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All TP1 and Some TP2 > Physiology And Pharmacology > Flashcards

Physiology And Pharmacology Flashcards

1
Q

Define homeostasis

A

Dynamic equilibrium in the internal environment of living beings

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2
Q

Homeostatic mechanisms

A

Counteract changes in internal environment

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3
Q

Types of homeostatic control:

A 
Nutrient and oxygen supply
Blood flow
Body temperature
Removal of carbon dioxide and waste
PH
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4
Q

4 main features of body control systems

A

Communication
Control centre
Receptor
Effector

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5
Q

4 examples of communication in the body

A

Nervous system → action potentials
Endocrine → hormones
Paracrine → local hormones
Autocrine → signalling molecules released by the cell that act on the same cell

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6
Q

Role Of control centre

A

Determines set point for homeostasis
Analyses input and determines response
Eg brain

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7
Q

Receptor

A

Stimuli acts on a sensor that signals the control centre= afferent pathway
Afferent pathway affects brain

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8
Q

Effector

A

Control centre sends stimuli to effector - efferent pathway

Efferent pathway= brain does something to cause effect

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9
Q

Feed back loops

A

Positive and negative

Feedback loops help stop disease

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10
Q

Negative feedback loop

A

Effecter opposes stimulus

Eg thermoregulation

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11
Q

Thermoregulation - hyperthermia

A

Core temp > 37.2°c

  1. Signals temperature receptors in skin and hypothalamus
  2. Communication through afferent nerves to control centre
  3. Control centre has thermoregulatory centre, hypothalamus
  4. Response carried by efferent nerves to effector
  • vasodilation
  • increased sweating
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12
Q

Thermoregulation, hypothermic

A

Core temp <37.2°c

  1. Signals temperature receptors in skin and hypothalamus
  2. Communication through afferent nerves to control centre
  3. Control centre has thermoregulatory centre, hypothalamus
  4. Response carried by efferent nerves to effector
  • vasoconstriction
  • increases metabolism and shivering
  • decreased sweating
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13
Q

Positive feedback

A

Stimulus produces response which increases effect of stimulus
Out of control system → catastrophic change

Eg- blood clotting, ovulation, muscle contraction in child birth

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14
Q

Circadian / diurnal rhythm

A
  • Biological process that displays an untrainable oscillation-within an organism of about 24 hours
  • things occur at different set points during the day
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15
Q

Circadian / diurnal rhythm examples

A

Blood cortisol - pecks at 7am, body gets ready for action, dips at 7pm and rises overnight to reach 7 am peak
Biological clock built into hypothalamus
Menstrual cycle
Melatonin → secreted at night levels decrease during day

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16
Q

Clinical applications - pyrexia (fever)

A

• Raises core body temp above set point to speed up immune system
PGE2 acts on thermoregulatory centre to reset the set points to a higher value
- PGE2 is formed when enzyme cycle-oxygenase 2 acts on arachidonic acid
- anti fever drugs like paracetamol block the enzyme and inhibit PGE2 production so set points and temperature can’t be increased - no fever

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17
Q

Chincal applications of hyperthermia and hypothermia

A

Artificially induced hyperthermia= used in some cancer treatments
Artificially induced hypothermia= used in treatment of stroke, traumatic head injury, brain and cardiac surgery to reduce tissue carnage

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18
Q

Where is water distributed

A
  • Extracetular fluid= interstitial fluid between cells
  • intracellular fluid - water in the cells
  • blood plasma
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19
Q

Body water

A

70 kg mole = 42l water

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20
Q

Osmolarity of blood plasma

A

Increase osmolarity (a lot of solute compared to water)
release ADH from pituitary
Increase reabsorption of water from urine → blood
Leading to decreased osmolarity

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21
Q

HPA axis _ hypothalamic pituitary adrenal axis

A

CRH released from hypornalamus
CRH stimulates secretion of ACTH from anterior pituitary gland
ACTH transported through blood and acts on adrenal cortex
-ACTH inhibits CRH release
- cortisol inhibits release of CRH and ACTH

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22
Q

Ligand

A

Small molecule that binds specifically to receptors site

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23
Q

Agonist

A

Birds to receptor and activates it

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24
Q

Antagonists

A

Bird to receptors but do not activate, block it instead

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25
Q

Endogenous

A

Naturally formed within the body

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26
Q

4 types of endogenous signalling molecules

A

Endocrine - hormones
Paracrine - local hormones
Autocronine- act on themselves
Neurotransmitters

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27
Q

Exogenous

A

Substances from outside the body that we introduce in the body

  • drugs
  • hormones used as drugs = insulin - adrenaline
  • drugs that mimic hormones (hydrocortisone acts as cortisol)
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28
Q

Endocrine system - signaling molecule examples

A

Hydrophilic 1 amines → amino acid derivatives, small charged and hydrophilic act as receptors in membrane - synthesis of second messengers

Hydrophilic 2 peptides and proteins → short chains to complexes receptors in membrane - synthesis of second messengers

Lipophinlic -steroids → derived from cholesterols, intracellular receptors can pass through membrane - nuclear, receptor hormone complex controls transcription and stability

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29
Q

Paracrine signalling molecules exumpees

A

Eicoscenoids - important for inflammatory response

  • prostaglandin
  • leukotrin

Cytosine - communication in immune system

  • interleukines
  • chemokines
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30
Q

Neurotransmitters examples

A

Amino acids

  • glutamate - excitatory
  • glycine - inhibitory
  • GABA - inhibitory

Monoamines

  • adrenaline-excitatory
  • noradrenaline - excitatory
  • dopamine - excitatory and inhibitory
  • serotonin - excitatory

Peptides
-acetylcholine

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31
Q

Signal transduction process

A
  1. Receptors capture extracellular changes in environment

2. Receptor transmits change into intracellular environment

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32
Q

4 targets for drugs

A

Receptors
Ion channels
Transporters
Enzymes

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33
Q

4 receptor (rite) sub types

A

Kinase linked receptors
Ion channel
Nuclear / intraceliaar
G protein coupled receptors

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34
Q

Kinase linked receptors (king) example

A

Tyrosine kinase

  1. Exist as 2 monomers when inactive
  2. Ligand molecule binds to each monomer to activate it → monomers join to form dimer
  3. Activates phosphorylation of tyrosine in receptor = conformational change
  4. Now receptor can bind to activate previously inactive proteins through phosphorylation
    .
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35
Q

Ion channels / ligand gated (king) (rite) examples

A

Enables flow of ion down electrochemical gradient
Eg
- calcium channels
- nicotinic acetylcholine receptor - 2 acetylcholine molecules bind to receptor causing conformational change= channel opens up allow entryof sodium ions

I. Normally inactive

  1. When bound by ligand - channels open for as long as ligand is bound
  2. Changes membrane permeability to ion, allows entry
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36
Q

Nuclear / intracellular receptor examples (king)

A

Ligand that binds to receptor must be lipid soluble

  1. Receptors bind to ligand
  2. Ligand receptor complex migrates to nucleus
  3. Complex binds to gene transcription factor - activates / inactivated it

Ligand examples= thyroid hormones + vitamin D as they resemble steroids

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37
Q

G protein couple receptors example (king)

A

Gs = stimulatory
Gi - inhibitory
Gq = act on other things

Variety of ligands act on these receptors (neurotransmitters and hormones)

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38
Q

Transporters examples (rite)

A

SSRIs eg fluoxetine antidepressant
- innibrits reuptake of serotonin so it remains in synaptic cleft longer.

PPIs proton pump inhibitors eg omeprazole

  • inhibits H.+ influx (movement) into stomach to keep it less acidic
  • reduce gastric reflux

Loop diuretics

  • increase sodium, potassium, chorine ion symport activity
  • treat fluid retention
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39
Q

Enzymes (rite) examples

A

Convert signalling molecules to different forms
- aspirin binds to cyclo oxygenase enzyme
Competitive inhibition

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40
Q

Methods to measure core body temp

A
  • ear = most common
  • forehead
  • oral
  • armpit
  • rectum
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41
Q

3 aspects of signal transduction

A

→ respond to signals by producing a series of cascading signal events resulting in a response
1. Reception of the signal
2 transduction
3. Response

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42
Q

Receptors - signal transduction

A
  • > can be intracellular (in cytoplasm) but majority of extracellular signalling molecules don’t cross membrane
  • as receptors are usually located as cell surface they used transduction pathway to generate a response
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43
Q

GPCR structure

A

Located within plasma membrane

3 components

  • inactive G protein made of 3 subunits - alpha, beta,gamma
  • receptor
  • inactive effector

Exiracelular regions-e
Cystolic regions-c
- transmembrane regions hi-h7

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44
Q

GPCR mechanism of action overview

A
  1. Ligand binds to gpcr → conformational changes lg protein)
  2. GPCR activates the guanine nucleotide binding protein
  3. Conformational changes happen and effector is activated

4 leading to production of secondary mess angers - amplification

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45
Q

GPCR agonists

A

Bind to receptors and activate response = signal transduction

Beta2 adrenoreceptor agonists - salbutamol, salmetrol
U opioid receptor agonists - morphine, fentanyl

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46
Q

GPCR antagonists

A

Bind to receptor but do not activate it - block effects

  • beta adrenoreceptor antagonists - propranolol, atenolol d2
  • dopamine receptor antagonists - haloperidol,sulpride
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47
Q

How does gpcr activate G protein

A
  1. Inactive gpcr - no ligand binding so G protein alpha subunit is bound to GDP
  2. Ligand binds to gpcr = conformational changes to gpcr and G protein
  3. GDP released from alpha subunit on G protein and GTP is bound = activated G protein
  4. Alpha subunit bound to GTP dissociates from beta gamma subunit
  5. Subunits can now interact with effector proteins

When signal is weak - opposite happens, alpha subunit releases G tp due to conformational changes and binds GDP

