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Physiology and Pharmacology I > BS2013 > Flashcards

BS2013 Flashcards

1
Q

Name the four different classes of receptors

A

Ligand-gated ion channels
RTKs
GPCRs
Nuclear receptors

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2
Q

What is an agonist?

A

A drug that binds to a receptor, evoking a response

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3
Q

How does an agonist work?

A

1) Binding of the drug to the receptor

2) Activation of the receptor leading to a response

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4
Q

Define occupancy?

What is the equation?

A

The proportion of receptors that are occupied by the drug

Number of receptors occupied/total number of receptors

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5
Q

How can occupancy be measured directly?

A

Radioligand binding (radiolabelled agonist)
Method:
(i) Prepare cells or membranes e.g. guinea pig ileum –
detergent treatment and centrifugation
(v) Count radioactivity of filter
(iv) When equilibrated remove unbound drug by
filtration (bound drug remains attached to filter)
(iii) Add radiolabel to samples/filters at different
concentrations and equilibrate
(ii) Aliquot out membranes onto filters

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6
Q

What is the law of mass action?

A

Rate of a reversible chemical reaction is
proportional to the product of the concentration of the
reactants.

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7
Q

What is Kd?

A

A measure of affinity

A high Kd means a low affinity

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8
Q

What is a drug?

A

A substance that can modify biological functions of living organisms

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9
Q

What are statins?

A

Competitive inhibitors of the enzyme HMG-CoA reductase which is a key enzyme in the rate-limiting step of cholesterol synthesis

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10
Q

Why do pro-drugs need enzymes?

A

They are more stable forms of drugs which require chemical/enzymic modification before they become active

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11
Q

What are the different types of protein drugs can target?

A

Enzymes
Transporters (inhibitors or false substrates)
Ion channels (blockers or modulators)
Receptors (agonists and antagonists)

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12
Q

Describe GPCRs

A

7 transmembrane receptors
No intrinsic enzyme activity
Transmembrane alpha-helices
Coupled to heterotrimeric G-proteins
Higher diversity between families in the extracellular, ligand-binding domain
Larger conformational changes in the intracellular downstream signalling module
N-terminal on the outside, C-terminal on the inside

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13
Q

What happens when a GPCR is activated

A

TM5 (extends) and 6 (displaced) are shifted upon activation (uncovers binding site for GEFs)
GDP exchanges for GTP on the G-protein, causing dissociation of the beta-gamma sub-unit. This is stimulated by GEFs (guanine nucleotide exhcange factors)

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14
Q

How is a G-protein turned off?

A

They have their own GTPase activity (alpha sub-unit) which cleaves GTP to GDP

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15
Q

What do the different G-protein sub-types do?

A 
Galpha-i = inhbits adenylyl cyclase
Galpha-s = activates adenylyl cyclase
Galpha-q = activates phospholipase C-beta
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16
Q

Gs pathway

A

Adrenaline/noradrenaline is the ligand which acts on B-adrenoceptors
Activates adenylyl cyclase, which, in turn, produces cAMP, which, in turn activates cAMP-dependent protein kinase (PKA), this inhibits myosin light-chain kinase (MLCK) which causes vasodilation
Pertussis toxin inhibits G alpha-s GTPase activity

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17
Q

Gi pathway

A

Adrenaline/noradrenaline is the ligand which acts on A2-adrenoceptors
Inhibits adenylyl cyclase activity, decreasing the production of cAMP from ATP, which, in turn, results in decreased activity of cAMP-dependent protein kinase
Inhibited by Cholera

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18
Q

Gq pathway

A

Adrenaline/noradrenaline is the ligand which acts on A1-adrenoceptors
Activates PLC which cleaves PIP2 into diacyl glycerol (DAG) and IP3.
DAG remains bound to the membrane and can activate PKC
IP3 is released as a soluble structure into the cytosol.
IP3 binds to IP3 receptors, in the sarcoplasmic reticulum (SR) to cause them to open and release calcium ions into the cell.

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19
Q

Give an example of an action the beta-gamma sub-unit does when activated

A

In the heart
ACh is the ligand that works on M2 muscarinic receptors (Gi-linked)
Beta-gamma sub-unit has receptors on the potassium channels and causes a conformational change in them, increasing permeability to K+ and hyperpolarising the membrane

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20
Q

How is GPCR signalling terminated?

