Anti-emetics

1. Anti-emetics Physiology, pharmacology and some learning tools

2. What is vomiting? • To forceful expulsion of gastric contents co-ordinated within the medulla of the brainstem • Nausea and vomiting can exist as separate entities

3. Vomiting • Area Postraema

4. Input to the area postraema

5. Anxiety Fear Pain Psychological stimuli Anticipatory nausea Emotions Smell HIGHER CENTRES Cortex Limbic system VESTIBULAR APARATUS (motion sickness/vertigo) Biochemical abnormality (i.e. ↑Ca2+) Uraemia Drug toxicity Opiods Toxins (bacterial/tumour) Chemotherapy Dopamine 2 AREA POSTREMA Raised intracranial pressure Integrated vomiting centre Nucleus tractussolitarius Vagus nerve Glossopharyngeal nerves Pharyngeal irritation 5HT Neurokinin 1 CN nuclei Systemic circulation Sympathetic nerves Splanchnic nerves Visceral stretch Gastric irritation Gastric distension Abdominal radiotherapy Bowel distension/obstruction Chemotherapy Capsular stretch Vagus nerves GI TRACT LIVER Portal vein

7. Vestibular system http://en.wikipedia.org/wiki/Vestibulo-ocular_reflex

8. Vestibular nuclei

9. Anti-emetics • Anti-emetics act on all different parts of the vomiting ‘reflex’ • They have a synergistic effect as they act on different parts of the reflex. • Allows clinicians to select the most appropriate anti-emetic for each clinical scenario • Several agents available – used for specific conditions

10. The anti-emetic classes:

11. H1-receptor antagonists (anti-histamines) • H1 is a G-coupled protein receptor • Expressed in smooth muscle, heart, CNS and vascular endothelial cells • Activated by endogenous histamine • Released from hypothalamus (tubomamillary nucleus) • ‘Anti-histamines’ only act on H1 receptors (not H2 as well) • Also have anticholinergic activity • They are ‘inverse agonists’ rather than antagonists per se. • http://pharmacologycorner.com/pharmacodynamics-animation-full-agonists-partial-agonists-inverse-agonists-competitive-antagonists-and-irreversible-antagonists/

12. H1-receptor antagonists Examples: cinnarizine, cyclizine, meclizine, promethazine (NASA + mums to be) Indications: vestibular apparatus-mediated N&V, raised ICP, motion sickness, liver capsular stretch, pharyngeal irritation, irritants in the stomach • Not effective against things that directly affect the vomiting centre Contra-indications: do not give with metoclopramide • Anticholinergic action will negate pro-motility effect of m Side-effects: Drowsiness and sedation K+

13. Muscarinic antagonists Examples:Hyoscine (scopolamine) Indications: prophylaxis and treatment of motion sickness Give: orally, transdermal patch Side effects: Blurred vision, dry mouth, drowsiness

14. Selective 5-HT3 receptor antagonists • Act on the vomiting centre • 5-HT is both a neurotransmitter and a local hormone in the peripheral vascular system. • It is found in the wall of the intestine (90%, enterochromaffin cells and ENS), in platelets (released at sites of tissue damage), in the CNS • 7 types of receptor – found in different places. 5-HT5-7 are unknown! • Actions of 5-HT: • Increased gastric motility – excitation of smooth muscle • Contraction of other smooth muscle – bronchi, uterus • Mixture of vascular constriction and dilation • Platelet aggregation and control of haemostasis • Inflammatory mediator • Stimualtion of peripheral nociceptive nerve endings • CNS: control of appetite, sleep, mood, hallucinations, steroetyped behaviour, pain perception and vomitting

15. Selective 5-HT3 receptor Examples: Ondansetron, granisetron, tropisetron, dolasteron Indications: post-operative N&V, radiotherapy-induced N&V, chemotherapy-induced N&V • For ACUTE N&V, less effective with delayed N&V Given by: orally, infection (useful in N is already present) Side effects: Constipation, Headache, GI upset

