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Flashcards in Pharmacology Deck (37):
1

Erythropoietin

Glycoprotein produced in the kidney in response to anemia or hypoxia

Recombinant rhEpo made in mammalian cells - must be fully glycosylated (not done by bacteria cells)

Main risk - some patients develop anti-Epo antibodies upon administration of rhEpo

Clinical uses

  1. Anemia
    1. Renal failure
    2. Prematurity (infants)
    3. Chronic disease
    4. Post-chemotherapy
  2. Myelodysplasia
  3. Surgery - to stimulate RBC formation for autologous transfusion

2

Granulocyte Colony Stimulating Factor (G-CSF)

Glycoprotein produced by monocytes, lymphocytes, fibroblasts, and endothelial cells

Stimulates proliferation and maturation of granulocyte precursors and activates circulating forms

rhG-CSF - filgastrim - produced in bacteria (non-glycosylated)

  • 2-3 hr half-life
  • Use - prevent severe neutropenia post-chemotherapy, mobilize stem cells for transplantation
  • Dose - 5 ug/kg/d until ANC > 1000
  • Pegylated rhG-CSF (pegfilgastrin) - longer half life, used once per chemotherapy cycle
  • AEs - bone pain, edema

GM-CSF no longer used therapeutically

3

Thrombopoietin (TPO)

Stimulates proliferation of megakaryocyte precursors and platelet production

Glycoprotein produced in liver, destroyed by binding to receptors on platelets and megakariocytes

Produced by bacteria, modified by pegylation (prevents antibody development)

TPO level regulation

  • Thrombocytopenia - low platelet plus megakaryocyte mass increases circulating free TPO (less TPO destruction by binding receptors) to allow increased stimulation of marrow precursors
  • Thrombocytosis - high platelet/megakaryocyte mass decreases free TPO levels to decrease stimulation of precursors

 

4

Hematinics

Drug form of nutrients needed for RBC production

B12, folate, iron

5

Megaloblastic Anemia

Macrocytosis and hypersegmented PMNs

Seen in B12 and/or folate deficiency - involved in DNA synthesis

Causes:

  • Diet and age
  • GI disease/surgery
  • Pernicious anemia
  • Medications - PPIs, anticonvulsants, sulfas, long-term anti-metabolites (methotrexate, hydroxyurea, anti-virals)

Corrected by purines and thymadine
 

6


B12

Cyanocobalamin (natural B12), hydroxocobalamin, methylcobalamin, 5-doxyadenosylcobalamin

Porphyrin-like structure with central cobalt atom

Deficit impairs DNA synthesis - causes megaloblastic anemia and neurologic disorders

Binds IF (from stomach parietal cells), absorbed in distal ileum

Preparations - IM (preferred) or IV - 100-500 ug qWeek x4 week, then monthly indefinitely

7

Folate

Variety of formulations, specific form used depends on clinical scenario

Involved in DNA synthesis, DNA methylation, methionine synthesis

Natural in green fresh vegetables

Increased requirements during pregnancy, hemolytic anemias

Absorbed in proximal jejunum-ileum

Stores variable - deficit can appear as early as one week after deprivation

PO - 1 ug

Folinic acid (leucovorin) - 5-formyl derivative, bypasses methotrexate inhibition

8

Iron


Iron-deficiency anemia - microcytic, hypochromic RBCs

Highly recycled - most stored in RBCs

Highest requirements in infancy due to growth, women require more than men due to menstruation - requirements massive in late pregnancy

Causes of deficiency - bleeding, malabsorption, increased demands, poor diet

Only 5-10% of iron consumed is absorbed - dosing high, duration of therapy long

PO - 3-4 tablets qDay

Parenteral only due to intolerance to PO, malabsorption, massive iron loss - risk of anaphylaxis

9


Hemostasis

Primary - platelet plug

  • Requires platelets, vWF, vessel walls
  • Measured by bleeding time

Secondary - coagulation

  • Requires clotting factors
  • PT, aPTT, thrombin time

10


Platelet receptors

GPIb, GPVI - bind collagen

alpha IIb beta-3 - bind fibrinogen

PAR1, PAR4 - bind thrombin

P2Y1, P2Y12 - bind ADP

TPalpha - bind thromboxane

11


Platelet granules

Dense granules - small molecules

  • ATP
  • ADP
  • 5-HT
  • Epi

Alpha granules - proteins

  • alpha 2b beta 3 receptors
  • Fibrinogen
  • P-selectin

 

12


Summary of direct platelet inhibitors

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13


COX-1 inhibitors

COX-1 converts arachidonic acid to TXA2

TXA2 permeates out and potentiates TXA2 production via the TP-alpha receptor

Aspirin

  • Peak levels in 30-40 min
  • Platelet inhibition within 1 hour
  • 15-20 minutes half-life, but inhibitory effects irreversible
    • 7-10 day lifespan of platelet
  • Gold standard anti-platelet therapy
  • AEs - GI intolerance (rare allergies)
  • Resistance rare except in CV disease

