CPT: Vasodilator 2

Question 1

What is RAAS responsible for?

Answer 1

regulates fluid absorption which influences extracellular volume, influencing blood volume, impacting BP

Question 2

1. How does a reduction in renin affect ANG II?
2. What does ANG II act on?

Answer 2

1. Reduction in ANG II
2. AT1 and AT2 receptors

Question 3

1. What is renin and what else is it called?
2. Where is it produced?

Answer 3

1. Proteolytic enzyme also called angiontensinogenase
2. Juxtaglomerular cells of the kidney

Question 4

What stimulates renin secretion?

Answer 4

in response to:

1. Decrease in aterial blood pressure (baroreceptor response)
2. Decrease in Na+ in the maccula densa
3. Increased sympathetic NS
   
   • Mainly B1 which is stimulated by SNS which can be stumulated by AII

Question 5

What are the steps in activation of the Angiotensin receptors?

Answer 5

1. The Plasma glycoprotein angiontestinogen is synthesised and secreted into the blood stream by the liver
2. Renin cleaves angiotensinogen to produce the decapeptide Angiotensin I
3. Angiontensin I is rapidly converted to ANG II (octapeptide) by ACE (present in the luminla surfaces of vasculae endothelium)
4. Peptidases further degreade ANG II to produce ANG III
5. AT1 receptor is activated by ANG II and AT2 is activated by ANG III
6. Both ANG II and ANG III stimulates aldosterone secretion by the adrenal cortex

Question 6

What effects does ANG II have?

Answer 6

1. Powerful arteriolar vasoconstrictor– direct action and release of Adr/NA release
   
   • Promotes movement of fluid: vascular - extravascular
   • More potent vasopressor agent than NA
   • It increases myocardial force of contraction (Ca2+ influx promotion) and increases heart rate by sympathetic activity, but reflex bradycardia occurs
   • Cardiac output is reduced and cardiac work increases
2. Aldosterone secretion stimulation
   
   • retention of Na+ in body
3. Vasoconstriction of renal arterioles
   
   • rise in IGP – glomerular damage
4. Decreases NO release
5. Decreases Fibrinolysis in blood
6. Induces drinking behaviour and ADH release by acting in CNS
   
   • increase thirst
7. Mitogenic effect
   
   • cell proliferation

Question 7

What are pathophysiological roles of ANG II?

Answer 7

1. Aldosterone secretion
2. Electrolyte, blood volume and pressure homeostasis: Renin is released when there is changes in blood volume or pressure or decreased Na+ content
   
   • Intrarenal baroreceptor pathway – reduce tension in the afferent glomerular arterioles by local production of Prostaglandin – intrarenal regulator of blood flow and reabsorption
   • Low Na+ conc. in tubular fluid – macula densa pathway – COX-2 and nNOS are induced – release of PGE2 and PGI2 – more renin release
   • Baroreceptor stimulation increases sympathetic impulse – via beta-1 pathway – renin release
3. Renin release – increased Angiotensin II production – vasoconstriction and increased Na+ and water reabsorption
4. Long term stabilization of BP is achieved
5. Hypertension
6. Secondary hyperaldosteronism

Question 8

ANG II effects in VSM

Answer 8

1. Vasoconstriction
2. Migration, proliferation and hypertrophy of cells
   
   • As cells increase in number and size they begin to encroach in the blood vessel lumon, increasing BP

Question 9

Effect of ANG II on endothelial cells?

Answer 9

1. Decrease NO production - (therefore vasoconstriction and increased BP)
2. Modifies adhesion molecule expression - more likely that platlets adhere to cells (Promotes blood clotting)
3. Endothelial dysfunction

Question 10

ANG II effects on cardiac muscle

Answer 10

1. Hypertrophy
   
   • Increase and growth od muscle cells, monocytes and fibroblasts
   • This influences remodeling of the heart which decreases ventricular volume as cells grow in size and encroach on the ventricles
   • Proliferation may also interfere with cell to cell communicstion in the hart and lead to impacting on conduction of the heart

Question 11

ANG II effects on the extracellular matrix

Answer 11

• Increases cross linking between collagen and elastic fibres and size of extracellular matrix
• This leads to the vessel becoming much more rigid and less complient
• It is therefore less likley to respond to vasodilatory treatment

Question 12

What do all the following effects of ANG II lead to and may result in?

