Transcript INTERPRETATION OF LAB TESTS with a

INTERPRETATION OF LAB TESTS
with a Pharmaceutical Focus
Barb Bancroft, RN, MSN, PNP
Chicago, IL
www.barbbancroft.com
[email protected]
AUGUST 5, 2010
Rule number one …
• Know your own lab’s normal values
• The reference values are affected by many
variables, including patient population and
laboratory methods used
Rule #2--READ the package insert for
suggested testing intervals
• This is specifically a CYA (Cover your “donkey”)
procedure for prescribing purposes
• Every drug and every pharmaceutical company
has different testing intervals—it would be wise
to know them
• Examples: Amiodarone (Cordarone)—liver
function tests (LFTs) at baseline and every six
months (if the LFTs are greater than 3x the ULN,
or doubles in a patient with elevated baseline
LFTs, decrease the dose or d/c the drug)
Another example:
• Spironolactone (Aldactone) and eplerenone (Inspra)—
check potassium and renal function (serum creatinine)
at baseline, three and seven days after initiation,
monthly for three months, then quarterly; restart
monitoring cycle if ACE or ARB is added or their dose is
increased;
• Do not start if serum creatinine is greater than 2.5
mg/dL (221 mmol/L) in men or greater than 2 mg/dL
(176.8 mmol/L) in women (for spironolactone ≥ 200
mmol/L per Canadian Cardiovascular Society)
• Reduce dose or d/c if serum potassium > 5.5 mEq/L
(same as mmol/L in Canada)
Is genotyping necessary with certain
drugs?
• Carbamazepine—baseline HLA-B*1502 testing
in Asians—severe skin reactions can occur
• High prevalence (15%) in Hong Kong, Thailand,
Malaysia, and parts of the Philippines,
followed by Taiwan (10%), North China (4%),
and Japan and Korea (1%). In South Asians,
including Indians, risk is 2-4% (Novartis
Pharmaceuticals Corporation—Product information.
February 2009)
Serum protein electrophoresis
• List the plasma proteins
1) albumin
2) globulins
3) fibrinogen
• Is there a difference between plasma proteins
and serum proteins?
Yes. The removal of fibrinogen
• So, the serum proteins are albumin and the
“globulins”.
• Fibrinogen—(1.4-4.0 mg/dL or 140 to 400g/L)
• Hyperfibrinogenemia (greater than 4.0 g/dL or
400 g/dL) increases the risk of clotting
What conditions increase the risk of
clotting?
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Venous catheters
Heart failure/Atrial fibrillation
Immobilization
Trauma
Surgery
Pregnancy and postpartum
Prolonged travel (economy class syndrome—air
travel)
• Heparin-induced thrombocytopenia
• Estrogen therapy (?)
What about the estrogen controversy?
• Estrogen excess increases fibrinogen
• COC’s? The “old days” vs. today
• HT? (hormone therapy—E + P—po, not patch or gel
or any other topical route)
• How about your own ovaries, ie, endogenous
estrogen?
What else increases fibrinogen?
• Smoking increases fibrinogen
• So how about smoking and estrogen, eg, oral contraceptives
or HT in the PMF? (use patch)
• Smoking accelerates aging
• Aging and fibrinogen—increases by 1% per year after age
30
• How many 30 –year-olds are on warfarin/Coumadin?
Biological rhythms and clotting
• DVT (venous clot or red clot) may take a few hours or a
few weeks to form depending on the circumstances;
attached to the deep veins of the legs and pelvis; breaks
off in early a.m. due to standing up and moving around;
takes 30 minutes to travel to the lungs—Up at 7 a.m.?
Pulmonary embolism at 7:30 a.m.
• Coumadin/Heparin inhibit clotting factors (red clots)
• If the pulmonary embolism is huge, tissue plasminogen
activator (Activase/alteplase or reteplase/Retavase;
streptokinase) may be infused
• Incidence varies based on AGE(0.2 cases/100,000 in kids
under 15 ; 700 cases per 100,000 in patients over 85
Coagulation profile
• Platelet counts and platelet
aggregation/clumping (how well platelets
aggregate as measured by the bleeding time—
3 to 6 minutes)
• PT (prothrombin time)—11.3 to 13.3 seconds
• INR is used to measure PT in patients on
Coumadin (2-3)
• aPTT—22.1 to 34 seconds (stable aPTT on
heparin is 60 to 84 seconds)
Quantitative and qualitative platelet
dysfunction
• Platelet counts and bleeding times—
quantitative and qualitative measurements
• WHAT IS PLATELET TYPE BLEEDING?
• Normal platelet count--150,000 to 450,000;
• Platelet counts above 100,000 do well w/
hemostasis;
• 50,000 to 100000 may show increased
bruising;
• platelet counts less than 50,000 need
monitoring;
• spontaneous hemorrhage under 10,000
Platelet-type bleeding
• Acute DIC -- Severe thrombocytopenia due to
meningococcemia
Platelet type bleeding –
thrombocytopenia; chronic DIC
• Secondary to malignancy
The most common drugs that cause
thrombocytopenia
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heparin
sulfa drugs, piperacillin, linezolid, rifampin
quinine and quinidine
cimetidine (Tagamet)
valproic acid (Depakene, Depakote)—check
platelet count and coagulation tests baseline,
periodically, and prior to planned surgery
• Don’t forget ETOH abuse also causes
thrombocytopenia
ASA , NSAIDS and clopidogrel (Plavix)
cause qualitative platelet dysfunction
• Cause a qualitative dysfunction NOT
quantitative (numbers are normal, bleeding
time is prolonged)
• ASA and NSAIDs inhibit the enzyme
cyclooxygenase (COX), which in turn prevents
the formation of thromboxane A2 and
prostaglandins
• Clopidogrel (Plavix) blocks platelet aggregation
by inhibiting the ADP receptor
Glycoprotein IIb/IIIa receptor
inhibitors
• Abciximab (ReoPro)
• Eptifibatide (Integrillin)
• Tirofiban (Aggrastat)
• gpIIb/IIIa is a molecule necessary for platelet
aggregation
• Aspirin’s effect on platelets is irreversible and
lasts 7 to 10 days; d/c aspirin 7 days prior to
major surgery
• d/c NSAIDs (short-acting) 24 hours prior to
surgery; long-acting 7 days prior to surgery
Alternative therapies and platelet
aggregation
• If it starts with a G it inhibits platelet
aggregation—gingko, garlic, glucosamine,
ginseng, ginger, grapeseed extract
• SJW does too as does feverfew (used for
migraines)
• Fish oil can decrease the ability of platelets to
aggregate especially if the patient is taking other
G’s + ASA and/or NSAIDS and/or Plavix
• d/c feverfew, garlic, ginger, and ginseng 7 days
prior to surgery; gingko 36 hours prior to surgery
Arterial clots
• Liver produces clotting factors (II, VII, IX, X), cholesterol,
glucose, and inflammatory mediators overnight
• Spits them all out in the a.m.
• MI (arterial clot or white clot)—inflammation is the
operative word
• inflammatory mediators are highest in the morning;
triggers an unstable plaque in one of the coronary
arteries to rupture; platelets are stickiest in the early
a.m. due to the highest blood sugar of the day; platelet
plug forms, triggers clotting cascade; takes 2-3 hours to
form; up at 7? MI between 9 and 10 a.m.