16. Dopamine (D2) antagonists • Antipsychotic phenothiazines and other antipsychotics • Act mainly by blocking dopamine D2 receptors in the vomiting centre • Also block histamine and muscarinic receptors Examples: Chlorpromazine, perphenazine, prochlorperazine, trifluoperazine. Haloperidol Given by: orally, IV, suppository Side effects (frequent): sedation (chlorpromazine), postural hypotension (blocks α2 receptors), extra-pyramidal symptoms (dystonia and tardivedyskinaesia) • Postural hypotension may be potentiated by poor fluid intake and refractory V See document on Wiki about antipsychotics for more info about these drugs and explanation of SEs

17. D2 receptor antagonists: Metoclopramide + domperidone • Occulogyric crisis • Dystonic reaction to certain drugs • ‘Oculogyric’ refers to the rotation of the eyeballs but several other responses are also seen • Drug causes: neuroleptics, carbamezipine, cisplatin, levodopa, metoclopramide, lithium, domperidone, nifedipine • S+S: intiallyfatugue, restlessness, fixed stare. Then characteristic upward deviation of the eyes. Also backward flexion of the neck, widely open mouth and protrusion of the tongue, occular pain. Also lacrimation, mutilism, drooling, dilated pupils, respiratory dyskinaesia • Rx: Immediate IV antimuscarinicbenzotropine or procycladine – effective after 5 mins, may repeat doses if no response → benadryl • Dopamine antagonists and pro-kinetic anti-emetics • Central action on vomitting centre AND peripheral action on GIT • Work by countering the dopamine inhibition of motility and stimulating motility as a 5-HT4 agonist Half-life: 4-5 hours Indications: aid gastric empyting, GORD Side effects (due to dopamine blockade elsewhere in CNS): movement disorders (children and young adults), fatigue, motor restlessness, spasmodic torticollis, occulogyric crises (involuntary upward eye movements), galactorrhoea and menstruation disturbance (stimulates prolactin) • Domperidone does not cross the BBB – no EPSEs

18. Cannabinoids • Naloxone antagonises the antiemetic effect – implies opiod receptors play a role Examples:nabilone Indications: refractory N&V, vomitting-centre-induced N&V Given by: orally • A (GI), D, M (diffusely, half-life 120 mins), E (urine + faeces) Side effects (frequently occur): drowsiness, dizziness, dry mouth, mood changes, postural hypotension, hallucinations and psychotic reactions

19. Neurokinin-1 antagonists • G-protein coupled receptor • Broad spectrum of action • Substance P • A ‘tachykinin’ neuropeptide (neurotransmitter and neuromodulator) • Found in brain and spinal cord • Endogenous receptor – neurokinin-1 (NK1R). Found in close association to 5HT receptors (?anti-depressant) • Function – pain perception (transmission of pain info to CNS; capsaicin ↓ SP), stress, vomiting (high conc of SP in VC), vasodilator (NO-dependent) • Examples: Aprepitant • Indications: to treat DELAYED emesis associated with some chemotherapy regimens

20. Steroids • High-dose glucocorticoids • Mechanism of action unclear • ?reduces permeability of BBB and sensitivity of AP to emetogenic substances - ↓ GABA release in brainstem • Frequently deployed with another anti-emetic • Phenothiazine, ondansetron, NK-1 antagonist • Examples: dexamethasone • Indications: cytotoxic-induced N&V

21. Anxiety Fear Pain Psychological stimuli Anticipatory nausea Emotions Small Steroids HIGHER CENTRES Cortex Limbic system VESTIBULAR APARATUS (motion sickness/vertigo) D2 receptor antagonists Biochemical abnormality (i.e. ↑Ca2+) Uraemia Drug toxicity Opiods Toxins (bacterial/tumour) Chemotherapy Dopamine 2 H1-receptor antagonists Canabinoids AREA POSTREMA Opiod receptors Raised intracranial pressure Integrated vomiting centre Nucleus tractussolitarius Vagus nerve Glossopharyngeal nerves Pharyngeal irritation 5HT Neurokinin 1 CN nuclei Systemic circulation Muscarinic receptor antagonists Sympathetic nerves Splanchnic nerves Aprepitant 5HT3 receptor antagonists Visceral stretch Gastric irritation Gastric distension Abdominal radiotherapy Bowel distension/obstruction Chemotherapy Capsular stretch Vagus nerves GI TRACT LIVER Portal vein

