This presentation is on co-drug design, two drugs are chemically linked together for their improved delivery properties so as to reach a site simultaneously achieving better absorption as compared to when co-administered in separate dosage forms.

1. CO-DRUG STRATEGY FOR
TREATING HYPERTENSION IN
TYPE- II DIABETES
Presented by: Guided by:
Latika Budhalakoti Dr. Suneela Dhaneshwar
M.Pharm (Pharm chem.) Professor
Department of Pharmaceutical Chemistry
Poona College of Pharmacy
Bharati Vidyapeeth Deemed University
Erandwane, Pune -411 038 1

2. CONTENTS
• Introduction
• Drug therapies
• Disadvantages and advantages of co- drug
therapy.
• Drugs profile
• References
2

3. Diabetes mellitus (DM)
• DM is a chronic metabolic disorder
characterised by a high blood glucose
concentration. 1
• Preprandial plasma glucose (before
a meal)-70–130 mg/dl .
• Postprandial plasma glucose (after a
meal) – 120- 160 mg/dl. 2hr after a
meal.
 TYPE-I DIABETES: Insulin
deficiency.
Insulin dependent diabetes
mellitus(10%)
 TYPE-II DIABETES: Insulin
resistance.
Non-insulin dependent diabetes
mellitus.(90%) 1
Pathophysiology of Diabetes Mellitus3

4. Drug therapy 2
Insulin secretogogues:
● Sulfonyl ureas:
 First generation:
Tolbutamide,Tolazamide
 Second generation:
Glimepiride,gliclazide
● Meglitinides:
Repaglinides,Nateglinides
Tolbutamide
Gliclazide
Repaglinide
4

5.  Biguanides:
Metformin
 Insulin sensitizers:
 2,4-Thiazolidine diones:
Pioglitazone,Rosiglitazone
 Glycogen like peptide-1
analogues(GLP-1):
Exenatide,Liraglutide
Pioglitazone
Liraglutide
Metformin
5

6. 6

7. Drawbacks of the current
therapies 1
7

8. Hypertensive diabetes
• Hypertension is an extremely common co-morbidity of
diabetes, affecting 20–60% of diabetics depending on
age, ethnicity and obesity.
• In type II diabetes, hypertension is often present as part
of the metabolic syndrome of insulin resistance also
including central obesity and dyslipidemia.
• The prevalence of hypertension in the diabetic
population is 1.5–3 times higher than that of non-
diabetic groups.
8

9. Pathogenic mechanisms of
hypertension in type II diabetes 7
● Sympathetic nervous system activation.
● Abnormal ion transport.
● Renin–angiotensin–aldosterone system activation.
● Endothelial dysfunction altering vascular tone.
9

10. • Hypertension substantially increases the risk of
cardiovascular complications twice in diabetics than
nondiabetics.
• The macrovascular and microvascular complications
include stroke, coronary artery disease, and peripheral
vascular disease, retinopathy, nephropathy, and
possibly neuropathy.
• Cardiovascular disease is the most costly
complication of diabetes and is the cause of 86% of
deaths in diabetics.
Cardiovascular complications of diabetics
10

11. Proportion of diabetic complications
attributable to high
blood pressure 6,7
Complication
Proportion attributable to
hypertension%
 Stroke
 Coronary artery disease
 End-stage renal disease
 Eye disease
 Leg amputation
 75 %
 35 %
 50 %
 35 %
 35 %
11

12. • Diabetic patients with blood pressures >130 mmHg systolic
or >80 mmHg diastolic are candidates for antihypertensive
treatment aimed at lowering blood pressure to <130/80
mmHg.
• Well-designed randomized clinical trials have demonstrated
the effectiveness of aggressive antihypertensive treatment in
reducing diabetes complications.
• In the U.K. Prospective Diabetes Study (UKPDS), each 10-
mmHg decrease in mean systolic blood pressure was
associated with reductions in risk of 12% for any
complication related to diabetes, 15% for deaths related to
diabetes, 11% for myocardial infarction, and 13% for
microvascular complications.
12

13. Hypertension in diabetes
 The association of arterial hypertension and diabetes
mellitus is frequent.
 The majority of people with diabetes have
hypertension and 17% of those with hypertension
(blood pressure 140/90 mmHg or greater, or on
treatment) have been diagnosed with diabetes. 8
 Excess hypertension frequency is marked in type II,
non insulin-dependent diabetes.2
 Treatment of high blood pressure in people with
diabetes results in large reductions in death,
disability and reduces overall health cost.
13

14. Drug treatment in hypertensive
patients with type II diabetes 2
14
Ca2+ channel blockers
Nifidipine
Diuretic Hydrochlothiazide

15. ACE inhibitors:
First line treatment for hypertensive diabetes
 Benefits of ACE inhibitors as the first-line agents for
treating macrovascular and microvascular complications
in hypertensive diabetes:
 Cardioprotective benefits.
 Specific renoprotective actions.
 Delayed progression of microalbuminuria to overt
nephropathy.
 Retarded deterioration of established renal impairment.
 Positive impact on glucose metabolism.
15

