Drugs Used For The Treatment Of Hypertension III: Drugs Acting On The Renin-angiotensin-aldosterone System Flashcards
Where is renin produced?
Kidney
Where is angiotensinogen produced?
The liver
What is the action of renin?
Converts angiotensinogen to angiotensin I
Where is ACE found?
Plasma
What is the action of ACE?
Converts AT1 to AT2
What is the effect of ACE on bradykinin?
ACE inactivates bradykinin
What tissues does angiotensin II work on?
Adrenal cortex
Blood vessels
What receptors do angiotensin II work on?
AT-1
Angiotensin 2 type 1 receptors
What is the action of ACEIs?
Inhibit the conversion of AT1 to AT2
What is the action of ATII on the adrenal cortex?
Release of aldosterone
Which part of the adrenal cortex is aldosterone released from?
The zone glomerulosa
What is the effect of ATII on the blood vessels?
Vasoconstriction
What drug inhibits renin?
Aliskiren
What accumulates as a result of the action of aliskiren?
Angiotensinogen
What does the use of aliskiren prevent the accumulation of?
ATI
What does the use of ACEI result in the accumulation of ?
ATI and bradykinin
What does the use of ACEI result in the decreased formation of?
ATII
What is the receptor for ARBs?
Angiotensin II type 1 receptors
What are the effects of aliskiren, ARBs and ACEIs?
Vasodilation
Decreased aldosterone secretion
What is the action of aldosterone?
Na+ and water retention
Do ARBs interfere with bradykinin degradation?
No
As ACE is not affected when ARBs are used
Why are ARBs and ACEIs protective in diabetic nephropathy?
ATII constricts the efferent arterioles of the kidney. If ARBs and ACEs are used there is no ATII action so there is dilation of the efferent arteriole. Therefore filtration pressure and GFR decreases — this decreases the work of the kidney and reduces the risk of proteinuria.
What is the action of PG on the afferent arteriole of the kidney?
Vasodilation
When is there maximum filtration pressure and maximum GFR?
When PG dilates the afferent arteriole and ATII constricts the efferent arteriole
What is the clinical indication of aliskiren?
Mild to moderate hypertension
What are the clinical indications of ARBs and ACEIs?
Mild to moderate hypertension
Protective of diabetic nephropathy
CHF
What are the side effects of ACEIs, ARBs and aliskiren?
Hyperkalemia Acute renal failure in renal artery stenosis Angioedemia Dry cough (only in ACEIs) Hypotension
When do we not use aliskiren, ACEIs, ARBs?
Pregnancy
Bilateral renal artery stenosis
Hypotension
Why does aliskiren, ARBs and ACEIs cause hyperkalemia?
Aldosterone promotes K+ wasting, if there is no aldosterone action then no K+ wasting resulting in hyperkalemia
Why are ARBs, ACEIs and aliskiren not advised in renal artery stenosis?
In renal artery stenosis there is already a decreased GFR. If you prevent the vasoconstriction of the efferent arteriole via the use of one of these drugs, then the GFR decreases further as the filtration pressure is reduced.
What are the enhancers of renin release?
Decreased blood flow or hypotension
NaCl excretion
SY stimulation via Beta 1 receptors
What are the clinical indications for RAAS inhibitors?
Hypertension Diabetic nephropathy Metabolic syndrome: insulin sensitivity increases and insulin resistance decreases CHF IHD LVH
Which drugs do RAAS inhibitors interact with?
K+ sparing diuretics
Lithium (can increase Li toxicity)
Antidiabetic drugs (hypoglycemic effects may be enhanced)
Cytostatics and immunosuppressants (there is a risk of hypersensitivity)
Name the ACEIs
Captopril Fosinopril Zofenopril Perindopril Enalapril Lisinopril Ramipril
How are ACEIs administered?
Orally
Where are the ACEIs eliminated?
The kidney (apart from fosinopril)
Which ACEI is not eliminated in the kidney?
Fosinopril
Where is Fosinopril eliminated?
Partly in the liver
Which of the ACEIs are pro drugs?
Fosinopril
Zofenopril
Perindopril
Enalapril
Ramipril
Where and how are the pro-drugs ACEIs activated and how?
Hydrolysis in the liver
Where does glucuronidation of ACEIs take place?
The liver
What is the bioavailability of ACEIs?
Mild to moderate
What is the plasma half life of Captopril?
2h
What is the plasma half life of Fosinopril?
4h
What is the plasma half life of Zofenopril?
5-6h
What is the plasma half life of Perindopril?
9h
What is the plasma half life of Enalapril?
11h
What is the plasma half life of Lisinopril?
12.5h
What is the plasma half life of ramipril?
15h
Which ACEI has the longest plasma half life?
Ramipril
Which ACEI has the shortest half life?
Captopril
What is the mechanism of action of ACEIs?
There is a decrease in ATII which leads to decreased aldosterone secretion. There is decreased Na+ and water retension which reduces pre and after load — decreasing the work of the heart.
In addition decreased ATII results in a decrease in peripheral vascular resistance which results in a decrease in BP.
Name the ARBs
Losartan Eprosartan Valsartan Candesartan Irbesartan Telmisartan
Which ARB has the largest bioavailability?
Irbesartan
Which ARB has the smallest bioavailability?
Eprosartan
Which ARB has the longest plasma half life?
How long is it?
Telmisartan
> 20h
Which ARBs has the shortest plasma half life?
What is it?
Losartan
2-3h
Why would you use ARBs over ACEIs?
If the patient has tried ACEIs and developed dry cough or angioedema
What are the effects of ARBs?
Arteriolar and venous dilation and block of aldosterone secretion.
Decreased BP and Na+ and H20 retention
What is the dose of Valsartan?
1 x 80-320mg
How is aliskiren administered?
Orally
How is aliskiren eliminated?
Without inactivation (mainly)
In reference to aliskiren, when is P-glycoprotein involved?
Absorption and biliary excretion
What are the drug interactions of aliskiren?
P-glycoproteins inducers (e.g., Rifampicin) decrease the bioavailability
P-glycoproteins inhibitors (e.g., ketoconazole, verapamil) enhance the plasma level.
What should be avoided when ACEI are prescribed?
Potassium supplements and potassium sparing diuretics
Why should potassium sparing diuretics be avoided when using ACEI?
Because it can cause hyperkalemia
aldosterone promotes the retention of Na and H20 and the excretion of K. If there is no aldosterone action, then K is not increased therefore there is the risk of hyperkalemia when used with potassium sparing diuretics.
What may occur when ACEI are introduced to patients with HF who are already taking high dose diuretics?
Profound first dose hypotension
What should be checked before starting ACEI? (or before increasing the dose)
Renal function and electrolytes
When should ACEI be completely avoided?
in patients with severe bilateral renal artery stenosis (or severe stenosis of the artery supplying a single functioning kidney).
When should ACEI be used with caution?
if the patient may have undiagnosed or clinically silent renovascular disease: this includes patients with peripheral vascular disease or those with severe generalised atherosclerosis.
