Flashcards in Pharmacology Deck (320):
what 2 endogenous substance act on the B1-adrenoceptors in the heart?
noradrenaline (sympathetic transmitter)
what G protein do B1-adrenoceptors in the heart couple to?
when a B1-adrenoceptor is stimulated, what does the Gs coupled protein do?
acitvates adenylyl cyclase to increase intracellular cAMP concentration
stimulates pKA (within myocytes)
what does increasing intracellular cAMP concentration within the pacemaker cells do?
increases slope of pacemaker potential and so increases heart rate
(positive chronotrophic effect)
what endogenous substance acts on M2 muscarinic cholinoreceptors in the heart?
What G protein do M2-adrenoceptors in the heart couple to?
when a M2 muscarinic receptor is stimulated, what does the Gi coupled protein do?
1. decreases activity of adenylyl cyclase to decrease intracellular concentrations of cAMP
2. opens potassium channels to cause hyperpolarisation of SA node
what does decreasing intracellular concentrations of cAMP and opening potassium channels within pacemaker cells do?
decreases slope of pacemaker potential and so decreases heart rate
(negative chronotropic effect)
what are the 3 internodal pathways between the SA node and the AV node? (contained within the right atrium)
anterior internodal pathway
middle internodal pathway
poterior internodal pathway
what is pathway goes to the left atrium from the SA node?
(apart from cell-cell spread of excitation through gap junctions)
anterior interatrial myocardial band
what does the bundle of his split up into?
right bundle branch
left bundle branch (which splits into anterior division and posterior division)
what is the hierarchy of pacemakers?
SA > AV > other cells within the heart
why is it necessary that the AV node can produce an AP?
in case the SA node fails
why is it necessary that other cells within the heart can produce an AP? (ie like within the conducting fibres)
in case both the SA and AV nodes fail
what is the inwards current of the pacemaker potential also known as?
what stimulates the inwards current of the pacemaker potential? (funny current)
(ie turning resting potential negative)
what does blocking HCN (hyperpolarisation-activated cycline neucleotide gated) channels do to the pacemaker potential slope?
decreases the slope
(negative chronotrophic effect)
what does ivabradine do?
a selective blocker of HCN channels so slows the heart rate down
what medical condition is ivabradine used in and why?
because slower rate reduces O2 consumption and so reduces coronary artery supply requirement
what does isoprenaline do?
a agonist of B-adrenoceptors and so increases intracellular cAMP concentration and so increases heart rate
what do thyroid hormones do to heart rate?
increase heart rate
(positive chronotrophic effect)
what does adenosine do to the heart rate?
decreases heart rate
(negative chronotropic effect)
what does nitric oxide do to the heart rate?
increases heart rate
(positive chronotrophic effect)
what are the 6 effects of the sympathetic system on the heart?
1. increases heart rate
2. increases contractility
3. increases conduction velocity in AV node (decreases delay)
4. increases automacity (tendancy for non-nodal regions to acquire spontaneous activity)
5. decreases duration of systole
6. decreases cardiac efficiency (with respect to O2 consumption)
what are the 4 effects of the parasympathetic system on the heart?
1. decreased heart rate
2. decreased contractibility
3. decreased conduction in AV node (increased delay)
4. overaction may cause dysrhythmias in the atria (not fatal)
what is the Frank-Starling mechanism?
the more the myocardium is stretched, the greater force it exerts upon contraction
(despite of autonomic control)
[ie the greater the venous return, the greater the stroke volume]
what autonomic control can tweak the frank-starling curve?
what happens to the frank-starling curve in cardiac failure?
curve fails as force is not able to match the venous return (stretch)
what 3 factors contribute to increased venous return? (and therefore increased stretch)
1. increased skeletal muscle activity
2. adrenergic effects on blood vessels (increased venous tone)
3. respiratory pump (increased depth and freq)
what does increased intracellular calcium cause?
what is excitation coupling?
coupling mechanical force to electrical excitation
for the action potential to excite a ventricular muscle cell what must it do when it sweeps across the cell?
dive down into the T-tubules
during depolarisation of a ventricular muscle cell (fast Na influx) what happens?
voltage-gated L-type Ca channels located in the T tubule membrane are opened by depolarisation and let a small amount of Ca in
what does the small calcium influx within a ventricular muscle cell cause?
the activation of RyR (ryanodine) receptors which cause the release of large amounts intracellular calcium from the SR.
what is the process called by which RyR receptors in the ventricular muscle are stimulated cause the release of calcium from the SR?
