- 2 - Rama Nada - Malik · hypo/hyperthyroidism we should revise the thyroid hormones (we took them in physiology if you remember : ’)). - Thyroid gland releases two hormones from

- 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