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
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
3
Q
what is the equation for BP?
A
BP = CO x TPR
4
Q
how can cardiac output be lowered in order to reduce the BP?
A
reduce the:
- heart rate
- stroke volume
- plasma volume
5
Q
how is TPR reduced in order to reduce BP?
A
dilating arterioles
6
Q
how does SNS increase CO?
A
by stimulating the heart to contract more frequently and with more force
7
Q
how does the SNS increase TPR?
A
by causing arterioles to constrict
8
Q
what do they kidneys control?
A
blood volume by regulating electrolyte and water reabsorption — longer term regulation of BP
9
Q
describe minute-to-minute vs longer term control of BP
A
- minute-to-minute: SNS
- long term: kidney
10
Q
what is another name of B-adrenergic receptor blockers?
A
beta blockers
11
Q
what do names of beta blockers end in?
A
‘olol’
12
Q
where is adrenaline released from?
A
chromaffin cells in the adrenal gland
13
Q
what is noradrenaline released from?
A
sympathetic nerves
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
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
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
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
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
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
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
21
Q
where do diuretics act?
A
in the nephron = functional unit of the kidney
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
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
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
25
what process do diuretics interfere with and result in?
reabsorption process, resulting in an increased loss of salt and water
26
what are the 2 main sites in the nephron where diuretics work?
loop of Henle and the distal convoluted tubule
27
where is impermeable to water but permeable to ions?
the walls of the ascending limb
28
in the thick ascending limb, what moves ions into epithelial cells?
sodium, potassium, and 2 chloride co-transporter (symporter)
29
how is the epithelial cell’s (in ascending wall) ion composition maintained?
there are transporters on the opposite basolateral side of the cell that export the ions to the IF — water doesn’t follow here
30
what happens to the interstitial fluid on the other side of the ascending wall? what happens here?
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
31
what do loop diuretics block and what is the effect of this?
- 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
32
apart from the thick ascending limb, where is salt also reabsorbed?
distal convoluted tubule (DCT) (although a smaller proportion of the total)
33
what transporter is used in the DCT?
NaCl co-transporter
34
what do thiazide diuretics target?
NaCl co-transproter
35
what do thiazide diuretics inhibit?
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
36
epithelial cells in the distal tubule and collecting duct express receptors for what hormone?
mineralocorticoid
37
what is the main endogenous activator of the mineralocorticoid receptor?
aldosterone
38
where is aldosterone produced?
adrenal cortex (zona glomerulosa)
39
what is the result of aldosterone activating the receptors?
- 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
40
what drug blocks the mineralocorticoid receptor and what is its effect?
- spironolactone (K+ sparing diuretic)
- prevents the action of aldosterone
- causes increased excretion of Na+ and water, while preventing K+ ions in the circulation
41
what kind of drug is spironolactone?
potassium-sparing diuretic
42
name a loop diuretics
furosemide
43
name some thiazide diuretics
- chlorothiazide
- bendroflumethiazide
- hydrochlorthiazide
- INDAPAMIDE
- chlorthalidone
- metolazone
44
loop diuretic vs thiazide diuretic vs potassium-sparing diuretic
loop - furosemide - NaKCl blocker
thiazide - indapamide - NaCl blocker
potassium-sparing - spironolactone - aldosterone antagonist
45
what kind of diuretic is likely to cause hypokalemia?
loop diuretics
46
what diuretic can cause dangerous hyperkalaemia?
potassium-sparing eg. spironolactone
47
why are thiazide and thiazide-like diuretics safer?
- as effective as loop diuretics but don’t cause such profound salt and water loss
- have few side effects and are well tolerated
48
what do vasodilator drugs do?
dilate blood vessels to directly lower TPR
49
what are the main vasodilator drugs used in hypertension treatment?
- calcium antagonists
| - a1-adrenoceptor blockers
50
what provides the driving force to push blood through blood vessels?
the pressure drop (ΔP) between the inlet and the outlet of a blood vessel
51
what makes it harder to push blood through a blood vessel?
- narrower or longer vessel
| - more viscous blood
52
describe Poiseuile’s Law
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
what is the easiest variable to change to affect flow?
diameter, as vessel length and blood viscosity stay relatively constant
54
what is the key mediator of contraction?
the interaction between actin and myosin to form a cross bridge
55
in smooth muscle, what does the interaction between actin and myosin depend on?
phosphorylation of the light chain of myosin — depends on 2 enzymes
56
what 2 enzymes mediate the degree of phosphorylation of the light chain of myosin and what do they do?
