bms 235

Question 1

If Patmos > Palveolar then air will (enter/leave) the lungs?

Answer 1

Enter. Air will travel down the concentration gradient during Inspiration.

Question 2

The chest wants to (collapse/expand), but the lungs want to (collapse/expand). Therefore the …… space is ……. in pressure at rest.

Answer 2

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.

Question 3

What is compliance?

Answer 3

Lungs ability to stretch.

Question 4

What does high compliance mean?

Answer 4

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)

Question 5

What does low compliance mean?

Answer 5

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)

Question 6

Compliance equation?

Answer 6

compliance= Change in Volume/ change in pressure.

Question 7

What is Alveolar pressure?

Number at rest, inspiration and expiration?

Answer 7

Pressure of air in alveoli.
No airflow: Palv=Patmos, therefore 0.
Inspiration: PalvPatmos, therefore 15.

Question 8

What is Airway Pressure?

Number at rest, inspiration and expiration? Constant throughout?

Answer 8

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.

Question 9

What is transpulmonary pressure?

Answer 9

The pressure difference between alveolar and intrapleural space. Always 5.

Question 10

What is Intrapleural pressure definition?

Answer 10

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.

Question 11

What is transmural pressure?

Number at rest, inspiration, expiration?

Answer 11

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.

Question 12

Explain inspiration?

Answer 12

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.

Question 13

What region on the brain controls the respiratory rhythm?

Answer 13

Medulla Oblongata of the brainstem.

(The dorsal respiratory Group and the Ventral Respiratory Group)

Question 14

What is the function of the Dorsal Respiratory Group?

Answer 14

Think: “Walk in through the door quietly”

Quiet Inspiration. (expiration is elastic recoil so passive)

Question 15

What does the DRG innervate?

Answer 15

Phrenic Nerve: Contract Diaphragm
Spinal Nerves: External Intercostals.
Think: “In through the door quietly after Exiting the IC”

Question 16

What is the function of the Ventral Respiratory Group?

Answer 16

Think: “Venting forcefully”

Controls forced inspiration and expiration

Question 17

What does the VRG Innervate?

Answer 17

Inspiration: Same as DRG but also Cranial nerves.
Expiration: Spinal nerves: Internal intercostal and abdominal muscles.
Think: “Venting forcefully letting internal feeling out”

Question 18

What complex causes the basic rhythm of breathing?

Answer 18

Pre- Botzinger Complex in the VRG

Question 19

What is special about the Pre-Botzinger Complex cells?

Answer 19

It contains pacemaker cells.

Question 20

What are the three busting patterns of the Pre-Botzinger complex

Answer 20

Eupneic (normal)
Sigh (Higher output, longer intake)
Gasp (short intake)

Question 21

What are the two types of neuron in the Pre-botzinger complex?

Answer 21

Pacemaker cells, and non pacemaker cells.

Question 22

What are the two patterns the pacemaker cells can make?

Answer 22

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.

Question 23

What’s the significance of the NALCN channel in the Pre-Botzinger Complex?

Answer 23

It is a sodium leak channel into the neuron. It contributes to the depolarisation. Important for initial slow depolarisation.

Question 24

Whats the significance of potassium and the Pre-Botzinger Complex?

Answer 24

If high levels of potassium, the resting potential is increased, say -90 to -80mv. Therefore the intensity of bursting is increased, as more depolarised.

Question 25

Bursting activity depends on which two types of currents?

Answer 25

The persistant sodium channel (I NAP)
The CAN Cation current (I CAN) (calcium dependent cation channel)
(ADD)

Question 26

Neurons relying on I NAP for bursting can be classified as ……. Whereas those relying on I CAN are…..

Answer 26

Cadmium insensitive
Cadmium sensitive (Cadmium can block these)

Question 27

Is the DPG and VRG always active?

Answer 27

DRG: It inactivates after inspiration, then the neurones have a period of activity again etc.
VRG: Inacitve during quiet respiration.

Question 28

What two ions are high inside a general cell, and which two are kept low?

Answer 28

High: K+, PO4^2- (phosphate in ATP etc)
Low: Na+, Cl- (used for signalling in cell)

Question 29

Rate of ions per s moved, by carriers, channels, and pumps?

Answer 29

Pumps: <100 ions per second (active and conformational change so slow)
Carriers: 100-1000 (conformational change also)
Channels: 10^6-10^8

Question 30

How are pumps, carriers, and channels controlled?

Answer 30

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.

Question 31

Three types of Carriers?

Answer 31

Antiport/exchanger, symporter/cotransporter, uniport.

Question 32

Electrochemical driving force depends on which two things?

Answer 32

Electrical membrane potential + Concentration Gradient

Question 33

What is the Patch Clamp Technique?

Answer 33

Measures the membrane voltage across.

Question 34

What is the difference between cell attached conformation and whole cell?

Answer 34

Cell attached: Measures a single ion channel.

Whole cell: measures current through the whole cell.

Question 35

How does the Patch technique work?

Answer 35

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.

Question 36

What is the equation for the Patch clamp technique?

Answer 36

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))

Question 37

Structure of Na/K ATPase?

Answer 37

Tetramer 2Beta, 2Alpha

Question 38

What is the Nernst equation? (definition)

Answer 38

Works out the equilibrium potential for a particular ion

Question 39

What is the Nernst equation?

Answer 39

61/z x log [(ion)outside / (ion)inside]

z= charge of ion

Question 40

What is the equilibrium potential? (definition)

Answer 40

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.

Question 41

Sodium/Potassium ATPase is responsible for ….% of the negative charge of most cells

Answer 41

20% (also sets grad for other channels, e.g. high K inside so goes out through channels- loss of positive ions)

Question 42

What is the Goldman Equation? (definition)

Answer 42

Works out the equilibrium potential for all ion channels using their relative permeability.

Question 43

What is the Goldman Equation? say for Na and K

Answer 43

Vm=61/z x log [ Pna(Na)o + Pk(K)o] / [Pna(Na)i + Pk(K)i ]

Question 44

PH is on a ……. scale. So the change from PH 6 to PH7 is a …… difference.

Answer 44

logarithmic scale.

Tenfold.

Question 45

What are the three methods of control of PH in a cell?

Answer 45

Buffering, Acid extrusion, Acid loading

Question 46

What is buffering?

Answer 46

It minimises the PH change, but does not reverse the direction. Buffering proteins (COOH and NH2 donate and receive protons.

Question 47

What is buffering power?

Answer 47

the amount of strong base or acid that must be added to raise the PH a given amount

Question 48

If PH increases how does buffering reduce?

Answer 48

PH increases, therefore gets more alkali. COOH (double bond of hydroxyl group to Carbon) releases a H+ ion.

Question 49

If PH decreases how does buffering increase?

Answer 49

Ph decreases. More acidic. NH2 can accept a H+ ion, to reduce.

Question 50

What is the link between H+ ions and PH?

Answer 50

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.

Question 51

What is the Acid extrusion method?

Answer 51

“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.

Question 52

In acid extrusion if PH rises?

Answer 52

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.

Question 53

What is an allosteric modification?

Answer 53

Allosteric modification is a binding site on the protein for the ligand separate to the active site.

Question 54

How does an allosteric modification help in the acid extrusion method?

Answer 54

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

Question 55

NHE1 is inhibited by ……. This is very sensitive to, so even comparatively concentrations (compared to ENaC or NHE3) affects.

Answer 55

Amiloride. (and EIPA homologue)

Question 56

What can bind to NHE1 to upregulate it? This causes an …. shift?

Answer 56

Calcium carmodulin.

Alkaline (as upregulates- therefore moves more H+ ions out of cell, increasing the PH)

Question 57

What is Acid Loading?

Answer 57

“Heating system”

Uses the Cl/HCO3 exchanger.(AE1- Anion exchanger 1) Cl- into the cell for HCO3 out.

Question 58

How does Acid Loading affect PH?

Answer 58

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.

Question 59

What is AE1 Cl/HCO3 exchanger inhibited by?

Answer 59

Stilbene derivatives drug DIDS

Question 60

How do microelectrodes work?

Answer 60

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))

Question 61

Microelectrodes are good for …. cells and …. but not …. cells.

Answer 61

big cells and tissues (e.g. muscles, xenopus oocytes, nerves,
but not small epithelial

Question 62

If volume above FRC in lungs, system …..

If volume below FRC in lungs, system wants to …

Answer 62

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

Question 63

At low volume the compliance is high/low. Whereas at low volume the compliance is high/low

Answer 63

At low volume: compliance is high- easy to inflate
Whereas at higher volumes the lungs become harder to inflate so low compliance
Sigmoid curve

Question 64

What two components make up the elastic recoil of the lung?

Answer 64

Anatomical component: elastic nature of cells and the extra cellular matrix

Surface tension: at the air fluid interface due to surfactant

Question 65

Concentrations of extracellular and intracellular Na?

