Revision Cards Flashcards

Question

What is atrial tachycardia?

Answer 1

Electrical impulse originates in atrial tissue different than the sinoatrial node. Rate faster than 100 bpm, although occasionally the rate may oscillate and be slower. Can be due to abnormal automaticity, triggered activity, or reentry in the atrial tissue. There are multiple p waves/atrial waves that are trying to hit AVN, but the ventricles can only respond to some of the hundreds fired from the atria. Gives a variable ventricular response.

Answer 2

Classified by a rate of greater than 120 bpm and at least three wide QRS complexes in a row. The impulse is either being generated from increased automaticity of a single point in either the left or the right ventricle, or due to a reentry circuit within the ventricle. Most commonly caused by a scarring of the heart muscle by a previous myocardial infarction.

Answer 3

Rapid and irregular beating of the atria. Normal regular impulses generated by the SAN are overwhelmed by disorganised electrical impulses originating in the roots of the pulmonary veins. This leads to irregular conduction of ventricular impulses that generate the heartbeat. Atria show fibrillation rather than true P waves or atrial rhythm. Irregular ventricular response. Leads to the possibility of an atrial thrombus which can lead to a stroke. Treated with anti-coagulants.

Answer 4

The heart quivers instead of pumping due to disorganised electrical activity in the ventricles that is so chaotic that the heart muscles can’t pump blood effectively. No defined rhythm or output. This type of heart condition is life-threatening, and must be treated immediately or the person will likely die. Treated with electrocardioversion to reset heart rhythm.

Answer 5

Sympathetic stimulation of the heart increases heart rate (positive chronotropy), inotropy and conduction velocity. Effects mediated by B1-adrenoreceptors that lead to cAMP activation which acts as an intracellular messenger. Increased slope of pacemaker potential so it is easier to reach the threshold potential. Increased automaticity (risk of arrhythmias).

Answer 6

Parasympathetic stimulation of the heart reduces increases heart rate, inotropy and conduction velocity. Mediated by muscarinic (M2) acetylcholine receptors found in nodal and atrial tissue. Decreased slope of pacemaker potential, takes longer to reach the threshold level. Decreased automaticity. Inhibits atrioventricular conduction. Vagal tone (activity of vagal nerve) causes P-R interval increases because the vagal nerve slows the AVN, increasing the delay, slows firing of SAN too.

Answer 7

- Class 1: Sodium channel blockers that preferentially affect channels that are in-use (wide open or refractory). Can be used to treat tachycardia. 'Use-dependent'. These drugs can suppress heart function because electrical activation is intrinsically linked to contractility. 1a: disopyramide, quinidine, procainamide 1b: lidocaine, mexilitene 1c: flecainide, propafenone -Class 2: B-adrenoreceptor antagonists (b-blockers) Propanolol, nadolol, carvedilol: non-selective Bisoprolol, metoprolol: B1-selective - Class 3: Act to prolong the action potential (plateau phase) amiodarone and sotalol. Encourages refractory. - Class 4: Calcium channel blockers: verapamil and diltiazem

Answer 8

Digoxin is type of cardiac glycoside extracted from foxgloves. Acts to inhibit Na/K pump to slow heart. Main effects: -Bradycardia (increased vagal tone) -Slowing of atrioventricular conduction (increased vagal tone) -Increased ectopic activity, by blocking Na/K you end up with more Na inside the cell than normal, no Na gradient to activate Na-Ca pump, so more Ca stays within the cells. -Increased force of contraction (caused by increased intracellular Ca) Commonly used in atrial fibrillation to reduce venrticular rate response by blocking AVN. Used in severe heart failure as a positive inotropic.

Answer 9

Narrow therapeutic range (levels in blood must reach a certain point to be active). Symptoms: Nausea, vomiting, diarrhoea, confusion.

Answer 10

Amiodarone and Sotalol (class 2 but has class 3 effects) can cause other cardiac arrhythmias. - QT prolongation: longer time between Q and T. Can lead to a life threatening ventricular arrhythmia known as torsades de pointes which can result in sudden cardiac death. - Polymorphic venrticular tachycardia: Form of ventricular tachycardia in which there are multiple ventricular foci with the resultant QRS complexes varying in amplitude, axis and duration.

Answer 11

- Can cause QT prolongation and Polymorphic venrticular tachycardia - Wide distribution in the body: can cause interstitial pneumonitis (large inflammation response in the lung) - Abnormal liver function - Hyperthyroidism/Hypothyroidism: iodine in drug interferes with thyroid metabolism - Sun sensitivity: gives a high risk of burning - Slate grey discolouration of skin (after 10/15/20 yrs) - Corneal micro deposits: symptoms such as visual halos or blurred vision in as many as 10% of patients. Reversible. - Optic neuropathy (damage to optic nerve): 2-fold increased risk. Characterised by an insidious onset, slow progression, bilateral simultaneous visual loss, and protracted disc swelling. - Multiple drug interactions: protein bound in the bloodstream, can misplace other drugs - Very large volume of distribution: take 3 months after terminating dosage before the drug leaves the body.

Answer 12

Cardiac output is the amount of blood pumped by the heart per minute. Can be increased by an increase in HR or volume per beat. Measured in litres/min. Cardiac output = heart rate x stroke volume Normally at rest it is 4.9 litres/min = 70 beats/min x 70mls. The total blood in the vasculature is 5 litres so the entire blood volume is pumped every minute. BUT in exercise, ~35 litres/min so total blood pumps in less than 10 seconds.

Answer 13

Measured in %. Refers to the percentage volume of blood ejected with each cardiac contraction. Normally ~55-60% at rest, creating a reserve than remains in the heart. In a heart failure patient, may only have an ejection fraction of 20/30%.

Answer 14

- Sympathetic nervous system: when we start to exert ourselves, SNS instantaneously acts on SAN to increase HR and therefore CO. - Parasympathic nervous system: decrease HR but doesn't effect contractility. - Circulating catecholamines (adrenaline & noradrenaline) slower than SNS because it takes time for adrenal gland to release and distribute catecholamines for effect on the heart. - Drugs: for example salbutamol is a B-adrenoreceptor agonist which can act on the heart, as well as the lungs, to increase HR and CO.

Answer 15

Intrinsically the muscle has to be viable. In MI, this is not the case. Intrinsic FACTORS -Intracellular calcium: Acts to maintain plateau phase of AP but also initiates contraction through actin-mysoin action. Disturbing Ca, disturbs contractility. -Oxygen, free fatty acids, ATP (nutrients): Must be available for the heart to function. In a failing heart, these things may be lacking.

Answer 16

Factors outside of the heart that affect its behaviour. - Preload/filling pressure: Loading of the heart prior to contraction. Blood flow follows a continuous hydrolic system, pulsatile blood flow on arterial side which goes through the capillary bed and follows a continuous flow on the venal side. Blood filling is required for the heart to work. Measured by left ventricular end-diastolic pressure (LVEDP). - Afterload: Resistance to ejection. Circulation has resistance due to the maintenance of BP by pre-capillary resistance vessels. Afterload determines how much blood the heart ejects according to that pressure. - Sympathetic activity has a positive ionotrophic and chronotrophic effect. Independent of preload and afterload.

Answer 17

L-type calcium channels are present in the cardiac muscle. Voltage-dependent (activated by AP) calcium channels are present on the PM of the cardiac cells. Calcium comes in but it is not enough, instead it acts as a trigger to cause the ryanodine receptors on the sarcoplasmic reticulum to release Ca from the store [chain reaction].

Answer 18

Within the cardiac muscle, there are hundreds of actin filaments, covered with troponin and tropomyosin which block off its binding sites. When Ca is added, it binds to the troponin and the change in the configuration exposes the myosin binding sites. As myosin head binds to actin, release of Pi initiates 'power-stroke' whereby the myosin head changes conformation so that the filaments are forced to slide past one another. ADP is released and ATP binds, causing it to release actin.

Answer 19

The actin-myosin crosslinkages are important because they - Allow the AP to reach all of the muscle simultaneously - Allow the whole muscle to contract simultaneously

Answer 20

Otto Frank and Ernest Starling Frank performed work in frogs and found that if you stretch a cardiac cell before it is stimulated, it contracts more than if it was non-stretched. Starling found this to be the case in humans too. The graph shows that increases in filling pressure/LVEDP/myocardial fibre stretching leads to an increase in the force of contraction which leads to an increase in stroke volume and cardiac output. (heart rate stays the same).

Answer 21

Frank-Starling curve is relatively steep in a normal heart which means that if you have changes in venous return (preload) you simply move up (increase in VR) or down (decrease in VR), it doesn't move the graph as a whole. Changes in VR don't tend to have a major impact on CO because the SNS usually kicks in. However in heart transplant patients, they don't have SNS/PNS so CO is controlled by F-S mechanism or catecholamines.

Answer 22

The ventricle operates on a family of curves determined by afterload and contractility. Curve moves down: If a patient suffers from a MI, they experience DECREASED CONTRACTILITY, reducing stroke vol. To rescue this, LVEDP increases to maintain CO. Same applies id you have an INCREASED AFTERLOAD. For example if you have an increased BP, there is an initial drop in SV causing LVEDP to increase. Curve moves up: INCREASED CONTRACTILITY or DECREASED AFTERLOAD due to vasodilation causes the gradient of the curve to become steeper. Shows an increase in SV but decrease in LVEDP.

Answer 23

Isoprenaline is a cardiac stimulant. if you give a cardiac muscle cell a stimulus, tension/contraction occurs due to increased Ca. However, if you have a background of a drug which is sympathomimetic the same stimulus gives an enhanced calcium influx and enhanced contraction. For any particular LVEDP there is a greater stroke volume under sympathetic stimulation. No change in preload/afterload.

Answer 24

In heart failure, the curve is a lot flatter. In order to establish the F-S mechanism you have to increase the filling pressure with very little return in stroke volume. This increase in left ventricle pressure, eventually leads to increased pressure in pulmonary veins, leading to pulmonary oedema due to fluid escaping from the vasculature into the lungs. Untreated heart failure may have both symptoms of pulmonary congestion and the fatigue due to a low cardiac output.

Answer 25

Diuretics can bring the patient back down the curve to remove symptoms of pulmonary congestion, but have to be careful not to push them into low cardiac output symptoms. ACE inhibitors can help by offloading the heart, causing vasodilation increasing the cardiac output. Digoxin is a positive inotrope which acts to increase the contraction caused by the same stimulus. Puts the patient in a better CO state so you can use diuretics without pushing them into low CO.

Answer 26

The arteries of the coronary circulation that transport blood into and out of the cardiac muscle. They are mainly composed of the left and right coronary arteries both of which give off branches and themselves branch from the aorta. On the surface of the heart within fatty layers (clinically easily accessible). Perfuse into the muscle.

Answer 27

Coronary blood flow = Perfusion pressure (difference between aortic diastolic pressure and LVEDP) / Resistance Coronary flow only occurs in diastole because capillaries get squashed in systole.

