Leki w zaburzeniach

gospodarki wapniowej

dr hab. med. Ivan Kocić, prof.

nadzw. AMG

Calcium-Wapń

• Ca2+:
• Jony niezbędne do funkcji błon

biologicznych i

• skurczów mięśni,
• W płynie pozakomórkowym stężenie

mmol –istotne dla krzepnięcia krwi i
metabolizmu kości

Zasoby wapnia

CALCIUM

• Skeleton- 99% całkowitej
zawartości wapnia w
organizmie [Ca10(PO4)6(OH)2]
• + Na+, K+, Mg2+

CALCIUM ABSORPTION AND

EXCRETION

• 75% z mleka i nabiału
• Odpowiednia norma to 1300 mg/d u młodzieży i

1000 mg/d u dorosłych

• Po 50 r. życia-1200 mg/d.
• Ca2+ wchodzi do organizmu przez jelita za

pomocą transportu aktywnego wymagajacego

obecność Vit. D (dwunastnica) i przez jelita

cienkie procesem ułatwionej dyfuzji-w większości.

Jednak, organizm również traci codziennie wapń

w ilości około 150 mg/d (żółć, śluz, stracone

komórki jelit)

Regulacja metabolizmu wapnia

i fosforu

• PTH
• Vit D

Parathyroid Hormone (PTH)

• PTH-to hormon polipeptidowy,

regulujacy poziom jonów Ca2+ w
osoczu, poprzez wpływ na kości
(bone resorption/formation), Ca2+
eliminacje i wychwyt zwrotny w
nerkach i syntezę calcitriolu (Vit.D3)-
co zwieksza wchłanianie Ca2+ z
przewodu pokarmowego.

SYNTHESIS, SECRETION,

AND IMMUNOASSAY

• PTH is synthesized as a 115-amino-acid translation

product called preproparathyroid hormone. This

single-chain peptide is converted to

proparathyroid hormone by cleavage of 25 amino-

terminal residues as the peptide is transferred to

the intracisternal space of the endoplasmic

reticulum. Proparathyroid hormone then moves to

the Golgi complex, where it is converted to PTH by

cleavage of six amino acids. PTH(1–84) resides

within secretory granules until it is discharged into

the circulation. Neither preproparathyroid hormone

nor proparathyroid hormone appears in plasma.

PHYSIOLOGICAL

FUNCTIONS

• The primary function of PTH is to

maintain a constant concentration of
Ca2+ in the extracellular fluid. The
principal processes regulated are
renal Ca2+ absorption and
mobilization of bone Ca2+

Effects on Bone

• PTH increases bone resorption and thereby

increases Ca2+ delivery to the extracellular fluid.

This process involves the release of organic and

mineral matrix components (see below). The

apparent skeletal target cell for PTH is the

osteoblast, although evidence for the presence of

PTH receptors on mammalian osteoblasts is

limited. PTH also recruits osteoclast precursor cells

to form new bone remodeling units (see below).

• Direct effects of PTH on osteoblasts in vitro

generally are inhibitory and include reduced

formation of type I collagen, alkaline phosphatase,

and osteocalcin.

Vitamin D

• Vitamin D traditionally was viewed as a permissive

factor in calcium metabolism because it was thought

to permit efficient absorption of dietary calcium and

to allow full expression of the actions of PTH. We now

know that vitamin D exerts a more active role in

calcium homeostasis.

• Vitamin D is actually a hormone rather than a

vitamin; it is synthesized in mammals and, under

ideal conditions, probably is not required in the diet.

Receptors for the activated form of vitamin D are

expressed in many cells that are not involved in

calcium homeostasis, including hematopoietic cells,

lymphocytes, epidermal cells, pancreatic islets,

muscle, and neurons.