Answer 65

Extracellular: 145mM
Intracellular: 15mM

Question 66

Why is Na kept low inside the cell? examples?

Answer 66

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

Question 67

Na/K pump is inhibited by what?

Answer 67

Cardiac Glycosides e.g. digoxin, Oubain

Question 68

What does electrogenic mean?

Answer 68

Able to produce a charge in the electric potential of a cell

Question 69

Concentrations of calcium inside and out?

Answer 69

(Ca2+)o =1mM (1 000 000nm)
(ca2+)i =100nm
x 10,000

Question 70

Why is calcium kept low in cells? Examples (3)

Answer 70

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

Question 71

Two ways calcium is kept low in the cell?

Answer 71

Ca ATPase

Na/Ca exchanger

Question 72

What does the Na/Cl exchanger do?

Answer 72

transports 3Na in for 1 Cl out

Question 73

If a lung is reduced down to residual capacity (collapsed) how can one re-inflate it?

Answer 73

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

Question 74

In terms of breathing what is negative and positive pressure?

Answer 74

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.

Question 75

If the air in the lungs is smooth and steady what is this called?

Answer 75

Lamina Flow

Question 76

At lamina flow the movement of air into and out lungs is propertional to ………. and inversely to …….

Answer 76

The pressure gradient (Palv-Patmos)

Resistance

Question 77

If flow rate increases beyond a critical value currents are made and low becomes ….?

Answer 77

Turbulant

Question 78

How does turbulant flow velocity equation differ from lamina?

Answer 78

Now the flow rate is proportional to the square root of the pressure gradient.

Question 79

One disadvantage and one advantage of turbulant flow over lamina?

Answer 79

(+) 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)

Question 80

Many bifurcations can cause a third flow type. What is this?

Answer 80

Transitional Flow

Swirlings and eddies are created.

Question 81

What can be used to determine the flow type?

Answer 81

Reynolds number

Question 82

Reynolds number calculation?

Answer 82

Re= 2radius x Velocity x Density of gas/ Viscosity

Question 83

If Reynolds no. less than 1000 which flow?
1000-1500?
Over 1500?

Answer 83

Lamina
Lamina/Turbulant mix
Turbulant

Question 84

What happens to the flow rate as goes through the airways?

Answer 84

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)

Question 85

Poiseuille’s law suggests that airway resistance is proportional to …… and …….
but inversely proportional to the……..

Answer 85

Gas viscosity
Length of the tube
inversely proportional to the 4th power of the radius

Question 86

Airway resistance in the lung percentages for:
Pharynx and Larynx:
Airways greater than 2mm diameter
Airways less than 2mm diameter

Answer 86

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

Question 87

How do the resitance lung percentages differ for COPD people?

Answer 87

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.

Question 88

Factors that affect airway resitance? (2)

Answer 88

Increased mucus secretion- diameter down, resitance up

Oedema- increased fluid retention, swelling, resistance up, velocity down.

Question 89

What happens to resistance as inspire?

Answer 89

Decreases as dilates.

Question 90

………. attatches the alveoli to the walls by tethering. In people with ……. this is broken down causing the collapse. This then ….. resistance.

Answer 90

Elastin
Emphysema
Increases

Question 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?

Answer 91

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.

Question 92

How is the Calcium gradient made so large?

Answer 92

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)

Question 93

There are 3 mammal forms of the calcium/ sodium exhanger called what?

Answer 93

NCX1-3

remember by NaCl-Xchanger 1 to 3- probably isnt actually called this

Question 94

What are the three types of Ca ATPases? By location (3)

Answer 94

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.

Question 95

4 type of operated Ca channels?

Answer 95

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

Question 96

Two types of Ca channels on the store membrane?

Answer 96

IP3 receptors,

Ryanodine Receptors

Question 97

How do IP3 calcium receptors work?

Answer 97

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.

Question 98

How are the calcium stores refilled?

Answer 98

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.

Question 99

How do Ryanodine Receptors work?

Answer 99

These ca receptors are activated at low levels of ryanodin. High levels inhibit.

Question 100

What is laplaces equation?

Answer 100

Pressure=2T(surface tension)/Radius

Question 101

Air will move from small alveolar sacs to large why?

Answer 101

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.

Question 102

How is the risk of smaller air sacs collapsing reduced?

Answer 102

Surfactant.

Question 103

What cells make surfactant? Made of?

Answer 103

Type II Pneumocytes.

Phospholipids mostly e.g DPPC

Question 104

What does surfactant do?

Answer 104

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.

Question 105

How does surfactant work?

Answer 105

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.

Question 106

What is surace tension?

Answer 106

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.

Question 107

Parasympathetic ….. the airways, whereas sympathetic ….. them.

Answer 107

Parasympathetic: Constricts (bronchoconstriction)
Sympathetic: Dilates (Bronchodilation)

Think: Lion chasing you, need lots of air, dilate airways

Question 108

How does the Gq pathway cause the contraction of airway smooth muscle?

Answer 108

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.

Question 109

receptors acting through the Gq pathway?

Answer 109

M3 muscarinic
H1 histamine
BK brandykinin

Question 110

How does the Gs pathway cause relaxation of airway smooth muscle?

Answer 110

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-

Question 111

How does an ECG trace differ for people with long QT or short QT syndrome?

Answer 111

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.

Question 112

What are the time differences in QT interval between normal, long QT and short.

Answer 112

Normal: 0.36s
Long: 0.45+
Short: 0.34-

Question 113

What are the two implication events that can happen with long QT?

Answer 113

Triggered activity- additional ectopic beat

Re-entrant excitation- excitability looping back on itself (spatial or temporal)

Question 114

What happens in Triggered activity in long QT?

Answer 114

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

Question 115

What happens in Re-entrant excitation in long QT?

Answer 115

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

Question 116

Symptoms of long QT?

Answer 116

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

Question 117

Long Qt can be loss or gain of function. How so?

Answer 117

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)

Question 118

Potassium channel structure?

Answer 118

6TMD, 4 subunits

Question 119

Why do some of the mutations that cause long QT also affect the ear?

Answer 119

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.

Question 120

What is the treatment for long QT?

Answer 120

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.

Question 121

What are inotropic and chronotropic?

Answer 121

Inotropic drugs affect the force of cardiac contraction. Chronotropic drugs affect the heart rate.

Question 122

Short QT incidences?

Answer 122

75% males, late adolescence

Question 123

What happens to the Qt interval as exercise? in patients?

Answer 123

This decreases, however in people with short QT doesn’t change as already short.

Question 124

Gain and loss of function in short QT?

Answer 124

Gain of function of Kv (SQT 1 2 3) so repolarise earlier, and loss of function of Nav or Cav (SQT4)

Question 125

treatment for short QT?

Answer 125

Implant defibrillator which can step in to help with co-ordination.
Drug Quinidine is a K channel blocker

Question 126

Why do myocardial cells have intercalated discs?

Answer 126

these have gap junctions between to help the propagation of AP between

Question 127

What are terminal cisternae?

Answer 127

Enlarged areas of sarcoplasmic reticulum surrounding the transverse tubules. Store Ca.

Question 128

How is calcium kept low in the cytoplasm when muscle is relaxed?

Answer 128

SR pumps mop up Ca- SOCC

Binds to Calquestrin binds to to store and lower ca conc so more can enter.

Question 129

When muscle AP comes in, what happens?

Answer 129

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.

Question 130

Why is there a max length for sarcomeres?

Called Length tension relationship.

Answer 130

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.

Question 131

How can the length tension relationship be measured?

Answer 131

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

Question 132

Isotonic vs isometric?

Answer 132

Isotonic: tension remains the same as length changes e.g. heart
Isometric: contraction but no change in length e.g. push something heavy,

Question 133

What’s the Langmuir equation?

Answer 133

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

Question 134

What is KD?

Answer 134

Measure of affinity. When 50% receptors are occupied. Half of Bmax If a partial agonist.

Question 135

Whats a scatchard plot? How do you find the slope?

Answer 135

Bound/ free plotted against bound radioligand at different concentrations.
Slope= -1/KD
KD= x intercept

Question 136

What’s the hill number?

Answer 136

the number of drugs that have to bind to a receptor to get a response, e.g. most 1

Question 137

Whats the schild plot?

Answer 137

x axis is the log10(antagonist) conc

Y axis is the log10(DR-1)

Question 138

When the log10(DR-1)= 0 this is the…?

Answer 138

-PA (where PA2= -log10

Question 139

What is the dose ratio?

Answer 139

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

Question 140

How do irreversible competitive antagonists work?

Example?

Answer 140

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

Question 141

Chemical antagonist definition?

Answer 141

Binds to the drug/ligand so that it cannot bind to receptor

Question 142

Pharmacokinetic antagonist?

Answer 142

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

Question 143

Physiological antagonist?

Answer 143

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.

Question 144

non- competitive antagonist?

Answer 144

Block step in process between receptor activation and response.
e.g. block and intermediate channel.

