DM Pharmacology Summary PDF

Pharmacology of Diabetes Mellitus (summary) __________________________________________________________ - Insulin Anabolic Anticatabolic The Unit units/ml Source - Pork, Beef-Pork , Human (recombinant DNA technology) In DM1 we have no choice but to give insulin In DM2 indications to give insulin: 1...

Pharmacology of Diabetes Mellitus (summary) __________________________________________________________ - Insulin Anabolic Anticatabolic The Unit units/ml Source - Pork, Beef-Pork , Human (recombinant DNA technology) In DM1 we have no choice but to give insulin In DM2 indications to give insulin: 1- Uncontrolled glucose level for any reason 2- During surgery, we will stop all the oral drugs and start the patient on insulin 3- During pregnancy 4- During severe infections or any crisis - Insulin has a tyrosine receptor Has alpha and beta units Alpha is extracellular Beta is trancellular Alpha is the insulin binding site Beta has the tyrosine kinase activity 1/2 life of insulin is short only few minutes Blood glucose level and the amino acid level controls the insulin secretion Basal insulin secretion, the background secretion of insulin Peak of insulin secretion after every meal Insulin is short acting , its what we use the most. It forms a complex with the zinc like what the body normally do. It acts within 30 minutes to an hour. So its taken before meals in 30 minutes If i give a patient has taken the insulin during eating not before eating in half an hour, what will happen? Early postprandial hypoglycemia bcz there is no match between the glucose levels and insulin. suppose another person was so hungry and he didn’t take his insulin shot, what will happen to him? Hyperglycemia Changing the properties of insulin preparation can alter the onset and duration of action Type Duration Lispro Rapid-acting insulin - Absorbed to the circulation very rapidly Aspart Rapid-acting insulin -Absorbed to the circulation very rapidly “the fastest” (mcq) Regular Regular insulin Lent insulin Intermediate-acting insulin NPH Intermediate-acting insulin Insulin Glargine Long-acting insulin - Absorbed rapidly but slower than lispro and aspart - Amorphous precipitate of insulin and zinc and insoluble crystals of insulin and zinc. Releases insulin slowly to the circulation - Glent insulin given 2x a dayily - R-insulin + Protamine zinc insulin - Releases insulin slowly to the systemic circulation - Given 2x a dayily - One time a day - Prepared by modification of the insulin structure - Precipitate after S.C. injection to form microcrystals that slowly release - Humalin Control over a period of time insulin to the systemic circulation (N.B. cannot be mixed with other insulins) Long-acting insulin marketed under the names Lantus - NPH + Regular - Given 2x a dayily !1 - Drugs interfering with glucose tolerance Diazoxide Thiazide diuretics Corticosteroids Oral contraceptives Streptazocine - Phenytoin *All these drugs increase the blood glucoseconcentration • Methods of Insulin Administration - Insulin syringes and needles - Pen-sized injectors - Insulin Pumps Pharmacotherapy: Type 1 DM - The insulin regimen has to mimic the physiological secretion of insulin - More intense insulin regimen require more intense monitoring I. Example: 1- Morning dose (before breakfast): Regular + NPH or Lente II. Before evening meal: Regular + NPH or Lente III. Require strict adherence to the timing of meal and injections Pharmacot herapy - NPH evening dose can be moved to bedtime - 3 injections of regular or rapid acting insulin before each meal + long acting insulin at bedtime (4 injections) - The choice of the regimen will depend on the patient - Dose: A good starting dose is 0.6 U/kg/day The total dose should be divided to: 45% for basal insulin - 55% for prandial insulin The prandial dose is divided to - 25% pre-breakfast 15% pre-lunch 15% pre-supper DM Example: For a 50 kg patient - The total dose = 0.6X50 = 30 U/day - 13.5 U for basal insulin (45% of dose) Administered in one or two doses 16.5 U for prandial insulin (55% of dose). divided to: - 7.5 U pre-breakfast (25%) - 4.5 U pre-lunch (15%) - 4.5 U pre-supper (15%) Monitoring require 0. 