1
Q
Cholesterol is _____ made in plants and is called an ______ molecule due to its dual properties
A
not
amphipathic
2
Q
The 4 fates of cholesterol synthesised in the liver are?
A
- Transported to the tissues first must have the 3-OH group esterified so we get a uniformly fatty molecule (cholesterol ester). Assembled into VLDL for transport to tissues
- Bile acid stored in the gall bladder, used on demand to emulsify fatty meals
- Steroid hormoned and Vitamin D-Synthesised from cholesterol in gonads/adrenal glands and skin
- Membranes-Cholesterol forms 10-50% of the phospho-lipid bylayer. Cholesterol is a steric hinderer of the phospholipids and limits fluidity of the membrane
3
Q
membrane rafts
A
are regions of the membrane where signalling molecules can congregate as well as glycolipid and sphingolipid
4
Q
Cholesterol synthesis in the liver?
A
- Start with acetyl CoA and then this links to another two acetly CoA to form HMG CoA
- This is converted to Mevalonate acid by HMG-CoA reductase
- Mevalonate goes through a few more conversions to form Cholesterol.
- Cholesterol then provides negative feedback to HMG-CoA reductase
5
Q
Activated Isoprene
A
Is an intermediate of the cholesterol synthesis pathway and is involved in the synthesis of many other molecules
6
Q
Chylomicrons, LDL, VLDL, HDL
arrange in order of size
density
and protein contents
A
Largest to smallest: Chylomicrons, VLDL, LDL, HDL
Density (low to high): Chylomicrons, VLDL, LDL, HDL
Protein content (low to high): Chylomicrons, VLDL, LDL, LDL
7
Q
Chylomicrons
A
- made in the intestine and take TAGs and cholesterol ester from gut and transfer it to tissues via the lymphatics and blood and then take the chylomicron remnant and returns to the liver.
- Apolipoproteins: B-48 involved in structure and ApoE is involved in uptake of chylomicron remnants
- *ApoCII** activates lipoprotein lipase in tissues so that the TAGs can be removed
8
Q
VLDL
A
- VLDL formed in liver and carry TAGs and cholesterol ester from liver to tissues via the blood and lymphatics through the action of lipoprotein lipase which removes TAGs in muscle and adipose tissue and then the VLDL heads back to the liver again
- Apo B-100 (same gene as Apo B-48) and Apo E for strucuture and uptake into liver
- They also have ApoCII which activates lipoprotein lipase
VLDL packaged with TAGs and cholesterol ester
9
Q
LDL
A
- When VLDL loses Apo-E it can become LDL
- LDL derived from VLDL circulates around longer, lost most of the Apo lipoproteins except Apo B-1 and Apo-A-V
10
Q
HDL
A
- HDL made in liver and intestine
- Good cholesterol involved in reverse cholesterol transport
- converts free cholesterol to cholesterol ester and takes it back to liver and it also acts on macrophages and stops them becoming foam cells
- Two Apo A-1 proteins make a hydrophobic ring to round up cholesterol-ester and phospholipids to mature into HDL
- Apo A-1 binds SR-B1 receptor in liver and transfers its cargo of cholesterol-ester
11
Q
Cholesterol pathway
A
12
Q
ACAT
A
acyl co-A cholesterol acyl transferase-makes cholesterol ester for VLDL in liver
13
Q
LCAT
A
LCAT in plasma helps HDL scavenge cholesterol from membranes and takes up cholesterol and turns it into cholesterol ester
14
Q
Hypercholesteroleamia
A
- Is an increase in total cholesterol in the blood above 6.2mM is high and 5.2-6.2 is boderline
- Oxidised LDLs are particularly atherogenic
15
Q
Atherosclerosis
Put the steps in order:
- White cells (monocytes and T-cells) invade the tissue and secrete inflammatory mediators (cytokines).
- Endothelial cells in the artery react by displaying adhesion molecules.
- Modified (oxidised) LDL accumulates in an artery wall (favoured by high LDL).
- Macrophages appear, take up the modified LDLs using scavenger receptors.
- Fibrous tissue develops to trap the foam cells.
- Macrophages become engorged with cholesterol. At this stage they are called foam cells.
- Foam cells produce “tissue factor” that can lead to a blood clot in the artery upon rupture of the plaque.
A
Fatty Streak
- Modified (oxidised) LDL accumulates in an artery wall (favoured by high LDL).
- Endothelial cells in the artery react by displaying adhesion molecules.
- White cells (monocytes and T-cells) invade the tissue and secrete inflammatory mediators (cytokines).
- Macrophages appear, take up the modified LDLs using scavenger receptors.
- Macrophages become engorged with cholesterol. At this stage they are called foam cells.
- Fibrous tissue develops to trap the foam cells.
- Foam cells produce “tissue factor” that can lead to a blood clot in the artery upon rupture of the plaque.
16
Q
Cholesterol in diet
A
Apparently makes a small contribution to the overall cholesterol blood levels as those predisposed to make more cholesterol will
17
Q
Statins
A
- Inhibit synthesis of cholesterol through inhibiting the rate limiting enzyme HMG CoA reductase enzyme
- competitve inhibitor
- Importantly this also results in upregulation of the LDL and HDL receptor in the liver so more cholesterol is transported back to the liver for making into new VLDL
18
Q
Side effects of Statins?
A
- Statins reduce Q10 (coenzyme Q) production, which is involved in mitochondrial bioenergy transfer.
- The clinical use of HMG CoA-reductase inhibitors (statins) can cause skeletal and cardiac muscle complications.