Ca-induced Ca release
for contraction within the ventricular muscle cell to occur what does calcium activate?
once the myofilaments within the muscle cell have been activated what occurs?
the Ca is removed from the cytoplasm by the SR CA ATPase (SERCA) and the sarcolemma Na/Ca exchanger
what does the decreased intracellular concentration of calcium after myofilament activation cause?
what do positive chronotropic drugs/hormones do to the calcium transients within the cardiac myocyte?
cause bigger and faster calcium transients
what is the function of the RyR within the myocyte?
when stimulated by calcium cause the Ca-induced Ca release from SR
what is the function of SERCA 2a within the myocyte?
removal of Ca at the end of a beat (puts Ca++ back into stores
what are the 4 sites of protein kinase A action within the myocyte?
RyR (ryanodine receptor)
LTCC (L-type calcium channels on T-tubule membrane)
what does protein kinase A phosphrylation of LTCC cause within the myocyte?
increases trigger calcium and so increases Ca-induced Ca release (causing increased force of contraction)
what does protein kinase A phosphorylation of RyR do within the myocyte?
increases size of Calcium transient (ie amount leaving SR) and therefore increases force of contraction
what does protein kinase A phosphorylation of PLB do?
increases uptake by SERCA and so:
1. accelerates relaxation (makes contraction shorter)
2. increases SR calcium content
what is the function of troponin?
regulates the actin/myosin interaction using calcium
what does protein kinase A phosphorlation of troponin do?
phosphorylation of troponin reduces the affinity for calcium, there is a minor reduction in contraction but this accelerates relaxation
what is the principal determinant of calcium binding to troponin C to cause contraction?
the rate calcium diffuses from the SR
(ie phosphorylation of RyR)
what is the principle determinant of the unbinding of calcium once a contraction has occured?
phosphorylation of troponin
what is dobutamines effect on the heart?
selective b1-adrenoceptor agonist so increases force and rate
when is exogenous adrenaline used?
during cardiac arrest
emergency treatment of asthma
when is dobutamine used?
for acute, but potentially reversible, heart failure
(eg following cardiac surgery)
why are b-1 adrenoceptor agonists regarded as 'toxic'?
because long term stimulation of sympathetic system causes heart failure
what is propanolol?
a non-selective b-blocker
(antagonist of b1 and b2 adrenoceptors)
at rest, what is the effect of b-adrenoceptor antagonists on the heart and why?
little effect on rate, force
this is due to the sympathetic system not being too active during rest
during exercise, what is the effect of b-adrenoceptor antagonists on the heart?
rate and force are significantly depressed
coronary vessel diameter are marginally vasodilated
(as myocardial O2 requirement falls there is more effective oxygenation of the heart)
what do b2-adrenoceptors stimulation cause on the coronary vessels?
what is atenolol?
a selective B1-blocker
what is metoprolol?
a selective B1- blocker
what are the 4 clinical uses of B-adenoceptor antagonists?
4. heart failure
what are the 6 adverse effects of b-blockers?
(* which have a lesser risk is B1 selective agents are used)
2. aggravation of cardiac failure
3. bradycardia (or heart block)
4. hypoglycaemia* (in patients with poorly controlled diabetes)
5. fatigue (due to decreased CO and skeletal muscle perfusion)
6. cold extremities (loss of vasodilation in cutaneous vessels)
why might b-blockers cause aggravation of cardiac failure?
patients with heart disease may rely on sympathetic drive to maintain an adequate CO for perfusion of their body tissues
what is atropine?
a non selective muscarinic receptor antagonist
what are the effects of atropine on the cardiovascular system?
1. increase in heart rate (modest in normal subjects, pronounced in athletes who have increased vagal tone)
2. no effect on TPR (no parasympathetic innervation to blood vessels)
3. no effect upon the respone to exercise
what are the 3 clinical uses of atropine?
1. to reverse bradycardia following an MI (in which vagal tone is elevated)
2. as an adjunt to anaesthesia
3. in anticholinesterase poisoning (to reduce excessive parasympathetic activity
what is the pharmocodynamic effect of digoxin?
increases contractility of the heart?
what type of drugs are digoxin and dobutamine?
what is the clinical use of digoxin?
in heart failure
(especially in patients with AF- due to effects on AV node)
how does digoxin work?
