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Clinical pharmacology and therapeutics > S5: sex steroids, insulins & oral hypoglycaemics > Flashcards

S5: sex steroids, insulins & oral hypoglycaemics Flashcards

1
Q

How are sex steroids synthesised?

A

Synthesised from cholesterol

Complex series of reactions, with multiple enzymes and intermediates

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2
Q

Describe steroid hormone receptors

A

Classic nuclear receptors
Exerts effects through gene transcription
For oestrogen, there is also a membrane receptor

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3
Q

Outline the major effects of oestradiol, progesterone and testosterone

A

Oestradiol: stimulates growth of the endometrium and breast, stimulates the production of PR
Progesterone: stimulates growth of the endometrium and breast, maintains pregnancy, inhibits production of ER
Testosterone: stimulates male characteristics, increased body hair, deep voice, anabolism, aggression

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4
Q

List actions and side effects of oestrogen

A

Actions: mild anabolic, sodium and water retention, raises HDL lowers LDL, decrease bone resorption, impair glucose tolerance, increase blood coagulability
Side effects: breast tenderness, nausea, vomiting, thromboembolism, endometrial ovarian & breast cancer

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5
Q

List actions and side effects of progesterone

A

Actions: secretory endometrium, anabolic, increases bone mineral density, fluid retention, mood changes & maintains pregnancy
Side effects: weight gain, fluid retention, anabolic, acne, nausea/vomiting, depression, lack of concentration

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6
Q

List actions and side effects of testosterone

A 
Male secondary sex characteristics 
Anabolic 
Acne 
Voice changes 
Increases aggression 
Metabolic – adverse effects on lipid profiles, hence increased risk of atherosclerotic disease
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7
Q

Describe oestrogen pharmacokinetics

A

Natural and synthetic oestrogens well absorbed in the GI tract
Also, readily absorbed from skin and mucous membranes
Metabolised in liver
Excreted in the urine as glucuronides and sulfates

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8
Q

Describe progesterone pharmacokinetics

A

Injected progesterone is bound to albumin with some stored in adipose tissue (allows it to be a LARC)
Metabolised in liver
Excreted in the urine conjugated to glucuronic acid

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9
Q

Describe pharmacokinetic points of oral contraceptives

A

COCP and POP contraceptives are metabolised in the liver by CYP450 enzymes
Therefore, oral contraceptive efficacy is reduced by enzyme inducing drugs (eg. anti-epileptics, St John’s Wort) as they all increase the production of hepatic CYP450

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10
Q

Why is HRT prescribed?

A

Helps with the symptoms of menopause eg. hot flushes/sweats
Helps with osteoporosis
NOT USED FOR HEART DISEASE

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11
Q

List steroids used in HRT

A

Oestradiol
Premarin
Levonorgestrel

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12
Q

List the different routes of administration of HRT

A 
Oral 
Transdermal 
Implant 
Transvaginal 
Nasal
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13
Q

List risks of HRT

A

Unopposed oestrogen – increases risk of developing endometrial and ovarian cancers
Increase risk of VTE
Increased risk of stroke

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14
Q

Describe bisphosphonates

A

Osteoporosis treatment and prophylaxis
Class of drugs that reduce bone turnover – act by controlling osteoclast activity
(other uses = management of other diseases involving bone)

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15
Q

Outline important pharmacokinetic considerations and ADRs of bisphosphonates

A

PK – long biological half-life, poor gut absorption, absorption affected by food
ADRs – upper GI effects, hypocalcaemia

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16
Q

Describe the mechanism of action of mifepristone (RU486)

A

Progesterone (and glucocorticoid) receptor antagonist
Acts as an anti-progesterone
Sensitises the myometrium to prostaglandin-induced contractions
Used for termination of pregnancy

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17
Q

What is a SERM?

