Week 4: Steroid Hormone Pharmacology Flashcards
Steroids are transported bound to…
bound to albumin and sex hormone-binding globulin (SHBG), except progestogens which binds transcortin.
Describe the content of The Combined Oral Contraceptive Pill (COCP). How does it work?
The COCP includes a variety of synthetic oestrogen doses in combination with a 1st-4th generation progestogen. This supresses ovulation by inhibiting FSH and LH and has an adverse effect on cervical mucous and the endometrium. The efficacy of COCP is due to its multiple sites and actions throughout the endocrine and reproductive tract.
What are the different regimes for the COCP?
Monophasic: the dose of oestrogen and progestogen is constant in the active tablets (majority of pills), taken for 21 days followed by 7 day break
Phasic: the amount of oestrogen and progestogen varies through the cycle. This may be biphasic (two different doses) or triphasic (three different doses) taken over 21 days with 7 day break.
Everyday: in addition to 21 days of oestrogen and progestogen 7 placebo pills are also provided.
COCP adverse effects
The COCP is largely safe, although relatively minor adverse effects are common, e.g. weight gain.
Serious ADRs are rare eg. thromboembolism in second generation pills: 1.5/1000 users vs 1/1000 non pregnant control vs 6/1000 pregnant non-users per year. Increased blood pressure is an ADR in a small percentage of women.
COCP drug interactions
COCPs undergo metabolism by both Phase I and II hepatic pathways and are affected by CYP inducers including rifampicin, carbamezepine and St John’s Wort. Use of broad-spectrum antibiotics can result in reduced efficacy due to effects on intestinal flora. These flora play a part enterohepatic recycling and as they decrease so does the amount of drug re-entering the systemic circulation. The risk of COCP related cardiovascular events is much higher in smokers
How does the progestogen only pill and progestogen implants act?
The POP or ‘mini pill’ is a progestogen only pill whose mode of action differs from the COCP. It primarily acts to thicken cervical mucus, secondarily hindering ovulation and endometrial implantation. Efficacy is about 96-98% and is usually offered to women for whom the COCP is contraindicated. A number of progestogen implants (IM, SC or as IUD) provide long term contraception for between 3 months and 5 yrs.
How do Selective oestrogen receptor modulators (SERMs) act? Outline some risks.
This group of drugs exhibit mixed agonist/antagonist properties the pharmacodynamics of which is tissue dependent. The specific action is dependent on; tissue specific expression of the nuclear oestrogen receptors; the genes associated with these receptors; presence of transcription co- factors.
Clomiphene is an example of an oestrogen antagonist acting in the pituitary and induces ovulation by inhibiting negative feedback. Tamoxifen and Raloxifene have differing agonist/antagonist tissue profiles for oestrogen sensitive cancer risk. In women at high risk of breast cancer both reduce the risk by about 50%. However, Tamoxifen increases the longer term risk of endometrial cancer whilst Raloxifene decreases it and also protects against osteoporosis.
How do Antiprogestogens act? How is it used?
Mifepristone or RU486 is a competitive partial agonist to progesterone, effectively reducing the magnitude of it normal action. It is used alone or in combination with a prostaglandin to induce early termination of pregnancy within the first trimester. It is also used in induction of labour.
compare the actions of glucocorticoids vs. mineralocorticoids
Glucocorticoids primarily affect intermediate metabolic activity, whilst mineralocorticoids primarily have actions on water and electrolyte balance.
The actions of the two types are not completely separate and there is a degree of functional overlap between the two.
Outline the General pharmacology of corticosteroids
Whilst endogenous corticosteroids are about 90% bound in plasma, synthetic ones vary in their degree of plasma binding. After crossing the cell membrane, they first bind with intracellular receptors. The hormone receptor (HR) complex forms a dimer with another HR complex. The dimer then translocates to the nucleus where it binds with a Glucocorticoid Response Element (GRE). The bound form of the GRE then modulates transcription of the associated genes.
This has profound effects on mRNA expression, as it appears at least 10% of nuclear genes can be regulated by the above pathway. Therapeutic effects of changes in gene expression may only be apparent some hours after administration.
Outline the General physiological effects- Glucocorticoids (GCs)
The broad and systemic effects of Glucocorticoids on intermediary metabolism are manifest as increases in nutrient availability, raising blood glucose, amino acid and triglyceride levels. In response to stress, this ensures critical organs receive adequate substrate supply.
