Sally thompson

Question 1

where are the cell bodies located for all pre-ganglionic sympathetic neurons innervating smooth muscle?

Where are those specific to smooth muscle of heart?

Smooth muscle of abdomen i.e. splanchnic nerves?

specific to the adrenal medulla (catecholamine release)

Answer 1

Lateral horns of grey matter T1 -> L2

Heart: T1 -> T5

Abdomen: T5 -> L2

Adrenal medulla (T10-L1)

Question 2

What receptors are present on vascular smooth muscle that when stimulated cause vasoconstriction?

Answer 2

Alpha-1-adrenergic receptors (Gq-coupled)

Question 3

The cell bodies of pre-ganglionic fibres T1-L2 are directly stimulated by excitatory neurons travelling from where?

Answer 3

from the RVLM area of the vasomotor centre within the medulla.

Question 4

What 2 responses linked to the ANS control BP?

Answer 4

(1) The presence or absence of excitatory impulses sent from RVLM to pre-ganglionic cell bodies of sympathetic neurons can either cause vasoconstriction (if excited) or less vasoconstriction (if not)

(2) The presence or absence of excitatory signalling sent from NTS

through the parasympathetic fibres of CN X towards to SA/AV node; can decrease HR (if excited) or increase HR (if not excited).

Question 5

define hypertension

Answer 5

Hypertension is a persistent systolic BP of greater than or equal to 140mmHg, and/or a diastolic BP of greater than or equal to 90mmHg. It occurs as a result of increases in either or both CO/ PVR

Question 6

What findings would indicate a pheochromocytoma and how does this tumour cause hypertension?

What is the classic triad associated with pheochromocytoma (3 P’s)

Answer 6

Findings: elevated free metanephrines in plasma OR elevated fractionated metanephrines in urine in a 24 hour collection

Causes hypertension through its hypersecretion of catecholamines (norepinephrine and epinephrine) which vasoconstrict blood vessels via alpha 1 adrenergic receptors and cause increased HR via Beta 1 receptors.

Triad:
Pressure (headache)
Palpitations
Perspiration

Question 7

How might the COCP cause hypertension

Answer 7

The estrogen component in particular can increase serum renin concentrations which ultimately causes increased angiotensin II and aldosterone activity which will increase sodium and water retention in the kidney.

Question 8

How can anxiety cause parasthesaie (e.g. around the mouth and fingers) as well as muscle spasms?

Answer 8

Anxiety can cause hyperventilation which results in more Co2 being breathed out which ultimately reduces H+ ions in the blood, increasing blood pH and causing alkalosis.

The alkalosis causes more protein to bind calcium, reducing ionized calcium concentrations which are needed for proper nerve signaling and muscle function. This causes the parasthesia and spasms.

Question 9

Essential hypertension is that which is not caused by a specific medical condition but more as a result of genetic and environmental factors.

Outline 4 potential causes of this

Answer 9

(1) Mutations in proteins which are responsible for sodium reabsorption may result in increased sodium retention
(2) Failure of the body to respond to naturetic hormone e.g. ANP
(3) Gene defects in enzymes responsible for aldosterone metabolism
(4) Defects in vascular smooth muscle and structure may cause increased vascular wall thickness

Question 10

name and describe the 2 most common pathological features of hypertension seen in the kidney

Answer 10

(1) Hyaline arteriolosclerosis
- Glomerular endothelial damage caused by long standing hypertension results in plasma protein deposition within the vessel wall (hyalinisation)
- Chronic haemodynamic stress can also stimulate the SMC’s to synthesise ECM
- The result is thickened arteriole walls and a narrowed lumen which can lead to glomerular scarring i.e. nephrosclerosis

(2) Hyperplastic arteriolosclerosis
- Mostly associated with malignant HTN, acute rises in HTN and severe HTN.
- There is an onion skinned appearance due to laminated layers of smooth muscle cells and duplicated basement membranes.
- The narrowed lumen can cause ischemic damage to the glomerulus which manifests as glomerular wrinkling.
- In malignant HTN, there is an addition of fibrinoid deposition, vessel wall necrosis resulting in necrotising arteriolitis.
- stroke
- retinal ischemia
- renal ischemia causing ATN

Question 11

What type of anemia may be associated with hypertension?

