Do antihypertensive drugs precipitate diabetes?

A longitudinal population study of 1462 women aged 38-60 was carried out from 1968-9 to 1980-1 in Gothenburg, Sweden. The initial and follow up examinations included questions concerning history of diabetes and antihypertensive treatment. A considerably increased risk of developing diabetes was observed for subjects with hypertension taking diuretics (895 patient years), subjects taking beta blockers (682 patient years), and subjects taking a combination of diuretics and beta blockers (281 patient years) compared with subjects not taking antihypertensive drugs (13 855 control years). When diuretics and beta blockers were compared no difference was found in relative risk. Despite this increased risk, and because little is known about the relation between other forms of antihypertensive treatment and diabetes, diuretics and beta blockers should remain the treatments of choice in arterial hypertension.     

Design and synthesis of novel antihypertensive drugs

AT1 antagonists constitute a new generation of drugs for the treatment of hypertension and are designed and synthesized to mimic the C-terminal segment of Angiotensin II (Ang II) and to block its binding action on AT1 receptor. For this reason, the conformational analysis of Ang II and its derivatives as well as the AT1 antagonists belonging to SARTANs class of molecules were studied. Such studies offer the possibility to reveal the stereoelectronic factors responsible for bioactivity of AT1 antagonists and to design and synthesize new analogues with better pharmacological and financial profiles. An example of a novel synthetic non-peptide molecule is given which mimics the His(6)-Pro(7)-Phe(8) part of Ang II and is based on the (S)-pyroglutamic acid.     

Laboratory monitoring of patients treated with antihypertensive drugs and newly exposed to non steroidal anti-inflammatory drugs: a cohort study

Background

Drug-Drug Interactions between Non Steroidal Anti-Inflammatory Drugs (NSAIDs) and Angiotensin Converting Enzyme Inhibitors (ACEIs), Angiotensin Receptor Blocker (ARBs) or diuretics can lead to renal failure and hyperkalemia. Thus, monitoring of serum creatinine and potassium is recommended when a first dispensing of NSAID occur in patients treated with these drugs.

Methods

We conducted a pharmacoepidemiological retrospective cohort study using data from the French Health Insurance Reimbursement Database to evaluate the proportion of serum creatinine and potassium laboratory monitoring in patients treated with ACEI, ARB or diuretic and receiving a first dispensing of NSAID. We described the first dispensing of NSAID among 3,500 patients of a 4-year cohort (6,633 patients treated with antihypertensive drugs) and analyzed serum creatinine and potassium laboratory monitoring within the 3 weeks after the first NSAID dispensing.

Results

General Practitioners were the most frequent prescribers of NSAIDs (85.5%, 95% CI: 84.3–86.6). The more commonly prescribed NSAIDs were ibuprofen (20%), ketoprofen (15%), diclofenac (15%) and piroxicam (12%). Serum creatinine and potassium monitoring was 10.7% (95% CI: 9.5–11.8) in patients treated by ACEIs, ARBs or diuretics. Overall, monitoring was more frequently performed to women aged over 60, treated with digoxin or glucose lowering drugs, but not to patients treated with ACEIs, ARBs or diuretics. Monitoring was more frequent when NSAIDs'' prescribers were cardiologists or anesthesiologists.

Conclusion

Monitoring of serum creatinine and potassium of patients treated with ACEIs, ARBs or diuretics and receiving a first NSAID dispensing is insufficiently performed and needs to be reinforced through specific interventions.     

QSAR study on the antibacterial activity of some sulfa drugs: building blockers of Mannich bases

Sulfa drugs are building blockers of several types of Mannich bases. Consequently, the antibacterial activities of sulfa drugs are reported in this paper, which will help in explaining and understanding antibacterial activities of Mannich bases. Reported QSAR is carried out using distance-based topological indices and discussed critically on the basis of statistical parameters.     

Hypertension and new antihypertensive drugs: clinical perspectives

The nature of the clinical problem posed by hypertension has been changed fundamentally by 30 years of successful drug therapy. Cardiovascular pathology directly related to the high pressure is no longer the main problem. Complications of atheroma, particularly in the coronary arteries, are the main cause of hypertension-related deaths. Most patients now starting treatment have mild hypertension and the benefits, although significant, are small (two deaths prevented per 1000 patient-years of treatment). These two considerations dictate that new drugs must have a very low incidence of toxicity, a low incidence of symptomatic side effects, and preferably, a favorable effect on morbidity and mortality from ischemic heart disease. Several possible approaches have promise: 1) reduction of ischemic heart disease mortality by beta-adrenergic blockade; 2) use of calcium entry blocking drugs, which may combine vasodilation with antiarrhythmic effects; 3) non-thiol-converting enzyme inhibitors, which may have a particularly low incidence of side effects; 4) prostanoid derivatives that may combine vasodilatation with an antiplatelet action.     

