exportcsv Flashcards
Cardiac channel blockers
What are the two types?
- mechanism of each
- adverse effects
Cardioselective; or vascular selective
mechanism
- block L-type Ca2+ channels in cells -> slow the entry of Ca into the cell
Cardioselective (verapamil) -
slow entry of Ca -> decreases heart rate -> increases time for perfusion of cardiac muscle - decreases cardiac contractility -> decrease SV and CO -> decreasing demand for O2; increasing perfusion of muscle
adverse effects:
- flushing; headache (overdilation)
- oedema
- bradycardia
vascular selective (nifedipine): - L-type channels block -> arterial dilation -> reduces afterload on heart -> less O2 demand
adverse effects: - flushing; headache; oedema - hypotension - reflex tachycardia - AV block
cholesterol
- biochemical structure
- how many carbons
- rough structure
- hydrophilic/phobic?
- what part of molecules is cleaved off in derivatives?
- C27
- 4 fused rings
- ABCD + YvY tail
- amphiphilic
- has a hydroxy group at C3; rest of molecule is hydrophobic
- at C17 have YVY tail
- this is cleaved off
cholesterol is a greasy solid; insoluble in water -> forms gallstones
Cholesterol is a precursor for..
- steroid hormonse
- bile salts
- vitamin D
cholesterol synthesis pathway
acetyl CoA (mitochondria) -> moves out as citrate (oxaloacetate + acetyl CoA = citrate) -> back to acetyl coa in cytosol
acetyl CoA + acetyl Coa -> acetoacetyl CoA + acetyl CoA -> HMG CoA
HMG CoA -> when in cytosol will form cholesterol (in mitochondria; forms ketone bodies)
HMG CoA -> via HMG reductase + 2 NADPH -> mevalonic acid
mevalonic acid (5c) -> isoprene (5c) -> squalene (30C) -> cholesterol (27C)
-> need 6 mevalonic acid molecules for cholesterol
Complications of MI
- immediate/within hours (2)
- days (6)
- months/years (4)
immediate
(1) arrhythmias (VT; VF; asystole; AF..) - often within an hour
(2) acute cardiac failure - LV fails -> decreased CO; if severe enough - acute pulmonary oedema
days
(1) progressive cardiac failure
(2) rupture: 1-10 days (before scar tissue) - generally in free wall; papillary muscle; IV septum
(3) -> rupture may cause mitral incompetece; left-to-right shunt; tamponade
=> LV mural thrombus formation
(4) arrhythmias
(5) infarct expansion
(6) fibrinous pericarditis - acute inflammation in underlying muscle - sharp; well-localised pain
months/years
(1) ongoing caridac failure
(2) arrhythmias
(3) papilary muscle dysfunction
(4) ventricular aneurysm
- usually no rupture but can lead to: thrombus; arrhythmias; heart failure
Definition of cardiac failure
Is it usually a systolic or a diastolic failure?
