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Endocrine passmedicine (1)

Terms in this set (100)

General
Weight reduction
the gold-standard treatment for PCOS, and improves ovulation, androgen levels, hirsuitism and metabolic features associated with insulin resistance.
(loss in weight of only 5% reduces hirsuitism by up to 40%.)

Hirsutism and acne
For associated hirsutism Dianette® (cyproterone acetate) combined oral contraceptive pill (COC) is the most effective, along with cosmetic treatments like waxing, shaving, plucking or electrolysis.
Possible options include a third generation COC which has fewer androgenic effects or co-cyprindiol which has an anti-androgen action. Both of these types of COC may carry an increased risk of venous thromboembolism
Co-cyprindrol because it contains cyproterone, an anti-androgen, may be more effective than the COCP in controlling acne and hirsuitism and acne in PCOS.
**if doesn't respond to COC then topical eflornithine may be tried
spironolactone, flutamide and finasteride may be used under specialist supervision
A Cochrane meta-analysis has suggested that metformin is not effective in controlling hirsuitism and acne versus other options such as the COCP or co-cyprindrol

Infertility
weight loss the most important initial step.
anti-oestrogen therapies such as ***clomifene the most effective treatment (work by occupying hypothalamic oestrogen receptors without activating them.) This interferes with the binding of oestradiol and thus prevents negative feedback inhibition of FSH secretion
***metformin is also used as a second line after clomifene, either combined with clomifene or alone,
gonadotrophins: usually reserved for patients who are resistant to clomifene

Other notes
Surgical intervention with wedge ovarian resection can reduce androgen secretion and symptoms.
treatment should be discontinued if weight loss is less than 5% after the first 12 weeks.
Combination drug therapy is contraindicated drugs should never be used as the sole element of treatment (should only be prescribed as part of an overall plan for managing obesity).

Orlistat
Action: pancreatic lipase inhibitor, blocks the breakdown and hence the absorption of dietary fat. used in the management of obesity.
Adverse effects
faecal urgency/incontinence and flatulence.

criteria for the use of orlistat.
BMI of 28 kg/m^2 or more with associated risk factors ( (eg: diabetes mellitus, coronary heart disease, hypertension and obstructive sleep apnoea))
BMI of 30 kg/m^2 or more in whom at least three months of managed care involving supervised diet, exercise and behaviour modification fails.
continued weight loss e.g. 5% at 3 months
orlistat is normally used for < 1 year

Sibutramine
withdrawn January 2010 by the European Medicines Agency due to an increased risk of cardiovascular events
centrally acting appetite suppressant (inhibits uptake of serotonin and noradrenaline at hypothalamic sites that regular food intake)
adverse effects include ***hypertension (monitor blood pressure and pulse during treatment), constipation, headache, dry mouth, insomnia and anorexia
contraindicated in psychiatric illness, hypertension, IHD, stroke, arrhythmias


Rimonabant
was withdrawn in October 2008 after the European Medicines Agency warned of serious psychiatric problems including suicide
a specific CB1 cannabinoid receptor antagonist,
The best way to reduce the incidence of type 2 diabetes in individuals with IGT is Intensive lifestyle change

Tolerates metformin:
metformin is still first-line and should be offered if the HbA1c rises to 48 mmol/mol (6.5%)* on lifestyle interventions
if the HbA1c has risen to 58 mmol/mol (7.5%) then a second drug should be added from the following list:
sulfonylurea
gliptin
pioglitazone
SGLT-2 inhibitor

if despite this the HbA1c rises to, or remains above 58 mmol/mol (7.5%) then triple therapy with one of the following combinations should be offered:
metformin + gliptin + sulfonylurea
metformin + pioglitazone + sulfonylurea
metformin + sulfonylurea + SGLT-2 inhibitor
metformin + pioglitazone + SGLT-2 inhibitor
OR insulin therapy should be considered

if triple therapy is not effective, not tolerated or contraindicated then we consider combination therapy with metformin, a sulfonylurea and a glucagonlike peptide1 (GLP1)

Cannot tolerate metformin or contraindicated
if the HbA1c rises to 48 mmol/mol (6.5%)* on lifestyle interventions, consider one of the following:
sulfonylurea
gliptin
pioglitazone
if the HbA1c has risen to 58 mmol/mol (7.5%) then a one of the following combinations should be used:
gliptin + pioglitazone
gliptin + sulfonylurea
pioglitazone + sulfonylurea
if despite this the HbA1c rises to, or remains above 58 mmol/mol (7.5%) then consider insulin therapy

***meglitinides (insulin secretagogues) should be considered for patients with an erratic lifestyle
**However, you can consider using sitagliptin or a thiazolidinedione instead of insulin if there would be employment (eg: truck driver), social, recreational or personal issues.
Exenatide should be used only when insulin would otherwise be started, obesity is a problem (BMI > 35 kg/m^2) and the need for high dose insulin is likely. Continue only if beneficial response occurs and is maintained (> 1.0 percentage point HbA1c reduction and weight loss > 3% at 6 months)
In patients with diabetes starting thyroxine, doses of antidiabetic drugs including insulin may need to be increased.
Block-and-replace regimes are usually of a shorter duration than carbimazole titration
therapy

*TSH is used to assess the response of patient to carbimazole for treating Grave's

Treatment options include titration of anti-thyroid drugs (ATDs, for example carbimazole), block-and-replace regimes, radioiodine treatment and surgery.

