Endocrine and Reproductive systems

Question 1

Name some examples of bisphosphonates

Answer 1

Alendronic acid, disodium pamidronate, zoledronic acid

Question 2

What are bisphosphonates indicated for?

Answer 2

1. Alendronic acid is used as the first-line drug treatment option for patients at risk of osteoporotic fragility fractures
2. Pamidronate and zoledronic acid are used in the treatment of severe hypercalcaemia of malignancy after appropriate IV rehydration
3. For patients with myeloma and breast cancer with bone metastases, pamidronate and zoledronic acid reduce the risk of pathological fractures, cord compression and the need for radiotherapy or surgery
4. Bisphosphonates are used as first-line treatment of metabolically active Paget’s disease, with the aim of reducing bone turnover and pain

Question 3

How do bisphosphonates work?

Answer 3

They reduce bone turnover by inhibiting the action of osteoclasts, the cells responsible for bone resorption
As bone is resorbed, bisphosphonates accumulate in osteoclasts, where they inhibit activity and promote apoptosis
The net effect is reduction in bone loss and improvement in bone mass

Question 4

What are the important adverse effects of bisphosphonates?

Answer 4

Common side effects include oesophagitis (when taken orally) and hypophosphataemia
A rare but serious adverse effect is osteonecrosis of the jaw, which is more likely with high-dose IV therapy
Another rare AE is atypical femoral fracture

Question 5

What are the warnings for bisphosphonate prescription?

Answer 5

They are renally excreted and should be avoided in severe renal impairment. They are contraindicated in the context of hypocalcaemia.
Oral administration is contraindicated in patients with active upper GI disorders. Because of the risk of jaw osteonecrosis, care should be exercised in prescribing bisphosphonates for smokers and dental disease patients

Question 6

What are the important interactions with bisphosphonates?

Answer 6

They bind with calcium, therefore their absorption is reduced if taken with calcium (inc milk), as well as antacids and iron salts

Question 7

How are bisphosphonates prescribed?

Answer 7

For osteoporosis, alendrinic acid is prescribed orally, 70mg once weekly
For severe hypercalaemia and bone mets, pamidronate or zoledronic acid are prescribed as slow IV infusions, in single or divided doses. Calcium-lowering effects may not become apparent for 3-4 days and are maximal at 7-10 days, so re-prescription should not be considered before 1 week
For Paget’s disease, risedronate is given orally and pamidronate as an IV infusion

Question 8

How are bisphosphonates administered?

Answer 8

Alendronic acid tablets should be swallowed whole at least 30 mins before breakfast or other medications, and taken with plenty of water (it is poorly absorbed)
The patient should remain upright after taking to reduce oesophageal irritation

Question 9

How are bisphosphonate medications monitored?

Answer 9

In osteoporosis, check and replace calcium and vit D before treatment. Monitor efficacy using DEXA scans every 1-3 years to check whether bone density is stable or increasing

For hypercalcaemia, monitor efficacy by symptom enquiry and reduction in calcium levels

In the treatment of myeloma, bone metastases and Paget’s disease, enquire about symptoms e.g. bone pain and bone complications e.g. pathological fracture

Be alert for symptoms of oesophagitis, osteonecrosis of the jaw and atypical fractures, and monitor CA and phosphate

Question 10

Which of the bisphosphonates is the cheapest?

Answer 10

Alendronic acid (£1 a month)
Others are around £200 a month

Question 11

Can bisphosphonates be prescribed without a DEXA scan?

Answer 11

Yes, you can assume a diagnosis of OP in women aged >75 who have had a fragility fracture
Bisphosphonates reduce recurrent fracture by 50%

Question 12

Name some examples of systemic corticosteroids

Answer 12

Prednisolone, hydrocortisone, dexamethasone

Question 13

What are systemic corticosteroids indicated for?

Answer 13

1. To treat allergic or inflammatory disorders e.g. anaphylaxis, asthma
2. Suppression of autoimmune disease e.g. IBD, inflammatory arthritis
3. In the treatment of some cancers as part of chemotherapy or to reduce tumour-associated swelling
4. Hormone replacement in adrenal insufficiency or hypopituitarism

Question 14

How do systemic steroids work?

