S5: sex steroids, insulins & oral hypoglycaemics Flashcards
How are sex steroids synthesised?
Synthesised from cholesterol
Complex series of reactions, with multiple enzymes and intermediates
Describe steroid hormone receptors
Classic nuclear receptors
Exerts effects through gene transcription
For oestrogen, there is also a membrane receptor
Outline the major effects of oestradiol, progesterone and testosterone
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
List actions and side effects of oestrogen
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
List actions and side effects of progesterone
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
List actions and side effects of testosterone
Male secondary sex characteristics Anabolic Acne Voice changes Increases aggression Metabolic – adverse effects on lipid profiles, hence increased risk of atherosclerotic disease
Describe oestrogen pharmacokinetics
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
Describe progesterone pharmacokinetics
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
Describe pharmacokinetic points of oral contraceptives
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
Why is HRT prescribed?
Helps with the symptoms of menopause eg. hot flushes/sweats
Helps with osteoporosis
NOT USED FOR HEART DISEASE
List steroids used in HRT
Oestradiol
Premarin
Levonorgestrel
List the different routes of administration of HRT
Oral Transdermal Implant Transvaginal Nasal
List risks of HRT
Unopposed oestrogen – increases risk of developing endometrial and ovarian cancers
Increase risk of VTE
Increased risk of stroke
Describe bisphosphonates
Osteoporosis treatment and prophylaxis
Class of drugs that reduce bone turnover – act by controlling osteoclast activity
(other uses = management of other diseases involving bone)
Outline important pharmacokinetic considerations and ADRs of bisphosphonates
PK – long biological half-life, poor gut absorption, absorption affected by food
ADRs – upper GI effects, hypocalcaemia
Describe the mechanism of action of mifepristone (RU486)
Progesterone (and glucocorticoid) receptor antagonist
Acts as an anti-progesterone
Sensitises the myometrium to prostaglandin-induced contractions
Used for termination of pregnancy
What is a SERM?
Selective oestrogen receptor modulator
Distinct in having varying effects in different tissues
Eg. tamoxifen and raloxifene
Describe clomiphene
Used in the treatment of anovulation
Competes with oestrogen for ER binding
Leads to ovulation induction through increased production of anterior pituitary hormones
Describe tamoxifen
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)
Describe ulipristal acetate
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)
Describe insulin regulation
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)
Describe diagnostic factors of type 1 diabetes mellitus
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
Compare glucose and HbA1c
Glucose – immediate measure of glucose levels in blood mmol/L
HbA1c (glycated haemoglobin) – reflects average blood sugar over last 10-12 weeks
Describe diabetic ketoacidosis
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
Describe the pharmacokinetics of insulins
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
Outline the classes of insulin analogues
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
What are the adverse effects, warnings, contraindications & important drug interactions of insulins?
Adverse effects: hypoglycaemia, lipodystrophy
Warnings, contraindications: renal impairment (hypoglycaemia risk)
Important drug interactions: dose needs increasing with systemic steroids, caution with other hypoglycaemic agents
What is basal-bolus dosing?
Common dosing schedule for young active T1DM patients which provides some flexibility
Rapid acting – bolus
Long acting – basal
Describe diabulimia
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)
Describe type 2 diabetes
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
Describe management of type 2 diabetes
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
Describe the mechanism of action of biguanides
Decreased hepatic glucose production by inhibiting gluconeogenesis
Supress appetite so limit weight gain
Typically first drug offered
What are the adverse effects, warnings, contraindications & important drug interactions of biguanides?
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
List examples of biguanides
Metformin
Describe the mechanism of action of sulfonylureas
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
What are the adverse effects, warnings, contraindications & important drug interactions of sulfonylureas?
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
List examples of sulfonylureas
Gliclazide
Describe the mechanism of action of glitazones
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
What are the adverse effects, warnings, contraindications & important drug interactions of glitazones?
Adverse effects: GI upset, fluid retention, fracture risk, bladder cancer
Warnings, contraindications: heart failure because of fluid retention
Important drug interactions: other hypoglycaemic agents
List examples of glitazones
Pioglitazone
Rosiglitazone
Describe the mechanism of action of gliflozins
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
What are the adverse effects, warnings, contraindications & important drug interactions of gliflozins?
Adverse effects: UTI and genital infection, thirst and polyuria
Warnings, contraindications: hypovolaemia – possible hypotension
Important drug interactions: antihypertensive and other hypoglycaemic agents
List examples of gliflozins
Dapagliflozin
Canagliflozin
Outline physiological effects of GLP-1
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
Describe the mechanism of action of gliptins
Prevent incretin degradation – increased [plasma] incretin
Glucose dependent – does not stimulate insulin secretion at normal blood glucose -> lower hypoglycaemic risk
Supress appetite ~ weight neutral
What are the adverse effects, warnings, contraindications & important drug interactions of gliptins?
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
List examples of gliptins
Sitagliptin
Saxagliptin
Describe the mechanism of action of glucagon-like peptide-1 receptor agonists (incretin mimetics)
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
What are the adverse effects, warnings, contraindications & important drug interactions of incretin mimetics?
Adverse effects: GI upset, decreased appetite with weight loss
Warnings, contraindications: renal impairment
Important drug interactions: other hypoglycaemic agents
List examples of incretin mimetics
Exenatide
Liraglutide
Compare primary, secondary and population interventions for CVD
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
