AF Flashcards

Question

what occurs in the 3rd stage of thyroid hormone synthesis

Answer 1

The thyroglobulin molecule is taken up into the follicular cell by endocytosis. In the endocytic vesicles then fuse with lysosomes and proteolytic enzymes act of thyroglobulin, releasing T4 and T3 to be secreted into the plasma. The surplus MIT and DIT, which are released at the same time, are scavenged by the cells and the iodine is removed enzymatically and reused.

Answer 2

The initial steps in thyroid hormone synthesis (iodide incorporation into tyrosine residues of thyroglobulin and covalent binding of the residues) are catalyzed by haeme-containing peroxidases. Theoretically, severe iron deficiency could lower thyroperoxidase activity and interfere with thyroid hormone synthesis. Animal studies have documented that weanling rats fed iron-deficient diets have significantly lower T3 and T4 compared to rats fed adequate iron

Answer 3

- T3 – triiodothyronine, T4 - thyroxine thyroxine (T4) and triiodothyronine (T3) are produced from thyroid follicular cells within the thyroid gland, a process regulated by the thyroid-stimulating hormone secreted by the anterior pituitary gland. Linking two moieties of DIT produces T4. Combining one particle of MIT and one particle of DIT produces T3.

Answer 4

MIT and DIT are rapidly degraded by halogenases to free the iodide, which is then re-utilised by combination with thyroglobulin. The T3 and T4 leave the follicular cells and enter the blood stream for distribution to the target tissues. Approximately 95% of the thyroid hormone leaving the thyroid gland is in the form of T4 not active but biologically stable (thyroxine).

Answer 5

- Within the target tissues deiodinase enzymes convert the T4 to either T3 (80%) or reverse-T3 (20%). - T3 has a biological activity approximately 40 times greater than that of T4, whilst reverse-T3 is biologically inactive. - Up to 90% of the biologically active thyroid hormone within the cell is in the form of T3. - The plasma half-life of T4 is 6 - 8 days whilst that of T3 is one day.

Answer 6

1. Thyrotrophin releasing hormone (TRH), released from the hypothalamus in response to various stimuli, releases thyroid stimulating hormone (TSH also known as Thyrotrophin) from the anterior pituitary. 2. The production of TSH is also regulated by a negative feedback effect of thyroid hormones on the anterior pituitary gland 3. T3 is more active than T4 in this respect 4. Somatostatin (also known as growth hormone-inhibiting hormone (GHIH)) also reduces basal TSH release. 5. The other main factor influencing thyroid function is the plasma iodine concentration. About 100 nmol of T4 is on the site daily, necessitating uptake by the gland of approximately 500 nmol iodine each day (equivalent 70 µg of iodine). A reduced iodine intake, with reduced plasma iodine concentration, will result in a decrease of hormone production and an increase in TSH secretion. An increase plasma iodine has the opposite effect.

Answer 7

Thyrotropin-releasing hormone (TRH), is produced by neurons in the hypothalamus, that stimulates the release of thyroid-stimulating hormone (TSH) and prolactin from the anterior pituitary. Thyroid-Stimulating Hormone (TSH) Thyroid stimulating hormone is produced by the pituitary gland. Its role is to regulate the production of hormones by the thyroid gland. Thyroid-stimulating hormone (TSH) levels test Thyroid function test, looks at levels of thyroid-stimulating hormone (TSH) and thyroxine (T4) in the blood.

Answer 8

Thyroid hormones are insoluble in water, therefore are transported in blood bound to plasma proteins usually albumin which is the rate controlling step. The nutritional value will have an effect on the albumin levels ,patient is 50kg so she may not be getting enough protein so her plasma and albumin levels will be low Over 99% of the circulating thyroid hormones are protein-bound: • the majority ( approximately 75%) of T4 binding is to thyronine-binding globulin (TBG). If you are malnourished, the circulating thyroid levels goes down. • 15-20% is bound to thyroxine-binding pre-albumin (TBPA) • 5-10% is bound to albumin. Only free (unbound) hormone is biologically active

Answer 9

The receptors for the thyroid hormones are intracellular, more specifically nuclear. - That hormone needs to get inside the cell before it binds with an appropriate receptor - Because Thyroid hormones influence gene transcription and thus protein synthesis;

Answer 10

- increased in carb metabolism - increased in the synthesis, metabolism and degradation of lipids increased protein synthesis

Answer 11

the thyroid hormone produces a general increase in the metabolism of carbs, fats and proteins and regulates the processes and most issue by controlling the activity of some of the enzymes however most effects are brought about in conjunction with other hormones such as insulin gucagon, corticosteroids. there is an increase in oxygen consumption and heat production which manifests as an increase measured basal metabolic rate the administration will result in augmented cardiac rate and output and increased tendency for AF

Answer 12

the TH have a large effect on growth because of the actions of cells and indirectly influencing growth hormone production and potentiating its effects on its target tissue the thyroid hormone is important for a normal response to parathyroid hormone and calcitonin as well as skeletal development thyroid hormone is also important for normal growth and maturation of the CNS.

Answer 13

- each cell at a cellular level, the mitochondria is working a bit harder . - all carbohydrates metabolic increase so glycogenesis occurs in the muscle tissue and there will be effects in insulin - this will affect patients w diabetes. If the patient was overweight, if you give her thyroid hormone and she was taking insulin, there will be a greater effect. - Can also have an effect on catecholamines such as adrenaline, noradrenaline and the increase in glucose absorption in the GI tract

Answer 14

* In normal cardiac function, The Ca2+ is released by the sarcoplasmic reticulum which slows down the repolarisation and we get a plateau phase. * Then the Ca2+ re-enters the sarcoplasmic reticulum causing the contraction of cardiac tissue so you get the big spike. * This normal functioning goes wrong in hyperthyroidism. * In hyperthyroidism, we have an increase in T3 which are biologically active. * In cardiomyocytes, cellular Ca2+ storage capacity is increased by thyroid hormone . Effects of thyroid hormone on Ca21 handling in cultured chick ventricular cells. Modulation of SERCA2 expression by thyroid hormone and norepinephrine in cardiocytes: role of contractility. * This results in increased outward currents and decreased inward currents => shorter Action Potential (AP) duration => atrial fibrillation

Answer 15

- Pathogenies of AF in hyperthyroidism which is mediated by the effects of T-3. - The T-3 effects has an increased sensitivity to the beta-1 adrenergic receptors and decreases sensitivity in the muscarine-2 receptors - Also there is decreased heart rate variability which is mediated by the vagolytic effect of the T-3. T-3 can cause excitation of the vagal nerves - Has decreased APD action potential duration – the length of time the whole PQRST takes to do. So it gets squashed which is AF because there is irregular rhythm so It goes faster. - Medicated by T-3 affects the ionic channel activity (calcium). It does this by causing a decrease in the L-type calcium channel through mRNA expressions. This causes a genetic change to occur and this genetic change takes about 6-8 weeks to express itself - Have an increased expression of the Kv or the potassium voltage channels where gene transcription is influenced. There is an increase in rate of potassium X flux which results in a shorter atrial refractory period - There is an increase in automaticity in the pulmonary vein into the cardiomyocytes and therefore an increase in sopra (above) ventricular depolarisation which means in there is depolarisation across both the atriums and in the structures surrounding those spaces

Answer 16

in those who have hyperthyroidism it is found that the beta 1 adrenergic and m2 muscarinic altered the receptors causing in increased sympathetic functions such as tachycardia and decreased atrial refractory period. also alters the ionic channels by: - decreasing the L-type calcium channel mRNA expression - increased expression of voltage gated potassium channel these changes resulted in increased outward current and decreased inwards current resulting in shorter action potential duration

Answer 17

1. Thyroid hormone regulates a wide range of genes after its activation from the prohormone, thyroxine (T4), to the active form, triiodothyronine (T3). 2. There are two genes that express the major thyroid hormone receptor isoforms. Mutations in both these genes have given rise to Resistance to Thyroid Hormone (RTH) syndromes (RTHβ, RTHα) that can have variable phenotypes for mutations. 3. There are thyroid hormone receptors (TRs) with two TR isoforms: TRα and TRβ. 4. TRα has one T3-binding splice product, TRα1, predominantly expressed in brain, heart, and skeletal muscle, and two non–T3-binding splice products, TRα2 and TRα3, with several additional truncated forms. 5. TRβ has three major T3-binding splice products: TRβ1 is expressed widely; TRβ2 is expressed primarily in the brain, retina, and inner ear; and TRβ3 is expressed in kidney, liver, and lung.

Answer 18

Hormone levels will influence the brain , heart and skeletal muscle. The 2 non T-3 binding places produce a thyroid hormone receptor alpha 2 and thyroid hormone receptor alpha 3. Thyroid hormone receptor beta has 3 major T-3 bonding splices beta 1 is expressed everywhere in the body. Beta 2 expressed primarily in the brain, retina, inner ear, kidney, liver, lung. Stimulation of these receptors will have a clinical effect for patients on these sites - Here is the pituitary gland, the brain and you have normal or high levels of thyroid stimulating hormone. - It acts on the thyroid gland and causes a release of T-4 and T-4 which goes into the peripheral tissues and has a clinical action. - In diagram A, the beta occurs in tissue expressing thyroid hormones receptor beta are caught and causes a rise in T-3 and T-4 due to impaired negative feedback - In diagram B, the thyroid hormone receptor alpha because tissue is expressed predominantly thyroid hormone receptor alpha which appears in bone, gut and heart - In contrast with TH-beta there is no effect on the negative feedback on the hypothalamic access by thyroid hormone - However patients have an increase in serum of T-3 and T-4 ratio suggesting there is a downstream effect such that deiodinase will be affected.

