in this teach we are going to coverdrugs used for diabetes so let’s get right into itdiabetes mellitus is a chronic illnes characterized by high levels of bloodglucose that result from either inadequate insulin production orresistance of the body’s cadres to the action of insulin now the two mostcommonly encountered each type of diabetes are kind 1 in which insulin producingcells are destroyed thus eliminating insulin production and the second istype 2 in which there is insulin resistance and gradual insulindeficiency but first things first what is insulin and how does it work well itall starts with the menu that we eat which for the best part comes broken downby our digestive system into glucose following a meal when the blood glucoselevels rise beta cells of the pancreas islets start secreting insulin insulinis a peptide hormone that fastens to the insulin receptor and stimulates glucoseuptake by our cells now under the influence of insulin liver and skeletalmuscle place assimilated glucose in constitute of glycogen many other cadres instantly breakdown absorbed glucose to acquire ATP a molecule which provides immediatelyavailable force so in summary you can think of insulin as a key for entranceof glucose into cadres which either expend it immediately for power or collect it inorder to meet future demand so now what happens when blood glucose levels falltoo low well if that’s the case alpha cells of the pancreatic islets freeing adifferent peptide hormone that is glucagon glucagon simply has theopposite effect of insulin so for example when it acts on the liverit cases breakdown of stored glycogen into glucose which is then released intothe bloodstream so now let’s switch paraphernaliums and let’s talkabout medicines used to support diabetes the first group of agents I would like to discussis insulin and it’s analogs so human insulin can be reproduced by recombinantDNA technology exploiting bacteria or yeast the amino battery-acid cycle of the human rights insulincan also be altered to produce insulin analogs with different onset andduration of act now because insulin is a polypeptide it is prone todegradation in the gastrointestinal parcel therefore in order to be effectiveit’s generally determined by subcutaneous infusion insulinpreparations are generally divided into three major categories based on howquickly and how long they labour so firstly we have rapid and suddenly acting insulinspreparations that fall into this category are insulin Lispro insulinAspart and insulin Glulisine which are considered as rapid-acting producingpeak effect in as quickly as 30 hours and period of action of up to 5 hoursanother analog that belongs to this group is regular insulin which isconsidered as short-acting with pinnacle accomplish as quick as 2 hours andduration of act often less than 8 hours now you may wonder what givesthese analogs the ability to act quickly well here’s the thing insulin moleculesnaturally like to stick together forming so-called hexamers that is six insulinmolecules bound together these hexamers are too large to bridge from thesubcutaneous material into the bloodstream therefore they must first separate intosingle insulin molecules before absorption can occur so now what theclever scientists did is they adapted amino acid cycle of insulin moleculesto attain them less likely to aggregate which contribute to analogs with fasterabsorption and more rapid act next we intermediate acting insulin preparationthat falls into this category is NPH insulin also known as Isophane insulinunlike the rapid acting insulins NPH insulin has a little slower onset ofaction it causes peak influence somewhere around 6 hour marking and lastsabout 18 hours these longer lasting effects are accomplished simplyby addition of zinc and protamine to regular insulin which results in acomplex that is less soluble the final outcome is delayed absorption and thuslonger span of activity finally we have long-acting insulins with slowonset of activity lotions that fall into this category are the followinginsulin Detemir with a crest impact between 6 and 8 hours and durationof action of up to 24 hours next insulin Glargine which doesn’tproduce peak effect due to its continuous bringing of insulin for about 24 hoursand finally we have insulin Degludec which too doesn’t make peak effectand lasts beyond 24 hours and again all these long-lasting impacts are theresult of modifications to the insulin molecule in case of insulin Detemirfatty acid side chain was added to the insulin molecule which allows it to bindto albumin and thus slow down its freeing into the bloodstream insulinGlargine on the other hand was modified to have low-grade solubility at neutral pHwhich causes it to words precipitate