Of phenylephrine

Release from intracellular pools Hormonal stimulation of Phenylephrine 254 ... 

DS Chien, RD Schoenwald. (1986). Improving the ocular absorption of phenylephrine. Biopharm Drug Disp 7 453-462. 

MVW Bergamini, DL Murray, PD Krause. (1979). Pivalyl phenylephrine (PPE), a mydriatic prodrug of phenylephrine with reduced cardiovascular effects. Invest Ophthalmol Vis Sci 20 187. 

FIG. 2. Mechanism of phenylephrine (PE)-mediated wave-like [Ca2+] oscillations in the rabbit inferior vena cava. (A) PE-mediated [Ca2+]j oscillations are completely inhibited by 10 fiM cyclopiazonic acid (CPA), but the average [Ca2+ ]j remains elevated. (B) PE-mediated [Ca2+]j oscillations are abolished by 75 /iM 2-aminoethoxydiphenyl borate (2-APB). (C) Application of 10 piM nifedipine (Nif) reduced the frequency of PE-mediated [Ca2+]j oscillations while additional application of SKF96365 (SKF) completely abolished the remaining [Ca2+] oscillations. (D) Application of 100 /iM 2,4-dichlorobenzamil (2,4-DCB) completely inhibited nifedipine-resistant PE-induced [Ca2+]j oscillations and lowered the [Ca2+]j to a level that is slightly higher than baseline. Additional application of SKF96365 returned the [Ca2+]j level to baseline. (Experimental traces reproduced with permission from Lee et al 2001.)... 

Lee CH, Poburko D, SahotaP, Sandhu J, Ruehlmann DO, van Breemen C 2001 The mechanism of phenylephrine-mediated [Ca2+] oscillations underlying tonic contraction in the rabbit inferior vena cava. J Physiol 534 641-650... 

Dissolve 0.25 g of phenylephrine hydrochloride in water to make 8.9 mL of an isotonic solution, and adjust the preparation to 50 mL with isotonic boric acid solution. 

This synthetic drug has both chemical and pharmacological similarities to norepinephrine. A characteristic quality of phenylephrine is the distinctly expressed selectivity to a-adrenoreceptors, especially aj-adrenoreceptors. Although phenylephrine increases the contractibility of blood vessels, in practical terms it is not considered a cardiostimulant. 

Carvedilol also (1) attenuates the pressor effects of phenylephrine, (2) causes vasodilation, and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration. 

When the base is in the form of a salt of a weak acid, removal of an anionic counter ion prior to titration is not necessary, e.g. for salts of bases with weak acids such as tartrate, acetate or succinate. However, when a base is in the form of a chloride or bromide salt, the counter ion has to be removed prior to titration. This is achieved by addition of mercuric acetate the liberated acetate is then titrated with acetous perchloric acid. This is illustrated in Figure 3.9 for the example of phenylephrine.HCl. 

The chromophore of phenylephrine is not extended but its structure includes a phenolic hydroxyl group. The phenolic group functions as an auxochrome under both acidic and alkaline conditions. Under acidic conditions it has two lone pairs of electrons, which can interact with the benzene ring and under basic conditions it has three. Figure 4.11 shows the bathochromic and hyperchromic shift in the spectrum of phenylephrine, which occurs when 0.1 M NaOH is used as a solvent instead of 0.1 M HCl. Under acidic conditions the X max is at 273 and has an A (1 %, 1 cm) value of 110 and under alkaline conditions the X max is a 292 nm and has an A (1%, 1 cm) value of 182. 

UV spectrum of phenylephrine under acidic and basic conditions. 

Assign the protons in the H NMR spectrum of phenylephrine. (Note protons B and C are non-equivalent since they are next to an asymmetric centre). 

Pharmacokinetics Phenylephrine is irregularly absorbed from and readily metabolized in the GI tract. After IV administration, a pressor effect occurs almost immediately and persists for 15-20 minutes. After IM administration, a pressor effect occurs within 10-15 minutes and persists for 50 minutes to 1 hour. After oral inhalation of phenylephrine in combination with isoproterenol, pulmonary effects occur within a few minutes and persist for about 3 hours. The pharmacologic effects of phenylephrine are terminated at least partially bythe uptake of the drug into the tissues. Phenylephrine is metabolized in the liver and intestine by the enzyme monoamine oxidase (MAO). The metabolites and their route and rate of excretion have not been identified. 

Vasoconstriction in regional anesthesia IV The manufacturer states that the optimum concentration of phenylephrine HCl is 0.05 mg/ml (1 20,000). Solutions maybe prepared for regional anesthesia by adding 1 mg of phenylephrine HCl to each 20 ml of local anesthesia solution. Some pressor response can be expected when at least 2 mg is injected. 

Cycloplegia Topical One drop of the preferred cycloplegic is placed in each eye, followed in 5 minutes by one drop of phenylephrine HCl 2.5%. 

Blanching test Topical One or two drops of phenylephrine HCl 2.5% should be applied to the injected eye. 

Contraindications Ophthalmic solutions (both strengths) of phenylephrine HCl are contraindicated in patients with anatomically narrow angles or narrow-angle glaucoma, severe arteriosclerotic cardiovascular or cerebrovascular disease, use during intraocular operative procedures when the corneal epithelial barrier has been disturbed, and in persons with a known sensitivity to phenylephrine, sulfites, or any of its components including preservatives. The 10% solution is contraindicated in patients with aneurysms. 

There have been reports associating the use of phenylephrine HCl 10% ophthalmic solutions with the development of serious cardiovascular reactions, including ventricular arrhythmias and myocardial infarctions. These episodes, some ending fatally, have usually occurred in patients with preexisting cardiovascular diseases. 

