reproduction v0.1
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Introduction
Growth and development of sex structures
Behaviour
Sex hormones are produced in the body, which are required for several
important processes
Therefore, if we try to change something, the body will resist our changes
Generally, we want to modify sex hormone release to treat a disease
The production of these hormones are under feedback control
In early pregnancy, progeterone, estrogen and hCG (Human chorionic
gonadotropin) are produced
Hormonal release tends to be tied to circadian rhythms, so hormone release
tends to be pulsatile (released with visible peaks)
Control and secretion of hormones
Factors stimulate the hypothalamus to release gonadotropin releasing
hormone (GnRH) to the anterior pituitary
GnRH stimulates the anterior pituitary to secrete Follicular Stimulating
Hormone (FSH) and Luteinizing Hormone (LH)
Testosterone from the testes
Oestrogen and Progesterone from the ovaries
They stimulate the release of either
Finally, the whole system is under negative feedback control, where these
sex hormones will prevent the production of more sex hormone
The secretion of sex hormones ultimately depends on control by the brain
Gonadotropin releasing hormone
Pharmacology of sex hormones
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Responsible for stimulating the anterior pituitary to secrete LH and FSH
Also released in pulses
Give GnRH continuously
But this is accompanied by a flare of sex hormone release due
to the initial agonist action by GnRH
This causes the receptors in the anterior pituitary to become
desensitised, and stop releasing FH and LSH to reduce sex hormonerelease
Remember back to oncology, groselin injections is an injection
of GnRH. This comes with tumour flare as well.
Used to treat testicular cancers and endometriosis (extra
endometrium growing where it shouldn't be)
Decreasing sex hormones
Needs to be given in pulses (otherwise the receptors in the pituitary
will become desensitised, leading to a decrease of hormones as seen
above)
Increasing sex hormones
Has two clinical uses:
Removes the negative feedback, makes the body think it doesn't have
enough sex hormone so it makes more
Another way to increase sex hormone production is to block the action of the sex
hormone against the receptors in the hypothalamus and anterior pituitary
The action of estrogen
17 beta-estradiol
17 beta-estrone
17 beta-estriol
Actually a group of three steroids (in order of potency):
Estrogen receptor (ER) alpha
ER beta
They bind to estrogen receptors, which there are two types of
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Intracellular
Exist in dimers
The dimers are able to be made up of either just alpha, beta or a mix of the
two types
The receptors are
Binds to a specific response element in the DNA, called the estrogen
response element (ERE)
OR it can bind to and activate kinases in the cytosol
Once an estrogen binds to the receptor dimer:
Either way, gene transcription is activated
Because there are two types of receptors, and at least three combinations
available, different tissues will be affected differently by estrogens.
Functions of estrogens
Produce sex structures
During development
Breasts and uterus developed
Prepares body for producing babies
Deposition of fat around the abdomen
This is called bone arrest
Stop bones from growing longer, stops vertical growth
At puberty
Increases HDL
Decreases bone resorption (prevents osteroporosis)
Retention of salt and water as it has mineralcorticoid activity
Increased coagulability (especially deep vein thrombosis , DVT)
During menstral cycles
Increase uterine blood flow to keep the baby alive
Growth of the breast duct system to prepare for milk production
During pregnancy
Neuroprotective
Causes mood swings
Develops structures in the brain for women
Effects on the CNS
Estrogen as a drug
Contraception
As shown above, estrogen is used for different reasons in the body depending on
age
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Protect against osteoporosis
Menstrual disorders
Some cancers
Ethinyl estradiol is orally active as it is resistant against first pass
metabolism (natural estrogens have low bioavailability due to extensive
first pass)
Synthetic estrogens also have a longer half-life (hours, instead of minutes)
Synthetic estrogens are much more potent compared to their natural
counterparts
Although natural estrogens can be used, synthetic estrogens (especially ethinyl
oestradiol) are much better as a drug:
Progesterone
Produced mainly by the corpus luteum and the placenta
Developing the breast duct system (in conjunction with estrogen) to
prepare for milk production
Allows the smooth muscle in the uterus to relax, to allow the uterus to
grow in size to accomadate for the growing foetus.