Answer 14

They exert mainly glucocorticoid effects, and are commonly prescribed to modify the immune response
They upregulate anti-inflammatory genes and downregulate pro-inflammatory genes e.g. cytokines, TNF-a). Direct actions on inflammatory cells include suppression of circulating monocytes and eosinophils.

Their metabolic effects include increased gluconeogenesis from increased circulating amino and fatty acids, released by calabolism (breakdown) of muscle and fat. These drugs also have mineralocorticoid effects, stimulating Na- and water retention K+ excretion in the renal tubule

Question 15

What are the important adverse effects of steroids?

Answer 15

• Infection risk from immunosuppression
• Metabolic effects include diabetes mellitus and osteoporosis
• Increased catabolism causes proximal muscle weakness, skin thinning with easy bruising and gastritis
• Mood and behavioural changes include insomnia, confusion, psychosis and suicidal ideas
• Hypertension, hypokalaemia and oedema can result from mineralocorticoid actions
• Steroid treatment suppresses ACTH secretion, which can cause adrenal atrophy in prolonged treatment. If treatment is stopped suddenly, an acute Addisonian crisis with CV collapse may occur.
• Symptoms of chronic glucocorticoid deficiency that occur during treatment withdrawal include fatigue, weight loss and arthralgia

Question 16

What are the warnings for prescribing systemic steroids?

Answer 16

They should be prescribed in caution in people with infection and in children

Question 17

What are the important interactions for steroid treatment?

Answer 17

They increase the risk of peptic ulceration and GI bleeding when used with NSAIDs and enhance hypokalaemia in patients taking B2-agonists, theophylline, loop or thiazide diuretics

Their efficacy may be reduced by cytochrome P450 inducers e.g. phenytoin, carbamazepine, rifampicin

Corticosteroids reduce the immune response to vaccines

Question 18

How are the potencies different for systemic steroids?

Answer 18

They have different potencies-
Dexamethasone is the most potent- with a dose of 750mcg being equivalent to prednisolone 5mg and hydrocortisone 20mg
Systemic corticosteroid treatment can be given orally or by IV or IM injection

Question 19

How are steroids prescribed in emergencies/ short-term treatment?

Answer 19

In emergencies (e.g. treatment of the vasogenic oedema that may surround brain tumours), dexamethasone is prescribed at a high dose e.g. 8mg BD orally or IV), then weaned slowly as symptoms improve

In acute asthma, prednisolone is usually prescribed at a dose of 40mg orally daily

When oral administration is appropriate (e.g. IBD flares, anaphylaxis), IV hydrocortisone may be used

Question 20

How are steroid prescribed in long-term treatment?

Answer 20

In inflammatory arthritis, use the lowest dose or oral prednisolone that control disease while limiting adverse effects. This may require co-prescription of a steroid-sparing agent (e.g. azathioprine methotrexate)

Consider bisphosphonates and PPIs to mitigate adverse effects

Question 21

When should systemic corticosteroids be administered?

Answer 21

Once-daily corticosteroid treatment should be taken in the morning, to mimic the natural circadian rhythm and reduce insomnia

Question 22

How should steroids be monitored?

Answer 22

Depends on the condition being treated e.g. peak flow in asthma, blood inflammatory markers for RA

Monitor for adverse effects in prolonged treatment by HBA1C and glucose, and a DEXA scan (to measure bone density)

Question 23

How should steroid treatment be changed in acute illness?

Answer 23

Dose should be doubled, as atrophic adrenal glands may be unable to increase cortisol secretion in response to stress

Question 24

Name some examples of Dipeptidylpeptidase-4 (DPP-4) inhibitors

Answer 24

Sitagliptan, linagliptan, saxagliptin

Question 25

What are DPP-4 inhibitors used for?

Answer 25

T2DM Used in combination with metformin (and/or other hypoglycaemic agents) where blood glucose is not adequately controlled on a single agent OR as a single agent to control BG and reduce complication where metformin is CI'd or not tolerated

Question 26

How do DPP4 inhibitors work?

