Pharm Exam 4

  1. Therapy Goals and Drugs/devices for Stage A Heart Failure (ACC-AHA stages of Heart Failure)
    • (def: at hi risk w/o structural heart dz or HF sx; at risk for HF)
    • --------------------------------------------------
    • Goals:
    • tx HTN
    • smoking cessation
    • tx lipid disorders
    • inc exercise
    • dec EtOH, illicit drug use
    • control metabolic syndrome
    • --------------------------------------------------
    • Drugs:
    • ACEI or ARB (when appropriate)
  2. Therapy Goals and Drugs/devices for Stage B Heart Failure (ACC-AHA stages of Heart Failure)
    • (def: structural heart dz w/o HF sx; at risk for HF)
    • -----------------------------------------------
    • Goals: *same as Stage A*
    • tx HTN
    • smoking cessation
    • tx lipid disorders
    • inc exercise
    • dec EtOH
    • illicit drug use
    • control metabolic syndrome
    • -------------------------------------------------
    • Drugs:
    • ACEI or ARB (when appropriate)
    • Beta-blockers (when appropriate)
    • -------------------------------------------------
    • Devices (in select pts):
    • implantable defibrillators
  3. Therapy Goals and Drugs/devices for Stage C Heart Failure (ACC-AHA stages of Heart Failure)
    • (def: structural heart dz w/ prior/current HF sx; in HF)
    • ----------------------------------------------------
    • Goals:
    • all measures of stage A & B
    • dec dietary salt
    • -------------------------------------------------
    • Drugs: (for routine use)
    • diuretic
    • ACEI
    • Beta-blocker
    • ---------------------------------------------
    • Drugs in select pts:
    • aldosteron antagonist
    • ARB
    • Digitalis
    • Hydralazine/nitrates
    • -------------------------------------------------
    • Devices in select pts:
    • biventricular pacing
    • implantable defibrillatorsTherapy Goals and Drugs/devices for Stage B Heart Failure
  4. Therapy Goals and Drugs/devices for Stage D Heart Failure (ACC-AHA stages of Heart Failure)
    • (def: refractory HF, req's specialized interventions; in HF)
    • ---------------------------------------------------
    • Goals:
    • measures under staged A, B &C (when appropriate)
    • --------------------------------------------------
    • Options:
    • end of life care
    • extraordinary measures:
    •      heart transplant
    •      chronic inotropes
    •      permanent mechanical support
    •      experimental surgery or drugs
  5. Primary drugs for Chronic Heart Failure to REDUCE MORTALITY
    • ACEI
    • ARBs (angiotensin receptor blockers)
    • B-blockers
    • Aldosterone inhibitors
    • Hydralazine-isosorbide (specific combo for AfAm)
  6. Primary drugs for Chronic Heart Failure to REDUCE SX
    • loop diuretics
    • digoxin (he said: maybe last resort @ very end)
    • nitrates
  7. Diuretics in HF
    • relieve sx of HF
    •       dec pulm & peripheral edema
    •       faster benefits than other drugs
    •       do NOT stop HF progression
    • only class of HF meds that can control fluid retention
    • appropriate use key to success of other drugs
    • use loop diuretics and thiazides
  8. Loop diuretics for HF
    • Drug of choice = furosemide (Lasix)
    •       IV or oral (F = 50% --> very different doses)
    •      NKCC2 inhibitor (ascending limb)
    • start @ lo dose and titrate up
    • maintenance dose in HF dep on daily wt (adjust dose)
    • can taper and stop when patient euvolemic
    • other loop diuretics used:
    •      Bumetinide (Bumex)
    •      Torsemide (Demedex)
  9. Loop diuretics: Adverse effects
    • hypovolemia & renal failure (from kidney hypoprofusion)
    • hypotension & syncope
    • hypokalemia (must monitor potassium)
    •     may --> sudden death (esp w/ digoxin)
    • hyponatremia, hypomagnesemia, & hypocalemia (2+ ions)
    • metabolic alkalosis
    • ototoxicity @ hi doses or IV too fast
    • Drug interaction: NSAIDS dec diuretic effect
  10. Thiazide diuretics for HF
    • Inhibit Na reabsorption in distal tubule of kidney
    • only inc excretion by 5-10% (not dramatic effect)
    • only effective during early stages of HF
    • Drug of choice: hydrochlorothiazide or chlorthalidone (his fav in general)
    •      HTN dose: 12.5 - 25 mg QD
    •      HF dose: 25 mg QD or BID
    • Metolozone = preferred thiazide in combo w/ furosemide (added for synergy)
  11. Diuretic Resistance
    • inc as progress in HF
    • hi dose loop diuretics necessary
    • use IV furosemide to bypass GI
    • use metolazone (thiazide diuretic) w/ furosemide (synergy)
    •      given 30 min before IV furosemide
    • can add IV inotropic agents
    • *avoid NSAIDs & OCX-2 inhibitors!!
    •      antagonize diuretic effect
  12. Potassium sparing diuretics for Chronic HF
  13. ACEI in HF
    • dec MORTALITY in HF
    • avoid NSAIDs (1 dose aspirin probably ok)
    • must correct fluid retention for amx effect
    • -------------------------------------------------
    • >mech:
    • block ATI --> ATII (rxn)
    •      some ATII still made fron non-ACE mechanisms
    • block bradykinin metabolism
    •      additional benefit for HF pts
    •      BUT inc kinin --> cough
    • -------------------------------------------------
    • >Effects on HF Sx:
    • relieve dyspnea
    • prolong exercise tolerance
    • improve EF
    • dec doses of diuretic
    • -------------------------------------------------
    • >Effects on Morbidity & Mortality: (trial)
    • used captopril, enalapril, lisinopril
    • dec mortality 16-28% (big)
    • dec hospitalizations
    • --------------------------------------------------
    • >Doses:
    • hi doses (hi'er than w/ HTN)
    • enalapril, lisinopril > 20 mg/day
    • titrate slowly
    • QD or BID
    • --------------------------------------------------
    • see chart on slide 29 for specific ACEI indicated for HF
  14. ACEI in HF: Adverse Effects
    • hypotension
    • hyperkalemia
    • renal failure, esp w/ one/more of following:
    •      severe HF
    •      hypovolemia
    •      renal aa stenosis
    •      NSAID use
    •      > 30% inc in serum Cr from baseline (otherwise acceptable)
    • dry, non-productive cough (5-15%)
    •      inc bradykinin met --> inc kinin --> cough
    •      rule out pulm congestions or asthma
    •      cosider d/c & re-challenge
    • angioedema
    •      4x more prevalent in black pop
    • Teratogenic - avoid in preg (category D)
  15. Angiotensin II Receptor Blockers in HF
    • block AT1 receptors
    • do not block AT2 receptors or affect bradykinin met (vs ACEI)
    •     mb less benefit than ACEI in HF pt
    • only 2 approved for HF
    •      Diovan (valsartan) & Atacand (candesartan)
    •      only after try ACEI
    • drugs of choice in HF if ACEI --> cough or angioedema
    • --------------------------------------------------
    • >ADE:
    • hypotension, hyperkalemia, renal failure
    • teratogenic - avoid in preg
    • -----------------------------------------------
    • see slide 30 for ARB indicated for HF
  16. ACEI and ARB in Renal Failure
    • Should they be avoided in renal failure?
    • ACEI therapy associated w/ long-term preservation of renal func
    • ACEI dec incidence of renal failure in pt w/ neuropathy & proteinuria
    • ACEI indicated for renal failure
    • --------------------------------------------------
    • see slides 32-36 for more detail
  17. B-blockers in HF
    • in old tx paradigm, they were contraindicated for HF
    • now shown: dec mortality (33%) in pt already on ACEI
    • Carvedilol (Coreg) = 1st B-blocker to show long term benefit in HF
    •      easier to use than metoprolol b/c small dose pills exist
    • start w/ very lo doses and titrate up slow (every 1-2 wks)
    •      carvedilol (generic) 3.123 BID
    •      Coreg CR 10 mg (= 3.125 BID)
    •      metoprolol succinate (Toprolol XL) 12.5 QD
    •      Bisoprolol 1.25 QD
    • -------------------------------------------------
    • Patient selection:
    •       mild-moderate CHF (NYHA Class II-III)
    •       stable on ACEI, diuretics, +/- digoxin
    • avoid if accutely ill, unstable, hypotensive
    • ---------------------------------------------------
    • >Mech:
    • block SNS
    • block stim of B1-receptors in heart --> dec HR, contractility, & CO
  18. B-blockers in HF: Adverse Effects
    • worsening HF
    • hypotension
    • bradycardia
    • caution in pt w/ asthma, COPD, diabetes, heart block
    •      metoprolol & bisoprolol = cardioselective
    •      carvedilol is NOT cardioselective
  19. Spironolactone in HF
    • >Mech:
    • aldosterone antagonist
    • potassium sparing diuretic
    •      inc K reabsorption iat distal tubule
    • can cause gynecomastia & impotence (b/c androgen antagonist)
    • -------------------------------------------------
    • trial: pt on lots of meds, and still got dec in death & hospitalizations w/ spironolactone
    • only need 25 mg/day
    • reduce diuretic (lasix) dose due to syndergistic effect
    • monitor for hypokalemia
    •      risk w/ renal failure, ACEI
    • not recommended if K> 5 mg/dL or CrCl < 30 ml/min
  20. Eplerenone (Inspra) in HF
    • new aldosterone antagonist indicated for HF and HTN
    • less anti-androgenic ADE than spironolactone
    • sill cz hypokalemia
    • use in pt intolerant to endo ADE of spironolactone
    • dose: 25-50 mg QD
    • $$$ compared to spironolactone
  21. Digoxin in HF
    • >Mech:
    • = digitalis glycoside (from foxglove)
    • pos inotropic agent
    •      inc systolic contraction
    •      do NOT use for diastolic failure
    • inc PR interval, dec QT interval
    • -------------------------------------------------
    • can improve sx and quality of life
    • NOT shown to dec overall mortality
    • usual dose 0.125 mg/day
    •      give less if elderly &/or dec renal func
    •      T1/2 = 1-2 d
    • (narrow therapeutic index)
    • -------------------------------------------------
    • >Mech:
    • inhibit Na/K ATPase & inc intracellular Ca --> inc SV
  22. Digoxin in HF: Adverse Effects
    • ADE associate w/ serum levels > 1ng/ml
    • arrhythmias, heart block, GI complaints, visual disturbances, confusion
    • avoid hypokalemia, hypomagnesemia
    •      potentiate arrhythmias
    • must order periodic serum digoxin levels
    • digoxin immuno Fab - AB to tx severe digoxin toxicity
    • inc digozin levels w/ addition of quinidine, verapamil, diltiazem, & amiodarone
  23. Traditional Vasodilators in HF
    • part of traditional (old approach) drug therapy using hemodynamic model
    • Only short term symptomatic benefit
    • -----------------------------------------------
    • Nitrates:
    • vv dilation --> dec preload
    • isosorbide dinitrate (Isordil), NG
    • avoid phosphodiesterase inhibitors (ie sildenafil)
    • -------------------------------------------------
    • Hydralazine:
    • dilates aa --> dec afterload
    • hypotension, reflex tachycardia
    • most likely will need diuretic & B-blocker
  24. Hydralazine-Isosorbide (BiDil)
    • combo Hydralazine (37.5mg) Isosorbide (20 mg) -> TID
    • marketed exclusively for African-Americans (study based)
    •      overall dec mortality
    • ADE: HA (primary ADE)
    • Marketing suspended bc poor sales
  25. Polyunsaturated Fatty Acids for HF
    • (fish oils)
    • PUFA dec sudden death after MI
    • dec mortality (NNT = 56)
    • dec death/admission to hospital for CV cz (NNT = 44)
  26. Drugs for Acute, Decompensated HF
    • >Vasodilators:
    • Nitroprusside: IV to dec afterload
    •      - can get cuanide toxicity w/ overuse
    • Nesiritide (Natrecor) - recombinant B-type natriuretic peptide (BNP) --> vasodil & Na excretion.  (IV)
    •       -latest: didn't show benefit over placebo
    • --------------------------------------------------
    • >Parenteral Inotropic agents:
    • Dopamine: lo dose --> inc renal bld flow & inc CO
    • *Dobutamine: inc CO in short term but blunted effect w/ B-blocker
    •      =B1-agonist w/ immed inotroppic effect
    • Milrinone (Primacor): phosphodiesterase (PDE-3) inhibiotr which inc peripheral aa and vv dilation
    •      limited to short term bc of tachyarrhythmias
  27. Monitoring HF TX:
    Diurectics, ACEI/ARB, B-blockers, Spironolactone, digoxin
    • >Diuretics: electrolytes (esp K+), renal func, wt
    • >ACIE/ARB: renal func, K, bld pressure
    • >B-blocker: HR, BP
    • >Spironolactone: K, synecomastia
    • >Digoxin: HR, K, serum levels (occasionally)
  28. Corticosteroids Agonists
    1. Mineralocorticoids --> stimulate mineralocorticoid receptors (aldosterone, fludorcortisone) maintain sodium and potassium balance

