PCC SOM 2026 Pharmacology and Therapeutics PDF

PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.09.01 PANCREATIC HORMONES & ANTI-DIABETIC DRUGS PHARMACOLOGY LECTURE LECTURER: Dr. Marcelino Salango DATE: February 5, 2024 OVERVIEW OF EGREGIOUS ELEVEN Currently, there are 11 accepted possible defects that may contribute to Diabetes. Each pa;ent will ha...

PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.09.01 PANCREATIC HORMONES & ANTI-DIABETIC DRUGS PHARMACOLOGY LECTURE LECTURER: Dr. Marcelino Salango DATE: February 5, 2024 OVERVIEW OF EGREGIOUS ELEVEN Currently, there are 11 accepted possible defects that may contribute to Diabetes. Each pa;ent will have any of these defects. We may have pro-diabe;c genes that if switched on may manifest diabetes later in life. From those genes, there are at least 250 iden;fied genes located in different chromosomes. Gene for type 1 diabetes is located in chromosome 6 Even though you have those genes if they are not switched on, you won’t develop diabetes. The goal is not to ac;vate those genes. All diabe;c pa;ents have different combina;on of ac;vated genes. Those genes may manifest any of the 11 presenta*ons: 1. PANCREATIC BETA CELL 2. INCRETIN EFFECT 3. ALPHA CELLS DEFECT 4. ADIPOSE 5. SKELETAL MUSCLE 6. LIVER 7. BRAIN 8. COLON/ BIOME 9. IMMUNE DYSREGULATION/ INFLAMMATION 10. STOMACH/ SMALL INTESTINE 11. KIDNEYS 1. PANCREATIC BETA CELL For instance, if you acquired the gene encoded for a long-living Pancrea;c B cells, even though there will be a lot of insult, it won’t result to Diabetes. Beta cell func;on is related to pancrea;c mass. The bigger the mass, the more beta cells you have, there is more insulin produc;on. In the brain, if you have a destroyed sa;ety center, you tend to eat more, you develop more fats which causes hyperfunc;oning of beta cells and eventually its destruc;on. Whatever your problem is, the end result is β-cell destruc;on. GOLD STANDARD of treatment is to preserve the beta cell 2. INCRETIN EFFECT GLP-1 s;mulates the β-cells to produce lower amount of insulin because it becomes more sensi;ve to the amount of glucose. It s*mulates β-cells to produce insulin but blocks alpha cells’ produc*on of glucagon. No incre;n effect causes maximal s;mula;on of insulin which may result to destruc*on of β- cells N OT E TA K E R : TONY. L.JANELLE.XYRA.BOY 3. ALPHA CELLS DEFECT Normally, when Beta Cells produce Insulin, Alpha Cells simultaneously produce Glucagon Hyperac;ve α-cells results to produc;on of more glucagon that s;mulate an increase in blood concentra;on of glucose. Nos. 4,5,6 contributes to INSULIN RESISTANCE - usually TABAIN and has fady liver, 4. ADIPOSE Adipose ;ssue releases fady acids that block insulin to join the receptor. 5. SKELETAL MUSCLE If the Skeletal muscle doesn’t u;lize glycogen (such as in cases of sarcopenia or immobiliza;on) or is not able to get glucose from the blood or decreased peripheral uptake (such as in cases of defec;ve or lack of Glut 4), this will result to hyperglycemia. Unlike the liver, muscles can’t share its glycogen 6. LIVER Liver overproduces glucose especially during the fas;ng state (very ac;ve gluconeogenesis) as manifested by very high glucose level in the morning. 7. BRAIN Diabetes Mellitus type 3, appe;te center damage, dopamine surge, If there is nutri;on deficiency during pregnancy, Stress hormones are increased. There will be an increased sympathe;c tone in the baby. 8. COLON/ BIOME There are certain bacteria in the gut that if they are dominant, alter how the gut absorbs food. They may also inhibit L cells to produce GLT-1 or alter GLT-1 secre;on. Fecal transplanta;on=transplanta;on of bacteria through NGT or Rectally. 