Answer 26

``` The incretins (GLP1 and GIP) are released by the intestine throughout the day, but particularly in response to food. They promote insulin secretion and suppress glucagon release, lowering blood glucose. They are rapidly inactivated by the enzyme DPP4. DPP4-inhibitors (the 'gliptins') therefore lower blood glucuse by preventing integrin degredation. ``` The actions of integrins are glucose dependent, so they do not stimulate insulin secretion at normal blood glucose conc or suppress glucagon release in response to hypoglycaemia, therefore they are less likely to cause hypos than sulphonylureas, which stimulate insulin secretion irrespective of blood glucose

Question 27

What are the important adverse effects of DPP4 inhibitors?

Answer 27

Generally well tolerated. Patients may experience GI upset, headache, nasopharyngitis, or peripheral oedema Hypoglycaemia can occur, particularly where DPP4 inhibitors are prescribed in combination with sulphonlyureas and insulin There is a small risk of acute pancreatits, affecting 0.1-1% patients. This should be suspected in patients experiencing persistent abdo pain and ususally resolves on stopping the drug

Question 28

What are the warnings for DPP4 inhibitors?

Answer 28

They are contraindicated in people with a history of hypersensitivity to the drug class and should not be used in the treatment of T1DM or ketoacidosis They should not be used pregnancy or breastfeeding Use with caution in over 80s and people with a history of pancreatitis As they are renally excreted, a dose reduction may be required for patients with moderate-to-severe renal impairment

Question 29

What are the important interaction for DPP4 inhibitors?

Answer 29

Risk of hypoglycaemia increased by co-prescription of other anti-diabetic drugs e.g. sulphonylureas and insulin and by alcohol (beta blockers may mask symptoms of hypoglycaemia) The efficacy of DPP4 inhibitors is reduced by drugs that elevate blood glucose e.g. prednisolone, thiazide and loop diuretics

Question 30

How are DPP4 inhibitors prescribed?

Answer 30

Orally, usually OD, with or without food e.g. sitagliptin 100mg daily, linagliptin 5mg daily, saxabliptin 5mg daily They are also formulated in fixed-dose combinations with metformin As metformin needs to be taken 2-3 times daily, these fixed dose combinations contain half the daily dose of the DPP4 inhibitor (e.g. sitagliptin 50mg with metformin 1g) and are prescribed twice-daily +ves- combined preparations include reduced tablet burden and improved treatment adherence -ves- limited dose options, culprit of AEs more difficult to identify

Question 31

How is DPP4 inhibitor treatment monitored?

Answer 31

HBA1C When a DPP4 inhibitor is used as a monotherpy, the target HBA1C is <48mmol/mol When used as a combination therapy, the target is <53mmol/mol An HBA1C >58mmol/mol is generally a trigger to intensify therapy with another agent Measure renal function before treatment

Question 32

What are SGLT2 inhibitors?

Answer 32

e.g. dapaglifozin, empagliflozin They are an up-and-coming drug that can reduce risk of vascular complications without causing significant risk of hypos, whereas DPP4 inhibitors don't They work by interfering with resorption of glucose from the renal tubule, increasing urinary glucose loss

Question 33

What is insulin indicated for?

Answer 33

1. For insulin replacement in people with T1DM and control of blood glucose in people with T2DM where oral hypoglycaemic treatment is inadequately or poorly tolerated 2. Given IV, in the treatment of diabetic emergencies such as diabetic ketoacidosis and hyperglycaemic hyperosmolar syndrome, and for perioperative glycaemic control in selected diabetic patients 3. Alongside glucose to treat hyperkalaemia

Question 34

How does insulin therapy work?

Answer 34

It stimulates glucose uptake from the circulation into tissues, including skeletal muscle and fat, and increases the use of glucose as an energy source It stimulates glycogen, lipid and protein synthesis and inhibits gluconeogenesis and ketogenesis For the treatment of hyperkalaemia, insulin drives K+ into the cells, reducing serum K+ concentrations

Question 35

What are the different types of insulin therapy?

Answer 35

