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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
What is the effect of nitrates on collateral vessels?
- increases dilatation of collateral vessels - bypasses obstruction - increases blood flow to ischaemic area
26
Give properties of GTN
- 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
27
Give properties of isosorbide mononitrate
- 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
28
Describe unwanted effects of organic nitrates
- 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)
29
Why is GTN administered IV with aspirin in unstable angina?
- high risk of MI (due to atheromatous plaque) - aspirin = anti-platelet drug - relieves ischaemia + reduces risk of infarct
30
Describe the role of endothelium in vascular smooth muscle contraction
- 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
31
What is endothelin?
- 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)
32
What factors (if increased) can cause altered gene expression (+ production of endothelin)?
- adrenaline - angiotensin 2 - ADH (vasopressin)
33
What factors (if decreased) can cause altered gene expression (+ production of endothelin)?
- nitric oxide - natriuretic peptides (A/B/C) - shear stress
34
Name 2 antagonists of the ETa receptor
- ambrisentan | - bosentan
35
What do ET A receptor antagonists treat?
- pulmonary hypertension
36
What does the RAAS play a major role in the regulation of?
- sodium excretion | - vascular tone
37
What can increase the production of renin from the juxtaglomerular apparatus in kidney?
- increased renal sympathetic nerve activity - decreased renal perfusion pressure - decreased glomerular filtration
38
Where is angiotensinogen produced?
- liver
39
What does angiotensinogen do?
- converts renin to angiotensin 1
40
What converts angiotensin 1- 2?
- angiotensin converting enzyme (ACE)
41
What does angiotensin 2 bind to?
- AT 1 receptor (G protein coupled receptor)
42
When angiotensin2 binds to AT1 what is the effect on the organs?
- contraction of vasc smooth muscle - cell growth (heart/arteries) - aldosterone secretion from renal cortex
43
Why does angiotensin 2 cause vasc smooth muscle contraction?
- activation of smooth muscle AT1 receptors | - increased release of adrenaline from sympathetic nerves
44
What is the effect of aldosterone secretion from adrenal cortex?
- tubular sodium reabsorption and salt retention
45
Overall what are the 2 major outcomes of RAAS?
- increased MABP | - increased blood volume (+ MABP)
46
Where is ACE found? What is it?
- on the surface of endothelial cells | - membrane-bound enzyme
47
What does ACE do?
- converts inactive angiontensin 1 - active angiotensin 2 (vasoconstrictor) - inactivates bradykinin (vasodilator in endothelin pathway)
48
Name 2 ACEI
- lisinopril | - enalapril
49
What do ACEI do?
- blocks conversion of angiotensin 1-2 - venous dilation (decreases preload) - arteriolar dilation (decreases after load + TPR) - Decreases cardiac load + blood pressure
50
What is the effect of ACEI on cardiac contractility?
- none | - CO may increase as a result of reduced TPR
51
What are ACEIs effect on aldosterone?
- reduce (don't abolish) release | - promotes loss of salt and water
52
Where do ACEI have the greatest effect?
- angiotensin selective vascular beds (AT1 receptors) | - situated in brain/heart/kidneys: maintains perfusion of critical organs
53
Why do ACEIs cause dry cough?
- accumulation of bradykinin in airways - irritation of sensory nerves in lung - cough reflex
54
What are ARBs?
- angiotensin 1 (AT1) receptor blockers
55
Name an ARB
- losartan
56
What is the effect of ARB?
- similar properties to ACEI - do not affect metabolism of bradykinin - useful in patients with dry cough who find ACEI intolerable
57
Describe 3 uses for ACEIs + ARBs
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
What is an adrenoceptor?
- g protein coupled receptor | - activated by sympathetic transmitter NA/adrenaline
59
What do beta1 adrenoceptors do?
- increase HR; force; AV node conduction velocity
60
What do beta2 adrenoceptors do?
- relax vascular smooth muscle
61
Give an alternative name for beta blockers
- Beta adrenoceptor antagonists
62
What are b blockers used to treat?
- angina (stable/unstable) NOT VARIANT - hypertension - heart failure
63
Why are b1 selective agents preferred?
- 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
Why are b blockers used in hypertension?
- 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
Why are b blockers used to treat heart failure?
- in combo with other drugs | - suppress adverse effects of elevated activity of RAAS
66
What are calcium antagonists mechanism of action?
- prevent opening of LTCC in excitable tissues in response to depolarisation - reduces influx of Ca2+
67
What do LTCC mediate?
- 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
What are ROCs?
- receptor operated channels | - cation selective channels
69
What do ROCs do?
- open - allow Na+ to enter smooth muscle - cause depolarisation - opening of LTCC - Ca2+ influx
70
Name 3 calcium blockers
- verapamil - amlodipine - diltiazem
71
Which of these 3 calcium blockers a) reduces HR b)reduces BP?
a) verapamil + diltiazem | b) amlodipine (causes relfex tachycardia)
72
What is amlodipine?
- dihydropyridine compound | - relatively selective for smooth muscle LTCC
73
What is the effect of calcium blockers on hypertension?
- reduces Ca2+ entry into vasc smooth muscle - arteriolar dilation - reduced TPR/MABP - little effect on veins
74
Why are drugs acting on smooth muscle LTCC preferred (e.g. amlodipine) to drugs acting on cardiac LTCC?
- minimises unwanted effects on cardiac muscle | e. g. in patients with hypertension + heart failure/block
75
What other conditions are calcium blockers advised for?
- angina | - systolic hypertension
76
What is the effect of calcium blockers in angina?
- 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
What is the effect of diltiazem + verapamil on angina?
-negative inotropic effects; later offset by baroreceptor activation in response to vasodilation + increased sympathetic activity
78
What else can calcium blockers treat?
- dysrhythmias - ventricular rate in rapid atrial fibrillation reduced by suppression of conduction through AV node - verapamil is usually used
79
What is the contraindication of treating dysrhythmias with verapamil + a b blocker in HEART FAILURE?
Both cause reduction of conduction through AV node | Can cause heart block
80
Describe the mechanism of potassium channel openers
- 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
Name 2 potassium channel openers and their mechanism of action
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
What do alpha 1 adrenoceptor antagonists do?
- cause vasodilation - block vascular a1 adrenoceptors - reduced sympatehtic transmisson - decreased MABP
83
Name 2 alpha adrenoceptor antagonists
- prazosin | - doxasozin
84
What else can alpha 1 adrenoceptors be used for?
- benign prostatic hyperplasia (abnormally enlarged prostate that compresses the urethra) - particularly indicated for hypertensive patients with this condition
85
Name an adverse effect of alpha1 adrenoceptor antagonists
- postural hypotension (decrease in BP upon standing)
86
What do diuretics do?
- act on the kidney - increase excretion of sodium, chlorine and water - exert additional relaxant effects upon vasculature
87
What is the mechanism of action of thiazide diuretics?
- 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
What is the mechanism of action of loop diuretics?
- 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
Name a thiazide + conditions it is used in
bendroflumethiazide - mild heart failure - hypertension
90
What is the effect of loss of salt/water on cardiac output/BP?
- 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
Name a loop diuretic + conditions it is used in
furosemide - acute pulmonary oedema (IV) - chronic heart failure Used to reduce salt/water overload associated with these conditions
92
Diuretic induced reduction of blood volume exerts which benefit?
- absorption of extracellular fluid (contributing to oedema) into capillaries
93
What condition can be treated with both a thiazide + loop diuretic?
- severe resistant oedema
94
What is an undesirable effect of diuretic treatment?
- 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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