bms 235 Flashcards
1
Q
If Patmos > Palveolar then air will (enter/leave) the lungs?
A
Enter. Air will travel down the concentration gradient during Inspiration.
2
Q
The chest wants to (collapse/expand), but the lungs want to (collapse/expand). Therefore the …… space is ……. in pressure at rest.
A
Chest wants to expand, but the elastic nature of the alveolar makes them want to collapse. Therefore the intrapleural space is sub-atmospheric in pressure at rest.
3
Q
What is compliance?
A
Lungs ability to stretch.
4
Q
What does high compliance mean?
A
High compliance: Less work is needed to inspire, but have more difficulty expiring. This may be due to the elastic tissue, so recoils less.
e.g. emphysema- larger vol of lungs, so lower alveolar pressure, so air rushes in.
(Think high off nicotine)
5
Q
What does low compliance mean?
A
Low compliance: More work needed to inspire
e.g. Pulmonary fibrosis- lungs more rigid less elastic so can’t expand so much, so lower pressure gradient. Lower residual capacity.
(Think feeling low as have fibrosis)
6
Q
Compliance equation?
A
compliance= Change in Volume/ change in pressure.
7
Q
What is Alveolar pressure?
Number at rest, inspiration and expiration?
A
Pressure of air in alveoli.
No airflow: Palv=Patmos, therefore 0.
Inspiration: PalvPatmos, therefore 15.
8
Q
What is Airway Pressure?
Number at rest, inspiration and expiration? Constant throughout?
A
Pressure of air in the airways (conducting)
No airflow: same as Palv and Patmos, therefore 0.
Inspiration: Think of gradient from atmospheric to alveolar, where Patmos=0 and Palveolar=-15, starts from around -4 to -12 as go down trachea.
Expiration: Opposite gradient, so 4-12.
9
Q
What is transpulmonary pressure?
A
The pressure difference between alveolar and intrapleural space. Always 5.
10
Q
What is Intrapleural pressure definition?
A
The difference between the Visceral pleura (inside) and the thoracic Pleura (outside).
Where the pressure across the visceral pleura is constant (Transpulmonary pressure=5) can work out the intrapleural from the alveolar pressure.
11
Q
What is transmural pressure?
Number at rest, inspiration, expiration?
A
The pressure between two sides of a wall, In respiration usually refers to pressure across the visceral pleura so between the intrapleural space and airways. (Transpulmonary is an example of this always 5)
further up the airways these change as go down trachea.
12
Q
Explain inspiration?
A
Stimulated by the phrenic nerve, the diaphragm contracts. The external intercostals move the ribs out (bucket handle) and the sternum lifts up. (Pump)
Volume of thorax increases, therefore alveolar pressure decreases.
Air rushes in down pressure gradient.
13
Q
What region on the brain controls the respiratory rhythm?
A
Medulla Oblongata of the brainstem.
(The dorsal respiratory Group and the Ventral Respiratory Group)
14
Q
What is the function of the Dorsal Respiratory Group?
A
Think: “Walk in through the door quietly”
Quiet Inspiration. (expiration is elastic recoil so passive)
15
Q
What does the DRG innervate?
A
Phrenic Nerve: Contract Diaphragm
Spinal Nerves: External Intercostals.
Think: “In through the door quietly after Exiting the IC”
16
Q
What is the function of the Ventral Respiratory Group?
A
Think: “Venting forcefully”
Controls forced inspiration and expiration
17
Q
What does the VRG Innervate?
A
Inspiration: Same as DRG but also Cranial nerves.
Expiration: Spinal nerves: Internal intercostal and abdominal muscles.
Think: “Venting forcefully letting internal feeling out”
18
Q
What complex causes the basic rhythm of breathing?
A
Pre- Botzinger Complex in the VRG
19
Q
What is special about the Pre-Botzinger Complex cells?
A
It contains pacemaker cells.
20
Q
What are the three busting patterns of the Pre-Botzinger complex
A
Eupneic (normal)
Sigh (Higher output, longer intake)
Gasp (short intake)
21
Q
What are the two types of neuron in the Pre-botzinger complex?
A
Pacemaker cells, and non pacemaker cells.
22
Q
What are the two patterns the pacemaker cells can make?
A
Individual neurons depolarisations summate to create the inspiration and expiration pattern in the Pre-Botzinger Complex.
Spiking: More steady consistant spikes.
Bursting: AP’s very close together getting stronger in frequency
just different activity states of the same neurons.
23
Q
What’s the significance of the NALCN channel in the Pre-Botzinger Complex?
A
It is a sodium leak channel into the neuron. It contributes to the depolarisation. Important for initial slow depolarisation.
24
Q
Whats the significance of potassium and the Pre-Botzinger Complex?
A
If high levels of potassium, the resting potential is increased, say -90 to -80mv. Therefore the intensity of bursting is increased, as more depolarised.
25
Bursting activity depends on which two types of currents?
The persistant sodium channel (I NAP)
The CAN Cation current (I CAN) (calcium dependent cation channel)
(ADD)
26
Neurons relying on I NAP for bursting can be classified as ....... Whereas those relying on I CAN are.....
```
Cadmium insensitive
Cadmium sensitive (Cadmium can block these)
```
27
Is the DPG and VRG always active?
DRG: It inactivates after inspiration, then the neurones have a period of activity again etc.
VRG: Inacitve during quiet respiration.
28
What two ions are high inside a general cell, and which two are kept low?
High: K+, PO4^2- (phosphate in ATP etc)
Low: Na+, Cl- (used for signalling in cell)
29
Rate of ions per s moved, by carriers, channels, and pumps?
Pumps: <100 ions per second (active and conformational change so slow)
Carriers: 100-1000 (conformational change also)
Channels: 10^6-10^8
30
How are pumps, carriers, and channels controlled?
Channels: can be gated, either voltage, mechanically, ligand
Pump: Active so controlled by ATP- hydrolyses
Carriers: Controlled by other ions also e.g. NKCC2, needs Na, K and 2 Cl.
31
Three types of Carriers?
Antiport/exchanger, symporter/cotransporter, uniport.
32
Electrochemical driving force depends on which two things?
Electrical membrane potential + Concentration Gradient
33
What is the Patch Clamp Technique?
Measures the membrane voltage across.
34
What is the difference between cell attached conformation and whole cell?
Cell attached: Measures a single ion channel.
| Whole cell: measures current through the whole cell.
35
How does the Patch technique work?
The cell membrane voltage is set to a certain voltage different to what it is. The current required to get it to this voltage is measured by a glass pipette attached to an electrode.
36
What is the equation for the Patch clamp technique?
I (current)= N (no. of channels) X PO (open probability 1-0) X G (channel ions/s) X (Vm X Ei) (Membrane potential - Equilibrium potential (Nerst))
37
Structure of Na/K ATPase?
Tetramer 2Beta, 2Alpha
38
What is the Nernst equation? (definition)
Works out the equilibrium potential for a particular ion
39
What is the Nernst equation?
61/z x log [(ion)outside / (ion)inside]
z= charge of ion
40
What is the equilibrium potential? (definition)
Its the potential reached, where there is no net movements of ions. So the number of ions moving due to the concentration gradient = the number of ions moving due to the electrochemical gradient.
41
Sodium/Potassium ATPase is responsible for ....% of the negative charge of most cells
20% (also sets grad for other channels, e.g. high K inside so goes out through channels- loss of positive ions)
42
What is the Goldman Equation? (definition)
Works out the equilibrium potential for all ion channels using their relative permeability.
43
What is the Goldman Equation? say for Na and K
Vm=61/z x log [ Pna(Na)o + Pk(K)o] / [Pna(Na)i + Pk(K)i ]
44
PH is on a ....... scale. So the change from PH 6 to PH7 is a ...... difference.
logarithmic scale.
| Tenfold.
45
What are the three methods of control of PH in a cell?
Buffering, Acid extrusion, Acid loading
46
What is buffering?
It minimises the PH change, but does not reverse the direction. Buffering proteins (COOH and NH2 donate and receive protons.
47
What is buffering power?
the amount of strong base or acid that must be added to raise the PH a given amount
48
If PH increases how does buffering reduce?
PH increases, therefore gets more alkali. COOH (double bond of hydroxyl group to Carbon) releases a H+ ion.
49
If PH decreases how does buffering increase?
Ph decreases. More acidic. NH2 can accept a H+ ion, to reduce.
50
What is the link between H+ ions and PH?
H+ ions make something more acidic.
PH=-log(H+)
They interact with water as they are free to bond and make it more acidic.
Or to CO2 to make bicarbonate.
51
What is the Acid extrusion method?
"cooling system"
To do with Na/H exchanger, which normally moves Na into the cell (set conc by Na/K ATPase) and H+ out.
The NHE has a set point PH which acts as an on/ off switch.
52
In acid extrusion if PH rises?
If gets more alkali, more H+ ions in the cell would reverse this change. Therefore when it surpasses the PH set point, the NHE inactivates.
Therefore, H+ are not moved out of the cell, so reduces the PH.
53
What is an allosteric modification?
Allosteric modification is a binding site on the protein for the ligand separate to the active site.
54
How does an allosteric modification help in the acid extrusion method?
This helps the acid extrusion method as the NHE has one, in which protons can bind to. These induce a conformational change which increases the activity of the exchanger. This happens when there are lots of protons therefore when very acidic, to counteract this
55
NHE1 is inhibited by ....... This is very sensitive to, so even comparatively concentrations (compared to ENaC or NHE3) affects.
Amiloride. (and EIPA homologue)
56
What can bind to NHE1 to upregulate it? This causes an .... shift?
Calcium carmodulin.
| Alkaline (as upregulates- therefore moves more H+ ions out of cell, increasing the PH)
57
What is Acid Loading?
"Heating system"
| Uses the Cl/HCO3 exchanger.(AE1- Anion exchanger 1) Cl- into the cell for HCO3 out.
58
How does Acid Loading affect PH?
Cl/HCO3 exchanger removes HCO3 from the cell, so it cannot combine with H+ ions to produce carbonic acid. Therefore, H+ ions are left behind making it more acidic.
Low activity in acidic, but high in alkaline conditions.
59
What is AE1 Cl/HCO3 exchanger inhibited by?
Stilbene derivatives drug DIDS
60
How do microelectrodes work?
Measure voltage across membrane by using two electrodes. They use an ion sensitive resin. PD is proportional to PH change. The PD is then compared to a calibration curve to get PH.
Voltage= Slope x PH (+offset (intercept c))
61
Microelectrodes are good for .... cells and .... but not .... cells.
big cells and tissues (e.g. muscles, xenopus oocytes, nerves,
but not small epithelial
62
If volume above FRC in lungs, system .....
If volume below FRC in lungs, system wants to ...
Above FRC: after inspiration- elastic forces in lung favour collapse, and chest expansion small. System wants to collapse.
Below FRc: after forced expiration
Forces favouring lung collapse smaller, chest wants to expand. System expands
63
At low volume the compliance is high/low. Whereas at low volume the compliance is high/low
At low volume: compliance is high- easy to inflate
Whereas at higher volumes the lungs become harder to inflate so low compliance
Sigmoid curve
64
What two components make up the elastic recoil of the lung?
Anatomical component: elastic nature of cells and the extra cellular matrix
Surface tension: at the air fluid interface due to surfactant
65
Concentrations of extracellular and intracellular Na?
Extracellular: 145mM
Intracellular: 15mM
66
Why is Na kept low inside the cell? examples?
Driving force
e. g. Thick ascending limb of loop of henle- NKCC2 needs low (Na)I, which transports NaCl back into blood so that this doesn't compete with water reabsorption
e. g. excitable cell- action potential when Na rushes in
67
Na/K pump is inhibited by what?
Cardiac Glycosides e.g. digoxin, Oubain
68
What does electrogenic mean?
Able to produce a charge in the electric potential of a cell
69
Concentrations of calcium inside and out?
(Ca2+)o =1mM (1 000 000nm)
(ca2+)i =100nm
x 10,000
70
Why is calcium kept low in cells? Examples (3)
e. g. Used as a secondary messenger, therefore has to be kept low (e.g Gs)
e. g muscles sarcomere, and muscle contraction.
e. g. at synapse
71
Two ways calcium is kept low in the cell?
Ca ATPase
| Na/Ca exchanger
72
What does the Na/Cl exchanger do?
transports 3Na in for 1 Cl out
73
If a lung is reduced down to residual capacity (collapsed) how can one re-inflate it?
Artificial ventilator: increase pressure of air, so air rushes in down concentration gradient. Or by positive pressure, blow up lung e.g. mouth to mouth
Iron Lung: where the atmospheric pressure is raised above alveolar, thus still creating a concentration gradient
74
In terms of breathing what is negative and positive pressure?
Negative: Normal way of breathing whereby the alveolar pressure is lower than the atmospheric so air is sucked into lungs.
Positive: Artificial, where air is pushed into the lungs.
75
If the air in the lungs is smooth and steady what is this called?
Lamina Flow
76
At lamina flow the movement of air into and out lungs is propertional to .......... and inversely to .......
