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Glossary of BLock 6 PBL drugs

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Clarithromycin (Biaxin)
usually bacteriostatic; can be bactericidal at high concentrations; reversibly binds to 50S ribosomal subunit. It inhibits the translocation step of protein synthesis where the tRNA-amino acid complex moves from the acceptor site to the peptidyl site on the ribosome
Cyclophosphamide (Cytoxan)
Alkylating agent that prevents cell division by cross linking DNA strands and decreasing DNA synthesis and cell division. Cyclophosphamide is activated by CYP2B to yield 4-OHcyclophosphamide and aldophosphamide. These are carried to tumor cells where they are cleaved to phosphoramide mustard (has antitumor effects) and acrolein (causes hemorrhagic cystitis as adverse effect)
Doxorubicin (Adriamycin)
Inhibits DNA and RNA synthesis by intercalation between DNA base pairs leading to breaks in DNA, and by forming a tripartite complex with topoisomerase II and DNA. TopoII produces ds breaks in DNA, allowing uncoiling of supercoiled DNA. Doxorubicin inhibits the re-ligation of the broken strands, leading to apoptosis. Powerful iron chelator, and the doxo-iron complex can bind DNA and cell membranes and produce free radicals that immediately cleave DNA and cell membranes (thought to be main mechanism for cardiac toxicity)
5-fluorouracil
Acts during the S phase of the cell cycle; pyrimidine antimetabolite that inhibits thymidylate synthase along with interfering with RNA synthesis and function. 5-FU undergoes enzymatic conversion to FUMP and then to FUTP which leads to RNA inhibition, and conversion to FdUDP which inhibits thymidylate synthase, preventing DNA synthesis (thymidylate is precursor of dTTP needed in DNA)
Hydroxychloroquine (Plaquenil)
anti-inflammatory effects may result from inhibiting neutrophil and eosinophil migration, antagonizing histamine and serotonin, or by inhibiting the synthesis of prostaglandins. Slow onset of action (maximal effect not seen until third month). May also increase pH in IC vacuoles leading to decreased breakdown of protein into fragments that would bind MHC (downregulation of immune response)
Omeprazole (Prilosec)
Prodrug activated in acidic environment. Irreversibly binds the H+/K+ ATPase enzyme in gastric parietal cells leading to inhibition of H+ secretion into the gastric lumen leading to an increase in pH. Blocks the final step of gastric acid production via inhibition of both the basal and stimulus induced acid secretion.
Fluticasone/Salmeterol (Advair)
Fluticasone inhibits the release of allergic mediators such as histamine and leukotrienes as well as IgE synthesis, and suppresses inflammatory cell influx. Salmeterol is a highly sensitive beta-2 agonist-->activation of AC-->increased cAMP-->PKA activation-->phosphorylation of myosin light chain kinase (inactive)-->myosin light chain stays dephosphorylated-->relaxation of bronchial smooth muscle-->bronchodilation and increased bronchial airflow.
Amitriptyline (Elavil)
Blocks the reuptake pump for 5HT and/or NE leading to increased NT in the synapse. Receptors down-regulate in response to long-term TCA reuptake pump inhibition.
Lisinopril
Inhibits ACE. Competes with ATI for the active site of ACE, preventing conversion of ATI to ATII (leading to vasodilation) and decreased metabolism of bradykinin (potentiates the effect of bradykinin: vasodilation and adverse effects). Reduction in aldosterone secretion with subsequent decrease in Na and water retention-->decreased BP. In CHF: decreases afterload, decreases adverse LV remodeling.
Carvedilol (Coreg)
antagonist of alpha1 and nonselective beta receptors. Beta 1: decreased cAMP-->decreased IC Ca2+-->decreased inotropy and decreased HR-->decreased CO and myocardial oxygen demand. Vasodilation due to alpha1 antagonism. Beta 2: bronchoconstriction. Class II antiarrhythmic in conduction tissues.
Losartan (Cozaar)
Directly antagonizes the actions of AT II by reversibly and non-competitively binding to the AT1 receptor; blocks the vasoconstrictor and aldosterone-secreting effects of AT II.
