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Oral hypoglycemic drugs

Oral hypoglycemic drugs can be categorized into several classes based on their mechanism of action: 1) Insulin secretagogues like sulfonylureas and meglitinides which bind to sulfonylurea receptors and modulate K+ ATP channels to stimulate insulin secretion. 2) Insulin sensitizers like biguanides (e.g. metformin) and thiazolidinediones which improve insulin sensitivity. 3) Alpha-glucosidase inhibitors like acarbose which slow carbohydrate absorption from the intestine. 4) Newer drug classes targeting incretin pathways like GLP-1 agonists and DPP-4 inhibitors or affecting other processes like amylin

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Oral hypoglycemic drugs Dr Reham ellisy Assistant lecturer pharmacology department
Oral hypoglycemic 1_Insulin secretagogues Drugs that bind to sulfonylurea receptors (K+ATP channel modulators) They include A) sulfonylureas 1- First generation e.g.tolbutamide,chloropropamide 2-Second generation e. g. Glibenclamide, glimepride, glipizide, gliclazide. B) Non sulfonylurea (meglitinides) :e.g.repaglinide&nateglinide
Oral hypoglycemic 2-Insulin sensitizers: A) Biguanides e.g.metformin B)Thiazolidendiones e.g:rosiglitazone&pioglitazone 3-Drugs that affect absorption of glucose from intestine : alpha-glucosidase inhibitors:acarbose& miglitol. new antidiabetics: 4-Glucagon like peptide -1(GLP-1)agonists (incretin like) :e.g.exendin_4(exenatide) &liraglutide 5-Dipeptidy peptidase inhibitors(DPP_4 inhibitors): E. G. Sitagliptin, saxagliptin. And vildagliptin. 6-Amylin analogue:pramlintide. 7-Sodium glucose co transporters2 inhibitors.
1-Secretagogues A)Sulfonylurea Members • First generation 1-Tolbutamide. 2-Acetohexamide. 3-Chlorpropamide. • Second generation 1-Glibenclamide(glyburide) 2-Glipizide :30 min b meal. 3-Gliclazide(diamicron) 4-Glimepride(amaryl)
Sulfonylureas • Mechanism of action 1-Bind to(SUR)-close k channel-depolarization Ca dependent exocytosis of insulin 2-↓glucagon release 3-↓gluconeogenesis
Pharmacokinetic 1-Absorption :food and hypoglycemia decrease absorption. 2- Distribution :high bound to p.p (90_99%)-pass bbb-pass placeta. 3-Metabolism:in liver by HME 4-Excretion :kidney • Therapeutic uses 1. Type 2 diabetes mellitus (NIDDM).after failure diet & exercise. 2. Chlorpropamide:central diabetes insipidus.
Sulfonylurea drug interactions Decrease action of sulfonyl ((hyper glycemia Enhance action of sulfonyl (hypoglycemia) 1-Counter regulatory hormones: oral contraceptives,glucagon, .corticosteroids 1-Displace from protein binding: salicylates,sulfonamides. 2-HME inducers:Phenobarbitone, phenytoin, Rifampicin. 2-HME inhibitors : Cimetidine ketoconazole, Chloramphenicol,MAO-inhibitors. 3-Suppress insulin release: Thiazides , furosemide, diazoxide,phenytoin Verapamil. B2 agonist increase glycogenolysis. 3-Synergise with or prolong pharmacodynamic action: Salicylates , alcohol. Propranolol.
Side effects(sulfonylureas) 1-Hypoglycemia :esp overdose,elder,hepatic,renal. 2-weight gain:Appetite center stimulation. 3-Allergy. 4-Bone marrow inhibition.Chloropropamide. 5-Cholestatic jaundice chloropropamide -CNS manifestation. 6-↑coronary heart disease esp first genereation. 7-Edema due to antiduritic effect. chloropropamide 8-Failure of response. 9-GIT upset. 10 –Teratogenic& fetal hypoglycemia.
