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
What are the pyramidal neurons
These are UMN from the CNS that can be inhibitory or excitatory and modulate involuntary reflexes.
Brain blood supply (species differences) and its purpose
Cerebral arterial circle ensures constant pressure in the end arteries, allowing for collateral perfusion of the parenchyma in the event of arterial occlusion
Dogs get blood from basilar a and internal carotids similar to people. cats have craniocadal blood flow in the basilar artery (opposite) and most of the brain blood supply comes from EXTERNAL carotid arteries.
What factors determine cerebral blood flow and how do MAP, CO2 and O2 affect them
CF = cerebral perfusion pressure / cerebral vascular resistance
Maintained at constant if MAP is 50-150mmHg in health.
MAP increase causes vasoconstriction and decrease BP –> dilation.
CO2 increase causes vasodilation and decrease constriction (O2 is the opposite)
Mechanisms that pathogen can enter brain and what occurs after entry
Paracellular pathways
Transcellular transport
Intracellularly within leukocytes
Or trauma causing direct penetration
Once a pathogen enters the BBB there is stimulation of the host inflammatory response.
–> activation of host inflammatory response:
- IL1,6,10 activate inflammatory pathways, chemoattractants (TNFa, IL 8 ) allow entry of cells
- MMP breakdown ECM –> leukocyte migration
–> ongoing inflammation causes breakdown of BBB
Difference b/w cardiac myocytes and skeletal muscle
Have sarcoplasmic reticulum and myofibrils but are shorter and coupled by intercalated discs to allow continuity of the cytoplasm b/w adjacent cells –> spread of depolarisation
Higher resting membrane potential –> reach threshold faster than skeletal muscle cells
More reliant on extracellular Ca supplies than Sk musc (no sarcoplasmic reticulum stores)
The influx of Ca during phase 2 (voltage gated Ca channels) electrically balances with the efflux of K+ and prolongs the contraction –> prevents further contraction
Which is why in hypocalcaemia the cardiac myocytes are hyperexcitable and why Ca can help stabilise membrane potentials in hyperkalaemia
Differences b/w smooth and skeletal muscle
Smooth muscle has no T tubules, relies on transmembrane diffusion of Ca from ECF
Do not have uniform structure so contraction result sin ‘wrinkling’ (actin filaments anchored to dense bodies)
Have gap junctions b/w cells and can operate as a functional syncytium with cell to cell transmission of contraction potential
Autonomic innervation - ACh and Norad and receive input from >1 neuron
Can also contract in response to self induced generation of electrical activity, hormone actions or stress
ca binds to calmodulin (not troponin) and activates myosin kinase which generates myosin changes that result in contraction
Different contraction AP types in smooth muscle
Spike potentials - same as sk musc
Plateaus - due to slower closing of Ca channels
Slow wave - self excitatory, rhythmic. Changes membrane potential to make contraction more or less likely (does not result in contraction on its own)
Normal Pain pathway components
TRANSDUCTION
Initial stimulus (mechanical, thermal or chemical)
–> activates peripheral sensory neurons
(d fibre for fast mechanical or thermal; C fibre slower for chemical)
TRANSMISSION
Signal ascends sensory neuron to the dorsal root ganglion where the nerve cell body is then enters the dorsal horn and synapses with interneuron (Sub P)
–> Interneuron (2nd order neuron) crosses to other side of spinal cord and ascends to the, via the spinothalamic tract brain somatosensory cortex (contralateral side to injury)
PERCEPTION
–> 2nd order neuron synapses on 3rd order neuron in thalamus which relays signal to somatosensory cortex
(contralateral
DESCENDING PATHWAY
- can be inhibiting or facilitating
- Inhibitory substances (GABA, 5HT, NorAd, CBD, Dopa)
MODULATION
- Descending inhibitory pathway from brain is constitutively active and releases 5HT and NorAd that inhibit the release of sub P from 1st order neuron
- Descending neuron also stimulates other interneurons in the dorsal horn –> release of endogenous opioids (enkephalin)
–>inhibits presynaptic neuron sub P release, and inhibits 2nd order neuron activation (stops signal to brain
- Also descending facilitatory signals that release Sub P, glutamate –> increasing sensitivity to stimuli
Chemical stimuli that trigger pain response
PGs
LT
5HT
Histamine
K+
NGF
