3. Treating Emesis Flashcards
Vomiting is not just controlled by the gut; it is more than just gut motility
Emesis is under control of the CNS (Medulla Oblongata)
- Chemoreceptor trigger zone (CTZ)
- Vomiting centre
- Nuclei (group of neuron cell bodies) recieve input from several sources
+ The Cortex- eg. exam stress, or if you see or smell someone else vomiting
+The vestibular nuclei - when there is a mismatch between proprioception and visual information- eg: motion sickness
+ the nucleus iof the solitary tract (NTS) the gag reflex- eg. blood borne toxins, drugs, etc, which may cross the blood brain barrier or directly stimulate the GIT
How is vomiting stimuli transmitted?
Vomiting stimuli are transmitted from the brain to the smooth muscle of the GIT and abdominal muscles via the VAGUS and SOMATIC MOTOR NERVES (part of the peripheral nervous system associated with voluntary control).
Explain Vomiting reflex unfer control of the CNS
Vomiting is regulated centrally by the vomiting centre and the chemoreceptor trigger zone (CTZ), both of which lie in the medulla. The CTZ is sensitive to chemical stimuli, and is the main site of action of many emetic and anti emetic drugs. The BBB in the neighbourhood of the CTZ is relatively permeable, allowing circulation mediators to act directly on this centre. The CTZ also regulates motion sickness. Impulses from the CTZ pass to those areas of the brainstem collectively known as the vomitting centre. The final common pathway involves impulses from the vomiting center to the skeletal and visceral smooth muscles. The vomiting centre recieves impulses from the CTZ and the nucleus of the solitary tract, as well as from higher centres (the cortex)
Vomiting is best stopped by targeting the cause
We control vomiting by blocking the receptor types in these nuclei.
What are the FOUR CELL TYPES we block!
Nucleus of vestibular nuclei, solitary tract & vomiting centre = muscarinic & hisamine receptors
Chemoreceptor Trigger Zone = Dopamine and Serotonin receptors.
The best drugs control the CTZ- metaclopromide (dopamine antagonists)- which then controls the activity of the vomiting centre.
Brain Centre: Chemoreceptor Trigger Zone - what is the receptor?
Dopamine (D2) and Serotonin (5-HT3)
Brain Centre: Vomiting Centre- what is the receptor?
Cholinergic: Muscarinic and Histamine (H1)
Brain Centre: Nucleus of the Solitary Tract - what is the receptor?
Cholinergic: Muscarinic and Histamine (H1)
Brain Centre: Vestibular Nuclei: what is the receptor?
Cholindergic: Muscarinic and Histamine (H1)
OUTSIDE THE CNS: visceral afferent receptors within the GIT- what is the receptor?
Serotonin (5-HT3)
Name some Dopaminergic Antagonists
Metoclopramide (Maxolon) - Most commonly used
Prochlorperazine (Stemetil)
Domperidone
Theithylperazine
What are the pharmacodynamics of Metoclopramide?
First drug of choice for treating excessive vomitting due to a range of causes including:
- Alcohol abuse- can actually be used with alcohol poisoning
- Uraemia, radiation
- GI disorders and Cytotoxic drugs
What are the pharmacokinetics ? Ie. Cellular effects of of Metoclopramide?
Antagonists- therefore inhibits gastric smooth muscle relaxation due to dopamine, and increases gut motility- this assists and increases gut motility
Assists stomach emptying
Decreases vomiting reflex
What are the side effects of Metoclopramide?
Due to blockage of CNS dopamine receptors:
- Parkinsonian-like symptoms : eg tremors. This occurs especially in children and young adults or with an overdose situation. Tremors are short lived, and wear off as the drug does. BBB penetration is higher in children/young adults.- because BBB is much less developed
Drowsiness and fatigue are common
Motor restlessness, spasmodic torticollis (involuntary movement of neck) & oculogyric crises (eyes roll back into head) can also occur
Can stimulate the release of prolactin from the anterior pituitary - galactorrhoea (breast milk production) and menstrual disturbances may occur.
Increase gut motility and therefore may result in diarrhea
Pharmacodynamics of Prochlorperazine (Stemetil)
Useful in treating migraines, vestibular disorders eg. vertigo as seen in Meniere’s disease and motion sickness
Typically used as an antisphycotic agent; however, the anti-emetic dose of anti-psychotic drugs are generally less than one third of those used to treat psychoses.
Pharmacokinetics of Stemetil
Acts on the D2 (dopamine) receptors in the chemoreceptor trigger zone - antagonist.
Inactive in the GUT- not useful against emetic stimuli originating in the gut
Side effects of Prochlorperazine (Stemetil)
Seizures Cardiac arrest Dysrhythmias Myocardial depression Nausea Anaphylaxis Respiratory arrest
Domperidone
Does not readily cross the BBB
All react with alcohol hence not as widely used
Thiethylperazine
Commonly used for treating severe nausea
- Radiation, cytotoxic, and anasthesia induced emesis
all react with alcohol, enhancing alcohol effect so not to used totreat alcohol abuse
What is the exact cellular mechanism of Dopamine at the D2 receptor?
Blocks the Dopamine type 2 receptors.
