Hypertension Flashcards
1
Q
What is the annual death toll due to hypertension?
A
20 million deaths per year
Represents 31% of all deaths globally
2
Q
What percentage of cardiovascular disease deaths are attributed to heart attack or stroke?
A
85% of CVD deaths
Indicates the severity of hypertension-related complications
3
Q
Is hypertension only a problem in developed countries?
A
No, 75% of CVD deaths occur in low-middle income countries
Highlights the global impact of hypertension
4
Q
What are the common lifestyle factors associated with hypertension?
A
- Diet —> high Na+ and low K+ intake increases BP via renal mechanisms
- Obesity —> increased insulin resistance so high BP and over activation of RAAS
- Inactivity —> increased SNS activity and/or weight gain
- Smoking —> nictotine causes adrenaline release and thus vasoconstriction & damage to lining of blood vessels
- Alcohol —> activation of SNS and the RAAS
- Chronic stress —> overproduction of cortisol causes increase in BP
- Poor sleep —> linked to high hypertension risks
5
Q
What is the normal blood pressure measurement?
A
120/80 mm Hg
Systolic (heart contracting) over diastolic (heart relaxing)
6
Q
What are the three stages of hypertension according to the NHS?
A
Stage 1
Clinal values = 140/90 – 159/99 mm Hg
HBPM or ABPM = 138/85 - 149/94 mm Hg
Stage 2
Clinical values = 160/100 – 180/120 mm Hg
HBPM or ABPM = >150/95 mm Hg
Stage 3
Systolic >180 mm Hg or diastolic >120 mm Hg
Medical emergency = risk of organ damage & CV complications
7
Q
What is primary hypertension also known as?
A
Essential or idiopathic hypertension
Characterized by no identifiable cause
8
Q
What are some risk factors for hypertension?
A
- 30-60% genetic
- Angiotensin converting enzyme (ACE) = important drug target for antihypertensive drugs
- Angiotensinogen = precursor of angiotensins (involved in BP control)
- AT1R = angiotensin II receptor type 1 = most important receptor in angiotensin hormone
- Nitric oxide synthase 3 = enzyme that produces nitric oxide and releases gaseous signals that regulate blood vessels
- Lifestyle factors
9
Q
What is the ASCOT trial known for?
A
Prompting a change in hypertension treatment guidelines in 2006
For under 55 year olds, ACE inhibitors or angiotensin receptor blockers are used
For over 55 year olds or Black African ancestry, thiazides or calcium channel blockers (CCB) are used
The trial prompted that ACE inhibitors/CCBs lower rates of heart attack and stroke & lower rates of type 2 diabetes
10
Q
What lifestyle changes are recommended for managing hypertension?
A
- Lose weight
- Moderate alcohol intake
- Stop smoking
- Increase exercise
- Limit sodium intake
- Maintain potassium, calcium, and magnesium levels
- Reduce saturated and trans fats
11
Q
What is the first-line drug treatment for hypertension in patients under 55?
A
ACE inhibitors
Most common initial treatment option
12
Q
What are the side effects of ACE inhibitors?
A
- Persistent dry cough (common) = due to breakdown of a peptide called bradykinin by AC6
- Bradykinin has a role in pain signalling, inflammation and vasodilatory effects —> accumulation of it causes a cough
- Angioedema (rare) = more common in people of black African or black Caribbean origin —> swollen tissue and blood vessels become more permeable (due to build up of bradykinin) which is life-threatening
- Postural hypotension = dizziness when changing positions suddenly
- GI tract problems
- Headache
13
Q
What do angiotensin receptor blockers (ARBs) do?
A
Reduce blood pressure
Alternative to ACE inhibitors with fewer side effects
14
Q
What is a common side effect of thiazide diuretics?
A
- Increased urine output
- Electrolyte loss
- Increased risk of diabetes
- GI tract problems
- Headache
- Postural hypotension
15
Q
What is the role of the renin-angiotensin-aldosterone system (RAAS) in hypertension?
