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Cardiovascular Block > Week #4 > Flashcards

Week #4 Flashcards

1
Q

Arteries are _____ compliant than veins

A
  • less compliant
  • So for a given volume entering the vessels the BP will rise more in the arteries than it will in the veins
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2
Q

The left ventriclke has _____ compliant walls than the right ventricle and so there is a ____ pressure within the left ventricle

A
  • less
  • higher
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3
Q

The end systolic volume in the left ventricle is?

What is the SV of the left ventricle?

What is the early-diastolic pressure in the LV?

A
  • 75ml
  • 75ml
  • 5mmHg
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4
Q

Increasing HR will ________ stroke volume

A

decrease

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5
Q

Increasing contractility of the heart will result in an ______ stroke volume for a given ________

A
  • increase
  • end diastolic volume
  • increased with sympathetic activity
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6
Q

Does parasympathetic activity impact on heart contractility?

A
  • perhaps marginly but for all intents and purposes NO
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7
Q

What is meant by the term “afterload”?

A
  • The load encountered by the ventricle as it commences contraction
  • a pressure load imposed by
    • arterial hypertension
    • LV outflow tract obstruction
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8
Q

What is the rough distribution of blood in the CV system?

Systemic veins

Systemic arteries

Systemic capillaries

Lungs

Heart

A
  • 65%
  • 13%
  • 5%
  • 10%
  • 7%
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9
Q

A reduction in total peripheral resistance will lead to ____ blood in the arteries

A
  • less blood in the arteries
  • as now more blood will flow into the veins
    • i.e. blood will not be kept in the arteries as well
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10
Q

Vasculature function curve

As CO increases Venous pressure _______

A
  • Decreases
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11
Q

Is this CO venous pressure curve shift a result of:

Decreasing TPR?

or

Venoconstriction?

A

Venoconstriction (or increase blood volume)

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12
Q

Is this CO venous pressure curve shift a result of:

Decreasing TPR?

or

Venoconstriction?

A

decreasing TPR

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13
Q

What is the central venous pressure in a normal person?

A

Pressure is 1-5mmHg in the great veins just outside the heart

IVC, SVC

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14
Q

If venous pressure drops CO _____

A
  • drops
  • as there is not a high enough pressur to fill the heart as much
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15
Q

So CO goes up as venous pressure goes up

What is this curve called?

A

Cardiac function curve

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16
Q

Describe what will happen to CO and Venous pressure when the following things occur:

Increase Blood volume?

Increase in Heart contractility?

Decrease TPR?

A
  • Venous BP will rise and CO will rise
  • CO will rise, Venous Pressure will decrease
  • Venous pressure will rise, CO will risep
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17
Q

What is the equilibrium point between CO and Venous pressure?

A
  • Where there is adequate Venous pressure to increase CO but the CO isnt too great to so that it lowers vebous pressure
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18
Q

Why is cnetral venous pressure

A
  • filling pressure for the heart
  • needs to be adequate to maintain CO
  • rises as a result of a failing heart
  • falls when venous return is poor
    • blood loss, upright posture, inadequate muscle & respiratory pumps
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19
Q

What factors are released from the Endothelium to control vessel tone and what do they do?

i.e. vasoconstriction

or

vasodilationd

A
  • Nitric oxide-potent vasodilator
  • Endothelin-vasoconstrictor
  • Prostoglandins-can be either
  • Thrombin-vasoconstriction
  • ADP-vasoconstriction
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20
Q

Define the following terms:

Panncytopeania

Anaemia

Leukopenia

Lymphopenia

Thrombocytopenia

A
  • Not enough of all cells
  • Not enough red cells
  • Not enough white blood cells
  • Not enough neutrophils
  • Not enough lymphocytes
  • Not enough platelets
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21
Q

Define the following terms:

Polycthaemia

Leukocytosis

Throbocytosis

Dyserythropoiesis

A
  • Too many RBC
  • Too many WBC
  • Too many platelets
  • RBC don’t function properly
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22
Q

What is Anaemia?

Not enough red cells
We measure Haemoglobin (Hb) rather than RBC count

Anaemia is defined as a Hb level bellow that which is normal for age and gend

A
  • Not enough red cells
  • We measure Haemoglobin (Hb) rather than RBC count
  • Anaemia is defined as a Hb level bellow that which is normal for age and gender
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23
Q

What is the equation for tissue oxygen delivery?

A
  • CO x Hb x %O2Satn x 1.34
    • (1.34 is a constant, which is the number of mls of oxygen carried by a gram of normal Hb)
  • L/min x g/L x % x mLs/g = mLs/min
  • CO = HR x SR
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24
Q

What is the impact of anaemia?

A
  • Reduced oxygen to tissues unless we can increase cardiac output to compensate
  • Ability to maintain increased cardiac output varies
  • Ability to compensate depends on time
  • The number (Hb) alone is never the only factor
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25
Q

What are the clinical signs of anaemia?

A
  • Pale
  • Lethargic
  • Failure to thrive
  • Hypoxic
  • Ischaemia
  • Tachycardia—fast HR
    • Acute blood loss—HR will jump up quickly
    • If chronic iron deficiency then perhaps not as high
      • Stroke volume may have increased over time instead
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26
Q

What are the three causes of anaemia?

A
  • Failure of production
  • Increased destruction/loss
  • Inappropriate production
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27
Q

Full Blood Examination (FBE, FBC, CBC)

What is each of the measurements and what are the units?

