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204 Cards in this Set

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What is heart failure?
-clinical syndrome characterized by abnormalities of left ventricular function and neurohormonal regulation, accompanied by effort intolerance, fluid retention, and reduced longevity
What causes chronic heart failure?
Systolic dysfunction
-impaired contractility
-reduced ejection fraction (<40%)
-can be w/ or w/o HF sx
o reduction in muscle mass
o dilated cardiomyopathies (idiopathic, hypertensive, toxic/drug, infectious)
o ventricular hypertrophy (inc resistence/ pressure overload or inc ventricular flow/ fluid overload)

Diastolic dysfunction
-impairment in ventricular relaxation
-LVEF>45-50%
-HF sx
o inc. ventricular stiffness
o ventricular hypertrophy
o myocardial ischemia or infarction
o infiltrative myocardial diseases (amyloidosis, sarcoidosis, and endometrial fibrosis)
o mitrial or tricuspid valve stenosis
o pericardial disease
Name the four compensatory responses to CHF
-increased preload
-vasoconstriction
-tachycardia and increased contractility (SNS activation)
-ventricular hypertrophy and remodeling
What are the beneficial effects of increased preload? What are the detrimental effects of increased preload?

What drugs increase preload?
-Beneficial: optimize stroke volume via Frank-Starling mechanism
-Detrimental: pulmonary/ systemic congestion and edema; increased MVO2

-Drugs: diuretics; possibly nitrates
What are the beneficial effects of vasoconstriction? What are the detrimental effects of vasoconstriction?

What drugs increase vasoconstriction?
-Beneficial: maintain BP in face of reduced CO and shunt blood from nonessential tissues to the heart
-Detrimental: increased MVO2; inc afterload-> dec SV + further activates compensatory responses

-Drugs: BB, ACEI/ ARBs
What are the beneficial effects of tachycardia and increased contractility? What are the detrimental effects of tachycardia and increased contractility?

What drugs induce tachycardia and increase contractility?
-Beneficial: maintain CO
-Detrimental: inc MVO2; shorten diastolic filling time; B-receptor downregulation and dec responsiveness; ventricular arrhythmias; inc risk of myocardial cell death

-Drugs: BB, ACEI/ ARBs
What are the beneficial effects of ventricular hypertrophy and remodeling? What are the detrimental effects of ventricular hypertrophy and remodeling?

What drugs cause ventricular hypertrophy and remodeling?
-Beneficial: maintian CO; reduce myocardial wall stress; dec MVO2
-Detrimental: diastolic and systolic dysfunction; risk of myocardial cell death and ischemia; risk of arrhythmias; fibrosis

-Drugs: aldosterone antagonists
What hormones affect CHF? (think about treatment and causes)
-norepinephrine
-angiotensin II
-aldosterone
-arginine vasopressin
-counterregulatory peptides (natriuretic peptides, bradykinin, nitric oxide)
-others
What factors precipitate CHF?
-lack of compliance
-uncontrolled hypertension
-cardiac arrhythmias
-environmental factors
-inadequate therapy
-pulmonary infection
-stress
What drugs precipitate CHF through the negative inotropic effect?
-antiarrhythmatics (disopyramide, flecainide,etc)
-BB (atenolol, metoprolol, propanolol, etc)
-CCB (verapamil, diltiazem,etc)
-Itraconazole
Which drugs precipitate CHF through a cardiotoxic effect?
-doxorubicin
-daunomycin
-cyclophosphamide
-trastuzumab
-blue cohosh
-imatinib
-ethanol
-amphetamines (cocaine, methamphetamines)
What drugs precipitate CHF through increased preload?
-glucocorticoids
-androgens/ estrogens
-NSAIDs and Cox-2 inhibitors
-rosuglitiazone and pioglitiazone
-sodium containing drugs (carbenicillin DiNa+; ticarcillin DiNa+)
-normal saline

All though Na+/ H2O retention
What are the s/sx of right ventricular failure?
Symptoms:
-abdominal pain
-anorexia
-nausea
-bloating
-constipation

Signs:
-peripheral edema
-jugular venous distention
-hepatojugular reflex
-hepatomegaly
-ascites
What are the s/sx or left ventricular failure?
Symptoms:
-dyspnea on exertion (DOE)
-orthopnea
-paroxysmal nocturnal dyspnea (PND)
-tachypnea
-cough
-hemoptysis

Signs:
-rales
-S3 gallop
-pulmonary edema
-pleural effusion
-Cheyne-Stokes respiration
What are the major s/sx or pulmonary congestion?
-exertional dyspnea (SOB w/ exercise)
-orthopnea (SOB when relaxed)
-paroxysmal nocturnal dyspnea (up at night coughing; feel like drowning)
-rales (crackling paper)
-pulmonary edema (wispy lines on CXR)
What are s/sx of systemic venous congestion? (RV failure)
-peripheral edema
-jugular venous distension (JVD): height of angle of sternum to pulsing jugular vein (>4-5 cm)
-hepatojugular reflex (HJR): push on liver abdomen and see fluid go up into jugular vein
-hepatomegaly: distended liver
-ascites: fluid in belly
Name some major non-specific findings of CHF.
-fatigue, weakness, and exercise intolerance
-nocturia
-cardiomegaly: cardiac silhouette more than 1/2 ribs length
What is completed for a laboratory and clinical assessment in CHF pts?
-s/sx
-ECG
-CXR
-LVEF
-hemodynamic evaluations
-CBC, serum electrolytes, BUN, CR, thyroid function tests
-B-type natriuretic peptide
Explain the four classes of the New York Heart Association Functional Classification (NYHA FC)
1) cardiac disease w/o limitations in physical activity
2)cardiac disease w/ slight limitations of physical activity with ordinary physical activity
3) cardiac disease w/ limitations of physical activity with less than ordinary physical activity
4) cardiac disease w/ inability to carry on any physical activity w/o discomfort
Which NYHA-FC classes have symptomatic disease?
Classes II-IV
Explain the four stages in the development of heart failure.
A) HF risk (cardiac diseases); however no structural or functional abnormalities of heart
B) structural heart disease w/o s/sx of HF
C) current or prior sx of HF associated with underlying structural heart disease
D) advanced structural heart disease and marked symptoms of HF at rest; req special interventions
Name the three goals of therapy

Which is most important for NYHA Class I-II?

