Paricalcitol

Paricalcitol

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Systematic (IUPAC) name
(1R,3R,7E,17β)-17-[(1R,2E,4S)-5-hydroxy-1,4,5-trimethylhex-2-en-1-yl]-9,10-secoestra-5,7-diene-1,3-diol
Clinical data
Trade names	Zemplar
AHFS/Drugs.com	monograph
MedlinePlus	a682335
Pregnancy category	AU: C US: C (Risk not ruled out)
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral, Intravenous
Pharmacokinetic data
Bioavailability	72%
Protein binding	99.8%
Metabolism	Hepatic
Biological half-life	14-20 hours
Excretion	Faeces (74%), urine (16%)
Identifiers
CAS Number	131918-61-1 Y
ATC code	H05BX02 (WHO)
PubChem	CID: 5281104
IUPHAR/BPS	2791
DrugBank	DB00910 N
ChemSpider	4444552 Y
UNII	6702D36OG5 Y
KEGG	D00930 N
ChEBI	CHEBI:7931 N
ChEMBL	CHEMBL1200622 Y
Synonyms	(1R,3S)-5-[2-[(1R,3aR,7aS)-1-[(2R,5S)-6-hydroxy-5,6-dimethyl-3E-hepten-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-cyclohexane-1,3-diol
Chemical data
Formula	C27H44O3
Molecular mass	416.636 g/mol
InChI InChI=1S/C27H44O3/c1-18(8-9-19(2)26(3,4)30)24-12-13-25-21(7-6-14-27(24,25)5)11-10-20-15-22(28)17-23(29)16-20/h8-11,18-19,22-25,28-30H,6-7,12-17H2,1-5H3/b9-8+,21-11+/t18-,19+,22-,23-,24-,25+,27-/m1/s1 Y Key:BPKAHTKRCLCHEA-UBFJEZKGSA-N Y
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Paricalcitol (chemically it is 19-nor-1,25-(OH)₂-vitamin D₂. Marketed by Abbott Laboratories under the trade name Zemplar) is a drug used for the prevention and treatment of secondary hyperparathyroidism (excessive secretion of parathyroid hormone) associated with chronic renal failure. It is an analog of 1,25-dihydroxyergocalciferol, the active form of vitamin D₂ (ergocalciferol).

Medical uses

Its primary use in medicine is in the treatment of secondary hyperparathyroidism associated with chronic kidney disease. In three placebo-controlled studies, chronic renal failure patients treated with paricalcitol achieved a mean parathyroid hormone (PTH) reduction of 30% in six weeks. Additionally there was no difference in incidence of hypercalcemia or hyperphosphatemia when compared to placebo. A double-blind randomised study with 263 dialysis patients showed a significant advantage over calcitriol (also known as activated vitamin D₃; a similar molecule to 1,25-dihydroxyergocalciferol, adding a methyl group on C₂₄ and lacking a double-bond in the C₂₂ position). After 18 weeks, all patients in the paricalcitol group had reached the target parathormone level of 100 to 300 pg/ml, versus none in the calcitriol group. Combination therapy with paricalcitol and trandolapril has been found to reduce fibrosis in obstructive uropathy. Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in 227 patients with chronic kidney disease.

Adverse effects

Adverse effects by frequency:
Very common (>10% frequency):

• Nausea

Common (1-10% frequency):

• Diarrhoea^†
• Oedema
• Allergic reaction
• Arthritis
• Dizziness^†
• Stomach discomfort^‡
• Gastroesophageal reflux disease^†
• Acne^†
• Hypercalcaemia^†
• Hypocalcaemia^†
• Hyperphosphataemia
• Decreased appetite^†
• Headache
• Breast tenderness^†
• Taste changes
• Hypoparathyroidism
• Vertigo
• Rash^‡

Uncommon (0.1-1% frequency):