The pressure gradient (Palv-Patmos)
| Resistance
77
If flow rate increases beyond a critical value currents are made and low becomes ....?
Turbulant
78
How does turbulant flow velocity equation differ from lamina?
Now the flow rate is proportional to the square root of the pressure gradient.
79
One disadvantage and one advantage of turbulant flow over lamina?
(+) Mixes the air well
(-) A higher pressure gradient is needed for the same flow rate to be achieved therefore more effort is needed to be put in. (as square rooted)
80
Many bifurcations can cause a third flow type. What is this?
Transitional Flow
| Swirlings and eddies are created.
81
What can be used to determine the flow type?
Reynolds number
82
Reynolds number calculation?
Re= 2radius x Velocity x Density of gas/ Viscosity
83
If Reynolds no. less than 1000 which flow?
1000-1500?
Over 1500?
Lamina
Lamina/Turbulant mix
Turbulant
84
What happens to the flow rate as goes through the airways?
It decreases as cross sectional area increases into very low in the respiratory zone
(Think: going town a water slide on a rubber ring- go very fast in tube but as opens up at the bottom, slow down massively (same gradient (here height) but pressure is higher when constricted by cross sectional area) and more currents= turbulant flow)
85
Poiseuille’s law suggests that airway resistance is proportional to ...... and .......
but inversely proportional to the........
Gas viscosity
Length of the tube
inversely proportional to the 4th power of the radius
86
Airway resistance in the lung percentages for:
Pharynx and Larynx:
Airways greater than 2mm diameter
Airways less than 2mm diameter
Pharynx and Larynx: 40%
over 2mm: 40%
under 2mm: 20% (although smaller with higher resistance, they are added in parallel not series so 1/R1 + 1/R2 etc
87
How do the resitance lung percentages differ for COPD people?
L&P: 12%
AIrways greater 2mm: 18%
Airways less than 2mm: 18%
Huge increase in airway resistance of small vessels due to inflammation, whereas the same actual values for Larynx and Pharynx and greater than 2mm airways, percentages decreased due to massive increase in less than 2mm.
88
Factors that affect airway resitance? (2)
Increased mucus secretion- diameter down, resitance up
| Oedema- increased fluid retention, swelling, resistance up, velocity down.
89
What happens to resistance as inspire?
Decreases as dilates.
90
.......... attatches the alveoli to the walls by tethering. In people with ....... this is broken down causing the collapse. This then ..... resistance.
Elastin
Emphysema
Increases
91
As the breaths per minute increases, only at about 50 does the volume of air decrease in normal people, but those with COPD it falls from around 10. Why?
In those with COPD their FEV1 is much lower, so after a normal inspiration they may breathe in a similar volume of air but over a longer period of time. Therefore, as the number of breaths per minute is increased, whereas in a normal person at 25 breaths per min the volume has not fallen, its fallen but over 30% in COPD.
They have increased resistance of their airways due to narrowing, therefore the flow rate is slower so cannot breathe as fast.
92
How is the Calcium gradient made so large?
Because there is a gradient of 10 of Na set up by the sodium potassium ATPase, which is then cubed due to the stoichiometry of the Na/Ca exhanger as it transports 3Na for 1 Ca. (DONT UNDERSTAND LOOK UP)
93
There are 3 mammal forms of the calcium/ sodium exhanger called what?
NCX1-3
| remember by NaCl-Xchanger 1 to 3- probably isnt actually called this
94
What are the three types of Ca ATPases? By location (3)
PMCA: Plasma membrane calcium pump. Pump out of the cytoplasm across PM
SERCA: Sarcoplasmic Endoplasmic Retriculum Calcium pump. Pumps into stores from cytoplasm
SPCA: Calcium pump on the golgi.
95
4 type of operated Ca channels?
1. Voltage operated VOCC- in excitable cells e.g. at synapse.
2. Receptor operated ROCC- e.g. NMDA- glutamate binds
3. Mechanically activated- e.g. stretch activated
4. Store operated SOCC, activated following the depletion of calcium stores e.g. ER
96
Two types of Ca channels on the store membrane?
IP3 receptors,
| Ryanodine Receptors
97
How do IP3 calcium receptors work?
These are activated by the binding of IP3. This is part of the Gq pathway. Gq alpha dissociates as the associated GDP is phosphorylated to GTP. This activated Phospholipase C, which catalyses the hydrolysis of PIP2 into DAG and IP3. The IP3 binds to the calcium receptor and releases calcium from the ER stores.
98
How are the calcium stores refilled?
As the calcium levels in the stores is reduced, there is a conformational change in the STIM1 (ER ca sensor). This causes 8 subunits to come together on the ER membrane. The STIM 1 interracts with ORAI1 channel on the PM. Calcium enters the cell and refills the stores in the ER.
99
How do Ryanodine Receptors work?
These ca receptors are activated at low levels of ryanodin. High levels inhibit.
100
What is laplaces equation?
Pressure=2T(surface tension)/Radius
101
Air will move from small alveolar sacs to large why?
Because as laplaces equation suggests, when the radius is smaller the surface tension is less "diluted" so the pressure is larger, so air moves to larger bubbles where the pressure is lower. The smaller sacs then risk collapsing.
102
How is the risk of smaller air sacs collapsing reduced?
Surfactant.
103
What cells make surfactant? Made of?
Type II Pneumocytes.
| Phospholipids mostly e.g DPPC
104
What does surfactant do?
It reduces surface tension so can help inflate the alveoli initially. As the alveoli expands the surface area increases so the surfactant gets diluted. Surface tension increases and expansion is slowed. This prevents over inflation.
105
How does surfactant work?
The hydrophobic tails pull up into the air, whereas the hydophillic heads are in the water at the air water boarder. This disrupts the unit of the water molecules.
Prevents Oedema also by reducing the amount of fluid into the lungs.
106
What is surace tension?
At an air/water boarder water molecules are attracted equally to each other, so where the molecules at the surface only interract with those below and to the sides, they are pushed downwards and act as a unit. This compresses down on the alveoli making them collapse.
107
Parasympathetic ..... the airways, whereas sympathetic ..... them.
Parasympathetic: Constricts (bronchoconstriction)
Sympathetic: Dilates (Bronchodilation)
Think: Lion chasing you, need lots of air, dilate airways
108
How does the Gq pathway cause the contraction of airway smooth muscle?
Agonist- Gq- GDP phosphorylated to GTP-Gq alpha dissociates- activates PLC- Stimulates the hydrolysis of PIP2 to DAG and IP3.
IP3- IP3 receptors on calcium stores Ca2+ into the cytoplasm- binds to CaM- Activates MLCK (myosin light chain kinase)-contracts smooth muscle.
More Ca enters the cytoplasm to replenish stores also.
109
receptors acting through the Gq pathway?
M3 muscarinic
H1 histamine
BK brandykinin
110
How does the Gs pathway cause relaxation of airway smooth muscle?
Gs- GDP to GTP on alpha subunit- Activates adenyl cyclase- ATP to cAMP- PKA stimulated.
- PKA phosphorylates IP3 receptors making them less sensitive, so promotes relaxation (against Gq)
- PKA phosphorylates MLCK- reduces sensitivity- against Gq
- PKA phosphorylates MLCP-
111
How does an ECG trace differ for people with long QT or short QT syndrome?
The QT interval varied. Where QRS is ventricular depolarisation and T is repolarisation- so its a time lag for repolarisation in Long QT or shortening in short.
112
What are the time differences in QT interval between normal, long QT and short.
Normal: 0.36s
Long: 0.45+
Short: 0.34-
113
What are the two implication events that can happen with long QT?
Triggered activity- additional ectopic beat
| Re-entrant excitation- excitability looping back on itself (spatial or temporal)
114
What happens in Triggered activity in long QT?
There is a delay in repolarisation meaning that by the time another AP could fire the potential is still high 'after depolarisations' so reaches threshold. Another ectopic beat can be caused as ventricular myocytes contract again.
Ventricular tachycardia- fibrillation- CARDIAC DEATH
115
What happens in Re-entrant excitation in long QT?
additional electrical activity (Temporal dispersion only time when fired, and spatial, only some areas)which can feed back on itself in a circular path, propagating another AP here.
Ventricular tachycardia- fibrillation- CARDIAC DEATH
116
Symptoms of long QT?
```
Syncope (fainting)
May have an extra ectopic beat
Only show at teenager years
Sudden death (Torsades de pointes type)
enhanced in exercise (football) and cold water
```
117
Long Qt can be loss or gain of function. How so?
Loss: LQT1 and 2 are loss of Voltage gated Potassium channels Kv, so less repolarisation. (7.1a and 11.1)
Gain: LQT3 gain In Nav sodium channel doesn't close as early.
Also.. Mink regulates a Kv channel type, only works normally with, so if loss of function in Mink also causes. (LQT5)
118
Potassium channel structure?
6TMD, 4 subunits
119
Why do some of the mutations that cause long QT also affect the ear?
The endolymph is very high in K, so that this enters hair cells when they open, causing an AP. so if loss of function in Kv, reissners membrane cannot secrete K so deafness.
120
What is the treatment for long QT?
Beta blockers- Atenolol, slow heart rate so reduce the risk of cardiac episode. Negative chronotrophic and inotropic effect. Problem if have asthma as can cause bronchioconstriction.
121
What are inotropic and chronotropic?
Inotropic drugs affect the force of cardiac contraction. Chronotropic drugs affect the heart rate.
122
Short QT incidences?
75% males, late adolescence
123
What happens to the Qt interval as exercise? in patients?
This decreases, however in people with short QT doesn't change as already short.
124
Gain and loss of function in short QT?
Gain of function of Kv (SQT 1 2 3) so repolarise earlier, and loss of function of Nav or Cav (SQT4)
125
treatment for short QT?
Implant defibrillator which can step in to help with co-ordination.
Drug Quinidine is a K channel blocker
126
Why do myocardial cells have intercalated discs?
these have gap junctions between to help the propagation of AP between
127
What are terminal cisternae?
Enlarged areas of sarcoplasmic reticulum surrounding the transverse tubules. Store Ca.
128
How is calcium kept low in the cytoplasm when muscle is relaxed?
SR pumps mop up Ca- SOCC
| Binds to Calquestrin binds to to store and lower ca conc so more can enter.
129
When muscle AP comes in, what happens?
Ca diffuses out SR, binds to troponin, conformational change in troponin, tropomyosin complex. Myosin head can now bind to tropomyosin and with ATP cross bridges can be made and contract the muscle.
130
Why is there a max length for sarcomeres?
| Called Length tension relationship.
Individual lengths the same so just overlapping that varies.
Too short- thin filaments already overlap or close to, so can't shorten much more.
Too long- thin and thin filaments barely overlap so very few cross bridge sites. Less tension.
131
How can the length tension relationship be measured?
1. Record start muscle length
2. Electrically stimulate the muscle with electrode
3. Measure the tension created (contraction- eg. for the illium experiment)
4. Create a graph for different muscle lengths
132
Isotonic vs isometric?
Isotonic: tension remains the same as length changes e.g. heart
Isometric: contraction but no change in length e.g. push something heavy,
133
What's the Langmuir equation?
Bound= Bmax-Xa/ Xa + KD
Where
Bmax= Max specific binding, total no of receptors if drug binds 1:1
Xa= total conc of drug added
KD= when 50% occupancy
134
What is KD?
Measure of affinity. When 50% receptors are occupied. Half of Bmax If a partial agonist.
135
Whats a scatchard plot? How do you find the slope?
Bound/ free plotted against bound radioligand at different concentrations.
Slope= -1/KD
KD= x intercept
136
What's the hill number?
the number of drugs that have to bind to a receptor to get a response, e.g. most 1
137
Whats the schild plot?
x axis is the log10(antagonist) conc
| Y axis is the log10(DR-1)
138
When the log10(DR-1)= 0 this is the...?
-PA (where PA2= -log10
139
What is the dose ratio?
How much the dose curve shifts to the right, so how many times more agonist conc is needed in presence of antagonist .
DR= Ec50 of agonist with antagonist/ in absence of antagonist
or
DR= (Conc of Antagonist (Xb)/KD of antagonist) +1
140
How do irreversible competitive antagonists work?
| Example?
Normally an equilibrium forms as agonist binds and dissociates, but as disassociates in presence of irreversible competitive, these bind and do not dissociate so over time less and less agonist is bound.
e.g. Aspirin
141
Chemical antagonist definition?
Binds to the drug/ligand so that it cannot bind to receptor
142
Pharmacokinetic antagonist?
indirectly anatagonise, e.g. a drug that is absorbed by through the GI tract, if a drug slows down gut motility then will affect, e.g. opiates
143
Physiological antagonist?
Opposing action e.g. sympathetic vs parasympathetic.
e.g
Salbutamol B2 sympathetic opposes histamine in airways
NorA and adrenaline oppose histamine (vasodilation) in blood pressure.
144
non- competitive antagonist?
Block step in process between receptor activation and response.
e.g. block and intermediate channel.
145
What is the flick principal?
