PHAR 505 EXAM II Lecture Review - WordPress.comPHAR 505 Exam II: Lecture Review (2/12) Bruzik Lecture: Chemistry of Lipid Disorders – I – Return of the Bruzer As you may know,

PHAR 505 Exam II: Lecture Review

(2/12) Bruzik Lecture: Chemistry of Lipid Disorders – I – Return of the Bruzer As you may know, Cardiovascular Disease (CVD) accounts for 1 in every 2.8 deaths in the US. Recently in 2010, a massive GWAS project identified 59 loci where CHD and lipid traits were significantly associated. To determine the pathophysiology of these lipid traits, let’s first take a dive into cholesterol. Atherosclerotic Plaques: The deposit of atherosclerotic plaques will decrease the diameter of the lumen within blood vessels. The deposition rate increases with age, severely compromising blood flow. However, symptoms usually do not present until the problem is advanced. Cholesterol Biosynthesis

Carbon Counting Initial: Acetyl-CoA (2C) + AcetoAcetyl-CoA (4C) = HMG-CoA (6C) Enzyme: HMG-CoA Synthase. Formation of HMG-CoA is reversible “The Bottleneck”: HMG-CoA à à Mevalonic Acid (6C) Enzyme: HMG-CoA Reductase, using NADPH cofactor Formation of Mevalonic Acid/Mevalonate is irreversible It is the slowest step, this is where drugs (statins) target “Crucial Intermediate”: ATP dependent phosphorylation of mevalonate -OH coupled with decarboxylation forms crucial Prenyl intermediates Dimethylallyl-PP (5C) Isopentenyl-PP (5C) Oligomer isomerization can interconvert the two prenyl intermediates. Combining them forms Geranyl-PP (10C) “Monoterpene”: Geranyl-PP is by definition an acyclic monoterpene since it has 10 carbons. Addition of another 5C dimethylallyl-PP will: Geranyl-PP (10C), a monoterpene add 5C intermediate Farnesyl-PP (15C), a sesquiterpene X2 + NADPH Squalene (30C) Squalene is 30C linear molecule. Following epoxidation by squalene epoxidase, ring-opening of the epoxide triggers a 1 step series of ring-fusion events, forming 4 fused rings: Lanosterol (30)

- Formation of Lanosterol provides the base structure. It has additional methyl groups that must be trimmed off, oxidation events are required to form the C=C. 15 more steps will produce cholesterol. Accumulation of the late intermediates in between lanosterol and cholesterol is toxic to the cell. Therefore, there are no drug targets following lanosterol synthesis. Accumulation would kill the cell

Cholesterol Fatty Esters - Supply: Esterification of long chain fatty acids (LCFA) may produce two different products depending on the

availability of the required enzymes. High density lipoprotein (HDL) is produced by the donation of an acyl group to cholesterol by ACAT transferase (using Acyl-CoA). If overburdened, excess cholesterol will receive fatty acid groups from Lecithin via LCAT. 80% of cholesterol is synthesized in the liver.

- Demand: Natural catabolism of cholesterol occurs during the formation of bile acids. Bile acid formation involves hydroxylation and reduction of the cholesterol molecule, shortening and polarizing the side chains. This is critical for the function of bile acids, as they are used to emulsify fats by acting as a detergent. Cholic acid may be further modified by amidation using Taurine. Overall, this will reduce the circulating cholesterol

Lipoproteins - Lipoproteins are special lipid carriers responsible for transporting cholesterol

throughout the body. They are structured as spherical agglomerates, with the polar components at the surface to interact with the aqueous environment and a lipophilic core to interact with the cholesterol residues.

- Recognition: Apoproteins on the cell surface function as recognition sites for receptors on peripheral cells, such that the lipoproteins may be taken up

- Density: Lipoprotein density is based on the relative content of protein. Proteins are more dense than fat.

o In terms of protein content and density: HDL > LDL > IDL > VLDL > Chylomicrons. Chylomicrons are very light and float to the surface during a blood sample centrifugation. HDL lipoproteins sink.

Cholesterol Content - Source: The daily summation = 1.6g cholesterol

o Diet (1.2g): The largest contributor towards daily cholesterol, dietary fat in the intestine as taken up by chylomicrons and is brought to the liver.

o De novo synthesis (0.4g) - Transport: As the lipoprotein particles continue to pass through the liver and other tissues, they acquire different

apoproteins. Additionally, their cholesterol content changes following exchange with peripheral cells o VLDL leaves the Liver with endogenous and diet-processed cholesterol to move through the circulation

Low-Density Lipoprotein (LDL) - LDL is the primary transport vehicle for cholesterol in the body. Containing ~1500 cholesterol esters and 500

unesterified cholesterol molecules, the Apo-B100 protein wraps around the LDL particle to support its contents

- LDL Receptor: Present within the liver and on extrahepatic tissues, receptor-mediated endocytosis of LDL by the LDL receptor occurs upon recognition of the Apo-B100 protein. Interaction promotes invagination via the associated intracellular clathrin triskelion coated pit. The LDL receptor structure includes:

o LA repeats: Ligand binding area. There are 7 on each side of the receptor, each with a Ca2+ o EG: Similar to epidermal growth factor, it is a repeat o LY: Highly glycosylated Serine and Threonine residues, used to dissociate the receptor o Alpha Helix: Buried in the membrane o Familial Hypercholesterolemia (FH): Heredity disorder involving a genetic defect in the sequence of LDL

receptor, leading to x5 the normal cholesterol level. Affected individuals rarely live past 20yo, as they have increased risk of atherosclerosis and CHD

- Endosome Activity: LDL Apo-B100 is interacting with the LA repeats at pH = 7. Upon pH change to 5, the 2 Asp (+Cys) residues within the LA repeats become protonated which weakens their association with Ca2 and alters their structure resulting in LDL dissociation and receptor folding. The receptor will recycle back to the membrane.

Strategies to combat high cholesterol in CHD and lipid disorders - Preferred: Although obvious, 75% of overall cholesterol intake is from the diet. The obvious answer would be to

avoid dietary cholesterol, although this would require a change in lifestyle people are not comfortable with - Inhibitors of Cellular Production - Increase catabolism: A certain amount of cholesterol is dedicated to the synthesis of bile acids. Formation of bile

acids requires a lot of energy and cholesterol. Inhibiting the recycling can reduce overall cholesterol (2/14) Bruzik Lecture: Chemistry of Lipid Disorders – II – Back at it again Switches and Feedback Regulation: Responsive mechanisms of cholesterol uptake and metabolism

- Excess Intracellular Cholesterol: High concentrations of cholesterol is associated with having a high concentration of cholesterol metabolites. These metabolites have 2 main regulatory feedback mechanisms:

o (1) Inhibition of HMG-CoA Reductase, thereby inhibiting de novo synthesis of cholesterol o (2) Inhibit LDL Receptor Expression

- Bile Acid Recycling Status: Cholesterol is used during the synthesis of bile acids. Individuals with efficient recycling will effectively inhibit cholesterol synthesis and uptake, since less is needed for bile acid synthesis

- Esterification: In order to be transported within lipoproteins, cholesterol requires esterification to migrate via Cholesterol Ester Transport Protein. Esterification relatively decreases free cholesterol, thereby signaling the need for and synthesis of more cholesterol.

Learning from past mistakes: Development of the early experimental drugs Triparanol and Diazacholesterol demonstrated the toxicity associated with accumulation of late metabolites. Inhibitors of cholesterol biosynthesis late in the biosynthetic pathway led to accumulation of desmosterol in the serum and liver, leading to severe side effects.

- Lesson: Cholesterol synthesis should be stopped at the earlier stages.

Modern Approach: After testing thousands of strains of microorganisms for inhibitors of sterol biosynthesis, Mevastatin/compactin was found in 1972. Due to poor efficacy, it was redeveloped into Lovastatin (1978)

- Target: Inhibition of HMG-CoA reductase decreases de novo cholesterol biosynthesis within cells.

- Biochemical MoA: HMG-CoA +2NADPH !"#$%&')*+,-./0*

Mevalonate. Naturally, reduction of HMG proceeds through a chiral tetrahedral intermediate. The reduction is stereoselective. HMG-CoA reductase catalyzes this slow, irreversible step.

o (1) Hydride Attack: Round 1: A hydride ion (H-) from a NADPH cofactor attacks the HMG carbonyl, producing a short-lived tetrahedral intermediate (sp2àsp3) transition state

§ Transition state sp3 is stabilized by basic activity of a Lys residue (K267) o (2) Hydride Attack: Round 2: CoA dissociates as a leaving group, substantiating concerted collapse of

HMG-O+ into an aldehyde, which is attacked by the second hydride equivalent, producing the reduced alcohol Mevalonate

- Inhibitor MoA: Lovastatin is a transition state analog that functions as a competitive inhibitor of HMG-CoA, but non-competitive for NADPH. This is due to its homology to the transition state, and HMG-like pharmacophore.

o Potency: The Km of HMG for the enzyme is 4µM, Lovastatin is sub-nanomolar (0.1-2.3nM) – Potent! Statin Therapy

- Within the Hepatocyte: Statins directly decrease the synthesis of cholesterol in the liver. As a result, intracellular cholesterol decreases. Homeostatic mechanisms respond by:

o (1) Upregulate synthesis of LDL receptors (mRNAÝ) § Leading to increased removal of B- and E- containing

lipoproteins from circulation (VLDL, IDL) o (2) Reduction in lipoprotein synthesis and secretion of lipoproteins from the liver.