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48
Q

Gi

A

Inhibits adenylyl cyclase

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49
Q

Gs

A

Stimulates adenylyl Cyclades

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50
Q

Gq

A

Effects phospholipase c

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51
Q

Alpha subunits and adrenaline/noradrenaline pathway

A

Beta adrenoreceptor G.s stimulates adenylyl Cyclase - increase cAMP
Alpha 2 adrenorecptor gi inhibits adenylyi cyclase - decrease cAMP

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52
Q

Alpha subunits and acetylcholine pathway

A

Alpha adrenoreceptor Gq - stimulates phospholipase c
m 2 muscarinic gi inhibit adenylyl cyclase
m 3 muscarinic gq stimulate phosprolipase c

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53
Q

Effector - adenylyl cyclase

A
  • Same signal can produce both a stimulartory alpha subunit - more cAMP or an inhibitory alpha subunit - less cAMP
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54
Q

Calcium ions in intracellular fluids

A

Normally maintained at extremely low concentration inside cells at a concentration at least 10000 times less than in extracellullar fluid

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55
Q

Calcium in extracellullar fluid

A

Free calcium
Protein bound calcium
Chelated calcium - bound to complexes

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56
Q

Regulation of calcium

A

Regulated by parathyroid hormone - stimulates calcium release and activates vitamin D which increases calcium absorption

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57
Q

Dysregulation of calcium ions

A

Hypercalacemia

Hypocalacaemia

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58
Q

Physiological functions of calcium ions

A
  • Muscle contraction = action potential that releases calcium stored in sarcoplasmic reticulum
  • gene expression
  • apoptosis
  • second messengers
  • fertilisation
  • hormone release
  • metabolism
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59
Q

3 storage spaces for calcium ions

A
  • extracellular fluid
  • cytoplasmic endoplasmic reticulum
  • mitochondria
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60
Q

3 calcium extrusion protein

A

ATP dependent

  • SERCA = is a calcium ATP ase that actively transports calcium into the er
  • PMCA = plasma membrane calcium ATP ase actively transports calcium from cytoplasm to the outside of the cell

Transporter mechanism
- NCX = sodium calcium exchanger that uses sodium gradient to drive calcium, 3 sodium needed to move one calcium

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61
Q

Mechanisms that increase intracellular calcium.

A
  • voltage operated (gated) calcium channels - at significant depolarisation channels open and calcium moves into cell
  • ligand gated channels - open when bound by a ligand cause influx of calcium
    IP3R channels = ligand bind t activate receptor associated to G protein that associates with phospholipase C - produce IP3 that acts as a ligand and induces efflux of calcium former
    Ryanodine receptor = increase calcium in er which causes it to open and release calcium into cytosol
  • storage operated
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62
Q

Increase cytosolic calcium.

A
  • influx of extracellular calcium from PMCA

- influx calcium from internal stores ligand gated channels

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63
Q

Decrease cytosolic calcium

A

ATP dependant= SERCA + PMCA

Transporter=NCX

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64
Q

Calcium sensors

A

Calcium signalling may be mediated using ere binding of calcium to proteins that go and regulate other proteins

Calmoduin

  1. calcium binds to calmodulin
  2. Binding causes conformational change in calmodulin structure
  3. Modifies and interacts with target proteins
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65
Q

3 properties of membranes

A

Communication
Reception
Selectivity

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66
Q

General structure of plasma membranes

A 
Phospholipid bilayer
Integral proteins
Peripheral proteins
Carbohydrates
Schwann cells
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67
Q

What can move across the membrane

A

Hydrophobic, small uncharged polar molecules → pass through membrane via passive diffusion

Large uncharged polar molecules → pass through membrane via facilitated diffusion

  • channel proteins
  • carrier proteins
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68
Q

Proteins - plasma membrane

A

Integral: span whole width membrane from one side to another
Peripheral: only present on one side of the belayer

Structure + selectivity
Functions:
- produce signals
- response
- communicate
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69
Q

Carbohydrates- plasma membrane

A

Glycoproteins
Glycolipids
Glycocalx

Cell recognition

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70
Q

Plasma membrane atpases

A

Use energy from ATP hydrolysis to transport ions and molecules against the concentration grader

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71
Q

Sodium potassium atpase

A

Removes 3 sodium ions from inside cell and allows 2 potassium ions to enter

  • regulation of calcium ion concentration
  • regulation of ph
  • regulation of cell volume
  • regulation of ion gradients and nutrient uptake
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72
Q

Sodium potassium ATP ase and control of calcium

A
  1. Sodium potassium ATP ase hyclrolyses ATP allows ion gradient by reducing the sodium ions concentration in cells (3 move out)
    2 drives action of NCX exchanger that exchange 3 sodium for 1 calcium
    - direction of ion exchange depends on membrane potential
    - in polarised cells calcium is transported out of the cell and sodium moves in
    - in depolarised cells sodium is transported out of the cell and calcium moves in
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73
Q

4 ion transporters controlling intracellular calcium

A

PMCA - exchange calcium for hydrogen - remove calcium from cell
SERCA - exchange calcium for hydrogen - pump calcium into er
NCX - exchange calcium for sodium
Calcium uriporters move calcium into mitochondria

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74
Q

Sodium potassium ATP ase, NCX and the heart

A

Ventricular systole - pumping - cells are depolarised calcium enters through NCX
Ventricular diastole - filling -polarised cells, calcium leaves through NCX

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75
Q

4 transporters that regulate intracellular ph

A

NHE - sodium hydrogen exchanger, acid extrusion remove h+ ions
NCBE - co transporter, transports ions (sodium, chloride, hydrogen, carbonate) allows alkali influx and acid extrusion
NBC - co transporter allows influx of sodium and carbonate ions - alkali influx
AE- anion exchanger - alkali extrusion (acidifies cell)

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76
Q

Cellular ph regulation

A

Regulated by movement of hydrogen or carbonate ions

Alkalinisation of ph (too alkali) activates AE or NBC to remove carbonate ions and reduce ph
Acidification of ph (too acid) activates NHE or NBC to remove hydrogen ions and increase ph

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77
Q

Cell volume regulation

A

Sodium, potassium and chloride ions regulate osmotic stability of cells → control cell size by manipulating movement of ions as water follows ions

  • cells extrude ions in response to swelling (efflux) - hypotonic stress
  • cells influx ions in response to cell shrinking - hyertonic stress
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78
Q

Ions in intracellular fluid

A

High potassium

Low sodium, calcium, chloride

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79
Q

Ions in extracellular fluid

A

Low potassium

High sodium, calcium, chloride

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80
Q

2 synapse types

A

Chemical

Electrical

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81
Q

Electrical synapses

A

→ synaptic celft is bridged by proteins called connexons that from a connexon = allow direct passage of an action potential from one neuron to another

  • Found on Neuronal and non-neuronal cells
  • direct transfer of ionic current
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82
Q

Chemical synapse

A

→ neurotransmitter is released into the synapse by presynaptic neuron and effect post synaptic neuron
- Occurs in brain, spinal cord, autonomic nervous system, and skeletal muscle
Normal synapse with vesicles

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83
Q

3 types of synapse ‘

A
  • axodendritic: axon terminal to dendrites of neighbouring cell
  • axosomatic: axon terminal to soma of neighbouring cell
  • axoaxonic: axon terminal to axon of neighbouring cell
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84
Q

Convergence

A

several presynaptic neurons communicate to one postsynaptic neuron at the same time

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85
Q

Divergence

A

single presynaptic neuron communicates with many postsynaptic neurons

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86
Q

Asymmetrical synapse

A

Excitatory

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87
Q

Symmetrical synapse

A

Inhibitory

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88
Q

3 classifications of neurotransmitters

A

Amino acids
Amines
Peptides

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89
Q

3 neurotransmitters

A

Glutamate
GABA
Glycine

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90
Q

Glutamate

A

Most abundant in brain
Present in all cells

1. Glutamate released
2. Acts on glutamate receptors – sodium channels
3. Channeles open 
4. Depolarise membrane
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91
Q

GABA

A

an inhibitory neurotransmitter of the brain synthesized only by neurones that release them

1. GABA released
2. Binds to GABA type A receptor 
3. Conformational change
4. Open up chloride ion channel
5. Hyperpolarise membrane
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92
Q

Glycine

A

Inhibitory neurotransmitter of spinal cord

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93
Q

Steps of neurotransmitter release

A
  1. As action potential sweeps down membrane, voltage gated calcium channels detect depolarisation
    1. Opens calcium channels
    2. Influx of calcium ions
    3. Raises intracellular calcium levels
    4. Activates mechanism to transport vesicle to membrane
    5. Vesicles fuse with membrane
    6. Neurotransmitter release
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94
Q

3 ways to remove neurotransmitter

A
  • Diffusion = neurotransmitter diffuses away
    • Reuptake mechanism into presynaptic terminals using proteins recycle
    • Enzymatic degradation – enzyme breaks down neurotransmitter
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95
Q

Why remove neurotransmitters from the synapse

A

it it remains around a receptor it will continue to stimulate the receptor
receptor desensitisation

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96
Q

Depolarising EPSP -excitatory post synaptic potential

A

e.g. glutamate and sodium ion channels, glutamate binds and opens up sodium ion channels = deoplarise membrane

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97
Q

Hyperpolarising IPSP inhibitory post synaptic potential

A

e.g. GABA and chloride ions – GABA acts on receptor, opens chloride ion channel,membrane more permeablt to ions = hyper polarise

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98
Q

Quanta

A

Smallest unit in which transmitter is released

- Number of quanta may vary but quantal size if fixed

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99
Q

Temporal summation

A

• Neuron fires action potential causes release of action potentials in sequential fashion
- summation of stimuli in close span of time at same synapse

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100
Q

Spatial summation

A

. • Several neurons fire action potentials at one target neuron
- summation of stimuli at more than one synapse on some cell

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101
Q

2 factors affecting synaptic transmission

A

Distance of synapse from spike initiation zone
- stronger when closer to spike initiation zone
Depolarisation decreases with distance

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102
Q

Presynaptic modulation

A

• Receptors on the presynaptic terminal may regulate the release of the neurotransmitter
Can inhibit neurotransmitter release
Can stimulate more release of neurotransmitter

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103
Q

Inhibitory modulation

A
  • receptors hyperpolarise cell
  • lack of signal for vesicle to fuse with active zone
  • inhibit calcium or potassium channels to inhibit neurotransmitter release
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104
Q

2 types of presynaptic receptors

A
  • autoreceptors

- heteroreceptors

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105
Q

Autoreceptors

A

receptor recognises the transmitter that is released from that terminal of that neuron

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106
Q

Heteroreceptor

A

recognise other transmitters which are different from that released by that terminal

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107
Q

Motor neurons

A

→ one motor neuron can innervate many muscle fibres

-axons run out from ventral root.

