Pharm Exam 4

• (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)

• (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

• (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

• (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

• ACEI
• ARBs (angiotensin receptor blockers)
• B-blockers
• Aldosterone inhibitors
• Hydralazine-isosorbide (specific combo for AfAm)

• loop diuretics
• digoxin (he said: maybe last resort @ very end)
• nitrates

• 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

• 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)

• 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

• 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)

• 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

spironolactone

• 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

• 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)

• 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

• 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

• 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

• worsening HF
• hypotension
• bradycardia
• caution in pt w/ asthma, COPD, diabetes, heart block
•      metoprolol & bisoprolol = cardioselective
•      carvedilol is NOT cardioselective

• >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

• 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

• >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

• 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

• 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

• 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

• (fish oils)
• PUFA dec sudden death after MI
• dec mortality (NNT = 56)
• dec death/admission to hospital for CV cz (NNT = 44)

• >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

• >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)

1. Mineralocorticoids --> stimulate mineralocorticoid receptors (aldosterone, fludorcortisone) maintain sodium and potassium balance

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

3. Adrenal androgens --> DHEA

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

• 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

• 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

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

• 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

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

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

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

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

• Advair Diskus or MDI --> fluticasone and salmeterol, $330-420/device
• Symbicort MDI --> budesonide and formoterol, $290/device
• Dulera MDI --> Mometasone and formoterol, $280/device

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

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

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

• 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

Slides 42-52

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

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

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)

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)

inhaled bronchodilators, theophylline, and systemic steroids are effective. 

Consider addition of roflumilast

May need antibiotics for infections

For types of Allergic Rhinitis, pathophysiology, Signs, and Sx see slides 65-68

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

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)

Peripherally selective, less CNS penetration (non-sedating) 

Cetirizine (Zyrtec) OTC, Levocetirizine (Xyzal), Fexofendadine (Allegra) OTC, Loratadine (claritin) OTC, Deloratadine (Clarinex)

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

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

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

• 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

MOA: blocks acetylcholine

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

Only relieves rhinorrhea

Adverse effects: HA, nasal dryness, epistaxis

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

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

• 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

• 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

• 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

• 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

Structurally similar to ganciclovir

• Not absorbed orally
• ONLY AVAILABLE AS TOPICAL FORMULATION
• Cream formulation for herpes labialis

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

Differing doses dependent on whether it is initial, recurrent, or chronic episodic 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

• 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

• 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

• 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

• 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

• 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

• Nucleotide analog of adenosine 5-monophosphate
• First line used against HBV infection
• Also used against active HIV
• Primarily GI adverse effects (diarrhea, pain, etc)

• Nucleoside analog of guanosine
• Generally well-tolerated

• Interferon alfa, Peginterferon alfa-2a
• ---------------------------------------------------
• >MOA:
• Host cytokine with antiviral, immunomodulatory and antiproliferative actions
• Inhibits HBV and HCV penetration, transcription maturation, and release

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

• 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

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

• 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

• 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

• 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

• 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

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

• 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

• 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

• 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

• .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

• Helicobacter pylori
• NSAID-induced
• Stress-related
• Hypersecretory conditions (zollinger-ellison)
• Miscellaneous (cigarette, chronic illness)

• Stop Smoking
• Avoid alcohol
• Avoid NSAIDs or aspirin
• Avoid irritating foods

• Eradication of H.pylori if present
• Antacids
• Histamine H2 receptor antagonists
• PPI
• Sucralfate
• Bismuth subsalicylate
• Prokinetic agents
• Misoprostol

• 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

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

• 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)

• 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

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

Preferentially use Famotidine, then Ranitidine - avoid Cimetidine

• 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

• PPI - Prototype
• Generic, OTC
• Rx 40mg, OTC 20mg

• PPI
• Immediate release powder, 460mg Na and 4gm glucose/dose
• Rx and OTC

• PPI - S-isomer of omeprazole
• 25 mg omeprazole = 20mg esomeprazole
• Rx only, 20 or 40mg
• also available IV

