CVD Flashcards

Question

Whats the heart doing in diastole?

Answer 1

Diástole heart is relaxing and filling. The AV valves are closed and the aortic pulmonary valves are closed and this is when the heart fills with blood from the veins. The ventricles are relatively empty and atria start to fill with blood as the diastole proceeds, the weight of the blood starts to eventually open the AV valves but the aortic and pulmonary valves will remain closed so blood will pass from Atria into the ventricles and ventricles start to fill with blood. End stage of diastole the AV valves are open and this is when the atria begins to contract to push remaining blood into the ventricles but the aortic and pulmonary valves remain closed. This is where the blood is being transferred to the ventricles ready for pumping into the arteries.

Answer 2

This is an active phase where contraction and emptying occurs. Start of systole the AV valves will close this prevents back flow of blood blood from ventricles into atria but the aortic and pulmonary valves remain closed. At this point ventricles begin to contract so the blood now remains inside the ventricles and start to feel pressure, no change in volume cause blood can’t go back into atria cause AV valves are closed and can’t be pushed into arteries cause the aortic and pulmonary valves are closed. The heart begins to contract so the pulmonary and aortic valves are open and at this point the blood is pushed into aortic and pulmonary arteries

Answer 3

Systole and Diastole Systole: contraction and emptying Isovolumetric ventricular contraction (valves closed) Ventricular ejection (valves open) *End systolic volume- amount of blood in ventricle at end of systole. Diastole: relaxation and filling Isovolumetric ventricular relaxation (valves closed) Ventricular filling (80% before atrial contraction) End diastolic volume- amount of blood at end of diastole. *Stroke volume= end diastolic volume-end systolic volume* Stroke volume amount of blood ejected by heart in a single beat For the heart to work efficiently, all the cardiomyocytes have to be connected. There are two important types of connections between cells; desmosome and this provides mechanical support so cells are attached and can’t pull away from each other and gap junctions provide transmission of action potential. This mechanical system needs to be protected via lubricants otherwise heart will rub against other surrounding tissue. Therefore, the heart so surrounded by a pericardial sac, this is a double walled sac, tough covering. Has two functions anchors the heart and it has a secretory lining, pericardial fluid (lubrication). If this is inflamed or infected Pericarditis- painful rubbing due to viral or bacterial infection fluid become inflamed it is very painful.

Answer 4

Describe anatomy and related function of heart Explain how the conduction system coordinates activity in the heart. Explain the ionic movements that underlay electrical activity in the heart. Describe the cardiac cycle including the ECG

Answer 5

The heart is a simultaneous dual pump avg 70 bpm Each beat is triggered by depolarisation of the membrane via action potential. Regions of autorhythmicity: •SA node top right atria pace maker region where most of the action potential is generated. Intermodal pathway; 30millisecond for action potential to pass across right atria into the AV node only point of conduction between atria and ventricles. All electrical activity pass from atria to the ventricles must pass into the AV node this takes 100milli-seconds. Once across into the ventricles the action potential follows the bundle of his which stretches down the septum and round into the walls of right and left ventricles and Branches out into purkinje vibres that continue to pass the action potential around this takes 30ms. The action potentials then get passed through ventricles walls via the cardiomyocytes. •AV node •Bundle of his •Purkinje fibres

Answer 6

Sanoatrial node SAN are autorhythmic cells 1% And they initiate and conduct action potentials or electrical activity in the heart. Pace maker cells in the heart Slowly drift to threshold because they only depolarise or re-polarise no resting potential. One membrane fully polarised there is a slow depolarisation step. What is causing this slow drift? ion channels in pace maker cells start to allow this slow drift to happen and start to allow sodium ions into the cells causing increase in the charge of membrane potential and start slow depolarisation. As they approach threshold the transient Ca ion channels open to let Ca in this starts to build the depolarisation. when threshold is reached these transient Ca ion channels close and the long lasting Ca ion channels open to let lots of Ca ions in and there is a rapid depolarisation event. At the peak these long lasting channels close and potassium channels open letting potassium out quick repolarisation and there is no resting potentials and this process repeats No resting potentials- the pace maker potentials is a relatively slow depolarisation caused by slow drift towards threshold and rapid depolarisation and depolarisation events. What changes in membrane permeability can underline this depolarisation? Na+ Increased influx of Na+ ions due to activation of Voltage gated cation channels called funny channels close with depolarisation. There is also decreased efflux of K+ this is because delayed rectifier of K+ channels are closed. There is a voltage calcium channel open as well towards end of slow drift of thresholdetting Ca in as well but these are closed by time threshold is reached At threshold the long lasting voltage gated calcium channel ions open and much larger influx of Ca and much rapid depolarisation. At peaks these are closed and the delayed rectifier K+ channels open letting potassium out so a rapid repolarisation of membrane occurs. Process starts again

Answer 7

Normal rate of action potential discharge in auto-rhythmic tissues of the heart. Tissue SA node (normal pacemaker) action potential per minute 70-80 AV node 40-69 action potential per mins Bundle of His and Purkinje fibres 20-40 action potentials per minute. SAN define how regular your heart is beating. Pace maker cells Cardiac action potentials in contractile cells cardiomyocytes can also carry action potentials, they can’t generate their action potentials but they can pass action potentials from the prukinjie fibres across the cardiomyocytes into the next cardiomyocytes; has a different action potential to the pace maker cells this is because it has a resting potential or phase. 1- Influx of Na+ ions that causes a rapid depolarisation, this is partly rectified by opening of K+ channels to pump K+ out. There is a plateau phase of action potential where Ca2+ starts to slowly enter these cells. At the end of Plateau phase there is a rapid repolarisation caused by the K+ being pumped out again. This eventually reach the resting potentials till next action potential is received to fire again.

Answer 8

•After membrane depolarisation: Voltage gated calcium channels open L type (long lasting) Decreased K+ permeability •Repolarisation: Ca+ channels inactivate K+ channels (delayed rectifiers) open to cause repolarisation Similar channels but very different action potentials

Answer 9

How do cardiomyocytes couple the electrical activity to the functional contraction of the cell once it receives the action potentials? In plateau phase this lets Calcium into the cardiomyocytes cells, calcium is essential for contraction of cardiomyocytes cells. The action potentials will increase cytosolic calcium and this Ca is coming from extracellular space crossing into the cardiomyocyte via long lasting calcium channels and then this Ca will bind to the Ryanodine receptors on the external surface of the sarcoplasmic reticulum. This leads to the opening of Ca2+ channels intrinsic to these receptors and cause more Ca to leave the endoplasmic reticulum and increases intercellular Ca further. This Ca activities troponin and cross bridge formation. The Ca sensitive receptors on SR, there are also two types of channels that remove Ca from they cytoplasm to switch off contraction and these are the Ca2+ ATPass pumps on the sacriolasmic reticulum and the Na+—Ca2+ exchanger removes Ca2+ from the cytosol back to the extracellular space

Answer 10

Abnormal levels of K+ resting potentials: Increase or decrease results in decreased cardiac excitability and contractility. Rise in extracellular K+ reduces resting potentials (depolarisation) Inactivates Na+ channels Arrythmias and fatalities Decreased extracellular K+ increases resting potentials (hyperpolarisation) Bradycardia; cardiac rhythm abnormalities. Ca2+: Changes in extracellular Ca2* affect membrane permeability which in turn causes cardiac rhythm abnormalities. Ca2+ blockers reduce force of contraction inotropy Digoxin increases cytosolic Ca2+ contractility.

Answer 11

When Action potential Plateau phase occurs, the contractile response starts to build up due to influx of Ca2+ this would peak and as the membrane starts to repolarise and Ca2+ gets put back into scaroplasmic reticulum or pump out of cell so we’ll lose the contractile response. There is a refractory period this prevents the heart from starting from staring a second cycle or contraction before first cycle is complete so one beat at the time, cardiomyocytes can’t start an another contraction.

Answer 12

ECG records the activity of the heart. ECG works by putting sensors on arms ankle and around the heart and it detect the activity of the heart. ECG generates a trace of the heart activity: P QRS T P-wave depolarisation of atria in response to SA node triggering PR interval: delay of AV node to allow filling of ventricles QRS complex: depolarisation of ventricles triggers main pumping contractions. ST segement: Beginning of ventricle repolarisation should be flat T wave: ventricular repolarisation This shows global activity of the heart. ECG can diagnose: •Abnormalities in rate •Abnormalities in rhythm: Atrial flutter Atrial fibrillation Ventricular fibrillation Heart block •Cardiomyopathies: Ischemia Infract

Answer 13

Importance of CV assessment Tools to estimate CV risk: Framingham study ASSIGN QRISK NICE recommendations Communication of CV risk to patients

Answer 14

Lipid modification- cardiovascular risk assessment abd the modification of blood lipids for the primary and secondary prevention of CVD NICE 2014 updated 2016 JBS joint British societies, consensus recommendations for the prevention of cardiovascular disease. Both guidelines state that there must be a multifactorial approach to assess the risk CVD risk

Answer 15

CVD is leading cause of premature death and morbidity in uk. High NHS costs (9-billion for heart and circulatory disease) Improvements in mortality since NSF for CHD in 2000 Since 2008 NICE guidance systematic strategy to ID all 40-47yrs likely to be at high risk.

Answer 16

Different tools for estimation of CVD risk 1- Framingham equations consists of CV risk assessment charts Based on equations developed from the Framingham heart study in 1948 Estimation of CVD risk based on: Age Gender BP Smoking status Cholesterol Study aims to identify risk factors for the development of CVD Baseline+ follow-up every 2 years 1971 second generation recruits 2002 third generation recruits Limitations: dose not take into account risk factors like ethnicity, family history of CVD, BMI, Socioeconomic status. Framingham based equations for risk reflect risks of CVD in 1960-1989 in a North America cohort. Tend or overestimate risk in current uk population by 50% but underestimate in other ethnic origins and diabetic populations.

Answer 17

Developed in 2006, includes social deprivations and family history. Score for risk factor 1-99 High risk is a score more than 20 Approved for use by SIGN and Scottish gov health directories. Compute based online system

Answer 18

Recommended by NICE QRISK updated annually Includes ethnicity, treated HT, social deprivations, BMI, family history of premature CVD, other conditions, (AF, DM, CKD, RA) Undergone independent external validation Computer based online system. QRISK-3 includes CKD stage 3 as well as 4 or 5 Migraine Corticosteroids SLE Atypical antipsychotic Severe mental illness Erectile dysfunction Variability in systolic bp readings

Answer 19

Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of CVD. 1- identifying and assessing CVD risk ID of people for full formal risk assessment: Systemic strategy All >40 years Full formal risk assessment is recommended if: 10 year risk CVD >10%

Answer 20

Remember: tools only provide an approximation of CVD risk so interpretation of CVD scores should always reflect informed clinical judgement. Use QRISK to assess CV risk for primary prevention up to age 84 yrs. Use QRISK to assess CV risks in type 2 DM Don’t use QRISK for: Type-1 diabetes mellitus Pre-existing CVD Risk of familial hypercholesterolaemia/other inherited lipid abnormalities >85yrs (especially if smoke/HT) All considered high risk and need to be managed. Remember underestimation of risk may occur: If underlying medical conditions or treatment increased CV risk eg HIV In patients already treated with antihypertensive or lipid modification therapy, or recently stopped smoking. Smoking status Patients who have stopped smoking in previous 5 years should be considered as smokers for CV risk. Risk from smoking more than 5 years ago depends on life time exposure and risk will lie somewhere between non smoker and smoker thus use clinical judgment. Pack years: a pack year is smoking 20 cigarettes a day for one year. Number of pack years= packs smoked per day x years as a smoker Or to calculate the number of pack years if it’s not given: number of cigarettes smoked per day x number of years smoked/20 (1 pack has 20 cigarettes) Patient who has smoked 15 cigarettes a day for 40 years has a 15x40/20= 30 pack years smoking history 10 cigarettes a day for 6 years has 10x6/20= 3 year smoking history.

Answer 21

NICE recommends all aspects of CVD disease and risk should be explained to patients so they can make an informed decision about therapy and lifestyle changes. Patients vary in what they consider to be an acceptable risk. Easy for healthcare professionals Not necessarily so easy for patients to decide Explain absolute risk, likely benefits and likely harms. Provide information without framing: Without any treatment there is a 1in5 chance of having a heart attack or storke in the next years. However I can reduce this risk by 30% if I prescribe a statin. Always present absolute risk and not relative risk if both disease and treatments. 30% relative risk reduction 5% absolute risk reduction

Answer 22

Thromboxane TXA2 and Prostacyclin PGI2 are formed the degradation of cell membrane phospholipids via the action of phospholipase A2 which catalyse phospholipids into Arachidonic acid, this is further metabolised via cyclooxygenase COX into prostaglandin-G2 PGG2 (aspirin inhibits this specific step). Arachidonic acid is further metabolised into leukotrienese but this is not affected by aspirin. PGG2 is unstable and is further metabolised into prostaglandin H2. The pathway splits here to allow for the synthesis of thromboxanes A2, prostacyclin PGI2 and PGD2, PGE2, PGF2alpha. Thromboxane is platelet aggregations inducer. Prostacyclin is a Platelet aggregation inhibitor. Aspirin inhibition of COX results in the inhibition of all three pathways.

Answer 23

Prostaglandin synthase Membrane embedded protein Hydrophobic channel into active site Allows entry of hydrophobic Arachidonic acid directly from its synthesis site in membrane. Active site is a heme moiety. There are two major isoforms of COX and aspirin inhibits COX-1 isoform. COX-1 is a homodimer consisting of along narrow hydrophobic channel buried in the lipid bilaterally, with a hairpin bend at the end, leads to the active site. Arachidonic acid binds close to this site and a number of transformations take place simultaneously, products also released from same channel. Aspirin does not compete for the active site or for the binding site. Instead it undergoes a reaction with specific amino acid residue. Aspirin reacts with serine 529. Serine 529 where aspirin binds is not the active site. Step to focus on is transformation of Arachidonic acid into prostaglandin G2 PGG2 via the action of COX. Aspirin inhibits this step! COX facilitates two steps to the mechanism as it acts as an Endoperoxide synthase, which allows introduction of oxygen and cyclisation, then secondly it acts as an oxidase enzymes to convert peroxide into an alcohol.

Answer 24

COX facilitates two steps to the mechanism as it acts as an Endoperoxide synthase, which allows introduction of oxygen and cyclisation, then secondly it acts as an oxidase enzymes to convert peroxide into an alcohol. 1-COX facilitates removal of the hydrogen, from the Arachidonic acid, because this enzyme is catalysed, this removal is steroselective and it is therefore very precise. The removal of the hydrogen results in the formation of a radical and that radical can be arranged through resonance to have the radical in the optimal position for introduction of oxygen. Once radical has rearranged it reacts with a molecule of oxygen forming a bind between Arachidonic acid and oxygen. The resulting peroxide now contains a radical and this reacts again with the Arachidonic acid through addition to double bond. At this point, a cyclisation reaction occurs between the 2 chains to form a five membered ring. Further arrangement, relocates the radical and introduction of a second molecule of oxygen. COX undertakes its second action of introduction of a peroxide and its conversion to an alcohol to give prostaglandin G2. PGG2 is very unstable and is readily transformed into PH2. a peroxide and it is conversion At the active site heme, simultaneous insertions of two oxygens and cyclisation occurs.

Answer 25

Aspirin undergoes a reaction with serine 529. This is a unique mechanism of action. All of the salicylates and other anti-inflammatory drugs, like ibuprofen, are competitive inhibitors. Aspirin reaction with serine 529 is anchored through the involvement of 2 nearby tyrosine residues; tyrosine 385 and tyrosine 348. Tyrosine 385 forms a hydrogen bond with acetyl portion of aspirin and that positions it in the correct place for the reaction. That hydrogen bond is strengthened through a second hydrogen bond between tyrosine 385 and tyrosine 348. This docking allows the serine hydroxyl group to undergo a transesterification reaction. The nucleophilicity of the hydroxy group of serine is improved by the carboxylate anion of aspirin extracting the proton and the oxygen is then able to attack the electron poor base of the carbonyl resulting in formation firstly of the tetrahedral intermediate and subsequently breaking if the bind between the acetyl group and rest of the aspirin. This leaves the serine residue acetylated. This acetylated residue blocks the access of Arachidonic acid into the active site. It is an irreversible reaction and can only be overcome by synthesis if a new COX enzyme by the cell.

Answer 26

It irreversibly inhibits COX-1 Thromoxane A2 an inducer of platelets aggregation will not be synthesised. Platelets are unable to synthesis COX-1 so synthesis of theomboxanes is halted for the lifetime of the platelet Prostacyclin an inhibitor of aggregation will also not be synthesised but prostacyclin synthesis is more common in endothelial cells which can regenerate COX enzymes. This means even with very low dose aspirin can work to inhibit platelets aggregation

Answer 27

Two classes of ADP receptor antagonist Thienopyridines: Eg Clopidogrel, Prasugrel Antagonise the P2Y12 subtype of the ADP receptor Not active in vivo undergoes metabolism Once activistas the think forms a disulphide bind with the receptor Irreversible antagonist. Draw mechanism of active metabolite of clopidogrel active group thiol SH Draw SAR of clopidogrel and prasugrel Other P2Y12 antagonists Gangrelor (intravenous use only prior to surgery doesn’t require metabolism) Ticagrelor used in combination with aspirin (alloetwric inhibitor does not directly compete for binding with ADP Structurally different Drugs have also been developed for other receptors and enzyme involved in the process of aggregation including Selexipag which is a prostacyclin receptor agonist so inhibits aggregation by enhancing the activity if prostacyclin. Cilostazol; phosphodiesterase inhibitor and eptifibatide, which is an antagonist of glycoprotein 2A/3b receptors. Eptifibatide is natural product found in snake venom and competes with binding with fibrinogen as it contains the same arginine, glycine, glutamic acid better known as RGD motif. Summary: Aspirin is a highly effective drug for reducing platelet aggregation due to its unique chemical reaction with COX enzyme and halts prostaglandin synthesis.

Answer 28

Treatment for high cholesterol and lipid levels. There are 5 types of treatment: Fibrates (ciprofibrate) Bile acid and sequestrants (colestyramine) Statins (mevastatin) Ezetimibe (ezetimibe) Plant sterols and stanols (sitosterols)

Answer 29

Affect both lipid and cholesterol levels. Prodrug active drug is the acid SAR of Fibrates Para chloro or chloro containing groups increases half life. Ring area can be extended Spacer Methyl groups essential Acid group is essential for activity. Overall it is an isobutyric acid group. It is then possible for there to be a spacer group between that unit and the rest of the molecule. The ring area can be extended and in particular substitution with a chloro group at the para position or a group that includes the chloro unit is useful for increasing the half life based on the enhanced lipiophilicity. This SAR can be seen in marketed Fibrates. Gemfibrozil has the spacer included Fenofibrate an extended ring structure and the acid masked as a pro-drug. Bezafibrate and Ciprofibrate have the enhanced lipophilicity because of inclusion of halogen moieties. Clofibrate Gemfibrozil Fenofibrate Bezafibrate Ciprofibrate

Answer 30

Anion exchange resins Polymers consisting of cationic backbone Neutral by presence of conjugated anions In presence of another anion, exchanged if anion has higher affinity for binding. Large 1millionMW not absorbed not metabolised. Bile acid sequestrants: are a type of chemical drug that don’t have a specific biological target. Bile acid sequestrants are anion exchange resins. They are polymers with a cationic backbone but overall neutral due to the presence of weakly bound anions. Colestyramine and Colestipol are chloride anions when these polymer are in the presence of an anion that can be bound more tightly. The two anions exchange. The polymers are very large which means they can’t be absorbed and they are not metabolised as they don’t contain readily degradable bonds. Thus excreted as whole polymer. These are 2 major bile acids in humans; glycocholic acid and Taurochilic acid and they are synthetically produced in the body from cholesterol. If patient takes sequestrants, the anion exchange and the polymer is excreted with the bile acid attached to it. This means increases secretion of the bile acids. So more are produced from cholesterol, and that means overall cholesterol levels are lower/reduced.

Answer 31

Screening of over 8000microbial extracts Two natural products identified From fungi Statins major treatment for high cholesterol. Lovastatin no longer used but is twice as potent and was a prodrug Mevastatin

Answer 32

•Synthesis of mevalonate form acetyl CoA synthetic pathway towards cholesterol. •Statins interfere with the process of steroid biosynthesis •Early stage of steroid synthesis begins with the synthesis of mevalonate form acetyl CoA. This involves 2 molecules of acetyl CoA reacting together through a Claisne reaction to give acetoacetyl CoA. A third acetyl group is then introduced through an aldol reaction to give hydroxy-3-methyl CoA or HMG CoA. This is the substrate for an enzyme, HMG CoA reducatse, that produce mevalonate. That enzyme reaction is the rate determining step of cholesterol biosynthesis. Which means if we alter step we alter not only synthesis of cholesterol but because cholesterol is a precursor to adrenocorticoids and the sex hormones. Mevalonate is also the precursor for any terpenes that are synthesised in the body. The reaction of HMG CoA resultase is a two step reaction. In the first step, the ester is reduced, resulting in the carbonyl being converted to a hydroxyl. Second step there is an oxidation and the CoA unit is removed, leading to mevalonate. Both substrate and product are drawn in two orientations because orientation is important for understanding the mechanism of action of statins. Slide 10: Statins inhibit HMG CoA reductase and they do this because they naturally mimic the intermediate, the product of that first reduction mevaldic acid hemithioacetal. To do this mimicking they have to be metabolised. The lactan ring in the natural product is opened: hence why we call it a pro drug. Both have same functional groups and stereochemistry. The statin binds 10,000 times better than the substrate, because it mimics the intermediate and because the more hydrophobic section of the drug molecule can bind into a secondary binding site which is normally occupied by CoA part of the substrate m. The statins are highly selective inhibitors working specifically on this enzyme and they can categorise as non covalent reversible inhibitor.

Answer 33

1- semi synthetic derivatives 2-simvastatin 2-3x more potent than lovastatin 3-pravastatin not a pro-drug, already has lactam ring opened, comes form mevastatin and is synthesised by microbial hydroxylation reaction. Better a/e profile and it is pharmacokinetic ms are altered. It is less lipophilic. Simvastatin more potent and is. A prodrug longer half life due to its steric interference of the additional methyl groups on ester side chain. 2nd generation: Synthetic and not prodrugs. This generation involves alterations of the decal in ring structure. The part of molecule that binds the CoA binding site. It is replaced by a highly hydrophobic ring structure. Fluvastatin, atorvastatin, rosuvastatin. Designed to have reduced lipophilicity to involve better targeting to the liver where it can have more action.

Answer 34

Intermediate mimic Can be ring closed Can contain a double bond Can’t change distance OH to ring CoA binding site (natural products) Decalin ring Variation of ester Variation at position Y CoA binding site (synthetic products) Nitrogen containing ring (5or6 membered) Same ortho substituents Statins binding interactions Simvastatin Atorvastatin Slide 13 If we look at the structure activity relationship for the statins. The molecules all contain an intermediate mimic which can be closed as the lactone or be the free acid. That unit can also include a double bond as in rosuvastatin, but can't be altered in length. Then for binding to the CoA binding site. In the first generation of natural products, a decalin ring is required. But modification of that structure is possible both at position Y and in the nature of the ester that's attached to the decalin ring. In the second generation of synthetic products, a more variable structure activity relationship is possible. What's required is an aromatic ring containing nitrogen. Although that ring can be 5 or 6 membered and the position of the nitrogen can be changed within it. However, consistently that ring structure then needs to be ortho substituted with all of the successful molecules having exactly the same substituents.

Answer 35

Inhibits absorption of cholesterol at intestinal wall related to inhibition of Norman-Pick C1-like 1 NPC1L1protein. Lead compound SCH 48461 Designed as an Acyl-coenzyme A:cholesterol acyltransferase ACAT inhibitor. ACAT involved in cholesterol uptake in the intestines through catalysing formation of cholesterol esters. ACAT inhibitor is also involved in cholesterol uptake because it changes cholesterol into cholesterol esters. Azetidinone skeleton good for activity 48461 was extensively metabolised. That occurred in the body through three different processes; de methylation hydroxylation and ring opening of the azetidinone ring. •Demethylation can occur on both of the methyl ethers and hydroxylation could occur on both the ring structure shown and on the aliphatic chain. Structure was further modified to enhance metabolism so hydroxyl groups were introduced where hydroxyl was useful in the aliphatic chain and demethylation product on one of the rings. Fluorine groups were introduced to both those ring structures, stopping in one case de methylation and in another hydroxylation. Ezetimibe is 50 times more active than lead molecule 48461.

Answer 36

Azetidinone essential for activity Mono substituted more active than Di Arylalkyl group length of chain matters, Stereochemistry doesn’t. Substitution by aromatic group essential on the nitrogen drinks thagveit be an alkoxy aryl S stereochemistry required Oxygen group required. An SAR was designed based on 150 different products and gave rise to the most important features. Firstly, we need the azetidinone ring. Without it, no activity. And we also need this ring to be attached with a fixed stereochemistry. It's the S configuration that's required, and that ring substituent also needs to contain an oxygen. The nitrogen must also be substituted by a ring. But that ring doesn't have to have an oxygen substituent present. The aryl alkyl group. the stereochemistry doesn't matter, but the length of the chain does matter for activity. And finally, at that same position, you can introduce 1 or 2 substituents, but it's better to introduce just that single substituent.

Answer 37

Slide 20 So that brings us to the end of the prescription based mediations that are used for the treatment of high cholesterol. But before we finish, if we have a look at the plant sterols and stanols, the molecules which are used in products like Benacol and Flora Proactiv. These molecules do naturally occur in our diets, but levels can be increased by incorporating more within food and encouraging people to use them as substitutes for other dairy products. They're incorporated into these foods as their esters and they lower blood cholesterol by inhibiting the absorption from the gut. And they themselves are not absorbed. Interestingly, although I've said they're natural Benacol was invented in Finland, where the steroid is actually obtained as a product or by-product of the wood pulping industry. Slide 21 How do they work? Well, when cholesterol is absorbed from the gut, it's absorbed in the form of mixed micelles, formed between bile salts and cholesterol. The plant sterols and stanols compete for the formation of the mixed micelles. And because they compete with the cholesterol more cholesterol is excreted. The mixed micelles containing the bile acids are less able to be absorbed. Slide 22 So that's the med chem of drugs used in treatment of high cholesterol. This graph shows the projected impact of ezetimibe moving the treatment of high cholesterol away from statins into either ezetimibe, on its own or actually quite commonly in combination therapy with statins.

Answer 38

•Cholesterol Cholesterol is a 27 carbon compound with a unique structure with a hydrocarbon tail, a central sterol nucleus made of four hydrocarbon rings, and a hydroxyl group. The center sterol nucleus or ring is a feature of all steroid hormones. •Triglyceride 3 fatty acid chains and glycerols Definition. A triglyceride (TG) molecule consists of a glycerol backbone esterified with three fatty acids. Triglycerides are the main constituent of vegetable and animal fats in the diet, and are the main constituent of the body's fat stores. •Fatty acids: a carboxylic acid consisting of a hydrocarbon chain and a terminal carboxyl group, especially any of those occurring as esters in fats and oils. Saturated single bond Unsaturated double bond: mono-unsaturated and poly-unsaturated

Answer 39

Essential fatty acids for hormones and cell membranes Gene expression Hormones prostaglandins Energy and store 1g=37kj Phospholipids Structural eg brain Protects organs Insulation Vitamins antioxidants

Answer 40

Lipids are only broken down in the duodenum and small intestines. Dietary fat: triglycerides In the duodenum, lipids combine with bile salts to form fat droplets. Lipase from pancreas digests triglycerides to monoglycerides and fatty acids. Monoglycerides and fatty acids diffuse into epithelial cells where the recombine with proteins to form lipo-proteins called chylomicrons these enter lymphatic capillary and go to liver and other tissues where they are required. Fat is broken down in the duodenum and it is emulsified via bile salts that is released by gall bladder then pancreatic lipase can hydrolyse the fat micelle droplets into monoglycerides and free fatty acids. They get absorbed into epithelial cell and reaggregate to form triglycerides that aggregate and coated with lipoprotein to form chylomicrons that transport lipids around the body. These passively diffuse through lipid bilayer of the luminal membranes.

