Drugs & The CVS - Vasculature

Question 1

Peripheral vascular resistance and vascular tone?

Answer 1

Peripheral vascular resistance influences vascular tone

Question 2

SNS nerve and vascular tone?

Answer 2

Has varicosities along its length and these primarily release NA to stimulate vasoconstriction

Question 3

VSM mediators that increase [Ca2+] and stimulate VSM contraction?

Answer 3

• ANGII –> AT1r
• PGG2, PGH2 –> TP (T-prostanoid receptor)
• ET1 –> ETa/b

Question 4

Endothelial cell agonists that can stimulate a relaxation from an increase in [Ca2+]?

Answer 4

• NO
• CNP (C-type Naturietic Peptide)
• PGI2
• EDHF (endothelial hypopolarising factor)

Question 5

What is BP mediated by?

Answer 5

CO & TPR

BP = CO X TPR

Question 6

What contributes greatest to BP regulation in regards to vascular tone and resistance?

Answer 6

Arterioles
• exhibit ‘vascular tone’ and so always display a partial state of constriction
• hypertensive patients tend to have a raised base vascular tone = more TPR = more BP

E.g. If all arteries are constrcited, less likely for blood to elave the arteries so BP goes up

Question 7

r, R and F in terms of contraction and relaxation in arterioles?

Answer 7

Contraction
 • r = FALLS
 • R = INCREASE
 • F = FALLS
= vasocontraction

RELAXATION
 • r = INCREASE
 • R = FALLS
 • F = INCREASE
= vasodilation

r=radius ; R=resistance ; F=blood flow

Question 8

Hypertension facts?

Answer 8

• > 140/90mmHg CONSISTENTLY
• most common RF for stroke
• major RF for MI & CKD
• ~25% of HF cases

Question 9

Treatment overview for hypertension?

Answer 9

Step 1 – Single Therapy:
• Under 55 – ACEi or ARB (Angiotensin Receptor Blocker)
• Over 55, Afro-Caribbean – CCB or Thiazide diuretic

Step 2 – Dual Therapy:
• ACEi and CCB
• ACEi and thiazide diuretic

Step 3 – Triple Therapy:
• ACEi, CCB and thiazide diuretic

Step 4 – Symptomatic Relief:
• Low-dose spironolactone (diuretic therapy)
• a-blockade or b-blockade

Question 10

Drugs that target peripheral vessels to reduce TPR?

Answer 10

• ACEI
• ARB
• CCB
• A-blocker

Question 11

ACEi and an example?

Answer 11

ACE Inhibitors

e.g. Enalapril

Question 12

What stimulated RAS?

Answer 12

• LOW renal Na+ reabsorption
• LOW renal perfusion pressure
• HIGH SNS activation

Question 13

What does ACEi cause?

Answer 13

DECREASES ANGII production

AND

INCREASES Bradykinin

Question 14

Uses of ACEi?

Answer 14

Main two:
• Hypertension
• HF

• Post MI
• Diabetic nephropathy
• Progressive renal insufficiency
• High CVS-disease-risk patients

Question 15

What type of drugs have a -ipril ending?

Answer 15

ACEi

Question 16

How does ACEi help with hypertension?

Answer 16

REDUCES TPR
• more bradykinin & less ANGII
• = reduces TPR via. less AT1R-mediated vasoconstriction
• = less BP & MORE bradykinin vasoDILATION

SODIUM RETENTION
• less Na+ retention in kidneys via. blocked actions of ANGII on the AT1R
AND
• less aldosterone secretion as blocked AT1R in the adrenal medulla

THIRST DRIVE
• less SNS activation of thirst in the brain via AT1R

Question 17

How does ACEi help with HF?

Answer 17

REDUCE TPR
• less vasoconstriction via. AT1R in the peripheral vasculature
• SO less TPR = less afterload on the heart
• SO the ionotropic effects of the heart decrease

REDUCE PRELOAD
• VENOdilation (?bradykinin) = less preload

(onenote explains it!)

Question 18

ARB and example?

Answer 18

ANG Receptor Blocker

e.g. Losartan

Question 19

How does ARB work and uses?

Answer 19

Same as ACEi so same uses

BUT

Prevent binding of ANGII to the AT1R
(rather than inhibiting ACE)

Question 20

SEs of ACEi & ARB?

Answer 20

• Cough - ACEi
- as STOP bradykinin breakdown (pro-cough)

• Hypotension - BOTH
- feel dizzy due to fluctuating BP e.g. standing from sitting

• Hyperkalaemia (BOTH)

• care with K+ supplements & K+-sparing diuretics
• aldosterone promotoes K+ loss so aldosterone inhibitors produce a hyperkalaemia

• Renal failure (in patients with renal artery stenosis) - BOTH
- glomerular filtration maintained by ANGII so need to be careful (onenote explains!)

Question 21

Are ACEi and ARB generally well tolerated?

Answer 21

YES - especially ARB

Question 22

Effect of Ca2+ on SMC?

Answer 22

1. Membrane depolarisation o pens VGCCs
2. Ca2+ enters and binds to CaM
3. Ca2+-CaM complex activates MLCK
4. MLCK mediated phosphorylation = VSM contraction

Question 23

Specific CCB in treatment of hypertension?

Answer 23

DHPs = selective for blood vessels (non-rate limiting)
• AMLODIPINE - no negative ionotropic effect
• prophylactic treatment of angina

Non-DHPs = for heart & vessels (rate-limiting)
• VERAPAMIL = negative ionotropic effect

Question 24

CCBs examples?

Answer 24

AMLODIPINE
• NO negative ionotropic effect
• DHP (non-rate limiting)

VERAPAMIL
• negative ionotropic effect
• Non-DHP (rate-limiting)

Question 25

DHPs?

Answer 25

Dihydropyridines

Question 26

Which CCB is used in hypertension treatment?

Answer 26

AMLODIPINE (aka DHPs)!

Inhibit Ca2+ entry into VSMCs
• so less contraction of the cells = less TPR = less BP
• does NOT have an ionotropic effect on the heart (so good)

NOTE
powerful vasodilation can lead to a reflex tachycardia and increased ionotropy thus increased myocardial oxygen demand

Question 27

Why are the drugs chosen in the way they are in Step 1 of treating hypertension?

Answer 27

Under 55 – ACE or ARB (Angiotensin Receptor Blocker).
• The reason those drugs are the first line drugs is due to the good patient adherence as seen in studies (left figure).
• Higher adherence = less side effects.
• Not much difference between ACEi and ARB in reducing BP.

Over 55, Afro-Caribbean – CCB or Thiazide diuretic.
• This group of people have a different drug schedule due to low plasma renin activity and so ACEi doesn’t work as well – the studies into this are not confirmed

Question 28

Why might alpha-blockers be used as anti-hypertensives?

Answer 28

Block A1-mediated vasoconstriction

• helps TPR = helps BP

Question 29

Examples of alpha-blocker drug for anti-hypertensive?

Answer 29

Prazosin
• a1 antagonist (PLC/PIP2)

Phentolamine
• a1/a2 antagonist
• action against the a2 blocks the -VE feedback of NA release = enhances NA release & SNS response = lead to increased HR (not reflex)