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Chapter 22 Antihypertensive Drugs Hypertension Defined (JNC-8) Pharmacology Overview 7 main categories of drugs to treat HTN Adrenergic drugs (old friend) Angiotensin-converting enzyme (ACE) inhibitors Angiotensin II receptor blockers (ARBs) Calcium channel blockers (CCBs) Diuretics Vasodilators Direct renin inhibitors A. Adrenergic Drugs: 5 Subcategories and where they act A1. Adrenergic neuron blockers (central and peripheral)- we won’t talk about this A2. Alpha1 receptor blockers (peripheral) A3. Alpha2 receptor agonists (central) A4. Beta receptor blockers (peripheral) A5. Combined α and β receptor blockers (peripheral) A2. Peripherally Acting Adrenergic DrugAlpha1 Blockers (we’ve met these) Doxazosin, prazosin, alfuzosin Block alpha1-receptors which causes BP to decrease Reduces peripheral vascular resistance and BP by dilating both arterial and venous blood vessels Main Use: benign prostatic hyperplasia (BPH) Alpha1 Blockers REMEMBER Tamsulosin (Flomax)* is an α1 blocker BUT *Tamsulosin is not used to control BP, just for BPH. A3. Centrally Acting Adrenergic DrugsAlpha 2 agonist Clonidine and methyldopa 1- Stimulate alpha2-adrenergic receptors. in the brain Decreases sympathetic outflow from the CNS which decreases NE production 2. Stimulate alpha2-adrenergic receptors in kidneys remember alpha 2 opposes alpha 1 Dilates peripheral blood vessels → lowers peripheral resistance → Results in decreased BP So ….Clonidine (Catapres) Used primarily for its ability to decrease blood pressure in an urgent setting Also use in opioid withdrawal as previously discussed Oral (multiple times a day), and topical patch formulations Do not stop abruptly as it may lead to rebound hypertension In reality, Clonidine and methyldopa Not prescribed as first-line home antiHTN drugs High incidence of unwanted adverse effects: orthostatic hypotension, fatigue, and dizziness MIGHT be uses as adjunct drugs after other drugs have failed, in conjunction with other antiHTN such as diuretics A4. Adrenergic Drugs Selective Beta 1 Blockers Metoprolol, Atenolol Reduction of HR through β1 receptor blockade (remember adrenergic blocking of this receptor???) HR results in BP Cause reduced secretion of renin = BP A4. Adrenergic Drugs Selective Beta1 Blockers Nebivolol (Bystolic) Uses: hypertension and HF Action: blocks β1 receptors and produces vasodilatation, which results in a decrease in SVR High doses loses selectivity and blocks both β1 and β2 Less sexual dysfunction All BB- Do not stop abruptly; must be tapered over 1 to 2 weeks A4. Adrenergic Drugs NONSelective Beta Blockers Propranolol Acts equally on β1 and β2 Other uses include situational anxiety associated with public speaking, test taking As mentioned on previous slide, nebivolol at high doses becomes beta nonselective A5. Dual-Action Adrenergic Drugs α1 and β Receptor Blockers Dual antihypertensive effects of reduction in heart rate (beta1 receptor blockade) and vasodilation (alpha1 receptor blockade) Examples are carvedilol (common) and labetalol (not as common) A5. Dual-Action Adrenergic Drugs α1 and β Receptor Blockers Carvedilol (Coreg) Widely used drug that is well tolerated Uses: HTN, mild to moderate HF in conjunction with digoxin, diuretics, and ACE inhibitors Contraindications: severe bradycardia or unstable HF, bronchospastic conditions such as asthma, and various cardiac conduction problems Adrenergic Drugs Indications - HTN But also for Glaucoma (topical) BPH: doxazosin, prazosin, and terazosin (2 for 1) Management of severe HF when used with cardiac glycosides and diuretics Contraindications Acute HF- have to stabilize first MOAIs- yeah doesn’t everything interact with MAOIs? Peptic ulcers Severe liver/kidney disease Asthma (with beta blockers) Adrenergic Drugs: Adverse Effects Orthostatic hypotension 1st-dose syncope Rebound hypertension with abrupt discontinuation Most common: Dry mouth, drowsiness, constipation, sedation Interactions- always check for specific drug interactions Can cause additive CNS depression with alcohol, benzodiazepines, opioids Question #1 When administering an alpha-adrenergic drug for hypertension, it is most important for the nurse to assess the patient for the development of what response? Hypotension Hyperkalemia Oliguria Respiratory distress Answer A Hypotension This is a key point in patient education These drugs have strong vasodilating properties and may cause severe hypotension, especially at the beginning of