BMS235 Physiology and Pharmacology Flashcards

Question

What is the difference between the patch clamp method and the traditional intarcellular method?

Answer 1

The tip of the electrode in the patch clamp method is 1x10^-6 but in the traditional method the tip is much smaller

Answer 2

- It directly contributes 20% of the membrane potential due to its electrogenic nature - It also indirectly contributes to the intracellular Na+ K+

Answer 3

- K+ moves out of the cell due to the concentration gradient leaving a negative charge inside the cell - This produces a potential gradient going the opposite way (Positively charged K+ ions will travel down gradient back to negatively charged inside of the cell) - Eventually the concentration gradient and potential gradients are equal so K+ movement in both directions are equal => no net movement of K+ ions

Answer 4

Elon = 61/Z x log (5/150)

Answer 5

Because it is never just one type of ion channel open e.g. K+ and Na+ channels will be open so Nernst equation for just K+ won be accurate

Answer 6

- Na+ moves into cell down its concentration gradient leaving a positive charge - Na+ then repels the positive charge so creates a driving force going the opposite way - Eventually movement of Na+ becomes equal in both directions so no net movement

Answer 7

Membrane potential for Na+ is +64mv but resting potential is -70mv suggesting Na+ channels are closed Membrane potential for K+ is -90mv suggestion that K+ channels are open

Answer 8

Vm = 61/7 log (PNa[Na+]o + Pk[K]o) / (PNa[Na]I + Pk[K+]I)

Answer 9

Na+K+ ATPase

Answer 10

- Massive opening of Na+ channels driving membrane potential towards nernst potential for Na+ (depolarisation) - Na+ channels close driving Vm towards nernst potential for K+ (hyper polarisation)

Answer 11

Extracellular - 145mM | Intracelular - 15mM

Answer 12

- Thick ascending limb - NaK2Cl cotransporter uses the Na+ gradient produced by the Na/K ATPase - Excitable cells - Na+ ions move into the cell down the concentration gradient causing depolarisation

Answer 13

- Requires 1 ATP molecule - ATP phosphorylates the pump leading to a conformational change, changing the binding site for Na+ releasing it - K+ then binds causing dephosphorylation and a structural change causing the release of K+ inside the cell

Answer 14

Because it has a maximum rate | Saturable function of [Na]I[k]o and ATP

Answer 15

Glycosides - ouabain and digoxin

Answer 16

- Electrogenic transport of 3Na+ out and 2K+ in - make cell more negative - Accumulation of K+ inside the cell creating a driving force for K+ to leave the cell through K channels

Answer 17

Extracellular - 1mM | Intracellular - 100nM

Answer 18

It acts as an important second messenger in many signalling pathways e.g. Muscle contraction

Answer 19

To provide a huge gradient for quick calcium entry

Answer 20

Na/Ca exchanger | CaATPase

Answer 21

Exchanges extracellular Na for intracellular Ca | It keeps intracellular so low by exchanging 1Ca for 3Na - electrogenic

Answer 22

3Na+:1Ca2+ Because if the Na gradient was 10 fold but Ca 10000 then intracellular Ca would not be kept low if the exchanger was 1:1. Therefore 3Na means that the effect of the 10 fold gradient is cubed

Answer 23

- They are members of the SLC8 gene family and the much larger CaCA superfamily - Three forms exist in mammals names NCX1-3

Answer 24

- Member of the P-type ATPase family which also includes Na/K pump - Also pump protons in the opposite direction at the same time as transporting Ca2+

Answer 25

PMCA - plasma membrane calcium pumps SERCA - Ca pumps found on the sarcoplasmic and endoplasmic reticulum membranes SPCA - Ca pumps found o the Golgi apparatus

Answer 26

Act to pump Ca2+ across the plasma membrane out of the cell

Answer 27

Act to pump Ca2+ out of the cytoplasm into the organelles which act as calcium stores

Answer 28

Transport Mn2+ as well as Ca2+

Answer 29

1. Voltage operated Ca Channels (VOCC) 2. Receptor operated Ca channels (ROCC) 3. Mechanically activated Ca Channels - found in many cells respond to deformation (e.g. stretch activated channels) 4. Store operated Ca Channels (SOCC)

Answer 30

Found in excitable cells and activated by depolarisation

Answer 31

Found in secretory cells and nerve terminals and are activated by the binding of an agonist e.g. NMDA receptor

Answer 32

Found in many cells and respond to deformation eg. stretch activated channels

Answer 33

Activated following he depletion of calcium stores

Answer 34

- IP3 receptors | - Ryanodine receptors

Answer 35

A class of calcium channel in store membranes that is activated following the binding of IP3. This type of receptor is expressed in most cell types

Answer 36

A class of calcium channel found in store membranes that are activated by low concentrations of Ryanodine and inhibited by higher concentrations. - Found in excitable cells - Also stimulated by caffeine and cADP ribose

Answer 37

- Phospholipase C (PLC) stimulates receptor in membrane forming DAG and IP3 - IP3 activates IP3 receptor channels in the stores releasing Calcium into the cytoplasm - Signalling also from the ER to Ca channel in membrane (SOCC) which activates store refill.

Answer 38

- When Ca2+ decreases in the store, the stim protein in the ER membrane senses this and undergoes a conformational change - It stretches and binds to other stim proteins forming an 8 unit complex which binds to the cell membrane - This interacts with ORAI1 causing Ca2+ to enter the cell - When this happens the circa pump is stimulated favouring Ca2+ uptake into ER

Answer 39

A Ca channel in the membrane involved in refilling the Ca stores - Tetramer like

Answer 40

pH = -log[H+]

Answer 41

``` plasma = 7.35-7.45 IC = 7-7.1 ```

Answer 42

Can cause change in protein charge, conformation or function e.g. Apical K+ channel ROMK is pH specific (activates when alkaline)

Answer 43

- Microelectrodes | - Fluorescent indicators

Answer 44

- Uses two ion sensitive micro electrodes where one measures the voltage of all ions and the other measures everything except protons - Take these voltages away to get the voltage of H+ - Calibrate electrodes with pH standards to work out what pH the voltage of H+ is proportional to - Convert voltage into pH

Answer 45

When the cells are big e.g. in the xenopus

Answer 46

A small molecule that allows pH in a cell to equilibrate to pH outside

Answer 47

- Cells loaded with a lipid soluble form of indicator - Inside the cell the indicator is lazed into an active form (Lipid insoluble) - Indicator is excited with light of a specific wavelength and the amount of emitted fluorescent light at a second wavelength is measured - Fluorescence is proportional to IC pH

Answer 48

- Calibrated inside the cell - membrane permeabilised with a proton ionopore - pH of ionopore bath is changed - In the presence of an ionopore bath the pH=IC pH

Answer 49

When the cells are small eg. kidney or cardiac

Answer 50

- Buffering - Acid extrusion - Acid loading

Answer 51

To minimise pH changes and protect cells from damage | - Cant revers pH change or prevent pH changes

Answer 52

moderates the effect of acid/alkali by reversibly consuming or releasing protons

Answer 53

The amount of strong base that must be added to a solution in order to raise the pH by a given amount

Answer 54

When pH increases, the COOH group from the amino acid donates a H+ becoming COO- When pH decreases the amino acid gains a H+ on NH2 group becoming NH3+

Answer 55

When pH decreases

Answer 56

- Na/H exchanger (NHE) pumps Na+ in and H+ out - set up Na+ gradient - When pH is more than NHE set point then the exchanger is inactive - Ca2+ binding to the c terminus of NHE stimulates acid extrusion

Answer 57

Protons other than the one being transported bind to the NHE protein leading to conformational change which increases the activity of the protein

Answer 58

Controls cell volume and regulates pH

Answer 59

low conc of amiloride and its analogue EIPA

Answer 60

- reduced pH as pH increases so does Cl/HCO3 exchanger activity - moves HCO3- out of the cell and H+ in (acidification) - has allosteric modification

Answer 61

- 4 subunits - all inhibited by stilbene derivative drug DIDS - independant of Na+

Answer 62

- Predominantly in red blood cells, some in kidney - responsible for chloride/hamburger shift

Answer 63

``` Inspiration = Patoms > Palv Expiration = Palv > Patmos ```

Answer 64

- Elastic recoil of tissues - Surface tension in alveoli - Airways resistance

Answer 65

Elastic nature of the lungs would tend to cause them to collapse inwards The chest wall would tend to expand - At rest these two forces balance - as a result the pressure in the intrapleural space is less than atmospheric pressure

Answer 66

The measure of elasticity | The ease with which the lungs and thorax expand during pressure changes

Answer 67

C = ΔV/ΔP

Answer 68

Pulmonary fibrosis - more work required to inspire - Decrease in FRC

Answer 69

Emphysema - difficulty when expiring - Increase in FRC

Answer 70

When the force of the lungs matches the expanding force of the chest wall Palv=Patoms

Answer 71

Forces favouring elastic collapse are low and forces on the chest favour expansion Overall system wants to expand

Answer 72

Forces favouring elastic collapse are high and forces on the chest favouring expansion are high Overall the system wants to collapse

Answer 73

- Anatomical component: Elastic nature of cells and extracellular matrix - Surface tension: generates elastic recoil at air fluid interfaces

Answer 74

Occurs at air water interfaces | - differences in forces on water molecules at this interface, surface tension develops

Answer 75

Laplaces equation | - P=2T/r

Answer 76

As explained in Laplaces equation - smaller alveoli are of a higher pressure than larger alveoli meaning air would move down the pressure gradient cause the small alveoli to collapse - It reduces surface tension on the alveoli

Answer 77

By type II pneumocytes

Answer 78

Lipids and proteins - 30-40% DPPC - 30-45% other phospholipids - 5-10% protein (SP-A, B, C and D) - Cholesterols

Answer 79

It is water soluble and has a role in innate immunity

Answer 80

Lipid soluble and speeds up formation of monolayer

Answer 81

Lipid soluble and speeds up formation of monolayer

Answer 82

Water soluble and has a role in innate immunity

Answer 83

- Density of surfactant determines rate of alveolar inflation - Decreases lung compliance - Prevents oedema - reduces fluid entering alveoli - Prevent over inflation

Answer 84

Type of air flow Resistance of the pathway Pressure gradients generated across the airways

Answer 85

Proportional to each other

Answer 86

Airflow is inversely proportional to the resistance

Answer 87

Laminar flow Turbulent flow Transitional flow

Answer 88

The steady flow sown a tube at uniform speed and direction | - Flow rate is maximal in the centre of the tube and reduces towards the edges

Answer 89

When the flow rate moves past a critical value and irregular currents (vortices) develop - Greater pressure gradient is required to obtain the same flow as seen under laminar conditions

Answer 90

Gas movement is proportional to the square root of the pressure difference

Answer 91

In the airways there is a high number of bifurcations (branches) the flow is disrupted causing eddies - Air flow changes between turbulent and laminar

Answer 92

Governed by Reynolds number Re = (2*radius*velocity*density of gas)/viscosity Re<1000 - Laminar flow Re between 1000 and 1500 - Unstable flow Re>1500 - Turbulent flow

Answer 93

Terminal part of the airways - by alveoli | - Because of velocity of air decreases and cross sectional area is high meaning Reynolds number will be as low as 10

Answer 94

Trachea - Velocity of air very high - Cross sectional area low

Answer 95

Determines the impact of resistance on airflow Airway resistance is proportional to gas viscosity and the length of the tube but is inversely proportional to the fourth power of the radius

Answer 96

yes big impact and hence flow rate

Answer 97

1.5cm H2O.s.litres-1

Answer 98

Pharynx - Larynx = 40% Airways>2mm diameter = 40% Airways <2mm diameter = 20%

Answer 99

5cm H20.s.litres-1

Answer 100

Pharynx - Larynx = 12% Airways>2mm diameter = 18% Airways <2mm diameter = 70%

Answer 101

Mucas secretion - Reduce airway diameter | Oedema - Fluid retention - narrow airways

Answer 102

Interplural pressure becomes more negative (-5 to -15cm H2O) Transmural pressure gradient decreases as it moves up from alveoli to trachea meaning that pressure increases to more than interplural pressure Airways expand and airflow increases

Answer 103

Interplural pressure increases to +10cm H2O Transmural pressure +15 in alveoli and increases up the trachea This makes positive pressure gradient from alveoli to atmosphere causing constriction and air to move out

Answer 104

Because the alveolar walls have broken down so have the risk of collapse Slow breathing reduces the effect of dynamic pressures making airway collapsing less likely - Also breath out through pursed lips to create a big resistance to slow airflow

Answer 105

- As lung volume decreases so does cross sectional area off airways causing increases resistance - Dynamic pressure effect causes constriction of airways - No matter how much effort required flow rate won't increase

Answer 106

When there breathing rate increases they are not able to bring enough O2 before their next breath due to decreased lung volume - Tidal volume decreases by as much as a half - Not enough O2 to reach metabolic demands

Answer 107

Heavily dependant on GPCR cascades - Gq pathway - Gs pathway - Gj pathway

Answer 108

Gq pathway

Answer 109

- Activation if alpha q unit of membrane receptor - Activates phospholipase C (PLC) - Causes increased production of IP3 - IP3 activates receptors in calcium stores in the ER moving calcium into the cytoplasm - Ca binds with calmodulin forming CaM complex - This complex phosphorylates MLCK acting on myosin and causing contraction of smooth muscle

Answer 110

When phospholipase C is activated it stimulates the breakdown of PIP2 and its conversion to diacylglycerol (DAG) DAG stimulated protein kinase C This stimulates cell growth

Answer 111

- M3 muscarinic receptors - H1 histamine receptors - BK bradykinin receptors

Answer 112

- Alpha s subunit is activated by GTP - This stimulates adenylate cyclase producing CAMP - Stimulates protein kinase A - Protein kinase A phosphorylates IP3 receptor inhibiting it and therefore promoting relaxation - Protein kinase A also phosphorylates MLCK reducing its action - It also phosphorylates MLCP stimulating phosphatase promoting relaxation of muscle fibres - Alpha s subunit interacts with K channels in membrane increasing the efflux of K+ causing hyperpolarisation - This reduces Ca influx through voltage gated calcium channels promoting relaxation

Answer 113

Reduction of gene activation an cell growth

Answer 114

- Phosphorylates IP3 receptor inhibiting its action - Phosphorylates MLCK stopping it from phosphorylating myosin - Phosphorylates MLCP promoting phosphatase, dephosphorylating myosin promoting relaxation

Answer 115

- Stimulates adenylate cyclase producing CAMP stimulating protein kinase A - It also interacts with K channels in the membrane increasing the efflux of K+ causing hyperpolarisation reducing Ca influx through voltage gated calcium channels

