Module 13 - Drugs for Hypertension

Question 1

what is hypertension

Answer 1

Hypertension is simply defined as elevated systemic arterial blood pressure.

Blood pressure is a measurement of the force against the walls of your arteries as the heart pumps blood through the body.

Question 2

In order to accurately measure blood pressure

Answer 2

1. The patient should be seated for at least 5 minutes.
2. No caffeine or nicotine within 30 minutes of measurement.
3. Feet should be touching the floor (not dangling).
4. Arm should be elevated to heart level.
5. Two measurements in each arm should be taken 5 minutes apart.
6. Before a diagnosis of hypertension, the patient should have this repeated 3 times at least 2 weeks apart.

Question 3

systole

Answer 3

when heart contracts

Question 4

diastole

Answer 4

period of time when the heart fills after a contraction

Question 5

Normal blood pressure

Answer 5

anything less than 120 and less than 80
normal = 120/80

Question 6

prehypertension

Answer 6

120-139 OR 80-89

Question 7

Stage 1 hypertension

Answer 7

140 - 159 OR 90- 99

Question 8

Stage 2 hypertension

Answer 8

anything greater than 160 systolic OR greater than 100 diastolic

Question 9

Primary Hypertension

Answer 9

Hypertension of no known cause.

Approximately 92% of all cases of hypertension.
- 90% of people over the age of 55 have high blood pressure.

Question 10

Secondary Hypertension

Answer 10

Hypertension with an identifiable cause.
Causes include:
1. Kidney disease
2. Hyperthyroidism
3. Pregnancy
4. Erythropoietin
5. Pheochromocytoma – tumour on the adrenal gland that causes excess epinephrine release.
6. Sleep apnea
7. Contraceptive use

Question 11

Consequences of hypertension

Answer 11

Chronic hypertension is associated with increased morbidity and mortality.

If untreated, hypertension can cause myocardial infarction, kidney failure, stroke or retinal damage.

Unfortunately, hypertension is a “silent killer” as many patients may have elevated blood pressure for years before they show any symptoms.

Question 12

determinants of blood pressure

Answer 12

Cardiac Output - Is determined by heart rate, heart contractility, blood volume and venous return.
- An increase in any of these results in an increase in blood pressure.

Peripheral Resistance - Is determined by arteriolar constriction.
- constriction of the arteries and arterioles will cause blood pressure to rise

blood pressure - cardiac output X peripheral resist

Question 13

3 systems that regulate blood pressure

Answer 13

1. The sympathetic nervous system.
2. The renin-angiotensin-aldosterone system (RAAS)
3. Renal Regulation of Blood Pressure

Question 14

sympathetic nervous system

Answer 14

Helps us respond to stress, i.e. the fight-or flight response.
- Is also constantly active to help keep body functions (including blood pressure) in homeostasis.

The sympathetic nervous system has a reflex circuit called the baroreceptor reflex that helps keep blood pressure at a set level.

Question 15

Baroreceptor Reflex

Answer 15

Baroreceptors on the aortic arch and carotid sinus sense blood pressure and send the info back to the brainstem.

If BP is too low, the brainstem sends impulses along sympathetic neurons that stimulate the heart to cause increased cardiac output and smooth muscle on arteries causing vasoconstriction. This increases BP.

If BP is too high, sympathetic activity is decreased. This causes decreased cardiac output and vasodilation.

The activity of baroreceptors can oppose our attempts to lower BP with drugs since the “set point” in patients with hypertension is high.

The baroreceptor reflex responds rapidly

Question 16

The renin-angiotensin-aldosterone system (RAAS)

Answer 16

The renin-angiotensin-aldosterone system (RAAS) is comprised of a series of protein hormones.

The renin-angiotensin-aldosterone system plays a critical role in regulating blood pressure, blood volume and electrolyte balance.

Activation of the RAAS affects the kidney and vascular smooth muscle to control blood pressure.

The RAAS is a target for many blood pressure-lowering drugs.

Unlike the baroreceptor reflex, activation of the RAAS may take hours or days to influence blood pressure.

Question 17

Renin

Answer 17

Catalyzes the formation of angiotensin I from angiotensinogen.

This represents the rate-limiting step in angiotensin II formation.

Renin is synthesized and secreted by the juxtaglomerular cells of the kidney into the blood.