Involved in two things during pregnancy:
The synthetic forms are orally active, while progesterone itself will be
orally inactive due to extensive first pass metabolism
Again, synthetic forms of progesterone are available
Androgenic activity, women may grow beards
Acne (therefore, progesterone is not recommended for people with acne)
Fluid retention (due to mineralcorticoid activity)
Three common side effects are:
Oxytocin
Causing contractions in the uterus
Milk production in the breasts
Maternal behaviours in the CNS
Oxytocin is responsible for three things:
It is secreted by the posterior pituitary (GnRH is released from the anterior
pituitary)
Prolactin
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Hormone responsible for triggering milk release from the breasts
Causes the release of Prolactin Releasing Factor (PRF) to the anterior
pituitary
PRF causes the anterior pituitary to release prolactin
Prolactin then acts on breast tissue to trigger milk release
Triggered by suckling action
Therefore, a dopamine agonist may be used to prevent excess
prolactin/milk production
Dopamine will prevent the release of prolactin from the anterior pituitary
Menopause
Usually occurs around 50 years of age
Menopause is accompanied by some unpleasant symptoms due to
hormonal changes
Menopause is when a female stops ovulating for the rest of her life
First stage
Estrogen is reduced while FSH is increased (this is due to the
feedback loop kicking in, trying to get estrogen back up)
Periods get close and less frequent
Peri-menopause
Last stage
This is where the classic symptoms present themselves
Post-menopause
Split into two stages:
Hot flushes due to reduced estrogen release
This can lead to dryness, which can either be painful or itchy
Vaginal atrophy
Chance of osteoporosis, as estrogen normally prevents bone reabsorption
Mood disorders (as if they were having a period)
Symptoms of menopause are:
Hormone replacement therapy and menopause
Hormone replacement therapy (HRT) may be used to relieve the symptoms of
menopause
Estrogen-only replacement is for people who don't have uteruses,
because they don't have an endometrial layer anymore
Otherwise, HRT involves estrogen and progesterone to prevent
endometrial cancers
Use of estrogen alone will lead to an increase in endometrial cancer
However, there are some limitations
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Associated with greater chances of stroke (hypercoagulation due to
estrogen) and breast cancer (estrogen exposure is linked to breast cancer)
Associated with reduced hip fractures (estrogen prevents bone
breakdown)
Protection against colorectal cancers
Reduced symptoms
Then what's the point of HRT?
The recommendation now is to use it for healthy people under 60 for no longer
than 5 years
Testosterone
A bit produced in adrenal cortex and ovaries
Produced mostly in the testes of males
Growth of hair (and loss of hair later!)
Spermatogenesis
Muscle growth
Erythropoiesis (production of red blood cells)
Prevent bone reabsorption
Responsible for several different functions:
Again controlled by pulsatile release
98% bound to proteins, 2% free (active form)
40% of testosterone is tightly bound to sex hormone binding globulins,
while the rest is loosely bound to others, including albumin
Is affected by protein binding
Used as a replacement if testosterone can't be secreted normally due to
pituitary or gonad damage.
Only problem is it can lead to a long-term suppression of secretion of GnRH
(because the exogenous testosterone will cause the hypothalamus to
reduce secretion as a part of a negative feedback mechanism)
Testosterone is used clinically
Cyproterone is a partial agonist at androgen receptors. It works by
reducing GnRH production by negative feedback
Low doses are useful to prevent acne and as a contraceptive
High doses are used against testosterone dependent cancers
It may also be used in psychiatry to blunt the sex drive in aggressive males
Anti-testosterone activity also has some uses:
Decreased libido, osteoporosis, decreased body hair etc. suggests
reduction in testosterone
This may not be attributed to reduced production of testosterone, but
rather may be due to increased binding with sex hormone binding globulin,which leads to less free testosterone
However, this field is not well researched (i.e. ignore it)
Does male menopause exist?
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What are the hormones controlling the menstrual cycle?
GnRH
FSH
LH
Estrogen
Progesterone
GnRH release will cause FSH and LH release from the anterior pituitary
Causes endometrial regeneration (gets endometrium ready for
implantation)
Causes the cells responsible for LH secretion to become more
sensitive to GnRH, causing a massive spike in LH release
The follicles will produce estrogen which is important for two processes
The spike in LH and estrogen causes ovulation
FSH will stimulate follicles to grow, especially the Graafian follicle, which is the'main' follicle. Normally 10 or so eggs are stimulated per cycle, but only one
develops to maturity.
