Diabetes and Endocrine

Question 1

Insulin

Answer 1

Use: insulin replacement in T1DM, control of blood glucose in T2DM, DKA, HSS, perioperative glycemic control, hyperkalaemia
MOA: stimulates glucose uptake from the circulation into tissues (incl. skeletal muscle and fat), and increases the use of glucose as an energy source. Insulin stimulates glycogen, lipid and protein synthesis. Insulin inhibits gluconeogenesis and ketogenesis. For the treatment of hyperK+, insulin drives K+ into cells, reducing serum K+ concentrations. However, this effect stops when insulin is stopped.
Adverse effects: hypoglycaemia, lipohypertrophy at injection sites
Cautions: increased risk of hypoglycaemia in renal impairment
Interactions: co-prescription with hypoglycaemia agents increases risk of hypo, concurrent therapy with steroids increases insulin requirements

Question 2

Insulin formulations

Answer 2

Rapid acting - immediate onset, short duration e.g. Insulin aspart
Short acting - early onset, short duration e.g. Actrapid
Intermediate acting - intermediate onset and duration e.g. Humulin I
Long-acting e.g. Lantus (insulin glargine), Levemir (insulin detemir)
Biphasic insulin - mixture of rapid and intermediate acting insulin’s e.g. NovoMix 30 (30% insulin aspart, 70% insulin aspart protamine)
Others: Humulin-S® (human quick-acting), Insulin lispro (analogue quick-acting), Insulatard® (human isophane[NPH]), Humulin M3® (human biphasic), Humalog Mix25® (analogue biphasic), Insuin degludec (analogue long-acting)

Question 3

Sulfonylureas

Answer 3

E.g. Gliclazide, Glimepiride
Use: in T2DM in combination with metformin (where a single agent has not elucidated good control) or as a single agent if metformin is contraindicated/not tolerated
MOA: stimulate pancreatic insulin secretion, reducing blood glucose. They block ATP-dependent K+ channels in pancreatic beta-cell membranes, causing depolarisation of the cell membrane and opening voltage-gated calcium channels. This increases IC Ca2+ conc., stimulating insulin secretion.
Adverse effects: weight gain (insulin is an anabolic hormone) which can worsen diabetes in the long-term, dose-related GI upset, hypoglycaemia, hypersensitivity reactions incl. hepatic toxicity, drug hypersensitivity syndrome and haematological abnormalities (agranulocytosis)
Cautions: effective only in patients with residual pancreatic function, reduce dose in hepatic impairment (gliclazide is metabolised in the liver), monitor blood glucose in renal impairment, prescribe with caution for those at risk of hypo (hepatic impairment, malnutrition, adrenal or pituitary insufficiency, elderly)
Interactions: co-prescription of antidiabetic drugs or alcohol increases risk of hypo, beta-blockers can mask hypo symptoms, efficacy is reduced by drugs which increase blood glucose (prednisolone, thiazides, loop diuretics)

Question 4

Meglinitides

Answer 4

E.g. Repaglinide
Use: T2DM as mono therapy or in combination with metformin
MOA: activity depends on presence of functioning beta-cells and glucose. It potentiates the effect of EC glucose on ATP-sensitive K+ channels. It is more effective at reducing postprandial blood glucose levels. Takes ~1 month before effects are seen.
Adverse effects: abdo pain, diarrhoea, hypo.
Cautions: increased risk of hypo when used with other hypoglycaemic. Contraindicated in ketoacidosis. Caution in elderly and malnourishment. Avoid in pregnancy and breast feeding, and severe hepatic impairment. Caution in renal impairment.

Question 5

Biguanides

Answer 5

E.g. Metformin
Use: first-choice in T2DM either alone or in combination with other oral hypoglyacemics
MOA: reduces hepatic glucose output (glycogenolysis and gluconeogenesis) and increases glucose uptake and utilisation by skeletal muscle. Its effect on glucose metabolism can cause weight loss.
Adverse effects: GI upset (nausea, vomiting, taste disturbance, anorexia, diarrhoea), lactic acidosis
Cautions: dose reduction in renal impairment (as it is really excreted) with drug stopped if GFR <30, withheld in AKI or severe tissue hypoxia (severe sepsis, cardiac or respiratory failure, MI), caution in hepatic impairment (clearance of excess lactate may be impaired). Withhold in acute alcohol intoxication, use with caution in chronic alcohol use (risk of hypo)
Interactions: withhold before and for 48 hours after IV contrast media (increased risk of renal impairment, metformin accumulation and lactic acidosis). Use with caution if taking other drugs which impair renal function (ACEi, NSAIDs, diuretics). Efficacy reduced by prednisolone, thiazide and loop diuretics (increase glucose).