Answer 41

•Lipids and cholesterol transported in the blood as complexes of lipids and proteins called lipoprotein. •Hydrophobic core of lipid consists of (triglycerides and cholesteryl esters) •Hydrophilic coat of polar phospholipids, free cholesterol and apoprotein. Apoproteins act as ligands for specific receptors that are present on different cells throughout our body help facilitate those lipoproteins to be taken up into target cells. Components of lipoprotein determine it is target cell or what role. We differentiate lipoproteins in size and density. Lipoprotein with larger amount of protein are generally more dense because proteins are heavier than lipids and those consisting of more lipids have lower density.

Answer 42

•Differ in relative proportion of core lipids and types of apoproteins. •Apoproteins bind to specific receptors on liver and other tissues. •lipoproteins 5 classes differ in size and density each with different functions. •Chylomicrons mainly triglycerides •Very low density lipoproteins VLDL •Low density lipoproteins LDL •Intermediate density lipoproteins IDL •High density lipoproteins HDL good cholesterol

Answer 43

•Cholesterol and TG from the diet are absorbed in the ileum, transports in the chylomicrons to the lymph, blood then capillaries to the muscles and adipose tissue. •TG is hydrolysed by lipoprotein lipase—> glycerol and free fatty acids released, which are taken up into tissues. •Remaining chylomicrons remnants with cholesteryl esters travel to the liver bind to receptors and are endocytosed. •Cholesterol is then stored, oxidised to bile acids or enters the endogenous pathway.

Answer 44

Cholesterol (from diet and newly synthesised in the liver) and newly synthesised TG travel as VLDL to muscles and adipose tissue. TG is hydrolysed in tissues by lipoprotein lipase to glycerol and FFA liberated. Lipoprotein particles become smaller but retain cholesteryl esters and become LDL, which binds to LDL receptors on cells LDL receptors recognise apoB100 on LDL particles. Cholesterol deposited in tissues for cell memebranes and other functions Cholesterol can return to plasma and liver for tissue via HDL reverse cholesterol transport. Cholesterol esterified with LCFA in HDL and transferred to VLDL or LDL in plasma by cholesteryl ester transfer protein CETP.

Answer 45

The lipid endogenous pathway and exogenous pathway are two interconnected processes involved in the metabolism and transport of lipids in the body. The endogenous pathway refers to the synthesis of lipids within the body. It involves the liver, which produces lipoproteins such as very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL). VLDL is synthesized in the liver and carries triglycerides, cholesterol, and other lipids to peripheral tissues. As VLDL circulates in the bloodstream, triglycerides are gradually removed, converting VLDL into LDL. LDL is responsible for delivering cholesterol to peripheral tissues for various cellular functions. On the other hand, the exogenous pathway involves the absorption of dietary lipids from the intestine. When we consume food rich in fats, they are broken down into fatty acids and monoglycerides in the small intestine. These products are then absorbed by the intestinal cells and reassembled into triglycerides. The triglycerides are packaged into chylomicrons, which are large lipoproteins. Chylomicrons transport dietary lipids from the intestine to various tissues, including adipose tissue and muscle. The interlink between the two pathways occurs through the exchange of lipids between VLDL and chylomicrons. After dietary lipids are transported to peripheral tissues by chylomicrons, the remnants of chylomicrons are taken up by the liver. The liver then processes these remnants, synthesizing VLDL and incorporating them into the endogenous pathway. This interplay between endogenous and exogenous pathways ensures the proper metabolism and distribution of lipids in the body. Overall, the endogenous and exogenous pathways work together to regulate lipid metabolism, ensuring a balance between the production, transport, and utilization of lipids in the body.

Answer 46

ApoB48: In chylomicrons, essential for intestinal absorption of dietary lipids ApoE: In chylomicrons mediates uptake of chylomicrons remnants into liver by LDL receptor. ApoB100: In VLDL, IDL, LDL- main physiological ligand for LDL receptor and synthesised in liver. ApOA1: In HDL promotes cholesterol efflux from tissues to liver for excretion.

Answer 47

LDL lipoprotein enter liver cells bind to it is receptors on the liver hepatocytes which causes receptor mediated endocytosis and when this happens the LDL receptor basically taken up into coated vesicles in these vesicles there is a drop in PH levels from pH7 to 5 which causes the LDL to dissociate from the LDL receptor —>LDL lipoproteins and LDL receptor separation. Vesicle pinches apart into smaller vesicles one that contains free LDL lipoproteins and the other contains receptors which no longer have the LDL bound to it. The vesicle that has the LDL in fuses with the lysosomes, do endosome fusing with lysosomes the enzymes in the lysosomes can cause the release of cholesterol into the cytosol where it can be used in cell membrane formation in the synthesis of steroid hormones and bile acids and to make further lipoproteins and further regulatory action. Vesicle that contains empty receptors and basically recycle these back into cell surface. Recycling vesicle fuses with cell membrane turns it inside out via exocytosis. LDL receptors return to the cell surface so they can be used again so we can have another LDL.

Answer 48

Net movement of cholesterol from peripheral tissues back to liver. When body has excess cholesterol it gets removed from the cells and returns to liver where it can be excreted. Make HDL in liver and small intestine Pre-beta HDL they take up cholesterol from tissues when they circulate around, the LCAT enzyme esterifies cholesterol and HDL molecules and causes the HDL particles to become more spherical and it changes it shape HDL3 these get transferred via the enzyme CETP so HDL returns back into liver and gets taken into hepatocytes so the cholesterol it isn’t carrying can be excreted.

Answer 49

ACAT-acyl CoA: cholesterol acyltransferase Catalyse intracellular synthesis of cholesteryl ester in macrophages, adrenal cortex, gut, liver. Tamoxifen is a potent ACAT inhibitor. LCAT- lecithin cholesterol acyltransferase PLTP phospholipids transfer protein Transfer of cholesterol and TG between different classes of lipoprotein particles in plasma

Answer 50

Disorder of lipid metabolism including lipoprotein overproduction and deficiency. Due to genetic variations and inherited diseases Genetics May be manifested by: Increased total cholesterol TC eg atherosclerosis Increased low density lipoproteins eg increase cholesterol that could be deposited in arteries Increased triglycerides Decreased high density lipoprotein Could be due to genetics, inherited conditions, malfunction. Major risk factors for coronary heart disease, with the risk directly related to cholesterol levels.

Answer 51

Injury in endothelial cells can be cause by high blood pressure, high cholesterol levels can also damage the blood vessels so does smoking and diabetes. Endothelial cells line up the blood vessel so damage or endothelial cells can cause adhesion molecules to come to surface of endothelial cells and monocytes also start to bind to endothelial cells and get into lower layer of blood vessel. Oxidised LDL so cholesterol can be deposited which becomes oxidised and combines with macrophages to form a foam cell. As foam cells starts to form the start to stick to blood vessels underneath the endothelial cell layer this results in plaque formation. Plaque formation leads to Smooth muscles migration, adherence and aggregation of platelets, adherence entry of leukocytes and smooth muscle migration and T cell activation and as this plaque starts to enlarge and expand a necrotic core forms where blood doesn’t reach these cells anymore so no supply of oxygen or nutrients and fibrous cap formation on top of endothelial cells. perpetuation of inflammatory response and necrotic core leads to thinning of fibrous cap and plaque ruptures. Haemorrhage from plaque micro-vessels which can lead to heart attack or stroke.

Answer 52

•LDL ("bad cholesterol") • 60-70% of TC • Oxidised- deposited in blood vessels, leads to atherosclerosis •HDL ("good cholesterol") • 20-30% of TC • Transports excess cholesterol from peripheral tissues to the liver • Antioxidant- decreased adverse effects of LDL • VLDL • Mostly cholesterol and little protein • TG • Fatty acids and glycerol • Absorbed from intestine • Circulates in blood, stored in adipose tissue (obesity in liver etc) • Associated with risk of CHD

Answer 53

Targets •Until 2014, NICE recommended: • TC <4.0 mmol/L • LDL <2.0 mmol/L • HDL > 1.0 mmol/L • TG <2.3 mmol/L •Now: • No specific targets by NICE • (<5 mmol/L TC and <3 mmol/L LDL considered OK by experts, unless family history or existing heart disease. • Aim for >40% decrease in non-HDL cholesterol

Answer 54

Epidemiology •UK population has one of the highest rates of dyslipidemia in the world • 60% adults in England have TC>5 mmol/L • Average TC in middle aged men and women between 5 and 6 mmol/L • Increases as you get older • Western diet leads to high TC/LDL •South Asian populations- higher% of population with HDL <1.0 mmol/L e.g 20% Pakistani men have low HDL

Answer 55

Primary dyslipidaemia (60%) • Combination of diet and genetics • Genetics - 5 inherited conditions • Diet and Lifestyle - • High saturated fat • Physically inactive • Overweight or obese • Smoking • Large waist circumference Secondary dyslipidaemia (40%) • Underlying cause • Disease or certain drugs eg diabetes, liver disease, thiazides, GC • Natural rise as age and after menopause

Answer 56

Inherited conditions that increase blood lipids. Familial hypercholesterolaemia (FH) Inherited higher level from birth Average- 1 person/day has FH has a heart attack. Mutations in LDLR or APOB or PCSK9 Honozygous rare 1/250,000 > 20mmol/L Heterozygous 1/250 populations, CHD 20 years before general population of untreated-8mmol/L. Familial combined hyperlipidaemia Inherited 1in100 of uk population High cholesterol and triglycerides- raised by age 20-30 Raises VLDL and more compact and dense LDL normal. Fasting TG> 1.5mmol/L Type 3 hyperlipidaemia Inherited 1/5000–1/10,000 High cholesterol and triglycerides Mutations in ApoE Primary dyslipidaemia • Polygenic hypercholesterolaemia • More than 1 gene with changes • >12 genes linked to high cholesterol • Primary hypertriglyceridaemia • Lipoprotein lipase deficiency • Affects 1 in a million • Very high triglyceride • Lysosomal acid lipase deficiency • Breaks down fat in lysosomes normally but instead fat builds up in cells • Rare condition- affects <1 in a million in UK

Answer 57

Corneal arcus Tendon xanthomas Xanthelesma

Answer 58

*Underlying disorders: Diabetes mellitus Hypothyroidism Chronic renal failure Alcoholism Liver disease *Certain drugs: Thiazide diuretics Loop diuretics Beta Blockers Oral contraceptives Ciclosporin Glucocorticoids Isotretinoin Tamoxifen Protease inhibitors of HIV

Answer 59

LDL species strongly associated with atherosclerosis. Localised in atherosclerotic lesions. Apo(a) structurally similar to palsminogen. Lpa inhibits binding of plasminogen to receptors on endothelial cells- leads to less plasminogen generation and promotion of thrombosis (Plasminogen is the precursor of plasmin, which lyses fibrin clots to fibrin degradation products (FDP) and D-dimer; the conversion to active protease is mediated by tissue-type (tPA) and urokinase-type (uPA) plasminogen activators. Generated plasmin is quickly inactivated by its main inhibitor alpha2-antiplasmin.)

Answer 60

Non-pharmacological treatment of dyslipidaemias: - Dietary modification • Low saturated fat, low trans fat, high mono or polyunsaturated fat - to decrease LDL and increase HDL • Oily fish twice weekly • Plant sterols and stanols to decrease cholesterol absorption from gut • High fibre - soluble fibre (from fruit and veg) may decrease cholesterol absorption from gut. • Weight loss - BMI <25 • Smoking • Physical activity - 30 min x 5 times per week • Reduce alcohol

Answer 61

Statins inhibit an enzyme involved in the synthesis of cholesterol in the liver . Statins inhibit the (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) HMG-CoA reductase enzyme which is the Rate limiting enzyme in the synthesis of cholesterol in the liver. Drugs not routinely recommended: Fibrates Inhibitors of cholesterol absorption Nicotinic acid Alirocumab and evolocumab (biologics anti-monoclonal antibodies) Inclisiran (interferon molecule) Lomitapide Omega 3 fatty acids no longer recommended at all Combination with diet therapy and correction of other modifiable risk factors.

Answer 62

Atorvastatin Rosuvastatin Simvastatin Pravastatin Statins are HMG-CoA reductase inhibitors which is a rate limiting enzyme involved in cholesterol synthesis as it catalyses conversion of HMG-CoA to mevalonic acid. Inhibit HMG CoA reductase Competitive and reversible non covalent inhibitor Decrease in cholesterol synthesis Increase in LDL receptors Increased cholesterol uptake Reduction of blood LDLs More effective at reducing cholesterol that other drugs Not great for moderate to high TG Reduce CV events and mortality irrespective of initial cholesterol concentration.

Answer 63

Acetyl-CoA enzyme which metabolised into acetoaceytl-CoA and this is then converted into HMG-CoA which’s the substrate for the enzyme which the statins target. HMG-CoA is usually converted to L-Mevalonate by the HMG-CoA reductase enzyme. Once converted to L-Mevalonate through a series of biosynthetic alterations which result in cholesterol production, prenylated proteins eg G proteins and Ras. ***Cholesterol is synthesized in the body through a pathway known as the mevalonate pathway. This pathway involves a series of enzymatic reactions that occur mainly in the liver and other tissues. Here are the key steps involved in cholesterol synthesis: 1. Acetyl-CoA Formation: Acetyl-CoA, which is derived from the breakdown of carbohydrates, fats, and proteins, is the starting point of cholesterol synthesis. 2. Formation of HMG-CoA: Acetyl-CoA is converted into 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) by the enzyme HMG-CoA synthase. 3. Mevalonate Formation: HMG-CoA is then converted into mevalonate by the enzyme HMG-CoA reductase. This step is considered the rate-limiting step of cholesterol synthesis. 4. Conversion of Mevalonate: Mevalonate undergoes a series of enzymatic reactions to form isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are important building blocks for cholesterol synthesis. 5. Cholesterol Synthesis: IPP and DMAPP are condensed to form geranyl pyrophosphate (GPP), which is then converted to farnesyl pyrophosphate (FPP). FPP is further converted into squalene, which is the precursor for cholesterol synthesis. Squalene is then converted into lanosterol and finally into cholesterol. The end product of cholesterol synthesis is cholesterol itself, which is a vital component of cell membranes and is involved in various physiological processes. Cholesterol is necessary for the production of hormones such as cortisol, estrogen, and testosterone. It is also important for the synthesis of vitamin D and bile acids, which aid in digestion. While cholesterol is essential for the body, it is important to maintain a balance. Excess cholesterol can accumulate in the arteries and lead to the development of atherosclerosis, a condition characterized by the buildup of plaque and narrowing of the arteries. This can increase the risk of heart disease and stroke. Therefore, it is crucial to maintain a healthy cholesterol level through a balanced diet and lifestyle choices.

Answer 64

Use of statins decrease cholesterol synthesis and unregulates LDL receptors synthesis, leading to LDL-C clearance from plasma to liver, ie. Reduces plasma LDL-C. Reduces plasma TG and increases HDL-C. Statins are fast acting: Simvastatin and Pravastatin: Specific, reversible, competitive HMG-CoA reductase inhibitors (Ki 1nM) inhibitory constant. Extensively metabolised via CYP450 and glucuronidation. Simvastatin-inactive prodrug metabolised in liver to active form. Long lasting: Atorvastatin, Rosuvastatin. Statins mechanism of action: Statins target HMG-CoA reductase enzyme this reduces cholesterol synthesis in the liver. Decrease in cholesterol synthesis this results in decrease of intracellular cholesterol. This causes the body to increase LDL receptor (B-E receptor) synthesis on the cell surface so liver takes up more cholesterol so this leads to more VLDL binding to the LDL receptors recognising the ApoB100 proteins on the VLDL surface, this leads to reduction in serum LDL concentration. Small TG effect slightly reduced. Statins are a class of medications commonly prescribed to lower cholesterol levels in the body. They work by inhibiting an enzyme called HMG-CoA reductase, which plays a key role in the synthesis of cholesterol. Here's a breakdown of the mechanism of action and pharmacology of statins: 1. Inhibition of HMG-CoA Reductase: Statins primarily exert their effects by blocking the activity of HMG-CoA reductase, the enzyme responsible for converting HMG-CoA to mevalonate in the cholesterol synthesis pathway. By inhibiting this enzyme, statins reduce the production of cholesterol in the liver. 2. Decreased Cholesterol Synthesis: With reduced levels of HMG-CoA reductase activity, the liver cells respond by increasing the number of LDL receptors on their surface. These receptors help in the uptake and clearance of LDL cholesterol from the bloodstream, leading to a decrease in circulating LDL cholesterol levels. 3. Lowering LDL Cholesterol: By reducing LDL cholesterol levels, statins help prevent the buildup of cholesterol in the arterial walls, reducing the risk of atherosclerosis and related cardiovascular diseases. 4. Modulation of Inflammatory Processes: Statins have been found to have anti-inflammatory effects independent of their cholesterol-lowering properties. They can reduce the production of inflammatory markers and cytokines, which play a role in the development and progression of atherosclerosis. 5. Increase in HDL Cholesterol: Statins may also increase the levels of high-density lipoprotein (HDL) cholesterol, often referred to as "good" cholesterol. HDL cholesterol helps remove excess cholesterol from the arteries and transports it back to the liver for excretion. 6. Pharmacokinetics: Statins are typically administered orally and are absorbed in the digestive tract. They are extensively metabolized in the liver by various enzymes, including cytochrome P450 enzymes, before being eliminated from the body through bile and feces. The dosage and frequency of statin administration depend on the specific medication prescribed. It is important to note that statins are generally well-tolerated, but they may have potential side effects such as muscle pain, liver enzyme abnormalities, and, rarely, muscle damage. It is crucial to discuss any concerns or potential interactions with other medications with a healthcare professional before starting statin therapy. Regular monitoring of liver function and muscle symptoms is typically recommended during statin treatment.

Answer 65

Statins protective effects: Plaque stability reduce risk of plaque rupture and decrease risk of MI or stroke. Decreases cell infiltrate and MMP Increase collagen, VSMC, TIMP Increase Neovascularisation of ischemic tissues (increase blood flow to plaque area so reduce necrotic core) Anti-thrombotic: Decrease TF, PAI-1, platelet aggregation Increase fibrinolytic activity, tPA, eNOS. Anti-oxidant: Decrease NADPH oxidase. Superoxide, oxidation of LDL Increase radical scavengers. Anti-inflammatory: Decrease NF-KapaB, IL-1, TNF, MMP, CRP. Leukocytes-endothelial interactions Adhesion molecules Macrophages/T-cell activation Complement injury Smooth muscle cell proliferation Monocytes chemotaxis

Answer 66

•CYP 3A4, 3A5, 2C8, 2C9, 2D6 metabolise statins •ABCs-A1, G1, G5, G8, B1, C2, MCT4, OATP2 •Lipoproteins lipase •ApoA1, A2, C3, A4, A5, B, E •Cholesteryl ester transfer protein •Lecithin cholesterol acyltransferase •PPAR alpha •SREBP 1&2 IL-1beta, IL6 polymorphisms influence response to Pravastatin. ******************************** You've mentioned several genetic factors that can influence the response to statins. Here's a breakdown of how these genetic factors may impact the effectiveness and metabolism of statins: 1. Cytochrome P450 Enzymes: Genetic variations in CYP3A4, CYP3A5, CYP2C8, CYP2C9, and CYP2D6 can affect the metabolism of statins. These enzymes are involved in the breakdown of statins in the liver. Genetic variations in these enzymes can result in differences in how quickly or slowly statins are metabolized, which can impact their effectiveness and potential side effects. 2. ATP-Binding Cassette (ABC) Transporters: ABC transporters, such as ABCA1, ABCG1, ABCG5, ABCG8, ABCB1, and ABCC2, play a role in the transport of statins and cholesterol in the body. Genetic variations in these transporters can affect the uptake, distribution, and elimination of statins, potentially influencing their efficacy and safety. 3. Lipoproteins and Apolipoproteins: Genetic variations in lipoproteins, such as lipoprotein lipase, and apolipoproteins, including ApoA1, ApoA2, ApoC3, ApoA4, ApoA5, ApoB, and ApoE, can impact lipid metabolism and the response to statin therapy. These variations can influence the levels of LDL cholesterol, HDL cholesterol, and triglycerides, which are key targets of statin treatment. 4. Cholesteryl Ester Transfer Protein (CETP): CETP is involved in the transfer of cholesteryl esters between lipoproteins. Genetic variations in CETP can affect the levels of HDL cholesterol and the response to statins. 5. Lecithin Cholesterol Acyltransferase (LCAT): LCAT is an enzyme involved in the conversion of free cholesterol to cholesteryl esters, which are then incorporated into lipoproteins. Genetic variations in LCAT can impact cholesterol metabolism and potentially influence the response to statin therapy. 6. Peroxisome Proliferator-Activated Receptor Alpha (PPARα): PPARα is a nuclear receptor that regulates lipid metabolism and inflammation. Genetic variations in PPARα can affect the response to statins, particularly in terms of lipid-lowering effects. 7. Sterol Regulatory Element-Binding Proteins (SREBPs): SREBPs are transcription factors that regulate the expression of genes involved in cholesterol synthesis and metabolism. Genetic variations in SREBPs can impact the response to statins by affecting cholesterol homeostasis. 8. Interleukin Polymorphisms: Polymorphisms in genes encoding interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) have been associated with variations in the response to specific statins, such as pravastatin. It's important to note that while genetic factors can influence the response to statins, they are just one piece of the puzzle. Other factors such as lifestyle, diet, and overall health also play a significant role in the effectiveness of statin therapy. Consulting with a healthcare professional can provide personalized guidance regarding statin therapy based on individual genetic factors and overall health status.

Answer 67

Limited systemic bioavailability 50-80% first pass so high first pass metabolism 50-80% is metabolised in the liver. This is not a problem cause target organ is liver. Some are prodrugs eg Simvastatin and lovastatin Some work better if taken at night Typical LDL reduction from 20-40% eg lovastatin to 40-60% atorvastatin 10-20% reduction in triglycerides 5-10% increase in HDL. Nester CV outcomes and effects on inflammation and oxidative stress. Widespread use primary and secondary prevention of CVD from RCT results-effective. Benefits outweigh the harm in high risk patients increase risk of developing type 2 diabetes with more lipophilic statins. Studies in COPD no benefit, pneumonia, cancer, spinal cord injury, mainly lack evidence,

Answer 68

Fibrates are derivatives of fibric acid- structurally related to thiazolidiones not widely used but used when statins are contraindicated or to reduce hypertrigylcerdemia. Fibrates mechanism of action: Agonists for PPARalpha-subfamily of nuclear receptors that modulate lipid and carbohydrates metabolism and induce differentiation of adupocytes. Lipoproteins lipase results in breakdown of VLDL. ApoA1 and ApoA5 results in increase in HDL production. Increase hepatic LDL-C uptake, from LDL with higher affinity to the LDL receptor. Increase fatty acids uptake and conversion to acyl vi-A by the liver, therefore fatty acids aren’t even available for TG synthesis. Decrease of VLDL from liver and hence TG levels reduced x Anti-inflammatory effects: Decrease APP synthesis-CRO and fibrinogen Inhibits VSMC inflammation via NF-kB Fibrates increases these proteins: ApoAI ApoAII ABCA1 The above proteins increase HDL production that can reverse cholesterol transport and can increase HDL production that is involved in reverse cholesterol transport. Fibrates decrease: ApoCIII TG FFA Fibrates increase Acyl-CoA synthase which increases amount of FFA that is converted to Acetyl CoA in the liver and cause there are lower free fatty acids FFA body can’t make as much triglycerides decrease in TG and decrease in VLDL production and increase clearance of VLDL and they decrease LDL particle too Fibrates not recommended by NICE Can be prescribed for hypertriglyceridemia-serum TG>10 mmol/L Given when statins are contra-indicated or not tolerated.

Answer 69

•Ezetimibe inhibits cholesterol absorption-used where statin contraindicated or in addition to statin •Bile acid binding resins no longer recommended except in special circumstances as can aggravate hypertriglyceridemia •plant sterols and stanols supplements and functional foods

Answer 70

Specifically blocks absorption of cholesterol without affecting absorption of fat soluble vitamins, TG or bile acids. Higher potency than bile acid resins because it specifically inhibits or binds to proteins in GI epithelial cells that are responsible for cholesterol absorption, including: NCPC1L1, aminopeptidase N and caveolin 1-Annexin A2 complex Conjugated in intestine to Ezetimibe glucuronide (also pharmacologically active) and excreted in stools. No important drug or food interactions reported But only Lowers LDL-C by 17% as most of cholesterol is made in the liver. Ezetimibe mechanism of action: Inhibits cholesterol absorption in the intestine so decrease in chylomicrons production and remnant so therefore reducing VLDL and LDL that transports cholesterol around the serum.

Answer 71

Nicotinic acid water soluble B vitamin 1.5-3g per day lowers both LDL and cholesterol and TG by inhibiting synthesis Increases HDL cholesterol Inhibits TG production and VLDL secretion No longer recommended by NICE for primary/secondary prevention of CAD or CKD or diabetes of vasodilators effects. Occasional use in combination with statin if not adequately controlled Mechanism of action: Mobilisation of FFA so that decrease amount of TG synthesis and decrease in VLDL secretion which leads to decrease in serum LDL

Answer 72

Proprotein convertase subtilisin/kexin type-9 PCSK-9 Binds to hepatic LDL receptors and promotes their lysosomal degradation. Prevents recycling of the LDL receptors back onto the cell surface of hepatocytes limits LDL uptake into the liver. PCSK-9 involved in preventing the amount of LDLR recycling through PCSK9 inhibition. Monoclonal antibodies that inhibit PCSK9, results in increasing receptor number and LDL uptake Treatment of primary hypercholesterolemia or mixed dyslipidaemia as adjunct to diet. Combination with statin or with other lipid lowering drugs if statin not tolerated. Approved by NICE in 2016 Action of PCSK9 inhibitors: PCSK9 bind to LDL receptor and it promotes LDL receptor degradation via the lysosomes and therefore it can’t be recycled or retaken up on cell surface membrane and it can’t function as usual or take other LDL particles. However, anti-PCSK9 antibodies bind it PCSK9, preventing it from binding to the LDL receptors PCSK9 inhibitors are a class of medications that work by targeting the PCSK9 protein in the body. Here's a brief explanation of their mechanism of action: 1. Role of PCSK9: PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) is a protein that plays a key role in regulating levels of low-density lipoprotein cholesterol (LDL-C) in the bloodstream. PCSK9 binds to LDL receptors on liver cells, leading to the degradation of these receptors and reducing their ability to remove LDL-C from the blood. 2. Inhibition of PCSK9: PCSK9 inhibitors, such as evolocumab and alirocumab, work by blocking the action of PCSK9. These medications are typically administered as subcutaneous injections on a biweekly or monthly basis. By inhibiting PCSK9, these drugs prevent the degradation of LDL receptors and increase their availability on liver cells. 3. Increased LDL Receptor Activity: With PCSK9 inhibitors, the increased availability of LDL receptors on liver cells allows for more efficient removal of LDL-C from the bloodstream. This leads to a significant reduction in LDL-C levels, which is the primary target for these medications. Lowering LDL-C is important because high LDL-C levels are associated with an increased risk of cardiovascular diseases, such as heart attacks and strokes. 4. Additional Effects: In addition to lowering LDL-C, PCSK9 inhibitors may also have other positive effects on lipid metabolism. They can increase high-density lipoprotein cholesterol (HDL-C) levels and reduce triglyceride levels to some extent. These medications have also been shown to reduce the risk of cardiovascular events in patients with a history of cardiovascular disease. It's important to note that PCSK9 inhibitors are usually prescribed as an adjunct to diet and maximally tolerated statin therapy for patients with elevated LDL-C or familial hypercholesterolemia who have not achieved their target LDL-C levels with other treatments alone. The use of PCSK9 inhibitors should be done under the guidance of a healthcare professional who can assess the patient's individual risk factors and determine the most appropriate treatment approach.

