Recap the Endocrine Control of Reproduction
Describe the general pharmacology of natural gonadal steroids
Both oestrogen and progesterone have two nuclear receptor isoforms.
The action of these receptors, when bound by either agonist or antagonist ligands, is dependent on the specific array of genes with which the receptors are associated with and in which target tissue they occur – so gene transcription is affected.
These receptors have particularly high levels of expression in the female tract.
Progesterone, Oestrogen and Testosterone are all derive from cholesterol with many having shared anabolic pathways. They all have different structures; the basic steroid ring structure has many variable side groups that affect signalling function.
Synthetic sex hormones can be produced to act on their receptors with good effect; minor modifications of the parent groups can produce clinically useful drugs. It is oestrogen and progesterone that are used in contraception and HRT.
Describe the actions and consequences of oestrogens
- Mild anabolic
- Sodium and water retention
- Raise HDL, lower LDL
- Decrease bone reabsorption
- Impair glucose tolerance
- Increase blood coagulability
- ? improve mood, concentration
- ? reduce Alzheimer’s Disease
- ? avoiding first pass effect more favourable
- Breast tenderness
- Nausea, vomiting
- Water retention
- Increase coagulability - risk of Thromboembolism (grey area)
- Impaired glucose tolerance
- Endometrial hyperplasia and cancer
Describe the actions and side effects of Progestogens/Progesterone
- Secretory endometrium
- Increased bone mineral density
- Fluid retention
- Mood changes
- Weight gain
- Fluid retention
- Nausea vomiting
- Irritability, Depression, PMS and Lack of concentration (particularly in latter half of menstrual cycle)
Describe the actions and side effects of Testosterones
- Male secondary sex characteristics (including final stages of hair growth => hirsuitism in PCOS)
- Voice changes
- Metabolic adverse effects on lipid
What are the three types of drug groups
Sex steroids: oestrogens, progestogens, androgens
Inhibitors & Antagonists
Selective oestrogen receptor modulators (SERM)
What are the routes of administrations for these drugs?
- Oestrogens – Synthetic derivatives: ethinyloestradiol, methoxy derivative (mestranol), valerate
- Progestogens – Synthetic derivatives:
- 1 – progesterone derivatives – Medroxyprogesterone, Dyhydrogesterone
- 2 – testosterone derivatives: Norethisterone, norgestrel, ethynodiol
Testosterone Routes of Administration
IM: enanthate, proprionate
Oral: undecanoate, mesterolone
Describe the transport of steroids
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)
What are the components of the COCP?
The Combined Oral Contraceptive Pill (COCP)
The COCP includes a variety of synthetic oestrogen doses in combination with a 1st-4th generation progestogen.
- Oestrogens: high/low dose: 50,35,30,20mg/day (all pretty much have the same efficiacy)
- Ethinylestradiol, Mestranol
- Progestogens: which generations?
2nd: levonorgestrel, norethisterone
3rd: desogestrel, gestodene, norgestimate
4th: drospirenone (Yasmin: anti-mineralocorticoid, antiandrogen), norelgestromin (Evra: patch)
Describe the mode of action, metabolism and types of COCP regimes
The efficacy of COCP is due to its multiple sites and actions throughout the endocrine and reproductive tract. Mode of action:
- Suppression of ovulation: inhibit FSH, LH (so development of Graafian follicles, no ovulation)
- Adverse effect on cervical mucus – thickening (due to progestogen component – thickening reduces sperm penetration)
- Adverse effect on the endometrium
Undergoes both hepatic Phase I and II pathways including being metabolised by cytochrome P450 hence COCP’s efficacy is therefore reduced by enzyme inducing drugs (PCBRAS: phenytoin, carbamazepine, barbituates, rifampicin, alcohol and sulphonylureas)
- Monophasic (constant dose of oestrogens and progestogens throughout the cycle)= 21
- Triphasic (altered doses of oestrogens and progestogens throughout the cycle) = 21
- Every Day: ED = 21+ 7 placebo
NB: all appear to be as effective as each other – no difference
What are the adverse effects of the COCP?
The COCP is largely safe, although relatively minor adverse effects are common, e.g. weight gain.
Serious ADRs are rare e.g. thromboembolism in second-generation pills: 1.5/1000 users vs 1/1000 non-pregnant vs 6/1000 pregnant non-users per year.
