Cardiovascular Block Flashcards
What is the function of the pericardium in heart contraction?
It provides a frictionless layer for heart movement between the lungs.
Does the pericardium normally affect cardiovascular function?
Normally has no affect on ventricular compliance. Only affects it when its abnormal - full of fluid, inflammation of distensible tissue and cancer
For any given volume in the heart what contributes to pressure?
The compliance of the heart wall (diastole) and active tension in the wall (systole)
Which os these LV pressures and volumes are within the normal range at rest?
- ESV = 75mL
- Stroke volume = 500mL
- End diastolic pressure = 50mmHg
- Early diastolic pressure = 5mmHg
Which os these LV pressures and volumes are within the normal range at rest?
- ESV = 75mL
- Early diastolic pressure = 5mmHg
What does the systolic and left ventricle volume curve look like and its implication?
Looks like the frank-starling curve which says that the greater the volume the greater the force generated.
What can increase stroke volume?
Increase in EDV and increase in ventricular contractility (this is a shift in the frank-starling curve).
What is the implication of the Frank-sterling relationship?
The more stretch the more tension results. The larger the EDV the larger the SV.
What happens to the Frank-Sterling curve when contractility increases?
Contractility increases as result of:
- Acidosis
- Sympathetic nerve activation
- Parasympathetic nerve deactivation
- Caffeine
- Adrenaline
- Hypercapnia
Contractility increases as result of:
- Acidosis (no decreases)
- Sympathetic nerve activation (Yes)
- Parasympathetic nerve deactivation (No are not involved in contractility in a major degree, more for HR)
- Caffeine (increases contractility)
- Adrenaline (yes)
- Hypercapnia (this is increased carbon dioxide partial pressures - no it is usually a waste product and associated with acidosis.
Which of the following is/are correct?
- During diastole the mitral valve is closed
- During isovolumetric contraction the aortic valve is closed
- During systole the tricuspid valve is open
Which of the following is/are correct?
- During diastole the mitral valve is closed (mitral valve is between L atrium and L ventricle - therefore it has to be open)
- During isovolumetric contraction the aortic valve is closed (Yes)
- During systole the tricuspid valve is open (No, it is the right atria and right ventricles so its closed)
What are the valves in the heart and where are they located?
Mitral (bicuspid atrial/ventricle left), aortic, tricuspid (atrial/ventricle right), pulmonary valve
Described the pressure changes that occurs during systole.
Describe the pressure changes in diastole.
Describe the pressure changes in the isovolumetric contraction.
Explain what happens along the curves, include ejections and valves?
Explain the different segments of this curve and include where valves open and close.
ESV, EDV and where is the stroke volume found?
What does an increase in contractility result in?
Results in low ESV and increase in SV. The increased force generation keeps the valves open longer.
What does reduced left ventricular compliance result in?
Results in a decrease in EDV and decrease in SV. The increased pressure in the ventricle will lead to reaching aortic pressure sooner yet it still closes at the same time.
What is the significance of high ventricular pressure on the atrium?
It will also need higher pressure to push the blood into the ventricles and may lead to backflow of pressure into the veins
What does an increase in aortic pressure result in?
A decrease in SV and increase in ESV. Since it requires a larger pressure to push through. This also means that the valves will close sooner.
What is meant by afterload in the CV system?
This is the load encountered by the ventricles when it starts to contract.
What may contribute to afterload?
A pressure load may be imposed by arterial hypertension and left ventricular outflow tract obstruction (aortic valve stenosis)
What is meant by the preload in the CV system and what may contribute to it?
This is the amount of blood the heart has to pump (indication of filling). A volume load is imposed by an increase in venous return.
What is the distribution of blood around the CV system estimated to be? (Arterial, Venous, Heart, Systemic capillaries and Lungs)
Systemic veins - 65%
Systemic arteries - 13%
Systemic capillaries - 5%
Lungs - 10%
Heart - 7%
Why is the total blood volume found in the systemic capillaries so small and its function?
Very small blood vessels so the amount of blood found here is small. The large CSA means that the velocity in these areas are much slower - allows for nutrient exchanges.
Which of the following would increase the proportion of blood in systemic arteries?
- Decreased cardiac output
- A reduction in total peripheral resistance
- Vasoconstriction
Which of the following would increase the proportion of blood in systemic arteries?
- Decreased cardiac output
- A reduction in total peripheral resistance (This will allow more blood enter the veins)
- Vasoconstriction (pressure increases in veins which means greater flow into atrial pressure, more filling of ventricles which means greater stroke volume -> end up with more blood in the systemic artery.)
Which of the following would increase the proportion of blood in systemic veins?
- Decreased cardiac output
- A reduction in total peripheral resistance
- Venoconstriction leads to squeezing of blood into the arteries.
Which of the following would increase the proportion of blood in systemic veins?
- Decreased cardiac output (Yes, less goes to arteries)
- A reduction in total peripheral resistance (Yes more blood enters the vein)
- Venoconstriction leads to squeezing of blood into the arteries.
Are arteries or veins more compliance? How does this affect their sensitivity to changes in volume?
Veins are much more compliant than arteries. This makes arterial pressure much more sensitive to volume changes.
What is autotransfusion of the CV system?
This involves the vasoconstriction of the veins which will transfer the blood to the arterial system to allow for more blood to be used for blood flow.
What is the Mean Capillary Filling Pressure?
If the heart stops moving the blood will equalise on both sides. The eventual pressure depends on blood volume and vessel compliance.
- 7 mmHg
An increase in cardiac output will:
- Increase venous pressure
- Decrease venous pressure
- Venous pressures stays the same
An increase in cardiac output will:
- Increase venous pressure
- Decrease venous pressure (correct)
- Venous pressures stays the same
What is the vascular function curve? And how do we interpret it? What are the implications?
Shows what happens to venous return when cardiac output varies.
What happens to the vascular function curve when there is increased blood volume or vasoconstriction?
More blood means that there will be a larger mean circulatory filling pressure. This also means that there will be larger pressures at all points.
What happens to the vascular function curve when there is a decrease in TPR?
This means more blood will be in the veins. TPR does not cause the blood pressure to go up itself. As your CO increases there will be a larger volume pumped into the veins (increasing it more than usual).
What is the central venous pressure usually around? Why is it important?
1-5mmHg in the great veins right outside the heart. It is slightly higher than the right atria to allow flow. This can be assessed by JVP (Jugular Venous Pressure)
What is the cardiac function curve?
This curve shows the effect of venous pressure on cardiac output.
What does a decrease in venous pressure do to our cardiac output?
A decrease in venous pressure:
- Increase cardiac output
- decrease cardiac output (correct)
What happens to our cardiac output and venous pressure when there is an increase in blood volume and venoconstriction?
This can be done by combining both cardiac and vascular function curves. But this would increase venous pressure and thus increase cardiac output.
What does an increase in contractility do to our cardiac output and venous pressure?
This will increase the cardiac output and decrease venous pressure.
How does a decrease in TPR affect cardiac output and venous pressure?
It will increase cardiac output and increase venous pressure.
What is central venous pressure?
This is the pressure needed to fill the heart. Failing heart causes it to rise. It falls when venous return is pool
What is the endothelium’s role in the cardiovascular function?
Can alter smooth muscle contraction by releasing substances.
NO (dilator), endothelin (irreversible constrictor) and prostaglandins (does both)
Also mediates circulating angiotensin, thrombin and bradykinin (vasodilator)
What can cause the release of nitric oxide and what does that result in?
Results in vasodilation and occurs due to hypoxia, physical stimuli, circulating factors or paracrine factors.
What vasodilators do white blood cells secrete?
NO, histamine and cytokine
What vasoactive factors are released by platelets and what do placelets do in the CV system?
Thrombin, ADP (vasoconstriction) and Thromboxane A2. These enhance coagulation and platelet aggregation.
What are the different types of antagonism?
Competitive antagonism and non-competitive (functional, pathway inhibitors or modulators)
What is antagonism and what determines its potency?
It is simply binding to the receptor without eliciting a response. It is mostly dependent on affinity.
How does propranolol act as an antagonist at B-receptors?
It competitively binds to B-adrenoceptors
What does verapamil do to act as an antagonist in the B-agonist pathway?
It inhibits the actions of L-type calcium channel and it is slightly cardio selective (pathway inhibition).
How does acetylcholine act as an antagonist to the B-adrenoceptor pathway?
It inhibits any positive inotropic stimulus by acting as a functional antagonist.
What is allosteric modulation?
This is drug binding to an alternative binding site other than the orthostatic binding site. This will then modulate the receptor’s response to stimulus.
What do allosteric modulators modulate on the receptors?
- Modulate orthosteric ligand affinity.
- Modulation of orthsteric ligand efficacy.
- Modulation of receptor activation
What are the implications of highly conserved receptors?
It makes it very hard to make selective drugs. But allosteric sites are very variable that allow for selectivity.
What are the advantages of using allosteric receptors?
There is selectivity between sub-type receptors. It is safe in overdoses because it simply modulates receptors - meaning normal physiological control is in place.
What is surmountable antagonism?
This is when the response maximum is unchanged but only the dosage needed.
Competitive reversible antagonism: generally surmountable in vivo but sometimes not.
Non-competitive antagonism is generally insurmountable (at high levels)
What is ADME in pharmacokinetics?
Absorption, distribution, metabolism and excretion.
What will influence the choice of drug adminstration?
Patient convenience, cost, bioavailability and local/systemtic?
What is the advatange of local administration drugs and how do we achieve this?