Question 6

Thiazolidinediones

Answer 6

E.g. Pioglitazone
Use: T2DM either alone or in combination with other oral hypoglyacemics
MOA: reduces peripheral insulin resistance, reducing blood glucose.
Adverse effects: bone fracture, increased risk of infection, numbness, visual impairment, weight gain.
Cautions: contraindicated in hx of HF, previous or active bladder cancer, un-investigated macroscopic haematuria. Caution with insulin (risk of HF), elderly (HF/fractures/bladder cancer), increased risk of bone fractures. Avoid in pregnancy and breast feeding.

Question 7

Dipeptidyl peptidase-4 inhibitors

Answer 7

E.g. Sitagliptin, Saxagliptin
Use: in T2DM in combination with metformin or as a single agent if metformin is contraindicated/not tolerated
MOA: lower blood glucose by preventing incretin degradation and increasing plasma concentrations of their active forms. Incretins (GLP-1 and GIP) are usually released in response to food, they promote insulin secretion and suppress glucagon release. The actions of incretins are glucose-dependent, so less likely to cause a hypo.
Adverse effects: GI upset, headache, nasopharyngitis, peripheral oedema. Hypo may occur when these are prescribed with other oral hypoglycaemic. Small risk of pancreatitis.
Cautions: contraindicated if hx of hypersensitivity or in the treatment for T1DM and ketoacidosis. Do not use in pregnancy or breastfeeding. Use with caution in the elderly, those with hx of pancreatitis and moderate-severe renal impairment (as renal excreted so dose reduction required)
Interactions: hypo risk is increased when prescribed with other oral antiglycaemics and alcohol. Beta blockers may mask hypo symptoms. Efficacy is reduced by prednisolone, thiazides and loop diuretics.

Question 8

ɑ-Glucosidase inhibitors

Answer 8

E.g. Acarbose
Use: DM
MOA: delays digestion and absorption of starch and sucrose
Adverse effects: diarrhoea, GI discomfort, GI disorder, N&V.
Cautions: contraindicated in disorders of digestion/absorption, hernia, IBD. Caution with use of insulin and sulfonylureas (hypo risk). Avoid in pregnancy, breast feeding, severe hepatic impairment, eGFR <25.
Interactions: hypo risk if taken with other oral hypoglycaemic.

Question 9

SGLT2 inhibitors

Answer 9

E.g. Canagliflozin, Empagliflozin
Use: in T2DM in combination with metformin or as a single agent if metformin is contraindicated/not tolerated
MOA: reversibly inhibit SGLT2 in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion
Adverse effects: balanoposthitis, hypoglycaemia (in combination with insulin or sulfonylurea), increased risk of infection, skin reactions, thirst, urinary disorder, urosepsis
Cautions: contraindicated in DKA. Caution in complicated UTIs, elderly, hypotension, risk of volume depletion. Avoid in pregnancy, breast feeding, severe Hepatic impairment, eGFR <45.
Interactions: increased risk of hypotension and hypoglycaemia with other drugs which have these effects

Question 10

GLP-1 mimetics

Answer 10

E.g. Exenatide, Liraglutide, Bydureon
Use: T2DM in combination with metformin or sulfonylurea, or both, or with pioglitazone, or with M+P
MOA: binds to and activates GLP-1 receptor, to increase insulin secretion, suppress glucagon secretion and slow gastric emptying
Adverse effects: decreased appetite, asthenia, constipation, diarrhoea, dizziness, GI discomfort/disorder, headache, nausea, skin reaction, vomiting
Cautions: contraindicated in ketoacidosis and severe GI disease. Caution in elderly. Avoid in pregnancy and breast feeding. Avoid if GFR <30 (standard release) or <50 (modified release)
Interactions: increased risk of hypo when used with other hypoglycaemic

Question 11

Glucagon

Answer 11

GlucaGen® HypoKit
Use: diabetic hypoglycaemia (SC or IM injection), beta blocker poisoning
MOA: binds to glucagon receptor, activating adenylate cyclase and increasing IC cAMP and activating PKA. This ultimately increases IC Ca2+. Glycogen is broken down and SM of the stomach/duodenum/SB/colon is relaxed.
Adverse effects: nausea, vomiting
Cautions: contraindicated in pheochromocytoma. Caution in glucagonom. Ineffective in chronic hypoglycaemia, starvation, and adrenal insufficiency.
Interactions: increases anticoagulant effect of warfarin

