Thyroid , antithyroid , parathyroid & Calcium metabolism

Suharti K SuhermanDept. of Pharmacology & TherapeuticMedical Faculty, Univ. of Indonesia

Thyroid secreted by thyroid gland → source of 2 different type of hormones :

a. tetraiodothyronine (T4) & triidothyronine (T3)

essential for normal growth & b. calcitonin secreted by parafollicular

cells

Synthesis unique & complex - TH are synthesized & stored as AA residues

of thyroglobulin = a protein component of thyroid follicular colloid

Thyroid H the only hormone that contains iodine 2 important functions :* in developing phase determinants

of normal development espsl CNS devepl.

* in adult it maintains metabolic homeostasis affecting the function of all organ

• Steps of thyroid h synthesis & secretion 1 - uptake or active transport of I- – by the gland 2 - oxidation of iodide & iodination of tyrosyl residues

in thyroglobulin 3 - coupling of iodotyrosine molecules within

thyroglobulin to form T4 & T3 4 - proteolysis of thyroglobulin, with release of

free iodothyronines & iodotyrosines into the circulation

5 – deiodination of iodotyrosines within the thyroid cell

6 – intrathyroidal conversion of T4 to T3 as well as in peripheral tissue

** thyroid H in the circulation is bound in thyroxine –

binding globulin (TBG) major carrier of TH

T4 is also bound to TB prealbumin a small number is bound to albumin or free

**degradation & excretion :eliminated slowly from the body t½ 6–8 dayshyperthyroidism shortened to 3 – 4days hypothyroidis 9 – 10days

pregnancy ↑ binding to TBG retarded clearence

** metabolism liver

Factors that alter binding of Thyroid to TBG

↑ Binding ↓ Binding estrogen glucocort clofibrate androgen

5–fluorouracil salicylates tamoxifen mefenanic acid

SERM phenytoin, carbarmazepin

Treatment Hypothyroidism• levothyroxine Na (L-T4) tablet & as

lyophilized powder for inj, replacement dose 0.05 – 0.2 mg/d with a mean of about 0.125 mg/d;

• Liothyronine Na (L-T3) tab & injectable form mixture of L-T4 & L-T3 = Liotrix

• L-T4 prefer for thyroid replacement longer duration of action, 50 – 80% of the dose is absorbed

• blood level is easily monitored by FT4 & TSH serum level

• T1/2 7 days once daily

• Side effects : allergic reactions, signs of hyperthyroidis

• Drugs interactions: # cholestyramin,iron,calcium,Al (OH)3

& soy product interfere L-T4 absorption

# phenytoin, carbamezepin & rifampin ↑ biliary excretion of L-T4 often necessary ↑ the dose

# pregnant woman/oral contracept the dose of levothyroxine need to be ↑ due to ↑ serum TBG induced by estrogen

Hyperthyroidism antithyroid

• propylthiouracil ( PTU), methimazole & carbimazol (a carbethoxy derivative of

methimazole it inhibits thyroglobulin to form T4 & T3 within the thyroid gland

• PTU , but not methimazole, block peripheral conversion T4 to T3

PTU Methim• plasma prot binding --- 75%.........nil• plasma t1/2 ……………75 min…..4–6 hrs• concentrated in thyroid…yes…….yes• metab in severe liver disease…………..normal…….⇓ kidney disease………..normal…….normal* dosing frequency……..1- 4 x/d…..1–2 x/d

transplacental/ breast milk………………low……… ↑.

Side effects

• Skin rash ( 3% & 7%)• Agranulocytosis ( 0.44 & 0.12% )

Parathyroid & vit D• a polypeptide hormone, regulates plasma

Ca++ by affecting boneformation & resorption, renal Ca++ excretion/ reabsorption, & calcitriol synthesis ( indirectly regulates GI calcium absorption

• importance role in calcium metabolism • secreted by parathyroid gland Ca++

plasma = the most powerful regulator for its secretion

• Ca++ plasma is low PTH secretion ↑ , if the hypocalcemia is sustained hypertrophy & hyperplasia of the gland

Fig-1 .Whole body daily turnover of calcium

Fig-2 .Calcium homeostasis & its regulation by PTH & 1.25-dihydroxyvitamin D.

• effects on bone PTH ↑ bone resorption , ↑ Ca++ delivery to the extracellular fluid

• the cellular terget for PTH is the osteoblast

• it recruits osteoclast precursors to form new bone remodeling units (fig-3)

• Effects on kidney

Fig-3 Bone remodeling sequence in healthy subjects

Other fac tor to bone s treng th : bone turn over

Calcitonin• hormone produced by parafollicular C cells• A single chain peptide hormone IM /

nasal spray• Postmenopausal oeteoporosis calcitonin

inhibit osteoclast activity in bone resorption osteoklast ↑ BMD = Bone Mineral Density)

enough intake Calcium cukup & vitamin D

• Preparations : synthetic salmon calcitonin nasal spray 50 IU 2x/ day or injection ampul 50 IU 1 x / 2 days

• Adverse reactions : nausea, flushing, dose-dependent

Calcitriol• active metabolite of vit. D3• synthesized by the kidney from its

precursor 25-OH cholecalciferol

• Its productions per day ± 0,5 – 1,0 µg ↑ in pregnancy during bone

development • Normal fuction ↑ GI absorption of

Ca++ & regulates bone mineralisation

• Osteoporotic postmenopausal woman calcitriol ↓ bone resorption

• cegah hilangnya massa jaringan • tulang, tetapi pembentukan tulang • tidak berubah• Dosis : 0,25 ug 1 x / 2 x / hari dapat

menyebabkan hiperkalsemia & hiperkalsiuria

OK dosis awal dimulai 0.25mg/h -- setelah itu dapat di ↑ 0.5 mg/h monitor kadar Ca++• Adverse reactions : hypersens