Emetics, Antiemetics, and Anorexogenics

Motion Sickness

Results from a mismatch between the vestibular system (receiving signals from the labyrinth structure of the inner ear) and visual sensations Prophylactic use of drugs more effective than treatment once sickness begins

Fenfluramine --- side effects

Sedation Mild euphoria in some subjects. Rapid weight gain occurs after cessation of drug; depression can also occur. Toxic effects --- high incidence of pulmonary hypertension --- some cases of fibrotic damage to heart valves [Removed from the market because of these effects]

Prochlorperazine --- side effects

Sedation (80%) Diarrhea (40%) Mainly because of anti-M1 activity.

Lorcaserin --- MOA

Serotonin 2C receptor (5-HT2C) agonist. 5-HT2C receptors are present in the CNS and smooth muscle. CNS action is responsible for promoting *satiety* [Approved in 2012]

Mazindol --- contraindications

Severe cardiovascular disease Extreme care is needed if used concomitantly with pressor amines

*Dextroamphetamine*, methamphetamine --- MOA

act in the central nervous system stimulate release and inhibit uptake of the catecholamines such as norepinephrine and dopamine.

Other gastric stimulants

apomorphine alum ammonium carbonate salt water fingertip stimulation of the pharynx no longer recommended due to respiratory depression or incomplete emptying of the gut

Liraglutide --- MOA

approved in 2014 Promotes satiety. Glucagon-like peptide 1 (GLP-1) agonist

Nausea and Vomiting in Pregnancy --- treatment

avoid drugs if possible If absolutely necessary, pharmacologic intervention may be necessary. Always start with the mildest drug possible

Mazindol --- MOA

blocks reuptake of norepinephrine, dopamine, and serotonin Effects are similar to amphetamines. Appetite suppressant effect is short lived (a few weeks).

Ipecac syrup --- side effects

can be toxic to the heart in large doses.

Emesis (vomiting)

consists of a complex pattern of events coordinated by the central nervous system. It results in the emptying of the contents of the small intestine and the stomach. Both autonomic and somatic nervous reflex elements are involved. Respiratory, cardiovascular, gastrointestinal motor and secretory elements participate in the emetic reflex

Vomiting Center (VC) --- receptors

contains high levels of --- muscarinic (M1) --- histamine (H1) --- neurokinin (NK1) --- serotonin (5-HT3) receptors

Ipecac syrup --- MOA

contains the active ingredient *Emetine* -- Directly stimulates peripheral sensory afferents in stomach to induce reflex vomiting (primary mechanism of action). -- Can eventually be absorbed into the circulation, where it can stimulate the CTZ.

Obesity --- epidemiology

incidence of obesity is reaching epidemic proportions in the U.S. 25%- 30% of adults in the U.S. are obese (BMI greater than 30) 4% of adults are considered severely obese (BMI = 40) Obesity is a causative factor in many diseases, including heart disease, diabetes and cancer.

Orlistat --- MOA

inhibits pancreatic and intestinal lipases thus preventing fat absorption (up to 1/3 of ingested fat).

Emesis is usually preceded by

nausea (subjective sensation associated with the anticipation of vomiting) and retching (a series of weak and unproductive vomiting movements)

*Aprepitant* Rolapitant ---administration

oral

*Dextroamphetamine*, methamphetamine --- administration

oral

DImenhydrinate Meclizine --- administration

oral

Dronabinol --- administration

oral

Fenfluramine --- administration

oral

Ipecac syrup --- administration

oral

Mazindol --- administration

oral

Appetite is controlled by

orexigenic signals (appetite stimulating) and anorexigenic signals (appetite inhibiting). These signals take the form of hormones, neuropeptides and neurotransmitters that control actions in the hypothalamus and the periphery. These systems evolved when food was scarce and thus are geared towards conservation of energy/calories.

Pentermine + Topiramate --- side effects

paraesthesia (burning or prickling sensation, usually in the hands and feet) dizziness dysgeusia (alterations in sense of taste) insomnia constipation dry mouth

Liraglutide --- administration

parenteral

Liraglutide --- contraindications

patients being treated with other GLP-1 receptor agonists ---- such as the diabetes drug Victoza (contains a lower dose of Liraglutide).

