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Flashcards in Pharmacology Deck (320):
1

what 2 endogenous substance act on the B1-adrenoceptors in the heart?

noradrenaline (sympathetic transmitter)
adrenaline (hormone)

2

what G protein do B1-adrenoceptors in the heart couple to?

Gs proteins

3

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)

4

what does increasing intracellular cAMP concentration within the pacemaker cells do?

increases slope of pacemaker potential and so increases heart rate
(positive chronotrophic effect)

5

what endogenous substance acts on M2 muscarinic cholinoreceptors in the heart?

ACh

6

What G protein do M2-adrenoceptors in the heart couple to?

Gi

7

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

8

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)

9

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

10

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
(Bachmann's Bundle)

11

what does the bundle of his split up into?

right bundle branch
left bundle branch (which splits into anterior division and posterior division)

12

what is the hierarchy of pacemakers?

SA > AV > other cells within the heart

13

why is it necessary that the AV node can produce an AP?

in case the SA node fails

14

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

15

what is the inwards current of the pacemaker potential also known as?

I(f)
funny current

16

what stimulates the inwards current of the pacemaker potential? (funny current)

1. hyperpolarisation
(ie turning resting potential negative)
2. cAMP

17

what does blocking HCN (hyperpolarisation-activated cycline neucleotide gated) channels do to the pacemaker potential slope?

decreases the slope
(negative chronotrophic effect)

18

what does ivabradine do?

a selective blocker of HCN channels so slows the heart rate down

19

what medical condition is ivabradine used in and why?

angina
because slower rate reduces O2 consumption and so reduces coronary artery supply requirement

20

what does isoprenaline do?

a agonist of B-adrenoceptors and so increases intracellular cAMP concentration and so increases heart rate

21

what do thyroid hormones do to heart rate?

increase heart rate
(positive chronotrophic effect)

22

what does adenosine do to the heart rate?

decreases heart rate
(negative chronotropic effect)

23

what does nitric oxide do to the heart rate?

increases heart rate
(positive chronotrophic effect)

24

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)

25

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)

26

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]

27

what autonomic control can tweak the frank-starling curve?

sympathetic

28

what happens to the frank-starling curve in cardiac failure?

curve fails as force is not able to match the venous return (stretch)

29

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)

30

what does increased intracellular calcium cause?

contraction

31

what is excitation coupling?

coupling mechanical force to electrical excitation

32

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

33

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

34

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.

35

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

36

for contraction within the ventricular muscle cell to occur what does calcium activate?

the myofilaments

37

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

38

what does the decreased intracellular concentration of calcium after myofilament activation cause?

relaxation

39

what do positive chronotropic drugs/hormones do to the calcium transients within the cardiac myocyte?

cause bigger and faster calcium transients

40

what is the function of the RyR within the myocyte?

when stimulated by calcium cause the Ca-induced Ca release from SR

41

what is the function of SERCA 2a within the myocyte?

removal of Ca at the end of a beat (puts Ca++ back into stores

42

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)
PLB
Troponin

43

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)

44

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

45

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

46

what is the function of troponin?

regulates the actin/myosin interaction using calcium

47

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

48

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)

49

what is the principle determinant of the unbinding of calcium once a contraction has occured?

phosphorylation of troponin

50

what is dobutamines effect on the heart?

selective b1-adrenoceptor agonist so increases force and rate

51

when is exogenous adrenaline used?

during cardiac arrest
emergency treatment of asthma
anaphylactic shock

52

when is dobutamine used?

for acute, but potentially reversible, heart failure
(eg following cardiac surgery)

53

why are b-1 adrenoceptor agonists regarded as 'toxic'?

because long term stimulation of sympathetic system causes heart failure

54

what is propanolol?

a non-selective b-blocker
(antagonist of b1 and b2 adrenoceptors)

55

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

56

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)

57

what do b2-adrenoceptors stimulation cause on the coronary vessels?

vasodilation

58

what is atenolol?

a selective B1-blocker

59

what is metoprolol?

a selective B1- blocker

60

what are the 4 clinical uses of B-adenoceptor antagonists?