The following increase renin release:
1. Decreased blood volume.
2. Low blood pressure.
3. Stimulation of beta 1 receptors on juxtaglomerular cells of the kidney.

Note: juxtaglomerular = beside the glomerulus

Question 18

Angiotensin Converting Enzyme (ACE)

Answer 18

Angiotensin-converting enzyme (ACE) converts the inactive angiotensin I into active angiotensin II.

• Activated Angiotensin II is:

potent vasoconstrictor by binding to its receptor (the AT1 receptor) to produce vasoconstriction.

stimulates release of aldosterone from the adrenal cortex. Aldosterone acts on the kidneys to increase sodium retention, which can increase water retention.

Angiotensin II also acts on the posterior pituitary gland to release antidiuretic hormone (ADH also called vasopressin). ADH causes water retention by the kidney.

Question 19

Renin Angiotensin Aldosterone System – Summary

Answer 19

The RAAS system is present to help our bodies regulate blood pressure.

When the RAAS system is activated it causes vasoconstriction and renal retention of sodium and water.

Vasoconstriction increases blood pressure by increasing peripheral resistance.

Increased retention of water and sodium cause an increase in blood volume, which in turn increases cardiac output.

Question 20

Renal Regulation of Blood Pressure

Answer 20

The kidney is a critical organ in terms of blood pressure regulation.

If blood pressure decreases for a prolonged time period, the kidney retains water.

This increased water retention leads to increased blood volume.

Increased blood volume causes increased cardiac output and therefore increased blood pressure.

Question 21

Non-pharmacological interventions for hypertension

Answer 21

• Non-pharmacological interventions are the initial recommendation for patients with a diastolic blood pressure of approximately 90 – 95 mmHg.
• Further, non-pharmacological treatments augment the effectiveness of drug therapy in patients with higher blood pressure.

Non-pharmacologic interventions include:
1. Decreasing body weight.
2. Restricting sodium intake.
3. Physical exercise.
4. Potassium supplementation.
5. The DASH diet.
6. Smoking cessation.
7. Alcohol restriction.

Question 22

Decreasing Body Weight

Answer 22

Obesity is thought to cause hypertension by 2 mechanism

1. Obese patients have increased insulin secretion, which causes tubular reabsorption of Na+ and, therefore, water reabsorption and a higher blood volume.
2. Obese patients also have increased activity of the sympathetic nervous system.

Weight loss lowers blood pressure in up to 80% of obese patients

Question 23

Restricting Sodium Intake

Answer 23

Salt is necessary to our bodies, however when sodium chloride (salt) intake is too high, it has a negative effect on blood pressure.

The kidney regulates the amount of salt in our body, eliminating excess salt in the urine.

When salt levels are too high, it causes water to be reabsorbed from the kidney into the blood.

This causes increased extracellular (blood) volume and therefore increased blood pressure.

Limiting salt intake to 5 g per day decreases systolic BP by approximately 12 mmHg and diastolic BP by 6 mmHg.

Question 24

Physical Exercise

Answer 24

Regular exercise decreases blood pressure by an average of 10 mmHg.

Regular exercise decreases extracellular fluid volume and circulating levels of plasma catecholamines (like epinephrine).

Importantly, the benefits of exercise are seen even if patients don’t restrict sodium or lose weight during the training period.

Question 25

Potassium Supplementation

Answer 25

Just as total body sodium levels are positively correlated with blood pressure, total body potassium levels are inversely correlated with blood pressure.

This means high total body potassium results in lower blood pressure.

High potassium diets decrease blood pressure by increasing sodium excretion, decreasing renin release and causing vasodilation.

Preferred sources of potassium are fresh fruits and vegetables.

IMPORTANT Patients taking ACE inhibitors should not be on a high-potassium diet.

Question 26

DASH diet

Answer 26

The “DASH diet” was derived from the dietary approaches to stop hypertension studies.
These studies gave subjects one of three diets and evaluated blood pressure. The three diets included:

1. Standard North American diet
2. Standard North American diet plus extra fruit and vegetables.
3. A diet rich in fruits, vegetables, low-fat dairy, lean meats (poultry and fish), whole grains, nuts and legumes. The diet also excluded foods high in saturated fat, total fat and cholesterol.

