Pharmacotherapy of GIT and Respiratory Disorders RPB20403 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: Wave-like muscle contractions that move food through the digestive tract Antiemetics Are used to treat Nausea & Vomiting Because uncontrolled vomiting, may cause Dehydration & Electrolyte imbalance, and sometimes Aspiration & Pneumonia. Vomiting: 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: ? What causes vomiting ?? Etiology: Gastrointestinal (GI) Disorders: - Gastroenteritis: Viral, bacterial, or parasitic infections of the GI tract. - Food poisoning: Ingestion of contaminated food or water. - Indigestion: Overeating, excessive alcohol consumption, oily or spicy food. - Peptic ulcers: Erosions in the lining of the stomach or small intestine. - Gastritis: Inflammation of the stomach lining. - Gastroparesis: Delayed emptying of the stomach. - Intestinal obstruction: Blockage of the intestines. - Appendicitis: Inflammation of the appendix. - Gastroesophageal reflux disease (GERD). REMEMBER: Antiemetic drugs can mask the cause. The cause of the vomiting needs to be identified !! Etiology: Other Conditions - Motion sickness (disturbances of the middle ear): Sensitivity to movement & infections. - Pregnancy: Hormonal changes and increased pressure on the stomach. - Migraines: Severe headaches. - Medications: Side effects of certain drugs. - Neurological disorders: Brain injuries, tumors, or infections. - Emotional distress: Anxiety, stress, depression, sleep deprivation. - Toxic exposure: Ingestion of poisons or toxins, or exposure to radiation. - Metabolic disorders: Liver or kidney disease. - Cancer. - Surgery and Pain. REMEMBER: Antiemetic drugs can mask the cause. The cause of the vomiting needs to be identified !! Vomiting Symptoms The most common symptom of vomiting is the feeling of Nausea and Retching, which is a sudden urge to vomit. Other symptoms of vomiting may include: Sweating: Cold sweats. Salivation: Increased production of saliva. Dizziness: A feeling of lightheadedness or faintness. Pale skin: Loss of color in the skin. Headache: Pain in the head. Abdominal cramps (peristalsis): Stomach pain. Weakness: Fatigue or lack of energy. Loss of appetite: Reduced interest in eating. Dehydration: Fluid loss due to vomiting and diarrhea. Weight loss: Decreased body weight due to inability to keep food down. Tachycardia : Increased heart rate. Vomiting Treatment Strategies The appropriate treatment for vomiting depends on the underlying cause. However, some general strategies may help alleviate symptoms and prevent dehydration: 1. Pharmacological: Over-the-counter or prescription medications to stop vomiting. 2. Non-pharmacological: - Hydration: Drink fluids, such as water, clear broth, or sports drinks, to avoid dehydration and replenish electrolytes lost through vomiting. - Bland diet: Consume bland foods like toast, crackers, or applesauce. Avoid spicy, greasy, or acidic foods. - Rest, relax, breath fresh air, decrease noxious stimuli, allow the body to recover. In case of severe vomiting or inability to keep fluids down, hospitalization is needed for intravenous (IV) fluids and medications. Prevention of Vomiting While it's not always possible to prevent vomiting, here are some strategies that can help reduce vomiting risk: Avoid foods and drinks that trigger vomiting. Eat small, frequent meals (avoid overeating). Eat a balanced diet with plenty of fruits, vegetables, and whole grains. Stay well-hydrated by drinking plenty of fluids, especially water. Get enough rest and sleep and fresh air. Avoid alcohol and caffeine. Take medications for motion sickness when traveling. Practice good food hygiene to prevent food poisoning. Manage stress, use relaxation techniques like deep breathing or meditation to reduce stress.  Where is the sensation of nausea created? An area of the medulla, called the vomiting center, inside the blood brain barrier, is stimulated by the central & peripheral neural pathways. When stimulated, it activates & control the vomiting cascade. The vomiting center receives stimulatory signals from four major neural pathways: 1. The Chemoreceptor Trigger Zone (CTZ): This is a zone located in the brainstem outside the blood brain barrier. Therefore, emetogenic stimuli can reach this area through the bloodstream. It contains receptors: Dopamine (D2), Serotonin (5-HT3) and Neurokinin (NK-1) receptors. 2. The vagal afferent neuron from the gastrointestinal system, which express Serotonin (5-HT3) and Neurokinin (NK-1) receptors. Stimulated by gastric stretch, and chemoreceptors. 3. The central vestibular nuclei, from the labyrinth (inner ear), which express Muscarinic (M) and Histamine 1 (H1) receptors. Stimulated by motion. 