*ANIMATED*: How Drugs Affect the Kidneys | Shayne McKee
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Here I made an animated PowerPoint slideshow that animates how certain medications cause certain effects on the kidneys. This powerpoint also goes into detail on how mechanisms that trigger renin secretion, renal artery stenosis, animations of the mechanisms of action and mechanisms of side-effects caused by ACEi and ARBs, loop diuretics, thiazide diuretics, and K+ sparing diuretics.
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*ANIMATED*: How Drugs Affect the Kidneys | Shayne McKee
- 1. Mechanisms of Renin Release 1) Activating the afferent arteriole 2) Cardiopulmonary baroreceptor activation 3) Macula Densa cells in the distal tubule sensing volume change
- 2. Afferent Arteriole Arteriole Efferent Arteriole JGAJGA JGA JGAJGA JGA β1 β1 Efferent Arteriole Bowman’sCapsule baroreceptors Renin Renin Renin Mechanism of Renin Release: Afferent arteriole • Context: Baroreceptors are interconnected with JGA cells (the cells responsible for making renin) • Baroreceptors detect decreased stretch (decreased blood pressure/blood volume) on afferent arteriole • Triggers JGA cells to secrete renin β1 β1 β1 β1
- 3. JGAJGAJGA Afferent Blood volume falls, Cardiac baroreceptors unload and detect decreased stretch Triggers activation of nucleus of the solitary tract NTS triggers activation of the intermediolateral cell column IML sends efferent projection to renal nerve NE released onto adrenergic receptors of JGA cells Renin Renin Renin JGA cells secrete renin
- 4. Afferent Arteriole Arteriole Efferent Arteriole JGAJGAJGA Afferent JGAJGA JGA JGAJGA JGA β1 β1 Efferent Arteriole Bowman’sCapsule baroreceptors Renin Renin Renin Mechanism of Renin Release: Macula Densa 2Cl- Na+ Cl- Na+ DCT TALH Reduced NaCl concentration results in less volume delivered to Macula Densa K+ Macula Densa feeds that information back onto JGA cells triggers renin release via prostaglandins β1 β1 β1 β1
- 5. ACEi and ARBs: Side-effects and considerations • Mechanisms of Renal insufficiency/ • Due to reduced renal blood flow (e.g. in Bilateral renal artery stenosis)
- 6. Afferent Arteriole Arteriole JGAJGAJGA Afferent JGAJGA JGA JGAJGA JGA β1 β1 Efferent Arteriole Bowman’sCapsule baroreceptors Renin Renin Renin Renal Artery Stenosis By stenosing, we are DECREASING the amount of blood that can flow into the afferent arteriole. Constriction of the artery means the baroreceptor is "sensing" low blood volume (even though the volume may just be fine). Filtration becomes impaired. Renin levels elevate. β1 β1 β1 β1
- 7. Afferent Arteriole Arteriole Efferent Arteriole JGAJGA JGA JGAJGA JGA β1 β1 Efferent Arteriole Bowman’sCapsule Renin Renin Renin Renal Artery Stenosis AT1R ANG II One way to compensate for an inability to filter is for ang II (remember, you made more ang II because you caused renin release due to the stenosis) to bind an AT1R on the efferent arteriole. This causes the efferent arteriole to constrict . This will decrease renal blood flow, but increase glomerular pressure in the glomerulus and increase filtration (bloodflow will be shunted into the bowman's capsule). GFR is maintained in stenosis AT THE COST OF increased glomerular capillary pressure (causing HTN). This is a pathophysiological adaptation to stenosis. β1 β1 β1 β1
- 8. Afferent Arteriole Efferent Arteriole JGAJGAJGA Afferent JGAJGA JGA JGAJGA JGA β1 β1 Efferent Arteriole Bowman’sCapsule Renin Renin Renin Treating HTN when the cause is (unknowingly) Renal Artery Stenosis AT1R A patient comes into the clinic with HTN. They have stenosis and thus a constricted efferent arteriole allowing them to maintain GFR. As a clinician, you are not aware this is the cause of their HTN. ANG II You give them an ACE inhibitor no more ANGII With the ACE inhibitor preventing constriction, the efferent arteriole relaxes (dilates) With dilation, glomerular filtration pressure falls Lack of pressure in glomerular capillaries causes inability to filter acute renal failure (renal insufficiency) - RARE β1 β1 β1 β1
- 9. • Hyperkalemia ACEi and ARBs: Side-effects and considerations
- 10. ENaC channels are formed (indirectly) from aldosterone If we give our patient an ARB, it prevents the synthesis of Aldosterone. No more ENaC channels. Less sodium reabsorbed Lumen becomes more positive In addition, if you block aldosterone (and thus MR activation), you decrease the potassium conductance in the potassium/chloride co-transporter of the apical membrane Promotes favorable gradient for potassium reabsorption This causes an increase in intracellular potassium, pushing more K+ out of the cell In addition, if you downregulate MR and ALDO due to the ARB, you also downregulate the sodium potassium ATPase (its activity is directly linked to MR) That means even less potassium can enter the cell even more potassium accumulates in the serum/interstitial space. Hyperkalemia
