The Physiology and Pharmacology of Hypertension - Essay Example

The Physiology and Pharmacology of Hypertension Hypertension or elevated blood pressure is a medical condition in which the blood pressure is crucially high. It is considered to be a substantial public health problem, which affects about 25% of adult populations in the industrialized world. This disorder leads to many others malfunctions in the human body including myocardial infarction, congestive heart failure and endostage renal disease. (Lifton RP, 2001). The molecular genetic studies have identified mutations in 8 genes that lads to mendelian form of Hypertension. These genes are known to have a large impact on blood pressure.Normally, the kidnet filters over 170 lit of plasma containing 23 moles of salt. The maintainenece of salt homeostasis on a typical 100meq sodium diet requires the kidney to reabsorb 99.5% of the filtered salt. The integrated system of ion channels , exchangers and the transporters performs the job. Filtered sodium (60%) is reabsorbed in the proximal tubule (PT) of the nephron, mainly by the sodium ion or hydorgen ion exchange. The rest 30% is reabsorbed in the thick ascending limb of Henle (TAL) by Na-K-2CL cotransport. The seven percent is reclaimed by the sodium-chlorine cotransport in the distal convulated tubule. The final 2% s reabsorbed via the epethelial sodium channel (ENaC) in the cortial collecting tubule (CCT). The final stage is only although responsible for a small fraction of salt reabsorption, this site mainly determines for stability of the net salt balance. The decrease in the salt delivery to the thick ascending limb of Henle lead to increased secretion of the aspartyl protease renin, that results in increased secretion of the aspartyl protease renin, that results in increased formation of the short peptide hormone angiotensis II. This hormone binds to its specific G protein-coupled receptor in the adrenal glomerulaosa inducing secretion of aldosterone. Aldosterone, the principal mineralocorticoid steroid hormone binds to the mineralocorticoid receptor (MR) that leads to the intiation of the sequence of the events to increased activity of the ENac and increased salt reabsorption. (Lifton RP, 2001). To establish long term determination of blood pressure, research was carried out in the families that have history high or severely low pressure and it was identified that the mutations in many steps of the above mantioned pathway is the main cause. Mutations increase renal salt reabsorption raises blood pressure and those that diminish salt reabsorption lower blood pressure. The pathophysiologic link between salt and blood pressure can be known form the relationship between salt and vascular volume homeostasis. The increased net renal salt reabsorption leads to increase in water reabsorption in order to maintain sodium concentration at or near 140mM. This results in increased intravascular volume augments venous blood return to the heart, thus increasing the cardiac output and finally leading to elevated bolld pressure. In the opposite end, if there is an impaired reabsorption of salt will lead to decrease in blood volume and blood pressure. Affecting the Circulating Mineralocorticoid Hormones Glucocorticoid-Remediable Aldosteronism; Defective Aldosterone synthesis Syndrome of Apparent Minralocorticoid excess Mutations in the Minaralocorticoid Receptor Hypertension Exacerbated in Pregnancy Autosomal Dominant PHA1 Mutations altering Renal Ion Channels and Transposrters Liddle syndrome Giddleman and Barterr syndromes The Pathophysiologic characteristics of Hypertension: There is no established known cause of the pathophysiologcal condition of hypertension. The diastolic presuusre repeatedly is more than 90 mm Hg and the total peripheral resistance is usyally increased. The pulse presuusre possibly icreases or decreseases. The Cardiac output is normal or elevatedin the early stages of the disease. The cardiac work is also elevated. There is altered renal physiology with accelerated natriuresis and reduced renal flow. In hypertension, the normal blood flows to most of the regions of the human body. But there is diminshed renal and skin blood flow and increased muscl flow may develop. In addition to that, the Plasma volume may be inversely related to disatolic presurre. Further, there is hyper-reacivity of presuure to stress, abnormal vascular reactivity and impaired homeostatsis. (Vikrant S, 2001) Pharmacology of hepertension: Drugs of different classes are used to control hypertension, either alone or in combination. The choice of drug was evaluated based on physio-chemical condition of patient. various parameters were taken in consideration like age, ethnicity, severity of hypertension, contraindications etc. When a single drug fails to give adequate control; drugs from other classes are added, in a stepwise manner. For any addition in drug regimen At least 4 weeks should be allowed between each addition to determine the effects of the change in treatment. This may imitate the fact that a drug-induced fall in blood pressure can slowly reverse some of the pathological changes that have developed in the vascular wall. There are different groups of drugs administered as antihypertension agents and have different mode of action toward control of hypertensions. 