1. blocks the sarcolemma Na/K ATpase which results in calcium unable to leave cell causing more to go into the SR
2. increases AV node refractory period
what effect does digoxin have on the autonomic system?
what happens if you give digoxin to a patient with hypokalaemia?
effects of digoxin are dangerously enhanced
what are the 2 most serious effects of digoxin?
1. excessive depression of AV node conduction- heart block
what is levosimendan?
a calcium-sensitiser: inotropic drug
how does levosimendan work?
1. binds to troponin C in cardiac muscle sensitising it to the action of calcium
2. causes vasodlation
what is the clinical use on levodimendan?
treatment of acute decompensated heart failure
what does contraction of vascular smooth muscle depend on?
intracellular concetration of calcium
in a vascular smooth muscle cell what are the 2 ways calcium concentration can be increased?
influx of Ca across membrane gradient (conc or electrical gradient)
Ca released from intracellular stores (eg SR)
in smooth muscle cell (very different to cardiac and skeletal muscle), how does calcium cause contraction?
1. calcium binds to calmodulin to form a calcium-camodulin complex.
2. this complex activates myosin light chain kinase (MLCK) which phosphorylates myosin-light chain.
3. the phosphorylated myosin-LK can form cross bridges and allow myosin and actin to slide over each other and contract.
how does relaxation occur in a vascular smooth muscle cell?
1. cGMP activates myosin-LC-phosphotase
2. myosin-LC-phosphotase strips a phosphate from the phosphorylated myosin-LC converting it into inactive myosin-LC.
3. the cross bridges break and relaxation occur
compare the functions of MLCK and MLC-phosphotase
MLCK phosphorylates inactive Myosin-LC
MLC-phosphotase strips a phosphate from active mysoin-LC
what 3 vasodilating substances work through NO production?
what type of manner does NO signal in?
paracrine (induces an effect in cells near by)
what does NO do within a vascular smooth muscle cell?
1. activation of guanylate cyclase
2. activates calcium-dependent potassium channels
what is the role of guanylate cyclase within a vascular smooth muscle cell?
(activated by NO)
converted GTP to cGMP
cGMP initiates the relaxation pathway
what happens when calcium-dependent potassium channels are activated?
cause potassium to leave the cell causing repolarisation.
this repolarisation closes voltage gated calcium channels and causes relaxation
what 2 ways can calcium-dependent potasssium channels become activated?
stimulation by NO
what is the function of organic nitrates?
relax all type of smooth muscle
why are organic nitrates a first choice for angina patients?
1. they redirect the blood from unhealthy vessels to healthy vessels to bypass the block
2. decreased myocardial oxygen requirement
why is there a decreased myocardial oxygen requirement when using organic nitrates?
decreased preload (due to reduced venomotor tone)
decreased afterload (de to reduced vasomotor tone)
how do organic nitrates redirect blood from unhealthy vessels to bypass blockages?
dilate collateral vessels
why are arterioles downstream to a blockage already fully dilated?
due to local factors such as hypoxia etc
what are the 2 main types of organic nitrates used in practice?
compare glyceryltrinitrate and isosorbide mononitrate in terms of length of acting?
GTN- short acting (30 min)
isosorbide mononitrate- long acting (4 hours)
compare glyceryltrinitrate and isosorbide mononitrate in terms of effect of first pass metabolism?
GTN- extensive first pass metabolism
isosorbide mononitrate- resistant to first pastt metabolism
how it GTN administered?
sublinguial tablet or spray or transdermal patch
how should organic nitrates be used for angina?
(GTN can also relieve attacks)
what can happen with repeated administration of organic nitrates?
tolerance- diminished effect
how can you minimise tolerance of organic nitrates?
(usually at night)
what is a common effect of organic nitrates which may occur initially?
headaches due to dilation of cranial circulation
what 3 things down regulate the production of endothelin?
what are bosentan and ambrisentan?
antagonists of the ETa receptor (which endothlin acts on)
when are bosentan and ambrisentan (antagonists of the ETa receptor) used?
in treatment of pulmonary hypertension
what is a long term effect of angiotensin II?
promotes cell growth
what are the 2 functions of ACE?
converts angiotensin I to angiotensin II
where is ACE found?
bound to the membrane of endothelial cells
what is the role of ace inhibitors?
block the conversion of angiotensin I to angiotensin II
compare the effect of ACE inhibitors in normal subjecs and hypertensive patients?
