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LEC 06:
LEC 06: ANTI-THYROID DRUGS AND THYROID HORMONE
ANTI-THYROID DRUGS AND THYROID HORMONE
Exam 8 | Dr. Acampado| November 26, 2012
Exam 8 | Dr. Acampado| November 26, 2012
OUTLINE OUTLINE
THERAPEUT
THERAPEUTIC IC OVERVIEWOVERVIEW
In terms of treatment, thyroid problems are easier to treat thanIn terms of treatment, thyroid problems are easier to treat than
diabetes. diabetes.
HYPOTHYROIDISMHYPOTHYROIDISM
o
o Administer exogenousAdminister exogenous thyroxine (Tthyroxine (T44)) or or triidothyronine (Ttriidothyronine (T33))
HYPERTHYROIDISMHYPERTHYROIDISM
o
o SurgerySurgery – – typically reserved mostly for nodules that are typically reserved mostly for nodules that are
suspicious for cancer. Note: Functioning nodules in a thyroid suspicious for cancer. Note: Functioning nodules in a thyroid patient are usually NOT cancer. In these cases, use drugs, and if patient are usually NOT cancer. In these cases, use drugs, and if unresponsive, use radioactive iodine.
unresponsive, use radioactive iodine.
o
o Radioactive iodine - especially for long-Radioactive iodine - especially for long-term disease like Grave’sterm disease like Grave’s o
o Drugs: Thioureylenes,Drugs: Thioureylenes, o
o Adjuncts: Beta- Adrenergic Receptor Blockers, Corticosteroids,Adjuncts: Beta- Adrenergic Receptor Blockers, Corticosteroids,
Iodides Iodides
THYROID PHYSIOLOGY THYROID PHYSIOLOGY
Thyroid gland maintains metabolic homeostasis by regulating:Thyroid gland maintains metabolic homeostasis by regulating:
o
o growthgrowth and development,and development,
Cretinism: stunted growth, physically and mentallyCretinism: stunted growth, physically and mentally
o
o body temperature, andbody temperature, and o
o energy levelsenergy levels
Multiple functions are accomplished through two hormones, T3 andMultiple functions are accomplished through two hormones, T3 and
T4 T4
Table 1. Comparison Between T3 and T4. Table 1. Comparison Between T3 and T4. Hormones
Hormones Triiodothyronine Triiodothyronine TetraiodothryonineTetraiodothryonine Alias
Alias T3 T3 T4 T4 or or thryoxinethryoxine Molecular
Molecular composition composition MIT + MIT + DIT DIT DIT DIT + + DITDIT Iodine
Iodine Content Content (%) (%) 59 59 65 65 (larger (larger contentcontent because it’s 4 because it’s 4 molecules, not 3) molecules, not 3) Throid-hormone-thyroglobulin ratio thyroglobulin ratio 1 1 55
MIT = monoiodotyrosine, DIT = diiodotyrosine MIT = monoiodotyrosine, DIT = diiodotyrosine Thyroglobulin ratio
Thyroglobulin ratio – – proteinatious ratio in the colloid. Number of proteinatious ratio in the colloid. Number of thyroid hormones: more T4 in the thyroglobulin than T3. thyroid hormones: more T4 in the thyroglobulin than T3.
THYROID HORMONE SYNTHESIS THYROID HORMONE SYNTHESIS
A. SIX MAJOR STEPS A. SIX MAJOR STEPS
1.
1.Active Transport of Iodine across the basement membrane into theActive Transport of Iodine across the basement membrane into the thyroid cell ( called iodide trapping).
thyroid cell ( called iodide trapping). Remember that there is aRemember that there is a symporter across the cell membrane that transports iodine symporter across the cell membrane that transports iodine intracellularly.
intracellularly.
2.
2.(Inside the cell): Oxidation of iodide & iodination of tyrosyl residues(Inside the cell): Oxidation of iodide & iodination of tyrosyl residues in thyroglobulin. Result: monoiodothyroxines.
in thyroglobulin. Result: monoiodothyroxines.
3.
