Week #6 Flashcards
What is found in the anterior middle mediastinum
Ussually fat but before it was the thymus but is involuted in adolescents
What does the Brachiocephalic (left and right), subclavian, and Internal Jugular Vein drain?
So SVC then Brachiocephalic vein (left and right) then this splits into the subclavian vein and the internal jugular vein
The subclavian vein drain arms
And IJV drains the head and neck
What is the azygous vein and where does is drain to?
The Azygous vein collects blood from the thoracic walls and drains into the posterior of the SVC
how does the aorta arch
upwards, backwards and to the left
When does the aortic arch become the descending aorta
T4/T5 disc level
what is the ligamentum arteriosum?
similar to the fossa ovalis in that it is present in the foetal circulation and connects the aorta to the pulmonary trunk-now just a connection
Aortic arch supplies the head and neck through the…
…right brachiocephalic trunk which splits into the subclavial artery and the right common carotid and then on the left side we have the left common carotid and the left subclavian arteries
Retro-oesophageal right subclavian artery…?
can arise due to different arrangements of the aortic arch and branching veins and is when there is no right brachiocephalic artery and we get later branching of the right common carotid and it goes behind oesophagus and could cause swallowing issues.
C3, C4, C5 keeps the…?
Diaphragm alive
Phrenic Nerve…?
…passes between the subclavian vein and artery and then runs anterior to lung root and pierces diaphragm
Left and right Phrenic nerves are the most lateral structures of the mediastinum
Right Phrenic nerve will be lateral to venous structures and will go through diaphragm at the level of T8 with the IVC
the left phrenic nerve will be lateral to arterial structure and peireces the diaphragm on its own at the level of the apex of the heart
What does the phrenic nerve supply?
motor supply to the diaphragm and this is through the branching that occurs on the abdominal surface and also sensory nerves and sensory information is picked up from the diaphragmatic pleura and pericardium (i.e. structures is passes by)
Vagus nerve
Is a cranial nerve that runs postero-lateral to the common carotid artery. So starts in the cranium and then comes down. Vagus nerve will pierce the diaphragm at the T10 level with the oesophagus
Where does the oesophagus pierce the diaphragm?
At T10
where does the IVC pierce the diaphragm?
at T8
The vagus nerve has what kind of nerve fibres?
parasympathetic nerve fibres
Right vagus nerve pathway to diaphragm
runs down with the trache and then passes posterior to lung root and then pierces diaphragm at T10
Left Vagus nerve pathway to diaphragm
cannot move medially as it is impinged by the aorta so runs with that and then passes behind lung root and then pierces diaphragm with oesophagus at T10
Left recurrent Laryngeal nerve
given off by the left vagus nerve near the left lateral side of the arch of the aorta and hooks around ligamentum arteriosum and under arch of aorta and then ascend to the larynx through tracheal-oesophagus groove
Right recurrent laryngeal nerve
hooks under the right subclavian artery and then ascends thriugh the right side of the tracheal/oesophageal nerve
oesophagus
starts at C6 and peirces diagphragm at T10 and then comes forard and enters the stomach.
oesophagus is behind the trachea and is often flat-not a hard architecture like the trachea
Sites of narrowing are at the beging and the end and where the oesophagus is compressed by the aorta and the bronchi
Thoracic duct
Throracic duct is on the back of the esophagus and begins at the aortic hiatus.
At the level of T12 between crurer we have lymphatic collection sac cisterna chyli
cisterna chyli collect all the lymph from bellow the diagphragm and is immediately adjacent to T12 and the crurer and from that the thoracic duct ascends on the back of oesophagus and up it goes and then empties into the back of the IVC at the junction of the IVJ and right subclavian
What does the descending aorta supply?
descending aorta supplies the entire thorax through a series of branches and does so for each of the intercostal spaces. Other branches are bronchiol arteries and pericardial arteries and oesophageal arteries
What are the 4 components of the posterior mediastinum?
descending aorta, esophagus, thoracic duct, azygous vein and sympathetic trunk
TLR-4?
recognises LPS
TLR-3
Recognises LPS
Baceriostatic Vs Bacteriocidal
Bacteriostatic-enter premature bacterial plateu stage
Bactericidal-kill the bacteria
May not matter which we choose has essentially have the same effect in killing bacteria as bacteria not able to replicates suffeciently will be quickly destroyed by a healthy immune system
Ways we class antimicrobial agents…
Source: natural or synthetic or semi synthetic
bacteriocidal or bacteriostatic
Pharmacological class
Tetracyclines
Tetracyclines have the 4 rings
are now less widely used due to widespread resistance
can have activity modulated by addition of groups
e.g. tetracyclines are ussually removed from the body quickly but Doxycycline has the addition of an OH group to the #5 ring and this allows for increased half life
Beta Lactams
Beta lactams characterised by Beta-lactam ring
include Penicillins etc
Penicillin
Very good antibiotic in that it was very non-toxic to our own tissues
Problem with Penicillin G was that it was very acid labile and had to therfore be administered intravenously.