  • Hb
  • RCC
  • Hct
  • MCV
  • MCH
  • MCHC
  • RDW
  • Plts
  • WCC
A
  • Grams/L (normal=120-140)
  • Red cell count-4.5-5 *10^12 cells per Litre
  • Heamatocrit
    • Measure of what proportion of the blood is the cellular components and what portion of the blood is the plasma component—measured as a %. Normally 45% for men and 40% for women
  • Mean Corpuscular Volume
    • Average volume of a red blood cell within the body
  • Mean Corpuscular Heamaglobin
    • Average amount of heamaglobin per cell
  • Mean corpuscular haemoglobin concentration
  • Red cell distribution width—like a standard deviation around the mean
    • Shows us if the cells are all different or mostly the same
  • Platelet count
  • White cell count
    • differential
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28
Q

What is a Blood Film?

A
  • morphology of the red cells, white cells and plts
  • Red cells
    • Size (normocytic, microcytic, macrocytic)
    • Shape (many variations—each with different meaning)
    • Colour (normchromic, hypochromic, polychomasia)
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29
Q

What are some of the classifications of anaemia and what do they mean?

A
  • Regenerative
    • So either blood loss, or blood break down
    • Can be very rapid progression to death
  • Aregenerative
    • Bone marrow isn’t making enough cells
    • Can be slower progression
  • Microcytic, normocytic or macrocytic
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30
Q

What are some of the signs that would help differentiate between regenerative anaemia and aregenerative anaemia?

A
  • Signs of increased production
    • Reticulocytes, polychromasia
  • Signs of increased destruction
    • Jaundice (increased serum bilirubin)
      • Bi product of breakdown of RBC is bilirubin so jaundice
    • Haptoglobins-picks up bilirubin
    • LDH
      • Lactic dehydrogenase-picks up bilirubin
  • Blood loss
    • Overt/covert
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31
Q

What are the different sites of Haemopoiesis at different stages of devlopment?

A
  • Yolk sac—first few weeks
  • Liver and spleen—6weeks-7months
    • Sometimes if there is something wrong with the bone marrow than liver and spleen may compensate and blood is made from there instead
  • Bone marrow—7 months—throughout life
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32
Q

Explain why the ideal place to collect bone marrow from a child and from an adult differs and what is the site?

A
  • From an adult it would be best to collect bone marrow from the pelvis
  • from a child the bone marrow can be taken from the blood
  • throughout life bone marrow sites are replaced with fat as the bones stop growing
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33
Q

Heamopoeisis

What are the different stages?

What does the pluripotent stem cell differentiate into? and what are some of it’s other properties?

A
  • Pluripotent stem cell
    • Capable of self renewal
    • Differentiates into all haemopoietic cell lines
    • Also gives rise to lymphocytes, and osteoclasts
    • Exists in small numbers in the marrow
    • Mice studies 1 in 100,000 nucleated cell
    • As yet not definitevely identified
      • So we still cannot look at them down the microscope and identify them
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34
Q

What is the role of the bone marrow stroma in heamopoeisis?

What cells are included as bone marrow stromal cells?

and ECM?

A
  • Bone marrow stromal cells can take the form of macrophages, fibroblasts, endothelial cells, fat cells and reticulum cells.
  • ECM stroma can include fibronectin, laminin, collagen and proteoglycan, heamonectin.
  • Provides specific microenvironment for bone marrow to grow
  • Many elements required
  • Changes in adhesion molecules mark the progression of cells through the stroma
  • Every cell in the bone marrow is attached to the stroma
    • This is why when we do a bone marrow transplant we can inject into a vein because bone marrow cells go to their home
  • Bone marrow in continuity with blood circulation
    • Reason cells are able to stay in bone marrow due to the adhesion factors on the stromal cells
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35
Q

What are some dietary requirements for heamopoeisis?

A
  • iron, vitamin B12 and folic acid
  • Erythroblasts require folate and vitamin B12 for proliferation during their differentiation
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36
Q

Decribe the process of clot formation in simple terms providing a time frame

A
  • Injury
  • Primary haemostasis (immediately, seconds, minutes)
    • Vasoconstriction—stop blood loss
    • Platelet adhesion
    • Platelet aggregation
  • Secondary haemostasis (minutes)
    • Activation of coagulation factors
    • Formation of fibrin
  • Fibrinolysis (minutes, hours)
    • Activation of fibrinolysis
    • Lysis of the clot
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37
Q

Draw the coagulation cascade (intrinsic and extrinsic)

A
  • Factors are contained within the blood plasma
  • Remeber that Fibrin production results in mesh like formation which fixes platelets together and completes clot
  • Remember that Thrombin also activates thrombomodulin and TAFI
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38
Q

What are the three compenents of Virchow’s Triad?

A
  • Blood vessel wall
  • Blood composition
  • Blood flow
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39
Q

What is the role of the activation of TAFI and thrombomodulin by thrombin and Protein C

A
  • TAFI is for clot stabilisation
  • Thrombomodulin is for control of activation as it inhibits VIIIa and Va it does this with activated Protein C
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40
Q

What are some of the actions of thrombin outside of the coagulation system?

A

Activation of PAR’s (protease-activated receptors)

  • Group of cellular receptors that regulate platelet activation
  • Tumour growth and spread
  • New blood vessel formation
  • Inflammation
  • Atherosclerosis
  • Neutrophil and monocytes migration
  • Survival and growth of neurons

Importance in embryonic growth, tumour spread and vascular disease

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41
Q

Proteins of the coagulation cascade, letters or roman numerals?

A
  • Letters are inhibitors
  • roman numerals push the coagulation cascade forward
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42
Q

Name the 3 ways we could (theoretically) test the heamostatic nature of a patient?