Answer 116

B2 adrenergic receptors | VIP receptors

Answer 117

Oppose the action of the Gs pathway

Answer 118

Activation of the Gi receptors inhibit adenylate cyclase stopping the production of CAMP and stimulation of protein kinase A - Has a knock on effect which counteracts the stimulators effect of Gs activation - Opposes the relaxation of smooth muscle - Also inhibits BK channel

Answer 119

M2 muscarinic receptors

Answer 120

Autonomic nervous system - Parasympathetic and sympathetic Humoral factors - Epinephrine and histamine

Answer 121

Acetyl choline released from postganglionic vagus nerve stimulating M3 muscaranic receptors on airway smooth muscle causing contraction by the activation of Gq pathway

Answer 122

M2 receptors are present on the outer side of postganglionic nerve and are involved in a negative feedback loop - When M2 receptors detect Ach, it stops it release - Prevents overstimulation of airway

Answer 123

It is an agonist - leads to dilation of muscle

Answer 124

Its released during the inflammatory process and leads to constriction

Answer 125

Releases norepinephrine stimulation B2 adrenoreceptor on airway smooth muscle - Stimulates Gs pathway leading to relaxation - It changes the sensitivity of IP3 receptor so not as much calcium leaves the store

Answer 126

``` Atopic - Allergies, contact with inhaled allergens Non-atropic - Respiratory infections - Cold air - Stress - Exercise - Drugs ```

Answer 127

Movement of inflammatory cells into the airways, release of inflammatory mediators such as histamine and subsequent bronchoconstriction

Answer 128

If the FEV1 is lower then 80% of the forced vital capacity Overall vital capacity shouldn't change

Answer 129

Hypersensitivity of parasympathetic activity | - Decrease in neuronal M2 function - negative feedback loop not working - over stimulation of airway smooth muscle

Answer 130

- Change in M2 function is linked to eosinophils - They cluster around nerve fibres and release major basic protein (MBP) - MBP inhibited M2 receptors

Answer 131

Interferon causes down regulation of M2 gene expression | - hyperactivity of airway smooth muscle

Answer 132

``` B2 Adrenergic agonists - Salbutamol - short acting - Salmeterol with corticosteroids - long acting Anticholinergics - Block effects of Ach - Acts on M1 and M3 receptors - e.g.. tiotropium bromide Glucocorticoids - Anti inflammatory actions - e.g.. beclometasone - steroids ```

Answer 133

Basic respiratory rhythm is controlled by centres in the medulla

Answer 134

Essentially it is involuntary but can be altered consciously - Hyperventilation - Breath holding However these are overidden if required

Answer 135

Quiet inspiration | Not quiet expiration as that is just elastic recoil

Answer 136

Control of forced expiration (requires extra muscle groups) and forced inspiration

Answer 137

- Contains pace maker cells that are linked to control of breathing - Located near the ventral respiratory group - 12th cranial nerve (hypoglossal) sends inputs to diaphragm and muscles in chest wall to control inspiration

Answer 138

Because when brain slice were took, electrodes showed spontaneous bursts of action potentials which match activity shown in hypoglossal nerve

Answer 139

- Eupneic - Normal breathing rhythm - Sigh - increased level of activity - inhale more for a longer period of time - Gasp - often seen in hypoxic conditions - 'gasping for air'

Answer 140

All three patterns are generated from the same region of the brain and the same neurones but their inputs and modulation differs

Answer 141

Pacemaker cells and non pacemaker cells

Answer 142

- Regular spikes - Bursts which are linked to contraction of the muscles - depolarisation and therefore inspiration - A gap where cells depolarise and quiet expiration occurs (elastic recoil)

Answer 143

Sodium leak channel

Answer 144

- Contributes to the depolarisation phase

Answer 145

Breathing is irregular - mouse will stop breathing and then pant The nerve recording show very little burst in mutant but normal spikes and burst in wild type - Mimics what occurs in humans with CNS damage

Answer 146

[K+] has an important effect on resting potential | - increase in extracellular [K+] increases bursting pattern

Answer 147

- The persistent sodium current ( INaP) | - CAN cation current (ICAN)

Answer 148

- Neurones relying on ICAN for bursting are cadmium sensitive as cadmium blocks ICAN current - Neurones relying on INaP for bursting are cadmium insensitive

Answer 149

- Decreased O2 available - Cadmium sensitive bursting cells become inactive so rely on cadmium insensitive - Leads to basic gasping pattern of breathing

Answer 150

Increases the rate by shortening inspirations - inhibitory effect on inspiratry centre

Answer 151

Increases the depth and reduces the rate by prolonging inspiration - stimulates inspiratory centre

Answer 152

- Stops overinflation of the lungs - Negative feedback loop - Phrenic nerve causes contraction of diaphragm and lung inflation - Stretch receptors in lung cause vagus nerve to inhibit inspiratory centre

Answer 153

Central chemoreceptors | Peripheral chemoreceptors

Answer 154

Monitors conditions in the cerebrospinal fluid sensing CO2 and pH - Response to rise in CO2 so stimulation leads to ventilation

Answer 155

Located in the carotid body and aortic arch - Respond to an increase in CO2 and decrease in pH and O2 - Stimulation leads to ventilation

Answer 156

- Receptors - Enzymes - Transporters/carriers - Ion channels

Answer 157

Structure, pharmacology and signalling

Answer 158

Receptors show specificity in the classes of drugs that they recognise - no drug is completely specific

Answer 159

Structures are very similar but structure of the communication part (binding site) is slightly different - making finding specific drugs difficult

Answer 160

- Ligand gated - G protein coupled receptors - Kinase linked receptors - Nuclear receptors

Answer 161

Agonist + receptor ---> Drug receptor complex ----> active drug receptor complex ----> Response Its not enough for the drug and receptor to bind (affinity) it must also produce a conformational change (efficacy) causing a response

Answer 162

Efficacy induces a change that causes a response in the cell but affinity is just the likely hood that the drug and receptor will bind

Answer 163

High affinity for a drug means slow disassociation - dependant on structure of drug and receptor

Answer 164

No relationship between agonists and antagonists and affinity Antagonists may have a higher affinity than agonists and other way round

Answer 165

Proportion of receptors occupied will vary with drug concentrations

Answer 166

Number of receptors occupied/ total number of receptors | Varies between 0 and 1

Answer 167

Radio ligand binding assays | - Response and occupancy is not directly proportional so cannot rely on response to measure it

Answer 168

- Prepare cells or membranes that contain protein of interest - Aliquot out membranes onto filters - Add radio label at different concentrations and equilibrate - When equilibrated remove unbound drug by filtration - Rinse - Count radioactivity of filter

Answer 169

- Most ligands bind non specifically to tissue, filter paper, glass ect - Rinsing will not get rid of it all - use two test tubes where one measures specific and nonspecific binding of radioactive drug and other just non specific binding - Take them away from each other

Answer 170

- Starting material not 100% pure - drugs may bind to unwanted proteins - Drugs may enter fat (lipids) in plasma membrane

Answer 171

- Must be biologically active - Purity - e.g. no enantiomers - Radioactive - labelling- very high specific activity to allow low concentrations

Answer 172

- Tritium (3H) | - Iodine 125

Answer 173

- Labelled product indistinguishable from native compound - High specific activities can be obtained - Good stability - Long half-life (12.5 years)

Answer 174

- Specialised labs required | - Labelling is expensive and difficult

Answer 175

- If it has aromatic hydroxyl group can be incorporated at high specific activities - Iodination east in most labs and cheap

Answer 176

- More readily degraded - Biological activity of ligand can be reduced - Short half life (67 days)

Answer 177

To maintain the integrity of both ligands and binding sites

Answer 178

Range of 0.1-1mg membrane potential/ml with assay volumes of 0.25-1ml

Answer 179

Used to protect the tissue

Answer 180

Stop denaturation of receptor Stop enzymes from breaking down proteins as they are usually contained in lysosomes but they will have been disrupted during the process

Answer 181

- Filtration or centrifugation | - In solubized receptors - dialysis, column chromatography and precipitation is used

Answer 182

The rate of dissociation of ligand receptor complex | - Lower affinity (higher KD) requires faster more efficient separation

Answer 183

Scatchard plot - shows: - total bound - Specific binding - non specific binding

Answer 184

Semi logarithmic scale - because if drug had a low affinity it could not be represented on a linear scale axis Non specific binding only becomes a problem at a high concentration of ligand

Answer 185

Specific - total number of receptors in the tissue is limited Non specific is not saturable

Answer 186

It describes the relationship between receptor occupancy, affinity and drug concentration LR = RX/ X+KD

Answer 187

The dissociation constant - When 50% receptors are occupied by drugs the drug concentration is KD

Answer 188

Low KD - High affinity | High KD - low affinity

Answer 189

Effective concentration giving 50% of maximal response | - not 100% of receptors need to be occupied to give a maximum response (receptor reserve)

Answer 190

Not 100% of the receptors are occupied to give a max response Allows amplification of the signal

Answer 191

EC50 may be less than KD if we have less receptors

Answer 192

- Because efficacy of agonist may influence size of response - May activate multiple second messengers which would amplify the response

Answer 193

The machinery of response - e.g. used all the enzymes/2nd messengers

Answer 194

Response = (Maximum response[X]^slope factor) / ([X]^slope factor + [EC50]^slope factor)

Answer 195

Agonist potency | - If a drug requires a small concentration to receive a high response it would have a high potency

Answer 196

The sigmoidal line most left has the highest potency as a drug requires a small concentration to receive a high response

Answer 197

Affinity efficacy and spare receptors

Answer 198

Partial agonists are not capable of achieving the full response - Drugs may have the same EC50 but different maximal responses

Answer 199

A partal agonist could be more potent even though it is a partial agonist - no effect

Answer 200

Only by comparing the response to that of a full agonist

Answer 201

Because it doesn't evoke a full response - Less chance of overdose - Much less desensitisation of receptors e.g.. B2 inhaler - Easing of addiction

Answer 202

The previously bound to receptors and the a full agonist is added

Answer 203

The measure of a single agonist-recepor complex's ability to generate a full response

Answer 204

- Specificity - Affinity - Efficacy

Answer 205

The interaction with a structurally defined site/receptor

Answer 206

Ability to bind to a receptor

Answer 207

Ability to activate receptor

Answer 208

Evokes a response opposite to that of a normal agonist - Not an antagonist - Has an efficacy below 0 - Cannot consume an active configuration

Answer 209

GPRC's may have allosteric sites which make it easier for the agonist to evoke a response

Answer 210

Antagonists

Answer 211

A drug that prevents the response of an agonist

Answer 212

- Chemical antagonism - Pharmacokinetic agonist - Physiological antagonism - Non - competitive antagonism - Competitive antagonism by receptor block

Answer 213

The substance combines in a solution so that the effects of the active drug is lost - agonist is chemically altered by the antagonist

Answer 214

Adding a chelating agent (antagonist) to a heavy metal will inactivate toxicity

Answer 215

- Reduction in amount of drug absorbed | - Change in drug metabolism

Answer 216

Opiate will reduce absorption in the GI tract

Answer 217

Antibiotics may lead to metabolism of warfarin for those patients taking it - problem

Answer 218

The interaction of drug with opposing actions in the body

Answer 219

Noradrenaline raises arterial blood pressure by acting on the heart and peripheral blood vessels - while histamine lowers arterial pressure by causing vasodilation

Answer 220

Blocks some step in the process between receptor activation and response - does not compete with agonist for the receptor site

Answer 221

Smooth muscle interfering with gated Ca2+ channel which is required to bind to MLCK to contract - doesn't directly block channel non competitive

Answer 222

Competing with agonist for for binding site on a receptor - Similar structure - Does not create a response

Answer 223

Effects of atropine on response to acetylcholine for guinea pig ileum

Answer 224

Sigmoidal shape moves to right- more conc required for max response - EC50 increases

Answer 225

How many more times agonist is needed in the presence of an antagonist

Answer 226

[Concentration of agonist in presence of antagonist] / [Conecentration of agonist in absence of antagonist]

Answer 227

Measure antagonist affinity

Answer 228

Dose ratio = (conc of antagonist (Xd) / antagonist affinity constant (KD)) +1

Answer 229

Higher the number higher the affinity

Answer 230

Cannot be reversed by washing of the tissue | - Irreversible antagonism is time dependant

Answer 231

The effects of the alkylating drug dibenamine on histamine responses in the guinea pig ileum

Answer 232

- Absorption - Distribution - Metabolism - Excretion

Answer 233

Drug crosses the plasma membrane to travel between cells

Answer 234

The physiological properties of the drug and if it is non polar

Answer 235

Lipid solubility partition coefficient | - Measure of how easily the drug will dissolve into the lipid/aqueous phase

Answer 236

Non polar molecules dissolve through lipids freely | - Increasing rate of absorption from gut, penetration into brain and renal elimination

Answer 237

- Straight into plasma (fastest way) - Avoids metabolism - Quick in emergency situation - Not convenient

Answer 238

- e.g.insulin - Speed of effect depends on muscle - Short delay getting into plasma

Answer 239

- Inject into spinal cord - effects CNS | - eg. epidural

Answer 240

- Gas | - Potential route if the target is in the lungs e.g. inhaler (salbutamol)

Answer 241

- Most widely used route - Pass through the gut into plasma through diffusion within the intestines - Rate depends on gut contents - Drug capsules used to alter rate of absorption

Answer 242

Fraction of injected drug/fraction in plasma

Answer 243

- Through the gut - Used in paediatric medicine - also when local target

Answer 244

- Though the skin e.g. patches | - Can be used for when condition is in the skin

Answer 245

- Method of administration - Molecular weight - Lipid solubility - pH and ionisation

Answer 246

Most drugs are weak acids - be a salt so easily made into a tablet - Will be in its undissociated from in stomach acid so can easily pass though membranes as its not charged

Answer 247

pKa = pH +log(HA/A-) When the dissociation of he drug is HA H+ + A- - In stomach acid (pH 3), aspirin (pKa=3.5): 3. 2 = (HA/A-) meaning three times more of the drug is in its uncharged form so can pass through the membrane - In plasma (pH 7.4) - more drug in dissociated from so will stay in blood circulating the body - In kidney (pH 8) favours dissociated form so will be trapped and excreted

Answer 248

In poisoning situations | - Increases pH of plasma by sodium bicarbonate causing weak acid to be trapped an excreted

Answer 249

When 50% molecule is in its dissociated form

Answer 250

Blood brain barrier

Answer 251

Endothelial cells lining blood vessels in CNS form tight junctions impermeable to water soluble molecules Lipid soluble molecules e.g. ethanol cross it easily Tight junctions become laky during inflammation