therapy. B. Angiotensin-Converting Enzyme Inhibitorsaka ACE Inhibitors or ACEi Large group of safe and effective drugs Currently are 10 ACEi Often used as first-line drugs for HF and hypertension May be combined with a thiazide diuretic, loop diuretic, or Calcium Channel Blocker (CCB) You need to understand the basics ACE Inhibitors: Review RAAS ACE converts angiotensin I, formed through the action of renin, to angiotensin II Angiotensin 2 is a potent vasoconstrictor and also induces aldosterone secretion by the adrenal glands Aldosterone stimulates sodium resorption (H20 follows Na Both act to raise BP which causes kidneys to reduce renin production ACEi= Great drug to treat HTN BUT contraindicated in pregnancy (2nd,3rd trimester due to fetal renal damage) and breastfeeding first few weeks after birth B. ACE Inhibitors - PRIL Lisinopril (Prinivil) super common, often the 1st drug Enalapril (Vasotec) also common Captopril (Capoten) great if liver disease present Benazepril (Lotensin) Fosinopril (Monopril) Perindopril (Aceon) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik) Primary Effects of the ACE Inhibitors Prevent Na (and H2O) resorption by inhibiting aldosterone secretion (volume reduction) (GO BACK TO RAAS DIAGRAM) blood volume decreases work of the heart preload, or the left ventricular end-diastolic volume which is important in HF ACE SUMMARY OF ACTIVITY 1) Prevent vasoconstriction caused by angiotensin 2 (2) Prevent aldosterone secretion  less sodium and water resorption Cardioprotective Effects of ACEi They slow progression of left ventricular hypertrophy (ventricular remodeling) after MI so considered cardioprotective ACE inhibitors have been shown to decrease morbidity and mortality in patients with HF Renal Protective Effects of ACEi ACE inhibitors: reduce glomerular filtration pressure by volume reduction Cardiovascular drug of choice for patients with diabetes since it helps protect kidneys by reducing pressure. Sometimes used low dose for kidney protection with DM without HTN B. ACEi Enalapril (Vasotec) Only ACEi available in both oral and IV Enalapril IV does not require cardiac monitoring Oral enalapril: prodrug (metabolized in liver) Improves patient’s chances of survival after an MI Reduces the incidence of HF B. ACEi Captopril (Capoten) Uses: prevention of ventricular remodeling after MI; reduce the risk of HF after MI Shortest half-life Must be administered multiple times throughout the day so this limits its use Not a prodrug so good for patient with liver disease Question #2 A patient with diabetes has a new prescription for the ACE inhibitor lisinopril. She questions this order because her provider has never told her that she has hypertension. What is the best explanation for this order? The doctor knows best The patient is confused This medication has cardioprotective properties This medication has a protective effect on the kidneys for patients with diabetes Answer D ACE inhibitors have been shown to have a protective effect on the kidneys because they reduce glomerular filtration pressure. This property makes them the cardiovascular drug of choice for patients with diabetes. Question #3 A patient with a history of pancreatitis and cirrhosis is also being treated for hypertension. Which drug will most likely be ordered for this patient? Clonidine Prazosin Diltiazem Captopril Answer D Captopril Captopril is not a prodrug; therefore, it does not need to be metabolized by the liver to be effective. This is an advantage in patients with liver disease. ACE Inhibitors: Adverse Effects *Dry, nonproductive cough, which reverses when therapy is stopped. This is a class effect Dizziness- Note: First-dose hypotensive effect may occur Headache & Fatigue Possible hyperkalemia ** Angioedema: rare but potentially fatal Not safe in pregnancy-are contraindicated during the second and third trimesters of pregnancy because of increased risk of fetal renal damage C. Angiotensin II Receptor Blockers(ARB) Considered an alternative to ACEi Less likely to cause a dry cough and hyper K+ that is common with ACE inhibitors Angiotensin II Receptor Blockers: Mechanism of Action Go back to RAAS diagram! ARBs affect primarily 2 places 1. Vascular smooth muscle - blocks vasoconstriction 2. Adrenal gland -Selectively blocks the binding of Ang 2 to certain Ang 2 receptors inhibiting secretion of aldosterone Lowers volume retention and BP Angiotensin II Receptor Blockers -ARTAN Losartan (Cozaar)- very common Eprosartan (Teveten) Valsartan (Diovan) Irbesartan (Avapro) Candesartan (Atacand) Olmesartan (Benicar) Telmisartan (Micardis) Azilsartan (Edarbi) C. ARB Losartan (Cozaar) Beneficial in patients with HTN and HF Used with caution in patients with kidney or liver dysfunction and in patients with renal artery stenosis ***Not safe for breastfeeding women and should not be used in pregnancy (Cat C 1st trimester, Cat D 2nd-3rd trimester), potential fetal toxicity Appear to be equally effective for the treatment of hypertension and well tolerated ARBs less likely to cause cough and hyperK+ but can still happen Evidence that ARBs are associated with lower mortality after MI than ACE inhibitors Never take ACEi and ARBs at the same time* 5. Calcium Channel Blockers (CCB) Primary use: HTN, angina, some dysrhythmias Cause smooth muscle relaxation by blocking the binding of calcium to its receptors, preventing muscle contraction Results in: Relaxed blood vessels to the heart Decreased peripheral smooth muscle tone Decreased SVResistance Decreased BP E. Diuretics First-line antiHTN in JNC 8 guidelines Decreases fluid volume The results from diuresis: preload, Peripheral resistance Overall effect  Decreased workload of the heart and decreased BP Thiazide diuretics are the most commonly used diuretics for HTN Ie hydrochlorothiazide (HCTZ), chlorthalidone We will discuss diuretics further in the chapter on diuretics F. Vasodilators Directly relax arterial or venous smooth muscle (or both) Results in: Decreased SVR Decreased afterload Peripheral vasodilation Indicated for treatment of HTN May be used in combination with other drugs F. Vasodilators Hydralazine (Apresoline) Orally: routine cases of essential hypertension Injectable: hypertensive emergencies BiDil: specifically indicated as an adjunct for treatment of HF in African-American patients F. Vasodilators Sodium Nitroprusside (Nitropress) *Sodium nitroprusside and IV diazoxide are reserved for the management of hypertensive emergencies. Contraindications: severe HF, known inadequate cerebral perfusion (especially during neurosurgical procedures) F. Vasodilators Adverse Effects Hydralazine: dizziness, headache, tachycardia, edema, dyspnea, N/V/D, vitamin B6 deficiency, rash Sodium nitroprusside: hypotension, bradycardia, decreased platelet aggregation, rash G. Direct Renin Inhibitors Aliskirin (Tekturna) Blocks the RAS pathway at the point of activation. Inhibiting renin production prevents the downstream production of Ang II (potent vasoconstrictor) Adverse effects: N/V, severe hypotension, hyponatremia, hyperkalemia… Contraindicated in patients with DM taking ACEi or ARB Miscellaneous Antihypertensives Eplerenone (Inspra) Newer class of drugs called selective aldosterone blockers (remember RAAS?) Reduces BP by blocking the actions of aldosterone at its corresponding receptors in the kidney, heart, blood vessels, and brain Indications: routine treatment of hypertension and for post-MI HF Contraindicated if serum potassium levels are high (above 5.6 mEq/L) A Special Form of HTNTreatment of Pulmonary Hypertension Sildenafil and Tadalafil Commonly used for erectile dysfunction Used for pulmonary hypertension but with different trade names Sildenafil: Revatio* (Viagra for ED) Tadalafil: Adcirca* (Cialis for ED)

Continental Drift Theory. From the discussion of the rock cycle, it has been pointed out that through Earth's external and internal processes. Earth's surface is constantly changing. However, this idea of a changing environment did not conform with the belief of earlier scientists. Rather, they thought that the geographic positions of ocean basins and continents have been static since the beginning of time. It was around the 1500s when Leonardo da Vinci, upon his discovery of fossil seashells found at the high mountains of Italy, first thought of the idea that the areas where mountains are located may have been oceans in the past. Through time, other fossils of marine organisms found far above the current sea level further supported the idea that mountains were uplifted and weathering wore them down. At around the 1800s, most scientists have accepted the idea that Earth's crust is undergoing large vertical movements or uplifting. There was also evidence of possible horizontal movements, but the scientists then were not convinced about it. Alfred Wegener showed evidence of horizontal or lateral movement of the continents in his continental drift theory. According to him, the continents have drifted around the world and have once formed a giant landmass or supercontinent