Pathophysiology of Hypertension - Assignment Example

?HYPERTENSION Pathophysiology of hypertension Hypertension is one of the most common risk factors for cardiovascular diseases. It affects close to one-third of the adult population in the world (Cheriyan, McEniery and Wilkinson 2010). This hypertension is classified as unidentifiable primary hypertension and identifiable secondary hypertension. Secondary hypertension is caused by the presence of another disease condition and this account about 5 to 10% of the total patients. (Cheriyan, McEniery and Wilkinson 2010). Primary hypertension is predominant among the people (about 95%) and secondary hypertension is found only in 5% of the hypertensive patients. The blood pressure of the hypertensive persons will be above the normal range and could be greater than 140/90 or equivalent to it. The actual cause of hypertension is not known, yet many factors are said to influence hypertension in human. Some of them are lifestyle aspects, genetic factors, environmental factors, renal and metabolism of the organs and neurohormonal factors. (Porth 2010).The factors that cause primary hypertension are heredity, elevated cholesterol levels, excessive salt intake, obesity, excessive alcohol usage and presence of trace elements such as cadmium or nitrates in the food.(Beevers et al. 2007). The changes in the arterioles results in the increased diastolic blood pressure followed by the increase in the systolic blood pressure, leading to hypertension. If the changes are frequent, then the changes in the hemodynamic mechanism occur. This vascular alteration provides additional blood pressure to the arterioles, thereby raising the diastolic pressure to greater than 90 mm Hg in this case. The peripheral resistance increases because of this increase in the blood pressure. This peripheral resistance is caused by the small arterioles. The small arterioles are made up of smooth muscle cells and these cells contract and relax based on the ion channel transport. The contraction and relaxation is done with the help of the calcium ions. If the ion concentration increases, then the walls gets thickened by the release of the Angiotensin and peripheral resistance occurs. (Cheriyan, McEniery and Wilkinson 2010). The peripheral resistance will be usually increased with the increase in the pulse rate and ultimately leading to the increase in the diastolic blood pressure and systolic blood pressure. The cardiac output is found to be somewhat greater in the earlier stages and normal at the later stages. The renal blood flow gets decreased with alteration in the renal physiology. The little variations in the blood flow can be easily detected by the muscle part first and there will be response accordingly. The increase or decrease in the blood flow affects the kidney and skin first. The increase in the blood pressure decreases the plasma content of the blood. The increase in the blood pressure creates a lot of stress to the arteries and veins and this creates an abnormal vascular reaction and circulatory homeostasis gets impaired. (Cheriyan, McEniery and Wilkinson 2010). Some of the hypertensinogenic factors that increase the blood pressure are high salt intake, high alcohol intake and obesity. The intermediatary phentoypes are found to be related to hypertension. They are sympathetic nerve activity, rennin Angiotensin aldosterone, sodium excretion, vascular reactivity, cardiac contractility and renin – kallikrein – kinin systems, endothelial derived relaxing factors (EDRF), atrial natriuretic peptide (ANP) and bradykinin, endothelin, Ouabain, etc. - these factors are found to increase the peripheral resistance. (Toda, Ayajiki and Okamura 2007). Blood pressure is found to be associated with the genes, providing necessary evidence for the confirmation of the relationship of genes in hypertension between the parent and sibling. This is further confirmed by the mutagenesis. Mutations in 10 genes have found to decrease the blood pressure. The Angiotensin gene, Angiotensin converting gene, adducin, rennin binding protein, G – protein B3 subunit, atrial natriuretic factor and insulin receptor have also found to be associated with the Hypertension. (Beevers et al. 2007). In addition, intake of higher concentration of sodium is found to increase the fluid volume, finally increasing the cardiac output. (Karppanen and Mervaala 2006). Sodium salt increases the blood pressure by affecting the renal reactivity and renal function.