CARDIO PHARMACOLOGY Flashcards
what receptors do adrenaline and noradrenaline act on in the heart
b1
what kind of receptor is B1
g protein coupled receptor
Gs protein
what happens when B1 receptors are stimulated
Gs coupled protein stimulates adenylyl cyclase to increase intracellular cAMP
what does increased intracellular cAMP do in monocytes
stimulates pKA
what does increased intracellular cAMP do to pacemaker cells
increases the slope of the PMP and so increases heart rate
what receptor does ACh act on in the heart
M2
what kind of receptor is M2
G-protein coupled receptor
Gi protein
what happens when M2 receptors are stimulated
Gi coupled protein decreases the activity of adenylyl cyclase to decrease intracellular cAMP and opens K+ channels to hyper polarise the SA node
what is the effect of M2 receptor stimulation in the heart
decreased slope of PMP and so decreased heart rate
what is Bachmann’s bundle
anterior interatrial myocardial band - pathway going to LA from SAN
what is the funny current
inwards current of the PMP
what is the funny current stimulated by
hyperpolarisation and cAMP
what are HCN channels
hyperpolarisation-activated cyclone nucleotide gated channels
what does the blockage of HCN channels do
decreases the PMP slope
give an example of a selective HCN channel blocker
ivabradine
true / false
sympathetic stimulation decreases the cardiac efficiency with respect to O2 consumption
true
what happens to the frank starling curve in heart failure
the curve fails as force not able to match the VR
what is the frank starling law
the more the myocardium is stretched the greater the force it exerts upon contraction i.e. the greater the VR the greater the stroke volume
increased skeletal muscle activity
increased venomotor tone
increased respiratory pump
all do what to the VR
increase VR
how do APs reach the ventricular muscle cells
t tubules
how is depolarisation of ventricular muscle cell initiated
fast Na+ influx
what does the fast Na+ influx do to the T tubule membranes
Voltage-gated L-type Ca2+ channels located in the T tubule membrane are opened by depolarisation and let a small amount of Ca2+ in
what does the small Ca2+ influx cause
activation of RyR (ryanodine) receptors
what does the stimulation of RyR receptors cause
CICR - release of large amounts of intracellular calcium within the SR into the cell
for contraction to occur within the ventricular muscle cell what must the calcium do
activate myofilaments
how is the calcium removed from the cytoplasm back into the SR
Ca ATPase (SERCA)
how is the calcium removed from the cytoplasm out of the cell
sarcolemma Na+/Ca2+ exchanger
how is relaxation achieved
decreased intracellular Ca2+
what are 4 sites of PKA phosphorylation action
Ryanodine receptors
L-type calcium channels on T tubule membrane
PLB
troponin
what does phosphorylation of RyR cause
increases the size of calcium transient i.e. the amount leaving the SR causing increased force of contraction
what does phosphorylation of LTCC cause
increases trigger calcium so increases CICR causing increased force of contraction
what does phosphorylation of PLB cause
increases uptake by SERCA so accelerates relaxation (makes contraction shorter) and increases SR calcium content
what does phosphorylation of troponin cause
reduces affinity for calcium - minor reduction in contraction which accelerates relaxation
what is the principle determinant of calcium binding to troponin C to cause contraction
rate calcium diffuses from the SR (i.e. phosphorylation of RyR)
what is the principle determinant of the unbinding of calcium once a contraction has occurred
phosphorylation of troponin
what do thyroid hormones do to the HR
increase HR
what 2 ways can intracellular [Ca2+] be increased in vascular smooth muscle cells
influx of Ca2+ across membrane gradient (conc or electric)
released from intracellular stores
what does calcium do to initiate contraction in a smooth muscle cell
calcium binds to calmodulin to form a calcium-calmodulin complex
what does the calcium-calmodulin complex do
activates myosin light chain kinase MLCK which phosphorylates myosin light chain
what does the phosphorylated myosin light chain do
forms cross bridges and allows myosin and actin to slide over each other and contract
how does cGMP initiate smooth muscle relaxation
activates myosin-LC-phosphotase
what does myosin-lc-phosphatase do
strips a phosphate from the phosphorylated (active) Myosin-LC converting it to inactive myosin-LC
this causes the bridges to break and relaxation to occur
what does NO do to the HR
increases HR
how does NO signal
paracrine
true / false
bradykinin, ANP and serotonin are vasodilators that work through NO
true
what does NO do within vascular smooth muscle
activates guanylate cyclase - converts GTP to cGMP which initiates the relaxation pathway
activates calcium-dependent potassium channels - causes potassium to leave the cell causing repolarisation - closes VGCC and causes relaxation
how do calcium dependent potassium channels become active
NO or depolarisation
what do NO, NPs and sheer stress do to the production of endothelin
down regulate endothelin production
what is the long term effect of AT II
promotes cell growth
where is ACE found
bound to membrane of endothelial cells
what 2 things does ACE do
converts AT I to AT II
inactivated bradykinin
what is better for variant angina - BB or CCBs? and why?