It has less side effects. Use a poorly absorbed drug or a low enough concentration to just elicit a local response.
What are the different methods for systemic admistration?
Oral, skin, lungs, rectal, nose, injections (subcutneous, intramuscular and intravenous).
Only intravenous is directly entering tthe blood.
What is the rapid one body IV administration model? At what rate are these drugs eliminated.
This model assumes that the drug distributes very quickly to reach distribution equilibrium. Then most drugs are eliminated at a rate proportional to their concentration.
What factors affect how the drug is distributed?
Molecular size, binding to plasma proteins and lipid solubility. Also the blood flow to carry it around.
How can drugs access the blood brain barrier?
Only lipid soluble drugs can access the BBB. Any polar compounds cannot cross it (such as proteins).
What are drug reservoirs in the body and their functions/effects?
These are sites around the body where drugs accumulate.
They can prolong drug action, end it earlier or lead to slow distribution.
Usually the reservoirs are fat (poor blood supply), plasma proteins and cells.
What is the volume of distribution?
This tells us how concentrated a drug is in the plasma?
Vd = X/C
Explain renal excretion of drugs.
There is glomerular filtration, tubular secretion and tubular reabsorption.
How do drugs cross a cell membrane?
This is depending on the lipid solubility and the different pH levels. Such as acidic drugs in acidic pH will be able to cross cell membranes.
How can we take advantage of the different pH levels for drugs to manipulate aspirin overdose at the tubular reabsoprtion?
We can give NaHCO3 which makes the urine basic. This increases ionised aspirin making it unable to reabsorb -> increased excretion.
What is the renal clearance composed of?
This is the amount of drug cleared by the kidney.
CLrenal = GFR + TS - TR
As well as being excreted drug can be metabolised, list the different results of drug metabolism.
Biotransformation of drugs usually in the liver. Aims to increase water solubility to facilitate drug excretion.
Inactivation, active metabolic, new activity, be toxic, undergo phase I metabolism (creates functional group on the drug - cytochrome P450), conjugates a water soluble molecule to a functional group.
What is the formula used to determine the clearance ratio * blood?
What are the cells found in blood and their function?
Red cells - oxygen delivery, White cells - fight infections, platelets - stop bleeding, plasma - clots or bleeds
What is the terminology of having too little cells in the blood (for all cells)?
Pancytopenia - lack of all cells
Anaemia - Lack of blood cells
Leukopenia - Lack of WBCs
Neutropenia - Lack of neutrophils
Lymphopenia - lack of lymphocytes
Thrombocytopenia - lack of Thrombin
What is the terminology for too many RBC, WBC and platelets?
Polycthaemia - RBC
Leukocytosis - Leukocytes
Thrombocytosis - Platelets
How should we be measuring anaemia?
Measure Hb instead of RBC count - defined as lower levels for the particular age and gender
What is the formula for tissue oxygen delivery?
Delivery = CO x Hb x %saturation x 1.34
1.34 = mL of oxygen carried by one gram of normal cell.
Why is the tissue oxygen delivery equation so important?
Allows us to determine when to use blood, inotropes or oxygen
What is the impact of anaemia?
It reduces oxygen to tissues. It can be compensated by CV changes. Therefore Hb numbers is not the only factor.
What are a few clinical symptoms of anaemia?
Pale, tachycardia, ischaemia, hypoxic (confused and disorientated), failure to thrive, lethargic
What clues do HR give in anaemic patients about short vs long term?
Short term generally shows a quicker jump. Whereas it is not as significant in the long term causes because of adaptation of increased SV (usually it can only be changed over a long time).
What are the possible causes of Anaemia?
Either unable to produce RBC, active loss/destruction of RBC or inappropriate production.
What do the following parameters in a FBE stand for and mean?
Hb, RCC, Hct, MCV, MCH, MCHC, Plts, WCC (differential) and Blood film
Hb - reported in grams/L
RCC (red cell count) - how much RBCs per litre (5 x 10^12 per L)
Hct (Hermatocrit) - Proportion of RBC volume compared to plasma volume
MCV (mean corpuscular volume) - Allows for differential diagnosis to categorise the type of anaemia.
MCH (mean corpuscular haemogloblin) - Amount of Hb in the cell
MCHC - Concentration
RDW - is the standard deviation around the mean of MCH and MCV
Plts - Count of platelets
WCC (white cell counts) - Differential for lymphocytes, eosinophils and basophils
Blood film - microscope of blood. Looks at morphology of cells
What are the different terms to describe the morphology of a RBC under blood film?
Size (normocytic, microcytic, macrocytic)
Shape (many variations - each with different meaning)
Colour (normchromic, hypochromic, polychromasia)
What are the two classifications of Anaemia and what does it imply?
Regeneration and Aregenerative.
Regenerative: This implies that it was an acute event that caused a rapid decrease in Hb.
Aregenerative: Means there is a gradual loss of cells which allows the body to adapt slowly
What is the difference between increased production vs increased destruction/loss? And the signs which can be taken?
Increased production: see reticulocytes and polychromasia (formation of Hb)
Increased destruction: Jaundice (serum bilirubin), Haptoglobins, LDH
Why is it important to detect increased destruction/loss for Anaemia?
This means there could be rapid reduction in Hb > rapid reduction in oxygen delviery. So we may have limited time to compensate - Haemolysis is extremely dangerous.
How much cells are found in the blood?
RBC - 3-5 x 10^12 cells/L 120 days
WBC - 2-6 x 10^9 cells/L replaces 3-5 days
Platelets - 150-400 x 10^9 / L replaced every 10 days
Where does haemopoiesis occur?
First few weeks: Yolk sac
6weeks - 7months: Liver and spleen (could be recruited later again)
7months - life: bone marrow
What is the characteristic of the pluripotent stem cell found in haemopoiesis?
Self renewal, ability to differentiate, few found in bone marrow, cannot identify
What is the function of Bone Marrow Stroma in haemopoiesis?
It provides a specific microenvironment for bone marrow to grow. Changes in CAM will change the progression of the cells through the stroma and when it is ready to enter the circulation.
Bone marrow is in continuity with the circulation.
What is the bone marrow stroma made up of?
Cells and ECM.
Just know that it is involved in cell processing
What are the growth factors that affect haemopoiesis and what are their characteristics?
The growth factors are usually glycoprotein hormones with local and circulating actions. There is a lot of redundancy of the growth factors.
- Effects varies on where it is found: Premature cells GM-CSF proliferates but in neutrophil stage it will be activation instead.
- Can use factors for therapeutic treatment in specific cases
What are the haematinics and their function?
Iron, Vitamin B12, Folate
Iron: essential for haemoglobin function and maintain RBC population (usually troubling in large blood loss)
Vitamin B12: Needed for blood cell production. Deficiency usually from poor diet (in animal products) or poor absorption.
Folate: Important in RBC production. Deficiency usually from diet or drugs that affect uptake
What is haemostasis and what interactions does it involve?
Haemostasis is the stopping of blood flow in the case of injury. Involves platelets, coagulation factors and inhibitors, fibrinolytic processes and blood vessels/endothelium
This means that the haemostasis you see will be different in different parts of your body.
What is the primary haemostasis?
This is the initial platelet plug to stop the bleeding.
Vasocontraction, platelet adhesion and aggregation.
What is secondary haemostasis?
This involves formation of fibrin and activation of coagulation factors. This is then shaved off until it is smooth (fibrinolysis process - not part of secondary haemostasis).
What are the three aspects of the Virchow’s Triad - abnormal clotting?
Vessel wall, blood flow and blood composition
What is the vessel wall component in the Virchows Triangle?
This is the endothelial cell surface which is ery dynamic - which can be antithrombotic or prothrombotic depending on what is expressed on the wall.
- Unable to test for its integrity so usually diagnosed by exclusion.
What are the basic principles in the coagulation system?
Intrinsic and extrinsic pathways lead to common pathway. Usually it is Extrinsic signals.
VII > activated X > activates II > catalyses fibrinogen to form fibrin.
Intrinsic signals: XII > XI > IX (not as important)
THROMBIN is key in this process
What are the three steps to the coagulation process?
- Initiation: Vessel exposed which has TF (tissue factor) that activates XII. These then activate IX and X. X binds to Va on the cell surface.
- Amplification: X/V activates thrombin (II).
- Propagation: This is when the thrombin burst occurs to form fibrin from fibrinogen
How do we inactivate thrombin?
Binding to thrombomodulin will inactivate thrombin by irreversible inhibition.
What are haemostatic testing used for?
It is a test of artificial construct to predict clinical behaviour. Must be validated against clinical outcomes. Used to test the integrity of the blood.
What are the three types of haemostatic tests we can conduct?
Bleeding (no effective test), platelets (number, function and appearance) and the coagulation system.
What are the various tests for the coagulation system? (Global and specific assays)
What are some key priniciples to remember for coagulative tests?
Sample integrity, standard curve, control samples, duplicate testing and multiple consistent tests.
What is APTT in the global tests for bleeding?
Involves taking blood and adding calcium. Then activate XII (intrinsic pathway) and time how long it takes for fibrinogen to activate. Just gives information about pathway integrity.
- Can also test for presence of warfarin or lupus anti-coagulant
What is the PT test in the global testing of bleeding?
It is similar to APTT but instead it tests for the VII pathway (extrinsic).
Values given in INR = (PT/PTavg)^(ISI)
Simply a standardised value.
What do the specific assays for bleeding test for?
Usually tests for functioning enzymes/proteins.
Functional, chromogenic (colour change when binds to particular cell) or immunological.