    2. Glucocorticoids --> stimulate glucocorticoid receptors (cortisole, prednisone, dexamethasone) 

    3. Adrenal androgens --> DHEA
  29. Hypothalamic-Pituitary-Adrenal Axis
    Stress --> increased CRH in hypothalamus --> release of ACTH from pituitary --> release of cortisol from adrenal gland --> cortisol provides feedback inhibition of CRH and ACTH release
  30. Cortisol Production
    • Physiologic --> 20-30 mg/day  (stress=200-300mg/day)
    •     - Cortisol 20 mg =hydrocortisone 20 mg= 
    •       Prednisone 5 mg 
    •     - stimulates gluconeogenesis, lypolysis and
    •       abnml fat distribution
    •     - wasting of muscle, connective tissue, etc
    •     - Immunosuppressive
    •     - Anti-inflammatory
  31. Clinical uses of Glucocorticoids
    • 1. Primary adrenal insufficiency
    • 2. Acute and chronic inflammation
    • 3. Allergic reactions
    • 4. Autoimmune disorders
    • 5. Leukemias and lymphomas
    • 6. Organ transplants 

    Adverse effects --> Adrenal atrophy, Cushing's, dyslipidemia, HTN, psychosis, bleeding, peptic ulcer, immunosuppression, infections

    Adverse effects of prolonged therapy --> skin atrophy, muscle atrophy, cataracts, glaucoma, Na+ retention and K+ exretion, hypogonadism, delayed puberty
  32. Acute adrenal insufficiency
    Steroid use with abrupt withdrawal --> fatigue, joint pain, weight loss, abdominal pain, nausea, diarrhea, postural hypotension

    Prevent with alternate  day therapy or slow taper of weeks to months. If on chronic therapy supplement steroids in times of stress
  33. Inhaled Corticosteroids
    • MOA: reduce inflammatory changes in airway and reduce hyper-responsiveness 
    • Preferred for long term asthma treatment
    • Equipototent doses provide equivalent effect

    Once daily inhalation works best if given in evening

    Kinetics = dose response curve flat at higher doses 

    • Types 
    • 1. Metered Dose Inhalers --> Chlorofluocarbon propellant, Hydrofluroalkane propellant, use spacer for effectiveness
    • 2. Dry powder inhalers --> no dydrocarbons, so no spacer needed, coordination easier for user, lower cost per dose, better compliance
  34. Systemic Corticosteroids
    Use--> mainly for severe asthma attacks to decrease relapse rate, use of beta-agonists, and hospitalizations (oral prednisone as effective as IV methylprednisone)

    Dosing- burst/pulse, no taper necessary

    Adverse effects: increased risk vs. inhaled --> glucose intolerance, diabetes, weight gain, increased BP, osteoporosis, immunosuppression, decreased linear growth in children, acute adrenal insufficiency
  35. Short-Acting Inhaled Beta-Agonists
    MOA: increased cAMP --> smooth muscle relaxation, bronchodilation

    • 1. Albuterol (proventil HFA, ventolin HFA) 
    • Dosing: PRN, inhaled/nebulized
    • MDI more effective with spacer
    • Switch from CFC to HFA --> increased cost
    • 2. Levalbuterol (Xopenex HFA) 
    • R-isomer of albuterol (S-isomer has no bronchodilator activity), nebulized 
    • Promoted as less tachycardia, palpitations, and tremors
  36. Long Acting Beta Agonists
    Usually combined w/inhaled steroid

    • Salmeterol --> dry powder diskus (50 mcg) 
    • Formoterol (Foradil) --> dry powder aerolizer, also indicated for exercise induced asthma

    Delayed onset of effect --> not used PRN or for acute attacks. BID dosing for patients no controlled on inhaled steroids alone (add on)

    Contraindicated for asthma if used w/o steroid

    Adverse effects: increase severe and life-threatening asthma exacerbation and asthma related deaths
  37. Oral Beta-Agonists
    Slower onset, increased systemic side effects (terbutaline

