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Biomedical subjects

B N Prichard

Publications and source records attributed to B N Prichard.

At least 19 recordsLinked to original sources
PubMed1992

Clinical pharmacology of carvedilol.

Animal work has shown that carvedilol is a nonselective beta-blocking drug. It has a vasodilator action from alpha-receptor blockade, but there is evidence that it has further action to relax smooth muscle, possibly from calcium channel antagonism. Carvedilol is lipid soluble and 25% bioavailable, and it has a half-life of about 7 h. It lowers blood pressure at rest and reduces the tachycardia and the rise of blood pressure on exercise. It reduces the level of blood pressure reached during isometric exercise or the cold pressor test. Cardiac output at rest is maintained, and the haemodynamics in the compromised heart is improved. It has an important peripheral vasodilator action, peripheral flow being maintained to important organs, e.g. kidneys, despite the fall in blood pressure. Exercising renin and noradrenaline levels are increased, as are the latter at rest. Carvedilol is lipid neutral. Carvedilol shifts the dose-response curve to isoprenaline to the right, as well as to alpha-stimulants such as phenylephrine. Responses to angiotensin are little affected. The ratio of beta- to alpha-blockade has been found to be 7.6 for 50 mg and 12.5 for 100 mg of carvedilol. There is no evidence of a decline in alpha-blockade after 1 week of continuous administration.

Adrenergic beta-Antagonists↗
PubMed1992

Plasma and platelet free catecholamine concentrations in patients with familial hypercholesterolaemia.

1. Plasma and platelet free catecholamine concentrations were measured in 22 normal subjects and in 10 treated and 11 untreated patients with heterozygous familial hypercholesterolaemia. 2. Plasma noradrenaline concentrations were significantly higher in both treated and untreated hypercholesterolaemic patients than in normal subjects. Adrenaline concentrations did not differ. 3. Platelet noradrenaline levels were higher in untreated hypercholesterolaemic patients than in normal subjects. 4. Positive correlations between the plasma noradrenaline concentration and the platelet noradrenaline concentration were observed in both normal subjects and hypercholesterolaemic patients. 5. Combining the data for normal subjects and hypercholesterolaemic patients revealed that the plasma noradrenaline concentration correlated positively with the plasma cholesterol concentration. The platelet noradrenaline concentration was also found to correlate with the plasma cholesterol concentration. 6. Our results suggest that an increased plasma cholesterol concentration may be associated with increased sympathetic nervous system activity as indicated by elevated plasma and platelet noradrenaline levels. Increases in circulating catecholamines may contribute to the platelet hyperaggregability seen in familial hypercholesterolaemia.

Adult↗
PubMed1992

Adverse reactions to diuretics.

Diuretics can result in various undesired biochemical changes, such as impotence, skin rashes, nausea, dizziness and lethargy as well as subjective side effects. The side effects are mostly predictable, their effects depending on both the circulatory blood volume and on the transport of water and solute in the renal tubules. Two of the commonest side effects are mild hypovolaemia, when any diuretic is used, and mild hypokalaemia when the non-potassium-sparing diuretics, such as thiazides and frusemide are used. Its occurrence is dose dependent and can be corrected by potassium supplements, but potassium-retaining diuretics, which also correct the often associated fall in serum magnesium, are preferable. Many reports link hypokalaemia with cardiac arrhythmias, but some dispute this association in the absence of the concomitant use of digoxin. Hyponatraemia rarely occurs, but can be life threatening. Calcium excretion is markedly reduced, but unlike other electrolyte disturbances from diuretics, this may be valuable: some suggest diuretics have an anti-osteoporotic action. Diuretics increase glucose and insulin resistance and should be used sparingly in diabetics. They rarely cause a non-ketotic hyperosmolar coma. Urate is raised, but clinical gout is not common. Cholesterol elevation has been reported in some studies, but long-term studies indicate that lipid changes are minor. Other rare side effects are not predictable from their pharmacological actions and these include the occurrence of skin rashes, thrombocytopenia, pancreatitis and interstitial nephritis; and ototoxicity from frusemide.

