4. Drugs Used to Treat Diabetes Mellitus Flashcards
Diabetes
Diabetes is a multisystem disorder that gives the anaesthetist the challenge of managing
potential co-morbidity while maintaining effective perioperative glucose homeostasis
Types
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.
Drugs Used to Treat Type 1 and Type 2 Diabetes Mellitus
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
Mechanisms Insulin
: 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
Insulin preparations
: 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
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.
Oral Hypoglycaemic Agents
Biguanides
Sulphonylureas
α-Glucosidase Inhibitors
Thiazolidinediones
Meglitinides
Biguanides
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).
Sulphonylureas
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.
α-Glucosidase Inhibitors
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.
Thiazolidinediones
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
Meglitinides
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 Agonists and DPP-4 Inhibitors
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).
GLP-1 analogues
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.
DPP-4 inhibitors
: these inhibit the breakdown of endogenous GLP-1. Drugs of this
class that are available include saxagliptin, sitagliptin, linagliptin, alogliptin and
vildagliptin.