Which is most important for NYHA Class IV?
Goals
1) slow disease progression and reverse cardiac and peripheral dysfunction
2) Reduce symptoms and improve QOL and prevent/ reduce hospitalizations and need for emergency care
3) Reduce mortality

Class I-II: reduce mortality most imp
Class IV: reduce symptoms/ improve QOL
What are some non-PCOL treatment for the treatment of CHF?
-Exercise in stable pts with NYHA class I-III for 20-60 minutes 3-5 times per week, inc HR to 60-80% of max
-Restrict sodium to 2-3 g/day (severe<2g)
-abstain from alcohol if alcohol-induced ventricular dysfunction; otherwise 2 drinks for men and 1 drink for women/day
-Restrict fluid intake to <2L/day if severe hyponatremia (<130mEq/L)
-Weight reduction if obese
-Smoking Cessation
-Immunizations (flu, pneumonia)
What are the four pharmacologic strategies of treatment of CHF?
1) reduce intravascular volume (diuretics)
2) increase myocardial contractility (+ ionotrope)- kill pts except digoxin
3) decrease ventricular afterload (ACEI, vasodilators)
4) neurohormonal blockade (BB, ACEI, ARBs, spironolactone)
What three drug classes are most important in treatment of CHF?
-diuretics
-ACEI
-BB
Who should receive a diuretic w/ CHF?

What type is most efficacious?
-everyone who is symptomatic

-loop diuretics
What are the goals of therapy of diuretics in CHF?
-dec edema
-dec pulmonary congestion
-dec. cardiac filling pressures by reducing preload

