Lecture 10: Drugs to Treat High BP II Flashcards
What are the three types of adrenergic receptors?
- Alpha 1
- Beta 1
- Beta 2
What are the effects when an agonist binds to alpha 1 receptors?
Vasoconstriction of organs that are no required for the fight of flight response
What are the effects when an antagonist binds to alpha 1 receptors?
Vasodilation of organs that are not required for the fight or flight response
What are the effects when an antagonist bind to beta 1 receptors?
Increased cardiac contractility and rate
What are the effects when an antagonist binds to beta 1 receptors?
Decreases cardiac contractility and rate
What are the effects when an agonist binds to beta 2 receptors?
Relaxation of airway vascular smooth muscle
What are the effects when an antagonist binds to beta 2 receptors?
Constriction of the airway vascular smooth muscle
Where are beta 1 receptors found?
In the heart
Where are Beta 2 receptors found?
In the lungs
What is the main effect of beta blockers?
Decrease cardiac output by decreasing contractility and heart rate
What does RAAS stand for?
Renin Angiotensin Aldosterone System
What does the RAAS system control?
It controls blood volume, salt balance and blood pressure
What drugs target the RAAS system?
- Angiotensin receptor blockers (ARBs)
* Angiotensin Converting Enzyme inhibitors (ACEis)
What is Renin secreted by?
The kidney
What does Renin do?
It cleaves Angiotensinogen to Angiotensin I
What does ACE stand for?
Angiotensin Converting Enzyme
What does ACE do?
Cleaves Angiotensin I (ATI) to Angiotensin II (ATII)
What does ATII do?
It causes vasoconstriction of vascular smooth muscles and aldosterone release
What is Aldosterone?
A steroid hormone that promotes reabsorption of Na+ and H2O in the kidney increasing blood volume
Where does ATI come from?
The cleavage of Angiotensinogen by Renin
Where does ATII come from?
ACE converting ATI to ATII
What causes Aldosterone to be secreted?
ATII
Where is Aldosterone produced?
In the adrenal glands
What is the release of Renin stimulated by?
B1 activation due to low blood pressure
What is the end goal of the RAAS system?
To increase blood volume and blood pressure
What is the end goal of the RAAS system?
To increase blood volume and blood pressure
How do beta 1 blockers reduce BP?
By reducing cardiac output and by decreasing renin secretion
What is the signal pathway that increases release of Renin?
Adrenaline binds to B1 receptors activating Gs which activates AC and cAMP resulting of increased renin secretion
How do B1 antagonists affect Renin secretion?
They will block B1 agonists from starting the Gs cascade suppressing renin secretion and RAAS system
Where does ACE primarily exist?
In the pulmonary capillary endothelium as a membrane bound protein
What receptor does ATII bind to?
The ATI receptor
What kind of G receptors are ATI receptors that bind to ATII?
Gq receptors
What are the two main target tissues of ATII?
- The Adrenal cortex
* Vascular smooth muscle
What does the Adrenal Cortex release?
Aldosterone
What does ATII do the adrenal cortex and vascular smooth muscle?
Causes the release of aldosterone from the adrenal cortex and vasoconstriction of vascular smooth muscle
What is the intracellular pathway that leads to release of Aldosterone in the adrenal glands?
- ATII binds to ATI receptors which are Gq linked
- Increased calcium binds to calmodulin
- Calmodulin triggers synthesis and release of aldosterone
What is the intracellular mechanism that ATII causes vasoconstriction?
- ATII binds to ATI receptors which are Gq linked
- Increased calcium binds to calmodulin
- Calcium Calmodulin activates MLCK
- MLCK which phosphorylates the MLC causing constriction of the muscles
How is Aldosterone able to interact with its receptor and why?
Aldosterone must cross the plasma membrane to interact with its receptor because it is a steroid hormone
What is the intracellular cascade that allows aldosterone to work?
- Aldosterone crosses the membrane to bind with receptor
- Receptor causes unbinding of chaperone protein
- Translocates to the nucleus
- Affects transcription of target genes
- Generates mRNA and proteins
- Leads to biological effects
Which part of the kidney does Aldosterone target?
The Distal convoluted tubule
Which three parts of the DCT does Aldosterone target?
- Na+/K+ pump
- Epithelial Na+ channel (ENaC)
- NCC (Na+/Cl- symporter)
What is the net effect of aldosterone?
To promote Na+ and therefore water reabsorption to increase BP
What does NCC do?
Transports sodium into the epithelial cell of the nephron so that the sodium potassium exchange pump can pump sodium into the interstitium blood
What does aldosterone do to the sodium transported in the DCT?
Causes them to be upregulated in order to increase water reabsorption
What level does aldosterone, a steroid hormone act?
At the level of gene transcription
What is the main ACE inhibitor drug?
Captopril
What do ACE inhibitors do?
The prevent the cleavage of ATI to ATII
What does the prevention of ATI converting to ATII by ace inhibitors do?
Prevent the Vasoconstriction and aldosterone secretion of ATII
What is the most common side effect of ACE inhibitors and why?
Dry cough because ACE also causes the breakdown of bradykinin which causes bronchoconstriction
What is the overall effect of ACE inhibitors?
By blocking Vasoconstriction and Aldosterone secretion it decreases BP
What is the main ATI blocker (ARB)?
Losartan
What binds to ATI receptors?
ATII
What is the effect of ARBs?
They have a vasodilatory effect
Why do ARBs have a vasodilatory effect?
Because they block the ATI receptors and don’t allow ATII to bind
Why are ARBs better tolerated than ACE inhibitors?
Because they don’t have the dry cough side affect cause by bradykinin not being broken down
What is the main Aldosterone Antagonists?
Spironolactone
What is Spironolactone?
A competitive antagonist of the aldosterone receptor
What do Aldosterone Antagonists do?
The prevent aldosterone receptors from being activated
What are the effects of Aldosterone inhibitors?
They have diuretic actions be stopping the reabsorption of Na+