Increased blood pressure is an ADR in a small percentage of women.
Decreased glucose tolerance
Increased risk of stroke in women with focal migraine
Increase incidence of gallstones
Describe COCP Drug-Drug Interactions and drug monitoring
COCP Drug Interactions
- Use of broad-spectrum antibiotics can result in reduced efficacy due to effects on intestinal flora.
- These flora play a part in 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.
- Before commencing contraception with COCPs, proper evaluation of risk factors including for BMI, blood pressure, migraines and smoking history needs to be carried out. Monitoring of blood pressure and enquiry about other ADRs should continue over the period of prescription.
- Advice for taking COCP involves taking it every day (any missed days will require use of other contraception for 7 days following), any vomiting or diarrhoea may make COCP ineffective and blood pressure check every 3-6 months.
Describe the POP including types, mode of action and efficacy
The POP or ‘mini pill’ is a progestogen-only pill whose mode of action differs from the COCP (does not generally inhibit ovulation). 28 days progestogen
- Etynodiol diacetate
- Medroxy Progesterone Acetate (Depot provera: MPA) – doesn’t require a daily dose but very high dose injection. Association with reduced bone density
- Etonogestrel (female implants: Implanon (week on, week off) ; male implants; vaginal ring)
It primarily acts to thicken cervical mucus, secondarily hindering ovulation and endometrial implantation (by thinning endometrium)– adverse effect on cervical mucus and endometrium (makes endometrial lining very thin).
- NB: poor cycle control (poor endocrinological effects)
POP has a much narrower window of use, much less reliable and more side effects than COCP (‘spotting’ may occur). Efficacy is about 96-98% and is usually offered to women for whom the COCP is contraindicated e.g. risk factors for thromboemboli, smokers or hypertensive.
A number of progestogen implants (IM, SC or as IUD) provide long term contraception for between 3 months and 5 years.
What are the types of emergency contraception?
Up to 72 hours
- Levonorgestrel (levonelle) 1.5mg (very effective)
Up to 120 hours
- Ullipristal acetate (ellaOne) 30mg – progesterone receptor modulator
- Cu IUD (toxic to sperm)
Describe post-menopausal HRT and the steroids used in HRT
Clinical indications in postmenopausal women are described – vasomotor symptoms e.g. hot flushes/sweats
- Limit the effects of osteoporosis
- NOT effective for the prevention of Heart Disease and should not be prescribed for that indication.
There are issues with long term use of single or combined HRT as clinical trial evidence points to increased risk of ADR.
Currently it is proposed to treat those symptoms with lower dose of HRT for shortest time.
Steroids in HRT:
Describe the risks of HRT and combined therapy (as opposed to oestrogen-only therapy)
Risks of HRT:
- Unopposed oestrogen: increased risk of endometrial cancer and ovarian cancer so give combined HRT to women with a uterus to avoid continuous endometrial stimulation (which could lead to endometrial hyperplasia and cancer)
- Increased risk of breast cancer
- Increased risk of ischaemic heart disease and stroke
- Increased risk of venous thromboembolism, DVT
- Uterine bleeding
- Adverse effect on lipid profile
- Adverse effect on thrombophilia profile
Sequential combined: fixed dose of oestrogen (28 days) but dose of progesterone varies (12-14 days) so there is endometrial bleeding every month which is protective against endometrial hyperplasia.
Continuous combined (like a monophasic pill), normally no monthly bleeding
Describe the routes of administration of HRT
Before starting any woman on HRT, all side effects should be discussed and baseline investigations e.g. blood pressure should be undertaken.
What are anti-oestrogens? Give examples
Anti-oestrogen: weak oestrogens that block receptors
- Clomiphene is an example of an oestrogen antagonist acting in the pituitary and induces ovulation by inhibiting negative feedback. It is used a lot in fertility treatment
Ovulation induction by inhibiting oestrogen binding to anterior pituitary, inhibiting negative feedback, resulting in increased GnRH, FSH and LH.
- Tamoxifen (treatment of breast cancer – if tumour expresses oestrogen receptors - and ovulation induction) 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% (anti-oestrogenic action in breast tissue)). However, tamoxifen increases the longer term risk of endometrial cancer (oestrogenic in endometrium) whilst Raloxifene decreases it and also protects against osteoporosis.
