Drugs Available For Treatment Of Chd Biology Essay
Blood supply to the myocardium is via the coronary arteries. In Coronary Heart Disease, blood supply to the myocardium is reduced due to an occlusion in the coronary arteries. The occlusion is made up of an atherosclerotic plaque. This results in myocardial ischemia and hypoxia, leading to symptoms of angina. Men are more likely to get CHD than women.
Medical treatments improve prognosis or treat symptoms. Aspirin and lipid lowering drugs are prognostic treatments. Glyceryl Trinitrate treats symptoms by inducing vasodilation thus restoring myocardial perfusion. Beta blockers reduce heart rate, allowing the myocardium to cope with reduced blood flow. Angiotensin I Converting Enzyme inhibitors reduce vasoconstriction to allow adequate blood flow.
Surgical treatments are Percutaneous Transluminal Coronary Angioplasty (PTCA) or Coronary Artery Bypass Graft (CABG). In PTCA, a wire is guided up to the occlusion and a balloon inflated to restore normal arterial diameter. In CABG, vessels from the body are used as grafts to bypass the occlusion. Surgical therapies are only used if medical therapy is ineffective.
The best treatment is prevention. Promoting healthier lifestyles can prevent CHD. Prevalance of CHD is increasing as better diagnostic and treatments techniques mean people with CHD live longer.
Coronary Heart Disease is a disease where the blood supply to the myocardium is reduced due to an occlusion in the coronary arteries. This leads to lack of oxygen in the myocardium and therefore can lead to myocardial ischemia or a myocardial infarction. To understand the treatments of Coronary Heart Disease we need to understand the cardiac cycle in relation to supplying the myocardium and the anatomy of the coronary arteries (Kumar and Clark, 2005).
The myocardium is supplied by coronary arteries which arise at the base of the ascending aorta, from the sinuses of the right and left semi lunar cusps (Figure 1).
Figure 2 shows the path of the right coronary artery and the branches that it gives off.
Figure 3 shows the path and the branches of the left coronary artery. In some people the left coronary artery gives off the sino atrial nodal branch and the posterior interventricular branch, as shown in Figure 3.
Figure 2 The right coronary artery follows the path of the coronary sulcus and gives off an immediate branch superiorly, called the sino atrial nodal branch, which supplies the anterior portion of the sino atrial node and the right atrium. As it follows the course of the coronary sulcus, it gives off a right marginal branch which supplies the right ventricle. Continuing posteriorly the right coronary artery gives off a posterior interventricular artery which supplies the posteroinferior one third of the interventricular spetum. It also supplies a part of the posterior part of the left ventricle (Drake et al, 2005).
Figure 3 The left coronary artery originates from the left semi lunar valve. It passes between the pulmonary trunk and the left auricle. It immediately bifurcates into an anterior interventricular artery and a circumflex artery. The anterior interventricular artery supplies the interventricular septum. It also gives off two diagonal branches which supply the anterior part of the left ventricle. The circumflex branch loops around posteriorly and anastomoses with the right coronary artery. It supplies the left atrium and gives off a left marginal branch which supplies the lateral wall of the left ventricle (Drake et al, 2005).
The most important ion that causes contraction of the myocardium is the calcium ion. Depolarisation activated calcium ion channels are the point of entry for calcium ions into the myocardium. The influx of calcium through these channels causes more calcium to be released from the sarcoplasmic reticulum (Bers, 2002). The calcium now binds to the troponin C on the myofilaments and triggers the contraction mechanism (Bers, 2002).
This results in isovolumetric contraction and ventricular ejection as the ventricles contract (Bers, 2002). Blood is then forced out of the ventricles into the aorta and the pulmonary arteries through the semi lunar valves. As the ventricles go through isometric relaxation, the blood pressure in the ascending aorta becomes greater than that in the ventricles, forcing the semi lunar valves shut. Blood now flows through the aortic sinuses and into the coronary arteries.
The formation of an atheroma (thickening of the walls of the arteries) predisposes to and causes an increase in Angiotensin I Converting Enzyme (ACE), which catalyses the conversion of Angiotensin I to Angiotensin II. Angiotensin II stimulates expression of intercellular adhesive molecules type 1 (ICAM-1) on the artery endothelium (Ridker, 1998). The monocytes then attach to the endothelium and they are endocytosed. Angiotensin II stimulates the differentiation of monocytes to for macrophages (Diet et al, 1996). Macrophages then absorb the excess LDL and differentiate into foam cells, reinforcing the core of the atheroma (Hansson, 2005).
