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【Pharmacology】Drug for diabetes

Drug for diabetes

1. Diabetes mellitus
2. Diabetes mellitus type
3. Insulin
4. Drug for diabetes
    a. Insulin & analogs
    b. Synthetic amylin
    c. Incretin mimetics
    d. DPP-4 inhibitors
    e. Sulfonylureas
    f. Glinides
    g. Biguanides
    h. Thiazolidinediones
    i. Sodium-glucose cotransporter-2 inhibitors
    j. Alpha-glucosidase inhibitors
5. Reference

1. Diabetes mellitus

Diabetes mellitus is a chronic disorder characterized by high levels of blood glucose.

This results from inadequate insulin production or resistance of the body's cells to the action of insulin.

Symptoms:

  • Increased thirst
  • Frequent urination
  • Extreme hunger
  • Unexplained weight loss
  • Presence of ketones in the urine (ketones are a byproduct of the breakdown of muscle and fat that happens when there's not enough available insulin)
  • Fatigue
  • Irritability
  • Blurred vision
  • Slow-healing sores
  • Frequent infections, such as gums or skin infections and vaginal infections


2. Diabetes mellitus type

Type 1: Insulin producing cells are destroyed thus eliminating insulin production 

Risk: 

  • Family history
  • Environmental factors. 
    • Circumstances such as exposure to a viral illness likely play some role in type 1 diabetes.
  • The presence of damaging immune system cells (autoantibodies). 
    • People with the presence of diabetes autoantibodies have an increased risk of developing type 1 diabetes. 
    • But not everyone who has these autoantibodies develops diabetes.
  • Geography. 
    • Certain countries, such as Finland and Sweden, have higher rates of type 1 diabetes.


Type 2: Insulin resistance and gradual insulin deficiency

  • Weight
    • The more fatty tissue, the more resistant cells become to insulin.
  • Inactivity
    • Physical activity helps control weight, uses up glucose as energy and makes cells more sensitive to insulin.
  • Family history
  • Race or ethnicity. 
    • Black, Hispanic, American Indian and Asian American people — are at higher risk.
  • Age
    • Risk increases as you get older. 
      • may due to old people tend to exercise less, lose muscle mass and gain weight
    • But type 2 diabetes is also increasing among children, adolescents and younger adults.
  • Gestational diabetes
    • Women who developed gestational diabetes when pregnant, may increase risk of developing prediabetes and type 2 diabetes increases. 
    • Women who gave birth to a baby weighing more than 4 kg, you're also at risk of type 2 diabetes.
  • Polycystic ovary syndrome
    • A common condition characterized by irregular menstrual periods, excess hair growth and obesity 
  • High blood pressure. 
    • Having blood pressure over 140/90 millimeters of mercury (mm Hg) 
  • Abnormal cholesterol and triglyceride levels. 
    • Low levels of high-density lipoprotein (HDL)
    • High levels of triglycerides 


3. Insulin

Overview

Insulin is a hormone that comes from a gland situated behind and below the stomach (pancreas).

  • The pancreas secretes insulin into the bloodstream.
  • The insulin circulates, enabling sugar to enter cells.
  • Insulin lowers the amount of sugar in your bloodstream.
  • When blood sugar level drops, the secretion of insulin from pancreas also decrease.


Storyline

  • Digestive system digest food into glucose
  • Blood glucose levels rise
  • Beta cells of the pancreas islets start secreting insulin
  • Insulin binds to the insulin receptor and stimulates glucose uptake by cells
  • Liver and skeletal muscle store absorbed glucose in form of glycogen
  • Many other cells quickly break down absorbed glucose to make ATP a molecule which provides immediately available energy 


When blood glucose levels fall too low

  • Alpha cells of the pancreatic islets release glucagon
  • Glucagon acts on the liver it causes breakdown of stored glycogen into glucose 
  • Glucose released into the bloodstream
  • Blood glucose levels rise

