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Heme/Onc > Heme Pharm > Flashcards

Heme Pharm Flashcards

1
Q

Erythropoietin (EPO)

  • Epoetin alfa
  • Darbepoetin alfa
A
  • Glycoprotein of 166 AA (MW 18Kd) produced in the kidney in response to anemia or hypoxia.
  • Recombinant forms (rhEpo) are made in mammalian cells.
  • rhEpo is fully glycosylated and some new forms are hyper glycosylated (Aranesp).

MOA:

  • Renal cortex percieves O2 levels in blood–> produces EPO in response to low O2
  • EPO acts on bone marrow to stimulate RBC production

Clinical uses:

  • Anemia of renal failure
  • Anemia of prematurity
  • Myelodysplasia (refractory anemia; sideroblastic anemia)
  • Post-chemotherapy anemia
  • Anemia of chronic disease (inflammatory or malignant)
  • With surgical procedures (autologous transfusion)
  • DO NOT INITIATE with Hg > 10

Adverse events:

  • Antibody development: despite similar AA composition, occasional patients have developed anti-Epo antibodies.
  • Receptor can be expressed on tumor cells (can encourage tumor growth)

Special considerations:

  • Bone Pain: Antihistamine (Loratidine)
  • Avoid use within 24 hours of chemotherapy: Pegfilgrastim: chemo can not be administered within 14 days of administration
  • NO improvement in outcome, symptoms of anemia, quality of life, fatigue, well-being
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2
Q

Filgrastim

Pegfilgrastim

A

Granulocyte colony stimulating factor (G-CSF):
Responsible for maturation and function of neutrophils
- Glycoprotein (18 Kd) normally produced by monocytes, lymphocytes, fibroblasts and endothelial cells.
- Stimulates the proliferation and maturation of G-precursors. Also activates circulating forms.
- Produced in bacteria: 2-3 hour t1/2

Use:

  • Prevent severe neutropenia following chemotherapy
  • Mobilize stem cells for transplantation
  • eradicate serious fungal/bacterial infections

Side effects: bone pain, edema

Forms: Pegylated rhG-SCF (more prolonged half-life, used once per chemo cycle)

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3
Q

Thrombopoietin (TPO)

A

Stimulates the proliferation of megakaryocyte precursors and platelet production. Involved in hemostasis (forms clots)

  • Produced in liver, destroed by binding to receptor in platelets, megakaryocytes
  • Produced in bacteria–> modified to pegylated form
  • TPO mimetics used (not biological copy) as there’s fewer antibodies formed against smaller molecule

Regulation: body homeostasis modeled by levels of platelets and megakaryocytes:

  • Decreased platelets/ megakaryocytes–> thrombocytopenia–> increased TPO
  • Increased platelets/ megakaryocytes–> thrombocytosis–> decreased TPO

Adverse events: development of antibodies against pegylated form

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4
Q

Hematinics: nutrients for RBC production

A
  1. Vitamin B12
  2. Folate
  3. Iron

Need adequate intake, needs to be absorbed and transported to tissues of utilization/storage, recycle if possible (IRON)

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5
Q

Vit B12

A 
Structure: porphyrin-like structure with Co atom
Forms used in medicine;
- Cyanocobalamin
- Hydroxocobalamin
- Methylcobalamin
- 5'Deoxyadenosylcobalamine

Deficiency: elevations in homocysteine, MMA

Function: synthesis of methionine and co-factor of folic acid function. Deficit impairs DNA synthesis.

PK:

  • Absorption (in the ileum) requires binding to I.F., produced by stomach parietal cells.
  • Transported by specific plasma carriers (transcobalamin II) at a normal concentration of 200-900 pg/ml.
  • Deficit produces megaloblastic anemia, neurological disorders.

Therapeutic preparations: cyanocabalamin and hydrocobalamin for I.M. or I.V. injections. Doses are usually 100-500 ug/ weekly and then once a month. (bypass digestive tract in pernicious anemia- will never be absorbed in GI tract due to antibodies)

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6
Q

Folic acid

A

Metabolism:

  • Present in green fresh vegetables.
  • Standard diet provides the required 100-500 ug/day.
  • Increased requirements during pregnancy and hemolytic anemias.
  • Absorbed in the proximal jejunum-ileum.
  • Storages are variable, but deficit may appear as early as ONE WEEK of deprivation.
  • Deficiency–> increase in homocysteine

Therapeutics:

  • oral tablets containing 0.4, 0.8 and 1.0 mg (almost always use 1 mg- no issue with excess)
  • Aqueous solution for injection or addition to I. V. saline solutions.
  • Folinic acid (leucovorin): is the 5-formyl derivative that bypasses methrotrexate inhibition.
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7
Q

