The following article was written by user ‘canal_of_schlemm‘ from r/steroids Reddit
“There has a been a lot of talk regarding water retention while on cycle and the use of diuretics. I figured I would throw something together to give everyone a better idea about the physiology behind fluid and electrolyte balance and how the use of diuretics plays into that. This is all written under the assumption that no one here has any preexisting renal pathologies that would impact fluid homeostasis. I will start broadly and talk about all the relevant pieces that play into this, because people have a tendency to oversimplify it.
The typical volume of body water in a 150 lb male is approximately 40 L. Of that total volume, 65% makes up your intracellular fluid and 35% makes up your extracellular fluid. Fluid balance between these two compartments is maintained through the established osmotic gradient. There are two places in the body where fluid exchange between these two compartments occur: cell membranes which separate intracellular fluid from interstitial fluid, and capillaries, where fenestrations and sinusoids allow for fluid permeability.
Capillary exchange and lymphatic drainage are two of the most important factors when dealing with fluid balance. The exchange of fluid through capillaries is dictated by the net filtration in and out of capillaries. There are several factors that play into the net filtration.
Arterial net filtration
Arterial NFP will be dictated by the blood hydrostatic pressure (BHP) (~35 mmHg), the blood colloid osmotic pressure (BCOP) which draws fluid from the interstitium back into the plasma (~26 mmHg), and the interstitial fluid osmotic pressure (IFOP) which draws fluid from the plasma into the interstitium (~1 mmHg). All together, that creates a NFP of 10 mmHg.
Venous net filtration
Venous NFP will be dictated by almost all of the same factors, but the pressures will be different due to the exchange of fluids that occurred on the arterial side. BHP will be reduced to ~16 mmHg, BCOP remains at 26 mmHg, but now we are dealing with interstitial fluid hydrostatic pressure (IFHP), which will be ~0 mmHg. This results in a NFP of -9 mmHg. The difference between these two pressures is how much fluid is retained in the interstitium and lymphatic system. The biggest impact to this is your BCOP, which is dictated by electrolytes and plasma proteins. An increase in BCOP will result in more fluid being pulled osmotically from the interstitum, resulting in increased blood volume (hypervolemia) and possibly hypertension. A decrease in BCOP will result in more fluid being pulled osmotically from the plasma, resulting in edema.
Water loss is primarily mediated by the kidneys, which typically excrete around 1500 mL of fluid a day, and minimum urine output is 300 mL/day. Evaporation and perspiration through the skin account for 600 mL, fluid loss from breathing accounts for 300 mL, and the GI tract accounts for another 100 mL. Our bodies account for this loss and uses stimulation of thirst and reabsorption of water to regulate our fluid balance. The hormone that has the greatest impact on fluid balance would be Anti-Diuretic Hormone, or Vasopressin. However, regulation of electrolytes and your kidney’s ability to retain them can greatly impact the amount of water you excrete or retain.
Our bodies closely regulate electrolytes because they are critical to our daily function. Under typical conditions, you will not impact electrolyte homeostasis from diet alone. Here are a list of the main electrolytes, their function, and how they are regulated:
Na+ is crucial in establishing resting membrane potentials in all cells, which help drive electrical and chemical gradients for ion and nutrient exchange. Na+ is mostly known for its role in generating action potentials in neurons, however, through the use of Na+/K+ ATPase, we can establish electrical/chemical gradients that can drive secondary active transport proteins such as symporters and antiporters. Na+ is found at the highest concentrations in interstitial fluid and plasma, with minimal amounts intracellularly due to the action of Na+/K+ ATPase.
Na+ accounts for 90-95% of extracellular fluid’s osmolarity. Dietarily, only 0.5 g/day of Na+ is needed, however the typical diet has 3 to 7 g/day. While this difference may seem large, Na+ concentrations are heavily mediated through homeostasis. Our bodies maintain a 135-145 mEq/L range for Na+. Because of this, it is difficult to induce hypernatremia through dietary intake of sodium. Hormones that are directly involved in Na+ homeostasis are Aldosterone, ADH, and Atrial Natriuretic Peptide (ANP)
Plasma Na+ concentrations higher than 145 mEq/L result in hypernatremia. The most common causes of hypernatremia are dehydration and iatrogenic IV saline use. Less common causes could be hyperaldosteronism and diabetes insipidus. When it comes to hypernatremia, fluid volume is an important factor. Hypovolemia can be the result of inadequate fluid intake or excessive water loss through vomiting, perspiration, diarrhea, or other means of osmotic diuresis such as glycosuria. Euvolemia is the result of diabetes insipidus, which inhibits ADH from acting on the collecting duct of the kidney, inhibiting water reabsorption. Hypervolemia is the result of hypertonic solution intake. This can be IV fluids or even sea water. It can be associated with hyperaldosteronism and Conn’s syndrome, but this is easily fixed with increase in water intake.