Answer 73

Approved by NICE in 2021 Inclisiran is a small interfering RNA siRNA treatment that inhibits the translation of PCSK9 mRNA—> gene silencing Can be designed for one specific gene in this case its PCSK9 gene so they cat to reduce gene transcription of that target . 1-GalNAC targets Inclisiran to the hepatocyte ASGPR. 2-Endosomal uptake, GalNAc cleavage, ASGPR revealed to cell membrane. 3-Inclisiran is slowly released from endosomes into the cell cytoplasm, resulting in a sustained therapeutic effect. 4-Inclisiran enters the RNA-induced silencing complex 5-Inclisiran sense, antisense strands separate. 6-Inclisiran antisense strands directs RISC to bind PCSK9 mRNA strands, triggering catalytic cleavage and reducing production of the PCSK9 protein. 7- Reduced PCSK9 results in increased LDL-C receptor recycling to the hepatocytes surface and increased clearance of circulating LDL-C.

Answer 74

Understand development and progression of atherosclerosis. The stages of atherosclerosis: Artery wall made up of three layers: •Inner most layer consists of endothelial cells and basement membranes. •Middle layer made up of smooth muscle cells and elastic components That allows the blood vessels and arteries to stretch and recoil in response to changes in blood flow and blood pressure •Outer most layer consists of connective tissues These 3 layers allow the blood vessel to form a tube and in the lumen in the middle hollow part of the tube is where the blood will flow. The endothelial cells detect blood flow. Blood consists of many different types of components and cells eg RBC. *** Blood vessels, including arteries, play a crucial role in the circulatory system by transporting blood throughout the body. Here's a brief overview of the physiology of blood vessels and arteries: 1. Structure of Blood Vessels: Blood vessels are composed of three layers: the tunica intima, tunica media, and tunica externa. The tunica intima is the innermost layer, consisting of a single layer of endothelial cells that provide a smooth surface for blood flow. The tunica media is the middle layer, made up of smooth muscle cells and elastic fibers, which allow the vessel to contract and relax. The tunica externa is the outermost layer, consisting of connective tissue that provides support and protection to the vessel. 2. Arterial Function: Arteries carry oxygenated blood away from the heart to various tissues and organs. They have thicker walls compared to other blood vessels to withstand the high pressure generated by the heart during systole (contraction). Arterial walls are highly elastic, allowing them to expand and recoil with each heartbeat, maintaining continuous blood flow and preventing pressure fluctuations. 3. Vasodilation and Vasoconstriction: The smooth muscle cells in the arterial walls can contract (vasoconstriction) or relax (vasodilation) to regulate blood flow and blood pressure. Vasoconstriction narrows the arterial lumen, increasing resistance to blood flow and raising blood pressure. Vasodilation, on the other hand, widens the arterial lumen, reducing resistance and lowering blood pressure. 4. Endothelial Function: The endothelial cells lining the blood vessels have several important functions. They regulate vascular tone by releasing vasoactive substances such as nitric oxide, which promotes vasodilation. Endothelial cells also help prevent blood clot formation by releasing substances that inhibit platelet aggregation and promote the formation of smooth, non-thrombotic surfaces. 5. Capillaries and Exchange of Substances: Arteries branch into smaller vessels called arterioles, which further divide into capillaries. Capillaries are the smallest blood vessels, with thin walls consisting of a single layer of endothelial cells. Their primary function is to facilitate the exchange of oxygen, nutrients, and waste products between the blood and surrounding tissues. This exchange occurs through the process of diffusion. Overall, the physiology of blood vessels, including arteries, is vital for maintaining proper blood flow, regulating blood pressure, and facilitating the exchange of substances between the blood and tissues. Dysfunction of blood vessels can lead to various cardiovascular conditions, such as hypertension, atherosclerosis, and peripheral artery disease, highlighting the importance of maintaining vascular health.

Answer 75

Aging causes these endothelial damage, this is due to many reasons eg LDL, smoking, free radicals. Overtime they start to leak and rupture so they let out blood into artery walls and they will leak out LDLs. Once LDL cross endothelial layer it gets into basement memebrane and start to accumulate, this become oxidised and this becomes a trigger for endothelial cells to start expressing markers that bind and attract immune cells to cross. This leads to dysfunction and inflammation in the basement membrane, immune cells start to attack oxidised LDL and fragments of cells so macrophages switch to foam cells. This triggers smooth muscle cells to start migration and proliferation this results in a fibrous cap to block blood from entering the content of this plaque this forms a necrotic core. Ovetime this fibrous cap thins cell death proliferation will stop and this results in an unstable plaque that can rupture. This necrotic lipid core is now exposed to the blood and this triggers a cascade of event that will eventually block blood vessels due to clotting. If this happens in an artery it can starve the brain or the heart from oxygen. ******************************** Atherosclerosis is a chronic inflammatory disease that affects the arteries, leading to the formation of plaques and narrowing of the blood vessels. Here's an overview of the pathophysiology of atherosclerosis: 1. Endothelial Dysfunction: The development of atherosclerosis begins with the dysfunction of the endothelium, the inner lining of the blood vessels. Risk factors such as high blood pressure, smoking, high cholesterol levels, and diabetes can damage the endothelial cells, impairing their normal functions. This dysfunction leads to increased permeability, adhesion of white blood cells, and the release of inflammatory molecules. 2. Formation of Fatty Streaks: In response to endothelial dysfunction, low-density lipoproteins (LDL) cholesterol particles penetrate the damaged endothelium and accumulate within the arterial wall. Macrophages engulf the modified LDL particles, forming foam cells. These foam cells, along with other immune cells, accumulate to form fatty streaks, which are the earliest visible signs of atherosclerosis. 3. Formation of Fibrous Plaques: Over time, the fatty streaks undergo further changes. Smooth muscle cells migrate from the middle layer of the arterial wall to the intima, where they proliferate and produce extracellular matrix components. This results in the formation of fibrous plaques, which consist of a lipid core covered by a fibrous cap. The fibrous cap is composed of smooth muscle cells, collagen, and elastin. 4. Complications and Plaque Rupture: As the plaques grow, they can narrow the arterial lumen, restricting blood flow. The fibrous cap of the plaque can become thin and vulnerable to rupture. If a plaque ruptures, it exposes its lipid core to the bloodstream, triggering the formation of blood clots (thrombosis). These blood clots can partially or completely block the artery, leading to severe ischemia or even complete occlusion of the vessel. 5. Consequences: Atherosclerosis can affect any artery in the body, leading to various complications depending on the affected site. In coronary arteries, it can cause angina (chest pain) or myocardial infarction (heart attack). In the carotid arteries, it can lead to stroke. Peripheral arteries can be affected, causing peripheral artery disease with symptoms such as leg pain and impaired wound healing. Atherosclerosis can also affect renal arteries, leading to renal artery stenosis and hypertension. The pathophysiology of atherosclerosis involves a complex interplay between inflammatory processes, lipoprotein metabolism, and the immune response. Understanding these mechanisms is crucial for developing strategies to prevent and treat atherosclerosis, focusing on risk factor modification, lifestyle changes, and medications to reduce inflammation and cholesterol levels.

Answer 76

When blood vessel is damaged, bleeding will occur and this activates a series of events that allows the blood vessel to stop leaking blood. This know as haemostasis, process of arresting blood loss from damaged blood vessels. Wound—> vasoconstriction—> platelet activist ion and adhesion—> formation of haemostatic plug coagulation—> fibrinolysis Atherosclerotic induced coagulation cascade is there no bleeding so this known as thrombosis and thrombosis is formation of clot in vasculature in the absence of bleeding there is no vasoconstriction, this is because platelet activation step is activated and everything downstream—> platelets activation and adhesion—> formation of haemostatic plug coagulation—fibrinolysis. Thrombosis pathological formation of clot in vasculature in the absence of bleeding. When a blood vessel is damaged, it triggers a series of events known as hemostasis, aimed at stopping blood loss. This involves vasoconstriction, platelet activation and adhesion, the formation of a hemostatic plug, coagulation, and fibrinolysis. Thrombosis, on the other hand, is the pathological formation of a clot within blood vessels without bleeding. This occurs when the atherosclerotic-induced coagulation cascade is activated, leading to platelet activation and adhesion, followed by the formation of a hemostatic plug, coagulation, and fibrinolysis, despite the absence of bleeding. Drugs for haemostasis and thrombosis Thrombosis prevention-extensively used Drugs affect Haemostatsis and thrombosis by affecting: Platelet adhesion and activation Blood coagulation (fibrin formation) Fibrin removal (fibrinolysis)

Answer 77

Arterial thrombosismay be caused by a hardening of the arteries, called arteriosclerosis. This happens when fatty or calcium deposits cause artery walls to thicken. This can lead to a buildup of fatty material (called plaque) in the artery walls. This plaque can suddenly burst (rupture), followed by a blood clot. Haemostasis represents a physiological response to prevent bleeding, the term thrombosis typically refers to the pathologic formation of a thrombus (clot). Drugs for haemostasis and thrombosis: Some drugs act as haemostasis promotion-rarely necessary except when defects: Haemophilia Extensive anticoagulation therapy Haemorrhage after surgery Menorrhagia Some drugs act as Thrombosis prevention-extensively used Drugs affect haemostasis and thrombosis by affecting: •Platelet adhesion and activation •Blood coagulation fibrin formation •Fibrin removal fibrinolysis

Answer 78

Maintain integrity of circulation Essential for Haemostatsis, healing of vessels and inflammation. Various properties: •Adhesion following vascular damage •Shape changes •Secretion of granule content •Biosynthesis of PAF and prostaglandins •Aggregation •Exposure if acidic phospholipid on surface.

Answer 79

Usually platelets are not active and just float around in the blood. If platelets get exposed to damage they will become activated. Many pathways activate platelets. Two components that activate platelets of the matrix are collagen and von willebrand factor and there receptors for both on the platelets so when exposed to these extracellular matrix components they can bind and start to activate platelets activation. There are also soluble factors and there are lots of other receptors on the platelets and they bind different things, so things like thromboxane-A2 ADP, aIIbB3, GPIb/V/IX and many others. Platelet aggregation leads to further platelets activation, receptors bind to fibrin and fibrin forms links between the platelets causing aggregation and further stimulating activation of platelets. Change in shape is driven by change in the cytoskeleton of the platelets. *Platelet adhesion and aggregation: Exposure of collagen or Von Willebrand Factor (vWF) will bind to receptors on the platelets and lead to activation. This leads to platelet activation will trigger platelets aggregation which will further stimulate activation of platelets around the plug or the activated aggregated mesh work forming and this will form a plug. Incase of bleeding plug stops bleeding but incase of thrombi without bleeding this will block blood vessel. The platelets also contract and this is given by cytoskeletal changes and this will lead to concentration affect and further block the blood vessel. Substances can stimulate aggregation or activation. Eg ADP, thromboxane A2, Von Willbrand factor or collagen . All lead to activation of platelets and aggregation. There are also factors that prevent the activation of platelets and these include nitraic oxide and and prostacyclin both made by endothelial cells and they are released into the blood and these serve to inhibit aggregation and activation. Endothelial cells also reduce levels of ADP via AMP enzyme cleavage. Platelet adhesion, activation, and secretion are crucial processes in hemostasis, the body's mechanism for preventing excessive bleeding. Here's a breakdown of each process: 1. **Platelet Adhesion**: - **Vascular Injury**: When a blood vessel is damaged, exposing the underlying collagen and von Willebrand factor (vWF), platelet adhesion is initiated. - **Glycoprotein Receptors**: Platelets express glycoprotein receptors on their surface, such as glycoprotein Ib (GPIb) and glycoprotein VI (GPVI), which interact with vWF and collagen, respectively. - **Initial Adhesion**: The interaction between vWF and GPIb leads to the initial adhesion of platelets to the exposed collagen fibers in the injured vessel wall. 2. **Platelet Activation**: - **Agonists**: Various agonists, such as thrombin, adenosine diphosphate (ADP), and thromboxane A2, are released or generated at the site of injury. - **Receptor Activation**: These agonists bind to specific receptors on the platelet surface, triggering intracellular signaling cascades. - **Intracellular Signaling**: Activation of receptors leads to an increase in intracellular calcium levels, activation of protein kinases, and phosphorylation of various proteins, ultimately resulting in platelet activation. - **Shape Change and Granule Secretion**: Activated platelets undergo shape change, extending filopodia and lamellipodia. They also secrete granules containing factors such as ADP, serotonin, and thromboxane A2, which further amplify platelet activation and recruit additional platelets to the site of injury. 3. **Platelet Secretion**: - **Granule Release**: Platelet granules, including alpha granules and dense granules, contain various molecules involved in hemostasis and wound healing. - **Alpha Granules**: These contain factors such as fibrinogen, von Willebrand factor, and growth factors, which promote platelet aggregation, clot formation, and tissue repair. - **Dense Granules**: These contain molecules like ADP and calcium, which enhance platelet activation and aggregation. - **Autocrine and Paracrine Signaling**: The substances released from platelet granules act in an autocrine (affecting the releasing platelet) and paracrine (affecting nearby platelets and cells) manner, further enhancing platelet activation and aggregation. Overall, platelet adhesion, activation, and secretion are tightly regulated processes that ensure rapid and effective hemostasis following vascular injury. Dysregulation of these processes can lead to bleeding disorders or thrombotic diseases.

Answer 80

Inhibition of platelets activation and aggregation can occur via targeting of promoters like thromboxane A2 production or activity same for ADP. Cell aggregation can also be inhibited via blockers that will block binding to Von willbrand factor or collagen the extracellular matrix components that lead to platelet activation. The stimulation of inhibitor production like stimulation of HNO3 acid production but this strategy is short lived so not very effective. Increase of prostacyclin formation will inhibit platelet activation or increase removal of ADP which decreases platelet activation. Platelet activation and aggregation via GP surface proteins eg GPIbeta bind to VWfactor extracellular matrix activation GPIIalpha bind to fibrinogen and fibrinogen lead to platelets aggregation.

Answer 81

Decrease platelet aggregation and inhibit thrombus formation in arterial circulation. Aspirin Thienopyridines: clopidogrel (prasugrel, ticlopidine) Ticagrelor Glycoprotein IIb/IIIa inhibitors Eptifibatide Tirofiban Abciximab Dipyridamole What is the role of anti-platelet activity? Inhibit pathways that activate platelet activation or aggregation. So targeting thromboxane synthesis or TXA2 binding to receptors, ADP pathways or glycoproteins GPI or GPII Or target aggregation set by nitric oxide which is very short lived so not a therapeutic option or target prostacyclin. ,

Answer 82

Aspirin irreversibly inactivates cyclooxygenase COX COX1 and COX2 •COX1 is found in platelet Homeostasis Platelet aggregation •COX2 is found in endothelial cells Platelet aggregation COX 1 important due to their ability to synthesis thromboxane A2 in platelets which will stimulate further activation of platelets. In endothelial cells COX 2 is important for the production of prostacyclin which is an inhibitor of platelets activations and aggregations. Aspirin irreversibly inactivates COX1 in platelets Reduces thromboxane A2 formation Reduces platelet aggregation Irreversibly inactivates COX2 in endothelium Reduces prostacyclin formation Increases platelet aggregation Net effect zero Endothelial cells can synthesis new COX 2 and platelets can’t because no nuclei. Lower doses just inhibit platelets Higher doses both.

Answer 83

Thienopyridines- pro drugs additive effects to aspirin, because they work on separate pathway. Inhibit ADP induced aggregation ADP receptor antagonist Antagonise the platelet P2Y12 receptor (purinergic receptor) Ticagrelor Nucleoside analogue- like adenosine Blocks P2Y12 ADP receptors on platelets Different binding sites than ADP so allosteric inhibitor and blockage reversible and therefore acts faster and for shorter period. PLATO trial Ticagrelor less mortality from all CV causes than clopidogrel Side effects- more non lethal bleeding effects more quickly reversible Though.

Answer 84

Antagonist antagonise the ability of the glycoprotein receptor to bind to fibrinogen and therefore lead to reduced or inhibition of platelet aggregation and activation. • Inhibit all pathways of platelet activation because bind to glycoprotein Ilb/Illa receptors, blocking fibrinogen binding so inhibiting aggregation. • Abciximab - monoclonal antibody • Adjunct with heparin and aspirin for prevention of complications in patients undergoing percutaneous coronary intervention • Used ONCE only, very expensive - approx £260 *• Cyclic peptides - Eptifibatide and Tirofiban • Adjunct with heparin and aspirin to prevent early MI in, patients with unstable angina or non-STEMI

Answer 85

Haemostasis and thrombosis: Haemostasis is the arrest of blood loss from damaged blood vessels. Thrombosis pathological formation of clot in vasculature in the absence of bleeding. Thrombosis leads to activation of platelets and the downstream activation of coagulation. The formation of blood clot: In endothelial cell damage if platelets are exposed to extracellular matrix such as VWF and collagen fibres the platelets will bind to and become activated and this will lead to platelet aggregation, platelets start to initiate the coagulation cascade to form a fibrin polymer. Wound or injury leads to vasoconstriction then platelet activation and adhesion. This leads to the formation of a plug and this leads to fibrinolysis. Coagulation: Formation of a fibrin clot or thrombus Reinforces platelet plug May trap blood cells •white thrombus •red thrombus Thrombus is insoluble, strong and traps RBC and WBC and this reinforces the platelet plug. This formation of clot or thrombus is regulated by the coagulation cascade. Coagulation cascade: Complex enzyme cascade that ultimately leads to the conversion of soluble fibrinogen to insoluble fibrin.

Answer 86

Coagulation cascade complex series of enzymic steps (proteolysis each enzyme will cleave and catalyse the next enzyme in the cascade). Intrinsic or contact pathway all; components present in blood already Extrinsic or in vivo pathway; component from outside of blood/requires external input eg tissue factor/gets activated due to tissue damage which induces tissue factor and thus activates coagulation cascade. Both pathways converge at factor x (ten) and this leads to its cleavage to activated form xa and this is either initiated by factor 9a or 7a depending on whether it is intrinsic or extrinsic pathway activation. Xa cleaves prothrombin to thrombin. Thrombin will cleave fibrinogen to insoluble fibrin which will then form a polymeric system and mesh work that will form into blood clot. Thrombi or atherosclerosis it is the extrinsic pathway and it is tissue factor release that gets switched on. Activation of factor x to xa leads to the conversion or cleavage of prothrombin to thrombin then cleaves soluble fibrinogen to insoluble fibrin the fibrin will then form polymers and this will lead to a highly insoluble plug which will trap the blood cells and form a clot.

Answer 87

Platelet aggregation and platelet pathways interact with coagulation cascade at different levels. Platelet activation/aggregation will lead to formation of platelet plug. Platelets secrete thromboxane A2 and ADP to stimulate aggregation. Platelet activation lead to the exposure of acidic phospholipids to the outside of the cell and this step switches on the coagulation cascade and it feeds into the in vivo pathway or the extrinsic pathway and also in the activation of 7a or 10 or 10a or cleaves of thrombin too. The coagulation pathway or components of the coagulation feed back to further stimulate platelet aggregation and activation and factors that induce this step are thrombin and fibrinogen binds to GPII/IIIbeta to stimulate further aggregation so both pathways interact to form a thrombus and block a blood vessel.

Answer 88

•Thrombin cleaves fibrinogen to fibrin, producing fragments that polymerise to form insoluble fibrin. •Activated factor XIII activates thrombin— strengthens fibrin links. •Platelets aggregation. •Cell proliferation. •Regulates smooth muscle contraction.

Answer 89

Liver synthesis many of the coagulation factors and liver is absolutely essential for the synthesis of these clotting factors. Vitamin K lipid soluble (phytomenadione) and it is called “Koagulation” vitamin as its required for the synthesis of factors II, VII, IX, X Vit K from Dietary sources and Synthesis in the GIT. Bile salt synthesises is essential for Vitamin K absorption and vitamin K absolutely essential for these coagulation factors.

Answer 90

Drugs used in coagulation disorder Warfarin and heparin anticoagulants low molecular weight and unfractioned fractionated vs unfractionated heparin? LMWH is obtained by fractionation of polymeric heparin. LMWH differs from unfractionated heparin in a number of ways, including the average molecular weight; the need for only once or twice daily dosing; the absence of monitoring the aPTT; and the lower risk of bleeding, osteoporosis, and HIT.

Answer 91

Main drugs used for platelet-rich white thrombi: Anti-platelet drugs-aspirin Main drugs to prevent or treat red thrombi: Injectable anticoagulants (heparin and newer thrombin inhibitors) act immediately. Oral anticoagulants (warfarin and related compounds) take several days Patients with venous thrombosis given injectable anticoagulants until effects of warfarin established. Warfarin act on factor XI, X and prothrombin (II) and factor VII in the extrinsic pathway. Xa inhibitors act in Xa Heparin acts on Xa and thrombin IIa inhibitors act on thrombin IIa tPA act on plasminogen Anticoagulants prevent thrombosis in the coagulation cascade by targeting different steps of the clotting process. They inhibit the enzymes or factors involved in clot formation, thereby reducing the formation of blood clots. Some common mechanisms of action include inhibiting the activation of clotting factors, blocking the conversion of fibrinogen to fibrin, or interfering with platelet activation and aggregation. By preventing excessive clotting, anticoagulants help maintain blood flow and prevent the formation of dangerous blood clots.

Answer 92

Extracted form the liver Present in mast cells Mechanism of actions of heparin- activates antithrombin III: •ATIII inactivates thrombin and Xa and other serine proteases •Heparin binds to ATIII and it changes conformation of ATIII this accelerates the rate of thrombin inhibition. •Accelerates rate of action of ATIII accelerating thrombin inhibition. Inhibiting a single molecule of Xa helps prevent the formation of 100s of thrombin molecules. Heparins structure are highly acidic sulphate groups- administered as heparins 3 D-glucosamines 2 Uronic acid Heparins are a family of GAGs (mucopolysaccharides) Compounds: •Unfractioned UFH •Low molecular weight heparins (LMWH) Unfractionated heparin inhibits both thrombin and Xa, however, LMWH inhibits mainly Xa and therefore its effect is more predictable. Unfractioned heparin-Hospitals Unfractioned Heparins work to inhibit multiple enzymes in the coagulation cascade whereas LMWH only inhibit specific enzyme Xa only. Heparin + ATIII inhibit IXa, XIa, XIIa, Xa and IIa (thrombin) which inhibits XIII from producing XIIIa; converts fibrin into stabilised fibrin

Answer 93

Not absorbed orally Large size Degradation Partially metabolised in the liver by heprainase to uroheprain 20-50% is excreted unchanged Parenteral administration IV or SC t1/2 40-90mins Acts immediately

Answer 94

LMWH bind less to endothelium and plasma proteins hence greater bioavailability and plasma half life than unfractioned heparin. Predictable dose response (only effect Xa) Laboratory monitoring is rarely required. Reduced frequency of dosing Less side effects Can be used at home (convenience/cost).

Answer 95

Pharmacology of warfarin Inhibits vitamins K reductase Competitive inhibition Vitamin K essential for the synthesis for the coagulation cascade factor (2,7,9,10) The enzyme warfarin targets is essential for the function of vitamin K by inhibiting vitamin K reductase this reduces or inhibits the synthesis of coagulation factors.

Answer 96

Inhibits hepatic vitamin K dependent synthesis of factors II, VII, IX and X and of anticoagulation protein C and it cofactor protein S. Since Warfarin acts in directly it has no effect on existing clots. Takes at least 48-72hrs to achieve an antithrombolytic effect. Meantime administer LWMH

Answer 97

Readily absorbed through GIT Quite lipophillic Placenta Breast milk Extensively bound to plasma proteins 99% Plasma half life of 37 hours variable Metabolised by cytochrome P450 Difficult drug to control so needs constant monitoring.

Answer 98

The fibrinolytic system refers to the body's natural mechanism for breaking down blood clots. It is a complex cascade of biochemical reactions that involves the conversion of inactive plasminogen into active plasmin, which is responsible for the breakdown of fibrin, the protein that forms the structure of blood clots. When a blood clot forms in the body, it is necessary for it to be eventually dissolved to restore normal blood flow. The fibrinolytic system plays a crucial role in this process. The key components of the fibrinolytic system include: 1. Plasminogen: This is an inactive form of the enzyme plasmin. Plasminogen is present in the blood and is converted into plasmin when it is activated. 2. Tissue plasminogen activator (tPA): tPA is a protein that is released by the endothelial cells lining the blood vessels. It is responsible for initiating the conversion of plasminogen into plasmin. tPA binds to fibrin within the blood clot and activates plasminogen specifically at the site of the clot. 3. Plasmin: Plasmin is the active enzyme that breaks down fibrin into smaller fragments called fibrin degradation products. Plasmin also degrades other proteins involved in clot formation, including fibrinogen and some clotting factors. The activation of the fibrinolytic system is tightly regulated to prevent excessive clot breakdown or bleeding. Abnormalities in the fibrinolytic system can lead to an increased risk of clot formation or difficulty in clot dissolution. Fibrinolytic drugs, such as alteplase or streptokinase, are synthetic or recombinant versions of tPA. They are used therapeutically to enhance the fibrinolytic process and rapidly dissolve blood clots in conditions like acute myocardial infarction or ischemic stroke.

Answer 99

When homeostasis has been restored. Clot removal: Fibrinolytic pathway Plasmin formation Plasmin is a potent proteolytic enzyme and it attacks fibrin at 50 different sites. Plasmin formed by plasminogen (pro enzyme) Has high affinity for fibrin but must be activated via: •Tissue Plasmin activators tPA •Urokinase plasminogen activator uPA •Kallikren. In the fibrin clot there is Plasmin but it is inactive and won’t cleave fibrin until it gets activated via tPA and urokiases upon damage. These activators stimulate the catalytic activity of Plasmin and this will lead to break down of fibrin. There are also inhibitors PAI plasminogen activator inhibitors released by the endothelial cells and this acts as balance between activation and inhibition pathways. Once activated Plasmin will degrade the fibrin polymers to fibrin breakdown products and starts to break the clot. Free Plasmin floats in the blood it can be inhibited by a2-antiplasmin to form antiplasmin/Plasmin complexes that are inactive.

Answer 100

Drugs can convert plasminogen to Plasmin. •Streptokinase •Recombinant human tPA Reteplase Alteplase Tenecteplase •Urokinase Streptokinase From streptococci Cleared by liver Antigenic antibodies form after 4days can’t use due to antigenic effects and production of antibodies it can’t be used for a year after one dose is given due reaction. Half life= 20minutes Can’t use for a year after dose given

Answer 101

Reduce mortality in MI Treatment of acute ischemic stroke, DVT, and PE. More active on fibrin-bound plasminogen than plasma plasminogen, therefore clot selective. Not antigenic Given iv-half life of 5-mins Given within 6-12h, ideally within 1hour.

Answer 102

Reduce mortality in MI More active on fibrin bound plasminogen than plasma therefore clot selective. Not antigenic Reteplase given within 12h ideally <1h Tenecteplase given within 6h, ideally <1h

Answer 103

uPA not selective for clot bound fibrin so less useful.