5-1.0 U/kg/d The initial regimen should be modified based on (Symptoms - SMBG - HbA1C) Insulin Pump Therapy - This involves continuous SC administration of short-acting insulin using a small pump - The pump can be programmed to deliver basal insulin and spikes of insulin at the time of the meals - Requires intense SMBG Adolescent Type 2 DM - Type 2 DM is increasing in adolescent - Lifestyle modification is essential in these patients - If lifestyle modification alone is not effective, metformin the only labeled oral agent for use in children (10-16 years) Gestational DM - Dietary control - If blood glucose is not controlled by dietary control, insulin therapy is initiated - One dose of NPH or NPH + regular insulin (2:1) given before breakfas - Sulfonylureas: Effective, but require further studies to demonstrate safety !2 Adverse effects of insulin Side effect Treatment - Oral administration glucose - IV dextrose in patients with lost consciousness - 1 gm glucagon IM if IV access is not available Hypoglycemia Skin rash at injection site Lipodystrophies - Use more purified insulin preparation - (increase in fat mass) at injection site - Treatment: rotate the site of injection Weight gain - Diabetes Mellitus Complications Complication Hypoglycemia Features Treatment - Cause: Missing meals or excessive exercise or too much insulin - Symptoms: Tachycardia, palpitation, sweating, nausea, and - Candy or sugar IV glucose Glucagon 1 gm IM vomiting. Progress to mental confusion, bizarre behavior and coma Diabetes retinopathy - Microaneurysm, Hemorrhage, Exudates, Retinal edema Diabetes nephropathy - Manifested as Microalbuminuria - Progressive diabetic nephropathy leading to end- stage renal - Diabetes neuropathy Peripheral vascular disease & foor ulcers - - ACE-inhibitors are recommended to decrease the progression of nephropathy disease All diabetic patients should be screened annually for microalbuminurea to detect patients at high risk of developing progressive diabetic nephropathy - Manifested by orthostatic hypotension, diabetic diarrhea, erectile - dysfunction, and difficulty inurination. - Incidence of gangrene of the feet in DM is 20 fold higher than - Derbitol as a treatment (due to control group Dr. Waleed) Diabetic ketoacidosis Treatment - It is a true - emergency Give small dose of long acting insulin glargine (lantus) Signs & symptoms Diagnosis - Fatigue, nausea, - Hyperglycemia - Acidosis vomiting, - Low serum evidence of dehydration, rapid deep breathing, fruity breath odor, hypotension and tachycardia bicarbonate - Positive serum ketones Abnormalities - Dehydration, Management - Fluid acidosis, sodium and potassium deficit - - administration: Rapid fluid administration to restore the vascular volume IV infusion of insulin to restore the metabolic abnormalities Potassium & phosphate can be added to the fluid if needed Follow up - Metabolic improvement is manifested by an increase in serum bicarbonate or pH. !3 Oral Drugs for DM2 Drug Classes MOA Sulfonylurea 1st generation Tolbutamide, Chlorpropamid Acetohexamide - ⬇ potency, - ⬆ potential for DDI & SE - All sulfonylurea drugs are equally effective in reducing the blood glucose when given in equipotent doses. 2nd generation Glimepiride Glipizide Glyburide) - ⬆ efficacy - ⬇ potential for DDI & SE - It works through inhibiting ATP sensitive K channels - Hyponatremia (used to - For type 2DM Because they have insulin If they don’t have insulin so the drug will not be effective - Fascial flushing • - Doses Glimepiride 1-2 mg Glyburide 5mg Glipizide 10mg • Efficacy - - Nateglinide Glinidies - Biguanides Metformin (Glucophage) (within days) *the most important (Within months) • - - Repaglinide - Hypoglycemia - Stimulate the pancreatic secretion of insulin + Increase - Weight gain insulin receptor sensitivity – HbA1c: 1.5 – 1.7% reduction – FPG: 50 – 70 mg/dL reduction – PPG: 92 mg/dL reduction Short-acting secretogogues Side effects happen with 1st generation drugs) “following alcohol ingestion” - Drug Drug interaction bcz it’s? metabolitized