called Pangaea. To support his theory, Alfred Wegener presented a set of geographical, biological, and climatic evidence.Wegener's geographical evidence included the jigsaw puzzle fit of the current continents. He pointed out that the coastlines of South America and Africa seem to fit together. He also pointed the presence of mountain ranges having similar rock types and age but separated by vast oceans, like that of the folded rocks of the Caledonian mountains. The same folded rocks run through West Africa, North America, Newfoundland, Ireland, Wales, Scotland, Greenland, and Norway, all of which are now separated by the Atlantic Ocean. A geographical evidence on the similar rock types in West Africa, North America, Greenland, and Europe is found. The biological evidence came in the discovery of similar plant and animal fossils in different continents separated by oceans. The animal fossils of Mesosaurus and Lystrosaurus indicate that they were not capable of crossing the oceans to reach the other continents. If they were, the fossils should have been more widely distributed Africa, Australia, India, and South America were too large to be carried by wind. This indicates that the areas where the fossils were found were closely linked. It has also been found out that the plant only grew in areas with subpolar climate, which would indicate that the landmasses were located near the South Pole.Lastly, for his climatic evidence, Wegener discovered that a glacial period occurred during the late Paleozoic era in Southern Africa, South America, Australia, and India. The initial explanation for this event was global cooling, but it was rejected because large tropical swamps with so much vegetation were found at the same time in the Northern Hemisphere. This further supported the idea that the supercontinent was indeed near the South Pole, and the continents in Northern Hemisphere were once near the equator. The glacial period also left glacial striations, or the scratches glaciers make as they move across on the underlying bedrock, on the aforementioned continents. For such an event to happen, the continents would have to be connected. SCIENCE PIONEER. Alfred Wegener (1880-1930). Alfred Wegener was a German polar researcher, geophysicist, and meteorologist. He was known for his work on the continental drift theory. In his effort to defend his work, he went to the Greenland ice sheet where he died.Even with all the compelling evidence, the continental drift theory hardly convinced the scientific community at that time because Wegener was unable to identify a credible mechanism that drives the continental drift. He was unable to clearly explain how the continents moved and how the larger continents broke through the ocean floor. Eventually, critics of the continental drift began to accept the theory when new evidence supporting the theory was discovered. The new evidence led to a more encompassing theory the theory of plate tectonics. This theory provided a more convincing explanation as to how the continents moved. The evidence that paved the way for the theory of plate tectonics was the idea of wandering poles. Scientists began studying volcanic rocks to determine the location of the magnetic poles. When volcanic rocks crystallize, the minerals with magnetic properties align themselves parallel to Earth's magnetic field at the time the minerals were formed. This finding allowed scientists to determine the polarity of Earth's magnetic field and the magnetic inclination that showed the location of the poles. Upon studying the paleomagnetism of the rocks, geophysicists found out that rocks from various locations point to different magnetic north poles, suggesting that the poles have wandered. Since movement of magnetic poles is very unlikely, scientists have accepted the idea that the continents are indeed moving. And if the continents are moving, scientists thought that maybe the ocean basins are moving too. They also discovered that some rocks showed magnetic reversals, which led them to believe that the magnetic north pole now was not always the magnetic north pole. Seafloor Spreading. After World War II, exploration on the ocean floor became the focus of many geologic studies. It was only then that the ocean ridge system was discovered. A geologist in Princeton University named Harry Hess, along with other scientists, studied this ocean ridge system and hypothesized that the oceanic crust was moving away from the ridge. His hypothesis, known as seafloor