HTN and Anti-hypertensive medications - Part 1 (PDF)

Pharmacology I (PLC 301) Hypertension & Antihypertensive Medications Part 1 Dr. Ghada Osama 07/10/2024 Intended learning outcomes (ILOs): 1- Define Hypertension and mention the homeostatic regulation of BP. 2- Identify the Etio...

Pharmacology I (PLC 301) Hypertension & Antihypertensive Medications Part 1 Dr. Ghada Osama 07/10/2024 Intended learning outcomes (ILOs): 1- Define Hypertension and mention the homeostatic regulation of BP. 2- Identify the Etiology, clinical picture, diagnosis, and complications of HTN. 3- Illustrate the classification system of HTN. 4- Distinguish the non-pharmacological options for HTN management 5- Characterize the different Pharmacological classes of antihypertensive medications regarding the mechanism of action and side effects. Definition of Hypertension HTN is one of the leading causes of the global burden of disease. HTN is a persistent, non- physiologic elevation of blood pressure (BP). There is no clear-cut BP threshold separating normal from high BP, but it is arbitrarily defined as a systolic blood pressure equal to or greater than 130 mmHg and/or diastolic blood pressure equal to or greater than 80 mmHg. Normal Control of Blood pressure (BP): BP means the force exerted by the blood against the vessel wall. Blood pressure is dependent on: 1- Blood volume and viscosity 2- Cardiac output 3- Peripheral vascular resistance Mean arterial B.P (MABP) = cardiac output x peripheral vascular resistance = (CO x PVR). CO= (stroke volume X heart rate) = (SV X HR) MABP= (SV X HR X PVR) Altering any of the factors on the right side of the blood pressure equation results in a change in blood pressure. 1 Dr. Ghada Osama 07/10/2024  Homeostatic regulation of blood pressure 1. Sympathetic nervous system: Baroreceptors (pressure receptors) in the carotids and aortic arch respond to changes in blood pressure. Responsible for minute-to-minute changes in BP. DECREASE IN B.P ✓ Increase in HR and CO ✓ Increase in PVR MABP= CO X PVR ✓ Increase in the BP Peripheral vessels 2.Renin–angiotensin–aldosterone system (RAAS): A decrease in the B.P results in sympathetic stimulation and a decrease in the blood supply to the kidney stimulates the release of renin by the kidney (juxtaglomerular apparatus of the kidney). RAAS is responsible for the long-term control of BP. Angiotensin II has several important functions in the regulation of B.P: a. It is considered a potent vasoconstrictor agent that causes vasoconstriction of resistance vessels, which increases peripheral vascular resistance and arterial pressure. b. It stimulates the release of aldosterone from the adrenal gland, which results in increased sodium reabsorption, fluid volume, and blood pressure. 2 Dr. Ghada Osama 07/10/2024  Etiology 1- Primary hypertension (Essential hypertension): In 90–95% of cases of hypertension, there is no underlying medical illness to cause high blood pressure or in other words of unknown cause. Environmental factors include excess intake of salt, obesity, and a sedentary lifestyle. Some genetically related factors: inappropriately high activity of the renin- angiotensin-aldosterone system and the sympathetic nervous system and susceptibility to the effects of dietary salt on blood pressure. Another common cause of hypertension is the stiffening of the aorta with increasing age. This causes hypertension referred to as isolated or predominant systolic hypertension (ISH) characterized by high systolic pressures (often with normal diastolic pressures), which are found primarily in elderly people. 3 Dr. Ghada Osama 07/10/2024 2- Secondary hypertension: In 5-10% of the cases of hypertension, there is an underlying medical illness to cause high BP. a. Renal diseases. b. Endocrine diseases: ✓ Hyperaldosteronism (Conn’s syndrome). ✓ Hyperglucocorticoidism (Cushing’s syndrome). ✓ Growth hormone excess: acromegaly. ✓ Phaeochromocytoma. c. Drugs such as: ✓ Oral contraceptive pills, non-steroidal anti-inflammatory drugs NSAIDs, and Steroids. Clinical presentation: Hypertension is asymptomatic in most cases (the silent killer) and severe cases may present with occipital headache, visual disturbances, or evidence of target organ damage (including stroke, ischemic heart disease, renal failure, or retinopathy). Benefits of lowering BP: 1. Decreasing the risk of stroke by 40%. 2. Decreasing the risk of Myocardial Infarction (MI) by 25%. 