Different use of reagents have impacts on the testing and assays, how?
They affect the data retrieved and are to be adjusted to the appropriate age groups.
Purpose of chromogenic assay?
Simply to confirm whether my protein is functional or not
What is haemoglobin?
This is an allosteric tetrameric protein that is used to carry oxygen.
The haem moieties in Hb and Mb binds to oxygen.
What is the structure of Fe (II) in the haem structure?
Fe (II) has 6 co-ordinating bonds. 4 in the same ring, 1 up and 1 down. Oxygen is found in one of these and the other one binds to proximal histidine.
What is myoglobin and its function?
This is the globular protein found in muscle tissues to deliver oxygen.
What are the cooperative characteristics needed for haemoglobin?
Needs to have high affinity to bind many oxygen. Be able to transfer oxygen to myoglobin when it reaches the tissues (sigmoidal curve).
What is the structure of myoglobin?
It is a monomer with a compact globular structure with haem. There is transient breathing of alpha helices to allow oxygen to bind. It has high oxygen affinity to take oxygen from Hb.
What is the structure of Hb?
It has two alpha and beta chains that forms a tetramer. Haem group present and there is cooperativity in binding and release of O2 (changes with O2 concentrations).
Explain the cooperativity binding of Hb
When oxygen binds it pull the Fe into plane > conformational change affects adjacent subunits.
- Explains the sigmoidal O2 binding
What do the oxygen saturation curves for Hb and Mb look like?
How does 2,3-BPG act as a heterotropic allosteric efforter on Hb?
It is a ligand that does not bind to the normal ligand site that modulates function. It stabilises deoxy-Hb so locks out oxygen from rebinding.
- Synthesised via glycolytic pathway in RBC.
- Decreases Hb affinity for O2 > shifts curve right (at high altitudes this is good so that more oxygen is given up in the tissue)
Relationship betwen Hb and carbon dioxide?
CO2 produced in tissue is carried by Hb (15%). deO2 Hb binds CO2 with more affinity than O2Hb.
Dumps CO2 in the lungs which gets converted to acid leading into the Bohr Effect
What is the Bohr effect on haemoglobin?
Bohr effect is lower shift in pH levels (acidic). This stabilises the ‘T’ state. Shifts the affinity curve to the right (decrease affinity) but also means it can deliver more oxygen at the tissue level.
What is the difference found in Foetal Hb?
It it made up of two alpha and two gamma chains and has a greater affinity than the mother’s HbA - allows foetus to access the oxygen.
What are the T and R states in the haemoglobin and what do they usually confer?
T - Tense: usually has low affinity for oxygen
R - Relaxed: usually has high affinity for oxygen
What are the major sites for pharmacological action along a nerve?
Synthesis, storage, release, receptor, reuptake/metabolism and degradation.
What is the autonomic nervous system distribution look like?
Exception is that Ach goes to sweat glands and adrenal glands
How is acetylcholine synthesised?
Choline transported by choline carrier into the cell. Choline + Acetyl CoA with choline-acetyltransferase produces ACh. ACh is then carried into the vesicle via ACh carrier.
How is Noradrenaline synthesised?
Tyrosine is taken up into the cell. Tyrosine hydroxylase then acts on it to produce L-DOPA. L-DOPA is then acted on by DOPA decarboxylase to produce Dopamine. Dopamine is take up into the vesicles by carriers to be acted on by Dopamine B-hydroxylase to produce NA.
How is Adrenaline formed?
It follows the same pathway as NA but has one extra step in the vesicle.
PNMT (phenylethanolamine-N-methyl-transferase) acts on NA to produce Adr.
What is co-transmission and what does it include?
This is the release of more than one transmitter substance. Usually ATP or NPY
How is ACh deactivated or inactivated?
It has acetylcholine-esterases found in the synapses of the vesicles which breakdown ACh.
How is NA inactivated?
The NA is taken up from the synapse through neuronal high affinity uptake-1 channels.
Where is ACh and NA found in the peripheral nervous system?
ACh - somatic, parasympathetic, pre-ganglionic transmission and exception at sweat and adrenal glands.
NA - found on the sympathetic system
What receptors do ACh act on?
Nicotinic Receptors (NicR - ligand gated ion-channel)
Muscarinic Receptors (M1,M2,M3 - GPCR)
What receptors do NA act on?
alpha and beta adrenoceptors (GPCRs)
What receptors does atropine antagonise?
Muscarinic receptors
What does d-Tubocurarine do?
It is a nicotinic antagonist.
What is the selective agonist of a and B adrenoceptors?
Phenylephrine - alpha agonist
Isoprenaline - Beta agonist
What is the structure of a nicotinic receptor?
It is a pentamer - ligand gated ion channel
What does alpha-Bungartoxin do and show?
It binds to NicR with high affinity and antagonises it. Shows selectivity of receptors.
How does Botulinum Toxin affect the ACh transmission pathway?
It prevents the formation of SNARE proteins which is needed for vesicle docking onto the membrane. This prevents the exocytosis process.
- Enzyme does the cleaving of SNAP-25, synaptobrevin so only needs small doses.
- Used cosmetically and for Blepharospasm.
What do anticholinesterase do to our ACh pathway?
This inhibits acetylcholine-esterase enzyme which prevents ACh breakdown in the synapse.
What is Edrophonium used for clinically? And for what disease?
It is used to Myasthenia Gravis (autoimmune disease against own NicR). It is an antcholinesterase which will increase ACh in synapse to diagnose for Myasthenia.
- Can be treated with neostigmine
What are some clinic use of nicotinic agonists?
Can be used to help with smoking cessation - nicotine patches
What are some clinical uses of nicotinic antagonists?
These can be used as pre-surgery muscle relaxants.
- Non-depolarising: tubucurarine
Or ganglion blockers: hexamethonium
What are the effects of activating ACh (muscarinic) receptors?
Generally rule is SLUD
Salivation, lacrimation, urination and defecation
Furthermore: sweating, bradycardia, bronchoconstriction
Pilocarpine: used in glaucoma to increase drainage
How does cocaine affect the NA transmission pathway?
It inhibits the neuronal high-affinity uptake 1 channel. NA can no longer be taken up from the synapse.
How do MAO inhibitors work to increase NA levels?
It inhibits monoamine oxidase found in the neurons that metabolise NA. Which will increase the amount of NA in the synapse. COMPT is found on the post-glanglionic cell to metabolise NA.
How do indirectly acting sympathomimetics work?
These are administered which is taken up through the same reuptake channel as NA. They are also taken up through the vesicle channels so that it now displaces NA. This case is now a passive leakage of NA into the synapse.
What are examples of indirectly acting sympathomimetic?
Amphetamine, Ephedrine and Tyramine.
Tyramine can cause unwanted CV effects. Since it is normally broken down by MAO in the gut usually. When used with MAOi it can lead to high BP
What are the following agonists selective to?
Isoprenaline, dobutamine and salbutamol
In the same order: non-selective B, B1 and B2
What are the following antagonists selective to?
Propranolol and atenolol
Propranolol - non selective B
Atenolol - B1
What do phentolamine, phenylephrine and prazosin do?
Phenotolamine: non selective alpha agonists
Phenylephrine: a1 agonists
Prazosin: a1 antagonists
How do local mediators only act locally?
They are rapidly metabolised or diluted beyond their biologically active range close to their site of release
Where is histamine usually found and released from?
Mast cells (tissues and particular mucosal surfaces/skin) and basophils (blood)
It is also secreted by enterochromaffin-like cells (GIT) that regulate stomach acid
How is the mast cell stimulated to release histamine?
Induced by antigen via IgE, complement fragments (C3a/C5a), cytokines, physical trauma and bacterial components.
What receptors do histamine act on?
They act on histamine receptors (H1,2,3,4) which are all GPCRs
What does the activation of histamine result in? (Triple response)
Reddening - Vasodilation
Wheal - increase in vascular permeability (local oedema)
Flare - spreading through sensory fibres
What are the three types of antihistamines?
Competitive reversible H1 receptor antagonists
Sedative: promethazine (was able to enter CNS) - affected lifestyle
Non-sedative: terfenadine - caused sudden ventricular arrhythmia
Newer non-sedative: loratidine, cetirizine (reduced cardiac risk)
What is a H2 receptor antagonist?
Cimetidine blocked H2 receptors and was used for peptic ulcers by limiting stomach acid production.
What is bradykinin and how is it produced?
This is a local peptide mediator in pain and inflammation.
It is produced AFTER plasma exudation during inflammation.
Prekallikrein > kallikrein (by factor XII when it becomes active outside the blood).
Acts on HIGH molecular weight kininogen to bradykinin
How is bradykinin degraded?
Kininase II (also known as ACE) cleaves the bradykinin.
What do bradykinins actually do when activated? What are the receptors it acts on?
Dilates arterioles and venules, increases permeability, stimulates pain sensory nerve endings.
Also contracts uterus, airways and gut
Acts on B1 and B2
What is icatibant used in and why does it work?
Used in hereditary angioedema. It is a selective B2 antagonist.
The HA is caused by C1esterase inhibitor deficiency - this means the Kallikrein pathway is overactivated which can cause deep tissue swelling.
Why did ACh have two different effects when in in-vivo and in-vitro?
In-vivo it vasodilated whereas in-vitro it vasoconstricted.
Turns out that the endothelium was releasing a relaxing factor.
What is the endothelium derived relaxant factor?
