Part 4: Drugs affecting the cardiovascular system.

I: Antihypertensives

If the pressure becomes too high, the person is said to be hypertensive. If the pressure becomes too low and blood cannot be delivered effectively, the person is said to be hypotensive. Helping the patient to maintain the blood pressure within normal limits is the goal of drug therapy.

Hypertension:

When a person’s blood pressure is above normal limits fora sustained period, a diagnosis of hypertension is made. Untreated hypertension increases a person’s risk for thefollowing conditions:coronary artery disease, and cardiac death, stroke, heart failure, renal failure and peripheral vascular disease.The classification scheme used to categorize individual cases of hypertension has been simplified to the following four stages based on blood pressure measurements: normal, prehypertension, stage 1 hypertension, and stage 2 hypertension.

Hypertension can also be defined by its cause. When the specific cause of hypertension is unknown, it may be called essential, idiopathic, or primary hypertension. About 90% of cases of hypertension are of this type. Secondary hypertension accounts for the other 10%. Secondary hypertension is most commonly the result of another disease such as pheochromocytoma (adrenal tumor), preeclampsia of pregnancy, or renal artery disease. It also may result from the use of certain medications. If the cause of secondary hypertension can be eliminated, blood pressure usually returns to normal.

Hypotension:

If blood pressure becomes too low, the vital centers in thebrain, as well as the rest of the tissues of the body, may notreceive enough oxygenated blood to continue functioning.Hypotension can progress to shock, in which the body is inserious jeopardy as waste products accumulate and cells diefrom lack of oxygen. Hypotensive states can occur in thefollowing situations:

• When the heart muscle is damaged and unable to pumpeffectively.

• With severe blood loss, when volume drops dramatically.

• When there is extreme stress and the body’s levels ofnorepinephrine are depleted, leaving the body unable torespond to stimuli to raise blood pressure.

Antihypertensive agents:

Because an underlying cause of hypertension is usuallyunknown, altering the body’s regulatory mechanisms is thebest treatment currently available. Drugs used to treat hypertensionwork to alter the normal reflexes that control bloodpressure. See Figure below for a review of the sites of action ofdrugs used to treat hypertension.

Treatment for essentialhypertension does not cure the disease but is aimed at maintainingthe blood pressure within normal limits to prevent thedamage that hypertension can cause.

Not all patients respondin the same way to antihypertensive drugs because differentfactors may contribute to each person’s hypertension. Patientsmay have complicating conditions, such as diabetes, that make it unwise to use certaindrugs.Several different types of drugs that affect different areasof blood pressure control may need to be used in combinationto maintain a patient’s blood pressure within normal limits.

There are essentially seven main categories of pharmacologicdrugs:

  1. Angiotensin-convertingenzyme inhibitors (ACEIs).
  2. Angiotensin II–receptor blockers (ARBs).
  3. Calcium channel blockers (CCBs).
  4. Direct vasodilators.
  5. Diuretic agents.
  6. Beta-blockers.
  7. Alpha-blockers.
  8. others

1-Diuretics:

The diuretics are a highly effective class of antihypertensive drugs. They may used as a monotherapy or in combination with other drugs. Their primary therapeutic effect is decreasing the plasma and extracellular fluid volumes, which results in decreased preload. This leads to decrease in cardiac output and total peripheral resistance, all of which decrease the workload of the heart. The thiazide diuretics are the most commonly used for treatment of hypertension.

2-Beta blockers:

  1. The beta-blocker (atenolol (Tenormin), betaxolol (Kerlone), bisoprolol, metoprolol ,and propranolol (Inderal).:

These drugs are discussed in more detail before. Their antihypertensive effects are related to their reduction of the heart rate through beta1- receptor blockade. Furthermore, they also cause a reduction in the secretion of renin, which in turn reduces vasoconstriction. Long term use of beta-blockers also reduces peripheral vascular resistance.

  1. Two dual-action alpha1 and beta receptor blockers (labetalol and carvedilol.):

Which act in the periphery at the heart and blood vessels. They have dual antihypertensive effects of reduction in heart rate (beta1 receptor blockade) and vasodilation (alpha1 receptor blockade). Patients often complain of fatigue, loss of libido, inability to sleep, and GI and genitourinary disturbances.

