Drugs and the Cardiovascular System: The Vasculature Flashcards
What are the main molecules involved in vascular tone / peripheral vascular resistance?
- NO: causes vasodilation
- Angiotensin 2: causes vasoconstriction
- ACE: needed to get AT2
- Endothelin A/B
- ATP: can influence contraction
- Prostaglandin: can cause contraction or relaxation, depends on which prostaglandin it is
- NA: can influence contraction
=> there are more!!
What mainly drives vascular tone/peripheral vascular resistance?
- SNS (SNS discharge to arterioles -> increased arteriolar constriction -> increased peripheral restistance -> increased arterial pressure)
- but other factors including all the molecules such as NO or AT2 also play a role
Arterioles contribution to BP
- When arterioles contract, resistance goes up and BF to that particular tissue goes down
- When arterioles dilate, resistance decreases and BF to that area increases
Important: arteriolar smooth muscle normally displays a state of partial constriction, which allows both rapid constriction as well as dilation.
Hypertension
- BP above 140/90 mmHg on multiple occasions (consistently)
- Single most important risk factor for stroke, causing about 50% of ischaemic strokes
- Accounts for ~25% of heart failure (HF) cases, this increases to ~70% in the elderly
- Major risk factor for myocardial infarction (MI) & chronic kidney disease (KD)
BP calculation
BP = CO x TPR
What is the ultimate goal of hypertension therapy?
reduce mortality from cardiovascular or renal events
Hypertension treatment guidelines
STEP 1
Angiotensin converting enzyme (ACE) inhibitor OR angiotensin receptor blocker (ARB) for under 55s
Calcium channel blocker (CCB) or thiazide-like diuretic for over 55s or afro-Caribbean’s
STEP 2
CCB or thiazide-like diuretic & ACEi or ARB
ARBs preferred to ACEi for AfroCaribbean’s
STEP 3
Combination of ACEi/ ARB with CCB and thiazide-like diuretic is recommended
STEP 4: Resistant Hypertension
Consider low-dose spironolactone
Consider beta-blocker or alpha blocker
What effects does AT2 have?
- vasoconstriction
- increased Na+ and water reabsorption and retention (direct action)
- increased thirst
- increased aldosterone (indirect action on salt retention in kidenys)
- increased SNS activation
=>AT1R mediates these effects
What increases renin?
↓renal Na+ reabsorption
↓ renal perfusion pressure
↑ sympathetic NS
When are ACEi used?
- hypertension
- heart failure
- post-myocardial infarction
- diabetic nephropathy
- progressive renal insufficiency
- patients at high risk of cardiovascular disease
MOA of ACEi
Inhibit the somatic form of angiotensin converting enzyme (ACE)
Prevent the conversion of angiotensin I to angiotensin II by ACE
What is the suffix fo ACEi?
- pril
e. g. Enalapril
How do ACEi help in hypertension and HF?
- Hypertension: reduces overall volume as well as TPR (BP=COxTPR)
- HF: it reduces the TPR and therefore the afterload so the heart has to work less (decreased cardiac work). There is also less venous return due to the decreased amount of fluid in the system and therefore preload decreases.
ARB
- Angiotensin Receptor blockers
- Antagonists of type 1 (AT1) receptors for Ang II, preventing the renal and vascular actions of Ang II.
- used in hypertension and HF
- diminish: vasoconstriction, salt and water retention, aldosterone secretion
- e.g. losartan
Losartan
angiotensin receptor blocker
How are ACEi and ARBs tolerated? (SIDE EFFECTS)
- generally well tolerated
Side effects:
- ACEi can cause cough because ACE is also responsible for the breakdown of bradykinin. Bradykinin accumulation causes cough.
- both can cause hypotension, e.g. not enough reactive hypertension when standing up.
- Hyperkalaemia (care with K supplements or K sparing diuretics)
- Renal failure in patients with renal artery stenosis (both)
How can ACEi and ARBs make renal failure worse or cause it in some patients?
Normal physiology:
- if the pressure in the glomerulus falls, mediators such as AT2 and NA can cause the efferent arteriole to constrict which increases the pressure in the glomerulus
- this restores GFR and filtering function
- in patients with renal artery stenosis there is already not enough blood supply to the kidney, by taking away this control via angiotensin their GFR can drop and kidney function worsens, there can be buildup of things in the blood that should be removed
- in renal failure patients are already struggling to regulate glomerular pressure and they have a low GFR. It can exacerbate and worsen the renal failure if you take away their ability to regulate the pressure via AT2
CCBs in hypertension
- Dihydropyridines (DHPs)
- More selective for blood vessels
- Amlodipine -does not cause any negative inotropy
- Also licensed for prophylaxis of angina
- Dihydropyridines inhibit Ca2+ entry into vascular smooth muscle cells:
↓ T.P.R. = ↓ B.P.
- Non-DHPs (aka rate-limiting)
- Verapamil - large negative inotropic effect
To treat hypertension you would give amlodipine because you are interested in improving the vasculature resistance.
Remember that powerful vasodilation can be associated with reflex tachycardia.
Smooth Muscle Contraction
- Membrane depolarisation opens voltage-gated calcium (Ca2+) channels (VGCCs)
- Ca2+ enters & binds to calmodulin (CaM)
- Ca2+-CaM complex binds to & activates myosin light chain kinase (MLCK)
- MLCK mediated phosphorylation smooth muscle contraction
Out of all the drugs, what should you use for hypertension?
- all drugs have similar effects on mortality
- you tend to give the drugs with better adherence
- follow guidelines
- which drug you use is also dependant on comorbidities.
Why do you go for a different first line treatment in people over 55 or in afro-carribeans of any age?
- The older they get the more the hypertension come down to things like atherosclerosis (vessles narrower) and less to renin etc and the BP becomes less sensitive to Renin (desensitisation), also less sensitive to CCB
- Afrocarribeans have a lower plasma renin activity genetically (but the evidence is not perfect so this might change over the years) They have lower plasma renin but it densn’t necessarily mean they don’t respond well to ACEi.
Why would you use alpha blockers in hypertension?
- vasoconstriction is mediated by alpha-1 R
- e.g. prazosin or phentolamine
Name some alpha blockers that are used as hypertensives?
Prazosin
Phentolamine
How do ACEi and ARBs cause hyperkalaemia?
- they interfere with the salt reuptake (N+/K+ pump is promoted via aldosterone/AT? check.)
- by having less salt reuptake there is less water retention and therefore blood volume and BP drop which is what you want
- by reducing amount of salt reuptaken there is a buildup of K+ in the blood which would regularly be removed in the urine by the pump
