Antihypertensive Drugs Pharmacology–I PHL-313 Antihypertensive Drugs Dr. Hassan A. Madkhali Assistant Professor Department of Pharmacology E mail: h.madkhali@psau.edu.sa 1

Introduction

Hypertension overview Can be define as a persistent diastolic blood pressure greater than 90 mm Hg and systolic pressure greater than 140 mm Hg. Asymptomatic; silent killer. A specific cause of hypertension can be established in only 10–15% of patients. A) Essential or primary hypertension B) Secondary hypertension. The disability-adjusted life year (DALY) is a measure of overall disease burden, expressed as the number of years lost due to ill-health, disability or early death. SBP: systolic blood pressure DBP: diastolic blood pressure When the left ventricle ejects blood into the aorta, the aortic pressure rises. The maximal aortic pressure following ejection is termed the systolic blood pressure (SBP) As the left ventricle is relaxing and refilling, the pressure in the aorta falls. The lowest pressure in the aorta, which occurs just before the ventricle ejects blood into the aorta, is termed the diastolic blood pressure (DBP) A specific cause of hypertension can be established in only 10–15% of patients. Patients in whom no specific cause of hypertension can be found are said to have essential or primary hypertension . Patients with a specific etiology are said to have secondary hypertension. It is important to consider specific causes in each case, however, because some of them are amenable to definitive surgical treatment: renal artery constriction, coarctation of the aorta, pheochromocytoma, Cushing’s disease, and primary aldosteronism. Pheochromocytoma: a small vascular tumor of the adrenal medulla, causing irregular secretion of epinephrine and norepinephrine, leading to attacks of raised blood pressure, palpitations, and headache. Cushing's disease is a serious condition of an excess of the steroid hormone cortisol in the blood level caused by a pituitary tumor secreting adrenocorticotropic hormone (ACTH). ACTH is a hormone produced by the normal pituitary gland. ACTH stimulates the adrenal glands (located on top of the kidneys) to produce cortisol, commonly referred to as the stress hormone. Both cardiac output and peripheral resistance have been reported to be elevated in Cushing’s syndrome Primary aldosteronism, also known as primary hyperaldosteronism or Conn's syndrome, is excess production of the hormone aldosterone by the adrenal glands resulting in low renin levels. Often it produces few symptoms. Most people have high blood pressure which may cause poor vision or headaches. Secondary to: renal artery constriction, coarctation of the aorta, pheochromocytoma, Cushing’s disease, and primary aldosteronism.

Hypertension Individuals Hypertension Prevalence in Saudi Arabia Hypertension is the most common cardiovascular disease. The fourth‐ranked risk factor for disability‐adjusted life years (DALYs) in the Kingdom of Saudi Arabia in 2010. In males > Females In Obese > Non-obese In Diabetic > Non-diabetic Increase with age. Varies by regions of Saudi Arabia. 90% diagnosed with primary hypertension whereas 10% with Secondary hypertension. Uncontrolled & sustained arterial hypertension damages blood vessels in kidney, heart, and brain, and ultimately might leads to an increased incidence of renal failure, coronary disease, cardiac failure, and stroke. Hypertension Individuals Prevalence (%) Males 17.7% Females 12.5% Aged 65 or older 65.2% Obese 26.4% Non-Obese 10.2% Diabetic 38.9% Non-Diabetic 11.9% The disability-adjusted life year (DALY) is a measure of overall disease burden, expressed as the number of years lost due to ill-health, disability or early death. Source: Hypertension at a glance

Hypertension Complications Heart diseases Myocardial infarction (MI) Heart failure Angina pectoris Kidney disease Stroke

Regulation of Blood Pressure (BP) BP is controlled mainly by CO, HR, SV, & peripheral resistance (PR), in which an increase in any of these can result in an increased BP. Sympathoadrenal activity (adrenal medulla and sympathetic nervous system activity) increases BP by arteriole vasoconstriction & increased CO. Kidney plays role in BP by regulating blood volume & thus stroke volume

Regulation of Blood Pressure (BP) BP= CO X PR Increase BP (hypertension)= increase CO X increase PR -SV x HR -EDV -Contractility -Blood viscosity -Vessels diameter (arteriolar)

Summary of the regulation of CO, HR and SV Note: CO= SV x HR

BP regulation by Baroreceptor, Symp/Parasymp pathways Barorecptor reflex control of BP Video: https://www.youtube.com/watch?v=G2nLL_O_U7w

Treatment of Hypertension

Sites of action of the major classes of antihypertensive drugs I. Diuretics: bumetanide, furosemide, hydrochlorothiazide, spironolactone, triamterene II. Sympathoplegic agents: methodopa, clonidine, guanfacine, thrimethaphan, guanethidine, propranolol, reserpine, methoprolol, nadolol, carteolol, pindolol, labetalol, prazosin III. Direct vasodilators: hydralazine, minoxidil, sodium nitroprusside, diazoxide IV. ACE inhibitors and angiotensin receptor antagonists: captopril, enalapril, benazepril, quinapril, losartan, valsartan, saralasin

