Diabetes Mellitus - Pharmacotherapy G O ALS O F TREATMENT

Include: 1. Correction of symptoms such as polyuria, nocturia, blurred vision, tiredness,pruritus vulvae in women and balanoposthitis in men. 2. Maintenance of a healthy, cheerful life free of the fear of DM. 3. Prevention of macrovascular and microvascular complications.

G LYCAEMIC CONTROL
Good diabetic control should include maintaining a normal body mass index,
blood pressure and lipid levels. The best way of assessing glycaemic control is by estimating the glycosylated haemoglobin (HbAlc) level. HbAlc should be lowered to less than 2 per cent above the upper limit of normal or less than 7 %. Aim for 6.5%- not possible due to severe hypoglycaemia. This is not possible for certain patients : In the presence of significant co-morbid illness. Old age People with a defective state of mind. In routine practice, a level less than 8% is acceptable.

UMST- Clinical Pharmacy- Diabetes Mellitus

UMST- Clinical Pharmacy- Diabetes Mellitus

Diet

Patients should be encouraged to consume a well-balanced diet: 10 to 20 per cent of the caloric intake from protein 60 to 70 per cent from unrefined carbohydrate Less than 10 per cent from saturated fat. vitamin and mineral supplements should not be necessary if a balanced diet is consumed. Dietary regulation, with the goal of reducing the total body fat, is the first line therapy for controlling type 2 DM. 5 per cent reduction in fat = better glycaemic control. Dietary modification: Smoothes the glycaemic control, improves efficacy of oral or insulin treatment and helps in reducing dyslipidaemia. A successful diet programme should include a combination of: sensible caloric reduction, behaviour modification and patient education.

Goals of dietary management in diabetes

BMI 20-25 kg/m2 Maintain blood glucose levels at 4 -8mmol/L. Improvement of overall health. Prevention and treatment of anti-diabetic therapy complications e.g. hypoglycaemia. Prevention of diabetic complications. Optimising lipid levels .

Dietary advice
Regular meals based on starchy foods. Reduce intake of fatty foods. S ubstitute saturated fats e.g. ghee with
unsaturated fats e.g. olive oil. Five portions of fruit and vegetables a day. Reduce sugar intake. Reduce salt intake- use herbs to spice foods up. Moderate alcohol intake. Diabetic foods are not necessary.

Exercise

Should be initiated early in treatment. 3

UMST- Clinical Pharmacy- Diabetes Mellitus

Drug therapy of diabetes Oral Anti-diabetics

Sulphonylureas : Include chlorpropamide, glibenclamide, gliclazide and tolbutamide. Act mainly by augmenting insulin secretion and are effective only when
residual pancreatic -cell function is present. They are not the drugs of choice for obese type 2 DM, since they can cause weight gain. The main concern with their use is hypoglycaemia. Sulphonylurea induced hypoglycaemia can persist for several hours. Such patients should always be admitted to hospital. Care in the elderly. Approximately 20 to 25 per cent of patients with type 2 DM encounter primary failure of sulphonylurea therapy. Sulphonylureas should be used with caution in patients with increased cardiovascular risks. Sulphonylureas are primarily metabolised in the liver and should be used with caution in patients with hepatic dysfunction.

Biguanides Biguanides have been used in the treatment of DM since mediaeval times. French lilac, rich in guanidine, has a hypoglycaemic effect, but guanidine is too
hepatotoxic for clinical use. Metformin was introduced in 1957. Metformin carries a risk of causing lactic acidosis. It inhibits hepatic gluconeogenesis. Increases peripheral utilisation of glucose. Contraindications: Include: renal failure, hepatic impairment, alcohol abuse, cardiac disease and intercurrent illness. Metformin is the drug of choice in obese type 2 DM as it enhances weight loss, while controlling hyperglycaemia. It is effective as monotherapy and can also be used in combination with sulphonylureas and insulin. Used alone, it reduces fasting blood glucose by 22 to 26 per cent and HbAlc by 12 to 17 per cent. 4

UMST- Clinical Pharmacy- Diabetes Mellitus

 Around 20 to 30 per cent of patients experience abdominal discomfort,

nausea, anorexia and a metallic taste in the mouth. Long-term treatment improve tolerability Metformin should always be started slowly, and the dose built up in a matter of weeks rather than days. Again, secondary failure develops at the rate of 5 to 10 per cent per year.

Acarbose
Inhibits the a-glucosidase enzyme in the i ntestine and prevents the absorption of starch and sucrose. If tolerated, the drug is often useful in obese type 2 DM. Treatment with acarbose may reduce the insulin demand by decreasing postprandial hyperglycaemia. Flatulence and diarrhoea are the common side effects. These symptoms get better with continued use and treatment should be started with a small dose.

Repaglinide
A novel enantiomeric benzoic acid derivative. It promotes the secretion of insulin by closing ATP-sensitive potassium
channels in the -cell membrane. Repaglinide, unlike glibenclamide, does not stimulate insulin secretion in the absence of glucose. Effective in reducing postprandial hyperglycaemia.

Thiazolidinediones Include rosiglitazone and pioglitazone. Thiazolidinediones directly enhance insulin sensitivity, thereby reducing insulin
resistance, the major defect in type 2 DM. Thiazolidinediones bind to peroxisome proliferator-activated receptor, a molecule implicated in the transcription of insulin responsive genes. Work in the presence of glucose to: Increase both basal and insulin-stimulated glucose uptake in muscle and adipose tissue Enhance the expression of glucose transporter receptors in the cell wall. It has also been shown to protect the -cell from exhaustion.