Question 12

IV glucose

Answer 12

Use: 5% to provide water in patients unable to take enough orally, 10%/20%/50% for hypoglycaemia, 10/20/50% with insulin for hyperkalaemia, 5% for reconstitution and dilution of drugs by injection or infusion
MOA: 5% - glucose content is isotonic with serum so it does not induce osmotic lysis of red cells; glucose is rapidly taken up by cells and metabolised leaving hypotonic water that distributes across all body water compartments. Higher concentrations used in hypoglycaemia. For hyperkalaemia, soluble insulin is given to stimulate the Na/K ATPase and shift K+ into cells.
Adverse effects: glucose 50% is irritant to veins and may cause pain, phlebitis and thrombosis. Hyperglycaemia will occur if glucose administration exceeds utilisation.
Cautions: can cause Wernicke’s in patients at risk of thiamine deficiency (give thiamine before glucose in this case). Monitor fluid balance in renal failure. Hypotonic fluid administration to patients with hyponatraemia or at risk of (children, brain injuries), may precipitate hyponatraemic encephalopathy
Interactions: antagonistic effects with insulin, give at fixed rate

Question 13

Thionamides

Answer 13

E.g. Carbimazole, Propylthiouracil
Use: hyperthyroidism
MOA:
Adverse effects: BM disorder, haemolytic anaemia, thrombocytopenia, agranulocytosis
Cautions: contraindicated in blood disorders. Avoid in severe hepatic impairment. Dose reduction if GFR <50.
Interactions: increased risk of myelosuppression with other drugs, affects digoxin conc.

Question 14

Beta blockers

Answer 14

E.g. Propranolol
Use: hyperthyroidism to treat symptoms, IHD, chronic HF, AF, SVT, HTN
MOA: reduce force of contraction and speed of conduction in the heart, relieving myocardial ischaemia (by reducing cardiac work and O2 demand) and increasing myocardial perfusion. ‘Protect’ the heart in HF from chronic sympathetic stimulation. Slow the ventricular rate in AF by prolonging the refractory period of the AV node. Reduce renin secretion by the kidney in HTN.
Adverse effects: fatigue, cold extremities, headache, GI disturbance, sleep disturbance, impotence
Cautions: do not use in asthmatic patients (cause bronchospasm by blocking beta-2 adrenoreceptors in the airways). Avoid if haemodynamically unstable. Contraindicated in heart block. Dose reduce in hepatic failure.
Interactions: do not use with non-dihydropyridine CCBs (verapamil, diltiazem) as will cause HF and bradycardia.

Question 15

Radioiodine and oral iodine solutions

Answer 15

E.g. Radioiodine (I131), Aqueos Iodine oral solution
Use:
MOA: 
Adverse effects:
Cautions:
Interactions:

Question 16

Levothyroxine

Answer 16

Use: primary hypothyroidism, hypothyroidism secondary to hypopituitarism
MOA: synthetic T4 (inactive form), converted to T3 in target tissues. Regulates metabolism and growth.
Adverse effects: diarrhoea, vomiting, weight loss, palpitations, arrhythmias, angina, tremor, restlessness, insomnia [manifestations of excessive doses/hyperthyroidism]
Cautions: may precipitate cardiac ischaemia in people with CAD (as they increase HR and metabolism). Corticosteroid therapy must be initiated before this in hypopituitarism to avoid Addisonian crisis.
Interactions: GI absorption is reduced by antacids/calcium and iron salts. Increased dose may be required if taking cytochrome P450 induces (phenytoin, carbamazepine). May increase insulin/oral hypoglycaemia requirements in DM, and enhances warfarin effects.

Question 17

Systemic glucocorticoids

Answer 17

e.g. Hydrocortisone, Prednisolone, Dexamethasone
Use: allergic/inflammatory disorders (anaphylaxis, asthma), autoimmune disease (IBD, arthritis), cancer, hormone replacement in adrenal insufficiency or hypopituitarism
MOA: bind to cytosolic glucocorticoid receptor which translocate to the nucleus and bind glucocorticoid-response elements, which regulate gene expression. They up regulate anti-inflammatory genes and down regulate pro-inflammatory genes. Metabolic effects incl. increased gluconeogenesis (from increased circulating AA and FAs released by catabolism of muscle and fat). Mineralocorticoid effects incl. Na+ and H20 retention, and K+ excretion.
Adverse effects: immunosuppression increases risk/severity of infection. Increased catabolism causes proximal muscle weakness, skin thinning, easy bruising and gastritis. Mood changes incl. insomnia, confusion, psychosis and suicidal ideas. HTN, hypoK+ and oedema can result from mineralocorticoid effects. Prolonged treatment switches off the stimulus for normal cortisol production (ACTH), causing adrenal atrophy. If steroids are withdrawn quickly, an acute Addisonian crisis will result.
Cautions: children (suppresses growth) and those with infection
Interactions: increase risk of peptic ulceration and GI bleeding when used with NSAIDs, enhance hypoK+ if taking beta-2 agonists/theophylline/loop or thiazide diuretics. Efficacy reduced by cytochrome P450 inducers (phenytoin, carbamazepine, rifampicin). Reduce immune response to vaccines.

