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NAPLEX
Basic Principles of
Drug Metabolism
2
Pg. 51
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
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.
Examples of Drug Metabolism
phenytoin
p-hydroxyphenytoin
hydroxylation
glucuronidation
glucuronide
conjugate of
phenytoin
cefuroxime axetil
cefuroxime
hydrolysis
aspirin
hydrolysis
salicylic acid
+
glucuronidation
glucuronide
acetic acid
acetaminophen
glucuronide and sulfate conjugates
conjugation
Drug Interactions
Introduction to drug interactions

Types of drug interaction

Reasons for occurrence

Clinical significance
Go to Chapter 17, pg. 445
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
Metabolic or Biotransformation Interactions
Enzyme Induction Interactions:
Enzyme inducers:

Barbiturates

Rifampin

Cigarette smoking - also charred meats / foods

Phenytoin

Phenylbutazone

Griseofulvin

Carbamazepine

Alcohol (chronic ingestion)
Enzyme inhibitors:

Alcohol (acute ingestion)

Amiodarone

Cimetidine

Co-trimoxazole

Cyclosporine

Erythromycin

Metronidazole – also other “azole” antifungals

Reverse transcriptase inhibitors

Fluvoxamine / Fluoxetine

Ritonavir
Excretion Interactions
Probenecid-penicillins
- naproxen
- cephalosporins
Lithium-diuretics
- ACE inhibitors
- Fluoxetine
- NSAIDs
Potassium-amiloride
- triamterene
- spironolactone
Review list of interactions
on pg. 452469.
Examples of Drug Metabolism
phenytoin
p-hydroxyphenytoin
hydroxylation
glucuronidation
glucuronide
conjugate of
phenytoin
cefuroxime axetil
cefuroxime
hydrolysis
aspirin
hydrolysis
salicylic acid
+
glucuronidation
glucuronide
acetic acid
acetaminophen
glucuronide and sulfate conjugates
conjugation
Patient Laboratory Tests
Go to page 363, Chapter 12.
SMA 6 Versus SMA 12
Both us automated continuous- flow blood chemistry assays.
SMA 6 (Profile 1)
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 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
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.
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
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.
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.
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.
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 >3 upper limit of
normal
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.
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.
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.
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 < 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.
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 patient’s PT value with the
mean normal PT value. Values in the range of 2.0 to 3.0
are desired.
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
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
Therapeutic Drug Plasma Levels
Digoxin – 1 to 2 ng/mL ( >2 ng/mL may be toxic)
Phenytoin – 10 to 20 μg/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 <2 μg/mL; measure approximately 1 h
before next dose
Vancomycin – 24 to 40 μg/mL; trough <10 g/mL (synergistic
nephrotoxicity with aminoglycosides)