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PBL SEM 2 > PBL 6 - PHARMACOLOGY - anti-hypertensive drugs > Flashcards

PBL 6 - PHARMACOLOGY - anti-hypertensive drugs Flashcards

1
Q

what are the aims of anti-hypertensive drugs?

A
  • reduce BP
  • show a predictable dose-effect relationship
  • reduce the incidence of hypertensive complications (eg. CHD, stroke)
  • provide 24h control
  • be effective as a once daily tablet
  • have an acceptable profile of side effects
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2
Q

why is there poor adherence with anti-hypertensive drugs?

A
  • hypertension often has no side effects
  • medications often have side effects
  • patients feel worse while taking medication
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3
Q

what is the equation for BP?

A

BP = CO x TPR

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4
Q

how can cardiac output be lowered in order to reduce the BP?

A

reduce the:

  • heart rate
  • stroke volume
  • plasma volume
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5
Q

how is TPR reduced in order to reduce BP?

A

dilating arterioles

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6
Q

how does SNS increase CO?

A

by stimulating the heart to contract more frequently and with more force

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7
Q

how does the SNS increase TPR?

A

by causing arterioles to constrict

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8
Q

what do they kidneys control?

A

blood volume by regulating electrolyte and water reabsorption — longer term regulation of BP

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9
Q

describe minute-to-minute vs longer term control of BP

A
  • minute-to-minute: SNS

- long term: kidney

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10
Q

what is another name of B-adrenergic receptor blockers?

A

beta blockers

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11
Q

what do names of beta blockers end in?

A

‘olol’

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12
Q

where is adrenaline released from?

A

chromaffin cells in the adrenal gland

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13
Q

what is noradrenaline released from?

A

sympathetic nerves

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14
Q

what do beta blockers do?

A
  • compete with noradrenaline and adrenaline for binding to b1-adrenergic receptors in the heart and kidney
  • reduces HR, force of ventricular contraction and renin release from the kidney
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15
Q

describe the b1-adrenergic receptors

A
  • 3 types of B-adrenergic receptor found in different tissues — B1-subtype in heart and kidney
  • they are all G-protein coupled receptors that employ Gs to simulate adenylate cyclase, cAMP formation and the activation of protein kinase A
  • stimulating the SNS increases HR, the force of ventricular contraction and renin release from the kindey
  • these effects are mediated by NAdr and Adr acting at b1-adrenoceptors in the SA node, ventricular muscle and juxtaglomerular cells in the kidney
  • all suppressed by beta blockers
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16
Q

name and describe some beta blockers

A 
b1-selective blockers:
- atenolol 
- metoprolol
- bisprolol
(all used 1x daily)
  • propranolol and caverdilol are not usually used to treat hypertension
  • propranolol is a non-selective B-blocker — inhibit both B1 and B2 receptors
  • carvedilol is additionally an antagonist at a-adrenergic receptors
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17
Q

describe the clinical use of beta blockers in hypertension treatment

A
  • no longer used as a 1st line drug for treating hypertension
  • used when hypertension is associated with another condition that can benefit from B-receptor blockade eg. angina or HF
  • does not reduce mortality and are not as effective at preventing stroke or MI
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18
Q

what are some common side effects of beta blockers?

A

less well tolerated than other anti-hypertensive drugs

  • cold hands, due to loss of the B2-receptor mediated vasodilation in the skin
  • fatigue, due to the fall in CO and impaired B2-receptor mediation vasodilation in skeletal muscle
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19
Q

what are some less common side effects of beta blockers?

A
  • cardiac depression — loss of response to the sympathetic drive to the heart causes bradycardia — can progress to heart block or heart failure. occurs mainly in elder patients. more likely if given with a calcium channel antagonist
  • bronchoconstriction — due to inhibition of B2 receptors in airways. exacerbation of asthma. more common with non-selective B blockers
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20
Q

describe diuretics

A
  • by reducing salt and water reabsorption from the glomerular filtrate in the kidney, the drugs increase the excretion of Na+, which is followed by water to maintain osmolarity
  • reduces plasma volume and causes a drop in CO
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21
Q

where do diuretics act?

A

in the nephron = functional unit of the kidney

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22
Q

what does the nephron do?

A

separates water, ions and small molecules from the blood, filters to waste and returns components that are needed back to the blood

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23
Q

what does arterial blood pass through as it enters the cortex of the kidney?

A

Bowman’ s capsule — contains glomerulus = tuft of capillaries that filters blood as it flows through

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24
Q

on its journey through the kidney, why are ions and water reabsorbed into the blood?

A

to maintain plasma electrolyte composition and plasma volume

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25
Q

what process do diuretics interfere with and result in?