- But Q10 supplements do not seem to be working in rectifying this i.e. do not decrease mytotoxicity
19
Q
4 factors impacting on coronary artery blood flow are?
A
- perfusion pressure-blood pressure (i.e. amount of blood)
- cornoary vascular resistance
- external compression (contracting muscle pushes on the vessels
- intrninic regulation (endothelial and myocyte metabolistes) e.g. prostocyclin, nitric oxide, endothelin
20
Q
Transmural infarct vs Non-Transmural infarct
A
Non transmural infarct is not as severe and primarily effects the subendocardium
whereas transmural infarct effects the myocardium as well once infarct has spread out
Note that the endocardium (like the intima) is able to gain blood supply from the blood in the ventricle and so is left unnafected
So order is endocardium, subendocardium, myocardium (responsible for contraction), epicardium (outer layer) and the fiborus sac, the pericardium
21
Q
Supply of heart by coronary arteries
A
22
Q
Myocardial infarction at 0 to 30 minutes
A
Angina
- 30 minutes
- reversible injury
- intracellular changes that cannot be seen may be abe to see only on electronic microscopy-mitochondrial swelling etc
- functionally there is a rapid loss of contractility
- May see ECG changes
- ST depression and/or T wave inversion
23
Q
Myocardial Infarction at 30 minutes to 12 hours
A
- Irreversibe cell injury
- disruption of the cell membrane
- cardiac proteins (Troponin and Creatin Kinase) start to leak out-can be measured in the blood
- calcium starts to leak out as well and this can lead to ECG changes
- ST Segment Elevation (STEMI)
- ST Segment Depression (NSTEMI)
- “Myocardial Irritability”
- So to help diagnosis at this stage we would measure protein levels in the blood as well as taking an ECG
Under the microscope
- irreversible injury
- cell death
- heammorhage
- oedema
- Coagulative necrosis=Mycocytes with blood in between and the fading of the nuclei with maniantance of cell strucutre
- may not see any gross morphological changes
24
Q
Myocardial infarction at 12:00 to 24:00 hours
A
- Inflammation
- Neutrophils enter
- contraction band necrosis-looks like tiger stripes
- shows that myocytes are dying
- Gross morphology may show some reddening of the heart walls
25
Myocardial infarction at 1 to 3 days
* At this stage there are few myocytes left in the site of the infarct-i.e. mainly neutrophils and debris-pus
* and gross morphology also looks like pus
* so no muscle-is just yellow soft pus
* at around this time-1 days the troponin level is at its highest
* and then gradually decreases after that
* we can look at the troponin levels and perhaps guess as to what stage the myocardial infarction is at
26
Myocardial infarction at 3 to 7 days
* Macrophages now enter and lay down granulation tissue so still a bit like a jelly, not that strong.
* macroophages ingest dead myocytes
* fibroblasts and vessels of granulation tissue appear
* collagen begins to be laid down at 5-6 days
**Gross mophology**
* red ring of vascular granulation tissue with central yellowing
27
List some of the complications that can occur in myocardial infarction at days 1 to 3
* The damaged myocytes are unstable-ARRHYTHMIA
* The damaged myocytes are being destroyed-CARDIAC FAILURE
* The damaged wall isn’t moving normally-MURAL THROMBUS
* The wall is necrotic and weakened-RUPTURE
* Inflammatory mediators abound-PERICARDITIS
28
Cardiac tamponade
* Rupture of the lateral wall and blood is pushed into the pericardium and can actually push back on the heart and stop it from beating
29
What are the three ways in which the heart can rupture?
and in each case what are the consequences?
1. Rupture of Free Ventricular Wall
* Blood into pericardium “Haemopericardium”
* Compressing the heart until it stops “Cardiac Tamponade”
2. Rupture of Papillary Muscle
* New onset murmur
* Mitral regurgitation
* Cardiac Failure
3. Rupture of IV Septum
* New onset murmur
* Ventricular Septal Defect
* Cardiac Failure
30
Myocardial infarction at 1-8 weeks
**Under the microscope**
* early and then late granulation tissue
* is initially very cellular and vascular with neutrophils and then more collagen is laid down as vessels and cell number decreases
**Gross Morhology**
* at 3 weeks
* collagen is pale grey and white flecks appearing but still some granulation tissue
* at this point the collagen tissue is still quite flexible and may stretch causing thinning of the wall
* at 6 weeks
* more fibrous white tissue building up
*
*
31
List some complications that could arise from myocardial infarction at weeks 1 to 8
arrythmia and cardiac failure are now somewhat less likely but we can get:
* Mural Thrombus
* and
* Aneurysm (infarct expansion)
This is due to the still immature collagen and though the wall is strong again, it is soemwhat flexible to wall stress and may stretch, thin and bulge out. which can lead to aneurysm which can lead to thrombus due to blood stasis
32
Mycocardial Infarction at 8 weeks and beyond
**Under the microscope**
* Extensive fibrosis in the area of infarction
* fixed dense collagen with the occasional cell
**Gross Morhology**
* wall may be thinner and is white fibrotic tissue
* may see evidense of aneurysms or mural thrombi
*
33
Complications of myocardial infarction 8 weeks and beyond
Now the risks are not as great and the damage has pretty much healed but heart may still be susceptible to:
* **Arryhtmia** is now less likely but possibel due to fibrosis which could result in the formation of electrical islands
* **Cardiac failure** could occur as remainign myocytes will have to compensate for the death of the other myocytes and this could result in hypertrophy and then eventual decompensation
