Dawes: Antihypertensive Drugs

Question 1

What is essential hypertension?

Answer 1

This is the level of BP above which treatment does more good than harm.

Question 2

What is hypertension a risk for?

Answer 2

It is a major risk for stroke, coronary artery disease and renal disease. The risk of CVS death doubles for each 20mmHg systolic rise and 10mmHg of diastolic rise.

Question 3

What is the problem with hypertension in the general population?

Answer 3

The prevalence of hypertension increases with age with over 50% of people aged 65 and above suffering from it. This is especially common in the developing world where it accounts for 80% of the CVS disease burden and 90% of the $50 billion of global expenditure on antihypertensives.

Question 4

What is the problem with hypertension in the general population?

Answer 4

It is poorly diagnosed and treated with 30% of people being undiagnosed, 50% of patients being diagnosed but untreated and only 25% of patients on treatment actually being controlled.

Question 5

What is the differing influence of hypertension on the absolute risk of stroke and MI?

Answer 5

As Systolic Blood Pressure increases the risk of stroke and myocardial infarction increase exponentially.

Question 6

What is the differing influence of hypertension on the relative risk of stroke and MI?

Answer 6

Question 7

Does treatment help?

Answer 7

10 mmHg systolic BP fall means that the risk of…

• CVA falls 20%
• MI falls 40%
• Reduced Mortality
  
  • CVS death risk falls 25%

Question 8

What is the treatment for hypertension?

Answer 8

• Lifestyle Changes
  
  • Diet - Sodium < 80mmol/day = 5g NaCl
  • Weight loss (1kg roughly equates to 1mmHg)
  • Exercise
  • Reduce Alcohol
• Drug Therapy
  
  • Polypharmacy (30% need 3 or more)

Question 9

What is the problem with the treatment of hypertension?

Answer 9

It is a lifelong disease that results in concurrent diseases. There are perceived benefits of treatment but most people are asymptomatic.

The trouble with therapy is that it needs to be taken daily (adherence) and has side effects.

Question 10

What is the target for hypertension treatment?

Answer 10

Blood Pressure below 140/90 normally

In young people or those with target organ damage like diabetes, renal damage, heart attacl then aim for closer to 130/80

Question 11

What drugs are available for the treatment of hypertension?

Answer 11

• ACEi and Angiotensin II antagonists
• Beta-Blocker
• Calcium Channel Blockers
• Diuretics
  
  • Thiazide
  • Loop
  • Aldosterone Antagonists
• Alpha Blockers

Question 12

What ACEi are used in the treatment of hypertension?

Answer 12

Generally 1st line treatment

Cilazapril 1-5mg o.d. is used as it induces hypotension. it also leads to the development of a cough, angioedema and hyperkalemia.

Question 13

What AII antagonists are used in the treatment of hypertension?

Answer 13

1st line for those with contraindications to ACEi

Candesartan 4-32mg o.d. as it induces hypotension and hyperkalemia.

Question 14

What are the effects of Angiotensin II binding to Type 1 AII receptors?

Answer 14

• Vasoconstriction
• Increased Sympathetic Tone
• Oxidant Stress
• VSM hypertrophy
• Vascular Fibrosis
• Increased release of endothelin
• Increased release of aldosterone

Question 15

What is the effect of Angiotensin II binding to Type II AII Receptors?

Answer 15

• Antiproliferation
• Tissue Repair
• Apoptosis
• Vasodilation
• Kidney Development

Question 16

What are the contraindications of ACEi / Angiotensin Antagonists?

Answer 16

• Bilateral Renovascular Disease
  
  • AII acts to maintains perfusion gradient and therefore ACEi/AII antagonists lead to marked hypotension.
  • Ultimately causes the deterioration of renal function.
• Pregnancy
  
  • They cross the placenta and reduce renal development.

Question 17

What are the mechanisms of how beta-blockers reduce blood pressure?

Answer 17

It is unclear but it is thought that they act to reduce cardiac output, reset baroreceptors, inhibit renin, reduce sympathetic activity and reduce norepinephrine release from the presynaptic terminal.

Question 18

What are the side effects of beta-blockers?

Answer 18

• Fatigue
• Bradycardia
• Negative Inotropy
• Erectile Dysfunction
• Wheeze/Asthma Exacerbation
• Cold Peripheries

Question 19

What is the function of nifedipine?

Answer 19

A dihydropyridine that acts as an L-type calcium channel blocker on resistance vessels. As a result, it causes flushing, headaches and oedema.

Question 20

What is the function of verapamil?

