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PubMed2001

High performance liquid chromatography with UV detection for the simultaneous determination of sympathomimetic amines using 4-(4,5-diphenyl-1H-imidazole-2-yl)benzoyl chloride as a label.

A high performance liquid chromatographic method has been developed for the simultaneous determination of (+/-) fenfluramine (Fen) and phentermine (Phen) in addition to three other sympathomimetic amines-ephedrine (E), norephedrine (NE) and 2-phenylethylamine (2-PEA), using cyclohexylamine (CX) as an internal standard in plasma. The compounds were derivatized with 4-(4,5-diphenyl-1H-imidazole-2-yl)benzoyl chloride (DIB-Cl) to give the DIB-derivatives. The derivatives were then separated using an isocratic HPLC system with UV detection. The limits of detection for Fen, Phen, E, NE and 2-PEA in plasma ranged from 0.32 to 22.9 pmol on column at a signal-to-noise ratio of 3. The recoveries following alkaline extraction from plasma samples of known concentrations were found to be more than 94% for the studied compounds. This method might be useful for the screening of the studied sympathomimetic amines in human plasma samples in forensic as well as toxicological studies. Furthermore, the developed method was modified for the simultaneous determination of Fen and Phen in human and rat plasma using fluoxetine as an internal standard. The methods are reproducible and precise. Finally, the two drugs were administered intraperitoneally to rats in combination, and their plasma levels over the investigated time course were successfully determined.

Amines↗

PubMed1993

(+/-) isoprenaline revisited: adverse effects of sympathomimetics in asthma.

It is a matter of concern that regular, excessive use of contemporary sympathomimetics has been associated with morbidity and mortality from asthma. As a consequence, restrictions on sympathomimetic usage have recently been advocated in asthma management guidelines. he association between excessive use of inhaled (+/-)isoprenaline and an epidemic of asthma deaths in the 1960s provides a precedent; hence, we have reviewed the numerous clinical and experimental reports concerning (+/-) isoprenaline to provide insight into the present controversy.

Asthma↗

PubMed1993

Post-natal development modulates the rat seminal vesicle sensitivity to sympathomimetic agonists.

The post-natal development-related changes in the sensitivity to sympathomimetic agonists were studied in the seminal vesicle of 40-, 60- and 120-day old rats by determining the pD2 values for adrenaline, phenylephrine and methoxamine. The age-related changes in the neuronal and extraneuronal uptake of sympathomimetic agonists were also determined. The seminal vesicle sensitivity to adrenaline, phenylephrine and methoxamine increased in sexually mature rats (60- and 120-day old) (concentration-effect curves shifted to the left and pD2 values increased) when compared with immature rats (40-day old). Cocaine, a neuronal uptake inhibitor, induced supersensitivity to adrenaline at all ages, but did not affect the sensitivity to methoxamine. The ratio between the EC50 values for adrenaline in the presence and in the absence of cocaine was reduced in tissues of mature animals. This reduction suggests a loss of function of the neuronal uptake system with sexual development. In the presence of cocaine the pD2 value for adrenaline was increased during sexual development. Thus, the age-related changes in the adrenaline sensitivity were observed even when neuronal uptake was not operative, suggesting age-related changes at the post-junctional level, which was confirmed by the increase in the seminal vesicle sensitivity to methoxamine. In the presence of the extraneuronal uptake inhibitor, corticosterone, the sensitivity to adrenaline did not change and the age-related changes persisted.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1986

The role of co-transported sodium in the effect of indirectly acting sympathomimetic amines.