1. dysrhythmias
2. hypertension
3. angina
4. heart failure

61

what are the 6 adverse effects of b-blockers?
(* which have a lesser risk is B1 selective agents are used)

1. bronchospasm*
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)

62

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

63

what is atropine?

a non selective muscarinic receptor antagonist

64

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

65

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

66

what is the pharmocodynamic effect of digoxin?

increases contractility of the heart?

67

what type of drugs are digoxin and dobutamine?

inotropic drugs
(enhance contractility)

68

what is the clinical use of digoxin?

in heart failure
(especially in patients with AF- due to effects on AV node)

69

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
(incresed contactility)
2. increases AV node refractory period

70

what effect does digoxin have on the autonomic system?

none

71

what happens if you give digoxin to a patient with hypokalaemia?

effects of digoxin are dangerously enhanced

72

what are the 2 most serious effects of digoxin?

1. excessive depression of AV node conduction- heart block
2. dysrhythmias

73

what is levosimendan?

a calcium-sensitiser: inotropic drug

74

how does levosimendan work?

1. binds to troponin C in cardiac muscle sensitising it to the action of calcium
2. causes vasodlation

75

what is the clinical use on levodimendan?

treatment of acute decompensated heart failure

76

what does contraction of vascular smooth muscle depend on?

intracellular concetration of calcium

77

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)

78

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.

79

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

80

compare the functions of MLCK and MLC-phosphotase

MLCK phosphorylates inactive Myosin-LC
MLC-phosphotase strips a phosphate from active mysoin-LC

reverse roles

81

what 3 vasodilating substances work through NO production?

bradykinin
ANP
serotonin (5-HT)

82

what type of manner does NO signal in?

paracrine (induces an effect in cells near by)

83

what does NO do within a vascular smooth muscle cell?

1. activation of guanylate cyclase
2. activates calcium-dependent potassium channels

84

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

85

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

86

what 2 ways can calcium-dependent potasssium channels become activated?

stimulation by NO
depolarisation

87

what is the function of organic nitrates?

relax all type of smooth muscle

88

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

89

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)

90

how do organic nitrates redirect blood from unhealthy vessels to bypass blockages?

dilate collateral vessels

91

why are arterioles downstream to a blockage already fully dilated?

due to local factors such as hypoxia etc

92

what are the 2 main types of organic nitrates used in practice?

glyceryltrinitrate
isosorbide mononitrate

93

compare glyceryltrinitrate and isosorbide mononitrate in terms of length of acting?

GTN- short acting (30 min)
isosorbide mononitrate- long acting (4 hours)

94

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

95

how it GTN administered?

sublinguial tablet or spray or transdermal patch

96

how should organic nitrates be used for angina?

prophylactically
(GTN can also relieve attacks)

97

what can happen with repeated administration of organic nitrates?

tolerance- diminished effect

98

how can you minimise tolerance of organic nitrates?

nitrate-low periods
(usually at night)

99

what is a common effect of organic nitrates which may occur initially?

headaches due to dilation of cranial circulation

100

what 3 things down regulate the production of endothelin?

nitric oxide
natriuretic peptides
shear stress

101

what are bosentan and ambrisentan?

antagonists of the ETa receptor (which endothlin acts on)

102

when are bosentan and ambrisentan (antagonists of the ETa receptor) used?

in treatment of pulmonary hypertension

103

what is a long term effect of angiotensin II?

promotes cell growth

104

what are the 2 functions of ACE?

converts angiotensin I to angiotensin II
inactivated bradykinin

105

where is ACE found?

bound to the membrane of endothelial cells

106

what is the role of ace inhibitors?
(-pril)

block the conversion of angiotensin I to angiotensin II

107

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)

