13 Pharm: Nausea and Vomiting, Prokinetics and Antiemetics Flashcards Preview

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Flashcards in 13 Pharm: Nausea and Vomiting, Prokinetics and Antiemetics Deck (29):
1

Nausea and vomiting (p.2+4-7)

  • Nausea 
  • nausea and vomiting
  • gastroparesis and slow GI transit often cause/
  • increased intracranial pressure (e.g. central nervous system tumor expansion) may cause/
  • Vomiting is caused mainly by/
  • Vomiting
    • ?
    • the vomiting center

  • Nausea
    • a subjective, unpleasant, queasy sensation referred to the epigastrium and abdomen that often precedes vomiting.
    • a distinct perception, different from pain or distress.
  • nausea and vomiting
    • often associated
    • don’t always take place together.
  • gastroparesis and slow GI transit often cause significant nausea without vomiting,
  • increased intracranial pressure (e.g. central nervous system tumor expansion) may cause a person to vomit without experiencing nausea.
  • Vomiting is caused mainly by stimulation of one or more of four sites:
    • the gastrointestinal tract,
    • the vestibular system,
    • the chemoreceptor trigger zone (CTZ) in the area postrema of the floor of the fourth ventricle
    • higher centers in the central nervous system (CNS).
  • Vomiting
    • the forceful expulsion of gastric contents by a complex neuromuscular process that includes voluntary and involuntary components.
    • One or more of the four sites involved in nausea stimulates the nucleus of the tractus solitarius and the reticular formation of the medulla oblongata, which make up ‘the vomiting center.’

2

Conditions associated with nausea and vomiting (p.8-9)

  • Gastroenteritis
  • Pregnancy—morning sickness or hyperemesis gravidarium
  • Anesthesia and post-surgery
  • Medications—especially chemotherapy, opioid analgesics, NSAIDs, and antibiotics
  • Gastroparesis (frequently encountered in patients who are diabetic although it’s often idiopathic)
  • Inflammatory bowel disease—common in Crohn’s disease patients who have strictures and obstructions
  • Acute ethanol intoxication—especially if you work in the emergency department
  • Surgical scarring due to abdominal adhesions

3

3 basic phases to vomiting (p.11-13)

  • pre-ejection phase: gastric relaxation and retroperistalsis
  • retching phase: rhythmic contraction of abdominal muscles, intercostal muscles and diaphragm against a closed glottis
  • ejection phase: intense contraction of the abdominal musculature with relaxation of the upper esophageal sphincter.

4

Patient related Risk factors for Nausea and Vomiting

  • Two major types of nausea and vomiting
  • Patient risk factors for nausea and vomiting (and CINV and PONV)

  • Two major types of nausea and vomiting
    • post-operative nausea and vomiting (PONV)
      • associated with certain types of general anesthesia as well as certain surgical and patient factors.
      • triggered bygynecological surgery, urological surgery, strabismus correction, and middle ear surgery
      • greater risk of having nausea and vomiting with subsequent surgeries.
    • chemotherapy-induced nausea and vomiting (CINV).
  • Patient risk factors for nausea and vomiting (and CINV and PONV)
    • Female gender
    • Non-smoker
    • Women with a history of morning sickness
    • History of anxiety
    • Age less than 50 years
    • Non-drinker or light drinker
    • History of motion sickness
    • History of nausea and vomiting from previous chemotherapy or following previous surgery

5

Non-adaptive vs. adaptive nausea and vomiting (p.16-17)

6

Triage of the patient with acute onset of nausea and vomiting

  • Findings favoring self-limited symptoms
  • Findings that support serious disease