Answer 11

Microangiopathic hemolytic anemia

Arteriolar damage results in activation of the coagulation system and fibrin deposition. RBC’s can become fragmented by fibrin meshwork which then undergo intravascular hemolysis.

Question 12

Distinguish between malignant and accelerated hypertension

Answer 12

Both malignant and accelerated HTN are types of hypertensive emergencies

Accelerated hypertension is a significant rise in blood pressure beyond baseline and which is associated with end-organ damage but WITHOUT papilloedema

Malignant hypertension is a severe hypertension (>180/120) which is associated with end organ damage involving at least 3 different organs AND/OR Papilledema.

Question 13

distinguish between hypertensive emergency and urgency

Answer 13

Emergency: A systolic BP of >180/120 with signs of end-organ damage.

Urgency: A systolic BP of systolic >220 OR diastolic >120 without signs of end organ damage

Question 14

Dihydropyridines e.g. Amlodipine are a type of calcium channel blocker. What accounts for their selectivity for vascular smooth muscle over cardiac muscle?

Answer 14

Dihydropyridines, such as amlodipine, are selective for vascular smooth muscle over cardiac muscle because they preferentially bind to L-type calcium channels in their inactivated state. These channels are more prevalent in vascular smooth muscle, which depolarizes less frequently than cardiac muscle, where channels are more often in the active or open state.

Question 15

Where in the nephron do thiazaide diuretics work?

Answer 15

Thiazide diuretics work in the early distal convoluted tubule, specifically in the proximal diluting segment.

They inhibit the Na+/Cl− cotransporter (NCC) on the luminal side of the epithelial cells, which blocks the reabsorption of sodium and chloride into the cells. This, in turn, reduces the activity of the Na+/K+-ATPase pump on the basolateral side, further preventing sodium reabsorption into the bloodstream.

Even though the early DCT is impermeable to water, blocking sodium reabsorption here leads to a decrease in the body’s sodium load. As a result, in the later nephron segments (like the collecting ducts), where water permeability is regulated by antidiuretic hormone (ADH), the reduced sodium reabsorption diminishes the osmotic driving force that would normally promote water reabsorption. Consequently, more sodium and water are excreted in the urine, which leads to a decrease in blood volume and, subsequently, blood pressure.

Question 16

Distinguish between the mechanism behind short term and long term benefits of diuretics on blood pressure.

Answer 16

Short-term mechanism:
In the short term, diuretics lower blood pressure by increasing sodium and water excretion, which leads to a reduction in blood volume. This decrease in blood volume causes a corresponding reduction in cardiac output and, subsequently, blood pressure. However, the renin-angiotensin-aldosterone system (RAAS) is activated in response to the drop in blood volume and blood pressure. Over time, this compensatory mechanism tends to attenuate the initial effect by promoting sodium and water retention, limiting the sustained reduction in blood volume.

Long-term mechanism:
The long-term antihypertensive effect of thiazide diuretics is less dependent on blood volume reduction and more related to their direct vasodilatory effects on peripheral vasculature. Although the exact mechanism isn’t fully understood, it is believed that chronic thiazide use leads to a reduction in peripheral vascular resistance, which may involve effects on vascular smooth muscle cells and altered sodium handling in the vessel walls. This vasodilation contributes to the sustained lowering of blood pressure, independent of blood volume changes.