3-Alpha blockers:

  1. Periphery the alpha1-blockers (doxazosin (Cardura), prazosin,and terazosin):

They are able to block the postsynaptic alpha1-receptor sites.This decreases vascular tone and promotes vasodilation,which reduces peripheral vascular resistance and subsequently decreases blood pressure.These drugs do notblock the presynaptic alpha2-receptor sites, and thereforethe reflex tachycardia that accompanies a fall in bloodpressure does not occur.

  1. The centrally acting alpha2-adrenergic drugs(clonidine, and methyldopa):

Acts centrally, stimulate the alpha2-receptors in the CNSand inhibit the cardiovascular centers,leading to a decrease in sympathetic outflow from theCNS and a resultant drop in blood pressure. These drugsare associated with many adverse CNS and GI effects, as well as cardiac dysrhythmias.

Indications:

All of the drugs mentioned are used primarily for the treatment of hypertension, either alone or in combination with other antihypertensive drugs. Methyldopa is indicated to treat hypertension in pregnant women. The alpha1-blockers have been used to relieve the symptoms associated with BPH.

4-Angiotensin-Converting enzyme inhibitors (captopril, enalapril, lisinopril and ramipril):

These drugs are very safe and efficacious and are often used as first line drugs in the treatment of both heart failure and hypertension. ACE inhibitors as a class are very similar and differ in only a few of their chemical properties, but there are significant differences among them in their clinical properties.

All of the ACE inhibitors or administered orally. Enalaprilalso has the advantage of parenteral use. Captopril has the shortest half-life.It may be best to start with a drug that has a short half-life in a patient who is still very critically ill and may not tolerate medications well. Both captopril and enalapril can be dosed multiple times a day.

Captopril and lisinopril is an important advantage in treating a patient with liver dysfunction; because all of the other ACE inhibitors are prodrugs.All ACE are classified as pregnancy category C in first trimester and as pregnancy D drugs in their second or third trimester.

Mechanism of action:

They inhibit angiotensin—converting enzyme, which is responsible for converting angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor and induces aldosterone secretion by adrenal glands. The primary effects of the ACE inhibitors are cardiovascular and renal. Their cardiovascular effects are due to their ability to reduce blood pressure by decreasing SVR. They do this by preventing the breakdown of vasodilating substance bradykinin and also of substance P, and preventing the formation of angiotensin II. These combined effects decrease afterload, or the resistance against which the left ventricle must pump to eject its volume of blood during contraction.

The ACE inhibitorsthey also prevent sodium and water resorptionby inhibiting aldosterone secretion. This causes diuresis, which decreases blood volume and return to the heart. This in turn decreases preload and the work required of the heart, so this class can beneficial in treatment of heart failure.

Indications:

  • Hypertension and HF (either alone or in combination with diuretics or other drugs)
  • Slow progression of left ventricular hypertrophy after MI (cardioprotective)
  • Renal protective effects in patients with diabetes (Drugs of choice)
  • Drugs of choice in hypertensive patients with HF

Adverse effects:

  • Fatigue, Dizziness, Headache, postural hypotension and Mood changes
  • Impaired taste and possible hyperkalemia
  • Persistence dry, nonproductive cough, which reverses when therapy is stopped
  • Angioedema: rare but potentially fatal.
  • are teratogenic and should not be used in pregnant women

Interactions:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the antihypertensive effect of ACE inhibitors.
  • The use of NAIDs and ACE inhibitors may also predispose patients to the development of acute renal failure.
  • Potassium supplements and potassium-sparing diuretics when administered with ACE inhibitors may result in hyperkalemmia.

5-Angiotensin II receptor blockers: Valsartan, Candesartan,Losartan.

The ARBs selectively bind with the angiotensin II receptorsin vascular smooth muscle and in the adrenal cortex to blockvasoconstriction and the release of aldosterone. These actionsblock the blood pressure–raising effects of the renin–angiotensin system and lower blood pressure.. Both are well tolerated but ARBs do not cause cough. Both can’t be used in pregnant women.