Propranolol is often given initially to block adrenergic effects
Propranolol, a nonselective beta blocker, may help to lower the heart rate, control tremor, reduce excessive sweating, and alleviate anxiety. Propranolol is also known to reduce the conversion of T4 to T3.
In patients with underlying asthma, beta-1 selective antagonists, such as atenolol or metoprolol, would be safer options.
In patients with contraindications to beta blockers (eg, moderate to severe asthma), calcium channel antagonists (eg, diltiazem) may be used to help control the heart rate.

ATD titration
carbimazole is started at 40mg and reduced gradually to maintain euthyroidism
typically continued for 12-18 months
Long-term remission following antithyroid drugs is of the order of 15%, with the vast majority relapsing. Thus, frequently, radio-iodine is advocated as a primary treatment -particularly for multi-nodular or toxic solitary nodules.

Radioiodine iodine (RAI) treatment
contraindications include pregnancy (should be avoided for 4-6 months following treatment) and age < 16 years.
Thyroid eye disease is a relative contraindication, as it may worsen the condition
Hypothyroidism is the most common adverse effect. the proportion of patients who become hypothyroid depends on the dose given, but as a rule the majority of patient will require thyroxine supplementation after 5 years
**approximately 80% will have long-term hypothyroidism following radio-iodine.

Goitre shrinkage may occur in up to 30% following RAI.
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Decreased levels of GLP-1 are seen in type 2 diabetes mellitus

Glucagon-like peptide-1 (GLP-1) mimetics (e.g. exenatide)
- causes vomiting

GLP analogs such as exenatide, liraglutide, slow gastric emptying, promote weight loss and lower glucose

Metabolic effect of exenatide
increase insulin secretion
inhibit glucagon secretion.
inhibits glucose production in the liver,
slows gastric emptying
Suppresses appetite

When to choose exenatide as an alternative to insulin or sulphonylurea as first choice add-in options to metformin?
morbid obesity
or risk of hypoglycaemia, (eg : HGV drivers)

Both sitagliptin and exenatide are not recommended in patients sever renal impairment, and metformin is contraindicated.

Liraglutide is the other GLP-1 mimetic currently available.
One the main advantages of liraglutide over exenatide is that it only needs to be given once a day.
It is a particularly useful medication as it can be used in renal impairment with an estimated glomerular filtration rate [eGFR] as low as 30 mL/min/1.73 m2.
weight loss of approximately 6% at 6 months can be achieved with liraglutide 1.8 mg.
Liraglutide is associated with an approximately 7 beats per minute increase in heart rate versus control in diabetes
Dapagliflozin, tolbutamide, gliclazide and metformin are all contraindicated in renal impairment.

Both exenatide and liraglutide may be combined with metformin and a sulfonylurea.
Standard release exenatide is also licensed to be used with basal insulin alone or with metformin.

Combination of GLP-1 and DPP- 4 inhibitors trials of DPP- 4 inhibitor and GLP-1 together suggest no added efficacy versus GLP-1 alone.
Adding a GLP-1 analogue has the advantage of improving glycaemic control, with modest weight loss, without increasing the risk of hypoglycaemia compared with uptitration of insulin.

Current NICE guidance suggests the use of GLP-1 mimetics only if BMI is above 35 and there are specific medical or psychological problems associated with high body weight.
Water deprivation test
(A dramatic improvement in the ability of the kidneys to concentrate urine following the administration of DDAVP points towards a diagnosis of cranial diabetes insipidus)

Method
prevent patient drinking water
patients are deprived of fluids for a period of 8 h or until 5% of body weight is lost.
ask patient to empty bladder
Patients should be weighed hourly.
hourly urine and plasma osmolalities
Plasma osmolality is measured 4-hourly, with urine volume and osmolality measurements occurring every 2 h.
The patient is then given 2 μg intramuscular (i/m) desmopressin with urine volume and urine
and serum osmolality measured over the next 4 h.
If serum osmolality rises above 305 , then the patient is said to have diabetes insipidus and the test is stopped.
Urine osmolality less than 300 after fluid deprivation, rising to above 800 mOsmol/kg after desmopressin indicates cranial diabetes insipidus (DI).
Urine osmolality less than 300, remaining at less than 300 mOsmol/kg after desmopressin indicates nephrogenic DI.
Where urine osmolality reaches levels above 800 without desmopressin, then the diagnosis is primary polydipsia.
Where urine osmolality is intermediate (300-800), and fails to rise above 800 after demopressin, the diagnosis may be partial DI or polydipsia.

Psychogenic polydipsia
Patients with this disorder ingest and excrete up to 6L of fluid/day and are often emotionally disturbed.
they do not have nocturia, nor does increased thirst wake them at night.