It was found to be NO
Other endothelium derived vasoactive factors are:
PGI2, NO and endothelin (constricts)
What happens in the endothelial cells when the bradykinin receptor is activated or mechanical shear force is applied?
Leads to increased calcium, that activates NOS (nitric oxide synthase) which converts arginine to NO and citrulline.
NO is released by the endothelial cells which is released and acts on SMC, how does it result in vasodilation?
NO activates guanylate cyclase, which produces cGMP. The cGMP is what causes relaxation of the SMC.
What are the three different types of NOS
nNOS (nerves), iNOS (inducible macrophages and smooth muscle) and eNOS (endothelial cells)
What is the physiological role of NO?
There is a basal level of NO that regulates vascular tone.
Inhibits platelet adhesion and aggregation
And flow-dependent vasodilation
Nitrovasodilator drugs can be explained by NO now, why?
Most of these drugs are actually NO donors which elicit the response. Glyceryl trinitrate (GTN) and nitroglycerin.
What is arachidonic acid?
It is an eicosatetranoic acid (20:4) omega 6 fatty acid that make biologically active molecules
Where can we get AA?
Can be found in our diet indirectly (linoleic acid - which must be transformed) or directly.
Where is AA stored?
It is stored in the plasma membrane by esterification of C2 glycerol onto the AA.
How is AA released from the membrane?
This is done by PLA2 which can be activated by ERK or increase intracellular calcium
What happens to AA once it is removed from the plasma membrane?
The AA is metabolised by COX (1 - constitutively active, 2- inducible by inflammatory stimuli) - found in all cells
Or it can be metabolised by 5-lipoxygenase to produce leukotrienes. Only found in inflammatory cell (mast cells and eosinophils).
What are cyclic endoperoxides?
These are products of COX which are highly unstable and are only intermediates to the product.
What enzyme acts on cyclic endoperoxides and what are its products?
Produces stable prostaglandins by isomerases that act on the reactant. Produces PGD2, PGE2 and PGF2a.
- PGF and PGD are bronchoconstrictors.
PG is broken down by endothelial cells in the pulmonary capillaries.
What are the outcomes of NSAIDs?
Anti-inflammatory, anti-pyretic and analgesic
What is the role of PGE2 in the mechanism of inflammatory responses?
- Increases blood flow > tissue reddening and oedema (affects vasculature not cells)
- Sensitises pain fibres but does not cause it.
- Causes fever by having PGE2 produced in the hypothalamus which acts to increase temp set point.
- Promotes blood flow, angiogenesis, mucus secretion and reduce acid secretion in the stomach
What do prostacyclins do and where is it produced?
These are short lived (T1/2 = 3 min)
- Produced by endothelial cells that cause vasodilator and reduces platelet aggregation.
Protect against coronary artery disease
What do Thromboxane A2 do and where is it produced?
It is produced in the platelets.
- Increases platelet activation and vasoconstricts
Opposes prostacyclin and promotes coronary disease.
What does aspirin do and why is it special?
- Acetylation of COX and vascular protection. Inhibits COX irreversibly so that it cannot re-synthesis COX in platelets for 8 days. Endothelium can re-sysnthesise in hours. Leads to PGI2/TxA2 ratio increased.
- Aspirin triggers lipoxins (15-epi leukotrienes) which are analogous to those found in the body. Inflammatory resolvers.
What happens to people who have omega-3 rich diets and their AA pathway?
They will produce PGI3 and TxA3. Because of the structure the thromboxane is dysfunctional. Causing an increase in PGI/TxA ratio.
What does 5-lipoxygenase form and what does it act on?
Acts on AA and produces leukotriene A4. Seems to only be involved in inflammation.
What are the two final produces of LTA4 and their function?
LTB4 and LTE4
These are highly active compounds that cause vasodilation and bronchoconstriction - trouble in allergy, inflammation and asthma
What is the function of LTB4?
Bronchoconstrictor, vasoactive, leaky vessels. It can be antagonised by leukotriene receptor antagonist cysteinyl-leukotrienes blocking by montelukast
No action on SMC but promotes inflammation by attrack leukocytes
What are the two types of research questions that are asked?
Descriptive (how common is a particular disease) and analytical (cause and effect)
How can we classify study designs for research?
There are observation and intervention studies. Some fall under descriptive and analytical.
Case reports, cross-sectional studies, ecological - descriptive
Case-control, cohort, clinical trials (intervention) - analytical
What classification of study designs fall under longitudinal studies?
Cohort and clinical trials.
Case reports, ecological, cross-sectional and case-control are non-longitudinal
What are non-longitudinal studies?
These have no follow up on the subjects - information collected in one encounter
What are longitudinal studies?
Information collected over multiple encounters and follows up on study subjects
What is meant by prevalence?
Number of existing cases of an outcome in a defined population at one defined point in time. Usually given a proportion or percentage.
% of current smokers
% of 65y.o with CHD
What is meant by incidence?
These are the number of new cases of an outcome arising from a defined population during a time interval
- Expressed as a rate (denominator includes time component)
- Drawn from longitudinal studies
- Number of non-smokers start smoking in 2012
What is defined as risk in research studies?
Probability of disease occuring in disease free population during a specific time period.
- Risk = n/P
n - new cases in defined period, P - population at risk
What is meant by rate?
Probability of disease happening in a disease free population during total person-time of follow up
E.g. rate = 3/1000 person-years for cases of lung cancer
What are the two associations we can make in Epidemiology?
Cause and effect, correlation
What is Absolute Risk/Rate?
This is an isolated measure of risk/rate.
- There is no indication of association with exposure (no indication of cause)
What is the use of relative risk and attributable risk?
Provides indication of association by using the comparison of 2 absolute risk/rate measurements
How is relative risk measured and its indication?
RR= R(exposed)/R(unexposed)
Indicates relative magnitude of change in risk/rate of outcome associated with exposure
How is attributable risk measured and what does it indicate?
AR = R(exposed) - R(unexposed)
Indicates the absolute magnitude of change in risk/rate of outcome associated with exposure
What is the attributable risk percent?
AR% = [(Re- Ru)/ Re] x 100
Proportion of incident disease among exposed people that is due to exposure
What is the population attributable risk?
PAR = Rt* - Ru
Rt - incidence measure in the total population
What is the attributable population risk percentage?
Known as the preventable fraction
Significant relationship between the risk and population size
Small increase in risk/rate of common disease leading to greater additional disease than large increase in risk/rate of rare disease
Where are the baroreceptors found?
Carotid sinus, aortic arch and includes juxtaglomerular apparatus (pre-arteriole kidney)
Where is the cardiovascular control centre found?
It is found in the brain stem - medulla. It has both pressor and depressor centres which operates via sympathethic and parasympathethic nerves
What does the activation of the sympathethic nervous system cause?
- Increases heart rate
- Decreases AV conduction time
- Increases cardiac contractility (by increasing intracellular calcium during depolarisation)
- Increases TPR
- Increases Venous tone
What does the activation of the parasympathethic nervous system cause?
- Reduces HR
- Increases AV conduction time
- Reduces TPR (dilates a few blood vessels but it will not reduce the TPR)
The pathway of initial blood pressure change to possible actions
What is the baroreflex buffer?
This is the baroreflex that stabilises the pressure and smooth out variations such as posture, eating, defecation and noise
What are the functions of the chemoreceptors in the control of blood pressure?
These are used as detection when the blood pressure drops below 60mmHg (baroreceptors stop firing).
Found on carotid and aortic bodies outside the arteries.
- Stimulated by low flow, low O2, high CO2 and low pH
What does high blood pressure predispose you to?
CHD, stroke, cardiac hypertrophy, heart failure, kidney failure
NOT liver failure
What does the blood pressure distribution look like?
It is unimodal distribution with skewing of the curve to the upper values
How does the gender affect blood pressures?
Men typically have higher blood pressure than woman.
This is representative of the average there are cases when women BP are higher than men.
What is the implication of age on BP?
Blood pressure increases with age
What happens to pulse pressure we as get older?
Pulse pressure increases due to the decrease in compliance of the arteries in elder people. Typically diastolic no longer increases and may even decrease.
Normal blood pressure development of western male with age and the difference with women.
The bigger the body size the higher the BP
What are the diurnal variation of blood pressure?
Lower night BP (20mmHg), less variability at night, less sympathethic activity at night
Why is the BP 3mmHg lower in the summer?
Sweat > loss of blood volume and reduce cardiac output. Vasodilation during summer due to heat. Body weight changes between summer and winter (winter usually gains weight)
What is the definition of hypertension?
It is simply the upper end of the distribution defined arbitrarily. It has been falling over time - about 140mmHg at the moment.
What is the population paradox?
In a population where more deaths occur in the larger number of people at moderate risk than in the smaller number of people at highest risk
Describe what the breast is composed of and the vessel systems that are present.
Breast has glandular tissue that secrete milk. Also made up of fibrous, adipose tissue, blood vessels, nerves and lymphatics.
It is located on the lateral border of the sternum out to the mid axillary line.
Also notice the axillary process superior laterally - which means there is more glandular tissue in the upper quadrant of the breast (thats why more carninomas occur here)
What are the main components in this diagram? And the different compartments that are relevant.
Vertically the breast extends from the 2nd to 6th rib. The deep aspect of the breast is concaved due to having 2/3 of it being over the pectoralis major. The remaining 1/3 lies over the serratus anterior.
Another significant landmark is the retromammary space which separates the glands from the muscles and ribs. This allows the breast some degree of movement and is also the location for breast implants.
What is the blood system like for the breast?