Rapid acting- NovoRapid Short acting- Actrapid Intermediate acting- Humlin I Long-acting- Lantus, Levimir Biphasic insulin preparations contain a mixture of rapid and intermediate acting insulins e.g. NovoMix 30 Where IV insulin is required (e.g. hyperkalaemia, diabetic emergencies, peri-operative glucose control) Actrapid is used

Question 36

What are the important adverse effects of insulin?

Answer 36

Hypoglycaemia, which can be severe enough to lead to coma and death Can cause lipohypertrophy where SC insulin is used (fat overgrowth)

Question 37

What are the warnings with insulin therapy?

Answer 37

In patients with renal impairment, insulin clearance is reduced, so there is an increased risk of hypoglycaemia

Question 38

What are the important interactions with insulin?

Answer 38

Combining insulin with other hypoglycaemic agents increases the risk of hypoglycaemia Concurrent therapy with systemic steroids increases insulin requirements

Question 39

What is a basal-bolus regime and twice-daily regime in insulin therapy?

Answer 39

Basal-bolus e.g. Lantus (long acting) OD, NovoRapid with snacks and meals Twice-daily- Novomix 30 BD Insulin is prescribed in units, and a typical daily requirement is 30-50 units

Question 40

How is insulin prescribed in diabetic emergencies?

Answer 40

1 unit/mL IV solution which is made up by diluting Actrapin 50 units in 0.9% NaCl 50ml Glucose and potassium are also infused

Question 41

How is insulin prescribed in hyperkalaemia?

Answer 41

Must be prescribed with glucose to avoid hypos e.g. Actrapid 10 units in 20% glucose 100ml, infused over 15 mins

Question 42

How is insulin administered?

Answer 42

It is often administered using 'pens' containing insulin in solution (100units/ml). These allow patients to 'dial-up' the number of units required and administer insulin discretely

Question 43

What are the symptoms of hypoglycaemia? | What is the advice to a patient if hypoglycaemia develops?

Answer 43

Dizziness, agitation, nausea, sweating and confusion | Have something sugary then something starchy e.g. a sandwich

Question 44

How is insulin therapy monitored?

Answer 44

capillary blood glucose regularly HBA1C at least annually Measure serum K+ at least every 4 hours when insulin is given as a continuous IV infusion

Question 45

What is metformin prescribed for?

Answer 45

T2DM, as a 1st choice medication

Question 46

How does metformin work?

Answer 46

It is a biguanide, lowering blood glucose primarily be reducing hepatic glucose output (glycogenolysis and gluconeogenesis) and to a lesser extent, increasing glucose uptake and utilisation by skeletal muscle It does not stimulate insulin secretion and therefore does not cause hypoglycaemia It can also cause weight loss, which can be a desirable side effect

Question 47

What are the important adverse effects of metformin?

Answer 47

Can cause GI upset- N&V, taste disturbance, anorexia and diarrhoea Lactic acidosis has been associated very rarely with metformin use

Question 48

What are the warnings surrounding metformin use?

Answer 48

It must be used with caution in renal impairment, with dose reduction required if the eGFR is <45ml/min and stopped if it falls below 30 It should be withheld acutely where there is AKI or severe tissue hypoxia e.g. sepsis, cardiac or resp failure, MI It should be withheld during acute alcohol intoxication and be used with caution in chronic alcohol abuse ,where there is a risk of hypos

Question 49

What are the important interactions with metformin?

Answer 49

It must be withheld before and for 48 hours after injection of IV contrast media e.g. for CT scans, coronary angiography, when there is an increased risk of renal impairment, metformin accumulation and lactic acidosis Other drugs (e.g. ACEi, NSAIDs, diuretics) with potential to impair renal function should also be used with caution e.g. renal function monitoring Prednisolone, thiazide and loop diuretics elevate blood glucose, hence oppose the actions and reduce efficacy of metformin

Question 50

How is metformin prescribed?

Answer 50

Orally GI adverse effects of metformin are usually transient and are best tolerated if metformin is started at a low dose and increased gradually A common regimen is to start metformin 500mg OD with breakfast, increasing the dose by 500mg weekly to 500-800mg 3x daily with meals

Question 51

How should metformin be administered?

Answer 51

It should be swallowed with a glass of water with or after food to minimise GI side effects

Question 52