-dec blood volume
-increase Na+/H2O excretion
When will thiazide diuretics be used in a pt with CHF?
-mild HF and small amts of fluid retention
-never use it alone in CrCl< 30ml/min
-use if resistant to single drug therapy w/ loops as add on therapy
Why are loop diuretics most efficacious?
exert additional benefits:
-enhance renal release of prostaglandins which inc renal blood flow and enhances venous capacitance
How should diuretics dosages be adjusted in CHF pts?
-inc dose if impaired renal function
-adjust d/t daily weight and subjective/objective measures
-torsemide advantageous in pts with brittle HF
When should potassium sparing diuretics be used in pts with CHF?
-only if pts req potassium sparing effect
What are the adverse effects of diuretics?
•Hypomagnesemia
•Hypokalemia
•Hyponatremia
•Volume depletion, reduced renal function, pre-renal azotemia (BUN/Cr>20)
•Postural hypotension
•Hyperuricemia (thiazides)
•Hyper or hypocalcemia (loops)
What are the monitoring parameters for diuretics?
•I/O
•Body weight
•BP (watch for hypotension)
•Serum electrolytes (K+ and Mg2+)
•Renal function
•s/sx of systemic and pulmonary congestion
What are the initial and target doses of enalapril?
•Initial: 2.5-5mg BID
•Target: 10 mg BID
What are the initial and target doses of captopril?
•Initial: 6.25-12.5mg TID
•Target: 50mg TID
What are the initial and target doses of lisinopril?
•Initial: 2.5-5mg daily
•Target: 20 mg daily
How should ACEI be titrated?
•Slowly titrate to target dose
•Assess pt’s volume status; wait until not dehydrated
•Monitor renal function for 1-2 weeks prior to dose inc and at 3-6 month intervals or when other meds that change renal function are added
•Use lower doses(1/2 target dose) if SCr>3.0mg/dL and/or CrCl<30ml/min
•Monitor BP 2-3 and 6-8 hours after dosing if volume depletion, LVEF<40%, SBP<100mmHg, Na+<135mEq/L, SCr>3.0mg/dL, or age>75yo
What are the absolute contraindications of ACEI?
•Pregnancy
•Hx of angioedema or hypersensitivity
•Bilateral renal artery stenosis
•Hx of intolerance d/t symptomatic hypotension, decline in renal function, hyperkalemia, or cough
What are the adverse effects of ACEI?
•Hypotension
•Functional renal insufficiency (will return to normal when ACEI d/c’ed)
•Hyperkalemia
•Skin rash and dysgeusia (captopril)
•Cough
•Angioedema
What are the monitoring parameters of ACEI?
•BP
•Electrolytes (K+)
•Renal function (BUN/Cr, CrCl, GFR)
•CBC
•Cough
•Angioedema
How do ARBs differ from ACEI?
•No cough
•Probably no angioedema
What are the initial and target doses of losartan?
•Initial: 12.5mg daily
•Target: 50-100 daily
What are the initial and target doses of valsartan?
•Initial: 20-40mg daily
•Target: 160mg BID
What are the initial and target doses of candesartan?
•Initial: 4-8mg daily
•Target: 32 mg daily
When and Why are isosorbide dinitrate/ hydralazine used in CHF pts?
•Used in AA pts as an adjunct to standard therapy when other therapies (ACEI, diuretics) maximized
•ISDN/hydralazine combo reduces mortality, reduces preload and afterload, and supplements nitric oxide (ISDN=venous vasodilator; hydralazine=arterial vasodilator)
What are the adverse effects or ISDN/hydralazine?
•HA
•Nausea
•Flushing
•Dizziness
•Tachycardia
•Lupus-like syndrome
•Hypotension
•Inc HR
•Myocardial ischemia
•Fluid retention
What are the initial and target doses of ISDN and hydralazine?
•ISDN initial: 10mg TID
•ISDN target: 40mg TID (max 80mg TID)
•Hydralazine initial: 10-25mg daily
•Hydralazine target: 75mg TID (max 100mg TID)
What are the treatment recommendations for pts with symptomatic ventricular systolic dysfunction?
•ACEI-all pts (asymptomatic and symptomatic)
•ARB- if can’t tolerate ACEI d/t cough, angioedema
•ISDN/hydralazine- if can’t tolerate ACEI d/t hyperkalemia, renal dysfunction, or hypotension or in AA not well controlled
When should BB be used in CHF pts?
•Pts with stable symptomatic HF NYHA Class II-III and possibly Class IV; no marked signs of fluid retention
•Do not use if acute or active HF sx
•Low doses improve mortality
What is the appropriate dose of carvedilol in mild/moderate CHF?
•Carvedilol IR 3.125mg BID x 2 weeks, then double dose every 2 weeks until highest dose tolerated
•Target: 6.25-50mg BID
What is the appropriate dose of bisoprolol in moderate/ severe CHF?
•Initial: 1.25 mg daily
•Target: 10mg daily
What is the appropriate dose of metoprolol XL in mild/moderate CHF?
•25 mg daily x 2 weeks then double dose until highest dose tolerated
•Target: 200mg daily (max)
What are the adverse effects of BBs?
•Bradycardia
•Depression, fatigue, sexual dysfunction, dizziness, worsening HF
How long will it take to see a difference with BB therapy?
•6-12 months
What considerations are made for BB therapy if symptoms worsen or SE appear?
•Adjust dose of diuretic or other vasoactive medication
•Continue titration to target dose when sx return to baseline
•Prolong titration interval, reduce target dose, or refer to HF specialist if repeated problems
What should be done for a pt on BB if he has an acute exacerbation?
•Maintain therapy if possible
•Reduce dosage if necessary, slowly and reinstate gradually before discharge
What are some cautions for CHF pts on BB?
•Dec LVEF
•DM, CKD
•Active bronchospasm or severe outpt asthma- do not use
Is aldosterone inc or dec in CHF patients? What does this lead to?
•Aldosterone is elevated even when treated with ACEI/ARB
•Leads to continued sympathetic activation, parasympathetic inhibition, and vascular remodeling
What are the benefits of treatment with spironolactone or eplerenone?
•Dec K+ and Mg2+ losses: may protect against arrhythmias
•Dec Na+ retention: dec fluid retention
•Dec sympathetic simulation
•Blocks direct fibrotic action on myocardium
What are the recommendations for use of spironolactone or eplerenone in CHF pts?
•Addition to conventional therapy in Classes III-IV or consideration for Classes I-II w/ s/sx of HF
•Start with low doses (Spironolactone 12.5mg daily or eplerenone 25mg daily) esp. in elderly, DM, and CrCl<50ml/min
•Not recommended if SCr> 2.5mg/dl or CrCl<30ml/min or serum K>5mEq/L, hx of severe hyperkalemia or worsening renal failure
•Dec or d/c potassium supplements
•Avoid NSAIDs, high dose ACEIs and ARBs and triple therapy (ACEI, ARB, aldosterone antag)
What are the monitoring parameters for aldosterone antagonists in CHF pts?
•Renal function and K+ within 3 days and again in 1 week after any change or addition, then monthly x 3 months; then every 3 months
•If K+>5mEq/L then d/c potassium supplements or reduce dose/ D/C med
What is the mechanism of action of digoxin?
•Binds to and inh the Na+/K+ ATPase altering excitation-contraction coupling -> inc. intracellular Ca2+ -> inc. myocardial contraction
•Mild (+) inotrope: sensitization of baroreceptor reflex function, inh renal tubule Na+ reabsorption and suppression of rennin release
•Vagolytic effects at AV and SA node: dec HR and slowed AV nodal conduction
