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Minerals

medicines

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Minerals:

Fe2+

Hemoglobin → O2 Transport




Supports electron transport chain → Complex III/IV

When decreased = Possible mental retardation in children

Ca2+

Necessary for muscle contraction

o       All muscles need INTRACELLULAR Ca2+

o       Cardiac & Smooth Muscle need EXTRACELLULAR Ca2+

Needed for atrial contraction

IP3/DAG Second messenger system

Mg2+

Co-factor for ALL KINASES and PTH

Cu2+

Need for the hydroxylation of lysine

Deficiency

o       Minky’s kinky hair

Orange hair

Feels like copper wiring

Excess = Wilson’s Disease = hepatolenticular degeneration

o       Lenticular → Basal ganglia

o      

Trace Elements:

Chromium - neede in Insulin action

Selenium - necessary for heart

Manganese - xanthine oxidase

 
Hepato → liver

o       Keisher-fleisher rings in iris

o       Ceruloplasmin deficiency

Zn

Hair, taste buds, dysgusia, sperm

Biochemistry:

CONCEPT:

Low Energy State= the default illness state affecting all organ systems.

  • Organs:
    • CNS mental retardation
    • Muscle weakness
    • CV Heart Failure
    • Cilia Respiratory infection, shortness of breath
    • GI diarrhea initially due to malabsorption, then followed by constipation due to lack of motility
    • Hair falls out
    • Cuticles brittle
    • Skin dry
    • Vascular endothelium breaks down
    • Bone marrow:
      • RBC anemia
      • WBC agranulocytosis
      • Platelet bleeding disorder
    • Renal Proximal convoluted tubules
    • Reproductive low sperm count
    • Bladder slows down → hemorrhagic cystitis
    • Endometrium no menstruation
    • Germ cells CA
  • Signs and Symptoms:
    • Most Common Symptom = weakness and SOB
    • Most Common Sign = Tachypnea and Dyspnea
    • Most Common infection = UTI and respiratory infections
    • Most Common cause of death = Heart Failure

Proteins:

Body is made up of mostly proteins.

o       Recall that enzymes are proteins

But body likes to hang on to FAT (9 Kcal/1g)

SUGARS and AMINO ACIDS (4 kcal/ 1g)

Structure of Amino Acids: Exception: Proline:

NH3 COOH NH2 COOH

Amino Acid Imino

Imino group creates kinks and bends

Found in: hair, muscle, skin, collagen, cartilage,

 
R

(determines structure of AA)

 

  • Every acid group starts without a charge.
  • Ex:  As an amino acid group dissociates it becomes less soluble and more bioavailable.
 
Buffers:

Proteins are the most important intracellular buffers

Bicarbonate is the most important extracellular buffer

Dissociation= loss of H+

Soluble = has charge and will attract H2O → Can not cross Blood Brain Barrier

Bioavailable = neutral, can cross a fat soluble membrane.

o       When talking about Bioavailability think about Volume of distribution or t ½

Example:

NH3+ → NH2 = ↓ Solubility (by losing a charge); ↑ Bioavailability (by making it neutral)

COOH → COO- = ↑ Solubility (by adding charge); ↓ Bioavailability (b/c no longer neutral)

pKa:

1 2 3 4 5 6 7 8 9 10 11 14


Titration Curve:


Histadine has pK = 6.7 which is closest to pH of 7.4 it is the best buffer in humans.

* Liver handles fat-soluble content

 


Dissociation relationship:

pH = pK + 2 99% dissociated =99% soluble 1% bioavailable

pH = pK + 1 90% dissociated =90%soluble 10% bioavailable

pH = pK 50% dissociated Best Buffer

pH = pK - 1 10% dissociated =10% soluble 90% bioavailable

pH = pK - 2 1% dissociated =1% soluble 99% bioavailable

In order to absorb molecules they need to remain neutral = bioavailable. Follow these rules to keep molecules neutral.

To absorb more acid need to place in a stronger acid

o       Acid + Strong Acid = Behaves as a BASE

To absorb more base place in a stronger base

o       Base + Strong Base = Behaves as a ACID

Understand that the body makes 20x more HCO3- than acid

o       Because we ingest primarily acidic substances

Example:

  1. Crossing the Blood Brain Barrier need to remain neutral.
  2. If ingest acid need to keep it charged so it will not be absorbed give base (NaHCO3)
    1. Recall Activated Charcoal in the ER
  3. If ingest base keep charged by giving acid (coke, juice) will absorb less base.
  4. Patient taking Aspirin and eating acidic food can cause increased dissociation of ASA and then ASA poisoning.

