Steroids Flashcards
What are the different types of oestrogen? What are some common ADRs of oestrogen?
Estrone, estradiol, estriol
note: some old HRT drugs contain oestrogen compounds derived from horses
note: combined oral contraceptive pill contains ethinyl estradiol
note: diethylstilbestrol (DES) used to be used to treat vaginitis (but now known to be associated with vaginal cancer)
ADRs:
- breast tenderness
- nausea & vomiting
- endometrial hyperplasia & cancer
- reduced bone resorption (therefore protective against osteoporosis)
- reduced glucose tolerance
- increased coagulability
- Na+ & water retention
What are some different types of progestogen? What are some common ADRs of progestogens?
Progesterone, medroxyprogesterone acetate
ADRs:
- nausea & vomiting (less so than oestrogen)
- irritability, depression, PMS (latter half of menstrual cycle)
- fluid retention
- increased bone mineral density
What are some different drugs containing testosterone? What are some common ADRs associated with testosterone?
Levonogestrel (morning after pill), desogestrel
ADRs:
- virilisation inc. acne, hirsutism
Describe how steroids are absorbed, distributed, metabolised, and excreted.
Transported through cell membrane by binding to ligand, then bind to nuclear receptors to exert their effect
Transported bound to sex hormone binding globulin and albumin
note: exception is progesterone (which is bound to transcortin)
Metabolised in the liver
note: progesterone almost completely metabolised in the first pass effect)
Metabolites excreted in urine as glucuronides & sulfates
Describe the contents and dosing regimens of the combined oral contraceptive pill.
Oestrogen AND progestogen
Dosing timings:
- MONOPHASIC = constant dose of oestrogen & progestogen for 21 days
- TRIPHASIC = doses altered at different phases of the cycle, but drug is still taken for 21 days
- EVERY DAY = 21 active doses + 7 placebo pills (ferrous sulfate)
note: no difference in efficacy between regimens
Dose ranges:
- 20mg/day
- 30mg/day
- 35mg/day
- 50mg/day
note: little difference in efficacy between doses, so would usually prescribe the lowest possible dose to reduce the risk of ADRs
Describe the mode of action of the combined oral contraceptive pill.
Oestrogen = inhibition of FSH & LH —> suppression of ovulation (main mode of action)
Progestogen = increased thickness of cervical mucus & reduced thickness of endometrium
What are some of the common ADRs associated with the combined oral contraceptive pill?
Metabolised by CYP450 therefore affected by CYP450 inhibitors and inducers
note: also affected by broad spectrum antibiotics due to alteration of intestinal flora reduced enterohepatic recycling of steroids
ADRs:
- increased risk of venous thromboembolism (2nd generation COCPs have 1.5/1000 risk, 4th generation COCPs have a larger risk)
- increased risk of MI
- hypertension
- headaches (note: increased risk of stroke in women with focal migraines)
- increased incidence of gallstones
- reduced glucose tolerance
- weight gain
Describe the administration and mode of action of the progestogen-only pill (POP/”minipill”).
Administration:
- minipill = levonogestrel, desogestrel
- depot provera (IM every 3 months) = medroxy progesterone acetate (MPA) (increased risk of osteoporosis)
- Implanon implant & vaginal ring = etonogestrel
Mode of action:
- increased thickness of cervical mucus —> reduces sperm penetration
- reduced thickness of endometrium —> cannot support implantation
note: progestogen implants (IM, SC, IUD) can be used to provide contraception for 3 months-5yrs
Describe the different options for emergency contraceptives and the difference in time frames.
Up to 72hrs: levonorgestrel 1.5mg (high dose)
- unknown mechanism of action (suppression of ovulation?)
Up to 120hrs:
- ullipristal acetate 30mg (progesterone receptor modulator)
- copper IUD (toxic to sperm)
Outline the indications and dosing regimens of post-menopausal HRT.