It shares the blood vessel system with the thoracic and upper limbs. So laterally the artery that supplies the breast are the axillary artery. The medial aspect is suppled by the internal thoracic artery.
Similar system is found for the veins. Laterally it is drained by the lateral mammary vein or the lateral thoracic vein. Medially drained by internal thoracic vein which all drain to the internal jugular vein.
What are the lymhpathic vessels involved in the drainage of the breast and what are their implications?
Laterally drained to axillary lymph nodes and medially to the intercostal lymph nodes. Carcinoma of the breast can use the lymphatic vessels to metastasise into the thoracic wall.
Describe how the ribs articulate to the thorax
Ribs articulate anteriorly with costal cartilages. The upper 1-7 articulate with the sternal complex. Costal cartilage 8,9,10 articulate with the costal cartilage from above. This forms the costal margin. 11-12 do not articulate at all (called floating ribs).
Explain the articulation of ribs onto the posterior surface of the thorax
Ribs articulate with the facets found on the vertebra with the head first. Then the smooth facet on the tubercle is what articulates with the transverse process.
Describe the typical middle rib.
Consists of the head which has a superior and inferior articular facet for attachment to the vertebral body. Then forms the tubercle which has two facets - smooth medial (for articulation) and rough lateral (for ligaments). This leads into the body and finally the anterior sternal end where it slots in with the costal cartilage.
Costal groove is found inferior to the body of the rip where the blood vessels and nerves are located.
What are the differences of the other ribs other than the typical middle ribs?
11-12 are atypical ribs because they have no neck or tubercle. 1-2 ribs, particularly the first rib it is almost horizontal and short. Bares distinct grooves for the subclavian vessels. It only articulates with T1 so it only has a single facet on the head.
Where are the costal facets located on the thoracic vertebra?
Costal facets on the body (superior and inferior), facets on the transverse process and long vertically spinous process helps identify thoracic vertebral body.
Describe what the costavertebral joint is made up of.
Head of the ribs articulate with the vertebral body. Articulates onto the IV disc and on two consecutive vertebras. Exception to T1. There are strong radiate ligament of head which reinforces the joints.
What are the contents and structure of the costatransverse joints?
Between the transverse process of the vertebra and the tubercle of the rib. Between the medial facet of the rib with the facet on the transverse process. This joint also has an incredibly strong three part costotransverse ligament of neck and tubercle. These joints are very strong and typically rib fractures occur first before these joints are broken.
What is the shape of the thorax and the aperture like?
The superior aperture is narrow compared to the inferior aperture. The supre-pleural membrane further narrows the superior aperture but does not close it off entirely.
The inferior aperture is completely closed off by the diaphragm
What is the implication of a flail chest and how does it arise?
Usually with blunt traumas it will cause fractures of the ribs. Typically these form different rib segments. It impacts on respiration and does not influence of the join itself.
Causes independent movement of the different sections.
What does the diaphragm consist of and its attachment ?
It is a muscle that has a circumferential origin of the inferior aperture. It attaches to the xyphoid process, costal margin, to the tips of the 11-12 ribs then we head towards the vertebral volume. Posteriorly there is a lateral and medial arcuate ligaments which are overlying the muscles. The medial arcuate ligament is thickening in the psoas fascia. The most posterior attachment is onto the lumbar vertebra.
What is the right and left crus of the diaphragm?
This is the tendinous structures that is found extended inferiorly from the diaphragm to the vertebral column.
The right one is higher than the left one due to the liver.
What are the three different vessels that pass through the diaphragm?
Clubbed shaped central tendon.
Three many hiatus in the diaphragm: IVC passes through the central tendon at the level of T8 (to the right of the mid line). Oesophagus passes the level at T10 (to the left). Aorta passes more behind the diaphragm rather than through it (between the pleura).
What is the implication of a paralysed hemi-diaphragm?
Where one lung is paralysed the functional diaphragm will go down with inspiration. Because it simply moves substances (organs) will go up instead up the other dome.
- Each dome is supplied independently by the phrenic nerve.
What are the external, internal and innermost intercostal muscles orientation?
EICM: the fibres are directly downwards and forwards like our hands in our pockets.
- Anterior part of each space is replaced by external ICM membrane.
- This is used to elevate and expand the rib cage (expand it)
IICM: It is a back pocket muscle with fibres directly downwards and backwards. The muscle fibres fill the space anterior and laterally and replaced by membrane posteriorly.
- It will pull the ribs down and in which is a muscle that splits and holds down the ribs during expiration.
Innermost is the same as direct of muscles as IICM but it is usually only found laterally and deepest layer. There are some muscles found anterior and posteriorly. Sub-costalis is the name for the muscle fibres in the posterior aspect of the rib.
- Discontinuous lining of the rib
What are the implications of having the bundle vessels found in the costal groove?
Each space has its only vein, artery and nerve (same order from superficial to deep). They run at the top of the space and runs just in the groove of the costal groove. The bundle lies between the internal and innermost ICM. Usually we see smaller branches (co-lateral branches) of each of these nerves and blood vessels running in the bottom of the space (only small amounts).
How do the blood vessels and nerves run for the intercostal areas?
Ventral ramus of the thoracic spinal nerve forms the intercostal muscle nerves.
Anterior intercostal artery comes from the internal thoracic artery. Posterior intercostal artery usually comes from the aorta. Feeds anteriorly and posteriorly which joins to anatomise later together laterally. Anterior comes from the internal thoracic artery and the posterior comes from descending thoracic aorta.
- The veins mirror the arteries so there are anterior and posterior intercostal vein which will drain into the internal thoracic vein. Posterior intercostal veins are different its equivalent and drains into the azygous veins.
What are the dimensions of the thorax?
A-P directions, vertical and lateral directions
What happens to changes in volume of the thorax?
Any increase in volume of the thorax will drop the pressure inside the thorax. This will create a gradient for air to flow into the thorax.
What happens to changes in A-P direction?
Lifting it up will push the sternum superior and anteriorly which will change the AP dimension. Expansion of AP will increase volume and decrease pressure
What happens when the lower ribs are elevated to the thorax volume?
When elevated the ribs will move laterally and increase lateral dimension of the thorax
What are the scalenes, sternocleidomastoid, abdominal muscles and their effect on respiration?
These are muscles that attach to the ribs which can affect respiration by acting as accessory muscles
What is the pericardium surrounding and what does it attach to prevent movement?
It surrounds the heart and attaches to the central tendon of the diaphragm to prevent it from falling down
What is the mediastinum?
This is the cavity in the thoracic cage
Where is the border of the mediastinum superior and inferior?
Division is at T4/5
How is the inferior mediastinum split into three different regions?
Anterior, middle and posterior
Where is the heart located in the mediastinum?
It is found in the middle region in front of T5-8. Behind the body of the sternum.
What is the fibrous layer outside the heart?
It is the tough layer found outside of the heart and outside of the serous membrane too. It consist of the parietal layer.
What is the serous membrane outside of the heart?
It is a serous pericardial envelop that is punched in by the heart. This forms a continous membrane with two layers. Contains the visceral layer.
What is the pericardial cavity and what is it’s function?
This is the potential space created by the serous membrane that allows the heart to have frictionless movement
Describe any significant landmarks and orientations that is seen in the anterior view of the heart.
The heart is twisted so that we mainly see the right atrium and ventricles but still see some left ventricle. Right border of heart RA > RV> LV.
Apex of the heart at bottom and the base is where the major vessels are.
The different compartments are divided by a sulcus: coronary sulcus, anterior interventricular sulcus.
Auricle are like ear lobes out of the atrium that wraps around the vessels (indicates anterior orientation)
Blood drains into RA by SVC and IVC then pumped out through pulmonary artery.
Ligamentum arteriosum found between aorta and pulmonary artery
Describe the significant landmarks and orientation of the posterior view of the heart.
Similar to anterior there is mostly LA, LV and little bit of RA.
Right border is still formed by the RA. Most other complexes are similar to the anterior view such as the coronary sulcus and posterior interventricular sulcus
What are the structures that can be found in an opened right atrium (lateral view)?
Thin posterior wall, fossa ovalis, coronary sinus, IVC and SVC supplies, tricuspid valve, musculi pectinati (rough end found anterior to this section), crista terminalis (smooth area) and sinus venarum (smooth posterior wall)
What are the structures found in the right ventricles from an anterior view?
Tricuspid valve, chordae tendinae, papillary muscle, thicker wall, trabeculae carnae (rough surface found around the ventricles), conus arteriosus/infundibulum smooth area right before the pulmonary valve.
Three papillary muscles that are simply extensions of the trabeculae carnae (still ventricles)
Describe the features of the left ventricles and atrium
LV has a much thicker wall. the valve present is the mitral valve (bicuspid) - so only two papillary muscles are found.
RA simply has four openings for the four pulmonary veins.
What is the function of the fibrous skeleton in the valves during systole?
Muscle fibres of the heart is anchored to the fibrous skeleton. It has four rings that surround the orifices of the valves. Atrial and ventricular muscle mass are two separate muscle masses that are separated by the fibrous skeleton. This means that they are electrically isolated too.
- Also the fibrous skeleton provides an attachment for the base of each valve cusp
What are the tricuspid valves made of?
Anterior, posterior and septal cusps
The chordae tendinae and papillary muscle have nothing to do with valves closing
What does the ventricular surface of the valves look like and how does it function?
It is a rough surface with chordae tendinae. Closure of valves are due to changes in ventricular pressures. The papillary muscles simply keep the valves closed longer to prevent back flow
How are the chordae tendinae attached to the valve cusps?
