Hypertension and Its Mechanisms PDF

# Hypertension and Its Mechanisms ## Understanding Hypertension * Normal systolic BP is: <120mmHg * Normal diastolic BP is: <90mmHg * Any increase above this level is considered as hypertension. ## Causes of Hypertension * Unknown (primary 90%) * Systemic disorders (secondary 10%). ## Occurrence...

# Hypertension and Its Mechanisms ## Understanding Hypertension * Normal systolic BP is: <120mmHg * Normal diastolic BP is: <90mmHg * Any increase above this level is considered as hypertension. ## Causes of Hypertension * Unknown (primary 90%) * Systemic disorders (secondary 10%). ## Occurrence of Hypertension * Due to increase in peripheral vascular arteriolar S.Ms tone, which leads to increase in arteriolar resistance and reduced capacitance of the venous system. ## Classifications of Hypertension * Normal: Systolic <120 & Diastolic < 80 * Elevated: 120-129 & <80 * Stage1: 130-139 & 80-89 * Stage2: >140 & >90. ## Mechanisms for Controlling BP * Arterial BP is *directly* proportional to COP and peripheral vascular resistance. * They are controlled mainly by two mechanisms: * Baroreflexes * Renin angiotensin aldosterone system. ### I-Baroreceptors and the S.N.S * Baroreflexes act by changing the activity of the S.N.S and the PS.N.S having receptors (baroreceptors) in the aortic arch and carotid sinuses to send fewer impulses to cardiovascular centers in the spinal cord. ### II- Renin angiotensin aldosterone system * Kidneys provide long-term control of blood pressure by altering the blood volume. * Baroreceptors in Kidneys respond to reduced arterial pressure (and to the sympathetic stimulation of beta 1 adrenoceptors) by releasing the enzyme renin. * Low Na+ intake and high loss-> increase renin release. * Renin converts angiotensinogen to angiotensin 1 which converts by (ACE) to angiotensin 2 (mediated by AT1 receptor) which is a potent vasoconstrictor-> constricting both arteriols and veins-> high BP. ## Treatment strategies * Patients with systolic BP less than 130mmHg and diastolic BP less than 80mmHg it is recommended to start with Thiazide diuretics, ACEIs, ARBs, Ca channels blocker. ## Combined Therapy for Severe Hypertension * Patients with systolic BP greater than the goal by 20+ mmHg and diastolic greater than the goal by 10+mmHg should get combined therapy. ## Diuretics * Diuretics work by decreasing blood volume, leading to decreased BP. * Types of Diuretics: * Thiazide diuretics: * Hydrochlorothiazide * Chlorthalidone * Metolazone * They decrease BP by increasing sodium and water excretion, leading to a decrease in cardiac output and renal outflow. * Thiazide diuretics are not effective in patients with impaired kidney function, EXCEPT _Metolazone_. * Loop diuretics can be effective in these individuals. * **Loop diuretics:** * Torsemide * Bumetanide * Ethacrynic acid * They block sodium and chloride reabsorption in the kidneys (even in impaired kidneys). * They decrease renal vascular resistance and increase renal blood flow. * **Key difference** * They increase calcium content in urine opposite to Thiazide diuretics, it is rarely used as monotherapy for hypertension (used more in managing HF and edema symptoms) * **Potassium sparing diuretics** * Amiloride, * Triamterene, * Are inhibitors of epithelial sodium transport at the late distal and collecting ducts * Spironolactone, * Elepernone, * Are aldosterone receptors antagonists, * All these agents reduce potassium loss in urine, This type of diuretics is sometimes mixed with previous two to reduce potassium loss. ## Beta Blockers * **Definition and Usage of Beta Blockers** * Beta blockers are the treatment option for hypertensive patients with heart disease and HF. * **Actions of Beta Blockers** * Beta blockers reduce BP by decreasing COP, decreasing Sympathitic CNS stimulation as well as Inhibiting renin release, which leads to decreased formation of angiotensin 2 and secretion of aldosterone. * **Prototype and Types of Beta Blockers** * The prototype of beta blockers is *Propranolol*, which is a nonselective blocker. * *Metoprolol* and *Atenolol* are selective beta1 blockers. * *Nebivolol* can increase nitric oxide production, which leads to vasodilation. * **Usage of Beta Blockers** * Beta blockers should be used with *caution* in patients with acute HF or peripheral vascular disease. * Beta blockers are used in hypertension with other heart diseases such as supraventricular tachyarrhythmia (e.g. atrial fibrillation), MI, stable ischimic heart, and chronic HF. * **Conditions that discourage the usage** * asthma * second, third degree heart block * severe peripheral