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Endocrine MBCHB > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

What are the main indicators of insulin?

A
  • Mainstay of treatment for T1DM
  • Some T2DM patients may need endogenous insulin
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2
Q

What is the mechanism of action of insulin?

A
  • Lowers blood sugar
  • Aims to mimic normal physiological secretion of insulin so most T1DM patients will be on a basal-bolus regimen
    • Long-acting insulin 1-2 times a day and short-acting insulin before each meal
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3
Q

What are the short-acting insulins and when is it used?

A
  • Soluble insulins, e.g. Actrapid, Humulin S, reach a peak 2-4 hours after injection
    • Action tends to persist after meals - predisposes to hypoglycaemia
  • Insulin analogues, e.g. insulin aspart (NovoRapid), lispro (Humalog) and glulisine (Apidra), reach a peak 60-90 mins after injection
    • Disappear from circulation more rapidly than soluble insulin - preferred
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4
Q

What the intermediate and long-acting insulins? and when are they taken?

A
  • Isophane ‘basal’ insulins, e.g. Insulatart, Humulin, are intermediate to long acting with a peak action around 4-6 hours
  • Analogue basal insulins, e.g. lantus (glargine), levemir (dertermir), have a longer duration of action with less peak activity and may be given once or twice a day
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5
Q

What are the contraindications and cautions of insulin?

A

Injection site should be rotated to prevent lipohypertrophy

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6
Q

What are the adverse effects of insulin?

A
  • Weight gain
  • Risk of hypoglycaemia
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7
Q

How is insulin administered?

A
  • Intermittent SC injection
  • Continuous subcutaneous insulin infusion pump
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8
Q

What is metformin?

A

Currently the only avaliable biguanide - phenuformin and buformin withdrawn due to high risk of lactic acidosis

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9
Q

What are the main indications for metformin?

A

First line in all patients with type 2 diabetes

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10
Q

What is the mechanism of action of metformin?

A
  • Unclear but may involve the activation of AMP kinase, which regulates cellular energy metabolism
  • Metformin reduces hepatic glucose production (gluconeogenesis), and increases gut glucose utilisation and metabolism

Non-glucose effects

  • Cardiovascular benefit
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11
Q

What are the contraindications and cautions of metformin?

A
  • Contraindicated in renal impairment, cardiac failure and hepatic failure because of the risk of lactic acidosis
  • Metformin dose should be decreased as renal function fails
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12
Q

What are the adverse effects of metformin?

A
  • GI - anorexia, nausea, abdominal discomfort and diarrhoea
  • To reduce side effects initiate slowly, or use a modified release formulation
  • Metformin associated lactic acidosis (MALA)
    • Metformin increases lactate production (especially by the gut and liver)
    • Lactate is normally cleared by the liver and the kidneys
    • In acute kidney injury (often in the context of sepsis), metformin is associated with greater risk of lactic acidosis
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13
Q

How is metformin administered?

A

Orally

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14
Q

What is an example of a sulphonylurea?

A

gliclazide

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15
Q

What are the main indications of sulphonylurea?

A

Alternative first line treatment of type 2 diabetes where cost is a major issue (developing countries, private healthcare if no insurance)

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16
Q

What is the mechanism of action of sulphonylureas?

A
  • Act on the β-cell to induce insulin secretion - bind to the sulphonylurea receptor on the β-cell membrane, which closes ATP-sensitive K+ channels and promotes calcium influx which stimulates insulin release
  • No cardiovascular benefit
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17
Q

What are the contraindications and cautions of sulphonylureas?

A

Use with care in people with liver or renal disease

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18
Q

What are the adverse effects of sulphonylureas?

A
  • Weight gain - insulin concentrations increased, insulin is anabolic and stimulates appetite
  • Hypoglycaemia - SUs are glucose independent
    • Act via the triggering pathway - insulin release happens whatever the blood glucose
    • Increased risk with increased age, diabetes duration, impaired renal function, lower HbA1c
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19
Q

How are sulphonylureas administered?

A

Orally

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20
Q

What is an example of thiazolidinediones?

A

Pioglitazone is the only TZD available currently

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21
Q

What are the main indications of thiazolidinediones?

A
  • Follow on to metformin where cost is a major issue
  • Particularly potent in obese women
  • Generally avoided in patients 65+ due to side effects
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22
Q

What are the mechanisms of actions of thiazolidinediones?

A
  • Reduce insulin resistance by interaction with PPAR-𝛾 - nuclear receptor that regulates many genes including those involved in lipid metabolism and insulin action
  • Main effect is on adipocytes and the net result is increased insulin sensitivity
    1. Increase differentiation from pre-adipocytes to adipocytes
    2. Increases fat mass in subcutaneous depots
    3. ‘Lipid steal’ - free fatty acid uptake removes fat from liver and muscle which reduces lipotoxicity
    4. Increases adiponectin which acts on liver to increase insulin sensitivity
  • Probably reduces CVD risk
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23
Q

What are the contraindications and cautions of thiazolidinediones?