Pharmacological treatment for weight loss is only recommended for

patients with a BMI of 30 or greater or those with a BMI of 27 or greater with concomitant risk factors/diseases risk factors include hypertension, dyslipidemia, CHD, type 2 diabetes, and sleep apnea

Cannabinoids

principal psychoactive component of marijuana (delta-9- tetrahydrocannabinol) - *Dronabinol* - Nabilone Mechanism uncertain

Obesity

results from the long term imbalance between energy intake and energy expenditure. Factors contributing to obesity include genetic, environmental and behavioral. --- multi-factorial disease

Dronabinol --- side effects

sedation dry mouth orthostatic hypotension psychoactive effects increased appetite potential for abuse

Hyperemesis gravidarum

severe nausea and vomiting associated with pregnancy Occurs in about 0.5 - 2% of pregnancies, and often requires hospitalization. If untreated it will lead to: (i) Dehydration (ii) Starvation (iii) Electrolyte imbalance (iv) Hepatic dysfunction

*Dexamethasone* Methylprednisolone --- MOA

uncertain may be mediated through inhibition of prostaglandin and cytokine synthesis

Normal morning sickness

usually self-limiting and mild enough that it can be overcome. (i.e. the woman will adapt her environment/diet to gain relief from emetic stimuli) Note: the woman's perception of the severity of her symptoms and desire for treatment is more likely to influence a clinician's decision to prescribe medications rather than direct observation by the physician

Against an anticancer drug with low emetic potential

give a Phenothiazine + Dexamethasone

Nausea and Vomiting in Pregnancy --- incidence

"Morning sickness" 70 - 85% of women experience some degree of nausea and/or vomiting during pregnancy (usually the first trimester). 50% percent of women experience both symptoms

Emetic Drugs

(gastric stimulants) Ipecac syrup

Against anticancer drugs with higher emetogenic potential (or combinations that equal a high emetogenic potential), administer simultaneously:

(i) Serotonin antagonist (e.g. Ondansetron) to block acute emesis (ii) Aprepitant to block acute and delayed nausea (iii) Dexamethasone to block delayed emesis. This triple regimen is the most effective anti-emetic option available

DImenhydrinate Meclizine --- side effects

(mostly associated with anti-muscarinic activity) Sedation Dry mouth

NK1 Receptor Antagonists

*Aprepitant* Rolapitant

Corticosteroids

*Dexamethasone* Methylprednisolone

Anorexigenic Drugs

*Dextroamphetamine*, methamphetamine *Diethylpropion* *Phentermine* *Mazindol* *Fenfluramine* *Orlistat* *Lorcaserin* *Pentermine + Topiramate* *Buproprion + Naltrexone* *Liraglutide*

Benzodiazepines

*Lorazepam* Diazepam

Scopolamine --- uses

*Motion sickness* (most effective single agent) Not effective against CTZ-mediated nausea Side effects limit its chronic use in vertigo

5-HT3 receptor antagonists

*Ondansetron* Granisetron

Anti-Emetic Drugs

*Scopolamine* H1 Antagonists with Anti-muscarinic activity --- *Dimenhydrinate* --- *Meclizine* Dopamine D2 receptor antagonists --- *Metoclopramide* --- *Prochlorperazine* Cannabinoids --- *Dronabinol* --- Nabilone Corticosteroids --- *Dexamethasone* --- Methylprednisolone Benzodiazepines --- *Lorazepam* --- Diazepam 5-HT3 receptor antagonists --- *Ondansetron* --- Granisetron NK1 Receptor Antagonists --- *Aprepitant* --- Rolapitant

Chemotherapy Induced Nausea and Vomiting (CINV)

Nausea and vomiting resulting from the administration of drugs or irradiation to treat cancer is the single greatest reason patients avoid or stop therapy.

*Ondansetron* Granisetron --- MOA

5-HT3 receptor antagonists. block 5-HT3 receptors in the CTZ and VC, as well as in the GI system

*Dexamethasone* Methylprednisolone --- often coadministered with...

5-HT3 receptor antagonists. potentiates actions of 5-HT3 receptor antagonists and blocks delayed emesiss

Chemotherapy Induced Nausea and Vomiting (CINV) --- 3 distinct forms

Acute - within the first 4 hrs of chemotherapy and lasts a few hours. Delayed - approximately 24 hrs after chemotherapy and may last for days. Anticipatory - usually prior to treatment.