Answer 252

The chemoreceptor trigger zone

Answer 253

The chemoreceptor trigger zone is rich in dopamine receptors so when drugs fro Parkinson's disease are added nausea is caused - to stop this you have to co administrate a drug that inhibits the dopamine receptors in the chemoreceptor trigger zone - It only inhibits those dopamine receptors as the drug has a large structure so cannot surpass the blood brain barrier in most if the CNS but can in the trigger zone as the blood brain barrier is sparse

Answer 254

High solubility - However means it can easily enter body fat - Making dosage more difficult to calculate

Answer 255

Phase 1 - catabolic reactions | Phase 2 - synthetic reactions

Answer 256

Catabolic reactions - made more active to increase its size using microsomal enzymes such as cytochrome p450, alcohol dehydrogenase, MAO - to allow it to pass the plasma membrane

Answer 257

Synthetic reaction | - Involve conjugation to produce an inactive product

Answer 258

The active form of the drug isn't released until after metabolism - Slows doen rate of response - Can be useful in avoiding symptoms like tiredness

Answer 259

- Enters liver cells - Encounters cytochrome enzyme which swaps the acetyl group for a hydroxyl group - Conjugate into a larger molecule decreasing its access to tissues - Cant interact with its target - Excretion is promoted

Answer 260

By adding inducers of P450 (an enzyme involved in drug metabolism)

Answer 261

Because spree rugs are distributed and trapped in the milk meaning it could be passed on to the baby

Answer 262

Follows a memo-exponential decay - t-half value is the amount go time for the concentration to decrease by half - Rate of elimination may very even if the drugs are of the same concentration targeting the same receptors - t - half is not directly proportional to the concentration

Answer 263

Nodal cells Conducting cells Muscle cells Connections -- intercalated discs

Answer 264

- Initiated at sino-atrial node - Conduction to atria and atrioventricular node and then atrioventricular ring - Passage through bundle of his - Purkinjie system distribution to ventricular muscle cells

Answer 265

15mm x 5mm x 2mm

Answer 266

The posterior aspect of the heart | - Junction between superior vena cava and right atrium

Answer 267

1m/s | this is the pathway that allows spread of electrical activity from right atria to left

Answer 268

To atrioventricular node and left atrium

Answer 269

22mm x 10mm x 3mm

Answer 270

Posterior aspect | - Right side interatrial septum

Answer 271

Slow concussion through AN-N= 0.05m/s

Answer 272

Allow atrial contraction to finish

Answer 273

Prevents excess ventricular contraction | It increases at higher heart rate to allow the hart to move maximum amount of blood and therefore CO2

Answer 274

Squeeze maximum amount of blood out

Answer 275

Gradual and slow depolarisation of the membrane

Answer 276

Sinoatrial node | - The atrioventricular node had the ability to take over for the sinoatrial node if it fails

Answer 277

The muscle have a plateau phase in order to sustain contraction of the atria and ventricles

Answer 278

Would never allow the ventricles to actually contract so cardiac muscle cannot fire another action potential until first is completely done

Answer 279

AV node and purkinje fibres

Answer 280

Slow depolarisation, fast depolarisation and fast repolarisation

Answer 281

- A cation channel with a Nernst of 0 - K+ channels are closed from the last action potential - Hyperpolarition induced - so inactive when vm is positive

Answer 282

When vm goes over -40mv - Ca2+ channels open - Peaks at 0mv

Answer 283

- Ca2+ channels close and K+ open | - Shifts the membrane potential towards that of Nernst for K+

Answer 284

Innervation, temperature and by other pacemakers

Answer 285

``` Parasympathetic - ACh released from vagus nerve causes hyper polarisation and decreased pre potential slope Sympathetic - Noradrenaline released - Increase the prepotential slope - Increase the firing rate ```

Answer 286

``` Fast depolarisation - Na+ channels open (shifts membrane potential towards Nernst for Na+) - Na+ close and Ca2+ open Spike - Leakage of some K+ channels Plateau - Ca2+ channels balance with K+ as Ca2+ tries to drive it positive and K+ negative Repolarisation - Ca2+ channels close - Ca2+ is transported out - K+ open and moves in ```

Answer 287

Due to the Na+ channels Before they can become activating again, they have to go from open to inactive to closed - Stops summation

Answer 288

- Stimulus to get action potential must be higher as membrane is still slightly hyper polarised - Stops summation

Answer 289

Start of ventricular depolarisation to repolarisation

Answer 290

Short and long QT syndromes

Answer 291

``` Short QT - distance between Q and T is smaller - Repolarisation is accelerated Long QT - distance between Q and T is larger - Repolarisation is slower ```

Answer 292

Normal - 0.36 s Long - >0.45 s Short - <0.34 s Some pathologies only show variety QT interval when exercising

Answer 293

- Triggered activity | - Re entrant excitation

Answer 294

Long QT - Na+ channels may be closed and ready to be active and therefore open to early - Generates another action potential causing a ectopic beat - Ventricular tachycardia - Ventricular fibrillation

Answer 295

Lack of control of the heart

Answer 296

- Different layers of cells are impacted - Trigger of electrical activity but not in all of the ventricular muscle - Spatial and temporal dispersion of refractory period - extra electrical activity at certain parts of the muscle and at certain times - Leads to ventricular tachycardia - Ventricular fibrillation

Answer 297

- Fainting - Palpitations - Sudden death - Torsades de points on ECG

Answer 298

Teen years

Answer 299

When exercising or jumping into cold water

Answer 300

Seen on an ECG - loss of coordination

Answer 301

1:10000 to 1:150000

Answer 302

``` LQT1 -Loss of function in Iks channel - 30-35% of cases LQT@ - loss of function in Ikr channel - 25-30% ```

Answer 303

LQT5 - Loss of function in MinK - 1%

Answer 304

Most common type of long QT syndrome - K+ channel channelopathy - Caused by a mutation in KV7.1 - Lots of mutations in transmembrane domains - Loss of function

Answer 305

Deafness - Due to Q1 k+ channel and its regulators E1 role in the ear - In a E1 knockout mouse (MinK protein which is what is mutated in LQT5), there is no resigners membrane and no K+ rich endolymph meaning can't hear - Same in humans with these cardiac channelopathies

Answer 306

- Na+ channels stay open - Balance between anions and cations is lost - Depolarisation lasts longer and repolarisation is delayed - Long QT syndrome

Answer 307

- Ca2+ channels dont close - K+ channels can't repolarise - Repolarisation takes longer - - Long Qt

Answer 308

- Not as much K+ leaves as quickly - Repolarisation takes longer - Long QT

Answer 309

B blockers - Atenolol - B1 selective antagonist - slows down heart as has chronotrophic and ionotrophic actions but can't be used if asthmatic as causes bronchoconstriction

Answer 310

Arrhythmias, palpitations, fainting, sudden death

Answer 311

75% males | - Onsets at late adolescence

Answer 312

- Short/absent ST segment - Tall T wave - QT doesn't vary when exercising - normal people it gets shorter

Answer 313

- SQT1 - gain of function - K+ channel - SQT2 - gain - K+ - SQT3 - gain - K+ - SQT4 - loss - Ca2+ - SQT5 - loss - Ca2+

Answer 314

Loss of function in Ca2+ | - Repolarise too quickly as Ca2+ cant enter to balance K+

Answer 315

Gain of function in K+ - K+ moves in to quickly - Repolarisation to quick

Answer 316

Implant defibrillator

Answer 317

Mechanical and electrical events that repeat with every heartbeat

Answer 318

- Inflow phase - Isovolumetric contraction - Outflow phase - Isovolumetric relaxation

Answer 319

- AV valves open but little blood flows between atria and ventricles so ventricular pressure rises very slowly an approaches a plateau - Pressure in atria also rise very slowly

Answer 320

Because the capillaries in the lungs are one cell thick and have lots of gap junctions so would rupture if the pressure was high - would cause the lungs to fill with tissue fluid

Answer 321

Atrial contraction - After excitation contraction coupling, contraction of atria occurs and pushes the remaining blood into the ventricles - <20% of the blood from atria is moved to atria in this phase - Small rise in both chambers pressure

Answer 322

When the intraventricular pressure exceeds the atrial pressure

Answer 323

Ventricular contraction triggers contraction of the papillary muscles with their cordae tendinae that are attached to valve leaflets - this tension prevents them from bulging back too far into the atria

Answer 324

Closure of the AV valves | - Split sound (0.04 secs) as mitral valve is slightly before tricuspid

Answer 325

Isovolumetric contraction - Systole commences - As ventricles contract, pressure in the ventricles exceeds the pressure in the atria causing the AV valves to shut - Means ventricles are contracting with all the valves shut so that the pressure is increasing but the volume is staying the same causing a rapid increase in ventricular pressure - Pressure rises above the pressure in the aorta/pulmonary valve causing aortic/pulmonary valves to open

Answer 326

As aortic valves open, the pressure in the ventricles and aorta rise and this is followed by a fall in ventricular volume - Decrease in ventricular pressure becomes less rapid - 50ml blood remains in the ventricles

Answer 327

Early in Phase 3 (ejection) | Maximal aortic and pulmonary artery pressures are also achieved

Answer 328

No because during ejection the opening of healthy valves are silent

Answer 329

First part of phase 1

Answer 330

Intraventricular pressures fall causing the aortic and pulmonic valves close abruptly

Answer 331

When the aortic and pulmonary valves close it cases small back flow of blood into the ventricles

Answer 332

Isovolumetric relaxation - Blood flow across aortic/pulmonary valve becomes very slow so blood starts to flow backwards causing the aortic/pulmonary valve to close and blood continues o move forwards (dicrotic notch) - Both valves are closed so pressure falls and the volume stays the same

Answer 333

The rate of relaxation of the muscle fibres - rate of pressure decline in ventricles is determined by this

Answer 334

The sarcoplasmic reticulum | - responsible for re sequestering calcium following contraction

Answer 335

Because all the valves close | - Volume doesn't change but pressure decreases

Answer 336

The volume of blood left in the ventricles after systole | - usually around 50ml

Answer 337

The difference between the end diastolic volume and the end systolic volume - Usually around 70ml

Answer 338

So when start exercising, the cardiac output can increase immediately

Answer 339

Because of venous return from the lungs | - The peak at the end of the left atrial pressure line is termed v-wave (just before mitral valve open)

Answer 340

- When ventricular pressure falls below that in the atrium the AV valves opens causing rapid ventricular filling - Ventricular pressure continues to fall in this phase as its still undergoing relaxation

Answer 341

During rapid filling and it may represent the tensing of the chordate tendinae - low pitched so is best heard using the bell of a stethoscope

Answer 342

As the ventricles fill, they become less complaint and the intraventricular pressures rise - reduces pressure gradient across AV valves so slows filling

Answer 343

90% | - 90% of the filling occurs before atrial contraction

Answer 344

- Right atria contracts before left - Left ventricle before right - Right ventricular ejection before left

Answer 345

70-190 bpm

Answer 346

T -tubules and intercalated discs rapidly transmit action potentials in the myocardium Electrical excitation - muscle contraction

Answer 347

Myocyte plasma membrane

Answer 348

Formed by thousands of invaginations and inward foldings of sarcolemma forming transverse tubules

Answer 349

Allows the action potential to stimulate all parts, deep into myocyte simultaneously - Faster rate of contraction

Answer 350

Fluid filled membranous sac surrounding each myofibril | - Ca2+ store

Answer 351

Sarcoplasmic [Ca2+] is low = 0.1 micro molar | Ca2+ pumps moved Ca2+ from sarcoplasm to sarcoplasmic reticulum = [10 micro molar]

Answer 352

Present in sarcoplasmic reticulum - Binds ro Ca2+ to lower the [Ca2+] in sarcoplasmic reticulum so their is greater gradient and the pumps can work more efficiently

Answer 353

It obscures the myosin/actin binding site preventing the myosin head from sticking to the actin molecule

Answer 354

- Action potential propagates along transverse tubules - Activate Ca2+ channels - Ca2+ diffuses out of SR into sarcoplasm - Binds to troponin - Conformational change in troponin/tropomysoin complex exposed myosin/actin binding site - Myosin sticks to binding site - ATP causes crossbruge cycling - Muscle shortens

Answer 355

Muscle tension should be proportional to no of crossbridges | Number of cross bridges proportional to sarcomere length

Answer 356

Short - Overlapping thin filaments Long - Reduced areas for crossbridge formation So there is an optimum sarcomere length

Answer 357

Clamp a papillary muscle at specific length with a electrical stimulating electrode attached to a force transducer - Record length of muscle - Electrically twitch and record force - change length of muscle - repeat

Answer 358

- Short muscle - no force - When length increases so does force - 2.2 -2.6 micro meters - maximum response - free ti bind to any actin - Too long - no force

Answer 359

Contained in mediastinum | - However only tissue keeping to from contracting to far so can expand to much under certain conditions

Answer 360

The relationship between length and tension in muscle

Answer 361

Isotonic - Muscle length changes and tension stays the same | Isometric - Length doesnt change

Answer 362

Force velocity measure isotonic contraction which is what occurs in the heart Length tension - isometric

Answer 363

It is shown when an intact heart changes its output per beat when the end diastolic volume is constant

Answer 364

Changes in rates

Answer 365

- When more cross bridges form per stimulus - Dependant on the qualitative state of actin/myosin crossbridges - Noradrenaline increases max force

Answer 366

Positive or negative inotropic effects

Answer 367

Increases contractility

Answer 368

Increases tension Also increases by an extra beat Because of changes in Ca2+ availability

Answer 369

A way of measuring cardiac output cardiac output = O2 uptake/ [o2]pv - [o2]pa Can be measured using someones expired air

Answer 370

- Fink Principle - Indicator dilution - Thermodulation - Ultrasound

Answer 371

Thermodulation - Cold saline injected into right atrium ad moves with blood - Moves through system - Sensor measures temp change in artery - uses this and temp and volume of injection to calculate CO

Answer 372

Ultrasound - Measures real time changed in ventricular dimensions - stroke volume calculated - stroke volume x heart rate = cardiac output