Plasma Na+ concentrations lower than 130 mEq/L result in hyponatremia. Hyponatremia, much like hypernatremia, can be defined by fluid volume. Hypovolemia is typically the result of diuretic use. By using diuretics, the low blood osmolarity that results induces ADH secretion, thus diluting the osmotic concentration of the blood even further. Adrenal pathologies that inhibit synthesis of mineralocorticoids will also cause this, specifically Addison’s disease. Euvolemia is typically caused by Syndrome of Inappropriate ADH (SIADH), which results in excessive ADH secretion, and thus further dilution of the osmotic concentration of blood. Hypervolemia should not occur in any healthy individual. The causes are typically congestive heart failure (CHF), liver cirrhosis which inhibits the synthesis of plasma proteins which add to the osmotic concentration of blood, and renal disease.
As you can see, the impact of dietary sodium will have minimal effect in healthy individuals who do not have any of the issues listed above. I will discuss the specific hormones that act on Na+ further down.
Much like Na+, K+ is responsible in establishing resting membrane potentials in cells and propagating action potentials in neurons. K+ is found highest intracellularly due to the action of Na+/K+ ATPase, and is found in minimal concentrations in plasma and interstitial fluid. Our bodies regulate K+ very well, up to 90% of K+ in glomerular filtrate is reabsorbed by proximal convoluted tubule (PCT) in the nephron. However, potassium is the most dangerous electrolyte when it comes to imbalances. Luckily, aldosterone does an excellent job of regulating K+ concentrations.
Considering that there is supposed to be minimal concentrations of K+ in plasma (~4 mEq/L), hyperkalemia can be very dangerous. This typically occurs as a result of cellular damage. Crush injuries and rhabdomyolysis can release intracellular K+ very quickly, which can cause nerves and muscles to become spastic and easily excitable. However, a slow increase in blood K+ levels can have the opposite effect, inhibiting voltage-gated Na+ in neurons and myocytes from working properly due to interruption of the resting membrane potential. Most typically, hyperkalemia will be induced through medication. The biggest culprits are potassium-sparing diuretics and ACE inhibitors. NSAIDs and other medications can also have this effect. Mineralocorticoid deficiencies, such as Addison’s disease, can also result in hyperkalemia. Metabolic and respiratory acidosis can also lead to hyperkalemia due to the displacement of K+ from cells by H+, however this will in turn result in hypokalemia.
The biggest cause of hypokalemia will be from the use of loop or thiazide diuretics. As stated above, acidotic conditions such as diabetic ketoacidosis can also cause hypokalemia. Hypokalemia can result in hyper polarization of cells, which will cause muscle weakness and loss of muscle tonicity.
I won’t spend much time talking about chloride since there is no direct regulation of this ion. Hyperchloremia is usually the result of excessive hypertonic solution intake. Hypochloremia is the result of hyponatremia, so in an indirect way, aldosterone has some effect on Cl-.
Aldosterone is a mineralocorticoid steroid hormone that is released in either hyponatremic or hyperkalemic conditions. This hormone is synthesized in the zone glomerulosa of the adrenal cortex. Synthesis is stimulated by adrenocorticotropic hormone (ACTH), which is synthesized in the pars distalis of the pituitary gland. ACTH, in turn, is stimulated by corticotropin-releasing hormone (CTH) which is synthesized by the hypothalamus. This creates the HPA axis, which operates on negative feedback inhibition. The mechanism behind aldosterone is that the hormone acts on the distal convoluted tubule and proximal end of the collecting duct of the nephron is initiate synthesis of Na+/K+ ATPase on the basolateral side, which in turn, promotes reabsorption of Na+ from the filtrate and excretion of K+. Aldosterone has been shown to be inhibited by both testosterone and estrogen. Aldosterone can be released through two main pathways. The independent pathway, which is described above, and the Renin-Angiotensin-Aldosterone (RAAS) pathway. In this pathway, if blood pressure decreases, juxtaglomerular cells surround the afferent arteriole will release renin. Renin will cleave the liver peptide angiotensinogen to create angiotensin I, which will be converted into angiotensin II in the lungs by angiotensin-converting enzyme (ACE). Angiotensin II will cause vasoconstriction as well as stimulate the hypothalamus to stimulate thirst, release ADH, and release CTH resulting in the release of aldosterone. This is done to retain Na+ to restore blood volume. Both testosterone and estrogen have been shown to inhibit both aldosterone pathways.