- Systemic Effects o Lowered plasma concentrations of cholesterol-carrying lipoproteins, most prominently LDL. o Removal of remnant particles, such as VLDL and IDL. This is beneficial for hypertriglyceridemia pt. o Benefits are first seen after 1 week of therapy. Maximally at 4-6w.

- Patient Population: Individuals with Familial Hypercholesterolemia (FH) may see a minor benefit in the case of heterozygosity. Homozygous FH patients will not see a benefit.

Clinically Used Statins: The naturally obtained compounds are useful, but often too hydrophobic. Synthetic are improved - Lovastatin: Fungal metabolite + found in Red yeast rice - Pravastatin (Pravachol): While most statin therapies are prodrugs, Pravastatin is the active compound

with Hydroxyl + Carboxyl available to interact. Naturally-derived fungus metabolite. - Atorvastatin (Lipitor): Synthetic, more water-soluble with better bioavailability. Less AE. - Rosuvastatin (Crestor): The most potent of the statins. Sub-nanomolar.

Stain Metabolism - Bioactivation: As previously stated, many of the synthetic statins are prodrugs. Their lactone rings may be opened

to produce the active metabolite by esterases. - Inactivation: CYP3A4 of phase I metabolism hydroxylates statins to prepare them for phase II. - Excretion: Phase II metabolism most frequently involves glucuronidation for clearance in the urine.

Rhabdomyolysis: Rapid breakdown of the skeletal muscle usually due to physical damage of the muscle. Myoglobin is released from the lysed cells. It contains perforin, which is highly viscous and may block capillaries of the kidney potentially leading to renal failure. Cerivastatin (Baycol) led to 52 fatalities as of 2001. It was recalled. Alternative Approach: Interventions targeting cholesterol regulation and catabolism

- Cholesterol is used in the body to produce bile acids. They are oxidized and mixed with bile salts for excretion by the gallbladder to emulsify fats during digestion. Bile salts in the ileum may be sieved with bile acid resin therapy to reduce the amount of recycled cholesterol

- Bile Acid Resins: These resins are inert water-insoluble crosslinked polymers. Have like quaternary ammoniums. o MoA: Resins, such as cholestyramine, bind the negatively charged carboxylate groups of bile salts in the

intestines effectively reducing enterohepatic recirculation of bile acids through sequestration from the lumen. As a result, more cholesterol will be needed for bile acid synthesis to compensate for the loss. Upregulation of 7-a hydroxylase will promote greater cholesterol conversion into bile acids. Through a similar cascade to statins, this reduces the intracellular cholesterol content of hepatocytes, leading to upregulation of LDL receptors, thereby removing LDL and VLDL remnant particles from circulation.

o The Liver’s Response: The liver compensates by increasing cholesterol synthesis. Additionally, patients with elevated triglyceride levels will experience increased hepatic VLDL production, potentially raising serum triglycerides excessively.

o Drug: Cholestyramine: This sequestrant is primarily used to treat hypercholesterolemia. It has been found to slow the progression of coronary atherosclerosis and cause a net increase of coronary lumen

§ Reduces LDL via receptor pathway, and can work in combination with statins! o Drug: Colestipol: Less effective, also reduces LDL via receptor pathway and can be used with Statins.

- Monoclonal Antibodies: Newest and most efficacious therapies in terms of LDL lowering o PCSK9: PCSK9 is a protein responsible for reducing the number of LDL receptors on the cellular

surface. It binds to the EG-F motifs of the LDL receptors to prevent their recycling. o MoA: The mAb bind to and block the action of PCSK9, thereby allowing the LDL receptors to persist on

the cell surface and continue to remove LDL from circulation. There is effectively more LDLR present. o Drugs: Alirocumab (Praluent), Evolocumab (Repatha) o These drugs are great, but they are just too expensive

- Ezetimibe (Zetia) A Selective Cholesterol Absorption Inhibitor o MoA: Ezetimibe inhibits the absorption of biliary and dietary cholesterol from the small intestine without

affecting the absorption of fat-soluble vitamins, TG, or bile acids. Occurs in the Jejunum o Efficacy: Currently, there is controversy over the benefits of ezetimibe therapy. It is suggested to have

lipid-lower properties in monotherapy and synergistic activity with statins. 2008 trials found that the combo product with simvastatin (Vytorin) showed no benefit, whereas 2014 trials show 6.4% reduction of CHD sx compared to simvastatin alone.

- Stanols (Benecol): A margarine spread containing stanol esters. Stanols are not taken up by human cells, and have been shown to lower LDL by up to 15%, and greater benefits are seen when used with statins.

o DATA CHECK: Need to consume >1.3g/daily to observe cholesterol lowering effect - Xenical (Orlistat): A Gastrointestinal/Gastric Lipase Inhibitor

o MoA: b-lactone is attacked by a Ser-residue of GI lipase, forming a covalent adduct that inhibits the enzyme. Normally, GI Lipase hydrolyzes FA-TG to the mono/di-glycerides for chylomicron absorption

- Fibrates: Complex mechanism involving activation of a nuclear transcription factor (PPAR-a), inducing the expression of many genes involved in lipid metabolism. Drugs of this class, such as Gemfibrozil, are indicated for the lowering of TG. They do show increases in HDL, and higher risk of Rhabdo

(2/16) Hellenbart Lecture: Pharmacology and Pharmacotherapy of Lipid Drugs and Disorders Purpose of Treating Hyperlipidemia (HL) 1 in 4 deaths in the US is from Heart Disease

- Left untreated, HL will significantly increase the risk of coronary heart diseases (CHD), including: Coronary Artery Disease (CAD), Cerebrovascular Disease (CVD), Peripheral Vascular Disease (PVD)

- CHD or Hx of MI: Patients diagnosed with CHD or previous history of an event are at 5-7x higher risk of another event.

Pathogenesis of Atherosclerosis - Formation: Over time, fatty streaks in the endothelium develop into atheromas and eventually fibrous plaques.

These plaques have a soft lipid core, but a rough fibrous outer surface. Sufficient perturbation may rupture the plaques, producing microthrombi. Consequently, a clot will develop either fully or partially occluding the blood vessels. Even if these ruptures are stabilized, narrowing of the blood vessel will still develop.

- Complications: Impaired endothelial function may alter the release of Nitric oxide (NO), which significantly induce vasoconstriction, producing symptoms such as chest pain or ischemic-related events.

Lipids and Lipoproteins - Total Cholesterol (TC): Composed of LDL, HDL, and % of TG - Low Density Lipoprotein (LDL): “bad cholesterol”

o Greatest contributor to atherosclerosis. o LDL > 160? 1.5x more likely to have CHD than <130

- High Density Lipoprotein (HDL): “good cholesterol” o Transports cholesterol back to the liver for breakdown and removal o Higher levels are better

- Triglycerides (TG) o No longer a clinically viewed target, due to HDL greatly skewing it. o TG level is a secondary treatment goal, unless ³ 500 which indicates risk of pancreatitis

Relative Level

TC (mg/dL)

LDL (mg/dL)

HDL (mg/dL)

TG (mg/dL)

Healthy < 200 < 100 Higher < 150 Border Unhealthy

200-239 130-159 40s 150-199

Unhealthy ³ 240 ³ 190 £ 40 200-499

2013 ACC/AHA Guidelines – The new approach for treating cholesterol – Focus on ASCVD Risk Reduction - Previous 2001 goals: Individualized LDL therapy and treatment goals. NOW: Population-based ASCVD goals

o Evidence says: Appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit. Surrogate endpoints, like LDL lowering, support the precise therapy selection

- ASCVD: Atherosclerotic Cardiovascular Disease: Clinically diagnosed by occurrence of a coronary event. Patients with a history of CHD (MI, Angina), Coronary Artery Revascularization (PCI, CABG), Stroke or a Transient Ischemic Attach (TIA = mini-stroke), Peripheral Arterial Disease (PAD)