Iron supplementation

A

Elemental iron component most important

Oral therapy:
- Ferrous sulfate (hydrated, dessicated)
- Ferrous gluconate
- Ferrous fumarate
Complications: constipation, GI effects

IV therapy:
To be used in clearly indicated conditions:
- intolerance to oral iron
- malabsorption
- massive iron losses
Preparations:
- Iron Dextran (50 mg/ml): Ferric oxyhydroxide complexed with polymerized dextran (180.000 M.W.)
- Sodium ferric gluconate (Ferrlicit). 12.5 mg/ ml: FDA approved for patients on hemodyalisis on Epo treatment.
- Complications: anaphylactic reactions. Test dose required.

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8
Q

COX-1 Inhibitors

A

Aspirin
NSAIDs

MOA: blocks conversion of arachidonic acid to Thromboxane A2 (TXA2) by COX-1
- TXA2 can bind TP-alpha and enhance phospholipid conversion, creating more TXA2

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9
Q

Thrombin inhibitors

A

Direct thrombin inhibitors= Hirudins
Heparin
Anti-coagulants

MOA: bind to and inhibit thrombin activation in circulation

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10
Q

ADP receptor inhibitors (P2Y-12)

A

Clopidogrel
Ticlopidine
Presugrel
Ticagrelor

MOA: blocks P2Y12 receptor: prevents P2Y12 inhibition of conversion of ATP to cAMP–> thus enhances cAMP–> inhibits platelet activation
- Also directly blocks platelet aggregation (enhanced by P2Y12 receptor)

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11
Q

Alpha II-b Beta-3 inhibitors

A

Abciximab
Tirofiban
Eptifibatide

MOA:
Target IIb3a receptors–> blocks platelet aggregation

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12
Q

Phosphodiesterase inhibitors

A

Dipyrimadole

Cilostazole

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13
Q

Aspirin

A

MOA:
Antithrombotic effect is from inhibition of TxA2 synthesis (direct and irreversible inhibition of COX-1)

PK:
Absorbed in Stomach and upper intestines
Peak plasma level: 30-40 min. post ingestion
Half-life of 15-20 minutes in circulation

Clinical use

  • Gold standard for anti-platelet therapy
  • May not be sufficient for prevention of re-stenosis following coronary artery angioplasty or stent placement, recurrent arterial thrombosis or embolism following post-mitrial valve replacement.
  • Currently under investigation is whether anticoagulants (e.g. coumarin) in combination with aspirin is superior to aspirin alone to prevent recurrence of MI and/or stent retenosis.

Adverse effects :

  • gastrointestinal intolerance (25-30%) and aspirin allergy (rare).
  • Aspirin resistance is rare in otherwise healthy individuals, although resistance to aspirin has been reported in patients with cardiovascular disease ranging up to 50%.

Effects:
Platelets are inhibited within 1 hour
Irreversible inhibitory effects (lasts the lifespan of the platelet which is 7-10 days)

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14
Q

NSAID

A

MOA:
These drugs inhibit TxA2-dependent platelet function through competitive,
Reversible, inhibition of platelet activation.

Directly compete with aspirin for inhibition of COX-1

  • Aspirin given before NSAID, platelet inhibition irreversible (Aspirin effect)
  • NSAID given before Aspirin, platelet inhibition reversible (NSAID effect)
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15
Q

Dipyridamole

A

PDE-inhibitor:

MOA: Prevents cleavage of cAMP to AMP–> cAMP can thus inhibit platelet activation

This drug is a pyrimidopyrimidine derivative with vasodilator and anti-platelet properties

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16
Q

Cilostazole

A

Phosphodiesterase (PDE) inhibitor:

MOA: Prevents PDE cleavage of cAMP to AMP–> cAMP can thus inhibit platelet activation

A newer phosphodiesterase inhibitor: Promotes vasodilation and inhibition of platelet aggregation.
- Used to treat intermittent claudication

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17
Q

Clopidogrel (Plavix)

A

ADP (P2Y12) inhibitor:

MOA;

  • Inhibits ADP-induced aggregation through direct inhibition of P2Y12
  • No direct effects on arachidonic acid metabolism
  • Partially inhibits platelet aggregation due to collagen and low level thrombin (positive feedback through ADP in dense granule)

Clinical Use:

  • Full effect on platelets only occurs after 3-5 days.
  • Not the drug of choice when prompt anti-platelet action is needed.
  • Not currently available in some regions
  • Not widely used in the clinic (expected to increase use with time)

Adverse effects:

  • Severe and include:
  • diarrhea and other GI effects (20%)
  • neutropenia (2.4%).
  • Adverse effects due to Clopidogrel appear to be less severe than with Ticlopidine.