in Liver (cytochrome p450 DDI) Cytochrome p450 Inducers: rifampicin, phenytoin Inhibitors: cimetidine Displacement from protein binding sites: salicylates & sulphonamides Reduction of renal elimination: allopurinol & salicylates Same as sulfanoylureas but short acting Rapid & short acting Stimulation of the pancreatic secretion of insulin insulin release is glucose dependent and is decreased at low blood glucose Should be given before meal or with the first bite of each meal. If the meal is skipped, it shouldn’t be taken. Repaglinide is affected by Inducers or inhibitors of CYP3A4 Nateglinide is an inhibitor of CYP2C9 - DOC for DM2 - ⬇ potential for hypoglycemia - Drug Drug interaction bcz it’s? metabolitized in Liver (cytochrome p450 DDI) - Nausea (most 1- Reduces hepatic glucose production 2- Increases peripheral glucose utilization 3- Increase-insulin receptor sensitivity common) - Vomiting - Target dose around 2g in such case we start at 500mg so - Anorexia must increase dose saturation within 2 to 3 weeks to reduce SE diarrhea - Diarrhea - Phenformin: was taken off the market bcz it causes lactic - GI side “rare” - Lactic acidosis acidosis - Contraindicated in renal insufficiency, CHF, conditions that lead to about in hypoxia - Eexcreted exclusively by the kidney - Doesn’t increase weight, so it’s preferable in the obese !4 Drug Glitazones Classes MOA - Rosiglitazone - Peroxisome Proliferator Activated Receptor g gonists - Pioglitazone - Increase tissue insulin sensitivity but have serious ADRs TZDs they be suspended from the EU market - Rosiglitazone (most common) - Reduces insulin resistance in the periphery - The onset of action is slow taking 2-3 months to see the PPAR gama Agonists Side effects - Hepatotoxicity Edema Weight gain Cardiac arrest full effect - Rosiglitazone has high cardiovascular risks - Pioglitazone causes bladder tumors - Troglitazone causes hepatitis a-Glucosidase inhibitors - Acarbose - Miglitol - Meglitinides SGLT2 inhibitors - Nateglinide - Repaglinide - Stimulate the release of insulin from pancreas by closing ATP -dependent potassium channels Canagliflozin - Inhibitors of reabsorption of glucose (in kidney) - Prevents glucose reabsorption at the end (kidney), not - DPP-4 inhibitors Inhibits intestinal alpha-glucosidase The weakest antidiabetic Prevent breakdown of sucrose & complex carbohydrates Reduces postprandial blood glucose rise The effect is limited to the luminal side of the intestine with limited systemic absorption Majority eliminated in the feces Sitagliptin Vildagliptin like alpha-glucosidase inhibitor at the beginning inhibit glucose absorption Canagliflozin blocks in renal proximal tubule sodium / glucose co-transporter protein 2 (SGLT2), which reabsorbed 90% of the filtrated glucose. The result is increased glucosuria and plasma glucose levels are lowered. - Inhibitors of Dipeptidil peptidase-4 - Prevent degradation of incretin GLP-1 - They are not used as 1st line drugs, bcz they’re add on - Bloating (imp.) - Flatulence - Diarrhoea. - - Hypoglycemia ‘based on slides” - Vulvovaginal candidiasis (UTI) - Polyuria - Pancretitis therapy along with ”Metformin” - They’re not used with sulfonylurea because the risk of hypoglycemia will increase. GLP-1 agonists Exenatide Bydureon Liraglutide - Glucagon like peptide agonists agonists - Pancretitis Increase pancreatic secretion insulin Expensive Given Subcuotanously Exenatide 2x daily Bydureon once weekly Liraglutide once a day , reduces BM, HbA1c, systolic BP & improves function of B cells of pancreas - DM2 Obese Patients: Metformin or glitazone>> SU or short-acting insulin >>Add Insulin or glitazone - DM2 Non-obese Patients SU or short-acting insulin secretagogue>>Add Metformin or glitazone>>Add Insulin - Elderly Patients with newly diagnosed DM: SU or short-acting insulin or a-glucosidase inhibitor or insulin >>substitute insulin. We dont’s give metformin bcz old pt. have weak kidney - DM2 Early insulin resistance: Metformin or glitazone>>Add glitazone or metformin> Add SU or short-acting insulin secretagogue or insulin Done by Maha Albarrak Good Luck !5