Pharmacology Flashcards
Rituximab MOA
a chimeric monoclonal antibody targeted against CD20, a cell receptor found on the surface of B cells. It is used to treat CD20+ non-Hodgkin’s lymphomas and other diseases related to excessive B-cell function.
Infliximab MOA
Infliximab (Inf-li-xi-mab) is a chimeric monoclonal antibody targeted against TNF-α. It is used in the treatment of a number of autoimmune diseases (eg, rheumatoid arthritis and Crohn’s disease).
Certolizumab MOA
Certolizumab pegol (Certo-li-zu-mab) is a pegylated (pegol) humanized monoclonal antibody that targets TNF-α. It lacks the Fc region, which helps minimizes complement activation and cell-mediated cytotoxicity that can occur with other anti-TNF-α medications that contain Fc domains.
Imatinib MOA
Imatinib (Imati-nib) mesylate is used to treat specific cancers, including Philadelphia chromosome-positive chronic myelogenous leukemia and kit-positive gastrointestinal stromal tumors. It is an example of a small-molecule tyrosine kinase receptor inhibitor.
Etanercept MOA
Etanercept is a tumor necrosis factor-alpha (TNF-α) inhibitor added to methotrexate to treat moderate-to- severe rheumatoid arthritis in patients who have failed methotrexate alone.
It is a fusion protein linking a soluble TNF-α receptor to the Fc component of human immunoglobulin G1 (IgG1). Etanercept reduces the biological activity of TNF-α by acting as a decoy receptor: the TNF-α receptor component acts like a sponge to bind TNF-α and keep it away from functional TNF-α receptors, while the Fc component stabilizes the complex.
Question
B. Imiquimod
Imiquimod is a topical immunomodulatory drug that is used to treat many common dermatologic disorders associated with abnormal cell proliferation, including anogenital warts (ie, human papillomavirus infection), superficial basal cell carcinoma, and actinic keratosis. The antiviral and antiproliferative effects of imiquimod are primarily mediated through activation of toll-like receptor 7, which upregulates the proinflammatory transcription factor nuclear factor-kappa B (NF-κB).
NF-κB increases transcription of proinflammatory genes, activating antigen-presenting cells (eg, Langerhans cells in the skin) and initiating an immune response involving natural killer cells, cytotoxic T cells, and type 1 helper T cells. This results in increased cytokine production (eg, IL-1, IL-12, interferon-alfa/gamma, tumor necrosis factor-alpha) and enhanced immune-mediated killing of aberrant cells (eg, cancer cells, virus-infected cells).
Other antiproliferative effects of imiquimod include:
Induction of apoptosis of aberrant cells through caspase activation via inhibition of BCL-2
Inhibition of angiogenesis by downregulating proangiogenic factors (eg, fibroblast growth factor) and upregulating angiogenesis inhibitors (eg, interferon-gamma, IL-12)
(Choice A) Calcipotriene is a vitamin D analog (ie, activates the vitamin D receptor, a nuclear transcription factor) used to treat plaque psoriasis. It acts by inhibiting T-cell and keratinocyte proliferation and stimulating keratinocyte differentiation.
(Choice C) Pimecrolimus is a calcineurin inhibitor used to treat atopic dermatitis (eczema). It acts by blocking the translocation of NFAT (nuclear factor of activated T cells), resulting in reduced transcription of IL-2.
(Choice D) Topical salicylic acid is a keratolytic agent that acts by increasing sloughing of virus-infected epidermal cells. It is widely used to treat common warts but is not recommended for anogenital warts.
(Choice E) Silver nitrate is a caustic agent that coagulates cellular proteins to form an eschar. It is used to cauterize wounds to stop bleeding (eg, epistaxis) and to remove excess granulation tissue.
Educational objective:
Imiquimod is a widely used topical immunomodulatory agent that stimulates a potent cellular and cytokine-based immune response to aberrant cells (eg, human papillomavirus-infected cells in anogenital warts) by activating toll-like receptors and upregulating NF-κB. Other antiproliferative effects of imiquimod include inhibition of angiogenesis and induction of apoptosis.
Question
A. Abciximab
This patient likely has Glanzmann thrombasthenia, an autosomal recessive disorder that is caused by a deficient or defective glycoprotein (GP) IIb/IIIa on platelet surfaces and that typically presents in childhood with mucocutaneous bleeding. Peripheral smear shows no platelet clumping (an important clue for diagnosis).
