7.1 - 7.4 Flashcards
Cholesterol is an ___pathic molecule
Amphipathic
I.e. mostly hydrophobic molecule with single hydroxyl group (hydrophilic) = hydrophobic and hydrophilic.
Cholesterol is a ___pathic molecule
Amphipathic
I.e. mostly hydrophobic molecule with single hydroxyl group (hydrophilic) = hydrophobic and hydrophilic.
Cholesterol is a precursor to ___ hormones, ___ salts, and vitamin ___
Steroid hormones
Bile salts
Vitamin D
Cholesterol is a component of lipoproteins including:
Chylomicrons
VLDL
LDL
HDL
Fates of cholesterol produced in liver
Transport - into VLDL for transport to tissues.
Bile acids - amphipathic molecule to emulsify fats.
Steroid hormones/vitamin D.
Membranes - make membrane LESS fluid.
Cholesterol synthesis
Acetyl-CoA+Acetyl-CoA = HMG CoA.
HMG CoA by HMG CoA reductase to mevalonate to isoprene to … cholesterol.
Cholesterol negatively feeds back on HMG-CoA reductase.
How is cholesterol carried from one site in the body to another?
Cholesterol is not soluble in aqueous medium.
Esterify to cholesterol ester -> more hydrophobic!
Then incorporate cholesterol ester into lipoproteins!
Process of lipid transport
Diet: TAG and cholesterol-ester from diet -> chylomicrons -> transport to tissues -> chylomicron remnants - uptake by liver receptors.
In liver: VLDLs package TAG and cholesterol-ester made in liver, transport TAG to tissues (removed by lipoprotein lipase!) - VLDL remnants (called IDLs) taken up by liver.
OR VLDL may remove lipoprotein to change into LDL! - LDL circulates and delivers cholesterol-ester to tissues.
HDL = scavenger that takes up free cholesterol, esterifies and takes back to liver for bile salt production.
Chylomicrons are formed in ___ mucosa and carry ___ to tissues via lymphatics and blood
Intestinal
Carry TAGs from diet
Apolipoproteins of chylomicrons
ApoE - uptake of chylomicron remnants.
ApoCII - activates lipoprotein lipase - TAGs broken down to FAs in tissues.
Apolipoproteins of chylomicrons
ApoE - uptake of chylomicron remnants.
ApoCII - activates lipoprotein lipase - TAGs broken down to FAs in tissues.
VLDLs are formed in the ___, and carry ___ from liver to tissue via blood.
Liver
Carry TAGs from liver
VLDLs also have ___
ApoCII - activates lipoprotein
Same as chylomicrons
LDLs are derived from ___ and transport ___ to tissues
VLDLs
Transport cholesterol to tissues!
Most ___ are missing from LDLs
Lipoproteins!
Maintains ApoB-100 for structure and uptake.
HDLs are formed in ___ and ___, and are involved in ___ cholesterol transport.
Formed in liver and intestine.
Reverse cholesterol transport.
Can act on macrophages to prevent foam cell formation!!
In summary, chylomicrons and VLDLs are high in ___, and LDLs and HDLs are high in ___
TAGs
Cholesterol
Synthesis of cholesterol esters by ___ in liver, and ___ in plasma.
ACAT in liver helps VLDL form.
LCAT in plasma helps HDL scavenge cholesterol from membranes.
LDLs are derived from ___ and transport ___ to tissues
VLDLs
Transport cholesterol to tissues!
Synthesis of cholesterol esters by ___ in liver, and ___ in plasma.
ACAT in liver helps VLDL form.
LCAT in plasma helps HDL scavenge cholesterol from membranes.
Dyslipidaemias
Hypercholesterolaemia - ↑ total cholesterol (i.e. free AND esterified) in blood.
Hypertriglyceridaemia - ↑ blood levels of triglycerides (TGs)/triacylglycerols (TAGs).
↓ HDL-cholesterol
In atherosclerosis, oxidised ___ are taken up by scavenger receptors on ___
LDLs
Macrophages
HMG CoA reductase is the ___-___ enzyme in cholesterol synthesis
Rate-limiting
___ are competitive inhibitors of HMG CoA reducase.
Statins
Inhibition of HMG CoA reductase may lead to a reduction in coenzyme ___
Q10!
