Heme Pharm Flashcards
(41 cards)
Erythropoietin (EPO)
- Epoetin alfa
- Darbepoetin alfa
- 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
Filgrastim
Pegfilgrastim
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)
Thrombopoietin (TPO)
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
Hematinics: nutrients for RBC production
- Vitamin B12
- Folate
- Iron
Need adequate intake, needs to be absorbed and transported to tissues of utilization/storage, recycle if possible (IRON)
Vit B12
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)
Folic acid
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.
Iron supplementation
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.
COX-1 Inhibitors
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
Thrombin inhibitors
Direct thrombin inhibitors= Hirudins
Heparin
Anti-coagulants
MOA: bind to and inhibit thrombin activation in circulation
ADP receptor inhibitors (P2Y-12)
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)
Alpha II-b Beta-3 inhibitors
Abciximab
Tirofiban
Eptifibatide
MOA:
Target IIb3a receptors–> blocks platelet aggregation
Phosphodiesterase inhibitors
Dipyrimadole
Cilostazole
Aspirin
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)
NSAID
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)
Dipyridamole
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
Cilostazole
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
Clopidogrel (Plavix)
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
Ticlopidine (Ticlid)
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.
Presugrel, Ticagrelor
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%).
Tirofiban
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)
Epitifibatide
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
Abziximab (Rheopro)
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
Bivalirudin
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
Treatment of Acute Coronary Syndrome (ACS)
- Aspirin= life-saving and has held out as an optimal approach for anti-platelet therapy in these ACS
- very few contraindications - LMWH (avoid in renal failure= increased creatinine) + aspirin
- Reduction in death, MI over regular heparin - Heparin + aspirin
- ADP inhibitors= added protection.
- added risk of bleeding
- combination with aspirin has added risk of neutropenia and thrombocytopenia - 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.
