Blood & Inflammation

Blood & Inflammation 1 2 3 Anticoagulants and thromb thrombolytics olytics Dyslipidem Dyslipidemia ia Anti-inf Anti-inflammatory lammatory drugs 1.1 – “Hepar “Heparin in Season”: Hepari Heparin n & direct Fac Factor tor X inhibitor inhibitorss • Normally, thrombin—aka Factor II (beaver with II-shaped teeth)—cleaves fibrinogen to form active fibrin, which crosslinks to form a clot (throm-beaver is crosslinking sticks to build a dam). Prothrombin is activated to thrombin by Factor Xa complexing with … TSII (Factor X is represented by the fox). • Unfractionated heparin is a glycoprotein produced endogenously that polymerized to various lengths. When administered clinically in its unfractionated form, there are a variety of lengths of polymer chains. Indirectly inhibits Factor X and ergo thrombin, by activating the antithrombin III complex, which in turn irreversibly inactivates Factor X. (The Heppy Heparin Hunter standing in the stream is carrying a cage with 3 bars in the middle for antithrombin III. The cage inhibits a thrombin beaver and a Factor X fox.) o Prevents clot formation but does not lyse extant clots (the hunter can’t destroy the dam the beaver had already built o PTT levels need to be monitored continuously with UFH (woodpecker making PTTTTTT sound is being monitored by a second heppy hunter, with a second woodpecker in the tree to remind us of intrinsic pathway testing). Administration is IV (ivy around the tree) o Clinical indications include acute management of clot conditions: ▪ DVT, commonly in iliofemoral & popliteal veins (iliofemoral river) ▪ PE, with ischemia distal to the clot (woodpecker sitting in the lung-shaped tree, with leaves off the ranch distal to the bird) ▪ Acute MI (heart-shaped banjo with broken stings) o Safe for use in pregnancy because does not cross the placenta, although LMWH is preferred d/t ease of use (pregnant woman is standing next to LMWH girl) o Toxicity: ▪ Heparin-induced thrombocytopenia (HIT): antibodies produced against heparin:PF4 complex → widespread platelet activation via Fc component of IgG antibodies. This results in a paradoxical hypercoagulable state & thrombosis (hunter is skeet shooting, and broken clay plates lie around. Despite the hunter, the beaver continues to build a sheltering dam around him). If this process results in a thrombotic event, may be referred to as heparin induced thrombocytopenia & thrombosis (HITT) or HIT type 2. • Tx: immediate removal of all heparin products and administration of alternative rapid-acting anticoagulation, e.g. direct thrombin inhibitors like bivalirudin (“no intruding” sign), argatroban or dabigatran (gators in the water); ▪ Bleeding (no duh) ▪ Hypoaldosteronism → hyperkalemia (depleted mineral mine boarded up in the shape of a K) ▪ Osteoporosis (bone shaped tree branch weakened by termites) • Low molecular weight heparin (LMWH) (enoxaparin & others) is a smaller molecule – only the smaller polymers are delivered. As such, while it has the same MOA as UFH, only inhibits Factor X, not thrombin (girl hunting is smaller than the adult heppy hunter. She carries a similar antithrombin III cage, but only inhibits a fox; no beaver here!) o Has a longer half-life than UHF (white flag that looks like an exponential decay plot). o Doesn’t require PTT monitoring, as dose is based on pt. weight rather than PTT. o Eliminated renally. As such, renal insufficiency can prolong half-life (girl standing flag on a fractured, or insufficient, kidney shaped rock). o Less likely to cause HIT (young girl skeet shooting is missing) • Fondaparinux acts similarly to heparin, except binds to antithrombin III with greater specificity (Fido has a pair of antithrombin III cages, because he’s so good at binding them). Has the lowest risk of HIT (Fido cannot even pick up the gun) • Protamine sulfate can be used to reverse heparin action, decreasing bleeding risk. It is a positively charged molecule that binds to the negatively charged heparin, preventing its action (“Protected Area” fence that is positively charged keeps the hunters out). Most effective against UFH, not so much against LMWH or fondaparinux (girl hunter and dog are able to avoid the fence). • Direct factor Xa inhibitors include rivaroxaban, apixaban, darexaban, (-Xaban suffix) act in a self-explanatory fashion (guy directly grabbing fox without needing a trap). Do not require monitoring. Oral administration. Ease of use makes more appealing in managing A-fib & flutter (TV screen) o In cases of life-threatening bleeding, may administer andexanet alfa, a biologic that shares homology with Factor Xa but has no proteolytic effects. Functions as a decoy, binding to Xa receptors & enabling intravascular coagulation by increasing availability of endogenous factor Xa. Associated with significant thrombosis risk. 1.2 – “Warfari “Warfarin, n, what is it good for?” • Vitamin K (medics with VK symbol on helmets) promotes γ carboxylation of dependent clotting factors – factors II, VII, IX, & X (II: thrombin – beavers foxes; VII: seven deadly sins – devil; IX: cat of nine lives; X: foxes. The VK medic is working on VII, tying his wounds with a γ-shaped bandage.) Vitamin K also activates anticoagulation proteins C & S (Corporal C & Sergeant S in the background are holding back the troops from joining the coagulation war.) Vitamin K epoxide – the inactive form – is reduced to active form by hepatic Vitamin K epoxide reductase (VKOR). (Medic is grabbing a new kit from the VKOR boat.) • Warfarin inhibits VKOR (warfarin warhead has destroyed a VKOR boat), blocking restoration of Vitamin K and reducing systemic Vitamin K levels available to synthesize new clotting factors. This results in a long-lasting, delayed onset hypocoagulable state (undetonated warhead onshore has a ‘delayed onset’). Factor VII has the shortest half-life, so is the first to go down (VK medic is working on VII, who is the first man down). o Warfarin has a long half-life (trooper with a long, narrow white flag) and a narrow therapeutic range, so monitoring via PT/INR is important, testing the extrinsic pathway. Normal INR is 1; goal with warfarin therapy is 2-3. (Para Trooper is coming in as extrinsic reinforcements, with a devil to remind of testing factor VII. INtercom Radio is set between 2 & 3.) Metabolized by CYP450, so has significant drug-drug interactions; upregulation of CYP450 leads to decreased warfarin efficacy, and vice versa (Chrome plated tank with CYP450 license plate is squashing down a warfarin warhead). o Used as treatment/prophylaxis for high-risk coagulable states, including A-fib & DVT (boat with the A-fib monitor floating on the iliofemoral river). Note that in the case of acute thrombus, co-administer heparin for immediate effect. Administered orally (trooper popping pills in the foreground). o Side effects: ▪ Teratogenic, and can cross the placenta (teratogen tarantula on the foreground warhead). Outcome is fetal warfarin syndrome, with abnormalities including low birth weight, slow growth, mental retardation, microcephaly, and malformed bones, cartilage, and joints. LMWH is preferred for anticoagulation in pregnancy. ▪ New warfarin treatment can cause a hypercoagulable state. This results because endogenous antithrombin protein C has a short half-life, so is one of the first factors with levels to fall (warfarin warhead has taken out Corporal C, and troops in the background are charging past Corporal C). This results in patchy skin necrosis (black soot on corporal). Co-administer with heparin to prevent hypercoagulable state (heparin hunters on the bridge are controlling the overzealous coagulation fighters) o Reversal: ▪ Vitamin K has a delayed onset (new vitamin K medics coming in on a boat still in the distance). ▪ Fresh frozen plasma given for immediate effect to replenish factors short term (FFP planes are providing reinforcement in the moment) 1.3 – “Bad Ne News ws Platelet Platelets”: s”: Antiplatelet Agent Agentss Physiology • Primary Hemostasis can be thought of as occurring in three steps. o Adhesion: Damage to vascular endothelium exposes collagen, to which von Willebrand Factor (VWF) binds (The “von Wille Brand Field” is looking a bit beat up, rather like damaged vascular endothelium with exposed collagen). VWF provides a substrate for platelet adhesion, binding platelets via the GpIb receptor (Ib on the bat the players are handing off). VWF binding induces a conformational change in the platelet, activating (the batter is ready to play because he now has a bat). o Platelet activation (home plate activates the game) induces degranulation, releasing various compounds including ADP, 5HT, TXA2, & Ca2+ needed for the coagulation cascade. ▪ Adenosine diphosphate (ADP): Powerful inducer of aggregation. Binds to platelet P2Y12 receptor, inducing platelet expression of surface GpIIb/GpIIIa receptors (“aggregate da players!” sign, with “Play Youth Ball 2-12” for P2Y12). GpIIb/IIIa receptors bind either VWF or fibrinogen. • Platelet surface receptor Glycoprotein IIb/IIIa binds fibrin & stimulates aggregation (Fibrinogen fries; seats 2b & 3b spectators attacking fry man). GpIIb/IIIa is activated by adhering to VWF, upregulated TXA2 synthesis, or binding ADP & inducing a conformational change. Circulating fibrinogen binds GPIIb/IIIa receptors, crosslinking adjacent platelets & forming a plug. ▪ 5-HT: Serotonin stimulates local platelet aggregation and vasoconstriction (helmet with smiley-face; yellow platelet players are all aggregating on the base to try to tag the runner). ▪ Thromboxane A2 stimulates local platelet aggregation and vasoconstriction(thromboxane A2: 2 batter boxes labeled A2 on either side of the home plate). • TXA2 is a synthesized from arachidonic acid (AA league baseball) by either constitutively active COX-1 or inflammation induced COX-2. (Coach Cox is the head coach, and so is always active, while the second coach napping in the pit is only active when needed. Coach Cox is twisting his hat in his teeth, tightening it like with vasoconstriction.) o Platelets aggregate; as they are activated, they recruit more platelets and coagulation factors. Fibrin activation (coagulation cascades are considered secondary hemostasis) and crosslinking stabilizes the platelet plug. Circulating fibrinogen binds GPIIb/IIIa receptors, crosslinking adjacent platelets & forming a plug. Drugs • Aspirin o Irreversibly acetylates COX-1 & COX-2 in existing platelets, preventing TXA2 synthesis until new platelets are formed (ASA referee is blowing acetylation whistle at Coach Cox for cheating, expelling him from the field until the end of the game). o Indications: ▪ Reduces CV events & angina in patients with arterial disease (“greasy pipes”) ▪ Used as a preventative measure for ischemic stroke (painter with a black stripe on his hat, recurring symbol for ischemic stroke, will no doubt be told off next by the ref) ▪ Used in MI (banjo with broken strings). Should be chewed or crushed for more immediate effect (ump chewing ASA while chewing out coach). ▪ Used as part of dual antiplatelet therapy (ASA + ADPRI) to prevent coronary stent thrombosis (the corked bat used by the home team to cheat looks remarkably like a mesh stent). Dual antiplatelet Tx usually given for 12 mos. – 2 years post stent placement (“play youth ball 2-12 yo”) o Side effects: ▪ Pseudo allergy (referee has a red, inflamed face). Usually seen in patients with comorbidities, e.g. the combination of asthma and chronic rhinosinusitis with nasal polyposis or chronic