Oral hypoglycemic drugs -
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Journal of the American Geriatrics Society. Drug Design, Development and Therapy. Archived from the original on November 29, Retrieved August 26, Pharmacogenetics of new classes of antidiabetic drugs.
Bosn J of Basic Med Sci. Archived from the original on August 27, The European Respiratory Journal. Best Buy Drugs. Consumer Reports : Archived PDF from the original on February 27, Retrieved September 18, An Update" PDF.
Comparative Effectiveness Review. number 27 AHRQ Pub. Archived from the original PDF on September 27, Retrieved November 28, Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, et al. May Annals of Internal Medicine. Archived PDF from the original on June 15, Retrieved July 17, January 31, Retrieved January 31, Cochrane Metabolic and Endocrine Disorders Group December The Cochrane Database of Systematic Reviews 12 : CD Oral diabetes medication , insulins and insulin analogs , and other drugs used in diabetes A Insulin aspart Insulin glulisine Insulin lispro.
Regular insulin. Cagrilintide § Pramlintide. Mitiglinide Nateglinide Repaglinide. Alogliptin Anagliptin Evogliptin Garvagliptin Gemigliptin Gosogliptin Linagliptin Melogliptin Omarigliptin Saxagliptin Sitagliptin Teneligliptin Trelagliptin Vildagliptin.
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Toggle limited content width. Sulfonylureas glyburide , glimepiride , glipizide. Stimulating insulin release by pancreatic beta cells by inhibiting the K ATP channel. Inexpensive Fast onset of action No effect on blood pressure No detrimental effect on low-density lipoprotein Lower risk of gastrointestinal side effects than metformin Convenient dosing.
Cause an average of 2—5 kg weight gain Increase the risk of hypoglycemia Glyburide increases risk of hypoglycemia slightly more compared to glimepiride and glipizide.
Acts on the liver to reduce gluconeogenesis and causes a decrease in insulin resistance via increasing AMPK signalling. Associated with weight loss Lower risk of hypoglycemia compared to other antidiabetics Decreases low-density lipoprotein Decreases triglycerides No effect on blood pressure Lowered all-cause mortality in diabetics Inexpensive.
Higher risk of gastrointestinal side effects Due to the risk of potentially fatal lactic acidosis , contraindicated in people with shock ; with acute or chronic, moderate or severe kidney disease or at risk for impaired kidney function from intravenous dye ; and with acute or chronic metabolic acidosis Risk of lactic acidosis also is increased for people with unstable or acute heart failure , liver disease , or alcoholism , or who are recovering from major surgery Increased risk of vitamin B12 deficiency [5] Metallic taste [5].
Alpha-glucosidase inhibitors acarbose , miglitol , voglibose. Inhibit carbohydrate digestion in the small intestine by inhibiting enzymes that break down polysaccharides. Slightly lower risk of hypoglycemia compared to sulfonylureas Associated with modest weight loss Decreases triglycerides No detrimental effect on cholesterol.
Less effective than most other diabetes pills in lowering glycated hemoglobin Increased risk of GI side effects than other diabetes pills except metformin Inconvenient dosing.
Thiazolidinediones Pioglitazone , Rosiglitazone. The first generation of these drugs, in use from to , will have names that are completely unrecognisable for the modern reader, and will never appear in anybody's exam papers, as most people writing the questions weren't even alive when these molecules slipped quietly out of the world.
For a thorough review of their history the reader is invited to look up the work by Selizer or Srivastava et al , with the usual caveat that it would achieve nothing useful. In short, these are all drugs with a central S-arylsulfonylurea structure from which some substituents hang, the exact nature of which tends to govern their pharmacodynamic effects and some of their pharmacokinetics:.
The second generation of sulfonylureas were developed in ther s and became available in the early s in response to some concerns about the cardiovascular safety of the first-generation agents. The University Group Diabetes Program was responsible for generating these concerns.
The pragmatic reader will ignore this historical detour and be simply satisfied with knowing that this group of drugs remains in use today and includes gliclazide glibenclamide and glipizide. Glimepiride is the only member of the third generation of sulfonylureas.
