Pharmacotherapy of GIT and Respiratory Disorders PDF

Pharmacotherapy of GIT and Respiratory Disorders RPB20403 By Dr. Omar AH Topic 1: Antiemetic Drugs Learning Outcomes: 2.1 Pathophysiology of vomiting 2.2 Receptor antagonists 2.3 Antipsychotic drugs 2.4 Metoclopramide & domperidone 2.5 Cannabinoids 2.6 Steroids & neurokinin antagonists Definitions...

Pharmacotherapy of GIT and Respiratory Disorders RPB20403 By Dr. Omar AH Topic 1: Antiemetic Drugs Learning Outcomes: 2.1 Pathophysiology of vomiting 2.2 Receptor antagonists 2.3 Antipsychotic drugs 2.4 Metoclopramide & domperidone 2.5 Cannabinoids 2.6 Steroids & neurokinin antagonists Definitions Nausea: The immediate need to vomit, is associated with gastric stasis Retching: Make the sound and movement of vomiting before vomiting Vomiting: Forceful expulsion of gastric contents Peristalsis: intective small · Wave-like muscle contractions that move food through the digestive tract Antiemetics To treat nausea & vomiting Uncontrolled vomiting cause dehydration & electrolyte imbalance Aspiration & pneumonia Vomiting: also known as emesis, is the forcible expulsion of the stomach contents through the mouth and sometimes the nose. It is a reflex action that can be triggered by a variety of factors, including: Etiology: Food poisoning (food intolerance) Gastroenteritis Motion sickness Pregnancy Migraine Shock Head injury Certain medications Overeating Alcohol intoxication Etiology: Vomiting can also be a symptom of more serious medical conditions, such as: Stomach ulcers Gastroesophageal reflux disease (GERD) Liver Kidney disease Pancreatitis Cancer Surgery Pain Infections Some drugs effects Radiation Disturbances of the middle ear Antiemetics can mask the cause. The cause of the vomiting needs to be identified Symptoms of vomiting The most common symptom of vomiting is the feeling of nausea, which is a sudden urge to vomit. Other symptoms of vomiting may include: Sweating Dizziness Pale skin Headache Abdominal cramps Treatment for vomiting The goal of treatment for vomiting is to prevent dehydration and to relieve the symptoms. Treatment may include: 1. Over-the-counter or prescription medications to stop vomiting (Medical) Fluids to replace the fluids and electrolytes lost through vomiting (Non-Medical) Rest, relax, fresh air, decrease noxious stimuli If you are unable to keep fluids down or experiencing severe vomiting, you may need to be hospitalized for intravenous fluids and medications. Prevention of vomiting There are a number of things you can do to prevent vomiting, including: Avoiding foods and drinks that trigger your vomiting Eating small, frequent meals Avoiding overeating Drinking plenty of fluids Getting enough rest Avoiding alcohol and caffeine Taking medications for motion sickness if you are traveling  Medulla Oblongata Pathophysiology motion sickness/ear infection : jear) Nausea, retching and Hydrogen vomiting (emesis) are Sulfide H2S part of the body's defense against Vestible r ingested toxins ① ↓ send contess signals to ③ chemotheraphy ↓ Chemoreceptor Trigger Zone Outside the BBB i Vomiting Centre Inside BBB ④  Where is the sensation of nausea created? The Chemoreceptor Trigger Zone (CTZ): This is a zone located in the brainstem in the area postrema near the fourth ventricle, outside the blood brain barrier. The emetic fact that it is outside the BBB is critically important – it means that emetogenic stimuli can reach this area through the bloodstream! This zone contains several important receptors: Histamine (H1), Muscarinic (M1), Dopamine (D2), Serotonin (5-HT3) and Neurokinin (NK-1) receptors. The Vomiting Centre: The vomiting center (now sometimes called the Central Pattern Generator) is located in the medulla and is the effector/efferent pathway that activates vomiting. Individuals with severe brain damage and decortication can still vomit, because the Vomiting Centre does not depend on cortical input! VC  4 There are three important sources of inputs into the CTZ and Vomiting Centre - that start the nausea-generation cascade: Cortex (Higher Centers): Stimuli such as pain, anxiety, and stress Vestibular System: This is your inner ear/balance system, which is mediated by Histamine (H1) and Muscarinic (M1) receptor cascades GI Tract: The GI tract sends lots of feedback to the brain – in the form of visceral afferents, mechanoreceptors that are stimulated by gastric stretch, and chemoreceptors stimulated by luminal contents. These are primarily serotonin, or 5-HT3 mediated.  