Hypertension Flashcards
What is hypertension?
High blood pressure
What causes hypertension?
- Salt and volume retention
- Excess aldosterone can increase the amount of sodium in blood – increasing water
- Vasoconstriction
- Adrenaline/noradrenaline
- Endothelium dysfunction
What does angiotensin 2 do?
- Causes vasoconstriction of blood vessels
- Makes kidney reabsorb more salt and water
- Influence adrenal cortex which stimulates aldosterone
- Impacts brain – release of anti-diuretic hormone VASOPRESSIN – increases volume
How do the kidneys work?
- Blood comes in through bowmans capsule
- Filtered in glomerulus
- Reabsorption via NHE/SGLT (PCT)
- Leftover stuff goes through loop of henle
- Then through NKCC channels – target of loop diuretics – make kidney pass more fluid
- Then through distal convoluted tubule (DCT) NCC channel
What are the 3 targets of the kidney/nephron
- SGLT
- NKCC channel
- NCC channel
Diuresis vs natriuresis
Diuresis = passing out water Natriuresis = passing out sodium
What are baroreceptors?
• Receptors that sensor pressure
Where can baroreceptors be found
- Aortic arch
* Carotid sinus nerve
How do baroreceptors work
• LOW pressure detected = sends signals to the brain via vagus nerve to stimulate brain to send messages to increase heart rate and vasoconstriction etc
current Treatments for hypertension
- ACE inhibitor
- Low-cost angiotensin 2 receptors blocker
- Calcium channel blocker
- Thiazide like diuretic - work on DCT
- Spironolactone – aldosterone antagonist
- Alpha and beta blockers
What are the limitations for current therapy?
- Already many treatment options so a new medication needs something special
- Medication adherence for blood pressure medications is poor
Which drugs can we repurpose for hypertension?
- Entresto – meta-analyses show that it lowers blood pressure more than ARB alone
- Vericiguat = Victoria trial for heart failure suggested that vericiguat lowers blood pressure more than placebo
- SGLT2 inhibitors = reduce blood pressure
- Synthetic natriuretic peptide agonist – mimics natural natriuretic peptides
Tell me about natriuretic peptide agonists
- Currently available as intravenous agents
- Like neprilysin inhibitor it aims to increase the beneficial effects of natriuretic peptides
- e.g., increases natriuresis and diuresis and lower arterial tone
An example of a natriuretic peptide agonist
• Cenderitide was tested In heart failure and blood pressure – shown small reduction in blood pressure
What drug can give a prolonged effect for high blood pressure? Help with adherence
Angiotensin vaccines
How do vaccines help with adherence
• You give it once or twice and then done
Give an example of an angiotensin vaccine trial
- A phase 2 trial showed the effect of single dose angiotensin 2 vaccine lasting 14 weeks
- Trial did not reach phase 3 BECAUSE:
- The BP effects were small compared to ACEi
- Results not reproducible
- Can’t reverse effects maybe?
New treatment - What is firibastat?
Brain aminopeptidase a inhibitor
What does the Renin Angiotensin Aldosterone system do? RAAS
- Elevates blood volume via:
- Working on kidneys: Sodium and water reabsorption
- Working on blood vessels = vasoconstriction
- Heart
- Brain
How does RAAS affect the brain?
• Through the angiotensin process
How does brain control BP through RAS
- Increase in vasopressin – antidiuretic
- Activation of sympathetic premotor neuron activity
- Inhibition of the Baroreflex – baroreflex usually keeps pressure low
What is new in the angiotensin process?
- APA converts angiotensin 2 into 3
* APN converts angiotensin 3 into 4
What is APA
• Aminopeptidase A
What is APN
• Aminopeptidase N
What does angiotensin 3 do?
- It is produced in the brain
- Angiotensin 2 and 3 have a similar affinity for angiotensin 1 and 2 receptors
- They also have similar affinity for non-angiotensin 1 and 2 binding sites
- Increases arterial pressure
What is EC33 – Aminopeptidase inhibitor
- EC33 is a drug which STOPS APA so stops angiotensin 3 being made
- Angiotensin 2 ability to increase pressure is also reduced by aminopeptidase inhibitor (APA inhibitor)
What is RB150
- Known as firibastat
- A drug which crosses the blood brain barrier STOPS APA
- Decreases blood pressure
Clinical trial data on firibastat
- Phase 2 showed trials showed the higher the blood pressure the greater the firibastat BP lowering effect
- Acts as antihypertensive agent and NOT as a hypotensive agent
Summary of hypertension
- Significant room for repurposing other cardiovascular drugs to use in hypertension
- Potential for medicines that help more than one cardiovascular condition = SGLT2 inhibitors
- Vaccines are an interesting development to improve drug adherence
