ANEMIA - PHARMACOTHERAPY IV

what is anemia

Hgb

classification of anemia

blood loss

decrease RBC

increase RBC

classification of blood loss anemia

acute (trauma, ulcer, hemorrhoids)

chronic (ulcer, vaginal bleed)

classification of decreased RBC anemia

nutrition (decreased B12, decreased folate, decreased iron)

bone marrow (cancer, aplastic anemia, chemo, radiation, drugs)

chronic (renal, liver, infection, vascular)

classification of increased RBC anemia

intrinsic (decreased G6PD, abnormal Hbg)

extrinsic (autoimmune, drug, infection)

MCV classification of anemia

normal MCV

increased MCV

decreased MCV

normal MCV classification of anmeia

acute (trauma, ulcer, hemorrhoids)

chronic (ulcer, vaginal bleed, chronic disease)

increased MCV classification of anemia

nutrition (decreased b12, decreased folate)

bone marrow (cancer, chemo, radiation, drugs)

decreased MCV classification of anemia

nutrition (decreased iron)

chronic

lab evaluation for anemia

Hbg, Hct, RBC count

platelets

red cell morphology

reticulocyte count

bilirubin and LDH

peripheral blood smear

stool examination

bone marrow aspiration/biopsy

what does MCV measure

mean cell volume

how big/small the RBC are

what are MCH measure

mean cell hemoglobin

how dark or light the RBC are

lab values for iron deficiency anemia

LOW:

retic < (0.5-1.5%)

MCV < (80-100)

MCH < (27-31)

MCHC < (33-37)

Fe < (50-160)

Ferritin < (15-200)

low Hbg low Hct

HIGH:

TIBC > (250-400)

guaiac stool positive (blood in stool sample)

predisposing factors for iron deficiency anemia

blood loss (menstruation, GI loss (hemorrhoids, ulcer-NSAIDs, trauma)

decreased absorption (medication (tetracycline, calcium, bisphosphonates, levothyroxin), gastrectomy, enteritis, gastric carcinoma, malnutrition)

inadequate dietary intake (vegetarian)

increased requirement (pregnancy, infancy, lactation)

presentation of iron deficiency anemia

progressively worsening weakness, dizziness

fatigue, pallor

sob, decreased exercise tolerance

tachycardia, palpitations, hypotension, cold intolerance

blood loss (GI/menstrual loss), ecchymosis, petechiae (tiny, pinpoint red or purple spots that appear on the skin due to bleeding under the surface), hematomas

Fe deficiency: pale nail beds, spooning of nails (rare), angular stomatitis, brittle nails, cravings for clay, ice or cornstarch

what is ferritin

iron stores

acute phase reactanct

what is serum iron

iron bound to transferrin

what is transferrin

carrier protein for iron

what is the total iron binding capacity

iron-binding capacity of transferrin

what is the transferrin saturation

serum Fe divided by TIBC, transferrin binding site occupied by Fe

ferritin level in iron deficiency anemia

description of lab values for iron deficiency anemia

Fe store decreased before anemia

decreased serum ferritin

INCREASED TIBC

decreased serum iron Tsat

hypochromic (low MCHC) and microcytic (low MCV)

-microcytic (MCV less than 80, normal 80-100)

-hypochromic (MCH less than 27, normal 27-32)

thrombocytosis due to chronic blood loss

occult blood loss

Hgb and Hct will decrease in later stages

diet therapy in iron deficiency anemia

iron best absorbed from meat, fish, and poultry

OJ can double iron intake of a meal

tea and milk can reduce absorption

infants - breast milk

drug therapy for iron deficiency anemia

best absorption with non-enteric coated ferrous salts and separated from H2RA and PPIs

dose dependent on patient's ability to tolerate drug

recommended 200mg elemental Fe every day however 120mg tolerated by most

EXAMPLE - FeSO4 325mg TID on empty stomach for at least 3 mo

goals/monitoring for iron deficiency anemia

symptomatic improvement in weeks

increase reticulocyte count in 1 week, normal in second week

normalize hemoglobin and hematocrit in 1-2 months and increase in 1 month

Fe should normalize in 1-2 months

ADRs of iron therapy

dark discoloration of stools

constipation

diarrhea

nausea

vomiting

keep away from kids (potential for fatal OD)

