Appendix A: Four Short Articles Concerning Aspects Of Nausea And Vomiting
Appendix A: Four Short Articles Concerning Aspects Of Nausea And Vomiting
FOUR SHORT ARTICLES CONCERNING ASPECTS OF NAUSEA AND VOMITING.
An outline account of the anatomy of vomiting
Borison and Wang wrote an article entitled Physiology and Pharmacology of vomiting in 1953 in which they explained the anatomy of the vomiting centres.
They elicited vomiting in the cat by electrical stimulation of the lateral reticular formation in the immediate vicinity of the fasciculus solitaries. No other portion of the lower brainstem yielded such responses. At that time most physiologists had agreed only to the existence of the vomiting centre and not to its precise location in the medulla oblongata. This vomiting was elicited by electrical stimulation without prior retching following the short latency required for maximal inspiration and it was continuous for a period of five to fifteen seconds of stimulation. In a study of chronic dogs Wang and Borison found that superficial medullary lesions abolished the emetic response to intravenous apomorphine, certain cardiac glycosides (including digitalis) without disturbing the response to oral copper sulphate, whereas deeper lesions which also involved the lateral reticular formation impared the responsiveness of oral copper sulphate as well as to the intravenous apomorphine. These results were interpreted to mean that the vomiting centre is situated in the dorsal portion of the lateral reticular formation and that there exists in the medullary surface a specialised chemoreceptor trigger zone which serves as a receptor site for certain central emetic agents(1).
The importance of this finding is that digitalis the most significant drug for treating heart conditions such as auricular fibrillation or congestive cardiac failure, because it increases the force of the myocardial contractions, had the unfortunate side effect of causing nausea and vomiting. It is an interesting story that other researchers thought that the nausea and vomiting must have originated from the heart because it was so effective at treating conditions of the heart, or another possibility because the digitalis was concentrated in liver cells, these symptoms of vomiting arose from the liver. Borison and Wang’s interpretation of a chemoreceptor trigger zone which serves as the receptor site for certain emetic agents has proved correct (1).
The Human chemoreceptive trigger zone has been localised in the area of postrema (AP) in the floor of the fourth ventricle and has both a blood supply and is in contact with the cerebrospinal fluid. The vomiting centre itself is situated in the medulla oblongata can be stimulated directly by certain chemicals such as copper sulphate, but hormones or chemicals which stimulate the chemoreceptor trigger zone also effect the vomiting centre via nervous elements and connections in the mid-brain. The final act of vomiting or retching being controlled by the vomiting centre(2).
As the Chemoreceptor trigger zone is outside the blood brain barrier. Drugs which activate this centre have fewer side effects such as sedation and extrapyramidal effects which can induce incordinated muscle spasms. All the substances that excite the AP neurones are also emetic in the dog (3). The response to all excitatory substances (except glutamate) were similar long latency relatively low mixed discharge frequency, and very long duration (3). The ultimate experiment was done in humans, Lindstrom treated five humans who suffered from intractable nausea and vomiting with local AP ablation and all patients experienced total relief of symptoms(4).
AP neurones are excited by serotonin, (the urinary excretion of serotonin is not associated with the intensity of nausea and pregnancy(5)) Histamine, Epinephrine and Norepinephrine about half the time and at least for histamine and Epinephrine these responses are complicated in that some neurones show inhibitory responses to these substances (3).
To test the hypothesis that circulating emetic substances activate neurones in the AP, the effects of prostaglandins on electrical activity of neurones in canine area postrema were studied by Briggs and Carpenter using the techniques of extra cellular recording with iontophoresis. Excitatory responses were obtained upon application of prostaglandin A1, B1, B2, E1, F1 Alpha, F2 Alpha in between 24 and 50% of the cells studied. The percentage excitation was greatest in prostaglandin E1 47% and prostaglandin F2 Alpha 50%. The excitation was very similar in pattern to that observed for apomorphine, biogenic amines and several neuropeptides in that it had a relatively long latency, low frequency and prolonged duration. Since the area postrema is known to play a central receptive role in initiating emesis to circulating toxins these results suggest that prostaglandins may play a role in the initiation of some forms of emesis(6).
