CNS Pharmacology Flashcards
Who was the first to demonstrate the usefulness of nitrous oxide as an analgesic in the process of tooth extraction?
Horace Wells
William Morton was known for his use of ether as a volatile anaesthetic during tooth extraction, T or F?
T
What was J. Simpson’s contribution to general anaesthesia?
He was the first person to demonstrate that chloroform could render patients’ unconscious. Was also deemed the co-discoverer of general anaesthetics
What are the two classes of chemical general anaesthetics?
Inhalational and intravenous
What type of general anaesthetic is NO2?
Inhalational chemical general anaesthetic
Give an example of some intravenous chemical general anaesthetics?
Halogenated hydrocarbons such as isoflurane. Also steroids and barbiturates such as thiopental are also intravenous
Give some examples of physical general anaesthesias?
Low pressure, hypothermia
What is meant by the term surgical anaesthesia?
The point at which patients become unresponsive and unable to sense pain
What evidence is there to suggest that anaesthetics aren’t agonists acting on a receptor?
Steep dose-response curve which isn’t seen in agonist binding. Low pressure can also induce anaesthesia
What is significant about the dose-response curve of general anaesthetics?
They have very steep dose-response curves
What property of general anaesthetics is very closely related to their potency?
Lipid solubility
Describe what is meant by a MAC value and how this relates to the potency of the general anaesthetic?
MAC value – minimum alveolar concentration of anaesthetic to alleviate a response to surgical incision in 50% of patients. The lower the MAC value the higher the potency of the general anaesthetic
What is meant by the oil:gas partition coefficient?
The ease with which a substance dissolves, or partitions into oil
Drugs with a low oil:gas partition coefficient will have a high potency and thus a lower MAC value, T or F?
F – drugs with higher oil:gas partition coefficients will have a high potency and lower MAC values
What is meant by the Meyer-Overton rule?
The effect of an anaesthetic is proportional to the molar concentration of the agent in lipid
What is the effect of general anaesthetics on the plasma membrane?
General anaesthetics lead to a volume expansion in the plasma membrane
What is the impact of general anaesthetics on lipid fluidity?
General anaesthetics increase lipid fluidity
What aspects of the general anaesthetic mechanism of action are explained by the lipid theory?
As antibiotics are thought to lead to a volume expansion of the plasma membrane and an increase in lipid fluidity the lipid theory of antibiotic action accounts for the meyer-overton rule. In addition, the effect of pressure is also explained as we know that a decrease in pressure results in a volume expansion of the lipid membrane and thus will give rise to anaesthesia. Finally this also accounts for the fact that such a diverse range of compound can have anaesthetic effects
What aspects of the general anaesthetic mechanism of action aren’t explained by the lipid theory?
The fact that decreasing temperature can have anaesthetic effects despite the fact that it leads to a decrease in membrane fluidity. It also doesn’t explain that the binding of anaesthetics is saturable, implying a specific interaction with a protein. Finally there is a loss of actions in some compounds that are extremely lipid soluble and being homologous to known anaesthetics
It in fact turned out that the mechanism of action of anaesthetics was a combination of the lipid theory and a protein binding theory, T or F?
T
What is significant about the binding sites of anaesthetics that have been proven to bind to proteins in the plasma membrane?
General anaesthetic binding sites tend to be in hydrophobic domains deep within the membrane
What type of proteins do general anaesthetics tend to bind to?
Ion channels
Which specific receptor is it known that some general anaesthetics bind to and how does this lead to anaesthesia?
GABAA receptors – inhibition of regions in the central nervous system leading to anaesthesia
Different anaesthetics all interact with the same subunits of the proteins to which they bind, T or F?
F – different anaesthetics bind to different subunits
Where to intravenous anaesthetics tend to bind on the GABAA receptors?
β subunit
Where in the GABAA receptor structure do volatile liquid general anaesthetics tend to bind?
The interface between the α and β subunits
What is the function of the two-pore-domain potassium channels?
Regulate the excitability of neurons
How do general anaesthetics that bind to the two-pore-domain potassium channels exert their effects?
Increase the excitability of the channels and make the firing of actions potentials less likely
Explain ketamine’s anaesthetic effect?
Ketamine is an NMDA receptor antagonist and is known as a dissociative anaesthetic which prevents the action of excitatory glutamate
What type of protein is targeted by isoflurane and how does this cause anaesthesia?