vascular disease * **Kinetics** * *Propranolol* extensively first pass metabolized * oral form may take several weeks to develop their effects * *Propranolol*, *Esmolol*, *metoprolol* are available in I.V. * **Adverse effects** * decrease libido and sexual dysfunction * nonselective blockers may disturb lipid metabolism-> decreasing HDL, cholesterol and increasing triglycerides * **Drug withdrawal** * sudden withdrawal may induce severe hypertension, angina, MI, and even sudden death in ischemic heart disease * it should be withdrawal gradually with hypertension and ischemic heart disease ## ACE Inhibitors * **Definition and examples of ACE inhibitors** * ACE inhibitors are a class of medications used to treat high blood pressure and heart failure. * Examples of ACE inhibitors include * *Captopril*, * *Enalapril*, * *Lisinopril*. * **Recommendation for use in hypertension** * ACE inhibitors are recommended as the first line of treatment in hypertension with high coronary disease risk or history of diabetes, stroke, heart failure, myocardial infarction, or chronic kidney disease. * **Mechanism of action** * ACE inhibitors **block the angiotensin-converting enzyme (ACE)**, which converts angiotensin I to angiotensin II, a potent vasoconstrictor. * By blocking ACE, ACE inhibitors reduce peripheral vascular resistance without reflexively increasing cardiac output, leading to a decrease in blood pressure. * ACE inhibitors also **stop the breakdown down bradykinin**, which increases the production of nitric oxide and prostacyclin, both of which are potent vasodilators. * Additionally, ACE inhibitors **decrease aldosterone secretion**, leading to a decrease in sodium and water retention. * Overall, ACE inhibitors **decrease both preload and afterload**, resulting in a decrease in cardiac output. * **Usage of ACE inhibitors** * ACE inhibitors are used as the first line of treatment in systolic dysfunction, heart failure, and hypertension with chronic kidney disease and increased risk of coronary artery disease. * Also used in diabetic nephropathy by (slowing the progression and decrease albuminuria), decreasing intraglomerular pressure (increasing renal function), chronic treatment with ACEI leading to sustained BP reduction, regression of left ventricle hypertrophy, prevention of ventricular remodel after MI * **Kinetics of ACE Inhibitors** * They are well absorbed orally BUT * *Captopril* and *Lisinopril* undergo hepatic conversion to active metabolites (preferred in patients with severe hepatic impairment) * *Fosinopril* is the only ACEI that is not primarily eliminated by the kidneys * *Enalaprilat* is the only drug in this class available intravenously * **Adverse Effects of ACE Inhibitors** * Cough * Angioedema (rare but life threatening) * Potassium levels must be monitored (risk of Hyperkalemia) * Serum creatinine level should be monitored (especially in renal patients) increase above 30% of the baseline is acceptable * ACEI are PROHIBITED in pregnancy ## Angiotensin 2 receptor blockers (ARBs) * *Losartan* * *Irbesartan* * Block the AT1 receptor leading to decrease angiotensin 2 activity * Their mechanism of action is similar to ACEI (arteriolar and venous dilation, block aldosterone secretion...) * BUT they do not increase bradykinin levels * They have lower risk of cough and angioedema * They still have teratogenic effects * ARBs should NOT be combined with ACEI. ## Renin inhibitor * A selective renin inhibitor _Aliskiren_ directly inhibits renin so it is faster than ACEI and ARBS ## Calcium Channel Blockers * **Types of Calcium Channel Blockers** * Calcium channel blockers (nigros first line): * Classes of calcium channel blockers (3): * **Diphenylalkylamines (Verapamil)** * Work on both cardiac and smooth muscle cells * Used in hypertension, angina, supraventricular tachyarrhythmia and preventing migraine and clusters of headaches * **Benzothiazepines (Diltiazem)** * Same as *Verapamil* with lower negative inotropic effect and lower adverse effects * **Dihydropyridines** * *Nifedipine* (prototype) * *Almodipine* * *Felodipine* * *Isradipine* * *Nicardipine* * *Nisoldipine* * They have higher affinity for vascular calcium channels than in the heart which makes it preferable in hypertension * It has low interaction with digoxin or warfarin * **Action of CCBS** * They block the inward movement of calcium by binding to L-type calcium channels in the heart and in the smooth muscle of the coronary and peripheral arteriolar vasculature leading to arteriols dilation * CCBs do NOT dilate veins * **Uses of Calcium Channel Blockers** * Hypertension management may be used