3. Decreasing the risk of Heart Failure (HF) by 50%. Complications of untreated HTN: Untreated systemic hypertension, regardless of cause, results in inflammation and necrosis of the arterioles, narrowing of the blood vessels, and restriction of the blood flow to major body organs. When blood flow is severely compromised, target-organ damage ensues. The risk of complications doubles for each 20 mm Hg increase in SBP or 10 mm Hg in DBP. The most common complications include: Left ventricular hypertrophy (LVH) and Heart Failure (HF) Coronary artery disease (CAD) (Angina Pectoris and Myocardial Infarction) Cerebrovascular stroke Renal Failure Peripheral arterial disease (PAD) Retinal damage 4 Dr. Ghada Osama 07/10/2024  Non-pharmacological Management Recommended Lifestyle modifications Modification Recommendation Approximate SBP Reduction Weight reduction Maintain a normal body weight (BMI 5–20 mm Hg per 18.5–24.9 kg/m2) 10-kg weight loss Adopt a DASH eating plan Consume a diet rich in fruits, 8–14 mm Hg (includes substantial K vegetables, and low-fat dairy intake) products with a reduced content of saturated and total fat Reduce Na intake Reduce Na intake to < 1500 mg/day 2–8 mm Hg Reducing Na intake by at least 1000 mg/day will lower BP if desired daily Na intake goal is not achieved Physical activity Engage in regular aerobic physical 4–9 mm Hg activity such as brisk walking (at least 30 min/day most days of the week) BMI = body mass index; BP = blood pressure; DASH = Dietary Approaches to Stop Hypertension; Na = sodium; SBP = systolic blood pressure. Classification of hypertension BP categories Guidelines SBP DBP (mm Hg) BP target (mmHg) ACC/AHA Normal < 120 And < 80 ≤ 130/80 mm (2017) Hg Elevated 120–129 And < 80 Stage 1 130–139 Or 80–89 hypertension Stage 2 ≥ 140 Or ≥ 90 hypertension Hypertensive >180 Or >120 urgency/ emergency ACC/AHA: American College of Cardiology/American Heart Association 5 Dr. Ghada Osama 07/10/2024  Pharmacological Classes of Antihypertensive medications 1. Angiotensin-converting 2. Angiotensin receptor enzyme inhibitors (ACE blockers (ARBs) inhibitors) 3. Renin Inhibitors 4. β Blockers 5. α 1 receptor blocker 6. α- β Receptor Blocker 7. Calcium Channel Blockers 8. Vasodilators (CCBs) 9. Centrally acting adrenergic 10. Diuretics agents 1- Angiotensin-converting enzyme inhibitors (ACE inhibitors) Examples: Captopril, Enalapril, Lisinopril, Ramipril, Benazepril Mechanism of action: ACE enzyme is responsible for the cleavage of angiotensin I to form potent vasoconstrictor angiotensin II. Also, ACE is responsible for the cleavage of bradykinin which increases the production of nitric oxide and prostacyclin (vasodilators of blood vessels). ACE inhibitors decrease angiotensin II and increase bradykinin levels. Vasodilatation of both arterioles and veins occurs as a result of decreased vasoconstriction and enhanced vasodilatation. By decreasing the angiotensin II, aldosterone secretion decreases, reducing sodium and water retention. Advantages of ACE inhibitors as an antihypertensive class: ✓ Vasodilation of arteries and veins thus reducing both pre and after-loads. ✓ Do not cause reflex tachycardia as they decrease adrenergic activity. ✓ No fluid retention due to inhibiting aldosterone. ✓ Decrease in Left ventricular hypertrophy (LVH). 6 Dr. Ghada Osama 07/10/2024 ✓ Decrease in intra-glomerular capillary pressure with improvement in renal blood flow. ✓ Effective in diabetic nephropathy: Since they dilate efferent renal arterioles more than afferent, Slow the Progression of Diabetic Nephropathy (Decrease Albuminuria). ✓ They have no adverse metabolic effects on blood glucose or lipid profile. Side effects: Generally, well tolerated. The main side effect is dry cough (most common in women), due to an increase in bradykinin, and resolves within a few days of discontinuation. Rash, Fever, Altered taste Hypotension Hyperkalemia (Monitor K closely, especially if renal impairment exists or another K- sparing drug or K supplement is used.) Angioedema is an uncommon but potentially severe complication due to an increase in bradykinin. Can induce fetal malformation so should not be used in pregnancy (especially in the 2nd & 3rd trimesters). They can increase serum creatinine by as much as 30% because they reduce intraglomerular pressure and filtration (reversible functional change that is not harmful). An even greater increase in serum creatinine can occur if combined with diuretics. Contraindications: Contraindicated in bilateral renal artery stenosis. 