Pharmacology Of Antihypertensives

Question 1

AHA and WHO definitions of hypertension

Answer 1

AHA: 140/90
WHO: 160/95

Question 2

Hypertension diagnostic criteria

Answer 2

Two or more readings greater than normal at least 2-4 weeks apart

Question 3

Two types of hypertension and their prevalence

Answer 3

Essential/primary = 90%: idiopathic, genetic basis for incidence most often found in middle-aged adults
Non-essential/secondary = 10%: clinically identifiable cause

Question 4

Therapy choices for HTN depend on what kind of factors? (9)

Answer 4

1. Age
2. Ethnicity (37-40% African American men and women are currently being treated for HTN and 25% of US citizens overall are being treated for HTN)
3. Body-type
4. Obesity
5. Personality type
6. Athletic or sedentary lifestyle
7. Etiology of HTN
8. Rapidity of onset and severity
9. Presence of other risk factors for CV disease

Question 5

Lifestyle modifications for HTN management (8)

Answer 5

1. Weight loss
2. Limit alcohol intake (less than 1 oz per day)
3. Aerobic physical activity (30-45 min per day)
4. Reduce Na+ intake to less than 100mmol (6g) per day
5. Maintain intake of K+ to 90mmol (7g) per day
6. Maintain intake of Ca2+ and Mg2+
7. Smoking cessation
8. Reduce dietary sugar, saturated fat, and cholesterol intake

Question 6

HTN considerations for patients (5)

Answer 6

1. Once initiated, treatment is usually for life
2. Financial cost
3. Dosage should be carefully considered due to side effects and drug interactions
4. Patient compliance
5. Consider the Step-Care Therapy approach

Question 7

Step Care Therapy (4)

Answer 7

1. Lifestyle Modifications
2. • ACEI/ARB
3. • higher drug dose/substitute for another drug/add second drug
4. • second or third agent (at least one should be a diuretic)

Question 8

For each agent considered for HTN management, you must also consider what?

Answer 8

The baroreceptor reflex!

Question 9

The baroreceptor reflex does what?

Answer 9

Attemps to lower pressure activates reflex mechanisms that then act to raise the pressure: Na+ and H2O retention by the kidneys, sympathetically-induced increases in peripheral vascular resistance, heart rate, and cardiac output.

Question 10

Diuretics (General, MOA, Efficacy)

Answer 10

General: Includes thiazides, loop diuretics, K+-sparing diuretics.

MOA: Relatively unknown. Appears to decrease blood volume resulting in a decrease in CO.
Indapamide also has direct vasodilating properties.

Efficacy: Moderate monotherapy, 20/10, but augments antihypertensive effects of other drugs. Greater efficacy in African-Americans and elderly patients.

Question 11

Diuretics (Pharmacokinetics, ADRs, Contraindications)

Answer 11

PK: Taken PO with onset of action in 2-4 weeks; peak effects in 3-4 months. No additional efficacy from increased dosage, but incidence and severity of ADRs increase.

ADRs:

1. Hyperuricemia
2. Hypokalemia

Contraindications:

1. Diabetes (may induce hyperglycemia)
2. Hyperlipidemia (tend to elevate LDL and triglycerides)

Question 12

Beta-adrenergic antagonists [Beta Blockers] (General, MOA, Efficacy)

Answer 12

General: Propranolol (competitive, non-selective beta receptor antagonist)

MOA: Blocks beta-1 and beta-2 receptors. Decreases HR and contractility to decrease BP. Also decreases renin release and angiotensin II formation.

Efficacy: Moderate in monotherapy, better in combination therapy. Smokers respond poorly to these agents.