Voltage-gated Na+ channels – inhibition of these channels prevent depolarisation and action potential generation
What neurotransmitter is secreted at the giant synapse in the brain known as the Calyx of Held?
Glutamate
What is the effect of low concentrations of general anaesthetics?
Decreased synaptic transmission in the central nervous system
Decrease synaptic transmission at low concentrations of anaesthetics in which area of the brain are responsible for the amnesia experienced?
Hippocampus – new memory formation
Decrease synaptic transmission at low concentrations of anaesthetics in which area of the brain are responsible for the loss of consciousness?
Reticular formation
Decrease synaptic transmission at low concentrations of anaesthetics in which area of the brain are responsible for the analgesia experienced?
Thalamic sensory relay nuclei
What is the effect of high concentrations of general anaesthetics?
Decreased speed of conduction in the central and peripheral nervous system
What brain functions are lost at dangerously high anaesthetic concentrations?
Motor control, control of cardiovascular reflexes and respiration as well as autonomic regulation
What are the four stages of anaesthesia from lowest to highest drug concentration?
Analgesia, excitement, surgical anaesthesia, medullary paralysis
Why is the second stage of anaesthesia dangerous?
In the excitement phase there is an exaggeration of reflexes (i.e. gagging) due to imbalances in excitatory and inhibitory neurons.
What are the four ideals for controlling anaesthesia?
Rapid induction and loss of consciousness, analgesia, muscle relaxation and rapid recovery
Which types of general anaesthetics are usually used to induce anaesthesia?
Intravenous anaesthetics
What are the advantages of intravenous anaesthetics?
Easy administration, less stressful for patients, rapid induction, metabolised well and quickly due to high lipid solubility
What are the disadvantages of intravenous anaesthetics?
Pain at site of injection, complex pharmacokinetics, cardiovascular and respiratory depression, control of concentration difficult and little can be done to resolve overdose
Ketamine administration leads to complete loss of consciousness, T or F?
F
Ketamine is a powerful analgesic, T or F?
T
What are some of the side effects of ketamine use?
Cardiovascular excitement, involuntary movements, euphoria, hallucinations and delirium
What is the role of inhalation drugs in anaesthesia and why are they more suited to this?
Inhalational anaesthetics are useful in the maintenance of surgical anaesthesia. It is much easier to control the levels of these drugs in the body
The reason inhalation anaesthetics are easier to control is because they are metabolised instantly by the body, T or F?
F – there is little to no metabolism of inhalational anaesthetics
What four factors are needed to be controlled when maintaining inhalation anaesthetic blood concentration?
Initial drug concentration, pulmonary ventilation, rate of transfer from alveoli to the blood and the rate of loss of the drug from arterial blood
What can be done if the state of anaesthesia becomes too deep?
Increase ventilation rate
Inhalational drugs are extremely lipid soluble, T or F?
T
Inhalation anaesthetics are redistributed into the fat rapidly, T or F?
F – they are redistributed slowly due to poor fat perfusion
What does the high lipid solubility of inhalation anaesthetics allow?
Rapid equilibration between body fluid concentration and alveolar space concentration
What is malignant hyperthermia?
Condition associated with the use of general anaesthetics that results in a rapid rise in temperature, huge increases in muscle contraction, hypertension and tachycardia
What causes malignant hyperthermia?
Mutations in the ryanodine receptor
Where is the mutated protein in malignant hyperthermia found?
Sarcoplasmic reticulum in skeletal (and some smooth) muscle
What happens in malignant hyperthermia in the presence of a general anaesthetic?
The ryanodine receptor has an increased sensitivity to anaesthetics and so opens allowing Ca2+ efflux from the sarcoplasmic reticulum. This leads to a oxidative burst by the mitochondria and a massive increase in ATP and intracellular Ca2+
How can malignant hyperthermia be treated?
Dantrolene is a ryanodine receptor inhibitor that is given in conjunction with the general anaesthetic to prevent the symptoms
What is meant by ataxia?
Irregular, uncontrolled muscle contractions
Recall some of the main symptoms of ataxia?
Ataxia/shaking, trunk instability, vertigo, nausea, vomiting, poor balance, nystagmus, tendency to falls
What inheritance pattern is seen in Type I episodic ataxia?
Autosomal dominant
What is the typical age of onset for type I episodic ataxia?
20-30
What can be said about the duration of attacks seen in patients with Type I episodic ataxia?
