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The Cardiovascular System > Pharmacology 1 - Drugs Affecting Vasculature and Blood Pressure > Flashcards

Pharmacology 1 - Drugs Affecting Vasculature and Blood Pressure Flashcards

1
Q

What confers the ability for muscle contraction?

A

Concentration of intracellular calcium

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2
Q

By which two methods can calcium levels within vascular smooth muscle be elevated?

A
  1. Opening L-type calcium channels (depolarisation)
  2. Release of Ca2+ from sarcoplasmic reticulum (mediated by Gq11)
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3
Q

How is myosin light chain kinase activated?

A

When calcium binds to calmodulin it can activate MLCK

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4
Q

What happens to myosin light chain during relaxation?

A

Myosin light chain phosphotase will will dephosphorylate MLC allowing for relaxation

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5
Q

How is myosin light chain phosphotase activated?

A

Protein kinase G (activated by cGMP)

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6
Q

Name 3 vasodilating substances found naturally in the body

A
  1. Bradykinin
  2. ADP
  3. 5-HT (hydroxytryptamine) - serotonin
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7
Q

In vascular smooth muscle cells which G protein coupled receptor is activated upon to mediate vasodilatation?

A

Gq

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8
Q

Describe fully, the process involving calcium that results in vasodilatation in vascular smooth muscle

A
  1. Activation of Gq results in increased intracellular calcium concentration
  2. Calcium bind to calmodulin and activates endothelial nitric oxide synthase (eNOS)
  3. eNOS converts L-arginine (with oxygen) to nitric oxide (NO)
  4. NO diffuses across endothelium and promotes conversion of GTP to cGMP by activating guanylate synthase
  5. cGMP can activate protein kinase G which activates MLC phosphotase
  6. MLC is dephosphorylated and relaxation occurs

eNOS also directly stimulates potassium channels (calcium dependent) causing potassium efflux, hyperpolarisation and the prevention of an AP

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9
Q

Which pathway is utilised by the organic nitrates?

A

The pathway for vascular smooth muscle relaxation

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10
Q

How do organic nitrates induce vascular smooth muscle relation?

A
  1. Organic nitrates readily diffuse into smooth muscle cells
  2. Enzymes and thiol groups will convert the organic nitrates to nitric oxide and citrulline
  3. This allows the nitric oxide produced to act as normal and cause relaxation
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11
Q

At low doses organic nitrates preferentially act on the ______ system

A

Venous

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12
Q

Why is venorelaxtion, due to organic nitrates, of benefit?

A

Large veins dilate and venous return to right atrium decreases

Preload and stroke volume decrease

At modest doses cardiac output is maintained by an increase in heart rate

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13
Q

What 3 main effects does organic nitrate adminsitration induce?

A
  1. Venorelaxation
  2. Arteriolar dilatation
  3. Increased coronary flow
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14
Q

Organic nitrates are used as a treatment for ______ ______ and also _____ ________ ________

A

Stable Angina

Acute Coronary Syndrome

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15
Q

Which two effects allow organic nitrates to be a useful treatment for angina?

A
  1. Decreases myocardial oxygen requirement (decreases pre and afterload)
  2. Redirects blood flow from healthy to ischaemic zones using collateral vessels
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16
Q

How do organic nitrates affect coronary circulation?

A

They do not further dilate occluded vessels - these are already at maximum dilatation due to local factors

In long standing CAD vasculature remodelling occurs to bypass the occulsion - it is these collateral vessels which can be dilated

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17
Q

What are the three main organic nitrates?

A
  1. Glyceraltrinitrate - used for all forms of angina
  2. Isosorbide mononitrate
  3. Isosorbide dinitrate - must be metabolised first
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18
Q

What are the four types of angina?

A
  1. Stable - presents with exertion and relieved by rest
  2. Unstable - presents acutely at rest
  3. Decubitus - presents when lying flat
  4. Variant (Prinzmetal’s) - due to coronary artery spasm
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19
Q

Why can GTN not be administered orally?

A

Through its first circulatory pass through the portal system it is inactivated

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20
Q

How should GTN be administered? (4)

A

Spray - towards back of mouth

Sublingual tablet

IV (in ACS)

Transdermal patch with aspirin (in ACS)

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21
Q

What is isosorbide mononitrate primarily used for?

A

Prophylactic treatment of angina

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22
Q

What are some side effects of organic nitrates?

A
  • Tolerance
  • Postural hypotension
  • Heachaches (dilatation of cranial circulation)
  • Formation of methaemoglobin - unable to release oxygen
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23
Q

To avoid the problems associated with tolerance, how can organic nitrates be adminstered?

A

For morning/mid-afternoon use

This can reverse tolerance alowing the drug to be deplated from the body during the night

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24
Q

What is endothelin-1?

A

A vasoconstrictor produced in response to vasoconstricting substances

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25
Q

Name 3 vasoconstricting substances that initiate endothelin-1 production

A
  1. ADH
  2. Adrenaline
  3. Angiotensin II
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26
Q

What substances/events can suppress endothelin-1 production?

