Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5873_Библиотеки_им_академика_М_И_Перельмана.pdf
392 Chapter 15 Thyroid disorders and pharmacological methods of contraception
OH
the ovarian and menstrual cycles described above. ese
include:
• suppressing the release of follicle-stimulating hormone
(oestrogens)
• alteration of the endometrial structure and uterine
conditions which are then less favourable for
fertilization and implantation (progestogens and
oestrogens)
• inhibiting the surge of luteinizing hormone to prevent
ovulation (progestogens)
• production of thicker, more acidic mucus which is
more dicult for sperm to penetrate (progestogens)
• slowing the motility of the Fallopian tube, reducing the
movement of sperm through the oviduct
(progestogens).
15.4.1 Synthetic oestrogens
e most commonly used synthetic oestrogen is
ethinylestradiol (Figure 15.8). e alterations to its
structure make it less susceptible to rst-pass metabolism
than the natural oestradiol, and therefore improve its
bioavailability. e other commonly used synthetic
oestrogen is mestranol, the 3-methyl ester pro-drug of
ethinylestradiol, which undergoes conversion in the liver.
Given that about 70% of mestranol is converted to
ethinylestradiol, 50 g of mestranol is equivalent to 35 g
of ethinylestradiol.
Synthetic oestrogens are extensively metabolized by
cytochrome P450 enzymes in the liver, and are secreted
from hepatocytes as constituents of bile. Once emptied
into the intestines some of the metabolites of
ethinylestradiol are converted back to the parent
compound by bacteria in the gut, and can be reabsorbed
to enter the circulation via the hepatic portal vein. (is is
the enterohepatic circulation—the means by which the
body salvages and recycles cholesterol-containing bile
salts from the gut, thereby avoiding unnecessary
expenditure of energy in their de novo synthesis.) As a
result there are two peaks in the pharmacokinetic prole
of ethinylestradiol, the rst reecting initial absorption,
and the second from reabsorption from the small
intestine. Broad-spectrum antibiotics can potentially
interact with combined oral contraceptives containing
ethinylestradiol by reducing intestinal bacteria, thereby
decreasing the reabsorption from the small intestine.
While this could theoretically arise with any broadspectrum antibiotic, it is believed to contribute only to the
reduced eectiveness of oral contraceptives when used
alongside rifampicin and rifabutin, antibiotics used in
tuberculosis. Even then, the contribution of this
mechanism to reduced eectiveness of the synthetic
oestrogen is not clear cut, as these antibiotics are also
strong inducers of the CYP3A4 isozymes responsible for
metabolizing oestrogens (see below).
15.4.2 Synthetic progestogens
A number of synthetic progestogens (or progestins) are
used as hormonal contraceptives. ey can be roughly
divided into ve groups: progesterone analogues, older
testosterone analogues, newer testosterone analogues,
spironolactone analogues, and anti-androgens (Table 15.3).
e newer progestogens desogestrel, drospirenone,
gestodene, and cyproterone have less androgenic
activity and are generally reserved for patients who suer
adverse drug reactions with older progestogens, such as
acne, depression, and weight gain.
15.4.3 Combined oral contraceptive pills
ese hormonal contraceptive pills contain a
combination of synthetic oestrogens and progestogens.
e combined pills are often referred to as rst, second,
or third generation, based on the quantity and type of
oestrogen or progestogen they contain. First-generation
pills used high doses of oestrogen (more than 50 g of
ethinylestradiol, or its equivalent) and were withdrawn in
the 1970s because of increased risk of deep vein
thrombosis and pulmonary embolism (see below). e
CH
3
H
H
H
HO
Oestradiol Ethinylestradiol Mestranol
Figure 15.8 Structure of commonly used synthetic oestrogens.