Answer 28

``` Arrested heart (alive, not contracting) = 2 Resting heart rate = 8 In heavy exercise = 70 Something has to change to allow for this mega change. Brain = 3 Contracting muscle = 50 Skin = 0.2 Heart is a really dynamic tissue, oxygen consumption changes a lot. ```

Answer 29

Oxygen delivery = Arterial oxygen concentration x Coronary blood flow Very little oxygen dissolved in plasma. Mainly determined by oxygen bound to haemoglobin Anemia will cause reduced oxygen delivery. Since breathing 20% O2 gives you a blood concentration of 98% O2, can't increase that much more so coronary blood flow is the primary determinant of O2 delivery.

Answer 30

You can get a direct trace of arterial BP using an arm catheter. Every time the heart beats there is a change in pressure. Peak in pressure is systolic BP. When it relaxes, pressure doesn't drop to 0 because the aortic valve closes, maintaining a certain level of pressure (diastolic BP kept at about 80). Important that this is maintained (in aorta and hence all branches) so that you can get perfusion to the cardiac muscle.

Answer 31

As the left ventricule contracts, pressure wave reaches about 120. As it relaxes there is nothing to support diastolic pressure so pressure drops to almost zero, but as diastole is occuring ventricle is filling from the atria so it never truly reaches zero.

Answer 32

There is the same systolic blood pressure between the two. However, the diastolic pressures are very different. Arterial diastolic BP = 70 LVEDP = 10 This pressure difference causes perfusion. The window for coronary flow is between the two systoles. There are physical, local, nervous, humoral factors that can affect the size of the window. It can become bigger in either direction (if time is longer (HR) or if the gradient is bigger), this leads to more perfusion.

Answer 33

Time of systole doesn't tend to change majorly but diastole does. -Tachycardia: disproportionately reduces diastole by reducing time -Raised LVEDP: Due to high BP. Decreases perfusion pressure by moving bottom ventricle line upwards -Reduced diastolic pressure: Decreases perfusion pressure by moving arterial top line downwards ALL narrow the window for coronary flow. Patients with coronary artery disease can be fine at normal rest but will be symptomatic when exercising.

Answer 34

Ability of an organ to maintain a constant blood flow despite changes in perfusion pressure. Coronary blood flow = Perfusion pressure / Resistance If perfusion pressure begins at 100mmHg but drops suddenly due to septic shock, blood loss etc, there is a reduction in flow. You would think that this causes an increase in resistance but this is not the case because of autoregulation. Autoregulation means that the heart dilates the resistance circulation. This causes the flow to increase to an almost recovered level. This is maintained despite the reduced pressure. Autoregulation cannot occur if perfusion pressure is too high or too low. But there is a good sized window where it can recognise a drop in partial pressure of O2 reaching the heart.

Answer 35

Local control by metabolites are most important. Hypoxia (low pO2) causes a marked increase in coronary vasodilation in situ but not in an isolated coronary artery in vitro. This suggests that its not a property of the arteries themselves but of the local metabolites, namely adenosine. There are others which will build up when metabolism isn't fully aerobic: potassium ions, carbon dioxide, hydrogen ions, lactic acids.

Answer 36

Less important. In larger vessels, this is mediated by a-adrenoreceptor which causes vasocontriction. In smaller vessels, this is mediated by B2-adrenoreceptors which causes vasodilation.

Answer 37

This can be caused by one major stenosis of a coronary artery or in a more diffused fashion, multiple stenosis cause a 'string of sausages' look. If you have the correct perfusion pressure but have stenosis you won't have the reserve to supply the heart in activity.

Answer 38

The heart produces cardiac natriuretic peptides in response to stretch, increased pressure or volume overload. - Atrial natriuretic peptide (ANP) is produced in granules in atria that respond to stretch. - Brain natriuretic peptide (BNP) is produced by the ventricles in response to stretch. - C natriuretic peptide is produced by the endothelia

Answer 39

- Increase the renal excretion of sodium (natriuresis) and sodium (diuresis) - Relax vascular smooth muscle: dilates afferent, constricts efferent which increases perfusion pressure - Increased vascular permeability - Inhibit the release and actions of Aldosterone, Angiotensin II, Anti-diuretic hormone - Acts as a counter-regulatory system to the renin-angiotensin system

Answer 40

Cardiac natriuretic peptides are metabolised by neural endopeptisade (NEP, neprilysin). NEP inhibition increases levels of natriuretic peptides. Entresto is a heart failure drug that combines the action of Sacubitril (neprilysin inhibitor) and Valsartan (Angiotensin II blocker). Allows for vasodilation and increase in cardiac natriuretic peptides.

Answer 41

NICE: Complex clinical syndrome of symptoms and signs that suggest that the efficiency of the heart as a pump is impaired. ESC guidelines: Abnormality of cardiac structure or function leading to failure of heart to deliver oxygen at a rate commensurate with requirements of metabolising tissues despite normal filling pressures/at the expense of increased filling pressures. Secondary to coronary artery disease and/or MI, kidney failure, sleep apnea, viral infections which may cause loss of muscle activity,

Answer 42

1 million cases in the UK 50% increase predicted in the next 25 years due to the aging population (by 2032 16m will be over 65 - 23%). It is a disease of the elderly, rarely seen below 65 years, very common over 80. More common in men, MI more common in men, MI may lead to HF. 70% of HF budget towards hospitalisation which may require 2/3/4 weeks.

Answer 43

Poor prognosis >30% mortality within 1 year, then 10% per year. From 1988 to 1999, prognosis did improve for HF, but it still carries a similar prognosis to colorectal and breast cancer. Key aims include: Keep people out of hospital, keep people from dying, keep people free from symptoms. It is more cost-effective to develop drugs to keep people out of hospital.

Answer 44

Majority of HF patients have LVSD (left ventricular systolic dysfunction) meaning the ventricle doesn't contract properly usually due to a heart attack. Others have HFPEF (HF with preserved ejection fraction) whereby there is an abnormal diastolic function, which manifests as an increase in the stiffness of the heart's left ventricle and a decrease in left ventricular relaxation when filling with blood before the next beat. Most evidence for pharmacology is in chronic HF due to LVSD.

Answer 45

Acute HF: something has suddenly happened to cause the HF | Chronic HF: long-term problem over weeks and months, alternate between well, unwell, well etc

Answer 46

Main benefit is with vasodilator therapy via neurohumoral blockade (RAAS-SNS) and not from direct left ventricular stimulants. Following an insult to the heart (e.g. MI) you get a RAAS-SNS response. So best treatment is to target this response.

Answer 47

They are related but separate entities, you can have one without the other. You can see and measure LV dysfunction using an echocardiogram but HF is seen in the signs and the symptoms in the patient.

Answer 48

-Reduced cardiac output (forward flow) means patients experience fatigue and exercise intolerance. -Increased filling pressure (backward pressure). If output is impaired, filling pressure increases, heart dilates, increased pressure in pulmonary vein upstream of ventricles leading to pulmonary oedema. Patients want to be sat up to use all respiratory muscles. More commonly have chronically raised left atrial pressure (chronically congested). Breathless on exertion. If the right ventricular end diastolic pressure is raised you can see a raised jugular vein (pressure is reflected because there are no valves). When the pressure on the right side goes up, all venous pressure increases, congesting the liver, peripherally at the ankles. Also causes anasarca and ascites.

Answer 49

The curve is depressed for HF patients. Have the risk of experiencing pulmonary congestion and hypotension caused by low cardiac output. Diuretics and vasodilators can work to reduce preload without leading to abnormally low CO.

Answer 50

Help you lose Na and water to tackle oedema. Can be used in HF and Hypertension. CLASSES: -Thiazides and related drugs (act on distal tubule): weak diuretics, used more in hypertension -Loop diuretics (act on loop of Henle): very powerful, used for HF -Potassium-sparing diuretics: diuretics usually end up depleting K so these were developed to relieve loss of K -Aldosterone antagonists: weak diuretics, antognises Aldosterone which is part of RAAS

Answer 51

Thiazide and related diuretics: Bendroflumethiazide, Hydrochlorothiazide, Chlorthiazide Loop diuretics: Furosemide and Bumetanide (better absorbed) Potassium-sparing diuretics: Spironolactone, Eplerenone (aldosterone antagonists which also spare K). Amiloride and Triamterine (older tend not to be used).

Answer 52

Due to the chemical structure of Spironolactone, it has an eostrogen-like effect. Small percentage of men can get enlarged and painful breast tissue (gynecomastia). Eplerenone is more expensive but doesn't give these effects.

Answer 53

- Hypovolaemia and Hypotension (mainly loop diuretics) - Hypokalaemia - Hyponatraemia - Hypomagnesaemia - Hypocalcaemia - Erectile dysfunction (mainly thiazides) - Raised uric acid (hyperuricaemia - gout crysts in joints) - Impaired glucose tolerance, increase instance of diabetes

Answer 54

Vasodilators act to reduce the resistance (afterload) to increase cardiac output. Hydralazine (decreases blood pressure) combined with Isosorbide dinitrate (nitrates dilate veins and arteries). Dinitrate is metabolised to mononitrate so now we just used isosorbide mononitrate.

Answer 55

Trial in 1986: Effect of vasodilator therapy oon mortality in chronic congestive heart failure Used 642 men with HF symptoms. Given either placebo, prazosin (a-blocker) or combination of hydralazine and isosorbide dinitrate. Placebo and prazin group were almost identical but the combination did significantly reduce mortality (36% 3 year reduction) and improved ejection fraction.

Answer 56

In response to heart failure... - Cardiac: loss of arterial pressure, cardiac output, loss of perfusion to the kidneys - Systemic: this activates the baroreceptors which activate the sympathetic nervous system and the Renin-angiotensin-aldosterone system

Answer 57

Compensatory mechanism is thought to be targeted to blood loss rather than heart failure as it is a relatively new phenomenon. In blood loss, you lose volume, venous return to the heart decreases, preload decreases, BP decreases and there is decreased perfusion to the kidneys, this activates the baroreceptors and leads to SNS (fast) and RAAS (slow).

Answer 58

In RAAS, Angiotensinogen is converted to Angiotensin I using Renin, then Angiotensin I is converted to Angiotensin II using ACE. Angiotensin II is a powerful vascontrictor which also leads to salt retention, aldosterone release and tubular sodium reabsorption leading to sodium and water retension. SNS releases noradrenaline which acts to increase cardiac output and peripheral resistance, acting to control blood pressure. SNS (noradrenaline) also positively encourages the action of Renin, increasing the levels of Angiotensin I. Angiotensin II also increases peripheral resistance and cardiac output reinforcing SNS action.

Answer 59

- Tachycardia: increased cardiac output - Positive inotropic effect: increased cardiac output - Vasoconstriction: increased blood pressure - Sodium and water retension: increased circulatory volume Which is ALL GOOD!

Answer 60

Initiates same response to acute blood loss. - Tachycardia: increased workload and O2 demand - Positive inotropic effect: increased workload and O2 demand - Vasocontriction: increased afterload - Sodium and water retention: increased preload and oedema - Chronic adrenergic stimulation (bathed in noradrenaline): myocyte toxicity and arrhythmia Which is ALL BAD!

Answer 61

- Aldosterone antagonists prevent aldosterone and angiotensin II from being produced in the first place or block them. - ACE inhibitors block serum ACE in order to block the RAAS pathway to a certain extent - AR blockers can block angiotensin II that has got through - B-adrenergic antagonists can be used to block the sympathetic neurous system (noradrenaline action) - Renin inhibitors are used for hypertension

Answer 62

Spironolactone in Heart failure. Rales study in 1999 Drug vs. Placebo in blind trial Count the number of death over 36 months HF have a natural history of 75% survival after 1 year. Curves diverge early (within 2-3 months) and continue to diverge showing a significant increase in survival probability of the patients.

Answer 63

- 253 patients with severe heart failure. Enalapril vs. placebo. At 12 months, patients normally have 60% mortality, treatment reduces mortality to 40%. - 2006 patients with heart failure following a MI. Ramipril vs. placebo. At 12 months, patients normally have 30% mortality, treatment reduces mortality to 20%. - Mild-moderate heart failure group. Enalapril vs. placebo. At 12 months, patients normally have 10% mortality or hospitalisation, treatment imprpoves both. Therefore, irrespective of the the level of heart failure, there is a benefit from ACE inhibitors.

Answer 64

Used for hypertension, heart failure and diabetic neuropathy. Key ACE inhibitors: Ramipril, Perindopril, Enalapril and Trrandolapril. Usually 1 a day but in HF it is good to split the dose because you need the function 24/7 unlike in hypertension where it isn't really a problem at night,

Answer 65

- Related to reduced angiotensin II formation: Hypotension (AGII usually supports circulation), Acute renal failure (AGII usually supports glomerular filtration pressure), Hyperkalamia (Aldosterone usually causes K loss), teratogenic effects in pregnancy. - Related to increased Kinins: cough (10% of people have dry cough that last for duration of dose), Rash, Anaphylactoid reactions - angioedema/other allergic response. This is because ACE is a very non-specific enzyme so as well as converting AGI to AGII it also breaks down bradykinin into inactive peptides.

Answer 66

Angiotensin II Receptor Blockers (ARB) Hypertension (mainly) and Heart failure (used when ACE-I contraindicated or gives side effects). Candesartan, Valsartan, Losartan, Irbesartan, Telmisartan. Main adverse effects: Symptomatic hypotension (especially in vol depleted patients), Hyperkalaemia, Potential for renal dysfunction, Rash, Angio-oedema. Generally well tolerated. Contraindicated in pregnancy. Angiotensin II acts on the AT-1 receptor, ARB blocks it at the receptor level.

Answer 67

US Carvedilol HF study 1996. Tested in a milder heart failure group, showed that you have increased probability of survival with Carvedilol. Mortality benefits have been shown for Carvedilol, Bisoprolol and Metoprolol. Probablity of event-free survival is important to consider. Other B-blockers haven't been trialled in such a rigorous way, hence they are not licenced in the same way. Use very low doses of B-blockers to prevent collapsing of stimulation.

Answer 68

Digitalis Investigation Group in 1997. Placebo vs. Digoxin. In terms of 12 month mortality there is very little change. But looking at death or hospitalisation due to worsening heart failure shows that Digoxin is beneficial. Can be used as an add-on when other drugs are just not working.

Answer 69

Lancet study (2006). If is the funny current. It behaves differently to other channels and controls intrinsic sinus node pacemaker. Ivabradine can block If current, slowing sinus node rate. Used in angina and heart failure (HR>70).

Answer 70

Sacubitril = neprilysin inhbitor Valsartan = angotensin II blocker Neprilysin inhibition increases levels of natriuretic peptides. When it is trialled it is tested against Enalapril (no longer ethical to used a placebo). Benefit for heart failure patients is small but is there!

Answer 71

Following a MI, heart failure can lead to serious pulmonary oedema and breathlessness. -Oxygen -Diamorphine for pain -Nitrates to reduce preload/afterload, vasodilator -Loop diuretics You CANNOT give them ACE inhibitors or B-blockers because they are dependent on the sympathetic drive to keep them alive. -Inotropes (for a very short period) - adrenergic agonists and PDE III inhibitors.

Answer 72

Inotropes: - Adrenergic agonists including Inoconstrictors (Noradrenaline, adrenaline, dopamine) and Inodilators (Dobutamine, Dopexamine, Isoproternol) - PDE III inhibitors which will stimulate cAMP

Answer 73

Promise study in 1991, treated HF patients with Milrinone vs. Placebo. At the 12 month mark, placebo survival probablity is 60%, but Milrinone survival probablity is 45%. People do worse on this drug so patients are highly monitored. An ethical group will remove patient from treatment if it is worse than the disease. Stimulation of a failing heart is usually a no-go but can be used for very short time in acute heart failure.

Answer 74

The vasculature organises the delivery of oxygen/nutrients and removal of excretory products. - Arterial contraction/relaxation regulates blood pressure - Understanding mechanisms to identify drug targets - Artery wall dysfunction underlies pathophysiology particularly in artherosclerosis and hypertension

Answer 75

Large arteries - arterioles - capillaries - venules - large veins Artery structure has a lumen in the middle. The wall is composed of many layers. Thinnest layer is endothelium, the tunica intima, tunica media and tunica externa. There is elasticity present between layers allowing for movement for pulsatile pressure. Outer layer has fibrous collagen giving a more rigid structure for the artery. Vascular smooth muscle allows for contraction. There is important communication between the smooth muscle cells and endothelium.

Answer 76

Cells that line the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. It is a thin layer of simple squamous cells called endothelial cells. Largest organ - covering football pitch in an adult human. Mediates BP. Dysfunctional/activated endothelium can lead to early stages of disease.

Answer 77

Lubricant layer on the endothelia of the blood vessels. Intact in a non-activated endothelium Anti-coagulant Prevents circulating cells from binding to adhesion molecules on the endothelial surface.

Answer 78

The glycocalyx is shed when the endothelia is activated/dysfunctional. This occurs in response to inflammation, injury, healing, MMPs. This allows for the binding of adhesion molecules as the adhesion receptors are exposed without the glycocalyx. Monocytes can enter the artery wall. This initiates/progresses atherosclerosis in the presence of oxLDL. Also occurs when there is disturbed blood flow. When vasculature is straight, blood flow has the same pressure exerted on the artery wall. But when there are bends or 'shoulder regions' there is disturbed blood flow. Loss of glycocalyx and prone to plaque development.

Answer 79

ACh, Histamine, 5-HT, Bradykinin can bind to various receptors to cause an increase in Ca in the cell. This activates endothelial NO synthase to convert argenine to NO. NO leaves the cell and acts on other cells in the surrounding environment. High shear (blood flow) also activates NO production by increasing Ca.

Answer 80

IL-1, Thrombin, Endotoxin can activate various receptors to cause the production of endothelin 1 which can be released from the cell. There is also the upregulation of various transcription factors causing an increase in ROS, ICAM-1, VCAM-1, IL-8 and COX2. The increase in these molecules is also caused by disturbed blood flow. These molecules cause an increase in adhesion molecules causing an increase in monocytes.

Answer 81

Ca is REALLY important! Ca ATPase present in the PM and acts to pump Ca out, there are also calcium channels in the PM that allow Ca entry. Sarcoplasmic reticulum stores calcium and contains Ca-ATPase on its membrane to pump Ca in. Activation of Ca channel on PM causes an influx of Ca down concentration gradient. It interacts with calmodulin and activates myosin light kinase. MLCK phosphorylates inactive myosin which activates myosin. Actin crossbridge cycle starts leading to contraction.

Answer 82

There are other ways which can cause a release of calcium such as receptors that activate second messengers like IP3 which acts on the Ca channel on the sarcoplasmic reticulum. These include GPCRs for endothelin A/B, TP (prostanoid), AT1 (angiotensin), histamine and noradrenaline (a-AR) which all cause production of IP3. Calcium channels on the PM include voltage-selective (L-type), receptor generated (e.g. P2X), TRP channels and store-operated channels (Ora1).

Answer 83