Answer 373

5.5L per min at 69bpm

Answer 374

2.5-3.6L/min/m2

Answer 375

Cardiac output/body surface area

Answer 376

- Stroke volume - Heart rate - Innervation - Intrinsic and extrinsic control

Answer 377

Homeometric | Heterometric

Answer 378

``` The end diastolic volume is regulated by venous return influenced by - Blood volume (increase) - Vascular storage (decrease) - Muscle pump action - Vascular resistance - Atrial sucking - Gravity - Inspiration ```

Answer 379

Positive inotropic effects | - Treppe law - strength of contraction increases as heart rate does

Answer 380

Autonomous nervous system | Humoral factors

Answer 381

- Primary way of decreasing heart rate - ACh onto SA node - decrease slope taking longer to reach threshold - action potential propagation slower - Decreases heart rate, contractility and force per breath

Answer 382

- Speeds up heart and contractility | - Noradrenaline increases rate

Answer 383

B blockers | - Propanalol/atenolol

Answer 384

Parasympathetic

Answer 385

Thyroid hormone - Increase heart rate when hyperthyroid Insulin - increase in inotropic effects

Answer 386

In the arterials and small veins | - where blood first meets high resistance

Answer 387

R = 8hl/πr^4

Answer 388

That any change in diameter will have a large impact on the resistance and in the calculation the radius is to the power of 4

Answer 389

Tissue pressure will collapse vessels if blood pressure falls

Answer 390

Transmural pressure = tension/radius | The smaller the diameter of the tube, the greater the transmural pressure

Answer 391

Aneurysms | - Increases size, becomes easier to inflate, transmural pressure will decrease and the aneurysm will burst

Answer 392

Compliance = delta v/ delta P

Answer 393

They are more complaint then artiest meaning that blood tends to accumulate in venous side - At rest 54% of blood will be the venous system

Answer 394

Blood tends to stay at the bottom of body if person dies on their back

Answer 395

The further away from the heart the pulsatile (pumping) nature isn't as strong Pressure is stored in the vessels to ensure flow is continuous

Answer 396

Laminar moves slowly and turbulent is when laminar flows interfere with each other because pressure is to high

Answer 397

Measures the type of flow <2000 = laminar < 3000 = turbulent

Answer 398

In the respiratory system

Answer 399

Because only one red blood cell fits along the capillaries so don't interfere with each other

Answer 400

Would cause blood clots | - Stopped by papillary muscles and trabeculae carneae

Answer 401

Could cause red blood cells to burst or become damaged | - why red blood cells are constantly replaced

Answer 402

Pre - capillary sphincters

Answer 403

When the hydrostatic pressure is higher than the osmotic pressure so the plasma is pushed through gap junctions into capillaries into tissues

Answer 404

To push fluid back into the capillaries

Answer 405

Balance between hydrostatic pressure and osmotic pressure

Answer 406

By the limbic system | - Absorbs tissue fluid and is drained bak into right subclavian vein - superior vena cave - right atrium

Answer 407

Increases tissue fluid as balance between hydrostatic and osmotic pressures is lost - leads to oedemas

Answer 408

Lowers the amount of protein in blood - Can't produce high osmotic pressure so hydrostatic erasure outweighs out - Increased tissue fluid formation - People with malnutrition tend to have swollen belly due to excess tissue fluid

Answer 409

Because skull can't expand to decrease the pressure

Answer 410

Increases | - Makes capillaries leaky

Answer 411

Increases permeability of vessels in active muscles | - increases hydrostatic pressure - increase up to 25%

Answer 412

- Endothelium - Basement membrane - Tunica media - Tunica externa - Need to have their own blood supply but medium and small don't

Answer 413

To push the blood up towards the heart - stop gravity

Answer 414

Head and neck

Answer 415

Contraction to prevent expansion of the artery

Answer 416

By CO2/ pH e.g. in an exercising muscle - produced CO2, pH change, temperature - vasodilates vessels to increase flow and remove CO2 and lose heat through the skin

Answer 417

Parasympathetic - adrenergic - constrict | Sympathetic - cholinergic - dilate

Answer 418

Low innervation in brain - because it always needs oxygen | High innervation - skin - blood flow varies to muscle and skin (temperature)

Answer 419

``` Adrenaline - Vasoconstriction of skin - Vasodilation skeletal muscle/ liver - eg. in flight or fight response Kinins - Bradykinin - vasodilation peptide Angiotensin II -Increase blood pressure ```

Answer 420

- Prostaglandins - Serotonin - Histamine - Endothelium derived relaxing fator - Nitric oxide - released by endothelium cells in response to ACh - Stimulates cGMP causes relaxation

Answer 421

Inhibits the breakdown of cGMP which causes relaxation

Answer 422

- Thought to be converted into Nitric oxide - But actually increases diameter of venous system - Reduces contractility reduces o2 needed and reduces chest pains

Answer 423

The medullary centres - Cardioaccelatratory system - speeds up heart rate - Cardioinhibitory system slows down heart rate

Answer 424

Spinal cord - Sympathetic chain - ganglia - cardiac nerve - heart

Answer 425

- Repsond to changes in pH, pCO2, pO2 - Causes an increase in intracranial pressure - due to swelling after brain injury - leads to a fall in blood flow to the brain

Answer 426

Leads to an increase in vasoconstriction and blood pressure but causes bradycardia Risk of death is high

Answer 427

Baroreceptors - stretch receptors - Carotid sinus detect high pressure - Causes atria, left ventricle and pulmonary veins low pressure - High blood volume - Release ANP - Inhibition water uptake into kidney to control blood pressure Buffer nerves - Changes cardiac output to ensure blood pressure stables - Glossopharyngeal and vagus nerves - Short term regulation

Answer 428

Forcible expiration against a closed glottice - Increase in thoracic pressure and decrease in blood pressure - Venous return then decreases - Decrease in baroreceptor stimulation - tachycardia - Venous return increase

Answer 429

Mainly invloed in respiration Activation leads to an increase in blood pressure Cardiac chemoreceptors cause angina pain

Answer 430

``` Hypothalamus Cortex and limbic system - Used in emergency situations - Defence area - Thermoregulatory centres which cause vasodilation and vasoconstriction - Bradychardia hypotension ```

Answer 431

``` Diastolic - Less than 85 - normal - 90 -104 mild hypertension - 105-114 - moderates - Greater than 114 - severe Systolic - Less than 140 normal - 140-159 - systolic hypertension - Greater than 160 - severe ```

Answer 432

``` Essential hypertension - Risk factors but no clear cause - can effect anyone Secondary hypertension - Consequence of a clinical condition ```

Answer 433

- MABP is cardiac output x resistance - Cardiac dysfunction - essential hypertension increase response to stress and catecholamines - Vessel abnormalities - sympathetic nervous system abnormalities, muscle hypertrophy - changes in smooth muscle blood pressure - Kidney dysfunction - Volume induced hypertension

Answer 434

Correlated with relatives - Twins vs non twins - Varies with race - higher among African - Caribbean

Answer 435

- Diet and obesity - Adoption of western lifestyle - Salt intake - Vitamin D deficiency

Answer 436

Human studies - Reduced salt by 3g/day will decrease mean arterial blood pressure (MABP) by 5mm - Equivalent to a drug therapy reduces strokes - Must be NaCl not Na+ reduction

Answer 437

``` Renal disease - Nephron function impaired - Blood volume and blood pressure increases - More damage an kidney failure Renal artery stenosis - Narrowing - Renin production and blood pressure increase Pheochromocytomas - Chromaffin adrenaline increase, blood pressure increase Hormone imbalance - aldosterone increase - Blood pressure increase ```

Answer 438

- Flushing, sweating, blurred vision - Clinically described as asymptomatic - Arteriosclerosis/ atherosclerosis - Aneurysms - Stroke - Heart attack - Retinal attack

Answer 439

- Lose weight - Exercise - Diet - salt, alcohol, caffeine - Stop smoking - Relax - Pharmacology

Answer 440

Diuretics - Increase Na+ and Cl- excretion Sympatholytics - alpha blockers - decrease CNS sympathetic output - relaxes smooth muscle - B blockers - propranolol - decreae heart rate and contractility Ca2+ Channel blockers - Decrease cardiac contractility and vascular muscle

Answer 441

- ACE inhibitors | - AG II receptor blockers

Answer 442

Diuretic and something else - Better control - e.g. ACE inhibitor and Ca2+ blocker

Answer 443

1 in 2500 | 1 in 20 - carriers

Answer 444

Only require 20% protein function for normal function | Carriers have 50%

Answer 445

Causes clogging and infection

Answer 446

Blockage of bile ducts | - Found in 5% of patients

Answer 447

Blockage of ducts - prevents secretion of digestive enzymes - Can be used to check for it at birth with a heel prick - Treatment can be to give tablets with these enzymes in - 65% of patients

Answer 448

Obstructions due to thick content - effects 10% - known as meconium ileus

Answer 449

Excess secretion of NaCl via sweat glands

Answer 450

95% males are infertile - Absence of vas deferens Small number of females infertile

Answer 451

12 transmembrane domains - Regulatory domains - sequence of amino acids that plays a role in regulating the closing of the channel - target for phosphorylation by protein kinase A

Answer 452

Sequence of amino acids that bind nucleotides such as ATP - regulates opening and closing of the channel

Answer 453

Over 1900 - In transmembrane domains - In NBD1 and NBD2 - In intra ans extracellular loops

Answer 454

People with the same mutations have different symptoms - Environmental factors - don't follow treatment - Genetic - Non conducting regions

Answer 455

- Effect its mRNA - can lead to truncation - effect trafficking - Processing - Some effect more than one of these

Answer 456

``` F508 - 90% allelic frequency - Most severe G551d - 1-3% - In uk higher All others are less than 0.1% ```

Answer 457

Mucus is thicker Recurrent bacterial infections - antibiotic resistance Inflammation - Impacts immune system - hypersensitive - over inflammation - damages lung tissue - After each infection, parts of lung tissue is lost - 70% of deaths

Answer 458

On baslateral membrane | Pumps 3Na+ out in K+ in - creates driving force for Na+ to move in by NKCC1

Answer 459

On basolateral membrane - Moves Na+, 2Cl- and K+ into cell - Uses electrochemical driving force - Na+ and K+ recycle through the basolateral membrane - Leads to high intracellular Cl-

Answer 460

Cl- channel on apical membrane Cl- is secreted - Sets up driving force for Na+ and water to move from the basolateral side of the cell to the apical

Answer 461

Layer of water, Na+ and Cl- over epithelial cells in the airways Mucus sits on top of the layer Cilia in the layer - as cilia beat, layer and mucus moves up to be swallowed

Answer 462

On apical membrane - Na+ into cell through ENaC - Balance between this and Cl- secretion that deicides height of pericilliary layer

Answer 463

7μm | If height of layer disturbed then cilia don't work

Answer 464

- CFTR missing/ non functional - Usually CFTR surpasses ENaC slightly so it is hyperactive - Causes pericilliary layer to be small - Cilia are bent over so don't beat - patients can't clear their airways

Answer 465

- Trafficking and processing mutation - Causes the protein ti be misfolded meaning the cells checking system targets it for degradation - If the protein actually made it to the membrane function would be relatively normal

Answer 466

It provided protection against cholera - Cells in colon have CFTR which determines the water content of faeces - Enterotoxins activate CFTR and cause diarrhoea - Cholera killed due to diarrhoea - Carriers only had 50% of CFTR channels as everyone else so were more likely to survive

Answer 467

``` Physiotherapy - Losen Mucks and cough it up Bronchodilator drugs - Expand airways Antibiotics Steroids Mucolytics - Break down mucus ```

Answer 468

- It causes the delivery of CFTR to the target cell - for mutations in F508 this would make a relatively normal function - Problem is that it needs to repeat treatments as airways cell change often - expensive

Answer 469

Potentiators - Increase the potential of CFTR channels which must be trafficked - Normally the G551D mutation is a target for ivacaftor Correctors - Force mutatnt copies of CFTR into the membrane Combinations of these methods are being looked at

Answer 470

Clinical trial | - Compared with a placebo group: Massive improvement in infections, weight loss over a long period of time

Answer 471

Summation of cells depolarisation and repolarisation gives resultant vectors Measurement of vectors produce on ECG

Answer 472

Electrocardiograph - Machine | Electrocardiogram - Trace

Answer 473

When cardiac impulse passes through the heart, the electrical current spreads to all the adjacent tissues surround the heart and even reach the skin - electrical potentials can be recorded

Answer 474

Standard limb leads - Right and left arms - Left leg Produces einthovens triangle

Answer 475

At rest no net current flow toward any electrode so no deflections on the ECG

Answer 476

Net current flow towards an electrode cause an upward deflection on the recording

Answer 477

Cables join the surface self - adhesive electrodes are connected by cables to the ECG recorder machine A lead is the tracing of the voltage difference and what is actually produced by ECG recorder

Answer 478

Lead II | Lead I

Answer 479

Spread of electrical excitation through the heart - Atria begin their depolarisation - small muscle so deflection is small - Ventricular depolarisation begins at the apex - ventricles big so deflection big - Repolarisation of the atria happen at the same time but masked by electrical activity of ventricular depolarisation - Ventricular repolarisation

Answer 480

Atrial depolarisation

Answer 481

Ventricular depolarisation

Answer 482

Ventricular repolarisation

Answer 483

PR 0.12-0.20 QRS 0.8-0.10 QT 0.40 - 0.43 ST 0.32

Answer 484

Atrial hypertrophy - more muscle mass more to depolarise bigger deflection

Answer 485

Ventricular hypoxia - not enough o2

Answer 486

Acute myocardial infarction

Answer 487

Bradycardia and tachycardia - Exercise from 65 to 180bpm - Sinus arrhythmia - 15% increase on inspiration, 15% decrease on expiration

Answer 488

Non exercise tachycardia - 150-200bpm Flutter - 200-300bpm Fibrillation - 300bpm and irregular

Answer 489

Impairment of conducting pathways | Infarction, artery disease ect

Answer 490

Interruption somewhere between the SA and AV nodes slowing SA – AV conduction Causing an increased PR interval

Answer 491

Mobitz I | Mobitz II

Answer 492

Type of second degree heart block - SA impulses fail to evoke QRS - Progressive prolongation of the PR interval culminating in a non conducted P wave - The PR interval is longest immediately before the dropped beat - The PR interval is shortest immediately after the dropped beat

Answer 493

Type od second degree heart block? - Mobitz II is usually due to failure of conduction at the level of the His-Purkinje system (i.e. below the AV node). - Mobitz II is more likely to be due to structural damage to the conducting system (e.g. infarction, fibrosis, necrosis). - Patients typically have a pre-existing LBBB or bifascicular block, and the 2nd degree AV block is produced by intermittent failure of the remaining fascicle (“bilateral bundle-branch block”).

Answer 494

Unlike Mobitz I, which is produced by progressive fatigue of the AV nodal cells, Mobitz II is an “all or nothing” phenomenon whereby the His-Purkinje cells suddenly and unexpectedly fail to conduct a supraventricular impulse.

Answer 495

In complete heart block, there is complete absence of AV conduction – none of the supraventricular impulses are conducted to the ventricles. ‘Perfusing rhythm’ is maintained by a junctional or ventricular escape rhythm. Alternatively, the patient may suffer ventricular standstill leading to syncope (if self-terminating) or sudden cardiac death (if prolonged). Typically the patient will have severe bradycardia with independent atrial and ventricular rates, i.e. AV dissociation.