If know the oxygen content in the pulmonary artery, and in the pulmonary vein, can work out cardiac output. by the difference being the amount of oxygen exchanged.
146
Cardiac output equation? How can you measure this?
CO= O2 uptake / (o2)pv- (o2)pa (basically amount of oxgygen inspired over the O2 actually that enters the vein
Measure Q1 pulmonary artery with a catheter.
Q3 pulmonary vein
Q2, uptake rate X O2 volume in inspired air
or CO= HRx SV
147
How else can you measure cardiac output with a tracer?
E.g. insert tracer such as Indoccycnine green into the vein/R ventricle and then sample the artery, output is proportional to 1/tracer.
148
How can you measure Cardiac output with thermodilation? Ultrasound?
Put cold saline in R atrium, mixes with the blood moves to pulmonary artery and measure temp change.
Ultrasound measures real time canges in vol so CO=SVx HR (stroke vol= amount of blood ejected)
149
Average stroke volume?
80ml if x69= 5.5l per min with 69bpm
150
Calculation for cardiac index?
= Cardiac output/body surface area
Gives idea of tissue perfusion.
2.5-3.6l/min/m2
151
What are other indicators of the cardiac output?
Frank starlings law:
the strength of the heart's systolic contraction is directly proportional to its diastolic expansion with the result that under normal physiological conditions the heart pumps out of the right atrium all the blood returned to it without letting any back up in the veins
and sarcomeres length tension relationship.
152
What is the preload in the force velocity relationship?
The initial stretching of the sarcomere length, indicated by ventricular End diastolic volume. Initial contracting of the myocytes before contraction i.e. passive stretch.
153
What is afterload?
Pressure in the arteries and veins against which the ventricles have to eject blood.
154
If increase the preload, the velocity .... and the maximal force ... but the ..... stays the same
increases, increases
| the Vmax- maximal velocity of contraction (contractility)
155
What is the optimum sarcomere length?
2.2 um
156
Changes in the heart contractility are inotrophic/chronotrophic effects?
inotrophic- change the heart force of contraction (instead of rate)
157
What is contractility? How does it increase in the heart?
The force of contraction- velocity and tension generated. Increases when more crossbridges form (e.g. more Ca2+ released)
158
Noradrenaline impact on the heart?
both inotropic and chonotropic effects Po (maximal force) and Vmax (velocity therefore rate) is increased.
159
Whats the difference between tachycardia compared to noradrenaline?
Both increase the Vmax therefore the rate (chonotropic) but noradrenaline is inotropic also, whereas tachycardia has the same load (force)
160
What things largely dictate the stroke volume normally?
Heart size, contractility, preload and afterload, length tension relationship (preload chnages lenth of sarcomere)
161
What factor can alter a persons stroke volume?
Humeral factors, so sympathetic Increases, parasympathetic reduces.
162
What affects the EDV/ preload? (7)
Venous return back to the heart,(preload depends on how much blood there is)
which depends on:
- Blood vol- if increased, increased VR
- Vascular storage- if decreases, increases VR
-Gravity- VR increases if lie flat
-Atrial sucking- atrial pressure less than in veins so sucks, increasing VR
- Vascular resistance- If increases, decreases VR
- Muscle pumping/exercise increases VR, extravascular pressure increases.
-Inspiration- as interpleural pressure decreases, sucks blood from lower body so VR increases
163
Homeometric changes of control on CO?
humeral factors, e.g. adrenaline - sympathetic. Ach- para
| Treppe effect
164
What is the treppe effect?
Increase in the heart rate gives an increase in contraction also, as the heart 'warms up' there is excess Ca which isnt mopped up, and slight temperature increase.
165
What does parasympathetic stimulation do to the cardiac rate?
Chronotropic- Vagal stimulation slows down the heart rate by increasing the time between contractions (slow conduction through AVN- Bradycardia)
Ach to muscarinic receptors- reduces firing of pacemaker, and also reduces conductility so CO down.
166
How does sympathetic stimulation affect CO?
both chronotropic and iontropic. - Tachycardia
| Noradrenaline at B1 recptors, increase number of pacemaker cells to reach threshold, HR increases as SAN fires more.
167
How does the sympathetic nervous system affect the cardaic output? Mechanism
Adrenaline, Noradrenaline- binds to B1 receptors, Gs- adenyl cyclase ATP to CAMP- activates PKA, act on calcium Actn L channls on SR.
168
How does the parasympathetic NS affect the Cardiac output? Mechanism
Ach, Gq M2 receptors inhibit the convertion of ATP to cAMP so ihibits the sympathetic.
169
Affect of Beta Blockers on cardiac output?
Inhibits the sympathetic NS, so slows CO- slows heart rate.
170
Hypothyroid vs hyperthyroid?
Hypothyroid factors have low rates/cardaic outputs, whereas hyper have high
171
How do hyperthyroid hormones increase cardiac output?
Genomic action- promotes cardiac gene expression e.g. myosin and ATPase- more contraction
hypertrophy.
172
Blood flow=
Change in pressure/ resistance
| so pressure gradient pulling it through/ resistance stopping it
173
Another word for resistance for pulsatile flow?
Impedance
174
What are the resistance vessels? why?
Small arterioles where the blood first meets high pressure, as radius decreases and resitance is inverely proportional to the 4th power of radius (so small radius large resistance so slower flow)
175
What affect does an aneurysm have on flow?
e.g. in the aorta- weakening in artery wall, radius increases as bulges, so pressure decreases.
176
compliance=
change in volume/change in pressure
177
veins are more or less compliant? Therefore ... They are then called the .... vessels?
More, therefore veins store the most blood.- 54% of blood. Capacitance
178
What is the Windkessel effect?
Wave of pulsative flow evened out, into continuous flow, due to the elastic arteries.
179
An erythrocyte is ... wide whereas capillaries are ... therefore only one cell thick so there is ... flow
5um, 7um, lamina
180
What helps to ensure the blood flow in the ventricles is not lamina? (more mixing not clotting)
The traberculae carnia help to mix.
181
What controls the amount of blood flow into the capillaries?
Sphincters, when open- active, but when closed inactive through 'throughfore' channel
182
Tissue fluid formation depends on two opposing forces?
Hydrostatic pressure gradient pushing fluid out of capillaries (lower pressure out), and oncotic pressure, blood proteins making fluid omosasise back in
183
How does tissue fluid move out of the capillaries?
Gap junctions and aquaporins
184
where does tissue fluid drain?
Into lymphatics into R Subclavian artery
185
What factors vary the amount of tissue fluid?
- BP increases, increases hydrostatic pressure- more out into cells, oedema. Extravascular pressure increases, so impeded blood flow, causing ischaemia
- Malnutrition, decreased protein in blood, lower oncotic pressure- TF pushed out- oedema.
- Also capillary filtration co-efficient, how much can flow across.
186
What 3 factors affect the capillary filtration co-efficient?
- Histamine increases the leakiness of capillaries, can cause swelling
- Exercise a lot- odema in muscles so look like they grow immediately, not perminant.
- capillary damage
187
Structure of veins?
Endothelial lining tunica intima, basement membrane, tunica media (smooth muscle), tunica externa
and values to stop back flow as flowing back to the heart against gravity by extravascular pressure.
188
Structure of capillaries?
Only basement membrane and endothelial cells.
189
Structure of arteries?
Simialr to veins: but collagen between BM and tunica media.
| Medium sized elastic arteries have layers of elastic, whereas muscular arteries have more smooth muscle.
190
Most of the flow rate control is in which vessels?
arterioles, as the muscle to luman ratio is large so can control the size a lot.
191
What is myogenic regulation of blood vessels?
the smooth muscle contracting to bring the artery back to its resting tension - autoregulation.
192
Blood flow to a tissue can increase with what factors?
Co2 rise causing PH drop, lactic acid, O2 drop - show muscle exercising vasodilation.
temperature e.g. in skin- vasodilation so lose head through convection
K+ extracellular- tends to leak out as muscles exercise also.
193
What is the ECG?
The summation of the heart myocytes depolarisations and repolarisations. Can be measured from the skin.
194
Where are the lead electrodes placed to record an ECG?
Both arms and Left Leg- form Einthovens triangle. Vectors are:
I- from right arm to left.
II- From left leg to left arm
III- From Right arm to left leg.
195
What does the P wave represent?
Atrial depolarisation- its smaller as its a smaller muscle mass.
196
What does the QRS complex represent?
This is ventricular depolarisation- down the septum then up the ventricles- opposite direction therefore making a peak and back. Atrial repolarisation also is hidden in this.
197
what does the t wave represent?
This is ventricular repolarisation, but since its in the same direction as depolarisation its also a positive trace.
198
What is the U wave if it's seen?
repolarisation of the purkinje fibres,
199
What is the significance of having a high P wave?
signifys atrial hypertorophy, increased muscle mass
200
Significance of low T amplitude?
Ventricular hypoxia
201
Longer ST interval?
Acute Myocardial infarction.
202
How does the heart naturally vary its rhythm?
Bradycardia when sleep, tachycardia when stressed in exam or as exercise.
e.g. from 65bpm to 180bpm.
or 15% increase in inspiration, 15% decrease in expiration.
203
How can the heart abnormally vary?
-flutter 200-300bpm therefore low CO as not enough for ventricles to eject all of the blood.
-Fibrilation- 300bmp irregular
irregular rhythm often caused by heart blocks- breaks in the hearts conduction.
204
What are heart blocks?
impairement of conducting pathways e.g. by infarction, artery disease.
205
first degree heart block?
1- block in conduction between SAN and AVN, so slowing the conduction between, so increased PR interval.
2.
206
Second degree heart block? Type 1?
Mobitz I: Some SA impulses fail to evoke a QRS complex. This has progressive prolongation of the PR interval until drops a beat, so P wave without QRS.
207
Second degree heart block type 2?
MObitz II: Intermittent (often random) non-conductive P waves without prolongation of the PR interval. Ususally a failure of conduction at the hiss/purkinje system. Most likely due to structural damage e.g. infarction fibrosis, or where a LBBB (left bundle branch block- L V contracts after RV) or second degree AV block.
208
Third degree heart block?
Complete heart block, absence of the AV cnduction. Perusion is maintained by other measures, but may suffer from a ventricular standstill temporarily-sycope or for longer- cardiac death.
Bradycardia with disociated atria and ventricular rates.
Where the atria and ventricles may contract at the same time, blood is pushed back up and on the R can be seen as a pulse in the jugular vein. 'Cannon wave'
209
With the ehart blocks how serious are they?
First degree: Benign
Second degree- MObitz I- benign may be more obvious with heavy exercise.
Mobitz II- may need a pacemaker
Third degree- can cause death so is bad. Out of synchrony.
210
What is atrial fibrillation?
Most common type of arrhythmia , rapid beating of atria- palpitations during exercise- may cause shortness of breath (angina) or oedma of ankles.
211
What is the big problem with atrial fibrillation if mostly asymptomatic?
Blood may pool in the atria, clots form (thrombus) becomes a pulomanry embolism as is released into vessel to lungs, or cause stroke or myocardial infarction.
212
What treatment is there for the major problem with atrial fibrilation?
Clots:
Warafin anticoagulant but bleed easily (if need operation take Vitamin K which prevents momentarily)
Beta blockers e.g. sotalol.
213
What is Circus movement of the heart or re-entrant?
Where the electrical signal doesn't complete the normal circuit but loops back on itself.
e.g. caused if there is a bificating tract (in A shape), normally the two opposing directions and refractory period cant re-excite yet mean wouldnt travel across, but if one way is blocked may travel across and up again.
214
Most larger vessels have tonic Sympathetic/Para cholinergic/adrenergic input causing vasoconstriction/vasodilation
Sympathetic- adrenaline
Adrenergic
Vasoconstriction.
215
Pre-capillary muscles in sketal muscle have sympathetic/para input of ..... causing vasodilation/vasoconstriction? Skeletal muscle has no .... input
Sympathetic
Ach (cholinergic)
Vasodilation e.g. muscles get more blood to
Parasympathetic
216
Erectile tissue/ glands have symathetic/para innervation causing vasodilation/vasoconstriction?
Parasympathetic ACH
| Vasodilation
217
Where is there strong autonomic sympathetic vasoconstriction and where weak for example? WHy?
e.g. few sympathetic nerve fibres run through cerebrum as always want high blood flow to brain
whereas lots of fibres in cutaneous tissue so can vary dilation depending on heat, exercise to muscles etc.
218
What causes vasoconstriction in the vessels?
Smooth muscle contraction- constrict the lumen.
219
Which 3 humeral factors impact vessel diameter?
Adrenaline- Vasoconstriction of skin, dilation to skeletal muscle, liver (more glucose into blood stream)
Kinins- e.g. bradykinin- vasodilator inflammation
Angiotensin II- Vasoconstrictor, increase BP. (ACE RENIN PATHWAY)
220
Which 3 local agents impact vessel diameter?
- Prostaglandin- vasodilation at site of infection so WBC can come- inflammation
- Serotonin- Damaged platelets release- local constriction as aggregate together at a wound and stop bleeding.
