ORALHYPOGLYCAEMI

CAGENTS

DR. JAYESH VAGHELA

A. Enhance Insulin Secretion:1) Sulfonylurias

(KATP channel blockers)

2) Meglitinide / Phenylalanine analogues

3) GLP-1 receptor agonists

4) DPP-4 inhibitors

B. Overcome Insulin Resistance:1) Biguanides

(AMPK Activator)2) Thiazolidinedion

es

C. Miscellaneous:1) Alpha-

Glucosidase inhibitors

2) Amylin analogue

3) D2 receptor agonist

4) SGLT-2 inhibitor

CLASSIFICATION

SULFONYLUREAS(SU)

K+ ↑ K+

K+

Depolarization

Ca++

↑ Ca++

StoredInsulin Exocytosis

MECHANISM OF ACTIONSU / Megli

SUR1

EXTRAPANCREATIC ACTION• After few months of therapy,

• Down regulation of sulfonylurea receptors (SUR1) on beta cells⇓

Decreased insulinaemic action of SU⇓

But, improvement in glucose tolerance is maintained⇓

Increased insulin receptors⇓

It sensitizes the target tissue to action of insulin (esp. in liver)

Do not cause hypoglycaemia in - Pancreatectomized animals, and

- Type 1 DM⇓

Confirms its indirect action through pancreas

Drawback:• Increase insulin secretion at any glucose (even at low) concentration

⇓

Risk of severe & unpredictable hypoglycaemia

• Well absorbed Orally• Highly plasma protein bound – 90-98%• Low volume of distribution (0.2-0.4 L/kg)• Onset of action is approximately 1-3 hrs• Duration of action of second generation is around 24 hrs• Metabolized by the liver, and the metabolites are excreted in the

urine.• Second-generation agents are approximately 100 times more potent

than first generation.

PHARMACOKINETICS

Drug that enhances sulfonylureas action :

A) Displace from Protein binding:• Phenylbutazone, Sulfinpyrazone, Salicylates, Sulfonamides

B) Inhibit metabolism/excretion:• Cimetidine, warfarin, chloramphenicol

C) Synergise with or prolong PD action:• Propranolol, lithium, theophylline, Salicylates

DRUG INTERACTIONS

Drug that decrease sulfonylureas action:

A) Induce metabolism:• Phenobarbitone, Phenytoin, Rifampicin

B) Opposite action/suppress insulin release:• Corticosteroids, thiazides, OC pills, furosemide

Hypoglycemia:• Most common in elderly patients• With impaired renal and hepatic function• With long acting agents

Increase Weight: 1 – 3 kg

Hypersensitivity: Photosensitivity, rash, purpura

Disulfiram-like reaction if taken with alcohol Secreted in milk: - not given to nursing mothers

ADVERSE DRUG REACTIONS

MEGLITINIDEOR

D-PHENYLALANINEANALOGUES

Quick & Short-lastingInsulinaemic action

Mechanism of action:• Similar to SU

Indication:• Fast onset & short-lasting insulin release• Before each major meal to control postprandial hyperglycaemia• Dose is omitted if meal is missed

• Only in selected Type 2 DM patients who suffer P.P. hyperglycaemia, or

• To supplement Metformin / Long acting insulins

REPAGLINIDE

Action:• Mainly stimulates 1st phase of insulin secretion

⇓• Faster onset & shorter lasting action than repaglinide

Indication:• 10 min before meal

NATEAGLINIDE

ADRs:• Headache, Dyspepsia, Arthralgia, Weight gain• Dizziness, flu-like symptoms

• Dose: Repaglinide: - 0.25 - 4 mg Nateglinide: - 60 - 120 mg

GLP-1RECEPTORAGONISTS

INJECTABLEAGENTS

GLP – 1(GLUCAGON – LIKE PEPTIDE – 1)

Glucose ingestion⇓

GLP-1 released from gut⇓

Induces insulin releaseInhibits glucagon releaseSlows gastric emptying

Suppresses appetitePromotes beta cell health

⇓Degraded by DPP-4 (Dipeptidyl peptidase-4)

