Comprehensive Notes: Drugs Affecting Blood Pressure

Key Concepts in Blood Pressure Regulation

• Blood pressure (BP) control depends on three main determinants:

  • Heart rate (HR)

  • Stroke volume (SV): amount of blood pumped out of the ventricle with each heartbeat

  • Total peripheral resistance (TPR): resistance of the muscular arteries to the blood being pumped

• Mean arterial pressure (MAP) is determined by these factors. A compact relationship used in physiology is:
  MAP \,\approx\, CO \times TPR, where CO = HR \times SV.

• Autonomic nervous system and reflex mechanisms modulate BP:

  • Baroreceptors sense BP changes and adjust autonomic outflow

  • Renin–angiotensin–aldosterone system (RAAS) modulates vascular tone and blood volume

• RAAS is a key hormonal system regulating BP and fluid balance (see detailed RAAS section below)

• Essential hypertension is defined as elevated BP with no identifiable secondary cause in most adults

• Hypotension and orthostatic hypotension reflect inadequate BP regulation and can result from cardiac dysfunction, volume loss, autonomic failure, or medication effects

The Renin–Angiotensin–Aldosterone System (RAAS)

• Key components and sequence:

  • Juxtaglomerular cells in the kidney monitor perfusion pressure; decreased perfusion stimulates renin release.

  • Renin acts on angiotensinogen (produced by the liver) to form angiotensin I.

  • In the pulmonary capillary bed, angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II, a potent vasoconstrictor.

  • Angiotensin II acts on angiotensin II receptors in vasculature and heart, promoting vasoconstriction and aldosterone release from the adrenal cortex.

  • Aldosterone increases sodium reabsorption in the renal tubules, contributing to water retention and increased blood volume.

  • ADH (vasopressin) and water retention further increase blood volume.

  • Angiotensin II can be converted to angiotensin III, which also promotes aldosterone release.

• Major sites and actions:

  • Angiotensin II receptors on vascular smooth muscle contribute to vasoconstriction

  • Angiotensin II receptors in the heart influence sympathetic outflow and other cardiovascular effects

  • Adrenal cortex releases aldosterone -> increases renal Na^+ and water reabsorption

  • Kidneys: aldosterone effects on tubules increase sodium reabsorption, which raises blood volume

• Overall effect of RAAS activation: increased BP via vasoconstriction and increased blood volume; modulation occurs through lung ACE activity and renal signals

Hypertension: Overview and Clinical Significance

• Hypertension is BP above normal limits for a sustained period

• Most cases (about 90%) are essential/primary hypertension with no single identifiable cause

• Underlying danger includes organ damage and increased risk of atherosclerotic vascular disease; thickening of the heart muscle may occur

• Often asymptomatic for long periods; hence called the "silent killer"

Conditions Related to Untreated Hypertension

• Untreated hypertension can contribute to:

  • Coronary artery disease (CAD) and cardiac death

  • Stroke

  • Renal failure

  • Loss of vision

Risk Factors for Hypertension

• Age

• Cigarette smoking

• High-salt diet

• High alcohol intake

• Low physical fitness

• Obesity

• Insulin resistance

• Psychological stress

• Obstructive sleep apnea

• Family history of hypertension

Hypotension and Related Concepts

• Hypotension = BP is too low, risking inadequate oxygen delivery to vital tissues; can progress to shock

• Causes include:

  • Damaged heart muscle reducing pumping ability

  • Severe blood or fluid loss leading to dramatic volume depletion

  • Impairment of autonomic nervous system in increasing CO or vascular resistance

  • Medication-induced hypotension

Orthostatic Hypotension

• Definition: drop in BP when moving from lying/sitting to sitting/standing

• Symptoms: dizziness, light-headedness, nausea, vision changes, syncope

• Higher risk in:

  • Older adults

  • People using certain medications

Drug Therapy Across the Lifespan (Box 43.6 Focus on Drug Therapy Across the Lifespan)

Children

• BP reference standards for children are relatively new; hypertension may begin in childhood

• Secondary hypertension is more common in children (renal disease or congenital problems like coarctation of the aorta)

• Treatment should begin with lifestyle changes when possible (weight loss, increased activity)

• If drug therapy is used:

  • Consider diuretics first with regular monitoring of glucose and electrolytes

  • Beta-blockers have been used but may have limiting adverse effects in some children

  • Some calcium-channel blockers, ACE inhibitors, and ARBs have approved pediatric doses

  • Careful follow-up is essential to monitor BP and adverse effects

Adults

• Instruct adults on adverse reactions and safety precautions (hot weather, fluid depletion risks from diarrhea/vomiting)

• Evaluate drug interactions if on other medications; emphasize lifestyle measures (weight loss, smoking cessation, increased activity)