urticaria. reactions can be divided into four types: • Type 1 – NSAID-induced asthma and rhinosinusitis • Type 2 – NSAID-induced urticaria/angioedema in patients with chronic urticaria • Type 3 – NSAID-induced urticaria/angioedema in otherwise asymptomatic individuals • Type 4 – Blended (mixed respiratory and/or cutaneous) reactions in otherwise asymptomatic individuals • ADP receptor inhibitors (ADPRIs) o Include clopidogrel, prasugrel, ticlopidine (thienopyridines) & ticagrelor (a cyclopentyltriazolopyrimidine; only reversible agent). Note that the most common of these have “-grel-” somewhere in their name (hence the hot dog grill man). o Inhibit platelet aggregation by irreversibly the ADP P2Y12 receptor, preventing induction of further platelet activation (hot dog man is grabbing the ball, preventing the platelet players clustered around first base from working). o Indications: ▪ Reduce CV events & angina in patients with arterial disease (“greasy pipes”, and the angina anvil under the second grill) ▪ Used in MI (banjo with broken strings) ▪ Used as a preventative measure for ischemic stroke (painter with a black stripe on his hat is standing directly under the hot dog man) ▪ Used as part of dual antiplatelet therapy (ASA + ADPRI) to prevent coronary stent thrombosis (the corked bat looks like a mesh stent). Dual antiplatelet Tx usually given for 12 mos. – 2 years post stent placement (“play youth ball 2-12 yo”) o Adverse effects: ▪ Ticlopidine can cause neutropenia, thrombocytopenia, & granulocytopenia, even fatal (Ty Cobb shirt guy is holding a neutrophil hourglass) ▪ All can cause TTP, ticlopidine most. For both these reasons, ticlopidine is not used much nowadays. • Must obtain platelet count & WBC with differential every few weeks while on therapy. • Glycoprotein IIb/IIIa inhibitors o Include abciximab, a monoclonal antibody (ABC sports with IgG microphones); eptifibatide & tirofiban – “-fib-“ because also prevent platelet interaction with fibrinogen (tied for -ti - in names). o Have many of the same indications as APDRIs. o Block binding of the GPIIb/IIIa receptors (blocking conglomeration of the spectators by feeding fries) o Adverse effects: ▪ Thrombocytopenia (broken plates). Platelet count should be monitored ▪ Increased bleeding time (see this in all of the drugs d/t obstruction of platelet function). Used to ID patients with severe hemostatic defects (ketchup clock) • Phosphodiesterase inhibitors (“Don’t Phoster Disinterest”) o Include dipyridamole (pyramidal tent), cilostazol (3rd baseman has lost the ball) o Inhibition of PDE →↑cAMP within the platelet (green tent), which leads to activation of protein kinase A, ultimately inhibiting platelet function. o Causes arterial vasodilation (dilated sleeves). Direct coronary vasodilation associated with coronary steal (stealing a heart shaped base). ▪ In patients with stenotic coronary arteries d/t atherosclerosis, arteries beyond are already maximally dilated to maintain perfusion. When give a direct vasodilator, exacerbate ischemia by dilating other vessels and diverting blood away from stenotic area (crown-shaped red design on hat) o Can be helpful when treating claudication (dirt clods hitting legs); first line treatment for peripheral artery disease. o Dipyridamole used for coronary stress testing. 1.4 – “Warn “Warning: ing: Bleeding Hazard”. T Thrombolyt hrombolyt hrombolytics ics • In a normal setting, thrombin (Factor II) activates fibrinogen to fibrin, enabling fibrin mesh formation (stick wall looks like the thrombin beaver dam in the heparin sketch). In the case of thromboembolus, the goal is to break down the crosslinked fibrin and thrombin clots (activated general toy is breaking down the fibrin wall by shooting at it). Use of any of these will result in ↑PT, ↑PTT, and ↑D-dimer levels (other kid is blowing long PTTTTTT raspberries, playing with PT paratroopers; twigs from busted fibrin wall look like two-Ds). o tPA is released endogenously from damaged endothelium to break down fibrin (Toy Play set = tPA). tPA (alteplase) can be administered exogenously, or alternatives reteplase (rPA), tenecteplase (TNK-tPA) (playset sounds similar to -teplase.) o Streptokinase is derived from streptococci (purple beads in the playset look like Gram⊕ cocci chains). Can cause allergic reaction, including anaphylaxis in up to 0.5% of patients (kid is choking and flushed). • Indications for thrombolytic treatment: o MI, only if PCI is unavailable within 90 minutes (heart-shaped banjo with broken strings; banjo player is sitting in the sandbox but engaging with baseball player with a stent-styled bat). o Ischemic stroke, if administered within 4.5 hours (painter with black stripe on hat painting a T1-weighted MRI of a distant ischemic stroke. Note that typically there would be no findings on T1 MRI within the timeframe of 4.5 hours post-ictus!) o VTE (PE bird nest in the pulmonary tree) • Toxicities & contraindications: o Increased risk of bleeding (girl is wearing a red hat) o Contraindicated in patients with a recent h/o head trauma (shooting laser beams at MRI painting), intracranial or intraspinal surgery (bloodied scalpel), stroke (within 3 mos. except when within 4.5 hours); any h/o intracranial hemorrhage (girl has splattered red paint on her MRI painting); severe uncontrolled HTN (high pressure tube of paint squirting everywhere); evidence or high suspicion of hemorrhagic stroke (blood on T2 MRI) or intracranial conditions that may increase risk of bleeding. All d/t risk of new intercranial bleed/hemorrhagic stroke. o Non-specific reversal of thrombolytic therapy with aminocaproic acid or tranexamic acid (a mean teacher capping paint [for aminocaproic] with exams [tranexamic acid] in one hand has taken the plasmin activating general toy). FFP or cryoprecipitate may be used to reverse coagulation factor deficiencies (fresh fighter plane & cryopack on upset kid). 