Indications:

  • They may be used alone or in combination with diuretics to treat hypertension and heart failure.
  • Their use in HF is mainly as a substitute for ACEIs in those patients with severe cough or angioedema
  • they also were found to slow the progression of renal disease in patients with hypertension and type 2 diabetes

Adverse effects:

  • Symptoms of upper respiratory infections
  • May cause occasional dizziness, inability to sleep, diarrhea, dyspnea, heartburn, nasal congestion, back pain, fatigue, and headache.
  • Hyperkalemia much less likely to occur
  • have a lower incidence of cough and angioedema than ACEIs
  • should not be used in pregnant women

6-Calcium Channel Blockers:

Calcium channel blockers inhibit the movement of calciumions across the membranes of myocardial and arterial musclecells, altering the action potential and blocking muscle cellcontraction. This effect depresses myocardial contractility,slows cardiac impulse formation in the conductive tissues,and relaxes and dilates arteries, causing a fall in blood pressureand a decrease in venous return.

Their primary use is for the treatment of hypertension and angina. Amlodipine is the CCB mostcommonly used for hypertension.Calcium channel blockers are given orally and are generallywell absorbed, metabolized in the liver, and excreted in theurine. These drugs cross the placenta and enter breast milk. Nicardipine is alsoavailable in an intravenous form.

  • Benzothiazepines: Diltiazem.
  • Phenylalkamines: Verapamil.
  • Dihydropyridines:Amlodipine, Nicardipine, Nifedipine, Nimodipine.

Indications:

  • Angina, Hypertension, and Dysrhythmias
  • Migraine headaches

Adverse effects:

  • Cardiovascular: Hypotension, palpitations, tachycardia
  • Gastrointestinal:Constipation, nausea
  • Other:Rash, flushing, peripheral edema, dermatitis

7-Vasodilators (hydralazine, minoxidil, and nitroprusside):

Vasodilators act directly on arteriolar and/or venous smooth muscle to cause relaxation. They do not work through adrenergic receptors.

Mechanism of action:

Direct-acting vasodilators are useful as antihypertensive drugs because of their ability to directly elicit peripheral vasodialtion. This results in a reduction in SVR. In general, the most notable effect of vasodilators is their hypotensive effect. Diazoxide, Hydralazine, and Minoxidil work through arteriolar vasodilation, whereas nitroprusside has both arteriolar and venous effects.

Indications:

All of the vasodilators can be used to treat hypertension, either alone or in combination with other antihypertensives. Sodium nitroprusside and intravenous diazoxide are reserved for the management of hypertensive emergencies, in which blood pressure is severely elevated. Minoxidil in its topical form is used to restore hair growth.

Adverse effects:

  • hydralazine
  • Dizziness, headache, anxiety, tachycardia, nausea and vomiting, diarrhea, anemia, dyspnea, edema, nasal congestion, others
  • sodium nitroprusside
  • Bradycardia, hypotension, possible cyanide toxicity (rare)

Hypertensive emergency:

Hypertensive emergency is a rare but life-threatening situation characterized by severe elevations in blood pressure (systolic greater than 180 mm Hg or diastolic greater than 120 mm Hg) with evidence of impending or progressive target organ damage (for example, stroke, myocardial infarction). [Note: A severe elevation in blood pressure without evidence of target organ damage is considered a hypertensive urgency.]

Hypertensive emergencies require timely blood pressure reduction with treatment administered intravenously to prevent or limit target organ damage.

A variety of medications are used, including:

1-calcium channel blockers (nicardipine and clevidipine).

2-Nitric oxide vasodilators (nitroprusside and nitroglycerin).

3-Adrenergic receptor antagonists (phentolamine, esmolol, and labetalol).

4-The vasodilator hydralazine.

5-The dopamine agonist fenoldopam.

Treatment is directed by the type of target organ damage present and/or comorbidities present.