Outline the Effects of excess glucocorticoids
Increases in amino acid levels are bought at the expense of protein synthesis, which can lead to ‘fast twitch’ muscle wastage over time. They can also lead to negative calcium balance, affecting absorption in the GI. Over time they can increase bone resorption, resulting in a transfer of calcium from bone fluid to the blood. This will affect skeletal integrity and significantly increasing risk of fracture in the elderly and retarding linear bone growth in children.
Prolonged elevation of corticoid levels and the tendency to hyperglycaemia can lead to diabetes mellitus in susceptible individuals. Effects on the CNS are commonly reported ranging from euphoria to psychosis in susceptible individuals. These and other effects may be seen in Cushing’s syndrome as a result of endogenous pathology. However, iatrogenic Cushing’s due to excessive therapeutic exposure is more common.
Outline the Pharmacokinetics of Glucocorticoids
Aspects of PKs of GCs depend on their administration route, but their lipophilicity means they are easily absorbed. Targeted use (e.g. topical/inhaled) means that very high levels of the drug can be achieved limiting the risk of systemic toxicity. Additionally, some inhaled GCs (e.g. fluticasone) have been synthesised so that hepatic first pass is extensive.
With increasing systemic dosing PKs become non-linear, as plasma GC binding sites become saturated with a resultant increase in unbound plasma levels.
GC half-life relates to relative anti-inflammatory potency and varies between 8-72 hrs. Hepatic elimination involves both Phase I and II reactions.
What drug interactions should you keep in mind when prescribing GCs?
Specific GCs have their own set of interactions, but there are a considerable number of wide ranging drug interactions with GCs in general.
A number of drugs increase the rate of GC metabolism by the liver. These include phenytoin, primidone and the rifampicins.
Oral contraceptives act to increase plasma concentration of GCs.
A therapeutically important interaction is in combination with ‘steroid sparing’ agents to reduce the risk of GC iatrogenesis, e.g. azathioprine in transplant immunosuppression.
what should be monitored in a patient undergoing long term GC therapy?
Peak flow, alanine aminotransferase (ALT), C- reactive protein (CRP).
Abrupt cessation of GCs due to side effects or other reasons is not normally undertaken due to the risk of adrenal insufficiency. Even short term (> 3 weeks) treatment with greater than 20 mg of prednisolone can lead to suppression of the HPA axis. Gradual tapering of doses allows reactivation of the HPA axis and return to its normal function. Failure to do this can lead to chronic adrenal atrophy, which can be fatal if untreated.
what are the actions of oestrogen?
- Mild anabolic
- Sodium and water retention
- Raise HDL, lower LDL
- Decrease Bone Resorption
- Impair glucose tolerance
- Increase blood coagulability
- ? Improve mood, concentration, reduce Alzheimer’s Disease
- Metabolised by liver – strong first pass effect
what are the side effected of oestrogen?
- Breast tenderness
- Nausea, vomiting
- Water retention
- Increased coagulability, thromboembolism • Impaired glucose tolerance
- Endometrial hyperplasia & cancer (unopposed by progesterone)
what are the actions of progesterone?
- Secretory endometrium
- Anabolic
- Increase Bone Mineral Density
- Fluid retention
- Mood changes
what are the side effected of progesterone?
- Weight gain
- Fluid retention
- Anabolic
- Acne
- Nausea vomiting
- Irritability
- Depression, PMS
- lack of concentration
what are the actions/ side effects of testosterone?
- Male secondary sex characteristics • Anabolic
- Acne
- Voice changes
- Aggression
- Metabolic adverse effects on lipids
How are steroids transported in the body?
- Transport bound to SHBG (except progesterone) and albumin
- Liver metabolism, progesterone almost totally metabolised in one passage through liver
- Metabolites excreted in urine (as glucuronides and sulphates)
- SHBG = sex hormone-binding globulin
How does oestrogen exert its effects on cells?
Effective through binding to nuclear receptors
• Ligands to nuclear receptors
• Transcription factors
• Pleiotropic response
• Differs in different tissues
2 isoforms of the oestrogen receptor
Explains different responsiveness of tissues
3 isoforms of progesterone receptor exist
what are the two types of OCP?
• 2 types o oestrogen + progestogen (COCP) o > 99% effective o progestogen only (POP) o > 97% effective
How does The Combined Oral Contraceptive Pill (COCP) work?