108

what are the common adverse effects of ACE inhibitors?

initial hypotention (esp in patients on diuretics too)
dry cough (due to bradykinin accumulation)
renal dysfunction

109

what are the adverse effects of ACE inhibitors?

initial hypotention (esp in patients on diuretics too)
dry cough (due to bradykinin accumulation)

110

what is the role of AT1 receptor blockers (ARBs)?
(-sartan)

competitevly block the agonist action of angeiotensin I at AT1 receptors

111

what are ACEIs and ARBs contraindicated in?

pregnancy
bilateral renal artery stenosis

112

if a patient has a intolerable dry cough with ACE inhibitors what drug should they be switched to?

ARBs
(as there is no increase in bradykinin)

113

what are ACEIs and ARBs contraindicated in?

pregnancy
bilateral renal artery stnosis

114

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)

115

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
2. hypertenstion
reduce MAP and reduced renin release from the kidneys
3. heart failure
decreases cardiac work load

116

what is the function of calcium antagonists?

prevent the opening of L-type channels in response to depolarisation, this limits calcium influx

117

in the SA node what do calcium antagonists do?

reduce heart rate by reducing rate of upstroke of the AP

118

in the AV node what do calcium antagonists do?

reduce rate of conduction

119

in the ventricles what do calcium antagonists do?

reduce force of contraction by reducing Ca in plateau phase

120

what are the 3 main calcium antagonists?

verapamil (cardiac selective)
amlodipine (smooth muscle selective)
diltiazem

121

what are calcium antagonists clinically used in?

hypertension (reduce TPR and MAP)
angina (coronary vasodilation)
dysrhthmias (supression of AV conduction)

122

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)

123

what is the length of acting for amlodopine?

long acting

124

what calcium antagonists is used in dysrhthmias?

verapamil

125

what drug combination should be completely avoided in heart failure?

beta-blockers and verapamil

126

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

127

what are minoxidil and nicorandil?

potassium channel openers

128

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

129

what is nicorandil used in?

angina
(not used too commonly)

130

what is minoxidil used in?

hypertension (but only as a last resort)

131

what are the negative effects of minoxidil?

reflex tachycardia (prevented by a beta-blocker)
salt and water retention (alleviated by a diuretic)

132

what are prazosin and doxazosin?

a1-adrenoceptor antagonists

133

what is the dunction of a1-adrenoceptor antagonists?

cause vasodilation by blocking sympathetic/hormonal effect on a1-adrenoceptors

134

what is the clinical use a1-adrenoceptor antagonists?

hypertension (especially if patient has prostatic hyperplasia)

135

what is the function of diuretics?

act on kidneys to increase the excretion of Na, Cl and H20

136

where do thiazide diuretics inhibit NaCl reabsorption?

distal tubule

137

where do loop diuretics inhibit NaCl reabsorption?``

ascending limb of hte loop of Henle

138

what is the main adverse affect of using thiazide or loop diuretics?

loss of K+

139

how is the loss of K+ due to thiazide or loop diuretics corrected?

co-administration of a potassium sparring diuretic
k+ supplements

140

what are the clinical uses of thiazide diuretics? (eg bendroflumethiazide)

mild heart failure
hypertension

141

what are the clinical uses of loop diuretics?

acute pulmonary oedema
chronic heart failure

142

name 6 classes of anti-hypertensive drugs?

calcium antagonists
ACE inhibitors
ARBs
alpha blockers
beta blockers
thiazide diuretics

143

name 4 classes of anti-anginal drugs?

nitrates
beta blockers
calcium antagonists
nicorandil

144

name 3 classes of antithrombotic drugs?

antiplatelets (against platelets)
anticoagulants (against clotting factors)
fibrinolytics (dissolve preformed clots)

145

name 2 classes of anticholesterol drugs?

statins
fibrates

146

what is bendroflumethiazide?

thiazide diuretic

147

what is furosemide?

a loop diuretic

148

what are the 4 side effects of diuretics?