- these can be inhibitory pre- or post synaptic receptors
- Activation of D2 receptor inhibits cAMP signalling
+ Can serve an autoregulatory function, decreasing the release of dopamine OR
+ can decrease he amount of other neurotransmitters
D2 receptors ARE INHIBITORY RECEPTORS
- Vomiting increases dopamine levels, and dopamine binds to D2 in the chemoreceptor trigger zone which decreases the amoung of GABA produced by inhibitor neurons, thus stimulating the excitatory pathway. (GABA = inhibitory neurotransmitter which decreases the activity of the neuron)
Normally you have no/low dopamine, hence GABA can fire and inhibit excitatory neuron from stimulating the vomiting centre
Vomiting increases dopamine levels, activating the D2 receptors which inhibits GABA, therefore allowing CTZ to stimulate the vomiting centre
*Metoclopramide blocks D2 receptors so even with increased Dopamine, GABA can flow, giving more conrol over excitatory neurons
When are Muscarinic Antagonists used?
MOTION SICKNESS
Name a muscarinic antagonist and pharmacokinetics of the drug
HYOSCINE (Scopolamine)
Blocks the M1 receptor
- Mediates slow EPSPs (excitatory postsynaptic potential) -ie. the M1 is an excitatory receptor. Activation of M1 upregulates phospholipase C & inositol triphosphate and hence intracellular calcium signaling pathway.
Blockade
- Decreases production of GI secretions & acids
- Decreases involuntary movemnts
- Inhibits vomiting reflex
- One of the most POTENT agents available for MOTION SICKNESS
Name Histamin1 Antagonists!
Promethazine
Travacalm
When do you use Promethazine?
Promethazine is a HISTAMINE ANTAGONIST
Most effective as a prophylactic in nausea and vomitting- only partially effective once nausea is established
Also useful in treating labrynthitis- inflammation of the labrynth in the ear
What are the pharmicokinetics of Promethazine
Activation of the H1 receptors is thought to activate the same cellular signaling pathway as the M1 (excitatory) - where M1 is an excitatory receptor. Activation of M1 upregulates phospholipase C and inositol triphosphate and hence intracellular calcium signalling. IF YOU BLOCK IT
- decreases production of GI secretions and acids
- Decreases involuntary movements
- Inhibits vomiting reflex
What are the side effects of Promethazine
CROSSES BBB
- Drowsiness, diziness, causes seddation via some anti-cholinergic activity, hypotension, constipation, wheezing (increased mucous secretions)
Name some other antihistamine drugs
Cyclizine, cinnarizine, dimenhydrinate
What is Travacalm?
It is a common over the counter travel sickness treatment made by Pan Pharmaceuticals
- 0.2mg Hyoscine hydro bromide
- 50mg dimenhydrinate
- 20mg caffiene
LOTS OF ADVERSE REACTIONS: hallucinations, confusion, ataxia, blurred vision, consistent with Hyoscine poisoning. 24 patients were hospitalised
Name some SEROTONERGIC ANTAGONISTS
Odansetron, dolasetron, graniesetron, tropisetron
Explain where the 5-HT3 receptors are located
Serotonin receptors at the CTZ and also peripherally in the GIT
Serotonin is thought to act directly at the CTZ
Serotonin release from entero chromaffin cells in the small intestine is also thought to be important- serotonin activates the 5-HT3 receptors on afferent terminals within the vagus nerve, which activates the CTZ.
All serotonin receptors are G-protein coupled protein receptors
EXCEPT 5HT3 which is an ion channel blocker- 5HT3 is a receptor/ligand gated Na/K+ channel
When do you use Ondansetron?
What are the cellular mechanisms?
What are the side effects?
Ondansetron is a serotonin antagonist
- a long acting version used at RHH is Dolasetron mesylate
Serotonin release is commonly induced by cytotoxic chemotherapy- it is thought that its peripheral action in addition to its central action makes it primarily effective.
THEREFORE (due to EXPENSIVE)- Ondansetron is used for the management of nausea and vomiting associated with cytotoxic chemotherapy being used to treat malignancy
- When treating cytotoxic induced vomiting, drug combinations are usually used- with eg. metoclopiramide and dexamethasone
SIDE EFFECT= constipation
Which anti-emetic targets Substance P?
Aprepitant
What are the pharmacokinetics of Aprepitant
Aprepitant is a selective antagonist of the neurokinin 1 recetor.
- Substance P is found in the brian and gut- it binds the neurokinin 1 receptor; blocking this receptor may prevent vomitting.
Aprepitant is a selective antagonist of NK1- it crosses the BBB and has no affinity for serotonin or dopamine. Apprepitant also induces the metabolism of warfarin.
Aprepitant can be used in combination to treat severe chemotherapy induced nausea combined with ondansetron and dexamethasone
Name a Cannabinoid
Nabilone
- Synthetic cannabinol derivative
- Inhibits nausea caused by agents that stimulate CTZ
Side effects: mood changes, postural hypotension, dry mouth, drowsiness, diziness, also hallucinations and psychotic reactions
Anti Emetics and Children?
Children are still undergoing substantial nervos system development well into their teens and their BBB is not fully developed
- Children are also very sensitive to neurotransmitter blockage - dompaminergic blockade can cause adverse side effects such as Parkinsonion like symptoms- also a problem in treating the age.
General rule- if children are vomiting there is probably a good reason
- In general, children should be treated with fluids only
