05-10-22 - Pharmacological Treatment of Hypertension Flashcards
Learning outcomes
- To identify the stepped pharmacological management of hypertension.
- To understand the mechanism of action of ACE inhibitors and Angiotensin Receptor blockers (ARBs).
- To understand the mechanism of action of the different types of diuretics.
- To understand the mechanism of action of calcium channel blockers (CCBs).
- To understand the mechanism of action of beta-1 adrenoceptor antagonists.
- To identify the advantages and disadvantages of multi-drug treatment.
How do we diagnose hypertension?
What 2 questions do we ask?
What 5 questions do we ask after diagnosing stage 1 hypertension?
How do the answers to these questions influence treatment?
How do we treat stage 2 hypertension?
- Diagnosis of hypertension:
- Clinic BP and ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM) - average day time
- 2 questions we ask:
- End organ damage?
- Secondary hypertension diagnosis?
- Questions we ask after diagnosing stage 1 hypertension:
1) End organ damage? (More relevant for <80 years old?)
2) Cardiovascular disease?
3) Renal disease?
4) Diabetes?
5) 10-year CV risk of ≥10%? - If we answer no to all of these questions, we treat stage 1 hypertension by offering lifestyle modifications and monitoring BP
- If we answer yes to any of these questions, we treat by offering lifestyle modifications as well as therapeutic interventions
- We treat stage 2 hypertension with therapeutic interventions
What are 7 lifestyle modifications we may suggest to treat hypertension?
- Lifestyle modifications we may suggest to treat hypertension:
1) Weight loss
2) Reduced salt (Na+) intake <6g/day
3) Reduced alcohol consumption
4) Increased aerobic exercise
5) Increased fruit and vegetable intake
6) Smoking cessation – quitting smoking
7) (Stress reduction / relaxation techniques)
What are 8 antihypertensive drugs involved in the therapeutic treatment of hypertension?
- Antihypertensive drugs:
1) Angiotensin converting enzyme inhibitors (ACE inhibitors)
2) Angiotensin II receptor blockers (ARBs)
3) Loop diuretcs
4) Thiazide Diuretics
5) K+-sparing diuretics
6) (a1-adrenergic receptor blockers - not used commonly anymore)
7) b1-adrenergic receptor blockers
8) Calcium channel blockers (CCBs)
Nice/British hypertension society guidelines.
Who are the 2 different columns for?
What are medications A, C, D?
What is resistant hypertension?
What are the 4 steps of treatment for age column?
- Nice/British hypertension society guidelines.
- Column 1 is for patients with diabetes / <55 years old
- Column 2 is for patients of African/Caribbean descent / >55 years old
- Medications used:
1) A – ACE inhibitor / ARB
2) C – Ca2+ channel blocker
3) D – Thiazide diuretic - Resistant hypertension is when we need 3 blood pressure medications + a diuretic
What are the blood pressure measurements for hypertension for more and less than 80 years old?
What 2 things do we have to consider treatment of hypertension?
- Blood pressure targets for hypertension:
1) Age <80 years old
* Clinic BPM - <140/90mmHg
* ABMP/HBPM - <135/85mmHg
2) Age >80 years old
* Clinic BPM - <150/90mmHg
* ABPM - <145/85mmHg
- When thinking about treatment of hypertension, we have to think about:
1) Postural hypotension
* People can faint if they stand up too quickly, so we have to base our targets on standing BP
2) Frailty / multimorbidity
* Use Rockwood Frailty score
* Is it best for older patients to be on a lot of medication
* Use clinical judgement
What are 3 targets for blood pressure control?
- 3 targets for blood pressure control:
1) Heart – cardiac output (CO)
2) Blood vessels – total peripheral resistance (TPR)
3) Kidneys
What are the 4 antihypertensive drugs that target the kidneys?
- Antihypertensive drugs affecting the kidney:
1) Angiotensin converting enzyme inhibitors (ACE inhibitors)
2) Angiotensin II receptor blockers (ARBs)
3) Thiazide Diuretics
4) K+-sparing diuretics
What are the 4 steps of filtration/reabsorption in the kidney nephrons?
What is Na+ important for?
What must be balanced in terms of Na+?
- 4 steps of filtration/reabsorption in the kidney nephrons:
1) Blood is filtered at the glomerulus
2) Ultrafiltrate enters tubule and flows along distinct segments
3) Reabsorption (as well as secretion) of ions, solutes and water occurs along the length of the tubule
4) Remainder of ultrafiltrate flows to bladder and will leave as urine - Na+ is important for determining blood volume
- The Na+ excretion must match the intake
What are the 4 different places in the tubule of the nephron where Na+ is reabsorbed?