Mifepristone or RU486 is a competitive partial agonist to progesterone, effectively reducing the magnitude of its normal action.
It is used alone (sensitises the uterus to prostaglandins) or in combination with a prostaglandin to induce early termination of pregnancy within the first trimester.
It is also used in induction of labour for overdue babes (removes progesterone support) but this is not current practice in the UK.
Cyproterone: progesterone derivative
Weak progestogenic effect – partial agonist to progesterone receptor, competes with dihydrotestosterone
Used in combined contraceptive pill (Dianette)
What is a SERM? Give examples
Selective Oestrogen Receptor Modulators (SERMs)
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.
Examples include clomiphene, tamoxifen and raloxifene.
Protects against osteoporosis (but not first choice treatment)
No proliferative effects on endometrium and breast
Oestrogenic effects on bone, lipid metabolism and blood coagulation
Reduced risk of invasive breast cancer in postmenopausal women with osteoporosis
Increases hot flushes
Describe the significance of atheromatous disease and the importance of relative LDL and HDL levels in CHD
Atheromatous disease underlies the commonest cause of death and disability in industrialised societies.
LDLs provide a fundamental basis to their development. Atherosclerosis arises as a chronic inflammatory disorder which can manifest as early as adolescence.
At 50-60 years, the majority of the population have varying degrees of atherosclerosis.
The discovering and development of statins from 1976 onwards heralded a new in treatment of this disease by directly affecting LDL levels. These are a major risk factor in both MI and stroke.
Importance of relative LDL and HDL levels in CHD
Epidemiologic studies have established that both total and LDL cholesterol concentrations correlate with clinical coronary atherosclerosis. Importantly, with increasing HDL levels reduces CHD risk.
What is the ideal level of cholesterol? Is cholesterol a modifiable risk factor?
In the UK, lipids values are given in mmol/L, total cholesterol (TC) should be 5.0 mmol/L or less. Fasting LDL should be about 3 mmol/L or less and HDL about 1.2 mmol/L or above. Cholesterol is a modifiable risk factor and should be treated where possible.
In the literature LDL and HDL levels are sometimes quoted in mg/dL. Conversion to the more familiar mmol/L scale is by 40 mg/dL of cholesterol ~ 1mmol/L so a value of 5 mmol?L cholesterol ~ 200 mg/DL.
Cholesterol – a modifiable risk factor?
In the USA:
- 97 million people have total cholesterol 200 mg/dL (5.2nmol/L)
- 38 million people have total cholesterol 240mg/dL (6.2mmol/L)
10% reduction in total cholesterol results in:
- 15% reduction in CHD mortality (p<0.001)
- 11% reduction in total mortality (p<0.001)
- LDL cholesterol is the primary target to prevent CHD
- Intensity of intervention depends on total CV risk
- NB: relationship between TGs and CVD risk is unclear
- Factors are accumulative
Describe the mechanism of atherosclerosis and the pro-atherogenic effects of Ox-LDL
There are a number of stages underlying the aetiology, the primary one involving endothelial dysfunction, which leads to infiltration and entrapment of LDL in the arterial wall.
LDL oxidation leads to further pro-inflammatory changes. Over time this leads to deposition of connective tissue components and the formation of a fibrous cap over a lipid rich core.
Rupture of the plaque provides a substrate for thrombosis.
Pro-atherogenic effects of Ox-LDL
- Inhibits macrophage motility
- Induces T-cell activation and VSMC (vascular smooth muscle cell) division/differentiation => movement into lumen
- Toxic to endothelial cells
- Enhances platelet aggregation
How can you prevent atherosclerosis?
Drug treatments apart, exercise change in dietary and other habits can reduce LDL and increase HDL.
The main agents of clinical choice are: Statins, Cholesterol Lipase Inhibitors (e.g. Ezetimibe), Fibrates (Fenofibrate is most common), Bile Acid Sequestrants, Nicotinic acid/Niacin, Resins (Colestyramine), Omega-3 fatty acids – omacor, ? Plant sterols
Describe the pharmacological action of statins
Statins are the most common effective and best tolerated drug for lowering LDLs.
Depending on the dose and type of statin used, the range of LDL reduction falls between 5-35%, whilst raising HDLs by about 5% and lowering triglycerides by 10-35%.
