NEW INSIGHTS INTO THE TREATMENT OF HYPERTENSION

1. The choice of initial pharmacological therapy is one area where the different hypertension management guidelines vary in recommending either the use of diuretics and beta-blockers as preferred drugs or choosing from any of the five major classes of antihypertensives. 2. Improvement in cardiovascular morbidity and mortality may have been shown most conclusively with diuretics and beta-blockers, but the effects on coronary events with these drugs were less than predicted and the other agents have a number of theoretica. advantages. 3. Recent worries regarding the possible adverse effects of calcium antagonists have led to a reappraisal of the risks and benefits of these drugs and antihypertensives i. general. 4. Many patients, particularly the elderly, have other conditions that influence the choice of first-line therapy and ethnic variations in the effects of hypertension or the efficacy or side effects of drugs should also be taken int. account. 5. There is considerable heterogeneity within the major categories of antihypertensive drugs, so it is important to distinguish the different subgroups, dosages and formulations that may b. used.     

Eprosartan for the treatment of hypertension

Antihypertensive agents are proven to reduce the cardiovascular risk of stroke, coronary heart disease and cardiac failure. The ideal antihypertensive agent should control all grades of hypertension and have a placebo-like side effect profile. Angiotensin II (AII) receptor antagonists are a relatively new class of antihypertensive agent that block AII Type 1 (AT₁) receptors, and reduce the pressor effects of AII in the vasculature. By this mechanism, they induce similar pharmacological effects compared with angiotensin-converting enzyme (ACE) inhibitors, resulting in a lowering of blood pressure. However, AII receptor blockers differ from ACE inhibitors with respect to side effects, and induce less cough, a side effect which may be related to bradykinin or other mediators such as substance P. Within the class of AII blockers, eprosartan differs from other currently available agents in terms of chemical structure, as it is a non-biphenyl, non-tetrazole, non-peptide antagonist with a dual pharmacological mode of action. Eprosartan acts at vascular AT₁ receptors (postsynaptically) and at presynaptic AT₁ receptors, where it inhibits sympathetically stimulated noradrenaline release. Its lack of metabolism by cytochrome P450 enzymes confers a low potential for metabolic drug interactions and may be of importance when treating elderly patients and those on multiple drugs. In clinical trials, eprosartan has been demonstrated to be at least as effective in reducing blood pressure as the ACE inhibitor enalapril, and has significantly lower side effects. Eprosartan is safe, effective and well-tolerated in long-term treatment, either as a monotherapy or in combination with other antihypertensive drugs such as hydrochlorothiazide.     

Eprosartan for the treatment of hypertension

Antihypertensive agents are proven to reduce the cardiovascular risk of stroke, coronary heart disease and cardiac failure. The ideal antihypertensive agent should control all grades of hypertension and have a placebo-like side effect profile. Angiotensin II (AII) receptor antagonists are a relatively new class of antihypertensive agent that block AII Type 1 (AT(1)) receptors, and reduce the pressor effects of AII in the vasculature. By this mechanism, they induce similar pharmacological effects compared with angiotensin-converting enzyme (ACE) inhibitors, resulting in a lowering of blood pressure. However, AII receptor blockers differ from ACE inhibitors with respect to side effects, and induce less cough, a side effect which may be related to bradykinin or other mediators such as substance P. Within the class of AII blockers, eprosartan differs from other currently available agents in terms of chemical structure, as it is a non-biphenyl, non-tetrazole, non-peptide antagonist with a dual pharmacological mode of action. Eprosartan acts at vascular AT(1) receptors (postsynaptically) and at presynaptic AT(1) receptors, where it inhibits sympathetically stimulated noradrenaline release. Its lack of metabolism by cytochrome P450 enzymes confers a low potential for metabolic drug interactions and may be of importance when treating elderly patients and those on multiple drugs. In clinical trials, eprosartan has been demonstrated to be at least as effective in reducing blood pressure as the ACE inhibitor enalapril, and has significantly lower side effects. Eprosartan is safe, effective and well-tolerated in long-term treatment, either as a monotherapy or in combination with other antihypertensive drugs such as hydrochlorothiazide.     

