2.1 Anti emetics Flashcards
Nausea – subjective unpleasant sensation in throat and stomach, the sensation of being about to vomit (which may or may not ensue)
Vomiting – forceful propulsion of stomach contents out of the mouth
Causes of nausea and vomiting – multifactorial
- Stimuli is sensed by mechanoreceptors or chemoreceptors from peripheral organs – pharynx, stomach, duodenum, heart, bladder, uterus, viscera, testicles
o Ingested toxins in gut, trauma, infections, cancer
o Gut pathology e.g. peptic ulcer, gastric paresis, obstruction, allergy, pancreatitis, hepatitis
o Toxic exogenous or endogenous agents in blood – absorbed from GI tract, infections, cancer, chemotherapeutic agents, radiation damage, uraemia, morphine, cardiac glycosides e.g. ___________ used in heart failure, ___________ (early pregnancy), recovery from ___________________
o Motion – vestibular system (motion sickness)
o CNS stimuli – pain, repulsive sights and smells, emotional factors (fear, anticipation), migraine, raised intracranial pressure (head injury, infection, tumour)
- Nausea and vomiting are the most common symptoms of illness – treat with drugs only when the cause is known
o Otherwise treatment could mask the diagnosis of potentially serious conditions, e.g. digoxin excess, diabetic ketoacidosis
o Differential diagnosis is complex (often due to diseases outside GI tract)
digoxin; oestrogen; general anaesthesia
Consequence of severe nausea and vomiting – in many cases nausea and vomiting is transitory with no underlying severe cause
- Acute nausea interferes with mental and physical activity
- Chronic nausea is very debilitating (repeated retching can lead to _________________)
- Severe vomiting – dehydration and electrolyte imbalance
o Loss of gastric hydrogen and chloride ions may lead to ___________________ (raised blood pH)
o Renal compensatory mechanisms may lead to ___________________ if vomiting is prolonged and excessiv
Mallory-Weiss tears;
hypochloraemic metabolic alkalosis;
hypokalaemia
Neural and muscular coordination during vomiting
Pre-ejection
- Nausea (not a prerequisite to vomiting) often preceded by ANS activation
- ________________ that protects teeth and stomach lining, sweating and increased heart rate
- Gastric smooth muscle relaxes, triggers afferent nerve impulses, and retrograde peristalsis begins
Retching
- Respiratory and abdominal muscles contract
- Gastric contents forced into ______________ (but not propelled out of the body) and reflux back into stomach in rest phase between retching
Expulsive
- Deep inspiration – ________ closes to avoid aspiration, protecting respiratory tract)
- Contraction of upper small intestine
- _______________ (separates stomach from duodenum) closes
- _________________ (separates stomach from oesophagus) relaxes
- Retrograde contractions shift contents from lower to upper portion of stomach
- Abdominal and diaphragmatic muscles contract – intra-abdominal pressure increases
- Mouth opens and gastric contents are forcefully expelled
Pallor, profuse salivation and mucous production;
oesophagus;
glottis;
Pyloric sphincter;
Lower oesophageal sphincter
Input, CNS integration and output – emetic circulatory
- Different signals are transmitted by different pathways to the vomiting centre at the brainstem – higher centres and gut may send signals too
- The chemoreceptor trigger zone (CTZ) is at the __________________
o In pregnancy, elevated ______________ present in the bloodstream can reach the area postrema outside the blood-brain barrier that can detect factors in general circulation
- The CTZ relays signals to the vomiting centre – anatomically undefined nuclei in the ____________ that coordinates emesis
- Other modulation – psychogenic higher centres, motion (vestibular and visual) and GI input
- CNS outputs signals to somatic and visceral nerves – coordinate somatic respiratory, abdominal muscles and GI smooth muscle
floor of the 4th ventricle outside the blood-brain barrier;
oestrogen;
medulla (brainstem);
Where is 5-HT3R at?
GI tract, CTZ
where is AChMR at
NTS, vestibular system, sensory afferents, vomitting centre
Where is H1R at
NTS, vestibular system, sensory afferents, vomitting centre
Where is D2R at?
