Oral hypoglycemic drugs -
Speaking of solubility: as one can clearly see, only a handful of these drugs are well-dissolved in water, namely metformin sitaglipin and acarbose. For the rest, water solubility is described as "sparing" or "minimal".
These chemical properties are listed here not for some kind of deeper educational purpose, but because they can somewhat explain the distribution kinetics and protein binding in the following section.
The vast majority of oral hypoglycemic agents have a very small volume of distribution, mainly because they are almost completely protein-bound. This refers to all the agents with extremely poor water solubility. The exceptions are agents which are at least modestly water-soluble, like metformin and sitagliptin - their volume of distribution is larger, and their protein binding is lower.
Unsurprisingly, of this selection of heterogeneous chemicals, those that have good water solubility and minimal protein binding are also those that undergo renal elimination and little hepatic metabolism, like metformin and sitagliptin. Among the half-lives, the standouts are acarbose which is basically candy and repaglinide which is broken down over 60 minutes.
For the rest, hepatic metabolism plays a major role, which makes them slightly safer in renal failure. A note of caution must be left on the sulfonylureas, which undergo mainly hepatic metabolism, but among which many have active metabolites that are dependent on renal elimination.
The pharmacodynamics of oral hypoglycaemic agents is a tour of some dangerous metabolic back alleys. There must be some way to explain these mechanisms without the reader becoming lost and mugged by gangs of biochemists. What follows is a crude reductionist attempt to simplify and stereotype these drug effects into something that could be quickly and easily digested by a revising exam candidate.
Whatever detail is lost in that process can be recovered by any reader who can click and open a link, as references are offered pointing to detailed review articles of which there is a glorious abundance. Biguanides decrease blood glucose mainly by decreasing hepatic glucose production through their actions on AMP-activated protein kinase AMPK , though there are probably also multiple other mechanisms involved Rena et al, AMPK is a ubiquitous fuel-sensing enzyme present in basically all mammalian cells, and its main role is to coordinate a switch from energy consumption to energy generation, for example when exercising skeletal muscle needs to take more glucose from the bloodstream.
Hepatic AMPK also does something like this, and to activate this enzyme has a largely catabolic effect, stimulating fatty acid oxidation and suppressing protein synthesis and glucose release - mainly by AMPK phosphorylating all kinds of key enzymes in those pathways.
Metformin does not do anything to AMPK directly. Instead, that enzyme becomes activated as the reaction to an act of mitochondrial terrorism. Metformin is a highly positively charged molecule, and becomes concentrated inside mitochondria as a result, with the intramitochondrial concentrations several orders of magnitude higher than the extracellular fluid.
Once inside, it sabotages ATP synthesis by disabling Complex I of the respiratory chain. The result is a decreased ATP:ADP ratio, which is a potent stimulus for AMPK activation as it would normally be viewed as a signal that the cell is starving and requires immediate metabolic substrate support.
AMPK then dutifully activates the catabolic machinery of the hepatocytes, and abolishes all forms of charitable export behaviours, among them the production and systemic delivery of glucose by glycogenolysis and gluconeogenesis.
The onset of this effect is said to be about three hours following administration. The reader is reminded that metformin has whole PhDs of different mechanisms, but the only one the ICU trainee really needs to know about is this mitochondrial toxin aspect, mainly because it explains a common toxicological presentation.
By disabling the mitochondrial metabolism of oxygen, metformin produces lactic acidosis , which can be rather impressive in magnitude, and which comes up quite often in exam papers as a differential. Sulfonylureas act by stimulating insulin secretion, an activity which relies on the existence of residual pancreatic β-cells because otherwise where would it come from.
A secondary effect is the decrease of insulin clearance by the liver, which seems to occur over some weeks with sustained treatment Sola et al, Sulfonylureas achieve these effects by binding to a specific receptor on pancreatic β-cells which has come to be known as sulfonylureas receptor SUR1 , as we would not have found it otherwise.
This thing is a transmembrane protein which - together with several others - forms the ATP-sensitive potassium channels that mediate insulin release. The binding of sulfonylureas to this complex tends to have the same effect as ATP and raised blood glucose, i.
to block the outward flow of potassium, which results in the depolarisation of the β-cell and the release of insulin. This effect is fairly rapid in onset, i.
as soon as the drug is systemically absorbed. Meglitinides, like sulfonylureas, are "insulinotropic" or "secretagogue" molecules that stimulate the release of insulin from pancreatic β-cells.
They also bind to the SUR1 receptor, albeit with less affinity, and produce the same β-cells-depolarising effect. The main difference from sulfonylureas is the duration of effect, which is much shorter, and therefore much less likely to produce hypoglycaemia Guardado-Mendoza et al, α-Glucosidase inhibitors act as pseudocarbohydrates, i.
