Drug List 2 Flashcards
Lisinopril
Drug Class: ACE inhibitor
Indication:
- hypertension
- heart failure
- acute myocardial infarction
Mechanism:
- inhibits Angiotensin converting enzyme.
- which prevents the conversion of angiotensin 1 to angiotensin 2
Renin-Angiotensin-Aldosterone System (RAAS)
- One important mechanism that regulates blood pressure is the RAAS which is a cascade of events that increases blood pressure
- When blood pressure is low, blood flow to the kidneys decreases. The kidneys respond by secreting renin into the bloodstream.
- Renin is a proteolytic enzyme that breaks down a protein made in the liver called angiotensinogen, and this gives rise to angiotensin I.
- When it reaches the lungs, angiotensin I is converted into angiotensin II by an enzyme called Angiotensin-converting enzyme, or ACE for short.
- Angiotensin 2 binds to receptors in vascular smooth muscles in blood vessels and causes them to constrict which increases blood pressure.
- Angiotensin 2 also stimulates the release of aldosterone by the adrenal glands. Aldosterone increases reabsorption of sodium in the kidneys which also increases water reabsorption. This results in increased blood volume, which also increases blood pressure.
ACE Inhibitors
- inhibit ACE enzyme so prevent the formation of Angiotensin 2 and decrease its levels in the blood
- Less angiotensin 2, less vasoconstriction, lower bp
- Also no angiotensin 2, no aldosterone, no increase in water absorption so lower bp.
Ramipril
Drug class: Antihypertensive / ACE inhibitor
Indication:
- management of hypertension
Mechanism:
- Inhibit ACE
- Stops conversion of Angiotensin 1 to Angiotensin 2
Captopril
Drug class: ACE Inhibitor
Indication:
- management of hypertension
Mechanism:
- Inhibits ACE
- Stops the conversion of Angiotensin 1 to Angiotensin 2
Diuretics
- Diuretics are medications that act on the kidneys to increase production of urine, and to eliminate water, certain metabolic wastes, and electrolytes from the body.
5 types :
- carbonic anhydrase inhibitors
- osmotic diuretics
- thiazide and thiazide - like diuretics
- loop diuretic
- potassium sparing diuretics
Potassium sparing diuretics
- Potassium sparing diuretics act on the cortical collecting tubules.
- Here, there are principal cells and α-intercalated cells dispersed amongst the tubule cells.
- The principal cell has two pumps on the apical surface, an ATP-dependent potassium pump that pushes potassium into the tubule, and an epithelial sodium channel pump, called ENaC for short, that pulls sodium into the cell.
- There’s also a Na/K ATPase pump on the basolateral surface that again moves 2 potassium ions into the cell for every 3 sodium ions out.
- Now, the alpha intercalated cells mainly get rid of hydrogen ions from the blood, and they use two pumps on their apical surface for this.
- First, they have a H+/ATPase which uses ATP to pump hydrogen into the tubule. Second, they have a hydrogen potassium ATPase (H+K+ATPase) which uses ATP to push 1 hydrogen into the tubule in exchange for 1 potassium.
- Sodium and potassium levels in alpha intercalated cells are also controlled by Na/K ATPase pumps on the basolateral surface, which move two potassium ions into the cell and three sodium ions out of the cell.
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Potassium spring diuretics 2
-Now the reabsorption and secretion of these molecules in the distal convoluted tubule and collecting duct are hormonally regulated by aldosterone, a mineralocorticoid hormone made in the adrenal cortex.
-In the principal cells, aldosterone diffuses across the basolateral membrane and binds to a mineralocorticoid receptor in the cytoplasm.
-Then the aldosterone-receptor complex gets inside the nucleus of the cell where it triggers the increased synthesis of ENaCs, ATP-dependent potassium pumps, and the Na-K ATPase transporters.
-Together, they work to increase sodium reabsorption into the blood and potassium secretion into the urine.
- In the alpha intercalated cells, Aldosterone increases the synthesis of hydrogen potassium ATPase to increase H+ secretion.
Potassium sparing diuretics 3
- Now, potassium sparing diuretics come in two flavors according to their mechanism of action:
-first, we’ve got those that directly inhibit the aldosterone receptor like spironolactone and eplerenone
-then we have medications that indirectly inhibit the effects of aldosterone by blocking the ENaC channels on the cell membrane, like amiloride and triamterene.
- This decreases the level of sodium inside the principal cells which decreases the action of the Na+/K+ ATPase on the basolateral membrane.
- However, at the end of the day, both categories have the same effect; first, they increase the excretion of sodium, and since water flows where the sodium goes, they also increase water loss through the urine.
- Next, they decrease the excretion of hydrogen and potassium, hence the name, potassium sparing.
Indications of Potassium spring diuretics
- These medications increase sodium and water loss through the urine, which leads to decreased plasma volume and cardiac output, resulting in lower blood pressure.
- This also treats edematous states like pulmonary edema or ascites where fluid builds up in the extracellular space.
- Potassium sparing diuretics are usually pretty weak, so they are used in combination with other diuretics, like loop or thiazides that would normally cause renal potassium wasting and hypokalemia.
- The addition of a potassium sparing diuretic increases the reabsorption of potassium in the final stretches of the renal tubule, and therefore reduces potassium loss.