CCBs - 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 is the function of lipoproteins
transport non-polar lipids in blood
what makes up the hydrophobic core of a lipoprotein
esterified cholesterol and triglycerides
what makes up the hydrophilic coat of a lipoprotein
monolayer of amphipathic cholesterol, phospholipids and one or more apoprotein
what is the apoprotein of HDL
ApoA1
ApoA2
what is the apoprotein of LDL
ApoB-100
what is the apoprotein of VLDL
ApoB-100
what is the apoprotein of chylomicrons
apoB-48
what lipoprotein has the largest diameter
chylomicrons
where are chylomicrons formed
intestinal cells
where is VLDL formed
liver hepatocytes
what is VLDL assembled from
free fatty acids from adipose tissue and denovo synthesis
what is the function of apoB-containing lipoproteins
deliver triglycerides to muscle for ATP and adipocytes for storage
what are the 3 phases of ApoB containing lipoproteins
assembly
intravascular metabolism
receptor mediated clearance
what does intravascular metabolism of ApoB containing lipoproteins involve
hydrolysis of triglyceride core
how is a chylomicron formed
1) triglyceride broken down into monoglyceride and free fatty acids
2) absorbed by intestine
3) triglyceride resynthesised in the enterocyte
4) forms a droplet with apoB-48 inside
5) lipidation
6) cholesterol esters added
7) chylomicron leaves by exocytosis
8) goes to lymphatic system
how are chylomicrons and VLDL activated
transfer of apoC2 from HDL particles - activated to target triglyceride delivery to adipose and muscle tissue
what does apoC2 facilitate once transferred to the VLDL/chylomicron
binding to lipoprotein lipase
what is LPL associated with
endothelium of capillaries in adipose and muscle tissue
what is the function of LPL
hydrolyses the lipoprotein core triglycerides to free fatty acids and glycerol which enter tissues
what makes up the chylomicron/VLDL remnants
lipoprotein particles containing cholesteryl esters (depleted of triglycerides)
true / false
the chylomicrons and VLDL then dissociated from LPL
true
what is ApoC2 exchanged for when transferred back to HDL
apoE
what does ApoE cause
remnants to return to liver
what is the fate of the remnants once in the liver
metabolised by hepatic lipase
all apoB48 and 1/2 apoB100 containing remnants are cleared by receptor mediated endocytosis into hepatocytes
the other 1/2 of apoB100 lose further triglycerides through hepatic lipase so become smaller and more enriched in cholesteryl ester - become IDL then LDL
what does receptor mediated clearance of ApoB containing lipoproteins involve
attachment of lipoprotein to a receptor, endocytosis into the cell and removal
depends on the expression of LDL receptor expressed by liver and other tissues
what is receptor mediated endocytosis
uptake of LDL particles by hepatocytes
what happens once the LDL has been taken up by the hepatocyte
cholesterol is released from the cholesterol ester by hydrolysis
what does cholesterol released from LDL cause
inhibition of HMG CoA reductase
down regulation of LDL receptor expression
storage of cholesterol as an ester
what is HMG CoA reductase
rate limiting enzyme in de novo endogenous cholesterol synthesis
how do statins work
competitively inhibit HMG CoA reductase
–> decrease in hepatocyte cholesterol synthesis –> decreased [cholesterol] in hepatocyte –> increased LDL receptor expression –> enhanced LDL clearance
how is cholesterol absorbed by enterocyte
transport protein NPC1L1
how does HDL reduce cholesterol levels in the body
