Pharmacology CNS Nausea/GA Flashcards
Is there a target site for anaesthesia?
No as all brain function progressively affected such as motor control, relax activity, respiration (chemoreceptors) and autonomic regulation
Describe the stages of anaesthesia:
Loss of memory
Loss of motor reflex
Loss of response to painful stim
Changes in CV and resp physiology
Describe the first stage of anaesthesia:
Analgesia- mild depression of higher cortical neurons
Describe stage two of anaesthesia:
Delirium- excitation/ inhibition of reticular neurons
Involuntary movements and excitation of voluntary muscle
Describe stage three of anaesthesia:
Surgical anaesthesia
4 planes:
-gradual loss of thoracic resp
-decrease eye movements
-rapid loss of muscle tone
-loss of pharyngeal/larangeal reflexes
Describe stage four of anaesthesia:
Overdose; respiratory and circulatory paralysis
No CO= death
How is there a fine balance between anaesthesia and death?
As the conc of a GA is increased, the switch from being conscious to unconscious occurs over a very narrow conc range (around 0.2 of a log unit)
Non competitive antagonists identifies
Name the 2 classes of GA:
IV= induction
Inhalation= maintenance
Name examples of IV GA:
Ketamine
Thiopental
Propofol
Etomide
Name examples of inhaled GA:
Halothane
Nitrous oxide
Isoflurane
Sevoflurane
Desflurance
What is the elimination like in IV GA?
Unconsciousness occurs in seconds as soon as drug reaches the brain
Slow elimination from the body compared to inhalation
Describe the blood flow (CO) in different areas of the body:
Brain, heart, viscera, lungs (happens in secs/mins) -2/3 of CO
Muscle, skin (happens in 10’s of mins) -1/3 of CO
Fat (happens in hours) -2% of CO
Describe the elimination of thiopental and why this is bad:
Recovery has to await distribution into fat and elimination hangover
Thiopental displays saturation kinetics, large or repeated doses can cause the plateau in the blood conc to become more and more elevated as more drug accumulates in the body and the metabolism saturates
Name unwanted SEs for thiopental and propofol:
Causes CV and resp depression
Describe the elimination of propofol and why is this good:
Rapid onset and rapid rate of redistribution, can be used as a continuous infusion but maintaining desired levels are hard
No hangover- rapidly metabolised, so a limited cumulative effect
First order kinetics- no saturation
Useful for day case surgery
How does ketamine work as a GA?
Acts differently to all other anaesthetics as it increases BP and HR and has no effect on resp
Can be used in low tech healthcare situations (IM)
Powerful analgesic
Slower onset (1-2 mins)
What are the unwanted SEs of ketamine?
Can increase intracranial pressure
Hallucinations
Delirium during recovery
Describe the pharmacokinetics of inhalation GA:
Involves a series of equilibration events:
-the GA first eq with the alveoli
-equilibration in the blood should be rapid: an ideal inhalation anaesthetic rapidly reaches the required arterial blood conc and vice versa
-blood must become saturated for transfer of GA to the tissues (slow)
Describe the pathway of the inhaled GA:
Inhaled gas- alveoli- blood- tissues
Describe the structure of inhaled GA to work:
Small and lipophillic so rapidly cross alveolar membrane
What is the kinetics behaviour of the inhaled GA due to?
Solubility
Expressed as partition coefficients:
-blood: gas coefficient
-oil: gas coefficient
What are partition coefficients?
