Cardiovascular agents


Cardiovascular agents are drugs used to treat diseases associated with the heart or blood vessels. These medications are available for purchase only with a physician's prescription. They include, but are not limited to, drugs that target hypertension, hyperlipidemia and blood clotting to reduce the risk of cardiovascular diseases.
Antihypertensive agents are classified according to their mechanism of actions. The most common classes prescribed are diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers and beta-blockers.
Antihyperlipidemic agents most often prescribed are statins, ezetimibe and fibrates. They either lower low-density lipoprotein cholesterol or triglyceride levels in blood to manage hypercholesterolaemia.
Blood-thinning agents, particularly antiplatelets and anticoagulants, maintain smooth blood flow by preventing blood clot formation in blood vessels. Two main categories of antiplatelets are COX-1 inhibitors and ADP receptor inhibitors, while anticoagulants include vitamin K antagonists, direct oral anticoagulants and indirect thrombin inhibitors.
Since cardiovascular agents have narrow therapeutic windows, a slight rise in dose may result in severe toxicity. Hence, monitoring at baseline and during therapy is needed. For drug overdose, stabilisation and antidotes help lower drug concentrations.

Terminology

Cardiovascular agents are drugs that affect the rate and intensity of cardiac contraction, blood vessel diameters, blood volume, blood clotting and blood cholesterol levels. They are indicated to treat diseases related to the heart or the vascular system, such as hypertension, hyperlipidemia, coagulation disorders, heart failure and coronary artery disease. These drugs are prescription-only medicines, meaning that they should be administered strictly under a doctor's instruction and can only be obtained by means of a doctor's prescription.

Drug classes

Antihypertensive agents

comprise multiple classes of compounds that are intended to manage hypertension. Antihypertensive therapy aims to maintain a blood pressure goal of <140/90 mmHg in all patients, as well as to prevent the progression or recurrence of cardiovascular diseases in hypertensive patients with established CVD. An optimal blood pressure control is essential to prevent target-organ damage associated with complications of hypertension such as heart failure, ischemic heart diseases, stroke, and renal failure, ultimately reducing the risk of premature mortality. Antihypertensives are classified by different mechanisms or sites of action. Some of the most commonly used drugs to treat hypertension include diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and beta-blockers.

Diuretics

s act primarily by reducing the reabsorption of sodium at different sites of the renal tubular system and consequently promoting the elimination of sodium and water with increased urine output.
For loop diuretics, thiazide diuretics and thiazide-like diuretics, their common side effects include hypokalemia, hyponatremia, metabolic alkalosis and hyperglycaemia. For potassium-sparing diuretics, its common side effects include hyponatremia, hyperkalemia, metabolic acidosis and sexual dysfunction specifically for spironolactone.
The use of diuretics should be avoided in patients with severe dehydration, anuria. Diuretics are contraindicated in cases of severe electrolyte abnormalities and should not be administered until an electrolyte balance is restored. Special attention should be given to the use of thiazide and loop diuretics as they may exacerbate diabetes and gout.

Angiotensin-converting-enzyme inhibitors (ACEI)

block the conversion of angiotensin I to angiotensin II by inhibiting the action of angiotensin-converting-enzyme, causing the reduction of blood volume and peripheral vascular resistance.
Some side effects of ACEI include hypotension, renal insufficiency, and hyperkalemia. Dry cough is also a common side effect believed to be associated with decreased bradykinin breakdown. Angioedema is another possible but rare complication due to elevated levels of bradykinin.
ACEI should not be used in combinations with angiotensin II receptor blockers or direct renin inhibitors and is contraindicated in people with a history of angioedema and pregnancy. The concurrent use of an ACEI with diuretics and non-steroidal anti-inflammatory drugs, is also contraindicated as this combination has been correlated with an increased risk of acute kidney injury. ACEI should be used with caution in patients with renal impairment, and renal failure risk in severe bilateral renal stenosis.

