4 - Drugs for Cardiovascular Disorders: Part 1 (Hypertension and Heart Failure)

RAA Axis

Angiotensinogen is converted to Angiotensin I by RENIN

Angiotensin I is converted to Angiotensin II by ACE

Effects of Angiotensin II

- vasoconstriction

- increased sensation of thirst

- stimulates release of aldosterone (from adrenal glands)

- stimulates release of antidiuretic hormone (from pituitary gland)

Effects of Aldosterone

- increase sodium reabsorption

- increase water retention

- increase potassium excretion

- increase bicarbonate (HCO3-) and chloride reabsorption

Angiotensin-Converting Enzyme Inhibitors (ACEIs)

Benazepril (Lotensin)

Captopril (capoten)

Enalapril (Vasotec)

Fosinopril (Monopril)

Lisinopril (Prinivil, Zestril)

Moexipril (Univasc)

Quinapril (Accupril)

Ramipril (Altace)

Trandolapril (Mavik)

Perindopril (Aceon)

Mechanism of action of ACEIs

- block conversion of angiotensin I to angiotensin II

- block circulating and tissue levels of angiotensin II

- decreased angiotensin II = decreased aldosterone and ADH secretion

- decreased sodium reabsorption and decreased potassium excretion

- overall decrease in H2O reabsorption

Therapeutic effects of ACEIs

- lower BP (in patients with HTN)

- decrease afterload (in patients with HF)

- decrease development of overt HF

- increase survival in patients with MI

- decrease progression of diabetic nephropathy (renal protective)

Absorption of ACEIs

fairly rapid from the intestinte

Distribution of ACEIs

well-distributed

Metabolism of ACEIs

rapidly and extensively to active metabolite, following extensive first-pass effects

Excretion of ACEIs

hepatic clearance = main route of any unchanged drug, whereas metabolites are found in feces and urine

Clinical uses of ACEIs

reduction in BP (either alone or in combination with other antihypertensives)

When is an ACEI first line?

for HTN in diabetics and those with HF

Adverse reactions of ACEIs

CV: postural (orthostatic) hypotension

DERM: rash, angioedema

GU: impotence

HEM: leukopenia

META: hyponatremia, hyperkalemia (serum K+ > 5.5 mEq/L)

NEURO: headache, dizziness, fatigue, somnolence

PUL: persistent dry cough

RENAL: increased serum creatinine, renal failure

FETAL: oligohydramnios

Interactions of ACEIs

- diuretics (use lower dose), nitrates, excessive alcohol use, and anesthesia = increased risk of hypotension

- potassium-sparing diuretics, salt substitutes, indomethacin = increase risk of hyperkalemia

- NSAIDs = decrease antihypertensive effects

- antacids = decrease absorption

- ACEIs increase levels of digoxin and lithium and may induce toxicity

Contraindications of ACEIs

- cross-sensitivity exists among ACEIs

- pregnancy (category X)

- hypersensitivity

- renal artery stenosis

- history of angioedema

- use cautiously in cases of renal impairment, hypovolemia, hyponatremia, and the elderly

How are ACEIs renal protective?

- HTN causes damaged arterioles

- Diabetes causes proteinuria

ACEIs can prevent these effects

What is important to remember about ACEI/ARB use in the setting of renal hypoperfusion?

it can lead to renal failure (blocks body's compensatory function to maintain kidney function)

Conscientious considerations for ACEIs

- advise female patients to stop this medication if trying to conceive

- watch for dry cough

- watch for angioedema (can occur even after years of taking the medication)

- monitor potassium and creatinine levels

- recommend against use as monotherapy in African Americans

Patient/Family education for ACEIs

Advise patient to:

- take medicine at same time each day, and do not discontinue the medication before talking to a clinician

- avoid salt substitutes and foods with high K

- seek clinician's help when choosing any cold remedy

- change positions slowly to minimize hypotension

- watch for a change in taste, which can occur but will resolve within 8 to 12 weeks

Angiotensin Receptor Blockers (ARBs)

Candesartan (Atacand)

Irbesartan (Avapro)

Losartan (Cozaar)

Olmesartan (Benicar)

Telmisartan (Micardis)

Valsartan (Diovan)

Mechanism of action of ARBs

inhibits angiotensin II at its receptor sites (especially smooth muscle and adrenal glands) = reduces vasoconstriction (and increases dilation) = decreased peripheral resistance & BP

- blocks angiotensin type 1 (AT1) receptors

- increases angiotensin type 2 (AT2) receptor activation

What is the action of AT1 receptor activation?

vasoconstriction, Na & H2O reabsorption

What is the action of AT2 receptor activation?

