S5: sex steroids, insulins & oral hypoglycaemics

Question 1

How are sex steroids synthesised?

Answer 1

Synthesised from cholesterol

Complex series of reactions, with multiple enzymes and intermediates

Question 2

Describe steroid hormone receptors

Answer 2

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

Question 3

Outline the major effects of oestradiol, progesterone and testosterone

Answer 3

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

Question 4

List actions and side effects of oestrogen

Answer 4

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

Question 5

List actions and side effects of progesterone

Answer 5

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

Question 6

List actions and side effects of testosterone

Answer 6

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

Question 7

Describe oestrogen pharmacokinetics

Answer 7

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

Question 8

Describe progesterone pharmacokinetics

Answer 8

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

Question 9

Describe pharmacokinetic points of oral contraceptives

Answer 9

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

Question 10

Why is HRT prescribed?

Answer 10

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

Question 11

List steroids used in HRT

Answer 11

Oestradiol
Premarin
Levonorgestrel

Question 12

List the different routes of administration of HRT

Answer 12

Oral 
Transdermal 
Implant 
Transvaginal 
Nasal

Question 13

List risks of HRT

Answer 13

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

Question 14

Describe bisphosphonates

Answer 14

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

Question 15

Outline important pharmacokinetic considerations and ADRs of bisphosphonates

Answer 15

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

Question 16

Describe the mechanism of action of mifepristone (RU486)

Answer 16

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

Question 17

What is a SERM?

Answer 17

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

Question 18

Describe clomiphene

Answer 18

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

Question 19

Describe tamoxifen

Answer 19

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)

Question 20

Describe ulipristal acetate

Answer 20

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)

Question 21

Describe insulin regulation

Answer 21

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)

Question 22

Describe diagnostic factors of type 1 diabetes mellitus

Answer 22

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

Question 23

Compare glucose and HbA1c

Answer 23

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

Question 24

Describe diabetic ketoacidosis

Answer 24

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

Question 25

Describe the pharmacokinetics of insulins

Answer 25

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

Question 26

Outline the classes of insulin analogues

Answer 26

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

Question 27

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

Answer 27

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

Question 28

What is basal-bolus dosing?

Answer 28

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

Question 29

Describe diabulimia

Answer 29

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)

Question 30

Describe type 2 diabetes

Answer 30

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

Question 31

Describe management of type 2 diabetes

Answer 31

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

Question 32

Describe the mechanism of action of biguanides

Answer 32

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

Question 33

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

Answer 33

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

Question 34

List examples of biguanides

Answer 34

Metformin

Question 35

Describe the mechanism of action of sulfonylureas

Answer 35

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

Question 36

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

Answer 36

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

Question 37

List examples of sulfonylureas

Answer 37

Gliclazide

Question 38

Describe the mechanism of action of glitazones

Answer 38

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

Question 39

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

Answer 39

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

Question 40

List examples of glitazones

Answer 40

Pioglitazone | Rosiglitazone

Question 41

Describe the mechanism of action of gliflozins

Answer 41

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

Question 42

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

Answer 42

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

Question 43

List examples of gliflozins

Answer 43

Dapagliflozin | Canagliflozin

Question 44

Outline physiological effects of GLP-1

Answer 44

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

Question 45

Describe the mechanism of action of gliptins

Answer 45

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

Question 46

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

Answer 46

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

Question 47

List examples of gliptins

Answer 47

Sitagliptin | Saxagliptin

Question 48

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

Answer 48

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

Question 49

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

Answer 49

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

Question 50

List examples of incretin mimetics

Answer 50

Exenatide | Liraglutide

Question 51

Compare primary, secondary and population interventions for CVD

Answer 51

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