Exam 2: Lecture X, Thyroid Hormones Flashcards
Thyroid Gland contains….
Thyroid follicular cells and colloid
Follicular cells produce
Thyroxin (T4) and Triiodothyronine (T3)
Both derivatives of Tyrosine, affect all cells in body
exerts a calorigenic and stimulatory effect
Colloid is
extracellular storage site for thyroid hormones
Thyroid Hormone Synthesis
Enough Tyrosine is made, iodine need for Thyroid hormone must come from diet
Hypothalamic TRH Stimulates (+) AP to release….
TSH
Somatostatin has an….
inhibitory effect (-) upon TSH release
TSH Stimulates
(+) T3/T4 synthesis
T4/T3 through negative feedback….
Inhibit (-) both TRH and TSH
Small amounts of iodide stimulate…
(+) T4/T3 production
Large amounts of iodide inhibit….
(-) T4/T3 production
Hypothyroidism and cretinism occur in…
situation of sever iodine deficiency
Thyroid gland is efficient in extracting iodide from the blood
General outline T3/T4 synthesis….
Iodine is transported and undergoes per oxidation and organification with formation of MIT-DIT -> T3/T4
T3 (Triiodothyronine) made from…
1 MIT + 1 DIT
T4 (Thyroxine) made from….
1 DIT + 1 DIT
MIT made from….
1 Iodine + Tyrosine
DIT made from…
2 iodine + Tyrosine
T4 half-life
6-7 days
3-4 days in Hyperthyroidism
9-10 days in Hypothyroidism
T3 half-life
1 day
T4 degrade into….
T3
Liver major site of degradation
T3 further degraded to 3 different DIT
T3/t4 onset of action….
oral 3-5 days
IV 6-8 hrs
What binds T4 with….
Thyroxine-binding globulin
Thyroxin-binding prealbumin
Albumin
Lipoproteins (HDL2/3)
Percent of free T4/T3….
T4 = 0.03%
T3 = 0.3%
Plasma proteins effects on T4/T3
protects hormones from metabolism/excretion
results in longer half-life
Change in protein conc/bidning affinity = major effect upon T3/T4 conc in blood.
When conc of T3/T4 drops in blood then….
TSH is released from AP gland
90% of Thyroid hormone released in form of….
T4
How many times more potent is T3 vs T4?
4-10 times
T4 converted into T3 by…
stripping of iodine in liver and kidneys
Drugs that increase T4 binding to Thyroxine-binding globulin?
Estrogens Methadone 5-Fluorouracil Heroin Tamoxifen
Drugs that decrease T4 binding to Thyroxine-binding globulin?
Glucocorticoids Androgens L-Asparaginase Salicylates Phenytoin,Carbamazepine,Furosemide
Systemic factors affecting binding of T4 to Thyroxine-binding globulin?
Liver disease
Inheritance
Porphyria
Illness
HIV infection
Hypothyroidism disorders….
Cretinism in children
Myxedema in adults
Hyperthyroidism disorders….
Thyrotoxicosis,
Thyroid storm,
Grave’s disease
Plummer’s disease
Thyroid Storm/Crisis
DRAMATIC INCREASE IN METABOLISM
BODY TEMPERATURE RISES (HYPERPYREXIA)
LOSS OF BODY
FLUIDS/ELECTROLYTES
CNS EFFECTS (CONVULSIONS)
ARRHYTHMIA
SHOCK
Drugs for Hypothyroidism?
thyroid Agents
Drugs for Hyperthyroidism?
Antithyroid agents
Iodides
B-Blockers
Radioactive iodine
Physiological actions of T3/T4?
Every tissues is affected…..increases effect in all
Hypothyroidism Clinical effects?
tired
Decreased metabolism Decreased appetite Decreased cardiac output Muscle fatigue Hypoventilation Bradycardia, Hypotension
Impaired water excretion
Decreased erythropoiesis
Hormone deprivation in early life results in irreversible mental retardation
Dropping of eyelids
Essentially tired and decrease a bunch of stuff
Hyperthyroidism clinical effects?
