Drugs and the cardiovascular system: The vasculature Flashcards
Outline the sequential events that occur following a decrease in systemic arterial pressure, culminating with an increase in arterial pressure
- Decrease in arterial pressure results in decreased baroreceptor firing (due to decreased stretch of the arterial walls)
- Autonomic neurons within the medulla respond by increasing sympathetic outflow and decreasing parasympathetic (vagal) outflow (occurs because autonomic afferents from the baroreceptors synapse in the nucleus tractus solitarius which modulates the parasympathetic and sympathetic activity in the medulla)
- Decreased parasympathetic discharge to the heart => increased HR => increased CO
- Increased sympathetic discharge to the heart => increased HR, increased contractility and hence SV => increased CO
- Increased sympathetic discharge to the veins => increased (venous tone => venous pressure => venous return => ventricular filling) => increased end-diastolic volume => increased SV => increased CO
- Increased sympathetic discharge to the arterioles => increased arteriole constriction (in addition to normal vascular tone) => increased total peripheral resistance
The combination of an increase in CO and TPR results in an increase in arterial pressure.
Hypertension is defined as being consistently above what blood pressure? reading
140/90 mmHg
Summarise the dangers of hypertension and the ultimate goal of hypertension therapy.
- Single most important risk factor for stroke
- 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 (CKD)
- Ultimate goal of hypertension therapy = reduce mortality from cardiovascular or renal events
What is step 1 in the NICE guidelines for treatment of hypertension?
< 55 years = ACEi + ARB
>55 years or Afro-Caribbean of any age = CCBs or thiazide-type diuretics
What is step 2 in the NICE guidelines for treatment of hypertension?
ACEi or ARB
AND
CCB or thiazide diuretic
What is step 3 in the NICE guidelines for treatment of hypertension?
Combination of ACEi/ARB with CCB and thiazide-like diuretic is recommended
What is step 4 in the NICE guidelines for treatment of hypertension?
‘Resistant Hypertension’
- Consider low-dose spironolactone (aldosterone receptor antagonist)
- Consider beta-blocker or alpha blocker
What are the 3 factors that cause renin secretion from the kidneys. Which cells are involved?
- Reduction in afferent arteriole pressure (caused by systemic hypotension or renal artery stenosis); detected by Juxtaglomerular (JG) cells which secrete renin in response
- Decreased sodium reabsorption/elevated sodium concentration in the DCT; detected by the macula densa cells (which inhibit/stimulate renin release from the JG cells and trigger contraction of the afferent arteriole)
- Beta1-adrenoceptors located on the JG cells respond to sympathetic nerve stimulation by releasing renin.
Give a brief summary of how angiotensin II is produced
- Renin acts on liver-derived angiotensinogen in the blood, converting it (by proteolytic cleavage) to angiotensin I
- Vascular endothelium, particularly in the lungs, has angiotensin converting enzyme (ACE), that cleaves off two amino acids to form angiotensin II
What are some of the important functions of angiotensin II? FIVE
- Vasoconstriction
- Increases sodium and water retention (at several tubular sites)
- Acts on the adrenal cortex to release aldosterone, which in turn acts on the kidneys to increase sodium and water retention
- Stimulates vasopressin/ADH to increase fluid retention
- Stimulate thirst
- Augments sympathetic activity on the heart and blood vessels
Describe the two actions of ACE inhibitors
- Produce vasodilation by inhibiting the formation of angiotensin II (also prevents all the general actions of ang II)
- Since ACE also breaks down bradykinin (a vasodilator substance), ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, therefore contributing to the vasodilatory action
What are the beneficial effects of ACE inhibitors in heart failure?
- Reduced afterload, which enhances ventricular stroke volume and improves ejection fraction.
- Reduced preload, which decreases pulmonary and systemic congestion and oedema.
- Reduced sympathetic activation
List some other uses of ACE inhibitors. State the drug suffix
- post-myocardial infarction
- diabetic nephropathy
- progressive renal insufficiency
- patients at high risk of cardiovascular disease
Example: Enalapril (i.e. -pril suffix)
What do angiotensin receptor blockers do?
Block type 1 angiotensin II (AT1) receptors on bloods vessels and other tissues such as the heart. These receptors are coupled to the Gq-protein and IP3 signal transduction pathway that stimulates vascular smooth muscle contraction
What is a common side effect of ACE inhibitors but not of ARBs? Explain why?
Dry cough
Due to the accumulation of bradykinin in the presence of an ACE inhibitor
Explain the side effect of hyperkalaemia associated with ACE inhibitors and ARBs
Normally, potassium from the blood is actively pumped into the tubular cell in exchange for intracellular sodium.
Decreased aldosterone/angiotensin II production => decreased sodium reabsorption into the tubular cell => decreased K+ removal form blood
Explain why patients with bilateral renal artery stenosis may experience renal failure as a side effect if ARBs or ACE inhibitors are administered
Elevated circulating and intrarenal angiotensin II in this condition constricts the efferent arteriole more than the afferent arteriole within the kidney, which helps to maintain glomerular capillary pressure and filtration.
Removing this constriction can cause an abrupt fall in glomerular filtration rate => renal failure (problem if it occurs bilaterally)
What are the two main uses of ARBs. State the drug suffix
hypertension, heart failure
Example: losartan (i.e. suffix = -sartan)
Summarise the steps of calcium mediated 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
Which class of calcium channel blockers would you use to treat hypertension and why? State the drug suffix.
Dihydropyridines (suffix = -pine)
They are more selective for blood vessels; inhibit Ca2+ entry into vascular smooth muscle
Explain the reasons for using certain BP control drugs over others.
- The drug’s side-effect profile may influence the patient’s adherence to the drug.
- Afro Caribbean patients tend to have low plasma renin activity
Compare the effects of RAS inhibitors with that of CCBs (in terms of SBP reduction, heart failure, stroke and all-cause mortality)
CCBs decrease SBP more than RAS inhibitors
RAS inhibitors decrease risk of heart failure
RAS inhibitors increase risk of stroke
No difference for all-cause death
Compare the effects of RAS inhibitors with that of diuretics (in terms of SBP reduction, heart failure, stroke and all-cause mortality)
Thiazides decrease SBP more than RAS inhibitors
RAS inhibitors increase risk of heart failure
RAS inhibitors increase risk of stroke
No difference for all-cause death
Compare the effects of RAS inhibitors with that of beta-blockers (in terms of SBP reduction, CV events, stroke and all-cause mortality)
No difference in SBP reduction
RAS inhibitors decrease risk of CV events
RAS inhibitors decrease risk of stroke
No difference for all-cause death
Why might α1-adrenoceptor antagonists (alpha blockers) be used as anti-hypertensives?
- α1-adrenoceptor antagonists cause vasodilation by blocking the binding of norepinephrine to the smooth muscle receptors.
- They dilate both arteries and veins because both vessel types are innervated by sympathetic adrenergic nerves; effect is more pronounced in the arteries.
- α1 adrenergic receptors are linked to Gq-proteins that activate smooth muscle contraction through the IP3 signal transduction pathway
- α2 adrenergic receptors (not on sympathetic nerve terminals) are linked to Gi-proteins, and binding of an alpha-agonist to these receptors decreases intracellular cAMP, which also causes smooth muscle contraction.
When are alpha blockers most effective?
Under conditions of elevated sympathetic activity (e.g. during stress) or during pathologic increases in circulating catecholamines caused by an adrenal gland tumor (pheochromocytoma).
Give some side effects of alpha blockers
dizziness, orthostatic hypotension (due to loss of reflex vasoconstriction upon standing), headache*
*see other deck