Penicillin V was then made that can be administerred orally
as beta lactam Penicillin V and G are ussually most effective against gram positive organisms (cocci and rods) but also effective against gram negative cocci
Used against staphylococci and streptococci
Methicillin
Similar to Penicillin
However also effective against staphylococcus aureus
But disdvantages was that it had tobe IV administerred and was actually more toxic than penicillin
GPC (staphylococcus)
eventually stap aureus developed resistance to methicillin and that is MRSA-reistant to all Beta-lactams
Ampicillin
Broader spectrum of antimicrobial activity. can tackle the streptococci and staphylococci but also gram negative rods such as salmonella typhi, e.coli heamophillus infleunzae
GNC, GNR, GPC, and GPR
we dont use ampicillin that much anymore because some are now a bit more resistant
Carbenecillin
first antibiotic against Pseudomonas aeruginosa (gram negative) dont really use anymore though as we need such large doses
GNR (pseudomonas)
Match these antibiotics:
Beta lactams, glycopeptides
polymyxins, polyenes
aminoglycosides, chloramphenicol
rifamycins, quinolenes
sulphonamides, trimethoprim
With their targets:
Ribosomes
Nucleic acids
Cell wall
Cytoplasmic membrane
Folic acid
Beta lactams, glycopeptides-Cell wall
polymyxins, polyenes-Cytoplasmic membrane (not a great target i.e. too similar to mammalian cells)
aminoglycosides, chloramphenicol-Ribosomes
rifamycins, quinolenes-Nucleic acids (quinolenes target DNA folding)
sulphonamides, trimethoprim-Folic acid (we are unable to make folic acid but bacteria do synthesise it so we can target these enzymes)
Peptidoglycan structure and synthesis
Alternating amino sugars N-acetyl glucosamine (G) and N-acetyl muramic acid (M).
In staph aureus (gram +ve) we have comming off the “M” a 5 amino acid chain (L-ala-D-glu-L-lys-D-ala-D-ala)
extra D-ala on the end is clipped off when the peptidoglycan subunit is added to the cell wall after being synthesised within the cell. A glycine pentapeptide comes off the L-lysine and links to the first D-ala and the other D-ala is removed and this creates a kind of lattice
Cross-linking between amino acids in different linear amino sugar chains occurs with the help of the enzyme transpeptidase (penicillin binfign protein)
So alternating D and L for strength.
also remmeber that subunits are synthesised within the cytoplasm and then wait on the interior of the cell membrane before being transported to the exterior and then being added to the growing framework
Vancomycin use and function and bacterial resistance
used against methicillin resistant staph aureus.
last line drug therapy
Vancomycin and binds to the D-ala-D-ala directly to inhibitnthe linking
rmb vancomycin doesnt work on gram -ve bacteria at all because it is very large and very charged and cannot pass through the outer membrane
Resistance to Vancomycin
instead of using D-ala, D-ala Enterococci can use D-ala, D-lac
The solution for VRSA is to just get a thicker cell wall
i.e. extra peptidoglycan mops up the vancomycin
cannot just give more as vancomycin can be a bit toxic
What is the mechanism of action of Beta lactams (penicillin)
Penicillin mimics the structure of D-ala-D-ala and this resulots in the binding of transpeptidases or penicillin binding proteins to it and inactivation of them.
Penicillin is actually bacterocidal because when the cell wall manafacturing is dodgy the bacteria just break it down. Bacteria have enzymes they can use to break down there cellular enzymes and when this happens the cell bursts due to the hypertonic nature of the cell. i.e. no longer have the support of the cell to allow for stretching
What are the methods of resistance to Beta-lactams?