Question 145

What is the flick principal?

Answer 145

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.

Question 146

Cardiac output equation? How can you measure this?

Answer 146

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

Question 147

How else can you measure cardiac output with a tracer?

Answer 147

E.g. insert tracer such as Indoccycnine green into the vein/R ventricle and then sample the artery, output is proportional to 1/tracer.

Question 148

How can you measure Cardiac output with thermodilation? Ultrasound?

Answer 148

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)

Question 149

Average stroke volume?

Answer 149

80ml if x69= 5.5l per min with 69bpm

Question 150

Calculation for cardiac index?

Answer 150

= Cardiac output/body surface area
Gives idea of tissue perfusion.
2.5-3.6l/min/m2

Question 151

What are other indicators of the cardiac output?

Answer 151

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.

Question 152

What is the preload in the force velocity relationship?

Answer 152

The initial stretching of the sarcomere length, indicated by ventricular End diastolic volume. Initial contracting of the myocytes before contraction i.e. passive stretch.

Question 153

What is afterload?

Answer 153

Pressure in the arteries and veins against which the ventricles have to eject blood.

Question 154

If increase the preload, the velocity …. and the maximal force … but the ….. stays the same

Answer 154

increases, increases

the Vmax- maximal velocity of contraction (contractility)

Question 155

What is the optimum sarcomere length?

Answer 155

2.2 um

Question 156

Changes in the heart contractility are inotrophic/chronotrophic effects?

Answer 156

inotrophic- change the heart force of contraction (instead of rate)

Question 157

What is contractility? How does it increase in the heart?

Answer 157

The force of contraction- velocity and tension generated. Increases when more crossbridges form (e.g. more Ca2+ released)

Question 158

Noradrenaline impact on the heart?

Answer 158

both inotropic and chonotropic effects Po (maximal force) and Vmax (velocity therefore rate) is increased.

Question 159

Whats the difference between tachycardia compared to noradrenaline?

Answer 159

Both increase the Vmax therefore the rate (chonotropic) but noradrenaline is inotropic also, whereas tachycardia has the same load (force)

Question 160

What things largely dictate the stroke volume normally?

Answer 160

Heart size, contractility, preload and afterload, length tension relationship (preload chnages lenth of sarcomere)

Question 161

What factor can alter a persons stroke volume?

Answer 161

Humeral factors, so sympathetic Increases, parasympathetic reduces.

Question 162

What affects the EDV/ preload? (7)

Answer 162

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

Question 163

Homeometric changes of control on CO?

Answer 163

humeral factors, e.g. adrenaline - sympathetic. Ach- para

Treppe effect

Question 164

What is the treppe effect?

Answer 164

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.

Question 165

What does parasympathetic stimulation do to the cardiac rate?

Answer 165

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.

Question 166

How does sympathetic stimulation affect CO?

Answer 166

both chronotropic and iontropic. - Tachycardia

Noradrenaline at B1 recptors, increase number of pacemaker cells to reach threshold, HR increases as SAN fires more.

Question 167

How does the sympathetic nervous system affect the cardaic output? Mechanism

Answer 167

Adrenaline, Noradrenaline- binds to B1 receptors, Gs- adenyl cyclase ATP to CAMP- activates PKA, act on calcium Actn L channls on SR.

Question 168

How does the parasympathetic NS affect the Cardiac output? Mechanism

Answer 168

Ach, Gq M2 receptors inhibit the convertion of ATP to cAMP so ihibits the sympathetic.

Question 169

Affect of Beta Blockers on cardiac output?

Answer 169

Inhibits the sympathetic NS, so slows CO- slows heart rate.

Question 170

Hypothyroid vs hyperthyroid?

Answer 170

Hypothyroid factors have low rates/cardaic outputs, whereas hyper have high

Question 171

How do hyperthyroid hormones increase cardiac output?

Answer 171

Genomic action- promotes cardiac gene expression e.g. myosin and ATPase- more contraction
hypertrophy.

Question 172

Blood flow=

Answer 172

Change in pressure/ resistance

so pressure gradient pulling it through/ resistance stopping it

Question 173

Another word for resistance for pulsatile flow?

Answer 173

Impedance

Question 174

What are the resistance vessels? why?

Answer 174

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)

Question 175

What affect does an aneurysm have on flow?

Answer 175

e.g. in the aorta- weakening in artery wall, radius increases as bulges, so pressure decreases.

Question 176

compliance=

Answer 176

change in volume/change in pressure

Question 177

veins are more or less compliant? Therefore … They are then called the …. vessels?

Answer 177

More, therefore veins store the most blood.- 54% of blood. Capacitance

Question 178

What is the Windkessel effect?

Answer 178

Wave of pulsative flow evened out, into continuous flow, due to the elastic arteries.

Question 179

An erythrocyte is … wide whereas capillaries are … therefore only one cell thick so there is … flow

Answer 179

5um, 7um, lamina

Question 180

What helps to ensure the blood flow in the ventricles is not lamina? (more mixing not clotting)

Answer 180

The traberculae carnia help to mix.

Question 181

What controls the amount of blood flow into the capillaries?

Answer 181

Sphincters, when open- active, but when closed inactive through ‘throughfore’ channel

Question 182

Tissue fluid formation depends on two opposing forces?

Answer 182

Hydrostatic pressure gradient pushing fluid out of capillaries (lower pressure out), and oncotic pressure, blood proteins making fluid omosasise back in

Question 183

How does tissue fluid move out of the capillaries?

Answer 183

Gap junctions and aquaporins

Question 184

where does tissue fluid drain?

Answer 184

Into lymphatics into R Subclavian artery

Question 185

What factors vary the amount of tissue fluid?

Answer 185

• 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.

Question 186

What 3 factors affect the capillary filtration co-efficient?

Answer 186

• 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

Question 187

Structure of veins?

Answer 187

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.

Question 188

Structure of capillaries?

Answer 188

Only basement membrane and endothelial cells.

Question 189

Structure of arteries?

Answer 189

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.

Question 190

Most of the flow rate control is in which vessels?

Answer 190

arterioles, as the muscle to luman ratio is large so can control the size a lot.

Question 191

What is myogenic regulation of blood vessels?

Answer 191

the smooth muscle contracting to bring the artery back to its resting tension - autoregulation.

Question 192

Blood flow to a tissue can increase with what factors?

Answer 192

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.

Question 193

What is the ECG?

Answer 193

The summation of the heart myocytes depolarisations and repolarisations. Can be measured from the skin.

Question 194

Where are the lead electrodes placed to record an ECG?

Answer 194

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.

Question 195

What does the P wave represent?

Answer 195

Atrial depolarisation- its smaller as its a smaller muscle mass.

Question 196

What does the QRS complex represent?

Answer 196

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.

Question 197

what does the t wave represent?

Answer 197

This is ventricular repolarisation, but since its in the same direction as depolarisation its also a positive trace.

Question 198

What is the U wave if it’s seen?

Answer 198

repolarisation of the purkinje fibres,

Question 199

What is the significance of having a high P wave?

Answer 199

signifys atrial hypertorophy, increased muscle mass

Question 200

Significance of low T amplitude?

Answer 200

Ventricular hypoxia

Question 201

Longer ST interval?

Answer 201

Acute Myocardial infarction.

Question 202

How does the heart naturally vary its rhythm?

Answer 202

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.

Question 203

How can the heart abnormally vary?

Answer 203

-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.

Question 204

What are heart blocks?

Answer 204

impairement of conducting pathways e.g. by infarction, artery disease.

Question 205

first degree heart block?

Answer 205

1- block in conduction between SAN and AVN, so slowing the conduction between, so increased PR interval.
2.

Question 206

Second degree heart block? Type 1?

Answer 206

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.

Question 207

Second degree heart block type 2?

Answer 207

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.

Question 208

Third degree heart block?

Answer 208

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’

Question 209

With the ehart blocks how serious are they?

Answer 209

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.

Question 210

What is atrial fibrillation?

Answer 210

Most common type of arrhythmia , rapid beating of atria- palpitations during exercise- may cause shortness of breath (angina) or oedma of ankles.

Question 211

What is the big problem with atrial fibrillation if mostly asymptomatic?

Answer 211

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.

Question 212

What treatment is there for the major problem with atrial fibrilation?

Answer 212

Clots:
Warafin anticoagulant but bleed easily (if need operation take Vitamin K which prevents momentarily)
Beta blockers e.g. sotalol.

Question 213

What is Circus movement of the heart or re-entrant?

Answer 213

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.

Question 214

Most larger vessels have tonic Sympathetic/Para cholinergic/adrenergic input causing vasoconstriction/vasodilation

Answer 214

Sympathetic- adrenaline
Adrenergic
Vasoconstriction.

Question 215

Pre-capillary muscles in sketal muscle have sympathetic/para input of ….. causing vasodilation/vasoconstriction? Skeletal muscle has no …. input

Answer 215

Sympathetic
Ach (cholinergic)
Vasodilation e.g. muscles get more blood to
Parasympathetic

Question 216

Erectile tissue/ glands have symathetic/para innervation causing vasodilation/vasoconstriction?