A

reabsorption process, resulting in an increased loss of salt and water

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26
Q

what are the 2 main sites in the nephron where diuretics work?

A

loop of Henle and the distal convoluted tubule

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27
Q

where is impermeable to water but permeable to ions?

A

the walls of the ascending limb

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28
Q

in the thick ascending limb, what moves ions into epithelial cells?

A

sodium, potassium, and 2 chloride co-transporter (symporter)

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29
Q

how is the epithelial cell’s (in ascending wall) ion composition maintained?

A

there are transporters on the opposite basolateral side of the cell that export the ions to the IF — water doesn’t follow here

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30
Q

what happens to the interstitial fluid on the other side of the ascending wall? what happens here?

A

build up of ions and the tubular fluid becomes dilate/hypotonic — this is the site at which most of the Na+ is reabsorbed from the tubular fluid, into the IF and then back to the circulation

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31
Q

what do loop diuretics block and what is the effect of this?

A
  • block the NaKCl transporter
  • inhibits removal of ions from the tubular fluid in the thick ascending limb of the loop of Henle
  • renal fluid is more concentrated so when it reaches the distal convoluted tubule (permeable to H2O), water osmotic forces draw water from the epithelial cells into the tubular lumen
  • result is increased loss of salt and water from the body
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32
Q

apart from the thick ascending limb, where is salt also reabsorbed?

A

distal convoluted tubule (DCT) (although a smaller proportion of the total)

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33
Q

what transporter is used in the DCT?

A

NaCl co-transporter

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34
Q

what do thiazide diuretics target?

A

NaCl co-transproter

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35
Q

what do thiazide diuretics inhibit?

A

inhibit the NaCl transporter and prevent the removal of Na+ and Cl- from tubular fluid, along with the water that would have travelled with the ions to maintain osmolarity

increased loss of salt and water from the body

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36
Q

epithelial cells in the distal tubule and collecting duct express receptors for what hormone?

A

mineralocorticoid

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37
Q

what is the main endogenous activator of the mineralocorticoid receptor?

A

aldosterone

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38
Q

where is aldosterone produced?

A

adrenal cortex (zona glomerulosa)

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39
Q

what is the result of aldosterone activating the receptors?

A
  • increases the expression of basolateral Na/K pumps, thereby increasing pump activity
  • increases reabsorption of Na+ ions and its accompanying water, while decreasing the reabsorption of K+, which is lost in urine
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40
Q

what drug blocks the mineralocorticoid receptor and what is its effect?

A
  • spironolactone (K+ sparing diuretic)
  • prevents the action of aldosterone
  • causes increased excretion of Na+ and water, while preventing K+ ions in the circulation
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41
Q

what kind of drug is spironolactone?

A

potassium-sparing diuretic

42
Q

name a loop diuretics

A

furosemide

43
Q

name some thiazide diuretics

A
  • chlorothiazide
  • bendroflumethiazide
  • hydrochlorthiazide
  • INDAPAMIDE
  • chlorthalidone
  • metolazone
44
Q

loop diuretic vs thiazide diuretic vs potassium-sparing diuretic

A

loop - furosemide - NaKCl blocker
thiazide - indapamide - NaCl blocker
potassium-sparing - spironolactone - aldosterone antagonist

45
Q

what kind of diuretic is likely to cause hypokalemia?

A

loop diuretics

46
Q

what diuretic can cause dangerous hyperkalaemia?

A

potassium-sparing eg. spironolactone

47
Q

why are thiazide and thiazide-like diuretics safer?

A
  • as effective as loop diuretics but don’t cause such profound salt and water loss
  • have few side effects and are well tolerated
48
Q

what do vasodilator drugs do?

A

dilate blood vessels to directly lower TPR

49
Q

what are the main vasodilator drugs used in hypertension treatment?

A
  • calcium antagonists

- a1-adrenoceptor blockers

50
Q

what provides the driving force to push blood through blood vessels?

A

the pressure drop (ΔP) between the inlet and the outlet of a blood vessel

51
Q

what makes it harder to push blood through a blood vessel?

A
  • narrower or longer vessel

- more viscous blood

52
Q

describe Poiseuile’s Law

A

relates flow resistance (R) of a blood vessel to its radius (r) and length (L) and the viscosity (η) of the blood flowing through it

53
Q

what is the easiest variable to change to affect flow?

A

diameter, as vessel length and blood viscosity stay relatively constant

54
Q

what is the key mediator of contraction?

A

the interaction between actin and myosin to form a cross bridge

55
Q

in smooth muscle, what does the interaction between actin and myosin depend on?