- Major Statin Benefit Groups o (1) Clinical ASCVD – Have had an event o (2) Primary ÝLDL ³ 190 – No event, but ÝLDL o (3) 40-75yo + DM + LDL(70-189) o (4) LDL(70-189) and 10y-ASCVD risk ³ 7.5%

§ 10y-risk: Nonfatal MI, CHD KO, Stroke - Limitations

o Little evidence for >75yo o Little evidence for HF or Hemodialysis (HD) pts o ASCVD Risk Calculations: Often overestimate

risk due to heavy weighting on age o ~~limited to statin naïve pt

Dx HL - Proactive Monitoring: Age 20+, start getting Fasting

Lipid Profiles (FLP) every 5 years. 10y-ASCVD risk should be assessed every 4-6 years to check candidacy for medication therapy

- PE: Majority of pt will be asymptomatic - Cx: Assess potential secondary causes

o Meds, DM, Booze, Junk food, Liver disease - Risk Factors

o Non-Modifiable: Age (M ³45y, F ³55y), Sex, Family history of premature CHD

o Modifiable: Cigz, Obesity, DM, Physical Inactivity, High LDL, Low HDL, HT (BP ³140/90 w/ meds)

Treatment of Hyperlipidemia - Assess CV Risk

o Recognize the 4 major statin benefit groups and occurrence of coronary events.

o The pooled cohort equation is an equation that provides the estimated ASCVD risk within 10 years for patients 40-75yo. It accounts for age, gender, race, TC, HDL, LDL< SBC, DM, Smoking, meds

- Therapeutic Lifestyle Changes (TLC) o Diet: Veges, fruit, grains, low-fat diary, poultry and fish, nuts

§ Limit: Sweets, Red-meat, Sat fat < 5-6%cal, less trans-fat o Physical Activity: Aerobic Exercise 3-4 session per week, 40min ea o Smoking Cessation: May reduce risk within months, and can increase HDL o General Weight Management: Promote healthy weight loss, no fad diets. Maintain a healthy weight

(2/19) Hellenbart Lecture: Medication Therapy for the Treatment of Hyperlipidemia HMG-CoA Reductase Inhibitors (Statins): [LDL ß18-55%] The most potent oral LDL-lowering agents available, these drugs are first-line therapy for lipid lowering. Statins have been historically shown to reduce CHD death, nonfatal MI, revascularization procedures, strokes, and total mortality.

- MoA: Competitively inhibit/block HMG-CoA reductase at the rate-limiting step of cholesterol biosynthesis, downstream reducing the synthesis of LDL. See Bruzik for more detail.

- The Pharmacokinetics of individual statins have note-worthy implications o Half-Life: Endogenous cholesterol biosynthesis peaks during the late evening

hours. Therefore, short T1/2 statins should be taken at bedtime, whereas longer T1/2 such as atorvastatin and rosuvastatin may be taken any time of the day

o Solubility: Theoretically, the more hydrophilic the statin, the less prone in invoking myalgia. Pravastatin may be an efficacious option for individuals having difficulty tolerating statins

o Metabolism: Knowing the CYP metabolism is important for DDI, Ex: Dosing with Clarithromycin - Relative Statin Intensity: These classifications need to be memorized

o High Intensity: (1) atorvastatin 40,80 (2) rosuvastatin 20,(40) o Where’s simvastatin 80mg? No longer recommended by FDA, no

benefit seen with the higher dosing. - ContraX: Pregnancy. Statins are category X because cholesterol biosynthesis

is needed during pregnancy. Additionally: Lactation, Acute liver disease o Simvastatin contraX: 10mg – verapamil, diltiazem 20mg – amiodarone, amlodipine, ranolazine

- AE: Though generally well-tolerated, most prevalent is HA, Myalgia, fatigue, GI upset - Monitor: Myalgia – Muscle pain, tenderness, and/or weakness may be a sign of rhabdomyolysis

o Reports of unexplained muscle pain/weakness/tenderness? à Check Creatinine Kinase (CK) § Risk Factors: >65yo, Renal dysfunction, DDI. § There is a theoretical benefit in using hydrophilic statins

o Myopathy: Myalgia + CK(>10x ULN) This is a dose dependent effect. à Doseß o Rhabdomyolysis: CK(>10x ULN) + ÝSCr Sign of muscle break down with myoglobinuria. Patients

should not use statins in presence of elevated SCr à D/C o Tx of Muscle Sx: Statins are the best hypercholesterolemia therapy we have, thoroughly evaluate the

severity of the symptoms, and check for secondary causes. § Severe? à D/C the statin, potentially find another in the class

- Monitor: Elevation of LFTs: This is rare, but if it occurs the therapy should be held or decreased in dose until levels normalize. Check LFTs at baseline. Routine monitoring is no longer required.

o Fasting Lipid Panel (FLP): At baseline and within 4-12 weeks, then continue testing q3-12mo. We are not targeting a particular LDL level, rather for the expected response rate. This plays into adherence.

§ High-Intensity statin should decrease LDL by ³ 50% § Moderate-Intensity statin should decrease LDL by 30-50%

o Secondary goal/target = LDL < 70 o LDL < 40mg/dL at 2 consecutive visits? à Highly consider decreasing statin dose, unless pt is high-risk

- Clinical Pearls: Though there have been reports of cognitive impairment, such as memory loss and forgetfulness, it is uncommon and a causal relationship has not been determined. Some reports of ÝHbA1C and Ýfasting serum glucose levels have been identified as factual (and added to package insert) though causality not determined

o To optimize therapy, we should be using the maximally tolerated statin Cholesterol Absorption Inhibitors

- Ezetimibe (Zetia): [ß18-22%]: Selectively inhibits the absorption of dietary and biliary cholesterol at the brush border of the intestine. During the ENHANCE trial (2008), they found that Ezetimibe did not slow the progression of atherosclerosis. Nevertheless, the IMPROVE-IT trial (2015) now finds that Ezetimibe lowered risk of CV events (stroke and MI)

o ContraX: Pregnancy, Lactation, Acute liver disease, o AE: D, Abdominal Pain o DDI: Do not use with fibrates or cholestyramine

- PCSK9 Inhibitors: PCSK9 is a gain of function mutation associated with hypercholesterolemia. By binding to LDL-R, it reduces the LDL-R density on the hepatocellular surface thereby increasing circulating LDL The activity of PCSK9 is increased by inhibition of HMG-CoA-Reductase (statins), representing a homeostatic compensation mechanism. By inhibiting PCSK9 with a monoclonal antibody, we can increase statin efficacy

o MoA: mAb indirectly ßLDL by regulating LDL receptors. Binding to PCSK9 prevents LDL-R recycling o à Evolocumab (Repatha) and Alirocumab (Praluent) q2w/qmo

§ OSLER and ODYSSEY: Trials that respectively confirmed efficacy and safety àdrug approve § FOURIER: Post-hoc analaysis that showed CV event reduction 15% and 60% more LDLß.

• AE: Suggested that PCSK9mAb may produce neurocognitive effects • 2º evidence: Confirmed that higher LDL:higher rate of CV events

§ EBBINGHAUS: Said no there is not a risk of neurocognitive effects Selecting Hypercholesterolemia Therapy

- In 2017, the ACC developed a non-statin decision pathway following the release of FOURIER results. Ezetimibe and PCSK9 are both considered for add-on therapy for maximally tolerated statins depending on LDL status

Miscellaneous Hyperlipidemia Agents - Bile Acid Resins (BAR): Cholestyramine (Questran), Colestipol (Colestid), Colesevelam (WelChol)

o Taken before the heaviest meals, these drugs lower LDL [ß15-30%]. Their main effect is LDL lowering o MoA: Anion exchange agents that bind to the negatively charged bile acids and eliminate them in the

stool, leading to upregulation of LDL-R and decrease of LDL o DDI: Many, binding to negatively charged drugs decreasing absorption (Warfarin, Thiazides, b-blockers)

- Fibric Acid Derivatives (Fibrates): Gemfibrozil (Lopid), Fenofibrate (Tricor), Fenofibric acid (Trilipix) o These drugs are first-line therapy for severe hypertriglyceridemia (TG > 500mg/dL) due to the risk of

pancreatitis. TG [ß20-50%], potentially increasing LDL depending on TG. o AE: GI side effects, and DDI: increased risk of myopathy when used concurrently with statins

- Omega-3 Fatty Acids: Ethyl esters (Lovaza), Om3+DHA/EPA (not FDA regulated) o Used as add-on therapy for TG control if intolerant to fibrates. TG [ß14-40%] o AE: Dyspepsia and fish burps, and DDI: Use with ASA increased bleed risk

- Nicotinic Acids: Niacin (IR, ER = Niaspan). A B vitamin that is present in most multivitamins. Used in the past to lower TG and increase HDL, though these are no longer our clinical targets. We do not use Niacin.