2.1 – “Statin Stea Steampunks”: mpunks”: Stat Statins ins Production & metabolism of lipo lipoproteins proteins • Lipoproteins (various vehicles) traffic cholesterol & triglycerides between the liver, intestinal tract, and peripheral tissues. • Chylomicrons o The intestines absorb exogenous lipids – free fatty acids (FFAs) & cholesterol (gold bars imprinted with sterol molecular structure)– at the luminal brush border in the small intestine (airship with processing facility with brush border cell flags and intestinal piping). After being absorbed in GI tract, lipoproteins are bound in chylomicrons (Hot air balloons). ▪ FFAs absorbed from lumen are combined with glycerol to form triglycerides, which are the main component of chylomicrons (helmeted people with 3-pronged tridents = triglycerides) ▪ Cholesterol is confined to the outside of the chylomicrons ▪ While in the in the luminal epithelial cells, cholesterol is esterified. Cholesterol esters fill the inside of the chylomicrons (packaging gold bars into chests = cholesterol esters). ▪ Apolipoprotein B48 (ApoB48) is included into the cell membrane to facilitate exocytosis into circulation. o Chylomicrons enter into lymphatic system via villi lacteals → transport along lymphatics to thoracic duct → make their way into circulation. Interact with HDL to pick up ApoE which facilitates liver uptake. o Chylomicrons deliver triglycerides from the intestine to peripheral tissues en route to the liver. ▪ LPL is attached to luminal service of capillary endothelium in extrahepatic tissues (lipo-port lighthouse). Facilitates removal of triglycerides into tissues (helmeted people reaching land by way of lighthouse) ▪ FFAs can be used for energy by heart and SKM (muscular seaweed) ▪ Alternatively, FFAs can be converted back to triglycerides & stored in adipose tissue (fatty sea foam). o Once depleted of triglycerides, chylomicron remnants are returned to the liver (central processing facility). ApoE interacts with LDL receptors (LDL-R) (Load-L Receptor flags) to transport chylomicron remnants into the liver via endocytosis (Pulling in empty E balloon and offloading chests). Cholesterol remnants will be excreted in bile acids or repackaged & put back into circulation. • At the liver o Cholesterol may be synthesized endogenously by HMG-CoA reductase (HMG Ore Processing produces gold ingots); the first intermediate in this process mevalonic acid, aka mevalonate (process is being evaluated). o Liver packages cholesterol (either endogenous or exogenous from chylomicron remnants) into VLDL (chests containing gold being packed onto VLDL zeppelins). o Synthesizes HDL. • VLDL o Synthesized in liver of cholesterol & triglycerides (triglycerides make up 60% total weight) (zeppelins). Include ApoB100 in the lipoprotein exterior (B-shaped anchors). o Deliver triglycerides to peripheral tissues ▪ VLDL is hydrolyzed by LPL, releasing FFA (helmet people entering island via lighthouse). o VLDL depleted of triglyceride forms IDL (essentially VLDL remnants). Some of the IDL particles head to the liver. Many stay in circulation where interact with HPL (not in the picture). Density increases, which is remodeled into cholesterol rich LDL particles. • LDL o Lipid rich transport proteins (little boats). Cholesteryl ester-rich core. Also include ApoB100(B-shaped anchors).. o LDL is the main source of cholesterol for all the peripheral nucleated cells in the body. Nucleated cells contain LDL-Rs which can endocytose entire LDL particles. ▪ LDLRs are upregulated by cells that need more cholesterol, downregulated when cells need less. o About 70% of LDL is removed from circulation by the liver (same mechanisms as described above). ▪ Also adrenals for hormone synthesis ▪ Those that aren’t picked up by the liver can penetrate the vascular endothelium → atherosclerosis • HDL o HDL particles contain mostly protein by weight (HG Wellsian subs). Nascent HDL is secreted by the liver & intestine. A complicated process leads to acquisition of surface apolipoproteins, including ApoE, ApoAI, ApoCII. o HDL goes on to collect cholesterol from peripheral tissues – scavenged in form of free cholesterol from tissue cell membranes (scuba scavenger loading finds onto HDL platform). Esterified by LCAT (lecithin cholesterol acetyltransferase) (load catch platforms on subs). This is the mature HDL. ▪ Women less than 50 & men <40 with low cholesterol levels are ↑risk of CVD d/t low levels of HDL o HDL also loads cholesterol esters to LDL/VLDL using CETP (cholesterol ester transfer protein) (chest transfer platform on subs). Once on the LDL, cholesterol esters are returned back to the liver. o HDL can also deliver cholesterol esters direct to the liver via scavenger 1 receptor (HDL Scavenger 1 sub) Drugs Statins (pirates) • Before initiating therapy, lifestyle modification is first line. • Indications: o Most powerful drugs for lowering LDL cholesterol – can see reduction in the range of 30-60% (sinking LDL ship) Used in treatment of hypercholesterolemia = ↑↑LDL (recall these are cholesterol laden), usually above 200 ▪ May also modestly lower triglycerides, depending on the specific medication (pirate knocking triglyceride guy off of sinking ship) ▪ Modest increase in HDL ▪ Note that statins are not the most effective drugs for lowering triglycerides or increasing HDL. o Statins are the most important lipid lowering drug for preventing future CV events (angel over yellow-filled crown). Statins are the only lipid lowering drug consistently shown to reduce the risk of atherosclerotic HD. o Standard of practice to initiate statins following any