HO
HO
H
H
H
HO
H
H
O
H
15.4 Pharmacological methods of contraception 393
Table 15.3 Commonly used progestogens
Progesterone
analogues
Dydrogesterone Norethisterone Desogestrel Drospirenone Cyproterone
Medroxyprogesterone Norgestrel Norgestimate
Older testosterone
analogues
Levonorgestrel Gestodene
Newer testosterone
analogues
Etonogestrel
Spironolactone
analogues
Anti-androgens
oestrogen content of second-generation pills is 35–50 g
of ethinylestradiol or its equivalent, combined with older
testosterone analogues (e.g. levonorgestrel). e thirdgeneration pills combine oestrogens (sometimes with
doses as low as 20 g ethinylestradiol, or its equivalent)
with new, less androgenic progestogens (e.g. desogestrel).
Combination pills can also be classied as monophasic,
where the amounts of oestrogen and progestogen are
xed for all active tablets, or phasic, where the amounts
vary throughout the pill pack. Compared with
monophasic pills, phasic pills reduce the total amount of
hormone taken, and are also designed to match the
natural ovarian cycle more closely.
e oestrogen and progestogen components each
contribute to the contraceptive action (see above). When
used correctly, the combination pill is an extremely
eective method of contraception; the estimated
probability of pregnancy is 0.3%. It is taken once a day at
about the same time, but a dose is only considered missed
if not taken with 24 hours of that time.
Combination pills decrease the incidence of menstrual
bleeding, premenstrual tension, irregular periods,
anaemia, uterine broids, and ovarian cysts. Oestrogens
suppress lactation, and therefore the combined pill is not
suitable for use when breastfeeding. e common adverse
eects experienced include nausea, vomiting, weight
gain, acne, breast tenderness, and breakthrough bleeding.
Most of these can be addressed by changing the pill to one
with a dierent (usually lower) concentration of oestrogen
and/or a newer progestogen with less androgenic activity.
e adverse eect of greatest concern with combined pills
is increased risk of cardiovascular disease, arising from
enhanced coagulability of the blood. is includes
venous thromboembolism (deep vein thrombosis and
pulmonary embolism), myocardial infarction, and stroke.
e increase in the risk of thrombosis depends on the
oestrogen dose and the type of progestogen, and is
greatest with prolonged use and where additional risk
factors exist (e.g. smoking). e risk appears lowest with
low doses of ethinylestradiol in combination with older
progestogens (e.g. norethisterone or levonorgestrel). e
greatest risk is with high dose oestrogens, and
combinations using newer progestogens (e.g. desogestrel,
gestodene, or drospirenone). e combined pills may be
associated with a slightly increased risk of cervical cancer,
which again increases with prolonged use; patients are
advised to have regular cervical smear tests. e
association with an increased risk of breast cancer is
unclear, but is believed to be minimal.
Co-cyprindiol (cyproterone and ethinylestradiol) is used in
the treatment of severe acne in women of child-bearing age;
the anti-androgen properties of cyproterone are benecial
in reducing sebum production (see Chapter 8, Section
8.8.3). Hirsutism can also be treated with this combination
pill, as hair growth is also androgen-dependent.
e interaction of the combined oral contraceptive pill
with the antibiotics rifampicin and rifabutin has already
been mentioned. In addition the ecacy of the
combination pill is reduced by a number of other drugs
which are inducers of the cytochrome P450 3A4 isozyme.
ese include carbamazepine, phenytoin,
phenobarbitone, and some antiretroviral drugs, as well as
the herbal medication St John’s wort.
15.4.4 Transdermal patch
A combination of ethinylestradiol and the progestogen
norelgestromin is available as a transdermal patch,
applied once a week for three of the four weeks of the
menstrual cycle. Adverse eects are the same as those for
the combined pill, and additionally local irritation due to
the patch adhesive.
15.4.5 Progestogen-only pill
is type of contraceptive pill (also called the mini-pill)
contains only a synthetic progestogen, such as
desogestrel or levonorgestrel. e contraceptive action
394 Chapter 15 Thyroid disorders and pharmacological methods of contraception
largely results from the production of mucus that sperm
cannot survive in or penetrate. In addition progestogens
inhibit the production of luteinizing hormone to suppress
ovulation (desogestrel acts primarily in this way).