- Histamine- Allergy. Bronchioconstriction, vasodilation to flush out toxin.
221
How does endothelial derived relaxing factor work?
Released after stimulation by Ach, causes nitric oxide to be released from endothelial cells, activating cGMP in smooth muscle causing relaxation so vasodilation.
222
How does sildenafil work?
sildenafil, viagra, inhibits the breakdown of cGMP so the blood vessels in the penis stay vasodilated- therefore getting erect
223
How does nitroglycine work?
Spray for angina. Converted to nitric oxide, which activated cGMP causing relaxation so vasodilation of blood vessels increase oxygen to reduce chest pain..
224
Cardioexcitation is regulated by neurons in the medulla how?
Sympathetic chain- accellerator nerve to cardiac nerve in SC to increase HR
para- Vagus nerve until synapse at the cadiac plexus, and inhibitory interneurons cause a decrease in BP.
225
How can the crushing reflex be very bad if injured head?
If swelling, intercranial pressure is increased, which leads to a fall in blood pressure in the brain due to extravascular pressure on.
Crushing reflex because of this causes vasoconstriction of these vessels- Causes increase in BP in carotid sinus, so HR slows- bradycardia.
Risk of death due to hypoxia of the brain.
Need to artificially increase rate of ventilation.
226
Where are the baroreceptors? Detect?
Stretch receptors to blood pressure in the carotid sinus and aortic arch.
227
What is blood pressure change is detected by baroreceptors?
BP down- reduced firing of baroreceptors- sympathetic firing and vagal reduced to increase HR and SV, CO up.
BP up- increased baroreceptor firing- Parasympathetic firing, decreased CO.
228
What is the Valsava manoeuvre?
If try to forced expiration against a closed glottis:
1. Thoracic pressure increases here.
2. Low venous return (as its low pressure here that sucks the blood back to atria) so BP down.
3. Low BP, Baroreceptors firing low
4. tachycardia and vasoconstriction to increase BP
5. Venous return increases, CO up BP up.
6. This causes vasodilation and bradycardia as barorecptors fire- cycle until manoevre stopped.
229
Where are the para and sympathetic central control centre?
Hypothalamus
| Link to limbic system also e.g. if scared affects
230
What is considered a normal heart rate below?
Diastolic Below 85, then 90+ considered mild hypertension
| Systolic below 140mmHg
231
Two types of hypertension?
Essential hypertension: risk factors but no obvious cause
| Secondary hypertension: consequence of another condition e.g. renal failure, diabetes
232
MABP=
CO x TPR
233
What are the main causes of hypertension? (4 types)
MABP=CO x TPR
- TPR increases with age so BP increases
- Cardiac disfunction- stress releases catecholamines lead to vasoconstriction of peripheral vessels BP up.
- Vessel abnormalities- TPR up
e. g. Less NO released- less EDRF.
e. g. More sympathetic innervation- vasoconstriction
e. g. muscle hypertrophy/ rigidity (Smooth muscle increase so more constriction)
- Kidney disfunction- vol up, BP up TPR up.
234
What are the risk factors for essential hypertension?
Obesity (also secondary due to increase risk of diabetes)
High salt diet (NaCl)- ECV increased as water in
Sedation
Vitamin D deficiency.
Geneticc around 40%- angiotensinogen/ENac mutation
235
Evidence fort salt intake on hypertension?
If reduce diet by 3g of salt a day, reduce BP by 5mmHg
236
How does renal disease cause secondary hypertenson?
nephron function impaired, less water lost, EXC vol up, , BP up.
237
How does renal artery stenting cause secondary hypertension?
Less blood flow to kidneys, less ultrafiltration, EXC vol up, BP up. But also, BP reduced in kidneys so juxtoglomerular cells release Renin which increases BP
238
How can some types of cancer cause secondary hypertension?
Some release catecholamines e.g. norA, Adrenaline- which leads to HR to increase and vasoconstriction so higher BP
239
How can a hormone imbalance e.g. adrenal gland tumour cause secondary hypertension?
Aldesterone released from the adrenal gland, if this is released is a part of the Renin-Angiotensin system- causes less Na to be secreted so levels increase so water less secreted so BP up.
240
Arterioscerosis vs atherscorosis?
Artero- toughening of artery walls, as damaged then replaced by scar tissue which is less flexible, TPR up.
Athero- Build up of plaque in a vessel by fatty calcium deposits- narrow and increase TPR, therefore increasing BP further.
241
How can high blood pressure or atheroscorosis cause a stroke?
High blood pressure in small capillaries in brain split and cause stroke.
Or moving slowly past plaque- thrombosis can form and embolism let lose block vessel. (myocardial infarction also)
242
How can high blood pressure be seen in the retina?
Burst vessels haemorrage
high pressure may straighten them out.
cotton wool spots- high hydrostatic pressure so fluid pushed out of vessels.
243
Treatment of high blood pressure- pharmacologic? (not ACE)
Duiretics- reduce EXC volume, Bp reduced.
Beta Blockers- decreases HR so Bp down.
Sympatholytics e.g. Clonide- Alpha blocker- decrease sympathetic output, or Prazosin relaxes Smooth muscle
Calcium channel blockers
244
Treatment of high blood pressure (renin-aldesterone system)
```
Ace inhibitors (Angiotensin converting enzyme inhibitors stop angiotensin I to angiotensin II which increases BP)
AG II receptor blockers.
```
245
What percentage of the blood is filtered in ultrafiltration?
20%
246
What three parts make up the filtration barrier in the bowmans capsule? What determines what's filtered?
Endothelial cells- have fenstrations
Basement membrane- major filtration barrier depends on how permeable. (also filtration forces)
Podocytes
247
features of the Basement membrane?
BM- charged negative glycoproteins(collagin, fibronectin, laminin)- filters depending
on size, charge, shape
248
Features of Podocytes?
Podocytes- foot like projections, traberculae and pedicles which the filtrate moves between slit pores. Role in phagocytosis of things not meant to be filtered also
249
Filtred/Plasma ratio depends upon?
1- freely filtered
0- not filtered stay in plasma
Molecular weight- as this decreases the ratio does.
Also if uncharged higher ratio. (e.g. negative dextran repels BM so less through)
250
Equation for the Glomerular filtration Rate?
GFR proportional to (Pcap+ Pi bc)- (Pbc+Picap)
In other words.. Pressure pushing the filtrate out (= Hydrostatic prssure pushing out of capillary +Oncotic pressure pulling in of the bowmans capsule)
- Pressure pushing back into the capillary (=Oncotic pressure pf the capillary and hydrostatic of the bowmans capsule)
251
As filtration occurs the hydrostatic pressure..? Oncotic?
Hydrostatic pressure oc capillary decreases as the volume decreases, so less is filtered.
Also as more is filtered the protein content increases so the oncotic pressure of capillary is increased so less filtered.
BUT ALWAYS POSITIVE (unique to here)
252
What is meant by autoregulation of the GFR?
Between 80-200mmHg blood pressure filtration rate is regulated so the GFR doesn't change too much.
253
How is there autoregulation of the GFR?
if blood pressure drops- relax smooth muscle to dilate afferent arteriole so more blood flows into the glomerulus- increases capillary hydrostatic pressure back to normal.
If blood pressure rises - Constrict afferent atriole vasoconstriction- so less blood goes through the glomerulus so same amount filtered still.
254
What are the two opposing and potentially syncronous theories of how BP is detected in the kidney?
Myogenic theory: Stretch receptors in the afferent atriole.
Tubuloglomerular feedback theory: DCT passes above the glomerulus and the macula densa cells in here detect rate of flow in distal tubule and release vasoactive chemicals to alter constriction.
255
Equation for osmolality?
Osmolality= Conc of solutes x no. of particles that can dissociate
e.g. 100 mM of NaCl = 100 x 2 (Na and Cl) =200 mOsmol/kgH2o
256
The ascending limb/descending is impermeable to water? why?
Ascending- so pumps out solutes, and makes the medulla (interstitial) omolality high, driving water loss from the descending limb.
Due to the high interstitial ater also may be lost from the collecting duct.
Causes counter current multiplication.
257
What happens in the thin descending limb?
Lots of waterloss through Aquaporin 1- constitutively there. Very slight leak of NaCl in.
K/O AQP1- urine not as concentrated but other systems take over
258
Think ascending limb?
NKCC2 and Barttin cell type.
Na/K atpase ensures low Na inside cell so NKCC2 can work. K recycled again, whereas Cl- out through channel with barttin and Na out by Na/k Atpase.
Pumps Na and Cl- out.
259
Bartters syndrome?
```
Cl- not pumped out as problem in Barttin, ClCk, NKCC2, Na/K ATPase
Lower osmolality in the interstitial fluid, so less water reabsorbed, urine less concentrated.
-Salt wasting
-Polyuria
-hypotension
-Hypokalaemia
-Alkalosis
-Hypercalciuria- nephrocalcination
```
260
Diabetes Insipidus?
The principal cell of collecting duct.
lack of Vasopressin released, or inability for the collecting duct to respond to it.
Therefore less AQP2 channels are put in, so less water is reabsorbed.
Polyuria etc...
261
50% of the high interstitial fluid osmolality is created by...?
Urea.
In the collecting duct as H20 leaves, the conc of Urea increases until this is pumped out.
It is leaked back into the descending limb.
262
What happens if K/O mouse for UT urea channels?
Osmolality of interstitial fluid is half that of the WT, so less able to concentrate its urine when water deprived.
263
What is special about the vasa recta around the loop of henle?
Instead of just going cortext medulla out, it loops the whole loop of henle so back up to the cortex then out. This prevents the concentration gradients created being washed out.
264
How is there no wash out of the loop of henle by the vasa recta?
The permeability of both A and D limbs is the same.
As move down the descending limb, water is lost from vasa recta, (due to high osmolality in medulla) and solutes move in.
Everything moves in opposite direction in the ascending limb so nothing has changed. No washout (a little in reality)
265
What is UT-B?
Urea channel on RBC membrane, mediates loss from RBC in vasa recta.
If mutation- urea washout of the loop of henle, so struggle to concentration their urine.
266
From artery to veins the PH increases/decreases?
decreases (7.45 to 7.35)
267
How does cystic fibrosis affect organs?
Pancreas- blocks ducts secreting digestive enzymes.
Liver- blocks ducts e.g. bile
Small intestine- obstruction die to thick content
Reproductive tract- absence of vans defens in 95% of males so infertile
Skin- NaCl secretion- salty
268
what test shortly after birth tests for cystic fibrosis?
Guthrie test
269
Signs shortly after birth that a baby has cystic fibrosis?
Meconium ileus- small intestine symptoms seen v early
Pancreatic insufficiency- around 3 days not putting on weight
Distal intestinal obstruction- 3 weeks
Respiratory disease-4 weeks
liver disease and male infertility- 2 years
270
Where are the most common places for CFTR mutations in the protein?
The nucleotide binding domain e.g. ATP causing opening of channel. F508 (90%)
271
What are the 5 different CFTR problems that there can be meaning that the protein will not work as normal?
Trafficking- The CFTR doesn't get to the membrane
Processing- The CFTR is folded properly
Regulation- CFTR doesnt open when should
Conduction- The CFTR has lowered ability for ions to move through pore
Production- less made
272
Sequence of CFTR problems in airways?
More viscous airway mucus- bacteria live-infection- inflammation- replace with scar tissue lungs- doesnt regernate- degeneration
273
What is CFTR?
Cloride channel.
274
What does CFTR do?
It secretes chloride across the apical membrane in the upper airways(NKCC2 on basolateral), this causes the increase in osmolality therefore causing water to follow. This creates the periciliary layer on top of the epithelial cells, in which mucous sits on top.
BActeria gets stuck in this mucous and the cilia can move this periciliary liquid layer (as right thickness 7um) so moves the mucous back up respiratory tract to be swallowed. HCL destroys.
275
What happens if the CFTR doesn't function?
Na still moves into the cell but no Cl secreted into the periciliarly layer, so osmolality drops so less water osmososises in, so this layer drops to less than 7um. The cilia cant beat properly but are bent over, so cant move the mucous so bacteria accumulates here. (2-3um)
276
How is Enac involves in the CFTR process?
The periciliarly layer is determined by balance of Na inward movement through EnaC and Cl- out. So if CFTR isn't functioning, osmolality builds up inside the cell and the layer drops. This is compounded by the fact that CFTR normally inhibits the activity of ENaC.
(The Na is recycled out by the Na/K ATPase across basolateral so can come back in with Cl through NKCC2. )
277
What is the F508 mutation?
Mutation of the CFTR- problems with trafficking and processing.
Misfolded protein, which is degragated so doesn't make it to the PM, but if does make it to the membrane function is almost normal.
278
How did CFTR become so common?
1 in 20 carriers.
When the last Cholera outbreak happened, CF carriers offered a protection from, as the water content in the faeces is determined by the secretion of Cl from CFTR protein in the colon lumen. The cholera toxin activated these and upregulated so more water was lost- died of dehydration.
Carriers had only half amount of CFTR so fewer died.