Answer 12

Question 13

What are negative effects of ANG II

Answer 13

–Volume overload and increased t.p.r

• Cardiac hypertrophy and remodeling
• Coronary vascular damage and remodeling

–Hypertension – long standing will cause ventricular hypertrophy

–Myocardial infarction – hypertrophy of non-infarcted area of ventricles

–Renal damage

–Risk of increased CVS related morbidity and mortality

Question 14

What do ACEi do?

Answer 14

•ACE inhibitors reverse cardiac and vascular hypertrophy and remodeling

Question 15

Where do ACEi and ARB work?

Answer 15

Question 16

What can ACE inhibitors be used for?

Answer 16

1. Hypertension
2. MI
3. Congestive heart failure
4. Diabetic neuropathy
5. prophylaxis of high CVS risk subjects

Question 17

NOTE: ACE AND ARB SHOULD NOT BE USED IN COMIBINATION

Question 18

What does the renal do?

How does it do this?

Answer 18

• Long-term blood pressure control – by controlling blood volume
• Reduction in renal pressure - intrarenal redistribution of pressure and increased absorption of salt and water
• Decreased pressure in renal arterioles and sympathetic activity – renin production – angiotensin II production
• Angiotensin II:

–Causes direct constriction of renal arterioles

–Stimulation of aldosterone synthesis – sodium absorption and increase in intravascular blood volume

Question 19

What are examples of ACE inhibitors?

Answer 19

• Enalapril
• Ramapril
• Captorpil
• Lisinopril

Question 20

1. Describe Enalopril
2. and benefits over captopril

Answer 20

1. Prodrug - converted to enaloprilate
2. Advantages:
   
   • Absorption not effected by food
   • Rash and loss of taste less frequent
   • Longer onset of action
   • Less side effects

Question 21

Describe Ramipril

Answer 21

1. Prodrug
2. Long half life
3. Tissue specifiic - protective of heart and kidney
4. Uses: Diabetes with hypertension, CHF, AMI, Cario protective in angina pectoris

Question 22

Describe captopril

PK

Answer 22

1. Prodrug
2. Sulfhydryl containing dipeptide that abolishes pressor action of ANG I but not ANG II and does not block AT receptors
3. PK:
   
   • Food interferes with absorption
   • Available orally only - 70-75% absorbed
   • Party absorbed and partly excreted unchanged in urine

Question 23

Describe Lisinopril

Answer 23

• Not a prodrug
• Lysine dervivative
• Slow oral absorption - less chance of firts dose phenomenon (Inital dose is hypotensive)
• Absorbtion not effected by food and not metabolised - excreted unchange in the urine
• Long duration of action

Question 24

Adverse effects of ACEi

Answer 24

• Cough – persistent brassy cough in 20% cases – inhibition of bradykinin and substance P breakdown in lungs
• Hyperkalemia in renal failure patients with K+ sparing diuretics, NSAID and beta blockers (routine check of K+ level)
• Hypotension – sharp fall may occur – 1st dose
• Acute renal failure: CHF and bilateral renal artery stenosis
• Angioedema: swelling of lips, mouth, nose etc.
• Rashes, urticaria (hives) etc
• loss or alteration of taste (dysgeusia)
• Foetopathic: hypoplasia of organs, growth retardation etc
• Neutropenia (loss of neutrophil)
• Contraindications: Pregnancy, bilateral renal artery stenosis, hypersensitivity and hyperkalaemia

Question 25

Example of ARB and mechanism

Answer 25

• •Competitive antagonist and inverse agonist of AT1 receptor
• •Does not interfere with other receptors except TXA2
• •Blocks all the actions of A-II - vasoconstriction, sympathetic stimulation, aldosterone release and renal actions of salt and water reabsorption
• •No inhibition of ACE