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108
Q

Motor neurons receive input from

A
  • Upper motor neuron in brain
    • Sensory inputs from muscle spindles
    • Spinal interneurones – linke between sensory input and motor output
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109
Q

Motor unit

A

Alpha motor neuron and the muscle fibre it innervates

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110
Q

Neuromuscular junction structure

A
  • Large number of active zone = large neurotransmitter release
  • folded motor end plate - increases surface area and number of receptors

Neuron and muscle cell junction

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111
Q

Neurotransmitter release (nmj)

A
  1. Depolarisation ap opens voltage-gated Ca2+ channels (i.e. increased PCa)
    1. Ca2+ enters nerve terminal down electrochemical gradient – significant influx of calcium ions (increases intracellular calcium)
    2. fusion of vesicles with presynaptic membrane - Acetylcholine (ACh) released into neuromuscular junction
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112
Q

Neurotransmitter binding (NMJ)

A
  1. ACh binds to receptor (nicotinic AChR- 2 ACh each bind to one of 2 alpha subunits) on postsynaptic membrane (end-plate)
  2. These receptors are ligand gated ion channels
  3. Binding (conformational change) opens up the ion channel permeable to sodiuma and potassium ions
    1. Membrane is much more permeable to sodium ions, sodium ion influx = depolarisation of membrane to-20mv end plate potential
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113
Q

Transmission of electrical signals at NMJ

A
  • fast
    • EPP generated by ligand-gated channels → depolarise to –20mV opening voltage-gated channels(for sodium) (generate AP)
  • threshold for ap easily passed due to large number of sodium channels
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114
Q

Nicotinic receptor

A
  • Ligand-gated ion channel, 5 protein subunits (two alpha’s) which span plasma membrane
    • 2 alpha subunits – have binding sites for ACh, 2 ACh molecules must bind to activate receptor

Binding = pore opens

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115
Q

How is acetylcholine removed

A

Acetylcholine that dissociates from receptor is hydrolysed by acetylcholinesterase to form:
- acetyal groups
- choline
Both are recycled - new acetylendine

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116
Q

Myasthenia Gravis

A

Autoimmune disease → antibodies work against nicotinic receptors bind and block them
- acetylcholine is degraded

Treatment - reduce amount of acetal cholinesterase so more acetylcholine is in the NMJ

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117
Q

5 drugs that affect neuromuscular junction

A 
Hemicholinium
Botulinum toxin
Tubocurarine
Suxameethonium
Neostigmine
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118
Q

Botulinum toxin

A

Blocks release of acetylcholine

Paralysis of skeletal muscle

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119
Q

Hemicholinium

A

Blocks choline reuptake after acetylcholine is hydrolysed - no new acetylcholine formed

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120
Q

Tubocurarine

A

Blocks nicotinic receptors

Does not activate them

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121
Q

Suxameethonium

A

Blocks nicotinic receptors

This drug is 2 acetylcholine molecules bound together that can’t be broken down by acetylcholineesterase

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122
Q

Neostigmine

A

Inhibits acetylcholinesterase

Used in ancesiresia

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123
Q

Resting membrane potential

A
  • inside is negative
  • outside is positive
    Voltage across membrane at rest -normally -65 mV

Slightly more permeable to potassium - leaky ion channels

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124
Q

3 factors affecting distribution of electrical charge

A
  • Permeability to different ions
    • Concentration gradient across the membrane
    • Electrical gradient across membrane (due to voltage)
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125
Q

Membrane permeability

A 
-Ion channels in membrane
Greater permeability to an ion means it can easily flow into cell
- voltage gated
- ligand gated
- leak channels
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126
Q

Concentration gradient - ion concentrations

A

Inside cell

  • sodium, calcium, chorine-low
  • potassium- high

Outside cell

  • potassium -low
  • sodium, calcium, chorine - high

Ions move from high → low

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127
Q

Ion pumps

A

Go against concentration gradient

* The Na-K pump exchanges 3 internal Na + ions for 2 external K+ ions at the expense of ATP (pumps ions against concentration gradient) 
* The Ca2+ pump transports Ca2+ out of the cell (+ other mechanisms) - intracellular calcium levels = very low
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128
Q

Electrical gradient

A

Movement of ions depending on charge

  • positive → negative
  • negative → positive• K+ diffuses down conc gradient to move out of the cell but diffusion is self limiting due to electrostatic repulsion between potassium ions
    —> as electrical gradient drives K+ into the cell and conc gradient drives K+ out of cell = equilibrium
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129
Q

Glial cells

A

Support cells for neurones

Hoover up potassium ions

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130
Q

Nernst equation

A
  • Use x 10-3 to change units
    Out/in
  • equilibrium potential - membrane potential where net flow through any open channel =0
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131
Q

Importance of potassium

A
  • Increasing external potassium - depolarisation
  • huge influx of potassium
  • toxic in large amounts
  • cause arrhythmia or stop heart beating
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132
Q

Depolarisation

A

Sodium ions move into cell

Membrane becomes more positive

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133
Q

Repolarisation

A

Sodium ion channels close

Some potassium ion channels open

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134
Q

Hyerpolarisation

A

More potassium ions move out

Membrane becomes more negative

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135
Q

Threshold potential

A

Membrane potential required for an ap to form

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136
Q

Steps of an ap

A
  1. Resting potential - stimulus triggers change
  2. Depolarisation = sodium chanels open and starts further depolarisation of the membrane – to reach threshold potential
  3. Repolarisation - sodium channels close and potassium open
  4. Hyperpolarisation – undershoots, as excess number of potassium channels are open, excess potassium channels close and potassium leak channels remain
  5. Sodium potassium at pase works to restoreme membrane potential
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137
Q

Conductance of action potential

A

Depends on:

  • diameter of axon
    Longer= faster
  • myelination
    Myelinated= faster conduction skips to next node
    In CNS myelin formed by glial cells, in PNS - Schwann cells
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138
Q

Ion conductance

A

Measure of relative permeability for specific ions (g)

  • proportional to current when voltage is consistent
  • proportional to number of open ion channels
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139
Q

Action potentials

A

Are all or none events

- you either get an action potential or don’t

140
Q

Refractory period

A

Limit to frequency of firing action potentials
-absolute
Relative

141
Q

Absolute refractory period

A

period of time measured from the onset of the action potential, during which another action potential cannot be triggered

  • sodium channels inactivated
  • excess potassium channels open
142
Q

Relative refractory period

A

period of time following an action potential during which more depolarising current is required to achieve threshold than normal

  • need stronger stimulus due to hyperpolarisation
143
Q

Propagation of an action potential

A

Action potential depolarises membrane

  • insides becomes positive
  • outside becomes negative

→ action potential cannot change direction

144
Q

5 blockers of excitability -general action

A
  • Tetrodotoxin
  • scorpion toxin
  • cooling
  • sodium channel blockers
  • potassium channel blockers
    • Delay to threshold
    • slow rate of rise of action potentials
    • reduce rate of action potential conduction
    • eventual failure of action potentials
145
Q

Tetrodoxin

A 
-blocks the pore of Na+ channels in the membranes of excitable cells. = blocking sodium channels means no action potentials
Causes
-tingling in mouth
-numbness
- diarrhoea
- death
146
Q

Scorpion toxin

A
  • • Increases the probability of sodium channel opening (open at lower threshold,) and inhibit inactivation.