A

There are phosphorylation sites exposed with the shifting of TM5 and 6 which are phosphorylated by GPCR kinases
GPCR can no longer interact with G-proteins
New binding site for beta-arrestin which downregulates the activity of the GPCR. It interaxts with clatherin and AP2 to form clatherin-coated pits which internalise the receptor.
Beta arrestin can also show signalling activity
Becomes enclosed in an endosome, not responsive to ligand
The endosome either fuses with lysosymes or recycles the GPCR

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21
Q

What are RTKs?

A

Enzyme coupled transmembrane receptors (they have intrinisc enzyme activity)
Main ligands are growth factors (divalent)

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22
Q

What happens when an RTK is activated?

A

A conformational change resulting in dimerisation
The intracellular kinase domains phosphorylate each other’s tyrosine hydroxyl groups
The phosphorylation opens the substrate-binding site by pushing the activation loop away which makes the kinase fully active

Activated RTKs can activate phospholipase-C gamma by phosphorylating it

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23
Q

What two domains mediate protein recruitment to activated RTKs?

A

SH2 domain
PTB (phosphotyrosine binding) domain
Adaptor proteins act as the link when a protein doesn’t have one of these domains

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24
Q

What does the SoS protein do?

A

SoS binds to RTKs via the GRB2 adaptor protein
It’s a GEF for the G protein Ras which activates the protein kinase Raf -> Mek -> Erk -> phosphorylates transcription factors in the nucleus

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25
Q

What do cytokines do?

A

Recruit immune cells in response to pathogens

TGFs and tyrosine kinase-linked receptors are cytokines

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26
Q

What are hyrdophobic ligands?

A

Also known as nuclear receptors
Pass through the lipid bilayer (simple diffusion)
Zinc fingers for DNA binding
N-terminal varies in length and activates gene transcription
Ligand binding domain ends in the C-terminus and the ligand binds in the middle of the tertiary structure
3 groups:
Steroids
Non-steroidal lipophilic hormones
Orphans (unknown ligands)

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27
Q

How do steroid hormones work?

A

Diffuse through the membrane and binds
to steroid hormones attached to HSP complexes
Secondary signal is sent to another receptor in the nucleus attached to a response element, leading to a change in gene transcription

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28
Q

What converts cAMP to AMP?

A

cAMP phosphodiesterase

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29
Q

What does ATP stand for?

A

Adenosine Triphosphate

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30
Q

What is a use of cAMP?

A

Binds to the subunits of PKA causing them to dissociate, This allows PKA to reach its full level of activity

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31
Q

Where is adrenaline released from?

A

The hormone is released from chromaffin cells in the adrenal medulla just above the kidneys

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32
Q

Where is noradrenaline released from?

A

The neurotransmitter is released from noradrenergic neurones in the CNS and ANS (autonomic)

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33
Q

How is noradrenaline made?

A

Tyrosine -> Dopa -> Dopamine -> Noradrenaline (-> Adrenaline in chromaffin cells)
Tyrosine hydroxylase is the rate-limiting enzyme (tyrosine -> DOPA).

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34
Q

How is adrenergic transmission manipulated?

A

Alpha-methyl tyrosine is a competitive inhibitor of the tyrosine hydroxylase enzyme which is the rate limiting enzyme (tyrosine ->DOPA)
Alpha-methylDOPA is an analogue of DOPA. Converted to alpha-methyldopamine -> alpha-methylnoradrenaline which is more stable than noradrenaline and outcompetes it. It is also a selective agonist meaning it doesn’t stimulate all adrenoceptors

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35
Q

What are alpha2-adrenoceptors?

A

Presynaptic inhibitory autoreceptors which decrease noradrenaline release.
Coupled to Gi proteins which eventually leads to a reduction in VG Ca2+ channel opening (beta-gamma subunit)

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36
Q

What is the order of potency for alpha-adrenoceptor ligands vs beta-adrenoceptors?

A

Alpha:
Adrenaline >/ Noradrenaline > Isoprenaline

Beta:
Isoprenaline > Adrenaline ->/ Noradrenaline

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37
Q

What are the effects of beta-adrenoceptors on the body?