    Rarely used now for asthma

    Adverse effects --> tachycardia, hypertension, agitation, hyperactivity, nervousness/shaking, Tolerance 

    Drug interactions: beta-blockers
  38. Corticosteroids and LABA Combinations
    • Advair Diskus or MDI --> fluticasone and salmeterol, $330-420/device
    • Symbicort MDI --> budesonide and formoterol, $290/device
    • Dulera MDI --> Mometasone and formoterol, $280/device
  39. Anticholinergic Inhalers
    MOA: block the action of acetylcholine in the bronchial smooth muscle--> bronchodilation

    • 1. Ipratropium (atrovent HFA) --> short acting, approved for acute asthma exacerbation
    • 2. Tiotropium (Spiriva)--> once Daily inhalation, only approved for COPD

    Adverse effects: systemic side effects with excessive use
  40. Leukotriene Modifiers
    Leukotrienes increase airway inflammation and constriction

    • Leukotriene receptor antagonists --> block some but not all leukotriene receptors, improve lung function, control Sx, decrease beta agonists use, prevent exacerbations
    •    1. Montelukast (singulair and generic)--> only modifier approved for preventing exercise induced asthma, also approved for allergic rhinitis in adults and children >2yo
    •     2. Zafirlukast (Accolate) --> given twice daily, increased drug interactions, modest inhibitor of CYP 2C9 and 3A4
    • Less clinical benefits than low dose steroids 

    Adverse effects: minimal

    Potential add on Tx for mild-moderate persistent asthma
  41. Theophylline
    MOA: inhibits phosphodiesterase isozymes and blocks degradation of cAMP --> bronchodilation

    Kinetics: narrow TI (serum levels= 5-15 mcg/ml), half-life varies widely with age and smoking statues

    Adverse effects --> dose related, N/V, cardiac arrhythmias, tremor, seizures 

    Drug interactions --> inhibits macrolides, ciprofloxacin, and cimetidine. Induces phenytoin, carbamazepine, and nicotine
  42. Immunologic therapy --> Omalizumab (Xolair)
    • Recombinant humanized monoclone IgE antagonist
    • Use: moderate severe persistent asthma w/high allergen specific IgE levels, used along with inhaled steroids
    • Dosing: Subcu administration ever 2-4 weeks. 
    • Adverse effects --> very expensive (850/dose), risk anaphylaxis
  43. Guidelines for diagnosis and management of asthma
    Slides 42-52
  44. COPD
    Progressive pulmonary disease characterized by --> airflow limitation that is not fully reversible, chronic lung and airway inflammation, mucus hypersecretion, gas exchange abnormalities

    Risk factors ---> genetics (A1AT deficiency), airway hyper-responsiveness, Exposure --> tobacco smoke, occupational exposure, infections

    For classification of severity  see slide 54

    Objectives of Management --> prevent disease progression, relieve Sx and improve health, improve exercise tolerance, prevent/treat complications and exacerbations, reduce mortality, minimize side effects from Tx, avoid risk factors, influence vaccination

  45. Bronchodilators for COPD
    Bronchodilators in stable COPD --> beta agonists and anticholinergic inhalers + bronchodilators PRN/scheduled, prevent or reduce symptoms. Long acting inhaled bronchodilators are more effective and convenient  than short acting but increase costs. Combining bronchodilators to improve efficacy and decrease risk of side effects rather than increasing dose of single bronchodilator
  46. Inhaled Corticosteroids for COPD
    Inhaled steroids are appropriate for symptomatic COPD patients with an FEV1<50% predicted (stages III and IV) and repeated exacerbations in last three years

    Inhaled corticosteroid + LABA is more effective than the individual components

    Increased risk of PNA with inhaled steroids, increased risk osteoporosis with extended use. Avoid chronic systemic steroids (risk>benefit, Systemic steroids may be appropriate for COPD exacerbations)
  47. Roflumilast (Daliresp) for COPD
    MOA: Selective oral phosphodiesterase 4 inhibitor --> increases intracellular cAMP in inflammatory lung cells, new class of drugs, not a bronchodilator

    Approved by FDA in 2011, indicated for decreasing the risk of COPD exacerbations in pts with severe COPD with bronchitis and history of exacerbations (severe, or very severe disease with exacerbations)

    Adverse effects: nausea, diarrhea, insomnia, and weight loss

    Drug interactions: CYP 3A4 inhibitors and inducers 

    Cost: $260 for 30 tablets (1 month)
  48. Treatment of COPD exacerbations
    inhaled bronchodilators, theophylline, and systemic steroids are effective. 

    Consider addition of roflumilast

    May need antibiotics for infections
  49. Allergic Rhinitis
    For types of Allergic Rhinitis, pathophysiology, Signs, and Sx see slides 65-68
  50. 2nd generation oral antihistamines
    MOA: competitive H1-receptor antagonists, antagonize capillary permeability, wheal and flare formation, and pruritis, anticholinergic properties (1st generation), reduce nasal, salivary, and lacrimal gland secretion. Relieve sneezing, pruritis, rhinorrhea, allergic conjuctivitis

    Kinetics: good oral absorption, onset 30-60 min, peak 2-3 hrs, therapeutic effects long than predicted from T1/2, work best if given 30 mins before exposure to allergen
  51. 1st generation antihistamines (nonselective)
    Penetrate CNS

    OTC, Also used in OTC products for insomnia

    Brompheniramine, Chlorpheniramine, Clemastine, Diphenhydramine

    Adverse effects: Dry eyes/mouth/nose, blurred vision, urinary retention, constipation, tachycardia, CNS effects (sedation, cognitive impairment)
  52. 2nd generation oral antihistamines
    Peripherally selective, less CNS penetration (non-sedating) 

    Cetirizine (Zyrtec) OTC, Levocetirizine (Xyzal), Fexofendadine (Allegra) OTC, Loratadine (claritin) OTC, Deloratadine (Clarinex)
  53. Intranasal Antihistamine
    Azelastine (generic): 2 sprays each nostril BID, onset of action within minutes, peak at 3 hours

    Relieves sneezing, pruritis, rhinorrhea and can reduce nasal congestion

    Adverse effects: bitter taste, sedation, local irritation
  54. Oral Decongestants
    MOA: Alpha adrenergic agonists --> vasoconstriction of blood vessels in nasal mucosa

    • Direct acting --> phenylepherine (weak activity) 
    • Indirect acting/mixed --> pseudoephedrine (slower onset, longer duration, more effective) 

    Temporary relief of nasal congestion
  55. Systemic Decongestants
    Adverse effects: more likely in very old/young, cardiace stimulation, CNS stimulation 

    Interactions: MAO inhibitors increase BP 

    Precautions: hypersensitivity, idiosyncratic rxns, contraindicated with MAOI use, potential exacerbation of hyperthyroidism, glaucoma, HTN, BPH
  56. Intranasal decongestants
    • Short acting --> phenylephrine
    • Intermediate acting --> naphazoline, tetrahydrozoline
    • Long acting--> oxymetazoline

    Rhinitis medicamentosa: rebound nasal congestion, occurs with prolonged use > 3 days <-- Tx: withdraw decongestion 1 nostril at a time, intranasal corticosteroid, nasal mucosa normalized after 1-2 weeks
  57. Intranasal Anticholinergic
    MOA: blocks acetylcholine

    Ipatropium bromide --> generic, 0.03%, 2 sprays each nostril BID-TID

    Only relieves rhinorrhea

    Adverse effects: HA, nasal dryness, epistaxis
  58. Intranasal Cromolyn (Nasalcrom)
    MOA: Mast cell stabilizer --> prevents inflammatory mediator release (prophylaxis) 

    Dose: 1 spray in each nostril 4 times/day, may need to use w/ decongestants antihistamines 

    Max benefit in 2-4 weeks for preventing and treating allergic rhinitis

    Adverse effects: Local irritation, sneezing, stinging. 