o ContraX: Active liver disease or PUD. AE: Cutaneous flushing and HA o *AIM-HIGH trial showed Niacin may increase the risk of ischemic stroke

The Flow of Therapy (my interpretation from recitation)

- Who to treat à If they are a member of the Major Statin Benefit Groups (1) Clinical ASCVD Have had an event of atherosclerotic origin (MI, TIA, CABG, PAD) (2) Primary Elevations – LDL ³ 190mg/dL (3) Age 40-75 with DM + LDL 170-189mg/dL (4) LDL 70-189mg/dL + ASCVD 10-year ³ 7.5%

- Treat with what? à A Statin - Why a statin? à Because they are the most potent oral LDL-lowering agents. They have been proven to

significantly reduce CHD death, nonfatal MI, revascularization procedures, strokes, and total mortality. They work to restore endothelial function, reduce inflammation, reduce ischemic episodes, and reduce cardiac events

o Note: LDL-lowering (LDL<70) is not our primary goal. Our primary goal is to reduce ASCVD risk - Ok fine, but what intensity? There are not any ‘low-intensity’ recommendations on our flow-chart. Most

situations call for either medium or high-intensity statins. If you are left with the option to decide: o Reasons for High: Family history of premature ASCVD (Dad <55yo, Mom < 65yo), ßLDL ability o Reasons for Medium: Patient has much room for lifestyle modifications, not far from secondary LDL goal

- What about the non-lipid therapies? Yes, ok we have the non-statin decision pathway. But, in practice, PCK9 Inhibitors are generally reserved only for the highest risk patients and are usually only added following step therapy where Ezetimibe is trialed first. The key is, Check the comorbidities. Are we at the max-tolerated statin?

(2/21) DiDomenico Lecture: Pathophysiology of Atherosclerotic Cardiovascular Disease (ASCVD) Atherosclerotic Cardiovascular Disease (ASCVD): Put simply, is clogged arteries.

- Risk Factors: Each of the risk factors mentioned below promote endothelial dysfunction. Endothelial dysfunction allows for the enhanced progression of ASCVD.

o Non-modifiable: Male gender, Age, Genetics (FHx) At menopause, womens’ risk Ý o Modifiable: HT, Dyslipidemia, DM, Smoking

- Etiologies of Vascular Disease: When discussing VD, we are most often referring to the formation of atherosclerosis. The location of which largely determines the pathology and physiological consequences

o Cardiogenic emboli: Clot of the left atrium that mobilizes and leaves the heart, usually headed north, leading to acute thrombotic occlusion of the carotid vessels

o Arteriogenic emboli: An arterial clot that breaks off, may latch on elsewhere o Occlusion: Clotting may severely reduce blood flow and oxygenation of

downstream organs. Common is atherosclerosis of the carotid artery which feeds the brain, severe! More direct can be intracranial atherosclerosis

o Vasospasm: One feature that may or may not be present in atherosclerosis is vasospasm. This acute vasoconstriction can be severe as it decreases the already minimal lumen

Pathogenesis (Fatty Streak Formation) - LDL particles circulate in the blood, one will become atherogenic - In the event of: (1) endothelial dysfunction or (2) major [LDL] rise, LDL particles

will accumulate in within the endothelial wall. - Eventually, the LDL particles will oxidize (the dark particles) triggering a cascade

and amplification of this process – pro-coagulant process. - Plasminogen activator inhibitor, normally responsible for inhibiting the body’s ability

to break down clots, is stimulated to a pro-coagulant state. - Monocytes/leukocytes responding to the infiltration will recognize oxidized-LDL as

foreign and engulf the LDL, forming foam cells - The progressive building up of plaques will result in the formation of a fatty streak with a lipid core. - Overall:

o Coagulation: Plasminogen Activator Inhibitor o Vasoconstriction: Mediated by the Ýendothelin

production and ßNitric Oxide (NO) production o Inflammation: Mediated by the Ýendothelin production

and ßNitric Oxide (NO) production. Leukocyte accumulation may play a role

Pathogenesis (Impingement and the Necrotic Core): A few years later, the fatty streak advances, widening the intima - T Cells are showing up as inflammatory mediators, the plaque is impinging on the lumen

o Reduce collagen production in smooth muscle cells, and promote breakdown of collagen fibrils. The collagen was a healing mechanism that is now inhibited, allowing the plaque to balloon

- Foam cells induce chemotaxis, triggering smooth muscle cell migration from medial to intima layer. o They also recruit tissue Tissue-factor Pro-coagulant, promoting coagulation

- Debris from foam cell death and LDL engulfment experience reduced clearance, forming the Necrotic core Pathogenesis (Arterial Remodeling): Eventually, the plaque will rupture triggering a thrombotic cascade

- Upon plaque rupture, 1 of 2 things can happen (ASCVD development is unpredictable) o ‘Good’: Endogenous fibrinolytic system dissolves the clot/thrombus, inducing

eccentric healing in the blood vessel. Result: Fibrous, eccentric and occlusive o Bad: Thrombus formation overwhelms the fibrinolytic system, the clot forms

an arterial occlusion… and the clotting system goes haywire L Fluid Mechanics across stenoses

Variables: Pressure, Resistance, Cross-sectional area, distance/length of stenosis Small changes in the luminal area can cause large changes in the resistance and pressure gradient across a stenosis. Resistance is inversely proportional to the square of the cross-sectional area Distal. Check DiPiro book Perfusion

Intima

Media

Sober Up: 40% of us will develop ASCVD. It starts in the first decade of life and settles in during the next Target Organ Complications associated with ASCVD: Essentially, all of the vital organs and musculature can be affected by ASCVD. The sequelae of occlusion is ischemia

- Cerebrovascular disease (CVD): Most common. Associated with: Seizures, and - o Transient Ischemic Attack (TIA): Mini episodes, transient infarcts o Stroke: The worst-case scenario, killing brain cells, they don’t grow back.

- Coronary heart disease (CHD): Most common along with CVD. Associated with: o Arrhythmias: The heart equivalent of a seizure o Angina: The heart equivalent of a TIA o Myocardial Infarction (MI): The worst-case scenario for the heart. We do not grow back new myocytes.

Apart from potentially dying, heart failure is a common complication of chronic heart disease - Peripheral Vascular Disease (PVD): Affecting the limbs, primarily the lower extremities

o Intermittent Claudication: ~TIA/Angina, this is intermittent bouts of weakness, ischemic sx of the limbs o Acute limb ischemia: Worst-case scenario for the limbs, formation of a thrombus o Complications include: Gangrene, critical limb ischemia

Coronary Artery Disease (CAD): Also known as Coronary Heart Disease (CHD) - Oxygen Supply and Demand: Coronary blood flow is the major determinant for the heart’s oxygen supply

o Supply: Coronary blood flow, Arterial pO2 (oxygenation, [Hb]), diastolic filling time (heart rate) o Demand: Heart rate, myocardial contractility, ventricular wall tension

- Coronary Autoregulation: By this intrinsic mechanism, during exertion or emotional stress the distal coronary vessels will vasodilate to reduce resistance and improve blood flow via NO or PGI2

o In ASCVD, these vasodilatory mechanisms are occurring at rest, severely decreasing the available NO supply and reducing the effectiveness of autoregulation. Ischemia will occur, and potential infarction.

- Occlusion: In this case, the degree of occlusion can be interpreted as the %coronary stenosis. The body is very good at compensating, at 40% occlusion there generally are no symptoms

o > 40-50%, symptoms begin to present as NO is depleting o 70%: This is the ‘critical point’ at which “non-obstructive” CAD becomes obstructive. A lesion is more

than likely present, and symptoms will be present with exertion. § 40-70% is paradoxically the range with the most vulnerable plaques – most prone to rupturing

o 80-85%: Symptoms experienced while at rest. Cerebrovascular Disease (CVD)

- CPP = MAP – ICP. The brain requires constant perfusion. The cerebral perfusion pressure (CPP) is the driving force for cerebral capillary perfusion. MAP = mean arterial pressure, ICP = Intracranial pressure

o CPP is generally only dependent on MAP. ICP is almost always constant - Cerebral Autoregulation: Too little pressure à Ischemia Too much pressure à Edema

o When pressure increases, the blood vessels will dilate to accommodate the increased pressure o When pressure decreased, the blood vessels begin to collapse upon themselves, especially following

extended periods of increased pressure. This makes an ischemia-susceptible situation o At a critical threshold (~150), the body’s ability to adapt to the changing pressures is exhausted, the

cerebral vessels will experience force-mediated dilation, as well as vasogenic edema. Occlusion of a cerebral vessel upon rupture à bad news bears

