Transcript Anti-anemics

Anticoagulant, Thrombolytic,
and Antiplatelet Drugs
Cooper Woods, Ph.D.
[email protected]
Homeostasis: Cessation of bleeding from an
injured blood vessel
Primary Hemostasis
•
This stage occurs within seconds
•
1. Vasospasm: Vasoconstriction of the blood vessel by
Prostacyclin (PI2), Thromboxane A2 (TXA2) and serotonin
(5-HT). Slows down the bleeding.
•
2. Platelet Plug: Adherence of platelets to collagen of
damaged endothelial cells. Platelet aggregation: Role of
thrombin, adenosine diphosphate (ADP), PI2, TXA2, 5-HT
and prostaglandins.
Secondary Hemostasis
•
This stage takes several minutes. Stabilizes the soft clot
and maintains vasoconstriction.
•
3. Fibrin Clot: Conversion of prothrombin to thrombin.
Thrombin stimulates the conversion of fibrinogen (Blood
protein) to polymerized fibrin (mesh).
•
4. Dissolution of the clot by fibrinolysis: Plasminogen
is converted to plasmin, the enzyme that dissolves the
fibrin.
The hemostatic process is a protective mechanism
to prevent blood loss from the circulatory system.
Platelet Adhesion and Aggregation
• Injury exposes collagen and
von Willebrand Factor
• GPIa/IIa (low shear) and Ib
(high shear) on the platelet
surface bind collagen and
vWF
• Platelets become activated
– Thrombin (IIa) activates
PAR1/PAR4
– Activate gp IIb/IIIa receptors
and Cox-1
– Release thromboxane A2,
PAF, ADP
– P2Y1/ P2Y12 activated by ADP
Blood Coagulation:
•
Initiated by the Extrinsic Pathway
•
Each step of the cascades involves:
– VII binds TF exposed by vascular injury
– VIIa can also activate IX in the
presence of TF
– Activation of XII not required for
hemostasis
– Protease (from previous step)
– Zymogen
– Non-enzymatic cofactors
• V (Xa)
• VIII (IXa)
• TF (VIIa)
– Ca2+
– Organizing surface (platelets)
•
Thrombin cleaves peptides from
fibrinogen to produce fibrin monomers
(gel)
•
XIIIa crosslinks fibrin monomers with
transglutamination
Clotting Time
•
Prothrombin Time; Prothrombin Ratio(PR) and Internationalized
Ratio(INR)
– Measures of the extrinsic/common pathway
• PT reference range: 12-15 sec; measures factors II,V,VII,X and fibrinogen.;
Used in conjunction with aPTT
– PT: blood is combined with liquid citrate (chelates calcium;
anticoagulant) in a testtube. There is a specific ratio of blood to
citrate. The mixture is centrifuged and the plasma is collected.
Thromboplastin (Tissue factor) is added to plasma and analyzed for
clotting time.
• INR normal range: 0.8-1.2
•
Activated Partial Thromboplastin Time (aPTT)
– Measure of the intrinsic pathway
• aPPT normal range: 25-37 seconds
• aPPT:blood is combined with liquid citrate (chelates calcium; anticoagulant)
in a testtube. There is a specific ratio of blood to citrate. The mixture is
centrifuged and the plasma is collected. A phospholipid (silica, kaolin, etc)
and calcium are added to the plasma sample and analyzed for clotting time.
• Partial Thromboplastin: thromboplastin is not added to the plasma sample.