• ASA inhibits platelet aggregation and decreases
inflammation
• Chest pain? Chew a 325 mg ASA
Serum Proteins
• Albumin
• Globulin’s ‘
• Add the two together and you have the total serum
protein test or TSP
• Albumin comprises 2/3 of the total serum proteins;
globulins 1/3—this is called the A/G ratio
• Generally used as screening tests altho’ the albumin
level can be used to determine nutritional status
and/ or prognosis in liver disease
• A better test that gives you more bang for your buck
is the serum protein electrophoresis
Serum Protein Electrophoresis—based on molecular
weight and overall charge (positive or negative)
+
-
Well in the gel
Electrical current running through gel
Serum electrophoresis
albumin
globulins
α1
α2
β
Γ
The globulins…
The alpha 1 globulins—there are a few alpha-1 globulins;
however, we’ll only discuss the most clinically important for
today’s lecture and for YOUR health
1) High-density lipoprotein—the good guy
2) What do they do? HDL’s clear excess cholesterol from the
blood; HDL’s are also potent “anti-oxidants” and prevent LDL
from oxidizing; the HDLs are also potent “anti-inflammatory”
lipoproteins; keep levels above 40 mg/dL (1.04 mmol/L) and
above 60 mg/dL (≥ 1.55 mmol/L) would be ideal
3) For every 5 mg/dL (0.13 mmol/L) decrease in HDL below the
mean, the risk of CHD increases by 25%
So if HDLs are good for you, how can we
boost HDLs without drugs?
• Eat right— garlic (crush it, let it sit for 10
minutes, eat it raw or lightly sauteé it for less
than 6 minutes), beans, omega-3 fatty acids,
fiber, almonds (and other nuts), plant stanols
(Take Control, Benechol, Smart Balance,
Yoplait Yogurt, Minute Maid Heart Wise OJ)
• Decrease saturated and trans fats
What else boosts HDLs?
• Exercise
What else boosts HDLs?
• Estrogen
• Premenopausal women have fabulously high
HDLs—one of the major reasons the heart is
protected prior to menopause
Booze to boost HDLs… a little dab‘ll do
ya’…
• This is a yes…
• 5 oz of wine of any color—This amount→
• Guys, you can have 2 glasses
• How much of the hard stuff? 1-2 ounces for
women; 2-3 ounces for men
• How about a brewski? 12 ounces for women,
24 ounces for men
So, what’s my motto?
• Bike a mile, guzzle a brewski, and pop a
Premarin…OR…
• Have a delicious glass of Chardonnay with a
lovely salmon dinner with my Mom…
• OR…
Increasing HDLs with pharmacologic
agents
Say YES to drugs…
• Niacin/Niaspan boosts HDL the most—up to 25%
• Drugs— the “statin” sisters (prescribed to lower
LDL)– rosuvastatin/Crestor) gives you the most
bang for your buck in raising HDLs (boosts HDLs
by 12-14% vs. ~6% for the other statins)
• Metformin (Glucophage) increases HDLs
• Pioglitazone (Actos) increases HDLs
Other drugs that influence HDL levels
• Increase HDL--glucocorticoids, cyclosporine,
tacrolimus
• Decrease HDL—androgens/testosterone,
progestins, thiazide diuretics, beta-blockers,
valproate and related drugs, isotretinoin
Beta globulins—the bad guys
• LDLs (low density lipoproteins)—directly deposit into the walls
of the arteries via the process of oxidation
• The higher the LDLs, the greater the risk for atherosclerosis
• Familial hypercholesterolemia—heterozygous vs. homozygous
(Quebec)
Guidelines for LDLs
• A patient with CAD or a risk equivalent (diabetes),
the LDL should be ~70 mg/dL (2.2 mmol/L or even
lower, perhaps 1.8 mmol/L)
• For the rest of us with other risk factors—100 mg/dL
(<2.85 mmol/L)
• Unless you’re perfect…--130 mg/dL (<3.37 mmol/L)
• Size of the LDL particles…small and dense vs. large
and loose (diabetics tend to have small and dense
due to high triglycerides)
Risk factors for increased LDLs
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Diet high in trans and saturated fats
Smoking
High iron levels
High insulin levels
Couch potato
Fat around the middle
LDL reduction
• Exercise? Eat right?
• Foods; fiber; almonds; plant stanols
• Reduce red meat, sat fats and trans fats
How about drugs to reduce LDL? Say YES to the
“statin” sisters…
• Say yes to the “statin” sisters—lova (Mevacor),
atorva (Lipitor), prava (Pravachol), simva
(Zocor), fluva (Lescol), rosuva (Crestor), and
the newest statin “sister” is pitavastatin
(Livalo)
• Statin dose chosen should reduce the LDL by
30-40%
Statin doses
• Instead of starting with the lowest doses, begin with a dose
that drops the LDL-C by 30-40%
• Rosuvastatin/Crestor—5-10 mg = 39-45% LDL reduction
• Fluvastatin/Lescol—40-80 mg = 25-31% reduction
• Atorvastatin/Lipitor – 10 mg = 39% reduction
• Pravastatin/Pravachol – 40 mg = 34% reduction
• Simvastatin/Zocor – 20-40 mg = 35-41% reduction
• Lovastatin/Mevacor – 40 mg = 31% reduction
Drugs that influence LDL-cholesterol
• Increase LDLs: Progestins, androgens,
cyclosporines, tacrolimus, thiazide diuretics,
setraline, atypical antipsychotics
• Decrease LDLs: estrogens/estradiol
VLDL (very low density lipoproteins)-triglycerides
• Dietary causes? Copious amounts of refined sugars, high
fructose corn oil, and alcohol (?)
• Genetics
• Ideal is less than 150 mg/dL (1.70 mmol/L)
• Borderline high is 150-199 (1.70-2.25 mmol/L)
• TG are a major risk factor for peripheral neuropathy in the
diabetic
• TG and fatty liver disease
Drugs? Fish oil for TG reduction?
• Niacin/Niaspan (see slides at the end of
handout for titrating Niacin)
• Gemfibrozil (Lopid)
• How much fish oil?
• For fish oil? READ the label –1000 mg of
combined EPA and DHA per day for
maintenance; cardiologist may prescribe more
Lovaza—prescription omega-3s
• Or the cardiologist may prescribe a form of
fish oil which provides ALL YOU NEED in one
pill
• LOVAZA (old name, Omacor); used for very
high triglyceride levels; 4 g/day is the dose
Pharmacological management of
hypertriglyceridemia
• Triglyceride levels greater than 1000-1500 mg/dL
(11.3 to 16.9 mmol) require treatment with
fibrates to reduce the risk of acute pancreatitis
• “fibrates”--(TriCor, Lipofen, Triglide, and Lipidil in
U.S. and Bezalip in Canada)
• Lifestyle modifications—weight loss results in a
mild-to-moderate decrease (about 22%) and an
increase in HDL (about 9%), largely because of an
increase in HDL2, about 43%)
• The level of small, dense LDL particles may
decrease by as much as 40%
Drugs that increase triglycerides
• Alcohol
• Estrogens
• Androgens,
testosterone
• Glucocorticoids
• Cyclosporine
• Tacrolimus
• Thiazide diurectics
• Beta-blockers
• Sertraline (Zoloft)
possibly
• Protease inhibitors
• Valproic acid
• Isotretinoin
• (progestins decrease
TGs)
WBC and DIFFERENTIAL
• 5 types of mature WBC’s and one immature
WBC circulate in the “cold, cruel world”
known as peripheral blood
• Normal range 5,000 to 10,000 (3500-12000)
The differential…
• Neutrophils (polys, PMN, segs)(57-63%) of the
total white count; acute inflammation, acute
bacterial infections, acute necrosis (1.51-7.07)
Bands (0-4%) (0.00-.51)—precursor to the
neutrophil
• Too many? Neutrophilia.
• Too few? Neutropenia (usually preceded by
two words— “life threatening…”
• Lymphocytes (30%)-first responder to viruses;
cells of the immune system (0.65-2.8)
The differential, continued…
• Monocytes (4%)—macrophages in tissues; cells of
chronic inflammation; antigen processing cell (APC)
(0.00-0.51);
• Eosinophils (3%)—cells that respond to parasites and
allergies (0.00-0.42) (Carlotta)
• Basophils (less than 1%)—who cares? Contain
histamine (0.00-0.16) (basophilia—CML, PV)
• *all the cells with the last name “phil” are collectively
called granulocytes—hence, the term agranulocytosis
means a decrease of all three; but in clinical practice
agranulocytosis means neutropenia
Neutrophils
• Phagocytic functions-- their only job in the world is
to EAT until they die
• Cell of acute inflammation
• First responder to bacterial invasion (strep, staph, E.
