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
What are bile acid sequestrants/resins?
Examples
Mechanism
Precaution
Used in hypercholesterolaemia
- eg cholestyramine
Mechanism
- bind bile acid (cholesterol metabolites
- prevent their reabsorption by the gut
- increase their excretion
- increases demand for cholesterol to synthesise more -> upregulation of hepatic LDL receptors
Precaution: relatively nonspecific -> decreases absorption of other drugs
What are contraindications for beta-blocker use?
asthma
diabetes
AV block
take care with
- heart failure
- metabolic syndrome
what are fibrates - give example
mechanism of action
results
precaution
fibrates - used as adjunct to dietary changes for hypertriglyceridaemia
agonist at nuclear receptors - regulate gene expression
- increase synthesis of lipoprotein lipase
results
- moderate decrease in plasma TAG
- moderate increase in HDL
- variable effects on LDL
precaution: potential for liver toxicity - monitor serum aminotransferase
What are macroscopic pathological changes seen after MI
- hours
- 1-2 days
- 1-2 weeks
- 6-8 weeks
hours - nothing
1-2 days - pale yellow area
1-2 weeks - more pale area; patchy surrounding haemorrhage
6-8 weeks - scar tissue formed; thinned out wall
What are possible mechanisms behind nitrate tolerance? (4)
- “classic” - depletion of thiols required for NO production from GTN
- increase release/sensitivity to constrictors
- increased endothelial free radical production - reduce NO bioavailability
- decrease activity of muscle mitochondrial ALDH2; decreased NO production; increased free radicals
What are some adverse effects of ivabradine
- brightness in visual field (also have I-funny current in retinas) - conduction abnormalities
What are some adverse effects of nitrates
- postural hypotension
- headache; flushin
- excessive arterial dilation in head/neck
- reflex tachycardia - with large drop in BP
- react with viagra -> viagra decreases phosphodiesterase (breaks down cGMP) + NO increases production of cGMP -> heaps of cGMP and fatal drop in BP
What are some serious adverse effects of statins
When must you withhold statins?
reduce Q10 production -> can stop mitochondria functioning properly
- cause skeletal and cardiac muscle complications -> heart failure
withhold
- pregnancy
- infection
- pre-surgeery
- post-trauma
What are the 3 fates of cholesterol in the body?
- ester formation for storage in liver (then export as VLDL)
- ester - replaces the OH group at C3 with a fatty acid chain
- without OH group - will not insert into membrane - bile acid formation in liver
- liver synthesises bile salts
- which is then stored in gall bladder; then released to emulsify fatty meals
- bile: 3OH groups - detergent - membranes - C3 OH group lines up with polar heads of phospholipids
- cholesterol ensures that membranes are not too fluid
- rigid ring system - fine tunes membrane for 37C
What are the common sites of atherosclerosis in the coronary arteries?
Prinarily in the first few cm of LAD and LCX; along entire RCA
What are the consequences of increase Na+ and water retention by the kidneys in heart failure?
Increased pulmonary vein pressure -> pulmonary congesion Increased blood pressure -> oedema
What are the differences between stable and unstable angina
stable - occlusion >70%; symptoms with increased demand
unstable - occlusion >90%; symptoms even at rest
What are the long run consequences of increases SNS activation in heart failure?
Deleterious
- vasoconstrction
- icreases afterload on the heart
- ventricular arrhythmias
- direct toxic effect on myocardium of NA
What are the main sites of action for beta-blockers?
heart -> reduce heart rate; contractility
kidney - reduce renin release
What are the two forms of true aneurysm?
Saccular - berry aneurysm = only on one side = focal dilation
fusiform - entire circumference (most atherosclerotic aneurysms)
What are thrombi in the heart chamgers/aortic lumen called? Why are they formed?
mural thrombi form due to abnormal myocardial contraction
what changes in ventricular volumes are seen in cardiac decompensation? why does decompensation occur?
decompensates because LV dilates to extent that it can no longer maintain SV
- so have fall in systolic function and SV
See-
decreased ejection fraction
increased LVEDV
increased LVESV
What combination of drugs used for ischaemic heart disease must you never combine
beta-blocker + cardio-selective calcium channel blocker (verapamil)
-> both cardiodepressive
(can combine beta-blocker and vascular-selective - because this may cause tachycardia as well - can have atenolol + nifedipine)
what conditions cause increased preload on the heart?
mitral regurgitation
aortic regurgitarion
what conditions increase afterload in the heart?
hypertension
aortic stenosis
What do thrombi look like in aneurysms?
Have lines of Zahn
- grossly apparent laminations
- alternating pale layers of platelets mixed with some fibrin; and dark with more RBC
What do you often have to combine GTN with?
- combine with beta-blocker
- > GTN causes reflex tachycardia
- combine with N-acetyl cystein (because of tolerance)
What drugs are used in ishaemic heart disease (4)
nitrates
calcium channel blockers
beta blockers
ivabradine
What effect do ACE inhibitors have in heart failure?
ACE - blocks coversion of AngI to AngII
- reduce vasoconstriction
- reduce aldosterone production -> reduce salt; water retention
- reduce cardiac hypertrophy
ACE = kininase II - reduce bradykinin breakdown -> increase bradykinin -> vasodilation
What effects does angiotensin II have? (5)
- increases sympathetic activity
- increases tubular Na+; Cl- reabsorption; H2O retention; K+ excretion
- increases aldosterone secretion (further stimulating Na+; H2O retetion)
- increases vasoconstriction -> inc BP
- increases ADH secretion by pituitary -> increases H2O absorption in collecting duct
What is a short acting nitrate? Long acting nitrate?
