Nervous system questions Flashcards
What part of the nervous system does the somatic system refer to?
The point where voluntary motor outputs begin to be stimulated from - can also mediate some involuntary responses
What does the Blood Brain Barrier do?
Restricts transport of products to the CNS, acting as a gatekeeper.
This prevents 98% of drugs reaching the brain
Molecules generally have to be lipid soluble and less than 400 Da to cross the BBB.
Which part of the brain links the endocrine and nervous system?
The hypothalamus
Describe the structure of the neuron
Functions of the neuron?
- Obtain input via neurotransmitters acting on receptors in dendritic spines
- Depolarisation
- Action potential generation and propagation
- Neurotransmitter release to signal to Neurons, glands and muscles.
How does the neuron have a membrane potential?
There is higher sodium concentrations outside than inside and higher Potassium concentrations inside than outside.
There is a net Negative membrane potential (inside negative to outside).
Due to the balance of Sodium and Potassium, there is a ELECTRICAL and CHEMICAL force Inwards for sodium. But for potassium, there is a chemical force outwards but an inwards Electrical force.
This causes the membrane potential to be formed.
Na+/K+ ATPase pumps are responsible for maintaining these gradients.
The nodes of Ranvier have a higher….
Sodium concentration
Why does the refractory period occur?
By this stage the sodium channels are closed and the Potassium channels are lagging to close.
Afferent neurons go from…
Sensory receptors to the CNS
Efferent neurons go from…
The CNS to the Autonomic system reaching the glands and smooth muscle, or the somatic system, reaching the skeletal muscle.
function of myentric and submucosal plexus
Myenteric - motor functions
Submucosal - Sensory functions.
How many cell types does the brain have?
Neurones, astrocytes, microglia, and oligodendrocytes
How do spinal cords receive input?
Peripheral afferent inputs occur via the dorsal horn
Efferent input via the ventral horn.
What receptors does glutamate act upon?
NMDA, AMPA, Kainate and Metabotropic.
GABA acts on which receptors?
GABA-a and GABA-b
Describe the process of neurotransmission
What is required for neurotransmitter release?
Calcium ions.
How does cholinergic neurotransmission occur?
Acetyl-Coenzyme A and choline are converted into Acetylcholine via Choline acetyl transferase enzyme.
Once the membrane is depolarised, calcium channels are activated and calcium enters the cell, the calcium enters the synapse and prompts the release of the neurotransmitters.
Acetylcholinesterase converts acetylcholine back to choline and acetate, allowing the choline carrier to let the choline back in
What methods are available to uptake Noradrenaline
Presynatic uptake, whereby NA gets recycled
Postsynaptic uptake, which mops up any remaining NA
What is co-transmission?
Transmission through a single synapse by more than one transmitter
Examples include ATP, Neuropeptide Y, Dynorphin, NO
How does presynaptic modulation of synaptic transmission occur?
Synaptic Transmission primarily inhibits neurotransmitter release but can enhance it.
Autoreceptors - these act on its own presynaptic terminal to reduce release. E.g. mGlu2 modulation of glutamate release.
Heteroreceptor - neurotransmitter acting to modulate release other than its own ligand. GABA acting on GABA-B to reduce glutamate release.
Antagonists and agonists can have the same physiological effect
Yes it can - this depends on receptor location. E.g. Hysocine and Morphine in the GI tract would both reduce the muscle contractions and reduce the rate of peristalsis.
How do GABA-a receptors act?
They act via influx of chloride ions and have a hyperpolarising effect on the membrane potential
How do G-proteins get activated
Why are GPCR’s so important
Involved in numerous physiological processes
Target for >50% of all prescribed medicines
Why do we need reflexes?
Maintain Body homeostasis
Detect and react to changes in environment e.g. temp, toxins
Protect the body from noxious stimuli.
Examples of Simple Reflex
Knee-jerk reflex (Monosynaptic)
Pain withdrawal reflex (polysynaptic)
Learned Reflexes
No specific norm, can be learned and improved - Somatic involvement
Can exercise improve reflexes?
Although evidence is limited, there are some specific training methods which can improve reflexes.
These can be particularly useful following stroke, spinal cord injury etc.
Why are sensory systems required?
Maintain homeostasis.
Detect and react to changes in environment
Protect the body from noxious stimuli.
Examples of nociceptors
Mechanoceptors - Activated by Intense pressure on skin - A-delta fibres
Thermoceptors - Activated by extreme temperature (A-delta fibres)
Polymodal - Activated by high intensity mechanical, chemical, and thermal stimuli - C fibres
Pain transmits via A-delta and C..
These fibres have slightly unique methods of inducing pain.
A-delta causes pain in the first instance and mediates a sharp pain - these types of fibres are myelinated
C fibres - relatively slow fibres which end up mediating longer lasting second pain - these fibres are unmyelinated.
