- 2 - rama nada - malik · hypo/hyperthyroidism we should revise the thyroid hormones (we took them...
TRANSCRIPT
- 2
- Rama Nada
- Ensherah Mokhemar
- Malik
When you see * refer to the index at the bottom of the page
Quick revision:
in the previous lecture we talked about:
1- Growth Hormone physiology
2- Growth Hormone deficiency and drugs which are used to treat it
3- Excessive Growth Hormone secretion and drugs which are used to
treat it, we stopped here.
In today’s lecture we are going to discuss:
1- To continue our talking about excessive GH secretion medications
2- Prolactin hormone
3- We’ll start talking about Thyroid hormones
Let’s go…
Excessive Growth hormone secretion in children causes Gigantism, while
in adults it causes Acromegaly. In both cases we need to decrease the
secretion or the effect of Growth hormone by one of these methods:
Now we’ll discuss them:
1.Dopamine influences Growth hormone release, it inhibits the
secretion of GH at the level of pituitary gland and hypothalamus. We
give dopamine analogue as the half-life of dopamine is short.
2.Somatostatin is a 14 amino acid inhibitory peptide, it’s secreted in the
hypothalamus, CNS, pancreas, GIT. Somatostatin has an inhibitory effect
on Growth hormone release in addition to inhibiting all the functions of
How to antagonize GH?
1.Dopamine receptor
agonists, ex: bromocriptine
2.Somatostatin
analogs, ex: octreotide
3. GH receptor antagonists,
ex: pegvisomant
Inhibite the secretion
of GH
Inhibite the secretion
of GH
Inhibite the binding of GH
to its receptors (antagonist)
GIT starting from motility (Anti-diarrheal), secretion of gastrin and
secretin, acid secretion and pancreatic secretions including glucagon and
insulin. So, Somatostatin lack the specificity in its function on growth
hormone (anti-GIT + inhibit GH release).
Octreotide: its an analogue of somatostatin, more specific toward the
brain, consequently more active on inhibiting GH secretion than its anti-
GIT effect (but still have some activity on GIT). So, it won’t inhibit the
motility (won’t cause constipation) or insulin secretion (won’t cause
hyperglycaemia) as much as somatostatin. (45 times more potent than
somatostatin in inhibiting GH release but only twice as potent in
reducing insulin secretion, and that’s what we want).
- Its Half-life is around 80 min.
- it’s Given subcutaneously 3 times a day for treating acromegaly.
Therapeutic uses:
1- Reduces symptoms caused by a variety of hormone-secreting
tumors, especially for adenomas in the anterior pituitary which
secrete growth hormone: acromegaly, carcinoid syndrome,
gastrinoma, VIPoma, glucagonoma, insulinoma, and ACTH-
secreting tumor.
2- Severe diarrhoea* induced by something, such as: secretory, HIV
associated, diabetic, chemotherapy, or radiation induced.
3- Acute control of bleeding from oesophageal varices (portal
hypertension).
Adverse effect:
1- Hyperglycemia: as octreotide has inhibitory effect on insulin and
glucagon secretion, rare and may be transient.
2- Pain at site of injection.
3- GIT effect (as it inhibits GIT functions): nausea, vomiting,
abdominal cramps, flatulence, steatorrhea with bulky bowel
movements.
4- Vitamin B12 deficiency with long-term use (reduced absorption).
5- The most important adverse effect is to induce Biliary sludge and
gall stones (seen in 20-30% of patients after 6 months of use).
*Note: mild to moderate diarrhoea is treated by suppurative therapy (water and salts), but if it was severe
and induced by something you have to interevent, and sometimes to use strong drug such as octreotide.
6- Sinus bradycardia* (25%) and conduction disturbances in the
heart (10%), as a result of inhibiting GH secretion
3.Pegvisomant: it’s a GH receptor antagonist (more specific, doesn’t
affect GIT functions). However, it doesn’t replace octreotide and other
drugs, but why? Look to the first point of the adverse effects below.
- It doesn’t affect GH release instead it affects GH binding to its
receptors.
- Useful for treatment of acromegaly.
- Is a polyethylene glycol (PEG) derivative of a mutant GH (modified
version of GH).
- PEGylation reduces its clearance and improves its overall clinical
effectiveness (several polyethylene glycol polymers have been
covalently bound in order to slow clearance from blood).