CTZ
- Mixed receptor antagonists – PROMETHAZINE (a phenothiazine derivative) - Mode of action – competitive antagonist at ____________________
- Order of potency of antagonistic activity –_________________
o Other phenothiazines which are used as neuroleptic drugs have a different order of potency with greater antagonistic effects at D2 receptors - Use as an anti-emetic
o Motion sickness – normally used prophylactically, but some benefit may be gained if it is taken after the onset of nausea and vomiting
o Disorders of the labyrinth e.g., _____________
o Hyperemesis gravidarium – in 0.5 to 1.5% of pregnancy, severe vomiting increasing the risk of dehydration
o Pre- and post-operatively – _________________ are also useful to dry up secretions e.g. intubation in an operative setting - Other uses of promethazine – ______________________________
- Pharmacokinetic properties – administered orally, with onset of action of 1 to 2 hours, maximum effect of 4 hours and duration of action 24 hours
- Unwanted effects – dizziness, tinnitus, fatigue, sedation (advice patients not to drive or operate machinery), excitation in excess, convulsions (children more susceptible) and antimuscarinic side-effects (______________________ etc.)
histaminergic (type H1), cholinergic (muscarinic, M) and dopaminergic (type D2) receptors
H1> AChM > D2 receptors;
Meniere’s disease;
sedative and anti-muscarinic action;
relief of allergic symptoms, anaphylactic emergency, night sedation and insomnia;
dry mouth, blurred vision, constipation
- Dopamine (D2) receptor antagonists - METOCLOPRAMIDE, DOMPERIDONE
- Acts centrally especially at CTZ – order of antagonistic potency _____________________ (slight effect at AchM R)
- _____________ effects in the gastrointestinal tract – increases smooth muscle motility from oesophagus to small intestine, helps to counter _________ in nausea
o Accelerated gastric emptying
o Accelerates transit of intestinal contents from duodenum to ileocecal valve
- Use as an anti-emetic – to treat nausea and vomiting associated with:
o Uraemia – build-up in blood in severe renal failure
o Radiation sickness – e.g. cancer radiotherapy
o Gastrointestinal disorders
o Cancer chemotherapy (high doses) – e.g. ________ (intractable vomiting) - Parkinson’s disease treatments – stimulate dopaminergic transmission as Parkinson’s is due to ______________________
o Domperidone is preferred as it cannot penetrate the blood-brain barrier to interfere with Parkinson’s treatment (compared to metoclopramide) - Care must be taken with the bioavailability of co-administered drugs – due to the prokinetic effects on the GI tract, adsorption and hence effectiveness of e.g. digoxin may be reduced
o Nutrient supply may be compromised, especially important in conditions such as diabetes mellitus - Pharmacokinetic properties – may be administered orally, is rapidly absorbed and undergo extensive first pass metabolism (may also be given IV)
o Although metoclopramide crosses the placenta, it is not contraindicated in pregnancy as there is no epidemiologic evidence that it is tetragenic - Unwanted effects – CNS effects for metoclopramide only as domperidone does not cross blood-brain barrier (no anti-psychotic actions)
o Drowsiness, dizziness, anxiety
o Extrapyramidal reactions – children more susceptible than adults e.g. acute dystonia, oculogyric crisis (Parkinsonian-like syndromes of rigidity, tremor, motor restlessness)
§ Acute dystonia – sustained spasms of muscle contraction that distort a part of body
§ ____________ – subjective sense of restlessness, compulsive need to move
§ ______________________- with higher doses and long term use.
§ Galactorrhoea and amenorrhoea from pituitary dopamine receptor blockade
o In the endocrine system – hyperprolactinaemia, galactorrhoea and disorders of menstruation
§ Binds to dopaminergic receptors in the anterior pituitary gland especially in lactotroph cells, preventing inhibitory effects of dopamine on lactotrophs to produce _____________
D2»_space; H1»_space;> AchM receptors;
Prokinetic;
retrograde peristalsis ;
cisplatin;
degeneration of dopaminergic neurons controlling movement and the basal ganglia;
Akathisia;
Irreversible tardive dyskinesia;
prolactin
- Muscarinic receptor antagonists – HYOSCINE (a.k.a. SCOPOLAMINE)
- Acts centrally, especially in the ______________ to block activation of vomiting centre
o Order of antagonistic potency ________________- receptors
- Use as an anti-emetic – prevention of motion sickness, has little effects once nausea/emesis is established and this is prophylactic only
o In operative pre-medication – sedative and anti-muscarinic properties to reduce secretions
o Preferred for hyperemesis gravidum – no increased risk of teratogenicity - _________ is closely related to hyoscine but is less effective
- Pharmacokinetic properties – can be administered orally (peak effect in 1 to 2 hours), IV and transdermally
- Typical anti-muscarinic side-effects – drowsiness, dry mouth, cycloplegia, mydriasis and constipation (not usually at anti-emetic doses)
o Cycloplegia – failure to _______________________