What % of Na+ is absorbed at each part?
What does this reabsorption create?
What % of Na+ is excreted?
- 4 different places in the tubule of the nephron where Na+ is reabsorbed:
1) Proximal convoluted tubule (PCT) – 65-75% of Na+ reabsorbed
2) Thick Ascending Limb (TAL), Loop of Henle – 15-20% of Na+
3) Distal convoluted tubule (DCT) – 5%
4) Cortical collecting duct (CCD) – 5-7% - This reabsorption of Na+ creates an osmotic gradient for H2O to follow – wherever sodium goes, water goes
- About 1% of Na+ is excreted
What are the 3 roles of angiotensin 2?
What do all of these roles lead to?
- Roles of angiotensin 2:
1) Vasoconstriction - Angiotensin causes vasoconstriction of renal arteries, which increases total peripheral resistance and constricts blood flow via the kidneys
2) Release of aldosterone - Angiotensin 2 causes the release of aldosterone from the zona glomerulosa (outermost region) of the adrenal glands, which changes the volume of water excreted from the kidney by increasing Na+ and water reabsorption
3) Stimulation of release of ADH (vasopressin) from the pituitary - ADH increases blood volume by increasing water permeability in the renal collecting ducts, which decreases urine production
- All of these roles of angiotensin 2 lead to an increase in blood pressure
Where does angiotensin 2 especially stimulate Na+ reabsorption?
Where else does angiotensin 2 stimulate reabsorption of Na+ through aldosterone?
- Angiotensin II stimulates Na+ absorption, particularly in the proximal convoluted tubule (PCT)
- Angiotensin II stimulates aldosterone release from zona glomerulosa (outermost region) of the adrenal glands, which further stimulates Na+ reabsorption in the cortical collecting duct (CCD)
What line of treatment are ACE inhibitors?
What are 5 examples of ACE inhibitors?
How do ace inhibitors affect angiotensin 2?
What 3 effects of this helps to reduce blood pressure?
- ACE inhibitors are first- or second-line treatment
- Examples of ACE inhibitors:
1) Ramipril
2) Captopril
3) Enalapril
4) Perindopril
5) Lisinopril - ACE inhibitors inhibit Angiotensin converting enzyme (ACE), which prevents angiotensin 1 from being converted to angiotensin 2
- Reduced angiotensin 2 production leads to:
1) Decreased vasoconstriction – leads to decreased TPR
2) Decreased water retention – leads to decreased ECV (effective circulating volume)
3) Decreased Na+ retention – leads to decreased ECV - All of these effects lead to decreased blood pressure
What is a 2nd system ACE inhibitors have an effect on?
What is the role of Bradykinin?
How does it act as a vasodilator?
What is the role of angiotensin converting enzyme (ACE) the system?
How do ACE inhibitors alter this system?
What effect does this have on BP?
Why might bradykinin increase cause patients to be prescribed an ARB instead of an ACE inhibitor?
- ACE inhibitors are also involved in the kinin-kallikrein system
- Bradykinin is a protein that acts as a vasodilator
- Bradykinin acts a vasodilator by binding to B2 receptors, which triggers the release of vasodilators NO and PGl2
- Angiotensin converting enzyme (ACE) breakdown bradykinin into an inactive metabolite
- ACE inhibitors inhibit ACE, which leads to increased levels of Bradykinin
- Increased Bradykinin leads to increase vasodilation, which decreases TPR, and therefore blood pressure
- Increased bradykinin can cause bronchoconstriction which can give rise to a dry cough.
- Often patients are then prescribed an ARB instead
What line of anti-hypertensive treatment are angiotensin 2 receptor blockers (ARBs)?
What are 5 examples of ARBs?
How do ARBs work?
Why might Arbs be prescribed instead of ACE inhibitors?
- Angiotensin 2 receptor blockers (ARBs) are usually first- or second-line treatment
- Examples of ARBs:
1) Losartan
2) Irbesartan
3) Valsartan
4) Olmesartan,
5) Candesartan - ARBs inhibit Angiotensin 2 AT1 receptors, which has the same effect as ACE inhibitors, but due to specific effects on AT1 receptors, ARBs have no effect on bradykinin
- This will mean, there is no side-effect of dry cough that might be seen with ACE inhibitors
What are diuretics?
What is targeted to have this effect?
How does this affect BP?
What are the 3 different types of diuretics?