PK:

  • Rapidly absorbed orally
  • Half-life is 8 hours
  • Pro-drug: Metabolism is dependent on normal CYP2C19. Significant proportion of the population is reported to have a mutation in this enzyme and is therefore classified as a poor metabolizer of clopidogrel.
  • Inhibition of platelets begins 2 hours after oral dosing of 400 mg but a dose of 75 mg inhibits platelets by the second day and reaches a steady state between 4-7 days
18
Q

Ticlopidine (Ticlid)

A

ADP (P2Y12) inhibitor:

MOA:

  • Inhibits ADP-induced aggregation through direct inhibition of P2Y12
  • No direct effects on arachidonic acid metabolism
  • Partially inhibits platelet aggregation due to collagen and low level thrombin (positive feedback through ADP in dense granule)

Clinical use:

  • The anti-platelet effects of ticlopidine take approximately 2 weeks, therefore it would not be a rapid acting anti-platelet medication for acute situations such as unstable angina.
  • Rapidly absorbed orally
  • Peak plasma concentration occurs 1-3 hours after single oral dose of 250 mg
  • Half-life of 24-36 hours
  • Longer half-life after repeated dosing 96 hours (dosing for at least 14 days)

Adverse effects: Severe and include:

  • diarrhea and other GI effects (20%)
  • neutropenia (2.4%).
  • Adverse effects due to Clopidogrel appear to be less severe than with Ticlopidine.
19
Q

Presugrel, Ticagrelor

A 
New P2Y12 Inhibitors
- Newer class of ADP receptor antagonists

PK:
Not sensitive to CYP2C19

MOA:
Reversible inhibition of P2Y12 receptor

Clinical use:

  • Full effect on platelets only occurs after 3-5 days.
  • Not the drug of choice when prompt anti-platelet action is needed.
  • Not currently available in some regions
  • Not widely used in the clinic (expected to increase use with time)

Adverse effects:

  • Severe and include:
  • diarrhea and other GI effects (20%) and neutropenia (2.4%).
20
Q

Tirofiban

A

αIIbβ3 inhibitor

MOA:
Nonpeptide derivated of tyrosine: inhibits αIIbβ3 receptor on platelets (prevents binding to fibrinogen) with minimal effects on vitronectin receptors.
- > 60,000 αIIbβ3 receptors/platelet

Clinical use:
Acute: IV administration

AE:
Severe immunologic thrombocytopenia (rare)

21
Q

Epitifibatide

A

αIIbβ3 inhibitor

MOA:
Synthetic disulfide-linked cyclic heptapeptide: inhibits αIIbβ3 receptor on platelets (prevents binding to fibrinogen) with minimal effects on vitronectin receptors.
- > 60,000 αIIbβ3 receptors/platelet

Clinical use:
Acute: IV administration

22
Q

Abziximab (Rheopro)

A

MOA:
Monoclonal antibody that binds to αIIbβ3 receptor on platelets and megakaryocytes and blocks binding of fibrinogen and other ligands.

  • A definite correlation exists between the percentage of receptors blocked and inhibition of platelet aggregation. When the number of unbound receptors is reduced to below 20,000 per platelet, platelet aggregation decreases and is sufficient to prevent thrombus formation.

Clinical use:

  • IV adminstration: Effect is immediate
  • Other non-antibody inhibitors of αIIbβ3 work IV.
  • Oral αIIbβ3 receptor inhibitors are being developed so that this mode of therapy can be administered to outpatients.

Adverse effects:
- high risk of bleeding and thrombocytopenia (<1%).

PK:
The half-life of undbound abciximab is very short; less than 10-30 minutes

23
Q

Bivalirudin

A

Direct thrombin inhibitor

MOA:
Directly binds to and inhibits thrombin activation in circulation.

Adverse effects:

  • Increased risk of bleeding - use with caution in clinical situations where platelet activation and thrombosis is a more immediate concern relative to bleeding as DTI’s are irreversible.
  • Block PAR activation, but additionally inhibit thrombolysis and APC activation.

PK:
Half-life of 28 minutes.
Proteolytically broken down in circulation.