- 11. Loop Diuretics • Hypokalemia and RAAS activation (side-effect) • Metabolic alkalosis (side-effect)
- 12. Normal function without any drugs Na+ Na+ Na+ Sodium gets reabsorbed through the Na-K ATPase in the TALH A large concentration gradient is formed Na+ Na+ Na+ Na+ Na+ H2O H2O H2O The concentration gradient causes water to get reabsorbed from the thin ascending limb Increased volume increased (or normal) BP Next slide zooms in on this portion of the loop
- 13. Loop diuretics are blocking this channel Sodium and chloride can’t get into the cell and get excreted as urine Since water follows solutes, water flows out as well. Less extracellular volume less cardiac output decreased BP
- 14. Back in the loop, but with using the drug this time Na+ Diuretic causes sodium to be unable to get reabsorbed With less sodium reabsorbed, the concentration gradient gets ruined. H2O With no concentration gradient, water is no longer reabsorbed Potassium also gets excreted (remember in the last slide the Na-K-2Cl cotransporter was blocked) Side-effect Hypokalemia and (due to their high potency) activation of RAAS and elevated vasopressin (ADH) in an attempt to reabsorb water
- 15. Loop diuretics cause increased bicarb in the system (volume depletion promotes bicarb reabsorption) Drives reaction to the right H+ concentration goes down as it is used up to drive the reaction Less hydrogen concentration means pH increases Metabolic Alkalosis
- 16. Thiazide/Thiazide-like diuretics • Hypercalcemia (side-effect) • Also activates RAAS and potentiates hypokalemia (like loop diuretics) • With activation of RAAS comes increased aldosterone, which increases K+ secretion
- 17. Na+ Cl- Co- transporter Thiazide diuretics inhibit this apical membrane transporter Na and Cl can’t enter the cell (thus more sodium/water get excreted as urine) By preventing sodium from entering the cell, intracellular sodium concentration decreases Depletion of intracellular sodium increases activity of this calcium/sodium channel More Calcium gets reabsorbed Thiazide diuretics side effect – hypercalcemia
- 18. Afferent Arteriole Arteriole Efferent Arteriole JGAJGAJGA Afferent JGAJGA JGA JGAJGA JGA β1 β1 Efferent Arteriole Bowman’sCapsule baroreceptors Renin Renin Renin Thiazide Diuretics Causing RAAS Activation and Renin Release 2Cl- Na+ Cl- Na+ DCT TALH Blocking the transporters (particularly Na+ Cl- Co-transporter) with thiazide diuretics causes Macula Densa to sense volume depletion K+ Macula Densa feeds that information back onto JGA cells renin release/RAAS activation β1 β1 β1 β1
- 19. Potassium Sparing Diuretics (MR receptor antagonists) • Do NOT cause hypokalemia because they block aldosterone/MR receptors
- 20. In the case of high aldosterone (i.e. if someone was given a thiazide diuretic, ALDO would bind to the MR receptor to cause changes in gene expression and the transcription/translation of ENaC channels In addition, ALDO binding MR will over-activate the Na-K-ATPase Without the K+ Sparing diuretic Na+ Na+ Na+ More Na+ Reabsorption, causing volume expansion
- 21. With the K+ Sparing diuretic MR receptor blocked ALDO can no longer bind ENaC channels no longer synthesized Na+ Na+ Na+ Na+ Na+ Na+ Na+ Sodium doesn’t get reabsorbed as much, lumen Na+ concentration increases Lumen becomes more positive Potassium is pushed out and reabsorbed Blocking MR also downregulates the Na-K-ATPase Even less K+ can leave Potassium is spared The same effect occurs if you give a drug that blocks ENaC channels (like amiloride)
- 22. Thiazide diuretics: Interactions with ACEi or ARBS Thiazide diuretics cause increased RAAS activity and hypokalemia Combine with an ACEi/ARB to reduce both of these effects
- 23. WITHOUT ACEi/ARB RAAS activates due to Macula Densa sensing volume loss Aldosterone increases ALDO binds MR ENaC channels synthesized Reabsorbing more sodium Na-K ATPase over-activates More K+ Excreted Hypokalemia More sodium reabsorbed So ultimately with thiazide monotherapy you are: Excreting more potassium And therefore not excreting as much total volume as you may want to
- 24. Thiazide diuretic WITH ACEi/ARB ANG2/RAAS inhibited, ALDO is not increased ENaC channels not synthesized Increased solute concentration makes lumen more positive A favorable gradient is created for potassium reabsorption Decrease in ALDO activity also decreases K/Cl conductance, allowing for even more reabsorption Lack of ALDO activity also decreases activity of the Na/K ATPase Less potassium excreted Combination of Thiazides with ACEi/ARBs offer potassium-sparing effect