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INTERPRETATION OF LAB TESTS with a Pharmaceutical Focus
Barb Bancroft, RN, MSN, PNPChicago, IL
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?
• 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
• 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
globulins
albumin
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 guy2) 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
• 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)?
• 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”
• 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 non-myeloid 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 anti-
inflammatory 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!
• 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-inflammatoryDRUGS• 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…
macrophageWith CD4 receptor
IL-1 release T4 cell
T4 or helper T cell
IL-2
CD4CD4
“ON”
TNF-aIFN-gamma
B s, TsWBCs
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…
• 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…
• 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
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 non-dialysis 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
Parietal cell
Lumenal surface
Basilar surface
H2 receptors H2
H+, Intrinsic Factor-B12PPIs work here
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 – oxidant-induced 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, anti-inflammatory drugs—bone marrow aplasia, hypoplasia
Some numbers…
• Total RBC count—4.2-5.6 (M) million and 3.8-5.3 (F) million
• Hemoglobin adult females (11-15.5 g/dl) (110-155 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 drug-induced-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—L-
asparaginase• 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 CK-
MB)• Cardiac muscle (40% CK-2, CK-MB; 60% CK-
MM)• Brain (CK-1, CK-BB) (also large intestine, CK-
BB)
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 non-dose-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
AT2
Toilet
filter
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—10-fold > 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 creatininePotassium 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!
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• Barron A, Falsetti D. Polycystic Ovary Syndrome in Adolescents.
ADVANCE for Nurse Practitioners, 2008 (March);49-54.• Brent GA. Grave’s Disease. N Engl J Med 2008; 358(24):2594-
2605.• Brewster UC, Perazella MA. The Renin-Angiotensin-
Aldosterone System and the Kidney: Effects on Kidney Disease The Am J of Med 2004;116:263-72.
Bibliography• Charles EC, et al. Evaluation of cases of severe
statin-related transaminitis with a large health maintenance organization. www.mdconsult.com (accessed 4/30/07)
• Dharmarajan TS and Widjaja D. Erythropoiesis-stimulating agents in anemia. Geriatrics, 2008 (June);63(6):13-18.
• Flora KD, Keeffe EB. Significance of mildly elevated liver tests on screening biochemistry profiles. J Insur Med 1990:22:206-210.
• Goldstein P. Assessment and Treatment of hypoglycemia in elders: cautions and recommendations. MEDSURG Nursing; July/August 2009; 18(4):215-224.
Bibliography• Gupta S, de Lemos JA. Use and misuse of cardiac troponins
in clinical practice. Progress in cardiovascular diseases 2007 (September/October); 50(2):151-65
• Medical Letter. Acetaminophen Safety (2002); vol. 51(1316)• McKenney JM, et al. Final conclusions and
recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardio. 2006;97(suppl):88C-94C)
• Naughton CA. Drug-Induced Nephrotoxicity. Am Fam Phys 2008;78(6):743-50.
• Ostapowicz G, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the US. Ann Intern Med. 2002;137(12):947-954.
• Perez ME, Graham MG. Strategies for bridge anticoagulation therapy. Patient Care 2007 (October):7-14
• Ridker PM et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive . N Engl J Med 2008;359:2195-207.
• Williams Textbook of Endocrinology (11th ed. Philadelphia, Pa: WB Saunders;2007)
• Wu A. Tietz Clinical Guide to Laboratory Tests. Fourth edition. 2006. WB Saunders, Co
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 5Or• 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 (0.8-2 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 75-325 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