Coli, H. flu, meningococcus, Pseudomonas, C.
difficile)
• Loves acute necrotic tissue (gangrene, MI,
appendicitis)
• Fastest dividing cell in adult bone marrow
How do neutrophils grow up (the process
of differentiation)?
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Stem cells
Myeloblast (BM=bone marrow)
Promyeloctye (BM)
Myelocyte (BM)
Metamyelocyte (juvenile) (BM)
Band neutrophil (BM and PB=peripheral
blood)
• Segmented neutrophil (BM and PB)
Differentiation and the “shift to the left”
• During the time of acute need, the bone marrow is
functioning overtime…massive production results in a partial
loss of quality control concerning the immaturity of the cells
that are released into the peripheral blood
• WBC and diff will show an increased number of neutrophils
and bands and maybe even a metamyelocyte or two—
• shift toward immaturity— “more immature forms”
• Shift-to-the-left—increased number of bands
• What is the usual number of bands? 0-4%
• Bands and SIRS—the systemic inflammatory response
syndrome—greater than 10% bands
Clinical conditions with an increased WBC and
“shift-to-the-left”
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GABHS
Pyelonephritis
Acute appendicitis
Surgical site infection with MRSA
The Absolute Neutrophil Count (ANC)
• Neutropenia is defined as an absolute neutrophil count
(ANC) <500/mm3 or an ANC of <1,000/mm3 with an
expected decline.
• Serious bacterial infectious risk increases directly with
the following: (1) severity of neutropenia (ANC < 100
cells/mm3 imposes a greater risk than ANC < 500
cells/mm3), (2) rate of ANC decline (rapidly falling rate
imposes a greater risk than chronic neutropenia or
aplastic anemia), and (3) duration of neutropenia
• % segs + %bands x total WBC
• 57% segs + 3% bands x 10,000 = 6,000
Clinical cases…
• 46 y.o. female receiving chemotherapy for
breast cancer—total WBC is 2,000
• Is she neutropenic? Don’t know…Is she
leukopenic? Yes
• Segs = 57%, bands = 3%; ANC is 60% of 2000 =
1200
• She is NOT neutropenic
Clinical cases…
• 52 y.o. female receiving chemotherapy for
colon cancer—total WBC is 2,000
• Is she neutropenic? Don’t know…Is she
leukopenic? Yes
• Segs = 37%, bands = 3%; ANC is 40% of 2000 =
800
• She is neutropenic
Neupogen or Neulasta
• TO THE RESCUE: Filgrastim (G-CSF-granulocyte colony stimulating factor),
Neupogen, and pegfilgrastim (with
polyethylene glycol ), Neulasta—stimulates
neutrophil maturation and differentiation in
the bone marrow to reduce febrile
neutropenia in chemo patients—for nonmyeloid malignancies
Drugs and neutropenia
• Chemotherapy (all patients)
• Cimetidine (Tagamet), ranitidine (Zantac)
• Captopril (Capoten), enalapril (Vasotec), amiodarone,
quinidine
• Zidovudine (Retrovir)
• Clozapine (Clozaril)
• Antibiotics including metronidazole (Flagyl),gentamicin,
clindamycin, imipenem, PCNs, tetracyclines
• Azothiaprine (Imuran)
• PTU and methimazole
Anti-convulsants that cause
neutropenia
• Carbamazepine (Tegretol)—baseline, monthly for
2 or 3 months, then at least every-other-year
• Felbamate (Felbatol)—anticonvulsant; baseline,
frequently during therapy, and for a significant
time after discontinuation (dangerous drug, use
only if nothing else works)—if it doesn’t cause
neutropenia, it will kill your liver
• Phenytoin (Dilantin) can also cause neutropenia
NEUTROPHILS…normal function
• Margination, pavementing, migration,
engulfment, and degranulation
Yum.
Prednisone and the neutrophil
• Inhibits migration and degranulation, hence its antiinflammatory properties
• Prednisone also increases blood sugar by stimulating
glycogenolysis in the liver
• Hyperglycemia inhibits the function of neutrophils
• Diabetes– Blood glucose greater than 180 mg/dL (9.99
mmol/L) inhibits neutrophil migration (normal blood glucose
is 74-110 mg/dL or 4.1-6.1 mmol/L)
• Elderly with decreased migration of neutrophils, increases
infection susceptibility
• Fever increases the migration of neutrophils—is fever good
for you? YES!
STRESS!
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Stress and the WBC
Screaming kids
24-hours post-op
Last trimester of pregnancy
No bands
Inflammation—lab tests
• C-reactive protein -- < 1 mg/dL or < 10 mg/L; the CRP is
an acute phase reacting protein; rapid, marked increases
occur with inflammation, infection, trauma, tissue
necrosis, malignancies, and autoimmune diseases
• Increases quickly and dramatically in response to stimuli,
and decrease substantially with resolution of the
disorder
• May serve as a “marker” to determine how adequate the
treatment regimen is—ex. Antibiotics for osteomyelitis—
follow the CRP to gage clinical response
• Not a “diagnostic” marker, but used as a “prognostic”
marker
High sensitivity or hs-CRP reflects low levels of
inflammation in the vascular system and cardiac risk
• Patients with chronic vasculitis have an increased risk
of cardiovascular events—lupus, rheumatoid arthritis
• Use of hs-CRP + lipid values together are more
accurate at predicting risk than lipid studies alone
• Inflammatory mediators, IL-6 and TNF-α are
produced within unstable plaques as well as from
adipocytes in abdominal fat, which in turn increases
hs-CRP production by the liver
• The bigger the waistline the greater the hs-CRP and
the greater the risk for cardiovascular disease
(Ridker PM et al. N Engl J of Med 2000; 342:836-43)
In addition to losing the inches around the
waistline, what else can reduce hs-CRP?
• Exercise
• Omega-3 fatty acids
• Nuts
• The Mediterranean diet is anti-inflammatory
DRUGS
• JUPITER STUDY (2008) and rosuvastatin (Crestor) and
most likely all statins (Ridker)
• Pioglitazone (Actos)
• Aspirin and potentially other anti-inflammatory drugs
Monocyte/Macrophage
• Monocyte in blood, macrophage in tissue (Kupffer cell in liver,
microglial cell in brain, histiocyte in connective tissue)
• Phagocytes that respond much slower than the seg (2-4 days
vs. 5-10 minutes for the seg)
• Eats for months
• Cell of chronic inflammation
The macrophage—the link between
inflammation and immunity
• The macrophage is the antigen processing and
presenting cell (APC)
• It engulfs the pathogen
• Chews it up
• Processes it and presents it to the helper T cell
(T4 cell) of the immune system
• VITAL link in the functioning of the immune
system
Gulp, chew, process, spit, kick…
“ON”
CD4
IL-1 release
TNF-a
IFN-gamma
macrophage
With CD4 receptor
IL-2
T4 cell
CD4
T4 or helper T cell
B s, Ts
WBCs
How do drugs influence this immune
response
• Prednisone inhibits IL-1 (interleukin-1) release—
immunosuppressive
• Methotrexate induces lymphocyte apoptosis
• Hydroxychloroquine (Plaquenil)—inhibits antigen
processing by changing the pH of the
macrophage
• Cyclosporine inhibits IL-2—used to reduce tissue
transplant rejection
• Etanercept (Enbrel) binds with excess TNF-a
molecules—anti-inflammatory
• Azathioprine (Imuran)—blocks proliferation of
lymphocytes
Monoclonal antibodies (the “li” group)
• Adalimumab (Humira), infliximab (Remicade),
golimumab (Simponi), and certolizumab pegol
(Cimzia) block TNF-a
• Daclizumab (Zenapax)—blocks IL-2 on
activated T cells to prevent organ transplant
rejection
• Basiliximab (Simulect)—prevent organ
transplant rejection via same mechanism as
daclizumab
What else does IL-1 do?