Present in capillary endothelial cells, kidney, liver, immune cells⇓

Not suitable for clinical use

EXENATIDE• Mechanism of action:

• Synthetic analogue of GLP – 1 receptor• DPP – 4 resistant

Benefits: Lowers fasting & postprandial blood glucose Lowers HbA1c Lowers body weight

Dose: 5 – 10 mcg subcutaneous injection once daily

ADRs:• Nausea, vomiting

• Tightly bound to plasma proteins• T1/2: > 12 hours• Duration of action > 24 hours

ADRs:• Nausea, diarrhoea

• Safely given in renal failure patients

LIRAGLUTIDE

DPP – 4INHIBITORS

INTRODUCTION

• DPP-4 is a serine protease that is widely distributed throughout the body

• DPP-4 inhibitors provide nearly complete and long lasting inhibition of DPP-4• Increase the proportion of active GLP-1 from 10-20% to nearly 100%

• Sitagliptin and alogliptin: - Competitive inhibitors of DPP-4• Vildagliptin and saxagliptin - Covalent binding

Selective inhibition of DPP-4 enzyme which inactivates GLP-1⇓

Increased GLP-1 levelsProlonged actions

⇓

1) Increase insulin secretion 2) decrease glucagon release

3) delay gastric emptying4) decreases the appetite by acting at the level of hypothalamus.

MECHANISM OF ACTION

• Absorbed effectively from small intestine

• Circulate primarily in unbound form

• Excreted mostly unchanged in urine

• Saxagliptin is metabolized by CYP 3A4 , so should be used cautiously with CYP inhibitor and enhancer

Doses:• Sitagliptin: 100 mg OD before meals.• Vildagliptin:50 mg OD before meals.• Saxagliptin:5 mg OD before meals.

PHARMACOKINETICS

SITAGLIPTIN

• Actions:• Increases postprandial insulin release• Decrease glucagon secretion• Lowers meal-time & fasting blood glucose in Type 2 DM• HbA1c lowering: Sitagliptin = Metformin

• Used as monotherapy when metformin can not be used

ADRs:• Nasopharyngitis ∵ Prevention of Substance P degradation• Cough

Dose reduction:• Needed in renal impairment• Not in liver disease

VILDAGLIPTIN

The complex dissociates very slowly⇓

Persistent DPP-4 inhibition even after drug is cleared from circulation

⇓Longer duration of action (12 – 24 hours)

Despite short t1/2 (2 – 4 hours)

o Saxagliptin:• Recently marketed in India

o Alogliptin:• Marketed in Japan

o Linagliptin:• Recently approved for use in USA

BIGUANIDES

( AMPKACTIVATORS )

DIFFERENCES FROM SULFONYLUREAS

• Little / No hypoglycaemia in non-DM

• Even in DM patients, rare hypoglycaemia

• Does not stimulate pancreatic beta cells

• Improves lipid profile in Type 2 DM

MECHANISM OF ACTION

• Major action: Inhibition of hepatic gluconeogenesis, which decrease glucose output

• Increases uptake and disposal of glucose by skeletal muscle, which reduces insulin resistance

• Promotes peripheral glucose utilization through anaerobic glycolysis• By interfering with mitochondrial respiratory chain

• Retards intestinal absorption of glucose, other hexoses, vitamin B12

ACTIONS

o ADRs:• GIT: - anorexia, Nausea, abdominal pain, bloating, metallic taste• Lactic acidosis• Vit B12 deficiency

o Contraindications:• Hypotension• Heart failure• Severe respiratory, hepatic, renal diseases• Alcoholics (risk of acidosis)

o Advantages:• Non-hypoglycaemic• Weight loss promoting• Prevents macro & microvascular complications• No acceleration of beta cell exhaustion/failure in Type 2 DM• Efficacy is equivalent to other OHAs

o Uses:• 1st choice drug for all Type 2 DM patients (except when

contraindicated)• Infertility: improve ovulation in PCOD

• Mitigation of insulin resistance• Lowering insulin levels

THIAZOLI-DINEDIONE

Fatty tissue is the major site of action

Acts as agonist to a nuclear receptor called Peroxisome Proliferator Activated Receptor-gamma (PPAR-γ)