A

Selective oestrogen receptor modulator
Distinct in having varying effects in different tissues
Eg. tamoxifen and raloxifene

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18
Q

Describe clomiphene

A

Used in the treatment of anovulation
Competes with oestrogen for ER binding
Leads to ovulation induction through increased production of anterior pituitary hormones

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19
Q

Describe tamoxifen

A

Pro-drug: metabolised in the liver to active derivatives
Tamoxifen active metabolites compete with oestrogen for binding to the ER (selective oestrogen receptor modulator)
Has converse effects in breast tissue and endometrial tissue:
-endometrium: acts as ER agonist
-breast: acts an ER antagonist (binding of the ER following tamoxifen treatment causes cells to arrest the cell cycle)

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20
Q

Describe ulipristal acetate

A

Selective progesterone receptor modulator
When used for emergency contraception, primary mode of action = delay or inhibition of ovulation
(NB: also effective treatment of uterine fibroids)

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21
Q

Describe insulin regulation

A

Protein secreted by B-cells in response to:
-increased glucose
-incretins (GLP-1, GIP)
Inhibited by:
-decreased glucose
-cortisol
Role: decreases hepatic glucose output via inhibition of gluconeogenesis and glycogenolysis (overall increasing glycogen stores), promotes uptake of glucose into tissues (muscle and adipose especially)

22
Q

Describe diagnostic factors of type 1 diabetes mellitus

A

Polyuria, polydipsia, weight loss
Fatigue/lethargy, generalised weakness, blurred vision
Hyperglycaemia – fasting glucose > 6.9mmol/L or random plasma glucose > 11mmol/L
Plasma or urine ketones
HbA1c > 48mmol/mol
NB: single raised plasma glucose without symptoms not sufficient for diagnosis

23
Q

Compare glucose and HbA1c

A

Glucose – immediate measure of glucose levels in blood mmol/L
HbA1c (glycated haemoglobin) – reflects average blood sugar over last 10-12 weeks

24
Q

Describe diabetic ketoacidosis

A

Hyperglycaemia, ketonaemia, acidosis
Precipitating factors: infection, trauma, non adherence to insulin treatment, DDIs
Give iv fluids first, then ivi soluble insulin, then K+ correction in additional fluids

25
Q

Describe the pharmacokinetics of insulins

A

Routine delivery by s.c. injection (protein will be broken down in the digestive tract) – upper arms, things, buttocks, abdomen
Soluble insulin forms hexamers – delays absorption from site of injection (dosing 15-30 min prior to meals often prescribed)
Insulin analogues – changes PK not PD
Rotate sites of administration to limit lipodystrophy

26
Q

Outline the classes of insulin analogues

A

Rapid (eg. insulin aspart) – 10-20 mins onset of action, duration for 3-5 hours
Short (eg. soluble insulin: Humulin S, actrapid) – 30-60 mins onset of action, duration for 5-8 hours
Intermediate (eg. isophane insulin) – 60-120 mins onset of action, duration for 18-24 hours
Long (eg. insulin glargine) – 60-90 mins onset of action, duration for 20-24 hours

27
Q

What are the adverse effects, warnings, contraindications & important drug interactions of insulins?

A

Adverse effects: hypoglycaemia, lipodystrophy
Warnings, contraindications: renal impairment (hypoglycaemia risk)
Important drug interactions: dose needs increasing with systemic steroids, caution with other hypoglycaemic agents

28
Q

What is basal-bolus dosing?

A

Common dosing schedule for young active T1DM patients which provides some flexibility
Rapid acting – bolus
Long acting – basal

29
Q

Describe diabulimia

A

When a type 1 diabetic stops or reduces their insulin to control their weight
Insulin omission in order to lose weight is a clinical feature of anorexia and bulimia (not a recognised medical condition in itself yet)

30
Q

Describe type 2 diabetes

A

Slow progression of disease over many years
Insulin into cells reduced due to cellular resistance associated with obesity
Insulin resistance initially overcome by increased pancreatic insulin secretion but decreased insulin receptors -> decreased GLP-1 secretion in response to oral glucose and response reduced at B-cells -> insulin production reduction

31
Q

Describe management of type 2 diabetes

A

Lifestyle, education
Weight loss
Initially non-insulin therapies, but insulin may form part of treatment plan in poorly managed or later stage disease
Treat comorbidities – part of overall reduction in CVS risk

32
Q

Describe the mechanism of action of biguanides

A

Decreased hepatic glucose production by inhibiting gluconeogenesis
Supress appetite so limit weight gain
Typically first drug offered

33
Q

What are the adverse effects, warnings, contraindications & important drug interactions of biguanides?