ACS, regardless of cholesterol levels (broken stringed guitar). o Used as secondary prevention in high risk conditions including: ▪ Diabetes (guy with candy jar) ▪ Peripheral artery disease (gunky red pipe) ▪ Reduce long term risk with h/o TIA or stroke TIA (painter with black stroke on hat) • Mechanisms o Inhibit HMG-CoA Reductase → ↓endogenous cholesterol production (pirate at HMG-Ore Reductase) o Hepatocytes consequently increase LDLR to take up more cholesterol → ↑LDL clearance from circulation (pirate sitting on a huge pile of gold) o Statins have extensive first pass metabolism, so act largely in liver. • Adverse effects o May be teratogenic (Class C; never been tested, so risk to fetus/baby is unclear) (tarantula painting) o can cause myopathy (bite out of drumstick) ▪ usually within weeks to months of initiating ▪ usually with proximal symmetrical muscle weakness or soreness, ± functional impairments. ▪ Some patients will have ↑CK, but not always (Chicken) o Will have mild elevations in LFTs. Usually reversible with discontinuation. If asymptomatic, do not need to monitor; however, do need baseline values (LFT flag) o All metabolized by CYP450 except pravastatin (CYP450 tank) 2.2 – “Twenty Thousand Lipids Un Under der the Sea” Sea”:: Cholestyramine, ezet ezetimibe imibe Physiology • Bile acids are essentially cholesterol made a bit more polar to emulsify fats in GI tract. Hepatocytes metabolize cholesterol to cholic acid & deoxycholic acid • These are transported to the gall bladder & conjugated to form water soluble bile acids (aka bile salts) (liver station worker loading up seagulls). Bile acids are then secreted into the biliary tree, then injected into intestinal lumen. • 95% of bile acids delivered to duodenum will be recycled by the enterohepatic circulation. Retaken up at the ter minal ileum. Put back into the enterohepatic circulation → taken up in the liver & reused (bile covered ore usually dropped down to liver station). • Bile acids returned to the liver negatively feedback on liver to ↓endogenous cholesterol synthesis Drugs • Bile acid binding resins o Cholestyramine (chol-lobster), colestipol, colesevelam. o Useful in decreasing LDL, usually used in conjunction with statins o Lead to ↑LDLR synthesis (activating Load-L receptors). o Unlike statins, are not first line agents for hypercholesterolemia. Usually used as an adjunct to statin therapy. Work by binding bile acids & dietary cholesterol respectively in the intestines (sea gall droppings on intestinal ore), preventing absorption from intestine & disrupting bile acid recycling (falling liver → liver forced to use more LDL from blood (empty gold chests; HMG CoA-Reductase active). o Bile acid binding resins are large cationic resins insoluble in water. Bind bile acids and prevent reabsorption; secreted from the colon (lobster knocking off ore blocks from colon airship). ▪ Downregulates negative feedback cycles. • ↑HMG-CoA reductase activity to increase cholesterol synthesis for bile acid synthesis, depleting liver cholesterol stores (empty gold chests) • Increases LDLR and uptakes more LDL from circulation (LDL flags; guys pulling in LDL ship) o Used in patients with primary hypercholesterolemia; have up to 20% decrease in LDL cholesterol at maximal doses o Adverse effects ▪ Can result in hypertriglyceridemia, because hepatic VLDL & triglyceride synthesis rises in conjunction with hepatic cholesterol production (air ship with triglyceride trident wielders). Contraindicated if pts already have ↑triglycerides. ▪ Tendency for cholesterol gall stones d/t ↑cholesterol in bile (seagull sitting on a lot of stones) ▪ GI upset, usually constipation & bloating. May have steatorrhea, especially in pts with existing colonic disease (blocked brown pipe). Contraindicated in diverticulosis. ▪ May have ↓availability of fat-soluble vitamins (KADE) (DECK-A). Have to watch out for excess anticoagulation, especially in patients on warfarin/anticoagulation therapy ▪ Decrease absorption of many drugs, notably statins (fighting pirate). Bile acid resin & statins must be taken 4 h. apart. • Ezetimibe (Z-shaped eel) o Similar to bile resins in that it binds GI molecules, preventing dietary cholesterol absorption. Results in decreased chylomicrons, effectively restricting liver’s access to exogenous cholesterol. Forces increased activity of HMG-CoAReductase & LDLR synthesis. o Reduction of hyperlipidemia related mortality is as yet unclear. However, may reduce hyperlipidemia 25% on top of statins when used in conjunction o No gallstones or increased triglycerides! o Adverse effects ▪ Common: diarrhea (muddy water behind sea snake) ▪ Rare: increased LFTs (guy with LFT flag) • PCSK9 inhibitors o evolocumab (Doc Ock) and other antibodies. o PCSK9 is a liver protease that degrades hepatocyte LDLR. Inhibition increases LDLR (Doc Ock removing snails) → significantly decreased LDL levels. 2.3 – “Loch Niacin Monster”: F Fibrates ibrates & Niac Niacin in • Triglycerides, transported in VLDL & chylomicrons, are hydrolyzed to free fatty acids in and around extrahepatic tissues by LPL (trident passengers = triglycerides; VLDL airship; Lipo-port Lighthouse = LPL). FFAs can be converted back to triglycerides & stored in adipose tissues (adipocyte sea foam). VLDLs depleted of triglycerides go back to liver. • Total triglycerides level on lipid panel measures VLDL & chylomicrons (trident passengers). Severe hypertriglyceridemia (>1000) can cause acute pancreatitis. Less severely elevated levels are associated with atherosclerotic coronary artery disease. While cholesterol is the major driver of this, unclear if lowering triglycerides will lower risk of CVD. Clinical benefits of lowering serum triglycerides by any means have not been convincingly