Bleeding Disorders
• Primary Hemostasis
– Platelet Defects, von Willenbrand Disease
– Mucosal bleeding
• Gingiva
• Skin
• Heavy Menses
• Secondary Hemostasis
– Defects in clotting mechanism – Hemophilia
– Deep hemorrhage
• Joints
• Muscle
• Retroperitoneum
T
H
R
Thrombosis and Embolism
• White Thrombi
– Platelet rich
– Formed in high shear/flow
– artery
– Can cause ischemia/organ
failure
• Red Thrombi
–
–
–
–
Fibrin rich / RBCs trapped
Often Deep Venous Origin
Swelling and Pain
Pulmonary Embolism
• Acute right heart failure
 sudden death
• Lung ischemia
Fibrinolysis
• Removal of unwanted clots
• Balanced against removal of
clots necessary for hemostasis
• Activated by the conversion of
plasminogen to plasmin
• Plasmin
– non-specific protease that
cleaves fibrin as well as other
plasma proteins
– Binds fibrin
• t-PA
– released from ECs
– Binds fibrin (bound is blocked
from inhibition)
– Rapidly cleared
– Inhibited by PAI 1/2
Natural Anti-coagulant Mechanisms
• Prostacyclin (PGI2)
– Produced by ECs
– Vasodilator/Inhibitor of Platelet Activation
• Antithrombin
– Plasma protein
– Inhibits Intrinsic and Common Pathway
• Heparan Sulfate
– Produced by ECs
– Stimulates anti-thrombin
• Protein C + Protein S
– Degrades Va and VIIIa
– Activated by thrombin in the presence of anti-thrombin
• Tissue Factor Inhibitor Protein
– inhibits factor Xa and the factor VIIa–tissue factor complex
Anticoagulants (Parenteral)
• Heparin Sodium,
Heparin Calcium
– Glycosaminoglycan
secreted by mast cells
– Catalyzes the inhibition
of multiple coagulation
factors by antithrombin
– Thrombin (IIa), IXa,
and Xa
• Antithrombin
– “suicide substrate”
– Proteases become
trapped (1:1)
Anticoagulants (Parenteral)
•
Heparin Sodium, Heparin Calcium: Unfractionated: 5000-30,000 g/mol.
Naturally occurring mixture of sulfated muccopolysaccharides produced
by mast cells and basophils.
– Clinical Use: Prevention and treatment of embolism (i.e., post-op or following
myocardial infarction), deep vein thrombosis, pulmonary embolism. Initial
management of unstable angina or acute myocardial infarction.
– MOA: Increases the activity of antithrombin III and inactivates thrombin.
High doses will inhibit platelet aggregation.
– Pharmacokinetics: Administration: Not absorbed from the gut; i.v. and s.c..
Immediate onset (30-60 mins); Hepatic elimination and excretion, some
excreted unchanged in urine. Dosage is determined by the activated partial
thromboplastin time (aPPT; 1.5-2 times is normal).
– Side effects: Thrombocytopenia (early or delayed), hemorrhage.
– Contraindications: existing bleeding condition or bleeding tendency.
– Drug Interactions: Risk of bleeding is increased by salicylates
– In case of overdose: protamine sulfate (positive charge binds heparin).
Anticoagulants (Parenteral) cont.
• Enoxaparin, Dalteparin,
Tinzaparin: Heparin
Analog; Fractionated,
Low molecular weight
heparin (LMWH; 20009000 g/mol)
– Increased
bioavailability (s.c.)
– Less frequent dosing
– Equal efficacy
Factor IIa is thrombin
Anticoagulants (Parenteral)
•
Enoxaparin, Dalteparin, Tinzaparin: Heparin Analog; Fractionated,
Low molecular weight heparin (LMWH; 2000-9000 g/mol)
Fondaparinux (Pentasaccharide of active heparin residues)
– Clinical Use: Prevention and treatment of embolism (i.e., post-op or
following myocardial infarction), deep vein thrombosis.
– MOA: Inhibits factor Xa, very little effect on factor IIa; aPPT is not used
to measure its anticoagulant activity. Binds less to plasma proteins.
– Pharmacokinetics: Administration: i.v. and s.c. outpatient basis for DVT
patients. Immediate onset (30-60 mins); Hepatic elimination and
excretion, some excreted unchanged in urine.
– Side effects: Thrombocytopenia (early or delayed), hemorrhage.
– Contraindications: existing bleeding condition or bleeding tendency.
– In case of overdose:
• Enoxaparin, Dalteparin, Tinzaparin protamine sulfate (positive charge binds
heparin). – Limited Effectiveness
• Fondaparinux – none.