when cardiac output < body needs
usually systolic failure - contractility is lessened - can’t pump out the blood
may be diastolic failure (reduced LV compliance; so have an increased LVEDP that is required to maintain the same SV)
Describe lipoprotein movement around the body
- meal: lipases break down fats; gut mucosa takes them up and repackages as chylomicrons -> lymph -> plasma
- cells with ApoC-II (chylomicron etc) receptors - activate lipoprotein lipase -> cells take up free fatty acids from chylomicrons; form chylomicron remnannts
- remnants end up in liver -> repackaged as VLDL (formation uses ACAT)
- VLDL circulates plasma; taken up by liver again; or mature in plasma to become LDL (lose ApoC-II; retain ApoB-100)
- LDL circulates and donates cholesterol to tissues - cells that recognise ApoB-100 take up cholesterol
- HDL - formed in plasma from precursors (with LCAT) - has ApoA-1 protein -> scavenges cholesterol from membranes and cells
Difference between arterial and venous thrombus - how they form - how they look
Arterial thrombus formation - endothelial damage is very important
- tend to be pale: mesh of platelets; fibrin; RBC; leukocytes
- grow in retrograde direction from pt of attachment
- mostly due to atherosclerosis
Venous thrombus formation - hypercoagulability + blood stasis is more important
- tend to be red: formed in stasis - more RBCs along with fibrin; platelets
- extend in direction of blood flow
ECG findings in cardiac tamponade
QRS complexes are seen; but there is no cardiac output -> pulseless electrical activity
general structure of chylomicrons + HDL + LDL
inside: triacylglycerols + cholesteryl esters
outside: phospholipid monolayers - single layer because the interior is hydrophobic
outside: has Apolipoproteins - fit different receptors
- diff types have diff proteins -> gives protein different functions + target cells
Histology of infarcts what do you see at - up to 12hrs - 1-2 days - 1-2 weeks - 6-8 weeks
Infarcts demonstrate coagulative necrosis (except brain: liquefactive)
- hypereosinophilic - still have outline
- fading nuclei
- loss of detail of cytoplasm
6-12hrs - no change
1-2 days - acute inflammation - lots of neutrophils
1-2 weels - granulation tissue (macrophages; capillaries; fibroblasts; lymphocytes)
6-8 weeks - scar tissue
How do beta-adrenoceptor agonists work to help symptoms of acute heart failure? Example adverse effects
examples: noradrenaline; adrenaline; dobutamine (selective for b1)
increase activation of a- and b-adrenoceptors -> increase contractility
adverse effects
- increase cardiac work; and therefore O2 demand -> problem in heart failure
- may cause arrhythmias
- in long run - decrease receptor expression -> reduced sensitivity and sympathetic drive
How do beta-blockers help symptoms in ischaemic heart disease?
- block the effects of the SNS
- > decrease HR (in SA; AV nodes) -> increase time for perfusion of cardiac muscle
- > decrease contractility in muscle; decrease SV -> decrease CO so decrease demand for O2
how do beta-blockers work in heart failure? examples
beta-blockers have negative ionotropic effects and effects on heart rate -> should be harmful in heart failure - but experiments show an increased stroke volume
- also reduce renin release -> subsequent angII effects -> reduce afterload
b1 blockers - metoprolol b1 and a1 blockade - vascular only: carvedilol -> vasodilation
How do beta-blockers work in treating hypertension?
Block effects of sympathetic activity on kidney + heart (b1 adrenoceptors) kidney - decreased renin release -> decreased downstream effects of AngII/aldosteronne heart - decrease CO (rate; contractility)
How do PDE inhibitors work to relieve symptoms in acute heart failure?
reduce phosphorylation of b1-adrenoceptors -> less reduced sensitivity to b1-adrenoceptor agonists
PDE = phosphodiesterase - phosphorylates receptors to reduce their sensitivity
How do venodilators work in heart failure? Example
Eg. nitrates - more used in angina
venodilation -> reduces preload in heart failure
How do you diagnose MI
ECG
- STEMI - reflects transmural MI; loss of amplitude of R and small Q
- NSTEMI - usually reflects smaller infarction - generally subendocardial
Biomarkers
- troponins - cardiac specific; but don’t elevate till 6 hrs or so - peak at 36hrs
- CK-MB - somewhat cardiac specific - released from damaged muscle - peak 24hrs
How does aldosterone act to retain Na+ and water in kidneys?
What blocks this process
aldosterone
- activates Na+ channels - increase reabsorption of Na+ from lumen
- stimulates synthesis of Na/K pumps - actively pump Na+ from cells to interstitium -> drive Na+ reuptake from lumen
Blocked by aldosterone receptor antagonists - eg spironolactone
how does concentric hypertrophy compensate for high afterload? what are the consequences?
thicker wall - reduce wall stress and maintain pumping ability
- maintain systolic function
- diastolic dysfunction - thick wall; doesnt fill as well.
need increast EDP to get the same EDV (causing back pressure)
- contraction from left atrium becomes important to fill LV - can lead to atrial fibrillation
How does ivabradine work to control symptoms in ischaemic heart disease
“purely” reduces HR
- inhibits inward Na/K I-funny current in SA node
- decreases the slope of the I-f - decreases velocity of diastolic depolarisation
This decreases O2 demand by the heart (pumping less); and also increases O2 supply to cardiac muscle (allows muscle to perfuse)
How does niacin work in lowering cholesterol levels?