Interaction of digoxin with antihypertensive drugs via MDR1

The multidrug transporter MDR1 (P-glycoprotein)-mediated interaction between digoxin and 29 antihypertensive drugs of various types was examined by using the MDR1 overexpressing LLC-GA5-COL150 cells, which were established by transfecting MDR1 cDNA into porcine kidney epithelial LLC-PK1 cells. These cells construct monolayers with tight junctions, and enable the evaluation of transcellular transport. The MDR1 was highly expressed on the apical membrane (urine side). The basal-to-apical and apical-to-basal transcellular transport of [3H]digoxin in LLC-GA5-COL150 cells was time- and temperature-dependent. The basal-to-apical transport of [3H]digoxin was markedly increased, whereas the apical-to-basal transport was decreased in LLC-GA5-COL150 cells, compared with the host LLC-PK1 cells, suggesting that [3H]digoxin was a substrate for MDR1. Most of the Ca2+ channel blockers used here markedly inhibited basal-to-apical transport and increased apical-to-basal transport. Exceptions were diltiazem, nifedipine and nitrendipine, which hardly showed inhibitory effects on transcellular transport of [3H]digoxin. Alpha-blocker doxazosin and beta-blocker carvedilol also inhibited transcellular transport of [3H]digoxin, but none of the angiotensin converting enzyme inhibitors and AT1 angiotensin II receptor antagonists used here were active. These observations will promote understanding of the digoxin-drug interactions resulting from their actions on MDR1, and which may aid in avoiding these unexpected effects of digoxin.     

QSAR study of antiplatelet agents

A QSAR methodology that involves multilinear (Hansch-type) and nonlinear (ANN backpropagation) approaches was developed to correlate the antiplatelet activity of 60 benzoxazinone derivatives against factor Xa. The statistical characteristics provided by multilinear model (R2 = 0.821) indicated satisfactory stability and predictive ability, while the ANN predictive ability is somewhat superior (R2 = 0.909). The multilinear model provided insight into the main factors that modulate the inhibitory activity of the investigated compounds.     

Using bradykinin-potentiating peptide structures to develop new antihypertensive drugs

Angiotensin I-converting enzyme (ACE) is a dipeptidyl-carboxypeptidase expressed in endothelial, epithelial and neuroepithelial cells. It is composed of two domains, known as N- and C-domains, and it is primarily involved in blood pressure regulation. Although the physiological functions of ACE are not limited to its cardiovascular role, it has been an attractive target for drug design due to its critical role in cardiovascular and renal disease. We examined natural structures based on bradykinin-potentiating peptides (BPPs) extracted from Bothrops jararaca venom for ACE inhibition. Modeling, docking and molecular dynamics were used to study the conserved residues in the S2', S1' and S1 positions that allow enzyme-substrate/inhibitor contacts. These positions are conserved in other oligopeptidases, and they form tight and non-specific contacts with lisinopril, enalapril and BPP9a inhibitors. The only specific inhibitor for human somatic ACE (sACE) was BPP9a, which is instable in the N-sACE-BPP9a complex due to repulsive electrostatic interactions between Arg P4-Arg 412 residues. Specificity for the C-terminal domain in human sACE inhibition was confirmed by electrostatic interaction with the Asp 1008 residue. Peptide-like BPP structures, naturally developed by snakes across millions of years of evolution, appear to be good candidates for the development of domain-selective ACE inhibitors with high stability and improved pharmacological profiles.     

Comparative interaction of few antihypertensive drugs with cyclosporine-A in rats

The maximal endothelial dependent relaxation of isolated aortic rings to cumulative doses of acetylcholine was significantly decreased in the Cyclosporine-A (CSA, 20 mg kg(-1) day(-1)) treated animals compared to olive oil (CSA vehicle) treated control. Administration of antihypertensive drugs like diltiazem, enalapril or propranolol to CSA treated animals augmented the endothelial damage induced by CSA. These drugs also increased the bioavailability of CSA. However, administration of losartan to CSA treated animals produced a significant increase in endothelial dependent relaxation as compared to CSA treated control but did not affect the bioavailability of CSA significantly. The results suggest that losartan is safer compared to other antihypertensives for the treatment of CSA induced hypertension.     