3.Coupling of the monoiodotyrosine molecules within thyroglobulinCoupling of the monoiodotyrosine molecules within thyroglobulin to form T3 & T4
to form T3 & T4
Tyrosine + ITyrosine + I MIT (monoiodothyroxine) MIT (monoiodothyroxine)
Tyrosine + ITyrosine + I22 3, 5 DIT (diiodothyroxine) 3, 5 DIT (diiodothyroxine)
MIT + DITMIT + DIT3, 5, 3’ TIT (T3)3, 5, 3’ TIT (T3)3, 3’, 5’ TIT (rT33, 3’, 5’ TIT (rT3 =inactive reverse T3)DIT + DIT
=inactive reverse T3)DIT + DIT3, 5, 3’, 5’ (T4)3, 5, 3’, 5’ (T4)
Still attached to thyroglobulin. Must be released (see nextStill attached to thyroglobulin. Must be released (see next
step) step)
4.
4. Proteolysis of thyroglobulin - release of free iodothyronines &Proteolysis of thyroglobulin - release of free iodothyronines & iodotyrosines from colloid droplets (pinocytosis). They then find iodotyrosines from colloid droplets (pinocytosis). They then find their way to the circulation.
their way to the circulation.
5.
5. Deiodination of iodotyrosines within the thyroid cells & recyclingDeiodination of iodotyrosines within the thyroid cells & recycling of iodine
of iodine
6.
6. Intrathyroidal 5’Intrathyroidal 5’-deiodination of T4 to T3-deiodination of T4 to T3 *the
*the peripheral peripheral conversion of T4 conversion of T4 T3 is an important step and isT3 is an important step and is the target of the action of many anti-thyroid drugs
the target of the action of many anti-thyroid drugs THYROID HORMONE BIOSYNTHESIS THYROID HORMONE BIOSYNTHESIS
T3 is the chemically active hormone T3 is the chemically active hormone Figure 1.
Figure 1. Thyroid HoThyroid Hormone Biosynthesis.rmone Biosynthesis. Refer to Figure 1:
Refer to Figure 1: 1.
1. Iodide (IIodide (I--) absorbed in the GIT enters an extracellular pool from) absorbed in the GIT enters an extracellular pool from which the thyroid gland removes 75 mg daily.
which the thyroid gland removes 75 mg daily. 2.
2. II-- is taken up by thyroid follicular cells via a membrane Na is taken up by thyroid follicular cells via a membrane Na++/I/I --transporter.
transporter. 3.
3. II-- is then coupled to tyrosine residues on the thyroglobulin molecule is then coupled to tyrosine residues on the thyroglobulin molecule (process is called organification)
(process is called organification) *therefore, basic substrate is iodine! *therefore, basic substrate is iodine! 4.
4. Formation of monoiodo-tyrosine (MIT) and diiodo-tyrosine (DIT)Formation of monoiodo-tyrosine (MIT) and diiodo-tyrosine (DIT) 5.
5. Thyroid peroxidase (TPO) catalyzes the coupling of two molecules ofThyroid peroxidase (TPO) catalyzes the coupling of two molecules of DIT to form T4, and one molecule each of MIT and DIT to form T3 DIT to form T4, and one molecule each of MIT and DIT to form T3 6.
6. Thyroglobulin is stored as a colloid in the lumenThyroglobulin is stored as a colloid in the lumen 7.
7. TSH signals (for secretion) to hydrolyze thyroglobulin to free MIT,TSH signals (for secretion) to hydrolyze thyroglobulin to free MIT, DIT, T3 & T4
DIT, T3 & T4 8.
8. MIT and DIT are deiodinated for recycling while T3 & T4 areMIT and DIT are deiodinated for recycling while T3 & T4 are released by exocytosis
released by exocytosis
Thyroid peroxidase is active in oxidation and coupling (steps 2 andThyroid peroxidase is active in oxidation and coupling (steps 2 and
3) 3)
T4 will have peripheral conversion to t3T4 will have peripheral conversion to t3
T3 active hormone, reverse t3-inactive hormoneT3 active hormone, reverse t3-inactive hormone
I.