Platelets are responsible for formation of platelet plugs that stop bleeding from injured vessels (primary hemostasis). Vessel wall injury exposes the subendothelial collagen and matrix. Platelet attachment to exposed collagen is strengthened by GP Ib binding to von Willebrand factor on the vessel wall. The resulting platelet activation leads to the following:
Release of mediators (eg, ADP, thromboxane A2 [TXA2]) into circulation, which in turn activates other platelets
Conformational structural change of GP IIb/IIIa on platelet surfaces; this allows thousands of copies of GP IIb/IIIa to bind fibrinogen, thereby forming a platelet plug.
Abciximab, a GP IIb/IIIa receptor antagonist, inhibits binding of this receptor to fibrinogen. Abciximab and other GP IIb/IIIa inhibitors are useful for treatment of unstable angina and acute coronary syndrome, particularly in patients undergoing percutaneous coronary intervention.
(Choices B, E, F, and G) Argatroban (used in heparin-induced thrombocytopenia) and dabigatran (used in atrial fibrillation or venous thromboembolism) are direct thrombin inhibitors. Heparin potentiates antithrombin III activity, leading to inactivation of thrombin and factor Xa; warfarin prevents K-mediated carboxylation of several coagulation factors. All these medications have anticoagulant effects.
(Choices C and D) Aspirin, a cyclooxygenase (COX)-1 and 2 inhibitor, inhibits TXA2 (via platelet COX acetylation), thereby preventing platelet aggregation. Clopidogrel inhibits platelet aggregation by blocking P2Y12 on platelet ADP receptors.
Educational objective:
Abciximab is a blocker of glycoprotein (GP) IIb/IIIa receptor, which normally promotes platelet binding to fibrinogen. GP IIb/IIIa is either deficient or defective in patients with Glanzmann thrombasthenia.
Abciximab MOA
a GP IIb/IIIa receptor antagonist, inhibits binding of this receptor to fibrinogen.
Abciximab and other GP IIb/IIIa inhibitors are useful for treatment of unstable angina and acute coronary syndrome, particularly in patients undergoing percutaneous coronary intervention.
Argatroban MOA
(used in heparin-induced thrombocytopenia) is a direct thrombin inhibitors
dabigatran MOA
(used in atrial fibrillation or venous thromboembolism)
is a direct thrombin inhibitor
Heparin MOA
Heparin potentiates antithrombin III activity, leading to inactivation of thrombin and factor Xa
Warfarin MOA
warfarin prevents K-mediated carboxylation of several coagulation factors.
Question
A.
This patient with an acute intraparenchymal hemorrhage resulting in a midline shift was treated with mannitol. Mannitol, a sugar alcohol, is an osmotic diuretic that increases plasma osmolality, resulting in the flow of water down its concentration gradient from the intracellular space to the plasma. It does not cross the blood-brain barrier, therefore it is frequently used to treat elevated intracranial pressure because it draws water from the brain parenchyma into the vasculature, reducing intracranial volume and pressure.
As a result of the plasma volume expansion, the serum sodium concentration decreases (dilutional hyponatremia) and renal blood flow increases, resulting in increased glomerular filtration and renal tubular flow. Mannitol is freely filtered at the glomerulus but is not resorbed by the renal tubules; the resultant hyperosmolar glomerular filtrate reduces tubular reabsorption of free water, causing increased diuresis (Choices D and E).
Dehydration (decreased total body free water) can eventually result if free water is not replaced after mannitol therapy, resulting in hypernatremia, elevated glomerular filtrate osmolality, and reduced renal tubular blood flow. However, this is a delayed effect that does not occur acutely following administration (Choices B and C).
Educational objective:
Mannitol increases plasma osmolality, leading to the flow of water down its concentration gradient from the intracellular space to the plasma, helping to reduce intracranial pressure. The resulting plasma expansion also reduces serum sodium levels and increases glomerular filtration/tubular flow. Mannitol is freely filtered and not reabsorbed by the renal tubules, resulting in a hyperosmolar glomerular filtrate.
Mannitol MOA
Mannitol, a sugar alcohol, is an osmotic diuretic that increases plasma osmolality, resulting in the flow of water down its concentration gradient from the intracellular space to the plasma. It does not cross the blood-brain barrier, therefore it is frequently used to treat elevated intracranial pressure because it draws water from the brain parenchyma into the vasculature, reducing intracranial volume and pressure.
As a result of the plasma volume expansion, the serum sodium concentration decreases (dilutional hyponatremia) and renal blood flow increases, resulting in increased glomerular filtration and renal tubular flow. Mannitol is freely filtered at the glomerulus but is not resorbed by the renal tubules; the resultant hyperosmolar glomerular filtrate reduces tubular reabsorption of free water, causing increased diuresis
