Tutorial 4 - Cardiovascular Disease Flashcards
CASE 1, PART 1
Mr Jones is a 62 year old man who is registering with a new GP. He feels well and has had no major medical problems. On routine examination his blood pressure is 170/105 mmHg. He is asked to rest for 5 minutes and his blood pressure is measured again: it is very similar and remains at this level on a couple of further visits over the next month.
How would you describe Mr Jones’ blood pressure?
[CASE 1, PART 1]
Mr Jones’ blood pressure is significantly elevated.
Treatment for hypertension is usually recommended if blood pressure is 140/90 mmHg or above on three separate occasions.
In a majority of hypertensive patients there is no identifiable cause (it is idiopathic) and this is termed ‘essential hypertension’.
Mr Jones, who is overweight at 82kg and a height of 1.72m, is advised to lose weight, increase his exercise levels, reduce his salt intake and stop smoking.
How might this help?
[CASE 1, PART 1]
Obesity is linked with increased risk (3-4 times) of hypertension and ischaemic heart disease among other things. While Mr Jones’ BMI is 27.7 making him overweight rather than obese the extra weight will still increase his likelihood of hypertension, though the mechanisms are not well understood. Adipose tissue does contain components of RAS system, and the system is activated in obese individuals despite marked volume expansion.
Exercise will help encourage weight loss and has other cardiovascular benefits.
Body weight can be thought of in terms of energy balance. A reduction in energy intake and/or an increase in energy expenditure will result in weight loss. Exercise increases circulation to the skin/muscles and widens the arteries. Improves renal function.
High salt intake in the diet results in expanded circulating volume and increased blood volume. This increased blood volume can put pressure on the heart by increasing cardiac filling pressure (pre-load).
A reduction in salt intake will have a small but significant effect in most people. Some controversy. Approx 30% HT patients are sensitive to salt and found to have low levels of rennin. Salt restriction should help in these patients. Salt metabolism is complex.
Smoking has been associated with a 60% increase in the mortality in men aged 55-64 from coronary heart disease. Nicotine has been shown to have vasoconstrictor effects, both direct and indirect via the sympathetic nervous system.
CASE 1, PART 2
On returning to see his GP Mr Jones has managed to reduce his weight to 74kg but his blood pressure has not changed. Consequently the GP prescribes Mr Jones 2.5mg bendrofluazide daily
What are the two determinants of blood pressure?
[CASE 1, PART 2]
Blood pressure = Cardiac output x Peripheral vascular resistance.
What sort of drug is bendrofluazide and how does it act to lower blood pressure?
[CASE 1, PART 2]
Bendrofluazide belongs to group of diuretics called thiazides, which act on the distal tubule of the kidney to reduce the active reabsorption of sodium and chloride ions. The drug acts by inhibiting the Na+ / Cl- co-transport system.
The initial fall in blood pressure is thought to be due to the decreased blood volume resulting from indreased diuresis.
Later phase however seems to be due to a direct effect on the blood vessels themselves although the mechanism by which this occurs is obscure. Subtle alterations in the contractile response of vascular smooth muscle.
On returning to the GP eight weeks later Mr Jones blood pressure is measured at 165/100 mmHg. The GP tells Mr Jones to keep taking the bendrafluazide and further prescribes ramipril 2.5 mg daily.
What class of drug is ramipril and why is this the best choice for a second line treatment in this case?
[CASE 1, PART 2]
Ramipril is an angiotensin converting enzyme inhibitor (ACE Inhibitor)
Effects of Angiotensin II in the body
Vasoconstriction (particularly in the kidney)
Increased release of NA from sympathetic nerve terminals – reinforcing vasoconstriction
Stimulation of proximal tubular reabsorption of Na+ – increasing blood volume.
Secretion of aldosterone from adrenal cortex – further increasing Na+ reabsorption and increased blood volume.
The thiazide diuretic bendrofluazide increases the concentration of Na+ retained in the distal tubule of the kidney (decreasing the Na+ concentration in the filtrate) thereby activating the renin-angiotensin system by stimulating renin release from the juxtaglomerular cells. This actually increases the response to an ACE inhibitor, which then suppresses the renin-angiotensin system.
Afro-Caribbeans and elderly individuals, who tend to have low renin hypertension, respond less well to monotherapy with ACE inhibitors. Inhibition of ACE (kininase II) also leads to accumulation of kinins including bradykinin which promotes vasodilator activity and may contribute to the overall effectiveness of ACE inhibitors.
CASE 2
Mrs Smith is a 71 year old woman, who has long-standing atrial fibrillation. Recently widowed she has moved in with her daughter and family, with all the upheaval in her life however she has not been taking her prescribed medication.
On registering with her daughters GP Mrs Smith is discovered to have a ventricular rate of 120 /min and complains of becoming very short of breath on exertion and has swollen ankles.
The GP prescribes Digoxin and warfarin. Why would the GP prescribe these particular drugs?
