Physiological Basis Of Treatment Of Hypertension Biology Essay
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Published: Mon, 5 Dec 2016
Hypertension can be defined as a sustained elevation of systemic arterial pressure more than 140/90 mmHg. In normal healthy individual, arterial pressure is ranged around 100-140/70-90 mmHg. Hypertension is a frequently occurring abnormality in humans. It can be caused by many diseases and most commonly due to increased peripheral resistance. It leads to many serious disorders and it is the major cause of premature vascular diseases.
Hypertension can be graded as follows according to its severity. In grade 1, mild hypertension, blood pressure is around 140-159/90-99. In grade 2, moderate hypertension, it is about 160-179/100-109 and in grade 3 severe hypertension ≥180/ ≥109 (2).
Hypertension is discussed under two major categories according to the cause, essential or primary and secondary hypertension. In majority of cases (88%), cause of the elevated blood pressure is unknown. It may be a result of a combination of causes. It can be treatable, but not curable. Secondary hypertension is caused due to an identifiable and potentially treatable.
Causes of hypertension
Low birth weight
Environmental factors – obesity, alcohol intake, increased Na intake, stress
80% of cases are caused by renal diseases such as diabetic nephropathy, chronic glomerulonephritis, adult polycystic disease, chronic tubulointerstitial nephritis, renovascular disease, etc.
Endocrine causes – Conn’s syndrome, adrenal hyperplasia, phaeochromocytma, Cushing’s syndrome, acromegaly
Congenital cardiovascular diseases – coarctation of aorta
Drugs – contraceptive pills, steroids, sympathomimetics, vasopressin
Treatment of hypertension
Many kinds of treatments are used to manage hypertension. The treatment should be chosen according to the cause and also to the age, sex, ethnic origin and physiological status of the patient. Both pharmacological and non pharmacological therapies are used. Hypertensive patients excluding severe or malignant hypertensive ones, should be treated after a period of assessment with repeated blood pressure measurements (2). It should be combined with advice and non pharmacological therapy.
Several groups of drugs are used to this type of treatment. Those can be used as one drug therapy or as drug combinations. Using drug combinations is more effective than the other in most of the cases. Diuretics, β Adrenergic receptor blockers, Angiotensin II receptor antagonists, Angiotensin Converting Enzyme (ACE) inhibitors, Renin inhibitors, Calcium channel blockers, α Blockers , Vasodilators and centrally acting drugs are the main classes of drugs that used to treat hypertension. This therapy should be based on following guidelines.
What are the stages that hypertensive therapy should be started,
Drug therapy should be initiate subjects with sustained systolic blood pressure ≥ 160 or sustained diastolic blood pressure ≥ 100 mmHg.
Individuals with sustained systolic blood pressure 140-150 or sustained diastolic blood pressure 90-99 mmHg who have a risk of target organ damage or a 10 years cardiovascular disease risk > 20%.
Start therapy for subjects with systolic blood pressure sustained ≥ 140 or diastolic blood pressure sustained ≥ 90 mmHg associated with diabetes mellitus.
Targets of blood pressure reduction,
For most patients, a target of ≈140/85 mmHg is recommended. For patients with diabetes mellitus, renal impairment or cardiovascular disease, a lower target of ≈130/80 mmHg is recommended.
Nature of drug therapy,
Most of the hypertensive patients require a combination of drugs to achieve recommended targets. In most patients therapy with statins and aspirin is added to reduce the overall cardiovascular risk. According to the level of blood pressure reduction following treatment, patient should be recommended to give special drug therapies. But this specific drug therapy should be made only after a careful period of assessment of about 6 months with repeated blood pressure measurements.
Make awareness of patients,
Patient should be explained about the aim of the treatment that is to reduce the risk of complications of hypertension and about the changes of drugs. They should be given under the agreement of the patient. It is important to know that all of the drugs used for treatment have side effects. And also the results of the drug treatment are not immediately appearing ones. (2)
Diuretics have prompt natriuretic effect (3), which increases the excretion of sodium salts in the urine. Through this contraction of plasma and extracellular fluid (ECF) occur. Thiazide diuretics and some loop agents act as mild carbonic anhydrase inhibitors resulting reduce formation of HCO3_. And also they reduce reabsorption of Na+, HCO3_, Cl_ and water in proximal convoluted tubule of nephron.