3 important mediators: cyclic GMP (produced by guanylyl cyclase), cyclic AMP (produced by adenylyl cyclase) both of which cause a decrease in Ca. Thirdly K channels produce a K efflux that causes hyperpolarisation which also causes a decrease in Ca.

Answer 84

Guanylyl cyclase is activated by nitric oxide from endothelium and synthises cGMP. Increased cGMP can act in two ways to lead to relaxation. cGMP leads to activation of Protein Kinase G which increases the activity of myosin phosphatase. This means that active myosin is converted back to inactive myosin leading to muscle relaxation. Also cGMP decreases Ca which means no association with MLCK, meaning that active myosin is not produced - no contraction.

Answer 85

G-coupled receptors for B-agonists, Adenosine, prostaglandins activate adenylyl cyclase which synthesises cAMP. cAMP decreases Ca which means no association with MLCK, meaning that active myosin is not produced - no contraction.

Answer 86

In smooth muscle cells there are different K channels that you can having, including BK channels (large conduction), SK (small conductance) or B-agonists (via BY of G protein). The K efflux leads to hyperpolarisation which decreases intracellular Ca which means no association with MLCK, meaning that active myosin is not produced - no contraction.

Answer 87

Phosphodiesterase enzymes hydrolyse cAMP and cGMP so are important in regulating these pathways.

Answer 88

These mediators are often released by the endothelium which will cause contraction or relaxation of the artery via smooth muscle cells. They include nitric oxide, prostanoids, endothelin, angiotensin II.

Answer 89

NO regulates blood pressure and regional blood flow. eNOS is found in carveola of endothelium activated by blood-bourne mediators. eNOS is impaired by: -Smoking -High glucose and insulin -oxLDL depletes cholesterol from carveola leading to a loss of eNOS and a raised blood pressure. These are therefore all risk factors for cardiovascular disease.

Answer 90

Prostanoids are produced from the precursor arachidonic acid by COX1/2 to Prostaglandin H2. COx activity is activated by influx of Ca or increased ROS. PGH2 can produce Thromboxane A2 which is released from the endothelial cells and acts on the TP receptor on the membrane of the VSM cell. TP receptor activates PLC producing IP3 which activates Ca release from sarcoplasmic reticulum. Leading to MLCK conversion to active myosin and contraction! PGH2 can also produce PGE2 which acts on EP-R (the type 1-4 depends on the vasculature bed). Different types can either activate or inhibit adenylyl cyclase so may or may not increase cAMP. PGI2 is also produced which can act on IP-R which activates Gs proteins activating adenylyl cyclase and increasing cAMP leading to relaxation! So, prostaglandins can either lead to contraction or relaxation depending on which enzymes are expressed and which prostanoids are produced from PGH2.

Answer 91

Precursor is 'big endothelin' in endothelial cells which is transcriptionally upregulated by many different stimuli. These include IL-1, Thrombin, Glucose, OxLDL, Insulin, Angiotensin II, Cortisol, Adrenaline and Hypoxia. Endothelin converting enzyme cleaves big endothelin to make endothelin 1. ET-1 is the active mediator that acts on smooth muscle. Can act on ETa or ETb receptors (both expressed on VSM). Both lead to production of PLC and therefore IP3. Increased Ca leads to contraction.

Answer 92

Endothelial cells themselves also have ETb receptors so when Endothelin1 is produced it can act back on the endothelial cells. This causes an increase in Ca in endothelial cellsand the activation of eNOS. NO inhibits the ECE (neg feedback) but also freely diffuses to VSM cells to cause relaxation, opposing usual effect. Since ETb can lead to contraction and relaxation if you want to therapeutically target contraction should ETa.

Answer 93

Angiotensin II is produced by certain types of endothelial cells specifically in pulmonary and renal vasculature. ACE is expressed on the surface of the endothelial cells and converts circulating angiotensin I into angiotensin II by cleavage. Angiotensin II then acts on AT1 receptors on VSM cells. AT1 receptors couple to PLC and produce increased IP3 and therefore increased Ca and contraction! Activation of AT-1 receptors also activates MAPK pathways which give a more persistant long-term change in the vasculature (contractile response).

Answer 94

-Atherosclerosis: endothelial cells become further away from the VSM cells that they regulate, so atery wall is less able to respond to normal vasculature mediators for contraction/relaxation. Increased immune cells in artery walls release factors which cause VSM cells to proliferate in a disordered manner. -Loss of glycocalyx due to increased LDL or areas prone to atherosclerosis -Calcification: Ca deposits build up with age which stiffens the artery preventing it from being able to contract/relax in a coordinated manner. -Loss of elastin with age -Decrease in NO due to age, smoking, hypoxia ALL of the above lead to increase blood pressure.

Answer 95

High blood pressure. Affects about 30% of English population. Left untreated it can increase risk of heart attack or stroke. Leading risk factor for disease. Symptoms: breathlessness, fatigue, fluid retention as CO is inadequate to meet metabolic demands. Mostly secondary to atherosclerosis.

Answer 96

Oxygen supply to heart is insufficient upon exertion leading to chest pain. Tend to be only upon exertion (stable angina), if occurs at rest too (unstable angina). Due to coronary artery disease which is not sufficient in increased activity.

Answer 97

Pulmonary hypertension is a very rare disease of the vasculature. Abnormal changes lead to proliferation of smooth muscle cells, narrowing the pulmonary arteries. This increases pressure in the lungs and increases pressure on right side of the heart. Patients usually die of right heart failure. Typically 1-3 years life expectancy from diagnosis.

Answer 98

Inappropriate vasocontriction of smaller arteries/arterioles, commonly in the fingers in the cold. White then blue fingers, followed by reactive hyperaemia (return of blood flow). Severe cases lead to ulceration and gangrene. Treatments: Stop smoking, avoid cold, vasoactive therapies. Some heritable components (some more prone to it). Overactivation of sympathetic nervous system - spasm of arteries. Other conditions can lead to secondary RD.

Answer 99

It regulates blood vessel contraction and blood supply. Most therapies to treat diseases are vasodilators which requires relaxation of vascular smooth muscle cells.

Answer 100

NO donors generate NO to encourage vasodilation. - Glyceryl trinitrate (nitroglycerine) converted to NO by mitochrondrial aldehyde dehydrogenase enzyme. Commonly used for angina to increase blood flow by opening arteries to ischemic heart muscle. - Nitroprusside - used for severe hypertension. Intravenous administration in hospital. - Inhaled NO - used for pulmonary hypertension. Opens arteries in pulmonary sytsem, used in hospital.

Answer 101

Can either enhance IP-R which will increase cAMP to increase relaxation OR block TP receptor to reduce contraction. - Iloprost (stable analog of PGI2) so will act on IP-R. Commonly used in pulmonary hypertension and Raynauld's disease. - Epoprostenol (IP receptor agonist). Use in pulmonary hypertension. - Corticosteroids - suppress the overall formation of prostaglandins. Used to prevent hypotension in shock (vasocontriction).

Answer 102

Endothelin1 is a vascontraction mediator so inhibiton of both ETa/ETb receptors using Bosentan can be helpful in vasodilation. Used for pulmonary hypertension. Ideally people will develop ETa-specific drugs. Phas 3 clinical trials to treat ischaemic optic neuropathy from glaucoma.

Answer 103

Block ACE from converting Angiotensin I to Angiotensin II. Used in hypertension and heart failure after MI. - Captopril - blocks the active site of ACE so no conversion. Side effects include hypotension, cough, proteinuria, change in taste. - Enalapril and Lisinopril which are better shaped have been developed. They require conversion to active metabolite so they are longer lasting.

Answer 104

Blood pressure reduction. Sartans: Losartan, Valsartan. Block receptor but also inhibit production of angiotensins ar Renin-Angiotensin-Aldosterone system. Angiotensin I-IV are cleave from precursor protein Angiotensinogen (produced in liver) by various enzymes. Renin comes from RAAS and is produced in the kidney, produces Angiotensin I. AT1 receptors also present in kidneys so will be affected by antagonism (side-effects).

Answer 105

Vasculature smooth muscle cells contract through calcium influx so we can target the receptors on the smooth muscle themselves. Can target noradrenaline receptors (a-AR), calcium channels, adrenaline receptors (b-AR) and potassium channels. To cause vasodilation, we want to activate b-AR or K channels or block a-AR or calcium channels.

Answer 106

K channel activators include Minoxidil and Diazoxide which are used for severe hypertension. Nicorandil is also a NO donor so can be used to treat refractory angina (DUAL ACTION). Calcium channel blockers cause relaxation. Nifdedipine is an old drug used to treat hypertension, Raynauld's disease and angina. Verapamil used to treat hypertension and heart failure. Diltiazem used to treat hypertension and angina. Most sympathetic nervous system drugs that are effective in hypertension are rarely used due to multiple or severe side effects.

Answer 107

If we can block PDE which would otherwise hydrolyse cAMP and cGMP there will be an increase in the levels of cAMP and cGMP leading to overall relaxation of the smooth muscles. This will help to treat high BP and other vasoconstrictive diseases. Sildenafil (viagra) is a PDE V inhibitor which can be used for pulmonary hypertension. Cannot be used alongside angina treatment because if you increase NO, you increase cAMP and cGMP which will no longer have any inhibition. This could lead to too much relaxation and dangerously reduced blood pressure.

Answer 108

Hypertension is a important preventable cause of premature morbidity (care, disabling, hospitalisation) and mortality. Major risk factors: -Stroke (ischaemic: blockage of blood flow through thrombus/embolus, haemorrhagic: blood vessel bursting) -Myocardial infarction: Parts of heart muscle loses blood flow often due to atheroma -Heart failure: if BP is chronically raised, heart pumps at a higher pressure which can cause HF. -Chronic renal disease: kidneys control BP through RAAS, HT and CRD can contribute to each other. -Cognitive decline: cause by multiple tiny stroke in brain tissue linked to chronic hypertension -Increases the risk of atrial fibrillation, HF increases afterload on heart, atria dilate and conduct abnormally, P waves disrupted - chaotic. ALL of the above lead to premature death

Answer 109

Comaprison of population's average hypertension vs. morbitity and mortality it shows that each 2mmHg rise in systolic BPis associated with: -7% increased mortality from ischaemic heart disease -10% increased mortality from stroke Even within the normal range there is a difference in outcome depending on where you fall in that range. Could be dangerous depending where you are and how that changes in exertion.

Answer 110

Clinic BP 140/90mmHg or higher This may be due to nerves, stress etc. So patients offered ambulatory blood pressure monitoring (ABPM) to comfirm diagnosis. Records BP every 30mins in day, hour in night. Takes pressure in home environment. Measures diastolic/systolic means and heart rate.

Answer 111

Stage 1 hypertension: 140/90 (Clinic), 135/85 (ABPM) Stage 2 hypertension: 160/100 (Clinic), 150/95 (ABPM) Severe hypertension: SBP >180, DBP >110 Very few cases of severe hypertension as BP is taken frequently and identified and treated quickly.

Answer 112

Primary (essential) hypertension (no specific cause) - Lifestyle modification: cut out/down smoking, fat, salt, drinking, increase exercise - Anti-hypertensive drug therapy Consider secondary hypertension Resistant to medical treatment even when patient is concordant. Young patient. Clinical signs/symptoms of underlying cause e.g. chronic renal disease, Cushing's disease.

Answer 113

Offer antihyperensive drug treatment to people aged under 80 with stage 1 hypertension who have one or more of the following: - Target organ damage: increased heart muscle thickness, microaluminia, retina, kidney damage - Established cardiovascular disease - stroke, MI, peripheral vascular disease - Renal disease - Diabetes: increased risk of CV disease - A 10-year cardiovascular risk of 20% or greater (established by QRisk) Offer antihypertensive drug treatment to people of any age with stage 2 hypertension.

Answer 114

Under 80 years: <140/90 (Clinic), <135/85 (ABPM) Over 80 years: <150/90 (Clinic), <145/85 (ABPM) There are risks to do with hypotension as you get older.

Answer 115

- Cardiac output and peripheral resistance - Interplay between RAAS and sympathetic nervous system (noradrenaline) - Local vascular vasocontrictor and vasodilator mediators

Answer 116

Angiotensin II leads to vasoconstriction, acting positively on peripheral resistance. Angiotensin II can also stimulate growth of the vessels (hyperplasia and hypertrophy) and can cause salt retension through Aldosterone release and tubular sodium reabsorption. Noradrenaline can act on a-receptors to increase peripheral resistance and increase CO and Renin.

Answer 117

ACE inhibitor - reduce angiotensin II, reduce peripheral resistance and hence afterload on the heart ARB blocker - block the effects of angiotensin II on peripheral resistance and cardiac output. Aldosterone antagonist - Block the effects of Aldosterone like salt retension. B-blockers, calcium channel blockers, a-blockers, Renin inhibitors, thiazide-like diuretics and centrally acting drugs are also important. For hypertension, best to use thiazide-related diuretics (bendroflumethiazide, hydrochorothiazide, chlortalidone) or aldosterone antagonists but if it is really severe of K loss is a problem, use loop diuretics or potassium-sparing diuretics (Spironolactone).

Answer 118

Main clinical indications include Ischaemic heart disease, angina, heart failure, arrhythmia, hypertension. Bisoprolol, Carvedilol, Propanolol (licenced for HF) Nadolol, Metoprolol, Atenolol (not licenced for HF). All licenced for hypertension.

Answer 119

There are two well-recognised B-adrenoreceptors B1 and B2. Selective: More selective for B1 (Metaprolol, Biosoprolol) Non-selective: Equal for both B1 and B2 (Propanolol, Nadolol, Carvedilol) But there is a spectrum and Atenolol lies in the middle. Dangerous to give asthmatic B blockers, even selective ones, because there are B2 receptors in lungs which will react and selectivity is not absolute. COPD patients don't have the same reactivity - no severe attack or bronchospasm. Cardioselective is used to imply B1 selectivity but is nonsense because 40% of cardiac B-adrenoreceptors are B2.

Answer 120

- Fatigue: blocks catecholamine effects - Headache - Sleep distubance/nightmares - move through blood/brain barrier - Bradycardia - dizziness aggrevated - Hypotension - Cold peripheries - shuts down peripheral circulation to maintain central blood pressure and reduce CO - Erectile dysfunction - Worsening of Asthma, COPD, Claudication, Raynauld's, heart failure if given in standard dose or acutely.

Answer 121

Not calcium antagonists because Ca moves through L-type channels and doens't bind to a receptor. Direct action on peripheral resistance. Main clinical indications: Hypertension, Ischaemic heart disease, Arrythmias (tachycardia). Amlodipine (common), Nifedipine (oldest), Felodipine, Lacidipine [mainly used in Hypertension] Diltazem, Verapamil [rarely used in HT, used in heart disease, arrthymias, rate-limiting medications]. However if patient is already on B blockers, Amlodipine may be a good secondary actor.

Answer 122

-Dihydropyridines: Nifedipine, Amlodipine, Felodipine, Lacidipine. Preferentially affect vascular smooth muscle and act as peripheral arterial vasodilators.Nifedipine is relatively short acting so needs to be taken multiple times a day, controlled release has been developed or Amlodipine is a naturally long-lasting drug. -Phenylalkylamines: Verapamil. Preferentially acts on heart. Negatively chronotropic, negatively ionotropic. Not to be used in HF patients with HT because it would reduce heart function further (if any Amlodipine). -Benzothiazepines: Diltazem Intermediate heart/vascular effects. Can be used in HT and some arrythmias. Expense may be a consideration depending on whether the drug is on patent or a generic.

Answer 123

- Due peripheral vasodilation (mainly dihydropyridines). Flushing, (vascular) headache, Oedema, Palpitations (reflex sinus tachycardia to protect itself) Mainly in females. Due to permeability, leaking of fluid. - Due to negative chronotropic effects (mainly verapamil/diltazem). Bradycardia, atrioventricular block. - Due to negatively inotropic effects (mainly verapamil) - worsening of cardiac failure. - Vaerapamil causes constipation (smooth muscle inhibition.

Answer 124

Pacemakers can organise conduction by sensing the excitation of atria and ventricles and the inserting stimulation if the heart is lacking. If the patient has a pacemaker for heart block you can use verapamil or B-blockers or Diltazem because the heart will never slow down too much because the pacemaker will kick in.

Answer 125

A-blockers act on a-adrenoreceptors which are present on post-synaptic nerves. Can induce vasodilation by blocking smooth muscle contraction of vessels. Doxazosin (common), Indoramin, Terazosin and Prazosin (old). Posteral hypotension may be a problem. Bladder neck and prostate contain smooth muscle which can be constricted by a-adrenoreceptors. So a-blockers along with Alfuzosin, Indoramin, Tamsulosin can be used in benign prostatic hypertrophy to relax muscle. Will also act on vasculature.

Answer 126

Can block sympathetic nervous system upstream using centrally acting drugs in a2 receptors in pre-synaptic stimulation to reduce sympathetic flow (decreases noradrenaline). - Moxondine: Imidazoline type 1 receptor agonist - Methyldopa: activates pre-synaptic a2-receptors to decrease noradrenaline release and competitive inhibitior of DOPA decarboxylase, reducing dopamine (precursor of noradrenaline). - Clonidine: activates pre-synaptic a2 receptors to decrease noradrenaline release. Also impacts I1 receptors. If you suddenly come off Clonidine, you can get marked rebound hypertension.

Answer 127

Aliskiren Adverse effects include problems with hyperkalaemia, dizziness, Arthralgia, Diarrhoea. Cautioned use with other RAAS inhibitors. Concomitant use not recommended.

Answer 128

If you are under 55 years you begin with ACE inhibitor (or ARB if too many side effects) because it is likely to be renin-dependent hypertension. If you are over 55 years or Afro-Carribean of any age you begin with calcium channel blockers because it tends to be low-renin hypertension. If these don't work all patients have dual therapy, ACE-I/ARB and CCB. If this doesn't work, you have add-on therapy using thiazide diuretics which sometimes work really well. If none of this works and patient is taking drugs, it is resistant hypertension. Consider addition of Spironolactone, high dose thiazide-like diuretic, a-blocker, B-blocker and others. Some patients will never reach normal.

Answer 129

Coronary artery disease occurs when a fatty/fibrotic plaque with lipid core called atherosclerosis blocks the coronary artery lumen, restricting blood flow to downstream tissues. May lead to cell death in myocardium due to lack of O2 and nutrients (demand exceeds supply). Often presents in patients with chest pain (angina) or MI.

Answer 130

Kills more people worldwide than any other disease. Increased prevalence in older men. Death rates have halved in the last 10 years mainly due to reduction in risk factors. Non-modifiable risk factors: age, male gender, family history of IHD. Modifiable risk factors: BP, diabetes, smoking, cholesterol, poor diet, obesity, renal disease.

Answer 131

Flow restriction can lead to patient becoming susceptible to ACUTE CORONARY SYNDROMES including unstable angina, non-ST elevation MI (NSTEMI) and ST-elevation MI (STEMI). These occur when the plaque ruptures, creates a clot and blocks artery completely. Stable angina is NOT an ACS. Unstable angina is likely to lead to NSTEMI or STEMI. In order to see ECG changes in unstable angina you must have recurrent ischaemia.

Answer 132

In a normal patient, there is an open, free circular lumen. In stable angina, the lipid core of the plaque is kept separate from the blood flow due to healing creating a protective layer. Unstable angina: contains a thrombus, mature fibrous clot. Most of the lumen is blocked. Mural thrombus: complete blockage of lumen by clot and plaque together fully formed.

Answer 133

Rare in people under 35. Increasing number of cases in NSTEMI or unstable angina. STEMI patients from rural GPs will be taken straight to cardiology unit for insertion of stent.

Answer 134

