Emetic effect

Thehaine stands at the other end of the series from morphine and is a convulsant poison rather than a narcotic (see table, p. 261). Hildebrandt states that it excites the reflexes of cold-blooded animals but in dogs it exerts a narcotic and anti-emetic effect resembling that of morphine rather than that of chloromorphide. The alkaloid is scarcely used in medicine as such, but is a primary material for the preparation of certain of the modern morphine derivatives, such as hydroxydihj dro-codeinone and methyldihydromorphinor.e. 

Figure 15.5 Counteracting the emetic effect of (a) levodopa and (b) a dopamine agonist in the therapy of PD.

The answer is c. (Hardman, pp 932—933.) Metoclopramide antagonizes the emetic effect of apomorphine, which is mediated by a dopamine... 

The well-known emetic effect of ergot alcaloids in dogs was particularly pronounced with bromocriptine, even with oral doses of as low as 0.1 mg/kg. 

Foss JF, Bass AS, Goldberg LI. (1993) Dose-related antagonism of the emetic effect of morphine by methylnaltrexone in dogs. J Clin Pharmacol 33 747-751. 

The emetic effect disappears with repeated use because a direct inhibition of the emetic center then predominates, which overrides the stimulation of area postrema chemoreceptors. 

Opioids depress respiration via the ji2-receptor at the level of the medulla and thereby increase PCO2. Opioids reduce respiration, an effect that is fatal in the case of overdose, by a dual action. The opioids decrease both the sensitivity of the medulla to carbon dioxide concentrations and the respiratory rate. Cardiovascular function and the response to hypoxia are not compromised. By contrast, tolerance to the respiratory depressant effects of the opioids does not appear to occur, while tolerance to the emetic effects of the opioids occurs upon repeated administration. The area postrema chemoreceptor trigger zone of the medulla mediates opioid-induced vomiting. 

All of the opioid agonists produce some degree of tolerance and physical dependence. The biochemical mechanisms underlying tolerance and physical dependence are unclear. It is known, however, that intracellular mechanisms of tolerance to opioids include increases in calcium levels in the cells, increased production of cAMP, decreased potassium efflux, alterations in the phosphorylation of intracellular and intranuclear proteins, and the resultant return to normal levels of release of most neurotransmitters and neuromodulators. Tolerance to the analgesic effects of opioids occurs rapidly, especially when large doses of the drugs are used at short intervals. However, tolerance to the respiratory depressant and emetic effects of the opioids occurs more slowly. The miotic and constipative effects of the opioids rarely show tolerance. 

Rapidity of recovery has been one of the most consistent and compelling features of anaesthesia with xenon. After 2 hours of xenon anaesthesia recovery is two to three times as fast as recovery from equi-MAC mixtures of N20/sevoflurane and N20/isoflurane. Marked emetic effects after both nitrous oxide and xenon were reported in a volunteer study, but this was conducted under highly artificial conditions. 

Many of the drugs used in modern anaesthetic practice have an effect on the CT7 and vomiting centre either directly or indirectly, e.g. stimulation of the vestibular apparatus, stimulation of the CTZ by opioid agonist drugs, and an anti-emetic effect of propofol or emetogenic effect of nitrous oxide. Propofol... 

There is good evidence that propofol exerts an anti-emetic effect. The mechanism of this is unclear, but animal studies have shown that it may involve depleting the area postrema of serotonin as well as direct GABA-mediated inhibition, or inhibition of dopamine release in the brain. This probably requires a plasma concentration of over 350 ng-mL-1, and therefore will be seen when propofol is used as an induction agent for very short cases, or when it is used as an infusion in longer cases. Nitrous oxide... 

Chlorpromazine has direct effects on the CTZ and may also depress temperature control and prevent shivering. The effects are due to inhibition of dopamine centrally. It may potentiate the effects of hypnotics, sedatives and anaesthetic agents. It is rarely used in anaesthetic practice today. Promethazine was first developed for its antihistamine effects but is more commonly used for its sedative/anticholinergic, anti-emetic actions, and prevention of motion-related sickness. The sedative actions are quite marked and last longer than the anti-emetic effects. 

Perphenazine is now only available in oral formulation. It is used less and less in anaesthetic practice, usually given with premedication (2-4 mg, 1-2 h pre-operatively). The anti-emetic effects are well recognised but there may be marked sedation. It has a role in anxiety states and in the management of psychiatric cases. 

Trifluoperazine has potent anti-emetic effects but also causes marked sedation and extrapyramidal effects and is not used commonly as an anti-emetic. 