The results were remarkable, with most patients achieving lower blood pressure within 14 days without lowering salt intake.

The best results were seen in patients with prehypertension.

Patients with severe hypertension are encouraged to stick to this diet in combination with blood pressure-lowering medications.

Question 27

Smoking Cessation

Answer 27

Smoking acutely elevates blood pressure but has not been linked to causal in the development of hypertension.

Despite this, patients with hypertension should be encouraged to quit.

Both smoking and hypertension are risk factors for the development of cardiovascular disease.

Question 28

Alcohol Restriction

Answer 28

Excessive alcohol consumption increases blood pressure.

It also can decrease response to some antihypertensive medications.

Patients with hypertension or prehypertension should consume less than 2 drinks per day and less than 14 drinks per week for men and 9 drinks per week for women.

Question 29

Antihypertensive Medications

Answer 29

Drugs that decrease blood pressure do so by decreasing cardiac output or peripheral resistance.

Cardiac output is determined by heart rate, heart contractility, blood volume and venous return. Therefore decreasing any of these will decrease cardiac output and therefore decrease blood pressure.

Peripheral resistance is determined by artery/arteriolar constriction. Therefore decreasing constriction (or increasing dilation) will decrease blood pressure.

Question 30

Sites of Action for Antihypertensive Medications

Answer 30

vascular smooth muscle
- calcium channel blockers
- thiazide diuretics

RAAS
- beta-blockers, direct renin inhibitors, ACE inhibitors, ARBs, aldosterone receptor antagonists

Brainstem
- centrally acting alpha 2 agonists

Heart
- beta blockers, calcium channel blockers

Kidney
- thiazide diuretics, loop diuretics, potassium sparing diurectics

Question 31

Diuretics

Answer 31

Diuretics are the mainstay therapy for hypertension.
3 main classes of diuretics:
1. loop diuretics
2. thiazide diuretics
3. potassium sparing diuretics/aldosterone antagonists

Diuretics work by blocking sodium and chloride ion reabsorption from the nephron of the kidney.

By preventing reabsorption of Na+ and Cl- diuretics make an osmotic pressure within the tubule (“attracts the water”) that prevents the reabsorption of water.

The retention of water within the nephron promotes excretion of water and sodium/chloride ions.

Question 32

Diuretics - Sites of Action

Answer 32

Diuretics produce more effective decreases in blood pressure at sites of high sodium reabsorption.

For example, loop diuretics produce the largest decrease in blood pressure since 20% of sodium is reabsorbed at its site of action.

Question 33

Loop Diuretic

Answer 33

The most effective diuretics available.

They act by blocking sodium and chloride ion reabsorption in the thick ascending limb of the loop of henle.

Loop diuretics are usually reserved for situations that require rapid loss of fluid such as:
1. Edema
2. Severe hypertension that does not respond to milder diuretics.
3. In severe renal failure.

Remember, this fluid is then excreted out in the urine

Question 34

Adverse Effects of Loop Diuretic

Answer 34

Hypokalemia – may cause fatal cardiac dysrhythmias
2. Hyponatremia
3. Dehydration
4. Hypotension

Question 35

Thiazide Diuretics

Answer 35

Are the most commonly used class of drug to treat hypertension.

They act by two main mechanisms:

1. Blocking sodium and chloride ion reabsorption in the distal tubule.
2. Decreasing vascular resistance (the mechanism of which is unknown).

The maximum amount of diuresis (i.e. urine production) is much less than loop diuretics.

For many hypertensive patients thiazide diuretics alone are enough to control blood pressure.

Question 36

Adverse effects of thiazide diuretic

Answer 36

1. Hypokalemia – may cause fatal cardiac dysrhythmias
2. Dehydration
3. Hyponatremia

Question 37

Potassium Sparing Diuretics/Aldosterone Antagonists

Answer 37

Produce minimal lowering of blood pressure.

Act by inhibiting aldosterone receptors in the collecting duct.

Aldosterone normally causes sodium reuptake and potassium secretion.

Blocking aldosterone receptors causes increased sodium excretion and potassium retention (hence “potassium-sparing”) in the body.

The main use is in combination with thiazide and loop diuretics to counteract the hypokalemia side effect.

Potassium-sparing diuretics should not be used with ACE inhibitors or renin inhibitors as these drugs also conserve potassium.