They are short/brief
What causes episodic ataxia type I?
Loss of function mutation in KCNA1
What type of protein in affected by the mutation that causes type I ataxia?
Voltage-gated K+ channel
What triggers attacks or episodes in type I ataxia?
What triggers attacks or episodes in type I ataxia? Physical or emotional stress, impacts to the vestibular system or sudden changes in position
Where is the channel protein that is mutated in Type I ataxia found?
In the cerebellum and neuromuscular junction
What can be said about the pattern of possible mutations in the protein that results in type I ataxia?
There is no clear mutation pattern, mutations occur throughout the protein in no specific areas
What is the impact on K+ currents as a result of the expression of mutant KCNA1 protein in animal models and what does this tell you about the impact of these mutations on protein function?
Mutant KCNA1 expression results in a decrease in the size of the K+ currents in the neuron thus indicating the mutations are loss of function
What part of the action potential is mediated by voltage-gated K+ channels?
Repolarisation
How does the mutation in KCNA1 lead to the increase excitability of neurons and thus inappropriate shaking movements?
Loss of function of the voltage-gated K+ channels compromises repolarisation and thus extends depolarisation. This results in the increased excitability of the neurons
Explain how the location of the KCNA1 channels accounts for the double impact of their mutation?
As KCNA1 is present both in the cerebellum and neuromuscular junction then mutations will result in problems with muscle contraction at the level of the neuromuscular junction but also problems with the signals coming from the cerebellum in the first place.
Why is it thought that acetazolamide is effective in treating ataxia?
Acetazolamide is a carbonic anhydrase inhibitor. By inhibiting carbonic anhydrase there is more HCO3- secretion in the kidney and thus more excretion in the urine. Loss of bicarbonate from the body results in a decrease in body fluid pH which in turn causes a decrease in the excitability of neurons
Phenytoin and carbamazepine are also effective medications for the treatment of type I ataxia. What class of compounds are they and how do they work to alleviate symptoms?
Na+ channel blockers that reduce neuronal excitability by preventing depolarisation
What is the inheritance pattern of type II episodic ataxia?
Autosomal dominant
How does the onset of type II episodic ataxia differ from that of type I?
Type II ataxia has an earlier onset typically in childhood to teenage years
How do the attacks in type II ataxia differ from that in type I?
The duration of the attacks are much longer from 30mins to 24hours
How do they symptoms of type II ataxia differ from type I?
Type II episodic ataxia is more likely to lead to trunk instability, vertigo, nausea, vomiting and headaches
What triggers the onset of symptoms in type II ataxia?
Physical or emotional stress, impacts to the vestibular system and sudden changes in position
Episodic ataxia type II is caused by mutations in which protein?
CACNA1A
What type of protein is mutation in type II ataxia?
Voltage-gated Ca2+ channel
Where is the mutant protein found in type II ataxia?
In the cerebellum
Describe the structure of the CACNA1A protein?
Membrane protein with 24 transmembrane domains in 4 blocks of 6. Each block of 6 contains a pore region and the 4th TMD is the voltage sensor
CACNA1A is regulated by cGMP, T or F?
F – it is highly regulated by β accessory proteins
What are the two types of mutations seen in CACNA1A that result in episodic ataxia type II?
Substitution mutations and truncation mutations
Which type of type II ataxia mutation elicits the most severe symptoms in patients?
Truncation mutations
What can be said about the mutation patterns seen in CACNA1A?
There is no clear mutation pattern however there is some indications of clustering of mutations
A mutation in CACNA1A will cause episodic ataxia type II, T or F?
F – mutations in CACNA1A can cause one of three different allelic disorders. Missense mutations tend to cause familiar hemiplegic migraine whereas a repeat expansion of the c-terminus will result in spinocerebellar ataxia type VI
Episodic ataxia is a progressive neurodegenerative disease, T or F?
T
In which cells of the cerebellum is CACNA1A found?
Purkinje and granule cells
CACNA1A is found in the axons of the cells in the cerebellum, T or F?
F – it is more commonly found on the somas
What is the endogenous role of CACNA1A?
What is the endogenous role of CACNA1A? Mediates exocytotic neurotransmitter release
What is seen in CACNA1A knockout model mice?
They develop normally up until 10 days however after that they begin to show problems with balance, ataxia and twisting motions, mimicking the symptoms in human patients. They usually die after 3-4 weeks, relatively earlier than equivalent in humans
The G239R mutation is a common type II episodic ataxia mutation. What does this nomenclature represent?