The role of angiotensin II type 1 receptor antagonists in elderly patients with hypertension

Hypertension is a major risk factor for stroke and coronary events in elderly people and clinical trials have shown that treatment of hypertension with various drugs can result in a substantial reduction in cerebrovascular and cardiovascular events. The angiotensin II type 1 (AT1) receptor antagonists are the newest class of antihypertensive agents to be used widely in clinical practice. AT1 receptor antagonists can generally be given once-daily. They are also extremely well tolerated with minimal first-dose hypotension and an incidence of adverse effects similar to that seen with placebo. Adverse event rates are significantly lower than with other classes of antihypertensive drugs including ACE inhibitors. These factors result in improved compliance and increased rates of continuance on therapy. AT1 receptor antagonists show similar efficacy in lowering blood pressure to other classes of antihypertensive agents and their antihypertensive effect is potentiated when they are given concomitantly with low-dose thiazide diuretics. AT1 receptor antagonists are eliminated predominantly by the hepatic route but most are not subject to extensive metabolism and interactions with other drugs are uncommon. This is an advantage in the elderly, who are often receiving multiple medications which increases the risk for adverse drug interactions. Dose adjustments are not usually required in the elderly unless there is plasma volume depletion. Although plasma AT1 receptor antagonist concentrations are generally higher in the elderly than in younger subjects, this pharmacokinetic difference may be balanced by decreased activation of the circulating renin-angiotensin-aldosterone system in the elderly. Recent clinical studies in high-risk hypertensive patients with left ventricular hypertrophy or in patients with diabetic nephropathy or heart failure have demonstrated that AT1 receptor antagonists can improve clinical outcomes to a similar or sometimes greater extent than other antihypertensive agents. Many of these studies have included large numbers of older patients and have confirmed the excellent tolerability profile of these drugs. Thus, AT1 receptor antagonists should be considered as a possible first-line treatment or as a component of combination therapy in patients with type 2 diabetes mellitus and microalbuminuria or nephropathy and as an alternative or additional treatment to ACE inhibitors in patients with heart failure or left ventricular dysfunction. AT1 receptor antagonists also appear to reduce the onset of new diabetes compared with some other antihypertensive drugs. The benefits in terms of organ protection have mainly been seen in studies using higher doses of particular AT1 receptor antagonists and it is not certain at present whether these results can be extrapolated to other members of the class. As the elderly are more likely to have developed organ damage related to hypertension or to have heart failure or diabetes as concomitant conditions, AT1 receptor antagonists represent an appropriate option for many elderly patients. The main disadvantage of these drugs is the cost of the medication but this may be offset by their improved tolerability with fewer adverse reactions and thus increased compliance, resulting in better blood pressure control and fewer clinical events. Overall, AT1 receptor antagonists are well tolerated and efficacious for blood pressure-lowering when given as a single daily dose in elderly patients and have many potential benefits in high-risk hypertensive subjects.     

Drug interactions of clinical importance with antihyperglycaemic agents: an update.