A
  • Blood vessel wall
    • test bleeding time? no longer done
    • no other tests that could test this
  • Platelets
    • number, function, appearance
  • Coagulation system (and fibrinolytic system)
    • Lots of different tests could be done
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43
Q

List some of the Global Bleeding Funtional tests and how they work and what they cna be used for

A
  • ACT
    • activated clotting time
  • APTT-Activated partial thromoboplastin time
    • Takes patient sample at 37 degrees, we add calcium to reverse citrate in the tube and then we add an activator, an APTT reagent, that activates the system and measure the time in seconds until fibrin is formed
    • Just tells us about the integrity of the factors in that line
    • Doesn’t inform about the physiological situation
    • So this test can tell us about the presence or absence of a drug called heparin—most frequently used IV anti-coagulant
    • And also tells us the presence of a Lupus anti-coagulant, a non-specific inhibitor of the phospholipid antibody that gives a prolonged APTT-but actually causes a risk of clotting

So a prolonged APTT shows that the patient may have an increased risk of bleeding or indicates the presence of one of the two anti-coagulants

  • PT/INR-pro-thrombin time, converts to an INR
    • Add a thromboplastin and then measure time until fibrin is formed
    • Also the test used to monitor warfarin (for a long time the standard anti-coagulant for long term use)
    • INR is the international normalised ratio

This was to normalize the PT number
High level of standardization
Because the problem with these results is that they may use different reagents for the tests and different labs may get very different results
So there is a strong need for standardisation and we still don’t have it for the APPT measurements
INR= (patient PT/mean normal PT)ISI

ISI= international sensitivity index—reflects the sensitivity of reagent to reduction in Vit K dependent factors

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44
Q

What are some of the specific factor assays for bleeding

A
  • Factor assays
    • measure specific protein concentrations
  • Functional assays
    • measure how well Von-Willebrand factor binds collagen
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45
Q

Explain the following assays and outline positive and drawback to each:

Functional clot based assays (ACT, APTT, PT/INR etc)

Chromogenic assays

Immunological assays

A
  • Funtional clot based assays may better reflect the physiological situation (?) but are more technically difficult
  • Chromogenic assays—use substrate that will be clipped by protein of interest and illicit colour change and then we can compare to a standard and infer how much protein is present
    • More reproducible but may be less physiologically relevant
  • Immunological assays—measure amount of proteins, doesn’t tell us if the protein is working though
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46
Q

What process should you undertake to diagnosis a clotting problem?

Why do we need age matched controls?

A
  • Do global test to look at which part of the pathway we want to look at and then specific test to work out the specific protein deficiency
  • remember that factors vary in concentration as we age so we need age matched controls
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47
Q

What are the two main mechanisms by which neurotransmitters are removed from the synapse?

A
  • Re-uptake into the neuron that released it where it is then metabolised
  • Or metabolism in the synapse where it is degraded
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48
Q

What does the sympathetic nervous system innervate?

What does the parasympathetic nervous system innervate?

A
  • sweat glands, heart, blood vessels and glands which occurs through innervation from post ganglionic nerves which arose from the sympathetic chain where the pre-ganglionic neuron terminated. Also the adrenal gland which is directyl innevated by the pre-ganglionic neuron
  • Heart, glands and smooth muscle
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49
Q

What is the anatomy of the somatic and autonomic nervous system?

A

Somatic (Voluntary)

  • Single fibre leaves CNS
  • Innervates Skeletal Muscle

Autonomic (Involuntary)

  • Two fibre system:
    • Preganglionic fibres from CNS
    • Postganglionic fibres from autonomic ganglia
  • Innervates Most Organs/Tissues in the body
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50
Q

How is acetylcholine synthesised?

A
  • Choline acetyltransferase takes choline and adds AcetylcoA (from mitochondria) and makes acetylcholine which is then transported into the synaptic vesicle
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51
Q

How is noradrenaline synthesised?

A
  • Synthesis starts with tyrosine
  • Tyrosine hydroxylase then converts it to L-DOPA and then DOPA decarboxylase converts it into Dopamine.
  • Then dopamine is transported into the synaptic vesicle
  • If dopanergic neurons there would be no dopamine Beta-hydroxylase and dopamine would be released
  • In sympathetic nerves dopamine is conveted to noradrenaline and released at the synapse from synaptic vesicles
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52
Q

How is adrenaline synthesised?

A
  • PNMT is present in the secretory vesicles of the adrenal gland and converts noradrenaline to adrenaline
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53
Q

What is co-transmission?

A
  • Co-transmission is where autonomic nerves release more than one substance
  • For example ATP seems to be an immediate neurotransmitter that is released to exert effects
  • and Neuropeptide Y is a later released neurotransmitter
  • NA is the intermediate response
  • The degree of co-transmission that occurs can varry given the nerve in question
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54
Q

How is ACh inactivated?

A
  • Through the action of acetylcholine esterase (AChE), which is on the surface of the effector tissue cell, converts Acetylcholine to choline
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55
Q

How is NA inactivated?

A
  • transporter molecules pump NA out of the synapse
  • re-uptake through a neuronal receptor
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56
Q

What nerve fibres does the vagus nerve carry?

A
  • Parasympathetic nerve
57
Q

What is atropine?

A
  • Atropine is a muscurinic receptor antagonist
  • From deadly nightshade
58
Q

What is d-Tubocurarine (dTC)

A
  • Nicotinic receptor antagonist
59
Q

What happens to BP if Acetylcholine is injected into a rat?

What happens to BP if you add atropine and then add more acetylcholine?

A
  • Blood pressure drops due to decreased vascular tone and decreased HR
  • Blood pressure rises due to vasoconstriction and increased HR
60
Q

Please draw the nerves of the parasympathetic, sympathetic and somatic nervous system including neurotransmitters and receptors

A
61
Q

what is the structure of nicotinic receptor?

What is the structure of the muscurinic and alpha and Beta adrenoceptors?

A
  • Ligand gated ion channels
  • G-protein coupled receptors
62
Q

Why do we need an oxygen carrier?