  • Findings favoring self-limited symptoms
    • Younger age
      Family members with similar illness
      Myalgias, arthralgias (viral syndrome)
      Nonbloody diarrhea
    • Vertigo/motion sickness
      Typical migraine symptoms
      Associated with food ingestion
    • Associated with medication
      Recent excess alcohol ingestion
      Early pregnancy
  • Findings that support serious disease
    • Older age
    • Abdominal or chest pain
    • Late pregnancy
    • Bloody diarrhea
    • Anticoagulated state
    • Severe headache
    • Fever
    • Known Underlying Disease
      • Coronary artery disease
      • Prior GI tract surgery
      • IBD (strictures, obstruction)
      • Diabetes mellitus
      • Gallstones
      • Alcoholism

7

What happens when Nausea and Vomiting go untreated (p.18)

  • Nausea and vomiting may produce/
  • Sustained nausea may cause/
  • Nutrient deficiencies are a particular problem with conditions like/
  • Prolonged bouts of vomiting may produce/
  • Loss of fluid and hydrogen and chloride ions through vomiting leads to/
  • Hypokalemia
  •  hyponatremia

  • Nausea and vomiting may produce nutritional deficiencies and metabolic derangements through reduced caloric intake, loss of nutrients from vomiting, and loss of blood volume.
  • Sustained nausea may cause a significant reduction of food intake leading to malnutrition.
  • Nutrient deficiencies are a particular problem with conditions like cancer chemotherapy-induced sickness and hyperemesis gravidarum (a severe form of morning sickness), which may generate nausea for days, weeks, or even months.
  • Prolonged bouts of vomiting may produce dehydration, hypotension, hemoconcentration, oliguria, muscle weakness, and cardiac arrhythmias.
  • Loss of fluid and hydrogen and chloride ions through vomiting leads to hypochloremic alkalosis.
  • Hypokalemia is present with the loss of potassium ions from vomiting and renal potassium wasting resulting from alkalosis.
  • In more extreme cases of vomiting, hyponatremia can occur because of sodium loss (in the vomitus) and the release of vasopressin to conserve vascular volume.

8

Types of antiemetics and Prokinetics (p.20-21)

  • antiemetic drugs
    • antagonize/
    • classified according to/
  • Five neurotransmitter receptor sites that are of primary importance in the vomiting reflex
  • The area postrema
  • other central and peripheral sites play a role, including/
  • drug selection is based upon/

  • antiemetic drugs
    • antagonize the neurotransmitter receptors which are recognized as being involved in the physiology of nausea and vomiting.
    • classified according to their primary action;
      • some agents affect multiple receptors.
  • Five neurotransmitter receptor sites that are of primary importance in the vomiting reflex 
    • M1 – muscarinic
    • H1 – histamine
    • D2 – dopamine
    • 5-hydroxytryptamine (HT)-3 – serotonin
    • Neurokinin 1 (NK1) receptor – substance P
  • The area postrema is an important site for M1, D2, 5-HT3, and NK1 receptors,
  • other central and peripheral sites play a role, including
    • H1 receptors in the vestibular nucleus
    • 5-HT3 receptors on vagal afferent neurons.
  • drug selection is based upon empiricism, clinical experience, preferred route of administration, and safety.

9

Anticholinergic agents:
Scopolamine (Transderm Scōp®) (p.22)

  • ?
  • predominantly used/
  • delivered/
  • Side effects include/

  • ?
    • The M1-muscarinic receptor antagonist,
    • the major anticholinergic drug
    • an effective antiemetic.
  • predominantly used as prophylaxis against motion sickness.
  • delivered transdermally.
  • Side effects include dry mouth, drowsiness, and vision disturbance.

10

Antihistamines (p.23)

  • ?
  • primarily used for/
  • Available agents include
  • common side effects

  • ?
    • H1 blockers
  • primarily used for motion sickness, PONV, and vestibular disorders (nausea due to vertigo).
  • Available agents include:
    • diphenhydramine (Benadryl®)
    • dimenhydrinate (Dramamine®)
    • cyclizine (Marezine®)
    • meclizine (Antivert®)
    • promethazine (Phenergan®)
  • Sedation, dry mouth, urinary retention, nausea, and blurred vision are common side effects
    • Extrapyramidal effects may occur, especially with promethazine.