• Increases temperature set point by increasing
the production and release of prostaglandins
in the hypothalamus
• Acetaminophen and aspirin work in the
hypothalamus to inhibit prostaglandin
production (central inhibition)
IL-1 release…
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Increases serotonin release from brainstem—vomiting
Increases serotonin release from the duodenum—nausea
Duodenum—the organ of nausea
You are sick to your duodenum
“setrons” block serotonin release from the brainstem and
duodenum
• Granisetron, (Kytril), ondansetron (Zofran), doasetron
(Anzamet)
IL-1 release…
• Increases melatonin production and makes
you sleepy
IL-1 release…
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Lowers pain threshold—everything hurts
Your hair hurts
Your teeth hurt
Your skin hurts
Your tummy hurts
You’re miserable…
Amphoterrible B/Amphotericin B for
systemic fungal infections
• Triggers release of IL-1 from macrophages
• MISERY with fever, chills, rigors, nausea,
vomiting, and nephrotoxicity
• Newer liposomal preparations of
amphotericin (AmBisome, Abelcet, and
Amphotec) are associated with fewer side
effects
Other WBCs and drugs
• Eosinophilia – elevated eosinophils usually
means allergies or parasites
• Certain drugs can also elevate eosinophils as a
part of an allergic phenomenon to the drug;
drug allergies can also trigger a fever and rash
RBC’s-- drugs and anemia
Barb Bancroft, RN, MSN, PNP
www.barbbancroft.com
[email protected]
What do you need to make happy,
healthy red blood cells?
• One is good parents (genes and
hemoglobinopathies), and you can’t do
anything about that
• Hemoglobin electrophoresis
• What else do you need?
Healthy Kidneys…
• Erythropoietin production and hypoxia
• Renal failure and anemia (one of the first signs
of early renal failure is mild anemia)
• No kidneys? No problem…synthetic
erythropoietin is available
• Erythropoiesis-stimulating agents (ESAs)—the
“poietins”
• Epoetin alfa (Epogen) in 1989
• Darbepoetin (Aranesp) in 2000
Erythropoiesis stimulating agents—
ESAs
• Epoetin-alfa (Procrit) and darbopoietin
(Aranesp)—target to low side of the
hemoglobin range; higher range = more
deaths, hospitalizations, HF, stroke in nondialysis kidney failure pts. (Dharmaraja TS)
• To minimize risks, use the lowest dose to
maintain Hb between 10-12 g/dL
Healthy thyroid-Hypothyroidism…low metabolic rate
• Decreased metabolism decreases the
production of red blood cells
• Ladies, get those thyroid glands checked! 10:1
female to male ratio
• Starting testing at age 35-45…
Drugs and the thyroid
• Amiodarone—mixed bag--check TSH at baseline and
every six months; may cause hyperthyroidism (10%) OR
hypothyroidism (22%)
• Oxcarbazepine (Trileptal): consider evaluation of
thyroid hormone status (frequency not specified)—
may decrease total and/or free T4 (thyroxine) levels
• Lithium—TSH and T4 at baseline and yearly; Lithium
can cause hypothyroidism
• Check TSH if the patient is on a statin and muscle aches
and pains occur (hypothyroidism predisposes to
myopathy)
Iron
• FACT: you need iron produce RBCs
• You need iron to grow vertically, not…
You need iron to grow a baby…
• And you need LOTS of it!
Fact: You lose iron when you bleed
• Women have 20% less blood than men and
premenopausal women lose blood once a
month; hence, lower iron stores
• GI/GU?
• Cooking with an iron skillet?
Geriatrics and iron
• Elderly and iron absorption
• Decreased acid in stomach decreases iron absorption; PPIs for
GERD?
• If iron supplements are necessary, use vitamin C with
supplements to help absorb the iron
• Use calcium citrate in low acid situations, not calcium
carbonate
• PMF—??iron supplements?
• Not unless you’re symptomatic with iron deficiency
Iron storage
• Serum ferritin
•
adults –M = 20-250 ng/mL or mcg/L
F = 10-120 ng/mL or mcg/L
• Iron overload with >400 ng/mL in M and >200
ng/mL in females; consider hemochromatosis
• Iron deficiency with levels < 10 ng/mL (mcg/L)
Treating iron deficiency anemia
• Feosol Carbonyl Iron tablets or Feosol Ferrous Sulfate
Tablets
• Hemoglobin concentration usually increases by 1.0
g/dL weekly; continue treatment until anemia is
corrected and the serum ferritin concentration is
greater than 50 ng/mL. Microcytosis, if present,
typically resolves several months after iron stores are
replete. Completion of therapy in patients without
continuing blood loss typically requires several months
• Oral iron therapy often fails in patients who take
antacids, H2 Blockers, PPIs, or calcium supplements
B12 …
• 2,000 to 5,000 mcg of B12 is stored in the
liver for 5-7 years;
• Use about 1 mcg per day for making RBCs,
keeping the myelin in our central and
peripheral nervous system healthy, and
making serotonin in our “happy” centers
• Takes 5-7 years of no B12 intake to deplete
High-risk patients for B12 deficiency
• Over 55
• Lack of intrinsic factor (IF); autoimmune gastritis;
gastrectomy patients
• No animal protein in the diet; vegetarians; Tea and
Toasters; alcoholics
• Liver failure
• Malabsorption—Crohn’s disease, celiac disease; gastric
by-pass surgery
• Metformin (glucophage);
• Proton Pump Inhibitors—inhibit the pump that pumps
HCL acid AND Intrinsic factor; Intrinsic factor binds B12
and takes it to the ileum for absorption
• (Am J Clini Nutr (2007);86:1384)
The “prazoles”—Proton Pump Inhibitors
• MOA—Inhibition of the proton pump at the lumenal
surface of the stomach…especially after a meal
H+, Intrinsic Factor-B12
PPIs work here
Lumenal surface
Parietal cell
Basilar surface
H2 receptors
H2
H2 blockers work here
Clinical conditions associated with B12
deficiency
• Big, immature RBCs—called megaloblastic
anemia
• Cognitive dysfunction—#1 cause of nutritional
dementia
• Peripheral neuropathy (one of three top causes in
elderly)
• Depression (B12 is a co-factor in the production
of serotonin)
• So you have NO energy, you’re demented, can’t
feel your feet and depressed…JEEZZZZ…how
important is B12?
B12 replacement
• How can we replace B12? 4 ways…how much?
• With B12 dementia—B12 injections 1000mcg every
other day for 2 weeks, then once a week for 6 weeks,
then monthly
• With peripheral neuropathy—B12 injections
• Oral, nasal, or sublingual B12 in all others—1000
micrograms/day
• 4 S’s…shoot it, swallow it, snort it or suck it…
• Can you overdose on B12?
• No, the one dreaded side effect however is:
You need Folic acid (B9) to make happy,
healthy RBCs
• Dr. George Herbert
• 40 days and 40 nights to deplete bone marrow
stores
• Maintenance of healthy RBCs--anemia
• Maturation of the neural tube (first 28 days)-NTDs
• Take folic acid 400 mcg (0.4 mg) BEFORE you
get pregnant + eat
• Green leafys and citrus fruits
Drugs that block folic acid synthesis that are
taken longer than 40 days and 40 nights…
•
•
•
•
TMP/SFX (Bactrim, Septra)
Rheumatrex (Methotrexate)
Phenytoin (Dilantin)
Oral contraceptives
• Supplement with folic acid
How do RBCs grow up? The process of
differentiation and maturation…
• Stem cell (BM)(bone marrow)
• Erythroblast (BM)(nucleated)
• Pronormoblast (BM) (nucleated)
• Normoblast (BM) (nucleated)
• Reticulocyte (BM and PB)(no nucleus)
• Erythrocyte (PB)
(process takes 7-12 days)
The reticulocyte count
• The reticulocyte count…0.5-1.5% of total RBC
count; takes 7-12 days to make and release a
“retic” from the bone marrow
• Is this patient “reticking”?