    Drug interactions: none known
  59. Intranasal Corticosteroids
    MOA: anti-inflammatory actions on cells and mediators involved with inflammation --> relieve sneezing, rhinorrhea, pruritis, and nasal congestion

    Beclomethasone (beconase), budesonide (Rhinocort), flunisolide (Nasalide, generic), fluticasone (Flonase; generic), mometasone (Nasonex), triamcinlone (Nasacort) 

    most effective drugs of allergic rhinitis - drugs of choice

    Maximum benefit in 7 days

    Adverse effects: sneezing, stingin with administration, headache, epistaxis
  60. Nucleoside Analogs (Tx of what virus, mech of action? Which drugs?)
    • Tx of Herpes, also tx for CMV
    • Herpes require endog nucleosides
    • -------------------------------------------
    • Herpes Tx:
    • Acyclovir
    • Valacyclovir
    • Famciclovir
    • Penciclovir

    • CMV Tx:
    • Ganciclovir
    • Valganciclovir
    • -----------------------------------------
    • Nucleoside analogs compete with endogenous nucleosides for viral DNA polymerase, causing DNA chain termination
  61. Acyclovir
    • Analog of 2-deoxyguanosine
    • Inhibits viral DNA synthesis - competes as a substrate of viral DNA polymerase
    • For Herpes-simplex and varicella-zoster
    • ------------------------------------
    • Oral, IV, topical dosage forms
    • Poor oral availability (10-20%) and short half-life (2-3 hrs) - freq oral doses per day necessary
    • ---------------------------------------
    • Renal elimination - reduce dose in renal failure
    • -----------------------------------------
    • Adverse rxns:
    • Oral - GI Upset, headache
    • Renal neuropathy due to crystallization in tubules - poorly soluble in urine, adequate hydration important
    • -----------------------------------------
    • Pregnancy category B - SAFE
  62. Valacyclovir (Valtrex, generic)
    • Oral PRODRUG converted to acyclovir (Analog of 2-deoxyguanosineInhibits viral DNA synthesis - competes as a substrate of viral DNA polymerase)
    • Mostly same properties as acyclovir
    • Better bioavailability (50%) than acyclovir

    Requires less freq dosing per day

    Preg category B - safe
  63. Famciclovir
    • Nucleoside analog for HSV and VZV
    • Oral prodrug metabolized to penciclovir
    • Good absorption (80%), long intracellular half-life (7-20 hrs)
    • Renal elimination
    • Adverse rxns: headache, nausea, diarrhea
    • Preg category B
  64. Penciclovir
    Structurally similar to ganciclovir

    • Not absorbed orally
    • Cream formulation for herpes labialis
  65. HSV and VZV Nucleoside analog Tx

    Which drug to use? Topical?
    Acyclovir is available oral, IV, topical - BUT poor oral availability and short half life

    Valacyclovir - Better bioavailability than acyclovir

    Famciclovir - oral prodrug, metabolized to penciclovir

    Penciclovir - ONLY AVAILABLE AS TOPICAL for herpes labialis
  66. HSV Genital Infections
    Differing doses dependent on whether it is initial, recurrent, or chronic episodic tx.
  67. VZV (Shingles) Patients - Immunocompetent Patients Tx
    Doses of nucleoside analogs higher than for herpes simplex infection

    • Start within 72 hours
    • Acyclovir 800mg 5xd for 7-10 days
    • Use 10 mg/kg q8h for 7 days if patient is immunocompromised
    • Valacyclovir 1000mg tid for 7 days
    • Famciclovir 500mg tid for 7 days
  68. Ganciclovir
    • TX for Cytomegalovirus Infections
    • Mech of action and metab similar to acyclovir
    • Analog of nucleoside guanosine
    • ---------------------------------------
    • Converted intracellularly to GCV 5' - monophosphate by a viral kinase (encoded by CMV gene UL97)
    • Resistance occurs due to UL97 mutations
    • --------------------------------------------
    • Converted to GCV triphosphate by cellular kinases
    • ---------------------------------------------
    • Active against CMV, an opportunisitic infection after organ transplant or HIV infection (30% develop CMV retinitis that can lead to blindness)
    • --------------------------------------------
    • Primarily given IV, oral form replaced by valganciclovir
    • -------------------------------------------
    • Adverse rxns:
    • Bone marrow suppression (50%)
    • Renal neuropathy
    • Fever
    • Headache
    • Preg category C
  69. Valgancyclovir (Valcyte)
    • Prodrug of ganciclovir
    • Has largely replaced oral ganciclovir
    • Achieves plasma concentrations similar to IV ganciclovir

    Dose 900mg BID x 21 days followed by 900mg QD
  70. Foscarnet
    • Pyrophosphate analog, reversibly binds viral DNA polymerase
    • Not affected by UL97 (resistance gene) phosphotransferase mutations
    • Alternative tx for CMV, HSV, VZV
    • ----------------------------------------
    • IV only - poor oral bioavailability
    • ----------------------------------------
    • Renal clearance directly proportional to creatinine clearance
    • ----------------------------------------
    • Adverse:
    • Renal tubular toxicity - crystallization (saline loading)
    • Seizures
    • Hypocalcemia - drug binds free calcium
    • Genital ulceration due to high levels of drug in urine
  71. Cidofovir
    • Monophosphate nucleotide analog of deoxycitidine (dCTP)
    • Does not req viral kinase for phosphorylation
    • Alternative for CMV infections in HIV patients unresponsive to ganciclovir or foscarnet
    • --------------------------------------
    • IV only - poor oral bioavailability
    • 80% excreted by renal filtration and tubular secretion
    • --------------------------------------
    • Must give probenacid (a uricosuric drug) and saline load before and after infuction to prevent renal rubular secretion and toxicity
    • --------------------------------------
    • Adverse effects:
    • Nephrotoxicity
    • Neutropenia
  72. Drugs for Hepatitis B Virus (HBV) Infections (Goal, Duration, First Line Drugs)
    • Goal: Sustain suppression, slow progression of hepatic complications. Current tx do not eradicate HBV
    • Duration of therapy: lifelong
    • First line drugs: oral nucleotide/nucleoside analogs that inhibit DNA polymerase and cause viral DNA chain termination
    • Tenofovir, Entecavir
  73. Tenofovir (Viread)
    • Nucleotide analog of adenosine 5-monophosphate
    • First line used against HBV infection
    • Also used against active HIV
    • Primarily GI adverse effects (diarrhea, pain, etc)
  74. Entecavir (Baraclude)
    • Nucleoside analog of guanosine
    • Generally well-tolerated
  75. HBV Second Line Drugs
    • Interferon alfa, Peginterferon alfa-2a
    • ---------------------------------------------------
    • >MOA:
    • Host cytokine with antiviral, immunomodulatory and antiproliferative actions
    • Inhibits HBV and HCV penetration, transcription maturation, and release
  76. Peginterferon alfa-2a
    Second line tx for HBV (and HCV)

    Pegylated preparation of interferon alfa to increase half-life and allow weekly dosing

    Given IM or SC

    • Adverse effects:
    • Flu-like symptoms very common
    • Bone marrow suppression
    • Psychiatric disturbances
  77. Drugs for Hepatitis C Infection (HCV) (Goal, Duration, First Line)
    • Goal: eradication of HCV (unlike HBV)
    • --------------------------------------------
    • Duration: 24 weeks for HCV genotypes 2&3, 48 weeks for genotype 1
    • --------------------------------------------
    • First line therapy: peginterferon alfa-2a or 2b plus oral ribavarin (can cause severe hemolytic anemia)

    • If HCV genotype 1 infection, add:
    • Teleprevir or Boceprevir

    These are two new oral very expensive protease inhibitors approved for HCV in 2011

    Same adverse effects and drug interactions as PIs used for HIV infection
  78. Neuraminidase Inhibitors
    Tx for influenza

    • Olseltamavir (Tamiflu) and zanamivir (Relenza)
    • Inhibit neuraminidase on viral cell surface and decrease release of virus from infected cells
    • ----------------------------------------------
    • Indicated for prophylaxis and tx of influenza A and B in adults and children
    • ----------------------------------------------
    • Prophylaxis 70-90% effective in preventing illness
    • Tx: can reduce duration of uncomplicated illness by almost 1 day if given within 36 hrs of onset
    • Have NOT been shown to prevent serious influenza related complications or mortality in high risk groups
  79. Oseltamivir (Tamiflu)
    • Indication: prophylaxis and tx of influenza A and B
    • Kinetics: prodrug metabolized to active drug and excreted renally
    • Adverse rxns: nausea, vomiting, headache (2006 new warnings about delirium in children)
    • Pregnancy category C
    • Not indicated for children <1 yr
    • Capsule or suspension
  80. Zanamivir (Relenza)
    • Indication: prophylaxis and tx of influenza A and B
    • Kinetics: inhaled, any absorbed drug excreted renally
    • Adverse: Black box Warning - bronchospasm possible if hx of asthma or COPD

    Precautions: Preg Category C

    • Age limitations: not indicated for children <5 years
    • Dry powder inhaler - difficult for elderly pts
    • Original date showed no difference in outcome from placebo
  81. Adamantadine
    • Originally used for Parkinson's
    • Was used for influenza A, is now resistant
    • Kinetics: 90% renally eliminated
    • Adverse rxns:
    • CNS effects common (13%)
    • Mild: anxiety, insomnia, difficulty concentrating
    • Severe: delirium, hallucinations, seizures