11

Dopamine receptor antagonists:
Phenothiazines (p.24)

  • the first group of drugs to demonstrate substantial activity in the prevention of/
  • act predominantly by/
  • Prochlorperazine (Compazine®) 
    • frequency of use
    • moderately effective for/
    • can be given by/
  • Chlorpromazine (Thorazine®)/
  • Thiethylperazine (Torecan®)/
  • The main adverse effects 
  • delivery

  • the first group of drugs to demonstrate substantial activity in the prevention of CINV.
  • act predominantly by antagonizing D2-dopamine receptors in the area postrema of the midbrain,
    • also have M1-muscarinic and H1-histamine blocking effects.
  • Prochlorperazine (Compazine®)
    • the most commonly used antiemetic in this class;
    • moderately effective for nausea caused by various gastrointestinal disorders and mild to moderate but not highly emetogenic chemotherapy.
    • can be given by mouth, intravenously (IV) or intramuscularly (IM), or by rectal suppository.
  • Chlorpromazine (Thorazine®) is used less often than prochlorperazine.
  • Thiethylperazine (Torecan®) is another less frequently prescribed phenothiazine.
  • The main adverse effects
    • extrapyramidal reactions such as dystonia, restlessness and, with prolonged use, tardive dyskinesia.
      • Acute dystonia can be treated with IV or IM diphenhydramine (Benadryl®).
      • Tardive dyskinesia is an irreversible, rapid, repetitive muscle disorder which involves involuntary movements of the arms, legs, trunk, fingers and facial muscles.
        • changing from a phenothiazine to another type of antiemetic after a considerable length of time is recommended.
    • Hypotension, particularly in the elderly or with IV infusion.
  • IV delivery of phenothiazine medications should be done under close supervision on an inpatient basis.

12

Dopamine receptor antagonists:
Butyrophenones (p.24)

  • ?
  • primarily used as/
    • also effective for/
  • Droperidol (Inapsine®)/
  • haloperidol (Haldol®) 
    • half-life
    • receptor binding
    • ideal for/
      • also useful in the treatment of/
    • contraindicated in/
    • minimally/
    • can be given/
    • marketed as/
  • The side effect profile and antiemetic efficacy/
  • The need for this class of agents and their utilization/

  • ?
    • major tranquilizers
    • potentiate the actions of opioids
    • have an antiemetic effect when used alone.
  • primarily used as a pre-anesthetic agent or for procedural sedation,
    • also effective for PONV and nausea and vomiting
  • Droperidol (Inapsine®), a short-acting drug;
  • haloperidol (Haldol®)
    • has a longer half-life which limits its use.
    • has the strongest dopamine receptor binding, with little anticholinergic or antihistaminic effects,
    • ideal for opioid-related nausea
      • also useful in the treatment of delirium, dementia, and psychosis when sedation is undesirable.
    • contraindicated in Parkinson's disease.
    • minimally sedating.
    • can be given PO (tablet or liquid), IM, or by slow subcutaneous (SC) infusion.
    • marketed as an antipsychotic, so most physicians are not familiar with its use for nausea
  • The side effect profile and antiemetic efficacy is similar to those of the phenothiazines (extrapyramidal effects, etc).
  • The need for this class of agents and their utilization has declined recently due to the advent of the 5-H3 receptor antagonists.

13

Dopamine receptor antagonists:
Benzamides (p.24)

  • Metoclopramide (Reglan®)
    • ?
    • causes/
    • stimulates/
    • side effects
    • has a black box warning related to/
    • previously used/
    • replaced by/
    • primarily used/
  • Trimethobenzamide (Tigan®) 
  • Domperidone (Motilium®) 
    • ?
    • Its major advantage
    • risk
    • promotes/
  • Reglan 

