emetics & antiemetics

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Emetics & Ant emetics: 

Emetics & Ant emetics

Emesis (vomiting): 

Manikandan 2 Emesis (vomiting) Act of forceful expulsion of gastric contents through the mouth Often preceded by nausea & accompanied by retching

Emesis: 

Manikandan 3 Emesis Rational (valuable) reflex prevention of ingestion of noxious substances (sight, smell, taste, texture) local gut reflexes stimulate vomiting e.g. toxins backup blood monitoring system, should former two protective reflexes be breached Irrational reflexes labyrinth pregnancy ‘visual nasties’!

Neurotransmitters Involved: 

Manikandan 4 Neurotransmitters Involved Histamine via H 1 receptors Serotonin via 5HT 3 receptors Acetylcholine via M receptors Dopamine via D 2 receptors

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Manikandan 5 Emetic Centre CTZ Hormones Azotaemia Diabetes Dopamine 5 HT3 Acetylcholine Histamine Vestibular Sights Smell Taste Vomiting Gut Opioids Chemotherapy Anaesthetics BBB Hypotension Hypoxaemia

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Manikandan 6 Vomiting Centre (medulla) Cerebral cortex Anticipatory emesis Smell Sight Thought Vestibular nuclei Motion sickness Pharynx & GIT Chemo & radio therapy Gastroenteritis Chemoreceptor Trigger Zone (CTZ) (Outside BBB) Cancer chemotherapy Opioids Muscarinic, 5 HT 3 & Histaminic H 1 5 HT 3 receptors Dopamine D 2 5 HT 3, ,Opioid Receptors Muscarinic Histaminic H 1 Pathophysiology of Emesis

Emetics: 

Manikandan 7 Emetics They are required when an undesirable substance has been ingested

Emetic Drugs - Uses: 

Manikandan 8 Emetic Drugs - Uses Acute cases of poisoning (except in corrosives substances poisoning or if pt is not fully conscious) Alcoholic intoxication Removal of foreign bodies from the oesophagus Certain cases of paroxysmal tachycardia

Emetic Drugs - CIs: 

Manikandan 9 Emetic Drugs - CIs Hernias Aneurysm Severe heart diseases Peptic ulcer Hypertension Pulmonary TB Prolapse of rectum or uterus Threatened abortion Weak / debilitated persons Young children

Emetic Drugs: 

Manikandan 10 Emetic Drugs Centrally acting : Apomorphine directly stimulate the CTZ or VC Reflexly acting : Ipecacuanha stimulate the VC by irritating gastric & duodenal mucosa which stimulate afferent fibres of vagus nerve Locally acting: Alum, Sodium Chloride (Conc Solution) Other Drugs as Adverse Effect: Morphine, Digitalis, Emetine, Aspirin, Quinine & Anticancer drugs

Emetic drugs… : 

Manikandan 11 Emetic drugs… • Apomorphine • Ipecacuanha

Apomorphine: 

Manikandan 12 Apomorphine • Semi synthetic derivative of morphine • Given IM or SC • Dose is 6 mg (2-8mg) • Induces vomiting in 5 -10min • CNS depressant contraindicated in respiratory depression • Dose required is high so not given orally

Ipecacuanha : 

Manikandan 13 Ipecacuanha Contains two alkaloids- emetine & cephaeline Used as syrup ipecac. Produces effect in 15min. Acts by irritating gastric mucosa & through CTZ centre. Dose = 5ml in infants = 10-15ml in children = 15-20ml in adults

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Manikandan 14 Contraindications • Corrosive poisoning • CNS stimulant drug poisoning • Kerosene poisoning • Unconscious patients • Morphine poisoning

Anti-emetics: 

Manikandan 15 Anti-emetics

Introduction - Anti-emetics: 

Manikandan 16 Introduction - Anti-emetics Two centres: Emetic centre (EC) and chemoreceptor trigger zone (CTZ) Both near the floor of the fourth ventricle, close to the vital centres EC is within the blood brain barrier (BBB) CTZ outside in the area postrema They are connected together