Supplements do not appear to be very effective though in preventing myotoxicity due to Q10 (mitochondrial energy transfer) deficiency though.
Inhibition of HMG CoA reductase may lead to a reduction in coenzyme ___
Q10!
Supplements do not appear to be very effective though in preventing myotoxicity due to Q10 (mitochondrial energy transfer) deficiency though.
Acute IHD (3 types)
Unstable angina
Myocardial infarction
Sudden cardiac death
Chronic IHD (2 types)
Stable angina
Chronic myocardial ischaemia
Primary pathology underlying all IHD is coronary artery ___
Atherosclerosis
The heart has an ___ layer of vessels, which travel from ___ to ___
External layer
From outside to inside
So infarcts occur at inside first.
The subendocardium is vulnerable. A ___-___ infarct can progress to a ___ infarct.
Non-transmural -> transmural.
If there is permanent occlusion of coronary artery - transmural and spread to epicardium
The ___ is generally not affected by ischaemia because it:
Is oxygenated partially by some direct diffusion of blood in ventricles.
The anterior wall of the heart and 2/3 of septum is supplied by ___
LAD
The lateral wall of the heart is supplied by ___
LCX
The posterior wall (inferior wall) and 1/3 of septum is supplied by ___
PD
MI is most commonly caused by an acute ___ ___, due to rupture of atherosclerotic plaque
Acute plaque event
In 0 to 30 minutes of occlusion/ischaemia - angina/irreversible injury:
NO macroscopic or microscopic changes.
But intracellular changes seen on EM (mitochondrial swelling, myofibril relaxation).
Functional - loss of contractility.
May see ECG changes!
From 30 minutes to 12 hours of occlusion/ischaemia - IRREVERSIBLE injury:
Disruption of cell membrane called sarcolemma.
Leaking of cardiac proteins - troponin and creatine kinase..
Leaking of current -> STEMI or NSTEMI
Microscopic can start to see coagulative necrosis, and faint eosinophilia.
Macroscopic may see no changes!
STEMIs are associated with ___ infarcts and NSTEMIs are associated with ___ infarcts
STEMIs - transmural
NSTEMIs - non-transmural
Cardiac enzymes may be detected __ hours post infarction
3-4 hours
Early complications of infarction - from 30 minutes to 4 hours:
Arrhythmia
Cardiac failure - because myocytes cannot contract properly
From 12 hours to 24 hours of infarction - necrosis and early acute inflammation.
Neutrophils in vessels.
Contraction band necrosis - form stripes like irregular striations.
Vascular congestion and reddening!!!
From 1 day to 3 days - acute inflammation
Neutrophils and necrosis -> PUS
Macroscopic - see soft yellowing.
Troponin at peak after 1 day.
Complications from 1 day to 3 days post infarction
Arrhythmia Cardiac failure Rupture Mural thrombus Pericarditis
From 3 days to 7 days post infarction - end of acute inflammation and start of early granulation
Macrophages ingest dead myocytes
Fibroblasts and new vessels start to appear
Collagen starts being deposited at 5-6 days - stronger wall
Macroscopically - central yellowing and red rim (early vascular granulation tissue).
From 1-8 weeks post infarction - early and late granulation tissue
Initially, high vascularity and high cellularity with little collagen.
Slowly -> reduction in cells and vessels -> more collagen (strength).
Macroscopic at 3 weeks - some redness but flecks of grey/white collagen at margin of infarct.
Macroscopic at 6 weeks - grey/white translucent.
From 1-8 weeks post infarction - early and late granulation tissue
Initially, high vascularity and high cellularity with little collagen.
Slowly -> reduction in cells and vessels -> more collagen (strength).
Macroscopic at 3 weeks - some redness but flecks of grey/white collagen at margin of infarct.
Macroscopic at 6 weeks - grey/white translucent.