Anticoagulants (Parenteral)
•
Lepirudin: Hirudin analog
– Clinical Use: Approved for use in patients with heparin-induced
thrombocytopenia. Approved for use in PCI.
– MOA: Binds and inhibits thrombin.
– Pharmacokinetics: Administration: i.v. adjusted according to
aPTT. Kidney excretion.
– Side effects: Hemorrhage.
– Contraindications: existing bleeding condition or bleeding
tendency. Caution with patients with renal disfunction.
– In case of overdose: No antidote.
– Long-term treatment can lead to development of antibodies to
the lepirudin-thrombin complex
Anticoagulants (Parenteral)
• Bivalirudin: Hirudin analog
– Clinical Use: Approved for use in patients with as
an alternative to Heparin in PCI patients.
– MOA: Binds and inhibits thrombin. Also blocks
platelet activation. Thrombin cleaves bivalirudin
to eventually regain activity.
– Pharmacokinetics: Administration: i.v. adjusted
according to aPTT. Kidney excretion.
– Side effects: Hemorrhage.
– Contraindications: existing bleeding condition or
bleeding tendency. Caution with patients with
renal disfunction.
Anticoagulants (Parenertal)
• Argatroban: L-arginine analog
– Clinical Use: Approved for use in patients with
heparin-induced thrombocytopenia and PCI.
– MOA: Binds reversibly to and inhibits thrombin.
– Pharmacokinetics: Administration: i.v. adjusted
according to aPTT. Hepatic metabolism and bile
excretion.
– Side effects: Hemorrhage.
– Contraindications: existing bleeding condition or
bleeding tendency. Caution with patients with
hepatic dysfunction.
– Argatroban vs. Lepirudin – Renal Insufficiency =
Argatroban, Hepatic Insufficiency = Lepirudin
Anticoagulants (Parenteral)
• Drotrecogin Alfa: recombinant activated Protein C
– Clinical Use: reduction of mortality in adult
patients with severe sepsis.
– MOA: Proteolytic inactivation of factors Va and VIIIa .
– Pharmacokinetics: Administration: i.v.
– Side effects: Hemorrhage.
– Contraindications: existing bleeding condition or
bleeding tendency.
– In case of overdose: No antidote.
Anticoagulants (Oral)
• Coumarins: dicumarol and warfarin; warfarin is
structurally related to vitamin K.
– Clinical Use: Treatment of embolism, deep vein thrombosis or atrial
fibrillation, patients with prosthetic valves (at risk for thrombosis).
– MOA: Inhibits the synthesis of factors II, VII, IX and X by inhibiting the
production of active vitamin K.
Active
form
Anticoagulants (Oral)
• Coumarins: dicumarol and warfarin; warfarin
is structurally related to vitamin K.
Pharmacokinetics: Route of administration: p.o.; 100% absorbed;
99% bound to plasma proteins; 8-12 hour delay of onset of
activity; Hepatic elimination and excreted in the urine. Dicumarol
is incompletely absorbed from the gut.
– Side effects: Hemorrhage.
– Contraindications: Patients with Hemophilia. Pregnancy.
– Drug Interactions: Drugs that inhibit CytoP450
–
–
–
–
Enzymes will increase levels, ie cimetidine,
Macrolide antibiotics, antifungal agents. Drugs that induce
CytoP450 enzymes will decrease levels, ie rifampin and
Barbituates.
– In case of overdose: Vitamin K (phytonadione)
Fibrinolytic Drugs:
(Thrombolytics)
• Tissue Plasminogen
Activator (t-PA); alteplase,
reteplase, Tenecteplase
– MOA: It is a serine protease
which activates
plasminogen (bound to
fibrin) and increases
plasmin levels. Clot specific
and must bind to fibrin.
– Reteplase
• less fibrin specific
– Tenecteplase
• longer half-life
• more fibrin specific
Fibrinolytic Drugs:
(Thrombolytics)
• Urokinase; enzyme
obtained from urine
– MOA: Directly activates
plasminogen
– isolated from human kidney,
therefore less chance of
evoking an allergic reaction.