  • Only available by IV administration and primarily used where heparin is not a viable option (Heparin-induced thrombocytopenia).
  • NOT FDA approved for HIT
24
Q

Treatment of Acute Coronary Syndrome (ACS)

A
  1. Aspirin= life-saving and has held out as an optimal approach for anti-platelet therapy in these ACS
    - very few contraindications
  2. LMWH (avoid in renal failure= increased creatinine) + aspirin
    - Reduction in death, MI over regular heparin
  3. Heparin + aspirin
  4. ADP inhibitors= added protection.
    - added risk of bleeding
    - combination with aspirin has added risk of neutropenia and thrombocytopenia
  5. DTI: lower mortality in PCI from ACS compared to low molecular weight heparin.
    - DTI’s can also have far-reaching off-target effects compared to heparin.
25
Q

Treatment of atrial fibrillation

A
  1. Warfarin or Vitamin K= preferable meds in prevention of cardioembolic strokes in patients with AF compared to aspirin.
  2. Aspirin= controversial.
  3. Oral DTI’s= as efficacious as warfarin for AF.
    - DTI is not currently approved in the US for treatment of nonvalvular AF, but may be a promising future approach for anti-platelet treatment in these patients.
26
Q

Treatment of Transient ischemic attack

A
  1. High dose aspirin can reduce the incidence of TIA
    - most significant for men
    - increased GI side effects
    - excessive mortality due to intracerebral hemorrhage.
  2. Combination therapy:
    a) low dose aspirin with dipyridamole
    b) low dose aspirin with ADP antagonists
    - more protective than aspirin alone.
27
Q

Hirugen

A

Direct thrombin inhibitor- univalent (binds active site

NOT FDA approved for HIT treatment- derived from leeches

28
Q

Argatroban

A

Direct thrombin inhibitor (DTI)- univalent (binds active site only)

Clinical use: FDA approved from HIT treatment

  • Rapid therapeutic effect (30 minutes with IV infusion)
  • Easily monitored
  • Does not cross-react with heparin-induced antibodies
  • Allow overlap between DTI and oral anticoagulant in transition

MOA:

  • Antithrombin III independent
  • Inhibits clot bound thrombin
  • Lack of interaction with HIT Ab

PK:

  • Predictable dose response curve
  • Relatively short half life (40 minutes)
    • Primary metabolism= hepatic (caution in hepatic impairment)**

AEs:

  • No antidote (dosing when “sick”)
  • Does not effect thrombin generation*
  • Possible hypercoagulable state after discontinuation; rebound activation of coagulation occurs*
  • Use during cardiopulmonary bypass not well established
  • Narrow therapeutic window in the cardiology setting
  • Difficulty converting to warfarin sodium (PT effect)
  • Expense
  • Risk of major bleeding

Monitoring:

  • aPTT
  • Significant effects on INR
29
Q

Lepirudin

A

Direct thrombin inhibitor (DTI)- bivalent (binds Fibrinogen binding exosite and active site)
- Hirudin= anticoagulant from saliva of leeches (recombinant protein)

Clinical use: FDA approved from HIT treatment associated with thromboembolic disease

  • Rapid therapeutic effect (10 minutes with bolus, 40 minutes with IV infusion)
  • Easily monitored
  • Does not cross-react with HIT antibodies
  • Transition to oral anticoagulation: allow several days for warfarin to attain effect (DON’T rush to administer coumadin in Thromboembolic events)

MOA:

  • Antithrombin III independent
  • Inhibits clot bound thrombin
  • Lack of interaction with HIT Ab
PK: 
- Predictable dose response curve
- Relatively short half life
Elimination
- Half-life ~80 minutes
- **Primary excretion: RENAL**
- Half-life increased in patients with renal impairment

AEs:

  • No antidote (dosing when “sick”)
  • Does not effect thrombin generation*
  • Possible hypercoagulable state after discontinuation; rebound activation of coagulation occurs*
  • Use during cardiopulmonary bypass not well established
  • Narrow therapeutic window in the cardiology setting
  • Difficulty converting to warfarin sodium (PT effect)
  • Expense
  • Risk of major bleeding

Monitoring:

  • aPTT
  • NO significant effects on INR
30
Q

Pentasaccharide Heparin

A

Fondaparinux= binds factor X, antithrombin III

MAY be used in HIT- no conclusive evidence

31
Q

Oral thrombin inhibitor

A

NOT FDA approved yet, not tested for HIT

Promises: oral agent, easy to dose, no monitoring

Problems: Expensive, no antidote, renal clearance

32
Q

Post-HIT Heparin exposure

A

Antibody negative
Remote history of HIT
No comparative, alternative treatment
Limited exposure to heparin

33
Q

Alteplase

A

tPA (Tissue Plasminogen activator)
- CLOT BUSTER

Delivery:

  • IV
  • catheter directed (preferred)

PK:
- Short half-life (minutes)

Clinical use:

  • MI (within 6 hours of symptoms)
  • Peripheral arterial/graft occlusion (catheter deliver)
  • CVA (ischemic, within first 3 hours)
  • PE (massive, with associated shock, ischemia)
  • DVT (rare)
  • Require follow-up treatment with antiplatelet or anticoagulant

Contraindications:

  • Surgery, trauma within 10 days
  • Serious GI bleeding (past 3 months)
  • History of HTN (diastolic > 110)
  • CV bleeding
  • Active bleeding
  • Aortic dissection
  • Acute pericarditis
34
Q

Treatment of DVT, PE

A 
Heparin
LMWH
- Enoxaparin
- Dalteparin
- Tinzaparin
- Fondaparinux
Direct Factor Xa inhibitor
- Rivaroxaban

DON’T give Warfarin immediately, as APC inactivated by Warfarin (as well as clotting factors)

35
Q

Heparin

A

Indirect anti-thrombotic agent:
- Binds to factor Xa and IIa

PK:

  • Elimination= Reticuloendothelial System, small fraction renally excreted, not removed by hemodialysis
  • Half-Life: 1 to 1.5 hours, increases with higher doses
  • Bioavailability: 30%

** Reversing Agent: Protamine Sulfate #**

Dosing:

  • 5000 unit bolus
  • 1300 units per hour
  • Target aPTT 1.5-2.5 times baseline within first 24 hours of therapy (check every 6 hours)**

Weight-based dosing:

  • 80 IU/kg
  • Infuse 18 IU/kp
  • Still need to acheive target aPTT within first 24 hours (23% of patients NOT at goal have recurrent disease)
36
Q

Low Molecular weight heparins

A
  • Enoxaparin
  • Dalteparin
  • Tinzaparin
  • Fondaparinux= Pentasaccharide

MOA: bind antithrombin III, turn off factor Xa (don’t bind to IIa as well as Heparin)

PK: Renal Excretion #

  • Half-Life: 2.5 to 4.5 hrs enoxaparin, dalteparin, tinzaparin, Fondaparinux 17 to 21 hrs.
  • Bioavailability: 90%
  • *Reversing Agent: Protamine reverses 60% of enoxaparin, dalteparin, tinzaparin.
  • Fondaparinux is not reversed by protamine**
37
Q

Rivaroxaban

A

MOA: Binds Factor Xa

PK:

  • 60% Renal & 40% Liver excretion
  • Half-Life: 7 to 11 hrs

** Reversing Agent: Prothrombin Complex Concentrate

38
Q

Warfarin

A

Mechanism of Action: inhibits epoxide reductase and Vitamin K reductase

  • inactives factors II, VII, IX, X, Protein C&S
  • Takes 3-5 days to become effective (start with LMWH or heparin as well)

PK:
Mechanism of Elimination: Liver metabolized
- Half-Life: 40 hours
- Bioavailability: 100%

  • Reversing Agents: Vitamin K, PO, IV, SC; Fresh Frozen Plasma or Prothrombin Complex Concentrate

** Efficacy of Warfarin on anticoagulation best measured with PT (INR)**

39
Q

VTE prophylaxis (post-operative)

A

Balance risk of bleeding and development of clot after surgery

  • Use lowest dose of anticoagulant to prevent DVT and PE
  • Low risk for major bleeiding
  1. LMWH (less bleeding, more clots than Rivaroxaban)
  2. Pentasaccharide (17-21 hour, renally excreted, no reversing agent)
  3. Warfarin (4-6 weeks, managed by pharmacist)
  4. Rivaroxaban (better prevention of clot, more bleeding)
  5. Aspirin (only in young patients with no other risks for clots)
40
Q

Sargramostim

A

GM-CSF:
MOA:
- Promotes differentiation of cells in neutrophil and monocyte lineage;
- Increases levels of circulating neutrophils, eosinophils, and macrophages; Reduces neutrophil apoptosis and enhances macrophage phagocytosis

  • Also used for priming for stem cell collection, to increase stem cell recruitment

Special considerations:

  • Bone Pain: Antihistamine (Loratidine)
  • Avoid use within 24 hours of chemotherapy: Pegfilgrastim: chemo can not be administered within 14 days of administration
41
Q

Noloxone

A

Has no agonist activity
Displaces opiods from all receptors, reverses all of the effects of opioids
Effects are immediate (3-5 min)
Duration is 30-45 minutes

Heme/Onc (6 decks)

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