* Any Aneurysms formed will not be removed but with all the fibrotic tissue are now unlikely to rupture but are still a place for blood stasis and therefore potential **thrombosis**
34
Classify these as either acute or chronic ischemic heart disease:
Unstable angina, Stable angina, chronic myocardial ischemia, myocardial infarction, sudden death cardiac death
**Acute**
* myocardial infarction, sudden death cardiac death and unstable angina
**Chronic**
* Stable angina, chronic myocardial ischemia
35
Stable Angina
* Presents as reproducible cardiac chest pain that occurs on exertion and goes away with rest
* due to atherosclerotic narrowing
* endothelium will be dysfunctional and will not dilate itself-innapropriate vasoconstriction
* at 70% Stenosis symptoms ussually start
36
Unstable Angina
* Presents as cardiac chest pain that may occur at rest
or minimal exertion and may not resolve with rest
* acute plaque event that could occur via heamorrhage and thromobosis
* it does resolve though-i.e. we can break the clot down and there is no permenant damage
* can occur at rest or with exertion
37
Chronic Myocardial Infarction
* Small areas of subendothelial ischaemia
* ongoing chronic narrowing of the vessels and overtime we get little patches of necrosis and fibrosis due to gradual loss of blood supply
*
Similar to the sort of fibrosis you might see in myocardial hypertrophy
* Carries similar risk of cardiac failure and arrhythmia
38
Sudden Cardiac death
* defined as a sudden death due to cardiac causes in a time frame less than an hour in someone with no previous cardiac conditions
* mostly ischeamic heart disease and frequently due to an early arrythmia
* or could be a silent infarct and then we get an acute rupture and pass away- would be classified as sudden cardiac death even though disease progression may have been occuring for awhile
* Other causes include
* Anomalous coronary arteries
* Left Ventricular Hypertrophy (genetic, acquired)
* Floppy mitral valve
* Cardiomyopathy (genetic, acquired, infective)
* Cardiac Conduction Syndrome (genetic)
39
Glyceryl Trinitrate
converted in the body to form nitric oxide which is a powerful vasodilator
40
If someone presents with myocardial infarction what do you do?
* give oxygen
* give aspirin-blood thinner
* give GTN-decrease preload on the
* measure troponin levels and ECG
41
3 main fates of cholesterol are?
1. incorparated into VLDL in the liver for delivery around the body
2. made into bile acids for fat emulsification and stored in the gall bladder
3. used for membrane synthesis
42
Cholesterol transprt and metabolism
* *Cholesterol can be sythesised in liver or from diet**
* *From intestine** it is packaged into chylomicrons and then circulates
**From liver**, VLDL cholesterol
Once chylomicrons and VLDL reach capillaries lipoprotien lipase hyrodlyses the TGs and then we get release of free fatty acids and then they are taken up by tissue and used for energy
this means that the VLDL and chylomicirn remanats are now dense in cholesterol and then the remnant circualte in bloodstream and then if they are transported to liver they can be taken up through LDL hepatic receptors for re-use into VLDL
OR
they can be converted to LDL and then they can circualte and deposit cholesterol into extra-hepatic tissue
and then this can form atherosclerosis
HDL are good ad they are involved in reverse cholesteral transport, they take cholesterol that has been deposited in the tissues and take it back to the liver and may use it for bile acid synthesis
43
Apo B-100
Allow for cholesterol transport into tissues and into vessel walls
* IDL, LDL, VLDL
44
Statins _____ the levels of LDL and ____ the levels of HDL in the blood
lower, increase
45
Statins
Precautions
and
Adverse effects
**Precautions**
* avoid grapefruit juice due to common cytochrome p450 pathway
* avoid drugs with same metabolism pathway
* mild elevation in aminotransferase
* minor increases in creatine kinase
* can lead to muscle pain and tenderness
**Adverse effects**
* common adverse effects
* mild GI symptoms, headache, insomnia, dizziness
* rare but serious adverse effects
* myopathy (minimised by UQ10 treatment?)
* rhabdomyolysis (breakdown of muscle resulting in myoglobin release into the bloodstream)
* renal failure
* hepatitis, liver failure
* Contraindicated in preganancy
* impaired fetal myelination
* withold during infection, post surgery and post trauma
46
Bile acid sequestrants/resins
* bind bile acid (cholesterol metabolites) preventing gut absorption
* up to 10-fold increase in bile excretion
* increased demand for cholesterol for bile acid synthesis causes upregulation of hepatic LDL receptors, removal of LDL from plasma and more cholesterol metabolism
**Adverse effects**
* bile acid sequestrations can result in bloating and constipation etc so need to drink enough water
* more serious can get increase TGs, steatthorea and feacal impaction and decreased absorption of fat soluble vitamins
* can also get decreased absorption of other drugs
47
Ezetimibe
* specifically inhibits cholesterol absorption in the
intestine by binding to a sterol transporter (NiemannPick C1-like 1 protein)
* does not affect absorption of bile acids, fat soluble
vitamins
* lowers LDL
**Possible adverse effects**
* diarrhea, headache, tiredness
* allergic reactions, severe joint or stomach pain
48
Nicotinic acid=niacin=Vitamin B3
* Mechanism remains unclear
* decrease secretion of VLDL particles from liver
* reduces plasma LDL and triglycerides (so also for
mixed hyperlipidaemia)
* increases HDL
* can potentially lower athergenic lipoprotein Lp(a) formed from LDL.