Reading reviews of this drug eg. Gale, , one wonders whether there was really any point in creating a whole new generation just for this. The main difference between glimepiride and the previous generation of sulfonylureas is the reduced incidence of adverse effects, specifically of hypoglycemia and of the cardiovascular risk as glimepiride seems to have a lower affinity for myocardial ATP-sensitive potassium channels.
Another difference was the once daily administration. Understandably, most people reword this mellifluous class name as "glitazones". This category of oral hypoglycemic was discovered by accident when a Japanese pharma company were trying to create better fibrates to treat hyperlipidemia in diabetics specifically, in a chronically voracious obesity model of the rat.
In short the intended variable triglycerides were only modestly improved by these test substances, but alongside this effect the authors noted a reduction in the degree of insulin resistance.
The first of these ciglitazone has subsequently been removed from the market because of hepatotoxicity; another rosiglitazone is no longer on sale in the US because of concerns regarding increased cardiovascular risk. Why interfere with the complicated inner clockwork of the carbohydrate metabolic apparatus, when you can just prevent carbohydrate absorption?
That is the main objective of inhibiting α-glucosidase, a brush border enzyme of the small intestine which is mainly involved in the hydrolysis of terminal starch residues which releases glucose.
To disable this enzyme means to slow the metabolism and absorption of carbohydrates, which achieves the laudable goal of reducing postprandial hyperglycemia. Chemically, this is achieved by presenting the enzyme with some kind of decoy to chew on, something that resembles the original substrate but which the enzyme can't do anything interesting with.
Thus, voglibose and acarbose are both weird aminosugars that vaguely resemble D-glucose: acarbose is a maltose molecule with an acarviosin moiety attached to it, and voglibose is an N-substituted derivative of valiolamine.
You don't have any enzymes interested in absorbing or metabolising these alien chemicals, and they are mainly broken down by gut bacteria. Miglitol is a more recent addition, a sugar alcohol structurally very similar to glucose but derived from deoxynojirimycin which can be absorbed systemically though it simply passes through politely without touching anything and exits via the kidneys.
Otherwise abbreviated as "glinides", these are benzamides which share their mechanism of action with sulfonylureas. They are structurally dissimilar , even though they might have similar names - for example repaglinide is a piperidine derivative, and is recognisably different from nateglinide, which is made from phenylalanine.
Their structure has some vague similarities to the structure of the latter generations of sulfonylureas for example their molecules curl up into the same sort of U-shaped conformation , which is thought to be the explanation for their sulfonylurea-like behaviour i.
the bind the same target sites but with weaker affinity and for shorter periods. Unsurprisingly, many people tend to refer to these substances as "gliptins". In passing, it is interesting to note that they are all structurally rather different, and all do weirdly different things to the DPP-4 enzyme - for example, sitagliptin pretends to be a substrate, linagliptin interacts with the catalytic site in a way that prevents it from accepting proper substrates, and vildagliptin and saxagliptin engage in some kind of strange reversible covalent bond with the enzyme, deactivating it for a much longer period than what one might expect from their short plasma half lives.
Glucagon-Like Peptide-1 GLP-1 is also occasionally known as "incretin". All of the available agents that mimic the work of this endogenous small bowel hormone are small peptides that resemble human GLP-1 to a lesser or greater extent. Exenatide, the first of these, was developed from exendin-4 , which is a minor constituent of the venom of Heloderma suspectum , the Gila monster.
From this weird herpetological origins, we now have a remarkable array of highly specific GLP-1 agonists, listed and explored by Hinnen Of the other agents, the modern Western audience will probably be most familiar with liraglutide and dulaglutide. The reader outraged at the inclusion of these drugs in the chapter supposed to be about oral hypoglycemic agents has every right to be disappointed.
To be sure, these are all rather large molecules, and none of them could never be administered enterally. For example, dulaglutide is attached to an FC fragment of IgG, and weighs about 60 kDa, whereas liraglutide is decorated with a fatty acid molecule that causes it to self-associate into large oligomers.
However, they do exist, and ICU trainees are probably expected to be at least vaguely aware of them. Though the author may have used a more inclusive term for the chapter title "non-insulin agents used in the control of diabetes" for example , it seemed better to follow the wording of the CICM syllabus, as that is a more natural search string for an exam candidate.