Progestogen-only pills have the advantage over the
combination pill of not aecting breastfeeding, and can
therefore be used in the post-partum period. ey are
also useful in patients who cannot tolerate oestrogens,
for instance where the combination pill has led to
hypertension. ere is insucient data to compare the
ecacy of the progestogen-only pill with that of the
combined hormonal contraceptive pill. e
progestogen-only pill, however, has reduced exibility
in terms of when it is taken; this must be ± 3 hours of the
same time every day in order for it to be eective.
Changes to the menstrual cycle and increased or
decreased bleeding at menstruation are the most
common side eects. e long-term eects are less clear
than those of the combined pill, which has been in use
for longer.
15.4.6 Long-acting progesterone-only
contraception
Synthetic progesterone derivatives can be administered
by intramuscular or subcutaneous injection (e.g.
medroxyprogesterone) to provide long-acting
contraception for up to 12 weeks. With subcutaneous
implants (e.g. etonogestrel and levonorgestrel), this can
be extended for up to 5 years, providing an eective and
convenient method of contraception. Adverse eects are
similar to those of progestogen-only pills.
An intrauterine device impregnated with a synthetic
progesterone, such as levonorgestrel, can be inserted into
the uterus where it slowly releases progesterone, thereby
providing long-term contraception for a period of up to 5
years. Local irritation is the most common adverse
reaction. Once the device is removed, fertility rapidly
returns.
15.4.7 Post-coital or emergency
contraception (‘morning after pill’)
A very high dose of the synthetic progestogen
levonorgestrel administered within 72 hours of
unprotected sex prevents pregnancy in 75% of cases; it is,
though, more eective the sooner it is taken. e
mechanism of action is as detailed above. It can be taken
either as two tablets 12 hours apart (750 g
levonorgestrel) or as a single dose (1500 g
levonorgestrel). Nausea and vomiting are the most
common side eects, and are more likely with the single
dose. If vomiting occurs within 2 hours of taking the
tablet(s) a replacement dose should be taken.
Key references and suggested reading
Frye CA. An overview of oral contraceptives. Mechanism of
action and clinical use. Neurology 2006; 66: 29–36.
Zhang J, Lazar MA. e mechanism of action of thyroid
hormones. Ann Rev Physiol 2000; 62: 439–66.
SUMMARY OF DRUGS USED FOR THYROID DISORDERS
Therapeutic class Drugs Mechanism of action Common clinical uses Comments Common adverse drug reactions
Thyroid hormones Levothyroxine
(thyroxine)
Liothyronine (T3 or
triiodothyronine)
Radioactive iodide
131
I Taken up into the thyroid and
Thioureylenes Carbimazole
Propylthiouracil
Iodide ions Lugol’s solution Blocks synthesis and release of
-adrenoceptor antagonists
Propranolol Competitive antagonist at
(-blockers)
Thyroid hormone replacement Hypothyroidism Usually seen when excessive dose
taken)
Diarrhoea
Vomiting
Arrhythmia
Anginal pain
Excitability
Insomnia
emits -radiation, which destroys
follicles, reducing production of
Hyperthyroidism Very effective
Takes 3–4 months to see
full effect
Hypothyroidism
thyroid hormones
Block thyroperoxidase enzyme in
follicles to inhibit incorporation of
iodide into thyroglobulin molecule
Propylthiouracil also prevents
peripheral deiodination of T4 to T
thyroid hormones by inhibiting
iodide organification. This leads
to thyroglobulin accumulation and
Hyperthyroidism Mainstay of treatment for
hyperthyroidism
3
Thyrotoxicosis
Severe thyrotoxic crisis
Commonly used prior to
resection; facilitates surgery
by making gland firmer and
smaller
Bone marrow suppression
(agranulocytosis and neutropenia)
GI upset
Allergic reactions
Angioedema
Bronchitis
Laryngitis
Cold-type symptoms
a reduction in the number of
blood vessels in the thyroid gland