Each set attaches to the adjacent cusps of two cusps. So when it contracts it will create a water tight seal.
What are the valves involved in diastole?
Aortic and pulmonary valves
What are the structures of the aortic and pulmonary valves like?
These are semi-lunar valves with its base attached to the internal surface of the wall vessel it is in.
L and R are inverted in the picture
What are the structure of aortic valves like?
There are no chordae tendinae attached to the valves. It is semi-lunar valves (three). The origin of the coronary arteries are found in these valves.
What does the conduction system of the heart found in the right side consist of?
SA node, AV node, bundle of His, R bundle branches (Purkinje fibres)
SA node found in the RA right at the top at the cristae terminalis. AV node is also found in the RA. Bundle of His is the bridge between atrium to ventricles.
What are the nerves to the heart?
The cardiac plexus is found at the base of the heart which then splits off into SNS and PS nervous system.
Describe the coronary circulation system to the heart
Right and left coronary arteries come out from the aorta near the valves. Left coronary artery > circumflex branch and anterior interventricular branch. Right coronary artery > marginal branch and extends around posteriorly.
What do the different coronary arteries supply to?
Right coronary arteries supplies to SA node, AV node, RA and RV.
Left coronary arteries branch off to two vessels one that runs down the front of the heart and the circumflex branch around to the posterior which forms an anastomosis.
What is the significance of coronary arteries being functional end arteries?
This means that acute level blocks in these arteries will not give them sufficient time for the anastomoses to adjust adequately. Leading to myocardial infarction
What is the veinous system like in the heart?
Coronary sinus drains blood into the right atrium. Some anterior cardiac veins will also drain directly into the RA. However the great, middle and oblique will drain into the coronary sinus then into the RA.
How does the parasympathethic nervous system control heart rate? Where does it act? What are the transmitters involved? What are the receptors? And what is the response?
Acts by targeting the SA and AV node, by using the transmitted ACh to act on muscarinic receptors which eventually slows the heart rate (bradycardia)
What is the effect of using muscarinic blockers on the heart rate of healthy men? What does this also show?
Giving atropine caused the heart rate to increase from 60 HR (base)
This also shows that there is a baseline PS stimulation to maintain appropriate HR
How does sympathethic control of HR/Contractility work? Where? What? How? and result?
This targets SA nodes, conducting tissue and myocardial cells by using NA or Adr. The receptors are B-adrenoceptors. Results in increase HR as well as force (positive inotropic effect)
What is the effect of B-adrenoceptor blockers on the heart rate of healthy men? What does it imply?
Use of propranolol showed a decrease in Heart rate. Implies that there is a baeline sympathethic activation present.
Does the PS or SNS have the larger effect on heart rate?
The Parasympathethic nervous system affects the heart rate the most
What happens when we block all autonomic nervous system activity by using both propranolol and atropine?
The baseline heart rate was found to be at about 100beats/min
What ion channel do the parasympathethic and sympathethic nervous system act on?
The parasympathethic nervous system acts on K+ channels while the SNS acts on Ca2+ channels.
What do the P, QRS, T aspects of the ECG refers to?
P - atria contraction
QRS - ventricle contraction
T - ventricle contraction
Explain the different phases of SA node action potential.
Phase 0: Depolarisation which involves Calcium (+) ion influx
Phase 3: Repolarisation phase with influx of K+
Phase 4: Spontaneous depolarisation, influx of Na+ and Ca2+ influx - Involves Ifunny, I Calcium T and I Calcium L
Stable membrane potential - 60mV +/- 20mV
How does parasympathethic nerves slow down SA node - mechanism?
ACh acts on M2 muscarinic receptors > decreases cAMP > opens K+ channels
Efflux of K+ ions > slows Na+ and Ca2+ fluxes > slowed prepotential phase > longer to reach threshold potential in SA and slows rate of conduction (AV node)
How does the SNS affect heart rate - mechanisms?
NA, Adr acts on B-adrenoceptors > increases cAMP > opens Ca2+ channels
Increases slope of Phase 4 depolarisation (SA and AV node) > increased firing rate and more rapid conduction (AV node)
It can trigger dysrhythmias
Describe the different phases of ventricular action potential.
Phase 0: Depolarisation by Na+ in
Phase 1: Rapid depolarisation by K+ efflux
Phase 2: Extended plateu by Ca2+ in and K+ out
Phase 3: Repolarisation by K+ out
Phase 4: Stable membrane potential
Resting membrane is about -90mV
What is meant by dysrhythmia or arrhythmia?
This is any variation from the normal rhythm of the heart beat - seen as palpitations, fluttering or forceful contraction after a missed beat.
What are the symptoms of arrhythmia?
Shortness of breath, fainting, fatigue, chest pains
How can you properly diagnosis arrhythmias?
Need ECG to determine rhythm (flutter/fibrillation) and rate (tachycardia/bradycardia)
What is the underlying mechanism that causes dysrhythmias?
- Altered pulse formation: in pacemaker cells or genereation of AP other than SA node
Altered impulse conduction: Conduction blockage or by re-entry
Triggered activity: Early or late after-depolarisation from excess sympathethic activation
What are the four major classes of antidysrhythmic drugs?
Na+ blockers, B-adrenoceptor antagonism, K+ blockers and Ca2+ blockers
What do Na+ channel blockers affect?
Reduces Phase 0 slope and peak of ventricular action potential
What do B-adrenoceptor antagonists affect?
Decrease rate and conduction of SA node
What does K+ channel blockers affect?
Delay of phase 3 of ventricular activation potential, so it prolongs APD
What do Ca2+ channel blockers affect?
Most effective at SA and AV node which reduces rate and conduction
Class 1: Na+ channel blockers what they affect and examples?
Affects ventricular action potential: all of these shotern maximum AP and rate of depolarisation
1a: Quinidine: moderate Na+ block (also affects Ifunny no atrium)
1b: Lignocaine: mild Na+ block
1c: Flecainide: marked Na+
What is the concentration dependent side effects found with lignocaine?
Above 4ug/mL starts to show side effects.
The effective dosage is 2-3ug/mL so there is a small therapeutic window.
Na+ channels found in skeletal muscle and CNS so side effects are found with higher doses
Given IV in acute situations to restore rhythm. It’s also a local anaesthetic is given topically instead of IV.
Class 2: B-adrenoceptor antagonists: How it works? Side effects?
Prevents sympathethic activation on cardiac muscles. So it decreases sinus rate, conduction velocity and aberrant pacemaker activity.
Stabilises membranes in Purkinje fibres
Adverse effects include: Bradycardia, reduced exercise capacity, hypotension, AV conduction block and cause hypoglycemia and bronchoconstriction (Blocks B2 activation)
Class 3: K+ channel inhibitors: When to use? How it works? Examples?
Used for ventricular arrthymias caused by re-entry of conduction and muscle damage
- Prolongs cardiac action potential (slowing Phase 3 repolarisation of ventricles)
Leads to reduced re-entry but can cause increased trigger events (slower pulse and act during non-refractory periods)
- Example: Amiodarone - blocks Na+, Ca+ and B adrenoceptors.
Side effects: Reversible photosensitisation, skin discolouration and hypothyroidism and pulmonary fibrosis with long term use. UNIQUE.
Class 4: Calcium channel blockers - Example of cardioselective one, what does it do and side effects?
Verapamil acts preferentially on SA and AV nodal tissue (Ca2+ for initiation of AP - used for atrial tachycardias)
It slows conduction velocity and increases refractoriness
May cause facial flushing, peripheral oedema, dizziness, bradycardia, headache and nausea
What is chronic BP > 140/90 a risk factor for?
Stroke, AMI, ischemic heart disease, cardiac heart failure, aortic aneurism, renal failure, death
What are some risk factors that contribute to hypertension?
Smoking, diet, weight and stress
What is the principle treatment of hypertension before medication?
Reduce the known risk factors: risk, diet (alcohol, salt, saturated fats), weight and stress
What happens to the blood pressure threshold for hypertension when other co-morbidities exist?
This will lower our cut off for hypertension
What can sympathetic tone affect in response to blood control?
NA –> a1 adrenceptors, B1 adrenoceptors and the kidneys (Renin)
a1 - blood vessel constriction
B1 - heart (rate and contractility)
Kidneys - Renin -> ANG II
ANG II > acts on kidney to release renin, positive feedback to SNS, release of aldosterone, affect the heart contractility, vasoconstrict blood vessels
What are the four classes of antihypertensive drugs?
ABCD - Angiotensin system, B-adrenoceptor, Ca2+ blockers and Diuretics
What is the renin-angiotensin system and what does it result in?
B1 receptors on kidney > Renin > Ang I > (ACE) ANG II > acts on AT1 receptors
Cell growth (heart and blood vessels), vasoconstriction, aldosterone (salt and water retention) and enhances sympathetic system (positive feedback)
How do ACE inhibitors (‘prils’) work and their adverse effects along with a few examples?
It prevents the production of ANG I to ANG II. Reduces vascular tone, aldosterone production and cardiac hypertrophy.
Bradykinin is not broken down
Adverse effects: First dose hypertension, dry cough, loss of taste, hyperkalaemia (use with thiazide diuretics), acute renal failure.
Contraindications: Pregnancy, bilateral renal stenosis and angioneurotic oedema
E.g. Captopril, Enalapril. Perindopril
How do angiotensin receptor blockers (‘sartans’) work? Side effects? Examples?
Blocks AT1 receptors causes reduced vasoconstriction, aldosterone, cardiac hypertrophy, sympathetic activity.