Question 18

Mineralocorticoids

Answer 18

Fludrocortisone
Use: neuropathic postural hypotension, replacement in adrenocortical insufficiency
MOA: Na+ and H20 retention, and K+ excretion
Adverse effects: anxiety, cognitive impairment, Cushing’s syndrome, HTN, hypoK+, oedema, fatigue, GI discomfort, impaired healing, hirsutism, increased risk of infection, skin reactions, weight gain
Cautions: HF, DM, diverticulitis, glaucoma, TB, HTN, hypothyroidism, infection, myasthenia gravis, ocular herpes simplex, osteoporosis, peptic ulcer, recent MI, affective disorder, elderly
Interactions: increase risk of peptic ulceration and GI bleeding when used with NSAIDs, enhance hypoK+ if taking beta-2 agonists/theophylline/loop or thiazide diuretics. Efficacy reduced by cytochrome P450 inducers (phenytoin, carbamazepine, rifampicin). Reduce immune response to vaccines.

Question 19

Synthetic human GH

Answer 19

Somatropin
Use: Turner’s syndrome, deficiency of GH
MOA: synthetic GH
Adverse effects: carpal tunnel syndrome, fluid retention, headache, joint disorder, lipoatrophy, myalgia, oedema, paraesthesia, gynaecomastia, intracranial HTN, hyperglycaemia, hypothyroidism, hyperinsulinism, femur osteonecrosis, pancreatitis
Cautions: contraindicated in tumour activity, renal transplantation, severe obesity in Prader-Willi. Caution in DM, malignancy hx, hypoadrenalism, hypothyroidism, papilloedema.
Interactions: decreased activity when taken with steroids

Question 20

Synthetic ACTH

Answer 20

Tetracosactide
Use: diagnosis of adrenocortical insufficiency
MOA: synthetic ACTH
Adverse effects: lots
Cautions: contraindicated in acute psychosis, adrenogenital syndrome, allergy, asthma, Cushing’s syndrome, infectious disease, peptic ulcer, primary adrenocortical insufficiency. Caution in active disease, DM, diverticulitis, hx of asthma/atopic allergy/eczema/hayfever, HTN, myasthenia gravis, TB, ocular herpes simplex, osteoporosis. Avoid in pregnancy, breast feeding. caution in cirrhosis and renal impairment.

Question 21

Dopamine D2 agonist

Answer 21

E.g. Cabergoline, Quinagolide
Use: prevention of lactation, suppression of established lactation, hyperprolactinaemic disorder
MOA: stimulant of DA receptors in the brain and inhibits prolactin in the pituitary
Adverse effects: angina, asthenia, cardiac valvulopathy, confusion, constipation, dizziness, drowsiness, dyspepsia, dyspnoea, gastritis, hallucination, headache, hypotension, movement disorder,r nausea, oedema, pericardial effusion, pericarditis, sexual dysfunction, sleep disorder, vertigo, vomiting
Cautions: contraindicated in patients with hypersensitivity to ergot alkaloids. Avoid in pre-eclampsia, fibrotic disorder, puerperal psychosis. Caution in CVD, peptic ulcer hx, mental disorder, Raynaud’s. Avoid in pregnancy and severe hepatic impairment.
Interactions: risk of hypotension, effects increased by clarithryomycin

Question 22

Testosterone

Answer 22

E.g. Sustanon 250® (testosterone esters - IM depot), Testogel® (testosterone - transdermal)
Use: hypogonadism due to androgen deficiency
MOA: testosterone
Adverse effects: hot flush, HTN, polycythaemia, prostate abnormalities, skin reactions, weight gain, hypertriglycerideamia
Cautions: cardiac impairment, DM, elderly, epilepsy, IHD, migraine, pre-puberty