Only one initial action potential then stays open

147
Q

Cooling

A
  • cool to lower temp blocks action potential
148
Q

Sodium channel blockers

A

Blocking sodium channels should prevent pain

  • Lidocaine - prevent cardiac arrhythmia
  • tocainide - tested for use in neuropathic pain
  • phenytoin - control epileptic convulsions
149
Q

Potassium channel blockers

A
  • tetra-ethyl ammonium (TEA)
  • 4-amino-pyridine (4-AP)
    .
150
Q

Measuring resting membrane potential

A
  • Push hotglass rod electrode them through cell without damaging it
    • Make a circuit
    • Find voltage of cell inside relative to the outside
151
Q

Drugs + target

A
  • Drug exert effect when binding to targets
    • Targets can be proteins but there are other examples

Drug-receptor interactions mirror ligand- receptor interaction

152
Q

Ligand

A

-> something that binds to a receptor eg. Drug

Concentration of ligand molecules around receptor can help determine drug action
- can be selective for specific receptor

153
Q

Molarity

A
  • (g/L)/ molecular weight

- use molarity as it describes concentration of molecules per litre

154
Q

Gpcr superfamily

A

–> big area in drug targeting, over 800 discovered
Easy to identify these GPCRs but we do not know all the ligands that aGPCRs
• Orphan receptors - potential targets
Receptors that we don’t know what ligands bind to them – potential drug targets that can be explored

155
Q

Drug-receptor interactions

A
  • Most drugs bind reversibly to receptors
    Can either associate or dissociate
  • binding obeys law of mass action = the rate of chemical reaction is directly proportional to the concentrations of reactants and products
156
Q

4 benefits of knowledge of drugs ligands and receptors

A
  • Helps us to better understand physiology and pathology
  • Helps us to understand drug action
  • Informs clinical decisions
  • Allows development of new drugs
157
Q

Binding of ligand to receptor

A

Is dependent on the affinity of the ligand for the receptor

* For ligand to bind to receptor it must have an affinity 
* Higher affinity = stronger binding
* Impacts potency of drug 
* To do anything the ligand must bind to receptor
158
Q

Agonist efficacy

A

Binds to receptor to cause a measurable response

159
Q

Agonist intrinsic efficacy

A

Binds to receptor to activate it

160
Q

Affinity

A

Describes ability for an agonist or antagonist to bind to a receptor

161
Q

Molarity equation

A

MWt x molarity = g/L

MWt = molecular weight

162
Q

Units for concentration

A 
M = molar
mM = millimolar x10 -3
uM = micromolar x10 -6
nM = nanomolar x10 -9
pM = picomolar x10 - 12

Each goes down by a factor of 1000

163
Q

Molarity vs concentration

A

Molarity takes molecular weight into consideration

164
Q

Intrinsic efficacy

A

→ how effective an agonist is at eliciting an active receptor

165
Q

Ligand binding and response steps

A
  1. Ligand binds with receptor – forms complex
    1. Binding governed by affinity
    2. Receptor activation – governed by intrinsic efficacy
    3. Activated receptor – causes a response
    4. Response can be many things e.g. muscle contraction
166
Q

Efficacy

A

→ ability of a ligand to cause a response

Governed by:
• Intrinsic efficacy
• Other things that influence the response (cell and tissue dependent factors)

167
Q

Agonists - binding

A

Agonists have:

* Intrinsic efficacy - ability to activate the receptor
* Efficacy - ability to cause a measurable response
168
Q

Antagonists - binding

A
  • Only look at affinity to receptor - binding governed by affinity
    • No intrinsic efficacy or efficacy – receptor isn’t activated and there is no actual response
169
Q

Lock and key analogy

A 
Key = ligand or drug
Receptor = lock
  • Key can be an agonist or antagonist
  • affinity - does it fit / bind to lock
  • Turn the lock = intrinsic efficacy and drug is an agonist
  • Can’t turn the lock = antagonist
  • Opening the door = efficacy causes a response
170
Q

Clinical efficacy

A

—> does the treatment actually work - how well does treatment achieve aim

* Does drug bind to receptor
* Does it cause activation and an effect e.g. relaxation dilation
* Does the effect cause the desired thing e.g. decrease in blood pressure
171
Q

How to measure bindings

A

• Radioactively labelled liagnd
• Fluroscent labelled ligand
Label the ligands so they can be detected when bound to receptor

  1. Apply drug to cells
  2. Separate bound and free drug by washing it off
  3. Only bound drug remains on cell
  4. Quantify bound drug with radioactivity or fluoresence - incubate, measure bound ones to determine affinity
  5. Prepare a graph to compare bound ligands and overall ligand conc
172
Q

Quantifying binding affinity -graph

A

Graph
• Plot proportion of receptors bound against drug concentration (that you mad up)
• Increase drug concentration increases the proportion of receptors bound
• Levels off when the maximum number of receptors are bound = Bmax

Kd
Bmax

173
Q

Bmax

A

Max. Binding capacity of the receptor

- provides info on receptor number

174
Q

Kd dissociation constant

A

→ measures the affinity of the ligand, measured at 50% receptor capacity
- concentration of ligand required to occupy 50% of the available receptors

* Read halfway 0.5 across y axis to calculate Kd
* Lower Kd = higher affinity 
* Kd is recipricol of affinity lower kd means higher affinity - sigmoidal curve
175
Q

Importance of affinity

A

Very important

* Important in early stage drug delivery 
* If high drug concentrations are needed to occupy 50% receptors = not a good option

High affinity = binding at low concentrations of hormones, neurotransmitters etc. And drugs

176
Q

Log scale

A

Plot drug conc vs ligands bound graph - using logarithmic scale

  • easier to read = gives a more simple straight line in the middle
  • make sure to anti log Kd value

Log 10 = power by which 10 has to be raised to get that number

177
Q

Drug - response relationship

A

Response —> requires drug efficacy which comes from an agonist

→ Efficacy requires a response – this could be further downstream event
• e.g. GCR signally pathway events activating g protein etc .
• Change in cell or tissue behaviour (e.g. muscle contraction)
• Change in ion concentrations
• Many options for responses

178
Q

Measuring effectiveness - concentration, response curve

A

→ increase concentration increase % response
- log scale = straight bit in middle

Ec50
Emax

179
Q

Ec50

A

Effective concentration giving 50% of maximal response (50% effectiveness)
- measure of agonist potency

Depends on:

  • affinity of ligand for receptor
  • intrinsic efficacy
  • cell and tissue specific component
180
Q

Potency

A

→ Measure of the dose required to produce a pharmacological response of a specific intensity

  • potency can vary depending on cell tissue
  • increase number of receptors: increase potency
  • decrease number of receptors: decrease potency
181
Q

Concentration

A
  • Known concentration of drug at site of action

Eg. In cells and tissues

182
Q

Dose

A

-Concentration at site of action unknown

Eg. Dose to a patient in mg or mg /kg

183
Q

Asthma

A

→ Inflammatory disease – wheezing shortness of breath

  • Treatment – relax the contracted smooth muscles
  • Adrenaline can be used as treatement – act on beta 2 adrenoreceptors to cause relaxtion = functional antagonism
  • Salbutamol is the drug that is actually used
  • Functional antagonism = ligand causes an affect, antagonises the effect of smooth muscle
184
Q

Therapeutic target -asthma

A

–> beta 2 –adrenoceptors = receptors present in smooth muscle in airways

  • Target them using salbutamol (agonist)
    • Treatments activates the receptor but provides functional antagonism of contraction (causes smooth muscle to relax)
185
Q

Problem with therapeutic target - asthma

A

2 types of beta adrenoreceptors

→ Beta 1 adrenoreceptors are present in the heart – important not to use a medication that activates both types of adrenoreceptors
• Need specific and selective activation of beta 2 adrenorecewptos in the airways only to treat asthma

186
Q

2 types of asthma drugs

A
  • Salbutamol = less frequent use, inhaler or used for severely ill patients (via an iv)
  • salmeterol = better long acting
187
Q

Salbutamol

A

• Fairly selective to beta 2 adrenoreceptors

  • but selectivity is poor compared to salmeterol
  • But repeated dosage of salbutamol made cause more of it enter the heart and actually affect the beta 1 adrenoreceptors in the heart

Uses:
- not the main treatment but it can still be used
• Can be used as an inhaler for less frequent use

188
Q

Salmeterol

A
  • Overcomes problem of affecting beta 1 adrenoreceptors → good selectivity
    • Developed by drug companies
    • A lot more salmeterol is needed to have any effect on the beta one receptors in the heart

Problem = it is insoluble and can’t be given to severely ill asthma patients

189
Q

Spare receptors

A

• Expect that response increases as number of bound ligands increase - but you can’t get 100% response at <100% binding occupancy

But the response is controlled or limited by other factors:
• Muscle can only contract so much
• Gland can only secrete so much

Once the muscle/ gland has done as much as it can any occupied receptors are considered spare as the response doesn’t continue to double/ increase

190
Q

Use of spare receptors

A

Allow for responses when there is a low agonist concentration

Exist because of:
• amplification in the signal transduction pathway
• response limited by a post-receptor event

191
Q

Signal amplification

A
  1. Receptors are occupied by ligand eg beta adrenoreceptors are occupied by a few adrenaline
    1. Elicit response - large response
    2. G protein bound cause stimulation of adenylyl cyclase
    3. Increase amount of cAMP
    4. Increase activation Pk A enzyme
    5. Phosphorylate proteins

Not all receptors must be bound to give 100% response

192
Q

Spare receptors → asthma

A
  • Salmeterol used and only need 10% occupancy of muscarinic receptors to gain maximum contraction
    • 90% of receptors remain as spare
193
Q

Spare receptors + sensitivity

A

Spare receptors = increase sensitivity
→ allow responses at low concentrations of agonist

If a full response requires spare receptors e.g. 20000 receptors but only 50000 need to be affected
• Only 50% occupancy for full response
• Lower Kd – affinity does not need to be as high

194
Q

Receptor number

A

Change in receptor number –> changes agonist potency

  • up regulation = receptor numbers tend to increase with low activity
  • down regulation = receptor numbers tend to decrease with high activity (drugs - contribute to tolerance and withdrawal)
195
Q

Parkinson medication

A
  • As drug is introduced more and more to patient, receptors are down regulated, patient has less and lesss receptors
    • Eventually not enough receptors present to elicit the desired response
    • To increase response/ potency – increase dose or add a new drug, or switch the drug
196
Q

Full agonist

A
  • Likely to be an endogenous ligand
    • Ec50 < Kd
    • Plenty of spare receptors

→ intrinsic activity: gives full response

197
Q

Partial agonist

A
  • Ec50 is closer to the Kd
    • No spare receptors - all are occupied
    • Could occupy all receptor sites and not get full response

→ lower intrinsic activity and efficacy compared to full agonists

198
Q

Relevance of partial agonists as drugs

A

• More controlled response
• Work in absence or low levels of endogenous ligands
- can act as antagonist if high levels of full agonist

Pain relief - buprenorphine

199
Q

Burprenorphrine

A

Buprenorphine = has higher affinity to receptors but a lower affinity constant (lower efficacy) so it doesn’t produce the full euphoric pain relief/ respiratory depression as an opioid