20% of Na+ reabsorption occurs in Loop of Henle. Loop diuretics inhibit this action. Some agents inhibit the active transport of Cl_ ions at the ascending limb of Henle loop. Some diuretics competitively bind to aldosterone receptors in distal convoluted tubule and inhibit the action of aldosterone on increasing permeability to Na+ in that tubule. As this they reduce plasma Na+ concentration resulting decrease in fluid volume. This contraction of plasma and ECF volume causes a reduction of preload on the heart. It may cause reduction of cardiac output and arterial pressure. In this case blood pressure is reduced without changing total peripheral resistance. These drugs also reduce the risk of stroke.
Angiotensin II receptor antagonists;
These drugs selectively block the receptors for angiotensin II (2). Angiotensin II is a potent vasoconstrictor (1,2) and it also stimulates increased secretion of aldosterone by adrenal cortex. Aldosterone increase the permeability to Na+ in distal convoluted tubule and collecting tubule and cause Na+ and water retention. It increases fluid volume resulting increase in blood pressure. It mediates those actions by binding to specific membrane bound receptors. There are two types of receptors, AT1 and AT2. AT1 is responsible for major action on Renin Angiotensin System (RAS) (4). These drugs include peptide analogues and also antibodies of angiotensin II. Through them they block the receptor binding action of it, resulting inhibition of its action. These effects are independent of age and sex. Action of drugs is potentiated by negative salt balance and attenuated by positive salt balance.
Angiotensin Converting Enzyme (ACE) inhibitors;
These drugs block the conversion of angiotensin I to angiotensin II. It mediates RAS as above description. So, blocking its synthesis those actions are inhibited and may lower the blood pressure. And also they block the degradation of bradykinin (2). It is a potent vasodilator (2). By dilating vessels it help to reduce blood pressure.
These drugs directly inhibit the plasma renin activity. Renin is released from kidney in response to decrease of renal perfusion pressure and contribute to increase blood pressure by stimulating the conversion of angiotensinogen to angiotensin I. By inhibiting this reaction RAS is interrupted reducing arterial pressure occurs.
Beta adrenoceptor blockers;
Blood pressure reducing action of these drugs is depended on decreasing total peripheral resistance and cardiac output. Using β1 selective antagonists is more effective than non-selective drugs (5). They target β1 adrenergic receptor mRNA with antisense oligodeoxynucleotides (β1-AS-ODN). Main mechanism is to reduce efferent sympathetic activity underlying decrease in plasma noradrenaline level. Reduction of sympathetic activity significantly decreases cardiac contractility displaying a negative inotropic effect (1). According to Starling’s law of the heart, force of contraction is proportional to stroke volume. When the contractility is reduced stroke volume and cardiac output decrease. As this blood pressure lowers. As a second mechanism they inhibit RAS to produce sustained antihypertensive effect. Newer β blocking drugs also reduce blood pressure through NO mediated vasodilatation.
Calcium channel blockers;
They effectively reduce blood pressure by arteriolar dilatation and some agents also reduce the force of cardiac contraction. Ca2+ and Ca channels are more important in contraction of cardiac muscle. Contraction occurs due to movement of actin and myosin filaments (1). When action potential spreads to cardiac muscle membrane, Ca channels are opened. Large amounts of Ca2+ release from transverse tubules and ECF. They diffuse into myofibrils and bind to troponin c. It results in exposing of binding sites for myosin heads on actin. Myosin heads bind to actin and power stroke occur causing cardiac contraction. When these drugs block the Ca2+ channels, releasing Ca2+ is reduced. Above mechanism slows and force of contraction reduces. It may cause decrease in cardiac output and blood pressure.
L/N type calcium channel blockers inhibit aldosterone production which induced by angiotensin II.
α adrenergic receptors are present in peripheral vascular system and also in Central Nervous System (CNS). All in vascular system are innervated by sympathetic nervous system. These agents block postsynaptic α1 receptors. Sympathetic activity causes peripheral vasoconstriction. By blocking them, this action is reduced and blood pressure lowering occurs. But important thing is that α receptors in CNS have opposing action. So, by blocking them increase in blood pressure may occur. Because of that selective vascular α adrenoceptor blockers should be used. (3)
These drugs act directly on vascular smooth muscle and relax them without contribution of cell receptors. By relaxing smooth muscle, vasodilatation occurs. This reduces total peripheral resistance and venous return to the heart is reduced through it. As this, lowers the blood pressure. This antihypertensive effect is independent from the sympathetic tone.
Some vasodilating agents inhibit sympathetic nervous signals to the kidneys or block the action of sympathetic transmitter substance on renal vasculature. These drugs also directly relax the smooth muscle of renal vasculature and through it block the RAS. (3)
Centrally acting drugs;
These drugs act by central regulation of sympathetic nervous system.