``` Chest pain (angina) Characterised by 'heavy' or central 'crushing' pain on exertion, relieved by rest. In STEMI angina occurs all the time. Treatments for angina are based on what type it is. -Stable: reduce cardiac work (nitrates, Ca antagonists), treat the underlying condition (statin) and prophylaxis (an anti-platelet drug like aspririn). -Unstable: treat for MI with DAPT (dual anti-platelet therapy) often aspirin + clopidogrel ```

Answer 135

Unstable angina: relief with nitroglycerin, normal ECG unless there is a period of ischemia, normal troponin levels. NSTEMI and STEMI: no relief with nitroglycerin, abnormal ECG, raised levels of troponin. Troponin is a myocyte-specific protein measured in hospital setting to see if there is cardiac damage. If you measure it too early, myocyte death may not have occured.

Answer 136

Restore blood flow quickly to avoid myocyte death, scarring and pump defects (ultimately HF). - Reopen blocked arteries using insertion of stents - Reduce coagulability of blood by dual anti-platelet therapy - Control risk factors - Reduce myocardial oxygen demand

Answer 137

Non-surgical technique called Percutaneous coronary intervention (PCI). A dye is injected is injected into patient and viewed by thoracoscopy. Widen artery from within by placing a metallic stent. Stents come in lots of different sizes, must choose the right one to avoid damage, over-repair, narrowing vessel even further. Stents coated with drugs which will inhibit cell proliferation e.g. rapamycin (cell cycle blocker between G1 and S phase). Door-balloon time for STEMI must be within 120mins for the best outcome.

Answer 138

Stents are crimped down and sit on top of balloon. Cardiologist advances balloon and stent through patient's vessels past the area that has narrowed. Balloon is then inflated about 8 atmospheres and stent is placed against vessel wall. Don't want to underplace stent otherwise it will flow down with the blood. Patient must be prescribed DAPT to preventing clotting. Average 3/4 stents depending on susceptibility.

Answer 139

Our artery walls react very badly to foreign objects so when stents weren't well developed or designed and drugs weren't used it caused an innate repair and/or thrombosis response. Since drug eluting stents are not around there is a much lower incidence of restenosis but there is an increase risk of thrombosis especially with the use of sirolimus.

Answer 140

Control the platelets! Medical treatment after stenting... DAPT: Aspirin plus an anti-platelet or anti-clotting drug e.g. PLAVIX (Clopidogrel) or Brilinta (ticagrelor) Must be continued for up to a year after stenting. Adverse events - excess bleeding Unknown benefits - pleiotropic positive effects upon neutrophils an therfore pulomonary infections.

Answer 141

The effectiveness of DES may lead to stent thrombosis in extreme situations. In a bare metal stent there is a large amount of repair by the vesels which covers the stent preventing the metal interacting with the blood flow. But with a DES there is reduced repair which is good for the vessel diameter but bad because the exposure of the meta can lead to stent thrombosis. This is due to delayed or incomplete healing (endothelialisation) over the metal stent. Adverse clinical outcomes. Need for prolonged anti-platelet therapy.

Answer 142

To keep the coronary plaques as stable as possible to avoid acute clot blockage (occlusion) which can be partial or full and will translate to unstable angina or STEMI. To reduce pain.

Answer 143

-Symptomatic: reduce symptoms, reduce preload/afterload strain on the heart and increase vasodilation of arteries and veins. Using nitrates, aspirin and anti-platelet drugs, Ca channel blockers, K channel blockers, analgesics. -Prognostics: alleviate future negative outcomes later in life. Using Aspirin, Statins, B-blockers or ACE-inhibitors.

Answer 144

First-line agent. Discovered by Brunton in 1867 after using amyl nitrate to reduce BP, preload and cardiac work. Primary mechanism to relax smooth muscle and veins. Main effect is on larger muscular arteries (coronary vasodilation). Direct dilation effect which increases coronary flow. Secondary effects: reduces cardiac work, redirection of flow towards ischaemic areas through dilation of collateral channels in heart, improves coronary spasm. Mechanism of action: GTN metabolism releases NO which activates soluble guanylyl cyclase and increased cGMP. This activates PKG leading to relaxation of smooth muscles.

Answer 145

Very quickly inactivated by hepatic metabolism. Sublingual/intravenous delivery, effective in 1-2mins. Lasts 30 mins, longer acting transdermal patches are available. Isosorbide Mononitrate is longer acting and administered orally 2x with a nitrate-free period at night to avoid tolerance. Adverse effects: Possible hypotension, advised to administer sitting down, potential headaches. Tolerance can occur, possibly due to depletion of -SH groups, more common with longer acting agents.

Answer 146

Mechanism of action is to block receptor response, to prevent channels opening and prevent the influx of calcium through the cell membrane. Act on L-type calcium channels. Primary action is on cardiac muscle. Some are selective others are non-selective. Some have vasodilator action. Main classes of drugs include phenylalkylamines (e.g. verapamil), dihydropyridines (e.g. amlodipine) and benzothiazepines (e.g. diltazem).

