52.4.1 Main Drug Classes Used in the Treatment of Hypertension

Question 1

What are the main drug classes used in the treatment of hypertension?

Answer 1

*Diuretics
*Vasodilators
*Cardio-inhibitory drugs
*Centrally acting sympatholytic drugs

Question 2

What are the different types of diuretics?

Answer 2

Thiazide. loop, and potassium sparring

Question 3

What are the different types of vasodilators?

Answer 3

*Alpha-adreno antagonists (alpha blockers)
*ACE inhibitors
*ARBs
*Ganglionic blockers
*NO donors
*Ion channel modulators (Ca2+ channel blockers and K+ channel openers)
*Renin inhibitors

Question 4

When are ganglionic blockers and NO donors used?

Answer 4

In acute hypertensive emergencies

Question 5

What are the cardio-inhibitory drugs?

Answer 5

*Beta blockers
*Ca2+ channel blockers

Question 6

What is the most common class of diuretics used to treat diuretics?

Answer 6

Thiazides

Question 7

How do thiazide diuretics work?

Answer 7

• Inhibit the Na⁺-Cl^- co-transporter in the distal convoluted tubule.
• This leads to greater excretion of salt and therefore less water retention, lowering blood pressure.

Question 8

What are some examples of thiazide diuretics?

Answer 8

• Bendroflumethiazide
• Chlorothiazide
• Structurally unrelated drugs e.g. metolazone

Question 9

Is the diuresis produced by thiazide diuretics strong?

Answer 9

It is weaker than with loop diuretics, but this is usually sufficient for treatment.

Question 10

How do loop diuretics work?

Answer 10

Inhibit the NKCC (Na/K/2Cl transporter) in the thick ascending limb of the loop of Henle.

Additional effects include that they are vasodilators of:

• Systemic resistance arterioles -> Useful in lowering arterial pressure in hypertension and in reducing peripheral resistance in cardiac failure
• Renal resistance arterioles -> Useful in increasing GFR and so potentially increasing diuresis
• Vasa recta of the renal medulla -> Resulting in a “washout” of the accumulated osmotically active substances of the medullary interstitium, and so further reducing the osmotic potential there and increasing the potency of the diuresis

Question 11

Give some examples of loop diuretics.

Answer 11

Furosemide

Question 12

Compare the effects of loop and thiazide diuretics in terms of their effects on calcium.

Answer 12

• Loop diuretics increase calcium excretion
• Thiazide diuretics reduce calcium excretion -> This can be used in treatment of conditions such as stone formation in the urinary tract

Question 13

What are some side effects of thiazide and loop diuretics?

Answer 13

• Metabolic alkalosis and hypokalemia
• Hypovolemia
• Hypercalcaemia (thiazides) or hypocalcaemia (loop)

Question 14

How do potassium-sparing diuretics work?

Answer 14

There are two main classes:

• Aldosterone antagonists
• Inhibitors of the epithelial Na+ channel in the collecting duct

Question 15

What are some examples of potassium-sparing diuretics?

Answer 15

• Aldosterone antagonists -> Spironolactone
• Inhibitors of the epithelial Na+ channel in the collecting duct -> Amiloride

Question 16

When are potassium-sparing diuretics used?

Answer 16

They are used when:

• Aldosterone levels are too high in disease, such as:
  
  • Cardiac failure
  • Hypertension
• Aldosterone levels are too high as a natural response to diuretic therapy (sinc aldosterone conserves water indirectly by conserving salt)

Question 17

Why may aldosterone levels be raised in diuretic therapy?

Answer 17

• Diuresis activates the juxtaglomerular apparatus, which releases renin and causes the production of aldosterone.
• Potassium-sparing diuretics may be used in these cases.

Question 18

Describe how the kidney adapts to diuretics.

Answer 18

During diuretic action:

• Downstream nephron segments increase NaCl reabsorption as delivered NaCl load increases.

Post-diuretic NaCl retention (short term):

• As diuretic concentrations in the tubule decline, Na+ retention increases until the next dose of diuretic is administered.

Chronic increase in Na+ retention (the ‘braking phenomenon’):

• Ability to increase renal NaCl excretion declines over time. Due to both depletion of the extracellular fluid volume and structural (hyperplasia, hypertrophy) and functional (include increase in Na/K ATPase in basolateral membrane) changes in the kidney tubules.

Question 19

How do beta-blockers work in treating hypertension?

Answer 19

• Block of β₁-adrenergic receptors in the kidney, reducing renin release (remember that the juxtaglomerular cells receive sympathetic innervation)
• May also have a CNS effect to reduce sympathetic outflow to the heart and reduce cardiac output

Question 20

What are some examples of beta-blockers used to treat hypertension?