- It has increased affinity for one site of the GH receptor and
reduced affinity at the second binding site.
- This allows dimerization of the receptor but blocks the
conformational changes required for signal transduction.
- In acromegaly patients the level of both GH and IGF-1 are high
when they are treated with Pegvisomant, it Normalizes IGF-1
levels, but does not inhibit GH secretion thus it will remain high.
Adverse effect:
1- With long time of usage, it may lead to increased GH level and
possible adenoma growth, this adverse effect is the crucial one
which makes Pegvisomant doesn’t replace other nonspecific GH
secretion inhibitors. But why Pegvisomant causes adenomas
growth?
Because Pegvisomant interferes with GH binding to its receptor
and doesn’t affect the secretion. So, when it blocks the receptors
the body still needs the activity of GH, so it will response through
a positive feedback to increase the level of GH, in these patients
the level of GH will be twice time as normal GH level, and this is
bad as they have already high level of GH (acromegaly or giantism
patients). So, continues stimulation and positive feedback
response will cause adenoma growth.
2- Elevation of liver enzymes.
* Note: growth hormone and somatomedin are known to increase cardiac contractility and
heart strength, so inhibiting GH secretion causes bradycardia.
Prolactin
We have finished talking about Growth hormone, now well discuss a
related topic which is prolactin hormone.
Prolactin is a 198 A.A peptide hormone that is also secreted by the
anterior pituitary and similar in structure to growth hormone. Its
primary function is to stimulate and maintain lactation (breast feeding)
in the presence of estrogens, progestins, corticosteroids, and insulin.
It’s also important in men, high blood prolactin concentration interferes
with the function of the testicles, the production of testosterone (the
main male sex hormone), sperm production and cause infertility. Low
testosterone causes decreased energy, sex drive, muscle mass and
strength, and blood count (anemia).
Estrogen stimulates prolactin secretion in the pituitary gland cells, that’s
why there is prolactin secretion during pregnancy. It’s also stimulated by
TRH.
In pregnant women there is a relatively high level of prolactin, so why
there is no milk production?
Because estrogen inhibits prolactin receptors on milk producing cells
Milk production starts in the third day after delivery, when the estrogen
level decreases so it won’t inhibit prolactin receptors consequently, milk
production will occur.
During breastfeeding there is a high level of prolactin produced by
positive feedback, milk sucking will send neuronal stimulant to the
anterior pituitary to release more prolactin thus more milk.
Extra note mentioned by the Doctor:
How mammary glands produces milk? After delivery when the placenta gets out
from the body, estrogen level will return normal and prolactin will bind to its
receptors to produce milk. Prolactin binding will activate JAK/STAT signalling
pathway which increase the transcription and translation of several proteins, also it
will open transporters in these glands to pick up minerals, IgG, IgM and other
substances from mother’s blood. For that reason, breastfeeding is sufficient to feed
infants in the first 6 months even without give them water and it will give them a
great immunity (read about this topic, it’s very interesting).
Too much prolactin inhibits the release of GnRH from hypothalamus, so
Hyperprolactinemia causes hypogonadism (FSH and LH) and this leads
to:
In women infertility, oligomenorrhea or amenorrhea, and
galactorrhea in premenopausal women.
In men loss of libido, erectile dysfunction and infertility
- The prolactin-inhibiting hormone is dopamine.
- Dopamine agonists are used to manage hyperprolactinemia.
*If the nursing mother doesn’t produce sufficient milk its not applicable
to give her prolactin as prolactin half-life is short (However, it works in
animals), instead we antagonize dopamine effect.
* Hyperprolactinemia is the most common disorder of the anterior
pituitary gland.
How to antagonize Hyperprolactinemia? By giving dopamine* agonist
As dopamine has negative activity on prolactin production.
In reality we don’t give dopamine as most of it is broken down in the
periphery and doesn’t reach CNS. So, instead we give dopamine agonist.
The simplest one is Bromocriptine, it is given as one shot to inhibit
lactation and suppress breastfeeding.
Pharmacodynamics:
1- Suppress prolactin release effectively in patients with
hyperprolactinemia.
2- GH release in acromegaly is suppressed but less effectively**.
3- Improve motor function and reduce levodopa requirements in
Parkinson’s disease.