Adverse effects: similar to ACEi but without dry cough - has kyperkalaemia (+ thiazide diuretics), headache, dizziness.
Same contraindications are ACEi - pregnancy and renal stenosis
E.g. losartan, candesartan
What do the B-adrenoceptor blockers (‘olols’) do? Examples?
B-adrenoceptor antagonists which reduces cardiac output and reduce renin release (also affects blood volume, TPR)
Lipid solubility of these drugs can affect the CNS - lucid dreams
E.g. Propranolol (non-selective B), Atenolol (B1 selective)
What are the adverse effects associated with B-adrenoceptor antagonists?
Cold extremities - due to reflex a1 activation and blocking B2 receptors
Fatigue - reduced CO (B1 blocking) it is contraindicated in diabetes. As well as from B2 blockage (constriction of skeletal muscle vessels)
Dreams, insomnia - lipid solubility
Bronchoconstriction - B2 blockage in airway smooth muscle contraindicated in asthma
What are the different examples of B-adrenoceptor antagonists and their selectivity?
What are the contraindications of B-adrenoceptor antagonists? And the preferred selectivity?
Asthma, diabetes, AV block and take care with heart failure and metabolic syndrome.
Generally want to select for human heart/kidney therefore B1 selectivity is preferred
How do calcium channel blockers work and their cardiac vs vascular selectivity?
Inhibits L-type calcium channels found in the vasculature and in the myocardium > reduces cardiac/vasculature contractility
There are cardiac and vascular selective drugs.
Non-selective: verapamil, Diltiazem (less pronounce on cardiac cells)
Vascular selective: Dihydropyridines - Felodipine and Nifedipine
What are the adverse effects of the Calcium channel blockers and the reasoning behind most of them?
Both types of blockers show: oedema, flushing and headache (due to dilation of blood vessels)
Verapamil, Diltiazem - also causes bradycardia
Dihydropyridines - Reflex tachycardia since blood vessels cannot reflex contract
How do diuretics work to reduce blood pressure?
Decreases Na+/Cl- reabsorption in renal tubules this means there will be increase water excretion from kidney. Also means a loss of K+ from collecting duct. This lowers blood volume and decreases blood pressure.
What are the adverse effects of thiazide diuretics and an example of this class of drug?
K+ loss, gout, hyperglycemia, allergic reaction.
K+ loss is why you use it in combination with ACEi
E.g. Hydrochlorothiazide
How do cross-sectional studies work? How is information collected? What kind of outcome do you get at the end of the study? Does it show association or causality?
Information collected at one point in time, subject contributes data only once (no follow up subject)
Data is collected through questionaires, examinations investigations
Attain prevalance numbers
Can explore associations among variables but it provides weak evidence for causality
How do case control studies work? How is information collected? What kind of outcome do you get at the end of the study? Does it show association or causality?
Compares previous exposure status between people with and without the outcome. Controls are matched with cases to eliminate confounders.
- Researcher comes in once outcome has happened
Used to study rare disease
Key output = Odd ratios (approximation of relative risk conferred by exposure)
These are non-longitudinal so cannot estimate incidence measures
How to calculate Odd Ratio?
How do you interpret Odd ratios?
It is simply the same as relative risk.
How do Cohort studies work? How is information collected? What kind of outcome do you get at the end of the study? Does it show association or causality?
This is longitudinal study that has follow-up on the subjects. Can collect incidence data. Compares outcomes between subgroups (not exposed vs exposed to risk factor).
Derives relative risk
These studies can include multiple exposures and outcomes
- Difficult to study rare diseases
Research hypotheses can be addressed post hoc in established cohorts
What are the two different types of Cohort studies?
Prospective and retrospective cohort studies. The difference is when the researcher comes into the picture but they still follow up on the patients.
Key: explicit knowledge about the temporal relationship (time course) between exposure and outcome
What is the Framingham Heart Study?
Recruited 5000 people and follow up to them looking at the risk factors of stroke and cardiovascular disease.
What did the Framingham risk equation show and establish?
It confirmed risk factors and looked at the relationship/interplay of more than one risk factor
What is the RMH stroke registry and its merits?
All stroke patients have active follow up for three months after the episode. There are plans to do ‘passive’ follow up by database linkage across hospitals
What is bias and the two main types of bias found in studies?
Bias is an error or systematic difference between groups that cause under/over estimation of true results.
The two main types of bias is selection bias (from people) and information (measurement - how we collect data) bias
What is selection bias?
Usually the selection of participants (from those who volunteer) are systematically different from the other groups. Does not give a generalising cross-section of the population.
- May be systematic differences in the case and control groups purely because they are from different sources (hospital vs community)
- Systematic differences between those who drop out and those who don’t
How can we minimise selection bias?
- Recruit a representative sample and have case/controls from the same source
- Maximise response
- Minimise lost to follow-up
What are information bias? Some examples of these?
Systematic differences from method of information collection (especially subjectivity).
Recall bias: between subjects with and without MI
Women seeking help first: gives a suggestion that women are more biased to disease despite simply more volunteering
How can we minimise information bias?
Using standardised tools and objective assessment of the participants.
What are confounding factors?
This is a third factor involved that independently affects outcome but also has a relationship with the exposure
What are the universals confounders in studies?
Usually it is age and sex.
- Age: Association between use of blue hair rinse and bowel cancer
- Sex: Association between baldness (exposure) and CVD (outcome)
Men tend to be bald and also higher risk of CVD.
How can you minimise confounding?
Matching by confounder and restriction. In the analysis stage use restrictions, stratification (analysis by sub-group) and multivariate analysis
What are the three layers found in the heart?
Epicardium (outer), myocardium (muscle and capillaries) and endocardium (inner)
What is found in the epicardium of the heart?
Contains a simple squamous cell, sub-epicardial connective tissue, blood vessels, fat and nerve tissues
What does the endothelial layer of the heart contain?
Endothelial layer, sub-endocardial connective tissue and conducting tissue
What are some properties of the cardiac muscle cells?
Striated muscle forms myocardium that can contract spontaneously, cells are small, central nucleus, joined by intercalating discs, gap junctions - to electrically couple cells locally.
What is present to conduct electricity if the gap junctions can only couple electricity locally?
This is achieved via conduction pathway found in the endocardium - Purkinje fibres. DO NOT initiate heart beats.
What are Purkinjes fibres?
These are modified cardiac muscle cells - larger. It has loss its contractile function, full of glycogen and forms bundles in the sub-endocardium connective tissue
What are the three layers/tunica of blood vessels?
Tunica intima, media and adventitia (innermost to outer)
Which blood vessel layer makes contact with the blood?
Tunica Intima
What layer of the blood vessel binds the blood vessel to the surrounding tissue?
Tunica Adventitia
What is the structure of the tunica intima?
It has a simple squamous epithelium (endothelium), lies on a basal lamina which is then supported by a thin layer of connective tissue,
Endothelial cells bulge and are elongated in the direction of blood flow.
What is the role of the endothelium in the blood vessels?
Actively inhibits the clotting process, but in the underly sub-endothelial connective tissue there are Von Willebrand factors that cause clotting.
Endothelium also releases vasoactive substances such as NO and endothelin
What is the structure of the tunica media and its function?
Middle layer that contains smooth muscle which is arranged concentrically so it constricts lumen. This increases blood pressure.
Also has elastin in its structure.
What makes the connective tissue found in the media layer?
The smooth muscles themselves produce the connective tissue
What is found in the intima adventitia?
Connective tissue found - collagen type I, elastin, ground substance and fibroblasts. Acts to anchor to surrounding tissue.
If the vessel is large enough it has its own blood supply Vasa vasorum
Where are elastic arteries generally found and what is the structure that makes it up?
These are found closer to the heart due to the BP fluctuations. The elastin in the media stores energy and then compresses the blood for continuous flow.
What are muscular arterioles and where are they found and structure?
They distribute blood to tissue with elastin in the media. Elastin found in two places - internal and external elastic laminae. Internal (found subendothelial) and external found between media and adventitia.
Contractions regulate blood pressure
What are arterioles and their significance?
These are very small arteries and contribute the most to blood pressure - resistance is the power of 4 inversely.
What are meta arteriole?
These are intermediate vessel with incomplete smooth muscle coat. Single smooth muscle cells act as sphincters controlling capillary flows.
What are capillaries and their functions?
These have diameter less than that of RBC, thin walled to help exchange, most cells in the body are very close to a capillary.
- No identifiable media (SMC)
Made of single endothelial rolled into a tube, sealed with tight junction, basal lamina, sometimes it has pericytes (media), surrounded by only a few collagen fibres (adventitia)
What are fenestrated capillaries and where are they found?
These are thinner capillaries than normal which are found in pancreas, intestines and endocrine glands.
What are the functions of the vein and what does it contain?
Blood is collected in the veins - about 70% of blood and acts as a blood reserve.
What is the structure of veins and the function of valves and how blood flows through it?
Have the same layers as arteries. But which a thinner media and a thicker adventitia. Veins have valves to force blood one way.
Blood is pushed through the vein by muscular contraction
What are the structures and functions of venules?
Blood from capillaries then moves into the venules. The media is initially SMC but then replaced by smooth muscle.
- This is the site of diapedesis of leukocytes.
The changes from medium to large veins?
Adventitie is gradually enlarged at the expense of the media. This is to allow it to resist the hydrostatic pressure especially when the volume increases.
What is the function of the lymphatic system?
Extracellular fluid drainage, it has very thin walled and valves
What are the characteristics of the lymphatic vessels?