Progesterone causes endometrial build-up to prepare for implantationIt also triggers negative feedback to reduce the release of GnRH, FSH and
LH.
LH will stimulate the corpus luteum to develop, which then produces estrogens
and progesterone
Menstration (shedding of endometrium)
Secretion of FSH and estrogen to develop endometrium and follicles
Follicular phase (variable, days 1-14)
Growth of the endometrium
Development of the corpus luteum
Luteal phase (fixed, days 14-28)
The cycle is split into two phases:
Hormonal contraceptives
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How does the combination pill work?
Contains an estrogen and a progesterone analogue
Inhibit FSH secretion due to feedback loop
No FSH= no follicle production
Stops the endometrium from breaking down as well, stops bleeding
Estrogen will:
Inhibit LH secretion due to feedback loop
Prevents ovulation, as there is no LH spike
Also thickens up the mucus in the cervix, which makes it hard for the
sperm to get through
Progesterone will:
Both will work together to make the endometrium unsuitable for implantation
Remember: both progesterone and estrogen are released by the corpus luteum
and placenta during pregnancy. Therefore, the body thinks it is pregnant
How has the combination pill changed over the years?
Not suitable for use as the high doses of estrogen were linked to
thrombosis formation
Initially used high doses of estrogen and estrane progestins
One of the progestins is levonorgestrel, which is still used by itself in the
emergency pill
Problem is, the gonanes just have too much androgenic activity (women
growing beards)
The second generation used less estrogen and gonanes as the progestins
Not available in NZ, had too much DVT risk
But had a reduced androgenic effect due to other gonanes being used
The third generation used even less estrogen but still used gonanes
They have anti-mineralocorticoid and anti-androgenic effects, so they have
Fourth generation pills haven't dropped the estrogen levels, but have switched
to non-testosterone derived progestins
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a low side effect profile
Monophasic pills had the same amount of hormones in each pill
Biphasic pills has two types of pills in the pack with differing amounts of
hormone
Triphasic pills had three types of pills, each with a different amount of
hormones, making them more complicated
They thought having multiphasic pills would lead to better control
But it's not true
Another change we saw was to do with the amounts of hormones in the pills:
Useful due to a continuous release of hormones (making hormone
levels flat) while having a better adherence due to the long duration
of action per patch.
Otherwise same as the oral form
Not available in NZ
Patches
Can also be used long term (3 weeks), which leads to good
compliance
Beware of rings being displaced
Otherwise the same as the oral form
Not available in NZ
Vaginal rings
There are other routes of administration to consider:
Side effects of contraceptives
Breast tenerness
Mood
Weight gain
Estrogen
AcneProgestins
Nausea
Spotting/breakthrough periods
Longer, heavier bleeds or more severe cramps
Etc
Generally mild symptoms are common
Estrogen causes hypercoaguability (makes the blood more prone to
clotting)
Therefore, it is contraindicated for women suffering from
hypercoaguability; and treated as a caution for smokers
Note: although it increases the chance of DVT, pregnancy has a
greater chance for DVT
MI (myocardial infarction) , DVT (Deep Vein Thrombosis) and stroke
Remember: increased exposure to estrogen is a risk factor for breast
cancer
Increased chance of breast cancer
All reduced in chance
Endometrial cancer, colon cancer and ovarian cancer
But there are rarer (more severe) ones available
Contraindications and cautions
Might make it worseUndiagnosed endometrial bleeding
Estrogen causes hypercoaguability
Past or present circulatory disease
Thrombophillia
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Estrogen causes hypercoaguability
Would increase hypertension
Estrogen-induced hypertension
Migranes suggests reduced blood flow to the brain, estrogen increases the
chance of stroke
Migrane with aura
Metabolised by the liver
Liver disease
Lupus
Daughters have an increased chance of cancer of the uterus
Pregnancy
Smokers
Hypertension
Diabetes
Not contraindicated, but cautioned
Interactions
Therefore, need to be very careful with CYP3A4 inducers, as they can cause
failure (observe 7 day rule)
Phenytoin
Carbamazepines
Rifampacin
Anti-retrovirals
Metabolised by CYP3A4
Use barrier contraceptives during the unsafe period PLUS another 7 days
after treatment is finished
See workshop for more details
7 day rule is:
Normally, estrogen is conserved due to enterohepatic recycling
Only in combined oral contraceptives only, because estrogen is
important
Progesterone only pills have no estrogen, so they are not affected
If broad-spectrum antibiotics are used, the bacteria responsible for the
recycling may be killed off, leading to therapeutic failure
This has shown to be not true
Broad-spectrum antibiotics?