I. Therapeutic OverviewTherapeutic Overview II.
II. Thyroid PhysiologyThyroid Physiology III.
III. Thyroid Hormone SynthesisThyroid Hormone Synthesis IV.
IV. Pharmacokinetics of Thyroid HormonePharmacokinetics of Thyroid Hormone V.
V. Effects of Drugs on Thyroid Hormone ProductionEffects of Drugs on Thyroid Hormone Production VI.
VI. Mechanisms for Thyroid RegulationMechanisms for Thyroid Regulation VII.
VII. Thyroid Hormone Mechanism of ActionThyroid Hormone Mechanism of Action VIII.
VIII. Thyroid Hormone EffectsThyroid Hormone Effects IX.
IX. Thyroid preparationsThyroid preparations X.
X. HyperthyroidismHyperthyroidism XI.
XI. Anti-Thyroid Drugs and Radioactive Iodine TherapyAnti-Thyroid Drugs and Radioactive Iodine Therapy XII.
Figure 2. Steps in Thyroid Hormonogenesis. C oupling: thyroid peroxidase! (repeatedly mentioned, so don’t forget this enzyme)
PHARMACOKINETICS OF THYROID HORMONE
T3 & T4 are mostly bound to thyroxin binding globulin (TBG) Amounts of free or unbound hormones are minimal: 0.03% T4 and
0.3% T3
Only the unbound hormones have metabolic activity, used by
peripheral tissue for the actions of thyroid hormone
In peripheral tissues T4 is converted to T3 by iodothyronine 5’
-deiodinasefound mainly in liver, thyroid, and kidneys
The active hormone in most target tissues is T3
Figure 3. Peripheral Metabolism of Thyroxine. KINETICS: PERIPHERAL METABOLISM OF THYROXINE
Thyroid hormone released mostly as T4 because T4 to T3 ratio in
thyroglobulin is 5:1
Peripheral metabolism of T4 is mainly by deiodination to form:
[1] T3 which is 3-4 times more potent than T4, or [2] reverse T3 which is metabolically inactive
Total serum levels for T4 are higher because more of it is released
and metabolic clearance of T3 is faster. With regards in secretion of the thyroid, it is more t4.
Exogenous thyroid therapy is usually given as T4 to simulate
normal physiologic processes.
If you give T3 directly, patients will suffer from more adverse drug
reactions (palpitations)
Table 2. Summary of Thyroid Hormone Kinetics. Thyroid Hormones T3 T4 Daily Production (mg) 25 75 Daily Metabolic Clearance (L) 24 1.1
Total Serum Levels (nmol/L) 1.5-2.9 64-132 (more) Biologic Potency 3-4
(higher)
1 Oral Absorption (%) 95 80
Half-life (days) 1 7 (longer)
T3 is also the more potent of the two, as you can s ee above
(more side effects)
T4 lasts longer in circulation (see half life). However, both
are only once a day dosing.
EFFECTS OF DRUGS ON THYROID HORMONE PRODUCTION Table 3. Summary of Drugs that Act on Thyroid Hormone Synthesis.
Metabolic Step Inhibitors
Iodide Transport Large Amounts of I-, ClO-4, SCN-, TcO4
-(iodine and thiocyanates.) Iodide Oxidation Thionamide Drugs (PTU, MMI) Organification and Coupling
Colloid Resorption and Proteolysis
Iodine, Lithium
If you take a lot of iodine: Wolff Chaikoff effect – high dose
iodine impedes transport and release.
Thiocyanates = root crops, deep green vegetables, cassava,
broccoli
Thionamides – inhibit organification and coupling by
inhibiting thyroid peroxidase
Lithium – treats manic depressive conditions but also
inhibits thyroid hormone production!
Half –life of T4 > than T3
MECHANISMS FOR THYROID REGULATION 1. Paraventricular nuclei in the hypothalamus secrete TRH 2. TRH stimulates the anterior pituitary to release TSH 3. TSH acts on the thyroid to release T3 and T4
4. T3 and T4 act by negative feedback to inhibit formation of TRH and TSHStress is a negative inhibitor. There is a decrease in thyroid hormone.