A

All work the Gs pathways to stimulate adenylyl cyclase
Beta-1 adrenoceptors in the heart activate the sympathetic pathway having positive inotropic effects
Beta-2 andrenoceptors cause bronchodilation in the lungs and vasodilation elsewhere (alpha-1 causes vasoconstriction.

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38
Q

What can continuous asthma attacks lead to?

A

Irreversible thickening of the airways due to hypertrophy (increase in cell size) and hyperplasia (increase in cell division)
Increased volume of smooth muscle and thickening of the base membrane decrease the volume of the lumen

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39
Q

What is the FEV1?

A

The Forced Expiratory Volume in one second

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40
Q

What are the stages of an asthma attack?

A

(Acute) Early:
Mast cells build up in airways
When stimulated they release chemokines and spamogens (interact with smooth muscle causing contraction)

Late:
Eosinophills are attracted to airways and release factors which cause a second contraction hours after the first

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41
Q

How is asthma treated?

A

Prophylaxis:

  • anti-inflammatory agents e.g. cprticosteriods
  • overuse can cause Cushing’s syndrome
  • newer corticosteroids can be inhaled directly into the lungs, aren’t good at passing through to the bloodstream and are readily metabolised

Symptomatic relief:
Beta-2 selective adrenoceptor agonists (bronchodilation)
Only affect breathing not heart rate
PKA activity leads to a decrease in Ca2+ which inhibits MLCK and promotes MLCP

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42
Q

What is the difference between salbutamol and salmeterol?

A

Both beta-2 adrenoceptors
Salbutamol is fast acting but short-lived
Salmeretol is bad at reversing the acute attack but prevents bronchospasm for up to 18 hours. This is due to the long hydrophobic tail which tethers it to the ligand

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43
Q

What is neuropathic pain?

A

Feeling pain with no actual cause

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44
Q

What is the point of a biological assay?

A

To determine the biological activity of a substance

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45
Q

What are the aims of animal testing?

A

Look for side effects
Establish pharmokinetic properties
Determine the plasma concentration the the drug is most effective at

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46
Q

What are the phases of clinical trials?

A

Phase 1:

  • Small group of healthy individuals
  • Testing for side effects, metabolism and removal

Phase 2:

  • Small group of patients with the disease
  • Test of effectiveness
  • 2b = longer term testing

Phase 3:

  • Large groups of people
  • Confirm effectiveness
  • Comparisons to leading competitors

Phase 4:

  • Studies after the drug has been released to see -effects of long term use
  • Determine cost-effectiveness
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47
Q

What is Myasthenia Gravis?

A

An autoimmune neuromuscular disease with weakness and fatigue. It gets worse with more activity and recovery occurs during rest.
Produces antibodies that reduces sensitivity to nicotinic ACh receptors
Treated with acetylcholinesterase inhibitors

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48
Q

What does curare do?

A

Inhibits nicotinic acetylcholine receptors

High doses leads to asphyxiation due to paralysis of the diaphragm

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49
Q

How are platelets activated?

A

ADP is released at the site of tissue injuries and activates the P2Y12 GPCR on the platelets linked to Gs.

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50
Q

What is a prodrug?

A

A biologically inactive compound which can be metabolised in the body to produce a drug.

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51
Q

What is diabetic macular oedema?

A

Fluid leaking from capillaries in the retina
Occludes vision
Caused by an increase in the growth factors VEGF and Ang2

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52
Q

What is the function of the vascular system?

A

To supply oxygenated blood and nutrients to tissues and to remove waste products

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53
Q

What side of the heart deals with deoxygenated blood?

A

Right side

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54
Q

What are the layers of tissue in blood vessels?

A

Connective tissue
Smooth muscle
Endothelium

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55
Q

Describe the anatomy of the different blood vessels

A

Arteries:
- Large amount of elastic tissue (allows vessel to stretch with heart beats)

Arterioles:
- Less elastic tissue, more smooth muscle

Capillaries:

  • Only endothelium
  • One cell thick

Veins and venules:

  • Walls slightly thicker than capillaries
  • Small amounts of smooth muscle
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56
Q

What is interstitial fluid?