initial therapy or add-on * ALL CCBs are useful in angina. * *Diltiazem* and *Verapamil* are used in atrial fibrillation. * **Kinetics of Calcium Channel Blockers** * Most of them have a short half-life (3-8 hours), so there are sustained-releasing pills (once-daily dosing). * *Amlodipine* has a very long half-life and does not require a sustained-release formulation. * **Adverse Effects of Calcium Channel Blockers** * First-degree atrioventricular block and constipation are common dose-dependent *Verapamil* side effects. * *Verapamil* and *Diltiazem* must be avoided in patients with HF or atrioventricular block due to their negative inotropic (force of cardiac muscle contraction) and dromotropic (velocity of conduction) effects. * Dizziness, headache, and fatigue (due to decreased BP) and peripheral edema are more frequent with Dihydropyridines. * *Nifedipine* may cause gingival hyperplasia. ## Alpha Blockers * *Prazosin* * *Doxazosin* * *Terazosin* * These drugs block alpha1 receptor leading to decrease in the peripheral vascular resistance and lower arterial BP by causing relaxation for both arterial and venous smooth muscle * They have low effect on COP, renal blood flow and glomerular filtration rate * No long tachycardia but salt and water retention occur * By initiating the therapy Postural hypotension, reflex tachycardia occurs this class of drugs is commonly used in prostatic hyperplasia ## Alpha and Beta Blockers * *Labetalol* (Management of Gestational hypertension and hypertension emergency) * *Carvedilol*(HF and hypertension treatment) * Both of them block alpha1 and beta 1,2 receptors ## Central acting adrenergic drugs(2): * **Clonidine** * Clonidine: Centrally as an alpha 2 agonist-> Inhibiting sympathetic vasomotor centers and decreasing its outflow to the periphery. * Clonidine is used in hypertension when combination is not effective. * Clonidine does not affect renal function, well absorbed orally and excreted by kidneys. * **Adverse effects of Clonidine** * Sedation * Dry mouth and constipation * Rebound hypertension occurs if the drug withdrawal suddenly * **Methyldopa** * Methyldopa: Is an alpha2 agonist converted into methylnorepinephrine centrally to diminish adrenergic outflow from the CNS. * **Adverse effects of Methyldopa** * Sedation * drowsiness * **Usage of Methyldopa** * Its usage was limited duo to its adverse effects but it is used in hypertension pregnant women due to its SAFETY. ## Vasodilators definition and Mechanism of Action * Vasodilators are drugs that work directly on relaxing smooth muscles. * They are not primarily used to treat hypertension by their mechanism of action. * They decrease peripheral resistance and therefore blood pressure. * These drugs produce reflex stimulation of the heart resulting in the competing reflexes of increased myocardial contractility, heart rate, and oxygen consumption prompting angina pectoris, myocardial infarction, and heart failure. * **Adverse Effects:** * Vasodilators also increase plasma renin concentration, leading to sodium and water retention. * These adverse effects can be avoided by adding diuretics (decrease sodium retention) and beta-blockers (balance tachycardia reflex). * This combination of three leads to a decrease in cardiac output, plasma volume, and peripheral vascular resistance. ## Hydralazine * Hydralazine is accepted for controlling blood pressure in pregnancy-induced hypertension. * Hydralazine adverse effects include tachycardia, nausea, sweating, arrhythmia, and angina. * Lupus-like syndrome can occur in high dosage, but it is reversible when the drug is stopped. ## Minoxidil * Minoxidil causes hypertrichosis (growth of body hair) used to treat male pattern baldness. ## Hypertensive Urgency & Emergency * Increase in BP (systolic above 180 & diastolic above 120 mmHg) is considered a life threatening situation * Severe increases in BP with evidence of impending or progressive organ damage (e.g. stroke, MI) is considered as emergency and should be hospitalised and admitted to hospital and BP should be reduced by I.V treatment some drugs that are used * CCBs (Nicardipine and Clevidipine), * Nitric oxide vasodilators (Nitropris-side and Nitroglycerin), * Adrenergic receptor antagonists (phentolamine, esmolol and labetalol), * Vasodilators (Hydralazine and Fenoldopam) * Treatment is directed by the type of target organ damage * without any evidence of organ damage it is considered as urgencyу. ## Resistance hypertension * BP that remains above the goal despite medications it can be due to many reasons e.g. poor compliance, exccecive ethanol intake, diabetes, obesity.....).