Diabetes drugs

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DIABETES MELLITUS

2. o Diabetes is a chronic metabolic disorder
characterised by a high glucose
concentration in blood (hyperglycaemia).
o Fasting plasma glucose> 7.0 mmol/ℓ or a
plasma glucose> 11.1mmol/ℓ 2hrs after a
meal.
o Diabetes mellitus is caused by insulin
deficiency often combined with insulin
resistance.

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o When the renal threshold for glucose
reabsorption is exceeded, glucose spills
over into urine (glycosuria).
o Glycosuria causes osmotic diuresis
(polyuria).
o Polyuria results in dehydration, thirst and
increased drinking (polydipsia).
o Insulin deficiency causes wasting through
increased breakdown and reduced
synthesis of proteins.

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o Diabetes ketoacidosis:
o This is an acute emergency.
o Absence of insulin results in
accelerated fat breakdown to acetyl-
CoA.
o In the absence of aerobic
carbohydrate metabolism acetyl-CoA
is converted to acetoacetate and β-
hydroxybutyrate (which cause
acidosis) and acetone (a ketone).

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o There are two main types of diabetes
mellitus:- (i) Type 1 diabetes
(previously known as insulin
dependent diabetes mellitus { IDDM}
or juvenile onset diabetes). And (ii)
Type 2 diabetes (previously known as
non-insulin dependent diabetes
mellitus {NIDDM} or maturity-onset
diabetes mellitus ).

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o In Type 1 Diabetes,there is an
absolute defeciency of insulin due to
autoimmune destruction of β- cells.
o Without insulin treatment such
patients will ultemately die with
diabetic ketoacidosis.

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o Type 2 Diabetes is accompanied both
by insulin resistance and impaired
insulin secretion.
o Such patients are often obese and
usually present in adult life.
o Treatment involves dietary control
although oral hypoglycaemic drugs
become necessary.

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o Treatment of Diabetes Mellitus:
o Insulin Treatment
o Insulin for clinical use was once either
porcine or bovine.
o Now it is almost entirely human (made
by recombinant DNA technology).
o One of the main problems in using
insulin is to avoid wide fluctuations in
plasma concentration and thus blood
glucose.

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o Various formulations are available varying
in the timing of their peak effect and
duration of action.
o Soluble insulin produces a rapid and short
lived effect.
o Longer acting preparations are made by
precipitating insulin with protamine or zinc
thus forming finely divided amorphous
solid or relatively insoluble crystals
which are injected as a suspension from
which insulin is slowly absorbed.

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o Insulin Formulations
o Duration of Exa- Peak Duration
o Action mples effect of action
o Short soluble ins. 2-4hrs 6-12hrs
o Inter- i. isophane
o Mediate Insulin 5-12hrs 12-24hrs
o ii.Insulin zinc
o susp.(Amorph.) 3-6 12-16hrs
o Long Protamine zinc 5-14 24-30hrs
o Mixed i.short+interm
o (biphasic) 2-10 18-20hrs
o ii.Interm.+long
o (insulin zinc susp.) 3-8 16-24hrs

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o Insulin lysipro:
o An insulin analogue in which lysine
and proline residues have been
switched.
o It acts more rapidly but for a shorter
time than natural insulin.
o It enables patients to inject
themselves immediately before the
start of a meal

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o Insulin glargine:
o Provides a constant basal insulin supply
which mimic physiological post absorptive
basal insulin secretion.
o Insulin glargine, a clear solution,forms a
microprecipitate at the physiological pH of
sc tissue.
o The absorption from the sc site of injection
is prolonged.
o The risk of night time hypoglycaemia is
reduced.

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o Adverse effects:
o Hypoglycaemia if severe can cause brain damage.
o Treatment involves taking a sweet drink or snack.
o If the patient is unconscious iv glucose or im gucagon.
o Rebound hypoglycaemia (Somogyi effect) can follow
insulin hypoglycaeima which elicits ‘counter-regulatory’
hormones (Glucagon,Adrenaline,Glucocorticoids and
Growth hormone).
o These increase blood glucose.
o It is essential to appreciate this possibility to avoid the
mistake of increasing (rather than reducing) the evening
dose of insulin in this situation.
o Down effect is due to larger insulin dose in evening

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• Allergy to human insulin is unusual.
• There may be local or severe reactions.
• Effects of Hormone on Blood Glucose.
• Main regulatory hormone (Insulin): this
causes(i) an increase in glucose uptake
and an increase in glycogen synthesis (ii)
a decrease in glycogenolysis and a
decrease in gluconeogenesis.