small fall in MAP in normal subjects
large fall in MAP in hypertensive patients (since in these patients renin secretion is usually enhanced)
what are the common adverse effects of ACE inhibitors?
initial hypotention (esp in patients on diuretics too)
dry cough (due to bradykinin accumulation)
what are the adverse effects of ACE inhibitors?
initial hypotention (esp in patients on diuretics too)
dry cough (due to bradykinin accumulation)
what is the role of AT1 receptor blockers (ARBs)?
competitevly block the agonist action of angeiotensin I at AT1 receptors
what are ACEIs and ARBs contraindicated in?
bilateral renal artery stenosis
if a patient has a intolerable dry cough with ACE inhibitors what drug should they be switched to?
(as there is no increase in bradykinin)
what are ACEIs and ARBs contraindicated in?
bilateral renal artery stnosis
what are the clinical uses of ACE inhibitors and ARBs? (and explain)
1. hypertension (reduces TRP and MABP)
2. cardiac failure (reduces TPR to decrease cardiac work load, also causes regression of LVH)
3. following an MI (same as above)
what are the clinical uses of beta-blockers?
1. angina (only stable and unstable)
because the decrease myocardial O2 requirement and increase the amount of time spent in diastole which improves perfusion
reduce MAP and reduced renin release from the kidneys
3. heart failure
decreases cardiac work load
what is the function of calcium antagonists?
prevent the opening of L-type channels in response to depolarisation, this limits calcium influx
in the SA node what do calcium antagonists do?
reduce heart rate by reducing rate of upstroke of the AP
in the AV node what do calcium antagonists do?
reduce rate of conduction
in the ventricles what do calcium antagonists do?
reduce force of contraction by reducing Ca in plateau phase
what are the 3 main calcium antagonists?
verapamil (cardiac selective)
amlodipine (smooth muscle selective)
what are calcium antagonists clinically used in?
hypertension (reduce TPR and MAP)
angina (coronary vasodilation)
dysrhthmias (supression of AV conduction)
which calcium antagonists are preferred for hypertension and why?
smooth muscle selective
to minimise unwanted effects on cardiac muscle (important in heart failure or heart block)
what is the length of acting for amlodopine?
what calcium antagonists is used in dysrhthmias?
what drug combination should be completely avoided in heart failure?
beta-blockers and verapamil
why do calcium antagonists work in variant angina? (unlike beta blockers)
variant angina is caused by episodic coronary spasms, so calcium antagonists work well by not allowing the cell to obtain the calcium required for a spasm
what are minoxidil and nicorandil?
potassium channel openers
how do potassium channel openers work?
work on vascular smooth muscle to open calcium-dependent K channels. this causes hyperpolarisation which switches off L-type calcium channels- causing relaxation of vascular smooth muscle
what is nicorandil used in?
(not used too commonly)
what is minoxidil used in?
hypertension (but only as a last resort)
what are the negative effects of minoxidil?
reflex tachycardia (prevented by a beta-blocker)
salt and water retention (alleviated by a diuretic)
what are prazosin and doxazosin?
what is the dunction of a1-adrenoceptor antagonists?
cause vasodilation by blocking sympathetic/hormonal effect on a1-adrenoceptors
what is the clinical use a1-adrenoceptor antagonists?
hypertension (especially if patient has prostatic hyperplasia)
what is the function of diuretics?
act on kidneys to increase the excretion of Na, Cl and H20
where do thiazide diuretics inhibit NaCl reabsorption?
where do loop diuretics inhibit NaCl reabsorption?``
ascending limb of hte loop of Henle
what is the main adverse affect of using thiazide or loop diuretics?
loss of K+
how is the loss of K+ due to thiazide or loop diuretics corrected?
co-administration of a potassium sparring diuretic
what are the clinical uses of thiazide diuretics? (eg bendroflumethiazide)
mild heart failure
what are the clinical uses of loop diuretics?
acute pulmonary oedema
chronic heart failure
name 6 classes of anti-hypertensive drugs?
name 4 classes of anti-anginal drugs?
name 3 classes of antithrombotic drugs?
antiplatelets (against platelets)
anticoagulants (against clotting factors)
fibrinolytics (dissolve preformed clots)
name 2 classes of anticholesterol drugs?
what is bendroflumethiazide?
what is furosemide?
a loop diuretic
what are the 4 side effects of diuretics?