Where is the synapse for nociceptors?
Synapse is located in the dorsal horn of the spinal cord.
Glutamate is the excitatory neurotransmitter, modulated by many others.
How are nociceptive pathways projected to the brain?
Via spinothalamic tracts - descending inhibition and perception.
Where can pain signals be interrupted in the spinal cord?
The substantia gelitanosa.
How do local anaesthetics block sodium channels?
Unionised local anaesthetic enters the cell - the LA becomes ionised once inside the cell, and blocks the sodium channels, resulting in a reduction of pain signalling.
What is Aspirin’s mechanism of action?
Aspirin was the first NSAID and is the only one which irreversibly binds and inhibits COX-1
How do NSAID’s function?
Most NSAID’s act as a non-selective, reversible inhibitors of the cyclooxygenase enzymes
COX enzymes also known as Prostaglandin endoperoxide synthase (PTGS) enzymes
NSAID’s reduce the level of chemicals called prostaglandins which are involved in inflammation by blocking (inhibiting) their synthesis from arachidonic acid by COX enzymes.
What is the mechanism of action of paracetamol?
Not entirely clear but there is evidence for the analgesic effect arising by activation of descending serotonergic pathways.
Examples of COX-2 inhibitors
Celecoxib, parecoxib, etoricoxib
What is the aim of metabolism?
Break down drug into metabolites which can be excreted more easily, by increasing water solubility.
Phases of metabolism?
Phase 1 is activation by oxidation, reduction and hydrolysis, introduce or expose a functional handle for phase 2.
Phase 2 - conjugation to make more polar molecules.
How does the metabolism of paracetamol work?
How does codeine metabolism work?
What is the cytochrome p450 system?
It is found in the mitochondria or endoplasmic reticulum of cells
Most important phase 1 enzyme metabolic pathway
Family of isoenzymes
What is important about Cytochrome P450
It can be inhibited by different drugs (rapid onset), induced by different drugs (slow onset), the presence differs across population and age group, and there are many different forms.
Why can’t you take Nifedipine and Grapefruit juice together?
Grapefruit juice is believed to inhibit CYP450-3A4 which is supposed to metabolise the drug.
Why can paracetamol and codeine be used together?
Paracetamol phase 1 relies on CYP450-2E1
Codeine phase 1 relies on CYP450-3A4 and 2D6
There is a mix of phase-2 metabolism
How many lines of defence does the BBB have?
- Anatomic barrier of endothelial cells of the brain capillaries with tight junctions, the basement membrane and surrounding astrocytes.
- An enzymatic barrier of degrading enzymes localised in endothelial cells
- Transport systems actively transporting substances from the brain back to the blood
Purpose of the BBB?
-To provide essential nutrient supply to the brain
-To ensure a constant internal milieu within the CNS
-Functions as a gate-keeper to the CNS, strictly limiting transport to the brain.
What are the transport mechanisms at the BBB?
What pharmacological strategies are available to increase the passage of drugs via the BBB?
- Chemical modification - to increase lipophilicity - doesn’t work
- Use of trojan horse, whereby drug is conjugated to another molecule able to cross the BBB.
Conjugation can occur to a receptor-specific antibody which binds to the BBB receptor (OX26 antibody to the rat transferrin receptor).
How can the BBB be disrupted?
Due to limitation of paraceullular transport of large drugs across the BBB due to tight junctions, it is proposed that we can open the BBB by administering pharmacological agents or osmotic opening.
Which pharmacological agents could be used to disrupt the BBB?
Vasoactive agents such as peptidase inhibitors, angiotensin II and bradykinins.
How can the BBB be opened via osmotic opening?
An intracarotid injection of hypertonic solutions of mannitol or urea can be used.
- This will shrink the size of endothelial cells, and open the tight junction network.
Limitations to disrupting BBB?
Should be reversible and short lasting
Risk of neurological damage
Serious side effects of vasoactive agents
Additional mass effect in the brain (1.5% increase of brain fluid).
Aphasia and hemi-paresis (is reversible within 48h when treated with dexamethasone).
How does nasal delivery work?
Connection of the brain and the nasal cavity by the olfactory nerve system
BUT
lack of efficacy - <0.1% of drug in nasal cavity reach the brain.
What are the physiological causes of vomiting?
- Ingestion of toxic substances
- vestibular system - motion sickness
- Cranial nerve - irritation of pharynx
- Vagal and ENS - irritation of the gastro-intestinal tract
What is the vomiting centre?
Located in the medulla
Receives input from area postrema/ chemoreceptor trigger zone
Can also receive input from other brain regions involved depending on stimulus such as pain, light, smell, or movement, or memory/fear
The regions of the brain not protected by the BBB are known as..
the circumventricular organs -
- pineal gland
-subfomical organ - OVLT
-Posterior pituitary
-Median eminence
-area postrema
clinical uses of antiemetics?
