Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0010200 (cough)
 23,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The treatment of hypertension in patients with airway dysfunction is a delicate problem. This article focuses on the airway effects of some antihypertensive drugs. Early on, the beta-adrenoceptor antagonists were shown to be hazardous in patients with asthma. Nonselective beta-blockers could induce severe asthma attacks and the bronchodilating effect of beta-agonists was totally blocked. Also, the beta-blockers with partial agonist activity totally blocked the effect of bronchodilating beta-agonists. The selective beta 1-adrenoceptor antagonists were shown to have less pronounced effects on the airways, and it was possible to overcome the beta-blockade in the airways with high doses of beta-agonists. beta-Blockers are contraindicated in asthma patients, even if it is possible to give selective beta 1-adrenoceptor antagonists in some patients together with high doses of beta 2-agonists. Angiotensin converting enzyme (ACE)-inhibitors were recently shown to induce cough and bronchial hyperresponsiveness in some patients. This is probably due to an increased inflammation in the bronchial mucosa as substances (e.g., bradykinin) are not metabolized. Therefore, ACE inhibitors could be hazardous in asthmatic patients, as they can increase the underlying bronchial hyperresponsiveness. Calcium channel blockers were earlier considered to be beneficial in asthma, as it was shown that they had a small relaxant effect on bronchial tone, and could amplify the effect of bronchodilators. In studies of provoked bronchoconstriction, calcium channel blockers were shown to have some protective effect against allergens, histamine, methacholine, or exercise-induced bronchoconstriction. Calcium channel blockers do not have a major place in asthma treatment, but as they have no severe side effects on the airways, they could preferably be given to hypertensive patients with airways disease instead of other antihypertensive agents.
 ...
PMID:Antihypertensive drugs and airway function, with special reference to calcium channel blockade. 248 71

The non-specific bronchial reactivity and cough threshold of hypertensive patients on an ACE-I monotherapy regimen (either captopril or enalapril), a beta 1-antagonist monotherapy regimen (either atenolol or metoprolol) or a combination of an ACE-I with a beta 1-antagonist were determined in the present study. Forty-six hypertensives who were on these medications performed a histamine inhalation test (to assess bronchial reactivity) and a further 36 of these individuals participated in the citric acid test (to assess cough threshold). A control cohort consisting of 25 age-matched, drug-free subjects also performed the citric acid test. The incidence of bronchial hyperreactivity was not significantly different between the ACE-I monotherapy regimen and the beta 1-antagonist monotherapy regimen (Chi-squared = 0.248). However, when the monotherapy regimens were pooled and compared with the ACE-I and beta 1-antagonist combination regimen, the combination regimen was found to be associated with a significantly higher incidence of bronchial hyperreactivity (Chi-squared = 6.69). No difference was observed between the age-matched controls and the hypertensive patients in terms of their cough threshold.
 ...
PMID:The effect of angiotensin converting enzyme inhibitors (ACE-I) and selective beta 1-antagonists on bronchial reactivity and the cough reflex in man. 257 76

1. We tested the hypothesis that the pattern and the intensity of autonomic mechanisms causing vasoconstriction in the resting bronchial circulation of awake dogs also exists in awake sheep. It was also postulated that sighing behaviour and the associated bronchovascular dilatation induced by non-adrenergic, non-cholinergic (NANC) mechanisms observed in the dog exist in sheep. 2. Bronchial arterial blood flow to lower airways of both lungs of awake sheep was measured continuously using pulsed Doppler flow probes mounted on the bronchial artery at prior thoracotomy. 3. Cumulative and factorial analysis of responses to randomized combinations of autonomic alpha 1-, alpha 2-, beta 1- and beta 2-adrenoceptors and cholinoceptor autonomic blockade suggests that resting vasoconstrictor activity is less in sheep than in dogs. At normal aortic pressure, the autonomic activity of these receptor groups in the sheep lowers bronchial blood flow and conductance by 30%, whereas in the awake dog, the corresponding autonomic effect is 50%. 4. Tonic autonomic control of bronchial conductance can be partitioned in sheep to show significant and separate alpha- and beta-adrenoceptor vasoconstrictor activity at a ratio of 1.8:1, an effect normally offset by a weaker vasodilator alpha-/beta-adrenoceptor interaction. In contrast to the situation in awake dogs, cholinoceptors do not play a role in awake sheep. 5. Nitric oxide (NO) synthase inhibition in sheep using NG-nitro-L-arginine following blockade of alpha- and beta-adrenoceptors and cholinoceptors causes hypertension, but minor changes, if any, in pulmonary pressures or heart rate. Bronchial flow and conductance, however, fall from a higher resting conductance by approximately 50%, suggesting that, normally, resting bronchial flow conductance is dominated by strong tonic NO vasodilator effects that interact with weaker tonic autonomic vasoconstrictor effects. 6. Superimposed (respiratory) behaviours of sighing, sneezing and coughing, which involve negative swings in intrathoracic pressure and the movement of inspired air, evoke large active bronchovascular dilator effects. These appear to be largely NANC in origin and appear to be dependent, in part, on mechanisms associated with NO release. It is postulated that the C-fibre axon reflex using substance P, calcitonin gene-related peptide and neurokinin A may be involved. Vocalization and eructation do not evoke bronchovascular effects.
 ...
PMID:Autonomic control of bronchial circulation in awake sheep during rest and behaviour. 940 60

