Angina & Hyperlipidaemia Flashcards

Question

What is claudication?

Answer 1

Pain caused by ischaemia of muscles in the leg- it is due to atherosclerosis of arteries supplying the leg

Answer 2

Drugs that block dietary uptake of cholesterol

Answer 3

A liver cell

Answer 4

- Bile acids are synthesised from cholesterol in the liver - These emulsify lipids so they can be digested and absorbed - They then travel through the bile duct into the small intestine - In the small intestine, lipids are emulsified - 5% of the bile acids from the intestine are excreted (cholesterol is also lost as feaces) - 95% of bile acids are reabsorbed and returned to the liver to be recycled through the hepatic portal vein

Answer 5

- Acetyl-coenzyme A is converted into HMG-coA - HMG-coA is converted into Mevalonate = KEY STEP!! - This is done by HMG-coA reductase which catalyses the reaction —> this is the rate limiting step as it controls the overall rate of cholesterol synthesis - Mevalonate is converted into cholesterol - Steps 1 and 4 are under feedback inhibition

Answer 6

The body can replace lost cholesterol by absorbing it from the diet - Occurs in enteroctyes (cells lining the GI tract) - At the gut lumen, NPC1L1 (a cholesterol transporter) absorbs cholesterol so it can be esterfied in the ER - Golgi complex and ER produce a cholesterol ester - This exits as a chylomicron (class of lipoproteins) - Chylomicrons are secreted into the lymphatic system and then pass into the bloodstream

Answer 7

- ApoB-100 = has a structural role and enables the body to identify which class a particle belongs to - Phospholipid monolayer = consists of phospholipids & cholesterol - carbohydrate on ApoB-100 - cholesterol on phospholipid monolayer - Lipid core = triglycerides & cholesterol esters

Answer 8

1. HDL = >1.063 2. LDL = 1.019-1.063 3. IDL = 1.006-1.019 4. VLDL = 0.95-1.006 5. Chylomicrons = <0.95 Density is measured in g/mL

Answer 9

- Synthesised in the small intestine & secreted into the lymph before passing into the bloodstream - Deliver triglycerides to peripheral tissues where they are hydrolysed by lipoprotein lipases - Forms cholesterol-rich Chylomicron remnant particles

Answer 10

- Synthesised in the liver and released into circulation - Deliver triglycerides to peripheral tissues - Removal of them results in the formation of IDLs - This is done by lipoprotein lipase enzyme (the conversion to IDL)

Answer 11

- Taken up by the liver where it is either catabolised or has triglycerides removed by hepatic lipases - This forms LDL particles

Answer 12

- Carries cholesterol to tissues - Regulates cholesterol levels in the liver - Taken up by specific receptors that recognise ApoB-100 - High LDL increases risk of cardiovascular disease - High LDL and VLDL also increase that risk

Answer 13

- Produced in the liver and intestine - Mature in circulation by transferring phospholipids and apolipoproteins from Chylomicrons and VLDL - Able to remove cholesterol ester from peripheral tissues and deliver it to the liver for excretion as bile acids - High HDL lowers the risk of cardiovascular disease

Answer 14

HDL cholesterol

Answer 15

Cardiovascular disease

Answer 16

It’s protective against cardiovascular disease

Answer 17

- Total cholesterol —> below 5 mmol/L - Non-HDL cholesterol —> below 4 mmol/L - LDL cholesterol —> below 3 mmol/L - HDL cholesterol —> >1 men; >1.2 women - Total cholesterol to HDL ratio —> Lower the better = ratio of <4 is normal, 6 is high risk

Answer 18

- low cellular cholesterol regulates the expression of LDL receptors and PCSK9, the expression of both these proteins increases when cholesterol levels fall - the LDL receptor binding site for ApoB-100 faces the extracellular fluid - LDL receptors have a single transmembrane domain - PCSK9 is released into the extracellular fluid - once ApoB-100 binds to the receptor, it is endocytosed in a clathrin coated vesicle - PCSK9 is also able to bind to the LDL receptor complex and if this happens, the LDL receptor is not regulated and it will enter an endosome then a lysosome where its degraded (LDL receptor is not recycled) - in the lysosome, the LDL receptor and ApoB-100 are degraded into amino acids - cholesterol released from the LDL particle is transported into the cytoplasm by 2 proteins (NPC1 and NPC2) - mutations in NPC1 are strongly linked with obesity - LDL receptors not bound to PCSK9 can be recycled to the cell surface to bind more LDL