GTN - short acting (glyceryl trinitrate)
isosorbide dinitrate - longer acting
what is activated protein C
a natural anti-coagulant -> neutralises factor V
What is arteriosclerosis? What does it include
General term for thickening and hardening of walls of arteries
Includes
- atherosclerosis
- age related changes (may be exacerbated by high BP)
What is claudication in the legs?
Periods of ischaemia due to atherosclerosis + exertion
what is coronary steal? how do you avoid it?
if you vasodilate a coronary artery:
- blood will move away from poorly perfused area to well perfused -> takes blood away from ischaemic area
NO avoids this - because is a venodilator
what is dyslipidaemia?
abnormal lipid profile
includes
- hypercholesterolaemia
- hypertriglyceridaemia
- mixed hyperlipidaemia
What is familial hypercholesterolaemia? Clinical manifestation
Inherited dominant disorder
- mutations in LDL receptor gene -> elevate circulating LDL -> infiltrate arteries -> stops inhibition of cellular synthesis of cholesterol -> liver isn’t getting any LDL in so keeps making it (HMG-CoA reductase is not inhibited)
- atherosclerosis before puberty
- early heart attacks
- xanthomas: thick; waxy plaques of skin over elbows; knees; buttocks
what is lipoprotein lipase?
enzyme found on outside of muscle/adipose tissue which use fats as energy source
- take up fats from lipoproteins
What is Smith-Lemli-Opitz syndrome?
Defective enzyme that is used in the last step of cholesterol synthesis (squalene -> cholesterol)
- multiple malformations + behavioural problems -> illustrates importance of cholesterol in development
What is the aim of pharmacological treatment of ischaemic heart diseases?
relieves symptoms
Want to either:
Increase O2 supply
- dilate coronary arteries
- reduce heart rate
Decrease O2 demand
- reduce preload on heart (dilate veins; reduce venous return)
- reduce afterload on heart (dilate arterioles; decrease resistance)
What is the main risk factor for aortic dissection?
high BP also: Marfan’s
what is the mechanism of action of ezetimibe?
- binds specific sterol transporter -> specifically inhibits cholesterol absorption in the intestine -> lowers LDL
- doesn’t affect absorption of anything else
What is the primary role of chylomicrons and VLDL
deliver triacylglycerols to tissues
what is the primary role of HDL
scavenge cholesterol
what is the primary role of LDL
donate cholesterol
What is the significance of ApoA-I (apolipoprotein)
marks HDL
activates LCAT - converts phospholipids from cell membranes -> adds cholesterol to phospholipid to make an ester -> fills middle of HDL
What is the significance of ApoB-100
found on VLDL; LDL
- binds to LDL receptor on liver
what is the significance of ApoC-II
found on chylomicrons; VLDL; HDL
activates lipoprotein lipase
What is the two types of infarction in cardiac muscle? How long do they take to develop; and which direction What is their usual cause?
Transmural - involves full/nearly full thickness of the wall
- Develop over 6-8hrs
- begin in subendocardium and move outwards
- Usual cause: thrombosis following acute plaque event in atheromatous artery
Subendocardial - damage limited to subendocardium (inner 1/3 of wall)
Two types:
- regional (occurs with early intervention of local atherosclerotic narrowing)
- circumferential (occurs with >1 territory) -> only if all 3 vessels are occluded; or if there is prolonged reduction in systemic BP (shock)
What leads to an MI or sudden death?
Acute plaque event
- atherosclerosis with a unstable plaque
- rupture/fissure of the plaque -> blood exposed to subendothelial tissues -> thrombus formation -> platelets activated by exposed collagen -> adhesion; secretion; segregation -> tissue factor activates coagulation cascade -> fibrin is formed from fibrinogen
Which cells are most vulnerable to ischaemia?
Neurons
cardiac muscle cells (20mins)
Which classes of drugs are used symptomatic relief in heart failure?
Ionotropes - beta-adrenoceptor agonists; PDE inhibitors; glycosides
Diuretics
Venodilators
Which drug modifies risk of MI?
Only ivabradine
Which drugs improve mortality in heart failure?
beta blockers
ACE inhibitors
aldosterone antagonists
Which drugs increase O2 supply to the heart in ischaemic heart disease?
Drugs that reduce heart rate
- ivabradine
- betablockers
- calcium channel blockers
Which part of the cardiac muscle is most susceptible to ischaemia?
Subendocardial muscle
- endocardium: perfused through wall
- cardiac vessels run in epicardium; then myocardium;
- subendocardium is furthest away - also subject to greatest pressure; impairing flow
Whihc ionotropes are used in acute heart failure?
beta-adrenoceptor agonists
PDE inhibitors
Why do people vary in their probability of atherosclerosis?
Variation in activity of HMG-CoA reductase pathway -> we all regulate feedback inhibition of HMG-CoA differently
Why does cardiac failure lead to oedema?
kidneys can take care of increases of end diastolic pressure of 20-30mmHg; but above this; pressure in the capillaries is too great and fluid leaks into interstitium
in cardiac failure; body wants to increase EDP to maintain CO kidneys can take care of this to a certain point; but not beyond that
also exacerbated by Na+ ad water retention by kidneys
Why does pain occur in stable angina?
Hypoxia on exertion -> lactic acid + adenosine are formed -> act on nerve endings to cause pain