    • Drug Interctions:
    • CNS stimulants, antihistamines, anticholinergic drugs

    Precautions: elderly, renal failure, pregnancy

    Age limitations: none

    Also used as an adjunct agent for Parkinson's Disease
  82. Rimantadine (Flumadine)
    • Kinetics: 75% metab by liver
    • Adverse: CNS effects 6% and GI effects less frequent than amantadine
    • No significant drug interactions
    • Precautions: pregnancy, breast feeding
    • Age limitations: not indicated for tx in children <13 yrs
  83. CDC Guidelines for 2013-2014 Flu Season
    High level of influenza A resistance to amantadine and rimantadine - avoid use

    Influenza A: H1N1 and H3N2 strains

    • For prophylaxis: used Tamiflu or Relenza
    • For all who live or work in insitutions caring for people at high risk for complications
    • For all persons at high risk of serious complications if likely to be exposed to others

    • For TX: use Tamiflu preferentially
    • For any person with potentially life-threatening influenza related illness
    • For any person at high risk for serious complications if within 2 days of illness onset
    • Tx for 5 days
  84. GERD
    • Reflux of gastric contents into esophagus
    • Classified as symptoms with or without erosions
    • Not assoc w increased acid production
    • Inflammation and complications directly related to exposure time to gastric acid
  85. GERD - Stages
    • 1. Heartburn
    • 2. Reflux esophagitis
    • 3. Erosive esophagitis
    • 4. Complications: laryngitis, asthma, esophageal stricture, Barrett's esophagus

    Many cases secondary to transient lower esophageal sphincter (LES) relaxation

    • Also caused by increased intra-abdominal pressure
    • Weight gain, pregnancy, carobinared beverages, large meal size, straining, lifting
  86. GERD Management
    • Weight Loss
    • Head of bed elevation
    • Avoidance of meals 2-3 hrs before bed
    • Use antacids or H2 receptor antagonists if mild, non-erosive
    • If erosive - start 8 week PPI
    • PPI 30-60 mins before first meal QD
    • If partial response - double dose or switch to another PPI
  87. Peptic Ulcer Disease (PUD)
    • .5 million cases/year
    • Annual direct/indirect costs >$10 billion
    • Mucosal damage secondary to pepson/gastric acid secretion
    • Stomach/prox duodenum
    • Symptoms: episodic epigastric pain 2-5 hrs/post meal or on empty stomach
    • Complications: bleeding, obstruction, perforation
  88. Etiology of PUD
    • Helicobacter pylori
    • NSAID-induced
    • Stress-related
    • Hypersecretory conditions (zollinger-ellison)
    • Miscellaneous (cigarette, chronic illness)
  89. PUD - Non-pharma tx
    • Stop Smoking
    • Avoid alcohol
    • Avoid NSAIDs or aspirin
    • Avoid irritating foods
  90. PUD - Pharma Options
    • Eradication of H.pylori if present
    • Antacids
    • Histamine H2 receptor antagonists
    • PPI
    • Sucralfate
    • Bismuth subsalicylate
    • Prokinetic agents
    • Misoprostol
  91. Detection of H. pylori - test
    • Endoscopic:
    • Histology - Gold Standard, 95% sensitivity and specificity
    • Culture - resistance
    • Biopsy urease - 90% sensitivity and specificity

    • Non-Endoscopic:
    • Antibody detection
    • UREA BREATH TEST - 95% sensitive and specific
    • Fecal antigen test
  92. Tx of H. pylori
    Triple combo x 14 days: Two antibiotics (clarithromycin + amoxicillin/metronidazole) + PPI

    Quadruple combination x 14 days: Two antibiotics (tetracycline + metronidazole) + PPI + Bismuth subsalicylate

    • Sequential combination: Amoxicillin plus PPI 5 days, followed by Clarithromycin plus tinidazole x 5 days
    • ------------------------------------
    • Efficacy increases is two antibiotics used + PPI
    • Eradication rates lower with triple than w quad or sequential

    • Increasing resistance to clarithro and metronidazole
    • Shortage of clarithro and tetracycline

    Combination products improve compliance and overcome shortages but expensive
  93. Antacids
    • Quickly neutralize acid, provide symptomatic relief of dyspepsia or GERD
    • Do not heal erosions
    • Effect only lasts a few hours since they do not affect production of acid
    • Sodium bicarb - systemically absorbed, but sodium overload, metabolic alkalosis possible
    • Calcium carbonate - constipation, acid rebound, hypercalcemia - milk-alkali syndrome - headache, nausea, calcium stones
    • Aluminum hydroxide (AIOH)- very little absorption, constipation, phosphate binding, aluminum absorption
    • Magnesium hydroxide (MOM)- Very little absorption, diarrhea, magnesium accumulation in renal disease

    Usually use AIOH and MOM in combination to balance diarrhea and constipation (mylanta, maalox)
  94. Histamine H2 Receptor Antagonists
    • Dose-dependent inhibition of gastric acid secretion by blocking H2 receptors on parietal cells
    • Primarily inhibit basal (fasting) HCl production and some meal-stimulated acid
    • Slower onset, longer duration than antacids
    • Differ in onset, duration, incidence of drug interactions
    • Give low doses for heartbuen, higher doses for GERD, PUD
    • ------------------------------------
    • Adverse Effects:
    • High doses may cause confusion, delirium, headache, lethargy in elderly
    • Tolerance can occur with repeated use
    • Rebound acid hypersecretion can occur after abrupt discontinuation
    • -------------------------------------
    • Interactions:
    • Cimetidine is a moderate to strong inhibitor of CYP 2C9, 2D6, 3A4 - NO NEED FOR THIS DRUG - DO NOT PRESCRIBE
    • Should avoid Cimetidine in elderly and those on multiple drugs
    • Preg Cat B
  95. Histamine H2 Receptor Antagonists
    Cimetidine: First Agent, shortest duration, high potential for drug interactions - OTC 200 mg

    Ranitidine - Intermed duration, usually given BID - OTC 75 and 150mg

    Famotidine - Longest duration, BID or once @ bedtime - OTC 10 and 20 mg dose
  96. H2 Receptor Antagonists - which to use
    Preferentially use Famotidine, then Ranitidine - avoid Cimetidine
  97. Proton Pump Inhibitors (PPIs)
    • Bind irreversibly to H/K ATPase enzyme in parietal cells, blocking final step in HCl secretion
    • More complete acid suppression than H2 antagonists
    • Relieve symptoms, heal ulcers more quickly than H2 antagonists, although absolute healing rates are comparable
    • Equally efficacious for GERD and PUD
    • ----------------------------------------
    • Pharmacokinetics:
    • Inactive prodrugs, unstable in gastric acid
    • Enteric coated granules/tablets
    • Delayed onset
    • Short T1/2
    • Concentrated in parietal cell by pH trapping and converted to prodrug
    • Irreversible inhibitor of proton pump for >24 hrs
    • Given once faily 30-60 mins before first meal
    • -------------------------------------
    • Short term adverse:
    • Minor but may include headache, constipation, diarrhea, abdominal pain
    • -----------------------------------
    • Drug Interactions:
    • Inhibition of CYP 2C19 by omeprazole and esomeprazole
    • Clopidogrel - decreased antiplatelet effect but overall cardiovascular outcome still controversial
    • Increase in phenytoin plasma levels
    • Bisphosphonates - loss of efficacy in prevention and tx of osteoporosis
    • Decrease in gastric acid can reduce absorption of itraconazole and protease inhibitors
    • --------------------------------------
    • Long Term Effects:
    • Fractures, C. dificile infections, community acquired pneumonia, Vit B12 deficiency, hypomagnesia
    • Abrupt discontinuation after 3 months causes hyper gastric acid secretion - MUST TAPER
  98. Omeprazole
    • PPI - Prototype
    • Generic, OTC
    • Rx 40mg, OTC 20mg
  99. Omeprazole + sodium bicarb (Zegerid)
    • PPI
    • Immediate release powder, 460mg Na and 4gm glucose/dose
    • Rx and OTC
  100. Esomeprazole (Nexium)
    • PPI - S-isomer of omeprazole
    • 25 mg omeprazole = 20mg esomeprazole
    • Rx only, 20 or 40mg
    • also available IV
  101. Lansoprazole (Prevacid)
    • PPI
    • Absorption decreased 40% by food
    • Also liquid formulation (NG tube)
    • Generic, OTC available
  102. Dexlansoprazole (Kapidex)
    • PPI
    • R-isomer of Prevacid
  103. Pantoprazole (Protonix)
    • PPI
    • Also available IV
    • Preferred PPI in hospitals
    • Oral generic
  104. Rabeprazole (Aciphex)
  105. PPI Dosing
    High variation in dosing depending on drug used
  106. Stress Ulcer Prophylaxis
    For hospital inpatients at risk for stress-related mucosal injury and subsequent bleeding