* Lp(a) is found in plaques and inhibites thromboylsis
* so vitamin B is good in that it lowers Lp(a)
**Adverse effects**
* common adverse effects
* vasosodilation, flushing, hypotension
* nausea, vomiting
* tolerance develops to gastric upsets
* rare adverse effects
* itching
* glucose intolerance
* uric acid retention
* may increase hepatic impairment
* not widely used except in combination
49
Fibrates
* agonists at nuclear receptors, so regulate gene expression
* peroxisome proliferator activated receptor alpha (PPARalpha)
* PPARalpha is a nuclear receptor responsible for regulating gene transcription and its activation results in increased synthesis of lipoprotein lipase (LPL)
* Lipoprotien lipase breaks down TGs into free fatty acids so increase sythesis is good as we get more fatty acid release and less cholesterol
* increase lipolysis of lipoprotein triglyceride
* moderate reduction in plasma triglycerides
* moderate increase in HDL
* variable effects on LDL
* generally used as adjunct to dietary changes for high TGs, mixed hyperipidaemia, and second line therapy for hypercholesterolaemia
**Adverse effects**
* mild elevation of serum aminotransferase
* monitor at 3 month intervals, reduce dose or discontinue if necessary
* common adverse effects
* nausea, dry mouth, headache, rash
* rare adverse effects
* arrhythmias
* gallstones
* photosensitivity
* impotence
* depression
50
Treat hypercholeteroleamia with fish oils
* Results in reduced VLDL and reduced TGs
* and increased HDL
51
Summary of drug regulation of serum lipids
52
To increase flow through coronary arteries we must?
* dilate coronary arteries
* decrease heart rate-arteries less compressed
53
Angina
* strangled breast
* imbalance between O2 supply and O2 needs
* insufficient O2 to meet cardiac demands
* reduced perfusion rather than inadequate blood O2
54
Variant angina (vasospastic, Prinzmetal’s)
* coronary vasospasm at rest
* mediator unknown
55
Stable Angina diagram
56
To treat stable angina we want to
* decrease O2 demand
* increase O2 supply
57
How can we increase O2 delivery
* Dilate the coronary arteries
* But difficult to dilate arteries becasue they are stiff and cannot dilate that well and arterioles are already maximally dilated
* So we could reduce heart rate?
* reduce compression of arteries
* heart spends longer in relaxatio phase
* coronary arteries have longer time to fill
58
How can we decrease O2 demand of the heart to treat angina?
* reduce cardiac output
* decrease HR-Beta adrenoceptor antagonists
* decrease SV-Beta adrenoceptor antagonists, Calcium channel blockers
* Decrease preload-Nitrates (GTN)
* dilate veins and get less venous return
* Decrease afterload-Calcium channel blockers
* dilate arteries and reduce TPR
59
**_Nitrates_**
## Footnote
* Mechanism of action*
* Site of action*
* An example*
* Some side effects*
* A dangerous drug interaction*
* and*
* Tolerance*
**Mechanism**
cGMP dephosphorylates the myosin light chain so that it cannot bind to actin and we get vascular relaxation
**Site of action**
* nitrates work on all vessels but major site is the veins
**Example**
* GTN
* a pro-drug
* subject to first pass liver metabolism so we give sublingual therapy so it can be absorbed directly into blood for acute attack
* for an emergency we may use IV
* for prophylaxis can use sub-cutaneous injection
* care must be taken in storage as drug can be absorbed by plastics
**Side effects**
* effects on other smooth muscle
* brief relaxation of gut, airways
* not clinically significant
* postural hypotension - venous pooling
* headache, flushing - cerebral, head, neck arterial dilatation
* reflex tachycardia – usually used in combination with β-blockers or cardiac-selective calcium channel blocker to minimise this
**A dangerous drug interaction**
* Viagra and GTN can be fatal
* Viagra is phosphodiesterase inhibitor so it inhibts the breakdown of cGMP
* So could get a massive increase in cGMP and so we get too much increase of vasodilatation
**Tolerance**
Decreased effect of nitrates with prolonged use
* “classic” mechanism involves depletion of tissue thiols required for NO production from GTN
* treatment with N-acetyl cysteine restores GTN effect
* Increased release of and/or sensitivity to constrictors e.g. AII
* increased endothelial free radical production scavenging NO, reducing NO bioavailability
* reduced/abnormal activity of muscle mitochondrial ALDH2, decreased NO production, increased free radicals
* ALDH2 involved in NO production
* Drug-free period required to minimise tolerance remove patch over night
60
Calcium Channel Blockers
Calcium channel blockers can be vascular or cardio selective. Vascular:Cardio selectivity
* verapamil 1:1 (not for heart failure)
* diltiazem 7:1
* nifedipine 14:1 (also for hypertension)
So cardio selective drugs act on SA node and AV node to block Ca infux and therefore prevent depolarisation as frequently and lower HR. They also reduce the contractility of the cardiac muscle
Vascular selective Ca2+ channel blockers prevent cotnraction of the vascular smooth muscle-reduce arterial contraction and therefore reduce **afterload**
**Adverse effects**
Cardio selective Ca channel blockers
* flushing, headache, oedema
* bradycardia, atrioventricular (AV) block never taken with Beta-blocker
Vascular selective Ca2+ channel blockers
* flushing, headache, oedema
* hypotnesion
* reflex tachcardia
* so can be taken in combination with a Beta Blocker
61
Using Beta Adrenoceptor Blockers to increase perfusion of coronary arteries and decrease O2 demand of the heart in stable angina
Beta 1 adrenoceptor antagonists act on SA and AV node to decrease HR which can increase diastole and increase coronary perfusion and therefore increase O2 supply to heart
Beta-1 Adrenoceptor antagonists also act cardiac muscle to decrease contractility and therefore stroke volume which will also decrease cardiac output and decrease O2 demand of heart
**Adverse effects**
* Contraindicated in asthma due to potential B2 adrenoceptor activity that will constrict brinchiols
62
Novel therapy: ivabradine
* “pure” heart rate reduction
* “specific” and selective inhibition of the inward sodium-potassium If current in the sinus node
* decreases the velocity of diastolic depolarization by reducing the ‘steepness’ of the If current slope
* reduces myocardial oxygen demand and maximizes oxygen supply
**Uses and Adverse effects**
* used in patients with IHD and LV dysfunction and in patients with HR \> 70 bpm
* No reduction if HR is \< 70bpm
* brigtness in virual field due to retinal effects (same target, different site)
* conduction abnormalities (same target and site)
* levels increased by some antibiotics and antifungals
* small increased risk of MI(?) doesn't seem great...?