stimulate (72 -7 Drugs associated with a high incidence of nausea and vomiting Cisplatin chemotherapy -cancer Allopurinol Antimicrobials (oral use) Bromocriptine Cytotoxic agents (especially cisplatin, cyclophosphamide, doxorubicin, nitrosoureas) Digoxin Gold Iron (oral use) Levodopa Non-steroidal anti-inflammatory drugs Oestrogens (oral use) Opioid analgesics Penicillamine Sulfasalazine Theophylline The vomiting center, in the medulla cause vomiting, when stimulated: 1. Vomiting center stimulation Copenl 2. Relaxation of the lower -> like value esophageal sphincter 3. Contraction of the diaphragm and abdominal muscles spush de much 4. Increased Intraabdominal pressure 5. Closed Epiglottis ↳ prevent from entering lungs 6. vomiting occurs 1. Autonomic changes; Tachycardia : increased heart rate 2. Increased salvation sweating 3. Peristalsis  blockers Receptor antagonists Neurotransmitters antagonism  chemotherapy A Motion/Morning sickness Chemotherapeutic labyrinth + opioid drugs Dopamine d2 Serotonin type 3 outside BBB (Amy/trxim Neurokinin 1 Pain, Smell Emotion Dantagonist Sight [stimulateI anti-M/atagonists VC ACh - Muscarinic NK-1 antagonists - - Hasine IDomperidone Hyasine butyl - - - bromide Chemo, Radio, Gastrio prokinetic effect ↳ push down the stomach/GI7 Substance P content Histamine H1 R anti-histamine ↓ Sti allergic - sleepy/ HT3 - 5 dissiness Serotonin antagonists sedation -cross 5 classes of drug ↳ BBB Cyclizine classes -not relate to pain Muscarinic Labyrinth t Antiemetic Drug Classes 1. Anticholinergics (Muscarinic receptor antagonist) (Cholinergic antagonists): Dicyclomine, Hyoscine, Scopolamine 2. Histamine-1 (H1) receptor antagonists (Antihistamine) (Antiallergic) (Motion/morning sickness): Promethazine, Meclizine, Diphenhydramine, Dimenhydrinate. Betahistine Betaserc® (H3r antagonist) - high duse : Schizophre nic -> low dose/ antiemetics : 3. Dopamine 2 antagonists (D2-RA) (Neuroleptics) (Psychosis and Schizophrenia): quarter Chlorpromazine, Haloperidol, Domperidone , Metoclopramide, Trimethobenzamide 4. 5-HT3 (Serotonin) antagonists: Ondansetron (Zofran), Granisetron 5. Cannabinoids: Tetrahydrocannabinol, Nabilone, Dronabinol 6. Neurokinin 1 (NK1) antagonists: Aprepitant (Emend) 7. Steroids: Glucocorticoid: Dexamethasone 8. Adjuvant drugs I. Benzodiazepines: Lorazepam II. Prokinetics: Metoclopramide, Domperidone, Cisapride, Mosapride (5-HT4 agonist) Anticholinergics (Muscarinic receptor antagonist) (Cholinergic antagonists) Hyoscine, Scopolamine, Dicyclomine (Prophylaxis, motion sickness) [transdermal patch behind ear] (Not for chemotherapy induced vomiting) - not relate with CTI , act at vestibular system - SE: Dry mouth, blurry vision (mydriasis), drowsiness. Mechanism Of Action And Clinical Use: Muscarinic receptors are involved in the visceral afferent input from the gut to the vomiting center and in the tract that the eighth cranial nerve takes from the labyrinth to the CTZ via the vestibular nucleus. Hyoscine (known as scopolamine) is used for the treatment of motion sickness and postoperative vomiting. Some antihistamines such as promethazine and cyclizine, and dopamine receptor antagonists such as prochlorperazine, also have antimuscarinic activity. antagonist ( De Pharmacokinetics: Hyoscine is available for oral, parenteral or transdermal use. Oral absorption is good. The adhesive patch for transdermal delivery can be placed behind the ear and delivers a therapeutic dose for 72 h. Anticholinergics Histamine-1 (H1) receptor antagonists (Antihistamine) (Antiallergic) For (Motion/morning sickness in pregnancy, vestibular disturbance, opioid nausea) [not for chemotherapy induced vomiting] ↳> net effect CT2 but Vestioner e A mostly wse. Promethazine, Meclizine, Cyclizine, Diphenhydramine, Dimenhydrinate. Betahistine, Betaserc® (H3 antagonist anti-vertigo). Side effect: Drowsiness and sedation.  Antihistamines Mechanism Of Action And Clinical Use: Antihistamines prevent and treat vomiting by their antagonist action at histamine H1 receptors, and many also have antimuscarinic effects. Promethazine also blocks some 5-HT receptor subtypes. Antihistamines are effective against most causes of vomiting but, apart from the use of cyclizine for drug-induced vomiting, they are rarely treatments of choice. Promethazine is used to treat vomiting in pregnancy since it appears to be free from teratogenic effects. Pharmacokinetics: These drugs are well absorbed orally; both promethazine and cyclizine can also be given by intramuscular or intravenous injection. After oral dosing, promethazine undergoes extensive first-pass metabolism. Unwanted Effects: Sedation (particularly with promethazine) and headache. Antimuscarinic effects, especially dry mouth, urinary retention and blurred vision.  