Cold also sends signals to your hypothalamus, producing TRH Somatostatin, steroids, or dopamine can also inhibit TRH. Autoregulation within the thyroid modifies thyroid hormone
synthesis through blood iodine levels:
o High iodine levels inhibit iodide organification , leading to
reduced T3 & T4 synthesis (hypothyroidism)
Figure 4. Hypothalamic-Pituitary Regulation THYROID HORMONE MECHANISM OF ACTION
Figure 5. Mechanism of Action of Thyroid Hormone in Target Cell (PB, plasma binding protein; F, transcription factor; R, receptor; PP, proximal promoter proteins). Unique iodine-thyroxine association
T3 receptors belong to a superfamily of nuclear receptors (c-erb
includes receptors for steroid hormones and vitamins A and D)
Many T3 receptors are found in responsive tissues like pituitary,
liver, kidney, heart (tachycardia), skeletal muscle, lung, and intestine (hyperdefecation)
*hence, hyperthyroidism is a multi-system disease
T3 & T4 are dissociated from thyroid-binding proteins enter
target cells by diffusion or active transport in the cytoplasm 5’-deiodinase converts T4 to T3 T3 enters the nucleus to bind to T3
receptors more RNA are formed increased protein synthesis
* Hormone binding dissociates the co-repressors and allows the recruitment of coactivators that enhance transcription.
Interaction with coexpressors explains the fact that TR silences gene expression in the absence of hormone binding.
Figure 6. Role of T3 in RNA Synthesis.
T3 acts on Intracellular thyroid hormone receptors (TRs) located in
all cells of the body
TR monomers interact with retinoic acid X receptor (RXR) to form
heterodimers
In the absence of T3, the TR:RXR heterodimer associates with a
co-repressor complex that binds to DNA to inhibit gene expression
In the presence of T3, the co-repressor complex dissociates,
coactivators form to stimulate gene expression
Binding to TR dimmers, thus, serves as a molecular switch from
inhibition to activation of gene expression THYROID HORMONE EFFECTS
Generally responsible for optimal growth, development, function,
and energy levels in all tissues
o Excess hyperthyroidism (thyrotoxicosis) –the more
encompassing term. Any elevation of thyroid hormone,
regardless of cause. On the other hand, hyperthyroidism merely refers to problems in the thyroid gland.
o Inadequacy hypothyroidism (myxedema)
1. Nervous, musculoskeletal, and reproductive tissues:
o Nervousness o Restlessness o Emotional lability
o Muscle weakness and fatigue o Osteoporosis
o Menstrual irregularities o Hyper: irregular
o Hypo: metromenorrhagia
2. Calorigenic effect:
o Increased oxygen consumption o Sweating
3. Sympathetic hyperactivity due to increased b- adrenergic sensitivity leads to dramatic cardiovascular effects including
o Tachycardia
o Increased stroke volume and cardiac output
o High-output heart failure (heart very active but because of
decrease in diastolic function, heart is unable to relax to perfuse the coronaries)
o Arrhythmia
o Angina – if with coronary artery disease
4. Metabolic effects:
o Decreased cholesterol and triglycerides o Increased basal metabolic rate
o Hyperglycemia o Appetite
THYROID PREPARATIONS
Major clinical use of T3 & T4 is f or hormone replacement therapy in
hypothyroidism or cretinism
Involves replacement of thyroid hormone adequate to meet the
patient’s needs
100 mcg in a ~65 kg person
Dose for replacement: 1.6-1.7 mcg/kg
*drugs given in multiples of 25 (25, 50, 100, 150)
For the elderly, or with CAD or arrhythmia, implement SLOW
replacement (titrate the dose). If you replace too fast, erratic levels of thyroid hormones. You can develop vasospasm of coronary arteries, arrhythmias, etc. So, keep it slow!
For younger patients, you can give full replacement right away.
INDICATIONS
Post-procedural hypothyroidism – post surgery. Most common
cause of deficiency in the Philippines! Lack of iodine is second most common.
Endemic goiter
Congenital hypothyroidism: cretinism- thyroid hormone should be
replaced to prevent metnal retardation, it is good that we have newborn screening now to pick up earlier this disease.
Any cause of hypothyroidism, i.e. thyroiditis Suppression of growth of nodules, thyroid CA
o Dose for suppression: 2.2-3.0 mcg/kg
o A higher dose is necessary than that of the dose for replacement
Monitor effectiveness of therapy by measuring TSH levels
Treatment is therefore based on the weight of the patient, and
range of the patient’s response to the medications. Dose may be adjusted accordingly.
