Pharmacotherapeutics of Metoclopramide and Co-danthramer Drugs - Assignment Example

? Pharmacotherapeutics of Metoclopramide and Co-danthramer drugs Introduction The major aim of this paper was to explore various aspects related to the Pharmacotherapeutics of Metoclopramide 10mg and co-danthramer drugs on the patient with nausea and constipation as well as with gastric cancer. The patient condition can be probably be managed with these two drugs. By definition, constipation is a usual gastrointestinal problem that involves difficulties in stools passage or infrequent bowel movements. While on the other hand, nausea is a stomach uneasiness which normally arises prior to vomiting. Vomiting is the forcible involuntary or voluntary stomach contents emptying ("throwing up") through the mouth (Schnell F, 2003) .However vomiting, nausea and constipation might be as a result of gastric cancer related complications that the patient had. To really understand how this condition of the patient can be managed or treated, the Pharmacotherapeutics of these two suggested drugs has been discussed in detail. Metoclopramide 10mg is used in the treatment of vomiting, Digestive disorders, Nausea and Migraine. Metoclopramide increases the muscles contractions or movements in the intestines and stomach (Schnell F. 2003). These results to a decrease in the duration the stomach contents take to move through the digestive tract. On the other hand, Co-danthramer suspension and capsules have 2 active ingredients, Poloxamer 188 and Dantron. Both of these drugs are referred to as laxatives. Hence in combination it is called co-danthramer. Dantron is laxative type referred to as stimulant laxative. It acts by nerve endings stimulation in the intestines walls. This results to intestinal wall muscles to contract frequently with increased force. The gut’s contents are moved along the intestines as a result of these muscles contraction, hence relieving constipation. Poloxamer 188 is referred to as faecal softener. It aids in drawing water into the faecal material, hence the water content and stools volume is increased. This makes it easier and softer to pass. Therefore these drugs best suit the treatment of this patient condition and its Pharmacotherapeutics have been explored in the next section. Pharmacotherapeutics of Metoclopramide and Co-danthramer Pharmacokinetics of Metoclopramide Metoclopramide is well and rapidly absorbed. Relative to 10 mg intravenous dose, the absolute oral Metoclopramide bioavailability is 80% ± 15.5% (Baxter Healthcare Corporation, 2010) .This was indicated in a crossover study which had 18 subjects. Concentrations of Peak plasma are experienced at approximately 1 - 2 hours following a single oral dose. It is also observed that same time to peak can be experienced at steady state following individual doses (Baxter Healthcare Corporation, 2010). According to a single dose study carried out on 12 subjects, it was observed that the area under the drug concentration-time curve linearly increased with doses to 100 mg from 20(Jordan et al, 2004). This means that the Concentrations of Peak linearly increase with dose, but time concentrations of peak don’t change; whole body clearance doesn’t change; and the rate of elimination doesn’t change (remains the same) (Jordan et al, 2004). In normal renal function individuals, the half-life of average elimination is 5 - 6 hours. Processes of Linear kinetic describe the Metoclopramide elimination and absorption (Baxter Healthcare Corporation, 2010). In a certain study carried out, it was observed that about 85% of the radioactivity of Metoclopramide dose which was administered orally appeared in the urine within 72 hours. Out of this eliminated 85% in the urine, approximately half of it was present as conjugated or free Metoclopramide (Jordan et al, 2004). It is known that the drug is never bound extensively to plasma proteins (approximately 30%). The whole body distribution volume is relatively high, approximately 3.5 L/kg, implying that there is always extensive drug distribution to the tissues (Naeimet al, 2008). Metoclopramide clearance is normally affected by renal impairment. But the patient had no problem with his kidney, therefore the drug favored him. In a study that included patients with varying renal impairment degree, a reduction in clearance of creatinine was associated with a renal clearance, increase in elimination half-life, non-renal clearance and reduction in plasma clearance (Ballatori et al, 2007). However, the Metoclopramide kinetics in the renal impairment presence remained linear. As a result of renal impairment, the reduction in clearance suggests that accumulation of the drug can be avoided by adjusting maintenance dosage downward (Ballatori et al, 2007). Metoclopramide has the ability to inhibit gastric smooth muscle relaxation as a result of dopamine, therefore raising gastrointestinal smooth muscle cholinergic response. It will accelerate gastric emptying and intestinal transit of this patient with constipation by preventing gastric body relaxation and increasing the