Atrial natriuretic peptide
ANP is a peptide hormone released by cardiomyocytes in response to hypertension. Increased blood volume will stretch the atria of the heart, resulting in the release of ANP. ANP will inhibit both aldosterone and RAAS. ANP will then cause dilation of the afferent arteriole of the glomerulus while restricting the efferent arteriole, results in an increase glomerular filtration rate, which causes an increased excretion of Na+ and water. ANP will also inhibit sodium reabsorption in the distal convoluted tubule and collecting duct by inhibit cyclic GMP phosphorylation of sodium channels.
ADH is used to retain water by initiating synthesis of aquaporin II water channels in the collecting duct of the nephron. ADH is synthesized in the hypothalamus as a neurotransmitter and is sent to the pars nervosa of the pituitary gland via axonal transport where it is released. ADH is stimulated by high blood osmotic concentration in the hypothalamus.
So even after reading all of that, which essentially shows that diuretics are completely unnecessary (excluding competitions), and you still want to use them, here is a guide regarding them. Not all diuretics are created equal. Many of them operate under completely different mechanisms and depending on your goals, some will work better than others. There is definitely a hierarchy when it comes to diuretics so I have listed them in order of efficacy for this application. Please consult your physician before ever attempting to use diuretics and I will repeat the fact that I think they have no place as a PED and can be dangerous if you have no idea what you are doing.
Thiazides work by inhibiting Na+/Cl- symporters in the distal convoluted tubule. These are better than loop diuretics because they do not change the tonicity of the renal medulla. However, they are not free from typical diuretic side effects such as hyponatremia and hypokalemia.
Loop diuretics are named as such because they act on the loop of Henle of the nephron. These diuretics are more effective in those who have renal issues, making them a poor choice. These act on Na+/K+/2Cl- symporters in the thick ascending limb of the loop of Henle. In turn, this inhibits the reabsorption of all three electrolytes. Due to this inhibition, loop diuretics inhibit the intended hypertonicity of the renal medulla, which in turn inhibits the ability for water to be reabsorbed, thus leading to diuresis. These are typically used in patients who have CHF, various renal pathologies, hypertension, and liver cirrhosis. Their mechanism makes them a poor choice for iatrogenic cutaneous edema. Use of these diuretics can cause hyponatremia, hypokalemia, dehydration, gout, and syncope. The most common loop diuretic is furosemide, known by its trade name Lasix.
Carbonic anhydrase inhibitors
These are typically prescribed to patients with glaucoma and epilepsy. They work as a weak diuretic by inhibiting carbonic anhydrase in the proximal convoluted tubule. This inhibition increases bicarbonate and decreases sodium absorption. Not a practical choice for iatrogenic cutaneous edema.
There are two types of these. Aldosterone antagonists like spironolactone should be avoided by all costs. Spironolactone acts as an anti-androgen by competitively binding to androgen receptors, thus decreasing the efficacy and said receptors. Likewise, it inhibits the synthesis of DHT as well as displaces estradiol from SHBG, increasing the free estrogen/free androgen ratio. Most common side effect is gynecomastia. The second type is epithelial sodium channel blockers, such as triamterene. These work by blocking Na+ channels on the apical side of the distal convoluted tubule, inhibiting Na+ from entering the cells which Na+/K+ ATPase would normally act to reabsorb the Na+ and excrete K+. Both of these types can result in hyperkalemia since they inhibit the excretion of K+.
Ca2+ is the most closely regulated electrolyte in our bodies. This ion has a wide range of function including: Skeletal mineralization: calcium, along with phosphate, forms hydroxyapatite, the mineral that bones are made of. Muscle contraction: calcium plays a crucial role in myosin-actin crossbridge formation in all three types of muscle. Calcium binds to troponin, a regulatory protein in muscle that removes tropomyosin from the active site on g-actin, allowing myosin to bind. When action potentials are propagated in skeletal and cardiac muscle, voltage-gated calcium channels allow the diffusion of calcium from the sarcoplasmic reticulum into the sarcoplasm, initiating muscle contraction.