Complications from 1 to 8 weeks post infarction
Arrhythmia
Cardiac failure
Mural thrombus
Aneurysm
8 weeks beyond post infarction
Thin and pale white fibrotic wall at infarct
May see aneurysm
8 weeks beyond post infarction
Thin and pale white fibrotic wall at infarct
May see aneurysm
Unstable angina is due to an ___ ___ ___, that resolves by ___
Acute plaque event
Resolves by thrombolysis
A chronic atherosclerotic narrowing of vessels contributes to ___ ___ ___
Chronic myocardial ischaemia
(Normal wall and small vessels - may see small areas of subendothelial ischaemia/patchy myocyte necrosis and replacement by fibrosis).
Types of dyslipidaemia
Hypercholesterolaemia (high total cholesterol, including LDLs)
Hypertriglycerideaemia (high TAGs)
Mixed hyperlipidaemia (high LDL and TAGs)
Changes in diet to treat hypercholesterolaemia:
Mediterranean diet – reduce risk (independently of LDL cholesterol).
Plant sterol esters – reduce LDL cholesterol.
Fish oils – reduce triglycerides, increase HDL cholesterol.
Treatment of hypercholesterolaemia with statins
• Reduce mevalonic acid synthesis and therefore cholesterol synthesis:
o Body senses reduction in cholesterol -> compensatory increase in hepatic LDL receptors.
o Uptake of LDL (with bound cholesterol) from blood to liver -> reduced plasma cholesterol and LDL (and TGs to lesser extent).
o Increases plasma HDL (relative to LDL).
Note that doubling of doses has ___ additional effect on reducing LDL cholesterol - called a ___ effect
Little additional effect
A ceiling effect!
No point increasing dose too high - only increase side effects for no large benefits
Statins are indicated in
Hypercholesterolaemia (high LDL). Mixed hyperlipidaemia (high LDL, TGs).
Statins do not have an immediate effect so may lead to poor ___
Compliance!
Precautions of using statins: avoid ___ juice
Grapefruit juice - both use Cyt p450 pathway for metabolism!
Note that statin levels are ___ by some antibiotics/ antifungals/ fibrates, and are ___ by phenytoin, barbiturates, glitazones
Increased! - because they share Cyt p450
Decreased! - because they induce Cyt p450
Statins may cause minor increases in creatine kinase leading to muscle ___
Pain and tenderness
Side effects of statins
Common - mild GI symptoms, headache, insomnia, dizziness
Rare - myopathy, rhabdomyolysis, renal failure, liver failure.
Contraindications of statins
Pregnancy!
Impaired foetal myelination.
Contraindications of statins
Pregnancy!
Impaired foetal myelination.
And withhold during infection/pre-surgery/post-trauma due to interactions with some antibiotics etc.
If patient has renal failure of hits ceiling effect of statins, can use ___/___
Bile acids sequestrants/resins.
E.g. cholestyramine, colestipol.
Bile acids sequestrants/resins are taken orally and with ___
Meals!
Bile acids sequestrants/resins are NOT ___, but bind to bile acids preventing gut ___ of cholesterol
Absorbed - hence, taken with meals
Absorption of cholesterol
Bile acids sequestrants/resins reduce absorption of cholesterol from meals leading to:
Increased demand for cholesterol for bile acid synthesis - removal of LDL from plasma to produce cholesterol.
Indications for bile acids sequestrants/resins
Hypercholesterolaemia
Mixed hyperlipidaemia
Side effects of bile acids sequestrants/resins
Common - abdominal discomfort, bloating, constipation, flatulence
Rare - increased TGs, faecal impaction, decreased absorption of fat soluble vitamins.
Bile acids sequestrants/resins also decrease absorption of other ___!
Drugs!
So take drugs much earlier or later (hours) than resins
Ezetimibe inhibits cholesterol ___ in intestine by binding to a specific sterol transporter
Absorption
Ezetemibe does NOT affect absorption of ___ or ___ soluble vitamins
Bile acids or fat soluble vitamins
Or other drugs
Ezetimibe causes a reduction in ___
LDL
Some side effects of ezetimibe:
Diarrhoea, headache, tiredness.