(Safar et al. 2009) (Shils and Shike 2006). The renal Angiotensin system is considered as the most important system that controls the blood pressure, and plays a major role in hypertension. The renin is secreted by the kidney and this only converts the Angiotensinogen in to Angiotensin I, which is physically inactive. (Vandevoorde and Mitsnefes 2011). Angiotensin I is converted in to the active compound Angiotensin II by the Angiotensin converting enzyme. The Angiotensin II formed is responsible for the increase in the blood pressure of the cells. It also stimulates aldosterone release from the adrenal gland’s zona glomerulosa. If the Renin-Angiotensin system is not proper then the rise in blood pressure is significant. (Shils and Shike 2006). The dysfunctions of the endothelial cells are also having been found to have an important effect on the hypertension. As they produce nitric oxide, the vasodilator and endothelin, the vasoconstrictor, the vaso-active agents, they are found to play an important role in cardiovascular regulation system. The renal physiology will also be altered during early stages of hypertension. That is, the renal blood flow will be reduced and also there will be increased filtration fraction. With these changes in the renal system, the high sodium salt concentration is found to be present in the blood; these salts also retain the excess water in the extra cellular space. The final result is that the kidneys will not be able to remove the excess sodium salt resulting in the increased blood pressure. The important factors that worsen hypertension are also kidney related. Poor sodium handling by the kidney due to chronic kidney diseases could worsen hypertension. Renal artery stenosis, Pheochromocytomia with excessive catecholamine production and kidney perception along with hypervolemia can aggravate hypertension. Pharmacology of Drugs used in the treatment of Hypertension The treatment for hypertension can be done by the following methods: 1. Use of Angiotensin II receptors blockers. 2. Angiotensin converting enzyme inhibitors. 3. Calcium channel blockers. (Simons, Ortiz and Calcino 2008) Angiotensin II receptors: The Renin- Angiotensin receptors have been found to have the major hypertension like reno-vascular hypertension, congestive heart failure, and many renal diseases associated with it. The use of the Angiotensin II receptor blockers have been found to have a greater efficiency in reducing the adverse effects and are found to have increased clinical efficiency. The Angiotensin II receptor blockers are found to decrease the blood pressure by inducing the aldosterone release, water intake, vasocon – striction, catecholamine release, hypertrophic response and arginine vasopressin release. (Beevers et al. 2007), (Simons, Ortiz and Calcino 2008). The Losartan is the major active metabolite found in the Angiotensin II receptor blockers. Candesartan and Olmesartan are the pro-drugs which are metabolically inactive and undergo some metabolic changes and get converted into the active metabolite. They become active when they are adsorbed in the gastro intestinal tract. The parental compounds do not have the activity. The special feature of these drugs is that, if they are converted in to active metabolite then they never undergo any metabolism. The main side effect of these drugs is cough that are associated with them.(Simons, Ortiz and Calcino 2008), (Aksnes et al. 2006). Losartan is found to be interacting with the Angiotensin II receptor blockers and they rarely cause and have effect on the drug metabolism. If Phenobarbital is used then they are found to have greater effect. With Indomethacin, Losartan is found to decrease the hypotensive effect. (Amy and Cheryle 2003). Some of the important Angiotensin II receptor blockers are Candesartan, Eprosartan, Irbesatan and Telmisartan. The bioavailability percentages of these drugs are 42%, 15%, 70% and 43% respectively. Candesartan is the active metabolite that is used as such. Losartan is also the next active metabolite. The half life of these drugs varies from 2 – 24 hours. Telmisartan is found to have the greatest half life of 24 hours. Losartan has the shortest life of 2 hours. When Losartan and Candesartan are compared, it was found that Candesartan is more effective than Losartan. (Aksnes et al. 2006). Angiotensin converting enzyme inhibitors: Perindopril, captopril, enalopril, Fosinopril, Lisinopril, Quinapril, Ramipril and Trandolapril are the Angiotensin converting enzyme inhibitors that are widely used. Angiotensin converting enzymes are a type of the dipeptidyl carboxyl metallopeptidase which is present as the membrane bound enzyme in the endothelial cells. They cleave the C-terminal of the Angiotensin I and Brandykinin. Thus it converts the Angiotensin I into an active Angiotensin II metabolite. This metabolite reduces the sodium transport and