A

Fluid retention can precipitate heart failure

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24
Q

What are adverse effects of thiazolidinediones?

A
  • Weight gain - due to increase in fat mass and fluid retention
  • Fracture risk - fat accumulation in bone marrow and reduction in bone density, fracture risk doubles in the elderly
  • Mild anaemia
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25
Q

How are thiazolidinediones?

A

Orally

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26
Q

What are examples of GLP-1 Receptor antagonists?

A

liraglutide, semaglutide

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27
Q

What are the main indications for GLP-1 Receptor antagonists?

A
  • Diabetic patients with atherosclerotic CVD (e.g. previous MI) should be given metformin + GLP-1 receptor antagonist
  • Diabetic patients with heart failure or chronic kidney disease where SGLT2i are contraindicated/not tolerated should be given metformin + GLP-1 receptor antagonist
  • Valuable in diabetic patients who need to lose weight
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28
Q

What is the mechanism of action of GLP-1 Receptor Antagonists?

A
  • GLP-1 like molecules enhance the incretin effect by activating the GLP-1 receptors
  • They are modified to avoid breakdown by DPP4

Non-glucose effects

  • Act in many other tissues, especially hypothalamus to reduce appetite and intestines to reduce gastric emptying
  • Lower blood pressure
  • Reduction in cardiovascular mortality and HF hospitalisation
  • Reduction in new onet macroalbuminuria but no impact on eGFR
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29
Q

What are the contraindications and cautions of GLP-1 Receptor antagonists?

A
  • Contraindicated in patients with a history of pancreatitis due to a risk of acute pancreatitis
  • As incretin drugs act via the amplifying pathway (glucose-dependent mechanism) there is no risk of hypoglycaemia
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30
Q

What are the adverse effects of GLP-1 Receptor antagonists?

A
  • GI - nausea, vomiting, bloating, diarrhoea
    • Often improves after ~6 weeks but can be intractable
    • May be related to early satiety with reduced gastric emptying
  • Small increase in incidence of gallstones
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31
Q

How are GLP-1 Receptor antagonists administered?

A

SC injection (self-administered once a week)

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32
Q

What are examples of DPP4 Inhibitors?

A

sitagliptin, alogliptin, saxagliptin

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33
Q

What are the main indications for DPP4 inhibitors?

A
  • Most effective in the early stages of type 2 diabetes, when insulin secretion is relatively preserved
  • Can be used as a monotherapy when metformin not tolerated/contraindicated, or as an addon
34
Q

What is the mechanism of action for DPP4 inhibitors?

A
  • Inhibit DPP4 , which usually inactivate GLP-1 (incretin effect)
  • This in turn increases insulin secretion and reduces glucagon secretion

Non-glucose effects

  • Lower blood pressure
35
Q

What are the adverse effects of DPP4 Inhibitors?

A
  • Nausea
  • Increased risk of acute pancreatitis
  • As incretin drugs act via the amplifying pathway (glucose-dependent mechanism) there is no risk of hypoglycaemia
  • Weight neutral
  • Mixed results in studies of CV risk, may increase risk of HF
36
Q

How is DPP4 inhibitors administered?

A

Orally

37
Q

What are examples of SGLT2 inhibitors?

A

empagliflozin, dapagluflozin, canagliflozin

38
Q

What are the main indications for SGLT2 inhibitors?

A
  • Diabetic patients with heart failure or chronic kidney disease should be given metformin + an SGLT2i as first line
  • Valuable in diabetic patients who need to lose weight
39
Q

What is the mechanism of action of SGLT 2 inhibitors?

A
  • Specific inhibitors of renal sodium glucose transporter 2
  • Decrease renal afferent dilation which reduces filtration pressure
  • This lowers the renal threshold for glucose, which increases urinary glucose excretion
  • Removes glucose and calories from circulation - lowers blood glucose and facilitates weight loss

Non-glucose effects

  • Na+ reabsorption reduced and glucose loss results in osmotic diuresis → mild diuretic action which may explain some of the reduction in heart failure
  • Urate excretion increased so plasma urate concentration reduced - beneficial in terms of gout and CVD
  • Increased Na+ delivery to DCT causes increased Na+ uptake by Na/K/Cl transporter at macula densa → increase in adenosine secretion → reduction in renal affferent vasodilation → renal protection
  • Glucose reduction → decreased insulin and increased glucagon → increase in lipolysis → increase in FFA which also increases ketone body production
    • FFA and ketones are a fuel to cardiac myocytes - cardiac benefit
    • Can increase ketosis and risk of ketoacidosis
40
Q

What are the contraindications and cautions of SGLT2 inhibitors?