Increased metabolic rate Muscle wasting Heat intolerance Weight loss Insomnia Hyperventilation Dyspnea Tachycardia Increased heart rate Hypertension Polyuria Increased erythropoiesis Protrusion of eyeball Retraction of upper lid with wild stare
essentially wired and increase a bunch of stuff
thyroid Hormones replacement
Levothyroxine sodium (t4) = sodium salt of L-thyoxine
Liothyronine sodium (T3) = sodium salt of L-triiodothyronine
- Both prob better to avoid*
Thyroid tablets = extract of thyroid gland
Thyroglobulin = extract of pig thyroid
Equivalent Daily Doses
Levo sodium - 100 microgram
Liothyronine sodium - 25 microgram
Thyroid tab/Thyroglobulin = 60 mg
Levothyroxine sodium
Drug of choice
Long half-life (7 days)
Oral tablets/capsules;parenteral
Stable agent
Low cost
Lack of allergic foreign proteins
Intracellular conversion of T4 to T3
Liothyronine Sodium (Cytomel)
Not recommended for routine treatment
24 hr half-life
Reserved for care condition of Myxedema coma, rapid action required
Requires multiple daily doses, High cost
Greater risk of cardiotoxicity
Levothyroxine (T4) and Liothyronine (T3)
Mechanism of Action:
Activation of nuclear receptors > Gene Expression > RNA > Protein synthesis
Thioamide prototype?
Propylthiouracil (Generic)
Propylthiouracil (Generic)
2 hr half life
Methimazole (Tapazole)
rapidly absorbed
3-5 hr half life
Cross placenta/breast milk
conc in thyroid
renal excretion
Propylthiouracil (Generic) and Methimazole (Tapazole) MOA
Inhibit formation of thyroid hormones
Inhibit incorporation of iodine into residues of thyroglobulin
Block coupling of DIT and MIT
Inhibits peripheral conversion of T4 to T3
Suggested inhibition of peroxidase enzyme
Propylthiouracil (Generic) and Methimazole (Tapazole) Therapeutic Uses
Hyperthyroidism in children, young adults, and pregnant women
Before surgical treatment
May be used alone
May be used with radioiodine
Antithyroid Drugs Adverse effects
Idiosyncratic agranulocytosis (less with Methimazole)
Transient leukopenia
Hepatitis
Rash, fever, joint pain
Iodide Salts
Lugol’s solution (5% of iodine reduced to iodide + 10% potassium iodide)
Potassium iodide (solution/solid)
Iodide Salts MOA
Inhibit iodination of tyrosine + decrease vascularity of the thyroid gland
Iodide Salts Therapeutic Uses
Preoperatively in Grave’s disease
Preparation for thyroidectomy (10 days before the operation )
Acute Adverse effects Iodide Salts
Hypersensitivity
angioedema
cutaneous hemorrhages
Chronic Adverse effects Iodide Salts
Iodism
brassy taste, salivation,teeth and gum soreness,
eyelid swelling
symptoms of respiratory infection
inflammation of pharynx and larynx
skin lesions
Radioactive Iodine Pharmacokinetics
iodine 131 ( 131I )
t1/2 life 8 days
source of beta-particles, gamma-rays
Radioactive Iodine MOA
Radioactive sodium iodine 131 (131I) concentrates in the thyroid gland
Severely damages the gland without damaging other tissues.
Radioactive Iodine Therapeutic Uses
Highly effective in treatment of hyperthyroidism
Treatment of choice for recurrent hyperthyroidism
Useful diagnostic tool
**Can produce permanent cure
radioactive Iodine Preparations
Sodium iodide labeled with 131I or 125 I
Solutions/Capsules
Orally/Intravenously
Radioactive Iodine Adverse effects
Relatively high incidence of delayed hypothyroidism
Delayed onset in control of hyperthyroidism
Some suspicions of the effects of radioactivity
Contraindicated in pregnancy/nursing mothers
Iodinated Radiocontrast Media
Iodinated radiocontrast media (iodinated) – Ipodate
Effectively suppresses conversion of T4 to T3 in: liver, kidneys and other peripheral tissue
Ipodate proved to be very useful in rapidly reducing T3 level in thyrotoxicosis
B-Blocker
Beta-blockers are effective in counteracting wide-spread sympathetic activation during hyperthyroidism. Agents are effective by decreasing many symptoms of hyperthyroidism. An example of “functional” (noncompetitive) antagonism
B-blocker Therapeutic uses
Alleviate symptoms of Grave’s
hyperthyroidism(tremors, anxiety, palpitations)
Very useful in controlling tachycardia, arrhythmias, tremors, and agitation
Very useful in controlling severe thyrotoxicosis
May be used as a part of the treatment of thyroid storm
Moderate symptoms and may be used in preparation for surgery
Synthesis/secretion of thyroid hormone are not affected
Propranolol (only) inhibits deiodination of T4 to T3
Thyroid drug warning
Many of the effects of thyroid hormone and beta-receptors agonists are similar (tachycardia, increased metabolism, nervousness, and tremors).
Thus, combination of thyroid hormone and adrenergic agents (epinephrine/norepinephrine) may be synergistic!!!