• PPI
• Absorption decreased 40% by food
• Also liquid formulation (NG tube)
• Generic, OTC available

• PPI
• R-isomer of Prevacid

• PPI
• Also available IV
• Preferred PPI in hospitals
• Oral generic

PPI

High variation in dosing depending on drug used

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

• 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

• 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

• Increase gastric emptying, increase LES pressure
• Have been used to treat GERD
• Primary tx for diabetic gastroparesis

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

Pepto-bismol

• 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

• 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

• 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

• 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

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

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)
• MUST ADMIN BEFORE EXPOSURE TO CHEMO DRUGS
• NO extrapyramidal reactions

Negatives: high cost for brands - generics considerably cheaper

• Anticholinergic Transdermal patch
• Place behind ear at least 6 hrs before event
• Lasts 3 days - for prolonged exposure to motion

• SHOULD NOT BE USED
• Minimally effect, high list of major effects

Benzodiazepine

Anticipatory N&V before chemo

Similar to THC, Dronabil, Nabilone - for chemo induced vomiting, but less effective than other agents

Orthostatic hypotension, psychotomimetic rxns, high abuse potential

• Glucocorticoid
• Enhances antiemetic activity of 5-HT3 antagonists, metoclopramide

• Aprepitant (Emend)
• Dosaprepitant (Emend for injection)
• VERY EXPENSIVE

• 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

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

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

• Aminosalicylates
• Glucocorticoids

• Aminosalycilates
• Thiopurines

• Cyclosporine
• Infliximab

• = 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)
• -------------------------------------------------

• Mesalamine (5-ASA)
• Delayed release:
•      Asacol
•      Pentasa
•      Lialda & Apriso
• Rectal
•      Rowasa (suppository/enema)

• = Mesalamine-containing drugs (no sulfa component)
• active component of sulfasalazine
• avoids sulfapyridine component
• different dosage forms differ in delivery site

• = 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

• = Mesalamine-containing drug (no sulfa component)
• delayed release form
• capsule caoted w/ ethylcellulose
• for colon, ileum, & jejunum

• = Mesalamine-containing drug (no sulfa component)
• delayed release form
• for distal ileum & colon

• = Mesalamine-containing drug (no sulfa component)
• delayed release form
• for distal ileum & colon

• = Mesalamine-containing drug (no sulfa component)
• forms:
•      suppository - for rectum
•      enema - for rectum & distal colon

• 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)

• 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)

• 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

• 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

• = 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

• 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

• 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

• 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

• Non-pharmacologic
•      Fiber (soluble better than insoluble for IBS)
•      Hydration
•      Exercise
• Laxatives
•      Bulking Agents
•      Emollient
•      Saline
•      Hyperosmotics & lavage
•      Stimulants
• Herbals
• Chloride channel activators

• Bulking-soluble fiber
• stool softener - emollient
• Osmotic laxatives
• stimulant laxatives
• Herbal 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

• = 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

• 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)

• 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

• Aloe
• Chicory
• Dandelion
• Feverfew
• Licorice
• Rose hips

• 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

• 1. Prophylaxis - emollient
• 2. Low residue diet - bulk
• 3. Elderly - bulk
• 4. Pregnancy - bulk or emollient
• 5. Procedures - stimulant or osmotic
• 6. Opiates – stimulant

• 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

• 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: $$

• Anti-cholinergics
• Tricyclic antidepressants
• Antipsychotics
• Calcium-channel blockers (verapamil & diltiazem)
• Diuretics
• Antacids and supplements containing Al, Ca, or Fe
• Opiates

• 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

• = 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

• = 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

• 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)

• 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

• for abdominal pain & diarrhea
• ------------------------------------------------------
• Amitriptyline (Elavil and others)
• Relieve abdominal pain and diarrhea via strong anticholinergic effect
• Treat concomitant depression

• Antispasmodics
• Tricyclic antidepressants

• 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)
• $$$

• 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

• 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

• 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

normal saline or lactated Ringer's solution