (bc of toxin)
    • = anaerobic bacteria
    • ------------------------------------------------------
    • Tx:
    • discontinue inciting antibiotic
    • mild-moderate infection:
    •      oral metronidazole (TID for 10-14d)
    •      abs systemically but hi conc reach colon when inflammed
    • Severe Infection:
    •         oral vancomycin (QID for 10-14d)
    •         not abs => hi conc in colon    
    • Life threatening infection:
    •         oral vancomysin (QID) + IV metronidazole (TID) (for 10-14d)
  138. Antibiotics for Anaerobic infections
    • > metronidazole - best agent (oral or IV)
    • excellent tissue penetration, incld CNS
    • rapidly bactericidal
    • also has local anti-inflammatory activity in GI
    • pool activity vs mouth flora anaerobes
    • alcohol intolerance due to inhibition of aldehyde dehydrogenase - AVOID alcoholic beverages
    • every 8 hrs
    • -----------------------------------------------
    • > Clindamycin:
    • good anaerobic activity but more adverse effects, incld antibiotic-ass diarrhea & potential Clostridium difficile infection
    • ----------------------------------------------
    • > Penicillin/B-lactamase inhibitor combo:
    • oral: amoxicillin/clavulanate
    • IV: piperacillin/tazobactam (Zosyn)
  139. Aminoglycosides antobiotics
    • gentamicin, tobramycin, & amikacin
    • Use: primary agent for seious G- infections before fluoroquinolone
    • still use in combo w/ cephalosporins & quinolones for G- infections (esp Pseudomonas)
    • oly IV or IM
    • *Usually = single hi dose daily (conc dep killing) [one of few]
    • limited use b/c of renal toxicity & ototoxicity
    • monitor serum levels
  140. Pseudomonas aeruginosa infections
    • > Urinary tract:
    • Ciprofloxacin
    • ------------------------------------------------
    • > Systemic infections:
    • Pipperacillin/tazobactam +/- tobramycin
    • ceftazidime or cefepime +/- tobramycin
    • meropenem or doripenem +/- tobramycin
    • -------------------------------------------------
    • > Pulmonary infections:
    • same as above but add aminoglycoside
    • inhaled tobramycin also available for cystic fibrosis patients
  141. Hospital acquired pneumonia (HAP)
    see lecture "gram negative infections & STD" slides 35-40
  142. Bacteremia & Sepsis/Tx
    • Pos blood cultures: draw 2 sets, different IV sites
    • antibiotic choice dep on probable source:
    •      skin
    •      intra-abdominal
    •      pulmonary
    •      urinary (confusion & delerium in elderly)
    • also dep on immune status
    • usually give IV antibiotics
    • *use bacteriocidial antibiotics
  143. Deep seated infections
    • must isolate causative organism
    • hi'est doses of antibiotic necessary
    • usually IV
    • Osteomyelitis
    •      usually due to Staph
    •      multiple organisms ass w/diabetic foot wound
    • Menigitis
    •       blood-brain barrier must = penetrated
    •       inflammed (meningitis) meninges allow greater antibiotic penetration than uninflammed meninges (abcess)
    •      intrathecal route may be necessary
  144. Chlamydia Tx
    • (Chalmydia trachomatis)
    • Azithromycin: 1 dose, primary tx (good adherence)
    • doxycycline: 7d PO
    • Alternatives:
    •      erythromycin PO 7d
    •      levofloxacin PO 7d (no fluoroquinolones <18 yo)
    • doxycycline & levofloxacin contraindicated in pregnancy
  145. Gonorrhea Tx
    • (Neisseria gonorrhoeae)
    • ceftriazone (IM, 1 dose) PLUS azithromycin (1 dose) or doxycycline (BID, 7d)
    • co-treatment w/ azithromycin or doxycycline is for possible Chlamydia
    • fluoroquinolones or oral cephalosporins no longer recommended due to hi res rates (ceftriaxone is all we have left)
  146. Pelvic Inflammatory Disease (PID) Tx
    • polymicrobial infection possible involving Chlamydia trachomatis, Meisseria gonorrhea, anaerobic bacteria, & G- bacteria
    • Outpatient:
    •     ceftriaxone (IM, 1 dose) +
    •     doxycycline (BID, 14d) with or w/o
    •     metronidazole (BID, 14d)
    • Inpatient:
    •     give IV until able to tolerate oral antibiotics
    •     cefotetan (IV) plus
    •     doxyclycline (IV)
    •              OR
    •     clindamycin (IV) plus
    •     hi dose gentamicin IV daily
  147. Nongonococcal urethitis Tx
    • Ureaplasma urealyticum OR Mycoplasma genitalium
    • usually responds to azithromycin OR doxycycline at same doses as for Chlamydia trachomatis
  148. Trichomonas Tx
    • (Trichomonas vaginalis, an anaerobic protozoan)
    • Metronidazole (oral, 1 dose)
  149. Bacterial Vaginosis Tx
    • Gerdnerella vaginalis, Mycoplasma hominis, & various anaerobes
    • Metronidazole (PO, BID, 7d)
    • Metronidazole gel (intravaginally, QD, 5d)
  150. Syphilis Tx
    • (Treponema pallidium = spirochete)
    • Penicillin G benzathine (IM, 1 dose for primary or secondary infections)
    •       doxycycline (PO, BID, 14d): if allergy
    • Penicillin G benzathine IM weekly, 3 doses for tertiary infections
    • hi dose Penicillin G (IV, 10-14d for neurosyphilis)