• Burpronephrine is used to slowly ease patient off the opiod – less of the negative side affects like respiratory depression

It doesn’t cause the maximal response - inhibit heroin effect

200
Q

2 effects of buprenorphine in heroin addiction

A

Example: addict that frequently injects heroin but has now injected buprenorphrine
• Patient gets ill
• Withdral, abstinence syndrome
• Receptors are occupied by buprenorphrine but he doesn’t get the same feelings that he would get from heroin

201
Q

Withdrawal or abstinence syndrome

A
  • Continued drug taking = tolerance, crave more and more of the drug
    • Naloxone – better drug of choice when patient has overdosed (acts in the same way as buprenorphrine) = drug is a lot harsher
202
Q

Partial antagonism

A

Buprenorphine occupies opioid receptors but not giving a full effect = withdrawal symptoms

203
Q

3 types of antagonists

A

1.Reversible competitive antagonism
(commonest and most important in therapeutics)

  1. Irreversible competitive antagonism
  2. Non-competitive antagonism (generally allosteric – can even work post-receptor)
204
Q

Reversible competitive antagonism

A

→ compete with agonist for binding = whichever is more present agonist/antagonist will dominate binding

* Relies on dynamic equilibrium between ligands and receptors
* Concentration dependent
  • more antagonist = more inhibition

Naloxone

205
Q

Ic50

A

→ inhibitory concentration of antagonist giving 50% inhibition of the agonist

As antagonist conc increases Kd for agonist decreases and increases for antagonist

206
Q

Competitive antagonists

A
  1. Large amount of agonist
    1. increase concentration of antagonist
    2. Antagonist occupies receptors
    3. Increase concentration of agonist
    4. Agonist binds to receptors
    5. This just keepppps going
207
Q

Reversible competitive antagonists - graph

A

cause a parallel shift to the right of the agonist concentration-response

* Increase antagonist – need more of agonist to have an effect 
* Need more agonist to have same response
208
Q

Naloxone

A

Naloxone is a high affinity, competitive antagonist at μ-opioid receptors.

* Useful in an overdose situation 
* lifesaving treatment for overdosed addicts
209
Q

Irreversible competitive antagonism

A

→ occurs when antagonists dissociates slowly or not at all
• Response is not surmountable
• Keep increasing the agonist but this will not affect antagonist molecules that are already bound

210
Q

Irreversible competitive antagonist - graph

A

Irreversible competitive antagonists cause a parallel shift to the right of the agonist concentration-response curve
• at higher concentrations suppress the maximal response – response drops off
• Response drops off because the number of spare receptors has been surpassed
• Adding more antagonist = further right shift
• Keep increasing antagonist until there are no spare receptors = no response

211
Q

Irreversible competitive antagonists - clinical

A

Clinical response : Pheochromocytoma (tumour of adrenal glands, too much adrenal activate alpha 1 adrenreceptor - increased heart rate and pressure)

e.g. phenoxybenzamine – non-selective irreversible alpha 1 -adrenoceptor blocker used in hypertension episodes in pheochromocytoma
Irreversible used to treat this long term condition for patient – longer treatmenet period

212
Q

Non competitive antagonism

A
  • Does not sit in the receptor site that agonist is bound too (orthosteric site)
    • This binds to allosteric site ( another part of the receptor protein)
213
Q

Allosteric sites

A

Provide binding sites for:
• agonists (potential novel drug targets!)
• molecules that enhance or reduce effects of agonists

• Non competitive – not binding to the same site
214
Q

Pharmacokinetics

A

study of what the body is doing to the drugs

- kinetic energy change in body overtime

215
Q

4 underpinning principles of pharmacokinetics

A 
ADME
Absorption
Distribution
Metabolism
Excretion
216
Q

Pharmaceutical process

A

Is the drug getting into the patient

217
Q

Pharmacokinetic process

A

Is the drug getting to its site of action

218
Q

Pharmacodynamic process

A

Is the drug producing the required pharmacological effect

219
Q

Therapeutic process

A

Is the pharmacological effect being translated into a therapeutic effect

220
Q

Absorption → administration of drugs

A

Enteral = delivery into internal environment of body via gi tract

  • oral - mouth
  • sublingual - dissolve under tongue
  • Rectal- anus

Parenteral = delivery via all other routes, not gi track

  • intravenous - circulation
  • Subcutaneous-skin
  • intramuscular- muscle
221
Q

Oral administration

A
  1. Drug is absorbed orally
    1. Passes through GI tract
    2. Pass through first pass metabolism
    3. Move to extracellular fluids
222
Q

Parenteral administration

A

→ using parenteral fluid = iv
Avoids passage through gi tract and first pass metabolism
= drug goes straight to extracellular fluid

223
Q

Absorption - small intestine

A

Small intestine – primary site of drug absorption
• Huge SA = area for drug to pass through
• Portal vein –> liver

224
Q

Factors affecting absorption

A
  • Oral route = stability of drug in stomach acid, patient state
  • Transdermal l subcutaneous delivery = patches, apply to normal not broken skin
225
Q

2 drug absorption pathways

A

• Paraceullar
- Between the cells – passive diffusion

	• Transceullar 
	Pass through the cells 3 types:
	- passive (diffusion)
	-  carrier mediated (active facilitated, require ATP)
	- endocytosis (receptor mediated)
226
Q

Paracellular absorption

A

Passive diffusion of materials between cells

  • Very low molecular weight drugs pass between cells
  • Dependant on the drug properties (ionisation state, pH)
    • Membranes have lipids between cells – filter and let very small dissolved molecules pass through
    • Usually lipophilic molecules
227
Q

Transcellular absorption

A

Passive diffusion - crosses cells, not between cells
• Require hydrophobic drug particles – determined by log p
• Log p – ability of drug to dissolve in fat loving solvents and compare them to water loving solvents (help understand if drug will pass through)
• Concentration dependent, considers pH and ionisation state

Carrier mediated transport - depends on charge of drug

* Uses a transporter like pump that requires ATP
* Receptor mediated and requires energy – prone to saturation
* Influx and efflux transporters – movement of drug both ways 
* Drug-drug interactions can compete for transporter 
* Specific transporters exist for endogenous substances in the body
228
Q

Drug ionisation and ph - absorption

A

→ Important in drug absorption

  • Ionised molecules cannot cross through membranes
  • Unionised molecules can pass through membrane and be absorbed

e. g. acids may be ionised in basic environments
- WA in acidic environment = unionised
- WB in basic environment = unionised

229
Q

Henderson - hasselbalch equation

A

estimating the pH of a buffer solution and finding the equilibrium pH in an acid-base reaction. pH is the concentration of [H+], pKa is the acid dissociation constant
• PH = concentration of hydrogen ions
• PKa = acid dissociation constant

230
Q

Bioavailability - (drug absorption)

A

→ fraction of dose administered that actually reaches the systemic circuclation
- as some drug is lost eg - Oral route = must pass through Gi tract but not all of it absorbed

231
Q

Bioavailability - figures

A

→ Percentage that is absorbed compared to amount that was actually administered = F
• Number btw 0-1/ 0-100%

Calculating area under curve (exposure of drug to patient) = bioavailability

232
Q

Distribution

A

→ process of drug movement from circulation into tissues and organs

  • pharmacodynamic effects
233
Q

Factors affecting drug distribution

A

→ Blood flow to tissues often differs:
• Rapidly perfused: brain, liver, heart, kidney = faster response
• Slowly perfused: muscle, bone, skin = slower response
If the target tissue is slowly perfused, (e.g. muscle skin bone) it will often result in a delayed (slower) clinical response compared to a rapidly perfused tissue.

→ partioning ( from blood into tissues)
• The drug has to permeate across lipid bilayers

234
Q

Volume of distribution - definition

A
  • theoretical volume that helps converts dose of a drug into systemic plasma concentration
    • Determine right loading (starting) dose for a patient
235
Q

Volume of distribution - values and equation

A

Vd of a drug is different depending on drug properties
• Drug that distributes in the blood and is hydrophilic = lower volume of distribution
- low Vd = high drug conc in blood
• Drug that distributes in the tissues and is hydrophobic = higher volume of distribution
- high Vd = high drug conc in tissue

Vd = drug dose / [plasma drug]
- use to calculate drug conc for diff drugs

236
Q

Volume of distribution - drug examples

A

→ warfarin - drug just concentrated in blood stream
• Low volume of distribution

→ TCA tricyclic antidepressants - drug concentrated in tissues - distribute further out into muscle/fats
• High volume of distribution

237
Q

3 body fluid compartments and drugs

A

• Plasma
• Interstitial
• Intracellular
–> increasing penetration by drug into interstitial and interacellular fluid
= decrease in blood plasma drug conc = as you are increasing the volume that the drug can be present in
• Same drug present in a larger volume = lower concentration
- increasing Vd

238
Q

Patient factors influencing volume of distribution

A

• Weight

  • larger patient = greater volume = larger Vd = lower drug concentration (when given normal dose)
  • smaller patient - lower volume = smaller Vd = higher drug concentration (when given normal dose)

• Age

  • young = high volume, low fat
  • old = lower volume, higher fat

Vd increases as body size increases

239
Q

Body surface area

A

• More specific than weight as it also takes into account a person’s height
• Body surface area correlates with the capacity of the kidneys and liver, which are the organs that detoxify and eliminate poisons.
• To figure correct dosing of a drug with a narrow therapeutic range, body surface area is a oftern better to consider than weight.
BSA has been shown to correlate with cardiac output, total blood volume as well as renal function.