  • Metoclopramide (Reglan®)
    • both an antiemetic and a prokinetic.
    • causes central and peripheral dopamine D2 antagonism at low doses, and weak 5-HT3 blockade at the higher doses.
    • stimulates cholinergic receptors on gastric smooth muscle cells and enhances acetylcholine release at the neuromuscular junction, which is why it has prokinetic uses.
    • crosses the blood-brain barrier.
      • commonly causes neurologic side effects such as akathisia, dystonia, and tardive dyskinesia, especially in the elderly and at high doses.
    • has a black box warning related to risks of irreversible tardive dyskinesia with higher dosing and long-term use.
    • previously used in high dose IV combination therapy for highly emetogenic chemotherapy,
    • replaced by the 5-HT3 receptor antagonists due to their superior efficacy and safety.
    • primarily used as an adjunctive agent for the prevention of cisplatin-induced delayed emesis and when first-line treatment for emesis has failed.
      • used for emesis caused by cytotoxic drug therapy (chemotherapy)
  • Trimethobenzamide (Tigan®)
    • only mildly effective in patients receiving chemotherapy
  • Domperidone (Motilium®)
    • a D2-blocker with selective peripheral activity in the upper gastrointestinal tract.
    • Its major advantage is that it does not cross the blood-brain barrier and therefore lacks the neurologic side effects of metoclopramide.
    • not approved in the US for any indication due to the risk of ventricular arrhythmias and sudden death.
    • due to blocking dopamine receptors and increasing prolactin levels, it promotes breast milk production
  • Reglan
    • also increases milk production in lactating women but not as well.

14

Serotonin receptor antagonists (p.25)

  • ?
  • Four 5-HT3 receptor antagonists are currently approved in the United States
  • failed to demonstrate any difference/
    • Palonosetron/
    • palonosetron and palonosetron combined with dexamethasone/
  • The oral formulation of these drugs/
    • repetitive dosing/
  • The recommended prophylactic regimen for the most emetogenic chemotherapy consists of/
  • side effects
  • not been associated with/

  • ?
    • The 5-HT3 receptor antagonists
    • the most useful class of antiemetics for chemotherapy-induced nausea and vomiting (CINV).
  • Four 5-HT3 receptor antagonists are currently approved in the United States:
    • ondansetron (Zofran®)
    • granisetron (Kytril®, Granisol®)
    • dolasetron (Anzemet®) and
    • palonosetron (Aloxi®).
  • failed to demonstrate any difference in efficacy or tolerability between the first three agents when used at effective doses.
    • Palonosetron has a higher receptor binding affinity and much longer half-life.
    • palonosetron and palonosetron combined with dexamethasone have shown superiority to older 5-HT3 receptor antagonists.
  • The oral formulation of these drugs has comparable efficacy to IV dosing for both moderate and highly emetogenic chemotherapy.
    • repetitive dosing is not superior to a single dose given immediately before chemotherapy.
  • The recommended prophylactic regimen for the most emetogenic chemotherapy consists of a 5-HT3 receptor antagonist combined with dexamethasone and aprepitant.
  • side effects (generally well tolerated)
    • most frequent: mild headache 
    • Asthenia, constipation and dizziness 
    • EKG interval changes
      • a class effect of first-generation 5-HT3 antagonists given IV but not orally, including ondansetron, granisetron, and dolasetron.
      • mostly small and clinically insignificant,
      • most prominent 1-2 hours after a dose of these agents, and return to baseline within 24 hours.
      • potentially fatal cardiac arrhythmias, including torsade de pointes, have been reported in association with QTc prolongation.
  • not been associated with cognitive, psychomotor, or affective disturbances.