Diarrhoea.
It causes the loss of the pill, leading to treatment failure of both the
combined oral contraceptive and progesterone only pill
Observe 7 day rule
Then why do antibiotics cause therapeutic failure?
Progesterone only Pill (POP)
Given continuously
Compared to the COC which has 7 days of placebo pills
Also called the mini-pill
Only contains progesterone analogues (progestins)
Women with contraindications or cautions (see above)
Estrogen causes negative feedback inhibition of prolactin, caused
reduced milk production
Breastfeeding females
Used for:
May also be given as a long acting implant in case of poor compliance
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Only has a 3 hour window, compared to 12 hours for the COCs
Instead, the progesterone will cause the mucus around the cervix to
thicken, which prevents sperm from entering
Although it has a chance to prevent ovulation, its main mechanism of action
differs from COCs
But in reality, poor compliance leads to higher failure rates
Theoretically, it's just as effective as COC
Male pills
Females just don't trust males
Not a popular idea
Plus it's much easier to make a pill for females, as there are easy and safe
methods to prevent pregnancy
Continuous treatment with testosterone
Causes negative feedback inhibition as well
Problem is we don't know its long term health effects, and it takes 3
months to work and a 3 month washout
How would we pharmacologically use male contraception?
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Female hormones
Estrogen metabolism
High extraction, or first pass metabolism
Natural estrogens are rapidly metabolised by the body
Rapidly converted into estrone
And to estriol (least potent)
The most potent is 17-beta-estradiol
The metabolism of 17-beta-estrdiol is rapid, especially in the liver, which is why it
has high first pass metabolism, and has very little oral activity
Glucuronides can be formed. These can undergo hepatic recirculation
Sulfates can be formed, they may be converted back into the original
estrogen in tissues
In addition to this oxidation, natural estrogens will undergo conjugation:
Modified estrogens: orally active estrogens
Because 17-beta estradiol is the most active form, we want to keep it that way
without having it being rapidly converted to the weaker compounds
Because the 17 beta alcohol is oxidised, we can protect this from happening by
attaching something else at the 17 position:
Still widely used today
The above compound is ethinylestradiol, the first orally active estrogen
Modified estrogens: IM injection estrogens
For IM depot injections, we want something long lasting
Which is why these are prodrugs
The esters must be hydrolysed into free alcohols for the drug to become active
All about medchem
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Conjugated estrogens
Also known as equine estrogens
Works for hormone replacement therapy
These are structurally similar to human estrogens
Which is why they are water soluble (easy to inject)
Called conjugated estrogens as they are conjugated to sulfates
Progesterone
Ketones are reduced to alcohols OR
OH added at the 6 position
Also orally inactive due to first pass metabolism
Basic skeleton plus:
Two carbon chain sprouting from the 17 position
Two methyl groups
They are 21 carbon steroids
Semi-synthetic progestins: esterified
Again, these esterified hormones are good for a depot injection
Notice how an ester exists
The ester is hydrolysed to form the active 17-alphahydroxyprogesterone
(bottom right)
Medroxyprogesterone acetateis in depo-Provera (bottom left)
Semi-synthetic progestins: 19-nortestosterone derivatives
Fun fact: orally active progestins may be 19-nortestosterone derivatives
Notice how there is a bulky substituent at the 17 position. This is for oral
activity
Norethindrone (top) is one of them
If it is compared to testosterone (bottom), we can see the only chance between
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Because it's only a minor change, the older generations of progestins have
androgenic activity
Which means women can grow beards, get acne etc.
