IMCP II Exam One Study Guide PDF

- What is the chemical name for arachidonic acid? - 5, 8, 11, 14 -- eicosatetraenoic acid - 5,8,11,14 correspond to the location of double bonds - Eicosa=20 carbons - Where in the cell does arachidonic acid originate? - Plasma membrane (from the lipid portion...

- What is the chemical name for arachidonic acid? - 5, 8, 11, 14 -- eicosatetraenoic acid - 5,8,11,14 correspond to the location of double bonds - Eicosa=20 carbons - Where in the cell does arachidonic acid originate? - Plasma membrane (from the lipid portions) - What are the physiologic stimuli for the release of arachidonic acid from the plasma membrane? - Vascular Injury - Inflammation (acute or chronic) - Norepinephrine - Infection - What are the biochemical steps involved with the release of arachidonic acid from membrane phospholipids? - Physiologic stimuli (above) leads to PLA2 (phospholipase A2) activation; keep in mind that calcium is also required for PLA2 activation! - PLA2 cleaves arachidonic acid from the membrane phospholipids - What are the two possible biochemical pathways that arachidonic acid can enter? - COX (cyclooxygenase) pathway - LOX (lipoxygenase) pathway - What are the steps involved with the cyclo-oxygenase pathway? - Arachidonic acid interacts with COX, forming an unstable intermediate known as PGG2 (prostaglandin G2). This occurs via a bis-oxygenation reaction! - PGG2 interacts with COX forms PGH2! - PGH2 is more stable. - What are the two COX isoforms, and how do the differ in terms of their physiology? - COX-1 "housekeeping" COX; constitutively active (always active); involved with protective functionalities - PGE1 gastric protection - Increased bicarbonate in the intraluminal environment of the stomach - Increased mucus production - PGI2 (prostacyclin) vasodilation, mild anti-coagulatory functionality - TXA2 increased platelet aggregation; increased intracellular calcium concentration; vasoconstriction CLOTTING, COAGULATION - COX-2 inducible COX enzyme; activated in response to inciting events (inflammation, infection, vascular injury) - ONLY KNOW THE FUNCTIONS! DO NOT LEARN THE SPECIFIC ROLES OF PROSTAGLANDINS FOR COX-2! - Which NSAID serves as an irreversible inhibitor of COX enzmyes? - Aspirin (acetylsalicylic acid) - Why is aspirin irreversible? - Because of the acetyl group! - What are the steps involved with the Lipoxygenase (LOX) pathway? - Release of arachidonic acid from membrane phospholipids via PLA2 - Arachidonic acid will interact with 5-LOX to form 5-HPETE - "somewhat unstable" - 5-HPETE interacts with 5-LOX to form LTA4, which is EXTREMELY UNSTABLE! - Formed via an epoxidation reaction! - LTA4 can either interact with: - LTA4 hydrolase leads to LTB4 - LTB4 chemotaxis of immune cells, especially neutrophils; diapedesis - LTC4 synthase leads to the formation of: - LTC4 - Contains glutathionecysteine, glutamate, glycine - LTD4 - LTE4 - LTC4, LTD4, and LTE4 are known as \_\_\_\_\_\_\_\_\_\_\_\_. - Cysteinyl leukotrienes (contain cysteine) - NSAID'S - What were some of the defining characteristics which determined the clinical necessity of NSAID's? - Renal Function - Gastrointestinal integrity - Pharmacokinetic profile (half life, bioavailability) - Plasma protein binding (albumin) - DDI's (drug-drug interactions, especially within the scope of cytochrome P450 enzymes) - Elimination - Hepatic function - What are the mechanisms underlying: - Gastric Toxicity? - Inhibition of COX-1 decreased PGE1 decreased mucus production, decreased bicarbonate intravasation into the intraluminal environment of the stomach - Most NSAIDs are considered weak acids; as a result of this - In the intraluminal environment of the stomach drugs are non-ionized - Once they cross over into the mucosal cells of the stomach (which has an intracellular pH of 7.0 NSAID's become ionized, resulting in mucosal injury/damage, ulcer formation - Which class of NSAID's will more likely lead to gastric injury? - Cox-1 inhibitors! - Renal Toxicity - NSAID's can inhibit COX, meaning that they can decrease the production of prostacyclin (PGI2), resulting in decreased vasodilation, increased vasoconstriction of afferent and efferent renal arterioles DECREASED GFR! - Under normal conditions, prostaglandins also promote renin secretion from juxtaglomerular cells in response to renal hypoperfusion (decreased renal blood flow) - Decreased renin secretion occurs as a result of NSAID therapy impaired RAAS pathway activity decreased potassium excretion, INCREASED POTASSIUM RETENTION HYPERKALEMIA! - Hyperkalemia classic electrolyte abnormality associated with NSAID therapy! - What are 3 examples of drugs which can have decreased clearance secondary to NSAID therapy? - Lithium mood stabilizer for bipolar I disorder - Digoxin positive inotropic agent for severe systolic heart failure - Methotrexate immunosuppression, chemotherapeutic regimens - Aspirin - Indicated for the primary prevention of MI, ischemic stroke - IRREVERSIBLE COX INHIBITORS! Why? - Acetyl group binds to enzymes with very high affinity - COX-1 \>\>\> COX-2 - Dosages - Primary prevention of MI, stroke 81 mg PO daily - Analgesia 325-650 mg PO - AVOID concurrent use with ibuprofen BOTH compete for COX-1 binding sites! - Aspirin can cause respiratory alkalosis as well as an increased anion gap metabolic acidosis! - Why respiratory alkalosis? - Salicylic acid is acidic leads to an increased AGMA - The brain (medulla) responds by increasing respiratory rate, resulting in the expiration of CO2 leads to less CO2 in the bloodstream, which INCREASES BLOOD PH respiratory alkalosis! - Etodolac COX-2 selective; because of chemical structure, has fantastic penetration into synovial joints - Indomethacin extremely potent COX-1 inhibitor; closure of patent ductus arteriosus (PDA) in neonates - Nabumetone very similar to naproxen - Nabumetone is activated to form 6-MNA (6-methoxy-2-naphthylacetic acid) in the liver - Equi-potent COX inhibitor (COX 1 AND COX-2 inhibition) - Diclofenac undergoes EXTENSIVE FIRST PASS METABOLISM - First pass metabolism due to the extensive metabolism of diclofenac in the liver, only 50% of the drug is bioavailable (bind to target receptors and elicit a physiologic response) - Can be very highly hepatotoxic due to first pass metabolism trend liver function tests - Ibuprofen COX-1 \> COX-2, but has a short half life and is, therefore, suitable for analgesia for acute pain; can be dosed for multiple administrations - Naproxen Equi-potent COX inhibition; naproxen has a longer half life, so can be used for the management of chronic pain - Meloxicam has a high propensity to cause SJS (Steven-Johnsons Syndrome) when used with certain medications (e.g., carbamazepine, lamotrigine); COX-2 inhibitor - Celecoxib VERY highly selective for COX-2; fantastic choice for long-term arthritic, arthralgia, chronic pain/rheumatologic diseases - Low propensity for GI symptoms; if possible, AVOID combination therapy with other NSAID's - NSAID Affinity Profiles - IC50 value maximal inhibitory concentration; drug concentration at which 50% of a target enzyme's activity is inhibited - COX-1, COX-2; a ratio is also usually performed (NOT IMPORTANT FOR EXAM) - Lower IC50 value higher affinity for COX enzymes (less drug is required for inhibition) - Higher IC50 values lower affinity for a particular COX enzyme (because more drug is needed to achieve the inhibitory threshold)