• Streptokinase:
– protein obtained from
streptocci
– anistreplase (a preformed
complex of streptokinase
and plasminogen)
– MOA: Combines with
plasminogen to form an
active complex that converts
plasminogen to plasmin to
dissolve the fibrin.
Thrombolytics
– Clinical Use: pulmonary embolism with hemodynamic
instability, severe deep venous thrombosis, acute myocardial
infarction. t-PA – acute ischemia stroke
– Pharmacokinetics: Parental administration, i.v.
– Side effects: hemorrhage, hypersensitivity reactions and
reperfusion arrythmias.
– Contraindications: Bleeding disorders; recent surgery; severe
hypertension.
– Drug Interactions: Increases risk of bleeding with dicumarol,
warfarn, heparin, aspirin, ticlopidine, abciximab.
– In case of overdose: Aminocaproic acid inhibits fibrinolysis by
competitively blocking plasminogen activation.
Inhibitors of Fibrinolysis
•
Aminocaproic acid, Tranexamic
acid
– MOA: lysine analog that competes
for lysine binding sites on
plasminogen and plasmin blocking
binding to fibrin
– Clinical Use: adjunctive therapy
in hemophilia, as therapy for
bleeding from fibrinolytic therapy,
and as prophylaxis for rebleeding
from intracranial aneurysms
– Side Effects:intravascular
thrombosis from inhibition of
plasminogen activator
– Contraindications:
disseminated intravascular
coagulation or genitourinary bleeding
of the upper tract
Inhibitors of Fibrinolysis
• Aprotinin
– MOA: serine protease
inhibitor that inhibits
fibrinolysis by free plasmin
– Clinical Use: reduce
bleeding associated with
surgery
– Side Effects: Minimal
– Contraindications:
disseminated intravascular
coagulation or genitourinary
bleeding of the upper tract
Antiplatelet Agents
Antiplatelet Agents - Aspirin
•
Clinical Use: Prevention of
atherosclerosis, thrombosis, transient
ischemic attacks; unstable angina.
•
MOA: Irreversible cyclooxygenase
inhibitor and inhibits the formation of
thromboxane A2.
•
Pharmacokinetics: Oral administration
•
Side effects: Bleeding;
gastrointestinal irritation,
hypersensitivity reactions and
thrombocytopenia.
•
Contraindications: Bleeding disorders,
hypersensitivity and Reye’s syndrome.
•
Drug Interactions: Increased
hypoglycemic effects of sulfonylureas,
inhibits uricosuric effect of
probenecid.
•
In case of overdose: Forced Alkaline
Diuresis
Antiplatelet Agents - Dipyridamole
•
Clinical Use: Prosthetic valves; may be
used as an adjunct with aspirin or
warfarin therapy. Benefit of
Dipyridamole + aspirin is debatable
•
MOA: Lowers platelet calcium and
increases the formation of cAMP (weak
antiplatelet drug) , coronary
vasodilator.
•
Pharmacokinetics: Oral administration
•
Side effects: GI distress, headache,
dizziness and rash.
•
Contraindications: Hypersensitivity to
this drug
•
Drug Interactions: Increases risk of
bradycardia with Beta adrenergic
receptor antagonists.
Platelet
ATP
Adenosine
cAMP
Adenylate
cyclase
Adenosine A2
Receptor
Antiplatelet Agents -Ticlopidine (Ticlid ®)
•
Clinical Use: Patients intolerant to
aspirin; prevents thrombotic stroke.
•
MOA: Inhibits ADP-induced
expression of platelet glycoprotein
receptors and reduces fibrinogen
binding and platelet aggregation.
Effects on platelet function are
irreversible.
•
Pharmacokinetics: Oral
administration; eliminated in the
urine and feces
•
Side effects: Nausea, diarrhea,
bleeding; mild to moderate
neutropenia, leukopenia,
thrombocytopenia.