Because management of type 2 diabetes mellitus usually involves combined pharmacological therapy to obtain adequate glucose control and treatment of concurrent pathologies (especially dyslipidaemia and arterial hypertension), drug-drug interactions must be carefully considered with antihyperglycaemic drugs. Additive glucose-lowering effects have been extensively reported when combining sulphonylureas (or the new insulin secretagogues, meglitinide derivatives, i.e. nateglinide and repaglinide) with metformin, sulphonylureas (or meglitinide derivatives) with thiazolidinediones (also called glitazones) and the biguanide compound metformin with thiazolidinediones. Interest in combining alpha-glucosidase inhibitors with either sulphonylureas (or meglitinide derivatives), metformin or thiazolidinediones has also been demonstrated. These combinations result in lower glycosylated haemoglobin (HbA(1c)), fasting glucose and postprandial glucose levels than with either monotherapy. Even if modest pharmacokinetic interferences have been reported with some combinations, they do not appear to have important clinical consequences. No significant adverse effects, except a higher risk of hypoglycaemic episodes that may be attributed to better glycaemic control, occur with any combination. Challenging the classical dual therapy with sulphonylurea plus metformin, there is a recent trend to use alternative dual combinations (sulphonylurea plus thiazolidinedione or metformin plus thiazolidinedione). In addition, triple therapy with the addition of a thiazolidinedione to the metformin-sulphonylurea combination has been recently evaluated and allows glucose targets to be reached before insulin therapy is considered. This triple therapy appears to be safe, with no deleterious drug-drug interactions being reported so far.Potential interferences may also occur between glucose-lowering agents and other drugs, and such drug-drug interactions may have important clinical implications. Relevant pharmacological agents are those that are widely coadministered in diabetic patients (e.g. lipid-lowering agents, antihypertensive agents); those that have a narrow efficacy/toxicity ratio (e.g. digoxin, warfarin); or those that are known to induce (rifampicin [rifampin]) or inhibit (fluconazole) the cytochrome P450 (CYP) system. Metformin is currently a key compound in the pharmacological management of type 2 diabetes, used either alone or in combination with other antihyperglycaemics. There are no clinically relevant metabolic interactions with metformin, because this compound is not metabolised and does not inhibit the metabolism of other drugs. In contrast, sulphonylureas, meglitinide derivatives and thiazolidinediones are extensively metabolised in the liver via the CYP system and thus, may be subject to drug-drug metabolic interactions. Many HMG-CoA reductase inhibitors (statins) are also metabolised via the CYP system. Even if modest pharmacokinetic interactions may occur, it is not clear whether drug-drug interactions between oral antihyperglycaemic agents and statins may have clinical consequences regarding both efficacy and safety. In contrast, a marked pharmacokinetic interference has been reported between gemfibrozil and repaglinide and, to a lesser extent, between gemfibrozil and rosiglitazone. This leads to a drastic increase in plasma concentrations of each antihyperglycaemic agent when they are coadministered with the fibric acid derivative, and an increased risk of adverse effects.Some antihypertensive agents may favour hypoglycaemic episodes when co-prescribed with sulphonylureas or meglitinide derivatives, especially ACE inhibitors, but this effect seems to result from a pharmacodynamic drug-drug interaction rather than from a pharmacokinetic drug-drug interaction. No, or only modest, interferences have been described with glucose-lowering agents and other pharmacological compounds such as digoxin or warfarin. The effects of inducers or inhibitors of CYP isoenzymes on the metabolism and pharmacokinetics of the glucose-lowering agents of each pharmacological class has been tested. Significantly increased (with CYP inhibitors) or decreased (with CYP inducers) plasma levels of sulphonylureas, meglitinide derivatives and thiazolidinediones have been reported in healthy volunteers, and these pharmacokinetic changes may lead to enhanced or reduced glucose-lowering action, and thus hypoglycaemia or worsening of metabolic control, respectively. In addition, some case reports have evidenced potential drug-drug interactions with various antihyperglycaemic agents that are usually associated with a higher risk of hypoglycaemia.     

Aliskiren: new drug. Arterial hypertension: no evidence of clinical efficacy

(1) Pharmacological management of arterial hypertension is based on antihypertensive drugs with proven efficacy on morbidity and/or mortality endpoints. (2) Aliskiren is the first renin inhibitor to reach the market. (3) There are no published trials of aliskiren with clinical endpoints. Five double-blind short-term (8 weeks) placebo-controlled trials showed a moderate effect on blood pressure. This effect was not superior to that of other antihypertensive drugs with which aliskiren was compared: hydrochlorothiazide, amlodipine, irbesartan, losartan, valsartan, lisinopril and rampiril. (4) When added to another antihypertensive drug, aliskiren had little or no additional effect on blood pressure. In particular, there is no firm evidence that adding aliskiren to amlodipine 5 mg/day is any more effective than doubling the dose of amlodipine. (5) Aliskiren has not been tested in patients with renovascular hypertension or severe hypertension, but pharmacological data suggest that aliskiren might be less effective in these individuals. (6) Overall, the adverse effect profile of aliskiren does not seem to be any better than that of other antihypertensive drugs. Aliskiren contributes to the onset of angioedema, cough, diarrhea and abdominal pain, hyperuricaemia, gout attacks, kidney stones and skin rash. Pharmacovigilance should focus specifically on certain adverse effects that are known to occur with other drugs acting on renin-angiotensin axis, such as angioedema, muscle disorders and anaemia, even though few such cases were observed with aliskiren during clinical trials. (7) Aliskiren is contraindicated during pregnancy, as are other antihypertensive drugs acting on the renin-angiotensin axis. (8) In practice, it is better not to use aliskiren to treat hypertensive patients because better-assessed antihypertensive drugs with longer follow-up are available.     