demonstrated. • Fibrates o Gemfibrozil (gemmed steampunk jellyfish with fibrils), fenofibrate o Several physiologic effects, which together decrease circulating triglycerides by 35-50%: ▪ Lower triglycerides by targeting VLDL. Fibrates activate PPAR-α (newspaper); PPAR-α upregulates LPL at extrahepatic sites and downregulates other inhibitors of lipolysis (using newspaper to light lighthouse). Results in facilitated clearing of VLDL & chylomicrons of triglycerides in peripheral tissues (jellyfish attacking VLDL airship → trident wielders escaping). ▪ Decreases VLDL secretion from liver. ▪ Results in ↓LDL d/t decreased baseline VLDL. However, effect is modest & inconsistent (compare with statins) (sinking LDL ship) ▪ ↑HDL (HDL submarine lifted out of water). Directly activate ApoAI & ApoAII production by hepatocytes, allowing increased production of HDL; effect is mild. o Adverse effects ▪ Muscle toxicity, especially in pts also on statins (statin pirate eating drumstick) ▪ Modest increase in risk of cholesterol gallstones d/t increased bile cholesterol (seagulls on piles of stones). Should be used cautiously in patients with existing biliary tract disease. • Niacin = Vitamin B3 (steampunk sea monster “Nessie”) o At pharmacological doses, ↓VLDL secretion (sea monster eating VLDL ship over by liver base). Mechanism poorly understood. Can also decrease triglyceride release from adipose tissues. o ↓LDL d/t ↓VLDL (breaking LDL ship) o ↑HDL as much as 30%; most effective medication for increasing HDL currently available (lifting HDL sub). Mechanism poorly understood. Decreases HDL cholesterol transfer & delays HDL clearance o Adverse effects ▪ Poorly tolerated overall ▪ Cutaneous flushing and warmth mediated by prostaglandins on administration (sea monster is red & furnace driven; soldiers using a pro-slugger bat). Uncomfortable, but harmless. • NSAIDs can be used to prevent flushing from niacin. Aspirin ½ hour before niacin can help mediate this effect. ▪ ↑glucose, with hyperglycemia in already susceptible patients (rider with candy jar) ▪ ↑LFTs (white LFT flag). May cause severe hepatotoxicity, jaundice, fulminant hepatitis (burning liver base). Unpredictable. Regular monitoring of LFTs is mandatory. ▪ ↑urea. Occasionally precipitate gout (yellow needles – recurring symbol; yellow yarn for gout tophus) • Omega-3 fatty acids o Most often from fish oil (steampunk fish with omega-shaped tails). o Can decrease production of VLDL & ApoB; reduce serum triglycerides by as much as 30% (anchors & tridents in the water) o Has been shown to improve several CV risk factors, including mortality from CV disease, with little to no associated risk. 3.1 – “NSAID “NSAIDss in the outfield outfield”” Physiology • Arachidonic acid is the precursor molecule for prostanoids & leukotrienes (AA next to dugout; dugout players are the precursors). It is a membrane bound polyunsaturated fatty acid that must be released from the membrane prior to metabolism to prostaglandins. • Injury (chemical or physical) → ↑intracellular Ca → activation of Ca dependent translocation of phospholipase A2 (PLA2) (play ball) which hydrolyzes arachidonic acid membrane bonds. • Free arachidonic acid is metabolized to various inflammatory compounds (prostaglandins, thromboxane, and prostacyclin) by cyclooxygenases COX-1 or COX-2 (Head Coach Cox 1, Assistant Coach Cox 2). • COX-1 is constitutively active in many cell types and is responsible for housekeeping prostanoids (coach 1 constitutively active on the field),: o Prostaglandins (pro-slugger): maintain gastric mucus (pro-slugger protecting gastric-garbed umpire) ▪ Hence why COX-1 inhibition causes gastric ulcers o synthesized to TXA2 (batter’s box), which stimulates platelet aggregation. Is also a potent vasoconstrictor (twisting red hat) • COX-2 is expressed in vascular endothelial & smooth muscle cells, mainly in the setting of inflammation, and is responsible for many vascular effects (vascular endothelium pattern on wall of dugout) o markedly upregulated in inflammatory processes (assistant coach is running from fire). This is the main target of NSAIDS. o Prostacyclin (PGI-2) causes vasodilation & inhibits platelet aggregation (pro-cycler pitching machine; dilated cone; kids with plates being dispersed). Maintains non-thrombogenic vascular endothelial surfaces. ▪ NSAIDS that excessively blocks COX-2 can thus cause a hypercoagulable state. o prostaglandins → ↑vascular permeability (leaky sprinkler activated by pro-slugger), increase pain sensibility (pro slugger with painful inflamed foot), & induce fever (pro-slugger with flaming head) • COX-1 + COX-2 help maintain normal renal function. Produced in glomerular endothelium → afferent arteriolar dilation (prosluggers at the afferent tunnel). Activity is especially important in the situation of hypotension & ↓renal perfusion; in this case, prostaglandin maintains perfusion and limits ischemia. NSAIDs • Non-steroidal anti-inflammatory agents (NSAIDs) (fire extinguisher) decrease production of the prostaglandins that cause fever, edema, & pain associated with inflammation. Directly inhibiting cyclooxygenases COX-1 (constitutively expressed) & COX-2 (expressed in inflammation) (coach 1 constitutively active on the field; assistant coach 2 on fire). Various NSAIDs have differing affinities for the cyclooxygenases; most are non-selective (fire extinguisher dowsing both Cox coaches). • Include aspirin; ibuprofen; diclofenac & ketorolac (black sox) - ketorolac specifically is used mainly as an analgesic; indomethacin (indigo Sox) - used to accelerate closure of patent ductus arteriosus; meloxicam & piroxicam (Sox Cam) - meloxicam has some preference for COX-2; naproxen (approximately 110 mph) • Shared Adverse effects: ▪ D/t COX-1 inhibition o