Using drug combinations;
Majority of hypertensive patients need at least two drugs to control blood pressure under the level of 140/90 mmHg. Better combinations of antihypertensive drugs use agents from different classes with different primary actions. So, that hypotensive effects are obtained by use of low doses. By combination of drugs we can observe greater blood pressure reductions than mono drug therapy. It may cause fewer side effects than one drug therapy because of using small doses of two drugs. Improved cohesion to treatment and therapy can be taken in low cost are the other advantages of drug combination. Commonly using combinations are diuretics and β blockers, ACE inhibitors and angiotensin II receptor antagonists and as well as ACE inhibitors and calcium channel blockers.
Management of severe or malignant hypertension;
Treatment should initiate immediately for patients who have severe hypertension, malignant hypertension or patients with severe hypertensive complications such as cardiac failure. But it is not recommended to reduce blood pressure too rapidly because it may cause cerebral, renal and retinal damage and myocardial infarction. Blood pressure response to those therapies must be carefully conducted. In most cases the treatment is aimed to reduce the diastolic blood pressure to 100-110 over 24 hours. It can be normalized over 2-3 days only with oral medication. But in very severe cases rapid control of blood pressure is required. Intravenous sodium nitroprusside is used to such types of treatments.(2)
Management of hypertension in pregnancy;
Though cardiac output is increased in pregnancy, greater fall in total peripheral resistance occurs. So, blood pressure is reduced than normal. But in 8-10% of pregnant women are reported as pregnancy induced hypertensive patients. Pre- eclampsia is a syndrome consisting of pregnancy induced hypertension and proteinuria. Reduction of uteroplacental circulation causes hypertension (2). Placental ischaemia leads to dysfunction of maternal vascular endothelium that result in increased formation of endothelin and thromboxane and increased in vascular sensitivity to angiotensin II. And also causes decreased formation of vasodilators such as NO and prostacyclin. Maternal blood volume is about 30% above normal. This increases during latter half of pregnancy. Increasing aldosterone and oestrogen cause increased fluid retention by kidneys (6). And also bone marrow produces extra red blood cells (6). Those things cause fluid overload in pregnancy may leads to hypertension.
Many antihypertensive drugs are contraindicated in pregnancy. When blood pressure is increased to > 160/110 mmHg, treatment is responsible for protection of the mother. Labetalol and methyldopa are safety using drugs for mild hypertension. Pre-eclamsic hypertension can be treated by same agents or nifedipine. More severe hypertension or eclampsic hypertension require intravenous hydralazine and may require termination of pregnancy (2).
Non pharmacological treatment:-
Non pharmacological treatment of hypertension is used to all hypertensive patients and borderline hypertensive. Lifestyle modification through weight reduction, care of dietary intake, reducing smoking and alcohol consumption and dynamic exercise is help to prevent the risk of hypertension.
As the first step of lifestyle modification is aimed at increasing physical activity and weight reduction in more patients. Obesity is a major cause for essential hypertension. Cardiac output is increased because of extra requirement of blood flow to the extra adipose tissue in obese ones (6). And also hormones like leptin that are secreted from fat cells may stimulate hypothalamus resulting stimulation of Vasomotor Centre (VMC) (6). It may cause increased activity of sympathetic nervous system in overweight patients. It increases the activity of RAS. These things cause increase in blood pressure. By weight reduction, amount of extra adipose tissue is reduced and above mechanisms are lowered. Controlling Body Mass index (BMI) < 25kg/m2 (2) may indicate a healthy individual.
During exercise blood pressure rises by several mechanisms such as increase in sympathetic activity, cardiac output and heart rate. As this blood pressure rises as immediate effect of exercise. But as a long term effect blood pressure is reduced by exercise. Aerobic exercise that is intended to increase oxygen consumption is recommended for lowering blood pressure in hypertensive patients. Antihypertensive effects of exercise are mediated through several mechanisms.
NO level is increased by exercise. It plays a major role in regulating vascular tone and antiatherosclerotic effects. NO is produced by vascular endothelial cells. It is a potent vasodilator metabolite. Plasma NO2_ and NO3_ concentration increase significantly by aerobic exercise. And also cGMP concentration which helps to produce NO is increased. As this NO increases and vasodilatation occurs. This causes reduction of vascular resistance and then reduction of blood pressure. NO is sensitive to inactivation of superoxide radicals. Relationship between blood pressure lowering effect and NO bioactivity remains unknown.
Exercise needs high level of energy. So, excessive adipose tissue that accumulates in obese ones is used to gain energy. It helps to reduce obesity. Because of the reduction of adipose tissue, need of blood flow to them is reduced. This helps to lower cardiac output and blood pressure.