1. hypokalaemia (tiredness, arrhythmias)
2. hyperglycaemia (diabetes)
3. hyperuricaemia (gout)
4. impotence

149

what are cardioselective b-blockers used in?
eg atenolol

angina
hypertension
heart failure

150

what are non-selective b-blockers used in?
eg propanolol

thyrotoxicosis

151

what type of patients are beta blockers contraindicated in?

asthmatic patients
patients with reynaulds

152

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

153

what are the 2 types of calcium antagonists?

dihydropyridines eg amlodipine
rate-limiting calcium antagonists eg verapamil, diltiazem

154

what can be the adverse result of giving beta blockers and rate-limiting calcium antagonists together?

full heart block

155

what type of arrhythmias are rate-limiting calcium antagonists useful in treating?

superventricular arrthymias (AF, SVT)

156

what is the main side effect of alpha blockers?

postural hypotension

157

what is a rare, life threatening adverse reaction of ACE inhibitors?

angioneurotic oedema
(never give to a patient with previous angioneurotic oedema)

158

why should you avoid giving ACEI to women of childbearing ages?

they might not know they are pregnant yet, contraindicated in pregnancy

159

what type of drugs can pregnant women use to control pregnancy-induced hypertension?

calcium inhibitors and beta blockers

160

what type of heart failure can nitrates be used in?

acute heart failure not chronic

161

what is the function of antiplatelet agents?

prevent new thrombosis
(dont break down clots that have already formed)

162

when are antiplatelet agents used?

angina
acute MI
CVA/TIA
(patients at risk of MI/CVS)

163

what are the 3 main side effects of antiplatelet agents?

haemorrhage
peptic ulcer (leading to haemorrhage)
aspirin sensitivity (asthma)

164

what is the function of anticoagulants?

prevent new thrombosis

165

how is heparin administered?

IV

166

how is warfarin administered?

oral

167

what clotting factors does warfarin block?

2, 7, 9, 10

168

what is warfarin used in?

DVT
PE
NSTEMI
AF

169

what are the side effects of anticoagulants?

haemorrhage

170

how do you control the dose of warfarin?

using INR

171

how do you reverse an overdose of warfrin? (ie if there is a haemorrhage)

vitamin K

172

what clotting factor does rivaroxaban inhibit?

10a

173

what clotting factor does dabigatran inhibit?

2a

174

what does clotting factor Xa do?

convert prothrombin (II) into thrombin (IIa)

175

name 2 fibrinolytic drugs?

streptokinase
tPA

176

when are fibrinolytic drugs used?

STEMI
PE
CVA
(Selected cases only)

177

what is the adverse side effect of fibrinolytic drugs?

haemorrhage

178

when must you avoid using fibrinolytic drugs?

recent haemorrhage
trauma
bleeding tendencies (eg haemophilla)
severe diabetic retinopathy
peptic ulcer

179

how do statins work?

block HMG CoA reductase

180

when are statins used?

hypercholesterolaemia
diabetes
angina/MI
CVA/TIA
(high risk of MI/CVA)

181

what are the possible side effects of statins?

myopathy (muscle ache)
rhabdomyolysis renal failure (renal muscle break down)

182

when are fibrates used?

hypertriglyceridaemia
low HDL cholesterol

183

what 2 drugs are anti-arrhythmic drugs?

amiodarone
flecainide
(calcium antagonist
beta blockers
digoxin can also be used in SVAs but arent technically anti-arrhythmic drugs)

184

what drug do you use in the acute phase of an SVT?

adenosine

185

what are the 3 side effects of anti-arrhythmic drugs?

photoxicity
pulmonary fibrosis
thyroid abnormalities

186

what are the 2 main effects of digoxin?