The primary pharmacological action is by inhibiting the hepatic enzyme HMG-CoA reductase, which is involved in cholesterol synthesis. Decrease in hepatic cholesterol concentration stimulates production of LDL receptors, which then increase rate of LDL removal from plasma – increases clearance of IDL and LDL, and decreases production of VLDL and LDL
Consequently statins are used to reduce CVD risk; they are especially important in cases of familial hypercholesterolaemia.
Indications: CV risk prevention (CVD + diabetes mellitus), familial hypercholesterolaemia
Animal and in vitro studies suggest statins may have secondary pleitropic anti-atheromatous actions, although the specific contribution they may have in humans is not clear. Some secondary benefits of Statin treatment include: anti-inflammatory, plaque reduction, improved endothelial cell function and reduced thrombotic risk. Statins may also provide additional benefit in slowing neurodegeneration and prostate cancer prevention.
Describe the PK and PD of Statins include the difference between short-acting and long-acting ones
There is considerable variation in PK and PD of this important drug group, which is partly related to molecular structure.
Intestinal absorption varies between 30-85%.
Hepatic first pass uptake is extensive, but may occur by diffusion or active transport by OATP2.
Due to this and the requirement by some statins for activation, systemic availability may fall to 5-30% of administered dose.
Hepatic elimination includes CYP 3A4 for some statins whilst others are only metabolised by Phase 2 pathways.
In short acting statins e.g. Simvastatin, half life varies between 1-4 hours and these are usually given at night to coincide with peak cholesterol production in early morning.
The structurally distinct atorvastatin and rosuvastatin have half lives ~20 hours. This is likely to contribute to their superior efficacy and can be given any time of day.
Statins as a group also exhibit non-linear pharmacodynamics, where for any statin, a doubling of dose results in ~6% in LDL.
Describe the ADRs of statins
Statins appear to be well tolerated with the incidence of serious side effects, myopathy and rhabdomyolysis reported as ~0.01% at highest doses, also angioedema. In large-scale trials with low-intermediate doses, myalgia and myopathy rates were comparable to placebo. Significant elevation in plasma hepatic enzymes has been reported
Increased transaminase levels
- 0.1%-2.5% of treated patients develop increases of >3x upper-normal limit, especially at higher doses.
- Rapidly reversible, no evidence of chronic liver disease
- Diffuse muscle pain and CPK (creatine phosphokinase) > 10x upper-normal limity
- Primarily seen when higher doses of statins are used in combination with cyclosporine, gemfibrozil and occasionally erythromycin and niacin.
- Gastrointestinal complaints, arthralgias and headaches.
Describe drug-drug interactions re Statins?
Statins as a group and individual agent interact with a wide range of other drugs.
Predictably those metabolised via Phase I pathways are affected by CYP inducers/inhibitors. Notably, CYP inhibitors will increase the risk of myopathy due to increased statin levels e.g. grapefruit juice and verapamil.
Conversely, rifampicin and St John’s Wort acting as inducers will decrease plasma levels in those statins metabolised by this route.
OATP2 inhibitors can reduce the efficacy of those statins carried via this transporter. Interestingly, gemfibrizil is a fibrate that inhibits both OATP2 and statin glucorinidation. This increases statin plasma levels but co-administration also synergistically increases the risk of myopathy. Synergistic therapeutic interaction with other LDL lowering agents to augment this effect is sometimes employed e.g. Ezetimibe/Fibrate
Describe monitoring during statin therapy?
Not withstanding the low ADR profile of statins, liver function tests at baseline may be obtained especially with higher doses. It is more important to monitor functional endpoints with LDL lowering in combination therapy with statins and with drugs from other groups that may affect statin PK and PD.
Individuals placed on high doses of statins should have regular liver function tests, as well as constant LDL level monitoring.
Describe the evidence supporting the clinical use of statin therapy?
Clinical trial evidence of statin use.
There is also consideration with the criteria be used to determine therapeutic targets as informed by optimal levels and ratios of plasma lipids.
There is also consideration of which patient groups should receive statin therapy in primary or secondary prevention.
Individuals placed on high doses of statin should have regular liver function tests, as well as constant LDL level monitoring. Individuals should be placed on statins if they have CHD (4S Study) or raised LDL levels (CARE study) as statins reduce morbidity and mortality rates; studies have even statins causing improved morbidity and mortality outcomes for those with normal cholesterol levels.
What is Ezetimibe?