Insulin

4. Drug for diabetes

💉💉Inject

a. Insulin & analogs

💪Insulin can be reproduced by

  • recombinant DNA technology using bacteria or yeast 
  • altered the amino acid sequence of human insulin 

💪Typically administered by subcutaneous injection

  • as insulin is a polypeptide it is susceptible to degradation in the gastrointestinal tract

💪Three major categories:

  • Rapid and short acting insulins preparations
    • Rapid: Peak effect---30 minutes; Duration---up to 5 hours
      • insulin Lispro
      • insulin Aspart 
      • insulin Glulisine
    • Short: Peak effect---2 hours; Duration---less than 8 hours
      • Regular insulin
  • Intermediate acting insulin preparation
    • Peak effect---6 hour; Duration---18 hours
    • Longer lasting effects are accomplished by addition of zinc and protamine to regular insulin, results in a complex that is less soluble
      • NPH (Isophane insulin)
  • Long-acting insulins with slow onset of action preparations
      • Long lasting effect result from modifications to the insulin molecule
    • insulin Detemir
      • Peak effect---between 6 and 8 hours; Duration---up to 24 hours
      • fatty acid side chain was added to the insulin molecule that allows it to bind to albumin 
        • slow down its release into the bloodstream
    • insulin Glargine
      • Peak effect---N/A (steady); Duration---up to 24 hours
      • modified to have low solubility at neutral pH
        • form precipitate in the subcutaneous tissue that slowly releases insulin into the bloodstream
    • insulin Degludec
      • Peak effect---N/A (steady); Duration---up to 24 hours
      • form long chains of hexamers in subcutaneous tissue
        • serve as a depot from which insulin is continuously and slowly released 

insulin Detemir, insulin Glargine, insulin Degludec
insulin Detemir, insulin Glargine, insulin Degludec

What gives rapid and short acting insulins preparations the ability to act quickly?

  • Naturally, six insulin molecules bound together forming hexamers 
    • These hexamers too large to cross from the subcutaneous tissue into the bloodstream 
    • must first separate into single insulin molecules before absorption
  • Altered amino acid sequence of insulin molecules to make them less likely to aggregate
    • faster absorption and more rapid action 

Insulin & analogs

Side effect of using insulin

  • hypoglycemia
  • lipodystrophy: can develop at the site of repeated insulin injections

b. Synthetic amylin

Amylin:
  • secrete by pancreatic beta cells
  • Function:
    • delay gastric emptying to suppress postprandial glucagon secretion
    • promote satiety

Drug: Pramlintide
Benefit: allows insulin doses to be reduced

Side effect of using Pramlintide

  • hypoglycemia
  • nausea 
  • modest weight loss

c. Incretin mimetics

Incretins
  • a group of metabolic hormones that are secreted from the gut
  • stimulate pancreas to produce more insulin (in response to food ingestion)
Two primary incretin hormones:
  • glucagon-like peptide-1 (GLP-1)
  • glucose-dependent insulinotropic polypeptide (GIP)
    • actions are actually quite limited
      • due to rapid inactivation by the enzyme dipeptidyl peptidase-4 (DPP-4)

GLP-1 mimetics: resistant to degradation by DPP-4 enzyme
  • stimulating insulin secretion by slow gastric emptying and promote satiety
  • eg, Exenatide & Liraglutide


Side effect of using Incretin mimetics

  • increased risk of pancreatitis
    • thought to be due to their proliferative effects on pancreas

*Less common side effect

d. DPP-4 inhibitors

Function: enhance the effects of incretin by inhibit DPP-4 enzyme
Result: increase insulin secretion, decrease gastric emptying and reduce glucagon release
Drug: Alogliptin, Linagliptin, Saxagliptin and Sitagliptin