For hypothyroidism, no matter what the cause, the ONLY treatment
is THYROID HORMONE (particularly T4)
Surgery and radiation in thyroid cancer- lower the tsh values to
decrease the growth of the tumor.
THYROID HORMONE REPLACEMENTS IN THE MARKET SYNTHETIC LEVOTHYROXINE (T4)
Preparation of choice for replacement & suppression therapy
because of its:
o Stability
o uniform content o low cost
o long half-life (7 days)
o conversion to produce both T3 & T4
DESICCATED THYROID
In the past, desiccated animal thyroid preparations were used as
treatment. But this is not used anymore.
If you are fond of eating burgers, bopis, etc., beware! You may
develop thyrotoxicosis if the animal’s thyroid is mixed in with the meat.
Though inexpensive, it is not recommended for replacement
therapy because of its antigenicity, instability, and variable hormone content.
LIOTHYRONINE (T3)
3-4 times more active than levothyroxine
[T4 is still preferred over T3 despite the latter being stronger]
Not recommended for routine replacement therapy
o higher cost (than the two previous thyroid preparations) o short half-life (24 hours)
o greater potential for cardiotoxicity due to its potency and large
peaks (unpredictability) – greater induction of myocardial ishcemia
LIOTRIX
4:1 combination of synthetic T4 and T3 also expensive with the
same disadvantages as liothyronine
* currently we still use the pure levothyroxine or pure t3
THYROTOXICOSIS
Consequence of excessive thyroid hormone action due to Causes:
o Diffuse toxic goiter (Graves’ disease)
[Grave’s disease is the most common cause , accounting for 60-80% of thyrotoxicosis]
o Toxic adenoma
o Toxic multinodular goiter (Plummer’s) o Painful subacute thyroiditis
o Silent thyroiditis; e.g. lymphocytic and postpartum variations o Iodine-induced hyperthyroidism
o Excessive pituitary TSH or trophoblastic disease o Excessive ingestion of thyroid hormones
Clinical features
o Signs & symptoms are due to the effects of excess thyroid
hormone in the circulation
o Severity of signs & symptoms may be related to the duration of
the illness, magnitude of hormone excess & the age of the patient
Pwedeng mauna ung opthalmopathy but it very rare. If they have opthalmopathy, they have already hyperthyroidism.
Table 4. Signs and Symptoms of Hyperthyroidism.
Signs Symptoms
Weakness and Fatigue Goiter/Thyroid Bruit Heat Intolerance Hyperkinesis
Nervousness Ophthalmopathy Increased Sweating Lid retractions/stare
Tremor Lid lag
Palpitations Tremor Increased Appetite Warm, moist skin
Weight Loss Muscle weakness Dyspnea Hyperreflexia Menstrual Amenorrhea Tachycardia/arrhythmia –
most common is sinus tachycardia followed by atrial
fibrillation Hyperdefecation Widened Pulse Pressure ANTI-THYROID DRUGS AND RADIOACTIVE IODINE THERAPY 1. Thioamides: methimazole propylthiouracil
2. Iodides: potassium iodide solution 3. Radioactive Iodine (RAI)
4. Other Drugs: anion inhibitors b-adrenergic blockers THIOUREYLENE OR THIOAMIDES: Methimazole and Propylthiouracil
MAIN anti-thyroid drugs
Propylthiouracil, Methimazole/Thiamazole, Carbimazole (will be
converted to methimazole) *in US, only PTU and Methimazole are available
MOA: inhibit thyroid peroxidase-mediated iodination & coupling
steps (steps 2 and 3)
*because action is on the early steps, there is SLOW onset of action since it merely prevents the formation of new hormones but does
not inhibit the release of already preformed hormones; for RAPID action, the last steps of the process should be targeted
These drugs are preferentially iodinated, depriving thyroglobulin
of iodide and shutting down the synthesis of thyroid hormones
Accumulate readily in the thyroid gland for treatment of
thyrotoxicosis
Effects are not immediate. This mainly prevents f urther thyroid
hormone production.