What is important about the pharmacokinetics of digoxin therapy?
•Large Vd
•Initial distribution= 3-6 hrs
•Conc-effect curves only accurate at >12 hrs
What doses of digoxin are used? Is a loading dose needed?
•No LD in pts with normal sinus rhythm, may need if Afib + HF
•0.125mg daily with goal HF serum conc <1
After steady state, when is it necessary to check digoxin levels?
•Marked changes in renal function
•Suspected digoxin toxicity
•Suspected drug interaction
•Thyroid dysfunction or electrolyte abnormality changes
Name some important digoxin drug interactions and their recommendation for use?
•Erythromycin, clarithromycin, tetracycline- inc digoxin absorption; stop digoxin for the week of antibiotics
•Amiodarone- inc dig conc 70-100%; dec dose of dig by ½
•Itraconazole/ Ketoconazole: inc dig conc 50-100%; dec dose of dig by ½
•Quinidine: inc dig conc by 100%; dec dose of dig by ½
•Verapamil: inc dig by 70-100%: dec dose of dig by ½
What are the adverse s/sx of digoxin toxicity?
•Anorexia, N/V, abdominal pain
•Visual disturbances: halos, photophobia, altered color perception
•Fatigue, weakness, dizziness, HA, neuralgias, confusion, delirium, psychosis
•Ventricular arrhythmias: PVCs, bigeminy, trigeminy, VT, Vfib
•AV block: 1st, 2nd or 3rd degree
•AV junctional escape rhythms/ junctional tachycardia
•Atrial arrhythmias with slowed AV conduction or AV block
•Sinus bradycardia
What factors predispose a person to digoxin toxicity?
•Electrolyte disturbances (hypokalemia, hypomagnesemia, hypercalcemia)
•Advanced age
•Alkalosis
•Hypoxia
•Renal dysfunction
•Hypothyroidism
•Drug interactions
How is digoxin toxicity treated?
•Digibind
What is the place of digoxin in treatment of CHF?
•Does not improve mortality, but does dec hospitalizations
•Use in pts with BB, ACEI, diuretics, and probably aldosterone antag and still HF sx
•When used with diuretics, inc hypokalemia= greater dig effect and conc: monitor
What is the place of antiplatelet and anticoagulant therapy in the treatment of CHF?
•Long term 81mg ASA recommended if HF + CAD/ ASCVD . Use clopidogrel if ASA contraindicated
•Routine anticoagulation not recommended (controversial); use if hx of PE, recent Afib,or mobile LV thrombi
What is the place of ventricular antiarrhythmatic therapy in the treatment of CHF?
•Use only if symptomatic arrhythmias (ICD>amiodarone)
What is the place of CCB in the treatment of CHF?
•Do not use diltiazem, verapamil, and nifedipine
•May use amiodarone or felodipine to manage uncontrolled angina or HTN
If a pt has hyperkalemia and is taking both an ACEI and aldosterone antag, what should be done?
•d/c any potassium supplements
•check for changing renal function and stop decline if possible
•dec aldosterone antag if no supplements and can’t fix renal decline
What is the pathophysiology of rheumatoid arthritis?
•Chronic autoimmune disorder in which synovial joint space is infiltrated with inflammatory cells (macrophages, t-cells, and plasma cells)
•Cytokines are released and mediate the immune and inflammatory response leading to cell proliferation and death (IL-1, TNF, IL-6,IL-7)
•Pannus (inflamed proliferating synovium) invades cartilage and bone producing erosions which destroy joint
•As the disease progresses, there is less inflammation, but inc disability
What is the clinical presentation looked at for dx of rheumatoid arthritis?
•Need at least 1 joint w/ synovitis (swelling) not caused by another disease
•Dx if score= or >6 points
oJoint development
 1 medium-large joint (0pts)
 2-10 medium-large joints (1 pt)
 1-3 small joints (2 pts)
 4-10 small joints (3pts)
 More than 10 small joints (5pts)
oSerology
 (-) RF and (-)anti-citrullinated protein antibody (0pts)
 Either (+) RF or (+) ACPA (2pts)
 At least RF or ACPA> 3x normal limit (3pts)
oDuration of synovitis
 Less than 6 weeks (0pts)
 6 weeks or longer (1pt)
oAcute phase reactants
 Neither abnormal CRP nor abnormal ESR (0pts)
 Abnormal CRP or abnormal ESR (1pt)
What are the prodromal sx?
Fatigue
•Weakness
•Loss of appetite
•Joint pain
•Low grade fever
•Stiffness and muscle ache-> joint swelling
What joints are affected in rheumatoid arthritis?
•Common: hands, wrists, feet
•Possible: elbows, shoulder, hip, knees, ankles
Name the extra-articular manifestations of RA.
•Rheumatoid nodules: 20% of pts get nodules on pressure points
•Vasculitis: inflammation of small, superficial vessels->stasis ulcers and necrosis of extremities
•Pulmonary: pleural effusions, pulmonary fibrosis, or pulmonary nodules
•Ocular: inflammation of the sclera, episclera, and cornea; nodules possible; keratoconjunctivitis sicca (itchy, dry eyes + inflammation) =Sjorgens syndrome (RA+KS)
•Pericarditis, conduction abnormalities, and myocarditis (rare)
•Felty’s syndrome: hepatosplenomegaly, neutropenia
Lymphadenopathy
•Renal disease (d/t tx), renal disease, thrombocytosis, and anemia
What are the laboratory tests looked at for RA?
•Erythrocyte Sedimentation Rate: non-specific (>20)
•C-reactive protein: non-specific (>0.5; >10=bacterial infection)
•Rheumatoid Factor: specific for IgM
•Anti-cyclic citrullinated protein antibody (Anti-CCP) or anti-citrullinated protein antibody (ACPA): high specificity of inflammatory arthritis; marker of poor prognosis
•Antinuclear antibodies (ANA): shows autoimmune disorder
•Joint aspiration- turbid, inc WBC, dec. glucose
•Radiographic changes: joint space narrowing, bone erosions
What are markers of poor prognosis for RA?
•Low socioeconomic status
•Lack of formal education
•Psychosocial stress
•Low HAQ scores
•Extra-articular manisfestations
•Elevated CRP and ESR
•High RF
•Elevated anti-CCP/ACPA
•Bone erosion
•Duration of disease
What are the differences between rheumatoid arthritis and osteoarthritis?
•Age of onset: any age vs >40
•Disease distribution: systemic involvement vs joint localization
•ESR: elevated vs normal
•Inflammation: present vs absent/mild
•Joint involvement: bilateral/symmetric vs unilateral or bilateral/ symmetric or asymmetric
•Morning stiffness: >1hr vs <30min
•Osteophytes: Absent vs. present
•Pannus: often present vs absent
•RF: frequently present vs absent
•SQ nodules: present vs absent
Swelling: diffuse symmetric vs irregular, knobby
•Typical presentation: malaise, fatigue, MS pain, fever vs deep, aching pain
What are the goals of treatment for rheumatoid arthritis?
•Alleviate s/sx
•Preserve function
•Prevent structural damage and deformity
•Control/avoid extra-articular manifestations
What non-PCOL treatments are available for treatment of rheumatoid arthritis?
•Education
•Emotional/support groups
•Rest
•Heat
•Splints/ prosthetics
•Physical/occupational therapy
•Weight reduction if needed
•Surgery
What is the place in therapy for NSAIDs/ salicylates/ Cox-2 inhibitors?
•Effective in reducing pain, swelling, and stiffness
•does not alter the course of the disease or prevent joint destruction
•need anti-inflammatory doses (high)
•Do not use alone. Combine with DMARDs