Blood Volume↗
PubMed1992

Beta-blocking agents with vasodilating action.

beta-Adrenoceptor-blocking drugs in current use can be separated into two main groups: those nonselective and those selective for beta 1-receptors. Members of each group reduce cardiac output and lead to an increase in peripheral resistance with a concomitant reduction in blood flow. beta-Blocking drugs not only may occupy the receptor preventing stimulation but also may have intrinsic sympathomimetic activity. Those with marked partial agonist activity at the beta 2-receptor giving some beta 2-mediated vasodilation can be regarded as the first multiple-action beta-blocking drugs. Subsequently, drugs have been developed that in addition to blocking the beta-receptor have an important peripheral vasodilator activity. Labetalol was the first drug of this group to be developed; prizidolol followed but has been withdrawn because of toxicity. Several other agents have been described, including bucindolol, carvedilol, celiprolol, dilevalol (one of the isomers of labetalol), and medroxolol. Three mechanisms have been reported to be responsible for peripheral vasodilation: alpha-receptor blockade, beta 2-agonism, and a dilator action independent of either the alpha- or beta-receptors. Evidence for these various mechanisms is more readily obtainable from animal experiments, but some confirmatory evidence has been obtained in humans. Inhibition of alpha-stimulation had been found with labetalol, medroxalol, and carvedilol and suggested with celiprolol. beta 2-Mediated vasodilation has been demonstrated by, for example, celiprolol and dilevalol; evidence of a vasodilation independent of alpha-blockade or beta 2-stimulation has been reported with celiprolol and carvedilol.

Adrenergic alpha-Antagonists↗
PubMed1992

Hypertension and insulin resistance.

Insulin resistance and hyperinsulinemia is now recognized in non-insulin-dependent diabetes, essential hypertension, obesity, atherosclerotic heart disease, dyslipidemia, heart failure, and in heavy smokers. Several mechanisms have been proposed to explain hyperinsulinemia, insulin resistance and its relationship to hypertension; reduced sodium excretion, activation of the sympathetic nervous system, increased activity of the sodium/hydrogen pump, and stimulation of cellular growth. Some of the nonpharmacological methods to control hyperinsulinemia are of benefit in the management of hypertension, most notably weight loss, exercise program, and reduced salt intake. High-fiber and reduced-protein diets also reduce hyperinsulinemia. Thiazide diuretics can result in insulin resistance, and insulin secretion may be inhibited, possibly associated with concomitant hypokalemia. beta-Blockers result in some reduction of glucose tolerance and mask some of the features of hypoglycemia. Angiotensin-converting enzyme (ACE) inhibitors and alpha-receptor blockers do not effect insulin resistance; probably the same is true for calcium antagonists. Although the effect on risk factors should not be discounted, it is the effect of treatment on hard end points, cerebrovascular accidents, myocardial infarction, or death that is most important. Evidence in hypertension is at present restricted to diuretics and beta-blocking drugs.

Animals↗
PubMed1991

The effect of urapidil on responses to phenylephrine, angiotensin and isoprenaline in man.

Intravenous urapidil, 40 mg bolus followed by an infusion of 18 mg.h-1 for 2 h was administered to 6 female non-patient volunteers. Randomised cumulative dose response curves to angiotensin, phenylephrine and isoprenaline were performed before and commencing 30 min after the start of the infusion of urapidil. Urapidil significantly reduced supine systolic blood pressure, 118.5 mm Hg to 105.3. The diastolic blood pressure was not significantly reduced, heart rate was not affected. Urapidil did not affect the responses to angiotensin or isoprenaline. Urapidil inhibited the pressor response to phenylephrine. The dose required to increase systolic blood pressure by 20 mm Hg increased from 156.9 micrograms.min-1 before to 685 micrograms.min-1 during urapidil; Dose ratio from individual values of 4.58. Urapidil concentrations were not significantly different before and after each agonist infusion. It is concluded that urapidil has alpha 1-adrenoceptor blocking activity in man without any non specific vasodilator action and that it is devoid of beta adrenoceptor blocking action.