*
63
64
Using drugs to treat stable angina
65
Genetic basis of bacterial resistance to antimicrobials
* Can be intrinsic
* i.e. gram negative bacterial resisitnace to vancomycin
* acquire
* mutation
* horizontal gene transfer
66
Transfer of genes between bacteria
* transformation
* phage mediated
* plasmid mediated conjugation
67
Transfer of genes between bacteria: Transformation
* DNA uptake by competent cells
* Bacteria immune system can protect bacteria against the foreign DNA and cut DNA using restriction
* enzymes EcoR1 etc
* So only related DNA will be incorparated so there is some homologous recombination
* So must be some complimentary DNA
**Example**
* 90 different types of pneumococci due to their capsular antigen
* pneumococci that we live in us as part of of our micriobiota have a lot of resistance genes and can transfer resistance DNA to other more dangerous pneumococci (i.e. transformation can occur because of relatedness)
68
Transfer of genes between bacteria: Bacteriophages
Temparate Phage
Virulent Phage
* most bacteriophages are dsDNA they have enzymes that break down peptidoglycna and then inject DNA through the cell wall and then it will be intergrated in particular spots ogf the geneome does not require homologus recombination as the virus uses enzymes to integrate the DNA
* After isertion the bacteria may replicate with the phage DNA and this is the **temperate phage** i.e. nothing hapens (called the lysogenic cycle) may not kill the bacteria but may encode toxins and diptheria toxin is actually encoded by a bacteriophage
* **Virulent phage** or lytic cycle
the virus kills the bacteria-lysis from within.
This happens when the phage senses that there is somehting wrong with the bacterium
*
69
Some examples of bacterial toxins produced by bacteriophages
* shiga toxin
* cholera toxin
70
Why shouldn't we treat diarrhoea caused by E. Coli O157
* when we eat them we get diahrroea and we might use bacteria at which point the phage decides that the bacteira is no longer safe to stay there anymore and so the phage replicates and produces heaps of toxin and so it is not reccomended to take antibiotics for E.coli O157 diarrhoea
71
Transfer of genes between bacteria: Bacteriophage Transduction
* We can get transfer of genetic material and possibly antibacterial resistance
* staph epidermidis can tansfer resistance to staph aureus
* this is a very unlikely event but with that many bacteria and many phages and many people infected then it can easily occur and resistant variants arise
72
Transfer of genes between bacteria: plasmid mediated conjugation
* Bacteria can link together if there is contact between the bacteria and the plasmid makes a copy of itself as it moves through the cytoplasmic bridge and now there is a copy in each bacterial cells
* conjugation can occur between unrelated species
* so this is often the most dangerous method of transfer as it can go across different bacterial species
* E.coli in gut can transfer plasmid with resistance to more pathogenc bacteria
* we can also get **multi resistant plasmids**
* so by treating with one antibiotic you may be selecting for resistance of another antibiotic as well
73
Minimum inhibitory concentration
* Minimum concnetration of antibiotic that inhibits bacterial growth
* can be determined by either
* diffusion methods
* E test strip-read MIC straight off the strip
* dilution methods
74
Best guest therapy for some infections and presentations
Some clinical conditions must be treated before results are known from labratory testing
75
Antibiotic combinations are often used to:
* As a temporary measure in an ill patient
* To delay the emergence of resistance
* To treat mixed infections
* To reduce toxicity (?)
* To achieve a synergistic effect
Why do we often use 4 antibiotics to treat mycobacterium tuberculosis that is symptomatic in a patient?
* To delay emergence of resistance when we treat TB we treat with 4 drugs
* we know that it may be resistant to 2 drugs
* we want to use two effective antibacterials at least because we want to make sure that even if resistance emerges to one of the drugs the 2nd drug can kill the bacteria becasue the chance of getting resistance arising in the same bacteria to two antibiotics is very unlikely
76
What can be the different results of antibiotic combinatorial therapy?
* Indifference-or an additive effect
* i.e. adding the extra antibiotic "B" would produce the same effect as adding more of antibiotic "A"
* Antagonistic effect
* i.e. adding antibiotic "B" to antibiotic "A" reduces the efficacy of antibiotic "A" and we end up with the lower efficacy of antibiotic "B"
* Synergy
* i.e. adding antibiotic "B" to antibiotic "A" greatly improves the efficacy of "A"
77
Provide *two* examples of two antimicrobial drugs that when prescribed together result in an *antagonistic* effect.
**Penicillin G and tetracycline therapy**
* together did worse than patients treated with penicillin alone
* Becaue penicillin only acts on growing bacteria-on peptidoglycan synthesis
* but tetracycline is bacteriostatic and so penicillin has no effect anymmore sdo you are only getitng the effect of tetracycline
**ampicillin and piperacillin**
* ampicillin is destroyed by beta-lactamases and actually induces more beta lactamase production by the bacteria.