They are usually taken along with the first bites of a main meal. There are actually several α-glucosidase enzymes at the brush border, such as sucrase, maltase, dextranase and glucoamylase, and acarbose interferes with all of them. Their normal role is to digest more complex carbohydrates until they turn into the sort of monosaccharides that can be easily absorbed through the intestinal mucosa.
Theoretically, this means to block them all would result in the complete failure of all carbohydrate digestion, and the delivery of undigested carbohydrate directly to the colon, which is in fact what happened when Puls et al overdosed some rats with acarbose.
Thiazoledinediones operate in the shadowy world of peroxisome-proliferator—activated receptors PPARs , which are another group of nuclear receptors that regulate gene expression much like the receptors for corticosteroids.
Under normal circumstances, the natural ligands for these receptors are all sorts of fatty acids and bile acids. Cheatham and Yki-Järvinen explain the function much better, but if "better" is not as good as "shorter" for the reader, the function of thiazoledinediones can be simplified as "increased insulin sensitivity".
The exact mechanisms of how they do this are still being determined, but it appears that the presence of activated PPARγ receptors enhances the transcription of all the proteins involved in the machinery of glucose uptake and processing, especially in adipose tissue.
In this fashion, the response to any insulin binding to that cell is enhanced. By this mechanism it appears the glitazones redistribute the deposition of fat into the fatty tissue and away from the liver , increase the sensitivity of the liver and fatty tissue to insulin, and increase insulin secretory responses from the pancreas.
Because of their indirect gene-transcription-modifying function these drugs also have a host of nonglycemic effects, some antiinflammatory and some antiatherogenic. Their target, DPP-4, is a member of a large family of transmembrane proteins, and is also known as CD when it is observed on the surface of lymphocytes.
It is found in many tissues, particularly the vascular endothelium, and some part of it seems to be able to break off and sail the bloodstream as a soluble enzyme, retaining full activity.
That activity is to basically break down hormones - theoretically anything with a proline or an alanine in the penultimate position on the N-terminal will get cleaved, but practically in humans the only known substrates for this thing are glucose-dependent insulinotropic polypeptide GIP and glucagon-like peptide 1 GLP GIP and GLP-1 are released in response to food ingestion, and their most interesting effect is to increase the secretion of insulin.
Over longer timeframes an increased exposure to GLP-1 also leads to the increased synthesis of insulin and β-cell hypertrophy. GLP-1 also suppressess the secretion of glucagon, which possibly has an equally great importance in controlling postprandial sugar levels.
Additionally, GLP-1 receptors are expressed in the CNS where it appears to affect satiety, with all sorts of positive flow-on effects on behaviour modification and weight loss. In short, if you are an obese diabetic, you want more GLP-1 in you, and that is what DPP-4 inhibitors produce. GLP-1 receptor agonists bypass the need to reactive DPP-4 and go straight to the source.
In fact GLP-1 agonist drugs out-GLP the native enzyme by having higher affinity for its receptors and a more stable pharmacokinetic profile, remaining active for longer Cornell, Their pancreatic and extrapancreatic effects are otherwise the same as those of GLP If the outcome is the same, what would help you choose between DPP-4 inhibitors and GLP-1 agonsist, apart from the convenient oral availability of the former?
To discriminate between the two classes, Brunton reviewed the available clinical trials and concluded that GLP-1 agonists were actually more effective at achieving all kinds of meaningful targets eg. HbA1c reduction. SGLT-2 inhibitors block the Type 2 sodium-glucose cotransporter that you tend to find in the kidney.
SGLT-1, on the other hand, is mainly intestinal, and to block this would have an acarbose-like malabsorption effect Dardi et al, That was the mechanism of action of phlorizin, the original precursor of this drug class. The blockade of SGLT-1 would unfortunately do nothing about the release of glucose from the liver.
Instead, the blockade of SGLT-2 prevents the reabsorption of already circulating glucose. Probably one of the main reasons that we have such a vast plethora of different antidiabetic medications apart from the inherent attractiveness of marketing something for elderly Westerners to take every day for many years is that most of them have some fairly serious side-effects, some of which are merely embarrassing, whereas others may be life-threatening.
Probably the single best paper on these is a review by Lorenzati et al , which also happens to cover the pharmacodynamics of each class in just enough detail for the tired exam candidate. Biguanides can, by the direct extension of their mechanism of action, cause severe lactic acidosis.
This is not very common at least not as common as it was with phenformin but it still happens, particularly where metformin accumulates due to renal failure. Its other side effects consist of gastro-abdominal stuff, for example a metallic taste in your mouth, diarrhoea, abdominal discomfort, anorexia, etc.