Answer 147

Selective action: Verapamil is more active on the heart, Nifedipine on smooth muscle. These drugs also dilate coronary vessels. Half-life varies and direct prescribing. Side-effects are few: flushing and headache due to vasodilator aciton. Verapamil can cause constipation due to its effects on gastrointestinal nerves or smooth muscle. Amlodipine has a much longer elimination time (1x day) compared to the others.

Answer 148

One of the oldest drugs (from willow bark). AKA acetylsalicyclic acid Reduces mortality and risk of future MI. Given immediately on presentation and daily thereafter (75mg/day). Inhibits the COX-1 receptor on platelets and reduces platelet aggregation. Irreversibly acetylates COX enzymes and platelets which the platelets cannot replenish because they don't have a nucleus (no de novo synthesis) so have to wait 10 days before new platelets are produced. Reduces aggregation by preventing the conversion of arachadonic acid to thromboxane A2 which would otherwise cause platelet aggregation. Given in prophylaxis if patient has already had an event.

Answer 149

Given orally. Weak acid so it is protonated in the stomach and able to cross through the muscosa. Rapidly hydrolysed in 30mins by esterases especially in the liver but also in the plasma into salicylate in tissues. Has anti-inflammatory actions through the inhibition of NFkB. Plasma half-life depends on the dose. Side-effects: gastric bleeding, deafness/tinnitus (with large doses/overdoses). Risk of self-poisoning. Drug interactions with Warfarin which increase its concentration. Resistance to Aspirin is known but there are no genetic tests for it.

Answer 150

Anticoagulants prevent the clotting of blood and they inhibit clotting factors in the clotting cascade. Heparins are glycosaminoglycans found in mast cells and basophils. Prevent venous thrombus and thrombus propagation. Enoxaparin activates antithrombin IIIa which inactivates thrombin and factor Xa thus preventing the formation of a stable clot. Adverse reactions include bleeding. For a second antiplatelet approach, use Aspiring and thienopyridines, clopidogrel or ticagrelor. There is a diminished risk of MI/death by using Aspirin and Heparin vs. Aspirin alone.

Answer 151

e.g. Nicroandil (nitrate derivative of nicotinamide) Second-line agent to treat refractory symptomatic angina. Trials show a 15% reduction in risk of MI and the number of hospital admissions with chest pain. DUAL-ACTION: Donates NO to relax smooth muscle an opens ATP-sensitive K channels leading to dilation. Adverse effects: headaches, gastrointestinal ulceration. Contraindications: Given with phosphodiesterase inhibitors like Sildenafil can lead to hypotension.

Answer 152

Often morphine will be given. Morphine binds to the mu opoid receptor (Gi/Go coupled to ion channels) in the brain as a partial agonist. Morphine is a phenathrene derivative and key parts of the molecule are important for opoid activity. Generally well-tolerated if given at right dose. Side-effects: respiratory depression (modulated by mu receptors), nausea and vomiting (opoids have effect in area postrema where chemical stimuli cause vomiting), reduced tone and mortality in the gut, histamine release, tolerance. Anti-emetic such as Metclopramide can be given alongside.

Answer 153

DAPT (aspirin plus clopidogrel or tricagrelor) Heparin (usually) Analgesics Once stablised, organised to have PCI. Secondary prevention: Statin, ACE inhibitor or B blocker.

Answer 154

Anti-platelet and anti-thrombotic therapy Possibly an additional platelet inhibitor if ECG changes are rapid. Analgesics PCI within 72 hours to determine lesion severity and suitability for stenting or bypass surgery.

Answer 155

Primary PCI first act local heart attack centre. If centre is too far away use clot buster drug (e.g. Streptokinase) intravenously, will break down the stable fibrin clots. Not to be used with anti-platelets. Antiplatelet medications - Aspirin plus Lifelong medications after stenting are Aspirin 75mg/day, antiplatelet agent for 1 year, statins, ACE inhibitors and B blockers to aid myocardial recovery.

Answer 156

Inflammation is known to occur throughout development of atherosclerosis and inflammation in the artery wall is thought to be the trigger for plaque rupture. Master controller IL-1 could be important, studies shown that deletion of IL-1 in animals leads to decrease in plaque size.

Answer 157

Pros: Inflammation is a key process to target There appear to be master regulators Excess inflammation in plaques is bad Cons: Inflammatory protein responses are individualised Blocking master regulators may make the patient susceptible to infection. Aggressive reductions in inflammation may lead to thinner caps on plaques making some more prone to rupture.

Answer 158

Interleukin-1 was named in 1940s. Known to be involved in the pathogenesis of fever. IL-1 produced by macrophages and vessel walls. IL-2 from lympocyctes. IL-1 can induce itself (positive feedback loop). IL-1a, IL-1B both of which are pro-inflammatory. Natural antagonist IL-1ra. Increased in fever, lymphocytosis and hematopoiesis. Released in MI as an acute phase reactant in autocrine or paracrine manner. It decreases contractility on the heart, increases apoptosis and increases leukocyte infiltration. There is increase IL-1B expression in the endothelium of atherosclerotic human coronary arteries. Galea et al (1996) immunohistochemistry and in situ hybridisation showing increased protein and mRNA. Secreted as Pro-IL-1B which is chopped down to become biologically active. Pro-IL-1B triggered by cholesterol crystals, neutraphil extracellular traps, atherprone flow (sheer stress) and hypoxia.

Answer 159

IL-1 is intimately involved with vascular repair and atherosclerosis. IL-1 regulates blood pressure in fat-fed mice. IL-1 may link traditional risk factors such as fatty diets with inflammatory cell biology in the vessel wall. Inhibition of IL-1 reduces inflammation in the vessel wall (mainly neutrophils).

Answer 160

Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (2017) Canakinumab is a monoclonal antibody which blocks IL-1. First time that an anti-cytokine approach has been used. Directly-targeting approach. They measured CRP (C-reactive protein) which is an acute phase reactant measured clinically. Protein made by the liver released into the bloodstream within hours of injury, infection of inflammation (including MI). Too difficult to measure IL-1 in the blood (attached to a lot). 10,000 people. 39 countries. Different groups and different doses.

Answer 161

Placebo: natural reduction in CRP after MIdue to repair and recovery. With Canakinumab there is a greater reduction in hsCRP (high sensitivity) even at 50mg, better results at 150mg or 300mg. Given subcutaneously every few months. No effects on lipids (TGs, LDL, HDL) MACE (major adverse clinical events) reduced with Canakinumab. Conclusion: Canakinumab substantially lowered the inflammatory biomarker. Reduced MACE was seen at 150mg and 300mg. But costs £10,000 per patient. Risk of fatal infection.

Answer 162

``` Usually protein based. Large (>150kDa). Heat sensitive drugs. Often administered parentally. Highly selective and specific. Slowly absorbed. Small volume of distribution. Transcellular movement into tissues. Long half-life and may be immunogenic. ```

Answer 163

New drugs that inhibit inflammation specifically are becoming more attractive. Mechanisms of action will need to be examined in detail to make sure that any negative effects are minimised. Other molecules that selectively influence the IL-1 pathway may be attractive targets.

Answer 164

Platelet or physiology based. Platelet: PASTOR study in 2015 used a bedside device at the time of PCI after STEMI to measure individual platelet reactivity and assigned the anti-platelet medication on the basis of this. Physiology Individualised maps of a patient's coronary arteries and fluid dynamics help decide which of the lesions within an artery needs attention. Uses measures of physiology to determine the need for drug eluting stent.

Answer 165

Left side of the heart pumps oxygenated blood to the body. Right side of the heart pumps deoxygenated blood to the pulmonary circulation to perform gaseous exchange. Whilst systemically, blood pressure is maintained at about 100-140mmHg the right ventricle needs a high flow and a low pressure (15-30mmHg) for optimal gaseous exchange.

Answer 166

Pulmonary hypertension is classified as a pulmonary arterial pressure of >25mmHg (normal is 15-18mmHg). The drivers of this rise in pressure will determine diagnosis and prognosis. Pulmonary arterial hypertension is when the hypertension is driven by constriction and redmodelling of the pulmonary arterial circulation. PAP >25mmHg, LVEDP (PCWP) < 15mmHg, PVR >3 WU/ >240 dyn.sec.cm-5

Answer 167

Perform right heart cardiac catheterisation usually into the jugular vein, vena cava, into right atria, right ventricle into pulmonary artery, here you measure the pressure. In RA there is a very small pressure (2-5mmHg healthy) but in RV there is a much more dynamic range (20mmHg Sys 1mmHg Dia). In pulmonary arteries systolic remains but diastolic increases (20mmHg Sys 15mmHg Dia). This remains until capillaries where pressure is much lower for gaseous exchange.

Answer 168

Mean pressure = 2/3 Dia + 1/3 Sys Resistance = change in presssure / velocity Cardiac output is an important factor. Pulmonary capillary wedge pressure also affects diagnosis. PVR = (mean PAP - PCWP) / Cardiac Output Mean PAP = PVR X CO + PCWP

Answer 169

Typically affects females 3/4:1 gender bias although males tend to have a more severe presentation and worse prognosis. Progressive exertional breathlessness and chest pains. Syncopal episodes following exertion.

Answer 170

ECG - looking for markers of right heart strain Chest X-ray - looking for increased heart size and PAs Lung function tests Echocardiogram - looking for raised pulmonary artery systole pressure and dilated heart Refer to Pulmonary Vascular disease Unit. CT pulmonary angiogram to measure size of PAs High resolution chest CT to look at lungs MRI scan Q scan - look for mismatches in areas of blood flow and ventilation.

Answer 171

``` Systolic PAP: 70 mmHg Diastolic PAP: 25 mmHg Mean PAP: 40mmHg PCWP: 8mmHg CO: 3.2 l/mmin PVR: 10 WU // 800 dyn.s.cm-5 ```

Answer 172

- Pulmonary arterial hypertension: very rare - PH due to left heart disease: most common, defect in left ventricular function, can be systolic, diastolic, valvular. Relatively mild, no specific treatment. - PH due to lung disease/hypoxia: can be caused by COPD, interstitial tissue disease, sleep apnoea,high altitude. - CTEPH (chronic thromboembolic PH): only curable form, clot lodges within pulmonary circulation and blocks off flow to the lung. - Unclear/multifactorial: rare associations, multiple drivers, can be due to hematolgic, systemic, metabolic disorders.

Answer 173

- Idiopathic PAH (1/3): unknown cause - Heritable PAH: 80% mutation in BMF receptor type 2, 5-6 other gene mutations. - Drug or toxin induced: phentamine or dexfenfluramine in diet pills (major outbreak in 60s/70s). Methamphetamine abuse. - Associated PAH: linked to underlying cause, develop PAH which leads to death. Linked to connective tissue diseases, HIV infection, portal hypertension, congenital heart disease, schistosomiasis

Answer 174

15-50 per million population, 2-3 per million per year. No curative treatment. 40% have IPAH, 10% have heritable, 40% have associated (usually due to CTD and CHD) 4 times more common in women. CTEPH occurs in 4% of people following a pulmonary embolism. Important to decipher which group and subgroup that a patient falls into to establish survival prospects. 5 years survival after diagnosis: IPAH (50%), PAH due to CHD (80%), PAH due to CTD (30%).

Answer 175

In a healthy patient, angiogram shows tree-like structures of pulmonary arteries and arterioles. Histological staining of pulmonary arteriole shows narrow smooth muscle layer, large lumen. LV has strong cyclindrical shape and RV is a small crescent on ECG. In PAH, vasoconstriction of arteries due to increased ET-1, hypoxia and decreased PGI2 and NO. Vascular pruning/remodelling occurs reducing size further. Change from a purely constriction/relaxation function to a more synthetic action. Far more smooth muscle present with a small lumen due to increased proliferation and dysfunction/apoptosis of endothelial cells. Pressure backs up causing the right heart has to push against greater resistance. RV hypertrophy and dilation occurs until it becomes 2/3 x bigger. Impairing function of LV and RV. Decreased CO.

Answer 176

- Genetic - BMPR2, Alk1 - Inflammation - increase in cytokines, inflammatory cells, IL-1, IL-6, TNF in plasma - Vasoactive- PGI2, NO, ET1 levels are disturbed which would normally control. - Growth factors- PDGF, VEGF stimulate vascular remodelling - Transcription factors- PPAPg, FOXO abnormalities, reduced blood flow, reduced O2 leads to activation of HIF.

Answer 177

- Endothelin pathway: EndothelinA/B receptor is coupled to Gq. When activated it activates phospholipase C which converts PIP2 to IP3 and DAG. IP3 binds to receptor to cause CA influx which causes vasodilation and proliferation. - NO pathway: endogenous vasodilator produced by endothelial cells, activates guanylyl cyclase and converts GTP to cGMP. Via PKG inhbits calcium influx and promotes vasodilation and anti-proliferation. - Prostaglandin pathway: endogenous vasodilator, acts on IP3 receptors via G protein to activate cAMP and PKA to promote relaxation of smooth muscle and anti-proliferation.

Answer 178

Include Bosentan, Macitentan, Ambrisentan. Given orally. Bind to and block endothelin receptors in smooth muscle cells, also expressed in fibroblasts and endothelial cells. Remove vasoconstriction and promote vasodilation. Binding of ET to ETa and ETb on VSMC causes vasocontriction, binding of ET to ETb on endothelial cells causes vasodilation. Combination with PDE5 inhibitors proves effective. Side-effects: Abnormal liver function tests (bosentan), headache, nasopharyngitis, peripheral oedema (ambrisentan), anaemia (macitentan).

