Section 4.6: Clinical Pharmacology: Cardiovascular Disorders

Clinical Pharmacology: Cardiovascular Disorders

Hypertension Management

Hypertension treatment is guided by the 2017 ACC/AHA Guidelines and Saudi National Hypertension Guidelines.

• First-Line Classes: Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin Receptor Blockers (ARBs), Calcium Channel Blockers (CCBs), and Thiazide Diuretics.
• Compelling Indications:
  • Chronic Kidney Disease (CKD) or Diabetes with Albuminuria: ACEIs (e.g., lisinopril) or ARBs (e.g., losartan) are mandatory first-line because they dilate the efferent arteriole, reducing intraglomerular pressure and slowing renal disease progression.
  • Post-Myocardial Infarction: Beta-blockers and ACEIs are indicated to prevent cardiac remodeling.
• Contraindications: ACEIs and ARBs are absolute contraindications in pregnancy (teratogenic: renal dysgenesis). Use methyldopa, labetalol, or nifedipine ER instead.
• Hypertensive Crisis:
  • Hypertensive Urgency: $\text{BP} > 180/120 \text{ mmHg}$ without acute target organ damage. Treat with oral agents (e.g., clonidine, captopril) to lower BP slowly over 24–48 hours.
  • Hypertensive Emergency: $\text{BP} > 180/120 \text{ mmHg}$ with acute target organ damage (e.g., encephalopathy, stroke, acute coronary syndrome, aortic dissection). Treat with IV infusions (e.g., clevidipine, nicardipine, labetalol, nitroprusside). Reduce mean arterial pressure (MAP) by no more than 25% within the first hour to prevent cerebral ischemia.

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Dyslipidemia Management

• Statin Intensities: High-intensity statins lower LDL-C by $\ge 50%$; moderate-intensity statins lower LDL-C by 30% to 49%.
  • High-Intensity: Atorvastatin 40–80 mg, Rosuvastatin 20–40 mg.
  • Moderate-Intensity: Atorvastatin 10–20 mg, Rosuvastatin 5–10 mg, Simvastatin 20–40 mg, Pravastatin 40–80 mg.
• Myotoxicity Management: Statin-associated muscle symptoms (SAMS) range from mild myalgia to rhabdomyolysis. If a patient presents with muscle pain/weakness: check serum creatine kinase (CK) levels. If CK is $>10 \times \text{ULN}$ or symptoms are severe, discontinue the statin immediately. Once symptoms resolve, re-challenge with a lower dose of the same statin or switch to a different statin (e.g., rosuvastatin or pravastatin, which are hydrophilic and have lower muscle penetration).
• Non-Statin Therapies:
  • Ezetimibe: Inhibits cholesterol absorption at the brush border of the small intestine by targeting NPC1L1. Add to statin therapy if LDL targets are unmet.
  • PCSK9 Inhibitors (Evolocumab, Alirocumab): Monoclonal antibodies that prevent PCSK9 from degrading LDL receptors, dramatically increasing hepatic LDL clearance.

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Ischemic Heart Disease (IHD) & Acute Coronary Syndromes (ACS)

ACS includes Unstable Angina (UA), Non-ST-Elevation Myocardial Infarction (NSTEMI), and ST-Elevation Myocardial Infarction (STEMI).

• Dual Antiplatelet Therapy (DAPT): Post-ACS, patients must receive Aspirin (81 mg daily indefinitely) + a $\text{P2Y}_{12}$ inhibitor (Clopidogrel 75 mg daily, Ticagrelor 90 mg BID, or Prasugrel 10 mg daily) for at least 12 months to prevent stent thrombosis.
• Acute GDMT: Beta-blocker (started within 24 hours if no heart failure/cardiogenic shock), ACEI/ARB (especially if LVEF $<40%$, HTN, or CKD), high-intensity statin, nitroglycerin sublingual as needed.

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Heart Failure with Reduced Ejection Fraction (HFrEF)

GDMT for HFrEF ($\text{LVEF} \le 40%$) targets mortality reduction through the "Four Pillars":

1. Angiotensin Receptor-Neprilysin Inhibitor (ARNI - Sacubitril/Valsartan): Preferred over ACEIs/ARBs. Sacubitril inhibits neprilysin (increasing vasoactive peptides like BNP), while valsartan blocks $\text{AT}_1$ receptors. Clinical pearl: If switching from an ACEI to ARNI, a 36-hour washout period is mandatory to prevent angioedema.
2. Beta-blockers: Only three beta-blockers are evidence-based for mortality reduction in HFrEF: Carvedilol, Metoprolol Succinate (extended release), and Bisoprolol. Do not initiate during acute decompensation.
3. Mineralocorticoid Receptor Antagonists (MRAs): Spironolactone or Eplerenone. Contraindicated if serum potassium $> 5.0 \text{ mEq/L}$ or $\text{CrCl} \le 30 \text{ mL/min}$.
4. SGLT2 Inhibitors: Dapagliflozin or Empagliflozin. Shown to reduce cardiovascular mortality and heart failure hospitalizations regardless of diabetes status.

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Arrhythmias & Atrial Fibrillation (AF)

• Atrial Fibrillation Rates vs. Rhythm Control:
  • Rate Control: Preferred in most patients. Target HR $< 80 \text{ bpm}$ (acute) or $< 110 \text{ bpm}$ (lenient). First-line: Beta-blockers or Non-dihydropyridine CCBs (Diltiazem/Verapamil). Avoid non-dihydropyridine CCBs in HFrEF due to negative inotropic effects.
  • Rhythm Control: Used for symptomatic patients despite rate control. Antiarrhythmics include Amiodarone (requires extensive monitoring: thyroid, liver, pulmonary, ophthalmic toxicities due to high iodine content), Dofetilide, or Flecainide.
• Anticoagulation in AF: Guided by the $\text{CHA}_2\text{DS}_2\text{-VASc}$ score. A score of $\ge 2$ in men or $\ge 3$ in women mandates oral anticoagulation. Direct Oral Anticoagulants (DOACs - Apixaban, Rivaroxaban, Dabigatran) are preferred over Warfarin unless the patient has moderate-to-severe mitral stenosis or a mechanical heart valve.

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Venous Thromboembolism (VTE)

• Treatment Options: DOACs (Apixaban 10 mg BID for 7 days, then 5 mg BID; Rivaroxaban 15 mg BID for 21 days, then 20 mg daily) do not require parenteral bridging.
• Warfarin Bridging: If starting Warfarin, it must be co-administered with a parenteral anticoagulant (e.g., Enoxaparin or UFH) for a minimum of 5 days AND until the INR is $\ge 2.0$ for at least 24 hours. Warfarin initially depletes proteins C and S, causing a transient prothrombotic state.