Note that Dopamine agonists differ from each other by the half-life and
the dosage, as shown in the following table:
Cabergoline 65 hours Twice weekly, or once daily with small dose
Quinagolide 20 hours Once daily
Bromocriptine 7 hours 3 times daily
* Dopamine is also called “prolactin inhibiting hormone” PIH
**if you forget it refer to page 2, point 1
Therapeutic uses:
1- Hyperprolactinemia:
• Shrink pituitary prolactin-secreting tumors.
• Lower circulating prolactin levels.
• Restore ovulation in ~ 70% of women with microadenomas and
~ 30% of those with macroadenomas.
2- Suppression of physiologic lactation to prevent breast
engorgement when breastfeeding was not desired. (discouraged
use, as breastfeeding is desired for infants).
Too much milk within the breast without sucking it by the baby
will cause breast engorgement, this will increase the pressure and
cause fever to the mother, so she need to go to hospital and suck
the milk.
3- Acromegaly.
4- Parkinsonism
Adverse effects:
1- Remember when we took anti-emetics in the GIS, we said that
they work on dopamine or serotonin, so they are anti-
dopaminergic, as dopamine and dopamine agonists cause Nausea,
vomiting, headache, fatigue and light-headedness.
2- Orthostatic hypotension remember that dopamine has kidney
dose, cardiac dose and vessels dose as it binds to alpha and beta
receptors depending on the dose. The kidney dose dilates the
vessels of the kidney thus increase the perfusion, so it decreases
the pressure and causes “Orthostatic hypotension”.
3- Psychiatric manifestations even at lower doses and may take
months to resolve (don’t appear in all patients).
Our life and personality are based on dopamine, serotonin and
norepinephrine. Dopamine is responsible for excitement and
movement*.
Schizophrenia patients have hallucinations and positive thoughts,
and this is due to excessive dopamine, so they are treated with
dopamine antagonist. Consequently, patients who take dopamine
agonists suffer from schizophrenia and psychiatric manifestations.
* Dopamine controls movement, Parkinson patients have low dopamine level, so they are treated with
dopamine or dopamine analogue.
4- Erythromelalgia (paroxysmal throbbing and burning pain in the
skin, affecting one or both legs and feet, sometimes one or both
hands).
5- Pulmonary infiltrates with chronic high dose therapy
6- No apparent increase in spontaneous abortion or congenital
malformations if given during pregnancy for macroadenomas.
7- Stroke or coronary thrombosis in postpartum women taking
bromocriptine to suppress postpartum lactation.
Dr.Malik advice you to revise prolactin physiology
We’ve finished our talking about prolactin you deserve 15 minutes
break…
Now let’s continue…
Thyroid gland
it’s very important as thyroid gland disorders (hyper, hypo) are common
among ladies (female: male 4:1).
Thyroid gland physiology:
pituitary gland is stimulated by TRH (Thyroid releasing hormone) from
hypothalamus to release TSH (Thyroid stimulating hormone), which act
on thyroid gland and stimulate it to release T3 and T4.
Hypothalamus is stimulated to release TRH by cold (as thyroid hormone
increases body temperature), acute psychosis*, circadian and pulsatile
rhythms.
Sever stress inhibits the release of thyroid hormones by acting on
hypothalamus gland and inhibiting TRH secretion.
T3 and T4 affect hypothalamus and pituitary gland by feedback
inhibition to decrease the release of TRH and TSH.
All these words are summarized in the following figure (see the next
page):
* it’s a symptom of serious mental disorder, acute psychosis is caused by hypothyroidism, so it
stimulates the hypothalamus to increase TRH level and consequently T3 and T4 level
Before we start pharmacology and learn how to treat
hypo/hyperthyroidism we should revise the thyroid hormones (we took
them in physiology if you remember : ’)).
- Thyroid gland releases two hormones from follicular cells, they are
T3 (triiodothyronine) and T4 (thyroxin).
- Thyroid gland is a trapper for iodide (uptake iodide from all the
body).
- Thyroid gland has Co-transporter for iodide, when iodide enter
the cell it’s converted to organic iodine by peroxidase enzyme,
then iodine binds to tyrosine residues within thyroglobulin
molecule, if one iodine bind to one tyrosine the resulting molecule
will be mono tyrosine and if two iodine molecules bind to one
tyrosine residue the resulting molecule will be diiodotyrosine.
