Ipecac emetine

Ipecac is prepared from the dried roots and rhizomes of Cephaelis ipecacuanha (Brot.) A. Rich, and contains the alkaloids emetine [483-18-1] (17) and cephaeJine [483-17-0] (18) in a ratio between 2 1 and 4 1. It has been used extensively in cough preparations and is beheved to act by gastric reflex stimulation. Toxic effects include vomiting, irritation of the gastrointestinal tract, and cardiac arrhythmias (19). Ipecac symp is available over-the-counter in the United States only in 30-mL containers for use as an emetic in treating poisonings. 

The most widely used emetic is syrup of ipecac, containing the alkaloids, emetine and cq haeline. Emetine induces vomiting by activation of sensory neurons in the vagus and sympathetic nerves to the stomach and centrally in the medulla, possibly at the CTZ. The release of serotonin and SP may be involved as 5-HT3 and NKi receptor antagonists prevent emesis induced... 

Ipecac syrup is prepared from the dried rhizome and roots of Cephaelis ipecacuanha or Cephaelis acuminata, plants from Brazil and Central America that have the alkaloid emetine as their active principal ingredient. It acts directly on the CTZ and also indirectly by irritating the gastric mucosa. Ipecac is cardiotoxic if absorbed and can cause cardiac conduction disturbances, atrial fibrillation, or fatal myocarditis. If emesis does not occur, gastric lavage using a nasogastric tube must be performed. 

The antidiarrhoeal drug ipecac, which was introduced into Europe from Brazil in 1658, contains the amoebicidal alkaloids emetine (12) and cephaeline. Emetine remained the major remedy for amoebic dysentery and amoebic hepatitis for many years. Cephaeline is less active and more toxic. ( j-2-Dehydroemetine, which is made by synthesis, is equiactive with (—)-emetine and less toxic, but other chemical modification has not yielded better amoebicides. From investigations of synthetic routes to the benzoquinolizine moiety the tranquilizer tetrabenazine (13a) was discovered. The very similar compound benzquinamide (13b) is also a tranquilizer and antiemetic. 

Ipecac contains 2-2.5% of alkaloids, the principal ones being emetine and cephaeline (Figure 6.67). Typically, in C. ipecacuanha the emetine to cephaeline ratio might be about 2 1, whereas in C. acuminata the ratio ranges from about 1 2 to 1 1. Minor alkaloids characterized include psychotrine and O-methylpsychotrine (Figure 6.68), which are dehydro variants of cephaeline and emetine respectively. 

When the heart can no longer pump an adequate supply of blood to meet the metabolic needs of the tissues or in relation to venous return, cardiac failure may ensue. The causes of cardiac failure are complex, but stem from mechanical abnormalities (e.g., pericardial tamponade), myocardial failure (e.g., cardiomyopathy and inflammation), and arrhythmias. In high-output failure, the cardiac output, which may be normal or even higher than normal, is not sufficient to meet the metabolic requirement of the body. Cardiac failure may predispose a patient to congestive heart failure, which is a state of circulatory congestion. Toxic injury, caused by agents such as doxorubicin, the alkaloid emetine in ipecac syrup, cocaine, or ethyl alcohol, is another way by which the functional integrity of the heart may also be compromised. 

Ipecac, the root of a Brazilian plant, contains several alkaloids of which two, emetine and cephaeline, produce local irritation and nausea and emesis, by central and local action, without danger of side effects. 

Ipecac is the root of Cephaetis ipecacuanha, or of C. acuminata, a perennial shrub growing in Brazil and other South American states (Figure 44.1). It contains three alkaloids — emetin, cephaelin, and psychotrin. The dose of the powdered drug as an expectorant is from 1/2 to 2 grain (0.03 to 0.13 g) as an emetic, 15 to 30 grain (1.0 to 2.0 g) (Table 44.1). 

Ipecac ( Brazil root ) was long employed by the native people of Brazil in the treatment of diarrhea. It was sold as a secret remedy to the French government in 1658, and its use in dysentery rapidly spread throughout Europe and India. Its employment was entirely empirical until 1912 when Vedder demonstrated the in vitro efficacy of emetine against E. histolytica and suggested that ipecac be used in amebic infections. The source of ipecac is the dried root or rhizome of C. ipecacuanha or C. acuminata, plants native to Brazil and Central America, but also cultivated in India, the Straits Settlements, and the Federated Malay States (see Grollman, 1962). 