A
  • Oxygen can be dissolved in water but at a fairly low concentration and it would not be enough for us to survive
  • O2 is soluble at <0.1mM = 1% of needs
  • Also oxygen is very reactive = oxidation
63
Q
  • The haem moieties in Hb and Mb bind O2 (not the protein)
  • Myoglobin is the oxygen storage molecules found in muscles
  • What is the structure of Heme?
A
  • Fe(II) has 6 coordinating bond positions
    • 4 bonds to nitrogens in the porphyrin ring
    • 5th bond to histidine F8 (His F8, i.e. 8th residue of the F helix)=proximal histidine
    • 6th bond is unoccupied in deoxygenated Hb; histidine residue from helix E7 hovers; in oxygenated Hb, oxygen binds here
    • Oxygen binds to Fe at 120 degree angle—easily removed
64
Q

What are some other roles of heme, aside form O2 transport?

A
  • Electron transport e.g. cytochrome C
  • Enzymes that perform redox reaction e.g. catalase reduced hydrogen peroxide to water
65
Q

What happens to the heam molecule structure when oxygen binds?

A
  • Notice when oxygen binds the Fe is pulled back into the plane of the haem
  • Which then pulls on the proximal histidine
  • Has dramatic effects for the whole organisation of the protein
66
Q

What is the color of the following molecules?

  • HbO2
  • Hb deO2
  • HbCO—
  • MetHb
A
  • scarlet red
  • dark red (looks at bit blue through skin)
  • cherry red (CO binds 200 x more tightly than O2)
  • MetHb is when Fe2+ is oxidised to Fe3+
    • old (aged) blood—dark brown (old meat and dried blood)
67
Q

What is meant by the co-operativity of the Hb?

A
  • Hb needs to have high affinity for O2 in the lungs (Hb is 90% saturated)
  • Once the Hb—O2 molecules reach the tissue that consumes oxygen, the O2 needs to be transferred to myoglobin. (Hb in venous blood is 60% saturated)
  • Sigmoidal curve represents weak-binding state at low pO2 and strong binding state at high pO2. So we want the Hb to pick up as much oxygen as possible when the partial pressure is above a certain threshold but then give away as much oxygen as possible when the oxygen pressure is below a certain level
    • Curve A is high affinity
    • Curve B is low affinity
    • We want the sigmoidal curve
68
Q

What is the structure of the Myoglobin molecule and what therefore are its properties?

A
  • Myoglobin in monomeric
  • 153 amino acids (Mr 16,700)—single polypeptide chain
  • O2 storage protein => mainly in skeletal muscle
  • Compact globular structure
  • Tertiary structure 8 alpha helices (A-H)
  • Haem bind in pocket between helix F and E.
  • Involves His (F8) (i.e. the 8th histidine on the F alpha helix) and His (E7)
  • Transient “breathing” of the alpha helices allow O2 to access haem in its buried hydrophobic pocket
  • Myoglobin has a high O2 affinity. Affinity does not change with O2 concentration (P50 is the partial pressure of a O2 giving 50% saturation. Mb P50 = 2 Torr)
    • So Mb will actually take O2 from Hb
  • Monomer => no cooperativity hyperbolic curve.
69
Q

What is the structure of Heamoglobin and therefore its properties?

A
  • (Mr 64,500)—two alpha chains of 144 residues; two beta chains of 146 residues
  • The alpha and beta subunits (50% identity) associate more strongly with each other than the same subunits
    • so alphaneta binds to alphabeta
  • 3D structures look very similar to each other and to Mb
  • Cooperativity in binding and release of O2, i.e. affinity for O2 varies with O2 concentrations
70
Q

How does the Heamoglobin have this co-operativity?

What causes the conformstion change and what is the effect on the Hb?

What is involved in th switch between deoxy (T) and oxy (R) states?

A
  • When oxygen binds it pulls the iron atom into
    the plane of the haem.
  • Histidine F8 is also pulled changing the tertiary structure of the entire subunit.
  • Conformational changes at one subunit affects adjacent subunits. When one changes they all change cooperatively.

The switch between deoxy [T] and oxy [R] states
involves:

  • Fe2+ moves relative to the porphyrin ring (pulls His F8) => initiates conformational change
  • alpha/beta subunits slide past each other and rotate
  • 8 electrostatic bonds in deoxy Hb are broken
  • H‐bonds between α and β‐subunits reorganise (Tyr‐Asp in T, Asp‐Asn in R)
    • so this is a lock in, break, and lock in again
  • BPG (bisphosphoglycerate) (which locks deoxy Hb) is released
71
Q

How does the co-operativity of the Hb actually work and how does it explain the sigmoidal curve?

What is meant by the allosteric interaction? and what is the specific name for it

A
  • As the first oxygen is added the Hb becomes more relaxed and then the other molecules change conformational state as well and become more “open” for oxygen binding
  • We call this a homotrophic allosteric modulataor
72
Q

Oxygen saturation curves of Mb and Hb?

A
73
Q

What is the role of 2,3‐bisphosphoglycerate (2,3‐BPG)

how many negative charges does it have?

How is it made?

How does it exert its effect and why is it important at high altitudes?

A
  • heterotrophic allosteric effector
  • 2,3‐BPG binds at a cavity between the subunits of the deoxy‐Hb molecule. It is the 5 negative charges on the molecule that enables it to bind
  • 2,3‐BPG stabilises deoxy‐Hb and locks out oxygen from rebinding.
  • 2,3‐BPG is obliged to dissociate when oxygen binds in the lungs and closes the cavity.
  • 2,3‐BPG is synthesised in RBC through the glycolysis pathways

How does it exert its effect and why is it important at high altitudes?

  • Decreases Hb affinity for oxygen so we can give more off in the tissues
  • In situations of high altitude the partial pressure of oxygen is lower so we can change the concentration of 2,3-BPG so that we can move the oxygen dissociation curve.
74
Q

Heamoglobin carries CO2

How?