Orexigenic substances include

Agouti Agouti-related peptide Galanin Ghrelin Melanin concentrating hormone Neuropeptide Y Orexins A and B

*Lorazepam* Diazepam --- side effects

Amnesia Impaired mentation and motor function at high doses.

Lorcaserin --- side effects

Non-diabetic patients -- headache -- dizziness -- fatigue -- dry mouth -- constipation Diabetic patients -- hypoglycemia -- headache -- back pain -- cough -- fatigue

Drugs administered to stimulate weight loss generally affect two different subjective sensations

Appetite - Produce aversion to food Satiety - Promote a satisfied, full feeling

Pentermine + Topiramate --- MOA

Approved in 2012. Appetite suppressant. Phentermine - causes release of dopamine and norepinephrine Topiramate - anti-epileptic drug. --- Blocks voltage gated sodium channels --- potentiates inhibitory effects of GABA --- depresses excitatory effects of kainite.

Bupropion + Naltrexone --- MOA

Approved in 2014. Appetite suppressant. Bupropion - antidepressant. --- Promotes presynaptic release of norepinephrine and dopamine --- prevents dopamine and norepinephrine reuptake. Naltrexone --- opioid antagonist --- Used to treat alcohol and opioid dependence

Chemotherapy Induced Nausea and Vomiting (CINV) --- prevention

As with motion sickness-induced emesis, prevention is far more effective than treatment once emesis has begun. Chemotherapeutic agents exhibit different levels of emetogenic potential, which is generally defined as low, medium and high. When prescribing multiple chemotherapy drugs, the emetogenic potentials of the drugs are additive. To prevent emesis caused by chemotherapy, one must prescribe antiemetic compounds according to the total emetogenic potential of the chemotherapy.

Dopamine D2 receptor antagonists

Benzamide: *Metoclopramide* --- D2 antagonist Phenothiazine: *Prochlorperazine* --- D2, M1, and H1 antagonist --- Anti-emetic properties are due to D2 and M1 activities

Metoclopramide Prochlorperazine --- MOA

Block dopamine D2 receptors in the CTZ (Metoclopromide) Prochlorperazine may also block M1 receptors in the VC. Inhibit peripheral transmission to the VC via the vagus nerve.

*Lorazepam* Diazepam --- MOA

CNS depressant, anxiolytic

Phentermine --- side effects

CNS effects are considerably lower than with amphetamine Incidence of insomnia is greater as compared to diethylpropion. Psychic and physical dependence can occur. Contraindication s --- Cardiovascular disease or hypertension --- Pregnancy

Diethylpropion --- side effects

CNS side effects are considerably less than amphetamine Psychic and physical dependence can occur. Contraindications --- Severe cardiovascular disease or marked hypertension --- Pregnancy

*Dextroamphetamine*, methamphetamine --- side effects

CNS stimulation -- nervousness -- irritability -- agitation -- insomnia -- euphoria -- addiction Sympathetic stimulation -- dry mouth -- blurred vision -- arrhythmias -- hypertension. Contraindicated in pregnancy

Dronabinol --- use

Cancer chemotherapy [Not effective against motion sickness] Co-administration with phenothiazines such as prochlorperazine provides synergistic anti-emetic activity.

Metoclopramide Prochlorperazine --- uses

Cancer chemotherapy (against mildly emetic regimens) Irradiation therapy Post-operative nausea [Not effective for motion sickness]

Drugs that block all other VC stimulation

Chemicals in bloodstream -- cancer chemotherapy or irradiation -- emetogenic drugs and drug metabolites -- products of cell damage from anesthesia, surgery Prophylactic use of drugs more effective than treatment once sickness begins.

Emetic signals can originate from four main areas of the body:

Chemoreceptor trigger zone (CTZ) --- *dopamine D2* --- *opioid* --- 5-HT3 --- NK1 Vestibular system (inner ear) --- muscarinic M1 --- histamine H1 receptors. Cerebral cortex - mainly psychogenic input. Vagal and spinal afferent nerves traveling from the gastrointestinal tract to the CTZ and VC. ---- Chemical or mechanical stimulation of the GI tract causes the local release of serotonin, which stimulates 5-HT3 receptors and activates these nerves

Anorexigenic hormones include

Cholecystokinin Cocaine and amphetamine regulated transcript Corticotropin releasing hormone Insulin Leptin Peptide YY alpha-MSH Serotonin

H1 Antagonists with Anti-muscarinic activity

DImenhydrinate Meclizine

Mazindol --- side effects

Does not produce euphoria Dependence has not been reported Adverse effects are similar to the amphetamine-derivatives, but the incidence is lower and the reactions less severe.