What is the mechanism of action of salicylates/NSAIDs/COX-2 inhibitors?
•Inhibits COX and thus inhibits formation of prostaglandins and inflammatory mediators
•Involved in pain and inflammation
What is the dose of celecoxib (Celebrex)?
•100-200mg BID
Caution: sulfa allergy
What is the place in therapy for DMARDs?
•Potential to decrease/prevent joint damage and preserve joint integrity
•Started at first signs of disease
•Onset of action is delayed, often up to 6 months
What is the mechanism of action of methotrexate?
•Inhibit dihydrofolic acid reductase
•Inhibit neutrophil adhesion and chemotaxis
What is the dosing regimen and time of onset for methotrexate? What other medications should be given with methotrexate?
•7.5mg po q weekly or IM (up to 15-20mg q weekly dose taken in 1 day)
•Onset: 1-2 months
•Folic acid 1mg po daily + BC
What are some important pharmacokinetics about methotrexate?
•35-50% bound to albumin
•Some renal excretion
•Liver metabolism
What are the adverse effects of methotrexate?
•Bone marrow suppression
•N/V/D
•Stomatitis/ mucositis
•Cirrhosis, hepatitis, fibrosis
•Pneumonitis, fibrosis
•Rash, uticaria, alopecia
•Teratogenic; start BC 1 month prior; stop 3 month before trying to become pregnant
What are the CI for using methotrexate?
•Pregnant
•Chronic liver disease (from EtOH abuse)
•Immunodeficiency
•Pre-existing blood dyscrasias
•Pleural/peritoneal effusion
•CrCl< 40ml/min
What are the MP for methotrexate (baseline and maintenance)?
•Baseline: CXR, CBC w/ plts, SCr, LFTs, Alb/ Alk Phos, T. Bili, Hep B&C studies
•Maintenance (every 1-2 months): CBC w/ plts, LFTs, Alb, SCr
What is the mechanism of action of sulfasalazine?
•Prodrug cleaved in colon to sulfpyradine and S-ASA
•Inhibits IL-1 (pro-inflammatory mediator)
What is the dosing regimen and onset of action of sulfasalazine (SSZ)?
• 500mg po BID
• Up to 1g BID-TID
• Onset: 1-2 months
What are the adverse effects of sulfasalazine?
• N/V/D
• Anorexia
• Rash, uticaria
• Photosensitivity
• Leukopenia, thrombocytopenia
• Rare: hemolytic and aplastic anemia
• Caution: sulfa allergy
What is the MP for sulfasalazine?
• CBC w/ plts every 2-4 wekks then every 3 months
• LFTs if at risk
What is the mechanism of action of hydroxychloroquine (HCQ)?
• Modification of cytokine infiltration in joint
What is the dosing regimen and onset of action of hydroxychloroquine?
• 200mg po BID
• Onset: 2-4 months (D/C if no effect in 6 months)
What important pharmacokinetics does hydroxychloroquine have?
• Hepatic metabolism
• Renal excretion
What are the adverse effects of hydroxychloroquine?
• Retinal toxicity (risk: >70yo, cumulative dose>800g, changes in peripheral/ night vision
• N/V/D- take with food
• Increase skin pigment, rash , alopecia
What are the MP of hydroxychloroquine?
• Vision exam: baseline and every 6-12 months
What is the place in therapy for RA of corticosteroids?
• Anti-inflammatory and immunosuppressive properties
• Not monotherapy d/t toxicity
• Used as burst therapy (acute flares), bridge therapy (combo w/ DMARD until DMARD onset), long term/low dose (advanced disease)
• Use in pts with extra-articular manifestations
What is the mechanism of action of corticosteroids?
• Inhibit IL-1 production
What are the dosing regimens of corticosteroids in RA?
• Aim: physiologic dose to reduce ADRs (5 mg daily)
• Burst: 20-40mg daily for 3 days
• Bridging therapy: 5 mg daily
• Continuous low-dose: 5 mg daily
• Intra-articular injections: 10-25mg/inj of hydrocortisone per joint; do not use> every 2-3 months
What are the adverse effects of corticosteroids?
• Short term: hyperglycemia, gastritis, mood changes, and elevated BP
• Long term: aseptic necrosis, cataract, obesity, growth failure, HPA suppression, osteoporosis
What are the MP of corticosteroids?
• Baseline: BP, Glucose
• Maintenance: BP every 3 months, glucose every 3 months, UA annually
What is the mechanism of action of leflunomide (Arava)?
• Immune modulator
• Prodrug that inhibits de novo biosynthesis of pyrimidines
• Interferes with tyrosine kinase activity
• Inhibits cell cycle progression
What is the dosing regimen and onset of action of leflunomide?
• 100mg po daily x 3 days, then 20mg daily
• Onset: 1 month
• Caution: if also taking methotrexate b/c liver toxicity
What important pharmacokinetics does leflunomide have?
• t(1/2)=14-16 days
• hepatobiliary clearance
What are the adverse effects of leflunomide?
• Diarrhea
• Rash
• Alopecia
• Increased LFTs
• Teratogenic for males and females
If a pt decides to become pregnant when taking leflunomide, what should be done?
• D/C drug immediately
• Take cholestyrimine 8g TID x 11 days to achieve levels<0.02mcg/mL
What are the MP of leflunomide?
• Baseline: LFTs
• Maintenance: LFTs every month
What are the warnings/ precautions for all BRM/ DMARD/TNF blockers
• Risk of infection (TB, opportunistic)
• Do not use in combination w/ anakinra (IL-1) d/t increased risk of infection
• Some agents have blackbox warnings
• Demyelinating disorders
• Malignancies
• Congestive heart failure
• No concurrent live vaccination administration
What are the adverse effects of all BRM/ DMARDs/ TNF blockers?
• HA
• Rash
• Risk of infection (URI most common)
• Injection site reaction
• Excerbations of CHF
• Risk of malignancy
• Risk of evidence of demyelinating disease
What is the mechanism of action of etanercept (Enbrel)?
• Dimeric protein with two soluble TNF receptors fused to the IgG1 molecule
• Binds to and inhibits TNF
• Binding occurs before the cytokine can interact with cell-surface TNF receptors that would produce an inflammatory response
What is the dosage regimen of etanercept (Enbrel)?
• 50mg SQ weekly
What are the MP of all BRM/ DMARDs/TNF blockers?
• TB test prior
• No laboratory monitoring necessary except Golimumab (Simponi)
• Golimumab: CBC w/ plts, LFTs
What is the mechanism of action of infliximab (Remicade)?
• Binds to and inhibits TNF
• Chimeric antibody, immunoglobulin w/ mouse and human portions to reduce antigenic potential
What is the dosage regimen of infliximab?
• 3mg/kg IV at 0,2, + 6 weeks, then every 8 weeks
• Can increase dose to 10mg/kg OR as often as every 4 weeks
• Pts w/ CHF class III &IV should not receive doses >5mg/kg
What is the mechanism of action of adalimumab (Humira)?
• Recombinant human IgG1 monoclonal antibody specific for human TNF
• Binds to TNF-alpha and blocks interaction with p55 and p75 cell surface TNF receptors
What is the dosing regimen of adalimumab?
• 40mg SQ every other week
• If not taking MTX, can increase to 40mg SQ every week for improved response
What is the mechanism of action of golimumab (simponi)?
• Human monoclonal antibody specific for TNF-alpha (soluble and transmembrane forms)
• Prevents binding of TNF-alpha to receptors
What is the dosage regimen of golimumab (simponi)?
• 50mg SQ once monthly
What is the mechanism of action of certolizumab pegol (Cimzia)?
• Binds to membrane associated and soluble TNF-alpha and neutralizes