Emetine was first described in 1817 by Pelletier, the discoverer of quinine. However, Pelletier was actually dealing with a mixture of the alkaloids of ipecac, that is, emetine, cephaeline, and psychotrine (see Grollman, 1962). 

The efficacy of ipecac in amebic infections depends upon its content of alkaloids, the principal ones being emetine and cephaeline. Both are amebicidal, but emetine is much more active. Cephaeline is more toxic than emetine, except for the heart, and causes more nausea and vomiting. Emetine constitutes more than one half of the total alkaloidal content of ipecac. 

Note The most commonly used emetics are ipecac and apomorphine. Induced emesis is the preferred means of emptying the stomach in awake patients who have ingested a toxic substance or have recently taken a drug overdose. Emesis should not be induced if there is central nervous system depression or ingestion of certain volatile hydrocarbons and caustic substances. Ipecac syrup is prepared from the dried rhizome and roots of Cephaelis ipecacuanha or of C. accuminata, plants from Brazil and Central America, in which the alkaloid emetine is its active principal ingredient. 

Emetine, an alkaloid derived from ipecac, and dehydroemetine, a synthetic analog, are effective against tissue trophozoites of E histolytica, but because of major toxicity concerns they have been almost completely replaced by metronidazole. The drugs are administered parenterally because oral preparations are absorbed erratically. They accumulate in tissues and are eliminated slowly via the kidneys. 

During the period from 1983 to 1991 there has been a continual decline in the use of syrup of ipecac to induce emesis. Ipecac contains a number of plant alkaloids including emetine. It induces emesis through stimulation of the chemoreceptor trigger zone in the brain and local irritation of the gastrointestinal tract. The latency period for... 

Emetine [EM e teen] and dehydroemetine [de hye dro EM e teen] are alternate agents for the treatment of amebiasis. They inhibit protein synthesis by blocking chain elongation1. Intramuscular injection is the preferred route. Emetine is concentrated in the liver where it persists for a month after a single dose. It is slowly metabolized and excreted and can accumulate. Its ty2 is 5 days. The use of these ipecac alkaloids is limited by their toxicities. Dehydroemetine is probably less toxic than emetine. Close clinical observation is necessary when these drugs are used. Among the untoward effects are pain at the site of injection, transient nausea, cardiotoxicity (e.g., arrhythmias, congestive heart failure), neuromuscular weakness, dizziness, and rashes. 

Emetine in A Emetine in B Cephaeline in A Cephaeline in B Psychotrine in A Alkaloids in A Ipecac alkaloids in B Emetine Emetine in A Emetine in B Emetine in C Cephaeline Cephaeline in A Cephaeline in B Emetine Emetine Emetine in B Ipecac alkaloids in B Emetine Emetine in A Emetine in B Cephaeline Emetine Emetine in A Emetine in B Cephaeline in A Emetine Emetine in B Emetine in C Cephaeline... 

The monoterpene isoquinoline alkaloids are constituents of the genus Cephaelis and selected other Rubiaceae species. C. ipecacuanha (ipecac) is a powerful emetic whose active principle is emetine, derived through the condensation of dopamine and secologa-nin (Fig. 33). Emetine is also a powerful amebicide, antiviral, and inhibitor of protein synthesis. It is now largely replaced by synthetic dehydroemetine. 

Emetine and Dehydroemetine. Tlic alkaloids emetine and dehydroemetine are obtained by separation from extracts of ipecac. They occur as Icvorotatnry. light-.sensitivc white powders that are insoluble in water. The alkaloids readily farm water-soluble salts. Solutions of the hydnx hlo-ridc salts intended for intramu.scular injection shnuld be adjusted tn pH 3.5 and. stored in light-resistant containers. 

The root of the ipecac is commonly used as an expectorant in the treatment of bronchitis, croup, asthma amoebacide and whooping cough, as an emetic in cases of poisoning, and an amoebacide in amoebic dysentery. It has appeared in the Japanese Pharmacopoeia (2001) as ipecac, powdered ipecac and ipecac S)nxip [6]. The ipecac is rich in isoquinoline alkaloids such as emetine, cephaeline, psychotrine. 