A

The fluid surrounding the capillary bed

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57
Q

How are substances transported through the capillaries? (Besides the blood-brain barrier)

A

Lipid soluble substances diffuse through
Lipid-insoluble substances diffuse through endothelial pores
Water moves by bulk transport
Endo/excocytosis

58
Q

What is the blood-brain barrier made of?

A

The endothelium of the cerebral capillaries and the chordis plexus epithelium
Only water, CO2 and oxygen can cross easily, the rate of exchange is slow to help maintain a constant environment

59
Q

What is the importance of lymphatics?

A

Acts as a filter at the lymph nodes and removes foreign particles such as bacteria

60
Q

What is oedema?

A

Block of lymph flow, the resultant buildup of proteins from capillaries promotes water retention and subsequent swelling

61
Q

What does blood pressure measure?

A

Systolic (force of the heart)/ Diastolic (basal BPin the system)

62
Q

What are the causes of secondary hypertension?

A

Renovascular disease or endocrine disease

63
Q

How is blood pressure measured in the body?

A

Baroreceptors which work by stretch. Found in the aortic arch and carotid sinus. Frequency of action potentials increases with increases in blood pressure
The input from the baroreceptors goes to inhibitory
interneurons in the brain which synapse with pre-synaptic sympathetic neurones
Increased baroreceptor activity – decreased sympathetic activity

64
Q

What are the different ways to block artery contraction?

A

Block NA release
Adrenoceptor antagonists
Effects on calcium

65
Q

Name and describe the effects of two different adrenergic neuron blockers

A

Resperine:

  • affects storage of noradrenaline
  • absorbed by the uptake 1 system and prevents it from collecting NA
  • side effect of depression

Guanethidine:

  • also taken up by uptake 1
  • outcompetes NA because it has a higher affinity for the NA pump
  • can also block action potential propagation
66
Q

How is artery contraction initiated by calcium

A

Calcium + Calmodulin –> Calcium-calmodulin –> stimulates MLCK –> phosphorylates myosin –> contraction

67
Q

What are L-type blockers?

A

Calcium channel antagonists

Used as hypertensives e.g. DHPs

68
Q

How is lumen size of blood vessels controlled?

A

Smooth muscle contraction/relaxation

Vasoactive substances released by the endothelium (endothelins)

69
Q

What are endothelins?

A

Peptides that cause contraction in blood vessels
Types I, II and III found in the endothelial cells, kidney and brain & lungs respectively
Type I is made as and when it’s needed because endothelial cells don’t have storage vesicles
Paracrine/autocrine function

70
Q

What is the mechanism for endothelium derived relaxing factor (EDRF/NO) production?

A

L-argenine is converted to NO + citrulline by NOS
NOS activity is mediated by calmodulin
NO diffuses into the smooth muscle and stimulates guanylate cyclase
Guanylate cyclase converts GTP->cGMP which stimulates PKG, leading to relaxation

71
Q

What is renin?

A

An enzyme that converts angiotensinogen -> angiotensin I by cleaving the first 10 amino acids
Synthesised, stored and secreted by granular juxtaglomerular cells in the kidneys

72
Q

How is renin release mediated?

A

Decrease in NaCl/renal BP leads to renin release

Stimulation of beta 1-adrenoceptors on juxtaglomerular cells leads to renin release

73
Q

What effects does angiotensin II have on the body?

A
  • Vasoconstriction
  • Stimulates the adrenal cortex to produce aldersterone which stimulates the kidneys to reabsorb sodium
  • Acts on the brain to induce thirst and causes an increase in ADH
74
Q

What are diuretics?

A

Drugs that increase the rate of urine flow

They decrease the rate of sodium and chloride re-absorption from the filtrate

75
Q

What is the basic functional unit of the kidney?

A 
The nephron which is made of two parts:
the glomerulus (filter)
tubular portion (re-absorption)
76
Q

What are the commonly used diuretics?

A

Loop acting diuretics

  • most powerful
  • inhibits movement of NaCl out of the thick section of the loop of Henle by inhibiting the Na/K/2Cl carrier in the luminal membrane
  • also act as vasodilators

Early distal tube diuretics
- not very effective as most ions have moved out

Potassium sparing diuretics
- block excretion of K into urine

Osmotic diuretics

  • Pharmalogically inert (don’t act at receptors)
  • Filtered in the glomerulus and poorly reabsorbed
  • Less passive water reabsorption
77
Q

What is an arrhythmia?