NSAIDs

  • Competitive, reversible inhibition of COX-1
  • Compete with each other and aspirin for inhibition
    • Effects determined by whichever is given first

 

 

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14

PDE inhibitors

cAMP normally stimulatory - in platelets, inhibitory

cAMP normally broken down by PDE

PDE inhibitors allow cAMP to build and inhibit platelets

Dipyridamole

  • Vasodilator, anti-platelet

Cilostazole - newer, same effects, used for intermittent claudication

15

P2Y12 ADP receptor inhibitors

ADP activation of P2Y12 receptor - prevents cAMP formation, activates platelets

Clopidogrel (Plavix)

  • Prodrug, converted to active form by P450 CYP2C19
  • 20-30% of patients have a mutation preventing activation of the drug
  • PO
  • Takes 4-7 days for inhibition
  • Secondary inhibitor - given as add-on therapy
  • Irreversible inhibitor

Ticlopidine

  • PO
  • Longer half-life
  • 2 weeks for effect - not for acute situations
  • Not well-tolerated

Prasugrel, Ticagrelor

  • Not sensitive to CYP2C19
  • Reversible inhibitors
  • Still not available everywhere, but gaining favor

Use

  • AEs - severe diarrhea, other GI
  • Clopidogrel AEs less severe than Ticlopidine

16

Integrin a2bB3 antagonists

Alpha2bBeta3 - promotes platelet aggregation and cross-linking by fibrinogen binding

IV only, immediate effects

Abciximab

  • Monoclonal anti-a2bB3 receptor antibody, binds to block fibrinogen
  • Effects seen once available receptors drops from normal >60,000 to <20,000
  • Short half-life - 10-30 minutes
  • Good for immediate, short-acting effects (e.g. emergency clot prevention)

Tirofiban

  • Non-peptide tyrosine derivative
  • Causes severe reversible thrombocytopenia in some patients

Eptifibatide

  • Synthetic

AEs - high risk bleeding, thrombocytopenia (<1%)

17

Direct thrombin inhibitors

Bivalirudin

Directly bind and inhibit thrombin in circulation

28 minute half-life

Broken down by proteolysis

Only IV - used mainly when heparin is not viable (e.g. HIT)

AE - increased bleeding risk

  • Irreversible - weigh risk of bleeding vs. thrombosis before administering
  • Also inhibit thrombolysis

18


Acute Coronary Syndrome

Aspirin life-saving, few CIs

ADP inhibitors give added protection - but carry increased risk of bleeding, neutropenia, thrombocytopenia with aspirin

DTIs improve mortality vs. heparin but carry increased off-target effects

19

Atrial Fibrillation

Aspirin controversial - warfarin or vit K preferable to prevent cardioembolic strokes

DTIs shown to be as effective as warfarin - but not approved in US

20

Transient ischemic attacks

Brief interruption in brain blood flow

High dose aspirin reduces incidence, but GI and cerebral bleeds cause mortality

Low dose aspirin with dipyridamole or ADP antagonists best

21

Heparin-Induced Thrombocytopenia (HIT)

1-3% of patients

50% risk of developing life or limb-threatening thromboembolic complications (TECs)

Management - immediate cessation of heparin, use of an alternative

Paradoxes

  • Anticoagulant-induced coagulation
  • Clotting disorder
  • Platelet transfusions increase thrombosis risk
  • Stopping heparin may not prevent thrombosis
  • Warfarin contraindicated as acute monotherapy

Usually occurs in 4-14 days after exposure in naive patients, in 12 hours if recent heparin exposure (Abs persist for 9-120 days)

22


HIT Mechanism

Anti-heparin/platelet factor 4 IgG antibodies (HIT Ig)

HIT Ig activates platelets

  • Aggregation - clotting
  • Release of further PF-4 - self-perpetuation
  • TxA2 synthesis - amplifies platelet function

HIT Ig activates monocytes - cytokines, TF production

Activates epithelial cells - cytokines, TF production

Activates coagulation cascade

All aspects mediated by thrombin

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23

Heparin use and HIT

Naturally occuring product

Unfractioned heparin (UFH) - raw isolated of varying MW

Low molecular-weight heparin (LMWH) - refined form with higher bioavailability

HIT can occur with any type of heparin, but more common with:

  • UFH
  • High dose
  • Long-term exposure
  • IV, catheters, heparin-coated devices
  • Especially in cardiac, orthopedic, and intensive care procedures

