12. Drugs and the vasculature Flashcards
how is vascular smooth muscle directly affected?
- endothelial cells contain angiotensin converting enzyme which produces angiotensin II which acts on the AT1 receptor on vascular smooth muscle
- sympathetic nerves releases NA, neuropeptide Y and ATP
- there are drugs that directly interfere with AT1 receptors
how do arterioles contribute to BP?
arterioles are the biggest contributors to BP - the biggest drop in BP takes place from one end of an arteriole to the other showing that arterioles are the major resistance vessels
what does arteriolar smooth muscle normal display?
a state of partial tone (partially constricted) that allows further constriction/dilation
what is the pathophysiology of hypertension?
- consistently over 140/90mmHg
- important risk factor for stroke, heart failure, MI and chronic kidney disease
how is hypertension treated?
lifestyle changes: drinking, smoking, diet
STEP 1: ACE inhibitor
(ACEi) or angiotensin receptor blocker (ARB) for under 55s, calcium channel blocker (CCB) or thiazide-like diuretic for over 55s/afro-caribbeans
STEP 2: CCB or thiazide-like diuretic & ACEi or ARB
STEP 3: combination of ACEi/ARB with CCB and thiazide-like diuretic
STEP 4: consider low-dose spironolactone, b-blocker or a-blocker
why are over 55s not offered ACEi or ARB in step 1?
they have low renin/low renin sensitivity so will be less responsive to ACEi or ARB - the RAS probably isn’t causing high BP so will have little effect
which drugs involved in the treatment of hypertension directly affect the vasculature?
- ACEi and ARB (trying to inhibit ATII effects on vasculature)
- CCBs (targeting channels on vascular smooth muscle)
- a-blockers
what are the 3 major stimuli for renin production?
- low [Na+] in the DCT detected by macula densa cells (–> low Na+ reabsorption)
- decreased renal perfusion pressure
- increased sympathetic activity
what does ATII do?
- very powerful vasoconstrictor (increases TPR)
- directly affects kidney to promote salt and water retention –> increased blood vol.
- indirectly affects kidney by stimulating aldosterone production
- sympathetic activation
- thirst activation
what does ARB do?
block the receptors that AT11 targets
what are the uses of ACEi?
- hypertension and heart failure
- post-MI
- diabetic nephropathy
- progressive renal insufficiency
- patients at high risk of CVD
how does ACEi treat hypertension?
blocking ATII (vasoconstrictor) will reduce TPR and decrease BP
how does ACEi treat heart failure?
decreased venous return (due to reduced salt and water retention) –> decreased congestion in the system –> stress on heart alleviated
what are the side effects of ACEi and ARB?
- cough (ACEi)
- hypotension
- urticaria(rash) /angioedema(swelling) (ACEi rarely)
- hyperkalaemia
- foetal injury
- renal failure in patients with renal artery stenosis
what are the steps in smooth muscle contraction?
- Membrane depolarisation opens voltage-gated calcium (Ca2+) channels (VGCCs)
- Ca2+ enters and binds to calmodulin (CaM)
- Ca2+-CaM complex binds to and activates myosin light chain kinase (MLCK)
- MLCK mediated phosphorylation –> smooth muscle contraction
what do dihydropyridines (DHPs) do?
- affect smooth muscle only (non-rate limiting CCB)
- more selective for blood vessels
- used to treat hypertension
- also used for prophylaxis of angina
what do non-DHPs do?
- rate-limiting CCBs
- affect heart and smooth muscle
- verapamil causes large negative inotropic effect
what is the primary reason why ACEi and ARBs are used?
10-15% of patients stay on them
what do RAS inhibitors include?
ACEi and ARBs
compare RAS inhibitors and CCBs
- ACEi are more effective for heart failure patients
- CCBs are more effective if you are likely to develop stroke
compare RAS inhibitors and thiazides
- thiazides are more effective for both heart failure and stroke
- thiazides also have a more profound effect on systolic BP
what are a1 blockers and when are they used?
- a1-receptors are the predominant vasoconstricting receptor in the vasculature
- a1 blockers (a1 adrenoceptor antagonists) are used as a last resort in antihypertensive treatment
- blocking a1 receptors reduces vasoconstriction –> reduces TPR –> decreased BP