vasodilation

Absorption of ARBs

fairly rapid from the intestine

Distribution of ARBs

well distributed

Metabolism of ARBs

rapidly and extensively to active metabolite, following extensive first-pass

Excretion of ARBs

hepatic clearance = main route of any unchanged drug, whereas metabolites are found in feces and urine

Clinical uses for ARBs

most effective when used to reduce BP in those with:

- diabetic neuropathy

- HF (especially with systolic dysfunction)

- cardiac protection in high-risk caridac patients (post-MI and stroke)

Adverse reactions of ARBs

CV: postural (orthostatic) hypotension

DERM: rash, angioedema

GU: impotence

HEM: leukopenia

META: hyponatremia, hyperkalemia (serum K+ > 5.5 mEq/L)

NEURO: headache, dizziness, fatigue, somnolence

PUL: persistent dry cough

RENAL: increased serum creatinine, renal failure

FETAL: oligohydramnios

Interactions of ARBs

- ACEIs, diuretics, and other antihypertensives = may provide additional antihypertensive effects

- Lithium, MAOIs, NSAIDs, K+ sparing diuretics = increase the risk of hyperkalemia

- NSAIDs = may decrease antihypertensive effects

Contraindications to ARBs

- pregnancy (category X)

- hypersensitivity

- renal artery stenosis

- history of angioedema

- use cautiously in cases of renal impairment, hypovolemia, hyponatremia, and the elderly

Conscientious considerations of ARBs

- watch for hyperkalemia and hyponatremia

- the med can increase serum creatinine

- pregnancy: can cause birth defects (neonatal skull hypoplasia, anuria, renal failure, oligohydramnios, death)

- lactation: excretion mild or not determines, not recommended

- recommend against use as monotherapy in African Americans

When are ARBs first line, and what is their main advantage over ACEIs?

can be first-line antihypertensive in patients with diabetes and/or CHF, main advantage over ACEIs is that they are not as likely to produce the persistent cough

Patient/Family education for ARBs

- instruct that continuous treatment is necessary and to not stop the medication abruptly

- if a dose is missed, instruct patients to take the next dose as soon it is remembered, but not to double the dose if it is near time for the next dose

- advise patients about possible postural hypotension and not to rise abruptly from a sitting or lying down position

- advise women about the risks of becoming pregnant and why they should use a contraceptinve

- patients should be aware that these medications may cause dizziness

Direct Renin Inhibitors

Aliskiren (150-300mg PO daily)

Mechanism of action of direct renin inhibitors

decreased renin = decreased conversion of angiotensinogen to angiotensin I

Clinical uses for direct renin inhibitors

treatment of HTN

Absorption of direct renin inhibitors: when do peak plasma concentrations occur?

1-3 hours

Distribution of direct reinin inhibitors

well distributed

Metabolism of direct renin inhibitors: what is the major pathway?

extent of metabolism unknown, major pathway via CPY3A4

Excretion of direct renin inhibitors: how much of the medication if excreted in urine as unchanged drug?

1/4 in urine as unchanged drug

Adverse effects of direct renin inhibitors

CV: postural (orthostatic) hypotension

DERM: angioedema

GI: diarrhea

META: hyponatremia, hyperkalemia (serum K+ > 5.5 mEq/L)

NEURO: headahce, dizziness, fatigue, somnolence

RENAL: renal failure, increased serum creatinine

FETAL: oligohydramnios

Interactions of direct renin inhibitors

- ACEIs, diuretics, and other antihypertensives may prodive additional antihypertensive effects

- Lithium, MAOIs, NSAIDs, K+ sparing diuretics may increase the risk of hyperkalemia

- NSAIDs may decrease antihypertensive effects

Contraindications of direct renin inhibitors

- pregnancy (category X)

- hypersensitivity

- history of angioedema

- use cautiously in cases of renal impairment, hypovolemia

- DO NOT use Aliskiren with ARBs or ACEIs in patients with diabetes.

What is the shorter/more common name for B Adrenergic Receptor Antagonists?

Beta Blockers

Where are B-1 receptors found and what is their action?

myocardial tissue (SA node, AV node) - when stimulated, increase HR and contractility

Where are B-2 receptors found and what is their action?

uterine, vascular, and pulmonary tissue - when stimulated, produce vasodilation and bronchodilation

Where are A-1 receptors found and what is their action?

vascular - when stimulated, produce vasoconstriction

Cardioselective beta blockers with ISA activity

Acebutolol +

Cardioselective beta blockers without ISA activity

Atenolol

Betaxolol

Bisprolol

Metoprolol

Esmolol

Noncardioselective beta blockers with ISA activity

Carteolol ++

Penbutolol +

Pindolol +++

Noncardioselective beta blockers without ISA activity

Carvedilol

Labetalol

Nadolol

Propanolol

Sotalol

Timolol

Beta blockers with aplha blocking properties

Carvedilol and Labetalol

Mechanism of action of non selective beta blockers

block stimulation of B1 and B2 adrenergic receptors

Mechanism of action of selective beta blockers

selectively block B1 adrenergic receptors

Mechanism of action of beta blockers with alpha-blocking activity

block B1 and B2 receptors, with some alpha-blocking activity

Intrinsic Sympathomimetic Activity (ISA)

partial agonist at B1 receptors = less effect on the heart, more peripheral effects