What does this nomenclature represent? This means that it is a glycine (G) to arginine (R) transition mutation that occurs at position 239 in the protein
When measuring Ca2+ in cells, why are barium ions used instead of Ca2+?
Barium is in the same group as calcium and thus also forms a 2+ ion. Calcium currents are difficult to measure because during Ca2+ influx there is a feedback mechanism whereby Ca2+ influx results in the closure of the channels through which they move through. By using Ba2+ this effect is prevented
What are the results of the G239R mutation on Ca2+ currents and the downstream effects on action potential generation?
There is a decrease in the size of the Ca2+ currents and thus there is less Ca2+ coming into the cell. This means that there is a decrease in the amount of neurotransmitter released into the synaptic cleft and therefore less likely action potential generation in the postsynaptic cells
In contrast to type I episodic ataxia, where there is an increase in neuronal excitability, the mutation that causes type II ataxia leads to a decrease in excitability of cells in the cerebellum, T or F?
T
Explain the double effect of CACNA1A mutations?
As a result of a CACNA1A mutation there is a loss of function of the voltage-gated Ca2+ channels. This causes a decrease in the Ca2+ currents generated in the neurons in the cerebellum and thus less neurotransmitter release and less neuronal excitability. In addition to the smaller Ca2+ currents there is a change in the voltage dependency of the CACNA1A channel so that its highest activity is seen at a more positive membrane potential. This increases the time taken until the voltage-gated Ca2+ channels are activated thus decreasing the overall effectiveness of the channel
Explain the overall summary of effects of CACNA1A mutations in episodic ataxia type II?
Decreased Ca2+ influx, less neurotransmitter release leading to problems with the control of skeletal muscle
Name an effective treatment for type II episodic ataxia?
Acetazolamide
What are seizures?
Episodic neuronal discharge
What are the four main causes of epilepsy?
Tumour, trauma, genetics/inherited, infection
What are the two main types of epilepsy and how can they be further subdivided?
Partial epilepsy – where only one area of the brain is affected. Generalised epilepsy – where the whole brain is affected and symptoms are more severe. These can be subdivided into simple epilepsy where the patient doesn’t lose consciousness and complex epilepsy where they do
Complex generalised epilepsy is the most severe type, T or F?
T
Epilepsy can be acquired, T or F?
T – can be acquired as a result of neuronal damage or in autoimmune disease
What causes seizures at the neuronal level?
Increase excitability of neurons
Epilepsy is usually only caused by mutations in ion channels of excitatory neurons that leads to an increase in excitability, T or F?
T or F? F – mutations in ion channels that cause epilepsy have been found in excitatory and inhibitory neurons
Inhibitory neurons modulate the levels of excitation in the excitatory neurons, T or F?
T
Increased excitability of the neurons can happen via two mechanisms, what are these?
Mutations that lead to a direct increase in excitation of the excitatory neurons or that lead to a decrease inhibition of the excitatory neurons by the inhibitory neurons
Which phase of the action potential is mediated by the voltage-gated Na+ channels?
Depolarisation
Which phase of the action potential is mediated by the voltage-gated K+ channels?
Repolarisation
What aspect of electrical excitation in the nervous system is mediated by the voltage-gated Ca2+ channels?
Release of neurotransmitters from the presynaptic neurons in synaptic transmission
On the membrane of which type of neurons are AchRs found?
Postsynaptic excitatory neurons
What type of receptor is the AchR?
Ligand-gated ion channel
Activation of AchRs causes what in the neuron?
Opening of the channel and Na+ influx
On the membrane of which type of neurons would you find GABAA receptor?
Postsynaptic membrane of inhibitory neurons
What type of receptor is the GABAA receptor?
Ligands gated ion channel
Activation of the GABAA receptor causes what?
Opening of the channel and Cl- influx shifting the membrane potential more negative towards hyperpolarisation
What is the role of the HCN or hyperpolarisation-activated cyclic nucleotide gated channel?
The HCN channels is a voltage-gated channel that becomes activated when the membrane is hyperpolarised. As the membrane potential shifts more negative the open probability of the channel increases and its action is increased, shifting the membrane potential back towards depolarisation. This channel is regulated by cyclic nucleotides such as cAMP and cGMP and is important in determining the timing of action potential firing.