279
What is the treatment of CF?
Cough mucous up for hours
Bronchodilator so widen lumen, less blocked
antibiotic steroids to protect lungs
mucolytics- breakdown mucous- make less thick so easier to cough up.
Gene therapy
280
How does gene therapy for CF work?
Deliver CFTR gene to target cells e.g. inhale. DNA then transcribed to mRNA and protein produced/
281
Problem with gene therapy for CF?
Fast regenration rate for epithelial cells so have to do this often, very expensive.
282
Other methods of CF treatment?
Potentiators: increase Po of CFTR, but must be trafficked normally
Correctors: Force mutant CFTR protein to PM e.g. good for F508
Modulators: force production of full length of CFTR when truncation
283
Example of a Potentiator that Louise was particularly fond of?
Ivacafter
causes increase in height of liquid layer, decreased complications e.g. lung infection, weight loss etc.
Lowered salt in sweat.
284
What are NSAIDs?
Non Steroidal Anti Inflammatory Drugs.
They inhibit cyco-oxygenase COX enzyme.
e.g. Paracetemol, ibuprofin, Aspirin.
285
What do COX enzymes do?
Regulate the production of inflammatory mediators e.g. Prostoglandin, thromboxines, leukotrienes.
286
COX 1 vs COX-2?
COX-1 is constitutional whreas COX-2 is inducible.
COX-1: activates cytoprotective prostaglandins which protects mucous by regulating acid secretion.
COX-2: Actvated inflammatory mediators - Prostaglandin D2 an E
287
What do the two COX-2 inflammatory mediators do?
Prostaglandin D2: Platelet aggregation
| Prostaglandin E: Vasodilator, hyperalgesic, increase noiceceptor sensitivity, rise in body temp
288
What do the COX enzymes do? In sequence.
Phospholipids release arachidonic acid by phospholipase A. This activates leukotrienes (brochodilator) and under under the COX enzymes is metabolised to the prostaglandins.
289
How can aspirin reduce the likelihood of a stroke?
Targets prostaglandin D2, so less platelet aggregation.
290
What COX do ideally want to target?
Selective NSAID's target COX-2 as these are inducible when inflammatory response.
291
Which of the three NSAIDs is a pooor anti-inflammatory?
Paracetemol, it only desensitizes the noiceceptors not actually reducing the inflammatory response.
292
What is an analgesic?
This decreases the production of prostaglandins, which sensitize noiceceptors to inflammatory mediators such as 5HT, BK
293
What is the structure of the COX enzyme?
It is made up of two identical subunits, on the ER membrane. The COX site is deep inside so drugs can block so arachidonic acid cant bind.
294
WHat is the difference in structure between COX 1 and 2?
COX2 has a wider channel, so a bulkier (selective) drug can be used. This is because of an AA change from isoleucine to Valine in COX 2 (lsoleucine bigger)
295
Name a drug that can block the COX channel?
Aspirin. It bonds with an ester bond (covalent) so cannot dissocate therefore is a suicide inhibitor, works for around 4 hours until the body can synthesise more COX enzymes.
296
Chronic use of Anti-inflammitories side effects? Gut?
Gut: alsers formdue to too much acid causing damage, as COX-1 normally reduces. Also, gastric bleeding, holes in stomach.
297
Chronic use of Anti-inflammitories side effects? Renal?
Prostaglandin maintains renal blood flow so can cause renal failure. As well as acid problems.
298
Chronic use of Anti-inflammitories side effects? Liver?
Liver damaged by reactive toxic intermediate of paracetemol
299
Chronic use of Anti-inflammitories side effects? Lungs?
Prostaglandins are Bronchioconstrictors, so can be bad if have asthma (like Beta blockers),
300
Incidences of Rhumatoid arthiritis?
3x more common in women, late onset 40's, but are some child incidences.
Inflammation of the sinovian joint, autoimmune disease
301
How do immunosupressents help with arthiritis?
these reduce the immune response
e.g. Methotrexate (The T-rex ate Meth which inhibited the T-helper cells)
Inhibits T helper cells so lowers cytokines.
e.g. cyclosporin-
intracellular calcium increases after T cell activation, which activates calcineurin (calcium dependent phosphotase which adds a P to NFKappa Beta, acitvating T cells)
Cyclosporin binds to calcineurin and blocks, so reduces immune response.
302
What is the sequence that causes the autoimmune nature of rhumatoid arthiritus?
The T-helper cells are acitvated which activates and recruits macrophages. This leads to the release of Interleukin 1 and TNF alpha.
These are cytokines which cause inflammation and sinovian joint damage.
303
How do DMARDs help with rhumatoid arthiritus?
Disease modifying anti rhumatoid drugs
| reduce symptoms, by acting as free radical scavengers
304
How do glucocorticoids help with rhumatoid artiritus?
act at the level of transcription to decrease cytokine production.
305
What causes an allergy?
Hypersensitivity to allergen due to body making antibodies (Ig-E) against it, e.g. causing anaphylactic shock.
306
Explain Ig-E mediated hypersensitivity? How long does it take to develop?
Ig-E antibodies made against the allergen. So when experienced they bind to the allergen and through Fc receptors bind to a mast cell- releases histamine and prostaglandins- inflammatory response
(think- mast of ship lots of dust in cause coughing)
2-3 weeks
307
Whatis the late phase reaction of allergy?
50% of cases
Activation of transcription factors e.g NF Kappa Beta, causing cytoskines etc to be released, can cause chronic damage to the tissue
308
What is NF Kappa Beta?
Nuclear factor Kappa Beta- it regulates cytokine production (increasing)
309
What is asthma?
hyperreactive airways, inflammatory response to not just allergens but innoculous stimuli. Causes obstruction to the airways as causes brochoconstriction which is usually reversible (if not damages lungs)
310
Treatment for asthma? Inhaler?
Salbutamol- B2 adrenergic sympathetic bronchodilator, that relaxes smooth muscle. (polymorphisms can reduce efficacy of this)
311
How are biologicals used to treat rhumatoid arthiritus?
antibodies to TNF alpha or IL-1 to block- Expensive
312
Treatment for asthma glucocortocoids?
Glucocortocoids- reduce the cytokine release at TH-2 level.
| e.g. Prednisclone
313
Biologicals for asthma?
Xolair- monoclonal antibody- binds to Ig-E so cant bind to allergens or mast cells. Very Expensive.
314
Chronic use of steroids side effects?
Moon face, visceral fat, poor wound heeling (clotting prevented), hypertension, euphoria sometimes depression though
315
What three things does the plasma PH affect?
Excitability of muscles, ion channels here are sensitive to PH causing a change of activity
Enzyme activities e.g. denature etc
k extracellular conc, can swap H inside for K (inversely via NHE and Na/K ATPase)
316
Where do we get most of the acid input?
Diet, western especially higher.
317
What are the three ways for the body to regulate PH?
1. Buffers, also acid extrusion, acid loading. (within 2 secs)
2. respiration (within mins)
3. Renal system (hours or days) but only way for the body to actually get rid of acid/alkali.
318
How is bicarbonate a buffer?
HCO3, can bind with H+ to become H2CO3 (carbonic acid) which lowers the H+ ions in the Extracellular fluid/
319
What is the link between respiration and PH?
CO2 + H20- H2CO3- HCO3 + H+
| Can bind to water to make carbonic acid, which can dissociate into bicarbonate and H+ ions.
320
PH=
-log[H+]
also PH= PK + Log[HCO3/H2CO3]
PK constant at 6.1 at 37degrees
H2CO3 roughly CO2 conc
321
What is the Davenport diagram?
Graph showing PH against the conc of HCO3, depending on direction of shift can predict whether its respiratory problem or metabolic.
322
On the davenport diagram, what is each shift? Why?
If PH decreases (Acidic), and HCO3 decreases = Metabolic Acidosis (Both low) -Less HCO3 for the H ions to combine with, therefore PH decreases.
If PH low but HCO3 high- Respiratory acidosis- Excess CO2 so shifts equilibrium to carbonic acid to H ions and HCO3.
If PH high and HCO3 high- Metabolic alkalosis- excess bicarbonate, more combines with H+ so PH increases.
If PH high but HCO3 low- Respiratory alkalosis- Lack of CO2 equilibrium shifts to left, H+ + HCO3- to carbonic acid and CO2 and H to replenish. Use bicarbonate, hence low and PH high.
323
What is hypercapnia?
High CO2
324
How to the peripheral chemoreceptors go to the medulla?
Aortic chemoreceptors to medulla via the Vagus
| Carotid sinus chemoreceptors to medulla via the Glossopharyngeal nerve.
325
How do the periphery chemoreceptors work?
Glomus cells, resting potential around -60mv as K is pumped out.
If pO2 decreases or pCO2 increases or Ph down, theres inhibition of the BK K channels causing depolarisation until threshold, Ca opens and Ca influx,- AP is fired which signal to the nerves, which go to the respiratory centre and change ventilation rate.
326
Structure of the periphery chemoreceptor?
Glomus cells:
- High blood flow (x40 of brain) through arterioles into area
- Neuronal phenotype
Type II supporting cells maintain structure
Afferents away after NT released, signals to Vagus or Glossopharyngeal
327
What are some of the neurotransmitters released by the glomus cells?
Ach, Dopamine, 5HT, NA, substance p, ANP
328
How is the periphery chemoreceptor system linked to SIDS?
Sudden Infant Death Syndrome
Thought to be related to higher levels of dopamine and NA so can't control rate and stop breathing.
Or lack serotonergic neurons in central chemoreceptors.
329
Whereas in the periphery chemoreceptors the primary driving force is ...., in the central the main driving force is ...?
pO2
| pCO2 (PH actual parameter though)
330
Where are the central chemoreceptor neurons found?
Ventromedulla
| In the brain parenchyma, where they are bathed in Brain extracellular fluid, separated by the arterial blood by the BBB.
331
The BBB had poor ion permeability so how do the central chemoreceptor neurons detect H+ ions?
Co2 is lipid soluble so can pass.
| If high CO2, acidosis here.
332
Why is there a larger change in CO2 In the CSF BECF than rest of body?
Fewer non-bicarbonate protein buffers to mop up H+ ions.
333
For the same PH change, why does metabolic disorders change the PH less than that of respiratory diseases?
Because the BBB has poor ion solubility, so for respiratory acidosis the excess CO2 can diffuse through, whereas the H+ ions cannot (when low HCO2- cannot combine so charged) in metabolic.
334
What are the two antagonistic neurotransmitters for the central chemoreceptors?
Acidic activated by Serotonin
| Acid inhibited by GABA
335
Within the normal oxygen range which central or peripheral jump in to respiratory acidosis?
Both but Periphery more- works faster (protein buffers etc)
336
For respiratory acid/base changes how do the peripheral and central chemoreceptors respond?
Hyperventilation if severe acidosis, peripheral for acute response and central for longer term
337
What is the only 2 ways that the PH can actually change in the long term?
HCO3- handling in proximal cells then either;
Urine acidification
Ammonia synthesis
338
How can the proximal cells buffer PH?
When low PH: Carbonic anhydrase dissociates (under carbonic anhydrase) into CO2 and H2O (AQP1) so can diffuse into the principal cell. On the apical membrane is a NHE reliant on the low Na grad which pumps out H+. The HCO3- left is pumped with Na to be reabsorbed and H is secreted. (bound to ammonia or Phosphate)
339
How does ammonia synthesis work?
Ammonia synthesis- Buffer- H+ + NH3 = NH4+ Ammonia to ammonium- accepting H+ ions, making it impermeable so gets trapped in urine cannot be reabsorbed in the kidney.
(Ammonia is let off as glutamate is converted to alpha ketoglutarate)
340
What is mostly used ammonia synthesis or Urine acidification?
Ammonia synthesis 75%
341
How does Urine acidification work?
Alkaline Phosphate (Na2HPO4-) donates Na to go into the proximal cell through NHE, but accepts H+ (from carbonic acid) making it Acid Phosphate (NaH2PO4). This enables the H to be lost in the urine bound to phosphate.
342
Renal (and respiratory) compensation for the 4 types of acid/alkali problems?
Respiratory Acidosis- CO2 high- Right shift- H secreted increases, Renal: H secreted more and HCO reabsorption increases. (gets even higher but PH rises which Is primary issue)
Respiratory: this is the issue e.g. emphysema so no measures.
Respiratory Alkalosis- Low CO2-L shift- H secreted decreases and HCO reabsorption decreases.
Metabolic Acidosis- respiration increases, loss of arteriole CO2 (so induce L shift), also Renal same as above.
Metabolic Alkalosis- respiration deceases, pCO2 up, causing R shift, more H+ created. Kidney makes this worse initially, but evens out as eat more food
343
What can cause the 4 types of acid/alkali problems?
Respiratory Acidosis: Emphysema, chronic bronchitis- where less CO2 is lost.
Respiratory Alkalosis: hyperventilation, stress (breathing increases)
Metabolic Acidosis: Ingest acid, excrete alkali- Cholera, diarrhoea, diabetic ketoacidosis
Metabolic Alkalosis: Ingest alkaline, Vomiting HCO- out.