• PPAR-γ is expressed mainly in adipose tissue, skeletal muscle and liver• Activation of PPAR- γ

⇓

Promotes transcription of insulin responsive genes which control glucose and lipid metabolism

MECHANISM OF ACTION

2) Increase the number of GLUT-4 glucose transporter in cell membrane of skeletal muscles and adipose tissue

⇓

promotes peripheral uptake and utilization of glucose

3) Inhibits gluconeogenesis

⇓

decrease hepatic glucose output

PIOGLITAZONE• Also acts on PPARα to induce expression of reverse cholesterol

transporter & some apoproteins⇓

↓ TG, ↑ HDLo ADRs:• Plasma volume expansion• Edema• Weight gain

o C/I:• Liver disease & CHF

o Use:• Type 2 DM to supplement SUs / Metformin, & insulin resistance• Not effective if beta cell failure has set in

• Stopped if HbA1c reduction is < 0.5 % at 6 months

• Not to be used in pregnancy

ALPHA-GLUCOSIDASE

INHIBITORS

• Inhibits α - glucosidase enzyme(which facilitates digestion of complex starches, oligosaccharides and disaccharides into monosaccharides which is important for absorption)

⇓Reduces postprandial digestion and absorption of carbohydrates

Lowers the post meal hyperglycemia.

• Pk: mainly excreted through kidney .

MECHANISM OF ACTION

Adverse Effect :• Flatulence, Diarrhea• Abdominal pain (fermentation of undigested carbohydrates in lower

GIT)• Cutaneous hypersensitivity

C/I:Bowel obstruction, Inflammatory Bowel diseaseRenal failure

Doses:Acarbose : 50-100 mg Miglitol : 50-100 mg Voglibose: 0.4-0.6 mg

AMYLINANALOGUE

AMYLIN• Synonym: “IAP – Islet Amyloid Polypeptide”

PRAMLINTIDE

• Synthetic amylin analogue• S.c. injection before meal

⇓Decrease postprandial hyperglycaemia

Centrally mediated anorectic action Benefit:

• Decreased body weight

SGLT – 2INHIBITOR

• Kidney continuously filters glucose through glomerulus• Most of it reabsorbed back from the proximal tubule by a

transporter called SGLT- 2 (Sodium-Glucose cotransport – 2)

• Inhibiting SGLT- 2⇓

Decreases the amount of glucose reabsorption from PT,Increases its excretion

MECHANISM OF ACTION

DAPAGLIFLOZIN

• Single daily dose - Round the clock glucosuria- Decreased blood glucose levels

o Disadvantages :• Because of polyuria there would be more polydipsia• Increased risk of urinary bacterial/fungal infection• Risk of Na+2 loss• Electrolyte imbalance• Urinary frequency

o Advantages:• No hypoglycemia as they are excreting only the excess of

glucose from the blood and not inducing insulin secretion• Weight loss• Improve insulin resistance by depleting toxic level of glucose• Beneficial for HT with DM because of their diuretic effect.

DOPAMINED – 2

AGONIST

BROMOCRIPTINE

• US-FDA approved it in 2009 as adjunctive treatment to Type 2 DM

• Taken early in the morning⇓

Act on the hypothalamic dopaminergic control of circadian rhythm of hormones release (GH, PRL,

ACTH, etc.)⇓

Reset it to reduce insulin resistance• Dose: - started at 0.8 mg OD orally up to 4.8 mg

OD

NEWER ANTIDIABETIC

DRUGS

• Bile acid metabolism is abnormal in Type 2 DM• There are reports that bile acid binding resins lowers plasma

glucose in DM 2 patients• Bile acid sequestrants could reduce intestinal glucose

absorption • They may act as a signaling molecules through nuclear

receptors, which act as a glucose sensor.