Side effects of DPP-4 inhibitors

  • nasopharyngitis
  • headache 

👄👄Oral

e. Sulfonylureas

Mechanism of glucose
  • Dependent insulin secretion from pancreatic beta cells, so available glucose enters beta cell through glucose transporter 2 (GLUT2)
  • Once inside the cell, glucose gets metabolized to create a bunch of ATP
  • Rising levels of ATP 
    • → inhibition of ATP-sensitive potassium channels 
    • →blocking the inflow of potassium 
    • → depolarization of the cell's membrane 
    • → triggers activation of voltage-gated calcium channels 
    • → influx of calcium 
    • → mediate fusion of insulin containing vesicles with the membrane
    • → insulin release

Sulfonylureas
  • Action: bind to and inhibit the activity of ATP-sensitive potassium channels
    • increased sensitivity of beta cells to glucose
    • reduced hepatic glucose production
  • eg, Glimepiride, Glyburide, Glipizide
Sulfonylureas

Side effects of using Sulfonylureas

  • hypoglycemia 
  • weight gain

**As sulfonylureas are highly protein bound and most are extensively metabolized in the liver by cytochrome p450 enzymes, they tend to interact with wide variety of other drugs

f. Glinides

Glinides (act like sulfonylureas)
  • stimulate insulin secretion from pancreatic beta cells 
  • accomplish that by binding to ATP-sensitive potassium channels at a different site and with different kinetics than sulfonylureas, so it has more rapid onset and shorter duration of action
    • good choice for patients with primarily postprandial hyperglycemia
  • eg. Nateglinide and Repaglinide

Side effects of using Glinides (Risk lower than Sulfonylureas)

  • hypoglycemia 
  • weight gain

g. Biguanides

Exact cellular mechanism of action of biguanides is not entirely understood that being said the main blood glucose lowering activity appears to be primarily through
  • reduction of hepatic glucose production
  • slow intestinal absorption of glucose
  • increase insulin sensitivity 
  • enhances peripheral glucose uptake

Drug: Metformin

Side effects of Metformin

  • Limited to GI tract
    • nausea 
    • vomiting 
    • diarrhea
    • loss of appetite which may lead to weight loss
  • Increase risk of lactic acidosis
    • particularly in patients with organ dysfunction, such as congestive heart failure or renal impairment 
    • This is because Metformin decreases hepatic uptake of lactate

h. Thiazolidinediones

Thiazolidinediones 
  • work primarily by selectively activating nuclear receptor, peroxisome proliferator-activated receptor gamma (PPAR-γ)
  • activated this receptor binds to DNA
  • triggering expression and repression of specific genes encoding proteins that regulate glucose and lipid metabolism as well as insulin signal transduction 
  • Lead to
    • increased insulin sensitivity in adipose tissue skeletal muscle and liver 
    • inhibition of hepatic glucose production
    • promote fatty acids uptake and utilization in adipocytes
      • decrease in fatty acid concentrations & increased uptake and utilization of glucose

Drug: Pioglitazone and Rosiglitazone

Side effects of Thiazolidinediones 

  • lowering blood glucose levels 
  • increase HDL levels (especially in Pioglitazone)
  • increase LDL levels (limited only to larger less atherogenic LDL particles)
  • weight gain and fluid retention → peripheral edema
  • hepatotoxicity (Few)

i. Sodium-glucose cotransporter-2 inhibitors

  • inhibit glucose transporter located in the proximal convoluted tubules of the kidneys that is responsible for about 90% of glucose reabsorption
  • Lead to 
    • increased urinary glucose excretion 
    • reduced levels of blood glucose 
    • increase in glucose and sodium in urine, generate mild osmotic diuresis which may contribute to small reduction in blood pressure and weight loss

Drug: Canagliflozin and Dapagliflozin 

Sodium-glucose cotransporter-2 inhibitors

Side effects of Sodium-glucose cotransporter-2 inhibitors 

  • thirst 
  • increased urination 
  • increased risk of urinary tract and genital infections

j. Alpha-glucosidase inhibitors

Alpha-glucosidase
an enzyme located in the intestinal brush border
responsible for breaking down carbohydrates into simple sugars such as glucose 