Scopolamine --- side effects

Drowsiness Dry mouth Blurred vision Should not be used in patients with glaucoma or benign prostatic hypertrophy (typical of anti-muscarinics)

*Ondansetron* Granisetron --- use

Drug of choice for *acute* nausea caused by CINV. --- not effective against delayed or anticipatory emesis. Postoperative nausea and vomiting Nausea and vomiting during pregnancy. [Not effective for motion sickness]

Scopolamine --- transdermal delivery system

Drug released at a uniform rate for up to 72 hours Decreases incidence of side-effects by maintaining low plasma levels Less effective for severe motion sickness than oral or parenteral route

*Aprepitant* Rolapitant --- side effects

Fatigue Dizziness Diarrhea

Fenfluramine --- MOA

Fenfluramine and its d-isomer stimulate the release of serotonin and block its uptake. Unlike the amphetamine-like drugs, fenfluramine and its d-isomer promote satiety rather than producing aversion to food. After cessation, body weight is regained. Was often prescribed in combination with Phentermine ("Fen-Phen")

*Ondansetron* Granisetron --- side effects

Generally well tolerated. Reactions may include -- headache -- dizziness -- constipation

*Aprepitant* Rolapitant --- MOA

High affinity antagonists of Neurokinin 1 (NK1) receptors in the CTZ and VC.

DImenhydrinate Meclizine --- MOA

Histamine H1 receptor antagonists with muscarinic M1 receptor antagonist activity. It is the M1 receptor antagonism that accounts for their anti-emetic effects. Blocks vestibular system stimulation of the VC.

*Aprepitant* Rolapitant --- uses

Inhibit both *acute and delayed* CINV. They are very effective against highly emetogenic drugs such as cisplatin

Pharmacologic Intervention-several routes of prevention exist.

Inhibit stimulation from GI tract --- serotonin antagonists) inhibit stimulation from CTZ --- serotonin, neurokinin and dopamine antagonists Inhibit stimulation from the vestibular system --- muscarinic antagonists Inhibit psychogenic stimulation --- benzodiazepines

*Lorazepam* Diazepam --- use

Lorazepam used as adjunct to prevent anticipatory emesis, a conditioned response in patients who responded poorly to antiemetic drugs during previous chemotherapy. Also used as a treatment for vertigo. [not effective against motion sickness]

Ipecac syrup --- clinical use

May be used if a patient presents with acute poisoning as an alternative to administration of activated charcoal or gastric lavage. Sometimes administered at home to treat childhood poisonings, ideally under the supervision of a physician or poison control center. Not recommended when corrosive agents or petroleum distillates have been ingested, since these agents will cause damage to the esophagus upon vomiting or may be aspirated

*Aprepitant* Rolapitant --- drug interactions

Metabolized by CYP3A4 P450 enzymes, and may adversely affect metabolism of other drugs by CYP3A4. Doses of some chemotherapeutics that are normally metabolized by CYP3A4 must be monitored --- e.g. docetaxel --- vinblastine --- vincristine

Metoclopramide Prochlorperazine --- administration

Metoclorpramide --- oral --- parenteral Prochlorperazine --- oral

Bupropion + Naltrexone --- side effects

Most common complaints are --- nausea, vomiting --- constipation --- headache --- dizziness --- insomnia --- dry mouth --- diarrhea More rarely, suicidal thoughts and behavior associated with antidepressants Possible increases in blood pressure and heart rate

*Dexamethasone* Methylprednisolone --- use

Most often used to treat delayed nausea associated with cancer chemotherapy. [Not effective against motion sickness]

Common causes of emesis

Motion sickness Cancer chemotherapy and irradiation Pregnancy Psychogenic stimuli (cortical input resulting from pain, smells, tastes, sights and anxiety). Surgery Vertigo Drugs --- drugs with central emetic effects, e.g. digitalis, morphine --- drugs that induce gastric irritation, e.g. salicylates, aminophylline

DImenhydrinate Meclizine --- use

Motion sickness Vertigo (Meclizine) Pregnancy (with great caution) Postoperative nausea and vomiting

Scopolamine --- MOA

Muscarinic receptor antagonist --- reduces transmission from the vestibular system --- depresses the excitability of the labyrinthine receptors Synergistic with ephedrine

Metoclopramide --- side effects

Restlessness Extrapyramidal effects (e.g. restlessness, anxiety, dystonia - i.e. muscle spasms) Contraindicated in Parkinson's patients

Orlistat --- clinical use

Only moderately successful in producing weight loss. Approved for long term use; just approved for sale w/o prescription (called "Alli"). Must supplement diet with fat soluble vitamins (A, D, E and K).