The adrenergic nerve endings of vasa deferentia of either untreated or reserpine (R) and/or pargyline (P) pretreated rats were loaded with 3H-noradrenaline; COMT was inhibited by U-0521 (U). After 100 min of wash-out with Ca2+-free solution, the efflux of tritium (and of 3H-noradrenaline) from the tissue was largely of neuronal origin and remained constant with time (when expressed as fractional rate of loss; FRL). After 110 min of wash-out the effect of inhibition of the Na+,K+-ATPase (by low K+ or ouabain) on basal and on sympathomimetic amine-induced efflux of tritium (or 3H-noradrenaline, under the condition U) was studied in paired experiments. Inhibition of the Na+,K+-ATPase caused a time-dependent increase in the efflux of tritium (or 3H-noradrenaline) which was inhibited by desipramine. Inhibition of the Na+,K+-ATPase also caused a time-dependent reduction of the initial rate of neuronal uptake of 3H-noradrenaline. The effectiveness of the sympathomimetic amines tyramine and amphetamine in inducing "release" (i.e., outward-transport) of noradrenaline depended on the experimental condition: it was most pronounced under the condition RPU, followed by the condition PU and lowest under the condition U (i.e., in tissue of untreated rats). Inhibition of the Na+,K+-ATPase caused an early and transient enhancement of the "release" of noradrenaline induced by tyramine or amphetamine. This enhancement was seen already within the first min after inhibition of the ATPase, i.e., before a pronounced inhibition of uptake (of noradrenaline) and before a pronounced increase of the basal efflux was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗

PubMed2003

Cerebrovascular complications of alcohol and sympathomimetic drug abuse.

Alcohol abuse has been linked to intracranial hemorrhage, both intracerebral and subarachnoid. Some studies have found a dose-response relationship, so that increasing levels of abuse are associated with greater risk of hemorrhage. However, alcohol abuse has not been clearly linked to cerebral infarction, and some studies find that mild-to-moderate drinking appears to be associated with a decreased risk of cerebral infarction. Intravenous administration of drugs of abuse predisposes to endocarditis, which may lead to embolic stroke. Associations have been reported between various sympathomimetic drugs and cerebral infarction. A possible mechanism for cerebral infarction is focal arterial vasoconstriction and occasionally cerebral vasculitis. Associations have also been reported between various sympathomimetic drugs and intracranial hemorrhage. A likely mechanism for intracranial hemorrhage is acute arterial hypertension. With the exception of endocarditis, management of stroke related to drug abuse is largely supportive, with emphasis on supportive care to prevent stroke complications, physical and occupational therapy, and aggressive addiction rehabilitation.

Alcohol Drinking↗

PubMed1982

Cardiac safety of acute beta blockade: intrinsic sympathomimetic activity is superior to beta-1 selectivity.

Regional myocardial function was assessed by multidirectional echocardiography from eight standardized segments around the left ventricle. Thirty-six subjects (healthy, severe angina pectoris, or acute myocardial infarction) were studied 15 minutes either after the beta 1-selective beta-blocking drug metoprolol had been administered in total doses of 2 and 10 mg intravenously or after pindolol, a beta blocker with intrinsic sympathomimetic activity (ISA), in total doses of 0.2 and 1.0 mg intravenously had been given. Metoprolol and pindolol reduced rate-pressure product (p less than 0.001 each), heart rate (p less than 0.001), and systolic blood pressure (p less than 0.05 to 0.001) in almost the same way. In patients with acute myocardial infarction, 0.2 mg pindolol improved ST segments by 33% and 2 mg metoprolol by 18%. Left ventricular diameter increased (p less than 0.001) and ejection fraction decreased (p less than 0.05) after metoprolol but not after pindolol. Pindolol did not reduce wall motion amplitudes of healthy myocardial segments, while metoprolol did ( p less than 0.01). The overall contractile function of the left ventricle is characterized by composite segmental amplitudes from both ischemic and healthy ventricular regions. In ischemic hearts this function remained unchanged after metoprolol but improved markedly after pindolol (p less than 0.005). Thus, while intravenous pindolol and metoprolol produced equal reductions in rate-pressure product, pindolol, a beta-adrenergic-blocking drug with intrinsic sympathomimetic activity, evoked less cardiac depression and thus provided a cardiac safety factor not afforded by the beta- 1-selective metoprolol.