9. IMMUNE DYSREGULATION/ INFLAMMATION There are diseases that may cause hyper/hypoac;va;on of immune system that may cause damage of the β-Cells or the mitochondria of the β-Cells. Presence of inflammatory mediators such as reac;ve oxygen species that may damage the β- cells. 10. STOMACH/ SMALL INTESTINE Rate of absorp;on of glucose. Gastric emptying ;me or Intes;nal emptying ;me is altered to the point that it enhances absorp;on of nutrients. JOAN. JUDAH PORL. AFRIL Page 1|5 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.09.01 PANCREATIC HORMONES & ANTI-DIABETIC DRUGS 11. KIDNEYS Normally Kidneys filter sugar. Reabsorbs sugar back in about 180 g/day in normal selng when you are fas;ng. If kidney reabsorbs sugar during the plenty state, it ❖ The interplay of the following causes diabetes: a. Genes you inherited b. Genes that were switched on c. Response of the cell in relation to the genes activated and in the inflammatory mediators. MEDICATIONS FOR DIABETES ARE BASED ON THE EGREGIOUS 11: 1. BETA-CELL a. Insulin lowers blood sugar immediately while keeping the beta cells to rest. b. GLP-1 receptor agonist or GLP-1 analogs: GLP-1 is tweaked so that it can work longer (In vivo, GLP-1 release is only 10 minutes) c. DPP 4 inhibitor: Found in intes;nal lining, lumen, and in the blood. Digest GLP-1. Hyperac;ve DPP 4 consumes GLP-1. Inhibi;on of DPP-4 prolonged the ac;on of GLP-1 d. Ranolazine s;mulates beta cell-like GLP-1 2. INCRETIN EFFECT a. GLP-1 Analog b. DPP-4 3. ALPHA CELL DEFECT a. GLP-1 o blocks Alpha cell from producing glucagon b. DPP-4 c. Pramlin;de specific for alpha cell inhibi;on 4. ADIPOSE a. Me[ormin: No exact mechanism b. Thiazolidinediones Inhibit lipolysis; Hastens adipose cell differen;a;on or ac;vates the adipocytes to mature immediately to limit division of these cells. Pag ang mga adipocytes are immature or not yet differen;ated, there is a tendency for them to divide and divide N OT E TA K E R : TONY. L.JANELLE.XYRA.BOY 5. SKELETAL MUSCLE a. Me[ormin: No exact mechanism b. Thiazolidinediones Regulate gene expression by binding with PPAR-y and PPAR-a. Nuclear receptors are found in the cytoplasm that when they pair to an external ac;vator. They enter the nucleus and s;mulates the group of genes that encode for glut 4 and specific enzyme that enhance glycose entry and metabolism which promotes increase of insulin sensi;vity. 6. LIVER a. Meoormin: Acts on AMP kinase - has a blocking effect on one of the pathways of gluconeogenesis in the liver and kidneys Side effects: Gastrointes;nal problems Delays reac;on ;me for athletes Meoormin is best given at NIGHT because hepa;c glucose produc;on happens during fas;ng. Usual dose starts to 500mg to 2grams daily( in divided doses) b. Thiazolidinediones: Regulate gene expression by binding with PPAR-gamma and PPAR-alpha. Effects are not immediate Nuclear receptors are found in the cytoplasm when they pair to an external ac;vator. They enter the nucleus and s;mulates the group of genes that encode for glut 4 and specific enzymes that enhance glycose entry and metabolism which promotes the increase of insulin sensi;vity What are PPAR? PPAR alpha: S;mulates lipid metabolism Beta: S;mulates carbohydrate metabolism PPAR pairs with RXR Re;noic Acid Receptor-a light sensi;ve protein which is ac;ve during the day;me Thiazolidinediones are best given at NIGHT. Side effects: Edema, Bone Fracture 7. BRAIN a. GLP-1 Receptor Agonist: acts on the stomach and delays gastric emptying, decrease appe;te JOAN. JUDAH PORL. AFRIL Page 2|5 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.09.01 PANCREATIC HORMONES & ANTI-DIABETIC DRUGS b. DDP-4: same effect with GLP-1 but with shorter effect (Best Time To Give Before Breakfast) c. Dopamine Agonist Receptor d. Appe*te Suppresant 8. COLON/BIOME a. GLP-1 Receptor Antagonists b. DDP-4 c. Pre/Probio*cs d. Me[ormin: Good bacteria tends to grow faster 9. IMMUNE DYSREGULATION/ INFLAMMATION a. An*-inflammatory agents: NSAID such as ASPIRIN (non specific) b. GLP-1 Receptor Antagonists c. DPP-4 10. STOMACH/SMALL INTESTINE a. AGI (Alphaglucosidase Inhibitor) Alpha-glucosidase cuts alpha glycosidic bond of starch. If we inhibit this it causes delayed absorp;on of starch. Usually given to pa;ent who has a high postprandial blood sugar. Best ;me given just before or during meals. Side Effect: Flatulence b. GLP-1 Receptor Antagonists c. Pramlin;de: amylin analog; binds to amylin receptor Every ;me the pancreas releases insulin, AMYLINE is also produced. It has an effect on the stomach on rela;on with sa;ety, gastric emptying and GIT mo;lity. Amyline deposits in brain causes premature senile demen*a 11. KIDNEY a. SGLT-1 inhibitor: Block Renal Glucose Resorp;on Improves cardiovascular status of pa;ents. ►The primary underlying mediator of diabetes-related complica7ons is the damage wrought by hyperglycemia and other excess fuels engendered by reduced insulin or a reduced insulin effect due to abnormal b cell func7on. The development and progression of any given complica7on depends on the interplay between gene7c predisposi7on, environmental cues, insulin resistance (IR), immune dysregula7on and inflamma7on, intracellular fuel excess, and comorbidi7es (such as hypertension and hyperlipidemia). Abbrevia7ons: AGI, Alphaglucosidase inhibitors; b/A, b-hydroxybutyrate/acetoacetate; DPP-4, Dipep7dyl pep7dase-4; GLP-1 RA, glucagon-like pep7de 1 receptor agonists; L/P, lactate/pyruvate; QR, quick release; SGLT2, Sodiumglucose co-transporter 2; SH/SS, reduced thiol cysteine/oxidized thiol cysteine; TZDs, thiazolidinediones. ❖ Complica;ons of diabetes are generally mediated by ROS ❖ Drugs for dyslipidemia, cholesterol, triglycerides will only work if the BP is low ❖it is complicated to manage diabetes since it requires mul;ple drug therapy N OT E TA K E R : TONY. L.JANELLE.XYRA.BOY JOAN. JUDAH PORL. AFRIL Page 3|5 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.09.01 PANCREATIC HORMONES & ANTI-DIABETIC DRUGS ►Chronic exposure to hyperglycemia and glucolipotoxicity from excess fuel leads to the release of reac7ve oxygen species (ROS). This ac7vates pathways including polyol flux, advanced glyca7on end-product (AGE) forma7on, ac7va7on of protein kinase C (PKC), and hexosamine flux, resul7ng in inflamma7on. These trigger signaling pathways, induc7on of transcrip7on factors, gene transcrip7on, and epigene7c modifica7ons, such as histone modifica7ons, DNA methyla7on, noncoding RNA in miRNAs, and long noncoding RNAs (lncRNAs). Gene transcrip7on favors cell hypertrophy, prolifera7on, remodeling, and apopto7c signaling, which physiologically manifest as coronary artery disease (CAD), peripheral artery disease (PAD), re7nopathy, neuropathy, and kidney impairment (reviewed in ). Systemic effects include the exacerba7on of the diabe7c state, especially as insulin secre7on from the laboring b cells decreases and as cardiovascular (CV) func7on