Angiotensin II receptor blockers (ARBs)

s work by inhibiting the action of angiotensin II on, specifically AT1 receptors to prevent the vasoconstrictor effects of this receptor and block the peripheral sympathetic activity.
ARBs are generally well-tolerated, in which they are less likely to cause cough or angioedema compared to ACEI. Common side effects include hypotension, renal insufficiency, and hyperkalemia.
The contraindications of ARBs are similar to those of ACEI, including the contraindicated combinations with ACEI or direct renin inhibitors, "triple whammy" and in patients with a history of angioedema and pregnancy. In addition, ARB should be used with caution in patients with renal impairment and renal failure risk in severe bilateral renal stenosis

Calcium channel blockers (CCBs)

s preferentially block the L-type voltage-gated calcium channels to prevent the flow of calcium influx in the blood vessels and the heart, thereby reducing peripheral vascular resistance and cardiac output respectively.
In general, the side effects of CCBs include peripheral edema and gingival hyperplasia when CCBs are used chronically. To add on, DHP may cause reflex tachycardia and peripheral edema, while non-DHP may cause bradycardia and worsening of cardiac function due to reduced cardiac contractility and cardiac conduction.
Non-dihydropyridines are contraindicated in patients with heart failure with reduced ejection fraction, and second- or third-degree atrioventricular block. Special attention should be given to the coadministration of non-DHP with beta-blockers or ivabradine due to the increased risk of bradycardia. Since both DHP and non-DHP are metabolized through the CYP3A4 system, grapefruit juice containing furanocoumarins should be avoided.

Beta-blockers

act as competitive antagonists that block the effects of catecholamines at beta-adrenergic receptor sites, resulting in reduced rate and force of contraction of the heart, as well as reduced peripheral vascular resistance.
Some common side effects include increased airway resistance for non-selective beta-blockers, exacerbation of peripheral vascular diseases, and hypotension
Beta-blockers are contraindicated in patients with second- or third-degree atrioventricular block. In particular, beta-blockers with intrinsic sympathomimetic activity are contraindicated in patients with myocardial infarction, heart failure or severe bradycardia. Beta-blockers should be used with caution in patients with asthma or chronic obstructive pulmonary disease due to bronchoconstriction, and in patients with diabetes mellitus due to masking of hypoglycaemia.

Antihyperlipidemic agents

are drugs used for the treatment of dyslipidemia, a condition of abnormal lipid levels in the body. It is characterised by elevations of low-density lipoprotein cholesterol and triglycerides in the blood. Hypercholesterolaemia induces the formation of plaques due to the buildup of excess cholesterol within the arterial wall. This increases the risk of, or aggravate, atherosclerotic cardiovascular disease. Therefore, antihyperlipidemic drugs are introduced for primary and secondary coronary heart disease prevention, as well as for reduction in mortality from acute coronary outcomes. These drugs include statins, ezetimibe and fibrates.

Statins

s, also known as beta-hydroxy-beta-methylglutaryl-Coenzyme A reductase inhibitors, are the first-line drugs for hypercholesterolaemia. Examples of this drug class are atorvastatin, rosuvastatin, fluvastatin, simvastatin, pravastatin and lovastatin.
Most efficacious in lowering LDL-C levels, statins block the action of HMG-CoA reductase through competitive inhibition. HMG-CoA reductase, an enzyme found in hepatocytes, is responsible for the conversion of HMG-CoA to mevalonic acid for cholesterol biosynthesis. Inhibition of this enzyme reduces the synthesis and thus, availability of endogenous cholesterol. This reduction in intracellular cholesterol, in turn, causes an increase in the number of LDL receptors on hepatic cells. The elevation of LDL receptor expression decreases the plasma LDL-C level by promoting hepatic uptake of LDL from circulation.
While statins are generally well-tolerated, severe adverse effects such as hepatotoxicity and myotoxicity may occur in rarity. Statin-induced hepatotoxicity can cause autoimmune hepatitis and an elevation in serum levels of hepatic enzymes such as alanine aminotransferase, impairing liver function. Myotoxicity is commonly presented with statin-associated muscle symptoms, which include myalgia and myositis. In rare cases, they may progress into rhabdomyolysis, a condition manifested by muscle necrosis and myoglobinuria due to heightened creatine kinase levels. Another consequence of taking statins is the risk of developing new-onset diabetes, which is more prominent in individuals with high TG levels and body mass index. However, the risk is far outweighed by the benefits from statin therapy for the reduction in cardiovascular outcomes.
Given the potential of statins to exacerbate liver and muscle abnormalities, contraindications of statins include decompensated liver cirrhosis, acute liver failure, unexplained and persistent elevations of serum transaminases, and myopathy. Moreover, statins are not recommended in pregnancy as they may cause foetal harm because of their mechanism of action.
Metabolised by the Cytochrome P450 enzyme, a major metabolic enzyme, simvastatin and lovastatin may accumulate in blood when administered with CYP450 inhibitors. Some of these inhibitors are azole antifungals, macrolides, CCBs, ticagrelor and grapefruit juice. Concomitant use of statins with CYP450 inhibitors, along with gemfibrozil, increases the risk of myopathy. This is especially significant in patients under polypharmacy.