Basic Principles of Drug Metabolism

Basic Principles of Drug Metabolism

2NAPLEX

Pg. 51

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 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 MetabolismGeneral Pathways of Drug Metabolism

- 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.

- 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)Phase II (conjugation)

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

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 MetabolismExamples of Drug Metabolism

Introduction to drug interactions

Types of drug interaction

Reasons for occurrence

Clinical significance

Introduction to drug interactions

Types of drug interaction

Reasons for occurrence

Clinical significance

Drug InteractionsDrug Interactions

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

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

Enzyme Induction Interactions:

Enzyme inducers:

Barbiturates

Rifampin

Cigarette smoking - also charred meats / foods

Phenytoin

Phenylbutazone

Griseofulvin

Carbamazepine

Alcohol (chronic ingestion)

Enzyme Induction Interactions:

Enzyme inducers:

Barbiturates

Rifampin

Cigarette smoking - also charred meats / foods

Phenytoin

Phenylbutazone

Griseofulvin

Carbamazepine

Alcohol (chronic ingestion)

Metabolic or Biotransformation InteractionsMetabolic or Biotransformation Interactions

Enzyme inhibitors:

Alcohol (acute ingestion)

Amiodarone

Cimetidine

Co-trimoxazole

Cyclosporine

Erythromycin

Metronidazole – also other “azole” antifungals

Reverse transcriptase inhibitors

Fluvoxamine / Fluoxetine

Ritonavir

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

Excretion Interactions

Probenecid-penicillins

- naproxen

- cephalosporins

Lithium-diuretics

- ACE inhibitors

- Fluoxetine

- NSAIDs

Potassium-amiloride

- triamterene

- spironolactoneReview list of interactions on pg. 452469.

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

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 MetabolismExamples of Drug Metabolism

Patient Laboratory TestsPatient Laboratory Tests

Go to page 363, Chapter 12. Go to page 363, Chapter 12.

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)

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

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

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.

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.

Individual Test Values: ElectrolytesIndividual Test Values: Electrolytes

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

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

PotassiumPotassium

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.

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.

BicarbonateBicarbonate

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 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.

CalciumCalcium

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.

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.

Enzyme TestsEnzyme Tests

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

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 TransaminasesSerum Transaminases

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)

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)

Serum CreatinineSerum Creatinine

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.

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

PlateletsThrombocytes necessary for blood clotting.

Normal is 150-300,000; low levels can cause bruising, bleeding.

WBC differential counts aid in diagnosis

Neutrophils Lymphocytes Eosinophils Basophils Monocytes

PlateletsThrombocytes necessary for blood clotting.

Normal is 150-300,000; low levels can cause bruising, bleeding.

Miscellaneous Blood Tests

Hematocrit (Hct) Hematocrit (Hct) % of packed red blood cells

Hemoglobin test (Hgb) Hemoglobin test (Hgb) – amount of hemoglobin

Mean corpuscular volume (MCV) – Mean corpuscular volume (MCV) – average of volume of RBC

Mean corpuscular hemoglobin (MCH) – Mean corpuscular hemoglobin (MCH) – hemoglobin content of the average RBC

Desirable blood TOTAL cholesterol level is < 200 mg/dL. Desirable blood TOTAL cholesterol level is < 200 mg/dL. Desirable volume of low density lipoproteins (LDL) and very Desirable volume of low density lipoproteins (LDL) and very low-density lipoproteins (VLDL) are < 130 mg/dL.low-density lipoproteins (VLDL) are < 130 mg/dL.

High density lipoproteins (HDL) are desirable. High density lipoproteins (HDL) are desirable.

Coagulation Times

• HeparinActivated 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)Prothrombin time (PT or pro-time)

•• International normalized ration (INR)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)