Answer 19

- Smoking = lowers HDL & oxidises LDL = atherosclerosis - NAFLD = liver disorders which increase production of VLDL and serum levels of LDL - Genetics - Poorly controlled diabetes = lowers HDL & raises LDL - Diet of highly saturated and trans fats = increases non-HDL and cardiovascular risk - Medication = some increase non-HDL cholesterol e.g. corticosteroids - Obesity = raises serum LDL & VLDL as inflammation in the liver alters production of them

Answer 20

Individuals are at a higher risk for cardiovascular problems associated with LDL cholesterol Caused by mutations in 3 components 1. LDL receptor —> can’t recognise ApoB-100 and thus prevents uptake of LDL by the liver, causing it to accumulate in circulation 2. ApoB-100 —> structure is altered so can’t bind to LDL receptors, reducing the ability of the liver to clear LDL from circulation 3. PCSK9 —> - Binds to receptor and directs it to the lysosome where its broken down - This reduced the number of LDL receptors on the surface of the hepatocytes and reduces LDL clearance from the bloodstream - GOF mutations (increase stability or activity) results in fewer LDL receptors being available - Thus LDL levels in the blood and cardiovascular risk increases - LOF mutations are associated with reduced cardiovascular risk

Answer 21

Hardening of the arteries - Fatty streak builds after 10 years - After 30 years this becomes atheroma - After 40, it progresses further into a fibrous plaque - At 30 & 40 years, this results in angina and TIA (a small mini stroke that lasts a few minutes) - At 40 years, this can also progress into thrombosis or ruptured plaque which can cause a heart attack or stroke - This is where fatty atherosclerotic plaques form in blood vessels and restrict blood flow & can make tissues temporarily ischeamic

Answer 22

This is a chronic inflammatory condition that occurs in response to injury to the endothelium lining of blood vessels A major risk factor is hypercholesterolaemia as well as hypertension, diabetes and smoking which all cause blood vessel damage In a microscopic image, we see dark areas which are the nuclei of foam cells - the main component of the plaque

Answer 23

- excess LDL in circulation enters the intima of the blood vessel (connective tissue between endothelium and smooth muscle layer) - monocytes also migrate into the intima and transform into macrophages - LDL becomes oxidised = free radicals and enzymes oxidise the fatty acids, cholesterol esters and ApoB-100 in LDL particles, making them more likely to be taken up by macrophages - macrophages take up the oxidised LDL and transform it into foam cells - foam cells release cytokines and other growth factors that recruit smooth muscle cells - foam cells attach to the endothelium and form the fatty streak - smooth muscle cells thicken the streak into stable plaque

Answer 24

- left sided chest pain - can radiate to the arm, back, neck and jaw - pain caused by ischaemia = releases pain signals such as adenosine, protons, bradykinin and K+ ions - other symptoms include breathlessness, dizziness and sweating

Answer 25

1. Stable angina 2. Acute coronary syndromes (ACS)

Answer 26

- HMG CoA is inhibited so the liver can’t synthesise as much cholesterol - To maintain production of bile acids, the liver compensates by removing cholesterol from the circulation - It does this by increasing the number of LDL receptors on the surface of hepatocytes

Answer 27

Atorvastatin and simvastatin Reduce cardiovascular risk by reducing LDL (through inhibiting HMG CoA reductase) Decrease LDL by 18-55%, Triglycerides by 7-30% and increase HDL by 5-15% Overall, has anti-inflammatory effects that work against atherosclerotic plaque formation and rupture

Answer 28

- Generally well tolerated but can produce headaches and GI tract issues - 10% of people get myalgia (muscle pain) - Myositis (muscle inflammation) and rhabdomyolysis (muscles break down and release myoglobin which is toxic to the kidneys and can lead to kidney failure) - Small increased risk of diabetes

Answer 29

**Primary prevention** - to reduce risk of heart attack or stroke - aims to reduce non-HDL cholesterol by 40% - QRISK3 score of 10% or higher - Consequence is that 11% of the UK population is on statins **Secondary prevention** - to reduce risk of a further heart attack or stroke - usually for patients who have had a heart attack or stroke/have angina - aims to get non-HDL cholesterol below 2.6 mmol/L - prescribed routinely

Answer 30

- NPC1L1 transports dietary cholesterol into enterocytes - Ezetimibe blocks the absorption of dietary cholesterol by blocking NPC1L1