Spironolactone (Aldactone)
Competitively binds receptors at the aldosterone dependent sodium-potassium exchange in the distal convoluted tubule, increasing NaCl and water excretion while conserving potassium and hydrogen ions. Exhibits its effects only in the presence of aldosterone.
Digoxin
Increases myocardial contractility by inhibiting the Na/K ATPase-->increased IC Na-->this activates the Na/Ca exchanger to pump sodium out and calcium in-->leads to increased IC Ca-->more Ca in SR-->increased inotropy. Also alters electrical activity of the heart: decreases HR and slows AV conduction (vagal suppression of electrical signal through AV node)
Acetylsalicylic acid (Aspirin)
irreversibly inhibits COX 1 &2; acts on the hypothalamus heat-regulating center to reduce fever, blocks PG synthetase preventing the formation of TXA2
Rosuvastatin (Crestor)
Binds reversibly to and inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase), which catalyzes the rate-limiting step in cholesterol synthesis. Blocked endogenous synthesis of cholesterol results in a compensatory increase in the expression of LDL receptors in hepatocyte membranes and stimulation of LDL catabolism (takes up LDL precursors from the circulation, leading to decreased serum cholesterol levels).
Amlodipine (Norvasc)
Binds to the transmembrane portions of domains III and IV of the alpha1 subunit of the L-type Ca channel and allosterically alters it, decreasing Ca flux through the channel-->leads to vascular smooth muscle relaxation (vasodilation and decreased BP) and coronary vasodilation. At high doses, can decrease inotropy.
Levothyroxine (Synthroid)
Lansoprazole (Prevacid)
Prodrug activated in acidic environment. Irreversibly binds the H+/K+ ATPase enzyme in gastric parietal cells leading to inhibition of H+ secretion into the gastric lumen leading to an increase in pH. Blocks the final step of gastric acid production via inhibition of both the basal and stimulus induced acid secretion.
Nitrofurantoin (Macrobid)
bacterial enzymes reduce the drug forming reactive intermediates, which in turn damage bacterial ribosomal proteins and other macromolecules. This inhibits multiple cellular processes: DNA/RNA synthesis, aerobic metabolism, cell wall synthesis (particularly of E. coli and enterococci species).
Tolterodine (Detrol)
Competitive antagonist of the muscarinic receptors of smooth muscle to decrease the normal tone and amplitude of ureteral and bladder contractions, thereby decreasing the strong urge to urinate and associated urinary incontinence.
Prednisone
Binds to a cytosolic receptor and is transported into the nucleus where its receptor, a zinc finger binding protein, transactivates response genes. Inhibits production of proinflammatory cytokines by inhibiting NFkappaB.
Lithium carbonate
MOA not completely known. Effects on the CNS may be due to the following: alters cation transport across the cell membrane in nerve and muscle cells and appears to interfere with the synthesis, storage, release and reuptake of NE; 2nd messenger systems involving the phosphatidylinositol cycle are inhibited blunting the hyperactive pathways; postsynaptic D2 receptor supersensitivity is inhibited.
Heparin
potentiates the action of ATIII-->inactivation of thrombin and activated coagulation factors IX, X, XI, XII, and plasmin-->prevents conversion of fibrinogen to fibrin
Warfarin (coumadin)
Inhibits synthesis of Vit K dep clotting factors (II, VII, IX, and X and proteins C and S) by inhibiting epoxide reductase which is needed to convert VitK to its active form.
Loratidine (Claritin)
2nd generation long-acting tricyclic antihistamine which competively inhibits peripheral histamine H1-receptors. 2nd gen are not as lipid soluble so they don't cross the BBB as easily, causing less sedation. Antagonizes constricting action of histamine, most notably at bronchial and vascular smooth muscle, and antagonizes the increased capillary permeability that normally leads to edema and wheal formation.
Furosemide (Lasix)
inhibits the Na/K/2Cl symport at the TAL of the loop of Henle. Prevents net reabsorption of NaCl. Ca and Mg reabsorption is also diminished. Increases excretion of K.