Wapń reguluje bardzo wiele

procesów zachodzących w

organizmie:

•

• Reguluje pH krwi ,co ma decydujący wpływ na nasze

zdrowie

• reguluje krzepliwość krwi, zmniejsza kruchość naczyń,

zwiększa ich przepuszczalność,

• zmniejsza reakcje alergiczne,

• niezbędne jest przy normalnej pracy mięśnia sercowego,

• kontroluje kurczenie i rozkurczanie mięśni,

• reguluje układ nerwowy, poprawiając przekazywanie

impulsów nerwowych,

• wspomaga działanie wielu bardzo ważnych enzymów,

• dobrze działa na płodność i donoszenie ciąży,

• pomaga w wyprowadzeniu z organizmu metali ciężkich,

• jest podstawowym składnikiem kości, zębów i paznokci,

wzmacnia włosy,

• zapobiega osteoporozie,

• obniża ciśnienie krwi,

• jest mocnym antyutleniaczem i antystreserem.

•

Niedobór wapnia objawia

się następującymi

symptomami

• zaburzeniami w rozwoju dziecka (późne ząbkowanie i

chodzenie, nadmierna potliwość, deformacje kości,

wczesna próchnica, nadmierna płaczliwość w nocy.

• skrzywieniem kręgosłupa i kończyn dolnych,

• skłonnością do alergii i wysypek,

• złą krzepliwością krwi (częste krwotoki, siniaki),

• skurczami mięśni i padaczką,

• bezsennością, zawrotami głowy, osłabieniem

pamięci, szybkim męczeniem się,

• bólami pleców, nóg, stawów oraz drętwieniem

kończyn,

• osteoporozą i skłonnością do złamań,

• częstymi zaparciami

HYPOCALCEMIA

• Mild hypocalcemia [i.e., reduction in ionized serum

Ca2+ concentrations from normal to concentrations

above 3.2 mg/dl (0.8 mM), approximately equal to a

total serum Ca2+ concentration of 8 to 8.5 mg/dl (2

to 2.1 mM)] is usually asymptomatic.

• The signs and symptoms of hypocalcemia include

tetany and related phenomena such as paresthesias,

increased neuromuscular excitability, laryngospasm,

muscle cramps, and tonic-clonic convulsions. In

chronic hypoparathyroidism, ectodermal changes—

consisting of loss of hair, grooved and brittle

fingernails, defects of dental enamel, and cataracts

—are encountered; calcification in the basal ganglia

may be seen on routine skull radiographs. Psychiatric

symptoms such as emotional lability, anxiety,

depression, and delusions often are present.

• Hypoparathyroidism is most often a

consequence of thyroid or neck surgery but

also may be due to genetic or autoimmune

disorders. In hypoparathyroidism,

hypocalcemia is accompanied by

hyperphosphatemia, reflecting decreased

PTH action on renal phosphate transport.

• Pseudohypoparathyroidism is a diverse

family of hypocalcemic and/or

hyperphosphatemic disorders.

Pseudohypoparathyroidism results from

resistance to PTH rather than PTH

deficiency; this resistance is not due to

mutations of the PTH receptor but rather to

mutations in Gs (GNAS1), which normally

mediates hormone-induced adenylyl

cyclase activation

• Neonatal tetany resulting from hypocalcemia

sometimes occurs in infants of mothers with

hyperparathyroidism; indeed, the tetany may

call attention to the mother's disorder.

• Hypocalcemia is associated with advanced

renal insufficiency accompanied by

hyperphosphatemia. Many patients with this

condition do not develop tetany unless the

accompanying acidosis is treated, which

decreases the ionized calcium. High

concentrations of phosphate in plasma inhibit

the conversion of 25-hydroxycholecalciferol

to 1,25-dihydroxycholecalciferol.

• Hypocalcemia also can occur following

massive transfusions with citrated blood,

which chelates calcium.

Preparaty wapnia

HYPERCALCEMIA

• Symptoms include fatigue, muscle

weakness, anorexia, depression, diffuse

abdominal pain, and constipation.

• Hypercalcemia can result from a number of

conditions. Ingestion of large quantities of

calcium by itself generally does not cause

hypercalcemia; exceptions are hyperthyroid

subjects, who absorb Ca2+ with increased

efficiency and subjects with the uncommon

milk-alkali syndrome, a condition caused by

concurrent ingestion of large quantities of

milk and absorbable alkali, resulting in

impaired renal Ca2+ excretion and

attendant hypercalcemia.