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
what does calcium interact with and form to activate myosin light chain kinase to phosphorylate myosin?
a Ca++ binding protein called calmodulin — makes a Ca++-calmodulin complex
58
contraction begins when what?
there is a rise in the conc of free Ca++ in the cell cytoplasm
59
what can both inhibit the myosin light chain kinase reaction?
eg. cAMP and cGMP — inhibit reaction and cause relaxation of the muscle
60
what are cAMP and cGMP produced by?
cAMP — beta-2 adrenergic agonists
| cGMP — nitrovasodilators like GTN
61
what inhibits myosin phosphatase?
Rho kinase and protein kinase C — activated by several vasoconstrictors
62
what do Rho kinase and protein kinase C do?
inhibit the dephosphorylation of myosin, so that contraction remains even after the Ca++ conc has fallen — calcium sensitisation
63
how can contraction be sustained and why is this good?
minimum consumption of ATP, therefore blood vessels are able to maintain constriction for prolonged periods without consuming energy
64
the Ca++ conc in smooth muscle can be increased by activating what?
G-protein coupled receptors that empty the Gq/G11 family of G proteins
65
what happens when G-protein coupled receptors that employ the Gq/G11 family of G proteins are activated?
- 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
what are examples of GPCRs that mediate contraction via IP3 and DAG? which are most important in anti-hypertensive drugs?
- a1 adrenoceptor
- angiotensin receptors
- vasopressin receptors
- endothelin receptors
- serotonin receptors
a1 adrenergic and angiotensin receptors are most important in anti-hypertensive drugs
67
what is the main route of reuptake of Ca++ into the SR?
sarco-endoplasmic reticulum ATPase, or a Ca pump (SERCA)
68
what pump also pumps Ca out of the cell?
Ca ATPase or PMCA in the plasma membrane
69
how can Ca also be removed from the cell, apart from PMCA?
Na/Ca exchanger
70
what is the key channel for contraction?
L-type voltage operated Ca channel
71
what happens when L-type Ca channels open?
Ca++ enters the cell and directly triggers contraction
72
are most cation channels more permeable to Na+ or Ca++? hence what is the main function of these channels?
more permeable to Na+ — main function is to mediate the influx of Na+ and inhibit Ca++ influx
73
what do drugs that reduce cytoplasmic Ca++ evoke?
vasodilation
74
what are the main drugs that reduce cytoplasmic Ca++?
- a1-adrenoceptor antagonists
- angiotensin 1 receptor blockers
- L-type calcium channel blockers
75
describe a1-adrenoceptor blockers
- 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
describe a1-adrenceptors
- widely expressed n arterial smooth muscle
- mediate the vasoconstrictor actions of noradrenaline, released from sympathetic nerves, and adrenaline from the adrenal medulla
77
name 2 a1-adrenoceptor blockers
- doxazosin
- terazosin
given as a once daily tablet
78
the names of all a1-antagonists end in what?
‘osin’ but most ‘azosin’
79
what are the adverse effects of a1-adrenoceptor antagonists?
- 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
describe calcium antagonists
- 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
what do all dihydropyridine calcium antagonists end in?
dipine
82
name a dihydropyridine
amlodipine = 1st line antihypertensive drug
83
calcium antagosntis are the drug of choice for who?
newly diagnosed patients of Black African or African-Caribbean origin, or aged at least 55 years
84
what are the adverse effects of calcium antagonists?
- 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
explain the renin angiotensin aldosterone system (RAAS) in full and all of its effects
- 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
what 2 types of drugs can inhibit RAAS?
- ACE inhibitors — 1st line treatment for HT
| - renin inhibitors — new group of drugs not yet a standard treatment
87
where is angiotensinogen made?
liver
88
where is renin made?
kidneys - juxtaglomerular cells
89
what do angiotensin receptor blockers do?
prevent the actions of angiotensin 2 by competing with angiotensin for the AT1 receptor
90
what do ACE inhibitors, angiotensin receptor blockers and renin inhibitors all result in?
vasodilation and reduced plasma volume
91
who are ACE inhibitors the drug of choice for and why?
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
why can ACE inhibitors cause a persistent dry cough?
- 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
what is prescribed as an alternative to an ACE inhibitor to remove the dry cough?
angiotensin receptor blocker
94
name an ACE inhibitor
ramipril
95
what do ACE inhibitor names end in?
‘pril’
96
name an ARB?
candesartan
97
when do the names of ARBs end in?
‘sartan’
98
what is the only renin inhibitor currently available for treating hypertension?
aliskiren
99
what are some adverse effects caused by inhibiton of angiotensin 2 production or action?
- 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
summarise which drug is used when