Answer 19

* Increased in carbohydrate metabolism. * Increased in the synthesis, mobilisation and degradation of lipids. * Increased protein synthesis.

Answer 20

* Thyroid gland * Anterior pituitary gland * Brain * Uterus * Testes * Spleen

Answer 21

* Hypothyroidism affects between 4% and 10% of the population, and the prevalence of subclinical hypothyroidism is reported to be as high as 10% in various studies. * Hypothyroidism is diagnosed when low levels of the thyroid hormones result in elevated levels of thyroid-stimulating hormone (TSH). * subclinical hypothyroidism is diagnosed when TSH levels are elevated above the upper limit of the assay reference range with normal thyroid hormone levels. * Thyroid hormones play an important role in the normal function of heart and vascular physiology, and hypothyroidism produces profound cardiovascular effects. * Arrhythmia and Hypothyroidism. * It is well known that hyperthyroidism is associated with atrial fibrillation (AF). Similarly, hypothyroidism is associated with increased cardiovascular risk factors as well as subclinical and diagnosed

Answer 22

* It is well known that hyperthyroidism is associated with atrial fibrillation (AF). * Similarly, hypothyroidism is associated with increased cardiovascular risk factors as well as subclinical and diagnosed cardiovascular disease, both of which are thought to predispose one to AF.

Answer 23

``` Usual Lethargy Mild weight gain Cold intolerance Constipation Facial puffiness Dry skin Hair loss Hoarseness ```

Answer 24

Athyreosis: an abnormal condition caused by absence or functional deficiency of the thyroid gland. Ectopic thyroid is any thyroid tissue not located in its usual position Thyroid dyshormonogenesis is a rare condition due to genetic defects in the synthesis of thyroid hormones. Patients develop hypothyroidism with a goiter. It is due to either deficiency of thyroid enzymes, inability to concentrate, or ineffective binding. -iodine deficiency

Answer 25

``` iodine deficiency autoimmunity antithyroid drugs iodine excess thyroid irradiation ```

Answer 26

Autoimmune destruction of thyroid gland. May or may not be associated with hypothyroidism - Hashimoto's thyroiditis is caused by the immune system attacking the thyroid gland, making it swell and become damaged. - As the thyroid is destroyed over time, it becomes unable to produce enough thyroid hormone. This leads to symptoms of an underactive thyroid gland (hypothyroidism), such as tiredness, weight gain and dry skin. - The swollen thyroid may also cause a goitre (lump) to form in your throat. - It may take months or even years for the condition to be detected because it progresses very slowly. - It's not understood what causes the immune system to attack the thyroid gland. Hashimoto's thyroiditis is usually seen in women aged 30 to 50 and it sometimes runs in families. - It cannot be cured, but symptoms can be treated with levothyroxine, thyroid hormone replacement medication usually taken for life. - Surgery is needed only rarely – for instance, if your goitre is particularly uncomfortable or cancer is suspected.

Answer 27

Replacement therapy with thyroxine. Monitor by measuring TSH: sufficient T4 will suppress TSH secretion. Typically also need calcium and vitamin D therapy.

Answer 28

Drugs which can induce goitre: • Lithium - used in the treatment of bipolar depression, • Iodides - contained in vitamin preparations and some cough remedies. • Amiodarone – used for the treatment of atrial fibrillation: the structure contains iodine which will affect thyroid function

Answer 29

Hyperthyroidism = more thyroid hormones than is needed by the body (also referred to as thyrotoxicosis, or an overactive thyroid). It can occur if you have: • Graves’ disease - the most common cause. – If the TSH level is low and the T4 level is high (below and above the reference range respectively) usually indicates an over-active thyroid. – The ‘TSH receptor antibody’ test can establish Graves’ disease. • A toxic multinodular goitre (a goitre is an enlarged thyroid gland). • A solitary toxic thyroid adenoma (an adenoma is a clump of cells). • Thyroiditis (inflammation of the thyroid gland) when it is temporary and self-limiting. • It can also occur when too much replacement thyroxine (levothyroxine) is taken as a treatment for an underactive thyroid (hypothyroidism).

