Diabetic Medication

Insulin

Short-acting insulins:• These are used for treatment of DKA• To cover operations and illnesses in patients with diabetes• Sometimes in the long term control of diabetes combined

with longer acting insulin• The are the only insulins suitable for IVI use. • Following subcutaneous injection their action starts after

about 30 minutes and lasts up to 8 hours. After intravenous injection the onset is much quicker but it only lasts for about 30 minutes. They include Humulin and Human Actratpid.

• The human insulin is the preferred insulin for a pregnant lady.

• Insulin Lispro and Insulin Aspart are modified forms of human insulin, they are very rapidly mobilized from the subcutaneous injection site.

• They act quicker than the soluble insulin onset of 15 minutes after subcutaneous injection and last up to 4 hours.

• Their place in management of diabetes are not settled, they may be useful if given directly before a meal to control the rise in blood sugar and thus mimicking more closely the response of the normal pancreas.

• Insulin Glulisine is a fast-acting synthetic recombinant insulin analogue differing form human insulin in its amino acid sequence.

• It is marketed as Apidra• It is injected subcutaneously immediately

before meals and when necessary after food. • When given subcutaneously it appears in the

blood earlier than human insulin and it should be given 15 min before a meal or within 20 minutes after a meal.

Intermediate-acting Insulin

• These insulins act for varying periods depending on the mix of rapid and slow-acting components.

• The blood glucose starts to fall in 1-2 hours after injection and this effect continues for 16-24 hours. The are usually given once or twice daily and may be combined with soluble insulin.

• Insulin Zinc suspension: It was found that if insulin was buffered with acetate its action was prolonged, and a further tow types of insulin could be prepared: amorphous, in which the particles were small, and a crystaline form with larger particles.

• The action of amorphous insulin is rapid and short-lived, but that of crystaline insulin is more prolonged.

• By using a mixture of theses insulins a smooth and prolonged effect can be achieved.

• Among those available are Human Monotard (30% amorphous, 70% crystaline and Human Ultratard (crystaline).

• Biphasic Isophane insulins : – Biphasic insulins consist of insulin complexed with

protamine. – This can then be mixed with varying amounts of

soluble insulin to produce and immediate and longer effect.

– These include Human Mixtard 30/70 and Humulin M1, M2, M3, M4 (varying proportions of soluble and isophane insulin).

• Insulin Glargine (Lantus) – It is a preparation of insulin as an acidic solution

that is given subcutaneously once daily at bedtime and forms microcrystals under the skin.

– These microcrystals dissolve slowly and release insulin into the bloodstream.

– The onset of action is 1 hour after injection, full activity is reached with in 4-5 hours. This activity is maintained at a constant level for 24 hours.

– In contrast to insulin zinc suspension (Lente) and isophane insulin (NPH), insulin glargine produces no significant peak in the bloodstream.

• Adverse effects of Insulin Glargine:– Similar to those of NPH insulin– Hypoglycaemia– Reactions at the injection site– Rashes– Pruritus and – Allergic reactions – The incidence of hypoglycaemic events are similar

to those of NPH insulin. – Insulin glargine has been claimed that it causes

less nocturnal hypoglycemia than the once a day dose of NPH insulin.

Long-acting insulin

• Protamine zinc insulin – Produced by adding protamine zinc to insulin. – It’s action is prolonged, starting after 6 hours and lasting

24-30 hours. – It is bovine insulin and may give rise to skin rashes and

painful lumps at the site of injection.– If soluble and PZI insulin are mixed in the syringe before

injection, some of the soluble insulin becomes PZI insulin.

– To minimize this, the soluble insulin should be drawn up first and the mixture of insulins injected immediately.

• Human Ultratard– Alternatively, the crystalline form of human insulin zinc

suspension (Human Ultratard) also has a prolonged action and is not immunogenic.

• Insulin detemir– A recombinant form of long-acting insulin, marketed as

Levemir. – This is identical to insulin in amino acid sequence and

composition, but has been made more fat-soluble through addition of a fatty-acid moiety to the last amino acid on the end of the B chain.

– This makes the insulin more slowly absorbed from the fat stores after subcutaneous injection, thereby making it more long-lasting.

– Also fatty-acid addition causes it to be bound to circulating albumin, which holds it in the bloodstream longer.

Injection of Insulin

• Patients should be taught how to inject themselves – if possible.

• Best sites for injection are the front of the thighs, the abdomen and the outer sides of the arms and on the buttocks.

• A different site should be used each time, but it must be remembered that the rate of absorption of insulin into the circulation varies with different parts of the body.

• Therefore it is better to use the same area but not the same site at the same time of the day.

• For example you give the evening dose on the buttocks and the morning dose on the abdomen.

Oral hypoglycemic agents

• The sulphonylureas• Metformin• Thiazolidinediones• Prandial glucose regulators• Acarbose

Sulphonylureas

• Chlorpropamide• Glibenclamide• Gliclazide• Glimepiride• Glipizide• Gliquidone • Tolbutimide

Mechanism of Action

• This group of drugs are related to the sulphonamides

• They lower blood glucose levels by increasing insulin production by the pancreas. They may also increase the sensitivity of the tissues to insulin.

Clinical Use

• All given orally and differ largely in their duration of action.

• They are used in patients with NIDDM who are usually middle-aged or elderly and obese.