Question 17

list 4 ADRs to thiazide diuretics

Answer 17

1. Hyperuricemia and gout
   - At the PCT, thiazides compete with uric acid for secretion into the lumen, therefore with more thiazide secretion, there is less uric acid secretion meaning uric acid builds up in blood. This can result in hyperuricemia and gout if it accumulates in the joints.
2. Hypokalemia
   - Because there is an increased sodium load delivered to the collecting tubule now that the NCC in distal tubule was blocked, there is more K+ secreted in response to sodium reabsorption in the collecting tubules. The effects of which are heightened by the effects of aldosterone. This can lead to hypokalemia as more K+ is lost in the urine.
3. Glucose intolerance
   - prolonged hypokalemia can result in decreased insulin secretion and decreased glucose uptake into cells.
4. Hyponatremia
   -due to sodium loss in the urie
5. Hyperlipidemia
   - There is a dose dependant increase in LDL and triacylglyceride production with thiazides.

Question 18

Describe the MOA of Atenolol (Beta-1 selective antagonist) in the lowering of blood pressure

Answer 18

Atenolol is a Beta-1 selective adrenergic receptor antagonist that primarily acts on Beta-1 receptors in the heart and kidneys. In the heart, it blocks the effects of norepinephrine and epinephrine, leading to a decrease in heart rate (negative chronotropy) and contractility (negative inotropy), which lowers cardiac output and reduces blood pressure.

In the kidneys, atenolol inhibits renin release from juxtaglomerular cells, thereby reducing the activation of the renin-angiotensin-aldosterone system (RAAS). This lowers sodium and water retention, further contributing to the antihypertensive effect. By targeting both cardiac function and fluid retention, atenolol effectively reduces blood pressure over time

Question 19

1. How do beta blockers selectively decrease blood pressure without significantly affecting normal blood flow to peripheral tissues?

Answer 19

This can be achieved by choosing a Beta-1 selective antagonist which will selective target Beta-1 receptors of the heart and kidneys and should largely spare the beta-2 receptors found in the vasculature of skeletal muscle which normally act to mediate vasodilation and therefore perfusion of tissue. If Beta 2 receptors were antagonised, it may result in more vasoconstriction in skeletal muscle vasculature which may exacerbate the ill-effects of PVD.

Question 20

Explain what a chylomicron and what is its function?

Answer 20

Chylomicrons are a type of lipoprotein primarily responsible for transporting dietary triglycerides, cholesterol, and other lipids from the intestines to tissues in the body. They are formed in enterocytes (intestinal epithelial cells) after dietary fats are broken down in the lumen of the intestine by pancreatic lipases and emulsified by bile salts. The resulting fatty acids and monoglycerides are absorbed by enterocytes, where they are reassembled into triglycerides and packaged along with cholesterol, phospholipids, and apolipoproteins to form chylomicrons.

Chylomicrons are released into the lymphatic system via lacteals (lymphatic vessels in the intestines) and eventually enter the bloodstream through the thoracic duct. They transport lipids to adipose tissue and muscle for storage or energy use.

Apo C-II on the surface of chylomicrons activates lipoprotein lipase (LPL) on the endothelial cells of capillaries, particularly in adipose tissue and muscle. LPL hydrolyzes the triglycerides in the chylomicrons into free fatty acids (FFA) and glycerol. The FFAs are then taken up by tissues for storage (in adipose tissue) or oxidation (in muscle for energy).

The chylomicron remnants, now depleted of triglycerides but still containing cholesterol and other components, are taken up by the liver via interactions with Apo E receptors for further processing, such as cholesterol storage or conversion into bile acids

Question 21

Explain how statins reduce plasma cholesterol/hyperlipidemia

Answer 21

Statins acts by inhibiting cholesterol synthesis in the liver by inhibiting HMG COA Reductase, thereby preventing the synthesis of mevalonate, a key precursor for cholesterol synthesis.

The reduced intracellular cholesterol promotes a compensatory increased expression of LDL receptors on the surface of hepatocytes, allowing for increased LDL uptake and removal from plasma.