Where does the rest of CO2 go?

A
  • Hb carries ~15% of CO formed in tissues to the lungs on the amino terminal groups of deoxy‐Hb as carbamate:
    • CO2 + Hb-NH2 <=> H+ + NH‐COO-
  • O2Hb binds CO2 less readily than deO2Hb
    • => CO2 is released in the lungs
  • The rest of the CO2 is converted to HCO3- by carbonic anhydrase
    • CO2 + H2O <=> HCO3-
  • HCO3- is soluble in plasma and is so transferred to the lungs
  • Both these reactions cause decreased pH but we use this to our advantage as the Bohr effect

*

75
Q

What is the Bohr effect?

A
  • Acid is produced in the tiissues\the binding of protosn to Hb decreases its affinity for O2
  • Explanation: Two histidines that salt bond
    become more positively charged in acid => stabilises the T state
  • This stimulates HbO2 to yield more O2 in the tissues in a state of low pH
  • It also transports ~40% of the protons produced back to the lungs and kidneys.
  • This Bohr effect is another example of allosteric iinteraction which involves communication between the different subunits
76
Q

What are the combined effects of CO2 (the Bohr effect) and BPG, draw on the curve

A
77
Q

What are the properties of Foetal Hb that allow the fetus to ensure that it gains oxygen form its mother?

A
  • HbF(α2γ2)binds oxygen with greater affinity than the mother’sHbA (the adult form of haemoglobin)
  • This gives the foetus access to oxygen carried by the mother’s HbA.
  • This is due to the fact that HbF binds 2,3 BPG less avidly than adult Hb
78
Q

Image of the Heamoglobin types at various stages of life

A
79
Q

Mutants of Hb

A
  • HbS, HbE, HbC, Hb D, Hb H
  • Different Hb may protect against malaria and so may be selected for.
80
Q

What is HbS?

What is its cause and impact on physiology?

A
  • HbA has a glutamate at position 6 whereas HbS has a valine, caused by one base change.
  • So is a hydrophobic residue
    • hydrophobic pocket in deoxyHb leads to binding to the surface and results in a polymer of HbS and if it gets large enough it can precipitate
    • So in low O2 we can get vaso-occlusions and crisis
  • HbS, HbS homozygositgy is partciularly susceptible to sickle cell crisis-RBC removed by spleen etc
  • Homozygosity is very bad but heterozygosity is protective from malaria whithoout as bad symptoms
81
Q

What is a situation where the post ganglionic sympathetic fibres are not releasing noradrenaline?

A
  • Innervation of the sweat glands
    • post ganglionic nerves release ACh
82
Q

Where does Botulinin Toxin act? (BoToX)

How can it be used therapeutically?

How does it actually work?

A
  • Acts to prevent vesicualr exocytosis of the synaptic vesicle and blocks process of membrane fusion
  • Can result in muscle weakness and even paralysis
  • Can used therapeuticallyh to combat some conditions such as muscle dystonias etc
    • also can be used for powerful sweating

How does it actually work?

  • Botulinum toxin is an enzyme/ a protease
  • Normally the synpatic vesicles (containing ACh) use surface proteins (SNARE proteins) to bind to proteins on the innersurface of the membrane which leads to fusion of the membranes and then ACh is released.
  • However once Botulinum toxin is in its active form it cleaves some of the SNARE proteins, which results in the lack if release of the ACh
83
Q

How do Anticholinesterases work?

What are some of the ways drugs in this class can differ from one another?

A
  • Blocks the action of acetlycholine Esterase (AChE)
  • Some of the drugs in this group show some selectivity in their action
    • Can be utilised clinically
    • may also vary in CNS activity
      • i.e. ablity to cross the BBB
  • Also have variable length of activity
    • short acting, medium duration and irreversible
84
Q

What is the characteristic and use of the following drugs:

Edrophonium

Neostigmine/ Pyridostigmine

Donepezil

A

Edrophonium

  • short acting
  • used in the diagnosis of myasthenia gravis

Neostigmine/ Pyridostigmine

  • medium duration drugs
  • used to reverse effects of (non-depolarising) neuromuscular blockers (nicotinic receptor)
  • used in the treatment of myasthenia gravis

Donepezil

  • Enters CNS well
  • Used in the treamtent of Alzheimer’s disease
    • one componenet of AD is decreased cholinergic signalling in CNS
85
Q

What is Myasthenia Gravis?

A
  • Autoimmune disease where Ab against nicotinic cholinergic receptors on skeletal muscle
    • Ab target the skeletal muscle ones (there are different forms)
  • Ab binding leads to complement recruitment and this can lead to destruction of the post junctional membrane
  • Local immune response triggers loss of architecture and we get re-distribution of the receptors
  • binding itself can lead to internalisation of the receptors
  • there are also some indications that Ab may out-compete the ACh
  • Disease tends to start with face and then moves to the skeletal muscle
86
Q

How can anticholinergics be used to treat Myasthenia Gravis?

A
  • Blocking degredation of the ACh can lead to higher ACh and longer ACh half life and so there may be enough nicotinic receptors left that can be bound ACh
87
Q

How can anticholinergics be used to diagnose Myasthenia Gravis?

A
  • The Tensilon test
  • to see if short acting ant-cholinergic improves symptoms
  • Tensilon=Edrophonium
88
Q

Nicotinic receptor

What is it?

How do they differ?

What are the two types, and what are they called?

A
  • The Nicotinic receptor is a Ligand-gated ion channel
  • Depending on the subunits of the nicotinic receptor it may have different uses and be targetted by different drugs-5 subunit structure
  • The muscle for is Nm type
  • the ganglion type is reffered to as Nn type
89
Q

What are some of the uses of Nicotinic receptor agonists?

