09-drug metabolism -labs.ppt

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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

09-drug metabolism -labs.ppt

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