When are beta blockers with ISA preferred?

in patients prone to developing severe bradycardia

Absorption of beta blockers

all are well absorbed after oral administration

Distribution of beta blockers

well distributed and crosses placenta; enters breast milk (due to their high lipid solubility)

Metabolism of beta blockers

extensive hepatic metabolism using cytochrome P450 (CYP) isoenzymes; also, first-pass metabolism can be extensive

Excretion/elimination of sotalol and metoprolol

mostly renal

Excretion/elimination of carvedilol

mostly feces

Excretion/elimination of atenolol

both feces and urine (metabolism is incomplete)

Clinical uses for beta blockers

- cardiac arrhythmias, prevention of MI, and decreased mortality in patients with recent MI

- angina pectoris

- hypertension (not first line)

- management of stable, symptomatic HF due to ischemic hypertensive or cardiomyopathic origin

- migraine prophylaxis, tremors, aggressive behavior, anxiety

- all patients with symptomatic HF (stage C, NYHA II-IV) and all patients with left ventricular dysfunction (stage B, NYHA I) after MI

Adverse reactions of beta blockers

CV: postural hypotension, bradycardia, syncope, atrioventricular (AV) block

GU: impotence

META: hypertriglyceridemia, hyperglycemia, hypoglycemia mask/mimis, weight gain, weakness

NEURO: dizziness, fatigue, headache, depression

PUL: bronchospasm, asthma (in non-cardioselective agents)

Interactions of beta blcokers

- Additive bradycardia may occur with digoxin

- other antihypertensive medications (alpha blocker, CCB), alcohol, and nitrates may result in additive hypotension

- thyroid medication administration may decrease effectiveness

- may see altered effects of insulin and oral hypoglycemics

Contraindications of beta blockers

- hypersensitivities

- acute decompensated HF

- cardiogenic shock

- second- or third-degree block

- severe sinus bradycardia

- severe COPD or asthma

- severe hypotension

Conscientious considerations of beta blockers

- watch for effects on the lipid profile (especially increased triglyceride levels and decreased HDL levels with nonselective beta blockers)

- watch for signs of abrupt withdrawal (could be the precursor to an angina attack or an increase in BP as a result of an increase in adrenergic tone)

Patient/Family education for beta blockers

- instructions the same as those for ARBs

- Patients may find they are more sensitive to cold

- Patients with diabetes should closely monitor their blood sugar

- patients should report slow pulse, difficult breathing, wheezing, cold hands and feet, dizziness, light-headedness, and depression

- Should NOT discontinue medication abruptly

What is the mechanism of action of diuretics?

increase sodium and water excretion by the kidney

- decreases intravascular volume, which decreases preload, stroke volume, and cardiac output

decreased SV = decreased CO, and decreased CO = decreased BP

What are the six classes of diuretics, and what are they classified by?

Potassium-sparing, loop, thiazide, thiazide-like, osmotic, carbonic anhydrase inhibitors

Classified by site of action in the nephron

Where do potassium-sparing diuretics work?

late distal convoluted tubule and collecting duct

Where do loop diuretics work?

ascending limb of the loop of Henle

Where do thiazide and thiazide-like diuretics work?

distal convoluted tubule

Where do osmotic diuretics and carbonic anhydrase inhibitors work?

proximal convoluted tubule

Drug tolerance

The body's ability to adapt to repeated administration

Diuretic braking

Adaptation occurs as compensatory changes in the body occur once a diuretic's effective concentration falls and sodium retention increases while ion transporters becomes enhanced

Potassium-Sparing Diuretics

Amiloride

Spironolactone

Triamterene

Eplerenone

Mechanism of action of potassium-sparing diuretics (or aldosterone antagonists)

inhibit Na+ reabsorption in the kidney while saving K+, antagonizes aldosterone receptors (aldosterone causes Na+ and H2O reabsorption, so antagonizing aldosterone receptors leads to less Na+ and H2O reabsorption)

Absorption of potassium-sparing diuretics

low (amiloride), moderate (triamterene), or good (spironolactone) absorption from the GI tract when given PO

Distribution of potassium-sparing diuretics

Amiloride and triamterene are widely distributed, all cross the placenta and enter breast milk, spironolactone is 90% protein bound

Metabolism of potassium-sparing diuretics

- 50% of spironolactone and amiloride are metabolized in the liver

- Spironolactone is converted by the liver to its active compound (canrenone)