A
  1. Nitric oxide
  2. Natriuretic peptides (A, B and C)
  3. Shear stress on endothelium from blood flow
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27
Q

How is endothelin-1 produced by vasoconstricting agent release?

A

Vasoconstricting agents alter gene expression to allow for precursors of endothelin to be produced

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28
Q

How does the production of endothelin-1 lead to vasoconstriction?

A
  • Endothelin-1 is exported from endothlial cells
  • It binds to a g protein coupled receptor (Gq11) called ETA
  • Intracellular calcium is increased causing contraction
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29
Q

In the therapeutic treatment of hypertension, which agents can be used as antagonists for endothelin-1

A

Bosentan and ambrisentan

(for pulmonary hypertension)

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30
Q

In what circumstances would renin be released?

A
  1. Decreased renal perfusion pressure
  2. Increase in renal sympathetic nerve activity
  3. Decrease in glomerular filtration
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31
Q

The renin-angiotensin-aldosterone system aims to restore ______ blood pressure

A

Higher/normal

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32
Q

Where is renin secreted from?

A

The juxtaglomerular cells (in the kidney)

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33
Q

What is the role of renin in the RAAS pathway?

A

It splits off 10 amino acids from angiotensinogen (produced in the liver) which comine to form angiotensin 1

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34
Q

How is angiotensin II formed?

A

Angiotensin converting enzyme coverted angiotensin I to angiotensin II

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35
Q

After angiotensin II is formed, how does it exert its effect?

A

Via AT1 receptors (G protein coupled) in vascular smooth muscle cells. Angiotensin II binds to sympathetic neurones increasing noradrenaline release (acts on alpha 1 receptors) which initiates vasoconstriction

Angiotensin II also stimulates aldosterone release from the adrenal cortex

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36
Q

Where is aldosterone released from?

A

Adrenal cortex

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37
Q

What does aldosterone do?

A

Causes salt and water reabsorption from the kidneys increases circulating volume and blood pressure

38
Q

What is aliskiren?

A

A renin inhibitor

39
Q

What is an ACE inhibitor?

A

An angiotensin converting enzyme inhibitor

40
Q

Besides inhibiting ACE direcetly, how else can the action of angiotensin II be inhibited?

A

Blocking AT1

41
Q

As well as converting angiotensin I to II, what else does ACE do?

A

Inactivates bradykinin - a vasodilator

42
Q

Give an example of an ACEI

A

Lisinopril

43
Q

Give an example of an angiotensin II receptor blocker

A

Losartan

44
Q

ACE inhibitors have which two outcomes?

A
  1. Decreased preload by venous dilatation
  2. Decreased afterload and TPR due to arteriolar dilatation
45
Q

Why is aldosterone production not completely abolished usder the influence of an ACEI?

A

Its release is also controlled by plasma potassium levels

46
Q

Why do ACEIs lower blood pressure?

A
  1. Bradykinin is not inactivated - vasodilation can occur
  2. Aldosterone is reduced which decreases salt and water uptake by the kidneys decreasing blood volume
  3. Arterial and venous dilatation occurs
47
Q

Why do healthy individuals have little response to ACEIs?

A

The RAAS system is not particularly active

48
Q

Which two factors affect how active the RAAS system is except for health?

A
  1. Age
  2. Ethnicity - more active in black individuals
49
Q

In which parts of the body will ACEIs have the biggest effect?

A

Brain, kidneys, heart

(tissues with highest levels of angiotensin I receptor)

50
Q

What are some side effects of ACEIs?

A
  1. Initial hypotension
  2. Dry cough - build up of bradykinin in airways
51
Q

Which key side effect is avoided by using a angiotensin receptor blocker (ARB) instead of an ACEI?

A

Dry cough

(bradykinin metabolism is not affected)

52
Q

What three clinical uses are there for both ACEI and ARBs?

A
  1. Hypertension
  2. Cardiac failure
  3. MI
53
Q

Beta blockers act on which type of receptor in the heart?

A

B1 adrenoceptors

(G protein coupled (Gs))

54
Q

What are the two groups of adrenoceptors?

A

Alpha (I and II)

Beta (I, II and III)

55
Q

What are B blockers used to treat and why?

A

Angina

They help to promote vasodilatation

56
Q

Why is it recommended to use a selective beta blocker versus a non selective variant?

A

B1 adrenoceptor antaginists will promote vasodilatation

B2 adrenoceptor antagnists will block the natural vasodilation conferred by agonist binding

57
Q

Blocking B2 adrenoceptors worsens which type of disease?

A

Variant angina

(caused by intermittent coronary artery spasm)

58
Q

B1 blockers decrease myocardial ______ ___________.

A

Oxygen requirement

(by reducing HR, SV and CO)

59
Q

How do beta blockers aid ventricular perfusion?

A

Ventricles can only be perfused during diastole as the coronary arteries become occluded during systole.

By slowing the heart rate, the length of time the heart is in diastole increases inceasing the time the heart is perfused

60
Q

What are some of the side effects that have lead beta blockers to no longer be top of the list as a treatent for hypertension?