• Pregnancy considerations:

  • ACE inhibitors, ARBs, and renin inhibitors should not be used during pregnancy

  • Women who can become pregnant should use barrier contraception while taking these drugs

  • Calcium-channel blockers and vasodilators should not be used in pregnancy unless clearly necessary; some drugs can enter human milk

  • Labetalol (a beta-blocker) and/or magnesium are often used first for hypertension during pregnancy

Older Adults

• More likely to be on one or more antihypertensive drugs

• Increased susceptibility to drug toxicity; comorbidities can affect metabolism and excretion

• Renal or hepatic impairment necessitates dose reductions and close monitoring

• Polypharmacy: coordinate drug regimens and watch for interactions

• Caution with dehydration risk (diarrhea/vomiting, limited fluid intake, heat exposure with reduced sweating)

• BP should be measured immediately before administering an antihypertensive in institutional settings to avoid excessive BP lowering

• Caution with sustained-release antihypertensives that cannot be crushed or chewed to avoid dosing errors

Stepped Care Management of Hypertension

• Step 1: Lifestyle modifications

• Step 2: Add drug therapy

• Step 3: Change drug dose or switch class or add another drug

• Step 4: Add a second or third agent or a diuretic

Antihypertensive Agents: Overview

• Antihypertensive drugs work to alter reflexes that regulate BP

• Not all patients respond the same way; combination therapy is common

• Drug categories include:

  • ACE inhibitors

  • Angiotensin II receptor blockers (ARBs)

  • Calcium-channel blockers

  • Vasodilators

  • Other agents

Drugs Affecting the RAAS

• ACE inhibitors

• ARBs

• Renin inhibitors

ACE Inhibitors (ACEIs)

ACE Inhibitors: Common agents

• Benazepril (Lotensin)

• Captopril (generic)

• Enalapril (Epaned, Vasotec)

• Enalaprilat (generic)

• Fosinopril (generic)

• Lisinopril (Prinivil, Zestril, Qbrelis)

• Moexipril (generic)

• Perindopril (generic)

• Quinapril (Accupril)

• Ramipril (Altace)

• Trandolapril (generic)

Therapeutic actions

• ACEIs block ACE in the lungs from converting angiotensin I to angiotensin II

• Result: decreased BP, decreased aldosterone production

• Consequences: increased serum potassium; decreased serum sodium and fluid loss

Indications

• Hypertension, heart failure, left ventricular dysfunction, diabetic nephropathy

Pharmacokinetics

• Well absorbed; widely distributed; metabolized in the liver; excreted in urine and feces

• Cross placenta and can enter human milk

Contraindications

• History of allergic reaction

• Impaired renal function

• Acute heart failure exacerbation

• Salt/volume depletion

• Pregnancy and lactation

Adverse effects

• Vasodilation-related effects; generally well tolerated

• Serious allergic reactions including angioedema

• Hyperkalemia

• Some agents (captopril, moexipril, perindopril) may have more serious effects

Drug–drug interactions

• Allopurinol

• NSAIDs

• Diuretics and other antihypertensives

• Potassium supplements and potassium-sparing diuretics

• Lithium

• Drugs that alter RAAS

• Other ACE inhibitors, ARBs, or renin inhibitors

ACE Inhibitor Prototype: Captopril

Indications

• Hypertension, heart failure, diabetic nephropathy, LV dysfunction after MI

Actions

• Blocks ACE from converting angiotensin I to angiotensin II → BP reduction; reduced aldosterone; small increase in serum potassium; salt and fluid loss

Pharmacokinetics

• Route: Oral

• Onset: 15 min; Peak: 30–90 min

• Half-life (T1/2): 2 hours; excreted in urine

Adverse effects

• Allergic reactions, angioedema, neutropenia, hypotension, tachycardia, rash, pruritus, GI irritation, dysgeusia, proteinuria, bone marrow suppression, cough, renal impairment, hyperkalemia

Angiotensin II Receptor Blockers (ARBs)

ARB agents

• Azilsartan (Edarbi)

• Candesartan (Atacand)

• Irbesartan (Avapro)

• Losartan (Cozaar)

• Olmesartan (Benicar)

• Telmisartan (Micardis)

• Valsartan (Diovan)

Therapeutic actions

• Selectively bind to angiotensin II receptors in vascular smooth muscle and adrenal cortex

• Block vasoconstriction and aldosterone release; lower BP

Indications

• Hypertension (alone or in combination)