- 80% of triamterene is metabolized by the liver

Excretion of potassium-sparing diuretics

- 50% of amiloride and spironolactone are excreted unchanged by the kidney

- Triamterene is excreted in the bile

Clinical uses of diuretics

- help restore normal serum K+ levels in patients who develop hypokalemia when taking other diuretics

- prevent development of hypokalemia in patients who would be exposed to particular risk if hypokalemia were to develop

- Spironolactone is effective in lowering SBP and DBP in primary hyperaldosteronism and essential HTN

- Cirrhosis

- Nephrotic syndrome

- Heart failure

Adverse reactions of potassium-sparing diuretics

CV: arrhythmias

ENDO: gynecoamastia (more with spironolactone)

GI: gastric problems, including peptic ulcer

GU: impotence (triamterene = blue-colored urine)

HEM: thrombocytopenia, blood dyscrasias (spironolactone and triamterene)

META: hyperkalemia, hyponatremia, metabolic acidosis

NEURO: weakness, fatigue, dizziness, headache, dry mouth

RENAL: azotemia, elevated BUN and creatinine, renal stones

MISC: photosensitivity (triamterene)

Interactions of potassium-sparing diuretics

ACEIs = potentiate hyperkalemia

NSAIDs = reduce diuretic efficacy

Contraindications to potassium-sparing diuretics

hyperkalemia, renal impairement

Conscientious considerations of potassium-sparing diuretics

- Although they are weak diuretics, they are often used as adjunctive therapy because they conserve potassium

- Potassium-conserving agents may cause hyperkalemia

- The incidence of hyperkalemia is greater in patients with renal impairment, diabetes mellitus, and the elderly

- It is essential to monitor serum K+ levels carefully, particularly when the drug is first introduced, when adjusting the dose, and during any illness that could affect renal function

- periodic ECG if the patient is on prolonged therapy

- administer in the morning to avoid disrupting sleep cycle

Patient/Family education for potassium-sparing diuretics

- advise against OTC decongestants, cough, or cold preparations, and appetite suppressants taken concurrently because of the potential for increased BP

- if the patient is on triamterene, advise about possible photosensitivity and what to do about it (also advise that triamterene will discolor urine)

- may cause GI upset; take with food

- notify clinician if muscle weakness, fatigue, or muscle cramps occur

- may cause dizziness, headache, or visual disturbances; observe caution while driving or performing other tasks requiring alertness, coordination, or physical dexterity

- avoid K+ supplements and foods containing high levels of K+, including salt substances

Loop diuretics

Bumetanide

Furosemide

Torsemide

Ethacrynic Acid

Mechanism of action of loop diuretics

inhibit reabsorption of Na+ and Cl- from the loop of Henle (ascending limb) and distal renal tubule

- increases renal excretion of H2O, Na, Cl, Mg, K, and Ca

- effects are reduced edema and lowering of BP

induce renal synthesis of prostaglandins, which contributes to their renal action

Absorption of loop diuretics

~2/3 is absorbed after oral administration; also absorbed from IM sites

Distribution of loop diuretics

protein-bound; crosses the placenta and enters breast milk

Metabolism of loop diuretics

Liver

- furosemide (30-40%)

- bumetanide (50%)

- torsemide (80%)

Excretion of loop diuretics

the unchanged drug is mostly excreted by the kidney, but some is excreted in feces

Clinical uses for loop diuretics

- edema

- renal insufficiency

- ascites

- nephrotic syndrome

- pulmonary edema

- congestive heart failure

- hypertension

- hypercalcemia

- hyperkalemia (in emergencies)

Adverse reactions of loop diuretics

NEURO: dizziness, encephalopathy

CV: orthostatic hypotension

EENT: dose-related hearing loss (ototoxicity)

GI/GU: constipation, dry mouth, dyspepsia, erectile dysfunction

ENDO: hyponatremia, hypokalemia, metabolic alkalosis, hypomagnesemia, hypochloremia, dehydration, metabolic acidosis, hyperuricemia, hyperglycemia

HEM: blood dyscrasias (with furosemide)

MISC: increased BUN, photosensitivity

Interactions of loop diuretics

- Hypokalemia increases digoxin toxicity

- NSAIDs reduce diuretic efficacy

- Beta blockers potentiate hyperglycemia and hyperlipidemia

- Corticosteroids enhance hypokalemia

- Aminoglycosides enhance ototoxicity and nephrotoxicity

- Can increase the levels of lithium

Contraindications of loop diuretics

- anuria

- renal decompensation

- hypersensitivity to sulfonamide-derived drugs (ethacrynic acid OK to give in sulfa allergies)

- hepatic encephalopathy, hepatic coma (seen in patients with cirrhosis)