Prostaglandins arise in tissue after irradiation and the time course of increase is very similar to that of radiation induced emesis in that there is an initial peak of one-four hours often followed by a subsequent fall. The neurones of the AP could be excited by circulating prostaglandins evoking emesis (7).
The results are consistent with a possibility that c’amp is the common second messenger for common excitatory substances (3). A common messenger is probably the reason for all these substances having the same effect. The majority of cells were excited by eight-bromo-c’amp as well as forskolin an activator of adenyl cyclase. All twenty one substances effect cells mediated by a common second messenger c’amp (3).
A prolonged action from the brief application of a transmitter onto a single neuron is usual. These observations suggest the possibility that responses to all of these substances have a common step or are mediated through a common second messenger. The responses are indeed mediated through c’amp. Pretreatment of an animal with phosphodiasterase inhibitor should retard the breakdown of c’amp and if involved in mediation of the response should reduce the threshold dose necessary to induce emesis. We tested theophylline. Thresholds of all substances were reduced (8).
Multiple applications of several substances would cause the neurone to become spontaneously active at a low frequency; this spontaneous discharge would be maintained for many minutes (8).
One of the major difficulties of the study of the emetic reflex is its great variability among animal species (9). Rodents do not vomit at all and the sensitivity of other species various considerably. Man and dog are clearly among the most sensitive species to emesis from humoral agents, while both show emesis in response to motion, ionising radiation and drugs for cancer chemotherapy. Monkey and cat are considerably less sensitive to most of these stimuli (9).
References For An outline account of the anatomy of vomiting
1. Borison HL, Wang SC.
Physiology and Pharmacology of Vomiting.
Pharmacol Review 1953; 5: 192-230.
2. Brizzee KR, Clara PM.
The structure of the mammalian area prostrema.
Fed Proc 1984; 43: 2944-2948
3. Carpenter DO, Briggs DB, Knox AP, Strominger N.
Excitation of the prostrema neurones by transmitters, Peptides and cyclic Nunceotides.
J Neourphysiol 1988; 59(2): 258-369
4. Lindstrom PA, Brizzee KR.
Relief of intractable vomiting from surgical lesions in the area prostrema.
J Neoursurg 1962; 19 : 228-236
5. due Bois A, Kriesinger- Schroeder H, Meerphol HG.
The role of serotonin as a mediator of emesis induced by different stimuli
Support Care Cancer 1995; 3 : 285-290
6. Briggs DB, Carpenter DO.
Excitation of neurones in the canines of prostrema by Prostaglandins.
Cell moll Neurobiol 1986; (6) 4 : 421-426
7. Carpenter DO, Briggs DB, Knox AP, Strominger NL,
Radiation- induced emesis in the dog: Effects of lesions and drugs.
Radiation Research 1986; 108 : 307-316
8. Carpenter DO.
Neural mechanisms of emesis.
Can J Physiol Pharmacol 1988; 68 : 230-236
9. Borison HL, Borison R, McCharthy LE.
Phylogenic and neurologic aspects of the vomiting process.
J Clin Pharmacol 1981; 21 : 235-395
Vomiting Centre Excitation
In animals with ablation of the area postrema (AP), vomiting seen in control animals upon
IV administration of a variety of drugs is abolished, as in the vomiting that follows motion,
ionising irradiation and chemotherapeutic drugs, at least in the species like the dog, which
show emetic responses similar to that of humans (1).
2. The AP, which lies outside the blood brain barrier, has the role of surveying the blood for
noxious substances (1).
3. All the substances that excite the AP neurones are also emetic in the dog (1).
4. The ultimate experiment was done in humans (2). Lindstrom treated 5 humans who
suffered from intractable nausea and vomiting, with local AP ablation and all patients
experience total relief of these symptoms.