-Morning sickness
- Radiation therapy
- motion sickness
- cytotoxic chemotherapy drugs
Where are the target locations/receptors for Anti-emetics?
-GABA
-Chemoreceptor trigger zone
-cerebral cortex
-vestibular nucleus
Which otc antiemetics are currently available?
Cinnarizine - H1 antagonist
Promethazine - H1 antagonist and weak muscarinic acetylcholine antagonist
Hyperemesis Gravidum?
This is where a female patient experiences excessive nausea and vomiting during pregnancy
-no clear reason but believed to have heriditary cause
- treated with antiemetics, vitamins, steroids, IV fluids
All amino acids have s-stereochemistry except…
cysteine
Which amino acid does not have chiral centre?
Glycine
Antihistamines (H1’s) need to have….
stronger binding effects than histamine itself in order to elicit effect to help with nausea and vomiting
When cinnarizine binds at the H1 receptor….
It binds in a slightly different position due to lipophilic interactions, and whilst histamine may also still bind, it stops the conformational change needed to activate the receptor
Phenothiazine
is even more rigid than cinnarizine and prevents the conformational change of the G-protein change required for activation even more
Referring to ANS function - how do ganglia neurotransmitters act?
Acetylcholine acts via both sympathetic and parasympathetic via the ganglia, acting on nicotinic acetylcholine receptors
Where is ganglia located?
For sympathetic - close to spinal cord
For parasympathetic - close to or within target organs.
What type of receptors are muscarinic acetylcholine?
GPCR’s
What type of receptors are nicotinic acetylcholine ones?
Ligand-gated ion channels.
Glutamate acts on…
Both ionotropic and metabotropic receptors.
Gamma-aminobutyric acid acts on…
Ionotropic (GABA-a) and metabotropic (GABA-b) receptors.
How is Glutamate formed?
Glutamine converted to Glutamate via glutaminase
How is noradrenaline released in neurotransmission?
Tyrosine is converted to L-Dopa via tyrosine hydroxylase (this part is rate limiting) - L-Dopa is then converted to dopamine via Dopa decarboxylase, and then dopamine is converted to Noradrenaline via Dopamine B-hydroxylase.
When an action potential is generated and depolarization occurs, there is an influx of calcium ion channels, and this stimulates the release of vesicles of Noradrenaline.
Noradrenaline then either binds to its receptor (beta or alpha adrenergic receptors) and excess Noradrenaline is either uptaken by the pre-synaptic terminal and recycled for usage, or is uptaken by postsynaptic cells.
How does cholinergic neurotransmission occur?
Choline and Acetyl-coenzyme A converts to acetylcholine due to acetyl transferase.
Once the terminal is depolarised, calcium passes into the synapse and this leads to exocytosis of acetylcholine.
Action of Acetylcholine is ceased via degredation - acetylcholinesterase breaks down choline and acetate - the choline is transported back into the cell via choline carrier.
What is physiological antagonism?
When 2 drugs counteract each other by producing opposing effects on different receptors?
What is chemical antagonism?
When one drug antagonises the action of another via chemically reacting to it.
What is pharmacological antagonism?
When drugs counteract each other by acting on the same receptor.
Where can pain signals be interrupted?
The substantia gelitanosa
All opioid receptors (mu, delta, kappa) are?
GPCR’s - they all work with Gi/o coupled proteins. These are responsible for causing the Calcium channel function to be inhibited, to increase neuronal hyperpolarisation via Potassium channel activation, and modulate release machinery.
Which sodium channels are believed to play a role in inflammatory/ muscular pain?
Sodium channels 1.8 and 1.9
Which sodium channels are believed to play a role in neuropathic pain?
Sodium channel 1.3
Pain is a comorbidity to which kinds of diseases?
IBS, cancer, and arthritis
What enzyme conducts paracetamol phase 1 metabolism?
CYP4502E1
What enzymes conduct codeine phase 1 metabolism?
CYP450 3A4 AND 2D6
Can paracetamol and codeine be used together?
Yes, as there is no interaction between the metabolism of both. Phase 2 is rather mixed for both so should not cause any issues.
An example of genetic variations
Some people have limited function of the 2D6 CYP enzyme, which means they are unable to convert codeine to morphine
Some people have increased function of such enzymes, meaning that the drug gets metabolised much faster, to the point they do not attain any therapeutic affect.
How does age affect metabolism?
As we get older, we are less efficient at metabolising drugs, and also less efficient at eliminating drugs
This may cause build up of drug and thus toxic side effects.
Made more complex as most likely concomittant medication will be the case on older people.
Types of patches for drug administration
Matrix patch - Backing layer, drug/adhesive layer, Release liner
Reservior patch - Backing layer, drug reservior, rate controlling membrane, adhesive layer, release liner
Stages of change model
Pre-contemplation, contemplation, preparation/decision, action, maintenance