Answer 104

1. Antiplatelets: These drugs, such as aspirin or clopidogrel, work by inhibiting the aggregation of platelets, which are responsible for blood clot formation. By preventing platelets from sticking together, antiplatelets help reduce the risk of blood clots, particularly in conditions like heart disease or stroke. 2. Anticoagulants: Anticoagulants, like heparin or warfarin, target different steps in the coagulation cascade to prevent blood clot formation. They inhibit the activity of specific clotting factors or enzymes involved in the clotting process, thereby slowing down or preventing the formation of blood clots. Anticoagulants are commonly used to treat or prevent conditions such as deep vein thrombosis, pulmonary embolism, or atrial fibrillation. 3. Fibrinolytics: Fibrinolytic drugs, such as alteplase or streptokinase, are used to dissolve existing blood clots. They work by activating the body's natural clot-dissolving system, known as the fibrinolytic system. Fibrinolytics promote the breakdown of fibrin, the protein that forms the structure of blood clots, thereby restoring blood flow in conditions like acute myocardial infarction or ischemic stroke. 4. Anti-anginal drugs: These medications, such as nitroglycerin or beta-blockers, are used to relieve angina, a symptom of coronary artery disease. Anti-anginal drugs work by dilating the blood vessels, increasing blood flow to the heart, and reducing the workload on the heart. They can also help relax the coronary arteries, improving oxygen supply to the heart muscle and relieving chest pain. 5. Anti-arrhythmic drugs: Anti-arrhythmic medications, like amiodarone or beta-blockers, are used to treat or control abnormal heart rhythms, known as arrhythmias. These drugs work by modulating the electrical activity of the heart, either by blocking specific ion channels or by affecting the autonomic nervous system. By restoring normal heart rhythm, anti-arrhythmic drugs help maintain proper heart function and prevent complications associated with arrhythmias. It's important to note that the specific mechanisms of action and uses of these drugs may vary, and they should always be used under the guidance of a healthcare professional.

Answer 105

What is angina pextoris? When oxygen supply to myocardium is insufficient for its needs. Atherosclerosis blockage of blood vessel that supply the heart. Overtime the heart myocytes and tissue start to starve cause of low oxygen levels or nutrient supply for heart muscle. Retrosternal cardiac pain (Retrosternal chest pain refers to pain that occurs in the space behind the sternum.) Intense, diffuse, gripping, constricting, suffocating chest pain. “Bear hug” May radiate to arms, neck and jaw Difficult to distinguish from heart burn A symptom not a disease usually a symptom of atherosclerosis. Coronary blood flow: Coronary arteries surround the heart to provide blood supply to the heart and the cardiomyocytes are very sensitive to distribution of blood flow as it could lead to their death. The atherosclerosis will cause the lumen of the blood vessel or in this case the coronary artery to get smaller cause the atherosclerotic growth blocks the artery over time this plaque becomes unstable and eventually rupture and this will lead to the release of plaque material. This will then trigger platelet activation and clotting and form a thrombus which will completely block the downstream blood supply.

Answer 106

Alleviate acute symptoms Minimise frequency of ischaemia Reduce progression of atherosclerosis (Secondary prevention- statins, aspirin, ACEI in diabetes)

Answer 107

cardiomyocytes in the heart and the coronary blood supply will balance the oxygen needs with the oxygen supply. Oxygen needs= cardiac workload and this could be increased due to many factors eg exercise or emotional instability. This balanced with the oxygen supply but could be restricted due to narrowing of the coronary arteries (artheroma) and there limits to dilation, aortic stenosis. Normally demand and supply is balanced but in angina it can become imbalanced. Normally due to atherosclerosis or coronary arteries become narrowed thus limiting oxygen supply to the cardiomyocytes and this results in angina.

Answer 108

Reduce cardiac workload Reduce perfusion demands Eg rest, stress, smoking, weight Reduce pre-load: Venodilator eg nitrates Reduced afterload: Arterial dilator eg calcium channel blocker, nitrate. Reduce cardiac rate/contractility: Negative inotrope/chronoteope eg B-blocker, calcium channel blockers Improve efficiency of the heart, Stop smoking, exercise Preload is the initial stretching of the cardiac myocytes (muscle cells) prior to contraction. It is related to ventricular filling. Afterload is the force or load against which the heart has to contract to eject the blood.

Answer 109

Increase coronary flow Arterial dilator eg calcium channel blocked, nitrate. Surgery eg bypass, angioplasty, stent Reduce progression of atherosclerosis

Answer 110

Organic nitrates- acute attacks Calcium channel blockers Beta-adrenoreceptor antagonist; slow heart rate so reduce metabolic demand Potassium channel activators Vasodilators.

Answer 111

1-Amyl nitrate vapour causes flushing, tachycardia, fall in BP Glyceryl trinitrate (nitroglycerin): Explosive Effective in angina Quick onset/short duration of action Isosorbide mononitrate Longer duration of action. Nitric oxide NO released from organic nitrates Relaxes all smooth muscles Main effects on CV system Lower doses: Marked dilatation of large veins Reduction in central venous pressure (reduced pre-load) Reduction in cardiac output and oxygen consumption Little effects on arteriales/ little change in BP Higher doses/chronic use Arteriolar dilation, fall in BP, reduced cardiac output which will result in a headache. Nitric oxide is normally used in the cardiovascular system as a vasodilator and endothelial cells will send shear stress and this will trigger them to make NO, diffuses across membranes so gets into smooth muscle cells and cause vascular relaxation.

Answer 112

Nitrates serve as a nitric acid donar so will release nitric acid radicals this will lead to activivation of guanylate cyclase and the production of cyclicGMP and this will lead to dephosphorylation of myosin light chain and vasodilation of smooth muscle cell relaxation and this will reduce workload and decrease oxygen consumption of the heart. Effective in treating angina.

Answer 113

Increase coronary flow in normal subjects Reduction of vascular resistance Dilation of coronary arteries despite a fall in BP Diverts blood from normal to ischaemic areas serves as a Pharmacological By pass of narrowed segments Nitrates have several effects on coronary circulation. They can increase coronary flow in normal subjects by reducing vascular resistance. Additionally, despite a decrease in blood pressure, nitrates can cause dilation of coronary arteries. This dilation helps divert blood from normal areas to ischemic areas, effectively serving as a pharmacological bypass for narrowed segments.

Answer 114

Glycerol trinitrate (Nitroglycerin) Absorbed sublingually (under tongue) rapid relief Rapidly metabolised in liver (30min activity) Can’t be swallowed (1st pass metabolism effects) Sprays Tablets; glass bottles as volatile substances Patches

Answer 115

Reduce oxygen consumption only: Slow the heart rate (-ve chronotropy) Depress the myocardium (-ve inotropy) No effect on coronary arteries Provide secondary prevention Improve exercise capacity Contraindicated in coronary spasm Slow withdrawal (up-regulated receptors) Slow withdrawal (up-regulated receptors) Indications: Angina prophylaxis Unstable angina Propranolol Acebutolol Atenolol Bisoprolol Carvedilol Celiprolol Labetolol Metoprolol Nadolol Nebivolol Oxprenolol Pindolol Timolol Mechanism of action: Block beta-1 adrenoreceptors in the heart and beta-2 adrenoreceptors in the peripheral vasculature, bronchi, pancreas and liver. Exact mechanism of action in HT unknown, although known to decrease CO. Side effects: Bradycardia Heart failure Hypotension Arrhythmias Bronchospasm Peripheral vasoconstriction Gastrointestinal disturbances Fatigue Sleep disturbances Sexual dysfunction Exacerbation of psoriasis Contraindications: Asthma Uncontrolled heart failure Bradycardia Heart block Severe peripheral vascular disease Caution: Diabetes-May cause deterioration in glucose tolerance and mask the symptoms of hypoglycaemia If no alternatives in asthma, use cardioselective beta blockers Therapeutics use: Appropriate add-on therapy step 4 for patients uncontrolled by other agents Drugs of choice to treat HT in patients who also has CCF or is post MI Choice of B-blocker will depend on their relative characteristics: Cardio selectivity: Eg Atenolol, bisorprolol, metoprolol Tendency to block B1receptors in heart rather than B2 receptors in lungs but not cardiospecific and still have potential to block B2 receptors in lungs therefore caution required. Can be used with caution in asthmatics if no other option available Also less likely to be a problem in diabetics Initrinsic sympathomimetic activity (ISA) Eg Oxprenolol, pindolol, acebutolol, celiprolol. Capacity to stimulate as well as block adrenergic receptors. Less bradycardia & cold extremities than other B blockers. Lipid/water solubility: Eg water soluble: atenolol, celiprolol Lipid soluble: propanol Water soluble less likely to cross blood brain barrier and therefore cause less sleep disturbances and nightmares Water soluble excreted by the kidneys and may accumulate in renal impairment therefore dose reduction maybe necessary. Dose: Bisoprolol 5-10mg daily max 20mg daily Propranolol 80mg twice daily increased at weekly intervals if required to Maintaince of 160-320mg

Answer 116

3 main classes: Phenylalkylamines eg verapamil Dihydropyridines eg nifedipine, amlodopine Benzothiazepines eg diltiazem Block calcium ions entering cells through preventing opening of voltage-gated L-types calcium channels. Binds alpha-1 subunit of the cardiac L-type calcium channels but at different sites. Pharmacological effects of CCB: Main affects on cardiac and vascular smooth muscles, inhibiting Ca2+ entry caused by depolarisation in these tissues. Verapamil is relatively cardioselective Nifedipine is relatively smooth muscle selective Diltiazem is intermediate Cardiac action: Antidysrhythmic effects mainly atrial tachycardia because of impaired atrioventricular conduction Reduced contractility Negative inotropic and chronotropic effects (but little effect on cardiac-output due to reduction in peripheral resistance) Verapamil contraindication in heart failure Vascular smooth muscle mainly nifedipine Arteriolar dilation- reduce blood pressure ( reduce after load) Coronary vasodilation used in patients with variant angina (spasms) ******************************** This text explains the three main classes of calcium channel blockers (CCBs) and their pharmacological effects on cardiac and vascular smooth muscles. The three main classes of CCBs are: 1. Phenylalkylamines (e.g., verapamil) 2. Dihydropyridines (e.g., nifedipine, amlodipine) 3. Benzothiazepines (e.g., diltiazem) CCBs block calcium ions from entering cells by preventing the opening of voltage-gated L-type calcium channels. They bind to the alpha-1 subunit of the cardiac L-type calcium channels, but at different sites. The pharmacological effects of CCBs include: 1. Effects on cardiac and vascular smooth muscles: CCBs inhibit the entry of calcium ions caused by depolarization in these tissues. - Verapamil is relatively cardioselective, meaning it has more pronounced effects on the heart. - Nifedipine is relatively smooth muscle selective, meaning it has more pronounced effects on vascular smooth muscles. - Diltiazem has intermediate effects on both cardiac and smooth muscle tissues. In terms of cardiac action, CCBs have the following effects: - Antidysrhythmic effects: CCBs are effective in treating atrial tachycardia by impairing atrioventricular conduction. - Reduced contractility: CCBs have negative inotropic and chronotropic effects, meaning they reduce the force and rate of contraction of the heart. However, they have little effect on cardiac output due to the reduction in peripheral resistance. - Verapamil is contraindicated in heart failure patients. In terms of vascular smooth muscle, nifedipine has the following effects: - Arteriolar dilation: Nifedipine causes dilation of arterioles, which leads to a reduction in blood pressure (reducing afterload). - Coronary vasodilation: Nifedipine is used in patients with variant angina (spasms) to dilate the coronary arteries and improve blood flow.

Answer 117

What is a cardiac arrhythmia? An arrhythmia is a problem with the rate or rhythm of the heart beat. During an arrhythmia, the heart can beat too fas, too slow, or with an irregular rhythm

Answer 118

ECG records total electrical activity of the heart. Map single activity of cardiomyocytes in the ventricles into this. So the major QRS complex is associated with main depolarisation event of the ventricular cardiomyocytes and repolarisation is associated with the T wave. The electrocardiogram (ECG) reading and ventricular action potential are closely related but represent different aspects of cardiac physiology. 1. **ECG Reading**: An ECG measures the electrical activity of the heart over time. It represents the summed electrical activity generated by all of the heart's cells. The ECG consists of waves and intervals that correspond to specific events in the cardiac cycle, such as depolarization and repolarization of the atria and ventricles. 2. **Ventricular Action Potential**: The ventricular action potential represents the electrical activity specifically within the ventricular myocardium. It describes the changes in membrane potential that occur in ventricular muscle cells during the cardiac cycle. The action potential consists of several phases: depolarization, plateau, and repolarization. The relationship between the two can be understood as follows: - **P Wave**: Represents atrial depolarization on the ECG. During this time, ventricular muscle cells are in their resting state, maintaining a stable negative membrane potential. - **QRS Complex**: Represents ventricular depolarization on the ECG. This corresponds to the rapid depolarization phase of the ventricular action potential, where voltage-gated sodium channels open, allowing an influx of sodium ions into the cell. - **ST Segment**: Represents the plateau phase of the ventricular action potential on the ECG. During this phase, the ventricular muscle cells maintain a stable positive membrane potential due to the balance between inward calcium and outward potassium currents. - **T Wave**: Represents ventricular repolarization on the ECG. This corresponds to the repolarization phase of the ventricular action potential, where voltage-gated potassium channels open, allowing potassium ions to exit the cell, leading to membrane potential returning to its resting state. Overall, while the ECG provides a macroscopic view of the heart's electrical activity, the ventricular action potential offers a more detailed understanding of the cellular processes underlying cardiac electrical activity within the ventricles.

Answer 119

Drugs affecting the cardiac action potential Drugs can be used to extend or change the ventricular cardiomyocytes action potential and the ECG trace, these will work at different phases of the cardiomyocytes action potentials and there 4 classes of drugs. Class-1 Sodium channel blockers consists of 3 subclasses and they affect action potentials: IA moderate Na channel blockers IB weak Na channel blockers IC strong Na channel blocker Class-2 Beta blockers ( propranolol, metoprolol) extend firing of Phase 4 will be longer and there will be Less action potentials in a minute Class-3 K+ channels blockers Amiodarone, sotalol work on repolarisation step third phase of the cardiomyocytes action potential. Class-4 Ca2+ channel blockers verapamil, diltiazem high function on the plateau phase of the cardiomyocytes

Answer 120

What are the effects of these drugs on the action potentials? Class-1 drugs sodium transport blockers and they fall into 3 categories depending on how they affect action potential. They all reduce depolarisation but have no effects on duration of action potential. •Class 1A agents: Reduce rate of rise of phase 0b Lengthen action potentials •Class 1B agents Reduce rate of rise of phase 0 Shorten action potentials •Class 1C agents Reduce rate of rise of phase 0 No effect on duration of action potentials

Answer 121

Predominant action on sinus node and they act on pace maker cells action potential not on the cardiomyocytes action potential. The pace maker cells action potential has a drift to thresh hold and beta blockers reduce the rate of this slow drift and extend this phase and this will lead to lengthened of time between action potential firing. This decreases the heart rate. Propranolol Esmolol Timolol Metoprolol Atenolol Bisoprolol Decrease myocardial infraction mortality Prevent recurrence of tachyarrhythmias

Answer 122

Potassium required for repolarisation event and is pumped out of the cardiomyocytes by the rectifier channels and these K+ channel blockers block the rectifier channels. Widen action potentials due to slowing of repolarisation of cardiomyocytes membrane and this leads to widening extension duration of the action potential.

Answer 123

Block Ca2+ entry into cardiomyocytes drawing the plateau phase this reduces the force of contraction it does work on the AV node as well. This slows down the transmission of the action potential from the atria to the ventricle so slows the spread of action potential to the cardiomyocytes. The secondary affect is on cardiomyocytes contraction it will slow the rate of Ca2+ getting in and it will reduce the force of contraction as well. Verapamil Diltiazem Prevent recurrence of paroxysmal supraventricular tachycardia. Reduce ventricular rate in patients with atrial fibrillation.

Answer 124

Class V: Adenosine Digoxin Magnesium sulfaté Works by unknown mechanism direct nodal inhibition Used in supra-ventricular arrhythmias, especially in heart failure with atrial fibrillation, contraindicated in ventricular arrhythmias or in the case of Mg sulfaté,

Answer 125

Inhibition of Na/K ATPase Reversal of Na/Ca exchanger Increase intracellular Ca levels Digoxin: Inhibition of Na/K ATPase Reversal if Na/Ca exchanger Increases intracellular Ca levels Normally, Na leaks into and K leaks out of myocyte cells. Action potentials increased Na in and K out of myocytes. Na/K ATPase pump normal restores levels. Requires energy ATP hence ATPase Inhibition increased Na inside myocytes. Na/Ca exchanger pumps Na out and Ca into myocytes. Increased Ca in myocytes so increased force of contraction. ******************************** The pharmacology of digoxin involves the inhibition of Na/K ATPase, the reversal of the Na/Ca exchanger, and an increase in intracellular calcium levels. Normally, sodium (Na) leaks into myocyte cells while potassium (K) leaks out. During action potentials, there is an increase in sodium entering and potassium leaving the myocytes. The Na/K ATPase pump normally restores the levels of sodium and potassium by actively transporting them across the cell membrane, and this process requires energy in the form of ATP. Digoxin works by inhibiting the Na/K ATPase pump, which leads to an increased concentration of sodium inside the myocytes. This disrupts the normal balance of sodium and potassium in the cells. Additionally, digoxin reverses the Na/Ca exchanger, causing more sodium to be pumped out of the myocytes and more calcium to be pumped into the myocytes. As a result of these mechanisms, there is an increased level of calcium inside the myocytes, which leads to an increased force of contraction. This positive inotropic effect of digoxin enhances the contractility of the heart muscle.

Answer 126

Digoxin: Inhibition of Na/K ATPase Reversal if Na/Ca exchanger Increases intracellular Ca levels Normally, Na leaks into and K leaks out of myocyte cells. Action potentials increased Na in and K out of myocytes. Na/K ATPase pump normal restores levels. Requires energy ATP hence ATPase Inhibition increased Na inside myocytes. Na/Ca exchanger pumps Na out and Ca into myocytes. Increased Ca in myocytes so increased force of contraction. ******************************** The pharmacology of digoxin involves the inhibition of Na/K ATPase, the reversal of the Na/Ca exchanger, and an increase in intracellular calcium levels. Normally, sodium (Na) leaks into myocyte cells while potassium (K) leaks out. During action potentials, there is an increase in sodium entering and potassium leaving the myocytes. The Na/K ATPase pump normally restores the levels of sodium and potassium by actively transporting them across the cell membrane, and this process requires energy in the form of ATP. Digoxin works by inhibiting the Na/K ATPase pump, which leads to an increased concentration of sodium inside the myocytes. This disrupts the normal balance of sodium and potassium in the cells. Additionally, digoxin reverses the Na/Ca exchanger, causing more sodium to be pumped out of the myocytes and more calcium to be pumped into the myocytes. As a result of these mechanisms, there is an increased level of calcium inside the myocytes, which leads to an increased force of contraction. This positive inotropic effect of digoxin enhances the contractility of the heart muscle.

Answer 127

Adenosine binds to receptor and will reduce firing at the sinus node and this is working on the pace maker cells. When adenosine binds to A1 receptor and A1 receptor is coupled with Gi protein so inhibitor protein, GI is released and this will inactivate Adenyl cyclase this will decrease cAMP production and decrease in action potential firing in the pace maker cells so this will serve to extend the time between action potential production in pace maker cells. Adenosine is a medication that is commonly used in cardiovascular diseases (CVD) for its pharmacological effects. Here are some key aspects of the pharmacology of adenosine in CVD: 1. Coronary Vasodilation: Adenosine acts as a potent vasodilator in the coronary arteries, which supply blood to the heart muscle. By activating specific receptors called adenosine receptors, adenosine relaxes the smooth muscles in the blood vessels, leading to an increase in blood flow to the heart. This effect is particularly beneficial in conditions such as angina, where there is inadequate blood supply to the heart. 2. Antiarrhythmic Effects: Adenosine has antiarrhythmic properties and is widely used for the rapid termination of supraventricular tachycardias (SVTs). It works by slowing down the electrical conduction through the AV node, interrupting the reentry circuits responsible for the SVTs. Adenosine can effectively convert SVTs like atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia back to normal sinus rhythm. 3. Blood Pressure Regulation: Adenosine can also modulate blood pressure by affecting the tone of blood vessels and the control of sympathetic nerve activity. It can cause a transient decrease in blood pressure due to its vasodilatory effects, particularly in the coronary arteries. However, adenosine-induced hypotension is usually short-lived and well-tolerated. 4. Antiplatelet Effects: Adenosine has been shown to inhibit platelet aggregation, which plays a crucial role in the formation of blood clots. By inhibiting platelet activation and aggregation, adenosine may have potential benefits in preventing thrombotic events in CVD, such as myocardial infarction and stroke. It is important to note that the pharmacology of adenosine can vary depending on the dose, route of administration, and individual patient characteristics. Therefore, it is essential to use adenosine under the supervision of a healthcare professional who can determine the appropriate dosage and monitor its effects closely.

Answer 128

CHD Coronary heart disease Thromboembolic disease: •Arterial thrombosis: Acute myocardial infraction Transient ischaemic attacks Cerebral vascular infarcts/ accidents CVA’s •Venous Thrombosis: Deep vein thrombosis DVT Pulmonary embolism PE •Inherited/Acquired thrombophilia

Answer 129

•Occurs as a result of rupture of atherosclerotic plaques •Platelet deposition and vessel occlusion •White thrombi

Answer 130

•Often occurs in normal vessels •Majority deep vein of leg •Red thrombi

Answer 131

CHD is a condition in which the vascular supply to the heart is impeded by atheroma, thrombosis or spasm. This results in reduction of blood flow to the heart, this results in ischaiema or lack of oxygen secondary to lack of blood supply, and has potential to damage cardiac muscle. This inadequate blood supply leads to decreases oxygen supply to the heart and this results ischaemic chest pain. IHD ischaemic heart disease and depending on extent can cause: Stable angina Acute coronary syndrome (MI + unstable angina) Sudden death

Answer 132

• About 4% UK population have symptoms of CHD • More common in males (until women reach menopause) & increase with age • About 124,000 AM| / year of which about 15-20% die • in UK, S. Asians have ~45% increase risk of death & Black African Caribbean have ~ 50% decrease risk

Answer 133

Atherosclerosis: Complex inflammatory process initiated due to injury or dysfunction of the endothelium. Increase permeability to oxidised lipoproteins these lipoproteins get taken up by macrophages in cell wall which then produce lipid laden foam cells this produces fatty streaks. This results in migration and proliferation of smooth muscle cells which secrete collagen, proteoglycans, elastin and glycoproteins which form a fibrous cap which known as plaque. This results in the narrowing of blood vessels within the heart and reduction in blood flow. These atherosclerotic plaques can rupture and cause complete blockage.

Answer 134

Main: Age, gender, FH, smoking, diet, obesity, HT, hyperlipidaemia. Others: DM, sedentary lifestyle, ethnicity, alcohol, stress.

Answer 135

For primary prevention Treat if 10% risk Of already have CVD then assessment not applicable, assume high risk and treat. CV risk assessment: QRISK3

Answer 136

Imbalance between oxygen demand and supply *Oxygen demand: HR, contractility, systolic wall tension *Oxygen supply: Coronary blood flow and oxygen carrying capacity of blood.

Answer 137

Stable angina Acute coronary syndrome (STEMI/NSTEMI/Unstable angina) Myocardial infarction

Answer 138

Narrowing of coronary arteries due to atheromatous plaques m. Chest pain typically provoked by exercise, stress, heavy meals or extremes of temperatur Relieved by rest by reducing the demand in the heart or s/l GTN Stable angina Pathophysiology is demand ischaemia Narrowed coronary arteries unable to meet increase in oxygen demand during exercise or stress

Answer 139

Central crushing chest pain May radiate to jaw, neck, back or arms Constricting, choking, heavy weight or stabbing, burning or like a knife. Induced by exercise etc and relieved by rest/GTN. Lack of ECG/ cardiac enzymes changes

Answer 140

Symptom control: Sublingual GTN for acute angina Antianginals: 1st line beta blockers, calcium channel blockers. Add on: long acting nitrate ( Isosorbide mononitrate dose —10 mg twice daily to 120 mg daily in divided doses. Isosorbide dinitrate dose — 30–120 mg daily in divided doses), ivabradine, ranolazine or nicorandil. Secondary prevention: Lifestyle changes ( smoking, weight, loss, diet, exercise) Anti-platelets aspirin Statins

Answer 141

Myocardial infraction (MI) ST elevated MI (STEMI) Non ST elevated MI (NSTEMI) Unstable Angina (troponin positive ACS).

Answer 142

History of ischaemic chest pain but sometimes it can be gastric chest pain ECG changes Increased cardiac enzymes production form damaged muscles which show in blood test results. First assessment 12 lead ECG identification of site of pain and what has occurred or changes occurring, Normal ECG shows P wave= contraction QRS= contraction of the ventricles T wave= represent relaxation of the ventricles ECG changes that occur in STEMI: ST elevated myocardial infarction This ST elevation is not seen in NSTEMI or unstable angina Other ECG changes aid differential diagnosis: STEMI: Left bundle branch block BBB NSTEMI: T wave inversion/ ST segment depression Q wave changes When cardiac events occurs either MI or unstable angina as a consequence of lack of blood supply to the cells in The cardiac muscles a number of enzymes are released when cardiac muscle is damaged these can be used a part of the differential diagnosis. Cardiac enzyme: Two isomers Troponin T and Troponin I (Trop I): Highly specific Released after 2-4hrs, peaks at 12 hrs and can persist up to 7 days. Measured on admission Standard Troponin assays- repeated after 10-12hrs High sensitivity Troponin assays Repeated after 3 hrs (enables early rule out of NSTEMI)

Answer 143

•STEMI/NSTEMI diagnosis in terms of rise of Troponin. >99th percentile cut-off/upper reference limit varies according to specific assay used. •Unstable angina leads to some change in Troponin level but deis not meet criteria for MI •<0.4ng/ml ACS unlikely •Size of rise equals size of infract

Answer 144

Pulmonary embolism Heart failure Myocarditis CKD Sepsis

Answer 145

•Creatine kinase CK: Peaks within 24hrs Normal within 48hrs Also in skeletal muscle and brain CK-MB cardiac specific isoform •Aspartate Transaminase AST and lactate dehydrogenase LDH Non specific Released from other parts of body Not used routinely LDH peaks at 3-4 days and remains high for up to 10days can be useful in late presentations

Answer 146

Differences between angina and heart attack? Angina: Narrowing of blood vessel increase in demand form heart where there isn’t enough blood supply atherosclerosis Myocardial Infraction: Formation of blood clot at the site of rupture of atheromatous plaque Thrombosis forms at site of rupture of the atheromatous plaque. Severe and prolonged ischaemia which results in the death of cardiac muscle cells and this releases enzymes such as troponin. STEMI= damage to full thickness of cardiac muscle. NSTEMI= damage to partial thickness of cardiac muscle.

Answer 147

Myocardial infraction and unstable angina Stable angina demand ischaemia Supply ischaemia vs demand ischaemia of stable angina Decreased Coronary blood flow and decrease in oxygen supply due to thrombus formation. This leads to partial blockage in unstable angina and complete blockage in (STEMI/NSTEMI) Thrombus forms as a result of plaque rupture and this leds to activation and aggregation of platelets.

Answer 148

Severe chest pain, sudden onset, often at rest and constant. 20% of AMI have no symptoms Silent MI’s more common in elderly and DM. Additional symptoms: Sweating Breathlessness Nausea ans vomiting Restlessness Pale Grey

Answer 149

Sudden deterioration in angina symptoms Often at rest, not relieved by rest or sublingual GTN. Unstable angina does not follow a pattern. It may be new or occur more often and be more painful than stable angina. Unstable angina can occur with or without physical exertion. Rest or medicine may not relieve the pain. Unstable angina is a medical emergency because it can progress to a heart attack. You may need medical attention right away to restore blood flow to your heart muscle.