5. The response to all excitatory substances (except glutamate) were similar, long latency,
relatively low mixed discharge frequency and a very long duration (1)
6. A prolonged action from the brief application of a transmitter on to a single neurone is
usual. These observations suggest the possibility that responses to all of these substances
have a common step or are mediated through a common second messenger (3). The
responses are indeed mediated through C’AMP. Pre-treatment of an animal with a
phosphodiasterase inhibitor should retard the breakdown of cyclic AMP and if involved in
mediation of the response, should reduce the threshold dose necessary to induce emesis.
We tested theophylline. Thresholds for all substances tested were reduced (3).
7. Our results are consistent with the possibility that C’AMP is the common second
messenger for these common excitatory substances. (1)
8. AP neurones were excited by serotonin (the urinary excretion of serotonin is not associated
with the intensity of NVP (2)) Histamine, Epinephrine and Norepinephrine about half the
time and at least for Histamine and Epinephrine, these responses are complicated in that
some neurones show inhibitory responses to these substances (1).
9. The percentage of responses from AP cells is so high, an average 50% of neurones studied
responded to the excitatory substances, the rate of responsiveness is so high as to suggest
that all of the cells have all of the receptors (1).
10. Dogs with bilateral subphrenic vagotomy show no change in their sensitivity of IV
Apomorphin and vomited after irradiation with a pattern almost identical to that of the
controls. Therefore, radiation induced emesis is humorally mediated through some agent
released into the circulation subsequent to irradiation (4).
11. The effects of PH on electrical activity of neurones in the canine AP were studied.
Excitatory responses were obtained upon application of PGs A1, B1, B2, F1a and F2a in
between 25-50% of cells studied. The excitation was very similar in pattern to that
observed to apomorphine, in that it had a relatively long latency, low maximal frequency
and prolonged duration (60 seconds). Since the AP is known to play a central receptive role
in initiating emesis to circulation toxins, these results suggest that prosaglandins may play a
role in the initiation of some forms of emesis (5).
12. Glucose application to 16 cells and zinc to 14 cells never had any effect (6).
13. Frequently multiple applications of several substances would cause the neurone to become
spontaneously active at a low frequency; this spontaneous discharge would be maintained
for many minutes (3)
14. The area postrema of the human brain does not have a blood brain barrier and is known to
be involved in nausea and vomiting reflexes. It contains LH/hCG receptors which suggests
they are involved in nausea and vomiting of preganancy (7).
References for vomiting centre excitation
1. Carpenter D O, Briggs D B, Knox A P, Strominger N.
Excitation of Area Postrema Neurons by Tramsmitters
Peptides and Cyclic Nuceotides.
J Neurophysisol 1988 59(2) 358-369.
2. Lindstrom P A, Brizzee K R
Relief of intractable vomiting from surgical lesions in the area postrema.
J Neurosurg 1952 19
3. Carpenter D O
Neural mechanisms of emesis
Can J Physiol Pharmacol 1988 68 230-236.
4. Carpenter D O, Briggs D B, Knox A P, Strominger N L
Radiation-induced emesis in the dog: Effects of lesions and drugs.
Radiation research 1986 108 307-316.
5. Briggs D B, Carpenter D O
Excitation of neurons in the canine Area Postrema by prostaglandins.
Cellular and Mollecular Neurobiol 1986 6 (4) 421-426.
6. Carpenter D O, Briggs D B
Insulin excites neurones of the Area Postrema and causes emesis.
Neuroscience letters 1986 68 85-89.
7. ROA CH V
The beginning of a new era in reproductive biology and medicine: Expression of low levels
of functional luteinizine hormone/human chorionic gonadotrophin receptors in non-gonadal
J.Physiology and Pharmacology 1996;42(2) Supplement:41-43
Clinical and treatment similarities for nausea and vomiting associated with palliative care
and the nausea and vomiting associated with pregnancy (NVP).
In one study related to palliative care 62% have both nausea and vomiting 34% had nausea alone
and 4% had isolated vomiting (1). In one study of nausea and vomiting of pregnancy 73% had
nausea with vomiting, 32% had nausea alone and 0.6% had vomiting alone.
In the palliative care study, nausea was aggravated by movements and alleviated by resting (1) a
most significant way to improve nausea and vomiting of pregnancy is getting more rest
(2 section 39).