22. Prescribing skills • First-line drug – identify most likely cause of N&V and select appropriately (see table) • Administer by a suitable route • V preventing PO administration • Second-line drug – or combination therapy – to be introduced if symptoms persist after 24 hours • Chemo – use levomepromazine(broad spec) • Correct reversible causes of N&V?: • Hypercalcaemia • Hydration • Stop emetogenic drugs • Drain ascites • Manage bowel obstruction

23. Case Scenario – Motion sickness • Patients usually complain of feeling sick depending on their ambulatory state • Motion sickness depends upon the influential effect of the environment on the vestibular system • The effects of this are mediated by the cholinergic system through CNVIII • Which drug would be most clinically relevant in this case? • Anticholinergics – e.g. hyoscine • Dopamine antagonists such as metoclopramide and 5-HT3 antagonists such as ondansetron are inneffective in the treatment or prevention of motion sickness.

24. Case Scenario – Parkinson’s • Parkinson’s is caused by a lack of dopamine normally produced by the substantianigra . • Which group of antiemetics would be contraindicated in this case? • Dopaminergic antagonists – the symptoms of Parkinson’s would be exacerbated • Prochlorperazine • Metoclopramide • HOWEVER – domperidone is a dopamine antagonist that does not cross the BBB (metoclopramide does) and therefore this can be used

25. With regard to anti-emetics which of the following is true? • Cyclizine acts on the histaminergic system • Ondansetron primarily acts on the dopaminergic system • Prochlorperazine acts on the cholinergic system • Metoclopramide is the drug of choice for motion sickness • Metoclopramide is the anti-emetic of choice in Parkinson’s disease

26. G-protein coupled receptor • Large protein family of receptors that sense molecules outside the cell and activate inside signal transduction pathways and ultimately cellular responses • The ligands that bind to and activate these receptors range from light-senstiviecompunds, odors, pheremones, hormones and neurotransmitters • GPCRs are the targets for 40% of medicinal drugs • 2 principal signal transduction pathways: • cAMP • Phosphatidylinositol signal pathway • Ligand binds to the GPCR→ conformational change in the GPCR→ allows it to act as a guanine nucleotide exchange factor (GEF). • GPCR can then activate an associated G-protein by exchanging its bound GDP for a GTP • G-protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits → further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type • http://pharmacologycorner.com/g-protein-coupled-receptors-3-d-video-and-text/

27. Anticipatory nausea • Common in patients undergoing chemotherapy • Associated with anxiety • Rx: Lorazepam (short-acting benzo)

28. antihypertensives Based on NICE guidelines and BHS guidelines

29. Routine investigations • Urine dip test for protein and blood • Renal function - Serum creatinine and electrolytes • Diabetic? – blood glucose (ideally fasted) • Hypercholesterolaemia? – blood lipid profile • Arrythmias or HF? - ECG

30. ACE-inhibitors • INDICATIONS • Heart failure • LV dysfunction • Post-MI • Established CVD • Type I diabetic nephropathy • Secondary stroke prevention • CAUTIONS • Renal impairment • Peripheral vascular disease • CONTRAINDICATIONS • Pregnancy • Renovasculardsiease

31. ARBs • Candesartan, losartan, eprosartan, irbesartan, olmesartan, telmisartan, valsartan • INDICATIONS • ACE-inhibitor-intolerance • Hypertension with LVH • Heart failure in ACE-intolerant patients • Post-MI • CAUTIONS • Renal impairment • Peripheral Vascular Disease • CONTRA-INDICATIONS • Pregnancy • Renovascular disease

32. Beta-blockers • INDICATIONS • MI • Angina • CAUTIONS • HF • Peripheral Vascular Disease • Diabetes • CONTRAINDICATIONS • Asthma/COPD • Heart block

33. Thiazide diuretics • INDICATIONS • Elderly • Heart failure • Secondary prevention of stroke • CONTRA-INDICATIONS • Gout

34. Alpha-blockers • Doxazosin, Indoramin, Prozosin, Terazosin • INDICATIONS • BPH • CAUTIONS • Postural hypotension • Heart failure • CONTRA-INDICATIONS • Urinary incontinence