Adrenergic alpha-Antagonists↗
PubMed1991

Trace element and vitamin deficiency in alcoholic and control subjects.

A wide range of trace elements and vitamins was studied in alcoholic patients admitted for detoxification and in healthy controls. Alcoholic subjects were found to be deficient relative to controls in magnesium and vitamin E, while a relative excess of serum iron and copper, and sweat nickel, was noted. A surprisingly wide range of deficiencies, as compared with standard laboratory ranges, was seen in the control group. This finding emphasizes the need for adequate control groups in nutritional studies of alcoholism, the insufficiency of an adequate diet alone to guarantee adequate nutrition, and the likely high prevalence of undetected nutritional deficiency in the general population. Further research is required on the clinical benefits of nutritional supplementation as part of the treatment of alcoholism, and the value of conventional supplements as a routine treatment is questioned.

Adult↗
PubMed1991

Heart and catecholamines.

Catecholamines mediate their effects in the heart through beta 1- and beta 2-receptors. Beta 1-receptors mediate the effects of sympathetic nerve stimulation. Alpha-receptors may have a role but, unlike the beta-receptor mediated responses, act without producing any increase in cyclic AMP. Prolonged receptor stimulation results in a reduction in beta-receptor sensitivity. In contrast blockade with a non-agonist agent is associated with an increase in catecholamine sensitivity which may be responsible for the withdrawal reactions that can occur when beta-blocking drugs are rapidly withdrawn in patients with ischaemic heart disease. Experimentally, prolonged noradrenaline infusions result in ventricular hypertrophy. Catecholamines have been implicated in several pathologies. High and rising catecholamine levels are associated with worsening of prognosis in patients with heart failure. These patients show a decreased beta-receptor number and cellular concentration of catecholamines. On the other hand cardiomyopathy is associated with an increased sensitivity to catecholamines. Catecholamines aggravate cardiac damage in ischaemia. Excessively high catecholamine loads cause myocardial damage in otherwise normal hearts, for example in patients with a phaeochromocytoma and those with various forms of cerebral damage such as subarachnoid haemorrhage, cerebrovascular accidents, and head injury.

Adrenergic beta-Antagonists↗
PubMed1990

Withdrawal phenomena after atenolol and bopindolol: hormonal changes in normal volunteers.

1. In order to observe and compare the withdrawal phenomena which follow treatment with the beta-adrenoceptor blocking drugs, bopindolol (with partial agonist activity PAA) and atenolol (without PAA), two groups of six normal volunteers were studied before, during and after 16 days drug administration. 2. Measurements of plasma levels of cortisol, prolactin, insulin, noradrenaline, adrenaline, glucose and potassium were made during a pre-treatment baseline period, on maximum dose and for 21 days after drug withdrawal. Isoprenaline infusions were given to determine sensitivity of heart rate responses and haemodynamic changes measured in response to physiological manoeuvres. 3. Following atenolol withdrawal the results show hormonal evidence of adrenergic overactivity in the form of elevation of plasma cortisol, insulin and glucose levels. After bopindolol withdrawal there was, in contrast, an overshoot of plasma prolactin and a persistent elevation of plasma potassium and adrenaline post-isoprenaline. 4. The hormonal changes which follow withdrawal of atenolol and bopindolol are associated with haemodynamic changes reported elsewhere (Walden et al., 1990). 5. These observations provide confirmatory evidence of a post beta-adrenoceptor blockade withdrawal syndrome which differs between the two drugs studied and this may reflect the properties of the drugs, in particular the PAA of bopindolol.

Adrenergic beta-Antagonists↗
PubMed1990

Withdrawal phenomena after atenolol and bopindolol: haemodynamic responses in healthy volunteers.

