Systemic Pharmacology Of Anti-Emetics PDF

SYSTEMIC PHARMACOLOGY PHA 451 PHARMACLOGY OF DRUGS USE IN THE TREATMENT OF EMESIS, REFLUX AND DIGESTIVE DISORDERS (2 CREDITS UNITS). BY FELIX KENEOLISA ASOGWA (B. PHARM, PHARMD, M. PHARM.) Nausea and Vomiting The sensation of nausea and the act of vomiting occur as a response to...

SYSTEMIC PHARMACOLOGY PHA 451 PHARMACLOGY OF DRUGS USE IN THE TREATMENT OF EMESIS, REFLUX AND DIGESTIVE DISORDERS (2 CREDITS UNITS). BY FELIX KENEOLISA ASOGWA (B. PHARM, PHARMD, M. PHARM.) Nausea and Vomiting The sensation of nausea and the act of vomiting occur as a response to both physiological and pathological conditions. In the acute setting, these responses ideally serve a physiological role to protect the host from ingested substances that are potentially harmful. Unfortunately, chronic nausea and vomiting is often a pathological response that occurs with a variety of gastrointestinal and non-gastrointestinal conditions such as bacterial infection (gastro enteritis), pregnancy, CNS cause (migraine), medication (cancer chemotherapy), post operative nausea and vomiting. Nausea is the unpleasant sensation of having the urge to vomit, whereas vomiting (emesis) is a physical event and is the forceful expulsion of intestinal and gastric contents through the mouth. The act of emesis and the sensation of nausea that accompanies it generally are viewed as protective reflexes that serve to rid the stomach and intestine of toxic substance and prevent their further ingestion. Antiemetic drugs are medications used to treat nausea and vomiting. These two symptoms are very common and can be caused by many different conditions, therapies, procedures, and medications (such as opioids). Though vomiting is considered to be a protective reflex of the body to expel toxic substances in the stomach and gut, antiemetic drugs are often necessary to suppress vomiting, especially if there’s a pathological conditions. Dopamine is an organic chemical of the catecholamine and phenethylamine families. Dopamine function as neurotransmitter in the brain. Dopaminergic signaling is associated with reward motivated behavior and motor control. Loss of dopaminergic secreting neurons lead to neurodegenerative disease such as Parkinson’s disease. Dopamine receptors are widely distributed in the gastrointestinal tract and dopamine regulate the gastrointestinal tract function on the movement, secretion, and gastric mucosal blood flow. Dopamine is currently one of the protective factors involved in the gastrointestinal mucosa. It can resist gastrointestinal mucosal damage, likely owing to several factors as follows: (1) DA reduces gastric tension, intragastric pressure, and staged contractions. 1 (2) DA receptor agonists inhibit gastric acid secretion. (3) DA increases blood flow of the gastric mucosa. The chemoreceptor trigger zone (CTZ) has high concentrations of receptors for serotonin (5-HT3) and dopamine (DA). A variety of these neurotransmitters are involved in nausea and vomiting and an understanding of their nature has allowed a rational approach to the Pharmacological treatment of nausea and vomiting. To enhance coordinated GI motility and transient of material, prokinetic agents such as metoclopramide, domperidone, promethazine (Dopamine receptor antagonist) is used. (1) Dopamine Receptor Antagonist: Dopamine (DA) is present in significant amount in the GIT and has several inhibitory effects on motility including reduction of lower esophageal sphincter and intra gastric pressure. These effects which apparently result from suppression of Ach release from myenteric motor neuron are medicated by dopaminergic receptors. By antagonizing the inhibitory effect of dopamine on myenteric motor neuron, DA receptor antagonists are effective as prokinetic agents. They have the additional advantage of relieving nausea and vomiting by antagonism of DA receptor in the chemoreceptor trigger zone (CTZ). Examples of such agents are Metoclopramide, domperidone and Promethazine. (i) Metoclopramide, Mechanisms of action and Pharmacological properties. The MOA are complex and involve 5-HT4 receptor agonism, vagal and central 5-HT3 antagonism and possible sensitization of Muscarinic receptors on smooth muscle in addition to DA receptor antagonism. Metoclopramide is one of the oldest times prokinetic agents. Its administration result in coordinated contractions that enhance transit. Its effects are confined largely to the upper digestive tract where it increases lower esophageal sphincter tone and stimulates antral and small intestine contractions. Pharmacokinetics: Metoclopramide is absorbed rapidly after oral ingestion, undergoes sulfation and glucuronide conjugation by the liver, and is excreted principally in the urine with half life of 4-6 hours. Peak concentration occurs within I hour after single oral dose. The duration of action is 1-2 hours. Therapeutic use: Metoclopramide has been used in patient with gastro esophageal reflux disease to produce symptomatic relief of, but not healing of associated esophagitis. It is less effective than modern acid 2  suppressive