Drugs and the vaculature Flashcards
What mechanisms regulate vascular tone and peripheral vascular resistance?
1. Arterial pressure drops Decreased baroreceptor firing Reflexes via medullary centres Increased symp discharge to arterioles (exc brain, heart) Increased arteriolar constriction (a1) Increased peripheral resistance Increases arterial pressure to normal
- Endothelial cells produce substances that impact on smooth muscle tone: NO, PGI2, PGG2, PGH2, ET1, AT2, CNP, EDHF
What drugs impact vascular tone?
- ACE inhibitors
- Angiotensin receptor blockers
- CCAs
- Thiazide-type diuretics
Explain the steps in hypertension treatment
- ACEi or ARB for under 55s, CCA or thiazide diuretic for over 55s/Afro-Caribbean’s
- CCA or thiazide diuretic + ACEi or ARB
ARBs better for Afro-Caribbean’s - Combination of ACEi/ARB with CCA and thiazide diuretic recommended
- Resistant hypertension
Consider low-dose spironolactone
Consider beta-blocker or alpha blocker
How do ACE inhibitors work in general?
Prevent conversion of ATI–>ATII by inhibiting somatic forms of ACE (angiotensin converting enzyme)
What are ACE inhibitors used to treat?
Hypertension Heart failure Post-MI Diabetic neuropathy Progressive renal insufficiency Patients at high risk of cerebrovascular disease
How does ACE inhibitors work as anti-hypertensives?
- Inhibit ATI dependent vasoconstriction –> reduce TPR –> reduces BP
- Reduce aldosterone production –> reduces blood volume –> reduces venous return –> reduces preload –> reduces CO
ACEis reduce TPR and CO to reduce BP
BP = TPR x CO
How do ACE inhibitors work to treat heart failure?
- Cause vasodilation –> decreases TPR –> decreases afterload –> reduces cardiac work
- Reduce aldosterone –> reduces salt and water reabsorption –> reduces venous return –> reduces preload –> reduces cardiac work
What are the side-effects ACE inhibitors?
- Hypotension
- Dry cough
- Rarely, angioedema
How do angiotensin receptor blockers work?
- Non-competitive antagonists at type 1 (AT1) receptors for Ang II
- Prevent vasoconstriction, salt and water retention, aldosterone secretion
What do ARBs treat?
Hypertension
Heart failure
What are the 2 types of calcium channel blockers? Compare and give example
- Non-rate slowing = dihydropyridines (DHPs)
E.g. amlodipine
- More selective for BVs
- Don’t cause any negative inotropy
- Bind on extracellular surface of protein
- Inhibit Ca entry into VSMCs - Rate-slowing = non-DHPs
E.g. verapamil
- Large negative inotropic effect
- Bind on intracellular surface
Why are DHPs preferred over non-DHPs as anti-hypertensives?
- DHPs inhibit Ca entry into VSMCs
- More powerful effect on VSM
- So greater effect in reducing TPR
What are the side effects of CCBs?
BP decrease causes reflex tachycardia
But massive reduction in TPR outweighs HR increase so BP decreases
How do alpha blockers work as anti-hypertensives?
Block a1 receptor
Profound vasodilation
Drop in TPR
What is the problem with using alpha blockers as anti-hypertensives?
SELECTIVITY
Need a relatively selective a1 blocker bc a2R = negative feedback receptor for SNS
a2 receptor must be stimulated to reduce NA production and hence depress symp function
If alpha blocker also blocks a2R –> enhancement of symp function
Opposite of wanted effect
How do aldosterone antagonists affect vascular tone?
E.g. spironolactone
- Inhibits the sodium retaining effects of aldosterone
- Limited diuretic effects, but is useful in heart failure and resistant cases of hypertension
What are the side effects of aldosterone antagonists?
- Hyperkalaemia
- Unwanted steroid-like effects, e.g. gynaecomastia, menstrual disorders and testicular atrophy
Which drugs are vasodilators?
- Calcium channel antagonists
- Hydralazine, nitroprusside and (organic nitrates), (potassium channel openers)
- Alpha blockers and sympatholytics
How does hydralazine cause vasodilation? When is it used?
- Direct vasodilator that acts mainly on arteries and arterioles
- Anti-hypertensive in pregnancy
What are the side effects of hydralazine?
- In absence of beta-blockade, it causes a reflex tachycardia as a result of its vasodilator effects
- Long term use - lupus-like disorder
How do alpha blockers cause vasodilation? When are they used?
- Competitive antagonists of α1-adrenoceptors
- Act as arterial vasodilators by inhibiting vasoconstrictor effects of SNS acting via α1‑adrenoceptors on vascular smooth muscle
- Anti-hypertensive but 3rd/4th line
- Irreversible nonselective alpha antagonist used in pheochromocytoma-induced hypertension (combined with a beta blocker)
What are the unwanted effects of alpha blockers?
Postural hypotension
How do sympatholytics cause vasodilation? When are they used?
- Centrally acting antihypertensive agents include clonidine and methyldopa (α2-adrenoceptor agonists) moxonidine (imidazoline agonist) and reserpine (depletes neuronal noradrenaline)
- All act by reducing sympathetic activity.
- Poor side effect profile
- Short acting ganglion blockers (cholinoceptor antagonists), e.g. trimethaphan, are occasionally used in anaesthesia to lower BP
What drugs are used to cause vasoconstriction?
- Sumatriptan and Ergot alkaloids
- Sumatriptan (5HT1D receptor agonist) causes vasoconstriction of some large arteries and inhibits trigeminal nerve transmission
- Treats migraine attacks, but contraindicated in coronary disease as it also causes coronary vasoconstriction
- Other ergot alkaloids are also used in migraine and probably act as 5HT1 receptor partial agonists
- Bad side effects - Sympathomimetic agents
- Adrenaline used in cardiac arrest and anaphylactic shock
Summarise how external Ca can cause smooth muscle contraction
- Membrane depolarisation opens VGCCs
- Ca enters and binds to calmodulin (CaM)
- Ca-CaM complex binds to and activates myosin light chain kinase (MLCK)
- MLCK mediated phosphorylation –> smooth muscle contraction