4. The higher centers of the brain (Limbic system). Stimuli like pain, memory, anxiety, and stress. Pathophysiology Nausea, retching and 2 vomiting (emesis) are part Hydrogen of the body's defense against ingested toxins Sulfide H2S 1 3 Chemoreceptor Trigger Zone Medulla Oblongata Outside the BBB Vomiting Centre Inside BBB 4 Drugs associated with a high incidence of nausea & vomiting 1. Chemotherapy agents: Drugs used to treat cancer often induce nausea and vomiting, especially in high doses. (cisplatin, carboplatin, doxorubicin, cyclophosphamide). 2. Opioid analgesics: Pain relievers like (morphine, codeine, and oxycodone) can cause nausea and vomiting. 3. Antibiotics: Certain antibiotics, such as (erythromycin and amoxicillin), can upset the stomach and lead to nausea. 4. Nonsteroidal anti-inflammatory drugs (NSAIDs): Medications like (ibuprofen and naproxen) can irritate the stomach lining. 5. Antidepressants: Some antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) (Fluoxetine, Sertraline), can cause nausea as a side effect. 6. Antipsychotics: Medications used to treat mental health conditions like schizophrenia can induce nausea and vomiting (Haloperidol). 7. Disease-modifying antirheumatic drugs (DMARDs): like (Sulfasalazine, Penicillamine) 8. Others: Gout med, (Allopurinol); HF med (Digoxin); Parkinson’s med (Levodopa, Bromocriptine); chronic obstructive pulmonary disease (COPD) med (Theophylline); Sex hormones (Oestrogens); Iron supplement. The vomiting cascade 1. Vomiting center stimulation 2. Relaxation of the lower esophageal sphincter 3. Contraction of the diaphragm and abdominal muscles 4. Increased Intraabdominal pressure 5. Closed Epiglottis 6. Vomiting occurs Receptor antagonist concept Neurotransmitters antagonism  Motion/Morning sickness Chemotherapeutic + opioid drugs Dopamine d2 Serotonin type 3 Neurokinin 1 Pain, Smell Emotion Sight ACh Muscarinic Chemo, Radio, Gastrio Domperidone Substance P Histamine H1 R Serotonin Cyclizine Labyrinth 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) 3. Dopamine 2 antagonists (D2-RA) (Neuroleptics) (Psychosis and Schizophrenia): 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) 1. Anticholinergics (Muscarinic receptor antagonist) (Cholinergic antagonists) E.g. (Hyoscine, Scopolamine, Dicyclomine) Prophylaxis for motion sickness, transdermal patch behind ear, not for chemotherapy induced vomiting. SE: Dry mouth, blurry vision (mydriasis), drowsiness. Mechanism of Action & Clinical Use: Muscarinic receptors are involved in the visceral afferent input from: 1) The gut to the vomiting center and 2) The cranial nerve from the labyrinth to the CTZ via the vestibular nucleus. Hyoscine (known as scopolamine) is used for the treatment of motion sickness and preoperative. Some antihistamines such as promethazine and cyclizine, and dopamine receptor antagonists such as prochlorperazine, also have antimuscarinic activity. 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  2. Histamine-1 (H1) receptor antagonists (Antihistamine) (Antiallergic) Used for motion sickness & morning sickness in pregnancy, vestibular disturbance, opioid nausea. But not for chemotherapy induced vomiting. E.g. (Promethazine, Meclizine, Cyclizine, Diphenhydramine, Dimenhydrinate). Betahistine, Betaserc® = (H3) antagonist, anti-vertigo. Side effect: Drowsiness, sedation, constipation (particularly with promethazine). CNS depression, Headache. Antimuscarinic effects: Dry mouth, urinary retention and blurred vision.  Antihistamines Mechanism of Action and Clinical Use: Antihistamines prevent vomiting by their antagonist action at histamine H1 receptors, and many also have antimuscarinic effects. Promethazine can block some 5-HT receptor subtypes. Antihistamines are effective against most causes of vomiting, but 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, and promethazine undergoes extensive first-pass metabolism. Both promethazine and cyclizine can be given by intramuscular or intravenous injection. Promethazine Promethazine Meclizine Cyclizine Meclizine Cyclizine Betahistine & Betaserc  3. Dopamine antagonists (D2-RA) (Neuroleptics) (Psychosis and Schizophrenia) 1. (Chlorpromazine & Prochlorperazine) used for chemotherapy & radiation vomiting SE: Sedation, hypotension, extra pyramidal side effects, restlessness. 2. (Substituted benzamides) Metoclopramide (it can cross BBB). MOA (D2RAn + 5- HT3RAn & GIT Motility 5-HT4 agonist effects) [prokinetic action], Trimethobenzamide: (for chemotherapy and radiation, toxins). SE: Fatigue, extra pyramidal side effects (Akathisia; restlessness, tardive dyskinesia, dystonia; involuntary muscle contractions). 