decreases the blood pressure at the kidney. The elevated blood pressure is sensed easily by these metabolites and they regulate the renal blood delivery. The Angiotensin converting enzyme inhibitors differ in their activity from the other anti-hypertensive drugs. They differ in their chemical structure too. The potency, bioavailability, half life and the route of administration varies from other types of anti-hypertensive drugs. The Angiotensin converting enzyme inhibitors are classified into three types based on their chemical structure. Sulfhydryl containing Angiotensin converting enzyme inhibitors, the Phosphinyl group containing Angiotensin converting enzyme inhibitors and the Carboxyl group containing Angiotensin converting enzyme inhibitors respectively. The Phosphinyl containing Angiotensin converting enzyme inhibitors (ACE inhibitors) are accepted as a drug by the overseeing bodies. The most important Phosphinyl group containing ACE inhibitors is Fosinopril. This Fosinopril is rapidly metabolized into fosinoprilat, the active metabolite and inhibits the ACE. (Edgar et al. 2011). Fosinopril is used to treat mild and moderate hypertension only and is administered orally. The hydrolysis of this drug occurs in the gastrointestinal mucosa and the liver. After administration, the renal blood pressure is reduced and thus activates the Tenin synthesis. The ACE inhibitors bind to the two domains of the ACE and regulate the blood pressure and the proliferation and differentiation of the hematopoietic stem cells. In addition, Renin is also produced in the tissues. Captopril is the most important Sulfhydryl containing ACE inhibitor. These types of drugs are able to deliver the free radicals and effects on prostaglandin. The clinical effects of these types are yet to be detailed. (Davis, Davies and Lip 2007). Captopril differs from the other drugs in its half life period only. These drugs are administered as oral drugs and hence have larger concentration of the product. They remain inactive until they reach the kidney where they are hydrolyzed. Because of this pharmacology, the bioavailability of the drug gets reduced very much when compared with the other drugs. ACE is present in the plasma and other parts of the body and hence they are not able to inhibit the other ACE. The order of the potency of the drug is Quinaprilat = Benazaprilat > Perindoprilat > Lisinoprilat > Fosinoprilat. (Ravina and Kubinyi 2011). The ACE inhibitors are thus found to be the best potent drugs for hypertension. These drugs not only reduce the blood pressure but also prevent the end organ damage and mortality. (Mitsnefes 2005) Calcium channel blocker: The calcium channel blockers are the third category. Lercanidipine, Amlodiupine, Felodipine, Nifedipine, Verapamil, Diltiazem are some of the important drugs used for hypertension. These drugs inhibit the calcium that is entering the smooth muscle of the vasoconstricted arterioles, enabling vasodilation. Because of these changes, the arterial pressure and renal vascular resistance reduces a lot. In addition, there will be increase in the renal flow due to these heightened activities of the drugs. The calcium channel blockers reduce the hypertension and importantly also prevents the post transplantation acute tubular necrosis. The dilation of the afferent arterioles counteracts the vasoconstriction. The final outcome of this development is the increased renal blood flow. The calcium channel blockers are found to have the immunosuppressive activity. Multiple intracellular functions are regulated by these calcium channel blockers. In all these three types of available drugs, the most common side effect is the renal function dysfunction and the mortality in few cases. (Vandeevoorde and Mitsnefes 2011). Hence the need for new drugs with fewer side effects is necessary. Although, the Angiotensin II receptors blockers, Angiotensin converting enzyme inhibitors and calcium channel blockers are providing good result in reducing hypertension, intensive researches are needed for finding a better solutions or drugs for hypertension. References: Aksnes, TA., Reims, HM., Guptha, S., Moan, A., Os, I and Kjeldsen, SE 2006, Improved insulin sensitivity with the angiotensin II-receptor blocker losartan in patients with hypertension and other cardiovascular risk factors, Journal of Human Hypertension, vol.20, pp.860–866. Beevers, DG., Lip, GYH., and O’Brien, E 2007, ABC of Hypertension, Wiley- Blackwell. Cheriyan, J., McEniery, C., and Wilkinson, IB 2010, Hypertension, Oxford University Press. Davis, RC., Davies, MK., and Lip, GYH 2007, ABC of Heart failure, Wiley-Blackwell. 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