1. hypokalaemia (tiredness, arrhythmias)
2. hyperglycaemia (diabetes)
3. hyperuricaemia (gout)
what are cardioselective b-blockers used in?
what are non-selective b-blockers used in?
what type of patients are beta blockers contraindicated in?
patients with reynaulds
what are the effects of beta blockers in short term heart failure vs long term heart failure?
beta blockers can worsen heart failure in short term
improve heart failure in long term
what are the 2 types of calcium antagonists?
dihydropyridines eg amlodipine
rate-limiting calcium antagonists eg verapamil, diltiazem
what can be the adverse result of giving beta blockers and rate-limiting calcium antagonists together?
full heart block
what type of arrhythmias are rate-limiting calcium antagonists useful in treating?
superventricular arrthymias (AF, SVT)
what is the main side effect of alpha blockers?
what is a rare, life threatening adverse reaction of ACE inhibitors?
(never give to a patient with previous angioneurotic oedema)
why should you avoid giving ACEI to women of childbearing ages?
they might not know they are pregnant yet, contraindicated in pregnancy
what type of drugs can pregnant women use to control pregnancy-induced hypertension?
calcium inhibitors and beta blockers
what type of heart failure can nitrates be used in?
acute heart failure not chronic
what is the function of antiplatelet agents?
prevent new thrombosis
(dont break down clots that have already formed)
when are antiplatelet agents used?
(patients at risk of MI/CVS)
what are the 3 main side effects of antiplatelet agents?
peptic ulcer (leading to haemorrhage)
aspirin sensitivity (asthma)
what is the function of anticoagulants?
prevent new thrombosis
how is heparin administered?
how is warfarin administered?
what clotting factors does warfarin block?
2, 7, 9, 10
what is warfarin used in?
what are the side effects of anticoagulants?
how do you control the dose of warfarin?
how do you reverse an overdose of warfrin? (ie if there is a haemorrhage)
what clotting factor does rivaroxaban inhibit?
what clotting factor does dabigatran inhibit?
what does clotting factor Xa do?
convert prothrombin (II) into thrombin (IIa)
name 2 fibrinolytic drugs?
when are fibrinolytic drugs used?
(Selected cases only)
what is the adverse side effect of fibrinolytic drugs?
when must you avoid using fibrinolytic drugs?
bleeding tendencies (eg haemophilla)
severe diabetic retinopathy
how do statins work?
block HMG CoA reductase
when are statins used?
(high risk of MI/CVA)
what are the possible side effects of statins?
myopathy (muscle ache)
rhabdomyolysis renal failure (renal muscle break down)
when are fibrates used?
low HDL cholesterol
what 2 drugs are anti-arrhythmic drugs?
digoxin can also be used in SVAs but arent technically anti-arrhythmic drugs)
what drug do you use in the acute phase of an SVT?
what are the 3 side effects of anti-arrhythmic drugs?
what are the 2 main effects of digoxin?
1. degree of AV node block
2. increased ventricular contraction
what are the side effects of digoxin?
bradycardia and heart block
ventricular arrhythmias (fatal)
how are non-polar lipids transported in the blood?
what ratio of LDL:HDL is strongly associated with cardiovascular disease? (atherosclerosis)
what are the 2 main sections of an lipoprotein?
what does the hydrophobic core of the lipoprotein contain?
esterified cholesterol and triglycerides
what does the hydrophilic coat of the lipoprotein contatin?
a monolayer of amphipathic cholesterol, phospholipids and one or more apoprotein
what are the 4 main lipoproteins?
what is the biggest lipoprotein in terms of diameter?
cholesterol within the hydrophilic coat of the lipoprotein are amphipathic. where does the hydrophobic part face and where does the hydrophilic part face?
hydrophobic part of cholesterol face into the centre of the sphere
hydrophilic part of the cholesterol face the aqeuous component of the blood
what apoproteins are associated with HDL?
what apoproteins are associated with LDL?
what apoproteins are associated with VLDL?
what apoproteins are associated with chyomicrons?
what are apoproteins?
markers which say if the lipoprotein is LDL or HDL
what is familial hypercholesterolaemia?
a genetic condition in which the patient is unable to clear LDL from the blood due to lack of LDL receptors on hepatocytes
what type of lipoproteins deliver triglycerides to muscle (for ATP) and adipocytes (for storage)?
apoB -containing lipoproteins
where are chylomicrons formed?
what is the function of chylomicrons?
transport dietary triglycerides to muscle and adipocytes
what is the 3 phase life cycle of an ApoB-containing lipoprotein?
