Pharmacology of

Metabolic Drugs

Nurlaili Susanti
Learning Objective:

1. To explain pharmacokinetic and

pharmacodinamic of antidiabetic drugs

2. To explain pharmacokinetic and

pharmacodinamic of antidislipidemic drugs
Antidiabetic Drugs
- Insulin
- Oral Hypoglycemic Drugs
 INSULINS

 Insulin is a hormone secreted by β-cells of the Langerhans

islets of pancreas  endogenous insulin
 Exogenous Insulin work as substitute and have same
effects as endogenous insulin to restores the action of
insulin in various tissues
 Goal: tight glucose control and reduce the incidence of
long-term complications of hyperglicemia
Action of Insulin on Various Tissues

Liver Muscle Adipose

↓ glucose production ↑ Glucose transport ↑ glucose transport

↑ glycolysis ↑ glycolysis ↑ lipogenesis&

lipoprotein lipase
activity
↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis

↑ Protein synthesis ↑ protein synthesis

 Classification
 Based on its origin: human insulin, pig and cow
They are different in one or two amino acid chains
causing different physicochemical properties.
Human insulin is chemically identical to endogenous
insulin, made using recombinant DNA technology.

 Insulins differ in onset and duration of action:

short, rapid, intermediate and long acting.
 Rapid acting insulin
 More effective in decreasing post-prandial hyperglycemia
 Route of administration is SC before meal
 Can be given continuous infusion (but not IV bolus) in
emergency (e.g. diabetic ketoacidosis)
 Most rapid onset of action (0-15 min), but short duration
 Usual administration 2 – 3 times/day or more

Insulin Onset Peak (hrs) Duration (hrs)

(mins)
aspart (Novolog) 2-33 1-3 3-5
lispro (Humalog) 2-33 30mins – 2.5 3-6.5

glulisine (Apidra) 2-33 30mins – 1.5 1.-25

 Short acting Insulins
 More effective in decreasing post-prandial hyperglycemia
 Route of administration is SC before meal
 Can be given IV bolus or continuous infusion in
emergency (e.g. diabetic ketoacidosis)
 Onset is 30-45 min, Usual administration 2 – 3
times/day or more

Insulin Onset (mins) Peak (hrs) Duration (hrs)

Humulin R 30 mins to 4 hrs 2.5-5 5-10

Novolin R 30 2.5-5 8
 Intermediate acting Insulins
 Injected SC Only
 Usually given 1-2x/day, not used during emergencies
 Insulin Onset (hrs) Peak (hrs) Duration (hrs)
Isophane (NPH):
Humulin N 1-4 4-12 16-28
Novolin N 1-5 4-12 24
Isophane & Insulin:
Humulin 50/50 0.5 4-8 24
Humulin 70/30 0.5 4-12 24
Novolin70/30 0.5 2-12 24
lispro protamine & lispro:
Humalog Mix 75/25 0.25-0.5 0.5-1.5 12-24
Novolog Mix 70/30 0.2-0.33 2.4 24
Insulin Zinc Suspension:
Lente Iletin II 1-1.5 8-12 24
Novolin L 1-4 7-15 20-28
 Long acting Insulin

 Once daily at bedtime

 More safe than intermediate acting insulins due to
reduced risk of hypoglycemia

Insulin Onset Peak Duration

glargine (Lantus 2-5 hr 5-24 hr 18-24 hr

detemir (Levemir) 4-6 hr 14-20 hr 20-36 hr

Using Insulin
 Sites for injection: upper arm, front & side parts of the
thighs & the abdomen.
 Not to inject in the same place (rotate)
 Should be stored in refrigerator & warm up to room
temp before use, must be used within 30 days.
 Degradation: 60% kidney, 40% liver
 Category B (not teratogenic)
Methods of Adminisration
 Insulin Syringes

 Pre-filled insulin pens

 External insulin pump

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 Complications of Insulin Therapy