Body temperature rises during exercise. To regulate the body temperature, compensatory mechanisms are activated. They increase heat loss by increasing ventilation, radiation, dilatation of skin blood vessels and sweating vasodilatation decreases peripheral resistance and decreasing blood pressure occurs. By sweating, loss of body fluids includes water and electrolytes such as Na+ are increased. It causes reduction of blood volume and blood pressure. As this exercise benefits low blood pressure for hypertensive patients.
Taking a controlled diet is used in non pharmacological therapy in hypertension. Reducing intake of total fat, saturated fat and salt in diet and taking vegetables, fruits, potassium and fish oil included diet is recommended for hypertensive patients. In addition to that high intakes of vitamin D, protein, amino acid, tea, dark chocolate and foods high in NO3_ help to reduce blood pressure.
Total fat, saturated fat and unsaturated fat –
Dietary fat specially unsaturated fatty acids have an effect of increasing circulating lipoproteins. They increase the level of Low Density Lipoprotein (LDL). They may cause increased risk of obesity and atherosclerosis. They also increase arterial stiffness and cause oxidative stress. Those things contribute to increase blood pressure. So reducing intake those things help to reduce blood pressure. Unsaturated fatty acids which are in fish oil also contribute to reduce blood pressure.
Vegetables, fruits –
Oxidative stress, which is known as bioavailability of Reactive Oxygen Species (ROS) causes hypertension. It is due to excess ROS generation, decreased NO production and reduced antioxidant capacity in cardiovascular, renal and nervous systems. It amplifies blood pressure elevation in the presence of other prohypertensive factors. Major source of cardiovascular ROS is family of non phagocytic NADPH oxidase and AT1 receptors. Antioxidants prevent those free radicals. Increase consumption of antioxidants such as vitamin C, E………. help to prevent oxidative stress and decrease the risk of hypertension. Vegetables and fruits which include those things reduce the level of ROS. And also antioxidants decrease level of total cholesterol, triglycerides, LDL, VLDL and they increase HDL and NO levels. These things reduce the risk of atherosclerosis and hypertension.
Salt intake –
Excessive salt intake can cause elevation of arterial pressure mainly by increasing Extracellular Fluid (ECF) volume. Though pure water is excreted by kidney as rapidly as it is taken, salt is not excreted easily. Excessive salt accumulation of the body increases ECF volume by two basic causes.
Osmolality (osmoles per kg) is increased because of excess salt. And also it stimulates the centre in the brain making the person to drink extra amount of water to correct the Na+ concentration in ECF to normal. This increases the ECF volume (6).
Increase in osmolality also stimulates the hypothalamic posterior pituitary gland secretary mechanism to secrete increased amount of antidiuretic hormone. It stimulates the kidney to reabsorb greater quantity of water from renal tubular fluid (6). By this, volume that excretes as urine is diminished and ECF volume is increased.
As this amount of salt that accumulate in the body is the major constituent that determines the ECF volume. A little increase in ECF and blood volume can greatly increase the arterial pressure. So, even a small amount of extra salt in the diet can lead to significant increase in arterial pressure. So, hypertensive patients are recommended to take diet with low salt content < 6g NaCl per day (2).
Chronic smoking and secondhand smoke exposure are major risk factors of cardiovascular disease. Substances in tobacco and cigarette smoke adversely change the structural and mechanical properties of arteries (7). Structural features such as wall thickness and functional features as NO production and bioactivity and endothelin 1 levels may be altered (7). Smoke reduces NO bioactivity as a result of oxidative stress. These things acutely increase arterial stiffness (7). Compliancy of the arteries is reduced and difficult to dilate. Total peripheral resistance is increased and also heart is reduced during smoking. This results increase in cardiac output and blood pressure. So, stopping smoking benefits more healthy life than smokers.
Reducing alcohol consumption;
Excessive intake of alcohol can leads to hypertension. Excessive alcohol causes arterial stiffness. And also it has psychological effects that lead to increase in blood pressure. So, reducing intake of alcohol benefits reduction of blood pressure.
Hypertension may caused by many causations and it may cause many serious disorders. Treatment of hypertension is based on age, sex, ethnic origin and physiological status. Both pharmacological and non pharmacological therapies are used to treatments. Pharmacological therapy is conducted by using one drug or drug combinations. But the problem is all antihypertensive drugs may cause side effects. Non pharmacological therapy is used with the association of drug therapy. Weight reductions, dietary control, reduce smoking and alcohol consumption help to diminish the risk of hypertension.
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