ORAL ANTI-DIABETIC DRUGS Rx of DM (Type II) CLASS EXAMPLES st Sulphonylureas 1 gen: (Drugs to Tolbutamide increase insulin (Rastinon) secretion)

Cautions: Newly diagnosed: risk of hypoglycaemia There is beta cell recovery when blood glucose is normalised *tolbutamide and gliclazide are preferred to glibenclamide in the following situations -Renal impairment, -Elderly Tolbutamide and gliclazide have short duration of action and are metabolised in the liver INDICATION -Efficacy: very effective (good blood glucose lowering capacity) M.O.A Main action ->Promote insulin >secretion(secretogauge). ->Closure of membrane bound K channels ->opening of calcium channels. ->Calcium entry causes degranulation of beta cells of pancreas. Other possible actions (long term effects) ->Increase insulin receptor number at target tissue ->Increase glucose uptake by muscle ->Reduced glycogenolysis t1/2: 8h Duration of action: 5-8h Admin: 1-3x/daily Time of admin: w meals Suitability: -in renal impairment:OK -in elderly :OK -in pregnancy/breast feed: x ok SIDE EFFECTS ->Hypoglycaemia: -more with long acting -Glibenclamide > tolbutamide **Hence:
Take regular meals and snacks Do not skip meals. If a meal is delayed: take a snack at the meal time Additional strenuous exercise needs an additional snack Do not increase the dose without medical advise Avoid long acting SU drugs in elderly and in renal impairment

-Suitability : Non obese diabetics and those who can take meals at regular times c/i : *Type 1 diabetes *Pregnancy: relative contraindication *Breast feeding: *Liver disease *Stressful states eg. severe infections, myocardial infarction, surgery *Hyperglycaemic emergencies(DKA )

->Weight gain **Hence:

Use a minimum dose to prevent excessive hunger

Very rare : Nausea, vomiting , diarrhoea, neutropenia, thrombocytopenia, skin rashes, liver impairment **Hence: Avoid in liver disease

2 gen: Glibenclamide (Dionil) Gliclazide (Diamicron) Glipizide (Minidiab)

nd

t1/2: 10h Duration of action: 12-24h Admin: 1-2x/daily Time of admin: w meals Suitability: -in renal impairment: x ok -in elderly :x ok -in pregnancy/breast feed: x ok

Biguanides (Drugs to improve insulin action (insulin sensitivity) Adv: ->Do not cause hypoglycaemia when used as mono-therapy ->Do not cause weight gain; may contribute to weight loss

Metformin (Glucophage Glycomet) Caution : ->Elderly ->people with renal impairment ->Should be discontinued 24 hours before procedures requiring intravenous contrast dye ->Can be restarted 48 hours after the procedure if renal function is normal

Suitability : -Newly diagnosed - When hypoglycaemia is a risk to life (eg. driving, working with machinery and at heights) -When meals cannot be taken on time Inquire about the occupation, driving and the meal pattern c/i: -Major organ failure (liver, heart, respiratory, renal) -Surgery Type 1 diabetes -Hyperglycaemic emergencies (DKA)

1.

2.

3.

4. 5.

Inhibition of hepatic gluconeogenesis (glucose production from amino acids and fatty acids) Increased glucose uptake by muscle in the presence of insulin Increased insulin receptor number and affinity of target tissue Reduced intestinal glucose absorption Reduced appetite (results in weight loss)

COMMON: -GI disturbances -loss of appetite -nausea, vomiting -diarrhoea Hence: 1.Start with a low dose and gradually increase the dose 2.Take with meals or immediately after meals 3.Avoid taking before meals RARE: - Lactic acidosis Hence: Avoid in Major organ failure and before surgery (perioperatively) Reduce maximum daily dose to 2g in elderly VERY RARE: hypoglycaemia Problems: 1. Bacterial action on undigested food in the colon leads to intolerable GIT side effects- abd distension , gas formation 2. Liver toxicity (hepatitis

