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Basic Principles of
Drug Metabolism 2NAPLEX
Pg. 51
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Phase I (functionalization)
Oxidation (most important), reduction, and hydrolysis
Function: introduce a polar group to make molecules more
hydrophilic
Method: catalyzed by hepatic CYP450 system enzymes
General Pathways of Drug Metabolism
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- Function is to attach small, polar, and ionizable
components.
-Form water soluble conjugated products.
-Conjugated metabolites are easily excreted in the
urine and generally have little or no pharmacologic
activity or toxicity.
Phase II (conjugation)
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phenytoin p-hydroxyphenytoin glucuronide
hydroxylation glucuronidation conjugate of
phenytoin
cefuroxime axetil cefuroxime
hydrolysis
aspirin salicylic acid glucuronide
hydrolysis + glucuronidation
acetic acid
acetaminophen glucuronide and sulfate conjugates
conjugation
Examples of Drug Metabolism
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Introduction to drug interactions
Types of drug interaction
Reasons for occurrence
Clinical significance
Drug Interactions
Go to Chapter 17, pg. 445
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Absorption Interactions
Tetracycline-divalent and trivalent cations
Ciprofloxacin antacids
Digoxin-cholestyramine
Thyroid-cholestyramine
Digoxin-metoclopramide
Ciprofloxacin-sucralfate
Distribution Interactions
Warfarin-aspirin
Warfarin-chloral hydrate
Warfarin-clofibrate
Warfarin-ciprofloxacin
Methotrexate-aspirin
Pg. 451
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Enzyme Induction Interactions:Enzyme inducers:
Barbiturates
Rifampin
Cigarette smoking - also charred meats / foods
Phenytoin
Phenylbutazone
Griseofulvin
Carbamazepine
Alcohol (chronic ingestion)
Metabolic or Biotransformation Interactions
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Enzyme inhibitors:
Alcohol (acute ingestion)
Amiodarone
Cimetidine
Co-trimoxazole
Cyclosporine
Erythromycin
Metronidazolealso other azole antifungals
Reverse transcriptase inhibitors
Fluvoxamine / Fluoxetine
Ritonavir
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Excretion Interactions
Probenecid-penicillins
- naproxen
- cephalosporins
Lithium-diuretics
- ACE inhibitors
- Fluoxetine
- NSAIDs
Potassium-amiloride
- triamterene- spironolactone
Review list of interactions
on pg. 452469.
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phenytoin p-hydroxyphenytoin glucuronide
hydroxylation glucuronidation conjugate ofphenytoin
cefuroxime axetil cefuroxime
hydrolysis
aspirin salicylic acid glucuronide
hydrolysis + glucuronidation
acetic acid
acetaminophen glucuronide and sulfate conjugates
conjugation
Examples of Drug Metabolism
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Patient Laboratory Tests
Go to page 363, Chapter 12.
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Normal blood range Intracellular
Sodium 135 to 145 mEq/L 7 to 10 mEq/L
Potassium 3.5 to 5 mEq/L 140 mEq/L
Chloride 100 mEq/L 4 mEq/L
CO2 (bicarbonate) 25 mEq/L 10 mEq/L
BUN 7 to 20 mg/L
Glucose 100 mg/dL
SMA 6 Versus SMA 12
Both us automated continuous- flow blood chemistry assays.
SMA 6 (Profile 1)
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Total proteins 6 to 8 g/dL
Bilirubin up to 1 mg/dL
reported as total, conjugated and unconjugated
Alkaline phosphatase 30-85 IU
Calcium 10 mg/dL (5mEq/L) (does not
indicate body supply of Ca)
Creatinine (SCr) 1 mg/dL
Albumin 3.5 to 5 g/dL
SMA 12 (Profile 2) includes all of the above, plus:
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Sodium - fluid statuswater follows sodium
Sodium is the main extracellular cation.
Decreased values may be caused by diarrhea, heat
exhaustion, kidney disorders, or ileostomates.
also dilutional hyponatremia excess fluid intake
Symptoms include nausea, vomiting, anorexia, blurred vision,
muscle cramps, and CNS changes.
Both sodium and water are retained in such chronic disease states as
congestive heart failure, cirrhosis, and nephrosis.
Hypernatremia caused by dehydration. This is major problem of the
geriatric population.
Individual Test Values: Electrolytes
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Potassium is found mainly in cells and not serum.
Decreased values may be caused by diarrhea, kidney disease,
prolonged vomiting, administration of insulin and glucose in
diabetes, prolonged IV therapy, or use of thiazides or loop diuretics.
Lowered values may cause cardiac arrhythmias, confusion, muscleweakness, fatigue, and dizziness.
Symptoms of increased values include arrhythmias, depression,
lethargy, coma, and electrocardiographic changes.
Drugs causing hyperkalemia: ACE inhibitors, ARBs,
K+ sparring diuretics, K+ supplements
Potassium
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An increase in carbonic acid results in metabolic alkalosis andrespiratory acidosis.
A decrease in carbonic acid results in metabolic acidosis and
respiratory alkalosis.
must also evaluate pH and pCO2 to determine true acid-base
status
The most common therapeutic use of sodium bicarbonate
injection is to overcome metabolic acidosis.