A
  • Relies on renal glucose function so patients with reduced eGFR will see little benefit in terms of glucose lowering (but will still see renal benefits)
  • Use with caution in patients on other diuretics or with low blood pressure due to diuretic effect
  • Due to hypovolaemia and DKA risks, SGLT2i should be omitted in prolonged fasting or acute illness
41
Q

What are the adverse effects of SGLT2 inhibitors?

A
  • Genital candidiasis - secondary to glycosuria
  • Fournier gangrene - rare but severe
  • Hypovolaemia and hypotension - due to diuretic effect
  • Dehydration
  • DKA
  • Slight increase in LDL and HDL cholesterol
42
Q

How are SGLT2 inhibitors administered?

A

Orally

43
Q

What are the main indications for levothyroxine?

A
  • Hypothyroidism
  • Hypopituitarism
44
Q

What is the mechanism of action of levothyroxine?

A

Manufactured form of thyroxine

45
Q

What are the contraindications and cautions of levothyroxine?

A
  • Some medications can impair absorption, including PPIs, iron tablets and calcium tablets
  • Dose requirements may increase by 25-50% in pregnancy (increased TBG)
46
Q

What are the adverse effects of levothyroxine?

A

Usually occur when dose is too high, resulting in hyperthyroidism - increased appetite, weight loss, increased sweating etc.

47
Q

How is levothyroxine administered?

A

PO before breakfast

48
Q

What are the indications for carbimazole?

A

First line for hyperthyroidism

49
Q

What is the mechanism of action of carbimazole?

A

Inhibition of TPO thereby blocking thyroid hormone synthesis

50
Q

What are the contraindications and cautions of carbimazole?

A
  • Risk of aplasia cutis in early pregnancy
  • Other side effects on foetus when taken in pregnancy:
    • Scalp abnormalities
    • GI abnormalities
    • Choanal and oesophageal atresia
  • Due to the impacts on the foetus propylthiouracil is used in first trimester then switch to CBZ, but try and wait as long as possible to prescribe either and use as low a dose as possible
51
Q

What are the adverse effects of carbimazole?

A
  • Generally well tolerated
  • Incidence of side effects is lower than in PTU
  • 1-5% of patients on ATDs will develop allergic type reactions - rash, urticaria, arthralgia (usually self-limiting)
  • Agranulocytosis - 0.1-0.5% of patients on ATDs
    • ATDs cannot be used again
    • Risk highest in first 6 weeks
    • Warn patient verbally and in writing to stop drug and have urgent FBC checked in the event of fever, oral ulcer or oropharyngeal infection
52
Q

How is carbimazole administered?

A

PO - once daily

53
Q

What is the main indication for propylthiouracil?

A

First line for hyperthyroidism only in first trimester of pregnancy

54
Q

What is the mechanism of action of propylthiouracil?

A

Inhibits DIO1 which decreases conversion of T4 to T3

55
Q

What are the contraindications and cautions of propylthiouracil?

A
  • Risk of aplasia cutis in early pregnancy
  • Risk of liver toxicity to foetus
56
Q

What are the adverse effects of propylthiouracil?

A
  • Allergic type reactions, agranulocytis as above
  • Cholestatic jaundice, increased liver enzymes, 1: 10 000 risk of fulminant hepatic failure → monitor LFTs
57
Q

How is propylthiouracil administered?

A

PO - twice daily

58
Q

What are the main endocrine indications for beta blockers?

A

Immediate symptomatic relief of thyrotoxic symptoms

59
Q

What is the mechanism of action of beta blockers?

A
  • β-adrenoceptor blockade, reduced activity of sympathetic nervous system
  • Propranalol is the drug of choice - additional benefit of inhibition of DIO1
60
Q

What are contraindications and cautions of beta blockers?

A
  • Use with caution in those with asthma
    • Risk of provoking bronchospasm
    • CCBs e.g. diltiazem can be useful instead
61
Q

What are the adverse effects of beta blockers?

A
  • Generally well tolerated
  • Nausea, headaches, tiredness
62
Q

How are beta blockers administered?

A

PO

63
Q

What are the main indications of testosterone?

A

Hypopituitarism resulting in testosterone deficiency

64
Q

What are the contraindications and cautions of testosterone?

A
  • Contraindicated in:
    • Confirmed hormone responsive cancer (e.g. prostate/breast)
    • Possible prostate cancer (e.g. raised PSA, suspicious prostate on DRE)
    • Haematocrit >50%
    • Severe sleep apnoea, heart failure
  • Can cause polycythaemia (cause risk of stroke/MI) - monitor FBC
  • Does not cause prostate cancer but may cause it to grow - monitor PR exam and PSA at start
  • Hepatitis (oral tablets)
65
Q

How is testosterone administered?