Answer 179

Evidence only in patients with acute vasodilator response. If when they are given inhaled NO during right heart catheterisation and there is a drop in mean PAP by 10mmHg CCB could be effective treatment. Diltiazem and Nifedipine, given orally. Only approx 10% of patients with IPAH/HPAH. Side effects: Systemic hypothension, bradycardia, peripheral oedema.

Answer 180

Ricociguat is a soluble guanynyl cyclase stimulator so acts independently of NO to activate vasodilation.Guanylyl cyclase will stimulate PKG which has multiple vasodilatory actions. It activates MLCP which promotes dephosphorylation of myosin. It activates potassium channels which promotes hyperpolarisation of cell membrane and inhibits postassium dependent Ca channel. It promotes the uptake of Ca into the SR. Licenced for CTEPH. Avoid combination with PDE5 inhibitors (hypotension). Side effects: Headaches, dizziness, indigesion, diarrhoea.

Answer 181

Sildenafil or Tadalafil usually given. Both given orally. Will block enzymes that cause cGMP to GMP which allows for PKG to signal for vasodilation. Often the first line of therapy. Often dual therapy with ERA used after a couple of months. Sildenafil recently became a generic reducing the treatment costs dramatically. Avoid in combination with nitrates (hypotension). Useful combination with inhaled iloprost. Side-effects: headaches, flushing, epistaxis, altered colour vision and non-ischaemic optic neuropathy and priapism more rarely.

Answer 182

Most efficacious treatment. Include Epoprosterol, Iloprost, Treprostinil and Beraprost. Bind to IP receptor and activate pathway to increase cAMP, activate PKA and cause vasodilation. Improves right ventricular function (and PAP) by reducing pulmonary vascular resistance and afterload. Antiproliferative: prostacyclin will slow or reverse the vascular remodelling in PAH.

Answer 183

Macitentan is a relatively new Endothelin Receptor Antagonist. Improved tissue pentration due to greater lipid solubility (not much evidence). Slower receptor dissociation rate giving a prolonged effect on the receptor (need for a lower dose). SERAPHIN trial: largest clinical trial (742 patients). Showed delayed clinical worsening, where end points were enhanced treatment, referral for transplant and death after 6 months.

Answer 184

Not very stable so has a very short half life, at best an hour or so but ususally only 20-30mins. Given by infusion e.g. inhalation, pumped into the bloodstream which causes potential issues of infection, thrombosis and pump failure. Development of tolerance. Side effects: diarrhoea, flushing, headaches £100,000 a year per patient Has to be made up daily and kept cold 6-9 inhalations daily, each taking up about half an hour to administer. Patient compliance is low. Sub-cutaneous delivery gives irritation, severe reactions. High patient dropout.

Answer 185

Selexipag is a novel non-prostanoid IP receptor-specific agonist. Selexipag and its active metabolite are agonists of the prostacyclin receptor, which leads to vasodilation in the pulmonary circulation. Could be a good alternative treatment to prostanoid derivatives which have various issues. Currently in Phase III clinical trials.

Answer 186

- Receptor TK inhibtors have potential as drug targets. Idea to target PDGFR/VEGFR. Phase 3 trials in Imatinib (PDGFR inhibitor) showed modest benefit and limited side-effects. Not approved by FDA. Soradenib (kinase inhibitor) has Phase 1 studies underway but is limited by cardiotoxicity. - Biological agents: ideas to target specific cytokines e.g. IL6, potential for immunosuppression e.g. anti-TNF or experimental studies aiming to increase BMPR in mutated forms of PAH

Answer 187

- Anticoagulation: Mainstay treatment for CTEPH, historical benefit does suggest benefit to tackle microthrombi found in PAH vascular lesions. Recommended in patients on IV therapy. No benefit seen in PAH-CTD. - Oxygen: Evidence based on trials in COPD. Administered if low oxygen at rest or ambulatory if symptoms benefit. - Diuretics: treat oedema due to right heart failure

Answer 188

Appropriate stopping of blood flow. Two main types: -Primary: Platelet activation and aggregation. Platelets bind to collagen using Von Willibrand factor, once bound there is activation by GPVI which leads to the addition of more platelets. -Secondary: The coagulation cascade. Tissue injury activates factor VIIa which lies underneath the blood vessels. This can activate factor X directly or indirectly. Indirectly factor VIIa activates IX which activates IXa (more efficient). Factor IXa acts with factor VIII to activate X. X leads to the formation of factor Xa which activates factor II and then factor IIa (thrombin). Fibrinogen is mixed with thrombin to form fibrin to form a haemostatic plug. Fibrinolytic activity eventually breaks this down to repair vessel damage.

Answer 189

Patients with unknown bleeding could be given fresh whole blood containing RBCs, platelets and clotting factors however blood donation centres test the blood so cannot be delivered instantly. It is divided into platelets (5-7 days at room temp), RBCs (35 days at 4 C) or fresh frozen plasma, You could give the patient fresh frozen plasma if you were unsure about their deficiency. However, many factors have now been isolated and can be delivered according to deficiency (I, VII, VIII, VWF, IX, X XI, XIII). Cannot get factor V because the need is so small (5-10 patients in UK).

Answer 190

-Due to a reduced number (thrombocytopenia) Can be inherited or acquired. -Due to an abnormal/reduced function Can be inherited (very rare) or acquired (commonly due to anti-platelet drugs. Treatment: Platelet transfusion.

Answer 191

Most common inherited bleeding disorder (autosomal dominant). 1% of the population have reduced VWF levels. There are 3 main types with multiple subtypes. Milder than haemophilia. Sites of bleeding: Bruising, cuts, gums, epistaxis, menorrhagia, post-operative, post trauma. Treatment involves getting more VWF into blood: -Intermediate purity factor VIII (contains VMF) from plasma -Desmopressin - stimulates endothelial cells to release granules containing VWF into the circulation

Answer 192

Haemophilia A (deficiency in factor VIII) Haemophilia B (deficiency in factor IX) Both of which are X-linked and have identical clinical features. Can also get deficiency in II, V, VIII, X, XI, XIII but this is autosomal recessive. Sites of bleeding in haemophilia: joints, muscles, post-trauma, post-operative. There is different severities in A (FVIII usually 50-150% in WT) <1% Severe (bleed 20-40 x spontaneously a year) 1-5% Moderate (bleed 1-2 x spontaneously a year_ >5% Mild (only bleeds following injury)

Answer 193

Bleeds in joints can be very painful. If bleeding is present in the joints it can prevent motility leading to muscle wastage, making the joint less stable, increasing the likelihood of falling over and bleeding again. Blood can destroy the joints themselves, reducing the cartilage leading to bone-on-bone interactions. Only solution is to replace the joint. Muscle haematoma can occur following injury but also through intramuscular injections.

Answer 194

Inappropriate blood coagulation within a vessel. Two types: -Arterial: high pressure system, platelet rich clots. e.g. myocardial infarctions, thrombotic stroke -Venous: low pressure, fibrin rich clots. e.g. leg deep vein thrombosis, pulmonary embolism Different pathophysiology and different treatments needed.

Answer 195

Arterial thrombosis: Antiplatelet drugs, namely Aspirin, Clopidogrel, Prasugrel, Ticagrelor, Cangrelor, Abciximab, Eptifibatide, Tirofiban. Venous thrombosis: Anticoagulant drugs of various types, intravenous (unfractionated heparin), subcutaneous (low molecular weight heparin), oral (warfarin, rivaroxaban, apixaban, edoxaban)

Answer 196

Vitamin K antagonists: 96% Warfarin, 4% Acenocoumarol Direct oral anticoagulants: Dabigatran, Rivaroxaban, Apixaban and Edoxaban.

Answer 197

Heparin is an glycosaminoglycan which aims to stop coagulation by inhbiting the coagulation cascade at different points. It doesn't act directly, it acts via naturally occurring antithrombin. Antithrombin inhibits XIa, IXa, Xa and Thrombin. When bound, heparin enhances its activity Two types: unfractionated heparin and low mol weight heparin. Both inhibit IXa, Xa, IIa. Monitored with the APTT test. Given by continuous infusion.

Answer 198

Essentially the same as unfractionated herparin except a lot purer and smaller (only contains 7000Da component). Less variation in dose. Given subcutaneously once daily. Dose is weight adjusted. Renally excreted. Used for treatment and prohylaxis.

Answer 199

Anti-coagulant given orally and rapidly absorbed. 99% plasma protein bound. Inhibits the production of factors II, VII, IX, X which are all vitamin K dependent. Exhibits a slow on and off action: peak effects occurs 3-4 days after starting and effect is still present 4-5 days after stopping (due to liver breakdown and factors still present in the system). Side-effects: bleeding, embryopathy To monitor Warfarin, measure the INR (international normalised ratio). Dose of warfarin is based on INR (normal is 1.0, target for DVT 2-3). Can be variable due to Vit K in diet. Frequency of monitoring depends on the stability of the INR, could be anywhere between 1-8 weekly.

Answer 200

Average dose of Warfarin is 5mg/day but can be anywhere between 1-10mg. Appropriate dose for presenting patient is unknown. Can give trial and error dose and look at effects. A more personalised approach involves testing the genotype of the patient and give dose according to genotype of VKOR and CYP2C9.

Answer 201

In the liver the factors II, VII, IX, X, PC, PS (+8 others) are made but they are not functional until they have been carboxylated by gamma-glutamyl carboxylase. This enzyme requires Vit K for its action but when it is used it becomes oxidised. VKOR (vitamin K reductase) transforms oxidised Vitamin K into reduced Vitamin K so that it can be used again. Warfarin inhibits VKOR so vitamin K cannot be recirculated. Polymorphisms in VKOR mean that Warfarin has sensitivities. Warfarin is broken down by CYP2C9 but there are polymorphisms in CYP2C9 which affect how warfarin is broken down.

Answer 202

A new field of anticoagulants seeking to replace Heparin and Warfarin. Dabigatran inhibits factor IIa whereas Rivaroxaban, Apixaban, Edoxaban inhibit factor Xa. Licensed for PE, DVT and AT. Not yet licensed for general thromboprophylaxis. No monitoring needed. Standard dosing. No alcohol or food interactions, very few drug interactions. Short half-life (10-15 hours). More expensive. Peak effect is within a couple of hours. All protein bound.

Answer 203

-Dabigatran Antidote is Idarucizumab (humanised monoclonal antibody fragment). Recently licensed, very expensive. -Rivaroxaban, Apixaban and Edoxaban Antidote is Andrexanet (recombinant, modified inactive Xa molecule). Short half life. Given by continuous IV infection. Clinical trials underway.

Answer 204

Advantages: Rapid onset of action, fixed oral dosing with predictable anticoagulant effect. Low potential for alcohol or food interactions. Low potential for drug interactions. No need for blood monitoring. Disadvantages: Renal elimination. No specific antidotes for the Xa inhibitors. Licensed for only specific indications. Recently introduced.

Answer 205

- Identification of drug target - Medicinal chemistry: design and optimisation of drug - Preclinical studies: Proof of in vio efficacy and tolerability and toxicity - Phase 1: First-in-man studies, usually healthy volunteers - Phase 2: Small scale studies in target population - safety, tolerability, efficacy - Phase 3: Large scale studies of satefy and efficacy in target population

Answer 206

Narrowing of arteries due to atherosclerosis which are full of lipids, cholesterol and lots of inflammatory cells. AT can manifest as Myocardial infarction, Ischaemic stroke, critical leg ischemia, cardiovascular death.

Answer 207

Platelets are a core component of arterial thrombosis. At rest they are disc-shaped but once activated they change shape and become spiculated with pseudopodia to increase surface area and cell-cell interactions. Designed to stop bleeding but inappropriate action causes plaque rupture. Once plaque rupture has occurred the blood is exposed to endothelial agents primarily collagen and VWF. Under high flow conditions platelets are able to adhere to agonists, activating them, recruiting platelets to vascular injury. ADP and thromboxane A2 lead to further expansion of thrombi. Thrombin production at site of vascular injury leads to fibrin formation. Fibrin connects platelets in aggregation.

Answer 208

Glycoprotein IIb/IIIa receptor is an on the surface of the platelet (50,000-100,000) in resting state. AKA Integrin a IIb B3 Under platelet activation there is an increase in the number of receptors, increase in the affinity of receptor for fibronogen and fibrinogen links receptors binding the platelets together (platelet aggregaation).

Answer 209

Intravenous: Abciximab, Tirofiban, Eptifibatide Block the GPIIb/IIa (aIIbB3) receptor. Increased risk of major bleeding offsets their benefit in reducing ischaemic events. Very narrow therapeutic window, not effective at a low dose, too much bleeding at a high dose (explains why oral antagonists have been failed). Evidence supports continuing use in highest risk patients undergoing PCI (acute MI or STEMI).

Answer 210

Aspirin is an effective but weak anti-platelet therapy. Evidence of aspirin is effective (1988) for patients with STEMI compared to streptokinase. Targets COX1 enzyme, blocking it in platelets. COX1 leads to the production of prostaglandin H2 which is the substrate for Thromboxane synthase. Thromboxane leads to platelet aggregation. At low doses Aspirin targets COX1, at high doses it targets COX2. COX2 leads to the production of prostacyclin in endothelial cells. Prostacyclin inhibits platelets (counterproductive at high dose). Cardiovascular dose is about 75-100mg/day. Targets COX1.

Answer 211

Aspirin blocks COX1 by irreversibly acetylating the enzyme. Effects last the lifetime of the platelet (7-10 days). Effect is established by preventing conversion of arachidonic acid to prostaglandin H, blocking the pathway that leads to platelet thromboxane A2 release. Thromboxane A2 activates platelets via a surface receptor.