All these factors cause a reduction in the coronary artery diameter, which increases the resistance and therefore reduces the blood flow to the myocardium, leading to myocardial ischemia and hypoxia (Figure 3).
Figure 3 Diagram showing how atherosclerosis can lead to a reduction in diameter of the artery. Everyone contains a fatty streak (changes in the artery endothelium). A fatty streak is something that precedes an atheroma and can lead to atherosclerosis. The atheroma contains foam cells and extracellular lipid droplets, which form the core, and collagen rich matrix and smooth muscle cells, which form a cap that surrounds the core. The atheroma retains low density lipoprotein (LDL) which is modified in the artery to form adhesive molecules (Hansson, 2005).
Chronic hypoxia leads to increased response to Urotensin II (UII), a hormone found in the myocardium. It is a potent constrictor of arteries and due to increased sensitivity of the myocardium to UII, more vasoconstriction of the coronary arteries can occur leading to further myocardial ischemia. UII has paracrine or an autocrine activity so myocardial hypoxia will only result in the vasoconstriction of arteries near that area (Zhang et al, 2001).
Hypoxia can also lead to apoptosis of the myocyte. Apoptosis is brought about by increased neutrophils in areas of hypoxia but the mechanism of why this happens is still unclear (Fliss and Gattinger, 1996). Apoptosis of myocytes can then lead to decreased force of contraction and therefore reduced blood supply to the myocardium.
There are many factors that cause an increased chance of getting CHD. Men are generally more likely to develop CHD than women. The difference is due to the protective properties of oestrogen (Goldstein and Stampler, 1995). A family history of CHD is also a risk factor but this is more likely to do with genetic predispositions to factors like Diabetes, which is itself a risk factor for CHD (Slyper and Schectman, 1994). End Stage Renal Disease (ESRD) increases the chance of CHD by a factor of 10 (McCullogh, 2007).
Drugs available for treatment of CHD are aimed at either improving prognosis or reducing the symptoms of angina. Prognostic drugs include Aspirin (75mg daily) and lipid lowering drugs. Lipid lowering drugs are commonly used in patients with blood cholesterol above 4.8mmol/l and are especially effective if Low Density Lipoprotein (LDL) is greater than 3.3mmol/l and High Density Lipoprotein (HDL) is less than 1.0mmol/l (Kumar and Clark, 2005).
Glyceryl Trinitrate (GTN) is an example of symptomatic treatment for angina. It is administered either as a spray or given sublingually as a tablet (Kumar and Clark, 2005). The mechanism of GTN is outlined in Figure 4.
Ischemia due to occlusion
GTN (in the systemic circulation)
Administration of GTN (spray or sublingually)
Restored blood flow to the myocardium
Figure 4 The effect of glyceryl trinitrate on the body. GTN is a prodrug so once it enters the body it is converted to Nitric Oxide (NO) by an enzyme called mitochondrial Aldehyde Dehydrogenase (mtALDH). NO is a potent vasodilator so it dilates the coronary arteries, allowing more blood flow to the ischemic myocardium (Miller et al, 2008). It gives an almost immediate relief from angina and its effect lasts for 25 to 30 minutes but this medicine is only effective in mild cases of angina due to CHD (Kumar and Clark, 2005).
However, prolonged use of GTN can cause resistance in patients. This is because it resets the sympathetic and the rennin angiotensin systems, leading to a larger base tone. As a result, the arteries remain more constricted than they would normally under the effect of GTN (Cheesman and Benjamin, 1994).
Figure 5 The sites of actions of beta blockers and other drugs used to treat myocardial ischemia as a result of CHD. Beta blockers act by reducing the heart rate and therefore the myocardial oxygen demand allowing the myocyte to cope with reduced blood flow. Beta blockers act as antagonists for the β1 receptors on the myocardium and therefore decrease the sensitivity of the myocardium to sympathetic stimulation and thus reducing the heart rate (Bristow, 1997).
Beta blockers: It is found that patients are more compliant to use beta blockers for CHD (Kumar and Clark, 2005). Tenolon, a beta blocker, is given once a day in doses of 50-100mg. For patients with impaired renal function, Metropol 25-50mg is used (Kumar and Clark, 2005). Figure 5 outlines the site of action of beta blockers and other drugs used to treat CHD.
Non selective beta blockers are more effective than selective beta blockers (Gottlieb and McCarter, 2001). Normally beta blockers are avoided for patients already on drugs affecting their renal function and in diabetic patients as it interferes with their glucose metabolism (Gheorgiade et al, 2003).