Question 13

Beta-adrenergic antagonists [Beta Blockers] (Pharmacokinetics, ADRs, and Considerations)

Answer 13

PK: PO/IV, lipophilic (wide distribution), extensive first-pass metabolism with production of active metabolites

ADRs: 7-9% of patients discontinue use

1. Minor GI and CNS nausea
2. Asthma exacerbation
3. Hyperlipidemia (increases triglycerides and lowers HDL)
4. Male sexual dysfunction
5. Diabetes (masks signs and symptoms of hypoglycemia which may lead to increased incidence of coma and death)
6. CHF exacerbation

Considerations (labetalol and carvedilol):

1. Block beta-1, beta-2, alpha-1
2. Very good efficacy in lowering BP especially in presence of HF
3. PO for long-term management of CHF and HTN; IV for HTN emergencies

Question 14

Centrally-acting Sympatholytics [Clonidine] (General, MOA, Efficacy)

Answer 14

General: Clonidine has a number of clinical uses

MOA: Post-synaptic alpha-2 agonist in CNS - inhibits sympathetic outflow at the level of the NTS resulting in decreased HR and TPR. Acts upon presynaptic alpha-2 agonists in the periphery - decreased NE release from postganglionic nerve terminals.

Efficacy: 35/20, monotherapy (combination with a diuretic is common).

Question 15

Centrally-acting Sympatholytics [Alpha-Methyldopa] (General, MOA, ADRs)

Answer 15

General: Analog of DOPA, converted in CNS neurons to alpha-methylnorepinephrine

MOA: Stimulates inhibitory presynaptic alpha-2 receptors. Acts as “false transmitter” at post-synaptic terminals. Drug choice for treatment of chronic HTN in women during child-bearing years.

ADRs:

1. Prominent sexual dysfunction
2. Dry mouth
3. Sedation
4. Positive direct Coombs test producing frank hemolytic anemia

Question 16

Peripherally-acting Sympatholytics [Reserpine] (General, MOA, Efficacy)

Answer 16

General: Diminished use due to CNS effects

MOA: Destroys both central and peripheral catecholamine storage granules in nerve terminals (NE, 5-HT, and DA) - produces a tremendous decrease in SNA and increases parasympathetic tone; prominent decrease in HR, MAP, CO, and renal function

Efficacy: 5/5, monotherapy, 15/10 with diuretic

Question 17

Peripherally-acting Sympatholytics [Reserpine] (Pharmacokinetics and ADRs)

Answer 17

PK: Rapid oral absorption; onset of action observed within 2-3 weeks. Highly lipid soluble (access to CNS). Half life = 33 hours (full recovery can take weeks)

ADRs:

1. Parkinson-like syndrome (extrapyramidal effect)
2. GI disorders (increases parasympathetic tone)
3. Male sexual dysfunction
4. Prominent orthostatic hypotension

Question 18

Peripherally-acting Sympatholytics [Trimethaphan - Discontinued] (General, MOA, Efficacy)

Answer 18

General: Autonomic ganglion-blocking action.

MOA: Nicotinic receptor antagonists. Produces a significant decrease in peripheral sympathetic and parasympathetic activity. Use in controlled management in MAP during aortic dissection and other surgery.

Question 19

Peripherally-acting Sympatholytics [Trimethaphan - Discontinued] (Pharmacokinetics, ADRs)

Answer 19

PK: Short half-life with reversal of effects in 10-30 minutes after discontinuation.

ADRs:
1. Prominent orthostatic hypotension

Question 20

Peripherally-acting Sympatholytics [Prazosin, Terazosin, Doxazosin, etc.] (General, MOA, Efficacy, and ADRs)

Answer 20

General: Added benefits include lowered LDL and total cholesterol.

MOA: Selective antagonist at vascular smooth muscle alpha-1 receptors; by sparing alpha-2 presynaptic receptors, NE release is not induced

Efficacy: 15/10, monotherapy; 25/15 with diuretic.

ADRs:

1. Mild tolerance development to antihypertensive effect
2. Reflex tachycardia
3. Sexual dysfunction

Question 21

Calcium Channel Antagonists [Verapamil, Diltiazem] (MOA, Pharmacokinetics, Efficacy, and ADRs)

Answer 21

MOA: Direct vasodilator activity by inhibiting both Ca2+ entry into vascular smooth muscle and Ca2+ release from the SR.