Indications:
- relieving symptoms of menopause e.g. hot flushes, night sweats (PRIMARY INDICATION)
- protective against osteoporosis
- protective against heart disease? (but should NOT be prescribed for this purpose)
Dosing regimens:
- usually oestrogen + progestogen (progestogen to reduce the risk of endometrial hyperplasia)
- oestrogen-only can be used in hysterectomy
- continuous combined (i.e. monophasic) —> usually don’t bleed
- cyclical/sequential (fixed dose of oestrogen & variable dose of progestogen given monthly or 3 monthly) —> bleed, but have reduced risk of endometrial hyperplasia
- oral or transdermal administration
- tibalone (oestrogen + progestogen + androgen; indicated for short-term oestrogen deficiency)
What are the common ADRs associated with HRT?
- increased risk of endometrial, ovarian, and oestrogen-positive breast cancer (unopposed action of oestrogen)
- increased risk of ischaemic heart disease & stroke (particularly in the 4th year of treatment)
- increased risk of venous thromboembolism
- uterine bleeding
- increased risk of migraines
- increased risk of diabetes
- increased risk of gallbladder disease
Give some examples of anti-oestrogens, their mode of action, and their indications.
Weak oestrogens which block oestrogen receptors
Clomiphene inhibits oestrogen binding to the ant. pituitary —> inhibits negative feedback —> increased GnRH —> increased FSH & LH —> ovulation
(used as fertility treatment - anovulation)
Tamoxifen used to treat oestrogen-positive breast cancer AND induction of ovulation in infertility
- increased risk of endometrial cancer
- hot flushes
- menorrhoea
- vaginal discharge
- GI disturbances
- headache
- light headedness
- increased risk of thromboembolism
Alternative to tamoxifen is raloxifene (reduced risk of endometrial cancer and protects against osteoporosis)
Give an example of an anti-progestogens, its mode of action, and its indication.
Mifepristone
Partial agonist to progesterone receptor —> inhibits action of progesterone
Sensitises uterus to prostaglandins —> reduces placental support
Indicated for termination of early pregnancy (+ prostaglandins) and for induction of labour (not in the UK)
Give an example of an anti-androgen, its mode of action, and its indications.
Cyproterone
Partial agonist to progesterone receptors —> competes with dihydrotestosterone
Used in combined oral contraceptive pill and to treat hirsutism
Give an example of a selective oestrogen receptor modulator, its ADRs and its protective effects.
Raloxifene
- protective against osteoporosis (but not first line treatment)
- no proliferative effects on endometrium or breast (no increased risk of cancer)
ADRs:
- hot flushes
Give an approximate range of normal values of total cholesterol, fasting LDLs, and HDL.
Total cholesterol = 5.0mmol/l or less (200mg/dl or less)
Fasting LDLs = 3.0mmol/l or less
HDLs = 1.2mmol/l or above
Give some examples of studies which support the relationship between cholesterol and cardiovascular risk and mortality.
Framingham study (cholesterol and CVD risk)
Seven Countries study (cholesterol and mortality)
What are some pro-atherogenic effects of oxidised LDL?
- inhibits macrophage motility
- induces T cell activation & vascular smooth muscle cell proliferation
- toxic to endothelial cells
- enhances platelet aggregation
What are the indications and mode of action of statins?
Indications:
- reduce risk of CVD e.g. diabetes, history of CVD
- familial hypercholesterolaemia (~1/5 of population)
Mode of action:
- inhibits HMG-CoA reductase (in hepatocytes) —> reduced conversion of acetyl-CoA to cholesterol —> increased synthesis of LDL receptors —> increased uptake of LDLs —> reduced [LDL]serum
- increased clearance of IDLs & LDLs
- decreased production of VLDLs & LDLs
What are some of the common ADRs associated with statins?
- increased transaminases (note: rapidly reversible when statins are ceased, no evidence of chronic liver disease) —> check LFTs 3 months after starting statins
- myopathy (0.01%) (diffuse muscle pain & increased creatine kinase - only measure if symptomatic) - usually seen with high dose or due to interactions with other drugs (some of which are CYP inhibitors) e.g. cyclosporin, gemfibrozil (fibrate), erythromycin, niacin (solution is to switch/stop drugs)
- GI complaints
- arthralgias
- headaches
Give some examples of studies which support the prescribing of statins for reducing the risk of CVD & mortality.
WOSCOPS & CARE = statin better than placebo for reducing non-fatal MIs & CHD death
LIPID = statin better than placebo for reducing the cumulative risk of death from CHD
AFCAPS/TexCAPS = statin better than placebo for reducing the risk of fatal and non-fatal MIs, sudden cardiac death, and unstable angina
Give some examples of statins, contrasting their duration of action.
