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Flashcards in Hypertension 2 Deck (69)
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1
Q

What system are calcium channels normally classified according to?

A

A system based on their location or functional characteristics. This system uses single letters and defined groups of channels that share similar characteristics

2
Q

What alpha subunits do L type calcium channels have and where are they found?

A
  • subunits Cav 1.1-1.4

- found in heart, smooth muscle and CNS

3
Q

What alpha subunits do P/Q type calcium channels have and where are they found?

A
  • Cav 2.1

- found in Purkinje neurons, cerebellar granule cells

4
Q

What alpha subunits do N type calcium channels have and where are they found?

A
  • Cav 2.2

- found in brain and peripheral nervous system

5
Q

What alpha subunits do R type calcium channels have and where are they found?

A
  • Cav 2.3

- found in cerebellar granule cells

6
Q

alpha subunits do T type calcium channels have and where are they found?

A
  • Cav 3.1-3.3

- found in neurons, pacemaker cells and the thalamus

7
Q

Which calcium channel is an ideal target for modulating blood pressure and why?

A

L type because it is found in both cardiac muscle and vascular smooth muscle

8
Q

Why can we avoid blocking the L type channel in skeletal muscle?

A

There are several different types of L type channel, and the one in skeletal muscle is sufficiently different from that in cardiac and smooth muscle, that we can avoid blocking it

9
Q

What is peripheral resistance determined by?

A

Peripheral resistance determined by diameter of vessels – smooth muscle contraction changes diameter of resistance vessels

10
Q

What is smooth muscle contraction triggered by?

A

stimulation of the sympathetic nervous system

11
Q

How does noradrenaline affect vascular tone?

A
  • Noradrenaline acts on alpha1 adrenoceptors
  • This activates phospholipase C
  • Activation of Phospholipase C triggers release of inositol triphosphate (InsP3) release
  • This triggers the calcium store to open and release intracellular calcium (this doesn’t trigger muscle contraction though)
  • This leads to calcium sensitive chloride channels being activated
  • There is then a Cl- efflux which leads to depolarisation
  • This depolarisation leads to opening of L-type calcium channels
  • Leads to Ca2+ influx
  • And then contraction via Ca-calmodulin Ca2+ release
12
Q

What stops the opening of L type calcium channels and what does this mean?

A
  • L type calcium blockers

- This stops contraction of smooth muscle and so will dilate resistance vessels

13
Q

Give examples of Calcium Channel blockers

A
  • Diltiazem (a benzothiazepine – heart L type calcium channels)
  • Verapamil (a phenylalkylamine – heart L type calcium channels)
  • Amlodipine and Nifedipine (a dihydropyridine – vascular L type calcium channels)
14
Q

Give a summary of what calcium channel blockers do

A
  1. Reduce the opening of L-type calcium channels
  2. Target organs: vasculature (and heart)
  3. Vessels: inhibit Ca2+ entry
  4. Heart: reduced contractility and A-V conduction
15
Q

What are the side effects from Calcium Channel blockers?

A

headache, constipation, sometimes hypotension (most pronounced when patient takes first dose: initial dose hypotension, also when patient changes position: postural hypotension) which produces momentary faintness

16
Q

What are some useful drug name hints?

A
  1. ACE inhibitors – pril
  2. ATII antagonists – artan
  3. Ca2+ blockers (DHP) – ipine
  4. B-blockers – olol
  5. A-blockers – zosin
17
Q

What do all diuretics cause?

A

diuresis

18
Q

What is diuresis?

A

Increased urine output

19
Q

What do diuretics cause?

A
  • Intravascular salt and water depletion
     Short term effect
     Renal failure
20
Q

Apart from hypertension what else are diuretics used to treat?

A
  • Also used to treat oedema
     Pulmonary oedema due to heart failure
     Side effects of other therapy
21
Q

What are the general considerations to do with Diuretics?

A
  • Increase excretion of Na+, Cl- and water
  • Pattern of electrolyte excretion and max response varies with class
     The closer to the glomeros the diuretic is acting the larger the maximum effect)
  • Effects can be additive or synergistic
22
Q

What are the three main classes of diuretics?

A

 Loop
 Thiazide
 Potassium sparing

23
Q

How does the loop of Henley work?

A

 Descending limb: no active transport, water permeable
 Ascending limb: active transport Na+, active transport K+, Cl-, water impermeable
 Ascending limb pumps salt into surrounding tissues, creates a gradient, water leaves from descending limb

24
Q

How do loop diuretics work?

A

Block ion transport processes in ascending limb:
- If we block salt-sodium chloride transport process we will stop moving salt out of the urine and into the surrounding tissues, therefore water cannot be absorbed from the descending limb

25
Q

What are the main examples of loop diuretics?

A

furosemide (frusemide) and bumetanide

26
Q

What does the loop diuretic inhibit in the loop of Henle?

A

Loop diuretic inhibits Na+/K+/2Cl- co-transporter in ascending limb of the loop of Henle

27
Q

What are the clinical uses of loop diuretics?