Absense of red cells, some white cells present, with valves and the large vessels look like veins
What is the normal function of blood vessels?
Contain blood in normal pressure, not leaky and not clotting. As well as interact with blood components when appropriate - inflammation and coagulation
Can the tunica intima heal after being damaged?
Yes it can but this will cause thickening/fibrose
Tunica Media in the blood vessels - elastin and how much of it is present in arteries compared with veins?
Elastic arteries - has many layers
Muscular arteries - has two layers internal and external elastic lamina
- This layer is thicker in the arteries than veins to allow for pulsatile blood flow and maintain blood pressure
What is the primary component of tunica adventitia?
Primarily made of connective tissue filled with fibroblast, collegan and blood vessels
What are some vascular pathologies that can occur?
Disease of wear and tear (arterioslerosis and arteriolosclerosis), atherosclerosis, aneurysm, dissection, thrombosis, embolism all leading to
Ischaemia and infarction
What is the result of wear and tear on blood vessels?
The intima is damaged and leads to thickening of arteries.
What is arteriosclerosis?
This is commonly seen in ageing and hypertension. It leads to arteries losing elasticity and narrowing lumen.
What is the implication of arteriosclerosis?
It impairs the artery’s ability to control blood pressure and can impair blood supply to subsequent tissues
What is the mechanism of intimal damage and thickening of arterioles?
SMC produce too much matrix and protein from the blood then leaks through damaged endothelium (immunoglobulin and albumin).
This is known as_ hyaline arteriolosclerosis_ this is just a glossy look and smooth walls.
What is hyaline arteriolosclerosis and its implications?
This is the damage and thickening of the intima in the arterioles - that has a glossy look.
Leading to poor blood supply to tissues and possibility of microaneurysms and haemorrhage (gunk that can be extended and bleed)
What are some sequelae of arteriolosclerosis?
Cerebral haemorrhage, benign nephrosclerosis (ischaemia from narrowed arterioles) and retinopathy
What is atherosclerosis?
This is the blocking of arteries that involves a build up of inflammatory, fibrotic, necrotic and fatty materials.
Must have fibrous cap and necrotic lipid core
What is the implication of atherosclerosis?
It can slowly narrow arteries or rupture catastrophically
What are the four different stages of atherosclerosis?
- Fatty streaks
- Damage, inflammation, cholesterol and fibrosis
- Stable atherosclerotic plaque
- Unstable atherosclerotic plaque
What are fatty streaks?
These are foam cells (macrophages that ingested lipids) found in the intima.
What is an atherosclerotic plaque?
It is a fibrous cap with a necrotic lipid core and chronic inflammatory cells
What are the microscopic features of atherosclerotic plaque?
Foam cells, inflammatory cells (mononuclear), cholesterol clefts (clean needle shaped spikes), calcification, thickened intima, narrowed lumen, fibrous cap, necrotic core, thinned media (inability to get blood through thickened intima) and neovascularisation
What are the two ways calcification can occur in atherosclerosis?
- Dystrophic calcification - areas of cell degeneration
- Metastatic calcification: serum calcium levels are too high that they are above the precipitation threshold and form in blood vessels and kidneys.
What is the difference between stable and vulnerable plaques?
Vulnerable Plaques are prone to acute plaque event, which is rupturing. Often occurs in plaques with thin fibrous cap (with ulceration), larger necrotic core and has more inflammatory cells. But vulnerable plaques take up less stenosis so are generally asymptomatic
What are acute plaque events?
When something goes wrong in the plaque.
- Plaque rupture, haemorrhage into plaque or erosion of endothelium.
Leads to thrombosis, thromboembolism, atheroembolism
What are the sequelae of acute plaque events?
Chronic ischaemia when >70% stenosis - leading to stable angina or peripheral vascular disease (claudication - ischaemic leg disease)
Aneurysm - weakening of media and can risk rupture/haemorrhage
What are the non-modifiable and modifiable risk factors for atherosclerosis?
Non-modifiable: Age, gender, family history, certain genes, already having atherosclerosis
Modifiable: smoking, diabetes, high BP, cholesterol and sedentary lifestyle
What is the role of the endothelium in atherosclerosis?
Endothelial dysfunction/activation is the start of atherosclerosis. The endothelium becomes leaky and adhesive to WBC, produce cytokines and growth factors and is now pro-coagulant.
Takes up LDLs into intima (once activated and gets oxidised) and becomes pro-inflammatory. Also allows monocytes into intima (macrophages enters phagocytose oxidised LDL and produce inflammatory cytokines.
What is the role of cholesterol/LDL in atherosclerosis?
HDL take up lipid from the peripheral.
LDL accumulates in the intima and oxidises. Toxic to endothelium and other cells. Taken up by macrophages and SMC (form foam cells). Which stimulates inflammatory cytokines and produces free radicals in intima
What is dissection in vascular pathology?
This is when we get blood in the media (rupture of intima and blood enters media). Highly associated with hypertension.
Classified into type A and B dependent on how close it is to the aorta
What are the two patterns of hypertrophy of the heart?
Concentric (Increase LV mass and wall thickness) and eccentric (increase LV mass and no change to wall thickness)
And remodeling - normal LV mass and increase wall thickness
What are the four patterns of hypertrophy?
Thick, dilated, thick and dilated, intermediate
What does a decrease in contractility (cardiac failure) to do to my Starling curve?
The curve is lower in CO at every point of LVEDP.
What structures pierce through the diaphragm and at what level?
T8 - caval opening
T10 - Oesophageal hiatus
T12 - Aortic hiatus
(From top to bottom in the picture)
How does the left vagus nerve route progress through the thorax?
Vagus nerve heads posterior as the phrenic nerve heads anteriorly.
Lateral to aortic arch, moves behind the lung root, then runs anterior to the oesophagus.
What are some examples of B-lactam antibiotics?
Penam (penicillin) first one to be discovered.
What is the structure of peptidoglycan?
The layer is made up of alternating N-acetyl-glucosamine and N-acetyl muramic acid (derived from the glucosamine).
Off the Muramic acid it has a peptide chain coming off it which then binds to a pentapeptide bridge to connect the layers (to the next peptide chain)
What is the structure of the peptidoglycan specifically for Staph. Aureus?
The peptide chain has alternating D and L-amino acids - giving it the rigid effect.
L-Lys binds to above pentapeptide bridge. D-ala binds to the bottom pentapeptide bridge.
How is the peptidoglycan synthesised in the bacteria?
Precursor made in the cytoplasm. Becomes immobilised on inner aspects of plasma membrane.
Then synthesis of building block. Once this is down its exported to the exterior membrane and links to the growing peptidoglycan chain.
How does cross linking peptidoglycan occur?
The cross linking process is catalysed by transpeptidases or penicillin binding proteins. Drugs are able to bind to this enzyme that catalyse these reactions.
What is aortic stenosis? Impacts it has on the pressures and how it was formed?
Narrowing of aortic valve by fibrosis or calcification. The pressure gradient could increase to > 50mmHg.
Increase in ventricular pressure with no changes to aortic.
What are systolic murmurs and how does it usually sound?
Due to aortic stenosis - and the pressure gradient rises during systolic ejection.
The murmur is crescendo decrescendo meaning that it becomes louder, louder then slower. This is the murmur that comes after S1 then followed by S2.
What are the effects of Aortic regurgitation on the LV? What is the effect of the pressures due to aortic regurgitation?
Volume leaks back into LV, to maintain SV needs to pump more per beat. Volume overload, Increase EDV, Increase ejection fraction leading to normal ESV.
- There is no gradient across the valve. But aorta pressure will increase with the increase SV too.
- We see a very wide pulse pressure in aortic regurgitation.
What is the mumur of the mitral stenosis like?
Lub Dub kajflksdjf (long sound in the diastolic period)
What are the pathophysiological mechanisms of cardiac hypertrophy and its consequences?
Myocardial hypertrophy > impaired perfusion > ischaemia > arrhythmia & cardiac failure.
Cardiac failure > increase EDV > eccentric hypertrophy > LV stiffness > cardiac failure
Catecholamines worsen these situations
What are the main differences from the countries with extremes of life expectancy?
What are the four stages of different epidemiological transition?
Stage 1: No growth
Stage 2: Birth > death
Stage 3: Birth > death (begins to diminish)
Stage 4: Birth = death
How is cholesterol transported around the body with lipoproteins -specifically what are the roles of chylomicron, VLDL, LDL, chylomicron remnants, lipoprotein lipase and HDL?
Chylomicron delivers cholesterol-esters and TGs from gut. VLDL carries cholesterol from liver to capillaries. In the capillaries the lipoprotein lipases free up the TGs and form FFA. Chylomicrons and VLDL remnants carry concentrated cholesterol back to the liver.
Sometimes VLDL will split and form LDL which will last in the blood longer and deposit cholesterol on other tissues.
HDL is involved in reverse cholesterol transport (removal of cholesterol from the tissues back to the liver - for bile salt formation)
Summary of the different drugs that act on lipids and their result.
How can we interpret drug assay of concentrations in vitro?
If white is found below the drawn lines it is synergistic combination. If it is above it will be antagonistic. MIC can be derived from these tests as well.
Where is the apical segment of the lower lobe found?
Between the anterior and posterior segments
What happens in alpha-thalassemia and who does it affect?
Affects adult and fetal Hb. Produces homotetramers of gamma and beta chains which are less soluble. The severity of the phenotype is highly dependent on the genotype. Since there is two alpha genes found on each chromosome.
