Hypertension Treatments and Lisinopril Pharmacokinetics

Hypertension Treatments

• ACE Inhibitors (e.g., Lisinopril, Catopril):
  • Mechanism: Blocks angiotensin-converting enzyme in the renin-angiotensin-aldosterone system, preventing angiotensin 2 formation.
  • Side effects: Cough, diarrhea, electrolyte imbalance, gastrointestinal discomfort, headache, dizziness, and postural disorders. Angina, angioedema, and alopecia (more common in African-Caribbean patients) are also potential side effects.
  • Precautions: Renal function needs to be checked prior to initiating treatment. Cautions exist regarding effectiveness in African-Caribbean patients, diabetes, and atherosclerosis. Combining ACE inhibitors with renin inhibitors is contraindicated. Cholestatic jaundice, hepatitis, hepatic necrosis, and hepatic failure have been reported in some cases. Use with caution in patients with renal impairment, starting at low doses and adjusting according to response.

Lisinopril Pharmacokinetics

• Administration: Oral
• Bioavailability: 25%
• Peak Plasma Concentration: Lasts approximately 4-6 hours
• Half-life: 12 hours
• Metabolism: Water-soluble, not metabolized in the liver
• Excretion: Renal excretion unchanged
• Mechanism of action (additional): Inhibits Kininase 2, blocking the inactivation of bradykinin, which helps lower blood pressure.

Angiotensin Receptor Blockers (ARBs) (e.g., Losartan)

• Mechanism of Action: Selective competitive blockers of angiotensin 2 at the AT1 receptor
• Pharmacokinetics:
  • Bioavailability: 32% orally, with 14% converting to an active metabolite.
  • Half-life: 2-9 hours (for the active metabolite)
  • Excretion: Urine and bile
• Side effects: Abdominal pain, headache, dizziness, diarrhea, nausea, postural hypotension, and renal impairment. Specific side effects with Losartan include anemia, hypoglycemia, and postural disorders.
• Precautions and Contraindications:
  • Cautions in African-Caribbean patients, those with left ventricular hypertrophy, and elderly patients, particularly regarding severe cardiac failure, pregnancy, and severe hepatic impairment.
  • Contraindicated when combined with a renin inhibitor, with patients who have reduced eGFR, or those with diabetes mellitus.

Calcium Channel Blockers (e.g., Amlodipine)

• Mechanism of Action: Blocks calcium channels in the heart and myocardium, reducing contractility.
• Side effects: Dizziness, headache, nausea, palpitations, rash, vomiting, diarrhea, constipation, headache, dizziness, gastrointestinal disorders, and vision disorders including dyspnea.
• Precautions and Contraindications: Cardiogenic shock, significant aortic valve disease, unstable angina (chest pain), hepatic and renal impairment. Dosage may need reducing if half-life is prolonged.
• Pharmacokinetics:
  • Administration: Oral
  • Bioavailability: ~60%
  • Half-life: 30-50 hours
  • Metabolism: Liver (CYP450) and renal elimination
  • Renal impact: Poor renal function does not significantly reduce renal elimination.

Calcium Channel Blocker Mechanism of Action (Detailed)

• Mechanism: Causes vascular smooth muscle relaxation. Nitric oxide (NO) is broken down by guanylyl cyclase, producing cGMP, which activates myosin light chain phosphatase. This converts myosin light chain (MLC) to the unphosphorylated state, causing relaxation.

Thiazide-Like Diuretics (e.g., Indapamide):

• Mechanism of Action: Inhibits the Na+/Cl- symporter in the distal convoluted tubule, reducing sodium reabsorption.
• Side effects: Constipation, electrolyte imbalance, headache, postural disorders; a caution exists concerning hypokalaemia in cardiovascular conditions, and in those taking cardiac glycosides. Additional concerns are hypersensitivity and skin reactions, especially in the elderly.
• Precautions: Hypokalaemia is a concern, especially in patients with severe cardiovascular disease and those using cardiac glycosides.

Indapamide Pharmacokinetics:

• Administration: Oral
• Duration of Action: 12-24 hours (acting more quickly the earlier in the day that it is administered)
• Bioavailability: ~75%
• Other Considerations: High doses show more changes in Na+, K+, uric acid, glucose, and lipids compared to low-dose treatment; dosing should be carefully considered in patients with gout, diabetes, hyperaldosteronism, malnourishment, nephrotic syndrome, or a history of sulphonamide hypersensitivity. It is less effective with low renal function and can cause acute polyuria.

Resistant Hypertension Treatments:

• Drugs: Spironolactone, Alpha Blockers, Beta Blockers