Answer 216

Parasympathetic ACH

Vasodilation

Question 217

Where is there strong autonomic sympathetic vasoconstriction and where weak for example? WHy?

Answer 217

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.

Question 218

What causes vasoconstriction in the vessels?

Answer 218

Smooth muscle contraction- constrict the lumen.

Question 219

Which 3 humeral factors impact vessel diameter?

Answer 219

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)

Question 220

Which 3 local agents impact vessel diameter?

Answer 220

• 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.

Question 221

How does endothelial derived relaxing factor work?

Answer 221

Released after stimulation by Ach, causes nitric oxide to be released from endothelial cells, activating cGMP in smooth muscle causing relaxation so vasodilation.

Question 222

How does sildenafil work?

Answer 222

sildenafil, viagra, inhibits the breakdown of cGMP so the blood vessels in the penis stay vasodilated- therefore getting erect

Question 223

How does nitroglycine work?

Answer 223

Spray for angina. Converted to nitric oxide, which activated cGMP causing relaxation so vasodilation of blood vessels increase oxygen to reduce chest pain..

Question 224

Cardioexcitation is regulated by neurons in the medulla how?

Answer 224

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.

Question 225

How can the crushing reflex be very bad if injured head?

Answer 225

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.

Question 226

Where are the baroreceptors? Detect?

Answer 226

Stretch receptors to blood pressure in the carotid sinus and aortic arch.

Question 227

What is blood pressure change is detected by baroreceptors?

Answer 227

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.

Question 228

What is the Valsava manoeuvre?

Answer 228

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.

Question 229

Where are the para and sympathetic central control centre?

Answer 229

Hypothalamus

Link to limbic system also e.g. if scared affects

Question 230

What is considered a normal heart rate below?

Answer 230

Diastolic Below 85, then 90+ considered mild hypertension

Systolic below 140mmHg

Question 231

Two types of hypertension?

Answer 231

Essential hypertension: risk factors but no obvious cause

Secondary hypertension: consequence of another condition e.g. renal failure, diabetes

Question 232

MABP=

Answer 232

CO x TPR

Question 233

What are the main causes of hypertension? (4 types)

Answer 233

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.

Question 234

What are the risk factors for essential hypertension?

Answer 234

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

Question 235

Evidence fort salt intake on hypertension?

Answer 235

If reduce diet by 3g of salt a day, reduce BP by 5mmHg

Question 236

How does renal disease cause secondary hypertenson?

Answer 236

nephron function impaired, less water lost, EXC vol up, , BP up.

Question 237

How does renal artery stenting cause secondary hypertension?

Answer 237

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

Question 238

How can some types of cancer cause secondary hypertension?

Answer 238

Some release catecholamines e.g. norA, Adrenaline- which leads to HR to increase and vasoconstriction so higher BP

Question 239

How can a hormone imbalance e.g. adrenal gland tumour cause secondary hypertension?

Answer 239

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.

Question 240

Arterioscerosis vs atherscorosis?

Answer 240

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.

Question 241

How can high blood pressure or atheroscorosis cause a stroke?

Answer 241

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)

Question 242

How can high blood pressure be seen in the retina?

Answer 242

Burst vessels haemorrage
high pressure may straighten them out.
cotton wool spots- high hydrostatic pressure so fluid pushed out of vessels.

Question 243

Treatment of high blood pressure- pharmacologic? (not ACE)

Answer 243

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

Question 244

Treatment of high blood pressure (renin-aldesterone system)

Answer 244

Ace inhibitors (Angiotensin converting enzyme inhibitors stop angiotensin I to angiotensin II which increases BP)
AG II receptor blockers.

Question 245

What percentage of the blood is filtered in ultrafiltration?

Answer 245

20%

Question 246

What three parts make up the filtration barrier in the bowmans capsule? What determines what’s filtered?

Answer 246

Endothelial cells- have fenstrations
Basement membrane- major filtration barrier depends on how permeable. (also filtration forces)
Podocytes

Question 247

features of the Basement membrane?

Answer 247

BM- charged negative glycoproteins(collagin, fibronectin, laminin)- filters depending
on size, charge, shape

Question 248

Features of Podocytes?

Answer 248

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

Question 249

Filtred/Plasma ratio depends upon?

Answer 249

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)

Question 250

Equation for the Glomerular filtration Rate?

Answer 250

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)

Question 251

As filtration occurs the hydrostatic pressure..? Oncotic?

Answer 251

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)

Question 252

What is meant by autoregulation of the GFR?

Answer 252

Between 80-200mmHg blood pressure filtration rate is regulated so the GFR doesn’t change too much.

Question 253

How is there autoregulation of the GFR?

Answer 253

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.

Question 254

What are the two opposing and potentially syncronous theories of how BP is detected in the kidney?

Answer 254

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.

Question 255

Equation for osmolality?

Answer 255

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

Question 256

The ascending limb/descending is impermeable to water? why?

Answer 256

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.

Question 257

What happens in the thin descending limb?

Answer 257

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

Question 258

Think ascending limb?

Answer 258

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.

Question 259

Bartters syndrome?

Answer 259

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

Question 260

Diabetes Insipidus?

Answer 260

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…

Question 261

50% of the high interstitial fluid osmolality is created by…?

Answer 261

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.

Question 262

What happens if K/O mouse for UT urea channels?

Answer 262

Osmolality of interstitial fluid is half that of the WT, so less able to concentrate its urine when water deprived.

Question 263

What is special about the vasa recta around the loop of henle?

Answer 263

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.

Question 264

How is there no wash out of the loop of henle by the vasa recta?

Answer 264

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)

Question 265

What is UT-B?

Answer 265

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.

Question 266

From artery to veins the PH increases/decreases?

Answer 266

decreases (7.45 to 7.35)

Question 267

How does cystic fibrosis affect organs?

Answer 267

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

Question 268

what test shortly after birth tests for cystic fibrosis?

Answer 268

Guthrie test

Question 269

Signs shortly after birth that a baby has cystic fibrosis?

Answer 269

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

Question 270

Where are the most common places for CFTR mutations in the protein?

Answer 270

The nucleotide binding domain e.g. ATP causing opening of channel. F508 (90%)

Question 271

What are the 5 different CFTR problems that there can be meaning that the protein will not work as normal?

Answer 271

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

Question 272

Sequence of CFTR problems in airways?

Answer 272

More viscous airway mucus- bacteria live-infection- inflammation- replace with scar tissue lungs- doesnt regernate- degeneration

Question 273

What is CFTR?

Answer 273

Cloride channel.

Question 274

What does CFTR do?

Answer 274

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.

Question 275

What happens if the CFTR doesn’t function?

Answer 275

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)

Question 276

How is Enac involves in the CFTR process?

Answer 276

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. )

Question 277

What is the F508 mutation?

Answer 277

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.

Question 278

How did CFTR become so common?

Answer 278

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.

Question 279

What is the treatment of CF?

Answer 279

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

Question 280

How does gene therapy for CF work?

Answer 280

Deliver CFTR gene to target cells e.g. inhale. DNA then transcribed to mRNA and protein produced/

Question 281

Problem with gene therapy for CF?

Answer 281

Fast regenration rate for epithelial cells so have to do this often, very expensive.

Question 282

Other methods of CF treatment?

Answer 282

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

Question 283

Example of a Potentiator that Louise was particularly fond of?

Answer 283

Ivacafter
causes increase in height of liquid layer, decreased complications e.g. lung infection, weight loss etc.
Lowered salt in sweat.

Question 284

What are NSAIDs?

Answer 284

Non Steroidal Anti Inflammatory Drugs.
They inhibit cyco-oxygenase COX enzyme.
e.g. Paracetemol, ibuprofin, Aspirin.

Question 285

What do COX enzymes do?

Answer 285

Regulate the production of inflammatory mediators e.g. Prostoglandin, thromboxines, leukotrienes.

Question 286

COX 1 vs COX-2?

Answer 286

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

Question 287

What do the two COX-2 inflammatory mediators do?

Answer 287

Prostaglandin D2: Platelet aggregation

Prostaglandin E: Vasodilator, hyperalgesic, increase noiceceptor sensitivity, rise in body temp

Question 288

What do the COX enzymes do? In sequence.

Answer 288

Phospholipids release arachidonic acid by phospholipase A. This activates leukotrienes (brochodilator) and under under the COX enzymes is metabolised to the prostaglandins.

Question 289

How can aspirin reduce the likelihood of a stroke?

Answer 289

Targets prostaglandin D2, so less platelet aggregation.

Question 290

What COX do ideally want to target?

Answer 290

Selective NSAID’s target COX-2 as these are inducible when inflammatory response.

Question 291

Which of the three NSAIDs is a pooor anti-inflammatory?