24


HIT consequences

HIT Ig detectable in up to 50% of cardiopulmonary bypass patients, 10% of all other patients

30-50% of HIT Ig patients develop asymptomatic thrombocytopenia

30-80% of asymptomatic thrombocytopenia patients develop overt thrombosis

Both arterial and venous thromboses

  • 20% require limb amputation
  • 30% die

25


HIT treatment

Upon clinical suspicion or diagnosis, stop all forms heparin immediately

Monitor platelets

Strongly consider therapy with direct thrombin inhibitors (DTIs)

Perform confirmatory tests

26


Direct thrombin inhibitors (DTIs)

Act by binding thrombin's active site and/or exosite (non-active binding site)

DTIs approved for HIT

  • Argatroban - univalent at active site
  • Lepirudin - bivalent (both sites)

Promising properties for HIT treatment

  • Inhibit thrombin bound to clot
  • Do not interact with HIT Ab
  • Predictable dose-response curve
  • Short half-life
  • Rapid effect
  • Easy monitoring
  • Antithrombin-independent

Potential problems

  • No reversal agent
  • Does not effect thrombin generation
  • Possible rebound coagulation after withdrawal
  • Narrow therapeutic window in cardiology
  • Expensive

27


Lepirudin

Recombinant form of hirudin (anticoagulant from leeches)

For HIT anticoagulation and TEC prevention

IV

Rapid effect - 10 minutes with bolus, 40 minutes without

80 minute half-life - renal excretion only

Immune sensitization - cannot be used a second time, antibodies cause AEs

Used as a transition to warfarin

  • Allow several days for warfarin to take effect
  • Do not discontinue lepirudin until INR consistently >2.0, no new TECs, platelet recovery

 

28


Argatroban

Synthetic

For prophylaxis or treatment of thrombosis, HIT

Univalent thrombin inhibitor (active site)

Inhibits clot-bound and soluble thrombin

No antidote

Rapid effect - 30 minutes - no bolus

40-50 minute half-life - hepatic elimination only

No immune sensitization

Also used as transition to warfarin

29


Anticoagulants contra-indicated in HIT

Warfarin - not as monotherapy

LMWH - cross-reactivity with heparin Abs

Pentasaccharide heparin - may cross-react, no evidence

30


Re-exposure to heparin after HIT

If antibody negative and HIT occured >4 months ago

If no comparative alternate treatment

But still limit re-exposure if at all possible

31


Fibrinolysis

Plasminogen - converted to plasmin by uPA (urokinase - in uroepithelial cells), tPA (tissue - throughout body)

Plasmin degrades cross-linked fibrin, releases D-dimers

Normal inhibition of fibrinolysis

  • Plasminogen activator inhibitor (PAI-1)
  • Alpha-2 antiplasmin (binds free plasmin)
  • Thrombin-activatable fibrinolysis inhibitor (TAFI) - unknown role

Use

  • Usually given catheter-directed to site of action - can be IV
  • Short half-life
  • For MI (<6 hr), arterial or graft occlusion, CVA (<3 hr), PE (only if massive with shock, hypoxia), DVT (rarely)
  • Always requires follow-up with antiplatelet and/or anticoagulant agent to prevent recurrence

Contraindications

  • Surgery or trauma within 10 days
  • GI bleed within 3 months
  • HTN
  • Active bleeding
  • Previous or current CVA
  • Aortic dissection
  • Acute pericarditis

32


Clotting/testing review

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33


Heparin (UFH)

Binds anti-thrombin, inhibits Xa and IIa

Metabolized by RES to inactivate, very minimal renal extraction

1-1.5 hour half-life

Antidote - protamine sulfate

Goal of therapy - achieve therapeutic aPTT within 24 hours

  • To reduce propagation of clotting
  • Check aPTT every 6 hours during first 24
  • Adjust dosing as needed - start by weight guidelines

34

LMWH

No aPTT monitoring

90% bioavailable from SQ injection

Longer half-life than UFH

Same MOA as UFH - but less activity against IIa, most against Xa

Renal excretion

60% reversal by protamine

Drug names - "-parin"

35


Rivaroxaban

Directly binds Xa

60% renal, 40% liver excretion

Reversal poor - prothrombin complex concentrate

36


Warfarin

Affects factors II, VII, IX, X, Protein C&S

Inhibits vitamin K-mediated reductase and epoxide reductase

40 hour half-life

100% bioavailable

Liver metabolism

Reversed by Vit K, FFP, PCC

Assessed by PT

Start with UFH/LMWH until PT/INR is in therapeutic range for 2 consecutive days

37


DVT/PE Prophylaxis

Lowest dose to reduce clotting while minimizing bleeding risk

Warfarin - begin evening before, maintain 4-6 weeks

LMWH - for 4-6 weeks, rarely used