Sports Pharmacology of Chronic Disease

Statins

• Statins are some of the most commonly prescribed drugs worldwide.

• Statin drugs are widely used to prevent and treat coronary artery disease and cerebrovascular disease in adult patients.

• Fifty-six million Americans aged 40–75 years are now considered candidates for statin use and 87% of men aged over 60 years meet the eligibility criteria for statin treatment based on application of current guidelines.

Alternative Lipid-Lowering Medications

• Two pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were approved for use in 2015: evolocumab and alirocumab.

• PCSK9 is an enzyme that binds to the low-density lipoprotein (LDL) receptor and prevents the LDL receptor from appropriately removing LDL cholesterol.

• Inhibition of PCSK9 has been shown to be a powerful method of reducing LDL cholesterol, with initial trials showing 60% reduction in LDL levels after 12 months of treatment.

• PCSK9 inhibitors are administered by subcutaneous injection every 2–4 weeks.

• Annual treatment cost is $7000–$12,000, which may limit its regular use.

• Neurocognitive side effects (e.g., confusion and inattention) have been reported in several clinical trials. Myalgias, although reported, were rare.

• PCSK9 inhibitors are likely to be considered for athletes at high risk for coronary artery disease (e.g., familial hypercholesterolemia) who cannot tolerate statin drugs because of their adverse effects.

Background

• Hypertension (HTN) is the most common cardiovascular condition affecting adults in the United States. It is common in athletes of all ages and is a leading risk factor for cardiovascular morbidity and chronic kidney disease (CKD).

• HTN is associated with decreased exercise capacity in elite athletes.

• Systolic blood pressures continue to rise throughout life because of arterial stiffening, whereas diastolic pressures plateau in the sixth decade of life and subsequently decline.

• Approximately 55% of men and 65% of women will have HTN by the age of 60.

Mechanism of Action and Side Effects

Multiple medication classes can be utilized to treat HTN. More typical medication classes are reviewed here:

• Angiotensin-converting enzyme (ACE) inhibitors (lisinopril, enalapril, and captopril) primarily act by suppressing the renin-angiotensin-aldosterone system via inhibition of conversion of angiotensin I to angiotensin II; this blocks the breakdown of bradykinin, which can lead to side effects such as cough and angioedema. Other side effects include hyperkalemia and elevated creatinine associated with renal artery stenosis.

• Angiotensin receptor blockers (ARBs; losartan, valsartan, and olmesartan) block binding of angiotensin II to angiotensin type I receptors, thereby effectively reducing the ability of angiotensin II to cause vasoconstriction, sodium retention, and aldosterone release. Side effects are similar to ACE inhibitors, but cough is rare.

• Beta-blockers: Beta-1 receptor blockers (metoprolol and propranolol) inhibit sympathetic stimulation of the heart, thereby reducing heart rate. Others (labetalol and carvedilol) work by blocking alpha-1 receptor activity to cause peripheral vasodilation, and others have intrinsic sympathomimetic activity (acebutolol), which reduces systemic vascular resistance while maintaining heart rate and cardiac output.

• Calcium-channel blockers (CCBs): Dihydropyridine CCBs (amlodipine and nifedipine) bind calcium channels in vascular smooth muscles, leading to vasodilation. Nondihydropyridine CCBs (verapamil and diltiazem) bind to calcium channels in the sinoatrial and atrioventricular nodes, leading to negative inotropic effects. Side effects may include lightheadedness, hypotension, and lower extremity swelling.

• Diuretics: Thiazide diuretics (hydrochlorothiazide and chlorthalidone) inhibit reabsorption of sodium and chloride, primarily in the distal tubules, which can lead to hyponatremia. Potassium-sparing diuretics (triamterene and spironolactone) inhibit sodium reabsorption in the distal tubules but are rarely used in monotherapy. Loop diuretics (furosemide, torsemide, and bumetanide) inhibit the reabsorption of sodium and chloride at the ascending loop of Henle and may commonly lead to hypokalemia.

Treatment of Hypertension

• The eighth Joint National Committee (JNC8) recommends initiation of treatment for blood pressures >150/90 mmHg in adults aged ≥60 years and at 140/90 mmHg in anyone aged <60 years and patients with CKD and diabetes.

• Athletes should begin treatment with nonpharmacologic options, including lifestyle modifications, such as decreased sodium intake, decreased fat intake, weight loss, decreased alcohol consumption, stimulant avoidance, limited nonsteroidal anti-inflammatory drug (NSAID) use, smoking cessation, relaxation techniques, and aerobic exercise.

• Choosing HTN medications in athletes can be challenging: the best choice of drug is one that reliably lowers blood pressure, has limited negative effects on exercise hemodynamics, and is legal for the athlete to use.

• Other existing medical comorbidities, drug–drug interactions, and response to previous medications must also be considered.

• ACE inhibitors, ARBs, and CCBs are typical first-line agents in athletes because they are well tolerated and have no major effects on energy metabolism or cardiovascular adaptation to exercise.

• Thiazide diuretics are also considered first-line agents but have certain negative effects that makes them less desirable choices in athletes.

• In patients with CKD, ACE inhibitors and ARBs should be the initial or first add-on choice of therapy.

• ACE inhibitors and ARBs should be cautiously used in women of reproductive age, as they are contraindicated during pregnancy.

• African Americans typically respond better to CCBs and thiazide diuretics.

Considerations in Athletes

• The prevalence of HTN in athletes is unknown but is thought to be half of that in the general population. However, in preparticipation cardiac screening, HTN is the most common abnormal finding. Among adolescent athletes with HTN, the blood pressure continues to remain elevated at the 1-year follow-up in approximately 80% of cases.

• Athletes at a greater risk for HTN include male athletes, strength-trained athletes, African Americans, obese individuals, athletes with diabetes, those with renal disease, and those with a family history of HTN. Collegiate and professional football players have higher rates of HTN compared with nonfootball athletes (19.2% vs. 7% and 13.8% vs. 5.5%, respectively).