Physiology Flashcards
Components of BBB
Endothelium with tight junctions and no fenestrations
Pericytes
Astrocyte processes that surround endothelium and have K+ and aquaporin pores for solute transfer
Requirements for drugs that can cross BBB
Low degree of ionisation at physiological pH
Low degree of plasma protein binding
High degree of lipid solubility in unionised state.
Inflam increases BBB permeability
Drugs enter the CSF predominantly via passive diffusion down a concentration gradient, the main determinant is high lipid solubility.
Drugs usually have a longer half life in the CSF than serum which may be beneficial as the BBB is repaired.
What is neuron electrochemical gradient/how is it generated
Na/K ATPase uses ATP to export 3Na and import 2K → [Na] greater outside the cell, [K] greater inside the cell and establishment of an electrical gradient (more negative inside the cell).
Impulse generation in neuron
- Neuron depolarized to the threshold of -55mV through summation of EPSP at axon hillock → opening of voltage gated Na channels
(inhibited by anti-seizure medications) - Na diffuses INTO cell towards concentration and electrochemical equilibration
- Inactivation gate closes the channel just before this equilibrium potential is reached (35mV), preventing further Na influx for a brief period
(inhibited by excitatory toxins like pyrethrins) - Na/K ATPase starts response to depolarisation → rapid influx of K until its equilibrium threshold is reached at -90mV.
(inhibited in low energy states like hypoxia and hypoglycaemia –> hyperexcitability) - After-hyperpolarization of the membrane occurs until it reaches RMP of -65mV by passive diffusion of K out of cells
What affects transmission speed of AP
axon internal diameter and myelination
Diameter - ↑ results in ↓ in resistance to flow of ions, However this also ↑ the difference in charge between the inside and outside of cell (capacitance) → resistance to flow
Myelination - ↓ ability of membrane in that area to store a charge (↓ capacitance) without affecting resistance. Prevents exchange of ions so AP jumps between nodes of Ranvier
(demyelination thus results in increased capacitance and slowing of conduction velocity)
What occurs when AP reaches nerve terminal
Depolarisation of nerve terminal → activation of voltage-gated Ca channels → influx of Ca → activation of synaptic proteins (syntaxin, SNAP-25, synaptotagmin) that dock vesicles to presynaptic membrane for it to fuse → release contents into the synapse
4 classes of NT and whether they are excitatory or inhibitory
Class 1; Ach; mostly excitatory, except vagus
Synthesised from acetyl coA, plus choline, with choline acetyltransferase.
Preganglionic in all Autonomic (PSNS & SNS) nerves
Postganglionic neurons bear nicotinic Ach receptors.
Postganglionic in PSNS (muscarinic)
Class 2; Amines
NorAdr – Brainstem, hypothalamus – excitatory (Postganglionic SNS – may be inhibitory or excitation)
DOPA – Inhibitory
Serotonin – Inhibitory
Class 3; Amino Acids
Glycine – Inhibitory, mostly SC
GABA (gamma aminobutyric acid) – Inhibitory (SC, Cerebellum)
Glutamate – Excitatory
Class 4 (atypical); NO
Produces more long term metabolic changes (memory)
Atypical neurotransmitters are actually produced by the post-synaptic neuron following normal synaptic transmission they diffuse back across the synapse to affect the function of the presynaptic neuron (endocannabinoids and nitric oxide)
Main ionotropic receptors
Nicotinic -> Na channel opening
(blocked by MG autoantibodies)
GABA –> opens Cl channels
(antiseizure meds block)
AMPA and NMDA Glutamate receptors –> permeable to MG and Ca respectively
(overactivation results in excitotoxicity)
How is muscle contraction caused
ACh is released from motor neurons and binds nic ACh R on the muscle cell, these are ligand-gated Na channels which depolarise the muscle fibre.
This depolarisation is sufficient to activate voltage-gated Na channels
–> transmitted to the interior of the muscle fibre along the T tubules.