Answer 30

``` weight loss lack of energy heat intolerance anxiety increased sweating increased appetite thirst palpitations loose bowel ```

Answer 31

* The TSI level is abnormally high in persons with hyperthyroidism due to Graves' disease. * TSI is a form of immunoglobulin G (IgG) that can bind to thyrotropin (TSH) receptors on the thyroid gland. TSIs mimic the action of TSH, causing excess secretion of thyroxine and triiodothyronine * Exophthalmos (bulging of the eye anteriorly out of the orbit.) * Goitre (swelling in the neck resulting from an enlarged thyroid gland) * Pre-tibial myxoedema infiltrative dermopathy, resulting as a rare complication of Graves' disease. It is most commonly seen on the shins (pretibial areas) and is characterised by swelling and lumpiness of the lower legs.

Answer 32

Causes of hyperthyroidism 0.2-0.4% population 8x more common in females - Autoimmune thyroid diseases: Graves’ disease - Toxic nodular goitre - Toxic adenoma

Answer 33

Management: Prescribing information 1. Propylthiouracil - prevents the peripheral conversion of T4 to T3. 2. Carbimazole - The anti-thyroid drugs carbimazole and methimazole act by inhibition of the synthesis of thyroid hormones by preventing the incorporation of the iodide into the thyroglobulin. 3. Management: Prescribing information

Answer 34

Beta-blockers may be used for the rapid relief of adrenergic symptoms, and may be used in conjunction with specialist antithyroid drugs such as carbimazole and propylthiouracil. The beta-blockers propranolol (used most commonly), metoprolol, and nadolol are licensed for the treatment of thyrotoxicosis as an adjunct to antithyroid drug treatment

Answer 35

Side effects of anti-thyroid drugs - Nausea - Vomiting - Pruritus and urticarial rashes - Leucopaenia (<0.1%) - Fever - Cholestatic jaundice

Answer 36

- Any group of conditions in which electrical activity to the heart is irregular or is consistently faster or slower (bradycardia)than normal. A normal heart rhythm is a sinus rhythm which consists of p waves, QRS complex (most obvious part in an ECG) and a t wave and they occur regularly. Normal resting heart rate is around 60-100 bpm. - The causes of dysrhythmia is altered impulse formation- the site or the rate of the formation of action potentials has changed - or altered impulse conduction- the action potential originates from the sinus node which passes down the atria to the AV node to the bundle of his and then branches out into the left and right bundle branch then into the purkinje fibres

Answer 37

- in altered impulse formation this can relate to decreased automaticity of the SA node leading to a decrease in heart rate or it can cause increase in automaticity in the SA node leading to heart rate becoming too fast (tachycardia) - automaticity means the ability of particular cells to generate an action potential which leads to ventricular contraction.

Answer 38

- These are cells which have pacemaker activity but are supressed by action potential being generated by the SA nodes. - HOWEVER… under certain circumstances they can increase their automaticity above that in the SA nodes and start to drive the rhythm. - Abnormal automaticity is when cells that don’t have any pacemaker activities. These happen in conditions of damage, cells that don’t produce action potentials and suddenly will have that property to generate action potentials and so drives the function of the heart. - Triggered activity occurs when a single action potential is initiated in the SA node drives the formation of more than a single depolarisation or action potential in the atrial muscle wall. So a single action potential form a SA node may lead to multiple depolarisation of the atrial muscle or the ventricle muscle cell. - Altered impulse conduction- for example a conduction block is where there is a block in the action potential through the AV node in the ventricles. This is called a AV block which can vary in severity for example you can see an increase in time in the conduction for an action potential to occur through the AV node or the action potential may fail to get through to the ventricles and this depends on the severity of the block.

Answer 39

- Atrial fibrillation and ventricular fibrillation is an example of dysrhythmia as it involves a lot of re- entrant loops. - This where part of the atria become self- excitatory. - So rather than the action potential passing through all the cells all at once and depolarise them once, the action potential is blocked and so goes round which produces lots of action potentials. - They all spread out and depolarise the other muscle cells in the atrium and then work their way up to the AV node.

Answer 40

- Generates action potential which passes through to the atrial muscle cells and then go to the AV node. - The action potential is passed through the AV node with a delay which goes to the bundle of his and then branches out to the left and right bundle branches into the purkinje fibres where this cause a contraction of the ventricles. - This forces blood wither to the lung (right ventricle) or through the circulation through the aorta to supply to the rest of the body with oxygen and nutrients.

Answer 41

Here is a normal SA node action potential which a resting potential around -60 millivolts. The SA node has a pacemaker potential which drives this slow depolarisation until it hits the threshold. After it reaches the threshold it rapidly depolarises and then repolarises back to his resting membrane potential. Through the autonomic nervous system you can change the rate of generation of action potential in the SA nodes and the sympathetic activity through the release of adrenaline and noradrenaline will increase heart rate through its actions on beta-1 receptors on the heart. These effects re occurring at the level of the pacemaker current. - For example if we start to exercise then our sympathetic system will start to become activated and if we are resting after a meal then our parasympathetic system through the Vagus nerve will release AcH that will slow down the pacemaker current which will slow down the depolarisation and therefore slows down the rate of action potentials that are being generated.

Answer 42

Sick sinus syndrome is where in the SA node it automatically goes fater or slower than normal Sick sinus syndrome thyrotoxicosis, infection, anaemia, alcohol and drug therapy. - If you have an over active thyroid gland, will affect the heart rate - Infection through an increase on body temperature can affect heart rate - the ion channels are proteins which are designed to allow certain action potential to be the shape it is and all proteins are affected by temperature - if you are anaemic your heart rate might go up because it is trying to pump blood and therefore oxygen around the body to demand the demand of your body. - alcohol can affect the muscles in the heart - drug therapy can affect heart rate

Answer 43

Ectopic beats are usually nothing to worry about. Where certain conditions have caused the pace maker cells that is normally being suppressed by SA nodes to increase it rate of action potential generation

Answer 44

Exercise, stress, pregnancy, menopause, and ageing. • Fluctuations in potassium and magnesium levels in the blood. • Intake of caffeine, alcohol, recreational drugs or some prescribed medications (decongestants, asthma medications beta-2 antagonists) • Conditions affecting heart muscle including prior MI and heart failure

Answer 45

* Similar to previous section but these cells normally do not have pacemaker activity. * Damage (e.g. following and MI as causes damage to the cells) causes cells to spontaneously depolarise. * Although there may not be an ion channel there that allows the influx of positive ions, the damaged membrane allows positive ions to diffuse through it

Answer 46

- Early or EADs (1st picture) – After depolarisation occurs early in the action potential. Normal atrial action potential. Starts to repolarise and then generates theses 3 depolarisations before the final repolarisation back to the resting membrane potential. This is generated from a single SA node action potential will generate 4 depolarisations in the ventricular muscle cell so therefore 4 contractions of the heart muscle cells which will lead to faster heartbeat. - Late or LADS/DADs (2nd picture)- DADS happen after the repolarisation of the initial action potential. - The delayed after depolarisation generates 2 action potentials for every stimulus that has arrived from the SA node

Answer 47

Early: dues to increases in action potential width. Late: Due to large increases in intracellular Ca2+ or sometimes called calcium overload. Altered conduction (Re-entrant rhythms)

Answer 48

Cause atrial/ventricular tachycardias and can degenerate to cause fibrillation. They can be local (atria or ventricular) or global (involved in both) (see Wolff-Parkinson White syndrome) They require changes in the conduction velocity (usually a slowing in the conduction velocity) and refractory period (an increase) of part of the cells that from part of the re-entrant circuit to set up the tachycardia. Useful atrial fibrillation link - An action potential that passes down and it meets an area of non-conducting tissue in the heart - The action potential has to pass down the left hand side and the right hand side of this non- conducting tissue - When it comes out the other end, it passes along the bottom and will die when it meets an action potential from the other side because all excitable cells have a refractory period, a period where it can’t be re-excited. - A single action potential will generate a single action potential that comes out of the system - HOWEVER… if there damage to some of the muscle cells in the circuit and these properties of conduction velocity and refractory period are changed appropriately. - an action potential can pass down but can’t go down the blue region (bottom RHS) because it is refractory so it passes down another route from route 1 to 3 and up to 2 and because pathway 2 is recovered comes through this tissue slowly. - by the time it comes out of the end pathway 1 is recovered so the action potential can just pass around the circuit generating lots of action potentials. - will lead to tachycardia and if the number f action potentials are high enough can lead to fibrillation

Answer 49

In people with heart block, also called AV block, the electrical signal that controls the heartbeat is partially or completely blocked from reaching the ventricles. Heart block is classified as Type 1, 2(number of action potentials don’t make it through the ventricles) or 3 with 3 being the most serious( practically no action potential doesn’t reach the ventricles) Heart block can be caused by damage to the AV node or drug therapy.

Answer 50

Cause atrial/ventricular tachycardias (doesn’t contract properly so cardiac output is reduced ) and can degenerate to cause fibrillation. They can be local (atria or ventricular) or global (involved in both) (see Wolff-Parkinson White syndrome) They require changes in the conduction velocity (usually a slowing in the conduction velocity) and refractory period (an increase) of part of the cells that from part of the re-entrant circuit to set up the tachycardia.

Answer 51

Types of re-entrant rhythms- they all have one thing in common there is an imbalance between the conduction velocity and the refractory period in order to allow for the rhythm to be set up.

Answer 52

* Sinus node re-entrant tachycardia (SNRT), in which the re-entrant circuit involves the sinus node. * AV nodal re-entrant tachycardia (AVNRT), in which the re-entrant circuit involves the AV node. * Atrial re-entrant tachycardia, in which the re-entrant circuit is contained within the atria. * Atrioventricular re-entrant tachycardia (AVRT), in which the re-entrant circuit contains an electrical connection (a “bypass tract”) between the atria and the ventricles. There are several varieties of bypass-tract re-entrant tachycardia, but the most well known is Wolff-Parkinson-White syndrome (WPW). * Atrial flutter, which is a special type of atrial re-entrant tachycardia in which the re-entrant circuit is especially large. * Atrial fibrillation is generally regarded as a special type of re-entrant atrial tachycardia in which multiple re-entrant circuits can develop within the atria.

Answer 53

• Caused by the following changes to one part of the circuit – Increase in the refractory period and – Slow retrograde conduction • For many the re-entrant rhythm starts and stops instantaneously. • Conditions can be caused following ischaemic event like tissue could change it properties, but also ageing.

Answer 54

- A re-entrant rhythm is set up when an action potential hits an area of non-conducting tissue (shown by the triangle in the middle) - The action potential from the SA node could hit an area of non-conducting tissue and the action potential passes down the left hand arm and down the right hand arm around the non-conducting tissue. - When it passes to can start to migrate backwards (bottom part of the 1st picture) where it will die out because all of the excitable cells have a refractory period. - Refractory period is a period of time where no matter what you do you cannot re-excite the cell or stimulate it. The refractory period is relative to the width of the cardiac action potential. - A single action potential and will pass around the non- conducting tissue and it will die when it meet the action potential coming from the other side. - Every muscle cell and conducting cell in the system where the arrows are passing will only get excited once for a single action potential from the SA node. Second picture explanation - The grey area is where there is damage to the conducting tissue in one arm of the re-entrant. This arm will have slightly different conducting properties to the tissue that is present in the other arm of the loop - Because the arm that has been damage there will be an increase in refractory period so it takes longer to recover and therefore has a longer time delay before that tissue can be re-excited. - If a second action potential comes down the tissue on the left hand side with a normal refractory period has recovered and can conduct the action potential. - HOWEVER… the tissue on the other side because it has an increased refractory period still hasn’t recovered and therefore the action potential hits that tissue and dies out (shown with red line) - The action potential passes down and comes along the bottom and doesn’t die out because the tissue hasn’t been excited because of the block from the damaged arm and so it carried on and will start to work its way back up the arm of the damaged arm. Third picture explanation (Left picture where conditions are normal and haven’t been damaged. - If it hits the action potential hits the tissue on the broken arm the tissue has been recovered and therefore it is not refractory. - The action potential can pass up through the tissue and as it comes out of the other sided, under normal conditions It will hit the tissue which is now in a refractory state because it has just been excited by this action potential

Answer 55

No because if a single action potential coming down has excited the tissue once, excited the bottom part of the tissue once and comes up through to the right hand side of the tissue and excites that tissue once. - For every action potential coming down, these conducting or muscle cells are only being excited once per action potential. - There will be a slight difference in the conduction route but no increase in the number of depolarisation seen per section from the SA node and so there will be a slight difference of muscle contraction per SA node action potential.

Answer 56

- If it hits the action potential hits the tissue on the broken arm the tissue has been recovered and therefore it is not refractory. - The action potential can pass up through the tissue and as it comes out of the other sided, under normal conditions It will hit the tissue which is now in a refractory state because it has just been excited by this action potential

Answer 57

- There will be a slight increase in refractory period and there will also be an altered conduction velocity. - The conduction velocity is slowed (Shown by wavy line) so when the action potential slowly passes through that bit of tissue as it re-enters the tissue that isn’t damaged which has recovered and so the action potential can re-excite this tissue for the non-damaged arm. - This mechanism occurs over and over and therefore becomes a self-sustaining loop. - This self-sustaining loop can lead to many action potentials and more contractions of the heart muscle cells occurring for a single stimulus from the SA node. For it to be self -sustaining it has to be in perfect balance. - The slight increase in refractory period that occurs and how slow the conduction velocity must match for the time it takes for the action potential to migrate arounf the circuit/system.

Answer 58

If the refractory period is slightly too slow, when the action potential comes round it wouldn’t be able to go through the non- damaged arm wouldn’t have recovered. If the conduction velocity is not slow enough the tissue wouldn’t have recovered if another action potential occurs again. An action potential might come from the SA node and re-excite this tissue so will become refractory There will be lots of re-entrant loops and when an imbalance occurs this will maintain atrial fibrillation in patients who have AF.

Answer 59

We might need to use drug therapy to somehow change the refractory period of the damaged tissue or to change the conducting velocity. By using drug therapy we might be able to stop re-entrant rhythms because we then imbalance this circuit so that the rhythm dies out - Class 1 drugs will alter the conduction velocity - Class 3 drugs will change the refractory period of this tissue.

Answer 60

Parasympathetic system releases AcH slows heart rate and sympathetic system release adrenaline and noradrenaline which increases the heart rate

Answer 61

• Brady dysrhythmias- slow heart rate To treat an abnormally slow heart rhythm you want to use drugs that block the parasympathetic system or mimic the sympathetic system. For example atropine – Modify autonomic input: to the SA or AV node a) anticholinergics: blocks AcH b) Beta agonists c) Pacemakers-need to implant an artificial pacemaker which may pacemaker the ventricles, the atria of the ventricles.

Answer 62

• Tachydysrhythmias – Increased automaticity: the increased ability of tissue to produce action potentials faster than normal. Could be SA node or tissues. a) Reduce rate of depolarisation so cell takes longer to reach threshold so rapid upstroke wouldn’t be as sharp and therefore takes longer for repolarisation to occur. Slowing the rate at which the cells are generating action potentials. b) Increase Resting membrane potential of the cell (make it more negative)- this causes threshold to be reached much later so the automaticity is reduced c) Make action potential threshold less negative: so slowed down the automaticity of the cells. • Re-entrant Rhythms – Decrease conduction velocity – Increase Refractory Period

Answer 63

• Triggered Activity – Shorten action potential duration. The cardiac action potential becomes wider so there will be more depolarisation in the muscle cells. So need to give a drug that will shorten the action potential – Correct conditions of calcium overload. The calcium in the muscle cells becomes much higher than normal so more depolarisation will occur. Need to correct calcium overload.

Answer 64

– Multiple re-entrant loops that are set up in the atria. self-excited that are generating lots of action potentials. For every stimulus they receive from the SA node – 350-600 action potentials per minute. Doesn’t have time to contract so the heart will quiver. – Irregularly irregular pulse, can be fast or slow. This is because there is lots of action potentials which will hit the AV node and its refractory and will die out. An action potential may hit an AV node when it is excited and will pass through and will allow the ventricles to depolarise and therefore contract. – This process is random because it depends if the AV node has recovered or no because if it has recovered from refractory then an action potential will pass into the ventricle causing it to depolarise and contract if it hasn’t recovered then the action potential will die out. – Loss of clear p-waves on ECG- a p wave is the atrial depolarisation on an ECG. You will be able to see a clear p wave because those atrial muscle cells are depolarising approximately the same time. There is a slight delay as it takes a little bit of time for the action potential to pass from the SA node across to the atrial muscle cells. They should be done at the same time however someone with AF the synchronisation is lost as the muscle cells quiver depending if they’ve been excited by an action potential. Because loss of synchronicity the p wave is lost on the ECG so it makes it easier to dignose someone with AF as you wouldn’t see the p waves on an ECG. – Thrombi -because the atria is quivering and they are not relaxing and contracting properly there is an increase in blood volume around the atria walls so thrombi can occur which can break off and form a clot in the ventricles, pulmonary artery or the aorta. • Treatment

Answer 65

– Beta Blocker: first line therapy effective at maintaining sinus rhythm and controlling ventricular rate during AF – Calcium Channel Blockers: verapamil and diltiazem. Both can increase myocardial tissue refractoriness and decrease conduction velocity in the AV node, thus reducing ventricular rates in AF. – Digoxin (controls heart rate) to control ventricular rate – Cardiogenic shock or Class 1 or 3 to restore atrial rhythm – Warfarin, DOACs. ALL AF PATIENTS MUST BE ON ANTICOAGULANTS!!

Answer 66