Inhibition of COX-1 → ↓ production of gastric mucus, even at low NSAID concentrations. Can result in gastritis, erosions, ulcerations (burning catcher). ▪ Can change anti-inflammatories or add a gastric acid inhibitor o Are the number one cause of GI bleeds (ketchup on GI pads). o inhibition of thromboxane production → ↓ platelet aggregation. Long-term use can increase risk of hemorrhagic stroke & other bleeding. ▪ Inhibition of COX-1 can prolong bleeding time (ketchup on clock) ▪ Contraindicated in patients with preexisting platelet defects o Pseudo-allergic reactions can be elicited by COX-1-inhibiting NSAID; likelihood is related to the strength with which that drug inhibits COX-1. Reactions usually seen in patients with one of the following comorbidities: the combination of asthma and chronic rhinosinusitis with nasal polyposis or chronic urticaria. Reactions can be divided into four types: ▪ Type 1 – NSAID-induced asthma and rhinosinusitis ▪ Type 2 – NSAID-induced urticaria/angioedema in patients with chronic urticaria ▪ Type 3 – NSAID-induced urticaria/angioedema in otherwise asymptomatic individuals ▪ Type 4 – Blended (mixed respiratory and/or cutaneous) reactions in otherwise asymptomatic individuals ▪ D/t COX-2 inhibition o COX inhibition in the kidney → ↓sodium excretion → ↑BP (exploding fire extinguisher). Occurs in both normotensive & hypertensive patients. Usually mild. o Can cause acute interstitial nephritis (baseballs in blue kidney shaped container = acute leukocyte infiltrate). May have eosinophilia, casts in urine, systemic dysfunction. o AKI d/t afferent arteriolar constriction (constricted proximal end of fire extinguisher hose) →↓GFR. use should be minimized in patients at high risk for AKI (fire extinguisher behind cracked kidney glass by emergency exit) ▪ May cause renal papillary necrosis (sloughing off cleat spikes) o Reduced GFR →↓excretion of renally excreted drugs ▪ e.g. lithium (lithium balloons – “liftium”) can lead to ↑serum lithium & lithium toxicity o Aplastic anemia (rare) (bone balloon); indomethacin specifically. o Neutropenia (all NSAIDs) o ↓ renal prostaglandin synthesis → ↓renin →↓aldosterone → decreased K excretion. ▪ Hypoaldosteronism (depleted mineral mine) ▪ Hyperkalemia (K shaped board) o Contraindicated in 3rd trimester d/t risk of premature closure of the ductus arteriosus (indomethacin & ibuprofen are highest risk) (pregnant lady bounding toward emergency exit) Aspirin (ASA on coat) • Irreversibly acetylates COX-1 & COX-2 in existing platelets, preventing TXA2 synthesis until new platelets are formed (ASA referee is blowing acetylation whistle at Coach Cox for cheating, expelling him from the field until the end of the game, permanently). All other NSAIDs are reversible. Thromboxane production doesn’t begin again until platelets are reborn (~1 week) • Indications (nowadays used less as an anti-inflammatory & more as an antiplatelet): o Reduces CV events & angina in patients with arterial disease o Used as a preventative measure for ischemic stroke o Used post-MI o Used as part of dual antiplatelet therapy (ASA + ADPRI) to prevent coronary stent thrombosis o Used as an anti-inflammatory in Kawasaki’s disease, the most common vasculitis syndrome of childhood (Kid on ATV). ▪ Characterized by systemic inflammation manifesting as fever, erythema of lips & oral mucosa, cervical lymphadenopathy, rash, & conjunctivitis. ▪ Tx with high-dose aspirin during acute phase of illness. Generally transitioned to low dose ASA when fever subsides. • Side effects: o Can cause Reye’s syndrome when given to children with viral infection (rays on shirt). ▪ Presents as rapidly progressive encephalopathy (confusion, vomiting, seizures, coma) (brain cap) with hepatic dysfunction (hepatic steatosis, hepatomegaly) (liver spotted goat) o Anion gap metabolic acidosis (Mud pile). ▪ Stimulates respiratory center directly → initial respiratory alkalosis before metabolic acidosis sets in (blowing bubbles on pitcher mound) ▪ MUD PILES – causes of anion-gap metabolic acidosis: methanol, uremia, DKA, propylene glycol, iron OD or isoniazid, lactic acidosis, ethylene glycol, salicylates o Tinnitus (tin cans). Common with acute poisoning or chronic intoxication o Poisoning ▪ Activated charcoal can be used in setting of acute toxicity; indicated in all patients appearing within 2 hours of acute toxicity (dark paint under eyes) ▪ Alkalization of urine with sodium bicarb since salicylate is weak acid (hose is loading bases). Increasing urine to pH 8 from normal of ~5 can increase excretion 5x COX-2 selective inhibitors (coxibs) • Celecoxib (celebrating catcher) o No inhibition of COX-1, so no effects on platelet aggregation, thus minimizing bleeding risk. ▪ ↓ risk of GI bleed (happy colonic catcher) o Cause reduced synthesis of prostacyclin, decreasing smoothness of endothelial surface ▪ may increase risk of ischemic CV disease (blood cubes). Relatively contraindicated in ACS. o Sulfa drug (sulfa eggs) • Acetaminophen (paracetamol) o Equivalent for use as an antipyretic & analgesic, but lacks anti-inflammatory effects (icy medicine spray) o Used in treatment of mild to moderate pain when anti-inflammatory effect is less desirable (e.g. Osteoarthritis) o Poisoning is common. ▪ Metabolized by liver, with small percentage metabolized to the toxic metabolite NAPQI by CYP450. Generally NAPQI is conjugated to glutathione; at toxic levels, NAPQI is produced in excess and depletes available glutathione (hepatic goat [goat-a-thione] scared by icy spray) ▪ Toxic metabolites can cause widespread hepatocyte injury ▪ TX: • N-acetylcysteine given IV or oral (N-flower seeds). Probably restores glutathione stores (glutathione goat eating seeds) • Oral activated charcoal can be given within 4 hours of OD (dark paint under eyes). 