The ratio of the conc of an inhalation anaesthetic in two different phases at equilibrium
Describe how the blood: gas coefficient is used to determine pharmacological effect:
Conc of GA in the brain closely tracks that in arterial blood (BBB)
Describe the effect of a low solubility drug on equilibrium:
E.g NO, B:G coefficient= 0.5
Inhaled- slow blood absorption (low alveolar conc), more breaths taken so build up of drug, medium conc but slow blood absorption as not very soluble
Eventually equilibrium occurs- faster equilibration
Describe the effect of a high solubility drug on the equilibrium:
E.g ether= 12, halothane= 2.4
Inhaled- dissolves rapidly into blood (low alveolar conc), more breathes so fast blood absorption (low alveolar partial pressure of drug) so low pp, equilibrium not reached, slow rate, takes longer
Describe how the oil:gas partition coefficient is used to determine pharmacological effect:
Transfer of anaesthetic between blood and tissues affect the kinetics of eq
Body fat is around 20% of the total volume of body
Many GA 100x more soluble in fat than in water so after eq 95% will be in fat
Venous blood coming from fat is only 2% of total and so change in GA conc in the venous blood as a result of uptake or leakage will be very small
What are factors affecting the rate of eq of the inhaled GA in the body?
Ventilation rate
CO (blood flow):
-Lean tissue (increase CO), fast perfusion, small partition coefficient, rapid eq
-Fat, slow perfusion, large partition coefficient, slow eq
What is true about a patient’s body fat in terms of GA response?
It takes hours for the drug to enter and leave the fat due to slow blood flow
Halothane has a high O:G coefficient, extremely fat soluble, the more fat a patient has the slower the recovery, longer the surgery, longer the hangover/recovery
What is the partition coefficient for nitrous oxide and its induction/recovery rate:
O:G= 1.4
B:G= 0.5
Fast
What is the partition coefficient for halothane and its induction/recovery rate:
O:G= 220
B:G= 2.4
Medium
What is the partition coefficient for ether and its induction/recovery rate:
O:G= 65
B:G= 12
Slow
What is the minimal alveolar conc (MAC)?
MAC required to abolish the response to surgical incision in 50% of subjects
Correlation between MAC and the lipid solubility of the drug, linear
No correlation with chemical strucutre
What is the general principle of how GA work?
Anaesthetic molecules bind to hydrophobic pockets within specific membrane protein targets
Which targets could be responsible for anaesthesia?
GABAa receptor
Glutamate receptor
VG Na+, K+ and Ca2+ channels
Describe how GABAa receptors are involved in GA:
Most anaesthetics enhance activity of GABA at GABAa r including propofol
GABAa receptors are ligand gated Cl- channels consisting of 5 subunits (2a,2B,1g or 1 epsilon subunit)
Anaesthetics bind to hydrophobic pockets within different GABAa receptor subunits, this is complex as there are different subunit composition in different r
What occurs if there is a mutation in the a subunit of the GABAa r?
Inhibits action of volatile anaesthetic but not IV GA, but the B subunit is important for both
Describe how the glutamate receptors are involved in GA:
Major excitatory NT in CNS
NMDAr are the site of action for NO, xenon and isoflurane
Mutation in membrane domain M3 and M4 decreases alcohol induced inhibition of these receptors
Xenon and isoflurane inhibit NMDAr by competing with glycine for its regulatory site
NO blocks the channel pore, ketamine is a selective antagonist (allosteric)
Describe how the VG Na+ and K+ channels are involved in GA:
Two pore domain K+ channels from a family of background K+ channels which modulate neuronal excitability
Consist of TREK1, TREK2, TASK1, TASK3 or TRESK subunits
Activated by low conc of volatile and gaseous anaethetics to decrease membrane excitability
What occurs if there is a mutation in the VG channels for GA?
Mutation in TM3, a reduction in response to GA
Not affected by IV anaesthetics
Which NS are the nicotinic receptors located?
CNS, a motor neurons synapse at nicotinic receptor (Ach) at neuromuscular junction in somatic efferent system
Also in sympathetic (adrenal medulla- release of adrenaline) and parasympathetic NS
Name the different subtypes of nicotinic receptors:
Muscle
Ganglionic
CNS types
How do nicotinic receptors signal?