A
Regulates blood pressure through vasoconstriction and fluid retention
Involves hormones such as renin, angiotensin II, and aldosterone
16
Q
What is a characteristic of calcium channel blockers (CCBs)?
A
Vasoselective
They selectively act on vascular smooth muscle
17
Q
What is the main action of beta blockers in hypertension treatment?
A
Reduce heart rate and contractility
They decrease cardiac output and renin release
18
Q
What is the significance of the ALL-HAT trial?
A
Influenced AHA/ACC guidelines on hypertension treatment
Focused on thiazides, CCBs, ARBs, and ACE inhibitors
19
Q
What are the two types of diuretics mentioned for hypertension treatment?
A
- Thiazide diuretics
- Potassium-sparing diuretics
20
Q
What are common side effects associated with calcium channel blockers?
A
- Headache
- Flushing
- Dizziness
- Swollen ankles
- GI tract issues
- Palpitations
- Reflex tachycardia
21
Q
What is the mechanism of action for thiazide diuretics?
A
Lower blood volume by promoting water and sodium excretion in urine
This results in a decrease in blood pressure
22
Q
What is the purpose of the NICE guidelines in hypertension management?
A
Set the scope, gather evidence, and make recommendations based on effectiveness and safety
Involves healthcare professionals and patient representatives
23
Q
What is the effect of lifestyle changes on hypertension management?
A
Can significantly lower blood pressure and reduce medication needs
Includes weight loss, exercise, and dietary adjustments
24
Q
What is rational drug design?
A
Targeting a specific physiological process via a specific receptor
Rational drug design involves creating medications that interact with specific biological targets.
25
What was the hypothesis regarding beta adrenoceptors in angina?
Blocking beta adrenoceptors would be beneficial in angina
## Footnote
This hypothesis guided the development of beta-blockers.
26
Which drug was used as a starting point for developing beta blockers?
Isoprenaline
## Footnote
Isoprenaline is a non-selective beta-adrenergic agonist.
27
What is Alderlin (pronethalol) known for?
Effective but safety concerns
## Footnote
Alderlin was one of the earliest beta blockers but had significant side effects.
28
How does Inderal (propranolol) differ from Alderlin?
Effective and safer
## Footnote
Propranolol was developed to provide a safer alternative to Alderlin.
29
What is the purpose of developing more selective drugs like Atenolol?
Developed as a 'clean beta blocker'
## Footnote
Atenolol aimed to reduce side effects associated with non-selective beta blockers.
30
What conditions can propranolol be used to treat?
* Heart failure
* Asthma
* Risk of diabetes
## Footnote
Propranolol has multiple applications but can have adverse effects on respiratory conditions.
31
What is Cimetidine?
H2 histamine receptor antagonist used to treat heart burn and gastric ulcers
## Footnote
Cimetidine was a significant advancement in treating gastric conditions.
32
What milestone did Cimetidine achieve in terms of sales?
First drug to exceed $1 billion/year sales
## Footnote
This marked a significant commercial achievement in the pharmaceutical industry.
33
By 1987, what percentage of sales of the world’s top 20 medications did H2 antagonists and beta blockers account for?
>30% of sales
## Footnote
This statistic highlights the impact of these classes of drugs on the market.
34
What recognition did contributions to drug discovery and development receive in 1988?
1988 Nobel Prize in Physiology or Medicine
## Footnote
This prize acknowledged significant advancements in pharmacology and therapeutics.
35
What is ACEi?
A drug that inhibits angiotensin converting enzyme
36
What is ACC/AHA?
The American College of Cardiology/ the American Heart Association - treat cardiovascular disorders
First line treatment is thiazides, CCBs, ARBs, ACEi with the former 2 preferred in older patients or patients with African background and the latter 2 preferred in diabetic patients
37
What is ALL-HAT?
Antihypertensive and Lipid Lowering treatment to prevent a heart attack.
Clinical trial that heavily influenced US guidelines on hypertension treatment
38
What is an alpha blocker?
An antagonist of alpha adrenoreceptors
39
What’s amlodipine?