``` works mainly by blocking the sodium channels in the open or inactivated state. inhibition of sodium channels decreases the rate if rise in phase 0 depolarisation and slows down conduction velocity. class one drugs are subdivided into 3 subclasses: class 1A, class 1B and class 1C ```

Answer 67

depresses the phase 0 depolarisation by blocking fast sodium channels and prolongs repolarisation by blocking some potassium channels. there is a prolonged action potential and prolonged refractory period drugs includes quinadine, disopyramide, procainamide. used to treat a wide range of arrhythmia such as ventricular tachycardia and recurrent AF. side effects includes headaches, blurred vision and tinnitus

Answer 68

has weak effects on phase 0 depolarisation due to minimal blockage of fast sodium channels. they shorten repolarisation by blocking sodium channels that activate during the late phase 2 of the action potential. results in a shorter action potential and shorter refractory period drugs includes lidocain, mexiletine which are mainly used for ventricular arrhythmias. nausea cns toxicity and seizures are side effects.

Answer 69

are fast sodium channel blockers which depresses the phase 0 depolarisation. they also inhibit the purkinje conduction system with a limited effect on repolarisation and refractory period. drugs includes flecanide, propafenone. used in the treatment of refractory ventricular arrhythmias

Answer 70

are beta blockers These are the drugs that will reduce the effect the sympathetic system on the heart muscle. • Stress and Emotion can trigger dysrhythmias (MI) that releases adrenaline and noradrenaline into the heart muscle cells. • Decrease automaticity so they can reduce the ability of the SA nodes cell to generate action potential • Decrease cardiac rate, increase the refractory period in the AV node and reduce excitability in ventricles. They do this by delaying the action potential in the SA node. • Used – To control ventricular rate in AF or atrial flutter by reducing the excitability of the AV node therefore slow down the number of action potentials that get into the ventricles. Slows ventricular rate – Post-MI to reduce effects of adrenaline on damaged myocytes. Excessive adrenaline acting on damaged myocytes causes them to increase their automaticity and drive the abnormal rhythms – to treat re-entrant rhythms which use the AV-node (WPW). They can convert a patient who has re-entrant rhythms which involves the AV node back into the sinus rhythm. Only occurs in re-entrant rhythms that use the AV node- Wolf Parkinson syndrome. THEY ARE NOT USED TO TREAT RE-ENTRANT RHYTHMS OF THE ATRIA OR THE VENTRICLE. They are not used for restoring a sinus rhythm in patients with AF or ventricular fibrillation. Can only be used for restoring a sinus rhythm in abnormal rhythms that use in AV nodes. – E.g. metoprolol, atenolol, sotalol (L-isomer)- used for controlling the ventricular rate. Blue text shows the drugs can have a bad effect by causing an AV block • Possible conduction block/bradycardia. Can be life threatening if you don’t use beta blockers correctly. - Beta blockers will reduce the slope of phase 4 depolarisation because they block the effects of adrenaline on the funny current and the effects of adrenaline on the L-type calcium current. - So a decrease in phase 4 decreases the firing rate and will reduce automaticity. - They prolong the repolarisation in the AV node therefore increasing the refractory period hence decreasing the ventricular rate. - Used to treat patients who have AF or atrial flutter or they can be used to treat automaticity in cells that have become overactive.

Answer 71

Repolarisation is caused potassium ions leaving the cardiac muscle cells. By reducing the efflux of potassium ions the prolong the action potential. • Prolong the action potential (increasing the width) – Increase refractory period and therefore decrease re-entrant rhythms and return the rhythm to a normal sinus rhythm. Controls rhythm • Used to treat WPW and both atrial and ventricular fibrillation • E.g. Amiodarone, dronedarone and sotalol (D and L isomers). These are beta blockers that has some potassium channel blocking activities. • By increasing the width of the action potential, you are increasing the refractory period of the cells. • The drugs are really useful drugs for decreasing re-entrant rhythms and returning the patient to a normal sinus rhythm. Used to control rhythm control. • May precipitate Torsades de Pointes. An example of ventricular tachycardia. May be life threatening. • After depolarisation it causes and increase in the width of the action potential, this can lead to a ventricular tachycardia after the use of the drugs of potassium channel blockers. - Here is the normal cardiac action potential and by giving a potassium channel blocker we are prolonging the plateau phase and increasing the width of the action potential and therefore increasing the refractory period. - This is useful when treating re-entrant rhythms and restoring the patients sinus rhythm.

Answer 72

Blocks potassium, sodium and calcium channels and has lots of side effects. Has a lot of iodine so can affect thyroid function so need to monitor this • Resembles Thyroxine • CYP3A4 main route for metabolism, metabolite active. • Both amiodarone and metabolite have long half-lives (58 and 36 days respectively). Needs a loading dose because it has a long half-life and so to get it to the concentration of the therapeutic level to the patient quickly. • Hepatic excretion. So any impairment in the liver will increases the levels of amiodarone in the bloodstream • Amiodarone interacts with a range of drugs (

Answer 73

* No iodine so no thyroid side effects * Less lipophilic than amiodarone so its half life is shorter (24 hours) and so is the half life of its active metabolite (20-25 hrs). * The advantage can be stopped and removed if there is any problems as the half life is short * The disadvantage is that if you miss a dose the levels of the drug will drop off quickly and therefore you may not be protected. * Still metabolised and excreted in the liver. Need to dose adjust accordingly if patient has liver impairment. * Less interactions than amiodarone.

Answer 74

• are calcium channel blocker Decrease automaticity in the SA node • Slow conduction through AV nodes- regulates ventricular rate in patients that have supraventricular tachycardia. • Used to regulate ventricular rate in supraventricular (SVTs) tachycardias such as AF. Would use them if you wanted to control ventricular rate in a patient who was contraindicated to a beta blocker eg. In a patient who has severe asthma ou wouldn’t give them a beta blocker because it would make their asthma symptoms worse so you would give them a calcium channel blocker instead. • E.g. Diltiazem and Verapamil ( these are non-dihydropyridine) : cardiac selective calcium channel blockers. • Bradycardia and possible conduction block

Answer 75

- They don’t slow the rate of the initial depolarisation phase but they slow the rapid upstroke and this is due to the calcium entering through the L-type calcium channels. - The drugs blocks the L-type calcium channels in the cardiac muscle. So the atria/ventricular muscle cell or the SA/AV node. - They can increase the threshold potential of the SA node by blocking the calcium channels. - This therefore decreases heart rate and reduce automaticity. - If we want to control ventricular rate in the case of super ventricular tachycardia, they do this by decreasing the conduction velocity of the AV node and by doing so increasing the refractory period. - Calcium channel blockers focus on the L-type calcium channels and beta blockers focuses on both the If and L-type calcium channels.

Answer 76

Miscellaneous which includes digoxin and adenosine

Answer 77

– Increases refractory period in AV node caused by release of AcH in the AV node cells and the ability of digoxin to increase the action potential – Stimulates the parasympathetic system to release AcH – Prolongs the action potential duration – Mechanisms of action of digoxin explained-1 – Mechanisms of action of digoxin explained-2 – Possible conduction block/bradycardia – Has a narrow therapeutic index which means that the therapeutic dose is very close to the dose of toxicity so if the levels of digoxin is too high can cause bradycardia or a tachycardia. – The reason why can get tachycardia is because there is an increase in calcium levels inside the body. – By having a calcium overload you can have a delayed after depolarisation in the atrial or ventricular muscle cell which can cause tachycardia.