Plasma half lives: 6hr for MMI and 1.5 hrs for PTU
Methimazole (5 mg; more expensive, can be given once a day) is
10x more active than PTU (50 mg)
Additional MOA: PTU, but not methimazole, affects by inhibiting
the processing of T4 to T3 in the peripheral tissues
[PTU is therefore the preferred drug in thyroid storm treatment]
Since T3 is 10x as active as T4 this conversion step is important
METHIMAZOLE VS. PROPYLTHIOURACIL (PTU)
Slow onset of action requiring 3 -4 weeks to deplete T4 stores Methimazole is 10x more potent than PTU! In PTU you need to
give more tablets, more often.
PTU is cheaper
Methimazole is the antithyroid drug of choice Avoid PTU, due also to excessive hepatic risks. Multiple mechanisms of action including:
o Major action: prevent hormone synthesis by inhibiting thyroid
peroxidase reactions to block iodine organification and iodotyrosine coupling (both Methimazole and PTU)
o Inhibit peripheral deiodination of T3 & T4 (only PTU)
Adverse reactions occur in 3-12% of treated patients (in the
Philippines, almost 20%, but effects are transient):
Most common: maculopapular pruritic rash
Rarely: urticarial rash, vasculitis, arthralgia, lupus-like reaction,
jaundice, hepatitis hypothrombinemia
Most dangerous: agranulocytosis (rapid fall in WBC count,
manifests with fever, soar throat, cough – stop the drug then have the CBC done. If not discontinued, later: GI complications, diarrhea, sepsis; usually with high doses) Angioedema (severe allergy): therefore if symptoms above are seen, just discontinue drug then have CBC done.
SIDE EFFECTS OF THIOUREYLENES
Rash, urticaria – in as much as 20% of users; usually transient even
w/o treatment
Auto-immune (lupus-like) nephritis, PAN
Granulocytopenia,a granulocytosis: RARE but potentially fatal Watch out sore throat for, fever, diarrhea
* If minor side effects result , patient may either continue therapy but with antihistamine, lower the dose of the medication, or shift to another drug.
* If life-threatening side effects result , NEVER reintroduce the precipitating agent.
B. OTHER ANTI-THYROID DRUGS: ADJUNCTIVE TREATMENT
MONOVALENT CATIONS
Block thyroid hormone synthesis by competitively inhibiting the
active transport of iodide into the thyroid
o Pertechnetate, Perchlorate: little clinical use
o High dose iodides: Potassium Iodide, SSKI, Lugol’s solution,
Intravenous Contrast Agents (recall Wolff Chaikoff effect)
o Watch out for angioedema with iodides
ANION INHIBITORS AND B-ADRENERGIC BLOCKERS
Monocovalent ions such as perchlorate (ClO4-), pertechnetate
(TcO4-), and thiocyanate (SCN-): block iodide uptake through competitive inhibition of the iodide transport mechanism, but their effectiveness is unpredictable. This time, they prevent the transpot of iodine to the gland. Thus these are not commonly used.
Potassium perchlorate is no longer used clinically because it causes
aplastic anemia
diatrizoate IV) though not FDA approved, act by inhibiting conversion of T4 to T3 in liver, kidney, pituitary, and brain
Since many symptoms of thyrotoxicosis result from sympathetic
hyperactivity, guanethidine or b-adrenergic blockers have also been used for treatment
IODIDES: POTASSIUM IODIDE SOLUTION
Used in the past to decrease size and vascularity of hyperplastic
thyroid gland in Graves Disease, but no longer done because it is dangerous. Instead, make the patient euthyroid (normalized hormones) before sending them off to surgery. Why dangerous? Patients tended to lower the dose or discontinue meds after surgery, then develop hypothyroidism.
Many thyroid actions including:
o Inhibition of hormone release by reducing thyroglobulin
proteolysis
o Decrease in size and vascularity of the hyperplastic gland
Given in HIGH doses (gram doses) to inhibit iodide transport; if
given in small (microgram doses), iodine actually enhances synthesis
* Wolff-Chaikoff effect is the phenomenon wherein excess iodide actually blocks organification and prevents further synthesis of new hormones in the thyroid gland.