A dihydropyridine L-type calcium channel blocker used as an antihypertensive
40
What’s Atenolol?
A selective beta adrenoreceptor antagonist used as a antihypertensive
41
What is Atherosclerosis?
Clogging of the arteries with cholesterol
42
What is bisoprolol?
A selective beta adrenoreceptor antagonist used as an antihypertensive
43
What is Bradykinin?
- A peptide that causes blood vessels to dilate, leading to a reduction in blood pressure
- It is involved in the inflammatory response and is broken down by angiotensin-converting enzyme (ACE)
- A build up of bradykinin can cause a cough
44
What is candesartan?
An angiotensin receptor blocker used as an antihypertensive
45
What is Captopril?
An ACE inhibitor used as an antihypertensive
46
What are dihydropyridines?
a group of drug that inhibit vascular L-type calcium channels
47
What is diltiazem?
A calcium channel blocker that is used to treat high blood pressure and certain types of angina by relaxing blood vessels and reducing workload on the heart
48
What is Doxazosin?
An alpha 1 adrenoreceptor antagonist used as an antihypertensive
49
What is hyperlipidaemia?
Too much cholesterol in the blood
50
What is juxtaglomerular apparatus?
A specialised structure in the kidney that regulates blood pressure by releasing renin, an enzyme that activates the RAAS
51
What range is normal blood pressure in?
120-180 mm Hg
52
What is RAAS?
A hormone cascade important in the long term control of blood pressure
53
What is systolic blood pressure?
BP when the heart is contracting
The first of the 2 numbers given when blood pressure is reported
54
What are Thiazide/ Thiazide-like diuretics?
Drugs that inhibit Sodium and Chloride transport out of the urine, resulting in more water being retained in the urine
Used as antihypertensives
55
What is thrombosis?
The formation of a blood clot (thrombus) within a blood vessel which can obstruct blood flow and lead to complications such as a stroke or heart attack
56
What is white coat hypertension?
An increase in blood pressure due to anxiety when in a medical environment
57
What is diastolic blood pressure?
When the heart is relaxing and filling
58
NHS stages of hypertension
3 stages
Measurements done in clinic but confirmed using
- home BP measurements
- ambulatory BP measurements
Patients wear a device that measures their BP at various points during the day —> values are normally lower the clinical values
59
US staging system for hypertension
ACC/AHA blood pressure guideline —> 4 stages (more emphasis on mildly elevated BP)
Normal = systolic <120 mm Hg
Elevated = systolic 120-129 mm Hg
Stage 1 = systolic 130-139 mm Hg
Stage 2 = systolic >/= 140 mm Hg
60
What is primary hypertension?
Most common type
Identifiable but the cause is unknown —> risk factors can still be identified
61
What is secondary hypertension?
Hypertension is a symptom of another condition/medication
E.g. diabetes, kidney disease and abnormal production of adrenal/thyroid hormone
62
Consequences of hypertension
- damage to the kidney & kidney failure
- damage to the eyes (blindness)
- heart failure
63
Renal artery stenosis
Occurs when the renal artery becomes blocked by atherosclerosis
Narrowing of artery
Results in reduced blood flow to the affected kidney & hypertension as the cardiovascular system tries to compensate by increasing BP using the RAAS
64
Phaeochromocytoma
Tumour of the adrenal medulla formed from neuroendocrine chromaffin cells
Phaeochromocytoma synthesises adrenaline and release it into the blood stream —> happens paroxysmally (in attacks) and the patient will thus have periods of overactivation of their SNS
Leads to increased HR and force of contraction = increased BP
65
Patient characteristics that treatment depends on
Age
Diabetic status
Family origin
ARBs preferred over ACE inhibitors for African/African Caribbean patients
66
Treatment options via NICE guidelines
Step 1:
- Split patients into diabetic and non-diabetic then further subdivision of non-diabetic group via age and background
- With diabetes = ACEi or ARB
- Aged under 55 and not black = ACEi or ARB
- Aged 55+ or of black family origin = CCB
Step 2
- Given a combination of drugs
- With diabetes or under 55 (not black) = ACEi or ARB combined with CCB or thiazide-like diuretic
- Aged 55+ or of black family origin = CCB combined with ACEi or ARB or thiazide-like diuretic
Step 3
- Given a more complex combination of drugs
- ACEi or ARB + CCB + thiazide-like diuretic
Step 4
- Patient requires even more drugs added to their treatment
- E.g. adrenoreceptor antagonist drug or spironlactone
67
What is polypharmacy?