them (ignoring the 17 substituent) is the lack of the methyl group on the 19
position
But they give a higher risk of CVD, a second generation one is
recommended
New generations have reduced androgenic effects
Produced from spironolactone instead of a testosterone backbone
Gives antimineralocorticoid activity (like spirinolactone)
Causes reduced breast tenderness and blood pressure
Drospirenone is quite interesting
If added to COCs, it inhibits 5-alpha-reductase (normally responsible for
converting androgens to the more active form)
Therefore, it stops androgenic effects, which is important for women with
acne (remember: androgenic effects cause acne)
Cytoproterone goes further
Pharmacokinetics
Along with enterohepatic recycling
Again, first pass metabolism is something we need to keep in the back of our
minds
May be induced by ethinyl estradiol
Note: personally, I'm going to guess here and say that means more
progestins bind to SHBG, so they are less available. I don't think that has
any clinical effects though, which is why both are put into the same pills inCOCs
Sex hormones are bound to Sex Hormome Binding Globulin (SHBG)
10 (plasma):2 (milk) for levonogestrel and 10:1 for norethindrone
Little distribution into the milk occurs
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Misc. hormones
Odd because it has no phenol ring (but it still has effects)
Has several metabolites which have their effects around the body
The hydroxy metabolites have estrogenic effects on bone (prevent
osteoporosis) and vagina (prevent dryness and itching)
The delta metabolites have progesteronic effects on the endometrium,
and androgenic effects on the brain
Tibolone is a pro drug used in hormone replacement therapy
Actually causes more estrogen to be released, because it inhibits the
negative feedback loop
i.e. makes the brain think there isn't enough estrogen, because it's
sensor (estrogen receptors) have been blocked
The E isomer is anti-estrogenic (antagonist)
The Z isomer is estrogenic (agonist)
Clomiphene is very interesting due to its isomerism
We've met this drug in GI, where it can be used to reduce gastric acid
production to protect against the harmful effects of NSAIDs
Uncouples the placenta, pushes it out
It is also able to cause uterine contractions
Good for either abortions, or helping induce contractions during childbirth
Misoprostol is a synthetic form of prostaglandin E1
Male hormones
5-alpha reductase
Testosterone can have its double bond reduced to a single bond to make it into
dihydrotestosterone
It is 3 times more potent compared to testosterone
Remember this when it comes to SAR
Structure Activity Relationship
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At least in androgens, this causes a drop in activity, but at least it's orally
active
Alkylation at the 17 position in pretty much all steroids allows a orally active
form to be made
Along with the 17 beta esterification for IM depot injection
And the 9 alpha fluro which improves activity
As stated above, 5a reduction increases the activity
Note: the androgens will have anabolic effects and vice versa
Therefore, when making an anabolic steroid, it will always have androgenic
effects (keep this in mind as a side effect)
Different modifications can improve this anabolic:androgenic ratio (like
removing the 19 carbon)
We will talk more about this in the MS module instead
Although it is not shown on the diagram below, removing the 19 carbon (themethyl group above the double bond) will improve the anabolic effects
And finally, the 3 ketone is essential for activity
Erectile dysfunction
Alpha 1 stimulates phospholipase C to produce IP3 to increase calcium
levels to maintain contraction (prevents the blood leaking into the
lacunae)
Alpha 2 inhibits adenylate cyclase to reduce cAMP levels to stop the
calcium levels from dropping, maintaining contraction
Treat pripratism (painful, long lasting erections)
PHENTOLAMINE is a potent antagonist which can be injected
Alpha antagonists can work here to prevent erections
Erection is prevented by a continuous stimulation by the sympathetic system
acting on alpha 1 and 2 adrenoceptors of the smooth vascular muscle to prevent
blood flowing into the lacunae of the corpus cavenosum of the penis
Alloprostadil (synthetic E1) works here
Activation by prostaglandin E1 stimulates adenylate cyclase to produce more
cAMP to reduce intracellular calcium levels, causing relaxation, which allows
blood to flow into the lacunae
Although it is not shown here, nitric oxide (NO) will stimulate cGMP production,