Adult↗

PubMed1989

Fetal and neonatal cardiovascular complications from beta-sympathomimetic therapy for tocolysis.

beta-Sympathomimetic drugs cross the placenta freely. Just as these agents cause serious cardiovascular changes in the mother, they may cause severe cardiovascular complications in the fetus. beta-Sympathomimetic agents for tocolysis have been associated with fetal heart rate and rhythm disturbances, hydrops, stillbirth, neonatal cardiac failure, myocardial ischemia and infarction, and neonatal death. Prospective studies have documented changes in interventricular septa of babies exposed to these drugs. Histologic changes have been reproduced in animal models and in vitro similar to those seen in infants with myocardial disease caused by beta-mimetic therapy. The mechanism of beta-mimetic toxicity appears to be increased myocardial intracellular calcium leading to overexcitation and cell necrosis. Since serious fetal cardiovascular effects may occur with beta-mimetic use, benefits should clearly outweigh risks before these drugs are administered.

Biomechanical Phenomena↗

PubMed1989

Nebivolol is devoid of intrinsic sympathomimetic activity.

Nebivolol is a chemically novel, potent and selective beta 1-adrenoceptor-blocking agent that acutely lowers arterial blood pressure in hypertensive patients and rats without depressing, or even enhancing, left ventricular function. These properties could be compatible with a partial agonistic effect of beta-adrenoceptor-blocking agents. It was the aim of the present study to investigate whether nebivolol has intrinsic sympathomimetic properties. The study was performed on reserpinized dogs and spontaneously hypertensive rats, and on various isolated tissues from various species. Unlike pindolol and practolol, nebivolol did not exert a stimulating effect on the heart rate and left ventricular function in reserpinized animals and/or in isolated atria of reserpinized rats at doses that are clinically active. Nebivolol did not induce relaxation of isolated coronary arteries and saphenous veins at concentrations that block beta-adrenoceptors. These findings indicate that nebivolol is devoid of intrinsic sympathomimetic activity at clinically relevant doses.

Adrenergic beta-Antagonists↗

PubMed1978

Uropharmacology: VIII. Sympathomimetic agents.

Sympathomimetic drugs stimulate the receptors of the sympathetic nervous system. Although the bladder possesses sympathetic receptors, sympathomimetic drugs, in general, have little effect on bladder function. Their most useful clinical applications on the urinary tract are to increase or decrease bladder resistance.

Animals↗

PubMed1988

The effects of metabolic acidosis and alkalosis on the response to sympathomimetic drugs in dogs.

Sympathomimetic drugs are commonly used in many circumstances to increase cardiac output, blood pressure, and myocardial contractility. However, factors such as acidosis or alkalosis are known to influence the action of these drugs. This study looked at the response to the administration of epinephrine, norepinephrine, dopamine, dobutamine, isoproterenol, and glucagon at normal pH and under acidotic (pH 7.2 +/- 0.01) and alkalotic (pH 7.59 +/- 0.01) conditions in 17 dogs. Acidosis was produced with an infusion of hydrochloric acid and alkalosis by infusion of sodium bicarbonate. The infusions were given over one hour followed by a 15- to 30-minute stabilization period. With the administration of each sympathomimetic drug at each pH level, hemodynamic parameters and measurements of myocardia; contractility were recorded. Epinephrine increased cardiac output at normal pH, but decreased cardiac output under conditions of both acidosis and alkalosis; the net change from values at pH 7.40 was nearly 3 L/min. The only other drug to demonstrate this reversal of cardiac output, though to a lesser degree, was dopamine, 10 microg/kg/min, and only in the alkalotic state. Dobutamine was the only drug that decreased contractility under acidotic conditions, while all other drugs caused an increase. In sum, epinephrine was the only drug markedly affected by metabolic acidosis and alkalosis. Isoproterenol's hemodynamic effects were altered the least by changes in acid-base balance. Alkalosis had an equally adverse effect on the cardiovascular system as compared with acidosis.