Sulfonylureas have a distinct tendency to cause undesirable hypoglycaemia, which is a direct extension of their therapeutic effect. They stimulate insulin secretion no matter the glucose concentration, and therefore remove the normal regulatory safeguards that prevent insulin release during periods of normal and low blood glucose.
The result is essentially an insulin overdose. Other side effects can include hypokalemia, weight gain, skin eruptions and photosensitivity. α-glucosidase inhibitors are essentially osmotic laxatives, as their mechanism of action is centered on creating malabsorption. They leave a lot of unfinished carbohydrate scraps in the lumen of the bowel, and as you might imagine, there are plenty of microbial scavengers down there who are ready to pounce on these molecules, gladly metabolising them into clouds of flatus and torrents of diarrhoea.
These are potentially dinner-party-ending consequences, as these drugs are taken immediately at the commencement of a meal. Meglitinides , like sulfonylureas, directly stimulate the release of insulin, but because they are very short-acting and taken immediately before a meal, the possibility of severe hypoglycaemia is somewhat diminished.
Other weird, unexpected adverse effects in studied populations were headaches, and an increased risk of upper respiratory tract infections - for some reason specifically sinusitis.
Thiazolidinediones are generally not likely to cause life-threatening hypoglycaemia, even though they increase insulin sensitivity. Unfortunately, by making adipose tissue more interested in glucose, they make it grow in size, and noticeable weight gain results.
They also effect PPAR receptors in bone, and are associated with an increase in the risk of fracture. PPAR activation in renal tubular cells, on the other hand, leads to fluid retention, and oedema results.
Additionally, individual agents have distinct and unpleasant risk profiles: rosiglitazone is associated with myocardial ischaemia and pioglitazone slightly increases the risk of bladder cancer. Dipeptidyl peptidase DPP-4 inhibitors have a fairly benign side effect profile.
They are generally said to be "weight-neutral", i. the population of patients starting sitagliptin therapy remain as obese as they were before treatment.
The incidence of serious hypoglycaemia with this class is also fairly low. The most commonly reported adverse effects were sinus infections and headache. GLP-1 receptor agonists are also rather free from serious life-threatening side effects, with the exception of some idiosyncratic pancreatitis episodes reported with exenatide.
Nausea and anorexia are also reported. SGLT-2 inhibitors are basically osmotic diuretics, and have a tendency to produce polyuria and volume depletion. At the same time the urine becomes sweeter, and the incidence of urinary tract infection increases. The most interesting side effect is probably euglycaemic ketoacidosis , where a sustained low BSL produces a downregulation of insulin release and a concomitant increase in ketogenic hormones like glucagon adrenaline and cortisol.
Lorenzati, Bartolomeo, et al. Oral hypoglycemic pills are medicines to control diabetes. Oral means "taken by mouth. This article focuses on a type called sulfonylureas.
An overdose occurs when someone takes more than the normal or recommended amount of this medicine. The result is a drop in blood sugar level that affects normal function of the body's organs.
An overdose may occur by accident or on purpose. This article is for information only. DO NOT use it to treat or manage an actual overdose.
If you or someone you are with overdoses, call your local emergency number such as , or your local poison control center can be reached directly by calling the national toll-free Poison Help hotline from anywhere in the United States.
There are many types of oral hypoglycemics. The poisonous ingredient depends on the specific drug. The main ingredient in sulfonylurea-based oral hypoglycemics makes cells in the pancreas produce more insulin.
People who have had a stroke in the past may appear to be having another stroke if their blood sugar drops too low. Your local poison control center can be reached directly by calling the national toll-free Poison Help hotline from anywhere in the United States.
This national hotline will let you talk to experts in poisoning. They will give you further instructions. This is a free and confidential service.
All local poison control centers in the United States use this national number. You should call if you have any questions about poisoning or poison control. Retrospective chart review of patients with health record coded T1DM seen between January and January was done. OHA use, comorbidities, demographics, vital signs, and cardiometabolic risk surrogates were extracted for analyses..
All subsequent analyses included T1DM, LADA, type 1. OHA use in T1DM was not associated with any significant change in weight, BMI nor blood pressure. There was however a statistically significant decline in total cholesterol, LDL and HBA1c but not fasting triglycerides.
No significant differences were found in hypoglycemia related admissions or DKA admissions with OHA use including among SGLT-2 users. OHAs may have utility as adjunctive therapy and require more structured study to enable development of therapeutic algorithms for their use in T1DM therapeutics.
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Inflammation and sleep quality G. ROMOWILLIAM A. WESTGABRIEL I. Oral hypoglycemic drugs P: Use Otal Oral Orao Agents in Type 1 DM. Obesity prevalence in T1DM is increasing. While T1DM is typically treated exclusively with insulin, the changing obesity trends and T1DM heterogeneity has raised interest in use of various oral hypoglycemic agents OHA as adjunctive therapy.
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