    one of the few times penicillin is 1st line/used
  151. Where is the most up to date info about STD guidelines for tx?
    CDC web stie
  152. Hypertension: Basic Principles
    • 1. BP= CO x PVR
    • 2. Regulated at different sites throughout the body
    •      a. Arterioles
    •      b. capacitance venules
    •      c. Cardiac output
    •      d. Renin-Angiotensin- Aldosterone system
    • 3. Regulated by many different mechanisms/substances
    •    e.g. sodium, catecholamines, dilators,          
    •          autoregulation, etc
  153. Primary vs. Secondary HTN
    • 1. Primary/essential HTN is 95% of cases
    • 2. Seconday causes --> obesity, sleep apnea, drug induced (NSAIDS, corticosteroids, contraceptives, cocaine, etc), pheochromocytoma, primary aldosteronism, Cushing syndrome, Coarctation of aorta, thyroid/parathyroid disease, pregnancy
    • 3. White Coat HTN --> occurs only in medical setting mostly in young females w/o long HTN Hx --> consider outpatient BP monitoring for all HTN patients
  154. Reasons to treat HTN
    • Target organ damage
    •     1. Stroke/TIA
    •     2. Retinopathy
    •     3. Heart Disease --> LVH, HF, angina, ACS
    •     4. Chronic kidney disease
    •     5. Peripheral artery disease 

    *note --> most clinical trials for HTN measure long term effects on target organs (improvement/prevention of TOD)
  155. HTN Treatment guidelines- General
    • 1. JNC 7 --> came out in 2003 but is outdated
    • still the standard for the US. 
    • 2. Individual fields of specialty have come out with more recent guidelines
    • --------------------------------------------
    • Note: most patients will need at least 2 anti-HTN drugs to reach BP goal (esp if BP is >20/10 mm Hg above goal) --> ALWAYS EMPHASIZE LIFESTYLE MODIFICATIONS
  156. JNC 7 Classification of HTN
    • 1. Normal < 120/80
    • 2. Pre-HTN = 120-139/80-89
    • 3. HTN 
    •     a. Stage one--> systolic 140-159 or Diastolic 90-99  
    •     b. Stage 2 --> systolic >160 or diastolic > 100
  157. Blood Pressure Goals (JNC 7 and others)
    • JNC 7
    •  1. Uncomplicated HTN < 140/90
    •  2. DM/CKD < 130/80

    American Heart Associated (2007) 

    • 1. Documented CAD , 130/80
    • 2. Heart Failure in Stages B-D < 120/80
    • 3. (2001) Systolic BP goal of 140-145 in the very old (80+ yo) 

    • NKF-KDIGO (2012
    • 1. CKD patient with <30 mg albumin loss/24 hrs < 140/90
    • 2. CKD patient with >30 mg albumin loss/24 hrs <130/80
  158. Treatment Guidelines for HTN
    • 1. Start with lifestyle modifications --> weight loss, DASH Diet to decrease salt intake, physical activity increase, reduce EtOH intake
    • 2. No compelling indications --> add diuretics (normally start with Thiazide for stage 1 and add other meds such as Beta-blockers for stage 2) 
    • 3. Compelling co-morbidities --> add HTN medications that will help with co-morbities
    • -------------------------------------------------------
    • Initial Combinations of HTN drugs --> Thiazide diuretic + ACEI or ARBs + Calcium antagonists
    •       -at least 2 of these 3 
    • Then add beta-blocker with compelling indication (MI, angina, LV dysfunction)
    • --------------------------------------------------------
    • Resistant HTN --> caused by improper BP measurement, volume overload, no lifestyle modifcation, medications (NSAIDS, OTC meds)--> investigate these possibilities before adding other drugs 

