Lecture 10: Drugs to Treat High BP Flashcards
What is Blood Pressure Generated by?
Beating of the heart and resistance of the circulatory system
What is Systolic Pressure?
The pressure at the peak of ventricular contraction
What is increased blood pressure associated with?
A higher hazard ratio for most cardiovascular outcomes
What will increase blood pressure?
Increased beating of the heart or higher resistance of the vasculature
Where are the three places where drugs regulate blood pressure?
- The heart
- Resistance vessels
- RAAS (Renin-Angiotensin-Aldosterone System)
What are the main effects of the RAAS?
Regulates blood volume and peripheral resistance
What is the main organ in the body that regulates fluid balance?
The kidneys
Which part of the Nephron is targeted by Thiazide Diuretics?
The Distal Convoluted Tubule
How do Thiazide Diuretics work?
They inhibit sodium and chloride reabsorption in the distal convoluted tubule
Which transporter do Thiazides work on?
The Sodium Chloride transporter (NCC)
How does the NCC work?
It brings Na+ and Cl- from the lumen of the nephron into the cell of the nephron and then the sodium potassium exchange pump takes sodium out of the cell into the blood
What happens with water when sodium is reabsorbed in the kidneys?
Sodium reabsorption drives water reabsorption
How does Thiazide affect blood pressure?
By blocking NCC they block sodium uptake with is coupled to water uptake and water uptake increases blood pressure
What is the commonly used Thiazide?
Bendroflumethiazide
What kind of receptors are Adrenergic Receptors?
G-protein coupled Receptors (GPCRs)
What are Adrenergic Receptors activated by?
Catecholamines like adrenaline and noradrenaline
What are the two subtypes of adrenergic receptors?
Alpha and Beta receptors
What are the predominant adrenergic receptors in the heart?
B1 receptors
What are B1 receptors in the heart responsible for?
Acceleration of the heart rate and causing the heart to pump harder during a fight or flight response
What kind of alpha G protein are Adrenergic receptors coupled to?
Gs
What are the key substrates that get phosphorylated in the heart?
- Voltage-gated ca2+ channels (L-type)
- Ryanodine receptors
- SERCA pumps
What is the first step during the beating of the heart?
Voltage gated calcium channels allow a small amount to calcium into the cell
What does the calcium that enters the heart cells during depolarization do?
Triggers calcium release by binding to ryanodine receptors
What do SERCA pumps do?
They reuptake the calcium
How does PKA affect the calcium reuptake pump?
It increases its overall activity
Where is Beta 2 the prominent adrenergic receptor?
In the lungs and some vasculature
What do beta 2 receptors do?
Cause bronchioles to dilate and enhance perfusion of skeletal muscle during a flight-or-fight response
What G signalling cascade are Beta 1 and Beta 2 coupled to?
The Gs signalling cascade
What is the key difference between the Beta 1 and Beta 2 signalling cascade?
Their effects are different in the tissues because different effectors are present
In cardiac muscle, what are the key targets of PKA?
- Voltage gated Ca2+ channels that increase Ca2+ during a heartbeat
- Ryanodine receptors that increase Ca2+ release from intracellular stores during a heartbeat
- SERCA pumps remove Ca2+ by taking it into the ER
What are the targets of PKA in Vascular/Bronchiolar smooth muscle?
PKA phosphorylates myosin light chain kinase causing smooth muscle to relax
What do Beta Blocker do at the receptor?
Beta blockers are competitive antagonist of adrenergic receptors
Which adrenergic receptors are used to treat hypertension?
Beta blockers
Why would administering beta blockers work to treat HBP?
Because they would decrease cardiac output by blocking calcium activity in the heart by decreasing the force of contraction
What does Ionotropic refer to?
Changes in the contractility of the heart
What does Chronotropic refer to?
Changes in heart rate
What do alpha adrenergic receptors have a role in?
Peripheral resistance
What is the problem with some beta blockers like Carbedilol?
They have non-specific inhibition of alpha receptors as well as beta receptors
What harms may arise from using beta blockers?
Inhibiting Beta 2 receptors can cause bronchial spasm
Where are Alpha Adrenergic receptors present?
In tissues that don’t require increased blood flow during the fight or flight response
What does activation of alpha adrenergic receptors lead to?
Constriction of blood vessels
How do Beta blockers with non-specific alpha effects affect alpha adrenergic receptors?
They inhibit the constriction of blood vessels not needed in the fight or flight response leading to peripheral vasodilation reducing blood pressure
Which type of G receptor are alpha adrenergic receptors coupled to?
Gq receptors
What occurs when alpha receptors are activated?
They are g-coupled do they then go on to increase calcium in the cell through IP3. The calcium binds to calmodulin which binds to MLCK and increases the contraction of smooth muscle
What does blocking of alpha adrenergic receptors cause?
It blocks the activation of calcium calmodulin so that it cannot activate MLCK and activate smooth muscle constriction which doesn’t allow vessels around blood vessels not needed to constrict during fight or flight
What is the main mechanism by which beta blockers reduce blood pressure?
By reducing cardiac output
What receptors need to be targeted in order to have an effect on cardiac output?
Beta one receptors
What is a Beta 1 selective beta blocker?
Atenolol
What do non-selective beta blockers target?
Both beta 1 and beta 2
What do nonselective beta blockers do?
They reduce cardiac output but also have to potential to block dilation in the lungs causing bronchospasm
What is the benefit of Carvedilol?
It reduces peripheral resistance by causing vasodilation in tissues with alpha adrenoreceptors and reduce cardiac output