- Diuretics are substances that help the body get rid of water
- They target Na+ absorption in order to reduce ECV, which decreases BP
- 3 different types of diuretics:
1) Loop diuretics
2) Thiazide diuretics
3) K+ sparing diuretics
Which diuretic is the most powerful?
What do they cause?
What are 2 examples of loop diuretics?
How do they work?
When it the only time loop diuretics are used to treat hypertension?
When else might it be used?
- Loop diuretics are the most powerful class of diuretics
- Loop diuretics cause a torrential urine flow
- 2 examples of loop diuretics:
1) Furosemide
2) Bumetanide - Loop diuretics work by inhibiting the NKCC2 ((Na+/K+/2Cl- co-transporter) in TAL (Thick Ascending Limb, loop of Henle), which accounts for about 15-20% of Na+ reabsorption
- Loop diuretics are only used in the treatment of hypertension when renal function is impaired
- They may also be used in other fluid overload conditions, such as heart failure
What are 3 examples of thiazide diuretics? How do they work?
What line of treatment are they?
- 3 examples of thiazide diuretics:
1) Bendroflumethiazide
2) Indapamide
3) Hydrochlorothiazide - Thiazide diuretics work by inhibiting the NCC in the DCT
- (Na+/Cl- co-transporter)
- Thiazide diuretics are 2nd/3rd line treatment
Are K+ sparing diuretics strong or weak?
What are the 2 different types of K+ sparing diuretics?
What are 2 examples of each?
How do K+ diuretics work?
Why are they rarely used?
- K+ sparing diuretics have limited diuretic action alone, but powerful in combination with loop/thiazide diuretics
- 2 different types of K+ sparing diuretics:
1) Aldosterone receptor antagonists (aka aldosterone antagonists)
* Block receptors that aldosterone binds to
* Examples:
* Spironolactone
* Eplerenone
2) ENaC inhibitors
* Amiloride
* Triamterene
* K+ diuretics work by Inhibiting ENaC in the CCD (Epithelial Na+ channel)
- Rarely used due to also blocking K+ excretion (coupled to ENaC), causing hyperkalaemia (K+ sparing)
How intracellular and extracellular levels of calcium, sodium, and potassium compare?
What 2 ion channels maintain resting membrane potential?
What 2 structures do calcium channel blockers inhibit contraction in?
- Intracellularly there is:
- Very low calcium (10^-4mM)
- Low Sodium (15mM)
- High potassium (150mM)
- Extracellularly there is:
- Slightly more calcium (1mM)
- High sodium (142mM)
- Low potassium (4mM)
- Resting membrane potential is maintained by:
1) The Na+/K+ ATPase
2) Kleak channels - Calcium channel blockers inhibit contraction in cardiac muscle and vascular smooth muscle
What is the threshold potential of the SA node pacemaker cells?
What are the 2 phases in the depolarisation of SA node pacemaker cell?
What then happens with this depolarisation in the pacemaker cell?
What are the 7 steps in the contraction of the cardiomyocyte?
- The threshold potential of the SA node pacemaker cells is around -40mV
1) Phase 1 - Gradual drift increases in resting membrane potential due to an increase in gNa+ as F-type (funny type) Na+ channels open (opposite to how regular voltage gated sodium channel’s function)
- This is known as the pacemaker potential, which is the slow, positive increase in voltage across the cell’s membrane that occurs between the end of one action potential and the beginning of the next action potential
- As the we get closer to the threshold frequency of the SA node (-40mV), the more likely the F-type Na+ channels are to close
- Transient (T) Ca2+ channels help with the final push towards the threshold potential
- There is also a decrease in gK+ as K+ channels slowly close
- As the potassium tries to repolarise the cell after an action potential, this increases the permeability of the F-type Na+ channels
2) Phase 2
* Moderately rapid depolarisation due to Ca2+ entry via slow (L) channels
- The depolarisation in the pacemaker spreads through gap junctions to cardiomyocytes (contractile cells), leading to contraction
- The steps in the contraction of the cardiomyocyte:
1) The cardiac action potential is generated on the surface of the cardiac muscle by the SA node cells and is delivered across cardiomyocytes via gap junctions connecting the cardiac cells together
2) The change in membrane potentials of cardiomyocytes is delivered deep into the muscle fibres by t-tubules, which are invaginations of the cardiac muscle cell membrane
3) This change in membrane potential will activate voltage-gated L-type calcium channels (DHP receptor channels, where the receptor sensed change in voltage) on the sarcolemma, but most L-type calcium channels are found on t-tubules
4) Calcium will flow into the cell and bind to the type 2 ryanodine receptors (RYR) on the SR membrane in a process called calcium induced calcium release.