240
Q

Plasma proteins

A

–> control if the drug stays in the blood or partitions into the tissue

Proteins that the drugs can bind to

  • drugs bound to proteins = no therapeutic effect as can’t diffuse out of circulation to target cell → high Vd
  • drugs that aren’t bound = diffuse out of circulation to produce clinical response at target-cell
241
Q

Clinical action of drug

A

A result of the drug which is unbound / free and not the total drug concentration

  • total concentration - bound and unbound drug
242
Q

Plasma protein - examples

A
  • Albumin [Acidic and neutral drugs]
    • AAG (α1-acidic glycoprotein) [Basic drugs]

Phenytoin

• Protein bound drug = won't pass the membrane
• Free drug = pass the membrane and move into the cell  As drug moves into cell – concentration will shift due to gradient –more drug will rlease from protein and move into the cell
243
Q

Factors influencing protein binding

A
  • Certain disease states = hypoalbenaemia
    • Pregnancy
    • malnutrition
    • Acute ilness
244
Q

Pk

A

PK defines the kinetic change in a drug in the body over time.

A poor PK profile can limit drug effectiveness

245
Q

Metabolism

A

→ the enzymatic conversion of a drug to an alternative form
- breaking down the drug

Too much metabolism = clearance too high – not effective does
Not enough metabolism = drug accumulation = toxic

246
Q

Excretion

A

→ Removal of drug from the body

247
Q

Elimination

A

Combination of metabolism and excretion,

  • both irreversible processes
  • process by which drugs leave the body

Something is eliminated from the body when it has been excreted or chemically changed into something else and irreversibly removed from body

248
Q

Drug metabolism enzyme

A

Enzymes in liver - cytochrome P450 (CYP450)
3 main groups
• CYP1
• CYP2 - lower abundance BUT metabolises around 25% of all drugs and especially basic drugs
• CYP3 - high abundance, most important, metabolises many drugs

• Genetic polymorphisms have been identified for CYP enzymes. → phenotypes of persons who have extremely poor to extremely fast metabolism.

249
Q

Drug metabolism - process

A

2 phases

Phase 1: convert parent drug to more active metabolites
• Breakdown - oxidation, reduction,hydrolysis
• Chemical modification
• If it makes the drug more polar = excretion via renal route = urine production

Phase 2: conjugation - convert parent group to inactive metabolites
• Adding of sugar molecules (glucuronidation)
• Billiary elimination secreted via stools

250
Q

Drug clearance - metabolic clearance

A

• Rate at which the liver clears drug from the body
• Reflect loss of blood across the liver
Loss = can be from metabolism or escape
Clearance= volume of plasma that is cleared of drug per unit time

251
Q

Drug clearance - process

A

Blood enters liver

Metabolic clearance

Blood coming out of liver contains blood that has either:
• Drug that has escaped the metabolism process
• Drug that was metabolised

Perfusion → how well liver is perfused with blood

252
Q

Perfusion - drug clearance

A

Perfusion = how well liver is perfused with blood
• bear in mind that the PERFUSION of the organ is really important, with maximum liver flow being around 1500 mL/minute.
• Change in perfusion affects rate of drugs being meabolised

253
Q

Extraction ratio - drug clearance

A

→ measurement of renal plasma flow to evaluate renal function

E= (in - out) /in

254
Q

Hepatic clearance - drug clearance

A

Hepatic clearance = hepatic blood flow x extraction ratio

→ tells you how much blood is coming in and how much is extracted due to metabolism

255
Q

Extracted drugs

A

High extracted drugs → metabolised a lot

  • high blood flow, low protein binding
  • lack of binding = more liver metabolism

Low exctrated drugs → not metabolised much, remain in circulation

  • low blood flow, high protein binding
  • high binding reduces permeability to liver for metabolism
256
Q

Poor clearance

A

Results in drug remaining in circulation

= toxicity /death

257
Q

Clearance

A

→ volume of blood or fluid from which drug is completely removed per unit time. Total of hepatic
And renal clearance

  • Through liver and kidneys - balance
  • lungs and sweat (but not by a significant amount)

Drug in = drug out - balance
Blockage and same amount of drug in - toxicity, reduce amount of drug in
Leak and same amount of drug in -increase drug dose to maintain amount

258
Q

Hepatic impairment

A

Hepatically impaired patient – liver not working as well

• Lower the drug dosage to prevent build up

259
Q

Premature babies - drug extraction

A

Extraction ratio in premature baby
• Premature baby not properly developed – liver is actually a bit larger
• More extraction would occur than actually expected
• Balance this with their less developed renal side – if drug undergoes renal elimination

260
Q

Dosage regimens

A
  • high clearance drugs: multiple doses daily (Paracetamol)
  • low clearance drugs: single daily dose
    (Blood pressure drugs)
261
Q

First pass effect - dose regimens

A
  • First pass that drug has through the liver = lots of drug removed
  • Oral route of taking drug – stomach – absorbed through GI tract – hepatic portal vein – liver

• May lose drug before in the liver = may want to avoid the first pass effect when you need a fast acting drug
-IV – introduced straight into bloodstream avoids first pass effect – have more drug available

262
Q

Determine clearance

A

Total of hepatic clearance + renal clearance
• Can be determined via blood plasma samples and urine samples
• Blood tends to show a decrease in drug conc as it moves to urine
• Urine may be more specific to renally cleared drugs – detect drug or metabolities (increase in conc)
• Determine maintenance dose you need to take to keep plasma concentration steady within a patient

263
Q

Drugs - impact on metabolism

A 
Drug inhibits metabolism (inhibitor)
	• Less enzyme function
	• Inhibits enzyme = drug build up 
	• Time to see the effect depends on half life of drug – time taken to reach steady state 
Eg. St John's wort
Drug that induces metabolism (Inducer) 
	• Can take a few weeks to see makes effect
	• Switch enzymes on – work faster 
	• Takes time to see effect 
Eg. Grapefruit juice
264
Q

Kidneys - elimination

A

• Filtering system of body
Healthy kidneys filter blood, removing wastes and extra water to make urine via filtering units – glomeruli
- glomerular filtration Unbound drug is filtered at a rate which is called the GFR (around 120 mL/min of plasma)

* Small moleules like drugs pass through 
* Proteins, endogenous things remain in blood

Renal clearance

265
Q

Factors affecting renal elecirance

A
  • Age – premature babies, babies (kidney formation)
    • Kidney function
    • Hormones ?? Pregnancy
    • Number of kidneys – patient on one kidney or on dialysis
266
Q

Half life, clearance and Vd

A
  • Affect how drugs are cleared out of the body
    • Affect drug clearance
    • Affect drug dosage

Maintain drug levels are between effective concentration range – therapeutic concentrations

* Increase Vd = increases half life = drug is distributed around the body more, takes longer to leave body = longer half life
* Increase clearance = decreases half life = gets rid of drug faster = half life is less as drug has spent less time in the body
267
Q

First order kinetics

A

• As drug concentration decreases so does rate of change
Rate of change of drug depends on amount of drug present

• 1st order = half life is the same (half of the other half life) difference between half lifes is the same because it is concentration dependent
268
Q

Half life

A

→ time-taken for a 50 % drop in drug levels

  • 4-5 half lifes needed to remove all drug from body

Dependent on:
• Distribution of drug
• Elimination of drug

269
Q

ANS

A

→ part of the nervous system which controls all vegetative (involuntary) functions = that you don’t think about - largely controls smooth muscle
- separate from somatic system

2 divisions

1. Sympathetic division - fight or flight
2. Parasympathetic division - rest and digest
270
Q

Sympathetic nervous system - function

A
  • Responds to stressful situations
    • And controls basic body functions
    • Responsible for fight or flight response

Fight or flight response:
• Heart beating rate
• Forces of contraction
• Blood pressure

271
Q

Parasympathetic nervous system - function

A
  • Regulates basal activities
    • Relaxed conditions
    • Rest and digest response – e.g. basal heart rate
272
Q

Nervous system - overview

A 
• Divided into CNS, PNS 
	• PNS – motor and sensory functions
(Further divided into visceral and somatic)
	• ANS – sympathetic and parasympathetic
- sensory inputs and motor outputs
273
Q

Sympathetic division - anatomy

A
  • Short myelinated pre ganglionic nerve fibres
    (From spinal cord CNS - lateral horn of thoracic and lumbar parts)

Ganglia (where neurons change)- located in paravertebral chain close to spinal cord

Long unmyleinated post ganglionic nerves to target tissues

→ Not all of the sympathetic neurons will change neurons in the ganglia
• Some neurons pass through ganglia
• Form ganglia in another part of the body
• These nerves innervate the liver, GI tract, bladder

274
Q

Parasympathetic division - anatomy

A
  • Long myelinated pre ganglionic nerve fibres
    (from lateral horn of brainstem (medulla) and sacral part of spinal cord)
    Long so they reach / enter target tissues

Ganglia - located in innervated tissues

Short unmyleinated post ganglionic nerves near / in target tissue

275
Q

Ganglia

A

where upstream neuron networks meet downstream neurons – lots of neuronal cells bodies and synaptic connections

Myelinated neurons meet unmyleinated neutrons

276
Q

General structure of ANS

A

Disynaptic structures: pre ganglionic and post ganglionic neurons

  1. Neurons initiate from CNS
  2. come out to form PNS – change neurons in ganglia
    • Pre ganglia nerves – myelinated
    • Post ganglia nerves - unmyelinated go to inervaye target tissues
277
Q

Principle neurotransmitters in ans

A
  • acetylcholine (ACh)
  • noradrenaline (NA) (US: norepinephrine)

ATP, nitric oxide, serotonin, neuropeptides - used along neurotransmitters above to help fine tune response

278
Q

Cholinergic

A

use ACh as their neurotransmitter

- act on nicotinic receptors or muscarinic receptors

279
Q

Adrenergic

A

use noradrenaline as principle neurotransmitter
• NA interacts with one to 2 major classes of adrenoreceptors
– alpha receptors = on blood vessels, cause constriction
- beta receptors = on heart and lungs, cause increase in heart rate and bronchodilation