How is metformin prescription monitored?

Answer 52

Assess control with HBA1C target is initially <48mmol/mol. Treatment is intensified by adding a second agent if the HBA1C is >58, and a new target of <53 is set (balancing the risks of hyperglycaemia with hypos from the Rx) For safety, measure renal function before starting treatment, then at least annually during therapy

Question 53

What are oestrogens and progestogens prescribed for?

Answer 53

1. Hormonal contraception | 2. HRT

Question 54

How do oestrogens and progestogens work?

Answer 54

FSH and LH control ovulation and ovarian production of oestrogen and progesterone. In turn, O+P exert predominantly -ve feedback on LH and FSH release. In hormonal contraception, oestrogens (e.g. ethinylestradiol) and/or progestogens (e.g. desogestrel) are given to suppress LH/FSH and hence ovulation There are other additional benefits as well as contraception- reduced menstrual pain and bleeding, and improvements in acne At menopause, a fall in oestrogen and progesterone cause symptoms of hot flushing and dryness, oestrogen replacement (usually combined with a progestogen) alleviates these

Question 55

What are the important adverse effects of oestrogens and progestogens?

Answer 55

They may cause irregular bleeding and mood changes The oestrogens in COCP double the risk of VTE, but the absolute risk is still low They also increase the risk of CV disease and stroke, breast and cervical cancer (for breast cancer it stops after stopping the pill) Progestogen-only pills do not increase the risk of VTE or CV disease The AEs for HRT are similar but as baseline rates are higher, the relative risks have more sigf events

Question 56

What are the warnings for taking oestrogens and progestogens?

Answer 56

They are CI'd in patients with breast cancer They should be avoided in patients at increased risk for VTE (CI'd if personal history or known thrombogenic mutation, warned if FH) Also warned in CV disease (e.g. age >35, risk factors, migraine with aura, heavy smoking history)

Question 57

What are the important interactions with oestrogens and progestogens?

Answer 57

Cytochrome P450 inducers e.g. rifampicin, carbamazepine may reduce contraceptive efficacy, particularly of progestogen-only forms Absorption of lamotrigine may be reduces, potentially impairing seizure threshold

Question 58

How are oestrogens and progestogens prescribed?

Answer 58

COC- 30 or 35mcg ethinylestradiol POP- where COC is contraindicated For HRT, combined O-P therapy is preferred, although women who have had a hysterectomy may receive oestrogen alone

Question 59

How is the COC pill administered?

Answer 59

If a COC pill is started within the first 6 days of the woman's cycle, no additional contraception is needed If started from day 7 onwards, a barrier method should be used or sex avoided for the first 7 days Missing 2 or more pills necessitates additional contraception for 7 days

Question 60

What should be monitored during prescription of a contraceptive pill?

Answer 60

Baseline assessments should include a relevant history, BP check and BMI A woman starting a COC pill should be seen again at 3 months for a BP check and to discuss any issues She should then be seen again yearly to discuss health changes and for BP and BMI checks

Question 61

Name an example of an sulphonylurea?

Answer 61

Gliclazide

Question 62

Name the common indications for sulphonylureas?

Answer 62

In T2DM: 1. In combination with metformin where blood glucose is not adequately controlled by a single agent 2. As a single agent to control blood glucose and reduce complications where metformin is contraindicated or not tolerated

Question 63

How do sulphonylureas work?

Answer 63

They lower blood glucose by stimulating pancreatic insulin secretion. As insulin is an anabolic hormone, it can cause weight gain

Question 64

What are the important adverse effects of sulphonylureas?

Answer 64

GI upset- N&V, diarrhoea and constipation Hypoglycaemia is a potentially serious adverse effect, which is more likely with high doses Rare hypersensitivity reactions include hepatic toxicity (e.g. cholestatic jaundice,) drug hypersensitivity syndrome (rash, fever, internal organ involvement), and haematological abnormalities (e.g. agranulocytosis)

Question 65

What are the warnings for sulphonylureas?

Answer 65