15

Neurokinin receptor antagonists (p.26)

  • Substance P 
    • ?
    • emetogenic effects are mediated through
  • NK1 receptor antagonists 
  • for the prevention of/
  • They seem to work best when used in conjunction with/
  • should be used with caution in patients receiving/

  • Substance P
    • a mammalian neuropeptide found in neurons that innervate the brainstem nucleus tractus solitarius and the area postrema, two areas intimately involved in the induction of vomiting.
    • emetogenic effects are mediated through the neurokinin-1 (NK1) receptor, a member of the G protein receptor superfamily.
  • NK1 receptor antagonists 
    • the oral agent aprepitant and its parenteral version fosaprepitant, brand name for both--Emend®
    • a relatively new class of antiemetics
  • for the prevention of chemotherapy-induced emesis.
    • prevent not only acute but also delayed emesis in patients treated with highly emetogenic chemotherapy drugs, such as cisplatin.
  • They seem to work best when used in conjunction with serotonin receptor antagonists and dexamethasone
  • should be used with caution in patients receiving concurrent drugs that are primarily metabolized through CYP3A4 given their moderate inhibitory activity for the CYP3A4 metabolic pathway.

16

Glucocorticoids (p.27)

  • efficacy and toleration
  • common side effects
  • used prophylactically with/
  • the favored medication in this class
  • used in combination with/
  • They are not completely benign and can/
    • patients reported moderate to severe problems with/
  • There is a theoretical concern about their use in patients/

  •  effective and well tolerated antiemetics for chemotherapy-induced nausea and vomiting.
  • Insomnia, increased energy, and mood changes are common side effects.
  • used prophylactically with mildly emetogenic chemotherapy;
  • dexamethasone is the favored medication in this class.
  • With more emetogenic types of chemotherapy, they are used in combination with other agents
  • They are not completely benign and can decompensate diabetes, cause psychosis, or reactivate an ulcer.
    • patients reported moderate to severe problems with insomnia, indigestion/epigastric discomfort, agitation, increased appetite, weight gain, and acne the week after chemotherapy.
  • There is a theoretical concern about their use in patients undergoing immunosuppressive chemotherapy because of a potential increased risk for infection and interference with the antitumor effects of chemotherapy.
    • Their use in the bone marrow transplant setting and in some hematologic malignancies remains provider- and institution-specific.

17

Cannabinoids (p.28)

  • two cannabinoids medications currently marketed in the United States, 
  •  

  • two cannabinoids medications currently marketed in the United States, 
    • dronabinol (Marinol)
    • nabilone (Cesamet).
  • The potential antiemetic utility
    • improved emetic control in patients using marijuana during chemotherap
  • The mechanism of the antiemetic action of dronabinol probably relates to stimulation of the CB1 subtype of cannabinoid receptors on neurons in and around the vomiting center.
  • Dronabinol and its metabolites are “highly” bound (>95%) to plasma proteins.
    • Because of its large volume of distribution, a single dose of dronabinol can result in detectable levels of metabolites for several weeks
  • side effect profile (vertigo, xerostomia, hypotension, dysphoria), especially in older patients,
    • some side effects (eg, sedation and euphoria) could be seen as beneficial
  • used only as 2nd line therapy for CINV, when other agents have failed.

18

Benzodiazepines (p.29)

  • treat/
  • most commonly used drugs 
  • As single agents/
  • given as adjunctive agents to/
  • useful in/
  • second line therapies for/
  • main side effect

  • treat anxiety, panic attacks, depression and insomnia
    • also have valuable effects as muscle relaxants and antiemetics.
  • most commonly used drugs
    • lorazepam (Ativan)
    • alprazolam (Xanax).
  • As single agents, they are relatively weak antiemetic agents.
    • rarely prescribed alone.
  • given as adjunctive agents to reduce anxiety and akathisia associated with dexamethasone and metoclopramide, respectively.
  • useful in reducing anticipatory emesis (when anxiety plays a role such as when a patient is receiving emetogenic chemotherapy or undergoing surgery)
  • second line therapies for CINV.
  • Sedation is the main side effect.