Alpha-glucosidase inhibitors
Blocks Alpha-glucosidase → the absorption of glucose is delayed → lower postprandial glucose levels 

Drug: Acarbose and Miglitol

Side effects of alpha-glucosidase inhibitors 

  • Significant gastrointestinal side effects
    • abdominal cramps 
    • bloating 
    • flatulence
    • diarrhea

5. Reference

https://youtu.be/LWDQyaKVols
https://www.mayoclinic.org/diseases-conditions/diabetes/symptoms-causes/syc-20371444


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【TCM】糖尿病 / 消渴症 Diabetes mellitus


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 5/5/2025  居銮德教会义诊 - 罗达盛医师 （五）六味地黄丸 一位 68 岁的患者因跌倒后肩痛前来就诊，老师处方柴胡疏肝散合筋骨跌伤丸、六味地黄丸。我一如既往地认为，六味地黄丸是为了顾护患者体质、益肾固本。老师却追问：“除此之外呢？”我一时语塞，百思不得其解。老师笑着点拨：筋骨跌伤丸性属活血化瘀、消肿止痛，药性偏散；而年长患者肝肾渐亏、正气不足，为防其药性太散而伤正，故加六味地黄丸以滋阴潜阳、固护根本，取散中有收、攻中有补之意。 见我对六味地黄丸的理解仍偏狭，老师又举一例启发思考：一位 87 岁肩痛伴肢体麻木的患者，所用方为半夏天麻白术汤合镇肝熄风汤，并配伍六味地黄丸。六味地黄丸虽以滋阴补肾、顾护体质见长，但其中更蕴含“滋水涵木”之意——通过滋养肾阴，濡养肝阴，以平肝潜阳、调和风动，正契合本证肝肾同调的治则。   （六）天麻钩藤饮 VS 镇肝熄风汤 接着，老师提出一个思辨性问题：“这个患者是否可以改用天麻钩藤饮替代镇肝熄风汤？”我尝试分析其异同：天麻钩藤饮主治肝火上扰，方中用栀子、黄芩等清泄肝火，适用于肝火亢盛。而患者并未表现热象故不适宜使用。老师笑笑点头说，也要注意年龄大的患者不宜过于寒凉、攻下之品。而镇肝熄风汤则偏于肝阳上亢、因肾阴亏虚所致，其立法中存在明确的因果关系——肾虚不能制肝，致肝阳上亢、化风动扰。方中怀牛膝归肝肾经，入血分，性善下行，故重用以引血下行，并有补益肝肾之效为君。相比之下，天麻钩藤饮虽也含补肾药，但偏于平补肾气，且未必强调肝火与肾虚之间的因果链条。 此外，两方证候所对应的舌象亦有所区别：镇肝熄风汤适用于阴虚火旺之体，舌质多红、舌面偏干；而天麻钩藤饮则多用于夹湿之象，方中配伍茯神、杜仲、益母草等，具一定祛湿之功。此患者舌润，加之肢体的酸胀不适与痰有密切联系。若一味用镇肝熄风汤，恐不相宜，故原方以镇肝熄风汤为基础，加半夏天麻白术补脾燥湿、化痰熄风，以调和偏颇，契合实情。   （七）五行关系 咳嗽、干咳无痰、喉咙痛一个星期，曾有伤风史，现在已无鼻塞、流涕。舌苔腻，舌两旁有点紫。脉弦细滑。其舌脉提示有肝郁之症。但患者主诉是咳嗽，病位应属肺。故我的思路还是用桑菊饮、桑杏汤等治疗。定睛一看老师开方为柴胡疏肝散、小柴胡汤合白果定喘汤。“有一分恶寒便有一分表证”，其脉也无浮脉，说起外感病已转内。根据五行相生相克...
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【方剂学】 涩肠固脱剂--真人养脏汤（原名纯阳真人养脏汤）