Thyrotoxic symptoms improve within 2-7 days, but should not be
used alone because the gland “escapes’ from iodide block after 2-8 weeks and withdrawal may result in severe thyrotoxicosis
Avoid chronic use in pregnancy as iodides cross the placenta and
can cause fetal goiter.
Advantages:
o Simplicity o Inexpensive o Relatively nontoxic
o Absence of glandular destruction
Adverse reactions (MANY):
o Acneiform rash (most common form) o Swollen salivary glands
o Mucous membrane ulceration o Conjunctivitis o Rhinorrhea o Metallic taste o Drug fever o Bleeding disorders o Anaphylaxis Disadvantages
o “Escape”- after around a week, escape from Wolff Chaikoff, and
becomes incorporated into thyroid hormones and become hyperthyroid again.
o Aggravation of thyrotoxicosis o Allergic reactions
o Increased intraglandular iodine which can delay onset of
thioamide therapy or prevent use of radioactive iodine therapy for several weeks
o If done with radioactive scan, Iodide should be washed off first so
that the radioactive scan will be more accurate.
BETA-ADRENERGIC RECEPTOR BLOCKING DRUGS
Examples: Propanolol, Atenolol
* Better to select the non-cardiac selective b eta-adrenergic receptor blocking drugs
Act peripherally rather than at the thyroid gland (prevent T4 to T3
conversion)
When to use: tachycardic, tremors, sweatiness; many drugs already
being used and yet persistently elevated T3
MOA: uncertain but may relate to inhibition of deiodination no
peripheral conversion of T4 to T3 (ex. Propanolol)
Also blocks the sympathetic (adrenergic) effects of hyperthyroidism
esp. on the heart
* Helpful in the control of adrenergic symptoms, especially in the early stages before anti-thyroid drugs take effect.
Avoid in patient with asthma
Calcium channel blockers can also be used.
CORTICOSTEROIDS
Inhibit peripheral conversion of T4 to T3 (like B-adrenergic Receptor
Blocking Drugs)
Can suppress thyroid-stimulating antibodies (Graves) Antipyretic
May be used to treat adrenal insufficiency in patients with thyroid
storm
Graves’ disease is an autoimmune disorder which can manifest with
thyroid storm because of increase stress.
Figure 7. Summary of thyroid treatment and steps affected RADIOACTIVE IODINE THERAPY
Used for definitive therapy or ablation
The only isotopes used for treatment of thyrotoxicosis Uses the following radioisotopes: I123 or I131
Basically we are using the I131
Side-effects are minimal: avoid in children (may inhibit bone
growth, but unsure if it were the treatment or the previous hyperthyroidism) and pregnant women or those intending pregnancy
Contraceptives are encouraged among those who are sexually
active
But we do not give RIT to a pregnant woman. Make sure do a
pregnancy test before giving the drug,
RADIOACTIVE IODINE (RAI)
Given as oral solution, I131 is rapidly absorbed and concentrated in
the thyroid gland
Iodine123 or Iodine131 are the radioisotopes used Used for definitive therapy or ablation
Radioiodine causes progressive destruction of thyroid cells
o Thyroid parenchymal destruction becomes evident within weeks
in the form of epithelial swelling, necrosis, follicular disruption, edema, and leukocyte infiltration
Therapeutic effect depends on emission of beta rays with:
(1)Penetration range of 400-2000 mm,(2) Effective half-life of 5 days
Advantages: easy administration, effectiveness, low expense (3-5k if
charity ward), & absence of pain
Major disadvantage is induction of hypothyroidism. 90% develop
this in the next few years. You need lifelong l evothyroxine treatment. But side effects are minimal.
Side effect will have hypothyroidism. However it is easier to manage
the hypothyroidism. You should have only to f ind the replacement dose for the patient. But the patient ’ s condition is stable.
Avoid in children (inhibit bone growth) and pregnant women or
those intending pregnancy. RAI crosses the placenta and is excreted in breast milk. Misconception: “causes sterility” – no, it does not.
Preferred treatment over surgery/thyroidectomy in Grave’s disease. Advice patient to dispose of their body wastes properly (because it’s
radioactive)
Figure 7. Drugs Affecting T3 and T4 Synthesis
Anions (perchlorate, pertechnetate, & thiocyanate) compete with
I- uptake.