Is it widely used?
End up with a better lipid profile (lower LDL; higher HDL etc)
- but mechanism is unclear
- reduce secretion of VLDL from liver
- reduce plasma LDL and triglycerides
- increase HDL
Not widely used - except in combo after others haven’t worked
hypoxia - definition - causes (3)
Deficiency of oxygen in tissues
Causes include:
– Reduction of blood supply (ischaemia)
– Impaired respiratory function
– Decrease in oxygen carrying capacity of the blood - eg decrease Hb
Infarcts of the circumflex artery typically involve..
lateral LV wall
Infarcts of the RCA (30-40% of cases) typically involve..
inferior/posterior wall of LV
posterior part of IV septum (if right dominant)
inf/posterior RV free wall in some cases
Mechanism of action of statins What do they result in (change in blood levels)
competitive inhibitors of HMG-CoA reductase
also there is a compensatory increase in hepatic LDL receptors -> increase clearance of LDL from blood
result in
- reduced plasma total cholesterol and LDL
- increased plasma HDL
Nitrates -mechanism
nitrates cause vasodilation -> decrease preload on heart -> less to pump; so needs less O2
mechanism
- NO is released
- NO stimulates guanylate cyclase in vascular smooth muscle -> GTP converted to cGMP - cGMP -> dephosphorylation of myosin light chain -> can’t interact with actin -> relaxation
Potassium sparing diuretics - what are the 2 different groups
Spironolactone triamterene + amiloride
structure of HDL
has a circular ApoAI protein
- makes a hydrophobic ring rounds up cholesterol + phospholipids in plasma
Sudden cardiac death
- definition
- mechanism
- other causes
unexpected fatal event occuring within 1hr of the beginning of symptoms; or asymptomatic in an apparently healthy subject
mechanism
- most often: lethal arrhythmia
- usually related to coronary atherosclerosis - unstable plaque
- acute ischaemia in myocytes -> these are electrically unstable; initiate an abnormal rhythm
eg. VF; asystole; Ventricular tachycardia
other causes - tamponade -> haemopericardium
The most commonly occluded coronary artery is the LAD. Its infarcts usually involve..
Anterior wall of LV near apex Anterior portion of IV septum Apex circumferentially
Typical sequence of events in an MI
- initial event: sudden change in morphology of atheromatous plaque (disruption: intraplaque haemorrhage; erosion; ulceration; rupture; fissuring)
- platelets are exposed to subendothelial collagen and necrotic plaque contents
- platelets undergo adhesion; aggregation; activation; release of aggregators
- vasospasm is stimulated by platelet aggregation and release of mediators
- coagulation extrinsic pathway is triggered by other mediators
- thrombus evolves to completely occlude lumen
Consequeces
- decreased ATP
- generation of ROS
- irreversible cell injury after 20-40 mins of severe ischaemia
Unstable angina
- mechanism
- signs/symptoms
- consequences
mechanism
- usually induced by disruption of atherosclerotic plaque with superimposed partial thrombosis and possible embolism or vasospasm
signs
- pain
- increasingly frequent; less exertion required
- crushing pain
often prodrome for MI
Upper limit of recommended cholesterol levels in australia
5.5 mmol/L
Ventricular tachyarrhythmias - pathophysiology
- diseased myocardium has automaticity
- diseased muscle disturbs propagation of the ventricular impuse -> and develop intraventricular re-entry
What are 3 mechanisms through which cardiac failure occurs
- Loss of myocardial muscle (therefore loss of contractility) -> most common eg. Ischaemic heart disease; cardiomyopathy
- Pressure overload eg. valve stenosis; aortic stenosis; hypertension
- Volume overload eg. aortic regurgitation; shunts