which has the same effect as increasing cAMP
Also not shown below
The penis has mostly PDE-5 and some PDE-2
There are 11 types in the body, so PDE-5 blockers are partially specific to
the penis
Lastly, cGMP is broken down by phosphodiesterase (PDE)
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Phosphodisesterase (PDE) inhibitors
Notice the far right ring (two heterocyclic rings, called a pyrimidinone)
Again, they break down cGMP. Remember: keeping cGMP allows the male to
have an erection by keeping the vascular smooth muscle relaxed
See how the two heterocyclic rings are similar to caffeine
So it's not surprising to see caffeine is a weak inhibitor of this enzyme
Weak PDE inhibitor
Long term use can cause fibrosis of the penis
Papaverine is a antispasmodic
Tertiary nitrogen is basic enough to allow the citrate salt to beproduced for greater solubility
Notice the heterocyclic ring to the left of the molecule, it is there to mimic
the cyclic phosphate on cGMP to allow for better binding
Vardenafil uses a electronically rich ring compared to sildenafil, gives
greater selectivity against PDE-5
It's ironic because Viagra comes as blue pills
Because sildenafil isn't perfectly selective for PDE-5, it can also
inhibit PDE-6 in the retina to cause blue vision (only has 10 times
selectivity of PDE-5 over PDE-6)
The ring on the right copies the pyrimidinone in cGMP, and it gives
selectivity against PDE-5
Has a half-life of around 4 hours for both
High solubility and permeability
However, they are extensively cleared by first pass metabolism
Metabolites are active
CYP3A4 is the major metaboliser of both drugs
Class I BCS drug
Sildenafil is a popular PDE-5 inhibitor
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Avoid grapefruit juice
Beware of CYP3A4 inhibitors and inducers
Taking a dose after a fatty meal reduces absorption AND delays
absorption (as tmax) as well
Sildenafil (but not vardenafil) is affected by the food effect
Looks nothing like sildenafil
Salt formation is not possible
No blue vision
Potent and selective for PDE-5
Low solubility/high permeability
Remember: no salt formation, may lead to this low solubility
Classified as Class II BCS drug
One for the weekend, keeps it up
Half-life is at least 4 times longer (17 hours) than the other two
Inactive catchecol metabolite
May be glucouridated (enterohepatic recirculation?)
Avoid grapefruit juice
Is also metabolised by CYP3A4
Very long half-life
Has a larger volume of distribution and lower clearance compared to the
other two drugs
Taladafil is another popular PDE-5 inhibitor
Different selectivities against PDE-5 (leads to reduced side effects)
Different pharmacokinetics (especially the food effect)
Longer half-life in the case of vardenafil
Why does sildenafil sell better? Probably good marketing...
It appears both tadalafil and vardenafil have advantages over sildenafil:
Must NOT be used with nitrates (taken for people who have heart disease)
Remember: nitrates release nitric oxide to cause an increase in cGMP
Since cGMP breakdown is inhibited by these drugs, cGMP builds up in the
muscle
It might be alright if this effect was locallised to the penis, but it happens
systemically (remember: none of these are perfectly selective)
Therefore, since a lot of the blood vessels dilate around the body, it causes
massive hypotension, and the person could die due to it
All PDE-5 inhibitors have a very important contraindication
Other side effects include
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Headache
GI disturbances
Nasal congestion
Postural hypotension (if you stand up, due to the minor systemic
vasodilation caused by the blockers, your brain can lose quite a bit of
blood, responsible for headaches and lightheadedness)
And again, blue vision is possible for sildenafil
Less side effects (including cardiac vasodilation)
No food effects
Fast acting
Best choice if they are taking nitrates (although it might still be a bad idea)
Avanafil is a pyrimidine derivative which is very selective for PDE-5
Apomorphine
Is a D1 and D2 dopamine agonist
Although there are some D1 and D2 receptors in the penis, they don't do very
much
The main activity is in the brain
Will actually cause erection
Give sublingually to reduce this effect somehow
However, the problem is, because it's a dopamine agonist, it also hits the
vomiting centers in the brain
Because of the side effects, it's generally not used much
Benign prostatic hypertrophy (BPH)
The prostate will actually grow over time
It can grow so large that it can block the urethra to prevent normal urination