Renin release and the sympathetic nervous system

This review describes the pharmacological aspects of renin release with special emphasis on the role of sympathetic nervous system, catecholamines, adrenoceptor blocking drugs, humoral agents, adrenalectomy and chemical sympathectomy. The effect of antihypertensive drugs and other pharmacological agents on plasma renin activity and the role of renin levels in their antihypertensive effects are also discussed. The role of renin inhibitors as a possible therapeutic class of antihypertensive agents, which could eventually expand the spectrum of antihypertensive therapy and improve our understanding of the role of the renin angiotensin system, is also addressed.     

Interactions of NSAIDs with diuretics and beta-blockers mechanisms and clinical implications

Indomethacin attenuates the antihypertensive effect of both thiazide diuretics and beta-adrenoceptor blocking drugs. The mechanisms of these interactions are poorly understood but sodium and water retention, suppression of plasma renin activity, alterations in adrenoceptor sensitivity and impaired synthesis of vasodilator prostaglandins may all contribute to this effect. Other non-steroidal anti-inflammatory drugs (NSAIDs) may share this property of indomethacin but sulindac, which is a selective inhibitor of extrarenal prostaglandin synthesis, appears not to. This may have important clinical and theoretical implications. Clinicians must beware of this potential interaction in any patient receiving treatment for hypertension. NSAIDs may also inhibit the natriuretic response to diuretics with resultant adverse effects in patients with heart failure and other forms of oedema. NSAIDs may also have adverse nephrotoxic effects which may be exacerbated by diuretic therapy.     

The choice of antihypertensive drugs in patients with erectile dysfunction

It is well established that hypertension and the more traditional anti-hypertensive drugs are associated with erectile dysfunction (ED). There is evidence showing that two antihypertensive drugs--doxazosin and losartan--have a positive effect on erectile function. Therefore these drugs may decrease the incidence of ED in patients who need treatment for hypertension. Doxazosin and/or losartan can also be beneficial in patients who develop ED after starting treatment with other antihypertensive drugs. These options could, in turn, ensure better compliance and blood pressure control. A fall in the overall cost of treatment will also be anticipated if there is a reduced need for drugs prescribed for ED in patients with hypertension.     

Metabolites of antihypertensive drugs. An updated review of their clinical pharmacokinetic and therapeutic implications.

Many antihypertensive drugs are extensively metabolised in humans. Since some metabolites are active and may therefore contribute to the pharmacological activity of the parent drugs, knowledge of the pharmacokinetic properties of active metabolites is important for understanding the overall effects of drugs. Four categories of antihypertensive drugs with active metabolites are dealt with, with selected examples described in some detail. First, drugs with effects relying totally on active metabolites include agents such as methyldopa, cadralazine and many angiotensin converting enzyme (ACE) inhibitors. Secondly, those with effects primarily due to active metabolites include drugs such as triamterene and spironolactone. Thirdly, agents with effects primarily due to the parent drug, but with active metabolites providing significant contributions to the overall pharmacological effect, include drugs such as indoramin, alprenolol, acebutolol, diltiazem and verapamil. Lastly, agents with pharmacological effects with only minor (if any) contributions from active metabolites include drugs such as propranolol, metoprolol, carteolol and others.     

The antihypertensive action of several beta-adrenoreceptor-blocking drugs.

The antihypertensive and pulse-slowing effects of racemic propranolol, oxprenolol, pindolol, practolol and d-propranolol were assessed in 54 hypertensive patients. Drug dosage was selected to be proportionate to beta-adrenoreceptor-blocking potency; d-propranolol dosage equalled approximately that of racemic propranolol. D-propranolol had onlyslight antihypertensive effect; the four other drugs were found to have a considerable and approximately equal antihypertensive effect. The degree of slowing of heart rate varied with the different drugs, being greatest with racemic propanolol. The effect on pulse rate did not correlate with the effect on blood pressure for most of the drugs. The falls in blood pressure induced by racemic propanolol were strongly correlated with those induced by each of the other drugs. The small falls in blood pressured induced by d-propranolol correlated also with those induced by practolol (which had no membrane activity) and are presumably due to its weak beta-adrenoreceptor-blocking action. The beta-adrenoreceptor-blocking action per se is responsible for the antihypertensive action of these drugs.     