* piperacillin alone is a low inducer of beta-lactamases
78
Provide *three* examples of two antimicrobial drugs that when prescribed together result in an *synergistic* effect.
1. aminolgycoside and Beta lactam
* aminoglycosides enter cell poorly but Beta lactam disrupt petidoglycna wall and allows for better entry of aminoglycoside
2. Sulmphonamides and Trimethoprim
* act on different stages of folic acid synthesis in bacteria
3. amoxycillin and clavulonic acid
* co-amoxycillin therapy, clavulonic acid is a weak beta lactam antibiotic but a strong anti beta lactamase and so it inhibits the breakdown of amoxycillin which is a strong beta-lactam
79
Jawetz's Laws
* Bacteriostatic + bacteriostatic = additive or indifferent
* Bacteriostatic + bactericidal = antagonistic
* Bactericidal + bactericidal = synergistic
## Footnote
*Note that there are exceptions*
80
visceral pleura
parietal pleura (different names)
pleural cavity (and pathology)
* **Visceral pleura** surrounds the organ then folds back on itself at the lung hilum and forms the **parietal pleura**
* different areas of the parietal pleura is named for the areas it is arround (see image)
* The **Parietal cavity** is a potential sopace beteeen the two layers and allows for a friction free glide of the lung as it expands
* pneumothrax-area is filled with air
* heamothorax-area is filled with blood
81
Pulmonary Ligament
* The visceral pleura is not tight around the lung root and it hangs down
* This is called the pulmonary ligament-provides some slack so the neurovascular structures can expand
82
Q1=If inflammation of the lung is contained to the visceral pleura will the pain be dull or sharp and well localised?
Q2=If inflammation of the lung spreads to the parietal pleura will the pain be dull or sharp and well localised?
A1=dull and not well localised
A2=sharp and well localised
If we get inflammation of the visceral pleural the pain is quite dull and poorly localised, as is the pain from pericardium as they share nerve supply from structures that they cover.
So they have a visceral nerve supply and pain refferred from the visceral nerve supply will not be localised and will be quite dull
But if the inflammation reaches the parietal pleura the pain will be severe and sharp as the parietal pleura lines the internal surface of the thoracic walls where they get there nerve supply from and these strucutres that have a somatic nerve supply and so pain is sharp, severe and well localised
83
Tracher and Bronchi
start point
end point
left bronchus vs right bronchus
* Trachea starts at C6 and devides into the left and right main Bronchus at T4/T5
* Right main bronchus is shorter and wider and more vertical than the left
84
Trachealis Muscle
* trachea is series of U shaped cartilage rings and is closed posteriorly by trachealis muscle that flattens trachea posteriorly
85
Oder the airway components in a descending order
Segental bronchi, Trachea, Lobar Bronchi, Main Bronchi
Trachea, Main Bronchi, Lobar Bronchi, Segmental Bronchi
86
Bronchopulmonary segments
* Each segmental bronci supplies a bronchopulmonary segment
* Bronchopulmonary segments are pyramid shaped and has its point towards the hilum of the lung and the base of the pyramid on the lung surface
* Each segment has its own segmental bronchus, own artery and own vein.
* Each segment is functionally distinct section so that if something goes wrong with one or two the rest of the lung can continue to function
Segments can be surgically resected
87
Right Lung
* Each lung has a concave inferior surface and apex protruding up and rounded costal surface baring imprints of the ribs and a mediastinal surface that bares the imprint of mediastinal structures
* The right lung is larger than the left
* The right lung has three lobes
* Two fissures devide right lung into three lobes
* long oblique fissure and shorter horizontal fissure
*
88
Left Lung
* Left lung only has one fissure that seperates the uppper lobe from the lower lobe
* On the left lung there is a point which is cut out on the from the heart which is called the cardiac notch
* bellow that is a lump which is called the lingular
89
Structures at the hilum:
**Right Lung**
* The right main bronchus has already devided into the right upper lobe bronchus and the bronchus intermedius.
* Can see arterial structures anterior to the bronchus strucutres
* The two pulmonary veins are the most anterior and inferior structures-i.e. one anterior and one inferior
* There also must be a blood supply and they are bronchiol arteries and bronchiol veins, lymphatics and nerves entering the hilum as well (cannpt be seen)
* Lymphatics drain to the hilar lymph nodes and can see them stained black due to carbon
90
Structures at the hilum:
## Footnote
**Left Lung**
* Left side only one main bronchus and one artery going in at the hilum and then an anterior an inferior pulmonary vein and carbon stained lymph nodes
* can see a large imprint from aorta and the left ventricle
91
Bronchiol veins enter into the \_\_?\_\_
Azygous system
92
Autonomic nerves in the thorax
* autonomic nerve supply to the lungs where we have the sympathetics coming from the ganglia from the sympathetic trunk and the parasympathetics come from the vagus nerve
* There is a pulmonary plexus associated with the devision of the trachea and then nerves enter the hilums of the lung
93
Pulmonary Lymphatics
* Surface of the lungs have a reticulated pattern of dark staning-superfical lymphatics just bellow the visceral pleura
* a spiderweb appearance coloured black due to carbon
* There is also a deeper system that follows airways and vessels that then head to the hilum and drain into hilar lymph nodes.
* From those hilar lymph nodes we have lymphatic channels that will head to thoracic duct on the left and right lymphatic duct on the right and that lymph will then be emptied into the venous system around the junction of the internal jugular veins and subclavian veins.