Combivent (Ipratropium bromide and albuterol)
Ipratropium: blocks all 5 muscarinic subtypes equally, but its effects on the M3 receptor most likely leads to bronchodilation. Prevents increases in cGMP resulting in decreased contractility of smooth muscle. Albuterol activates B2 adrenoreceptor, thus stimulating AC-->increased cAMP-->activation of PKA-->phosphorylaton of myosin light chain kinase (inactive)-->myosin light chain stays dephosphorylated leading to smooth muscle relaxation and bronchodilation.
PGI2 infusion
Counteracts vasoconstriction and proliferation of smooth muscle cells. Continuous IV infusion of epoprostenol (prostacyclin) has been shown to improve hemodynamics and survival in PAH. Potent, short-acting (must be continously infused due to half-life of 3 minutes in circulation).
Amiodarone
Amiodarone alters the lipid membrane, affecting several ion channels. Its Class III action involves blocking outward potassium channels, prolonging action potential duration. It slows automaticity in the SA node, thus slowing the heart rate. Conduction is slowed and AV node refractoriness is increased due to prolongation of the action potential. Its Class III activity prolongs the QTc interval, and increases both atrial and ventricular refractoriness.
Hydrochlorothiazide
Inhibits NaCl reabsorption in the DCT resulting in increased Na and water excretion. Calcium reabsorption is increased; this allows thiazides to be used in the treatment of kidney stones caused by hypercalciuria.
Atropine
Interferes with the action of Ach at muscarinic receptors on smooth muscle, cardiac muscle, and gland cells; in peripheral ganglia; and in the CNS. Counteracts the vagal (parasympathetic) input that suppresses SA and AV node in heart block.
Midazolam (Versed)
Short-acting benzodiazepine. Binds to a specific recognition site on the GABA-A receptor to potentiate the action of the inhibitory NT GABA (no effect in its absence) and increases the frequency of channel opening of neurons.
Acetaminophen (tylenol)
reversibly inhibits COX (Arachidonic Acid-->PGs), better in CNS than in peripheral tissues
Quinapril and Ramipril
Inhibits ACE, thus preventing the conversion of angiotensin I to angiotensin II; this causes a decrease in systemic vascular resistance. ACE also inactivates bradykinin; ACE inhibitors increase bradykinin (see above for more info)
Atorvastatin (Lipitor)
selective, competitive inhibitor of HMGCoA reductase-->decreased cholesterol synthesis in hepatic cells-->upregulation of LDL receptors and increased hepatic uptake of LDL from the circulation-->reduces levels of circulating LDL, total cholesterol, and triglycerides
Simvastatin/ezetimibe (Vytorin)
Simvastatin: see above for MOA of statins. Ezetimibe: potent cholesterol absorption inhibitor that selectively blocks the intestinal absorption of cholesterol and related phytosterols at the brush border of the small intestines. This decreases delivery of intestinal cholesterol to the liver which reduces hepatic cholesterol stores and increases clearance of cholesterol.
Hydroxyurea
Inhibits ribonucleotide reductase, the rate-limiting enzyme of DNA synthesis--enzyme is responsible for converting ribonucleotides to deoxyribonucleotide triphosphates, which are critical to DNA synthesis and repair. Causes immediate inhibition of DNA synthesis, but does not affect RNA or protein synthesis. In sickle cell: induces the production of fetal hemoglobin (decreases hemolytic and vaso-occlusive crisis in some pts)
Metoprolol (Toprol XL)
B1 adrenergic competitive antagonist. Leads to decreased cAMP, decreasing IC Ca, leading to decreased inotropy. Slower heart rate, decreased CO, and decreased myocardial O2 demands. Conductive tissue: decreases phase 4 slope in pacemaker cells-->decreased HR: Increases refractory period at AV node, preventing arrhythmias and inhibiting ectopic foci.