A

A condition in which the heart beats with an irregular or abnormal rhythm e.g. tachycardia or bradycardia
Caused by electrical signalling passing through the heart in the wrong order

78
Q

What are the different valve and where are they located?

A

Tricuspid (between right atrium and ventricle)
Pulmonary (between right ventricle and pulmonary artery)
Mitral (between left atrium and ventricle)
Bicuspid (between left ventricle and aorta)

79
Q

What is isovolumetric contraction?

A

Pressure in the arteries leaving the heart is greater than that of the ventricles which is why the semi-lunar valves are closed.
During ventricular systole, ventricular pressure increases but the volume remains the same. No work is done until the valve opens but energy is still lost as heat

80
Q

What is cardiac contractility?

A

How powerfully the heart muscle contracts

Sympathetic stimulation increases contractility which is known as the positive inotropic effect

81
Q

What does the Frank-Starling mechanism show and do?

A

It shows the intrinisic control of the heart
It shows that increased ventricular filling leads to an increase in output via an increased stroke volume.
The mechanism:
- balances the output of the two ventricles over time
- contributes to increased stroke volume in exercise
- contributes to postural hypotension (cardiac output falls on standing)

82
Q

What is the order of movement of electrical activity during a heartbeat?

A

SAN –> AVN (delay) –> Bundle of His –> Ventricular action potential

83
Q

What influences depolarisation at the SAN?

A

Ca influx
Slow opening of If cation channels at negative membrane potentials. It is hyperpolarisation activated
Slow closing of V.D. K+ channels

84
Q

How does the NCX help with depolarisation?

A

Pumps 3xNa in for every 1 Ca out

85
Q

What are T-tubules?

A

Transverse tubules are extensions of extracellular space with V.D. Ca channels

86
Q

How is the concentration of Ca in the heart cells decreased during diastole?

A

V.D. Ca channels close at the end of the action potential
SERCA pumps Ca back into SR using ATP
NCX works against the calcium gradient but doesn’t require ATP as it is an antiporter

87
Q

What is the vagal tone?

A

The continuous basic level of parasympathetic activity which makes the heart beat at a slower rate than the intrinsic rate of the SAN

88
Q

How are changes in cardiac function modulated?

A

Baroreceptors detect pressure and send signals to the medulla which makes the heart reduce cardiac output and surrounding blood vessels to reduce peripheral assistance
Chemeoreceptors in the aortic arch and carotid body respond to hypoxia and cause the heart to increase peripheral assistance and heart rate due to increased respiration.
Lung stretch receptors and skeletal muscle mechanoreceptors increase heart rate by inhibiting vagal neurones

89
Q

What does the autonomic nervous system do?

A

Regulates heart rate and contractile force

90
Q

What do sympathetic nerves do?

A

Increase heart rate (+ve chronotropy)
Increase contractility (+ve inotropy)
Increase automacity (nonpacemaker regions are more likely to initiate APs)
Increase speed of conduction through the AVN
Decrease cardiac efficiency (cardiac O2 consumption rises faster that work done)

91
Q

What do parasympathetic nerves do?

A

Decrease heart rate (-ve chronotropy)
Decrease contractility in atria
Decrease automacity
Slow the speed of conduction through the AVN

92
Q

How does noradrenaline control sympathetic events in the heart?

A

Binds to beta-1 adrenoceptors which are coupled to Gs G-proteins leading to increases in cAMP and PKA activity which both have a hand in heart rate and contractility
cAMP increases If activity meaning quicker depolarisation
PKA phosphorylates L-type calcium channels making them more active at lower membrane potentials, lowering the threshold for the action potential

93
Q

What controls pacemaker depolarization?

A

If channels opening slowly and VD potassium channels closing slowly at negative membrane potentials
Membrane potential moves towards reversal potential of If channels

94
Q

What do parasympathetic nerves release and how does that influence the heart?

A

ACh binds to M2 muscarinic receptors coupled to Gi
Less cAMP and PKA activity
Beta-gamma subunit activates Kach channels which causes hyperpolarisation of the membrane as it tries to get to the K equilibrium potential

95
Q

What are the different autonomic drugs?