Answer 212

Very rare. Continued secretion of thromboxane A2 by platelets in response to appropriate agonist stimulation (such as AA, collagen) despite therapy with aspirin at standard dose. High platelet reactivity doesn't necessarily equate to aspirin resistance. Current evidence suggests that Aspirin is an effective drug and there is no support for the routine screening for aspirin resistance following PCI. Should be given at low doses and platelet function testing to adjust doing is not recommended.

Answer 213

96 patients received 100mg/day. Measured their Thromboxane B2 at baseline which gave a median of 322pg/ul (range 209-402). On aspirin it dropped to 3 (2-5) pg/ul. Only one patient still had Thromboxane B2 levels of 113pg/ul but after reloading with 300mg of Aspirin there was complete suppression. Some patients don't show a significant reduction in platelet aggregration until reloading of 300mg after 7 days. It may be the case that there is a lack of patient compliance rather than aspirin resistance.

Answer 214

Patients that have received aspirin following ibruprofen have less platelet inhibition. This may be due to Ibuprofen blocking COX2 enzyme. Therefore drug interactions are important to consider.

Answer 215

There are 3 purinergic receptors: P2Y1, P2Y12, P2X1. The main focus is on P2Y12 because it plays a key role in the amplification process in platelet activation. Others have a weak role in initiation. Once platelets adhere to endothelin agonists, they change shape and secrete thromboxane A2 and ADP. ADP targets P2Y12 and leads to platelet activation. PAR-1 is the thrombin receptor which also leads to platelet activation, along with lots of receptors such as PAR4, TPa, GPVI, 5HT2A, P2X, P2Y1.

Answer 216

In preclinical studies, P2Y12 +/+ mice with induced thrombi show a clear variability in the thrombus area, but in P2Y12-/- mice there is a huge suppression in thrombus area. There are 3 drugs that target P2Y12 including Clopidogrel, Prasugrel and Ticagrelor.

Answer 217

Clopidogrel is a thienpyridine prodrug so it requires conversion to the active metabolite in order to be effective. Metabolism of clopidogrel is not very efficient and requires the CYP450 enzyme in liver. Only 15% becomes active metabolite that targets receptor. CURE study outcomes was a Phase III trial done in 12,000 patients with acute coronary syndrome with STE. Clopidogrel plus Aspirin vs. Aspirin. Clopidogrel patients did better by primarily reducing recurrent MI. High percentage of patients had low/no response which can lead to stent thrombosis. Patients with diabetes are known to have a poor response to Clopidogrel.

Answer 218

Unknown mechanism of action between Clopidogrel and Omeprazole but the combination gives higher platelet reactivity. Rifampicin makes the metabolism of Clopidogrel more effective (induces CYP450 enzyme) leading to greater platelet inhibition. CYP2C19 is identified as a risk factor.

Answer 219

VerifyNow P2Y12 assay measures platelet aggregation using beads coated with agonists such as ADP and thrombin-like protein. Measures platelet reactivity. Using assay in patients that have had stents has shown that in patients with high platelet reactivity are at risk of stent hypothesis (x4 as likely) which may lead to another MI.

Answer 220

-Dose: increasing the dosemay give increased platelet reactivity -Age and weight -Disease states: diabetes mellitus and chronic kidney disease -Drug-drug interactions e.g. orreprazole and strong CYP3A inhibitors -CYP2C19 loss-of-function or gain-of-function alleles Complexity of factors influencing the response to Clopidogrel means it is impossible to predict accurately. Pharmacodynamic monitoring is required to assess response.

Answer 221

A more effective thienopyridine prodrug than Clopidogrel. Requires metabolism to give active metabolite but it is more efficient because more enzymes can metabolise Prasugrel. As a result there is more consistent platelet inhibition in almost all patients. In a healthy volunteer crossover study of Clopidogrel and Prasugrel in 2005, there was a higher concentration of Prasugrel in the plasma and a higher potency.

Answer 222

TRITON-TIMI38 study design 13,600 patients with ACS (STEMI or NSTEMI) and planned PCI. Randomised patients to Clopidogrel or Prasugrel. Prasugrel showed improved outcomes primarily by preventing MI and stent thrombosis. However does increase risk of major bleeding/life-threatening bleeding and due to the potency an increased risk of intracranial hemorrhage risk.

Answer 223

Ticagrelor is the first oral reversibly-binding platelet P2Y12 receptor antagonist. Belongs to CPTP class. In preclinical studies using P2Y12 +/+ mice and P2Y12 -/- mice ticagrelor showed a significant decrease in the thrombus area.

Answer 224

Phase II ONSET/OFFSET trial studied the pharmacodynamic effects of Ticagrelor. Patients that received Ticagrelor loading dose of 180mg compared to Clopidogrel loading dose 600mg there was more potent platelet inhibition and more rapid effects. Offset of action with Ticagrelor is more predictable because its reversible (3-5 days after stopping treatment). Phase III PLATO study recruited 18,600 patients (moderate-to-high risk ACS patients UA, STEMI, NSTEMI, PCI etc) randomised to have Aspirin+Clopidogrel or Aspirin+Ticagrelor. Ticagrelor reduced chances of CVD, stroke, MI. Some increase in major bleeding events but no increase in life-threatening bleeding.

Answer 225

NICE cost-effective analysis established that TIcagrelor is cost-effective compared with generic Clopidogrel for ACS patients. Adoption in clinical practice in Sheffield for management of acute coronary syndromes. Any patients with positive Troponin and ACS are treated with Ticagrelor.

Answer 226

Dual therapy of Ticagrelor and Aspirin is given for 12 months to reduce risk of MI but unsure whether risk goes away after 12 months because 20% of patients have recurrent events 3 years after treatment. Recruited 21,000 patients who have had history of MI and certain risk factors randomised to receive Ticagrelor 90mg, 60mg and placebo (with Aspirin background). Both doses improved incidence of MI, Stroke etc but at the expense of major bleeding in some. For prolonged therapy over 12 months is only considered for high-risk patients. In Sheffield patients come for an angiogram and their ischaemic risk is determined. If they are high risk Aspirin+Ticagrelor for a year, then dropped to 60mg Ticagrelor.

Answer 227

The wall of an artery consists of three layers. The innermost layer, the tunica intima (also called tunica interna), is simple squamous epithelium surrounded by a connective tissue basement membrane with elastic fibers. The middle layer, the tunica media, is primarily smooth muscle and usually the thickest layer. It provides support for the vessel and changes vessel diameter to regulate blood flow and blood pressure. The outermost layer, which attaches the vessel to the surrounding tissue, is the tunica externa or tunica adventitia. This layer is connective tissue with varying amounts of elastic and collagenous fibers. The connective tissue in this layer is quite dense where it is adjacent to the tunic media, but it changes to loose connective tissue near the periphery of the vessel.

Answer 228

Good for attacking pathogens and parasites, fighting against tumours and organising wound healing. Bad when there is too much inflammation or dislocation. In Myocardial reperfusion injury, atherosclerosis, ischaemic heart disease, rhematoid arthritis, asthma, inflammatory bowel disease, shock, excessive wound healing and restenosis.

Answer 229

Athero = paste Sclerosis = hardness Prinicipal cause of HA, stroke and gangrene of extremeites. Major cause of death in Europe, USA, Japan. LDV first recognised it as a closing up of the arteries. Intially thought of as being a solely lipid-storage disease due to increase nourishment. Now known to be a chronic inflammatory disease influenced by many factors involving a vast array of inflammatory cells and cytokines, although lipids are a major part of disease progression. Main problem occurs when plaque rupture can lead to thrombus formation and death.

Answer 230

Influenced by a multitude of lifestyle choices, medical conditions and haemodynamics of blood flow itself. Turbulence at joints can increase likelihood of development. Can begin at birth (maternal hypercholesterolaemia) or can take years to develop. Often remain symptomless for majority or entire life. Start of symptoms signals advanced disease. Always begins with an insult to the artery wall.

Answer 231

Non-modifiable: Genetic component, Sex (male increased risk), Age, Inflammation, Family history. Modifiable: Alcohol consumption, Hypertension, Overweight/obese, Diet, Physical inactivity, Type 2 diabetes, Infection, Smoking (dyslipidaemia), raised lipoprotein A, high LDL cholesterol, low HDL cholesterol.

Answer 232

Found within peripheral and coronary arteries. Focally distributed along the artery length however distribution may be governed by haemodynamic factors like changes in flow/turbulence (i.e. at bifurcations) cause the artery to adjust its wall thickness, developing neointima. Also alters gene expression.

Answer 233

A complex lesion consisting of lipids, necrotic core, connective tissue, fibrous 'cap' made of connective tissue and smooth muscle cells. Eventually the plaque will either occlude the vessel lumen resulting in a restriction of blood flow (angina) or it may "rupture" (thrombus formation).

Answer 234

First suggested in 1856 by Rudolph Virchow and updated by Richard Ross in 1993 and 1999. Initiated by an injury to the endothelial cells which leads to endothelial dysfunction. Healthy endothelium produces NO and other mediators to protect against atheroma. Injury alters NO biosynthesis - affects BP control, regional blood flow, predisposes to atherosclerosis. Signals sent to inflammatory cells which then accumulate and migrate into the vessel wall.

Answer 235

Chemoattractants (chemicals that attract leukocytes) are released from the site of injury (damaged ECs) and a concentration gradient is produced. Gradient causes leukocytes to transmigrate into vessel wall underneath the endothelium starting the development of the disease (adhesion cascade). Damaged ECs also express adhesion molecules. Monocyte encounters concentration gradient and becomes captured onto the endothelium. Begins to roll quite quickly then slows. Once stopped they transmigrate through endothelium and into the vessel wall. Aided by selectins and integrins.

Answer 236

LDL can pass in and out of arterial wall in excess and acccumulate in arterial wall. ECs and macrophages generate free radicals. LDL is oxidised by free radicals into oxLDL. oxLDL is engulfed by macrophages via scavenger receptors to form foam cells. Foam cells release more pro-inflammatory cytokines boosting the cycle and increasing number of foam cells.

Answer 237

- Earliest lesion appears at a very early age (<10yrs). Accumulation of lipid-laden macrophages (foam cells) and a few T-lymphocytes within the intimal layer form fatty streaks. Asymmtomatic. - Intermediate lesions composed of foam cells, vascular smooth muscle cells, T-lymphocytes and isolated pools of extracellular lipid/cholesterol released by FCs. Adhesion and aggregation of platelets to vessel wall. Small and grows outwards. Asymmtomatic. Lesion tending to hit a balance between growing and the protective mechanisms. - Fibrous/advanced lesions occur when the balance is upset (added impetus e.g. risk factor). Cytokine release by cells causes SMC proliferation and deposition of connective tissue. Leads to a dense fibrous cap overlaying a lipid-rich core. Cap+core make up atheromatous plaque (may be calcified) which impedes blood flow and is prone to rupture. Angina symptoms. - Plaque rupture. Plaques are constantly growing and receding. Fibrous cap has to be reabsorbed and redeposited in order to be maintained (balance between LDL and HDL). Large numbers of VSMC and matrix proteins will stabilise the plaque. Large numbers of macrophages predisposes plaque to rupture, increased matrix metalloproteinases and gelationase, cap becomes weak. Plaque rupture provides a substrate for thrombus formation and vessel occlusion, blood is exposed to necrotic core underneath. Cholesterol crystals can rupture by tearing out (large necrotic core) or by erosion (small necrotic core).

Answer 238

Pathway for plaque reduction using HDL. HDL contains apolipoprotein A1 particles that interact with foam cells to collect cholesterol from foam cells. Mature HDL then travels to liver to release cholesterol for excretion or packaging. HDL then recirculates back to the heart to repeat the process. Remain asymmptomatic for as long as this protective mechanism is in place.

Answer 239

Hematopoietic stem cells participate in atherosclerosis. Evidence: Intimal SMCs differ from medial SMCs in their gene expression patterns. Nature Medicine 2002 showed that bone marrow stem cells can differentiate into endothelial and smooth muscle cells. Dendritic cells can function as an alarm system capable of activating a response to danger signals. Evidence: DCs reside in intima and adventitia of healthy arteries. Found in aorta, carotid and coronary arteries where atherosclerosis is most common and most dangerous. Possible that DCs respond in overdrive to a dysfunctional endothelial cell signal to cause an excess of inflammatory cells.

Answer 240

CAP: ECM proteins including collagen (strength) and elastin (flexibility) LIPID CORE: necrotic and apoptotic debris, SMCs, foam cells, macrophages, T-lymphocytes

Answer 241

Lipids are transported around the body as lipoproteins. Central core of a hydrophobic lipid (triglycerides and cholesterol esters) surrounded by hydrophobic coat (phospholipids, free cholesterol, apolipoporteins). The apoplipoprotein type determines the type of lipoprotein molecule that you have.