Nausea and vomiting have been reported to be frequently undertreated in palliative care and
surprisingly it is patients with more severe symptoms who often miss out on anti-emetic treatment
(1). If you heard that a women might be left to suffer from nausea and vomiting for at least a
couple of months without any nursing or medical attention you would perturbed. This is exactly
what happens when women suffer from severe pregnancy sickness (2 section 42).
Nausea and vomiting rarely occur in isolation but tend to occur with other symptoms for example
fatigue, drowsiness, lack of energy or lack of appetite (1). This is similar to nausea and vomiting of
pregnancy when in the most severe symptoms patients are unable to get out of bed due to their
severe vomiting plus fatigue, lack of energy and become depressed due to the constant awful
nausea they suffer (2 section 42).
The history of nausea should include questions which aid determination of the cause of the nausea
in palliative care. Intermittent nausea associated with early satiety and postprandial fullness or
bloating. Nausea is relived by vomiting which is usually small volume, occasionally forceful and
may contain food. This clinical picture suggests impaired gastric emptying in both palliative care
and pregnancy nausea and vomiting(1).(2). In either group of patients nausea is aggravated by sight
and smell of food or relived by vomiting again similar in both conditions(1),(2). This suggests
chemical causes activating chemoreceptor trigger zone(1),(2).
The picture of the treatments of nausea and vomiting associated with palliative care is very similar
to these same treatments of pregnancy (NVP). These substances and their affects are well
expressed by the table 4 in the article nausea and vomiting palliative care (1). Incidentally their
definition of nausea is very appropriate, the sensation that immediately precedes vomiting. One or
two additions in their script which goes with that table. Prokinetic agents stimulates the upper
gastrointestinal tract, block aid 5HT3 receptors releasing a break on gastric emptying. These agents
include metaclopromide (maxolon) which is a dopamine antagonist(1). Glare and his colleagues
make two points, first the dose of metaclopromide is 10mgs three of four times daily. The
dopamine antagonist affect is only achieved with high doses 10mgs every four-six hours orally.
Secondly, in America the food and drug administration state administration of metaclopromide
beyond a twelve week period is not recommended in elderly patients due to side effects of
restlessness, drowsiness and fatigue. Domperidone is a similar drug to metaclopromide but has the
advantage that it does not cross the blood brain barrier so only acts on peripheral dopermine
receptors releasing the doperminergic brake. As a result side effects particularly uncoordinated
movements are much less likely to occur. However cardiac toxicity associated with QT
prolongation may occur.
Phenothiazines are antipsychotic agents which block D2 receptors in the chemoreceptor trigger
zone, also blocking histamine serotonergic and alpha-adrenergic receptors. They may cause side
effects notably sedation, hypotension and extrapyramidal symptoms such as in coordination with
muscle spasms. When given to elderly patients who have dementia with aggression they were
found to increase the incidence of deep vein thrombosis and fatal pulmonary embolism. This has to be borne in mind when treating nausea and vomiting of pregnancy but these clinical conditions
have not been recorded as complications when treating NVP. The dosage of prochlorperazine
(stemetil) is 5-10mgs tds orally.
Antihistamines. First generation H1 receptor antagonist block H1 receptors in the medullary
vomiting centre and in the Chemoreceptor trigger zone. Cyclizine 50mgs 1tds (valoid) or Avomine
25mgs are the most frequently used H1 receptor antagonist antihistamines in treating NVP in this
country as Diclecetin is not at present available here. Avomine (Promethazine Theoclate) is
available in a dose of 25mgs two at night plus one twice during the day. The side effect is sedation,
but tolerance to sedation usually develops in a few days. Phenergan another Promethazine Maleate
usually causes more sedation than Avomine.