2. intravascular metabolism
3. receptor mediated clearance
where does assembly of an ApoB-containing lipoprotein occur?
apoB100-containing lipoproteins: liver
apoB46-containing lipoproteins: intestine
what does intravascular metabolism of an apoB-containing lipoprotein involve?
hydrolysis fo the triglyceride core
what does receptor mediated clearance of an apoB-containing lipoprotein involve?
lipoprotein attaches to a receptor and is endocytsosed into the cell and removed
what needs to happen to the triglyceride to be absorbed in the intestine?
broken down into monoglyceride and free fatty acids
after absorption in the intestine what happens to the monoglyceride and free fatty acids?
triglyceride is resynthesised from them
how is cholesterol absorbed by an enterocyte?
a transport protein:
where within the enterocyte is apoB-48 made?
once the triglycerides have reformed in the enterocyte what happens?
1. they form a droplet with apoB48 incorporated inside
2. lipidation occurs
3. cholesteryl esters are added
4. particle (now called a chylomicron) leave by exocytosis
where do chylomicrons go once having left the enterocyte?
where are VLDL particles assembled?
in liver hepatocytes
what are VLDL partcles (containing triglycerides) assembled from?
from free fatty acids derived from adipose tissue and de novo synthesis
to target triglyceride delivery to adipose and muscle tissue, chylomicrons and VLDL particles must become activated. How does this occur?
activation of chylomicrons and VLDL occurs by the transfer of apoCII from HDL particles
what does apoCII facilitate once transfered to the VLDL or chylomicron?
binding of chylomicrons and VLDL particles to lipoprotein lipase (LPL)
what is lipoprotein lipase? (LPL)
a lipolytic enzyme associated with the endothelium of capillaries in adipose and muscle tissue
what does lipoprotein lipase (LPL) do?
LPL hydrolyses the lipoprotein core triglycerides to free fatty acids and glycerol which enter tissues
what are chylomicron and VLDL remnants?
lipoprotein particles depleted of triglycerides (due to the action of LPL) but still containing cholesteryl esters
once LPL has enriched the chylomicrons and VLDL with cholesterol ester by removing triglyceride what happens?
chylomicrons and VLDL dissociate from LPL and apoCII is transferred back to HDL particles in exchange for apoE
apoE causes the remnants to return where?
to the liver
once in the liver what happens to the VLDL and chylomicron particles?
further metabolised by hepatic lipase and then all apoB48-containing remnants and 50% of apoB100 containing-remnants are cleared by receptor-mediated endocytosis into hepatocytes
what happens to the remaining 50% of apoB100-containg remnants which havent been taken into the hepatocytes?
they loose further triglycerides through hepatic lipase, so become smalle and more enriched in cholester ester and eventually beome LDL particle
(only have apoB100 now, lost apoE)
during triglyceride metabolism by hepatic lipase of the remaining apoB100-containing remnants, what particle forms first before the LDL forms?
what is clearance of LDL particles dependent upon?
expression of the LDL receptor expressed by the liver (and other tissues)
how do hepatocytes uptake the LDL particles?
once the LDL has been taken up by the hepatocyte, how is cholesterol released from the cholesterol ester?
what 3 things does the cholesterol released from the LDL cause?
1. inhibition of HMG CoA reductase
2. down regulation of LDL receptor expression
3. storage of cholesterol as cholesterol ester
what is HMG-CoA reductase?
the rate limiting enzyme in de novo cholesterol synthesis
what does inhibition of HMG-CoA cause?
suppression of de novo endogenous cholesterol synthesis
when an endothelium lining is damaged, what is it able to do?
uptake LDL from blood into the intima of the artery
when LDL is within the intima of the artery what occurs?
oxidation to OXLDL
(arthrogenic oxidised LDL)
why do monocytes migrate to the intima of the damaged endothelium?
(where they become macrophages)
to try mop up the cellular debris
what do macrophages turn into when they take up the OXLDL in the damaged endothelium?
foam cells that form a fatty streak
what starts to lay down on top of this fatty streak?
smooth muscle cells and collagen
what makes up an atheromatous plaque?
lipid core (Dead foam cells) and a fibrous cap (smooth muscle and connective tissue)
what is the role of HDL?
transports excess cholesterol from cells to liver
(reverse cholesterol transport)
how is cholesterol removed from the body?
synthesised to make bile salts or secreted in bile
what are the 2 mechanisms of reverse cholesterol transport?