Answer 242

Classified according to density and characterised by apolipoproteins. - Chylomicrons: 100-1000nm characterised by ApoB-48 - Very-low-density lipoprotein (VLDL) 30-80nm, characterised by ApoB-100 - LDL 20-30nm, characterised by ApoB-100 - HDL 7-20nm, characterised by ApoA1 and ApoA2

Answer 243

- Exogenous - lipids from diet to tissue - Endogenous - lipoproteins from liver to tissue - Reverse Cholesterol - cholesterol from tissue to liver for processing and excretion

Answer 244

Ingest lipids which are digested in small intestine into lipid vessel which is transported to lymphatic vessel via NPC1L1 transport protein. Packaged with ApoB-48 into nascent small and inactive chylomicrons. Reaches liver and into blood stream where it interacts with HDL. HDL donates apoC-11 and apoE making it mature. Mature chylomicron transported around bloodstream, when it hits the tissues ApoC interacts and activates lipoprotein lipase. LPL catalyses hydrolysis releasing glycerol and fatty acids from chylomicrons which can be absorbed by the tissue. Chylomicrons become remnant but will be carried by the bloodstream to the liver where it is taken up via ApoB-48 or ApoE which bind to receptors. Cholesterol is released in the liver which will be stored, secreted in bile, oxidised to bile acids or converted into VLDL. Remnants are endocytosed and hydrolysed within lysosomes releasing glycerol and fatty acids. p.s. ApoC can only bind to adipose tissue receptors and ApoE can only bind to hepatocyte receptors

Answer 245

Cholesterols synthesised in the liver or delivered to the liver by exogenous or reverse cholesterol pathways are packaged into the VLDL molecule with ApoB-100. This nascent VLDL is released into the bloodstream and becomes a mature molecules once it has interacted with HDL. HDL donates ApoC-11 and E. VLDL will transport through the bloodstream to the tissues which ApoC-11 activates LPL causing hydrolysis of VLDL and release of glycerol and fatty acids. Glycerol and fatty acids can be absorbed by adipose tissue and muscle. VLDL has lost some of its central components so it shrinks in size and becomes IDL. IDL is transported back to the liver (via ApoE binding to LDLR) where hepatic lipase will hydrolyse it to LDL OR the IDL will remain in circulation where it will act via ApoC to become further hydrolysed converting back to LDL. LDL binds to tissues via ApoC, endocytosed, hydrolysed with lysosomes, releasing cholesterol OR LDL binds to LDLR on liver via ApoB100 removing it from circulation.

Answer 246

Removes cholesterol from peripheral tissues and returns to the liver. ApoA1 of HDL binds to transport proteins ABC-A1 or ABC-G1 in macrophages/foam cells in the atherosclerotic region, allowing it to absorb cholesterol and transport it to the HDL. HDL cholesterol then transports cholesterol to liver via either: -INDIRECT: cholesterol esters transfer to VLDL and LDL particles via cholesterol ester transport protein (CETP). LDL binds to LDLR on liver where cholesterol will be released into the liver. -DIRECT: ApoA1 of HDL binds SRB1 transport receptor on liver allowing for cholesterol to be transferred to the liver and for HDL to recirculate to collect some more cholesterol. Cholesterol in the liver is processed and secreted in bile or transported to intestine via ABC-G5/G8 for excretion.

Answer 247

An abnormal amount of lipids in the blood, usually hyperlipidemias. May be primary or secondary to a disease. - Primary: due to a combination of diet and genetics. Usually polygenic although can be monogenic. - Secondary: a consequence of other conditions e.g. diabetes, alcoholism, chronic renal failure, liver disease and drugs (isotretinoin for acne, tamoxifen, ciclosporin and protease inhibitors for HIV). Secondary forms are treated where possible by correcting the underlying cause.

Answer 248

Primary dyslipidaemia is classified in this way according to which lipoprotein particle is abnormal. Six phenotypes. The higher the LDL the lower the HDL the higher the risk of Ischaemic Heart Disease (and atherosclerosis). Types Ia, Ib, Ic have increased chylomicrons but there is no increase in the atherosclerotic risk. Type IIa however Familial Hypercholesterolaemia has increased LDL which gives a high atherosclerotic.

Answer 249

Genetic disorder causing very high LDL levels in the blood which causes early CVD. Most have mutations in either LDLR gene encoding LDLR which removes LDL from circulation or Apolipoprotein B which is part of LDL which binds with receptor. Mutations in other gene are rare. Most thought to be polygenic (60%). - HETEROGZYGOUS: 1 in 500, LDLR gene defect may have premature CVD at 30-40. Treated with statins, bile acid sequestrants or other lipid lowering agents that lower cholesterol levels. - HOMOZYGOUS: 1 in 1M, LDLR gene defect may cause severe CVD in childhood. Doesn't respond to medical therapy and may require other treatments including LDL apheresis and occasionally liver transplantation.

Answer 250

``` Main treatment aimed at decreasing levels of LDL. Drug therapy used alongside dietary changes. Main drugs available: -Statins: HMG-CoA reductase inhibitors -Inhibitors of cholesterol absorption -PCSK9 inhibitor -Fibrates ```

Answer 251

HMG-CoA reductase inhibitors. HMG-CoA is a rate-limiting enzyme in cholesterol synthesis (HMG-CoA to mevalonic acid). Specific, reversible, competitive HMG-CoA reductase inhibitors include Simvastatin, Lovastatin, Pravastatin. Long-lasting inhibitors include Atorvastatin and Rosuvastatin. Must be processed by the liver to become active. Short-acting statins are given orally at night to reduce peak cholesterol synthesis in the early morning. Efficiently absorbed and extracted by the liver (their site of action). Subject to extensive presystemic metabolism via chrochrome P450 (all statins) and glucuronidation pathways (Pravastatin).

Answer 252

Statins reduce cholesterol synthesis in the liver. The liver will respond to this by increaseing the no. of LDL receptors synthesised to get cholesterol from the bloodstream. Increased LDLR causes increased LDL clearance from plasma into liver. Therefore statins reduce plasma LDL and decrease risk of atherosclerosis. Also reduce plasma triglyceride and increase HDL.

Answer 253

- Products of the mevalonate pathway are involved with lipidation i.e. react with protein to add a hydrophobic group. - The fatty groups severe as anchors to localise the proteins in organelles - Several important membrane-bound enzymes e.g. endothelial NO synthase are modified in this way - Therefore inhibiting mevalonate pathway, statins also affect lipidation.

Answer 254

Improved endothelial function Reduced vascular inflammation Reduced platelet aggregability Increased revascularisation of ischaemic risk Increased circulating endothelial progenitor cells Stabilisation of atherosclerotic plaque Inhibition of germ cell migration during development Protection against sepsis Antithrombotic action Enhanced fibrinolysis Immune suppression

Answer 255

- Primary prevention of arterial disease in at risk patients (elevated serum chol conc, other risk factors for arthero) - Secondary prevention of MI and stroke in patients who have symptomatic atherosclerotic disease (angina, transient ischaemic attacks or previous MI or stroke). - Atorvastatin lowers serum chol in homozygous familial hypercholesterolaemia. - In severe drug-resistant dyslipidaemia (heterozygous familial hypercholesterolaemia), statin treatment is combined with other drugs to increase effectiveness. - Statins are not used during pregnancy: HMG-CoA reductase normally guides primordial germ cells.

Answer 256

Muscle pain (myopathy) Insomnia Angio-oedema (rare) Gastrointestinal disturbance Rash Raised concentrations of liver enzymes in plasma Skeletal muscle damage (myositis, rhabdomyolysis [severe, rare, dose-related). More common in patients with low lean body mass or uncorrected hypothyradism.

Answer 257

- NICE proposes to lower treatment threshold but low-risk patients see no benefit (99.3%), are side-effects worth it? - Side effects are negligible compared to decreased heart disease risk in high risk patients - Statins increase risk of diabetes by 1% especially in women (same as reduction in risk of MI or stroke). - Key findings on statins effectiveness and side effects come from industry-funded studies. Not all data has been made available. Bias. - No statin treatment has been compared with lifestyle inteventions for the prevention of CVD. - Interaction between medication and lifestyle, statin users consumer more calories, gain weight and exercise less.

Answer 258

Fibrates/fibric acid derivatives Bezafibrate, Ciprofibrate, Gemfibrozil, Fenofibrate and Clofibrate etc. Fibrates activate peroxisome proliferator-activated receptors (PPAR) especially PPARa. PPARs are intracellular receptors that modulate carbohydrate and fat metabolism and adipose tissue differentiation. Activating PPARs induces transcription of a number of genes that facilitate lipid metabolism (LPL, apoA1, apoAII). Fibrates are metabolised by Cytochrome P450 3A4 (CYP3A4) an enzyme found in the liver and intestine. Oxidises small organic molecules (xenobiotics) such as toxins or drugs so that they can be removed from the body.

Answer 259

Fibrates markedly decrease circulating VLDL therefore decrease triglyceride levels. Modest (10%) decreased in LDL and modest (10%) increase in HDL. - Rarely used in clinic due to adverse effects - Only used when Eztimibe or statins are not tolerated - Can be combined with other lipid-lowering drugs in patients with severe treatment-resistant dyslipidaemia - Haven't been shown to improve survival but do reduce number of non-fatal MI.

Answer 260

- Mild stomach upset and myopathy. - Clofibrate increases risk of gallstones (increases cholesterol content of bile) - only given to gallbladder-removed patients. - Combination of a statin and a fibrate increases the risk of muscle damage (rhabdomyolysis) - leads to kidney failure. - Fibrates should not be taken by patients with advanced kidney disease (increase risk of rhadomyolysis, impaired drug elimination). - Fibrates should not be taken by alcoholics (risk of severe muscle inflammation in injury).

Answer 261

Ezetimibe is one of a group of azetidinone cholesterol absorption inhibitors. Blocks intestinal absorption of cholesterol by blocking a transport protein (NPCILI) in the brush border of enterocytes, preventing packaging into chylomicron in exogenous pathway. Doesn't affect absorption of fat-soluble vitamins, triglycerides or bile acids. Has high potency, only 10mg/day reduces LDL cholesterol by 17-19%. Ezetimibe+Stain = 25% LDL reduction. Administered by mouth, absorbed into intestinal epithelial cells and localises to the brush border. Extensively (80%) metabolised to an active metabolite. Enterohepatic recycling results in slow elimination, half life is 22hrs.

Answer 262

Advantages: Very low potential to interact with other medications Convenience of taking single 10mg tablet once a day Disadvantages: Expensive Mild diarrhoea, abdominal pain, headache, rash, angioedema (swelling of deep layers of skin).

Answer 263

- Patients who experience side effects from high dose statins to reduce dose to one that is tolerated. - Supplementary treatment to statins in patients with severe dyslipidaemia. - Enters milk so contraindicated for women who are breastfeeding.

Answer 264

Another inhibitor of cholesterol absorption. First cholesterol lowering drug to be used clinically e.g. Colestyramine, Colestipol, Colesevelam. Taken orally. Remain in intestinal tract and sequester bile acids to prevent their absorption into the bloodstream. Liver componsates by increasing metabolism of endogenous cholesterol into bile acids, increasing expression of LDLR and clearing of LDL from blood. Side effects: bloating, constipation, diarrhoea, nausea (bulky and unpalatable). Interfere with the absorption of fat-soluble vitamins, digoxin, diuretics, warfarin, thyroid hormones, beta-blockers, calcium channel blockers. Need to be taken 1 hr after or 4-6hr before other medication. Very rarely used in clinic due to intolerance.

Answer 265

Isolated from wood pulp and used to make margarines or yoghurts. Stanol ester is hydrolyed into stanol and fatty acids in digestive tract. Sterols and Stanols are structurally similar to cholesterol, can be incorporated into chylomicrons or mixed micelles to replace cholesterol. The result is less cholesterol (40-45%) is absorbed into the bloodstream. Less absoption means there is reduced serum total and LDL cholesterol concentrations. May also activate transporter proteins (ABCG5/ABCG8 heterodimer) within enterocytes - increases movement of cholesterol from enterocytes back into the intestinal lumen to be excreted. For optimal efficacy, should be taken as part of a meal. Plant stanols particles are virtually unabsorbed in the body so they retain efficacy long term.

Answer 266

Inhibitor of Cholesterol absorption. Niacin = Nicotinic acid/Vitamin B3 Need high levels (3g/day) of niacin to improve cholesterol (13-17mg/day RDA) Converted to Nicotinamide which inhibits hepatic VLDLD secretion. Causes decrease in circulating triglyceride, decrease in LDL including Lp(a), increase in HDL. Mechanism is poorly understood, thought to be initiated by lipolysis via a G protein-couple orphan receptor (HM74A) present in adipocyte membranes.

Answer 267

Flushing, palpitations, itching/redness of face, arms and chest, headaches and gastrointestinal disturbances. Large doses of niacin can be toxic to the liver, taken under medical supervision only. Almost never used clinically. HSP2-THRIVE trial: Niacin & statin does not improve cardiovascular outcome but does increasse serious adverse effects.

Answer 268

Evolocumab/Rapatha is a human monoclonal antibody (IgG2) to inhibit Proprotein Convertase subtilisin/kexin Type 9 (PCSK9). PCSK9 is a natural negative regulators of LDLR. PCSK9 binds to LDLR and the complex internalises, receptor undergoes lysosomal degradation and LDL continues to circulate. Supplied as an injection for subcutaneous administration.

Answer 269

Evolocumab binds to PCSK9 preventing circulating PCSK9 from binding to LDLR, preventing PCSK9-mediated LDLR degradation. LDL binds to LDLR, internalises and LDL is released. LDLR recycles back to the liver cell surface. Increases the number of LDLRs available to clear LDL from the blood, lowering circulating LDL levels.

Answer 270

- Addition to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical CVD who require additional lowering of LDL-C - Addition to diet and other LDL-lowering therapies (Stains, Ezetimibe, LDL, Apheresis) for treatment of homozygous familial hypercholesterolemia who require additional lowering of LDL-C. In HoFH there is a monthly dosage and measure LDL-C levels 4-8 weeks after startingg Repatha. Response to therapy will depend on degree of LDLR function.

Answer 271

In studies looking at levels of circulating LDL levels: - Statin alone: relatively high levels of LDL - Ezetimibe and Statin: reduced levels of LDL - PCSK9 inhibitor and Statin: reduced even further

Answer 272

Nasopharyngitis, Upper respiratory tract infection influenza, back pain, injection site reactions (erythema, pain, bruising, hypersensitivity reactions e.g. rash, eczema, erythema, urtucaria) if occur discontinue treatment.

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