A
  • Smoking cessation
    • nicotine (patches etc)
    • Varenicline (particla agonist)
90
Q

What are the uses of Nicotinic receptor Antagonists?

A
  • Preventing skeletal muscle contraction
  • Pre-surgical skeletal muscle relaxants (may allow for lower dose of anaesthetic
    • non depolarising (e.g. tubocurarine/vecuronium)
      • reversed by neostigmine (anti-cholinesterase)
        • reverse paralysis
  • Ganglion blockers (rare) act on the nN type
    • Hexamethonium
91
Q

What are muscurinic receptors?

What nervous systme are they a part of and what is the effects of there activation in different tissues?

A
  • G-protein coupled receptor
  • Parasympathetic receptors
    • Salivation, Lacrimation, Urination, Defecation
    • Sweating
    • Slowing of heart
    • Bronchoconstriction
    • Vasodilation
  • Clinical uses of agonists
    • Pilocarpine
      • enhances drainage from eye in glaucoma and can reduce the pressure
92
Q

What could be some uses of some Anti-muscurinic drugs?

A
  • Atropine
    • reduce secretiins and produce bronchodilation (in anaesthesia)
    • for certain types of bradycardia
    • pupil dilation (for examination of the eye)
    • AChE-inhibitor poisoning (organophsophates)
  • Hyoscinne
    • motion sickness
  • Ipratropium/Tiotropium (inhaled)
    • COPD
    • and maybe asthma too
93
Q

How do some drugs modulate the actions NA?

What are the three ways in which this is achieved and procide examples of each one

A
  • Blocking the uptake of NA
    • Cocaine blocks the re-uptake resulting in more NA in the synapse
    • can produce a tachycardia and increase in BP
  • Blockage of metabolism
    • Monamine oxidase deals with leaked NA and metabolises it
    • Can use Monoamine oxidase inhibitors (MOAinhibitor)
      • more leakage of NA
  • Indirectly acting Sympathomimetics
    • cause release of NA but in a Non-exocytotic release (calcium independent)
    • Indirectly acting sympathomimetics are taken up by the presynpatic neuron from the synapse where they procede to displace some of the NA from the synaptic vesicle within the neuron which then leaks out some of the NA inot the synapse
    • Amphetamines, ephedrine (psuedoephedrine) and tyramine
    • Tyramine can be in vegamite and cured sausage and cheese etc but nis ussually no a problem due to the action of the Monoamine oxidase
      • but if patients are on MAO-inhibitors are taken then we could get HR increase and BP increase
94
Q

What is the selctivity fo the following drugs?

Adrenaline?

Isoprenaline?

Phenylephrine?

A
  • Alpha and Beta Adrenoceptors
  • Beta selective
  • alpha selective
95
Q

What is the site of Beta1 and Beta2 adrenoceptors?

name some example drugs that are active at these sites

A
  • B1 receptors on the heart and B2 receptors in the airways
  • Isoprenaline used t beused for asthma treatment but is now replaced with salbutomol due to the increased specificty for B2 receptors
96
Q

What is Atenolol?

A
  • B1 Adrenoceptor antagonist
  • to treat hypertension
97
Q

What is propranolol?

A
  • B1 and B2 adrenoceptor antagonist
98
Q

What are some examples of alpha1 adrenoceptor agonists and antagonists? and their uses

A
  • alpha1 adrenoceptors arte foound on blood vessels and cause vasocontriction
  • Agonist-phenylephrine-nasal decongestent
  • antagonist-praxosin-hypertension treatment
99
Q

What is histamine, bradykinin and Nitric oxide?

A
  • small amine
  • peptide
  • gas
100
Q

What can stimulate Histamine release from the Mast cell?

A
  • Antigen via IgE
  • Complement fragments C3a, C5a
  • Neuropeptides
  • Cytokines and chemokines
  • Bacterial components
  • Bacterial components
  • Physical trauma
101
Q

What kind of receptors are the histamine receptors?

A
  • H1, H2, H3, H4
  • All are GPCR
102
Q

What is the triple response from histamine?

A
  • Reddening-vasodilation
  • Wheal-increase in vascular permeability
  • Flare-spreading response through sensory fibres
103
Q

What are some uses for H1 receptor antagonists?

A
  • Useful in treating
    • hayfever
    • atopic dermatits
    • urticaria
    • anaphylaxis and angiodema
    • bites and stings
    • pruritus
    • motion sickness
    • (not effecitve in asthma)
104
Q

What are some of the classes of H1 receptor antagonists?

A
  • Sedative-chlorpheniramine. promethazine
    • sedation may be neutral/beneficial in treatment of allergic condition, but sifficient to interfere with lifestyle
  • Non-sedative (poor entry into CNS)-terfenadine, astemizole
    • lack of anti-muscurinic activity and GIT effects but can cause rare, sudden ventricukar arrythmia (withdrawn)
  • Nwe non sedative agents-citirizine, loratidine
    • reduced risk of unwanted cardiac effects
105
Q

What is the use of the H2 receptor antagonists?

A
  • Used to be used for peptic ulcer treatment
    • but now we know that the disease is bacterial
  • prevented gastric acid secretion
  • HA released from Enterochromaffin-like cell acts on the parietal cells of the stomach and causes H+ release from the cell and acidification of the stomach
106
Q

What is Bradykinin?

How is it made?

A
  • Bradykinin is a local peptide mediator in pain and inflammation
  • Generated after plasma exudation during inflammation
  • Upon increased vascular permeability and leak of plasma proteins we get Prekallikrein (inactive plasma protein) being activated by Hageman factor (factor XII) converting is to Kalikrein
  • Kalikrein acts on plasma protein High molecule weight kininogen
  • HMWK is cleaved into bradykinin
107
Q

How is Bradykinin degraded?