Nursing implication:

Before beginning therapy, obtain a thorough health history and head-to-toe physical examination, assess for contraindications to specific antihypertensive drugs and for conditions that require cautious use of these drugs

Educate patients about the importance of not missing a dose and taking the medications exactly as prescribed, and instruct patients to check with their physician for instructions on what to do if a dose is missed; patients should never double up on doses if a dose is missed

Monitor BP during therapy; instruct patients to keep a journal of regular BP checks

Instruct patients that these drugs should not be stopped abruptly because this may cause a rebound hypertensive crisis, and perhaps lead to stroke

Oral forms should be given with meals so that absorption is more gradual and effective

Administer IV forms with extreme caution, and use an IV pump

Remind patients that medication is only part of therapy. Encourage patients to watch their diet, stress level, weight, and alcohol intake and instruct patients to avoid smoking and eating foods high in sodium. Encourage supervised exercise

Teach patients to change positions slowly to avoid syncope from postural hypotension

Instruct patients to report unusual shortness of breath; difficulty breathing; swelling of the feet, ankles, face, or around the eyes; weight gain or loss; chest pain; palpitations; or excessive fatigue

Male patients who take these drugs may not be aware that impotence is an expected effect, and this may influence compliance with drug therapy

If patients are experiencing serious adverse effects, or if they believe the dose or medication needs to be changed, they should contact their physician immediately

Hot tubs, showers, or baths; hot weather; prolonged sitting or standing; physical exercise; and alcohol ingestion may aggravate low blood pressure, leading to fainting and injury; patients should sit or lie down until symptoms subside

Patients should not take any other medications, including over-the-counter drugs, without first getting the approval of their physician

Monitor for adverse effects (dizziness, orthostatic hypotension, fatigue) and for toxic effects

Monitor for therapeutic effects

Blood pressure should be maintained at less than 130/90 mm Hg

If a patient with hypertension also has diabetes or renal disease, the BP goal is less than 130/80 mm Hg (JNC-7)

II. Diuretics:

Overview:

Diuretics are drugs that accelerate the rate of urine formation via a variety of mechanisms. The result is the removal of sodium and water from the body.

Before we discuss the classes of diuretic drugs, it is important to quickly review kidney function, because all diuretics work primarily in the kidneys.

The kidney plays a very important role in the day-to-day functioning of the body. It filters out toxic waste products from the blood while simultaneously conserving essential substances. This delicate balance between elimination of toxins and retention of essential chemicals is maintained by the nephron. The nephron is the main structural unit of the kidney. Diuretics exert their effect in the nephron.

The initial filtering of the blood takes place in the glomerulus. The rate at which this filtering occurs is referred to as the glomerular filteration rate (GFR). The GFR can be estimated mathematically by calculating creatinine clearance. GFR is regulated by afferent arteriols and efferent arterioles. The proximal tubule returns (60-70) % of the sodium and water from the filtered fluid back into the bloodstream. Another (20-25) % is reabsorbed back into the bloodstream in the ascending loop of henle. The remaining (5-10) % of sodium resorption takes place in the distal tubule. In the distal tubule, sodium is actively filtered in exchange for potassium or hydrogen ions, a process regulated by the hormone aldostrone. The collecting duct is the final common pathway for the filtrate that started in the glomerulus. It is here that antidiuretic hormone ADH acts to increase the absorption of water back into bloodstream.

The hypotensive activity of diuretics is due to many different mechanisms:.

They cause arteriolar dilation, which decreases peripheral vascular resistance PVR.

Reduce extracellular fluid volume, plasma volume, and cardiac output.

Advantages:

Their relatively low cost and their favorable safety profile.

Main problem:

The metabolic adverse effects that can result from excessive fluid and electrolyte loss

Pharmacology overview:

1-Carbonic Anhydrase Inhibitors CAIs:

The site of action of the CAIs is the location of carbonic anhydrase enzyme system along the nephron, primarily in the proximal tubule. Acetazolamide is the most commonly used.

Mechanism of action:

In the proximal tubules, an active transport system operates that exchanges sodium for hydrogen ions. For sodium and thus water to be reabsorbed back into the blood, hydrogen must be exchanged for it. Without hydrogen, this cannot occur, and the sodium and water will be eliminated with the urine. Carbonic anhydrase helps to make hydrogen ions available for this exchange. When its actions are inhibited by CAIs, little sodium and water can be resorbed into the blood and they are eliminated with the urine.