Answer 291

Paracetemol, it only desensitizes the noiceceptors not actually reducing the inflammatory response.

Question 292

What is an analgesic?

Answer 292

This decreases the production of prostaglandins, which sensitize noiceceptors to inflammatory mediators such as 5HT, BK

Question 293

What is the structure of the COX enzyme?

Answer 293

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.

Question 294

WHat is the difference in structure between COX 1 and 2?

Answer 294

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)

Question 295

Name a drug that can block the COX channel?

Answer 295

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.

Question 296

Chronic use of Anti-inflammitories side effects? Gut?

Answer 296

Gut: alsers formdue to too much acid causing damage, as COX-1 normally reduces. Also, gastric bleeding, holes in stomach.

Question 297

Chronic use of Anti-inflammitories side effects? Renal?

Answer 297

Prostaglandin maintains renal blood flow so can cause renal failure. As well as acid problems.

Question 298

Chronic use of Anti-inflammitories side effects? Liver?

Answer 298

Liver damaged by reactive toxic intermediate of paracetemol

Question 299

Chronic use of Anti-inflammitories side effects? Lungs?

Answer 299

Prostaglandins are Bronchioconstrictors, so can be bad if have asthma (like Beta blockers),

Question 300

Incidences of Rhumatoid arthiritis?

Answer 300

3x more common in women, late onset 40’s, but are some child incidences.
Inflammation of the sinovian joint, autoimmune disease

Question 301

How do immunosupressents help with arthiritis?

Answer 301

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.

Question 302

What is the sequence that causes the autoimmune nature of rhumatoid arthiritus?

Answer 302

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.

Question 303

How do DMARDs help with rhumatoid arthiritus?

Answer 303

Disease modifying anti rhumatoid drugs

reduce symptoms, by acting as free radical scavengers

Question 304

How do glucocorticoids help with rhumatoid artiritus?

Answer 304

act at the level of transcription to decrease cytokine production.

Question 305

What causes an allergy?

Answer 305

Hypersensitivity to allergen due to body making antibodies (Ig-E) against it, e.g. causing anaphylactic shock.

Question 306

Explain Ig-E mediated hypersensitivity? How long does it take to develop?

Answer 306

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

Question 307

Whatis the late phase reaction of allergy?

Answer 307

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

Question 308

What is NF Kappa Beta?

Answer 308

Nuclear factor Kappa Beta- it regulates cytokine production (increasing)

Question 309

What is asthma?

Answer 309

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)

Question 310

Treatment for asthma? Inhaler?

Answer 310

Salbutamol- B2 adrenergic sympathetic bronchodilator, that relaxes smooth muscle. (polymorphisms can reduce efficacy of this)

Question 311

How are biologicals used to treat rhumatoid arthiritus?

Answer 311

antibodies to TNF alpha or IL-1 to block- Expensive

Question 312

Treatment for asthma glucocortocoids?

Answer 312

Glucocortocoids- reduce the cytokine release at TH-2 level.

e.g. Prednisclone

Question 313

Biologicals for asthma?

Answer 313

Xolair- monoclonal antibody- binds to Ig-E so cant bind to allergens or mast cells. Very Expensive.

Question 314

Chronic use of steroids side effects?

Answer 314

Moon face, visceral fat, poor wound heeling (clotting prevented), hypertension, euphoria sometimes depression though

Question 315

What three things does the plasma PH affect?

Answer 315

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)

Question 316

Where do we get most of the acid input?

Answer 316

Diet, western especially higher.

Question 317

What are the three ways for the body to regulate PH?

Answer 317

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.

Question 318

How is bicarbonate a buffer?

Answer 318

HCO3, can bind with H+ to become H2CO3 (carbonic acid) which lowers the H+ ions in the Extracellular fluid/

Question 319

What is the link between respiration and PH?

Answer 319

CO2 + H20- H2CO3- HCO3 + H+

Can bind to water to make carbonic acid, which can dissociate into bicarbonate and H+ ions.

Question 320

PH=

Answer 320

-log[H+]
also PH= PK + Log[HCO3/H2CO3]
PK constant at 6.1 at 37degrees
H2CO3 roughly CO2 conc

Question 321

What is the Davenport diagram?

Answer 321

Graph showing PH against the conc of HCO3, depending on direction of shift can predict whether its respiratory problem or metabolic.

Question 322

On the davenport diagram, what is each shift? Why?

Answer 322

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.

Question 323

What is hypercapnia?

Answer 323

High CO2

Question 324

How to the peripheral chemoreceptors go to the medulla?

Answer 324

Aortic chemoreceptors to medulla via the Vagus

Carotid sinus chemoreceptors to medulla via the Glossopharyngeal nerve.

Question 325

How do the periphery chemoreceptors work?

Answer 325

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.

Question 326

Structure of the periphery chemoreceptor?

Answer 326

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

Question 327

What are some of the neurotransmitters released by the glomus cells?

Answer 327

Ach, Dopamine, 5HT, NA, substance p, ANP

Question 328

How is the periphery chemoreceptor system linked to SIDS?

Answer 328

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.

Question 329

Whereas in the periphery chemoreceptors the primary driving force is …., in the central the main driving force is …?

Answer 329

pO2

pCO2 (PH actual parameter though)

Question 330

Where are the central chemoreceptor neurons found?

Answer 330

Ventromedulla

In the brain parenchyma, where they are bathed in Brain extracellular fluid, separated by the arterial blood by the BBB.

Question 331

The BBB had poor ion permeability so how do the central chemoreceptor neurons detect H+ ions?

Answer 331

Co2 is lipid soluble so can pass.

If high CO2, acidosis here.

Question 332

Why is there a larger change in CO2 In the CSF BECF than rest of body?

Answer 332

Fewer non-bicarbonate protein buffers to mop up H+ ions.

Question 333

For the same PH change, why does metabolic disorders change the PH less than that of respiratory diseases?

Answer 333

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.

Question 334

What are the two antagonistic neurotransmitters for the central chemoreceptors?

Answer 334

Acidic activated by Serotonin

Acid inhibited by GABA

Question 335

Within the normal oxygen range which central or peripheral jump in to respiratory acidosis?

Answer 335

Both but Periphery more- works faster (protein buffers etc)

Question 336

For respiratory acid/base changes how do the peripheral and central chemoreceptors respond?

Answer 336

Hyperventilation if severe acidosis, peripheral for acute response and central for longer term

Question 337

What is the only 2 ways that the PH can actually change in the long term?

Answer 337

HCO3- handling in proximal cells then either;
Urine acidification
Ammonia synthesis

Question 338

How can the proximal cells buffer PH?

Answer 338

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)

Question 339

How does ammonia synthesis work?

Answer 339

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)

Question 340

What is mostly used ammonia synthesis or Urine acidification?

Answer 340

Ammonia synthesis 75%

Question 341

How does Urine acidification work?

Answer 341

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.

Question 342

Renal (and respiratory) compensation for the 4 types of acid/alkali problems?

Answer 342

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

Question 343

What can cause the 4 types of acid/alkali problems?

Answer 343

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.

Question 344

What if have mixed acid/alkali disorders?

Answer 344

If different- cancel each other mild problems, but if opposite are additive so can be life threatening.

Question 345

Example of 3 subtractive mixed disorders?

Answer 345

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.

Question 346

Example of 1 additive disorder?

Answer 346

Asthma- respiratory acidosis (high CO2) and lactic acidosis due to lack of O2 so met acidosis

Question 347

What are the two routes of administration for chemical general anaesthetics?

Answer 347

1. Inhilation e.g. NO

2. Intravenous e.g. barbiturates, steriods, halogenated hydrocarbons

Question 348

There is no obvious link between structure and function for how efficient a general anasthetic is, but what is important?

Answer 348

Lipid solubility: the higher, the less is needed.

Question 349

What is the parameter used to show how much of a drug is needed (vs solubility)?

Answer 349

MAC value- Minimal Alveolar Concentration to abolish response in 50% of patients to surgical incisions.

Question 350

What are two examples of physical anaesthetics?

Answer 350

Low atmospheric pressure, hypothermia

Question 351

What is the Meyer-Overton Rule?

Answer 351

Regarding general anaesthetics, that the drugs effect is directly proportional to the lipid solubility

Question 352

What three factors supported the lipid theory of GA, what four disputed?

Answer 352

+ 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

Question 353

What was the Lipid Expansion theory of GA?

Answer 353

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.

Question 354

What is the protein theory for GA?

Answer 354

GA regulate activities of neuronal ion channels. (different GA interract with different ion channels)

Question 355

Where does Ketamine bind?

Answer 355

Blocks NMDA receptors

Question 356

Where do many GA bind? How do the volatile and intravenous differ from each other?

Answer 356

GABA A
Volatile alpha and Beta subunits
Intravenous only Beta

Question 357

What are the effects of GA on neurotransmission? At low conc, at high?

Answer 357

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

Question 358

What are the 4 stages of Anaesthesia?