Pyridoxine= Vitamin B6 has been shown to be effective in treating the nausea of NVP shown in
two randomised controlled trials (3,4). The safety of pyridoxine was confirmed in a cohort study
which found no association with major malformations (5). Pyridoxine has been shown to be non-
teratogenic when combined with Doxylamine in the tablet called diclectin 10mgs of each up to
four times a day. Pyridoxine may be used to treat NVP on its own up to 10mgs one four times
daily. In that dosage it causes no significant side effects and no increased risk of a foetal
Selective 5HT3 receptor antagonists. Ondansetron is the oldest selective 5HT3 receptor
antagonist. It exerts its antiemetic effects via blockaid of peripheral and central 5HT3 receptors.
These receptors are found in the vagus nerve which feeds into the emetic centre, in the nucleus
tractus solitaries and the chemoreceptor trigger zone(1). The 5HT3 receptor antagonists block the
amplifying effect of serotonin on the vagus nerve(1). They are primary used for chemotherapy
induced emesis but are increasingly used to treat nausea and vomiting of pregnancy particularly in
America(7). A recent paper published in the New England Journal Of Medicine by Pasternak B et
al found that in 1233 women exposed to ondansetron after 6 weeks from LMP caused no increase
risk of any major birth defect(7).
Corticosteroids have chiefly been studied as anti-emetics in chemotherapy induced emesis but are
also used in treatment of severe nausea and vomiting of pregnancy (NVP) and hyperemesis
gravidarum (HG). Jarvis S and colleague in their article management of nausea and vomiting of
pregnancy published in the BMJ(8) state one small RCT showed that compared with placebo
corticosteroids improved symptoms with reduced dependence on intravenous fluids. This treatment
is best undertaken in secondary care so that the dosage regime can be carefully monitored with
maternal blood electolytes controlled. There is some evidence steroids are best used only after the
end of the tenth week from LMP to avoid a small increased risk of oral clefting. They should only
be used for intractable cases of severe hyperemesis gravidarum cases after other treatments have
References for Clinical and Treatment Similarities of Nausea And Vomiting associated with
palliative care and the nausea and vomiting associated with pregnancy (NVP).
1. Glare P, Miller J, Nikolova T, Tickoo R.
Treating nausea and vomiting in palliative care: A review.
Clinical Interventions in Aging 2011;6: 243-259.
2. Gadsby R, Barnie-Adsehead AM.
Nausea and Vomiting of Pregnancy: A Literature Review.
3. Sahakian V, Rouse D, Sipes S, Rose N, Niebyl J.
Vimatin B is Effective therapy for nausea and vomiting of pregnancy: A randomised,
Double-Blind Placebo- Controlled Study.
Obstet Gynecol 1991; 78 : 33-36.
4. Vutyavanich T, Wongtra-Rigan S, Ruansari R-A.
Pyridoxine for nausea and vomiting of pregnancy: A randomised Double-Blind Placebo-
Am J Obstet Gynecol 1995; 173: 881-88.4
5. Shrim A, Boskovic R, Maltepe C, Navios F, Garcia- Bournissen, Koren G.
Pregnancy outcome following use of large doses of Vitamin B6 in the first trimester.
J Obstet Gynaecol 2006; 26(8): 749-751.
6. Briggs GG, Freeman RK, Yaffe SJ.
In drugs in Pregnancy and Lactation 6th Edition Philadelphia: Lippincott Williams &
7. Pasternak B, Svanstrom H, Hviid A.
Ondansetron in pregnancy and risk of adverse fetal outcomes.
N Engl J Med. 2012; 368 (9): 814-823
8. Jarvis S, Nelson- Pericy C.
Management of nausea and vomiting in pregnancy.
BMJ 2011; 342 : 1407- 1412
9. Mazzotta P, Magee LA.
A risk- benefit assessment of pharmacological and non-pharmacological treatments of
nausea and vomiting of pregnancy.
Drugs 2000; 50(4) : 781-800.