 涩肠固脱剂 适用于泻痢日久不止，脾肾虚寒，以致大便滑脱不禁的病证 代表方如真人养脏汤、四神丸等。   1. 真人养脏汤（原名纯阳真人养脏汤） 《太平惠民和剂局方》 ---- 涩肠固脱，温补脾肾 【用法】 上锉为粗末。每服二大钱（ 6g ），水一盏半，煎至八分，去滓，食前温服。忌酒、面、生、冷、鱼腥、油腻（现代用法：水煎服）。   【运用】 本方为治泻痢日久，脾肾虚寒之常用方。 以大便滑脱不禁，腹痛喜温喜按，食少神疲，舌淡苔白，脉迟细为辨证要点。 原书注曰： “ 如脏腑滑泄夜起久不瘥者，可加炮附子三四片煎服。 ” 可资临证参佐。   组成：罂粟壳、诃子、肉豆蔻、肉桂、人参、白术、当归、白芍、木香、炙甘草   a. 组成 君：罂粟壳 ---------------- 去蒂萼，蜜炙，三两六钱（ 9g ） ·          涩肠固脱止泻   臣： a. 诃子 ---------------- 去核，一两二钱（ 9g ） ·          苦酸温涩，功专涩肠止泻   b. 肉豆蔻 ---------------- 面裹，煨 ，半两（ 8g ） ·          温中散寒，涩肠止泻 ·          & 诃子：助君药以增强涩肠固脱止泻之功 ·          君臣相配，体现 “ 急则治标 ” 之法   佐： a. 肉桂 ---------------- 去粗皮，各八钱（各 6g ） ·          温肾暖脾，兼散阴寒   泻痢日久，气血亏虚 👇 b. 人参 ---...
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【Pharmacology & 方剂学】Traditional Chinese Medicine (TCM) – Does its contemporary business booming and globalization really reconfirm its medical efficacy & safety?

Traditional Chinese Medicine (TCM) – Does its contemporary business booming and globalization really reconfirm its medical efficacy & safety? 笔记 1. Introduction 有几个国家同意中医 Promoting the globalization of TCM, Traditional Chinese medicine has been spread to 183 countries and regions around the world.  According to the World Health Organization,  103 member states have given approvalto the practice of acupuncture and moxibustion 29 have enacted special statutes on traditional medicine 18 have included acupuncture and moxibustion treatment in their medical insurance provisions  2. What's in the TCM bottle? The philosophy behind Chinese medicine is a melding of tenets from Buddhism, Confucianism, and the combined religious and philosophical ideas of Taoism.  TCM is based on the concept that illness occurs when a person's “internal Qi” falls out of balance.  Qi: the word the Chinese use to describe the un-measurable energies that theoretically permeate ev...
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【Pharmacology】Antidepressants

Antidepressants Depression: experience unusually long periods of sadness guilt and decreased interest in activities can occur alone or a part of a larger disorder such as bipolar disorder  people with bipolar disorder experience periods of depression alternating with periods of mania in which person feels abnormally optimistic euphoric and energetic  Treatment: Antidepressant drugs which work by elevating levels of certain neurotransmitters in the brain led to development of monoamine hypothesis Content: 1. Monoamine hypothesis 2. Five different classes 3. Serotonergic neuron & Noradrenergic neuron 4. Drug      a. Selective serotonin reuptake inhibitors (SSRIs)      b. Serotonin norepinephrine reuptake inhibitors (SNRIs)      c. Tricyclic antidepressants (TCAs)      d. Monoamine oxidase inhibitors (MAOIs)      e. Atypical antidepressants 5. Lithium 6. Reference 1. Monoamine hypothesis states th...
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【方剂学练习题】 各论：第一章　解表剂