• Symptoms and signs of primary

hyperparathyroidism include fatigue,

exhaustion, weakness, polydipsia, polyuria,

joint pain, bone pain, constipation,

depression, anorexia, nausea, heartburn,

nephrolithiasis, and hematuria. This

condition frequently is accompanied by

significant hypophosphatemia owing to the

effects of PTH in diminishing renal tubular

phosphate reabsorption. Some patients

have renal calculi and peptic ulceration, and

a few display classical parathyroid skeletal

disease.

• Familial benign hypercalcemia (or familial

hypocalciuric hypercalcemia) is a genetic

disorder generally accompanied by extremely

low urinary calcium excretion. Hypercalcemia

usually is mild, and circulating PTH often is

normal to slightly elevated. The importance

of making this diagnosis lies in the fact that

patients mistakenly diagnosed as having

primary hyperparathyroidism may undergo

surgical exploration without discovery of an

adenoma and without therapeutic benefit.

• Diagnosis is established by demonstrating

hypercalcemia in first-degree family

members and a decreased fractional

excretion of calcium.

• Choroby nowotworowe:

Newly diagnosed hypercalcemia in

hospitalized patients is caused most often by a systemic

malignancy, either with or without bony metastasis. PTH-related

protein (PTHrP) is a primitive, highly conserved protein that may

be abnormally expressed in malignant tissue, particularly by
squamous cell and other epithelial cancers.

• Other tumors release cytokines or prostaglandins

that stimulate bone resorption. In some patients

with lymphomas, hypercalcemia results from

overproduction of 1,25-dihydroxyvitamin D by the

tumor cells owing to expression of 1 -hydroxylase.

A similar mechanism underlies the hypercalcemia

that is seen occasionally in sarcoidosis and other

granulomatous disorders.

• Nadmiar Vit.D może spowodować hypercalcemie jeżeli

wystarczająca iłość 25-hydroxyvitamin D jest obecna aby

spowodować zwiększony wychwyt Ca2+ z jelit

doprowadzając do hypercalcemii i zahamowaniu

wydzielania i obnizeniu poziomów PTH i 1,25-

dihydroxyvitamin D. Pomiar 25-hydroxyvitamin D jest

potrzebny do Dg.

• Pacjenci z hyperthyroidism mogą mieć umiarkowaną

hypercalcemie, chyba dzięki zwiększonej akcji kości

• Immobilization may lead to hypercalcemia in growing

children and young adults but rarely causes hypercalcemia

in older individuals unless bone turnover is already

increased, as in Paget's disease or hyperthyroidism.

• Hypercalcemia sometimes is noted in adrenocortical

deficiency, as in Addison's disease, or following removal of

a hyperfunctional adrenocortical tumor.

• Hypercalcemia occurs following renal transplantation owing

to persistent hyperfunctioning parathyroid tissue that

resulted from the previous renal failure.

• The differential diagnosis of hypercalcemia may pose

difficulties, but advances in serum assays for PTH, PTHrP,

and 25-hydroxy- and 1,25-dihydroxyvitamin D permit

accurate diagnosis in the great majority of cases.

Leki w leczeniu hiper-Ca2+

• Re hidratacja i wymuszona diureza

(furosemid): 500-1000ml/h

• Bisfosfonaty: Pamidronian 60-90mg jako wlew

i.v. przez 2-4h i zolendronian 4mg i.v. przez
15 min

• Kalcytonina 200 m.j. efekt po 4-6h i trwa 6-

10h

• Gallium Nitrate (leczenie nadmiaru wapnia u

chorych z nowotworami i choroba Pageta) :
200mg/m2 BSA/d w 5% dekstrozie przez 5 dni

• Plikamicyn (Mitramycin): 25-50 microg/kg

i.v. obniza istotnie poziom wapnia w
surowicy w trakcie 24-48h. Efekt utrzymuje
się przez kilka dni. Czasami występuje nagła
trombocytopenia

• Fosfaty: P, 1,5g w trakcie 6-8h: bardzo

pewna metoda obnizenia wapnia,ale
niebezpieczna, może doprowadzic do
gwałtownej hipocalcemii

• Sterydy: Przewlekła hipercalcemia w ramach

sarkoidozy, zatrucia Vit.D czy niektórych
nowotworów: prednizon 30-60 mg/per os