UMST- Clinical Pharmacy- Diabetes Mellitus

Primary failure of oral Anti-diabetic therapy

Glyceamic control not improved on initiation of the therapy. The usual causes of primary failure are : Dietary discordance Wrongly selected patients (eg, cases of type l DM) And severely impaired -cell function (advanced type 2 DM). Among those who achieve initial control, 5 to 10 per cent develop secondary failure every year.

COMBINATION THERAPY
Monotherapy with oral agents is often unsuccessful. Combination of a sulphonylurea with metformin or acarbose has long been used successfully. Rosiglitazone and pioglitazone are also used in combination therapy . When glycaemic control is not achieved by combining oral agents, insulin can be used along with oral agents. Insulin is used once daily at night to suppress the hepatic glucose output. The injection frequency is increased when acceptable glycaemic control is not achieved.

UMST- Clinical Pharmacy- Diabetes Mellitus

INSULIN THERAPY

Most patients with type 2 DM secrete enough insulin to be treated with diet, exercise and oral agents, at least initially. As the disease progresses (and it almost always does), insulin secretory capacity declines to a level requiring exogenous insulin. All type 1 DM require insulin due to absolute deficiency.

Insulin

Insulin preparations are classified according to The duration of action : (long,intermediate, short or ultra-short acting) Source: (porcine,bovine or human) and purity : (conventional, purified and highly purified).

Short action
Have a relatively rapid onset of action e.g. soluble insulin and insulin lispro

Intermediate action e.g. isophane insulin

Long Action Action is slower in onset and lasts for long periods, e.g. insulin zinc suspension.

The currently available preparations are highly purified and the human insulins are prepared by DNA recombinant technology.

UMST- Clinical Pharmacy- Diabetes Mellitus

Insulin analogues
Have a different amino acid sequence or composition of the insulin molecule. The rapidly acting analogues reduce the stability of the insulin monomermonomer interaction. Leads to a more rapid sub-unit dissociation and subcutaneous absorption of insulin. Hence, their onset of action is quicker and matches well with postprandial hyperglycaemia. Most patients prefer analogues because it is not necessary to leave any time period between the injection and meals. Insulin lispro (produced by changing the sequence of lysine and proline at the 29th and 30th position of the B-chain). It is an ultra-short acting insulin. Insulin aspart (proline replaced by aspartic acid at the 28th position of the B-chain). Insulin glargine Long acting. These analogues are associated with less hypoglycaemic episodes, better glycaemic control and less weight.

Adverse effects of Insulin

The two main problems of insulin use are weight gain and hypoglycaemia.
Hypoglycaemia: Concomitant medical conditions such as hypothyroidism, Addisons disease and liver and renal disease can contribute to hypoglycaemia. (Dose and/or timing)- mismatch between food and insulin injection Other side effects of insulin use are : lipoatrophy, lipohypertrophy and, rarely, insulin allergy.

Dosage and administration

Insulin administration Insulin is inactivated by gastro-intestinal enzymes. Insulin is generally given by subcutaneous injection: Syringes Pen Infusion devices for intensive regimens 8

UMST- Clinical Pharmacy- Diabetes Mellitus

Subcutaneous Administration: The subcutaneous route- Insulin is usually injected into the upper arms, thighs, buttocks, or abdomen. Problems with subcutaneous insulin injections : Fat hypertrophy can be reduced by locating the injection in different sites. Absorption from a limb site may be increased if the limb is used in strenuous exercise after the injection on sites in rotation. Local allergic reactions are rare. The intravenous route is used to deliver soluble insulin for: Urgent treatment For fine control in serious illness And in the perioperative period

Insulin regimens Designing an appropriate regimenis the most important aspect of prescribing
insulin. Should consider: the age of the patient, the patients wishes, co-morbid diseases glycaemic profile.

Twice daily injections: Mix of intermediate action insulin plus soluble insulin to be given before breakfast and evening meal. Ready mix preparations e.g. Mixtard 30 Multiple injections: Soluble insulin given before the three main meals(60% of total dose) PLUS an intermediate or long acting prep to cover the night basal (40%)

Monitoring Many patients now monitor their own blood-glucose concentrations Patients should maintain a blood-glucose concentration of :
47 mmol/litre before meals and less than 9 mmol/litre after meals

Patients must monitor Glucose daily and adjust dosages as required. 9

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PANCREATIC TRANSPLANT

Pancreatic transplantation was first carried out in 1966. Selective islet cells transplants are also used. Operative/ post-operative morbidity and mortality are reduced because o the need for life-long immunosuppression.

Advising Patients on anti-diabetic drugs

Explain the disease and its complications. How to recognise hypoglycaemia:
Fatigue, irritability, confusion, pallor, rapid pulse, blurred vision and anxiety. Eat at regular times to avoid hypoglycaemia. Anticipate increased need or energy when taking exercise etc.. How to recognise hyperglycaemia. Disposal of used lancets and needles. Provide easy to carry cool bags for insulin on the go. Use and storage of insulin. Using of oral hypoglycaemic drugs. Foot care. Cardiovascular risks. Regular medical and opthalmologic tests. Blood and urine testing.

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UMST- Clinical Pharmacy- Diabetes Mellitus