in the subcutaneous material that slowlyreleases insulin into the bloodstream lastly insulin Degludec wasdesigned to form long series of hexamers in subcutaneous tissue that serve as a terminal from which insulin is continuously and slowly liberated nowwhen it comes to side effects not amazingly hypoglycemia or low-pitched bloodglucose is the most common one associated with the use of insulinanother adverse effect is lipodystrophy which can develop at the site ofrepeated insulin injections now let’s move away from the insulins and let’stalk about different type of injectable analog used in treatment of diabetesthat is synthetic amylin so first of all what is amylinwell pancreatic beta cells not only secrete insulin but also another peptidehormone called amylin amylin’s job is to delay gastricemptying to suppress postprandial glucagon secretion and to promote satietythe only amylin mimetic that’s currently available on the market is Pramlintide one of the biggest benefits of Pramlintide is that it allows insulindoses to be reduced nonetheless the risk of hypoglycemia is still there other commonside effects associated with Pramlintide are nausea and meagre weight lossnow let’s move on to the last group of injectable analogs that is incretinmimetics so first off what are incretins well incretins are a group of metabolichormones that are exuded from the intestine in response to food ingestion and theirjob is to stimulate pancreas to produce more insulin the two primary incretinhormones are glucagon-like peptide-1 GLP-1 for short and glucose-dependentinsulinotropic polypeptide GIP for short-lived so in theory increasingconcentrations of these hormones would benefit patients with diabetes howeveras it turns out their actions are actually quite limitedas a result of rapid inactivation by the enzyme dipeptidyl peptidase-4 DPP-4 forshort to solve this problem scientists were able to develop GLP-1 mimeticsthat are resistant to decline by DPP-4 enzyme example of agents thatbelong to this class are Exenatide and Liraglutide in addition to stimulatinginsulin secretion GLP-1 mimetics slow-witted gastric emptying and promote satiety asa outcome patients squandering these workers often ordeal weight loss some commonside effects also include GI difficulties such as nausea puke diarrhea andconstipation lastly there have been some reportssuggesting increased risk of pancreatitis associated with the use of GLP-1mimetics this is thought to be due to their proliferative results on pancreas now let’s substitution paraphernaliums and let’s talkabout oral antidiabetic agents so first I would like to discuss a class of drugsclosely related to GLP-1 mimetics namely DPP-4 inhibitors so another wayto enhance the effects of incretin hormones is to simply inhibit DPP-4enzyme who has responsibility for the inactivation of GLP-1 and GIP bypromoting the activity of GLP-1 and GIP hormones we increase insulin secretiondecrease gastric emptying and shorten glucagon liberate pharmaceuticals that belong tothis class include Alogliptin Linagliptin Saxagliptin and Sitagliptin side effects of DPP-4 inhibitors are identical to those of GLP-1 mimeticswith the most commonly reported being nasopharyngitis and headache now let’smove on to another class of oral antidiabetic negotiators that is sulfonylureas so in order to understand how sulfonylureas act first we need toreview the mechanism of glucose dependent insulin secretion frompancreatic beta cadres so accessible glucose enrolls beta cell through glucosetransporter 2 abridged as GLUT2 once inside the cell glucose getsmetabolized to create a bunch of ATP next the rising levels of ATP lead toinhibition of ATP-sensitive potassium paths thus blocking the inflow ofpotassium this in turn leads to depolarization of the cell’s membranewhich initiations activating of voltage-gated calcium channels and theninflux of calcium ultimately increased levels of calcium mediate fusion ofinsulin containing vesicles with the layer leading to insulin release sonow what sulfonylureas do is they bind to and impede the activity of ATP-sensitive potassium channels this just like incoming glucose initiations membranedepolarization calcium flow and eventually insulin secretion otheractions of sulfonylureas include increased sensitivity of beta cadres toglucose and shortened hepatic glucose production speciman of drugs that belongto this class are Glimepiride Glyburide and Glipizide some of the common sideeffects reported with sulfonylureas are hypoglycemia and weight income lastlybecause sulfonylureas are most protein cover and most are extensivelymetabolized in the liver by cytochrome p450 enzymes they tend to interact withwide variety of other drugs now let’s move on to another class of