It is metabolised in the liver, therefore a dose reduction may be needed in patients with hepatic impairment and blood glucose should be monitored in patients with renal impairment They should be prescribed with caution in people at increased risk of hypoglycaemia including those with hepatic impairment, malnutrition, adrenal or pituitary insufficiency

Question 66

What are the important interactions with sulphonylureas?

Answer 66

Risk of hypoglycaemia is increased by co-prescription of other anti-diabetic drugs, including metformin, DPP-4 inhibitors e.g. sitagliptin, insulin and alcohol Beta blockers may mask the symptoms of hypoglycaemia They become less effective with acute illness- insulin treatment may be required temporarily The efficacy is reduced by drugs that elevate blood glucose e.g. prednisolone, thiazide and loop diuretics

Question 67

How are sulphonylureas prescribed?

Answer 67

Gliclazide (standard release) is usually started at a dosage of 40-80mg OD. It is increased gradually until blood glucose is controlled, with higher doses (160mg-320mg daily) being given as 2 divided doses It is also available as a MR form. 30mg MR has an equivalent glucose-lowering effect to 80mg standard release tablets

Question 68

When should sulphonylureas be taken?

Answer 68

Taken with meals- either once daily with breakfast or twice daily with breakfast and tea

Question 69

How are sulphonylureas monitored?

Answer 69

HBA1C, same targets as metformin

Question 70

Name some examples of thyroid hormones?

Answer 70

Levothyroxine, liothyronine

Question 71

What are thyroid hormones indicated for?

Answer 71

1. Primary hypothyroidism | 2. Hypothyroidism secondary to hypopituitarism

Question 72

How do thyroid hormones work?

Answer 72

The thyroid gland produces throxine (T4) which is converted to the more active form (T3) in target tissues. Thyroid hormones regulate metabolism and growth. Deficiency of these hormones causes hypothyroidism, with clinical features including lethargy, weight gain, constipation, and slowing of mental processes It is treated with long-term replacement of thyroid hormones, most usually as levothyroxine (synthetic T4). Liothyronine (synthetic T3) has a shorter half-life and a quicker onset and offset, so it is reserved for emergency treatment of severe or acute hypothyroidism

Question 73

What are the important adverse effects of thyroid hormones?

Answer 73

Symptoms similar to hyperthyroidism- GI (diarrhoea, vomiting, weight loss), cardiac (palpitations, arrhythmias, angina) and neurological (tremor, restlessness, insomnia)

Question 74

What are the warnings for prescribing thyroid hormones?

Answer 74

As they increase heart rate and metabolism, they can precipitate ischaemia in people with CAD, in whom replacement should be started cautiously at a low dose with monitoring. In hypopituitarism, corticosteroid therapy must be initiated before thyroid hormone replacement to avoid precipitating an Addisonian crisis.

Question 75

What are the important interactions with thyroid hormones?

Answer 75

As GI absorption of levothyroxine is reduced by antacids, calcium and iron salts, administration of these drugs needs to be separated by about 4 hours An increase in levothyroxine dose may be required in patients taking cytochrome P450 inducers e.g. phenytoin, carbamazepine. Levothyroxine-induced changes in metabolism can increase insulin or oral hypoglycaemic requirements and enhance the effects of warfarin

Question 76

How are thyroid hormones prescribed?

Answer 76

Levothyroxine-oral Starting dose of 50-100mcg daily, except in the elderly or people with cardiac disease, who should start on 25mcg daily The dose is adjusted monthly in 25-50mcg increments to a usual maintenance dose of 50-200mcg OD Liothyronine may be prescribed for IV administration in emergency care If patients take calcium or iron replacement, advise them to leave a gap of about 4 hours between these treatments and levothyroxine

Question 77

How are thyroid hormone prescriptions monitored?

Answer 77

Initially review the patient monthly TFTs should be measured 3 months after starting treatment or a change in dose In primary hypothyroidism, TSH is the main guide to dosing. It is elevated due to loss of negative feedback of T4 on the pituitary. It should return to normal concentrations. Stable patients should have annual clinical review and thyroid function tests