spreading, showed that the ocean floor is split along the ridge where the magma rises to form the new ocean floor.Because of this, rocks located near the ridge are younger than those that are located magnetic polarity of Earth is also preserved in those rocks. Withe ridge scientists were able to see the magnetic reversals in the ocean floor, and they were able to make use of information to determine that the ocean floor is moving at a rate of about 10 cm per year. Plate Tectonics. Confirmation of the seafloor spreading hypothesis proved that continents are not moving above the ocean floor. Rather, it is the fragments of the lithosphere. The lithosphere is the rigid layer that is composed of the uppermost mantle and the crust that carry the continents and the ocean basins along. These fragments of the lithosphere are called plates. Underneath the lithosphere is a weaker region in the mantle known as asthenosphere that behaves like a fluid. Thus, the lithosphere floats above the asthenosphere, making it detached and free to move. This became the basis of the theory of plate tectonics. Now that it has been made clear that it is the plates which are moving, the question as to how they move remained. Sir Arthur Holmes proposed the driving force for this plate movement in 1919. He suggested that the movement in the mantle carries the plates along. It was previously discussed that Earth's interior is very hot due to the heat produced by radioactive decay. Convection takes place in the mantle, keeping the asthenosphere hot and weak. The convection currents produced in the asthenosphere are the ones carrying the lithospheric plates and making them move. However, convection currents are not enough. Mechanisms such as ridge push and slab pull aid the convection currents to slowly move the lithospheric plates. Ridge push occurs at mid ocean ridges which are higher in elevation than the surrounding trenches and abyssal plains. The new ocean floor from the ridge is hot and relatively thin. As it moves away from the ridge, it cools down and gets denser, heavier, and thicker. Below this cooling ocean floor is the asthenosphere, which is less dense. This area becomes a massive shear zone and the new ocean floor will effectively slide down the slope of the asthenosphere. When the plate collides with another plate with lesser density, the denser plate sinks and a subduction zone is formed. When the subducting plate sinks, it pulls on the rest of the plate behind it. These mechanisms explain the movement of the plates.Earth has seven major lithospheric plates that account for 94% of Earth's surface. These are the North American Plate, South American Plate, Pacific Plate, African Plate, Eurasian Plate, Indo-Australian Plate, and Antarctic Plate. These plates are constantly moving relative to the other plates. Thus, the interaction of plates occurs mostly along the boundaries. These movements are plotted using information from earthquakes and volcanic activities. There are three main types of plate boundaries: convergent, divergent, and transform boundaries Convergent boundaries are boundaries where two plates move towards each other A convergent boundary is also known as destructive margin since this is where the collision between two plates occhins. There are three types of convergence-oceanic oceanic, oceanic-continental, and continental-continental. Trenches are features of the ocean floor that are present in both oceanic-oceanic boundary and oceanic-continental boundary. Subduction occurs at the trenches, therefore, these are characterized as the deepest parts of Earth. A divergent boundary is the opposite of convergent boundary: two plates move away from each other. Divergent boundaries create new crust; thus, they are also known as constructive margins. The ocean ridge system is a divergent boundary where new ocean floor is produced as magma rises, pushing the older rocks aside.Transform boundary is also known as conservative plate margin since two plates just move past one another, neither creating nor destroying land. Earthquake epicenters are usually detected at transform boundaries because the rocks tend to break and not fold or sink, like in convergent boundaries. Evolution of the Ocean Basins. Both the movement of the plates and seafloor are responsible for the evolution of ocean basins. Along the divergent boundary where ocean ridge systems are found, magma is released and new ocean floor is created. Along convergent boundaries, the ocean floor is being