Answer 150

Management of: STEMI NSTEMI unstable angina UA Acute/ immediate care Secondary prevention Differential diagnosis is important to accurately diagnose and treat conduction appropriately. Need to differentially diagnose different types of ACS as acute treatment is different for STEMI

Answer 151

1-Acute/immediate care: Pain relief, thrombolysis/reperfusion and minimisation of infract size. 2-Management of complications: Left ventricular heart failure of LVF, arrhythmias 3-Secondary prevention: Drug therapy and lifestyle changes Immediate treatment: Oxygen if indicated depending on oxygen saturation levels Relieves ischaemia Diamorphine: Pain relief Anxiolytic Vasodilatation Antiemetic eg cyclizine, metoclopramide as opioids cause nausea or vomiting. Aspirin: 300mg stat ASAP Clopidogrel or Ticagrelor or prasugrel 300mg stat (or 180mg or 60mg) surgical intervention is primary percutaneous coronary intervention (PPCI) this is necessary and must be done as it is first line management of STEMI. Or if PPCI not available Thrombolysis: reperfusion eg streptokinase, alteplase, tenecteplase, reteplase. “Call to needle time” 1 hour and “door to needle time” 30mins C/I: CVA recent surgery, peptic ulcer, uncontrolled HT, > 6 hrs since symptoms S/E: haemorrhage, stroke, reperfusion arrythimias, allergy (SK) antigenic b’ncl Heparin ( for first 4hrs after thrombolysis)

Answer 152

1-Arrhythmias 2-Heart failure Treat if they occur

Answer 153

Drug therapy: Antiplatelets (aspirin + clopidogrel/tricagrelor/prasugrel) Dual antiplatelets therapy DAPT for 12 months, Aspirin for life Beta blocker (review at 12 months continue if also heart failure) -ACEI -Statin Atorvastatin 80mg OD Lifestyle changes: smoking/weight loss/ diet/ exercise etc

Answer 154

Immediate: -oxygen -Diamorphine -Aspirin -Clopidogrel or Tricagrelor or Prasugrel -*Fondaparinux (inhibitor of factor-xa) prevents formation of new blood clots which can occur after NSTEMI or UA will be continued until chest pain is stable or controlled In NSTEMI No thrombolysis or PPCI FURTHER TREATMENT: Further treatment requirement depends on predication of 6-month risk of mortality/further CV events. Use GRACE (global registry of acute cardiac events) scoring system •If intermediate/higher risk >3% this could lead to angio and PCI •If low risk <3% conservative management (no angio/PCI)

Answer 155

Drug therapy: -Antiplatelets (aspirin + clopidogrel/tricagrelor/prasugrel) •Dual antiplatelets therapy DAPT for 12months, aspirin for life -Beta blockers (review at 12months continue if also heart failure) -ACEI -Statin-Atorvastatin 80mg OD •Lifestyle changes: weight loss, smoking cessation, diet/ exercise etc.

Answer 156

Angiography: Thin radiopaque tube (catheter) Introduced into coronary circulation X-ray contrast material injected into coronary artery via catheter. Angiography allows observation of severity of narrowing (stenosis) due to atherosclerotic plaque

Answer 157

Percutaneous coronary intervention PCI: Angioplasty: Balloon mounted on tip of very thin catheter inserted through obstruction and inflated. Restenosis common Stenting: Wire mesh inserted with balloon to keep stenosis open. Bare metal stent BMS or drug eluting stent DES. Elutes anti-proliferative drug (eg Tacrolimus, Paclitaxel) Stops overgrowth of stent by wall tissue. Stops over growth of stent by wall tissue. •Coronary artery by-pass graft (CABG) Both angioplasty and stents can damage vessel wall and increase blood clotting (in stent thrombosis) Long term aspirin and 12 months clopidogrel/Ticagrelor/ Prasugrel DAPT Drug eluting balloon: -Balloon covered with anti-proliferative drug eg Paclitaxel -Released into vessel wall during inflation -Lipophilic absorbed into vessel wall -Reduces restoensis -No problem of in stent thrombosis

Answer 158

Gold standard treatment of STEMI (instead of using thrombolysis) Better outcomes and less people contraindicated compared to thrombolysis Patient taken straight to angio suite for angio then angioplasty (with or without stenting) Clot is removed during procedure Call to balloon time 120mins Door to balloon time 30mins

Answer 159

Coronary artery by-passing grafting CABG Veins grafted to by-pass stenosis in coronary artery. ******************************** Coronary artery bypass grafting (CABG) is a surgical procedure used to treat coronary artery disease (CAD). In this procedure, veins or arteries from other parts of the body are grafted to bypass stenosis (narrowing) in the coronary arteries. Here's a brief overview of the procedure: 1. Indication for CABG: - CABG is typically recommended for patients with severe CAD who have significant blockages in their coronary arteries that cannot be effectively treated with medications or less invasive procedures like angioplasty. - It is commonly performed in patients with multiple or diffuse coronary artery blockages, left main coronary artery disease, or those with decreased heart function. 2. Procedure: - CABG is performed under general anesthesia. The surgeon makes an incision in the chest to access the heart and the blocked coronary arteries. - Veins or arteries, known as grafts, are harvested from other parts of the body, such as the saphenous vein in the leg or the internal mammary artery from the chest wall. - The graft is then attached (grafted) to the aorta (main artery leaving the heart) and to the coronary artery beyond the blockage, creating a new pathway for blood flow. - Multiple grafts may be used depending on the number of blocked arteries. 3. Recovery and Rehabilitation: - After the surgery, the patient is transferred to the intensive care unit (ICU) for close monitoring. They will typically spend a few days in the hospital before being discharged. - Recovery time varies, but most patients can expect to return to their normal activities within 6 to 12 weeks. - Cardiac rehabilitation programs are often recommended to help patients regain strength, improve cardiovascular health, and reduce the risk of future heart problems. 4. Benefits and Risks: - CABG can relieve symptoms of CAD, such as chest pain (angina), improve heart function, and reduce the risk of heart attack. - However, like any surgical procedure, CABG carries some risks, including bleeding, infection, blood clots, stroke, and complications related to anesthesia. - The choice between CABG and other treatment options should be carefully evaluated by a healthcare professional based on the individual patient's condition and risk factors. It's important to note that CABG is a major surgery and should only be considered after a thorough evaluation by a cardiovascular specialist. The procedure aims to improve blood flow to the heart muscle and alleviate symptoms of CAD.

Answer 160

Stroke CVA Cerebrovascular accident Stroke is defined as a clinical syndrome consisting of rapidly developing signs of focal disturbance of cerebral function, lasting for more than 24hrs or leading to death with no apparent cause other than vascular origin. Stroke is the unrelated term used to describe an event where the blood supply to part of the brain is disrupted. Strokes can be broadly classified into two categories; those cause by ischaemia (infraction) and those caused by haemorrhage (bleeding) and are therefore called ischaemic or haemorrhagic stroke. •Cerebral function The largest part of the brain, the cerebrum initiates and coordinates movement and regulates temperature. Other areas of the cerebrum enable speech, judgment, thinking and reasoning, problem-solving, emotions and learning. Other functions relate to vision, hearing, touch and other senses. Depending on the area and side of the cerebrum affected by the stroke, any of these functions may be impaired: Movement and feeling. Speech and language. Chewing and swallowing. •Hemorrhage is an acute loss of blood from a damaged blood vessel. The bleeding can be minor, such as when the superficial vessels in the skin are damaged, leading to petechiae and ecchymosis. •Clinical Features of Ischemia The term myocardial infarction reflects cell death of cardiac myocytes caused by ischemia, which is the result of a perfusion imbalance between supply and demand. Ischemia in a clinical setting most often can be identified from the patient's history and from the ECG. 85% if strokes are due to cerebral infraction 10% due to primary haemorrhage ICH 5% due to subarachnoid haemorrhage SAH Ischaemic stroke is 7-8 times more common than haemorrhagic stroke. It is preventable and treatable disease Ischaemic: disruption to oxygen supply to the brain Haemorrhagic: bleeding of blood vessel into the cerebral tissue of the brain. Brain cells need a constant supply of oxygen to function (blood supply) if this supply is cut off brain cells. Become damaged or die, this can lead to permanent brain damage or even death.

Answer 161

The brain is the most metabolically active organ in the body requiring an adequate oxygen supply to be able to function stroke symptoms occur if this supply is disrupted. Patients symptoms will different depending upon the area of the brain affected. Studies of Arterial anatomy and the brain territories supplied by the cerebral arteries to determine which vessels/areas or the brain are involved And the consequence of this on the patient. Therefore, strokes can be classified further by the vessels that they affect. The cerebral hemisphere are supplied by 3 paired major arteries-anterior (ACA), middle (MCA) and posterior (PCA) cerebral arteries. 1-ACA-supplies the medial portion of the frontal and parietal lobes and anterior portion of the basal ganglia. 2-MCA-supplies the lateral portions of the frontal and parietal lobes and lateral portions of the temporal lobes. It is the dominants source of vascular supply to the hemispheres. 3-PCA supplies the thalami, brainstem, posterior and the medial, temporal and occipital lobes. The cerebrum or forebrain is divided into to 2 halves the right and left cerebral hemispheres. The nerves that originate in the right hemispheres are responsible for the motor control of the left side of the body. Right side is associated with creativity, spatial tasks, imagination, body language, pattern recognition. The nerves originating int he left hemisphere are responsible for the motor control of the right side of body. This side of the brain is associated with: speech, language, analysis, interpretation. Frontal lobe function include: voluntary motor function, motivation, aggression, mood and behavioural traits and taste. Parietal lobe function include touch, temperature, pressure, and pain sensation reception and evaluation and object recognition. Temporal lobe functions include: evaluating auditory and olfactory input and an important role in memory, throught and judgment. Occipital lobe function include: reception and integration of visual input ( colour, shape, and distances).

Answer 162

A primary haemorrhagic stroke occurs when a blood vessel bleeds into the deep cerebral tissue of the brain, intracerebral haemorrhage (ICH), whereas a Subarachnoid haemorrhage SAH occurs when a blood vessel on the surface of the brain ruptures and bleeds into the subarachnoid space.

Answer 163

Defined as the acute loss of focal cerebral or ocular function with symptoms lasting less than 24hrs. The symptoms of a TIA usually resolve within minutes or a few hours at most. All cerebrovascular events need to be taken seriously and treated with urgency. TIAs don’t cause permanent brain damage. However they are important because they are often a warning sign for a stroke. TIAs are mini strokes bloood supply temporarily impaired.

Answer 164

Stroke is the second leading cause of death worldwide wide. There are more than 100,000 strokes in the uk 6.2% and 4th highest cause of death. Incidence of stroke increases with age Men are at a higher risk than women Ethnicity Black people are almost twice as likely to have stroke as white people. Morbidity/economic impact: 1.2million strokes Third if survivors will experience depression, two thirds of stroke survivors leave hospital with a disability. TIAs estimated to affect 50 people per 100,000 of population each year. TIA is associated with very high risk of stroke within first month after event and up to 1 year afterwards. Systemic review has highlighted that risk of stroke at 2days was 2.1% SAH affects 6-12 people per 100,000 of population per year. Risk factors: High blood pressure High cholesterol Diabetes Age High alcohol intake Smoking

Answer 165

Hypertension Sex male risk greater than females Advanced age more likely in over 65 years. Smoking Previous stroke/TIA Illicit drug use Diabetes mellitus Cardiac disease Ethnicity south Asian, African or Caribbean increased incidence Risk factors for thrombosis Hypercholesterolaemia Carotid stenosis Physical inactivate Excess alcohol Fibromuscular dysplasia Family history of TIA or stroke Obesity Genetic predisposition (In ischemic stroke, the damage is caused by a lack of blood supply, while in hemorrhagic stroke, it is caused by bleeding into the brain tissue)

Answer 166

Hypertension Sex male Advanced age Smoking Previous history of TIA or stroke Illicit drug use Diabetes mellitus arrhythmia and valvular disease Use of anticoagulants increased risk of bleeding Risk factors for thrombosis

Answer 167

Atherosclerosis Cardiac or carotid emboli Aterial stenosis Hyper-coagulable states Arterial dissections Vasoconstriction associated with substance misuse Hypotension Hypertensive haemorrhage Hypoxia

Answer 168

High BP Vessel abnormalities Head injury Bleeding disorders Vasculitis Excessive anticoagulation Cocaine or amphetamine use Amyloid angiopathy

Answer 169

Aneurysm (cogential or due to chronic high BP) Arteriovenous malformations Head injury An aneurysm is an abnormal swelling or bulge in the wall of a blood vessel, such as an artery. Aneurysms can occur anywhere throughout the circulatory system, but most commonly develop along the aorta (the body's main artery that runs the length of the trunk) and in blood vessels of the brain.

Answer 170

AF is the most common sustained cardiac arrhythmia resulting in haphazard generally rapid atrial contraction. In a normal heart beat the atria communicates with the ventricles ( via the atrioventricular node) to ensure subsequent contraction to eject blood from the heart. However in AF only a few pulses pass through to the ventricles leading to irregular and incomplete (varied forces) contraction. Turbulent flow and blood stasis in the heart increase the risk of emboli formation. Probable that any stroke occurring in these individuals has been caused by formation of a thrombus within the heart. Atherosclerosis is another major underlying process involved in the development of a stroke. The concept of blood stasis was considered that it is stagnant blood within the body, which has lost its physiological function, and a pathological product as well as a pathogenic factor that causes organ dysfunction from the results. (THROM-bus): A blood clot that forms on the wall of a blood vessel or in the heart when blood platelets, proteins, and cells stick together. A thrombus may block the flow of blood. Emboli: A blood clot, air bubble, piece of fatty deposit, or other object which has been carried in the bloodstream to lodge in a vessel and cause an embolism.

Answer 171

1-Arterial thrombosis: This type of stroke occurs when a thrombus forms in one of the arteries that supply the brain with blood and oxygen. This is commonly caused by atherosclerotic plaques within the vessels. 2-Arterial embolism: This type of stroke occurs when a thrombus or other debris forms/accumulates at a site away from the brain. This or part of it, may be dislodged and travel to the brain. In this case the causative occluding body is called an embolus. AF is an example of a condition that causes cardiormbolic stroke. *The blockage can occur within the extra- or intra cranial vasculature (vessels outside the skull and those within at the base of the skull). Both the scenarios can prevent passage of blood (containing nutrients and oxygen) to the area of brain tissue around and beyond the infract. This causes a central core of cells to die. Areas peripheral to the infract, where there is reduced or marginal perfusions are termed the ischaemic penumbra; this tissue can remain viable for several hours. Therefore, the aim of treatment is to preserve as much tissue as possible and restore blood flow to as much of the penumbra as possible. •The size of the embolus dictates which size vessel it will occlude, the larger the embolus the larger the vessel it will affect and the greater impact it will have on the brain and the brain function. Small emboli will block smaller vessels and have a smaller impact on brain function. In some cases where embolus is small and there are other vessels feeding the same area (collateral circulation) there may be minimal damage to the brain tissue and a decreased physiological change for the patient. The position of the thrombus or eventual position of the embolus will dictate the types of brain functions that are affected. Complications haemorrhagic transformation up to 6% of ischaemic stroke patients will sustain asymptomatic haemorrhagic transformation (will also suffer a brain haemorrhage) and more will have asymptomatic bleeding. This is more likely following cardio-embolic stroke or those with larger infract size.

Answer 172

Pathological processes occurring at the ischaemic core are extremely complex and still being researched. 1-Neuronal cells swell due to impaired metabolism and cellular depolarisation (caused by depleted ATP). 2-Impairment of the sodium calcium exchange causes calcium influx leading to release of neurotransmitters. 3-Other neurones become depolarised due to their release with increasing calcium influx. 4-The abnormal calcium Influx activates various degradative enzymes leading to the destruction of the cell membrane and other cellular components. 5-Substances generated int his process (free radicals, Arachidonic acid, and nitric oxide) lead to further neuronal damage. 6-Breakdown of the blood brain barrier ( with 4-6hours of infraction) lead to further oedema. 7-Death of supportive brain cells also occurs. 8-Eventually tissue undergoes necrosis and is removed by macrophages.

Answer 173

Weakened arteries burst and release blood into the surrounding brain tissue. This increases the pressure in that area of the brain and causes the release of excitatory amino acids and the infiltration of immune cells. The area served by the damaged vessel has its blood supply compromised leading to increased damage to the brain tissue. Complications haematoma formation, increase intracranial pressure ICP, hydrocephalus, compression, can damage the surrounding brain area.

Answer 174

An artery on or near the surface of the brain bursts and releases blood into the subarachnoid space between the brain and the skull. SAH results in elevated intracranial pressure and impairs cerebral autoregulation. These effects can occur in combination with acute vasoconstriction, micro vascular platelet aggregation and loss of micro vascular perfusion, resulting in a profound reduction in blood or and cerebral ischaemia. Complications-haematoma formation, hydrocephalus, compression.

Answer 175

Area of brain affected Extent of the damage Patients underlying health Symptoms Alone are not specific enough to distinguish ischaemic stroke from haemorrhagic stroke. Generalised symptoms such as: nausea, vomiting, sudden onset headache and altered level of consciousness (non-focal neurological symptoms) may indicate increases ICP and are therefore more common in haemorrhagic or large ischaemic strokes. Seizures are more common in haemorrhagic stroke occurring in up to 28% of patients either at the onset or witihin 24hours of the event. *Focal Symptoms of ischaemic stroke include: 1-Weakness or paresis that may affect a single extremity (monoparesis) one half for the body hemisphere or rarely all four extremities (quadraparesis) 2-Hemisensory deficit loss of sensation in one side of the body. 3-Facial droop unilateral sagging of the face which indicates paranoid facial muscle or effect on the facial nerve 4-Monocular or binocular blindness affecting the sight in one or both eyes. 5-Blurred vision and or visual field deficits loss of some aspects of sight 6-Dysarthria and trouble understanding speech difficulties in articulating words due to difficulties in coordinating the muscles used in speech. 7-Vertigo sensation of rotation or movement of oneself or surroundings 8-Ataxia failure of muscular coordination or irregularity or muscular action. 9-Aphasia partial or total loss of the ability to communicate verbally or using written words. The patients may have difficulty speaking, reading, writing and recognising the names of objects.

Answer 176

Stroke is a medical emergency *FAST Face Arm Speech Time Screening tools-Clinical guidance 1- FAST recognition 2-Specialist stroke unit 3-Physical examination, imaging and blood tests Patient with ongoing neurological symptoms who have a positive FAST or negative FAST but where stroke is strongly suspected should be transferred to a hospital with acute stroke unit. There is a strong evidence in favour of specialist stroke unit care to deliver effective acute treatment that reduces long term brain damage and disability if given within few hours. From the recognition of neurological symptoms patient should be made nil by mouth NBM. Screening of a patients swallow will occur during admission (within 4hr of admission) by trained staff SALT speech and language therapist. No fluid, food or medication should be given orally until assessment has occurred. Until a safe swallowing method is established, patients should be: 1-Considered for alternative fluids, 2-Be considered for nasogastric tube feeding within 24hours, 3-Be referred to a dietician for assessment, advice and monitoring, 4-Have a comprehensive specialist assessment of their swallow, 5-Receive hydration, nutrition and medication by alternative means. Stroke patients require SALT assessment and should be made NBM due to risk of food/ fluid aspiration Need to check if they can swallow properly and to detect if they have dysphagia. Patient with an acute onset if neurological syndrome with persisting symptoms requires a full diagnosis to differentiate between an acute cerebrovascular cause and other causes. In A&E this should be conducted by ROSIER recognition of stroke in the emergency room- a scale used to establish the diagnosis if stroke or TIA. Factors assessed include blood pressure, glucose concentration; loss of consciousness and seizure activity; physical assessment including facial weakness, arm weakness, leg weakness, speech disturbance and visual field defects. *brain imaging MRI or CT: Immediate scanning is most cost-effective strategy imaging enables identification of the presence of a haemorrhage or ischaemic infract and the extent of cerebral damage (core and penumbra) and aetiology as this will dictate treatment. *NICE RECOMMENDATIONS: Brain imaging immediately if any of the following applies: Indication for thrombolysis or thrombectomy Anticoagulation treatment Knowing bleeding tendcy Depressed level of consciousness use GCScale Unexplained progressive or fluctuating symptoms Papilloedma, neck stiffness or fever Severe headache at onset of symptoms For all other circumstances imaging should be carried out within as soon as possible but within 24hrs. *•-Carotid Doppler: This non-invasive test using sound waves to measure the flow of blood through the carotid arteries which supply blood to the brain. It’s used to identify narrowing of these arteries. In some specialist stroke unit this will be preformed after the MRI/CT to decide whether surgery is appropriate. *Additional tests (underlying causes of stroke ie heart disease, diabetes, hypertension require determination/diagnosis/exclusion as the cause of symptoms. 1-Blood glucose BM: To determine whether the symptoms are related to a hypoglycaemic episode, this can present with similar symptoms and requires specific treatment. 2-Clotting (APTT, PT, and INR) to determine whether there is any underlying bleed risk which may be a causative factor in the presentation or dictate treatment. 3-ECG to determine whether the patient is suffering with any type of arrhythmia which could be the cause of the stroke. 4-Fasting lipids to determine the likelihood of atherosclerosis. 5-Blood culture to determine the presence of an infective cause. 6-Full blood count FBC may reveal a cause if the stroke (ie thrombocytosis, polycythaemia, leukaemia, thrombocytopenia). 7-Urea and electrolytes (U&E) baseline study to determine whether there are any other likely cause of the symptoms like hyponatraemia or evidence of concurrent illness ie renal impairment. *•-Physical examination: Used to determine the area and extent of damage to the brain and includes: Cranial nerve examination Motor function examination Sensory function Cerebellar function Gait Deep tendon reflex Language (expressive abs receptive capabilities) Lumbar puncture (removal and examination of cerebral spinal fluid to rule out meningitis or SAH) TIA: For patients whose symptoms resolve quickly ie TIA patients there is an increased risk that these patients will develop a stroke. CT brain scanning should not be used unless there is a clinical suspicion (symptoms or history that indicate it is not a TIA) of an alternative diagnosis. Patients will be assessed by a specialist physician who will make the decision whether imaging is required or not. Scans will be carried out if; The area of the brain affected is unknown, the cause if the symptoms is unknown, to detect haemorrhage, those on anticoagulation when scanning should be immediate or if these factors will influence treatment. *dependent on the area of the brain affected, may dictate a patients treatment ie carotid surgery.

Answer 177

Aims of treatment: •To maintain/improve vascular perfusion of the brain •To prevent further deterioration of neurological symptoms by preventing the advancement of the penumbra (area peripheral to infraction with reduced blood flow) Patient centred care: treatment and care should take into account people’s needs and preferences, informed decision on care and treatment. All patients based in initial assessment should be admitted to a specialist stroke unit. Acute phase care: From the time of onset of symptoms and covers the first 24hours and up to 7days depending on the severity of the disease; for most people this stage is over in approximately 3days. 1-Immediate management: Urgent treatment has been shown to improve the outcome in stroke. Once the patient has a diagnosis of ischaemic stroke, the most appropriate urgent treatment for that patient can be decided: •Thrombolysis use of drugs such as alteplase, to break up a clot. Unless contraindicated or outside of its marketing authorisation, Alteplase is recommended for treating ischaemic stroke. Its use should only be undertaken in units A&E where staff are trained and experienced in its provision and monitoring where imagine has occurred to confirm the differential diagnosis of ischaemic rather than haemorrhagic stroke. Treatment should be given as soon as possible after the onset of stroke. The benefits of treatment quickly finish with time and beyond 4.5hrs are unproven. *The licensing for use of thrombolysis Altepase refelects this: Treat as early as possible within 4.5hrs of known symptom onset for those who have been shown to not to have an intracerebral haemorrhage or other contraindications. *After 24hrs all patients who have undergone thrombolysis should be started on an antiplatelets (unless contraindicated). Contraindications: Significant bleeding disorder Taking anticoagulants Recent or manifest severe/dangerous bleeding Suspected uncontrolled hypertension Major surgery or trauma in last 3months Any history of CNS damage eg Aneurysm, intracranial or bacterial endocarditis/pericarditis or spinal surgery. Ulcerative colitis GI disease Severe liver disease Acute pancreatitis Evidence of intracranial haemorrhage ICH seen in CT scan If symptoms suggest SAH even if CT is normal. Severe stroke Minor neurological deficits if rapidly improving symptoms. Prior history of stroke and diabetes Last stroke within last 3months Platelet count below 100,000mm3 SBP > 185 or DBP>110 Blood glucose <2.8mm if >22.2mm Administration if heparin within 48hrs and thromboplastin have upper limit of normal. *•-Common side effects: Haemorrhage (ICH major adverse reaction in treatment of ischaemic stroke) Includes: ICH GI haemorrhagic Urogenital haemorrhage Site of injection haemorrhage Pharyngeal haemorrhage Ecchymosis Decision to thrombolyse a patient will be a clinical decision based on the individual patient characteristics and comorbidities. Alteplase use outside of the 4.5hours is unlicensed. *Thrombectomy (Thrombectomy involves using a specially-designed clot removal device inserted through a catheter to pull or suck out the clot, to restore blood flow.) for people with acute ischaemic stroke and have occlusion if the proximal anterior circulation. As soon as possible and within 6hrs of symptom onset. With intravenous thrombolysis (if not contraindicated and within the licensed time window) Or thrombectomy should be offered to those patients with acute ischaemic stroke, have occlusion of the proximal anterior circulation and who were last known to be well between 6hrs and 24hrs. Potential to salvage brain tissues where imaging has shown a small core area and therefore the surrounding area may be able to re-perfused if clot is removed. Take into account patients co-morbidities, functional status prior to the stroke. *•-Anti-platelets: All patients with acute stroke, where primary intracerebral haemorrhage has been excluded by brain imaging, should receive: Aspirin 300mg OD for 2 weeks. For patients that been thrombolysed the aspirin should be started 24hrs after alteplase treatment unless contraindicated. For patients that have not been thrombolysed, aspirin should be started ASAP but within 24hrs. Aspirin should be given orally if the patient is not dysphagic or rectally/ via NG tube if the patient is dysphagic. At the 2 week point long term antithrombotic treatment should begin. If patients are discharged prior to completion of the initial 2week their long term treatment can be started earlier at the time of discharge. For patients whom previous dyspepsia associated with aspirin has been reported a proton pump inhibitor eg lansoprazole can be given in addition to aspirin. Patients with ischaemic stroke who are allergic or genuinely intolerant of aspirin should be given an alternative antiplatelet agent eg clopidogrel. *•-Lipid management Immediate initiation of statin treatment is not recommended in people with acute stroke. However those who were already receiving statins should continue their statin treatment. Maintenance of homeostasis: Key element of care for patients with acute stroke is the maintenance of cerebral blood flow and oxygenation to prevent further brain damage. Supplemental oxygen, maintenance of normoglycaemia and blood pressure manipulation are considered below: Supplemental oxygen: stroke patients should only receive supplemental oxygen if their oxygen saturation drops below 95%. Blood sugar control: stroke patients should be treated to maintain a blood glucose concentration between 5 and 15mmol/L right control has not been shown to improve outcome in stroke patients. Blood pressure control post stroke remains an area where there is little evidence to guide care. Excessive or too rapid reduction of blood pressure may compromise cerebral blood flow and lead to development of penumbra (death of brain tissue). Elevated BP in acute phase following ischaemic injury is common however in most patients this resolves on its own after 4-10days. However continued or excessively high blood pressure is associated with the development of oedema and haemorrhage. Immediate treatment of hypertension following an acute stroke is only recommended if there is a hypertensive emergency with one or more of the following medical issues: Hypertensive encephalopathy Hypertensive nephropathy Hypertensive cardiac failure/MI Aortic dissection Intracerebral haemorrhage with systolic blood pressure over 200mmHg Pre-eclampsia/eclampsia Where a reduction in blood pressure is required (as above, plus prior to thrombolysis (where the target BP is = 185/110mmHg oral either by mouth or NG tube) or parenteral therapy may be used. For example: Calcium channel blockers eg amlodipine Parenteral beta blocker eg Labetolol. In practise blood pressure is allowed to run high be slightly raised for at least the few first day to ensure adequate perfusion. For stroke patients: those admitted already taking anti hypertensive therapy- treatment can be safely withheld until patients are medically and neurologically stable and have suitable oral or enteral intake.