Use of multiple medications (normally over 5)
- 60% of people with hypertension are taking 2+ drugs
- 25% UK adults are taking 3+ drugs
- 33% people over 75 are taking 6+ drugs
- Sometimes unavoidable due to the complex needs of the individual
Negative consequences = drug interactions, lots of side effects, drugs to treat side effects
68
General pathway of RAAS
- Activated by the SNS or decreased blood flow to the kidney
- Activates renin which provides long term control of BP & operates on a minutes to hours time scale
- Renin activates Angiotensin II
- Angiotensin II triggers vasoconstriction which increases BP
- Also triggers release of aldosterone and antidiuretic hormone which promote salt and water retention by the kidney = increased BP
69
Peptide signalling pathway of RAAS
- Angiotensinogen is connected to a globin which is an inactive serum protein
- Renin (a protease) cleaves the precursor angiotensinogen from the above molecule
- This produces angiotensin I
- Angiotensin I is inactive and becomes activated by ACE to produce angiotensin II
- Angiotensin II binds to 2 receptors which are angiotensin II receptor types 1 and 2 (ATR1 and ATR2)
- In hypertension, the most important one is ATR1 as it stimulates aldosterone release from the adrenal cortex and causes vasoconstriction
- Angiotensin III is activated AP-A and is partially active at ATR1s
- Angiotensin IV also plays a role
- Net result is vasoconstriction & aldosterone secretion
70
Tissue distribution of renin, angiotensinogen and ACE
- Renin is secreted by cells of juxtaglomerular apparatus
- The glomerus is the basic filtration unit of the kidney
- Angiotensinogen is secreted by the liver into circulation
- ACE, aminopeptidases AP-A and AP-N are produced locally in the tissues where angiotensin II is made = local fine-tuning
- Renin and angiotensinogen is secreted into the circulation = global control of RAAS
71
What is Renin release stimulated by?
- (Nor)Adrenaline —> Beta1 adrenoreceptors
- Actions of other hormones
- Prostacyclin
- Decreased blood pressure in the kidney
- Decreased Na+ in the distal convoluted tubule
72
Properties of calcium channel blockers
Used for people aged over 55 years or of African/African-Caribbean origin
Can be cardioselective or vasoselective, the latter used mainly in hypertension
These block L-type voltage gated calcium channels
73
Vasoselective calcium channel blockers
Dihydropyridines —> all have ‘dipine’ in the name
- 1,4-Dihydropyridine = all derived from this
- Amlodipine
- Nifedipine
- Nicardipine
74
Cardioselective calcium channel blockers
Verapamil and Diltiazem
75
What determines selectivity in calcium channel blockers?