RAI causes selective thyroid destruction
Iodide (high levels) reduce T3-T4 release by inhibiting
thyroglobulin proteolysis.
Thioamides inhibit peroxidase to block organification
Some Scenarios: (not mentioned in lecture)
1. For young patients with small goiter and mild hyperthyroidism, give antithyroid drugs for a few months. To induce
remission, give a large dose then taper it off – (only 30% success rate.
2. For patients with large goiters and nodules, give drugs for 2-3 months then subsequently send for surgery.
3. Give antithyroid drugs till normothyroid, then give another definitive form of treatment: radioactive iodine.
END OF TRANSCRIPTION
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PHIerless! <3 <3 <3 Long weekend! Hi 20G roomies! :D Hi to you reading this. Sarap ng buhay diba Jow and Erik?
Charles: Greetings!
The drug of choice for the treatment of hypothyroidism (whether primary or secondary) is:
a. Liothyronine c. Potassium iodide b. Levothyroxine d. Dessicated iodine
Dose of levothyroxine in a 55 kg pe rson for treatment of post-s urgical hypothyroidism (round off please to the nearest exact dose):
a. 50 mcg OD
b. ½ of 150 mcg tablet OD c. 100 mcg OD
d. 50 mcg BID
Your friend from surgery referred a patient with hypo thyroidism to you for management prior to planned cholecystectomy for gall bladde r stones. On the average, how soon can you render this patient euthyroid if you w ill give the patient methimazole?
a. Two weeks b. Eight weeks c. Four weeks d. Six months
Proper course of action in a patient w ho developed agranulocytosis secondary to methimazole:
a. Shift methimazole to PTU
b. Continue methimazole but decrease the dose to less than 40 mcg/day c. Administer RAI upon admission for ablation of go iter
d. Discontinue thionamides permanently
The following is true about the treatment o f Graves’ disease:
a. Over-all long term remission rate for medical therapy with thionamide drugs in Grave’s disease is high in making it the most popular form of definitive treatment.
b. The majority of patients with diffuse toxic goiter from Grave’s disease should receive some form of definitive treatment i.e. radioactive iodine ablation therapy or surgery
c. Anti-thyroid drugs can be discontinued as soon as the patients are euthyroid since cure has been achieved.
d. Use of thionamide drugs w ill lead to regression of goiter
The most common side effect of thionamide drugs: a. Jaundice
b. Agranulocytosis c. Joint pains d. Pruritus
The drug of choice for the OPD medical treatment of patients with hyperthyroidism:
a. Propylthiouracil b. Beta-blockers c. High dose iodides d. Methimazole
A patient diagnosed with hyperthyroidism is currently taking PTU 50 mg 2 tablets 3x a day. His recent Free T4 result is already normal. He requests that you change his medication because he finds PTU very bitter and tend to forget to take his last dose for the day. You decide to prescribe methimazole which is in the 5mg tablet preparations. How many tablets of methimazole should you give that is equivalent to the current dose of PTU?
a. 3 tablets b. 9 tablets c. 6 tablets d. 12 tablets
What is the principle behind giving of Iodide in th yroid storm a. Wolff-Parkinson-White effect
b. Wolff-Chaikoff effect c. Jod-Basedow effect d. Jod-White effect
What drug acutely inhibits the release of preformed thyroid hormone, making it very useful in the treatment of thyroid storm?
a. Propylthiouracil b. Propanolol c. Iodide
d. Dexamethasone
Choose from the items below w hich anti-thyroid drug is being described by the numbered statements.
A – Methimazole B – Carbimazole C – Propylthiouracil D – All of the above
C 1. Thionamide drug that inhibits peripheral conversion of T4 to T3 D 2. Attenuate(s) or reduce serum concentrations of thyrotropin receptor antibodies
C 3. Preferred agent in thyroid storm
D 4. Inhibit(s) organification of iodides and coupling of iodothyronines C 5. Used to prepare patient for definitive treatment such as RAI ablation Answers to first part: B, C, C, D, B, D, D, C, B, C