PK: IV/PO (extended-release PO prep available)

Efficacy: Verapamil, 30/20, diltiazem, 20/15

ADRs:

1. Cardiodepression (may counteract reflex tachycardia)
2. Others as an antidysrhythmic agent

Question 22

Calcium channel antagonists [Nifedipine] (General, MOA, Efficacy, and ADRs)

Answer 22

General: Dihydropyridine class of CCB

MOA: Direct vasodilator activity by inhibiting both Ca2+ entry into vascular smooth muscle and Ca2+ release from the SR. Greater vascular effect than verapamil/diltiazem. Significantly less cardiodepressant activity.

Efficacy: 30/20

ADRs:
1. Prominent reflex tachycardia (use with beta blockers!)

Question 23

Direct-acting vasodilators [Hydralazine] (MOA, Efficacy, and Considerations)

Answer 23

MOA: Direct vasodilation via guanylate cyclase stimulation (similar to nitrovasodilators). Increases intracellular cGMP activation. Increases Ca2+ sequestration = smooth muscle relaxation. Primary effect on arterioles (afterload) with little effect on venous tone (preload).

Efficacy: 25/25

Considerations: Tolerance development (tachyphylaxis) - due to prominent baroreflex perturbation leading to increased HR, CO, and Na+/H2O retention (sympathetic stimulation of renin release). Beta blockers and diuretics as concomitant therapy.

Question 24

Direct-acting vasodilators [Hydralazine] (ADRs)

Answer 24

1. SLE-like symptoms (metabolism by N-acetylation)
2. Palpitations, tachycardia
3. Use limited to resistant, fulminant hypertension and management of hypertensive emergency

Question 25

Direct-acting vasodilators [Minoxidil] (General, MOA, and Considerations)

Answer 25

General: Topical (Rogaine) for alopecia. Oral (Loniten) for HTN. Loniten used only for severe, refractory HTN. MOA: Direct arteriolar vasodilation via stimulation of vascular smooth muscle K+ channel opening resulting in membrane hyperpolarization. Considerations: Tachyphylaxis due to baroreflex-mediated increases in sympathetic tone. Use in combination with beta blockers and diuretics.

Question 26

Direct-acting vasodilators [Sodium Nitroprusside] (General, MOA, and ADRs)

Answer 26

General: Parenterally infused agent use in HTN emergencies and rapid management of CHF. Very potent vasodilator with rapid onset and short duration of action. Decreases both afterload and preload (venodilation). MOA: Like other nitrovasodilators. Donates NO (EDRF) to increase cGMP-mediated Ca2+ sequestration. ADRs: 1. Extended continuous infusion may produce methemoglobinemia, cyanide poisoning, and cell death due to inhibition of cellular respiration.

Question 27

Angiotensin converting enzyme inhibitors (ACE-I) [Captopril, enalapril, lisinopril, etc.] (MOA)

Answer 27

MOA: Blocks conversion of angiotensin I to angiotensin II, reducing vasoconstriction at the level of the arterioles and inhibiting aldosterone secretion from the adrenal glands.

Question 28

Angiotensin converting enzyme inhibitors (ACE-I) [Captopril, enalapril, lisinopril, etc.] (Pharmacokinetics, Efficacy, and ADRs)

Answer 28

PK: PO administration. Should be taken without food. Maximal effects in 4-8 weeks. Efficacy: 25/20. Less efficacy in African-Americans as monotherapy. ADRs: 1. Dry, persistent cough 2. Proteinuria, angioedema 3. Maculopapillary rash and altered taste sensation 4. Pregnancy contraindication!

Question 29

Angiotensin receptor blockers (ARBs) [Losartan, candesartan, irbesartan, valsartan, etc.] (General, MOA, and ADRs)

Answer 29

General: newest anti-HTN drug class. Most popular anti-HTN drug class due to minimal ADRs. MOA: Specific antagonists of angiotensin II at AT1 receptors on vascular smooth muscle. Losartan is a competitive antagonist (half life = 2 hours). ADRs: 1. Relatively few 2. Pregnancy contraindication!