【方剂学练习题】 各论：第一章　解表剂 一、填空题 1 ．麻黄汤和大青龙汤中，麻黄和桂枝的配伍比例分别是 _______ 、 _______ 。             ANS: 3:2 ； 3:1       解析：麻黄汤：麻黄 9g ；桂枝 6g             大青龙汤 : 麻黄 12g ；桂枝 6g   2 ．桂枝汤证和麻黄汤证的脉象分别是 ______ 、 ________ 。         ANS: 浮缓 ； 浮紧       解析：桂枝汤：外感风寒表虚证             麻黄汤：外感风寒表实证   3 ．桑菊饮的功用是 _______ ，主治 _______ 。         ANS: 疏风清热 ， 宣肺止咳；风温初起   4 ．以组方原则论，败毒散中人参属于 ______ 药；参苏饮中人参属于 ________ 药。         ANS ：佐 ； 佐   5 ．被称为“四时发散之通剂”的方剂是 _______ ；被称为“辛凉轻剂”的方剂是 _______ 。         ANS: 九味羌活汤 ； 桑菊饮   6 ．银翘散中，为助君药发散外邪，透邪外出而加入辛而微温的两味药分别是 _______ 、 _______ 。         ANS: 荆芥穗 ； 淡豆豉       解析：风温之邪居卫，恐惟用辛凉难开其表，遂入辛而微温之 ...
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【TCM & Western Medicine】阿片类药物（Opioids）& 中药

阿片类药物（Opioids） 是治疗中重度疼痛的首选药物。 其不良反应主要包括： 便秘 恶心呕吐 瘙痒 头晕 尿潴留 嗜睡 谵妄 认知障碍 呼吸抑制 Related link:  【Pharmacology】OPIOIDS 内容： 1. 癌性疼痛 2. 便秘 3. 阿片类成瘾慢性稽延症状 4. 参考文献 1. 癌性疼痛 是晚期恶性肿瘤最常见症状之一 被列为“第五生命体征” 生命四大体征：呼吸、体温、脉搏、血压 癌痛治疗的药物： 非甾体类抗炎药物 (Non-Steroidal Anti-Inflammatory Drug) 阿片类药物 (Opioids) 中医 癌性疼痛属“痛证”范畴 病因：正气亏虚、邪毒内侵 病机：“毒、瘀”壅塞经络 治疗：行气活血、化瘀解毒功效的中药组方外敷联合西药治疗 好处： 增强止痛效果 缩短止痛起效时间 延长镇痛时间从而减少爆发痛次数 提高患者的生活质量 一定的抗肿瘤作用 中药方： “双黄散结散” 全方具有清热解毒、散结止痛的作用。 君： a. 大黄 (Rhubarb) 苦寒泻热：荡涤胸腹之邪热 b. 黄柏 (Phellodendron amurense Rupr) 苦寒泻热：清下焦热 & 大黄：清热解毒散结 臣： a. 苦参 (Sophora flavescens) b. 蒲公英 (Dandelion Herb) 加强清热解毒之功 c. 三棱 (rhizoma sparganii) d. 莪术 (Curcuma) 破血逐瘀 佐使： a. 乳香 (frankincense) 行气舒筋 b. 没药 (Myrrh) 行气化瘀 & 乳香：活血定痛 c. 冰片 (Borneol) 通窍散火、消肿止痛 **现代研究亦表明，大黄、黄柏、冰片、乳香、没药、三棱、莪术、蒲公英等药物均有有很好的抑制肿瘤、止痛等作用。 另外一方： 川芎、白芷、姜黄、乳香、没药、肿节风、山慈姑、蚤休、麻黄、白芥子、王不留行 11味中药精细加工成粉并与凡士林调和而成膏状 功能：扶正气、消肿痛、活血化瘀，调畅经脉，透皮达里，引诸药直达病所。 好处： 避免了异体蛋白过敏现象 因其主要成分为植物 避免药物通过肝脏时的首过效应 其中药有效成分透过皮肤屏障，直接进入人体循环，无胃肠降解和胃肠刺激作用 治疗疼痛效果明显、持续时间长 无不良反...
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