Common Acids: ASA, Myoglobin (d/t crush injury), phenobarbiltal.

Common Bases: Amphetamines

 
Common pHs:

Stomach pH = 1-2

Duodenum pH = 3-5

Early Jejunum pH = 5-7

Late Jejunum pH = 7-9

Ileum pH > 9

Example: ASA has pK = 4.3 (like other NSAIDs), therefore it would be absorbed best in stomach pH of 1-2, when 1% will be dissociated and 99% will be bioavailable for absorption.

Key Concept: Acid + Base will decrease absorption.

Example: When muscle breaks down releasing myoglobin, give bicarbonate to prevent secretion and further loss of myoglobin.

pI = pk1 + pK2

2

 
Isoelectric Point:

pI = Zwiterion = NO NET charge.

When you have more than two groups:

o       “like” groups will have isoelectric point that will balance out opposite “like” group isoelectric point.

Gel Electrophoresis

Cathode – is where cations GO

Anode – is where anions GO

Amino Acids:

Groups

Amino Acid



Abbreviation

Alanine

Ala

Glycine

Gly

Leucine

Leu

Proline

Pro

Threonine

Thr

Cysteine

Cys

Histidine

His

Isoleucine

Ile

Methionine

Met

Serine

Ser

Valine

Val

Arginine

Arg

Asparagine

Asn

Aspartate

Asp

Glutamate

Glu

Glutamine

Gln

Phenylalanine

Phe

Tyrosine

Tyr

Tryptophan

Trp

Lysine

Lys

Acidic Groups = Asp, Glu

Basic Groups = Arg, Lys

Sulfur = Cys, Met

O-Bonds = Ser, Thr, Trp

N-Bonds = Asp, Gln

Branched aa = Leu, Ile, Val

Bulky (aromatic) =Phe, Thr, Trp

Small =Gly

Kinky =Pro

Ketogenic = Lys, Leu

(made and broken down to acetyl Co-A)

Glucogenic + Ketogenic = Phe, Iso, Thr, Trp

Glucogenic = All the rest.

GABA is a suppressor causing:

Bradycardia, Lethargy, Constipation, Impotence

 
GABA concept:

Essential Amino Acids:

Body will break down protein to look for essential amino acids if not provided by the diet.

PVT TIM HALL

Phenylalanine

Valine

Tryptophan

Threonine

Isoleucine

Methionine

Histidine

Arginine

Leucine

Always guess Autosomal recessive.

 
Lysine

Childhood screening:

PKU, galactosemia, hypothyroidism, congenital adrenal hypoplasia, biotindase.

 
Disorders:

  • PKU:
    • Phenylalanine hydroxylase is deficient
    • It is needed to make tyrosine
      • Therefore Tyrosine becomes an essential amino acid.
    • Signs and Symptoms:
      • Tyrosine is used to make:

Dopamine, Epinephrine and Norepinephrine mental retardation

    • PKU cont.

Melanin for pigment pale, blond, blue eyes

Build up of phenylacetate + phenylpyruvate = musty odor

Screened in childhood GUTHIRE testing.

  • Maple Syrup Urine Disease:
    • Deficiency in branched amino acids → Leu, Iso, Valine
    • Defective transport of branched amino acids in kidney collecting ducts will cause amino acids to “leak out”.
  • Cystinuria: Autosomal Dominant
    • Cystathione synthase enzyme is missing.
    • 4 Amino Acids show up in Urine
      • Cysteine
      • Ornithine
      • Lysine
      • Arginine
    • Develop Cysteine stones that have a crystal/envelope shape.

Protein Structure:

L R

R

N—C—N—C

R

Transfiguration

 
1 AA sequence including the peptide bonds:

All Bonds are planar = flat

Restricted mobility

R groups face away from each other

2 a-helix vs. b- pleated sheet

Proline

 

Humans have L-amino acids à will attack the D-amino acids

Adipose layers have the least amount of blood supply will take longer to heal.

 


GI, vessels, hair flat bones, skin

3 3D- determined by:

Hydrophobic

Hydrophilic interactions.

Covalent bonds begin to form.