* Remember that the thoracic duct on the left drains 3/4 of the body and the right lymhatic duct only drains the right side of head and neck and right upper limb and right side of thorax
94
Radiography
* Electron beam from a piece of metal heated up then hits an anode and X rays are given off
* X rays convert silver-halide crystals to black
* more X rays passing through = black
* less X rays=white
* The image is not 3D though and everything is collapsed down flat
* X rays interacts with electrons so anything with high atomic number in high concentration, i.e. bone, has lots of calcium and X rays are stopped
95
Silhouette sign
* We must have something different around the tissue to seperate the different structures
96
Position of patient for X-ray
* X-ray is done in full inspiration
* X ray passes from posterior to anterior because we want the heart to be as close to the detector as possible so we don't get any magnification
* Get scapulae out of the way so hug the X ray cassette
* Erect so that we can determine blood flow distribution in the lungs
97
How can we tell if a heart is enlarged on X-ray?
* If all conditions are right then the maximal transverse diameter of the cardiac silhouette must be less than 50% of the maximmal transverse diameter of the thoracic cavity from the inside of the ribs
* if greater than 50% then patient has a big heart
98
Division of the lung in X ray
* Apex, upper, middle, lower and base
* becasue we cannot see the fissures in an X-ray unless they are inflamed
* or lateral view-the fissure can be more easily seen
99
Angle of Louis
* Angle of louis is an anatomical line that goes from menuebrio-sternal junction to the T4/T5 disc on the back
* We use the angle of louie to devide the mediastinum-superior and inferior
100
Air vs Fluid in the pleural spaces
101
Pleural effusion
hydrothorax vs hydropneumothorax
* There will be a meniscus in the hydrothorax but no meniscus in the hydropneumothorax
* this is due to the negative pressur ein the pleural cavitity
102
CT scan
* very similair to X ray in the method which X rays are produced
* However film is not used to detect
* instead use a radiation detector
* and the beam of X-rays rotate around the person in the CT machine
* Get 3D image of the person as it rotates around the patient
* Can look at any part of the image with post processing
* CT has poorer spatial resolution than plain X-ray
* CT has far better contrast resolution than plain X-ray
* Can add IV dye to better diferentiate-i.e. iodine-highelectron density
* can easily identitify fissures in the lung using CT scan
103
Housfield units
* absolute measure of x-ray attenuation
* digital “grey scale” rather than film density
* maintains the convention of film
* air = black, bone = white
104
What is the orientation of CT images
* axial – from the feet up
* coronal – from the front
* sagittal – from the left
105
Post processing and contrast
* can post process and look exclusively at a smaller section of spectrumm and use contrasting to better differrentiate between differences in electron densities and thus different strucutures
106
Red Green colour blindness
Blue yellow colour blindness
Red green
* X-linked recessive disorder
* Men=8%
* Women=0.4%
Blue yellow
* autosomal dominant
107
Thalidomide
* R isomer works as intended to assist in morning sickness
* S isomer caused horrible congenital defects
108
Phenylketonuria
* autosomal recessive
* 1 in 14,000
* 1 in 60 are carriers
* Cause mental retardation, seizures, tremors and
behavioral disorders
* Caused by a lack of phenylalanine hydroxylase
* Nn normal people excess Phe is converted to Tyr by penylalanine hydroxylase
* but if we don't have this enzyme Phe is converted by a different pathway to phenylpyruvate which builds up
* this can damage the brain and also inhibit the tyrosinase enzyme (responsible for syntheisiing melanin)
* Now we can easily screen for the disease using the **Guthrie test**
* And treat the disease by limiting phenylalanine in the diet
109
Cystic Fibrosis
* most common life threatening genetic disorder in australia
* autosomal recessive disorder
* 1 in 25 people are carriers
* 1 in 2,500 live births
* CF primarily affects the respiratory system (lungs), digestive system (pancreas and sometimes liver) and reproductive system.
* People with CF will have a persistent cough and recurrent lung infections due to mucous build up
* Guthrie heal prick test also used for diagnosis which detects elevated immunoreactive trypsin (IRT)
* also salty sweat
* Product of the mutated gene is a cystic fibrosis transmembrane conductance regulator (CFTR)
* This mutation effects the permeability of conducatance of a membrane-allows chloride to go through a cloride channel
* diminised chloride perfusion into the airway results in build up of mucous
* 3 base deletion deletes Phe508 in the large protein
*
110
Collagen structure
* Gly-Pro-Ala repeating subunits
* about half of the prolines are hydroxylated
* this allows for the OH group to form cross links with other collagen chains
* alpha chain structure with glycines positioned in the middle
111
Osteogenesis imperfecta
* The glycine at position 748 becomes cysteine
* now the collagen is kinky and this can make bones incredibly weak.
* Some people have bad teeth and some people cannot walk
* can be autosomal dominant or autosomal receissive
112
Ehlers Danlos syndrome
* Can be caused by mutation in one of a family of collagen genes
* most forms are autosomal dominant can be varrying degrees of disease
* Mutations in these genes alter the structure, production, or processing of collagen or proteins that interact with collagen or proteins that interact with
collagen.
* Get extra bendy limbs etc
113
Albinism
* Mutation in tyrosinase which is responsibelt for the synthesis of melanin
* Tyrosinase initially maked DOPA from tyrosine and there are variations of DOPA which are then made into polymers which are melanin
* Melanocytes-make melanin and give to skin cells-unfortuantely they can become melanomas and move off and lodge in the brain (often)
114
Sickle cell anaemia
* autosomal recessive pattern of inheritence
* Sickle cell anaemia single base change that results in hydrophilic Glutamic acid to Valine change in the Beta globin gene
* hydrophobic Valine binds to a hydrophobic pocket that is present in deoxy-haemoglobin and forms an insoluble structure-leads to sickle cells that can lodge in caplillaries
**Symptoms**
* Anaemia and weakness
* Failure to thrive
* Splenomegaly
* Repeated infections
* Crises:
* ischaemia, thrombosis, infarctions, (especially in spleen, brain, lungs, and kidneys)
**Under the microscope**
* Severe normocytic
* or macrocytic
* haemolytic anaemia
* can see the sickle cells
* sufferers may have normal MCV and MCH
* Hb significantly decreased
* Can see HbS on HPLC
115
Marfan Syndrome
* Skeletal system involvement is characterized by bone overgrowth and joint laxity. The extremities are
disproportionately long for the size of the trunk (dolichostenomelia).