Ligand gated cation channels, mediate fast excitatory synaptic transmission
Name the endogenous agonists at the nicotinic receptor:
Ach
Nicotine mimic the action of Ach also
Describe the structure of the nicotinic receptor:
Pentameric (5 subunits) a,B,g,d,epsalon
All nicotinic r have at least 2a subunits- binding pocket between a subunits for Ach
Describe the subunit structure of the nicotinic receptor:
a subunit:
4 TMD
M2 domain lines the central pore
Has a.a residues which are -ve charged, line the pore, which allows selectivity of cation to pass
How does the nicotinic receptors cause skeletal muscle contraction?
As Ach binds, gate opens, cations flow down gradient (Na+ from out to in) causes depolarisation
At NMJ, mediating contraction at skeletal muscle
Name a drug that is selective for the muscarinic nAch receptor:
Suxamethonium (succinylcholine)
How can inhibition of transmission at the NMJ be achieved?
Competitive inhibition of the nicotinic receptor (nAchR antagonists e.g tubocurarine), non depolarising block
Depolarising block (caused by nicotine agonist)
Describe how a non depolarising block occurs:
Tubocurarine is a non depolarising neuromuscular blocking drug (active component of curane- causes paralysis)
Inhibition is competitive (overcome by increased Ach)
Causes small depolarisation at end plate but not enough for AP propagation so no contraction of muscle
Describe how a depolarising normally occurs:
Nicotine- when a neurone is depolarised, the VG Na+ channels are in an inactivated state- however much the neurone is stim it can’t be stimulated
Needs to go back to resting potential until another AP can occur
Describe how a depolarising block occurs:
Block is not competitive, increase agonist exacerbates the effect
Persistent stimulation leads on to ‘phase II block’ due to desensitisation of the nAchRs
-repolarisation but still can’t be stimulated
Name and describe depolarising blocking agents:
Nicotine
Ach (in presence of choline esterase inhibitor)
Suxamethonum- only clinically used, used if fast brief NM block is required e.g tracheal incubation prior to surgery
Very short acting (10 mins), hydrolysed by plasma (butyryl) cholinesterase
What is the major SE of suxamethonum?
Prolongued (hours) paralysis in neonates, patients with liver disease (as liver synthesises choline esterase) or genetic variants lacking choline esterase activity
Why is tubocurarine no longer clinically used?
SEs:
-severe hypotension (due to ganglion block)
-release of histamine (not releated to nAchR antagonism)
Name clinical non-depolarising blocking agents:
Pancuronium- long DOA (1hr)
Vencuronoim- intermediate DOA
Atracurium- intermediate DOA
Mivacurium- short DOA (15 mins)
How do depolarising blocking agents work at the NMJ?
Depolarising blocking ages produce transient muscle twitching (fasciculations) followed by NM block caused by maintained depolarisation of muscle cells
Name different inputs that can stimulate the vomit reflex:
Stim of back of throat- gag reflex
Noxious chemicals (inc drugs)
Distension or irritation of the stomach or duodenum
Rotation or acceleration of the head
Elevated intracranial pressure- haemorrhage
Emotional factors- psychogenic vomiting
How do noxious chemicals stimulate the vomit reflex?
On the chemoreceptor trigger zone
How does distension or irritation of the stomach or duodenum stimulate the vomit reflex?
Mechanoreceptors- stretch of stomach/dueodenum
Chemoreceptors- noxious chemicals
How does rotation or acceleration of the head stimulate the vomit reflex?
Vestibular apparatus (semi-circular canals) in the inner ear feeding into the vestibular nuclei
Dizziness
Motion sickness
Where is the vomiting centre located?
In the medulla- nucleus of the solitary tract (NTS)
Where is the CTZ located?
Adjacent to the 4th ventricle
Describe the structure and function of the CTZ:
Fenestrated capillaries- gaps between endothelial pass through
Has no BBB if not its function would not be possible:
-samples blood to detect noxious chemicals e.g bacterial toxins, poisonous alkaloids, drugs
Describe the structure and function of the NTS:
Adjacent the CTZ
Network of pathways in the medulla
Dendrites from the NTS project into the CTZ
Relay centre/integration centre
-multiple inputs including CTZ
Co-ordinates the motor side of the vomiting reflex
Why are dopamine agonists pro-emetic?