1. HDL reaching liver interacts with receptor that allows transfer of cholesterol and cholestryl esters into hepatocytes
2. in plasma, cholesterol ester transfer protein (CETP) mediates transfer of cholesterol esters from HDL to VLDL and LDL (indirectly returning cholesterol to the liver)
what is secondary dislipidaemia?
lipidaemia as a consequence of another disease
(eg type 2 diabetes, hypothyroidism, alcoholism, liver disease)
by competitively inhibiting HMG CoA reductase, what effect to statins have?
decrease in hepatocyte cholesterol synthesis causes a decreased cholesterol concentration in the hepatocyte which results in a compensatory increased LDL receptor expression and enhanced LDL clearance
why are statins ineffective in familial hypercholesterolaemia?
LDL receptors are lacking, so increased clearance of LDL doesnt occur
when and how are statins administered?
orally at night
what is the first line drug for patients with very high triglycride levels?
how to fibrates work?
act as agonists of a nuclear receptor (PPARalpha) to enhance the transcription of LPL
what type of patients should you avoid giving fibrates in and why?
because even though they are predisposed to hypertriglyceridaemia they are also exposed to rhabdomyolosis
what type of drug are colestyramine, colestipol and colsevelam?
bile acid binding resins
what is the function of bile acid binding resins?
interrupt enterohepatic recycling of cholesterol
non-absorbable so cause the excretion of bile salts thus resulting in more cholesterol to be converted to bile salrs
what 2 main effects do bile acid binding resins have?
1. decreased absorption of bile salts and triglycerides
2. increased LDL receptor expression
what is the adverse effect of bile acid binding resins?
how does ezetimibe work?
inhibits NPC1L1 to reduce cholesterol absorption
when is ezetimibe contraindicated?
in what type of heart condition should calcium antagonists not be used?
they make it worse as they are negative inotropes
what is the process of haemostasis?
preventing blood loss from a damaged vessel
what are the 3 features of haemostasis?
1. local vasoconstriction
2. adhesion and activation of platelets at site of injury
3. formation of fibrin (a insoluble mesh)
what is type of haemostasis is thrombosis?
what is thrombosis?
a haemotological plug formed in the absence of bleeding
what are the predisposing factors to thrombus formation?
1. injury to vessel wall
2. abnormal blood flow.
3. increased coaguablity of the blood
what is an arterial thrombus?
a white thrombus made of mainly platelets in a fibrin mesh
what is a venous thrombus?
a red thrombus rich in red blood cells and fibrin. has a white head and a jelly-like red tail
compare the sites of an embolism formed from an arterial thrombus and a venous thrombus?
embolism from an arterial thrombus lodges in an artery in the systemic circulation
embolism from a venous thrombus lodges in an artery in the pulmonary circulation
what is the main event in blood coagulation?
fibrinogen (a soluble agent) turning into fibrin (an insoluble agent)
what activated clotting factor converts fibrinogen to fibrin?
how are clotting factors activated?
what activated clotting factor activates prothrombin? (II)
how is factor X activated?
in vivo pathway or contact pathway
what are the contact pathway factors?
XIa and XIIa
what are the in vivo pathway factors?
tissue factor and VIIa
what activates the in vivo pathway or contact pathway which ultimately ends up in fibrin formation?
upon activation of plateltes what aggregation factors do they release?
preformed (ADP, 5-HT)
synthesised on demand (TXA2)
what do platelets do to help the coagulation cascade?
provide surfaces which bring clotting factors together
before a clotting factor can attach to the negative phospholipids on the platelet surface what must occur?
gamma- carboxylation of glutamate residues of the cloting factor
(clotting factors are still inactive at this point)
what co-factor does the carboxylase enzyme that mediates gamma-carboxylation of the glutamate residues of clotting factors require?
vitamin K (in it's reduced form)
what happens to the reduced vitamin K co-factor in the process of gamma-carboxylation of the glutamate residues of clotting factors?
(forms oxidised vitamin K)
what is the job of vitamin K reductase?
converts oxidised vitamin K back into reduced vitamin K
what enzyme does warfarin block?