Answer 496

Benign | - found in athletes

Answer 497

Mobitz I - Benign - in atheletes Mobitz II - May require pacing

Answer 498

- Chamber contractions out of synchrony - Atrial contraction against closed tricuspid - Reduced perfusion - dizziness and syncope

Answer 499

Cannon wave’ in jugular vein- R atria contracting at same time as R ventricle so a pressure wave is sent back up the jugular veins. The external jugular vein can be seen pulsing.

Answer 500

Atrial fibrillation

Answer 501

Abnormal heart rhythm- irregular, rapid beating of the atria | Starts with brief episodes abnormal rhythm which become longer even constant

Answer 502

Usually asymptomatic but AF is usually accompanied by symptoms related to a rapid heart rate. Rapid and irregular heart rates may be perceived as palpitations or exercise intolerance and occasionally may produce angina. Congestive symptoms such as shortness of breath or oedema of ankles.

Answer 503

flecainide beta-blockers, particularly sotalol amiodarone dronedarone (only for certain people)

Answer 504

Circus movement or re-entry Electrical signal not completing the normal circuit, but rather an alternative circuit looping back upon itself rapidly. Refractory muscle normally prevents re-excitation If wave of excitation meets non-refractory tissue it will carry on

Answer 505

Aspirin Paracetamol Ibuprofen

Answer 506

bark of a willow tree

Answer 507

Acetyl salicylic acid | - Used to be just salicylic acid but adding the acetyl group reduces some of its side effects (damages stomach)

Answer 508

Effect the activity of any cells within their range

Answer 509

Normally - Phospholipase A converts phospholipid to arachidonate - Cyclo oxygenase (cox) converts it to cyclic endoperoxides which leads to inflammatory responses - Anti-inflammatories interfere with cyclo-oxygenase

Answer 510

- Prostaglandin E causes vasodilation - by blocking this, inflammation decreases

Answer 511

- PGE2 causes more pain as receptors for it on pain receptors making surrounding more sensitive to pain - blocking this is a painkiller

Answer 512

Favours blood clotting

Answer 513

Favours blood clots | - Controlling them limits chances of strokes and blood clots

Answer 514

Decrease vasodilation and in turn oedemas | - but is ineffective against mediators that contribute to tissue damage associated with chronic inflammatory conditions

Answer 515

Decreases production of prostaglandins which sensitises nociceptors (pain receptors) to inflammatory mediators e.g. bradykinin, serotonin

Answer 516

They lower raised temperatures | - Thermostat in the hypothalamus activated via IL-1 induced COX2 production of prostaglandin E (PGE)

Answer 517

Because mostly exerts its effects on CNS not PNS

Answer 518

COX-1 - Found in all cells COX-2 - Induced in the inflammatory cells COX-3 - Variant of COX-1

Answer 519

COX 2 because it is only induced in the immune response | If COX 1 is targeted - leads to side effects because it is always active and has roles in tissue homeostasis

Answer 520

COX 3 | Does work on others but much less

Answer 521

Inhibits COX 1 and 2

Answer 522

Made up of two identical subunits, each with two catalytic sites (peroxidase and cyclo oxygenase) - Drugs restricting access of substrate effectively blocking it

Answer 523

Binds covalently to a ser residue in COX preventing arachidonic acid from reaching COX site

Answer 524

Because it covalently bonds meaning the body has to completely resynthesises the COX enzyme, it doesn't unbind

Answer 525

In COX 1 there is isoleucine present in the channel but in COX 2 it is switched for valine Valine is smaller meaning that the channel is bigger Bigger molecules are therefore synthesised so that they will fir in COX 2 but not COX1

Answer 526

- Prostaglandins inhibit acid secretion and protect mucosa in the gut - Dyspepsia, diarrhoea, nausea, vomiting, gastric bleeding, ulceration could be stopped by co-administration of misoprostol (PG analogue) may be protective - Renal Function, PGs maintain renal blood flow – Renal failure - Liver Damage – Paracetamol - Bronchospasm asthma attacks, Skin Rashes

Answer 527

It creates a dangerous intermediate during it's metabolism | Only occurs in large excess of paracetamol or already impaired liver function

Answer 528

Ads - Antithrombotic (stops blood clots) Dis - Gastrotoxicity

Answer 529

Ads | - Anti-inflammatory, analegestic, less side effects

Answer 530

``` Aspirin - Anti-platelet action - Reduced risk of colonic and rectal cancer - Reduced risk of Alzheimer’s - Weak acid, rapid and efficient absorption in the ileum Paracetamol Weak anti-inflammatory - COX-3 selective - Wellabsorbed, metabolized in liver - Less side-effects than aspirin with long term use, but large doses may increase kidney damage - N-acetyl-p-benzoquinone imine is hepatotoxic in uncongugated form - Competitive Inhibitor ```

Answer 531

Destruction of cartilage (joint swelling) More common in women Late onset Increased risk of heart attacks and strokes

Answer 532

Not entirely clear Genetic component Environmental component eg. smoking

Answer 533

Because it is caused by Th1 cells in the immune system | - Recruits macrophages which are involved in destruction of cartilage and bone

Answer 534

- Was originally an anticancer drug - Has cytotoxic and immunosuppressant activity - Inhibits activation of T helper cells -stopping its conversion into Th1 cells - Limiting the production of cytokines that cause inflammatory response - Usually, t helper cells recruit macrophages that release cytokines which cause inflammation

Answer 535

Work at the level of transcription to stop the production of these cytokines

Answer 536

Directly interfere with cytokines actions and therefore reduce inflammation

Answer 537

Often used to stop rejection of transplants | Inhibit transcription of pro inflammatory cytokines

Answer 538

Usually - During the activation stage of T cells intracellular [Ca2+] increases - This activates calcineurin - a phosphatase which targets the transcription factor NF kappa B (activates the immune cells and inflammatory response) - Removal of phosphate of NF Kappa B allows it to move in nucleus and transcribe - Ciclosporin binds to it and stops it from entering the nucleus

Answer 539

Causes immunosuppression so is more susceptible to infection

Answer 540

- Antibodies being used to target cytokine itself - preventing it attaching to receptor - Drugs that target IL1 - Mimic small soluble receptors for cytokines - mopping up free cytokines so cannot bind to its receptors

Answer 541

Interleukin 1 - family of cytokines that contribute to rheumatoid arthritis

Answer 542

Highly specific and effective Depends on the cytokines the Individual releases Long half life Needs to be injected but one every 6 months

Answer 543

5.4 million in UK | 1/5 households

Answer 544

Bronchodilators - salbutamol | Anti inflammatory agents - glucocorticoids

Answer 545

Polymorphisms in B2 adrenoreceptors associated with reduced efficacy of bronchodilators

Answer 546

Inject patients with a small amount of a known allergen and look for immediate ad late phase reactions

Answer 547

IgE are a class of antibodies produces against allergen - indviduals become sensitised (2-3 weeks) - IgE antibodies bind tightly to IgE Fc receptors on mast cells basophils (mast cells in blood) and eosinophils - Mast cells are designed to fight against parasites and recruit other immune cells - In some people allergens pass through skin and mucous surface (due to illness) - Mast cells confuse them for parasites - allergic reaction

Answer 548

Release of histamine and prostaglandins | Causes the first phase of an asthma attack

Answer 549

Intermediate - B2 inhaler | Late phase - Glucocorticoids

Answer 550

50% of patients

Answer 551

- Activation of transcription factors e.g. NF Kappa B - Controls the prodiuction of cytokines which attract other immune response to the tissue (in this case lungs) - Leads to inflammation and tissue damage

Answer 552

``` Th2 - type of T helper cell Activates IL4 (type of cytokine) which is what produces IgE antibodies that cause the allergic problems ```

Answer 553

Work at the level of Th2 cells - limit production of IgE - Effect mast cells and stop the release of cytokine - Also work on eosinophils

Answer 554

- Easy bruising - Poor wound healing - Increased abdominal fat - Cataracts - Hypertension

Answer 555

Filters plasmas Allows H20 and small molecules through Restricts the passage of blood cells and proteins 180l/day of filtrate

Answer 556

Epithelial cells Basement membrane Endothelial cells

Answer 557

They are flat cells with large nuclei Make up the capillary wall Circular fenestrations - gaps between them - allows filtrate to move through

Answer 558

``` It is the main barrier Continuous Made of collagen, laminin, fibronectin Negatively charged Filters based shape, size and charge ```

Answer 559

They have extensions form the cell body known as trabeculae. Coming off these are finger like protections called pedicles which crossover each other making pores for filtrate to move through

Answer 560

Basement membrane is negatively charged so will repeal negatively charged molecules - making it less likely for them to cross the barrier

Answer 561

The filtration co efficient

Answer 562

Hydrostatic pressure in capillaries Hydrostatic pressure in Bowman's capsule Oncotic pressure in capillaries Oncotic pressure in Bowmans capsule

Answer 563

GFR = Kf (Hydrostatic in cap+Oncotic in bc)–(Hydrostatic in bc+Onoctoc in cap)

Answer 564

Volume in fluid in bowman capsule doesn't change as it is constantly flowing and draining into the proximal tubule so hydrostatic pressure doesn't really change - 20mmHg

Answer 565

In normal capilaries, half way along the over powering force swap but not in glomerular capillaries - this is to ensure filtration always occurs

Answer 566

Because arterial blood pressure effects the filtration rate so has to be maintained when the blood pressure changes

Answer 567

Between 80-200 mmHg the glomerular filtration rate is regulated so doesn't really change - The range when the body is capable of adapting to different blood pressures

Answer 568

Resistance in the afferent arteriole decreases, causes vasodilation Renal blood flow goes up, hydrostatic pressure increases, filtration increases

Answer 569

If vasoconstriction occurs in the afferent arteriole, less blood, renal flow decreases, hydrostatic pressure decreases and decrease in arterial blood pressure

Answer 570

Increase in arterial blood pressure, increase in blood flow, increases GFR, auto regulation increases resistance in afferent arteriole, decrease in resistance blood renal flow and glomerular filtrate drops back down to normal level

Answer 571

Myogenic theory | Tubuloglomerular feedback theory

Answer 572

Detects change in blood pressure by smooth muscle in afferent arteriole - When arterial blood pressure increases - Stretch afferent arteriole - Afferent arteriole constriction - Increase afferent arteriole resistance

Answer 573

Juxtaglomerular apparatus - Macula densa cells detect the rate of flow in glomerular filtrate - They can then release vasoactive chemicals to return the GFR back to normal

Answer 574

Concentration

Answer 575

= [X]*n Where n = the number of particles x dissociates into Eg. 100mM NaCl = 200mOsmol/kgH20

Answer 576

Only ones with a loop of henle

Answer 577

Loop of henle | Collecting duct

Answer 578

- Interstitial fluid osmolality in the cortex starts at 290 - Cl- and Na+ are lost from the thick ascending limb causing the osmolality to change to 600 in the medulla - This creates a driving force for the loss of water in the loop of henle making the osmolality of the interstitial fluid 1400 - This then makes driving force for loss of Cl- and Na+ again making osmolality 90 in thick ascending limb - Change in osmolality in the cortical collecting duct to 290 drives water out making concentrated urine

Answer 579

Ascending limb not permeable to water but is to Cl and Na | Descending limb is permeable to water but not to Na and Cl

Answer 580

Osmoreceptors detect a change in osmolality by +- 3mosmol/Kg Causes the release of vasopressin - It is thought that vasopressin causes the insertion of aquaporin 2 channels into the apical membrane of the principle cell in the collecting duct. Aquaporin 3 and 4 on the basolateral membrane are not regulated by vasopressin meaning net increase in reabsorption of water

Answer 581

The driving force created by the loss of water and Na+ and Cl- - causing changes in the osmolality The vertical gradient - The osmolality decreases as you go down - If you compare the gradients of the thick ascending and the thin ascending limb they are different

Answer 582

Thin descending limb

Answer 583

Have problems with their urine concentration but other pathways compensate for it

Answer 584

Basolateral membrane - Na+K+ATPase and a K+ channel - creates a strong electrochemical gradient (high Na+ and also strong positive charge) - CLCK - assisted by Barttin an causes the net reabsorption of Cl- Apical membrane - NKCC2 - Transports Na+, 2Cl- and K+ - ROMK - Recycles K+ on apical

Answer 585

Bartters syndrome - Genetic inheritence - Salt wasting and Polyuria - can't concentrate urine - Hypokalemia - Metabolic alkalosis - Hypercalciuria

Answer 586

``` Basolateral - Na+K+ATPase - gradient - Kir2.3 - K+ transport - Aquaprin 3 and 4 - always active to reabsorb water Apical - ENaC - Na+ channel into cell - ROMK - K+ out - Aquaporin 2 - active in the presents of vasopressin to reabsorb water ```

Answer 587

When water is reabsorbed in the collecting duct the concentration of urea increases so creates a driving force for urea to diffuse out into the interstitial fluid Some urea is reabsorbed back into the the thin ascending limb

Answer 588

Basolateral - UT-A3 Apical - UT-A1

Answer 589

When allowed water - Osmolality of knockouts urine is half of wild type When water deprived (osmolality should increase o conserve water) - Knockouts stays the same but wild types doubles

Answer 590

Because if it was a normal blood supply so that it wen from the cortex to the medulla and out then the H20 would be moved out and solutes in

Answer 591

That the kidneys specialise blood supply (the vasa recta) loops - Goes from the cortex to the medulla and then back to the cortex As plasma moves down ascending limb - driving forces (osmotic and conc) for H20 and solutes in Moves to medulla and driving forces pus solutes back out and water back in - Keeps osmolality the same

Answer 592

Mediates the movement of urea in blood cells

Answer 593

Struggle to concentrate their urine | - Counter current multiplication works but counter current exchange doesn't

Answer 594

pH = -log[H+]

Answer 595

Typically arterial end of tissue bed is 7.35 and venous is 7.45

Answer 596

Excitability of muscle and nerve Enzyme activities K+ levels

Answer 597

Gastric secretions - 0.7 pH units Cerebrospinal fluid - 7.3 Pancreatic secretions - 8.1 Final urine - 5.4