BILE ACID BINDING RESINS

• Only bile acid sequestrate specifically approved for the treatment of T2DM

o Adverse Effect : • Constipation• Abdominal pain• Dyspepsia• Nausea• Triglyceridemia

COLESEVELAM

• Glucokinase enzyme plays a key role in glucose homeostasis

• Glucokinase activators can lower glucose levels in type 2 diabetes

• Piragliatin is a glucokinase activator

• Has an acute glucose lowering action

PIRAGLIATIN

• Found in the skin of red grapes and in other fruits

• Activator of Silent mating-type Information Regulation 2

homolog 1 (SIRT1)

• Useful in the therapy of DM 2 because 1) It possesses the ability to scavenge oxidatively generated free

radicals2) enhanced activity of multiple proteins, including peroxisome-

proliferator activated receptor gamma (PPAR gamma)

RESVERATROL

EPALRESTAT

• Glucose → Aldose reductase → Sorbitol → Excess in DM → Deposited in nerves → Diabetic neuropathy• Epalrestat → Aldose reductase inhibitor →delays sorbitol

deposition in sciatic nerve / other tissues → Delays diabetic neuropathy• Trials → Improvement in nerve conduction, Neuropathic pain• ADRs: Nausea, Vomiting, Elevated liver enzymes• Dose: 50 mg TDS before meals

CHOICE OF INITIAL GLUCOSE LOWERING AGENT

• The level of hyperglycemia should influence the initial choice of therapy

• Drugs approved for monotherapy:• Insulin secretagogues - Biguanides• Thiazolidinediones - alpha-glucosidase inhibitors

• Each class has its unique advantages.

Hyperglycaemia FPG (mg / dl) Treatment

Mild to moderate < 250 Single agentModerate 250 – 300 Add 2nd agentSevere > 300 Insulin

OHA Are Most Effective In Patients With

• Age > 40 years at onset of disease• Obesity at time of presentation• Duration of disease < 5 years when starting therapy• FBS < 200 mg/dl• Insulin requirement < 40 U/day• No complication e.g. ketosis, others.

• Insulin secretagogues, biguanides,DPP-4 inhibitor and TZd improve glycemic control to a similar degree (1-2% reduction in A1c) and are more effective than alfa-glucosidase inhibitor.• Insulin secretagogues and α -glucosidase inhibitors begin to lower the

plasma glucose immediately, • whereas the glucose-lowering effects of the biguanides and

thiazolidinediones are delayed by several weeks to months• Biguanides, α-glucosidase inhibitors, DPP-IV inhibitors, and Tzd do not

directly cause hypoglycemia• Most individuals will eventually require treatment with more than one

class of oral glucose-lowering agents or insulin, reflecting the progressive nature of type 2 DM

Algorithm for DM treatment

Algorithm forDM treatment

• Combination therapy with drugs that affect different molecular targets, and that have different mechanisms of actions

Advantage:• Improves glycemic control while using a lower dose of each drug• Reduces adverse reaction

Example:• Combination of - An insulin sensitizer (e.g., a TZD or metformin)

- Insulin or an insulin secretagogue (e.g., a sulfonylurea) 1. improve glycemic control in a poorly controlled Type II diabetic

patient and2. lower the dose of each drug required to achieve a therapeutic

effect

COMBINATION THERAPY

Tzds and metformin:• Both are insulin sensitizers but with different mechanisms of

action• Can also be used together effectively

• Combining two different insulin secretagogues does not improve therapeutic outcomes

• The exact combination of therapies can be guided by an estimation of the beta cell secretory reserve in the patient.

• Alvin C. Powers and David D’Alessio. Endocrine pancreas and pharmacotherapy of diabetes mellitus and hypoglycaemia.In : Bruton LL, editor. Goodman & Gilman’s – The Pharmacological basis of therapeutics. 12th edition. New York : Mc Graw Hill Publication; 2011. p. 1237- 54.

• Olanow CW, Schapira AH. Diabetes Mellitus. In: LongoDL, editor :Harrisons’s principles of internal medicine. 18th edition. New york:Mc Grew hill;2012. P.3317-35.

• Tripathi KD. Essentials of Medical Pharmacology. 6th ed. New Delhi : Jaypee brothers medical publishers; 2009. p. 270-80.

• Sharma HL & Sharma KK. Principles of Pharmacology. 2nd ed. New Delhi: Paras publication; 2012. p. 636-41.

References