1. Severe Hypoglycemia (< 50 mg/dl)– Life threatening

Overdose of insulin
Excessive (unusual) physical exercise
A meal is missed
2. Weight gain
3. Local or systemic allergic reactions (rare)
4. Lipodystrophy at injection sites
Oral Hypoglycemic Drugs
 Classifications
 Insulin secretagogues:
 Sulfonylureas (oldest)
 Meglitinides
 Insuline sensitizers:
 Biguanide
 Thiazolidinediones
 Alpha-glucosidase inhibitors
 Acrabose
 Miglitol
 Incretin
 GLP-1 analogue
 DPP-4 inhibitors
 Sodium-glucose transport proteins
 1. Sulfonylureas
 Mechanism: stimulate insulin secretion from the beta cells
of the pancreas, thus increasing insulin levels
 Beta cell function must be present
 Result: lower blood glucose levels
 First-generation drugs not used as frequently now
 Therapeutic Use: Controlling hyperglycemia in patients
with type 2 diabetes mellitus who can not achieve
appropriate dietary controls
 Contraindications
1) Type 1 DM (insulin dependent)
2) Parenchymal disease of the liver or kidney
3) Pregnancy, lactation
 First Generation Sulphonylurea Compounds

Tolbutamid Acetohexamide Tolazamide Chlorpropamide

short-acting intermediate- intermediate- long- acting
acting acting

Absorption Well Well Slow Well

Metabolism Yes Yes Yes Yes
Metabolites Inactive* Active +++ ** Active ++ ** Inactive **
Half-life 4 - 5 hrs 6 – 8 hrs 7 hrs 24 – 40 hrs
Duration of Short Intermediate Intermediate Long
action (6 – 8 hrs) (12 – 20 hrs) (12 – 18 hrs) ( 20 – 60 hrs)
Excretion Urine Urine Urine Urine

* Good for pts with renal impairment

** Pts with renal impairment can expect long t1/2
 Second Generation Sulphonylurea Compounds

Glipizide Glibenclamide Glimepiride

Short- acting (Glyburide) Long-acting
Long-acting

Absorption Well Well Well

Metabolism Yes Yes Yes
Metabolites Inactive Inactive Inactive
Half-life 3 – 4 hrs Less than 3 hrs 5 - 9 hrs
Duration of action 10 – 16 hrs 12 – 24 hrs 12 – 24 hrs
Excretion Urine Urine Urine
 Side Effects of Sulphonylureas

 Nausea, vomiting, abdominal pain, diarrhea

 Hypoglycaemia
 Chlorpropamide: Dilutional hyponatraemia & water
intoxication
 Weight gain
 Blood dyscrasias (not common; less than 1% of patients)
- Agranulocytosis
- Haemolytic anaemia
- Thrombocytopenia
 Cholestatic obstructive jaundice (uncommon)
 Dermatitis (Mild)
 Muscle weakness, headache, vertigo (not common)
 Increased cardio-vascular mortality with longterm use ??
 2. Meglitinides
(Repaglinide, Nateglinide)

 Action similar to sulfonylureas, but more rapid acting

 Increase insulin secretion from the pancreas
 Use in allergic to sulfur or sulfonylurea
 When used in combination with other oral agents they
produce better control than any monotherapy.
 Should be taken before or up to 30 minutes before a
meal. Dosage and frequency is flexible depending on food
intake.
 Metabolized by liver
 Side Effects: Hypoglycemia, weight gain, caution in pts
with renal & hepatic impairement
 3. Biguanides
Metformin (Glucophage)

 Mechanism: increases insulin sensitivity  increase

peripheral glucose utilization, decreases hepatic glucose
production, inhibits gluconeogenesis, impaired
absorption of glucose from the gut
 Does not increase insulin secretion from the pancreas 
Does not cause hypoglycemia and weight gain
 May be used alone or in combination with sulfonylurea
 Use for obese patients with type 2 DM
Side Effect:
1. Metallic taste in the mouth
2. Gastrointestinal (anorexia, nausea, vomiting, diarrhea,
abdominal discomfort)
3. Vitamin B12 deficiency (prolonged use)
4. Lactic acidosis (rare – 01/ 30,000-exclusive in renal &
hepatic failure)

Contraindication:
1. Hepatic impairment
2. Renal impairment
3. Alcoholism
4. Heart failure
 4. Thiazolidinediones/ TZDs
(Glitazones)

 Mechanism : selective agonist Peroxisome

Proliferator Activated-Receptor (PPAR)–γ, activate
insulin responsive genes that regulate carbohydrate and
lipid metabolism
 decrease insulin resistance
 stimulate insulin receptors on muscle, fat, and liver cells
 Results in increased uptake of glucose in periphery
 decreased glucose production by the liver
 May be used as monotherapy or in combination with
insulin, metformin or sulfonylurea
 Caution in patients with heart failure
 Contraindicated in patients with liver disease or who
have ALT levels > 2.5 of normal
 Mechanism of Action TZD: These agents act through the activation of
peroxisome proliferator-activated receptor-γ (PPAR-γ). Ligands for PPAR-
γ regulate adipocyte production, secretion of fatty acids and glucose
metabolism. Agents binding to PPAR-γ result in increased insulin
sensitivity is adipocytes, hepatocytes and skeletal muscle.
 5. Alpha glucosidase Inhibitors
Acarbose (Precose) and miglitol (Glyset)