- Ischemic Cycle o ßCPP may occur due to atherosclerotic plaques. o In response, an increase in NO and other vasodilator mediators will

be secreted to increase cerebral blood volume CBV o The skull can only hold ~150mL. As CBVÝ, ICPÝ o If intracranial pressure (ICP) increases, there will be decreased

perfusion, thereby promoting continuation of the loop - Cerebral Autoregulation during Stroke

o During a stroke, cerebral blood flow continues#$%$@#$

Note: PAD = PVD Note: CAD = PHD

Collateral Circulation: Chronic ischemia and the continued release of NO will stimulate the production of growth factors. This is a self-preservation mechanism called collateral circulation. It promotes arterio/angiogenesis

- Vascular endothelial growth factor (VEGF) and Basic Fibroblast growth factor (BFGF) will stimulate the maturation of smaller capillary-like vessels from pre-existing arteries to preserve blood flow around the plaque formation. It is collateral flow. Seen primarily in elderly patients

Infarction and Ischemic Penumbra: Severe and/or prolonged ischemia will inevitably lead to infarction, also known as an acute thrombotic occlusion. The ischemic penumbra is the tissue surrounding the occlusion/necrotic tissue that is metabolically active and vulnerable to infarction

- Penumbra Growth: In the absence of intervention, the penumbra will grow as a result of the metabolic toxins and oxygen-free radicals that accumulate. Depolarization of adjacent cells may lead to seizures or arrhythmias

- The penumbra is at risk of complications associated with the acute thrombotic occlusion due to the metabolites - Irreversible cell death/necrosis: Brain (4-10 mins), Heart (20 mins)

(2/23) DiDomenico Lecture: Pharmacology of Antiplatelet Medications Platelets are responsible for adhering to damaged areas in the circulation. They have an average lifespan of 5-9 days Platelet Mechanisms of Action

- (1) Vascular Injury: In the event that the smooth layer of endothelial cells is ruptured, internal components are exposed, including collagen and von Willebrand Factor (vWF)

- (2) Platelet Adhesion: Receptors on platelets are capable of recognizing these components, which upon binding will stimulate an internal cascade

o à Platelet adheres to the vascular endothelial wall at collagen (via GPVI) and vWF (via GPIb) - (3) Platelet Activation: Binding to endothelial components activates the platelet, stimulating release of

Thromboxane (TxA2) and ADP to recruit/activate other platelets o Meanwhile, platelet activation will induce the

upregulation of GPIIb/IIIa expression. This is a critical receptor that uses fibrinogen to link platelets together

- (4) Platelet Aggregation: Fibrinogen binds the platelets together via ~50k fibrinogen-linked receptors

- (5) Thrombus Formation: When fibrinogen converts to fiber, thrombus formation is complete. This may be a complete occlusion of the vascular space

Most antiplatelet medications try to inhibit the activation and aggregation of platelets

Primary Prevention Patient has not had a clinical CVD event Medication is used to help prevent the event

Secondary Prevention Patient has already had a clinical CVD event Medication is used to help prevent another event

Aspirin (ASA): ASA is the most versatile medication for antiplatelet therapy, and it is used as first-line therapy for primary prevention and even more significantly secondary prevention

- Target: Cyclooxygenase-1 (COX-1). An enzyme of the arachidonic acid pathway that catalyzes TxA2 formation - MoA: ASA acetylates a Ser-residues near COXI active site, irreversibly inhibiting TxA2 production for the

lifespan of the platelet. Essentially, ASA dosing poisons the platelet population for ~5-9 days. TxA2 normally stimulates vasoconstriction and platelet activation/aggregation. Preventing its influence is beneficial

o Low Doses (50-325mg): Inhibit COXI completely at 75mg/day. Provides vasculo-protective effects o High Doses (>325mg): Inhibits COXI and COXII, additionally inhibiting inflammation (Arthritis Tx)

- ASA Non-responsiveness: 25% of pt do not respond. We can check using platelet function assays P2Y12 Inhibitors: Clopidogrel (Plavix), Prasugrel (Effient), Ticagrelor (Brilinta), Cangrelor (Kengreal), Ticlopidine

- Class: This class of compounds was previously known as thienopyridines. However, recently added members of the class do not fit this description so they are now called P2Y12 Inhibitors

o Unique: Cangrelor is parenteral clopidogrel and prasugrel are prodrugs - Clopidogrel: Reversible inhibitor of P2Y12, duration of action < 5 days

o Majorly (85%) metabolized by 2C19. Highly Polymorphic! Black Box Warning o *1/*1 – The native form, Extensive

metabolizer (ideal), it is associated with a higher degree of activity

o Non-ultra-rapid metabolizers, particularly individuals of Asian descent, should change therapy

o Clinical PGen testing kits are available, however cost may wall utilization o Efficacy: Inhibits platelet activation by about 50%, taking 2-6h to reach peak activity. May require LD

- Prasugrel: Bioactivation of this compound via hydrolysis does not require 2C19. However the active metabolite is inactivated by CYP, so inducers or inhibitors of 3A4 will alter the effects of the drug

o Efficacy: Same inhibition as clopidogrel in 30 mins, peaking higher at 90% inhibition of platelet activity GP IIb/IIIa Inhibitors: Abciximab (Reopro), Eptifibatide (Integrilin), Tirofiban (Aggrastat) Parenteral only!

- Target: Arg-Gly-Asp (RGD) sequence is the GP IIb/IIIa receptor specificity - MoA: These compounds block the receptors responsible for platelet aggregation. At 60-80% blockade, platelets

are unable to aggregate, and at >80%, thrombus formation is prevented and bleeding time is increased. o All members of this class achieve 80% blockade, preventing platelet aggregation and thrombus formation o Abciximab: mAb specific for GPIIb/IIIa,, short-half life but long duration (2 days) of effect o Eptifibatide: KGD-containing peptide, blocks the receptor specifically. Requires renal dose adjustment

§ Duration of effect = 2-4 hours o Tirofiban: RGD-mimetic non-peptide, blocks the receptor specifically. Requires renal dose adjustment

§ Duration of effect = 3-4 hours PAR-1 Receptor Antagonist: Vorapaxar (Zontivity) Phosphodiesterase Inhibitors (PDE-I): Dipyridamole (Persantine), Cilostazol (Pletal)

- By inhibiting phosphodiesterase, platelet activation can be effectively decreased. Antiplatelet Adverse Reactions: By the nature of their pharmacodynamics effect, all of the discussed compounds produce an increased risk of bleeding. However, we should monitor for serious AE

- Bleeding: GI bleed is the most common, Intracranial is the most severe, and it is common for vascular access sites to bleed excessively

- Idiosyncratic AE (rare but possible) o ASA: Dyspepsia, Hypersensitivity o Clopidogrel: Rash, Thrombotic thrombocytopenia purpura (TTP) o Ticagrelor: Dyspnea, bradycardia, ventricular pauses o Ticlopidine: Myelosuppression ß This medication is no longer used due to its ADR o Dipyridamole/ASA: Dyspepsia, GI discomfort, HA o Cilostazol: HA, Tachycardia, Infection, Diarrhea

(2/28) Schlemmer Lecture: Pharmacology of Drugs used to treat Angina Coronary Artery Disease (CAD): Also known as ASCVD, Coronary Heart Disease (CHD), and Ischemic HD

- Epidemiology: 1 in 3 adults has a variation of cardiovascular disease, >13mil have CAD and ~9mil have Angina o #1 cause of death, higher in AA. The greater the number of vessels occluded à worse outcome

- Pathophysiology: Fatty streaks can be considered normal, essentially all adults have them. However, when plaques build up, they can become obstructive atherosclerotic plaques. Associated inflammatory processes further promote occlusion, and although often clinically silent, severe occlusions may require bypass surgery

- Complications: Angina pectoris, MI, HF, Ventricular arrhythmias, Death Angina: Term for chest pain or discomfort attributed to Coronary artery disease (CAD)

- Sx: Pressure, squeezing, pain in the center of the heart ~ sternum/left side of chest - Cx: Pain results from acidic metabolites stimulating myocardial pain nerve-endings. The accumulation of

metabolites secondary to myocardial ischemia will effectively decreasing oxygen supply to the extent that the demands of myocardial oxygen balance are not met.

- Electric: The ST segment connects the QRS complex to the T wave, and represents the ventricular repolarization phase. Normally, it is flat.

- Stable Angina: Inducible by moderate effort. Coronary artery functions on reduced capacity, quickly relieved by rest or nitroglycerin

- Unstable Angina: Also referred to as acute coronary syndrome, this type of angina may be provoked even when resting. Atherosclerotic plaques rupture, clotting to form a plug, blocking flow to the heart muscle. Unstable angina should be treated as a medical emergency

- Prinzmetal’s Angina: An unstable variation of angina whereby spasms cause reductions in blood flow. This may occur in or in absence of atherosclerotic disease. It is also referred to as Vasospastic angina

Treatment of Angina - The aim of treatment dictates the style of treatment. To impart long-term prevention, we must stop the progression

of atherosclerosis, made possible inhibiting platelet activation, fibrinolytic activities, and inflammatory abnormalities. Sometimes, to relieve or avert the onset of pain, we require significant lifestyle changes and potentially even surgery. Surgery includes, angioplasty, stents, and coronary bypass.

o Short-term goals: Reduce or prevent angina symptoms that impair quality of life o Long-term goals: Prevent MI, arrhythmias, HF, and extend the patient’s life.