Diuretic Mechanism of action Water follows Na+ PCT reabsorbs 65 % of filtered Na, 20-25% of all Na is reabsorbed in the loop of Henle, 5-10% in distal convoluted tubule (DCT) & 3% in collecting ducts If it can not be absorbed it is excreted with the urine Diuretics act on the kidney to enhance sodium and water excretion  urine output by the kidney (i.e., promote diuresis)  blood volume preload Reducing blood volume not only reduces central venous pressure, but even more importantly, reduces cardiac output Side Effects: electrolyte losses [Na+ (hyponatremia) & K+ (hypokalemia)], fluid losses [dehydration], myalgia, N/V/D, Dizziness, hyperglycemia, hyperlipidemia, hypercalcemia Example: Thiazides: Chlorothiazide (Diuril®) & Hydrochlorothiazide (HydroDIURIL®) Loop Diuretics: Furosemide (Lasix®), bumetanide (Bumex®) Potassium Sparing Diuretics: Spironolactone (Aldactone®)

ACE inhibitors Mechanism of action. Therapeutic uses: Dilate arteries and veins by blocking formation of angiotensin II (AII, a vasoconstrictor)  vasodilatation, thus reduces arterial pressure, preload and afterload on the heart Promote renal excretion of sodium and water. This reduces blood volume, venous pressure and arterial pressure Therapeutic uses: Hypertension Heart failure Myocardial infarction (MI) Diabetic and nondiabetic nephropathy Adverse effects: Dry cough*, Angioedema, Hyperkalemia, Renal failure, Neutropenia, rashes, hypotension Contraindications: Pregnancy - renal failure in infants, renal impairment. Examples: Captopril (Capoten®), Enalapril (Vasotec®), Lisinopril (Prinivil® & Zestril®), Quinapril (Accupril®), Ramipril (Altace®), Benazepril (Lotensin®), Fosinopril (Monopril®) This is accomplished by altering how the kidney handles sodium. If the kidney excretes more sodium, then water excretion will also increase. Most diuretics produce diuresis by inhibiting the re-absorption of sodium at different segments of the renal tubular system.

Angiotensin Receptor Blockers (ARBs) Mechanism of action: ARBs are receptor antagonists that block type 1 angiotensin II receptors on blood vessels and other tissues such as the heart Cause dilation of arterioles and veins Decrease release of aldosterone Increase renal excretion of sodium and water Reduce excretion of potassium These drugs have similar effects to ACE inhibitors Can be used in certain conditions when ACEIs are contraindicated (angioneurotic edema, cough) Therapeutic uses: Hypertension, Heart failure, Diabetic nephropathy, Myocardial infarction, Stroke prevention, Migraine headache Adverse effects: Angioedema, Fetal harm, Renal failure Examples: Losartan (Cozaar), Valsartan (Diovan), Irbesartan, Candesartan, Telmisartan, Olmesartan This is accomplished by altering how the kidney handles sodium. If the kidney excretes more sodium, then water excretion will also increase. Most diuretics produce diuresis by inhibiting the re-absorption of sodium at different segments of the renal tubular system.

Example: Aliskiren (first-in-class oral renin inhibitor) Renin Inhibitors Mechanism of action: Renin inhibitors produce vasodilation by inhibiting the activity of renin, which is responsible for stimulating angiotensin II formation These drugs have similar effects to ACE inhibitors and ARBs and are used for the same indications (hypertension, heart failure) Example: Aliskiren (first-in-class oral renin inhibitor)

Calcium Channel Blockers (CCBs) (cause vasodilation): Mechanism of action. These drugs bind to L-Type calcium channels located on the vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue (sinoatrial and atrioventricular nodes). These channels are responsible for regulating the influx of calcium into muscle cells, which in turn stimulates smooth muscle contraction and cardiac myocyte contraction. Therefore, by blocking calcium entry into the cell, CCBs cause vascular smooth muscle relaxation (vasodilatation), decreased myocardial force contarction, decreased heart rate, and decreased conduction velocity within the heart, particularly at the atrioventricular node. Therapeutic Uses: Angina pectoris, Tachycardia, Hypertension Side Effects: Cardiovascular: hypotension, palpitations & reflex tachycardia Gastrointestinal: constipation & nausea Other: rashes, facial flushing & peripheral edema Examples: diltiazem (Cardizem®), verapamil (Calan®, Isoptin®), nifedipine (Procardia®, Adalat®), Amlodipine (Norvasc), Felodipine (Renedil) Mechanism of action. Potassium-channel openers are drugs that activate (open) K+-channels in vascular smooth muscle. Opening these channels hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium. With less calcium available to combine with calmodulin, there is less activation of myosin light chain kinase and phosphorylation of myosin light chains. This leads to relaxation and vasodilation This promotes K+ efflux and the cell hyperpolarizes, thereby preventing voltage-operated Ca2+ channels (VOCs) from opening