1. degree of AV node block
2. increased ventricular contraction

187

what are the side effects of digoxin?

bradycardia and heart block
ventricular arrhythmias (fatal)
nausea
vomitting
yellow vision

188

how are non-polar lipids transported in the blood?

within lipoproteins

189

what ratio of LDL:HDL is strongly associated with cardiovascular disease? (atherosclerosis)

high LDL
low HDL

190

what are the 2 main sections of an lipoprotein?

hydrophobic core
hydrophilic coat

191

what does the hydrophobic core of the lipoprotein contain?

esterified cholesterol and triglycerides

192

what does the hydrophilic coat of the lipoprotein contatin?

a monolayer of amphipathic cholesterol, phospholipids and one or more apoprotein

193

what are the 4 main lipoproteins?

HDL
LDL
VLDL
chylomicrons

194

what is the biggest lipoprotein in terms of diameter?

chylomicrons

195

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

196

what apoproteins are associated with HDL?

apoA1
apoA2

197

what apoproteins are associated with LDL?

apoB-100

198

what apoproteins are associated with VLDL?

apoB-100

199

what apoproteins are associated with chyomicrons?

apoB-48

200

what are apoproteins?

markers which say if the lipoprotein is LDL or HDL

201

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

202

what type of lipoproteins deliver triglycerides to muscle (for ATP) and adipocytes (for storage)?

apoB -containing lipoproteins

203

where are chylomicrons formed?

intestinal cells

204

what is the function of chylomicrons?

transport dietary triglycerides to muscle and adipocytes
(exogenous pathway)

205

what is the 3 phase life cycle of an ApoB-containing lipoprotein?

1. assembly
2. intravascular metabolism
3. receptor mediated clearance

206

where does assembly of an ApoB-containing lipoprotein occur?

apoB100-containing lipoproteins: liver
apoB46-containing lipoproteins: intestine

207

what does intravascular metabolism of an apoB-containing lipoprotein involve?

hydrolysis fo the triglyceride core

208

what does receptor mediated clearance of an apoB-containing lipoprotein involve?

lipoprotein attaches to a receptor and is endocytsosed into the cell and removed

209

what needs to happen to the triglyceride to be absorbed in the intestine?

broken down into monoglyceride and free fatty acids

210

after absorption in the intestine what happens to the monoglyceride and free fatty acids?

triglyceride is resynthesised from them

211

how is cholesterol absorbed by an enterocyte?

a transport protein:
NPC1L1

212

where within the enterocyte is apoB-48 made?

ribosome

213

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

214

where do chylomicrons go once having left the enterocyte?

lymphatic syste,

215

where are VLDL particles assembled?

in liver hepatocytes

216

what are VLDL partcles (containing triglycerides) assembled from?

from free fatty acids derived from adipose tissue and de novo synthesis

217

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
(apo C2)

218

what does apoCII facilitate once transfered to the VLDL or chylomicron?

binding of chylomicrons and VLDL particles to lipoprotein lipase (LPL)

219

what is lipoprotein lipase? (LPL)

a lipolytic enzyme associated with the endothelium of capillaries in adipose and muscle tissue

220

what does lipoprotein lipase (LPL) do?

LPL hydrolyses the lipoprotein core triglycerides to free fatty acids and glycerol which enter tissues

221

what are chylomicron and VLDL remnants?

lipoprotein particles depleted of triglycerides (due to the action of LPL) but still containing cholesteryl esters

222

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

223

apoE causes the remnants to return where?

to the liver

224

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

225

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)

226

during triglyceride metabolism by hepatic lipase of the remaining apoB100-containing remnants, what particle forms first before the LDL forms?