• In other words, is this patient actively making
RBCs?
Making retics, but destroying them
• High retic count…RBC’s are being destroyed in the
peripheral blood (hemolysis) and the bone marrow is
working overtime to produce more
• Hemolytic anemias
• 27-year-old African American female with anemia
• RBC=3,000,000 (normal range = 4.5-6 million)
• Retic count 35% (normal range = 0.5-1.5%)
• What should you think about?
Hemolytic anemias
• Hereditary--Sickle cell? Thalassemia? G6PD
deficiency
• Autoimmune hemolytic anemia (lupus)
• Is she pregnant? HELLP syndrome (hemolysis,
elevated liver enzymes, low platelets)
• Coomb’s test—what is it used for?
Drug/medication exposure and
anemias
• Penicillin, cephalosporin, procainamide,
quinidine, quinine, sulfonamide—drug-induced
hemolytic anemia
• Dapsone, naphthalene, and fava beans – oxidantinduced hemolysis (G6PD deficient patients)
• Cancer chemo (recent use) (bone marrow
aplasia;hypoplasia, oxidant damage, fluid
retention/dilutional anemia, megaloblastic
anemia
Underproduction anemia
•
•
•
•
Low retic count
Usually due to a deficiency of a nutrient
Iron, B12, folic acid
Cancer chemo (past use)(bone marrow
hypoplasia), myelodysplasia, acute myeloid
leukemia
• Chloramphenicol, gold salts, sulfonamides, antiinflammatory drugs—bone marrow aplasia,
hypoplasia
Some numbers…
• Total RBC count—4.2-5.6 (M) million and 3.85.3 (F) million
• Hemoglobin adult females (11-15.5 g/dl) (110155 g/L)
males (13-17.3)(130-173 g/L
• Hematocrit
females—39-50 (0.39-0.50)
males—35-47 (0.35-0.47)
What is anemia defined as?
Anemia
• Anemia is defined by the WHO as a
hemoglobin level less than 12 g/dL for women
and less than 13 g/dL for men.
• Prevalence of anemia in the over 65 group is
~10.6%, and the prevalence increases with
age to more than 20% in the over 85+ group
RBC indices…(morphology)
• **MCV (mean cell volume) – 90 (83-97) fL;
microcytic, normocytic, macrocytic
• MCH (mean cell hemoglobin) – 29 (27-31) pg (27-35);
hypochromic, normochromic, polychromic
• MCHC (mean cell hemoglobin concentration)—34 (32-36)
g/dL
• How do we define anemias? Based on morphology, the MCV
is the most important test…
Microcytic anemia
•
•
•
•
•
•
•
RBC 3,000,000
MCV 65 (normal 83-97)
9/10 with iron deficiency anemia
Where’s the bleed? Female? Male? Exercise? NSAIDS?
Growing kid?
Tea drinking?
Two other causes of microcytic anemia—lead poisoning,
Thalassemia
• You need to correct the iron deficiency in patients on
erthropoiesis stimulating agents in order for the patient
to benefit from using these drugs
And don’t forget your occult fecal blood
tests…every year
• Blood in the stool is a primary sign of colon
cancer
Macrocytic anemia
•
•
•
•
RBC 3,000,000
MCV greater than 100 fL
MCV between 100 and 120—think booze
MCV greater than 120—think B12 or Folic acid
deficiency
• Who’s at risk?
•
•
•
•
•
•
Gastrectomy patients
Chronic atrophic gastritis
Chronic malabsorption
Alcoholics
Competition for B12 (tapeworms)
Strict vegetarianism
Drugs that cause megaloblastic
anemia
•
•
•
•
•
•
•
•
•
•
Acyclovir
ASA
Anticonvulsants
Azathioprine (Imuran)
Colchicine
INH
Metformin
MTX
Neomycin
Proton Pump inhibitors
Normocytic anemia
• RBCs 3,000,000
• MCV normal
• The anemia of chronic disease—CKD,
hypothyroidism, chronic inflammation (TB),
cancer (unless a bleed is involved)
Liver function tests, serum
enzymes and drugs…
Liver function tests (LFTs)
• Hepatocellular integrity (SGOT, SGPT)—also
known as AST, ALT
• Hepatobiliary integrity--Bile formation and
flow (bilirubin, GGT, alkaline phosphatase)
Hepatocellular enzymes
• AST (SGOT) is NON-specific…in other words, it is
found in many tissues and therefore not specific as a
liver enzyme
• ALT (SGPT) is found almost exclusively in liver cells
and is therefore highly specific for the liver
• If a “healthy” person demonstrates an elevated ALT, a
thorough history is warranted with special questions
such as hepatitis exposure, hepatotoxin exposure,
and drug effects
Hepatocellular enzymes
• If enzymes are not terribly elevated (less than
2x normal—(some hepatologists say up to 3x
normal), have the patient stop all drugs that
are NOT necessary and recheck the enzyme
levels in 2 weeks before doing a multi-million
dollar work-up
Hepatotoxin exposure and drug effects
• Chemicals (cleaning chemicals such as CCl4 ),
vinyl chloride
• Occupational hazards—dry cleaners, painters, chemists
• Vitamin A toxicity
• Hundreds, if not thousands, of drugs can
elevate liver enzymes and cause druginduced-liver-injury
Drug induced liver injury (DILI)—who’s
at risk?
• Children are more prone to DILI w/ salicylates
and valproic acid
• Obesity increases the risk of liver injury due to
halothane and methotrexate (Rheumatrex dose
pack, Trexall)
• Acetaminophen-induced liver injury is more likely
in persons who are fasting or malnourished, as
well as those who chronically abuse ETOH (more
than 3 adult beverages per day)
Acetaminophen overdose
• The minimum toxic single dose in healthy
adults is between 7.5 and 10 grams and ≥ 150
mg/kg in children.
• Variability among patients re: toxic dose is
most likely due to a genetic variation
Drug-induced liver injury—who’s at
risk?
• Women are more likely to experience DILI
caused by diclofenac*, isoniazid, or
nitrofurantoin, while azathioprine (Azasan,
Imuran) is a more likely cause in men
• The incidence of liver injury varies among the
NSAIDs and appears to be the most common
with diclonfenac (1-5 cases per 100,000) and
sulindac (Clinoril)
What should be done?
• Discontinue the drug if all non-drug causes of
liver injury have been investigated and ruled
out
• What are the nondrug causes? Hepatitis A-E,
biliary disease, biliary obstruction, alcohol
abuse autoimmune hepatitis or cholangitis,
bacterial infections that can mimic acute
hepatitis (Camplobacter, Salmonella, and
Listeria) and Wilson’s disease.
• But what if it’s the only drug that works for
that specific condition?