When cells send vesicles, often filled with proteins, outside of the cell, calcium is used to initiate exocytosis. Best example is in the case of neurons. On the presynaptic end bulb of a neuron, voltage-gated calcium channels will open, allowing calcium ions to enter the neuron, causing exocytosis of neurotransmitters into the synaptic cleft.
Calcium is crucial in almost every step of the clotting cascade. Way too much to get into regarding the physiology of blood clotting, but it is worth looking into if you are interested. While calcium plays a critical role in our daily function, concentrations are kept minimal and almost exclusively extracellular. Plasma concentrations are ~5 mEq/L which intracellular concentrations are ~0.2 mEq/L. Biggest reason for extremely low intracellular concentrations is to prevent calcium phosphate crystal precipitation since phosphate levels are have intracellularly due to their function as a buffer.
Several hormones are involved in calcium homeostasis: Parathyroid Hormone (PTH), Calcitriol (Vitamin D), and Calcitonin. Calcium imbalances can be extremely lethal.
Increased levels of calcium in the blood can cause many negative effects including ectopic ossification in the form of stone formation, polyuria from exceeding the calcium transport maximum in the nephron, and tachycardia. The latter being especially detrimental, as calcium is closely regulated in cardiac muscle and hypercalcemia will increased cardiac muscle contractility. Inversely, hypercalcemia disrupts the resting membrane potential in smooth and skeletal muscle, which can lead to flaccid paralysis. Most common cause is due to hyperparathyroidism, leading to increased mineral resorption from bone. Too much vitamin D can also result in hypercalcemia, as it is fat-soluble. Fluids, loop diuretics, and exogenous Calcitonin are the usual methods of treatment.
Low levels of calcium in the blood are arguably one of the worst forms of electrolyte imbalance, and if untreated immediately can result in death. Hypocalcemia will decrease the resting membrane potential, leading to spastic paralysis, tetany, convulsions and numbness. Carpopedal tetany (contractions in hands) are the most notable sign. Hypocalcemia will also decrease heart rate and contractility of cardiac muscle. Most common causes are hypoparathyroidism, often from accidental resection of the parathyroid glands during the thyroidectomy, and pseudohypoparathyroidism. Pseudohypoparathyroidism is caused by resistance to PTH and is noticeable visually thanks to my favorite thing, the “knuckle knuckle dimple dimple sign.” Excessive magnesium supplementation, vomiting, anorexia, and inadequate levels of Calcitriol can also cause hypocalcemia. Treatment is IV calcium gluconate.
PTH is a polypeptide hormone synthesized in the chief cells of the parathyroid gland, which are four small nodules located on the posterior side of the thyroid. PTH is stimulated by low levels of calcium in the blood. From here, PTH will act on bones to initiate resorption of hydroxyapatite, leading to increased levels of calcium in the blood. It accomplishes this by acting directly on osteoblasts in bone, which in turn activate osteoclasts to secrete HCl to break down hydroxyapatite. PTH also stimulates the kidneys to initiate synthesis of Calcitriol.
Calcitriol is another hormone that is used to increase the concentration of calcium in the blood. It is synthesized from Vitamin D. 7-dehydrocholestrol reacts with UV radiation and forms Cholecalciferol (Vitamin D3). From the skin, Cholecalciferol will be transported to the liver where a hydroxyl group is added to form Calcidiol. From there, under the influence of PTH, another hydroxyl group is added in the kidneys to form Calcitriol. From there, Calcitriol acts similarly to PTH increase osteoclastic activity and also increases absorption of dietary calcium in the GI tract as well as reduces excretion of calcium in the kidneys. This is why vitamin D must be taken to calcium supplements in order to be effective. Calcitriol will also cause excretion of phosphate in the kidneys as a protective measure against mineral deposition. Calcitonin: Calcitonin is a hormone produced in the parafollicular cells of the thyroid. It is used to decrease blood calcium levels but serves no practical purpose in adults.
I use firstname.lastname@example.org – they stock pharmaceutical grade diuretic drugs. Shipping to the UK usually takes 1-2 days and they do ship internationally too. Just send them an email explaining that you got their email address from this website and ask for a price list and they will send over a full list of products and prices.