Answer 598

``` Metabolism: Large amounts acid - 15 moles/day of CO2 (lungs) - 40 mmol/day net H+ - Western diet an excess of H+ Diet: Alkali (fruit ) and acid in food 20 mmol/day H+ Loss base: 10 mmol/day OH- Net excess 70 mmol/day H+ ```

Answer 599

1. Blood and tissue buffers – seconds 2. Respiration – minutes 3. Renal – hours/days - only mechanism for extrusion (add/remove) where as the others only minimise

Answer 600

Blood Extracellular fluid Intracellular fluid Urine

Answer 601

Haemoglobin HCO3- Inorganic phosphate Weak acids/bases on proteins

Answer 602

Bicarbonate

Answer 603

CO2+H2O H2CO3 H+ +HCO3

Answer 604

Increase in CO2 - Will bind with water to form biarbonate which will dissociate into H+ and HCO3 - Increase pH Increase in H+ ions - Will bind with HCO3 forming H2CO3 and dissociate into CO2 and H2O - Decrease in pH

Answer 605

pH = pK + log [HCO3]/[H2CO3} ``` Where pK is a constant and at body temperature its 6.1 Normally [HCO3}/{CO2] - 20:1 6.1 + log 20 = 6.1 +1.3 = 7.4 => normal pH ```

Answer 606

Metabolic acidosis

Answer 607

Metabolic alkalosis

Answer 608

Respiratory alkalosis | - Suggests problems with the lungs

Answer 609

Respiratory acidosis | - Suggests problems with the lungs

Answer 610

Carotid and aortic bodies

Answer 611

Hypoxia - Fall in pO2 in presence of low oxygen

Answer 612

Glomus cells depolarise and fire action potentials which go to nerves and signal the respiratory system to change rate

Answer 613

Small - 2mg 40 times more blood going through chemoreceptors than brain High metabolic rate Glomus cells Type II cells - supporting role Have sympathetic and parasympathetic inputs

Answer 614

- A decrease in pO2, pH or an increase in pCO2 causes inhibition of BK K channels - Causing depolarisation of glomus cell and an action potential is fired - Causes Ca channels to open - Increase Cai - Causes the release of neurotransmitters (Act, dopamine, NA, 5-HT, substance P and ANP) - Causes stimulation of afferent nerve fibres

Answer 615

Hypercapnia | - High CO2

Answer 616

Within the brain parenchyma, ventrolateral medulla and other brain stem nuclei - Bathed brain in extracellular fluid - Separated from arterial blood by blood brain barrier

Answer 617

It has poor ion permeability - Doesn't allow H+ to cross - But does allow CO2 - causes acidosis of the brain extracellular fluid - stimulates chemoreceptors

Answer 618

So that the pH change there will be greater than in the blood so that central chemoreceptors will be activated

Answer 619

Respiratory - Because metabolic changes ion concentration of the blood but this can't pass the brain blood barrier due to its low permeability

Answer 620

- Acid activated - activated by serotonin | - Acid inhibited - activated by GABA

Answer 621

They are believed to be lacked acid activated neurones so can't regulate their blood pH well enough

Answer 622

Both respond - Peripheral respond first - Central will be responsible for 65-80% of the drive to change the pH because the o2 levels will be normal - which is the main drive for peripheral

Answer 623

Peripheral have an acute repsonse and central a longer term role Will cause severe hyperventilation in an attempt to decrease the pCO2 - this will cause the hydrogen ions to decrease and therefore raise the pH

Answer 624

Hyperventalte - decrease in CO2, decrease in H+ and increase pH - Cause mild alkalosis Slow breathing - High CO2, Increase in H+ and decrease in pH - Cause mild acidosis

Answer 625

HCO3- handling Urine acidification Ammonia synthesis

Answer 626

90% in the proximal tubule | 10% in the distal tubule

Answer 627

Basolateral - Na+K+ATPase creates a electrochemical driving force for Na+ - Na+ HCO3- cotransporter Apical - H2CO3 filtered from proximal tubule and dissociates into H2O and CO2 - CO2 diffuses through - H20 moves in through aquaporin 1 - These combine forming carbonic acid - dissociates unto H+ and HCO3- - H+ is recycled back out the apical membrane via the Na+H+ exchanger - HCO3 moves out basolateral - net reabsorption

Answer 628

Acidification of urine - 25% | Ammonia synthesis - 75%

Answer 629

Start with an alkaline salt and convert it to an acid salt | e.g. Na2HPO2 ----> NaH2PO4

Answer 630

Na2HPO4- loses a Na+ through Na+H+ exchanger The H+ goes to the NaHPO4- to form NaH2PO4 - This H+ comes from the dissociation of H2CO3 inside the cell -HCO3- net reabsorbed

Answer 631

Doesn't necessarily have to be the proximal tubule | - Anywhere in the nephron where there is a Na+H+ exchange

Answer 632

Diffusion trapping - Ammonia diffuses out of the cells and is added to H+ to form NH4+ - NH3 formed by the conversion of Glutamate to alpha keto glutamate as it loses NH3 and H+ - H+ diffuses out of the Na+H+ exchanger

Answer 633

- Increase in H+ excretion - Normal HCO3- excretion - Decrease in urine pH - Increase in plasma pH

Answer 634

- Decrease in H+ excretion - Increase in HCO3- excretion - Increase in urine pH - Decrease in plasma pH

Answer 635

Decrease in CO2 elimination - seen in lung disease, emphysema, chronic bronchitis - Leads to high CO2, low pH and HCO3

Answer 636

``` Lungs not functioning properly so can't be fixed by respiration Fixed at the level of the kidney - Increases secretion of H+ - Increases reabsorption HCO3- - Rises pH but causes further rise HCO3- ```

Answer 637

CO2 elimination is high | Caused by ventilation due to fear stress or pain

Answer 638

``` Lungs not functioning properly so can't be fixed by respiration Fixed at the level of the kidney - Decrease in secretion of H+ - Decrease in reabsorption HCO3- - lowers pH but causes fall in HCO3- ```

Answer 639

Ingestion of acid | Loss of alkaline fluid - diarrhoea, cholera, diabetic ketoacidosis

Answer 640

``` Respiratory compensation - Increased respiratory rate - increase in pH and drop in CO2 Renal correction - Increased secretion H+ - Increased reabsorption HCO3- ```

Answer 641

Ingestion of alkaline fluid Loss of acid Vomiting - increase in pH and HCO3-

Answer 642

Respiratory compensation - decrease in respiratory rate - decrease in pH and rise in CO2 Kidney doesn't not help - not understood why

Answer 643

More than one primary disorder | eg. respiratory acidosis and metabolic acidosis

Answer 644

Both same type e.g. Respiratory acidosis and metabolic acidosis Because the pH add together do is life threatening

Answer 645

Asthma - Cant get enough CO2 out so respiratory acidosis - Anaerobic respiration occurs due to lack of O2 so lactic acid is formed - metabolic acidosis

Answer 646

Alcoholics - Metabolic acidosis - breakdown of alcohol - Metabolic alkalosis - vomiting COPD - Respiratory acidosis - can't get CO2 out - Diuretics - metabolic alkalosis promotes loss of H+ Salicylate Poisoning -Respiratory alkalosis - Metabolic acidosis

Answer 647

Gain of function | Autosomal dominant

Answer 648

``` Na+ retention Fluid retention Hypertension Hypokalaemia Metabolic alkalosis Low renin and aldostrerin levels ```

Answer 649

Mutation in ENaC channel which is found on the apical membrane of an epithelial cell - Mutation is in the proline rich motifs in the beta or gamma subunit of ENaC - This is responsible for tagging the protein for endocytosis - This means that ENaC is not removed so Na+ reabsorption is too high and therefore so is water reabsorption

Answer 650

Made of three subunits: alpha, beta and gamma In a 1:1:1 Can transport a small amount of Na+ with just alpha but requires all three for normal function

Answer 651

Much higher amount of Na+ channels opening | Bigger current meaning more Na+ transport - double the current of that of the wild type

Answer 652

(Low plasma K+) - The more Na+ reabsorbed then the more K+ that is recycled across the apical membrane through ROMK as Na+ is exchanged for K+ on the basolateral

Answer 653

- Na+ is possibly charged so if that leaves the cell then it will leave a negative charge - Forming a large transepitheial potential - Creates a big driving force for H+ excretion causing metabloic alkalosis

Answer 654

Hypertension will lead to low renin and aldosterone which in a normal person would lead to ENaC being removed from the apical membrane of the principle cell to stop Na+ and therefore water reabsorption to lower blood pressure - However, in a Liddle's person the ENaC channels cannot be removed as the domain that targets it for endocytosis is mutated - Therefore Na+ and Water + reabsorption does not decrease - Hypertension persists

Answer 655

Amiloride | - Blocks ENaC channels and therefore stops reabsorption of Na+

Answer 656

Usually works as an antagonist against aldosterone | Ineffective in Liddle's as aldosterone doesn't really have an effect

Answer 657

Polyuria Polydipsia (thirst) Dehydration - serious

Answer 658

Massive suppression of vasopressin production | Excessive H2O intake

Answer 659

Found in pregnant women - Placenta produces enzymes that break down vasopressin - Managed by controlling fluid intake - Goes back to normal after birth

Answer 660

Impaired vasopressin production - Acquired - Infection, Head trauma, Surgery - Congenial - Neurohypophyseal D1 mutation, 67 mutations found and anyone of them cause them, some of the mutations cause problems in the trafficking of vasopressin from the hypothalamus to the posterior pituitary

Answer 661

Impaired effect of vasopressin Acquired - more common - Lithium disrupts vasopressin system - bipolar treatment - Some antibiotics, antifungals - Hypokalaemia and hypercalciuria - Acute or chronic renal failure Congenital - Mutation sin ACPR2 (vasopressin receptor) x linked - Mutation in AQP2 gene - impact trafficking (dominant) or function (recessive)

Answer 662

Hypernatrimic dehydration Poor feeding Skin dryness Depressed anterior fontanel - soft spot on babies head

Answer 663

Desmopressin - Nasal spray - Agonist

Answer 664

Difficult to treat - Possibilites are modulator drugs which work when proteins are misfiled but would still be functional if got to the membrane - When misfolded they are sent for degradation instead - These drugs take them to where they need to go instead

Answer 665

``` Nitrous oxide - Horace Wells Ether - William Morton Chloroform - Simpson - stole it from graduate student Robert Glover ```

Answer 666

``` Chemical - Inhalation - Intravenous Physical (not commonly used in medicine) - Hypothermia ```

Answer 667

``` Halogenated hydrocarbons - Isoflurane Barbiturates - Thiopential Steroids - Alphahexane ```

Answer 668

The minimal alveolar concentration to abolish response in 50% of patients to surgical incision

Answer 669

That there is a relationship between lipid solubilty and its potency - Nitrous oxide requires a large volume to admit a response so is safe - Halothene - only requires a small volume

Answer 670

It was thought that the drug entered the plasma membrane and it undergoes lipid expansion causing the membrane to be more fluid in the CNS

Answer 671

Pros - Relationship between lipid solubility and potency - No relationship between structures of the drugs Cons - Temperature effect - If lower temperature then the membrane became more solid even though it acts as a physical anaesthetic -Binding was saturable - suggesting that there is a protein binding site

Answer 672

General anaesthetics can associate with GABAa receptors in the central nervous system

Answer 673

Mutagenises of proteins that were thought to be targets for the anaesthetics

Answer 674

GABAa - receptor for GABA - most common inhibitory protein in the CNS

Answer 675

alpha and beta

Answer 676

Because the binding sites are deep within the protein and to gain access to the set they must enter the plasma membrane - explains the relationship between lipid solubility and potency

Answer 677

Synaptic transmission to CNS decreases - Reticular formation effected causes patient to become unconscious - Effects on hippocampus - short term amnesia - Thalamic sensory relay nuclei parts of complex - analgesia (pain dulling) - Some volatile also inhibit spinal reflexes

Answer 678

Effects all areas of brain function | - Loss of motor control, reflexes, respiration and autonomic regulation

Answer 679

1. Analgesia - Reduces response to pain 2. Excitement - Dangerous - Unconscious - Reflexes are exaggerated and breathing becomes erratic 3. Surgical anaestheisa - Unconscious - Breathing regular - Loss of response to painful stimuli - Short term amnesia 4. Medullary paralysis - Central regulation of cardiovascular is lost - death

Answer 680

``` Rapid induction Loss of consciousness Analgesia Muscle relaxation Rapid recovery Avoid stages 2 and 4 ```

Answer 681

Propofol Thiopental Etomidate

Answer 682

``` Advantages - Easy to administer - Rapid induction - Propofol has rapid metabolism, good for induction of anaesthesia - Rapid recovery Disadvantages - May hide on body fat - difficult to maintain level of anaesthesia - Painful at site of injection - Respiratory depression - Cardiovascular depression ```

Answer 683

The intravenous injection leads to patient being unconscious - Conc falls quickly so another injection would have to be administered in order to keep the patient asleep - After the patient is unconscious an inhaled anaesthetic is used to maintain the level as its easily controlled

Answer 684

Nitrous Oxide, Isoflurane, Desflurane, Sevoflurane

Answer 685

Because the only route of entry/exit is via the lungs

Answer 686

If patient has a specific mutation - Can be triggered by halogenated general anaesthetics - Ca2+ quickly moves out of ER which activated mitochondria to quickly produce lots of ATP and lead to muscle contraction - Uses all available O2 so little available for other parts of the body - Can lead to death

Answer 687

By administrating a drug to block this receptor causing it before using the anaesthetic

Answer 688

``` Powerful analgesia Amnesia Sensory loss Hallucinations Involuntary movements Irrational behaviour on recovery ```

Answer 689

Concentration of drug in inspired gas - less lipid soluble - father equilibrium Pulmonary ventilation - Increase rate of ventilation to increase rate at which a change occurs in the concentration in blood brain barrier

Answer 690

Irregular, uncontrolled muscle contractions - occurs in less than 1 in 100000 - At least 6 types - Type I and II are more understood and affect more people

Answer 691

``` Autosomal dominant Onset 10-20 years Ataxia, dizziness Brief attacks Caused by a mutation in KCNA1 ```

Answer 692

Autosomal dominant Onset child to teens Ataxia, vertigo, nausea, headache Attacks can be 30 mins to 24 hours

Answer 693

``` Trunk instability Vertigo Vomiting Dizziness Nystagmus Nausea Headache Visual blurring ```

Answer 694

Physical or emotional stress, vestibular system, abrupt change position

Answer 695

Loss of function mutation - found in the cerebellum and neuromuscular junction - Causes a decrease in the voltage from it - Will cause a delay of repolarisation in neurones in the cerebellum - Role of the cerebellum is to coordinate groups of muscles - If signal isn't normal then loss of this coordination

Answer 696

``` Acetazolomide - Carbonic anhydrase inhibitor - Changes the pH of body fluid and therefore lower the excitatory of cerebellar cells Carbamazpine and phenytoin - Na+ channel blockers ```

Answer 697

Physical or emotional stress

Answer 698

Many different point mutations Mutation is usually around one of the poor in the protein - not exclusive Mostly truncation mutations