Beta-lactamases hydrolyse the bond-actually beta lactamases are very similar to the penecillin binding proteins they just have a different catalytic unit
Altered transpeptidases MRSA makes a new transpeptidase that cannot be inactivated by methecillin
Anti-Beta-lactamases
Clavulonic acid is similar isn structure to the Bet-lactams but actually has no antimicrobial activity of it’s own and just functions to inhibit the function of beta-lactamses by covalently binding to a serine residue in the active site of the β-Lactamase
note it only acts on plasmid encoded Beta-lactamases
Clavulonic acid is combined with other Beta-lactamases to induce anti-bacterial effects-for example co-amoxyclav=amoxycillin and clavulonic acid
Aminoglycoside action?
Antiobiotic that acts on the recognition stage of protein synthesis
Aminoglycosides intefere with protein synthesis by binding to the site where the amino-tranferyl RNA binds so that it doesn’t look like the codon anymore-could be a stop codon or a nonsense mutation.
Aminoglycosides are highly charged so perhaps not great at getting in the cell across the membranes.
So at the start they go in slower but eventually as the cell wall gets weaker then they are more readily taken up and then they can kill off the cell wall completely.
Aminoglycoside resistance?
- There are sites on the molecule that the bacteria can create enzymes that will modify the functional group that could make the drug not as lipid soluble
- Efflux
- Modified outer membrane leading to reduced entry
- Ribosomal mutation leading to reduced binding
Platelets
Stick to injured surface (GpIb sticks to Von Willebrand factor vWF)
Change shape when they activate and release granules containing fibrinogen and factors
form solid clot with fibrin
Basics of the coagulation cascade?
- A big and complex cascade of plasma proteins
- Triggered by Tissue Factor
- End products include Thrombin and Fibrin
- Thrombinm activates fibrin from fibrinogen also activates platelets, inflammation, healing…
- Fibrin: sticks to things.
The normal endothelium as an anti-coagulent
- Endothelium secretes factors (Thrombomodulin, Protein C and Protein S) that modify thrombin and casue it to become an inhibitor
- Normal endothelium would not bind platelets or clotting cascade factors
- Normal endothelium produces tPA which activate plasmin which breaks down fibrin.
Thrombus
and Lines of Zahn
Abnormal clotting of a blood vessel that can contain red cell, white cell and platelets
form red and white layers termed Lines of Zahn
Arterial thrombosis and
venous thrombosis
Arterial thrmobosis is more white clot-i.e. caused by endothelial dysfunction and damage more platelets and thus we use aspirin to stop them. often occur in heart and or other vessels and sometime sreuslt in embolism where they end up blocking off blood supply to a organ or tissue etc
Venous thrombosis is caused by hypercoagulability of the blood and blood stasis- red clots and more due to RBC and clotting factors so we use warfarin stop them
Virchow’s triad?
- abnormal endothelium
- abnormal blood flow
- abnormal blood contnets
Abnormal Endothelium
Damaged-exposes collagen and wVF which can bind Gp1b
Or activated or dysfunctional can be caused by inflammatory cytokines, toxins, hypertension, cholesterol, smoking, etc
OR can be due to decreased production of less protein C less protein S and less tPA or increased clotting promotion with increased production of Tissue Factor
Abnormal blood flow
- Turbulence
- Stasis
- Loss of laminar flow
stasis cause contact of platelets with vessel wall which can activaye the endothelium
Digoxin
increases Cardiac contractility by increasing Ca++ stores in the Sarcoplasmic reticulum.
So Digoxin inhibits Na/K ATPase
so now we stop Sodium leaving cell and we get increased calcium in SR and so when we get the AP we get an increased Ca++ release but if applied for too long there is too much calcium within the cell and it starts flowing out of the cell at innapropriate times
Digoxin has a large volume of distribution as it binds muscle and so it also has a long half life
Digoxin effects at 25 minutes vs Digoxin effects at 45 minutes
Give digoxin and after 25 minutes the calcium goes up and we get increased contractility
But if you lave it in for 45 minutes there is too much calcium within the cell and it starts flowing out of the cell at innapropriate times, bit unstable and we get a late depolarisation—possible that this may course an arrythmia
Beta1 Aderenoceptor Agonist mechanims and function
Increases the Contractility and rate of the heart by acting on the Beta1 Adrenoceptors on the cardiomyocytes and the SA node
Can get the same side effects as when using digoxin i.e. increased risk of arrythmias due to increased calcium and also toxicity to cardiomyocytes
Chronic overactivation of B1 adrenoceptors we can get down-regulation of the B1 adrenoceptors and impaired B1 adrenoceptor coupling results in reduced sensitivity to β 1-adrenoceptor agonists or sympathetic drive
Amrinone
Amrinone inhibites phosphodiseterase and inhibit the breakdown of cAMP and get increased calcium channel activation and increased contractility
How can the Compensatory Mechanisms of reduction in cardiac output result in worsening pathology if there is already some underlying pathology?