5) Calcium will flow down its concentration gradient from the SR into the cytoplasm, where calcium can bind to the contractile machinery (troponin-c)
6) When calcium binds to troponin-c, this moves tropomyosin out of the way, which opens up the actin binding site on the sarcomere
7) Myosin globular heads can now form cross-bridges to these actin binding sites and initiate contraction of the cardiomyocyte
How do Calcium channel blockers (CCBs) work on the mechanisms of contraction in the heart?
How do they affect mechanisms in the SA node pacemaker cells and cardiomyocytes (contractile cells)?
What does this prevent in both cells?
How do these mechanisms in the heart compare with that of the smooth muscle?
- Calcium channel blockers (CCBs) inhibit L-type voltage gated calcium channels in both SA node pacemaker cells and cardiomyocytes (contractile cells)
- By inhibiting the L-type voltage gated calcium channels in the pacemaker cell, this stops the signal from being spread into the contractile cells
- By inhibiting the L-type voltage gated calcium channels in the contractile cell, we prevent calcium induced calcium release from occurring
- Both of these prevent a bigger depolarisation happening in both cells
- These mechanisms work the same in smooth muscle cells, and will prevent vasoconstriction from occurring
What are the 2 different types of Calcium Channel blockers?
What are 2 examples of each?
What muscles do each affect?
What are the 5 cardiac effects of these drugs?
What are the 4 smooth muscle effects of these drugs?
Which type of CCBs are favoured and why?
- 2 different types of Calcium Channel blockers:
1) Non-dihydropyridines
* Has two different types:
* Phenylalkylamines (example is Verapamil)
* Benzothiazepines (example is Diltiazem)
* Non-dihydropyridines affect both cardiac and smooth muscle
1) Dihydropyridines
* Examples:
* Amlodipine
* Felodipine
* Dihydropyridines only affect the smooth muscle
- 5 cardiac effects of non-dihydropyridines:
1) Decreased contractility
2) Decreased heart rate
3) Decreased conduction velocity
4) Decreased CO
5) Decrease the BP - 4 smooth muscle effects of non-dihydropyridines and dihydropyridines
1) Decreased artery constriction
2) Decrease peripheral vessel constriction
3) Decrease TPR
4) Decreased BP - Dihydropyridines are preferred over non-dihydropyridines, as sometimes we don’t want the cardiac effects on the heart that non-dihydropyridines bring
Describe the effects of Adrenaline, Noradrenaline, and Isoprenaline on β1 and β2 receptor tissues.
What are these 3 receptor tissues?
Which catecholamine has a higher affinity for each receptor?
- The effects of Adrenaline, Noradrenaline, and Isoprenaline on β1 and β2 receptor tissues.
- Which catecholamine has the highest affinity for each receptor
Nice/British hypertension society guidelines. Who are the 2 different columns for?
What are medications A, C, D?
What is resistant hypertension?
What are the 4 steps of treatment for age column?
- Nice/British hypertension society guidelines.
- Column 1 is for patients with diabetes / <55 years old
- Column 2 is for patients of African/Caribbean descent / >55 years old
- Medications used:
1) A – ACE inhibitor / ARB
2) C – Ca2+ channel blocker
3) D – Thiazide diuretic - Resistant hypertension is when we need 3 blood pressure medications + a diuretic
What are side effects of:
* Ace inhibitors
* ARBs
* Thiazide diuretics
* K+ sparing diuretics
* Calcium Channel Blockers (CCBs)
- Side effects:
1) Ace inhibitors
* Persistent dry cough
* Dizziness
* Tiredness
* Headaches
* Risk of angioedema (Afro-Caribbean)
* Risk of hyperkalaemia
* Renal impairment
* Avoid in bilateral artery stenosis teratogenic
2) ARBs
* Dizziness
* Headaches
* Back/leg pain
* Hyperkalaemia
* Renal impairment
* Avoid in bilateral artery stenosis
* Teratogenic
3) Thiazide diuretics
* Hypokalaemia
* Hyponatraemia
* Gout
* Impotence
* Monitor for dehydration
* Ineffective in moderate to severe renal impairment
4) K+ sparing diuretics
* Hyperkalaemia
* Renal impairment
* GI upset
* Spironolactone – oestrogen related side effects
5) Calcium Channel Blockers (CCBs)
* Flushes
* Headaches
* Ankle oedema
* Dizziness