1) Thiazide diuretics. The thiazide diuretics include bendroflumethiazide (bendrofluazide), cyclopenthiazide, hydrochlorothiazide and hydroflumethiazide. These drugs enter the lumen of the renal tubule by glomerular ultrafilteration and active secretion in proximal convoluted tubule. During secretion it binds to the Cl− site of the electro neutral Na+/Cl− transporter in the luminal wall of cells of the distal convoluted tubule. Thus inhibits the active reabsorption of Na+ and Cl−. Increase in concentration of Na+ and Cl− leads to more retention of water in lumen of renal tubules and activation of K+ secretion mechanism along with enhance Na+ absorption. The net effect is increased urine volume with increased loss of Na+, K+ and Cl−. The diuresis induced by the thiazides leads to a reduction in circulating blood volume. This has the effect of reducing end diastolic volume and hence lowering cardiac output and mean arterial blood pressure (Frank–Starling law of the heart). But there are certain disadvantages or side effects of thiazide have to be considered like Hypokalaemia aggravation of gout, hyper glysamia and impotence. Thus lower dose of thiazide (2.5mg/day) gives maximum results with minimum side effects. (Elliot H, 2002) 2) β-adrenoceptors : A number of competitive antagonists at β-adrenoceptors (e.g.atenolol) are used in the treatment of hypertension. The process by which β-adrenoceptors reduce blood pressure is not clear, but it involves a reduction in cardiac output, a reduction in renin release,a central action involving reduced outflow of sympathetic neural impulses to the periphery, increased baroreceptor sensitivity or a combination of these actions. Examples of some of these antagonists at β-adrenoceptors are summarized in Table 1. They possess vasodilator activity, but this does not be advantageous for antihypertensive action. There are some unwanted effects of the antagonists at β-adrenoreceptors and these are the aggravation of bronchial asthma (caused by the blockade of β2-adrenoceptors on airways smooth muscle). These antagonists also mask the sympathetically-mediated sweating and tremor that warns the insulin-dependent, diabetic patient of impending hypoglycemia. The properties of these agents that influence the incidence of the harmful effects are also discussed in Table: 1. Table 1: Summarization of the properties antagonists at β-adrenorecpetors that are used as antihypertensive agents. The properties of these agents that influence the incidence of the harmful effects are also discussed. (Elliot H, 2002) 3) Ca2+ influx inhibitors The calcium influx inhibitors are dihydropyridines (amlodipine, felodipine, isradipine, lacidipine, lercanidipine hydrochloride,nicardipine hydrochloride, nifedipine, nimodipine and nisoldipine), phenylalkylamines (verapamil hydrochloride) and benzothiazepines (diltiazem hydrochloride). These compounds inhibit the cellular influx of Ca2+ through the L-type voltage-sensitive Ca2+ channel. The binding site for the dihydropyridines is located on the extracellular surface of the α-subunit of the L-type Ca2+ channel. This is the reason that the blockade of the L-type channel by dihydropyridines does not depend on the frequency at which the channel opens. Still the binding of dihydropyridines to the L-type channel is enhanced when the resting membrane potential of the cell is relatively low; a situation in which a significant proportion of the channels will be in an inactivated state. This reasons encounters the mmore importance of Dihydropyridines in depressing the activity of vascular smooth muscle than that of cardiac tissue. The main principle with which the dihydropyridines works is in lowering blood pressure is to dilate arterioles and thus to lower peripheral resistance. Because, the dihydropyridines have little cardio depressant activity those cause a rapid lowering of blood pressure may evoke some reflex tachycardia. (Elliot H, 2002) 4) Angiotensin-converting enzyme inhibitors The ACE inhibitors include captopril, cilazapril, enalapril maleate, fosinopril sodium, imidapril hydrochloride, linisopril, moexipril hydrochloride, perindopril erbumine, quinapril, ramipril and trandolapril. Captopril and linisopril are active on their own but the other members of this group are pro-molecules of drugs that require the assistance by bioactivation by hepatic metabolism. These agents are used to control hypertension when the thiazides and antagonists at β-adrenoceptors fails to produce adequate lowering of blood pressure, or are contraindicated or poorly tolerated. Since ACE inhibitors can sometimes cause a profound fall in blood pressure, the first dose (e.g. captopril 12.5 mg) is best given at bedtime. (Elliot H, 2002) 5) Antagonists at the angiotensin II receptor subtype 1 These agents include candesartan cilexetil, eprosartan, irbesartan, losartan potassium, olmesartan medoxomil, telmisartan and valsartan. They compete with angiotensin II for occupancy of its subtype 1 receptors (AT1) on vascular smooth muscle, noradrenergic nerve terminals and cells of the zona glomerulosa in the adrenal cortex. The arteriolar dilatation evoked by AT1 antagonists leads to a fall in peripheral resistance and hence leads to a fall in mean arterial blood pressure. Not like the ACE inhibitors, the AT1 antagonists do not inhibit the metabolism of bradykinin and thus do not cause dry cough. (Elliot H, 2002) Alternate antihypertensive drugs The drugs mentioned above are widely used in clinical parctice but there are other drugs that are potentailly benefical. Angiotensin receptor antagonists Selective α1-adrenoreceptor antagonists (α-blockers) Drugs with vasodilator properties Centrally active agents. Recently (March 6, 2007) , the FDA announced the approval of the first a new class of antiphypertensive drugs, aliskerin. This drug will be applied for the traetment of hypertension such asmonotherapy and in combination with other medications. The main principle with which this drug works is that is blocks the action of renin at the beginning of the renin-angiotensin-aldosterone sysytem, and causes complete suppression of the angiotensin II. It has side effects similar to placebo when given in dose less than 600mg/day, but id does produce dose-related adverse GI effects. Diarrhea along with abdominal pain, dyspepsis and GI reflux are the other side effects. (Maren M, 2007). Bibliography Cohen JD. "Overview of Physiology, Vascular Biology and Mechanisms of Hypertension." Journal of Managemnt Care Pharmacy (2007): S6-S8. Elliot H. "Antihypertensive Treatment." Medicine (2002): 174-178. Lifton RP, Gharavi AG. "Molecular Mechanisms of Hypertension." Cell (2001): 545-556. Mayhew M. "New Drug available for treating hypertension." Journal of Nurse Practitioners (2007): 410-411. Vikrant S, Tiwari SC. "Essential Hypertension- Pathogenesis and Pathophysiology." Indian Academy of Clinical Meidicine (2001): 139-161. Read More