when should you use parenteral iron therapy

when evidence of iron malabsorption, intolerance to oral preparations, or noncompliance suspected

may bee given IM as multiple slow injection undiluted (tissue necrosis or atrophy) or IV infusion of diluted preparation

when is parenteral iron used in CKD

if Tsat

when should you NOT use parenteral iron therapy

current guidelines recommend against use of iron if ferritin is >500ng/ml

dose of iron dextran

bolus: 500-1000mg over 4-6h

100mg iv q dialysis X 10 doses

dose of iron gluconate

125mg iv q dialysis x 8 doses

dose of iron sucrose

100mg iv q dialysis x 10 doses

dose of ferumoxytol

510mg given by IV push (15 min) x 2 doses, 3-8 days apart

dose of ferric carboxymaltose

750mg

two doses given by IV push 7 days apart or 15mg/kg single dose (max 1000mg)

labs for megaloblastic anemia

LOW:

vitamin b12 < (200-1000)

low Hbg low Hct

HIGH:

MCV >(80-100)

MCH >(27-33)

NORMAL:

retic (0.5-1.5%) (lower end)

MCHC (33-37%)

Fe (50-160)

ferritin (>100)

TIBC (250-400)

RBC folate (200-1000)

characteristics of megaloblastic anemia

abnormal forms of precursors for RBCs

deficiency is a result of inadequate intake, decreased absorption or inadequate utilization

FOLIC ACID / VITAMIN B12 catalyze reactions necessary for synthesis of DNA/RNA

pernicious anemia

what is pernicious anemia

decreased production of intrinsic factor, which causes vitamin B12 malabsorption characterized by atrophic gastritis

predisposing factors for b12 deficiency anemia (megaloblastic)

vegetarian

gastrectomy

inherent deficiency

pancreatic disease

malnutrition

thyroid disease

rheumatoid arthritis

gastric cancer

alcoholism

drugs : AZT (azothiaprine)

presentation of b12 deficiency anemia (megaloblastic)

progressively worsening weakness, dizziness

fatigue

pallor

sob, decreased exercise tolerance

tachycardia, palpitations, hypotension, cold intolerance

ecchymosis, petechiae, hematomas

vitamin b12 deficiency:

neurological deficits

sore red tongue

anorexia

dysphagia

psychosis

irritability

visual disturbances

description of lab values for B12 anemia

decreased RBC, Hgb, Hct

Increased MCV

elevated LDH and bilirubin

increased iron and transferrin

low retic count

thrombocytopenia, leukopenia

b12

treatment example for b12 deficiency anemia

cyanocobalamin 100-1000mcg IM or deep SQ QD - week until Hgb and Hct normalize, then monthly forever

increase B12 diet - meat?, dietary products and eggs

goals and monitoring for b12 deficiency anemia

neurological symptoms should improve in 24 hours, but it may take months for a complete response

hematologic symptoms and retic count should improve within days and normalized within 1-2 mo

CBC q 2-6 mo

watch for symptoms

lab values for folic acid deficiency anemia

LOW:

RBC < (3.5-5.0)

RBC folate < (200-1000)

low Hgb and Hct

HIGH:

MCV < (80-100)

MCH < (27-33)

LDH < (50-1500

bilirubin < (0.1-1)

NORMAL:

Retic (0.5-1.5)

vitamin B12 (200-1000)

predisposing factors for folic acid deficiency anemia

inadequate intake, decreased absorption, hyper or inadequate utilization

alcoholism

pregnancy

leukemia and lymphoma

malnutrition

chronic hemodialysis

spure, crohn's, enteris

drugs (trimethoprim, pyrimethamin, methotrexate, sulfasalazine, oral contraceptives, anticonvulsants)

presentation of folic acid deficiency anemia

progressively worsening weakness, dizziness

fatigue

pallor

sob, decreased exercise tolerance

tachycardia, palpitations, hypotension, cold intolerance

ecchymosis, petechiae, hematomas

(no hallmark signs)

description of lab values for folic acid deficiency anemia

macrocytic anemia -> low hct/hgb, high MCV, pancytopenia, low folate, normal b12, decreased retic count, decreased transferrin

hemolysis: increased LDH, increased bilirubin

absence of neurological manifestations

may see dysphasia, weight loss, ecchymosis, and loss of skin elasticity

treatment of folic acid deficiency anemia

improve diet: dietary sources of folate include fresh fruits and veggies, mushrooms and liver

folic acid 1mg po QD until corrected (months)

counseling: anorexia, alcohol and cocaine

goals and monitoring for folic acid deficiency anemia

RBC morphology and retic count improvement in 1-2 days

CBC improvement in 10 days

LDH and bilirubin normalize in 1-3 weeks

folic acid increase in 2-4 weeks

anemia correction in 1-2 months

improvement in symptoms, monitor diet

lab values for anemia of chronic/anemia of inflammation

LOW:

retic

presentation of anemia of chronic/anemia of inflammation

progressively worsening weakness, dizziness

fatigue

pallor

sob, decreased exercise tolerance, cold intolerance

tachycardia, palpitations, hypotension

swollen feet

decreased mental acuity

description of lab values for anemia of chronic/anemia of inflammation

no rise in erythrocyte production in response to anemia

normal MCV

decreased Hbg, retic count, iron and TIBC

renal failure

-kidneys unable to produce erythropoietin

-decreased RBC lifespan causing increased need for production

-may become iron deficient due to blood and iron loss from hemodialysis

what is erythropoietin

glycoprotein normally produced in the kidney

what does erythropoietin do

stimulates RBC production

where is synthetic erythropoietin derived from

recombinant DNA techniques

what are the synthetic erythropoietin drugs available

Epoetin alpha (Epogen, Procrit)

Darbopoetin alfa (Aranesp)

Methoxy polyethylene glycol-epoetin beta (Mircera)

indication for synthetic erythropoietin

treatment of anemia due to CKD

adr's of synthetic erythropoietin

hypertension

nausea

diarrhea

arthralgia

fatigue

fever

headache

clotted access

edema

chest pain

what is necessary for erythropoietin to function

TSAT >20% and ferritin >100 ng/ml

--consider iron treatment if a patients TSAT

route of administration differences for erythropoietin

subq administration requires 15-50% less epoetin alfa than IV administration

IV is associated with less administration-related side effects than subq adminisrtaion

BBW of erythropoietin

ESAs increase the risk of death, MI, stroke, VTE, thrombosis of vascular access and tumor progression or recurrence

use the lowest dose of ESAs that will gradually increase the hemoglobin concentration to the lowest level sufficient to avoid the need for RBC transfusion

recommendation to withhold, not reduce ESA dose, when Hb is greater than 12g/dl

warnings of erythropoietin regarding CKD

in controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke, when administered erythropoiesis-stimulating agents to target a hemoglobin level greater than 11g/dl

no trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks

use the lowest dose sufficient to reduce the need for RBC transfusions

warnings of erythropoietin regarding cancer

ESAs shortened overall survival and/or increased risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers

use the lowest dose to avoid RBC transfusions

use ESAs only for anemia with myelosuppresive chemotherapy

ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure

d/c following the completion of a chemotherapy course

warnings of erythropoietin regarding peri-surgery

due to increased risk of DVT, DVT prophylaxis is recommended

brand name of epoetin alfa

epogen

procrit

retacrit

indications for epoetin alfa

treatment of anemia due to CKD

zidovudine in patients with HIV infection

the effects of concomitant myelosuppressive chemotherapy, and upoe initiation, there is a minimum of two additional months of planned chemotherapy

reduction of allogenic RBC transfusions in patients undergoing elective, noncardiac, nonvascular surgery

dose of epoetin alfa for treatment of anemia due to CKD

50-100 units/kg 3 times weekly

dose of epoetin alfa for zidovudine in patients with HIV infection

100 units/kg 3 times weekly

dose of epoetin alfa for the effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy

40000 units weekly

dose of epoetin alfa for reduction of allogenic RBC transfusions in patients undergoing elective, noncardiac, nonvascular surgery

300 units/kg per day for 15 days or 600 units/kg weekly

contraindications to epoetin alfa

uncontrolled HTN

pure RBC aplasia (failure of an organ or tissue to develop or to function normally)

allergy

warnings to epoetiin alfa

uncontrolled HTN, pure RBC aplasia, allergy

seizures

cutaneous reactions

adr's of epoetin alfa

HTN

arthralgia

muscle spasm

pyrexia

dizziness

medical device malfunction

vascular occlusion

brand of darbepoetin

aranesp

indications for darbepoetin

CKD in patients on dialysis and patients not on dialysis

the effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy

dose of darbepoetin for CKD patients on dialysis

0.45mcg/kg IV or SQ weekly

OR

0.75mcg/kg IV or SQ every 2 weeks

dose of darbepoetin for patients with CKD not on dialysis

0.45mcg/kg IV or SQ at 4 week intervals

dose of darbepoetin for patients with cancer on chemotherapy

2.25mcg/kg SQ weekly

OR

500 mcg SQ every 3 weeks

contraindications and warnings of darbepoetin

uncontrolled HTN, pure RBC aplasia, allergy

seizures

cutaneous reactions

adr's of darbepoetin

HTN

dyspnea

peripheral edema

cough

procedural hypotension

abdominal pain

thrombovascular events

general guidelines for treatment of anemia

address all correctable causes of anemia (including iron deficiency and inflammatory states) PRIOR to initiation of ESA therapy

in initiating and maintaining ESA therapy, we recommend balancing the potential benefits of reducing blood transfusions and anemia-related symptoms against the risks of harm in individual patients (stroke, vascular access loss, htn)

we recommend using ESA therapy with great caution, if at all, in CKD patients with active malignancy - in particular when cure is the anticipated outcome - a history of stroke or a history of malignancy

CKD non-dialysis guidelines for treatment of anemia

for adult CKD ND patients with hbg >10.0g/dl, we suggest that ESA therapy NOT be initiated

for adult CKD ND patients with hbg

CKD 5 dialysis guidelines for treatment of anemia

for adult CKD 5D patients, we suggest that ESA therpay be used to avoid having the hbg concentration fall below 9.0g/dl by starting ESA therapy when the hemoglobin is between 9.0-10.0g/dl

goals/monitoring for anemia of chronic/anemia of inflammation

goal of therapy is to haise Hbg to 11g/l within 2-4 mo

monitor hbg/hct every 2-4 weeks, ferritin/Tsat every 3 months

monitor bp at each visit

monitor adr's at each visit

what are HIF stabilizers

HIF transcription factors are key regulators of cellular activities in response to hypoxia

in conditions of hypoxia, the prolyl hydroxylase is inhibited and favors a stable heterodimer which in turn up-regulates genes involved in erythropoiesis and angiogenesis

PHD inhibitors/HIF stabilizers serve to increase the levels of HIC and ultimately endogenous erythropoietin production

HIF stabilizers also increase the avaliability of iron for erythropoiesis possibly by suppressing hecpidin (hepcidin antagonist)

what are the avaliable HIF stabilizers

daprodustat

molidustat

roxadustat

vadadustat

dose of daprodustat

1-24mg po qd

dose of vadadustat

150-600mg po qd

key points of HIF stabilizers

treatment of anemia due to CKD in adults who have been receiving dialysis x 4 mo

minimal transient increase in observed EPO levels

decreased hepcidin, increase iron absorption, increase hgb

lower requirement for transfusion, IV iron and EPO analogue

similar major cardiovascular events and all cause mortality v placebo

what are the adr's of HIF stabilizers

GI side effects

arterial and venous thrombotic events

HF

seizures

hepatotoxicity