• PEGylated anti-TNF therapy
What is the dosage regimen of certolizumab pegol (Cimzia)?
• 400mg (2 inj of 200mg) SQ at 0, 2, + 4 weeks then 200mg every 2 weeks OR 400mg every 4 weeks
Which BRM/ DMARDs/ TNF blockers can be used without MTX?
• Etanercept (Enbrel)
• Adalimumab (Humira)
• Certolizumab Pegol (Cimzia)
Which BRM/ DMARDs/TNF blockers require additional treatment with methotrexate?
• Infliximab(Remicade)
• Golimumab (Simponi)
What is the indication for anakinra(Kineret)?
• Mod-severe RA pts who have failed 1+ DMARDs
• Use alone or with other DMARDs
What is the mechanism of action of anakinra (Kineret)?
• Recombinant, non-glycosylated version of the human IL-1 receptor antagonist
• Selectively blocks IL-1 by binding to the IL receptor
What is the dosage regimen of anakinra (Kineret)?
• 100mg SQ daily
• If CrCl<30ml/min, then use 100mg SQ every other day
• Do not use with TNF agents d/t inc risk of infection
What are the adverse effects of anakinra (Kineret)?
• Injection site rxns
• HA, N/V, flu-like sx
• Hypersensitivity to e.coli-derived proteins
• Inc risk of serious infection
• Dec. neutrophils
What are the MP of anakinra (Kineret)?
• Neutrophil count: prior to start, monthly x 3, then quarterly x 1 yr
What is the indication for abatacept (Orencia)
• Mod-severe RA
• Inadequate response to 1+ DMARDs
• Monotherapy or combo with other DMARDs (not with anakinra or TNF blockers)
What is the mechanism of action of abatacept (Orencia)
• Selective T-cell co-stimulation modulator
• Inh T-cell activation by binding to CD80 and CD86 thereby blocking interaction with CD28
What is the dosage regimen of abatacept (Orencia)?
• <60kg: 500mg IV over 30 min
• 60-100kg: 750mg IV over 30 min
• >100kg: 1g IV over 30 min
What are the warning/precautions for abatacept (Orencia)?
• Do not use w/ TNF blockers or anakinra
• Inc risk of infection
• No live vaccine administration
• Caution in pts with COPD
What are the adverse effects of abatacept (Orencia)?
• HA, N, URI, nasopharingitis
• Infusion rxns
• Serious infections
• Malignancy
What are the MP for abatacept (Orencia)?
• No hemotologic monitoring
What is the indication for tocilizumab (Actrema)?
• Mod-severe RA
• Inadequate response to 1+ TNF blocker
What is the mechanism of action of tocilizumab (Actrema)?
• IL-6 receptor inhibitor (binds to soluble and membrane bound IL-6)
What are the warnings/precautions of tocilizumab (Actrema)?
• Blackbox warning: serious infections
• CI: liver toxicity, thrombocytopenia, and neutropenia
What are the adverse effects of tocilizumab (Actrema)?
• Serious infection
• Liver toxicity
• Thrombocytopenia
• Neutropenia
• Infusion rxns
• Lipid abnormalities
• Intestinal perforations
What are the MP of tocilizumab (Actrema)?
• Neutrophil count every 4-8 weeks
• Plt count every 4-8 weeks
• LFTs every 4-8 weeks
• Lipid profile after 4-8 weeks then every 6 months
What is the indication for rituximab (Rituxan)
• Mod-severe RA
• Inadequate response to 1+ TNF blockers
• Use in combo w/ MTX
What is the mechanism of action of rituximab (Rituxan)?
• Binds specifically to CD20 antigen and mediates B-cell lysis
What is the dosage regimen of rituximab (Rituxan)?
• Two 1g IV infusion separated by 2 weeks
• Can retreat at 6 month intervals
• Administer methylprednisolone 100mg IV 30 min prior to infusion
What are the warnings/precautions for rituximab (Rituxan)?
• Blackbox warning: fatal infusion rxns, tumor lysis syndrome, and mucocutaneous rxns
What are the adverse effects of rituximab (Rituxan)?
• Tumor lysis syndrome
• Mucocutaneous rxns
• Viral infection
• Hypersensitivity
• Renal toxicity
• Bowel obstruction
• Hep B reactivation
• Cardiac arrhythmia
What are the MP for rituximab (Rituxan)?
• CBC w/ plts
• SCr
• Vital signs during infusion
What are possible treatment combinations for RA?
• MTX + HCQ, SSZ, or all three
• MTX + leflunamide
• MTX + BRM
What is the ACR 20?
• American College of Rheumatology created measurement for clinical trials
• Criteria for defining improvement and clinical remission
• 20% improvement in the tender and swollen joint count
AND
20% improvement in 3 of 5
• Pt global assessment
• Physician global assessment
• Pt assessment of pain
• Degree of disability
• Level of acute-phase reactant
What are the three assessments used for clinical trials?
• ACR 20, 50, 70
• HAQ (Health assessment questionnaire)-20 questions scored 0 (able to fxn) to 3 (not able to fxn)
• TMSS (Total modified sharp score)- joint space narrowing, erosions, based on point scale (0-398)
What is hyperuricemia?
increased serum urate
What is tophi?
monosodium urate crystal deposits in the tissues around joints
What is gout?
clinical spectrum of disease w/
-hyperuricemia
-recurrent attacks of acute arthritis associated with tophi in synovial fluid
-tophi in tissues around joints
-interstitial renal disease
-uric acid nephrolithiasis
What is an overproducer?
Pt with abnormalities in the regulation system leading to gout
-too much dietary purines
-inc. conversion of tissue nucleic acids to purine nucleotides
-inc. de novo synthesis of purine bases
-inc. breakdown of tissue nucleic acids, excessive rates of cell turnover
-myeloproliferative, polycythemia, psoriasis, cytotoxic agents
What is an underexcretor?
Pt with decreased renal excretion leading to decreased elimination of uric acid and gout
What is the clinical presentation of gout?
-intense pain with rapid onset (overnight)
-warmth
-increased serum uric acid
-fever
-swelling
-leukocytosis
-erythema
-inflammation of the involved joint (typically podagra (big toe))
-tenderness to palpation
-tophi or crystals in synovial fluid
What factors may precipitate gout?
-inc. age
-male gender (9:1)
-weight
-dec. renal function
-HTN/HLD
-dietary intake/ EtOH
-Medications (diuretics, EtOH, nicotinic acid, salicylates, pyrazinamide, levodopa, ethambutol, cytotoxic drugs, cyclosporine)
-triggers: stress, trauma, infection, surgery
What is the pathophysiology of gout?
-increased uric acid in body through overproduction or underexcretion
-development of tophi
-cystal-induced inflammation
-phagocytosis of urate crystals
-vasodilation, inc. vascular permeability, complement activation, chemotactic activity for PMN leukocytes
How long will it take for untreated gout to resolve?
3-14 days
What are the American College of Rheumatology criteria for dx of gout?
Must have 6 of 13
1) 1+ attack of acute arthritis
2) max inflammation developed in 1 day
3) monoarthritis attack
4) redness observed over joints
5) 1st metatarsophalangeal joint attack
6)unilateral 1st metatarsophalangeal joint attack
7)unilateral tarsal joint attack
8) tophus
9) hyperuricemia
10) asymmetric swelling w/in a joint on x-ray
11) subcortical cysts w/o erosions on x-ray
12) monosodium urate monohydrate microcrystals in joint fluid during attack
13) joint fluid culture negative for organisms during attack
How is hyperuricemia classified?
-serum monosodium urate level
-Men>7mg/dL
-Female>6mg/dL

