Drugs and the cardiovascular system: The vasculature

Question 1

Outline the sequential events that occur following a decrease in systemic arterial pressure, culminating with an increase in arterial pressure

Answer 1

• 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.

Question 2

Hypertension is defined as being consistently above what blood pressure? reading

Answer 2

140/90 mmHg

Question 3

Summarise the dangers of hypertension and the ultimate goal of hypertension therapy.

Answer 3

• 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

Question 4

What is step 1 in the NICE guidelines for treatment of hypertension?

Answer 4

< 55 years = ACEi + ARB

>55 years or Afro-Caribbean of any age = CCBs or thiazide-type diuretics

Question 5

What is step 2 in the NICE guidelines for treatment of hypertension?

Answer 5

ACEi or ARB
AND
CCB or thiazide diuretic

Question 6

What is step 3 in the NICE guidelines for treatment of hypertension?

Answer 6

Combination of ACEi/ARB with CCB and thiazide-like diuretic is recommended

Question 7

What is step 4 in the NICE guidelines for treatment of hypertension?

Answer 7

‘Resistant Hypertension’

• Consider low-dose spironolactone (aldosterone receptor antagonist)
• Consider beta-blocker or alpha blocker

Question 8

What are the 3 factors that cause renin secretion from the kidneys. Which cells are involved?

Answer 8

1. Reduction in afferent arteriole pressure (caused by systemic hypotension or renal artery stenosis); detected by Juxtaglomerular (JG) cells which secrete renin in response
2. 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)
3. Beta1-adrenoceptors located on the JG cells respond to sympathetic nerve stimulation by releasing renin.

Question 9

Give a brief summary of how angiotensin II is produced

Answer 9

• 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

Question 10

What are some of the important functions of angiotensin II? FIVE

Answer 10

• 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

Question 11

Describe the two actions of ACE inhibitors

Answer 11

1. Produce vasodilation by inhibiting the formation of angiotensin II (also prevents all the general actions of ang II)
2. 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

Question 12

What are the beneficial effects of ACE inhibitors in heart failure?

Answer 12

• Reduced afterload, which enhances ventricular stroke volume and improves ejection fraction.
• Reduced preload, which decreases pulmonary and systemic congestion and oedema.
• Reduced sympathetic activation

Question 13

List some other uses of ACE inhibitors. State the drug suffix

Answer 13

• post-myocardial infarction
• diabetic nephropathy
• progressive renal insufficiency
• patients at high risk of cardiovascular disease

Example: Enalapril (i.e. -pril suffix)

Question 14

What do angiotensin receptor blockers do?

Answer 14

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

Question 15

What is a common side effect of ACE inhibitors but not of ARBs? Explain why?

Answer 15

Dry cough

Due to the accumulation of bradykinin in the presence of an ACE inhibitor

Question 16

Explain the side effect of hyperkalaemia associated with ACE inhibitors and ARBs

Answer 16

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

Question 17

Explain why patients with bilateral renal artery stenosis may experience renal failure as a side effect if ARBs or ACE inhibitors are administered

Answer 17

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)

Question 18

What are the two main uses of ARBs. State the drug suffix

Answer 18

hypertension, heart failure

Example: losartan (i.e. suffix = -sartan)

Question 19

Summarise the steps of calcium mediated smooth muscle contraction

Answer 19

1. Membrane depolarisation opens voltage-gated calcium (Ca2+) channels (VGCCs)
2. Ca2+ enters & binds to calmodulin (CaM)
3. Ca2+-CaM complex binds to & activates myosin light chain kinase (MLCK)
4. MLCK mediated phosphorylation => smooth muscle contraction

Question 20

Which class of calcium channel blockers would you use to treat hypertension and why? State the drug suffix.

Answer 20

Dihydropyridines (suffix = -pine)

They are more selective for blood vessels; inhibit Ca2+ entry into vascular smooth muscle

Question 21

Explain the reasons for using certain BP control drugs over others.

Answer 21

• 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

Question 22

Compare the effects of RAS inhibitors with that of CCBs (in terms of SBP reduction, heart failure, stroke and all-cause mortality)

Answer 22

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

Question 23

Compare the effects of RAS inhibitors with that of diuretics (in terms of SBP reduction, heart failure, stroke and all-cause mortality)

Answer 23

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

Question 24

Compare the effects of RAS inhibitors with that of beta-blockers (in terms of SBP reduction, CV events, stroke and all-cause mortality)

Answer 24

No difference in SBP reduction
RAS inhibitors decrease risk of CV events
RAS inhibitors decrease risk of stroke
No difference for all-cause death

Question 25

Why might α1-adrenoceptor antagonists (alpha blockers) be used as anti-hypertensives?

Answer 25

• 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.

Question 26

When are alpha blockers most effective?

Answer 26

Under conditions of elevated sympathetic activity (e.g. during stress) or during pathologic increases in circulating catecholamines caused by an adrenal gland tumor (pheochromocytoma).

Question 27

Give some side effects of alpha blockers

Answer 27

dizziness, orthostatic hypotension (due to loss of reflex vasoconstriction upon standing), headache*

*see other deck