Metoclopramide is structurally related to orthoclopramide, a procaine derivative, and it can prolong the action of suxamethonium because of competition for cholinesterase. However, its common side effects are similar to those seen with phenothiazine derivatives. In high doses, a range of extrapyramidal symptoms may develop. The anti-emetic effects of metoclopramide are due to two main actions. Centrally, it blocks dopamine in the CTZ and peripherally, it hastens gastric emptying, abolishes irregular intestinal contractions, and increases... 

Cyclizine has antimuscarinic properties and is a potent anti-emetic, effective for the control of postoperative and drug-induced nausea and vomiting. It has been used to prevent motion sickness, although diphenhydramine and promethazine are more effective. It is available in oral and parenteral formulations. In contrast to many other first-generation antihistamines sedation is not marked. It is available in tablet form as the hydrochloride and in injectable form as the lactate. Because of its anticholinergic action, blurred vision and dry mouth are associated with clinical doses. When given by rapid intravenous injection tachycardia may be a problem. Meclozine is a related drug which, like cyclizine, is used primarily for motion sickness. 

When levodopa is given without a peripheral decarboxylase inhibitor, anorexia and nausea and vomiting occur in about 80% of patients. These adverse effects can be minimized by taking the drug in divided doses, with or immediately after meals, and by increasing the total daily dose very slowly antacids taken 30-60 minutes before levodopa may also be beneficial. The vomiting has been attributed to stimulation of the chemoreceptor trigger zone located in the brain stem but outside the blood-brain barrier. Fortunately, tolerance to this emetic effect develops in many patients. Antiemetics such as phenothiazines should be avoided because they reduce the antiparkinsonism effects of levodopa and may exacerbate the disease. 

Nausea and emesis are common unpleasant side-effects of opioids (Campora et al., 1991 Aparasu et al., 1999). They are most intensively experienced at the beginning of the treatment. During chronic administration, tolerance may occur, which reduces the emetic sequelae. Nausea and emesis are induced via activation of chemoreceptors which are located in the trigger zone of the area postema of the formatio reticularis. The receptors are at the tissue surface and in contact with the circulating blood. Thus the emetic effect of opioids is not mediated centrally, i.e. after penetration of the blood-brain barrier, but rather peripherally via the amount of the compound, which is distributed in the circulating blood. 

After passage through the blood brain barrier, opioids have an anti-emetic effect (Blancquaert et al., 1986). Emesis inhibition is induced via blockade of an emesis centre located in a more central area of the formatio reticularis. This explains why the emetic effect of opioids is most apparent immediately after anministration, especially after rapid intravenous administration and is reduced or terminated when the compound has reached the CNS. The more hydrophilic opioids like morphine have stronger emetic side-effects than lipophilic compounds like methadone or fentanyl (Barnes et al., 1991), which are rapidly transported into the CNS. 

Opioids in the circulating blood induce nausea and emesis and an anti-emetic effects after penetration of the blood brain barrier... 

Emetics are used to induce vomiting and are frequently administered to help empty the stomach of poisons or ingested toxins. The two primary emetics are apo-morphine and ipecac. Both agents seem to work by stimulating the medullary emetic center, and ipecac also exerts a direct emetic effect on the stomach. 

The required properties of such an agent Included (1) selectivity for peripheral vascular dopaminergic receptors versus < -and 6-adrenerglc receptors which could mediate pressor and cardiac effects, (2) absence of central dopaminergic and emetic effects, and (3) potent oral renal vasodilator effects. Dopamine has been associated with diuresis and natriuresls. Possible mechanisms include a direct tubular effect on sodium transport, indirect effects produced by changes in total or regional renal blood flow, or effects resulting from a dopamine Induced decrease in aldosterone release from the adrenal (9). Since diuretics play a key role in antihypertensive therapy, the addition of a natriuretic/diuretic component to the renal vasodilator profile would be valuable and appeared to be feasible. 

The introduction of bromine in the hydrogenated derivatives of the ergotoxine alkaloids (Hydergine) reduces their adrenolytic properties, but the central hypotensive effects remain intact (Fig. 8a). The other central effects, particularly the emetic effect, and toxicity are decreased. 

The emetic effect of high doses of milnacipran may reduce the risk of serious adverse effecfs... 

Trichothecenes can be absorbed through the gastrointestinal tract, the lungs, and the skin (Madsen, 2001). Most of the information on toxicokinetics is based on i.v. administration because of the powerful emetic effects of these toxins. Limited information is available on oral and inhalation routes of exposure. Inhalation would be the most likely route of exposure for weaponized mycotoxins... 

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