280
Q

Sympathetic nerves + neurotransmitters

A
  • Pre ganglionic = cholinergic (ACh and nicotinic)
  • post ganglionic = adrenergic (Noradrenaline and adrenoreceptors)

Specialised post ganglionic neurons that are cholinergic innovate sweat glands and hair follicles

281
Q

Parasympathetic nerves + neurotransmitters

A
  • Pre ganglionic = cholinergic (ACh and nicotinic)

- Post ganglionic = cholinergic (ACh and muscarinic)

282
Q

Receptors in ans

A

• 5 mACH receptors subtypes – muscaruinic ACh receptors (M1, M2, M3, M4, M5)

  • parasympathetic - post ganglionic
  • GPCRs

• 2 nACh receptors subtypes – nicotinic ACh receptors - N1, N2

  • sympathetic and parasympathetic pre ganglionic
  • ligand gated ion channels

• Adrenoreceptors = alpha 1 and apha 2, beta 1 and beta 2 and beta 3subtypes

  • sympathetic post ganglionic
  • GPCRs
283
Q

Adrenal glands - ans

A
  1. Neurons initiate from spinal cord
    1. Come out of CNS and pass ganglia chain
    2. Directly innervate adrenal medulla
    3. Adrenal medulla cells are activated
      = Release adrenaline
284
Q

Sympathetic postganglionic neurons - in adrenal gland

A
  1. differentiate to form neurosecretory chromaffin cells in the adrenal medulla
    1. Chromaffin cells are innervated by pre-ganglionic sympathetic neurons
      • they can be considered as postganglionic sympathetic neurons that do not project, innervate to a target tissue
    2. Instead they release adrenally into the bloodsteam = hormone
285
Q

2 pharmacological divisions of ans

A

→ Sympathetic nervous system
• contains alpha and beta NA receptors in the target tissue/cell

→ Parasympathetic nervous system
• contains muscarinic ACh receptors in the target tissue/cell (nicotinic in post-ganglionic neuron)

286
Q

Sympathetic release of noradrenaline causes

A

Heart
• Beta one receptors= Heart rate increase

Smooth muscle
• Arteriolar contraction
• Sites that control blood pressure
• Bronchiolar/ intestinal/ uterine relaxation – relaxation of airway by beta 2 receptors

Glandular
• More secretion

Kidney - renin release

287
Q

Parasympathetic release of acetyl choline causes

A

Release decreases heart rate with M2 receptors
• Rest and digest response

Smooth muscle – cause bronchiolar contraction M3
Receptors

Glandular - increased sweat m1/m3

288
Q

Afferent/sensory inputs - and

A

→ Constantly modulate activity of efferent neurons of ANS – to form the homeostasis if the ANS

Sensory neurons monitor 
• levels of CO2 , O2 in the blood send signals to →autonomic respiratory centres 
• nutrients in the blood 
• arterial pressure 
• GI tract 
• content and chemical composition
289
Q

Ans controls:

A

→ internal body processes

* Blood pressure
* Heart breating weights
* Water balance
* Metabolism
* Body temp
* Etc
290
Q

Dysautonomia

A

Umbrella term for distinct malfunction in ans

  • Neurocardiogenic syncope
  • Multiple system atrophy
  • Postural orthostatic tachycardia syndrome (POTS)
291
Q

Enteric nervous system - ans

A

→ one of the main division of ans

• Mesh like system of neurons and their circuits in gi tissues
- controls the function of the GI (blood flow, mucosal transport and secretions…)
• capable of operating independently of the ANS and CNS
• communication with brain-”gut-brain axis”

292
Q

Synaptic transmission - overview

A
  1. Nerve impulse (action potential) pre-synaptic axon
  2. Neurotransmitter releasing
  3. neurotransmitter reach Postsynaptic receptor
  4. Post-synaptic neuron or cell reaction
293
Q

Neurotransmission - steps

A
  1. Uptake of precursors – material used to synthesise neurotransmitter
    1. Synthesis of neurotransmitter – with enzymes
    2. Vesicular storage of neurotransmitter
    3. Degradation of neurotransmitter – to control amount of neurotransmitter in neuron
    4. Depolarisation by propagated action potential
    5. Depolarisation dependent influx of calcium ions
    6. Exocytotic release of neurotransmitter – vesicles come to to and fuse with end of nerve
    7. Diffusion to post synaptic membrane
    8. Interaction with post synaptic receptors
    9. Inactivation of neurotransmitter – removing neurotransmitter to avoid over excitation
    10. Reuptake of neurotransmitter
    11. Interaction with pre synaptic recepetors – feedback to regulate the neurotransmitter
294
Q

5 common sites of drug action

- neurotransmission

A

• Degradation of neurotransmitter
– to control amount of neurotransmitter in neuron

• Interaction with post synaptic receptors

• Inactivation of neurotransmitter
– removing neurotransmitter to avoid over excitation

• Reuptake of neurotransmitter

• Interaction with pre synaptic recepetors
– feedback to regulate the neurotransmitter

295
Q

Acetylcholine synthesis

A

Acetyl coa + choline → acetylcholine + coenzyme A
• Enzyme – choline acetyltransferase (cat)
• Synthesised and stored in pre synaptic neuron

296
Q

Acetylcholine release

A
  1. Depolarisation signal comes into pre synaptic cell = influx of calcium ions
  2. triggers fusion of storage vesicles with active zone of pre synaptic cell = exocytosis of neurotransmitter
  3. acetylcholine enter synaptic cleft taken up by:
    - nicotinic receptors (sympathetic)
    - muscarinic ( parasympathetic),
297
Q

Acetylcholine degradation

A

Acetylcholine → acetate + choline

* Enzyme acetylcholinesterase 
* The enzyme is on the post synaptic neuron on the membrane
* Choline is reused in cycle
298
Q

Receptor/target therapeutic interventions

Cholinergic

A

→ Nicotinic acetylcholine receptors (nAChRs)
• at autonomic ganglia and the neuromuscular junction differ in structure.
• some drugs have actions selectively at autonomic ganglia (e.g. the ganglion-blocking drug trimethaphan, which is used in hypertensive emergencies

→ 5 muscarinic acetylcholine receptor (mAChR) subtypes (M1 -M5 )
- M1 - nerves, m2 -heart, m3 - smooth muscle
• at present few subtype-selective mAChR agonists or antagonists are available clinically.
• some newer agents do display limited tissue selectivity (e.g. the mAChR antagonist, tolterodine, which is used to treat “overactive bladder”)

Acetylcholinesterase inhibitors - prevent degradation

(e.g. pyridostigmine, used to treat myasthenia gravis; donepezil, used to treat Alzheimer’s disease)

299
Q

Cholinergic drugs - side effects

A

—> due to lack of sleectivity of cholinergic drugs

Eg.
• Heart – decrease heart rate and cardiac output
• Smooth muscle – increase bronchoconstriction and Gi tract peristalsis
• Exocrine glands – increase sweating and salivation

300
Q

Sludge syndrome - symptoms

A

SLUDGE symptoms caused by over-discharge of the parasympathetic cholinergic nervous system

Salivation = increased stimulation of salivary glands

Lacrimation = stimulation of lacrimal glands

Urination = relaxed urethral internal sphincter muscle
and detrusor muscle contraction

Defecation

GI upset = smooth muscle tone changes, diarrohea

Emesis (vomiting)

301
Q

Sludge syndrome - causes and tre alt ment

A
  • Drug overdose
    • Ingestion of magic mushrooms
    • Expose to organophosphorus
    • Insecticides
    • Nerve gases

Over stimulation of muscarinic acetylcholine receptors, in the innervated target tissues.

Treatment: atropine, pralidoxime, or other anti-cholinergic agents (for example: mAChR antagonists).

302
Q

Muscarinic MAChR agonists

A
  • Pilocarpine used to treat glaucoma

* Bethanechol to stimulate bladder emptying

303
Q

Muscarinic MAChR antagonists

A
  • Atropine and pralidoxime – treat SLUDGE syndrome
    • ipratropium and tiotropium are used to treat some forms of asthma and chronic obstructive pulmonary disease (COPD).
    • tolterodine, darifenacin and oxybutynin are used to treat overactive bladder.
304
Q

Noradrenaline synthesis

A
  • Tyrosine → DOPA - by tyrosine hydroxylase
  • DOPA → dopamine - by DOPA decarboxylase
  • dopamine → noradrenaline - by DOPA beta hydroxylase (in vesicle)
  • Noradrenaline → adrenaline -

Stored in vesicles

305
Q

Noradrenaline degradation

A

Degradation – within pre-synaptic terminal or after releasing by 2 enzymes:

* MAO monoamine oxidase – main enzyme can breakdown NA or adrenaline
* Catechol O-methyltransferase (COMT)

Reuptake for reuse (2 methods)
Uptake 1
• NA actions are terminated by re-uptake into the pre-synaptic terminal by high affinity transporter

Uptake 2
• NA not re-captured by Uptake 1 is taken up by a lower affinity, non-neuronal mechanism

306
Q

Noradrenaline release

A

Post-ganglionic sympathetic nerves generally possess:
• a highly branching axonal network with numerous varicosities,
• each varicosity is a specialized site for Ca2+ - dependent noradrenaline release

After release Na is taken up:

  • alpha receptors = action response
  • beta receptors = relaxation response
307
Q

Varicosity

A

—> noradrenergic varicosity = similar to synaptic site

* Synthesis of NA
* Storage of NA into vesicles
* Vesicles moved to membrane 
* NA released
* NA reaches receptors in target tisue cells
308
Q

Noradrenaline - pre and post adrenoreceptors

A

→ post synaptic adrenoreceptors
• NA diffuses across the synaptic cleft (varicosity) and interacts with post-synaptic adrenoceptors to initiate signalling in the effector tissue (function)

→ pre synaptic adrenoreceptors
• NA interacts with pre-synaptic adrenoceptors to regulate processes within own nerve terminal – e.g. NA release (feedback) synthesis, storage and relase

309
Q

Adrenoreceptor drugs

A

→ β2 -adrenoceptor-selective agonists (e.g. salbutamol)
- are used in asthma treatment to reverse bronchoconstriction.