    Risk factors: mechanical ventilation, coagulopathy, burns >35%, multiple trauma, hx of GI ulceration

    • PPIs usually used IV or oral
    • Also can use H2 antagonists IV or sucralfate

    Overuse: up to 2/3 of inpatients have been reported to receive PPIs or H2 antagonists, with many being continued on the agents post-discharge
  107. Sucralfate
    • Aluminum hydroxide complex of sucrose
    • At low pH of gastric contents, binds to damaged and ulcerated tissue forming physical barrier to prevent further injury
    • Ineffective if gastric pH raised by H2 blockers or PPIs
    • Similar in efficacy to H2 antagonists in healing of ulcers
    • Not systemically absorbed
    • May cause constipation

    • Dose 4x/day, separated from meals
    • Can bind to other drugs, prevent their absorption
    • Used more for patients with ulcers
  108. Bismuth subsalicylate
    • Active ingredient of Pepto
    • At pH <3.5, reacts w HCl to form bismuth oxychloride (not absorbed) AND salicylic acid (absorbed)
    • Can cause salicylate poisoning similar to aspirin

    Inhibits pepsin, antimicrobial acitivy against H. pylori

    Forms bismuth sulfide which turns tongue and stool temporarily black
  109. Prokinetic Agents
    • Increase gastric emptying, increase LES pressure
    • Have been used to treat GERD
    • Primary tx for diabetic gastroparesis
  110. Metoclopramide (Reglan)
    • Prokinetic agents
    • Given 4x/day before meals
    • Dose related adverse effects: extrapyramidal reactions (dopamine antagonists), drowsiness, diarrhea, abdominal cramps
    • Must reduce dose in renal failure
  111. Cisapride (Propulsid)
    • Prokinetic agent
    • Now only available on a compassionate use basis per protocol
    • Inhibition of metabolism by CYP 3A4 inhibitors resulted in deaths from proarrhythmias of QT interval and development of arrhythmias
  112. NSAID induced gastritis, peptic ulcers
    • COX-1 enzyme helps maintain homeostasis and mucosal integrity (PGs protect mucosal layer)
    • Gastritis occurs secondary to COX-1 inhibition by NSAIDs
    • Risk Factors: >65 y/o, hx of ulcer, steroid use, high NSAID dose, multiple NSAIDs, H. pylori inf, smoking, alcohol
    • Drugs to avoid: warfarin, bisphosphonates, steroids
  113. TX options for NSAID induced gastric ulcers
    • Discontinue NSAID
    • Lower NSAID dose
    • Add PPI
    • Change to COX-2 inhibitor
    • Add misoprostol
    • If used for osteoarthritis:
    •      Switch too acetaminophen
    •      Topical NSAIDs
    •      Exercise
    •      Glucosamine/chondroitin
  114. Misoprostol (cytotec)
    • PG analog
    • Can prevent ulcers in patients on chronic NSAIDs
    • Must give 3-4x/day
    • Athrotec = Diclofenac + misoprostol
    • Poorly tolerated (abdominal pain and dose-related diarrhea)
    • Pregnancy category X - abortifacient
    • PPIs, when added to NSAID therapy, just as effective in healing or preventing ulcer as misoprostol + NSAID or COX-2 inhibitor alone
  115. Neuropharmacology of Emesis
    • Dopamine D2 receptors:
    • Chemoreceptor trigger zone (CTZ) - mediates emesis caused by blood borne drugs and toxins - also in GI tract

    • Serotonin (5-HT3) receptors
    • Primarily in GI tract, chemotherapy-induced N&V thought to be caused by release of serotonin from enterochromaffin cells in upper GI tract

    • Cholinergic Receptors:
    • Increased stimulation at level of CTZ and vomiting center (VC) during motion sickness

    • Neurokinin-1 receptor:
    • Stimulated by Substance P in the brain when exposed to such emetics as chemo, radiation, morphine, nicotine
  116. Principles of Drug TX of Emesis
    • Nausea and vomiting common symptoms of many drugs/disorders
    • Determine potential causes of N&V
    • Usually no therapy req for viral inf or excessive food/alcohol intake
    • If mild-moderate N&V <48 hrs, monitor hydration status:OTC antiemitics useful, Oral rehydration solution for excessive fluid/electrolyte loss
    • Spefici therapies for motion sickness, post-op N&V, or N&V from chemo/radiation
  117. OTC for N&V
    • Antacids
    • H2- antagonists such as ranitidine (Zantac)

    • Anticholinergic/antihistamines (H1):
    • Dimenhydrinate (Dramamine)
    • Meclizine (Dramamine less drowsy)

    • Phosphorated carb solution:
    • Hyperosmolar sugars with phosphoric acid
    • Reduce sm musc contraction
    • Emetrol, Nausetrol

  118. OTC for N&V - Product selection guidelines
    • Simple, uncomplicated N&V (oral):
    • Nausea from overeating/disagreeable foods: antacids, H2 antagonists, Pepto

    Motion Sickness: 1st gen antihistamines (expect drowsiness/anticholinergic effects)

    Food poisoning: oral rehydration
  119. N&V in Pregnancy
    • Avoid foods w strong odors, eat smaller, more freq meals
    • Doxylamine (antihistamine) 12.5-25mg plus pyridoxine (B6) up to 3x/day
    • Drug combo of choice - but is just Unisom + B6 (which is a much cheaper combo)

    Combination used to be Bendectin, but taken off the market for unfounded fear of birth defects

    Diclegis - new drug just approved, very expensive
  120. Dopamine D2 Receptor Antagonists: Phenothiazines
    • Prochlorperazine (compazine)
    • Promethazine (Phenergan) - also a potent antihistamine

    Block dopamine D2 receptors at CTZ level of brain

    Commonly used for post-op nausea, vomiting - less efficacious than serotonin antagonists

    • Positives: available oral, rectal, parenteral dosages
    • Negatives: hypotension, sedation, extrapyramidal rxns such as acute dystonias
  121. Metoclopramide
    • D2 Receptor Antagonist
    • Blocks D2 recptors at CTZ level
    • Blocks serotonin receptors at GI level in higher doses
    • Positives:
    • Prokinetic effect on GI tract
    • PO, IV
    • Negatives:
    • Extrapyramidal rxns, diarrhea, sedation, dizziness
    • Reduce dose if renal dysfunction
  122. Droperidol (Inapsine)
    D2 receptor antagonist (used as anti-emetic)

    • Butyrophenone  - structurally related to haloperidol (Haldol)
    • Recent black box warning concerning QT interval prolongation, Torsades
    • Need EKG
    • Less like to cause hypotension than phenothiazines
    • Only available for IV/IM admin
  123. Serotonin (5-HT3) Antagonists
    Ondansetron (generic, Zofran) most common

    Granisetron (Kytril) and Dolasetron (Anzemet) - T1/2 4-8hrs

    Palonosetron (Aloxi) - T1/2 40 hrs, only IV

    Dose and combincation with other drugs depends on emetic potential of chemotherapeutic drugs

    • Positives: Oral, IV
    • Very effective for prophylaxis of chemo induced vomiting or PONV (post-op N&V)
    • NO extrapyramidal reactions

    Negatives: high cost for brands - generics considerably cheaper
  124. Scopolamine
    • Anticholinergic Transdermal patch
    • Place behind ear at least 6 hrs before event
    • Lasts 3 days - for prolonged exposure to motion
  125. Trimethobenazmine - Tigan
    • Minimally effect, high list of major effects
  126. Lorazepam

    Anticipatory N&V before chemo
  127. Synthetic Cannabinoids
    Similar to THC, Dronabil, Nabilone - for chemo induced vomiting, but less effective than other agents

    Orthostatic hypotension, psychotomimetic rxns, high abuse potential
  128. Dexamethosone
    • Glucocorticoid
    • Enhances antiemetic activity of 5-HT3 antagonists, metoclopramide
  129. Neurokinin-1 Receptor Antagonists
    • Aprepitant (Emend)
    • Dosaprepitant (Emend for injection)