Allergic reactions, severe joint or stomach pain.
Nicotinic acid/niacin is vitamin ___
B3
The mechanism of niacin is unknown but it:
Decreases secretion of VLDL from liver.
Reduces plasma LDL and TAGs (so also used for mixed hyperlipidaemia).
Increases HDL
And novel effect of lowering potentially atherogenic lipoprotein (a) - formed from LDL, found in plaques and is pro-coagulant.
The novel effect of niacin c.f. other drugs used for hypercholesterolaemia is:
Lowers potentially atherogenic lipoprotein (a) - formed from LDL, found in plaques and is pro-coagulant.
Common side effects of niacin:
Vasodilation, flushing and hypotension.
Nausea and vomiting.
Initially unpleasant but tolerance develops to flushing and gastric upsets.
Rare effects = itching, glucose intolerance, uric acid retention.
Common side effects of niacin:
Vasodilation, flushing and hypotension.
Nausea and vomiting.
Initially unpleasant but tolerance develops to flushing and gastric upsets.
Rare effects = itching, glucose intolerance, uric acid retention.
Treatment of HYPERTRIGLYCERIDAEMIA (others were used for hypercholaterolaemia) with fibrates: fibrates are ___ agonists
PPARa agonists
Examples of fibrates
Gemfibrozil, fenofibrate
Fibrates are agonists of ___, activation increases synthesis of ___
PPARa nuclear receptors
Increases synthesis of lipoprotein lipase - which increases lipolysis of lipoprotein TGs to FAs
Fibrates have ___ effects on LDL, so not first line in patients with hypercholesterolaemia, only for patients with hyperTG exclusively
Variable effects!
Side effects of fibrates
Common - nausea, dry mouth, headache, rash
Rare - arrhythmias, gallstones, photosensitivity, impotence, depression
Fish oils e.g. eicosapentaenoic acid/docosahexaenoic acid - reduce ___ and ___, and cause modest increase in ___
Reduce TAGs and VLDL
Increase HDLs
Summary of drugs regulating serum lipids:
Statins in liver – inhibit endogenous synthesis of cholesterol.
Bile acid resins and ezetimibe – mainly in intestine to decrease absorption of dietary cholesterol.
Niacin - unknown mechanism, but reduces LDL and TGs and increases HDL and novel effect of reducing atherogenic lipoprotein A
Fibrates at lipoprotein lipase – increase hydrolysis of triglycerides into FFAs.
Fish oils decrease TAGs and VLDLs and increase HDLs.
Summary of drugs regulating serum lipids:
Statins in liver – inhibit endogenous synthesis of cholesterol.
Bile acid resins and ezetimibe – mainly in intestine to decrease absorption of dietary cholesterol.
Niacin - unknown mechanism, but reduces LDL and TGs and increases HDL and novel effect of reducing atherogenic lipoprotein A
Fibrates at lipoprotein lipase – increase hydrolysis of triglycerides into FFAs.
Fish oils decrease TAGs and VLDLs and increase HDLs.
Coronary arteries fill during ___
Diastole
To increase coronary blood flow, ___ coronary arteries and/or ___ heart rate.
Dilate coronary arteries
Decrease heart rate - more diastole, less compression of vessels, more filling.
Oxygen demand of heart depends on cardiac ___
Work - influenced by HR, SV, preload and afterload
In angina, during exercise - arterioles cannot ___, and arteries dilate ___ -> insufficient oxygen supply!
During exercise, demand increases but arterioles cannot dilate (already maximally dilated, decreased coronary flow reserve) and arteries dilate minimally (due to stiffness and coronary artery disease e.g. atherosclerosis) -> insufficient oxygen supply.
Dilate coronary arteries or decrease HR?
Difficult to dilate coronary arteries because atherosclerosis and likely maximally dilated!
Target HR!
Need to decrease oxygen demand of heart - but how?
Reduce HR/SV, reduce preload (dilate veins to reduce venous return), reduce afterload (dilate arterioles to decrease resistance).
Preload - use ___
Afterload - use ___
Myocardium work - use ___, ___ and ___
Preload - nitrates
Afterload - calcium channel blockers
Myocardium - calcium channel blockers, beta-adrenoceptor antagonists, ivabradine
Mechanism of action of nitrates
Nitrates are prodrugs -> biotransformation to active form to release NO - activate GC in vSMC - convert GTP to cGMP - dephosphorylation of MLC wich cannot interact with actin - relaxation!
Nitrates cause relaxation of ___ vessels
ALL vessels, but MAINLY VEINS!
Decrease preload.
Minor sites = large arteries to decrease afterload (but minimal due to coronary artery disease) and coronary arteries.
GTN is a ___ acting nitrate, a prodrug activated by first pass metabolism
Short-acting
Must be stored carefully because adsorbed by plastic, unstable and light sensitive!
Isosorbide dinitrate is a ___ acting nitrate, a prodrug.
Long-acting
Isosorbide dinitrate is a ___ acting nitrate, a prodrug.
Long-acting
Adverse effects of nitrates
Reflex tachycardia!!!
!!! So used in combination with beta blockers or cardiac selective calcium channel blockers!!!!!
Effects on other smooth muscle
If excessive vasodilation - postural hypotension and venous pooling
Headache, flushing
___ develops to continuous use of nitrates
Tolerance
Mechanism = depletion of tissue thiols required for NO production from GTN - use N-acetyl cysteine to restore effect.
DRUG-FREE PERIOD OVER NIGHT to minimise tolerance!
Calcium channel blockers may be vascular or cardiac selective: effects =
• Block Ca2+ entry into HEART (SA and AV nodes, muscle) through L-type channels:
o Decreased HR = increased supply.
o Decreased HR, SV, CO = decreased demand.
o Mostly verapamil and diltiazem.
• Block Ca2+ entry into VESSELS through voltage operated (L-type) and receptor operated channels.
o Arterial dilation = reduced afterload and demand (heart work).
o Nifedipine and felodipine (vascular selective – all end in “dipine”, all dihydropyridines).
Adverse effects of calcium channel blockers depend on selectivity:
o Verapamil (cardiac selective):
Flushing, headache, oedema (if excessive dilation).
Bradycardia, atrioventricular block.
Therefore, cardiac selective calcium channel blockers NEVER taken with β-blockers – NEVER combine drugs with cardiodepressive effects.
o Nifedipine (vascular selective):
Flushing, headache, oedema (if excessive dilation).
Hypotension.
Reflex tachycardia – combine with β-blockers.
Beta blockers act on __/__ nodes and on cardiac ___
SA and AV nodes (decrease HR) and on cardiac muscle (decrease contractility and SV)
Examples of beta blockers as first line therapy for prophylaxis of IHD
o Atenolol – selective (cardiac β1)
Cardiac selective (β1) is better to avoid non-selective effects like fatigue and bronchoconstriction (due to β2).
o Propranolol – non-selective (β1/ β2)
Novel therapy - ivabradine - for IHD
- “Pure” heart rate reduction i.e. ONLY HR.
- “Specific” and selective inhibition of inward sodium-potassium If (funny) current in sinus node.
- Decreases velocity of diastolic depolarization – decreases gradient of If current slope (increases duration to threshold) -> slow APs and slow HR.
- Decreases myocardial oxygen demand and increases oxygen supply.
Ivabradine appears to be the first drug that can ___ disease
MODIFY - decrease risk of MI and decrease need for revascularisation.
Other drugs are NOT disease-modifying.
Treatment for VARIANT angina:
• Relieve coronary spasm with short acting nitrate.
• Prophylaxis with dihydropyridine (vascular selective) Ca2+ channel blocker.
• Β-adrenoceptor antagonists contraindicated.
o Vasospasm via α-adrenoceptor may be worse if β2-mediated coronary dilation blocked.
Combination therapy is often required for prophylaxis of angina:
o Maximise effects to increase supply and decrease demand.
o Minimise adverse effects (e.g. nitrates cause reflex tachycardia but atenolol (β1-specific blocker) or verapamil (cardiac selective calcium channel blocker) decrease HR).