Answer 178

The risk of patients having recurrent stroke is 26% within 5yrs of the first stroke and 38% by 10yrs. Risk of vascular event is highest after a TIA or stroke; 25% risk with the first 3 months half of which is within the first 4-days. Additional risks of other vascular events ie myocardial infraction. Secondary prevention should be started at soon as possible as this significantly reduces the risk of recurrent events. All patients with stroke or TIA should get a comprehensive and personalised strategy for vascular prevention including medication and lifestyle factors, this should be implemented asap and continue long term with review and monitoring occurring in primary care at least once a year. *•-Blood pressure: Treatable risk factor of stroke and is estimated to cause about 50% of ischaemic strokes. Relationship between blood pressure and cerebral perfusion pressure means that changes to BP in acute stroke may influence the extent of brain damage. Treatment recommendations differ when considering the acute setting and long term secondary prevention. The PROGRESS study demonstrated that blood pressure reduction after stroke or TIA (using 2 different anti-hypertensive) prevented further vascular events. Normotensive patients, a reduction in blood pressure (of 12/5mmHg) resulted in 42% reduction in recurrent stroke and 35% fewer major coronary events. Meta-analysis found BP lowering treatment significantly reduced cardiovascular events and deaths. Overall 10mmHg reduction in systolic BP reduced the risk of the cardiovascular disease by 20% and stroke by 27%. Recommended target blood pressure <130mmHg patients with TIA or stroke should have their BP and treatment should be started or increased to achieve a clinic systolic of <130mmHg. Initiation BP lowering treatment for stroke and TIA patients should be initiated prior to the transfer of care out of hospital or at least 2 weeks. Control/monitoring: monitoring should occur frequently and dose increased to achieve a target BO as quickly as tolerated and safe. Treatment choices: 55years or over African or Caribbean patients of any age: First line dihydropyridine calcium channel blocker or where this is ineffective add: Angiotensin converting enzyme inhibitors or angiotensin-II receptor blocker or thiazide-like diuretic. Not African or Caribbean origin or younger than 55 years of diabetic any age: first choice angiotensin converting enzyme inhibitor or angiotensin-II receptor blocker. If this is not effective add dihydropyridine calcium channel blocker if thiazide like diuretic. The PROGRESS trial demonstrated the benefits of 2 anti-hypertensive drugs an ACE inhibitor and thiazide diuretic (perindopril and indapamide) *•-Long term use of antiplatelets: For long term vascular prevention in people with ischaemic stroke or TIA without atrial fibrillation. The antithrombotics trialists. CAPRIE, ESPIRIT, PRoFESS comparative studies show that aspirin plus modified release dipyridomole and clopidogrel mono-therapy are equally effective and both superior to aspirin mono-therapy. Recommendations for STROKE: Treatment first line clopidogrel 75mg OD. Second line when clopidogrel contraindicated is Aspirin 75mg OD plus modified release dipyridamole 200mg BD. Third line when clopidogrel and aspirin or dipyridamole are contraindicated, aspirin or modified release dipyridamole mono-therapy. *•-Lipid management Raised lipid levels, especially hypercholesterolaemia is a risk factor for atherothrombotic events especially MI. Lowering these levels is effective in primary and secondary treatment of vascular events, including stroke. The heart protection study HPS looked at effects of Simvastatin 40mg OD in individuals at high risk of CV events and showed 17% reduction in vascular deaths, 27% in coronary events and 25% in stroke. SPARCL investigated effect of atorvastatin 80mg OD in patients with TIA or Stroke within 6 months and demonstrated a relative risk reduction of 15% in stroke and 35% in major coronary events. Lipid lowering lipoproteins LDL cholesterol by 1mmol/L reduces the relative risk of major vascular events by 21% and total mortality by 9% and stroke by 15%. Therefore, the decision to initiate treatment should be determined by their Cardiovascular risk rather than their cholesterol levels. *Risk with statins a number of studies have shown an increase in the risk of haemorrhagic stroke with the initiation of statin therapy. This helps to explain why statins are not introduced in the immediate acute period first 48hrs. Patients should be offered advice on lifestyle factors that may modify lipid levels (diet, physical activity, weight, alcohol and smoking? Patient who have had a stroke should be offered treatment with a statin unless contraindicated. Begin with a high intensity statin (atorvastatin 80mg) change to an alternative statin at maximum tolerated dose if high intensity statin is unsuitable or not tolerated. NICE lipid modification advised a target of >40% reduction in non-HDL cholesterol. *•-Anticoagulation: Anticoagulations should be started for patients with confirmed ischaemic stroke who have had a cardioembolic stroke, particularly in AF atrial fibrillation, AF. Anticoagulantions are not more effective than Antiplatelets therapy in people with non cardioembolic ischaemic stroke or TIA and carries a greater risk of bleeding. 12% attributes risk of recurrent stroke per year associated with AF which for most patients tips the risk benefit balance in favour of anticoagulation. •The CHA2DS2-VASc assessment tool is used to assess stroke risk in patients with AF. One or two points are awarded to the patient based on each characteristics of this tool. The value is used to guide whether the risk is high and if anticoagulants should be started. A value of 1 for man and 2 for woman indicates anticoagulation should be started. C congestive heart failure H hypertension A2 age >75 =2points D diabetes mellitus S2 prior to stroke or TIA (2points) V vascular disease A age >65 Sc sex female 1point •ORBIT assessment tool is used in conjunction with CHA2DS2VASc score to estimate the risk of major bleeding for patients on anticoagulations for AF. Dependent on the number of points awarded the risk of bleeds per year can be estimated. This helps guide the decision whether anticoagulation should be started. ORBIT: Hb haemoglobin <13g/dl female 2points Age >74 1point Bleeding history GI/intracranial/haem stroke (2points) Renal function eGFR<60ml/min/1.73m2 1point Antiplatelets treatment (1point) Using the value from ORBIT a clinical decision must be made as to whether anticoagulation should be used or not (unlike the CHA2DS2VASc score there are no threshold value to guide this decision, however an ORBIT score of 0-2 is considered low risk, 3 medium risk and 4-7 high risk of bleeding). If despite addressing modifiable risk factors for bleeding the risk of bleeding is still too high; aspirin is not regarded as a safer option. •When to start anticoagulation: medical team should base their decision on RISK of HAEMORRHAGIC transformation (the risk is increased with increasing size of infract and occurs in around 6% of stroke patients) and the risk of further infracts as a result of AF. Patients with severe disabling strokes should be deferred from anticoagulants treatment till at least an arbitrary 14days post onset. They should receive 300mg until this time. The larger the infract, the greater the risk of haemorrhagic transformation. Patients with less significant, non disabling infracts should should be deferred for an interval at the discretion of the prescriber but no later than 14days. *Warfarin: Contraindications avoid use within 48hrs in postpartum, haemorrhagic stroke, significant bleeding. Cautions do not use during first trimester of pregnancy, all women of child bearing age should be warned of teratogenic. If possible avoid on pregnancy, peperic ulcer, GI bleeds, hypothyroidism, hyperthyroidism, uncontrolled HT. Side effects: Haemorrhage (common), alopecia, nausea, vomiting. Monitoring: Baseline prothrombin time should be determined. Daily monitoring of INR during early day of treatment then larger intervals then every 12weeks in severe renal impairment monitor more frequently. Direct Oral Anti-Coagulant DOAC Factor Xa inhibitor or direct thrombin inhibitor Dabigatran Rivaroxaban Apixaban Edoxaban DOACs: Contraindications: avoid if creatinine clearance <15ml/minute Risk of bleeding Active bleeding Recent brain/spinal injury Use with other anticoagulants stop before administering a new anticoagulant to prevent risk of over anticoagulants and bleeding. Cautions avoid in pregnancy and breastfeeding Avoid in hepatic diseases with coaguopathy and bleeding eg moderate severe cirrhosis. Caution if creatinine clearance is 15-29ml/minute body weight <60kg. Side effects: common- anaemia, haemorrhage, hypotension, headache, nausea, vomiting and wound complications. Monitoring: No routine anticoagulant monitoring required patients should be monitored for signs of bleeding or anaemia stop treatment if severe bleeding occurs. *•-NICE NG196 atrial fibrillation: diagnosis and management, last updated April 2021 recommends use of a DOAC as first line for secondary stroke prevention for people with non valvular AF. Warfarin is second line when DOACs are contraindicated not tolerated or not suitable. Current DOAC recommendations is dependent upon their specific characteristics ie side effects profile, cautions. The DOAC have a rapid onset of action, have fewer interactions with other drugs and food and don’t require regular coagulation monitoring. 3 studies RELY, ROCKET-AF and ARISTOTLE have demonstrated a more effective stroke prevention with reduced intracranial bleeding compared to Warfarin. No significant differences seen in relation to major and GI bleeding risk. Quality of warfarin anticoagulation is determined by the time in therapeutic range TTR the time that a patient on warfarin is maintained at the desired therapeutic range;average in uk 72%. Warfarin monitor INR INTERNATIONAL NORMALISED RATIO; is a measure of the time taken for blood to clot (expressed as a ratio against population data, the higher the number the greater time the blood will take to clot. Advantages and disadvantages of Warfarin: Used for many years, antidote available, requires regular INR monitoring efficacy/compliance monitoring. Many food and drug interactions, requires loading to be therapeutic, requires INR monitoring which is costly and time consuming. Advantages and disadvantages of DOACs: Rapid onset no loading required, coagulation monitoring not required, predictable anticoagulant effects, fewer interactions with with drugs and no known food interactions compared to warfarin, fixed dosing. But disadvantages relatively new to market, unable to monitor efficacy/compliance, short lived half life meaning missed doses could leave patients unprotected, only for use in patients with creatinine clearance greater than 30ml/min *Idraucizumab antidote for dabigatran limited use. Andexanet antidote for apixaban, edoxaban, rivaroxaban and other antidotes in trials. Increased cost Long term adverse effects unknown. ********************************* For patients with ischaemic stroke or TIA and AF anticoagulation should be the standard long term antithrombotic treatment, It should not ge given till haemorrhage has been excluded by imaging. It should be given to those with uncontrolled hypertension. For those with disabling ischaemic stroke, imitation should be deferred until at least 14days form onset-aspirin 300mg should be used in the meantime. For those with non disabling ischaemic stroke initiation should be deferred for an interval at the discretion of the prescriber, put no later than 14days from onset. ****Anticoagulation for those with TIA or ischaemic stroke should be with either: A direct thrombin or factor Ca inhibitor Or Warfarin adjusted to an INR of 2.5 range 2-3 with a target time in the therapeutic range greater than 72%. (Direct thrombin inhibitors inactivate thrombin in an antithrombin-independent fashion. Unlike heparin, they can inactivate thrombin that is bound to fibrin. Examples include hirudin (lepirudin), bivalirudin, and argatroban.)

Answer 179

Initial management of suspected time or confirmed TIA: To reduce the risk of having a stroke Give aspirin 300mg OD immediately unless contraindicated. Refer for specialist investigation/assessment within 24hours if the onset of symptoms. Once diagnosis is confirmed: Clopidogrel monotherpay (300mg STAT) followed by 75mg OD thereafter) •Secondary prevention should be introduced: Hypertension control High intensity statin therapy (atorvastatin 80mg) Discussion of individual risk factor management. *•- Surgery patients with suspected TIA assessed by medial team may undergo carotid imaging to determine the amount of stenosis in the carotid vessels if indicated. Following this, for those in which it is indicated a CAROTID Endarterectomy may be carried out. Those with symptomatic carotid stenosis-50-99% referred for urgent endarterectomy plus best medication treatment (BP control, cholesterol lowering, lifestyle advice) those with less than 50% no surgery but best medical treatment plan. * Carotid endarterectomy is a surgical procedure used to treat carotid artery disease, which involves the buildup of plaque in the carotid arteries that supply blood to the brain. Here's a step-by-step overview of the procedure: 1. Anesthesia: The patient is given either general anesthesia (puts the patient to sleep) or local anesthesia with sedation (numbs the area and keeps the patient relaxed). 2. Incision: A small incision is made in the neck, usually along the side of the affected carotid artery. 3. Artery clamped: The surgeon carefully clamps the carotid artery above and below the area where the plaque is located. This temporarily stops the blood flow through the artery. 4. Plaque removal: The surgeon makes a small incision in the artery and carefully removes the plaque from the inner lining of the artery, using specialized tools. This process is called endarterectomy. 5. Patch angioplasty: After the plaque is removed, the surgeon may use a patch to widen and strengthen the artery. The patch is sewn onto the artery, reinforcing the weakened area and restoring normal blood flow. 6. Blood flow restoration: Once the plaque is removed and the artery is repaired, the clamps are released, and blood flow is restored to the brain. During the procedure, a shunt may be used to temporarily bypass blood flow around the clamped area of the artery. This ensures that the brain continues to receive adequate blood supply while the surgeon works on the carotid artery. It's important to note that carotid endarterectomy is a complex surgical procedure and should only be performed by experienced vascular surgeons. The decision to undergo this procedure is based on a careful assessment of the individual's medical condition and the risks and benefits associated with the surgery. Additional considerations: Where AF is identified to be the cause of the TIA, anticoagulation therapy, with an agent with rapid onset should be given immediately once haemorrhage is excluded. Other management strategies for stroke and TIA patients: Lifestyle measures: Lifestyle changes are as important in secondary prevention as they are in primary prevention. Eg smoking cessation, physical activity, improved dietary intake. Stroke and TIA patients should be advised to stop immediately using appropriate individualised interventions. •Rehabilitation centre Complete and relevant information transfer from secondary to primary care. Supported discharge to deliver stroke specialist rehabilitation at home or in a care home. Specialist follow up at 6-months and annually after a stroke including review and monitoring of risk factors, GP support and social services. Mental health after stroke all patients should be screened to Identify mood disturbances and cognitive impairment. End of life care 1 in 20 acute stroke patients will receive EOL within 72hrs as 1in7 die in hospital. This is core activity for MDT.

Answer 180

Mechanism of blood clotting: Haemostasis- the arrest of blood loss from damaged blood vessels, a process which is essential to life. Damage to a blood vessel causes vasoconstriction plus adhesion and activation of platelets to form a plug and formation of fibrin (reinforcing network) to stop the bleeding. Thrombosis is the formation of haemostatic plug in the vasculature without the presence of bleeding. •Arterial thrombus consist mainly of platelets and is usually the result of atherosclerosis. •Venous thrombus consist of a small white head (platelets) and large red tail (RBC). A thrombus can break away form primary site and travel to a secondary sit in which cause it is termed embolus. Venous emboli usually lodge in the lungs whereas arterial emboli affect other organs such as the brain or heart. •Blood Coagulation is a complex process involving many different factors working together, these include clotting factors, vessel endothelium and blood components such as platelets. Coagulation cascade this process sees the formation of a gel/solid form of blood. Each of the components of clotting cascade are called factors and are found in the blood as inactive precursors of proteolytic enzymes and co-factors (active forms are denoted by a) each factor in turn activated another down cascade and amplifies the downstream effects. 2 pathways for fibrin formation and stabilisation: extrinsic (some of the components come from outside of the blood vessels) and intrinsic (all components are present within the blood vessel wall). Atherosclerotic plaque rupture culminates in the formation of a thrombus. Adhered and activated platelets provide co-factors and expose phospholipids important in activating the clotting cascade. Prothrombotic factors are synthesised and stored in endothelium eg Tissue Factor. Both pathways converge on the activation of factor X and have a shared final ending with the last enzyme thrombin, derived from prothrombin II, converting soluble fibrinogen to an insoluble meshwork of fibrin in which cells and platelet become trapped. *•-•*Platelets activation: When platelets are activated, the undergo a sequence of reactions essential for haemostasis, healing and inflammation. Eg: Adhesion-to areas of vascular damage via the glycoprotein 1b receptors in the platelets. Shape changes-the smooth disc structure changes to spiny spheres to enable entrapment within the fibrin mesh. Secretion of platelet agonists ADP and coagulation factors to further activate other platelets factors and the clotting cascade. Biosynthesis of factors such as TXA2 and platelet activating factor responsible for platelet aggregation and vasoconstriction. Aggregation agonists lead to expression of GPIIb/IIIa receptors that bind fibrinogen linking adjacent platelets. Phospholipids exposures-promote thrombin formation. However, this pathway may be inappropriately activated eg when an artery wall is diseased via atherosclerosis resulting in appropriate thrombosis. There are also physiological mechanisms for inhibition/reversal of the clotting system, the fibrinolytic system. Endogenous plasminogen activators, for example, tissue plasminogen activator t-PA is released and diffuses into a thrombus where plasminogen is deposited on the fibrin strands. The t-PA activates plasminogen to form active plasminogen which cleaves fibrin and a number of clotting factors. It acts locally to lyse the thrombus and halt further clotting action. Thrombolytics such as alteplase a recombinant t-PA. Aspirin irreversible inhibition of COX-I in platelets preventing the formation of thromboxane A2 preventing the downstream steps needed for platelet aggregation. Alteplase: thrombolytics, lyses the thrombus and halts further clotting Aspirin: irreversible inhibition of COX-I precursor formation of TXA2 and prevents platelet aggregation. Clopidogrel P2Y receptor antagonist on platelets responsible for promoting aggregation: inhibits binding of ADP, prevents further platelet aggregation. Dipyridamole inhibits platelet aggregation by several mechanism Warfarin inhibits clotting factor II which is prothrombin and factors VII, IX, X factors whose formation relies upon the presence of vitamin K. Vitamin K must be in the reduced form to do this; warfarin inhibits the enzyme vitamin K reductase allowing formation of the active form of vitamin K and therefore preventing formation of the clotting factors. (Patients need to eat same amount of vitamin K eg spinach to keep INR stable. DOACs Rivaroxaban-direct factor Xa inhibitor. Apixaban direct factor Xa inhibitor. Dabigatran etexilate is a prodrug which is converted to dabigatran by hydrolysis in the plasma and liver. In this form it is potent, competitive, reversible direct thrombin inhibitor. Edoxaban direct and reversible inhibitor of factor Xa.

Answer 181

Ongoing care: High risk of developing dehydration, malnutrition, infections, hypoxia, and hyperglycaemia. Patient ms physiological state should be closely monitored to include: Blood glucose 5-15mmol/L Blood pressure Oxygenation supplemental oxygen should be given if saturation drops to below 95% Nourishment and hydration Temperature Early mobilisation and positioning. MDT team: doctor, nurse, speech and language therapist, occupational therapist, physiotherapist, dietician, pharmacist, psychologist, social worker.

Answer 182

1-How and where is an NG tube positioned? 2-What are the different types of NG tube? 3-What are the pharmaceutical care issues associated with the administration of medication via an NG tube? An NG tube, also known as a nasogastric tube, is positioned by inserting it through the nose and down into the stomach. The tube is guided through the esophagus and into the stomach using gentle pressure and swallowing movements. There are several types of NG tubes available, including: 1. Levin Tube: This is a soft, flexible tube made of rubber or plastic. It is commonly used for short-term feeding or medication administration. 2. Salem Sump Tube: This tube has two lumens, one for aspiration of gastric contents and the other for the administration of fluids or medications. It is often used for gastric decompression or drainage. 3. Dobhoff Tube: This is a smaller, more flexible tube that is inserted into the stomach through the nose and then advanced into the small intestine. It is used for long-term enteral feeding or medication administration. When administering medications via an NG tube, there are several pharmaceutical care issues to consider: 1. Tube Placement Verification: It is crucial to verify the correct placement of the NG tube before administering any medications. This is typically done by confirming the tube's position through an X-ray or pH testing. 2. Compatibility: Certain medications may not be suitable for administration via an NG tube due to their formulation or pH. It is important to check the compatibility of the medication with the tube and the administration method. 3. Tube Clogging: NG tubes can become clogged with medication residue or formula, leading to ineffective medication administration. It is essential to flush the tube before and after medication administration to prevent clogging. 4. Medication Formulation: Some medications may need to be modified or crushed before administration via an NG tube. However, not all medications can be crushed, as it may affect their efficacy or cause adverse effects. It is important to check the medication's instructions for administration via an NG tube. 5. Patient Comfort and Education: Administering medications via an NG tube can be uncomfortable for patients. It is crucial to provide proper education and support to ensure patient understanding and cooperation. It is recommended to consult with a healthcare professional or pharmacist for specific guidance regarding the administration of medications via an NG tube. Enteral feeding tubes are routinely used in patients with dysphagia and those unable to take adequate nutrition and fluids orally to administer nutritional support. The most common type of feeding tube used in the acute treatment of patients with dysphagia is the nasogastric NG tube.

Answer 183

Aneurysm - Ballooning of a weakened region of a blood vessel occurring mainly at branching points of arteries and are causes by constant pressure from blood flow. of pneumonia. Aspiration - Presence of food/fluid/saliva in the airway which increases the risk Ateriovenous malformation - Cluster of abnormally formed blood vessels diverting blood directly from arteries to veins bypassing brain tissue. Atherosclerosis - Fatty deposits that harden on the inner wall of the arteries (atheroma) and roughen its surface making it more susceptible to blockage either by narrowing or the formation of a clot. Carotid arteries - Main blood vessels in the neck, which supply oxygenated blood to the brain. Cerebral amyloid angiopathy - Neurological condition in which proteins called amyloid build up on the walls of the arteries in the brain. Crescendo TIA - Two or more TIAs in alweek. Penumbra - Brain tissue that is ischaemic but not yet infracted (still viable), and is therefore at risk of further damage unless flow is restored. Fibromuscular dysplasia - Arterial disorder where the blood vessels develop fibrous tissue within their walls causing them to narrow. Hydrocephalus - Build up of fluid within the skull. Hypertensive encephalopathy - Brain damage caused by raised blood pressure. Hypoxia - Blood oxygen levels outside the normal range (e.g. below 95%). Ictus - sudden attack or stroke. Ischaemia - A decrease on the blood supply to a bodily organ, tissue, or part, caused by constriction or obstruction of the blood vessel. Quality of Life - QoL - Refers to the level of comfort, enjoyment, and ability to pursue daily activities. Vasculitis - Condition involving inflammation of the blood vessels.

Answer 184

According to the National Institute for Health and Care Excellence (NICE) in the UK, the treatment guidelines for stroke management and secondary prevention of stroke include the following: 1. Acute Stroke Management: - Rapid assessment and diagnosis to determine the type of stroke (ischemic or hemorrhagic). - Thrombolysis within 4.5 hours of symptom onset for eligible patients with acute ischemic stroke. - Aspirin should be given within 24 hours of symptom onset for patients who are not eligible for thrombolysis. - Admission to a specialist stroke unit for comprehensive care and rehabilitation. - Early mobilization and rehabilitation to improve recovery. 2. Secondary Prevention of Stroke: - Antiplatelet therapy with aspirin or clopidogrel for patients with non-cardioembolic ischemic stroke or transient ischemic attack (TIA). - Anticoagulation therapy with warfarin or direct oral anticoagulants for patients with atrial fibrillation or other cardioembolic sources. - Blood pressure control with antihypertensive medications to target levels recommended by NICE. - Statin therapy for patients with ischemic stroke or TIA, regardless of cholesterol levels. - Lifestyle modifications, including smoking cessation, healthy diet, regular exercise, and alcohol moderation. - Carotid endarterectomy or carotid artery stenting for patients with severe carotid artery stenosis. - Closure of patent foramen ovale (PFO) in selected cases. These guidelines are subject to individual patient assessment and may vary based on specific clinical circumstances. It is important to consult with healthcare professionals for personalized advice and treatment options.

Answer 185

Dysphagia, which refers to difficulty in swallowing, is an important consideration in medication administration. It is a common concern for pharmacists on the ward, as 4 out of 10 medicine administrations are found to be inappropriate. Patients with dysphagia are three times more likely to experience medication administration errors. Unlicensed administration may occur when a licensed alternative is available, and there is a risk of mixing multiple tablets together, which can lead to variations in patient experience. It is important to note that tablet crushing has been known to be fatal in some cases. The learning outcomes of this lecture include the ability to define swallowing difficulties, describe the issues surrounding medication administration to patients with swallowing difficulties, outline the issues related to tablet crushing, and understand the role of the pharmacist in managing medicines for patients with dysphagia. Dysphagia is a physical problem that causes difficulties with swallowing and can be associated with conditions such as stroke, Parkinson's disease, Huntington's chorea, and gastroesophageal reflux disease. Swallowing difficulty is a term used to encompass dysphagia but strictly refers to a psychological aversion to swallowing tablets, which is common in children. Dysphagia can lead to complications such as aspiration (inhaling food or liquid into the lungs) and asphyxiation. The swallowing process itself can be affected by dysphagia. When managing medication administration for patients with dysphagia, various interventions can be considered. Alternative non-oral formulations such as patches and suppositories can be used, but these options are limited and costly. Intravenous (IV) administration of medicines is another option, but it comes with the risk of cost and infection. Liquid medicines are less likely to block the pharynx, but if the consistency is too runny, it can cause aspiration. Percutaneous endoscopic gastrostomy (PEG) or jejunostomy (PEJ) tubes can be used for patients who require long-term enteral feeding. However, tampering with the formulation of medications should be done cautiously, as it can alter the bioavailability of the drug and render the administration unlicensed, leading to shared responsibility between the prescriber and administrator. Switching from solid to liquid medications in patients with dysphagia should be carefully considered due to factors such as taste, change in bioavailability, limited availability, stability issues, and cost. Water can cause hydrolysis and loss of active ingredients, and other diluents like alcohol may not be well received by regulatory authorities. Specials, which are unlicensed medicines, can be an option but can be costly. When considering the use of PEG or PEJ tubes, it is important to understand when to use each tube and the differences between them. The assessment of a patient with dysphagia involves evaluating their ability to swallow. If swallowing is not possible, alternative routes or formulations such as patches, suppositories, or sublingual administration can be considered. If the patient can swallow liquids, licensed liquid medicine may be used, but unlicensed liquid medicine or formulation tampering may be required in some cases, with authorization from the prescriber. If all else fails, formulation tampering, such as tablet crushing or dispersing, may be considered, but it is important to be aware of the altered bioavailability and potential impact on compliance. This renders the administration unlicensed. Normal tablets that do not have a coating can be appropriate and safe for dispersion or crushing, unless the medicine is very unstable in water. Insufficiently crushed tablets can block enteral tubes. Generally, crushing tablets will increase the bioavailability of the drug. However, it is important to consider which tablets this is clinically important for. Modified release tablets are designed to release the medication slowly, providing a controlled release over time. Examples of such tablets include theophylline, nifedipine, felodipine, and MST. Crushing or altering these tablets can disrupt the modified release mechanism and affect the intended drug release profile. Enteric-coated tablets have a special coating that prevents the medication from being released in the stomach and instead allows it to dissolve in the intestines. Examples of enteric-coated tablets include diclofenac, omeprazole, and sulfasalazine. If the coating is crushed, the medication may be released in the stomach, potentially leading to reduced effectiveness or adverse effects. In the case study mentioned, the patient is prescribed various medications, including diclofenac 50mg enteric-coated tablets, dipyridamole 200mg modified-release capsules, aspirin 75mg tablets, simvastatin 20mg tablets, zimovane 7.5mg tablets, and slophyllin 225mg capsules. To determine whether these medications can be switched from tablets to crushed, IV, or liquid formulations, it would be best to consult reliable reference sources such as

Answer 186

Heart function overview: Two pumps working together working together. Blood from muscles and organs enters right side. Heart pumps the blood to the lungs Takes up oxygen and eliminates carbon dioxide. Oxygen rich blood enters left side of the heart. Pumped through arteries to organs and tissues. Regulated by a system of valves Ensures blood flows in the correct direction. In health: Cardiac output 5L/min Mean heart rate 70bpm Stroke volume 70ml systole heart ejects blood during contraction Filled ventricle 130ml fraction ejected>50% of ventricles contents (diagnosis and investigation) in diagnosis of heart failure this is important. Superior vena cava bring blood from body to right side of atria passes into right ventricle which pumps it into pulmonary artery into lungs to become oxygenated. Pulmonary vein brings oxygenated blood back to left atria into left ventricle this pumped via aorta back to the body.