The Choice of Antihypertensive Drugs in Patients with Erectile Dysfunction

Summary

It is well established that hypertension and the more traditional anti-hypertensive drugs are associated with erectile dysfunction (ED). There is evidence showing that two antihypertensive drugs - doxazosin and losartan - have a positive effect on erectile function. Therefore these drugs may decrease the incidence of ED in patients who need treatment for hypertension. Doxazosin

and/or losartan can also be beneficial in patients who develop ED after starting treatment with other antihypertensive drugs. These options could, in turn, ensure better compliance and blood pressure control. A fall in the overall cost of treatment will also be anticipated if there is a reduced need for drugs prescribed for ED in patients with hypertension.     

Delapril plus indapamide: a review of the combination in the treatment of hypertension

Although many data indicate that the management of hypertension has improved over the last two decades, there is still a large proportion of hypertensive individuals who do not receive adequate management of their blood pressure (BP). Combination therapy with two or more antihypertensive agents from different drug classes is increasingly being recognised as the most effective means of achieving target BP values by pharmacological means, particularly in the large number of patients in whom monotherapy proves to be ineffective. Use of an angiotensin-converting enzyme (ACE) inhibitor combined with a diuretic is a well established antihypertensive combination that is very effective because of the different, yet synergistic, mechanisms of actions of agents from these two drug classes. Delapril is a potent antihypertensive ACE inhibitor, and indapamide is a thiazide-like diuretic with additional antihypertensive properties. The combination of delapril and indapamide provides renoprotective effects, and indapamide is also cardioprotective. Use of these two drugs together is therefore a rational selection for combination therapy, and one that has consistently demonstrated lowering of BP to target values with a level of efficacy that is at least as good as other combinations of ACE inhibitors and diuretics. This combination has also been found to provide favourable effects on haemodynamic parameters, including left ventricular mass index and ejection fraction. Furthermore, combining an ACE inhibitor and a thiazide-type diuretic has been associated with a decreased risk of stroke and is recommended for patients with cerebrovascular disease, a setting in which the combination of delapril and indapamide has therapeutic potential. Because of the additive mechanisms of delapril and indapamide, the dose required for an effective antihypertensive effect is relatively low, and the combination is well tolerated at such doses. In particular, metabolic effects normally associated with diuretics are rare at the therapeutic dose of indapamide used in combination with delapril, making the combination suitable for patients with metabolic disorders in whom diuretic therapy would otherwise not be recommended. Delapril 30 mg and indapamide 2.5mg have been combined in a fixed combination, offering the convenience of a one-tablet-per-day antihypertensive drug regimen for most patients, which, along with good tolerability, helps to address the issue of noncompliance.     

The effects of antihypertensive therapy on haemostatic parameters

There is extensive trial-based evidence showing that antihypertensive drugs reduce the risk of vascular events (e.g. stroke and myocardial infarction) as well as target organ damage (e.g. left ventricular hypertrophy and microalbuminuria). However, some of these benefits appear to be, at least partially, independent of the extent of blood pressure (BP) lowering. It is also evident that in certain clinical situations some antihypertensive drugs are more effective than others. In this review we discuss the effects of antihypertensive drugs on the endothelium, platelets, fibrinolysis and coagulation. These properties may account for the observed BP-independent actions. Antihypertensive drugs exert multiple effects on the vascular endothelium. These include effects on nitric oxide (NO) and angiotensin II-mediated actions. Many BP lowering drugs can inhibit platelet activity, although the relevance of this property is unknown, especially if patients are also taking platelet inhibitors (e.g. aspirin). Antihypertensive drugs also influence fibrinolysis and coagulation. These effects may be mediated by a variety of mechanisms, including altering insulin sensitivity. The haemostatic actions of antihypertensive drugs deserve greater recognition and further investigation.     

Cholinergic adverse effects of cholinesterase inhibitors in Alzheimer's disease: epidemiology and management.

Cholinergic adverse effects of acetylcholinesterase inhibitors (AChEIs) are caused by their central and peripheral pharmacological actions on a variety of organ tissues. Gastrointestinal adverse effects predominate and these were relatively common in the phase II and III randomised clinical trials of AChEIs for the treatment of probable Alzheimer's disease. However, in these studies forced and rapid titration of drugs was used, which is not the case in clinical practice. Although there is a risk of pharmacodynamic interactions with other drugs leading to enhanced cholinergic adverse effects, very few of these interactions have proven to be clinically significant. Unresolved issues include the mechanism of syncope and neuromuscular weakness, which should be resolved through structured pharmacovigilance programmes and clinical studies. Loss of bodyweight may prove to be a long term significant complication. As a class, the AChEIs have proven to be well tolerated in the symptomatic treatment of Alzheimer's disease in its mild-to-moderately severe stages. The incidence and clinical significance of cholinergic adverse events will need to be carefully studied if the drugs are used for indications other than Alzheimer's disease.     