Question 23

Bisphosphonates

Answer 23

E.g. Alendronic acid, Residronate, Zolendronic acid
Use: alendronic for patients at risk of osteoporotic fragility fractures, zoledronic for severe hypercalcaemia of malignancy and to reduce risk of pathological fractures/cord compression/need for radiotherapy in patients with myeloma and breast cancer with bone mets, metabolically active Paget’s disease
MOA: reduce bone turnover by inhibiting osteoclast action
Adverse effects: oesophagitis, hypophosphataemia, jaw necrosis (more likely with high-dose IV therapy), atypical femoral fracture
Cautions: avoid in severe renal impairment (renal secretion), hypocalcaemia and upper GI disorder. Caution when prescribing in smokers and patients with dental disease.
Interactions: absorption is reduced if taken with calcium salts, antacids and iron salts

Question 24

Vitamin D

Answer 24

E.g. Alfacalcidol (1a-hydroxycholecalciferol), Calcitriol (1,25-dihydroxycholecalciferol), Ergocalciferol (vitamin D2)
Use: in osteoporosis to ensure +ve calcium balance when dietary intake and/or sunlight exposure are insufficient, in CKD to treat and prevent secondary hyperparathyroidism and renal osteodystrophy, prevention and treatment of vitamin D deficiency
MOA: Calcium homeostasis is controlled by PTH and vitamin D (increase Ca2+ levels and bone mineralisation), and calcitonin (reduces Ca2+ levels). Vitamin D and calcium help to restore +ve calcium balance, reducing the rate of bone loss. In severe CKD, impaired phosphate excretion and reduced vitamin D activation causes hyperphosphataemia and hypocalcaemia; this stimulates secondary hyperparathyroidism, leading to renal osteodystrophy. Giving supplements means vitamin D does not depend on renal activation.
Cautions: avoid in hypercalcaemia

Question 25

Calcium salts

Answer 25

E.g. Calcichew® (oral supplement), Calcium gluconate (Parenteral - IV), Calcium chloride (Parenteral - IV)
Use: in osteoporosis to ensure +ve calcium balance when dietary intake and/or sunlight exposure are insufficient, in CKD to treat and prevent secondary hyperparathyroidism and renal osteodystrophy, calcium gluconate in severe hyperkalaemia (prevent arrhythmias), hypocalcaemia that is symptomatic (paraesthesia, tetany, seizures)
MOA: calcium is essential for normal function of muscle/nerves/bone/clotting. Calcium homeostasis is controlled by PTH and vitamin D (increase Ca2+ levels and bone mineralisation), and calcitonin (reduces Ca2+ levels). Vitamin D and calcium help to restore +ve calcium balance, reducing the rate of bone loss. In severe CKD, impaired phosphate excretion and reduced vitamin D activation causes hyperphosphataemia and hypocalcaemia; this stimulates secondary hyperparathyroidism, leading to renal osteodystrophy. Giving supplements means vitamin D does not depend on renal activation. In hyperK+, calcium reduces the myocardial threshold potential, reducing excitability and the risk of arrhythmias.
Adverse effects: dyspepsia and constipation (oral), cardiovascular collapse if given too fast IV, local tissue damage if given int SC tissue
Cautions: avoid in hypercalcaemia
Interactions: reduces absorption of iron, bisphosphonates, tetracyclines and levothyroxine

Question 26

Vasopressin analogues

Answer 26

E.g. Desmopressin, Terlipressin
Use: diabetes insipidus, primary nocturnal enuresis, post-op polyuria or polydipsia, mild/moderate haemophilia and VWD
MOA:
Adverse effects: hyponatraemia, nausea, abdo pain, aggression (children), allergic dermatitis, fluid retention
Cautions: contraindicated in cardiac insufficiency, diuretic use, hyponatraemia, alcohol dependent polydipsia, psychogenic polydipsia, inappropriate ADH secretion, VWD type IIB. Caution in asthma, fluid overload, CVD, CF, elderly, epilepsy, HF, HTN, migraine, nocutira.
Interactions: drugs which increase risk of hyponatraemia e.g. lamotrigine

Question 27

Selective vasopressin receptor 2 antagonist

Answer 27

Tolvaptan
Use: autosomal dominant polycystic kidney disease with CKD 1-4, hyponatraemia secondary to inappropriate antidiuretic hormone secretion
Adverse effects: appetite decreased, asthenia, constipation, dehydration, diarrhoea, dizziness, dry mouth, dyspnoea, GI discomfort, headache, hepatic disorder, hyperglycaemia, hypernatramiea, hyperuricaemia, insomnia, muscle spasm, palpitations, polydipsia, skin reaction, thirst, urinary disorder, weight loss
Cautions: contraindicated in anuria, hypernatraemia, hypovolaemia hyponatraemia, impaired thirst perception. Caution in abnormal LFTs, DM, dehydration risk, urinary outflow obstruction.
Interactions: avoid concurrent use of drugs which increase Na+ conc.