Basic Principles of Drug Metabolism

1
Basic Principles of Drug Metabolism
2
NAPLEX
Pg. 51
2

• General Pathways of Drug Metabolism

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
3

• Phase II (conjugation)

• - 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.

4

• Examples of Drug Metabolism

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
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• Drug Interactions

• Introduction to drug interactions
• Types of drug interaction
• Reasons for occurrence
• Clinical significance

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
7

• Metabolic or Biotransformation Interactions

• Enzyme Induction Interactions
• Enzyme inducers
• Barbiturates
• Rifampin
• Cigarette smoking - also charred meats / foods
• Phenytoin
• Phenylbutazone
• Griseofulvin
• Carbamazepine
• Alcohol (chronic ingestion)

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• Enzyme inhibitors
• Alcohol (acute ingestion)
• Amiodarone
• Cimetidine
• Co-trimoxazole
• Cyclosporine
• Erythromycin
• Metronidazole also 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. 452?469.
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• Examples of Drug Metabolism

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
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Patient Laboratory Tests

• Go to page 363, Chapter 12.

12
SMA 6 Versus SMA 12 Both us automated
continuous- flow blood chemistry assays.
SMA 6 (Profile 1)
13

• SMA 12 (Profile 2) includes all of the above,
  plus

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
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• Individual Test Values Electrolytes

• Sodium - fluid status water 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.

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• Potassium

• 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, muscle weakness, 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

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• Bicarbonate

• An increase in carbonic acid results in metabolic
  alkalosis and respiratory 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.

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• Calcium

• 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.

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• Enzyme Tests

• 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 duct obstruction.
• 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 for troponins.

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• Serum Transaminases

• 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 gt3? upper limit of
  normal

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• Serum Creatinine

Endogenous substance that will reflect kidney
function. Normal value 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)
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 cells Hemoglobin 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 lt 200 mg/dL. Desirable volume of low
density lipoproteins (LDL) and very low-density
lipoproteins (VLDL) are lt 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 test measure 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 ( gt2 ng/mL may be toxic) Phenytoin 10 to
20 µg/mL ( gt30 ? 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 lt2 µg/mL measure approximately 1 h
before next dose Vancomycin 24 to 40 µg/mL
trough lt10 ?g/mL (synergistic nephrotoxicity with
aminoglycosides)