31/01/2013

What you need to know…

• Definition & classification
Drugs for diabetes mellitus and • Complications
thyroid disease • Aims of treatment
• Therapeutic strategies
• What regimen?
• Diabetic emergencies
Raymond MacAllister and Derek Adigbli
Centre for Clinical Pharmacology, UCL
m.okorie@ucl.ac.uk

Actions of Insulin
Normal glucose disposal

Glucose

•Glycogen 
•Gluconeogenesis 
Insulin Insulin Glucose
+ •Lipolysis 
Beta Glucose
cell
+
Liver
Fat Cells
Muscle
Liver
Skeletal Muscle
Cell growth 

Classification of diabetes
Definition of diabetes

1985 1999 Primary diabetes Secondary diabetes

Fasting 7.8 7.0 Type I (early onset) Insulin deficiency:

Type II (late onset)
Random 11.1 11.1 Gestational Pancreatitic insufficinecy
Frequency
Genetic (e.g. Pancreatectomy
of Haemochromatosis)
individuals
World Health Counterreg hormone XS:
Organisation
Cushing’s
Acromegaly
Phaeo

Glucose Other:
Liver cirrhosis
Drugs

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Primary diabetes
Complications of diabetes
Type I Type II
Microvascular Macrovascular
Age of onset children (10-12) middle age

Prevalence 1/400 2-16%

Retinopathy Atherosclerosis
Onset rapid slow
Coronary artery disease
Symptoms severe mild/absent Nephropathy
Renal artery disease
Ketoacidosis prone resistant

Serum insulin low/absent usu low Neuropathy Peripheral vascular disease

occ. Raised

Treatment INSULIN diet

oral hypoglycaemics
insulin
Diabetic foot
Complications Macro and microvasc Macro and microvasc Erectile dysfunction

Aims of management of diabetes Treatment of diabetes

•Treat symptoms of hyperglycaemia • Patient education

• Nutritional control
•Prevent long-term complications • Pharmacological treatment
•Limit the adverse effects of treatment

• Monitoring of glycaemic control

• Screening for complications

Therapeutic strategies to treat diabetes

• Limit glucose
absorption
Type I diabetes: management

↑Glucose •Stimulate insulin

secretion Diet correct balance between energy input and output

•Replace insulin
- Exercise regular aerobic exercise
•Promote insulin-
Insulin Insulin
mediated
+ glucose uptake Insulin
Beta
cell
+

Muscle
Liver

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Insulin Therapy
Aim to mimic physiological background and post prandial peaks of Insulin preparations
Insulin without hypoglycaemia
Vary by type
What regimen? Human insulin
Porcine insulin
Once or Twice daily, soluble and intermediate or long acting Beef insulin
Multiple injections (x4)
Continuous infusion Vary by presence/absence of retardant

What dose do I start with? onset peak duration example

No fixed rule
~0.5 Units/kg/day Very rapid 15-30min 1h 5-6h Humalog
2/3 in morning and 1/3 in evening Soluble insulin 30 min 1-2h 6-8h Actrapid
Intermediate 2h 4-6h 8-12h Insulatard
2/3 as intermediate acting
Long acting 4h 6-24h >24h Ultratard
By what route?
Subcutaneous during normal therapy
IV for DKA, around the time of surgery

Twice daily regimen Once daily regimen

I I I

Short acting insulin Meals/snacks Intermediate/long acting insulin Meals/snacks

Intermediate acting insulin

Four times daily regimen Insulin treatment during intercurrent illness

Infections including GI upsets increase insulin
requirements. Insulin should never be stopped
even if the patient cannot tolerate a normal diet.
Stopping insulin runs the risk of precipitating DKA.

•Increase fluid intake

I I I I
•Eat a little frequently
•If vomiting and unable to eat sip sugary drinks
•Increase frequency of glucose monitoring
Short acting insulin Meals/snacks •Stick test urine for ketones
•Maintain usual insulin regime, increase soluble insulin
Intermediate acting insulin
if sugars are high

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Monitoring glycaemic control: type I diabetes Adverse effects of insulin therapy

Self-monitoring of blood glucose
No role for urine glucose testing in monitoring of type I DM Complication Management
Blood glucose monitoring with glucose stix at least
x2/daily pre insulin Hypoglycaemia scrutiny of regimen, diet
exercise, alcohol
Target pre-meal 4-7 mmol/L
post-meal <10mmol/L Lipoatrophy problem with porcine
insulin
HbA1C
Glycated Hb Lipohypertrophy vary injection site
Index of glycaemic control over preceding 2-3 months

