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Cardiology > Drugs used in vasculature + hypertension > Flashcards

Drugs used in vasculature + hypertension Flashcards

1
Q

What does vascular smooth muscle contraction rely on?

A
  • intracellular (+ extracellular) calcium
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2
Q

Which two methods increase intracellular calcium?

A

1) influx down electrochemical gradient
- 1.2 mmol calcium (intracellular); 1-2 x10^7 moles calcium (extracellular) - big drive to move calcium into cell
- calcium is positively charged; inside cell is -ve charged
2) calcium induced calcium release from SR within cells

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3
Q

How does calcium enter the cell?

A
  • plasma membrane is impermeable to calcium (cannot enter by diffusion)
    1) Voltage activated calcium channels open in response to depolarisation of muscle cell
  • L type calcium channels open
  • Calcium moves inwards

2) G protein coupled receptor activation can callow calcium entry + contraction
- alpha 1 adrenoceptor binds to Gqg11
- causes IP3 activation
- IP3 acts on receptors in SR
- CICR from SR

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4
Q

Describe the stages in which calcium causes contraction

A
  • calcium binds to intracellular calcium binding protein called calmodulin
  • forms activated calcium-calmodulin complex
  • converts myosin light chain kinase from inactive-active form
  • MLCK phosphorylates myosin light chain (in contractile proteins)
  • actin-myosin crossbridges form
  • sliding filament action
  • contraction
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5
Q

What is the role of myosin light chain phosphatase + how does it cause vascular smooth muscle relaxation?

A
  • myosin light chain phosphatase requires activation
  • this activation comes from cyclic guanosine monophosphate (cGMP)
  • phosphate added to MLCK is stripped off
  • myosin light chain in contractile proteins no longer phosphorylated
  • cross bridges turn off
  • relaxation
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6
Q

What does endothelium separate?

A
  • smooth muscle from blood
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7
Q

Describe the properties of nitric oxide

A
  • readily diffuses across cell membranes
  • soluble
  • ideal for signalling between endothelial and smooth muscle cells
  • acts in paracrine manner (signals between adjacent cells)
  • readily inactivated
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8
Q

What mediates the production of NO by endothelial cells?

A

VASODILATING SUBSTANCES

  • bradykinin
  • 5-hydroxyl tryptine (serotonin)
  • ADP
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9
Q

What do these mediator substances do?

A
  • modulate tone of vasculature

- act on G protein receptors (apical membrane of endothelial cell)

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10
Q

Increasing intracellular calcium causes what?

A
  • binding of calcium to calmodulin - formation of calcium-calmodulin complex
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11
Q

What does calcium-calmodulin stimulate?

A
  • synthesis of enzyme endothelionitric oxide synthase (eNOS)
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12
Q

What does eNOS do?

A
  • binds L-arginine and O2

- converts them to nitric oxide + citrulline

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13
Q

Once NO diffuses across endothelial cell membrane into vascular smooth muscle what does it do?

A
  • activates guanylate cyclase
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14
Q

What does gaunylate cyclase do?

A
  • converts GTP to guanosine monophosphate (cGMP) (liberates 2 phosphates)
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15
Q

What does cGMP do?

A
  • stimulates production of protein kinase G
  • activates myosin light chain phosphatase
  • removes phosphorylate from contractile proteins (myosin light chain)
  • turns of cross bridges
  • relaxation
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16
Q

How does NO cause hyper polarisation?

A
  • Calcium channel is activated by NO
  • Calcium dependent K+ channel activated (by depolarisation and Ca2+ entry)
  • K+ flows down electrochemical gradient (leaves cells)
  • hyperpolarisation occurs
  • relaxation
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17
Q

What do organic nitrates do?

A
  • act like a pharmacological endothelium
  • bind to tissue enzymes/thiol groups in vasc smooth muscle
  • allows conversion of GTP-cGMP
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18
Q

What type of muscle do organic nitrates relax?

A
  • ALL TYPES OF SMOOTH MUSCLE (via their metabolism to NO)
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19
Q

How do clinical does of organic nitrates act upon vasculature?

A
  • act preferentially upon vasculature
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20
Q

How do organic nitrates affect veins?

A
  • causes VENORELAXATION
  • decreases central venous pressure (decreased preload)
  • reduces SV
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21
Q

Do organic nitrates affect cardiac output?