Answer 358

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)

Question 359

3 Advantages and 4 disadvantages of intravenous anaesthetics?

Answer 359

+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

Question 360

How can the effects of an intravenous anasthetic be prolonged?

Answer 360

Using a inhaled GA, do doesnt drop below threshold for conciousness but flatlines.

Question 361

2 advantages and 2 disadvantages to inhalation anasthetics?

Answer 361

+ 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.

Question 362

Lean tissue has fast/slow perfusion, rapid/slow equilibriation and high/low partition co-efficient?

Answer 362

Fast, rapid, low (how much can dissolve here)

Opposite for fat- but can get stuck there.

Question 363

What is the big risk with GA’s? Symptoms?

Answer 363

Malignant hyperthermia can be triggered by Halogenated GA’s.
Have to monitor patients, check temp isn’t rising, tachycardia, hypertension,increase muscle contraction.

Question 364

Why is ketamine a GA?

Answer 364

sensory loss, amnesia, but no respiratory depression or complete loss of conciousness.

Question 365

Ketamine symptoms?

Answer 365

hallucination, CV excitement, involuntary movement, irrational behaviours on recovery

Question 366

What is Liddle’s syndrome?

Answer 366

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.

Question 367

In liddle syndrome why is there a gain of function of EnaC?

Answer 367

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.

Question 368

Why is there hypokalaemia with Liddle syndome?

Answer 368

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.

Question 369

What is the mutation in Liddle EnaC channel?

Answer 369

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.

Question 370

Why is there metabolic Alkalosis in Liddles?

Answer 370

Na reabsorbed so more positive tissue fluid in kidney, which drives the loss of H+ ions, so metabolic alkalosis.

Question 371

What is a treatment for Liddles syndrome?

Answer 371

Amiloride- blocks ENaC.

Question 372

What causes diabetes insipidus?

Answer 372

Lack of Vaspopressin or irresponsiveness to, so few AQP2 (P by PKA) on apical so less water reabsorbed. This causes Polyuria with polydipsia.

Question 373

What are the 4 types of diabetes insipidus?

Answer 373

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

Question 374

How can central diabetes insipidus be got?

Answer 374

Aquired: Infection, headtrauma, surgery
Congenital: Neurohypophyseal diabetes insipidus mutation in site important for transport from hypothalamus to pituitary

Question 375

How can nephrogenic diabetes insipidus be brought on

Answer 375

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)

Question 376

Treatment for central diabetes insipidus?

Answer 376

v easy- Desmopressin nasal spray-agonist at the vasopressin receptor

Question 377

Treatment for nephrogenic diabetes insipidus?

Answer 377

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

Question 378

If there are central nervous system channelopathies what can the result be?

Answer 378

Episodic Ataxia and epilepsy.

Question 379

What is episodic ataxia? symptoms?

Answer 379

irregular uncontrolled muscle contractions

Shakes, trunk instability, nausea, nystagmus- flickering eyes, visual blurring headache, look drunk

Question 380

What causes type 1 episodic ataxia?

Answer 380

Mutation in KCNAI mutation- Kv at neuromuscular junction in cerebellum
Autosomal dominant, symptoms showing 10-20 with brief attacks

Question 381

What causes type II episodic ataxia?

Answer 381

Mutation in CACNA1A Cav, autosomal dominant, attacks lasting 30mins to 24hrs. Onset child-teens

Question 382

Type 1 ataxia triggers for attack?

Answer 382

stress emotional or physical (leicester football club)

sudden vestibula system change e.g stand up fast

Question 383

Mutation for the type 1 ataxia details?

Answer 383

Loss of function Kv, so increase in excitability in cerebellum, control of movement not as good.
current massively lower voltage than WT.

Question 384

Treatment for type 1 episodic ataxia?

Answer 384

Phenytoin and Carbamazpine Nav inhibitors

Question 385

Type II episodic ataxia mutation?

Answer 385

Cav channel CACNA1 A in cerebellum also.

Mutations largely on the pores, point mutation often or truncation with more severe symptoms.

Question 386

2example of Type II ataxia mutations?

Answer 386

Familial hemiplegic migraine- misense

Spinocerebellar ataxia- repeat expansion of C terminus

Question 387

What can be really bad with ataxia? especially type II?

Answer 387

Neurodegeneration of cerebellum often kills

Question 388

Details on CACNA1A:where and mechanism?

Answer 388

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

Question 389

CACNA1A K/O mouse?

Answer 389

Upto 10days it’s normal, mimics onset in humans 10. Then, balance problems, ataxia, death 3-4weeks

Question 390

How can one see experimentally that there is a reduction in the calcium currents in type II ataxia?

Answer 390

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.

Question 391

What does the CACNA1A mutation do to the threshold?

Answer 391

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.

Question 392

Treatment for episodic ataxia type II?

Answer 392

Acetazolamide, carbonic anhydrase inhibitor. (so less CO2 and H20 converted to carbon acid, so increases Calcium in cells)

Question 393

4 causes of epilepsy?

Answer 393

Brain trauma, infection (e.g. Meningitis), inherited cause-mutation, tumors

Question 394

what are the two types of two versions of epilepsy? MOst serious?

Answer 394

Partial vs Generalised - depending on how widespread in brain the discharge is
Simple or complex- complex if loss of conciousness

Generalised complex most serious

Question 395

Why can epilepsy occur?

Answer 395

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)

Question 396

Role of GABAA vs ACH R on a post synaptic neuron? HCN?

Answer 396

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)

Question 397

Example of a loss of Inhibiton causing epilepsy?

Answer 397

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

Question 398

Example of a gain of exciatory mutations causing epilepsy? Loss?

Answer 398

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.

Question 399

Structure of a Nav channel?

Answer 399

4 subunits each with 6TMD so 24 in total- 6 pore regions and 4 voltage sensors.

Question 400

Nav 1.1 K/O?

Answer 400

A.P firing reduced of inhibitory neurons, excess electrical discharge= epilepsy seizures.

Question 401

Nav 1.7 mutation in PNS sensory neurons?

Answer 401

loss of function-don’t feel pain
Gain of function- pain without trigger chronic
Polymorphisms of this channel give pain threshold

Question 402

What is generalised anxiety?

Answer 402

No clear reason, symptoms interfer with normal life, longer than 2 weeks

Question 403

Other anxieties that aren’t general? (4)

Answer 403

PTSD, OCD, Phobias, Panic disorder

Question 404

Animal model to test anxalitic drugs?

Answer 404

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

Question 405

Example of a common anxalitic drug?

Answer 405

Benzodiazepine e.g. Diazepam/ Valium (also sedative)

Question 406

Treatment prescribed for short term anxiety e.g. for an exam?

Answer 406

Beta blockers, slow heart rate etc by blocking so inhibiting sympathetic nervous system. (B adrenergic blocker)

Question 407

function of GABA A receptor?

Answer 407

Inhibitory- Ionotropic, found post synaptic reduces excitability e.g. hyperpolarising by Cl- in.

Question 408

Structure of the GABA A receptor?

Answer 408

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.

Question 409

Orthosteric vs allosteric site?

Answer 409

Allosteric is a regulation site for the orthosteric active site, needs a ligand bound to orthosteric for a response.

Question 410

Drugs that can bind to GABA A allosteric site?

Answer 410

Agonist: Diazepam
Antagonist: Flumeazenil (not v zen(may get ill) if go down a flume Flume-a-zen-il

Question 411

Drugs that can bind to GABA A orthosteric site?

Answer 411

Agonist: muscimol, GABA
Antagonist: (competitive) Picrotoxin, bicuculline

Question 412

Three other types of drugs that can bind to GABA A receptors to regulate?

Answer 412

Barbiturates, neurosteroids, general anaesthetics, sedatives, anti-convulsants, hypnotics, ethanol

Question 413

GABA B characteristics?

Answer 413

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.

Question 414

Agonist and antagonist at GABA B?

Answer 414

Agonist – baclofen

Antagonist - Phaclofen

Question 415

What gives GABA A the huge variety?

Answer 415

2a, 2B, Y - can have many subunits come together e.g. a1, a2 etc

Question 416

How did Marlyn Monroe die?

Answer 416

Overdose of Diazepam with vodka- summates with the action of other drugs e.g. ethanol

Question 417

Physiological effects of Benzodiazepine?

Answer 417

Anxiolytic, Sedation,
Hypnosis- and amnesia e.g. Rohypnol
Anticonvulsant- Muscle tone reduction

Question 418

Benzodiazepines work at which site?

Answer 418

Allosteric site of GABA A receptor, increasing the inhibition of CNS.

Question 419

How does Benzodiazapine increase activity of the receptor it binds to? How can tell? vs Barbiturates?

Answer 419

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.

Question 420

WHat is the risk of Barbiturates?

Answer 420

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

Question 421

How does the half life dictate the pharmalogical use?

Answer 421

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)

Question 422

Adverse affects with Benzodiazepine?