Acidosis↗

PubMed2005

A kinetic study on the inhibitory action of sympathomimetic drugs towards photogenerated oxygen active species. The case of phenylephrine.

Kinetics and mechanism of the aerobic Riboflavin (Rf, vitamin B2) sensitized photodegradation of Phenylephrine (Phen), a phenolamine belonging to the sympathomimetic drugs family, has been studied in water, employing continuous photolysis, polarographic detection of oxygen uptake, steady-state and time-resolved fluorescence spectroscopy, time-resolved IR-phosphorescence and laser flash photolysis. Results indicate the formation of a weak dark complex Rf-Phen, with an apparent association constant of 5.5+/-0.5M(-1), only detectable at Phen concentrations much higher than those employed in the photochemical experiments. Under irradiation, an intricate mechanism of competitive reactions operates. Phen quenches excited singlet and triplet states of Rf, with rate constants of 3.33+/-0.08 and 1.60+/-0.03x10(9)M(-1)s(-1), respectively. With the sympathomimetic drug in a concentration similar to that of dissolved molecular oxygen in water, Phen and oxygen competitively quench triplet excited Rf, generating superoxide radical anion and singlet molecular oxygen (O2((1)Deltag)) by processes initiated by electron- and energy-transfer mechanisms respectively. As a global result, the photodegradation of the vitamin, a known process taking place from its excited triplet state, is retarded, whereas the phenolamine, practically unreactive towards these oxidative species, behaves as a highly efficient physical deactivator of O2((1)Deltag). The phenolamine structure in Phen appears as an excellent scavenger of activated oxygen species, comparatively superior, in kinetic terms, to some commercial phenolic antioxidants.

Kinetics↗

PubMed1981

Vascular responses to REN-293 (2-amino-3[3, 5-dihydroxyphenyl]-1-propanol hydrochloride)--a new sympathomimetic agent.

In this study the effects of REN-293 have been examined on the rat tail artery "in situ'. It was found that the drug was totally dependent on the sympathetic nerves for its vasoconstrictor action. This action was blocked by phentolamine and attenuated by pre-treatment of the vessel with tyramine. When a comparative study of the vasoconstrictor effects of several sympathomimetics was performed, it was found that REN-293 was more potent than tyramine and ephedrine, but less so than etilefrine. It would appear that REN-293 is of interest as a pharmacological tool for examining sympathetic nerve function, but its usefulness in the therapy of orthostatic hypotension is likely to be limited, due to the very indirect nature of its sympathomimetic action.

Animals↗

PubMed2001

Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium.

1. The present study investigated whether or not there may be differences in the direct cardiac actions of the novel, highly beta(1)-selective adrenoceptor antagonist nebivolol (NEB) in comparison to metoprolol (MET), bisoprolol (BIS), carvedilol (CAR) and bucindolol (BUC) in human myocardium (n=9). 2. The rank order of beta(1)-selectivity as judged by competition experiments to (3)H-CGP 12.1777 in the presence of CGP 207.12 A (300 nmol l(-1), K(i)beta(2)) or ICI 118.551 (50 nmol l(-1), K(i)beta(1)) were NEB(K(i)beta(2)/K(i)beta(1): 40.7) > BIS(15.6) > MET(4.23) > CAR(0.73) > BUC(0.49). 3. The rank order of the negative inotropic potency of the beta-adrenoceptor antagonists measured in left ventricular trabeculae (dilated cardiomyopathy, DCM) as judged by the concentration needed to induce a 50% decrease in isoprenaline (1 micromol l(-1))-stimulated force (IC(50)) was: MET (0.6 micromol l(-1)) > CAR (4.1 micromol l(-1)) > NEB (7.0 micromol l(-1)). 4. NEB, BUC, MET and CAR did not not exert an intrinsic sympathomimetic activity (ISA) as determined by measurements of force development in forskolin (0.3 micromol l(-1)) pre-treated left ventricular trabeculae, nor by measuring adenylate cyclase activity in forskolin (0.3 micromol l(-1))-stimulated assays (crude membranes). This also holds true for radioligand binding assays with or without guanine nucleotide guanyl-5'-yl imidodiphosphate (Gpp(NH)p). 5. Although all studied beta-adrenoceptor antagonists lack intrinsic sympathomimetic activity (ISA), they differ in the beta(1)-selectivity as well as in their direct negative inotropic action. These differences as well as the mode of extracardiac action may have an impact on outcome of patients treated with beta-adrenoceptor antagonists.