destroyed. The evolution of the ocean basins started during the time when Pangaea was still present and was surrounded by the vast ocean or superocean known as Panthalassa, also called Paleo-Pacific or "old Pacific." Upon the initial break up of Pangaea into Laurasia and Gondwanaland, the Tethys Sea began to form. Then, the Eurasian and North about, forming the North Atlantic. The South Atlantic only started to form when the African Plate and South American Plate separated. The continued movement of the plates created the Himalayas at one side and separated the Pacific Ocean and Atlantic Ocean at the other side, which consequently formed the current ocean basins. Both the movement of the plates and seafloor are responsible for the evolution of ocean basins. Along the divergent boundary where ocean ridge systems are found, magma is released and new ocean floor is created. Along convergent boundaries, the ocean floor is being destroyed. The evolution of the ocean basins started during the time when Pangaea was still present and was surrounded by the vast ocean or superocean known as Panthalassa, also called Paleo-Pacific or "old Pacific." Upon the initial break up of Pangaea into Laurasia and Gondwanaland, the Tethys Sea began to form. Then, the Eurasian and North about, forming the North Atlantic. The South Atlantic only started to form when the African Plate and South American Plate separated. The continued movement of the plates created the Himalayas at one side and separated the Pacific Ocean and Atlantic Ocean at the other side, which consequently formed the current ocean basins.Continents do not immediately end at the point where the ocean meets the land. They may extend slightly into the oceans. The portion of the continent that is submerged is called continental margin. There are two types of continental margin: passive margin and active margin. A passive continental margin consists of a continental shelf, continental slope, and continental rise. It is not associated with plate boundaries; thus, there are very little tectonic activities. An active continental margin only has a continental shelf and a continental slope. It is associated with plate boundaries; thus, a main feature of this boundary is a trench. The different features of a continental margin are the following: 1. The continental shelf is the gently-sloping submerged portion of the continent. 2. The continental slope is the steep slope after the continental shelf. It is still part of the continent. 3. The continental rise is the gently-sloping area after the continental slope and before the ocean floor. 4. The trenches are the deepest parts of the ocean. These are narrow depressions caused by the subduction of the ocean floor along the convergent boundaries. 5. The mid-oceanic ridge is the mountain range system in the ocean. It is responsible for the production of new ocean floor. This is the region where new magma constantly emerges from. SCIENCE CAREER. A scientific illustrator uses art to inform and communicate complex details and concepts of science. He/She makes use of scientifically informed observations and research along with his/her technical art and aesthetic skills to make accurate representations. In Natural History, the scientific illustrators recreate how the extinct species look like by working with scientists and fossil records. Moreover, with the advances in technology, illustrators are now into 3D modelling, animation, and video making. Earth's History. All the processes that have been discussed require long periods of time to create a noticeable change on Earth's surface. You can just imagine how long it would take to create an oceanas vast as the Pacific Ocean if the ocean floor moves only at about 10 cm/year. It is then important to know the history of Earth to learn the complexities of its past and be able to use it to understand the present. Just like learning the history of a country that requires one to read a lot of books, learning the history of Earth involves studying a lot of rocks. Rocks, especially sedimentary rocks, contain a lot of information about Earth's past. It holds the key to most of the geologic processes that happened on Earth and the key to uncovering how life on Earth evolved. But these discoveries are worthless if there is no time perspective. Thus, one of the most important contributions of geologists to mankind is the geologic time scale, which holds a history that is exceedingly long.

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