Different subunit combinations
Different states of the channel predominate
- Cardiac channel = more in open state
- Vascular channel = more in an inactivated state
76
Structure of a typical resistance arteriole
The diameter of these determine blood pressure
- Capillary
- Sympathetic nervous system contracts smooth muscle when activated
- Even at rest, there’s a small underlying level of activation = vessel is always partially constricted
- Smooth muscle cells around capillary
- Arteriole
- Contraction of smooth muscle reduced diameter of arteriole
- This increases blood pressure
77
Signalling in vascular smooth muscle
- Noradrenaline/adrenaline activates Alpha1 adrenoreceptors (Gq pathway) in resistance arterioles
- This causes muscle depolarisation which activates L-type calcium channels
- Blocking these channels means smooth muscle is unable to contract and the diameter of resistance arterioles will increase
- This is the mechanism used by CCBs to decrease blood pressure
- Activation of the L-type channels will allow calcium entry which leads to smooth muscle contraction and narrowing of resistance arterioles
- Results in muscle contraction
78
Side effects of CCBs
These are normally well tolerated by patients and are considered safe drugs but side effects include:
- Headache (caused by dilation of blood vessels in the brain)
- Flushing
- Dizziness
- Swollen ankles
- GI tract issues (e.g. nausea and abdominal pain)
- Palpitations
- Reflex tachycardia (where body tries to compensate for lowered blood pressure by speeding up the heart)
79
Drug targets in RAAS
4 main classes of drugs used clinically
In hypertension = ACEi and angiotensin receptor blockers
Others = Renin inhibitors and aldosterone antagonists
80
ACE inhibitors
First line treatment for people under 55 (most common) and second line treatment for older people (in combination with CCBs)
Examples:
- Captopril
- Lisinopril
- Ramipril
All end in ‘pril’
81
Actions of ACE inhibitors
Blocks ACE and prevents conversion of inactive angiotensin I to angiotensin II (and III)
Prevents activation of angiotensin II type 1 receptors causing a decrease in vasoconstriction and aldosterone secretion
Ultimately decreases blood pressure
82
What is used as an alternative to ACEi ?
Angiotensin receptor blockers
Preferred for people of African background
Have become cheaper so used more in recent years
83
Examples of ARBs
All end in ‘artan’
Losartan & Candesartan
84
Actions of ARBs
Angiotensin receptor antagonists
ARB drug acts on the opposite end of RAAS, competitively antagonising the AT1R
Causes a decrease in vasoconstriction and aldosterone secretion = reduced blood pressure
85
Side effects of ARBs
- Lower risk of cough as no bradykinin is accumulated (as ACE is not blocked)
- Lower risk of angioedema in African/African-Caribbean patients
- Headaches, GI tract issues and postural hypotension
86
Kidney reabsorption and excretion
1. Glomerulus filters blood
2. Reabsorption of substances such as Na+, K+, H2O etc —> goes through the proximal convoluted tube, loop of henle, distal convoluted tube and then finally the collecting duct
3. Distal convoluted tube absorbs Na+ and Cl- and is regulated by hormones such as aldosterone
4. Collecting duct reabsorbs water under the influence of antidiuretic hormone = urine formation
87
Ion movement in the distal convoluted tube
Thiazides contain a particular chemical structure which is found in Bendroflumethiazide but NOT Chlortalidone
- Na+/Cl- cotransporter (NCC) is the target of thiazide diuretics e.g. Bendroflumethiazide and thiazide-like diuretics e.g. Chlortalidone
- These block NCC which cause a high urine volume and less water is absorbed
- Results in short term decrease in blood pressure as water and salt is lost
- Results in long term changes in vasculature
88
Use of thiazides
Widely used —> 30% of patients in North America/Western Europe
It is a first line option in the US but a second line in the UK = use has declined in the UK with only 10-20% of people with hypertension taking them
89
Thiazide side effects
- Increased urine output in 50-100% of patients —> 1-2 litres per day but this decreases once the patient is stabilised on the drug
- Electrolyte loss (Na+, K+, Mg2+) —> can be counter acted by dietary supplements
- Increased risk of type 2 diabetes
- Headaches, GI tract issues and postural hypotension
90
Autonomic control of blood pressure
Sympathetic NS acts on vasculature (blood vessels) and the heart to increase blood pressure —> blocking these effects will reduce blood pressure
Parasympathetic NS also modulates blood pressure but there are no drugs that can directly exploit these effects
91
Adrenoceptor signalling systems
**Alpha 1 = Gq pathway**
- vasoconstriction (increases BP)
- contract visceral smooth muscle
- relax GI tract
**Beta1 = Gs pathway**
- if antagonised will reduce HR and force of contraction
- increase heart rate and force of contraction
- increases release of renin
- lipolysis
**Beta 2 = Gs pathway**
- Bronchodilation
- Vasodilation (decreases BP)
- Relax visceral smooth muscle
- Glycogenolysis
- Muscle tremor