    • Newest class of antiemetics
    • Used in combination with a serotonin antagonist and dexametasone for highly emetogenic chemotherapy

    Metabolized by and moderate inhibitor of CYP 3A4

    Dose: 125mg on day 1 followed by 80mg on days 2&3

    Cost: $250 for 3 oral doses, $175 for 115mg injection
  130. Chemotherapy Induced Nausea/Vomiting
    More likely in females, younger patients, those with a high pretreatment expectation of severe nausea

    • Two Stages:
    • Acute - 1-2 hrs after chemo, subsiding 18-24hrs

    Delayed: recurs 48-72 hrs post-chemo

    Treatment objectives: prevent both acute and delayed nausea and vomiting secondary to chemo w moderate or high risk potential
  131. Recommended Antiemetic Tx before and after chemo
    Low Risk: Dexamethosone before, nothing after

    • Moderate Risk:
    • Before - 5-HT3 antagonist + dexamethosone +/- aprepitant
    • After - 5-HT3 antagonish or dexamethosone or aprepitant on days 2&3

    • High Risk:
    • Before - 5-HT3 antagonist + dexamethosone + aprepitant
    • After - Dexamethosone on days 2+4 AND aprepitant on days 2&3
  132. Ulcerative Colitis: Drugs for induction of remission
    • Aminosalicylates
    • Glucocorticoids
  133. Ulcerative Colitis: drugs for maintenance tx
    • Aminosalycilates
    • Thiopurines
  134. Ulcerative Colitis: Drugs for refractory tx
    • Cyclosporine
    • Infliximab
  135. Sulfasalzine (Azulfidine)
    • = aminosalicylate
    • prototype agent
    • = sulfapyridine + 5-aminosalicylic acid (5-ASA or mesalamine)
    • cleaved by colonic bacteria to deliver mesalamine (active) to site of action
    • -------------------------------------------------
    • MOA:
    • blocks arachidonic acid metabolism (responsible for formation of proinflammatory cytokines)
    • -------------------------------------------------
    • ADE (45%) secondary to sulfapyridine:
    •      N/V, diarrhea, arthralgias, HA
    •      Severe: hepatotoxicity, BM supression
    • Hypersensitivity: avoid is sulfa allergy (sulfa allergy) or aspirin allergy (b/c of salycilate component)
    • -------------------------------------------------
  136. Mesalamine-containing drugs (only no sulfa component)
    • Mesalamine (5-ASA)
    • Delayed release:
    •      Asacol
    •      Pentasa
    •      Lialda & Apriso
    • Rectal
    •      Rowasa (suppository/enema)
  137. Mesalamine (5-ASA)
    • = Mesalamine-containing drugs (no sulfa component)
    • active component of sulfasalazine
    • avoids sulfapyridine component
    • different dosage forms differ in delivery site
  138. Asacol
    • = Mesalamine-containing drug (no sulfa component)
    • delayed release form
    • tablet coated w/ delayed-release acrylic resin that dissolves at pH of 7.0 - for proximal colon & terminal ileum
  139. Pentasa
    • = Mesalamine-containing drug (no sulfa component)
    • delayed release form
    • capsule caoted w/ ethylcellulose
    • for colon, ileum, & jejunum
  140. Lialda
    • = Mesalamine-containing drug (no sulfa component)
    • delayed release form
    • for distal ileum & colon
  141. Apriso
    • = Mesalamine-containing drug (no sulfa component)
    • delayed release form
    • for distal ileum & colon
  142. Rowasa
    • = Mesalamine-containing drug (no sulfa component)
    • forms:
    •      suppository - for rectum
    •      enema - for rectum & distal colon
  143. Mesalamine prodrugs
    • Olsalazine (Dipentum)
    •      has 2 mesalamine molecules linked by azo bond designed to deliver drug to colon
    • Balsalazide (Colazal)
    •      mesalamine attached to inactivate molecule that is cleaved by bacteria in colon
    • Avoid is aspirin allergy (as w/ sulfasalazine)
  144. Corticosteroids for Ulcerative Colitis
    • for acute tx of moderate to severe dz
    • oral prednisone for mild to moderate dz if aminosalicylates ineffective
    • IV methylprednisolone if severe acute dz
    • Hydrocortisone rectal tx
    •      enema - reaches splenic flexure
    •      rectal foam - last 20 cm of colon
    • After acute inflammation under control, usually tapered & discontinued to prevent long term adverse rxn (short term use)
  145. Thiopurines
    • for ulcerative colitis
    • immunomodulatory agents that inhibit purine synthesis & induce apoptosis in T cells
    • Azathioprine (Immuran)
    •     for maintaining remission
    •     effect often delayed by several wks or mos
    •     steroid sparing, allows reduction or discontinuation of steroids
    • 6-Mercaptopurine (6-MP)
    •      active metabolite of azathioprine
    •      ADE: myelosupression, neutropenia
    •      denetic polymorphism of TPMT enzyme that metabolites 6-MP (low enzyme levels)
    • Low TPMT enzyme levels associated w/ higher toxicity - genotypig recommended
  146. Cyclosporine for ulcerative colitis
    • Used for fulminant UC refractory to other agents
    • Last resort before surgery
    • Calcineurin inhibitor often used in organ transplantation
    • Inhibits T-cell signal transduction
    • Given by continuous intravenous infusion
    • Narrow TI drug – need to monitor serum levels
    • Metabolized by CYP3A4: drug interactions
    • High incidence of ADRs: nephrotoxicity, neurotoxicity, and hypertension
  147. Infliximab (Remicade)--for UC
    • = tumor necrosis factor (TNF-α) inhibitor
    • Human/murine chimeric monoclonal antibody that binds to membrane-bound and soluble TNF-α
    • Given as an IV infusion at 0, 2, and 6 weeks, and then every 8 weeks thereafter
    • Recently approved for moderate to severe UC unresponsive to conventional therapies
    •      Up to 70% response
    • also used for severe Crohn's disease
    • $$$
    • --------------------------------------------------
    • Adverse effects:
    •      Increased risk of serious infections including reactivated and disseminated tuberculosis
    •      Must get PPD and chest x-ray before therapy
    •      Increased risk of hepatitis B reactivation
    •      Also increased risk of lymphoma and leukemia
  148. Crohn's Dz: Drug Tx
    • Same medications as for ulcerative colitis, plus:
    • Budesonide (Entocort EC)
    •      Only 10% absorbed – less systemic effects than prednisone
    •      Reaches ileum and ascending colon
    • Methotrexate 25mg weekly
    •      Folate antagonist, reduces interleukin production
    •      Adverse effects: stomatitis, neutropenia, hepatotoxicity
    •      Pregnancy category X
    • Metronidazole and/or ciprofloxacin for perianal disease
    • Tumor Necrosis Factor (TNF-alpha) Inhibitors:
    •      For severe disease not responding to steroids
    •      81% response rate vs 17% for placebo
  149. Tumor Necrosis Factors (TNF-alpha) Inhibitors
    • Infliximab (Remicade)
    •      –IV infusion, same dose as for UC
    • Adalimumab (Humira) –can give SC at home every 2 weeks
    • Certolizumab (Cimzia) – can give SC at home every 4 weeks rather than every 2 weeks
    • All carry the same risk for serious infections as well as lymphoma and leukemia
    • All very expensive
    • --------------------------------------------------
    • used for severe chron's disease that isn't responding to steroids
    • also used of moderate - severe UC unresponsive to conventional tx
  150. Tx for IBS (general categories)
    • Diet
    •      Reduce food triggers such as raw fruit and vegetables, high fat foods, caffeine, fructose, and sorbitol
    • If constipation-predominant IBS (IBS-C)
    •      Fiber
    •      Laxatives
    •      Chloride channel activators
    • If diarrhea-predominant IBS (IBS-D)
    •      Antidiarrheal agents
    •      Antispasmodics
    •      Tricyclic antidepressants
    •      Rifaximin
    •      Alosetron
  151. Constipation Tx
    • Non-pharmacologic
    •      Fiber (soluble better than insoluble for IBS)
    •      Hydration
    •      Exercise
    • Laxatives
    •      Bulking Agents
    •      Emollient
    •      Saline
    •      Hyperosmotics & lavage
    •      Stimulants
    • Herbals
    • Chloride channel activators
  152. Laxatives (general types)
    • Bulking-soluble fiber
    • stool softener - emollient
    • Osmotic laxatives
    • stimulant laxatives
    • Herbal laxatives