A
  • no (SV is reduced but HR is increased to maintain CO)
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22
Q

How do organic nitrates affect arteries?

A
  • arteriolar dilatation
  • decreases arterial pressure
  • reduces afterload
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23
Q

How do organic nitrates affect blood flow?

A
  • increase coronary blood flow (in normal people)

- in angina, there is no increase in blood flow but blood is REDIRECTED TOWARDS ISCHAEMIC ZONE

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24
Q

What are the benefits of organic nitrates in patients with angina?

A

DECREASED MYOCARDIAL REQUIRMENT via:

1) decreased preload
2) decreased after load
3) improved perfusion of ischaemic zone

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25
Q

What is the effect of nitrates on collateral vessels?

A
  • increases dilatation of collateral vessels
  • bypasses obstruction
  • increases blood flow to ischaemic area
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26
Q

Give properties of GTN

A
  • short acting (30 mins)
  • undergoes extensive first pass metabolism (via liver)
  • therefore unsuitable for oral administration
  • liver inactivates it - doesn’t enter systemic circulation
  • administered sublingually (as spray/tablet)
  • rapid effect before exertion (stable angina)
  • can be given IV (in conjunction with aspirin) in unstable angina
  • more sustained effect is obtained if delivered via transdermal patch
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27
Q

Give properties of isosorbide mononitrate

A
  • longer acting than GTN
  • half life = 4.5 hours
  • reistant to 1st pass metabolism (can be given as tablet)
  • administered orally for prophylaxis + more sustained effect
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28
Q

Describe unwanted effects of organic nitrates

A
  • repeated administration may be associated with diminished affect (can be minimised by nitrate low periods e.g. at night)
  • throbbing headaches (due to cranial vasodilation)
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29
Q

Why is GTN administered IV with aspirin in unstable angina?

A
  • high risk of MI (due to atheromatous plaque)
  • aspirin = anti-platelet drug
  • relieves ischaemia + reduces risk of infarct
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30
Q

Describe the role of endothelium in vascular smooth muscle contraction

A
  • altered gene expression
  • releases endothelia precursors
  • produces ENDOTHELIN 1
  • endothelin 1 binds to endothelia A receptor (smooth muscle membrane)
  • couples with Gqg11
  • increase in intracellular Ca2+
  • contraction
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31
Q

What is endothelin?

A
  • 3 types in body
  • endothelin 1 determines CVS function
  • peptide synthesised by endothelial cells
  • released from basal side (facing vasculature)
  • cause smooth muscle contraction by acting upon G protein coupled receptors (Eta)
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32
Q

What factors (if increased) can cause altered gene expression (+ production of endothelin)?

A
  • adrenaline
  • angiotensin 2
  • ADH (vasopressin)
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33
Q

What factors (if decreased) can cause altered gene expression (+ production of endothelin)?

A
  • nitric oxide
  • natriuretic peptides (A/B/C)
  • shear stress
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34
Q

Name 2 antagonists of the ETa receptor

A
  • ambrisentan

- bosentan

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35
Q

What do ET A receptor antagonists treat?

A
  • pulmonary hypertension
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36
Q

What does the RAAS play a major role in the regulation of?

A
  • sodium excretion

- vascular tone

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37
Q

What can increase the production of renin from the juxtaglomerular apparatus in kidney?

A
  • increased renal sympathetic nerve activity
  • decreased renal perfusion pressure
  • decreased glomerular filtration
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38
Q

Where is angiotensinogen produced?

A
  • liver
39
Q

What does angiotensinogen do?

A
  • converts renin to angiotensin 1
40
Q

What converts angiotensin 1- 2?

A
  • angiotensin converting enzyme (ACE)
41
Q

What does angiotensin 2 bind to?

A
  • AT 1 receptor (G protein coupled receptor)
42
Q

When angiotensin2 binds to AT1 what is the effect on the organs?

A
  • contraction of vasc smooth muscle
  • cell growth (heart/arteries)
  • aldosterone secretion from renal cortex
43
Q

Why does angiotensin 2 cause vasc smooth muscle contraction?

A
  • activation of smooth muscle AT1 receptors

- increased release of adrenaline from sympathetic nerves

44
Q

What is the effect of aldosterone secretion from adrenal cortex?

A
  • tubular sodium reabsorption and salt retention
45
Q

Overall what are the 2 major outcomes of RAAS?

A
  • increased MABP

- increased blood volume (+ MABP)

46
Q

Where is ACE found? What is it?