-adrenoceptor
Reduces sympathomimetic
actions of thyroid hormones
Hyperthyroidism Used for rapid relief of
thyrotoxic symptoms
Can be combined with
thioureylenes or adjunct to
See Drug summary table in Chapter 5
radioiodine
15.4 Pharmacological methods of contraception 395
SUMMARY OF DRUGS USED FOR CONTRACEPTION
396 Chapter 15 Thyroid disorders and pharmacological methods of contraception
Therapeutic
Drugs Mechanism of action Common clinical uses Comments Common adverse drug
class
Oestrogens Ethinylestradiol
Synthetic
progestogens
Mestranol
Progesterone analogues:
e.g. Dydrogesterone
Medroxyprogesterone
Older testosterone
analogues:
e.g. Norgestrel
Levonorgestrel
Newer testosterone analogues:
e.g. Desogestrel
Gestodene
Spironolactone analogues:
Drospirenone
Anti-androgens: Cyproterone
Inhibit secretion of folliclestimulating hormone to
suppress development of
ovarian follicle
Alter uterine conditions to
discourage implantation
Promote production of acidic
cervical mucus impenetrable to
sperm
Inhibit secretion of luteinizing
hormone to prevent ovulation
Contraception
Hormone replacement
therapy
Contraception Used alone. e.g. desogestrel,
In combination with progesterone
as combined oral contraceptive
pill
levonorgestrel, in progestogenonly pill
Combined with oestrogen in
combined oral contraceptive pill
Analogues with less androgenic
activity, e.g. desogestrel,
gestodene, and drospirenone,
useful for patients who suffer
adverse drug reactions such as
acne, depression, and weight
gain with other progestogens
reactions
Hypertension
Oedema
Weight gain
Venous thromboembolism
Menstrual disturbances
Premenstrual-like symptoms
WORKBOOK 12
Treatment of thyroid disorder
and contraception
Sunita: a simplified case history
Sunita has lost a lot of weight recently, and has been complaining of palpitations and insomnia.
She has also been quite irritable. She has not had a period for 2 months, but several pregnancy
tests have been negative. Last night the palpitations got worse, and she knew it was time to
admit that something was not quite right. Her husband Eoin has persuaded her to go to
hospital.
A table of clinical clerking abbreviations is given on page xviii.
CLINICAL CLERKING FOR SUNITA KAISER
Age: 27 years
PC: Severe palpitations, fatigue, and minor difficulties in swallowing. Throat protruding and eyes bulging.
HPC: These symptoms have gradually got worse over the last 2 months. She has also lost weight and
missed two periods.
PMH: Nil significant
Sunita has had no significant illnesses.
DH: Oral contraceptives
SH: Married, lives with husband, no children
O/E: Flushed moist skin, tremor and nervousness, muscle weakness, thinning of hair, exophthalmos,
and mild goitre.
Pulse = 120 beats/min (normal: <70)
Although non-specific, Sunita’s symptoms are consistent with hyperthyroidism.
Her swallowing difficulties are the result of a mild goitre due to enlargement of the thyroid gland.
Exophthalmos—protrusionoftheeyeballs—isasignofGraves’disease,oneformof
hyperthyroidism.
The doctor decides to admit her and to check her thyroid function tests.
Biochemistry:
1) Thyroxine (T4) = 180 nmol/l (reference: 64–154 nmol/l)
398 Chapter 15 Thyroid disorders and pharmacological methods of contraception
2) Triiodothyronine (T3) = 4 nmol/l (reference: 1.1–2.0 nmol/l)
3) Thyroid-stimulating hormone (TSH) = 0.1 mIU/l (reference: 0.5–4.7 mIU/l)
Sunita’s results are consistent with hyperthyroidism. Note that T4 and T3 are elevated, while
TSH is low.
Diagnosis: Hyperthyroidism (Graves’ disease)
Plan:
• Administer Lugol’s solution
• Commence propranolol and carbimazole
The doctor tells Sunita that she most likely has a type of hyperthyroidism called Graves’
disease. He explains that thyrotoxicosis is caused by excessive activity of the thyroid
hormones, which increases metabolic rate.
1a) What are the two thyroid hormones called?