- Nitrate Therapy: Nitrates are the classic prototype drugs used for short-term relief of Angina o à Reduce myocardial O2 demand o Sublingual and Translingual formulations are used to terminate acute angina and as acute prophylaxis o Ointments and Patches are used for sustained protection against angina attacks throughout the day

- b-Blocker Therapy: The mainstay therapy for Chronic stable angina o à Reduce myocardial O2 demand

Nitrates: Nitroglycerin - MoA: Upon entering the vascular smooth muscle, Nitroglycerin dissociates off

Nitric Oxide (NO) which activates guanylyl cyclase. Guanylyl cyclase increases cGMP formation which dephosphorylates myosin light chains à Vascular smooth muscle relaxes

o Predominantly act at the venous capacitance vessels and large coronary arteries to induce relaxation - Standard Dose: Dilation of systemic veins, causing blood to pool within veins (Ývenous capacitance), and

decreasing venous return to the heart. This reduces the workload of the heart, reducing myocardial O2 demand. o Coronary/Epicardial Arteries: Will be relaxed. This reduces spasm of variant angina and increases

coronary perfusion thereby aiding oxygen delivery. - Higher Doses:, Arteriolar resistance begins to decrease, further reducing the workload of the heart due to lack of

an afterload resistance. Extensive venous pooling continues, and overall blood pressure will decrease. - AE: High doses may trigger the baroreceptor reflex, producing reflex tachycardia and dizzy spells. This may

frighten the patient, so it is worth counseling them on – it is safe and to be expected. Additionally: o Headaches (cerebral vasodilation), Cutaneous flushing (arterial dilation of face), postural hypotension

- ContraX: Nitrates should not be used in combination with other nitrates. A PDE-5 inhibitor, sildenafil (Viagra) increases cGMP thereby potentiating nitrate activity. Due to the risk of life-threatening hypotension, drugs for sexual-activity should not be used. Try some meditation therapy or something instead

o Viagra: Avoid nitrate therapy for 24 hours following most recent Viagra/Levitra dosing o Cialis: Avoid nitrate therapy for 36 hours following most recent Cialis dosing (longer duration of action)

- Metabolism/PK: Nitrates have very low oral bioavailability (<10-20%) due to both chemistry and a significant first-pass effect by nitrate reductase in the liver. As a result, sublingual dosing is preferred as it avoids first-pass

o Onset: 2-5 mins, effects wear off within 30 minutes. - Dosing: To treat angina, allow 1 tablet to dissolve under tongue. If there is no pain relief after 5 minutes or if pain

worsens, contact emergency medical services. Take maximum 3 tablets DIV q5min while waiting for ambulance Nitrates: Isosorbide dinitrate: This compound is an improved PO formulation that has 4-6 hours of action. Still, the sublingual route for this drug is preferred.

- Mononitrate? The activate metabolite of the dinitrate formulation. Isosorbide mononitrate is an available prescription medication with excellent bioavailability and longer T1/2

o IR (Ismo, Monoket): Take 1 tab 2 times daily spaced 7 hours apart [provides nitrate free interval] o SR (Imdur): Take 1 tab Qdaily [Has a built-in interval]

- Tolerance: Sustained use will lead to desensitization producing tachyphylaxis – meaning there will be a loss of hemodynamic and anti-anginal effects following repeated dosing. This effect can develop in as little as 24 hours. Tolerance can be avoided by including nitrate-free intervals – of which is considered in the formulation of patches

- AE + ContraX: Refer to those listed for Nitroglycerin Beta-Blockers (BB): Each BB is equally effective in its treatment of angina. YES, can be combined with nitrates. The added benefit of combined therapy is that BB can help prevent the reflex tachycardia associated with Nitrates. WOW!

- MoA: Competitively inhibit catecholamine binding at b adrenoceptors (specifically b1). As a result, left ventricular wall stress is reduced thereby reducing blood pressure, in addition to heart rate and contractility. It is also hypothesized there is an increase in coronary blood flow due to Ýdiastole resonance

- Non-Selective: Propranolol - Cardioselective: Atenolol and Metoprolol are the most common. However, this cardioselectivity can be lost at the

higher doses when used to treat angina. - AE: BB are generally well-tolerated. However, high doses or intolerant individuals can produce a therapeutic

response that is too intense, such as bradycardia or excessive fatigue/CNS fatigue o Bronchoconstriction due to b2 adrenergic blockade (Non-selective agents or high dose cardioselective) o Worsening of PAD or Raynaud’s Fatigue CNS effect (nightmares, insomnia) o Erectile Dysfunction related to hypotension

Calcium Channel Blockers (CCB) - MoA (Myocytes): Block initial Ca2+ influx associated with formation of Ca2+-Troponin complexes in the heart

muscle. Ca2+-Troponin allows actin and myosin to contract. CCB à Decreased contractility - MoA (Vasculature): Block initial Ca2+ influx associated with formation of Ca2+-calmodulin complexes in the

vascular smooth muscle. Normally, this complex permits actin + myosin to contract. CCB à Vasodilation - Dihydropyridines: Exhibit greater selectivity for the vascular smooth muscle than myocardium

o Efficacy: Vasodilate the coronary arteries and reduce resistance, improving coronary blood flow o AE: Strong reflex tachycardia, so significant that it can lead to ischemia. Peripheral vasodilation may lead

to peripheral edema, flushing headaches - Verapamil: A negative inotrope (force) and negative chronotrope (~HR), Verapamil will lower the systemic

blood pressure, decreasing myocardial oxygen o Caution: Excessive negative inotropic/chronotropic effects may occur in combination with a BB

Ranolazine (Ranexa) - Place in Therapy: Used in late treatment for patients with chronic stable angina who have failed other therapies

o May be used concurrently with BB, Nitrates, and Amlodipine (but not other CCB) - MoA: Inhibits late entry of Na+ into cardiac myocytes; thereby reducing intracellular Na+. As a result, Na+/Ca2+

antiporter will attempt to compensate, thereby significantly reducing intracellular Ca2+, which is proposed to help the myocardium use energy more efficiently

- AE: May cause prolongation of QT interval, as well as increase BP o ContraX: Patients taking potent or moderately potent inhibitors of CYP3A4 (diltiazem, verapamil) are at

increased risk of QT prolongation.

(3/2) Groo Lecture: Coronary Artery Disease: Chronic Stable Angina Coronary Artery Disease (CAD): Also known as ASCVD, CAD is the number 1 cause of death and is characterized by the build-up of atherosclerotic plaques As lesion-related plaques increase in size, CAD starts being considered clinically significant (usually > 50%). At this point, the patient is considered obstructed and symptoms start presenting

- Sx: Chest Pain ~ of course! But get information about where? What brings it on? For how long? What relieves it? o Classic Sx: Substernal chest “pain” heaviness or discomfort (like something is sitting on their chest),

Associated with exercise, radiates to the left arm or jaw, lasts for 30 seconds to 30 minutes, and can be relieved with rest or Nitros (Nitroglycerin – NTG)

o Atypical Sx: Some individuals present with atypical sx, which is common in women, DM, and geriatrics. Includes: dyspnea, isolated jaw/neck pain, epigastric burning, N/V, diaphoresis (sweating), lightheaded, back pain/discomfort, and fatigue. In this case, it is likely silent ischemia is occurring

- Classifying Chest Pain – “Angina” o Stable (“Consistent”: Reproducible with consistent amount of effort, relieved in a consistent manner, and

occurring at a consistent frequency o Unstable (accelerating): Angina is occurring at rest and may occur for a prolonged duration (>20min).