• Continue treatment with the drug if the ALT is
less than 5x the ULN, as long as the patient
remains asymptomatic and the serum
bilirubin remains within normal limits (Scott)
Positive criteria that implicates a drug
• Drug levels elevated
• Allergic manifestations (peripheral eosinophilia,
rash, fever)—occur in about 23% of the patients
• Latency period of 1 month or less
• Rapid development of symptoms upon
rechallenge (not that you would do this to prove
your point…it would have to be an inadvertent
challenge)
• Liver biopsy—with eosinophilic infiltration,
granulomas
Acetaminophen (Tylenol) and the liver
• Acetaminophen is in over 300 OTC products
• Drippy, coughy, hacky, sneezy, wheezy,
headachy, achy, sleepy, ouchy products
• Prescription products—with the last name
“cet”—Darvocet, Percocet
• Acetaminophen overdose is the most frequent
cause of acute liver failure in the U.S.
population, accounting for 39% of cases
(Ostapowicz)
AST/ALT ratio
• AST 8-20 U/L (0.43-1.28 μKat/L—adult males;
11-26 U/L (0.19-0.44 μKat/L—adult females)
• ALT 10-40 U/L (0.17-0.68 μKat/L—adult males;
7-35 U/L (0.12-0.60)
• The normal AST/ALT ratio should be 1
If the AST/ALT ratio is greater than 1…
• Consider ETOH…
• AST is especially sensitive to alcohol
• If alcohol damages liver cells, the AST will
increase higher than the ALT
• Ratio in alcohol- induced hepatitis is usually 3:1
to 8:1*
• Also consider any other cause of a fatty liver (see
next slide for the causes of non-alcoholic fatty
liver disease)
*It is rare for the AST level to be more than 8 times
the normal value in patients with alcohol abuse
Causes of non-alcoholic fatty liver
disease
• Obesity
• Diabetes
• The above two have traditionally been the “only”
causes of NAFLD, but there are more…
• Males greater than females
• Drugs—prednisone, MTX, synthetic estrogens,
amiodarone (Cordarone, Pacerone), tamoxifen,
nifedipine, and diltiazem
• Heavy exposure to organic solvents
• Long-term IV feeding
• Rare genetic diseases
AST/ALT ratio of less than 1
• If less than 1 consider drugs other than those
that cause fatty liver disease, viruses,
autoimmune hepatitis, hemochromatosis,
Wilson’s disease, alpha-1 antitrypsin
deficiency
• Always check the TSH—may see mild increase
in liver enzymes with hypothyroidism
• Eating lots of fast foods can also increase liver
enzymes
Extremely high levels of hepatocellular
enzymes
• Marked elevation of ALT and AST is typical of
severe acute viral hepatitis, toxic or drug-induced
hepatic necrosis, and shock or ischemia to the
liver
• The finding of extremely high levels (greater than
2000 to 3000 U/L) should always raise concern
for acetaminophen OD, use of excessive
therapeutic doses of acetaminophen by an
alcoholic patient, or shock and/or ischemia to the
liver
Alkaline Phosphatase (ALP, or AP)
• 35-105 U/L
• Think Biliary and Bone
• Any disturbance in the synthesis, secretion, or
excretion of bile leads to the accumulation of bile
acids in the liver increasing the synthesis of ALP
• Sensitive indicator of cholestasis—estrogen can
cause cholestasis
• Infiltrative processes such as liver metastasis
Alkaline Phosphatase (ALP, or AP)
• Alkaline phosphatase is produced in the
osteoblasts to build bone
• Increased with growth spurts—1st year and
adolescence
• Pagets disease—hypermetabolism of bone
• Osteogenic sarcoma
• Metastatic disease to bone (breast, prostate)
Pancreatic enzymes
• Amylase 3 – 100 (U/L) and lipase 1.3 – 6 (U/L)
• Amylase also found in the parotid gland
(mumps)
• With pancreatitis, amylase and lipase rise
rapidly within 2 to 6 hours, reaching a
maximum in 12 to 30 hours
• Serum lipase remains elevated for 8 to 14
days; serum amylase usually reaches baseline
after 2 to 3 days; urinary amylase remains
elevated for 8 days
Pancreatic enzymes
• What are the 2 major causes of elevated
pancreatic enzymes?
• Booze and gall stones cause 70% of cases
• Perforated peptic ulcer
• Peritonitis
• Ruptured ectopic pregnancy
• Mumps orchitis (why do they call them
“orchids”?
Drugs and acute pancreatitis (partial
list)
• Sulfasalazine (Azulfidine)
and other sulfas
• Furosemide, Thiazides
• Azathioprine (Imuran)
• Gliptans
• Exanatide (Byetta)
• Chemotherapy—Lasparaginase
• HAART drugs
• Sulindac (Clinoril)
•
•
•
•
•
•
•
•
•
•
Acetaminophen
Alphamethyldopa
Cannibis
Azothiaprine
Benazapril
Bezafibrate
Cimetidine
Clozapine
Codeine
Corticosteroids
Creatine Kinase—Total CK—55-170 units/L
(male); 30-135 units/L (female)
• Found in high-energy tissues including:
• Isoenzymes for specific tissues—1 (BB),2 (MB),
3 (MM)
• Skeletal muscle (98% CK-3, CK-MM; 2% is CKMB)
• Cardiac muscle (40% CK-2, CK-MB; 60% CKMM)
• Brain (CK-1, CK-BB) (also large intestine, CKBB)
Rhabdo “skeletal” myo “muscle” lysis
• Myopathy is defined as any muscle symptom—pain,
tenderness, or weakness—accompanied by a creatine
kinase concentration greater than ten times the ULN
(also called myositis)
• Severe myopathy with muscle breakdown and
myoglobin release into the circulation, which can cause
brown discoloration of urine and risk of renal failure
• Rhabdomyolysis is usually diagnosed when the CK
concentration is greater than 40 times the ULN or
there is evidence of end organ damage (acute renal
failure or worsened renal function)
Rhabdomyolysis
• Statins get all of the press, but in reality over 150 drugs
and toxins (including alcohol) have been known to
cause rhabdomyolysis
• Who are the statin sisters? Lova/Mevacor,
prava/Pravachol, simva/Zocor, fluva/Lescol,
atorva/Lipitor, rosuva/Crestor, and pitavastatin (Livalo)
• cerivastatin/Baycol was removed from the market
because she caused more cases of rhabdomyolysis
than all of the other statins combined— ”ceriva” was
associated with a 7-fold increase in myopathy
compared to atrovastatin
Rhabdomyolysis
• Patients on statins who are at highest risk?
Concomitant use of gemfibrozil (Lopid), over 80,
hypothyroidism, renal impairment, higher doses)
• Overall risk of myopathy with monotherapy statin
use is 4- 1 per 100,000 person-years of follow-up,
with the risk of rhabdomyolysis about one-third
of this (3 to 4 per 100,000 person-years)(Armitage)
• Renal failure develops in up to 50% (Naughton)
• Check renal function
Amiodarone (Cordarone, Pacerone)
and simvastatin (Zocor)
• High risk of rhabdomyolysis with the above
combination
• Amiodarone inhibits CYP3A4 which increases
concentrations of drugs metabolized by this
enzyme—lova, simva, and to a lesser extent
atorvastatin
• Don’t prescribe more than 20 mg of
simvastatin or 40 mg of lovastatin per day
with amiodarone
Recommendations to Healthcare Professionals
Regarding the Muscle and Statin Safety
• Whenever muscle symptoms or an increased CK level is
encountered in a patient receiving statin therapy,
health professionals should attempt to rule out other
etiologies—increased physical activity, trauma, falls,
accidents, seizure, shaking chills, hypothyroidism,
infections, carbon monoxide poisoning, polymyositis,
dermatomyositis, alcohol abuse, and drug abuse
(cocaine, amphetamines, heroin, or PCP) (McKenney
JM)
• Vitamin D deficiency causes muscle aches and pains
• ED drugs cause muscle aches and pains
• Exercise causes muscle aches and pains
One last note on rhabdomyolysis
• Many drugs of abuse have been reported to
cause rhabdo
• Cocaine, heroin, ketamine (Ketalar),
methadone, and methamphetamine
• Drugs and alcohol are causative factors in up
to 81 percent of the cases of rhabdomyolysis
• (Naughton)
DRUGS AND THE KIDNEY
Gross anatomy
•
•
•
•
•
Renal capsule
Renal cortex (glomeruli)
Renal medulla (tubules)
renal papillae
the renal interstitium
(columns)
• renal pelvis (pyelo)/calyces
• Pyelonephritis vs.
glomerulonephritis
The kidney as an innocent bystander
• Drugs that cause tubular cell toxicity—ie.
Acute tubular necrosis with drugs such as
cisplatinin (Platinol), aminoglycosides,
amphotericin B, antiretrovirals, contrast dye,
foscarnet (Foscavir), and zoeldronate (Zometa)
• What’s the good news about acute tubular
necrosis?