Admin: 1-3x/daily Time of admin: w meals OR immeadiately after meal Suitability: -in renal impairment: Reduce dose when Cr clearence < 45ml/ minute/Avoid when Cr 2 Clearence is <30ml/minute/1.73 -in pregnancy/breast feed: OK

Others

Alpha glucosidase inhibitors acarbose

Delayed conversion of disaccharides to monosaccharides in the intestines

Thiozolidinediones pioglitazone

Problems: oedema, weight gain, heart failure and liver failure New evidence: -Myocardial infarction -Fractures (women)

Latest experimental antidiabetes drug Incretins: Secreted by the small intestine

->glucose dependent insulinotropic polypeptide ->glucagon like polypeptide 1 ->stimulate beta cells to increase insulin secretion in response to oral carbs ->Drug causing increased incretins: Sitagliptin

Monitoring of patients Fasting blood glucose: fasting for 8-12 hours Post prandial blood glucose: ->At 2hours following a main meal (break-fast , lunch and dinner) Haemoglobin A1c(HbA1c): non fasting blood test, gives the control over the previous 3 months Newly diagnosed patients should be tested preferably once a week and blood glucose targets should be achieved early preferably in one month Special situations: pregnancy and breast feeding Type 2 diabetes Metformin is recommended in pregnancy and breast feeding Gestational diabetes: Metformin should be discontinued after delivery Sulphonylureas are relative contraindications: SU need to be discontinued only with the commencement of insulin/ metformin, in pregnancy Important to note: The essential part of treatment of type 2 diabetes is dietary adjustment (non-pharmacological management) Principles of therapy Start with a suitable low dose (mono -therapy) Continue with dietary adjustment during therapy Monitor fasting blood glucose and 2 hour postprandial blood glucose Adjust the dose accordingly The relevant meal (quality and quantity ) should be considered when adjusting the dose Add a second drug in low dose, early if needed Try to achieve targets for control early Prevent adverse effects of treatment The principles of combination therapy Add a second oral anti-diabetes drug that has a different mechanism of action eg. metformin +sulphonylurea Two medications in low doses rather than increase in initial medicine to maximum dosage Fewer side effects than mono-therapy at higher doses Do not combine 2 sulphonylureas Summary Lifestyle changes first; the diet, weight and exercise Prevent glucotoxicity by avoiding sugar containing food and drinks Start with a suitable oral antidiabetes drug early; metformin is suitable in newly diagnosed if there a Commonest cause of treatment failure is poor compliance to the diet and the treatment Combining with a low dose SU is recommended for optimum blood glucose control Do not delay adding insulin if the blood glucose control is poor.

Class of medicine

Likely to cause weight gain

Likely to cause hypoglyca emia +

Likely to cause heart failure -

Likely to cause liver damage RARE

Sulphonylureas + Biguanides Glitazones Alphaglucosidase inhibitors Incretin mimetic agent

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Review question 1
Select the correct answer regarding sulphonylureas a. They inhibit gluconeogenesis b. Tolbutamide has a long duration of action c. The tablets should be taken 20 minutes before meals d. Glibenclamide is recommended in elderly e. They act by increasing insulin secretion

Review question 2
Which of the following statements IS FALSE with metformin?
a. Likely to cause weight loss b. Should not be taken before the meal c. Commonly associated with hypoglycaemia d. Causes gastrointestinal side effects e. May be given in pregnancy

Review question 3
1.Which of the following adverse reactions is unlikely with pioglitazone therapy?
a. Oedema b. Diarrhoea c. Heart failure d. Weight gain e. Liver failure

Review question 4
When educating a patient about sulphonylureas, what is the most important thing to discuss?
a. What and when to eat? b. When to take the medication? c. How to recognize and treat hypoglycaemia? d. How to prevent hypoglycaemia? e. When to see the doctor again?