• They supplement but do not replace, treatment and diet.

• Not used in young people with diabetes.

• Glyclazide, glipizide, glimeride and glibenclamide are now most commonly prescribed.

• Gliclazide is the one most used. • Its effects last up to 24 hours and it rarely

causes hypoglycaemic episodes.• It can also be taken once or twice a day. • Takes about 5 hours to achieve peak response. • This means that it can be taken before

breakfast and gives good cover before lunch and supper.

• Tolbutamide and Chlorpropamide are not used now as much as before.

• Tolbutamide is very safe if used correctly. – Duration of action is about 6 hours and for this reason it

is particularly recommended in elderly patients, as the risk of hypoglycaemia is reduced and it is given orally two or three times daily.

• Chlorpropamide – Similar to Tolbutamide– Action lasts a full 24 hours, so once daily dose is

appropriate. – Due to adverse effects it should only be used in patients

who have been successfully treated with it for some time.

Adverse effects

• Gastrointestinal upsets • Blood dyscrasias (abnormalities)• Fluid retention• Hypoglycaemia• Skin rashes

Drug interaction

• NSAIDS like aspirin enhance the effect • Thiazide diuretics reduce the effect of

sulphonylureas.

Metformin

• Belongs to a group called biguanides

Mechanism of Action

• Reduces glucose absorption from the gastrointestinal tract

• Stimulate uptake of glucose into muscle • Inhibit gluconeogenesis (biosynthesis of

glucose from non-carbohydrate sources, e.g. amino acids).

• Reduces glucose release from the liver.

Other effects

• Metformin inhibits plasma low-density lipoproteins (LDL). It may therefore, reduce the danger of atheroma in some patients.

• Metformin does not reduce the production of ketone bodies

• Metformin does not cause hypoglycaemia• Metformin does not cause weight gain, possibly

because it does not stimulate appetite.

Clinical use

• Its main use is combined with one of the sulphonyureas when the patient is not responding satisfactorily toe diet or to these drugs alone. Metformin is also occasionally used combined with insulin in patients with IDDM whose disease is providing difficult control.

Thiazolidinediones

• Pioglitazone• Rosiglitazone• They belong to a group of chemicals called

glitazones. The first such drug to be marketed in the UK was troglitazone which was withdrawn due to liver toxicity.

Machanism of Action

• They seem to reduce tissue resistance to insulin.

Clinical Use

• They have been very satisfactory in controlling NIDDM when combined with other agents.

• They can be combined with either Metformin or Sulphonylureas.

• Onset of action is slow, and patients may need encouragement to persist with treatment.

• About 25% of patients do not respond, and these tend to be more obese patients with longstanding insulin resistance and lower pancreatic reserves.

Adverse reactions

• Liver toxicity (although not many reports)• Weight gain• Increase in plasma LDL

Contraindications

• Pregnancy • Breastfeeding• Liver disease• History of Heart Failure• Do not give with insulin

Drug Interactions

• Calcium channel blockers• Erythromycin• Ciclosporin• Statins• Glucocorticoids (Prednisone)

Prandial Glucose regulators

• Nateglinide and repaglinide – Act post prandial, they deal with the rise in

circulating glucose that occurs immediately after a meal.

– They stimulate insulin release from the pancreas in the same way oral sulphonylureas do, but in contrast to the latter it does not promote insulin release in the absence of glucose.

– Nateglinide works by restoring early-phase insulin release.

– Both drugs are quickly absorbed from the GIT and both are very short-acting.

– Nateglinide synergizes with metformin, i.e. the drug increases the effects of a given dose of metformin.

– Both drugs are taken before a meal, and both are omitted if the meal is missed.

Adverse effects

• Anorexia• Nausea • Lactic acidosis• Drowsiness• Abdominal pain• Vomiting • Shock

Acarbose

• Mechanism of action: Acarbose is an inhibitor of the enzyme intestinal α-glucosidase. This enzyme is part of the gastrointestinal mechanism for converting carbohydrate to glucose.

• Clinical use: Taken orally before meals, this agent inhibits the digestion of complex carbohydrates such as sucrose and starches, thus preventing their absorption, but it does not interfere with glucose absorption. The post-prandial rise in the blood sugar is reduced. However the unabsorbed carbohydrates may cause flatulence and diarrhoea.

Glucagon

• Glucagon is released in response to high plasma levels of amino acids, especially arginine, e.g. After high-protein meal.

• It is also released in response to circulating adrenaline and increased sympathetic or parasympathetic activity.

• Release is inhibited by another hormone, somatostatin which is released from other cells in the pancreatic islets, called D cells.

• In contrast to insulin, however, plasma concentrations of glucagon do not fluctuate but remain fairly steady throughout the day.

Actions of Glucagon

• Stimulates glycogen breakdown to glucose in the liver• Stimulates gluconeogenesis• Inhibits glycogen synthesis• Inhibits glucose oxidation • Causes lipolysis in fat• Increases breakdown of muscle• Increases release of Insulin• Overall result is to increase blood glucose. Glucagon’s

actions oppose those of insulin. It also limits its own actions by stimulating insulin release.

Clinical Use

• Glucagon is used to raise blood sugar in patients who are hypoglycaemic, e.g. after and overdose of insulin. It can be administered intramuscularly, subcutaneously or intravenously.