  153. Bulking Laxatives
    • = soluble fiber (must be soluble)
    • Initial choice - simulate natural mechanism
    • Polycarbophil (Fibercon), psyllium (Metamucil), methylcellulose (Citrucel)
    • Hydrophilic colloids - swell with water
    • Caution: esophageal obstruction, fecal impaction
  154. Stool softener laxatives
    • = emollient
    • Docusate (Colace)
    • Anionic surfactant  (= soap) - softens fecal mass by facilitating mix of aqueous and fatty substances
    • Only for prophylaxis (ie w/  opiate use)
    • Avoid with mineral oil: gets absorbed
  155. Osmotic Laxatives
    • Saline osmotic
    • Poorly absorbed ions: Magnesium (Milk of Magnesia/MOM), phosphate (Fleet’s Phospho-Soda)
    • Osmotically pull water into gut
    • For acute evacuation
    • May cause fluid and electrolyte imbalance
    • -------------------------------------------------
    • Other osmotic
    • Glycerin suppository: combined osmotic and local irritant
    • Lactulose, sorbitol
    •      –Nonabsorbable sugars
    •      –Lactulose more expensive
    • Polyethylene glycol
    •      –Golytely (liquid with electrolytes) - preserve electrolytes
    •      –Miralax (powder, no electrolytes)
  156. Stimulant Laxatives
    • Irritant effect, induce peristalsis
    •      Effects are dose related
    • Anthraquinones (colon)
    •      Senna (Senokot, Ex-Lax)
    •      Drug of choice for constipation from opioids
    • Bisacodyl (Dulcolax) – oral or suppository
    • Castor oil (small intestine)-use not recommended
    • Safety: cramping, electrolyte imbalance
  157. Herbal Laxatives
    • Aloe
    • Chicory
    • Dandelion
    • Feverfew
    • Licorice
    • Rose hips
  158. Laxatives Classified by onset of effect
    • Cause feces softening in 1-3 days
    •      Bulk agents
    •      Docusate
    •      Lactulose
    •      Sorbitol
    • Cause softening in 6-12 hours
    •      Bisacodyl
    •      Senna
    •      Magnesium hydroxide (low dose MOM)
    • Cause watery evacuation in 1-6 hours
    •      Magnesium sulfate
    •      Sodium phosphate
    •      Bisacodyl (rectal)
    •      Polyethylene glycol/electrolytes
  159. Laxatives for the following indications:
    1. prophylaxis
    2. low residue diet
    3. elderly
    4. pregnancy
    5. procedures
    6. opiates
    • 1. Prophylaxis - emollient
    • 2. Low residue diet - bulk
    • 3. Elderly - bulk
    • 4. Pregnancy - bulk or emollient
    • 5. Procedures - stimulant or osmotic
    • 6. Opiates – stimulant
  160. Laxatives to avoid
    • Mineral oil
    •      Can get significant absorption (--> droplet is plasma)
    •      Affects absorption of drugs/ vitamins
    • Phenolphthalein
    •      Misbranded list
    •      Cancer and genetic damage in rats
    •      Stevens-Johnson syndrome
    • Cascara, casanthrol – taken off OTC market in 2005
  161. Chloride Channel Activators
    • New drugs:
    • Drugs:
    •      Lubiprostone (Amitiza)
    •      Linaclotide (Linzess) approved August, 2012
    • -----------------------------------------------
    • Increase intraluminal fluid and subsequent bowel movements by increasing secretion of chloride and bicarbonate ions 
    • Indicated for IBS-C and ideopathic constipation
    • Adverse effects: nausea, diarrhea, headache
    • Linzess: Black Box Warning against use in patients < 18 years old (deaths in young
    • mice)
    •      already blackbox warning
    • Cost: $$
  162. Common Drugs Causing constipation
    • Anti-cholinergics
    • Tricyclic antidepressants
    • Antipsychotics
    • Calcium-channel blockers (verapamil & diltiazem)
    • Diuretics
    • Antacids and supplements containing Al, Ca, or Fe
    • Opiates
  163. Tx of diarrhea (general)
    • Antidiarrheal compounds for symptomatic relief
    • Antispasmotic agents
    • Tricyclic antidepressants for IBS-D
    • Rifaximin
    • Probiotics for altered intestinal microbial flora
    • Alosetron (5-HT3 antagonist) for IBS-D
    • Fluid and electrolyte replacement for dehydration
  164. Loperamide (Imodium AD and others)
    • = Rx Antidiarrheal agents
    • = Weak opioid derivative
    • >Loperamide (Imodium AD and others)
    •      –4mg x 1, then 2mg after each loose stool up to 8 tablets/day
    •      –Most common and effective OTC agent
    •      –Minimal CNS effects
  165. > Diphenoxylate w/ atropine (Lomotil)
    • = Rx Antidiarrheal agents
    • = Weak opioid derivative
    • C-V controlled substance requires prescription
    • No more effective than loperamide andmore adverse effects secondary to atropine
    •      atropine added to can't take too much
  166. OTC drugs for diarrhea
    • Loperamide (Imodium AD & others)
    • Adsorbent drugs
    •      Kaolin and pectin (only generic)
    •      Attapulgite (Donnagel)
    • Bismuth subsalicylate (Pepto-Bismol, Kaopectate)
    •      Anti-secretory effect on intestinal lumen
    •      Localized anti-inflammatory action
    • Polycarbophil (Equalactin chew tabs)
    •      absorbs water
    • Lactase enzyme (for deficiency syndrome)
  167. Antispasmodics
    • for abdominal pain & diarrhea
    • -------------------------------------------------
    • Hyoscyamine (L-isomer of atropine)
    • Dicyclomine (Bentyl)
    • Chlordiazepoxide/clidinium (Librax)
    • Induce smooth muscle relaxation via anticholinergic effect
    • Typical anticholinergic adverse effects
  168. Tricyclic antidepressancy
    • for abdominal pain & diarrhea
    • ------------------------------------------------------
    • Amitriptyline (Elavil and others)
    • Relieve abdominal pain and diarrhea via strong anticholinergic effect
    • Treat concomitant depression
  169. Drugys for abdominal pain & diarrhea
    • Antispasmodics
    • Tricyclic antidepressants
  170. Rifazimin (Xifaxan)
    • Poorly absorbed oral antibiotic recently approved for hepatic encephalopathy and travelers’ diarrhea
    • Off-label use for IBS-D
    • Recent RDBPC trial in patients with IBS without constipation showed improvement in global symptoms for up to 3 months after 2 weeks of therapy (NNT = 10)
    • $$$
  171. Probiotics
    • Bacteria or yeast given to recolonize intestine with beneficial microbes
    • Prevent overgrowth of pathogenic bacteria as a result of antibiotic use or illness
    • Diarrhea can result from imbalance of beneficial and pathogenic microbes
    • Can prevent antibiotic-associated diarrhea
    • Most common are bifidobacteria and lactobacilli
    • Yogurt: Choose product with National Yogurt Association’s “Live and Active Cultures” seal on label (Dannon, Yoplait)
    • Available in capsules, tablets, powder, and specialty drinks
    • recent study showed significant improvement in IBS w/ probiotics
  172. Alosetron (Lotronex)
    • Serotonin (5-HT3) antagonist
    • Decreases intestinal motility and pain signals
    • Initially approved in early 2000 for diarrhea predominant IBS in females
    • Removed from market in late 2000 secondary to reports of ischemic colitis resulting in bowel resection
    • Reintroduced in 2002 with new restrictions:
    •      Black Box warning: Can only be prescribed by physicians enrolled in GSK Prescribing Program for Lotronex
    •      Mandatory drug guide, lower starting dose, program stickers on vials, and patient consent agreement
  173. oral Rehydration solutions
    • Glucose and sodium essential
    •      –Need glucose for active uptake of Na+
    •      –Ideal mix: low glucose and moderate Na+ (50 mEq/L)
    •      –Also potassium, chloride, citrate
    • Dose:
    •      –Mild dehydration: 50 ml/kg
    •      –Moderate dehydration: 100 ml/kg
    • --------------------------------------------------
    • Homemade Oral rehydration solution:
    • 1 Liter water
    • 4 tbs sugar
    • 1/2 tsp table salt
    • 1/2 tsp baking soda
    • 1/4 tsp lite salt (salt substitute with KCl)
    • -------------------------------------------------
    • Solutions to avoid:
    • Hyperosmolar (high sugar), low sodium
    •      Soft drinks, Gatorade, Jell-O, juices
    • Low sodium
    •      Tea
    • High sodium
    •      Chicken broth
  174. IV rehydration
    normal saline or lactated Ringer's solution
Card Set
Pharm Exam 4
Pharm exam 4