The kidney as an innocent bystander
• Drugs can cause inflammatory changes in the
glomerulus, renal tubular cells, and the
surrounding interstitium, leading to fibrosis
and renal scarring
• Glomerulonepthritis—ampicillin and
penicillin, apresoline, interferon-alfa (Intron
A), lithium, NSAIDs, PTU, pamidronate
(Aredia),
The kidney as an innocent bystander
• Acute interstitial nephritis—idiosyncratic nondose-dependent—allopurinol (Zyloprim), beta
lactam antibiotics, quinolones, rifampin,
sulfonamides, and vancomycin, acyclovir
(Zovirax) and indinavir (Crixivan), thiazide and
loop diuretics, NSAIDs, phenytoin (Dilantin),
PPIs (especially omeprazole, pantoprazole
(Protonix) and lansoprazole (Prevacid) and
ranitidine (Zantac)
The kidney as an innocent bystander
• Chronic interstitial nephritis—acetaminophen,
aspirin and NSAIDS when used in high doses
for more than two years (greater than 1 gram
per day)
• Cyclosporine, tacrolimus, Chinese herbals
containing aristocholic acid, and lithium
Serum creatinine
• Female: 0.5 – 1.1 mg/dl or 44-97 μmolL
• Male: 0.6 -1.2 mg/dl or 53-106 μmol/L
• Measures the amount of creatinine in the blood
which is made via creatine (breakdown of
muscle); excreted mainly by the kidneys and
therefore is directly proportional to renal
excretory function
• Metformin (glucophage)—contraindicated when
serum creatinine is higher than 1.5 mg/dL in men
and 1.4 mg dL in women
Serum creatinine
• Trimethoprim-sulfamethoxazole and
cimetidine can decrease the secretion of
creatinine and falsely elevate serum creatinine
• Cefoxitin increases serum creatinine by
interfering with the assay
• BUN does NOT change
The kidney as an innocent bystander…
• Altered intraglomerular dynamics—
intraglomerular pressure is maintained by the
action of angitotensin II – mediated
vasoconstriction of the efferent arteriole
• Renal perfusion depends on circulating
prostaglandins to vasodilate the afferent
arterioles
Drugs and the kidney
• Drugs, such as cyclosporine (Neoral) or
tacrolimus (Prograf) cause dose-dependent
vasoconstriction of the afferent arterioles,
leading to renal impairment in high-risk patients
• Drugs with anti-prostaglandin activity (NSAIDs) or
those with anti-angiotensin-II activity (ACE
inhibitors or ARBs) can interfere with the kidney’s
ability to autoregulate glomerular pressure and
decrease GFR
•
“Angie” and the healthy kidney…
•
•
•
•
•
Afferent arteriole
(vasodilated via
(prostaglandins)
Blood entering
glomerulus
Glomerulus→filter
Efferent arteriole
(vasoconstricted via
(angiotensin 2)
Blood exiting
glomerulus
PG
filter
AT2
Toilet
Proteinuria—a manifestation of kidney
disease
• Activation of the renin-angiotensin-aldosterone
system exacerbates proteinuria
• Glomerular capillary hypertension leads to an
increase in glomerular permeability and excessive
protein filtration
• Although proteinuria is considered a marker of
renal disease risk, it also contributes to kidney
damage. Proteins present in the urine are toxic to
the tubules and can result in tubulointerstitial
inflammation and scarring (Brewster UC and
Perazella MA)
Drugs that block the renin-angiotensin-aldosterone
system and reduce proteinuria
•
•
•
•
•
•
•
•
•
Captopril (Capoten)
Enalapril (Vasotec)
Lisinopril (Prinivil, Zestril)
Perindopril (Aceon)
Moxepril (Univasc)
Benazepril (Lotensin)
Quinapril (Accupril)
Trandolapril (Mavik)
Ramipril (Altace)
• losartan (Cozaar),
• valsartan (Diovan),
candesartan (Atacand),
telmisartan (Micardis)
irbesartan—Avapro
olmesartan—Benicar
eprosartan--Teveten
The Diabetic Kidney…hyperglycemia/HTN (the deadly
duo)
•
Afferent arteriole
(  vasodilation by
(  prostaglandins)
• Blood entering
glomerulus
• Glomerulus→filter
• Efferent arteriole
(  vasoconstriction via
(  angiotensin 2)
• Blood exiting
glomerulus
Microalbuminuria
(between 30 mg—300 mg
of alb/g creatinine—10fold > risk of RD & CKD)
Why is microalbuminuria a “bad” thing?
• There is a 4-fold increase in acute coronary
syndromes in Type 1 DM greater than 35 years old;
• When microalbuminuria is present the risk is
increased by a factor of 140!
• The presence of albuminuria suggests that large
vessel walls are more permeable to lipoproteins or
damage from the local release of growth factors
• PRILS and SARTANS can decrease the decline in renal
function by 50% or MORE in the diabetic kidney
K+ levels and ACE inhibitors
• Use cautiously in patients with creatinine
levels > 3 mg/dL, or potassium levels greater
than 5.5 mEq/L (> 5.0 mEq/L in diabetics)
• Check K+ level no later than one week after
starting spironolactone (low risk patients
check at 7 days; moderate and high risk
patients check at 4 and 10 days, after a dose
increase or if diuretic doses are increased)
K+ and serum creatinine
Potassium levels?
• 5-5.5 recheck in 7 days
• 5.6 to 6.0 stop ACE and check in 7 days
• 6.1-6.5 stop ACE and treat hyperkalemia; diet
restriction; oral diuretics including loops or
metolazone (the most K+ wasting); oral NaHCO3
• Greater than 6.5 stop ACE and check urgently (may
need to head to the ER for ECG
• Greater than 8? Hospitalize; ECG changes with
peaked T waves, prolonged PR interval, loss of P
waves, widened QRS;
Potassium potassium potassium
• K+ sparing diuretics and K+ supplements should be
d/c’d unless there is continuing hypokalemia
• Diuretics should be withheld for 2-3 days before
commencing therapy if possible, to reduce risk of
first-dose hypotension
• NSAIDs should be avoided if possible during the
initiation phase
• The effects of ACE inhibition on blood pressure are
potentiated by restriction of salt intake
Serum creatinine and ACE inhibitors
• Creatinine—a rise of greater than 20-30% is
considered to be significant; smaller rises are
common and are to be expected in many
patients
Spironolactone, eplerenone, and
drospirenone and K+ levels
• Yasmin (drospirenone and ethinyl estradiol)
marketed to treat PCOS because of its
progestin component (drospirenone) is an
analog of spironolactone, an anti-androgenic
agent for hirsutism
• can cause hyperkalemia
• Used in gals with PCOS who also might be on
an ACE inhibitor because of the associated
hypertension and type 2 diabetes with PCOS
Last but not least, discontinue foods with
high potassium…
•
•
•
•
•
•
•
•
Banana (1m) 422 mg
Potatoes (with skin) 540 mg
French fries (1med) 924 mg
Halibut (3 oz) 490 mg
Spinach (1c) 839 mg
Pasta sauce (1c) 940 mg
Oranges 1 m 237 mg
Prunes (elderly) 10 615 mg
YOU TRY TO PRY THOSE PRUNES OUT
OF THAT ARTHRITIC DEATH GRIP!
Whew. Finito. Thanks.
• Barb Bancroft, RN,
MSN, PNP
• www.barbbancroft.com
• [email protected]
Bibliography
• Aronow WS. Hypercholesterolemia: The evidence supports
the use of statins. Geriatrics 2003; 58 (8): 1832.