B) Non sulfonylureas (insulin secretagogues) - Meglitinides • Members: Repaglinide , Nateglinide • Structurally different from sulfonylureas. • Mechanism of action as sulfonylurea. • Rapid onset-short duration-used orally(preprandial uses). • Metabolism in liver-adjust in hepatic insufficiency • Side effects: hypoglycemia • Secondry failure
Meglitinides (mechanism of action)
2-Insulin sensitizers A-(Biguanides) • Metformin • Euglycemic-not hypoglycemic • MOA:Inhibit mitochondrial complex 1 • ATP↓&AMP↑→↑ AMP-dependent Protein kinase(AMPK) 1-↑Fatty acid oxidation. 2-↑Glucose uptake, 3-↑Anaerobic glycolysis. 4-↑ Insulin sensitivity. 5- ↓Lipogenesis & ↓ Gluconeogenesis. 6- ↓Glucagon release. 7-↓Intestinal glucose absorption.
Biguanides Kinetics • Not bound to P.P • Drug transported by (OCT1)to liver &sk muscle • Eliminated by kidney unchanged by (OCT2) Therapeutic uses: 1-Monotherapy&combination with oral hypo in type 2 DM 2-Reduce the risk of diabetes in high risk pts 3-Treatment of infertility in women with PCO. improve ovulation,menstrual cyclicity ,reduce androgen.
Biguanide side effects 1-Gastrointestinal :nusea, vomiting , diarrhea and abdominal cramps. 2-Metallic taste. 3-Lactic acidosis: presence of concurrent illness as sepsis,mycordial infarction,heart failure and renal failure. 4- Vit B12 malabsorption 5-Drug interaction: cimetidine, furosemide and nifedipine.(How?)
B-PPARᵧ Activators (Thiazolidinediones) • Pioglitazone,rosiglitazone,troglitazone. • Mechanism of action: bind to PPARᵧ present in muscle,fat,liver.
Thiazolidinediones • Therapeutic uses: -Alone or with sulfonylurea-or metformin –or insulin.the combination has advantage of not causing hypoglycemia. • Side effects: 1-weight gain &oedema .Macular oedema. 2-Increased risk of heart failure. 3-Hepatotoxic,teratogenicity. 4-Rosiglitazone ↑ risk of myocardial ischemia. 5-Increased risk of osteoprosis and bone fracture. 6-Pioglitazone ↑risk of cancer bladder.
3-Alpha glucosidase inhibitors Mechanism of action:
3-Alpha glucosidase inhibitors • Examples : acarbose , miglitol.orally taken • Slow absorbtion of carbohydrates • Best one decrease post prandial plasma glucose • Side effects: 1. Malabsorption,↓absorption of metformin (cannot combined with it ) 2. Flatulence 3. Diarrhea 4. Don’t stimulate insulin release,don’t induce hypoglycemia.
4-Glucagon like peptide -1(GLP-1)agonists • Mechanism of action :
(GLP-1)Incretin like • Exenatide-liraglutide. • Given SC. • Used in combination with metformin or sulfonylurea. • Side effects: 1. Nusea,vomiting. 2. Weight loss 3. Acute pancreatitis 4. Hypoglycemia esp with sulfonylurea
5-DIPEPTIDYL PEPTIDASE-4 inhibitors • Mechanism of action:
DPP-4 INHIBITORS • Sitaglitin,saxagliptin. • Used orally. • Used as montherapy or in combination with metformin. • Side effects: 1. Headache 2. Nasopharyngitis 3. Upper respiratory drug infections
6-PRAMLINTIDE Mechanism of action:
PRAMLINTIDE • Amylin analogue. • Binds to amylin receptors → reduction of glucagon release Delay gastric emptying & satiety. • Used SC prior to meals. • Used adjunct therapy to insulin in type 1&type 2 diabetes. • Side effects: 1. Nusea 2. Hypoglycemia especially with insulin.
9-Sodium-glucose co-transporter 2 inhibitors • Canagliflozin,dapagliflozin,empagliflozin. • used orally in type 2 DM. • Side effects: 1-↑Incidence of genital & Urinary infections. 2-Osmotic diuresis → Intravascular volumeDepletion &hypotension Contraindicated with low GFR
Oral hypoglycemic drugs
Oral hypoglycemic drugs