A
  • on the surface of endothelial cells

- membrane-bound enzyme

47
Q

What does ACE do?

A
  • converts inactive angiontensin 1 - active angiotensin 2 (vasoconstrictor)
  • inactivates bradykinin (vasodilator in endothelin pathway)
48
Q

Name 2 ACEI

A
  • lisinopril

- enalapril

49
Q

What do ACEI do?

A
  • blocks conversion of angiotensin 1-2
  • venous dilation (decreases preload)
  • arteriolar dilation (decreases after load + TPR)
  • Decreases cardiac load + blood pressure
50
Q

What is the effect of ACEI on cardiac contractility?

A
  • none

- CO may increase as a result of reduced TPR

51
Q

What are ACEIs effect on aldosterone?

A
  • reduce (don’t abolish) release

- promotes loss of salt and water

52
Q

Where do ACEI have the greatest effect?

A
  • angiotensin selective vascular beds (AT1 receptors)

- situated in brain/heart/kidneys: maintains perfusion of critical organs

53
Q

Why do ACEIs cause dry cough?

A
  • accumulation of bradykinin in airways
  • irritation of sensory nerves in lung
  • cough reflex
54
Q

What are ARBs?

A
  • angiotensin 1 (AT1) receptor blockers
55
Q

Name an ARB

A
  • losartan
56
Q

What is the effect of ARB?

A
  • similar properties to ACEI
  • do not affect metabolism of bradykinin
  • useful in patients with dry cough who find ACEI intolerable
57
Q

Describe 3 uses for ACEIs + ARBs

A

1) hypertension: reduce TPR + MABP; suppression of proliferation of smooth muscle in media of resistance vessels
2) cardiac failure: associated with inappropriate activation of RAAS; decrease vascular resistance (improves perfusion); increases sodium/water excretion; regresses LVH
3) MI: similar as cardiac failure

58
Q

What is an adrenoceptor?

A
  • g protein coupled receptor

- activated by sympathetic transmitter NA/adrenaline

59
Q

What do beta1 adrenoceptors do?

A
  • increase HR; force; AV node conduction velocity
60
Q

What do beta2 adrenoceptors do?

A
  • relax vascular smooth muscle
61
Q

Give an alternative name for beta blockers

A
  • Beta adrenoceptor antagonists
62
Q

What are b blockers used to treat?

A
  • angina (stable/unstable) NOT VARIANT
  • hypertension
  • heart failure
63
Q

Why are b1 selective agents preferred?

A
  • decrease myocardial O2 requirement (decrease HR/SV/cardiac work)
  • counter elevate sympathetic activity associated with ischaemic pain
  • increase diastole (decrease HR + AV node conduction velocity) = IMPROVES PERFUSION OF LEFT VENTRICLE (via coronary arteries)
64
Q

Why are b blockers used in hypertension?

A
  • reduce CO
  • reduce MAP
  • CO returns to normal over time
  • TPR resets itself to lower level = MAP decreases
  • reduces renin release from kidneys
  • reduced sympathetic activity
65
Q

Why are b blockers used to treat heart failure?

A
  • in combo with other drugs

- suppress adverse effects of elevated activity of RAAS

66
Q

What are calcium antagonists mechanism of action?

A
  • prevent opening of LTCC in excitable tissues in response to depolarisation
  • reduces influx of Ca2+
67
Q

What do LTCC mediate?

A
  • upstroke of AP in SA/AV nodes (calcium antagonists reduce rate and conduction through AV node)
  • Plateau phase of ventricular AP (calcium antagonists reduce force of contraction)
68
Q

What are ROCs?

A
  • receptor operated channels

- cation selective channels

69
Q

What do ROCs do?

A
  • open
  • allow Na+ to enter smooth muscle
  • cause depolarisation
  • opening of LTCC
  • Ca2+ influx
70
Q

Name 3 calcium blockers

A
  • verapamil
  • amlodipine
  • diltiazem
71
Q

Which of these 3 calcium blockers a) reduces HR b)reduces BP?

A

a) verapamil + diltiazem

b) amlodipine (causes relfex tachycardia)

72
Q

What is amlodipine?

A
  • dihydropyridine compound

- relatively selective for smooth muscle LTCC

73
Q

What is the effect of calcium blockers on hypertension?