Diltiazem (Tiazac ER)
inhibits influx of Ca ions (blocks L type channels) during membrane depolarization of cardiac and vascular smooth muscle with resultant decrease in IC Ca2+: relaxation of vascular smooth muscle (decreased SVR) and coronary vasodilation-->increased myocardial O2 delivery; increases refractory period at AV and SA node; decrease HR and inotropy
Allopurinol (Zyloprim)
Inhibits xanthine oxidase (catalyzes hypoxanthine-->xanthine-->uric acid), which converts purines from DNA breakdown into uric acid, thus reducing uric acid production. Urinary concentration of uric acid is greatly reduced after enzyme inhibition with a simultaneous increase in the excretion of the more soluble xanthine and hypoxanthine. Allopurinol is metabolized to oxypurinol (AKA alloxanthine), which is also an inhibitor of xanthine oxidase.
ASA
irreversibly inhibits COX 1 &2; acts on the hypothalamus heat-regulating center to reduce fever, blocks PG synthetase preventing the formation of TXA2
Tamsulosin (Flomax)
Antagonist of alpha 1 adrenoreceptors in the prostate. Smooth muscle tone (prostate) mediated by alpha 1 receptors with 1a and 1b activity (more selective for 1a); receptor blockade leads to releaxation of smooth muscle in the bladder neck and prostate causing an mprovement of urine flow and decreased sxs of BPH.
Thalidomide
Not entirely understood; immunomodulator and anti-tumor agent that is antiproliferative/proapoptotic (via inhibition of NF-kB transcriptional activity and anti-apoptotic genes) and antiangiogenic (inhibits production, release, and signaling of cytokines). Also increases NK activity, decreases TNFalpha, and interferes with tumor cell adhesion.
Dexamethasone
Immunomodulator and anti-inflammatory agent. Binds to its cytosolic receptor and affects gene transcription. Thought to exert effects by increasing lipocortins, which are phospholipase A2 inhibitory proteins that control the synthesis of inflammatory mediators (PGs, LTs) by decreasing the amount of arachidonic acid released.
Calcium gluconate
Reduces cardiotoxic effects of hyperkalemia while other measures are taken to correct increased K+. Also used as a calcium supplement.
Na polystyrene sulfonate (Kayexalate)
Resin that releases Na in the large intestine and absorbs K+, some Ca2+, and some Mg2+. Onset of action is hours to days, with variable effects.
Insulin
Increases use of glucose, amino acids and fatty acids, and decreases breakdown of glycogen, fat, and protein through its activity on its surface tyrosine kinase receptor (acts on surface TK receptors in all mammalian cells-->most notably hepatocytes, myocytes, and adipocytes). In our case: enhances the activity of membrane-bound Na/K ATPase, increasing cellular uptake of K in the liver and in skeletal muscle.
Antithymocyte globulins (ATG)
Horse and rabbit ATG reduce lymphocyte counts and target the autoimmune attack in order to allow the HSC to repopulate the BM space. ATG reduces cytotoxic T cells by inducing apoptosis through Fas and TNF pathways. Also produces a state of tolerance by preferential depletion of activated T cells. ATG also contains Ab specificities for the IL-2 receptor, which is present on activated T cells.
Cyclosporine
Blocks T cell activation-->inhibits IL-2 production by T lymphs and therby prevents expansion of cytotoxic T cells in response to IL-2.
TMP/SMX (Bactrim)
TMP: inhibits DHFR (prevents recycling of folic acid in bacteria and thus nucleic acid and protein metabolism). SMX: structural analogues of PABA that competitively antagonize dihydropteroate synthetase (synthesizes folate from PABA in an earlier step than TMP)
Acyclovir
Guanosine analogue. Phosphorylated to acycloGMP by thymidine kinase, then to acycloGTP by cellular enzymes. Acts as a chain terminator and viral DNA polymerase inhibitor.
Methylphenidate (Ritalin)
Mild CNS stimulant, especially in the cerebral cortex and thalamus; similar to amphetamine and results in increased dopamine and most likely NE in synaptic cleft of nerves (promotes release and blocks reuptake)

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