oralantidiabetic workers that is glinides so just like sulfonylureasthe glinides likewise stimulate insulin secretion from pancreatic beta cellshowever they accomplish that by binding to ATP-sensitive potassium directs at adifferent site and with different kinetics than sulfonylureas as a resultthey have a more rapid onset and shorter period of act this reaches glinidesa good alternative for cases with principally postprandial hyperglycemiaexample of drugs that belong to this class are Nateglinide and Repaglinide common side effects include hypoglycemia and value gain nonetheless therisk appears to be lower in comparison to sulfonylureas now let’s move on toanother class of oral antidiabetic workers that is biguanidesso unfortunately the exact cellular mechanism of action of biguanides is notentirely understood that being said the main blood glucose levels depres activityappears to be primarily through decreased hepatic glucose productionadditionally biguanides appear to slow intestinal absorption of glucose andincrease insulin sensitivity which increases peripheral glucose uptake theonly biguanide that’s currently available on world markets is Metforminmost common side effects of Metformin are limited to GI tract and includenausea upchuck diarrhea and loss of appetite which may lead to weight losslastly because Metformin abridges hepatic uptake of lactate it mayincrease probability of lactic acidosis particularly in patients with organdysfunction such as congestive heart failure or renal impairment now let’smove on to another class of oral antidiabetic agents that is thiazolidinediones thiazolidinediones labour primarily byselectively initiating nuclear receptor called peroxisome proliferator-activatedreceptor gamma PPAR-gamma for short-lived when activated this receptor fixes to DNAtriggering expression and repression of specific genes encoding proteins thatregulate glucose and lipid metabolism as well as insulin signal transduction thisleads to consequences such as increased insulin sensitivity in adipose tissueskeletal muscle and liver as well as inhibition of hepatic glucose productionadditionally thiazolidinediones promote fatty battery-acids uptake andutilization in adipocytes this decrease in fatty battery-acid concentrations in turnleads to increased uptake and utilization of glucose example of drugsthat belong to this class are Pioglitazone and Rosiglitazone now whenit comes to side effects in addition to lowering blood glucose levelsthiazolidinediones increase HDL levels this increase is especially pronouncedwith the use of Pioglitazone in part because of its effects not only on PPAR-gamma but also on PPAR-alpha as you may recall from my video discussing drugsfor hyperlipidemia PPAR-alpha is the main target offibrates which promote the formation of HDLprecursors on the other hand thiazolidinediones may also increase LDL levelshowever this increase appears to be limited simply to large less atherogenic LDL specks as for the other side effects the use ofthiazolidinediones has been associated with weight gain and fluid retentionleading to peripheral edema few cases of hepatotoxicity have also been reportednow let’s move on to yet another class of oral antidiabetic negotiators that issodium-glucose cotransporter-2 inhibitors so these agentssimply hinder glucose transporter are contained in the proximal convolutedtubules of the kidneys that is responsible for about 90% of glucosereabsorption inhibition of sodium-glucose cotransporter-2 leads toincreased urinary glucose excretion and thus reduced levels of blood glucosefurthermore this increase in glucose and sodium in urine produce mildosmotic diuresis which may contribute to small-time reduction in blood pressure andweight loss treats that belong to this class include Canagliflozin and Dapagliflozin when it comes to side effects the most common ones are thirstincreased urination and increased risk of urinary tract and genital infections nowlet’s move on to the final class of oral antidiabetic agents that isalpha-glucosidase inhibitors so firstly what is alpha-glucosidase wellalpha-glucosidase is an enzyme located in the intestinal graze territory that isresponsible for breaking down carbohydrates into simple sugars such asglucose so when alpha-glucosidase inhibitor blocks this enzyme theabsorption of glucose is retarded arising in lower postprandial glucoselevels stimulants that belong to this class include Acarboseand Miglitol now one of the biggest disadvantages of these agents is theirsignificant gastrointestinal side effects which include abdominal crampsbloating ga and diarrhea and with that I wanted to thank you forwatching I hope that members can experienced this video and as ever abide chanted for more