Very common at old age
They don't have much life left anyway, why put them through quality of
life reducing treatments
The most common treatment is to monitor the growth to prevent it from causing
too much trouble
Microwaving to destroy tissue
Surgically removing the prostate
Non-pharmacological treatment includes
Relaxes muscles at the urethra to let urine pass through more easily
Alpha-1 receptor antagonists
Prevents conversion of testosterone into the more active DHT
Finasteride is the drug most commonly used
Because the prostate relies on androgenic activation for growth,
reducing androgen potency will reverse growth and may delay
surgery
Note: finasteride may also be used to treat male balding as DHT is
also responsible for balding as well
5-alpha reductase inhibitors
Pharmacological options include:
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Pre-eclampsia
Need to have both, no protein in urine is just pregnancy-induced
hypertension
High blood pressure AND protein in the urine during pregnancy
Note: this means there's a good chance they are taking an ACE inhibitor
(renoprotective effect + reduced blood pressure)
They MUST come off the ACE inhibitor/AT2 antagonist during pregnancy,
and replaced with another drug
Women with pre-existing diabetes or hypertension are more likely to have it
For diabetic patients who are normotensive (normal blood pressure), they
can temporarily come off the ACE inhibitor during pregnancy
Regardless of what type of diabetes they might have, they need keep a
tight control of blood glucose with insulin only (not the other drugs)
Without proper blood glucose control, the developing baby will convert allthe extra glucose into fat, which makes the baby much larger, and harder
to give birth to.
Notes about diabetics and pregnancy:
140/90 can be cut-offs
Hypertension
300mg/day
Proteinurea
May be caused by a protein imbalance in the blood
Peripheral odema
Hb levels decreased, free Hb causes kidney damage
Hemolysis
Elevated Liver enzymes
Low Platelets
HELLP syndrome
Headaches
Even more severe odema
Higher blood pressure
Spots in vision (due to micro-haemorrhages in the blood vessels of the
eyes)
Severe pre-eclampsia also has:
Tonic-clonic seizures (affects the whole brain, bad news for the baby as
well)
The disease progresses to eclampsia where seizures and organ failure occur ifuntreated
Signs and symptoms
Orally, 500mg tid
Alpha 2 antagonist
This leads to a decrease in blood pressure
Works at the brain, presynaptically to trigger a negative feedback
mechanism to slow down sympathetic activity
Caution: renal failure patients need a smaller dose (renally secreted)
Contraindicated with hepatic disease and depression
Side effects:
Alpha-methyldopa
Treatments
Therapeutics
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Haemolytic anaemia (watch for headaches, tiredness, paleness,
darker urine etc. discontinue)
Liver damage (watch for fever or jaundice. discontinue)
Headaches are common (continue medicine obviously)
Given IV as an emergency measure for severe pre-eclampsia
Prevents seizures from occuring
Magnesium sulfate
Beta-1 antagonist
Can be given IV during severe pre-eclampsia to counter high blood pressure
Safe for pregnancy
Labetalol
Used as a last-ditch attempt to prevent eclampsia if the symptoms can't be
controlled by the IV drugs
Only needed in premature babies
Betamethasone is given IV to encourage surfactant production in the foetal
lungs (make them a bit more mature) so the baby can breath properly
Caesarean section (C-section)
Oral contraceptives
Combined Oral Contraceptives (COC)
Progestin only pill (POP)
There are two general types of oral contraceptives available:
COCs have a 12 hour window, while POPs have a 3 hour window (Cerazette
doesn't count)
Theoretically, both the COC and POP have the same efficacy (around 99%).
However, the COC tends to be more effective as the POP has a much narrower
safety margin when it comes to compliance
Migranes with aura
History of heart or cardiovascular disease (includes hypercoagulability)
Smokers over 40
Suspected breast cancer
Liver damage/dysfunction
Obese and/or hyperlipidemia
COCs are given as a first line treatment, unless there's an absolute
contraindication present:
Smoking
Taking CYP3A4 inducers
Being overweight
And we have to be cautious in certain cases:
So if there is a contraindication present, the POP is given
Increased exposure to estrogen
Breast cancer
Hypercoagulability of the blood
Note: risk of DVT is higher in pregnancy anyways...
