Antihypertensive Pharmacology

Question 1

Diuretic Agents
What do they do?
What ones can we use?

Answer 1

Act on nephron to increase urine output

Can use:

Thiazides (hydrochlorothiazide) - block NCC in distal conv. Tubule

Loop diuretics (furosemide) - block NKCC in ascending loop of Henle

Potassium-sparing diuretics (spironolactone)

Question 2

ACE Inhibitors
Example
Actions
Overall effect

Answer 2

Example - Ramipril
Actions:
1) inhibits vasoconstriction
2) inhibits aldosterone secretion
3) inhibits NaCl reabsorption
4) increases vasodilation via bradykinin

Overall effect: decreased SVR and increased Na and H2O excretion (decreased preload)

Question 3

ACE inhibitor
- adverse effects
- contraindications

Answer 3

Adverse effects:
- Cough (due to bradykinin)
- hyperkalemia (due to reduced aldosterone)
- renal dysfunction (decreased renal blood flow)
- hypotension
- angioedema (rare, due to bradykinin)

Contraindications:
- pregnancy (teratogenic and increased complications)
- renal artery stenosis

Question 4

Angiotensin Receptor Blockers
Example
Actions
Overall effect

Answer 4

Example - Losartan
Actions:
1) inhibits vasoconstriction
2) inhibits aldosterone secretion
3) inhibits NaCl reabsorption
4) no effect on bradykinin metabolism

Overall effect:
Decreased SVR, increased Na and H2O excretion (decreased preload)

Question 5

ARBs
Adverse effects:
Contraindications:

Answer 5

Adverse effects:
- Less cough and angioedema
- dizziness and hypotension (most common side effects)
- hyperkalemia (due to reduced aldosterone)
- renal dysfunction

Contraindications:
Pregnancy (teratogenic)

Question 6

Renin Inhibitors
Example
Actions
Overall effect

Answer 6

Example - Aliskiren
Actions:
1) inhibit vasocontriction
2) inhibits aldosterone secretion
3) inhibits NaCl reabsorption

Overall effect:
- decreased SVR, increased Na and H2O excretion (decreased preload)

Question 7

Renin Inhibitors
Adverse effects:
Contraindications:

Answer 7

Adverse effects:
1) diarrhea (unknown mechanism)
2) angioedema (rare)

Contraindications:
- pregnancy (teratogenic)

Question 8

Calcium Channel Blockers
Examples:
Actions

Answer 8

Action:
1) decreases smooth muscle contraction (decreased SVR)
2) decreases cardiac conduction and contractility (decreased HR and CO)
3) blocks Ca-signaling to adrenal cortical cells to release aldosterone

Examples:
1) dihydropyridines - amlodipine
2) non-hydropyridines:
A) benzothiazepines (diltiazem)
B) Phenylalkylamines (verapamil)

Question 9

Dihydropyridine Ca-channel blockers
Example:
Action:
Overall effect:

Answer 9

Example - amlodipine

Act primarily on vasculature as a vasodilator
- weak effect on cardiac Ca-Channels

Overall effect:
Decreased SVR, a slight decrease in cardiac contractility

Question 10

Non-Dihydropyridine Ca-channel blockers
Example:
Action:
Overall effect:

Answer 10

Example:
Two subclasses:
- Benzothiazepines (diltiazem)
- Phenylalkylamines (verapamil)

Action:
Affect cardiac and vascular Ca-channels (cardiac > vascular)

Overall effect:
- Decreases HR and contractility and SVR

Question 11

Ca-Channel blockers
Adverse effects:
Contraindications:

Answer 11

Adverse effects:
- dizziness and headache
- flushing, peripheral edema, reflex tachycardia
- bradycardia, hypotension

Contraindications:
- dihydropyridines - conditions worked by tachycardia (e.g. severe aortic stenosis)
- non-dyhydropyridines
A) conduction disorders (wolff-Parkinson-White syndrome, AV block)
B) Acute congestive heart failure
- pregnancy (use nifedipine instead)

Question 12

Adrenergic effect receptors

Answer 12

B1 receptors — increased contraction, HR and renin secretion
B2 — bronchodilation, vasodilation of Sk. Muscle arterioles (sm muscle relaxation)
B3

A1 - vasoconstriction and venoconstriction of non-skeletal muscle vessels (smooth muscle contraction)
A2

Question 13

Beta-blockers
Examples:
Actions:
Overall effect:

Answer 13

Examples - propranolol, metoprolol
Actions:
1) decreases SNS activity
2) decreases HR and contractility
3) decreases renin secretion

Overall effect: decreased HR and CO

Question 14

Beta-blocker classification

Answer 14

Cardioselective B-blockers - only block B1 receptors
- metoprolol, atenolol, bisprolol

Non-Cardioselective B-blockers - blocks all B receptors
- propranolol (B1, B2)

Mixed a and B-blockers
- carvedilol, labetalol (a1, B1, B2)

Partial Agonists
- acebutolol (partial B1 agonist)

Question 15

Beta-blocker
Adverse effects:
Contraindications:

Answer 15

Adverse effects:
- fatigue (due to increase CO)
- bradycardia
- bronchoconstriction (B2 blockade)
- rebound hypertension (if abruptly discontinued)

Contraindications:
- asthma (especially if non-Cardioselective agent)
- bradycardia or 2nd or 3rd degree heart block
- acute congestive heart failure

Question 16

Alpha-1 blockers
Examples
Actions
Overall effect

Answer 16

Examples - prazosin, terazosin
Actions:
1) decreases vasoconstriction (arteries and arterioles)
2) decreases venoconstriction (veins)

Overall effects - decreased SVR

Question 17

Alpha-1 blockers
Adverse effects:

Answer 17

Orthostatic hypotension

Not typically used for hypertension (used to treat benign prostatic hypertrophy)

Question 18

Direct Vasodilators:
Example
Action
Overall effect

Answer 18

Example: hydralazine
Action:
- arteriolar vasodilation
- mechanism is uncertain (possibly opens potassium channels)

Overall effect: decreased SVR

Question 19

Direct Vasodilators
Adverse effects:

Answer 19

Reflex tachycardia
Flushing
Hypotension
Immunological lupus-like reaction

Not commonly used for hypertension

Question 20

Central-acting agents
Example:
Action:
Overall effect:
Adverse effects:

Answer 20

Example - clonidine
Action - inhibit presynaptic release of NE
Overall effect - decreased HR, VS, and SVR

Adverse effects:
- sedation (central inhibition of NT release)
- dry mouth
- Orthostatic hypotension
- rebound hypertension (if abruptly discontinued)

Not commonly used for hypertension

Question 21

Why treat Hypertension?

Answer 21

Untreated increases risk for:
Morbidity (57 million disability-adjusted life years)
- coronary artery disease, heart failure, stroke, peripheral vascular disease, kidney injury, vision loss
Mortality - 7.5 million deaths annually

Question 22

Which antihypertensive to use?
- in absence of cardiovascular risk factors or disease

Answer 22

Low-dose thiazides are first line
- ACE inhibitors and Ca-Channel blockers may be equally as effective, but lower evidence

Question 23

Which antihypertensive to use?
- in heterogeneous populations with cardiovascular risk factors or disease

Answer 23

Can use RAAS inhibitors, Ca-Channel blockers, thiazides and beta blockers

• thiazides caused less HF and stroke than RAAS inhibitors
• Ca-channel blockers increased HF but decreased stroke compared to RAAS inhibitors
  - increase in HF exceeded the decrease in stroke