HbA1C Weight gain trophic effect of insulin

difficult to manage
8

8
Mean blood glucose

Therapeutic strategies to treat diabetes Drugs used in the treatment of type II DM

• Limit glucose
absorption Drug class Example Mechanism of action Comment

Biguanides Metformin promotes muscle G uptake Obese type II

↑Glucose •Stimulate insulin decreases hepatic G production avoid in renal failure
secretion no effect on insulin secretion & heart failure

Sulphonylureas Tolbutamide close -cellSUR/K ATP channel Non-obese

•Replace insulin Gliclazide depolarises cell, Ca entry type II DM
- Glibenclamide ↑ INSULIN secretion use short acting drugs
•Promote insulin- Glimepiride Hypo
Insulin Insulin Wt gain
mediated
+ glucose uptake
Repaglinide rapid onset sulphonylurea can be taken premeal
Beta
cell
+ Thiazolenediones Pioglitazone activate PPAR
(Glitazones) sensitise peripheral tissues
to insulin

-glucosidase Acarbose slows breakdown of complex CH GI disturbance

Muscle inhibitor reduces postprandial G rise poorly tolerated
Liver
Other drugs

Other drugs used in the treatment of type II DM Management of type II diabetes

Diagnosis
GLP-1 mimetics – Exenatide

Diet
Glucose Weight reduction

Poor control Poor control

Obese Non-obese

Metformin Sulphonylurea

Metformin+sulphonylurea Metformin+sulphonylurea
Insulin
Glitazones
Exenatide/Gliptins
GLP-1 enhancers – Gliptins

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Diabetic ketoacidosis
BP and glucose control in the
management of diabetic complications Background Hyperglycaemic emergency in type I
diabetics. First presentation or precipitated
by infection.
Intervention Type I DM Type II DM
Complication Pathophysiology Insulin deficiency leads to ketogenesis, hyperglycaemia
Microvascular Macrovascular Microvascular Macrovascular osmotic diuresis and volume loss

Diagnosis Raised G
Metabolic acidosis
Ketonuria
BP control beneficial beneficial beneficial beneficial Identify precipitant-blood cultures, MSU, CXR etc.

Complications Hypovolaemic shock

Hyperkalaemia
Gastroparesis
Glycaemic control beneficial beneficial
Coma

Treatment Treat on ITU/HDU

IV access
FLUIDS – 0.9% NaCl (1L/30 min, 1L/1h, 1L/2h, 1L/4h etc)
IV soluble insulin by infusion pump (Fixed rate 0.1 units/kg)
K replacement titrated according to plasma K

Diabetic ketoacidosis
Hypoglycaemia in diabetics
Monitor Every hour Potential complication of therapy with insulin/sulphonylureas
capillary glucose
blood ketones G<3.5 adrenergic symptoms
G<2.5 neuroglycopaenic symptoms
Every 2h
VBGs for acidosis , K
Management:
Complication of Rx Cerebral oedema
prevent by limiting rate of fall of Posm • Mild episodes sugary drink
switching to 5% glucose when G 12mmol/L • More severe Glucogel to buccal mucosa
IV 25-50ml 50% dextrose (sclerosant to veins)
Criteria of success Normoglycaemia IM Glucagon (1mg) – mobilises hepatic glycogen
Absence of ketonuria stores
Clinical recovery
Review cause
Can then reinstate SC insulin regime

thyroid • Hyperthyroidism

• Blood tests
– TSH is low
– Thyroxine is high

What’s the underlying cause?

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PERIOXIDASE,
How do you treat it? converts iodide to
iodine

Inhibition of this by

CARBIMAZOLE
or
PROPYTHIOURACIL

Reduce synthesis
of hormone

Drugs for hyperthyroidism

Alternatives?

Carbimazole Propylthiouracil
• Delayed onset • Delayed onset • Radioactive iodine
• Rash • Reserved for those – Complete destruction of the gland by beta
• GI upset intolerant of carbimazole
radiation
• Agranulocytosis • Higher rate of
agranulocytosis – decays with half life of 8 days
• Rx 1-2 years, relapse is 50%
• Inhibition of peripheral de-
iodination

hypothyroid
Low levels of circulating T3 and T4
High levels of TSH

Identify a cause (atrophic, primary

myxoedema, Hashimotos, drugs eg
lithium, amiodarone)

Replace the hormone using:

LEVOTHYROXINE

Delayed onset of action

Monitor clinical status and TSH
Aim to achieve a normal TSH