Pharmacology of the endocrine pancreas -...

Pharmacology of the endocrine pancreas

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Tri Widyawati – Datten BangunPharmacology and Therapeutic Department School of Medicine

Universitas Sumatera Utara

2008

An illustration…….

At her annual check up, 55-years old Mrs Sweetie complains of fatique

and frequent urination (polyuria), even at night. She also reports drinking

large volumes of fluids (polydipsia) to quench her thirst. Although these symptoms have been ‘going on for a while’ and are getting worse, Mrs.

Sweetie has difficulty pinpointing their exact onset. She denies other

urinary symptoms such as pain on urination, blood in her urine, dribbling, and incontinence. Her past medical history is remarkable for

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and incontinence. Her past medical history is remarkable for hyperlipidemia of 10 years duration. Both of her parents died of coronary

heart disease in their early 60s.

On physical examination, Mrs Sweetie is moderately obese but otherwise appears normal. Glucose is detected in her urine, but proteins and

ketones are not. Mrs. Sweetie’s blood tests are significant for elevated

glucose (240 mg/dl), elevated total cholesterol (340 mg/dl), and elevated HbA1c ( a measure of glucose colavently bound to hemoglobin) (9,2%).

The physician discusses with Mrs Sweetie the importance of decreasing her caloric intake and increasing her exercise to improve her metabolic state. The physician also prescribes metformin ( a biguanide) for Mrs. Sweetie’s diabetes.

Apollonius (250 SM, Memphis) :

• Diabetes = “untuk menggunakan” atau “mengeringkan”

• (harfiah) = “siphon” atau mengalirkan ⇒⇒⇒⇒ volume urin besar

• Mellitus = bahasa latin dari madu = sweet ⇒⇒⇒⇒ ada glukosa dalam urin

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Diabetes Mellitus : a group of diseases characterized by high levels of blood glucoseresulting from defects in insulin production, insulin action, or both

Physiologic and Pharmacologic Regulation of Glucose Homeostasis

GITDietary complex carbohydrates

Glucose

αααα-glucosidase

inhibitors β β β β cell

Other tissues

Metabolism

Glucosidases

Glucose

(from GIT

& liver)

To tissues To tissues

Endogenous insulin

(from ββββ cell) or

Exogenous insulin

Glucose Metabolism

Insulin

secretionATP

DiazoxideSulfonylureas,

meglitinides

Blood

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Glucose Glycogen

InsulinInsulinLiver cell

Insulin

Adipose cell

glucose Triglyceride

PPARγγγγThiazolidinediones

GlucoseGlycogen

GlucoseGlucagon

Gluconeogenesis

Biguanides

Muscle

cell

Dietary complex CH are broken down to simple sugars in the GIT by the action of glucosidases; simple sugar then absorbed by GI epithelial cells and

transported into the bloodstream. Glucose in the blood is taken up by all metabolically active tissues in the body. In pancreatic β cells, glucose metabolism ↑levels of cytosolic ATP, which stimulates insulin secretion. Insulin then acts on plasma membrane insulin receptors in target tissues (muscle, adipose, liver)

to ↑ glucose uptake and storage as glycogen or TG. Glucose is also taken up by other cells and tissues to fuel metab. In muscle cells, ins. Promotes

glucose storage as glycogen. In adipose cells, ins. Promotes glucose conversion to TG. Peroxisme proliferator-activated rec’r γ (PPARγ) also promotes the

conversion of glucose to TG in adipose cells. In liver cells, insulin promotes glucose storage as glycogen. Glucagon promotes both the conversion of

glycogen back to glucose and gluconeogenesis; glucose generated from glycogen or by gluconeogenesis is transported out of the liver cell into the

bloodstream. Pharmacologic interventions that ↓ blood gluc. Levels include : inhibiting intestinal α-glucosidase; administering exogenous ins; using

sulfonylurea or meglitinides to augment secretion of insulin by β cells; and using biguanides or thiazolidinediones to enhance the action of insulin in liver or

adipose cells, respectively. Diazoxide inhibits insulin scretion from pancreatic β cells.

