Diabetic pharmacology, Thesis of Pharmacology

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Endocrine Pharmacology

Section VIII

Presented by : Dr. Gyanendra Swar (David) 1

A) Antidiabetic Drugs

Diabetes Mellitus 2 major categories:

• (^) Type- I or

Insulin Dependent Diabetes Mellitus (IDDM)

• (^) selective B cell destruction and severe or absolute insulin deficiency.
  • (^) Type- II or

Non-Insulin Dependent Diabetes Mellitus (NIDDM)

• (^) insulin is produced by the B cells, it is inadequate to overcome the resistance, and the blood glucose rises.
• (^) Type 3 Diabetes Mellitus : nonpancreatic diseases.
• (^) Type 4 Diabetes Mellitus : Gestational Diabetes (GDM) is defined as any abnormality in glucose levels noted for the first time during pregnancy.

Prediabetes

• (^) IFG and IGT are not diabetes
• (^) IFG and IGT are prediabetes
• (^) Have higher risk of developing diabetes

and CVD.

• (^) Any type of diabetes (other than type1)

can pass through IFG or IGT.

• (^) Treated by lifestyle modification;
• (^) Drugs may be used, specially in IGT
• (^) Some cases may revert to normal. 4

Clinical presentation

• (^) Asymptomatic
• (^) Typical
• (^) Atypical
• (^) With micro/macro-angiopathy Typical features: Glycosuria: loss of glucose in urine. Begins after the blood glucose level has gone above the individual’s ‘renal threshold’ for glucose. Polyuria Polydipsia Polyphasia Weight loss General weakness Atypical manifestation
• (^) Non-healing infection
• (^) Infertility or repeated pregnancy loss
• (^) Undue fatigability
• (^) Pruritus vulvae etc (^5)

Procedures for documenting glucose intolerance:

• (^) OGTT (Oral glucose tolerance test),
• (^) RBS (Random blood sugar),
• (^) FBS (Fasting blood sugar) Diagnosis of DM 7

Interpretation of OGTT:

Inference 0 min glucose level

(VP)

120 min glucose

level (VP)

DM ≥ 7.0 mmol/L ≥ 11.1 mmol/L

IGT < 7.0 mmol/L ≥ 7.8 to < 11.1 mmol/L

IFG ≥ 6.1 to < 7.0 mmol/L < 7.8 mmol/L

(if measured)

Normal < 6.1 mmol/L < 7.8 mmol/L

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Targets of glycemic control HbA1c <7.0% Fasting BG <6.1mmol/L[110mg/dl] Post-prandial BG <8.0mmol/L[145mg/dl] Bed time BG <7.0mmol/L[125mg/dl] 10

HbA1c HbA1c occurs when haemoglobin joins with glucose in the blood. When glucose sticks to these molecules it forms a glycosylated haemoglobin molecule, also known as A1c or HbA1c. The more glucose found in the blood the more glycated haemoglobin (HbA1c) will be present. Normal levels of HbA1c For non-diabetics , the usual reading is 4-5.9%. For people with diabetes , an HbA1c level of 6.5% is considered good control, although some people may prefer their numbers to be closer to that of non-diabetics. People at greater risk of hypoglycemia may be given a target HbA1c of 7% 11

Treatment modes of DM

• (^) Non pharmacological [lifestyle modifications] and
• (^) pharmacological [oral agent and insulin].
• (^) Non pharmacological approach initially can be

sufficient for some cases of type2 DM;

• (^) but all type1 DM and most of the type2 DM require

both of these together.

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Antidiabetic agents

• Insulin

• Oral hypoglycemic agents

Insulin receptor

• (^) Its cytoplasmic domain contains tyrosine kinase.
• (^) Its contains two alpha sub-units and two beta sub-units; the tyrosine kinase resides within the beta sub-units.
• (^) The extracellular domain, ie, that part of the receptor which projects into the ECF, combines with the ligand (eg.insulin) ----- this results in autophosphorylation of the receptor and tyrosine kinase becomes active ------- eventually the physiological-pharmacological actions (eg. Entry of glucose molecule from the ECF into the inside of the cell) occur.
• (^) Instead of tyrosine kinase, the receptor (when it is not insulin receptor) can contain serine kinase or guanylyl cyclase. Examples : receptors of insulin , platelet derived growth factor PDGF; epidermal growth factor EGF

Fig : - Insulin receptor

Insulin release

• (^) insulin release from the pancreatic B cell by glucose and by sulfonylurea drugs.
• (^) In the resting cell with normal (low) ATP levels, potassium diffuses down its concentration gradient through ATP-gated potassium channels, maintaining the intracellular potential at a fully polarized, negative level. Insulin release is minimal.
• (^) If glucose concentration rises, ATP production increases, potassium channels close, and depolarization of the cell results.
• (^) As in muscle and nerve, voltage-gated calcium channels open in response to depolarization, allowing more calcium to enter the cell. Increased intracellular calcium results in increased insulin secretion.
• (^) Insulin secretagogues close the ATP-dependent potassium channel, thereby depolarizing the membrane and causing increased insulin release by the same mechanism.