[CASE 2]
Mrs Smith has a very high ventricular rate (normal rate usually below 80 beats/min at rest) and is showing signs of cardiac failure.
Digoxin is a cardiac glycoside, which is commonly used to treat cardiac failure in association with rapid atrial fibrillation.
Atrial fibrillation has been shown to predispose patients to atrial thrombus formation and subsequent systemic emboli, which commonly cause stroke. Consequently Warfarin, an oral anticoagulant, is given prophylactically to prevent thromboembolism.
What are there mechanisms of action?
[CASE 2]
Digoxin slows conduction at the atrioventricular node, partly by a direct effect and partly via activation of the vagus nerve. In any case the cellular mechanism is the same – inhibition of the Na+/K+ ATPase. This also induces some increase in contractile force in the heart (positive inotropic effect), though the importance of this is controversial – increase in intracellular calcium. Digoxin blocks Na+/K+ ATPase (competes with potassium for active site), so sodium builds up in the cell. This causes increased intracell calcium levels due to Na+/Ca2+ exchanger.
Digoxin currently sidelined due to increased risk of death in patients with atrial fibrillation. Could be due to increase in platelet activity. Currently replaced with beta blockers.
Warfarin blocks the formation of Vitamin K by inhibiting the hepatic reductase enzyme that converts vitamin K to its active (hydroquinone) form. Vitamin K is essential for the formation of the clotting factors II, VII, IX and X. Consequently warfarin affects blood clotting time.
CASE STUDY 3
Mr Brown, a relatively fit 50 year old, starts to suffer from chest pain following exertion. His GP prescribes sublingual GTN spray and refers Mr Brown to a specialist clinic for further investigations.
What is the likely diagnosis of Mr Brown’s condition?
[CASE 3]
Mr Brown is likely to be suffering from angina. Angina occurs when the oxygen supply to the myocardium is insufficient for its needs. The pain usually has a very characteristic distribution occurring in the chest, arm and neck and is brought on by exertion or excitement.
Stable angina is a predictable pain on exertion and is due to a fixed narrowing of the coronary vessels by atheroma.
Unstable angina is characterised by pain following less and less exertion culminating in pain on resting. This is usually associated with a thrombus (derived from an atheromatous plaque) partially occluding the vessel(s)
Glyceryl trinitrate is an organic nitrate, which acts by inducing marked vascular relaxation via the release of nitric oxide. GTN can be used prophylactically immediately before exertion.
The results of Mr Brown’s investigations are all within normal limits with the exception of his cholesterol level, which is 9.6 with an LDL cholesterol of 7.5. Mr Brown is prescribed three different drugs – simvastatin, bisoprolol and aspirin.
Why has Mr Brown been prescribed these drugs and by what mechanisms do these act?
[CASE 3]
Mr Brown has a high cholesterol level. Low density lipoproteins (LDL) provide the main circulating source of cholesterol in the body.
The definition of pathological hypercholesterolaemia is somewhat arbitrary as the normal range of plasma cholesterol concentration varies in different populations. However in Britain 25% of middle-aged people exhibit cholesterol concentrations higher than 6.5 mmol/l and there is a continuous gradation of risk with increased cholesterol concentration, with no threshold.
Hypercholesterolaemia is associated with a markedly increased risk of ischaemic heart disease, arising from rupture of atheromatous plaques in the coronary arteries and leading to myocardial infarction.
Simvastatin belongs to a class of drugs known as the statins, which act by specifically inhibiting the enzyme HMG-CoA reductase.
The conversion of HMG-CoA to mevalonic acid is the rate-limiting step in cholesterol synthesis in the body and is catalysed by the enzyme HMG-CoA reductase.
The fall in cholesterol synthesis produces a compensatory increase in expression of LDL receptors on the hepatocyte and increased clearance of circulating levels of LDL cholesterol. NB HMG-CoA reductase is active when blood glucose is high.
The rise in heart rate is one of the main precipitating factors for angina, consequently the use of Bisoprolol, a β-blocker, is an appropriate treatment.
β-blockers act as competetitive antagonists of catecholamines at β-adrenoreceptors thereby reducing heart rate and contractility. The effects are most marked during exercise.
Arachidonic acid is converted to thromboxane A2 by the action of cyclooxygenase. Thromboxane is produced by platelets and promotes platelet aggregation.
Aspirin irreversibly inhibits cyclooxygenase activity thereby reducing the risk of thromboembolism.
Prophylactic use.
CASE STUDY 4
Mrs Green is a 78 year old woman who complains to her GP of increasing tiredness, shortness of breath on exertion and swollen ankles. She is diagnosed as suffering from congestive heart failure.
What do you understand by the term congestive heart failure?
[CASE STUDY 4]
Heart failure is a global term for the physiological state in which cardiac output is insufficient for the body’s needs. This may occur when the cardiac output is low (often termed “congestive heart failure”).
Inability of cardiac output to balance the needs of the tissues, leading to fluid accumulation (eg. In lungs and lower limbs) Fluid overload is a common problem for people with heart failure, but is not synonymous with it.