Answer 78

– Targets AV node to regulate ventricular rate. – Increases K+ current decreases node excitability – Possible conduction block/bradycardia – Link to patient being given iv adenosine - Regulate the ventricular rate and it does this by increasing the potassium current. - Adenosine binds to the adenosine receptor on the nodal cells that activates a G protein and the Beta- Gamma subunit can stimulate a potassium channel. - As a result, reduces ventricular rate and potentially can cause and potential conduction block or bradycardia

Answer 79

* Patients with AF may have symptoms such as breathlessness, palpitations, chest pain… or may be completely asymptomatic. * AF may be paroxysmal, persistent or permanent

Answer 80

• Atrial fibrillation causes a five-fold increase in the risk of stroke

Answer 81

– Detection of the AF – Identifying the cause of AF – can this be treated – Treating the arrythmia itself : rhythm control v rate control – Reducing stroke risk : ANTICOAGULATION

Answer 82

perform manual pulse palpitation to assess for the presence of an irregular pulse if there is suspicion of AF perform a 12 step ECG to make Diagnosis

Answer 83

used to assess the risk of a stroke with any of the following Symptomatic or asymptomatic paroxysmal persistant or permanent AF AF flutter IF the Chadvasc score is greater than 2 need anticoags

Answer 84

you assess the risk of bleeding when considering anticoagulation in people with AF and reviewing people who are already taking anti coagulants. using the ORBIT bleeding risk score because there is a higher accuracy in predicting absolute bleeding risk

Answer 85

- It is looking at the one year major bleeding rate and the two year major bleeding rate in people who have AF. - The more points that you score similar to the one in HASBLED , then the higher the persons bleeding risk. - Takes into account gender, haemoglobin levels bleeding history, renal function, and treatment with antiplatelets agents.

Answer 86

uncontrolled hypertension poor control of INR in patients on vitamin k antagonists concurrent medication, including anti-platelets, antidepressants and NSAIDs harmful alcohol intake

Answer 87

when discussing the benefits and risk of anticoagulation use clinical risk profiles and personal preference to guide treatment choices for most people the benefit of anti coagulation outweighs the risk if not careful monitoring needs to be done

Answer 88

Apixaban or dabigatran or edoxaban or rivaroxaban | offer this when the chadvasc score is above 2 taking into account the blleding risk

Answer 89

consider anticoag when the chadvasc score is 1 or above in men taking into account the bleeding score

Answer 90

if doac is not tolerated or there is contraindication then offer vitamin k antagonist

Answer 91

do not offer stroke prevention therapy with anticoags to people under 65 with AF and no risk factors other than gender do not withold anticoags because of persons age in people who have AF do not stop anticoags because their AF is no longer detectable

Answer 92

to calculate the heart rate on an ECG it is determined by the interval between two successive QRS complexes. The heart rate is calculated by dividing the number of large boxes between 2 successive QRS complexes into 300. If you have an irregular heart rate need to find the average by looking at the number of R waves in 30 larges squares which is equivalent to 6 seconds then x10 to give bpm

Answer 93

``` class a- sodium channel blockers 1A Procainamide/Disopyramide • Prolong conduction and repolarisation ``` 1B Lignocaine/ Mexiletene (oral equivalent) • No effect on conduction, shortens repolarisation 1C Flecanide/ Propafenone • Prolong conduction, no effect on repolarisation class 2 beta blockers • Reduce force of contraction and heart rate (Decrease conduction thorough AV node) • Reduce adrenergic stimulation • Improve electrical homogeneity (sotalol) • Shorten QT (not sotalol) ``` class 3: amiodarone/ sotalol • Prolong action potential and therefore refractory period • Improve electrical homogeneity • Prolong QT (increased risk of TDP) • Inhibit K+ ion channels • Slow HR ``` ``` class 4 calcium channel blocker • Slow AV node conduction ```

Answer 94

Procainamide / disopyramide 1A • Atrial and ventricular arrhythmias • Procainamide (unlicensed UK) • Disopyramide has anticholinergic side effects • May prolong QT (TDP) • Renally excreted • Rarely used as lots of side effects like dizziness, dry mouth, blurred vision

Answer 95

Lignocaine – lidocaine 1B (local anaesthetic drug) • Used for suppression of VT – only used to treat ventricular arrhythmia. • Only available as an IV preparation so has a very short heart life so it needs a loading dose ECG monitor • Liver metabolised: it inhibits its own metabolism so need to cut down on infusion rate • More sensitive : hepatic impairment, heart failure, elderly • Caution in severe renal impairment (CrCl<10) • ADE- neurological, hypotension • Dose (short t ½): – 100mg IV bolus over few minutes, followed by – 4mg/minute IV Infusion for 30 minutes, – 2mg/minute for 2 hours, then – 1mg / minute + reduce further if continued for >24 hrs • Mexiletine is oral equivalent ( unlicensed UK) • Nausea and vomiting common: take with /after food

Answer 96

Flecanide / Propafenone 1C * Indicated for atrial and ventricular arrhythmias * Flecanide is a fluorinated analogue of procainamide (1A) * Not for use heart failure or any CHD * Use with caution as often causes other arrhythmias (5% patients) * Propafenone only under specialist supervision

Answer 97

Beta-blockers II • Reduce affects of sympathetic system on automaticity and conductivity • Indicated in atrial and ventricular arrhythmias • Can be co-prescribed with digoxin • BUT not with verapamil as slows down the conduction through the AV node and there is a risk of causing an AV block and care with care with diltiazem • C/I in asthma • Caution in COPD, PVD and (diabetes) • Sotalol has class III action and should only be used to manage arrhythmias • Bisoprolol, metoprolol, atenolol……. • In hospital esmolol (IV) for SVT

Answer 98

• Sotalol is racemic mixture of D & L isomers – D - sotalol is pure class III (antiarrhythmic) has a different side effect profile than beta blockers. Causes an effect on repolarisation and therefore prolonging the QT interval which can result in a polymorphic ventricukar tachycardia – L - sotalol has class III and BB activity • Low dose (80mg OD) = beta-blocker effects • Doses >160mg /day class III effect is prominent • May prolong the QT interval (TDP) • Avoid hypokalaemia • Used for SVT including AF and AFlutter (and VT) • May convert to SR

Answer 99

Amiodarone III • Pharmacology – Blocks sodium channels (class I action), – Inhibits sympathetic stimulation (class II action), – Blocks potassium channels (class III action) and – Blocks calcium channels (class IV action). – Lengthens the action potential duration and increases the refractory period so it slows the heart rate down – Prolong the QT interval (TDP) • Slows heart rate • Improve electrical homogeneity - convert to SR! Amiodarone dosing III • Highly lipophilic • Loading dose required due to long t ½ (30-100 days). Need to give the patient a good loading dose to saturate the tissue stored within the body • Licensed oral loading dose – 200mg tds for 7 days then, – 200mg BD for 7 days then, – 200mg OD thereafter. • IV – Central vein with ECG monitoring very irritating to the tissues – Indications include: SVT’s, AF, VT, VF ... ``` …adverse effects • Cardiac worsen arrhythmia new arrhythmia (2-5%) QT prolongation sinus or AV nodal block new/worsening heart failure ``` • Skin photosensitivity ‘blue grey discolouration’ because it has a high iodine content • Optic corneal microdeposits optic neuropathy- advise patient to see their optician. ``` • Thyroid hypo and hyperthyroidism baseline TFTS all new patients • Hepatic baseline LFTs all new patients • Pulmonary pulmonary fibrosis – higher doses and long term Rx • Neurological tremor, peripheral neuropathy • GI nausea, vomiting, anorexia ```

Answer 100

* Non-permanent atrial fibrillation, i.e for maintenance of SR post DCCV not controlled by other drug therapy * Measure Creatinine 7 days after initiation. * Monitor liver function * May prolong QT interval (as per amiodarone) * Dose 400mg BD (avoid if eGFR <30ml/min) * Reduce digoxin dose by 50% (as per amiodarone) * Not for HF patients (NYHA III or IV)(EF <35%) * Increased risk mortality / Limited data

Answer 101

``` amiodarone iodine containing long half life 30-100 days accumulation in tissue including the thyroid requires intensive monitoring used in HF treated for AF,SVT ```

Answer 102

• Inhibits Na/K ATPases. Increases intracellular calcium concentration by inhibiting Na/Ca exchange – Positive inotropic effect (increase force of myocardial contraction) – Negative chronotropic effect (reduces heart rate) • Ensure K+ in range- digoxin toxicity as has narrow therapeutic index • May cause ST and T wave changes • Peak conc 6hrs after oral dose • Excreted by kidneys so have to be careful for people with renal impairment. • TDM: Level 0.8-2.0 micrograms/litre • Indications include: AF, AFlutter,

Answer 103

``` • Blocks at AV node • Used to terminate SVT • t ½ = 0.5 -5 seconds • On administration effect occurs after 20 seconds • Side effects – Flushing – chest pain – Metallic taste • Distressing to the patient (but S/E short lived) ```

Answer 104

``` Bradycardia <60 bpm • Sinus node disease (Sinus bradycardia) • Age related, loss of pacemaker cells • Hypothyroidism • Ischaemia • Pharmacological therapy • AV nodal disease (Heart block - 1st, 2nd & 3rd degree) • Ischaemia • Pharmacological therapy ```

Answer 105

amiodarone, verapamil, diltiazem, digoxin | donepezil, carbamazepine, lithium, tricyclic antidepressants

Answer 106

• Patient symptoms vs. cardiac output (40bpm) • Withdraw / correct the cause • Atropine IV to stimulate the parasympathetic system Isoprenaline infusion (unlicensed in UK)- a beta agonist which will increase the rate of contraction • Temporary pacemaker – AV node often recovers e.g post Inferior MI (RCA)

Answer 107

- The pacemaker sits on tissue and wires are fed into the heart to make a contraction if the heart doesn’t do that by itself.