• Armitage J The safety of statins in clinical practice. The Lancet
2007;370:1781-90)
• Bakerman S. ABCs of Interpretive Laboratory Data 2002;
Scottsdale, AZ
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Niacin titration schedule to minimize side
effects
• Niaspan (niacin extended-release)
weeks 1-4 500 mg @ hs
weeks 5-8 1000 mg @ hs
If needed: weeks 9-12 1500 mg @ hs (as two 750
mg tablets or three 500 mg tablets)
weeks 13 and on: 2000 mg hs (as two
1000 mg tablets or four 500 mg tablets)
Do not alternate between two 750 mg and three 500 mg
tablets—not interchangeable)
Niacin titration schedule
• Niacin immediate-release (IR)--Niacor (also called crystalline
niacin and can be purchased OTC or by prescription)
250 once daily following dinner. Increase dose every 4 to 7 days,
divided two or three times daily, until the desired HDL and/or
triglyceride goal is met, or a total daily dose of 1,500 mg to
2,000 mg, divided two or three times daily. After two months,
may increase by 500 mg every two to four weeks to 1000 mg
three times daily. Maximum total daily dose is 6000 mg (note:
NCEP III lists maximum as 4500 mg)
Prescribers Letter, 2010.
P.S. tell patients to NOT use long-acting (Slo-Niacin) products or
the “no-flush” Niacin—first one is toxic, second type is
ineffective)
Niacin Titration Schedule
• Niacin IR—maximum daily dose 4,500 mg
Week 1: 100 mg w/ bkfst and dinner
Increase by 100 mg/week to week 5
Or
• Niacin IR—maximum daily dose 4,500 mg
Week 1: 100 mg TID w/ food
Week 2: 200 “
Week 3: 250 mg TID w/ food
Week 4: 500 mg TID w/ food
Week 8: reassess lipids and if needed, increase to 750 mg TID
with food
Week 10: as above and increase to 1000 mg TID w/food.
Drugs and platelet aggregation
• Heparin -- heparin-induced
thrombocytopenia—type I and type II
• Patients with a hx of type II HIT should not
receive either UFH or LMWH (Use direct
thrombin inhibitors or fondaparinux (Arixtra)
• DTIs are structurally different from heparin
and do not cross-react with HIT antibodies
• (Perez ME, Graham MG)
Thyrotropin (TSH) 0.4 – 4.5. mIU/L; 0.6
– 4.5 μU/dL
• Primary hypothyroidism is usually the result of
Hashimoto’s thyroiditis, thyroidectomy for
hyperthyroidism, goiter or cancer, or radioactive iodine
therapy for hyperthyroidism
• May take 2-3 weeks before the resolution of symptoms
and but steady-state free T4 (FT4) concentrations (0.82 ng/dL)(12-21 pmol/L) and optimal TSH levels (0.4-4.5
mIU/L may not be achieved for 6-8 weeks)
• Treat to what level? The general rule of thumb is to
maintain the level between 1.0 and 2.0-2.5 mU/L, but
make sure you pay attention to the patient’s overall
state of health (Williams)
Check the thyroid!
• Thyroid replacement. The dose to initiate thyroid
replacement should be the patient’s weight in kilograms
(pounds divided by 2.2) x 1.6 = mcg dose. Then titer the dose
to keep the patient’s TSH less than 3. If the patient says…“I am
feeling fabulous…” check the TSH level and keep it at that
level. Brilliant. (Michigan NP group discussion—2007, Lansing
NP meeting)
Monitoring patients on thyroid
replacement
• TSH at baseline, every six to eight weeks until normal,
then every six to 12 months
• TSH six weeks to three months (eight to 12 weeks per
labeling) after change in dose or product
• Also check if clinically indicated, or if there is a change
in patient health
• Patients over 50 years of age with cardiac disease:
monitoring interval four to six weeks
• Adults less than 50 years of age with severe
hypothyroidism: monitoring interval two to four weeks
(Prescriber’s Letter, Detail Document #260704)
Drugs that may decrease
levothyroxine’s effect
• Amiodarone, antacids, colestyramine, calcium
supplements, ciprofloxacin, iron,
phenobarbital, phenytoin, raloxifene, rifampin
ritonavir, sertraline, sucralfate (Medical Letter
August 2009)
Drugs and hypoglycemia
• Secretagogues—sulfonylureas are associated
with hypoglycemic events by enhancing
insulin secretion from pancreatic beta cells;
older the patient, the higher the risk
• In the U.S. glylburide (Micronase, Diabeta)
has been associated with the highest number
of serious hypoglycemic episodes (Goldstein
P)
Statin doses
• Instead of starting with the lowest doses, begin with a dose
that drops the LDL-C by 30-40%
• 30-40% reduction—Atorvastatin 10 mg-20 mg; simvastatin 40
mg; lovastatin 20 mg + ezetimibe 10 mg; pravastatin 20 mg +
ezetimibe 10 mg
• 40-50% reduction—Atorvastatin 20 mg-40 mg; simvastatin 80
mg; rosuvastatin 5 mg; simvastatin 10-20 + 10 mg ezetimibe;
pravastatin or lovastatin 40 mg + 10 mg ezetimibe
• 50-60% reduction—rosuvastatin 10-20; atorvastatin 80 mg;
Atorvastatin 20 mg + ezetimibe 10 mg; simvastatin 40-80 mg +
ezetimibe 10 mg
Clopidogrel (Plavix)
• Inhibits ADP-induced platelet aggregation via the glycoprotein
IIb IIIa complex
• Irreversible action
• Reduces CV events in established CVD patients—75 mg daily
• Give to patients with ACS (unstable angina and NSTEMI
patients)—300 mg loading dose and then 75 mg daily with 75325 mg of ASA
• ASA and Plavix for unstable angina or a new stent—combo for
9 months for unstable angina and 12 months after a stent
(Lancet 2004:364:331)
• Adding aspirin to clopidogrel after stroke doesn’t improve
endpoints but doubles the risk of life-threatening bleeding
episodes (Lancet 2004; 364:331-337)
Hyperthyroid drugs and the liver
• PTU causes severe allergy-mediated hepatic
failure in 0.1 –0.2% of patients; about 30% will
have transient elevations in AST/ALTs
• Liver failure has occurred in 1 in 2000 to 1 in
4000 children treated with PTU; no reports of
liver failure with methimazole
• Methimazole infrequently causes liver
dysfunction including cholestatic jaundice
(elevated bilirubin, alkaline phosphatase, GGT)
Thyroid drugs and neutropenia
• The thionamides—the antithyroid drugs, methimazole
(thiamazole in some countries) and propylthiouracil (PTU) –
• Agranulocytosis (neutropenia) occurs in ~0.1 to 0.4% of
patients, generally within the first 3 months of Rx. But, it
can occur anytime
• More frequent in elderly and with re-introduction of the
drug in a patient who previously used it uneventfully
• Dose-response with methimazole; doses over 30 mg daily
have highest risk
• Not so with PTU—any dose can cause a reaction
• discontinue drug and have a WBC drawn if a fever or other
evidence of infection develops (Brent GA and Med Letter
2009/August)
Caution: Ayervedic medicines, heavy
metals, and anemia + more
• A study in JAMA (August 2008;300:915) found that
21 percent of 193 traditional Indian Ayurvedic
medicines bought on the Internet from U.S. or Indian
sources contained high amounts of lead, mercury, or
arsenic. One sample of a preparation called E Kangvir
Ras had 26,000 parts per million of lead. This
compares with a U.S. legal limit of 2 ppm in
pharmaceutically produced calcium tablets for the
elderly. A subset of preparations called Rasa Shastra
are prepared with heavy metals such as mercury and
arsenic.
As an FYI…
• Patient with triglycerides above 250 mg/dL (2.81 mmol/L) and
an HDL less than 40 mg/dL (1.04 mmol/L)—THINK either …
1) Type 2 Diabetes (check the fasting blood sugar or Hemoglobin
A1C), OR…
2) Hypothyroidism (TSH) (0.4-4.5 μU/mL or mU/L) for 21-54
y.o.; 0.5-8.9 μU/mL or mU/L for 55-87);
incidence is 10:1 female/male;
**One in seven people with high cholesterol has underlying
hypothyroidism; seventy percent of hypothyroid patients have
high TC and TG