344
What if have mixed acid/alkali disorders?
If different- cancel each other mild problems, but if opposite are additive so can be life threatening.
345
Example of 3 subtractive mixed disorders?
Alcoholic- Met acidosis (ingest acid) but met alkalosis by vomiting.
COPD- Respiratory acidosis, but diuretics promote loss of H+.
Salicylate poisoning- stimulates repiratory centre- hyperventilation- respiratory alkalosis, and is acidic so met acidic.
346
Example of 1 additive disorder?
Asthma- respiratory acidosis (high CO2) and lactic acidosis due to lack of O2 so met acidosis
347
What are the two routes of administration for chemical general anaesthetics?
1. Inhilation e.g. NO
| 2. Intravenous e.g. barbiturates, steriods, halogenated hydrocarbons
348
There is no obvious link between structure and function for how efficient a general anasthetic is, but what is important?
Lipid solubility: the higher, the less is needed.
349
What is the parameter used to show how much of a drug is needed (vs solubility)?
MAC value- Minimal Alveolar Concentration to abolish response in 50% of patients to surgical incisions.
350
What are two examples of physical anaesthetics?
Low atmospheric pressure, hypothermia
351
What is the Meyer-Overton Rule?
Regarding general anaesthetics, that the drugs effect is directly proportional to the lipid solubility
352
What three factors supported the lipid theory of GA, what four disputed?
+ The lipid solubility vs MAC graph (Meyer overton rule)
+ No link between structure and function
+ Pressure experiments on PM affects leakiness
- Temperature- doesnt get more fluid at lower temp
- Loss of activity with homologous series of lipids
- Binding is saturable so suggests binding, therefore the protein theory w as established and proven.
-GA can associate with GABAa R
353
What was the Lipid Expansion theory of GA?
Meyer-Overton theory- GA enter into the PM, but as bulky they disrupt and cause expansion of it, altering the function and leakiness, hence causing the effects.
354
What is the protein theory for GA?
GA regulate activities of neuronal ion channels. (different GA interract with different ion channels)
355
Where does Ketamine bind?
Blocks NMDA receptors
356
Where do many GA bind? How do the volatile and intravenous differ from each other?
GABA A
Volatile alpha and Beta subunits
Intravenous only Beta
357
What are the effects of GA on neurotransmission? At low conc, at high?
At low conc: Synaptic transmission in CNS decreases, retincular fomation (plays a role in conciousness)= unconcious
Hippocampus- short term memory loss
At high conc: Decreased in both CNS and PNS
loss of motor control, reflexes, respiration, autonomic NS- Death
358
What are the 4 stages of Anaesthesia?
1. Analgesia- Decreased responsivenessto pain
2. Excitement- reflexes exaggerated, limbs flaling, sponatenous movements, coughing gagging, erratic breathing rate
3. Surgical Anasthesia- CNS not PNS, unconcious, regular breathing, loss of reflex and pain, short term amnesia, muscle tone reduced
4. Medullary Paralysis- loss of cardiovascular reflexes, respiratory paralysis (death)
359
3 Advantages and 4 disadvantages of intravenous anaesthetics?
+Easy to administer
+ rapid induction 20-30s
+Propofol rapid metabolism and low hangover, so good for short operations.
- Pain at site of injection
- Side effects: repiratory and cardiovascular (not etomidate) depression
- Complex pharmacokinetics e.g Thiopental Can get lost in body fat hangover,
- Need to cross blood brain barrier
360
How can the effects of an intravenous anasthetic be prolonged?
Using a inhaled GA, do doesnt drop below threshold for conciousness but flatlines.
361
2 advantages and 2 disadvantages to inhalation anasthetics?
+ Useful for maintaining unconciousness- flatlines
+ Lipid soluble molecules so can diffuse across alveolar membrane.
- Route of administration through lungs, problem if problem with lungs
- Hard to guage quantity of fat so volume needed.
362
Lean tissue has fast/slow perfusion, rapid/slow equilibriation and high/low partition co-efficient?
Fast, rapid, low (how much can dissolve here)
| Opposite for fat- but can get stuck there.
363
What is the big risk with GA's? Symptoms?
Malignant hyperthermia can be triggered by Halogenated GA's.
Have to monitor patients, check temp isn't rising, tachycardia, hypertension,increase muscle contraction.
364
Why is ketamine a GA?
sensory loss, amnesia, but no respiratory depression or complete loss of conciousness.
365
Ketamine symptoms?
hallucination, CV excitement, involuntary movement, irrational behaviours on recovery
366
What is Liddle's syndrome?
autosomal gain of function of EnaC on principal cell.
More Na is reabsorbed, so H2O follows (through AQP 2 then 3 and 4), causing hypertension, hypokalaemia, metabolic alkalosis.
367
In liddle syndrome why is there a gain of function of EnaC?
Low levels of renin and aldesterone, yet still high reabsorption of Na. There are too many EnaC channels in the membrane as they have lost the ability to be ubiquinated.
368
Why is there hypokalaemia with Liddle syndome?
Increased EnaC activity across the apical membrane, so high Na in principal cell. More Na ions for Na/K to pump K into cell, and ROMK pumps across apical to be secreted.
369
What is the mutation in Liddle EnaC channel?
Alpha, Beta and Gamma subunit, mutation in the COOH tail of Beta or Gamma subunit, which allows endocytosis of the channel by ubiquitin, so too many.
370
Why is there metabolic Alkalosis in Liddles?
Na reabsorbed so more positive tissue fluid in kidney, which drives the loss of H+ ions, so metabolic alkalosis.
371
What is a treatment for Liddles syndrome?
Amiloride- blocks ENaC.
372
What causes diabetes insipidus?
Lack of Vaspopressin or irresponsiveness to, so few AQP2 (P by PKA) on apical so less water reabsorbed. This causes Polyuria with polydipsia.
373
What are the 4 types of diabetes insipidus?
Primary-Supressed ADH production
Gestational Type- ADH broken down by placental enzymes
Central- aquired or congenital impaired ADH production
Nephrogenic- 90% aquired, impaired effects of ADH
374
How can central diabetes insipidus be got?
Aquired: Infection, headtrauma, surgery
Congenital: Neurohypophyseal diabetes insipidus mutation in site important for transport from hypothalamus to pituitary
375
How can nephrogenic diabetes insipidus be brought on
Aquired: Lithium bipolar medicine, some antibiotics, antifungals, chemotherapy, hypokalemia and hypercalciuria, renal failure
Congenital: Mutations in AVP R2 (xlinked) or AQP2 (impact on trafficking dominant, or function of protein recessive)
376
Treatment for central diabetes insipidus?
v easy- Desmopressin nasal spray-agonist at the vasopressin receptor
377
Treatment for nephrogenic diabetes insipidus?
Difficult as the receptors wouldnt repond to Desmopressin, possible use of modulator drugs (if protein misfolded but still working if can get to PM)
also pharmacological chaperones, heat shock protein 90, statins etc
378
If there are central nervous system channelopathies what can the result be?
Episodic Ataxia and epilepsy.
379
What is episodic ataxia? symptoms?
irregular uncontrolled muscle contractions
| Shakes, trunk instability, nausea, nystagmus- flickering eyes, visual blurring headache, look drunk
380
What causes type 1 episodic ataxia?
Mutation in KCNAI mutation- Kv at neuromuscular junction in cerebellum
Autosomal dominant, symptoms showing 10-20 with brief attacks
381
What causes type II episodic ataxia?
Mutation in CACNA1A Cav, autosomal dominant, attacks lasting 30mins to 24hrs. Onset child-teens
382
Type 1 ataxia triggers for attack?
stress emotional or physical (leicester football club)
| sudden vestibula system change e.g stand up fast
383
Mutation for the type 1 ataxia details?
Loss of function Kv, so increase in excitability in cerebellum, control of movement not as good.
current massively lower voltage than WT.
384
Treatment for type 1 episodic ataxia?
Phenytoin and Carbamazpine Nav inhibitors
385
Type II episodic ataxia mutation?
Cav channel CACNA1 A in cerebellum also.
| Mutations largely on the pores, point mutation often or truncation with more severe symptoms.
386
2example of Type II ataxia mutations?
Familial hemiplegic migraine- misense
| Spinocerebellar ataxia- repeat expansion of C terminus
387
What can be really bad with ataxia? especially type II?
Neurodegeneration of cerebellum often kills
388
Details on CACNA1A:where and mechanism?
In cerebellum- purkinje and granule cells, and cell bodies in CNS.
Ca causes the release of Neurotransmitters across the synpase, so when mutated less motor control
389
CACNA1A K/O mouse?
Upto 10days it's normal, mimics onset in humans 10. Then, balance problems, ataxia, death 3-4weeks
390
How can one see experimentally that there is a reduction in the calcium currents in type II ataxia?
Barian can be used as an indicator of calcium influx as calcium can have feedback mechanisms which affects normal messuring, whereas Barian doesn't but can flow through calcium channels and indicate Po.
391
What does the CACNA1A mutation do to the threshold?
Shifts the threshold more positive, Open probability greatest in the mutant shifted right on the graph so now at a higher membrane potential than WT. e.g. 10mv vs 0mv.
392
Treatment for episodic ataxia type II?
Acetazolamide, carbonic anhydrase inhibitor. (so less CO2 and H20 converted to carbon acid, so increases Calcium in cells)
393
4 causes of epilepsy?
Brain trauma, infection (e.g. Meningitis), inherited cause-mutation, tumors
394
what are the two types of two versions of epilepsy? MOst serious?
Partial vs Generalised - depending on how widespread in brain the discharge is
Simple or complex- complex if loss of conciousness
Generalised complex most serious
395
Why can epilepsy occur?
Electrical activity is a balance between excitatory and inhibitory neurons, so either reduction in inhibitory or upregulation of the excitatory can cause excess electrical discharge (seizure)
396
Role of GABAA vs ACH R on a post synaptic neuron? HCN?
GABA A causes inhibition of a EPSP by releasing Cl- in, so causing hyperpolarisation, compared to AchR- Na.
HCN= Hyperpolarisation activated cyclic nucleotide gated channel- cause depolarisation (cation channel) but Po highest at -mv (hyperpolarisation activated)
397
Example of a loss of Inhibiton causing epilepsy?
Nav 1.1- causes depolarisation in inhibitory cells, causing the release of GABA - to GABA A Receptor on post- CL- release so hyperpolarising.
misesnse of truncation, misense= febrile seizures (temp dependent) if mild or generalised seizures if bad
Truncation= Bad seizures- cognitive impairment and ataxia also
398
Example of a gain of exciatory mutations causing epilepsy? Loss?
Ach R on excitatory post. Upregulate so excess electrical discharge.
Nav 1.2 depolarisation on excitatory
loss of HCN=loss of firing control also increases excitatory.
Loss of Kv7.2- less repolarisation- longer excitation.
399
Structure of a Nav channel?
4 subunits each with 6TMD so 24 in total- 6 pore regions and 4 voltage sensors.
400
Nav 1.1 K/O?
A.P firing reduced of inhibitory neurons, excess electrical discharge= epilepsy seizures.
401
Nav 1.7 mutation in PNS sensory neurons?
loss of function-don't feel pain
Gain of function- pain without trigger chronic
Polymorphisms of this channel give pain threshold
402
What is generalised anxiety?
No clear reason, symptoms interfer with normal life, longer than 2 weeks
403
Other anxieties that aren't general? (4)
PTSD, OCD, Phobias, Panic disorder
404
Animal model to test anxalitic drugs?
Mouse put on elevated cross platform, mouse will stay on the side that has walls on one side so doesn't fall of, but if given anxalitic drugs will go on both sides equally, no longer fear falling
Or Mouse in put in a box stays in dark side- hidden from potential preditors, runs away from bright light
405
Example of a common anxalitic drug?
Benzodiazepine e.g. Diazepam/ Valium (also sedative)
406
Treatment prescribed for short term anxiety e.g. for an exam?
Beta blockers, slow heart rate etc by blocking so inhibiting sympathetic nervous system. (B adrenergic blocker)
407
function of GABA A receptor?
Inhibitory- Ionotropic, found post synaptic reduces excitability e.g. hyperpolarising by Cl- in.
408
Structure of the GABA A receptor?
Ionotropic. 5 subunits coming together. Allows Cl- through.
| 2alpha, 2 Beta, 1 gamma- 2 Orthosteric sites between alpha and beta's, allosteric between alpha and Y.
409
Orthosteric vs allosteric site?
Allosteric is a regulation site for the orthosteric active site, needs a ligand bound to orthosteric for a response.
410
Drugs that can bind to GABA A allosteric site?
Agonist: Diazepam
Antagonist: Flumeazenil (not v zen(may get ill) if go down a flume Flume-a-zen-il
411
Drugs that can bind to GABA A orthosteric site?
Agonist: muscimol, GABA
Antagonist: (competitive) Picrotoxin, bicuculline
412
Three other types of drugs that can bind to GABA A receptors to regulate?
