Spasmolytics and Antiemetics 24 PDF

Spasmolytics Antispasmodics/Spasmolytics They are agents that inhibit or reduce contractions and particularly find application as antimotility agents. Spasmolytics are grouped into: 1) Antimuscarinics: these agents act as antagonists at muscarinic (M3) receptors....

Spasmolytics Antispasmodics/Spasmolytics They are agents that inhibit or reduce contractions and particularly find application as antimotility agents. Spasmolytics are grouped into: 1) Antimuscarinics: these agents act as antagonists at muscarinic (M3) receptors. Examples include, hyoscine (scopolamine), propantheline, and dicycloverine. They produce typical muscarinic side effects like dry mouth, constipation, mydriasis, etc. 2) Opioids. Loperamide acts selectively in the gastrointestinal tract and doesn’t cross the blood brain barrier. It undergoes enterohepatic recycling. Loperamide also has anti-secretory effect against cholera and E. coli toxin b) Diphenoxylate lacks morphine’s activity on the central nervous system, however at high doses, it can cross the blood barrier. Diphenoxylate is usually combined as a fixed dose with atropine in order to reduce the dose of diphenoxylate. Diphenoxylate is given orally and has an active metabolite, Diphenoxin, which contributes to its long half life. Side effects of diphenoxylate include megacolon, dry mouth and blurred vision. 3) Sympathomimetics. Clonidine is an α2 receptor agonist, which inhibits gastrointestinal motility by binding to α2 receptors (Gi protein coupled) in the GIT. Emetics Emetics are agents used to stimulate vomiting. They are sometimes used to stimulate the removal of ingested substances which are harmful/poisonous to the body. Due to the deleterious effects associated with their use, their clinical application is diminished. 1 (Not for sale or reprinting. O. Edosuyi. PharmD. Ph.D.) Fig: Areas of the nervous system involved in the emesis. Adapted from Katzung; Basic and Clinical pharmacology. a) Apomorphine Apomorphine is a centrally acting emetic. It is usually administered subcutaneously or intravenously. It causes vomiting that is accompanied with sedation. It is a non-selective dopamine receptor agonist. Side effects include hypotension, syncope, tremors and restlessness b) Hypertonic sodium chloride is administered orally where it acts peripherally, by withdrawing fluid from the cells of the stomach, causing irritation and subsequent emesis. c) Ipecacuanha (emetine) It is derived from the dry root of Cephalis ipecacuanha which contains emetine as the active constituent. Emetine acts both centrally, through the chemoreceptor trigger zone and peripherally through by irritating the gastric mucosa, to stimulate vomiting. It is usually formulated as ‘syrup of ipecac’ for administration. Other agents that can induce vomiting include anticancer agents, ergot derivatives, metronidazole, and amiodarone. 2 (Not for sale or reprinting. O. Edosuyi. PharmD. Ph.D.) Contraindications for use of emetics include in unconscious patients, solvent and volatile hydrocarbon poisoning and in corrosive alkaline poisoning. Anti-emetics Anti-emetics are agents that suppress the vomiting reflex and thus prevent vomiting. Classification i. Serotonin 5HT3 antagonists e.g ondansetron, dolasetron, granisetron. ii. Dopamine (D2) receptor antagonists. e.g chlorpromazine, prochlorperazine, metoclopramide. iii. Antihistamines (H1) antagonists e.g diphenhydramine, cyclizine, promethazine, cinnarizine. iv. Muscarinic M1/M3 receptor antagonists e.g Scopolamine v. Cannabinoid CB1 receptor agonists e.g Nabilone, Dronabinol. vi. Neurokinin NK1 antagonists e.g aprepitant, fosaprepitant, rolapitant. vii. Adjuvants e.g benzodiazepines, corticosteroids. 1. Serotonin antagonists. Ondansetron is administered orally, intravenously and intramuscularly. It is well absorbed from the gastrointestinal tract (GIT) and extensively metabolized in the liver and undergoes sulphate or glucuronide conjugation. Hepatic dysfunction reduces the plasma clearance of these drugs. The metabolism of granisetron is affected by ketoconazole (CYP3A inhibition by ketoconazole). The effects of these drugs persist after the drug has disappeared from the circulation and are thus administered once daily. Ondansetron also binds to serotonin 5HT3 receptors found in the GIT and this serves as an additional mechanism against emesis Palonosetron is a second generational agent with better receptor affinity and longer halflife (>30 hours). Ondansetron is well tolerated with mainly gastrointestinal side effects like diarrhoea, headache, and light headedness. They well tolerated and may cause constipation and QT elongation. They are effective for chemotherapy-induced and post-operative emesis. 