(and what is the result?)
blocks vitamin K reductase
prevents formation of reduced vitamin K and therefore gamma-carboxylation of the glutamate residues of clotting factors can't occur and the coagulationg pathway is interrupted
what type of thrombosis are anticoagulants used in the prevention and treatment of?
what are 4 uses of warfarin?
prevention of post-operative thrombosis
patients with artificial heart valves
what is the name of the reduced form of vitamin K?
what is the name of the oxidised form of vitamin K?
what factors does warfarin render inactive?
II, VII, IX, X
describe the onset/duration of warfarin?
slow onset, long half life (40 hrs)
what type of therapeutic index does warfarin have?
low therapeutic index
what are the 3 main factors that potentiate warfarin action and so increase risk of haemrrhage?
high metabolic rate
why might liver disease potentiate warfarin?
decreased clotting factors
why might high metabolic rate potentiate warfarin?
increased clearance of clotting factors
what 3 types of drug interactions might potentiate warfarin?
1. agents that inhibit hepatic metabolism of warfarin
2. agents that inhibit platelet function (eg some NSAIDS)
3. agents that inhibit decrease availability of vitamin K
what are the 3 main factors which might lessen warfarin action? (risk of thrombosis increased)
1. physiological state
2. vitamin K consuption
3. drugs interactions
what types of physiological states may lessen warfarin action and increase risk of thrombosis?
low metabolic states (decreased degradation of clotting factors)
what is antithrombin III? (AT III)
clotting factor inhibitor
(binds to clotting factors rendering them inactive)
how does heparin work?
binds to antithrombin III and increases its affinity for clotting factors (particularly Xa and IIa) to increase their rate of inactivation
compare heparins effect on Xa and IIa
heparin must bind to both AT III and IIa to inhibit IIa
heparin only needs to bind to AT III to inhibit Xa
what factors do LMWHs inhibit?
(cant inhibit IIa because they cant bind to both AT III and IIa at the same time, for Xa they only need to bind to AT III)
what is the order of elimination of herparin?
zero order kinetics
what is the order of elimination of LMWHs?
first order kinetics
why is heparin preferred to LMWH in renal failure?
LMWH is excreted by renal ecretion
why should the inibility of LMWH to inhibit factor IIa not be important?
because it inhibits factor Xa which is upstream to IIa, so should indirectly inhibit IIa
what are the 4 adverse affects of heparin gnd LMWHs?
osteoporosis (long term)
what is the treatment for a patient on heparin or LMWH wo gets a haemorrhage?
discontiunue the heparin or LMWH
administer protamine sulfate (inactivated heparin)
what is the benefit of dabigatran and rivaroxaban over heparin and LMWHs?
orally active agents
(no need for IV)
less haemorhage risk
what factor does dabigatran inhibit?
what factor does rivaroxaban inhibit?
when are rivaroxaban and dabigatran used clinically?
to prevent venous thrombosis in patients undergoing hip and knee replacements
what is the function of von willebrand factor?
allows platelets to adhere to endothelium
what do ADP, 5HT and TXA2 do?
act on the cell surface receptor of platelets to cause aggregation and cross linking via fibrinogen
what enzyme does aspirin block irreversibly?
(and what effect does this have?)
in platelets: prevents the synthesis of thromboxane A2 (TXA2) and so prevents stimulation of aggregation and cross-linking (adhesion)
what does clopidogrel block irreversibly?
P2Y(12) receptor on platelets
prevents ADP binding to receptor and stimulation of aggregation and cross-linking (adhesion)
what does tirofiban block?
GPIIb/IIa receptor on platelt to prevent the cross-linking by fibrinogen
what type of thrombosis are anti-platelet drugs used in?
how and why is tirofiban administered?
IV in short term treatment to prevent MI in high risk patients with unstable angina
(with aspirin and heparin)
describe the fibrinolytic cascade?
opposes coagulation cascade
plasminogen is converted to plasmin which breaks down the fibrin into fibrin fragments causing clot lysis
what type of agents up regulated the conversion of plasminogen to plasmin?
fibrinolytic agents eg tPA, strptokinase
how are fibrinolytic drugs administered?
(within as short a period as possible of the event)
what are fibinolytics used for clinically?
reopen occluded arteries eg MI or stroke
less freq: reopen life-threatening venous thrombosis or PE
why are fibrinolytics not given to every patient who has had an acute MI?
because PCI is superior if aviable promptly
why is action of streptokinase blocked after 4 days?
generation of antibodies
to what patients should you not give streptokinase?
to patients with recent streptococcal infections