Adrenergic beta-Antagonists↗

PubMed2000

Vasodilatory response of fetoplacental vasculature to adrenomedullin after constriction with the thromboxane sympathomimetic U46619.

OBJECTIVE: This study was undertaken to determine whether adrenomedullin, a hypotensive peptide, decreases vasomotor tone in fetoplacental vasculature that has been constricted with the thromboxane sympathomimetic U46619. STUDY DESIGN: The fetoplacental vascular beds of 20 perfused human placental cotyledons were vasoconstricted with a continuous infusion of U46619 (10(-8) mol/L). The vasculature was then sequentially injected with deionized water, 30 ng adrenomedullin, 300 ng adrenomedullin, and 3000 ng adrenomedullin. Any change in perfusion pressure was noted after each dose. In a separate experiment the fetoplacental vasculature in 2 perfused cotyledons from each of 10 placentas was vasoconstricted with U46619 (10(-8) mol/L). Adrenomedullin was infused continuously at either 200 ng/min (n = 5) or 2000 ng/min (n = 5) for 40 minutes. A corresponding control cotyledon from each placenta had isotonic sodium chloride solution added to its perfusion. Perfusion pressures were recorded every minute during the infusion and for 40 minutes afterward. Analysis of variance was used to compare pressure changes in the cotyledons that received bolus doses of adrenomedullin. Paired t tests of mean percentage pressure changes were used to compare the study and control groups that received the continuous infusions. RESULTS: In the cotyledons that received bolus doses of adrenomedullin, the mean (+/-SEM) percentage perfusion pressure changes from the baseline were -6.7 +/- 0.5 for 30 ng adrenomedullin (P =.0039), -8.5+/- 0.7 for 300 ng adrenomedullin (P <.0001), and -13.1 +/- 1.0 for 3000 ng adrenomedullin (P <.0001). With the continuous adrenomedullin infusion of 200 ng/min, there was no significant difference in the mean percentage pressure change from baseline between the study and control groups (-0.57%). At 2000 ng/min there was a significant difference (-15.34%; P <.0001). CONCLUSION: Adrenomedullin caused vasodilatation of fetoplacental vasculature previously constricted with the thromboxane sympathomimetic U46619 in the isolated perfused placental cotyledon. This vasodilatation occurred in a dose-dependent manner.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2000

Tolerance develops to the sympathomimetic but not the local anesthetic effects of cocaine.

OBJECTIVES: The cardiovascular effects of cocaine are complex and include sympathomimetic as well as local anesthetic effects. The aim of the present study was to delineate cocaine toxicity in a model simulating cocaine binging patterns. DESIGN: Prospective laboratory investigation. Twelve dogs were randomized to receive 6 intravenous boluses of cocaine 5.25 mg/kg (high dose, n = 5), 3.5 mg/kg (low dose, n = 4), or placebo (n = 3) at 15-minute intervals. Arterial pressure, electrocardiogram, and serum cocaine were measured at control, then at fixed time intervals after each bolus of cocaine or placebo. Statistical significance was determined by ANOVA. RESULTS: Peak serum cocaine concentrations were 3500 ng/mL and 2167 ng/mL in the high- and low-dose groups. There were progressive decreases in mean arterial pressure in the high-dose cocaine group by as much as 32% (p = .003) after each cocaine bolus. However, in the low-dose group, increases in mean arterial pressure were observed after the initial cocaine boluses by as much as 31% (p = .013). Significant QRS prolongation was observed in both the high- and low-dose cocaine groups by as much as 65% (p < .001) and 10% (p < .03), respectively. However, the prolongation observed in the high-dose group was more pronounced and cumulative, while in the low-dose group the prolongation was transient. CONCLUSIONS: At low doses, cocaine's sympathomimetic properties predominate but tolerance develops. At high doses, cocaine's local anesthetic properties predominate, become more pronounced with repeated administration, and may have implications for cocaine-related dysrhythmias, cardiovascular collapse, and sudden death.