The primary adverse event associated with potassium-sparing diuretics is hyperkalemia, which may result in fatal dysrhythmias.

Question 38

Beta Blockers

Answer 38

• Beta blockers are effective at treating hypertension by two distinct mechanisms:
  1. Blocking cardiac beta 1 receptors
  Binding of catecholamines (i.e. epinephrine, norepinephrine) to cardiac beta receptors causes increased cardiac output.
  Blocking beta receptors decreases cardiac output and therefore decreases blood pressure.

2. Blocking beta 1 receptors on juxtaglomerular cells
   Juxtoglomerular cells release renin which activates the RAAS pathway causing vasoconstriction.
   Beta blockers decrease renin release therefore decreasing RAAS mediated vasoconstriction (peripheral resistance).

Beta blocker drugs all have the suffix “olol”. For example propanolol, metoprolol etc. Remember, these are antagonists since they block receptors!

Question 39

Classes of Beta Blockers

Answer 39

Beta blockers can be classified as either first generation or second generation.

1st generation beta blockers
These drugs produce non-selective blockade of beta receptors.
Inhibit both beta 1 (in the heart and juxtaglomerular cells) and beta 2 (in the lung) receptors.

2nd generation beta blockers
These drugs produce selective blockade of beta 1 receptors.

Question 40

Adverse Effects of Beta Blockers

Answer 40

Selective beta 1 receptor blockers have the following adverse events:
Bradycardia (slow heart rate)
Decreased cardiac output
Heart failure (rare)
Rebound hypertension/cardiac excitation if withdrawn abruptly. The dose of beta blockers should be tapered slowly over 10 – 14 days to prevent this.

Non-selective beta blockers have the same adverse events as selective beta blockers but also cause:
- Bronchoconstriction due to blockade of beta 2 receptors in the lung. Non-selective beta blockers should be avoided in patients with asthma or other pulmonary diseases.
- Inhibition of hepatic and muscle glycogenolysis. This can be dangerous in patients with diabetes if they accidentally take too much insulin.

Question 41

Angiotensin Converting Enzyme Inhibitors (ACEI)

Answer 41

ACEI decrease blood pressure by two mechanisms:

1. Decreasing the production of angiotensin II
   Angiotensin II is a potent vasoconstrictor so decreasing it causes vasodilation.

Decreased angiotensin II also decreases total blood volume, therefore ACEI reduces cardiac output and peripheral resistance.

2. Inhibiting the breakdown of bradykinin.
   Elevated levels of bradykinin cause vasodilation.

ACEI all have the suffix “pril”. For example captopril, ramipril.

Question 42

Adverse Effects of ACEI

Answer 42

Adverse effects can be linked to the reduction of angiotensin II or elevated bradykinin.

1. Side effects from decreased angiotensin II
   1st dose hypotension – first few doses should be low.

Hyperkalemia – decreased angiotensin II causes decreased aldosterone release. Decreased aldosterone leads to potassium retention. Potassium supplements and use of potassium sparing diuretics should be avoided.

2. Side effects from increased bradykinin
   Persistent cough (in 5-10% of patients).
   Angioedema (rare but potentially fatal).

Use with certain NSAIDs may decrease the effect of ACE inhibitors.

Question 43

Angiotensin Receptor Blockers (ARBs)

Answer 43

ARBs have a similar action to ACEI in that they decrease the actions of angiotensin II, although the mechanism differs.

ARBs act by blocking the binding of angiotensin II to its receptor (the AT1 receptor).

Therefore ARB’s block the actions of angiotensin II but do not affect its synthesis.

ARBs cause vasodilation by blocking the action of angiotensin II on arterioles.

ARBs also decrease aldosterone release from the adrenal cortex causing increased sodium and water excretion.

ARBs all have the suffix “sartan”. For example losartan, valsartan etc.

Question 44

Adverse Effects of Angiotensin Receptor Blockers (ARBs)

Answer 44

ARBs don’t inhibit bradykinin breakdown as well as ACEI do, so they don’t produce persistent cough.

Incidence of angioedema is much lower than with ARBs than with ACEI.

ARBs still cause hyperkalemia due to the same mechanism as ACEI

Question 45

Direct Renin Inhibitors (DRIs)

Answer 45

DRI’s bind to renin and block the conversion of angiotensinogen to angiotensin I.