Answer 20

It acts as an L-type calcium channel blocker that effects cardiac tissue and the GI tract. As a result, it can cause heart block, negative inotropy and constipation. (not used to lower BP)

Question 21

What is the mechanism of action for thiazide diuretics such as bendrofluazide or chlorthalidone?

Answer 21

It acts by inhibiting Na⁺/Cl^- in DCT (we pee out salt)

It acts to reduce BP with subdiuretic doses

causes vasodilation as it opens vascular K⁺ channels (this is how they lower BP)

The effects of diuretics may take 12 weeks to start.

Question 22

How do thiazide diuretics work?

Answer 22

They act to inhibit renal tubular reabsorption resulting in a reduction of body salt and water. The mechanism of long-term blood pressure reduction still is not completely clear but is thought to be through their vasorelaxcation through K+ channels.

• The RAAS system will actually counter the diuretic effects producxed by the low amount of drug given.

Question 23

What are the side effects of thiazide diuretics?

Answer 23

• Metabolic
  
  • Increased glucose (reduce glucose tolerance)
  • Increased urate (reduced urate clearance) - think gout!
  • Decreased K⁺, Na⁺ and Mg²⁺
• Diuresis (very rarely recognised)
• Erectile Dysfunction

Question 24

What are the mechanisms behind the action of loop diuretics such as frusemide?

Answer 24

They act by inhibiting Na+/K+/Cl-cotransporters in the ascending Loop of Henle. These diuretics are potent and have little antihypertensive effects alone. As a result, they are used in severe/resistant hypertension and have a potent effect if used with ACEi (blocking the RAAS compensation)

Better for fluid overload

Question 25

What are the pharmacokinetics of frusemide?

Answer 25

These drugs are secreted in the proximal tubule and concentrated. They act on the ascending limb and effect the Na⁺/K⁺/2Cl^- cotransporters on the luminal side.

Question 26

What are the pharmacodynamics of frusemide?

Answer 26

It has a steep dose-response curve and is the most effective diuretic.

Question 27

What are the side effects of loop diuretics?

Answer 27

* Dehydration/polyuria * Metabolic * Reduced Na⁺, K⁺ and Mg²⁺

Question 28

What are the properties of spironolactone (K+-sparing diuretics)?

Answer 28

Spironolactone acts as aldosterone antagonist that inhibits the distal N⁺/K⁺ exchange in the collecting duct. Its use can lead to gynecomastia, hyperkalemia and dehydration. Has a role in people with resistant hypertension but due to causing retaining of K+ can lead to Hyperkalaemia.

Question 29

How do alpha-1 blockers such as doxazosin reduce hypertension?

Answer 29

Blocks tonic sympathetic activity on resistance vessels.

Question 30

What are the properties of doxazosin?

Answer 30

It is a reversible alpha blocker that acts as a vasodilator, reduces prostatic symptoms and can cause postural hypotension. As a result, it is taken once daily and patients need to be started on a low dose and titrated.

Question 31

What are the miscellaneous antihypertensive drugs used?

Answer 31

* Vasodilators such as minoxidil (K+ channel opener)- makes you very hairy! and Hydralazine. * Centrally acting that act to reduce sympathetic tone such as methyldopa, clonidine and minoxidine.

Question 32

When do you start to use drugs to treat hypertension?

Answer 32

* persistent BP \> 160/100 * BP \> 140/90 + Target Organ Damage/Comorbities * 10 year CVS risk \> 20%

Question 33

How do doctors decide which antihypertensive drugs to prescribe?

Answer 33

Young person whose hypertension is often defined by increased renin activity should take an ACEi or a Beta Blocker as 1st line An older person who has hypertension independent of renin should take a Ca Channel blocker or Diuretic 2nd line is swapping over to one of the other class not already used **ACEi, vasodilator and diuretic (eg. cilazapril, felodipine and bendrofluazide)**

Question 34

What are the sensible drug prescriptions?

Answer 34

Question 35

What is special about pregnancy and hypertension?

Answer 35

There are both maternal and fetal complications and it is defined as a BP \> 140/90 mmHg

Question 36

When should beta-blockers be used?

Answer 36

Usually, 2nd/3rd line in hypertension but should be used if patient has MI, CCF and/or AF.

Question 37

What is the polypill?

Answer 37

This is a pill that combines all four drugs that target hypertension at levels lower than what causes side effects. As a result, they all combine in their little amounts to achieve reduced BP. * There are thoughts being put forward that these should be prescribed to everyone over a certain age to reduce the prevalence of MI, CCF and AF.