16. Disadvantages of combination therapy
 Frequent dosing in a day.
 Non compliance
 Increased cost
 When two drugs are co-administered in separate
dosage forms or in a multicomponent formulation,
their ADME is independent of each other.
16

17. Advantages of co- drug therapy
● In co-drug design, two drugs are chemically linked together
for their improved delivery properties so as to reach a site
simultaneously achieving better absorption as compared to
when co-administered in separate dosage forms.
 Extended release possible by selection of appropriate linkage.
 Both drugs available at the activation site.
 Improved patient compliance.
 Cost effective.
 ADME fate of both the drugs is same till the prodrug gets
activated.
17

18. Drug profile
CAPTOPRIL
• IUPAC name:
1-[(2S)-2-methyl-3-sulfanylpropanoyl]
pyrrolidine-2-carboxylic acid
• Chemical formula: C9H15NO3S
• Molecular weight : 217.2853 g/mol
• Melting point : 160 °C
• Log P : 0.272 (n-octanol: water)
• Aqueous solubility : 160 mg/ml
• Bioavailability: 70–75%
• Half life: 1.9 h
• Metabolism: Hepatic
• Excretion: Renal
• Protein binding : 25-30%
• Route: Oral.
• Dose: 25-150 mg b.i.d or t.i.d
18

19. Captopril
 First ACE inhibitor developed (1978).
 Blocks the convertion of Ang - I to Ang -II by inhibiting ACE.
 Indicated in diabetic nephropathy in patients with type 2 non
insulin-dependent diabetes mellitus.
 It decreases the rate of progression of renal insufficieny.
● Other indications- Hypertensive crises, reno-vascular
hypertension, chronic kidney diseases, stroke prevention.
 It shows positive impact on glucose metabolism in hypertensive
diabetes.
● Side effects:
Persistent cough, urticaria and taste disturbance. 19

20. Drug profile
• IUPAC name:
N,N-dimethylimidodicarbonimidic diamide
• Chemical formula: C4H11N5
• Molecular weight : 129.163 g/mol
• Melting point : 223- 226 °C
• Log P : - 1.43 (n-octanol: water)
• Aqueous solubility : 1.38 g/l
• Bioavailability: 50-60%
• Half life: 6.2 h
• Metabolism: Not metabolized
• Excretion: Renal
• Protein binding : Negligible
• Route: Oral.
• Dose: 500 mg b.i.d .
METFORMIN•Alkyl substitution at N 1 increases activity through
n-pentyl, but decreases with longer chain length,
branching, or with cyclic alkyl substituents.
1
20

21. Metformin
 Lowers blood glucose, increases glucose uptake and utilisation in
muscle , reduces hepatic glucose production (gluconeogenesis).
 Drug of choice for non-insulin dependent diabetes mellitus
patients.
● Indications: Type II DM, obese patients and those who fail to
respond to treatment with diet alone. It does not cause
hypoglycemia.
● Side effects:
 GIT disturbances (anorexia, weight loss, diarrhea) transient,
lactic acidosis rare but potencially fatal.
 Metformin should be avoided in patients who predispose to lactic
acidosis (renal and hepatic disease, heart failure).
 Excess hypertension frequency is marked in type II, non insulin-
dependent diabetes. 21

22. References
1 Lippincott Illustrated Review Pharmacology; Pamela, C. C.; Richard, A. H.;
Eds 4th.; Lippincott Williams & Wilkins, a Wolters Kluwer business: USA,
2009; pp 352-354.
2 Foye’s Principles of Medicinal Chemistry; Lemke, T. L.; Williams, D. A.;
Roche, V. F.; Zito, S. W.; Eds 6th.; Lippincott Williams & Wilkins, a Wolters
Kluwer business: USA, 2008; pp 738-768 .
3 Huttunen, K.M.; The First Bioreversible Prodrug of Metformin with Improved
Lipophilicity and Enhanced Intestinal Absorption. J. Med. Chem. 2009, 52(
14), 4142–4148.
4 Thomas M. D.; Metformin – Cysteine Prodrug. US Patent Pub lication. 2011,
US 2011/0257432.
22

23. References
5 Bild, D.; Teutsch, S.M. The control of hypertension in persons
with diabetes. A public health approach. Public Health.
1987;102:522-529.
6 Hypertension in diabetes: A call to action, NRC Campbell
Leiter, L.A.; Larochelle, P.; et al. Hypertension in diabetes. A
call to action, , NRC Campbell . 2009, 25(5), 299-302.
7 Steven, J. H.; Patrick, M. B. Diabetes and hypertension.
MEDICINE, Elsevier Ltd, 34, (2), 2006, 76.
8 Canadian Diabetes Association clinical practice guidelines for
the prevention and management of diabetes in Canada. Can J
Diabetes. 2008, 32, S1-S201.
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