A
  • Sustanon - IM every 3-4 weeks)
  • Skin gel (testogel, tostral)
  • Nebido - prolonged IM injection 10-14 weeks
  • Oral tablets (rarely used)
66
Q

What are the main indications of somatostatin analogues?

A
  • GH-secreting pituitary adenoma resulting in acromegaly/gigantism
  • Reduce GH in most patients
  • Shrink tumour but re-expands after treatment cessation
    • 30-50% decrease in tumour size over 6 months to a year
    • Re-expansion of tumour 6 weeks after stopping treatment
  • Can be used before surgery - relieves some symptoms e.g. headache, marginally improves outcome
67
Q

What is the mechanism of action of somatostatin analogues?

A

Selectively act on somatostatin receptor subtypes which are highly expressed on GH-secreting tumours

68
Q

What are the adverse effects of somatostatin analogues?

A
  • Local stinging
  • Short term - flatulence, diarrhoea, abdominal pains
  • Long term - gallstones (inhibit gallbladder contraction)
69
Q

How is somatostatin analogue administered?

A

Given as monthly injections - sandostain LAR (IM), lanreotide (SC), pasireotide LAR (IM)

70
Q

What is an example of a dopamine agonist?

A

Usually cabergoline (Dostinex)

71
Q

What are the main indications of dopamine agonists?

A
  • Prolactinoma - shrinks tumour in most cases so no need for surgery
  • GH-secreting pituitary adenoma resulting in acromegaly/gigantism - works in around 10-15% of patients
    • Increased efficacy if co-secreting prolactin
72
Q

What is the mechanism of action of dopamine agonists?

A

Act on D2 receptors

73
Q

What are the adverse effects of dopamine agonists?

A
  • Nausea and vomiting
  • Low mood/ severe depression
  • May cause fibrosis of heart valves/retroperitoneal fibrosis
    • Seen in patients on higher doses of dopamine agonists used in Parkinson’s but has not been seen in patients with prolactinomas who are on lower doses
74
Q

How are dopamine agonists administered?

A

PO

75
Q

What is an example of GH antagonists?

A

Pegvisoman

76
Q

What are the main indications of GH antagonists?

A
  • GH-secreting pituitary adenoma resulting in acromegaly/gigantism
    • 85% response rate but tumour size does not decrease - occasional small increase in tumour size
    • IGF-1 decreases but serum GH concentrations may increase
    • Last line in therapy as very expensive
77
Q

What is the mechanism of action of GH Antagonists?

A

Binds to GH receptor - blocks GH activity

78
Q

How is GH antagonists administered?

A

SC injection

79
Q

What is the mechanism of action of glucocorticoids?

A
  1. Glucocorticoids bind to the ligand binding domain of the glucocorticoid receptor (GR)
  2. The steroid-bound GR regulates the transcription of genes
  3. As a dimer, the GC-bound GR activates transcription while it represses transcription as a monomer
  4. The DNA sequence of a glucocorticoid response element (GRE) in the promoter dictates activation vs repression of a target gene
    1. If +GRE sequence favours GR dimer formation → target gene expression induced
    2. If nGRE sequence suppresses GR dimer formation → target gene expression repressed by GR as a monomer or by GR tethering other transcription factors, especially NFkappaB
80
Q

What is the influence of genetic polymorphisms for glucocorticoids?

A
  • Mutations/polymorphisms can cause reduced sensitivity to glucocorticoids by altering the protein structure of the GR
  • This results in a compensatory elevation of circulating cortisol and ACTH (but no clinical evidence of hypercortisolism)
  • Excess ACTH → increased adrenal steroid production with increased mineralocorticoid and/or android receptor activation
  • Possible clinical features:
    • Mineralocorticoid excess e.g. hypertension and hypokalaemic alkalosis
    • Androgen excess e.g. precocoius puberty, acne, hirsutism and infertility, male-pattern hair loss, menstrual irregularities and oligo-anovulation in females
    • Clinical spectrum broad - many subjects asymptomatic
81
Q

What is the effect of glucocorticoids on mineralocorticoid receptors?

A
  • Glucocorticoids also activate the mineralocorticoid (aldosterone) receptor
  • Cutaneous adverse effects of glucocorticoids (skin atrophy and delayed wound healing) may be partially triggered by glucocorticoids acting on the mineralocorticoid receptor
  • Co-administration of anti-mineralocorticoids can inhibit glucocorticoid-induced delay in wound healing and glucocorticoid-induced skin atrophy

Endocrine MBCHB (13 decks)

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