Answer 422

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)

Question 423

What does tolerance mean?

Answer 423

Reduced effectiveness over time, body needs more and more to have the same response.

Question 424

Withdrawal symtoms of Benzodiazepine?

Answer 424

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.

Question 425

Other Anxiolytics?

Answer 425

Newer receptor selective benzodiazepine agonist, which removes the side effects as more selective.
Buspirone- 5HT receptor agonist

Question 426

Mutation in voltage gated sodium channel can cause?

Answer 426

Familial epilepsy.

Question 427

What are the three different seizure types that can be seen on an ECG?

Answer 427

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.

Question 428

What can trigger an epileptic seizure?

Answer 428

altered blood glucose, flashing lights, stress, fatigue, ‘aura’ when about to happen.

Question 429

Why is Treatment for epilepsy so importnt?

Answer 429

As the extra Ca release can induce apoptosis in cells leading to cell death,

Question 430

What is a treatment for epilepsy?

Answer 430

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.

Question 431

How can the GABA NT be increased for epileptic people?

Answer 431

Uptake inhibitors e.g. Tiagabine
Metabolic inhibitors e.g. Vigabatrin (problem: depression), Valproate (problem: affect foetus growth, occasionally toxic also can improve mood)

Question 432

How are Na channel blockers used for epilepsy?

Answer 432

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

Question 433

Hw is Vigabatrin thought to work?

Answer 433

Inhibit the breakdown of GABA to Succinate by use of a suicide inhibitor to GABA Transaminase.

Question 434

How is Valproate thought to work?

Answer 434

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.

Question 435

How do 2 Ca channel blockers work for epilepsy?

Answer 435

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.

Question 436

New antiepileptic drug Levetricetam?

Answer 436

Decreases glutamate in vesicles of the excitatory neurons, so reduces.

Question 437

Bipolar disorder vs unipolar depression?

Answer 437

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

Question 438

Depression symptoms:

Answer 438

Anhedonia: Low mood
Apathy: loss of interest in daily activities
Weight flunctuations, low esteem
sleep disturbances- insomnia or excessive
diminished concentration

Question 439

Depression risk factors?

Answer 439

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

Question 440

Effects of depression?

Answer 440

1/6 USA

15-30% people commit suicide, greater risk than heart disease etc

Question 441

What features in the brain are implicated in those with depression?

Answer 441

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

Question 442

What is post- natal depression?

Answer 442

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.

Question 443

Model on rodents to demonstrate acute stress? (2 experiments)

Answer 443

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

Question 444

Model on rodents for chronic stress?

Answer 444

Hate being immobile- if force for 2 weeks, cortisol levels increase - chronic stress
- Epigenetic changes

Question 445

Causes of depression in body?

Answer 445

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

Question 446

HIgh levels of glutamate leads to?

Answer 446

to NMDA receptors causing neural apoptosis (depression)

hence why ketamine (antagonist) reduces symptoms of depression

Question 447

High stress and cortisol mechanism?

Answer 447

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)

Question 448

Low BDNF levels leads to? What two other amines?

Answer 448

If high levels of BDNF to Trk B= beneficial gene transcriptional response = neurogenesis
If low, detrimental = neural apoptosis= depression

Same with 5HT and NA

Question 449

Summary of levels of hormones/ NT etc that lead to depression?

Answer 449

High glutamate, High cortisol
Low BDNF, Low 5HT, Low NA
all = neural apoptosis= depression

Question 450

What two drugs lead to observations that caused the monoamine theory of depression?

Answer 450

Reserpine- causes deplacement in the vesicles of monoamines= depression
Whereas,
Iproniazid- MAOI- Monoamine oxidase inhibitor, if stop breakdown there longer= antidepressant

Question 451

How do SSRI help with depression?

Answer 451

e.g. Fluoxetine-
Selective serotonin Inhibitors
block transporters so serotonin is available for longer- stimulate receptors more, so reduce neural apoptosis.

Question 452

What are the three uptake inhibitors which help with anti depression?

Answer 452

SSRI’s- serotonin
Classical tyricyclic antidepressants- both serotonin and NA
MAOI ‘s- Serotonin and NA

Question 453

Probelm with MAOI’s?

Answer 453

(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.

Question 454

While the biochemistry for antidepressents takes place after …. it takes … for mood to improve

Answer 454

immediately
3-4 weeks
suggest regulatory involvement.

Question 455

How does the tricyclic classical antidepressants work? Side effects?

Answer 455

Inhibit uptake of serotonin and NA, 
Anti-cholinergic side effects: dry mouth, blurred vision, constipation. 
Adrenergic side effect: hypotension, 
Histminergic: sedation
Also, dangerous overdose.

Question 456

Noradrenaline used for in the CNS? Depression link?

Answer 456

Pain, arousal, mood, blood pressure regulation, withdrawal, sleep, anorexia
Deficiency can = depression
NARI (NA Reuptake Inhibitors) help reduce.

Question 457

Synthesis of Noradrenaline?

Answer 457

Tyrosine- Dopa- Dopamine in vesicles- Noradrenaline (-Adrenaline)

Question 458

Noradrenaline action is stopped by what? (3)

Answer 458

COMT ( breaks down in synapse and pre) , MAO, reuptake inhibitors

Question 459

How are Noradrenaline and serotonin linked? (receptors)

Answer 459

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.

Question 460

How are the alpha 2 receptors linked to depression?

Answer 460

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.

Question 461

Use of Serotonin in the CNS?

Answer 461

Hallucinations, sleep, mood, emotion, feeding, vomiting, nociception

Question 462

Where is the main loci for serotonin?

Answer 462

Raphe nuclei- sends to the limbic, relating to Anhedonia- unable to feel pleasure for normally enjoyable experiences.

Question 463

Drugs acting on serotonin are used for?

Answer 463

Antidepressents, anxiety, migraine, chemotherapy, antipsychotics.

Question 464

Serotonin is synthesised from which amino acid?

Answer 464

Tryptophan (from diet so limited by intake and enzyme tryptophan hydroxylase)

Question 465

Serotonin is stopped by what?

Answer 465

Serotonin reuptake transporters (SSRI targets)

MAO

Question 466

Why is there a lag time between SSRI’s woking and feeling no better?

Answer 466

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.

Question 467

How are serotonin and BDNF linked? Sequence

Answer 467

Serotonin-Gprotein receptor Gs- ATP to cAMP- PKA- activation of CREB-1 - Increased production of BDNF

Question 468

What does BDNF do?

Answer 468

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)

Question 469

Summary NA: Serotonin: BDNF

Answer 469

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)

Question 470

What drug can be used to treat bipolar disease?

Answer 470

Lithium- permeates through Na channels- Affects ATK, Glycogen synthase kinase involved in apoptosis

Question 471

DNA methylation vs acetylation? (depression?)

Answer 471

Methylation-decrease transcription
Acetylation- Increase transcription

E.g. BDNF- increased or decreased transcription

Question 472

How can electroconvulsive therapy work for depression?

Answer 472

Can change neuronal circuits, and normalise circadium rhythms. Upregulate serotonin receptors.

Question 473

Schizophrenia, what is the NT involved?

Answer 473

Dopamine imbalance (too high to D2 receptors)

Question 474

What is schizophrenia?

Answer 474

Disturbances in perception, attention, thought, emotion, motor behaviour, hearing voices, paranoia, lack of energy, Anodonia, blunting of emotion
10% end in suicide

Question 475

Amphetamine, cocaine, opiates usually target what NT?

Answer 475

Dopamine.

Question 476

Function of dopamine?

Answer 476

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

Question 477

Structural difference between brain in schizophrenia and normal?

Answer 477

Larger ventricles in Schizophrenia, and smaller tissue volume in the L temporal lobe. High DA= positive schizophrenia.

Question 478

High dopamine? Low?

Answer 478

low= Parkinsons ADHD, Drug dependance addictive personality
high= Schizophrenia,

Question 479

Dopamine broken down by?

Answer 479

MAO, COMT,

Question 480

How do cocaine and Amphetamines affect amines?

Answer 480

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

Question 481

What kind of drugs are used to treat Narcolepsy and ADHD? Why?

Answer 481

Amphetamines, increase NA, but also DA- can cause hyperactive children

Question 482

Mice lacking the D1 receptor are insensitive to…

Answer 482

Cocaine and amphetamines (Dopamine)

Question 483

What drugs can induce psycotic symptoms?

Answer 483

Ketamine- to NMDA (glutamate also involved)

Question 484

Causes of schizophrenia?

Answer 484

Genetic, changes in early brain development, envirnmental e.g. Cannabis use

Question 485

Treatment of Schizophrenia?

Answer 485

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

Question 486

D2 receptors are…, whereas D1..?

Answer 486

D2= Gi
D1= Gs
Need to target D2.

Question 487

Many myofilaments make up a …many of these make a …. etc

Answer 487

Sarcomere- myofibrils-fibres (motor unit)-fasicle- muscle

Question 488

The more motor units the more/ less graded the response?