Mekanisme intrasel sekresi insulin oleh βcellsINSULIN

1) Glukosa masuk ke βcells dengan bantuan glucose transporters

(GLUT2).

2) Di dalam βcells glukosa difosforilasi ⇒

glucose-6 phosphate yang

dimetabolisme menghasilkan ATP

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dimetabolisme menghasilkan ATP (glycolysis, mitochondria).

3) ↑ rasio ATP/ADP ratio ⇒ tertutupnya

ATP sensitive K+ channels,membrane

depolarization dan membuka voltage-

dependent Ca2+ channels.

4) ↑Ca2+intrasellular ⇒ exositosis dari insulinsecretory granules.

� Diet : medical nutrition therapy

� Aktivitas Fisik/OR

� Farmakoterapi

� Kontrol BB

� Self-monitoring of blood glucose (SMBG)

Penatalaksanaan

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� Self-monitoring of blood glucose (SMBG)

� Patient self-management education

KEBERHASILAN MANAJEMEN

ASPEK METABOLIK DARI DM

Insulin Replacement Therapy

Farmakoterapi

1. Insulin dependent group (type 1) :

- virtually no insulin secretion

- depends on administration of exogenous insulin

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- depends on administration of exogenous insulin

2. Type 2 :

- most type 2 diabetics do not require exogenous insulin

for survival, but many need exogenous supplementation

of their endogenous secretion to achieve optimum

health

- 20% ⇒ taking insulin

Characteristics of Available Insulin Preparations

1. Rapid acting :

- very fast onset & short duration

- duration of action : 3-5 hours

4 principal types of insulins :

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2. Short acting: rapid onset of action :

- onset of action : within 30 minutes


3. Intermediate acting

4. Long acting : slow onset of action

Characteristics of Available Insulin Preparations

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Neutral Protamine Hagedorn/isophane

Insulin Delivery Systems

R, lispro

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1. Portable Pen Injectors

2. Continuous Subcutaneous Insulin Infusion

Devices (CSII, Insulin Pumps)

3. Inhaled insulinR, lispro,NPH, pre-mixed NPH 70%/R

• Perut : absorpsi cepat

• Lengan : absorpsi sedang

• Paha : absorpsi lambat

• Gluteus : absorpsi lambat

Contoh peta penyuntikan insulin selama 1 tahun

pada penderita DM tipe 1

Lokasi penyuntikan insulin yang dianjurkanLokasi penyuntikan insulin yang dianjurkanLokasi penyuntikan insulin yang dianjurkanLokasi penyuntikan insulin yang dianjurkan

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Complications of Insulin Therapy

1. Hypoglycemia

2. Immunopathology of Insulin Therapy

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3. Lipodystrophy at injection sites


1. Hypoglycemia

- Delay in taking a meal

- Inadequate carbohydrate consumed

- Physical over exertion

causes

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- Dose of insulin ⇒ too large for immediate needs

- Autonomic hyperactivity :

• Sympathetic : tachycardia, palpitations, sweating, tremulousness

• Parasympathetic : nausea, hunger

- Convulsions

- Coma

signs


1. Hypoglycemia

treatment

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- Glucose administration :

• Simple sugar/glucose

• Liquid form


1. Hypoglycemia

- Mild hypoglycemia : conscious and able to swallow :

• Orange juice

• Glucose gel

• Any sugar containing beverage/food

treatment

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• Any sugar containing beverage/food

- Severe hypoglycemia : unconsciousness/stupor :

• 20-50 ml of 50% glucose solution (IV infusion over 2-3 minutes)

• 1 mg glucagon : IM/SC

• small amounts of honey or syrup : buccal pouch

Contraindication : oral feeding


- Insulin allergy :

• Rare condition

• Urticaria

• Anaphylaxis

• Highly purified and human insulins : ↓ insulin allergy

treatment


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• Highly purified and human insulins : ↓ insulin allergy

- Immune insulin resistance :

• A low titer of circulating IgG anti-insulin antibodies that neutralize

the action of insulin to a negligable extent develops in most insulin-

treated patients.