Answer 20

‘Cardioselective’ β blockers -> e.g. Atenolol

Question 21

How do alpha-blockers work in treating hypertension?

Answer 21

They block alpha-1 receptors in the vasculature, causing vasodilation.

Question 22

What is the limitation of using alpha-blockers in treating hypertension?

Answer 22

Sympathetic innervation of the vasculature is important in everyday life, such as when standing up.

Question 23

What are some examples of alpha-blockers?

Answer 23

• Prazosin
• Terazosin

Question 24

How do potassium channel opener drugs work in treating hypertension?

Answer 24

• They open K_ATP channels on smooth muscle cells in the arteries
• This leads to hyperpolarisation and therefore vasodilation of the vessels

Question 25

What are some examples of potassium channel opener drugs?

Answer 25

* Diazoxide * Minoxidil * Hydralazine (maybe)

Question 26

How do nitric oxide donors work in treating hypertension?

Answer 26

* They are drugs that lead to the production or release of NO * This NO is responsible for the dilation of blood vessels, especially the venous system

Question 27

What are some example of nitric oxide donor drugs?

Answer 27

Nitroprusside

Question 28

How do ganglionic blockers work in treatment of hypertension?

Answer 28

* They lead to decreased activity of post-ganglionic nerves * Therefore, in theory, they should reduce both sympathetic and parasympathetic activity * However, since arteries receive only sympathetic innervation, this means that vasodilation is favoured

Question 29

What are some examples of ganglionic blockers used in treating hypertension?

Answer 29

Pentamethonium (C5) and hexamethonium (C6) found to be selective, non-depolarising ganglion blockers.

Question 30

What are sympatholytic drugs and what are the main types?

Answer 30

Drugs that block the sympathetic nervous system at different points: * Peripheral sympatholytic drugs (e.g. alpha-adrenoceptor and beta-adrenoceptor antagonists) block the influence of noradrenaline at the effector organ * Ganglionic blockers block impulse transmission at the sympathetic ganglia * Centrally acting sympatholytic drugs block sympathetic activity within the brain

Question 31

How do centrally acting sympatholytic drugs work in treating hypertension?

Answer 31

* They are agonists of α₂-adrenoceptors primarily in the brainstem. * This reduces sympathetic outflow to the heart and vasculature.

Question 32

What are some examples of centrally acting sympatholytic drugs?

Answer 32

* Clonidine * Methyldopa

Question 33

What are the three main classes of anti-hypertensive drugs that modulate the RAA axis that you need to know about?

Answer 33

* ACE inhibitors * Angiotensin receptor blockers * Renin inhibitors

Question 34

What are some examples of ACE inhibitors?

Answer 34

* Captopril was the first * Lisinopril, ramapril, enalapril, benazepril, cilazapril, fosinopril all have a slower onset of action that captopril * Some are pro-drugs converted in the body: ramipril to ramiprilat, enalapril to enalaprilat

Question 35

How do ACE inhibitors work?

Answer 35

* Block conversion of angiotensin I to angiotensin II (so that aldosterone is also not secreted) * This reduce peripheral resistance (passive dilatation) and sodium retention. * No direct effect on the heart.

Question 36

Aside from hypertension, when are ACE inhibitors used?

Answer 36

They can also be used to treat congestive heart failure.

Question 37

What are some examples of angiotensin receptor blockers?

Answer 37

Losortan

Question 38

How do angiotensin receptor blockers work?

Answer 38

* They block the AT₁ receptors that bind angiotensin II. * Angiotensin II usually causes vasoconstriction and aldosterone release (which leads to salt retention).

Question 39

What are some examples of renin inhibitors?

Answer 39

Aliskerin

Question 40

How do renin inhibitors work?

Answer 40

* They block the enzymatic activity of renin in converting angiotensinogen to angiotensin I. * Thus, they reduce peripheral resistance (passive dilatation) and sodium retention (thus reduce blood volume).

Question 41

What are the main classes of calcium-channel blocker?

Answer 41

Question 42

What are some examples of calcium channel blockers used to treat hypertension?

Answer 42

* Dihydropyridine calcium channel blockers, a group that includes amlodipine, felodipine and lacidipine, are a common choice for treatment. * Verapamil (more cardiac-specific tbf)

Question 43

How do calcium channel blockers work as antihypertensive drugs?

Answer 43

* Block calcium entry into cells * This prevent contraction of smooth muscles, which leads to vasodilation * They also inhibit cardiac contraction, which lowers cardiac ouput * In the kidney, the afferent arteriole appears to be more affected than the efferent, so that GFR is maintained despite the falling blood pressure