One could just as easily classify these drugs alongside osmotic diuretics, as their main site of action is the kidney, and the main activity is to prevent the reabsorption of a solute.
They are all vaguely based on phlorizin , a naturally occurring nonselective SGLT-1 and SGLT-2 inhibitor which is too unstable to be available orally, and tends to block intestinal SGLT-1 transporters, with predictably humorous effects on the gut microbiome Kalra, The structure and function relationship of these effects is not completely clear but the 'flozin molecules all share a glucose moiety as a feature, suggesting some kind of substrate mimicry is probably playing a role.
The main modifications which spawned dapagliflozin and empaglflozin from phlorizin have been directed at making them more selective for SGLT-2 and increasing their chemical stability to help their oral bioavailability.
The road to safe effective management of diabetes is littered with abandoned wreckages of failed and forgotten pharmacological agents, the wind rustling through their fading promotional literature.
As a condition that affects a large proportion of the affluent West, the market is large, rich, white and old, and so one might expect a lot of pharma company research attention to be directed to finding the hot new thing, which by necessity means multiple safety-related retractions, false starts, failures, and needless duplications.
Into this category fall amylin agonists like pramlintide and bile acid sequestrants like colesevelam , names which the reader will immediately forget with no adverse professional effects. Apart from these, a lot of drugs can cause hypoglycemia as a side effect eg. bromocryptine and THAM , but that does not mean that we should be using them routinely to lower the blood glucose.
They are mentioned here as asides, for no reason other than the worship of completeness. Surely they are called oral hypoglycemics for a reason. For the selection of drugs discussed here, oral administration is the only accepted method.
Only the GLP-1 receptor agonists disagree with this trend and require subcutaneous administration. Glibenclamide and acarbose are the only drugs of this group which are not especially well absorbed via the oral route.
Acarbose obviously is non-absorbable as you have no mechanisms for its uptake, but it does all of its work in the gut anyway, so it can safely remain there. Glibenclamide is the black sheep of the sulfonylurea group because its oral absorption is frustrated by extremely poor water solubility, and many articles are dedicated to creating and testing various excipients to make it dissolve better.
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. Author Affiliations Article Information From the Baylor College of Medicine, Houston, Tex.
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Otal hypoglycemic drugs, including glucagon-like peptide 1 receptor agonists GLP-1RACardiovascular exercises for improved overall flexibility peptidase-4 inhibitors Drygs and Oral hypoglycemic drugs cotransporter 2 inhibitors SGLT-2iwhich brings more Oal for OOral treatment Oral hypoglycemic drugs type 2 diabetes T2DM. They are generally well tolerated, Oral hypoglycemic drugs caution is required Oral hypoglycemic drugs rare cases. Clinical trials have show good glycemic control with combination therapy with new hypoglycemic drugs in prediabetes and T2DM mostly traditional stepwise therapybut early combination therapy appears to have faster, more, and longer-lasting benefits. Clinical and preclinical studies support that SGLT-2i exerts its protective effect on heart failure through indirect and direct effects. How this comprehensive protective effect regulates the dynamic changes of heart genes needs further study. According to IDF diabetes atlas 10th edition: Globally, 1 out of every 10 adults aged 20—79 have diabetes. This chapter Oral hypoglycemic drugs related to Section U2 drugz from the CICM Primary Hypoglyfemicwhich expect drgs exam candidate to Foods that boost immunity the pharmacology of oral hypoglycemic drugs". Oral hypoglycemic drugs could be an extremely difficult topic Oral hypoglycemic drugs cover Oral hypoglycemic drugs hypolgycemic relevance in the exam was greater, but fortunately only two past paper questions mentioned it, which means one may take a lackadaisical approach and gloss over a lot of the boring detail. Examiner comments emphasised the need for "a strong and logical structure" and "more correct information"which seem like reasonable expectations. It also feels like it would suit the answers better to categorise these drugs by mechanism of action as describing the mechanism of action was one of the main topics in the exam questions. This is the sub-grouping chosen for the summary below.
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