19

Chemotherapy induced nausea and vomiting (CINV) (p.30+32)

  • Nausea and vomiting 
  • Chemotherapeutic medications seem to induce nausea and vomiting by two pathwaysPatient symptoms vary from
  • Patient symptoms vary from/
  • Preventing nausea and vomiting during treatment/

  • Nausea and vomiting
    • ubiquitous occurrences when an individual receives chemotherapy.
  • Chemotherapeutic medications seem to induce nausea and vomiting by two pathways
    • acting as direct toxins in the chemoreceptor trigger zone (CTZ) in the area postrema,
    • by stimulating the release of serotonin (5-HT3) from enterochromaffin cells in the small intestine.
  • Patient symptoms vary from slight nausea to significant nausea and vomiting which may cause dehydration.
  • Preventing nausea and vomiting during treatment enhances quality of life as well as outcomes, because some patients have such severe nausea and vomiting that they have to delay or completely stop treatment.

20

Emetic risk of different forms of chemotherapy commonly used in the United States (p.33-36)

  • High Emetic Risk
    • For medications of high emetic risk, it is recommended to give/
  • Moderate Emetic Risk
    • For medications of moderate emetic risk, it is recommended to give/
  • Low Emetic Risk
    • For medications of low emetic risk, it is recommended to/
  • Minimal Emetic Risk
    • Medications of minimal emetic risk/

  • High Emetic Risk: carmustine, cisplatin, cyclophosphamide>1500 mg/m2, dacarbazine, dactinomycin, mechlorethamine, streptozocin, and combined anthracycline and cyclophosphamide regimens
    • For medications of high emetic risk, it is recommended to give an NK1 Antagonist, a 5‐HT3 Receptor Antagonist, and a corticosteroid (typically oral or IV dexamethasone) prior to and following administering chemotherapy.
  • Moderate Emetic Risk: azacitidine, alemtuzumab, bendamustine, carboplatin, clofarabine, cyclophosphamide<1500 mg/m2, cytarabine>1000 mg/m2, daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, oxaliplatin
    • For medications of moderate emetic risk, it is recommended to give a 5‐HT3 Receptor Antagonist and a corticosteroid (dexamethasone) prior to administering chemotherapy, and to also give a corticosteroid on days 2-3 following chemotherapy.
  • Low Emetic Risk: fluorouracil, bortezomib, cabazitaxel, catumaxomab, cytarabine <1000 mg/m2, docetaxel, doxorubicin HCL liposome injection, etoposide, gemcitabine, ixabepilone, methotrexate, mitomycin, mitoxantrone, paclitaxel, panitumumab, pemetrexed, temsirolimus, topotecan, trastuzumab
    • For medications of low emetic risk, it is recommended to only give patients a corticosteroid (dexamethasone) on the day of chemotherapy
  • Minimal Emetic Risk: 2‐Chlorodeoxyadenosine, bevacizumab, bleomycin, busulfan, cetuximab, fludarabine, rituximab, vinblastine, vincristine, vinorelbine
    • Medications of minimal emetic risk do not require an antiemetic to be administered before or after chemotherapy.

21

When combinations of different agents are given for chemotherapy

  • you should gauge antiemetic treatment towards/
  • If a patient receives numerous cycles of chemotherapy, the effects of your antiemetic(s) of choice/
  • If this is the case, ASCO (the American Society of Clinical Oncology recommends to:
  • Nausea and vomiting also occur from undergoing radiation therapy

  • you should gauge antiemetic treatment towards the most emetogenic agent.
  • If a patient receives numerous cycles of chemotherapy, the effects of your antiemetic(s) of choice may start to diminish.
  • If this is the case, ASCO (the American Society of Clinical Oncology recommends to:
    • Re‐evaluate emetic risk, disease status, concurrent illnesses, and medications;
    • Ascertain that the best regimen is being administered for the emetic risk;
    • Consider adding lorazepam or alprazolam to the regimen; and
    • Consider adding olanzapine or substituting high‐dose IV metoclopramide for the 5‐HT3 receptor antagonist or adding a dopamine antagonist to the regimen.
  • Nausea and vomiting also occur from undergoing radiation therapy.
    • The degree of N/V vary by which part of the body is irradiated
    • total body irradiation (used mainly for leukemia/lymphoma prior to bone marrow transplant) and upper body irradiation requiring strong antiemetic combinations
    • radiotherapy to the breasts or extremities often does not need significant treatment.