• Some also for heart failure and after MI

• Some slow progression of renal disease

Pharmacokinetics

• Well absorbed; hepatic metabolism via CYP450; excreted in feces and urine

• Cross the placenta; unknown if enter human milk

Contraindications

• Allergy; pregnancy and lactation

Cautions

• Hepatic or renal dysfunction; hypovolemia

Adverse effects

• Headache, dizziness, syncope, weakness

• GI issues; dry mouth, tooth pain

• URIs and cough; rash, dry skin, alopecia

Drug–drug interactions

• Other antihypertensives

• Potassium supplements or potassium-sparing diuretics

• Lithium

• NSAIDs

ARB Prototype: Losartan

Indications

• Hypertension (alone or in combination); diabetic nephropathy with elevated creatinine and proteinuria in type 2 diabetes with hypertension

Actions

• Blocks binding of angiotensin II to tissue receptors in vascular smooth muscle and adrenal glands; inhibits vasoconstriction and aldosterone release

Pharmacokinetics

• Route: Oral

• Onset: varies; Peak: 1–3 h

• Duration: 24 h

• Half-life: ~2 h, then 6–9 h; hepatic metabolism; excretion in urine and feces

Adverse effects

• Allergic reactions, angioedema, hypotension, dizziness, headache, GI symptoms, URIs, cough, back pain, fever, muscle weakness

Renin Inhibitors

Renin inhibitor prototype: Aliskiren (Tekturna)

Therapeutic action

• Directly inhibits renin, reducing plasma renin activity and conversion of angiotensinogen to angiotensin I

Pharmacokinetics

• Poorly and slowly absorbed from GI tract; liver metabolism; excreted in urine

• Crosses placenta and can enter human milk

Contraindications

• Pregnancy and lactation

Adverse effects

• Risk of hyperkalemia

• Angioedema with respiratory involvement

• Renal impairment

Drug–drug interactions

• Furosemide

• Other antihypertensives

• ACE inhibitors, ARBs, potassium-sparing diuretics

Calcium-Channel Blockers (CCBs)

Common agents

• Amlodipine (Katerzia, Norvasc)

• Diltiazem (Cardizem LA, Cartia XT, others)

• Felodipine

• Isradipine

• Nicardipine

• Nifedipine (Procardia XL)

• Nisoldipine (Sular)

• Verapamil (Calan SR)

• Clevidipine (Cleviprex): IV only for short-term management

Therapeutic actions

• Inhibit Ca^2+ influx in myocardial and arterial smooth muscle cells; alter action potentials; decrease muscle contraction

• Result: reduced cardiac workload and oxygen consumption; vasodilation and BP reduction

Indications

• Hypertension; angina

Pharmacokinetics

• Well absorbed; liver metabolism; excreted in urine

• Cross placenta; enters human milk

Contraindications

• Allergy

• Non-dihydropyridine CCBs: heart block or sick sinus syndrome, heart failure, acute MI

• Pregnancy and lactation

Adverse effects

• Related to changes in cardiac output

• CNS effects; GI effects; CV effects

• Flushing

Drug–drug and drug–food interactions

• Vary by specific drug

• Grapefruit juice can interact with several CCBs

CCB Prototype: Diltiazem

Indications

• Essential hypertension (extended-release); angina; tachyarrhythmias

Actions

• Inhibits Ca^2+ movement into cardiac and arterial muscle cells; slows conduction; decreases contractility; dilates arterioles

Pharmacokinetics

• Route: Oral extended release

• Onset 30–60 min; Peak 6–11 h; Duration 12 h

• Half-life: 5–7 h; liver metabolism; renal excretion

Adverse effects

• Dizziness, lightheadedness, headache

• Peripheral edema; bradycardia; AV block; flushing; nausea; hypotension

Vasodilators

Agents

• Hydralazine

• Minoxidil

• Nitroglycerin

• Nitroprusside (Nitropress)

Therapeutic actions

• Directly affect vascular smooth muscle to cause relaxation and vasodilation, lowering BP

• Used in severe or refractory hypertension and hypertensive emergencies

Pharmacokinetics

• Rapid absorption; wide distribution; hepatic metabolism; renal excretion

• Cross placenta and into human milk

Contraindications

• Known allergy

• Conditions worsened by sudden BP drop

• Pregnancy and lactation

Cautions

• Peripheral vascular disease, coronary artery disease (CAD), heart failure, tachycardia

Adverse effects

• BP-related effects; cyanide toxicity (specific to nitroprusside)

Drug–drug interactions

• Varies by drug; consult specific agent

Vasodilator Prototype: Nitroprusside

Indications

• Severe hypertension; maintenance of controlled hypotension during anesthesia; acute heart failure

Actions

• Direct vasodilation of vascular smooth muscle; does not suppress CV reflexes; can increase renin release

Pharmacokinetics

• Route: IV

• Onset: 1–2 min; Peak: rapid; Duration: 1–10 min

• Half-life: ~2 min; hepatic metabolism; urinary excretion

Adverse effects

• Apprehension, headache, retrosternal pressure, palpitations

• Cyanide toxicity; diaphoresis; nausea/vomiting; injection-site irritation; hypotension