1. The effect of withdrawal of atenolol and bopindolol administration was studied in 12 normal volunteers; six on each drug. 2. Following sub-maximal cycle-ergometer exercise training six sets of base-line observations were made of heart-rate (HR) and blood pressure (BP) responses; supine, 60 degrees head-up tilt, during graduated isoprenaline infusion and sub-maximal cycle exercise. 3. The results show that withdrawal phenomena occur following both drug treatments. Atenolol produced a hypersensitivity to isoprenaline and a small overshoot of HR in response to physiological manoeuvres. In contrast bopindolol produced a prolonged state of reduced sensitivity to isoprenaline and some evidence of overshoot of HR with physiological manoeuvres. The differences between the responses may be explained by the different properties of the two beta-adrenoceptor blocking drugs. 4. Some subjects showed clear evidence of overshoot of HR and BP on exercise demonstrating that certain individuals may be more prone to have withdrawal effects than others. 5. The length of time during which withdrawal phenomena can occur is probably longer than has previously been realised. 6. Hormonal changes were found in the withdrawal period (Walden et al., 1990).

Adrenergic beta-Antagonists↗
PubMed1990

Selective beta-adrenoceptor partial agonist effects of pindolol and xamoterol on skeletal muscle assessed by plasma creatine kinase changes in healthy subjects.

1. The effects of selective beta-adrenoceptor partial agonist activity on plasma creatine kinase (CK) and skeletal muscle symptoms were studied in normal volunteers. 2. A drug with beta 1-selective partial agonist activity (xamoterol) and one with partial agonist activity acting mainly through beta 2-adrenoceptors (pindolol) were each given for 3 weeks in a randomised double-blind crossover study in 10 subjects. Five additional subjects received only one drug. Plasma CK levels were monitored during a baseline placebo run-in phase, the active treatment period and a placebo washout phase which continued until CK levels returned to baseline. 3. The degree of beta-adrenoceptor antagonism was determined by the inhibition of exercise-induced tachycardia and was similar for the two drug doses used. 4. During pindolol administration plasma CK levels rose compared with pretreatment baseline levels and with levels during xamoterol administration which did not rise. After pindolol was withdrawn CK levels reached higher peaks in some subjects after 1-5 days. 5. Muscle cramps were reported by five subjects during pindolol administration and by one of these subjects but to a lesser extent during xamoterol administration. 6. Pindolol may produce this effect, which was not seen with xamoterol, because of its specific beta 2-adrenoceptor partial agonist activity. Elevations in plasma CK produced by this type of drug or its withdrawal may cause confusion in the diagnosis of muscle disease or myocardial infarction unless the myocardial isoenzyme is measured.

Adrenergic beta-Agonists↗
PubMed1990

Mode of action of beta-adrenergic blocking drugs in hypertension.

Although they have been in use for over 20 years, the antihypertensive mode of action of beta-blocking drugs remains a matter for debate. Blood pressure falls with beta-blockers that have beta 1-selectivity, intrinsic sympathomimetic activity and membrane activity, but not those with a high level of pure beta-stimulation. Several suggestions have been made to explain this effect; a direct action on the central nervous system, adrenergic neurone blocking, perhaps via pre-synaptic beta 2-receptors, anti-renin activity, an increase of vasodilator prostaglandins, effects secondary to reduced cardiac output, and resetting of baroreceptors secondary to reduced pressor peaks to various pressor stimuli from the reduction in cardiac activity consequent to beta-blockade. There are also beta-blocking drugs which additionally have direct action to reduce peripheral resistance, via beta 2-mediated vasodilation, an alpha-blocking action or a direct vasodilator activity. Most attention has been given to a possible correlation to the effect of beta-adrenoceptor blocking drugs on the blood pressure and renin levels. Several investigations have found patients with high renin levels respond best, normal renin patients respond less well and low renin patients relatively poorly. However, others have not found a clear relationship.