• Abnormal hepatic enzymes^‡
• Constipation^‡
• Dry mouth^‡
• Itchiness^‡
• Hives
• Hypersensitivity^‡
• Muscle spasms^‡
• Bleeding time prolonged
• Aspartate aminotransferase increased
• Laboratory test abnormal
• Weight loss
• Elevated blood creatinine
• Cardiac arrest
• Arrhythmia
• Atrial flutter
• Anaemia
• Leucopenia
• Lymphadenopathy
• Coma
• Stroke
• Transient ischemic attack
• Fainting
• Myoclonus
• Hypoaesthesia
• Paraesthesia
• Glaucoma
• Conjunctivitis
• Ear disorder
• Pulmonary oedema
• Asthma
• Shortness of breath
• Nose bleed
• Cough
• Rectal haemhorrhage
• Colitis
• Gastritis
• Indigestion
• Difficulty swallowing
• Gastrointestinal disorder
• Gastrointestinal haemorrhage
• Bullous dermatitis
• Hair loss
• Hirsutism
• Hyperhidrosis
• Joint pain
• Joint stiffness
• Back pain
• Muscle twitching
• Muscle aches
• Hyperparathyroidism
• Hyperkalaemia
• Hypocalcemia
• Breast cancer
• Sepsis
• Pneumonia
• Infection
• Pharyngitis
• Vaginal infection
• Influenza
• High blood pressure
• Hypotension
• Gait disturbance
• Injection site pain
• Fever
• Chest pain
• Condition aggravated
• Muscle weakness
• Malaise
• Thirst
• Breast pain
• Impotence
• Confusional state
• Delirium
• Depersonalization
• Agitation
• Insomnia
• Nervousness

^‡ These are adverse effects only seen in patients with grade 3 or 4 chronic kidney disease. ^† These are adverse effects only seen in patients with grade 5 chronic kidney disease.

Contraindications

Contraindications include:

• Vitamin D intoxication
• Hypercalcaemia
• Hypersensitivity to paricalcitol or any of its excipients

whereas cautions include:

• Impaired liver function
• It is also advised that physicians regularly monitor their patients' calcium and phosphorus levels.

Interactions

Drugs that may interact with paricalcitol include:

• Ketoconazole, as it may interfere with paricalcitol's metabolism in the liver.
• Digitoxin, hypercalcaemia due to any cause can exacerbate the toxicity of digitoxin.
• Thiazide diuretics or calcium supplements as hypercalcaemia may be induced by this combination
• Magnesium-containing products such as antacids may increase the risk of hypermagnesemia.
• Aluminium-containing products such as antacids may increase the risk of aluminium toxicity.
• Drugs that interfere with the absorption of fat-soluble vitamins, such as cholestyramine may interfere with the absorption of paricalcitol.

Overdose

Electrolyte abnormalities (e.g. hypercalcaemia and hyperphosphataemia) are common overdose symptoms. Treatment is mostly supportive, with particular attention being paid to correcting electrolyte anomalies and reducing intake of calcium in both the form of supplementation and diet. As it is so heavily bound to plasma proteins haemodialysis is unlikely to be helpful in cases of overdose.

Early symptoms of overdose can include:

• Weakness
• Headache
• Somnolence
• Nausea
• Vomiting
• Dry mouth
• Constipation
• Muscle pain
• Bone pain
• Metallic taste in the mouth.

It is worth noting, however, that may of these symptoms are also indicative of kidney failure and hence may be masked by the patient's condition.

Late symptoms of overdose include:

• Loss of appetite
• Weight loss
• Conjunctivitis (calcific)
• Pancreatitis
• Photophobia
• Rhinorrhoea
• Pruritis
• Hyperthermia
• Decreased libido
• Elevated BUN
• Hypercholesterolaemia
• Elevated AST and ALT
• Ectopic calcification
• Hypertension
• Cardiac arrhythmias
• Somnolence
• Death
• Psychosis (rare)

Mechanism of action

3D structure of paricalcitol

Like 1,25-dihydroxyergocalciferol, paricalcitol acts as an agonist for the vitamin D receptor and thus lowers the bloodparathyroid hormone level.

Pharmacokinetics

Within two hours after administering paricalcitol intravenous doses ranging from 0.04 to 0.24 µg/kg, concentrations of paricalcitol decreased rapidly; thereafter, concentrations of paricalcitol declined log-linearly. No accumulation of paricalcitol was observed with multiple dosing.