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Manikandan 17 Vomiting Centre (medulla) Cerebral cortex Anticipatory emesis Smell Sight Thought Vestibular nuclei Motion sickness Pharynx & GIT Chemo & radio therapy Gastroenteritis Chemoreceptor Trigger Zone (CTZ) (Outside BBB) Cancer chemotherapy Opioids Muscarinic, 5 HT 3 & Histaminic H 1 5 HT 3 receptors Dopamine D 2 5 HT 3, ,Opioid Receptors Muscarinic Histaminic H 1 Pathophysiology of Emesis

ANTIEMETIC DRUGS: 

ANTIEMETIC DRUGS A group of drugs which are used to control nausea and vomiting Provide symptomatic relief Removal of causative factor to have ultimate relief

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Manikandan 19

Classification - Antiemetic drugs: 

Manikandan 20 Classification - Antiemetic drugs 1. H 1 antihistamines Meclizine, Cinnarizine, Cyclizine, Dimenhydrinate & Diphenhydramine. 2. Muscarinic Antagonist Hyoscine (Scopolamine). 3. Selective 5-HT 3 Antagonists Ondansetron, Granisetron, Palonosetron & Dolasetron.

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Manikandan 21 Classification.. 4. D 2 Antagonists a. Substituted Benzamides Metoclopramide, Trimethobenzamide b. Butyrophenones Domperidone , Droperidol c. Phenothiazines Prochlorperazine, Promethazine & Thiethylperazine. 5. Cannabinoids Dronabinol , Nabilone 6. Glucocorticoids Dexamethasone, Methylprednisolone 7. Benzodiazepines Diazepam , Lorazepam 8. Neurokinin-I Antagonist Aprepitant (oral formulation), Fosaprepitant (IV formulation)

D2 Antagonists : 

D 2 Antagonists a. Substituted Benzamides Metoclopramide, Trimethobenzamide b. Butyrophenones Domperidone , Droperidol c. Phenothiazines Prochlorperazine, Promethazine & Thiethylperazine.

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Manikandan 23 Metoclopramide Chemistry : Substituted Benzamide MOA : Dopamine D 2 receptors antagonist It is potent Antiemetic & Prokinetic agent As Antiemetic It has potent Antiemetic & antinausea effect. Blocks D 2 receptors in CTZ of the medulla (area postrema ) As Prokinetic agent It can selectively stimulate gut motor function. Blocks D 2 receptor in GIT & blocks the normal inhibitory effect of Dopamine on cholinergic smooth muscle stimulation--- ↑ motility.

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Manikandan 24 Th. Uses - Metroclopramide Potent antiemetic controls / reduces vomiting due to Uremia Radiation Viral gastro enteritis, hepatic-biliary disease Anticancer drugs Migraine Post operatively & pre-operatively

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Manikandan 25 As prokinetic agent useful in GERD Only symptomatic relief. May be combined with anti- secretory agents in refractory cases. Impaired GI emptying After surgery (vagotomy , antrectomy) Diabetic gastropresis. To promote advancement of nasoenteric feeding tube from stomach to intestine. Non-ulcer dyspepsia Only symptomatic relief in chronic dyspepsia

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Manikandan 26 Metroclopramide… Pharmacokinetics Rapidly absorbed from GIT after oral administration. Undergoes a high degree first pass metabolism. It is excreted in the urine as free and as metabolites. It is also excreted in the breast milk . DOSE: 10-20mg orally or IV every 6 hrs

Adverse Effects - Metroclopramide: 

Manikandan 27 Adverse Effects - Metroclopramide Extrapyramidal reactions with facial and skeletal muscle spasms- Restlessness, Dystonias , Parkinsonian symptoms (Occulogyric crises). More common in young and very old. Usually occur shortly after staring treatment and subside with in 24 hours of stopping the drug. Bowel upsets, Diarrhoea Drowsiness and fatigue, dizziness, restlessness and anxiety. Galactorrhoea, Gynecomastia, impotence and menstrual disorders – due to increased prolactin levels

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Manikandan 28 Trimethobenzamide Substituted Benzamide Antiemetic like Metoclopramide . D 2 Antagonist & mild anti- histaminic activity DOSE: 250mg orally, 200mg rectally, 200mg IM