Antihistamine H1 H H1 Cyclizine Promethazine Meclizine Diphenhydramine H3 As 5-HT3 (Serotonin) antagonists (~setron) Ondansetron (Zofran), Granisetron, Palonosetron, Dolasetron. (Chemotherapy [cisplatin], post-radiation, post-surgery, pregnancy but not first trimester) The most potent antiemetic, mediated though central and peripheral action Orally or IV, long duration of action High first pass metabolism Side effects: Headache, dizziness, GIT upset constipation. 5-HT3 receptor antagonists Mechanism Of Action And Clinical Use: The 5-HT3 receptor antagonists block the 5-HT3 receptors in the CTZ and in the gut. They are particularly effective against the acute vomiting induced by highly emetogenic chemotherapeutic agents used for treating cancer (e.g. cisplatin) and for postoperative vomiting that is resistant to other agents. They are also used for prophylaxis when the consequences of retching and vomiting could be particularly deleterious, for example after eye surgery. Pharmacokinetics: Oral absorption of ondansetron is rapid, and it can also be given by intravenous or intramuscular injection or by rectal suppository. Granisetron has a similar profile and is available for oral or intravenous use. Palonosetron has a long half-life and is given intravenously.  At 12 (outside BBB) > Dopamine antagonists/Neuroleptics (D2-RA) (Psychosis and Schizophrenia) 1. Chlorpromazine: (Chemotherapy and radiation) SE: sedation, hypotension, ↳ - extra pyramidal side effects, sedation, restlessness. un contioliable muscle can work at twitching I VC I 2. (Substituted Benzamides) Metoclopramide (cross BBB) & (D2RAn + 5-HT3 + GIT - Motility 5-HT4 agonist), Trimethobenzamide: (Chemotherapy and radiation, reflux, toxins) SE: Fatigue, Extra Pyramidal side effects (Akathisia; restlessness, Tardive dyskinesia, Dystonia; involuntary muscle contractions). used top USAX widely , 3. Droperidol, Haloperidol, Domperidone (Can't cross BBB (D2RA on CTZ outside BBB - - - +GIT Motility 5-HT4 agonist))) (Chemotherapy, post-surgery, toxins) SE: No Extra Pyramidal side effects, cant cross BBB, galactorrhea Dopamine receptor antagonists Mechanism Of Action And Clinical Use: Domperidone, metoclopramide and the antipsychotic drugs are antagonists at dopamine D2 receptors and inhibit dopaminergic stimulation Do antagonist 1 Anti-emetic doses of antipsychotic drugs are generally less than one-third of those used to treat psychoses. Domperidone acts solely by dopamine receptor blockade. Metoclopramide is a dopamine antagonist at usual oral doses, but it also acts as a 5-HT3 receptor antagonist at higher doses. This enhanced efficacy is utilized by intravenous administration of high doses of metoclopramide to treat the vomiting induced by cytotoxic agents such as cisplatin. Metoclopramide also has prokinetic actions on the gut including increased tone of the gastro- oesophageal sphincter and enhanced gastric emptying and small intestinal motility. These effects arise from agonist activity at the 5-HT4 receptor subtype in the enteric nervous system, which leads indirectly to cholinergic stimulation. Dopamine receptor antagonists are mainly used to reduce vomiting induced by drugs and surgery. Pure dopamine receptor antagonists are ineffective in motion sickness. Antipsychotic drugs such as prochlorperazine are effective for vestibular disorders and motion sickness as a result of their antimuscarinic activity. Dopamine receptor antagonists Pharmacokinetics: Metoclopramide and domperidone are well absorbed orally, but have limited bioavailability due to extensive first- pass metabolism in the liver. Metoclopramide is also available for intravenous or intramuscular use, while domperidone can be given rectally by suppository. Metoclopramide has a shorter half-life (3– 5 h) than domperidone (12–16 h). Chlorpromazine Metoclopramide Domperidone v 12 children you. Withdrawn from US because of cardiac arrhythmias T Prolongation eye dry meth , disorder,  Prokinetics Enhance coordinated GIT propulsive motility pstomach + 1 2 1. Antagonize the inhibitory effect of dopamine on myenteric motor neurons 2. Relive nausea and vomiting by antagonism of dopamine receptors in the CTZ 3. 