Answer 31

- Sometimes used as a sole therapy in people who can’t tolerate statins (has similar but milder side effects) - The drug is less effective on its own and is often given in combination with statins - By targeting both cholesterol synthesis and absorption of dietary cholesterol, it’s effective for patients for whom statins don’t work alone - Works by inhibiting NPC1L1 cholesterol transporter

Answer 32

- Reduces LDL by 15-20% - Increases HDL by 4-9% - Decreases triglycerides by 8-11% Produces smaller changes than statins

Answer 33

- Older class of drugs used before statins - Main examples are Fenofibrate and Gemfibrozil - These are only used when statins can’t be tolerated or a patient has high triglycerides and low HDL - They can be combined with statins but there’s a high risk of rhabdomyolysis - Work by activating PPAR = a nuclear hormone receptor that modulates genes involved in lipid metabolism

Answer 34

- Small effect on LDL = reduces it by 5-15% - Big effect on HDL = increases it by 10-20% - Big effect on triglycerides = reduces them by 20-50%

Answer 35

Glyceryl trinitrate = nitroglycerin (highly explosive) but used dilutely in medication - Short duration of action - Main drug for relieving angina attacks - Prodrug = active form is nitric oxide - It is ineffective if taken as a tablet as it is subjected to extensive first pass metabolism

Answer 36

- An oral drug must be absorbed from the GI tract and enter the bloodstream - Most drugs are incompletely absorbed and are excreted without ever entering circulation. This is because: - Cells lining the GI tract have enzymes which detoxify foreign substances so the drug is metabolised before entering the bloodstream - The hepatic portal vein transports drugs to the liver which has even more enzymes that break down the drug - The end bioavailability is less than 1% when the drug is taken orally

Answer 37

The fraction of the drug that makes it into the systemic circulation

Answer 38

1. Rectal/vaginal 2. Injections/infusions 3. Topical/transdermal 4. Sublingual/buccal

Answer 39

This is usually a gel or ointment used for anal fissures Has a bioavailability of approximately 50%

Answer 40

This is usually intravenous and is used to treat more serious heart conditions e.g. unstable angina and congestive heart failure Has a bioavailability of 100% = all drug makes it into circulation

Answer 41

This is usually patches, gel, ointment or creams and is mainly used to prevent angina and cannot be used to treat acute angina as the drug gets slowly absorbed through the skin from the patch A tolerance to the drug will develop and it will become less effective so the use is limited to 12 hours a day Has a bioavailability of 70%

Answer 42

This is either a spray or tablet and is used to treat acute angina attacks but can also help prevent them The drug is sprayed or the tablet is placed under the tongue: - drug is absorbed through mucous membranes in the mouth and passes into circulation - this is the most common way to take GTN which will provide immediate relief but only for 20-30 minutes Has a bioavailability of 40%

Answer 43

- not subject to first pass metabolism - can be taken as a swallowed tablet - longer duration as the tablets are designed so that they release the drug slowly over a long time - has a slower onset so is not suitable for relieving acute angina attacks - used as an add-on or when other drugs aren’t tolerated

Answer 44

- Organic nitrates are prodrugs which are broken down in tissues to yield the active principle - The active principle is nitric oxide (NO) - NO converts soluble guanylyl cyclase from the inactive form to the active form - This then converts GTP to cGMP - cGMP converts protein kinase G to the active form which phosphorylates target proteins - Active PKG converts proteins into protein-PO4 - This then inhibit calcium entry - Produces vasodilation

Answer 45

Mainly related to vasodilation - headache (dilation of cerebral arteries) - hypotension = dizziness, reflex tachycardia - flushing (due to blood vessels in the face dilating)

Answer 46

**Beta blockers** - Beta1 adrenoreceptor antagonists - Reduce heart rate and force of contraction and thus oxygen demand - Also inhibit release of renin which causes dilation of peripheral vessels and thus a reduction in afterload **Cardiac selective CCBs** - Verapamil and Diltiazem - Reduce heart rate and force of contraction - Also produce some peripheral vasodilation which will reduce afterload **Combination therapy** - Beta blockers plus dihydropyridine - Beta blockers/CCBs plus long acting nitrate Dihydropyridines also used (CCBs)

Answer 47

This is an open heart surgery Removes non-essential blood vessels from another part of the body and uses it to restore blood flow to the part of the heart where blood flow is compromised Most common types of blood vessels used are an internal mammary artery (from chest) and the great saphenous vein (from leg) Can be single, double, triple or quadruple depending on the number of connections made