Pharmacology of Lipid-Lowering Drugs

Lipid-Lowering Drugs

• HMG-CoA reductase inhibitors, PCSK9 MAB, niacin, ezetimibe, and resins are used to treat hyperlipidemias, such as secondary sarcoidosis.
• These drugs work by reducing cholesterol levels, leading to increased bile acid synthesis.

Pulmonary Arterial Hypertension (PAH)

• Exertional dyspnea is the most common symptom of PAH.
• Chest pain and syncope may also occur.
• Characteristic physical examination findings include loud P2 (Pulmonic closure sound) and left parasternal heave (due to right ventricular hypertrophy).

Management of PAH

• Treatment should first involve addressing any underlying conditions, such as with anticoagulants or oxygen.
• If there is a positive response to acute vasodilator testing, oral calcium channel blockers can be used.

Pathophysiology of PAH

• Three pathways are involved in the development of PAH:
  • Nitric oxide pathway
  • Prostacyclin pathway
  • Endothelin pathway

Anticoagulants

• Warfarin is an oral anticoagulant with a long half-life, requiring several days to achieve a stable INR.
• Factors that may potentiate warfarin:
  • Liver disease
  • P450 enzyme inhibitors (e.g., amiodarone, ciprofloxacin)
  • Cranberry juice
  • Drugs that displace warfarin from plasma albumin (e.g., NSAIDs)
  • Drugs that inhibit platelet function (e.g., NSAIDs)
• Side effects of warfarin:
  • Hemorrhage
  • Teratogenic effects (although safe for breast-feeding mothers)
  • Skin necrosis (when warfarin is first started, biosynthesis of protein C is reduced)

Acute Vasodilator Testing

• Aims to determine which patients show a significant fall in pulmonary arterial pressure following vasodilator administration
• Vasodilators used: IV Epoprostenol, inhaled nitric oxide, prostacyclin analogues (iloprost, treprostinil), and phosphodiesterase-5 (PDE-5) inhibitors (sildenafil)

Blood Coagulation

Platelet Aggregation and Blood Coagulation

• Involved in antiplatelet drugs and anticoagulants

Antiplatelet Drugs

• No specific information provided

Anticoagulants

Injectable Anticoagulants

• Standard heparin: administered intravenously, short duration of action, side effects include bleeding, heparin-induced thrombocytopenia (HIT), and osteoporosis
• Low molecular weight heparin (LMWH): administered subcutaneously, long duration of action, side effects include bleeding, lower risk of HIT and osteoporosis

Monitoring

• Standard heparin: monitored using activated partial thromboplastin time (APTT)
• LMWH: monitored using anti-Factor Xa (although routine monitoring is not required)
• Heparin overdose may be reversed by protamine sulphate, although this only partially reverses the effect of LMWH

Indications

• Venous thromboembolism
• Atrial fibrillation
• Mechanical heart valves

Oral Anticoagulants

Warfarin

• Monitored using the INR (international normalised ratio)
• Has a long half-life, achieving a stable INR may take several days
• Factors that may potentiate warfarin:
  • Liver disease
  • P450 enzyme inhibitors (e.g. amiodarone, ciprofloxacin)
  • Cranberry juice
  • Drugs that displace warfarin from plasma albumin
• Thrombosis may occur in venules, leading to skin necrosis and purple toes

Direct Oral Anticoagulants (DOACs)

• Have a fixed dosing regimen and do not require frequent monitoring
• Offer greater convenience to patients compared to Vitamin K antagonists (e.g. warfarin)

Disorders of Lipid Metabolism

• Disorders of lipid metabolism can occur as primary conditions (familial or polygenic) or secondary to an underlying disease state or drug treatment.
• Risks of dyslipidemias include increased risk of atherosclerosis, ischaemic heart disease, cerebrovascular disease, and peripheral vascular diseases, directly related to increasing levels of serum cholesterol.

Management of Dyslipidemias

• Increase intake of unsaturated fats (e.g., olive oil, salmon, cashews, almonds) to help manage dyslipidemias.
• Increase physical activity to reduce risks of dyslipidemias.

Lipid-Lowering Drugs

• Statins: inhibit HMG CoA reductase, reducing cholesterol synthesis; examples include Atorvastatin, Simvastatin, and Rosuvastatin; adverse effects include muscle pain (myositis) and liver damage.
• Ezetimibe: decreases cholesterol absorption in the small intestine; adverse effects include headache.
• Nicotinic acid (Niacin, Vit B3): decreases hepatic VLDL secretion; adverse effects include myositis and flushing.
• Fibrates: agonist of PPAR-alpha, increasing lipoprotein lipase expression; examples include Gemfibrozil and Fenofibrate; adverse effects include myositis, pruritus, and cholestasis.
• Cholestyramine: binds bile acid, decreasing reabsorption in the small intestine; adverse effects include GI side-effects.

Pulmonary Arterial Hypertension (PAH)

• Defined as a sustained elevation in mean pulmonary arterial pressure (>25 mmHg at rest or >30 mmHg after exercise).
• Acute vasodilator testing: decides which patients show a significant fall in pulmonary arterial pressure following vasodilator administration (e.g., IV Epoprostenol or inhaled nitric oxide).
• Indications for PAH treatment include venous thromboembolism, atrial fibrillation, and mechanical heart valves.