5-HT4 agonist 1. Metoclopramide 2. Domperidone Which is a better antiemetic, Metoclopramide or Domperidone ? As CTZ is outside BBB, both have antiemetic effects But Metoclopramide cross the BBB, and has adverse effects, like Extra Pyramidal side effects, dyskinesia, galactorrhea, menstruation disorder, sedation. Domperidone is preferred antiemetic in children and levodopa ↳ induced vomiting. Parkinson's treatment Corticosteroids wealy antiemetic cannibal (last option Glucocorticoid: Dexamethasone, Methylprednisolone Effective in acute emesis (combined with Ondansetron), for vomiting by cytotoxic drugs SE: Hyperglycaemia, Hypertension, Cataract, Osteoporosis, Increased intraocular pressure, increased appetite and obesity. Dexamethasone and methylprednisolone are weak anti-emetics. However, they produce additive effects when given with high-dose metoclopramide or with a 5-HT3 receptor antagonist such as ondansetron. High doses of dexamethasone can be given intravenously before cancer chemotherapy, with subsequent oral doses to prevent delayed emesis. The mechanism of action may involve reduction of prostaglandin synthesis or release of endorphins. Corticosteroids LCT2 ~ -> Stomach Neurokinin 1 receptor antagonists -> Proding metabolized -> aprepitant Examples: Aprepitant, fosaprepitant. Mechanism Of Action: Aprepitant and its prodrug fosaprepitant are antagonists at NK1 receptors in the CNS, inhibiting the action of substance P. They augment the effects of 5-HT3 receptor antagonists and corticosteroids in preventing the acute and delayed emetic response to the cancer chemotherapeutic agent cisplatin. Pharmacokinetics: Aprepitant is well absorbed from the gut and has a long half-life. Fosaprepitant is given by intravenous infusion. Unwanted Effects: Fatigue, dizziness, headache, hiccups. Anorexia, abdominal pain, diarrhoea. Drug interactions: aprepitant is an inhibitor of the liver enzyme CYP3A4 and an inducer of CYP2C9. It may decrease the clinical effect of warfarin. Neurokinin 1 receptor antagonists  high flowering senses. Benzodiazepines barbiturates - Used before chemotherapy to reduce anticipatory vomiting caused by anxiety ↓ no effect after chemo Lorazepam, Diazepam (GABA) They have no intrinsic anti-emetic activity. They are given orally or intravenously before cancer chemotherapy to sedate and produce amnesia. They are especially useful if there has previously been vomiting with a cytotoxic treatment, since anticipatory nausea and vomiting are then common with subsequent courses. Cannabinoids Nabilone, Dronabinol (Psychoactive drugs) Used as adjuvant in chemotherapy induced vomiting SE: Sedation, hallucination, vertigo, ataxia, sleep disturbance, dry mouth and dysphoria Mechanism Of Action And Clinical Use: Nabilone, a synthetic derivative of tetrahydrocannabinol (a psychoactive substance in cannabis), is effective in combating vomiting induced by cytotoxic drugs, providing it is given before chemotherapy is started. The mechanism involve inhibition of cortical activity and anxiolysis. Cannabinoid CB1 receptors are found in several areas of the CNS and the action of nabilone at these receptors may inhibit neuronal serotonin release in the dorsal vagal nucleus. Pharmacokinetics: Nabilone is well absorbed from the gut. It is metabolised extensively in the liver and has a short half-life, but some of its metabolites have long half-lives and may contribute to the activity. Summary of therapeutic choices Motion sickness: Oralv 1. Hyoscine, cyclizine, promethazine: for short journey (Short half - durations , patch X promethazine. 2. hDiphenhydramine (first-generation antihistamine, anticholinergic): For long journey 3. metocloprolmide. (can cross BBB). thormone Vomiting with pregnancy (morning sickness): -> stomach. Avoid all drugs in first trimester, polive 1. Vitamin B6, or pyridoxine 2. Promethazine (first-generation antihistamine) 3. Metoclopramide Drug induced vomiting (CTZ) 1. Metoclopramide DLRA 2. Domperidone D2 a 3. Cyclizine (particularly for opioid-induced vomiting) 4- Prokinetics Vomiting due to cytotoxic drugs 1. Ondansetron 2. D2RA 3. Dexamethasone (Glucocorticoid) 4. Nabilone (cannabinoid) Adjunctive treatment, e.g. benzodiazepines Post-Operative vomiting chin anxiety) , Hyoscine, metoclopramide, domperidone, prochlorperazine, ondansetron