A

Beta adrenoceptor agonists e.g. adrenaline, isoprenaline or dobutamine (B1-selective)

Beta adrenoceptor antagonists (beta blockers) e.g. propanolol, atenolol (B1-selective) or alprenolol

Muscarinic receptor antagonists e.g. atropine

96
Q

What do cardiac glycosides do?

A

Increase Ca concentration in the cell and therefore contractile force
Decrease heart rate
Inhibit Na/K pump meaning Na stays in the cell so the NCX can’t work
Slows conduction at the AVN to allow time for filling of the ventricles leading to a greater cardiac output

97
Q

Where can arrhythmias originate from?

A

SAN
Atria
AVN
Ventricles (most dangerous)

98
Q

What does the local circuit theory suggest?

A

Depolarisation of a small region of neuronal plasma produces transmembrane currents in neighbouring regions tending to depolarise them

99
Q

How is the direction of the current in the heart tissue maintained?

A

Absolute and relative refractory periods prevent the current from being able to travel backwards and depolarise previous cells

100
Q

What is ischaemia and how can this affect the cardiac muscle?

A

Ischaemia is a restriction in blood flow to tissues and in the heart this can lead to unidirectional block as cells become unexcitable
It is also the cause of angina by activating pain fibres with substances like hydrogen

101
Q

What are the two types of afterpolarisation andwhat happens?

A

Early - another depolarisation before repolarisation is complete. Caused by premature reactivation of L-type calcium channels
Delayed - another depolarisation doesn’t occur until repolaristion is complete

102
Q

What is an ectopic beat?

A

Premature initiation of another heartbeat which occurs when delayed afterpolarisations are above threshold

103
Q

What happens during abnormal pacemaker activity?

A

Regions that don’t usually initiate impulses (quiescent) gain the ability to do so
More likely in the sympathetic pathway when beta-adrenoceptors are activated

104
Q

What is heart block caused by?

A

Damage to nodal regions
Complete -atria and ventricles beat independently (long P=wave
Incomplete - only some SAN impulses trigger the ventricles (no QRS)

105
Q

What are the different classes of anti-arrhythmic drugs?

A

I - Sodium channel blockers decrease excitability of quiescent cells
- Ib binds and unbinds quickly before the next action potential
- Ic binds and debinds slowly and prolongs refractory period
II - Beta-adrenoceptor antagonists decrease SAN action potential frequency by reducing the action of the the sympathetic system
III - Potassium channel inhibitors prolong action potentials and refractory periods
IV - Calcium channel blockers suppress ectopic beats

106
Q

Where does the heart get its blood supply?

A

From the coronary artery

107
Q

What is coronary circulation controlled by?

A 
Vasodilator signals:
Adenosine
Increase in K concentration
Decrease in pH
Decrease in pO2
108
Q

What are the different types of angina?

A

Stable

  • Pain on exercise
  • Fixed coronary narrowing

Unstable:

  • Pain on low level exercise
  • Caused by thrombosis
  • High risk of myocardial infarction

Variant:

  • Rare
  • Spasm in coronary artery
109
Q

What do anti-anginal drugs do? Give some examples

A

Reduce cardiac workload and increase oxygen efficiency through vasodilation of coronary arteries
Beta-blocker antgonists
Organic nitrates (fast-acting vasodilators)
Calcium channel blockers
K channel openers

110
Q

What do collateral vessels do?

A

Essentially bypass an ischaemic area and increase circulation in that area when they dilate

111
Q

What does PKG do?

A

Acts as a vasodilator by inhibiting IP3 receptors on SR
Opens some specific K channels leading to hyperpolarisation of the cell membrane making VD calcium channels inactive
Desensitises contractile machinery to calcium

112
Q

What is the effect of calcium channel blockers?

A 
l-type targetted 
Decrease in force of contraction
Decrease in O2 consumption in the heart
Vasodilation
Increased blood flow
Less CICR
113
Q

Describe the sequence of events that can lead from a plaque to a heart attack

A

Plaque rupture -> Platelet adhesion to glycoproteins -> Platelet aggregation to form thrombus (inhibited by asprin) -> Reinforced by fibrin -> Blocks coronary artery

114
Q

How is the hormonal control of reproductive function regulated?