The symptoms often noticeably accelerate, being provoked with less activity and occurring at Ýfrequency - Modifiable Risk Factors: Smoking cessation, tx of HT, Dyslipidemia, DM, diet, weight loss, exercise

Dx: A patient presents to the ED… - Electrocardiogram (ECG/EKG): Can be used to determine Hx of prior MI, or currently experiencing Sx

o à Stress Test: The goal is to elevate their heart rate and monitor the electrical activity for aid diagnosis o This will assess their tolerance to exercise. Have the patient walk on a treadmill. If they cannot,

administer drugs to induce angina/HRÝ - Angiogram (cardiac catheterization): If suspicions are high or the stress test is +, feed a wire into the heart and

shoot the coronaries with dye. This will help visualize the coronary arteries for obstructive lesions - Cardiac: Capable of showing scarring from prior events - Patient History: Assess for risk factors and pertinent medication history - Labs: BMP, Lipid profile, LFT, Glucose, Hemoglobin, hsCRP (inflammatory marker)

Treatment Goals: (1) Alleviate Sx, (2) Control/Modify Risk factors, (3) Prevent MI and/or Death - Meds to relieve Sx = Antianginal drugs: BB, CCB, Nitrates, Ranolazine - Meds to reduce MACE = BB, ACE-I/ARB, Antiplatelets, Lipid-lowering therapy (statins)

o Major Adverse Cardiac Events = MACE

In CAD, patients who are symptomatic have a higher oxygen demand than available supply. The major cause in decreased oxygen supply is due to reduced coronary blood flow. This is attributable to lesions

- Supply: ßCoronary flow: lesions ßArterial pO2: Lung disease or pneumo ßDiastolic filling: ÝHR - Demand: Higher preloads require more effort by the heart and therefore more O2. Tension… contractility…

Antianginal Therapy: All patients should have nitros for the acute relief of angina symptoms - *Consolidation: Prefer minimizing therapy to provide the best patient-specific coverage. Do not expose the pt tho

o If 1 drug can cover 2 of the patients maladies, chose that over adding on 2 agents - *Combination: When adding on therapy, the drug combinations should have different mechanisms of action - Beta-Blockers (BB): Considered first-line CAD therapy, touted to prolong life and decrease ischemic events

o Indication: (1) History of MI à 3 years therapy minimum with BB. (2) Chronic prophylaxis of angina o Goal of Therapy: Lower HR (~resting 60bpm, exercise £ 100). The lowering of BP is a bonus (if HT) o These drugs are really great for CAD, they reduce MACE and relieve Sx. Look at the chart!

- Calcium Channel Blockers (CCB): We have two classes, [Dihydropyridines~DHP] and [Verpamil, Diltiazem] o MoA: DHP- Primarily affected the vascular smooth muscle to produce vasodilation. +chronotrope

Vera/Dilt: Produce vasodilation and ßcontractility by reducing AV node conduction § Potent vasodilators, both classes will decrease oxygen demand by reducing BP. They are both

effective for relieve of vasospasm. However, they differ in their effects on HR. o Indication: Chronic prophylaxis of angina o Notable AE: Lower extremity edema, Hypotension (avoid IR products)

§ HR: DHP CCB will increase HR via reflex tachycardia, they should not be used as monotherapy § Bradycardia/Heart block: Vera/Dilt may cause this, avoid combination with BB and CHF patients

- Nitrates: Sublingual tabs, spray (NTG – Nitros) Long-acting tabs (Nitrates) o MoA: Open up arteries and decrease preload. Help relieve vasospasm. The effect on BP is minimal,

though at higher doses it will exhibit BPß o Indication: Acute relief of anginal symptoms, chronic prophylaxis of angina (long-acting nitrates) o Nitroglyerin (NTG, Nitros):

§ Dosing: I SL q5mins PRN chest pain. If no relief after 1st tab*5min, call 911 o Long-acting nitrates: Such as isosorbide mononitrate (Imdur) or NTG patch (Nitro-Dur)

§ YES – patients can use the long-acting nitrates and PRN Nitro together o AE: Headache is the most common AE. Patient should be wary of tachyphylaxis, they will need a nitrate-

free interval. - Ranolazine (Ranexa): Not frequently used. Should not be monotherapy, rather added onto traditional therapy

o Indication: Chronic stable angina (decrease sx) Advantage of this medication = minimal effect on BP o AE: May prolong QT interval. Patient should have normal baseline QT prior to initiating ranolazine

therapy. Ranolazine is also a 3A4 and PGP substrate, be wary of DDI Monitoring of Antianginal Therapy

- Short-term goal: Reduce symptoms o Patients and practitioners should document/keep a diary on what provokes angina, the duration,

frequency, and the use of Nitros - Long-term goal: Prevent CHD events/Prolong life --~ MACE

o MI, CVA (stroke), Death, Urgent revascularization (get vessels opened up in the ICU) MACE-Reduction Therapy Major Adverse Cardiac Events All pt with CAD should have ASA

- Beta Blockers: The reason BB are 1st line for tx angina is because they also reduce MACE o Additional Indications: Patients with reduced ejection fraction (LV function < 40%) require lifetime BB

- ACE-I and ARB: We generally only add these in high-risk patients o MoA: (1) Used for the prevention of endothelial dysfunction in coronary arteries via vasodilatory effect

§ (2) Possess plasminogen activator inhibitor properties, shifting fibrinolytic states to clot lysis § (3) Reduce the risk of death, MI, and stroke in high-risk patients

o Indication: In this setting, ACE-I/ARB will be used to reduce MACE, not as an antianginal § à CAN BE USED EVEN IF NORMAL BP

- Antiplatelets: As lesions grow, fibrous caps can explode. We want to prevent scab-formation - antiplatleet o ASA: All patients should be using. Decreases the risk of MI and death o Clopidogrel: Alternative for pt contraX or intolerant to ASA. Can be used in combination with it

Therapies to avoid: Rosiglitazone - Shit that doesn’t work: Estrogen therapy, Vit C,E, homocysteine, garlic, CoQ10, Se, Cr

(3/5) DiDomenico Lecture: Acute Coronary Syndrome I Acute Coronary Syndrome (ACS)

- ACS has a very similar presentation as angina, though symptoms of ACS persist for 20mins+ and can stutter/fluctuate in intensity. As a result, diagnosis relies upon a more in-depth investigation

- Presentation The classical symptoms are chest pain, most often associated with exercise, unrelieved by Nitros o Hemodynamics ßBP,ßHR, or even ÝBP,ÝHR-(trying to compensate). Hx of HF or cardiogenic shock o Conduction Disturbances o Cardiac Arrest o Death 15% of pt initially present as fatalities, it is important to initiate CPR and resuscitation

- Dx: Step 1: Electrocardiogram (ECG) o ST-Elevation or left bundle branch block

§ This is a HIGH-RISK patient, highly suggestive of MI § ST-segment elevations are associated with ischemia

o No ST-segment elevation § The findings are non-specific for MI § In this case, ongoing ischemia is a concern

- Dx: Step 2: Confirm with Cardiac Enzymes (Biomarker) o Measurement of the troponin enzyme level o This tool is more often used to rule out infarction o The URL (upper-reference limit) is 1. Any reading above 1 is considered to be a

positive test result that the patient has infarcted. o Patient interview is important: Ask when their symptoms began

§ Troponin levels related to MI rise in first 3-6 hours § Sx for just 1 hour may not be confirmed by troponin levels

- Dx: Step 3: Classification of MI (if present) o MI type 1: Spontaneous MI due to plaque rupture, thrombus formation, and acute ß in blood flow o MI type 2: MI due to imbalanced oxygen supply-demand relationship related to another condition. In

practice this is often dismissed as unimportant. We should investigate and involve a coronary angiogram - Acute Coronary Syndrome Spectrum of Diagnosis

o STEMI: ST-elevation Myocardial Infarction ~ ST-el, (+) biomarker o NSTEMI: Non-ST-elevation Myocardial Infarction ~ Non-ST, (+) biomarker o UA: Unstable Angina ~ (-) biomarker

Before Initiating Treatment (Non-emergency) - An adequate clinical assessment, involving risk scoring, labs, and patient interview is important for optimal tx - Risk Calculators for ACS pt Incorporates an analysis of Hx, ECG, Troponin, Age, Risk Factors, PE

o TIMI Score: A well-established old scoring system, but is not very discriminatory for tx decisions o HEART Score: The newer scoring system that is improved for discriminating the necessity of tx

- Physical Exam: Monitor for evidence of heart failure, such as pulmonary edema – need to know organ function - Labs: Thrombotic therapy can cause thrombocytopenia and increase the risk of bleeding, we need to know

baseline CBC, platelets, PTT, INR, and renal function Treatment Goals:

- Restore blood flow to limit the infarct size (if MI) - Prevent/minimize complications - Prevent re-occlusion - Relieve symptoms - Resolve ECG changes

Acute Treatment of Acute Coronary Syndrome Initial Measures Antithrombotic Interventional Initial Measures

- ALL PATIENTS RECEIVE 162-325mg ASA IR x1 dose – Put it in the patient’s mouth and tell them to chew o If concurrent Ticagrelor (Brilinta) therapy, ASA dose must be £ 100mg Qdaily

- Next: Most patients will receive reperfusion therapy if indicated - Then after: MONAAAAAAAAAAAAAA therapy (next lecture)

Antithrombic/Fibrinolytic Therapy: [Pt must qualify, Prepare the compound, Check for absolute ContraX, Inject] - Goal is to push drug (thrombolytics) within 30 minutes of presentation at the hospital (when indicated), the

earlier you act the more lives you save. But inappropriate use of fibrinolytic – call up your lawyer - Indication: Need 2 of the 3 factors to validate fibrinolytic reperfusion strategy

o (1) EKG Shows ST-elevation or new onset left bundle branch [Mandatory] o (2) History of MI and presenting within 12 hours of symptom onset o (3) If PCI cannot be performed within 120 minutes

§ Primary PCI is preferred for STEMI, but if it is unavailable for 120 mins, fibrinolytic therapy is preferred as it has a lower mortality rate than waiting any longer.

