Download Phar 722 Pharmacy Practice III

Phar 722
Pharmacy Practice III
Trace ElementsZinc
Spring 2006
Zinc Learning Objectives
•
•
•
•
•
•
•
Know the uptake, distribution and excretion of zinc.
Know the bioavailability of dietary zinc.
Know the biodistribution of zinc.
Know the biochemical functions of zinc.
Know the causes and symptoms of zinc deficiency.
Know the symptoms of zinc toxicity.
Know the current efficacy of zinc supplements in
certain diseases discussed in class.
• List the common side effects of oral zinc therapy.
• Know the RDAs for adults and ULs for children and
adults.
Zinc’s Three Biochemical Roles-1
• Catalytic Role
• Structural Role
• Regulatory Role
Zinc’s Three Biochemical Roles-2
• Catalytic Role
– Over 100 specific zinc metalloenzymes depend on
zinc for catalytic activity including:
•
•
•
•
•
•
•
Alcohol dehydrogenase
Ribonucleic acid polymerases
Carbonic anhydrase
Alkaline phosphatase
Carboxypeptidase
Glutamic dehydrogenase
Lactic dehydrogenase
– Mechanism
• Zinc is a Lewis acid accepting electrons (different from
oxidation-reduction reactions)
Zinc’s Three Biochemical Roles-3
• Structural Role
– Coordinates with electron rich amino acid
side chains of proteins stabilizing tertiary
and quaternary structure.
• Copper-zinc superoxide dismutase
– Copper is the cofactor in the oxidation-reduction
reaction and zinc stabilizes tertiary structure.
– Intracelluar binding of tyr kinase to T-cell receptors.
– Coordination with cys and his residues
produces “zinc finger-like” structure.
• Zinc fingers are important regulators of DNA
binding transcription factors.
Zinc’s Three Biochemical Roles-4
• Regulatory Role
– This function is poorly understood.
Examples include:
• Regulator of gene expression possibly by
changes in binding to transcription factors.
• Zinc transporter proteins
– Metallothionein gene producing a metalloprotein that
regulates zinc trafficking.
• Apoptosis
• Protein kinase C activity
– Cell signaling
Uptake, Utilization & Excretion-1
• Dietary zinc is bound in metalloproteins (see
previous slides).
• The digestive process frees it
– It then becomes bound to endogenous proteins
found in the intestinal lumen.
• There is active transport in the jejunum.
– Zinc transport speeds up in states of zinc
depletion.
• The human body contains about 2 gm zinc.
– Over 85% of these 2 gm is in skeletal muscle and
bone.
– 0.1% of total zinc (10 – 15 μmol/L) in plasma.
Uptake, Utilization & Excretion-2
• Zinc apparently uses the same
transport systems as other divalent
cations.
– Iron supplements might lower the percent
of zinc absorbed.
– Zinc supplements might lower the percent
of copper absorbed.
• Zinc elimination is by secretion into the
intestine followed by excretion in the
feces.
Zinc Deficiency
• Symptoms do not correlate with zinc’s biochemical
roles.
–
–
–
–
–
–
Depressed growth
Delayed sexual maturation
Immune dysfunction
Diarrhea
Altered cognition
Defects in carbohydrate utilization
• Causes
– Intestinal disease
• Sprue, Crohn’s Disease, short bowel syndrome
– Eating grains high in phytic acid (inositol hexaphosphate)
• May be an important consideration for strict vegetarians who
concentrate on grains.
• NOTE: There is no agreed-upon clinical test for zinc
status.
Zinc’s Possible Role in
Treatment of Disease-1
• “Common” Cold
– The results of zinc lozenges are mixed.
– There is risk of overdosing if these lozenges are used for
prolonged periods (6-8 weeks).
– Zinc is an astringent and may irritate the mound and GI
tract.
• Age-related macular degeneration.
– Three is no evidence that zinc either causes or reduces the
risk of this disease.
– There are ongoing trials of anti-oxidant vitamins and
selenium.
• Diabetes mellitus
– Zinc does affect glucose metabolism.
– Patients with diabetes taking zinc supplements should
carefully monitor their blood-glucose levels.
Age-Related Macular Degeneration
Zinc’s Possible Role in
Treatment of Disease-2
• Wound healing
– This claim has been made for nearly 40 years.
– There have been recommendations that zinc
supplements hastens healing of bed sores and
other forms of skin ulcerations.
• Immune system
– Zinc is required for a proper immune response.
– There is some evidence that HIV/AIDS patients
may benefit from zinc supplements.
• For these studies, it is important to check on the
nutritional status of HIV/AIDS patients.
– Otherwise, the results are mixed that zinc
facilitates the immune response.
Zinc Toxicities
• Zinc is a potent astringent.
• Acute Symptoms
– Many of the symptoms probably caused by zinc’s astringent
properties.
•
•
•
•
•
Epigastric pain
Nausea
Vomiting
Abdominal cramps
Diarrhea
• Chronic Symptoms
– Zinc competes with other metals at the transport sites.
• Suppression of immune response
• Decrease in HDL
• Decrease in copper levels
Dosages Forms
• Zinc acetate
• Zinc gluconate
• Zinc picolinate
– No evidence that the zinc in this salt is
more bioavailable.
• Zinc sulfate
• Zinc oxide
Dietary Reference Intakes-1
• AI
– Infants (0-6 months)
2.0 mg/day
• EAR
–
–
–
–
–
–
–
–
–
–
–
–
Infants (7-12 months)
Children (1-3 years)
Children (4-8 years)
Children (9-13 years)
Boys (14-18 years)
Girls (14-18 years)
Men (19-70+ years)
Women (19-70+ years)
Pregnancy (14-18 years)
Pregnancy (19-50 years)
Lactation (14-18 years)
Lactation (19-50 years)
2.5 mg/day
2.5 mg/day
4 mg/day
7 mg/day
8.5 mg/day
7.3 mg/day
9.4 mg/day
6.8 mg/day
10.0 mg/day
9.5 mg/day
10.9 mg/day
10.4 mg/day
Dietary Reference Intakes-2
• RDA
–
–
–
–
–
–
–
–
–
–
–
–
Infants (7-12 months)
Children (1-3 years)
Children (4-8 years)
Children (9-13 years)
Boys (14-18 years)
Girls (14-18 years)
Men (19-70+ years)
Women (19-10+ years)
Pregnancy (14-18 years)
Pregnancy (19-50 years)
Lactation (14-18 years)
Lactation (19-50 years)
3 mg/day
3 mg/day
5 mg/day
8 mg/day
11 mg/day
9 mg/day
11 mg/day
8 mg/day
12 mg/day
11 mg/day
13 mg/day
12 mg/day
Dietary Reference Intakes-3
• UL
–
–
–
–
–
–
–
–
–
–
–
–
–
Infants (0-6 months)
Infants (7-12 months)
Children (1-3 years)
Children (4-8 years)
Children (9-13 years)
Boys (14-18 years)
Girls (14-18 years)
Men (19-70+ years)
Women (19-70+ years)
Pregnancy (14-18 years)
Pregnancy (19-50 years)
Lactation (14-18 years)
Lactation (19-50 years)
4 mg/day
5 mg/day
7 mg/day
12 mg/day
23mg/day
34 mg/day
34 mg/day
40 mg/day
40 mg/day
34 mg/day
40 mg/day
34 mg/day
40 mg/day
Dietary Sources
•
•
•
•
Shellfish
Beef and other red meats
Nuts and legumes
The zinc in leavened whole grain
breads is more bioavailable.
– Yeast consumes some of the phytic acid.