* The fibrillin 1 gene FBN1 is mutated in Marfan
syndrome.
* FBN1 produces a protein which is
transported out of the cell and deposited in the
extracellular matrix.
* Fibrillin becomes part of extracellular matrix. Fibrillin becomes part of microfibrils, which in turn help build elastic fibres essential for the function of flexible structures such as blood vessels, the lungs, and skin.
116
Porhphyria
* defficiency in the synthesis of heme
* but symptoms are a result of accumulation of the intermediates
* 7 enzymes involved
* Can have mutations at each of the sites
* today treated with heme replacement therapy
117
alpha globin genes
* alpha-like globin genes clusterred on chromosome 16
* Zeta and pseudo Zeta and Psuedo alpha
* we have two copies of the alpha genes
118
Beta globin genes
* Beta-like genes on chromosome 11
* epsilon version
* two different gammas (only differ by one base)
* a pseudo Beta gene
* a delta gene
* and a single Beta gene
119
Developmental regulation of globin genes
What Hb do we have at:
Embryonic stage
Fetal
and postnatal
Embryonic Hb= ζ2ε2 and ζ2γ2 and α2ε2
Fetal= α2γ2 and α2β2
Postnatal= α2γ2 and α2β2 and α2γ2
120
Hereditary persistence of fetal haemoglobin (HPFH)
clinically benign
121
Alpha Thalassaemia
* Global distribution; high in South East Asia
* due to deficiency of alpha-globin chains
* Majority caused by large deletions
* we have 4 copies of the alpha gene and it depends on the number of mutations that determine phenotype
122
Beta thalassaemia
## Footnote
* Global distribution
* Increased frequency in Southern European and Middle Eastern countries as well as North Africa, South East Asia, Indian subcontinent due to deficiency of Beta-globin chains
* Majority caused by point mutations
* promoter mutations
* RNA splicing mutations
* mRNA capping or polyA tailing mutations
* nonsense
* frameshift
* alpha4 aggregates are insoluble and don't bind oxygen and can cause damage to blood cell membranes and then the RBCs are further destroyed-heamolytic aneamia
*
123
Systemic consequences of Beta Thalasseamia
* alpha4 aggregates are insoluble and don't bind oxygen and can cause damage to blood cell membranes and then the RBCs are further destroyed-heamolytic aneamia
* Most of the cells expressing Alpha4 would die as erythroblasts in the bone marrow
* Bone marrow can expand in volume in its attempts to make more Hb for the increasing O2 demand
* There is also a compensatory increase in iron aborption and this can lead to systemic iron overload.
* tissue anoxia can lead to skeletal deformities
* can also get enlarged liver and large spleen
* abnormal cells that are able to leave the bone marrow and destroyed in the spleen and so the spleen gets larger as well
124
Untreated Beta thalassaemia
## Footnote
* Hepatosplenomegaly
* Frontal bossing (forehead is pronounced
* thinning of long bones
* hair on end appearance of skull due to thinning of cranial bone
125
Blood films in Beta Thalassaemia
* In beta thalassaemia we can see microcytic (small cells) and hypochromic (pale cells) anaemia
* anisocytotic-irregular in size
* tear drop shaped cells-due to accumulation of the alpha monomeric globins
126
Treatment of Beta Thalassaemia
* Points of intervention
* people with an enlarged spleen may have it removed-now more susceptible to infection
* For the thalassaemia we can give regular blood transfusions-this can lead to more iron introduction though
* can be managed with chelation therapy-bind and excrete the iron
* combined cost of blood transfusions and iron chelation therapy is in excess of 120,000 per annum
* only real cure is a bone marrow transplant
127
Blood parameters of Sickle cell anaemia and Beta thalassaemia in homozygotes and heterozygotes
**Normal**
* **Hb(g/L)** Males=135-175. Females=120-160
* **MCV(fL)**=80-97
* **MCH(pg)=**27-34
* **HbA(%)**=97.5
* **HbA2(%)**=1.8-3.5
* **HbF(%)**\<1
**Beta thalassaemia (Heterozygotes)**
* Hb-moderately reduced (102)
* MCV-ussually decreased (80)
* MCH- less than 27
* HbA-decreased but \>90%
* HbA2-Elevated 3.5
* HbF=Elevated 1-2%
**Beta thalassaemia (Homozygotes)**
* Hb-30-50
* MCV-less than 80
* MCH- less than 27
* HbA-0
* HbA2-normal or elavated
* HbF=greatly elevated, 90%
**Sickle cell anaemia (Heterozygotes)**
* Hb-slightly or moderately reduced
* MCV-normal or slightly reduced
* MCH-normal or slightly reduced
* HbA-
* HbA2-
* HbF=
**Sickle cell anaemia (Homozygotes)**
* Hb-significantly decreased 60-80
* MCV-may be normal or slightly decreased
* MCH-may be normal or slightly decreased
* HbA-
* HbA2-
* HbF=
Cardiovascular Block
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