A
 Heart failure 
 Pulmonary oedema 
 Renal failure 
 All involve salt and water overload
 Hypertension with renal failure: also get vascular effects
28
Q

Why is the loop diuretic called a high ceiling diuretic?

A

Because it is one of the most powerful diuretics

29
Q

What do thiazide diuretics focus on?

A

They focus on the distal convoluted tube of the nephron. This is where sodium chloride is removed

30
Q

What happens if we block the sodium chloride removal process?

A
  • we can’t dilute urine as much
     Increased NaCl passes to more distal segments
     Less difference in osmolality between urine and plasma
     Lesser ability to reabsorb water in more distal portions
31
Q

What are the main examples of thiazide diuretics?

A

Bendroflumethiazide and Chlortalidone

32
Q

How do thiazide diuretics work?

A

Act by inhibiting Na+/Cl- cotransport in distal convoluted tubule

33
Q

What are the clinical uses of thiazide diuretics?

A

 Oedema due to heart failure
 Hypertension (lower doses)
 Initial effects due to diuresis
 Later, get vascular effect

34
Q

What strength are thiazide diuretics?

A

Mild/moderate

35
Q

What is a major problem with loop diuretics and thiazide and why?

A
  • Hypokalaemia (low potassium levels)
  • principle cells in collecting duct have potassium channels and ENaC and sodium potassium ATP pump on the other side
  • Increased NaCl passed on to collecting duct increases transport across PRINCIPAL cells
  • Increases lumen -ve potential leading to K+ loss
  • Increased volume of urine: increased flushing of K+
36
Q

What is the general mechanism of potassium sparing diuretics?

A

General mechanism: decrease trans-principal cell Na+ movement, decrease -ve lumen potential

37
Q

What are the main examples of potassium sparing diuretics?

A

Spironolactone and amiloride

38
Q

What does Spironolactone do?

A
  • Aldosterone antagonist
  • Aldosterone increases sodium absorption by:
  • Increasing number of Na+/K+ ATPases (genomic)
  • Stimulating ENaC Na+ channels via protein mediator
  • Spironolactone blocks genomic effects of aldosterone (competitive antagonist at hormone receptor - mineralocorticoid) may interfere at eNaC
39
Q

What does Amiloride do?

A

Blocks ENaC sodium channels in the luminal membrane

40
Q

Why are potassium sparing diuretics usually used in combination with other diuretics?

A

Because they have weak action on their own

41
Q

What is Spironolactone used in?

A

hyperaldosteronism
 Cirrhosis (failure to metabolise ALD)
 Conn’s syndrome (adrenal tumour)

42
Q

Give features of the Renin-angiotensin-aldosterone system (RAAS)

A

• Slow ‘compensatory’ control
• Under control of sympathetic nervous system
• Also responds to decrease in blood flow in kidney:
- leads to production of renin (not rennin)
- Leads to angiotensin being produced
- Leads to vasoconstriction and aldosterone being produced
- Aldosterone leads to increase salt and water retention
- This leads to increased blood pressure

43
Q

How are angiotensin hormones generated?

A
  • Renin cleaves angiotensinogen (plasma globulin) to produce angiotensin I (inactive)
  • ACE cleaves angiotensin I to produce angiotensin II (8mer) which is active
  • Aminopeptidase cleaves angiotensin II to produce angiotensin III (partially active)
44
Q

When angiotensin II binds to AT1R what do we see?

A
  • Aldosterone secretion

- Vasoconstriction

45
Q

What is the physiological control of renin secretion?

A
  • Secreted by cells of juxtaglomerular apparatus in kidneys
  • Responds to:
  • adrenaline (B-adrenoceptors)
  • Prostacyclins
  • Decreased Na+ in distal tubule
  • Decreased blood pressure in kidney
  • Actions of other hormones
46
Q

What are the tissue distributions of renin, angiotensin and ACE?

A
  • Renin – discrete (juxtaglomerular apparatus)
     Global control – secreted into circulation
  • Angiotensin – produced in liver – secreted into circulation
  • ACE – found in many tissues
     Several subtypes
     Local production of angiotensin’s
47
Q

What are the drugs acting on the RAA system?

A
  • Spironolactone acting on aldosterone
  • ACE inhibitors
  • Blockers of receptors for angiotensin II
  • Aliskiren (renin inhibitor)
48
Q

What did post market surveillance show about renin inhibitors?

A

They cause:
 Kidney problems
 Stroke
 Hypotension

49
Q

What did lessons learned from studying renin aid?

A

Research on HIV protease inhibitors

50
Q

What are ACE inhibitors and what do they do?

A
  • One of the first line drugs in NICE care pathways
  • If we can block ACE we can stop the forming of active forms of angiotensin
  • Stops aldosterone production
  • Stops vasoconstriction
51
Q

What are some main examples of ACE inhibitors

A

captopril (not widely used anymore), lisinopril

52
Q

What unwanted effects do ACE inhibitors have?