Since conversion of angiotensinogen to angiotensin I is the rate-limiting step in the RAAS pathway, DRIs can influence the entire pathway.

Despite DRI’s decreasing plasma renin activity by 50-80%, its blood pressure lowering effect is the same as other classes of drugs (i.e. ACEI and ARBs).

Question 46

Adverse Effects of direct Renin Inhibitors (DRIs)

Answer 46

Hyperkalemia – should not be used in combination with other drugs that may cause hyperkalemia (i.e. potassium sparing diuretics, ACEI) and potassium supplements.

Very low incidence of persistent cough and angioedema (much lower than ACEI).

Diarrhea

Question 47

Calcium Channel Blockers

Answer 47

Calcium channels bring calcium from outside the cell to inside the cell.

In the heart and smooth muscle that surrounds arteries, calcium is essential for contraction.

Therefore the activity of calcium channels plays an important role for contraction of the heart and smooth muscle that surrounds the arteries and arterioles.

Calcium channel blockers block the entry of calcium into heart cells and smooth muscle cells, therefore decreasing contraction.

Calcium channel blockers are classified into two categories:

1. Dihydropyridine calcium channel blockers
2. Non-dihydropyridine calcium channel blockers

Question 48

Dihydropyridine calcium channel blockers

Answer 48

Dihydropyridine calcium channel blockers significantly decrease calcium influx into smooth muscle of arteries.

This results in relaxation of the muscle around the arteries and causes vasodilation.

At therapeutic doses they do not act on the heart.

Suffix of drug names is always “dipine”. For example, nifedipine, felodipine etc.

Question 49

Adverse effects of Dihydropyridine calcium channel blockers

Answer 49

Flushing
Dizziness
Headache
Peripheral edema
Reflex tachycardia
Rash

Question 50

Non-dihydropyridine calcium channel blockers

Answer 50

These drugs block calcium channels in both the heart and smooth muscle of the arteries.

Therefore, in addition to producing vasodilation of arteries, non-dihydropyridine calcium channel blockers also decrease cardiac output.

Question 51

Adverse Effects of Non-dihydropyridine calcium channel blockers

Answer 51

Constipation
Dizziness
Flushing
Headache
Edema
May compromise cardiac function. Should be used with caution in patients with cardiac failure.

Question 52

Centrally Acting Alpha 2 Agonists

Answer 52

These drugs bind to and activate alpha 2 receptors in the brainstem.

Activation of these receptors decreases sympathetic outflow to the heart and blood vessels.

Sympathetic activity normally causes increased cardiac output and vasoconstriction.

By inhibiting sympathetic outflow, centrally acting alpha 2 receptor agonists decrease cardiac output and peripheral resistance.

Question 53

Adverse effects of Centrally Acting Alpha 2 Agonists

Answer 53

Drowsiness
Dry mouth
Rebound hypertension if withdrawn abruptly.

Question 54

Treatment Algorithms

Answer 54

Deciding how to treat patients with hypertension can be difficult.

The target blood pressure that most patients should achieve is less than 140/90 mmHg.

Patients with diabetes or chronic kidney disease should achieve a blood pressure less than 130/80 mmHg.

Keeping blood pressure below 130/80 mmHg in patients with chronic kidney disease slows the progression of kidney damage. In patients with severe renal disease, thiazide diuretics are ineffective so loop diuretics should be used.

Treatment algorithms exist for patients with just hypertension and for patients with hypertension plus diabetes or kidney disease.
These algorithms help guide dosing

Question 55

Treatment algorithm for prehypertension

Answer 55

lifestyle modifications
thiazide diuretic

Question 56

treatment algorithm for stage 1 hypertension

Answer 56

lifestyle modifications
thiazide diuretic
thiazide diuretic + ACEI, ARB, BB, or CCB

Question 57

Treatment algorithm stage 2 hypertension

Answer 57

lifestyle + thiazide diuretic + ACEI, ARB, BB, or CCB

Question 58

Treatment algorithm for moderate renal disease or diabetes

Answer 58

lifestyle + thiazide diuretic + ACE or ARB

Question 59

Treatment algorithm for SEVERE renal disease

Answer 59

lifestyle + loop diuretic + ACE or ARB