Types of p-Blockers

The basic structure shared by most p-sym-patholytics (p. 11) is the side chain of p-sym-pathomimetics (cf. isoproterenol with the p-blockers propranolol, pindolol, atenolol). As a rule, this basic structure is linked to an aromatic nucleus by a methylene and oxygen bridge. The side chain C-atom bearing the hydroxyl group forms the chiral center. With some exceptions (e.g., timolol, penbu-tolol), all p-sympatholytics exist as race-mates (p. 62). 

As cationic amphiphilic drugs, p-blockers can exert a membrane-stabilizing effect, as evidenced by the ability of the more lipophilic congeners to inhibit Na+ channel function and impulse conduction in cardiac tissues. At the usual therapeutic dosage, the 

Some p-sympatholytics possess higher affinity for cardiac p,-receptors than for p2-receptors and thus display cardioselect-ivity (e.g., metoprolol, acebutolol, atenolol, bisoprolol, p, p2 selectivity 20-50-fold). None of these blockers is suf ciently selective to permit use in patients with bronchial asthma or diabetes mellitus (p.96). 

The chemical structure of p-blockers also determines their pharmacokinetic properties. Except for hydrophilic representatives (atenolol), p-sympatholytics are completely absorbed from the intestines and subsequently undergo presystemic elimination to a major extent (A). 

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These three specific types of P-blockers shall now be treated individually in the sections that follows ... 

Two different types of P-adrenoceptors have been characterized and categorized as P - and P2-subtypes. The P -receptors are associated primarily with the cardiac muscle, whereas the P2-subtype is located peripherally. Selective P -blockers include practolol (121) and (122), atenolol (123) and (124), and betaxolol (125) and (126). 

Because the p-receptors of the heart are primarily of the pi type and those in the pulmonary and vascular smooth muscle are p2 receptors, Pi-selective antagonists are frequently referred to as cardioselective blockers. The intrinsic activity, cardioselectivity, and membrane-stabilizing actions of a number of p-blockers are summarized in Table 11.2... 

The reduction in plasma volume produced by p-blockers contrasts with the increased volume seen with other types of antihypertensives. Tolerance to the antihypertensive actions of p-blockers therefore is less of a problem than with the vasodilating drugs. An additional difference from the vasodilators is that plasma renin activity is reduced, rather than increased, by propranolol (Inderal). Orthostatic hypotension does not occur with p-blockers. 

Sasaki et al. [151] prepared nondegradable disc-type ophthalmic inserts of P- blockers using different polymers. They found that inserts made from poly(hydroxypropyl methacrylate) were able to control the release of tilisolol hydrochloride. 

Table 11-7 Physicochemical properties of P-blockers of the propranolol type (adapted from ref. [83] with permission of Taylor and Francis, UK).

The competitive (non-depolarising) neuromuscular blockers and depolarising neuromuscular blockers mentioned in this section are listed in Table 5.2 , (p.91). The modes of action of the two types of neuromuscular blocker are discussed in the monograph Neuromuscular blockers + Neuromuscular blockers , p.l28. It should be noted that mivacurium (a competitive blocker) and suxamethonium (a depolarising blocker) are hydrolysed by cholinesterase, so share some interactions in common that are not relevant to other competitive neuromuscular blockers. 

There are two main types of neuromuscular blockers competitive (non-depolarising) and depolarising, see Table 5.2 , (p.91). 

This double bond attachment is substantiated by carbon/hydrogen analysis before and after bonding. Furthermore, the basic high stability of the cyclodextrin bonded phases support the idea that a significant number of these types of double bond attachments are, in fact, present. In addition, it is not theoretically impossible that one cyclodextrin molecule could be anchored to the silica by three or more chains, although such attachment bonds have not been experimentally confirmed or identified. These types of phases have been used very successfully in the resolution of the enantiomers of a number of P- blockers (e.g. Propranolol, Atenolol,... 

Alak and Armstrong (107,108,112,113) investigated the influence of different silicas and binders on the separation behavior of P-cyclodextrin TLC plates. Besides nine racemates, three diastereomeric compounds and six structural isomers were separated. Wilson (109) impregnated silica plates with a 1% solution of P-CD in ethanol-dimethylsulfoxide (80 20 by volume) racemic mandelic acid was barely separated, and the antipode separation of P-blockers was not possible. Armstrong et al. (110) were the first to describe application of P-cyclodextrin as a chiral eluent additive for separations on reversed-phase TLC plates. The success of separation was strongly dependent on type and quantity of modifier applied, but above all on the concentration of P-CD. The low solubility of 3-CD in water (0.017 M, 2S C) can be improved by addition of urea sodium chloride stabilizes the binder of the RP plates. Compared to 3-CD bonded phases, a reversed retention behavior was noticed, the D-enantiomer eluting above the L-isomer. The separation of steroid epimers and other diastereomeric classes of compounds is also possible with this technique. Hydroxypropyl and hydroxyethyl P-... 

