Norepinephrine indirect sympathomimetics

Absence of one or both aromatic hydroxyl groups is associated with an increase in indirect sympathomimetic activity, denoting the ability of a substance to release norepinephrine from its neuronal stores without exerting an agonist action at the adrenoceptor (p. 88). 

B) Indirect sympathomimetic effects in the periphery due to release of norepinephrine... 

Tyramine acts as an indirect sympathomimetic to cause release of catecholamines from nerve terminals. It is present in a number of foods mature cheese, yeast extracts, some red wines, hung game, pickled herrings, broad bean pods. Normally, MAO-A in the intestinal mucosa will metabolise tyramine absorbed from the gut. In patients on the older MAOls, considerable amounts of tyramine will enter the circulation and this will lead to increased release of catecholamines stored in nerve terminals because the MAOI prevents their metabolism. For patients on RIMA drugs, high concentrations of tyramine can compete for MAO-A, thus mitigating some of the effects, and MAO-B is still available to metabolise noradrenaline (norepinephrine). MAO-B, however, has relatively much less effect on 5-HT and thus 5-HT function is still enhanced. 

The pharmacologic effects of direct agonists depend on the route of administration, their relative affinity for adrenoreceptor subtypes, and the relative expression of these receptor subtypes in target tissues. The pharmacologic effects of indirect sympathomimetics are greater under conditions of increased sympathetic activity and norepinephrine storage and release. 

Indirect sympathomimetics (B) in the narrow sense comprise amphetamine-like substances and cocaine. Cocaine blocks the norepinephrine transporter (NAT), besides acting as a local anesthetic. Amphetamine is taken up into varicosities via NAT, and from there into storage vesicles (via the vesicular monoamine transporter), where it displaces NE into the cytosol. In addition, amphetamine blocks MAO, allowing cytosolic NE concentration to rise unimpeded. This induces the plasmalemmal NAT to transport Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms... 

SYMPATHOMIMETICS LINEZOLID Risk of t BP when linezolid is co-ingested with either direct or indirect sympathomimetics Linezolid causes accumulation of norepinephrine at the nerve ends sympathomimetics stimulate the release of these T reserves of norepinephrine, which in turn causes vasoconstriction and a rise in BP Monitor BP closely watch for t BP. Warn patients taking linezolid not to take OTC remedies containing sympathomimetics... 

INDIRECT TCAs 1. Methylphenidate T TCA levels, which may improve their efficacy, but cases of toxicity with imipramine have been reported 2. TCAs possibly 1 efficacy of indirect sympathomimetics 1. Uncertain postulated to be due to inhibition of the hepatic metabolism of TCAs 2. Indirect sympathomimetics cause release of norepinephrine from the nerve endings this is blocked by TCAs 1. Warn patients to watch for early signs of t TCA efficacy such as drowsiness and dry mouth 2. Watch for poor response to indirect sympathomimetics... 

Figure 10.15. Stractures of several indirect sympathomimet-ics (a), and of the functionally similar drag ecstasy (b). Norepinephrine and sertotonin are shown for comparison.

Accidental local infiltration of potent alpha agonists such as norepinephrine may lead to tissue ischemia and necrosis if not promptly reversed infiltration of the ischemic area with phentolamine is sometimes used to prevent tissue damage. Overdose with drugs of abuse such as amphetamine, cocaine, or phenylpropanolamine may lead to severe hypertension because of their indirect sympathomimetic actions. This hypertension will usually respond well to alpha-blockers. Sudden cessation of clonidine therapy leads to rebound hypertension (Chapter 11) this phenomenon is often treated with phentolamine. 

Monoamine oxidase inhibitors used in depressive disorders (phenelzine, tranylcypromine) increase the stores of norepinephrine in sympathetic nerve endings. They also inhibit the metabolism of tyramine, which at high levels in the blood can act as an indirect sympathomimetic to release norepinephrine. The answer is (L). 

Indirect sympathomimetics cause norepinephrine release from presynaptic terminals, but do not bind to adrenergic receptors (Fig. 2.5, Table 2.1B). These drugs enter the presynaptic terminal and displace stores of norepinephrine from storage vesicles. Mixed sympathomimetics displace norepinephrine from presynaptic terminals and bind to adrenergic receptors. (Fig. 2.5, Table 2.1B). 

First, the extracts of the roots of Ruscus aculeatus at higher concentrations caused their contractions of canine cutaneous veins in part because the extracts could reveal an indirect sympathomimetic effect for the inhibition to the neuronal uptake such as cocaine (40) (Figure 11) of a serotonin-norepinephrine-dopamine reuptake inhibitor [31]. Here, a selective ai-adrenergic blocker prazosin (41) and a selective a2-adrenergic blocker rauwolscine (a-yohimbine. 42) (Figure 11) are present in the canine saphenous vein [32, 33] might greatly contribute to their contractile response to the extracts of the roots of Ruscus aculeatus. 