Barbiturates, neurosteroids, general anaesthetics, sedatives, anti-convulsants, hypnotics, ethanol
413
GABA B characteristics?
Metabotropic, not a target for anxylitic drugs, found pre and post synaptic, can inhibit presynpatic potential by ihibiting voltage gated calcium channels and activate potassium channels postsynaptically.
414
Agonist and antagonist at GABA B?
Agonist – baclofen
| Antagonist - Phaclofen
415
What gives GABA A the huge variety?
2a, 2B, Y - can have many subunits come together e.g. a1, a2 etc
416
How did Marlyn Monroe die?
Overdose of Diazepam with vodka- summates with the action of other drugs e.g. ethanol
417
Physiological effects of Benzodiazepine?
Anxiolytic, Sedation,
Hypnosis- and amnesia e.g. Rohypnol
Anticonvulsant- Muscle tone reduction
418
Benzodiazepines work at which site?
Allosteric site of GABA A receptor, increasing the inhibition of CNS.
419
How does Benzodiazapine increase activity of the receptor it binds to? How can tell? vs Barbiturates?
Patch technique can show when open/ closed etc so see if it's the open time, no. of channels open or conductance?
Increased the frequency of channel opening, but not time opened each of these.
Barbiturates- opposite, increase time open but not how often opened.
420
WHat is the risk of Barbiturates?
If increase the concentration of too much they not only act at the allosteric site but also act as an agonist so can cause too much CNS depression- stop breathing- DEATH
421
How does the half life dictate the pharmalogical use?
If short half life such as Zolpidem used as a sleeping pill, whereas Diazepam long 20-40hrs- used for generalised anxiety (as its actively metabolised)
422
Adverse affects with Benzodiazepine?
Tolerance, Sleepiness, withdrawal, amnesia, can be fatal if taken with alcohol for example as summates effect of depression on the CNS (on its own saturates can't go beyond hyponosis as only increases efficacy of those already active)
423
What does tolerance mean?
Reduced effectiveness over time, body needs more and more to have the same response.
424
Withdrawal symtoms of Benzodiazepine?
Make more anxious when not on, also insomnia, CNS exciability, convulsions.
problematic for sleeping pills with short half life as more anxious during the day time.
425
Other Anxiolytics?
Newer receptor selective benzodiazepine agonist, which removes the side effects as more selective.
Buspirone- 5HT receptor agonist
426
Mutation in voltage gated sodium channel can cause?
Familial epilepsy.
427
What are the three different seizure types that can be seen on an ECG?
Grand mal generalised seizure-loss of conciousness, whole body fits, contraction and relaxation of muscles
Petit Mal-Absence type- generalised- seen in children, attention switches on and off may just blank for few seconds without lose conciousness- Cav mutation (think petit=child)
Partial- only some areas other areas normal ecg, symptoms depend where is.
428
What can trigger an epileptic seizure?
altered blood glucose, flashing lights, stress, fatigue, 'aura' when about to happen.
429
Why is Treatment for epilepsy so importnt?
As the extra Ca release can induce apoptosis in cells leading to cell death,
430
What is a treatment for epilepsy?
Benzodiazepine- at GABA A - increase inhibition therefore reduce the excitation
e.g. Clonazepam, diazepam
Or increase GABA A at synapse by blocking the breakdown.
e.g. Vigabatrin, Valproate.
431
How can the GABA NT be increased for epileptic people?
Uptake inhibitors e.g. Tiagabine
Metabolic inhibitors e.g. Vigabatrin (problem: depression), Valproate (problem: affect foetus growth, occasionally toxic also can improve mood)
432
How are Na channel blockers used for epilepsy?
The inactive state is stabilised, so this would be more selective in those with epiplepsy and only work in those that are active (open to inactive to closed)
e. g. Penytoin- vertigo, ataxia,
e. g. Carbamazepine- widely
433
Hw is Vigabatrin thought to work?
Inhibit the breakdown of GABA to Succinate by use of a suicide inhibitor to GABA Transaminase.
434
How is Valproate thought to work?
Acetylation of histamines- opens up the DNA so easier for transcription factors to bind and transcribe. Valproate favours acetylation over methylation (opposite) so increases transciption of enzymes in GABA metabolism e.g.
It increases levels of GAD enzyme which catalyses the conversion of glutamate (from alpha ketogluterate) to GABA so inhibits excitability for epilepsy.
435
How do 2 Ca channel blockers work for epilepsy?
T-type Ca channels are used for absence seizures, these reduce the amount of excitability.
e.g. Ethosuximide
Or GABApectin- action on alpha 2 subunit of T-type Ca channels, stop their trafficking to membrane.
436
New antiepileptic drug Levetricetam?
Decreases glutamate in vesicles of the excitatory neurons, so reduces.
437
Bipolar disorder vs unipolar depression?
Unipolar- mood swings but constantly in the same direction- unhappy low mood
Bipolar- Mood swings, vary between manic excitement, and depression- can last several weeks each
438
Depression symptoms:
Anhedonia: Low mood
Apathy: loss of interest in daily activities
Weight flunctuations, low esteem
sleep disturbances- insomnia or excessive
diminished concentration
439
Depression risk factors?
75% reactive- brought on by an event e.g. berievement, stress, side effect to drugs e.g. Cushings syndrome
25% endogenous- 40% of that genetic
440
Effects of depression?
1/6 USA
| 15-30% people commit suicide, greater risk than heart disease etc
441
What features in the brain are implicated in those with depression?
Cingulate nucleus (limbic- emotion, learning and memory and motivation)
Nucleus Accumbens (cognitive processing of aversion, motivation, reward)
Amygdala-(limbic- fear, emotion)
Hippocampus (limbic- learning memory, stress, (cortisol stress hormone impacts here from adrenal gland, BDNF decreases)
Peripheral hormes e.g. Leptin, link to eating
442
What is post- natal depression?
About 6 months after birth, mother get get depressed and neglect child- impact n brain development, brain waves chnage if mother depressed- causes baby to become.
443
Model on rodents to demonstrate acute stress? (2 experiments)
Forced swim test- Animal foced to swim with no way out, if repeated the animal gives up and dispairs sooner.
Also if suspend roden by tail, wants to right itself but eventually will dispair and give up.
Drugs can affect the time taken to dispair
444
Model on rodents for chronic stress?
Hate being immobile- if force for 2 weeks, cortisol levels increase - chronic stress
- Epigenetic changes
445
Causes of depression in body?
Stress: corticotrophin releasing hormone (CRF) hyperfunctional (ACTH release) lead to Cortisol levels increased
Monoamine hypothesis: serotonin or Noradrenaline reduced.
Low BDNF levels- to Trk-B receptor
High glutamate to NMDA receptor
446
HIgh levels of glutamate leads to?
to NMDA receptors causing neural apoptosis (depression)
| hence why ketamine (antagonist) reduces symptoms of depression
447
High stress and cortisol mechanism?
Stress- increases Corticotropin releasing hormone from hypothalamus- increased ACTH (adrenocorticotropic hormone) from pituitaty- high cortosol release for adrenal gland= Detrimental gene transcription response= neural apoptosis (depression)
448
Low BDNF levels leads to? What two other amines?
If high levels of BDNF to Trk B= beneficial gene transcriptional response = neurogenesis
If low, detrimental = neural apoptosis= depression
Same with 5HT and NA
449
Summary of levels of hormones/ NT etc that lead to depression?
High glutamate, High cortisol
Low BDNF, Low 5HT, Low NA
all = neural apoptosis= depression
450
What two drugs lead to observations that caused the monoamine theory of depression?
Reserpine- causes deplacement in the vesicles of monoamines= depression
Whereas,
Iproniazid- MAOI- Monoamine oxidase inhibitor, if stop breakdown there longer= antidepressant
451
How do SSRI help with depression?
e.g. Fluoxetine-
Selective serotonin Inhibitors
block transporters so serotonin is available for longer- stimulate receptors more, so reduce neural apoptosis.
452
What are the three uptake inhibitors which help with anti depression?
SSRI's- serotonin
Classical tyricyclic antidepressants- both serotonin and NA
MAOI 's- Serotonin and NA
453
Probelm with MAOI's?
(monoamine oxidase inhibitors) e.g. Phenelzine
MAOI A in brain or B in PNS
want to target A as B causes unwanted side effects.
e.g postural hypotension, and 'cheese effect' as amines in built up.
454
While the biochemistry for antidepressents takes place after .... it takes ... for mood to improve
immediately
3-4 weeks
suggest regulatory involvement.
455
How does the tricyclic classical antidepressants work? Side effects?
```
Inhibit uptake of serotonin and NA,
Anti-cholinergic side effects: dry mouth, blurred vision, constipation.
Adrenergic side effect: hypotension,
Histminergic: sedation
Also, dangerous overdose.
```
456
Noradrenaline used for in the CNS? Depression link?
Pain, arousal, mood, blood pressure regulation, withdrawal, sleep, anorexia
Deficiency can = depression
NARI (NA Reuptake Inhibitors) help reduce.
457
Synthesis of Noradrenaline?
Tyrosine- Dopa- Dopamine in vesicles- Noradrenaline (-Adrenaline)
458
Noradrenaline action is stopped by what? (3)
COMT ( breaks down in synapse and pre) , MAO, reuptake inhibitors
459
How are Noradrenaline and serotonin linked? (receptors)
Serotonin secretion neurons also have receptors for NA. Activation of alpha 1 by NA causes increased release, whereas, activation at alpha 2 inhibits serotonin release at synapse (sympathetic) These receptors can desensitize though, removing the inhibition.
460
How are the alpha 2 receptors linked to depression?
Downregulation can be a form of antidepressant therapy- because this then increases the amount of serotonin increased with NA at the alpha 2 without inhibiting at the alpha 1.
461
Use of Serotonin in the CNS?
Hallucinations, sleep, mood, emotion, feeding, vomiting, nociception
462
Where is the main loci for serotonin?
Raphe nuclei- sends to the limbic, relating to Anhedonia- unable to feel pleasure for normally enjoyable experiences.
463
Drugs acting on serotonin are used for?
Antidepressents, anxiety, migraine, chemotherapy, antipsychotics.
464
Serotonin is synthesised from which amino acid?
Tryptophan (from diet so limited by intake and enzyme tryptophan hydroxylase)
465
Serotonin is stopped by what?
Serotonin reuptake transporters (SSRI targets)
| MAO
466
Why is there a lag time between SSRI's woking and feeling no better?
E.g. Prozac- fluoxetine
Because where the selective serotonin reuptakers are inhibited, the increase in serotonin stimulation on the receptors causes a negative feedback decreasing the amount released initially by GABAnergic inhibitory interneurons.
However over time (weeks), these are desensitized, so this inhibiton disappears.
467
How are serotonin and BDNF linked? Sequence
Serotonin-Gprotein receptor Gs- ATP to cAMP- PKA- activation of CREB-1 - Increased production of BDNF
468
What does BDNF do?
Brain Derived Neurotropic Factor. Especially in hippocampus (learning)
Stabilises active synapses, released from post and acts back on pre to stabilise.
(depression decrease in synpases)
469
Summary NA: Serotonin: BDNF
NA at Alpha 2 inhibits serotonin release, whereas Alpha 1 increases.
High Serotonin, Gs- PKA- CREB1- Increased BDNF (if reduced may = depression as doesn't stabilize synapses- neural apoptosis)
470
What drug can be used to treat bipolar disease?
Lithium- permeates through Na channels- Affects ATK, Glycogen synthase kinase involved in apoptosis
471
DNA methylation vs acetylation? (depression?)
Methylation-decrease transcription
Acetylation- Increase transcription
E.g. BDNF- increased or decreased transcription
472
How can electroconvulsive therapy work for depression?
Can change neuronal circuits, and normalise circadium rhythms. Upregulate serotonin receptors.
473
Schizophrenia, what is the NT involved?
Dopamine imbalance (too high to D2 receptors)
474
What is schizophrenia?
Disturbances in perception, attention, thought, emotion, motor behaviour, hearing voices, paranoia, lack of energy, Anodonia, blunting of emotion
10% end in suicide
475
Amphetamine, cocaine, opiates usually target what NT?
Dopamine.
476
Function of dopamine?
In motor control in the nigrostiatal pathway (e.g. parkinsons- dopamine antagonists can give parkinsons like symptoms)
Limbic and cortical- motivation, behaviour, emotion
Pituitary secretion e.g. prolactin
Medulla chemoreceptor: Vomiting
477
Structural difference between brain in schizophrenia and normal?
Larger ventricles in Schizophrenia, and smaller tissue volume in the L temporal lobe. High DA= positive schizophrenia.
478
High dopamine? Low?
```
low= Parkinsons ADHD, Drug dependance addictive personality
high= Schizophrenia,
```
479
Dopamine broken down by?
MAO, COMT,
480
How do cocaine and Amphetamines affect amines?
Amphetamines:
Stimulate the secretion of dopamine and NA, inhibit MAO and the metabolism of, displace NA and Da from vesicles- leak out so levels high in the cytosol causing reuptake transporters which work by conc grad to reverse thus releasing more across synapse.