Bicarbonate
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Calcium is important for bone formation, muscle contractions,blood clotting, nerve conduction, and effective enzyme
function.
Low values may be caused by celiac disease, sprue, and
certain kidney disease.
High values may be caused by hyperparathyroidism, certain
respiratory diseases, multiple myeloma, during vitamin D
toxicity, and drug therapy with thiazides.
Corrected calcium (mg/dl) = 4 [patient albumin (g/dl) [0.8 ] + current patient calcium
Patients on long-term steroid therapy experience a deficiency
in calcium.
Calcium
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Phosphatase is a group of enzymes that split phosphoric acid
from organic phosphate esters (alkaline phosphatase).
normally present in small amounts in serum, elevation
indicates tissue/cell damage and death causing release
Increased values may cause bone disease (e.g., Paget
disease), bone fractures, liver disease, or bile ductobstruction.
Creatine phosphokinase (CK or CPK) has normal values of 1 to 10
IU/L; CPK is used to diagnose myocardial infarction or muscular
dystrophy.
There are 3 subunits: CK-MB (cardiac), CK-MM (skeletal muscle), and
CK-BB (brain and kidney).
Evaluations using CPKs have been replaced in many settings by the
assays fort roponins.
Enzyme Tests
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These enzymes catalyze transfer of amino acid
groups:
Aspartate aminotransferase (AST) or SGOT
Alanine aminotransferase (ALT) or SGPT
Known as liver function tests (LFTs), along
with LDH. ALT is most sensitive and specific
for liver damage. Significant when elevated >3 upper limit of
normal
SerumTransaminases
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Endogenous substance that will reflect kidney function. Normalvalue is 1 mg/dL (range 0.8 1.2 mg/dL). Values above 2 mg/dL
indicate either renal or hepatic disease.
Creatinine clearance (CLCr)
Allows determination of kidney glomerular function;Normal range is 100 to 140 mL/min
Values for females are approximately 85% that of males.
Cockroft and Gault equation:
CLCr = (140 age [in years]) body weight (in KG)72 serum creatinine (mg/dL)
Serum Creatinine
Remember to multiply by 0.85 for females.
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Blood Counts
CBC = complete blood count.
Red blood cells (RBCs)
Erythrocytes contain hemoglobin, which carries oxygen.
Decreased values are caused by hemorrhage or anemia.
Increased values are caused by polycythemia.
White blood cells (WBCs)
Leukocytes are the defense mechanism against micro-organisms.
Normal counts are 4,000 (range of 4 10k)
Decreased values are caused by blood dyscrasias or drug or
chemical toxicities. Increased values (leukocytosis) are caused by
infections or blood disorders.
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WBC differential counts aid in diagnosis
Neutrophils
Lymphocytes
Eosinophils
Basophils
Monocytes
Platelets
Thrombocytes necessary for blood clotting.
Normal is 150-300,000; low levels can cause bruising, bleeding.
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Miscellaneous Blood Tests
Hematocrit (Hct) % of packed red blood cellsHemoglobin test (Hgb) amount of hemoglobin
Mean corpuscular volume (MCV)average of volume of RBC
Mean corpuscular hemoglobin (MCH)hemoglobin content of the average RBC
Desirable blood TOTAL cholesterol level is < 200 mg/dL.
Desirable volume of low density lipoproteins (LDL) and very
low-density lipoproteins (VLDL) are < 130 mg/dL.
High density lipoproteins (HDL) are desirable.
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Coagulation Times
Heparin
Activated partial thromboplastin time (APTT or PTT)
An accurate, low-cost test with normal values of 35 to 45
seconds. Used in hospitals to monitor heparin therapy.
Antidote for excessive anticoagulant activity of heparin is
protamine sulfate
Warfarin
Prothrombin time (PT or pro-time)
International normalized ration (INR)
A ratio obtained by comparing a patients PT value with the
mean normal PT value. Values in the range of 2.0 to 3.0
are desired.
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Blood Glucose
Normal fasting values range from 70 to 100 mg/dL.
Glucose is the main source of energy in body.
Hyperglycemia is present in diabetes mellitus and Cushing
syndrome.
Glucose tolerance testmeasure BG 2 h after glucose
load is ingested
HbA1c - % of Hgb molecules with a glucose molecule attached.
Provides average BG over the past three months
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Blood Urea Nitrogen (BUN)
Test kidney function
Urea is produced by the liver from ammonia.
Normal range is 9-20 mg/dL
High N, resulting in mental confusion, may be
caused by:
Kidney malfunction
Cardiac function
High protein intake (Atkins diet)
Low levels: may indicate liver disease
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Therapeutic Drug Plasma Levels
Digoxin 1 to 2 ng/mL ( >2 ng/mL may be toxic)
Phenytoin 10 to 20 g/mL ( >30 g/mL may be toxic)
Lithium 0.5 to 1.5 mEq/L
Aminoglycosides (gentamicin, tobramycin, netilmicin) peaks
of 5 to 8 ug/mL; troughs