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Manikandan 29 Phenothiazines & Butyrophenones Phenothiazines Prochlorperazine, Promethazine & Thiethylperazine Phenothiazines are antipsychotics with potent antiemetic property due to D 2 antagonism and anti-maucarinic properties Sedative property due to anti-histaminic property Mainly used as anti-emetic in severe N& V Main A/E: EPS , sedation , postural hypotension

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Manikandan 30 Butyrophenones Antipsychotic drugs , D 2 antagonists Droperidol Central D 2 antagonist Main A/E: EPS , postural hypotension QT prolongation may occur Domperidone Does not cross BBB. Only blocks D 2 in CTZ where BBB is leaky. May be used in N&V due to Levodopa, without affecting its efficacy. No EPS. Used as antiemetic , prokinetic agent & for post partum lactation stimulation.

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Manikandan 31 Which is a better antiemetic – Metoclopramide or Domperidone ? As CTZ is outside BBB both have antiemetic effects. But as metoclopramide crosses BBB it has adverse effects like extrapyramidal side effects. . Domperidone is well tolerated.

Selective 5-HT3 Antagonists: 

Selective 5-HT 3 Antagonists Ondansetron, Granisetron , Dolasetron & Palonosetron MOA Act as anti-emetic by Selectively blocking central 5HT 3 receptors in Vomiting center & CTZ & Mainly by blocking Periphery 5HT 3 receptors on intestinal vagal and spinal afferent fibers Antiemetic action is restricted to emesis caused by vagal stimulation (eg post op) & chemotherapy Palonosetron: newer with greater affinity for 5-HT3 receptor & comparatively longer half life No effect on Dopamine / muscarinic receptors

Ph. K - Selective 5-HT3 Antagonists : 

Manikandan 33 Ph. K - Selective 5-HT 3 Antagonists High first pass metabolism t 1/2 : 4-9 hrs ( Ondansetron, Granisetron & Dolasetron) 40 hrs (Palonosetron) Given once or twice daily – orally or intravenously Excreted by liver & kidney No dose reduction in renal insufficiency but needed in hepatic insufficiency ( Ondansetron)

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Manikandan 34 Th. Uses - Selective 5-HT 3 Antagonists Chemotherapy- Induced Nausea & vomiting Primary Agents - prevention of acute chemotherapy induced Nausea & vomiting Effective alone in most of the cases. Efficacy is enhanced in combination. Can be given I/V 1/2 hr before chemotherapy To prevent Delayed Nausea & vomiting occurring after 24 hrs of Cancer chemotherapy in combination with Dexamethasone & NK1 receptor antagonist . To prevent & treat post operative & post radiation Nausea & vomiting

Slide 35: 

Manikandan 35 A/Es - Selective 5-HT 3 Antagonists Excellent safety profile Headache, Dizziness & constipation All three drugs cause prolongation of QT interval, but more pronounced with dolasetron. DIs Hepatic clearance may decrease by enzyme inhibitors

Slide 36: 

Manikandan 36 H 1 antihistamines & Muscarinic Antagonists H 1 antihistamines Meclizine, Cinnarizine, Cyclizine & Diphenhydramine & its salt Dimenhydrinate. MuscarinicAntagonist Hyoscine (Scopolamine). Vestibular system is important in motion sickness via cranial nerve VIII - rich in Cholinergic M 1 & Histamine H 1 receptors Most effective drugs for motion sickness Scopolamine (hyoscine) – used as transdermal patch for motion sickness

H1antihistamines & Muscarinic Antagonists…: 

Manikandan 37 H 1 antihistamines & Muscarinic Antagonists… MOA They have anticholinergic & H1 antagonist sedating properties (1 st generation). They produce specific depression of conduction in vestibulocerebellar pathway. Th. Uses Effective for nausea & vomiting associated with motion sickness. Vestibular disorders ( Meniere’s disease) Meclozine is longer acting so useful in sea sickness Cinnarizine also has antivertigo effect. Act by inhibiting influx of calcium to vestibular sensory cells from endolymph

Cannabinoids (Dronabinol , Nabilone): 

Cannabinoids ( Dronabinol , Nabilone) Dronabinol Tetrahydrocannabinol (THC) main psychoactive chemical in marijuana Ph.K: complete absorption on oral adm, significant 1 st pass effect, metabolites excreted slowly over days to weeks in faeces & urine MOA : Act as antiemetic & appetite stimulant in addition to psychoactive action. MOA not clear. Cancer chemotherapy induced Nausea & vomiting with Phenothiazines – synergistic effect but AEs are added – not used as better drugs are available Nabilone closely related THC analog