Answer 187

Results from structural and or functional cardiac disorders. Usually of gradual onset. The ability of the heart to function as a pump is impaired. Unable to sustain an adequate delivery of blood. Therefore, oxygen and nutrients to the tissues. Epidemiology: relatively common increases with increasing age. Average annual incidence is: 0.3-2% overall population 3-5% 65yrs old 8-16% >75yrs Often complicates other conditions in elderly. Heart failure can be a complication of other conditions MI and AF. High mortality rate 50% die within 5yrs. Main causes of death: Recurrent pump failure Sudden cardiac death Recurrent MI Accounts for 5% of admissions to hospital wards half with HF have AF as contributory factor. *Increases risk of thromboembolic conditions.

Answer 188

1-Pump failure: damage to the heart muscle, reduction in myocardial contractility. 2-Overloading: Extra workload on the heart: •Decreases force and velocity of contraction and delayed relaxation. •Excessive afterload (pressure overload) •Excessive preload (volume overload) •Afterload: the pressure that the chamber of the heart has to generate in order to eject blood out of the chamber ie Total peripheral resistance. •Preload: Volume of blood present in a ventricle of the heart after passive filling and atrial contraction. Ie left ventricular and diastolic volume (amount of stretch of ventricle) •Pump failure= damage to the heart and leads to systolic failure failure of heart contraction. Common cause is ischaemic heart disease and this can occur acutely after MI or progressively chronically from diffuse fibrosis of mycocardial tissue. Causes of pump failure: Ischaemic heart disease Myocardial infraction Cardiomyopathy heart muscle disease Arrhythmias Inflammation Excessive alcohol consumption Diffuse fibrosis 2-Overloading: Overwork and overstretching the cardiac muscle can cause structural and biochemical abnormalities in cells. Can lead to: decreased force, velocity of contraction and delayed relaxation. Effects are usually irreversible. Causes of overloading: 1-Excessive afterload or 2-excessive preload. 1-Excessive afterload: if systemic vascular resistance is high eg hypertension= raised afterload on left ventricles and cause it to fail. •If pulmonary vascular resistance is high eg pulmonary hypertension secondary to chronic lung disease Right ventricular failure (cor pulmonale) •Valve dysfunction: Stenosis or incompetence (Systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) are two important factors in understanding the circulatory system. SVR refers to the resistance encountered by the blood flow in the systemic circulation, which includes the arteries, arterioles, capillaries, and veins throughout the body, except for the pulmonary circulation. It represents the overall resistance that the heart must overcome to pump blood to the body's tissues. SVR is influenced by factors such as blood vessel diameter, vessel length, and blood viscosity. It is an important determinant of blood pressure and cardiac workload. Increased SVR can result in elevated blood pressure, while decreased SVR can lead to decreased blood pressure. PVR, on the other hand, refers to the resistance encountered by the blood flow in the pulmonary circulation, which includes the arteries, arterioles, capillaries, and veins within the lungs. PVR represents the resistance that the right side of the heart, specifically the right ventricle, must overcome to pump blood to the lungs for oxygenation. PVR is influenced by factors such as the diameter of the pulmonary blood vessels and the lung's vascular bed. Increased PVR can lead to increased pressure in the pulmonary circulation, resulting in pulmonary hypertension and right heart strain. Decreased PVR allows for more efficient blood flow through the lungs. In summary, SVR represents the resistance encountered by blood flow in the systemic circulation, while PVR represents the resistance encountered by blood flow in the pulmonary circulation. Both SVR and PVR play crucial roles in maintaining proper circulation and can have significant implications for cardiovascular health and function.) •Excessive preload: Uncommon cause of failure: Hypervolaemia is usual cause Fluid retention eg in renal failure Excessive intravenous infusions risk in elderly patients Polycythaemia over production of RBC increase volume of blood and increase preload on heart. Drugs eg NSAIDs, steroids any drug that increases water and sodium retention can increase preload. Other causes of overloading: Excessive demand Anaemia oxygen carrying capacity of the blood is reduced this results in increased demand on the heart to pump more blood. Hyperthyroidism or thyrotpxicosis will increase metabolic rate of the body and increase demand on heart Valve dysfunction Bradycardia or tachycardia Widespread vasodilation eg septic shock or cardiac output increased to raise BP Precipitating factors Anything that increases myocardial workload: Arrhythmias Anaemia Hyperthyroidism Pregnancy Obesity Infective endocarditis Pulmonary infection Change in therapy including poor compliance

Answer 189

There are 2 classifications of heart failure acute and chronic. Acute heart failure is rapid in onset eg after an MI where contractility immediately drops due to damage to heart muscle cells. Reduction in contractility will cause cardiac output to fall. This results in the stimulation of a process of compensation in order to maintain cardiac output and perfusion. A sudden drop in Cardiac output stimulates the cardiovascular system to compensate and return cardiac output to normal. This is compensatory heart failure. If an MI is very severe—> extensive damage to heart muscles where a patient has ignored symptoms and thus has led to severe damage this results in sharp drop in cardiac output and there is no cardiac reserve, CVS unable to compensate and is overwhelmed. •Decompensated heart failure •Chronic heart failure is the same as acute but decline is progressive rather than a sudden fall. Patients can remain in compensated failure indefinitely. Severe stress can drive them into decompensation eg infection, fluid overload, exertion or anaemia.

Answer 190

The greater the volume of blood entering the heart during diastole, the greater the volume of blood ejected during systolic contraction. Achieved by increase in stretching of muscle fibres and increased force of contraction. Starlings law of the heart graph: A= normal B= mild HF C=moderate HF D= severe HF The heart muscles in HF can’t respond to the increase in preload so there is a decrease in cardiac output and initial compensatory leads to decompensation and drop off in cardiac output.

Answer 191

Not just reduction in cardiac output and tissue perfusion. The heart adapts to respond to changes: Cardiac

Answer 192

In heart failure or in other cases where a reduction in cardiac output and tissue perfusion occurs. The heart adapts to respond to changes by: 1-Cardiac enlargement 2-Arterial constriction 3-Increased sympathetic drive 4-Salt and water retention

Answer 193

To maintain cardiac output in heart failure the heart undergoes progressive alteration of ventricular size, shape and function. Cardiac muscles stretched from increased residual volume after contraction. This gives the heart the appearance of being enlarged with extra muscle although this is a short term compensatory mechanism this extra muscle is ineffectual and it becomes responsible for impairment in the heart. This is called Left ventricular hyper trophy LVH. Thickening and enlargement of left ventricle wall

Answer 194

When cardiac output is reduced: Arteries constrict to divert blood to organs from skin and GI tract. But can also raise systemic vascular resistance Increase afterload on the heart.

Answer 195

Failing heart and reduced tissue perfusion: Stimulates: sympathetic nervous system (SNS) via baroreceptors in the blood vessel walls this Exposes heart to catecholamines with positive ionotrophic (force of contraction) and chronotrophic (rate of contraction) effects. In attempt to increase cardiac output •levels of noradrenaline, angiotensin, aldosterone & vasopressin increased to cause ionotrophic and chronotrophic effects. Promotes excessive stimulation of the heart and widespread vasoconstriction. Increases contractility

Answer 196

*Reduced cardiac output: •Reduced renal perfusion, releases renin, renin leads to formation of angiotensin I&II (vasoconstrictors) Leads to adrenal aldosterone release •Aldosterone: Retains salt and water at distal renal tubule Expands blood volume and increases preload •Promotes the release of atrial natriuretic peptide (ANP) ( see diagnosis and investigations) Vasodilator to counteract increased preload ******************************** This explanation is about the relationship between reduced cardiac output and the factors that contribute to it. When there is reduced renal perfusion (blood flow to the kidneys), the kidneys release a hormone called renin. Renin then leads to the formation of two vasoconstrictor hormones called angiotensin I and angiotensin II. These hormones cause the blood vessels to constrict, which can further reduce cardiac output. In addition, the release of renin also stimulates the release of aldosterone from the adrenal glands. Aldosterone is a hormone that acts on the distal renal tubule (a part of the kidney) to retain salt and water. This leads to an expansion of blood volume and an increase in preload, which is the amount of blood that fills the heart before it contracts. However, the increased preload also triggers the release of another hormone called atrial natriuretic peptide (ANP). ANP acts as a vasodilator, meaning it causes the blood vessels to relax and dilate. This helps counteract the increased preload and can help improve cardiac output. So, while the initial release of renin and aldosterone can contribute to reduced cardiac output, the release of ANP acts as a vasodilator to counteract the effects of increased preload and support cardiac output.

Answer 197

3 classical symptoms: 1-exercise limitations fatigue: Due to decreased cardiac output, impaired oxygenation and decreased blood flow to exercising muscles. 2-Shortness of breath Back pressure from failing heart causes fluid to accumulate in lungs. Mostly occurs when exercising or lying down. Can be accompanied by a cough 3-oedema Swelling of ankles and feet Due to retention of salt and water Oedema, also known as swelling, occurs due to an abnormal accumulation of fluid in the interstitial spaces of tissues. This can happen as a result of various pathophysiological mechanisms. Here are some common reasons why oedema occurs: 1. Increased hydrostatic pressure: When the pressure within the blood vessels (capillaries) exceeds the pressure in the surrounding tissues, fluid can leak out into the interstitial spaces. This can happen in conditions such as congestive heart failure, where the heart is unable to effectively pump blood, causing a build-up of pressure in the blood vessels. 2. Decreased oncotic pressure: Oncotic pressure is the pressure exerted by proteins in the blood vessels. It helps to keep fluid within the blood vessels. If the level of proteins (especially albumin) decreases, such as in liver disease or malnutrition, the oncotic pressure decreases, allowing fluid to leak out into the tissues. 3. Lymphatic obstruction: The lymphatic system plays a crucial role in draining excess fluid from the tissues. If there is a blockage or damage to the lymphatic vessels or lymph nodes, the fluid cannot properly drain, leading to oedema. This can be seen in conditions like lymphedema or after lymph node removal during surgery. 4. Increased capillary permeability: Inflammatory processes or certain conditions, such as burns or allergic reactions, can cause an increase in the permeability of the capillary walls. This allows fluid, along with proteins and immune cells, to leak out into the tissues, resulting in oedema. 5. Sodium and water retention: Imbalances in the regulation of sodium and water in the body can lead to fluid accumulation. Conditions like kidney disease, hormonal imbalances (e.g., in congestive heart failure or liver cirrhosis), or certain medications can disrupt the normal balance of sodium and water, leading to oedema. It's important to note that oedema can occur as a result of a combination of these mechanisms and may vary depending on the underlying condition or disease. Proper diagnosis and treatment are essential to address the underlying cause of oedema and manage it effectively.

Answer 198

Most clinical features of HF result from either: •Hypoperfusion (forward component) Impaired flow ahead of the heart or chamber affected) •Congestion/oedema (backward component) increase in pressure in veins draining into the heart. Both conditions usually co-exist Different aspects, not different forms of heart failure. Cause different features and may vary according to which side of the heart is affected. Heart failure (HF) is a condition in which the heart is unable to pump enough blood to meet the body's needs. There are two main components of HF that contribute to its clinical features. The first component is hypoperfusion, also known as the forward component. This occurs when there is impaired blood flow ahead of the heart or in the chamber that is affected. In simple terms, it means that the heart is not able to pump enough blood out to the rest of the body, resulting in reduced blood supply to organs and tissues. The second component is congestion or edema, also known as the backward component. This happens when there is an increase in pressure in the veins that drain into the heart. This increased pressure can lead to fluid accumulation in various parts of the body, causing symptoms such as swelling in the legs, ankles, and abdomen. It is important to note that both hypoperfusion and congestion/edema usually coexist in heart failure and are not different forms of the condition. Instead, they represent different aspects of the same underlying problem. The features and symptoms of heart failure may vary depending on which side of the heart is affected. For example, if the left side of the heart is primarily affected, symptoms may include shortness of breath and fluid accumulation in the lungs, while if the right side is affected, symptoms may include peripheral edema and swelling in the legs. Overall, understanding these components helps healthcare professionals diagnose and manage heart failure by addressing both the reduced blood flow and the fluid accumulation in the body.

Answer 199

Cause of Hypoperfusion tends to be peripheral vasoconstriction. The increase in the afterload on the heart caused by peripheral vasoconstriction means that there is a reduction in the blood supply going forward in the heart. This results in fatigue and exercise intolerance due to lack of oxygen and nutrient supply to tissues. Patients tends to look pale and feels cold. Effects independent of which side of the heart fails. 1-Peripheral vasoconstriction 2-Fatigue and exercise intolerance 3-Cold and pale extremities 4-Fluid and electrolytes retention 5-Tachycardia and tachypnoea.

Answer 200

Congestion/oedema symptoms (Backward component) symptoms differ based on which side of the heart is affected 1-Right sided heart failure heart receives deoxygenated blood from the body which is then pumped to the lung so if right side of the heart fails this cause backlog of blood and fluids into the body and this will accumulate in ankles due to gravity as well. symptoms are: Peripheral oedema (swollen ankles) Hepatomegaly liver enlargement Raised jugular venous pressure Peripheral cyanosis Fluid & electrolytes retention 2-Left sided heart failure More common & usually more serious Left side of the heart receives oxygenated blood from your lungs if left side fails you get backlog of fluid and blood into the lung. So symptoms will mainly be in the lungs *Pulmonary oedema accumulation of fluid on the lung symptoms include: Dyspnoea breath shortness Orthopnoea shortness of breath when lying down due to redistribution of fluid to the lungs from abdominal pressure on the diaphragm that occurs when lying down. Patients notes 2,3,4 pillow orthopnoea number of pillows relates to N of pillows patient has to be propped on for sleeping. Paroxysmal nocturnal dyspnoea can sleep but can wake up at night due to severe shortness of breath. •Cough/wheeze •Central cyanosis •Tiredness •Breathlessness

Answer 201

NYHA Classification of heart failure symptoms Class I: no limitations. Ordinary physical activity does not cause fatigue, breathlessness or palpitations. Class II: slight limitation of physical activity. Such as patients are comfortable at rest. Ordinary physical activity results in fatigue, palpitations, breathlessness or angina pectoris ( mild heart failure) Class III: Marked limitation of physical activity. Although patients are comfortable at rest, less than ordinary physical activity will lead to symptoms (moderate heart failure). Class IV: inability to carry on any physical activity without discomfort. Symptoms of congestive cardiac failure are present even at rest, with any physical activity increased discomfort is experienced (severe heart failure).

Answer 202

Explain how HF is diagnosed Describe the treatment of HF

Answer 203

Symptoms alone can’t be relied upon to make a diagnosis. Need evidence of cardiac dysfunction: Investigations Objective measures of left ventricular structure and function. Cause should be established in all patients. May be reversible or correctable.

Answer 204

Review of signs and symptoms: Raised jugular vein eg 5cm above sternum Lung sounds Crackles at bases (crepitations) Swelling of ankles and legs

Answer 205

Measure of: Natriuretic peptides (BNP & NTproBNP) increased levels contribute to diagnosis of heart failure. * *Natriuretic peptides, specifically B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), play a crucial role in the diagnosis of heart failure. These peptides are released from the heart in response to increased pressure and stretching of heart muscle cells. The main function of natriuretic peptides is to regulate blood volume and blood pressure by promoting sodium and water excretion, reducing blood volume, and dilating blood vessels. In the context of heart failure, the levels of BNP and NT-proBNP are elevated due to the increased stress on the heart. Measuring the levels of BNP and NT-proBNP in the blood can aid in the diagnosis and management of heart failure. Elevated levels of these peptides indicate the presence of heart failure and can help differentiate it from other causes of shortness of breath. They also provide information about the severity of heart failure and can be used to monitor the response to treatment. Overall, BNP and NT-proBNP serve as reliable biomarkers for diagnosing heart failure and assessing its progression. *Echocardiography See heart in motion and assess performance of heart as a pump •Measures ejection fraction at systole Ejection fraction is measured as a percentage of the total amount of blood in your heart that is pumped out with each heartbeat. A normal ejection fraction is 50 percent or higher. An ejection fraction below 40 percent means your heart isn’t pumping enough blood and may be failing. •Left ventricular ejection fraction (LVEF) is the central measure of left ventricular systolic function. LVEF is the fraction of chamber volume ejected in systole (stroke volume) in relation to the volume of the blood in the ventricle at the end of diastole (end-diastolic volume). •Results of ejection fraction allow for classification of HF: HFrEF=HF with reduced ejection fraction (end diastolic dysfunction) (<40%)= > NICE 2018 guidelines HFpEF=HF with preserved ejection fraction (>50%) HFmrRF=HF with mid-range ejection fraction (41-50%) Others: •Chest X-rays show size of heart and lung consolidation •Heart rate and rhythm and sounds •Electrocardiogram detects AF •Blood pressure •Blood tests Anaemia, renal failure & thyroid disease

Answer 206

Refer back to hypertension pharmacology of diuretics/ACEIs/Angiotensin II antagonists/Beta-blockers. Aims of treatment to reduce morbidity, relieve symptoms and improve exercise tolerance. Reduce mortality Treatment choice depends on initial cause of HF: Disease of the myocardium Increase inotropy OR Excessive load: Reduce preload Reduce afterload

Answer 207

Diuretics (preload) ACEIs/AII receptor antagonists (pre and afterload) Beta-blockers (pre and afterload) Aldosterone antagonists (reduce pre-load and to block aldosterone) Digoxin (improve myocardial stimulation) Isosorbide dinitrate (preload) and hydralazine (afterload) Ivabradine (myocardial stimulation) ARNI-Angiotensin receptor Neprilysin inhibitor-Sacubitril-valsartan trade name entresto (pre&afterload) SGLT2 inhibitors (pre & afterload)

Answer 208

Intravenous diuretics For fluid removal as this will reduce preload in the heart and will reduce fluid and congestion symptoms associated with HF.

Answer 209

Heart failure diagnosed by specialist Offer diuretics for the relief of congestive symptoms and fluid retention in acute HF but chronic: Then classify HF: If HF with preserved ejection fraction (HFPEF) treat by: Managing co-morbid conditions such as high blood pressure, AF, ischaemic heart disease, diabetes melitus in line with NICE guidance. If HF with reduced ejection fraction (HFREF) treat by: First line: offer ACEi and Beta blockers, offer MRA (Mineralocorticoid receptor antagonist eg Spironolactone and eplerenone ) if symptoms continue. Consider ARB if intolerant of ACEI and consider hydralazine and nitrate if intolerant of ACEI and ARB. If symptoms persist despite optimal first line therapy, seek specialist advice and consider one or more of the following options. 1-replace ACEI or ARB with Sacubitril-valsartan if LVEF <35% in accordance with TA388. 2-Add ivabradine if in sinus rhythm with a HR >75bpm and LVEF <35% in accordance with TA267 3-Add hydralazine and nitrate especially if of African/Caribbean descent. 4-Digoxin worsening HF

Answer 210

The National Institute for Health and Care Excellence (NICE) in the UK provides guidelines for the management of acute and chronic heart failure. Here are the key recommendations from the NICE guidelines: 1. Acute Heart Failure: - Assess and stabilize the patient's condition promptly. - Administer oxygen if needed. - Give diuretics to relieve fluid overload. - Consider nitrates and/or morphine for symptomatic relief. - Initiate appropriate treatment for the underlying cause. - Monitor vital signs, fluid balance, and renal function. - Provide patient education and follow-up care. 2. Chronic Heart Failure: - Perform a comprehensive assessment of the patient's symptoms, physical examination, and relevant investigations. - Use a multidisciplinary approach involving specialists in cardiology, nursing, and other healthcare professionals. - Prescribe appropriate pharmacological treatment, including ACE inhibitors or angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists. - Consider other medications like diuretics, ivabradine, and digoxin based on the patient's symptoms and clinical condition. - Offer cardiac resynchronization therapy (CRT) for eligible patients with reduced ejection fraction and electrical dyssynchrony. - Provide lifestyle advice, including fluid and sodium intake management, physical activity, and smoking cessation. - Monitor and review the patient regularly, adjusting treatment as necessary. It's important to note that these are just a summary of the NICE guidelines. For more detailed information and specific recommendations, it is best to refer to the official NICE guidelines for acute and chronic heart failure.

Answer 211

Decrease preload Decrease symptoms of pulmonary and peripheral oedema. Decrease hospital admission and increase exercise performance. 1-Thiazides less potent diuretics used for mild HF eg bendroflumethiazide up to 5mg om but it is not effective at an eGFR of <20ml/min. 2-Loop diuretics Mainstay of HF treatment, More potent Eg furosemide, bumetanide, Can use high doses in severe HF Can use IV 3-Metolazone Atypical thiazide diuretic Effective in patients with low renal function Used in combination with loop diuretics in resistant heart failure STAT doses-2.5mg/5mg Short term 2.5mg/5mg od Long term maintenance 2.5mg/5mg 2 or 3 times a week

Answer 212

Pharmaceutical care issue related to diuretics Hypotension Dehydration Renal impairment Electrolytes disturbances Rate do administration of IV furosemide

Answer 213

First line therapy Decrease preload and afterload Improve symptoms and long term survival Compelling evidence for use of Start low dose then uptitrate

Answer 214

Angiotensin II antagonist Alternative in patients intolerant to ACEIs. Evidence for improvement in long term survival but not as good as ACEIs.

Answer 215

BB are joint forts like treatment with ACEIs **Only beta blockers licensed for heart failure (bisoprolol, carvediol, nebivolol)** Decrease preload and afterload Caution: can cause worsening of symptoms initially-start low, go slow-low start dose and slow uptitration-stable patients only.

Answer 216

Aldosterone antagonist also mineralocorticoidreceptor antagonists Eg spironolactone, Eplerenone Joint first- line treatment with ACEIs/B-blockers Low dose- some diuretic effect-block action of aldosterone in development of LVH. Long term survival and hospital admission.

Answer 217

Hydralazine &nitrates For patients intolerant/CI to ACEIs/angiotensin II antagonists. Add on therapy Especially if African or Caribbean origin Evidence from before ACEIs developed Trial used-ISDN di-nitrate- now use ISMN mono-nitrate **Ivabradine Lowers heart rate Selectivity and specifically inhibits If channel in SA node. Add on therapy in worsening heart failure in patients on optimal first line therapy.

Answer 218

ARNI ANGIOTENSIN RECEPTOR-neprilysin inhibitor-Sacubitril-valsartan (Entresto) Sacubitril-neprilysin inhibitor (stops degradation of atrial and brain natriuretic peptides) Neprilysin inhibition increases the levels of vasoactive substances, helping to counter the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and other maladaptive processes of HF Valsartan-Angiotensin II antagonist Add on therapy in worsening heart failure in patients on optimal first line therapy (need to stop ACEI/ARB 36hrs before) ESC recommends joint first line

Answer 219

Improves symptoms, exercise tolerance and hospital admissions but not mortality. Add on therapy for patients who remain symptomatic despite optimal treatment with other drugs.

Answer 220

Dapagliflozin Empagliflozin Add on therapy in worsening heart failure in patients on optimal first line therapy whether diabetic or not ESC recommends joint first line

Answer 221

•Define and describe different types of cardiac arrhythmias •Describe the non-drug management of cardiac arrhythmias What is an arrhythmia? Abnormality in heart rate or rhythm Some benign but some fatal About 5.3% UK population managing arrhythmia (many undiagnosed) Normal rhythm=sinus rhythm Medical notes NS normal sinus rhythm

Answer 222

*Where they occur: •Supraventicular above the AV node (atrial arrhythmias) At the AV junction Within AV node •Venticular: Within ventricles *Effect on heart rate: •Bradycardia slow HR <60bpm •Tachycardia Fast HR >100bpm

Answer 223

Common symptoms: Dizzy/ light headed Palpitations Chest pain Fatigue Can be asymptomatic Occasionally severe cardiac arrhythmias can cause a loss of consciousness secondary drop in blood pressure and in blood flow due to circulation problems due arrhythmias itself. Small number can be at risk of cardiac arrest.

Answer 224

An electrocardiogram (ECG) is a commonly used diagnostic tool to detect and diagnose arrhythmias and to assess the normal electrical activity of the heart. Here are some key differences between ECG findings in arrhythmias and a normal ECG: 1. Normal ECG: - Regular rhythm: The intervals between each QRS complex (RR interval) are consistent. - Normal P wave: The P wave represents atrial depolarization and should be upright and present before each QRS complex. - Normal QRS complex: The QRS complex represents ventricular depolarization and should be narrow (less than 0.12 seconds) and upright in most leads. - Normal T wave: The T wave represents ventricular repolarization and should be upright in most leads. - Normal PR interval: The PR interval represents conduction time from the atria to the ventricles and should be between 0.12-0.20 seconds. 2. Arrhythmias: - Irregular rhythm: The intervals between QRS complexes may vary in length. - Absent or abnormal P waves: In certain arrhythmias, the P wave may be absent, inverted, or not followed by a QRS complex. - Abnormal QRS complex: In some arrhythmias, the QRS complex may be widened (>0.12 seconds) or have an abnormal shape. - Abnormal T wave: In certain arrhythmias, the T wave may be inverted or have an abnormal shape. - Prolonged PR interval: In some arrhythmias, the PR interval may be prolonged (>0.20 seconds). It's important to note that this is a general overview, and there are many different types of arrhythmias with varying ECG findings. Proper interpretation of an ECG requires clinical judgment and expertise. If you have concerns about your ECG or suspect an arrhythmia, it is best to consult a healthcare professional for a thorough evaluation and diagnosis.

Answer 225

Find the underlying cause of the disease as some cardiac arrhythmias can be due to underlying pathology like thyroid disease, electrolyte imbalance eg Ca, Mg and K in the blood and cardiomyopathy. Drug therapy: anti-arrhythmic drugs Non-pharmacological: Electrical cardioversion Radio frequency ablation/cryoablation Pacemakers Defibrillators

Answer 226

Vaughan Williams Classification of antiarrhythmic drugs: •Class I: block sodium channels •Class II: beta-adrenoceptor antagonists (atenolol, sotalol) •Class III: prolong action potential and prolong refractory period (suppress re-entrant rhythms) (amiodarone, sotalol) •Class IV: calcium channel antagonist. Impair impulse propagation in nodal and damaged areas (verapamil) •Others Digoxin, adenosine Affect different stages of the action potential.

Answer 227

Slow heart rate pulse less than 60bpm *Sinus bradycardia: SA node fires at a slow rate *Sinus node disease: SA node fails to generate electrical impulse. This is mainly idiopathic (fibrosis of conduction tissue) Some secondary to AMI or cardiomyopathies *AV node disease: heart block Failure of AV node to conduct electrical impulse to ventricles. Frequently idiopathic, also secondary to AMI, congenital defects, infection, surgery (valve) and drugs like (Beta-blockers, digoxin, verapamil)

Answer 228

Underlying cause (stop drugs, treat disease eg hypothyroidism) Permanent pacemaker PPM: Inserted in skin-pocket below collar bone m. Leads inserted into heart and sense electrical activity within heart. Deliver small electrical impulses to myocardial tissue if detect inappropriate rhythm.

Answer 229

Tachyarrhythmias can be classified into: 1-Supraventicular arrhythmias: Atria: Sinus tachycardia Sinus node re-entry Tachycardia Atrial fibrillation Atrial flutter Atrial tachycardia 2-Ventricular tachycardias: Ventricular ectopics Torsades de pointes Ventricular fibrillation 3-AV junction: AV junctional tachycardias Wolff-parkinson white syndrome

Answer 230

Increased HR but normal rhythm Normal response to exercise infection, low blood pressure, anaemia, thryotoxicosis, hypovolaemia, shock, PE. S/E Drugs that cause sinus tachycardia: nicotine, B2-agonists, levothyroxine, salbutamol, aminophylline

Answer 231

Less frequent than AF, but similar underlying causes. Re-entry circuit within the R atrium Rapid atrial rhythm 300bpm ECG saw tooth pattern Ventricles usually best ockebfirnevery 2-4 atrial flutter waves. Stasis of blood in atria, need for anticoagulation.