22

Selection of Antiemetic by Clinical Situation

  • Migraine headache
    • Associated neurotransmitters
    • Recommended antiemetic
  • Motion sickness, Vestibular disease
    • Associated neurotransmitters
    • Recommended antiemetic
  • Pregnancy-induced nausea and vomiting 
    • Associated neurotransmitters
    • Recommended antiemetic
      • For nausea
        • 1st line
        • 2nd line
      • For hyperemesis gravidarum
  • Gastroenteritis
    • Associated neurotransmitters
    • Recommended antiemetic
      • 1st line
      • 2nd line
      • Use in children/
  • Postoperative nausea and vomiting 
    • Associated neurotransmitters
    • Recommended antiemetic
      • Prevention (High risk)
      • Treatment
  • Chemotherapy-induced nausea and vomiting 
    • Associated neurotransmitters
    • Recommended antiemetic
      • Prevention
      • Treatment

  • Migraine headache
    • Associated neurotransmitters: D2
    • Recommended antiemetic: metoclopramide, prochlorperazine, diphenhydramine
  • Motion sickness, Vestibular disease
    • Associated neurotransmitters: H1, acetylcholine
    • Recommended antiemetic: Scopolamine, dimenhydrinate, promethazine
  • Pregnancy-induced nausea and vomiting
    • Associated neurotransmitters: unknown
    • Recommended antiemetic
      • For nausea:
        • 1st line: ginger, vitamin B6 (rarely work)
        • 2nd line: promethazine, prochlorperazine, diphenhydramine
      • For hyperemesis gravidarum: 5-HT3 antagonists and corticosteroids
  • Gastroenteritis
    • Associated neurotransmitters: D2, 5-HT3
    • Recommended antiemetic:
      • 1st line: D2 antagonists
      • 2nd line: 5-HT3 antagonists
      • Use in children is controversial.
  • Postoperative nausea and vomiting
    • Associated neurotransmitters: D2, 5-HT3, histamine
    • Recommended antiemetic
      • Prevention (High risk): 5-HT3 antagonists, D2 antagonists, NK1 antagonists, dexamethasone
      • Treatment: 5-HT3 antagonists, D2 antagonists, NK1 antagonists, dexamethasone
  • Chemotherapy-induced nausea and vomiting
    • Associated neurotransmitters: 5-HT3, substance P
    • Recommended antiemetic
      • Prevention: 5-HT3 antagonists, NK1 antagonists, dexamethasone
      • Treatment: 5-HT3 antagonists, NK1 antagonists, dexamethasone

23

Prokinetic agents (p.38)

  • ?
  • used interchangeably with/
  • used clinically in/
  • affect/
  • use has been limited by/

  • drugs that increase contractile force and accelerate intraluminal transit.
  • used interchangeably with antiemetics to treat nausea and vomiting of GI origin.
  • used clinically in GERD, gastroparesis, and other forms of GI disease where dysmotility plays a role.
  • affect ubiquitous neuronal receptors,
  • use has been limited by CNS and cardiovascular side effects.

24

Prokinetic agents:
Erythromycin (p.39)

  • ?
  • rarely used as/
    • replaced by/
  • primarily used for/
  • used successfully off-label for the treatment of/
  • side effect
  • stimulates/
  • produces/
  • Both oral and intravenous (IV) erythromycin have been used for their prokinetic effect. 
    • The IV form is reserved for/
    • The oral form/

  • macrolide antibiotic
  • rarely used as an anti-biotic today
    • replaced by azithromycin and clarithromycin
  • primarily used for its “prokinetic” effect on the gastrointestinal (GI) tract.
  • used successfully off-label for the treatment of gastroparesis and other GI hypo-motility disorders.
  • side effect: abdominal pain.
  • stimulates motilin receptors in the GI tract.
    • Motilin receptors stimulate GI contractions, thereby increasing GI motility.
  • produces a dumping syndrome in the stomach (emptying too rapidly).
  • Both oral and intravenous (IV) erythromycin have been used for their prokinetic effect.
    • The IV form is reserved for acute conditions.
    • The oral form is given in lower dosages, works rapidly, and can be substituted when the IV form is unavailable.