Various kinds of ipecac contain different proportion of the principal alkaloids. The Rio variant (C. ipecacuanha) contains 2-4% dry weight alkaloids of which 60-75% is emetine. The varieties derived from C. acuminata yield 2-3.5% dry weight alkaloids, which may contain 30-50% emetine [4]. Thus C. ipecacuanha is regarded as the best source of ipecac. 

The supply of ipecac has fluctuated for many years because it is collected mainly from wild habitat. The Rio variant is now becoming difficult to obtain commercially, and the high price favors cultivation, but only modest success has been achieved from the efforts made to grow the plant in Malaya and India. The ipecac used in Japan is imported from abroad at a rate of 100%, consequently giving variation of alkaloid value and ratio of emetine and cephaeline [10]. 

Ipecac contains many isoquinoline alkaloids as mentioned above and the value of the regenerated plants through tissue culture greatly depends on their phytochemical similarities to the crude drug. Therefore, improved HPLC system for the analysis of the isoquinoline alkaloids, not only emetine and cephaeline but also minor constituents, was investigated [19]. 

Although the ion pair HPLC for emetine and cephaeline using sodium 1 -heptanesulfonate as a counter ion and methanol for a mobile phase was previously reported [20], compounds other than emetine and cephaeline in the leaf extract of ipecac were not well-separated. Therefore, a different type of ODS column, TSK gel ODS-120A column (4.6 mm i.d. x 250 mm, TOSOH Co., Japan) was selected because it previously provided a good separation of the tropane alkaloids [21-23] and the Papaver alkaloids [24]. 

In order to determine the rate of recovery, accurate amounts of emetine and cephaeline were added to the medium used for root culture where the adventitious roots of ipecac were cultured for 8 weeks and then extracted as follows twenty ml medium was mixed with 200 pi 10% ammonium hydroxide and 6 ml diethylether in a test tube for 5 min using vortex mixer. Four ml upper layer was accurately taken and concentrated under a stream of nitrogen gas. The extract was dissolved in an appropriate volume of methanol and quantitatively analyzed by HPLC. The HPLC system gave good recovery 104.4% for emetine and 104.8% for cephaeline (Table 6). 

Leaves of the ipecac regenerated plant were extracted and subjected to HPLC. As shown in Fig. (11), good separation of the peaks, protoemetine, cephaeline and emetine and also of other components was obtained and the peaks corresponding to protoemetine, cephaeline and emetine were confirmed by evaluating their UV spectra using a photodiode array detector. 

A one-year-old Cephaelis ipecacuanha plant propagated through shoot-tip culture (section 1.1) in a greenhouse accumulated ca. 2 mg emetine and ca. 2 mg cephaeline, respectively, in its roots ca. 0.2 g total dry weight). On the other hand, the root culture of ipecac cultured for 7 weeks in 50 ml MS medium containing 0.01 mg/1 5,6-Cl2-IAA yielded almost the same amounts of alkaloids, 0.6 mg emetine and 2.4 mg cephaeline. Thus the root culture of ipecac is a realistic economic source of the isoquinoline alkaloids. 

Ipecac alkaloids were extracted and analyzed by HPLC as previously reported [section 1.2]. Two flasks were used for each culture condition. The contents of isoquinoline alkaloids, protoemetine, cephaeline and emetine in the transformed roots, are shown in Fig. (54). 

The isoquinoline alkaloid contents in the transformed and non-transformed plants are indicated in Table 16. Alkaloid contents in the leaves were higher than those in the roots despite transformation. Cephaeline was the major alkaloid in all parts of in vitro plants as well as the root cultures. Alkaloid contents in the transformed plants, both in the leaves and roots, were lower than those of non-transformed plants except emetine in the roots. Any advantageous effects of T-DNA integration into ipecac on the alkaloid accumulation in the regenerated plants were not observed as previously reported for Duboisia hybrid [79] and Hyoscyamus muticus [103]. 

Syrup of ipecac is available as a nonprescription product in many countries. It is derived from the dried rhizome and roots of the Cephaelis ipecacuanha or Cephaelis acuminata plant. These plants contain the potent emetic alkaloids emetine and cephaeline, which induce vomiting by both direct local gastrointestinal effects and central nervous system actions. Emesis following syrup of ipecac ingestion typically occurs within 20 min of ingestion and persists for 30-120 min. 

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