Angiotensin I Converting Enzyme (ACE) inhibitors inhibit ACE (Figure 6). No angiotensin II, which is a vasoconstrictor, can be produced and therefore there is reduced progression of atherosclerosis (Diet et al, 1996). ACE inhibitors are not used in pregnant women as they may interfere with the metabolism of the foetus. In some cases they cause hyperkalaemia and hypotension at which point its use is discontinued (Khalil et al, 2001). If ACE inhibitors are used together with beta blockers in patients with heart failure due to CHD, mortality can be reduced (Gheorgiade et al, 2003).
General Systemic Vasoconstriction
Angiontensin I Converting Enzyme (ACE)
Angiotensinogen (in Liver)
Figure 6 This diagram shows us the pathway by which vasoconstriction occurs. If ACE is inhibited then production of angiotensin II from angiotensin I is halted and this reduces the general systemic vasoconstriction, thus allowing more blood flow to the myocardium. This also has another advantage in that it reduces the secretion of renin, which is brought about by vasoconstriction, and so the production of angiotensin I is reduced as well.
Calcium channel blockers reduce the force of contraction of the myocardium and therefore the oxygen demand (Kumar and Clark, 2005). Intense medical therapy is found to reduce ischemia by the same amount as a revascularisation therapy. In fact, future cardiac problems from medical therapy are lower than revascularisation therapy (Mahmarian, 2009).
There are two main types of surgical treatments for CHD: Percutaneous Transluminal Coronary Angioplasty (PTCA) and Coronary Artery Bypass Graft (CABG). Surgical treatments for CHD are considered in patients as a last resort, when the medical treatments are ineffective. Sometimes a Coronary Endarterectomy is also performed which involves dissecting the occluded artery and removing the plaque by using a spatula (ElBardissi et al, 2009).
In PTCA, the catheter, called a French guide wire, is inserted into the femoral artery. It is then guided up through the iliac artery, the abdominal aorta and the aortic arch until it reaches the opening of the occluded coronary artery. To visualise the degree of occlusion, the catheter has contrast medium within it which is injected into the lumen of the coronary artery.
Another flexible guide wire fits into the original catheter. This flexible guide wire can go past the opening to the actual point of stenosis. Here, it is poked through the plaque until it gets through to the other side. The tip of the flexible wire can bend into other coronary arteries if needed.
Figure 7 Diagrammatic view of how a coronary angioplasty is performed (adapted from Landau et al, 1994)A deflated balloon catheter is now placed through the French guide wire and it wraps around the flexible guide wire. It is pushed through from the femoral artery to the point of stenosis. Here, it is inflated for one to two minutes. Then another angiogram is performed to check if the occlusion is fully cleared (Figure 7). A coronary atherectomy can be performed using the same technique as PTCA (Figure 8).
Figure 8 Diagram showing the concept of coronary atherectomy. As the balloon is inflated, a rotating blade is wrapped around the balloon and this shaves off the atherosclerotic plaque. The debris is collected at the tip of the catheter (Landau et al, 1994). Diagram adapted from Brubaker et al, 2002.
Using a similar technique, a stent may be placed at the point of occlusion to prevent restenosis (Landau et al, 1994) (Figure 9).
Figure 9 A stent is a wire that keeps the artery open whilst also allowing blood to flow through. Diagram adapted from Brubaker et al, 2002.
Local anaesthesia is normally used for PTCA. Some patients prefer the use of intravenous sedation as this reduces the pain during the removal of the femoral sheath after the procedure (Ang et al, 2006). After PTCA the patient remains in hospital for 8 to 24 hours. This allows the effects of the medicine to wear off (Landau et al, 1994).
In CABG, defibrillators are connected before the start of the surgery to sort out any arrhythmias during surgery. The most common approach is a median sternotomy (Figure 10).
Figure 10 Diagram showing the median sternotomy approach. The body of sternum is cut through the middle, from superior to inferior, using an oscillating saw. The sternum is then split to reveal the pericardium (ElBardissi et al, 2009). A lateral thoracotomy is a less invasive approach but is more difficult. Diagram adapted from Brubaker et al, 2002.
During this procedure the heart must be stopped to ensure it is still when the surgeon performs the surgery. To ensure that the rest of the body still receives adequate oxygenated blood, a Cardiopulmonary Bypass (CPB) machine is used (Figure 11).