Ex. Hemoglobin

 
4 2 proteins interact with enzymes

Cooperativity

Allosterism (one site will affect another site)

HEMOGLOBIN

Vm

 

[S]

 

Allosterism

 


  • The most effective way to monitor drug intake → PEAK & TROUGH Measurements
    • Peak → taken 4 hours after dose → If Peak is ↑↑ = the dosage is too high
    • Trough → taken 1 hour after dose → If Trough is ↑↑ = Give the drug less often

Meds: usually exhibit 1st order kinetics

  • As [drug], degradation T less toxic

Chemo drugs exhibit 0 order kinetics

Same amount of drug metabolized over time regardless of concentration T more toxic

 

Acid Hydrolysis:

  • Dip protein in acid acid denatured protein.

o       Glutamine glutamate

o       Aspargine aspartate



Gel Electrophoresis:

  • Separated protein based on size

o       Smallest will move the farthest

o       Then separate by charge.

Ninhydrin Reaction:

  • Separate out proline

o       Proline will stain yellow

o       All others will stain purple.

Edmund’s Degradation

  • Degradation that needs Propylisothiocyanate (PITC)

o       Will react with one amino acid at a time

o       From the L amino terminal

o       Used in spectrophotometry

o       Good for only 100 amino acids.accuracy

Restriction Peptidase:

Amino Acids Sequencing

_ _ _ _ _

(lys, ala)  (ser, met, phe)

You need to know which was amino acid was sequenced first!!!

If you cut with trypsin, where does it cut?

Trypsin cuts to the RIGHT of of lys and arginine!!!

_ lys/___ = Therefore, in a question, find the answer that already contains lys in the second position

KNOW WHERE THE ENZYME CUTS

Restriction Peptidases:

ALL CUT TO THE RIGHT

  • Trypsin I - cuts arginine or lysine ( basic groups)
  • Elastase - gly, ala, ser
  • CNBr - met
  • Amino peptidase - repeatedly cleaves N-terminal from glycopeptides
  • Chymyotrypsin - phe, thr, trp
  • Mercaptoethanol - dissolves disulfide bonds

EXCEPTION:

Carboxy peptidase - cuts to the LEFT of any amino acid on carboxy terminal

Allosterism

  • Rate limiting Enzyme

o       Always the slowest

Inhibition:

o       Competitive vs. Non-Competitive.

Competitive looks like substrate fights for active site

Vmax = Vmax

Non-competitive competing for regulatory site.

o       No D in Km or affinity

o       Vmax

· Competitive vs. Non Competitive inhibitors:


VMAX

 

VMAX

 


[S]

 

[S]

 

Km

 

Km

 


Hemoglobin:

Hg

HbA 98%

HbA2 2%

HbF

Genes

a b

a D

a g


Anemias:

Microcytic Hypochromic anemia:

Sideroblastic Anemia:

Macrophages that eat iron:

o       Parasitic infection

o       Impaired iron absorption

o       Liver disease (live stores Fe)

Porphyrias:

Enzyme deficiencies causing inability to break up heme → Degradation problem

Symptoms: Red urine indicating hemolytic anemia.

Acute Intermittent Porphyria (most common)

Recurrent acute abdominal pain and neuropathy (remember this can be anything..headaches, ↑ ICP, etc…)

MCC = STRESS

o       Can be set off by menses

MC Drugs that can cause this

o       Sulfa

o       Anti – Malarial

o       Metroniazole

o       Barbituates

Treatment:

o       Hematin stop Daminolevulinic acid synthase decrease further production of porphyrin.

o       Fluids to flush it out

o       Sugar helps draw the excess porphyrins out

Porphyria Cutanea Tarda

-Sun blisters skin

-Starts in late childhood > 5 years old

Erythrocytic Protoporphyria

-Early childhood < 1 years old

-Blister in the su

Myoglobin vs. Hemoglobin

Fetal Hb:

Highest pO2 in umbilical vein coming from placenta (coming from mom)

o       pO2 = 80

After liver pO2 to 60%

After brain pO2 to 50%

In extremities pO2 to 40%

Through Foramen Ovale and Left side pO2 = 90%

SaO2 = 90% pO2 = 60

Hemoglobin

Normal values: Hg=15, Hct=45

1g of Hg has 4 Heme sites.