Analysis of Variance↗

PubMed1996

Topical beta-blockade with intrinsic sympathomimetic activity offers no advantage for the respiratory and cardiovascular function of elderly people.

Topical therapy with beta-antagonists, such as timolol, may cause unrecognized impairment of respiratory and cardiovascular function in elderly people. Beta-antagonists with intrinsic sympathomimetic or cardioselective properties, such as carteolol or betaxolol, may cause less impairment. In a randomized, double-masked study of glaucoma patients, over 60 years of age, without history of bronchospasm and who were using timolol (0.5%), 60 patients were allocated to betaxolol (0.5%) or carteolol (2%) or continued timolol (0.5%) treatment. Spirometry, pulse and blood pressure were measured on enrollment and after 4 weeks. In the timolol and carteolol groups there were no significant changes in mean spirometric values. Changing to betaxolol improved mean peak flow (PF) by 9.1%, from 310 to 3411/min (p < 0.05) and forced expiratory volume in 1 second (FEV1) by 9.4%, from 1.74 to 1.861 (p < 0.05). Differences in the changes in PF and FEV1 between betaxolol and timolol as well as betaxolol and carteolol groups were statistically significant (p < 0.05). Twenty-one per cent of those allocated to betaxolol showed clinically significant improvement in FEV1. There was no change in pulse or blood pressure when carteolol was substituted for timolol but an increase of 10 beats per minute (p < 0.05) in mean resting pulse in the betaxolol group. Therapy with cardioselective beta-blockade may offer significant advantages in respiratory function for elderly people with glaucoma over non-selective drugs, even if they have sympathomimetic activity.

Adrenergic beta-Antagonists↗

PubMed1989

Acute macular neuroretinopathy following intravenous sympathomimetics.

Three young women developed acute macular neuroretinopathy with persistent paracentral scotomas following acute hypertension caused by intravenous sympathomimetics. The temporal relationship of the acute onset of symptoms suggests either acute hypertension or a direct retinal effect of sympathomimetics as the cause of the retinal changes.

Acute Disease↗

PubMed1982

Vasodilating properties of beta-adrenoceptor blockers with intrinsic sympathomimetic activity.

1 In vitro experiments have been performed using 33 preparations of human arteries and veins and 10 human umbilical artery preparations. Changes in the tone of helical strips of vasculature were recorded isometrically following contraction of the tissues by exposure to 5-hydroxytryptamine (10(-6)--10(-5) M) or potassium (127 mM). 2 Isoprenaline included concentration-dependent relaxation and this effect could be competitively antagonized by propranolol or sotalol. 3 The beta-adrenoceptor antagonists pindolol and celiprolol, both of which possess intrinsic sympathomimetic activity, produced concentration-dependent relaxations of arteries and veins but not of umbilical vessels. 4 The relaxation produced by pindolol or celiprolol could be antagonized but not abolished by pretreatment with propranolol or sotalol. 5 It is concluded that the vascular relaxation produced by beta-adrenoceptor antagonists with intrinsic sympathomimetic activity is the result of beta 2-adrenoceptor stimulation. In the case of pindolol the relaxant effects were seen at concentrations within the range encountered after administration of normal therapeutic doses suggesting that this effect may contribute to the haemodynamic responses to pindolol seen in man.

Adrenergic beta-Antagonists↗