•
Contraindications: Bleeding
disorders, severe liver disease
•
Drug Interactions: Inhibits cytoP450
drug metabolizing enzymes.
Antiplatelet Agents - Clopidogrel (Plavix®)
• Clinical Use: Prevention of
atherosclerosis, thrombosis,
transient ischemic attacks;
unstable angina. Prevention of
stent thrombosis.
• MOA: Inhibits the binding of ADP
to its receptor which is involved in
the activation of platelet
glycoprotein receptors binding to
fibrinogen.
• Pharmacokinetics: Oral
administration; eliminated in urine
and feces.
• Side effects: Nausea, diarrhea,
bleeding; mild to moderate
neutropenia, leukopenia,
thrombocytopenia. – Less severe
than Ticlopidine
Antiplatelet Agents – Prasugrel (Effient)
• Clinical Use: Prevention of
atherosclerosis, thrombosis,
transient ischemic attacks;
unstable angina. Prevention of
stent thrombosis.
• MOA: Inhibits the binding of ADP
to its receptor which is involved in
the activation of platelet
glycoprotein receptors binding to
fibrinogen.
• Pharmacokinetics: Oral
administration; eliminated in urine
and feces.
• Side effects: Nausea, diarrhea,
bleeding; mild to moderate
neutropenia, Leukopenia,
thrombocytopenia.
Cumulative Kaplan-Meier Estimates of the Rates of Key Study End Points during the Follow-up
Period
Wiviott S et al. N Engl J Med 2007;357:2001-2015
Antiplatelet Agents
• Abciximab
– Clinical Use: Percutaneous
transluminal coronary
angioplasty as adjunct with
aspirin and heparin.
– MOA: Binds to platelet
glycoprotein IIb/IIIa receptors
and prevents binding to
fibrinogen. Also binds the
vitronectin receptor.
– Pharmacokinetics: Parental
administration, i.v.
– Side effects: Bleeding,
thrombocytopenia, hypotension
and bradycardia.
– Contraindications: Aneurysm,
bleeding, recent surgery,
stroke
– Drug Interactions: Unknown
Antiplatelet Agents –
Eptifibatide, Tirofiban
•
Clinical Use: Percutaneous
transluminal coronary angioplasty
as adjunct with aspirin and
heparin.
•
MOA: Binds to platelet
glycoprotein IIb/IIIa receptors
and prevents binding to fibrinogen.
–
Does not bind vitronectin.
•
Pharmacokinetics: Parental
administration, i.v.
•
Side effects: Bleeding,
thrombocytopenia, hypotension
and bradycardia.
•
Contraindications: Aneurysm,
bleeding, recent surgery, stroke
•
Drug Interactions: Unknown
Hemostatic Agents for Bleeding
Disorders
• Vitamin K
– confers biologic activity upon
prothrombin and factors VII,
IX, and X
• Plasma Fractions
– Factor VIII – Hemophilia A
– Factor IX – Hemophilia B
– Freeze-dried concentrates
• Factor IX
• Factor X
• Factor VII
• Desmopressin Acetate
– increases the factor VIII
activity
Anti-anemics
Hematopoiesis
• Countinous replacement of blood cells
– Mature erythrocytes
• Lack nucleus – cannot synthesize proteins/lipids
• Finite lifespan = ~120 days
– Anemia
– Hypoxemia
• Requires
– Minerals – iron, cobalt, and copper
– Vitamins – folic acid, B12, pyridoxine, ascorbic acid,
and riboflavin
– Deficiencies in these factors  Anemia
Hematopoiesis – Erythropoietin
• Stimulates proliferation
and maturation of
committed erthroid
progenitors
• Kidney senses changes
in oxygen and modifies
erythropoietin secretion
• Anemia or hypoxemia –
serum levels increase
• Suppressed by infection
or inflammation
Antianemia Agents –
Erythropoietins
• Recombinant human erythopoietin (epoetin
alfa), Epogen, Procrit, and exprex, darbapoetin
alfa (Aranesp)
– Clinical Use: anemia of renal insufficiency, inflammation, and
associated with cancer or the therapy of cancer
– MOA: Stimulates proliferation and maturation of red blood cells.