o Mydriasis – useful in inspection of the fundus of eye, dilation of pupils due to ________________________ - High incidence of adverse effects when given orally, often administered as a ______________ – anticholinergic effects is reduced with transdermal administration
vestibular nuclei, NTS, vomiting centre ;
AchM»_space;>D2 = H1 ;
Atropine;
accommodate for near-vision as parasympathetic input to ciliary muscles are blocked;
parasympathetic contractions in the light reflex is inhibited;
transdermal patch
- Serotonin (5-hydroxytryptamine) receptor antagonists – ________________
- Acts to block transmission in _____________________
- Use as an anti-emetic –
o Main use in preventing anticancer drug-induced vomiting, especially cisplatin
§ The first-line for chemotherapy-induced vomiting is 5-HT3 antagonist with or without corticosteroids over choosing ____________
§ More efficacious and has a lower probability of causing side effects compared to anti-dopaminergic drugs, as found in clinical trials
o Radiotherapy-induced sickness
o Post-operative nausea and vomiting - Pharmacokinetic properties – administered orally, well absorbed, excreted in urine
- Unwanted effects – headache, _____________________(due to vascular effects) and warmth and increased large bowel transit time (constipation)
- Used in combination with corticosteroids – 5-HT3 receptor antagonists may be used for low emetogenic chemotherapy
o Corticosteroids such as __________________ may be used in combination with 5-HT3 receptor antagonists for high or moderately high emetogenic chemotherapy
o Improved efficacy of combined therapy may be due to anti-inflammatory properties of corticosteroids
ONDANSETRON;
visceral afferents and CTZ;
anti-dopaminergic drugs;
sensation of flushing ;
methylprednisolone
- NK1 receptor antagonists – aprepitant (oral) and ______________ (IV prodrug converted to aprepitant in the body) act as antagonists at the NK1 receptors in the area postrema against ______________)
- Used in late phase of cytotoxic drug-induced emesis – substance P (neuropeptide) is released by GI vagal afferent nerves, involved in several physiologic activities including the vomiting reflex and chemotherapy induced emesis
o After chemotherapy, serotonin may be released from the __________ cells of the digestive tract which then activates visceral afferent neurons – terminate in the _____________ (high density location of substance P- NK1 peptide system) - Indicated for highly or moderately emetogenic chemotherapeutic regimens – costly
- Adverse effects – fatigue, dizziness, headache, diarrhoea, anorexia
- Drug interactions – inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of patients receiving concomitant medications that are also metabolised by CYP3A4
o Inducer of CYP2C9 (warfarin is a substrate) may decrease effect of warfarin – ___________ should be monitored if co-administered
fosaprepitant;
substance P;
enterochromaffin;
area postrema;
INR
- Antihistamines e.g. promethazine (1st generation antihistamine of phenothiazine family)
- Effects on H1R (++++) with activity at AChMR (++) and D2R (+) – suppression of conduction in __________________
- Usage – vomiting from _____________________
o Not effective against substances that act directly on CTZ
o Lipophilic – crosses BBB producing sedation - Administration – oral, deep IM or slow IV (FDA Black Box warning for severe tissue injury (including gangrene) with parenteral (IV or IM) route of administration)
- Adverse effects – sedation, anticholinergic side effects – __________________________
vestibulo-cerebellar pathway;
middle ear disorders, pregnancy, PONV and pruritus
dry mouth, blurring of vision, urinary retention
- Glucocorticoids – used prior to chemotherapy, during general anaesthesia (GA) for prevention of PONV
- ________________ is often combined with ondansetron and or aprepitant in chemotherapy - Benzodiazepines – enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor e.g. ______________
- No intrinsic antiemetic activity, adjunctive role
- Beneficial effects may be due to ____________________
o May be useful in anticipatory vomiting e.g. a patient who experienced nausea and
vomiting in a previous chemotherapy session - Cannabinoids – acts on cannabinoid (CB1) receptors in the CNS
- Effect on cannabinoid receptors (CB1) within CNS
- Used in treatment of ________________________
- Associated with euphoria, hallucinations and increased appetite
Dexamethasone;
lorazepam;
sedative, anxiolytic and amnesic properties;
refractory nausea and vomiting associated with chemotherapy
Terminology
Vomiting: Forceful involuntary oral expulsion of gastric contents associated with contraction of _____________________
Nausea: Unpleasant sensation of the imminent need to vomit, usually referred to the _________________, a sensation that may or may not lead to the act of vomiting
Emesis: The ____________________ through the mouth. It serves as a protective function to rid the body of harmful substances that have been ingested, rather than allowing them to be retained and absorbed by the intestine, inhibits or reduces vomiting and nausea
abdominal and chest musculature;
throat and epigastrium;
involuntary expulsion of the stomach’s contents;