IDL

227

what is clearance of LDL particles dependent upon?

expression of the LDL receptor expressed by the liver (and other tissues)

228

how do hepatocytes uptake the LDL particles?

receptor-mediated endocytosis

229

once the LDL has been taken up by the hepatocyte, how is cholesterol released from the cholesterol ester?

hydrolysis

230

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

231

what is HMG-CoA reductase?

the rate limiting enzyme in de novo cholesterol synthesis

232

what does inhibition of HMG-CoA cause?

suppression of de novo endogenous cholesterol synthesis

233

when an endothelium lining is damaged, what is it able to do?

uptake LDL from blood into the intima of the artery

234

when LDL is within the intima of the artery what occurs?

oxidation to OXLDL
(arthrogenic oxidised LDL)

235

why do monocytes migrate to the intima of the damaged endothelium?
(where they become macrophages)

to try mop up the cellular debris

236

what do macrophages turn into when they take up the OXLDL in the damaged endothelium?

foam cells that form a fatty streak

237

what starts to lay down on top of this fatty streak?

smooth muscle cells and collagen

238

what makes up an atheromatous plaque?

lipid core (Dead foam cells) and a fibrous cap (smooth muscle and connective tissue)

239

what is the role of HDL?

transports excess cholesterol from cells to liver
(reverse cholesterol transport)

240

how is cholesterol removed from the body?

synthesised to make bile salts or secreted in bile

241

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)

242

what is secondary dislipidaemia?

lipidaemia as a consequence of another disease
(eg type 2 diabetes, hypothyroidism, alcoholism, liver disease)

243

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

244

why are statins ineffective in familial hypercholesterolaemia?

LDL receptors are lacking, so increased clearance of LDL doesnt occur

245

when and how are statins administered?

orally at night

246

what is the first line drug for patients with very high triglycride levels?

fibrates

247

how to fibrates work?

act as agonists of a nuclear receptor (PPARalpha) to enhance the transcription of LPL

248

what type of patients should you avoid giving fibrates in and why?

alcoholics
because even though they are predisposed to hypertriglyceridaemia they are also exposed to rhabdomyolosis

249

what type of drug are colestyramine, colestipol and colsevelam?

bile acid binding resins

250

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

251

what 2 main effects do bile acid binding resins have?

1. decreased absorption of bile salts and triglycerides
2. increased LDL receptor expression

252

what is the adverse effect of bile acid binding resins?

GI irritation

253

how does ezetimibe work?

inhibits NPC1L1 to reduce cholesterol absorption

254

when is ezetimibe contraindicated?

breast-feeding females

255

in what type of heart condition should calcium antagonists not be used?

heart failure
they make it worse as they are negative inotropes

256

what is the process of haemostasis?

preventing blood loss from a damaged vessel

257

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)

258

what is type of haemostasis is thrombosis?

pathological

259

what is thrombosis?

a haemotological plug formed in the absence of bleeding

260

what are the predisposing factors to thrombus formation?

virchows triad:
1. injury to vessel wall
2. abnormal blood flow.
3. increased coaguablity of the blood

261

what is an arterial thrombus?

a white thrombus made of mainly platelets in a fibrin mesh

262

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

263

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

264

what is the main event in blood coagulation?

fibrinogen (a soluble agent) turning into fibrin (an insoluble agent)

265

what activated clotting factor converts fibrinogen to fibrin?

thrombin (IIa)

266

how are clotting factors activated?

proteolytic cleavage

267

what activated clotting factor activates prothrombin? (II)

Xa

268

how is factor X activated?

in vivo pathway or contact pathway

269

what are the contact pathway factors?

XIa and XIIa

270

what are the in vivo pathway factors?

tissue factor and VIIa

271

what activates the in vivo pathway or contact pathway which ultimately ends up in fibrin formation?

endothelial damage

272

upon activation of plateltes what aggregation factors do they release?

preformed (ADP, 5-HT)
synthesised on demand (TXA2)

273

what do platelets do to help the coagulation cascade?

provide surfaces which bring clotting factors together

274

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)

275

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)

276

what happens to the reduced vitamin K co-factor in the process of gamma-carboxylation of the glutamate residues of clotting factors?

becomes oxidised
(forms oxidised vitamin K)

277

what is the job of vitamin K reductase?

converts oxidised vitamin K back into reduced vitamin K

278

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

279

what type of thrombosis are anticoagulants used in the prevention and treatment of?

venous thromosis

280

what are 4 uses of warfarin?