– Pharmacokinetics: Route of administration: i.v., s.c. Hematocrit
should be monitored to determined appropriate dose.
– Side effects: Aggravation of hypertension. Thrombosis.
– Contraindications: Pre-existing uncontrolled hypertension.
– Iron deficiency: Virtually all patients will develop iron deficiency as
a result of an inability to mobilize iron stores in support of
increased erythropoiesis.
Iron Metabolism
Essential Iron
Male(mg/kg)
Female(mg/kg)
Hemoglobin
31
28
Myoglobin &
Enzymes
6
5
Storage
13
4
Total
50
37
Iron Deficiency
• Most common nutritional
disorder
• Insufficient dietary intake
– Usually mild
• Blood loss
– Usual cause of severe
cases
• Poor absorbance
– Gastrectomy
– Malabsorption in the small
intestine
• Pregnancy
• Infancy
Iron Deficiency - Diagnosis
• Microcytic anemia
– indicator of iron deficiency
– other tests must be used to confirm the
diagnosis
• Iron deficiency vs. iron deficient
erythropoiesis due to inflammation
– Iron stores are increased, but release
from RE is blocked
• Elevated plasma ferritin
– Plasma Iron is decreased
– Erythroid marrow supply is inadequate
Antianemia Agents
Oral Iron Therapy
• Ferrous sulfate, ferrous gluconate, ferrous fumarate,
polysaccharide-iron complex.
– Clinical Use: Iron Deficiency.
– MOA: Replaces the iron necessary for RBC’s to transport oxygen. Treatment
requires several months.
– Pharmacokinetics: Route of administration: p.o.; Eliminated in the feces,
urine and sweat.
– Side effects: Nausea, gastrointestinal discomfort, heartburn, diarrhea or
constipation.
– Contraindications: Patients with Peptic Ulcer disease, Ulcerative Colitis and
Hemolytic Anemia.
– Drug Interactions: Antacids may inhibit absorption.
– Iron Poisoning: High concentrations of ferric salts are toxic. Fatalities are
rare and may occur in children 1-2 yrs. Poisoning: Abdominal pain, diarrhea,
vomiting drowsiness, cyanosis.
• Treatment: Administer a laxative (clean out intestine) or IV deferoxamine mesylate
(chelates iron) or GI lavage (pump stomach) with sodium bicarbonate or phosphate
solution.
Antianemia Agents
Parenteral Therapy
• Sodium ferric gluconate, Iron Dextran, Iron
sucrose,
– Clinical Use: Iron Deficiency. Alternative to oral therapy.
– MOA: Replaces the iron necessary for RBC’s to transport
oxygen.
– Pharmacokinetics: Route of administration: i.m. or i.v.;
Eliminated in the feces, urine and bile. Sodium ferric gluconate
and iron sucrose are i.v. only.
– Side effects: Anaphylaxis.
• Sodium ferric gluconate – far fewer hypersensitivity reactions
• Iron Dextran – second line to sodium ferric gluconate
• Iron sucrose – similar to sodium ferric gluconate – limited data
– Contraindications: Patients with liver disease and asthma.
• Iron Dextran – patients with rheumatoid arthritis or allergies
Copper Deficiency
• Extremely Rare
– Intestinal bypass
– Parenteral nutrition
– Malnourished infants
– Excessive amounts of Zinc
• Low plasma copper + Leukopenia or
anemia
– Cupric sulfate, p.o.