Simvastatin (short-acting, half life = ~1-4hrs, therefore given at night (peak cholesterol is in the morning)
note: 10mg od simvastatin is available OTC
Pravastatin
Fluvastatin
Atorvastatin & Rosuvastatin (long-acting, half life = ~20hrs, therefore can be taken any time of day)
note: cerivastatin withdrawn due to increased mortality when combined with a fibrate (gemfibrazil inhibits transport & statin glucuronidation —> increased risk of myopathy)
What is the current guidance on prescribing statins?
Primary prevention of CVD: Offer atorvastatin (20mg/day) to those who have a 10%+ risk of CVD within 10yrs
Secondary prevention of CVD: Offer atorvastatin (up to 80mg/day) to those who present with CVD, aiming for a 40%+ reduction in LDL cholesterol (can increase dose, revisit lifestyle modification, or add other drugs to achieve this)
note: doubling dose of statin —> ~6% reduction in LDLs
What are the indications & mode of action of fibrates/fibric acid derivatives?
Indications:
- adjunct to diet modification
- hypertriglyceridaemia
- combined hyperlipidaemia & low HDLs who do not respond to nicotinic acid
Mode of action: act on peroxisome proliferator-activated receptor-alpha
- reduced triglyceride production
- increased fatty acid uptake & oxidation (by inhibiting lipoprotein lipase)
- increased LDL particle size (causing ~10%-20% reduction in LDLs)
- HDL-cholesterol level (15%-25%)
- direct vascular effects
What are some common ADRs associated with fibrates/fibric acid derivatives? When are fibrates/fibric acid derivatives contraindicated?
ADRs:
- GI upset
- cholelithiasis
- myositis (+ statin —> increased risk of myopathy & rhabdomyolysis; not due to CYP450)
- abnormal LFTs
Contraindications:
- hepatic/renal dysfunction
- gallbladder disease
Give some examples of studies which support the prescribing of fibrates/fibric acid derivatives.
Helsinki Heart Study
LOCAT
BECAIT
VA-HIT
BIP
What is the mode of action of nicotinic acid/niacin?
- inhibition of lipoprotein (a) synthesis
- reduced VLDLs & increased HDLs (at high doses)
- reduction in coronary events
What are some of the common ADRs associated with nicotinic acid/niacin? When is nicotinic acid/niacin contraindicated?
ADRs:
- flushing, itching, headache (reduce by adding low dose aspirin)
- hepatoxicity
- peptic ulcer disease/activation of peptic ulcers
- hyperglycaemia & reduced insulin sensitivity
Contraindications:
- active liver disease/unexplained LFTs elevation
- peptic ulcer disease
Give an example of a study supporting the prescribing of nicotinic acid/niacin.
Coronary Drug Project
Give an example and describe the mode of action of cholesterol-lipase inhibitors.
Ezetimibe (10mg —> 15%-20% reduction in LDLs, + statin —> further 20% reduction in LDLs)
- blocks specific cholesterol transport protein —> selective inhibition of intestinal cholesterol absorption —> reduced intestinal delivery of cholesterol to liver
- increased expression of hepatic LDL receptors
- reduced cholesterol content of atherogenic particles
note: drug circulates enterohepatically, so agent is delivered back to the site of action and there is limited systemic exposure
What are some of the common ADRs associated with cholesterol lipase inhibitors?
- headache
- abdominal pain
- diarrhoea
Give some examples of non-prescribed drugs which may play a role in managing cholesterol.
Resins
Omega-3 fatty acids
Plant sterols (compete with cholesterol for absorption)
What are some dietary factors which positively and negatively affect the level of cholesterol?
Positive:
- fish oils
- fibre
- vitamins C & E
- alcohol (increases HDLs)
Negative:
- dietary cholesterol/fat
- alcohol (increases triglycerides)
Outline the synthesis of steroids from cholesterol.
Cholesterol converted to pregnenolone via ACTH
Pregnenolone converted into different types of steroid:
- progesterone (which can be converted into aldosterone, or cortisol via 21-hydroxylase - absent in congenital adrenal hyperplasia)
- testosterone (which can be converted into oestrogen, or oestradiol via aromatase - inhibited using aromatase inhibitor drugs)
What are the metabolic actions of glucocorticoids?