Effects of autonomic blockade on the response to phenylephrine (Phe) in a human subject. Left The cardiovascular effect of the selective K-agonist phenylephrine when given as an intravenous bolus to a subject with intact autonomic baroreflex function. Note that the increase in blood pressure (BP) is associated with a baroreflex-mediated compensatory decrease in heart rate (HR). Right The response in the same subject after autonomic reflexes were abolished by the ganglionic blocker trimethaphan. Note that resting blood pressure is decreased and heart rate is increased by trimethaphan because of sympathetic and parasympathetic withdrawal. In the absence of baroreflex buffering, approximately a tenfold lower dose of phenylephrine is required to produce a similar increase in blood pressure. Note also the lack of compensatory decrease in heart rate. 

Gan XT, Rajapurohitam V, Haist JV, Chidiac P, Cook MA, Karmazyn M (2005) Inhibition of phenylephrine-induced cardiomyocyte hypertrophy by activation of multiple adenosine receptor subtypes. J Pharmacol Exp Ther 312(1) 27—34 Gardner NM, Yates L, Broadley KJ (2004) Effects of endogenous adenosine and adenosine receptor agonists on hypoxia-induced myocardial stunning in guinea-pig atria and papillary muscles. J Cardiovasc Pharmacol 43(3) 358-368... 

Wang and Porter [92] resolved the enantiomers of oxazepam, lorazepam, and temazepam using /1-cyclodextrin as the CMPA by CEC. The authors varied separation parameters such as voltage and mobile phase. Wei et al. [93] resolved the enantiomers of phenylephrine and synephrine by varying the concentration of /1-cyclodextrin (CMPA), pH, electrolyte concentration, and temperature. Lelievre et al. [99] separated the enantiomers of chlorthalidone using hydroxypropyl /1-cyclodextrin as the CMPA. Lammerhofer and Lindner [90] resolved the enantiomers of N-derivatized amino acids (e.g., 3,5-dinitrobenzoyl, 3,5-dinitro-benzyloxycarbonyl, 2,4-dinitrophenyl, and 9-fluorenylmethoxycarbonyl amino... 

Phenylephrine and entry 1, 30 and 10p,g/kg, respectively, were introduced into the vena femoralis through a polyethylene cannula. Compared with phenylephrine, the experimental agent exhibited a potency factor 2.73 times greater with regard to the contraction of the urethra and with a duration longer by a factor of 4.3. Moreover, the increase in blood pressure associated with entry 1 was only 1.39 times that of phenylephrine. Testing results are provided in Table 2. 

Tricyclic antidepressants act on both presynaptic and postsynaptic neurons, as well as on alpha- and beta-adrenoceptors. Because their principal action is to block the re-uptake of noradrenaline at the presynaptic neuron, they potentiate the hypertensive effects of both directly acting and indirectly acting amines (158,159). The hypertensive effects of phenylephrine are increased by a factor of 2-3, and of noradrenaline by a factor of 4-8. Even the administration of local anesthetics containing noradrenaline as a vasoconstrictor has proven fatal. The types of... 

Three patients developed priapism after taking cocaine or non-prescription weight loss formulations containing ephedrine (216). Intracavemous injection of phenylephrine and irrigation with heparinized saline, followed by an Al-Ghorab shunt procedure, was effective. 

SYMPATHOMIMETICS ANTIMUSCARINICS -ATROPINE Reports of hypertension when atropine was given to patients receiving 10% phenylephrine eye drops during eye surgery Atropine abolishes the cholinergic response to phenylephrine-induced vasoconstriction Use a lower concentration of phenylephrine... 

Figure 10.6. Effects of adrenergic agonists on the heart rate (A) and the systolic (0) and diastolic ( ) blood pressure in an anesthe-sizeddog. a Absolute values after application of phenylephrine b, c, d, differences relative to time zero after application of the respective drags.

Whitson JT, Love R, Brown RH, et al. The effect of reduced eyedrop size and eyeUd closure on the therapeutic index of phenylephrine.AmJ Ophthalmol 1993 115 357-359. 

Previous studies have shown that accommodation mediated via ciliary smooth muscle activity also receives sympathetic innervation. Sympathetic nerves reach the ciliary muscle through the uveal blood vessels in close association with arteries and terminal arterioles. The distribution of the adrenergic fibers in the ciliary muscle appears to vary across species. In primates sympathetic nerve terminals, mainly 3 receptors, can generally be found in the anterior portion of the ciliary muscle. The accommodative amplitude significantly decreased in human subjects after instillation of phenylephrine (an a agonist) or hydroxyamphetamine (an a and (3 agonist). Such observations provide evidence that both sympathetic and parasympathetic divisions of the autonomic nervous system can affect accommodation but not equally. Furthermore, the nature of sympathetic innervation can be summarized as follows ... 

Unintended local and systemic consequences can be caused by the topical instillation of phenylephrine (Table 8-2). 

In patients over age 50 years phenylephrine has been observed to cause a reboimd miosis the day after drug administration. Moreover, the instillation of phenylephrine at that time causes a diminished mydriatic response. Similarly, with long-term use of the drug reduced dilation can occur, which makes long-term frequent use clinically imsatisfectory. In addition, long-term use of phenylephrine at low concentrations for ocular vasoconstriction can result in rebound congestion of the conjunctiva. 

Systemic Effects. Ocular administration of phenylephrine has been reported to induce acute hypertension (see Table 8-2). Sixty patients were studied after three applications of the 10% solution in each eye at 10-minute intervals.Thirty minutes after the last drop, systolic elevations of 10 to 40 mm Hg and diastolic elevations of 10 to 30 mm Hg occurred in all subjects. In each case pulse rate decreased 10 to 20 beats per minute. In contrast to these observations, however, other investigators reported a lack of systemic vasopressor response with the 10% concentration. 

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