→ α1 -adrenoceptor-selective antagonists (e.g. doxazosin) and β1 -adrenoceptor-selective antagonists (e.g. atenolol)
- are used to treat a number of cardiovascular disorders, including hypertension.

310
Q

Saba

A

Short acting beta agonists

  • salbutamol
  • inhaled corticosteroid
311
Q

LABA

A

Long acting beta agonists

  • salmeterol - mimic ans stimulate beta 2 adrenoreceptors in airways to relax
  • fast response
312
Q

Thyrotoxicosis

A

→ clinical manifestations of excess thyroid hormone action at tissue ever

  • anxiety, fatigue - weight loss
  • sweating = sympathetic ans
  • heart beat irregularities = ans
  • muscle weakness
313
Q

Thyrotoxicosis - treatments

A

Beta blockers - block norpinephrine effect on heart to reduce bp

Radioactive iodine- absorbed by thyroid gland, kill cells, reduce thyroxine production

314
Q

Neuromuscular blocking agents

Cholinergic drugs

A

• Depolarising muscle block
• Non depolarising muscle block
Difference = depolarising causes an intital action potential but nothing happens after, non depolarising just blocks the receptor so there is no action potential

315
Q

Depolarising muscle blockers

A

Suxamethonium (succinylcholine) aka sux
• short half-life of 1-2 mins
• Used for intubation to relax muscle in the neck to intubate patient – so effect wears off quickly
• Structure = 2 molecules of acetylcholine joined together
• it binds to and blocks the nicotinic receptor as it is not broken down as fast due to structure
• Broken down by pseudocholinesterases – enzymes in the blood plasma

316
Q

Non depolarising muscle blocker + reversal

A
  • Long half lifes – up to hours – long acting
    • Competitive antagonists at nicotinic receptors/ neuromuscular junction
    • Bind to and block receptor – no initial depolarisation

Examples
• Pancuronium
• vecuronium
• Atracurium

Reversal of blockade
Work by paralysing patient during surgery to reduce tissue damage
• So before patient wakes up from surgery you want to reduce paralysis, reduce anesthetic dose
• Give a neostigmine drug to patient – inhibits anticholinesterase
• Inhibits anticholinesterase enzyme – increase acetylcholine level – overcome competitive antagonist

317
Q

Neuromuscular junction

A
  • Nicotinic receptors – act as ion channels

* Drugs block effect of acetylcholine prevent it binding to the enzyme

318
Q

Botulinum toxin

  • cholinergic drug
A

→ paralyse muscle (Botox or treat bad muscle spasm)
• neurotoxic protein – very toxic
• produced by the bacterium Clostridium botulinum - anaerobic, gram positive

319
Q

How botulinum toxin works

A
  1. Binds to SNARE proteins – responsible for moving acetylcholine vesicle to the membrane to fuse
    1. Botulinum toxin acts on SNARE proteins
    2. Stops vesicle moving to and fusing with the membrane
    3. Inhibits release of acetylcholine
    4. No acetylcholine = complete paralysis
320
Q

Myasthenia gravis

A

—> problem with communicating across synapse, autoimmune disease

* Antibodies complementary to nicotinic receptor re formed
* Antibodies bind and block nicotinic receptor
* Prevent acetylcholine from binding
* Antibodies act as antagonists 
* Muscular weakness and possible paralysis
321
Q

Myasthenia gravis -treatment

  • cholinergic drugs
A
  • Autoimmune disease – drugs to suppress immune system
    • Give an anticholinesterase e.g. pyridostigmine – inhibits that anticholinesterase increase acetylcholine levels
    • Also give immunosupressants
322
Q

Test for asthma

A

• Nitric oxide – produced as part of inflammation, can be breathed out and used as a test for asthma

323
Q

Asthma - symptoms

A

• Bronchoconstriction – airways narrow, limits airflow, breathlessness, wheezing
→ mucous gland secretes too much mucus
→ Smooth muscle layer – innervated by parasympathetic system that releases acetylcholine which causes bronchoconstriction

• Chronic inflammation of airways – inflammatory disease (real problem)

324
Q

Muscarinic receptor types

A
  • Odd numbered receptors = excitatory
    • Even numbered receptors = inhibitory
M1 = in the CNS
M2 = in the heart
M3 = smooth muscle cells surface
M4 = in the CNS
M5 = in the CNS
325
Q

M1, 3 and 5 = excitatory - process

A
  • Work through IP3 DAG system
    • GPCRs
    • Work through G proteins - Gq
    • Activates phospholipase C – make IP3 and DAG
326
Q

M2 and 4 = inhibitory

A
  • GPCR
    • Inhibit adenylyl cyclase
    • Reduce amount of cAMP
    • G protein = Gi
327
Q

Alleviating broncoconstriction = bronchodilators

Cholinergic drugs

A
  • That block M3 receptors that are present on smooth muscle cell walls
    • Use anticholinergic drugs – that bind to muscarinic receptor and block it
    • e.g. Ipratropium and Tiotropium = useful for certain types of asthma (also potentially toxic)

Ipratropium and Tiotropium
• Give the drugs as an inhaler so they are safe to use – go site of action

328
Q

Glaucoma

A

→ buildup of fluid (aqueous humour – produced by ciliary body) in anterior chamber of eye = pressure
- iris can fold and obstruct canal of schlemm

Normally:
• Aqueous humour secreted by epithelial cells of ciliary body
• Drains via canal of Schlemm
• Normal intraocular pressure is 10-15 mmHg

329
Q

Test for glaucoma

A
  • Puff of air onto eye ball

* Bounce of cornea used to determine pressure

330
Q

Glaucoma treatment

A

→ Constriction of iris (contraction of sphincter muscles of iris)

Use muscarinic agonist drugs
• Pilocarpine – administered as eyedrops – acts topically where you want it to act – make iris constrict

Use acetylcholinesterase inhibitor
• Physostigmine – administered as eye drops – boost acetylcholine effect – make iris constrict

331
Q

Treatment of bladder incontinence

A

→ target detrusor muscle = smooth muscle with m3 receptors

Muscarinic antagonist
• Oxybutynin
• Tolterodine
• Potentially toxic so don’t give high doses
• Block M3 receptors = alleviate problem

332
Q

Catecholamines synthesis

A
  1. All come from the tyrosine amino acid
    1. Make intermediate DOPA
    2. Convert it to dopamine (nt in brain)
    3. Convert to noradrenaline
    4. Form adrenaline
333
Q

Parkinson’s disease

A

• Lack of dopamine in a specific part of the brain – affects motor signals = Parkinson’s and tremors
• Treatment give dopa (precursor to dopamine) so dopamine is formed in brain but a problem is a lot of the dopa dosage is actually destroyed by the body (by enzyme dopa decarboxylase).
- Increase dopa uptake into blood by giving high dosage of dopa and give a drug that inhibits dopa decarboxylase enzyme

334
Q

Adrenoreceptor types

A

Alpha 1 = smooth muscle cell surface, Gq, contraction of smooth muscle
Alpha 2 = presynaptic in the neuron, Gi, inhibitory effect
Beta 1 – heart
Beta 2 = smooth muscle
Beta 3 = fat tissue
Betas = Gs = stimulatory

335
Q

Noradrenaline and mood

A

Noradrenaline levels in synapses link to mood
• Low mood = lack of noradrenaline
• Treatment – increase noradrenaline in synapse – inhibit uptake 1 (most antidepressant drugs)
• Noradrenaline is self limiting – negative feedback process acts on its own receptor

336
Q

Hypertension

A

• Increase contractivity of left ventricle
• Increase heart rate
• Increase cardiac output
• Narrowing of peripheral blood vessels (arterioles)
140/90 = hypertension

337
Q

Treatment of hypertension

A
  • Atenolol
    • Metoprolol
    • Bisoprolol
    • Block steps above to stop hypertension – reduce it back to normal range
338
Q

Shock

A

–> hypoperfusion or organs in body = lack of blood flow to key organs in the body

Hypovolemic shock – low blood volume, lose a lot pf blood
Anaphylactic shock – allergies

What happens in shock
• Peripheral blood flow is greatly reduced
• Body tries to keep blood flow to main organs – brain, heart, kidneys
• Blood flow shifted centrally to important organs
• Very life threatening – must act quickly

339
Q

Treatment of shock

A
  • Lifesaving drug – adrenaline
    • Dobutamine – beta 1 agonist
    • Target and stimulate heart to increase cardiac output and increase blood flow
340
Q

Pheochromocytoma

A
  • Tumour of adrenal glands
    • Benign tumour – adenoma – producing a lot of adrenaline and noradrenaline into blood

Causes
• Tachycardia
• Increase blodo pressure
• Summary of info on slide

341
Q

Treatment of pheochromocytoma

A
  • Alpha blockers

* Alpha 1 receptor blocker phenoxybenzamine – block receptors stop affects bring down blood pressure

342
Q

Treatment of asthma - adrenergic drugs

A

Beta 2 agoints – cause bronchodilation open up airways
• Salbulterol = short acting
• Salmeterol = long acting
Salmeterol is longer acting as it mimics adrenaline/noradrenaline to bind to beta 2 receptor, molecule is anchored and constantly bounces and stays bound tot receptor site

343
Q

Adult blood volume

A

5 litres

344
Q

Resting concentration of calcium ions in a cell

A

0.1 micromolar

345
Q

Spectrin

A

Protein that lines the membrane of red blood cells

All TP1 and Some TP2 (11 decks)

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