Answer 699

``` Familial hemiplegic migraine - Mis-sense mutations Spinocerebellar ataxia type 6 – repeat expansion C terminus Episodic ataxia type II - Point mutations ```

Answer 700

Mutation position and type determines the phenotype

Answer 701

Purkinje cells Granule cells Cell bodies central neurones

Answer 702

Mutation in CaV then struggle to release neurotransmitters which will control movement in skeletal muscle

Answer 703

- Up to 10 days normal (mimic episodic ataxia type II in humans as doesn't onset until teens) - After 10 days balance problems - Ataxia - Falls with twisting movements - Death 3-4 weeks after birth (more severe then human condition - maybe because completely knockout out where as in humans its just mutated)

Answer 704

The current through the wild type and mutant Ca channels were measured using barium - Results were normalised as the current was divided by the max current recorded - The peak current in the mutant channel was slightly more positive meaning the membrane will have to depolarise by another 8mv before it opens - Takes slightly longer - This reduced Ca2+ influx - Stops neurotransmitter release - Problems with control of skeletal muscle

Answer 705

Acetazolomide - Carbonic anhydrase inhibitor - Changes the pH of body fluid and therefore lower the excitatory of cerebellar cells

Answer 706

- Seizures - Episodic neuronal discharges - 0.5-1% population - The areas of the brain affected determine symptoms - Can be caused by inheritance, brain trauma, infection, tumours

Answer 707

Partial simple - part of brain with no loss of consciousness Generalised simple Partial complex Generalised complex - most of brain and loss of consciousness - most severe

Answer 708

Changes ion channels in response to damage | Autoimmune diseases

Answer 709

Due o balance between inhibitory and excitatory neurones - If too much activity in excitatory - neuronal discharge - seizure - If not enough activity in inhibitory - neuronal discharge - seizures

Answer 710

Depolarisation

Answer 711

Repolarisation

Answer 712

Neurotransmitter release

Answer 713

Post synaptic membrane activation

Answer 714

Post synaptic membrane inhibition

Answer 715

Hyperpolarisation - activate cyclic nucleotide gated channel

Answer 716

It is a voltage gated Na channel that mediates the regulation of inhibitory neurones. It activates the Cav channel triggering the release of ACh which binds to the GABA receptors on the post synaptic membrane of the excitatory neurone causing inhibition

Answer 717

24 transmembrane domains | 4 pores

Answer 718

Loads of different mutations Can be missense or truncation Different types of mutations lead to different types of epilepsy

Answer 719

50% of Nav1.1 channels - compared currents of that and wild type - Wild type has lots of action potentials - Mutant - action potential firing is reduced and gets worse as experiments on

Answer 720

Means less action potentials fired from inhibitory neurone - less GABA released so GABA receptors on excitatory neurones are not activated - depolarisation of excitatory neurone as there is less suppression - increased risk of firing an action potential as resting potential is lowered - seizures

Answer 721

Because there are also gain of function mutations which also cause epilepsy

Answer 722

Truncation

Answer 723

Body temperature rises very quickly in children and triggers a seizure

Answer 724

Loss of function mutation | - Causes an increase excitatory output due to loss of inhibition

Answer 725

Gain of function mutation | - Causes increased excitatory output due to excessive AchR activity so requires less Ach

Answer 726

Gain of function mutation | - Causes increased excitatory output

Answer 727

Don't play a role in production of action potential but change the rate of firing - Change the resting potential in a way that will increase/decrease the rate

Answer 728

Loss of function mutations | - Causes increased excitatory output due to loss of firing control

Answer 729

Pain is protective - to stop damage

Answer 730

Pain disorder - loss of pain - early death - could have an infection and wouldn't know

Answer 731

Pain disorder - Enhanced pain - erythromelalgia - Activated without nociceptor activation - Burning pain, redness, heat

Answer 732

Suggestion is that polymorphisms in Nav1.7 channel may affect peoples sensitivity to pain

Answer 733

No clear reason or focus symptoms interfere with normal productive behaviour

Answer 734

Panic disorder Phobias Post-traumatic stress disorder Obsessive compulsive disorder

Answer 735

Elevated plus maze or cross - Used with rodents - One bar has is open and other has railings - would stay by railings so don't fall off - Is given an anxiolytic then would go on both sides equally Light/dark box - try to hide in the dark compartment - with anti anxiety drugs - go into the light

Answer 736

Lie detector test but can also be used to test the effctiveness of anti anxiety drugs in humans - Measure the conduction of the skin - Conduction is measured better when skin is wet - Sweat when anxious

Answer 737

GABA ionotrophic receptor found on dendrites and somas of interneurones GABA is the most common inhibitory neurotransmitter in the CNS Cl- selective

Answer 738

Agonist binding site | - Causes activation of ion channel

Answer 739

Competitive - Bicuculline No competitive - Picrotoxin - binds inside the channel

Answer 740

5 - 2 alpha - 2 beta - 1 gamma

Answer 741

Beta carboline - Stabelises the closed form of the receptor - Can lead to seizures

Answer 742

Allosteric site | - found on the interface between alpha and gamma subunits

Answer 743

It modifies the activity of a receptor itself | - activation of the allosteric site does not activate the receptor - stops overdose of drugs

Answer 744

Cant overdose | - Doesn't activate GABAa receptors alone - needs the presence of GABA

Answer 745

Enhances the response of GABAa receptors in the presence of GABA

Answer 746

Barbiturates, neurosteriods, alcohol and some general anaesthetics

Answer 747

- Gi/o protein coupled receptor - Mediate slow transmission - Pre-andPostsynaptic - Inhibit voltage-gatedcalcium channels produces presynaptic inhibition - Activate Potassium channels (GIRK) produce postsynaptic inhibition

Answer 748

Found between the two alpha and beta subunits

Answer 749

Summates with the action of other drugs e.g. ethanol

Answer 750

Alpha 4 and 6 have a changed amino acid - histidine to threonine Makes it not sensitive to benzodiazepine

Answer 751

Replace alpha 2 subunit to alpha 4 or 6 y changing the one amino acid Mouse in light dark box won't move into the light given benzodiazepine

Answer 752

Sedation/Anxiolytic - decreased responsiveness to constant level of stimulation Hypnosis - latency of sleep onset is decreased, duration stage 2 (non-rem) -sleep increased, duration of rem sleep decreased Anterograde Amnesia - Prevent memory of events experienced while under their influence eg. Flunitrazepam / “Rohypnol” - Anti-convulsant inhibit development and spread of epileptiform activity - Reduction of muscle tone

Answer 753

Current of GABAa receptor increases with presence of diazepam When diazepam is washed out the current decreases again

Answer 754

Single channel studies were conducted

Answer 755

Increases the frequency of opening of the channel | Conductance is unaffected

Answer 756

Starts to act as an agonist - causes channels to open

Answer 757

Because when concentration increased they cause activation of all GABAa receptors in CNS- complete inhibition - CNS depression

Answer 758

High lipid solubility

Answer 759

Dependant on renal function, age and other medications

Answer 760

When being used for insomnia

Answer 761

Long half life - lasts for days | e.g. when diazepam is metabolised it releases active intermediates

Answer 762

Sleepiness, impaired psychomotor function, amnesia Addictive effects with other CNS depressants, fatal in overdose Tolerance Misuse Physical dependence

Answer 763

Because the highest benzodiazepines can go into is hypnosis - not coma because it is only an allosteric regulator of glutamate so can't overdose

Answer 764

Barbiturates are also allosteric regulators of glutamate but with increasing concentration can become an agonist

Answer 765

Summates in the presence of other CNS depressants - can overdose

Answer 766

Withdrawal effects | - Increased anxiety, insomnia, CNS excitability, convulsions

Answer 767

Benzodiazepine partial agonists Receptor selective benzodiazepine agonists - to remove unwanted side effects Buspirone 5HT agonist - effective in anti anxiety as well as antidepressants takes up to 6 weeks to feel effects B adrenoreceptor antagonists

Answer 768

``` Unprovoked seizures High frequency discharge by a group of neurones Focus Partial or generalised Diagnosis with an EEG ```

Answer 769

``` Head injury - loss of neurones - initiation site for seizures Local lesions Tumours Infection Genetic causes - ion channel mutations ```

Answer 770

Found in children - Do not lose consciousness but as if they switch off momentarily - Mutation in voltage gated Na+ channels

Answer 771

Generalised - all areas of the brain | Partial seizure - abnormal behaviour - only seen on one side on one side of the brain

Answer 772

Altered blood glucose pH Stress and fatigue Flashing lights

Answer 773

Apoptosis of neurones - slight brain death

Answer 774

If a seizure lasts more than two minutes then it is considered a medical emergency Will be given benzodiazepine

Answer 775

Inhibitory synapse - Target GABAa receptors - Cause increase un GABA release - GABA metabolism (enzymes that break down GABA)

Answer 776

Benzodiazepines Barbiturates Uptake inhibitors eg. tiagabine Metabolic inhibitors eg. vigabatrin, valproate

Answer 777

It has a low therapeutic index, causes sedation due to its complex pharmacokinetics

Answer 778

GAD enzyme converts glutamate into GABA - Valproate increases GAD It also uses epigenetic

Answer 779

- histones that are methylanated represses transcription which can be reversed by DNA demethylase - When DNA is acetylated it promotes transcription - valproate favours acetylated form an promotes transcription of enzymes that convert glutamate to GABA

Answer 780

GABA is broken down by GABA transaminase - vigabatrin irreversibly binds to it to stop GABA being broken down - Suicide inhibitor

Answer 781

Na+ channels go from open, closed to inactive before they can open again These drugs stabilise Na+ channels in an inactive state so stops channels from opening so readily - It only works on channels tat have been opened as if they are inactive them must have opened

Answer 782

Phenytoin Carbamazepine Lamatrigine

Answer 783

T type Ca channels e.g.. ethosuximide GABApentin - acts on a subunit on voltage gated Ca2+ channels - not selective for T type Ca channels

Answer 784

Levetriacetam - When associated with protein SV2A it some how decreases the amount of glutamate released from neurones Felbamate - Weak NMDA channel blocker

Answer 785

Mood swings always in same direction - Reactive - response due to events that happen in their life (75%) - Endogenous - can't explpain why (25%)

Answer 786

Patient oscillates between extreme excitement and a low mood Mania can last for several weeks

Answer 787

``` Low mood (aledonia) Suicidal thoughts Irritability Loss of interest in daily activities insomnia/ excessive sleep Loss of appetite Cant concentrate Low self esteem ```

Answer 788

More likely to get cancers, cardiovascular problems | 15-30% of untreated patients commit suicide

Answer 789

Singular cortex and nucleus accumbens

Answer 790

Part of the limbic system | - Causes an increase of BDNF in the brain when stimulated - relieves the symptoms

Answer 791

Important in processing fear in humans

Answer 792

Studies have shown that decreased levels of BDNF can lead to depression

Answer 793

Involved in memory, learning and responses to stress

Answer 794

Cortisol - Released from the hippocampus - Causes a decrease in BDNF - High blood cortisol linked to depression

Answer 795

Peripheral hormones such as leptin also exert centrally in the hypothalamus Leptin plays a role in the bodies control of eating

Answer 796

Usually occurs 2-8 weeks after delivery and in some cases lasts for a year after birth of the baby

Answer 797

Babies brain waves can become altered if the mother is depressed

Answer 798

Still stay depressed due to the biochemical changes at synapses

Answer 799

An animlal model for depression - Put rodent in water - tries to escape and then despairs because can't - Second time put in the tank, rodent gives up trying to escape - When given antidepressants - still tries to escape

Answer 800

The rat keeps trying to turn the right way round until it despairs and just hangs Second time despairs straight away After given antidepressants keeps trying

Answer 801

Immobilised Cortisol levels increase Can see brain change sin amine neurotransmitters

Answer 802

That n depression is caused by a defect in noradrenaline and serotonin Most dugs that affect these neurotransmitters don't effect the patients for 6 weeks even though it causes an immediate decrease in the transmitters - Suggests that they have long term trophic effects and could also effect synapse formation

Answer 803

Stress causes the release of cortisol which increases gene expression leading to neuronal apoptosis

Answer 804

Can cause activation of genes that cause neuronal apoptosis

Answer 805

They usually promote transcription of genes that cause neurogenesis - beneficial If this is lost then there is less neurogenesis

Answer 806

Low concentrations of ketamine can work as an antidepressant

Answer 807

Depletes stores of monoamine transmitters

Answer 808

Serotonin, Noradrenaline and dopamine

Answer 809

First specific antidepressant | Inhibitor of MAO which is an enzyme involved in the break down of monoamines

Answer 810

Eg. Prozac Stop the reuptake of serotonin to increase its action - low side effects - effective in patients whose primary biochemical problem is the 5HT pathway

Answer 811

eg. Imipramine | Work at the level of reuptake but are less selective then SSRIs as they uptake both serotonin and noradrenaline

Answer 812

MAO A enzymes are involved of the breakdown of monoamine transmitters in the central nervous system so by inhibiting them there will be more monoamines in the blood

Answer 813

Monoamine oxidase type B act in the peripheral nervous system so if inhibit them can lead to unwanted side effects eg. problems digesting amine rich foods such as cheese - build up of tyramine in blood which is a precursor for dopamine goes into periphery and causes red flashed skin and fast beating heart

Answer 814

Presynaptic | - Release auto inhibition to increase post synaptic activity

Answer 815

Paim is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage

Answer 816

Nociception is the detection of an innocuous stimulus up to the spinal cord but pain is decided at the brain

Answer 817

The primary order neurones are the first neurones to respond to the stimulus and the second order neurones are the go directly into the spinal cord

Answer 818

Peripheral nervous system

Answer 819

Can change the perception of pain

Answer 820

Because it just removes the limb from a potential innocuous stimulus and only goes to the spinal cord not the brain

Answer 821

``` Primary erythermalgia - Red hands and feet constant inflammation Paroxydmal extreme pain disorder - Pain when they chew - Pain when pass stools ```

Answer 822

CIP (complete insensitivity to pain) - Recessive condition - Can hurt themselves andd not know - Premature death

Answer 823

Acute - Alerts the body to chemical, thermal and mechanical stimuli that has potential to damage body tissue - Has a protective role Chronic - Accompanies chronic inflammatory diseases eg. arthritis - Neuropathic pain results from damage to nerves eg. trauma, diabetes, cancer treatment

Answer 824

$300 billion

Answer 825

The absence of pain without loosing consciousness

Answer 826

The pain circuit - Dorsal root ganglia - Spinal horn neurones - Pain processing areas of the brain

Answer 827

Non steroidal anti-inflammatory drugs (NSAIDS) Paracetamol Opioids

Answer 828

Cardiovascular risk - NSAIDs can cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction and stroke which can be fatal Gastrointensinal risk - Bleeding, ulceration and perforation of the stomach or intestines which can be fatal

Answer 829

``` Sedation - Apathy - Cognitive impairment Depression of respiration - Main cause of death - Combination with alcohol Inhibition of gastrointestinal trat Continuous use of opioids results in addiction ```