25

Prokinetic agents:
Metoclopramide (p.40)

  • ?
  • stimulates/
  • enhances/
  • Can be given orally or IV. 
    • IV is an alternative to/
  • has both/
  • what have reduced the use of this drug 
  • Long-term use side effects

  • substituted benzamide
  • stimulates cholinergic receptors on gastric smooth muscle cells
  • enhances acetylcholine release at the neuromuscular junction.
  • Can be given orally or IV.
    • IV is an alternative to IV erythromycin for patients who cannot take oral medications (trauma, ICU patients).
  • has both antiemetic and prokinetic activity
  • extrapyramidal side effects and the risk of tardive dyskinesia have reduced the use of this drug
  • Long-term use side effects: (anxiety, restlessness, depression) and hyperprolactinemia.
    • Black box warning for long-term or high dose usage.

26

Prokinetic agents:
Doperidone (p.41)

  • availability
  • efficacy

  • not approved in the United States because it may increase the risk of cardiac arrhythmias.
    • available in Canada and other countries and US citizens can buy it online.
  • The efficacy of domperidone in diabetic gastroparesis is less than that of metoclopramide but it has excellent anti-nausea properties.

27

Prokinetic agents:
Cisapride (p.42)

  • ?
  • Mode of action
  • Among oral prokinetic agents,
  • concern
  • availability

  • a substituted benzamide.
  • Mode of action involves facilitation of acetylcholine release from myenteric neurons through a 5-HT4 receptor–mediated effect.
  • Among oral prokinetic agents,
    • had the most diffuse gastrointestinal effects
    • was the most effective drug on the market for slow GI transit.
  • concern
    • proarrhythmic effect usually occurring in the context of co-therapy with other agents that impair cisapride metabolism or prolong the Q–T interval.
    • requirement of pre-therapy EKGs.
  • Cisapride remains available under restricted access programs.
    • It is very easily obtained by Canadians and remains an excellent option in more severe forms of gastrointestinal dysmotilities.

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Prokinetic agents:
Tegaserod (Zelnorm) (p.43)

  • ?
  • stimulates
  • previously indicated for the treatment of
  • side effect
  • availability

  • a partial neuronal 5-HT4 receptor agonist,
  • stimulates the peristaltic reflex and intestinal secretion, while it desensitizes visceral afferents.
  • previously indicated for the treatment of women with irritable bowel syndrome and chronic constipation.
  • side effect: increase in cardiac adverse events—namely, heart attack, stroke, unstable angina— in patients with underlying cardiac disease.
  • voluntarily recalled
    • can be prescribed in emergency situations.
    • “immediately life threatening or serious enough to qualify for hospitalization.”
    • direct authorization is required and the FDA may deny such authorization if there is any evidence of risk factors, such as cardiovascular disease, anxiety and depression, obesity, smoking and diabetes.

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Summary

  • žNausea and vomiting are complex processes that can be
  • what contribute to vomiting
  • žAntiemetics generally target
  • žThe two major prokinetics in the US
    • žSide effects of these meds
  • When treating CINV, choose the antiemetic regimen that corresponds with

  • žNausea and vomiting are complex processes that can be adaptive and non-adaptive
  • žHigher centers (emotions), the cerebellum, the inner ear (vestibular), the nucleus of the solitary tract, the area postrema (CTZ) and cells in the GI tract may all contribute to vomiting
  • žAntiemetics generally target 5-HT3, NK1, H1, M2, D2, and CB receptors. 
  • žThe two major prokinetics in the US are erythromycin and metoclopramide; prokinetics can also be used as weak antiemetics
    • žSide effects of these meds are mainly CNS and cardiac, and they can be severe
  • žWhen treating CINV, choose the antiemetic regimen that corresponds with the most emetogenic chemo agent.