Answer 488

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.

Question 489

Structure of the Ach R?

Answer 489

2A, B, Y, delta.
2 binding sites for Ach- 2 have to bind to open channel.
Non selective cation channel- depolarisation.

Question 490

What is myotonia?

Answer 490

Hyper-excitability of skeletal muscle as AP are too long, increases contraction causing muscle stiffness.
Delayed reactions, and myotonic seizures.

Question 491

What causes myasthenia Gravis?

Answer 491

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.

Question 492

What are the symptoms of Myasthenia Gravis

Answer 492

Weakness and tiredness in skeletal muscle- can be fatal as respiratory failure.

Question 493

Treatment for myasthenia Gravis?

Answer 493

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.

Question 494

How is calcium transported out of the Sarcoplasmic reticulum to T-tubules?

Answer 494

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.

Question 495

How is Calcium reuptaken from the cell membrane?

Answer 495

Calcium, hydrogen exchanger.

Ca ATPase. Ca in for H out

Question 496

How is calcium reuptaken from the sarcoplasmic reticulum? Stored?

Answer 496

Calcium ATPase, Ca in for H out

Calsequestrin stores calcium.

Question 497

What mutation causes myotonia Congenita?

Answer 497

CLC1 loss of function, decreases the Po (for a given voltage as increases with it)

Question 498

Two types of Myotonia congenita?

Answer 498

Thomsens autosomal dominant- less severe

Beckers autosomal recessive- carriers asymptomatic

Question 499

Fainting goats have…?

Answer 499

Myotonia Congenita ClC1 mutation

Question 500

Myotonia Congentia symptoms?

Answer 500

May spotenously collapse

Question 501

If Myotonia Congentia is loss of function of… what will happen to the membrane potential? Therefore?

Answer 501

ClC1- Nernst -70, so membrane will increase, nearer to threshold. Therefore more skeletal muscle contraction.

Question 502

Treatment for Myotonia Congenita?

Answer 502

Mexilitene blocks some of the Na channels so decreases sponatneous contractions.
Use muscles a lot.

Question 503

Cause of Paramytonia?

Answer 503

Nav 1.4 gain of function

Na not blocked by inactivation gate, so open for longer- depolarise more so K sruggle to repolarise.

Question 504

What triggers Paramytonia?

Answer 504

Cold- normally slows everything down so will increase Na levels slightly but in these people does significantly.

Question 505

WHat is malignant hyperthermia?

Answer 505

Autosomal dominant, abnormal response to Halothene GA- Death rate 80%.
Different mutations, one being gain of function Ryanodine Receptor– release Calcium (contraction)

Question 506

Symptoms of Malignant hyperthermia?

Answer 506

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)

Question 507

What do people with Malignant hyperthermia die of?

Answer 507

Repiratory acidosis and Lactic acidosis (additive)

This is due to high CO2 and muscle rigidity so lactic acid build up as contracting.

Question 508

Malignant hyperthermia in pigs?

Answer 508

Pigs with big muscle mass selected for but unknown because of a mutation so the incidence increased in pigs

Question 509

Triggers for Malignant hyperthermia?

Answer 509

Halothene, also caffeine v high conc, (also affect WT ryanodine receptors but at much higher concentrations that in mutation)

Question 510

How to treat Malignant hyperthermia?

Answer 510

Dantrolene- inhibits RyR1 channels.
Diuretics to get halothene out body.
NaHCO3 to counterract acidosis.
Mechanically ventilate to get rid of Co2

Question 511

What is pain?

Answer 511

Unpleasant sensory and emotional experience associated with actual or potential tissue damage

Question 512

Sequence of how we sense pain?

Answer 512

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.

Question 513

Pain involves…

Answer 513

the brain

Question 514

What do DRG neurons do?

Answer 514

Contains cell bodies of sensory neurons, conveys sensory info from the periphery to the spinal cord. Spinal/cranial ganglia collect info.

Question 515

Example of 2 diseases where individuals experience extreme pain?

Answer 515

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.

Question 516

Example of a disease where individuals experience no pain?

Answer 516

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.

Question 517

Acute pain?

Answer 517

alerts body to chemical, thermal or mechanical stimuli that could cause damage

Question 518

Chronic pain?

Answer 518

1. Inflammation e.g. Rheumatoid Arthritis

2. Neuropathic pain from damaging nerves e.g. diabetes, trauma, cancer treatment, herpetic infection

Question 519

Economic cost of chronic pain?

Answer 519

USA- $600 billion annually- 50% healthcare, 50% loss in productivity.
$300 billion across Europe (around x3 cancer)

Question 520

What is Analgesia?

Answer 520

Loss of pain without loss of consciousness

Question 521

Where do analgesics work?

Answer 521

at nociceptors, dorsal horn or brain, but issue when in area of multiple function e.g. the brain

Question 522

2 types of Analgesics?

Answer 522

Non-steroidal anti-inflammatory drugs NSAIDS- ibuprofen, aspirin
Opioids- morphine, fentanyl

Question 523

What is the major side effect to NSAIDS?

Answer 523

Increased risk of GI problems e.g. ulcering, bleeding and perforating stomach etc, because inhibits COX-1 cytoprotective prostaglandins.

Question 524

What is the major cause of death from opioid overdosing? 2 other side effects?

Answer 524

Depression of the respiratory system, combined with alcohol v dangerous.
sedation- apathy and cognitive impairment, inhibit GI tract.

Question 525

What are the 4 types of opioid categories how found/made?

Answer 525

Natural opioids- morphine, codeine, dermorphine
Semi-synthetic- heroin,
fully synthetic- fentanyl
Endogenous opioid particles- endorphins, enkephalins, endomorphins, dynorphins

Question 526

How are natural opioids made?

Answer 526

Dried juice of seeds of poppy flower =opium. Contains morphine 10% which can be extracted.

Question 527

Morphine binds to? How does it work as an analgesic?

Answer 527

Opioid receptors, G protein coupled R leads to inhibition of calcium influx, reducing the amount of NT released across synapse from central nerve.

Question 528

Types of opioid receptors?

Answer 528

Mu, Kappa, Delta

Mu- concentrated in dorsal horn receiving inputs from DRG neurons.

Question 529

Dermorphin found? Bind to? why effective?

Answer 529

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.

Question 530

Why was heroine synthesised after finding morphine?

Answer 530

Wanted to find a less addictive versio but it actually crosses 100x faster, and is highly addictive. Was originally marketed as a cough medicine.

Question 531

What are the three stages in analgesia?

Answer 531

Transduction- convert stimulus into ion flow
Conduction- along the nerve
Transmission- to central terminals in SC

Question 532

Fentanyl use?

Answer 532

Used as analgesic for surgery, 100x more potent than morphine.

Question 533

Where are opioid receptors normally found?

Answer 533

CNS- endorphins, endogenous encephalin, dynophorins bind, released during stress or prolonged exercise.

Question 534

What are endogenous opioids degraded by?

Answer 534

extracellular proteases hence short pain release only.

Question 535

New approaches to analgesics?

Answer 535

Block the sodium channels that allow the conduction of pain signals.

Question 536

How does Botulism neurotoxin work as an analgesia?

Answer 536

Blocks NT release for several months by cleaving SNAP 25 protein (SNARE protein bringing vesicles to PM)

Question 537

How are monoclonal antibodies used as an analgesia?

Answer 537

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.

Question 538

What is tetrodotoxin?

Answer 538

TTX- 10-100x more lethal than black widow spider, 10,000x than cyanide.
nm levels needed.

Question 539

Where is tetrodotoxin found?

Answer 539

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.

Question 540

Symptoms of puffer fish ttx poisoning?

Answer 540

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.

Question 541

Symptoms of ttx poisoning bite?

Answer 541

Faster time to death than eating puffer fish,

same symptoms but not facial but local to the bite area.

Question 542

How to treat ttx poisoning?

Answer 542

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

Question 543

How does TTX cause its toxicity?

Answer 543

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.

Question 544

How does TTX cause its toxicity? binds?

Answer 544

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.

Question 545

What other toxins can bind at the NMJ as well as tetrodotoxin?

Answer 545

Nav pre: Tetrodotoxin, saxitoxin
Cav pre: Conotoxin
Kv pre: Dendrotoxin
Ach vesicles: Botulism, tetanus toxin
Nav post: TTX, Saxitoxin, conotoxin

Question 546

WHat determines whether a channel is sensitive to TTX or not?

Answer 546

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.

Question 547

Example of an AA change in species that determines whether find TTX toxic?

Answer 547

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.

Question 548

What is dendrotoxin?

Answer 548

in snake venom.
inhibt Kv channels- repolarisation
Think (dendrites toxin)

Question 549

Symptoms of dendrotoxin?

Answer 549

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.

Question 550

What is Conotoxin?

Answer 550

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

Question 551

symptoms of conotoxin?

Answer 551

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