Recent advances in pharmacological management of hypertension in diabetic patients with nephropathy. Effects of antihypertensive drugs on kidney function and insulin sensitivity.

Hypertension is often seen in Type 1 and Type 2 diabetic patients, particularly in those with nephropathy, and the progression of diabetic nephropathy is closely related to blood pressure elevation. Thus, the effects of antihypertensive drugs on kidney function and insulin sensitivity in diabetic patients are of great clinical importance. Successful antihypertensive treatment has been shown to slow the progression of diabetic nephropathy. Several results from short term studies have suggested that angiotensin converting enzyme (ACE) inhibitors may be advantageous over other conventional antihypertensive agents in reducing albuminuria in both hypertensive and normotensive diabetics with microalbuminuria or persistent proteinuria. However, the decline in glomerular filtration rate during ACE inhibitor treatment is comparable to that during effective treatment with conventional antihypertensive drugs in hypertensive Type 1 diabetic patients with overt nephropathy. Whether ACE inhibitors possess a specific effect in preventing the development of diabetic nephropathy remains to be seen in properly designed long term studies. Although calcium antagonists may preserve kidney function or possess a renoprotective effect in hypertensive Type 2 diabetics with nephropathy, firm evidence supporting this contention seems to be lacking and also requires long term evaluation. Increasing attention is being directed toward the effect of antihypertensive drugs on insulin sensitivity in diabetic patients: ACE inhibitors and alpha 1-adrenoceptor blocking agents have been shown to improve this sensitivity. Despite the widespread involvement of calcium in hormone secretion and action, calcium antagonists appear to have little effects on the glucoregulatory and calcium-regulatory hormones within the drug dosages used in clinical practice. Several clinical variables, such as the presence or absence of hypertension, overt nephropathy and microalbuminuria, or a combination of variables should be accounted for when evaluating critically the cumulative data on the effects of antihypertensive drugs on kidney function and albuminuria in the variety of diabetic patient groups. Understanding the pharmacokinetic and pharmacodynamic characteristics of antihypertensive drugs will be of clinical importance in diabetic patients with advanced nephropathy (glomerular filtration rate of less than 30 ml/min) and/or other complications, such as impaired gastric motility or gastroparesis, and will thereby lead to a more rational management of hypertension in those patients.     

Drug interactions with angiotensin receptor blockers: a comparison with other antihypertensives.

The ever-increasing introduction of new therapeutic agents means that the potential for drug interactions is likely to escalate. Numerous different classes of drugs are currently used to treat hypertension. The angiotensin receptor blockers offer one of the newest approaches to the management of patients with high blood pressure. Compared with other classes of antihypertensive agents, the angiotensin receptor blockers appear overall to have a low potential for drug interactions, but variations within the class have been detected. Losartan and irbesartan have a greater affinity for cytochrome p450 (CYP) isoenzymes and, thus, are more likely to be implicated in drug interactions. There is pharmacokinetic evidence to suggest that such interactions could have a clinical impact. Candesartan cilexetil, valsartan and eprosartan have variable but generally modest affinity and telmisartan has no affinity for any of the CYP isoenzymes. In vitro studies and pharmacokinetic/pharmacodynamic evaluation can provide evidence for some interactions, but only a relatively small number of drug combinations are usually studied in this way. The absence of any pharmacokinetic evidence of drug interaction, however, should not lead to complacency. Patients should be made aware of possible interactions, especially involving the concurrent use of over-the-counter products, and it may be prudent for all patients receiving antihypertensive treatment to be monitored for possible drug interactions at their regular check-ups. The physician can help by prescribing agents with a low potential for interaction, such as angiotensin receptor blockers.     