A
  • Bradykinin is a 9 amino acid peptide and the end can be cleaved by Kininase I and II
  • Kininase II is otherwise commonly known as angiotensin converting enzyme (ACE)
108
Q

What are the actions of bradykinin, and how are they elicited?

A
  • Vacular
    • dilate arterioles and venules (released PGs/NO)
    • Increased vasculare permeability
  • Neural
    • stimulate sensory nerve endings-Pain
  • Other
    • contract uterus, airways and gut
    • epithelial secretion in airways and gut
109
Q

Bradykinin Receptors

A
  • Both are GPCRs
  • There are B1 and B2 receptors
110
Q

What is Icatibant?

A
  • B2 Bradykinin receptor antagonist
  • used to treat hereditary angioedema
    • patient have genetic C1esterase inhibitor deficiency (a SERPIN (serine protease inhibitor))
    • so a deficiency in the enzyme that inhibits kalikrein etc
    • so people have heightened levels of bradykinin and can cause deeper tissue swelling
111
Q

Explain the conundrom of ACh acting as a vasoconstrictor and a vasodilator?

A
  • People found that by adding NA the vessels would contract
  • But then upon adding ACh different labs found different things such that some labs noticed a further vasoconstriciton and other labs noted a vasodilation
  • People were confused by this
  • Turns out it was due to the different vascular preperations where:
    • The situation where ACh produced a vasodilation were using a transverse ring of the blood vessel
    • the situation where ACh produced a vasoconstriction the blood vessel was a helical strip where the endothelium had actually been removed
  • This lead to the realisation that the vascular endothelium was not just serving as a barrier but was a regulator of vascular tone
    • where ACh stimualtion would result in NO release and casue a vasodilatory response.
112
Q

What are some of the factors released from the endothelium that may modify vascular tone

A
  • Prostacyclin-Vasodilator
  • nitric oxide-Vasodilator
  • Endothelin-Vasoconstrictor
113
Q

How is NO being generated?

and how does NO exert its effects in the smooth muscle cells?

A

NO generation

  • receptor mediated genration of NO
  • ACh/Bradykinin stimualtion or mechanical shear stress
  • could result in intracellualr release of Ca2+
  • this would activate nitric oxide synthase (NOS)
  • NOS would convert arginine to liberate gas NO and citrulline
  • Endothelial cell would then release the NO

NO produces vasodilation

  • .NO enters smooth muscle cell and activates enzyme guanylate cyclase
  • Guanylate cyclase (active) then converts GTP to cGMP
  • cGMP produces vascular relaxation of the smooth muscle cell
    *
114
Q

What are the three isoforms of NOS?

A
  • nNOS-(nerves, epithelial cells)
  • iNOS (inducible-macrophages, smooth muscle)
  • eNOS (endothelial cells)
115
Q

What are some of the NOS inhibitors?

A
  • L-arginin analogues
    • (L-NAME)
  • Produce
    • vasoconstriction
    • hypertension
116
Q

What are some of the physiological roles of NO?

A
  • Flow-dependent vasodilation
    • NO release in response to shear forces
    • consequences for endothelial damage/dysfunction
  • Inhibits platelet adhesion and aggregation
  • Neurotransmitter
117
Q

What are some other terminologies used to decribe Arachadonic acid?

A
  • C20:4
  • 20 carbon molecules with 4 double bonds
  • Eicosatetraenoic acid
  • Omega-6
    • has its first C-C double bond at Carbon 6
118
Q

Where do we obtain the Arachodonic acid?

A
  • From poly-unsaturated fatty acids (PUFA)
  • Diet usually consists of omega-6 PUFA
  • Usually consumed as C18; 2 but that can be converted to C20;4 through elongation and desaturation
119
Q

How is Arachodonic acid stored?

A
  • Carefully stored
  • Esterified into the plasma and nuclear membranes
  • Arachadonic acid must be kept at lower concentrations so to avoid conversion to more active components
  • Esterified in the phospholipds and the PUFA are esterified at the C2 position
    • C3 position has the base
    • and C1 is commonly a mono-unsaturated or saturated fatty acids
120
Q

How is Arachidonic acid released?

Snake venom??

A
  • Through activation of phospholipase A2
  • cleavage at the seconf carbon of the glycerol backbone
  • The enzyme is controlled in tight ways
    • Cytoplasmic calcium dependent
    • can also be phosphorylated by Erk to increase activity
  • Many snale venoms contain Phospholipase A2 and works on the outside of the cell membrane and actually breaks it down
121
Q

What is the metabolism of Arachidonic acid?

3 enzymes? where and when are they expressed?

A
  • AA is not in itself biologically active and must be metabolised to form eicosanoids
  • The type of eicosanoids generated depends on the cell type
    • through the expression of particular enzymes that transform AA
      • these enzymes are COX-1…
        • the form that is making the pre-curser to make prostacyclin continuously
        • housekeeper role-constitutively expressed
      • …and COX-2…
        • inducible enzyme
        • In the promoter of the COX-2 there are components that respond to inflammigons
        • So COX-2 expression is increased inf inflammatory conditions
          • IL-1 etc
      • …and Lypoxygenases
        • 5-Lypoxygenase expressed highly in eosinophils, mast cells and neutrophils and restricted to these cells
122
Q

What are the “unstable” prostoglandins and what are they converted to?