is compromised. ❖ Glucotoxicity creates synthesis of polyols à many poly alcohols are being derived eg., Sorbitol ❖ Sorbitol is parang vitamin c na dinagdagan ng hydroxyl group. Thinking of it na madami ng glucose yung pa=ent ko, tas dadagdagan ko pa ng vitamin C à magcoconvert to sorbitol à that’s why I removed vitamin C in my diabe=c pa=ents kasi magiging sorbitol lang yan and pag ang sorbitol dumami, pwedeng mag-accumulate sa lens and ends up with cataracts ❖ Glucose can also connect with proteins, amino acids and it generates advanced glyca=on end- product ❖ SE of me(ormin is lac7c acidosis, so in pa0ents with high risk to develop lac0c acidosis à do not give me(ormin ❖ Condi7ons that are at high risk to develop lac7c acidosis: coronary artery disease, peripheral arterial occlusive disease, ongoing severe infec0ons, renal failure ►The release of insulin is through a biphasic process. It is released upon glucose absorp7on. The ini7al amount released depends on the amount available in storage. The second insulin release phase is ini7ated when the insulin in storage is depleted. Since insulin has to be synthesized, processed and secreted for the period when blood glucose levels are high, therefore the second released is prolonged. Also the beta cells have to regenerate the stores of insulin ini7ally depleted in the fast response phase ❖ Sulphonylureas work by s0mula0ng the β-cell to release more insulin. They work by binding to the ATP- sensi0ve potassium channel which they level as sulphonylurea receptor Danger: the sulphonylurea receptor or the ATP- sensi0ve potassium channel is found not only in the beta cell but is found in other cells as well esp. in the cardiac 0ssue. If you blocked that, it will cause depolariza0on à rhythm disturbances N OT E TA K E R : TONY. L.JANELLE.XYRA.BOY JOAN. JUDAH PORL. AFRIL Page 4|5 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.09.01 PANCREATIC HORMONES & ANTI-DIABETIC DRUGS REVIEW QUESTIONS 1. True or False: The gene for type 1 diabetes is located in chromosome 6. 2. True or False: The bigger the pancrea=c mass, the more beta cells are produced, resul=ng in more insulin produc=on. 3. True or False: GLP-1 s=mulates beta cells to produce lower amounts of insulin and blocks alpha cells' produc=on of glucagon. 4. True or False: Adipose =ssue releases faIy acids that block insulin from joining the receptor. 5. True or False: Liver overproduces glucose, especially during the fas=ng state, as manifested by very high glucose levels in the morning. 6. Which medicaEon is best given at NIGHT due to its effect on hepaEc glucose producEon during fasEng? a. MeLormin b. Thiazolidinediones c. GLP-1 Receptor Agonist d. DDP-4 7. What are the side effects of Thiazolidinediones? a. Gastrointes=nal problems b. Delays reac=on =me for athletes c. Edema, Bone Fracture d. None of the above 8. Which medicaEon acts on the stomach and delays gastric emptying, decreasing appeEte? a. GLP-1 Receptor Agonist b. DDP-4 c. Dopamine Agonist Receptor d. Appe=te Suppresant 9. Which medicaEon is usually given to paEents with high postprandial blood sugar and should be taken just before or during meals? a. GLP-1 Receptor Antagonists b. AGI (Alphaglucosidase Inhibitor) c. Pramlin=de d. SGLT-1 inhibitor 10. Which medicaEon blocks renal glucose resorpEon and improves cardiovascular status of paEents? a. SGLT-1 inhibitor b. GLP-1 Receptor Antagonists c. DPP-4 d. MeLormin N OT E TA K E R : TONY. L.JANELLE.XYRA.BOY 1-5. TRUE 6. A 7. C 8. A 9. B 10. A JOAN. JUDAH PORL. AFRIL Page 5|5