3.2 – “C “Confessions onfessions of a knit knit--wit wit”: ”: Gout drugs (al (allopurinol, lopurinol, fe febuxostat, buxostat, probenecid, peglotica pegloticase) se) Physiology • Purine metabolism: Nucleic acids broken down to nucleotides (purine-shaped collection plate). Purine is broken down into hypoxanthine by Xanthine oxidase (XO letter from hypo kid) → Xanthine (larger kid). Xanthine is broken down into uric acid by Xanthine oxidase, sent to kidney for excretion. • Uric acid is a poorly soluble product of purine metabolism that is generally excreted in the urine (yellow aisle = tubular lumen). Overproduction or underexcretion will result in hyperuricemia; underexcretion is more common. o Causes of increased urate production: idiopathic primary gout; myeloproliferative & lymphoproliferative disorders; tumor lysis syndrome; Lynch syndrome (HGPRT deficiency) o Causes of decreased clearance: CKD; thiazide & loop diuretics. • Gout is a metabolic disease characterized by deposits of uric acid. o Most often an initial attack of gout will occur in a single joint, classically a knee or the big toe (priest with flaming toe). Crystal precipitate induces local activation of prostaglandins & lysosomal enzymes, attracting neutrophils & increasing inflammation. o Over time, uric acid crystals can precipitate in the joints and skin, resulting in formation of tophi. o Uricemia can precipitate uric acid renal calculi, or even interstitial nephritis o Uric acid crystals are needle shaped & negatively birefringent under polarized light (knitting needles) • CPPD disease aka pseudo-gout o Calcium pyrophosphate crystal deposition disease o Presents like uric acid induced gout, but results from deposition of calcium pyrophosphate (it’s lying in looking like gout – hence “thou shall not lie”). Differentiated by microscopy: calcium pyrophosphate crystals are rhomboid-shaped & positively birefringent (blue rhomboid censor). o Deposition triggers an inflammatory response much like that seen in gout o Acute treatment is very similar to gout • Uric acid crystals can form in tumor lysis syndrome (cancer crab stained glass shattered into crystals); o most commonly occurs in treatment of aggressive lymphomas & acute lymphoblastic leukemia (white T-cell crusaders). o Allopurinol used preventatively. • Lesch-Nyhan syndrome o Deficiency of HGPRT results in excess uric acid production. o Skin and lips are common sites of deposition for uric acid crystals → pain (may be the stimulus for the self-injurious behavior) (kid poked in flesh with knitting needle) Treatment of ac acute ute gout (tr (tripping ipping over yarn) • All also suitable for CPPD • NSAIDs are first response; mediate inflammation (kid with fire extinguisher) • Glucocorticoids can be used in Tx of severe, systematic gout, depending on the level of pain (moon face). • Colchicine (chorus) o First line for acute gout. o Administered orally to relieve gout within 12-24 h o Binds intracellular tubulin, preventing polymerization into tubulin (palm fronds; kid binding fronds in hands). Disrupts cytoskeletal function, including phagocytosis, degranulation, and neutrophil migration (blocked first responders) o Brush border cells in GI tract are sensitive → diarrhea (muddy shoes) o N/V, Abd pain Manageme Management nt of chronic gout • Goal is to prevent recurrent of episodes and to minimize risk of urate nephrolithiasis • Allopurinol (pure nun) o First line for chronic management o Inhibits XO, ↓uric acid in the body (nun grabbing XO notes) o Adverse effects ▪ May precipitate acute attack after initiating therapy. Often started with concurrent NSAID or colchicine therapy. ▪ Can interfere with breakdown of purine analogs (e.g. 6-MP, azathioprine) → increased risk of toxicity (purine rosaries) ▪ Rashes. Risk of SJS/TEN (tengu mask) ▪ DRESS syndrome, with eosinophilia (eo-slingshot, eosinophilic dress) • Febuxostat (XO -stopped) o Inhibits XO, ↓uric acid in the body (nun grabbing XO notes) o Adverse effects ▪ May precipitate acute attack after initiating therapy. Often started with concurrent NSAID or colchicine therapy. ▪ Can interfere with breakdown of purine analogs (e.g. 6-MP, azathioprine) → increased risk of toxicity (purine rosaries) ▪ Rashes. Risk of SJS/TEN (tengu mask) ▪ DRESS syndrome, with eosinophilia (eo-slingshot, eosinophilic dress) • Probenecid (Cid the probation officer) o Uricosuric agent used to manage underexcretion. Second line agents for underexcretion o Inhibits organic anion transporter, site of active transport sites of reabsorption & secretion in the PCT (preventing punk kid grabbing yarn) o Adverse effects: ▪ Increase in uric acid in urine increases risk of uric acid stones (lots of yellow yarn balls) ▪ Can inhibit the excretion of many drugs (e.g. penicillin, anionic agents, antibiotics) (penicillin pencil) ▪ Can precipitate an acute attack. Must be started 2-3 weeks after resolution of an acute attack ▪ Sulfa drug (kid throwing stinky eggs) • Aspirin (ASA umpire) o At high doses prevents reabsorption of uric acid (ump blocking yarn collector); at low doses, can block urinary excretion (kid catching yarn) o d/t need for high dosing, should never be used as treatment for hyperuricemia. • Pegloticase o Urate oxidase enzyme that converts uric acid to more water soluble allantoin (holy water – just in case) o Used in refractory gout. o Used to prevent gout symptoms in patients at high risk for tumor lysis syndrome. o Adverse effects: ▪ Can cause hemolysis in G6PD deficiency (G6PD watermelon with bite) o Can cause anaphylaxis (kid suffocating). Seen in 6-15% of patients. Must be administered IV in an inpatient setting by a qualified provider d/t high risk of severe Adverse effects (ivy around door)