Stimulate the D2 receptors in the CTZ
How does input from the GIT cause nausea and vomiting?
Enterochromaffin cells are a type of enteroendocrine cell in the gastric epithelium
Chemoreceptors on the enterochromaffin cells detect noxious chemicals, mechanoreceptors detect stretch
Release 5-HT
Stimulate nerve endings of vagal afferents (from periphery to CNS)- 5HT3 receptors
Vagal afferents take info to the NTS
5HT released into systemic circulation, which can get into the CTZ
Name the different vomit reflex-output pathways:
Autonomic response
Somatomotor response
Describe what occurs in the autonomic response output pathway:
Increase salivation
Cutaneous vasoconstriction (pale)
Increased HR
Sweating
Retrograde contraction of the SI- moves up SI
Relaxation of the stomach, oesophagus and oesophageal sphincter- content can move up
Describe what occurs in the somatomotor response output pathway:
Contraction of diaphragm (deep inspiration)
Closure of the glottis- close airways
Closure of nasal cavities- soft palate moves up
Strong contraction of the diaphragm (down on stomach) and abdominal muscles (up on stomach)
Pressure forces stomach contents to move upwards and ejected via mouth
Name and describe different NT involved in the vomiting reflex:
Ach- vestibular system, muscarinic receptors, motion sickness
Histamine- vestibular, found in NTS, motion sickness and other
5HT-chromaffin
Dopamine- CTZ and gut
Substance P- NK1 r in gut and NTS
Endocannabinoids- CB1 r stim=anti-emetic
Enkephalins- stim receptors=anti-emetic
Vasopressin is released during nausea-although not a NT
Name different classes of antiemetic drugs:
Muscarinic antagonists
H1 antagonists (antihistamines)
5HT3 antagonists
Dopamine antagonists:
-phenothiazines (antipsychotics)
-D2 antagonists
NK1 antagonist
CB1 agonists
Corticosteroids
Name examples of muscarinic antagonists:
Hyoscine
Name examples of H1 antagonists:
Cinnarizine
Cyclizine
Promthazine
Name examples of 5HT3 antagonists:
Odansetron
Granisetron
Palonosetron
Name examples of phenothiazines and their MOA:
Prochlorperazine
Chlorpromazine
Block multiple receptors (inc H1 and mAchR) as well as D2R
Name examples of D2 receptor antagonists and their MOA:
Metoclopramide- also has direct effects on GIT
Domperidone- doesn’t cross BBB, block N&V, but not therapeutic effect on N&V causing drugs
Name SEs of dopamine antagonists:
Extrapyramdial SEs and hyperprolcatinaemia if cross BBB pituritary)
Name examples of NK1 antagonists:
Aprepitant
Fosaprepitant
Given as an adjunct
How do NK1 antagonists work?
Block substance P
Name an example of CB1 agonist:
Nabilone
How do CB1 agonists work?
Blocked by naloxone so MOA involves opioid receptors
Used for chemo if others haven’t worked
Name SEs of CB1 agonists:
Drowsiness
Psychotic episodes (hallucinations)
Name an example of a corticosteroid used in N&V and what type?
Dexamethasone
Used in N&V associated with chemo
What is the difference between general anaesthesia(GA) and local anaesthesia(LA) ?
GA acts on the brain to produce loss of sensation, whereas LA acts by blocking conduction in nerve trunks
How does GA work?
Affect synaptic transmission and neuronal excitability rather than axonal conduction
GA small, lipid soluble molecules that easily get across to brain by crossing BBB
Name the pathway for reticular formation:
Reticular formation- midbrain- hippocampus- thalamus- cortex
What is reticular formation?
Important for wakefulness
Complex network of neurons in the brain stem
Extends upwards into non specific nuclei of the thalamic sensory relay and connects to hypothalamus, cerebellum through to cerebral cortex
Arouses cerebral cortex into wakefullness
What occurs if reticular formation is inhibited?
Causes unconsciousness and analgesia
Amnesia is due to hippocampus inhibition