A
  • “Unstable” prostoglandins are termed Cyclic Endoperoxidases
  • They are converted to “stable” prostoglandins by isomerases.
    • And depending on the relative abundance of the different isomerases they can be converted to PGE2, PGF2, PGD2.
      • various substitutions on the cyclo-pentane ring are what define each of the molecules.
        • allows for highly selective action
      • these are relatively stable but still have quite a short half-lige
123
Q

What are the actions of PGE2, PGF2, and PGD2

A
  • PGE2
    • Relaxes vascular smooth muscle
    • vasodilator/natriuretic-decreased blood pressure.
    • hyperaslgesic-sensitises nerves to painful stimuli
      • but does not elicit oain itself
    • pyrogenic-fever producing
    • angiogenic (wound healing/ tumour growth)
      • in the long term
    • Bronchodilator
      • not used as a bronchodilator drug though… why?
  • PGF2
    • Bronchoconstrictor
  • PGD2
    • Bronchoconstrictor
124
Q

NSAIDs effects can predominatly be attributed to the inhibition of synthesis of?

What are the effects of NSAIDs

and what are some of the side-effects?

A
  • PGE2
  • Anti-inflammatory
    • acute and chronic conditions, e.g. RA, gout (not aspirin)
  • Analgesia
    • headache, menstrual pain, musculo-skeletal pain
  • Antipyretic
    • Paracetamol often preferred though
  • Side-effects are gastric irritationa nd ulceration
125
Q

What are some of the inflammatory actions that PGE2 is involved in?

(diagram)

A
126
Q

Explain the Hyperalgesia of PGE2?

A
  • If PGE2 is given in isolation to a subject than it causes vasodilation and heat but NO pain
  • But if PGE2 is given with a directly algesic substance like bradykinin the repsonse elicited by the bradykinin is much more intense and much more protracted
    • Does not matter what the pain stimulis is
127
Q

What does IL-1Beta induce (concerning PGE2)

A
  • IL-1Beta induced increases in Bradykinin-1 receptors and increase in COX-2 and phospholipase A2
  • So in inflammation the production levels of PGE2 is much higher and gives rise to all the symptoms
128
Q

How does PGE2 reuslt in fever?

A
  • Prostoglandins do not travel in the blood
  • pulmonary circualtion metabolises prostoglandins before they reach systemic circulation
  • But cytokines (TNF-alpha, IL-1Beta do travel in circulation and they can travel to regions of the hypothalumus where they can pass across in regions where the blood brain barrier is not as strong and at these site there is induction of phospholipase A2 and Cycloxygenase and PGE2 synthesis
  • This leads to cAMP release which raises the temperature set point
129
Q

What is the basis for the side effects of the NSAIDs

A
  • We lose the gastro-protective role of PGE2:
    • promotes blood flow
    • promotes angiogenesis
    • increases mucus secretion
    • reduces gastric acid secretion
  • So with a patient on NSAIDs chronically we can get significant ulceration
130
Q

Apart from the the prostoglandins what other compounds are the result of the isomerase conversion of cyclic endoperoxidases?

A
  • Prostacyclin and Tromboxane A2
131
Q

What is prostacyclin and what does it do?

A
  • Prostacyclin does not have the cyclo-pentane ring so is not a prostaglandin
  • chemically unstable-half life of 3 min
  • produced by thin layer of endothelial cells constitutively
  • reduced platelet activation
  • vasodilation
  • protects against coronary artery disease due to the vasodilationa and reduced platelet activation
132
Q

What is thromboxane A2 and what does it do?

A
  • Thromboxane is not a prostoglandin with a siz memberred ring
  • even more chemically unstable-half life of 30 seconds
  • Produced by mainly by platelets and a bit by macrophages
  • positive feedback as it causes further platelet activation
  • vasoconstrictor
  • Promotes coronary artery disease
  • These actions oppose those of prostacyclin (PGI2)
133
Q

Why is Aspirin “special”?

And how is it that it is cardioprotective?

A
  • Binds to a serine at the active site of the COX
  • Can be given at low dose to afford a cardioprotective effect
    • still high dose in the gastric circulation though so can target platelts in th gastric circulation
    • the platelets in the systemic circulation recieve less aspirin though
    • Because the aspirin has no nucleus you stop that platelets ability to make thromboxane.
    • But the Prostacyclin is still generated… why?
      • because the endothelial cells are only exposed to realatively low levels of COX they can require the ability to produce prostacyclin and thromboxane but the platelets (which poreviously produced the majority of the thromboxane) are now stunted so the balance has now shifted
134
Q

How is it that Aspirin triggers the production of different lipoxins and what is their character?

A
  • Aspirin covalenently acetylates the COX-2 but the oxygenation capacity is changed rather than destroyed so the acetylated COX-2 produces a 15-hydroxy version of arachadonic acid which can be further converted by other lypoxygenases which produce analogues of the endogenous lypoxins
    • inflammation resolving lipids which may reduce inflammation
135
Q

Why consume Omega-3 fatty acids

A
  • Consuming omega-3 fatty acids rather than omega-6 PUFA then we get the omega-3 version of arachadonic acid and this will results in a conversion from C18:3 to C20:5 and this kind of arachodonic acid confers prostoglandins with 3 double bonds for some reason prostacyclin (PGI3) is able to still function whereas thromboxane (TxA3) is not effective in this form
  • so it confers vascular disease protection
136
Q

What is the 5-Lipoxygenase pathway?

where does this pathway occur?

A
  • generates 5-HPETE which is converted into Leukotriene A-4
  • 5-Lypoxygenase is resticted to inflammatory cells
  • no known physiological role beyond inflammation
    • so is a good target for drugs-but it has been hard to get specificity
  • activated by increase in intracellular calcium by stimuli produced in infection, allergic responses and other forms of inflammation.
  • There are two sets of products made by transforming the Leukotriene A4
    • the important set is the cysteinyl leukotrienes
      • highly active lipid causing bronchospasm and vasodilation
      • targetted in asthma-antagonists
    • Leukotriene B4 is a chemoattractant but perhaps not that important.
137
Q

Sites of drug actions that modulate the arachadonic acid pathway

A
138
Q
A

Cardiovascular Block (4 decks)

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