Glucocorticoids: 

Glucocorticoids Dexamethasone , Methylprednisolone Antiemetic MOA not clear Enhance action of 5HT 3 antagonists in Cancer chemotherapy induced Nausea & vomiting

Benzodiazepines: 

Manikandan 40 Benzodiazepines Diazepam , Lorazepam Used prior to Cancer chemotherapy to reduce anticipatory vomiting Vomiting caused by anxiety

Neurokinin-1 (NK1 )Antagonists Aprepitant, Fosaprepitant: 

Neurokinin-1 (NK 1 )Antagonists Aprepitant, Fosaprepitant Ph.K Given orally BA = 65% , Crosses BBB. t ½ : 12 hrs, Metabolized by hepatic CYP3A4. MOA Act as Antiemetic : Selectively block NK 1 receptor in area postrema. No effect on Serotonin , Dopamine or Corticoid receptors .

Aprepitant: 

Manikandan 42 Aprepitant Non peptide, selective, Neurokinin type 1 (NK 1) receptors antagonist Block substance P from binding to NK1 receptor Broader spectrum and activity in delayed emesis (In Preclinical studies) Augment the antiemetic activity of 5HT3 receptor antagonists and dexamethasone Inhibit both acute and delayed CINV

Neurokinin-1 (NK1 )Antagonists: 

Manikandan 43 Neurokinin-1 (NK 1 )Antagonists Th. Uses Used in combination with 5HT 3 antagonists & Corticosteroids for prevention of acute & chronic nausea and vomiting from Cancer chemotherapy

Neurokinin-1 (NK1 )Antagonists: 

Manikandan 44 Neurokinin-1 (NK 1 )Antagonists A/Es Fatigue, dizziness & diarrhoea. Enzyme inhibition Metabolized by CYP3A4 & may inhibit metabolism of many anticancer drugs (Docetaxel, Paclitaxel, Etoposide, Vinblastine, Imatinib) ---- ↑ levels --- toxicity. Metabolism of Aprepitant may be inhibited by Ketoconazole, Ciprofloxacin, Clarithromycin, Nafazodone, Ritonavir, Nelfinavir, Verapamil & Quinidine) Aprepitant ↓ INR in patients taking warfarin.

Slide 45: 

Manikandan 45 Therapeutic Uses of Anti-emetics Motion sickness: Hyoscine Vestibular disorders( Menieres, disease): Cinnerazine Vomiting due to Uremia, Radiation, Viral gastro enteritis, Liver disease, Migraine , Prochlorperazine , Metroclopramide Vomiting due to pregnancy ( hyperemesis gravidarum), Meclizine with vit. B 6 (Navidoxine)

Slide 46: 

Manikandan 46 Vomiting due to Cytotoxic Anticancer drugs: 5HT 3 Antagonists Metroclopramide, Cannabinoids, corticosteroids , Aprepitant Anticipatory Vomiting due to Cytotoxic Anticancer drugs. Benzodiazepines (Diazepam) Post Operative Vomiting: Metoclopramide , Prochlorperazine , Dimenhydrinate, 5HT 3 Antagonists (Ondensetron)

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Manikandan 47 Thank You

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Manikandan 48

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Manikandan 49 Thank you

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Manikandan 50 Aprepitant: A new Drug for Chemotherapy Induced Nausea and Vomiting Girish C Dept. of Pharmacology, JIPMER, Pondicherry, INDIA

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Manikandan 51 Nausea and vomiting -- devastating side effects of antineoplastic agents Uncontrolled emesis affect quality of life and impair compliance with treatment About 70- 80% patients experience emesis & 10-44% have anticipatory emesis The potential for Chemotherapy induced Nausea and Vomiting (CINV) is influenced by Emetogenic potential of antineoplastic agents Patient related factors Introduction

Slide 52: 

Manikandan 52 Emetogenic Potential of Antineoplastic agents Navari RM. Pathogenesis-based treatment of chemotherapy – induced nausea and vomiting – Two new agents. J Support Oncol 2003;1:89-103