Answer 108

• Infection risk – antibiotics choice and timing • Bleeding risk – care if anticoagulated • Lead placement - movement shouldn’t lift their arm above shoulder level for a few weeks as this can cause movement of the leads that are fed into the heart and will not make the pacemaker working efficiently , analgesia • For patients with tachy-brady syndrome – where the patient has a fast and slow heart rate – will allow patient to be prescribed rate lowering drugs

Answer 109

Tachycardia: >100bpm • Sinus tachycardia- originates from the SA • Supraventricular tachycardia (atrial) – Atrial fibrillation (AF) – Atrial flutter (Atrial Flutter) – Re-entry / junctional tachycardia's (e.g. WPW) – Ventricular tachycardia – VT • Monomorphic- all of the complexes are the same • Polymorphic (TDP)- where there is lots of complex change pattern – Ventricular fibrillation (VF)- can cause death

Answer 110

• Caused by: – thyrotoxicosis, hypotension, pulmonary emboli, stress, caffeine, cocaine, alcohol, pain… • May be self-terminating (normal heart structure) • Treat underlying cause

Answer 111

- They are wide ventricular complexes at a rate greater than 120 bpm

Answer 112

Ventricular tachycardia • Defined as 3 or more consecutive ventricular beats • Broad complex • Monomorphic vs. Polymorphic (TDP) • PC – Dizziness, syncope +/- palpitations – LOC (reduced cardiac output) – Often self terminating (non-sustained) – May lead to VF → Death • Caused by – AMI (infarcted area) – Often drug induced: antiarrhythmics, amiodarone, sotalol , TCA, IV Erythromycin, Haloperidol etc – Low K+ and Mg 2+ – Cardiomyopathies- problems with the heart itself – Congenital defect (Brugada syndrome) – TDP • Treatment – Precordial thump – IV Amiodarone – IV Lidocaine – DCCV (once anaesthetised)- placing paddles onto the patient’s heart and shocking the heart into a normal rhythm. – Atenolol (non-sustained) or a beta blocker – Correct K+ and Mg2+ – May require ICD- implanted cardio defibrillator which is similar to a pacemaker but can also deliver electrical shocks

Answer 113

``` • Twisting axis • Long QT • Treatment – Reduce / treat the cause and correct electrolytes – Administer Magnesium – (BB to reduce QT (except sotalol which increases QT) – Temporary pacing – Is it drug induced? ```

Answer 114

``` Ventricular fibrillation (no pulse) • Irregular, rapid and chaotic - no organised contraction of the ventricle. • No cardiac output, = NO PULSE • Rapidly causes LOC and sudden cardiac death • Commonly caused by AMI • May be ppt by VT / TDP, electrolytes • Treatment is – DCCV – Precordial thump? – Resuscitation ``` Non pharmacological therapy • Electrical Cardioversion • Recent onset (AF)-may have to shock the patients heart back into rhythm • Pacing (anti-tachy) or (for SA Node disease or heart block) • Temporary • Permanent • Implantable Cardioverter Defibrillator (ICD) • If at risk of VT • Usually combined with drug therapy because you need to supress the arrhythmia. Don’t want to have a patient who has an implanted ICD who has frequent episodes of ventricular tachycardia • catheter ablation or cryotherapy (ablate myocardial tissue-to prevent electricity from travelling down an abnormal pathway ) • WPW, SVT, atrial flutter – often totally curable • Symptomatic AF or PAF : pulmonary vein isolation-isolate the origin of the arrhythmia. • Ventricular ablation • Surgical ablation for AF (during cardiac surgery) • Vagal manoeuvres- SVT- to convert patients heart rate back to a normal rhythm.

Answer 115

Atrial flutter (~150bpm) ``` • Narrow, saw tooth • Caused by – IHD, PE, caffeine, alcohol and stress • Originating from single atria focus (RA) • Treatments include – Adenosine (identification of flutter waves) – Anti-arrhythmic therapy IA, IC, III – Anticoagulation – Ablation ``` - Can be asymptomatic - Random pathways where there is irregular pattern on the ECG because the atrium is fibrillating so fast so its difficult to see the conduction pathway within the atria. - This causes the P wave to get lost into this sort of baseline response of just looking like a squiggly line and there is no definitive p wave.

Answer 116

• Irregularly, irregular - absent P waves on ECG • Usually originates from Left Atrium (pulmonary vein)- if you do freezing procedure you are burning/freezing around that pulmonary vein, which is origin to try and prevent progression of the pathway ¨ Very common in elderly (20-55% of population > age 70) • Reduced atrial contraction, therefore risk of thrombus / embolic event (anticoagulate)

Answer 117

``` • Causes include: – Ischemic Heart Disease – Hypertension – Valvular heart disease – Respiratory infection – Electrolytes – Infection – Alcohol – Cardiac surgery – Hyperthyroidism… may be resolved after cardiac surgery – Young patients – with no underlying structural heart disease often have an acute identifiable precipitant for their AF (e.g alcohol) ```

Answer 118

– Heart failure (40% pts affected) | – Ischaemic stroke

Answer 119

• Rate control non-inferior to rhythm control (and possibly superior in elderly and co-morbid patients) • No significant difference between groups -Trend favoured rate control because less invasive • Recommended anticoagulation for all patients, regardless of control

Answer 120

``` Rate control- slowing heart rate through the AV node Monotherapy • Beta Blockers (not sotalol) • Rate limiting CCB • Digoxin (sedentary) If uncontrolled • Combine two of the above • Never use a beta blocker with verapamil ```

Answer 121

* If rate controlled but symptoms continue or rate uncontrolled * DCCV * Dronedarone (post DCCV) * Beta B * 1C-commomly flecainide (not no structural / ischaemic heart disease) * Amiodarone * “pill in pocket” (PAF / cause known)- just give medication at the time of the arrhythmia

Answer 122

- The reason why patients who have AF may go into a stroke is to do with the formation of blood clotting especially in the left atrium appendage. - If part of the clot breaks off it can ravel up the circulation and through the bloodstream. - This may lead to a blockage in the artery in the brain and will cause a stroke

Answer 123

``` Congestion/heart failure Hypertension Age >75 Diabetes mellitus Stroke Vascualr disease Age 65-74 Sex (female) ``` ech category equals 1 point

Answer 124

* Offer anticoagulation to people with a CHA2DS2VASc score of 2 or above taking bleeding risk into account * Consider anticoagulation for men with a CHA2DS2VASc score of 1. • Do not offer anticoagulation to people aged <65 years with AF and no risk factors other than their sex (that is, very low risk of stroke equating to a CHA2DS2-VASc score of 0 for men or 1 for women)

Answer 125

``` Hypertension Abnormal renal and liver function Stroke Bleeding Liable INR Elderly >65 Drugs or alcohol ``` Patients with a high risk of bleeding (HAS-BLED score >/= 3) should undergo regular clinical review following the initiation of oral anticoagulation.

Answer 126

* Vitamin K antagonists (warfarin) * Warfarin * Acenocoumarol * Phenindione

Answer 127

Warfarin evidence • SPAF (1991) • Warfarin or aspirin vs placebo. • Aspirin or warfarin (on own) superior to placebo • SPAF II (1994) • Warfarin vs aspirin. • Aspirin sufficient in young & healthy. Warfarin may be necessary for higher risk patients. • SPAF III (1996) • Low fixed-dose warfarin and aspirin vs adjusted standard-dose warfarin. • In high-risk AF-patients, low fixed-dose warfarin plus aspirin was inferior to adjusted standard-dose warfarin in reducing stroke • Need to monitor INR

Answer 128

- for warfarin it is important to keep your patient in the target INR.If your patient has arterial fibrillation trying to reduce the risk of stroke - As INR becomes into the range between 2-3 this is your lowest level of stroke risk. Doesn’t reduce more as the INR increases. - The red line which is the risk of bleeding in the brain as your INR increases, once the INR goes above 4, there is an increase in the risk of intracranial bleeding

Answer 129

``` • Risk of bleeding vs. benefit to patient • Target and range INR • Educate the patient – Monitoring of INR – Adverse effects – Missed doses – Who to tell that you are taking – Dietary advice – Drug interactions (including OTC + herbals) – Ensure adherence ```

Answer 130

dabigatran

Answer 131

apixaban rivaroxaban edoxaban

Answer 132

* Dabigatran 110mg BD vs 150mg BD vs warfarin * Primary endpoint: stroke or systemic embolism * Results: 150mg Dabigatran significantly lower rate of stroke & embolism, similar rate of major bleeding but rate of GI bleeding was higher. * 110mg Dabigatran similar rate of stroke & embolism lower rate of major bleeding

Answer 133

* Rivaroxaban 20mg OD vs warfarin * Primary endpoint: Composite of stroke and systemic embolism. * Results: Rivaroxaban non-inferior for warfarin for prevention of stroke or systemic embolism. * Reduced risk of intracranial and fatal bleeding * No significant difference in the risk of major bleeding * GI bleeding was greater with Rivaroxaban

Answer 134

* Apixaban 5mg BD vs warfarin * Primary end point: Ischaemic or haemorrhagic stroke or systemic embolism * Results: Apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding and lower mortality. * GI bleeding similar between both groups

Answer 135

* Edoxaban 30mg OD vs 60mg OD vs warfarin * Primary endpoint: stroke or systemic embolic event * Results: Both doses non-inferior to warfarin * Higher dose more effective than warfarin at preventing stroke / systemic embolic event * GI bleeding increased with 60mg dose

Answer 136

- A baseline at looking at the different characteristics of the patients within the different trials. - If you have a higher risk of stroke in your patients that go into the study , then not surprising that they have a higher rate of stroke. - If you have a higher risk of bleeding in your patients that go into the study, again it is not surprising to see a higher rates of bleeding in that study - The patients who had a CHADS2 score between 3-6 then you can see in the different studies that different proportions of these patients had very high risk.

Answer 137

- When you look at forest plots you need to think about what are the endpoints in the studies for the different agents, the patients that went into the study aren’t the same, so you can’t say one drug is better than another. - The line of neutrality (vertical line) with the number 1 across it - If things falls to the right of that line it means that the treatment we’ve given favoured warfarin and warfarin was the better treatment. - If it fell to the left of the line it means that the treatment favoured DOAC/NOAC - The bigger the square the more confidence we have on that result. - The narrower the confidence intervals. If the confidence doesn’t cross the line of neutrality you can say that was significant. - If you combine all 4 of the studies, you get the diamond shape output and here you can see they’re actually reducing the risk of stroke or systemic embolic events. - Then the treatment for DOAC/NOAC is favoured over the treatment of warfarin

Answer 138

Significantly reduced stroke or systemic embolic event by 19% vs warfarin Significantly reduced all-cause mortality by 10% vs warfarin Increased GI bleeding vs warfarin Findings consistent over wide range of patients Not for mechanical valves / mitral stenosis/ end stage renal disease they all must have warfarin. For the NOAC/DOACs, absolute contra-indications would be for any patient who has a mechanical heart valve, they must have warfarin

Answer 139