Question 22

Name 3 subclasses of calcium channel blockers with an example of each

Answer 22

1. Dihydropyridines e.g. amlodipine - selective towards L-type calcium channels in peripheral vascular smooth muscle (i.e. those in inactivated state) and so only reduce PVR (not CO)
2. Benzothiazepines e.g. Diltiazem
3. Diphenylalkalamines e.g. Verapamil

-> both of these bind to L-type calcium channels in both the heart and peripheral vascular smooth muscle.
-> Reduces heart rate (reduces AV node conduction)
-> Reduces contractility
-> reduces PVR

Question 23

Explain the pathophysiology of rebound hypertension after sudden cessation of beta blockers

Answer 23

Rebound hypertension following sudden cessation of beta-blockers occurs due to upregulation of beta-receptors during prolonged blockade. When beta-blockers are abruptly stopped, there is a surge in sympathetic activity as catecholamines excessively stimulate these now upregulated receptors. The key mechanisms include:

1. Increased Beta-1 Stimulation
Leads to increased heart rate and contractility, raising cardiac output.

2. Renin-Angiotensin-Aldosterone System (RAAS) Activation: Beta-1 stimulation in the juxtaglomerular apparatus increases renin release, causing elevated angiotensin II levels, leading to vasoconstriction (increased peripheral vascular resistance) and increased blood volume.

3. Adrenergic Rebound
Increased catecholamine release further stimulates adrenergic receptors, exacerbating the hypertensive response

Question 24

Describe the intracellular pathway following beta 1 receptor activation in the heart.

Answer 24

Beta 1 adrenergic receptors are GsPCR.

1. Increased activity of adenylyl cyclase
2. Increase cAMP
3. increased Protein kinase A activity
4. PKA phosphorylates L-type calcium channels.
5. Increased calcium influx and release from SR increases contractility

SA node: Beta 1 activation causes increased activity of HCN channels allowing for increased SA node firing/ increased HR

AV node: Beta 1 activation increased AV node firing/ increased HR

Question 25

Describe the MOA of methyldopa in HTN

Answer 25

Methyldopa is a centrally acting alpha 2 receptor agonist.

Methyldopa is a prodrug that is converted to alpha-methyl noradrenaline in the body.

It then binds to alpha 2 receptors in the medulla, most notably at the nucleus tractus solitaris.

This therefore increases activation of the caudal-ventro-lateral medulla (CVLM) via the NTS which can then inhibit the Rostral-ventro-lateral medulla (RVLM) which results in less excitatory signals sent to the lateral horn cell bodies of the spinal cord meaning less sympathetic outflow and reduced HR/ PVR.

Question 26

Why might someone on alpha-blockers experience reflex tachycardia?

Answer 26

This can be caused by alpha-2 antagonism in the medulla which results in increased sympathetic output -> adrenalin binds to B1 receptors of the heart

It may also be due to reduced venous return to the heart/ reduced blood pressure stimulates the baroreceptors to increase sympathetic tone.

Question 27

Describe the MOA of clonidine in anti HTN

Answer 27

Clonidine acts as an agonist at both the alpha 2 receptor of the NTS and also the Imidazoline receptor of the RVLM. This reduces sympathetic outflow from the RVLM.

Question 28

MOA of Moxonidine in anti HTN

Answer 28

Imidazoline receptor agonist in the RVLM, reduces sympathetic outflow

Question 29

MOA of Aliskiren

Answer 29

Direct renin inhibitor

Binds to the active site of renin which prevents renin from converting angiotensinogen to angiotensin 1.

The downstream effects are reduced AT 1, AT II and Aldosterone

Question 30

ECG changes in LVH

Answer 30

1. S wave in V1 + R wave in V5 or V6 is >35mm
2. Left axis deviation –> Positive deflection lead I, Negative deflection leads II, III, aVF (Pointing away)
3. Left ventricular strain in leads I, aVL, V5, V6
   –> ST depression
   –> T wave inversion

Question 31

MOA or Amiloride and Triamterene

Answer 31

These are potassium sparing diuretcs

They work in the late DCT and cortical collecting ducts

Block ENaC on luminal side of epithelial cell