4. Drugs Used to Treat Diabetes Mellitus

Diabetes is a multisystem disorder that gives the anaesthetist the challenge of managing potential co-morbidity while maintaining effective perioperative glucose homeostasis

Type 1, or insulin-dependent diabetes mellitus, is caused by an absolute deficiency of insulin (10% of patients). Type 2, or non-insulin-dependent diabetes, is caused by a relative deficiency (90% of patients). This comprises either insulin resistance (as in obesity), reduced insulin secretion from the β-cells in the pancreatic islets of Langerhans, or both.

major anabolic hormone, which controls not solely carbohydrate metabolism but also intermediary metabolism. Carbohydrate: it stimulates glycogen synthesis and inhibits glycogenolysis in the liver while also increasing glucose uptake and utilization in muscle. Fat: it increases lipid synthesis Protein: it enhances protein synthesis (hence its abuse amongst bodybuilders) by enhancing amino acid uptake by muscle. It decreases protein catabolism

: the hormone binds to a specific insulin receptor on the cell membrane. This is a large transmembrane glycoprotein complex, comprising two α-extracellular-binding sites and two β-intracellular and transmembrane proteins

: there are numerous formulations whose purpose is to help diabetics stabilize blood glucose levels. • Soluble insulin (such as human Actrapid) works rapidly, but its action is evanescent • Newer rapidly acting insulin analogues such as insulin glusiline, insulin lispro and insulin aspart work even quicker than soluble insulin and have a shorter duration of action This allows insulin-dependent diabetics considerable flexibility with regard to their oral intake

Longer-acting preparations are made by precipitating insulin with substances such as zinc and protamine to form an insoluble depot compound from which insulin is more slowly absorbed Insulin glargine is a modified insulin analogue which, because of slow absorption, provides a basal insulin supply to mirror the normal physiological state Insulin detemir and insulin degludec are other long-acting recombinant human insulin analogues.

Biguanides Sulphonylureas α-Glucosidase Inhibitors Thiazolidinediones Meglitinides

The only biguanide in routine clinical use is metformin. biguanides increase glucose uptake and utilization in skeletal muscle while decreasing hepatic gluconeogenesis Reduce LDL Rarely, they may cause a severe lactic acidosis, particularly in patients with impaired renal function. Their precise mode of action is not fully known, but they act only in the presence of residual endogenous insulin Pharmacokinetics: metformin has an elimination t½ of 3 hours. It is excreted renally and will accumulate if renal function is compromised (common in diabetics).

glibenclamide and glipazide Sulphonylureas promote insulin secretion from β-cells after binding to high-affinity receptors on the cell membrane They block an ATP-sensitive potassium channel, thereby allowing membrane depolarization, calcium influx and insulin release glibenclamide (t½ 18–24 hours and duration 10 hours) or glipazide (t½ 16–24 h and duration 7 hours). Some (e.g. glibenclamide) have active metabolites, and these, like the parent compound, are excreted by the kidney. Renal impairment mandates caution with their use.

Acarbose Mechanisms: acarbose inhibits intestinal α-glucosidase, which delays the breakdown and absorption of carbohydrates (sugars and starch). Its inhibitory action is maximal against sucrase. most of the drug remains within the gut, with only about 1–2% being absorbed systemically. Duration of action varies greatly according to intestinal transit times.

pioglitazone reduce peripheral insulin resistance, enhance glucose uptake by muscle and decrease hepatic gluconeogenesis agonists at the nuclear PPAR γ-receptor which mediates lipogenesis and uptake both of glucose and of free fatty acids

analogous in action to the sulphonylureas nateglinide (licensed only for use in combination with metformin) repaglinide, which can be prescribed as monotherapy. Mechanisms: these also promote insulin secretion from β-cells by blocking the ATP-sensitive potassium channel in the cell membrane. The drugs are less potent than the sulphonylureas the time to peak effect is short, at about 55 minutes, and they also have a rapid t½ of around 3 hours. Inadvertent hypoglycaemia is therefore less likely with their use.

GLP-1 (glucagon-like peptide) is a gut-derived peptide, an incretin, which promotes pancreatic insulin secretion and suppresses the release of glucagon. The compound is metabolized rapidly by the enzyme DPP-4 (dipeptidyl peptidase 4).

These are synthetic analogues which are resistant to degradation by DPP-4 and include exenatide, liraglutide and lixisenatide. These agents are available in different formulations (exenatide, for example, is available as an ultralong- acting preparation that is given weekly) but otherwise are given in combination with other hypoglycaemic agents.

: these inhibit the breakdown of endogenous GLP-1. Drugs of this class that are available include saxagliptin, sitagliptin, linagliptin, alogliptin and vildagliptin.

Mechanisms: these drugs inhibit the Na+/Glucose co-transporter 2 in the proximal convoluted tubule in the kidney. This has the effect of reducing glucose reabsorption and increasing urinary glucose excretion. Drugs of this class include canagliflozin and dapagliflozin and can be used either as monotherapy or as part of a combination regimen

microvascular complications, whereas in type 2 it is macrovascular complications that predominate. Type 1 complications therefore include retinopathy, diabetic nephropathy, microangiopathy and peripheral and autonomic neuropathy 50% in type 1 diabetics as opposed to an incidence of 20% in patients with type 2 disease diabetic gastroparesis and postural hypotension.

Morbidity associated with type 2 diabetes include ischaemic heart disease, hypertension, peripheral vascular disease and cerebrovascular disease. Clearly there is much overlap between the conditions. Affected patients may also lose the normal sympathetic response to hypoglycaemia, of which they may remain unaware. Stiff joint syndrome may impair the mobility of the cervical spine and can make tracheal intubation more difficult. Some 20% of diabetics harbour occult infection which may evolve into overt sepsis under the stress of surgery.

estore the patient’s normal regimen as soon as possible while maintaining adequate glycaemic control in the meantime Major surgery will require postoperative insulin infusion GKI regimen (glucose 10% x 500 ml + KCl 10 mmol + Actrapid insulin 15 units) infused at 100 ml h−1, or as a separate infusion (typically using the patient’s total daily insulin dose/24 as the starting rate).

Variable rate infusions allow much better control and are associated neither with the potential fluid overload or the hyponatraemia that can follow the use of GKI infusions Giving insulin separately, however, means that there is a greater potential danger of hypoglycaemia. It is important to remember that insulin should always continue to be given no matter how low the measured blood sugar, because without some available insulin then intracellular glucose metabolism will ceas