Oestrogen:
• Inhibits ovulation by
suppressing FSH & LH
• Alters secretions & cellular structure of endometrial lining to prevent implantation
Progesterone:
• Inhibits ovulation by
suppressing LH
• Thickens cervical mucous → impairs sperm movement
• Alters endometrial lining to prevent implantation
Outline the Combined Oral Pill Formats
- One tablet daily for 21 days followed by a 7 day pill free period
- Monophasic
- fixed amount of an oestrogen and a progestogen in each active tablet
- Biphasic/Triphasic
- varying amounts of the two hormones according to the stage of the cycle
- Commonly oestrogen constant progestogen increases • ED (every day)
- includes 7 days of placebo tablets
which OCP has the fewest side effects?
Depends on patient… Monophasic with the lowest possible risk of side effects (VTE)
e.g. 20-35 micrograms of ethinyloestradiol plus levonorgestrel or norethisterone
Drug-drug interactions with OCP
Metabolised by cytochrome P450 (hepatic)
COCP’s efficacy therefore reduced by enzyme inducing drugs e.g.
carbamazepine, phenytoin
List adverse effects of the OCP
- Venous thromboembolism - clotting↑ • Myocardial infarction - smokers↑↑
- Hypertension – fluid retention
- Decrease glucose tolerance
- Increase risk of stroke in women with focal migraine • Headaches
- Mood swings
- Cholestatic jaundice
- Increase incidence of gallstones • Precipitate porphyria
When is the Mini-pill / “progestogen-only pill” prescribed?
- Taken continuously 28 pills – no break
- An alternative when oestrogens are contraindicated
- Efficacy dependent on the care of the user • 3 or 12 hour formats
- Progestogens used: oLevonorgestrel oNorethisterone oEtynodiol diacetate oDesogestrel
What options are available for Emergency contraception•
Up to 72 hrs
o Levonorgestrel (levonelle) 1.5mg
• Up to 120 hrs
o Ulipristal acetate (ellaOne) 30mg – progesterone
receptor modulator
o Cu IUD – causes inflammatory reaction in lining of womb
why is HRT prescribed?
- Symptoms: e.g. hot flushes/sweats
- ± Osteoporosis • X Heart disease
- HRT is NOT effective for the prevention of Heart Disease and should NOT be prescribed for that indication
Oestrogen replacement therapy
ERT
Only after hysterectomy
which steroids are contained in HRT?
Oestradiol e.g. valerate, enanthates, Micronised oestradiol,
1-2mg/day
Premarin 0.625-1.25mg/day
Medroxyprogesterone acetate (Provera) Norethisterone
Duphaston
Risks of HRT
• Unopposed oestrogen: increase endometrial cancer, and ovarian cancer
• Increased Breast cancer (see next slide)
• Increased Ischaemic Heart Disease, and stroke
• Increase risk of venous thromboembolism
• Uterine bleeding
• Adverse effect on lipid profile
• Adverse effect on thrombophilia profile
• Increased Breast cancer:
• Normal risk: 22 cases / 1000 menopausal women
• Combined HRT risk: 27 cases / 1000 menopausal women on HRT
• i.e. + 5 / 1000
• the risk of breast cancer decreases when HRT is
stopped
• level of risk returns to normal after about five years
• Advise to attend all breast cancer screening
Give two examples of Anti-oestrogen
- Weak oestrogens that block receptors
- Clomiphene: ovulation induction: inhibit oestrogen binding to anterior pituitary, inhibit negative feedback, results in increased GnRH and FSH, LH
- Tamoxifen: treatment of ER+ breast cancer (and ovulation induction)
Give an example of Anti-progestogens
• Mifepristone (RU486)
• Partial agonist to progesterone receptor, inhibits progesterone
action
• Sensitises the uterus to prostaglandins (e.g. mesoprostol)
• Used for medical termination of pregnancy, and induction of labour
Give an example of an Anti-androgen
• Cyproterone: Progesterone derivative
• Weak progestogenic effect. Partial agonist to progesterone
receptor, competes with dihydrotestosterone • Used in combined contraceptive pill (Dianette)
What is SERM and what is it used for?
- Selective oestrogen Receptor Modulators
- Raloxifene:
- Protects against osteoporosis
- No proliferative effects on endometrium & breast
- Oestrogenic effects on bone, lipid metabolism & blood coagulation
- Reduced risk of invasive breast cancer in postmenopausal women with osteoporosis
- Increases hot flushes
Metabolic action of glucocorticoids
- Stimulates glycogenolysis, gluconeogenesis
- Hyperglycaemia
- Proteinolysis
- Lipolysis (low conc.)
- Lipid deposition (high conc.)
- Redistribution of fat