-may be asymptomatic
What are the complications of gout?
-uric acid nephrolithiasis (kidney stones)
-gouty nephropathy (blockage of urine and renal parenchyma)
-tophaceous gout (tophi causing joint/nerve destruction, loss of functionality)
What are the goals of therapy for treatment of gout?
1) terminate acute attack
2) prevent recurrent attacks
3) prevent complications associated with chronic deposition of urate crystals in tissues
4) reverse contributing factors (obesity, inc TG, HTN)
What is the place in therapy of NSAIDs for gout? What should be monitored?
-Use for acute attack if no CI (PUD, HF, renal impairment)
-short course, high dose
-indomethacin: 25-50mg Q6h x 3 days, taper to BID x 4-7 days
-monitor SCr, BUN, resolution of s/sx
What is the place in therapy of colchicine in the treatment of gout?
-acute attacks for pts who cannot take NSAIDs and sx onset<48hrs
-Colchicine 1.2mg x 1, then 0.6mg 1 hr later (may add 0.6mg Q1hr to max 8mg or 6mg if renal impairment)
-ADE: Diarrhea!!!
What is the place in therapy of oral corticosteroids in the treatment of gout?
-acute tx of resistant cases, CI to NSAIDs/Colchicine, or polyarticular involvement
-prednisone 30-60mg po daily x 3-5 days, taper over 10-14 days to prevent rebound attacks
-ADE: GI, hyperglycemia, weight gain