Diuretics (Overview)

• Increase excretion of sodium and water from the kidneys to lower BP

• Often among first-line agents for mild hypertension

• Generally well tolerated

• Main classes for hypertension:

  • Thiazide and thiazide-like diuretics

  • Potassium-sparing diuretics

Sympathetic Nervous System Blockers

• Block the effects of the sympathetic nervous system on BP

• Drug classes include:

  • Beta-blockers

  • Alpha- and beta-blockers

  • Alpha-adrenergic blockers

  • Alpha1-blockers

  • Alpha2-agonists

Antihypotensive Agents (Vasopressors) and Sympathetic Adrenergic Agonists

Antihypotensive agents

• Used to raise BP in severe hypotension or shock

• Examples of vasopressors discussed include Droxidopa (Northera)

Vasopressor and adrenergic agonist concepts

• Drugs interact with sympathetic receptors to mimic the stress response

• Therapeutic goal: increase BP and restore cardiovascular balance while underlying cause is treated

Adverse effects and interactions

• Effects related to sympathetic stimulation; use caution in diseases with poor blood flow

• Interactions with other agents that increase HR or BP

Blood Pressure–Raising Agent: Midodrine

Therapeutic actions and indications

• Activates alpha-receptors in arteries and veins to increase vascular tone and BP

• Used for symptomatic orthostatic hypotension when other therapies have failed

Pharmacokinetics

• Rapid GI absorption; hepatic metabolism; urinary excretion

• Does not clarify transfer into human milk

Contraindications and cautions

• Supine hypotension or pheochromocytoma

• Severe heart disease; acute renal disease; urinary retention; thyrotoxicosis

• Pregnancy and lactation; visual problems; renal or hepatic impairment

Adverse effects and interactions

• Effects related to alpha-receptor stimulation

• Interactions with cardiac glycosides, beta-blockers, alpha-adrenergic agents, corticosteroids

Droxidopa

Indication and action

• Indicated for treatment of orthostatic dizziness, light-headedness, or near-blackout in adults with symptomatic neurogenic orthostatic hypotension

• Metabolized to norepinephrine by dopa decarboxylase; BP effects linked to norepinephrine

Pharmacokinetics

• Absorbed GI tract; widely distributed; metabolized via catecholamine pathways; excreted in urine

Contraindications, cautions, and adverse effects

• History of allergy; CV history; renal impairment; breast or chestfeeding

• Adverse effects tied to sympathetic activation; monitor for tachycardia, hypertension, etc.

• Drug interactions with dopa decarboxylase inhibitors

Practice Questions and Answers (from transcript)

Question 1

• Statement: The use of a loop diuretic is the first drug used in the stepped care management of hypertension.

• Answer: False

• Rationale: Step 1 is lifestyle modification; a diuretic may be added in Step 2.

Question 2

• Question: The mechanism of action of an ACE inhibitor is blocking ACE from converting angiotensin I to angiotensin II. What does this cause?

• Correct option: Decrease in aldosterone secretion

• Rationale: Inhibiting ACE reduces Ang II, a potent vasoconstrictor and aldosterone stimulant; this lowers BP and reduces aldosterone, increasing serum potassium and causing loss of sodium and fluid.

Question 3

• Question: For which drug will the nurse need to caution patients against drinking grapefruit juice?

• Answer: Clevidipine (Cleviprex)

• Rationale: Clevidipine is a calcium-channel blocker; grapefruit juice can raise levels of CCBs and other calcium-channel blockers, potentially causing toxicity

Additional Notes: Practical and Foundational Context

• Pregnancy considerations are critical for RAAS inhibitors:

  • ACE inhibitors, ARBs, and renin inhibitors are contraindicated in pregnancy; barrier contraception is advised for patients who can become pregnant

  • During pregnancy, labetalol and/or magnesium may be used as initial antihypertensive therapy

• Lactation considerations:

  • Many RAAS inhibitors cross into human milk; caution or alternate therapy may be required

• Aging and pharmacokinetics:

  • Older adults often have reduced renal/hepatic function, requiring dose adjustments and careful monitoring for adverse effects

  • Hydration status and volume depletion can drastically affect BP in older adults taking antihypertensives

• Drug interactions are important across classes:

  • NSAIDs can reduce efficacy of some antihypertensives

  • Potassium-sparing drugs can exacerbate hyperkalemia with RAAS inhibitors

  • Lithium and certain other agents require monitoring when combined with ACEIs or ARBs

• The stepped care approach emphasizes combining lifestyle interventions with pharmacotherapy and balancing drug efficacy with potential adverse effects and patient factors (age, pregnancy status, comorbidities)