AND
Drugs for stopping it
refer to ze image
Platelets adhere early and do what to initiate the early heamostatic responses
release granules containg 5-HT and ADP
ADP functions to activate other platelets and more adhere
and 5-HT is a powerful vasoconstrictor
and mediators such as thromboxane are sysnthesised
Pospholipase A2 liberating arachadonic acid and then Cycloxygenase converts it to thromboxane which is released along with 5-HT and ADP
Two pathways of the coagulation cascade that lead to prothrombin ► thrombin conversion.
- *Extrinsic pathway**: occurs in vivo due to release of thromboplastin from tissues (shorter in time)
- *Intrinsic pathway**-occurs in vitro: exposed collagen or other material, negative charges (e.g. glass)
Mechanisms of controlling blood coagulation (i.e. thrombomodulin, Protein C etc)
Refer to ze diagram, ya?
Action of Heparin
Heparin enchances the activity of antithrombin III which goes on to inactivate Xa and thrombin
Heparin must be either IV or LMW Heparin can self administerred by subcutaneous injection
Warfarin
All of the oral anticoagulents are derivatives of coumarin which inhibits the reduction of vitamin K
Warfarin has a delayed onset of action as it does not effect the existing clotting factors, i.e. only those that have already been made. Warfarin inhibits vitamin K reductase and reduced vitamin K is important for the gamma carboxylation of factors 2, 7, 9 and 10
Issues with compliance
Drugs impacting on platelet aggregation and adhesion
- ADP receptor antagonists-so stops platelets aggregating to one another
- (eg clopidogrel)
- Thromboxane synthesis inhibitors-thromboxane is a powerful vasoconstrictor and facilitates platelet aggregation
- (cyclo-oxygenase inhibitors eg aspirin)
- Glycoprotein IIb/IIIa receptor antagonists (Platelets aggregate and adhere via fibrinogen bridging between GPIIb/IIIa receptors)
- (eg tirofiban, abciximab) expensive mAb
This class of drugs are often used when there is not the severity of symptoms that would warrant the use warfarin or heparin-i.e. more low level inhibition of coagulation
Label the heart sounds and actions of the valves at each time point
Labels on image
Heart sounds of people with mitral and aortic valve stenosis and mitral and aortic valve regurgitation
on the pic dude
Aortic valve Stenosis?
AND
Ventricular Response?
Aortic valve Stenosis
most common valve lesion
often very well tolerated for a long time as heart can be compensatory
Progressive narrowing of the aortic valve due to calcification and fibrosis
reduction in valve area which we infer from measuring the pressure differences across the valves
Ventricular Response
ressure overload of left ventricle
conccentric hypertrophy
walls thicken and become stiffer-less compliant-increased LVEDP required to fill ventricle. No change in LVEDV.
Left ventricular changes are ussually reversible after surgery corrects the valve stenosis
Sound of an aortic valve stenosis?
crescendo and then decrescendo
Aortic valve regurgitation
AND
Causes
AND
Ventricular response
AND
Body Response
Aortic valve regurgitation is where part of each stroke volume leaks back into ventricle during diastole.
Can be caused by:
Aortic leaflet damage
- Endocarditis, Rheumatic fever
Aortic root dilated so leaflets don’t close
- Marfan’s syndrome (genetic disorder of the connective tissue)
- Aortic Dissection (blood flows into media)
- collagen disorders
- Syphilis
Left Ventricle Response
To maintain normal CO, LV must pump greater stroke volume.
Volume overload. Increased LVEDV. Increased Ejection Fraction. Normal LVESV
LV dilatation due to increased volume
Body Response
Increased Pulse Pressure
Reduced aortic diastolic pressure (collapsing pulse)
Mitral valve stenosis sounds
So there is a long low pitched sound in the diastolic period
Parathyroid hyperplasia
In normla thyroid follicle you can see speckled purple and speckled white-lots of fat with a few cells
In the hyperplasia we have lost the fat and cellular populaiton is quite dense
Graves Disease
- mixed hypertrophy and hyperplasia
- in normal situation we can see lots of colloid-the large eosinophilic follicles
- but in grave disease colloid has been pretty much removed and we have lots more cells with lots of basophilic nuclei
Microscopic appearance of yocardial hypertrophy
- Cannot really say if the cells are bigger
- but the nuclei are bigger and can get bi-nucleated mycocytes and there can be increased connective tissue
What are the complications of Mycardial hypertrophy?