Figure 11 The cardiopulmonary bypass pump. A tube takes venous blood from the body, oxygenates it and returns the oxygenated blood back to the circulation. A cannula is inserted into the right atrium near the appendage and this takes deoxygenated blood to the CPB. The cannula can either split into two tubes draning the superior and inferior vena cavae or the two vena cavae are drained separately. Once in CPB, the blood is oxygenated by an artificial oxygenator. A cannula is placed in the ascending aorta and the aorta is cross clamped underneath the point of entry of the cannula. This returns oxygenated blood to the circulation (Williams et al, 2008). Diagram adapted from Bailey and Love, 2008.
However, the myocardium is likely to be damaged with 30 to 45 minutes of hypoxia. To avoid this, local myocardial hypothermia is induced to reduce the metabolic demand of the myocardium. This process is call myocardial protection (ElBardissi et al, 2009).
Depending on where the occlusion is anatomically, different grafts may be used (Figure 12).
Figure 12 Diagrammatic view of a completed bypass. On the anterior interventricular artery, the left internal thoracic artery (LITA) is used. LITA is dissected of the chest wall. Proximally, LITA is left connected to the left subclavian artery and distally it is attached to the point distal to the site of the stenosis, thus bypassing it. For stenosis of other coronary vessels, vein grafts are often used (ElBardissi et al, 2009). Diagram adapted from Bailey and Love, 2008.
The most commonly used vein graft is the long saphenous vein of the leg. The vein is measured for the correct length and is dissected out. Alternatively, the use of the radial artery as a graft is becoming increasingly common. These grafts are attached at one end to the ascending aorta and the other at the point past the stenosis on the coronary artery (El Bardissi et al, 2009). After CABG, patients are placed in Intensive Care Unit (ICU) for 24 hours and discharged 5 to 8 days later (Williams et al, 2008).
Patients who have undergone PTCA have a greater chance of refractory angina than those undergone CABG. Therefore these patients require further percutaneous coronary interventions (PCI). There is a reduction in the rate of subjective ischemia in patients undergone PCI and CABG as compared to medical treatments (Hueb et al, 2007). PTCA is more expensive than medical therapy but is cheaper than bypass surgery (Landau et al, 1994).
Patients suffering from ESRD who also have CHD are found to respond better to CABG than other medical interventions (McCullogh, 2007). The use of surgical interventions is almost thought of as a last resort for the treatment of CHD. Patients who have had PTCA performed on them experience a reduction in angina but the chance of further surgical interventions is increased with this procedure. However, using medical treatments such as Beta blockers, antiplatelet agents, calcium blockers and nitrates is found to reduce the chance of further surgical interventions but the reduction in angina is not as great as that experienced with PTCA (Bucher et al, 2000).
Normally, surgery is seen as a last resort only if the medical treatments are found to be ineffective (Figure 13).
If medical unsuccessful in treating symptoms of angina
If flexible guide wire is not successful in getting through the atherosclerotic plaque
Figure 13 Normally CABG is found to give a better prognosis for patients whose atherosclerosis has progressed a lot. This is because PTCA can’t go past the site of stenosis, through the atherosclerotic plaque. If PTCA is used then there is a greater chance of the patient requiring CABG in the future. Stents decrease the risk of having CABG after PTCA (Rihal et al, 2003).
A new emerging idea is the use of stem cells to replace the lost myocytes due to CHD. It is found that four weeks after the injection of human embryonic stem cell derived cardiomyocytes there was improved myocardial function in ischemic rodent myocardium (vanLaake et al, 2008).
One idea is to replace saturated fatty foods with ones containing polyunsaturated fats to reduce the intake of saturated foods and therefore the risk of CHD. Furthermore, increasing taxes on smoking to deter people are also found to reduce deaths from CHD.
All these ideas are good for long term prevention of CHD. For short term it is proposed that patients who are at a high risk of getting CHD should be targeted with individual strategies, personalised to that person (Jackson et al, 2006).
Pravastatins are used in people with hypercholesterolaemia to reduce their LDL and increase High Density Lipoprotein (HDL). This reduces the risk of death from CHD and the need for surgical interventions (Shepherd et al, 1995).
The prevalence of CHD is increasing at a steady rate. However, the main reason for this is the success of diagnosing CHD earlier and treating it (Davies et al, 2007). Therefore people diagnosed with CHD are living longer. Thus an increased prevalence is a reflection on the improved techniques and technology.
There are advantages and disadvantages of all types of treatments for CHD. Therefore, what type of treatment is given to the patient should be carefully decided based on individual factors for that patient.
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