4. Drugs Used in the Treatment of Nausea and Vomiting

Question 1

Scoring systems:

Answer 1

there are various scoring systems, such as the Apfel score, which
estimate the likelihood of PONV according to the number of predisposing factors.

(Apfel uses
previous history,
non-smoking,
female gender and
administration of opioids).

The incidence of PONV in relation to the number of factors is quoted as
0–10%, 1–20%, 2–40%, 3–60% and 4–80%

This suggests that a non-smoking female
undergoing, say, routine day-case orthopaedic surgery, would have a 40% likelihood
of PONV. Clinical experience suggests that this would seem unduly, if not improbably
high, but validations of the various models suggest that they can be useful.

Question 2

Applied Pharmacology of Anti-Emetic Drug

Answer 2

Nausea and vomiting are mediated by a number of sites with different receptors. This
means that these symptoms can be treated by ‘balanced anti-emesis’ using drugs
of differing actions. Although some drugs act at more than one receptor, their
anti-emetic actions usually predominate at one.

Question 3

Vestibular nuclei and the labyrinth

Answer 3

These contain histamine (H1)
muscarinic ACh (M3) receptors.

Drugs acting at this site include
cyclizine,
promethazine (H1-antagonists),

hyoscine, atropine and glycopyrrolate (anticholinergic M3-antagonists).

Question 4

Visceral afferents

Answer 4

: these are mediated by serotonin (5-HT3) receptors in the gut
wall and myenteric plexus. Drugs acting at this site include ondansetron, granisetron

Question 5

Vomiting centre (VC)

Answer 5

Vomiting centre (VC):

this contains primarily muscarinic ACh (M3)

and some histamine (H1) receptors.

It may also contain μ-opioid receptors. Drugs acting at this

site are the same as those which affect the vestibular apparatus.

Question 6

Chemoreceptor trigger zone (CTZ):

Answer 6

mpulses from the CTZ to the VC appear to be

mediated mainly via dopamine (D2)
serotonin (5-HT3) receptors.

It may also contain δ-opioid receptors.
In addition, substance P, which is a slow excitatory
neurotransmitter, may have a role by acting at neurokinin-1 (NK1) receptors.

NK1-receptors are abundant in the brain stem where emetic afferents converge.

Drugs acting at the CTZ include

metoclopramide,
domperidone,
prochlorperazine,
, haloperidol
droperidol,

which has recently again become available in the UK (D2-antagonists).

The newest agents are NK1-antagonists of which
aprepitant is the example now available in the UK.

Its cost, if nothing else (each dose is approximately £15)
makes it a second-line treatment.

Question 7

Drugs of uncertain sites of action

Answer 7

1. Cannabinoids:
   synthetic derivatives such as nabilone appear
   to antagonize the emetic effects of drugs
   which stimulate the CTZ.

Because the cannabinoid effects can themselves
be antagonized by naloxone,

it is postulated that opioid receptors are involved in their actions.

There are at least two endogenous cannabinoid
receptors, CB1 and CB2, which modulate neurotransmitter release.

2. Corticosteroids:
   high-dose steroids such as dexamethasone or methyl prednisolone
   act as anti-emetics by mechanisms that are unclear.
3. Propofol:
   its antiemetic property is disputed,
   but its effective use in patients with
   chemotherapy-induced emesis suggests otherwise.

It would appear therefore to act at the CTZ.

Question 8

Significant side effects of anti-emetics.

Answer 8

Antimuscarinic drugs (atropine, hyoscine, glycopyrrolate): all are potent antisialogogues,
and so a dry mouth is almost invariable.

Hyoscine is sedative.

All three agents can cause the central anticholinergic syndrome,
although it is very much less
common with glycopyrrolate (as a quaternary ammonium compound, its ability to
cross the blood–brain barrier is very limited).

Question 9

Antidopaminergic drugs (

Answer 9

metoclopramide, prochlorperazine, haloperidol, droperidol):

1. acute extrapyramidal and dystonic effects which are caused
   by a preponderance of the antidopaminergic stimulatory actions over anticholinergic
   inhibitory actions in other parts of the CNS.

This imbalance can be restored
almost instantly with an intravenous anticholinergic agent such as procyclidine
5–10 mg.

2. The phenothiazines may also cause sedation
3. Droperidol is associated with prolongation of the QT interval
   (with the potential development of torsade de pointes)

so should be avoided in any patient with a prolonged QTc
(corrected QT interval)

Question 10

QT prolongation

Answer 10

is, however, dose-dependent, and in the
lower doses given for anti-emesis it does not present significant risk

in patients taking one of the many other drugs that have the same
effect. (These include Class Ia and Class III antiarrhythmic drugs, antihistamines
such as terfenadine, some 5-HT3 antagonists which might be prescribed as part of
multimodal antiemetic therapy, and some antibiotics, quinolones and macrolides,
including erythromycin)

Question 11

Antiserotoninergic drugs

Answer 11

(ondansetron, granisetron, palonosetron):

ondansetron and granisetron are associated with QT interval prolongation,
whereas palonosetron is not; otherwise their side effect profile is favourable,

with headache being reported as the main side effect, complicating treatment in 3–5% of patients.

Question 12

Cannabinoids

Answer 12

(nabilone, dronabinol): sedation is common, and the drugs may
sometimes exert psychotomimetic effects similar to those induced by the parent
compounds. Dry mouth and postural hypotension may also occur.

Question 13

Corticosteroids

Answer 13

(methyl prednisolone, dexamethasone): the list of acute side
effects includes steroid psychosis,
which is related to a sudden increase in plasma levels of corticoids,

metabolic disturbance,
including hyperglycaemia,
fluid retention
hypokalaemia.

Short courses of high-dose steroids may cause peptic ulceration