A
  • reduces Ca2+ entry into vasc smooth muscle
  • arteriolar dilation
  • reduced TPR/MABP
  • little effect on veins
74
Q

Why are drugs acting on smooth muscle LTCC preferred (e.g. amlodipine) to drugs acting on cardiac LTCC?

A
  • minimises unwanted effects on cardiac muscle

e. g. in patients with hypertension + heart failure/block

75
Q

What other conditions are calcium blockers advised for?

A
  • angina

- systolic hypertension

76
Q

What is the effect of calcium blockers in angina?

A
  • prophylactic treatment, used in combo with GTN
  • used if beta blockers are contraindicated
  • peripheral arteriolar dilation; decreases afterload/O2 requirement
    PRELOAD NOT CHANGED
  • coronary vasodilation (useful in variant angina)
77
Q

What is the effect of diltiazem + verapamil on angina?

A

-negative inotropic effects; later offset by baroreceptor activation in response to vasodilation + increased sympathetic activity

78
Q

What else can calcium blockers treat?

A
  • dysrhythmias
  • ventricular rate in rapid atrial fibrillation reduced by suppression of conduction through AV node
  • verapamil is usually used
79
Q

What is the contraindication of treating dysrhythmias with verapamil + a b blocker in HEART FAILURE?

A

Both cause reduction of conduction through AV node

Can cause heart block

80
Q

Describe the mechanism of potassium channel openers

A
  • K+ channel openers open ATP-modulated K+ channels (Katp) in vascular smooth muscle
  • They act by antagonising intracellular ATP (which closes Katp channels)
  • cause hyperpolarisation
  • switch off LTCC
  • act potently + primarily on arteriolar smooth muscle
81
Q

Name 2 potassium channel openers and their mechanism of action

A

a) MINOXIDIL: used as a drug of last resort in severe hypertension; causes reflex tachycardia (prevented by a beta blocker) and Na+/h20 retention (prevented by a diuretic)
b) NICORANDIL: has NO donor activity; used in angina refractory to other treatments

82
Q

What do alpha 1 adrenoceptor antagonists do?

A
  • cause vasodilation
  • block vascular a1 adrenoceptors
  • reduced sympatehtic transmisson - decreased MABP
83
Q

Name 2 alpha adrenoceptor antagonists

A
  • prazosin

- doxasozin

84
Q

What else can alpha 1 adrenoceptors be used for?

A
  • benign prostatic hyperplasia (abnormally enlarged prostate that compresses the urethra)
  • particularly indicated for hypertensive patients with this condition
85
Q

Name an adverse effect of alpha1 adrenoceptor antagonists

A
  • postural hypotension (decrease in BP upon standing)
86
Q

What do diuretics do?

A
  • act on the kidney
  • increase excretion of sodium, chlorine and water
  • exert additional relaxant effects upon vasculature
87
Q

What is the mechanism of action of thiazide diuretics?

A
  • inhibit NaCl absoorption in the distal tubule (block the Na+/Cl- co-transporter)
  • Cause upto 5% of filtered Na+ to be excreted alongside water
  • produces moderate diuresis
88
Q

What is the mechanism of action of loop diuretics?

A
  • inhibit NaCl reabsorption in the thick ascending limb of the loop of Henle
  • block Na+/K+/2Cl- co-transporter
  • cause upto 15-25% of filtered Na+ to be excreted alongside water
  • strong diuresis
89
Q

Name a thiazide + conditions it is used in

A

bendroflumethiazide

  • mild heart failure
  • hypertension
90
Q

What is the effect of loss of salt/water on cardiac output/BP?

A
  • loss of Na+/water contracts blood volume
  • initially reduces cardiac output
  • cardiac output eventually returns to normal
  • MABP remains depressed through lowering of TPR
91
Q

Name a loop diuretic + conditions it is used in

A

furosemide

  • acute pulmonary oedema (IV)
  • chronic heart failure

Used to reduce salt/water overload associated with these conditions

92
Q

Diuretic induced reduction of blood volume exerts which benefit?

A
  • absorption of extracellular fluid (contributing to oedema) into capillaries
93
Q

What condition can be treated with both a thiazide + loop diuretic?

A
  • severe resistant oedema
94
Q

What is an undesirable effect of diuretic treatment?

A
  • loss of K+ (occurring through Na+/K+ exchange in distal tubule)
  • can be corrected by co-administration of a ‘potassium sparing diuretic’ or K+ supplements

Cardiology (6 decks)

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