Answer 830

Natural opioids: Morphine Semi-synthetic opioids: Heroin Fully synthetic opioids: fentanyl Endogenous opioid peptides: endorphins

Answer 831

Opium is the dried juice of the seed head of the poppy flower Active ingredient morphine was isolated in 1806

Answer 832

Binds to opioid receptors: G protein coupled receptors which lead to inhibit calcium influx and stop release of glutamate

Answer 833

Mu, Kappa and delta

Answer 834

Because there are opioid receptors found everywhere in the body

Answer 835

Another natural opioid isolated from the skin of leaf frog - 30-40 times more potent than morphine on Mu receptors - stable due to a non natural amino acid so is longer lasting

Answer 836

Derived from morphine in 1874 | Acetate groups added which make it more hydrophobic and hence penetrated the brain barrier easier

Answer 837

A synthetic opioid - 100 times more potent than morphine - fast-acting opioid - Used during surgery

Answer 838

Naturally occurring peptide that are found mainly in the CNS - Release during stress and prolonged physical exercise

Answer 839

Enkephalin

Answer 840

Loss of function - Lead to absence of pain Gain of function - Lead to pathological pain - increased

Answer 841

Against never growth factor help in some chronic pain conditions Very expensive

Answer 842

- Block neurotransmitter release - Botox is internalised in presynaptic neurone - Releases enzyme that breaks down snare proteins that are required for neurotransmitter release

Answer 843

Pain, arousal, mood, blood pressure regulation | Regulating sensory processing relates it to withdrawal increased sleep. anorexia

Answer 844

Tyrosine amino acid is converted to DOPA which is precursor of dopamine Dopamine is converted to noradrenaline in neurones where dopamine B-hydroxylase enzyme is found

Answer 845

Neurones that release serotonin have NA receptor When these receptors are activated more serotonin is released - It is suggested that depressed people have less receptors

Answer 846

Found presynaptically and have inhibitory serotonin release through a feedback mechanism - Increase noradrenergic transmission will lead to desensitisation as they will be chronically activated and internalised - Removing feedback inhibition increases serotonin as less receptors

Answer 847

Hallucinations, sleep, wakefulness, mood and emotion, feeding behaviour

Answer 848

Depression, anxiety, migraine, anti-psychotic

Answer 849

The inability to gain pleasure from normally pleasurable experiences - the role of serotonin in regulating the limbic processing relates

Answer 850

Tryptophan - An essential amino acid that needs to be consumed - This is converted into 5HT

Answer 851

Through G protein coupled receptors - potential therapeutic target

Answer 852

Terminated through uptake mechanisms (target for SSRI drugs) and broken down by enzymes MAO (target for drugs) and COMT

Answer 853

Drugs like prozac- symptoms gets slightly worse before better 5HT1 receptors found in dendritic regions and on GABAnergic interneurones in the cortex promote inhibition of serotonin release causing increase in symptoms The receptors then becomes desensitised and internalised and therefore increases serotonin

Answer 854

People with depression have decreased levels of BDNF in hippocampus

Answer 855

Activation of serotonin receptors, increases cAMP (coupled to Gs), to activate protein kinase A, increases activity of transcription factor CREB ethic increases levels of BDNF

Answer 856

Serotonin activates receptors couples with Gs which activated transcription factor of BDNF but inhibits receptors coupled with inhibitory proteins which would inhibit the transcription factor

Answer 857

Because BDNF is responsible for stabilising synaptic connections and promoting synaptogensis in hippocampus so without it this doesn't happen - depression

Answer 858

``` Lithium - Permeates voltage gated ion channels, inhibits inositol monophosphatase and glycogen synthase kinase 3 signalling Antiepileptic drugs - Mood stabilisers - eg. valproate ```

Answer 859

1.1% of people over the age of 18

Answer 860

Negative - Blunting emotions, withdrawal from society, anhedonia, reluctance to perform everyday tasks - Increase with age Positives - Frightening and consist of hallucinations, delusion, thought disorders and aggression - May be accompanied by anxiety an depression

Answer 861

Hereditary and is a result of abnormalities which arise early in life and disrupt normal development - No single gene Als environmental - eg. overuse of cannabis

Answer 862

Larger lateral ventricles | Small volume of tissue in left temporal lobe

Answer 863

Increase positive schizophrenic like symptoms

Answer 864

Nigrostatial pathway - fine motor control - loss of this causes Parkinson's Mesocortical and mesolimbic system - Effects behaviour, compulsion and reward pathways - Schizophrenic Tuberohypophyseal pathway - Pituitary hormone secretion eg. prolactin Medullary chemoreceptor trigger zone - Nausea and vomiting -Side effects to drugs treating schizophrenia

Answer 865

By precursor of DOPA

Answer 866

With uptake mechanisms and broken down by COMT and MAO

Answer 867

Amphetamines stimulate secretion of DA and NA, inhibit MAO and metabolism of DA and NA, displace DA and NA from vesicles, cause re-uptake transporters to work in reverse - Increases motor activity that produces positive symptoms associated with schizophrenia - Effects of appetite

Answer 868

D2 antagonists - 80% occupancy to decrease postive symptoms Phenothiazines - antipsychotics - Long term use leads to tardive dyskinesia Atypical antipsychotic drugs - Reduced side effects

Answer 869

The neuronal action potential causes a muscle action potential which increases intracellular Ca2+ Ca2+ cause cross bridges between actin and myosin to form Myofilaments slide causing contraction More overlap between mysoin and actin before cross bridges form, the more tension

Answer 870

Th motor neurone and the muscle fibres it innervates

Answer 871

More graded contraction -spatial summation

Answer 872

Mediate depolarisation

Answer 873

Mediate repolarisation

Answer 874

Mediates influx of Ca2+ causing fusion of vesicles containing ACh to fuse with the membrane and be released

Answer 875

When activated by ACh causes the release of Ca2+ starting muscle contraction

Answer 876

Same as neuronal action potential

Answer 877

The measure of the number of ions crossing the membrane

Answer 878

Nicotinic and muscarinic - Nicotinic are ligand gated - Muscarinic are GPCR

Answer 879

A non selective ligand gated cation channel - permeable to Na and K so Nernst potential is 0mv Causes depolarisation when open

Answer 880

``` Has 4 types of subunits: 2alpha:beta:gamma:delta 2 binding sites - Both must be activated in order for the channel to be open 4 transmembrane domains ```

Answer 881

9 Gene = CHRNA CHRNA1 is found in skeletal muscle and the rest are found in neuronal tissue

Answer 882

When no agonist bound - closed (C) When one agonist bound -closed (A1C) When two agonists bound - momentarily closed (A2C) When two agonists bound - Open (A2O)

Answer 883

200 vesicles | - so 6000 to 10000 molecules

Answer 884

An autoimmune disease that generates antibodies that target neuromuscular junctions Affects 2-7 per 10000 in UK making it the most common neuromuscular junction disorder

Answer 885

Weakness and tiredness in skeletal muscle | Can be fatal due to respiratory failure

Answer 886

The antibodies bind to the AChR on postsynaptic skeletal muscle meaning that ACh can't bind Receptors that have an antibody bound to them become internalised - reduces amount of receptors

Answer 887

Women - 30's | Males- 60-70's

Answer 888

Individuals who don't have myasthenia gravis have much less antibodies against AChR as shown in an antibody experiment Individuals with varying severity of myasthenia gravis have a much higher amount of these antibodies

Answer 889

It will display mild symptoms of myasthenia gravis | Causes fewer action potentials fired and smaller compared to a control

Answer 890

``` Acetylcholinesterase inhibitors - For mild cases - Stops break down of Ach increasing it - e.g.. pyridpstigmine Corticosteroids and other immunosuppressant - From moderate to severe - reduces antibody levels - e.g. predinisolone, cyclosporin Iv immunoglobulins - Severe - Inject immunoglobulins so that the antibodies bind to them instead Plasmapheresis - For acute - Removal of the antibodies from the plasma like dialysis Thymectomy - Tumour removal - Mechanism not clear ```

Answer 891

Mouse with mild myosthenia gravis improve to normal with the addition of these inhibitors

Answer 892

Invaginations of the muscle fibre | Meaning the action potential drops down into transverse tubule allowing sufficient Ca2+ to be released for contraction

Answer 893

From outside the cell - Action potential causes L-type Ca2+ channels to open and Ca2+ enters cytosol of cell From the sarcoplasmic reticulum - Ca2+ enters the cytosol through ryanodine receptors which are activated by coupling with L type calcium channel

Answer 894

Calcium induced calcium release | - The open probability changes due to Ca2+ entering through L-type calcium channels

Answer 895

Ca2+ ATPase | Na+/Ca2+ exchanger

Answer 896

Ca2+ ATPase | Calrectulin - bind calcium and store it

Answer 897

Hyper excitability of skeletal muscle which affects the frequency and length of action potential Causes muscle stiffness and delays relaxation And myotonic seizures

Answer 898

1:23000 to 1:50000

Answer 899

Myotonia congenita | Paramyotonia

Answer 900

A type of myotonia caused by a loss of function mutation in CLC1 channel

Answer 901

Thomsen's autosomal dominant | Beckers autosomal recessive - more severe, earlier onset

Answer 902

Mutations in CLC1 channel like humans Animal model for myotonia congenita When seizure hits- falls over

Answer 903

Fainting goats Myotonic mice - Mutations in CLCL

Answer 904

Cl- channel that helps set the resting potential working with K+ channels - Nernst for Cl- is -70mv so when these channels open the membrane potential is drove towards it

Answer 905

About half

Answer 906

Causes myotonia congenita - Requires a more positive potential for the same amount of channels to be open compared to wild type - Cl- channels can't contribute to resting potential so it is less negative then it should be

Answer 907

Less - Resting membrane potential is closer to the threshold - Increases contraction

Answer 908

Mexilitene - Inhibits Na+ Channels - Must use lower possible dose otherwise it would block all skeletal muscle

Answer 909

A type of myotonia - Caused by a fain of function mutation in Nav1.5 - Causes issue with inactivation gate meaning channels do not close so more Na+ enters the muscle and depolarisation is prolonged

Answer 910

Cold enhances the trigger - In a normal individual - cold causes a small increase in [Na+] - In a Nav1.4 mutant - a massive increase in intracellular [Na+] in cold - much more sensitive

Answer 911

A inherited autosomal dominant disease that is asymptomatic until patient is under the general anaesthetic halothane

Answer 912

1 in 10,000-50,000

Answer 913

80% death rate | If treated 10% death rate

Answer 914

- Rise in body temperature by 1 degree every 5 mins - proteins will denature after 25 mins - Tachypnea (rapid breathing) - Low plasma O2 - High plasma CO2 - Tachycardia - Rigidity (high contraction of muscle) - Sweating - Shifts blood pressure

Answer 915

Would die of respiratory and lactic acidosis - The muscular rigidity causes muscle breakdown releasing K+ causing hyperkalemia - effecting cardiac and neuronal excitability - death

Answer 916

Because excessive muscle contraction will lead to excessive ATP hydrolysis (releasing heat) Because the ATP is being used up more must be made - also producing lots of heat

Answer 917

Many different gain of function mutations found on the N terminus of the ryanodine receptors found on the sarcoplasmic reticulum of skeletal muscle

Answer 918

Pigs - Mutation at position 614 on the N terminus of the ryanodine receptors causes malignant hyperthermia in both pigs and humans - In pigs it is called porcine stress syndrome as it is activated by both anaesthetics and stress - Causes pigs to have a bigger muscle mass so desirable to farmers - Incidence became higher

Answer 919

Model for malignant hyperthermia Affects with halothane - Wild type no change - Mutant -increase in intracellular [Ca2+] Affect with caffeine - Wild type - ryanodine receptors can be activated with very high levels (15mm) - Murant - responds at a much lower level of caffeine

Answer 920

Dantrolene - inhibits RyR1 IV hydration Diuretics - stops kidney damage from muscle breakdown products NaHCO3 - Counter acidosis Mechanical hyperventilation to remove CO2

Answer 921

A guanidinium neurotoxin that is produced by marine bacteria and founds in animals such as pufferfish and the blue ring octopus

Answer 922

10-100 times more than black widow spider venom | 10000 times more lethal than cyanide

Answer 923

``` Numbness lips and tongue Facial paraesthesia (tingling) Headache Nausea Dizziness Diarrhoea Vomiting Increasing paralysis Respiratory paralysis leading to death - 20 mins to 8 hours ```

Answer 924

Pretty much the same as ingested but without facial effects | - Faster time to death

Answer 925

``` Mechanical ventilation (because you die from not breathing) No anti venom as it binds too strongly to site of action ```

Answer 926

Inhibits voltage gated Na+ channels on both pre and post synaptic membrane - Inhibits depolarisation and loses the ability to contract - Causes failure of neurotransmission and reduction of neurotransmitter release

Answer 927

Because sensory nerves are on the outside of bundles so the toxin reaches them first

Answer 928

Nav1.1-1.7 are sensitive (not 1.5) | Nav1.5, 1.8 and 1.9 are insensitive

Answer 929

Determined by specific amino acids In rats - Wild type as concentration of tetrodotoxin increases inwards current decreases - E387Q mutants ( which changes glutamate to glutamine in the pore region of the channel) - sensitivity to TTX decreases

Answer 930

Tyrosine - Brain and muscle Nav at position 374 - tyrosine and is TTX sensitive - Heart Nav at 374 - cysteine - TTX insensitive - if you change heart Nav cysteine to tyrosine then it becomes sensitive

Answer 931

In garter snakes - Two types - bear lake snakes and willow creek snakes - Same species but different geographical locations - Bear lake are sensitive and willow creek aren't - Willow creeks can eat salamanders which have TTX meaning they are more likely to survive than those who are sensitive

Answer 932

A snake neurotoxin part of the mamba family | They inhibit Kv channels so inhibit repolarisation

Answer 933

``` Early - Weakness/numbness in the bitten extremity Systemic resposes - 30 mins to an hour - Ptosis (drooping eyelids) - Ophthalmoplegia (paralysis of eye muscles) - Dysphagia - Paresis - Respiratory failure - death ```

Answer 934

Kv channels - If blocked in sensory and motor neurones then it blocks repolarisation meaning access neurotransmitters initially released and then no more stores available so no more released - paralysis

Answer 935

A group of toxins released from a cone snail | - Has multiple targets and varying degrees of lethality

Answer 936

Affects nociceptor and spinal cord | Blocks Nav in nociceptors which stops pain

Answer 937

Varying depending on the species and toxin - Burning pain - Swelling - Numbness - Muscle weakness - blurred vision - Paralysis - Coma - If lips become stiff - associated with death

BMS235 Physiology and Pharmacology Flashcards

(986 cards)