- Then coupling occurs:
Monoiodotyosine + Diiodotyrosine Triiodothyronine (T3)
Diiodotyrosine + Diiodotyrosine Tetraiodothyronine
(T4/Thyroxine)
- Until now the products are present in the follicles, but how they
are secreted?
T3 and T4 within thyroglobulin molecule are back to the cells by
pinocytosis, then thyroglobulin is cleaved by protease within the
lysosomes to produce free T3 and T4 which are stored in the gland
and then released to the blood upon stimulation.
- The free forms of thyroid hormones, T4 and T3, dissociate from
thyroid-binding proteins, enter the cell by the active transporters.
- Within the cell T4 is converted to T3 by 5'deiodinase.
- T3 enters the nucleus where it binds to a specific T3 receptor
protein.
- The T3 receptor exists in two forms, α and β.
Notes:
T4 is secreted in larger amount but the active form is T3 (the
potency is 4 for T3 and 1 for T4), so T4 is converted to T3 inside
the cell by deiodinase.
There are drugs prevent the conversion of T4 to T3, and others
inhibit the secretion of T3 and T4 (we’ll discuss them in detail
Inshallah).
- Activation of nuclear receptor leads to increased formation of
mRNA and subsequent protein synthesis (delay in onset of action
hours-days).
- Affinity of the receptor for T4 is about 10 times lower than T3.
- The number of nuclear receptors may be altered to preserve body
homeostasis.
Remember:
We studied that there are 4 types of receptors; G protein coupled
receptors, enzyme linked receptors, channels ligand and
intracellular receptors, thyroid hormone receptors are example on
intracellular receptors the main feature of intracellular receptors
is delayed function (it may take days), as they are work on
nucleus, genes transcription and proteins translation.
- The receptors of thyroid hormones are distributed in all the cells
of the body, so their function and effect will be distributed.
- Thyroid hormones Normalize growth and development, body
temperature, and energy levels, aslo they are used as thyroid
replacement therapy in hypothyroidism.
- The half-life of T4 is 7 days while it’s only 1 day for T3, there is a
huge difference between them. Both T3 and T4 are bound to a
carrier protein in the blood, some of them are free to do their
activities*.
*remember from physiology we said that the majority of these hormones are bound to carrier
protein while only little amount are free to be functional).
This figure summarizes the previous steps.
But in case of hypothyroidism what we’ll give the patient T3 or T4 and
why?
In most cases we give T4 due to its long half-life compared to T3, but in
some cases when we need rapid action we give T3 (severe
hypothyroidism) to save that patient from lethal coma.
From slides:
T4 & T3 are available for replacement therapy as levothyroxine and
liothyronine, respectively.
T3 is not recommended for routine replacement therapy because of its
shorter half-life (24 hours), requiring multiple daily doses, and difficulty
in its monitoring by conventional laboratory tests. It is also more
cardiotoxic.
T3 and T4 increase the basal metabolic rate in the body, the
temperature and cardiac output. If there is hypersecretion the patient
will present tachycardia and arrythmia, so don’t give T3 except for the
sever cases which need rapid action other wise there is a likelihood to
develop hyperthyroidism manifestations especially tachycardia and
arrythmia, as T3 is difficult to be monitored.
Synthetic levothyroxine is the preparation of choice for thyroid
replacement and suppression therapy because of its stability, content
uniformity, low cost, lack of allergenic foreign protein, easy laboratory
measurement of serum levels, and long half-life (7 days), which permits
once-daily to weekly administration.
How to diagnose your patient with hyper/hypothyroidism?
By TSH level (not T3 and T4). In hypothyroidism T3 and T4 may be
normal or low but TSH will be high, while in hyperthyroidism T3 and T4
maybe normal or high but TSH will be low.
Finally, we reach the pharmacology part…
How to treat hyperthyroidism?
BY Antithyroid drugs:
1- Thionamides
Propylthiouracil (PTU)
Methimazole
Carbimazole (pro-drug converted to methimazole
2- Iodides, it is dose dependent; too much iodide will inhibit the
production of T3 and T4, but in low amount it will decrease the
production of T3 and T4 (will be discussed later Inshallah).
3- Radioactive iodine (I 131 instead of I 128); radioactive iodine will
kill the surrounding cells by radiation.