Adrenergic beta-Antagonists↗
PubMed1990

Pharmacological and clinical aspects of drug therapy in coronary heart disease: clinical aspects of therapy with beta-adrenoceptor antagonists.

beta-adrenergic blocking drugs reduce myocardial oxygen consumption, chiefly by reducing heart rate as the principal basis for their efficacy in ischaemic heart disease. Regardless of the presence of associated properties, beta, selectivity, partial agonist activity, all beta-blocking drugs have been found efficacious in the treatment of angina pectoris, both alone and in combination with drugs such as nitrates and calcium antagonists. Holter monitoring has demonstrated beta blockers also reduce the incidence of silent ischaemia. Finally, they are established in the treatment of acute infarction and secondary prevention of recurrences. There are inherent disadvantages of inhibition of the beta sympathetic, most notably the precipitation of asthma and heart failure in susceptible subjects. Recently, combined-action beta-blocking drugs have been developed, i.e. combining beta blockade with peripheral vasodilator activity, either by alpha 1, blockade, beta 2 stimulation or a direct effect independent of either receptor. They have a more favourable haemodynamic profile and, while initial studies are promising, it is not yet clear whether this will be translated into improved clinical benefit in ischaemic heart disease.

Adrenergic beta-Antagonists↗
PubMed1990

Serotonin: receptors and antagonists--summary of symposium.

Serotonin is a widely distributed amine, although 95% is found in the enterochromaffin cells of the gastrointestinal mucosa. Its effects are mediated via a large number of receptors differing in their physiological and pharmacological properties. Its principal actions are on the cardiovascular system, both directly and potentiating the effects of the vasoconstriction from noradrenaline, angiotensin and histamine; similarly it potentiates the effect of various platelet aggregating substances. There is evidence that 5-hydroxytryptamine releases endothelium-derived relaxing factor attenuating its direct constriction effect and in the human forearm an increase in flow is seen from serotonin. In the absence of endothelium as in atherosclerosis, vasoconstriction occurs. Serotonin antagonism may have useful therapeutic effects and ketanserin has undergone wide evaluation. There is evidence that ketanserin should be avoided with potassium-losing diuretics as an increased mortality has been reported with the combination.

Animals↗
PubMed1990

Dilevalol: a dose-response study in normal volunteers.

Dilevalol, 100 mg, 200 mg and 400 mg, and placebo were given to eight normal volunteers and the effect on blood pressure and heart rate studied at rest and on exercise. There was a dose-dependent fall in exercising heart rate and in the increased heart rate on exercise with dilevalol, while exercising systolic blood pressure and the rise in systolic blood pressure on exercise fell dose-dependently up to 200 mg, but the effect of 400 mg was similar. Diastolic blood pressure was not affected. Supine heart rate and blood pressure changes were not different from placebo. Tilt heart rate fell most constantly from 200 mg. Some fall in tilt systolic blood pressure was seen but this was not dose-dependent, diastolic blood pressure was not affected. There was wide variation in plasma concentration of dilevalol, as might be expected from a liver metabolised drug, with a relatively larger amount absorbed of the 400 mg dose compared to the 100 or 200 mg doses.

Adult↗
PubMed1989

Urapidil, a multiple-action alpha-blocking drug.

Investigations in animals indicate that urapidil has a number of actions that may be relevant to its antihypertensive effect. It has an alpha 1-blocking action, a weak beta 1-blocking effect, an interaction with a serotonin receptor and a central depression of sympathetic tone. Urapidil is well absorbed orally with a bioavailability of about 70% and a time to peak concentration of about 4 hours after a sustained release capsule. It is metabolized in the liver at a half-life of 4.7 hours. Peripheral alpha 1-blocking activity has been demonstrated in humans. A shift to the right in the dose-response curve to phenylephrine has been found after urapidil, whereas responses to angiotensin are not affected. Evidence for beta 1-blocking activity is marginal. Urapidil does not inhibit the exercise increase in heart rate. Some investigators have suggested a possible inhibition of isoprenaline tachycardia; others have found no evidence. There is some evidence suggestive of a central action of urapidil in humans as lower single doses result in a decrease in blood pressure and an increase in heart rate. With higher doses the hypotensive effect continues but the tachycardia no longer occurs. However, urapidil has been reported to increase noradrenaline levels, although there has been a report with a high dose reducing vanillylmandelic acid excretion. Evidence for changes in renin is inconsistent. Hemodynamic studies have revealed findings that are compatible with peripheral alpha 1 blockade. After intravenous administration, peripheral resistance is reduced along with arterial pressure, and cardiac output is increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