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 hydrolysis

cefuroxime

aspirin hydrolysis

salicylic acid + glucuronidation acetic acid

glucuronide

acetaminophen conjugation

glucuronide and sulfate conjugates

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

Review list of interactions on pg. 452469.

- spironolactone

Examples of Drug Metabolism

phenytoin p-hydroxyphenytoin hydroxylation glucuronidation glucuronide conjugate of phenytoin

cefuroxime axetil hydrolysis

cefuroxime

aspirin hydrolysis

salicylic acid + glucuronidation acetic acid

glucuronide

acetaminophen conjugation

glucuronide and sulfate conjugates

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 Sodium Potassium 135 to 145 mEq/L 3.5 to 5 mEq/L

Intracellular 7 to 10 mEq/L 140 mEq/L

Chloride
CO2 (bicarbonate) BUN Glucose

100 mEq/L
25 mEq/L 7 to 20 mg/L 100 mg/dL

4 mEq/L
10 mEq/L

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

Total proteins Bilirubin 6 to 8 g/dL up to 1 mg/dL

reported as total, conjugated and unconjugated Alkaline phosphatase Calcium Creatinine (SCr) Albumin 30-85 IU 10 mg/dL (5mEq/L) (does not
indicate body supply of Ca)

1 mg/dL 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 patients 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 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 <2 g/mL; measure approximately 1 h before next dose Vancomycin 24 to 40 g/mL; trough <10 g/mL (synergistic nephrotoxicity with aminoglycosides)