• Rarely, the titer of insulin antibodies will lead to insulin resistance

and may be associated with other systemic autoimmune processes

such as lupus erythematosus


3. Lipodystrophy at injection sites

- Atrophy

- Hyperthrophy

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- Hyperthrophy

Corrected by :

- avoidance of that spesific injection

- liposuction

Oral Antidiabetic Agents

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Major Classes of Medications

1. Drugs that stimulate the pancreas to make more insulin (Insulin secretagogues)

2. Drugs that sensitize the body to insulin

SulfonylureasMeglitinides

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2. Drugs that sensitize the body to insulin and/or control hepatic glucose production (Insulin sensitizers)

3. Drugs that slow the absorption of starches

ThiazolidinedionesBiguanides

Alpha-glucosidase inhibitors


Insulin secretagogues : sulfonylureas

• Mechanism of Action :

- To increase the insulin release from pancreatic cells

- Reduction of serum glucagon concentrations

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- Reduction of serum glucagon concentrations

- Potassium channel closure in extrapancreatic

tissues

Sulfonylureas

♦ 1st generation

- tolbutamide

- tolazamide

- chlorpropamide∴∴∴∴ may become dislodged �� delayed activity

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♦ 2nd generation

– Glipizide

– glyburide

- glimepiride

Re

l. P

ote

ncy



1. Tolbutamide :

- well absorbed but rapidly metabolized in the liver

- duration of effect : short

1st generation

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- duration of effect : short

- t1/2 : 4-5 hours

- safest for elderly diabetics

- dicumarol, phenylbutazone, some sulfonamide

⇒ inhibit the metabolism tolbutamide

⇒ hypoglycemia



2. Chlorpropamide :

1st generation

- slowly metabolized

- t1/2 : 32 hours

- 20-30% excreted unchanged in the urine

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- 20-30% excreted unchanged in the urine

- drug int. : dicumarol, phenylbutazone, some sulfonamide

- contraindicated : hepatic /renal insufficiency, elderly patients

- dosages > 500 mg daily increase the risk of jaundice

- side effects : hypoglicemia, hyperemic flush, hematologic

toxicity ( transient leukopenia, thrombocytopenia)

~ 1%



2. Tolazamide :

1st generation

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- more slowly absorbed than the other sulfonylurea

- t1/2 : 7 hours

- metabolized to several compounds that retain hypoglycemia

- dosages > 500 mg daily ~ divided twice daily



1. Glyburide /glybenclamide :

2 nd generation• fewer side effects

• fewer drug interaction

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1. Glyburide /glybenclamide :

- metabolized in the liver into products with very low hypoglycemic

activity

- usual starting dosage : 2,5 mg/d or less

- average maintenance dosage : 5-10 mg/d single morning dose

- maintenace dosages higher than 20 mg/d are not recommended

- adverse effects : hypoglycemia, flushing

- contraindication : hepatic impairment, renal insufficiency



2. Glipizide (Glucotrol ®)

2 nd generation

- shortest half life : 2-4 hours

- 30 minutes before breakfast

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- 30 minutes before breakfast

- 90% metabolized in the liver to inactive products

- 10% excreted unchanged in the urine

-starting dosage : 5 mg/d up to 15 mg/d as a single dose

max. 40 mg/d

- lower hypoglycemia compared long acting glyburide

- contraindicated : hepatic impairment, renal insufficiency



3. Glimepiride

- t1/2 : 5 hours

- long duration of effect

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- long duration of effect

- once daily use as monotherapy or in combination

with insulin ~ compliance

- lowets dose of anysulfonylurea compound : 1 mg

single daily dose, maximal 8 mg.

Oral Antidiabetic AgentsInsulin secretagogues : meglitinides

• Meglitinides stimulate insulin secretion (rapidly and for a short duration) in the presence of glucose.

• “quick-on, quick-off” (awal kerja cepat, masa kerja pendek) � kontrol postprandial yang lebih baik dan menurunkan insiden hipoglikemia postprandial.