Cholesterol Absorption Inhibitors e.g. Ezetimibe: these inhibit intestinal cholesterol uptake by blocking the specific cholesterol transport protein NPC1L1 in the brush border.
This reduction of dietary cholesterol reaching the liver secondarily induces LDL transporter expression (increases expression of hepatic LDL receptors) to further reduce circulating cholesterol levels (decreases cholesterol content of atherogenic particles).
A single 10mg dose of Ezetimibe can reduce LDL levels by about 15-20%.
Ezetimibe also undergoes repeated enterohepatic circulation
Ezetimibe and its active glucuronide metabolite circulate enterohepatically.
Delivers agent back to the site of action
Limits systemic exposure.
Ezetimibe is typically given as monotherapy in statin intolerant patients. It does however synergistically reduce LDL by a further 20% when given in combination with a statin. This is actually better than the reduction with a doubling of statin dose and also reduces the risk of statin ADRs.
ADRs: headache, abdominal pain and diarrhoea.
What are Fibrates/Fibric Acid derivatives?
: these ampipathic carboxylic acids act on the Peroxisome Proliferator-Activated Receptor-alpha (PPAR-alpha) (agonists) – increases production of lipoprotein lipase.
A complex mechanism of action modestly lowers LDL (10-20% lower but variable, depending on specific drug) and raises HDL, but provides impressive lowering of triglycerides.
Improved postprandial triglyceridemia?
Can be used in conjunction with statins but are typically only used as first choice in specific types of hypertriglyceraemias.
- Adjunctive therapy to diet
- Combined hyperlipidemia with low HDL who not respond to NA
Describe the efficacy, side effects and contraindications of Fibrates
- Decreases TG 25-50%
- LDL decreases but variable
- Increases HDL 15-25% in hypertriglyceridemia
Side Effects: GI upset (8%), cholelithiasis, myositis, abnormal LFTs
Contraindications: hepatic or renal dysfunction, pre-existing gallbladder disease (due to risk of cholelithiasis)
Intervention Trials: Helsinki Heart Study, LOCAT, BECAIT, VA-HIT, BIP
Describe Nicotinic Acid
Reduces VLDL and increases HDL at high doses
Best agent to raise HDL-c
Lipid-lowering effect by inhibition of lipoprotein(a) synthesis
Reduces coronary events (Coronary Drug Project)
- Flushing, itching, headache (reduced by immediate-release, Niaspan or combination with low-dose aspirin)
- Hepatotoxicity, GI (sustained-release)
- Activation of peptic ulcer
- Hyperglycemia and reduced insulin sensitivity
- Active liver disease or unexplained LFT elevations
- Peptic ulcer disease
Describe Combination Therapy
- Fibrate (not gemfibrozil)
- Nicotinic acid
- Omega-3 Fatty Acids
- Benefit (CV risk reduction)
Consider the combination of fibrates and statins
Combination fibrate and statin therapy may significantly improve triglyceride, LDL-c and HDL-c levels
But…fibrates plus statins are associated with increased risk for myopathy and rhabdomyolysis
Not thought due to cytochrome P450 drug interaction
Gemfibrozil may impair glucuronidation of statins (with cerivastatin being more susceptible than other statins such as simvastatin and atorvastatin)
Fenofibrate appears to have less potential for impairment of statin metabolism and thus this may account for the reduced reports
Remember polypharmacy increases risk of ADR so close monitoring is required.
What are the alternatives to lipid lowering drugs?
Consider plant sterols for those not willing to take tablets (sterols found in margarine, yogurt drinks etc compete with cholesterol for intestinal absorption).
Other dietary factors
- Fish oils
- Vitamin C/E
- Alcohol (HDL)
- Dietary cholesterol/fat
- Alcohol (triacylglycerides)
Is treating hypercholesterolaemia cost-effective?
Potential pharmacological cost of treating hyperlipidaemia in USA estimated at $3-17 billion per year…before the credit crunch
The cost (per event prevented) increases as the baseline risk of the patient falls – cue the term NNT= numbers needed to treat
Public Health or Public Harm OTC: Lipid Lowering Therapy
Simvastatin available OTC…10mg daily
Who is it for?
Who buys it?
Is it cost-effective?
What are the implications?
Or is it just to save the government (and us) some money?
What should I do next?
Read over both Week 3 lectures!