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Manikandan 53 Patient Related Risk Factors Navari RM. Pathogenesis-based treatment of chemotherapy – induced nausea and vomiting – Two new agents. J Support Oncol 2003;1:89-103

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Manikandan 54 Acute CINV : Nausea and vomiting with in the first 24 hrs of chemotherapy Delayed CINV : After 24 hrs lasting up to 5 days Anticipatory CINV : A fter a negative past experience with chemotherapy Breakthrough CINV : Occurs despite patient being treated with preventive therapy Refractory CINV : Occur during subsequent cycles of chemotherapy when antiemetic prophylaxis has failed in earlier cycles Types of CINV

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Manikandan 55 Vomiting Centre (medulla) Cerebral cortex Anticipatory emesis Smell Sight Thought Pharynx & GIT Chemo & radio therapy Chemoreceptor Trigger Zone (CTZ) (Outside BBB) Cancer chemotherapy Ach, 5 HT Histamine & Substance P 5 HT & Substance P Dopamine 5 HT, substance P Pathophysiology of CINV

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Manikandan 56 Approaches in the management of CINV Emetic center Serotonin Dopamine Substance P Endorphins Acetylcholine Histamine

Slide 57: 

Manikandan 57 Dopamine receptor antagonists( Metoclopramide, Phenothiazines, butyrophenones) 1990- First selective 5 -HT 3 receptor antagonist introduced (Ondansetron ) Addition of dexamethasone further improved these symptoms ( Acute emesis up to 60-70%)

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Manikandan 58 Ineffectiveness in delayed emesis Not effective in all patients Ineffective once symptoms develop Limitations

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Manikandan 59 Focus on New Targets… Substance P - belongs to tachykinin family of peptides Neurokinin A &B are other members Present in CNS( neurotransmitter), GIT( transmitter in enteric nervous system & act as local hormone) Implicated in behavior, anxiety, depression, nausea& vomitting Tachykinins act through Neurokinin type 1(NK1) , NK2 & NK3 receptor

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Manikandan 60 Substance P is the major ligand for NK1 NK1 receptors are dense in NTS, DMVN and vagal afferent nerve fibers in GIT Blockers of NK1 receptor lessen emesis in experimental studies Aprepitant is first drug of NK1 receptor antagonists

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Manikandan 61 Aprepitant Non peptide, selective, Neurokinin type 1 (NK 1) receptors antagonist Block substance P from binding to NK1 receptor Broader spectrum and activity in delayed emesis (In Preclinical studies) Augment the antiemetic activity of 5HT 3 receptor antagonists and dexamethasone Inhibit both acute and delayed CINV

Slide 62: 

Manikandan 62 5-[[(2 R ,3 S )-2-[(1 R )-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3 H -1,2,4-triazol-3-one Empirical formula: C 23 H 21 F 7 N 4 O 3 Chemistry

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Manikandan 63 Pharmacokinetics

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Manikandan 64 Orally active Bioavailability of 60-65%... unaffected by food T max -- after 4 hrs of oral dose Volume of distribution -70 L 95% bound to plasma proteins Crosses BBB & placental barrier Metabolism in liver (CYP3A4) Excreted in urine (50%) and in feces(50%)

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Manikandan 65 Drug Interactions

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Manikandan 66 A substrate, moderate inducer and moderate inhibitor of CYP3A4 Induces CYP2C9 Pimozide, terfenadine, astemizole and cisapride should not be used concurrently with aprepitant Docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, vincristine Interact with warfarin, dexamethasone, methylprednisolone, oral contraceptives

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Manikandan 67 Adverse Effects Asthenia(17.8%), hiccups(10.85%), diarrhoea(10.3%), heartburn(9.5%), dizziness, elevation in LFT values Case reports of angioedema, urticaria, Stevens- Johnson syndrome

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Manikandan 68 Indications and Dose FDA approved on March 2003 for prevention of acute and delayed CINV with single or repeated courses of highly emetogeneic chemotherapy 125 mg on day 1 (before chemotherapy) and then 80mg on days 2 and 3(after chemotherapy) Should be given with a 5HT 3 antagonist and dexamethsone Dose of dexamethasone should be reduced by 50%