3 (Not for sale or reprinting. O. Edosuyi. PharmD. Ph.D.) 2. Dopamine receptor antagonists. Chlorpromazine, prochlorperazine antagonize dopamine receptors in the chemoreceptor trigger zone (CTZ). They also possess anticholinergic and antihistaminergic actions that are beneficial to their antiemetic actions and gives these drugs an added effect in motion sickness. 3. Histamine H1 antagonists These drugs are primarily used in handling emesis associated with motion sickness and vertigo caused by labyrinthine disorders. They also possess anticholinergic action Antihistamines antagonize histamine H1 receptors present on the vestibular afferents. Examples include promethazine, diphenhydramine and cyclizine. s4. Muscarinic receptor antagonists Scopolamine is an alternative to antihistamines in preventing motion sickness. These drugs bind to muscarinic M1 receptors present in the chemoreceptor trigger zone and in the gastrointestinal tract to suppress emesis. They possess anticholinergic side effects. 5. Cannabinoids. The natural component, Δ9-tetrathydrocannabinol (THC) has antiemetic actions. The synthetic derivatives such as nabilone and dronabinol, stimulates CB1 receptors present around the vomiting center. Cannabinoids are psychoactive and highly lipid soluble compounds that are absorbed rapidly. They undergo extensive first pass with limited systemic bioavailability, are highly plasma protein bound and have a large volume of distribution. They are used in combination with other anti-emetics in chemotherapy induced emesis. Adverse effects include central nervous system effects with prominent sympathomimetic effects including palpitations, tachycardia, conjunctival redness (blood shot eyes). Other effects include(s); Euphoria, anxiety, insomnia, restlessness. 6. Neurokinin Nk1 receptor antagonist. 4 (Not for sale or reprinting. O. Edosuyi. PharmD. Ph.D.) Aprepitant is a neurokinin receptor antagonist (block the actions of substance P) with a delayed emetic action and is usually used as combination therapy for delayed emesis. Fosaprepitant is prodrug given i/v. It is extensively plasma protein bound and metabolized via CYP3A4 in the liver. Side effects include diarrhea, fatigue, hiccups. They are used in combination with other antiemetics for chemotherapy-induced emesis. 7. Adjuvant anti-emetics These agents are not very effective anti-emetics and are usually used in combination with other anti-emetics. They include. Benzodiazepines are helpful in anticipatory emesis due to their sedative and antianxiety actions e.g. Diazepam, lorazepam, alprazolam. Corticosteroids, e.g. Dexamethasone, prednisolone, methylprednisolone. They block the production of prostaglandins that trigger the emetogenic signal Phosphorylated carbohydrate solution, e.g. aqueous solution of glucose, fructose and phosphoric acid Metoclopramide Metoclopramide is a centrally acting dopamine D2 receptor antagonist. It stimulates gastrointestinal motility and is also known as a pro-kinetic agent. It can also block 5HT3 receptors. Metoclopramide is rapidly absorbed after oral administration and undergoes sulphation and glucuronide conjugation in the liver and is excreted in the urine. Metoclopramide can cause extra pyramidal symptoms like dystonia’s, Parkinsonism, Tardive dyskinesia, akathisia, and oculogyric crises. Domperidone Domperidone is an anti-nauseant and a dopamine D2 antagonist, both at the periphery and at the chemoreceptor trigger zone, which does not cross the blood brain barrier (BBB) and thus has less extrapyramidal side effects. Domperidone is administered orally and undergoes first pass 5 (Not for sale or reprinting. O. Edosuyi. PharmD. Ph.D.) metabolism which affects its metabolism. It can be given with centrally acting dopamine agonists to counter their emetic effect. Some side effects include Dry mouth, galactorrhoea, rashes and headache. 6 (Not for sale or reprinting. O. Edosuyi. PharmD. Ph.D.)