Understanding the mechanism of action and the pharmacokinetic properties of vasodilatory drugs facilitates optimal use in clinical practice. It should be kept in mind that a drug belongs to a class but is a distinct entity, sometimes derived from a prototype to achieve a specific effect. The most common pharmacokinetic drug improvement is the development of a drug with a half-life sufficiently long to allow an adequate once-daily dosage. Developing a controlled release preparation can increase the apparent half-life of a drug. Altering the molecular structure may also increase the half-life of a prototype drug. Another desirable improvement is increasing the specificity of a drug, which may result in fewer adverse effects, or more efficacy at the target site. This is especially important for vasodilatory drugs which may be administered over decades for the treatment of hypertension, which usually does not interfere with subjective well-being. Compliance is greatly increased with once-daily dosing. Vasodilatory agents cause relaxation by either a decrease in cytoplasmic calcium, an increase in nitric oxide (NO) or by inhibiting myosin light chain kinase. They are divided into 9 classes: calcium antagonists, potassium channel openers, ACE inhibitors, angiotensin-II receptor antagonists, alpha-adrenergic and imidazole receptor antagonists, beta 1-adrenergic agonist, phosphodiesterase inhibitors, eicosanoids and NO donors. Despite chemical differences, the pharmacokinetic properties of calcium antagonists are similar. Absorption from the gastrointestinal tract is high, with all substances undergoing considerable first-pass metabolism by the liver, resulting in low bioavailability and pronounced individual variation in pharmacokinetics. Renal impairment has little effect on pharmacokinetics since renal elimination of these agents is minimal. Except for the newer drugs of the dihydropyridine type, amlodipine, felodipine, isradipine, nilvadipine, nisoldipine and nitrendipine, the half-life of calcium antagonists is short. Maintaining an effective drug concentration for the remainder of these agents requires multiple daily dosing, in some cases even with controlled release formulations. However, a coat-core preparation of nifedipine has been developed to allow once-daily administration. Adverse effects are directly correlated to the potency of the individual calcium antagonists. Treatment with the potassium channel opener minoxidil is reserved for patients with moderately severe to severe hypertension which is refractory to other treatment. Diazoxide and hydralazine are chiefly used to treat severe hypertensive emergencies, primary pulmonary and malignant hypertension and in severe preeclampsia. ACE inhibitors prevent conversion of angiotensin-I to angiotensin-II and are most effective when renin production is increased. Since ACE is identical to kininase-II, which inactivates the potent endogenous vasodilator bradykinin, ACE inhibition causes a reduction in bradykinin degradation. ACE inhibitors exert cardioprotective and cardioreparative effects by preventing and reversing cardiac fibrosis and ventricular hypertrophy in animal models. The predominant elimination pathway of most ACE inhibitors is via renal excretion. Therefore, renal impairment is associated with reduced elimination and a dosage reduction of 25 to 50% is recommended in patients with moderate to severe renal impairment. Separating angiotensin-II inhibition from bradykinin potentiation has been the goal in developing angiotensin-II receptor antagonists. The incidence of adverse effects of such an agent, losartan, is comparable to that encountered with placebo treatment, and the troublesome cough associated with ACE inhibitors is absent.
 ...
PMID:Clinical pharmacokinetics of vasodilators. Part I. 964 8

The present study investigated the effect of the new ACE-inhibitor moexipril versus the beta 1-adrenergic blocker atenolol on metabolic parameters, adverse events (AEs) and sitting systolic (SSBP) and sitting diastolic blood pressure (SDBP) in obese postmenopausal women with hypertension (stage I and II). After a 4-week placebo run-in phase, 116 obese, postmenopausal women with primary hypertension were randomised into two treatment groups receiving once daily dosages of either moexipril 7.5 mg or atenolol 25 mg initially (mean age: 57 +/- 7 years in both groups; mean weight: 94 kg in the moexipril group and 89 kg in the atenolol group, corresponding to a body mass index (BMI) of 35.2 kg/m2 and 34.1 kg/m2 in both groups, respectively). After 4 and 8 weeks, the dosages were uptitrated to moexipril 15 mg, or if necessary to moexipril 15 mg/hydrochlorothiazide (HCTZ) 25 mg, or to atenolol 50 mg and atenolol 50 mg/HCTZ 25 mg, in patients whose blood pressure was not sufficiently controlled. At endpoint, metabolic parameters (total cholesterol, triglycerides, LDL, HDL, glucose, insulin) were not significantly altered in either treatment group. Most frequent adverse events under monotherapy (moexipril/atenolol) were asthenia (5.3/13.0%), headache (13.2/21.7%), cough (7.9/6.5%), pharyngitis (21.1/8.7%) and peripheral oedema (5.3/13.0%). Overall at least one AE was reported in 66% of the patients treated with moexipril and in 78% of those treated with atenolol. Reduction of SSBP/SDBP at endpoint was 14.7 +/- 1.9/10.0 +/- 1.1 and 8.7 +/- 1.9/8.4 +/- 1.1 mmHg after treatment with moexipril and atenolol, respectively. The results showed that moexipril and atenolol are equally effective in reducing blood pressure without adversely affecting blood lipids and carbohydrate metabolism.
 ...
PMID:Comparison between moexipril and atenolol in obese postmenopausal women with hypertension. 981 86