transports excess cholesterol from cells to liver where it is removed from the body - synthesised to make bile salts or secreted in bile
true / false
HDL reaching liver interacts with receptor that allows transfer of cholesterol and cholesteryl esters into hepatocytes
true
true / false
CETP mediates the transfer of cholesterol from LDL and VLDL to HDL in plasma
false
CETP mediates the transfer of cholesterol from HDL to LDL and VLDL in the plasma, indirectly returning cholesterol to the liver
what occurs in familial hypercholesterolaemia
homozygous
LDL receptors lacking
what does thrombin IIa do
converts fibrinogen to fibrin
how are clotting factors activated
proteolytic cleavage
what does activated clotting factor Xa do
activated prothrombin II
what are the 2 pathways factor X can be activated
in vivo pathway
contact pathway
true/false
factors XIa and XIIa are in vivo pathway factors
false
contact pathway factors
true/false
factor VIIa and tissue factor are in vivo pathway factors
true
what are 2 pre-formed aggregation factors released from activated platelets
ADP
5-HT
what is an aggregation factor synthesised on demand by activated platelets
TXA2
what do aggregation factors do
act on cell surface receptor of platelets to cause aggregation and cross linking via fibrinogen
how do platelets help the coagulation cascade
provide surfaces which bring clotting factors together
before a clotting factor can attach to the negative phospholipid on the platelet surface what must occur
gamma-carboxylation of glutamate residues of the clotting factor
what is hydroquinone
reduced vitamin k
what is epoxide
oxidised vitamin K
what does carboxylase enzyme that mediates gamma-carboxylation of glutamate residues of clotting factors require
vitamin K cofactor in reduced form - vit K becomes oxidised in the process
what is the purpose of vitamin K reductase
converts oxidised vitamin K into reduced vitamin K
how does warfarin work
blocks vitamin K reductase –> prevents formation of reduced vitamin K –> prevents gamma-carboxylation of glutamate residues of clotting factors
what is haemostasis
preventing blood loss from a damaged vessel
what is an example of pathological haemostasis
thrombosis - a haematological plug formed in the absence of bleeding
what are the 3 aspects of virchows triad
increased coagulability of blood
injury to vessel wall
abnormal blood flow
a thrombus is white, mainly platelets and fibrin mesh and produces emboli which lodge in systemic arteries
is it arterial or venous
arterial
a thrombus has a white head with a jelly like red tail, is rich in blood cells and fibrin and produces emboli which lodge in the pulmonary arteries
is it arterial or venous
venous
what are arterial thrombi treated with
antiplatelets
what are venous thrombi treated with
anticoagulants
what is antithrombin III
clotting factor inhibitor
binds to clotting factors rendering them inactive
what is Von Willebrand factor
allows platelets to adhere to endothelium
what cascade opposes the coagulation cascade
fibrinolytic
what occurs in the fibrinolytic cascade
plasminogen is converted to plasmin which breaks down the fibrin into fibrin fragments causing clot lysis
what order of kinetics is this
“2mg are eliminated per unit time”
zero order
same amount of drug is eliminated per unit time regardless of plasma conc
what order of kinetics is this
“2% of available drug is eliminated per unit time”
first order
same proportion of drug is eliminated per unit of time - variable amount eliminated based on plasma conc
what order of elimination is heparin
zero order
what order of elimination is LMWH
first order