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o Counter-regulatory hormones
(i)Glucagon:causes an increase in
glycogenolysis and an increase in
gluconeogenesis.
o (ii)Adrenaline:causes an increase in
glycogenolysis and a decrease in glucose
uptake.
o (iii)Glucocorticoids: cause an increase in
gluconeogenesis and a decrease in
glucose uptake.
o (iv)Growth hormone: causes a decrease
in glucose uptake.

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o Symptoms of hypoglycaemia: Adrenergic
stimulation:-
o Sweating,tachycardia, systolic
hypertension and hunger.
o Symptoms of neuroglycopenia are:- visual
disturbance,drowsiness,seizures and
coma.

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o Clinical Uses of Insulin:
o Patients with type 1 diabetes require long
term maintenance treatment with insulin.
o An intermediate acting preparation (eg
isophane insulin,to provide low back
ground level) is often combined with a
short acting preparation(eg soluble insulin)
taken before meals.

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o Soluble insulin is used iv in emergency
treatment of hyperglycaemic diabetic
emergencies (eg diabetic ketoacidosis).
o Many patients with type 2 diabetes
ultimately require insulin treatment.
o Short term insulin treatment of patients
with type 2 diabetes or impaired glucose
tolerance during intercurrent events(eg
operation or myocardial infarction).

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o Insulin may also be used during
pregnancy for gestational diabetes not
controlled by diet alone.
o In emergency treatment of hyperkalaemia
insulin is given with glucose to lower
extracellular K+ via redistribution into cells.

21. • Exenatide:
• This is a synthetic form of exendin-4,is
also an incretin mimetic.
• Given as a twice daily s.c. injection up to
an hour before meals (but not afterwards).
• May be considered as an alternative to
insulin therapy in obese patients who have
failed to achieve adequate glycaemic
control on maximum doses of established
oral treatment regimens.

22. • Exenatide has comparable efficacy to
insulin.
• Can cause significant weight loss (rather
than gain).
• Has some advantage due to the fixed
dose regimen.
• Adverse effects:
• Can cause significant hypoglycaemia.
• Git side effects particularly nausea.
• Interacts with warfarin (monitor INR
carefully)

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o Oral Hypoglycaemic Agents:
o 1.Biguanides eg Metformin.
o Actions:
o They lower blood glucose by (a) increasing
glucose uptake and utilisation in skeletal muscle
(thereby reducing insulin resistance) and (b)
reducing hepatic glucose production
(gluconeogenesis).
o These drugs reduce low density lipoprotein(LDL)
and very low density lipoprotein (VLDL).
o Pharmacokinetics:
o Half-life for Metformin is 3hrs and is excreted
unchanged in the urine.

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o Adverse effects:
o Dose related anorexia, diarrhoea , nausea
o Lactic acidosis (rare but potentially fatal)
may occur if the drug is given to patients
with renal or hepatic disease,hypoxic
pulmonary disease,heart failure or shock.
o It is contraindicated in pregnancy.
o Long term use may interfere with
absorption of vitamin B12.

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o Clinical Use:
o It does not stimulate appetite and
consequently useful in majority of type 2
patients who are obese and fail to control
with diet alone.
o It does not cause hypoglycaemia.
o Can be combined with
sulphonylureas,glitazones or insulin.

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o 2. Sulphonylureas:
o First generation: Tolbutamide and
Chlopropamide.
o Chlorpropamide has a long duration of action
and a substantial fraction is excreted in urine.
o Severe hypoglycaemia may occur in elderly
patients in whom renal function declines with
age.
o It causes flushing after alcohol because of
disulfiram-like effect.
o It has an ADH like action on the distal nephron
producing hyponatraemia and water intoxication.