 Mechanism : Inhibit alpha-glucosidase enzymes

(maltase, amylase, sucrase) in GI tract cause delaying
absorption of carbohydrate complex and reducing
postprandial increase in blood glucose
 Take at beginning of each meal
 Use for patients with Type 2 DM inadequately controlled
by diet
 Alone does not cause hypoglycemia
 Can be combined therapy with insulin or sulfonylurea
 Side Effect: Flatulence, Loose stool or diarrhea,
Abdominal pain
 Contraindicated in cirrhosis, malabsorption, severe renal
impairment
 INCRETINS

 Incretins : INtestine seCRETion INsulin

 Gut hormones that enhance insulin secretion in reponse to food
 Two hormones:
(1)glucagon-like peptide-1 (GLP-1)
(2)glucose-dependent insulinotropic polypeptide (GIP)
GLP-1
 GLP-1 is an incretin secreted from enteroendocrine cells
(L-cells) , the majority of which are located in the distal
ileum and colon, in response to nutrient ingestion.
 The release of GLP-1 appears to be biphasic. The first
response occurs shortly after food ingestion followed by
a second response which is more likely associated with
direct contact between nutrients and L-cells
 Mechanism of Action:
 Potentiates insulin release from β-cells
 inhibits glucagon secretion from α-cells  reduces hepatic glucose
output
 inhibiting gastric emptying  reduce the rate of nutrient
absorption), reduce appetite
 enhance insulin sensitivity
 stimulates β-cell mass  increased cellular differentiation, islet cell
proliferation, and reduced cellular apoptosis
Dipeptidyl Peptidase IV (DPP-4)
 First Isolated from rat liver in 1966
 Identical to CD26, a marker for activated T cells
 Its role in energy homeostasis was discovered which led
to the first patent application in 1996
 Cell surface serine dipeptidase belonging to the prolyl
oligopeptidase family
 Widely expressed
Ingestion of food
Pancreas
Glucose-dependent
 Insulin from beta cells Glucose
Release of gut (GLP-1 and GIP) uptake by
hormones : muscles
Incretins
Beta cells Blood
Alpha cells glucose
Active
GLP-1 & GIP Glucose
production
Glucose dependent by liver
DPP-4
 Glucagon from
enzyme
alpha cells
(GLP-1)
Inactive Inactive
GLP-1 GIP

Role of incretins in glucose homeostasis

33
Medication affecting the incretin system
 GLP-1 receptor agonists
 Exendin-4
 Exenatide
 GLP-1 analogues
 Liraglutide  a long-acting glucagon-like peptide-1
(GLP-1)
 DPP4 Inhibitors
 Sitagliptin (JANUVIA®)
 Enzymatic cleavage of GLP-1 by DPP-4
DPP-4 inactivates GLP-1
GLP-1 active
T1/2 = 2 min
H A E
GLP-1 inactive
H A E
Release of gut
hormones :
Incretins Beta cells
Alpha cells
Active
Ingestion of food GLP-1 & GIP
DPP-4
Exenatide
X enzyme

Sitagliptin
Inactive Inactive
GLP-1 GIP
 Incretin mimetics and DPP-4 inhibitors:
major differences

Properties/effect Incretin mimetics DPP-4 inhibitors

Restitution of insulin secretion Yes (exenatide) Yes

Hypoglycaemia No No

Maintained counter-regulation by Yes Not tested

glucagon in hypoglycaemia
Inhibition of gastric emptying Yes Marginal

Effects on satiety Reduces food intake None

Effect on body weight Weight loss Weight neutral

Side effects Nausea None observed

Administration Subcutaneous Oral

Dosage Twice daily Once daily

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 Sodium-glucose transport
(SGLT)-2 inhibitor

 Canagliflozin, Dapagliflozin, Empagliflozin

 inhibit glucose reabsorption by the kidney
 increase glucosuria
Summary – Action of Oral Antidiabetic Drugs