    For resistance to primary therapy --> switch for HCTZ or clorthalidone, add aldosterone antagonists, switch BB to labetelol, add alternatives such as alpha receptor blockers, central alpha receptor agonists, or vasodilators
  159. ALLHAT Trial
    Conclusion: "Thiazide type diuretics are superior in preventing one more major forms of CVD and are less expensive" 

    --> THIAZIDES ARE FIRST LINE FOR HTN
  160. Compelling indications for High risk conditions + HTN treatment
    Memorize this table in the slides. It comes up at least twice (slide 32 is the first)
  161. Renin-Angiotensin-Aldosterone System
    • 1. Process
    • Decrease in BP--> kidneys secret renin --> renin converts angiotensinogen to AT1 --> ACE converts AT1 to AT2--> sympathetic activation, vasc sm. mm. contraction, aldosterone secretion --> increase BP
    • 2. Several sites of action of drugs for this system
    •     a. Renin <-- aliskiren
    •     b. ACE <-- ACE inhibitors
    •     c. Angiotensin receptors <-- ARBs
  162. ACE Inhibitors
    1. MOA --> inhibit action of Angiotensin converting enzyme

    2. Generic names end in -pril --> Captopril (1st drug, only used for HTN emergencies now), Lisinopril (most frequently prescribed), Enalaprilat (IV formulation) 

    3. Most are prodrugs that are metabolized to active agent in the liver (except lisinopril) 

    4. Always start with low dose and titrate up slowly (wks-mos) to avoid adverse effects (esp in pts w/ renal dysfunction)

    5. given QD or BID (except Captopril) 

    6. AVOID NSAIDS--> lose ability to maintain renal autoregulation (renal failure potential) 

    7. Adverse Effects --> hypotension, hyperkalemia, renal failure (esp if CHF, hypovolemia, renal artery stenosis, and NSAIDS), rise in serum creatinine (use up to 30% rise), dry cough (5-15%, make sure its not asthma), angioedema (much more prevalent in African Americans), Teratogenic in pregnancy (Category D)
  163. Angiotensin II receptor blockers (ARBs)--> Losartan, Irbesartan etc
    1. MOA - block AT1 receptors in vasc sm. mm and adrenal complex --> vasodilation, decreased aldosterone release, decreased sympathetic activation

    2. Generic names end in -sartan --> Losartan, Irbesartan (most used) 

    3. Adverse Effects --> hyperkalemia, angioedema (less likely than with ACEI), cough (less likely than with ACEI), teratogenic in pregnancy (Category D) 

    4. Used to manage HTN in pts to avoid cough and angioedema
  164. Can you combine ACEIs and ARBS
    1. NO! 

    2. ONTARGET Study --> higher incidence of discontinuation, renal impairment, renal failure, in combo group
  165. Direct Renin Inhibitors
    1. MOA --> inhibit renin and prevent formation of AT1 and AT2

    • 2. Indications --> HTN either alone or in combo w/other agents. Safe in short term, well tolerated, similar in efficacy to ACE inhibitors and ARBs, give 150 or 300 mg QD
    • 3. Cost about $160/month

    4. Basically equal to ACEIs or ARBs, nothing too special

    5. Aliskiren approved in 2007 (only drug)
  166. Drugs for used in African American population
    • 1. HTN in AA population is mostly of the low renin type. 
    • 2. Use diuretics (HCTZ) first with diet modification to reduce salt intake
    • 3. Don't need to avoid ACEIs or ARBs entirely
    • 4. Generally two drugs are necessary for BP control in AA population, blunted response to anti-HTN drugs goes away with combination therapy such as...
    •       a. ACEIs and CCBs
    •       b. ACEIs and Thiazide diuretics
    •       c. ARBs and diuretics 
    •       d. Beta-blockers and diuretics
  167. Beta blockers in HTN
    1. MOA: block Beta-receptors in the heart and other tissues --> decrease myocardial O2 demand, renin secretion, and sympathetic outflow

    2. Selective -->  Atenolol, Esmolol (IV only), Metoprolol (most common) 

    3. Non-selective --> Propanolol, Nadolol, Timolol

    4. Renal elimination --> Atenolol, Nadolol

    5. Intrinsic sympathomimetic activity (less effect on resting HR) --> acebutelol, pindolol

    6. With alpha blocking activity --> Labetalol (greater decrease in BP, used for resistant HTN, hypertensive urgencies, hypertensive emergencies, both IV and oral, watch for orthostatic HTN), Carvedilol (used for heart failure) 

    7. Adverse effects --> bronchospasm, bradycardia (HF), masking of DM Sx, impaired peripheral circulation, sexual dysfunction, CNS toxicity, elevated TG, decreased HDL, exacerbation of angina and MI if discontinued suddenly. 