medications such as PPIs and H2-receptor antagonists and rarely used in this setting. It is indicated mainly in patient with gastroparesis, in whom it may cause mild to moderate improvement of gastric emptying. In general, its activity lies in its ability to ameliorate the nausea and vomiting that often accompany GI dysmotility. Metoclopramide has also been used in the treatment of persistent hiccups. Dose: The usual initial dose range is 10mg 30mins before each meal and at bed time. The onset of action is within 30-60mins after oral dose. In Patient with severe nausea, an initial dose of 10mg can be given IM (onset of action 10-15min) or IV (onset is 1-3min). Adverse effect: (1) Extrapyramidal effect in children and young adult at high dose (2) Dystonia usually occurring after IV administration (3) Parkinson like symptoms, treated with antihistamine or anticholinergic drug and also reversible after discontinuation (4) Tardive dyskinesia occurs with chronic treatment and it’s irreversible. (ii) Domperidone: The gastroprokinetic properties of domperidone are related to its peripheral dopamine receptor blocking properties. Domperidone facilitates gastric emptying and decreases small bowel transit time by increasing esophageal and gastric peristalsis and by lowering esophageal sphincter pressure. The antiemetic properties of domperidone are related to its dopamine receptor blocking activity at both the chemoreceptor trigger zone and at the gastric level. It has strong affinities for the D2 and D3 dopamine receptors, which are found in the chemoreceptor trigger zone, located just outside the blood brain barrier, which - among others - regulates nausea and vomiting In contrast to metoclopramide, domperidone predominantly antagonize the DA-receptor without major involvement of other receptors. It has a modest prokinetic activity in dose of 10-20mg tds. It does not readily cross the blood brain barrier (BBB) to cause extrapyramidal side effect. Domperidone exerts effect in the parts of the CNS that lack this barrier, such as those regulating emesis, temperature and prolactin release ie it promote breast milk production. Side Effect of domperidone are; dizziness, fainting, disorientation, irregular heartbeat, lightheadedness among others. (iii) Promethazine and other phenothiazines have antiemetic and sedative actions in addition to being antipsychotics. Promethazine has a 3  duration of action of 4-6 hours. Adverse effects include dryness of mouth and sedation. Intravenous administration can cause severe tissue injury, burning or thrombophlebitis, leading to even gangrene and the need for amputation. The preferred mode of administration is deep intramuscular. It is avoided in children less than 2 years old due to the risk of respiratory depression. It is metabolized in the liver (CYP2D6) and has a half-life of 10 hours (i.m.), 9-16 hours (i.v.), and 16-19 hours (oral). (iv) Ondansetron: This selective 5-HT3 antagonist acts mainly by affecting the peripheral 5-HT3 receptors on the spinal and vagal afferents. Therefore, vomiting related to vagal stimulation (like postoperative vomiting) and chemotherapy-associated emesis are effectively controlled with this drug. Motion sickness-related vomiting is poorly controlled. Ondansetron, Granisetron, and Dolasetron have a serum half-life of 4-9 hours. They are administered once daily orally or intravenously. They are usually administered 30 minutes prior to chemotherapy. How do antiemetics work? In summary; antiemetics work on the neural pathways involved with vomiting by blocking specific receptors that respond to neurotransmitter molecules, such as serotonin, dopamine, and histamine. Most of these are central receptors found in the vomiting center of the brainstem, while peripheral receptors are found in the vagus nerve. When the gastrointestinal tract senses a threat, it sends information to the peripheral receptors, which in turn convey the information to the central receptors in the vomiting center. In response, the vomiting center triggers nausea and vomiting by stimulating the gastrointestinal tract, abdominal muscles, and the diaphragm GASTRO ESOPHAGEAL REFLUX DISEASE (GERD) It is a common GIT disorder caused by reflux of gastric contents into the esophagus. Reflux from stomach causes symptoms like heartburn and regurgitation, which are the cardinal symptom of GERD and other symptoms, such as chest pain, asthma, hoarseness and sleep disturbance. There are many factors contributing to GERD, such as transient lower esophageal sphincter relaxation, reduced lower esophageal clearance, visceral hypersensitivity and delayed gastric emptying. Acid suppression is the mainstay of therapy for GERD and proton pump inhibitors (PPIs) are the most potent drug in this regard. Although the use of PPIs is the treatment of 4 choice for GERD, still approximate one third of patient with GERD fail to respond symptomatically to a standard dose of PPIs, in this regard, Prokinetic agents could be considered as an add-on therapy to PPIs. Examples of PPIs are omeprazole, lanzoprazole, rabeprazole, esomeprazole etc. 5