Propranolol is another type of antihypertensive agent called a p-adrenergic blocking agent (p-blocker) because it competes with epinephrine... 

A similar type of fragmentation dominates the spectrum of other local anaesthetics such as prilocaine and procaine and sympathomimetics such as ephedrine, salbutamol and terbutaline and P-adrenergic blockers such as propranolol and oxyprenolol. 

Molecular genetic techniques have confirmed the existence of multiple subtypes of p-adrenoceptors. Pi-Receptors and Pj-receptors have been cloned, and recent molecular biological evidence indicates the existence of at least one additional p-receptor sub-type, called the p3-receptor. It is suggested that the P3-receptor may mediate some of the metabolic effects of catecholamines, although no available p-blocker has been shown to rely on Pa-receptor antagonism for its therapeutic effectiveness. 

The available Ca channel blockers exert their effects primarily at voltage-gated Ca channels of the plasma membrane. There are at least several types of channels—L, T, N, P/Q and R—distinguished by their electrophysiological and pharmacological characteristics. The blockers act at the L-type channel at three distinct receptor sites (Fig. 19.2). These different receptor interactions underlie, in part, the qualitative and quantitative differences exhibited by the three principal classes of channel blockers. 

FKiURE 6 5C. Efficacy of dihydropyridine L-type calcium channel blockers. Mean deviation from euthymia ratings (number of days in parentheses) in a patient with bipolar 11 disorder with ultra-ultrarapid cycling showing the following efficacy of nimodipine monotherapy efficacy of nimodipine-carbamazepine combination therapy unsuccessful transition from nimodipine to verapamil successful reinstitution of nimodipine-carbamazepine combination therapy and, finally, successful transition to isradipine-carbamazepine combination therapy. P <. 05 "nimodipine slowly tapered to zero. 

Cypros Pharm. Corp. describes the use of polyguanidino derivatives as presynaptic N- and P/Q-type calcium channel blockers for i.v. (or i.c.v.) administration (Marangos et al. (Cypros Pharmaceutical Corp.), W09836743). Compound 5 was administered to gerbils (7.5 mg/kg i.v.) prior to bilateral carotid occlusion. After 72 h the animals were sacrificed. Brains were perfusion-fixed and sections were stained to enable quantitative cell counts of live and dead neurons. The number of damaged neurons in the subiculum was 91.5 compared to 214 for a control treated with saline. It has been claimed that this compound can be used for the treatment of neuropathic pain and for the protection of neurons from excitatory damage under conditions of cerebral hypoxia. 

Hasegawa, A.E. and Zacny, J.P. The influence of three L-type calcium channel blockers on morphine effects in healthy volunteers, Anesth. Analg. 1997, 85, 633-638. 

Aga IVA and ro-conotoxin GVIA are standard tools in elucidating the roles of P/Q-type and N-type calcium channels in synaptic transmission. In many types of synapses, application of either toxin may mediate moderate inhibition of neurotransmitter release, whereas co-application of both blockers may almost abolish synaptic transmission due to the nonlinear dependence of synaptic release on intracellular calcium concentration. On a final note, we should add that there are many other species of cone snails and spiders that produce active toxins which selectivity inhibit specific calcium channel subtypes (for example, co-conotoxins GVIB, GVIC, GVIIA, SVIA, SVIB), and it is likely that many more remain to be discovered (Olivera et al. 1994). 

The (—) isomer of the L-type calcium channel blocker (+)-niguldipine is dexniguldipine. This agent binds to an intracellular domain of P-gp with a K, of 10 nm. In addition, this compound can block RNA synthesis at 5 pM and possesses some anticancer activity (302). Currently, only a few studies have been conducted to evaluate the use of this compound as a P-gp modulator. Definitive results are yet to be reported. 

Clozel J-P, Ertel EA, Ertel SI (1997) Discovery and main pharmacological properties of mibefradil (Ro 40-5967), the first selective T-type calcium channel blocker. J Hypertension 15(5) S17-S25... 

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