Drugs & The CVS - Vasculature Flashcards
Peripheral vascular resistance and vascular tone?
Peripheral vascular resistance influences vascular tone
SNS nerve and vascular tone?
Has varicosities along its length and these primarily release NA to stimulate vasoconstriction
VSM mediators that increase [Ca2+] and stimulate VSM contraction?
- ANGII –> AT1r
- PGG2, PGH2 –> TP (T-prostanoid receptor)
- ET1 –> ETa/b
Endothelial cell agonists that can stimulate a relaxation from an increase in [Ca2+]?
- NO
- CNP (C-type Naturietic Peptide)
- PGI2
- EDHF (endothelial hypopolarising factor)
What is BP mediated by?
CO & TPR
BP = CO X TPR
What contributes greatest to BP regulation in regards to vascular tone and resistance?
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
r, R and F in terms of contraction and relaxation in arterioles?
Contraction • r = FALLS • R = INCREASE • F = FALLS = vasocontraction
RELAXATION • r = INCREASE • R = FALLS • F = INCREASE = vasodilation
r=radius ; R=resistance ; F=blood flow
Hypertension facts?
- > 140/90mmHg CONSISTENTLY
- most common RF for stroke
- major RF for MI & CKD
- ~25% of HF cases
Treatment overview for hypertension?
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
Drugs that target peripheral vessels to reduce TPR?
- ACEI
- ARB
- CCB
- A-blocker
ACEi and an example?
ACE Inhibitors
e.g. Enalapril
What stimulated RAS?
- LOW renal Na+ reabsorption
- LOW renal perfusion pressure
- HIGH SNS activation
What does ACEi cause?
DECREASES ANGII production
AND
INCREASES Bradykinin
Uses of ACEi?
Main two:
• Hypertension
• HF
- Post MI
- Diabetic nephropathy
- Progressive renal insufficiency
- High CVS-disease-risk patients
What type of drugs have a -ipril ending?
ACEi
How does ACEi help with hypertension?
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
How does ACEi help with HF?
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!)
ARB and example?
ANG Receptor Blocker
e.g. Losartan
How does ARB work and uses?
Same as ACEi so same uses
BUT
Prevent binding of ANGII to the AT1R
(rather than inhibiting ACE)
SEs of ACEi & ARB?
• 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!)
Are ACEi and ARB generally well tolerated?
YES - especially ARB
Effect of Ca2+ on SMC?
- Membrane depolarisation o pens VGCCs
- Ca2+ enters and binds to CaM
- Ca2+-CaM complex activates MLCK
- MLCK mediated phosphorylation = VSM contraction
Specific CCB in treatment of hypertension?
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
CCBs examples?
AMLODIPINE
• NO negative ionotropic effect
• DHP (non-rate limiting)
VERAPAMIL
• negative ionotropic effect
• Non-DHP (rate-limiting)
DHPs?
Dihydropyridines
Which CCB is used in hypertension treatment?
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
Why are the drugs chosen in the way they are in Step 1 of treating hypertension?
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
Why might alpha-blockers be used as anti-hypertensives?
Block A1-mediated vasoconstriction
• helps TPR = helps BP
Examples of alpha-blocker drug for anti-hypertensive?
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)