Diethylpropion --- administration

Oral

Phentermine --- administration

Oral

*Ondansetron* Granisetron --- administration

Oral Parenteral

Bupropion + Naltrexone --- administration

Oral --- dose gradually increased over 4 week span --- twice daily

Lorcaserin --- administration

Oral --- half-life in serum is 11 hrs --- Twice daily dosing reaches a steady state in 3 days.

Pentermine + Topiramate --- administration

Oral --- once daily

*Lorazepam* Diazepam --- administration

Oral Parenteral

Orlistat --- administration

Oral administration. Not absorbed systemically.

Scopolamine --- administration

Orally Parenterally Transdermally. Transdermal administration seems to be the best tolerated

Liraglutide --- side effects

Pancreatitis Gallbladder disease Renal impairment Suicidal thoughts Elevated heart rate. --- HR effects not great enough to preclude use in patients with heart disease though May increase the risk of thyroid cancers (it does so in mice).

Emesis consists of two stages:

Predromal Phase --- Sympathetic nervous stimulation causes cutaneous vasoconstriction, pupil dilation and tachycardia. --- Parasympathetic nervous stimulation causes salivation. --- Longitudinal contraction of the esophagus pulls the stomach into the thoracic cavity. --- Relaxation of the stomach and expulsion of the contents of the small intestine into the stomach. Vomiting Phase --- Increased abdominal pressure and decreased intrathoracic pressure. --- Relaxation of the esophageal sphincter and expulsion of the contents of the stomach.

Bupropion + Naltrexone --- contraindications

Pts with history of seizures

Phentermine --- MOA

Related to amphetamine MOA similar to amphetamine (release of DA and NE)

Diethylpropion --- MOA

Related to amphetamine MOA similar to amphetamine (release of dopamine and norepinephrine)

Drug regimens for long-term weight loss

There are no satisfactory drug regimens for inducing long term weight loss. Any successful drug regimen must include changes in diet, behavior, and exercise. For many amphetamine-like drugs, the weight loss is only a temporary effect.

*Dextroamphetamine*, methamphetamine

These agents were the first prescribed widely for control of appetite. However, they are marginally effective (weight loss is temporary) risk of dependence is great, so they are not recommended.

Categories of Anti-Emetic Drugs

Those that block Motion Sickness Those that block all other VC Stimulation

Fenfluramine

Toxic, no longer available in U.S.

Nausea and Vomiting in Pregnancy --- pharmacotherapy

Vitamin B6 has been used with varying efficacy If this doesn't work, one may consider treatment with doxylamine (anti-histamine) or metoclopramide --- good safety records in pregnant women. If these drugs don't work, a 5-HT3 receptor antagonist such as Odansetron is sometimes prescribed. ---- increasingly gaining favor with obstetricians, although the safety data for the fetus is not well studied. Patients with hyperemesis gravidarum are also sometimes given a 3-day course of corticosteroid, such as methylprednisolone. --- may cause cleft palate in the fetus, especially in the first 10 weeks of pregnancy --- considered a last resort treatment.

Emesis is controlled by the

Vomiting Center (VC), a loosely organized region in the brain stem

If anticipatory emesis is a problem...

a benzodiazepine such as Lorazepam is also administered prior to chemotherapy

Vertigo

a false illusion of motion causing dizziness and disorientation. It can result in nausea and vomiting. Motion sickness drugs are used for treatment of vertigo.

Orlistat --- side effects

due to unabsorbed fat in the large intestine. Common side effects include flatulence, steatorrhea, and fecal leakage. These effects can be so distasteful that a patient will modify diet (i.e. reduce fat intake) to avoid them. In 2010 the FDA required that Orlistat and Alli incorporate labels warning of an infrequent risk of severe liver damage with use.