1b) What is thyroglobulin and where is it found in the thyroid gland?
2) Elaborate the main steps in the synthesis, storage, and secretion of thyroid hormones.
3a) Name the hormones secreted by the hypothalamus and pituitary, which regulate the function of the
thyroid gland.
3b) List one aspect of thyroid hormone synthesis controlled by thyroid-stimulating hormone.
4) Why may thyroxine (T4) be regarded as a pro-hormone?
5) How do thyroid hormones act on target cells?
6a) What are the two main types of hyperthyroidism, and how do they differ?
6b) What are the symptoms of thyrotoxicosis?
6c) What is the cause of Graves’ disease?
6d) Why are Sunita’s levels of thyroid-stimulating hormone low?
The doctor explains to Sunita that three drugs will be used initially to manage her
hyperthyroidism and its symptoms. She may eventually need surgery if the drugs fail to work.
She spends two nights in hospital, but then returns home as many of her symptoms have
calmed down.
7) List three treatment options for hyperthyroidism.
8) What type of drug is carbimazole and how does it act?
WORKBOOK 12 Treatment of thyroid disorder and contraception 399
9) Why is propranolol used in hyperthyroidism even though it has no direct effect on the thyroid gland?
A month later Sunita is readmitted to hospital complaining of a sore throat and cough. She has
a full blood count, which reveals that her neutrophil count is extremely low.
10) What is the most probable cause of Sunita’s low neutrophil count?
Dr Knight, the senior doctor on the medical team, comes to see Sunita. She explains the cause
of the low white blood cell level.
ShechangesSunita’smedicationfromcarbimazoletopropylthiouracil.
Sunita seems to tolerate this better and is discharged after a few days.
Another four months on, during a follow-up, the doctors decide that her symptoms are not
improving. Surgery or radioactive iodine therapy are proposed. Sunita doesn’t like the idea of
an operation, and chooses radioactive iodine therapy.
Following the treatment blood tests reveal that Sunita’s thyroid hormone levels are lower than
normal. She is also feeling very lethargic, and is putting on weight. The doctor explains that
hypothyroidism is often seen after radioiodine therapy.
Sunita is told that she needs to start taking thyroid replacement tablets.
11a) Which tablets is the doctor referring to?
11b) How do these tablets work?
12) What are the signs and symptoms of hypothyroidism?
Sunita begins taking levothyroxine tablets.
Before the radioiodine treatment Sunita started taking contraceptive pills; she was advised
against getting pregnant while undergoing the treatment.
She takes one tablet each day. She knows that of the 28 tablets in a pack, only 21 of these are
active; the other seven are included only to increase compliance.
Since she started taking them her menstrual cycle has changed, and her periods are shorter
and more regular.
13a) What is the ovarian cycle?
13b) What are its two phases? When does ovulation occur?
13c) Which hormone dominates in each of the two phases?
14) What is the menstrual cycle?
400 Chapter 15 Thyroid disorders and pharmacological methods of contraception
15) What are the names of the hormones released by the anterior pituitary, which coordinate events in
the ovarian and menstrual cycles?
16a) At what stage of the ovarian cycle do oestrogen levels peak? What is the effect of this on the level
of luteinizing hormone, and what does it lead to?
16b) What is the name of the follicular cells that secrete oestradiol?
17) What is the corpus luteum? Which hormone does it mainly secrete?
18) What happens in the absence of pregnancy at the end of the luteal phase? What is this commonly
called?
19) What are the two main types of oral contraceptive pill?
20a) Explain the following:
Monophasic combined pill
Phasic combined pill
20b) What is the mechanism of action of the combined pill?
21) What is the mechanism of action of the progesterone-only pill?
22) List drugs that interact with oral contraceptives and explain why they do so.
Sunita decides she would rather not use any hormonal contraception because her friend
Monique suffered a severe adverse drug reaction whilst on the pill, and needed heparin and
warfarin to treat it (see Workbook 1).
23) What adverse drug reaction was Monique referring to?
Part 5
Central nervous
system