Tyramine, the only indirect-acting compound, exhibits sympathomimetic effects by causing the release of endogenic norepinephrine, and it has only found practical use in experiments. It inactivates monoaminooxidase very quickly. It has no practical clinical use. 

Metaraminol is a sympathomimetic amine of both direct and indirect action that has hemodynamic characteristics similar to norepinephrine. It has the ability to elevate both systohc and diastolic blood pressure. 

Substitutions at the a carbon block oxidation by monoamine oxidase (MAO) and prolong the action of such drugs, particularly the noncatecholamines. Ephedrine and amphetamine are examples of -substituted compounds (Figure 9-5). Alpha-methyl compounds are also called phenylisopropylamines. In addition to their resistance to oxidation by MAO, some phenylisopropylamines have an enhanced ability to displace catecholamines from storage sites in noradrenergic nerves (see Chapter 6). Therefore, a portion of their activity is dependent on the presence of normal norepinephrine stores in the body they are indirectly acting sympathomimetics. 

As noted previously, indirect-acting sympathomimetics can have one of two different mechanisms (Figure 9-3). First, they may enter the sympathetic nerve ending and displace stored catecholamine transmitter. Such drugs have been called amphetamine-like or "displacers." Second, they may inhibit the reuptake of released transmitter by interfering with the action of the norepinephrine transporter, NET. 

Sympathomimetics (indirect-acting) [HP] Hypertensive episode due to release of stored norepinephrine (amphetamines, ephedrine, isometheptene, phenylpropanolamine, pseudoephedrine). 

Tachyphylaxis refers to a quickly developing tolerance brought about by the rapid and repeated administration of drugs. For example, indirect-acting sympathomimetic agents such as tyramine, which exert their effects through the release of norepinephrine, are able to cause tachyphylaxis. If norepinephrine is not present, tyramine fails to act until the supply of norepinephrine in nerve terminals has been replenished (Figure 3.3). 

Sympathomimetics act directly on receptors at nerve endings (direct acting) or indirectly by stimulating the release of norepinephrine from the nerve terminals (indirect acting), Some act by both mechanisms (mixed), For the purposes of this section, mixed sympathomimetics will be considered as direct acting,... 

As of the mid-1990s, use of MAOIs for the treatment of depression is severely restricted because of potential side effects, the most serious of which is hypertensive crisis, which results primarily from the presence of dietary tyramine. Tyramine, a naturally occurring amine present in cheese, beer, wine, and other foods, is an indirectly acting sympathomimetic, that is, it potently causes the release of norepinephrine from sympathetic neurons. The norepinephrine that is released interacts with adrenoceptors and, by interacting with OC-adrenoceptors, causes a marked increase in blood pressure the resultant hypertension may be so severe as to cause death. 

When this enzyme is inhibited, the concentrations of norepinephrine within adrenergic neurons increase and drugs that stimulate its release can bring about an exaggerated response. Interactions between MAO inhibitors and indirectly acting sympathomimetic amines (e.g., amphetamine) develop by this mechanism. If amphetamine is administered to a patient whose stores of norepinephrine have been increased by MAO inhibition, the patient may experience severe headache, hypertension (possibly a hypertensive crisis), and cardiac arrhythmias. The serious consequences associated with these interactions contraindicate the use of these agents in combination. 

Indirect-acting Sympathomimetics Stimulate the release of norepinephrine from terminal nerve endings... 

The cause of the mydriatic action of cocaine is obscure. It is well known that cocaine potentiates the action of epinephrine (e.g., on blood pressure) and of other sympathomimetic amines which contain the catechol nucleus (62). It is also known that cocaine inhibits amine oxidase (63) so that it is tempting to attribute the mydriatic action of cocaine to the inhibition of this enzyme, which occurs in the iris (54) and is known to catalyze the oxidation of the sympathetic transmitter. At the same time it must be admitted that amine oxidase may not be the only enzyme concerned in the destruction of norepinephrine and epinephrine liberated at the peripheral endings of sympathetic nerves (64). All that can be said is that the sympathomimetic effects of cocaine, like mydriasis, are almost certainly not due to a direct action on effector cells resembling that of epinephrine and norepinephrine, since cocaine is ineffective on sympathetically denervated structures. It would seem that cocaine achieves mydriasis by some indirect action, and the likeliest explanation is that it inhibits some enzyme system concerned with the inactivation of the sympathetic transmitter. 

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