A

Hypothalamus secretes GNRH (gonadatropin releasing hormone)
GNRH -> anterior pituitary which produces the glycohormones FSH and LH which act on the gonads

Negative feedback:
Short loop inhibition - the sex hormones (including inhibin) go to the anterior pituitary to stop FSH and LH production
Long loop inhibition - the sex hormones go to the hypothalamus to reduce GNRH secretion

115
Q

What is the isthmus?

A

The narrowest part of the fallopian tube and closest to the uterus

116
Q

Where does fertilisation occur?

A

At the ampula

117
Q

How is genetic variation brought about in meiosis?

A

Crossing over (exchange of genes) between homologous chromosomes and random distribution of chromatids

118
Q

Describe the anatomy of the testes

A

Made mainly of seminiferous tubule
Mature sperm is stored in the Vans Deferens
Sertoli cells provide nutrients for the sperm and are stimulated by FSH. They form the blood-testes barrier and produce seminal fluids as well as inhibin and androgen-binding protein to increase testosterone solubility
The basement membrane removes waste and toxins
Leydig cells produce testosterone and are stimulated by LH

119
Q

How does the sperm find the ovum?

A

Thermotaxis towards warm egg
Chemotaxis towards the bourgenal chemical secreted by the egg which activates Golf which is like Gs
Progesterone is produced by cells in the zona pellucida and also attracts the sperm

120
Q

What is capacitation?

A

Maturation of spermatozoa
Initially, sperm can’t fertilise an oocyte because seminal fluid has inhibitory factory to reserve their limited energy
After ejaculation the seminal fluid is diluted which leads to initial capacitation
Full capacitation occurs after ovulation:
chemicals released by egg
reduction in inhibitory agents e.g. cholesterol
increase in cAMP increases ability to swim
Inner plasma and acrosome are modulated to allow acrosome reaction

121
Q

What happens during fertilisation?

A

Sperm binds to the zona pellucida
Acrosome reaction; calcium levels in acrosome increase, acrosin enzyme digests zona pellucida
Cortical reaction prevents polyspermy

122
Q

Describe the process of oocyte development in the ovaries

A

FSH stimulates follicles to grow during the menstrual cycle
A dominant oocyte emerges and begins expressing LH receptors which allows it to survive the drop in FSH unlike the rest which stop growing
The primary follicle surrounding the oocyte becomes a Graafian follicle which is surrounded by a granulosar cell which is surrounded by a theca cell
The structure explodes leaving the secondary oocyte and the remnants form the corpus luteum which secretes oestradiol, progesterone and inhibin A which organise the endometrial lining and signal to stop more oocyte development
Cholesterol -> androstenedione in the theca cell with LH receptor coupled to Gs
Androstenedione -> oestradiol in the granulosar cell with FSH receptor coupled to Gs

123
Q

What are the phases of the menstrual cycle?

A

Follicular
- development of single mature follicle and secondary oocyte

Ovulatory
- Release of secondary oocyte

Luteal
- Last until corpus luteum dies, it would degrade if fertilisation didn’t occur

124
Q

What is an ectopic pregnancy?

A

When the blastocyst embeds in the fallopian tube, mucin I and smooth muscle contraction act to prevent this

125
Q

Why is the site of embryo implantation important?

A

Placenta needs to be far from the cervix
Directly above = placenta previa
Also marginal and low-lying versions

126
Q

What glycoproteins control implantation?

A

Mucin 1
L-Selectin (stickiness to endometrial lining)
E-cadherin (makes cells stick together so needs to be degraded)

127
Q

Describe the process of implantation

A

Mucin layer of endometrium degrades
Apposition
- Trophoblast cells stick to pinopodes on lining

Stable adhesion
- Endometrial cells produce cytokines to stimulate integrin production in the embryo causing dhesion

Invasion
- Embryo embeds into lining as the syncytiotrophoblast produces enzymes to digest the endometrium

128
Q

Why does the syncytiotrophoblast produce NOS?

A

To prevent clotting in the endometrium as it’s being digested

129
Q

What are the effects of pregnancy on different organs?

A

Anterior pituitary:
Increased prolactin

Posterior pituitary:
Increased vasopressin (more water retention)

Adrenal cortex:
Cortisol, toxic to the embryo but suppresses the mother’s immune system

Kidney’s:
Increase in erythropoetin increases RBC count

130
Q

Where is the pancreas located?