Potassium Channel Openers (cause vasodilation): Mechanism of action. These are drugs that activate (open) ATP-sensitive K+-channels in vascular smooth muscle. Opening of these channels, hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium, leadings to muscle relaxation and vasodilatation, decreasing systemic vascular resistance and lowering blood pressure. Examples: Nicorandil, minoxidil sulphate [Loniten®] Mechanism of action. Potassium-channel openers are drugs that activate (open) K+-channels in vascular smooth muscle. Opening these channels hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium. With less calcium available to combine with calmodulin, there is less activation of myosin light chain kinase and phosphorylation of myosin light chains. This leads to relaxation and vasodilation This promotes K+ efflux and the cell hyperpolarizes, thereby preventing voltage-operated Ca2+ channels (VOCs) from opening

α1-Adrenoceptor Antagonists (α1-Blockers) Mechanism of action. These drugs block the effect of sympathetic nerves on blood vessels by binding to α-adrenoceptors located on the vascular smooth muscle. Most of these drugs acts as competitive antagonists to the binding of norepinephrine to the smooth muscle receptors α-blockers dilate both arteries and veins because both vessel types are innervated by sympathetic adrenergic nerves; however, the vasodilator effect is more pronounced in the arterial resistance vessels. Thus, they decrease systemic vascular resistance (SVR) and lower blood pressure (BP). Uses: Hypertension, Pheochromocytoma. Adverse effects: Drowsiness, excitation, headache, tachycardia, and dizziness. Examples: doxazosin (Cardura®), prazosin (Minipress®), terazosin (Hytrin®)

β-Blockers : Mechanism of action. β-blockers are drugs that bind to β-adrenoceptors and thereby block the binding of norepinephrine and epinephrine to these receptors. This inhibits normal sympathetic effects that act through these receptors. Thus, drugs decrease heart rate, conduction velocity and force of contraction The first generation of β-blockers were non-selective, meaning that they blocked both β1 and β2 adrenoceptors. Second generation b-blockers (β1-blockers) are more cardioselective in that they are relatively selective for β1 adrenoceptors. Uses: Hypertension, angina, prevent MI, tachyarrythmias. Adverse effects: Bronchospasm, sedation, reflex tachycardia, depression, and increased serum triglycerides. Examples: For non-selective β -blockers: Propranolol , carvedilol, Sotalol, timolol, For selective β1 blockers: Atenolol, Metoprolol β1 : Eye, Kidney, Heart, salivary glands β2 : Lung, blood vessels, GIT, liver, Mechanism of action. Potassium-channel openers are drugs that activate (open) K+-channels in vascular smooth muscle. Opening these channels hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium. With less calcium available to combine with calmodulin, there is less activation of myosin light chain kinase and phosphorylation of myosin light chains. This leads to relaxation and vasodilation This promotes K+ efflux and the cell hyperpolarizes, thereby preventing voltage-operated Ca2+ channels (VOCs) from opening

α2-Agonists (Centrally Acting Sympatholytics) Mechanism of action. Centrally acting sympatholytics block sympathetic activity by binding to and activating α2-adrenoceptors  inhibition of NE release. This reduces sympathetic outflow to the heart thereby decreasing cardiac output by decreasing heart rate and contractility Reduced sympathetic output to the blood vessels decreases sympathetic vascular tone, which causes vasodilatation and reduced systemic vascular resistance, which decreases arterial pressure Therapeutic Uses: Hypertension. Migraine prophylaxis, Adverse Effects: depression Examples: Clonidine (Catapress®), Methylopa (Aldomet®)

Peripheral Vasodilators Nitrovasodilators NO release Activate guanylyl cyclase and ↑cGMP ↓Intracellular calcium Smooth muscle relaxation Vasodilation Preload and afterload reduction Improved cardiac function

Hydralazine (Apresoline®): Reflex tachycardia, postural hypotension Mechanism of action Directly relaxes arteriole smooth muscle Decrease systemic vascular resistance (SVR) = decrease afterload Therapeutic Uses Hypertension Angina pectoris Heart failure Myocardial infarction Peripheral vascular disease Side effects: Hydralazine (Apresoline®): Reflex tachycardia, postural hypotension Sodium nitroprusside (Nipride®): Cyanide toxicity in renal failure, CNS toxicity = agitation, hallucinations, etc. Example: Hydralazine [Apresoline®] Sodium Nitroprusside [Nipride®] Diazoxide [Hyperstat®]

Renin-Angiotensin-Aldosterone system antagonists

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Types and Names of Diuretics Example Sites of Action Osmotic agents Mannitol PCT Descending loop Collecting duct Carbonic anhydrase inhibitors. Acetazolamide Thiazides Hydrochlorothiazide DCT Loop diuretic Ethacrynic acid Furosemide Loop of Henle K+ - sparing Spironolactone Amiloride Collecting tubule