``` • Risk of bleeding vs. benefit to patient • Target and range INR • Educate the patient – Monitoring of INR – Adverse effects – Missed doses – Who to tell that you are taking – Dietary advice – Drug interactions (including OTC + herbals) – Ensure adherence ```

Answer 140

- If have a bad headache or start feeling unsteady or feeling weak down one side got to the hospital urgently - Take pills everyday - Act on symptoms of bleeding  Coughing up blood  Blood in poo  Any bleeding that goes on for too long  Blood in vomit  Unusual headache, unsteady, weak down one side. - Ask for more information or help if you need it.

Answer 141

* Patient preference, risk vs benefit * Age * Co-morbidities * Renal / hepatic function * Current drug therapy * Allergies * Family history * Social history * Cost?

Answer 142

* The monitoring of therapeutic drugs involves measuring drug concentrations in plasma, serum or blood. * This information is used to individualise dosage so that drug concentrations can be maintained within a target range

Answer 143

- Each time we add a dose we see a rise towards a peak level of concentration (red dot). - See the elimination of that drug that is indicated y the fall phase (blue dot) - As have regular dose regimens/ maintenance dose we have a steady state concentration of that drug within the patient. - Aim is to reach the steady state concentration within the therapeutic window of that particular drug. - Once within the therapeutic window we know we are providing efficacy treatment for that patient. - Important to keep the green line within the therapeutic window. - As the green line shift from the therapeutic window it may enter the toxic region or may move to subtherapeutic window. Drug therapeutic monitoring is a means of sampling that concentration to make sure we keep the drug concentration within the therapeutic window.

Answer 144

1. Monitoring Compliance/Adherence 2. Individualising patient therapy • During early therapy • During dosages changes to keep withing therapeutic window. 3. Suspected/Avoiding toxicity 4. Diagnosing undertreatment 5. Monitoring and detecting drug interactions 6. Guiding withdrawal of therapy

Answer 145

- need to see symptoms by observing positive changes in the patient in terms of symptomatic improvement. - Measure biochemistry markers such as blood pressure - Can measure the concentration of the drug itself. Is the drug within the therapeutic window and is it efficacy. - Is the drug moving away from the therapeutic window into the toxicity range or the subtherapeutic range? - Take a blood sample where it is analysed by an array of different techniques - The data provided generates a concentration in order to make a clinical judgment. - Can personalise the dose to ensure that it is correct.

Answer 146

- If there is not enough data on randomised clinical trials in a range of different patient groups it’s going to be difficult to know the widespread behaviour of the drug when distributed to a wider patient cohort group. - Does the drug behave the same way with people with different conditions e.g. patients who have hepatic impairment or renal impairment. - Disease will affect the pharmacology of the drugs e.g. half time the elimination rate. - The drug may be giving similar toxic effects that the patient will already be having symptoms for with the disease they have so it can become difficult to know whether the patient is experiencing symptoms due to the disease to whether they are experiencing symptoms due to the toxicity of the drug. - Co-morbidities will not only affect the distribution of the drug and behaviour of the drug in that particular patient but also will introduce new drugs to a patient to treat other conditions. Therefore this means that there is a greater risk of drug interaction and influence on making sure that the drug dosing is correct for the patient. - Different state of the patients health will affect the drug concentration eg hepatic or renal function. Hepatic is important as it breaks down the drug into its metabolites and eliminates the drug out of the system. - Renal function eliminates the drugs itself. Will affect the drug concentration or alter the reactive metabolites that are also present. - Preanalytical- after the sample has been obtained what we do before the measurement. Need to purify the sample to selectively analyse the drug of interest. - Analytical observation needs to be doe such as repones time accuracy, measurement. Most important one is specificity – can it distinguish between reactive metabolites, different drug compounds that may be structurally similar?

Answer 147

- Urine sample - Blood - Hair - Sweat

Answer 148

Sample preparation: taking the blood sample and being able to get the drug out of it in the most accurate and precise way possible. To do this we need to preserve the concentration of the blood to replicate what it was like when the sample was obtained. Very time consuming process. Can be used to help you to make analysis easier however very slow process supress analyte concentration - interference- there will be other things in the blood from other drug compounds to other biological assays which will interfere - deteriorate the analyte - incompatible with instrument

Answer 149

- Blood in its normal form, we can prevent clotting by adding reagents then the blood will stay in its natural form in an un-coagulated manner. - If we leave the blood to clot then the blood will end up in the bottom of the test tube and a sample of serum. - The energy that is used to utilise to make the blood clot has been lost of that sample - If we centrifuge the blood you can separate the compound of the blood and the heavier compounds will settle at the bottom. - The blood will settle at the bottom then the white blood cells and the platelets just above it then the fluid part of the blood where this contains all the nutrients and all the proteins including fibrinogen. - This means can use blood in 3 ways:  The simplest form of blood preparation is to form a clot and therefore measure the serum.  We can prevent clotting and conduct centrifugation and obtain plasma.  The most common medium that is used in therapeutic drug monitoring is monitoring the serum it’s a means of measuring a sample where half of the big constituent of that sample is lost. All of the blood cells are removed. - Choosing serum as a medium to do all the therapeutic drug monitoring

Answer 150

- the constituent is made up of drugs and molecules and lots of proteins including plasma proteins that distribute the drug around the body - Albumin is very useful for allowing the binding of acidic drugs to its surface for its distribution around the body. Also basic drugs bind to glycoproteins in our bodies. - when they’re bound to these plasma proteins they have no effect In terms of the response. - For there to a change they need to be unbound and free and once they are free they can do things out of the vasculature into the target areas and have effects on that particular protein or molecular target - The measurement of the free concentration of the blood is important because it is the free concentration of the drug that has a therapeutic effect.if we measure the total concentration of the drug that were both bound and free then we only get some idea of the effects of the drug on the body. - Also if there is any changes or variation in the distribution of albumin by concentration it will have a bad effect on the concentration of free or unfree drugs. - Plasma protein binding is very important in drug therapeutic monitoring because it influences on the free concentration of the drug

Answer 151

Protein precipitation - The serum will be full of lots of different proteins. Albumin and glycoproteins is there and can be difficult to measure. So have to remove them from the sample. - The serum is at the bottom and we then add a reagent or a chemical that - Will completely denature the proteins. Can do this by either using an acid or a based at high concentrations that will break the structure of the protein. - Same process can occur if we added organic solvents like dichloromethane and methanol. - Lastly can use heat to denature the protein as the enzymes will denature at high concentrations - Once the enzymes have been denatured can centrifuge it and see the pellets at the bottom and the solution will become very clear which is the fault of any plasma protein present. Good method of removing protein interferences. - By removing the protein, this prevents all of those drugs from binding to the plasma protein from any proteins to bind to. all of the drugs are unbound. - This means in the solution now following protein precipitation you can only measure the concentration of the drug.

Answer 152

- Works in the same way as protein precipitation. - Green layer at the bottom and by adding an organic layer on the top we’ve moved a lot of the compound to the top and a very small number of compounds is left at the bottom layer. - You would do liquid-liquid extraction after protein precipitation as it allows for more precise measurement with having selectivity issues.

Answer 153

- The way in which it works is that there is a cartridge and in the cartridge it has a sorbent bed which is a layer of compound that allows for absorption of compounds to stay in the structure. - Add the sample and based on the samples affinity to interact with the properties of the material on the sorbent. - They will either stick to the material or move away from it - If it prefers to stay in the stay within the liquid part, it will come out first - If it stays in the column for longest they will have the same properties and will stick for longer . - This allows to pull out different samples at different timescales in the measurement. - If the solvent was water which is very polar the red dots would come out first because they are very polar and the yellow stars would come out last because they are the least polar and likes to stick to the non-polar sorbent bed. - A really good method because the different compounds will come out at different time so this increases the specify.

