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Pharmacology & Therapeutics > Steroids > Flashcards

Steroids Flashcards

1
Q

What are the different types of oestrogen? What are some common ADRs of oestrogen?

A

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
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2
Q

What are some different types of progestogen? What are some common ADRs of progestogens?

A

Progesterone, medroxyprogesterone acetate

ADRs:

  • nausea & vomiting (less so than oestrogen)
  • irritability, depression, PMS (latter half of menstrual cycle)
  • fluid retention
  • increased bone mineral density
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3
Q

What are some different drugs containing testosterone? What are some common ADRs associated with testosterone?

A

Levonogestrel (morning after pill), desogestrel

ADRs:
- virilisation inc. acne, hirsutism

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4
Q

Describe how steroids are absorbed, distributed, metabolised, and excreted.

A

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

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5
Q

Describe the contents and dosing regimens of the combined oral contraceptive pill.

A

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

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6
Q

Describe the mode of action of the combined oral contraceptive pill.

A

Oestrogen = inhibition of FSH & LH —> suppression of ovulation (main mode of action)

Progestogen = increased thickness of cervical mucus & reduced thickness of endometrium

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7
Q

What are some of the common ADRs associated with the combined oral contraceptive pill?

A

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
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8
Q

Describe the administration and mode of action of the progestogen-only pill (POP/”minipill”).

A

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

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9
Q

Describe the different options for emergency contraceptives and the difference in time frames.

A

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)
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10
Q

Outline the indications and dosing regimens of post-menopausal HRT.

A

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)
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11
Q

What are the common ADRs associated with HRT?

A
  • 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
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12
Q

Give some examples of anti-oestrogens, their mode of action, and their indications.

A

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)

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13
Q

Give an example of an anti-progestogens, its mode of action, and its indication.

A

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)

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14
Q

Give an example of an anti-androgen, its mode of action, and its indications.

A

Cyproterone

Partial agonist to progesterone receptors —> competes with dihydrotestosterone

Used in combined oral contraceptive pill and to treat hirsutism

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15
Q

Give an example of a selective oestrogen receptor modulator, its ADRs and its protective effects.

A

Raloxifene

  • protective against osteoporosis (but not first line treatment)
  • no proliferative effects on endometrium or breast (no increased risk of cancer)

ADRs:
- hot flushes

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16
Q

Give an approximate range of normal values of total cholesterol, fasting LDLs, and HDL.

A

Total cholesterol = 5.0mmol/l or less (200mg/dl or less)

Fasting LDLs = 3.0mmol/l or less

HDLs = 1.2mmol/l or above

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17
Q

Give some examples of studies which support the relationship between cholesterol and cardiovascular risk and mortality.

A

Framingham study (cholesterol and CVD risk)

Seven Countries study (cholesterol and mortality)

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18
Q

What are some pro-atherogenic effects of oxidised LDL?

A
  • inhibits macrophage motility
  • induces T cell activation & vascular smooth muscle cell proliferation
  • toxic to endothelial cells
  • enhances platelet aggregation
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19
Q

What are the indications and mode of action of statins?

A

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
20
Q

What are some of the common ADRs associated with statins?

A
  • 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
21
Q

Give some examples of studies which support the prescribing of statins for reducing the risk of CVD & mortality.

A

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

22
Q

Give some examples of statins, contrasting their duration of action.

A

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)

23
Q

What is the current guidance on prescribing statins?

A 
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

24
Q

What are the indications & mode of action of fibrates/fibric acid derivatives?

A

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
25
Q

What are some common ADRs associated with fibrates/fibric acid derivatives? When are fibrates/fibric acid derivatives contraindicated?

A

ADRs:

  • GI upset
  • cholelithiasis
  • myositis (+ statin —> increased risk of myopathy & rhabdomyolysis; not due to CYP450)
  • abnormal LFTs

Contraindications:

  • hepatic/renal dysfunction
  • gallbladder disease
26
Q

Give some examples of studies which support the prescribing of fibrates/fibric acid derivatives.

A

Helsinki Heart Study

LOCAT

BECAIT

VA-HIT

BIP

27
Q

What is the mode of action of nicotinic acid/niacin?

A
  • inhibition of lipoprotein (a) synthesis
  • reduced VLDLs & increased HDLs (at high doses)
  • reduction in coronary events
28
Q

What are some of the common ADRs associated with nicotinic acid/niacin? When is nicotinic acid/niacin contraindicated?

A

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
29
Q

Give an example of a study supporting the prescribing of nicotinic acid/niacin.

A

Coronary Drug Project

30
Q

Give an example and describe the mode of action of cholesterol-lipase inhibitors.

A

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
31
Q

What are some of the common ADRs associated with cholesterol lipase inhibitors?

A
  • headache
  • abdominal pain
  • diarrhoea
32
Q

Give some examples of non-prescribed drugs which may play a role in managing cholesterol.

A

Resins

Omega-3 fatty acids

Plant sterols (compete with cholesterol for absorption)

33
Q

What are some dietary factors which positively and negatively affect the level of cholesterol?

A

Positive:

  • fish oils
  • fibre
  • vitamins C & E
  • alcohol (increases HDLs)

Negative:

  • dietary cholesterol/fat
  • alcohol (increases triglycerides)
34
Q

Outline the synthesis of steroids from cholesterol.

A

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)
35
Q

What are the metabolic actions of glucocorticoids?

A
  • stimulate glycogenolysis & gluconeogenesis —> hyperglycaemia
  • proteinolysis
  • lipolysis at low conc., lipid deposition at high conc.
  • redistribution of fat
36
Q

Give some examples of ADRs associated with glucocorticoids.

A
  • 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
37
Q

What are the signs and symptoms of glucocorticoid deficiency and excess?

A

DEFICIENCY:

  • hypotension
  • nausea
  • weight loss
  • hypoglycaemia

EXCESS:

  • Cushingoid features
  • hyperglycaemia
  • weight gain
  • increased appetite
  • hypertension
38
Q

Give some examples of ADRs associated with mineralocorticoids.

A
  • fluid retention
  • hypertension
  • hypokalaemia
39
Q

What are the signs and symptoms of mineralocorticoid deficiency and excess?

A

DEFICIENCY:

  • hyperkalaemia
  • hypotension
  • dehydration
  • hyponatraemia

EXCESS:

  • hypernatraemia
  • hypertension
  • hypokalaemia
40
Q

Outline the pharmacokinetics of corticosteroids. What effect do they have on the immune system?

A

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
41
Q

What are the key methods of contraception?

A

Abstinence

Barrier method

Oral contraceptive pill (COCP and POP)

IUD (copper; risk of PID on insertion - take swab) and IUS (Mirena - progesterone)

Implant

42
Q

How do oestrogens provide contraception? How do progestogens provide contraception?

A

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
43
Q

What initial assessments should be undertaken when prescribing the COCP?

A

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
44
Q

What advice should be given if someone misses their contraceptive pills?

A

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

45
Q

How should people be counselled when considering HRT? What are the baseline investigations appropriate when prescribing HRT?

A

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

46
Q

How do different lipid-lowering drugs affect LDLs, HDLs, and triglycerides?

A

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

47
Q

Contrast the structure and qualities of simvastatin and rosuvastatin.

A

Simvastatin = lipophilic, fungal

Rosuvastatin = hydrophilic, synthetic

Pharmacology & Therapeutics (18 decks)

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