OR

-prophylaxis
-0.6-1.2mg daily-BID; inc if pt senses attack to 1.2mg Q2hr
When would a pt start gout prophylaxis?
one of 4
->2 attacks
-severe attack w/ serum uric acid>10mg/dL
-24hr urine uric acid excretion>1000mg
-complicated by uric acid nephrolithiasis or tophi
What is the place in therapy of allopurinol in treatment of gout?
-prophylaxis
-100mg daily; inc dose by 100mg weekly until uric acid<6mg/dL (up to 800mg/day)
-if CrCl 31-60=200mg/day; CrCl<30=100mg/dL
-ADE: rash, leukopenia, GI, hepatitis, interstitial nephritis
What is the place in therapy of probenacid?
-prophylaxis in underexcretors (inh.renal tubular uric acid reabsorption)
-probenacid 250mg daily x 7-14 days, then 500mg BID x 14 days; then inc daily dose by 500mg Q1-2 weeks until satisfactory response or 2000mg
-ADE: GI, rash, stone formation
What is the place in therapy of sulfinpyrazone?
-prophylaxis of underexcretors
-50mg BID x 3-4 days, then 100mg BID
-inc by 100mg each week up to 800mg/day
What is the place in therapy of febuxostat (Uloric)?
-prophylaxis (inh. xanthine oxidase like allopurinol)
-40-80mg daily
-CI: azathioprine, mercaptopurine or theophylline
-ADE: inc LFTs, nausea, arthralgia, rash
What is the place in therapy of pegloticase (Krystexxa)?
-prophylaxis or refractory gout
-urate oxidase: dec. uric acid production and reduces existing stores
-8mg IV infusion over 2 hrs every 2 weeks
-CI: G6PD deficiency; risk of hemolysis and methemoglobinemia; caution in HF
-ADE: N/V, confusion, nasopharyngitis, constipation, CP
What are some important patient education points for the treatment of SLE?
-avoid trigger foods (red meat, fish, lentils, spinach, asparagus)
-avoid EtOH
-control weight, BP, and cholesterol
-drink lots of water
-joint rest and icing
What is the definition of systemic lupus erythematosus (SLE)?
-chronic, inflammatory autoimmune disorder
-unpredictable course
-affects any organ or system in various combinations
What is the etiology of SLE?
-genetic: Af Am> White
-hormonal (estrogen): women>men
-environmental: UV light exposure, medications, infection
What are the precipitating factors of SLE?
-infection
-pregnancy
-stress
-sun exposure
-surgery
-sulfa meds
What is the pathophysiology of SLE?
-Type III hypersensitivity autoimmune
-over-activity of B-cells
-precipitates immune complexes on vascular membranes
-activation of complement
What are the clinical features of SLE?
-fatigue, fever, weight loss
-arthritis, arthralgia, myalgias
-malar rash, discoid rash, photosensitivity, oral ulcers, alopecia, raynaud's phenomenon, purpura, urticaria, vasculitis
-hematuria, proteinuria, casts, nephrotic syndrome
-N/V, abdominal pain, anorexia
-pleuisy, pulmonary parenchyma, pulmonary HTN, pneumonitis
-pericarditis, endocarditis, myocarditis, ECG changes, valvular heart disease
-lymphadenopathy, splenomegaly, hepatomegaly
-hemolytic anemia, thrombocytopenia, leukopenia, antiphospholipid Ab
-psychosis, seizures, cranial neuropathies, peripheral neuropathies, depression, anxiety
-anti-DNA Ab, anti-SM Ab, ANA
What is a malar rash?
-butterfly rash, involves bridge of nose
What is a discoid rash?
-red/purple and scaly rash
What is the American Rheumatology Association criteria for SLE?
Must have 4 of 11
-malar rash
-discoid rash
-photosensitivity
-oral ulcers
-arthritis
-serositis
-renal disorder
-neurologic disorder
-hematologic disorder
-immunologic disorder
- (+) ANA
What are the goals of therapy of SLE?
-management of sx
-induction of remission during flare-up
-maintenance of remission
What are some non-PCOL treatments for SLE?
-balance rest and exercise
-smoking cessation/ avoiding tobacco smoke
-limiting sunlight/ UV exposure
-routine health maintenance (gynecologic assessment, dental care, eye exams)
-preventative measures (vaccinations, HRT)
-treat CV risk factors
What topical treatments are used in SLE?
-Sunscreen in all pts > 15SPF
-Steroid creams (hydrocortisone, betamethasone, fluocinonide)
-tracrolimus ointment (Prograf): immunomodulatory
What is the place in therapy of NSAIDs in SLE?
1st line treatment for initial or mild disease
-Ibuprofen, naproxen, nabumetone
-ADE: GI bleeding, inc LFTs, renal toxicity, HTN, N/V, fluid retention
-Monitoring: CBC, SCr, AST/ALT, tarry stools, SOB, edema, N/V, dyspepsia, abdominal pain, CBC, SCr, LFTs
What is the place in therapy for hydroxychloroquine in SLE?
-inadequate response to NSAIDs or to provide steroid sparing effect in mild disease
-200-400mg po daily (time to effect:3-6 months)
-ADE: visual changes, macular damage, insomnia, pigmentation changes, rash, nausea, HA, nervousness
-Monitor: eye exam at baseline + every 6-12 months
What is the place in therapy for systemic glucocorticoids for SLE?
-pts with significant organ involvement with inadequate response to NSAIDs and antimalarials OR pulse therapy to induce remission in pts with severe, life-threatening disease
What is the appropriate dose of prednisone for treatment and maintenance of SLE nephrotic syndrome?
Treatment: 1-2mg/kg/day divided BID-TID
Maintenance: lowest possible dose (<1mg/kg/day)
What is the appropriate dose of methylprednisone for treatment and maintenance of SLE?
Treatment: 1g/day x 3-6 days
Maintenance: 1-1.5mg/kg tapered to lowest effective dose
What are the ADE and MP of systemic corticosteroids?
ADE: HTN, hyperglycemia, HLD, weight gain, osteoporosis, cataracts, infections, fluid retention, GI upset, immunosuppression

MP:
-Baseline: BP, Glu, FLP (TC, LDL, HDL, TRG), bone density
-polyuria, polydipsia, edema, BP, weight, infection
-urinary glucose every 3-6 months
-FLP and bone density yearly
What is the place in therapy for cyclophosphamide (Cytoxan) in SLE?
-Use for severe lupus nephritis/ severe disease manifestations
-0.5-1g/m2 IV monthly in SLE; 2.5-3mg/kg/day x up to 12 weeks for nephrotic syndrome
-ADE: myelosuppression, malignancy, hemorrhagic cystitis,infertility, alopecia, SJS, N/V
-Monitor: hematuria, myelosuppression, CBC w/ diff, UA monthly; PAP smear/ urine cytology yearly
What is the place in therapy for mycophenolate mofetil (CellCept) in SLE?
-alternative to cyclophosphamide in severe disease manifestations, autoimmune thrombocytopenia
-0.5-3g/day po (not interchangeable w/ Myfortic)
-ADE: myelosuppression, hepatotoxicity, malignancy, HTN, GI upset
-MP: LFTs monthly; CBC weekly x 4, twice monthly x 4, then annually
What medication should be used with cyclophosphamide? Why?
Mesna; hemorrhagic cystitis
What is the place in therapy for azathioprine (Imuran) in SLE?
-maintenance for lupus nephritis; steroid sparing effect
-1-3mg/kg/day
-ADE: myelosuppression, hepatotoxicity, lymphoproliferative disorders, N/V/D, pancreatitis
-MP: CBC every 1-2 weeks w/ dose change then 1-3 months after; LFTs and PAP test annually
What is the place in therapy for Methotrexate in SLE?
-serious life-threatening or organ-threatening SLE
-ADE: myelosuppression, cirrhosis, pulmonary infiltrates, fibrosis
-MP: CBC, AST/ALT and alb every 4-8 weeks, SCr, UA
When should a pt with SLE become pregnant? What medications should they use to treat the disease?
-remission for 6+ months and stable renal fxn

-NSAIDs
-Hydroxychloroquine
-low-dose glucocorticoids
What is the difference between nephritis and nephrotic syndrome?
Nephritis: inc SCr and BUN-> renal failure

Nephrotic syndrome: overweight, fluid accumulation
What drugs induce SLE?
-procainamide
-phenytoin
-hydralazine
-quinidine
-methyldopa
-isoniazid
What is neonatal lupus?
-passed from mother to child
-rash develops w/in 1st few weeks of life
-congenital heart block
What is discoid lupus?
-chronic, scarring, atrophy producing photosensitive dermatosis
-(-) ANA
-do not develop systemic illness