(sorry bit of an essay here)
- Heart grows too big for the blood supply and we get more wall than blood. i.e. coronary arteries cannot deliver enough blood due to impaired diffusion and increased demand
- and we can then get ischaemia of the heart and then we get irreparable myocyte death.
- so this can also cause arrthmia due to fibrosis and myocyte death
- heart function also decreases due to myocyte death itself
- can also get impairment of heart ability to relax and impaired diastolic filling
- Direct death from too much myocardial hypertrophy as a result of turning on those foetal genes-genes that cause physiological hypertrophy as we are growing up
- Via heart failure this may lead to eccentric hypertrophy (lecturer seems unsure ??) this could be due to more fluid retention and increased volume and delivery to heart.
Label and annotate the Nephron
Loop diuretics
Mechanism
and
Side Effects
and
Main uses
- most powerful
- excrete 15-20% of Na in filtrate
- cause torrential urine flow
Mechanism
- act on thick ascending limb of the loop of henle
- inhibit the Na+/K+/2Cl- carrier
- Note that ussually the interstitium would be hypertonic due to the action of the ion transporters
- Also leads to more Na in distal tubule
and then reduced water reabsorption there as well - well absorbed from gut
- onset
- plasma protein bound
- reach site of action via secretion
- so must be secreted into lumen for action
- duration of action 3-6 hours
Side effects
- Increased K+ loss from distal tubule due to increased Na+ reapsortion in distal tubule and accompaning loss of K+ through the Na+/K+/ATPas transporter
- so this is hypokalaemia
- usually prescribed with a K+ supplement
- H+ excretion
- metabolic alkalosis
- reduced extracellular fluid volume which can cause hypotension-worse in elderly as could pass out and fall
- hypovolaemia and hypotension
Main uses
- acute pulmonary oedema
- chronic heart failure
- ascites (liver cirrhosis)
- renal failure
- and hypertension
Thiazide Diuretics
Mechanism
and
Side effects
- Moderately powerful as they act more distally-distal convoluted tubule
- true thiazides and thiazide-like drugs
- used in hypertension
- in combination with loop diuretics
Mechanism
- inhibit Na+/Cl- on the luminal side
- orally active
- excreted in urine (tubular secretion)
- maximum effect 4-6 hours
- duration 8-12 hours
Side effects
- K+ loss from collecting ducts
- as for loop diuretics
- coadminstered with K+ supplemen
- ↑plasma uric acid
- inhibition of tubular secretion of uric acid
- gout
- these effects less with thiazide like diuretics
Potassium-sparing diuretics
Two classes
- limited diuretic effect
- used in combination with K+ losing diuretics to prevent K+ loss e.g. in patients with heart failure
Two classes are:
Spironolactone (aldesterone receptor antagonists) and Triamterene and amiloride (Na+ channel blocker in collecting duct)
Potassium-sparing diuretic
Spironolactone
- Is a Aldesterone receptor antagonist
- usually aldosterone activates the Na+ channel on the luminal side and causes synthesis of the Na+/K+ transporter on the interstitial side
- Spironolactone is a aldersterone receptor antagonsist so we get reduced activation of Na+ channels and reduced stimulation of Na+ synthesis
- Because the Spironolactone inhibits Na+ uptake in the collecting duct there is no compensatory K+ secretion and there is no other site further on where increased Na+ absorbance/K+ excretion can occur
- So often used in combination with loop diuretic or thiazide diuretic in cardiac failure etc also hyperaldersteronims
- orally active
- slow onset because we are interfering with aldesterone (a steroid) which has a slow action which will impact on gene transcription which is also slow
- So short half life (10 minutes) but long effects
Adverse effects
- hyperkalaemia (if used
- gastronitestinal upset
*
Triamterene and amiloride
- Blocks luminal sodium channels in collecting ducts and tubules
- So inhibits Na+ reabsorption and K+ secretion
pharmacokinetics
- triamterene
- well-absorbed
- onset 2 hours
- duration 12-16 hours
- amiloride
- poorly absorbed
- slow onset
- duration 24 hours