A

Adverse effects: GI upset – nausea, vomiting, diarrhoea
Warnings, contraindications: excreted unchanged by kidneys, stop if eGFR < 30mL/min, alcohol intoxication
Important drug interactions: ACEi, diuretics, NSAIDs – drugs that may impair renal function, loop and thiazide like diuretics – increase glucose so can reduce metformin action

34
Q

List examples of biguanides

A

Metformin

35
Q

Describe the mechanism of action of sulfonylureas

A

Stimulate B-cell pancreatic insulin secretion by blocking ATP-dependant K+ channels
Weight gain through anabolic effects of insulin
Typically in combination with other agents

36
Q

What are the adverse effects, warnings, contraindications & important drug interactions of sulfonylureas?

A

Adverse effects: mild GI upset – nausea, vomiting, diarrhoea, hypoglycaemia
Warnings, contraindications: hepatic and renal disease, those at risk of hypoglycaemia
Important drug interactions: other hypoglycaemic agents, loop and thiazide like diuretics increase glucose so can reduce SU action

37
Q

List examples of sulfonylureas

A

Gliclazide

38
Q

Describe the mechanism of action of glitazones

A

Insulin sensitisation in muscle and adipose, decreased hepatic glucose output by activation of PPAR-gamma -> gene transcription
Weight gain because of fat cell differentiation
Used much less frequently than other agents due to side effects

39
Q

What are the adverse effects, warnings, contraindications & important drug interactions of glitazones?

A

Adverse effects: GI upset, fluid retention, fracture risk, bladder cancer
Warnings, contraindications: heart failure because of fluid retention
Important drug interactions: other hypoglycaemic agents

40
Q

List examples of glitazones

A

Pioglitazone

Rosiglitazone

41
Q

Describe the mechanism of action of gliflozins

A

Decreases glucose absorption from tubular filtrate, increases urinary glucose excretion
Competitive reversible inhibition of SGLT-2 in PCT
Modest weight loss, hypoglycaemic risk is low

42
Q

What are the adverse effects, warnings, contraindications & important drug interactions of gliflozins?

A

Adverse effects: UTI and genital infection, thirst and polyuria
Warnings, contraindications: hypovolaemia – possible hypotension
Important drug interactions: antihypertensive and other hypoglycaemic agents

43
Q

List examples of gliflozins

A

Dapagliflozin

Canagliflozin

44
Q

Outline physiological effects of GLP-1

A

Pancreas – increased insulin secretion, decreased glucagon secretion, increased insulin biosynthesis
Brain – decreased food intake through increased satiety
Liver (indirect) – decreased glucose production
Stomach – decreased gastric emptying
Muscle (indirect) – increased glucose uptake

45
Q

Describe the mechanism of action of gliptins

A

Prevent incretin degradation – increased [plasma] incretin
Glucose dependent – does not stimulate insulin secretion at normal blood glucose -> lower hypoglycaemic risk
Supress appetite ~ weight neutral

46
Q

What are the adverse effects, warnings, contraindications & important drug interactions of gliptins?

A

Adverse effects: GI upset, small pancreatitis risk
Warnings, contraindications: avoid in pregnancy, history of pancreatitis
Important drug interactions: other hypoglycaemic agents, thiazide like and loop diuretics – increase glucose can oppose gliptin action

47
Q

List examples of gliptins

A

Sitagliptin

Saxagliptin

48
Q

Describe the mechanism of action of glucagon-like peptide-1 receptor agonists (incretin mimetics)

A

Subcutaneous injection
Increased glucose dependant synthesis of insulin secretion from B-cells
Activate GLP-1 receptor – resistant to degradation by DPP-4
Promote satiety – possible weight loss

49
Q

What are the adverse effects, warnings, contraindications & important drug interactions of incretin mimetics?

A

Adverse effects: GI upset, decreased appetite with weight loss
Warnings, contraindications: renal impairment
Important drug interactions: other hypoglycaemic agents

50
Q

List examples of incretin mimetics

A

Exenatide

Liraglutide

51
Q

Compare primary, secondary and population interventions for CVD

A

Primary prevention – targeting those at high risk of developing CVD
Secondary prevention – people who already have CVD/had a major CV event
Population interventions – small change in average risk can have a big impact -> public health promotion and campaigns

Clinical pharmacology and therapeutics (14 decks)

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