Influence of hypertension and of antihypertensive drugs on the arterial wall

This paper reviews some of the experimental data regarding the effects of hypertension and antihypertensive drugs on the arterial wall. Hypertension induces major changes in both the arterial media and intima. Experimental studies from our own and other laboratories have demonstrated that medial smooth muscle cells in several forms of hypertension in the rat undergo hypertrophy and nuclear polyploidy which contribute, along with connective tissue alterations, to a large increase in medial mass. Our studies in the deoxycorticosterone/salt-hypertensive rat indicate that such changes may be difficult to regress, despite prolonged control of the hypertension. In the arterial intima, major alterations in the endothelium are induced by hypertension in association with increase in arterial permeability. Marked enhancements of adherence of circulating white blood cells to the endothelium can also be demonstrated along with penetration of blood monocytes and their accumulation in the subendothelial space. Hypertension also appears to stimulate the migration and proliferation of smooth muscle cells in the intima, and evidence is beginning to accumulate that endogenous growth factors within the artery may be involved in this process. Essentially all of the intimal changes which we have observed as a result of arterial hypertension are also present with cholesterol feeding although intimal accumulation of lipid and formation of atherosclerotic plaques do not occur with hypertension alone. On the other hand, in hypercholesterolemic animals, hypertension appears to act as a promoter of atherogenesis. Several antihypertensive drugs may influence the atherosclerotic process. The experimental data regarding the effects of beta blockers and calcium antagonists in the cholesterol-fed rabbit are discussed. Though of considerable interest, the clinical relevance of the findings remains uncertain.     

Comparison of antihypertensive activity of beta-blocking drugs during chronic treatment.

The hypotensive activity of five beta-adrenoceptor antagonists with different ancillary pharmacological properties was compared in a randomised double-blind factorial trial in 25 untreated patients with stable, uncomplicated essential hypertension. In doses that produced similar reductions in exercise tachycardia all drugs had similar blood-pressure lowering activity, greater on systolic than diastolic pressure and greatest during exercise. With the exception of vasodilator activity the possession of any particular combinaton of ancillary pharmacological properties did not significantly influence the specific antihypertensive activity of these compounds.     

Blood pressure and heart rate and withdrawal of antihypertensive drugs.

The immediate effects on heart rate and blood pressure of withdrawing antihypertensive drugs were studied over three-day periods in 26 patients. Four groups of drugs were studied. After withdrawal all patients taking clonidine showed a considerable increase in heart rate and blood pressure with intense ectopic activity. Patients taking postganglionic neurone-blocking drugs showed a similar but less pronounced reaction with increased ventricular ectopic activity. No alarming reactions were seen after withdrawal of methyldopa or beta-blocking drugs. Methyldopa and, especially, beta-blocking drugs are less likely to produce withdrawal reactions than clonidine or the postganglionic neurone-blocking drugs, and patients taking these drugs are therefore less likely to suffer violent reactions if they forget to take their tablets.     

Structural basis for the hepatoprotective effects of antihypertensive 1,4-dihydropyridine drugs

Background

The 1,4-dihydropyridines (DHPs) are one of the most frequently prescribed classes of antihypertensive monotherapeutic agents worldwide. In addition to treating hypertension, DHPs also exert other beneficial effects, including hepatoprotective effects. However, the mechanism underlying the hepatoprotection remains unclear.

Incidence of myocardial infarction in elderly men being treated with antihypertensive drugs: population based cohort study.

OBJECTIVE: To analyse the association between use of antihypertensive treatment, diastolic blood pressure, and long term incidence of ischaemic cardiac events in elderly men. DESIGN: Population based cohort study. Baseline examination in 1982-3 and follow up for up to 10 years. SETTING: Malmŏ, Sweden. SUBJECTS: 484 randomly selected men born in 1914 and living in Malmŏ during 1982. MAIN OUTCOME MEASURES: Observational comparisons of incidence rates and rate and hazard ratios of ischaemic cardiac events (myocardial infarction or death due to chronic ischaemic cardiac disease). RESULTS: The crude incidence rate of ischaemic cardiac events was higher in those subjects who were taking antihypertensive drugs than in those who were not (rate ratio 2.6 (95% confidence interval 1.7 to 3.9)). After adjustment for potential confounders (differences in baseline smoking habits, blood pressure, time since diagnosis of hypertension, ischaemic or other cardiovascular disease, hypercholesterolaemia, hypertriglyceridaemia, diabetes mellitus, obesity, and raised serum creatinine concentration) this rate was reduced but still raised (hazard ratio 1.9 (1.0 to 3.7)). In men with diastolic blood pressure > 90 mm Hg, antihypertensive treatment was associated with a twofold increase in the incidence of ischaemic cardiac events (rate ratio 2.0 (1.1 to 3.6)), which vanished after adjustment for potential confounders (hazard ratio 1.1 (0.5 to 2.6)). In those subjects with diastolic blood pressure < or = 90 mm Hg, antihypertensive treatment was associated with fourfold increase in incidence (rate ratio 3.9 (2.1 to 7.1)), which remained after adjustment for potential confounders (hazard ratio 3.8 (1.3 to 11.0)). CONCLUSION: Antihypertensive treatment may increase the risk of myocardial infarction in elderly men with treated diastolic blood pressures < or = 90 mm Hg.