Athletes

pO2 between 40 → 60 = Hypoxic period

Begin anaerobic → ↑ lactic acidosis

The 2nd Wind Theory

An athlete must out last this hypoxic period so that Myoglobin can begin to drop oxygen

 


Ex; Normal pO2 in the body is between 60-90 so O2 sat will be > 90%

If pO2< 60, free Hg to de saturate and curve shift to Right

Hg lets go of O2 and shift to Left Hg holding on to O2

Fetal CirculationErythropoiesis

o       begins in the Yolk Sac at months gestation.

o       6 months liver, spleen and flat bones → close at 1 year

o       8 months long bones

o       After 1 year of age long bones are in charge of erythropoesis.

If long bones are damaged, in bone marrow > 1 year spleen will take over again = splenomegaly



Inhibitors to Hb:

Carbons Monoxide:

Competitive inhibitor of O2

o       Treatment = O2

Cyanide

o       Non-competitive inhibitor of O2

o       Km doesn’t change

o       Vmax will decrease

o       Treatment with O2 will not make saturation go up

Hemaglobenopathies:

Sickle Cell Disease:

Autosomal recessive, HbS

Protect Against Malaria

Amino Acid substitution: Val Glu @ position 6 of b chain

o       Valine = Neutral → goes inside

o       Glutamic acid = Negative (charged) → goes outside

o       THIS PROVIDES THE MECHANISM FOR SICKLING

When O2 decreases, the Val on opposite sides (positions 1 and 6) attract each other and change shape

SICKLE CELL = VASOOCLUSION

o       Symptoms:

o       Begin to feel cold, lightheaded, and experience syncope

o       Dactylitis – painful and swollen fingers and toes in new born

o       Present at 4-6 months of age when Hg F switches to Hg S

o       At 6 years → SPLENECTOMY

Sickle Cell Trait (SA)

Asymptomatic, but barred from extreme hypoxic situations or jobs

o       Fireman, pilot, diver

Hg C:

Autosomal recessive

Amino Acid substitution: Lys Glutamic acid @ position 6 of b unit. → NO SICKLING

o       Lys – (+) = outside

o       Glutamic acid – (-) = outside

o       BOTH STAY ON THE SURFACE = no sickling

Lys is charged so it remains hydrophilic even after lets go of O2

Methemaglobanemia

Fe3+ can’t pick up O2 = Ferric (oxidized)

o       methemaglobanemia- inborn

o       MCC = 2 methemaglobanemia- drug induced (sulfa) can oxidize Fe2+/Infections d/t free radicals

o       Low O2 saturation BUT pO2 will be normal

Treatment:

o       Methylene Blue – “Give them something blue to turn them pink”

Anyl Nitrite- will convert Hg to Fe3+ not allowing CN to act.

Sodium Thiosulfate will bind CN and recant thiocyanate

Blood transfusion

Thalassemias:

Hg made up of:

o       a subunit - 4 genes

o       b subunit – 2 genes

Thalassemia

# of Genes missing

% Hb Left

Hb

Symptoms

α – minor

No symptoms

? symptoms

(+) symptoms, basophilic stippling

α – major

Hydrops Fetalis

β – minor

Always have ↑ HbA2 and HbF

+/- symptoms based on lifestyle

β – Major

No HbA, asymptomatic until 6 mos. b/c time when HbF → HbA; All erythropoietic organs reopen

Cooley’s Anemia (Type of β Thalassemia)

Ineffective erythropoiesis → making useless RBC

Baby making blood from everywhere:

o       Frontal Bossing

o       Large sternum/ clavicles

o       Hepatosplenomegaly

o       Long tender extremities

o       HCT ↑↑↑, but Hb ↓↓↓

Treatment:

o       Total body transfusion every 60-90 days → TRANSFUSION DEPENDENT

o       Recall that a RBC only lives 120 days

o       1 unit of PRBC =

Hg by 1-2g

Fe by 3-4g

Will die within I 10 years of transfusion related infections

Can die d/t Iron overload = Hemochromatosis

Hemosiderosis:

o       Bone marrow overwhelmed with Fe due to frequent transfusions.

o      

Transfusion Infections

Hep B

Hep C

HIV

CMV

EBV

West Nile

Hep D

Malaria

Bacteria

Babesosis

Syphuliis

 
Sideroblastic anemia

Hemochromatosis: Deposit Fe into organs.

10 Hemochromatosis:

o       Congenital – rare autosomal recessive, HLA3 + Chr 6

o       Duodenum absorbing too much Fe leading to:

· Hemosiderosis

· Hemochromatosis

Hemochromatosis:

o       Acquired

o       Due to transfusions:

Bronzing accumulates in skin

o       Will die of:

1st decade of life transfusion related infections

2nd decade of life HF






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