A

initial dose hypotension, cough (caused by build up of bradykinin, a hormone which is broken down by ACE)

53
Q

How was Catopril developed?

A

by studying the venom of a Brazilian pit viper
 Viper kills it’s prey by causing a massive drop in blood pressure
 Compound in venom is a peptide
 Captopril was developed using computer modelling of the venom peptide

54
Q

What angiotensin receptors are there?

A
  • G protein coupled receptors – multiple subtypes
  • Angiotensin II type 1 receptor (AT1 Receptor)
     AT1 – vascular effects/ aldosterone release
  • Angiotensin II type 2 receptor (AT2 receptor)
     AT2 – growth and development
55
Q

What do angiotensin II antagonists (ARBs) do?

A
  • Block angiotensin II type 1 receptors

- Known as angiotensin II antagonist or angiotensin receptor blockers

56
Q

What are some examples of angiotensin II antagonists?

A

losartan and candesartan

57
Q

What are some side effects of ARBs?

A

hypotension but not cough (ACE is still available so it can degrade bradykinin)

58
Q

What are other clinical uses of ACE inhibitors (ACEIs) and Angiotensin receptor blockers (ARBs)?

A
  • Can be used in heart failure
  • Useful in decreasing sodium and salt retention
  • Useful after a heart attack
  • Some studies indicate centrally active ACEIs and ARBs may be useful in Alzheimer’s disease
59
Q

What are adrenoceptor antagonists subdivided into and what are these subdivisions used for?

A
  • Subdivided into alpha blockers and beta blockers
  • The alpha blockers are only really used for hypertension
  • Beta blockers are also valuable in other cardiovascular disorders and even in treating anxiety – not the first line treatment for hypertension
60
Q

What do alpha1 and beta1 adrenoceptors do?

A
• Alpha1: 
- Vasoconstriction (increase BP) 
• Beta1: 
- Increase heart rate and force of contraction 
- Release of renin 
- In the brain
61
Q

What is Doxazosin and what does it do?

A
  • alpha blocker
  • Dilates arterioles and veins by blocking a1-adrenoceptors
  • Used where other therapy has proved ineffective or unacceptable
62
Q

What are the unwanted effects of Doxazosin?

A
  • postural hypotension (fades with time)

 Urinary incontinence and retrograde ejaculation in males (relaxes bladder)

63
Q

What is propranolol?

A

 Competitive antagonist
 Beta blocker
 Non-selective B-adrenoceptor antagonists
 Blocks B1 and B2 adrenoceptors
 Relatively lipid soluble (good penetration of CNS)

64
Q

What are Atenolol and Bisoprolol?

A

 Competitive antagonists
 Beta blockers
 B1 selectivity: Bisoprolol > atenolol > propranolol)
 Relatively water soluble (poor penetration of CNS)

65
Q

Where are B1 adrenoceptors found in the heart what do they do there and so what will beta blockers do?

A
  • Target B1 adrenoceptors in heart – sympathetic nervous system innervated B1 adrenoceptors in nodes and muscle
     In the SA nodes B1 receptor increase HR when stimulated and increase conduction in AV node – B blockers decrease heart rate
     In muscle produce increase in contractility – B blockers decrease stroke volume
     Both effects lower cardiac output which decreases blood pressure
66
Q

What do Beta blockers do in the kidney?

A

block renin release in the juxtaglomerular apparatus which dampens the angiotensin system and decreases blood pressure

67
Q

What do B1 receptors in the CNS in the vasomotor centre and medulla oblongata do?

A

 Increase sympathetic tone

 So beta blockers decrease sympathetic tone

68
Q

What are the unwanted effects of beta blockers?

A
  • Bronchoconstriction (due to beta2 receptors in lungs)
     Bronchial asthma
     Bronchitis
     Emphysema
  • Precipitation of cardiac failure/ heart block (because they decrease cardiac output)
     Patients with heart disease
     Carvedilol, bisoprolol, nebivolol (UK), (Us: metoprolol) – used to help treat patients with compromised heart function)
  • Glucose control
     Patients with diabetes
     Type 2: reduced insulin sensitivity (can precipitate)
     Type 1 – masks hypoglycaemia warning signs
  • Cold extremities
     Raynaud’s phenomenon and claudication
  • Vivid dreams
     Propranolol (because penetrates CNS), not a problem with atenolol or bisoprolol
69
Q

What happens with beta blockers and hypoglycaemia?

A
  • Too much insulin leads to hypoglycaemia (with people with type 1 diabetes)
  • Glucose release from liver controlled by B-adrenoceptors can help counteract hypoglycaemia
  • Hypoglycaemia leads to sympathetic NS activation -> increased heart rate which provides a warning of hypoglycaemia
  • Non-selective beta blockers will stop the counteraction of hypoglycaemia and stops warning of hypoglycaemia
  • B1 selective beta blockers will stop the warning signs of hypoglycaemia being provided