Answer 232

Accessory pathway conducts electrical pulse direct from atria to ventricles (by-pass AV node) Ventricular rate up to 600bpm Serious, life-threatening condition

Answer 233

Occasional palpitations from extra ventricular beats (ectopics) common Frequent/runs of ectopic beat more serious. VT defined as when 5 or more ventricular beats occur consecutively Possible causes: AMI, IHD, cardiomyopathies, myocarditis, valvular disease.

Answer 234

Due to QT prolongation this increases Ventricular arrhythmias occurring. Causes: Congenital Hypokalaemia electrolytes imbalance Hypomagnesaemia Drugs that cause QT prolongation: Antiarhythmics class IA or III Eryhthromycin and clarithromycin Tricyclics antidepressants Cisapride Terfenadine & astemizole Haloperidol Lithium Phenothiazines

Answer 235

Rapid and unco-ordinated contraction of the ventricular tissue. Severely compromises cardiac output Lose consciousness within 10-30secs Most common cause of death due to AMI VF medical emergency without use of defibrillators patient will die, if patient survives there is a risk of irreversible cerebral and myocardial damage.

Answer 236

Direct current cardioversion DCDV: Used in AF & atrial flutter Cardioversion term means process of restoring hearts normal rhythm This can be done chemically or DC cardioversion •Chemical cardioversion—>drugs •DC cardioversion—> application of controlled electric shock across chest walls: Aim to Override disordered conduction Allows SA node to regain control of HR Patient briefly anaesthetised while shock is applied unpleasant process and this process has risk of thromboembolism completely associated with procedure itself so patient must be treated with anticoagulants with 3-4weeks prior to treatment and 4 weeks afterwards. 2-Radiofrequency ablation/cryoablation. Need exact location of point responsible for generating arrhythmia Catheter with electrode at tip guided to appropriate point. RF radio frequency energy/freezing destroys tissue and disrupts conduction pathway. •Defibrillation: Delivery of electric shock to the myocardium via the chest wall. Needs to be given ASAP Used in conjunction with cardiopulmonary resuscitation CPR. •Internal cardioversion defibrillators ICDs: Implanted into high risk patients with resistant VT’s Monitor rate and rhythm Initially deliver rapid rate impulses (faster than arrhythmia) to try to regain control and then slow down.! If fails, deliver internal electric shock Unpleasant for patient.

Answer 237

Epidemiology: most common causing supraventricular tachycardia About 1 in 29 of >65yrs in the uk 7% of uk admissions 5x higher risk of stroke Women

Answer 238

Risk factors for the development of AF 1-Cardiac: HT IHD Structural heart diseases 2-Non Cardiac: DM Thyrotoxciosis Alcohol COPD

Answer 239

Irregular, rapid atrial rate (300-600bpm) secondary to chaotic conduction within atria. Acute <48hrs Chronic >48hrs Paroxysmal-intermittent or self terminating in between paroxysms patient is normal atrial rhythm. Persistent-successfully converted by treatment. Permanent-failed or unsuitable treatment. The uncoordinated contraction of the atria results in potential of Stasis of blood within atria and this predispose to cerebral and systemic thromboembolism. Additionally the Sluggish atrial blood flow also allows partial activation of the clotting cascade. Ventricular rate 100-180 bpm

Answer 240

Atrial fibrillation (AF) is a type of abnormal heart rhythm characterized by irregular and rapid electrical impulses originating from the atria, the upper chambers of the heart. The ECG (electrocardiogram) of atrial fibrillation shows certain distinct features: 1. Absence of P-waves: In a normal ECG, the P-wave represents the electrical activity of the atria. In atrial fibrillation, the irregular and rapid electrical impulses cause the atria to fibrillate instead of contracting in a coordinated manner. This results in the absence of distinct P-waves on the ECG. 2. Irregular R-R intervals: The R-R interval represents the time between two consecutive ventricular contractions. In atrial fibrillation, the irregular electrical impulses cause irregular ventricular contractions, leading to irregular R-R intervals on the ECG. This irregularity is often described as "irregularly irregular" rhythm. 3. Fibrillation waves: Instead of regular P-waves, atrial fibrillation may show fibrillation waves or f-waves. These are irregular and rapid oscillations seen in place of the P-waves, representing the chaotic electrical activity in the atria. 4. Narrow QRS complexes: The QRS complex represents the electrical activity of the ventricles. In atrial fibrillation, the impulses from the atria reach the ventricles in an irregular and uncoordinated manner, resulting in narrow QRS complexes. This indicates that the ventricular activation is normal. 5. Rapid heart rate: Atrial fibrillation is often associated with a rapid heart rate, typically above 100 beats per minute. This is due to the irregular and rapid electrical impulses reaching the ventricles, leading to fast and irregular ventricular contractions. Atrial fibrillation occurs due to various factors, including age, structural heart disease, high blood pressure, heart valve problems, thyroid disorders, and excessive alcohol consumption. The irregular electrical impulses disrupt the normal electrical conduction system of the heart, leading to the chaotic rhythm observed in atrial fibrillation. It is important to note that this is a simplified explanation of the ECG findings in atrial fibrillation. A healthcare professional should be consulted for a comprehensive understanding and accurate interpretation of the ECG.

Answer 241

Some asymptomatic Common symptoms: Shortness of breath Dizziness Fatigue Palpitations Complications: Heart failure: (How does AFib lead to heart failure? Heart failure means that the heart isn't pumping enough blood to meet the body's needs. AFib can lead to heart failure because the heart is beating so fast that it never properly fills up with blood to pump out to the body.) Angina: (Occasionally, the rapid heart rate associated with atrial fibrillation can result in chest pain or discomfort (angina) because of reduced blood flow to the heart muscle. People who have pre-existing heart disease are particularly susceptible to this symptom of atrial fibrillation.) Thromboembolism: (When the upper chambers of the heart (atria) do not pump efficiently, as in atrial fibrillation, there's a risk of blood clots forming. These blood clots may move into the lower chambers of the heart (ventricles) and get pumped into the blood supply to the lungs or the general blood circulation.)

Answer 242

1-Stroke prevention 2-Rate control 3-Rhythm control

Answer 243

1-Assess stroke risk: CHA2DS2-VASc stroke risk score Consider anticoagulation >1men or >2 women the long-term risk of stroke in valvular atrial fibrillation (AF) depends on clinical predictors, which are collectively assessed in the CHADS2 scoring scheme, an acronym for Congestive heart failure,hypertension, Age>75, Diabetes mellitus, and prior Stroke (1): Condition Points C Congestive heart failure 1 H Hypertension 1 A Age > 75 years plus 2 points 65-74 1point <65 0 points D Diabetes Mellitus 1 S2 Prior Stroke or TIA or thromboembolism 2 Gender male 0 female 1 Vascular disease 1point Maximum 9 points * Score Risk Anticoagulation Therapy Considerations 0 Low Aspirin or no treatment No antithrombotic therapy (or aspirin) 1 Moderate Aspirin or Warfarin Aspirin daily or raise INR to 2.0-3.0, depending on factors such as patient preference 2 or greater Moderate or High Warfarin Raise INR to 2.0-3.0, unless contraindicated (e.g. clinically significant GI bleeding, inability to obtain regular INR screening) 2-Assess bleeding risk: ORBIT score to assess risk of bleeding in people who are starting or have started anticoagulation (previously HAS-BLED score- updated NICE 2021) Risk Factor For Bleeding Points Attributed: •(older (75 years or older) 1 point •reduced haemoglobin (<13 mg/dL in men and <12 mg/dL in women), haematocrit (<40% in men and <36% in women) or history of anaemia 2 points •bleeding history 2 points •insufficient kidney function (eGFR < 60 mg/dL/1.73 m2) 1 point •treatment with an antiplatelet agent 1 point ORBIT Score Risk group Bleeds per 100 patient-years 0-2 Low 2.4 3 Medium 4.7 4-7 High 8.1 3-For stroke prevention NICE recommends anticoagulation: DOACs: Apixiban Rivaroxiban Edoxaban Dabigatran Warfarin Left atrial appendage occlusion: alternative stroke prevention for patients with AF if anticoagulants are contraindicated. Its a small sac in the middle of the muscle wall in the atrium or left atria clots which form as a consequence of AF mainly from left atrial appendage so surgical procedure to seal off the left atrial appendage. Heart surgery high risk so only used if anticoagulation not tolerated or contraindicated. NICE suggest (3): use the CHA2DS2-VASc stroke risk score to assess stroke risk in people with any of the following: symptomatic or asymptomatic paroxysmal, persistent or permanent atrial fibrillation atrial flutter a continuing risk of arrhythmia recurrence after cardioversion back to sinus rhythm do not offer stroke prevention therapy to people aged under 65 years with atrial fibrillation and no risk factors other than their sex (that is, very low risk of stroke equating to a CHA2DS2-VASc score of 0 for men or 1 for women) anticoagulation may be with apixaban, dabigatran etexilate, rivaroxaban or a vitamin K antagonist consider anticoagulation for men a CHA2DS2-VASc score of 1. Take the bleeding risk into account apixaban, dabigatran, edoxaban and rivaroxaban are all recommended as options (3) offer anticoagulation to people with a CHA2DS2-VASc score of 2 or above, taking bleeding risk into account apixaban, dabigatran, edoxaban and rivaroxaban are all recommended as options (3) if direct-acting oral anticoagulants are contraindicated, not tolerated or not suitable in people with atrial fibrillation, offer a vitamin K antagonist (3) do not offer stroke prevention therapy to people aged under 65 years with atrial fibrillation and no risk factors other than their sex (that is, very low risk of stroke equating to a CHA2DS2-VASc score of 0 for men or 1 for women) do not withhold anticoagulation solely because of a person's age or their risk of falls (3)

Answer 244

Second aspect of AF management is rate control. This first like strategy for all patients with AF as it uses less toxic drug therapy This is first line strategy unless: Reversible cause eg infection Heart failure caused by AF New onset AF within last 48hrs Rather treat cause of AF instead. Standard Beta-blockers (eg Bisoprolol) or rate limiting calcium channel blocker (eg diltiazem, verapamil) Digoxin (only if sedentary lifestyle) as it doesn’t control exercise induced heart rate. If mono therapy doesn’t control combine 2 of B-blocker, diltiazem or digoxin as add on therapy if monotherpay doesn’t work.

Answer 245

Electrical cardioversion Drug therapy: First line: standard B-blocker Others: Dronedarone is recommended by NICE Amiodarone contraindicated in heart failure

Answer 246

Paroxysmal PAF: Pill in the pocket (eg flecainide)-treat attacks only. If frequent aim to reduce frequency/prevent paroxysms use traditional rate/rhythm control strategies. In PAF don’t use digoxin as it is known to increase rate and frequency, rapid and persistent paroxysms) Abstinence from alcohol/caffeine Antithrombotic needed depending on frequency of PAF as risk of stroke is high. Paroxysms (a sudden attack or outburst of a particular emotion or activity.)

Answer 247

If other treatments had failed to control symptoms of AF is unsuitable: Left atrial ablation: RF radio frequency ablation a point in left atrium where arrhythmia generated Pace and ablate: Radio frequency is used to destroy node and a pace maker is put in to take over packing of the heart ablation of AV node + pacemaker

Answer 248

Identify pharmaceutical care issues for a patient with bradycardia (heart block) Identify the pharmaceutical care issues for a patient with tachycardia (atrial fibrillation)

Answer 249

Mr CA, 81yr old man PC: Bradycardia GP referral HPC: 3/52 weeks lethargy, dizziness PMH: AF, hypothyroidism, HT, glaucoma. Drug history: Warfarin Diltiazem XL 180mg od Doxazosin MR 8mg od Lisinopril 20mg od Levothyroxine 125mcg od Omeprazolr 20mg od Bimatoprost E/D left eye nocte Brinzolamide E/D left eye tds Combigan (Brimonidine 0.2%/Timolol 0.5%) E/D left eye bd NKDA Diagnosis: ECG complete hearty block initially, now second degree heart block. Plan: PPM permanent pace maker Review drug therapy: Stop warfarin because pace maker insertion surgery due to risk of bleeding. Stop diltiazem-rate controlling calcium channel blocker Review combigan eyes drops contains Timolol which is Beta blocker as this can worsen bradycardia. In Heart block consider Rate and Rhythm Rate: Count number of squares between same point eg R peak. Rhythm: Regular? Check number of squares between each ORS complex P wave for every QRS complex 1:1 ratio In cardiac block Regular P wave but not always a QRS complex —> Heart block. But in AF no P wave as no atria contraction or coordinated atria contraction.

Answer 250

1-First degree heart block: 1:2 ratio of P waves to QRS complexes but abnormally long PR interval Conduction through AV node is delayed May develop into 2nd or 3rd degree heart block so carefully monitor 2-Second degree heart block: Not all P waves result in a QRS complex Atrial contraction not always followed by ventricular contraction May follow a pattern eg 2:2 ratio where alternate P waves are not conducted 3-Third degree heart block (complete heart block) No conduction through AV node so no QRS wave Atrial contraction continues due to SA node Ventricular contraction due to automatic rhythm of AV node (escape rhythm) but much slower so patient won’t die immediately but can’t be maintained for long. So it is a Medical emergency!

Answer 251

Dual chamber pace-maker insertion Pre-med: Flucloxacillin iv 1g STAT Co-dydramol ii STAT To prevent infection and pain killer Procedure: Gentamicin 80mg STAT used as antibiotic wash into the pocket to make sure no infection occurs Post PPM: Restart warfarin Restart Combigan Restart diltiazem Restart of rate controlling drugs depends on initial indication.

Answer 252

On admission: Strip rate controlling drugs Stop anticoagulants Review eyes drops Prior to discharge: Restart anticoagulants and eye-drops Consider restart rate controlling depending on indication/consider alternative.

Answer 253

Mr GH, 60yr old man PC: uncontrolled AF (GP referral) -ventricular rate 120bpm, irregular HPC: 2/52 racing heart PMH: AF, stable angina, HT Diagnosis: uncontrolled AF causing exacerbation of Angina. Previous failed D.C cardioversion Drug history: Dabigatran 150mg bd Bisoprolol 10mg od Perindopril 4mg od Amlodipine 5mg od ISMN MR 30mg od NKDA New prescription: Diltiazem XL 120mg OD 2nd line treatment Ventricular rate still 100bpm. 3rd line Rhythm control: Amiodarone: 200mg tds 1 week then increase to 299mg bd 1 week then 200mg of maintenance. Alternative unlicensed regime: 400mg tds 3days then 200mg od maintenance Rate control: Digoxin 500mcg x2 stat doses 6hrs apart then 125mcg od maintenance.

Answer 254

Amiodarone s/e: Side-effects: Bradycardia Phototoxicity Slate-grey skin Taste disturbances Corneal microdeposits Liver dysfunction Thyroid dysfunction Pulmonary toxicity due to pulmonary fibrosis report any problem with breathing or SOB Baseline LFT &TFT then every 3 months. Digoxin s/e: N&V Blurred vision Anorexia Bradycardia

Answer 255

Amiodarone causes increased levels of digoxin up to double levels of digoxin To avoid this interaction Reduce digoxin dose by 50% if continued use in combination with Amiodarone Often stop digoxin once ventricular rate reduced so not often an issue! 1 to 4 weeks

Answer 256

Amiodarone monitoring and counselling Digoxin monitoring and counselling Management of Amiodarone and digoxin interaction Anticoagulation

Answer 257

Objectives: Epidemiology, aetiology, risk factors, diagnosis and management of venous thromboembolism VTE: Deep vein thrombosis DVT Pulmonary Embolism PE

Answer 258

Extrinsic intrinsic pathway Intrinsic pathway The clotting pathway, also known as the coagulation cascade, is a complex mechanism that helps to prevent excessive bleeding and promote the formation of blood clots. It involves a series of sequential reactions that ultimately lead to the formation of a fibrin clot. The clotting pathway can be divided into two main pathways: the intrinsic pathway and the extrinsic pathway. Both pathways converge to activate a common pathway, leading to the formation of a fibrin clot. In the intrinsic pathway, the process is initiated when blood comes into contact with a foreign surface, such as damaged blood vessels. This activates a series of clotting factors, including Factor XII, Factor XI, and Factor IX. These factors interact with one another in a cascade, ultimately leading to the activation of Factor X. In the extrinsic pathway, the process is initiated by tissue damage and the release of tissue factor (Factor III). Tissue factor combines with Factor VII to form a complex that activates Factor X. Once Factor X is activated, it combines with Factor V to form a complex called prothrombinase. Prothrombinase then converts prothrombin (Factor II) into thrombin (Factor IIa). Thrombin plays a central role in the clotting pathway, as it converts fibrinogen (Factor I) into fibrin. Fibrin forms a mesh-like network that traps platelets and red blood cells, forming a stable blood clot. The clotting pathway is tightly regulated by various inhibitors to prevent excessive clot formation. One important inhibitor is antithrombin III, which inhibits several clotting factors, including thrombin. Another important inhibitor is tissue factor pathway inhibitor, which regulates the extrinsic pathway. Overall, the clotting pathway is a complex mechanism that involves multiple clotting factors and reactions. It plays a crucial role in maintaining hemostasis and preventing excessive bleeding.

Answer 259

Thromboembolic event occurring within the venous system: DVT PE

Answer 260

Thromboembolic event occurring within the venous system: DVT deep vein thrombosis PE pulmonary embolism Activation of clotting and coagulation in areas of reduced blood flow but unlike MI or Stroke vessel is normal without atherosclerotic plaque.

Answer 261

Epidemiology: 1in1000 people have DVT per year Higher incidence in hospitals Case fatality range if between 1-5% More common in males Patients over the age of 40 Aetiology: Stagnation/stasis of blood flow Hypercoagulability Vascular injury Endothelial injury Collagen exposure Platelet aggregation Thrombus Risk factors: Age Obesity Varicose veins Long haul flights Immobility bed rest >4days Pregnancy & puerperium Previous VTE Male sex Additional risk factors predisposing conditions: Trauma or surgery (especially to pelvis, hip or lower limb) Malignancy (chemo and radiotherapy) CCF, recent AMI Infection Hormone therapy (COCs, HRT, Tamoxifen) Inherited acquired disorders (thrombophilias) Vasculitis

Answer 262

•Clinical feature: Asymptomatic Unilateral leg swelling Tenderness, warmth, redness Superficial veins Calf pain Oedema

Answer 263

1-Wells clinical score: If alternative diagnosis (as likely or greater probability then DVT) Total of above score: High probability >3 Moderate probability 1or2 Low probability <0 Each clinical parameter below gets 1 point: Active cancer 1 Paralysis or recent plaster immobilisation 1 Bedridden for more then 3 days/major surgery on past 4 weeks. Entire leg swelling Localised tenderness along distribution of deep venous system Calf swelling of >3cm compared to asymptomatic leg CVD Pitting oedema Previous DVT Collateral superficial veins (nonvaricose) 2-D-dimer assay D-dimer is a Fibrin degradation product. Thrombus formation leads to fibrinolytic response which causes plasmin generation which leads to fibrin breakdown and this causes releases of fibrin degradation products (D-dimer). A D-dimer assay is a blood test that is used to help diagnose or rule out deep vein thrombosis (DVT). DVT is a condition where blood clots form in the deep veins, usually in the legs. The D-dimer test measures the levels of a substance called D-dimer in the blood. D-dimer is a protein fragment that is produced when blood clots break down. The test is helpful in the diagnosis of DVT because if there is no clotting occurring in the body, the D-dimer levels should be low. However, if there is a clot present, the D-dimer levels tend to be elevated as the body tries to break down the clot. A negative D-dimer result can help to rule out the presence of a clot, especially in patients with a low pre-test probability of DVT. This means that if the D-dimer test is negative, it is highly unlikely that a clot is present, and further testing may not be necessary. However, it is important to note that a positive D-dimer result does not confirm the presence of a clot. Other diagnostic tests, such as an ultrasound, may be needed to confirm the diagnosis of DVT. Overall, the D-dimer assay is a valuable tool in the evaluation of patients suspected to have DVT, as it can help guide further testing and treatment decisions. D-dimer tests: High negative predictive value especially if combine with low well-score then it confirms unlikelihood of DVT. Not good in positive predictive values because it is not specific to DVT. As D-dimer can form in many conditions due to clotting or thrombosis eg in cancer, trauma, injury, recent surgery, haemorrhage, sepsis and pregnancy. False positives common in the elderly D-dimer Affected by position of clot lower sensitivity in the lower calf pain of the reduction in the quantity of fibrin that’s produced by clots in that area. Affected by heparin use check d-dimer levels before starting heparin treatment. 3-Diagnostic imaging: •Venography Previously gold standard diagnostic test Not routinely used •Duplex ultrasonography Non-invasive High sensitivity •Magnetic Resonance imaging Not widely available Expensive

Answer 264

Physical trauma, tear in calf muscles, sprain, haematoma, tendon rupture, fracture. Cellulitis Ruptured Bakers cyst Oedema

Answer 265

Identify and treat any underlying cause Prevent damage to valves of veins Allow normal circulation to limbs ***prevent PE*** Immediate management with injectable anticoagulants Heparin first line choice 1-Unfractionated Heparin UFH: Intrinsic pathway binds to antithrombin III this then inhibits factor xa which inhibits thrombin formation. IV/SC administration Side effects Haemorrhage Thrombocytopenia (monitor platelets >5days) Hyperkalaemia Osteoporosis, alopecia Monitor unfractionated heparin via a blood test APTT Activated partial thromboplastin time Normal APTT=30-49secs Related to changes in intrinsic pathway APTT ratio= pts APTT at a given time/APTT reference value Target: APTT 80-100secs APTT ratio 1.5-2.5 if below that range increase amount of heparin given and if above reduce amount of heparin. Measuring blood clotting time normal APTT 30-40secs

Answer 266

Enoxaparin, Tinzaparin Less effect on thrombin m, more effect on factor Xa. Do not monitor APTT (specific anti-xa assay if needed-not routine) Longer half life-od admin Lower risk of thrombocytopenia and oestroprosis if used long term unlike UFH

Answer 267

•Coumarins: Warfarin Acenocoumarol (nicoumalone) Phenindione •DOACs (rivaroxaban, Dabigatran, apixiban, Edoxaban) •Duration: usually 3 months (can be longer) Warfarin acts in extrinsic pathway Inhibits metabolism of vitamin K and affects the activation of factors II, VII, IX and X. Onset 8-12hrs, but full effect not seen for 48-72hours Monitor: Baseline: clotting screen, Hb, Plts, LFTs INR and signs of bleeding Prothrombin Time PT & International Normalised Ration INR: Reference range: 10-14seconds Relates to changes in extrinsic or common pathways Expressed as a reference to a standard preparation—>INR Normal INR=1-1.2 Used to monitor warfarin therapy Target INR •Loading dose schedules Eg day 1 10mg, day 2 10mg, day 3 INR Dose may be less if: High PT, LFT CCF Parental feeding Elderly Weight less than 60kg Other drugs which may potentiate INR Loading dose eg day 1 10mg, day 2 INR Counselling points: Indication Dose/colour Time Monitoring INR/booklet Interactions: Drugs/food See BNF and Stockley P459 metabolism Haemorrhage and increased INR See BNF

Answer 268

Direct thrombin inhibitor Treatment of VTE + Prophylaxis of VTE post surgery Does not require TDM Haemorrhage Duration dependent on indication

Answer 269

Direct inhibitor of activated factor x Treatment of VTE +Prophylaxis of VTE post surgery Doesn’t require TDM Nausea and haemorrhage Duration dependent on indication

Answer 270

Compression stockings Assist calf muscle pump Decrease venous hypertension, venous valvular reflux and leg oedema. Aids microcirculation Prevention of venous ischemia

Answer 271

1 in 1000 people per year in the UK 2nd most common cause of unexpected death after IHD Increased frequency with age High mortality rate Adverse prognostic factors Clinically major embolism, cancer, congestive cardiac failure and previous or current DVT.

Answer 272

Blood clot it thrombus formed in the venous system Break free and embolise to lung Normally multiple clots Lower lobes more common Obstruct pulmonary artery system •Increase pulmonary artery pressure •Right heart failure •Infraction of lung tissue *Clinical manifestations: Acute onset chest pain General malaise Dyspnoea shortness of breath Haemoptysis coughing blood Cough Wheeze Tachypnea RR>16/min fast breathing Abdominal pain Anxiety Cardiac arrhythmias Syncope fainting temporarily

Answer 273

•Chest X-rays Pleural effusion excess fluid in pleural cavity Elevated diaphragm Western mark sign collapse of pulmonary blood vessels. •V/Q scan IV technetium 99m labelled human albumin Inhalation of xenon-133 gas Perfusion and ventilation High sensitivity Provide images of patient perfusion and ventilation of lungs when injecting a radioactive isotope in the blood this allows for visualisation of lung perfusion. Radioactive isotope inhaled gives image of lung ventilation In PE reduction of lung perfusion due to blood clot rather than ventilation. In other conditions both can occur but this result is specific to only PE •Laboratory tests Decreased arterial oxygen saturation’s PaO2. Increased WCC Increased ESR Increased D-dimer levels •ECG Often normal Tachycardia •CTPA computed tomographic pulmonary angiography 100% sensitive and 100% specific for large central emboli. Able to see small clots •Pulmonary angiography Injecting contrast media into main pulmonary artery +ve results shows obstruction to pulmonary artery blood flow Ideal diagnostic tool but invasive

Answer 274

ACS Pneumonia CCF AF Acute Anaemia COPD/Asthma

Answer 275

Supportive therapy Immediate anticoagulations •as DVT Fibrinolytic: Urokinase Streptokinase Alteplase Reteplase

Answer 276

Thrombolytics: Activating plasminogen—>breakdown of formed fibrin. Only used for massive PE Increase risk of haemorrhage C/I recent surgery, active bleeding sites renal/liver disease, history of stroke.

Answer 277

Principles of VTE prophylaxis Assessment of risk NICE Guidance Types of VTE prophylaxis

Answer 278

Risk of VTE is DVT & PE is x10 in patients who are: Hospitalised patients after trauma, surgery or immobilising medical illness. Pregnant and puerperal women. All hospital in patients require thromboprophylaxis Routine prophylaxis reduce morbidity, mortality and costs in hospitalised patients at risk of DVT and PE.

Answer 279

Assess individual risk factors: Active cancer or cancer treatment Age over 60years Critical care admission Dehydration Known thrombophilias Obesity (body mass index BMI over 30kg/m2 One or more significant medical comorbidities Eg heart disease, metaboli, endocrine, or respiratory pathologies; acute infectious diseases; inflammatory conditions. M Personal history/ first degree relative with a history of VTE

Answer 280

Orthopaedic surgery Cardiac surgery Vascular Urological Thoracic Gynaecological Neurosurgery

Answer 281

Active bleeding Acquired bleeding disorders eg liver failure Concurrent use of anticoagulants Lumbar puncture/epidural/spinal anaesthesia expected within the next 12hrs. Lumbar puncture/epidural/spinal anaesthesia within the previous 4hrs Acute stroke Thrombocytopenia (platelets less than 75x10/l) Uncontrolled systolic hypertension 230/120mmHg it higher. Untreated inherited bleeding disorders such as haemophilia.

Answer 282

Mechanical prophylaxis: Thigh length graduated compression stockings From admission until usual levels of mobility Pharmacological prophylaxis: LMWH dalteparin s/c 5000IU od Enoxaparin s/c 40mg od Fondaparinux Pre-existing anticoagulation/antiplatelet therapy Need extra caution if regional anaesthesia!! High risk surgery continue use of pharmacological prophylaxis for 4weeks post surgery

CVD Flashcards

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