    8. Contraindicated in --> symptomatic hypotension, symptomatic bradycardia, severe pulmonary disease, severe peripheral vascular disease, heart block, heart failure, and cardiogenic shock

    9. Used to treatment of HTN in patients with comorbities of angina, history of MI, or LV dysfunction
  168. Calcium Channel blockers in HTN
    1. MOA: bind L type CCBs to prevent influx of Ca2+ --> cause vascular smooth muscle relaxation, reduced BP, and reduced intramyocardial wall tension. 

    • 2. DHP-CCBs --> amlodipine is preferred for HTN, Nifedipine is prototype
    •    a. metabolized by CYP 3A4
    •    b. short T1/2 
    •    c. Adverse effects --> fatigue, HA, flushing, 
    •       peripheral edema, heart failure
    •    d. Severe hypertensive episodes with           
    •        sudden discontinuation

    3. Non-DHP CCBs --> not normally used for HTN, used as anti-arrhythmics (see previous cards for info)
  169. Peripheral Alpha-1 receptor blockers
    1. MOA: block peripheral alpha 1 receptors in sm. mm --> vasodilation and decrease PVR

    2. Doxazosin, prazosin, Terazosin

    3. Adverse effects --> orthostatic hypotension, first dose syncope. NOT FIRST LINE OR MONOTHERAPY 

    4. May be beneficial for patients with BPH
  170. Centra alpha-2 agonists
    1. MOA: stimulate alpha-2 receptors in the brain to decrease sympathetic outflow --> decrease PVR, HR, and CO 

    2. Clonidine (weekly patch or oral tablet)  and Methyldopa 

    3. Still used alot in hampton roads

    4. Adverse effects --> sedation, dry mouth, orthostasis, dizziness, erectile dysfunction, sever rebound HTN if stopped suddenly (tapered discontinuation ALWAYS) 
  171. Direct Vasodilators
    1. MOA --> direct arteriolar Sm. mm. vasodilation --> decreased PVR, but increased HR, CO, and renin

    2. Hydralazine (decreased afterload, must give 3x/day, give with diuretic and beta blocker for reflex tachy and water retention, may cause lupus like syndrome with higher doses), Minoxidil (give with beta-blocker and diuretic for reflect tachy and severe fluid retention, causes hirsutism) 

    3. not used often for HTN
  172. Drugs with favorable effects on Comorbitities
    • 1. Osteoperosis --> thiazide diuretics 
    • 2. Atrial Tachyarryhtmia, A-fib --> beta blockers/CCBS
    • 3. Migrain HA, tremor --> beta blockers 
    • 5. Thyrotoxicosis (short term) --> beta blockers
    • 6. Perioperative HTN --> beta blockers
    • 7. Raynaud's Syndrome, arrythmias --> CCBs
    • 8. BPH/Prostatism--> alpha blockers
  173. Potentially unfavorable effects on Comorbidities
    • 1. Asthma/RAD --> Beta blockers
    • 2. Gout or serious hyponatremia --> thiazide diuretics
    • 3. Heart block --> beta blockers, non-DHP CCP
    • 4. Pregnancy--> ACEI, ARB
    • 5. H/O angioedema --> ACEI
    • 5. Serum K > 5.0 meq/L not on meds --> aldosterone antagonists, and K sparing diuretics
  174. Pregnancy and Hypertension
    • 1. Special case --> HTN major cause of maternal/fetal/neonatal M/M --> may progress to pre-eclampsia or eclampsia
    • 2. Methyldopa --> drug of choice (Category B) 
    • 3. DO NOT USE ACEIS and ARBs (teratogenic) , as well as labetalol, atenolol, and diuretics 
    • 4. Labetalol can be used for pre-eeclampsia as well as hydralazine in emergencies
  175. Hypertensive Urgency
    • 1. Markedly increased BP > than 180/120 without acute target organ damage that normally does not require hospitalization
    • 2. Tx with oral short-acting agens --> captopril, clonidine, labetalol
    • 3. Antihypertensive therapy adjustment with combination therapy to improve adherance and close F/U
  176. Hypertensive Emergency
    1. Markedly increased BP > 180/120 with ACUTE target organ damage --> CVA, encephalopathy, MI, UA, pulmonary edema, HF, eclampsia, aortic dissection, renal failure 

    2. Requires hospitalization and IV drug therapy

    3. Tx --> Sodium nitroprusside by IV infusion but MONITOR thiocyanate levels (don't use too long), labetalol, fenoldopam by IV infusion (dopamine receptor agonist--> arteriolar vasodilation) --> decreased PVR and increased renal blood flow

    4. Goal to decrease MAP by 25% w/i 1 hr then BP to 160/100-110 within next 2 hrs, normal BP within 1-2 days

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