Amiloride
Drug class: Potassium sparing diuretics
Indication:
- hypertension
Mechanism:
- Amiloride works by inhibiting sodium reabsorption in the distal convoluted tubules and collecting ducts in the kidneys by binding to the amiloride-sensitive sodium channels.
- This promotes the loss of sodium and water from the body, but without depleting potassium.
Loop diuretics
- Loop diuretics act on the loop of henle - specifically they mainly target the thick ascending limb
- The thick ascending limb is impermeable to water and it is lined with cuboidal cells that have Na+K+2Cl- cotransporters on the apical surface.
- These transporters reabsorb sodium, potassium, and chloride from inside the thick ascending limb back into the blood.
- As such, they shuttle one sodium into the cell, down its concentration gradient, and that powers the movement of one potassium and two chlorides into the cell as well.
- Think of it as a revolving door where sodium is the guy doing all the pushing, and one potassium and two chlorides just follow him in.
-This way, approximately 25% of the filtered sodium is reabsorbed in the loop of Henle, mostly in the thick ascending limb
- Now, on the basolateral side of the tubule cell, a Na/K ATPase uses energy in the form of ATP to pump three sodium ions into the interstitial fluid in exchange for letting two potassium ions into the cell
- This helps to maintain the low sodium concentration inside the cell
- Finally, both chloride and potassium move from the cell back into the lumen of the thick ascending limb, through special channels on the apical side of the cells that simply “leak” these ions passively. Funnily enough, the passive movement of potassium generates an electrochemical gradient that increases the reabsorption of calcium and magnesium through a paracellular pathway - meaning, these ions don’t use any channels, but rather they sneak between two epithelial cells and go back in the bloodstream. Now that’s a lot of activity for such a tiny cell!
Loop diuretics examples
Just to get acquainted with our team here, there’s 4 main diuretics - 3 of them: furosemide, bumetanide and torsemide - are chemically related, in that they are sulfonamide derivatives. The last non-sulfonamide loop diuretic, ethacrynic acid, is a phenoxyacetic acid derivative.
Loop diuretics 2
- These medications can be administered orally or intravenously, and once they’re in the bloodstream, they get secreted from the peritubular capillaries into the proximal tubule. Then, they make their way to the thick ascending limb and bind to the Na+K+2Cl- cotransporters. Loop diuretics bind to the Cl- site on the transporter and block it, so now sodium, potassium, and chloride can’t be reabsorbed into the bloodstream and they get excreted out with the urine. Other ions that depend on sodium reabsorption, like calcium and magnesium are excreted as well. Now remember, water follows where sodium goes. So this means there will be more water molecules in the lumen as well, so more urine is produced.
- Okay, now regarding calcium, there’s an important distinction from thiazide diuretics, which is another important class of diuretics. Loop diuretics increase calcium excretion, while thiazide diuretics decrease calcium excretion. There’s a mnemonic to help you remember this fact! “Loops lose calcium”!
Loop diuretics 3
Okay, now, along with inhibiting these Na+K+2Cl- cotransporters, loop diuretics also stimulate the release of prostaglandins, which dilate the afferent arteriole. As a result, they increase the renal plasma flow and they also increase the glomerular filtration rate, or GFR. However, many individuals who take loop diuretics also take non-steroidal anti-inflammatory drugs, or NSAIDs, which inhibit prostaglandin synthesis and thus, they can decrease the loop diuretics’ effect.
Thiazide and thiazide like diuretics
- Thiazide and thiazide-like diuretics are taken perorally, and once in the blood, they travel to the kidneys where they are secreted by the proximal convoluted tubule into the lumen of the renal tubule.
- An important point to make here is that they are secreted by the same secretory system that secretes uric acid into the tubule, so they compete with the secretion of uric acid, therefore increasing uric acid levels in the blood.
- Next, they travel along with the filtrate until they reach the distal convoluted tubule. This part of the nephron is lined by epithelial cells.
- Now, on the luminal side of these cells, there’s a nifty little sodium-chloride transporter. This channel reabsorbs one sodium and one chloride ion together from the tubule, into the cell. Sodium is reabsorbed along with water into the interstitium, and then into the bloodstream.
-This tiny cell also has a calcium channel on its luminal side, which allows calcium from the lumen to diffuse into the cell. Once in the cell, calcium is transported out into the interstitium through a sodium-calcium exchanger, that pumps a sodium in, and a calcium out.
-Now, since thiazides decrease sodium reabsorption, there’s less sodium in the cell, so the sodium-calcium exchanger works overtime to pump more sodium in, and more calcium out. The decrease in intracellular calcium, in turn, leads to more calcium reabsorption from the urine.
Thiazide and Thiazide-like diuretics
- Thiazides are benzothiadiazine derivatives, like chlorothiazide, and hydrochlorothiazide, and they all end in -thiazide.
- Whereas thiazide-like diuretics, like metolazone, indapamide, and chlorthalidone, are sulfonamide derivatives.
- Now, the major indication for diuretics is for the management of hypertension and edematous states. Since these medications cause water loss through the urine, it leads to decreased plasma volume and cardiac output, resulting in lower blood pressure. This also treats edematous states like pulmonary edema or ascites, where fluid builds up in the extracellular space.
- These medications are less potent in their diuretic effect when compared to loop diuretics, but they’re much longer lasting.