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o Second generation suphonylureas:
o Glibenclamide,glipizide
o These are more potent on a mg basis,but the
hypoglycaemia they produce and failure of
treatment to control blood sugar are just as
common as with tolbutamide.
o Pharmacokinetics
o Have characteristics of weak acids.
o Most cross the placenta and will cause
hypoglycaemia at birth (glibenclamide is an
exception in this regard) and hence
sulphonylureas are contraindicated in
pregnancy.

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o Mechanism of action:
o They stimulate β-cells to secrete
insulin.
o The drugs produce the K+
permeability of β-cell by blocking KATP
channels causing depolarisation,Ca2+
entry and insulin secretion.

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o Adverse effects:
o Hypoglycaemia (chlorpropamide &
glibenclamide).Several metabolites of
glibenclamide are active and are excreted
in urine.
o Weight gain due to stimulation of appetite
o Git upset
o Allergic skin reactions
o Bone marrow damage
o Blockade of KATP in the heart and vascular
tissue could have adverse effects.

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o Drug interactions :
o Drugs which augment the
hypoglycaemic effect of sulphonylureas
are:-
NSAIDs,Coumarins,Sufinpyrazone,alcohol
,MAOIs,Sulphonamides,trimethoprim,chlor
amphenicol and imidazole antifungal
drugs.
o Drugs which decrease the action of
sulphonylureas include high doses of
thiazide diuretics and corticosteoids.

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o Clinical uses:
o Sulphonylureas require functioning β cells
and are therefore useful in the early stage
of type 2 diabetes.
o They may be combined with metformin or
with thiazolidinediones.
o 3.Other drugs that stimulate insulin
secretion (Meglitinides):
o Repaglinide and Nateglinide:
o These drugs block KATP channels in the
pancreatic β cell membranes (like the
sulphonylureas).

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o They have lower potency than
sulphonylureas.
o Have rapid onset and offset kinetics.
o Rapid absorption,T½ 3hrs and hence
have a short duration of action.
o Have a low risk of hypoglycaemia.
o They are administered slowly before a
meal to reduce postprandial glucose in
type 2 diabetic patients.
o Unlike glibenclamide,these drugs are
selective for KATP on β cells (and not those
in the CVS).

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o 4.Thiazolidinediones(glitazones):Examples
include:-Rosiglitazone and Pioglitazone.
o Effects:
o Reduce hepatic glucose output
o Increase glucose uptake into muscle
o Enhance the effectiveness of endogenous insulin
and reducing the amount of exogenous insulin
needed.
o The reduction in blood glucose is often
accompanied by a reduction in circulating insulin
and free fatty acids.
o A gain in weight of 1-4kgs may be attributed to
fluid retention.

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o Mechanism of action:
o Thiazolidinediones bind to a nuclear
receptor called Peroxime proliferator-
activated receptor-gamma (PPAR‫)ץ‬ which
is complexed with retinoidX receptor (RXR)
o PPAR‫ץ‬ occurs in adipose tissue but also in
muscle and liver.
o It mediates differentiation of adipocytes.
o Increases lipogenesis and enhances
uptake of fatty acids and glucose.

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• Thiazolidinediones change PPAR‫ץ‬-RXR
complex so that it binds DNA and
promotes transcription of several genes
with products that are important in insulin
signalling.

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o Pharmacokinetics:
o Both are well absorbed,Protein
binding>99% Metabolised in the liver
T½<7hrs of parent drugs.
o Metabolites have much longer half-
lives.

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o Adverse effects:
o Weight gain,fluid retention,headache
fatigue and git disturbances.
o The drugs are contraindicated in
pregnancy or breast feeding.
o Clinical use:
o In type 2 diabetes when insulin
resistance may be important in
pathogenesis.

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o 5.Alpha-glucosidase inhibitors:
o Acarbose
o Acarbose inhibits α-glucosidase.
o It delays carbohydrate absorption
reducing postprandial glucose.
o Adverse effects:
o Flatulence,loose stools or diarrhoea
o Abdominal pain and bloating.

39. • 6. Sitagliptin and Vildagliptin:
• These inhibit dipeptidylpeptidase-4,
increase insulin secretion and lower
glucagon secretion (enhancing the levels
of active incretin hormones).
• Adverse effects:
• Anaphylaxis, angioedema and Stevens-
Johnson syndrome.