2- Angiotensin II receptor blockers (ARBs): Examples: Losartan, Valsartan, Irbesartan, Olmesartan, Candesartan Mechanism of action: They inhibit the action of angiotensin II by blocking the tissue-binding receptor sites (AT1 receptor blockers). They are used as alternatives to ACE inhibitors Side effects: like ACE inhibitors, except ARBs do not cause cough since they don’t inhibit bradykinin degradation and rarely cause angioedema. ACEIs & ARBs have established clinical outcome benefits in patients with heart failure, post-myocardial infarction, and diabetic and non-diabetic CKD. 7 Dr. Ghada Osama 07/10/2024  In general, ACEIs & ARBs are more effective as monotherapy in reducing blood pressure in white patients than in black patients, possibly because the RAAS is less responsive in blacks. However, they are equally effective in reducing blood pressure in all ethnic and racial groups when combined with either CCBs or diuretics. Do not combine ACEI with ARB; no added benefit, more side effects (hyperkalemia and affect kidney functions). 3- Renin inhibitor (Aliskiren): Mechanism of action: It directly inhibits renin thus it acts earlier in the RAAS than ACE inhibitors or ARB Side effects: Diarrhea at high doses Cough & angioedema but less often than ACE inhibitors. Contraindicated in combination with ACE inhibitors or ARBs because of increased risk of renal impairment, hyperkalemia, and hypotension It is contraindicated during pregnancy Metabolized by CYP 3A4 (drug interaction), Avoid use in combination with cyclosporine or itraconazole. 4- β- Blockers: 8 Dr. Ghada Osama 07/10/2024  β-Blockers inhibit the sympathetic activation of the heart with a resultant reduction in heart rate (negative chronotropic effect) and force of contraction (negative inotropic effect) thus, lowering cardiac output. They also decrease the release of renin from the kidney. Nonselective: Propranolol, Timolol. The prototype β-blocker is propranolol which acts at both β1 and β2 receptors. Nonselective β-blockers with intrinsic sympathomimetic activity (ISA): Pindolol, Acebutolol They lower blood pressure by decreasing vascular resistance and appear to depress cardiac output or heart rate less than other β blockers, perhaps because of significantly greater agonist than antagonist effects at β2 receptors. This may be particularly beneficial for patients with bradyarrhythmias or peripheral vascular disease. Selective β1: Metoprolol, Atenolol, Nebivolol They are the most widely used for HTN. Nebivolol is a selective blocker of β1 receptors, which also increases the production of nitric oxide, leading to vasodilation. Uses and recommendations: β-Blockers are a treatment option for hypertensive patients with concomitant heart disease such as supraventricular tachyarrhythmia (for example, atrial fibrillation), ischemic heart disease (angina pectoris, myocardial infarction) or heart failure. It may take several weeks to give their full effect Always start at a low dose and increase gradually to the optimum dose over few weeks Side effects & precautions: Side effects are more prominent with the non-selective β-blockers Bradycardia, heart block in susceptible patients Hypotension Caution with asthma or severe chronic obstructive pulmonary disease (especially higher doses) because of the pulmonary β2-receptor blockade, especially with nonselective β- blockers or high-dose selective β-blockers. Erectile dysfunction and decreased libido. 9 Dr. Ghada Osama 07/10/2024  Non-cardio selective β-blockers may disturb lipid metabolism (decrease HDL and increase TG). β-Blocker therapy should be used with caution in patients with the following conditions: (i) Diabetes mellitus: Greater risk of developing DM than with an ACE inhibitor, ARB, and CCB; use caution in patients at high risk of DM (e.g., family history, obesity). β- Blockers can mask hypoglycemic symptoms, such as tachycardia and tremors. (ii) Raynaud phenomenon or peripheral vascular disease: Vasoconstriction can occur and, in predisposed patients, might result in a clinically significant problem. (iii) Neurological disorders: Several B-blockers enter the central nervous system (CNS), potentiating related side effects (e.g., fatigue, lethargy, poor memory, insomnia, weakness, or mental depression) Abrupt discontinuations of a β-blocker in cardiac patients increases the risk for a withdrawal syndrome presented as: (i) exacerbated anginal attacks, (ii) myocardial infarction, (iii) life-threatening rebound hypertension, or (iv) sudden death. Therefore, these drugs must be tapered over 2-3 weeks in patients with hypertension and ischemic heart disease. References: 1- Katzung BG, Trevor AJ, editors. Basic & clinical pharmacology (13th edition). New York, NY: McGraw-Hill 2015 2- Goodman LS. Goodman and Gilman's the pharmacological basis of therapeutics (13th edition). New York: McGraw-Hill; 2018. 3- American College of Clinical Pharmacy updates on therapeutics 2021. 10 Dr. Ghada Osama 07/10/2024