Effects of ketanserin on hemodynamics and baroreflex effects in conscious spontaneously hypertensive rats

Ketanserin is an antihypertensive compound that binds to 5-HT2 receptors as well as to alpha 1-adrenoceptors. The relative importance of the two pharmacological interactions is still unclear. In the present study we compared the central hemodynamic effects of ketanserin with those of the alpha 1-adrenoceptor antagonist prazosin in conscious, unrestrained spontaneously hypertensive rats (SHR). Both drugs rapidly reduced mean arterial pressure (0.1 mg/kg prazosin, -22 +/- 3%; 3 mg/kg ketanserin, -27 +/- 4%) and total peripheral resistance (30 +/- 4 and 26 +/- 4%, respectively). The compounds differed with respect to their effects on heart rate and cardiac output, which increased following prazosin treatment and did not change following ketanserin administration. To investigate involvement of the baroreflex in the latter phenomenon, SHR were challenged with angiotensin II and sodium nitroprusside to increase and decrease blood pressure. Ketanserin did not influence bradycardia following elevation of blood pressure. However, reduction of blood pressure with nitroprusside following ketanserin treatment resulted in extreme vagal bradycardia. This phenomenon was not observed following administration of other antihypertensive agents or serotonin antagonists in SHR. We conclude that this latter interaction with the baroreflex is specific for ketanserin and that it may substantially contribute to its antihypertensive effect. The exact pharmacological mechanism underlying this effect is still under investigation.     

Role of ACE inhibitors in patients with diabetes mellitus.

The adjective 'epidemic' is now attributed to the rapidly growing number of patients with diabetes mellitus, mainly type 2. and the specific complications linked to this disorder. Provided they are recognised early enough, these different complications can be treated; in some patients the evolutive course of these complications can be slowed or even stopped. Furthermore, some recent observations suggest that specific tissular lesions may be prevented or even reversed. Although glycaemic control is essential, other therapeutic measures that must also be taken include those to control blood pressure and to lower lipid levels. Of the agents available to control the complications of diabetes mellitus, cardiovascular drugs, and particularly ACE inhibitors, have a pre-eminent place. Experimental and epidemiological data suggest that activation of the renin-angiotensin-aldosterone system plays an important role in increasing in the micro- and macrovascular complications in patients with diabetes mellitus. Not only are ACE inhibitors potent antihypertensive agents but there is a growing body of data indicating that also they have a specific 'organ-protective' effect. For the same degree of blood pressure control, compared with other antihypertensive agents, ACE inhibitors demonstrate function and tissue protection of considered organs. ACE inhibitors have been reported to improve kidney, heart, and to a lesser extent, eye and peripheral nerve function of patients with diabetes mellitus. These favourable effects are the result of inhibition of both haemodynamic and tissular effects of angiotensin II. Finally, there are a growing number of arguments favouring the use of ACE inhibitors very early in patients with diabetes mellitus.     

Candesartan cilexetil: an angiotensin II-receptor blocker.

The mechanism of action, pharmacokinetics, pharmacodynamics, clinical efficacy, and adverse effects of candesartan cilexetil are reviewed. Candesartan is an angiotensin II-receptor blocker (ARB). It is administered as a pro-drug that undergoes activation during gastrointestinal absorption. The agent is excreted mostly unchanged and has a terminal half-life of about nine hours (slightly longer in the elderly). Candesartan differs from other agents in its class in that it is tightly bound to angiotensin II type 1 receptors, allowing prolonged activity. In clinical trials, candesartan cilexetil has produced a dose-dependent effect when given in dosages of 2-32 mg/day. Observed trough-to-peak blood pressure ratios support a once-daily dosage regimen. The antihypertensive effect of candesartan cilexetil 4-16 mg/day was as great as that of enalapril 10-20 mg/day and amlodipine 5 mg/day and larger than that of losartan potassium 50 mg/day. Adding candesartan cilexetil to hydrochlorothiazide 12.5-25 mg/day and amlodipine 5 mg/day led to enhanced blood-pressure reductions and was well tolerated. It appears that candesartan can decrease renal perfusion without adversely affecting renal blood flow and may mediate a decrease in albuminuria in hypertensive patients with type 2 diabetes. No clinically important drug interactions have been reported. Adverse effects include headache, dizziness, nausea, diarrhea, and transient elevations in liver transaminases. The frequency of cough is similar to that seen with placebo. Candesartan cilexetil is an effective antihypertensive agent that can be used alone or in combination with other antihypertensive drugs. It is generally well tolerated and may be an option for patients who cannot tolerate angiotensin-converting-enzyme inhibitors because of cough.