–> Opens sarcomeric voltage gated Ca channels
–> Ca release opens Ca-activated Ca channels
Ca binds troponin so it dissociates from myosin and allows excitation contraction coupling of myosin and actin
–> Ca actively pumped back into sarcomere at end of AP
Neostigmine and Pyridostigmine MOA and AEs
Both are Acetylcholinesterase inhibitors
–> longer duration of Ach in NMJ
–> increased stimulus for muscle AP generation
Used in MG where the number of nic ACh receptors are reduced
AEs: cholinergic effects and can be systemic, often dose depending
Pyridostigmine is less potent and slower in onset so is less likely to cause a cholinergic crisis
Nausea, diarrhoea, salivation, lacrimation, Bradycardia, Miosis,m bronchospasm and respiratory arrest, cramps and weakness
Where/How is CSF formed and how does it differ from plasma.
Ependymal cells in the chorid plexus (an invagination of the ependyma into the ventricular cavities.
Capillaries here are fenestrated unlike the rest of the BBB so solutes and water can move in/out.
The CSF has similar Na levels to plasma but more Mg and Cl and less K and HCO3. Osmolality is the same as plasma
This is mediated by apical Na/K ATPase on the apical surface of ependymal cells removing K from CSF. Because 3Na+ enter and 2K+ leave the CSF this generates a gradient to draw water and Cl into the CSF.
Intracellular carbonic anhydrase using CO2 produced by cells in the brain to generate H+ that is then actively exported into the blood in exchange for Na into the ependymal cell
Normal CSF circulation and drainage
In normal conditions produced at a rate similar to drainage.
Choroid plexus at the intraventricular foramen produces CSF and flows into lateral ventricles then into third ventricle (under pituitary) through cerebral aqueduct into fourth ventricle (under cerebellum) where it can either flow on through the ventral canal of the spinal cord or enter the median/lateral apertures and enter the subarachnoid space where it is absorbed by arachnoid microvilli in the dural venous sinuses
CSF functions
Removes waste from brain, brings in some vitamins/micronutrients (not brought in by BBB capillaries)
Acid base balance
Regulation of intracranial pressure
Maintains a chemical environment for neuronal signalling
Physical absorption of shock preventing brain injury
Indications of hyperexcitability on EMG and what it may mean
EMG measures the ECF electrical activity (as a surrogate for muscle) at insertion, contraction and in response to nerve stimulation
Normal muscle has short insertional activity due to mechanical damage to the myofibril) and low amplitude miniature end plate potentials representing tonic low grade nerve stimulation that do not depolarise the entire myofibre
In disease the muscle becomes hyperexcitable resulting in:
Increased insertional activity
Fibrillation potentials and positive sharp waves (spontaneous firing of hypersensitive myofibres); Complex repetitive discharges (repetitive uniform waves).
These are a result of abnormalities of the muscle caused by denervation which alters metabolism and makes the myofibre more sensitive to ACh. these changes take about 4-5d to ocurr after denervation (due to hypoTH, nerve tumours, polyrad, protozoal neuropathy)
Another differential though is myositis can also cause increased activity or muscular dystrophy can cause complex repetitive discharges
This differentiates denervation from atrophy of disuse where there may be fibrosis and reduced excitability.
Motor nerve conduction studies and causes of reduced amplitude, conduction velocity and prox vs distal CMAP.
Measures compound muscle action potentials CMAP after stimulation of motor nerve.
Reduced CMAP amplitude indicates loss of innervation (axonopathy) sucha s with polyradiculoneuritis, Myaesthenia gravis or severe myopathy.
Can also see with Botox or tick paralysis induced reduction in NM transmission
Reduced conduction velocity without loss of amplitude is seen with demyelination due to diabetic neuropathy, hypoTH
Prox vs distal CMAP difference = conduction block
Occurs when there is segmental demyelination
Also commonly seen in diabetic neuropathy or demyelinating polyneuropathy
disorders of muscle wont affect these