- stimulate glycogenolysis & gluconeogenesis —> hyperglycaemia
- proteinolysis
- lipolysis at low conc., lipid deposition at high conc.
- redistribution of fat
Give some examples of ADRs associated with glucocorticoids.
- osteoporosis (reduced calcium absorption in gut, inhibition of osteoblast formation, osteoclast proliferation, reduced sex steroid production)
- cataracts
- avascular necrosis
- peptic ulcers
- increased risk of infection
- hypertension
- diabetes
- impaired growth
- skin atrophy
- corneal damage
- Cushingoid features
- psychoactive effects
What are the signs and symptoms of glucocorticoid deficiency and excess?
DEFICIENCY:
- hypotension
- nausea
- weight loss
- hypoglycaemia
EXCESS:
- Cushingoid features
- hyperglycaemia
- weight gain
- increased appetite
- hypertension
Give some examples of ADRs associated with mineralocorticoids.
- fluid retention
- hypertension
- hypokalaemia
What are the signs and symptoms of mineralocorticoid deficiency and excess?
DEFICIENCY:
- hyperkalaemia
- hypotension
- dehydration
- hyponatraemia
EXCESS:
- hypernatraemia
- hypertension
- hypokalaemia
Outline the pharmacokinetics of corticosteroids. What effect do they have on the immune system?
Oral steroids all have similar bioavailabilities
Hepatic & renal clearance (clearance decreases with age)
Effects on immune system:
- inhibition of T and B-cells
- reduced transcription of cytokines
- reduced expression of cell adhesion molecules
- reduced phagocytic function
- immunosuppression
- reduced inflammation
What are the key methods of contraception?
Abstinence
Barrier method
Oral contraceptive pill (COCP and POP)
IUD (copper; risk of PID on insertion - take swab) and IUS (Mirena - progesterone)
Implant
How do oestrogens provide contraception? How do progestogens provide contraception?
Oestrogens: inhibit production of FSH & LH —> suppresses ovulation and maintains endometrium (risk of endometrial hyperplasia)
Progestogens:
- increased thickness of cervical mucus —> reduced sperm penetration and toxic to sperm
- reduced thickness of endometrium —> cannot support implantation
What initial assessments should be undertaken when prescribing the COCP?
Sexual history/activity (does not protect against STIs)
- ?sexual health screening
Medical history:
- CVD
- DVT
- BRACA
- hypertension
Family history:
- CVD
- DVT
- BRACA
Monitor BP and weight (increased risk of CVD and DVT)
Contra-indications:
- rifampicin (reduced efficacy of COCP)
- history of DVT
- migraine + aura
- gallstones
What advice should be given if someone misses their contraceptive pills?
Miss 1 pill = take next one as soon as you remember, then resume normal pill taking
Miss 2 pills = take next as soon as you remember, then resume normal pill taking, abstain from sex or use additional methods of contraception
How should people be counselled when considering HRT? What are the baseline investigations appropriate when prescribing HRT?
Benefits of treating symptoms compared to increased risk of IHD, DVT, endometrial cancer, breast cancer, gallbladder disease, ?endometrial cancer
Modify lifestyle to reduce symptoms?
- exercise
- reduce weight
- sleep in cooler room
- wear lighter clothing
Follow-up at 3 months, then annually
- BP
- weight
- ?bleeding
- cervical cancer screening
- breast and cervical exams
Refer if treatment is unsuccessful/red flags e.g. unexplained bleeding
How do different lipid-lowering drugs affect LDLs, HDLs, and triglycerides?
Statins: reduce LDLs, increase HDLs
Ezetimibe: reduce LDLs (reduce intestinal delivery to liver), increase HDLs (increase expression of hepatic LDL receptors)
Niacin: reduce VLDLs and increase HDLs
Omega-3-fatty acids: 20%-30% reduction in triglycerides
Fibrate: reduce LDLs by 10%-20%, increase HDLs, reduce triglycerides
Contrast the structure and qualities of simvastatin and rosuvastatin.
Simvastatin = lipophilic, fungal
Rosuvastatin = hydrophilic, synthetic