LIVER ADIPOSE MUSCLE

TISSUE

PANCREAS

1. GLUCOSE
PRODUCTION 3. PERIPHERAL
GLUCOSE UPTAKE
Biguanides 2. INSULIN SECRETION
Thiazolidinediones
Thiazolidinediones Sulfonylureas
Biguanides
Meglitinides

INTESTINE
5. INTESTINAL HORMONES
4. GLUCOSE Incretin
ABSORPTION
alpha-glucosidase inhibitors 41
Antidislipidemic Drugs
- STATIN
- DERIVAT FIBRAT ACID
- BILE ACID
SEQUESTRAN
- NIKOTINIC ACID
- INHIBITOR OF
INTESTINAL
STEROL ABSORBTION
- FISH OIL
1. STATIN
• Mevastatin, Lovastatin, Pravastatin, Simvastatin,
Atorvastatin, Rosuvastatin, Fluvastatin
Effect of Statin on LDL, HDL and Trigliserid level
The other effect of Statin (based on invitro study)

• Cardioprotective effect: Statins improve coronary

vasodilation response by increasing nitrogen monoxide
synthesis in endothelial cells, reduce platelet aggregation in
thrombus
• Anti-inflammatory effects : Statins inhibit infiltration of
monocyte into the arterial wall and secretion of matrix
metalloproteinases, reducing levels of C reactive protein
• Antioxidant: Statins stabilize paraoxonase
Pharmacokinetic

• all statins were given in the form of active β-hydroxy acid

except lovastatin and simvastatin in prodrug form which
would be hydrolyzed in the liver into the active form.
• Statins undergo first pass-metabolism and about 70%
are excreted by the liver, only 5-10% of the dose reaches
the circulation
• Excretion also through urine

Side Effect: Gastrointestinal symptoms, Hepatotoxicity,

myalgia, arthralgia

Contraindications: liver disease, pregnancy, lactation

Statin dose depends on the target of decreasing LDL

Rate of decreasing LDL

High Intensity: > 50 %
Moderate Intensity: 30-50 %
Low Intensity: < 30%
2. DERIVAT FIBRAT ACID
• Klofibrat, Gemfibrozil, Fenofibrat, Siprofibrat, Bezafibrat, Beclofibrat
• Mechanism: activates lipoprotein lipase (LPL) enzyme to solve
triglycerides,
• Decrease TG (25-50%), decrease LDL-C and increase HDL
Pharmacokinetic
• > 90% well absorbed when eating, but less efficient
when given on an empty stomach
• 95% bound to plasma protein (albumin)
• 60-90% is excreted in urine, a small part through feces
• Easily penetrate the placenta

Side Effect: Gastrointestinal simptom, increases cholesterol

stone formation (cholelithiasis), hepatotoxicity, myalgia
Contraindications: Hepatic or renal dysfunction, pregnancy,
lactation, pre existing gall bladder disease
3. BILE ACID SEQUESTRAN
• Derivates: Kolestipol, Kolestiramin, Kolesevelam
• Mechanism: act as positive charge that bind Bile Acid (negative
charge) in the intestinal lumen  prevent absorption and
increases bile acid excretion
Pharmacokinetic
• Exchange resin is not absorbed

Side Effect: constipation, bloating

How to use: resin mixed with water or juice, taken before

breakfast and dinner
4. NIKOTINIC ACID
• Vitamin B3 (Niasin)
• Mechanism : inhibit hormone sensitive lipase in adipose
tissue and lead to decrease in free fatty acid mobilization from
adipocytes to the liver  decrease TG and VLDL synthesis
Pharmacokinetic
• Niacin is converted to amide, absorbed into Niacinamide
Adenine Dinucleotide (NAD)
• Excreted through urine without being changed.

Side Effect: flushing, hepatotoxicity

5. INHIBITOR OF INTESTINAL STEROL
ABSORBTION

• Derivat: Ezetimibe
Mechanism : inhibit cholesterol absorption in intestine
Pharmacokinetic
• Easily absorbed and conjugated in the intestine to active
glucoronide
• Undergo enterohepatic circulation
• Excretion through feces

Side Effect: flushing, hepatotoxicity

Fish Oil (Omega-3 Fatty Acid )
 Contain EPA (Eicosapentanoic acid) and DHA
(Decohexanoic acid)
 Mechanism: decrease production of chilomycron and
VLDL
 Side Effect: dyspepsia, diarrhea, fishy odor to breath
Summary – Action of antidislipidemic drugs