DVT
prevention of post-operative thrombosis
patients with artificial heart valves
atrial fibrillation

281

what is the name of the reduced form of vitamin K?

hydroquinone

282

what is the name of the oxidised form of vitamin K?

epoxide

283

what factors does warfarin render inactive?

II, VII, IX, X

284

describe the onset/duration of warfarin?

slow onset, long half life (40 hrs)

285

what type of therapeutic index does warfarin have?

low therapeutic index

286

what are the 3 main factors that potentiate warfarin action and so increase risk of haemrrhage?

liver disease
high metabolic rate
drug interactions

287

why might liver disease potentiate warfarin?

decreased clotting factors

288

why might high metabolic rate potentiate warfarin?

increased clearance of clotting factors

289

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

290

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

291

what types of physiological states may lessen warfarin action and increase risk of thrombosis?

hypercoaguable states
low metabolic states (decreased degradation of clotting factors)

292

what is antithrombin III? (AT III)

clotting factor inhibitor
(binds to clotting factors rendering them inactive)

293

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

294

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

295

what factors do LMWHs inhibit?

Xa
(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)

296

what is the order of elimination of herparin?

zero order kinetics

297

what is the order of elimination of LMWHs?

first order kinetics

298

why is heparin preferred to LMWH in renal failure?

LMWH is excreted by renal ecretion

299

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

300

what are the 4 adverse affects of heparin gnd LMWHs?

haemorrhage
osteoporosis (long term)
hypoaldosteronism
hypersensitivity reactions

301

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)

302

what is the benefit of dabigatran and rivaroxaban over heparin and LMWHs?

orally active agents
(no need for IV)
less haemorhage risk

303

what factor does dabigatran inhibit?

IIa (thrombin)

304

what factor does rivaroxaban inhibit?

Xa

305

when are rivaroxaban and dabigatran used clinically?

to prevent venous thrombosis in patients undergoing hip and knee replacements

306

what is the function of von willebrand factor?

allows platelets to adhere to endothelium

307

what do ADP, 5HT and TXA2 do?

act on the cell surface receptor of platelets to cause aggregation and cross linking via fibrinogen

308

what enzyme does aspirin block irreversibly?
(and what effect does this have?)

cyclo-oxygenase 1
(COX 1)
in platelets: prevents the synthesis of thromboxane A2 (TXA2) and so prevents stimulation of aggregation and cross-linking (adhesion)

309

what does clopidogrel block irreversibly?

P2Y(12) receptor on platelets
prevents ADP binding to receptor and stimulation of aggregation and cross-linking (adhesion)

310

what does tirofiban block?

GPIIb/IIa receptor on platelt to prevent the cross-linking by fibrinogen

311

what type of thrombosis are anti-platelet drugs used in?

arterial thrombosis

312

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)

313

describe the fibrinolytic cascade?

opposes coagulation cascade
plasminogen is converted to plasmin which breaks down the fibrin into fibrin fragments causing clot lysis

314

what type of agents up regulated the conversion of plasminogen to plasmin?

fibrinolytic agents eg tPA, strptokinase

315

how are fibrinolytic drugs administered?

IV
(within as short a period as possible of the event)

316

what are fibinolytics used for clinically?

reopen occluded arteries eg MI or stroke
less freq: reopen life-threatening venous thrombosis or PE

317

why are fibrinolytics not given to every patient who has had an acute MI?

because PCI is superior if aviable promptly

318

why is action of streptokinase blocked after 4 days?

generation of antibodies

319

to what patients should you not give streptokinase?

to patients with recent streptococcal infections

320

how are tPAs administered?

IV (because of short half life)