3. (Droperidol, Haloperidol, Domperidone) They can't cross BBB, MOA: (D2RA on CTZ outside BBB + GIT Motility 5-HT4 agonist) Used for chemotherapy, post-surgery, toxins. SE: No Extra Pyramidal side effects, can't cross BBB, galactorrhea. Note: Anti-emetic doses of antipsychotic drugs are generally less than one-third of those used to treat psychoses. Metoclopramide & Domperidone, in addition to their antiemetic properties, exert prokinetic effects on the GIT. These agents increase the tone of the gastroesophageal sphincter, enhance gastric emptying, and stimulate small intestinal motility. Their actions are mediated through agonism at the 5-HT4 receptor subtype within the enteric nervous system. This stimulation indirectly leads to increased cholinergic activity, ultimately contributing to improved gastrointestinal function. Dopamine receptor antagonists are mainly used to reduce vomiting induced by chemotherapy drugs and surgery. Pure dopamine receptor antagonists are ineffective in motion sickness. The antipsychotic drug prochlorperazine is effective for vestibular disorders and motion sickness because of its antimuscarinic activity. 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 Withdrawn from US because of cardiac arrhythmias, QT prolongation, eye disorder, dry mouth, diarrhoea 4. Serotonin (5-HT3) antagonists (~setron) E.g. Ondansetron (Zofran®), Granisetron, Palonosetron, Dolasetron. Used for chemotherapy (cisplatin), post-radiation, post-surgery, pregnancy but not first trimester. The most potent antiemetic, mediated though central & peripheral action. Orally or IV, long duration of action High first pass metabolism. Side effects: Headache, dizziness, GIT upset constipation. Note: 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 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. Ondansetron Granisetron Palonosetron Dolasetron 5. Cannabinoids E.g. (Nabilone, Dronabinol) They are psychoactive drugs (5-HT3An). 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 5-HT3 release in the dorsal vagal nucleus. Pharmacokinetics: Nabilone is well absorbed from the gut. It is metabolized 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. Nabilone Dronabinol (marijuana) 6. Neurokinin 1 (NK1) receptor antagonists E.g. Aprepitant, fosaprepitant. Mechanism of Action and Clinical Use: Aprepitant and its prodrug fosaprepitant are antagonists at NK1 receptors in the CNS, inhibiting the action of substance P. They enhance the effects of 5-HT3 receptor antagonists and corticosteroids in preventing emetic response to cancer chemotherapeutic agent cisplatin. Pharmacokinetics: Aprepitant is well absorbed from the gut and has a long half-life. Fosaprepitant is given by intravenous infusion. SE: 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. Aprepitant Fosaprepitant 7. Corticosteroids Glucocorticoid E.g. (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 Pre-cancer chemotherapy, with subsequent oral doses to prevent delayed emesis. The mechanism of action may involve reduction of prostaglandin synthesis. Dexamethasone, Methylprednisolone 8. Adjuvant drugs i. Prokinetics E.g. (Metoclopramide & Domperidone) They enhance and coordinated GIT propulsive motility. MOA: 1. Dopamine receptor antagonism on myenteric motor neurons. 2. Relive nausea and vomiting by dopamine receptor antagonism in the CTZ. 3. Regulate motility by 5-HT4 agonist effect. Which is a better antiemetic, Metoclopramide or Domperidone ? What is the difference? Both have antiemetic and prokinetic effects. As CTZ is outside BBB. Metoclopramide (it can cross BBB), but has adverse effects, like extrapyramidal side effects, dyskinesia, galactorrhea, menstruation disorder, sedation. Domperidone is preferred antiemetic in children and levodopa induced vomiting.  ii. Benzodiazepines and barbiturates E.g. (Lorazepam, Diazepam) they are GABA-A agonists, reduce cerebral activity Used before chemotherapy to reduce anticipatory vomiting caused by anxiety 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. Summary of therapeutic choices Motion sickness: 1. Hyoscine, cyclizine: for short journey. 2. Promethazine and Diphenhydramine (first-generation antihistamine, anticholinergic): For long journey. 3. Metoclopramide. Morning sickness, (pregnancy vomiting) : Avoid all drugs in first trimester, 1. Vitamin B6, or pyridoxine 2. Promethazine, ondansetron 3. Metoclopramide, Diphenhydramine, Chemotherapy induced vomiting (CTZ) 1. D2Ra (metoclopramide, domperidone) 2. 5-HT3Ra (Ondansetron) 3. Adjunctive treatment, e.g. Benzodiazepines, Dexamethasone (Glucocorticoid), Cannabinoids (Nabilone) Cytotoxic drugs, gastrointestinal (GI) disorders & radiotherapy induced vomiting 1. Ondansetron 2. NK-1Ra Aprepitant Post-Operative vomiting Hyoscine, metoclopramide, domperidone, prochlorperazine