- Fibrinolytic Agent: The choice of agent depends on the institution, policy, and formulary o Alteplase (TPA) o Bolus Thrombolytics: Reteplase (RPA), Tenecteplase (TNK) – these are easier to give, and expedite

therapy. They are the suggested means to expedite pharmacologic reperfusion o Adverse effects: These drugs increase the risk of bleeding and intracranial hemorrhage

- Absolute Contraindications - essentially anything that additionally increases the risk of bleeding o Active bleed, previous intracranial hemorrhage, ischemic stroke (<3mo), head trauma, BP > 220/110,

Known bleeding disorder Interventional Therapy [Angiogram, Match PCI to Indication, Cut open, Anti-platelet therapy]

- Goal is to open the artery (Primary PCI) within 90 minutes of presentation at the hospital (when indicated) - Angiogram: The first step, the ‘gold standard’ for diagnosing CAD. Insert catheter via femoral or radial artery,

feed it up backwards through the arterial circulation, right to where the coronaries feed off the aorta. Inject dye – visualize the coronary artery blood flow…. Fancy words like Proximal Occlusion

- Percutaneous Coronary Interventions (PCI) – This is more common for STEMI – lower mortality o Primary PCI (STEMI) Preferred option for STEMI – higher survival o Early Invasive (NSTEMI/UA) This is elective PCI for stable CAD o Methods: Balloon angioplasty, Intracoronary stenting o Stent Types: Bare metal stent (BMS), Drug-eluting stent (DES)

§ BMS: Aluminum-based. They have been associated with re-stenosis. Adverse healing of the artery itself, they are the less preferred stent.

§ DES: Impregnated onto the stent are drugs that are slowly released to prevent healing, preventing the endotheliazing reaction.

- Patients receiving PCI will require additional anti-platelet therapy ~ we are essentially blowing up a clot, adding foreign objects, and causing all these debris to disperse. Huge clot risk, give them antiplatelet therapy

o Besides for the newer biodegradable products, these stents are in for the lifetime of the patient Conservative Strategy

- Medical Management is an early approach to manage NSTEMI if there is no PCI planned, or if the diagnosis of non-severe unstable angina.

Anti-platelet Therapy - ASA: All patients receive ASA as their first therapy to help decrease mortality. Following initial dose, patient will

continue 81mg EC as a daily dose. ASA reduces the risk of MACE, with a minor increase in major bleeds - P2Y12 Inhibitor - GP IIb/IIIa Inhibitor

Anticoagulation Therapy - Heparin - LMWH - Bivalirudin - Fondaparinux

(3/7) Didomenico Lecture: Acute Coronary Syndrome II Patient has presented to the ED, we’ve already given them some ASA, we’ve made the decision to commit to reperfusion therapy or not, now it’s Antiplatelet therapy Dual-Antiplatelet Therapy (DAPT) •Dominated by P2Y12 Inhibitors [MACEß20%]

- STEMI o +PCI à Prasugrel or Ticagrelor for ³12mo o +Fibrinolytic Therapy à Clopidogrel x14 days

- NSTEMI o +Invasive Surgery à Ticagrelor for ³12mo o +Medical Management à Clopidogrel or Ticagrelor for ³12mo

- Upcoming CABG Surgery? D/C drugs 5-7 days before bypass surgery or any other invasive surgery - Clinical Trial Results suggest….

o Dual-Antiplatelet Therapy decreases the risk of ischemic events by another 20%. The tradeoff is an increased risk of bleeds

o Avoid Prasugrel IF: Patient is small in stature, <60k or ³ 75yo, with history of TIA or stroke. In these patients, there is no benefit and only an increased risk of serious intracranial bleed

o Choose Ticagrelor IF: Coronary anatomy is unknown and/or there is a high likelihood of eventual non-urgent CABG (because Ticagrelor is quickly reversible)

o Use Clopidogrel IF: Patient is at a very high risk of bleeding •Utility of Glycoprotein IIb/IIIa Inhibitors [MACEß16%]

- The drugs are only available for parenteral administration, and are reserved for patients who undergo PCI - ContraX

o Using GIIb/IIIa Antagonists for anticoagulation shows no benefit and increases the risk of major bleeds o If the patient has received thrombolytic therapy, such as fibrinolytics, GIIb/IIIa should not be used

•Individualizing Platelet Therapy [MACEß5-10%] - There are two ways to individualize therapy: (1) Genetic Test (2) Assess platelet function after loading them - Recent study suggests that, YES, we can lower MACE rate by tailoring to the patient’s genetic profile

Anticoagulation Therapy [MACEß30-40%]

- Anticoagulation should be started before and continued during the PCI. It is indicated for intermediate-high risk (ACS) patients as well as individuals who have received Fibrinolytic (STEMI) therapy

•Heparin - Indx: Can be used for those being handled medically or if headed into the Cath lab (Versatile drug option) - Unique Dosing: Due to concurrent ASA and additional ongoing therapy, the max empiric dose is lower than is

regularly seen in other treatments. 60U/kg at a max of 1000U/hour. It is adjusted to the PTT - Duration à Treat for 48 hours or after the patient is done with PCI

•Bivalirudin - Indx: Only indicated for patients going into the Cath lab to get PCI. (It has a very low bleed risk!!! NICE!) - Duration à It is stopped at the conclusion of the PCI procedure

•Low Molecular Weight Heparin (LMWH) à Enoxaparin ß - Indx: This is simply an alternative for the less severe patients who are being medically managed. - Benefit: Risk of Major Bleed is less. Drug can be injected subcutaneously – patient is more mobile

•Fondaparinux - Cardiologists hate this drug. It is associated with some sort of arterial catheter thrombus - If a PCI is planned, do not use this

So 4-6 hours later here we are… Time to think about adjunctive therapy

Early Supportive Measures - MONA

o Morphine Sulfate (IV): 1-8mg IVP q5-15 mins usually only end up doing a dose or two § Most importantly, MS is a anxiolytic, it will calm our patients down. Additionally, a vasodilator,

it will increase venous flow to the heart. Monitor for respiratory depression o Oxygen: Patients who present with hypoxemia (O2 Sat is < 90%), give them oxygen! o Nitroglycerin: Though most patients will not be responding to nitros if they have a fully occlusive

thrombus, it is a vasodilator and is useful if Sx persist. It is IV, PO, and topically available § ADR: Headache, Hypotension, Reflex tachycardia (mild) § ContraX: Right ventricular heart infarct, PDE-I (Sildenafil, Vardenafil <24h, Tadalafil < 48h)

o Anti-anginal/Beta-Blockers: Patient should have b-blockade within 24 hours of presenting (lower MI/MACE). This is indicated especially in the case BP or HR are elevated

§ Metoprolol 5mg IV push q5mins x3doses § ContraX: If patient has heart failure or is at high risk for HF they must wait until their Sx have

subsided. o Atorvastatin (High-Intensity Statin) – Atorvastatin was chosen simply because it was studied the most

§ Unless absolutely contraX, patients require high-intensity statin therapy - When establishing the chronic outpatient regimen, the anti-RAAS (Ace-I, ARB, Eplerenone) therapies become

useful. These regimens should be started and introduced prior to hospital discharge. They should be considered for all patients with MI

o Typically ACE-I are the preferred add-on, switching to ARB only if unable to tolerate. o ALSO: Eplerenone can be added for post-MI pt with low LVEF and (DM or Symptomatic HF)

Chronic Therapy/Secondary Preventions So you came to the ED and decided to present with ACS? Well here are the drugs shown to decrease mortality and/or ischemic events after an MI

- (1) Everybody goes home on ASA Indefinitely - (2) Everybody goes home on a high-intensity statin Indefinitely - (3) Everybody goes home on a P2Y12 Antagonist to use for a while (14 days – 1 year) - Post MI patients

o (4) BB in the first 24 hours and continued for the next 3 years o (5) ACE or ARB o (~6) Have Low LVEF and DM or Symptomatic HF? Eplerenone

- (7) Everybody should go home with Nitroglycerin SL (tabs or spray) – This does not affect mortality You could be going home on 7 drugs