Deep Vein thrombosis and other CVD
Advise women the COC will increase chances of:
COC (and POP) timing
Timing is very important for contraceptives
But should be started within 5 days of menstruation
If it is started within 5 days, then no additional contraception is needed
This is because within those 5 days, another ovum can't be in the uterus,
because it just got flushed out during menstruation
Start pills on the same day as menstruation
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If you miss pills:
Vomiting and diarrhoea:
Circumstance When to take pill Other recommendations
Missed one on days
8-21 in COC
Take pill soon as you remember
(within 12 hours) or take two
the next day
Extra precautions not
needed
Missed one on days 1-7
in COC
Same as above Consider ECP if
unprotected intercourse
Missed 2 COC pills
within 7 days (during
days 1-14)
As above
7 day rule (->)
Extra precautions for 7
days (until 7 active pills
taken)
Consider ECP if
unprotected intercourse
Missed 2 COC pills
during 15-21 (last week)
Start next pack immediately
(pills during 22-28 are inactive
anyway, we're skipping it)
Missed POP by 3
hours/12 hours withCerazette
Take as soon as possible, can
combine 2 pills, carry on asnormal
Varies, check on pack
(generally extraprotection)
COC + vomiting/diarrhoea
for >24h
As
above
Addition contraceptive method + 7 day
rule
POP + vomiting/diarrhoea ? Varies, check info on pack
Originally thought to cause failure due to reduced enterohepatic
recycling of the estrogen
Normal antibiotics will not cause failure of the medicine
Rifampicin is the common one
St John's Wort is not an antibiotic, but it induces CYP3A4 as well
Practice 7 day rule, where you should use additional contraception
during the antibiotic course AND for 7 days (7 complete pills) after
treatment
NOTE: CYP3A4 inducers cause failure, not inhibitors (so grapefruit is
fine because it's an inhibitor, not an inducer)
But antibiotics which will cause CYP3A4 induction can cause failure of the
COC
In addition, antibiotics can cause vomiting and diarrhoea, follow
instructions as above
What about antibiotics?
Generally are made with copper
Copper prevents sperm motility and irritates the endometrium, preventing
implantation of the embryo
Sits inside the uterus, needs replacing every few years
Intrauterine devices
Tie the fallopian tubes
Surgery
Non-pharmacological treatments
Erectile dysfunction
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Tends to be experienced by older males
The body is fine, brain is not
Stress, anxiety and reduced libido etc.
Psychogenic
The body isn't fine, there's something stopping it from going up
Metoprolol and other beta blockers can cause it
Excessive alcohol
Smoking
Decreased physical activity
Surgery on or around the prostate
Neuropathy near the region (poor, poor diabetics)
Organic
But can also be a mix of the two
Has two causes:
Pharmacological treatments
Tadalafil, sildenafil
Prevents the breakdown of cAMP, which causes extended relaxation of
smooth muscles, allowing blood to flow into the lacunae of the penis
Taken orally
Which is a shame, people who are on nitrates tend to need it
If nitrates are taken, it causes systemic vasodilation and death
WARNING: contraindicated with nitrates
Postural hypotension (because of vasodilation)
Nausea and headaches
Vomiting
Sildenafil: Warning: can cause blue vision
Can cause vascular, GI or psychiatric disorders
Fatty foods should be avoided
Avoid grapefruit juice and its products
PDE-5 (phosphodiesterase-5) inhibitors
Synthatic prostaglandins (E1)
Stimulates adenylate cyclase to produce more cAMP for muscle relaxation
Given intraurethrally or injected
Works for people with CVD or nitrates
Can form nodules on the penis or cause pripatism (painful, long erections)
Alprostadil
Works at brain and penis
Mostly the brain, not so much at the penis
Dopamine agonist at D1 and D2
Given sublingually or injected into the penis
Remember: these receptors exist in the CTZ of the brain
Strong emetic ability
Also contraindicated in CVD and nitrate use
Apomorphine (not really used)
Reduce smoking and drinking
Increase exercise
Lifestyle modification
Good for psychogenic causes
Psychotherapy/ couples counselling
Penis pump
Non-pharmacological treatments
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Most effective non-pharmacological treatment for organic causes
Potentially painful
Insertion of things into the penis
Last line measure
Surgery
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Patient Assessment