A

phosphorylation of the light chain of myosin — depends on 2 enzymes

56
Q

what 2 enzymes mediate the degree of phosphorylation of the light chain of myosin and what do they do?

A
  1. myosin light chain kinase — promotes myosin phosphorylation by transferring a phosphate group from ATP
  2. myosin phosphatase — mediators the removal of phosphate from myosin
57
Q

what does calcium interact with and form to activate myosin light chain kinase to phosphorylate myosin?

A

a Ca++ binding protein called calmodulin — makes a Ca++-calmodulin complex

58
Q

contraction begins when what?

A

there is a rise in the conc of free Ca++ in the cell cytoplasm

59
Q

what can both inhibit the myosin light chain kinase reaction?

A

eg. cAMP and cGMP — inhibit reaction and cause relaxation of the muscle

60
Q

what are cAMP and cGMP produced by?

A

cAMP — beta-2 adrenergic agonists

cGMP — nitrovasodilators like GTN

61
Q

what inhibits myosin phosphatase?

A

Rho kinase and protein kinase C — activated by several vasoconstrictors

62
Q

what do Rho kinase and protein kinase C do?

A

inhibit the dephosphorylation of myosin, so that contraction remains even after the Ca++ conc has fallen — calcium sensitisation

63
Q

how can contraction be sustained and why is this good?

A

minimum consumption of ATP, therefore blood vessels are able to maintain constriction for prolonged periods without consuming energy

64
Q

the Ca++ conc in smooth muscle can be increased by activating what?

A

G-protein coupled receptors that empty the Gq/G11 family of G proteins

65
Q

what happens when G-protein coupled receptors that employ the Gq/G11 family of G proteins are activated?

A
  • G-protein is activated upon binding of an agonist
  • the Ga subunit stimulates the activity of phospholipase C
  • results in the cleavage of phosphatidylinositol to inositol triphopshate (IP3) and diacylglycerol (DAG)
  • IP3 diffuses to SR which acts as an IC store of Ca++
  • IP3 binds to and activates the IP3 receptor, which is a Ca++ permeable ion channel in the SR membrane
  • Ca++ ions flow out of the SR down their electrochemical gradient to stimulate contraction
  • the DAG causes Ca++ sensitisation due to inhibition of myosin phosphatase (contraction remains)
  • 2 pathways work together to trigger and sustain contraction
66
Q

what are examples of GPCRs that mediate contraction via IP3 and DAG? which are most important in anti-hypertensive drugs?

A
  • a1 adrenoceptor
  • angiotensin receptors
  • vasopressin receptors
  • endothelin receptors
  • serotonin receptors

a1 adrenergic and angiotensin receptors are most important in anti-hypertensive drugs

67
Q

what is the main route of reuptake of Ca++ into the SR?

A

sarco-endoplasmic reticulum ATPase, or a Ca pump (SERCA)

68
Q

what pump also pumps Ca out of the cell?

A

Ca ATPase or PMCA in the plasma membrane

69
Q

how can Ca also be removed from the cell, apart from PMCA?

A

Na/Ca exchanger

70
Q

what is the key channel for contraction?

A

L-type voltage operated Ca channel

71
Q

what happens when L-type Ca channels open?

A

Ca++ enters the cell and directly triggers contraction

72
Q

are most cation channels more permeable to Na+ or Ca++? hence what is the main function of these channels?

A

more permeable to Na+ — main function is to mediate the influx of Na+ and inhibit Ca++ influx

73
Q

what do drugs that reduce cytoplasmic Ca++ evoke?

A

vasodilation

74
Q

what are the main drugs that reduce cytoplasmic Ca++?

A
  • a1-adrenoceptor antagonists
  • angiotensin 1 receptor blockers
  • L-type calcium channel blockers
75
Q

describe a1-adrenoceptor blockers

A
  • compete with the agonist for the receptor
  • inhibit the vasoconstrictor response to sympathetic nerve stimulation
  • not 1st line drugs for hypertension — lower efficacy and more side effects than other drugs
  • widely prescribed as an add on to 1st line drugs when BP is not adequately controlled
76
Q

describe a1-adrenceptors

A
  • widely expressed n arterial smooth muscle
  • mediate the vasoconstrictor actions of noradrenaline, released from sympathetic nerves, and adrenaline from the adrenal medulla
77
Q

name 2 a1-adrenoceptor blockers

A
  • doxazosin
  • terazosin

given as a once daily tablet

78
Q

the names of all a1-antagonists end in what?

A

‘osin’ but most ‘azosin’

79
Q

what are the adverse effects of a1-adrenoceptor antagonists?

