Functional determination of McN-A-343 affinity for M1 muscarinic receptors.

The affinity (KA) of 4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343), acting as an agonist of M1 muscarinic receptors, has been estimated by means of fractional receptor inactivation, employing the irreversible muscarinic antagonist propylbenzylcholine mustard. Two M1-mediated responses elicited by McN-A-343 were studied: relaxation of the isolated rat duodenum and inhibition of twitch contractions in rabbit was deferens. A comparison was made with the affinity of McN-A-343 as an antagonist (KB) of acetylcholine-induced contraction in rat duodenum. Results showed that McN-A-343 displayed similar affinities as an agonist and as an antagonist: -log KA were 4.68 and 5.17 in duodenum and vas deferens, respectively, vs. -log KB of 4.96 in duodenum, indicating that the ability of McN-A-343 to selectively stimulate M1 receptors is not based on a greater affinity for this subtype. In both preparations examined, McN-A-343 reached maximum effect through occupation of a fraction of the total available receptors (approximately 30% in duodenum, approximately 80% in vas deferens), implying that occupation of M1 receptors is translated into effect in a highly efficient way.     

The pharmacology game

This article gives instructions for designing a visually attractive, entertaining, faculty-led computer game for pharmacology review in a nursing education program. The game uses Microsoft PowerPoint, a presentation program that is inexpensive, easy to master, and widely available. Instructions for using Visual Basic for Applications to customize the game are included to allow tracking questions asked and the score of groups playing the game. The game can be easily adapted to material by specific nursing programs with access to PowerPoint.     

The pharmacology of cardiac memory

Cardiac memory is an altered T wave during sinus rhythm that is induced by a period of ventricular pacing or arrhythmia. The T wave is characterized by a vector that tracks that of the previously paced or arrhythmic QRS complex. Although initially considered a clinical oddity, cardiac memory is of interest both as an example of the general biological property of memory - as studied most extensively in neural tissues - and because of its implications regarding the control of cardiac rhythm. Signal transduction of cardiac memory appears to involve an angiotensin II-regulated pathway initiated by altered stress/strain patterns in the myocardium. The end result is altered density and kinetics of the transient outward current and perhaps other ion currents as well, and an altered transmural gradient for repolarization. The altered repolarization pattern is accompanied by altered responses to specific antiarrhythmic drugs that may be anti- or proarrhythmic.     

The clinical pharmacology of beta-adrenoblockers

Beta-adrenoblockers (BAB) are highly-effective pharmaceuticals used broadly in treatment of cardial diseases. Response to BABs is known to display interindividual variability; pre-treatment analysis of allelic gene variants responsible for BAB pharmacokinetics, allows dose correction according to the genetic features of an individual patient. Pharmacogenetics is a young science, but it has already proven its practical significance in term of individualization of pharmacotherapy, which in some cases makes it possible to increase the effectiveness of the pharmaceuticals and avoid undesirable effects.     

The pharmacology of human anxiety

The human pharmacology of anxiety disorders, including panic disorder, is detailed. The major theories center around the role of benzodiazepine receptor, noradrenergic and serotonergic dysfunction. The contribution that challenge tests with lactate, hyper- and hypocapnia, beta- and alpha-2-adrenoceptor agonists, peptides, pentylenetetrazol, and caffeine make to our understanding of the biological basis of anxiety and these major theories are described and discussed.     

The pharmacology of acute pain

Multimodal analgesia is the cornerstone of acute pain management. Paracetamol and NSAIDs provide background analgesia to which opioids and or adjuvant analgesics can be added, once the cause of pain is identified. Although simple analgesics have fixed-dose regimens, individual patient titration of opioids is essential. Dispelling opioid myths is fundamental to achieving this. Different routes of administration should not affect the level of analgesia achieved. Prompt recognition and treatment of side-effects helps to optimise pain management.     

The cardiac pharmacology of tolbutamide.

Recent clinical studies have suggested an association of tolbutamide therapy with an increased incidence of cardiovascular deaths. Due to the paucity of information concerning the acute cardiac actions of tolbutamide, the effects of this agent upon cardiac contractility and automaticity were examined under in vivo and in vitro conditions in rabbit, cat and dog heart muscle preparations. Tolbutamide (10(-6) to 3 x 10(-3) M) produced a biphasic inotropic response with a peak positive inotropic response at 3 X 10(-3) M which was 13.7 +/- 5.1% of the maximal obtainable increase in tension. Similar studies in cat papillary muscle resulted in a response that averaged 19% of the maximal increase in contractile force. In contrast, canine papillary muscles as well as the intact canine heart failed to develop a positive inotropic response to tolbutamide. Responses of rabbit atrial strips to isoproterenol were not potentiated by previous exposure to tolbutamide. Exposure of rabbit atria to theophylline, 2.5 X 10(-4) M, did not potentiate the inotropic effects of tolbutamide. Stidies in spontaneously beating rabbit right atria and cat papillary muscle-Purkinje fiber preparations demonstrated that tolbutamide does not have the potential to augment automaticity in these tissues. In intact dog heart, the intracoronary administration of tolbutamide did not lead to disturbances in cardiac rhythm, providing additional evidence that tolbutamide does not increase ventricular automaticity. It is concluded that tolbutamide possess a species-specific positive inotropic effect in rabbit and cat but not in the dog. The inotropic effect is small when compared to the maximum inotropic response and is observed only in vitro. Tolbutamide lacks the ability to enhance cardiac pacemaker activity. These data do not support the conclusions of previous investigatirs concerning the possible deleterious cardiac effects of tolbutamide.