• Efficacy

– Decreases peak postprandial glucose

– Decreases plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L)

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– Decreases plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L)

• Other Effects

– Hypoglycemia (although may be less than with sulfonylureas if patient has a variable eating schedule)

– Weight gain

• Ex: repaglinide (Prandin), nateglinide (Starlix)

can be taken safely by people with impaired kidney function or sulfa allergies.


Insulin secretagogues : D- phenylalanine derivative

Nateglinide

• the latest insulin secretagogue to become clinically available

• stimulate release of insulin very rapidly and transiently from

B cells through closure of the ATP-sensitivie K+ channel

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• ingested just prior to meal

• absorbed within 20 minutes after oral administration

• t1/2 1,5 hours

• metabolized by CYP2C9 and CYP3A4

• hypoglycemia : lowest

• safe in : very reduced renal function


37Insulin secretagogues


Biguanides

Mechanisms of Action

1. Direct stimulation of glycolisis in tissues

2. Reduced hepatic & renal gluconeogenesis

3. Slowing of glucose absorption from GIT

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Metabolism & Excretion

4. Reduction of plasma glucagon levels

Metformin :

- t1/2 : 1,5-3 hours

- Is not bound to plasma protein

- Is not metabolized

- Is excreted by the kidney as the active compound


Biguanides

Clinical Use

• Insulin resistance syndrome

• Dosage : 500 mg to max 2,55 gr daily

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Toxicities

• anorexia, nausea, vomiting, abdominal discomfort, diarrhea

• lactic acidosis

Contraindication

• renal disease, alcoholism, hepatic disease, conditions

predisposing to tissue anoxia (eg. Chronic cardioplumonary

dysfunction)


Thiazolidinediones

• Pioglitazone (Actos), rosiglitazone (Avandia),

• [troglitazone (Rezulin) - (muncul 1997, ditarik tahun 2000 karena dicurigai menyebabkan idiosinkratik hepatoselular)

• Decrease : insulin resistance

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Alpha Glucosidase Inhibitors

• Alpha-glucosidase inhibitors block the enzymes that digest starches in the small intestine � slowing the rise in B.G.L.

• Efficacy

– Decrease peak postprandial glucose 40-50 mg/dl (2.2-2.8 mmol/L)

– Decrease fasting plasma glucose 20-30 mg/dl (1.4-1.7 mmol/L)

• Other Effects

– Flatulence or abdominal discomfort

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– Flatulence or abdominal discomfort

– No specific effect on lipids or blood pressure

– No weight gain

– Contraindicated in patients with inflammatory bowel disease or cirrhosis

• Examples:

– acarbose (Glucobay),

– miglitol (Glyset) → absorpsi oral yang lebih baik daripada acarbose

GLUCAGON

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GLUCAGON

Pharmacologic Effects

• metabolic effects : glucagon – rec’r liver cells-Gs protein-linked

increase I adenyly cyclase activity-cAMP> ~ catabolism of stored

glycogen and increases gluconeogenesis and ketogenesis

• release of insulin from normal pancreatic B cells, cathecolamines

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• release of insulin from normal pancreatic B cells, cathecolamines

from pheochromocytoma, calcitonin from medullary carcinoma cells

• cardiac effects : inotropic (+)ve and chronothropic (+)ve

• smooth muscle : profound relaxation of intestine

GLUCAGON

Clinical Use

• severe hypoglicemia

• endocrine diagnosis

• beta-blocker poisoning

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Adverse Reactions

• beta-blocker poisoning

• radiology of the bowel

• transient nausea and occasional vomiting

ISLET AMYLOID POLYPEPTIDE

(IAPP, AMYLIN)

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ISLET AMYLOID POLYPEPTIDE

(IAPP, AMYLIN)

• 37-amino-acid peptide

• derived from amyliod deposits in pancreas material from patients

with longstanding type 2 diabetes or insulinomas

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• inhibit the action of insulin to promote muscle uptake of glucose

• pramlintide (analog IAPP) : adjunct to insulin therapy in type 1

diabetic patients with recurrent episodes of severe insulin-induced

hypoglycemia. ⇒ still in clinical trial

Glucose meter

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Pharmacology of the endocrine pancreas -...

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