A
  • postural hypotension, dizziness or light headed ness caused by a loss of the baroreceptors reflex
  • this can cause severe hypotension when the 1st dose is administered, so patients are advised to take care when initiating treatment, to avoid situations where they could be injured as a result of dizziness or fainting
80
Q

describe calcium antagonists

A
  • inhibits of the voltage-dependent L-type calcium channel
  • prevent depolarisation-induced Ca++ influx into the vascualr smooth muscle cell
  • the calcium channels in cardiac muscle and conducting tissue are similar to the channels in vascular smooth muscle, so calcium antagonists can interfere with channel activity in both organs
  • the dihydropyridine group are a 1st line treatment for hypertension
  • the others are only used as anti-hypertensives when there is an associated cardiac disorder
81
Q

what do all dihydropyridine calcium antagonists end in?

A

dipine

82
Q

name a dihydropyridine

A

amlodipine = 1st line antihypertensive drug

83
Q

calcium antagosntis are the drug of choice for who?

A

newly diagnosed patients of Black African or African-Caribbean origin, or aged at least 55 years

84
Q

what are the adverse effects of calcium antagonists?

A
  • headache - dilation of cerebral arterioles
  • peripheral oedema — (mainly ankles) pre-capillary arterioles dilate more than post-capillary venules, causing hydrostatic pressure that pushes fluid out of the capillaries
  • flushing - dilation of the cutaneous vessels
  • constipation- relaxation of smooth muscle in the GI tract, which contains the same Ca channels
85
Q

explain the renin angiotensin aldosterone system (RAAS) in full and all of its effects

A
  • renin (circulating around body) cleaves angiotensinogen into angiotensin 1
  • ACE converts angiotensin 1 to angiotensin 2
  • angiotensin 2 interacts with angiotensin receptor 1 — vasoconstriction
  • also acts on AT1 receptors on sympathetic nerve endings as well as vascular smooth muscle — stimulation promotes NAdr release — amplifies the vasoconstrictor effect
  • also acts in AT1 receptors in the adrenal cortex — stimulates release of aldosterone
  • aldosterone is involved in the homeostatic control of plasma volume and electrolytes — acts on nearby kidney to promote the retention of Na+ and H2O — increases blood volume and hence CO — raises flow and BP
  • also acts on AT1 receptors to promote the growth of vascular smooth muscle cells, resulting in hyperplasia and hypertrophy — narrows blood vessel lumen, increasing resistance to flow
86
Q

what 2 types of drugs can inhibit RAAS?

A
  • ACE inhibitors — 1st line treatment for HT

- renin inhibitors — new group of drugs not yet a standard treatment

87
Q

where is angiotensinogen made?

A

liver

88
Q

where is renin made?

A

kidneys - juxtaglomerular cells

89
Q

what do angiotensin receptor blockers do?

A

prevent the actions of angiotensin 2 by competing with angiotensin for the AT1 receptor

90
Q

what do ACE inhibitors, angiotensin receptor blockers and renin inhibitors all result in?

A

vasodilation and reduced plasma volume

91
Q

who are ACE inhibitors the drug of choice for and why?

A

patients under 55 years if they are not black African or African-Caribbean — because this group of patients tend to have higher plasma renin activity

92
Q

why can ACE inhibitors cause a persistent dry cough?

A
  • as well as cleaving angiotensin 1, ACE breaks down other peptides like bradykinin and substance P - involved in cough reflex
  • therefore the inhibitors cause the levels of these substances to increase
93
Q

what is prescribed as an alternative to an ACE inhibitor to remove the dry cough?

A

angiotensin receptor blocker

94
Q

name an ACE inhibitor

A

ramipril

95
Q

what do ACE inhibitor names end in?

A

‘pril’

96
Q

name an ARB?

A

candesartan

97
Q

when do the names of ARBs end in?

A

‘sartan’

98
Q

what is the only renin inhibitor currently available for treating hypertension?

A

aliskiren

99
Q

what are some adverse effects caused by inhibiton of angiotensin 2 production or action?

A
  • all drugs interfering with RAAS can cause hypotension when the 1st dose is given, especially if administered with a diuretic
  • the effect usually wears off with time to leave a lower, but not hypotensive, BP
  • can also cause hyperkalaemia, due to inhibition of aldosterone secretion.
  • some patients experience a sudden drop in renal function when drugs from this group are 1st taken
    • > renal function is monitored within 2 weeks of initiating therapy or changing the dose and at regular intervals thereafter
    • > done my measuring serum creatinine levels - an increase over 25% prompting discontinuation of the drug
    • > patients with renal stenosis should not be given any drug that interferes with angiotensin production or action, because it can cause the development of severe and progressive renal failure as a result
100
Q

summarise which drug is used when

A

PBL SEM 2 (44 decks)

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