Cocaine: Inhibits the Pre dopamine reuptake transporters.
Increase in reward pathway, motor activity
481
What kind of drugs are used to treat Narcolepsy and ADHD? Why?
Amphetamines, increase NA, but also DA- can cause hyperactive children
482
Mice lacking the D1 receptor are insensitive to...
Cocaine and amphetamines (Dopamine)
483
What drugs can induce psycotic symptoms?
Ketamine- to NMDA (glutamate also involved)
484
Causes of schizophrenia?
Genetic, changes in early brain development, envirnmental e.g. Cannabis use
485
Treatment of Schizophrenia?
D2 Dopamine receptor antagonists
Side effects: Pro-lactin secretion, motor disturbances e.g. parkinsons like
e.g. chlorpromazine- irreversible muscle twitches, so now Clozapine etc
486
D2 receptors are..., whereas D1..?
D2= Gi
D1= Gs
Need to target D2.
487
Many myofilaments make up a ...many of these make a .... etc
Sarcomere- myofibrils-fibres (motor unit)-fasicle- muscle
488
The more motor units the more/ less graded the response?
More- if more motor units the more varaible the reposnse can be e.g. only 2 its either 0, 50% or 100% contracted, whereas if are 10 can be 30% etc.
489
Structure of the Ach R?
2A, B, Y, delta.
2 binding sites for Ach- 2 have to bind to open channel.
Non selective cation channel- depolarisation.
490
What is myotonia?
Hyper-excitability of skeletal muscle as AP are too long, increases contraction causing muscle stiffness.
Delayed reactions, and myotonic seizures.
491
What causes myasthenia Gravis?
An autoimmune disease that targets neuromuscular junctions, as it makes antibodies against AchR on Post. at NMJ.
Ach cant bind, and decrease in numbers of as internalised and broken down.
492
What are the symptoms of Myasthenia Gravis
Weakness and tiredness in skeletal muscle- can be fatal as respiratory failure.
493
Treatment for myasthenia Gravis?
Acetylcholinesterase inhibitors- if mild- stop breakdown of receptors e.g. Pyridostigmine
Corticosteroids- if moderate-severe, immunosupressant e.g. Prednisolone, cyclosporin
IV Immunogloblins- severe
Antibodies bind to do don't bind to ACh R, injected in hospital when in danger, mops up antibodies.
Also when life threatening- plasma taken out, immunoabsorbtion as IG bind to other molecules.
Thymectomy- Tumour in thymus gland can cause.
494
How is calcium transported out of the Sarcoplasmic reticulum to T-tubules?
From SR Ca out of Ryanodine receptors. Then physical link between ryanodine and L-type Ca channels(in array of 4), so when they open so do these, and Ca in from the excellular fluid into T-tubules.
Also calcium induced, calcium release, from Ryanodine sarcoplasmic reticulum.
495
How is Calcium reuptaken from the cell membrane?
Calcium, hydrogen exchanger.
| Ca ATPase. Ca in for H out
496
How is calcium reuptaken from the sarcoplasmic reticulum? Stored?
Calcium ATPase, Ca in for H out
| Calsequestrin stores calcium.
497
What mutation causes myotonia Congenita?
CLC1 loss of function, decreases the Po (for a given voltage as increases with it)
498
Two types of Myotonia congenita?
Thomsens autosomal dominant- less severe
| Beckers autosomal recessive- carriers asymptomatic
499
Fainting goats have...?
Myotonia Congenita ClC1 mutation
500
Myotonia Congentia symptoms?
May spotenously collapse
501
If Myotonia Congentia is loss of function of... what will happen to the membrane potential? Therefore?
ClC1- Nernst -70, so membrane will increase, nearer to threshold. Therefore more skeletal muscle contraction.
502
Treatment for Myotonia Congenita?
Mexilitene blocks some of the Na channels so decreases sponatneous contractions.
Use muscles a lot.
503
Cause of Paramytonia?
Nav 1.4 gain of function
| Na not blocked by inactivation gate, so open for longer- depolarise more so K sruggle to repolarise.
504
What triggers Paramytonia?
Cold- normally slows everything down so will increase Na levels slightly but in these people does significantly.
505
WHat is malignant hyperthermia?
Autosomal dominant, abnormal response to Halothene GA- Death rate 80%.
Different mutations, one being gain of function Ryanodine Receptor-- release Calcium (contraction)
506
Symptoms of Malignant hyperthermia?
Asymptomatic unless Halothene GA administered.
Rise in body temp 1degree every 5 mins
(proteins denature at 42)
rigid- muscle contractions. (Ca released from RyR1 as increased sensitivity to halothene)
sweating (release heat as contracting muscle as using lots of ATP)
Lactic acid production- acidosis
Low plama O2, high Co2 (as O2 used to make ATP)
Tachypnea- rapid breathing
Tachycardia to try to decrease this
Shifts in blood pressure.
Hyperkalemia (muscles release K when contracting)
507
What do people with Malignant hyperthermia die of?
Repiratory acidosis and Lactic acidosis (additive)
| This is due to high CO2 and muscle rigidity so lactic acid build up as contracting.
508
Malignant hyperthermia in pigs?
Pigs with big muscle mass selected for but unknown because of a mutation so the incidence increased in pigs
509
Triggers for Malignant hyperthermia?
Halothene, also caffeine v high conc, (also affect WT ryanodine receptors but at much higher concentrations that in mutation)
510
How to treat Malignant hyperthermia?
Dantrolene- inhibits RyR1 channels.
Diuretics to get halothene out body.
NaHCO3 to counterract acidosis.
Mechanically ventilate to get rid of Co2
511
What is pain?
Unpleasant sensory and emotional experience associated with actual or potential tissue damage
512
Sequence of how we sense pain?
Injury e.g. hand at peripheral terminal- up peripheral nociceptor- peripheral nerve (2nd)- through dorsal root ganglion- dorsal horn- (one may also loop back as effector- monosynaptic reflex) up the ascending pathway to the brain- descending pathway to effector e.g. move fingers away.
513
Pain involves...
the brain
514
What do DRG neurons do?
Contains cell bodies of sensory neurons, conveys sensory info from the periphery to the spinal cord. Spinal/cranial ganglia collect info.
515
Example of 2 diseases where individuals experience extreme pain?
PE- primary Erythermalgia (RBC, thermal pain, algia=pain)
Pain when walk and using physical activity hands and limbs always hot
PEDC- Paroxysmal extreme pain disorder whenever masticate or go to toilet.
516
Example of a disease where individuals experience no pain?
CIP- Complete insensitivity to pain- recessive mutation in voltage gated Na channel, don't know if damaging tissue to pull away so damage more, can die of internal damage as pain is protective.
517
Acute pain?
alerts body to chemical, thermal or mechanical stimuli that could cause damage
518
Chronic pain?
1. Inflammation e.g. Rheumatoid Arthritis
| 2. Neuropathic pain from damaging nerves e.g. diabetes, trauma, cancer treatment, herpetic infection
519
Economic cost of chronic pain?
USA- $600 billion annually- 50% healthcare, 50% loss in productivity.
$300 billion across Europe (around x3 cancer)
520
What is Analgesia?
Loss of pain without loss of consciousness
521
Where do analgesics work?
at nociceptors, dorsal horn or brain, but issue when in area of multiple function e.g. the brain
522
2 types of Analgesics?
Non-steroidal anti-inflammatory drugs NSAIDS- ibuprofen, aspirin
Opioids- morphine, fentanyl
523
What is the major side effect to NSAIDS?
Increased risk of GI problems e.g. ulcering, bleeding and perforating stomach etc, because inhibits COX-1 cytoprotective prostaglandins.
524
What is the major cause of death from opioid overdosing? 2 other side effects?
Depression of the respiratory system, combined with alcohol v dangerous.
sedation- apathy and cognitive impairment, inhibit GI tract.
525
What are the 4 types of opioid categories how found/made?
Natural opioids- morphine, codeine, dermorphine
Semi-synthetic- heroin,
fully synthetic- fentanyl
Endogenous opioid particles- endorphins, enkephalins, endomorphins, dynorphins
526
How are natural opioids made?
Dried juice of seeds of poppy flower =opium. Contains morphine 10% which can be extracted.
527
Morphine binds to? How does it work as an analgesic?
Opioid receptors, G protein coupled R leads to inhibition of calcium influx, reducing the amount of NT released across synapse from central nerve.
528
Types of opioid receptors?
Mu, Kappa, Delta
| Mu- concentrated in dorsal horn receiving inputs from DRG neurons.
529
Dermorphin found? Bind to? why effective?
Found originally from the skin of south American frog.
Most potent (greatest effect) at Mu opioid receptors in dorsal horn, v stable, not degraded by enzymes due to non-natural AA's so longer acting.
30-40x more potent than morphine.
530
Why was heroine synthesised after finding morphine?
Wanted to find a less addictive versio but it actually crosses 100x faster, and is highly addictive. Was originally marketed as a cough medicine.
531
What are the three stages in analgesia?
Transduction- convert stimulus into ion flow
Conduction- along the nerve
Transmission- to central terminals in SC
532
Fentanyl use?
Used as analgesic for surgery, 100x more potent than morphine.
533
Where are opioid receptors normally found?
CNS- endorphins, endogenous encephalin, dynophorins bind, released during stress or prolonged exercise.
534
What are endogenous opioids degraded by?
extracellular proteases hence short pain release only.
535
New approaches to analgesics?
Block the sodium channels that allow the conduction of pain signals.
536
How does Botulism neurotoxin work as an analgesia?
Blocks NT release for several months by cleaving SNAP 25 protein (SNARE protein bringing vesicles to PM)
537
How are monoclonal antibodies used as an analgesia?
Against nerve GF e.g. NGF
take out the sensitizing agent in synapse that lowers the threshold to pain,
e.g. for chronic pain but expensive.
538
What is tetrodotoxin?
TTX- 10-100x more lethal than black widow spider, 10,000x than cyanide.
nm levels needed.
539
Where is tetrodotoxin found?
Produced by marine bacteria, which are in a symbiotic relationship with many animals e.g. puffer fish- can get poisoning if poorly prepared, or octopus bite by blue ring.
540
Symptoms of puffer fish ttx poisoning?
Numbness of lips and tongue- local reaction as eat.
As spreads facial paraesthesia (unusual sensations)
Headache, nausea, dizziness, diarrhoea, vomiting
Increasing paralysis- respiratory- death 20mins-8hrs.
541
Symptoms of ttx poisoning bite?
Faster time to death than eating puffer fish,
| same symptoms but not facial but local to the bite area.
542
How to treat ttx poisoning?
mechanical ventilation- takes over breathing until broken down by body
No anti-venom as TTX binds too strongly so nothing will have higher affinity to, to mop up
543
How does TTX cause its toxicity?
Blocks Nav pre- prevent contraction by preventing NT releasase so no AP to skeletal muscle.
Post Muscle- decrease NT release at NMJ, muscle paralysis similar to above.
544
How does TTX cause its toxicity? binds?
Blocks Nav pre- prevent contraction by preventing NT releasase so no AP to skeletal muscle.
Post Muscle- decrease NT release at NMJ, muscle paralysis similar to above.
Not all Nv are sensitive- Nav 1.5, 1.8, 1.9 are insensitive, but all skeletal, some cardiac, CNS and PNS are.
545
What other toxins can bind at the NMJ as well as tetrodotoxin?
```
Nav pre: Tetrodotoxin, saxitoxin
Cav pre: Conotoxin
Kv pre: Dendrotoxin
Ach vesicles: Botulism, tetanus toxin
Nav post: TTX, Saxitoxin, conotoxin
```
546
WHat determines whether a channel is sensitive to TTX or not?
One AA change, glutamate to Glutamine in a pore region takes away sensitivity
Not all Nv are sensitive- Nav 1.5, 1.8, 1.9 are insensitive, but all skeletal, some cardiac, CNS and PNS are.
547
Example of an AA change in species that determines whether find TTX toxic?
Two isolated populations of Garter snakes, one in willow creek are insensitive, yet those in Bear Lake are sensitive. Willow creek can eat salamanders, wherea bear lake snakes would die due to toxicity.
Caused by spontaneous mutation, advantage, survived and reproduced.
548
What is dendrotoxin?
in snake venom.
inhibt Kv channels- repolarisation
Think (dendrites toxin)
549
Symptoms of dendrotoxin?
numbness where bitten, drooping eyelids, and paralysis of eye muscles, dysphagia- difficulty swallowing. Mild paralysis, respiratory failure= death.
If cant repolarise- cant refire AP, so same as blocking Nav.
550
What is Conotoxin?
Cone snail- depending on which type and which receptor it targets can either make ill or die.
Targets Cav on pre or post Nav on muscle at NMJ
Investigations into its ability to block pain- Nav 1.1
551
symptoms of conotoxin?
Dependent on toxin.
many similar to other toxins e.g. muscle weakness, headache, ptosis (drooping eyelids), swelling, cardiac and respiratory distress, if lips become stiff is associated with death.
Paralysis, coma, death