Answer 154

- The biggest challenge is the metabolism. In phase 1 and in phase 2 metabolism processes in the liver. - The drug undergoes a process of forming a reactive intermediate phase 1 through oxidation or reduction and reactant or intermediate can react with other species to conjugate into an inactive form of the drug. These may be glucuronides, sulphated forms or glutathione forms of the drug. - Once they’re conjugated, they can then be excreted out of the kidney into the urine for excretion. - So when we collect the urine we are collecting the conjugated drug. There will some presence of dree drug but majority is conjugated - To have a true estimation of the amount if drug that’s been eliminated from the patient, need to be able to measure the free drug and the conjugate. - Can directly measure the conjugate by measuring them as these different types of drugs or we can return the conjugate back into its original form by taking all the additional groups that have been chemically attached by the liver. - Do this by a process of hydrolysis. Do this by either acids or enzymes that can break down the bonds between the new additive groups and the drug itself which will cause a break between these two compounds. - This allows us to have a free drug and we can mix it with the free drug that was excreted from the urine and measure the total concentration excreted by this process.

Answer 155

 1st one is science techniques such as HPLC,GC or HPLC with mass spectrometry.  The second type is immunoassay. They offer a different way of measuring the drug by using biological entities as detection sites.

Answer 156

What is an immunoassay? An amino assay based on an antibody antigen interaction. Antibodies allow withing their structure the ability for different binding sites to occur. Antibodies commonly binds to antigens but actually an antibody combined with different drug molecule with different enzymes. There is a large variety of different biological and chemical structures that can actually bind with antibodies. Makes immunoassay slightly bias sensing where we are using the antibody as a recognition site for a molecule or analyte of interest.

Answer 157

- Have a sample of the drug and in this case the drug that we are interested in is donated by the red dots. The red dots are the drug molecules that we want to measure. - In an ELISA assay at the bottom of the plate where the blue band has a large concentration of drug already added to it. - Then add the sample, got the red dots and the interferants is the blue diamonds - Next add the antibody, the antibody that linked with an enzyme. The antibodies will bind to the red dot and will bind to whatever is left over will bind to the red dots at the bottom of the plate. Only one antigen bind to the red dot at the bottom of the plate. - Third step is to wash the sample, so you throw away the red dots which have got antibodies that is bound to them and everything that is left. - The only thing that is left is the antibodies that has managed to bind at the bottom of the plate. - Next step is to add a reagent/substrate which will convert in the presence of the enzyme to another product that has a colour in this case green. - We get a colour change on this sample and therefore can use a spectroscopy - If we get a low concentration of colour that means that there is lots of antibodies bound at the bottom of the plate - If we get a high concentration it means that not a lot of antibodies bound to the sample at the bottom of the plate There is an inverse linear relationship between concentration and absorbent in the assay.

Answer 158

- Looking at the admitted polarised fluorescent intensity of a species. - Got an antibody that is specific to the analyte that we are interested in and these antibodies are initially bound to the analyte that has a fluorescent tag. - The fluorescent tag will emit a fluorescent light when we have a polarised light placed on it - Initially when there is no light to measure we get a very big fluorescent signal. - When you add the biological sample, competition is created. The sample is donated by the orange tags . - The orange tags will come and compete on the antibody and displace the fluorescent tags analyte analogues. - As the analyte analogues comes away from the system, the fluorescence intensity that they were giving by the polarisation becomes lost. - There is a lack of polarised fluorescent intensity As we increase the amount of drug that we want to measure from the sample, we decrease the fluorescent intensity. Must be able to make a fluorescently labelled analyte tag Some drugs are naturally fluorescent and will give you a fluorescent signal in any way which makes the fluorescent polarisation immunoassay. It is a very sensitive detection method. Can have a better limited detection and linear range.

Answer 159

- Similar principles as fluorescent polarised immunoassay but the difference is the enzyme is now being the driver for the mechanism. - The initial setup of the assay has an antibody and onto that antibody is an analyte that has an enzyme bound to it - The reagent ( grey stars) cannot be converted into a product. - There is no signal because the active sites of that enzyme is not available for the substrate to be converted into a product. - When we add the analyte the drug that we want to measure we get competition again. The analyte sits onto the antibody and will displace this analyte that is enzymic bound - The enzyme becomes active and the grey stars becomes pink which means they can convert that substrate into a product - This conversion generates a product that has a colour and this can be measured by using colourimetry. As you increase the amount of analyte you therefore increase the absorbents that you can measure. Have to have a drug that is bound to an enzyme. Easier than fluorescent polarised signal because we know how many drugs will have enzyme bound onto them.

Answer 160

- Focuses on the concept of measuring the behaviour of singular oxygen of single oxygen which is very reactive. - In the reagent there is two parts, the first part is an antibody that is bound to a microbead that has a singular oxygen based on it. Has an excitation of energy or an energy associated with it. - There is another microparticle that has an antibody placed within it. - When we add the analyte, the two ends of the antibody binds together and there is a transfer in the reaction of a single oxygen that creates a hopping mechanism that generates emission of signal on the secondary placed bead. - It is the movement of a single oxygen atom that reacts and generate a signal called chemiluminescent signal which is a coloured light that is proportional to the binding of the analyte of the antibody A very complex mechanism because for this mechanism to work, the drug or the analyte we are trying to measure must bind to two distinct regions to antibodies for a signal to be detected.

Answer 161

- Based on a principle which involves nano chemistry where particles have absorbents or two compounds when they aggregate. - When we have microparticles that binds together, they have this formation of conjugates that generates a signal. - Here there is a microparticle that has been made with drugs bound to it so you have lots of drugs on the surface and those are the analyte drugs that we are interested in. - It is then placed in a solution of antibodies where they will bind to the drug and form a collection of solution. - The combined solution you will see an absorbents of light because we have changed the molecular size of these particles so this changes the absorbents that we see in the signals. - So when we add the analyte again, the analyte will compete for the antibody site and in this the aggregate where some of the particles. - By disaggregating the particles this prevents clumping of the particles, we have changed the distribution and therefore change the absorbents that we would have got by that aggregation. As we disaggregate the particle we decrease the absorbents that we observe which occurs with increasing the concentration of the analyte.

Answer 162

- An assay that uses a enzymatic donor fragment that is placed within the analyte. - The analyte has a fragment of enzyme that’s place on it which will interact with an enzymic site or enzymatic surface. - In this case we have a drug with a fragment and the enzyme will come in and will be attracted to sit on the fragment so it will stay on that site. - Now got an attachment on that particular surface. We then add the analyte in locations where we have complex reconstituted active enzymes that has now become present by attaching itself to the fragment and the drug will become released from these antibodies and can convert again (grey stars to pink stars) to give us a signal. - Similar process to EMIT but there is an extra step where it involves some sort of fragment to enzyme acceptor regions to make it an active functional enzyme system in place. An increase in analyte concentration is proportional to the absorbents if the drug

Answer 163

- First well is a blood sample that has lots of drugs added. The other well is also a blood sample that has little drugs added to it. - First add the blood from each sample into the ELISA plate. As you add the blood the drug that is present in the blood is free in the blood solution. Benefit is that there is no sample preparation. - Then add a fixed concentration of antibodies into the ELISA and as the antibodies are added, they bind to the drugs that is free in solution - However when they have run out of binding sites that is free in the solution, they bind to the drugs at the bottom - Once binding is done, we can throw away all of the antibodies. There is less antibodies bound to the bottom and more antibodies bound where there’s little drug added. - Throw away the sample and everything that is bound will disappear. The only antibodies that bind the drug at the bottom of the plate will remain. - Add secondary antibody that our enzyme found and they go into the solution and will only attach to the primary antibody - Remove any of the secondary antibodies that aren’t binding - Add chemical reagent that will react with the enzyme which will generate a different colour. If there is more enzyme there will be more colour and if there is less enzyme will be less colour When there is little mount of drug in the sample there is more colour and when there is lots of drug in the sample there is less colour.

Answer 164

once you have got the response, can take the plate with the 96 samples and put it into a spectroscopy meter and we can get a response of absorbance by drug concentration where there’s lots of drug - The absorbance will be darker at the top and lighter at the bottom

Answer 165

- Thrombin plays a key part in clotting. Can see in the device is at the top you can see an electrode. It is an electrochemical base of detection that detects the degree of coagulation. - Place the blood sample within that strip and allow thrombin to break down the compound. This is a peptide that is joined to phenyl-diamine. - Phenyl-diamine is a very oxidisable substance which means on the gold electrode we can then oxidise that and take off 2 electrons. - The electrons are proportional to the current and therefore will give us an indication if the efficacy of clotting. - To ensure that we have enough phenyl-diamine available, we can regenerate this compound in the presence of glucose which acts to donate electrons.

Answer 166

By the generation of electroactive compound through the actions of thrombin. Does this when thrombin breaks down a peptide bound electroactive substance, making it active for determination by electrochemical measurement.

Answer 167

• Effective plasma concentration (0.5 – 2.0 μg/L; 0.6 – 2.6 nmol/L) • Toxic effects observed at >2.3 μg/L (3.0 nmol/L) • Toxicity is inversely proportional to plasma potassium concentration – In hypokalaemia, toxicity can be observed at 1.2 μg/L (1.5 nmol/L) • Blood samples should be taken 6 hr post-dose

Answer 168

- The immunoassays and their ability to cause interference for particular species. Chromatography is not listed because it is used to separate out compounds so it generally wouldn’t cause any interference - All these compounds cause interferences because they affect these immunoassays at the antibody site. - The antibody is a target for a particular drug and that it helps us to get a reaction of the mechanism to be detected. - The compounds will be structurally similar, look the same and behave the same making them potential interferences on the on the assay. - Digoxin like interference substances (DLIF), Digibind and DigiFab which are used to remediate from digoxin and toxicity and digitoxin, they are going to be structurally similar. - Potassium canrenoate is a specific compound that influences the fluorescent polarisation - Spironolactone is a Aldosterone antagonist which is a compound that you can see effects on all immunoassays. This is because it has a very similar chemical structure to digoxin so therefore there will be no difference in the antibody

Answer 169

- Measurement of the free sample - Highly selective - Very sensitive

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