A
  1. Unfavourable effect on blood lipids encouraging bad cholesterol
  2. Increased triglyceride levels
61
Q

If a patient suffers from both angina and hypertension which class of drug may be utilised that normally wouldn’t be for hypertension?

A

Beta Blocker

62
Q

Why do beta blockers improve coronary circulation?

A

Heart rate is slowed, contractile force is reduced and the time the ventricles can be perfused (during diastole) is increased

63
Q

How do beta blockers affect renin production?

A

They reduce renin production

Beta blockers are as effective at this in low renin concentrations as they are in high concentrations

64
Q

Why are beta blockers administered at a very low initial dose?

A

Beta blockers have initially negative effects

To minimise this low doses are used which build to higher doses after the window for the most negative effects has passed

65
Q

How do calcium channel blockers affect the vascualture?

A

Calcium influx is limited meaning contractile ability of smooth muscle is reduced allowing for vasodilatation

66
Q

What three effects does a calcium antagonist have in the heart?

A
  1. Rate of SA node discharge is reduced
  2. AV node conduction is impaired
  3. Cardiac contractility is reduced (L-type channels in plateau phase blocked)
67
Q

How are calcium channels normally activated in the vasculature?

A

When noradrenaline is released it activates alpha I adrenoceptors which activate non-selective cation channels open causing sodium influx hyperpolarising the cell and activating voltage gated calcium channels which allows contraction to occur

68
Q

What are the three main type of calcium antagonist?

A
  1. Verapamil - act on L-type selectively (heart not vasculature)
  2. Amlodipine - selective for L-type channels in vasculature
  3. Diltiazem - intermediate selectively for channels in the heart and vasculature
69
Q

Clinically which three conditions can calcium antagonists be used for?

A
  1. Hypertension
  2. Angina
  3. Dysrhythmias
70
Q

Describe the effect amlodipine has on the vascualture

A

L-type channels are blocked reducing calcium entry

Vasodilatation is promoted

TPR and MABP are reduced

Arteries are most affected (more smooth muscle)

71
Q

Why would it be bad for a calcium channel blocker to block all calcium channel types?

A

This would inhibit contraction to dangerous levels and negatively impact the heart

72
Q

How are calcium antagonists used for angina?

A

Prophylactically

73
Q

Why are calcium antagonist particularly useful for angina?

A

They cause peripheral arterioar dilatation reducing afterload and therefore myocardial oxygen requirement

74
Q

Calcium antagonist allow for coronary _______________.

A

Vasodilatation

75
Q

Why is amlodipine superior to other calcium antagonists for angina?

A

It is long acting and does not have any negative ionotropic effects

76
Q

Verapamil is used in which instance?

A

Atrial fibrillation

But not in conjuction with a beta blocker or when heart failure is also present

77
Q

How do potassium channel openers work?

A
  1. Intracellualr ATP is antagonised which normally closes the channels
  2. Potassium efflux occurs - the cell becomes hyperpolarised
  3. The hyperpolarised state inhibits L-type calcium channels
  4. This will therefore prevent contraction
78
Q

Name two potassium channel openers

A
  1. Minoxidil - drug of last resort
  2. Nicorandil - used for angina
79
Q

What 3 effects does activiting alpha 1 channels have?

A
  1. Activates non-selective cation channels for sodium influx
  2. Depolarised state activates calcium channels for calcium influx
  3. Increases calcium release from sarcoplasmic reticulum
80
Q

Blocking alpha 1 receptors has what effect?

A

Vasodilatation occurs

(calcium channels cannot be activated)

MABP is decreased

81
Q

What are two alpha 1 receptor antagonists?

A
  1. Prazosin
  2. Doxazosin
82
Q

Which type of drugs will be used for benign prostatic hyperplasia?

A

Alpha 1 receptor antagonists

83
Q

What is the main side effect of alpha 1 antagonists?

A

Postural hypotension

84
Q

What are the two main classes of diuretics?

A

Thiazide and loop

85
Q

What is the effect of thiazide diuretics?

A

NACL reabsorption is reduced in the distal renal tubules

This occurs as a result of blocking the Na/Cl co-transporter

This confers a moderate diuresis

86
Q

What is the effect of a loop diuretic?

A

NaCl reabsorption is inhibited by blocking the Na/K/2Cl co-transporter in the ascending loop of Henle

This produces a strong diuresis

87
Q

What is the negative effect of the diuretic class of drugs and how is this counteracted?

A

Too much potassium is lost

  • Potassium supplements can be taken
  • Potassium sparing diuretics can be used
88
Q

Name a thiazide diuretic

A

Bendroflumethiazide

89
Q

Thiazide diuretics are used in what types of disease?

A
  • Mild heart failure
  • Hypertension
  • Severe resistant oedema (potentially also with loop)

(Also in pulmonary oedema)

90
Q

Name a loop diuretic

A

Furosemide

The Cardiovascular System (24 decks)

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