A

At the back of the abdomen, beneath the liver, behind the stomach
Close proximity to the proximal loop of the duodenum

131
Q

How is enzyme secretion in the pancreas carried out and regulated?

A

The hormones secretin and CCK in the duodenum
Secretin stimulates bicarbonate secretion
CCK stimulates acinar cells to secrete digestive enzymes

Regulation:
Acidic chyme entering the duodenum activates secretin cells
CCK and secretin enter the bloodstream and eventually end up back in the duodenum

132
Q

What digestive enzymes does the pancreas produce and how are they activated?

A

Pancreatic lipase
Pancreatic amylase
Trypsinogen and chymotripsinogen (stored in their inactive form to prevent auto-digestion)
Enteropepsidases activate trypsinogen and the active tripsin cleaves both chymotrypsinogen and trypsinogen

133
Q

How are the endocrine cells of the pancreas arranged and what do they do?

A

Small clusters called the Islets of Langerhans
They synthesise and secrete hormones e.g. via insulin (beta) and glucagon (alpha) via the pancreatic vein
Delta cells produce stomatostatin

134
Q

Describe insulin

A

Two peptide chains joined by disulphide bonds between cysteine residues
Stored as a hexamer around zinc
Release stimulated by ACh on M3 receptors, inhibited by noradrenaline on alpha-2 adrenoceptors

135
Q

Describe a beta cell with low glucose compared to high glucose levels

A 
Rest (low glucose):
Some glucose enters the cell through glucose transporters
Low metabolism
Low ATP levels
Katp channels open, K leaving cell
VD calcium channels closed

High glucose:
Glucose enters the cell through glucose transporters and immediately undergoes glycolysis and citric acid cycle
Increase in ATP which binds to and closes Katp channels
Membrane potential rises causes VD calcium to open
Calcium entering the cell stimulates the movement of stored insulin secretory granules to fuse with the membrane

136
Q

What are the insulin signalling pathways?

A

The insulin receptor is an RTK which phophorylates itself at tyrosine residues when activated.
This attracts IRS-1 which is also phosphorylated by the beta subunits of the receptor.
This recruits PI3Kinase which phosphorylates PIP2 -> PIP3 and this stimulates kinases to phosphorylate Akt which is needed for glucose transport

Ras-raf:
Autophosphorylation of the RTK attracts the Grb 2-Shc complex which activates the GTPase Ras whic activates Ras -> Mek -> ERK which promotes cell survival

137
Q

What are the symptoms of Diabetes Mellitus?

A 
Fatigue
Blurred vision
Passing more urine (flushing out excess glucose)
Unexplained weight loss
Slow healing of cuts and wounds
138
Q

How do you test for diabetes?

A

Urine test for glucose (a healthy person wouldn’t have much if any)
Glycated haemoglobin test measures the average plasma glucose concentration for 8-12 weeks (20-41 mmol/mol is normal)
Blood tests:
Fasting (over 7mM is too high)
Random (over 11 mM is too high)
Oral, consume 75g glucose (over 11 mM is too high)

139
Q

What is glycation?

A

Chemical binding of glucose to amino groups of proteins without using enzymes

140
Q

Describe the differentypes of diabetes

A 
Type 1:
Less common than type 2
Loss of pancreatic beta-cells caused by an auto-immune respone
Genetic pre-disposition 
Managed by insulin injection or pump

Type 2:
Usually in older people
Combination of insulin resistance and resulting beta-cell failure to produce insulin due to toxic levels of glucose
Genetics and lfestyle are both strong influences on risk
Gestational diabetes:
Onset of glucose intolerance in 2nd/3rd trimester
Increases the risk of type 2 diabetes

141
Q

How is type 2 diabetes treated?

A

Hypoglycaemic treatments:

1) increase insulin secretion
2) increase target organ sensitivity to insulin
3) decrease rate of glucose absorption

142
Q

What does metaformin do?

A

Stimulates glucose uptake in the liver, inhibiting gluconeogenesis
It inhibits the mitochondrial complex 1 which means there’s more AMP in the cells which activates AMPK, promoting glucose uptake and inhibiting gluconeogenesis

Physiology and Pharmacology I (1 decks)

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