Nausea and vomiting related to age, sex, postoperative recovery and chemotherapy
Recent evidence shows that postoperative recovery may differ between men and women. The
authors planned a prospective cohort study to examine the impact of gender or postoperative
outcome. Secondary endpoints included the incidence of complications one of which was
postoperative nausea and vomiting. The men (N.200) and women (N.222) in the authors study
were similar in terms of age, American society anaesthesiologists physical status and likely to have
a history of postoperative nausea and vomiting, 42 (19%) women versus 18(7.4%) men (P<0.001)
and to have received prophylactic antiemetic agents 102 (46%) women versus 70 (29%) men
(P<0.001) (1). The higher incidence of some complications among women, maybe attributable to
greater willingness to report them, however participants in the study were directly questioned about
nausea rather than being obliged to mention them without promoting. This makes it more likely
that the differences in nausea and vomiting between the sexes are genuine and important (1).
There is little available data on the incidence and causes of vomiting and nausea in an otherwise
healthy population. Therefore the authors of this article decided to undertake a survey to examine
the influence of age and sex on the emetic response. 596 participants completed questionnaires.
There were 65% female and 35% male participants ages ranging from 18-91years. The overall
incidence of vomiting and nausea at least once in the twelve months prior to completing the
questionnaire were 39%-54% respectively. There was no significant association between the
incidence of symptoms of gender although a higher frequency of nausea but not vomiting was
reported amongst women as compared to men (P<0.005). In contrast when the population was
grouped according to age 18-30years N=215, 31-60years N=197, >60years N=185. There was a
highly significant decrease in the incidence of both vomiting (P<0.0001) and nausea (P<0.0001)
with increasing age (2). Postmenopausal women (N=175) were less likely to vomit (P<0.0001) or
feel nauseous (P<0.0001) compared with those women who were still menstruating N=217(2). The
results show an age dependency in the incidence of emesis and support the evidence that many
autonomic functions become altered with age (2).
Age, sex, previous exposure to chemotherapy, type of chemotherapy, history of alcohol intake and
susceptibility to motion sickness have all been proposed as predictors of chemotherapy induced
emesis (3). Recently the authors analyzed the role of the new prognostic factor in chemotherapy
induced emesis in female patients receiving a first cause of FAC adjuvant chemotherapy; the
intensity of emesis during past pregnancy (EDPP)(3). 113 breast cancer patients receiving a first
course of FAC adjuvant chemotherapy in an out patients setting entered the study. The antiemetic
treatment was identical in all patients. The patients were classified in one of the following groups
according to the intensity of emesis during past pregnancy(EDPP).
Intensity of emesis in the first course of FAC chemotherapy according to EDPP grade.
EDPP= Intensity of emesis during past pregnancy.
A. Grade 0 EDPP no nausea and vomiting during any pregnancy.
B. Grade 1 EDPP nausea and vomiting limited to the early morning only in the first trimester
of pregnancy (normal emesis gravidarum).
C. Grade 2 EDPP nausea and or vomiting present during the entire day and/or extended to the
second or third trimester in at least one pregnancy (pathological emesis gravidarum)(3).
The mean age of the 87 evaluable patients was similar in the three groups (mean age 54, mean
age 55, mean age 50 groups ABC respectively.
The intensity of emesis in the first course of FAC chemotherapy in these three groups shows a
statistical analysis a significant positive correlation between the intensity of EDPP and the
intensity of FAC induced emesis (P<0.001). Eighty one percent of patients with grade 0 EDPP
obtained complete protection from FAC induced emesis while respective figures for grades 1
and 2 were 57% and 36% (3). This study suggests that EDPP may be an important prognostic
factor in FAC induced emesis and could be useful as a clinical marker for those patients who
require a more intensive antiemetic treatment(3).
Nausea and vomiting related to age, sex, postoperative recovery and chemotherapy
1. Myles PS, McLeod DM, Hunt JO, Fletcher H.
Sex differences in speed of emergent’s and quality of recovery after anaesthesia: Cohort
2. Rub R, Andrews PLR, Whitehead SA.
Vomting: incidence, causes, ageing and sex.
In Mechanisms and control of emesis.
Eds, Bianchi AL, Grelot L, Miller AD, King GL.
Inserm/ John Libby, Euro Text.
3. Martin M, Diaz- Rubio E.
Emesis during past pregnancy: A new prognostic factor in chemotherapy induced emesis.
Annals of oncology 1990;1:152-153.
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