4- Iodinated Contrast Media
5- β-Adrenergic Blockers; they don’t affect the thyroid gland, they
work in peripheral tissue by inhibiting the conversion of T4 to T3,
this will decrease the activity of thyroid hormones.
Now we will talk about each type in detail…
1- Thionamides
They are the most commonly used drug for hyperthyroidism.
Pharmacodynamics (the mechanism of action):
1. Prevention of thyroid hormone synthesis by inhibiting thyroid
peroxidase and blockade of iodine organification.
2. Block coupling of iodotyrosines.
3. PTU (Propylthiouracil) also blocks the peripheral conversion of T4 into
T3 by 5'-deiodinase (similar to β-Adrenergic Blockers).
This drug reduces the synthesis of T3 and T4
The effect is slow requiring 3-4 weeks before stores of T4 are depleted;
in other words, the half-life of T4 is 7 days, remember from
pharmacokinetics we need 5 half-life to eliminate it totally from the
body, so it takes 3-4 weeks to deplete all T4 stores in the thyroid gland.
To make sure that you get the idea:
Summary:
A middle age female patient with hyperthyroidism clinical features
come to your clinic, after testing TSH level and find it low you confirm
the diagnosis, then you decide to treat her with thionamides as they are
the most commonly used drug, when the patient start to take the drug
the synthesis of T3 and T4 will be stopped, T3 will be eliminated rapidly
from the body as its half-life is short, while T4 will need 3-4 weeks as its
half-life is longer.
The key words are marked with pink
The members of Thionamides family:
Methimazole is ~ 10x more potent than propylthiouracil and is the drug
of choice in adults and children, except pregnant women.
Propylthiouracil should be reserved for use during the first trimester of
pregnancy, in thyroid storm, and in those experiencing adverse reactions
to methimazole (other than agranulocytosis or hepatitis).
Both drugs can cross placenta and accumulate in fetal thyroid and cause
hypothyroidism. This is a disaster for the baby as if he/she doesn’t be
treated rapidly before 6 month of post-uterine life he/she will be
mentally retarded (in most countries including Jordan the level of TSH,
T3 and T4 MUST be tested in newborn babies).
Note that She is written in bold because it is more common in females.
But PTU less readily so because of high protein binding, actually 99% of
PTU will be bound to a protein and only little amount will be free to
function so it isn’t secreted in breast milk or cross the placenta in
sufficient quantities, this is the only case at which we prefer to use PTU
instead of methimazole.
The end result: always the drug of choice is methimazole except for
pregnant women we use PTU due to the reason mentioned above. We
don’t like to use PTU in other cases as it is a bad drug and has adverse
effects; the most dangerous one is Severe may be fatal hepatitis, so it’s a
contraindicated drug and you need a reason to prescribe it and the only
reasons are pregnancy or in case of thyroid storm (Thyrotoxicosis).
The others adverse effects will be continued in the next lecture Inshallah
The last thing to talk about is the half-life:
The half-life of PTU is 1.5 hours and given every 6-8 hours, while the
half-life of methimazole is 6 hours and given once daily, you may think
how this occurs.
the answer is that there are two half-life for these drugs one in the
plasma and the other in the thyroid gland itself, in the thyroid gland they
will act longer (4 times more than the normal half-life), remember that
the shorter half-life is associated with more rapid action, so PTU will go
to thyroid gland rapidly as it has shorter half-life in plasma (1.5 h), but on
the other hand you only need to give it every 6-8 hours (remember it is
given in thyroid storm when there is very high production of T3 and
T4)that is because it’s half-life in the thyroid gland itself is longer, while
methimazole will go to thyroid gland slower than PTU as it has longer
half-life (6 hours) and you give it only once daily also because it has
longer half-life in the thyroid gland.
Again, to catch the idea read the mind map in the sheet index (the
following page :p)
Best of luck
And Sorry for any mistake
Sheet index:
you have a patient with hyperthyroidism, what you will do?
Hyperthyroidism patient
Surgery
Subtotal thyroidectomy, the
surgeon removes all the thyroid
gland except 5% to avoid
hypothyroidism, it’s a difficult
surgery and not preferable so go
toward treatment
Treatment
Is she pregnant? / or is this a case
of thyrotoxicosis?
yes NO
PTU methimazole