phasic antrum activity. Simultaneously, it will be accompanied by upper small intestine relaxation, leading to an enhanced coordination between the antrum and the body of the upper small intestine and stomach ( Hesketh ,1999). Also Metoclopramide will decrease reflux into the esophagus of this patient by raising the lower esophageal sphincter resting pressure and enhancing acid clearance from the esophagus through increasing esophageal peristaltic contractions amplitude. Dopamine antagonist action of Metoclopramide will increase the patient activity threshold in the trigger zone of chemoreceptor and lowers the input from afferent visceral nerves (Rubensteinet al, 2006). Also according to Studies high Metoclopramide doses in animals can antagonize receptors of 5-hydroxytryptamine (5-HT) in the peripheral nervous system. Although Metoclopramide is related chemically to Procainamide, it lacks Antiarrhythmic or local anesthetic properties. Apart from being used to treating this patient who had constipation, vomiting, Metoclopramide can as well be employed to treat diabetic gastro-paresis, enhance GI, as an antinauseant motility and to facilitate small bowel intubation during radiologic examination. Emesis is a process that is highly organized and its coordination is through the vomiting center in the CNS and gets input in the GI tract from visceral afferent neurons. In animal models, dopamine D2 receptors stimulation at the chemoreceptor trigger zone (CTZ), located in the medulla oblongata in the postrema area, has been employed to classify vomiting together with correlates of gastrointestinal motor, that include relaxation of gastric and commencement retrograde giant contraction in the small bowel (Saito et al, 2009).Metoclopramide generates its effects of antiemetic by 5-HT3 and D2 receptors inhibition in the chemoreceptor trigger zone (Kris et al. 2006). In patients who are elderly or pediatric, the Metoclopramide pharmacodynamics after intravenous and oral administration varies greatly and the relationship of concentration-effect has not been established (Wit et al, 2005). There exist insufficient reliable data which can be based on to make conclusion whether the Metoclopramide pharmacokinetics in pediatric and adults population are similar (Kaiser, 2004). Despite insufficient data exist that support the Metoclopramide efficacy in pediatric and elderly patients with cancer chemotherapy-related vomiting and nausea or symptomatic gastroesophageal reflux (GER) such as this one who has constipation and vomiting, studies have been carried out on pharmacokinetics in these patient populations (Roila , Hesketh and Herrstedt, 2004). Basing on the information on the relationship between Metoclopramide pharmacokinetics in pediatric and adults, the condition of this patient with nausea and vomiting as well as with gastric cancer history can be correlated to really see if this medication is the most appropriate one if need arises. Other drugs can be recommended if it is found out that this drug is not suitable to this patient. Pharmacodynamics of Metoclopramide Drug. The patient’s condition relatively matches with the properties of this drug because it is used in treatment of vomiting, Digestive disorders, Nausea and Migraine. Metoclopramide increases the muscles contractions or movements in the intestines and stomach (Rang et al, 2007). Metoclopramide has the capacity to stimulate the upper gastrointestinal tract motility. It does this without stimulating biliary, pancreatic or gastric secretions (Hesketh, 2008). The mode of action of this drug is not clear. But probably it seems to be involved in tissue sensitization to the acetylcholine action. The Metoclopramide impact on motility is not based on vagal innervations that are intact, but it can be eliminated by anticholinergic drugs (Herrstedt and Dombernowsky, 2007). Metoclopramide is known to increase the gastric amplitude and tone (particularly antral) contractions; it relaxes the duodenal bulb and pyloric sphincter and increases the jejunum and duodenum peristalsis leading to accelerated intestinal transit and gastric emptying. The lower esophageal sphincter resting tone can be increased. It is also known to have a little, if any, impact on the motility of the colon or gallbladder (Ho and Gan, 2006). In this patient with low LESP (lower esophageal sphincter pressure) and gastroesophageal reflux, Metoclopramide single oral doses result to increase in LESP that is dose-related. The impacts begin at approximately 5 mg then later rise through 20 mg (the largest tested dose). The LESP rise from 20 mg lasts between 2 - 3 hours and that of 5 mg dose takes about 45 minutes. Stomach emptying increased rate has been experienced with 10 mg single oral doses (Niesler, 2008). The antiemetic Metoclopramide properties seem to result from its peripheral and central dopamine receptors antagonism. Dopamine produces vomiting and nausea by stimulating the medullary chemoreceptor trigger zone (CTZ) of this patient, on the other hand Metoclopramide has the capacity to block the stimulation of this CTZ of this patient with agents such as Apomorphine or l-dopa that have been known to raise the levels of dopamine or to possess dopamine-like effects. (Herrstedt, 1998). It is also known that Metoclopramide eliminates the gastric emptying slowness that results from Apomorphine (Blower, 2002). Just like the Phenothiazines and other associated drugs, which are as well known to be dopamine antagonists, Metoclopramide can result to sedation of this patient with constipation and vomiting and might lead to reactions that are extra pyramidal, despite these are relatively rare. Metoclopramide has the ability of inhibiting the peripheral and central Apomorphine effects, it induces prolactin release and results to a transient rise in circulating levels of aldosterone, that are associated with retention of transient fluid (Wit, 2003). The onset of Metoclopramide pharmacological action is about 1 - 3 minutes after an intravenous dose, About 10 - 15 minutes after intramuscular administration, and about 30 - 60 minutes after an oral dose; the pharmacological effects can persist for about 1 - 2 hours (Kaiser et al, 2002). Pharmacokinetics of co-danthramer drugs Just like other compounds of anthraquinone, Dantron is absorbed partially from the small intestine. Cramping and griping is not experienced like in other drugs because it has no drastic affect to the small intestine. Dantron starts acting between 6 to12 hours following administration. Poloxamer 188 is never absorbed from the intestines hence as a result of this it can be recovered fully in the faeces (Stoltz ,Cyong , Shah and Parisi ,2004). Co-danthramer suspension and capsules have 2 active ingredients, Poloxamer 188 and Dantron. Both of these drugs are referred to as laxatives. Hence in combination it is called co-danthramer. Dantron is laxative type referred to as stimulant laxative. It acts by nerve endings stimulation in the intestines walls. This will result to intestinal wall muscles of this patient with constipation to contract frequently with increased force. The gut’s contents will be moved along the intestines as a result of these muscles contraction, hence relieving constipation. Pharmacodynamics of co-danthramer drugs Co-danthramer attributes its action of laxative to Dantron mild purgative which is the monograph subject in the British Pharmacopeia (McEvoy, 2004). Dantron drug is related chemically to emodin and it is anthraquinone derivative, the active cascara principle as well as other naturally occurring products like aloes, rhubarb and senna. It is known to act on the myenteric plexus nerve endings as well as it has the ability to stimulate the large intestine muscles (Page et al, 2002). The condition of this patient can be correlated to the mode action of the drug hence he can be treated with this drug despite it being linked to causing tumor and having hepatocarcinogenic effect in rats and mice (Page et al, 2002). As a wetting agent, Poloxamer 188 is known to aid in the water penetration into faecal material. The Poloxamer surface activity has a lubricant impact on the contents of the gut. The patient had constipation and his faecal material could have been wetted and lubricated hence easy removal from the gut (Desta et al, 2002). Excoriation and irritation might be experienced as a result of prolonged contact with skin hence this needs to be avoided when handling this patient. The Dantron oral administration has been known to result to intestinal tumors in mice and rats. Also in both species, the drug is seen to be hepatocarcinogenic (Grunberg et al, 2009). There is no evidence on the insufficient effect of the drug. This might be risky in humans. Hypomagnesaemia might be experienced in patients with renal insufficiency/ failure (Musso et al, 2008). In conclusion, it is recommended that this drug should not be used in patients who are incontinent. According to the discussion on the pharmacokinetics and pharmacodynamics of these drugs it is clearly evident that these drugs can not be the final drugs to be used in the treatment of these patient’s conditions because of some of the disadvantages they have. For instance, co-danthramer drug has some extreme limitations such as it is known to cause tumors and hepatocarcinogenic effects in mice and rats and this can be linked to humans. Also the mode of Metoclopramide is not very clear. Differential patient’s responses to anti-emetic drugs can result from factors that include gender, age and variations in the enzymes activity, that are involved in the binding, uptake, activation or drug degradation. Just like the Phenothiazines and other associated drugs, which are as well known to be dopamine antagonists, Metoclopramide results to sedation and might lead to reactions that are extra pyramidal, despite these are relatively rare. Metoclopramide has the ability of inhibiting the peripheral and central Apomorphine effects, it induces prolactin release and results to a transient rise in circulating levels of aldosterone, that are associated with retention of transient fluid. 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