Pyridoxine (Vitamin B6)
• Sideroblastic anemia
– Impaired hemoglobin synthesis
– Accumulate iron in the perinuclear mitochondria of the erythroud
precursor
• Proven benefit in correcting sideroblastic anemia associated with
isoniazid and pyrazinamide (anti-tuberculous drugs, vitamin B6
antagonists)
• Drug interaction: Levodopa (Parkinson’s)
• Poor responsiveness in sideroblastic abnormalities associated with
lead, chlorampenicol and idiopathic acquired sideroblastic anemia
Megaloblastic Anemias
Vitamin B12 and Folic Acid
Vitamin B12 and Folic Acid Function
• Key roles in purine and
pyrimidine synthesis –
DNA
• Deficiency of either
– Decreased protein
synthesis
– Disrupted Methylation
Reactions
– Decreased polyamine
synthesis
– Shunting of folate into
methyltetrahydrofolate
• Ultimately leads to
megaloblastic anemia
Antianemia Agents
• Cyanocobalamin, Crystalline
– Clinical Use: Vitamin B
deficiency.
12
Deficiency or intrinsic factor
– MOA: Converted to methylcobalamin or deoxyadenosylcobalamin, cofactors for biochemical reactions which is
essential for growth, cell replication, hematopoiesis.
– Pharmacokinetics: Route of administration: p.o., or
i.m. ; Eliminated in the feces, urine and breast milk
– Adverse effects: Rare hypersensitivity.
Antianemia Agents
• Hydroxycobalamin, crystalline
– Clinical Use: Vitamin B
deficiency.
12
Deficiency or intrinsic factor
– MOA: Converted to methylcobalamin or deoxyadenosylcobalamin, cofactors for biochemical reactions which is
essential for growth, cell replication, hematopoiesis.
– Pharmacokinetics: Route of administration: p.o., or
i.m. ; Eliminated in the feces, urine and breast milk
– Adverse effects: Rare hypersensitivity.
– More sustained effect compared to cyanocobalamin
Anemia due to Folic Acid Deficiency
• Iron deficiency as a result of
intestinal disease or pregnancy
(increased demand on the system).
• Megaloblastic anemia
– Folic Acid
– Leucovorin Calcium
(Folinic Acid)
Antianemia Agents
• Folic Acid:
– Clinical Use: Folic acid Deficiency in alcoholism and
malabsorptive syndromes.
– MOA: Replaces the folic acid necessary for DNA
synthesis, cell proliferation and development.
– Pharmacokinetics: Route of administration: p.o., or
i.m. ; Eliminated in the feces, urine and breast milk
– Side effects: Flushing and allergy.
– Contraindications: Patients with other anemias, i.e.,
pernicous, aplastic or normocytic due to incomplete
treatment.
Antianemia Agents
• Leucovorin Calcium (Folinic Acid),
folic acid metabolite (Derivative of
tetrahydrofolic acid)
– Clinical Use: Folic acid Deficiency.
– MOA: Replaces the folic acid necessary for DNA
synthesis.
– Pharmacokinetics: Route of administration: p.o., or
i.m. ; Eliminated in the feces, urine and breast milk
– Side effects: Flushing and allergy.
– Contraindications: Patients with other anemias, i.e.,
pernicous, aplastic or normocytic.
Myeloid and Megakaryocyte
Growth Factors
Myeloid Growth Factors
•
G-CSF
–
–
–
•
Stimulates proliferation of progenitor
cells committed to the neutrophil
lineage
Activates neutrophil phagocytic activity
Prolongs their lifetime
GM-CSF
–
–
Broader stimulatory activity
Similar Neutrophil stimulatory activity
•
Clinical Use: Neutropenia (esp.
Chemotherapy related), Autologous
stem cell transplant
•
Toxicity:
–
–
G-CSF- Bone pain
GM-CSF - fever, malaise, arthralgias,
myalgias, and a capillary leak
syndrome
Megakaryocyte Growth Factors
•
IL-11
– MOA: Stimulates the growth of
primitive megakaryocytic
progenitors, Increases peripheral
platelets and neutrophils
– Clinical Use: Thrombocytopenia
– Side Effects: fatigue, headache,
dizziness, and cardiovascular
effects
•
Thrombopoietin
– MOA: stimulates the growth of
primitive megakaryocytic
progenitors
– Clinical Use: INVESTIGATIONAL
- thrombocytopenia